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Sample records for neuromuscular blockade induced

  1. 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...... blockade in patients induced and maintained under propofol anesthesia. However, sevoflurane anesthesia, unlike propofol, can prolong the effect of neuromuscular blocking drugs (NMBDs) such as rocuronium and vecuronium....

  2. Reversal of profound, high-dose rocuronium-induced neuromuscular blockade by sugammadex at two different time points: an international, multicenter, randomized, dose-finding, safety assessor-blinded, phase II trial

    DEFF Research Database (Denmark)

    Pühringer, Friedrich K; Rex, Christopher; Sielenkämper, Andreas W

    2008-01-01

    Sugammadex (Org 25969), a novel, selective relaxant binding agent, was specifically designed to rapidly reverse rocuronium-induced neuromuscular blockade. The efficacy and safety of sugammadex for the reversal of profound, high-dose rocuronium-induced neuromuscular blockade was evaluated....

  3. Reversal of profound, high-dose rocuronium-induced neuromuscular blockade by sugammadex at two different time points - An international, multicenter, randomized, dose-finding, safety assessor-blinded, phase II trial

    DEFF Research Database (Denmark)

    Puhringer, F.K.; Rex, C.; Sielenkamper, A.W.

    2008-01-01

    Background: Sugammadex (Org 25969), a novel, selective relaxant binding agent, was specifically designed to rapidly reverse rocuronium-induced neuromuscular blockade. The efficacy and safety of sugammadex for the reversal of profound, high-dose rocuronium-induced neuromuscular blockade was evalua...

  4. A comparison of sugammadex and neostigmine for reversal of rocuronium-induced neuromuscular blockade in children.

    Science.gov (United States)

    Ammar, A S; Mahmoud, K M; Kasemy, Z A

    2017-04-01

    Sugammadex is designed to be a reversal agent for steroidal muscle relaxants. The current trial was aimed to compare between sugammadex and neostigmine concerning the recovery time from neuromuscular blockade. We hypothesised that sugammadex might have shorter recovery time than neostigmine. Sixty paediatric patients aged 2-10 years scheduled for lower abdominal surgeries were randomly assigned into two equal groups to receive 4 mg/kg sugammadex (Group S) or 0.35 mg/kg neostigmine and 0.02 mg/kg atropine (Group N) as a reversal agent for rocuronium at the end of surgery. Primary outcome was the recovery time [time from starting of sugammadex or neostigmine till reaching train of four (TOF) ratio> 0.9] whereas secondary outcomes included number of patients who needed another dose of sugammadex or neostigmine to reach TOF ratio> 0.9, extubation time (time from stoppage of anaesthetic inhalation until the patient fulfilled criteria for safe extubation, post-anaesthesia care unit (PACU) discharge time and post-operative adverse effects. The mean recovery and extubation times were significantly shorter (P = 0.002 and 0.005) in Group S compared with Group N (2.5 and 2.0 min vs. 12.6 min and 4.3 min respectively). In the Group N, eight patients needed another reversal dose compared with one patient in Group S (P = 0.035). PACU discharge time showed no significant difference between both groups. Incidence of nausea, vomiting, tachycardia, and dry mouth were significantly higher in Group N. Sugammadex administration in children resulted in faster recovery and extubation times and lower incidence of adverse events compared with neostigmine. © 2017 The Acta Anaesthesiologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.

  5. [Clinical significance of posttetanic count (PTC) during onset and spontaneous offset of neuromuscular blockade induced by vecuronium].

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    Ueda, N; Masuda, Y; Muteki, T; Ohishi, K; Tayama, K; Yamashita, N

    1992-11-01

    To compare the clinical difference of posttetanic count (PTC) during onset and spontaneous offset, the changes of PTC during an intense neuromuscular blockade induced by vecuronium (0.08 mg.kg-1, i.v.) were measured using a neuromuscular transmission analyzer in 64 adult patients anesthetized with nitrous oxide and halothane. Furthermore, intubation score was evaluated when zero PTC was obtained. The obvious movement of diaphragm associated with endotracheal intubation was observed in 9 out of 20 patients (45%) even when it was performed after obtaining zero PTC. The difference of PTC responses between the onset and the offset was found. The difference was that, during the onset, a tetanic response was observed obviously and the height of the posttetanic single twitch was low, and during offset, even when no response was observed, the height of a posttetanic single twitch response was high with the same PTC. These facts indicate that the same PTC has different clinical significance during onset and offset.

  6. Neuromuscular blockade during laparoscopic ventral herniotomy

    DEFF Research Database (Denmark)

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

    2015-01-01

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

  7. Neuromuscular blockade during laparoscopic ventral herniotomy

    DEFF Research Database (Denmark)

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

    2015-01-01

    INTRODUCTION: Laparoscopic herniotomy is the preferred technique for some ventral hernias. Several factors may influence the surgical conditions, one being the depth of neuromuscular blockade (NMB) applied. We hypothesised that deep neuromuscular blockade defined as a post-tetanic count below eight......'s rating of surgical conditions during suturing, duration of surgery and duration of the suturing of the hernia. CONCLUSION: This randomised cross-over study investigated a potential effect on the surgical workspace in laparoscopic ventral herniotomy using deep NMB compared with no NMB. The study may...... provide knowledge relevant to other laparoscopic techniques. FUNDING: The study is funded by a research grant from the Investigator Initiated Studies Program of Merck Sharp & Dohme Corp. TRIAL REGISTRATION: NCT02247466....

  8. Myths and facts in neuromuscular pharmacology - New developments in reversing neuromuscular blockade

    NARCIS (Netherlands)

    Fink, H.; Hollmann, M. W.

    2012-01-01

    Pharmacologic reversal of neuromuscular blockade is a topic nor very well acknowledged and controversially discussed. Reasons for this are numerous and include missing perception of the potential complications of residual neuromuscular paralysis including an increased morbidity and mortality, as

  9. 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

  10. Deep Neuromuscular Blockade Improves Laparoscopic Surgical Conditions

    DEFF Research Database (Denmark)

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

    2017-01-01

    Hg; 'standard') insufflation pressure in a 2 × 2 factorial design. Primary endpoint was surgeon's overall satisfaction with surgical conditions, rated at end of surgery using an 11-point numerical scale. Post-operative pain scores were also evaluated. Data were analyzed using analysis of covariance. RESULTS......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......: Of 127 randomized patients, 120 had evaluable data for the primary endpoint. Surgeon's score of overall satisfaction with surgical conditions was significantly higher with deep versus moderate NMB indicated by a least-square mean difference of 1.1 points (95% confidence interval 0.1-2.0; P = 0...

  11. 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......Hg; 'standard') insufflation pressure in a 2 × 2 factorial design. Primary endpoint was surgeon's overall satisfaction with surgical conditions, rated at end of surgery using an 11-point numerical scale. Post-operative pain scores were also evaluated. Data were analyzed using analysis of covariance. RESULTS......: Of 127 randomized patients, 120 had evaluable data for the primary endpoint. Surgeon's score of overall satisfaction with surgical conditions was significantly higher with deep versus moderate NMB indicated by a least-square mean difference of 1.1 points (95% confidence interval 0.1-2.0; P = 0...

  12. Effect of hypocarbia and hypercarbia on the antagonism of pancuronium-induced neuromuscular blockade with neostigmine in man.

    Science.gov (United States)

    Wirtavuori, K; Salmenperä, M; Tammisto, T

    1982-01-01

    The effects of variations in carbon dioxide concentration on the antagonism of pancuronium-induced neuromuscular block by neostigmine were studied in 21 patients: normocarbia (PE'CO2 5.4%, PaCO2 4.93 kPa, n = 7), hypocarbia (PE'CO2 3.6%, PaCO2 3.30 kPa, n = 7) and hypercarbia (PE'CO2 7.5%, PaCO2 7.13 kPa, n = 7). Mechanical and electromyographic responses to ulnar nerve stimulation (0.1 Hz and 2 Hz) were recorded. A 90% block during nitrous oxide in oxygen anaesthesia was maintained by incremental single injections of pancuronium and reversed with neostigmine 0.35 mg kg-1 with atropine 0.0175 mg kg-1. The recovery of twitch tension up to 50% was similar in all groups but thereafter slower in the hypercarbia group. The recovery times from 25% to 75% twitch tension correlated with PaCO2 (r = 0.55, P less than 0.05). A residual block of about 10% was seen in hypercarbic patients. However, the recovery of e.m.g. amplitude and train-of-four ratios was similar in all groups. Thus, the impaired recovery of twitch tension seems to be the result of depressed contractility rather than failure of neuromuscular transmission.

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

    Directory of Open Access Journals (Sweden)

    Hemmerling Thomas

    2008-01-01

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

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

    DEFF Research Database (Denmark)

    Brueckmann, B; Sasaki, N; Grobara, P

    2015-01-01

    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], Pcare patients, 2 also had clinical evidence of partial...... paralysis. Time between reversal agent administration and operating room discharge-readiness was shorter for sugammadex vs usual care (14.7 vs 18.6 min respectively; P=0.02). CONCLUSIONS: After abdominal surgery, sugammadex reversal eliminated residual neuromuscular blockade in the PACU, and shortened...

  15. Is deep neuromuscular blockade beneficial in laparoscopic surgery?

    DEFF Research Database (Denmark)

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

    2016-01-01

    this in narrative form. We have shared our analysis and text with the authors of the 'Con-' side of these paired position papers during the preparation of the manuscripts. RESULTS: There are a few low risk of bias studies indicating that use of deep neuromuscular blockade improve surgical conditions and improve...

  16. 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 (P<0.0001). Despite this dose reduction, neuromuscular blockade reversal took 115 (± 69) s in the IW group versus 87 (± 40) s in the RW group, but with no significant difference between the two groups (P=0.08). The intervals between injection of sugammadex 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

  17. Sugammadex 4.0 mg kg-1 reversal of deep rocuronium-induced neuromuscular blockade

    DEFF Research Database (Denmark)

    Yu, Buwei; Wang, Xiangrui; Hansen, Søren Helbo

    2014-01-01

    and safety of sugammadex 4.0 mg kg-1 for reversal of deep rocuronium-induced NMB in Chinese and Caucasian patients. Methods: This was an open-label, multicenter, prospective Phase III efficacy study in adult American Society of Anesthesiologists Class 1-3 patients scheduled for surgery under general...

  18. Monitoring of intense neuromuscular blockade in a pig model

    DEFF Research Database (Denmark)

    Madsen, Matias V; Donatsky, Anders M; Jensen, Bente Rona

    2014-01-01

    Intense neuromuscular blockade (NMB) measured by post tetanic count (PTC) was monitored, reversed and verified in this pig model. In a cross-over assessor blinded design six pigs were randomized to either no NMB followed by intense NMB, or intense NMB followed by no NMB. Neuromuscular measurements...... were performed with acceleromyography [train-of-four (TOF) Watch SX]. In all pigs, the response to TOF nerve stimulation was stable and intense NMB (PTC 0-1) was established with rocuronium 3 mg/kg. For reversal, the pigs received sugammadex 20-35 mg/kg and returned to TOF-ratio above 0.90 within 2.......15 min after injection. We established a pig model for monitoring intense NMB with surface stimulation electrodes and acceleromyography. We verified total relaxation of the diaphragm and the abdominal muscles at the PTC 0-1 by suction test and with surface electromyography. This pig model is suitable...

  19. Neuromuscular blockade in children Bloqueadores neuromusculares em crianças

    Directory of Open Access Journals (Sweden)

    João Fernando Lourenço de Almeida

    2000-06-01

    Full Text Available Neuromuscular blocking agents (NMBAs have been widely used to control patients who need to be immobilized for some kind of medical intervention, such as an invasive procedure or synchronism with mechanical ventilation. The purpose of this monograph is to review the pharmacology of the NMBAs, to compare the main differences between the neuromuscular junction in neonates, infants, toddlers and adults, and moreover to discuss their indications in critically ill pediatric patients. Continuous improvement of knowledge about NMBAs pharmacology, adverse effects, and the many other remaining unanswered questions about neuromuscular junction and neuromuscular blockade in children is essential for the correct use of these drugs. Therefore, the indication of these agents in pediatrics is determined with extreme judiciousness. Computorized (Medline 1990-2000 and active search of articles were the mechanisms used in this review.Os bloqueadores neuromusculares têm sido amplamente utilizados para controlar pacientes que necessitem imobilidade para algum tipo de intervenção médica, desde a realização de procedimentos invasivos até a obtenção de sincronismo com a ventilação mecânica. O objetivo básico desta monografia é revisar a farmacologia dos principais bloqueadores neuromusculares, analisar as diferenças existentes na junção neuromuscular de neonatos, lactentes, pré-escolares e adultos, além de discutir suas indicações em pacientes criticamente enfermos internados em unidade de terapia intensiva pediátrica. Revisão computadorizada da literatura (Medline 1990-2000 associado a busca ativa de artigos compuseram o mecanismo de busca dos dados desta revisão.

  20. Neuromuscular blockade for improvement of surgical conditions during laparotomy

    DEFF Research Database (Denmark)

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

    2015-01-01

    scale every 30 min. Primary outcome is the average score for a patient's surgical condition. Secondary outcomes are, among others, surgical rating score during fascial closure, wound dehiscence, wound infection requiring surgical drainage and incisional hernia at the six-month follow-up. CONCLUSIONS......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...

  1. 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....... 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....

  2. The inhibitory effect of Camellia sinensis extracts against the neuromuscular blockade of Crotalus durissus terrificus venom

    Science.gov (United States)

    de Jesus Reis Rosa, Luana; Silva, Gleidy Ana Araujo; Filho, Jorge Amaral; Silva, Magali Glauzer; Groppo, Francisco Carlos; Oshima-Franco, Yoko

    2010-01-01

    In geographically isolated populations where intensive medical care or serum therapy is not easily accessible snake envenomation is a major cause for concern. The aim of the present study was to test Camellia sinensis extracts, theaflavin and epigallocatechin (two of the main C. sinensis components) against the irreversible neuromuscular blockade induced by Crotalus durissus terrificus venom in mouse phrenic-nerve diaphragm preparations. A quantitative histological study was also performed. The venom (20µg/ml) completely decreased twitch tension after 70min and 5µg/ml venom abolished 50% of twitch amplitude after 60min. C. sinensis extract induced intense facilitatory effect in the preparation activity at 0.2mg/ml and slightly facilitatory effect at 0.05mg/ml. Both 0.05mg/ml C. sinensis extract and 0.05mg/ml commercial theaflavin maintained partial muscular activity in presence of 5µg/ml venom. The histological data confirms that Cs is able to protect the muscle from the myotoxic activity of the venom. Commercial epigallocatechin gallate did not show pre-synaptic nor post-synaptic activities. C. sinensis extract was able to protect the mouse phrenic-nerve diaphragm against the irreversible neuromuscular blockade induced by C. durissus terrificus venom. PMID:21544176

  3. Sleep monitoring in children during neuromuscular blockade in the pediatric intensive care unit: a pilot study.

    Science.gov (United States)

    Carno, Margaret-Ann; Hoffman, Leslie A; Henker, Richard; Carcillo, Joseph; Sanders, Mark H

    2004-05-01

    Sleep is an important physiologic process that is known to be disrupted in the intensive care unit. Nevertheless, there is little information on how intensive care unit admission affects sleep in children. Because laryngotracheoplasty is elective but entails 5-7 days of neuromuscular blockade following surgery, children undergoing this procedure present a unique opportunity to analyze sleep during neuromuscular blockade apart from confounding variables resulting from critical illness. To determine the feasibility of using polysomnography to assess sleep patterns in children during neuromuscular blockade. Polysomnography recordings were obtained continuously for 4 days (96 hrs) in two children following laryngotracheoplasty. Medication administration (neuromuscular blockades, sedatives) and time of suctioning were also recorded. Both subjects had documented sleep. However, the proportion of time in each stage was markedly different from developmental norms, and a greater proportion of sleep occurred during the day. Furthermore, there was substantial day-night and day-to-day variability. Some rebound of consolidated sleep appeared by day 4. Sedative use varied considerably. However, neither bolus sedation administration nor endotracheal suctioning appeared to affect sleep. Few monitoring difficulties were encountered. Sleep can be monitored with minimal difficulty in children undergoing neuromuscular blockade in the pediatric intensive care unit. Sleep occurred throughout the day, and there was considerable fragmentation. To fully assess sleep in the intensive care unit, monitoring needs to be continuous over several days, rather than only at night or for < or =24 hrs. Further research is needed in the area to determine typical sleep patterns in children undergoing neuromuscular blockade.

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

    DEFF Research Database (Denmark)

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

    2015-01-01

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

  5. 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

    in adults. SEARCH METHODS: 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...... NMB from the second twitch (T2) to TOFR > 0.9 (MD 10.22 minutes, 95% CI 8.48 to 11.96; I2 = 84%; 10 studies, n = 835; GRADE: moderate quality).We compared sugammadex 4 mg/kg and neostigmine 0.07 mg/kg for reversal of rocuronium-induced deep NMB. Sugammadex 4 mg/kg was 45.78 minutes (16.8 times) faster...... of the block. Sugammadex 2 mg/kg is 10.22 minutes (˜ 6.6 times) faster in reversing moderate neuromuscular blockade (T2) than neostigmine 0.05 mg/kg (GRADE: moderate quality), and sugammadex 4 mg/kg is 45.78 minutes (˜ 16.8 times) faster in reversing deep neuromuscular blockade (PTC 1 to 5) than neostigmine 0...

  6. Influence of intense neuromuscular blockade on surgical conditions during laparotomy

    DEFF Research Database (Denmark)

    Madsen, Matias Vested; Donatsky, Anders Meller; Jensen, Bente Rona

    2015-01-01

    endotracheally intubated, mechanically ventilated, anesthetized with propofol and fentanyl, and randomized into two groups in a cross-over assessor-blinded design. Neuromuscular block was established with rocuronium. Artificial laparotomy for ileus was performed. We investigated the influence of intense......PURPOSE: Intense neuromuscular block may improve surgical conditions in ileus laparotomies; however, it is difficult to evaluate. The aim of this study was to investigate if neuromuscular block improved surgical conditions in pigs with artificial ileus laparotomy. METHODS: Six pigs were...... neuromuscular block on surgical conditions with a subjective rating scale, force needed to close the fascia, incidences of abdominal contractions while suctioning the lungs, width of the wound diastase and operating time as outcome parameters. RESULTS: In all six pigs no abdominal contractions occurred while...

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

    DEFF Research Database (Denmark)

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

    2013-01-01

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

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

    Science.gov (United States)

    Staehr-Rye, Anne K; Rasmussen, Lars S; Rosenberg, Jacob; Juul, Poul; Gätke, Mona R

    2013-02-01

    Laparoscopic cholecystectomy (LC) can be performed using low intra-abdominal pressure (space conditions using either deep, continuous muscle relaxation or moderate blockade during low-pressure (8 mmHg) LC. We hypothesized that a deep neuromuscular block would be associated with a higher proportion of optimal surgical space conditions. This was an investigator-initiated, patient- and assessor-blinded study. Up to 72 patients scheduled for elective LC were randomised to either deep neuromuscular blockade (post-tetanic count 0-1) or moderate neuromuscular blockade, where at least one response to train-of-four nerve stimulation was present. The primary outcome was surgical space conditions at the time during surgery when conditions were worst. The secondary outcomes included the proportion of procedures completed at pneumoperitoneum 8 mmHg, post-operative pain, and incidence of nausea and vomiting. This study was the first randomised study to assess the association between depth of neuromuscular blockade and surgical space conditions during low-pressure LC. The study findings may be applicable to a general surgical population undergoing LC. The University of Copenhagen, Denmark and Sophus Johansens Foundation of 1981, Denmark funded this study, which was also financed by a research grant from the Investigator Initiated Studies Program of Merck Sharp and Dohme Corp. NCT 01523886.

  9. Deep neuromuscular blockade leads to a larger intraabdominal volume during laparoscopy

    DEFF Research Database (Denmark)

    Lindekaer, Astrid Listov; Halvor Springborg, Henrik; Istre, Olav

    2013-01-01

    for measuring the intra-abdominal space available to the surgeon during laproscopy, in order to examine whether the relaxation produced by deep neuromuscular blockade can increase the working surgical space sufficiently to permit a reduction in the CO2 insufflation pressure. Using the laproscopic grasper...

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

    DEFF Research Database (Denmark)

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

    2013-01-01

    Laparoscopic cholecystectomy (LC) can be performed using low intra-abdominal pressure (surgical conditions may not be optimal. The present study aimed at comparing surgical space conditions using either deep, continuous muscle relaxation or moderate blockade during low-pressure (8 mm......Hg) LC. We hypothesized that a deep neuromuscular block would be associated with a higher proportion of optimal surgical space conditions....

  11. 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

    described, but deep neuromuscular blockade may be beneficial. We investigated if deep muscle relaxation would be associated with a higher proportion of procedures with "optimal" surgical space conditions compared with moderate relaxation during low-pressure (8 mm Hg) laparoscopic cholecystectomy. METHODS......). RESULTS: Optimal surgical space conditions during the entire procedure were observed in 7 of 25 patients allocated to deep neuromuscular blockade and in 1 of 23 patients allocated to moderate blockade (P = 0.05) with an absolute difference of 24% between the groups (95% confidence interval, 4......%-43%). Laparoscopic cholecystectomy was completed at pneumoperitoneum 8 mm Hg in 15 of 25 and 8 of 23 patients in the deep and moderate group, respectively (95% confidence interval, -2% to 53%; P = 0.08). Surgical space conditions during dissection of the gallbladder assessed by use of the numeric rating scale were...

  12. 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.

  13. 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.

  14. 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

    . A neuromuscular monitoring e-learning module might support consistent use of neuromuscular monitoring devices. OBJECTIVE: The aim of the study is to assess the effect of a neuromuscular monitoring e-learning module on anesthesia staff's use of objective neuromuscular monitoring and the incidence of residual...... as well as a multiple-choice test to assess knowledge. The e-learning module was developed based on a needs assessment process, including focus group interviews, surveys, and expert opinions. RESULTS: The e-learning module was implemented in 6 anesthesia departments on 21 November 2016. Currently, we...... are collecting postintervention data. The final dataset will include data from more than 10,000 anesthesia procedures. We expect to publish the results in late 2017 or early 2018. CONCLUSIONS: With a dataset consisting of thousands of general anesthesia procedures, the INVERT study will assess whether an e-learning...

  15. Clinical evaluation of a simultaneous closed-loop anaesthesia control system for depth of anaesthesia and neuromuscular blockade*.

    Science.gov (United States)

    Janda, M; Simanski, O; Bajorat, J; Pohl, B; Noeldge-Schomburg, G F E; Hofmockel, R

    2011-12-01

    We developed a closed-loop system to control the depth of anaesthesia and neuromuscular blockade using the bispectral index and the electromyogram simultaneously and evaluated the clinical performance of this combined system for general anaesthesia. Twenty-two adult patients were included in this study. Anaesthesia was induced by a continuous infusion of remifentanil at 0.4 μg.kg(-1) .min(-1) (induction dose) and then 0.25 μg.kg(-1) .min(-1) (maintenance dose) and propofol at 2 mg.kg(-1) 3 min later. The combined automatic control was started 2 min after tracheal intubation. The depth of anaesthesia was recorded using bispectral index monitoring using a target value of 40. The target value of neuromuscular blockade, using mivacurium, was a T1/T1(0) twitch height of 10%. The precision of the system was calculated using internationally defined performance parameters. Twenty patients were included in the data analysis. The mean (SD) duration of simultaneous control was 129 (69) min. No human intervention was necessary during the computer-controlled administration of propofol and mivacurium. All patients assessed the quality of anaesthesia as 'good' to 'very good'; there were no episodes of awareness. The mean (SD) median performance error, median absolute performance error and wobble for the control of depth of anaesthesia and for neuromuscular blockade were -0.31 (1.78), 6.76 (3.45), 6.32 (2.93) and -0.38 (1.68), 3.75 (4.83), 3.63 (4.69), respectively. The simultaneous closed-loop system using propofol and mivacurium was able to maintain the target values with a high level of precision in a clinical setting. © 2011 The Authors. Anaesthesia © 2011 The Association of Anaesthetists of Great Britain and Ireland.

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

    Science.gov (United States)

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

    2014-01-01

    This paper addresses the local identifiability and sensitivity properties of two classes of Wiener models for the neuromuscular blockade and depth of hypnosis, when drug dose profiles like the ones commonly administered in the clinical practice are used as model inputs. The local parameter identifiability was assessed based on the singular value decomposition of the normalized sensitivity matrix. For the given input signal excitation, the results show an over-parameterization of the standard pharmacokinetic/pharmacodynamic models. The same identifiability assessment was performed on recently proposed minimally parameterized parsimonious models for both the neuromuscular blockade and the depth of hypnosis. The results show that the majority of the model parameters are identifiable from the available input-output data. This indicates that any identification strategy based on the minimally parameterized parsimonious Wiener models for the neuromuscular blockade and for the depth of hypnosis is likely to be more successful than if standard models are used. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

  17. Deep neuromuscular blockade and low insufflation pressure during laparoscopic hysterectomy

    DEFF Research Database (Denmark)

    Madsen, Matias Vested; Istre, Olav; Springborg, Henrik Halvor

    2017-01-01

    . The gynaecologists registered increasing abdominal tensions in no versus eight procedures (p = 0.006) in the deep and standard NMB group, respectively. CONCLUSION: Deep NMB in combination with 8 mmHg pneumoperitoneum prevented sudden abdominal contractions during laparoscopic hysterectomy. FUNDING: This work......INTRODUCTION: Establishment of sufficient muscle relaxation is essential in laparoscopic surgery. During laparoscopy, surgeons can experience abdominal contractions in their patients. Deep neuromuscular block (NMB) has the potential to prevent such episodes. In this study, we explored if deep NMB...... reduces the incidence of sudden abdominal contractions as compared with standard NMB. METHODS: This was a pre-planned secondary analysis of a randomized, controlled study. A total of 110 patients scheduled for laparoscopic hysterectomy were randomized to either deep NMB and 8 mmHg pneumoperitoneum (deep...

  18. Deep neuromuscular blockade and low insufflation pressure during laparoscopic hysterectomy.

    Science.gov (United States)

    Madsen, Matias Vested; Istre, Olav; Springborg, Henrik Halvor; Staehr-Rye, Anne Kathrine; Rosenberg, Jacob; Lund, Jørgen; Gätke, Mona Ring

    2017-05-01

    Establishment of sufficient muscle relaxation is essential in laparoscopic surgery. During laparoscopy, surgeons can experience abdominal contractions in their patients. Deep neuromuscular block (NMB) has the potential to prevent such episodes. In this study, we explored if deep NMB reduces the incidence of sudden abdominal contractions as compared with standard NMB. This was a pre-planned secondary analysis of a randomized, controlled study. A total of 110 patients scheduled for laparoscopic hysterectomy were randomized to either deep NMB and 8 mmHg pneumoperitoneum (deep NMB group) or single-bolus NMB and 12 mmHg pneumoperitoneum (standard NMB group). NMB was established with rocuronium and reversed with sugammadex. Two gynaecologists registered episodes of sudden abdominal contractions, alarms from the insufflator due to increased intraabdominal pressure and incidences with tightness of the abdominal wall. No sudden abdominal contractions were detected in the deep NMB group as compared with 12 episodes in the standard NMB group (p deep and standard NMB group, respectively. The gynaecologists registered increasing abdominal tensions in no versus eight procedures (p = 0.006) in the deep and standard NMB group, respectively. Deep NMB in combination with 8 mmHg pneumoperitoneum prevented sudden abdominal contractions during laparoscopic hysterectomy. This work was funded in part by a research grant from the Investigator Initiated Studies Program of Merck Sharp & Dohme Corp, USA. The opinions expressed in this paper are those of the authors and do not necessarily represent those of Merck Sharp & Dohme Corp. The study was assigned with EudraCT number 2012-003787-51 and registered with clinicaltrials.gov (NCT01722097). Articles published in the DMJ are “open access”. This means that the articles are distributed under the terms of the Creative Commons Attribution Non-commercial License, which permits any non-commercial use, distribution, and reproduction in any

  19. The Benefit of Neuromuscular Blockade in Patients with Postanoxic Myoclonus Otherwise Obscuring Continuous Electroencephalography (CEEG

    Directory of Open Access Journals (Sweden)

    Christopher R. Newey

    2017-01-01

    Full Text Available Introduction. Myoclonus status epilepticus is independently associated with poor outcome in coma patients after cardiac arrest. Determining if myoclonus is of cortical origin on continuous electroencephalography (CEEG can be difficult secondary to the muscle artifact obscuring the underlying CEEG. The use of a neuromuscular blocker can be useful in these cases. Methods. Retrospective review of CEEG in patients with postanoxic myoclonus who received cisatracurium while being monitored. Results. Twelve patients (mean age: 53.3 years; 58.3% male met inclusion criteria of clinical postanoxic myoclonus. The initial CEEG patterns immediately prior to neuromuscular blockade showed myoclonic artifact with continuous slowing (50%, burst suppression with myoclonic artifact (41.7%, and continuous myogenic artifact obscuring CEEG (8.3%. After intravenous administration of cisatracurium (0.1 mg–2 mg, reduction in artifact improved quality of CEEG recordings in 9/12 (75%, revealing previously unrecognized patterns: continuous EEG seizures (33.3%, lateralizing slowing (16.7%, burst suppression (16.7%, generalized periodic discharges (8.3%, and, in the patient who had an initially uninterpretable CEEG from myogenic artifact, continuous slowing. Conclusion. Short-acting neuromuscular blockade is useful in determining background cerebral activity on CEEG otherwise partially or completely obscured by muscle artifact in patients with postanoxic myoclonus. Fully understanding background cerebral activity is important in prognostication and treatment, particularly when there are underlying EEG seizures.

  20. Association between levobupivacaine and pancuronium. Interference in neuromuscular transmission and blockade in rats.

    Science.gov (United States)

    Carvalho, Vanessa Henriques; Braga, Angélica de Fátima de Assunção; Braga, Franklin Sarmento da Silva; Potério, Gloria Maria Braga; Santos, Filipe Nadir Caparica; Junqueira, Fernando Eduardo Féres

    2016-07-01

    To evaluate the effects of levobupivacaine on neuromuscular transmission and neuromuscular blockade produced by pancuronium in vitro. Thirty rats were distributed into groups (n = 5) according to the drug used alone or in combination: Group I - levobupivacaine (5 µg.mL-1); Group II - pancuronium (2 µg.mL-1); Group III - pancuronium (2 µg.mL-1) + levobupivacaine (5µg.mL-1). The following parameters were evaluated: 1) amplitude of diaphragmatic response to indirect stimulation, before and 60 minutes after the addition of levobupivacaine and pancuronium alone, and after the addition of levobupivacaine combined with pancuronium; 2) membrane potentials (MP) and miniature endplate potentials (MEPP). Levobupivacaine alone did not alter the amplitude of muscle response and MP. In preparations previoulsy exposed to levobupivacaine, the block with pancuronium was significantly denser (90.2 ± 15.2%), showing a significant difference (p=0.031) in comparison to the block produced by pancuronium alone (48.9% ± 9.8%). There was a decrease in the frequency and amplitude of MEPPs. Levobupivacaine potentiated the neuromuscular blockade produced by pancuronium, confirming a presynaptic action by a decrease in miniature endplate potentials.

  1. Influence of local anesthetics on the neuromuscular blockade produced by rocuronium: effects of lidocaine and 50% enantiomeric excess bupivacaine on the neuromuscular junction.

    Science.gov (United States)

    Braga, Angélica de Fátima de Assunção; Carvalho, Vanessa Henriques; Braga, Franklin Sarmento da Silva; Rodrigues-Simioni, Léa; Loyola, Yolanda Christina S; Potério, Glória Braga

    2009-01-01

    The effects of local anesthetics (LA) on neuromuscular transmission and their influence on the neuromuscular blockade produced by competitive neuromuscular blockers have not been fully investigated. The objective of this study was to evaluate, in vitro, the effects of lidocaine and 50% enantiomeric excess bupivacaine (S75-R25) on the neuromuscular blockade produced by rocuronium. The rats were divided in five groups (n = 5) according to the drug used: isolated lidocaine, bupivacaine (S75-R25), or rocuronium (groups I, II, and II); and rocuronium in preparations previously exposed to LAs (groups IV and V). The concentrations used were as follows: 20 microg x mL(-1), 5 microg x mL(-1), and 4 microg x mL(-1) of lidocaine, bupivacaine (S75-R25), and rocuronium, respectively. The following parameters were evaluated: 1) the strength of muscular contraction of the diaphragm to indirect electrical stimulations, before and 60 minutes after the isolated addition of the LAs and rocuronium, and the association AL-rocuronium; and 2) the effects of LAs on membrane potential (MP) and miniature end-plate potentials (MEPP). The effect of LAs on muscle contraction in response to acetylcholine was evaluated in chick biventer cervicis preparations. Isolated lidocaine and bupivacaine (S75-R25) did not change the muscular response and the levels of MPs. In preparations exposed to LAs, rocuroniuminduced blockade was significantly greater than that produced by rocuronium alone. In chick biventer cervicis preparations, lidocaine and bupivacaine (S75R25) decreased contraction in response to acetylcholine. Lidocaine increased the frequency of MEPPs, which was followed by the blockade; bupivacaine (S75R25) caused a reduction in MEPPs followed by blockade. Local anesthetics caused a potentiation of the neuromuscular blockade produced by rocuronium. The results showed pre- and post-synaptic effects.

  2. 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

    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......The authors conducted a randomized controlled clinical trial to evaluate the usefulness of perioperative manual evaluation of the response to train-of-four (TOF) nerve stimulation. A total of 80 patients were divided into four groups of 20 each. For two groups (one given vecuronium and one...... pancuronium), the anesthetists assessed the degree of neuromuscular blockade during operation and during recovery from neuromuscular blockade by manual evaluation of the response to TOF nerve stimulation. In the other two groups, one of which received vecuronium and the other pancuronium, the anesthetists...

  3. Surgical space conditions during low-pressure laparoscopic cholecystectomy with deep versus moderate neuromuscular blockade: a randomized clinical study.

    Science.gov (United States)

    Staehr-Rye, Anne K; Rasmussen, Lars S; Rosenberg, Jacob; Juul, Poul; Lindekaer, Astrid L; Riber, Claus; Gätke, Mona R

    2014-11-01

    Laparoscopic cholecystectomy performed during low intraabdominal pressure (space conditions and safety of operating at lower pressures has not been adequately described, but deep neuromuscular blockade may be beneficial. We investigated if deep muscle relaxation would be associated with a higher proportion of procedures with "optimal" surgical space conditions compared with moderate relaxation during low-pressure (8 mm Hg) laparoscopic cholecystectomy. 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 as 1 on a 4-point scale). Secondary outcomes included the proportion of procedures completed at pneumoperitoneum 8 mm Hg and surgical space conditions on dissection of the gallbladder (numeric rating scale 0-100; 0 = optimal surgical space conditions; 100 = unacceptable surgical space conditions). Optimal surgical space conditions during the entire procedure were observed in 7 of 25 patients allocated to deep neuromuscular blockade and in 1 of 23 patients allocated to moderate blockade (P = 0.05) with an absolute difference of 24% between the groups (95% confidence interval, 4%-43%). Laparoscopic cholecystectomy was completed at pneumoperitoneum 8 mm Hg in 15 of 25 and 8 of 23 patients in the deep and moderate group, respectively (95% confidence interval, -2% to 53%; P = 0.08). Surgical space conditions during dissection of the gallbladder assessed by use of the numeric rating scale were 20 (10-50) (median [25

  4. Effect of depth of neuromuscular blockade on the abdominal space during pneumoperitoneum establishment in laparoscopic surgery.

    Science.gov (United States)

    Barrio, Javier; Errando, Carlos L; San Miguel, Guillermo; Salas, Boris I; Raga, Juan; Carrión, José L; García-Ramón, Jaime; Gallego, Juan

    2016-11-01

    To evaluate the effect of neuromuscular blockade (NMB) upon the abdominal space during pneumoperitoneum establishment in laparoscopic surgery, comparing moderate NMB and deep NMB. Prospective, randomized, crossover clinical trial. Operating room. Seventy-six American Society of Anesthesiologists 1 to 2 patients scheduled for elective laparoscopic surgery. Two independent evaluations were performed at the establishment of pneumoperitoneum for a preset intraabdominal pressures (IAPs) of 8 and 12 mm Hg, both during moderate NMB (train-of-four count, 1-3) and deep NMB (posttetanic count, <5). Rocuronium was used to induce NMB, and sugammadex was used for reversal. We evaluated (i) the volume of CO2 introduced in 41 patients and (ii) the skin-sacral promontory distance in 35 patients, at pneumoperitoneum establishment. Compared to moderate NMB, deep NMB increased, in a significant manner, both the intraabdominal volume of CO2 insufflated (mean [SD], 2.24 [1.10] vs 2.81 [1.13] L at 8 mm Hg IAP, P<.001, and 3.52 [1.31] vs 4.09 [1.31] L at 12 mm Hg IAP, P<.001) and the skin-sacral promontory distance (11.78 [1.52] vs 12.16 [1.51] cm at 8 mm Hg IAP, P=.002, and 13.34 [1.87] vs 13.80 [1.81] cm at 12 mm Hg IAP, P<.001). Increase in intraabdominal volume after inducing deep NMB was observed in 88% and 81.7% of patients at 8 and 12 mm Hg pneumoperitoneum, with a volume increase of mean of 36.8% (95% confidence interval [CI], 22.8-50.8) and 25% (95% CI, 13.7-36.4), respectively (P=.003). Increase in distance was observed in 61% and 82% of patients at 8 and 12 mm Hg pneumoperitoneum, with a mean distance increase of 3.3% (95% CI, 1.3-5.4) and 3.6% (95% CI, 1.9-5.2), respectively (P=.840). Deep NMB, in comparison to moderate NMB, increased in a significant manner the abdominal space at pneumoperitoneum establishment. However, the effective increase in the abdominal cavity dimensions could be low, the increase showed a great interindividual variability, and it was not observed in

  5. 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

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

    Science.gov (United States)

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

    2017-10-06

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

  7. Short-term effects of neuromuscular blockade on global and regional lung mechanics, oxygenation and ventilation in pediatric acute hypoxemic respiratory failure

    NARCIS (Netherlands)

    Wilsterman, Marlon E. F.; de Jager, Pauline; Blokpoel, Robert; Frerichs, Inez; Dijkstra, Sandra K.; Albers, Marcel J. I. J.; Burgerhof, Johannes G. M.; Markhorst, Dick G.; Kneijber, Martin

    2016-01-01

    Background: Neuromuscular blockade (NMB) has been shown to improve outcome in acute respiratory distress syndrome (ARDS) in adults, challenging maintaining spontaneous breathing when there is severe lung injury. We tested in a prospective physiological study the hypothesis that continuous

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

    Science.gov (United States)

    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.

  9. Effect of ropivacaine combined with pancuronium on neuromuscular transmission and effectiveness of neostigmine and 4-aminopyridine for blockade reversal: experimental study

    Directory of Open Access Journals (Sweden)

    Angélica de Fátima Braga

    2015-04-01

    Full Text Available BACKGROUND AND OBJECTIVES: The local anesthetic effects on neuromuscular junction and its influence on blockade produced by nondepolarizing neuromuscular blockers are still under-investigated; however, this interaction has been described in experimental studies and in humans. The aim of this study was to evaluate in vitro the interaction between ropivacaine and pancuronium, the influence on transmission and neuromuscular blockade, and the effectiveness of neostigmine and 4-aminopyridine to reverse the blockade. METHODS: Rats were divided into groups (n = 5 according to the study drug: ropivacaine (5 µg mL-1; pancuronium (2 µg mL-1; ropivacaine + pancuronium. Neostigmine and 4-aminopyridine were used at concentrations of 2 µg mL-1 and 20 µg mL-1, respectively. The effects of ropivacaine on membrane potential and miniature endplate potential, the amplitude of diaphragm responses before and 60 min after the addition of ropivacaine (degree of neuromuscular blockade with pancuronium and with the association of pancuronium-ropivacaine, and the effectiveness of neostigmine and 4-aminopyridine on neuromuscular block reversal were evaluated. RESULTS: Ropivacaine did not alter the amplitude of muscle response (the membrane potential, but decreased the frequency and amplitude of the miniature endplate potential. Pancuronium blockade was potentiated by ropivacaine, and partially and fully reversed by neostigmine and 4-aminopyridine, respectively. CONCLUSIONS: Ropivacaine increased the neuromuscular block produced by pancuronium. The complete antagonism with 4-aminopyridine suggests presynaptic action of ropivacaine.

  10. Quality of Recovery After Low-Pressure Laparoscopic Donor Nephrectomy Facilitated by Deep Neuromuscular Blockade: A Randomized Controlled Study.

    Science.gov (United States)

    Özdemir-van Brunschot, Denise M D; Scheffer, Gert J; van der Jagt, Michel; Langenhuijsen, Hans; Dahan, Albert; Mulder, Janneke E E A; Willems, Simone; Hilbrands, Luuk B; Donders, Rogier; van Laarhoven, Cees J H M; d'Ancona, Frank A; Warlé, Michiel C

    2017-11-01

    The use of low intra-abdominal pressure (<10 mmHg) reduces postoperative pain scores after laparoscopic surgery. To investigate whether low-pressure pneumoperitoneum with deep neuromuscular blockade improves the quality of recovery after laparoscopic donor nephrectomy (LDN). In a single-center randomized controlled trial, 64 live kidney donors were randomly assigned to 6 or 12 mmHg insufflation pressure. A deep neuromuscular block was used in both groups. Surgical conditions were rated by the five-point Leiden-surgical rating scale (L-SRS), ranging from 5 (optimal) to 1 (extremely poor) conditions. If the L-SRS was insufficient, the pressure was increased stepwise. The primary outcome measure was the overall score on the quality of recovery-40 (QOR-40) questionnaire at postoperative day 1. The difference in the QOR-40 scores on day 1 between the low- and standard-pressure group was not significant (p = .06). Also the overall pain scores and analgesic consumption did not differ. Eight procedures (24%), initially started with low pressure, were converted to a standard pressure (≥10 mmHg). A L-SRS score of 5 was significantly more prevalent in the standard pressure as compared to the low-pressure group at 30 min after insufflation (p < .01). Low-pressure pneumoperitoneum facilitated by deep neuromuscular blockade during LDN does not reduce postoperative pain scores nor improve the quality of recovery in the early postoperative phase. The question whether the use of deep neuromuscular blockade during laparoscopic surgery reduces postoperative pain scores independent of the intra-abdominal pressure should be pursued in future studies. The trial was registered at clinicaltrial.gov before the start of the trial (NCT02146417).

  11. Optimising abdominal space with deep neuromuscular blockade in gynaecologic laparoscopy--a randomised, blinded crossover study.

    Science.gov (United States)

    Madsen, M V; Gätke, M R; Springborg, H H; Rosenberg, J; Lund, J; Istre, O

    2015-04-01

    Insufflation of the abdomen during laparoscopy improves surgical space, but may cause post-operative shoulder pain. The incidence of shoulder pain is reduced using a lower insufflation pressure, but this may, however, compromise the surgical space. We aimed at investigating whether deep neuromuscular blockade (NMB) would enlarge surgical space, measured as the distance from the sacral promontory to the trocar in patients undergoing gynaecologic laparoscopy. Fourteen patients were randomised in an assessor-blinded crossover design. The distance from the sacral promontory to the trocar was measured during deep NMB and without NMB at pneumoperitoneum 8 and 12 mmHg both. Additionally, we assessed surgical conditions while suturing the abdominal fascia using a 4-point subjective rating scale. Deep NMB was established with rocuronium and reversed with sugammadex. At 12 mmHg pneumoperitoneum, deep NMB improved surgical space with a mean of 0.33 cm (95% confidence interval 0.07-0.59) (P=0.01, paired t-test) compared with no NMB. At 8 mmHg pneumoperitoneum deep NMB improved surgical space with a mean of 0.3 cm (95% confidence interval, 0.06-0.54) (P=0.005) compared with no NMB. Deep NMB resulted in significantly better ratings of surgical conditions during suturing of the fascia (P=0.03, Mann-Whitney U-test). Deep NMB enlarged surgical space measured as the distance from the sacral promontory to the trocar. The enlargement, however, was minor and the clinical significance is unknown. Moreover, deep NMB improved surgical conditions when suturing the abdominal fascia. © 2015 The Acta Anaesthesiologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.

  12. Deep neuromuscular blockade improves surgical conditions during low-pressure pneumoperitoneum laparoscopic donor nephrectomy.

    Science.gov (United States)

    Özdemir-van Brunschot, D M D; Braat, A E; van der Jagt, M F P; Scheffer, G J; Martini, C H; Langenhuijsen, J F; Dam, R E; Huurman, V A; Lam, D; d'Ancona, F C; Dahan, A; Warlé, M C

    2017-06-22

    Evidence indicates that low-pressure pneumoperitoneum (PNP) reduces postoperative pain and analgesic consumption. A lower insufflation pressure may hamper visibility and working space. The aim of the study is to investigate whether deep neuromuscular blockade (NMB) improves surgical conditions during low-pressure PNP. This study was a blinded randomized controlled multicenter trial. 34 kidney donors scheduled for laparoscopic donor nephrectomy randomly received low-pressure PNP (6 mmHg) with either deep (PTC 1-5) or moderate NMB (TOF 0-1). In case of insufficient surgical conditions, the insufflation pressure was increased stepwise. Surgical conditions were rated by the Leiden-Surgical Rating Scale (L-SRS) ranging from 1 (extremely poor) to 5 (optimal). Mean surgical conditions were significantly better for patients allocated to a deep NMB (SRS 4.5 versus 4.0; p < 0.01). The final insufflation pressure was 7.7 mmHg in patients with deep NMB as compared to 9.1 mmHg with moderate NMB (p = 0.19). The cumulative opiate consumption during the first 48 h was significantly lower in patients receiving deep NMB, while postoperative pain scores were similar. In four patients allocated to a moderate NMB, a significant intraoperative complication occurred, and in two of these patients a conversion to an open procedure was required. Our data show that deep NMB facilitates the use of low-pressure PNP during laparoscopic donor nephrectomy by improving the quality of the surgical field. The relatively high incidence of intraoperative complications indicates that the use of low pressure with moderate NMB may compromise safety during LDN. Clinicaltrials.gov identifier: NCT 02602964.

  13. The Safety of Neuromuscular Blockade Reversal in Patients With Cardiac Transplantation.

    Science.gov (United States)

    Barbara, David W; Christensen, Jon M; Mauermann, William J; Dearani, Joseph A; Hyder, Joseph A

    2016-12-01

    Neuromuscular blockade (NMB) reversal with neostigmine and glycopyrrolate has been reported to cause cardiac arrest in patients with a history of cardiac transplantation. The purpose of this study was to examine the safety of NMB reversal with acetylcholinesterase inhibitors and muscarinic anticholinergics in these patients. We queried the medical records of a large tertiary referral center for patients with a history of prior heart transplantation who underwent anesthesia including receipt of NMB reversal. Patient records were reviewed to investigate maximal decrease in heart rate (HR) after NMB reversal and incidence of death and cardiac arrest. Seventy-seven heart transplant patients underwent 118 subsequent anesthetics during which they received neostigmine and glycopyrrolate for NMB reversal. No patients had active pacemakers at the time of their anesthetics. Mean time from heart transplantation to NMB reversal was 2.9 ± 3.2 (median, 1.9; range, 0.01- 12.5) years. After NMB reversal, no patients received atropine or epinephrine, suffered cardiac arrest, or died within 30 days. Mean HR decrease, defined as the difference between the HR immediately before NMB reversal and the lowest HR within 5 minutes thereafter, after NMB reversal was 0.5 ± 3.2 with median 0 (range, -8 to 17) beats per minute. Mean HR decrease was not associated with transplantation type (biatrial versus bicaval, P = 0.2029) or with increasing duration of time from cardiac transplantation (P = 0.0874). Although rare cases of cardiac arrest after NMB reversal have been reported, our experience would support the safety of neostigmine and glycopyrrolate in cardiac transplantation patients.

  14. ATRACURIUM-INDUCED NEUROMUSCULAR BLOCK IN THE ISOLATED ARM

    NARCIS (Netherlands)

    ERIKSSON, LI; VANDENBROM, RHG; LENNMARKEN, C; AGOSTON, S

    1992-01-01

    A modification of the isolated arm technique was applied in 10 females under opioid-based i.v. anaesthesia for comparison of the offset of an atracurium-induced neuromuscular block in an isolated arm to an arm with maintained circulation. The neuromuscular blocking effect of a bolus dose of

  15. 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

  16. Influence of depth of neuromuscular blockade on surgical conditions during low-pressure pneumoperitoneum laparoscopic cholecystectomy: A randomized blinded study.

    Science.gov (United States)

    Barrio, Javier; Errando, Carlos L; García-Ramón, Jaime; Sellés, Rafael; San Miguel, Guillermo; Gallego, Juan

    2017-11-01

    To evaluate the influence of neuromuscular blockade (NMB) on surgical conditions during low-pressure pneumoperitoneum (8mmHg) laparoscopic cholecystectomy (LC), while comparing moderate and deep NMB. Secondary objective was to evaluate if surgical conditions during low-pressure pneumoperitoneum LC performed with deep NMB could be comparable to those provided during standard-pressure pneumoperitoneum (12mmHg) LC. Prospective, randomized, blinded clinical trial. Operating room. Ninety ASA 1-2 patients scheduled for elective LC. Patients were allocated into 3 groups: Group 1: low-pressure pneumoperitoneum with moderate-NMB (1-3 TOF), Group 2: low-pressure pneumoperitoneum with deep-NMB (1-5 PTC) and Group 3: standard pneumoperitoneum (12mmHg). Rocuronium was used to induce NMB and acceleromiography was used for NMB monitoring (TOF-Watch-SX). Three experienced surgeons evaluated surgical conditions using a four-step scale at three time-points: surgical field exposure, dissection of the gallbladder and extraction/closure. Low-pressure pneumoperitoneum (Group 1 vs. 2): good conditions: 96.7 vs. 96.7%, 90 vs. 80% and 89.6 vs. 92.3%, respectively for the time-points, p>0.05. No differences in optimal surgical conditions were observed between the groups. Surgery completion at 8mmHg pneumoperitoneum: 96.7 vs. 86.7%, p=0.353. Standard-pressure pneumoperitoneum vs. low-pressure pneumoperitoneum with deep NMB (Group 3 vs. 2): good conditions: 100% in Group 3 for the three time-points (p=0.024 vs. Group 2 at dissection of the gallbladder). Significantly greater percentage of optimal conditions during standard-pressure pneumoperitoneum LC at the three time points of evaluation. The depth of NMB was found not to be decisive neither in the improvement of surgical conditions nor in the completion of low-pressure pneumoperitoneum LC performed by experienced surgeons. Surgical conditions were considered better with a standard-pressure pneumoperitoneum, regardless of the depth of NMB

  17. [Comparison of laryngeal mask airway (LMA)- Proseal and the LMA-Classic in ventilated children receiving neuromuscular blockade].

    Science.gov (United States)

    Lardner, David R R; Cox, Robin G; Ewen, Alastair; Dickinson, Darren

    2008-01-01

    To determine whether a functional difference exists between the size 2 laryngeal mask airway (LMA)-Classic (CLMA) and LMA-Proseal (PLMA) in anesthetized children who have received neuromuscular blockade. Airway leak during intermittent positive pressure ventilation (IPPV) and adequacy of fibreoptic laryngeal view were the primary study outcomes. A randomized, controlled, single-blinded study of 51 ASA I or II children weighing 10-20 kg was undertaken. The anesthetic technique was standardized. Following insertion of the LMA and cuff inflation to 60 cm H(2)O, we measured oropharyngeal leak pressure and gastric insufflation and leak fraction during IPPV, and evaluated the adequacy of fibreoptic view. Oropharyngeal leak pressure measured by neck auscultation was higher for the PLMA compared to the CLMA (23.7 vs 16.5 cm H(2)O, P = 0.009) but, when measured by the inspiratory hold maneuver was not significantly different (24.8 vs 20.3 cm H(2)O, respectively, P = 0.217). Leak fraction values were similar for the CLMA and the PLMA (21.2%. vs 13.3%, respectively, P = 0.473). A satisfactory view of the larynx was obtained more frequently in the PLMA group (21/25 vs 10/25, P = 0.003). Gastric insufflation during leak determination was more common with the CLMA (12/26 vs 2/25 CLMA vs PLMA, respectively, P = 0.006). In children undergoing IPPV with neuromuscular blockade, the size 2 PLMA is associated with a higher leak pressure by auscultation and less gastric insufflation compared to the CLMA. Leak pressures assessed by manometric stability are similar with these two devices. The improved fibreoptic view of the larynx through the PLMA may be advantageous for bronchoscopy.

  18. The comparative efficacy and safety of sugammadex and neostigmine in reversing neuromuscular blockade in adults. A Cochrane systematic review with meta-analysis and trial sequential analysis

    DEFF Research Database (Denmark)

    Hristovska, A-M; Duch, P; Allingstrup, M

    2018-01-01

    We compared the efficacy and safety of sugammadex and neostigmine in reversing neuromuscular blockade in adults. Our outcomes were: recovery time from second twitch to train-of-four ratio > 0.9; recovery time from post-tetanic count 1-5 to train-of-four ratio > 0.9; and risk of composite adverse...... and serious adverse events. We searched for randomised clinical trials irrespective of publication status and date, blinding status, outcomes reported or language. We included 41 studies with 4206 participants. Time to reversal of neuromuscular blockade from second twitch to a train-of-four ratio > 0.9 was 2.......0 min with sugammadex 2 mg.kg-1 and 12.9 min with neostigmine 0.05 mg.kg-1 , with a mean difference (MD) (95%CI)) of 10.2 (8.5-12.0) (I2 = 84%, 10 studies, n = 835, Grades of Recommendation, Assessment, Development and Evaluation (GRADE): moderate quality). Time to reversal of neuromuscular blockade...

  19. Monitoring intraoperative neuromuscular blockade and blood pressure with one device (TOF-Cuff): A comparative study with mechanomyography and invasive blood pressure.

    Science.gov (United States)

    Veiga Ruiz, G; García Cayuela, J; Orozco Montes, J; Parreño Caparrós, M; García Rojo, B; Aguayo Albasini, J L

    2017-12-01

    The overall objective of the study is to determine the ability of TOF-Cuff device (blood-pressure modified cuff, including stimulation electrodes) to monitor with the same device the non-invasive blood pressure (NIBP) and the depth of a neuromuscular blockade (NMB) induced pharmacologically, by stimulation of the brachial plexus at the humeral level and recording evoked changes in arterial pressure. Clinical, single-centre, open-controlled study with 32 adult patients ASA I-III for scheduled elective surgery under general anaesthesia in supine position, for the validation of neuromuscular monitoring, comparing the values obtained from neuromuscular relaxation TOF-Cuff with those obtained by mechanomyography (MMG) (control method) during the recovery phase of NMB, when a TOF ratio>0.7 and>0.9 (primary endpoint) were reached respectively. And an additional consecutive study of 17 patients for validation of NIBP monitoring with TOF-Cuff device vs invasive blood pressure measured by an intra-arterial catheter. All data were analyzed using the Bland-Altman method. Recovery from NMB measured with the TOF-Cuff was earlier compared to MMG. Comparing TOF-ratio>0.9 measured with TOF-Cuff vs TOF-ratio>0.7 with MMG, a specificity of 91% and a positive predictive value of 84% were obtained. In NIBP measurement, the mean error and standard deviation of both systolic blood pressure (1.6±7mmHg) and diastolic blood pressure (-3.4±6.3) were within the European accuracy requirements for medical devices. The TOF-Cuff device has been shown to be valid and safe in the monitoring of NMB and in the measurement of NIBP, with no patient presenting any adverse events, skin-level lesions or residual pain. It is not interchangeable with MMG, having a TOF-ratio>0.9 quantified by the TOF-Cuff device, a good correlation with a TOF-ratio>0.7 on MMG. Copyright © 2017 Sociedad Española de Anestesiología, Reanimación y Terapéutica del Dolor. Publicado por Elsevier España, S.L.U. All rights

  20. Cyclosporine preserves the anergic state of human T cells induced by costimulation blockade in vitro.

    NARCIS (Netherlands)

    Koenen, H.J.P.M.; Fasse, E.; Joosten, I.

    2005-01-01

    BACKGROUND: Costimulation blockade based tolerance-inducing therapies might be disrupted by adjunct conventional immunosuppressive drug use. In the current study, we evaluated the compatibility of various immunosuppressive agents on costimulation blockade-based immunosuppression and T-cell anergy

  1. Neuromuscular fatigue induced by whole-body vibration exercise.

    Science.gov (United States)

    Maffiuletti, Nicola A; Saugy, Jonas; Cardinale, Marco; Micallef, Jean-Paul; Place, Nicolas

    2013-06-01

    The aim of this study was to examine the magnitude and the origin of neuromuscular fatigue induced by half-squat static whole-body vibration (WBV) exercise, and to compare it to a non-WBV condition. Nine healthy volunteers completed two fatiguing protocols (WBV and non-WBV, randomly presented) consisting of five 1-min bouts of static half-squat exercise with a load corresponding to 50 % of their individual body mass. Neuromuscular fatigue of knee and ankle muscles was investigated before and immediately after each fatiguing protocol. The main outcomes were maximal voluntary contraction (MVC) torque, voluntary activation, and doublet peak torque. Knee extensor MVC torque decreased significantly (P fatiguing protocols. Doublet peak torque decreased significantly and to a similar extent following WBV and non-WBV exercise, for both knee extensors (-25 %; P fatigue and did not change its causative factors compared to non-WBV half-squat resistive exercise in recreationally active subjects.

  2. Feasibility of full and rapid neuromuscular blockade recovery with sugammadex in myasthenia gravis patients undergoing surgery – a series of 117 cases

    Directory of Open Access Journals (Sweden)

    Vymazal T

    2015-10-01

    Full Text Available Tomas Vymazal,1 Martina Krecmerova,1 Vladimír Bicek,1 Robert Lischke2 1Department of Anaesthesiology and ICM, 2nd Faculty of Medicine, 23rd Surgical Department of 1st Faculty of Medicine, Charles University in Prague and Motol University Hospital, Prague, Czech Republic Purpose: Myasthenia gravis (MG is an autoimmune disease interfering with neuromuscular transmission. Patients are at risk of postoperative residual curarization (PORC if nondepolarizing muscle relaxants are used. Clinically inapparent insufficient muscle strength may result in hypoventilation and postoperative bronchopneumonia. We describe a cohort of 117 cases in which sugammadex was used in MG patients undergoing surgery with muscle relaxation with rocuronium.Methods and patients: We anesthetized 117 patients with MG using rocuronium and sugammadex as neuromuscular blockade reversal agent. One hundred five patients underwent surgical thymectomy and 12 underwent cholecystectomy (five laparotomic and seven laparoscopic. We measured time from sugammadex administration to recovery and to extubation, using the TOF-Watch® (series of four consecutive electrical impulses [the train-of-four] >0.9. We tracked peripheral capillary oxygen saturation (SpO2 <95%, elevation of partial pressure of carbon dioxide (pCO2 >10% above baseline, number of reintubations within the first 48 hours, and number of pneumonias within 120 hours, postoperatively. Results were processed as average, minimum, and maximum values.Results: The period needed to reach train-of-four of 0.9 following sugammadex administration was on average 117 seconds (minimum of 105 seconds/maximum of 127 seconds and differed within deviation <10%. The time to extubation following sugammadex administration was on average 276 seconds (minimum of 251 seconds/maximum of 305 seconds and differed minimally among patients as well. We observed no SpO2 <95%, no pCO2 elevation >10% above a baseline, no emergent reintubation within the

  3. Geographical venom variations of the Southeast Asian monocled cobra (Naja kaouthia): venom-induced neuromuscular depression and antivenom neutralization.

    Science.gov (United States)

    Tan, Kae Yi; Tan, Choo Hock; Sim, Si Mui; Fung, Shin Yee; Tan, Nget Hong

    2016-01-01

    The Southeast Asian monocled cobras (Naja kaouthia) exhibit geographical variations in their venom proteomes, especially on the composition of neurotoxins. This study compared the neuromuscular depressant activity of the venoms of N. kaouthia from Malaysia (NK-M), Thailand (NK-T) and Vietnam (NK-V), and the neutralization of neurotoxicity by a monospecific antivenom. On chick biventer cervicis nerve-muscle preparation, all venoms abolished the indirect twitches, with NK-T venom being the most potent (shortest t90, time to 90% twitch inhibition), followed by NK-V and NK-M. Acetylcholine and carbachol failed to reverse the blockade, indicating irreversible/pseudo-irreversible post-synaptic neuromuscular blockade. KCl restored the twitches variably (NK-M preparation being the least responsive), consistent with different degree of muscle damage. The findings support that NK-T venom has the most abundant curarimimetic alpha-neurotoxins, while NK-M venom contains more tissue-damaging cytotoxins. Pre-incubation of tissue with N. kaouthia monovalent antivenom (NKMAV) prevented venom-induced twitch depression, with the NK-T preparation needing the largest antivenom dose. NKMAV added after the onset of neuromuscular depression could only halt the inhibitory progression but failed to restore full contraction. The findings highlight the urgency of early antivenom administration to sequester as much circulating neurotoxins as possible, thereby hastening toxin elimination from the circulation. In envenomed mice, NKMAV administered upon the first neurological sign neutralized the neurotoxic effect, with the slowest full recovery noticed in the NK-T group. This is consistent with the high abundance of neurotoxins in the NK-T venom, implying that a larger amount or repeated dosing of NKMAV may be required in NK-T envenomation. Copyright © 2016 Elsevier Inc. All rights reserved.

  4. The neuromuscular blockade produced by pure alkaloid, mitragynine and methanol extract of kratom leaves (Mitragyna speciosa Korth.).

    Science.gov (United States)

    Chittrakarn, Somsmorn; Keawpradub, Niwat; Sawangjaroen, Kitja; Kansenalak, Supaporn; Janchawee, Benjamas

    2010-06-16

    The effects of pure alkaloid, mitragynine and a methanolic extract of kratom leaves were investigated on neuromuscular junction and compound nerve action potential. Wistar rats were killed by cervical dislocation and decapitated. The phrenic nerve-hemidiaphragms, hemidiaphragms and sciatic nerve were isolated. Kratom methanolic extract present at 0.1-1 mg/mL and mitragynine (0.0156 mg/mL) decreased the muscle twitch on the isolated phrenic nerve-hemidiaphragm and hemidiaphragm preparation. Muscle relaxation caused by kratom extract (1 mg/mL) was greater than the effect of mitragynine. Pancuronium and succinylcholine potentiated the effect of kratom extract. It also had a direct relaxation effect on the hemidiaphragm muscle. The muscle relaxation caused by kratom extract was not antagonized by neostigmine, tetraethylammonium and calcium chloride. High concentrations of kratom extract (10-40 mg/mL) and mitragynine (2 mg/mL) blocked the nerve conduction, amplitude and duration of compound nerve action potential. The mechanism of action of kratom extract might not act as a competitive antagonist of acetylcholine yet its dominant effect was at the neuromuscular junction and not at the skeletal muscle or somatic nerve. Copyright 2010 Elsevier Ireland Ltd. All rights reserved.

  5. Síndrome de Tako-Tsubo em decorrência de bloqueio neuromuscular residual: relato de caso Síndrome de Tako-Tsubo como consecuencia de bloqueo neuromuscular residual: relato de caso Tako-Tsubo syndrome secondary to residual neuromuscular blockade: case report

    Directory of Open Access Journals (Sweden)

    Marcos Guilherme Cunha Cruvinel

    2008-12-01

    neuromuscular residual. RELATO DEL CASO: Paciente del sexo femenino, 61 años, estado físico ASA I, sometida a la anestesia general asociada al bloqueo paravertebral cervical para la reparación artroscópica de lesión de manguito de los rotadores. Después de la extubación, quedó demostrado el bloqueo neuromuscular residual a través del examen clínico. En la sala de recuperación postanestésica, evolucionó con somnolencia, taquicardia, hipertensión arterial y acidosis respiratoria grave. Después de la reintubación evolucionó con parada cardíaca en actividad eléctrica sin pulso, revertida con adrenalina y masaje cardíaco externo. En el postoperatorio presentó una elevación de segmento ST, aumento de troponina y acinesia de segmento medio-apical del ventrículo izquierdo, con fracción de eyección estimada en un 30%. La cineangiocoronariografía mostró coronarias exentas de ateromatosis significativa y un grave comprometimiento de la función sistólica con acinesia inferior y ántero-septo-apical, con hipercontratilidad compensatoria de sus porciones basales. Con el tratamiento iniciado, hubo una recuperación funcional completa. CONCLUSIONES: El bloqueo neuromuscular residual asociado a la parálisis diafragmática y la posible atelectasia pulmonar, que conlleva a la insuficiencia respiratoria, hipercapnia y descarga adrenérgica, fueron los factores desencadenantes del síndrome de Tako-Tsubo con su grave repercusión clínica.BACKGROUND AND OBJECTIVES: Tako-Tsubo syndrome is a rare postoperative complication with a 5% mortality rate. The objective of this report was to present residual neuromuscular blockade as a trigger for this syndrome, discuss this disorder, and call attention to the risks of residual neuromuscular blockade. CASE REPORT: A 61-year old female, physical status ASA I, who underwent general anesthesia associated with paravertebral cervical block for arthroscopic repair of a rotator cuff lesion. Physical exam after extubation detected

  6. FAP positive fibroblasts induce immune checkpoint blockade resistance in colorectal cancer via promoting immunosuppression.

    Science.gov (United States)

    Chen, Lingling; Qiu, Xiangting; Wang, Xinhua; He, Jian

    2017-05-20

    Immune checkpoint blockades that significantly prolonged survival of melanoma patients have been less effective on colorectal cancer (CRC) patients. Growing evidence suggested that fibroblast activation protein-alpha (FAP) on cancer associate fibroblasts (CAFs) has critical roles in regulating antitumor immune response by inducing tumor-promoting inflammation. In this study, we explored the roles of FAP in regulating the tumor immunity and immune checkpoint blockades resistance in CRC experimental systems. We found that CAFs with high FAP expression could induce immune checkpoint blockade resistance in CRC mouse model. Mechanistically, CAFs with high FAP expression promoted immunosuppression in the CRC tumor immune microenvironment by up-regulating CCL2 secretion, recruiting myeloid cells, and decreasing T-cell activity. In human CRC samples, FAP expression was proportional to myeloid cells number, but inversely related to T-cell number. High FAP expression also predicted poor survival of CRC patients. Taken together, our study suggested that high FAP expression in CAFs is one reason leading to immune checkpoint blockades resistance in CRC patients and FAP is an optional target for reversing immune checkpoint blockades resistance. Copyright © 2017 Elsevier Inc. All rights reserved.

  7. CD154 Blockade Results in Transient Reduction in Theiler's Murine Encephalomyelitis Virus-Induced Demyelinating Disease

    OpenAIRE

    Howard, Laurence M.; Neville, Katherine L.; Haynes, Lia M.; Dal Canto, Mauro C.; Miller, Stephen D

    2003-01-01

    Transient CD154 blockade at the onset of Theiler's murine encephalomyelitis virus-induced demyelinating disease ameliorated disease progression for 80 days, reduced immune cell infiltration, and transiently increased viral loads in the central nervous system. Peripheral antiviral and autoimmune T-cell responses were normal, and disease severity returned to control levels by day 120.

  8. Short-term effects of neuromuscular blockade on global and regional lung mechanics, oxygenation and ventilation in pediatric acute hypoxemic respiratory failure.

    Science.gov (United States)

    Wilsterman, Marlon E F; de Jager, Pauline; Blokpoel, Robert; Frerichs, Inez; Dijkstra, Sandra K; Albers, Marcel J I J; Burgerhof, Johannes G M; Markhorst, Dick G; Kneyber, Martin C J

    2016-12-01

    Neuromuscular blockade (NMB) has been shown to improve outcome in acute respiratory distress syndrome (ARDS) in adults, challenging maintaining spontaneous breathing when there is severe lung injury. We tested in a prospective physiological study the hypothesis that continuous administration of NMB agents in mechanically ventilated children with severe acute hypoxemic respiratory failure (AHRF) improves the oxygenation index without a redistribution of tidal volume V T toward non-dependent lung zones. Oxygenation index, PaO2/FiO2 ratio, lung mechanics (plateau pressure, mean airway pressure, respiratory system compliance and resistance), hemodynamics (heart rate, central venous and arterial blood pressures), oxygenation [oxygenation index (OI), PaO2/FiO2 and SpO2/FiO2], ventilation (physiological dead space-to-V T ratio) and electrical impedance tomography measured changes in end-expiratory lung volume (EELV), and V T distribution was measured before and 15 min after the start of continuous infusion of rocuronium 1 mg/kg. Patients were ventilated in a time-cycled, pressure-limited mode with pre-set V T. All ventilator settings were not changed during the study. Twenty-two patients were studied (N = 18 met the criteria for pediatric ARDS). Median age (25-75 interquartile range) was 15 (7.8-77.5) weeks. Pulmonary pathology was present in 77.3%. The median lung injury score was 9 (8-10). The overall median CoV and regional lung filling characteristics were not affected by NMB, indicating no ventilation shift toward the non-dependent lung zones. Regional analysis showed a homogeneous time course of lung inflation during inspiration, indicating no tendency to atelectasis after the introduction of NMB. NMB decreased the mean airway pressure (p = 0.039) and OI (p = 0.039) in all patients. There were no significant changes in lung mechanics, hemodynamics and EELV. Subgroup analysis showed that OI decreased (p = 0.01) and PaO2/FiO2 increased (p = 0.02) in

  9. No synergy between ATG induction and costimulation blockade induced kidney allograft survival in rhesus monkeys.

    Science.gov (United States)

    Haanstra, Krista G; Sick, Ella A; Ringers, Jan; Wubben, Jacqueline A M; Kuhn, Eva-Maria; 't Hart, Bert A; Boon, Louis; Jonker, Margreet

    2006-11-15

    Costimulation blockade with antibodies directed against human CD40 and CD86 leads to prolonged kidney allograft survival in rhesus monkeys, but fails to induce permanent graft acceptance. We have tested whether costimulation blockade is more effective after peripheral T-cell ablation with antithymocyte globulin (ATG), with the aim to remove already primed autoreactive cells present in the normal repertoire. Rhesus monkeys were transplanted with a mismatched kidney allograft. ATG was given around the time of transplantation (day -1 and 0). Costimulation blockade with anti-CD40+anti-CD86 was given at tapering dosages from day -1 to 56. Cyclosporin A (CsA) was given from day 42 onwards and first rejections occurring after day 42 were treated with prednisone. We observed accelerated rejection in ATG-treated monkeys, compared to animals receiving only costimulation blockade. The accelerated rejection of the kidney allograft occurred despite the application of rejection therapy with steroids and CsA. Three of the five ATG-treated animals were found seropositive for donor-specific alloantibodies. Early biopsies (day 21) from animals treated with ATG and anti-CD40+anti-CD86 show substantially reduced expression of cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) and forkhead box P3 (FOXP3) in focal infiltrates as compared to animals treated with only costimulation blockade. Furthermore, we observed the rapid reappearance of CD8 T-cells with a memory phenotype (disappearance of naive CD95/CD11a T-cells) in peripheral blood. We conclude that (subtotal) T-cell depletion using ATG does not add to costimulation blockade induced kidney allograft survival.

  10. Neuromuscular Activity of Micrurus laticollaris (Squamata: Elapidae Venom in Vitro

    Directory of Open Access Journals (Sweden)

    Alejandro Carbajal-Saucedo

    2014-01-01

    Full Text Available In this work, we have examined the neuromuscular activity of Micrurus laticollaris (Mexican coral snake venom (MLV in vertebrate isolated nerve-muscle preparations. In chick biventer cervicis preparations, the MLV induced an irreversible concentration- and time-dependent (1–30 µg/mL neuromuscular blockade, with 50% blockade occurring between 8 and 30 min. Muscle contractures evoked by exogenous acetylcholine were completely abolished by MLV, whereas those of KCl were also significantly altered (86% ± 11%, 53% ± 11%, 89% ± 5% and 89% ± 7% for one, three, 10 and 30 µg of venom/mL, respectively; n = 4; p < 0.05. In mouse phrenic nerve-diaphragm preparations, MLV (1–10 µg/mL promoted a slight increase in the amplitude of twitch-tension (3 µg/mL, followed by neuromuscular blockade (n = 4; the highest concentration caused complete inhibition of the twitches (time for 50% blockade = 26 ± 3 min, without exhibiting a previous neuromuscular facilitation. The venom (3 µg/mL induced a biphasic modulation in the frequency of miniature end-plate potentials (MEPPs/min, causing a significant increase after 15 min, followed by a decrease after 60 min (from 17 ± 1.4 (basal to 28 ± 2.5 (t15 and 12 ± 2 (t60. The membrane resting potential of mouse diaphragm preparations pre-exposed or not to d-tubocurarine (5 µg/mL was also significantly less negative with MLV (10 µg/mL. Together, these results indicate that M. laticollaris venom induces neuromuscular blockade by a combination of pre- and post-synaptic activities.

  11. Influência da procainamida sobre o bloqueio neuromuscular produzido pelo rocurônio e investigação sobre o mecanismo de ação da procainamida na junção neuromuscular Influencia de la procainamida sobre el bloqueo neuromuscular producido por el rocuronio e investigación sobre el mecanismo de acción de la procainamida en la junción neuromuscular Influence of procainamide on the neuromuscular blockade caused by rocuronium and investigation on the mechanism of action of procainamide on the neuromuscular junction

    Directory of Open Access Journals (Sweden)

    Thalita Duque Martins

    2007-02-01

    : It has already been proved that procainamide potentiates the neuromuscular blockade of d-tubocurarine; however, the mechanism of this potentiation is controversial. The aim of this study was to assess the influence of procainamide on the neuromuscular blockade produced by rocuronium and investigate the mechanisms of this interaction. METHODS: Fifteen rats (250 to 300 g were used in the preparation described by Bülbring. They were divided in three groups (n = 5 each: procainamide - 20 µg.mL-1 (Group I; rocuronium - 4 µg.mL-1 (Group II; and rocuronium - 4 µg.mL-1 and procainamide - 20 µg.mL-1 (Group III. The following parameters were evaluated: 1 amplitude of muscle contractions under indirect stimulation, before and after the administration of the drugs; 2 miniature end plate potentials (MEPPs; and 3 the efficacy of 4-aminopyridine in reverting the muscular blockade. The mechanism of the interaction was studied in Biventer cervicis (n = 5 and in the denervated rat diaphragm (n = 5, observing the influence of procainamide in the response to acetylcholine. RESULTS: Procainamide alone did not change the neuromuscular responses. Group III presented a 68.6% ± 7.1% blockade, which represented a statistically significant difference (p = 0.0067 when compared with Group II (10.4% ± 4.5%, which was reverted by 4-aminopiridine. Procainamide increased the frequency of the MEPP, followed by a blockade that was reverted by 4-aminopiridine. In Biventer cervicis, procainamide increased the contraction in response to acetylcholine, which was not observed in the denervated diaphragm. CONCLUSIONS: Procainamide potentiated the blockade caused by rocuronium. The changes observed with MEPP and Biventer cervicis identified pre-synaptic action. The antagonism of 4-aminopiridine on the blockade of the MEPP suggested receptor desensitization by procainamide.

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

    DEFF Research Database (Denmark)

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

    1991-01-01

    of glycopyrrolate (7 micrograms.kg-1) or two doses of atropine (8 micrograms.kg-1 each), given with an interval of 1 min. There were no differences between the two methods with respect to percentage heart rate changes, salivation or arousal time. Four patients demonstrated cardiac arhythmias in the atropine group...

  13. 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.

  14. Oxidative stress induces overgrowth of the Drosophila neuromuscular junction.

    Science.gov (United States)

    Milton, Valerie J; Jarrett, Helen E; Gowers, Kate; Chalak, Salma; Briggs, Laura; Robinson, Iain M; Sweeney, Sean T

    2011-10-18

    Synaptic terminals are known to expand and contract throughout an animal's life. The physiological constraints and demands that regulate appropriate synaptic growth and connectivity are currently poorly understood. In previous work, we identified a Drosophila model of lysosomal storage disease (LSD), spinster (spin), with larval neuromuscular synapse overgrowth. Here we identify a reactive oxygen species (ROS) burden in spin that may be attributable to previously identified lipofuscin deposition and lysosomal dysfunction, a cellular hallmark of LSD. Reducing ROS in spin mutants rescues synaptic overgrowth and electrophysiological deficits. Synapse overgrowth was also observed in mutants defective for protection from ROS and animals subjected to excessive ROS. ROS are known to stimulate JNK and fos signaling. Furthermore, JNK and fos in turn are known potent activators of synapse growth and function. Inhibiting JNK and fos activity in spin rescues synapse overgrowth and electrophysiological deficits. Similarly, inhibiting JNK, fos, and jun activity in animals with excessive oxidative stress rescues the overgrowth phenotype. These data suggest that ROS, via activation of the JNK signaling pathway, are a major regulator of synapse overgrowth. In LSD, increased autophagy contributes to lysosomal storage and, presumably, elevated levels of oxidative stress. In support of this suggestion, we report here that impaired autophagy function reverses synaptic overgrowth in spin. Our data describe a previously unexplored link between oxidative stress and synapse overgrowth via the JNK signaling pathway.

  15. PD-1 blockade enhances the vaccination-induced immune response in glioma.

    Science.gov (United States)

    Antonios, Joseph P; Soto, Horacio; Everson, Richard G; Orpilla, Joey; Moughon, Diana; Shin, Namjo; Sedighim, Shaina; Yong, William H; Li, Gang; Cloughesy, Timothy F; Liau, Linda M; Prins, Robert M

    2016-07-07

    DC vaccination with autologous tumor lysate has demonstrated promising results for the treatment of glioblastoma (GBM) in preclinical and clinical studies. While the vaccine appears capable of inducing T cell infiltration into tumors, the effectiveness of active vaccination in progressively growing tumors is less profound. In parallel, a number of studies have identified negative costimulatory pathways, such as programmed death 1/programmed death ligand 1 (PD-1/PD-L1), as relevant mediators of the intratumoral immune responses. Clinical responses to PD-1 pathway inhibition, however, have also been varied. To evaluate the relevance to established glioma, the effects of PD-1 blockade following DC vaccination were tested in intracranial (i.c.) glioma tumor- bearing mice. Treatment with both DC vaccination and PD-1 mAb blockade resulted in long-term survival, while neither agent alone induced a survival benefit in animals with larger, established tumors. This survival benefit was completely dependent on CD8+ T cells. Additionally, DC vaccine plus PD-1 mAb blockade resulted in the upregulation of integrin homing and immunologic memory markers on tumor-infiltrating lymphocytes (TILs). In clinical samples, DC vaccination in GBM patients was associated with upregulation of PD-1 expression in vivo, while ex vivo blockade of PD-1 on freshly isolated TILs dramatically enhanced autologous tumor cell cytolysis. These findings strongly suggest that the PD-1/PD-L1 pathway plays an important role in the adaptive immune resistance of established GBM in response to antitumor active vaccination and provide us with a rationale for the clinical translation of this combination therapy.

  16. Blockade of maitotoxin-induced oncotic cell death reveals zeiosis

    Directory of Open Access Journals (Sweden)

    Schilling William P

    2002-01-01

    Full Text Available Abstract Background Maitotoxin (MTX initiates cell death by sequentially activating 1 Ca2+ influx via non-selective cation channels, 2 uptake of vital dyes via formation of large pores, and 3 release of lactate dehydrogenase, an indication of cell lysis. MTX also causes formation of membrane blebs, which dramatically dilate during the cytolysis phase. To determine the role of phospholipase C (PLC in the cell death cascade, U73122, a specific inhibitor of PLC, and U73343, an inactive analog, were examined on MTX-induced responses in bovine aortic endothelial cells. Results Addition of either U73122 or U73343, prior to MTX, produced a concentration-dependent inhibition of the cell death cascade (IC50 ≈ 1.9 and 0.66 μM, respectively suggesting that the effect of these agents was independent of PLC. Addition of U73343 shortly after MTX, prevented or attenuated the effects of the toxin, but addition at later times had little or no effect. Time-lapse videomicroscopy showed that U73343 dramatically altered the blebbing profile of MTX-treated cells. Specifically, U73343 blocked bleb dilation and converted the initial blebbing event into "zeiosis", a type of membrane blebbing commonly associated with apoptosis. Cells challenged with MTX and rescued by subsequent addition of U73343, showed enhanced caspase-3 activity 48 hr after the initial insult, consistent with activation of the apoptotic program. Conclusions Within minutes of MTX addition, endothelial cells die by oncosis. Rescue by addition of U73343 shortly after MTX showed that a small percentage of cells are destined to die by oncosis, but that a larger percentage survive; cells that survive the initial insult exhibit zeiosis and may ultimately die by apoptotic mechanisms.

  17. Influência do lítio no bloqueio neuromuscular produzido pelo atracúrio e pelo cisatracúrio: estudo em preparações nervo frênico-diafragma de rato Influencia del litio en el bloqueo neuromuscular producido por el atracurio y por el cisatracurio: estudio en preparo nervio frénico-diafragma del ratón Influence of lithium on the neuromuscular blockade produced by atracurium and cisatracurium: study on rat phrenic nerve-diaphragm preparations

    Directory of Open Access Journals (Sweden)

    Samanta Cristina Antoniassi Fernandes

    2007-06-01

    alteraciones en los potenciales de placa terminal en miniatura mostraron una acción presináptica.BACKGROUND AND OBJECTIVES: Lithium is widely used for the treatment of bipolar disorders and can interact with neuromuscular blockers. There is a controversy about the mechanisms by which it affects neuromuscular transmission and its interaction with neuromuscular blockers. The objective of this study was to evaluate, on the rat diaphragm, the effects of lithium on the muscular response and indirect stimulation, and the possible interaction with neuromuscular blockers. METHODS: Rats weighing between 250 and 300 g were sacrificed under urethane anesthesia. The phrenic nerve-diaphragm preparation was assembled according to the Bulbring technique. The diaphragm was kept under tension, connected to an isometric transducer, and submitted to indirect stimulation with a frequency of 0.1 Hz. The contractions of the diaphragm were registered on a physiograph. The analysis of the amplitude of the muscular responses evaluated: the effects of the isolated drugs: lithium (1.5 mg.mL-1; atracurium (20 µg.mL-1, and cisatracurium (3 µg.mL-1; the lithium-neuromuscular blockers association; and the effects of lithium on the neuromuscular blockade produced by atracurium (35 µg.mL-1 and cisatracurium (5 µg.mL-1. The effects were evaluated before and 45 minutes after the addition of the drugs. The effects of lithium on membrane potentials (MP and miniature end-plate potentials (MEPP were also evaluated. RESULTS: Lithium by itself did not change the amplitude of the muscular responses, but it decreased significantly the neuromuscular blockade produced by atracurium and cisatracurium. It did not change MP and caused an initial increase in MEPP. CONCLUSIONS: Lithium by itself did not compromise neuromuscular transmission and increased the resistance to the effects of atracurium and cisatracurium. It did not show any action on the muscle fiber, and the changes in miniature end-plate potentials

  18. Influência dos Hipnóticos no bloqueio neuromuscular produzido pelo cisatracúrio: emprego da aceleromiografia

    OpenAIRE

    Angélica de Fátima de Assunção Braga; Franklin Sarmento da Silva Braga; Glória Maria Braga Potério; José Aristeu Fachini Frias; Fernanda Maria Silva Pedro; Derli Conceição Munhoz

    2013-01-01

    BACKGROUND AND OBJECTIVE: Different drugs, including hypnotics, may influence the pharmacodynamic effects of neuromuscular blockers (NMB). The aim of this study was to evaluate the influence of propofol and etomidate on cisatracurium-induced neuromuscular blockade. METHOD: We included 60 patients, ASA I and II, undergoing elective surgery under general anesthesia in the study and randomly allocated them into two groups, according to their hypnotic drug: GI (propofol) and GII (etomidate). Pati...

  19. The influence of lidocaine and racemic bupivacaine on neuromuscular blockade produced by rocuronium: a study in rat phrenic nerve-diaphragm preparation Influência da lidocaína e da bupivacaína racêmica no bloqueio neuromuscular produzido pelo rocurônio: estudo em preparação nervo frênico-diafragma de rato

    Directory of Open Access Journals (Sweden)

    Vanessa Henriques Carvalho

    2009-06-01

    Full Text Available PURPOSE: To evaluate in vitro lidocaine and racemic bupivacaine effects in neuromuscular transmission and in neuromuscular blockade produced by rocuronium. METHODS: Rats were distributed in 5 groups (n = 5 in agreement with the studied drugs: lidocaine, racemic bupivacaine, rocuronium, separately (Groups I, II, III; rocuronium in preparations exposed to local anesthetics (Groups IV, V. The concentrations used were: 20 µg/mL, 5 µg/mL and 4 µg/mL, for lidocaine, bupivacaine and rocuronium, respectively. It was evaluated: 1 amplitude of diaphragm muscle response to indirect stimulation, before and 60 minutes after separately addition of lidocaine, racemic bupivacaine and rocuronium and the association of local anesthetics - rocuronium; 2 membrane potentials (MP and miniature end-plate potentials (MEPP. RESULTS: Lidocaine and bupivacaine separately didn't alter the amplitude of muscle response and MP. In preparations previously exposed to lidocaine and racemic bupivacaine, the rocuronium blockade was significantly larger (90.10 ± 9.15% and 100%, respectively, in relation to the produced by rocuronium separately (73.12 ± 9.89%. Lidocaine caused an increase in the frequency of MEPP, being followed by blockade; racemic bupivacaine produced decrease being followed by blockade. CONCLUSIONS: Local anesthetics potentiated the blockade caused by rocuronium. The alterations of MEPP identify presynaptic action.OBJETIVO: Avaliar in vitro os efeitos da lidocaína e bupivacaína racêmica na transmissão neuromuscular e no bloqueio neuromuscular produzido pelo rocurônio. MÉTODOS: Ratos foram distribuídos em 5 grupos (n = 5 de acordo com a droga estudada: lidocaina, bupivacaína racêmica, rocurônio, isoladamente (Grupos I, II, III; rocurõnio em preparações expostas aos anestésicos locais (Grupos IV, V. As concentrações utilizadas foram: 20 µg/mL, 5 µg/mL e 4 µg/mL, para lidocaína, bupivacaína e rocurônio, respectivamente. Avaliou-se: 1

  20. Influência dos Hipnóticos no bloqueio neuromuscular produzido pelo cisatracúrio: emprego da aceleromiografia Influencia de los hipnóticos en el bloqueo neuromuscular producido por el cisatracurio: uso de la aceleromiografía Influence of hypnotics on cisatracurium-induced neuromuscular block: use of acceleromyograhpy

    Directory of Open Access Journals (Sweden)

    Angélica de Fátima de Assunção Braga

    2013-06-01

    ésica, la inducción fue con propofol (2,5 mg.kg-1 o etomidato (0,3 mg.kg-1 precedido de fentanilo (250 µg y seguido de cisatracurio (0,1 mg.kg-1. Los pacientes fueron ventilados con oxígeno al 100% hasta la obtención de la reducción de un 95% o más en la amplitud de la respuesta del aductor del pulgar cuando se hizo la laringoscopia y la intubación traqueal. La función neuromuscular fue monitorizada con aceleromiografía. Se evaluaron el inicio de acción del cisatracurio, las condiciones de intubación traqueal y las repercusiones hemodinámicas. RESULTADOS: Los tiempos promedios y las desviaciones estándar para el inicio de acción del cisatracurio fueron: GI (86,6 ± 14,3" y GII (116,9 ± 11,6", con una diferencia significativa (p BACKGROUND AND OBJECTIVE: Different drugs, including hypnotics, may influence the pharmacodynamic effects of neuromuscular blockers (NMB. The aim of this study was to evaluate the influence of propofol and etomidate on cisatracurium-induced neuromuscular blockade. METHOD: We included 60 patients, ASA I and II, undergoing elective surgery under general anesthesia in the study and randomly allocated them into two groups, according to their hypnotic drug: GI (propofol and GII (etomidate. Patients received intramuscular (IM midazolam (0.1 mg.kg-1 as premedication and we performed induction with propofol (2.5 mg.kg-1 or etomidate (0.3 mg.kg-1, preceded by fentanyl (250 mg and followed by cisatracurium (0.1 mg.kg-1. The patients were ventilated with 100% oxygen until obtaining a reduction of 95% or more in the adductor pollicis response amplitude, with subsequent laryngoscopy and tracheal intubation. Neuromuscular function was monitored by acceleromyograhpy. We evaluated the onset of action of cisatracurium, tracheal intubation conditions, and hemodynamic repercussions. RESULTS: The mean time and standard deviations of cisatracurium onset were: GI (86.6 ± 14.3 s and GII (116.9 ± 11.6 s, with a significant difference (p < 0, 0001

  1. Systemic inflammatory response syndrome increases immobility-induced neuromuscular weakness.

    Science.gov (United States)

    Fink, Heidrun; Helming, Marc; Unterbuchner, Christoph; Lenz, Andrea; Neff, Frauke; Martyn, J A Jeevendra; Blobner, Manfred

    2008-03-01

    Inflammation and immobility are comorbid etiological factors inducing muscle weakness in critically ill patients. This study establishes a rat model to examine the effect of inflammation and immobilization alone and in combination on muscle contraction, histology, and acetylcholine receptor regulation. Prospective, randomized, experimental study. Animal laboratory of a university hospital. Sprague-Dawley rats. To produce systemic inflammation, rats (n = 34) received three consecutive intravenous injections of Corynebacterium parvum on days 0, 4, and 8. Control rats (n = 21) received saline. Both groups were further divided to have one hind limb either immobilized by pinning of knee and ankle joints or sham-immobilized (surgical leg). The contralateral nonsurgical leg of each animal served as control (nonsurgical leg). After 12 days, body weight and muscle mass were significantly reduced in all C. parvum animals compared with saline-injected rats. Immobilization led to local muscle atrophy. Normalized to muscle mass, tetanic contraction was reduced in the surgical leg after immobilization (7.64 +/- 1.91 N/g) and after inflammation (8.71 +/- 2.0 N/g; both p immobilization and saline injection, 11.03 +/- 2.26 N/g). Histology showed an increase in inflammatory cells in all C. parvum-injected animals. Immobilization in combination with C. parvum injection had an additive effect on inflammation. Acetylcholine receptors were increased in immobilized muscles and in all muscles of C. parvum-injected animals. The muscle weakness in critically ill patients can be replicated in our novel rat model. Inflammation and immobilization independently lead to muscle weakness.

  2. 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.

  3. Reversal of profound vecuronium-induced neuromuscular block under sevoflurane anesthesia: sugammadex versus neostigmine.

    Directory of Open Access Journals (Sweden)

    Lemmens Hendrikus JM

    2010-09-01

    Full Text Available Abstract Background Acetylcholinesterase inhibitors cannot rapidly reverse profound neuromuscular block. Sugammadex, a selective relaxant binding agent, reverses the effects of rocuronium and vecuronium by encapsulation. This study assessed the efficacy of sugammadex compared with neostigmine in reversal of profound vecuronium-induced neuromuscular block under sevoflurane anesthesia. Methods Patients aged ≥18 years, American Society of Anesthesiologists class 1-4, scheduled to undergo surgery under general anesthesia were enrolled in this phase III, multicenter, randomized, safety-assessor blinded study. Sevoflurane anesthetized patients received vecuronium 0.1 mg/kg for intubation, with maintenance doses of 0.015 mg/kg as required. Patients were randomized to receive sugammadex 4 mg/kg or neostigmine 70 μg/kg with glycopyrrolate 14 μg/kg at 1-2 post-tetanic counts. The primary efficacy variable was time from start of study drug administration to recovery of the train-of-four ratio to 0.9. Safety assessments included physical examination, laboratory data, vital signs, and adverse events. Results Eighty three patients were included in the intent-to-treat population (sugammadex, n = 47; neostigmine, n = 36. Geometric mean time to recovery of the train-of-four ratio to 0.9 was 15-fold faster with sugammadex (4.5 minutes compared with neostigmine (66.2 minutes; p Conclusions Recovery from profound vecuronium-induced block is significantly faster with sugammadex, compared with neostigmine. Neostigmine did not rapidly reverse profound neuromuscular block (Trial registration number: NCT00473694.

  4. 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.

  5. Increased pain sensitivity but normal function of exercise induced analgesia in hip and knee osteoarthritis - treatment effects of neuromuscular exercise and total joint replacement

    DEFF Research Database (Denmark)

    Kosek, E; Roos, Ewa M.; Ageberg, E

    2013-01-01

    To assess exercise induced analgesia (EIA) and pain sensitivity in hip and knee osteoarthritis (OA) and to study the effects of neuromuscular exercise and surgery on these parameters.......To assess exercise induced analgesia (EIA) and pain sensitivity in hip and knee osteoarthritis (OA) and to study the effects of neuromuscular exercise and surgery on these parameters....

  6. Blockade of Drp1 rescues oxidative stress-induced osteoblast dysfunction

    Energy Technology Data Exchange (ETDEWEB)

    Gan, Xueqi; Huang, Shengbin; Yu, Qing [Department of Pharmacology and Toxicology and Higuchi Bioscience Center, University of Kansas, Lawrence, KS, 66047 (United States); State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041 (China); Yu, Haiyang [State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041 (China); Yan, Shirley ShiDu, E-mail: shidu@ku.edu [Department of Pharmacology and Toxicology and Higuchi Bioscience Center, University of Kansas, Lawrence, KS, 66047 (United States)

    2015-12-25

    Osteoblast dysfunction, induced by oxidative stress, plays a critical role in the pathophysiology of osteoporosis. However, the underlying mechanisms remain unclarified. Imbalance of mitochondrial dynamics has been closely linked to oxidative stress. Here, we reveal an unexplored role of dynamic related protein 1(Drp1), the major regulator in mitochondrial fission, in the oxidative stress-induced osteoblast injury model. We demonstrate that levels of phosphorylation and expression of Drp1 significantly increased under oxidative stress. Blockade of Drp1, through pharmaceutical inhibitor or gene knockdown, significantly protected against H{sub 2}O{sub 2}-induced osteoblast dysfunction, as shown by increased cell viability, improved cellular alkaline phosphatase (ALP) activity and mineralization and restored mitochondrial function. The protective effects of blocking Drp1 in H{sub 2}O{sub 2}-induced osteoblast dysfunction were evidenced by increased mitochondrial function and suppressed production of reactive oxygen species (ROS). These findings provide new insights into the role of the Drp1-dependent mitochondrial pathway in the pathology of osteoporosis, indicating that the Drp1 pathway may be targetable for the development of new therapeutic approaches in the prevention and the treatment of osteoporosis. - Highlights: • Oxidative stress is an early pathological event in osteoporosis. • Imbalance of mitochondrial dynamics are linked to oxidative stress in osteoporosis. • The role of the Drp1-dependent mitochondrial pathway in osteoporosis.

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

    Directory of Open Access Journals (Sweden)

    Vivian V. Costa

    2017-04-01

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

  8. Differentiating the cellular and humoral components of neuromuscular blocking agent-induced anaphylactic reactions in patients undergoing anaesthesia

    NARCIS (Netherlands)

    Aalberse, R. C.; Kleine Budde, I.; Mulder, M.; Stapel, S. O.; Paulij, W.; Leynadier, F.; Hollmann, M. W.

    2011-01-01

    Background. The significance of IgE antibodies to neuromuscular blocking agent (NMBA)-induced anaphylactic reactions during anaesthesia is unclear. We investigated the relevance of IgE to rocuronium using an in vitro technique. Methods. Serum samples from 61 patients with anaphylactic reactions

  9. 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.

  10. Blockade of advanced glycation end product formation attenuates bleomycin-induced pulmonary fibrosis in rats

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    Liu Dai-Shun

    2009-06-01

    Full Text Available Abstract Background Advanced glycation end products (AGEs have been proposed to be involved in pulmonary fibrosis, but its role in this process has not been fully understood. To investigate the role of AGE formation in pulmonary fibrosis, we used a bleomycin (BLM-stimulated rat model treated with aminoguanidine (AG, a crosslink inhibitor of AGE formation. Methods Rats were intratracheally instilled with BLM (5 mg/kg and orally administered with AG (40, 80, 120 mg/kg once daily for two weeks. AGEs level in lung tissue was determined by ELISA and pulmonary fibrosis was evaluated by Ashcroft score and hydroxyproline assay. The expression of heat shock protein 47 (HSP47, a collagen specific molecular chaperone, was measured with RT-PCR and Western blot. Moreover, TGFβ1 and its downstream Smad proteins were analyzed by Western blot. Results AGEs level in rat lungs, as well as lung hydroxyproline content and Ashcroft score, was significantly enhanced by BLM stimulation, which was abrogated by AG treatment. BLM significantly increased the expression of HSP47 mRNA and protein in lung tissues, and AG treatment markedly decreased BLM-induced HSP47 expression in a dose-dependent manner (p Conclusion These findings suggest AGE formation may participate in the process of BLM-induced pulmonary fibrosis, and blockade of AGE formation by AG treatment attenuates BLM-induced pulmonary fibrosis in rats, which is implicated in inhibition of HSP47 expression and TGFβ/Smads signaling.

  11. Ca2+ channel blockade prevents lysergic acid diethylamide-induced changes in dopamine and serotonin metabolism.

    Science.gov (United States)

    Antkiewicz-Michaluk, L; Románska, I; Vetulani, J

    1997-07-30

    To investigate the effect of a single and multiple administration of lysergic acid diethylamide (LSD) on cerebral metabolism of dopamine and serotonin, male Wistar rats were treated with low and high doses (0.1 and 2.0 mg/kg i.p.) of LSD and the levels of dopamine, 3,4-dihydroxyphenylacetic acid, homovanillic acid, 3-methoxytyramine, serotonin and 5-hydroxyindoleacetic acid were assayed by HPLC in the nucleus accumbens, striatum and frontal cortex. Some rats received nifedipine, 5 mg/kg i.p., before each injection of LSD to assess the effect of a Ca2+ channel blockade. High-dose LSD treatment (8 x 2 mg/kg per day) caused a strong stimulation of dopamine metabolism in the nucleus accumbens and striatum, and serotonin metabolism in the nucleus accumbens: the changes were observed 24 (but not 1 h) after the last dose. The changes induced by the low-dose treatment (8 x 0.1 mg/kg per day) had a different pattern, suggesting the release of dopamine from vesicles to cytoplasm. Co-administration of nifedipine completely prevented the LSD-induced biochemical changes. The results suggest that Ca2+ channel blocking agents may prevent development of some behavioral consequences of chronically used LSD.

  12. Cesium blockade of delayed outward currents and electrically induced pacemaker activity in mammalian ventricular myocardium.

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    Meier, C F; Katzung, B G

    1981-05-01

    The effects of Cs+, 5-25 mM, were studied in cat and guinea pig papillary muscles using voltage clamp and current clamp techniques. In solutions containing normal K+, the major effects of Cs+ were depolarization of the resting potential and reduction of the delayed outward current (ixl) between -80 and -20 mV. Both inward and outward portions of the isochronal current voltage relation (l-s clamps) were reduced by extracellular Cs+. This resulted in a substantial reduction of inward rectification and, by subtraction from the normal I-V relationship, the definition of a Cs+-sensitive component of current. Under current clamp conditions, 5-10 mM Cs+ produced a dose-dependent slowing of repetitive firing induced by depolarization. At higher concentrations (25 mM) the resting potential was depolarized and repetitive activity could not be induced by further depolarization. However, release of hyperpolarizing pulses was followed by prolonged bursts of repetitive action potentials, suggesting partial reversal of blockade or participation of another pacemaker process. The experimental results and a numerical simulation show that under readily attainable conditions, reduction in an outward pacemaker current may slow pacemaker activity.

  13. TNF-α blockade induces IL-10 expression in human CD4+ T cells

    Science.gov (United States)

    Evans, Hayley G.; Roostalu, Urmas; Walter, Gina J.; Gullick, Nicola J.; Frederiksen, Klaus S.; Roberts, Ceri A.; Sumner, Jonathan; Baeten, Dominique L.; Gerwien, Jens G.; Cope, Andrew P.; Geissmann, Frederic; Kirkham, Bruce W.; Taams, Leonie S.

    2014-02-01

    IL-17+ CD4+ T (Th17) cells contribute to the pathogenesis of several human inflammatory diseases. Here we demonstrate that TNF inhibitor (TNFi) drugs induce the anti-inflammatory cytokine IL-10 in CD4+ T cells including IL-17+ CD4+ T cells. TNFi-mediated induction of IL-10 in IL-17+ CD4+ T cells is Treg-/Foxp3-independent, requires IL-10 and is overcome by IL-1β. TNFi-exposed IL-17+ CD4+ T cells are molecularly and functionally distinct, with a unique gene signature characterized by expression of IL10 and IKZF3 (encoding Aiolos). We show that Aiolos binds conserved regions in the IL10 locus in IL-17+ CD4+ T cells. Furthermore, IKZF3 and IL10 expression levels correlate in primary CD4+ T cells and Aiolos overexpression is sufficient to drive IL10 in these cells. Our data demonstrate that TNF-α blockade induces IL-10 in CD4+ T cells including Th17 cells and suggest a role for the transcription factor Aiolos in the regulation of IL-10 in CD4+ T cells.

  14. Influência de anestésicos locais sobre o bloqueio neuromuscular produzido pelo rocurônio: ação da lidocaína e da mistura enantiomérica em excesso de 50% de bupivacaína na junção neuromuscular Influencia de anestésicos locales sobre el bloqueo neuromuscular producido por el rocuronio: acción de la lidocaína y de la mezcla enantiomérica en exceso de 50% de bupivacaína en la junción neuromuscular Influence of local anesthetics on the neuromuscular blockade produced by rocuronium: effects of lidocaine and 50% enantiomeric excess bupivacaine on the neuromuscular junction

    Directory of Open Access Journals (Sweden)

    Angélica de Fátima de Assunção Braga

    2009-12-01

    acción presináptica y postsináptica.BACKGROUND AND OBJECTIVES: The effects of local anesthetics (LA on neuromuscular transmission and their influence on the neuromuscular blockade produced by competitive neuromuscular blockers have not been fully investigated. The objective of this study was to evaluate, in vitro, the effects of lidocaine and 50% enantiomeric excess bupivacaine (S75-R25 on the neuromuscular blockade produced by rocuronium. METHODS: The rats were divided in five groups (n = 5 according to the drug used: isolated lidocaine, bupivacaine (S75-R25, or rocuronium (groups I, II, and II; and rocuronium in preparations previously exposed to LAs (groups IV and V. The concentrations used were as follows: 20 µg.mL-1, 5 µg.mL-1, and 4 µg.mL-1 of lidocaine, bupivacaine (S75-R25, and rocuronium, respectively. The following parameters were evaluated: 1 the strength of muscular contraction of the diaphragm to indirect electrical stimulations, before and 60 minutes after the isolated addition of the LAs and rocuronium, and the association AL-rocuronium; and 2 the effects of LAs on membrane potential (MP and miniature end-plate potentials (MEPP. The effect of LAs on muscle contraction in response to acetylcholine was evaluated in chick biventer cervicis preparations. RESULTS: Isolated lidocaine and bupivacaine (S75-R25 did not change the muscular response and the levels of MPs. In preparations exposed to LAs, rocuroniuminduced blockade was significantly greater than that produced by rocuronium alone. In chick biventer cervicis preparations, lidocaine and bupivacaine (S75R25 decreased contraction in response to acetylcholine. Lidocaine increased the frequency of MEPPs, which was followed by the blockade; bupivacaine (S75R25 caused a reduction in MEPPs followed by blockade. CONCLUSIONS: Local anesthetics caused a potentiation of the neuromuscular blockade produced by rocuronium. The results showed pre- and post-synaptic effects.

  15. Quantum interference induced photon blockade in a coupled single quantum dot-cavity system.

    Science.gov (United States)

    Tang, Jing; Geng, Weidong; Xu, Xiulai

    2015-03-18

    We propose an experimental scheme to implement a strong photon blockade with a single quantum dot coupled to a nanocavity. The photon blockade effect can be tremendously enhanced by driving the cavity and the quantum dot simultaneously with two classical laser fields. This enhancement of photon blockade is ascribed to the quantum interference effect to avoid two-photon excitation of the cavity field. Comparing with Jaynes-Cummings model, the second-order correlation function at zero time delay g((2))(0) in our scheme can be reduced by two orders of magnitude and the system sustains a large intracavity photon number. A red (blue) cavity-light detuning asymmetry for photon quantum statistics with bunching or antibunching characteristics is also observed. The photon blockade effect has a controllable flexibility by tuning the relative phase between the two pumping laser fields and the Rabi coupling strength between the quantum dot and the pumping field. Moreover, the photon blockade scheme based on quantum interference mechanism does not require a strong coupling strength between the cavity and the quantum dot, even with the pure dephasing of the system. This simple proposal provides an effective way for potential applications in solid state quantum computation and quantum information processing.

  16. Molecular Mechanisms of Treadmill Therapy on Neuromuscular Atrophy Induced via Botulinum Toxin A

    Science.gov (United States)

    Tsai, Sen-Wei; Chen, Hsiao-Ling

    2013-01-01

    Botulinum toxin A (BoNT-A) is a bacterial zinc-dependent endopeptidase that acts specifically on neuromuscular junctions. BoNT-A blocks the release of acetylcholine, thereby decreasing the ability of a spastic muscle to generate forceful contraction, which results in a temporal local weakness and the atrophy of targeted muscles. BoNT-A-induced temporal muscle weakness has been used to manage skeletal muscle spasticity, such as poststroke spasticity, cerebral palsy, and cervical dystonia. However, the combined effect of treadmill exercise and BoNT-A treatment is not well understood. We previously demonstrated that for rats, following BoNT-A injection in the gastrocnemius muscle, treadmill running improved the recovery of the sciatic functional index (SFI), muscle contraction strength, and compound muscle action potential (CMAP) amplitude and area. Treadmill training had no influence on gastrocnemius mass that received BoNT-A injection, but it improved the maximal contraction force of the gastrocnemius, and upregulation of GAP-43, IGF-1, Myo-D, Myf-5, myogenin, and acetylcholine receptor (AChR) subunits α and β was found following treadmill training. Taken together, these results suggest that the upregulation of genes associated with neurite and AChR regeneration following treadmill training may contribute to enhanced gastrocnemius strength recovery following BoNT-A injection. PMID:24327926

  17. Molecular Mechanisms of Treadmill Therapy on Neuromuscular Atrophy Induced via Botulinum Toxin A

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    Sen-Wei Tsai

    2013-01-01

    Full Text Available Botulinum toxin A (BoNT-A is a bacterial zinc-dependent endopeptidase that acts specifically on neuromuscular junctions. BoNT-A blocks the release of acetylcholine, thereby decreasing the ability of a spastic muscle to generate forceful contraction, which results in a temporal local weakness and the atrophy of targeted muscles. BoNT-A-induced temporal muscle weakness has been used to manage skeletal muscle spasticity, such as poststroke spasticity, cerebral palsy, and cervical dystonia. However, the combined effect of treadmill exercise and BoNT-A treatment is not well understood. We previously demonstrated that for rats, following BoNT-A injection in the gastrocnemius muscle, treadmill running improved the recovery of the sciatic functional index (SFI, muscle contraction strength, and compound muscle action potential (CMAP amplitude and area. Treadmill training had no influence on gastrocnemius mass that received BoNT-A injection, but it improved the maximal contraction force of the gastrocnemius, and upregulation of GAP-43, IGF-1, Myo-D, Myf-5, myogenin, and acetylcholine receptor (AChR subunits α and β was found following treadmill training. Taken together, these results suggest that the upregulation of genes associated with neurite and AChR regeneration following treadmill training may contribute to enhanced gastrocnemius strength recovery following BoNT-A injection.

  18. Blockade of RAGE ameliorates elastase-induced emphysema development and progressionviaRAGE-DAMP signaling.

    Science.gov (United States)

    Lee, Hanbyeol; Park, Jeong-Ran; Kim, Woo Jin; Sundar, Isaac K; Rahman, Irfan; Park, Sung-Min; Yang, Se-Ran

    2017-05-01

    The receptor for advanced glycan end products (RAGE) has been identified as a susceptibility gene for chronic obstructive pulmonary disease (COPD) in genome-wide association studies (GWASs). However, less is known about how RAGE is involved in the pathogenesis of COPD. To determine the molecular mechanism by which RAGE influences COPD in experimental COPD models, we investigated the efficacy of the RAGE-specific antagonist FPS-ZM1 administration in in vivo and in vitro COPD models. We injected elastase intratracheally and the RAGE antagonist FPS-ZM1 in mice, and the infiltrated inflammatory cells and cytokines were assessed by ELISA. Cellular expression of RAGE was determined in protein, serum, and bronchoalveolar lavage fluid of mice and lungs and serum of human donors and patients with COPD. Downstream damage-associated molecular pattern (DAMP) pathway activation in vivo and in vitro and in patients with COPD was assessed by immunofluorescence staining, Western blot analysis, and ELISA. The expression of membrane RAGE in initiating the inflammatory response and of soluble RAGE acting as a decoy were associated with up-regulation of the DAMP-related signaling pathway via Nrf2. FPS-ZM1 administration significantly reversed emphysema in the lung of mice. Moreover, FPS-ZM1 treatment significantly reduced lung inflammation in Nrf2 +/+ , but not in Nrf2 -/- mice. Thus, our data indicate for the first time that RAGE inhibition has an essential protective role in COPD. Our observation of RAGE inhibition provided novel insight into its potential as a therapeutic target in emphysema/COPD.-Lee, H., Park, J.-R., Kim, W. J., Sundar, I. K., Rahman, I., Park, S.-M., Yang. S.-R. Blockade of RAGE ameliorates elastase-induced emphysema development and progression via RAGE-DAMP signaling. © FASEB.

  19. Antagonism of d-tubocurarine-induced neuromuscular blockade with a mixture of 4-aminopyridine and neostigmine in man.

    Science.gov (United States)

    Wirtavuori, K; Salmenperä, M; Tammisto, T

    1984-11-01

    The antagonistic properties of a mixture of 4-aminopyridine (4-AP) 3 mg X ml-1 and neostigmine 0.2 mg X ml-1 (in three patient groups) administered at 90 per cent d-tubocurarine block were compared with those of plain neostigmine (in three patient groups) in thirty-six patients during thiopentone-fentanyl-nitrous oxide-oxygen anaesthesia. The recovery variables included thumb twitch height, thenar e.m.g. peak-to-peak amplitude, and train-of-four ratio in response to supramaximal ulnar nerve stimulation. In addition, mean arterial pressure, heart rate, apnoea time and time to responsiveness to verbal command after nitrous oxide was turned off at 20 minutes of recovery were examined as circulatory and central nervous system responses to antagonism. The addition of 4-AP 30 mg to neostigmine 2 mg enhanced the recovery of train-of-four ratio from 54.2 +/- 5.2 to 80.2 +/- 5.2 per cent at 20 mins of antagonism (mean +/- SEM; p less than 0.01) while adding 4-AP 45 mg to neostigmine 3 mg increased the train-of-four ratio from 67.7 +/- 2.3 to 92.3 +/- 2.4 per cent (p less than 0.01) when compared with plain neostigmine. No statistically significant difference could be found between the groups in the recovery of twitch height or e.m.g. amplitude. The antagonism of d-tubocurarine block with 4-AP 30 mg plus neostigmine 2 mg was at least as effective as with neostigmine 3-4 mg. Mean arterial pressure increased in the group receiving 45 mg 4-AP plus 3 mg neostigmine.(ABSTRACT TRUNCATED AT 250 WORDS)

  20. [Functional respiratory imaging after neostigmine- or sugammadex-enhanced recovery from neuromuscular blockade in the anesthetised rat: a randomised controlled pilot study].

    Science.gov (United States)

    Schepens, Tom; Cammu, Guy; Maes, Sabine; Desmedt, Benny; Vos, Wim; Deseure, Kristof

    Reductions in diaphragm activity are associated with the postoperative development of atelectasis. Neostigmine reversal is also associated with increased atelectasis. We assessed the effects of neostigmine, sugammadex, and spontaneous reversal on regional lung ventilation and airway flow. Six Sprague-Dawley rats were paralysed with rocuronium and mechanically ventilated until recovery of the train-of-four ratio to 0.5. We administered neostigmine (0.06mg.kg -1 ), sugammadex (15mg.kg -1 ), or saline (n=2 per group). Computed tomography scans were obtained during the breathing cycle. Three-dimensional models of lung lobes were generated using functional respiratory imaging technology, and lobar volumes were calculated during the breathing cycle. The diaphragmatic surface was segmented for the end-expiratory and end-inspiratory scans. The total change in volume was reported by the lung volume change from the end-expiratory scan to the end-inspiratory scan. Chest wall movement was defined as the lung volume change minus the volume change that resulted from diaphragm excursion. The two rats that received neostigmine exhibited a smaller relative contribution of diaphragm movement to the total change in lung volume compared with the two rats that received sugammadex or saline (chest wall contribution (%): 26.69 and 25.55 for neostigmine; -2.77 and 15.98 for sugammadex; 18.82 and 10.30 for saline). This pilot study in rats demonstrated an increased relative contribution of chest wall expansion after neostigmine compared with sugammadex or saline. This smaller relative contribution of diaphragm movement may be explained by a neostigmine-induced decrease in phrenic nerve activity or by remaining occupied acetylcholine receptors after neostigmine. Copyright © 2016 Sociedade Brasileira de Anestesiologia. Publicado por Elsevier Editora Ltda. All rights reserved.

  1. Acute and delayed peripheral and central neuromuscular alterations induced by a short and intense downhill trail run.

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    Giandolini, M; Horvais, N; Rossi, J; Millet, G Y; Morin, J-B; Samozino, P

    2016-11-01

    Downhill sections are highly strenuous likely contributing to the development of neuromuscular fatigue in trail running. Our purpose was to investigate the consequences of an intense downhill trail run (DTR) on peripheral and central neuromuscular fatigue at knee extensors (KE) and plantar flexors (PF). Twenty-three runners performed a 6.5-km DTR (1264-m altitude drop) as fast as possible. The electromyographic activity of vastus lateralis (VL) and gastrocnemius lateralis (GL) was continuously recorded. Neuromuscular functions were assessed Pre-, Post-, and 2-day Post-DTR (Post2d). Maximal voluntary torques decreased Post (∼ -19% for KE, ∼ -25% for PF) and Post2d (∼ -9% for KE, ∼ -10% for PF). Both central and peripheral dysfunctions were observed. Decreased KE and PF voluntary activation (VA), evoked forces, VL M-wave amplitude, and KE low-frequency fatigue were observed at Post. Changes in VL M-wave amplitude were negatively correlated to VL activity during DTR. Changes in PF twitch force and VA were negatively correlated to GL activity during DTR. The acute KE VA deficit was about a third of that reported after ultramarathons, although peripheral alterations were similar. The prolonged force loss seems to be mainly associated to VA deficit likely induced by the delayed inflammatory response to DTR-induced ultrastructural muscle damage. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

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

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    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.

  3. 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

  4. 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.

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

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    Hu Huang

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

  6. Hyperfine-induced hysteretic funnel structure in spin blockaded tunneling current of coupled vertical quantum dots at low magnetic field

    Energy Technology Data Exchange (ETDEWEB)

    Leary, A.; Wicha, A.; Harack, B.; Coish, W. A.; Hilke, M. [Department of Physics, McGill University, Ernest Rutherford Building, 3600 rue University, Montreal, Quebec H3A 2T8 (Canada); Yu, G.; Gupta, J. A. [National Research Council of Canada, M50, Montreal Road, Ottawa, Ontario K1A 0R6 (Canada); Payette, C.; Austing, D. G. [Department of Physics, McGill University, Ernest Rutherford Building, 3600 rue University, Montreal, Quebec H3A 2T8, Canada and National Research Council of Canada, M50, Montreal Road, Ottawa, Ontario K1A 0R6 (Canada)

    2013-12-04

    We outline the properties of the hyperfine-induced funnel structure observed in the two-electron spin blockade region of a weakly coupled vertical double quantum dot device. Hysteretic steps in the leakage current occur due to dynamic nuclear polarization when either the bias voltage or the magnetic field is swept up and down. When the bias voltage is swept, an intriguing ∼3 mT wide cusp near 0 T appears in the down-sweep position, and when the magnetic field is swept, the current at 0 T can be switched from 'low' to 'high' as the bias is increased.

  7. Estimulação elétrica neuromuscular em cães com atrofia muscular induzida Neuromuscular electric stimulation in dogs with induced muscle atrophy

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    C. Pelizzari

    2008-02-01

    Full Text Available Empregou-se a estimulação elétrica neuromuscular (EENM de baixa freqüência no músculo quadríceps femoral de cães com atrofia induzida e avaliou-se a ocorrência de ganho de massa nessa musculatura. Foram utilizados oito cães com pesos entre 15 e 30kg, distribuídos aleatoriamente em dois grupos denominados de I ou controle e II ou tratado. A articulação femorotibiopatelar esquerda foi imobilizada por 30 dias pelo método de transfixação percutânea tipo II, com retirada de aparelho de imobilização após esse período. Decorridas 48 horas da remoção, foi realizada a EENM nos cães do grupo II, cinco vezes por semana, com intervalo de 24 horas cada sessão, pelo período de 60 dias. Foram avaliadas a circunferência da coxa, a goniometria do joelho, a análise clínica da marcha, as enzimas creatina-quinase (CK e aspartato-amino-transferase (AST e a morfometria das fibras musculares em cortes transversais do músculo vasto lateral colhido mediante biópsia muscular. A EENM foi empregada no músculo quadríceps femoral na freqüência de 50Hz, duração de pulso de 300 milisegundos e relação de tempo on/off de 1:2. Quanto à morfometria das fibras do músculo vasto lateral, no grupo tratado houve aumento significativo (PLow frequency neuromuscular electrical stimulation (NMES was used on the femoral quadriceps of dogs with induced muscular atrophy and the occurrence of gain in mass in these muscles was evaluated. Eight dogs from 15 to 30kg were randomly distributed in two groups named I, or control; and II, or treated. For the induction of muscular atrophy, the left femoral-tibial-patellar joint was immobilized for 30 days by percutaneous transfixation type II. After 30 days, the immobilization device was removed. The NMES treatment began 48 hours after the removal of the immobilization device of the dogs of group II, and it was carried out five times per week with an interval of 24 hours between each session, for 60 days. The

  8. Pralidoxime inhibits paraoxon-induced depression of rocuronium-neuromuscular block in a time-dependent fashion.

    Science.gov (United States)

    Narimatsu, Eichi; Niiya, Tomohisa; Takahashi, Kazunobu; Yamauchi, Masanori; Yamakage, Michiaki

    2012-07-01

    The composite effects of organophosphorus (OP)-cholinesterase (ChE) inhibitors and oximes on the actions of nondepolarizing neuromuscular blockers in acute OP-ChE inhibitor intoxication have not been evaluated in detail. We investigated the effects of paraoxon (Pox) (an OP-ChE inhibitor) and pralidoxime (PAM) (an oxime) on the nondepolarizing neuromuscular blocking action of rocuronium. Isometric twitch tensions of rat left phrenic nerve-hemidiaphragm preparations elicited by indirect (phrenic nerve) supramaximal stimulation at 0.1 Hz were evaluated. Analysis of variance with post hoc testing was used for statistical comparison, and P fashion. Paraoxon caused a rightward shift in the rocuronium concentration-twitch tension curve (IC(50), 15.48 [15.24-15.72] μM). The rightward shift was completely inhibited by previous copretreatment (IC(50), 9.98 [9.77-10.20] μM) and partially inhibited by simultaneous copretreatment (IC(50), 11.68 [11.45-11.91] μM) with PAM but was not inhibited by subsequent copretreatment (IC(50), 13.69 [13.39-13.99] μM) with PAM (P influence the rightward shift (P < .01, n = 6). Paraoxon depressed rocuronium-induced neuromuscular block by inhibiting ChEs, and the action of Pox was inhibited by PAM. Pralidoxime acts more intensely when applied earlier. The time-dependent effect of PAM indicates that the preceding presence of PAM in proximity to ChEs before Pox is necessary for definite suppression of the Pox-induced ChE inhibition. Copyright © 2012 Elsevier Inc. All rights reserved.

  9. Blockade of GM-CSF pathway induced sustained suppression of myeloid and T cell activities in rheumatoid arthritis.

    Science.gov (United States)

    Guo, Xiang; Higgs, Brandon W; Bay-Jensen, Anne-Christine; Wu, Yuling; Karsdal, Morten A; Kuziora, Michael; Godwood, Alex; Close, David; Ryan, Patricia C; Roskos, Lorin K; White, Wendy I

    2018-01-01

    Targeting the granulocyte-macrophage colony-stimulating factor (GM-CSF) pathway holds great potential in the treatment of inflammatory diseases. Mavrilimumab, a human monoclonal GM-CSF receptor-α antibody, has demonstrated clinical efficacy in RA. Our current study aimed to elucidate mechanisms of action and identify peripheral biomarkers associated with therapeutic responses of GM-CSF antagonism in RA. A 24-week placebo (PBO)-controlled trial was conducted in 305 RA patients who received mavrilimumab (30, 100 or 150 mg) or PBO once every 2 weeks. Serum biomarkers and whole blood gene expression profiles were measured by protein immunoassay and whole genome microarray. Mavrilimumab treatment induced significant down-regulation of type IV collagen formation marker (P4NP 7S), macrophage-derived chemokine (CCL22), IL-2 receptor α and IL-6 compared with PBO. Both early and sustained reduction of P4NP 7S was associated with clinical response to 150 mg mavrilimumab treatment. Gene expression analyses demonstrated reduced expression of transcripts enriched in macrophage and IL-22/IL-17 signalling pathways after GM-CSF blockade therapy. Myeloid and T cell-associated transcripts were suppressed in mavrilimumab-treated ACR20 responders but not non-responders. While CCL22 and IL-6 down-regulation may reflect a direct effect of GM-CSFR blockade on the production of pro-inflammatory mediators by myeloid cells, the suppression of IL-2 receptor α and IL-17/IL-22 associated transcripts suggests an indirect suppressive effect of mavrilimumab on T cell activation. Our results demonstrated association of peripheral biomarker changes with therapeutic response to mavrilimumab in RA patients. The sustained efficacy of mavrilimumab in RA may result from both direct effects on myeloid cells and indirect effects on T cell activation after GM-CSFR blockade.

  10. Glomerular and tubular function during AT1 receptor blockade in pigs with neonatal induced partial ureteropelvic obstruction

    DEFF Research Database (Denmark)

    Eskild-Jensen, Anni; Thomsen, Karsten; Rungø, Christine

    2007-01-01

    and in the present study we examined the effects of chronic AT1 receptor blockade using CV-11974 (0.12 mg/h candesartan from age 23 to 30 days) on kidney function development after PUUO was induced in 2-day-old piglets. Moreover, the effect of superimposed acute NO inhibition using N(G)-nitro-l-arginine methyl ester...... (l-NAME; 15 mg/kg) was examined to identify if this has diagnostic potential. PUUO significantly increased GFR in the nonobstructed contralateral kidney independent of candesartan. In candesartan-treated piglets, the l-NAME-induced GFR reduction seen in normal and nonobstructed kidneys was absent...... by PUUO evidenced by an increased fractional excretion of sodium which was enhanced by candesartan treatment. In conclusion, our findings suggest that the counterbalance between AT1 receptor-mediated vasoconstriction and NO-mediated vasodilatation which maintain GFR in normal young porcine kidneys...

  11. Autophagy Impairment in Muscle Induces Neuromuscular Junction Degeneration and Precocious Aging

    Directory of Open Access Journals (Sweden)

    Silvia Carnio

    2014-09-01

    Full Text Available The cellular basis of age-related tissue deterioration remains largely obscure. The ability to activate compensatory mechanisms in response to environmental stress is an important factor for survival and maintenance of cellular functions. Autophagy is activated both under short and prolonged stress and is required to clear the cell of dysfunctional organelles and altered proteins. We report that specific autophagy inhibition in muscle has a major impact on neuromuscular synaptic function and, consequently, on muscle strength, ultimately affecting the lifespan of animals. Inhibition of autophagy also exacerbates aging phenotypes in muscle, such as mitochondrial dysfunction, oxidative stress, and profound weakness. Mitochondrial dysfunction and oxidative stress directly affect acto-myosin interaction and force generation but show a limited effect on stability of neuromuscular synapses. These results demonstrate that age-related deterioration of synaptic structure and function is exacerbated by defective autophagy.

  12. The Triterpenoid Betulin Protects against the Neuromuscular Effects of Bothrops jararacussu Snake Venom In Vivo

    Directory of Open Access Journals (Sweden)

    Miriéle Cristina Ferraz

    2015-01-01

    Full Text Available We confirmed the ability of the triterpenoid betulin to protect against neurotoxicity caused by Bothrops jararacussu snake venom in vitro in mouse isolated phrenic nerve-diaphragm (PND preparations and examined its capability of in vivo protection using the rat external popliteal/sciatic nerve-tibialis anterior (EPSTA preparation. Venom caused complete, irreversible blockade in PND (40 μg/mL, but only partial blockade (~30% in EPSTA (3.6 mg/kg, i.m. after 120 min. In PND, preincubation of venom with commercial bothropic antivenom (CBA attenuated the venom-induced blockade, and, in EPSTA, CBA given i.v. 15 min after venom also attenuated the blockade (by ~70% in both preparations. Preincubation of venom with betulin (200 μg/mL markedly attenuated the venom-induced blockade in PND; similarly, a single dose of betulin (20 mg, i.p., 15 min after venom virtually abolished the venom-induced decrease in contractility. Plasma creatine kinase activity was significantly elevated 120 min after venom injection in the EPSTA but was attenuated by CBA and betulin. These results indicate that betulin given i.p. has a similar efficacy as CBA given i.v. in attenuating the neuromuscular effects of B. jararacussu venom in vivo and could be a useful complementary measure to antivenom therapy for treating snakebite.

  13. The Triterpenoid Betulin Protects against the Neuromuscular Effects of Bothrops jararacussu Snake Venom In Vivo

    Science.gov (United States)

    Ferraz, Miriéle Cristina; de Oliveira, Jhones Luiz; de Oliveira Junior, Joel Reis; Cogo, José Carlos; dos Santos, Márcio Galdino; Franco, Luiz Madaleno; Puebla, Pilar; Ferraz, Helena Onishi; Ferraz, Humberto Gomes; da Rocha, Marisa Maria Teixeira; Hyslop, Stephen

    2015-01-01

    We confirmed the ability of the triterpenoid betulin to protect against neurotoxicity caused by Bothrops jararacussu snake venom in vitro in mouse isolated phrenic nerve-diaphragm (PND) preparations and examined its capability of in vivo protection using the rat external popliteal/sciatic nerve-tibialis anterior (EPSTA) preparation. Venom caused complete, irreversible blockade in PND (40 μg/mL), but only partial blockade (~30%) in EPSTA (3.6 mg/kg, i.m.) after 120 min. In PND, preincubation of venom with commercial bothropic antivenom (CBA) attenuated the venom-induced blockade, and, in EPSTA, CBA given i.v. 15 min after venom also attenuated the blockade (by ~70% in both preparations). Preincubation of venom with betulin (200 μg/mL) markedly attenuated the venom-induced blockade in PND; similarly, a single dose of betulin (20 mg, i.p., 15 min after venom) virtually abolished the venom-induced decrease in contractility. Plasma creatine kinase activity was significantly elevated 120 min after venom injection in the EPSTA but was attenuated by CBA and betulin. These results indicate that betulin given i.p. has a similar efficacy as CBA given i.v. in attenuating the neuromuscular effects of B. jararacussu venom in vivo and could be a useful complementary measure to antivenom therapy for treating snakebite. PMID:26633987

  14. Transgenic mouse model reveals an unsuspected role of the acetylcholine receptor in statin-induced neuromuscular adverse drug reactions.

    Science.gov (United States)

    Grajales-Reyes, G E; Báez-Pagán, C A; Zhu, H; Grajales-Reyes, J G; Delgado-Vélez, M; García-Beltrán, W F; Luciano, C A; Quesada, O; Ramírez, R; Gómez, C M; Lasalde-Dominicci, J A

    2013-08-01

    High cholesterol levels are an established risk factor for cardiovascular disease (CVD), the world's leading cause of death. Inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A reductase (statins) are prescribed to lower serum cholesterol levels and reduce the risk of CVD. Despite the success of statins, many patients abandon treatment owing to neuromuscular adverse drug reactions (ADRs). Genome-wide association studies have identified the single-nucleotide polymorphism (SNP) rs4149056 in the SLCO1B1 gene as being associated with an increased risk for statin-induced ADRs. By studying slow-channel syndrome transgenic mouse models, we determined that statins trigger ADRs in mice expressing the mutant allele of the rs137852808 SNP in the nicotinic acetylcholine receptor (nAChR) α-subunit gene CHRNA1. Mice expressing this allele show a remarkable contamination of end-plates with caveolin-1 and develop early signs of neuromuscular degeneration upon statin treatment. This study demonstrates that genes coding for nAChR subunits may contain variants associated with statin-induced ADRs.

  15. Activity-Induced Synaptic Structural Modifications by an Activator of Integrin Signaling at the Drosophila Neuromuscular Junction.

    Science.gov (United States)

    Lee, Joo Yeun; Geng, Junhua; Lee, Juhyun; Wang, Andrew R; Chang, Karen T

    2017-03-22

    Activity-induced synaptic structural modification is crucial for neural development and synaptic plasticity, but the molecular players involved in this process are not well defined. Here, we report that a protein named Shriveled (Shv) regulates synaptic growth and activity-dependent synaptic remodeling at the Drosophila neuromuscular junction. Depletion of Shv causes synaptic overgrowth and an accumulation of immature boutons. We find that Shv physically and genetically interacts with βPS integrin. Furthermore, Shv is secreted during intense, but not mild, neuronal activity to acutely activate integrin signaling, induce synaptic bouton enlargement, and increase postsynaptic glutamate receptor abundance. Consequently, loss of Shv prevents activity-induced synapse maturation and abolishes post-tetanic potentiation, a form of synaptic plasticity. Our data identify Shv as a novel trans-synaptic signal secreted upon intense neuronal activity to promote synapse remodeling through integrin receptor signaling.SIGNIFICANCE STATEMENT The ability of neurons to rapidly modify synaptic structure in response to neuronal activity, a process called activity-induced structural remodeling, is crucial for neuronal development and complex brain functions. The molecular players that are important for this fundamental biological process are not well understood. Here we show that the Shriveled (Shv) protein is required during development to maintain normal synaptic growth. We further demonstrate that Shv is selectively released during intense neuronal activity, but not mild neuronal activity, to acutely activate integrin signaling and trigger structural modifications at the Drosophila neuromuscular junction. This work identifies Shv as a key modulator of activity-induced structural remodeling and suggests that neurons use distinct molecular cues to differentially modulate synaptic growth and remodeling to meet synaptic demand. Copyright © 2017 the authors 0270-6474/17/373246-18$15.00/0.

  16. Activity-Induced Synaptic Structural Modifications by an Activator of Integrin Signaling at the Drosophila Neuromuscular Junction

    Science.gov (United States)

    2017-01-01

    Activity-induced synaptic structural modification is crucial for neural development and synaptic plasticity, but the molecular players involved in this process are not well defined. Here, we report that a protein named Shriveled (Shv) regulates synaptic growth and activity-dependent synaptic remodeling at the Drosophila neuromuscular junction. Depletion of Shv causes synaptic overgrowth and an accumulation of immature boutons. We find that Shv physically and genetically interacts with βPS integrin. Furthermore, Shv is secreted during intense, but not mild, neuronal activity to acutely activate integrin signaling, induce synaptic bouton enlargement, and increase postsynaptic glutamate receptor abundance. Consequently, loss of Shv prevents activity-induced synapse maturation and abolishes post-tetanic potentiation, a form of synaptic plasticity. Our data identify Shv as a novel trans-synaptic signal secreted upon intense neuronal activity to promote synapse remodeling through integrin receptor signaling. SIGNIFICANCE STATEMENT The ability of neurons to rapidly modify synaptic structure in response to neuronal activity, a process called activity-induced structural remodeling, is crucial for neuronal development and complex brain functions. The molecular players that are important for this fundamental biological process are not well understood. Here we show that the Shriveled (Shv) protein is required during development to maintain normal synaptic growth. We further demonstrate that Shv is selectively released during intense neuronal activity, but not mild neuronal activity, to acutely activate integrin signaling and trigger structural modifications at the Drosophila neuromuscular junction. This work identifies Shv as a key modulator of activity-induced structural remodeling and suggests that neurons use distinct molecular cues to differentially modulate synaptic growth and remodeling to meet synaptic demand. PMID:28219985

  17. Colony-stimulating factor 1 receptor blockade prevents fractionated whole-brain irradiation-induced memory deficits.

    Science.gov (United States)

    Feng, Xi; Jopson, Timothy D; Paladini, Maria Serena; Liu, Sharon; West, Brian L; Gupta, Nalin; Rosi, Susanna

    2016-08-30

    Primary central nervous system (CNS) neoplasms and brain metastases are routinely treated with whole-brain radiation. Long-term survival occurs in many patients, but their quality of life is severely affected by the development of cognitive deficits, and there is no treatment to prevent these adverse effects. Neuroinflammation, associated with activation of brain-resident microglia and infiltrating monocytes, plays a pivotal role in loss of neurological function and has been shown to be associated with acute and long-term effects of brain irradiation. Colony-stimulating factor 1 receptor (CSF-1R) signaling is essential for the survival and differentiation of microglia and monocytes. Here, we tested the effects of CSF-1R blockade by PLX5622 on cognitive function in mice treated with three fractions of 3.3 Gy whole-brain irradiation. Young adult C57BL/6J mice were given three fractions of 3.3 Gy whole-brain irradiation while they were on diet supplemented with PLX5622, and the effects on periphery monocyte accumulation, microglia numbers, and neuronal functions were assessed. The mice developed hippocampal-dependent cognitive deficits at 1 and 3 months after they received fractionated whole-brain irradiation. The impaired cognitive function correlated with increased number of periphery monocyte accumulation in the CNS and decreased dendritic spine density in hippocampal granule neurons. PLX5622 treatment caused temporary reduction of microglia numbers, inhibited monocyte accumulation in the brain, and prevented radiation-induced cognitive deficits. Blockade of CSF-1R by PLX5622 prevents fractionated whole-brain irradiation-induced memory deficits. Therapeutic targeting of CSF-1R may provide a new avenue for protection from radiation-induced memory deficits.

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

    Directory of Open Access Journals (Sweden)

    Silvio A Oliveira-Junior

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

  19. In Vivo Costimulation Blockade-Induced Regulatory T Cells Demonstrate Dominant and Specific Tolerance to Porcine Islet Xenografts.

    Science.gov (United States)

    Wu, Jingjing; Hu, Min; Qian, Yi Wen; Hawthorne, Wayne J; Burns, Heather; Liuwantara, David; Alexander, Stephen I; Yi, Shounan; O'Connell, Philip J

    2017-07-01

    Although islet xenotransplantation is a promising therapy for type 1 diabetes, its clinical application has been hampered by cellular rejection and the requirement for high levels of immunosuppression. The aim of this study was to determine the role of Foxp3 regulatory T (Treg) cells in costimulation blockade-induced dominant tolerance to porcine neonatal islet cell cluster (NICC) xenografts in mice. Porcine-NICC were transplanted under the renal capsule of BALB/c or C57BL/6 recipients and given a single dose of CTLA4-Fc at the time of transplant and 4doses of anti-CD154 mAb to day 6. Depletion of Foxp3Treg cell was performed in DEpletion of REGulatory T cells mice at day 80 posttransplantation. Foxp3Treg cell from spleens of treated BALB/c mice (tolerant Treg cell), and splenocytes were cotransferred into islet transplanted nonobese diabetic background with severe combined immunodeficiency mice to assess suppressive function. In treated mice, increased numbers of Foxp3Treg cell were identified in the porcine-NICC xenografts, draining lymph node, and spleen. Porcine-NICC xenografts from treated mice expressed elevated levels of TGF-β, IL-10 and IFN-γ. Porcine-NICC xenograft tolerance was abrogated after depletion of Foxp3Treg cell. Tolerant Treg cell produced high levels of IL-10 and had diverse T cell receptor Vβ repertoires with an oligoclonal expansion in CDR3 of T cell receptor Vβ14. These tolerant Treg cells had the capacity to transfer dominant tolerance and specifically exhibited more potent regulatory function to porcine-NICC xenografts that naive Treg cell. This study demonstrated that short-term costimulation blockade-induced dominant tolerance and that Foxp3Treg cell played an essential role in its maintenance. Foxp3Treg cells were activated and had more potent regulatory function in vivo than naive Treg cells.

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

    Directory of Open Access Journals (Sweden)

    Ju Hee Yoon

    2015-01-01

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

  1. Concomitant gentamicin-induced nephrotoxicity and bilateral ...

    African Journals Online (AJOL)

    2015-11-20

    Nov 20, 2015 ... ototoxicity, and, more rarely, neuromuscular blockade. Gentamicin‑induced nephrotoxicity ranges between ... corrected with oral potassium chloride. She received a total of 4 sessions of hemodialysis with ... disease, and multiple dosing of gentamicin. Gentamicin nephrotoxicity presents commonly as.

  2. Acetylcholine-induced inhibition of presynaptic calcium signals and transmitter release in the frog neuromuscular junction

    Directory of Open Access Journals (Sweden)

    Eduard Khaziev

    2016-12-01

    Full Text Available Acetylcholine (ACh, released from axonal terminals of motor neurones in neuromuscular junctions regulates the efficacy of neurotransmission through activation of presynaptic nicotinic and muscarinic autoreceptors. Receptor-mediated presynaptic regulation could reflect either direct action on exocytotic machinery or modulation of Ca2+ entry and resulting intra-terminal Ca2+ dynamics. We have measured free intra-terminal cytosolic Ca2+ ([Ca2+]i using Oregon-Green 488 microfluorimetry, in parallel with voltage-clamp recordings of spontaneous (mEPC and evoked (EPC postsynaptic currents in post-junctional skeletal muscle fibre. Activation of presynaptic muscarinic and nicotinic receptors with exogenous acetylcholine and its non-hydrolized analogue carbachol reduced amplitude of the intra-terminal [Ca2+]i transients and decreased quantal content (calculated by dividing the area under EPC curve by the area under mEPC curve. Pharmacological analysis revealed the role of muscarinic receptors of M2 subtype as well as d-tubocurarine-sensitive nicotinic receptor in presynaptic modulation of [Ca2+]i transients. Modulation of synaptic transmission efficacy by ACh receptors was completely eliminated by pharmacological inhibition of N-type Ca2+ channels. We conclude that ACh receptor-mediated reduction of Ca2+ entry into the nerve terminal through N-type Ca2+ channels represents one of possible mechanism of presynaptic modulation in frog neuromuscular junction.

  3. Human-induced pluripotent stem cell-derived cardiomyocytes from cardiac progenitor cells: effects of selective ion channel blockade.

    Science.gov (United States)

    Altomare, Claudia; Pianezzi, Enea; Cervio, Elisabetta; Bolis, Sara; Biemmi, Vanessa; Benzoni, Patrizia; Camici, Giovanni G; Moccetti, Tiziano; Barile, Lucio; Vassalli, Giuseppe

    2016-12-01

    Human-induced pluripotent stem cell (hiPSC)-derived cardiomyocytes are likely to revolutionize electrophysiological approaches to arrhythmias. Recent evidence suggests the somatic cell origin of hiPSCs may influence their differentiation potential. Owing to their cardiomyogenic potential, cardiac-stromal progenitor cells (CPCs) are an interesting cellular source for generation of hiPSC-derived cardiomyocytes. The effect of ionic current blockade in hiPSC-derived cardiomyocytes generated from CPCs has not been characterized yet. Human-induced pluripotent stem cell-derived cardiomyocytes were generated from adult CPCs and skin fibroblasts from the same individuals. The effect of selective ionic current blockade on spontaneously beating hiPSC-derived cardiomyocytes was assessed using multi-electrode arrays. Cardiac-stromal progenitor cells could be reprogrammed into hiPSCs, then differentiated into hiPSC-derived cardiomyocytes. Human-induced pluripotent stem cell-derived cardiomyocytes of cardiac origin showed higher upregulation of cardiac-specific genes compared with those of fibroblastic origin. Human-induced pluripotent stem cell-derived cardiomyocytes of both somatic cell origins exhibited sensitivity to tetrodotoxin, a blocker of Na(+ )current (INa), nifedipine, a blocker of L-type Ca(2+ )current (ICaL), and E4031, a blocker of the rapid component of delayed rectifier K(+ )current (IKr). Human-induced pluripotent stem cell-derived cardiomyocytes of cardiac origin exhibited sensitivity to JNJ303, a blocker of the slow component of delayed rectifier K(+ )current (IKs). In hiPSC-derived cardiomyocytes of cardiac origin, INa, ICaL, IKr, and IKs were present as tetrodotoxin-, nifedipine-, E4031-, and JNJ303-sensitive currents, respectively. Although cardiac differentiation efficiency was improved in hiPSCs of cardiac vs. non-cardiac origin, no major functional differences were observed between hiPSC-derived cardiomyocytes of different somatic cell origins

  4. [Augmentation by succinylcholine of the neuromuscular blocking effect of vecuronium in children].

    Science.gov (United States)

    Yasuda, S; Takeda, J; Sekiguchi, H; Fukushima, K

    1995-07-01

    To evaluate the influence of succinylcholine (Scc) on the neuromuscular blocking effect of subsequently administered vecuronium in children, 30 patients aged 2-14 years scheduled for elective surgery were studied after obtaining the informed consent from the parents. Anesthesia was induced with inhalation of sevoflurane, nitrous oxide and oxygen. T1 of the adductor pollicis muscle to ulnar nerve stimulation elicited by train of four stimulation at 2 Hz was monitored continuously by an acceleration transducer. The patients were divided into two groups; group V (16 patients) received vecuronium (0.03 mg.kg-1) and group SV (14 patients) received vecuronium (0.03 mg.kg-1) after 100% recovery of twitch from neuromuscular blockade induced with Scc (1.0 mg.kg-1). Short onset of action and potentiation of maximal block were demonstrated in group SV. After vecuronium administration, a complete suppression of T1 was observed in 8 patients of group SV and only 1 patient of group V. The present study demonstrates that the neuromuscular blockade of vecuronium can be potentiated with the prior administration of Scc in pediatric patients.

  5. Neuromuscular disorders

    OpenAIRE

    Reed, Umbertina C.

    2002-01-01

    Objetivo: apresentar os dados essenciais para o diagnóstico diferencial entre as principais doenças neuromusculares, denominação genérica sob a qual agrupam-se diferentes afecções, decorrentes do acometimento primário da unidade motora (motoneurônio medular, raiz nervosa, nervo periférico, junção mioneural e músculo). Fontes dos dados: os aspectos clínicos fundamentais para estabelecer o diagnóstico diferencial entre as diferentes doenças neuromusculares, bem como entre estas e as causas de h...

  6. Blockade of Retinol Metabolism Protects T Cell-Induced Hepatitis by Increasing Migration of Regulatory T Cells

    Science.gov (United States)

    Lee, Young-Sun; Yi, Hyon-Seung; Suh, Yang-Gun; Byun, Jin-Seok; Eun, Hyuk Soo; Kim, So Yeon; Seo, Wonhyo; Jeong, Jong-Min; Choi, Won-Mook; Kim, Myung-Ho; Kim, Ji Hoon; Park, Keun-Gyu; Jeong, Won-Il

    2015-01-01

    Retinols are metabolized into retinoic acids by alcohol dehydrogenase (ADH) and retinaldehyde dehydrogenase (Raldh). However, their roles have yet to be clarified in hepatitis despite enriched retinols in hepatic stellate cells (HSCs). Therefore, we investigated the effects of retinols on Concanavalin A (Con A)-mediated hepatitis. Con A was injected into wild type (WT), Raldh1 knock-out (Raldh1−/−), CCL2−/− and CCR2−/− mice. For migration study of regulatory T cells (Tregs), we used in vivo and ex vivo adoptive transfer systems. Blockade of retinol metabolism in mice given 4-methylpyrazole, an inhibitor of ADH, and ablated Raldh1 gene manifested increased migration of Tregs, eventually protected against Con A-mediated hepatitis by decreasing interferon-γ in T cells. Moreover, interferon-γ treatment increased the expression of ADH3 and Raldh1, but it suppressed that of CCL2 and IL-6 in HSCs. However, the expression of CCL2 and IL-6 was inversely increased upon the pharmacologic or genetic ablation of ADH3 and Raldh1 in HSCs. Indeed, IL-6 treatment increased CCR2 expression of Tregs. In migration assay, ablated CCR2 in Tregs showed reduced migration to HSCs. In adoptive transfer of Tregs in vivo and ex vivo, Raldh1-deficient mice showed more increased migration of Tregs than WT mice. Furthermore, inhibited retinol metabolism increased survival rate (75%) compared with that of the controls (25%) in Con A-induced hepatitis. These results suggest that blockade of retinol metabolism protects against acute liver injury by increased Treg migration, and it may represent a novel therapeutic strategy to control T cell-mediated acute hepatitis. PMID:26537191

  7. Blockade and reversal of 5-methoxy-N,N-dimethyltryptamine-induced analgesia following noradrenaline depletion.

    Science.gov (United States)

    Archer, T; Minor, B G; Post, C

    1985-04-29

    The acute effects of the 5-hydroxytryptamine agonist, 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT), upon pain sensitivity, using shock titration, tail-flick and hot-plate methods, in noradrenaline- and 5-hydroxytryptamine-depleted rats were examined. Noradrenaline depletion, following the systemic administration of N-2-chloroethyl-N-ethyl-2-bromobenzylamine hydrochloride (DSP4, 2 X 50 mg/kg, i.p.), caused a reversal of the analgesic effect of 5-MeO-DMT on shock-titration from hypo- to hypersensitivity, and a total blockade of the antinociceptive effect of 5-MeO-DMT upon pain responses in the hot-plate and tail-flick tests. Pretreatment with either p-chloroamphetamine (2 X 10 mg/kg) or p-chlorophenylalanine (200, 100, 100 mg/kg), that depletes central 5-hydroxytryptamine stores, failed to alter the analgesia caused by acute 5-MeO-DMT. Strong evidence is provided for the effect of central noradrenaline depletion upon the analgesic effect of the 5-HT agonist. These findings suggest an important tonic influence of the noradrenaline system upon the descending spinal 5-HT pathway in rats.

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

    Energy Technology Data Exchange (ETDEWEB)

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

  9. Neuromuscular Scoliosis

    Science.gov (United States)

    ... to the optimal care of patients with spinal deformity Patients and Families Professionals About SRS Türkçe español ... unable to maintain appropriate balance / alignment of the spine and trunk. Neuromuscular curves are often associated with ...

  10. Presynaptic actions of morphine: blockade of cholecystokinin-induced noradrenaline release in the rat supraoptic nucleus.

    Science.gov (United States)

    Onaka, T; Luckman, S M; Guevara-Guzman, R; Ueta, Y; Kendrick, K; Leng, G

    1995-01-01

    1. This study aimed to establish the site at which morphine acts to inhibit oxytocin release in response to peripheral administration of cholecystokinin (CCK). 2. Conscious rats were given morphine or vehicle followed by CCK or vehicle (I.V.). Fos immunoreactivity was apparent 90 min after CCK injection in the supraoptic nucleus of vehicle- but not morphine-pretreated animals. 3. In the dorsomedial (C2/A2) and the ventrolateral (C1/A1) regions of the brainstem, about half of the cells immunoreactive for tyrosine hydroxylase (TH) expressed Fos-like protein after CCK injection. In the C2/A2 region, 20% of the Fos-positive cells also showed TH immunoreactivity, whereas in the C1/A1 region 68% did so. Morphine treatment did not significantly change the number of cells expressing Fos immunoreactivity, or the percentage of TH-positive cells expressing Fos-like protein. 4. Amine release was measured in the supraoptic nucleus of urethane-anaesthetized rats using a microdialysis probe. An I.V. injection of CCK increased the concentrations in the dialysate of noradrenaline and serotonin, but not of either adrenaline or dopamine. Pretreatment with morphine (I.V.) blocked the effects of CCK in a naloxone-reversible manner. 5. Inclusion of morphine in the dialysate also blocked the increase in noradrenaline and serotonin in response to CCK in a naloxone-reversible manner. 6. These observations indicate that morphine acts near or within the supraoptic nucleus to block CCK-evoked noradrenaline release presynaptically. This presynaptic action of morphine may be a cause of the blockade of oxytocin release after CCK. Images Figure 1 Figure 3 PMID:7730990

  11. New models of pulmonary hypertension based on VEGF receptor blockade-induced endothelial cell apoptosis

    Science.gov (United States)

    Nicolls, Mark R.; Mizuno, Shiro; Taraseviciene-Stewart, Laima; Farkas, Laszlo; Drake, Jennnifer I.; Al Husseini, Aysar; Gomez-Arroyo, Jose G.; Voelkel, Norbert F.; Bogaard, Herman J.

    2012-01-01

    In spite of treatment, severe angioproliferative pulmonary arterial hypertension (PAH) remains a disease characterized by great morbidity and shortened survival. New treatment strategies for patients with PAH are needed, and after drug development, preclinical studies are best conducted in animal models which present with pulmonary angio-obliterative disease and right heart failure. A rat model of severe pulmonary hypertension and right heart failure, described a decade ago, continues to be investigated and provide insight into the nature of the lung vascular lesions and mechanisms of cardiac adaptation to an altered lung circulation. This rat model is based on the combination of VEGF receptor blockade with Su5416 and chronic hypoxia; use of this pulmonary hypertension induction strategy led to developing the concept of apoptosis-dependent compensatory vascular cell growth. Although, often employed in experimental designs, chronic hypoxia is not necessary for the development of angio-obliterative pulmonary hypertension. Left pneumonectomy combined with Su5416 also results in severe pulmonary hypertension in normoxic conditions. Similarly, the immune insufficiency component of severe PAH can be modeled in athymic rats (lacking T-lymphocytes). In these rats housed under normoxic conditions, treatment with the VEGFR receptor blocker results in angioproliferative pulmonary hypertension; cardiopulmonary disease in these animals can be prevented by immune reconstitution of regulatory T-cells (Tregs). Finally, chronic hypoxia can be replaced with another stimulator of HIF-1α: Ovalbumin (Ova). Immunization of rats with Ova increases lung tissue HIF-1α protein expression, and in Su5416-treated rats causes lethal pulmonary hypertension. Finally, we postulate that these models may also be useful for “reverse translation”; that is, the mechanisms of lung vascular cell death and growth and the modifying influences of immune and bone marrow cells that have been identified

  12. Combined blockade of angiotensin II and prorenin receptors ameliorates podocytic apoptosis induced by IgA-activated mesangial cells.

    Science.gov (United States)

    Leung, Joseph C K; Chan, Loretta Y Y; Saleem, M A; Mathieson, P W; Tang, Sydney C W; Lai, Kar Neng

    2015-07-01

    Glomerulo-podocytic communication plays an important role in the podocytic injury in IgA nephropathy (IgAN). In this study, we examine the role of podocytic angiotensin II receptor subtype 1 (AT1R) and prorenin receptor (PRR) in podocytic apoptosis in IgAN. Polymeric IgA (pIgA) was isolated from patients with IgAN and healthy controls. Conditioned media were prepared from growth arrested human mesangial cells (HMC) incubated with pIgA from patients with IgAN (IgA-HMC media) or healthy controls (Ctl-HMC media). A human podocyte cell line was used as a model to examine the regulation of the expression of AT1R, PRR, TNF-α and CTGF by IgA-HMC media. Podocytic nephrin expression, annexin V binding and caspase 3 activity were used as the functional readout of podocytic apoptosis. IgA-HMC media had no effect on AngII release by podocytes. IgA-HMC media significantly up-regulated the expression of AT1R and PRR, down-regulated nephrin expression and induced apoptosis in podocytes. Mono-blockade of AT1R, PRR, TNF-α or CTGF partially reduced podocytic apoptosis. IgA-HMC media activated NFκB, notch1 and HEY1 expression by podocytes and dual blockade of AT1R with PRR, or anti-TNF-α with anti-CTGF, effectively rescued the podocytic apoptosis induced by IgA-HMC media. Our data suggests that pIgA-activated HMC up-regulates the expression of AT1R and PRR expression by podocytes and the associated activation of NFκB and notch signalling pathways play an essential role in the podocytic apoptosis induced by glomerulo-podocytic communication in IgAN. Simultaneously targeting the AT1R and PRR could be a potential therapeutic option to reduce the podocytic injury in IgAN.

  13. Immunotherapy of murine retrovirus-induced acquired immunodeficiency by CD4 T regulatory cell depletion and PD-1 blockade.

    Science.gov (United States)

    Li, Wen; Green, William R

    2011-12-01

    LP-BM5 retrovirus induces a complex disease featuring an acquired immunodeficiency syndrome termed murine AIDS (MAIDS) in susceptible strains of mice, such as C57BL/6 (B6). CD4 T helper effector cells are required for MAIDS induction and progression of viral pathogenesis. CD8 T cells are not needed for viral pathogenesis, but rather, are essential for protection from disease in resistant strains, such as BALB/c. We have discovered an immunodominant cytolytic T lymphocyte (CTL) epitope encoded in a previously unrecognized LP-BM5 retroviral alternative (+1 nucleotide [nt]) gag translational open reading frame. CTLs specific for this cryptic gag epitope are the basis of protection from LP-BM5-induced immunodeficiency in BALB/c mice, and the inability of B6 mice to mount an anti-gag CTL response appears critical to the initiation and progression of LP-BM5-induced MAIDS. However, uninfected B6 mice primed by LP-BM5-induced tumors can generate CTL responses to an LP-BM5 retrovirus infection-associated epitope(s) that is especially prevalent on such MAIDS tumor cells, indicating the potential to mount a protective CD8 T-cell response. Here, we utilized this LP-BM5 retrovirus-induced disease system to test whether modulation of normal immune down-regulatory mechanisms can alter retroviral pathogenesis. Thus, following in vivo depletion of CD4 T regulatory (Treg) cells and/or selective interruption of PD-1 negative signaling in the CD8 T-cell compartment, retroviral pathogenesis was significantly decreased, with the combined treatment of CD4 Treg cell depletion and PD-1 blockade working in a synergistic fashion to substantially reduce the induction of MAIDS.

  14. Lithium attenuated the behavioral despair induced by acute neurogenic stress through blockade of opioid receptors in mice.

    Science.gov (United States)

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

    2016-10-01

    Major depressive disorder is disease with high rate of morbidity and mortality. Stressful events lead to depression and they can be used as a model of depression in rodents. In this study we aimed to investigate whether lithium modifies the stressed-induced depression through blockade of opioid receptors in mice. We used foot shock stress as stressor and forced swimming test (FST), tail suspension test (TST) and open field test (OFT) to evaluation the behavioral responses in mice. We also used naltrexone hydrochloride (as opioid receptor antagonist), and morphine (as opioid receptor agonist). Our results displayed that foot-shock stress significantly increased the immobility time in TST and FST but it could not change the locomotor behavior in OFT. When we combined the low concentrations of lithium and naltrexone a significant reduction in immobility time was seen in the FST and TST in comparison with control foot-shock stressed group administered saline only. Despite the fact that our data showed low concentrations of lithium, when administered independently did not significantly affect the immobility time. Also our data indicated that concurrent administration of lithium and naltrexone had no effect on open field test. Further we demonstrated that simultaneous administration of morphine and lithium reverses the antidepressant like effect of active doses of lithium. Our data acclaimed that we lithium can augment stressed-induced depression and opioid pathways are involved in this action. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

  15. Motor improvement and corticospinal modulation induced by hybrid assistive neuromuscular dynamic stimulation (HANDS) therapy in patients with chronic stroke.

    Science.gov (United States)

    Fujiwara, Toshiyuki; Kasashima, Yuko; Honaga, Kaoru; Muraoka, Yoshihiro; Tsuji, Tetsuya; Osu, Rieko; Hase, Kimitaka; Masakado, Yoshihisa; Liu, Meigen

    2009-02-01

    We devised a therapeutic approach to facilitate the use of the hemiparetic upper extremity (UE) in daily life by combining integrated volitional control electrical stimulation with a wrist splint, called hybrid assistive neuromuscular dynamic stimulation (HANDS). Twenty patients with chronic hemiparetic stroke (median 17.5 months) had moderate to severe UE weakness. Before and immediately after completing 3 weeks of training in 40-minute sessions, 5 days per week over 3 weeks and wearing the system for 8 hours each day, clinical measures of motor impairment, spasticity, and UE functional scores, as well as neurophysiological measures including electromyography activity, reciprocal inhibition, and intracortical inhibition were assessed. A follow-up clinical assessment was performed 3 months later. UE motor function, spasticity, and functional scores improved after the intervention. Neurophysiologically, the intervention induced restoration of presynaptic and long loop inhibitory connections as well as disynaptic reciprocal inhibition. Paired pulse transcranial magnetic stimulation study indicated disinhibition of the short intracortical inhibition in the affected hemisphere. The follow-up assessment showed that improved UE functions were maintained at 3 months. The combination of hand splint and volitional and electrically induced muscle contraction can induce corticospinal plasticity and may offer a promising option for the management of the paretic UE in patients with stroke. A larger sample size with randomized controls is needed to demonstrate effectiveness.

  16. Mechanism for blockade of angiotensin subtype 1 receptors to lower plasma glucose in streptozotocin-induced diabetic rats.

    Science.gov (United States)

    Chan, P; Liu, I-M; Tzeng, T-F; Yang, T-L; Cheng, J-T

    2007-01-01

    reduction of elevated mRNA or protein level of hepatic PEPCK. Both of these effects were blocked by opioid micro-receptor antagonist. The results suggest that blockade of AT(1) receptor by valsartan may enhance the adrenal beta-endorphin secretion induced by ACh, activating the opioid micro-receptors to increase glucose utilization and/or to decrease hepatic gluconeogenesis, resulting in the reduction of plasma glucose in STZ-induced diabetic rats.

  17. The neuromuscular fatigue induced by repeated scrums generates instability that can be limited by appropriate recovery.

    Science.gov (United States)

    Morel, B; Hautier, C A

    2017-02-01

    The aim of this study was to evaluate the influence of the fatigue on the machine scrum pushing sagittal forces during repeated scrums and to determine the origin of the knee extensor fatigue. Twelve elite U23 rugby union front row players performed six 6-s scrums every 30 s against a dynamic scrum machine with passive or active recovery. The peak, average, and the standard deviation of the force were measured. A neuromuscular testing procedure of the knee extensors was carried out before and immediately after the repeated scrum protocol including maximal voluntary force, evoked force, and voluntary activation. The average and peak forces did not decrease after six scrums with passive recovery. The standard deviation of the force increased by 70.2 ± 42.7% (P scrum pushing instability associated with central and peripheral fatigue of the knee extensors. Active recovery seems to limit all these manifestations of fatigue. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  18. PLK1 blockade enhances therapeutic effects of radiation by inducing cell cycle arrest at the mitotic phase.

    Science.gov (United States)

    Inoue, Minoru; Yoshimura, Michio; Kobayashi, Minoru; Morinibu, Akiyo; Itasaka, Satoshi; Hiraoka, Masahiro; Harada, Hiroshi

    2015-10-27

    The cytotoxicity of ionizing radiation depends on the cell cycle phase; therefore, its pharmacological manipulation, especially the induction of cell cycle arrest at the radiosensitive mitotic-phase (M-phase), has been attempted for effective radiation therapy. Polo-like kinase 1 (PLK1) is a serine/threonine kinase that functions in mitotic progression, and is now recognized as a potential target for radiosensitization. We herein investigated whether PLK1 blockade enhanced the cytotoxic effects of radiation by modulating cell cycle phases of cancer cells using the novel small molecule inhibitor of PLK1, TAK-960. The TAK-960 treatment exhibited radiosensitizing effects in vitro, especially when it increased the proportion of M-phase cells. TAK-960 did not sensitize cancer cells to radiation when an insufficient amount of time was provided to induce mitotic arrest. The overexpression of a PLK1 mutant, PLK1-R136G&T210D, which was confirmed to cancel the TAK-960-mediated increase in the proportion of mitotic cells, abrogated the radiosensitizing effects of TAK-960. A tumor growth delay assay also demonstrated that the radiosensitizing effects of TAK-960 depended on an increase in the proportion of M-phase cells. These results provide a rational basis for targeting PLK1 for radiosensitization when considering the therapeutic time window for M-phase arrest as the best timing for radiation treatments.

  19. CB(1) blockade-induced weight loss over 48 weeks decreases liver fat in proportion to weight loss in humans.

    Science.gov (United States)

    Bergholm, R; Sevastianova, K; Santos, A; Kotronen, A; Urjansson, M; Hakkarainen, A; Lundbom, J; Tiikkainen, M; Rissanen, A; Lundbom, N; Yki-Järvinen, H

    2013-05-01

    Studies in mice have suggested that endocannabinoid blockade using the cannabinoid receptor type 1 (CB1) blocker rimonabant prevents obesity-induced hepatic steatosis. To determine effects of rimonabant on liver fat in humans, we measured liver fat content by proton magnetic resonance spectroscopy in 37 subjects who used either a CB1 blocker rimonabant or placebo in a double-blind, randomized manner. This was retrospectively compared with a historical hypocaloric diet weight loss group (n=23). Weight loss averaged 8.5±1.4 kg in the rimonabant, 1.7±1.0 kg in the placebo and 7.5±0.2 kg in the hypocaloric diet group (Pfat decreased more in the rimonabant (5.9% (2.5-14.6%) vs 1.8% (0.9-3.5%), before vs after) than in the placebo group (6.8% (2.2-15.7%) vs 4.9% (1.6-7.8%), before vs after, Ploss of liver fat (r=0.70, P>0.0001). The decreases in liver fat were comparable between the rimonabant and the young historical hypocaloric diet groups. We conclude that, unlike in mice, in humans rimonabant decreases liver fat in proportion to weight loss.

  20. Effect of Triggering Receptor Expressed on Myeloid Cells 1 (TREM-1) Blockade in Rats with Cecal Ligation and Puncture (CLP)-Induced Sepsis.

    Science.gov (United States)

    Shi, Xiaofeng; Zhang, Yue; Wang, Hao; Zeng, Sha

    2017-10-23

    BACKGROUND Blocking of TREM-1 signaling improves survival of mice with sepsis induced by Pseudomonas aeruginosa. However, whether TREM-1 blockade has beneficial effects in polymicrobial sepsis is poorly understood. Here, we aimed to investigate the effect of modulation of the TREM-1 pathway in rats with polymicrobial sepsis induced by cecal ligation and puncture (CLP). MATERIAL AND METHODS Normal Sprague-Dawley (SD) rats with sepsis induced by CLP were allocated randomly to received scramble peptide or LP17 via the jugular vein. Serum level of sTREM-1, IL6, TNF-α, and IL-1β were detected by ELISA assay. The mRNA and protein levels of JAK2 and STAT3 were detected by real-time PCR and Western blot analysis. RESULTS STREM-1 concentration was greatly and progressively increased in rats with CLP-induced sepsis, and the increase was attenuated by TREM-1 inhibitory peptide LP17. More than 60% survival was observed in rats at the experiment endpoint after LP17 treatment. TREM-1 blockade also attenuated the increased level of pro-inflammatory cytokines TNF-α, IL-6, and IL-1β, and thus attenuated systematic and distant inflammatory responses. Furthermore, TREM-1 blockade significantly attenuated the increased levels of pJAK2 and pSTAT3. CONCLUSIONS TREM-1 blockade by the use of an inhibitory peptide LP17 could prolong survival of rats with polymicrobial sepsis and attenuate systematic inflammatory responses through the JAK2/STAT3 signaling pathway. Our results suggest that modulation of TREM-1 by a synthetic peptide might be a potential therapeutic option for polymicrobial sepsis.

  1. Bradykinin receptor blockade restores the baroreflex control of renal sympathetic nerve activity in cisplatin-induced renal failure rats.

    Science.gov (United States)

    Abdulla, M H; Duff, M; Swanton, H; Johns, E J

    2016-11-01

    This study investigated the effect of renal bradykinin B1 and B2 receptor blockade on the high- and low-pressure baroreceptor reflex regulation of renal sympathetic nerve activity (RSNA) in rats with cisplatin-induced renal failure. Cisplatin (5 mg/kg) or saline was given intraperitoneally 4 days prior to study. Following chloralose/urethane anaesthesia, rats were prepared for measurement of mean arterial pressure (MAP), heart rate and RSNA and received intrarenal infusions of either Lys-[des-Arg9 , Leu8 ]-bradykinin (LBK), a bradykinin B1 receptor blocker, or bradyzide (BZ), a bradykinin B2 receptor blocker. RSNA baroreflex gain curves and renal sympatho-inhibitory responses to volume expansion (VE) were obtained. In the control and renal failure groups, basal MAP (89 ± 3 vs. 80 ± 8 mmHg) and RSNA (2.0 ± 0.3 vs. 1.7 ± 0.6 μV.s) were similar but HR was lower in the latter group (331 ± 8 vs. 396 ± 9 beats/min). The baroreflex gain for RSNA in the renal failure rats was 39% (P renal failure rats. Intrarenal LBK infusion in the renal failure rats normalized the VE induced renal sympatho-inhibition whereas BZ only partially restored the response. These findings suggest that pro-inflammatory bradykinin acting at different receptors within the kidney generates afferent neural signals which impact differentially within the central nervous system on high- and low-pressure regulation of RSNA. © 2016 Scandinavian Physiological Society. Published by John Wiley & Sons Ltd.

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

    Directory of Open Access Journals (Sweden)

    Selina Christen

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

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

    Science.gov (United States)

    Christen, Selina; Coppieters, Ken; Rose, Kerstin; Holdener, Martin; Bayer, Monika; Pfeilschifter, Josef M; Hintermann, Edith; von Herrath, Matthias G; Aurrand-Lions, Michel; Imhof, Beat A; Christen, Urs

    2013-01-01

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

  4. Effects of interleukin-13 blockade on allergen-induced airway responses in mild atopic asthma.

    Science.gov (United States)

    Gauvreau, Gail M; Boulet, Louis-Philippe; Cockcroft, Donald W; Fitzgerald, J Mark; Carlsten, Chris; Davis, Beth E; Deschesnes, Francine; Duong, MyLinh; Durn, Billie L; Howie, Karen J; Hui, Linda; Kasaian, Marion T; Killian, Kieran J; Strinich, Tara X; Watson, Richard M; Y, Nathalie; Zhou, Simon; Raible, Donald; O'Byrne, Paul M

    2011-04-15

    Extensive evidence in animal models supports a role for IL-13 in the pathobiology of asthma. IMA-638 and IMA-026 are fully humanized IgG(1) antibodies that bind to different epitopes and neutralize IL-13 bioactivity. We hypothesized that anti-IL-13 treatment would inhibit allergen-induced late-phase asthmatic responses, airway hyperresponsiveness, and inflammation in subjects with asthma. Fifty-six subjects with mild, atopic asthma were recruited for two double-blind, randomized, placebo-controlled, parallel group trials to compare IMA-638 and IMA-026 IL-13 antibody treatments with placebo treatment. Drug was administered on Days 1 and 8, and allergen challenges were performed on Days 14 and 35. The primary outcome variable was the late-phase area under the curve (AUC), and secondary outcome variables were the early- and late-phase maximum percent fall in FEV(1), early AUC, allergen-induced shift in airway hyperresponsiveness, and sputum eosinophils. The treatment difference with IMA-638 on Day 14 was -19.1 FEV(1) × hour (95% confidence interval: -36.2, -1.9) for the allergen-induced early AUC and -23.8 FEV(1) × hour (95% confidence interval: -46.4, -1.2) for the late AUC (both P humans. Further study is required to determine whether anti-IL-13 monoclonal antibodies will be beneficial clinically.

  5. GRP94 Regulates Circulating Cholesterol Levels through Blockade of PCSK9-Induced LDLR Degradation

    Directory of Open Access Journals (Sweden)

    Steve Poirier

    2015-12-01

    Full Text Available Clearance of circulating low-density lipoprotein cholesterol (LDLc by hepatic LDL receptors (LDLR is central for vascular health. Secreted by hepatocytes, PCSK9 induces the degradation of LDLR, resulting in higher plasma LDLc levels. Still, it remains unknown why LDLR and PCSK9 co-exist within the secretory pathway of hepatocytes without leading to complete degradation of LDLR. Herein, we identified the ER-resident GRP94, and more precisely its client-binding C-terminal domain, as a PCSK9-LDLR inhibitory binding protein. Depletion of GRP94 did not affect calcium homeostasis, induce ER stress, nor did it alter PCSK9 processing or its secretion but greatly increased its capacity to induce LDLR degradation. Accordingly, we found that hepatocyte-specific Grp94-deficient mice have higher plasma LDLc levels correlated with ∼80% reduction in hepatic LDLR protein levels. Thus, we provide evidence that, in physiological conditions, binding of PCSK9 to GRP94 protects LDLR from degradation likely by preventing early binding of PCSK9 to LDLR within the ER.

  6. Alpha-blockade and vasodilatation induced by nipradilol, arotinolol and labetalol in pithed rats.

    Science.gov (United States)

    Nakagawa, Y; Nakahara, H; Chin, W P; Imai, S

    1985-12-01

    In pithed rats two recently-introduced beta-blockers, nipradilol and arotinolol, as well as labetalol shifted the pressor dose-response curve for phenylephrine to the right. Labetalol and arotinolol did not modify the pressor dose-response curve for clonidine, while nipradilol induced a definite rightward shift. These results indicate that labetalol and arotinolol are selective alpha 1-blockers, while nipradilol is a non-selective one. In addition, all the three beta-blockers produced complex changes in the blood pressure in pithed rats. A fall of the diastolic blood pressure induced by labetalol and nipradilol was preceded by a slight rise, while arotinolol produced a fall at lower doses and a rise at higher ones. The hypotension by labetalol was abolished after propranolol, while the hypertension was suppressed by prazosin, indicating that labetalol has an intrinsic beta- and alpha 1-sympathomimetic effect. The hypertension and the hypotension produced by nipradilol and arotinolol persisted even in the presence of propranolol and prazosin or propranolol and yohimbine.

  7. Buspirone Counteracts MK-801-Induced Schizophrenia-Like Phenotypes through Dopamine D3 Receptor Blockade

    Directory of Open Access Journals (Sweden)

    Sebastiano Alfio Torrisi

    2017-10-01

    Full Text Available Background: Several efforts have been made to develop effective antipsychotic drugs. Currently, available antipsychotics are effective on positive symptoms, less on negative symptoms, but not on cognitive impairment, a clinically relevant dimension of schizophrenia. Drug repurposing offers great advantages over the long-lasting, risky and expensive, de novo drug discovery strategy. To our knowledge, the possible antipsychotic properties of buspirone, an azapirone anxiolytic drug marketed in 1986 as serotonin 5-HT1A receptor (5-HT1AR partial agonist, have not been extensively investigated despite its intriguing pharmacodynamic profile, which includes dopamine D3 (D3R and D4 receptor (D4R antagonist activity. Multiple lines of evidence point to D3R as a valid therapeutic target for the treatment of several neuropsychiatric disorders including schizophrenia. In the present study, we tested the hypothesis that buspirone, behaving as dopamine D3R antagonist, may have antipsychotic-like activity.Materials and Methods: Effects of acute administration of buspirone was assessed on a wide-range of schizophrenia-relevant abnormalities induced by a single administration of the non-competitive NMDAR antagonist MK-801, in both wild-type mice (WT and D3R-null mutant mice (D3R-/-.Results: Buspirone (3 mg⋅kg-1, i.p. was devoid of cataleptogenic activity in itself, but resulted effective in counteracting disruption of prepulse inhibition (PPI, hyperlocomotion and deficit of temporal order recognition memory (TOR induced by MK-801 (0.1 mg⋅kg-1, i.p. in WT mice. Conversely, in D3R-/- mice, buspirone was ineffective in preventing MK-801-induced TOR deficit and it was only partially effective in blocking MK-801-stimulated hyperlocomotion.Conclusion: Taken together, these results indicate, for the first time, that buspirone, might be a potential therapeutic medication for the treatment of schizophrenia. In particular, buspirone, through its D3R antagonist activity

  8. Blockade of N-methyl-D-aspartate induced convulsions by 1-aminocyclopropanecarboxylates

    Energy Technology Data Exchange (ETDEWEB)

    Skolnick, P.; Marvizon, J.C.G.; Jackson, B.W.; Monn, J.A.; Rice, K.C. (National Institutes of Health, Bethesda, MD (USA)); Lewin, A.H. (Research Triangle Institute, Research Triangle Park, NC (USA))

    1989-01-01

    1-Aminocyclopropanecarboxylic acid is a potent and selective ligand for the glycine modulatory site on the N-methyl-D-aspartate receptor complex. This compound blocks the convulsions and deaths produced by N-methyl-D-aspartate in a dose dependent fashion. In contrast, 1-aminocyclopropanecarboxylic acid does not protect mice against convulsions induced by pentylenetetrazole, strychnine, bicuculline, or maximal electroshock, and does not impair motor performance on either a rotarod or horizontal wire at doses of up to 2 g/kg. The methyl- and ethyl- esters of 1-aminocyclopropanecarboxylic acid are 5- and 2.3-fold more potent, respectively, than the parent compound in blocking the convulsant and lethal effects of N-methyl-D-aspartate. However, these esters are several orders of magnitude less potent than 1-aminocyclopropanecarboxylic acid as inhibitors of strychnine-insensitive ({sup 3}H)glycine binding, indicating that conversion to the parent compound may be required to elicit an anticonvulsant action.

  9. Antigen-specific induced Foxp3+ regulatory T cells are generated following CD40/CD154 blockade

    Science.gov (United States)

    Ferrer, Ivana R.; Wagener, Maylene E.; Song, Minqing; Kirk, Allan D.; Larsen, Christian P.; Ford, Mandy L.

    2011-01-01

    Blockade of the CD40/CD154 pathway potently attenuates T-cell responses in models of autoimmunity, inflammation, and transplantation. Indeed, CD40 pathway blockade remains one of the most powerful methods of prolonging graft survival in models of transplantation. But despite this effectiveness, the cellular and molecular mechanisms underlying the protective effects of CD40 pathway blockade are incompletely understood. Furthermore, the relative contributions of deletion, anergy, and regulation have not been measured in a model in which donor-reactive CD4+ and CD8+ T-cell responses can be assessed simultaneously. To investigate the impact of CD40/CD154 pathway blockade on graft-specific T-cell responses, a transgenic mouse model was used in which recipients containing ovalbumin-specific CD4+ and CD8+ TCR transgenic T cells were grafted with skin expressing ovalbumin in the presence or absence of anti-CD154 and donor-specific transfusion. The results indicated that CD154 blockade altered the kinetics of donor-reactive CD8+ T-cell expansion, delaying differentiation into IFN-γ+ TNF+ multifunctional cytokine producers. The eventual differentiation of cytokine-producing effectors in tolerant animals coincided with the emergence of an antigen-specific CD4+ CD25hi Foxp3+ T-cell population, which did not arise from endogenous natural Treg but rather were peripherally generated from naïve Foxp3− precursors. PMID:22143783

  10. Chronic Renin-Angiotensin System (RAS) Blockade May Not Induce Hypotension During Anaesthesia for Bariatric Surgery.

    Science.gov (United States)

    Salvetti, Guido; Di Salvo, Claudio; Ceccarini, Giovanni; Abramo, Antonio; Fierabracci, Paola; Magno, Silvia; Piaggi, Paolo; Vitti, Paolo; Santini, Ferruccio

    2016-06-01

    The use of angiotensin-converting enzyme inhibitors (ACE-I) and angiotensin II receptor blockers (ARB) for the treatment of hypertensive obese patients is steadily increasing. Some studies have reported that the use of these drugs was associated with an increased risk of hypotensive episodes, during general anaesthesia. The number of bariatric procedures is also increasing worldwide, but there is a lack of studies investigating the hypotensive effect of renin-angiotensin system (RAS) blockers in severely obese patients during general anaesthesia for bariatric surgery. The aim of this pilot study was to evaluate hemodynamic changes induced by general anaesthesia in obese patients chronically treated with ACE-I or ARB compared to a control group not treated with antihypertensive therapy. Fourteen obese subjects (mean body mass index (BMI) 47.5 kg/m(2)) treated with ACE-I or ARB and twelve obese (mean BMI 45.7 kg/m2) controls not treated with antihypertensive therapy underwent general anaesthesia to perform laparoscopic bariatric surgery. Systolic blood pressure, diastolic blood pressure, and heart rate were monitored continuously and registered at different time points: T0 before induction, then at 2, 5, 7, 10, 15, 20, 30, 60, 90, 120, and 150 min after induction, and the last time point taken following recovery from anaesthesia. A progressive reduction of both systolic and diastolic blood pressure values was observed without significant differences between the two groups. A similar trend of heart rate values was observed. In conclusion, our pilot study suggests that RAS blockers may be continued during the perioperative period in patients undergoing bariatric surgery, without increasing the risk of hypotensive episodes.

  11. Pain trajectory and exercise-induced pain flares during 8 weeks of neuromuscular exercise in individuals with knee and hip pain

    DEFF Research Database (Denmark)

    Sandal, L F; Roos, E M; Bøgesvang, S J

    2016-01-01

    with acute exercise-induced pain flares in persons with knee or hip pain. DESIGN: Individuals above 35 years self-reporting persistent knee or hip pain for the past 3 months were offered 8 weeks of supervised NEMEX, performed in groups twice weekly. The program consisted of 11 exercises focusing on joint......OBJECTIVE: Patients considering or engaged in exercise as treatment may expect or experience transient increases in joint pain, causing fear of exercise and influencing compliance. This study investigated the pain trajectory during an 8-week neuromuscular exercise (NEMEX) program together...... stability and neuromuscular control. Participants self-reported joint pain on a 0-10 numerical rating scale (NRS) at baseline and 8-weeks follow-up. NRS pain ratings were also collected before and immediately after every attended exercise session. RESULTS: Joint pain was reduced from baseline (NRS 3.6; 95...

  12. Chronic central nervous system MC3/4R blockade attenuates hypertension induced by nitric oxide synthase inhibition but not by angiotensin II infusion.

    Science.gov (United States)

    da Silva, Alexandre A; do Carmo, Jussara M; Dubinion, John H; Bassi, Mirian; Mokhtarpouriani, Kasra; Hamza, Shereen M; Hall, John E

    2015-01-01

    We examined whether central melanocortin 3 and 4 receptor (MC3/4R) blockade attenuates the blood pressure (BP) responses to chronic L-NAME or angiotensin II (Ang II) infusion in Sprague-Dawley rats implanted with telemetry transmitters, venous catheters, and intracerebroventricular cannula into the lateral ventricle. After 5 days of control measurements, L-NAME (10 μg/kg/min IV, groups 1 and 2) or Ang II (10 ng/kg/min IV, groups 3 and 4) were infused for 24 days, and starting on day 7 of L-NAME or Ang II infusion, the MC3/4R antagonist SHU-9119 (24 nmol/d, n=6/group; groups 1 and 3) or vehicle (saline 0.5 μL/h, n=6/group; groups 2 and 4) was infused intracerebroventricularly for 10 days. A control normotensive group also received SHU-9119 for 10 days (n=5). L-NAME and Ang II increased BP by 40±3 and 56±5 mm Hg, respectively, although heart rate was slightly reduced. MC3/4R blockade doubled food intake and reduced heart rate (≈40 to ≈50 bpm) in all groups. MC3/4R blockade caused only a small reduction in BP in normotensive group (4 mm Hg) and no change in rats receiving Ang II, although markedly reducing BP by 21±4 mm Hg in L-NAME-treated rats. After SHU-9119 infusion was stopped, food intake, heart rate, and BP gradually returned to values observed before SHU-9119 infusion was started. Ganglionic blockade at the end of L-NAME or Ang II infusion caused similar BP reduction in both groups. These results suggest that the brain MC3/4R contributes, at least in part, to the hypertension induced by chronic L-NAME infusion but not by Ang II. © 2014 American Heart Association, Inc.

  13. CHRONIC CENTRAL NERVOUS SYSTEM MC3/4R BLOCKADE ATTENUATES HYPERTENSION INDUCED BY NITRIC OXIDE SYNTHASE INHIBITION BUT NOT BY ANGIOTENSIN II INFUSION

    Science.gov (United States)

    da Silva, Alexandre A.; do Carmo, Jussara M.; Dubinion, John H.; Bassi, Mirian; Mokhtarpouriani, Kasra; Hamza, Shereen M.; Hall, John E.

    2014-01-01

    We examined whether central melanocortin 3 and 4 receptor (MC3/4R) blockade attenuates the BP responses to chronic L-NAME or angiotensin II (Ang-II) infusion in Sprague Dawley rats implanted with telemetry transmitters, venous catheters and intracerebroventricular (ICV) cannula into the lateral ventricle. After 5 days of control measurements, L-NAME (10 μg/kg/day, i.v. – groups 1 and 2) or Ang II (10 ng/kg/min, i.v. – groups 3 and 4) were infused for 24 days and starting on day 7 of L-NAME or Ang II infusion the MC3/4R antagonist SHU-9119 (24 nmol/day, n=6/group – groups 1 and 3) or vehicle (saline 0.5 μl/hr, n=6/group – groups 2 and 4) was infused ICV for 10 days. A control normotensive group also received SHU-9119 for 10 days (n=5). L-NAME and Ang II increased BP by 40±3 and 56±5 mmHg, respectively; while heart rate (HR) was slightly reduced. MC3/4R blockade doubled food intake and reduced HR (~40 to ~50 bpm) in all groups. MC3/4R blockade caused only a small reduction in BP in normotensive group (4 mmHg) and no change in rats receiving Ang II, while markedly reducing BP by 21±4 mmHg in L-NAME treated rats. After SHU-9119 infusion was stopped, food intake, HR and BP gradually returned to values observed before SHU-9119 infusion was started. Ganglionic blockade performed at the end of L-NAME or Ang II infusion caused similar BP reduction in both groups. These results suggest that the brain MC3/4R contributes, at least in part, to the hypertension induced by chronic L-NAME infusion but not by Ang II. PMID:25287400

  14. Suppression of peripheral pain by blockade of Cav2.2 channels in nociceptors induces RANKL and impairs recovery from inflammatory arthritis

    Science.gov (United States)

    Baddack, Uta; Frahm, Silke; Antolin-Fontes, Beatriz; Grobe, Jenny; Lipp, Martin; Müller, Gerd; Ibañez-Tallon, Ines

    2015-01-01

    Objective A hallmark of rheumatoid arthritis (RA) is the chronic pain that accompanies the inflammation and joint deformation. Patients with RA rate pain relief with highest priority, however, few studies have addressed the efficacy and safety of therapies directed specifically towards pain pathways. The conotoxin MVIIA (Prialt/Ziconotide) is used in humans to alleviate persistent pain syndromes because it specifically blocks the CaV2.2 voltage-gated calcium channel, which mediates the release of neurotransmitters and proinflammatory mediators from peripheral nociceptor nerve terminals. The purpose of this study was to investigate whether block of CaV2.2 can suppress arthritic pain, and to examine the progression of induced arthritis during persistent CaV2.2 blockade. Methods Transgenic mice (Tg-MVIIA) expressing a membrane-tethered form of the ω-conotoxin MVIIA, under the control of a nociceptor-specific gene, were employed. These mice were subjected to unilateral induction of joint inflammation using the Antigen- and Collagen-Induced Arthritis (ACIA) model. Results We observed that CaV2.2-blockade mediated by t-MVIIA effectively suppressed arthritis-induced pain; however, in contrast to their wild-type littermates, which ultimately regained use of their injured joint as inflammation subsides, Tg-MVIIA mice showed continued inflammation with an up-regulation of the osteoclast activator RANKL and concomitant joint and bone destruction. Conclusion Altogether, our results indicate that alleviation of peripheral pain by blockade of CaV2.2- mediated calcium influx and signaling in nociceptor sensory neurons, impairs recovery from induced arthritis and point to the potentially devastating effects of using CaV2.2 channel blockers as analgesics during inflammation. PMID:25733371

  15. Blockade of patch-based μ opioid receptors in the striatum attenuates methamphetamine-induced conditioned place preference and reduces activation of the patch compartment.

    Science.gov (United States)

    Horner, Kristen A; Logan, Mary Caroline; Fisher, Trevor J; Logue, Jordan B

    2017-02-05

    The behavioral effects of methamphetamine (METH) are mediated by the striatum, which is divided into the patch compartment, which mediates limbic and reward functions, and the matrix compartment, which mediates sensorimotor tasks. METH treatment results in repetitive behavior that is related to enhanced relative activation of the patch versus the matrix compartment. The patch, but not the matrix compartment contains a high density of μ opioid receptors, and localized blockade of patch-based μ opioid receptors attenuates METH-induced patch-enhanced activity and repetitive behaviors. Numerous studies have examined patch-enhanced activity and the contribution of patch-associated μ opioid receptors to METH-induced repetitive behavior, but it is not known whether patch-enhanced activity occurs during METH-mediated reward, nor is it known if patch-based μ opioid receptors contribute to METH reward. The goals of this study were to determine if blockade of patch-based μ opioid receptors alters METH-induced conditioned place preference (CPP), as well activation of the patch and matrix compartments following METH-mediated CPP. A biased conditioning paradigm was used to assess CPP, and conditioning occurred over an 8-d period. Animals were bilaterally infused in the striatum with the μ-specific antagonist CTAP or vehicle prior to conditioning. Animals were tested for preference 24h after the last day of conditioning, sacrificed and the brains processed for immunohistochemistry. Blockade of patch-based μ opioid receptors reduced METH-induced CPP, and reduced patch-enhanced c-Fos expression in the striatum following METH-mediated CPP. These data indicate that patch-enhanced activity is associated with METH-mediated reward and patch-based μ opioid receptors contribute to this phenomenon. Copyright © 2017 Elsevier B.V. All rights reserved.

  16. Relevance of dorsal raphe nucleus firing in serotonin 5-HT2C receptor blockade-induced augmentation of SSRIs effects

    NARCIS (Netherlands)

    Sotty, Florence; Folgering, Joost H. A.; Brennum, Lise T.; Hogg, Sandra; Mork, Arne; Hertel, Peter; Cremers, Thomas I. F. H.

    Selective serotonin reuptake inhibitors are the most widely prescribed antidepressant drugs. However, they exhibit a slow onset of action, putatively due to the initial decrease in serotonin cell firing mediated via somato-dendritic autoreceptors. Interestingly, blockade of 5-HT2C receptors

  17. Antibiotic-induced immediate type hypersensitivity is a risk factor for positive allergy skin tests for neuromuscular blocking agents.

    Science.gov (United States)

    Hagau, Natalia; Gherman, Nadia; Cocis, Mihaela; Petrisor, Cristina

    2016-01-01

    Skin tests for neuromuscular blocking agents (NMBAs) are not currently recommended for the general population undergoing general anaesthesia. In a previous study we have reported a high incidence of positive allergy tests for NMBAs in patients with a positive history of non-anaesthetic drug allergy, a larger prospective study being needed to confirm those preliminary results. The objective of this study was to compare the skin tests results for patients with a positive history of antibiotic-induced immediate type hypersensitivity reactions to those of controls without drug allergies. Ninety eight patients with previous antibiotic hypersensitivity and 72 controls were prospectively included. Skin tests were performed for atracurium, pancuronium, rocuronium, and suxamethonium. We found 65 positive skin tests from the 392 tests performed in patients with a positive history of antibiotic hypersensitivity (1 6.58%) and 23 positive skin tests from the 288 performed in controls (7.98%), the two incidences showing significant statistical difference (p = 0.0011). The relative risk for having a positive skin test for NMBAs for patients versus controls was 1.77 (1.15-2.76). For atracurium, skin tests were more often positive in patients with a positive history of antibiotic hypersensitivity versus controls (p = 0.02). For pancuronium, rocuronium and suxamethonium the statistical difference was not attained (p-values 0.08 for pancuronium, 0.23 for rocuronium, and 0.26 for suxamethonium). Patients with a positive history of antibiotic hypersensitivity seem to have a higher incidence of positive skin tests for NMBAs. They might represent a group at higher risk for developing intraoperative anaphylaxis compared to the general population. Copyright © 2015 The Authors. Production and hosting by Elsevier B.V. All rights reserved.

  18. Influência do sevoflurano e do isoflurano na recuperação do bloqueio neuromuscular produzido pelo cisatracúrio Influencia del sevoflurano y del isoflurano en la recuperación del bloqueo neuromuscular producido por el cisatracúrio The influence of sevoflurane and isoflurane on the recovery from cisatracurium-induced neuromuscular block

    Directory of Open Access Journals (Sweden)

    Angélica de Fátima de Assunção Braga

    2002-09-01

    índice de recuperación (T1(25-75% fueron respectivamente: Grupo I (66,2 ± 13,42 min y 23,6 ± 5,02 min, Grupo II (54,4 ± 6,58 min y 14,9 ± 3,82 min y Grupo III (47,2 ± 7,43 y 16,2 ± 2,93. En relación a la duración clínica hubo diferencia significante entre los grupos I y II, I y III, y II y III. Para el índice de recuperación hubo diferencia significante entre el grupo I y los demás grupos. CONCLUSIONES: La recuperación del bloqueo neuromuscular producido por el cisatracúrio fue más lenta durante la anestesia con los agentes volátiles de que con el propofol, siendo el efecto más pronunciado con el sevoflurano.BACKGROUND AND OBJECTIVES: The effects of neuromuscular blockers on the neuromuscular junction are potentiated by volatile anesthetics. This study aimed at evaluating the influence of sevoflurane and isoflurane on the recovery of cisatracurium- induced neuromuscular block. METHODS: Ninety ASA I and II patients undergoing elective surgeries under general anesthesia were included in this study. Patients were allocated in three groups: Group I (sevoflurane, Group II (isoflurane and Group III (propofol. All patients were premedicated with intramuscular midazolam (0.1 mg.kg-1 30 min before surgery. Anesthesia was induced with alfentanil (50 µg.kg-1, propofol (2.5 mg.kg-1 and cisatracurium (0.15 mg.kg-1. Patients were then ventilated under mask with 100% O2 until disappearance of all TOF responses when laryngoscopy and tracheal intubation were performed. Volatile agents for anesthetic maintenance were introduced immediately after tracheal intubation in 2% and 1% concentrations, respectively, for sevoflurane and isoflurane, as well as the propofol continuous infusion (7 to 10 mg.kg-1.h-1 for Group III. All patients received a 50% mixture of O2 and N2O. Neuromuscular function was monitored by adductor pollicis muscle acceleromyography with TOF stimulation at 15-second intervals. Clinical duration of neuromuscular block (T1(25% and recovery index (RI

  19. [Deep versus moderate neuromuscular block during one-lung ventilation in lung resection surgery].

    Science.gov (United States)

    Casanova, Javier; Piñeiro, Patricia; De La Gala, Francisco; Olmedilla, Luis; Cruz, Patricia; Duque, Patricia; Garutti, Ignacio

    Neuromuscular relaxants are essential during general anesthesia for several procedures. Classical anesthesiology literature indicates that the use of neuromuscular blockade in thoracic surgery may be deleterious in patients in lateral decubitus position in one-lung ventilation. The primary objective of our study was to compare respiratory function according to the degree of patient neuromuscular relaxation. Secondary, we wanted to check that neuromuscular blockade during one-lung ventilation is not deleterious. A prospective, longitudinal observational study was made in which each patient served as both treated subject and control. 76 consecutive patients programmed for lung resection surgery in Gregorio Marañon Hospital along the year of 2013 who required one-lung ventilation in lateral decubitus were included. Ventilator data, hemodynamic parameters were registered in different moments according to train-of-four response (intense, deep and moderate blockade) during one-lung ventilation. Peak, plateau and mean pressures were significantly lower during the intense and deep blockade. Besides, compliance and peripheral oxygen saturation were significantly higher in those moments. Heart rate was significantly higher during deep blockade. No mechanical ventilation parameters were modified during measurements. Deep neuromuscular blockade attenuates the poor lung mechanics observed during one-lung ventilation. Copyright © 2016 Sociedade Brasileira de Anestesiologia. Publicado por Elsevier Editora Ltda. All rights reserved.

  20. Blockade of adenosine A2A receptors prevents interleukin-1β-induced exacerbation of neuronal toxicity through a p38 mitogen-activated protein kinase pathway

    Directory of Open Access Journals (Sweden)

    Simões Ana

    2012-08-01

    Full Text Available Abstract Background and purpose Blockade of adenosine A2A receptors (A2AR affords robust neuroprotection in a number of brain conditions, although the mechanisms are still unknown. A likely candidate mechanism for this neuroprotection is the control of neuroinflammation, which contributes to the amplification of neurodegeneration, mainly through the abnormal release of pro-inflammatory cytokines such as interleukin(IL-1β. We investigated whether A2AR controls the signaling of IL-1β and its deleterious effects in cultured hippocampal neurons. Methods Hippocampal neuronal cultures were treated with IL-1β and/or glutamate in the presence or absence of the selective A2AR antagonist, SCH58261 (50 nmol/l. The effect of SCH58261 on the IL-1β-induced phosphorylation of the mitogen-activated protein kinases (MAPKs c-Jun N-terminal kinase (JNK and p38 was evaluated by western blotting and immunocytochemistry. The effect of SCH58261 on glutamate-induced neurodegeneration in the presence or absence of IL-1β was evaluated by nucleic acid and by propidium iodide staining, and by lactate dehydrogenase assay. Finally, the effect of A2AR blockade on glutamate-induced intracellular calcium, in the presence or absence of IL-1β, was studied using single-cell calcium imaging. Results IL-1β (10 to 100 ng/ml enhanced both JNK and p38 phosphorylation, and these effects were prevented by the IL-1 type 1 receptor antagonist IL-1Ra (5 μg/ml, in accordance with the neuronal localization of IL-1 type 1 receptors, including pre-synaptically and post-synaptically. At 100 ng/ml, IL-1β failed to affect neuronal viability but exacerbated the neurotoxicity induced by treatment with 100 μmol/l glutamate for 25 minutes (evaluated after 24 hours. It is likely that this resulted from the ability of IL-1β to enhance glutamate-induced calcium entry and late calcium deregulation, both of which were unaffected by IL-1β alone. The selective A2AR antagonist, SCH58261 (50 nmol

  1. Hyperfine-induced valley mixing and the spin-valley blockade in carbon-based quantum dots

    Energy Technology Data Exchange (ETDEWEB)

    Palyi, Andras; Burkard, Guido [Department of Physics, University Konstanz (Germany)

    2010-07-01

    Hyperfine interaction (HFI) in carbon nanotube and graphene quantum dots is due to the presence of {sup 13}C atoms. We theoretically show that in these structures the short-range nature of the HFI gives rise to a coupling between the valley degree of freedom of the electron and the nuclear spin, in addition to the usual electron spin-nuclear spin coupling. We predict that this property of the HFI affects the Pauli blockade transport in carbon-based double quantum dots. In particular, we show that transport is blocked only if both the spin and the valley degeneracies of the quantum dot levels are lifted, e.g., by an appropriately oriented magnetic field. The blockade is caused by four ''supertriplet'' states in the (1,1) charge configuration.

  2. Pain trajectory and exercise-induced pain flares during 8 weeks of neuromuscular exercise in individuals with knee and hip pain.

    Science.gov (United States)

    Sandal, L F; Roos, E M; Bøgesvang, S J; Thorlund, J B

    2016-04-01

    Patients considering or engaged in exercise as treatment may expect or experience transient increases in joint pain, causing fear of exercise and influencing compliance. This study investigated the pain trajectory during an 8-week neuromuscular exercise (NEMEX) program together with acute exercise-induced pain flares in persons with knee or hip pain. Individuals above 35 years self-reporting persistent knee or hip pain for the past 3 months were offered 8 weeks of supervised NEMEX, performed in groups twice weekly. The program consisted of 11 exercises focusing on joint stability and neuromuscular control. Participants self-reported joint pain on a 0-10 numerical rating scale (NRS) at baseline and 8-weeks follow-up. NRS pain ratings were also collected before and immediately after every attended exercise session. Joint pain was reduced from baseline (NRS 3.6; 95% CI 3.2-4.1) to 8-weeks follow-up (2.6; 95% CI 2.1-3.1), (P Pain decreased 0.04 NRS (95% CI 0.02-0.05, P pain decreased 0.04 NRS (95% CI 0.03-0.05, P induced pain in the last weeks. This study found a clear decrease in size of acute exercise-induced pain flares with increasing number of exercise sessions. In parallel, pain ratings decreased over the 8 weeks exercise period. Our findings provide helpful information for clinicians, which can be used to educate and balance patient expectation when starting supervised neuromuscular exercise. Copyright © 2015 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.

  3. Transforming growth factor-beta1 signaling blockade attenuates gastric cancer cell-induced peritoneal mesothelial cell fibrosis and alleviates peritoneal dissemination both in vitro and in vivo.

    Science.gov (United States)

    Miao, Zhi-Feng; Zhao, Ting-Ting; Wang, Zhen-Ning; Miao, Feng; Xu, Ying-Ying; Mao, Xiao-Yun; Gao, Jian; Wu, Jian-Hua; Liu, Xing-Yu; You, Yi; Xu, Hao; Xu, Hui-Mian

    2014-04-01

    Peritoneal dissemination is the most frequent metastatic pattern of advanced gastric cancer and the main cause of death in gastric cancer patients. Transforming growth factor-beta1 (TGF- ß1), one of the most potent fibrotic stimuli for human peritoneal mesothelial cells, has been shown to play an important role in this process. In this study, we investigated the effect of TGF- ß1 signaling blockade in gastric cancer cell (GCC)-induced human peritoneal mesothelial cell (HPMC) fibrosis. HPMCs were cocultured with the high TGF- ß1 expressing GCC line SGC-7901 and various TGF- ß1 signaling inhibitors or SGC-7901 transfected with TGF-ß1-specific siRNA. HPMC fibrosis was monitored on the basis of morphology. Expression of the epithelial cell marker, E-cadherin, and the mesenchymal marker, α-smooth muscle actin (α-SMA), was evaluated by Western blotting and immunofluorescence confocal imaging. GCC adhesion to HPMC was also assayed. In nude mouse tumor model, the peritoneal fibrotic status was monitored by immunofluorescent confocal imaging and Masson's trichrome staining; formation of metastatic nodular and ascites fluid was also evaluated. Our study demonstrated that GCC expressing high levels of TGF-ß1 induced HMPC fibrosis, which is characterized by both upregulation of E-cadherin and downregulation of α-SMA. Furthermore, HPMC monolayers fibrosis was reversed by TGF- ß1 signaling blockade. In vivo, the TGF- ß1 receptor inhibitor SB-431542 partially attenuated early-stage gastric cancer peritoneal dissemination (GCPD). In conclusion, our study confirms the significance of TGFß1 signaling blockade in attenuating GCPD and may provide a therapeutic target for clinical therapy.

  4. Edrophonium antagonism of intense mivacurium-induced neuromuscular block in children.

    Science.gov (United States)

    Abdulatif, M; Al-Ghamdi, A; Al-Sanabary, M; Abdel-Gaffar, M E

    1996-02-01

    .0), 4.8 (2.1) and 5.7 (1.4) min respectively). Ten minutes after development of maximum block, the numbers of patients who recovered adequately (TOF ratio 70% or more) were, respectively, 12 (80%), 8 (53%) and 1 (8%) in groups 1-3. We conclude that edrophonium antagonized intense (no response to TOF stimulation) mivacurium-induced block in children, with significant reduction in the recovery times of T1 and TOF ratio compared with conventional reversal and spontaneous recovery.

  5. Combined blockade of AMPA and NMDA receptors in the brain of rats prevents pentylenetetrazole-induced clonic and tonic-clonic seizures without ataxia.

    Science.gov (United States)

    Gmiro, V E; Serdyuk, S E

    2008-06-01

    Intramuscular injection of selective NMDA receptor antagonists memantine and arcaine 4-fold decreased the incidence of pentylenetetrazole-induced generalized tonic-clonic seizures in rats, while the incidence of clonic seizures decreased by 1.2-1.3 times. Memantine and arcaine are characterized by low therapeutic index, i.e. induced ataxia in rats in doses exceeding the effective anticonvulsant dose by only 3.5-10 times. Intramuscular injection of IEM-1913 (combined blockade of NMDA and AMPA receptors in the brain) decreased the incidence of pentylenetetrazole-induced clonic and tonic-clonic seizures in rats by 4-8 times. The therapeutic index of IEM-1913 surpassed that of memantine and arcaine by 200-600 times.

  6. Rapid synthesis of acetylcholine receptors at neuromuscular junctions.

    Science.gov (United States)

    Ramsay, D A; Drachman, D B; Pestronk, A

    1988-10-11

    The rate of acetylcholine receptor (AChR) degradation in mature, innervated mammalian neuromuscular junctions has recently been shown to be biphasic; up to 20% are rapidly turned over (RTOs; half life less than 1 day) whereas the remainder are lost more slowly ('stable' AChRs; half life 10-12 days). In order to maintain normal junctional receptor density, synthesis and insertion of AChRs should presumably be sufficiently rapid to replace both the RTOs and the stable receptors. We have tested this prediction by blocking pre-existing AChRs in the mouse sternomastoid muscle with alpha-bungarotoxin (alpha-BuTx), and monitoring the subsequent appearance of 'new' junctional AChRs at intervals of 3 h to 20 days by labeling them with 125I-alpha-BuTx. The results show that new receptors were initially inserted rapidly (16% at 24 h and 28% at 48 h). The rate of increase of 'new' 125I-alpha-BuTx binding sites gradually slowed down during the remainder of the time period studied. Control observations excluded possible artifacts of the experimental procedure including incomplete blockade of AChRs, dissociation of toxin-receptor complexes, or experimentally induced alteration of receptor synthesis. The present demonstration of rapid synthesis and incorporation of AChRs at innervated neuromuscular junctions provides support for the concept of a subpopulation of rapidly turned over AChRs. The RTOs may serve as precursors for the larger population of stable receptors and have an important role in the metabolism of the neuromuscular synapse.

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

    Science.gov (United States)

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

    2009-12-11

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

  8. Action of Micrurus dumerilii carinicauda coral snake venom on the mammalian neuromuscular junction.

    Science.gov (United States)

    Serafim, Francine G; Reali, Marielga; Cruz-Höfling, Maria Alice; Fontana, Marcos D

    2002-02-01

    The venoms of coral snakes (mainly Micrurus species) have pre- and/or postsynaptic actions, but only a few of these have been studied in detail. We have investigated the effects of Micrurus dumerilii carinicauda coral snake venom on neurotransmission in rat isolated phrenic nerve-diaphragm muscle and chick biventer cervicis preparations stimulated directly or indirectly. M. d. carinicauda venom (5 or 10 microg/ml) produced neuromuscular blockade in rat (85-90% in 291.8+/-7.3 min and 108.3+/-13.8, respectively; n=5) and avian (95.0+/-2.0 min; 5 microg/ml, n=5) preparations. Neostigmine (5.8 microM) and 3,4-diaminopyridine (230 microM) partially reversed the venom-induced neuromuscular blockade in rat nerve-muscle preparations. In neither preparation did the venom depress the twitch response elicited by direct muscle stimulation. The contractures induced by acetylcholine in chick preparations were inhibited by the venom (95-100%; n=4; p<0.05). In rat preparations, the venom produced a progressive decrease in the amplitude of miniature end-plate potentials (m.e.p.ps control frequency=69.3+/-5.0/min and control amplitude=0.4+/-0.2 mV) until these were abolished. Neostigmine (5.8 microM) and 3,4-diaminopyridine (230 microM) partially antagonized this blockade of m.e.p.ps. The resting membrane potential was not altered with the venom (10 microg/ml). M. d. carinicauda venom produced dose-dependent morphological changes in indirectly stimulated mammal preparations. Twenty-five per cent of muscle fibers were affected by a venom concentration of 5 microg/ml, whilst 60.7% were damaged by 10 microg of venom/ml. In biventer cervicis preparations, the morphological changes were slower in onset and were generally characterized by undulating fibers and, to a lesser extent, by zones of disintegrating myofibrils. A venom concentration of 5 microg/ml damaged 52.2% of the fibers. These findings indicate that M. d. carinicauda venom has neurotoxic and myotoxic effects and that the

  9. Efeito da administração do atracúrio sobre a recuperação do bloqueio neuromuscular induzido pelo pancurônio Efecto de la administración del atracúrio sobre la recuperación del bloqueo neuromuscular inducido por el pancuronio Effect of atracurium on pancuronium-induced neuromuscular block recovery

    Directory of Open Access Journals (Sweden)

    Luís Fernando Rodrigues Maria

    2004-06-01

    complementación con atracúrio no promovió alteración en la recuperación espontanea inicial del bloqueo neuromuscular inducido por el pancuronio y promovió diminución de 20% en el tiempo de recuperación total.BACKGROUND AND OBJECTIVES: Additional neuromuscular blocker doses are in general needed during wall closing after abdominal surgeries. This study aimed at determining during partial pancuronium-induced neuromuscular block recovery, the effect of additional atracurium dose on spontaneous neuromuscular block recovery. METHODS: Participated in this study 30 patients divided in two groups: pancuronium group (n = 14 and atracurium group (n = 16. Neuromuscular function was continuously monitored by accelerometry of abductor pollicis muscle using TOF to supramaximally stimulate ulnar nerve. Anesthesia was induced with propofol, fentanyl and 0.08 mg.kg-1 pancuronium, and was maintained with 60% N2O in oxygen and 0.5% isoflurane expired concentration. When T1 returned to 25% of control, 0.025 mg.kg-1 pancuronium or 0.20 mg.kg-1 atracurium were administered to pancuronium or atracurium group, respectively. Time for spontaneous T1 recovery = 10%, 25%, 75% of recovery index (RI 25-75% and time to T4/T1 equal 0.8 after complementary dose, were recorded. RESULTS: There were no differences between groups on T1 spontaneous recovery to 10% (45.00 ± 15.50 vs. 49.69 ± 9.41, 25% (61.64 ± 18.58 vs. 64.25 ± 12.51 and 75% (94.00 ± 28.52 vs. 84.69 ± 16.50. Recovery index (RI 25-75% and time to T4/T1= 0.8 were shorter in the atracurium group. CONCLUSIONS: In this study, atracurium complementation has made no difference in initial spontaneous recovery of pancuronium-induced neuromuscular block, but has decreased total recovery time in 20%.

  10. Angiotensin II AT1 receptor blockade decreases vasopressin-induced water reabsorption and AQP2 levels in NaCl-restricted rats

    DEFF Research Database (Denmark)

    Kwon, Tae-Hwan; Nielsen, Jakob; Knepper, M.A.

    2005-01-01

    Vasopressin and ANG II, which are known to play a major role in renal water and sodium reabsorption, are mainly coupled to the cAMP/PKA and phosphoinositide pathways, respectively. There is evidence for cross talk between these intracellular signaling pathways. We therefore hypothesized...... that vasopressin-induced water reabsorption could be attenuated by ANG II AT1 receptor blockade in rats. To address this, three protocols were used: 1) DDAVP treatment (20 ng/h sc for 7 days, n = 8); 2) DDAVP (20 ng/h sc for 7 days) and candesartan (1 mg·kg−1·day−1 sc for 7 days) cotreatment (n = 8); and 3...... receptor blockade in DDAVP-treated rats was associated with decreased urine concentration and decreased AQP2 and AQP1 expression. Moreover, FENa was increased in parallel with decreased expression of NHE3, NCC, and Na-K-ATPase. These results suggest that ANG II AT1 receptor activation plays a significant...

  11. Blockade of MEK and MDM2 synergistically induces apoptosis in acute myeloid leukemia via BH3-only proteins Puma and Bim

    Science.gov (United States)

    Zhang, Weiguo; Konopleva, Marina; Burks, Jared K.; Dywer, Karen C.; Schober, Wendy D.; Yang, Jer-Yen; McQueen, Teresa J.; Hung, Mien-Chie; Andreeff, Michael

    2010-01-01

    Molecular aberrations of the Ras/Raf/MEK/ERK and/or MDM2/p53 signaling pathways have been reported in 80% and 50% of primary AML samples and confer poor outcome. In this study, anti-leukemic effects of combined MEK inhibition by AZD6244 and non-genotoxic p53 activation by MDM2 antagonist Nutlin3a were investigated. Simultaneous blockade of MEK and MDM2 signaling by AZD6244 and Nutlin3a triggered synergistic proapoptotic responses in AML cell lines (CI = 0.06 ± 0.03 and 0.43 ± 0.03 in OCI/AML3 and MOLM13 cells, respectively) and in primary AML cells (CI = 0.52 ± 0.01). Mechanistically, the combination upregulated levels of BH3-only proteins Puma and Bim, in part via transcriptional up-regulation of the FOXO3a transcription factor. Suppression of Puma and Bim by short interfering RNA rescued OCI/AML3 cells from AZD/Nutlin-induced apoptosis. These results strongly indicate therapeutic potential of combined MEK/MDM2 blockade in AML and implicate Puma and Bim as major regulators of AML cell survival. PMID:20215498

  12. A prophylactic effect of proprioceptive neuromuscular facilitation (PNF) stretching on symptoms of muscle damage induced by eccentric exercise of the wrist extensors.

    Science.gov (United States)

    Khamwong, Peanchai; Pirunsan, Ubon; Paungmali, Aatit

    2011-10-01

    Stretching with proprioceptive neuromuscular facilitation (PNF) is frequently used before exercise. The prophylactic effect of PNF on symptoms of muscle damage induced by eccentric exercise of the wrist extensors was examined in this study. Twenty-eight healthy males were randomly divided into the PNF group (n = 14) and the control group (n = 14). PNF was used before eccentric exercise induction in the wrist extensors. All subjects were tested to examine muscle damage characteristics including sensory-motor functions at baseline, immediately, and from 1st to 8th days after the exercise-induced muscle damage (EIMD). The results demonstrated that the PNF group showed a lesser deficit in some sensory-motor functions (p PNF stretching application could be useful for attenuating the signs and symptoms of muscle damage after eccentric exercise. Copyright © 2010 Elsevier Ltd. All rights reserved.

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

    Science.gov (United States)

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

    2009-07-01

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

  14. Acute fatigue-induced changes in muscle mechanical properties and neuromuscular activity in elite handball players following a handball match

    DEFF Research Database (Denmark)

    Thorlund, Jonas Bloch; Michalsik, L B; Madsen, Klavs

    2008-01-01

    [maximal voluntary contraction (MVC)] and rate of force development (RFD) with synchronous electromyography (EMG) recording, while maximal vertical jump parameters were assessed using force plate analysis. Quadriceps and hamstrings MVC and RFD decreased significantly post-match (approximately 10%, P ...The purpose of the present study was to determine the acute fatigue development in muscle mechanical properties and neuromuscular activity in response to handball match play. Male elite handball players (n = 10) were tested before and after a simulated handball match for maximal isometric strength...... hamstring MVC, MAV was reduced in BF (31%, P Post-match maximal jump height was reduced (5.2%, P

  15. Pharmacological blockade of either, cannabinoid CB1 or CB2 receptors, prevents both cocaine-induced conditioned locomotion and cocaine-induced reduction of cell proliferation in the hippocampus of adult male rats.

    Directory of Open Access Journals (Sweden)

    EDUARDO eBLANCO-CALVO

    2014-01-01

    Full Text Available Addiction to major drugs of abuse such as cocaine has been recently linked to alterations on adult neurogenesis in the hippocampus. The endogenous cannabinoid system modulated this proliferative response since pharmacological activation/blockade of cannabinoid CB1 and CB2 receptors by modulating not only neurogenesis but also cell death in the brain. In the present study, we evaluated whether the endogenous cannabinoid system affects cocaine-induced alterations in cell proliferation . To this end we examined if pharmacological blockade of either CB1 (Rimonabant, 3 mg/kg or CB2 receptors (AM630, 3 mg/kg affects cell proliferation (labeled with BrdU, found in the subventricular zone (SVZ of the lateral ventricles and the dentate subgranular zone (SGZ. In addition, we measured cell apoptosis (monitored by the expression of cleaved caspase-3 and glial activation ( by analizing the expression of GFAP and Iba-1 in the striatum and hippocampus, during acute or repeated (4 days cocaine administration (20 mg/kg. Results showed that acute cocaine decreased the number of BrdU+ cells in SVZ and SGZ. In contrast, repeated cocaine reduced the number of BrdU+ cells in SVZ only. Both acute and repeated cocaine increased the number of cleaved caspase-3+, GFAP+ and Iba1+ cells in the hippocampus, an effect counteracted by AM630 or Rimonabant that increased the number of BrdU+, GFAP+ and Iba1+ cells in the hippocampus. These results indicate that changes on neurogenic, apoptotic and gliosis processes, which were produced as a consequence of repeated cocaine administration, were normalized by the pharmacological blockade of CB1 and CB2. The restoring effects of cannabinoid receptor blockade on hippocampal cell proliferation were associated with a prevention of the induction of conditioned locomotion, but not of cocaine-induced sensitization.

  16. KCC3 loss-of-function contributes to Andermann syndrome by inducing activity-dependent neuromuscular junction defects.

    Science.gov (United States)

    Bowerman, Melissa; Salsac, Céline; Bernard, Véronique; Soulard, Claire; Dionne, Annie; Coque, Emmanuelle; Benlefki, Salim; Hince, Pascale; Dion, Patrick A; Butler-Browne, Gillian; Camu, William; Bouchard, Jean-Pierre; Delpire, Eric; Rouleau, Guy A; Raoul, Cédric; Scamps, Frédérique

    2017-10-01

    Loss-of-function mutations in the potassium-chloride cotransporter KCC3 lead to Andermann syndrome, a severe sensorimotor neuropathy characterized by areflexia, amyotrophy and locomotor abnormalities. The molecular events responsible for axonal loss remain poorly understood. Here, we establish that global or neuron-specific KCC3 loss-of-function in mice leads to early neuromuscular junction (NMJ) abnormalities and muscular atrophy that are consistent with the pre-synaptic neurotransmission defects observed in patients. KCC3 depletion does not modify chloride handling, but promotes an abnormal electrical activity among primary motoneurons and mislocalization of Na+/K+-ATPase α1 in spinal cord motoneurons. Moreover, the activity-targeting drug carbamazepine restores Na+/K+-ATPase α1 localization and reduces NMJ denervation in Slc12a6-/- mice. We here propose that abnormal motoneuron electrical activity contributes to the peripheral neuropathy observed in Andermann syndrome. Copyright © 2017 Elsevier Inc. All rights reserved.

  17. CB1 blockade potentiates down-regulation of lipogenic gene expression in perirenal adipose tissue in high carbohydrate diet-induced obesity.

    Science.gov (United States)

    Vida, Margarita; Rivera, Patricia; Gavito, Ana Luisa; Suárez, Juan; Pavón, Francisco Javier; Arrabal, Sergio; Romero-Cuevas, Miguel; Bautista, Dolores; Martínez, Ana; de Fonseca, Fernando Rodríguez; Serrano, Antonia; Baixeras, Elena

    2014-01-01

    De novo lipogenesis and hypercaloric diets are thought to contribute to increased fat mass, particularly in abdominal fat depots. CB1 is highly expressed in adipose tissue, and CB1-mediated signalling is associated with stimulation of lipogenesis and diet-induced obesity, though its contribution to increasing fat deposition in adipose tissue is controversial. Lipogenesis is regulated by transcription factors such as liver X receptor (LXR), sterol-response element binding protein (SREBP) and carbohydrate-responsive-element-binding protein (ChREBP). We evaluated the role of CB1 in the gene expression of these factors and their target genes in relation to lipogenesis in the perirenal adipose tissue (PrAT) of rats fed a high-carbohydrate diet (HCHD) or a high-fat diet (HFD). Both obesity models showed an up-regulated gene expression of CB1 and Lxrα in this adipose pad. The Srebf-1 and ChREBP gene expressions were down-regulated in HFD but not in HCHD. The expression of their target genes encoding for lipogenic enzymes showed a decrease in diet-induced obesity and was particularly dramatic in HFD. In HCHD, CB1 blockade by AM251 reduced the Srebf-1 and ChREBP expression and totally abrogated the remnant gene expression of their target lipogenic enzymes. The phosphorylated form of the extracellular signal-regulated kinase (ERK-p), which participates in the CB1-mediated signalling pathway, was markedly present in the PrAT of obese rats. ERK-p was drastically repressed by AM251 indicating that CB1 is actually functional in PrAT of obese animals, though its activation loses the ability to stimulate lipogenesis in PrAT of obese rats. Even so, the remnant expression levels of lipogenic transcription factors found in HCHD-fed rats are still dependent on CB1 activity. Hence, in HCHD-induced obesity, CB1 blockade may help to further potentiate the reduction of lipogenesis in PrAT by means of inducing down-regulation of the ChREBP and Srebf-1 gene expression, and consequently in

  18. CB1 blockade potentiates down-regulation of lipogenic gene expression in perirenal adipose tissue in high carbohydrate diet-induced obesity.

    Directory of Open Access Journals (Sweden)

    Margarita Vida

    Full Text Available De novo lipogenesis and hypercaloric diets are thought to contribute to increased fat mass, particularly in abdominal fat depots. CB1 is highly expressed in adipose tissue, and CB1-mediated signalling is associated with stimulation of lipogenesis and diet-induced obesity, though its contribution to increasing fat deposition in adipose tissue is controversial. Lipogenesis is regulated by transcription factors such as liver X receptor (LXR, sterol-response element binding protein (SREBP and carbohydrate-responsive-element-binding protein (ChREBP. We evaluated the role of CB1 in the gene expression of these factors and their target genes in relation to lipogenesis in the perirenal adipose tissue (PrAT of rats fed a high-carbohydrate diet (HCHD or a high-fat diet (HFD. Both obesity models showed an up-regulated gene expression of CB1 and Lxrα in this adipose pad. The Srebf-1 and ChREBP gene expressions were down-regulated in HFD but not in HCHD. The expression of their target genes encoding for lipogenic enzymes showed a decrease in diet-induced obesity and was particularly dramatic in HFD. In HCHD, CB1 blockade by AM251 reduced the Srebf-1 and ChREBP expression and totally abrogated the remnant gene expression of their target lipogenic enzymes. The phosphorylated form of the extracellular signal-regulated kinase (ERK-p, which participates in the CB1-mediated signalling pathway, was markedly present in the PrAT of obese rats. ERK-p was drastically repressed by AM251 indicating that CB1 is actually functional in PrAT of obese animals, though its activation loses the ability to stimulate lipogenesis in PrAT of obese rats. Even so, the remnant expression levels of lipogenic transcription factors found in HCHD-fed rats are still dependent on CB1 activity. Hence, in HCHD-induced obesity, CB1 blockade may help to further potentiate the reduction of lipogenesis in PrAT by means of inducing down-regulation of the ChREBP and Srebf-1 gene expression, and

  19. 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...

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

    DEFF Research Database (Denmark)

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

    2015-01-01

    was measured during deep NMB and without NMB at pneumoperitoneum 8 and 12 mmHg both. Additionally, we assessed surgical conditions while suturing the abdominal fascia using a 4-point subjective rating scale. Deep NMB was established with rocuronium and reversed with sugammadex. RESULTS: At 12 mm...... resulted in significantly better ratings of surgical conditions during suturing of the fascia (P=0.03, Mann-Whitney U-test). CONCLUSION: Deep NMB enlarged surgical space measured as the distance from the sacral promontory to the trocar. The enlargement, however, was minor and the clinical significance...... is unknown. Moreover, deep NMB improved surgical conditions when suturing the abdominal fascia....

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2012-02-10

    The objective of this study was to observe possible interactions between the renin-angiotensin and nitrergic systems in chronic hypoxia-induced pulmonary hypertension in newborn piglets. Thirteen chronically instrumented newborn piglets (6.3 ± 0.9 days; 2369 ± 491 g) were randomly assigned to receive saline (placebo, P) or the AT{sub 1} receptor (AT{sub 1}-R) blocker L-158,809 (L) during 6 days of hypoxia (FiO{sub 2} = 0.12). During hypoxia, pulmonary arterial pressure (Ppa; P < 0.0001), pulmonary vascular resistance (PVR; P < 0.02) and the pulmonary to systemic vascular resistance ratio (PVR/SVR; P < 0.05) were significantly attenuated in the L (N = 7) group compared to the P group (N = 6). Western blot analysis of lung proteins showed a significant decrease of endothelial NOS (eNOS) in both P and L animals, and of AT{sub 1}-R in P animals during hypoxia compared to normoxic animals (C group, N = 5; P < 0.01 for all groups). AT{sub 1}-R tended to decrease in L animals. Inducible NOS (iNOS) did not differ among P, L, and C animals and iNOS immunohistochemical staining in macrophages was significantly more intense in L than in P animals (P < 0.01). The vascular endothelium showed moderate or strong eNOS and AT{sub 1}-R staining. Macrophages and pneumocytes showed moderate or strong iNOS and AT{sub 1}-R staining, but C animals showed weak iNOS and AT{sub 1}-R staining. Macrophages of L and P animals showed moderate and weak AT{sub 2}-R staining, respectively, but the endothelium of all groups only showed weak staining. In conclusion, pulmonary hypertension induced by chronic hypoxia in newborn piglets is partially attenuated by AT{sub 1}-R blockade. We suggest that AT{sub 1}-R blockade might act through AT{sub 2}-R and/or Mas receptors and the nitrergic system in the lungs of hypoxemic newborn piglets.

  2. Blockade of the IL-6 trans-signalling/STAT3 axis suppresses cachexia in Kras-induced lung adenocarcinoma.

    Science.gov (United States)

    Miller, A; McLeod, L; Alhayyani, S; Szczepny, A; Watkins, D N; Chen, W; Enriori, P; Ferlin, W; Ruwanpura, S; Jenkins, B J

    2017-05-25

    Lung cancer is the leading cause of cancer death worldwide, and is frequently associated with the devastating paraneoplastic syndrome of cachexia. The potent immunomodulatory cytokine interleukin (IL)-6 has been linked with the development of lung cancer as well as cachexia; however, the mechanisms by which IL-6 promotes muscle wasting in lung cancer cachexia are ill-defined. In this study, we report that the gp130F/F knock-in mouse model displaying hyperactivation of the latent transcription factor STAT3 via the common IL-6 cytokine family signalling receptor, gp130, develops cachexia during Kras-driven lung carcinogenesis. Specifically, exacerbated weight loss, early mortality and reduced muscle and adipose tissue mass were features of the gp130F/F:KrasG12D model, but not parental KrasG12D mice in which STAT3 was not hyperactivated. Gene expression profiling of muscle tissue in cachectic gp130F/F:KrasG12D mice revealed the upregulation of IL-6 and STAT3-target genes compared with KrasG12D muscle tissue. These cachectic features of gp130F/F:KrasG12D mice were abrogated upon the genetic normalization of STAT3 activation or ablation of IL-6 in gp130F/F:KrasG12D:Stat3-/+ or gp130F/F:KrasG12D:Il6-/- mice, respectively. Furthermore, protein levels of the soluble IL-6 receptor (sIL-6R), which is the central facilitator of IL-6 trans-signalling, were elevated in cachectic muscle from gp130F/F:KrasG12D mice, and the specific blockade of IL-6 trans-signalling, but not classical signalling, with an anti-IL-6R antibody ameliorated cachexia-related characteristics in gp130F/F:KrasG12D mice. Collectively, these preclinical findings identify trans-signalling via STAT3 as the signalling modality by which IL-6 promotes muscle wasting in lung cancer cachexia, and therefore support the clinical evaluation of the IL-6 trans-signalling/STAT3 axis as a therapeutic target in advanced lung cancer patients presenting with cachexia.

  3. Six Weeks Habituation of Simulated Barefoot Running Induces Neuromuscular Adaptations and Changes in Foot Strike Patterns in Female Runners

    Science.gov (United States)

    Khowailed, Iman Akef; Petrofsky, Jerrold; Lohman, Everett; Daher, Noha

    2015-01-01

    Background The aim of this study was to examine the effects of a 6-week training program of simulated barefoot running (SBR) on running kinetics in habitually shod (wearing shoes) female recreational runners. Material/Methods Twelve female runners age 25.7±3.4 years gradually increased running distance in Vibram FiveFingers minimal shoes over a 6-week period. The kinetic analysis of treadmill running at 10 Km/h was performed pre- and post-intervention in shod running, non-habituated SBR, and habituated SBR conditions. Spatiotemporal parameters, ground reaction force components, and electromyography (EMG) were measured in all conditions. Results Post-intervention data indicated a significant decrease across time in the habituation SBR for EMG activity of the tibialis anterior (TA) in the pre-activation and absorptive phase of running (Prunning, unhabituated SBR, and habituated SBR. Six weeks of SBR was associated with a significant decrease in the loading rates and impact forces. Additionally, SBR significantly decrease the stride length, step duration, and flight time, and stride frequency was significantly higher compared to shod running. Conclusions The findings of this study indicate that changes in motor patterns in previously habitually shod runners are possible and can be accomplished within 6 weeks. Non-habituation SBR did not show a significant neuromuscular adaptation in the EMG activity of TA and GAS as manifested after 6 weeks of habituated SBR. PMID:26166443

  4. Pharmacological blockade of either cannabinoid CB1 or CB2 receptors prevents both cocaine-induced conditioned locomotion and cocaine-induced reduction of cell proliferation in the hippocampus of adult male rat

    Science.gov (United States)

    Blanco-Calvo, Eduardo; Rivera, Patricia; Arrabal, Sergio; Vargas, Antonio; Pavón, Francisco Javier; Serrano, Antonia; Castilla-Ortega, Estela; Galeano, Pablo; Rubio, Leticia; Suárez, Juan; Rodriguez de Fonseca, Fernando

    2014-01-01

    Addiction to major drugs of abuse, such as cocaine, has recently been linked to alterations in adult neurogenesis in the hippocampus. The endogenous cannabinoid system modulates this proliferative response as demonstrated by the finding that pharmacological activation/blockade of cannabinoid CB1 and CB2 receptors not only modulates neurogenesis but also modulates cell death in the brain. In the present study, we evaluated whether the endogenous cannabinoid system affects cocaine-induced alterations in cell proliferation. To this end, we examined whether pharmacological blockade of either CB1 (Rimonabant, 3 mg/kg) or CB2 receptors (AM630, 3 mg/kg) would affect cell proliferation [the cells were labeled with 5-bromo-2′-deoxyuridine (BrdU)] in the subventricular zone (SVZ) of the lateral ventricle and the dentate subgranular zone (SGZ). Additionally, we measured cell apoptosis (as monitored by the expression of cleaved caspase-3) and glial activation [by analyzing the expression of glial fibrillary acidic protein (GFAP) and Iba-1] in the striatum and hippocampus during acute and repeated (4 days) cocaine administration (20 mg/kg). The results showed that acute cocaine exposure decreased the number of BrdU-immunoreactive (ir) cells in the SVZ and SGZ. In contrast, repeated cocaine exposure reduced the number of BrdU-ir cells only in the SVZ. Both acute and repeated cocaine exposure increased the number of cleaved caspase-3-, GFAP- and Iba1-ir cells in the hippocampus, and this effect was counteracted by AM630 or Rimonabant, which increased the number of BrdU-, GFAP-, and Iba1-ir cells in the hippocampus. These results indicate that the changes in neurogenic, apoptotic and gliotic processes that were produced by repeated cocaine administration were normalized by pharmacological blockade of CB1 and CB2. The restorative effects of cannabinoid receptor blockade on hippocampal cell proliferation were associated with the prevention of the induction of conditioned

  5. Effect of ipsilateral ureteric obstruction on contralateral kidney and role of renin angiotensin system blockade on renal recovery in experimentally induced unilateral ureteric obstruction

    Directory of Open Access Journals (Sweden)

    Shasanka S Panda

    2013-01-01

    Full Text Available Aims: To study, the effects of ipsilateral ureteric obstruction on contralateral kidney and the role of renin angiotensin system (RAS blockade on renal recovery in experimentally induced unilateral ureteric obstruction. Materials and Methods: Unilateral upper ureteric obstruction was created in 96 adult Wistar rats that were reversed after pre-determined intervals. Losartan and Enalapril were given to different subgroups of rats following relief of obstruction. Results: The severity of dilatation on the contralateral kidney varied with duration of ipsilateral obstruction longer the duration more severe the dilatation. There is direct correlation between renal parenchymal damage, pelvi-ureteric junction (PUJ fibrosis, inflammation and severity of pelvi-calyceal system dilatation of contralateral kidney with duration of ipsilateral PUJ obstruction. Conclusions: Considerable injury is also inflicted to the contralateral normal kidney while ipsilateral kidney remains obstructed. Use of RAS blocking drugs has been found to significantly improve renal recovery on the contralateral kidney. It can, thus, be postulated that contralateral renal parenchymal injury was mediated through activation of RAS.

  6. ABHD6 blockade exerts antiepileptic activity in PTZ-induced seizures and in spontaneous seizures in R6/2 mice

    Science.gov (United States)

    Cheah, Christine S.; Swinney, Katie; Hsu, Ku-Lung; Cao, Jessica K.; Marrs, William; Blankman, Jacqueline L.; Tu, Sarah; Cherry, Allison E.; Fung, Susan; Wen, Andy; Li, Weiwei; Saporito, Michael S.; Selley, Dana E.; Cravatt, Benjamin F.; Oakley, John C.; Stella, Nephi

    2014-01-01

    The serine hydrolase α/β-hydrolase domain 6 (ABHD6) hydrolyzes the most abundant endocannabinoid (eCB) in the brain, 2-arachidonoylglycerol (2-AG), and controls its availability at cannabinoid receptors. We show that ABHD6 inhibition decreases pentylenetetrazole (PTZ)-induced generalized tonic-clonic and myoclonic seizure incidence, and severity. This effect is retained in cnr1−/− or cnr2−/− mice, but blocked by addition of a subconvulsive dose of picrotoxin, suggesting the involvement of GABAA receptors. ABHD6 inhibition also blocked spontaneous seizures in R6/2 mice, a genetic model of Juvenile Huntington’s disease known to exhibit dysregulated eCB signaling. ABHD6 blockade retained its antiepileptic activity over chronic dosing and was not associated with psychomotor or cognitive effects. While the etiology of seizures in R6/2 mice remains unsolved, involvement of the hippocampus is suggested by interictal epileptic discharges, increased expression of vGLUT1 but not vGAT, and reduced Neuropeptide Y (NPY) expression. We conclude that ABHD6 inhibition may represent a novel antiepileptic strategy. PMID:25033180

  7. Low- and high-volume strength training induces similar neuromuscular improvements in muscle quality in elderly women.

    Science.gov (United States)

    Radaelli, Regis; Botton, Cíntia E; Wilhelm, Eurico N; Bottaro, Martim; Lacerda, Fabiano; Gaya, Anelise; Moraes, Kelly; Peruzzolo, Amanda; Brown, Lee E; Pinto, Ronei Silveira

    2013-08-01

    The aim of this study was to compare the effects of low- and high-volume strength training on strength, muscle activation and muscle thickness (MT) of the lower- and upper-body, and on muscle quality (MQ) of the lower-body in older women. Twenty apparently healthy elderly women were randomly assigned into two groups: low-volume (LV, n=11) and high-volume (HV, n=9). The LV group performed one-set of each exercise, while the HV group performed three-sets of each exercise, twice weekly for 13 weeks. MQ was measured by echo intensity obtained by ultrasonography (MQEI), strength per unit of muscle mass (MQST), and strength per unit of muscle mass adjusted with an allometric scale (MQAS). Following training, there was a significant increase (p≤0.001) in knee extension 1-RM (31.8±20.5% for LV and 38.3±7.3% for HV) and in elbow flexion 1-RM (25.1±9.5% for LV and 26.6±8.9% for HV) and in isometric maximal strength of the lower-body (p≤0.05) and upper-body (p≤0.001), with no difference between groups. The maximal electromyographic activation for both groups increased significantly (p≤0.05) in the vastus medialis and biceps brachii, with no difference between groups. All MT measurements of the lower- and upper-body increased similarly in both groups (p≤0.001). Similar improvements were also observed in MQEI (p≤0.01), MQST, and MQAS (p≤0.001) for both groups. These results demonstrate that low- and high-volume strength training promote similar increases in neuromuscular adaptations of the lower- and upper-body, and in MQ of the lower-body in elderly women. Copyright © 2013 Elsevier Inc. All rights reserved.

  8. Neuromuscular blocking properties of dioxonium.

    Science.gov (United States)

    Tammisto, T; Salmenperä, M

    1980-12-01

    The characteristics of the myoneural block caused by a new neuromuscular blocking agent, dioxonium (Dx), were evaluated in surgical patients. The force and the corresponding electromyogram (EMG) of the thumb adduction evoked by various modes of ulnar nerve stimuli were measured. Onset, maintenance and disappearance of blockade after sequential administration of Dx were compared with results obtained with d-tubocurarine (dTc) or suxamethonium (Sx). Initially the Dx block was shown to be depolarizing with a negligible fade in the 2 Hz train of four stimuli with a single twitch suppression of 90%. On a weight basis, Dx was found to be about 15 times as potent as dTc in suppressing twitch to the 90% level. During maintenance, the block gained nondepolarizing characteristics with profound fades in the 2 and 50 Hz trains. The transition was associated with tachyphylaxis and with a more pronounced suppression of EMG amplitude than that measured in the twitch force. After a total dose of about 100 microgram/kg of Dx, the sensitivity to Dx again increased and the discrepancy between twitch tension and EMG disappeared. This pattern of changes was also seen with Sx. Spontaneous recovery occurred slightly faster than after dTc blocks of corresponding duration. With neostigmine, reversal was hastened and a full recovery with restitution of prerelaxant twitch and disappearance of fades was reached in about 20 min. Some discrepancy in EMG amplitude and twitch force persisted, however.

  9. O uso de bloqueadores neuromusculares no Brasil El uso de bloqueadores neuromusculares en Brasil Neuromuscular blockers in Brazil

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    Maria Cristina Simões de Almeida

    2004-12-01

    BNM. Las complicaciones más apuntadas fueron el bloqueo prolongado, el broncoespasmo grave y la curarización residual. CONCLUSIONES: El atracúrio es el bloqueador neuromuscular más empleado en Brasil, hay alto percentual del uso de la succinilcolina en situaciones no emergenciales, el uso de monitores de la transmisión neuromuscular es raro, y, como un corolario, un percentual significativo de uso de criterios eminentemente clínicos para considerar el paciente descurarizado. Se registró que, cerca del 30% de los anestesiologistas tuvo algún tipo de complicación consecuente del uso de eses fármacos.BACKGROUND AND OBJECTIVES: There are no statistical data on the use of neuromuscular blockers in Brazil. This study aimed at statistically analyzing this topic. METHODS: Our study has compiled 831 answers to a questionnaire filled by anesthesiologists attending the 48th Brazilian Congress of Anesthesiology in Recife, 2001, and via Internet by anesthesiologists whose e-mail addresses are in the Brazilian Society of Anesthesiology web page (www.sba.com.br. The following data were evaluated: years of experience with the specialty, region where anesthesiologists practice, neuromuscular blockers (NMB usage in order of preference, indications for succinylcholine, neuromuscular transmission monitor usage, blockade recovery criteria, neostigmine usage, NMB administration routes and description of observed complications. RESULTS: Most anesthesiologists practice for more than 11 years and the highest number of answers have come from the Southeastern region of Brazil. Most common NMB is atracurium, followed by pancuronium and succinylcholine. Succinylcholine is more frequently used for rapid sequence induction and in children (80% and 25%, respectively. Neuromuscular transmission monitors are never used by 53% of anesthesiologists, and 92% of them use clinical signs as blockade recovery criteria. Neostigmine is routinely used by 45% of professionals and 94% of them administer

  10. Doenças neuromusculares Neuromuscular disorders

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    Umbertina C. Reed

    2002-08-01

    Full Text Available Objetivo: apresentar os dados essenciais para o diagnóstico diferencial entre as principais doenças neuromusculares, denominação genérica sob a qual agrupam-se diferentes afecções, decorrentes do acometimento primário da unidade motora (motoneurônio medular, raiz nervosa, nervo periférico, junção mioneural e músculo. Fontes dos dados: os aspectos clínicos fundamentais para estabelecer o diagnóstico diferencial entre as diferentes doenças neuromusculares, bem como entre estas e as causas de hipotonia muscular secundária ao comprometimento do sistema nervoso central ou a doenças sistêmicas não-neurológicas, são enfatizados, com base na experiência clínica vinda do atendimento a crianças com doenças neuromusculares durante os últimos 12 anos, no ambulatório de doenças neuromusculares do Hospital das Clínicas da Faculdade de Medicina, da Universidade de São Paulo. A revisão bibliográfica foi efetuada através do Medline e do periódico Neuromuscular Disorders, publicação oficial da World Muscle Society. Síntese dos dados: nas crianças, a maior parte destas afecções é geneticamente determinada, sendo as mais comuns a distrofia muscular progressiva ligada ao sexo, de Duchenne, a amiotrofia espinal infantil, a distrofia muscular congênita, a distrofia miotônica de Steinert, e as miopatias congênitas, estruturais e não estruturais. Polineuropatias hereditárias, síndrome miastênica congênita e miopatias metabólicas são menos comuns, porém mostram correlação geno-fenotípica cada vez mais precisa. Conclusões: na década passada, inúmeros avanços da genética molecular facilitaram imensamente o diagnóstico e o aconselhamento genético das doenças neuromusculares mais comuns das crianças, inclusive possibilitando diagnóstico fetal e, adicionalmente, vieram permitir melhor caracterização fenotípica e classificação mais objetiva.Objective: to discuss the most important aspects for performing a

  11. SCIB2, an antibody DNA vaccine encoding NY-ESO-1 epitopes, induces potent antitumor immunity which is further enhanced by checkpoint blockade.

    Science.gov (United States)

    Xue, Wei; Metheringham, Rachael L; Brentville, Victoria A; Gunn, Barbara; Symonds, Peter; Yagita, Hideo; Ramage, Judith M; Durrant, Lindy G

    2016-06-01

    Checkpoint blockade has demonstrated promising antitumor responses in approximately 10-40% of patients. However, the majority of patients do not make a productive immune response to their tumors and do not respond to checkpoint blockade. These patients may benefit from an effective vaccine that stimulates high-avidity T cell responses in combination with checkpoint blockade. We have previously shown that incorporating TRP-2 and gp100 epitopes into the CDR regions of a human IgG1 DNA (ImmunoBody®: IB) results in significant tumor regression both in animal models and patients. This vaccination strategy is superior to others as it targets antigen to antigen-presenting cells and stimulates high-avidity T cell responses. To broaden the application of this vaccination strategy, 16 NY-ESO-1 epitopes, covering over 80% of HLA phenotypes, were incorporated into the IB (SCIB2). They produced higher frequency and avidity T cell responses than peptide vaccination. These T cells were of sufficient avidity to kill NY-ESO-1-expressing tumor cells, and in vivo controlled the growth of established B16-NY-ESO-1 tumors, resulting in long-term survival (35%). When SCIB2 was given in combination with Treg depletion, CTLA-4 blockade or PD-1 blockade, long-term survival from established tumors was significantly enhanced to 56, 67 and 100%, respectively. Translating these responses into the clinic by using a combination of SCIB2 vaccination and checkpoint blockade can only further improve clinical responses.

  12. Recovery from ketamine-induced amnesia by blockade of GABA-A receptor in the medial prefrontal cortex of mice.

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    Farahmandfar, Maryam; Akbarabadi, Ardeshir; Bakhtazad, Atefeh; Zarrindast, Mohammad-Reza

    2017-03-06

    Ketamine and other noncompetitive N-methyl-d-aspartate (NMDA) receptor antagonists are known to induce deficits in learning and cognitive performance sensitive to prefrontal cortex (PFC) functions. The interaction of a glutamatergic and GABAergic systems is essential for many cognitive behaviors. In order to understand the effect of γ-aminobutyric acid (GABA)/glutamate interactions on learning and memory, we investigated the effects of intra medial prefrontal cortex (mPFC) injections of GABAergic agents on ketamine-induced amnesia using a one-trial passive avoidance task in mice. Pre-training systemic administration of ketamine (5, 10 and 15mg/kg, i.p.) dose-dependently decreased the memory acquisition of a one-trial passive avoidance task. Pre-training intra-mPFC injection of muscimol, GABAA receptor agonist (0.05, 0.1 and 0.2μg/mouse) and baclofen GABAB receptor agonist (0.05, 0.1, 0.5 and 1μg/mouse), impaired memory acquisition. However, co-pretreatment of different doses of muscimol and baclofen with a lower dose of ketamine (5mg/kg), which did not induce amnesia by itself, caused inhibition of memory formation. Our data showed that sole pre-training administration of bicuculline, GABA-A receptor antagonist and phaclofen GABA-B receptor antagonist into the mPFC, did not affect memory acquisition. In addition, the amnesia induced by pre-training ketamine (15mg/kg) was significantly decreased by the pretreatment of bicuculline (0.005, 0.1 and 0.5μg/mouse). It can be concluded that GABAergic system of the mPFC is involved in the ketamine-induced impairment of memory acquisition. Copyright © 2016 IBRO. Published by Elsevier Ltd. All rights reserved.

  13. Learn About Neuromuscular Disease

    Science.gov (United States)

    ... for MDA Blog Donate Search MDA.org Close Learn About Neuromuscular Disease Muscular dystrophy, ALS and related ... power of a multiple-disease approach, MDA leverages learnings from one disease to accelerate progress in others ...

  14. Combined phosphodiesterase inhibition and beta-blockade in the GI104313, decreases ischemia-induced arrhythmias in the rat.

    Science.gov (United States)

    Carceles, M D; Aleixandre, F; Fuente, T; López-Vidal, J; Laorden, M L

    2001-05-01

    The purpose of the present study was to evaluate the effects of GI104313, a chimeric molecule containing a phosphodiesterase inhibiting pyradazinone and a blocking phenoxpropanolamine, on ischemia-induced arrhythmias in anesthetized rats. The coronary artery was occluded 15 min after commencing drug administration and myocardial ischemia was maintained for 30 min during which the heart rate and mean blood pressure were recorded. Cyclic AMP and GMP were determined by radio-immunoassay. GI104313 (0.1 micromol x kg(-1) plus 0.01 micromol x kg(-1) x min(-1) or 1 micromol x kg(-1) plus 0.1 micromol x kg(-1) x min(-1)) decreased the incidence of ventricular tachycardia (86% and 75%), ventricular fibrillation (28%, P <0.01 and 12%, P <0.001) and premature ventricular beats (164 +/- 27.0 and 114 +/- 28.5, P <0.05) following coronary artery ligation, resulting in a decrease in mortality (29% and 12%, P <0.05). Changes in cyclic nucleotide concentrations have been implicated in the genesis of ischemia-induced arrhythmias. However, in the present study GI104313 did not change the concentrations of adenosine 3':5'-cyclic monophosphate (cyclic AMP) (1.0 +/- 0.07 pmol x mg(-1), 1.0 +/- 0.05 pmol x mg(-1)) or guanosine 3':5'-cyclic monophosphate (cyclic GMP) (0.025 +/- 0.008 pmol x mg(-1) protein, 0.017 +/- 0.004 pmol x mg(-1) protein) in the left ventricle during ischemia-induced arrhythmias in anesthetized rats compared to saline (0.9 +/- 0.1 pmol x mg(-1) and 0.013 +/- 0.002 pmol x m(-1), respectively). Our results demonstrate that, in rats, GI104313 induced a decrease in both incidence of arrhythmias and mortality which was not associated with changes in ventricular cyclic nucleotide content.

  15. Influência dos Hipnóticos no bloqueio neuromuscular produzido pelo cisatracúrio: emprego da aceleromiografia Influencia de los hipnóticos en el bloqueo neuromuscular producido por el cisatracurio: uso de la aceleromiografía Influence of hypnotics on cisatracurium-induced neuromuscular block: use of acceleromyograhpy

    OpenAIRE

    Angélica de Fátima de Assunção Braga; Franklin Sarmento da Silva Braga; Glória Maria Braga Potério; José Aristeu Fachini Frias; Fernanda Maria Silva Pedro; Derli Conceição Munhoz

    2013-01-01

    JUSTIFICATIVA E OBJETIVOS: Os efeitos farmacodinâmicos dos bloqueadores neuromusculares (BNM) podem ser influenciados por diferentes drogas, entre elas os hipnóticos. O objetivo deste estudo foi avaliar a influência do propofol e do etomidato sobre o bloqueio neuromuscular produzido pelo cisatracúrio. MÉTODO: Foram incluídos 60 pacientes, ASA I e II, submetidos a cirurgias eletivas sob anestesia geral, distribuídos aleatoriamente em dois grupos de acordo com o hipnótico empregado: GI (propofo...

  16. Disturbance and recovery of trunk mechanical and neuromuscular behaviours following prolonged trunk flexion: influences of duration and external load on creep-induced effects.

    Science.gov (United States)

    Bazrgari, Babak; Hendershot, Brad; Muslim, Khoirul; Toosizadeh, Nima; Nussbaum, Maury A; Madigan, Michael L

    2011-11-01

    Trunk flexion results in adverse mechanical effects on the spine and is associated with a higher incidence of low back pain. To examine the effects of creep deformation on trunk behaviours, participants were exposed to full trunk flexion in several combinations of exposure duration and external load. Trunk mechanical and neuromuscular behaviours were obtained pre- and post-exposure and during recovery using sudden perturbations. Intrinsic trunk stiffness decreased with increasing flexion duration and in the presence of the external load. Recovery of intrinsic stiffness required more time than the exposure duration and was influenced by exposure duration. Reflexive trunk responses increased immediately following exposure but recovered quickly (∼2.5 min). Alterations in reflexive trunk behaviour following creep deformation exposures may not provide adequate compensation to allow for complete recovery of concurrent reductions in intrinsic stiffness, which may increase the risk of injury due to spinal instability. STATEMENT OF RELEVANCE: An increased risk of low back injury may result from flexion-induced disturbances to trunk behaviours. Such effects, however, appear to depend on the type of flexion exposure, and have implications for the design of work involving trunk flexion.

  17. Gastrointestinal dysfunction induced by early weaning is attenuated by delayed weaning and mast cell blockade in pigs.

    Science.gov (United States)

    Moeser, Adam J; Ryan, Kathleen A; Nighot, Prashant K; Blikslager, Anthony T

    2007-08-01

    Our previous work has demonstrated that weaning at 19 days of age has deleterious effects on mucosal barrier function in piglet intestine that are mediated through peripheral CRF receptor signaling pathways. The objectives of the present study were to assess the impact of piglet age on weaning-associated intestinal dysfunction and to determine the role that mast cells play in weaning-induced breakdown of mucosal barrier function. Nursing Yorkshire-cross piglets were either weaned at 19 days of age (early-weaned, n = 8) or 28 days of age (late-weaned, n = 8) and housed in nursery pens. Twenty-four hours postweaning, segments of midjejunum and ascending colon from piglets within each weaning age group were harvested and mounted on Ussing chambers for measurements of transepithelial electrical resistance and serosal-to-mucosal [(3)H]mannitol fluxes. Early weaning resulted in reductions in transepithelial electrical resistance and increases in mucosal permeability to [(3)H]mannitol in the jejunum and colon (P piglets weaned at 28 days of age. Early-weaned piglet intestinal mucosa had increased expression of CRF receptor 1 protein, increased mucosal mast cell tryptase levels, and evidence of enhanced mast cell degranulation compared with late-weaned intestinal mucosa. Pretreatment of piglets with the mast cell stabilizer drug cromolyn, injected intraperitoneally 30 min prior to weaning, abolished the early-weaning-induced intestinal barrier disturbances. Our results indicate that early-weaning stress induces mucosal dysfunction mediated by intestinal mast cell activation and can be prevented by delaying weaning.

  18. Blockade of the formation of insoluble ubiquitinated protein aggregates by EGCG3"Me in the alloxan-induced diabetic kidney.

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    Shuxian Cai

    Full Text Available BACKGROUND: Renal accumulation of reactive carbonyl compounds (RCCs has been linked to the progression of diabetic nephropathy. We previously demonstrated that carbonyl stress induces the formation of amino-carbonyl cross-links and sharply increases the content of β-sheet-rich structures, which is the seed of insoluble aggregates formation, and tea catechin (--epigallocatechin 3-gallate (EGCG can reverse this process in vitro and in vivo. In this study, methylated derivative (--epigallocatechin-3-O-(3-O-methyl-gallate (EGCG3"Me was hypothesized to neutralize carbonyl stress mediating the formation of insoluble ubiquitinated protein (IUP aggregates, and reduce the early development of diabetic nephropathy. METHODS AND RESULTS: Diabetes was induced in mice by intraperitoneally injecting alloxan monohydrate (200 mg/kg/d twice and administering EGCG3"Me by gavage for 15 d. Reagent case and western blot results showed that, in diabetic kidneys, the carbonyl proteins in the serum increased; and in insoluble protein fraction, 4-hydroxynonenal-modified proteins, IUP aggregates and p62 accumulated; FT-IR study demonstrated that the lipid content, anti-parallel β-sheet structure and aggregates increased. EGCG3"Me treatment could effectively reverse this process, even better than the negative control treatment. CONCLUSIONS: EGCG3"Me exhibiting anti-β-sheet-rich IUP aggregate properties, maybe represents a new strategy to impede the progression of diabetic nephropathy and other diabetic complications.

  19. Synthetic tambjamine analogues induce mitochondrial swelling and lysosomal dysfunction leading to autophagy blockade and necrotic cell death in lung cancer.

    Science.gov (United States)

    Rodilla, Ananda M; Korrodi-Gregório, Luís; Hernando, Elsa; Manuel-Manresa, Pilar; Quesada, Roberto; Pérez-Tomás, Ricardo; Soto-Cerrato, Vanessa

    2017-02-15

    Current pharmacological treatments for lung cancer show very poor clinical outcomes, therefore, the development of novel anticancer agents with innovative mechanisms of action is urgently needed. Cancer cells have a reversed pH gradient compared to normal cells, which favours cancer progression by promoting proliferation, metabolic adaptation and evasion of apoptosis. In this regard, the use of ionophores to modulate intracellular pH appears as a promising new therapeutic strategy. Indeed, there is a growing body of evidence supporting ionophores as novel antitumour drugs. Despite this, little is known about the implications of pH deregulation and homeostasis imbalance triggered by ionophores at the cellular level. In this work, we deeply analyse for the first time the anticancer effects of tambjamine analogues, a group of highly effective anion selective ionophores, at the cellular and molecular levels. First, their effects on cell viability were determined in several lung cancer cell lines and patient-derived cancer stem cells, demonstrating their potent cytotoxic effects. Then, we have characterized the induced lysosomal deacidification, as well as, the massive cytoplasmic vacuolization observed after treatment with these compounds, which is consistent with mitochondrial swelling. Finally, the activation of several proteins involved in stress response, autophagy and apoptosis was also detected, although they were not significantly responsible for the cell death induced. Altogether, these evidences suggest that tambjamine analogues provoke an imbalance in cellular ion homeostasis that triggers mitochondrial dysfunction and lysosomal deacidification leading to a potent cytotoxic effect through necrosis in lung cancer cell lines and cancer stem cells. Copyright © 2016 Elsevier Inc. All rights reserved.

  20. Platelets induce apoptosis during sepsis in a contact-dependent manner that is inhibited by GPIIb/IIIa blockade.

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    Matthew Sharron

    Full Text Available PURPOSE: End-organ apoptosis is well-described in progressive sepsis and Multiple Organ Dysfunction Syndrome (MODS, especially where platelets accumulate (e.g. spleen and lung. We previously reported an acute sepsis-induced cytotoxic platelet phenotype expressing serine protease granzyme B. We now aim to define the site(s of and mechanism(s by which platelet granzyme B induces end-organ apoptosis in sepsis. METHODS: End-organ apoptosis in murine sepsis (i.e. polymicrobial peritonitis was analyzed by immunohistochemistry. Platelet cytotoxicity was measured by flow cytometry following 90 minute ex vivo co-incubation with healthy murine splenocytes. Sepsis progression was measured via validated preclinical murine sepsis score. MEASUREMENTS AND MAIN RESULTS: There was evident apoptosis in spleen, lung, and kidney sections from septic wild type mice. In contrast, there was a lack of TUNEL staining in spleens and lungs from septic granzyme B null mice and these mice survived longer following induction of sepsis than wild type mice. In co-incubation experiments, physical separation of septic platelets from splenocytes by a semi-permeable membrane reduced splenocyte apoptosis to a rate indistinguishable from negative controls. Chemical separation by the platelet GPIIb/IIIa receptor inhibitor eptifibatide decreased apoptosis by 66.6±10.6% (p = 0.008. Mice treated with eptifibatide in vivo survived longer following induction of sepsis than vehicle control mice. CONCLUSIONS: In sepsis, platelet granzyme B-mediated apoptosis occurs in spleen and lung, and absence of granzyme B slows sepsis progression. This process proceeds in a contact-dependent manner that is inhibited ex vivo and in vivo by the platelet GPIIb/IIIa receptor inhibitor eptifibatide. The GPIIb/IIIa inhibitors and other classes of anti-platelet drugs may be protective in sepsis.

  1. Platelets Induce Apoptosis during Sepsis in a Contact-Dependent Manner That Is Inhibited by GPIIb/IIIa Blockade

    Science.gov (United States)

    Sharron, Matthew; Hoptay, Claire E.; Wiles, Andrew A.; Garvin, Lindsay M.; Geha, Mayya; Benton, Angela S.; Nagaraju, Kanneboyina; Freishtat, Robert J.

    2012-01-01

    Purpose End-organ apoptosis is well-described in progressive sepsis and Multiple Organ Dysfunction Syndrome (MODS), especially where platelets accumulate (e.g. spleen and lung). We previously reported an acute sepsis-induced cytotoxic platelet phenotype expressing serine protease granzyme B. We now aim to define the site(s) of and mechanism(s) by which platelet granzyme B induces end-organ apoptosis in sepsis. Methods End-organ apoptosis in murine sepsis (i.e. polymicrobial peritonitis) was analyzed by immunohistochemistry. Platelet cytotoxicity was measured by flow cytometry following 90 minute ex vivo co-incubation with healthy murine splenocytes. Sepsis progression was measured via validated preclinical murine sepsis score. Measurements and Main Results There was evident apoptosis in spleen, lung, and kidney sections from septic wild type mice. In contrast, there was a lack of TUNEL staining in spleens and lungs from septic granzyme B null mice and these mice survived longer following induction of sepsis than wild type mice. In co-incubation experiments, physical separation of septic platelets from splenocytes by a semi-permeable membrane reduced splenocyte apoptosis to a rate indistinguishable from negative controls. Chemical separation by the platelet GPIIb/IIIa receptor inhibitor eptifibatide decreased apoptosis by 66.6±10.6% (p = 0.008). Mice treated with eptifibatide in vivo survived longer following induction of sepsis than vehicle control mice. Conclusions In sepsis, platelet granzyme B-mediated apoptosis occurs in spleen and lung, and absence of granzyme B slows sepsis progression. This process proceeds in a contact-dependent manner that is inhibited ex vivo and in vivo by the platelet GPIIb/IIIa receptor inhibitor eptifibatide. The GPIIb/IIIa inhibitors and other classes of anti-platelet drugs may be protective in sepsis. PMID:22844498

  2. The effect of AT1 receptor blockade on bax and bcl-2 expression in bleomycin-induced pulmonary fibrosis

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    L Safaeian

    2009-03-01

    Full Text Available ABSTRACT Background and the purpose of the study: Recent studies have indicated the role of apoptosis and angiotensin in the pathogenesis of bleomycin induced-pulmonary fibrosis. Losartan, an angiotensin type 1 receptor (AT1R antagonist, has ameliorated apoptosis and fibrosis from bleomycin. In this study, alterations in the expression of apoptosis-regulatory genes (bcl-2 and bax were investigated in different cells of lung tissue of mice treated with bleomycin in the presence of losartan. Methods: Losartan (10 mg/kg, i.p. was given to mice two days before administration of bleomycin (3 U/kg and throughout the test period. After two weeks, lung tissues of mice were evaluated for fibrosis by biochemical measurement of collagen deposition and semiquantitative analysis of pathological changes of the lung. The expression of bcl-2 and bax was assessed by immunohistochemical assay using biotin-streptavidin staining method on paraffin-embedded lung tissues. Results and major conclusion: Pre-treatment with losartan significantly (P < 0.05 reduced the increase in lung collagen content and also inhibited the histological changes induced by bleomycin. Immunohistochemical studies showed that losartan significantly (P < 0.05 reduced the bax/bcl-2 expression ratio in the alveolar epithelial cells, lymphocytes, macrophages and interstitial myofibroblasts. Losartan also inhibited the bcl-2 upregulation which was educed by bleomycin in neutrophils. By reduction of bax/bcl-2 ratio as a determinant of susceptibility of a cell to apoptosis, losartan exerted protective effects on the alveolar epithelial cells that may be important in the amelioration of pulmonary fibrosis. These results may help to better understanding of the role of angiotensin II and apoptosis in pulmonary fibrosis.

  3. Gap Junctional Blockade Stochastically Induces Different Species-Specific Head Anatomies in Genetically Wild-Type Girardia dorotocephala Flatworms

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    Maya Emmons-Bell

    2015-11-01

    Full Text Available The shape of an animal body plan is constructed from protein components encoded by the genome. However, bioelectric networks composed of many cell types have their own intrinsic dynamics, and can drive distinct morphological outcomes during embryogenesis and regeneration. Planarian flatworms are a popular system for exploring body plan patterning due to their regenerative capacity, but despite considerable molecular information regarding stem cell differentiation and basic axial patterning, very little is known about how distinct head shapes are produced. Here, we show that after decapitation in G. dorotocephala, a transient perturbation of physiological connectivity among cells (using the gap junction blocker octanol can result in regenerated heads with quite different shapes, stochastically matching other known species of planaria (S. mediterranea, D. japonica, and P. felina. We use morphometric analysis to quantify the ability of physiological network perturbations to induce different species-specific head shapes from the same genome. Moreover, we present a computational agent-based model of cell and physical dynamics during regeneration that quantitatively reproduces the observed shape changes. Morphological alterations induced in a genomically wild-type G. dorotocephala during regeneration include not only the shape of the head but also the morphology of the brain, the characteristic distribution of adult stem cells (neoblasts, and the bioelectric gradients of resting potential within the anterior tissues. Interestingly, the shape change is not permanent; after regeneration is complete, intact animals remodel back to G. dorotocephala-appropriate head shape within several weeks in a secondary phase of remodeling following initial complete regeneration. We present a conceptual model to guide future work to delineate the molecular mechanisms by which bioelectric networks stochastically select among a small set of discrete head morphologies

  4. Blockade of L-type calcium channel in myocardium and calcium-induced contractions of vascular smooth muscle by CPU 86017.

    Science.gov (United States)

    Dai, De-zai; Hu, Hui-juan; Zhao, Jing; Hao, Xue-mei; Yang, Dong-mei; Zhou, Pei-ai; Wu, Cai-hong

    2004-04-01

    To assess the blockade by CPU 86017 on the L-type calcium channels in the myocardium and on the Ca(2+)-related contractions of vascular smooth muscle. The whole-cell patch-clamp was applied to investigate the blocking effect of CPU 86017 on the L-type calcium current in isolated guinea pig myocytes and contractions by KCl or phenylephrine (Phe) of the isolated rat tail arteries were measured. Suppression of the L-type current of the isolated myocytes by CPU 86017 was moderate, in time- and concentration-dependent manner and with no influence on the activation and inactivation curves. The IC(50) was 11.5 micromol/L. Suppressive effect of CPU 86017 on vaso-contractions induced by KCl 100 mmol/L, phenylephrine 1 micromol/L in KH solution (phase 1), Ca(2+) free KH solution ( phase 2), and by addition of CaCl(2) into Ca(2+)-free KH solution (phase 3) were observed. The IC(50) to suppress vaso-contractions by calcium entry via the receptor operated channel (ROC) and voltage-dependent channel (VDC) was 0.324 micromol/L and 16.3 micromol/L, respectively. The relative potency of CPU 86017 to suppress vascular tone by Ca(2+) entry through ROC and VDC is 1/187 of prazosin and 1/37 of verapamil, respectively. The blocking effects of CPU 86017 on the L-type calcium channel of myocardium and vessel are moderate and non-selective. CPU 86017 is approximately 50 times more potent in inhibiting ROC than VDC.

  5. Novel lineage- and stage-selective effects of retinoic acid on mouse granulopoiesis: Blockade by dexamethasone or inducible NO synthase inactivation.

    Science.gov (United States)

    Xavier-Elsas, Pedro; Vieira, Bruno Marques; Masid-de-Brito, Daniela; Santos, Juliana; Barradas, Monica Gomes; de Luca, Bianca; Gaspar-Elsas, Maria Ignez

    2017-04-01

    Despite the close relationship of eosinophils and neutrophils, these granulocyte lineages respond to distinct cytokines and play unique roles in immune responses. They nevertheless respond to shared physiological/pharmacological regulators, including glucocorticoids and retinoids, and to ubiquitous mediators, including NO. Others showed that, in humans, all-trans retinoic acid (ATRA) suppresses eosinophil differentiation, but promotes neutrophil differentiation. Mechanisms of dual co-regulation of physiological granulopoiesis were here examined in murine bone-marrow, a model system suitable for exploration of immunopharmacological mechanisms, given the availability of experimental resources, including mutant/knockout mouse strains. We examined the effects of ATRA on mouse eosinophil and neutrophil production, using wild-type (BALB/c, C57BL/6) and mutant (iNOS-, CD95L-, or CD95-KO) bone-marrow cultures, further assessing the modification of ATRA activity by dexamethasone and iNOS blockade. ATRA (10(-6)-10(-8)M) significantly decreased eosinophil production relative to IL-5 controls. This effect was iNOS-independent, but CD95L- and caspase-dependent, and prevented by dexamethasone (10(-7)M in vitro; 1-20mg·kg(-1) in vivo). In myeloid colony formation assays, ATRA markedly suppressed GM-CSF-responsive progenitors, through an iNOS-dependent, CD95-independent, dexamethasone-sensitive mechanism. By contrast, ATRA potently enhanced GM-CSF-dependent neutropoiesis in liquid culture from BALB/c or C57BL/6 bone-marrow. This novel stimulatory effect was resistant to dexamethasone and abolished in iNOS-KO bone-marrow. ATRA injections also induced lineage- and stage-selective effects on granulopoiesis in vivo. ATRA therefore co-regulates eosinophil and neutrophil production in murine bone-marrow through multiple lineage- and stage-selective mechanisms. Copyright © 2017 Elsevier B.V. All rights reserved.

  6. Cell surface-bound TIMP3 induces apoptosis in mesenchymal Cal78 cells through ligand-independent activation of death receptor signaling and blockade of survival pathways.

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    Christina Koers-Wunrau

    exclusively cell surface-bound endogenous TIMP3 induces apoptosis in mesenchymal Cal78 cells through ligand-independent activation of death receptor signaling and blockade of survival signaling pathways.

  7. The antifibrotic effects of alveolar macrophages 5-HT2C receptors blockade on bleomycin-induced pulmonary fibrosis in rats.

    Science.gov (United States)

    Elaidy, Samah M; Essawy, Soha S

    2016-12-01

    The most widespread chronic fibrosing lung disease is idiopathic pulmonary fibrosis. Lung serotonin (5-HT) content is increased during pulmonary fibrosis with the implication of 5-HT2 receptors in the pathogenesis. Serotonin plays important roles in alveolar macrophages function through 5-HT2C receptors activation. Numerous studies described the important role of 5-HT2A/B receptor blockers in suppressing different types of fibrosis as idiopathic pulmonary fibrosis. The current study pointed to examine the antifibrotic effects of RS-102221 and/or terguride through in vivo model of pulmonary fibrosis. Induction of pulmonary fibrosis was through a single dose of intra-tracheal bleomycin instillation (5mg/kg dissolved in phosphate buffer saline) in adult male albino Wistar rats. Next day of bleomycin instillation, intraperitoneal injection of RS-102221 (0.5mg/kg/d) and/or terguride (1.2mg/kg/d) were administered and continued for 14 days. Noticeable increase in 5-HT2C receptors expression was observed in fibrotic lung tissues with marked allocation belonging to alveolar macrophages. Either RS-102221 or terguride reduced the increments in lung water contents, grading of lung fibrosis, lung tumor necrosis factor-alpha (TNF-α), transforming growth factor-beta1 (TGF- β1 ) and vascular endothelial growth factor (VEGF) levels in lung injury and fibrosis-induced by bleomycin. Moreover, collagen content and myofibroblasts-alpha smooth muscle actin (α-SМA) were significantly decreased. Additionally, the simultaneous administration of RS-102221 with terguride had a synergistic outcome compared to that obtained by individual monotherapy. These findings suggested the potential use of 5-HT2A/B/C antagonists as anti-fibrotic agents in lung fibrosis. Copyright © 2016. Published by Elsevier Urban & Partner Sp. z o.o.

  8. Changes of Excitability in M1 Induced by Neuromuscular Electrical Stimulation Differ Between Presence and Absence of Voluntary Drive

    Science.gov (United States)

    Sugawara, Kenichi; Tanabe, Shigeo; Higashi, Toshio; Tsurumi, Takamasa; Kasai, Tatsuya

    2011-01-01

    The aim of this study is to investigate excitability changes in the human motor cortex induced by variable therapeutic electrical stimulations (TESs) with or without voluntary drive. We recorded motor-evoked potentials (MEPs) from extensor and flexor carpi radialis (FCR) muscles at rest and during FCR muscle contraction after the application of…

  9. Hereditary neuromuscular diseases

    Energy Technology Data Exchange (ETDEWEB)

    Oezsarlak, O. E-mail: ozkan.ozsarlak@uza.be; Schepens, E.; Parizel, P.M.; Goethem, J.W. van; Vanhoenacker, F.; Schepper, A.M. de; Martin, J.J

    2001-12-01

    This article presents the actual classification of neuromuscular diseases based on present expansion of our knowledge and understanding due to genetic developments. It summarizes the genetic and clinical presentations of each disorder together with CT findings, which we studied in a large group of patients with neuromuscular diseases. The muscular dystrophies as the largest and most common group of hereditary muscle diseases will be highlighted by giving detailed information about the role of CT and MRI in the differential diagnosis. The radiological features of neuromuscular diseases are atrophy, hypertrophy, pseudohypertrophy and fatty infiltration of muscles on a selective basis. Although the patterns and distribution of involvement are characteristic in some of the diseases, the definition of the type of disease based on CT scan only is not always possible.

  10. 2B4 (CD244) induced by selective CD28 blockade functionally regulates allograft-specific CD8+ T cell responses

    Science.gov (United States)

    Liu, Danya; Krummey, Scott M.; Badell, I. Raul; Wagener, Maylene; Schneeweis, Lumelle A.; Stetsko, Dawn K.; Suchard, Suzanne J.; Nadler, Steven G.

    2014-01-01

    Mounting evidence in models of both autoimmunity and chronic viral infection suggests that the outcome of T cell activation is critically impacted by the constellation of co-stimulatory and co-inhibitory receptors expressed on the cell surface. Here, we identified a critical role for the co-inhibitory SLAM family member 2B4 (CD244) in attenuating primary antigen-specific CD8+ T cell responses in the presence of immune modulation with selective CD28 blockade. Our results reveal a specific up-regulation of 2B4 on antigen-specific CD8+ T cells in animals in which CD28 signaling was blocked. However, 2B4 up-regulation was not observed in animals treated with CTLA-4 Ig (abatacept) or CD28 blockade in the presence of anti–CTLA-4 mAb. 2B4 up-regulation after CD28 blockade was functionally significant, as the inhibitory impact of CD28 blockade was diminished when antigen-specific CD8+ T cells were deficient in 2B4. In contrast, 2B4 deficiency had no effect on CD8+ T cell responses during unmodified rejection or in the presence of CTLA-4 Ig. We conclude that blockade of CD28 signals in the presence of preserved CTLA-4 signals results in the unique up-regulation of 2B4 on primary CD8+ effectors, and that this 2B4 expression plays a critical functional role in controlling antigen-specific CD8+ T cell responses. PMID:24493803

  11. Radiotherapy-Induced Anti-Tumor Immunity Contributes to the Therapeutic Efficacy of Irradiation and Can Be Augmented by CTLA-4 Blockade in a Mouse Model

    Science.gov (United States)

    Yoshimoto, Yuya; Suzuki, Yoshiyuki; Mimura, Kousaku; Ando, Ken; Oike, Takahiro; Sato, Hiro; Okonogi, Noriyuki; Maruyama, Takanori; Izawa, Shinichiro; Noda, Shin-ei; Fujii, Hideki; Kono, Koji; Nakano, Takashi

    2014-01-01

    Purpose There is growing evidence that tumor-specific immune responses play an important role in anti-cancer therapy, including radiotherapy. Using mouse tumor models we demonstrate that irradiation-induced anti-tumor immunity is essential for the therapeutic efficacy of irradiation and can be augmented by modulation of cytotoxic T lymphocyte (CTL) activity. Methods and Materials C57BL/6 mice, syngeneic EL4 lymphoma cells, and Lewis lung carcinoma (LL/C) cells were used. Cells were injected into the right femurs of mice. Ten days after inoculation, tumors were treated with 30 Gy of local X-ray irradiation and their growth was subsequently measured. The effect of irradiation on tumor growth delay (TGD) was defined as the time (in days) for tumors to grow to 500 mm3 in the treated group minus that of the untreated group. Cytokine production and serum antibodies were measured by ELISA and flow cytometry. Results In the EL4 tumor model, tumors were locally controlled by X-ray irradiation and re-introduced EL4 cells were completely rejected. Mouse EL4-specific systemic immunity was confirmed by splenocyte cytokine production and detection of tumor-specific IgG1 antibodies. In the LL/C tumor model, X-ray irradiation also significantly delayed tumor growth (TGD: 15.4 days) and prolonged median survival time (MST) to 59 days (versus 28 days in the non-irradiated group). CD8(+) cell depletion using an anti-CD8 antibody significantly decreased the therapeutic efficacy of irradiation (TGD, 8.7 days; MST, 49 days). Next, we examined whether T cell modulation affected the efficacy of radiotherapy. An anti-CTLA-4 antibody significantly increased the anti-tumor activity of radiotherapy (TGD was prolonged from 13.1 to 19.5 days), while anti-FR4 and anti-GITR antibodies did not affect efficacy. Conclusions Our results indicate that tumor-specific immune responses play an important role in the therapeutic efficacy of irradiation. Immunomodulation, including CTLA-4 blockade, may be a

  12. Radiotherapy-induced anti-tumor immunity contributes to the therapeutic efficacy of irradiation and can be augmented by CTLA-4 blockade in a mouse model.

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    Yuya Yoshimoto

    Full Text Available PURPOSE: There is growing evidence that tumor-specific immune responses play an important role in anti-cancer therapy, including radiotherapy. Using mouse tumor models we demonstrate that irradiation-induced anti-tumor immunity is essential for the therapeutic efficacy of irradiation and can be augmented by modulation of cytotoxic T lymphocyte (CTL activity. METHODS AND MATERIALS: C57BL/6 mice, syngeneic EL4 lymphoma cells, and Lewis lung carcinoma (LL/C cells were used. Cells were injected into the right femurs of mice. Ten days after inoculation, tumors were treated with 30 Gy of local X-ray irradiation and their growth was subsequently measured. The effect of irradiation on tumor growth delay (TGD was defined as the time (in days for tumors to grow to 500 mm3 in the treated group minus that of the untreated group. Cytokine production and serum antibodies were measured by ELISA and flow cytometry. RESULTS: In the EL4 tumor model, tumors were locally controlled by X-ray irradiation and re-introduced EL4 cells were completely rejected. Mouse EL4-specific systemic immunity was confirmed by splenocyte cytokine production and detection of tumor-specific IgG1 antibodies. In the LL/C tumor model, X-ray irradiation also significantly delayed tumor growth (TGD: 15.4 days and prolonged median survival time (MST to 59 days (versus 28 days in the non-irradiated group. CD8(+ cell depletion using an anti-CD8 antibody significantly decreased the therapeutic efficacy of irradiation (TGD, 8.7 days; MST, 49 days. Next, we examined whether T cell modulation affected the efficacy of radiotherapy. An anti-CTLA-4 antibody significantly increased the anti-tumor activity of radiotherapy (TGD was prolonged from 13.1 to 19.5 days, while anti-FR4 and anti-GITR antibodies did not affect efficacy. CONCLUSIONS: Our results indicate that tumor-specific immune responses play an important role in the therapeutic efficacy of irradiation. Immunomodulation, including CTLA-4

  13. Activation and blockade of serotonin7 receptors in the prelimbic cortex regulate depressive-like behaviors in a 6-hydroxydopamine-induced Parkinson's disease rat model.

    Science.gov (United States)

    Zhang, Q J; Du, C X; Tan, H H; Zhang, L; Li, L B; Zhang, J; Niu, X L; Liu, J

    2015-12-17

    The role of serotonin7 (5-HT7) receptors in the regulation of depression is poorly understood, particularly in Parkinson's disease-associated depression. Here we examined whether 5-HT7 receptors in the prelimbic (PrL) sub-region of the ventral medial prefrontal cortex (mPFC) involve in the regulation of depressive-like behaviors in sham-operated rats and rats with unilateral 6-hydroxydopamine lesions of the medial forebrain bundle. The lesion induced depressive-like responses as measured by the sucrose preference and forced swim tests when compared to sham-operated rats. Intra-PrL injection of 5-HT7 receptor agonist AS19 (0.5, 1 and 2 μg/rat) increased sucrose consumption, and decreased immobility time in sham-operated and the lesioned rats, indicating the induction of antidepressant-like effects. Further, intra-PrL injection of 5-HT7 receptor antagonist SB269970 (1.5, 3 and 6 μg/rat) decreased sucrose consumption, and increased immobility time, indicating the induction of depressive-like responses. However, the doses producing these effects in the lesioned rats were higher than those in sham-operated rats. Neurochemical results showed that intra-PrL injection of AS19 (2 μg/rat) increased dopamine, 5-hydroxytryptamine (5-HT) and noradrenaline (NA) levels in the mPFC, habenula and ventral hippocampus (vHip) in sham-operated and the lesioned rats; whereas SB269970 (6 μg/rat) decreased 5-HT levels in the habenula and vHip, and the levels of NA in the mPFC, habenula and vHip in the two groups of rats. The results suggest that 5-HT7 receptors in the PrL play an important role in the regulation of these behaviors, which attribute to changes in monoamine levels in the limbic and limbic-related brain regions after activation and blockade of 5-HT7 receptors. Copyright © 2015 IBRO. Published by Elsevier Ltd. All rights reserved.

  14. Acute and Chronic Effects of N-acetylcysteine on Pentylenetetrazole-induced Seizure and Neuromuscular Coordination in Mice

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    Sasan Zaeri

    2015-03-01

    Full Text Available Background: N-acetylcysteine (NAC has been indicated against experimental seizures, but with relatively inconclusive results. This study was undertaken to evaluate whether NAC exerts a dose-dependent anticonvulsant effect and to determine NAC safe therapeutic dose range and its muscle-relaxant activity in both acute and chronic uses. Methods: Following intraperitoneal (i.p. administration of N-acetylcysteine acutely (50-300 mg/kg or chronically for 8 days (25-300 mg/kg, mice were injected with PTZ (90 mg/kg, i.p. and latency times to the onset of myoclonic and clonic seizures and protection against death were recorded. Changes in body weight and mortality rate were considered as parameters for drug safety. The muscle-relaxant activity of NAC was assessed by rotarod test. Results: Acute and chronic treatment with NAC delayed latency times to myoclonic and clonic seizures in a dose-dependent manner, but with no significant prevention against PTZ-induced death. Chronic administration of 300 mg/kg NAC was fully lethal while lower doses (100 and 150 mg/kg resulted in a significant weight loss and decreased stay time on rotarod. Acute treatment with NAC had no significant effect on stay time on rotarod at all studied doses. Conclusion: NAC exerts a dose-dependent anticonvulsant effect in acute and chronic uses, with no muscle relaxant activity. NAC has higher efficacy in preventing seizure in chronic than acute treatment, but its chronic use at higher doses of 75 mg/kg may be associated with side effects and/or toxicity. These findings suggest that low doses of NAC may have a potential use as a prophylactic treatment for absence seizure in human.

  15. Glial cell-derived neurotrophic factor alleviates sepsis-induced neuromuscular dysfunction by decreasing the expression of γ- and α7-nicotinic acetylcholine receptors in an experimental rat model of neuromyopathy.

    Science.gov (United States)

    Wang, Xin; Min, Su; Xie, Fei; Yang, Jun; Li, Liang; Chen, Jingyuan

    2018-02-05

    Sepsis-induced neuromuscular dysfunction results from up-regulation of the expression of γ- and α7-nicotinic acetylcholine receptors (nAChR). Although glial cell derived neurotrophic factor (GDNF) has been implicated in repairing and supporting neurons, little is known about the effects of GDNF on demyelination of nerves in sepsis. In this study, we tested the hypothesis that GDNF could alleviate sepsis-induced neuromuscular dysfunction by decreasing the expression of γ- and α7-nAChR in an experimental rat model of neuromyopathy. Rats were randomly divided into a sham group and a sepsis group. Levels of inflammatory factors, muscle function, and nicotinic acetylcholine receptors were tested in rats after cecal ligation and puncture (CLP). At 24 h after CLP, GDNF was injected around the sciatic nerve of sepsis rats, cytokines were detected by enzyme-linked immunosorbent assay (ELISA), and immunofluorescence staining was used to detect the expression of nAChRs. GDNF and its downstream effector (Erk1/2 and GFR-α), neuregulin-1 (NRG-1) and γ- and α7-nAChR were measured using Western blot analysis. The expression of GDNF reached a minimum at 24 h after CLP. Compared with the sham group, the release of cytokines and the expression of γ- and α7-nAChR were significantly increased in the sepsis group. The administration of GDNF significantly alleviated sepsis-induced neuromuscular dysfunction, as well as reducing the expression of γ- and α7-nAChR. In addition, the expression of Erk1/2, GFR-α, NRG-1 were significantly increased after GDNF treatment. GDNF administration may improve patient outcomes by reducing the demyelination of nerves and the expression of γ- and α7-nAChR. Copyright © 2018. Published by Elsevier Inc.

  16. Influência da freqüência de estímulos na instalação do bloqueio neuromuscular produzido pelo rocurônio e pancurônio: avaliação pelo método acelerográfico Influencia de la frecuencia de estímulos en la instalación del bloqueo neuromuscular producido por el rocuronio y pancuronio: evaluación por el método acelerográfico Influence of stimulation frequency on rocuronium and pancuronium-induced neuromuscular block onset: acceleromyography evaluation

    Directory of Open Access Journals (Sweden)

    Derli da Conceição Munhóz

    2004-02-01

    condiciones de intubación traqueal. RESULTADOS: Los tiempos medios (segundos para el inicio de acción e instalación de bloqueo neuromuscular total producido por el pancuronio fueron: Grupo I (159,33 ± 35,22 y 222 ± 46,56 y Grupo II (77,83 ± 9,52 y 105,96 ± 15,58; para el rocuronio: Grupo I (83 ± 17,25 y 125,33 ± 20,12 y Grupo II (48,96 ± 10,16 y 59,83 ± 10,36 con diferencia significativa entre los grupos. Las condiciones de intubación traqueal fueron satisfactorias en 117 pacientes (97,5% e insatisfactorias en 3 (2,5%. CONCLUSIONES: El inicio de acción y el tiempo para la obtención del bloqueo neuromuscular total en el músculo aductor del pulgar, producidos por el rocuronio y por el pancuronio, son más cortos cuando hay empleo de mayores frecuencias de estímulos.BACKGROUND AND OBJECTIVES: Factors associated to patients and neuromuscular blockers (NMB, as well as others inherent to neuromuscular function monitoring, may affect neuromuscular block onset. This study aimed at the influence of two different stimulation frequencies on rocuronium and pancuronium-induced neuromuscular block. METHODS: Participated in this study 120 patients, physical status ASA I and II, submitted to elective procedures under general anesthesia, who were randomly allocated in two groups, according to the stimulation frequency employed to monitor neuromuscular block: Group I - 0.1 Hz (n = 60 and Group II - 1 Hz (n = 60. Two subgroups were formed within each group (n = 30, according to the neuromuscular blocker: Subgroup P (pancuronium and Subgroup R (rocuronium. Patients were premedicated with muscular midazolam (0.1 mg.kg-1, 30 minutes before surgery. Anesthesia was induced with propofol (2.5 mg.kg-1 preceded by alfentanil (50 µg.kg-1 and followed by pancuronium or rocuronium. Patients were ventilated under mask with 100% oxygen until 75% or more decrease in adductor pollicis muscle response, when laryngoscopy and tracheal intubation were performed. Neuromuscular function was

  17. Membrane Receptor-Induced Changes of the Protein Kinases A and C Activity May Play a Leading Role in Promoting Developmental Synapse Elimination at the Neuromuscular Junction

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    Josep M. Tomàs

    2017-08-01

    Full Text Available Synapses that are overproduced during histogenesis in the nervous system are eventually lost and connectivity is refined. Membrane receptor signaling leads to activity-dependent mutual influence and competition between axons directly or with the involvement of the postsynaptic cell and the associated glial cell/s. Presynaptic muscarinic acetylcholine (ACh receptors (subtypes mAChR; M1, M2 and M4, adenosine receptors (AR; A1 and A2A and the tropomyosin-related kinase B receptor (TrkB, among others, all cooperate in synapse elimination. Between these receptors there are several synergistic, antagonic and modulatory relations that clearly affect synapse elimination. Metabotropic receptors converge in a limited repertoire of intracellular effector kinases, particularly serine protein kinases A and C (PKA and PKC, to phosphorylate protein targets and bring about structural and functional changes leading to axon loss. In most cells A1, M1 and TrkB operate mainly by stimulating PKC whereas A2A, M2 and M4 inhibit PKA. We hypothesize that a membrane receptor-induced shifting in the protein kinases A and C activity (inhibition of PKA and/or stimulation of PKC in some nerve endings may play an important role in promoting developmental synapse elimination at the neuromuscular junction (NMJ. This hypothesis is supported by: (i the tonic effect (shown by using selective inhibitors of several membrane receptors that accelerates axon loss between postnatal days P5–P9; (ii the synergistic, antagonic and modulatory effects (shown by paired inhibition of the receptors on axonal loss; (iii the fact that the coupling of these receptors activates/inhibits the intracellular serine kinases; and (iv the increase of the PKA activity, the reduction of the PKC activity or, in most cases, both situations simultaneously that presumably occurs in all the situations of singly and paired inhibition of the mAChR, AR and TrkB receptors. The use of transgenic animals and various

  18. Thiadiazolodiazepine analogues as a new class of neuromuscular blocking agents: Synthesis, biological evaluation and molecular modeling study.

    Science.gov (United States)

    El-Subbagh, Hussein I; El-Azab, Adel S; Hassan, Ghada S; El-Messery, Shahenda M; Abdel-Aziz, Alaa A-M; El-Taher, Kamal E H

    2017-01-27

    The synthesis, biological evaluation and molecular modeling study of 6,7-dihydro-[1,3,4] thiadiazolo[3,2-a][1,3]diazepine analogues as new class of neuromuscular blocking agents are described. The new compounds act via competitive mechanism with ACh which could be reversed by the anticholinesterase - Physostigmine. Compounds GS-53 (30) and AAH1 (33) induced dose-dependent neuromuscular blockade with onset time of 3 and 10 min, ED50 0.15 and 0.36 mmol/kg i.p., respectively, in rats. Compound 30 proved to be as twice as potent as 33 with rapid onset and shorter duration (P Molecular modeling analysis indicated that hydrogen bonding to Thr120 and Thr124 beside hydrophobic interactions play effective role incorporating the active ligands to nAChR. The obtained model could be useful for further development of new skeletal muscle relaxants. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

  19. [Characteristics of neuromuscular scoliosis].

    Science.gov (United States)

    Putzier, M; Groß, C; Zahn, R K; Pumberger, M; Strube, P

    2016-06-01

    Usually, neuromuscular scolioses become clinically symptomatic relatively early and are rapidly progressive even after the end of growth. Without sufficient treatment they lead to a severe reduction of quality of life, to a loss of the ability of walking, standing or sitting as well as to an impairment of the cardiopulmonary system resulting in an increased mortality. Therefore, an intensive interdisciplinary treatment by physio- and ergotherapists, internists, pediatricians, orthotists, and orthopedists is indispensable. In contrast to idiopathic scoliosis the treatment of patients with neuromuscular scoliosis with orthosis is controversially discussed, whereas physiotherapy is established and essential to prevent contractures and to maintain the residual sensorimotor function.Frequently, the surgical treatment of the scoliosis is indicated. It should be noted that only long-segment posterior correction and fusion of the whole deformity leads to a significant improvement of the quality of life as well as to a prevention of a progression of the scoliosis and the development of junctional problems. The surgical intervention is usually performed before the end of growth. A prolonged delay of surgical intervention does not result in an increased height but only in a deformity progression and is therefore not justifiable. In early onset neuromuscular scolioses guided-growth implants are used to guarantee the adequat development. Because of the high complication rates, further optimization of these implant systems with regard to efficiency and safety have to be addressed in future research.

  20. The neuromuscular activity of Micrurus pyrrhocryptus venom and its neutralization by commercial and specific coral snake antivenoms.

    Science.gov (United States)

    Camargo, Thiago Magalhães; de Roodt, Adolfo Rafael; da Cruz-Höfling, Maria Alice; Rodrigues-Simioni, Léa

    2011-01-01

    The neuromuscular activity ofMicrurus pyrrochryptus venom was studied in chick biventer cervicis (BC) and mouse phrenic nerve-diaphragm (PND) preparations. The venom (0.5-50μg/ml) caused irreversible, time- and concentration-dependent blockade, with BC being more sensitive than PND (50% blockade with 10μg/ml in 22±;3min and 62±4min, respectively; mean±SEM, n=6; p<0.05). In BC preparations, venom (0.5μg/ml) progressively abolished ACh-induced contractures, whereas contractures to exogenous KCl and muscle twitches in curarized preparations were unaffected. The venom neither altered creatine kinase release (venom: 25.8±1.75IU/l vs control: 24.3±2.2IU/l, n=6, after 120min), nor it caused significant muscle damage (50μg of venom/ml vs control: 3.5±0.8% vs 1.1±0.7% for PND; 4.3±1.5% vs 1.2±0.5% for BC, n=5). The venom had low PLA(2) activity. Neurotoxicity was effectively neutralized by commercial Micrurus antivenom and specific antivenom. These findings indicate that M. pyrrhocryptus venom acts postsynaptically on nicotinic receptors, with no significant myotoxicity.

  1. Disturbance and recovery of trunk mechanical and neuromuscular behaviours following repetitive lifting: influences of flexion angle and lift rate on creep-induced effects.

    Science.gov (United States)

    Toosizadeh, Nima; Bazrgari, Babak; Hendershot, Brad; Muslim, Khoirul; Nussbaum, Maury A; Madigan, Michael L

    2013-01-01

    Repetitive lifting is associated with an increased risk of occupational low back disorders, yet potential adverse effects of such exposure on trunk mechanical and neuromuscular behaviours were not well described. Here, 12 participants, gender balanced, completed 40 min of repetitive lifting in all combinations of three flexion angles (33, 66, and 100% of each participant's full flexion angle) and two lift rates (2 and 4 lifts/min). Trunk behaviours were obtained pre- and post-exposure and during recovery using sudden perturbations. Intrinsic trunk stiffness and reflexive responses were compromised after lifting exposures, with larger decreases in stiffness and reflexive force caused by larger flexion angles, which also delayed reflexive responses. Consistent effects of lift rate were not found. Except for reflex delay no measures returned to pre-exposure values after 20 min of recovery. Simultaneous changes in both trunk stiffness and neuromuscular behaviours may impose an increased risk of trunk instability and low back injury. An elevated risk of low back disorders is attributed to repetitive lifting. Here, the effects of flexion angle and lift rate on trunk mechanical and neuromuscular behaviours were investigated. Increasing flexion angle had adverse effects on these outcomes, although lift rate had inconsistent effects and recovery time was more than 20 min.

  2. Blockade of MEK and MDM2 synergistically induces apoptosis in acute myeloid leukemia via BH3-only proteins Puma and Bim

    OpenAIRE

    Zhang, Weiguo; Konopleva, Marina; Burks, Jared K.; Dywer, Karen C.; Schober, Wendy D.; Yang, Jer-Yen; McQueen, Teresa J; Hung, Mien-Chie; Andreeff, Michael

    2010-01-01

    Molecular aberrations of the Ras/Raf/MEK/ERK and/or MDM2/p53 signaling pathways have been reported in 80% and 50% of primary AML samples and confer poor outcome. In this study, anti-leukemic effects of combined MEK inhibition by AZD6244 and non-genotoxic p53 activation by MDM2 antagonist Nutlin3a were investigated. Simultaneous blockade of MEK and MDM2 signaling by AZD6244 and Nutlin3a triggered synergistic proapoptotic responses in AML cell lines (CI = 0.06 ± 0.03 and 0.43 ± 0.03 in OCI/AML3...

  3. O efeito facilitatório do óxido nítrico sobre a transmissão neuromuscular de preparações nervo frênico- diafragma isolado de ratos é Ca++ dependente - DOI: 10.4025/actascibiolsci.v26i4.1528 NO- induced neuromuscular facilitation in the phrenic nerve diaphragm preparation of rats is Ca++ dependent - DOI: 10.4025/actascibiolsci.v26i4.1528

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    Heraldo Esheveria Borges

    2004-04-01

    Full Text Available A pesquisa foi conduzida para verificar se os efeitos neuromusculares induzidos por óxido nítrico (NO poderiam depender dos níveis extracelulares de Ca++. O doador de NO, nitroprussiato de sódio (NPS, e o análogo de GMPc, 8-Br-cGMP, aumentaram a amplitude das contrações musculares (ACM em preparações indiretamente estimuladas a 0.2 Hz, mas não produziram efeitos quando a solução nutriente (Krebs normal foi trocada por Krebs com baixo Ca++/ alto Mg++. NPS e 8-Br-cGMP reduziram a ACM quando as preparações foram diretamente estimuladas, mas tal efeito não foi observado com o uso de Krebs com baixo Ca++/ alto Mg++. Dados sugerem que os efeitos neuromusculares induzidos por NO dependem dos níveis extracelulares de Ca++The research was carried out to verify whether the neuromuscular effects induced by nitric oxide (NO might depend on extracellular level of Ca++. The donor of NO, sodium nitroprusside (SNP, and the analogue of cGMP, 8-Br-cGMP, increased the muscular contraction amplitude (MCA in preparations indirectly stimulated at 0.2 Hz, but did not produce any effect when the nutrient solution was exchanged by Krebs buffer low Ca++/ high Mg++. SNP and 8-Br-cGMP reduced the MCA in preparations directly stimulated. Such effect was not recorded in Krebs buffer low Ca++/ high Mg++. Data suggest that the neuromuscular effects induced by NO or cGMP depend on extracellular level of Ca++

  4. Neuromuscular adaptation to actual and simulated weightlessness

    Science.gov (United States)

    Edgerton, V. R.; Roy, R. R.

    1994-01-01

    The chronic "unloading" of the neuromuscular system during spaceflight has detrimental functional and morphological effects. Changes in the metabolic and mechanical properties of the musculature can be attributed largely to the loss of muscle protein and the alteration in the relative proportion of the proteins in skeletal muscle, particularly in the muscles that have an antigravity function under normal loading conditions. These adaptations could result in decrements in the performance of routine or specialized motor tasks, both of which may be critical for survival in an altered gravitational field, i.e., during spaceflight and during return to 1 G. For example, the loss in extensor muscle mass requires a higher percentage of recruitment of the motor pools for any specific motor task. Thus, a faster rate of fatigue will occur in the activated muscles. These consequences emphasize the importance of developing techniques for minimizing muscle loss during spaceflight, at least in preparation for the return to 1 G after spaceflight. New insights into the complexity and the interactive elements that contribute to the neuromuscular adaptations to space have been gained from studies of the role of exercise and/or growth factors as countermeasures of atrophy. The present chapter illustrates the inevitable interactive effects of neural and muscular systems in adapting to space. It also describes the considerable progress that has been made toward the goal of minimizing the functional impact of the stimuli that induce the neuromuscular adaptations to space.

  5. Autoantibodies in neuromuscular transmission disorders

    National Research Council Canada - National Science Library

    Vincent, Angela

    2008-01-01

    .... The neuromuscular junction (NMJ) is the site of a number of different autoimmune and genetic disorders, and it is also the target of many neurotoxins from venomous snakes, spiders, scorpions and other species...

  6. p38alpha blockade inhibits colorectal cancer growth in vivo by inducing a switch from HIF1alpha- to FoxO-dependent transcription.

    Science.gov (United States)

    Chiacchiera, F; Matrone, A; Ferrari, E; Ingravallo, G; Lo Sasso, G; Murzilli, S; Petruzzelli, M; Salvatore, L; Moschetta, A; Simone, C

    2009-09-01

    Colorectal cancer cell (CRC) fate is governed by an intricate network of signaling pathways, some of which are the direct target of DNA mutations, whereas others are functionally deregulated. As a consequence, cells acquire the ability to grow under nutrients and oxygen shortage conditions. We earlier reported that p38alpha activity is necessary for proliferation and survival of CRCs in a cell type-specific manner and regardless of their phenotype and genotype. Here, we show that p38alpha sustains the expression of HIF1alpha target genes encoding for glycolytic rate-limiting enzymes, and that its inhibition causes a drastic decrease in ATP intracellular levels in CRCs. Prolonged inactivation of p38alpha triggers AMPK-dependent nuclear localization of FoxO3A and subsequent activation of its target genes, leading to autophagy, cell cycle arrest and cell death. In vivo, pharmacological blockade of p38alpha inhibits CRC growth in xenografted nude mice and azoxymethane-treated Apc(Min) mice, achieving both a cytostatic and cytotoxic effect, associated with high nuclear expression of FoxO3A and increased expression of its target genes p21 and PTEN. Hence, inhibition of p38alpha affects the aerobic glycolytic metabolism specific of cancer cells and might be taken advantage of as a therapeutic strategy targeted against CRCs.

  7. Smoldering myocarditis following immune checkpoint blockade.

    Science.gov (United States)

    Norwood, Timothy G; Westbrook, Brian C; Johnson, Douglas B; Litovsky, Silvio H; Terry, Nina L; McKee, Svetlana B; Gertler, Alan S; Moslehi, Javid J; Conry, Robert M

    2017-11-21

    Severe myocarditis associated with electrical conduction abnormalities and occasionally heart failure has been well documented following treatment with immune checkpoint blockade with an estimated incidence of less than 1%. However, the incidence, early detection, and management of less severe immune-related myocarditis are unknown since most immunotherapy trials have not included routine cardiac monitoring. Herein, we provide the first description of subclinical or smoldering myocarditis with minimal signs and symptoms following immune checkpoint blockade with a single dose of ipilimumab and nivolumab. Our patient was diagnosed with immune checkpoint blockade-induced myocarditis based upon an acute rise in serum cardiac troponin I beginning 2 weeks after the initial dose of ipilimumab/nivolumab consistent with the reported median onset of clinical myocarditis at 17 days, as well as a lack of other causes despite extensive cardiac evaluation. The patient initially presented with intractable nausea with no known gastrointestinal etiology. High dose glucocorticoid therapy led to rapid resolution of nausea and a four-fold decrease in troponin I over 4 days. Serum troponin I spiked again following a steroid taper to 13 times the upper limit of normal with endomyocardial biopsy revealing collagen fibrosis and lymphocytic inflammation predominantly comprised of CD8+ T cells consistent with chronic smoldering myocarditis. Serum anti-striated muscle antibodies were also detected with no evidence of rhabdomyolysis. Serum cardiac troponin I levels as an indicator of ongoing myocyte damage gradually improved with chronic prednisone at 10 mg daily. Late addition of intravenous immunoglobulin was associated with rapid normalization of creatine kinase-myocardial band. This case demonstrates that subclinical, smoldering myocarditis may occur following immune checkpoint blockade, with evidence of both humoral and cell-mediated immunity responsive to corticosteroid therapy

  8. Involvement of prelimbic medial prefrontal cortex in panic-like elaborated defensive behaviour and innate fear-induced antinociception elicited by GABAA receptor blockade in the dorsomedial and ventromedial hypothalamic nuclei: role of the endocannabinoid CB1 receptor.

    Science.gov (United States)

    Freitas, Renato Leonardo de; Salgado-Rohner, Carlos José; Hallak, Jaime Eduardo Cecílio; Crippa, José Alexandre de Souza; Coimbra, Norberto Cysne

    2013-09-01

    It has been shown that GABAA receptor blockade in the dorsomedial and ventromedial hypothalamic nuclei (DMH and VMH, respectively) induces elaborated defensive behavioural responses accompanied by antinociception, which has been utilized as an experimental model of panic attack. Furthermore, the prelimbic (PL) division of the medial prefrontal cortex (MPFC) has been related to emotional reactions and the processing of nociceptive information. The aim of the present study was to investigate the possible involvement of the PL cortex and the participation of local cannabinoid CB1 receptors in the elaboration of panic-like reactions and in innate fear-induced antinociception. Elaborated fear-induced responses were analysed during a 10-min period in an open-field test arena. Microinjection of the GABAA receptor antagonist bicuculline into the DMH/VMH evoked panic-like behaviour and fear-induced antinociception, which was decreased by microinjection of the non-selective synaptic contact blocker cobalt chloride in the PL cortex. Moreover, microinjection of AM251 (25, 100 or 400 pmol), an endocannabinoid CB1 receptor antagonist, into the PL cortex also attenuated the defensive behavioural responses and the antinociception that follows innate fear behaviour elaborated by DMH/VMH. These data suggest that the PL cortex plays an important role in the organization of elaborated forward escape behaviour and that this cortical area is also involved in the elaboration of innate fear-induced antinociception. Additionally, CB1 receptors in the PL cortex modulate both panic-like behaviours and fear-induced antinociception elicited by disinhibition of the DMH/VMH through microinjection of bicuculline.

  9. Chemoimmunotherapy by combining oxaliplatin with immune checkpoint blockades reduced tumor burden in colorectal cancer animal model.

    Science.gov (United States)

    Wang, Weiwei; Wu, Ling; Zhang, Jiansheng; Wu, Huiguo; Han, Enkun; Guo, Qiang

    2017-05-20

    Colorectal cancer (CRC) is among one of the top common cancers worldwide. Developing novel comprehensive treatment strategies is critical for improving survival of late stage CRC patients. Recent advances in immune checkpoint blockades provided a novel strategy for treating cancers via stimulating the antitumor immune response. However, the effects of immune checkpoint blockades were limited in CRC due to intrinsic resistance. Oxaliplatin (OXA) based chemotherapy was the foundation of CRC adjuvant chemotherapy. Here, we investigated the potential roles of OXA in inducing immunogenicity and synergizing with immune checkpoints in CRC. Immunogenicity of OXA was tested in CRC cell lines. Immune checkpoint blockades sensitive and resistant CRC models were used to study the potential synergistic roles of OXA with immune checkpoint blockades. We found CT26 mouse model was sensitive to immune checkpoint blockades, while MC38 mouse model was resistant. OXA could induce immunogenic cell death in several human and mouse CRC cell lines. Short term OXA treatment increased immune cell infiltration in MC38 mouse model and therefore enhanced the efficacy of immune checkpoint in MC38 mouse model. As a response to the OXA and immune checkpoint blockades combination, inhibitory immune checkpoints were down-regulated in MC38 tumors, while immune enhancing cytokines were up-regulated. Short term OXA treatment induced antitumor immune response in an immune checkpoint blockades resistant mouse model, therefore synergized with immune checkpoint blockades. Copyright © 2017 Elsevier Inc. All rights reserved.

  10. Neuromuscular disease classification system

    Science.gov (United States)

    Sáez, Aurora; Acha, Begoña; Montero-Sánchez, Adoración; Rivas, Eloy; Escudero, Luis M.; Serrano, Carmen

    2013-06-01

    Diagnosis of neuromuscular diseases is based on subjective visual assessment of biopsies from patients by the pathologist specialist. A system for objective analysis and classification of muscular dystrophies and neurogenic atrophies through muscle biopsy images of fluorescence microscopy is presented. The procedure starts with an accurate segmentation of the muscle fibers using mathematical morphology and a watershed transform. A feature extraction step is carried out in two parts: 24 features that pathologists take into account to diagnose the diseases and 58 structural features that the human eye cannot see, based on the assumption that the biopsy is considered as a graph, where the nodes are represented by each fiber, and two nodes are connected if two fibers are adjacent. A feature selection using sequential forward selection and sequential backward selection methods, a classification using a Fuzzy ARTMAP neural network, and a study of grading the severity are performed on these two sets of features. A database consisting of 91 images was used: 71 images for the training step and 20 as the test. A classification error of 0% was obtained. It is concluded that the addition of features undetectable by the human visual inspection improves the categorization of atrophic patterns.

  11. Double-blind comparison of the variability in spontaneous recovery of cisatracurium- and vecuronium-induced neuromuscular block in adult and elderly patients.

    Science.gov (United States)

    Pühringer, F K; Heier, T; Dodgson, M; Erkola, O; Goonetilleke, P; Hofmockel, R; Gaetke, M R; Mortensen, C R; Upadhyaya, B; Eriksson, L I

    2002-04-01

    This study was designed to compare variability in the offset of two neuromuscular blocking agents with different elimination pathways. The spontaneous recovery profiles of cisatracurium and vecuronium were compared in adult (18-64 years) and elderly (> or =65 years) patients receiving N2O/O2/fentanyl/propofol anaesthesia. Patients were randomised to receive an initial bolus dose and maintenance doses of 3xED95, respectively, 0.6xED95 for cisatracurium (0.15 and 0.03 mg.kg-1) or 2xED95, respectively, and 0.4xED95 for vecuronium (0.1 and 0.02 mg.kg(-1)), as recommended in their prescribing information. Administration of the study drugs was double-blinded, and neuromuscular transmission was monitored using mechanomyography of the evoked response of the adductor pollicis, following ulnar nerve stimulation. The clinically effective duration (minutes) of the initial bolus dose, defined as the mean time to 25% T1 recovery (+/-SD), for the adult and elderly patients was 53.5+/-9.8 and 57.3+/-11.5 for cisatracurium, respectively, and 34.1+/-9.0 and 47.5+/-14.4 for vecuronium, respectively. The duration of spontaneous sufficient recovery (SSR), defined as the mean (+/-SD) time interval in minutes from 25% T1 recovery to a T4:T1 ratio > or =0.8 after the last bolus dose, for the adult, respectively, elderly patients was 28.3+/-8.0 and 31.7+/-10.0 for cisatracurium and 38.5+/-13.2 and 60.3+/-26.1 for vecuronium. Whereas both the clinically effective duration and the duration of SSR are comparable between the adult and the elderly patients receiving cisatracurium, they differ substantially between these two age groups for vecuronium. Furthermore, the variability in offset is significantly lower in patients receiving cisatracurium, especially in the elderly, which may be of particular clinical interest.

  12. 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

    in subcutaneous tissue and skeletal muscle to head-up tilt whereas local blockade was able to prevent the response. Local mechanisms including the local veno-arteriolar reflex appear to play an important role for the observed maintenance of arterial blood pressure in the tilted position during central sympathetic......The effect of head-up tilt upon subcutaneous and skeletal muscle blood flow in the crus was studied before and during epidural blockade in 10 subjects. Relative changes in blood flow were estimated by the local 133Xe washout technique. In subcutaneous tissue head-up tilt induced a decrease in blood...... 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...

  13. 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...

  14. Blockade of Adrenal Medulla-Derived Epinephrine Potentiates Bee Venom-Induced Antinociception in the Mouse Formalin Test: Involvement of Peripheral β-Adrenoceptors

    Directory of Open Access Journals (Sweden)

    Suk-Yun Kang

    2013-01-01

    Full Text Available The injection of diluted bee venom (DBV into an acupoint has been used traditionally in eastern medicine to treat a variety of inflammatory chronic pain conditions. We have previously shown that DBV had a potent antinociceptive efficacy in several rodent pain models. However, the peripheral mechanisms underlying DBV-induced antinociception remain unclear. The present study was designed to investigate the role of peripheral epinephrine on the DBV-induced antinociceptive effect in the mouse formalin assay. Adrenalectomy significantly enhanced the antinociceptive effect of DBV during the late phase of the formalin test, while chemical sympathectomy had no effect. Intraperitoneal injection of epinephrine blocked this adrenalectomy-induced enhancement of the DBV-induced antinociceptive effect. Moreover, injection of a phenylethanolamine N-methyltransferase (PNMT inhibitor enhanced the DBV-induced antinociceptive effect. Administration of nonselective β-adrenergic antagonists also significantly potentiated this DBV-induced antinociception, in a manner similar to adrenalectomy. These results demonstrate that the antinociceptive effect of DBV treatment can be significantly enhanced by modulation of adrenal medulla-derived epinephrine and this effect is mediated by peripheral β-adrenoceptors. Thus, DBV acupoint stimulation in combination with inhibition of peripheral β-adrenoceptors could be a potentially novel strategy for the management of inflammatory pain.

  15. Radiation fibrosis syndrome: neuromuscular and musculoskeletal complications in cancer survivors.

    Science.gov (United States)

    Stubblefield, Michael D

    2011-11-01

    Radiation-induced toxicity is a major cause of long-term disability after cancer treatment. Radiation fibrosis describes the insidious pathologic fibrotic tissue sclerosis that can occur in response to radiation exposure. Radiation fibrosis syndrome describes the myriad clinical manifestations of progressive fibrotic tissue sclerosis resulting from radiation treatment. Radiation-induced damage can include "myelo-radiculo-plexo-neuro-myopathy," causing muscle weakness and dysfunction and contributing to neuromuscular injury. Similarly, radiation damage to neuromuscular structures contributes to radiation-induced trismus and cervical dystonia in head and neck cancer survivors. This narrative review discusses the pathophysiology, anatomy, evaluation, and treatment of neuromuscular, musculoskeletal, and functional disorders that can result as late effects of radiation treatment. Rehabilitation medicine physicians with extensive training in neuromuscular and musculoskeletal medicine as well as in the principles of functional restoration are uniquely positioned to help lead efforts to improve the quality of life for cancer survivors with radiation fibrosis syndrome. Copyright © 2011 American Academy of Physical Medicine and Rehabilitation. Published by Elsevier Inc. All rights reserved.

  16. Estimulação elétrica neuromuscular de média freqüência (russa em cães com atrofia muscular induzida Medium frequency neuromuscular electrical stimulation (russian in dogs with induced muscle atrophy

    Directory of Open Access Journals (Sweden)

    Charles Pelizzari

    2008-06-01

    Full Text Available A estimulação elétrica neuromuscular (EENM de média freqüência (Russa ou de Kotz pode ser empregada para a recuperação de massa muscular em animais apresentando atrofia muscular por desuso. Assim, o objetivo deste trabalho foi empregar a EENM de média freqüência no quadríceps femoral de cães com atrofia muscular induzida, avaliando-se a ocorrência de ganho de massa. Foram utilizados oito cães em dois grupos denominados de GI ou controle e de GII ou tratado. Para a indução da atrofia muscular, a articulação fêmoro-tíbio-patelar esquerda foi imobilizada por 30 dias. Após 48 horas da remoção, foi realizada a EENM nos cães do grupo II, três vezes por semana, com intervalo de 48 horas cada sessão, pelo período de 60 dias. Foram avaliadas a mensuração da perimetria da coxa, da goniometria do joelho, as enzimas creatina-quinase (CK e morfometria das fibras musculares em cortes transversais do músculo vasto lateral, colhido mediante a biópsia muscular. A EENM foi empregada no músculo quadríceps femoral numa freqüência de 2.500Hz, largura de pulso de 50% e relação de tempo on/off de 1:2. Não houve diferença significativa quanto aos valores de perimetria da coxa e a atividade da enzima CK entre os grupos I e II. Na goniometria, houve diminuição significativa (PThe medium frequency neuromuscular electrical stimulation (NMES (Russa or Kotz is designed for recuperation of muscle mass in dogs with muscular atrophy in disuse. This study aims to utilize medium frequency NMES on the femoral quadriceps of dogs with induced muscular atrophy and evaluate the occurrence of gain in mass. Eight dogs in two groups denominated GI, or control, and GII, or treated were used. For the induction of muscular atrophy, the left femoral-tibial-patellar joint was immobilized for 30 days. NMES treatment began 48 hours after the removal of the immobilization device on dogs from group II and was carried out three times per week, with an

  17. Neuromuscular ultrasound of cranial nerves.

    Science.gov (United States)

    Tawfik, Eman A; Walker, Francis O; Cartwright, Michael S

    2015-04-01

    Ultrasound of cranial nerves is a novel subdomain of neuromuscular ultrasound (NMUS) which may provide additional value in the assessment of cranial nerves in different neuromuscular disorders. Whilst NMUS of peripheral nerves has been studied, NMUS of cranial nerves is considered in its initial stage of research, thus, there is a need to summarize the research results achieved to date. Detailed scanning protocols, which assist in mastery of the techniques, are briefly mentioned in the few reference textbooks available in the field. This review article focuses on ultrasound scanning techniques of the 4 accessible cranial nerves: optic, facial, vagus and spinal accessory nerves. The relevant literatures and potential future applications are discussed.

  18. Doenças neuromusculares

    OpenAIRE

    Reed,Umbertina C.

    2002-01-01

    Objetivo: apresentar os dados essenciais para o diagnóstico diferencial entre as principais doenças neuromusculares, denominação genérica sob a qual agrupam-se diferentes afecções, decorrentes do acometimento primário da unidade motora (motoneurônio medular, raiz nervosa, nervo periférico, junção mioneural e músculo). Fontes dos dados: os aspectos clínicos fundamentais para estabelecer o diagnóstico diferencial entre as diferentes doenças neuromusculares, bem como entre estas e as causas de h...

  19. REHABILITATION PROGRAMS FOR PEOPLE WITH NEUROMUSCULAR DISORDERS

    OpenAIRE

    Anton Zupan

    2004-01-01

    Neuromuscular diseases are inherited, chronic, degenerative and progressive. The main characteristics of neuromuscular diseases are: muscular weakness, contractures, scoliosis, respiratory insufficiency, cardiac affection, nutrition disturbances, dependence on the help of others, possible social isolation and physiological problems. Appropriate rehabilitation programs should influence all mentioned characteristics. A special unit for rehabilitation of patients with neuromuscular diseases with...

  20. Neuromuscular activity of the venoms of the Colombian coral snakes Micrurus dissoleucus and Micrurus mipartitus: an evolutionary perspective.

    Science.gov (United States)

    Renjifo, Camila; Smith, Eric N; Hodgson, Wayne C; Renjifo, Juan M; Sanchez, Armando; Acosta, Rodrigo; Maldonado, Jairo H; Riveros, Alain

    2012-01-01

    The venoms of coral snakes (genus Micrurus) are known to induce a broad spectrum of pharmacological activities. While some studies have investigated their potential human effects, little is known about their mechanism of action in terms of the ecological diversity and evolutionary relationships among the group. In the current study we investigated the neuromuscular blockade of the venom of two sister species Micrurus mipartitus and Micrurus dissoleucus, which exhibit divergent ecological characteristics in Colombia, by using the chick biventer cervicis nerve-muscle preparation. We also undertook a phylogenetic analysis of these species and their congeners, in order to provide an evolutionary framework for the American coral snakes. The venom of M. mipartitus caused a concentration-dependant inhibition (3-10 μg/ml) of nerve-mediated twitches and significantly inhibited contractile responses to exogenous ACh (1 mM), but not KCl (40 mM), indicating a postsynaptic mechanism of action. The inhibition of indirect twitches at the lower venom dose (3 μg/ml) showed to be triphasic and the effect was further attenuated when PLA2 was inhibited. M. dissoleucus venom (10-50 μg/ml) failed to produce a complete blockade of nerve-mediated twitches within a 3 h time period and significantly inhibited contractile responses to exogenous ACh (1 mM) and KCl (40 mM), indicating both postsynaptic and myotoxic mechanisms of action. Myotoxic activity was confirmed by morphological studies of the envenomed tissues. Our results demonstrate a hitherto unsuspected diversity of pharmacological actions in closely related species which exhibit divergent ecological characteristics; these results have important implications for both the clinical management of Coral snake envenomings and the design of Micrurus antivenom. Copyright © 2011 Elsevier Ltd. All rights reserved.

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

    NARCIS (Netherlands)

    Schreuder, T.H.A.; Lotringen, J.H. van; Hopman, M.T.E.; Thijssen, D.H.J.

    2014-01-01

    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

  2. A neuromuscular monitoring system based on a personal computer.

    Science.gov (United States)

    White, D A; Hull, M

    1992-07-01

    We have developed a computerized neuromuscular monitoring system (NMMS) using commercially available subsystems, i.e., computer equipment, clinical nerve stimulator, force transducer, and strip-chart recorder. This NMMS was developed for acquisition and analysis of data for research and teaching purposes. Computer analysis of the muscle response to stimulation allows graphic and numeric presentation of the twitch response and calculated ratios. Since the system can store and recall data, research data can be accessed for analysis and graphic presentation. An IBM PC/AT computer is used as the central controller and data processor. The computer controls timing of the nerve stimulator output, initiates data acquisition, and adjusts the paper speed of the strip chart recorder. The data processing functions include establishing control response values (when no neuromuscular blockade is present), displaying force versus time and calculated data graphically and numerically, and storing these data for further analysis. The general purpose nature of the computer and strip chart recording equipment allow modification of the system primarily by changes in software. For example, new patterns of nerve stimulation, such as the posttetanic count, can be programmed into the computer system along with appropriate data display and analysis routines. The NMMS has functioned well in the operating room environment. We have had no episodes of electrocautery interference with the computer functions. The automated features have enhanced the utility of the NMMS.(ABSTRACT TRUNCATED AT 250 WORDS)

  3. Beta blockade and physical training in rats.

    Science.gov (United States)

    Harri, M

    1982-01-01

    Beta adrenergic blocking agents are widely used in the treatment of hypertension. Recent findings indicate that long-term physical training also could reduce elevated blood pressure and many physicians therefore recommend their patients to include physical training in their everyday program. However, it is not known whether a combination of beta blockade and physical training influences the responses of an organism to physical training. This problem was investigated using laboratory rats as an experimental animal model. Both swimming and running training were used, and a group of animals was trained without any medication while the other group performed their daily training session under the influence of 10 mg/kg of propranolol. Some of the effects produced by swimming training, such as hypertrophy of brown adipose tissue and heart muscle, resting bradycardia, increased tachycardic and tail skin temperature responses to isoprenaline, increased calorigenic response to noradrenaline and delayed cooling rate in cold water were similar to those produced by cold acclimation or repeated noradrenaline injections. It is thus tempting to conclude that the training-induced release of noradrenaline was responsible for the changes mentioned. Propranolol, when associated with the training, effectively hampered these changes. Running training increased the activity of oxidative enzymes in the skeletal muscle much more than did swimming training or repeated noradrenaline injections. Furthermore, running training neither induced hypertrophy of the brown fat nor enhanced calorigenic response to noradrenaline; it even led to enhanced rate of body cooling in cold water. Therefore the adaptive changes caused by running training most probably are not due to cold acclimation effects in spite of that propranolol, when associated with the running sessions, antagonized the development of running-induced changes, too. Some of these changes, such as cardiomegaly, training bradycardia and

  4. Muscle ultrasound in neuromuscular disorders.

    NARCIS (Netherlands)

    Pillen, S.; Arts, I.M.P.; Zwarts, M.J.

    2008-01-01

    Muscle ultrasound is a useful tool in the diagnosis of neuromuscular disorders, as these disorders result in muscle atrophy and intramuscular fibrosis and fatty infiltration, which can be visualized with ultrasound. Several prospective studies have reported high sensitivities and specificities in

  5. Palliative care in neuromuscular diseases

    NARCIS (Netherlands)

    de Visser, Marianne; Oliver, David J.

    2017-01-01

    Purpose of review Palliative care is an approach that improves the quality of life of patients and their families facing the problem associated with life-threatening illness. Neuromuscular disorders (NMDs) are characterized by progressive muscle weakness, leading to pronounced and incapacitating

  6. Vocational perspectives and neuromuscular disorders

    NARCIS (Netherlands)

    Andries, F.; Wevers, C. W.; Wintzen, A. R.; Busch, H. F.; Höweler, C. J.; de Jager, A. E.; Padberg, G. W.; de Visser, M.; Wokke, J. H.

    1997-01-01

    The present study analyses the actual occupational situation, vocational handicaps and past labour career of a group of about 1000 Dutch patients suffering from a neuromuscular disorder (NMD). On the basis of the likelihood of a substantial employment history and sufficient numbers of patients, four

  7. Blockade of growth hormone secretagogue receptor 1A signaling by JMV 2959 attenuates the NMDAR antagonist, phencyclidine-induced impairments in prepulse inhibition.

    Science.gov (United States)

    Engel, Jörgen A; Jerlhag, Elisabet; Svensson, Lennart; Smith, Roy G; Egecioglu, Emil

    2015-12-01

    Schizophrenic-spectrum patients commonly display deficits in preattentive information processing as evidenced, for example, by disrupted prepulse inhibition (PPI), a measure of sensorimotor gating. Similar disruptions in PPI can be induced in rodents and primates by the psychotomimetic drug phencyclidine (PCP), a noncompetitive inhibitor of the NMDA receptor. Mounting evidence suggests that the hunger hormone ghrelin and its constitutively active receptor influences neuronal circuits involved in the regulation of mood and cognition. In the present series of experiments, we investigated the effects of ghrelin and the growth hormone secretagogue receptor (GHS-R1A) neutral antagonist, JMV 2959, on acoustic startle responses (ASR), PPI, and PCP-induced alterations in PPI. Intraperitoneal (i.p.) administration of ghrelin (0.033, 0.1, and 0.33 mg/kg) did not alter the ASR or PPI in rats. Conversely, i.p. injection of JMV 2959 (1, 3, and 6 mg/kg), dose dependently decreased the ASR and increased PPI. Pretreatment with JMV 2959 at a dose with no effect on ASR or PPI per se, completely blocked PCP-induced (2 mg/kg) deficits in PPI while pretreatment with the highest dose of ghrelin did not potentiate or alter PPI responses of a sub-threshold dose of PCP (0.75 mg/kg). These findings indicate that the GHS-R1A is involved in specific behavioral effects of PCP and may have relevance for patients with schizophrenia.

  8. Effects of losartan on the blood-brain barrier permeability in long-term nitric oxide blockade-induced hypertensive rats.

    Science.gov (United States)

    Kucuk, Mutlu; Kaya, Mehmet; Kalayci, Rivaze; Cimen, Vedat; Kudat, Hasan; Arican, Nadir; Elmas, Imdat; Korkut, Ferruh

    2002-07-12

    Hypertension is closely associated with vascular endothelial dysfunction. The aim of this study was to investigate the effects of Angiotensin II (ANG II) receptor antagonist losartan on the blood-brain barrier (BBB) permeability in L-NAME-induced hypertension and/or in ANG II-induced acute hypertension in normotensive and hypertensive rats. Systolic blood pressure was measured by tail cuff method before, during and following L-NAME treatment (1 g/L). Losartan (3 mg/kg) was given to the animal for five days. Acute hypertension was induced by ANG II (60 microg/kg). Arterial blood pressure was directly measured on the day of the experiment. BBB disruption was quantified according to the extravasation of the albumin-bound Evans blue dye. Losartan significantly reduced the mean arterial blood pressure from 169 +/- 3.9 mmHg to 82 +/- 2.9 mmHg in L-NAME and from 171 +/- 2.9 mmHg to 84 +/- 2.9 in L-NAME plus losartan plus ANG II groups (p cerebral cortex significantly increased in L-NAME (p microvascular Evans blue dye efflux to brain, and losartan treatment attenuates this protein-bound dye transport into brain tissue presumably due to its protective effect on endothelial cells of brain vessels.

  9. Cardiorespiratory and neuromuscular responses to motocross riding.

    Science.gov (United States)

    Konttinen, Tomi; Kyröläinen, Heikki; Häkkinen, Keijo

    2008-01-01

    The aim of the present study was to examine physiological and neuromuscular responses during motocross riding at individual maximal speed together with the riding-induced changes in maximal isometric force production. Seven A-level (group A) and 5 hobby-class (group H) motocross-riders performed a 30-minute riding test on a motocross track and maximal muscle strength and oxygen uptake (VO2max) tests in a laboratory. During the riding the mean (+/-SD) VO2 reduced in group A from 86 +/- 10% to 69 +/- 6% of the maximum (P physical stress and demands on both skill and physical capacity of the rider. Physical stress occurs as the result of handling of the bike when receiving continuous impacts in the situation requiring both aerobic and anaerobic metabolism. Our data suggest that both maximal capacity and strain during the ride should be measured to analyze the true physiological and neuromuscular demands of motocross ride. For the practice, this study strongly suggests to train not only aerobic and anaerobic capacity but also to use strength and power training for successful motocross riding.

  10. Platelet-activating factor induces histamine release from human skin mast cells in vivo, which is reduced by local nerve blockade.

    Science.gov (United States)

    Petersen, L J; Church, M K; Skov, P S

    1997-05-01

    Intradermal injection of platelet-activating factor (PAF) causes wheal and flare reactions, which are inhibited by antihistamines. However, PAF does not release histamine from human dispersed skin mast cells in vitro. The purpose of this study was to investigate the extent and possible mechanisms of PAF-induced histamine release in human skin in vivo with the use of dermal microdialysis. Hollow dialysis fibers were inserted into the upper dermis in forearm skin and each fiber was perfused with Krebs-Ringer bicarbonate solution at a rate of 3.0 microliters/min. PAF (4.5 to 36 mumol/L), lyso-PAF (36 mumol/L), vehicle (negative control), and codeine 750 or 250 mumol/L (positive control) were injected intradermally above separate fibers. Dialysate was collected in 2-minute fractions for 20 minutes and histamine analyzed spectrofluorometrically. PAF, but not lyso-PAF, caused statistically significant dose-related histamine release and wheal and flare reactions. Intradermal mepivacaine administration significantly abrogated flare reactions by PAF and codeine and inhibited histamine release and wheal reactions by PAF but not by codeine. Long-term topical capsaicin administration inhibited histamine release and wheal reactions by PAF but not by codeine. It inhibited flare reactions induced by both compounds. PAF did not release histamine from blood basophils. These data suggest that PAF induced histamine release from mast cells in intact human skin indirectly via neurogenic activation. Further, on the intradermal injection of PAF histamine release and the skin responses, the wheal and the flare, are differentially regulated by neurogenic components.

  11. In vivo blockade of gamma interferon affects the influenza virus-induced humoral and the local cellular immune response in lung tissue.

    OpenAIRE

    Baumgarth, N.; Kelso, A

    1996-01-01

    Influenza virus infection induces the local production of gamma interferon (IFN-gamma) by T cells and non-T cells in the respiratory tract. To elucidate the possible functions of this cytokine, the humoral and local cellular immune responses to influenza virus were studied in BALB/c mice with or without in vivo neutralization of IFN-gamma by using monoclonal antibodies. Neutralization of IFN-gamma led to a significant reduction in virus-specific titers of immunoglobulins G2a and G3 in serum b...

  12. Transient blockade of the inducible costimulator pathway generates long-term tolerance to factor VIII after nonviral gene transfer into hemophilia A mice.

    Science.gov (United States)

    Peng, Baowei; Ye, Peiqing; Blazar, Bruce R; Freeman, Gordon J; Rawlings, David J; Ochs, Hans D; Miao, Carol H

    2008-09-01

    Formation of inhibitory antibodies is a common problem encountered in clinical treatment for hemophilia. Human factor VIII (hFVIII) plasmid gene therapy in hemophilia A mice also leads to strong humoral responses. We demonstrate that short-term therapy with an anti-ICOS monoclonal antibody to transiently block the inducible costimulator/inducible costimulator ligand (ICOS/ICOSL) signaling pathway led to sustained tolerance to hFVIII in hFVIII plasmid-treated hemophilia A mice and allowed persistent, high-level FVIII functional activity (100%-300% of normal). Anti-ICOS treatment resulted in depletion of ICOS(+)CD4(+) T cells and activation of CD25(+)Foxp3(+) Tregs in the peripheral blood, spleen, and lymph nodes. CD4(+) T cells from anti-ICOS-treated mice did not proliferate in response to hFVIII stimulation and produced high levels of regulatory cytokines, including interleukin-10 and transforming growth factor-beta. Moreover, CD4(+)CD25(+) Tregs from tolerized mice adoptively transferred dominant tolerance in syngeneic hFVIII plasmid-treated hemophilia A mice and reduced the production of antibodies against FVIII. Anti-ICOS-treated mice tolerized to hFVIII generated normal primary and secondary antibody responses after immunization with the T-dependent antigen, bacteriophage Phix 174, indicating maintenance of immune competency. Our data indicate that transient anti-ICOS monoclonal antibody treatment represents a novel single-agent immunomodulatory strategy to overcome the immune responses against transgene product after gene therapy.

  13. Preventing effect of L-type calcium channel blockade on electrophysiological alterations in dentate gyrus granule cells induced by entorhinal amyloid pathology.

    Directory of Open Access Journals (Sweden)

    Hamid Gholami Pourbadie

    Full Text Available The entorhinal cortex (EC is one of the earliest affected brain regions in Alzheimer's disease (AD. EC-amyloid pathology induces synaptic failure in the dentate gyrus (DG with resultant behavioral impairment, but there is little known about its impact on neuronal properties in the DG. It is believed that calcium dyshomeostasis plays a pivotal role in the etiology of AD. Here, the effect of the EC amyloid pathogenesis on cellular properties of DG granule cells and also possible neuroprotective role of L-type calcium channel blockers (CCBs, nimodipine and isradipine, were investigated. The amyloid beta (Aβ 1-42 was injected bilaterally into the EC of male rats and one week later, electrophysiological properties of DG granule cells were assessed. Voltage clamp recording revealed appearance of giant sIPSC in combination with a decrease in sEPSC frequency which was partially reversed by CCBs in granule cells from Aβ treated rats. EC amyloid pathogenesis induced a significant reduction of input resistance (Rin accompanied by a profound decreased excitability in the DG granule cells. However, daily administration of CCBs, isradipine or nimodipine (i.c.v. for 6 days, almost preserved the normal excitability against Aβ. In conclusion, lower tendency to fire AP along with reduced Rin suggest that DG granule cells might undergo an alteration in the membrane ion channel activities which finally lead to the behavioral deficits observed in animal models and patients with early-stage Alzheimer's disease.

  14. Donepezil: A cause of inadequate muscle relaxation and delayed neuromuscular recovery

    Directory of Open Access Journals (Sweden)

    Alka Bhardwaj

    2011-01-01

    Full Text Available A 74-year-old female with diabetes mellitus type II and Alzheimer′s disease, taking donepezil for 4 months was operated for right modified radical mastectomy under general anesthesia. During the procedure a higher dose of non-depolarizing muscle relaxant was required than those recommended for her age yet the muscle relaxation was inadequate intra-operatively. Residual neuromuscular blockade persisted postoperatively, due to the cumulative effect of large doses of non-depolarizing muscle relaxant, needing post-operative ventilatory assistance. After ruling out other causes of resistance to non-depolarizing muscle relaxants, we concluded that acetylcholinesterase inhibitor donepezil was primarily responsible for inadequate muscle relaxation and delayed post-operative neuromuscular recovery.

  15. Cortisol, growth hormone and prolactin responses to insulin-induced hypoglycaemia in hyperthyroid patients before and during beta-adrenoceptor blockade.

    Science.gov (United States)

    Nilsson, O R; Anderberg, B; Karlberg, B E; Kågedal, B

    1980-06-01

    Two beta-adrenoceptor blocking agents, metoprolol (beta-1-selective) and propranolol (non-selective), were used in the treatment of hyperthyroid patients. The response of pituitary stress hormones to insulin-induced hypoglycaemia was investigated before and during beta-adrenoceptor blockage. Treatment with metoprolol (n=10) or propranolol (n=10) produced no changes in the cortisol or prolactin responses to hypoglycaemia. Moreover the growth hormone response remained unaltered during treatment with metoprolol. A small, but statistically significant, augmentation of growth hormone response was obtained during treatment with propranolol. When twelve subjects, euthyroid after final conventional treatment (surger), radioiodine or thyrostatic drugs), were re-examined, the cortisol and prolactin responses were unchanged, although growth hormone concentrations reached a slightly higher maximum value (P less than 0.01). It was concluded that treatment with beta-blocking agents in hyperthyroid subjects has no clinically important influence on the release of pituitary stress hormones during hypoglycaemia.

  16. Porcine epidemic diarrhea virus inhibits dsRNA-induced interferon-β production in porcine intestinal epithelial cells by blockade of the RIG-I-mediated pathway.

    Science.gov (United States)

    Cao, Liyan; Ge, Xuying; Gao, Yu; Herrler, Georg; Ren, Yudong; Ren, Xiaofeng; Li, Guangxing

    2015-08-18

    The lack of optimal porcine cell lines has severely impeded the study and progress in elucidation of porcine epidemic diarrhea virus (PEDV) pathogenesis. Vero cell, an African green monkey kidney cell line, was often used to isolate and propagate PEDV. Nonetheless, the target cells of PEDV in vivo are intestinal epithelial cells, during infection, intestinal epithelia would be damaged and resulted in digestive disorders. The immune functions of porcine epithelial cells and interactions with other immune cell populations display a number of differences compared to other species. Type I interferon (IFN) plays an important role in antiviral immune response. Limited reports showed that PEDV could inhibit type I interferon production. In this study, porcine small intestinal epithelial cells (IECs), the target cells of PEDV, were used as the infection model in vitro to identify the possible molecular mechanisms of PEDV-inhibition IFN-β production. PEDV not only failed to induce IFN-β expression, but also inhibited dsRNA-mediated IFN-β production in IECs. As the key IFN-β transcription factors, we found that dsRNA-induced activation of IFN regulatory factor 3 (IRF-3) was inhibited after PEDV infection, but not nuclear factor-kappaB (NF-κB). To identify the mechanism of PEDV intervention with dsRNA-mediated IFN-β expression more accurately, the role of individual molecules of RIG-I signaling pathway were investigated. In the upstream of IRF-3, TANK-binding kinase 1 (TBK1)-or inhibitor of κB kinase-ε (IKKε)-mediated IFN-β production was not blocked by PEDV, while RIG-I-and its adapter molecule IFN-β promoter stimulator 1 (IPS-1)-mediated IFN-β production were completely inhibited after PEDV infection. Taken together, our data demonstrated for the first time that PEDV infection of its target cell line, IECs, inhibited dsRNA-mediated IFN-β production by blocking the activation of IPS-1 in RIG-I-mediated pathway. Our studies offered new visions in understanding of

  17. Assessment of Neuromuscular Function Using Percutaneous Electrical Nerve Stimulation.

    Science.gov (United States)

    Rozand, Vianney; Grosprêtre, Sidney; Stapley, Paul J; Lepers, Romuald

    2015-09-13

    Percutaneous electrical nerve stimulation is a non-invasive method commonly used to evaluate neuromuscular function from brain to muscle (supra-spinal, spinal and peripheral levels). The present protocol describes how this method can be used to stimulate the posterior tibial nerve that activates plantar flexor muscles. Percutaneous electrical nerve stimulation consists of inducing an electrical stimulus to a motor nerve to evoke a muscular response. Direct (M-wave) and/or indirect (H-reflex) electrophysiological responses can be recorded at rest using surface electromyography. Mechanical (twitch torque) responses can be quantified with a force/torque ergometer. M-wave and twitch torque reflect neuromuscular transmission and excitation-contraction coupling, whereas H-reflex provides an index of spinal excitability. EMG activity and mechanical (superimposed twitch) responses can also be recorded during maximal voluntary contractions to evaluate voluntary activation level. Percutaneous nerve stimulation provides an assessment of neuromuscular function in humans, and is highly beneficial especially for studies evaluating neuromuscular plasticity following acute (fatigue) or chronic (training/detraining) exercise.

  18. Effect of 50% enantiomeric excess bupivacaine mixture combined with pancuronium on neuromuscular transmission in rat phrenic nerve-diaphragm preparation; a pilot study.

    Science.gov (United States)

    de Assunção Braga, Angelica de Fátima; Carvalho, Vanessa Henriques; da Silva Braga, Franklin Sarmento; Potério, Gloria Maria Braga; Santos, Filipe Nadir Caparica; Junqueira, Fernando Eduardo Féres

    2015-11-01

    Local anaesthetics are drugs that are widely used in clinical practice. However, the effects of these drugs on the neuromuscular junction and their influence on the blockade produced by non-depolarising neuromuscular blocking drugs are still under investigation. The aim of this study was to evaluate, in vitro, the influence of a 50% enantiomeric excess bupivacaine mixture on neuromuscular transmission and neuromuscular block produced by pancuronium. Rats were distributed into three groups (n = 5) according to the drug studied namely, 50% enantiomeric excess bupivacaine mixture (5 μg/mL); pancuronium (2 μg/mL); 50% enantiomeric excess bupivacaine mixture + pancuronium. The following parameters were evaluated: (1) Effects of a 50% enantiomeric excess bupivacaine mixture on membrane potential (MP) and miniature endplate potentials (MEPPs); (2) amplitude of diaphragmatic response before and 60 min after the addition of a 50% enantiomeric excess bupivacaine mixture; the degree of neuromuscular block with pancuronium and pancuronium combined with a 50% enantiomeric excess bupivacaine mixture. A 50% enantiomeric excess bupivacaine mixture did not alter the amplitude of muscle response (MP) but decreased the frequency and amplitude of MEPP. The block produced by pancuronium was potentiated by a 50% enantiomeric excess bupivacaine mixture. A 50% enantiomeric excess bupivacaine mixture used alone did not affect neuromuscular transmission, but potentiated the neuromuscular block produced by pancuronium. No action was shown on the muscle fibre, and alterations on MEPPs demonstrated a presynaptic action.

  19. [Respiratory treatments in neuromuscular disease].

    Science.gov (United States)

    Martínez Carrasco, C; Cols Roig, M; Salcedo Posadas, A; Sardon Prado, O; Asensio de la Cruz, O; Torrent Vernetta, A

    2014-10-01

    In a previous article, a review was presented of the respiratory pathophysiology of the patient with neuromuscular disease, as well as their clinical evaluation and the major complications causing pulmonary deterioration. This article presents the respiratory treatments required to preserve lung function in neuromuscular disease as long as possible, as well as in special situations (respiratory infections, spinal curvature surgery, etc.). Special emphasis is made on the use of non-invasive ventilation, which is changing the natural history of many of these diseases. The increase in survival and life expectancy of these children means that they can continue their clinical care in adult units. The transition from pediatric care must be an active, timely and progressive process. It may be slightly stressful for the patient before the adaptation to this new environment, with multidisciplinary care always being maintained. Copyright © 2013 Asociación Española de Pediatría. Published by Elsevier Espana. All rights reserved.

  20. Neuromuscular fatigue in racquet sports.

    Science.gov (United States)

    Girard, Olivier; Millet, Grégoire P

    2008-02-01

    This article describes the physiologic and neural mechanisms that cause neuromuscular fatigue in racquet sports: table tennis, tennis, squash, and badminton. In these intermittent and dual activities, performance may be limited as a match progresses because of a reduced central activation, linked to changes in neurotransmitter concentration or in response to afferent sensory feedback. Alternatively, modulation of spinal loop properties may occur because of changes in metabolic or mechanical properties within the muscle. Finally, increased fatigue manifested by mistimed strokes, lower speed, and altered on-court movements may be caused by ionic disturbances and impairments in excitation-contraction coupling properties. These alterations in neuromuscular function contribute to decrease in racquet sports performance observed under fatigue.

  1. TNF-α-induced protein 3 (TNFAIP3)/A20 acts as a master switch in TNF-α blockade-driven IL-17A expression.

    Science.gov (United States)

    Urbano, Paulo C M; Aguirre-Gamboa, Raúl; Ashikov, Angel; van Heeswijk, Bennie; Krippner-Heidenreich, Anja; Tijssen, Henk; Li, Yang; Azevedo, Valderilio F; Smits, Lisa J T; Hoentjen, Frank; Joosten, Irma; Koenen, Hans J P M

    2017-12-14

    Anti-TNF inhibitors successfully improve the quality of life of patients with inflammatory disease. Unfortunately, not all patients respond to anti-TNF therapy, and some patients show paradoxical immune side effects, which are poorly understood. Surprisingly, anti-TNF agents were shown to promote IL-17A production with as yet unknown clinical implications. We sought to investigate the molecular mechanism underlying anti-TNF-driven IL-17A expression and the clinical implications of this phenomenon. Fluorescence-activated cell sorting, RNA sequencing, quantitative real-time PCR, Western blotting, small interfering RNA interference, and kinase inhibitors were used to study the molecular mechanisms in isolated human CD4 + T cells from healthy donors. The clinical implication was studied in blood samples of patients with inflammatory bowel disease (IBD) receiving anti-TNF therapy. Here we show that anti-TNF treatment results in inhibition of the anti-inflammatory molecule TNF-α-induced protein 3 (TNFAIP3)/A20 in memory CD4 + T cells. We found an inverse relationship between TNFAIP3/A20 expression levels and IL-17A production. Inhibition of TNFAIP3/A20 promotes kinase activity of p38 mitogen-activated protein kinase and protein kinase C, which drives IL-17A expression. Regulation of TNFAIP3/A20 expression and cognate IL-17A production in T cells are specifically mediated through TNF receptor 2 signaling. Ex vivo, in patients with IBD treated with anti-TNF, we found further evidence for an inverse relationship between TNFAIP3/A20 expression levels and IL-17A-producing T cells. Anti-TNF treatment interferes in the TNFAIP3/A20-mediated anti-inflammatory feedback loop in CD4 + T cells and promotes kinase activity. This puts TNFAIP3/A20, combined with IL-17A expression, on the map as a potential tool for predicting therapy responsiveness or side effects of anti-TNF therapy. Moreover, it provides novel targets related to TNFAIP3/A20 activity for superior therapeutic regimens

  2. The undesirable effects of neuromuscular blocking drugs

    DEFF Research Database (Denmark)

    Claudius, C; Garvey, L H; Viby-Mogensen, J

    2009-01-01

    Neuromuscular blocking drugs are designed to bind to the nicotinic receptor at the neuromuscular junction. However, they also interact with other acetylcholine receptors in the body. Binding to these receptors causes adverse effects that vary with the specificity for the cholinergic receptor...... in question. Moreover, all neuromuscular blocking drugs may cause hypersensitivity reactions. Often the symptoms are mild and self-limiting but massive histamine release can cause systematic reactions with circulatory and respiratory symptoms and signs. At the end of anaesthesia, no residual effect...... of a neuromuscular blocking drug should be present. However, the huge variability in response to neuromuscular blocking drugs makes it impossible to predict which patient will suffer postoperative residual curarization. This article discusses the undesirable effects of the currently available neuromuscular blocking...

  3. Endomicroscopy and electromyography of neuromuscular junctions in situ

    Science.gov (United States)

    Brown, Rosalind; Dissanayake, Kosala N; Skehel, Paul A; Ribchester, Richard R

    2014-01-01

    Objective Electromyography (EMG) is used routinely to diagnose neuromuscular dysfunction in a wide range of peripheral neuropathies, myopathies, and neuromuscular degenerative diseases including motor neuron diseases such as amyotrophic lateral sclerosis (ALS). Definitive neurological diagnosis may also be indicated by the analysis of pathological neuromuscular innervation in motor-point biopsies. Our objective in this study was to preempt motor-point biopsy by combining live imaging with electrophysiological analysis of slow degeneration of neuromuscular junctions (NMJs) in vivo. Methods We combined conventional needle electromyography with fiber-optic confocal endomicroscopy (CEM), using an integrated hand-held, 1.5-mm-diameter probe. We utilized as a test bed, various axotomized muscles in the hind limbs of anaesthetized, double-homozygous thy1.2YFP16: WldS mice, which coexpress the Wallerian-degeneration Slow (WldS) protein and yellow fluorescent protein (YFP) in motor neurons. We also tested exogenous vital stains, including Alexa488-α-bungarotoxin; the styryl pyridinium dye 4-Di-2-Asp; and a GFP conjugate of botulinum toxin Type A heavy chain (GFP-HcBoNT/A). Results We show that an integrated EMG/CEM probe is effective in longitudinal evaluation of functional and morphological changes that take place over a 7-day period during axotomy-induced, slow neuromuscular synaptic degeneration. EMG amplitude declined in parallel with overt degeneration of motor nerve terminals. EMG/CEM was safe and effective when nerve terminals and motor endplates were selectively stained with vital dyes. Interpretation Our findings constitute proof-of-concept, based on live imaging in an animal model, that combining EMG/CEM may be useful as a minimally invasive precursor or alternative to motor-point biopsy in neurological diagnosis and for monitoring local administration of potential therapeutics. PMID:25540801

  4. Rydberg Quantum Gates Free from Blockade Error

    Science.gov (United States)

    Shi, Xiao-Feng

    2017-06-01

    Accurate quantum gates are basic elements for building quantum computers. Recently, there has been great interest in designing quantum logic gates by using the blockade effect of Rydberg atoms. The fidelity and operation speed of these gates, however, are fundamentally limited by an intrinsic blockade error. Here we propose a type of quantum gate, which is based on the Rydberg blockade effect, yet free from any blockade error. In contrast to the "blocking" method in previous schemes, we use the Rydberg energy shift to realize a rational generalized Rabi frequency so that a π phase for one input state of the gate emerges. This leads to an accurate Rydberg quantum logic gate that can operate on a 0.1 -μ s time scale or faster because it works by a Rabi frequency which is comparable to the blockade shift.

  5. A discrete event simulation model of clinical and operating room efficiency outcomes of sugammadex versus neostigmine for neuromuscular block reversal in Canada.

    Science.gov (United States)

    Insinga, Ralph P; Joyal, Cédric; Goyette, Alexandra; Galarneau, André

    2016-11-16

    The objective of this analysis is to explore potential impact on operating room (OR) efficiency and incidence of residual neuromuscular blockade (RNMB) with use of sugammadex (Bridion™, Merck & Co., Inc., Kenilworth, NJ USA) versus neostigmine for neuromuscular block reversal in Canada. A discrete event simulation (DES) model was developed to compare ORs using either neostigmine or sugammadex for NMB reversal over one month. Selected inputs included OR procedure and turnover times, hospital policies for paid staff overtime and procedural cancellations due to OR time over-run, and reductions in RNMB and associated complications with sugammadex use. Trials show sugammadex's impact on OR time and RNMB varies by whether full neuromuscular recovery (train-of-four ratio ≥0.9) is verified prior to extubation in the OR. Scenarios were therefore evaluated reflecting varied assumptions for neuromuscular reversal practices. With use of moderate neuromuscular block, when full neuromuscular recovery is verified prior to extubation (93 procedures performed with sugammadex, 91 with neostigmine), use of sugammadex versus neostigmine avoided 2.4 procedural cancellations due to OR time over-run and 33.5 h of paid staff overtime, while saving an average of 62 min per OR day. No difference was observed between comparators for these endpoints in the scenario when full neuromuscular recovery was not verified prior to extubation, however, per procedure risk of RNMB at extubation was reduced from 60% to 4% (reflecting 51 cases prevented), with associated reductions in risks of hypoxemia (12 cases avoided) and upper airway obstruction (23 cases avoided). Sugammadex impact in reversing deep neuromuscular block was evaluated in an exploratory analysis. When it was hypothetically assumed that 30 min of OR time were saved per procedure, the number of paid hours of staff over-time dropped from 84.1 to 32.0, with a 93% reduction in the per patient risk of residual blockade. In clinical

  6. Monitoring strength training: neuromuscular and hormonal profile.

    Science.gov (United States)

    Bosco, C; Colli, R; Bonomi, R; von Duvillard, S P; Viru, A

    2000-01-01

    This study investigated changes induced by a single heavy resistance training session on neuromuscular and endocrine systems in trained athletes, using the same exercises for training and testing. Five different groups volunteered: track and field male sprinters (MS, N = 6), track and field female sprinters (FS, N = 6), body builders (BB, N = 6), and weight lifters performing low-repetition exercise (WLL, N = 4) and high-repetition exercise (WLH, N = 4). In training, the work performed during half and full squat exercise was monitored for mechanical power output as well as EMG analysis on leg extensor muscles of the subjects belonging to the MS, FS, and BB groups. Just before and immediately after the training session, venous blood samples were obtained for RIA determination of testosterone (T), cortisol (C), lutropin (LH), human prolactin (PRL), and follitropin (FSH) in FS and MS. In the other three groups (BB, WLH, and WLL), the hormonal profile was limited to T and human growth hormone (hGH) only. After training the power developed in full squat demonstrated a statistically significant decrease (P training session. Consequently, the EMG/Power ratio increased in both MS and FS, although only in MS a statistical significance was noted (P < 0.05). In MS immediately after the session the levels of C, T, and LH were significantly lower (P < 0.05). No changes were found in FS. In both groups and in BB significant negative correlation was found between changes in T level and EMG/Power ratio in half squat performance. It is likely that adequate T level may compensate the effect of fatigue in FT fibers by ensuring a better neuromuscular efficiency.

  7. Postoperative shoulder pain after laparoscopic hysterectomy with deep neuromuscular blockade and low-pressure pneumoperitoneum

    DEFF Research Database (Denmark)

    Madsen, Matias Vested; Istre, Olav; Staehr-Rye, Anne K

    2016-01-01

    BACKGROUND: Postoperative shoulder pain remains a significant problem after laparoscopy. Pneumoperitoneum with insufflation of carbon dioxide (CO2) is thought to be the most important cause. Reduction of pneumoperitoneum pressure may, however, compromise surgical visualisation. Recent studies......-pressure pneumoperitoneum (12 mmHg) and moderate NMB (single bolus of rocuronium 0.3 mg kg with spontaneous recovery) would reduce the incidence of shoulder pain and improve recovery after laparoscopic hysterectomy. DESIGN: A randomised, controlled, double-blinded study. SETTING: Private hospital in Denmark. PARTICIPANTS...... was the incidence of shoulder pain during 14 postoperative days. Secondary endpoints included area under curve VAS scores for shoulder, abdominal, incisional and overall pain during 4 and 14 postoperative days; opioid consumption; incidence of nausea and vomiting; antiemetic consumption; time to recovery...

  8. Neuromuscular interactions around the knee in children, adults and elderly

    National Research Council Canada - National Science Library

    Kellis, Eleftherios; Mademli, Lida; Patikas, Dimitrios; Kofotolis, Nikolaos

    2014-01-01

    Although injury and neuromuscular activation patterns may be common for all individuals, there are certain factors which differentiate neuromuscular activity responses between children, adults and elderly...

  9. 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.

  10. Kinship and interaction in neuromuscular pharmacology

    NARCIS (Netherlands)

    Schiere, Sjouke

    2006-01-01

    The background of this thesis is presented in the introductory chapters and stafts with a brief history of neuromuscular relaxants. It is followed by a short description of the neuromuscular physiology and pharmacology in chapters 2 and 3, respectively. In chapter 4 the aim of the thesis is

  11. Sugammadex Improves Neuromuscular Function in Patients ...

    African Journals Online (AJOL)

    2018-02-23

    Feb 23, 2018 ... with a modified gamma-cyclodextrin structure offers a viable alternative to the traditional decurarization by cholinesterase inhibitors in the context of the use of steroidal neuromuscular blocking agents. Sugammadex shows its effects through encapsulation of the steroidal neuromuscular blockers, its effects ...

  12. Improvement of Upper Extremity Deficit after Constraint-Induced Movement Therapy Combined with and without Preconditioning Stimulation Using Dual-hemisphere Transcranial Direct Current Stimulation and Peripheral Neuromuscular Stimulation in Chronic Stroke Patients: A Pilot Randomized Controlled Trial

    Directory of Open Access Journals (Sweden)

    Takashi Takebayashi

    2017-10-01

    Full Text Available In this study, we investigated the effects of dual-hemisphere transcranial direct current stimulation (dual-tDCS of both the affected (anodal tDCS and non-affected (cathodal tDCS primary motor cortex, combined with peripheral neuromuscular electrical stimulation (PNMES, on the effectiveness of constraint-induced movement therapy (CIMT as a neurorehabilitation intervention in chronic stroke. We conducted a randomized controlled trial of feasibility, with a single blind assessor, with patients recruited from three outpatient clinics. Twenty chronic stroke patients were randomly allocated to the control group, receiving conventional CIMT, or the intervention group receiving dual-tDCS combined with PNMES before CIMT. Patients in the treatment group first underwent a 20-min period of dual-tDCS, followed immediately by PNMES, and subsequent CIMT for 2 h. Patients in the control group only received CIMT (with no pretreatment stimulation. All patients underwent two CIMT sessions, one in the morning and one in the afternoon, each lasting 2 h, for a total of 4 h of CIMT per day. Upper extremity function was assessed using the Fugl-Meyer Assessment (primary outcome, as well as the amount of use (AOU and quality of movement (QOM scores, obtained via the Motor Activity Log (secondary outcome. Nineteen patients completed the study, with one patient withdrawing after allocation. Compared to the control group, the treatment improvement in upper extremity function and AOU was significantly greater in the treatment than control group (change in upper extremity score, 9.20 ± 4.64 versus 4.56 ± 2.60, respectively, P < 0.01, η2 = 0.43; change in AOU score, 1.10 ± 0.65 versus 0.62 ± 0.85, respectively, P = 0.02, η2 = 0.52. There was no significant effect of the intervention on the QOM between the intervention and control groups (change in QOM score, 1.00 ± 0.62 versus 0.71 ± 0.72, respectively, P = 0.07, η2

  13. Neuromuscular disorders in chronic alcohol intoxication

    Directory of Open Access Journals (Sweden)

    A. Yu. Emelyanova

    2015-01-01

    Full Text Available The paper reviews the present-day Russian and foreign literature on neuromuscular disorders in chronic alcohol intoxication. The most common manifestations of alcohol disease include alcoholic polyneuropathy (PNP and alcohol-induced skeletal muscle injury. The clinical polymorphism of alcoholic PNP is discussed. The paper considers a chronic sensory automatic form due to the direct toxic effects of ethanol and its metabolites during long-term alcohol intoxication, as well as acute/subacute sensorimotor neuropathy, the basis for the pathogenesis of which is B group vitamins, predominantly thiamine, deficiency that develops in the presence of drinking bouts concurrent with malnutrition and/or alcohol-related gastrointestinal tract diseases. In addition to nonuse of alcohol and a properly balanced diet, antioxidant therapy with alphalipoic acid and neurotropic B group vitamins is considered to be pathogenetic therapy for neuropathy. The most common and least studied clinicalform of alcohol-induced musculoskeletal injury is chronic alcoholic myopathy (AM, the diagnostic standard for which is morphometricand immunohistochemical examination of a muscle biopsy specimen. The morphological base for this form of myopathy is predominantly type 2 muscle fiber atrophy caused by impaired protein synthesis and a decreased regenerative potential of muscle fiber. The efficacy of antioxidants and leucine-containing amino acid mixtures in the treatment of chronic AM is discussed.

  14. Transport Through a Coulomb Blockaded Majorana Nanowire

    Science.gov (United States)

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

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

  15. Axillary brachial plexus blockade in moyamoya disease?

    Directory of Open Access Journals (Sweden)

    Saban Yalcin

    2011-01-01

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

  16. CCR2 gene deletion and pharmacologic blockade ameliorate a severe murine experimental autoimmune neuritis model of Guillain-Barre syndrome.

    Directory of Open Access Journals (Sweden)

    Furong Yuan

    Full Text Available The molecular determinants and signaling pathways responsible for hematogenous leukocyte trafficking during peripheral neuroinflammation are incompletely elucidated. Chemokine ligand/receptor pair CCL2/CCR2 has been pathogenically implicated in the acute inflammatory demyelinating polyradiculoneuropathy variant of Guillain-Barré syndrome (GBS. We evaluated the role of CCR2 in peripheral neuroinflammation utilizing a severe murine experimental autoimmune neuritis (sm-EAN model. Sm-EAN was induced in 8-12 week old female SJL CCR2 knockout (CCR2KO, heterozygote (CCR2HT and wild type (CCR2WT mice, and daily neuromuscular severity scores and weights recorded. In vitro and in vivo splenocyte proliferation and cytokine expression assays, and sciatic nerve Toll-like receptor (TLR 2, TLR4 and CCL2 expression assays were performed to evaluate systemic and local innate immune activation at disease onset. Motor nerve electrophysiology and sciatic nerve histology were also performed to characterize the inflammatory neuropathy at expected peak severity. To further determine the functional relevance of CCR2 in sm-EAN, 20 mg/kg CCR2 antagonist, RS 102895 was administered daily for 5 days to a cohort of CCR2WT mice following sm-EAN disease onset, with efficacy compared to 400 mg/kg human intravenous immunoglobulin (IVIg. CCR2KO mice were relatively resistant to sm-EAN compared to CCR2WT and CCR2HT mice, associated with attenuated peripheral nerve demyelinating neuritis. Partial CCR2 gene deletion did not confer any protection against sm-EAN. CCR2KO mice demonstrated similar splenocyte activation or proliferation profiles, as well as TLR2, TLR4 and CCL2 expression to CCR2WT or CCR2HT mice, implying a direct role for CCR2 in sm-EAN pathogenesis. CCR2 signaling blockade resulted in rapid, near complete recovery from sm-EAN following disease onset. RS 102895 was significantly more efficacious than IVIg. CCR2 mediates pathogenic hematogenous monocyte trafficking

  17. Autoantibodies in neuromuscular transmission disorders

    Directory of Open Access Journals (Sweden)

    Vincent Angela

    2008-01-01

    Full Text Available It is a great pleasure to be asked to honour the memory of Dr. Baldev Singh by reviewing the field of autoantibodies in myasthenia gravis and other neurotransmission disorders. The neuromuscular junction (NMJ is the site of a number of different autoimmune and genetic disorders, and it is also the target of many neurotoxins from venomous snakes, spiders, scorpions and other species. The molecular organization of the NMJ is graphically represented in [Figure 1A], where different ion channels, receptors and other proteins are shown. Four of the ion channels or receptors are directly involved in autoimmune diseases. This brief review will not only concentrate on these conditions but also illustrate how their study is helping us to understand the etiology of rare but treatable neurological syndromes of the central nervous system.

  18. FUNCTIONS OF A NEUROMUSCULAR CENTRE

    Directory of Open Access Journals (Sweden)

    Janez Zidar

    2004-12-01

    Full Text Available Main functions of a neuromuscular (NM centre are making diagnosis, treatment and counselling. Some other functions, e. g. forming a register and epidemiological endeavours, could be added. All these activities are expected to be achieved by multidisciplinary approach with the idea that members use the same guidelines and share the same knowledge.NM diseases affect lower levels of the nervous system that is motor units (motor cells in the brainstem and spinal cord, nerve roots, cranial and peripheral nerves, neuromuscular junction, and muscles. There are many such diseases; a few are more common others are rare.Rational approach in making a diagnosis can be divided into several steps. The process begins with a person with clinical symptoms and signs which raise the suspicion of NM disease. The first step is the description of the predominant pattern of muscular wasting and weakness (e. g. limb-girdle, distal, ocular, facio-scapulo-humeral. Each of these syndromes require a differential diagnosis within the motor unit territory what is achieved by means of EMG and muscle biopsy. The latter is even more important to define the nature of the abnormality. Disease nature can also be determined biochemically and, as NM disorders are commonly genetically determined, at the molecular genetic level. Treatment modalities include drugs (causative and symptomatic and other measures such as promoting and maintaining good general health, preventing skeletal deformities, physiotherapy, orthoses, surgery, and prevention of respiratory and cardiac functions. Counselling is mainly by social workers that focus on the practical aspects of coping with illness and disability and by genetic counsellors who gave advise on family planning.

  19. Impairment of diaphragm muscle force and neuromuscular transmission after normothermic cardiopulmonary bypass: effect of low-dose inhaled CO

    Science.gov (United States)

    Ermilov, Leonid G.; Pulido, Juan N.; Atchison, Fawn W.; Zhan, Wen-Zhi; Ereth, Mark H.; Sieck, Gary C.

    2010-01-01

    Cardiopulmonary bypass (CPB) is associated with significant postoperative morbidity, but its effects on the neuromuscular system are unclear. Recent studies indicate that even relatively short periods of mechanical ventilation result in significant neuromuscular effects. Carbon monoxide (CO) has gained recent attention as therapy to reduce the deleterious effects of CPB. We hypothesized that 1) CPB results in impaired neuromuscular transmission and reduced diaphragm force generation; and 2) CO treatment during CPB will mitigate these effects. In adult male Sprague-Dawley rats, diaphragm muscle-specific force and neuromuscular transmission properties were measured 90 min after weaning from normothermic CPB (1 h). During CPB, either low-dose inhaled CO (250 ppm) or air was administered. The short period of mechanical ventilation used in the present study (∼3 h) did not adversely affect diaphragm muscle contractile properties or neuromuscular transmission. CPB elicited a significant decrease in isometric diaphragm muscle-specific force compared with time-matched, mechanically ventilated rats (∼25% decline in both twitch and tetanic force). Diaphragm muscle fatigability to 40-Hz repetitive stimulation did not change significantly. Neuromuscular transmission failure during repetitive activation was 60 ± 2% in CPB animals compared with 76 ± 4% in mechanically ventilated rats (P < 0.05). CO treatment during CPB abrogated the neuromuscular effects of CPB, such that diaphragm isometric twitch force and neuromuscular transmission were no longer significantly different from mechanically ventilated rats. Thus, CPB has important detrimental effects on diaphragm muscle contractility and neuromuscular transmission that are largely mitigated by CO treatment. Further studies are needed to ascertain the underlying mechanisms of CPB-induced neuromuscular dysfunction and to establish the potential role of CO therapy. PMID:20089713

  20. REHABILITATION PROGRAMS FOR PEOPLE WITH NEUROMUSCULAR DISORDERS

    Directory of Open Access Journals (Sweden)

    Anton Zupan

    2004-12-01

    Full Text Available Neuromuscular diseases are inherited, chronic, degenerative and progressive. The main characteristics of neuromuscular diseases are: muscular weakness, contractures, scoliosis, respiratory insufficiency, cardiac affection, nutrition disturbances, dependence on the help of others, possible social isolation and physiological problems. Appropriate rehabilitation programs should influence all mentioned characteristics. A special unit for rehabilitation of patients with neuromuscular diseases within the Institute for rehabilitation of the Republic of Slovenia was established in 1993 at the initiative of the Muscular Dystrophy Association of Slovenia. The main aim of this establishment was to try to guide the patient and his family through the course of the disease. The article describes the work of the mentioned unit. Different clinical rehabilitation programs for people with neuromuscular diseases are presented and some research results of the unit are mentioned.

  1. Precipitated withdrawal during maintenance opioid blockade with extended release naltrexone.

    Science.gov (United States)

    Fishman, Marc

    2008-08-01

    Background There has been increasing interest in the use of extended release injectable naltrexone for the treatment of opioid dependence. Case description We report a case of precipitated withdrawal in a 17-year-old adolescent female receiving extended release naltrexone (Vivitrol) for opioid dependence, following her third serial monthly dose of the medication, several days after using oxycodone with mild intoxication. Conclusions This case suggests that, in some circumstances, the opioid blockade may be overcome when naltrexone levels drop towards the end of the dosing interval, producing vulnerability to subsequent naltrexone-induced withdrawal. This may provide cautionary guidance for clinical management and dosing strategies.

  2. Eccentric Exercise to Enhance Neuromuscular Control.

    Science.gov (United States)

    Lepley, Lindsey K; Lepley, Adam S; Onate, James A; Grooms, Dustin R

    Neuromuscular alterations are a major causal factor of primary and secondary injuries. Though injury prevention programs have experienced some success, rates of injuries have not declined, and after injury, individuals often return to activity with functionality below clinical recommendations. Considering alternative therapies to the conventional concentric exercise approach, such as one that can target neuromuscular injury risk and postinjury alterations, may provide for more effective injury prevention and rehabilitation protocols. Peer-reviewed sources available on the Web of Science and MEDLINE databases from 2000 through 2016 were gathered using searches associated with the keywords eccentric exercise, injury prevention, and neuromuscular control. Eccentric exercise will reduce injury risk by targeting specific neural and morphologic alterations that precipitate neuromuscular dysfunction. Clinical review. Level 4. Neuromuscular control is influenced by alterations in muscle morphology and neural activity. Eccentric exercise beneficially modifies several underlying factors of muscle morphology (fiber typing, cross-sectional area, working range, and pennation angle), and emerging evidence indicates that eccentric exercise is also beneficial to peripheral and central neural activity (alpha motorneuron recruitment/firing, sarcolemma activity, corticospinal excitability, and brain activation). There is mounting evidence that eccentric exercise is not only a therapeutic intervention influencing muscle morphology but also targets unique alterations in neuromuscular control, influencing injury risk.

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

    Science.gov (United States)

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

    2015-10-01

    The Notch ligand delta-like 4 (Dll4) has been identified as a promising target in tumor angiogenesis in preclinical studies, and Dll4 inhibitors have recently entered clinical trials for solid tumors, including ovarian cancers. In this study, we report the development of REGN421 (enoticumab), a fully human IgG1 monoclonal antibody that binds human Dll4 with sub-nanomolar affinity and inhibits Notch signaling. Administering REGN421 to immunodeficient mice engineered to express human Dll4 inhibited the growth of several human tumor xenografts in association with the formation of nonfunctional tumor blood vessels. In ovarian tumor xenograft models, Dll4 was expressed specifically by the tumor endothelium, and Dll4 blockade by human-specific or mouse-specific Dll4 antibodies exerted potent antitumor activity, which relied entirely on targeting Dll4 expressed by tumor stromal cells but not by the tumor cells themselves. However, Dll4 blockade reduced Notch signaling in both blood vessels and tumor cells surrounding the blood vessels, suggesting that endothelial-expressed Dll4 might induce Notch signaling in adjacent ovarian tumor cells. The antitumor effects of targeting Dll4 were augmented significantly by simultaneous inhibition of VEGF signaling, whereas this combined blockade reversed normal organ vascular changes induced by Dll4 blockade alone. Overall, our findings deepen the rationale for antibody-based strategies to target Dll4 in ovarian cancers, especially in combination with VEGF blockade. ©2015 American Association for Cancer Research.

  4. Neuromuscular function in healthy occlusion.

    Science.gov (United States)

    Forrester, S E; Allen, S J; Presswood, R G; Toy, A C; Pain, M T G

    2010-09-01

    This study aimed to measure neuromuscular function for the masticatory muscles under a range of occlusal conditions in healthy, dentate adults. Forty-one subjects conducted maximum voluntary clenches under nine different occlusal loading conditions encompassing bilateral posterior teeth contacts with the mandible in different positions, anterior teeth contacts and unilateral posterior teeth contacts. Surface electromyography was recorded bilaterally from the anterior temporalis, superficial masseter, sternocleidomastoid, anterior digastric and trapezius muscles. Clench condition had a significant effect on muscle function (P = 0.0000) with the maximum function obtained for occlusions with bilateral posterior contacts and the mandible in a stable centric position. The remaining contact points and moving the mandible to a protruded position, whilst keeping posterior contacts, resulted in significantly lower muscle activities. Clench condition also had a significant effect on the per cent overlap, anterior-posterior and torque coefficients (P = 0.0000-0.0024), which describe the degree of symmetry in these muscle activities. Bilateral posterior contact conditions had significantly greater symmetry in muscle activities than anterior contact conditions. Activity in the sternocleidomastoid, anterior digastric and trapezius was consistently low for all clench conditions, i.e. centric position, whilst with anterior teeth contacts, both the muscle activity and the degree of symmetry in muscle activity are significantly reduced.

  5. Effect of desiccating environmental stress versus systemic muscarinic AChR blockade on dry eye immunopathogenesis.

    Science.gov (United States)

    Chen, Yihe; Chauhan, Sunil K; Lee, Hyun Soo; Stevenson, William; Schaumburg, Chris S; Sadrai, Zahra; Saban, Daniel R; Kodati, Shilpa; Stern, Michael E; Dana, Reza

    2013-04-03

    A majority of experimental data on dry eye disease (DED) immunopathogenesis have been derived from a murine model of DED that combines desiccating environmental stress with systemic muscarinic acetylcholine receptor (mAChR) inhibition. However, to our knowledge the effects of pharmacologic mAChR blockade on the pathogenesis of experimental DED have not been evaluated systemically. The purpose of our study was to investigate the differential effects of desiccating environmental stress and mAChR inhibition on the pathogenesis of DED. DED was induced in female C57BL/6 mice by exposure to a desiccating environment in the controlled-environment chamber or to systemic scopolamine, or by performing extraorbital lacrimal gland excision. Clinical disease was assessed using corneal fluorescein staining (CFS) and the cotton thread test (CTT). Corneal CD11b(+) and conjunctival CD3(+) T-cell infiltration were evaluated by flow cytometry. T-cells from draining cervical lymph nodes (CLN) and distant inguinal lymph nodes (ILN) were analyzed for Th1, Th2, Th17, and Treg responses by flow cytometry and ELISA. Desiccating environmental stress and systemic mAChR blockade induced similar clinical signs of DED. However, desiccating environmental stress imparted higher conjunctival CD3(+) T-cell infiltration, and greater Th17-cell activity and Treg dysfunction than mAChR blockade, while mAChR blockade decreased tear secretion to a greater extent than desiccating environmental stress. Systemic mAChR blockade attenuated Th17 activity and enhanced Th2 and Treg responses without affecting Th1 activity. In vivo inhibition of mAChRs variably affects CD4(+) T-cell subsets, and desiccating environmental stress and systemic mAChR blockade induce DED through different primary pathogenic mechanisms.

  6. Perioperative β-adrenoceptor blockade in major non-cardiac surgery

    African Journals Online (AJOL)

    QuickSilver

    2003-05-08

    May 8, 2003 ... Poldermans in 1999 randomized high-risk patients (presence of both clinical risk factors and dobutamine inducible wall motion abnormalities) undergoing abdominal and infrainguinal vascular surgery to β-adrenoceptor blockade from one week prior to surgery until 30 days postoperatively.25 This study ...

  7. Acceleromyography and mechanomyography for establishing potency of neuromuscular blocking agents: a randomized-controlled trial

    DEFF Research Database (Denmark)

    Claudius, C; Viby-Mogensen, J; Skovgaard, Lene Theil

    2009-01-01

    BACKGROUND: Acceleromyography (AMG) is increasingly being used in neuromuscular research, including in studies establishing the potency of neuromuscular blocking and reversal agents. However, AMG is insufficiently validated for use interchangeably with the gold standard, mechanomyography (MMG......) for this purpose. The aim of this study was to compare AMG and MMG for establishing dose-response relationship and potency, using rocuronium as an example. METHODS: We included 40 adult patients in this randomized-controlled single-dose response study. Anaesthesia was induced and maintained with propofol...... difference between AMG and MMG is so small that it justifies AMG to be used for establishing the potency of neuromuscular blocking agents. However, the wide CIs show that we cannot rule out a 13% higher ED(50) and a 26% higher ED(95) for AMG....

  8. Employment profiles in neuromuscular diseases.

    Science.gov (United States)

    Fowler, W M; Abresch, R T; Koch, T R; Brewer, M L; Bowden, R K; Wanlass, R L

    1997-01-01

    Consumer and rehabilitation provider factors that might limit employment opportunities for 154 individuals with six slowly progressive neuromuscular diseases (NMD) were investigated. The NMDs were spinal muscular atrophy (SMA), hereditary motor sensory neuropathy (HMSN), Becker's muscular dystrophy (BMD), facioscapulohumeral muscular dystrophy (FSHD), myotonic muscular dystrophy (MMD), and limb-girdle syndrome (LGS). Forty percent were employed in the competitive labor market at the time of the study, 50% had been employed in the past, and 10% had never been employed. The major consumer barrier to employment was education. Other important factors were type of occupation, intellectual capacity, psychosocial adjustment, and the belief by most individuals that their physical disability was the only or major barrier to obtaining a job. Psychological characteristics were associated with level of unemployment. However, physical impairment and disability were not associated with level of unemployment. There also were differences among the types of NMDs. Compared with the SMA, HMSN, BMD, and FSHD groups, the MMD and LGS groups had significantly higher levels of unemployment, lower educational levels, and fewer employed professional, management, and technical workers. Nonphysical impairment factors such as a low percentage of college graduates, impaired intellectual function in some individuals, and poor psychological adjustment were correlated with higher unemployment levels in the MMD group. Unemployment in the LGS group was correlated with a failure to complete high school. Major provider barriers to employment were the low level of referrals to Department of Rehabilitation by physicians and the low percentage of acceptance into the State Department of Rehabilitation. The low rate of acceptance was primarily attributable to the low number of referrals compounded by a lack of counselor experience with individuals with NMD. Both consumer and provider barriers may

  9. Protein defects in neuromuscular diseases

    Directory of Open Access Journals (Sweden)

    Vainzof M.

    2003-01-01

    Full Text Available Muscular dystrophies are a heterogeneous group of genetically determined progressive disorders of the muscle with a primary or predominant involvement of the pelvic or shoulder girdle musculature. The clinical course is highly variable, ranging from severe congenital forms with rapid progression to milder forms with later onset and a slower course. In recent years, several proteins from the sarcolemmal muscle membrane (dystrophin, sarcoglycans, dysferlin, caveolin-3, from the extracellular matrix (alpha2-laminin, collagen VI, from the sarcomere (telethonin, myotilin, titin, nebulin, from the muscle cytosol (calpain 3, TRIM32, from the nucleus (emerin, lamin A/C, survival motor neuron protein, and from the glycosylation pathway (fukutin, fukutin-related protein have been identified. Mutations in their respective genes are responsible for different forms of neuromuscular diseases. Protein analysis using Western blotting or immunohistochemistry with specific antibodies is of the utmost importance for the differential diagnosis and elucidation of the physiopathology of each genetic disorder involved. Recent molecular studies have shown clinical inter- and intra-familial variability in several genetic disorders highlighting the importance of other factors in determining phenotypic expression and the role of possible modifying genes and protein interactions. Developmental studies can help elucidate the mechanism of normal muscle formation and thus muscle regeneration. In the last fifteen years, our research has focused on muscle protein expression, localization and possible interactions in patients affected by different forms of muscular dystrophies. The main objective of this review is to summarize the most recent findings in the field and our own contribution.

  10. Tumor necrosis factor-α blockade treatment decreased CD154 (CD40-ligand expression in rheumatoid arthritis.

    Directory of Open Access Journals (Sweden)

    Chien-Hsueh Tung

    Full Text Available CD154 (commonly referred to as CD40-ligand is a critical T cell factor that participates in the pathogenesis of autoimmune and is over-expressed in rheumatoid arthritis (RA. TNF-α blockade treatment had dramatic efficacy in RA.To investigate whether TNF-α blockade treatment can inhibit CD154 expression in RA.Blood samples were collected from 33 patients with rheumatoid arthritis before and 3 months after TNF-α blockade treatment. Clinical serological data determined by standard assays and T cell CD154 expression levels determined by flow cytometry were statistically analyzed for these two time points.The percentage of CD154 expression on gated CD4+ T cells of PBMCs from RA patients after 3 months TNF-α blockade treatment was significantly lower than before treatment (2.94 ± 3.21% vs. 7.21 ± 5.64%; p = 0.0001. The disease activity and anti-CCP antibody levels were also significantly reduced after TNF-α blockade treatment. The CD154 expression levels were positively correlated with disease activity index DAS28, and CRP. The post-stimulated CD154 expression percentage of purified CD4+ T cells between baseline and after TNF-α blockade treatment was not significantly different (p = 0.221. Baseline CD154 levels were positively correlated with treatment-induced changes in DAS28 (p = 0.014; r2 = 0.187.TNF-α blockade treatment significantly decreased the CD154 expression on CD4+ T cells, disease activity and anti-CCP antibody simultaneously in RA patients. However TNF-α blockade did not impair T cell capacity to express CD154 after stimulation. These results suggest that decreased CD154 expression after TNF-α blockade may be due to decreased RA disease activity but not direct inhibition of CD154 responsiveness of T cells.

  11. Tumor necrosis factor-α blockade treatment decreased CD154 (CD40-ligand) expression in rheumatoid arthritis.

    Science.gov (United States)

    Tung, Chien-Hsueh; Lu, Ming-Chi; Lai, Ning-Sheng; Wu, Shu-Fen

    2017-01-01

    CD154 (commonly referred to as CD40-ligand) is a critical T cell factor that participates in the pathogenesis of autoimmune and is over-expressed in rheumatoid arthritis (RA). TNF-α blockade treatment had dramatic efficacy in RA. To investigate whether TNF-α blockade treatment can inhibit CD154 expression in RA. Blood samples were collected from 33 patients with rheumatoid arthritis before and 3 months after TNF-α blockade treatment. Clinical serological data determined by standard assays and T cell CD154 expression levels determined by flow cytometry were statistically analyzed for these two time points. The percentage of CD154 expression on gated CD4+ T cells of PBMCs from RA patients after 3 months TNF-α blockade treatment was significantly lower than before treatment (2.94 ± 3.21% vs. 7.21 ± 5.64%; p = 0.0001). The disease activity and anti-CCP antibody levels were also significantly reduced after TNF-α blockade treatment. The CD154 expression levels were positively correlated with disease activity index DAS28, and CRP. The post-stimulated CD154 expression percentage of purified CD4+ T cells between baseline and after TNF-α blockade treatment was not significantly different (p = 0.221). Baseline CD154 levels were positively correlated with treatment-induced changes in DAS28 (p = 0.014; r2 = 0.187). TNF-α blockade treatment significantly decreased the CD154 expression on CD4+ T cells, disease activity and anti-CCP antibody simultaneously in RA patients. However TNF-α blockade did not impair T cell capacity to express CD154 after stimulation. These results suggest that decreased CD154 expression after TNF-α blockade may be due to decreased RA disease activity but not direct inhibition of CD154 responsiveness of T cells.

  12. Neuromuscular Fatigue during Prolonged Exercise in Hypoxia.

    Science.gov (United States)

    Jubeau, Marc; Rupp, Thomas; Temesi, John; Perrey, Stéphane; Wuyam, Bernard; Millet, Guillaume Y; Verges, Samuel

    2017-03-01

    Prolonged cycling exercise performance in normoxia is limited because of both peripheral and central neuromuscular impairments. It has been reported that cerebral perturbations are greater during short-duration exercise in hypoxia compared with normoxia. The purpose of this study was to test the hypothesis that central deficits are accentuated in hypoxia compared with normoxia during prolonged (three bouts of 80 min separated by 25 min) whole-body exercise at the same relative intensity. Ten subjects performed two sessions consisting of three 80-min cycling bouts at 45% of their relative maximal aerobic power in normoxia and hypoxia (FiO2 = 0.12). Before exercise and after each bout, maximal voluntary force, voluntary activation assessed with nerve stimulation and transcranial magnetic stimulation, corticospinal excitability (motor evoked potential), intracortical inhibition (cortical silent period), and electrical (M-wave) and contractile (twitch and doublet peak forces) properties of the knee extensors were measured. Prefrontal and motor cortical oxygenation was also recorded during each cycling bout in both conditions. A significant but similar force reduction (≈-22%) was observed at the end of exercise in normoxia and hypoxia. The modifications of voluntary activation assessed with transcranial magnetic stimulation and nerve stimulation, motor evoked potential, cortical silent period, and M-wave were also similar in both conditions. However, cerebral oxygenation was reduced in hypoxia compared with normoxia. These findings show that when performed at the same relative low intensity, prolonged exercise does not induce greater supraspinal fatigue in hypoxia compared with normoxia. Despite lower absolute exercise intensities in hypoxia, reduced brain O2 availability might contribute to similar amounts of central fatigue compared with normoxia.

  13. Immune Checkpoint Blockade in Cancer Therapy

    National Research Council Canada - National Science Library

    Postow, Michael A; Callahan, Margaret K; Wolchok, Jedd D

    2015-01-01

    ... agents that target these pathways. Treatment with both CTLA-4 and PD-1/PD-L1 blockade is associated with a unique pattern of adverse events called immune-related adverse events, and occasionally, unusual kinetics of tumor response are seen...

  14. [Ultrasound-guided peripheral nerve blockade].

    Science.gov (United States)

    Schwemmer, Ulrich; Markus, Christian K; Brederlau, Jörg; Roewer, Norbert

    2006-01-01

    Without miniaturization resulting in affordable hand-held ultrasound systems, ultrasound-guided regional anaesthesia would not be practicable. Nowadays facilitation of nerve blockade by means of ultrasound is achievable even in remote locations. Non-traumatic technique, visualisation of nerves, surrounding structures and the ability to assess the spread of the injected local anaesthetic combined with a high and predictable success rate are the major advantages when ultrasound is used in regional anaesthetic practise. After a short recapitulation of physical principles related to ultrasound this article focuses on the specific features related to ultrasound-guided identification and blockade of peripheral nerves. Technical pitfalls and their implications for a successful nerve block are put into perspective. Ultrasound can be used to facilitate blockade of the upper and lower extremity. The advantages and limitations of the technique when applied to the classical approaches for blockade of the brachial plexus and the femoral and ischiadic nerve are discussed. Ultrasound-guided regional anaesthesia is a valuable tool to improve safety, success rate and patient comfort in daily anaesthetic practise.

  15. Effects of Aldrin-transdiol on neuromuscular facilitation and depression

    NARCIS (Netherlands)

    Akkermans, L.M.A.; Bercken, J. van den; Zalm, J.M. van der

    The effects of aldrin-transdiol, one of the active metabolites of the insecticide dieldrin, on evoked transmitter release, neuromuscular facilitation and neuromuscular depression have been studied in frog sartorius nerve-muscle preparations. Conventional techniques of intracellular recordings were

  16. Quantitative skeletal muscle ultrasonography in children with suspected neuromuscular disease.

    NARCIS (Netherlands)

    Pillen, S.; Scholten, R.R.; Zwarts, M.J.; Verrips, A.

    2003-01-01

    We determined prospectively the diagnostic value of quantitative ultrasonography in detecting neuromuscular disorders in children. Ultrasonographic scans of four muscles were made in 36 children with symptoms or signs suggestive of neuromuscular disease, such as muscle weakness and hypotonia. The

  17. 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.

  18. Acute and chronic neuromuscular adaptations to local vibration training.

    Science.gov (United States)

    Souron, Robin; Besson, Thibault; Millet, Guillaume Y; Lapole, Thomas

    2017-10-01

    Vibratory stimuli are thought to have the potential to promote neural and/or muscular (re)conditioning. This has been well described for whole-body vibration (WBV), which is commonly used as a training method to improve strength and/or functional abilities. Yet, this technique may present some limitations, especially in clinical settings where patients are unable to maintain an active position during the vibration exposure. Thus, a local vibration (LV) technique, which consists of applying portable vibrators directly over the tendon or muscle belly without active contribution from the participant, may present an alternative to WBV. The purpose of this narrative review is (1) to provide a comprehensive overview of the literature related to the acute and chronic neuromuscular changes associated with LV, and (2) to show that LV training may be an innovative and efficient alternative method to the 'classic' training programs, including in the context of muscle deconditioning prevention or rehabilitation. An acute LV application (one bout of 20-60 min) may be considered as a significant neuromuscular workload, as demonstrated by an impairment of force generating capacity and LV-induced neural changes. Accordingly, it has been reported that a training period of LV is efficient in improving muscular performance over a wide range of training (duration, number of session) and vibration (frequency, amplitude, site of application) parameters. The functional improvements are principally triggered by adaptations within the central nervous system. A model illustrating the current research on LV-induced adaptations is provided.

  19. Neuromuscular Junction Dismantling in Amyotrophic Lateral Sclerosis

    Directory of Open Access Journals (Sweden)

    Valentina Cappello

    2017-10-01

    Full Text Available Neuromuscular junction assembly and plasticity during embryonic, postnatal, and adult life are tightly regulated by the continuous cross-talk among motor nerve endings, muscle fibers, and glial cells. Altered communications among these components is thought to be responsible for the physiological age-related changes at this synapse and possibly for its destruction in pathological states. Neuromuscular junction dismantling plays a crucial role in the onset of Amyotrophic Lateral Sclerosis (ALS. ALS is characterized by the degeneration and death of motor neurons leading to skeletal muscle denervation, atrophy and, most often, death of the patient within five years from diagnosis. ALS is a non-cell autonomous disease as, besides motor neuron degeneration, glial cells, and possibly muscle fibers, play a role in its onset and progression. Here, we will review the recent literature regarding the mechanisms leading to neuromuscular junction disassembly and muscle denervation focusing on the role of the three players of this peripheral tripartite synapse.

  20. [Electrodiagnosis in disorders of neuromuscular transmission].

    Science.gov (United States)

    Chumillas, M J; Cortés, V

    Electrophysiological studies are of recognized use in the confirmation of alterations of neuromuscular transmission in further determining their physiopathological characteristics, helping to differentiate them from other conditions with secondary effects on their function. In our study we review the physiopathology of these disorders which compromise the safety factor of the neuromuscular junction, by presynaptic or postsynaptic alterations, and forms the basis of the results of electrophysiological studies. We describe the techniques currently most used: repetitive stimulation and single fibre electromyography complemented by conventional electromyography. Their application and findings in the commonest syndromes are discussed. Finally, their sensitivity, specificity and difficulties are considered.

  1. Research highlights of partial neuromuscular disorders

    Directory of Open Access Journals (Sweden)

    Cheng ZHANG

    2014-05-01

    Full Text Available In order to understand the latest progression on neuromuscular disorders for clinicians, this review screened and systemized the papers on neuromuscular disorders which were collected by PubMed from January 2013 to February 2014. This review also introduced the clinical diagnosis and treatment hightlights on glycogen storage disease type Ⅱ (GSD Ⅱ, Duchenne muscular dystrophy (DMD, amyotrophic lateral sclerosis (ALS and spinal muscular atrophy (SMA. The important references will be useful for clinicians. doi: 10.3969/j.issn.1672-6731.2014.05.004

  2. 21 CFR 882.5860 - Implanted neuromuscular stimulator.

    Science.gov (United States)

    2010-04-01

    ... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Implanted neuromuscular stimulator. 882.5860... (CONTINUED) MEDICAL DEVICES NEUROLOGICAL DEVICES Neurological Therapeutic Devices § 882.5860 Implanted neuromuscular stimulator. (a) Identification. An implanted neuromuscular stimulator is a device that provides...

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

    Science.gov (United States)

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

    2002-04-01

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

  4. Use of rocuronium and sugammadex under neuromuscular transmission monitoring in a patient with multiple sclerosis

    Directory of Open Access Journals (Sweden)

    Chryssoula Staikou

    2017-01-01

    Full Text Available Multiple sclerosis (MS is a potentially disabling disease characterized by demyelinating lesions in the central nervous system. One of the anesthetic challenges encountered in surgical patients with MS is the management of neuromuscular blockade (NMB and its reversal. We report a case of a 31-year-old female patient suffering from MS, who underwent gynecological surgery under general anesthesia with sevoflurane, fentanyl, and rocuronium which was successfully reversed with sugammadex. Neuromuscular transmission (NMT monitoring was used to guide the intraoperative doses of rocuronium and also the reversal of NMB by the use of sugammadex to ensure a safe tracheal extubation. In addition, delivered volatile was titrated according to anesthetic depth monitoring (Bispectral Index while esophageal temperature was also monitored for the maintenance of normothermia. Postoperatively, a multimodal analgesic scheme offered a high-quality analgesia and sleep, minimization of anxiety, and increased patient satisfaction. At 1-month follow-up, the patient's course was uncomplicated without any MS exacerbation. We consider that the use of rocuronium and sugammadex under NMT monitoring may represent a useful and safe choice in patients with MS.

  5. Neuromuscular Exercise Post Partial Medial Meniscectomy

    DEFF Research Database (Denmark)

    Hall, Michelle; Hinman, Rana S; Wrigley, Tim V

    2015-01-01

    : In patients 3-12 months following a medial arthroscopic partial meniscectomy, a neuromuscular exercise program did not alter the peak knee adduction moment, a key predictor of osteoarthritis structural disease progression. Australia and New Zealand Clinical Trials Registry (#ACTRN12612000542897)....

  6. Experienced and physiological fatigue in neuromuscular disorders.

    NARCIS (Netherlands)

    Schillings, M.L.; Kalkman, J.S.; Janssen, H.M.; Engelen, B.G.M. van; Bleijenberg, G.; Zwarts, M.J.

    2007-01-01

    OBJECTIVE: Fatigue has been described as a typical symptom of neurological diseases. It might be caused both by changes at the peripheral and at the central level. This study measured the level of experienced fatigue and physiological correlates of fatigue in three genetically defined neuromuscular

  7. Postoperative neuromuscular function following non-depolarising ...

    African Journals Online (AJOL)

    2016-07-03

    Jul 3, 2016 ... speaking, difficulty swallowing, unsteady gait and sensations of fatigue and muscle weakness.8,10,24–26 These newer studies have resulted in a recovery to a TOF of 0.9 or greater prior to extubation becoming widely adopted as a standard of anaesthetic practice following non-depolarising neuromuscular ...

  8. Neuromuscular dysfunction associated with delayed weaning from ...

    African Journals Online (AJOL)

    Yehia Khalil

    2012-03-21

    Mar 21, 2012 ... Neuromuscular dysfunction associated with delayed weaning from mechanical ventilation in patients with respiratory failure. Yehia Khalil a. , Emad El Din Mustafa a. , Ahmed Youssef a. ,. Mohamed Hassan Imam b,. *, Amni Fathy El Behiry a a Department of Chest, Faculty of Medicine, Alexandria University, ...

  9. Effect of inherited abnormalities of calcium regulation on human neuromuscular transmission.

    Science.gov (United States)

    Maselli, Ricardo A; Books, Wendy; Dunne, Vanessa

    2003-09-01

    Synaptotagmins are abundant synaptic proteins that represent the best candidate for the calcium sensor at the nerve terminal. The pore-forming, voltage-sensing transmembrane alpha-1 subunit of the P/Q voltage-gated calcium channel (or Ca(v)2.1) encoded by the CACNA1A gene is another major component of the process of action potential-evoked exocytosis at the adult mammalian neuromuscular junction. Defects of these proteins, in nonhuman species, result in severe disruption of rapid synaptic transmission. This paper investigates the molecular bases of inherited presynaptic deficits of neuromuscular transmission in humans. Patients with congenital presynaptic failure, including two patients with episodic ataxia type 2 (EA-2) due to CACNA1A mutations, were studied with muscle biopsy, microelectrode studies, electron microscopy, DNA amplification, and sequencing. All patients, including EA-2 patients, showed selective failure of the action potential-dependent release without reduction of the spontaneous release of neurotransmitter. In addition, patients with EA-2 showed partial blockade of neuromuscular transmission with the N-type blocker omega-conotoxin not seen in controls. The EM showed a varied degree of increased complexity of postsynaptic folds. Mutational analysis in candidate genes, including human synaptotagmin II, syntaxin 1A, synaptobrevin I, SNAP 25, CACNA1A, CACNB2, and Rab3A, was unrevealing. Although no mutations in candidate genes were found in patients with inborn presynaptic failure, functional and structural similarities between this group and patients with EA-2 due to CACNA1A mutations suggest a common pathogenic mechanism.

  10. Assessment of neuromuscular block: comparison of three clinical methods and evoked electromyography.

    Science.gov (United States)

    Tammisto, T; Wirtavuori, K; Linko, K

    1988-01-01

    Three clinical methods, visual, tactile and 'spring', for the assessment of neuromuscular blockade were compared to the EMG recording evoked during enflurane anaesthesia and relaxation with vecuronium in 33 patients. During maintenance of the block, the tactile method, based on the recognition of the strength of movement of the patient's thumb against the observer's fingers, was more accurate than the two other methods. The correlation coefficient compared to the TI of the EMG was 0.77. The tactile method led to over-estimation of muscle strength in only 9-10% of the assessments made by the anaesthetists, while this happened in about one-third of the cases when the visual method was applied. The observers under-estimated the muscle power in about 30% of the assessments made with each of the clinical methods. During the recovery, the mean train-of-four (TOF) ratio of the EMG was less than 40% when the anaesthetists announced that they could detect no fade with the visual or tactile methods. The corresponding value obtained with the spring method (standardized preload with a rubber spring) was significantly higher, 66%. Using the spring, a clinically significant residual fade (TOF less than 0.50) could be detected in nine of the 11 cases. As residual relaxation cannot be ruled out using the clinical methods, quantitative recording of neuromuscular function is recommended in cases where complete recovery from muscle relaxation is of special importance. The spring method is the most reliable clinical method during recovery, while the tactile method is the most accurate during the maintenance of neuromuscular block.

  11. Sarcocystis fayeri in skeletal muscle of horses with neuromuscular disease.

    Science.gov (United States)

    Aleman, Monica; Shapiro, Karen; Sisó, Silvia; Williams, Diane C; Rejmanek, Daniel; Aguilar, Beatriz; Conrad, Patricia A

    2016-01-01

    Recent reports of Sarcocystis fayeri-induced toxicity in people consuming horse meat warrant investigation on the prevalence and molecular characterization of Sarcocystis spp. infection in horses. Sarcocysts in skeletal muscle of horses have been commonly regarded as an incidental finding. In this study, we investigated the prevalence of sarcocysts in skeletal muscle of horses with neuromuscular disease. Our findings indicated that S. fayeri infection was common in young mature horses with neuromuscular disease and could be associated with myopathic and neurogenic processes. The number of infected muscles and number of sarcocysts per muscle were significantly higher in diseased than in control horses. S. fayeri was predominantly found in low oxidative highly glycolytic myofibers. This pathogen had a high glycolytic metabolism. Common clinical signs of disease included muscle atrophy, weakness with or without apparent muscle pain, gait deficits, and dysphagia in horses with involvement of the tongue and esophagus. Horses with myositis were lethargic, apparently painful, stiff, and reluctant to move. Similar to humans, sarcocystosis and cardiomyopathy can occur in horses. This study did not establish causality but supported a possible association (8.9% of cases) with disease. The assumption of Sarcocysts spp. being an incidental finding in every case might be inaccurate. Copyright © 2015 Elsevier B.V. All rights reserved.

  12. Antisense Oligonucleotide-Based Therapy for Neuromuscular Disease

    Directory of Open Access Journals (Sweden)

    Valentina Sardone

    2017-04-01

    Full Text Available Neuromuscular disorders such as Duchenne Muscular Dystrophy and Spinal Muscular Atrophy are neurodegenerative genetic diseases characterized primarily by muscle weakness and wasting. Until recently there were no effective therapies for these conditions, but antisense oligonucleotides, a new class of synthetic single stranded molecules of nucleic acids, have demonstrated promising experimental results and are at different stages of regulatory approval. The antisense oligonucleotides can modulate the protein expression via targeting hnRNAs or mRNAs and inducing interference with splicing, mRNA degradation, or arrest of translation, finally, resulting in rescue or reduction of the target protein expression. Different classes of antisense oligonucleotides are being tested in several clinical trials, and limitations of their clinical efficacy and toxicity have been reported for some of these compounds, while more encouraging results have supported the development of others. New generation antisense oligonucleotides are also being tested in preclinical models together with specific delivery systems that could allow some of the limitations of current antisense oligonucleotides to be overcome, to improve the cell penetration, to achieve more robust target engagement, and hopefully also be associated with acceptable toxicity. This review article describes the chemical properties and molecular mechanisms of action of the antisense oligonucleotides and the therapeutic implications these compounds have in neuromuscular diseases. Current strategies and carrier systems available for the oligonucleotides delivery will be also described to provide an overview on the past, present and future of these appealing molecules.

  13. 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...

  14. Fatiguing exercise intensity influences the relationship between parameters reflecting neuromuscular function and postural control variables.

    Directory of Open Access Journals (Sweden)

    Sébastien Boyas

    Full Text Available The purpose of this study was to investigate the influence of fatiguing exercise intensity on the nature and extent of fatigue-induced changes in neuromuscular function and postural stability in quiet standing. We also explored the contribution of selected neuromuscular mechanisms involved in force production to postural stability impairment observed following fatigue using an approach based on multivariate regressions. Eighteen young subjects performed 30-s postural trials on one leg with their eyes closed. Postural trials were performed before and after fatiguing exercises of different intensities: 25, 50 and 75% of maximal isometric plantarflexor torque. Fatiguing exercises consisted of sustaining a plantarflexor isometric contraction at the target intensity until task failure. Maximal isometric plantarflexor torque, electromyographic activity of plantarflexor and dorsiflexor muscles, activation level (twitch interpolation technique and twitch contractile properties of plantarflexors were used to characterize neuromuscular function. The 25% exercise was associated with greater central fatigue whereas the 50 and 75% exercises involved mostly peripheral fatigue. However, all fatiguing exercises induced similar alterations in postural stability, which was unexpected considering previous literature. Stepwise multiple regression analyses showed that fatigue-related changes in selected parameters related to neuromuscular function could explain more than half (0.51≤R(2≤0.82 of the changes in postural variables for the 25% exercise. On the other hand, regression models were less predictive (0.17≤R(2≤0.73 for the 50 and 75% exercises. This study suggests that fatiguing exercise intensity does not influence the extent of postural stability impairment, but does influence the type of fatigue induced and the neuromuscular function predictors explaining changes in postural variables.

  15. hERG Blockade by Iboga Alkaloids.

    Science.gov (United States)

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

    2016-01-01

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

  16. Efficient Grover search with Rydberg blockade

    OpenAIRE

    Molmer, Klaus; Isenhower, Larry; Saffman, Mark

    2011-01-01

    We present efficient methods to implement the quantum computing Grover search algorithm using the Rydberg blockade interaction. We show that simple pi-pulse excitation sequences between ground and Rydberg excited states readily produce the key conditional phase shift and inversion-about-the mean unitary operations for the Grover search. Multi-qubit implementation schemes suitable for different properties of the atomic interactions are identifed and the error scaling of the protocols with syst...

  17. 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.

  18. Efficacy of brain-computer interface-driven neuromuscular electrical stimulation for chronic paresis after stroke.

    Science.gov (United States)

    Mukaino, Masahiko; Ono, Takashi; Shindo, Keiichiro; Fujiwara, Toshiyuki; Ota, Tetsuo; Kimura, Akio; Liu, Meigen; Ushiba, Junichi

    2014-04-01

    Brain computer interface technology is of great interest to researchers as a potential therapeutic measure for people with severe neurological disorders. The aim of this study was to examine the efficacy of brain computer interface, by comparing conventional neuromuscular electrical stimulation and brain computer interface-driven neuromuscular electrical stimulation, using an A-B-A-B withdrawal single-subject design. A 38-year-old male with severe hemiplegia due to a putaminal haemorrhage participated in this study. The design involved 2 epochs. In epoch A, the patient attempted to open his fingers during the application of neuromuscular electrical stimulation, irrespective of his actual brain activity. In epoch B, neuromuscular electrical stimulation was applied only when a significant motor-related cortical potential was observed in the electroencephalogram. The subject initially showed diffuse functional magnetic resonance imaging activation and small electro-encephalogram responses while attempting finger movement. Epoch A was associated with few neurological or clinical signs of improvement. Epoch B, with a brain computer interface, was associated with marked lateralization of electroencephalogram (EEG) and blood oxygenation level dependent responses. Voluntary electromyogram (EMG) activity, with significant EEG-EMG coherence, was also prompted. Clinical improvement in upper-extremity function and muscle tone was observed. These results indicate that self-directed training with a brain computer interface may induce activity- dependent cortical plasticity and promote functional recovery. This preliminary clinical investigation encourages further research using a controlled design.

  19. Non-invasive neuromuscular electrical stimulation in patients with central nervous system lesions: an educational review.

    Science.gov (United States)

    Schuhfried, Othmar; Crevenna, Richard; Fialka-Moser, Veronika; Paternostro-Sluga, Tatjana

    2012-02-01

    The aim of this educational review is to provide an overview of the clinical application of transcutaneous electrical stimulation of the extremities in patients with upper motor neurone lesions. In general two methods of electrical stimulation can be distinguished: (i) therapeutic electrical stimulation, and (ii) functional electrical stimulation. Therapeutic electrical stimulation improves neuromuscular functional condition by strengthening muscles, increasing motor control, reducing spasticity, decreasing pain and increasing range of motion. Transcutaneous electrical stimulation may be used for neuromuscular electrical stimulation inducing repetitive muscle contraction, electromyography-triggered neuromuscular electrical stimulation, position-triggered electrical stimulation and subsensory or sensory transcutaneous electric stimulation. Functional electrical stimulation provokes muscle contraction and thereby produces a functionally useful movement during stimulation. In patients with spinal cord injuries or stroke, electrical upper limb neuroprostheses are applied to enhance upper limb and hand function, and electrical lower limb neuroprostheses are applied for restoration of standing and walking. For example, a dropped foot stimulator is used to trigger ankle dorsiflexion to restore gait function. A review of the literature and clinical experience of the use of therapeutic electrical stimulation as well as of functional electrical stimulation in combination with botulinum toxin, exercise therapy and/or splinting are presented. Although the evidence is limited we conclude that neuromuscular electrical stimulation in patients with central nervous system lesions can be an effective modality to improve function, and that combination with other treatments has an additive therapeutic effect.

  20. 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.

  1. Divergent effects of RIP1 or RIP3 blockade in murine models of acute liver injury.

    Science.gov (United States)

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

    2015-05-07

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

  2. Extensor motoneurone properties are altered immediately before and during fictive locomotion in the adult decerebrate rat

    National Research Council Canada - National Science Library

    MacDonell, C. W; Power, K. E; Chopek, J. W; Gardiner, K. R; Gardiner, P. F

    2015-01-01

    .... Fictive locomotion was induced via electrical stimulation of the mesencephalic locomotor region in decerebrate adult rats under neuromuscular blockade to compare basic and rhythmic motoneurone...

  3. Improvement in Offaxis Neuromuscular Control Under Slippery Conditions Following Six-Week Pivoting Leg Neuromuscular Training.

    Science.gov (United States)

    Lee, Song Joo; Ren, Yupeng; Press, Joel M; Lee, Jungwha; Zhang, Li-Qun

    2017-11-01

    Knee injuries are usually associated with offaxis loadings in the transverse and frontal planes. Thus, improvement of lower limb offaxis neuromuscular control is important in knee injury prevention and post-injury rehabilitation. The goal of this paper was to investigate the effects of six-week pivoting offaxis intensity adjustable neuromuscular control training (POINT) using a custom-made offaxis elliptical trainer on lower limb offaxis neuromuscular control performance in trained and untrained functional tasks under slippery conditions. Twenty-six subjects participated in 18 sessions of POINT (three sessions per week for six weeks) and 25 subjects served as controls who did a regular workout. Offaxis neuromuscular control performance measures in terms of pivoting instability, sliding instability, and time-to-peak offaxis EMG entropy were evaluated on both groups under slippery conditions including a trained free pivoting task and untrained free sliding task and free pivoting and sliding task. Compared with the control group, the training group significantly decreased pivoting instability and the time-to-peak offaxis EMG entropy in lower limb muscles, indicating improvement in offaxis neuromuscular control performance. Furthermore, the training group showed reduced pivoting instability and sliding instability during the untrained free pivoting and sliding task. This paper may help us develop more focused and effective offaxis training programs to reduce knee injuries associated with offaxis loadings.

  4. Progressive inhibition of neuromuscular structures (PINS) technique.

    Science.gov (United States)

    Dowling, D J

    2000-05-01

    Progressive inhibition of neuromuscular structures (PINS) is a technique that can be included in the osteopathic manipulative treatment repertoire. It relies on knowledge of anatomy and neuromuscular physiologic features as well as on standard forms of osteopathic palpatory diagnosis and treatment. It is a variant of the inhibition technique that has been taught as an osteopathic manipulative technique for many years, and it bears some resemblance to other manual medicine techniques. The emphasis of the approach is the determination of the alteration of the tissues due to dysfunction, delivering treatment based on palpatory evaluation and patient feedback. Two related points are initially chosen, followed by a progression from one to the other. Relationships to similar techniques are also discussed. Theoretical as well as selected practical applications are presented.

  5. The Preparation Period in Basketball: Training Load and Neuromuscular Adaptations.

    Science.gov (United States)

    Ferioli, Davide; Bosio, Andrea; Bilsborough, Johann C; Torre, Antonio La; Tornaghi, Michele; Rampinini, Ermanno

    2018-01-18

    To investigate the 1) effect of the preparation period on the neuromuscular characteristics of 12 professional (PRO) and 16 semi-professional (SEMI-PRO) basketball players; 2) relationships between training load indices and changes in neuromuscular physical performance. Prior to and following the preparation period, players underwent a counter-movement jump (CMJ) test, followed by a repeated change of direction (COD) test consisting of 4 levels with increasing intensities. The peripheral neuromuscular functions of the knee extensors (peak torque, PT) were measured using electrical stimulations after each level (PT1, PT2, PT3 and PT4). Furthermore, PT Max (the highest value of PT) and PT Dec (PT decrement from PT Max to PT4) were calculated. Trivial-to-small (effect size, ES: -0.17 to 0.46) improvements were found in CMJ variables, regardless of the competitive levels. After the preparation period, peripheral fatigue induced by a COD test was similarly reduced in both PRO (PT Dec: from 27.8±21.3% to 11.4±13.7%, ES±90%CI= -0.71±0.30) and SEMI-PRO (PT Dec: from 26.1±21.9% to 10.2±8.2%, ES±90%CI= -0.69±0.32). Moderate-to-large relationships were found between session rating of perceived exertion training load and changes in PPO measured during the CMJs (r s ±90%CI: PPOabs, -0.46±0.26; PPOrel, -0.53±0.23) and in some PTs measured during the COD test (PT1, -0.45±0.26; PT2, -0.44±0.26; PT3, -0.40±0.27 and PT Max, -0.38±0.28). Preparation period induced minimal changes in the CMJ, while the ability to sustain repeated COD efforts was improved. Reaching high session rating of perceived exertion training loads might partially and negatively affect the ability to produce strength and power.

  6. Options for mechanical ventilation in neuromuscular diseases.

    Science.gov (United States)

    Unterborn, J N; Hill, N S

    1994-12-01

    A variety of mechanical devices may be used to provide assistance when ventilation and cough are severely impaired by progressive respiratory weakness caused by neuromuscular disease. Traditionally, positive pressure ventilation via a tracheostomy has been used, but if upper airway function is adequate, a variety of noninvasive devices also may be considered. Although positive pressure ventilation is the preferred noninvasive mode for assisting ventilation, other modes may be selected depending on patient needs, preferences, and physical characteristics.

  7. Neuromuscular adaptations to training, injury and passive interventions: implications for running economy.

    Science.gov (United States)

    Bonacci, Jason; Chapman, Andrew; Blanch, Peter; Vicenzino, Bill

    2009-01-01

    has also been observed. Muscle activity during running after cycling has yet to be fully investigated, and to date, the effect of alterations in muscle coordination on running economy is largely unknown. Stretching, which is another mode of training, may induce acute neuromuscular effects but does not appear to alter running economy. There are also factors other than training structure that may influence running economy and neuromuscular adaptations. For example, passive interventions such as shoes and in-shoe orthoses, as well as the presence of musculoskeletal injury, may be considered important modulators of neuromuscular control and run performance. Alterations in muscle activity and running economy have been reported with different shoes and in-shoe orthoses; however, these changes appear to be subject-specific and non-systematic. Musculoskeletal injury has been associated with modifications in lower limb neuromuscular control, which may persist well after an athlete has returned to activity. The influence of changes in neuromuscular control as a result of injury on running economy has yet to be examined thoroughly, and should be considered in future experimental design and training analysis.

  8. Anormalidades neuromuscular no desuso, senilidade e caquexia Neuromuscular abnormalities in disuse, cachexia and ageing

    Directory of Open Access Journals (Sweden)

    João Aris Kouyoumdjian

    1993-09-01

    Full Text Available É feita revisão de literatura sobre as principais alterações do sistema neuromuscular no desuso, senilidade e caquexia no ser humano e em modelos animais. A diminuição do diâmetro das fibras musculares após período de inatividade/imobilidade (desuso deve-se à perda de miofibrilas periféricas não ocorrendo formação de core-targetóides ou diminuição da atividade da miofosforilase, próprias da desnervação; mantêm-se a liberação espontânea de acetilcolina e fatores tróficos na junção mio-neural; em geral são afetadas preferencialmente fibras II, que podem assumir forma angular. Existe um processo contínuo intrínseco de envelhecimento de nervos e músculos, com desnervação e reinervação lenta e progressiva; o número de unidades motoras se reduz após 60 anos, sem ocorrência de atividade elétrica desnervatória; a quantidade de acetilcolina liberada nos neurônios terminais e a capacidade máxima de utilização de oxigênio estão diminuídas; a redução da capacidade oxidativa mitocondrial pode explicar o aumento de fibras I, mantendo-se o equilíbrio energético. Após poucas semanas de caquexia as fibras musculares podem ter o diâmetro reduzido em 30%, essa redução ocorre em ordem decrescente nos músculos dos membros inferiores, superiores e tronco; existe atrofia II preferencial com fibras angulares ocasionais, redução de RNA/síntese proteica, mantendo-se DNA normal.Cachexia, ageing and disuse and their effects on the human and animals neuromuscular system are reviewed. Disuse induces reduction of muscle fibers (mainly II diameter with peripheral myofibrils lost; there is no core-targetoid or even reduction on myophosphorilase activity, both typical of denervation; the acetylcholine spontaneous release and trophic factors on myoneural junction are maintained; muscle fibers could change to angular shape. Ageing affects nerve and muscle by a continuous and progressive process of denervation and reinner

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

    Science.gov (United States)

    Yamasato, Kelly; Kaneshiro, Bliss; Salcedo, Jennifer

    2015-07-01

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

  10. Neuromuscular Fatigue After Repeated Jumping With Concomitant Electrical Stimulation.

    Science.gov (United States)

    Neyroud, Daria; Samararatne, Jimmy; Kayser, Bengt; Place, Nicolas

    2017-12-18

    To evaluate the etiology and extent of neuromuscular fatigue induced by 50 squat jumps performed with and without neuromuscular electrical stimulation (NMES) of the knee extensors. Nine healthy, recreationally active men (24 ± 2 y) took part in 2 experiments. These consisted of 50 squat jumps performed with stimulation (NMES) or without (CON). Maximal voluntary contraction (MVC) force, maximal voluntary activation level (VAL), and forces evoked by single and double (10 and 100 Hz) stimulations were recorded before and after the 50 jumps. NMES was delivered at the maximal tolerated intensity. Despite average jump height being ∼16% lower in the NMES than in the CON session, a reduction over time in jump height was only found in the NMES condition (-6%). After the 50 jumps, MVC force was reduced to a greater extent in NMES than in CON (-25% ± 11% vs -11% ± 12%). Similarly, forces evoked by single stimulations, as well as by 10-Hz and 100-Hz paired stimulations, were reduced to a greater extent in NMES (-33% ± 12%, -42% ± 15%, and -25% ± 13%) than in CON (-21% ± 6%, -30% ± 9%, and -14% ± 11%). VAL was not significantly altered by either condition. Performing repeated squat jumps with concomitant NMES induced a greater fatigue than squat jumps performed alone and might potentially represent a stronger training stimulus.

  11. Botulinum neurotoxin C mutants reveal different effects of syntaxin or SNAP-25 proteolysis on neuromuscular transmission.

    Science.gov (United States)

    Zanetti, Giulia; Sikorra, Stefan; Rummel, Andreas; Krez, Nadja; Duregotti, Elisa; Negro, Samuele; Henke, Tina; Rossetto, Ornella; Binz, Thomas; Pirazzini, Marco

    2017-08-01

    Botulinum neurotoxin serotype C (BoNT/C) is a neuroparalytic toxin associated with outbreaks of animal botulism, particularly in birds, and is the only BoNT known to cleave two different SNARE proteins, SNAP-25 and syntaxin. BoNT/C was shown to be a good substitute for BoNT/A1 in human dystonia therapy because of its long lasting effects and absence of neuromuscular damage. Two triple mutants of BoNT/C, namely BoNT/C S51T/R52N/N53P (BoNT/C α-51) and BoNT/C L200W/M221W/I226W (BoNT/C α-3W), were recently reported to selectively cleave syntaxin and have been used here to evaluate the individual contribution of SNAP-25 and syntaxin cleavage to the effect of BoNT/C in vivo. Although BoNT/C α-51 and BoNT/C α-3W toxins cleave syntaxin with similar efficiency, we unexpectedly found also cleavage of SNAP-25, although to a lesser extent than wild type BoNT/C. Interestingly, the BoNT/C mutants exhibit reduced lethality compared to wild type toxin, a result that correlated with their residual activity against SNAP-25. In spite of this, a local injection of BoNT/C α-51 persistently impairs neuromuscular junction activity. This is due to an initial phase in which SNAP-25 cleavage causes a complete blockade of neurotransmission, and to a second phase of incomplete impairment ascribable to syntaxin cleavage. Together, these results indicate that neuroparalysis of BoNT/C at the neuromuscular junction is due to SNAP-25 cleavage, while the proteolysis of syntaxin provides a substantial, but incomplete, neuromuscular impairment. In light of this evidence, we discuss a possible clinical use of BoNT/C α-51 as a botulinum neurotoxin endowed with a wide safety margin and a long lasting effect.

  12. CD44 is expressed in non-myelinating Schwann cells of the adult rat, and may play a role in neurodegeneration-induced glial plasticity at the neuromuscular junction.

    Science.gov (United States)

    Gorlewicz, Adam; Wlodarczyk, Jakub; Wilczek, Ewa; Gawlak, Maciej; Cabaj, Anna; Majczynski, Henryk; Nestorowicz, Klaudia; Herbik, Magdalena Aneta; Grieb, Pawel; Slawinska, Urszula; Kaczmarek, Leszek; Wilczynski, Grzegorz M

    2009-05-01

    CD44 is a multifunctional cell surface glycoprotein which regulates cell-cell and cell-matrix interactions in a variety of tissues. In particular, the protein was found to be expressed in glial cells of developing, but not adult, peripheral nerves, where it takes part in signaling mediated by ErbB class of receptors for neuregulins. Here, we demonstrate, using high resolution morphological methods, tissue fractionation and RT-PCR, that CD44 is strongly expressed in terminal Schwann cell (TSC) at the neuromuscular junction (NMJ) of the adult rat skeletal muscle. As CD44 is also expressed by Schwann cells of the non-myelinated Remak bundles of the proximal peripheral nerves, it appears to be a marker of non-myelinating Schwann cell subpopulation. The analysis of transgenic rats bearing a mutated superoxide-dismutase gene (SOD1(G93A)) causing familial amyotrophic lateral sclerosis (ALS) revealed that TSC activation and morphological plasticity at the NMJ, caused by ongoing denervation-reinnervation is associated with a strong increase in CD44 expression therein. Notably, CD44 immunoreactivity is present in fine axon-escheating processes of the glial cells that guide reinnervation. In addition, we found that both in normal and SOD1(G93A) muscle, CD44 expressed in TSC partially colocalizes with immunoreactivities of neuregulin receptors ErbB2 and ErbB3. The colocalization appears to reflect a physical interaction, as evidenced by co-immunoprecipitation and fluorescence resonance energy transfer (FRET) analysis between CD44 and ErbB3. Importantly, TSC activation upon ALS-like neurodegeneration results in significant increase in molecular proximity of CD44 and ErbB3, which may have an impact on glial plasticity at the NMJ.

  13. INTERACTION OF VERAPAMIL AND LITHIUM AT THE NEUROMUSCULAR JUNCTION ON RAT ISOLATED MUSCLE-HEMIDIAPHRAGM

    Directory of Open Access Journals (Sweden)

    H. R. Sadeghipour

    1998-08-01

    Full Text Available It has been reported that cither lithium or verapamil can potentiate the neuromuscular blocking activity of certain neuromuscular blockers. In the present investigation, possible interaction of verapamil with lithium has been described. The dose ■ response effects of verapamil and lithium on diaphragmatic contractility were assessed in vitro. Mechanical responses of the muscle to indirect (nerve and direct (muscle electrical stimulation were recorded. Verapamil depressed rat diaphragm twitch tensions induced by nerve stimulation in a dose - dependent manner with the 50 percent depression of the original twitch tensions (ICSQ by 5.6 xlO^mmol/l."nThe IC50 of verapamil for direct stimulation of the muscle was LI x W'5 mmol II. Partial replacement of sodium chloride by lithium chloride (0.5, 1.5 and 5 mmol /1 in the medium did not change the depressant effect of verapamil on muscle twitches induced by direct (muscle or indirect (nerve electrical stimulation.

  14. Neuromuscular interactions around the knee in children, adults and elderly

    OpenAIRE

    Kellis, Eleftherios; Mademli, Lida; Patikas, Dimitrios; Kofotolis, Nikolaos

    2014-01-01

    Although injury and neuromuscular activation patterns may be common for all individuals, there are certain factors which differentiate neuromuscular activity responses between children, adults and elderly. The purpose of this study is to review recent evidence on age differences in neural activation and muscle balances around the knee when performing single joint movements. Particularly, current evidence indicates that there are some interesting similarities in the neuromuscular mechanisms by...

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

    OpenAIRE

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

    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...

  16. Atividade antiarritmogênica da levomepromazina em cães submetidos à anestesia pela quetamina The use of levomepromazine to blockade the arrhythmia induced by the epinephrine in dogs anesthetized with ketamine

    Directory of Open Access Journals (Sweden)

    Newton Nunes

    1999-06-01

    Full Text Available Este experimento teve por objetivo avaliar a viabilidade do emprego da levomepromazina no bloqueio da atividade arritmogênica da adrenalina, em cães anestesiados pela quetamina. Para tal, foram utilizados 30 cães adultos, machos e fêmeas, considerados sadios, com pesos compreendidos entre 7 e 14kg. Estes foram divididos em 3 grupos de 10 animais (G1, G2 e G3. Aos cães de G1 foi administrada, por via intravenosa, adrenalina em doses de 3, 6, 9, 12 e 15 mg/kg, em intervalos de 10 minutos. Deste grupo, foram colhidos o tempo de duração do efeito da catecolamina (TA, estabelecido pela contagem da freqüência cardíaca e o número total de batimentos cardíacos de origem ectópica, produzidos pela adrenalina (ESV. Aos animais do G2, foi administrada solução salina a 0,9%, na dose de 0,2ml/kg, por via intravenosa, seguida, 10 minutos após, da injeção, pela mesma via, de quetamina, na dose de 2mg/kg. Decorridos 5 minutos, iniciou-se a infusão contínua de quetamina, por via intravenosa, na dose de 0,2mg/kg/min. Aguardou-se 5 minutos e iniciou-se a administração de adrenalina e colheita das variáveis, conforme protocolado para o G1. Aos animais do G3, aplicou-se a mesma metodologia, substituindo-se o placebo pela levomepromazina, administrada por via intravenosa, na dose de 1mg/kg. A análise dos resultados mostrou que a levomepromazina reduz a duração do efeito da catecolamina e minimiza o aparecimento de batimentos cardíacos de origem ectópica. Os achados permitiram concluir que a levomepromazina é útil no bloqueio da arritmia produzida pela adrenalina em cães anestesiados pela quetamina.The use of levomepromazine to blockade the arrhythmia produced by the use of epinephrine in dogs given ketamine was evaluated. Thirthy adults crossbreed dogs, males and females with average weight from 7 to 15kg were used. The animals were alocated in three groups of 10 dogs each (G1, G2 and G3. To the G1 was administered epinephrine at 3, 6, 9

  17. Urgencias en patología neuromuscular Emergencies in neuromuscular pathology

    OpenAIRE

    T. Ayuso; I. Jericó

    2008-01-01

    La debilidad muscular aguda (DMA) es el síntoma predominante de las urgencias neuromusculares, especialmente si afecta a la musculatura respiratoria u orofaríngea. La DMA es un síndrome plurietiológico y con distintos niveles lesionales en la unidad motora. Dentro del amplio grupo de enfermedades neuromusculares, las que con mayor frecuencia provocan DMA e insuficiencia respiratoria son el síndrome de Guillain-Barré (SGB) y la miastenia gravis (MG). El SGB constituye la causa más frecuente de...

  18. Neuromuscular adaptations to concurrent training in the elderly: effects of intrasession exercise sequence.

    Science.gov (United States)

    Cadore, Eduardo Lusa; Izquierdo, Mikel; Pinto, Stephanie Santana; Alberton, Cristine Lima; Pinto, Ronei Silveira; Baroni, Bruno Manfredini; Vaz, Marco Aurélio; Lanferdini, Fábio Juner; Radaelli, Régis; González-Izal, Miriam; Bottaro, Martim; Kruel, Luiz Fernando Martins

    2013-06-01

    The aim of this study was investigate the effects of different intrasession exercise orders in the neuromuscular adaptations induced by concurrent training in elderly. Twenty-six healthy elderly men (64.7 ± 4.1 years), were placed into two concurrent training groups: strength prior to (SE, n = 13) or after (ES, n = 13) endurance training. Subjects trained strength and endurance training during 12 weeks, three times per week performing both exercise types in the same training session. Upper and lower body one maximum repetition test (1RM) and lower-body isometric peak torque (PTiso) and rate of force development were evaluated as strength parameters. Upper and lower body muscle thickness (MT) was determined by ultrasonography. Lower-body maximal surface electromyographic activity of vastus lateralis and rectus femoris muscles (maximal electromyographic (EMG) amplitude) and neuromuscular economy (normalized EMG at 50 % of pretraining PTiso) were determined. Both SE and ES groups increased the upper- and lower-body 1RM, but the lower-body 1RM increases observed in the SE was higher than ES (35.1 ± 12.8 vs. 21.9 ± 10.6 %, respectively; P muscles evaluated, with no differences between groups. In addition, there were increases in the maximal EMG and neuromuscular economy of vastus lateralis in both SE and ES, but the neuromuscular economy of rectus femoris was improved only in SE (P strength prior to endurance exercise during concurrent training resulted in greater lower-body strength gains as well as greater changes in the neuromuscular economy (rectus femoris) in elderly.

  19. Acute Effects of Static and Proprioceptive Neuromuscular Facilitation Stretching on Muscle Strength and Power Output.

    Science.gov (United States)

    Marek, Sarah M; Cramer, Joel T; Fincher, A Louise; Massey, Laurie L; Dangelmaier, Suzanne M; Purkayastha, Sushmita; Fitz, Kristi A; Culbertson, Julie Y

    2005-06-01

    activation at both slow (60 degrees .s) and fast (300 degrees .s) velocities. The effect sizes, however, corresponding to these stretching-induced changes were small, which suggests the need for practitioners to consider a risk-to-benefit ratio when incorporating static or proprioceptive neuromuscular facilitation stretching.

  20. Checkpoint Blockade in Lung Cancer and Mesothelioma.

    Science.gov (United States)

    Lievense, Lysanne A; Sterman, Daniel H; Cornelissen, Robin; Aerts, Joachim G

    2017-08-01

    In the last decade, immunotherapy has emerged as a new treatment modality in cancer. The most success has been achieved with the class of checkpoint inhibitors (CPIs), antibodies that unleash the antitumor immune response. After the success in melanoma, numerous clinical trials are being conducted investigating CPIs in lung cancer and mesothelioma. The programmed death protein (PD) 1-PD ligand 1/2 pathway and cytotoxic T lymphocyte-associated protein 4 are currently the most studied immunotherapeutic targets in these malignancies. In non-small cell lung cancer, anti-PD-1 antibodies have become part of the approved treatment arsenal. In small cell lung cancer and mesothelioma, the efficacy of checkpoint inhibition has not yet been proven. In this Concise Clinical Review, an overview of the landmark clinical trials investigating checkpoint blockade in lung cancer and mesothelioma is provided. Because response rates are around 20% in the majority of clinical trials, there is much room for improvement. Predictive biomarkers are therefore essential to fully develop the potential of CPIs. To increase efficacy, multiple clinical trials investigating the combination of cytotoxic T lymphocyte-associated protein 4 inhibitors and PD-1/PD ligand 1 blockade in lung cancer and mesothelioma are being conducted. Given the potential benefit of immunotherapy, implementation of current and new knowledge in trial designs and interpretation of results is essential for moving forward.

  1. Synergistic Effects of Proprioceptive Neuromuscular Facilitation and Manual Lymphatic Drainage in Patients with Mastectomy-Related Lymphedema

    OpenAIRE

    Kyung-Jin Ha; Sang-Yeol Lee; Hojun Lee; Seung-Jun Choi

    2017-01-01

    Purpose: Manual lymphatic drainage (MLD) and proprioceptive neuromuscular facilitation (PNF) are potential therapeutic strategies to reduce mastectomy-induced edema. The purpose of this study was to investigate whether the combination of these therapies would induce synergistic effects to treat lymphedema-related complications and to analyze a possible physiological mechanism involved in the observed effects.Methods: A total of 55 patients diagnosed with mastectomy-induced lymphedema were rec...

  2. Towards an integrated approach on RAAS-blockade

    NARCIS (Netherlands)

    Lely, Anna Titia

    2007-01-01

    The role of the RAAS in cardiovascular and renal disease is much more complicated than initially assumed. Whereas blockade of the system by ACEi or AT-1 blockade has turned out to be one of the most effective therapies in prevention and treatment of cardiovascular and renal disease, still in many

  3. 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...

  4. 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...

  5. Axillary plexus blockade in microvascular surgery, a steal phenomenon?

    NARCIS (Netherlands)

    J.F.A. van der Werff (John); G. Medici; S.E.R. Hovius (Steven); A. Kusuma (Ari)

    1995-01-01

    textabstractA case report is presented of an axillary plexus blockade following a second toe-to-hand transfer. After completion of the microvascular anastomoses and restoration of blood flow to the transplanted toe, the axillary plexus blockade was started. Together with the vasodilation of the hand

  6. [Genetic defects and disorders at the neuromuscular junction].

    Science.gov (United States)

    Ohno, Kinji

    2011-07-01

    Genetic defects in molecules expressed at the neuromuscular junction (NMJ) cause congenital myasthenic syndromes (CMSs), which are characterized by muscle weakness, abnormal fatigability, amyotrophy, and minor facial anomalies. Muscle weakness mostly develops under 2 years but is also sometimes seen in adults. Mutations identified to date include (i) muscle nicotinic acetylcholine receptor (AChR) subunits, (ii) rapsyn that anchors and clusters AChRs at the neuromuscular junction, (iii) agrin that is released from the nerve terminal and induces AChR clustering by stimulating the downstream LRP4/MuSK/Dok-7/rapsyn/AChR pathway, (iv) muscle-specific kinase (MuSK) that transmits the AChR-clustering signal from agrin/LRP4 to rapsyn/AChR, (v) Dok-7 that transmits the AChR-clustering signal from agrin/LRP4/MuSK to rapsyn/AChR, (vi) skeletal muscle sodium channel type 1.4 (Nav1.4) that spreads the depolarization potential from the endplate throughout muscle fibers, (vii) collagen Q that anchors acetylcholinesterase to the synaptic basal lamina, and (viii) choline acetyltransferase that resynthesizes acetylcholine from recycled choline at the nerve terminal. In addition, mutations in the heparin sulfate proteoglycan perlecan, which binds to many molecules including collagen Q and dystroglycan, causes Schwartz-Jampel syndrome. Interestingly, mutations in LRP4 cause Cenani-Lenz syndactyly syndrome but not CMS. AChR, MuSK, and LRP4 are also targets of auto-antibodies in myasthenia gravis. In addition, molecules at the NMJ are targets of many other disease states AChRs are blocked by the snake toxin alpha-bungarotoxin and the plant poison curare. The presynaptic SNARE complex is attacked by botulinum toxin. Acetylcholinesterase is inhibited by the nerve gas sarin and by organophosphate pesticides. This review focuses on the molecular bases underlying defects of AChR, rapsyn, Nav1.4, collagen Q, and choline acetyltransferase.

  7. Neuromuscular Manifestations of West Nile Virus Infection

    Directory of Open Access Journals (Sweden)

    A. Arturo eLeis

    2012-03-01

    Full Text Available The most common neuromuscular manifestation of West Nile virus (WNV infection is a poliomyelitis syndrome with asymmetric paralysis variably involving one (monoparesis to four limbs (quadriparesis, with or without brainstem involvement and respiratory failure. This syndrome of acute flaccid paralysis may occur without overt fever or meningoencephalitis. Although involvement of anterior horn cells in the spinal cord and motor neurons in the brainstem are the major sites of pathology responsible for neuromuscular signs, inflammation also may involve skeletal or cardiac muscle (myositis, myocarditis, motor axons (polyradiculitis, peripheral nerve (Guillain-Barré syndrome, brachial plexopathy. In addition, involvement of spinal sympathetic neurons and ganglia provides a plausible explanation for autonomic instability seen in some patients. Many patients also experience prolonged subjective generalized weakness and disabling fatigue. Despite recent evidence that WNV may persist long term in the central nervous system or periphery in animals, the evidence in humans is controversial. WNV persistence would be of great concern in immunosuppressed patients or in those with prolonged or recurrent symptoms. Support for the contention that WNV can lead to autoimmune disease arises from reports of patients presenting with various neuromuscular diseases that presumably involve autoimmune mechanisms (GBS, other demyelinating neu¬ropathies, myasthenia gravis, brachial plexopathies, stiff-person syndrome, and delayed or recurrent symptoms. Although there is no specific treatment or vaccine currently approved in humans, and the standard remains supportive care, drugs that can alter the cascade of immunobiochemical events leading to neuronal death may be potentially useful (high-dose corticosteroids, interferon preparations, and intravenous immune globulin containing WNV-specific antibodies. Human experience with these agents seems promising based on anecdotal

  8. Neuromuscular blockade of slow twitch muscle fibres elevates muscle oxygen uptake and energy turnover during submaximal exercise in humans

    DEFF Research Database (Denmark)

    Krustrup, Peter; Secher, Niels; Relu, Mihai U.

    2008-01-01

    We tested the hypothesis that a greater activation of fast-twitch (FT) fibres during dynamic exercise leads to a higher muscle oxygen uptake (VO2 ) and energy turnover as well as a slower muscle on-kinetics. Subjects performed one-legged knee-extensor exercise for 10 min at an intensity of 30 W...... fibres, respectively. From 127 s of exercise, muscle VO2 was higher (P muscle VO2 response...... was slower (P muscle homogenate CP was lowered (P muscle lactate production was similar in CUR and CON (37.8 +/- 4.1 versus 35.2 +/- 6.2 mmol). Estimated total muscle ATP turnover was 19...

  9. Alterações funcionais da junção neuromuscular provocadas em ratos pela administração diária e prolongada de um agente curarizante Functional changes of the neuromuscular junction induced in rats by a daily and prolonged ministration of a curare agent

    Directory of Open Access Journals (Sweden)

    Antonio Carlos Zanini

    1967-06-01

    after the injection, showed that a 5.5 gama/kg/daily dose induced an increase of the animals susceptibility to the blocking action of DMT; c the inhibitory effect induced by DMT 16.6 gama/kg daily dose increased at the beginning but decreased significantly after the 5th week of the trial, despite a progressive decrease in muscular force suggest independence of the two effects. Based on these results, some of the phenomena that may occur at the heginning and during treatment of myasthenia gravis are discussed.

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

    Science.gov (United States)

    2013-01-01

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

  11. In-vitro blockade of the CD4 receptor co-signal in antigen-specific T-cell stimulation cultures induces the outgrowth of potent CD4 independent T-cell effectors.

    Science.gov (United States)

    Vatter, Sarah; Schmid, Maximilian; Gebhard, Claudia; Mirbeth, Carina; Klobuch, Sebastian; Rehli, Michael; Herr, Wolfgang; Thomas, Simone

    2018-03-01

    T-cell receptor (TCR) redirected T cells are promising tools for adoptive cancer immunotherapy. Since not only CD8 but also CD4 T cells are key players for efficient antitumor responses, the targeted redirection of both subsets with the same antigen-specific TCR comes more and more into focus. Although rapidly evolving technologies enable the reliable genetic re-programming of T cells, the limited availability of TCRs that induce T-cell activation in both T-cell subsets without CD4/CD8 co-receptor contribution hampers the broad application of this approach. We developed a novel stimulation approach, which drives the activation and proliferation of CD4 T-cell populations capable of inducing effector functions in a CD4-independent manner. Naive-enriched CD4 T cells were stimulated against dendritic cells (DC) expressing allogeneic HLA-DP antigens upon RNA transfection and CD4/HLA interactions were blocked by the addition of CD4 binding antibody. Evolving CD4 T-cell populations were specifically activated independent of the CD4 co-signal and induced strong TCR-mediated IFN-γ secretion as well as cytolysis upon recognition of leukemia cells expressing HLA-DP antigen. Our novel stimulation approach may facilitate the generation of CD4 T cells as source for co-receptor independent TCRs for future immunotherapies. Copyright © 2017 Elsevier B.V. All rights reserved.

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

    Directory of Open Access Journals (Sweden)

    Estelle eTallet

    2011-09-01

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

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

    Science.gov (United States)

    Latusz, Joachim; Radaszkiewicz, Aleksandra; Bator, Ewelina; Wędzony, Krzysztof; Maćkowiak, Marzena

    2017-02-01

    Epidemiological data have indicated that memory impairment is observed during adolescence in groups at high risk for schizophrenia and might precede the appearance of schizophrenia symptoms in adulthood. In the present study, we used a neurodevelopmental model of schizophrenia based on the postnatal blockade of N-methyl-d-aspartate (NMDA) receptors in rats to investigate fear memory in adolescence and adulthood. The rats were treated with increasing doses of CGP 37849 (CGP), a competitive antagonist of the NMDA receptor (1.25mg/kg on days 1, 3, 6, 9; 2.5mg/kg on days 12, 15, 18 and 5mg/kg on day 21). Fear memory was analysed in delay and trace fear conditioning. Sensorimotor gating deficit, which is another cognitive symptom of schizophrenia, was also determined in adolescent and adult CGP-treated rats. Postnatal CGP administration disrupted cue- and context-dependent fear memory in adolescent rats in both delay and trace conditioning. In contrast, CGP administration evoked impairment only in cue-dependent fear memory in rats exposed to trace but not delay fear conditioning. The postnatal blockade of NMDA receptors induced sensorimotor gating deficits in adult rats but not in adolescent rats. The postnatal blockade of NMDA receptors induced fear memory impairment in adolescent rats before the onset of neurobehavioral deficits associated with schizophrenia. Copyright © 2016. Published by Elsevier Urban & Partner Sp. z o.o.

  14. Medical back belt with integrated neuromuscular electrical stimulation

    NARCIS (Netherlands)

    Bottenberg, E. (Eliza); Brinks, G.J. (Ger); Hesse, J. (Jenny)

    2014-01-01

    The medical back belt with integrated neuromuscular electrical stimulation is anorthopedic device, which has two main functions. The first function is to stimulate the backmuscles by using a neuromuscular electrical stimulation device that releases regular,electrical impulses. The second function of

  15. Motoneuron and sensory neuron plasticity to varying neuromuscular activity levels

    Science.gov (United States)

    Ishihara, Akihiko; Roy, Roland R.; Ohira, Yoshinobu; Edgerton, V. Reggie

    2002-01-01

    The size and phenotypic properties of the neural and muscular elements of the neuromuscular unit are matched under normal conditions. When subjected to chronic decreases or increases in neuromuscular activity, however, the adaptations in these properties are much more limited in the neural compared with the muscular elements.

  16. Thermal decay of Coulomb blockade oscillations

    Science.gov (United States)

    Idrisov, Edvin G.; Levkivskyi, Ivan P.; Sukhorukov, Eugene V.

    2017-10-01

    We study transport properties and the charge quantization phenomenon in a small metallic island connected to the leads through two quantum point contacts (QPCs). The linear conductance is calculated perturbatively with respect to weak tunneling and weak backscattering at QPCs as a function of the temperature T and gate voltage. The conductance shows Coulomb blockade (CB) oscillations as a function of the gate voltage that decay with the temperature as a result of thermally activated fluctuations of the charge in the island. The regimes of quantum T ≪EC and thermal T ≫EC fluctuations are considered, where EC is the charging energy of an isolated island. Our predictions for CB oscillations in the quantum regime coincide with previous findings by Furusaki and Matveev [Phys. Rev. B 52, 16676 (1995), 10.1103/PhysRevB.52.16676]. In the thermal regime the visibility of Coulomb blockade oscillations decays with the temperature as √{T /EC }exp(-π2T /EC) , where the exponential dependence originates from the thermal averaging over the instant charge fluctuations, while the prefactor has a quantum origin. This dependence does not depend on the strength of couplings to the leads. The differential capacitance, calculated in the case of a single tunnel junction, shows the same exponential decay, however the prefactor is linear in the temperature. This difference can be attributed to the nonlocality of the quantum effects. Our results agree with the recent experiment [Nature (London) 536, 58 (2016), 10.1038/nature19072] in the whole range of the parameter T /EC .

  17. Sugammadex and Reversal of Neuromuscular Block in Adult Patient with Duchenne Muscular Dystrophy

    Directory of Open Access Journals (Sweden)

    Ahmed Abdelgawwad Wefki Abdelgawwad Shousha

    2014-01-01

    Full Text Available Duchenne’s muscular dystrophy (DMD is the most common and severe form of myopathy. Patients with DMD are more sensitive to sedative, anesthetic, and neuromuscular blocking agents which may result in intraoperative and early postoperative cardiovascular and respiratory complications, as well as prolonged recovery from anesthesia. In this case report, we describe a 25-year-old male patient admitted for cholecystectomy under general anesthesia. We induced our anesthesia by oxygen, propofol, fentanyl, and rocuronium bromide. Maintenance was done by fentanyl, rocuronium bromide, sevoflurane, and O2. We report in this case the safety use of sugammadex to antagonize the neuromuscular block and rapid recovery in such category of patients.

  18. Predictors of the variability in neuromuscular block duration following succinylcholine: A prospective, observational study.

    Science.gov (United States)

    Dell-Kuster, Salome; Levano, Soledad; Burkhart, Christoph S; Lelais, Frédéric; Zemp, André; Schobinger, Elektra; Hampl, Karl; Kindler, Christoph; Girard, Thierry

    2015-10-01

    The duration of neuromuscular block (NMB) following succinylcholine administration is characterised by a high interindividual variability. However, this has not yet been quantified in a large sample of surgical patients. The significance of underlying clinical factors is unknown. The objective of this study was to profile the variability in NMB duration following a standard dose of succinylcholine and to investigate contributing clinical and genetic factors. A prospective, observational study. Tertiary referral centre. In a total of 1630 surgical patients undergoing a rapid sequence induction and intubation, clinical risk factors for a prolongation in NMB duration following succinylcholine were assessed. In a subset of 202 patients, additional biochemical and molecular genetic investigations of butyrylcholinesterase were performed. A standard 1 mg kg dose of succinylcholine after administration of an induction drug and an opioid. NMB duration measured as the time between administration of succinylcholine until reappearance of palpable muscular response to supramaximal transcutaneous ulnar nerve stimulation. NMB varied from 80 s to 44 min with a median duration of 7.3 min. Sixteen percent of patients had NMB duration in excess of 10 min. A multivariable survival model identified physical status, sex, age, hepatic disease, pregnancy, history of cancer and use of etomidate or metoclopramide as independent risk factors for a prolonged NMB. Three novel butyrylcholinesterase variants were identified: p.Ile5Thr; p.Val178Ile; and p.Try231Ser. Neuromuscular blockade duration in excess of 10 min occurred in 16% of a general surgical population following a single dose of succinylcholine. The multivariable model of clinical risk factors for prolonged NMB revealed a negative predictive value of 87%, thereby indicating that absence of such risk factors may reliably predict a shorter duration of NMB. In patients with clinical risk factors for a prolonged NMB or with

  19. Electrophysiological study in neuromuscular junction disorders

    Directory of Open Access Journals (Sweden)

    Ajith Cherian

    2013-01-01

    Full Text Available This review is on ultrastructure and subcellular physiology at normal and abnormal neuromuscular junctions. The clinical and electrophysiological findings in myasthenia gravis, Lambert-Eaton myasthenic syndrome (LEMS, congenital myasthenic syndromes, and botulinum intoxication are discussed. Single fiber electromyography (SFEMG helps to explain the basis of testing neuromuscular junction function by repetitive nerve stimulation (RNS. SFEMG requires skill and patience and its availability is limited to a few centers. For RNS supramaximal stimulation is essential and so is display of the whole waveform of each muscle response at maximum amplitude. The amplitudes of the negative phase of the first and fourth responses are measured from baseline to negative peak, and the percent change of the fourth response compared with the first represents the decrement or increment. A decrement greater than 10% is accepted as abnormal and smooth progression of response amplitude train and reproducibility form the crux. In suspected LEMS the effect of fast rates of stimulation should be determined after RNS response to slow rates of stimulation. Caution is required to avoid misinterpretation of potentiation and pseudofacilitation.

  20. Neuromuscular imaging in inherited muscle diseases

    Energy Technology Data Exchange (ETDEWEB)

    Wattjes, Mike P. [VU University Medical Center, Department of Radiology, De Boelelaan 1117, HV, Amsterdam (Netherlands); Kley, Rudolf A. [Klinken Bergmannsheil, Ruhr-University, Department of Neurology, Neuromuscular Centre Ruhrgebiet, Bochum (Germany); Fischer, Dirk [University Hospital of Basel, Department of Neurology, Basel (Switzerland); University Children' s Hospital Basel, Department of Neuropaediatrics, Basel (Switzerland)

    2010-10-15

    Driven by increasing numbers of newly identified genetic defects and new insights into the field of inherited muscle diseases, neuromuscular imaging in general and magnetic resonance imaging (MRI) in particular are increasingly being used to characterise the severity and pattern of muscle involvement. Although muscle biopsy is still the gold standard for the establishment of the definitive diagnosis, muscular imaging is an important diagnostic tool for the detection and quantification of dystrophic changes during the clinical workup of patients with hereditary muscle diseases. MRI is frequently used to describe muscle involvement patterns, which aids in narrowing of the differential diagnosis and distinguishing between dystrophic and non-dystrophic diseases. Recent work has demonstrated the usefulness of muscle imaging for the detection of specific congenital myopathies, mainly for the identification of the underlying genetic defect in core and centronuclear myopathies. Muscle imaging demonstrates characteristic patterns, which can be helpful for the differentiation of individual limb girdle muscular dystrophies. The aim of this review is to give a comprehensive overview of current methods and applications as well as future perspectives in the field of neuromuscular imaging in inherited muscle diseases. We also provide diagnostic algorithms that might guide us through the differential diagnosis in hereditary myopathies. (orig.)

  1. Neuromuscular dressing effects: a literature review

    Directory of Open Access Journals (Sweden)

    Calero PA

    2012-05-01

    Full Text Available The kinesio taping is a technique that was created in 1979 by Doctor Kenzo Kase I’m looking through it that could generate a new therapeutic option to control pain, improve athletic performance and reduce the impact of musculoskeletal disorders. From the Sydney 2000 Olympic Games, this technique as a therapeutic alternative PTO and is composed of health professionals in the field of sport and physical rehabilitation.Objetive: This article aims to identify theoretical approaches on the bandage neuromuscular. Material and methods: held today, for which conducted a literature search of databases such as como Proquest, Ovid, Cochraine, PEDro, Journal of Orthopedic and Sports Physical, Sciencedirect, Pubmed y Literatura Latinoamericana y del Caribe en Ciencias de la Salud (Lilacs.The paper proposes a scheme of contextualization of the current landscape of the use and effects of kinesio taping in the management of different pathologies of the musculo-skeletal system in sports. Conclusion: it is concluded that currently many health professionals, and take the neuromuscular bandage a good therapeutic option in the management of diseases affecting the human body is investigated and every day more about the subject, which makes these new therapeutic methods to acquire a scientific value and transcends knowledge.

  2. Prevalence of complications in neuromuscular scoliosis surgery

    DEFF Research Database (Denmark)

    Sharma, Shallu; Wu, Chunsen; Andersen, Thomas

    2013-01-01

    PURPOSE: Our objectives were primarily to review the published literature on complications in neuromuscular scoliosis (NMS) surgery and secondarily, by means of a meta-analysis, to determine the overall pooled rates (PR) of various complications associated with NMS surgery. METHODS: PubMed and Em......PURPOSE: Our objectives were primarily to review the published literature on complications in neuromuscular scoliosis (NMS) surgery and secondarily, by means of a meta-analysis, to determine the overall pooled rates (PR) of various complications associated with NMS surgery. METHODS: Pub......Med and Embase databases were searched for studies reporting the outcomes and complications of NMS surgery, published from 1997 to May 2011. We focused on NMS as defined by the Scoliosis Research Society's classification. We measured the pooled estimate of the overall complication rates (PR) using a random....... In regard to surgical complications affiliated with various surgical techniques in NMS, the level of evidence of published literature ranges between 2+ to 2-; the subsequent recommendations are level C. CONCLUSION: NMS patients have diverse and high complication rates after scoliosis surgery. High PRs...

  3. Of fads, fashion, surrogate endpoints and dual RAS blockade.

    Science.gov (United States)

    Messerli, Franz H; Staessen, Jan A; Zannad, Faiez

    2010-09-01

    Dual renin-angiotensin system (RAS) blockade, mostly by combining an angiotensin converting enzyme (ACE) inhibitor with an angiotensin receptor blocker (ARB), is increasingly used in patients with hypertension and diabetes and/or proteinuria and in those with resistant heart failure. However, in the zest of achieving greater nephroprotection and cardioprotection, even patients with uncomplicated essential hypertension are not uncommonly treated with dual RAS blockade. In 2003 the COOPERATE trial, seemed to confirm that dual RAS blockade was beneficial and that proteinuria reduction was synonymous with nephroprotection. This study had to be withdrawn recently attesting to the suspicion that the data looked to good to be true. Moreover, the large prospective ONTARGET data argue against a nephroprotective effect of dual RAS blockade and together with renal findings from ACCOMPLISH, cast doubt on albuminuria/proteinuria being a reliable surrogate endpoint for renal outcome. Although in heart failure, dual RAS blockade had some benefit without reducing mortality, there remains a distinct safety issue with regard to hyperkalemia and elevated creatinine. Neither in ischaemic heart disease nor in left ventricular hypertrophy had dual RAS blockade any benefits when compared with single RAS blockade. Of note, the combination of an ACE inhibitor with an ARB was recently shown to reduce the risk of dementia. All dual RAS blockade may be created equal and the combination of valsartan with aliskiren, a direct renin inhibitor will be evaluated in diabetic patients in the prospective, randomized ALTITUDE study. For the time being, given the adverse effects and lack of consistent survival benefits, the use of dual RAS blockade should be avoided unless ironclad data emerge to the contrary.

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

    CERN Document Server

    Kaufman, I Kh; Eisenberg, R S

    2014-01-01

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

  5. 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.

  6. Selective APRIL blockade delays systemic lupus erythematosus in mouse.

    Directory of Open Access Journals (Sweden)

    Bertrand Huard

    Full Text Available SLE pathogenesis is complex, but it is now widely accepted that autoantibodies play a key role in the process by forming excessive immune complexes; their deposits within tissues leading to inflammation and functional damages. A proliferation inducing ligand (APRIL is a member of the tumor necrosis factor (TNF superfamily mediating antibody-producing plasma cell (PC-survival that may be involved in the duration of pathogenic autoantibodies in lupus. We found significant increases of APRIL at the mRNA and protein levels in bone marrow but not spleen cells from NZB/W lupus mice, as compared to control mice. Selective antibody-mediated APRIL blockade delays disease development in this model by preventing proteinuria, kidney lesions, and mortality. Notably, this was achieved by decreasing anti-DNA and anti-chromatin autoantibody levels, without any perturbation of B- and T-cell homeostasis. Thus, anti-APRIL treatment may constitute an alternative therapy in SLE highly specific to PCs compared to other B-cell targeting therapies tested in this disease, and likely to be associated with less adverse effects than any anti-inflammatory and immunosuppressant agents previously used.

  7. Partial and transient reduction of glycolysis by PFKFB3 blockade reduces pathological angiogenesis.

    Science.gov (United States)

    Schoors, Sandra; De Bock, Katrien; Cantelmo, Anna Rita; Georgiadou, Maria; Ghesquière, Bart; Cauwenberghs, Sandra; Kuchnio, Anna; Wong, Brian W; Quaegebeur, Annelies; Goveia, Jermaine; Bifari, Francesco; Wang, Xingwu; Blanco, Raquel; Tembuyser, Bieke; Cornelissen, Ivo; Bouché, Ann; Vinckier, Stefan; Diaz-Moralli, Santiago; Gerhardt, Holger; Telang, Sucheta; Cascante, Marta; Chesney, Jason; Dewerchin, Mieke; Carmeliet, Peter

    2014-01-07

    Strategies targeting pathological angiogenesis have focused primarily on blocking vascular endothelial growth factor (VEGF), but resistance and insufficient efficacy limit their success, mandating alternative antiangiogenic strategies. We recently provided genetic evidence that the glycolytic activator phosphofructokinase-2/fructose-2,6-bisphosphatase 3 (PFKFB3) promotes vessel formation but did not explore the antiangiogenic therapeutic potential of PFKFB3 blockade. Here, we show that blockade of PFKFB3 by the small molecule 3-(3-pyridinyl)-1-(4-pyridinyl)-2-propen-1-one (3PO) reduced vessel sprouting in endothelial cell (EC) spheroids, zebrafish embryos, and the postnatal mouse retina by inhibiting EC proliferation and migration. 3PO also suppressed vascular hyperbranching induced by inhibition of Notch or VEGF receptor 1 (VEGFR1) and amplified the antiangiogenic effect of VEGF blockade. Although 3PO reduced glycolysis only partially and transiently in vivo, this sufficed to decrease pathological neovascularization in ocular and inflammatory models. These insights may offer therapeutic antiangiogenic opportunities. Copyright © 2014 Elsevier Inc. All rights reserved.

  8. PD-1-PD-L1 immune-checkpoint blockade in B-cell lymphomas.

    Science.gov (United States)

    Goodman, Aaron; Patel, Sandip P; Kurzrock, Razelle

    2017-04-01

    Cancer cells can escape T-cell-mediated cellular cytotoxicity by exploiting the inhibitory programmed cell-death protein 1 (PD-1)/programmed cell death 1 ligand 1 (PD-L1) immune checkpoint. Indeed, therapeutic antibodies that block the PD-1-PD-L1 axis induce durable clinical responses against a growing list of solid tumours. B-cell lymphomas also leverage this checkpoint to escape immune recognition, although the outcomes of PD-1-PD-L1 blockade, and the correlations between PD-L1 expression and treatment responses, are less-well elucidated in these diseases than in solid cancers. Nevertheless, in patients with Hodgkin lymphoma, amplification of the gene encoding PD-L1 is commonly associated with increased expression of this protein on Reed-Sternberg cells. Correspondingly, PD-1 blockade with nivolumab has been demonstrated to result in response rates as high as 87% in unselected patients with relapsed and/or refractory Hodgkin lymphoma, leading to the FDA approval of nivolumab for this indication in May 2016. The PD-1/PD-L1 axis is probably also important for immune evasion of B-cell lymphomas with a viral aetiology, including those associated with human immunodeficiency virus (HIV) and Epstein-Barr virus (EBV). This Review is focused on the role of PD-1-PD-L1 blockade in unleashing host antitumour immune responses against various B-cell lymphomas, and summarizes the clinical studies of this approach performed to date.

  9. 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.

  10. Reduction of metastasis, cell invasion, and adhesion in mouse osteosarcoma by YM529/ONO-5920-induced blockade of the Ras/MEK/ERK and Ras/PI3K/Akt pathway

    Energy Technology Data Exchange (ETDEWEB)

    Tsubaki, Masanobu [Division of Pharmacotherapy, Kinki University School of Pharmacy, Kowakae, Higashi-Osaka 577-8502 (Japan); Satou, Takao; Itoh, Tatsuki [Department of Pathology, Kinki University School of Medicine, Osakasayama, Osaka 589-8511 (Japan); Imano, Motohiro [Department of Surgery, Kinki University School of Medicine, Osakasayama, Osaka 589-8511 (Japan); Ogaki, Mitsuhiko [Department of Pharmacy, Higahiosaka City General Hospital, Higashi-osaka, Osaka 578-8588 (Japan); Yanae, Masashi [Division of Pharmacotherapy, Kinki University School of Pharmacy, Kowakae, Higashi-Osaka 577-8502 (Japan); Depeartment of Pharmacy, Sakai Hospital, Kinki University School of Medicine, Sakai, Osaka 590-0132 (Japan); Nishida, Shozo, E-mail: nishida@phar.kindai.ac.jp [Division of Pharmacotherapy, Kinki University School of Pharmacy, Kowakae, Higashi-Osaka 577-8502 (Japan)

    2012-03-15

    Osteosarcoma is one of the most common primary malignant bone tumors in children and adolescents. Some patients continue to have a poor prognosis, because of the metastatic disease. YM529/ONO-5920 is a nitrogen-containing bisphosphonate that has been used for the treatment of osteoporosis. YM529/ONO-5920 has recently been reported to induce apoptosis in various tumors including osteosarcoma. However, the mode of metastasis suppression in osteosarcoma by YM529/ONO-5920 is unclear. In the present study, we investigated whether YM529/ONO-5920 inhibited tumor cell migration, invasion, adhesion, or metastasis in the LM8 mouse osteosarcoma cell line. We found that YM529/ONO-5920 significantly inhibited metastasis, cell migration, invasion, and adhesion at concentrations that did not have antiproliferative effects on LM8 cells. YM529/ONO-5920 also inhibited the mRNA expression and protein activities of matrix metalloproteinases (MMPs). In addition, YM529/ONO-5920 suppressed phosphorylated extracellular signal-regulated kinase 1/2 (ERK1/2) and the serine/threonine protein kinase B (Akt) by the inhibition of Ras prenylation. Moreover, U0126, a mitogen-activated protein kinase kinase (MEK) 1/2 inhibitor, and LY294002, a phosphatidylinositol 3-kinase (PI3K) inhibitor, also inhibited LM8 cell migration, invasion, adhesion, and metastasis, as well as the mRNA expression and protein activities of MMP-1, MMP-2, MMP-9, and MT1-MMP. The results indicated that YM529/ONO-5920 suppressed the Ras/MEK/ERK and Ras/PI3K/Akt pathways, thereby inhibiting LM8 cell migration, invasion, adhesion, and metastasis. These findings suggest that YM529/ONO-5920 has potential clinical applications for the treatment of tumor cell metastasis in osteosarcoma. -- Highlights: ► We investigated whether YM529/ONO-5920 inhibited tumor metastasis in osteosarcoma. ► YM529/ONO-5920 inhibited metastasis, cell migration, invasion, and adhesion. ► YM529/ONO-5920 suppressed Ras signalings. ► YM529/ONO-5920

  11. Possible applications of Neuromuscular Taping in pain reduction in Multiple Sclerosis subject: a preliminary report

    Directory of Open Access Journals (Sweden)

    Carmine Berlingieri

    2016-12-01

    Full Text Available Pain is a common disabling symptom in patients with Multiple Sclerosis (MS. It has been indicated that pain prevalence in MS patients is between 29–86 %. It is evident that most MS patients requiring treatment will be also searching pain related treatments to assist in day to day activities. Neuropathic pain is a difficult symptom and is generally inadequately relieved even though different rehabilitative approaches may be used. Neuromuscular Taping inducing micro-movements by stimulating receptors in the skin has been described in literature as a possible intervention in neurological and orthopedic rehabilitation improving mobility and in pain reduction. The aim of this preliminary report was to analyze the effect and to evaluate the possible applications of Neuromuscular Taping (NMT in patients with MS in order to reduce pain in comparison to the Transcutaneous Electrical Nerve Stimulation (TENS and to physical rehabilitation treatment alone. We observed that NMT together with standard physical rehabilitation was able to reduce neuropathic pain to greater lengths, with statistically significant differences between pre and post treatment, compared to the other treatments evaluated. This study showed increased efficacy in pain reduction when NMT was applied to standard physical treatment in long standing pain conditions. Neuromuscular Taping may constitute a low cost treatment strategy for neuropathic pain conditions in MS.

  12. Distinct presynaptic and postsynaptic dismantling processes of Drosophila neuromuscular junctions during metamorphosis.

    Science.gov (United States)

    Liu, Zhiwei; Chen, Yan; Wang, Dan; Wang, Songyan; Zhang, Yong Q

    2010-09-01

    Synapse remodeling is a widespread and fundamental process that underlies the formation of neuronal circuitry during development and in adaptation to physiological and/or environmental changes. However, the mechanisms of synapse remodeling are poorly understood. Synapses at the neuromuscular junction (NMJ) in Drosophila larvae undergo dramatic and extensive remodeling during metamorphosis to generate adult-specific synapses. To explore the molecular and cellular processes of synapse elimination, we performed confocal microscopy, live imaging, and electron microscopy (EM) of NMJ synapses during the early stages of metamorphosis in Drosophila in which the expressions of selected genes were genetically altered. We report that the localization of the postsynaptic scaffold protein Disc large (Dlg) becomes diffuse first and then undetectable, as larval muscles undergo histolysis, whereas presynaptic vesicles aggregate and are retrogradely transported along axons in synchrony with the formation of filopodia-like structures along NMJ elaborations and retraction of the presynaptic plasma membrane. EM revealed that the postsynaptic subsynaptic reticulum vacuolizes in the early stages of synapse dismantling concomitant with diffuse localization of Dlg. Ecdysone is the major hormone that drives metamorphosis. Blockade of the ecdysone signaling specifically in presynaptic neurons by expression of a dominant-negative form of ecdysone receptors delayed presynaptic but not postsynaptic dismantling. However, inhibition of ecdysone signaling, as well as ubiquitination pathway or apoptosis specifically in postsynaptic muscles, arrested both presynaptic and postsynaptic dismantling. These results demonstrate that presynaptic and postsynaptic dismantling takes place through different mechanisms and that the postsynaptic side plays an instructive role in synapse dismantling.

  13. Seeking a better landscape for therapy development in neuromuscular disorders.

    Science.gov (United States)

    Larkindale, Jane; Porter, John D

    2018-01-01

    Although the neuromuscular field has seen accelerated approval of a drug for Duchenne muscular dystrophy (DMD) and full approval of one for spinal muscular atrophy, these experiences have shown that objective data and an adequate level of effect are essential for drug approval and reimbursement. The appropriateness and validity of biomarkers and clinically meaningful endpoints and an understanding of disease progression rates all played essential roles in the levels of evidence for these drugs. Such tools are best developed through integration of clinical data. The siloing of clinical data for rare neuromuscular diseases represents a considerable barrier to achieving better care and novel therapies for patients living with neuromuscular diseases. We discuss a data-sharing model implemented for DMD and urge cultural changes in the ways natural history and clinical trial data are collected and shared across all neuromuscular diseases in order to benefit the primary stakeholder, the patient. Muscle Nerve 57: 16-19, 2018. © 2017 Wiley Periodicals, Inc.

  14. The role of proprioception and neuromuscular stability in carpal instabilities.

    Science.gov (United States)

    Hagert, E; Lluch, A; Rein, S

    2016-01-01

    Carpal stability has traditionally been defined as dependent on the articular congruity of joint surfaces, the static stability maintained by intact ligaments, and the dynamic stability caused by muscle contractions resulting in a compression of joint surfaces. In the past decade, a fourth factor in carpal stability has been proposed, involving the neuromuscular and proprioceptive control of joints. The proprioception of the wrist originates from afferent signals elicited by sensory end organs (mechanoreceptors) in ligaments and joint capsules that elicit spinal reflexes for immediate joint stability, as well as higher order neuromuscular influx to the cerebellum and sensorimotor cortices for planning and executing joint control. The aim of this review is to provide an understanding of the role of proprioception and neuromuscular control in carpal instabilities by delineating the sensory innervation and the neuromuscular control of the carpus, as well as descriptions of clinical applications of proprioception in carpal instabilities. © The Author(s) 2015.

  15. Neuromuscular training for sports injury prevention: a systematic review

    National Research Council Canada - National Science Library

    Hübscher, Markus; Zech, Astrid; Pfeifer, Klaus; Hänsel, Frank; Vogt, Lutz; Banzer, Winfried

    2010-01-01

    The aim of this systematic review was to assess the effectiveness of proprioceptive/neuromuscular training in preventing sports injuries by using the best available evidence from methodologically well...

  16. Quantitative skeletal muscle ultrasound: diagnostic value in childhood neuromuscular disease.

    NARCIS (Netherlands)

    Pillen, S.; Verrips, A.; Alfen, N. van; Arts, I.M.P.; Sie, L.T.L.; Zwarts, M.J.

    2007-01-01

    In this study we investigated the diagnostic value of quantitative skeletal muscle ultrasonography in 150 consecutively referred children with symptoms suspect for a neuromuscular disorder. Muscle thickness and quantitatively determined echo intensity of four muscles and the distribution of these

  17. Effects of napping on neuromuscular fatigue in myasthenia gravis.

    Science.gov (United States)

    Kassardjian, Charles D; Murray, Brian J; Kokokyi, Seint; Jewell, Dana; Barnett, Carolina; Bril, Vera; Katzberg, Hans D

    2013-11-01

    The relationship between sleep and neuromuscular fatigue is understood poorly. The goal of this study was to evaluate the effects of napping on quantitative measures of neuromuscular fatigue in patients with myasthenia gravis (MG). Eight patients with mild to moderate MG were recruited. Patients underwent maintenance of wakefulness tests (MWT) and multiple sleep latency tests (MSLT). The Quantitative Myasthenia Gravis Score (QMGS) was measured before nap and after each nap to examine the effects of napping and sleep on neuromuscular weakness. Results showed that QMGS improves only after naps where patients slept more than 5 min but not where patients did not sleep or slept less than 5 min. Daytime napping mitigates neuromuscular fatigue in patients with MG, especially if patients slept for more than 5 min. Copyright © 2013 Wiley Periodicals, Inc.

  18. Genetics of Pediatric-Onset Motor Neuron and Neuromuscular Diseases

    Science.gov (United States)

    2015-08-24

    Spinal Muscular Atrophy; Charcot-Marie-Tooth Disease; Muscular Dystrophy; Spinal Muscular Atrophy With Respiratory Distress 1; Amyotrophic Lateral Sclerosis; Motor Neuron Disease; Neuromuscular Disease; Peroneal Muscular Atrophy; Fragile X Syndrome

  19. [Neuromuscular relaxation and CCMDP. The Zilgrei and Feldenkrais methods 2].

    Science.gov (United States)

    Santoro, F; Maiorana, C; Faccin, C

    1989-10-31

    The Authors show two neuromuscular release methods employed in the treatment of cranio-cervico-mandibular syndrome; these methods work at the place of origin of the pathology resolving the symptoms in different districts of the body.

  20. Exploring employment in consultation reports of patients with neuromuscular diseases

    NARCIS (Netherlands)

    Minis, M.A.H; Cup, E.H.C.; Heerkens, Y.H.; Engels, J.A.; Engelen, B.G.M. van; Oostendorp, R.A.B.

    2012-01-01

    Minis MA, Cup EH, Heerkens YF, Engels JA, van Engelen BG, Oostendorp RA. Exploring employment in consultation reports of patients with neuromuscular diseases. OBJECTIVES: To explore consultation reports for patient and employment characteristics and recommendations on employment regarding patients

  1. Neuromuscular adjustments of the quadriceps muscle after repeated cycling sprints.

    Directory of Open Access Journals (Sweden)

    Olivier Girard

    Full Text Available PURPOSE: This study investigated the supraspinal processes of fatigue of the quadriceps muscle in response to repeated cycling sprints. METHODS: Twelve active individuals performed 10 × 6-s "all-out" sprints on a cycle ergometer (recovery = 30 s, followed 6 min later by 5 × 6-s sprints (recovery = 30 s. Transcranial magnetic and electrical femoral nerve stimulations during brief (5-s and sustained (30-s isometric contractions of the knee extensors were performed before and 3 min post-exercise. RESULTS: Maximal strength of the knee extensors decreased during brief and sustained contractions (~11% and 9%, respectively; P0.05. While cortical voluntary activation declined (P 40% reduced (P<0.001 following exercise. CONCLUSION: The capacity of the motor cortex to optimally drive the knee extensors following a repeated-sprint test was shown in sustained, but not brief, maximal isometric contractions. Additionally, peripheral factors were largely involved in the exercise-induced impairment in neuromuscular function, while corticospinal excitability was well-preserved.

  2. EFFECT OF NEUROMUSCULAR TRAINING ON BALANCE AMONG UNIVERSITY ATHLETES

    OpenAIRE

    Mohansundar Sankaravel; Jeffrey Low Fook Lee; Ong Kuan Boon; Sanmuganathan Jeganathan

    2016-01-01

    Background: Proprioceptive deficiency followed by lateral ankle sprain leads to poor balance is not uncommon. It has been linked with increased injury risk among young athletes. Introducing neuromuscular training programs for this have been believed as one of the means of injury prevention. Hence, this study was aimed to determine the effects of six weeks progressive neuromuscular training (PNM Training) on static balance gains among the young athletes with a previous history of ankle sprains...

  3. Effect of Early Physical Activity Programs on Motor Performance and Neuromuscular Development in Infants Born Preterm: A Randomized Clinical Trial.

    Science.gov (United States)

    Valizadeh, Leila; Sanaeefar, Mahnaz; Hosseini, Mohammad Bager; Asgari Jafarabadi, Mohammad; Shamili, Aryan

    2017-03-01

    Introduction: Although the survival rate of infants born preterm has increased, the prevalence of developmental problems and motor disorders among this population of infants remains the same. This study investigated the effect of physical activity programs in and out of water on motor performance and neuromuscular development of infants born preterm and had induced immobility by mechanical ventilation. Methods: This study was carried out in Al-Zahra hospital, Tabriz. 76 premature infants were randomly assigned into four groups. One group received daily passive range of motion to all extremities based on the Moyer-Mileur protocol. Hydrotherapy group received exercises for shoulders and pelvic area in water every other day. A combination group received physical activity programs in and out of water on alternating days. Infants in a containment group were held in a fetal position. Duration of study was two weeks 'from 32 through 33 weeks post menstrual age (PMA). Motor outcomes were measured by the Test of Infant Motor Performance. Neuromuscular developmental was assessed by New Ballard scale and leg recoil and Ankle dorsiflexion items from Dubowitz scale. Data were analyzed using SPSS version 13. Results: TIMP and neuromuscular scores improved in all groups. Motor performance did not differ between groups at 34 weeks PMA. Postural tone of leg recoil was significantly higher in physical activity groups post intervention. Conclusion: Physical activities and containment didn't have different effects on motor performance in infants born preterm. Leg recoil of neuromuscular development items was affected by physical activity programs.

  4. Effects of Pivoting Neuromuscular Training on Pivoting Control and Proprioception

    Science.gov (United States)

    Lee, Song Joo; Ren, Yupeng; Chang, Alison H.; Geiger, François; Zhang, Li-Qun

    2014-01-01

    Purpose Pivoting neuromuscular control and proprioceptive acuity may play an important role in ACL injuries. The goal of this study was to investigate whether pivoting neuromuscular training on an offaxis elliptical trainer (POINT) could improve pivoting neuromuscular control, proprioceptive acuity, and functional performance. Methods Among 41 subjects, 21 subjects participated in 18 sessions of POINT (3 sessions/week for 6 weeks), and 20 subjects served as controls who did their regular workout. Both groups received pre-, mid-, and post-intervention evaluations. Propensity score analysis with multivariable regression adjustment was used to investigate the effect of training on pivoting neuromuscular control (pivoting instability, leg pivoting stiffness, maximum internal and external pivoting angles), proprioceptive acuity, and functional performance in both groups. Results Compared to the control group, the training group significantly improved pivoting neuromuscular control as reduced pivoting instability, reduced maximum internal and external pivoting angles, increased leg pivoting stiffness, and decreased entropy of time to peak EMG in the gluteus maximus and lateral gastrocnemius under pivoting perturbations. Furthermore, the training group enhanced weight-bearing proprioceptive acuity and improved the single leg hop distance. Conclusion Improvement of pivoting neuromuscular control in functional weight-bearing activities and task performances following POINT may help develop lower limb injury prevention and rehabilitation methods to reduce ACL and other musculoskeletal injuries associated with pivoting sports. PMID:24389517

  5. Effects of pivoting neuromuscular training on pivoting control and proprioception.

    Science.gov (United States)

    Lee, Song Joo; Ren, Yupeng; Chang, Alison H; Geiger, François; Zhang, Li-Qun

    2014-07-01

    Pivoting neuromuscular control and proprioceptive acuity may play an important role in anterior cruciate ligament injuries. The goal of this study was to investigate whether pivoting off-axis intensity adjustable neuromuscular control training (POINT) could improve pivoting neuromuscular control, proprioceptive acuity, and functional performance. Among 41 subjects, 21 subjects participated in 18 sessions of POINT (three sessions per week for 6 wk), and 20 subjects served as controls who did their regular workout. Both groups received pre-, mid-, and postintervention evaluations. Propensity score analysis with multivariable regression adjustment was used to investigate the effect of training on pivoting neuromuscular control (pivoting instability, leg pivoting stiffness, maximum internal, and external pivoting angles), proprioceptive acuity, and functional performance in both groups. Compared with the control group, the training group significantly improved pivoting neuromuscular control as reduced pivoting instability, reduced maximum internal and external pivoting angles, increased leg pivoting stiffness, and decreased entropy of time to peak EMG in the gluteus maximus and lateral gastrocnemius under pivoting perturbations. Furthermore, the training group enhanced weight-bearing proprioceptive acuity and improved the single leg hop distance. Improvement of pivoting neuromuscular control in functional weight-bearing activities and task performances after POINT may help develop lower limb injury prevention and rehabilitation methods to reduce anterior cruciate ligament and other musculoskeletal injuries associated with pivoting sports.

  6. Neuromuscular adaptations to concurrent training in the elderly: effects of intrasession exercise sequence

    OpenAIRE

    Cadore, Eduardo Lusa; Izquierdo, Mikel; Pinto, Stephanie Santana; Alberton, Cristine Lima; Pinto, Ronei Silveira; Baroni, Bruno Manfredini; Vaz, Marco Aurélio; Lanferdini, Fábio Juner; Radaelli, Régis; González-Izal, Miriam; Bottaro, Martim; Kruel, Luiz Fernando Martins

    2012-01-01

    The aim of this study was investigate the effects of different intrasession exercise orders in the neuromuscular adaptations induced by concurrent training in elderly. Twenty-six healthy elderly men (64.7 ± 4.1 years), were placed into two concurrent training groups: strength prior to (SE, n = 13) or after (ES, n = 13) endurance training. Subjects trained strength and endurance training during 12 weeks, three times per week performing both exercise types in the same training session. Upper an...

  7. Sleep polygraphic parameters in neuromuscular diseases

    Directory of Open Access Journals (Sweden)

    Márcia Pradella

    1994-12-01

    Full Text Available In a polysomnography study of 32 neuromuscular patients - 22 with a form of muscular dystrophy, 3 with a form of congenital myopathy, 4 with a form of spinal muscular atrophy, 1 with a recurrent form of polymyositis and 1 with osteogenesis imperfecta syndrome - of which 21 were nonambulatory, we observed sleep related respiratory disturbances represented by: drops in oxygen saturation (SaO2, cardiac arrythmia, sleep disruption, apneas, tachypnea, tachycardia and snoring. Nine out of the cohort of 32 patients presented with significant desaturations periods. These patients presented with an associated restrictive syndrome and thoracic deformities, some with tachypnea and/or SaO2 below 90% during wakefulness. In this group, snoring was observed in those patients with a form of muscular dystrophy while tachypnea was observed in patients who presented the highest desaturations levels. Sleep quantification revealed an increase of stage 1 sleep coupled with a decrease or even total absence of REM sleep. This is, we believe, a likely consequence of episodic desaturations that may accompany sleep hypoventilation which is potentialised during REM sleep stage.

  8. Neuromuscular Fatigue During 200 M Breaststroke

    Directory of Open Access Journals (Sweden)

    Ana Conceição

    2014-03-01

    Full Text Available The aims of this study were: i to analyze activation patterns of four upper limb muscles (duration of the active and non-active phase in each lap of 200m breaststroke, ii quantify neuromuscular fatigue, with kinematics and physiologic assessment. Surface electromyogram was collected for the biceps brachii, deltoid anterior, pectoralis major and triceps brachii of nine male swimmers performing a maximal 200m breaststroke trial. Swimming speed, SL, SR, SI decreased from the 1st to the 3rd lap. SR increased on the 4th lap (35.91 ± 2.99 stroke·min-1. Peak blood lactate was 13.02 ± 1.72 mmol·l-1 three minutes after the maximal trial. The EMG average rectified value (ARV increased at the end of the race for all selected muscles, but the deltoid anterior and pectoralis major in the 1st lap and for biceps brachii, deltoid anterior and triceps brachii in the 4th lap. The mean frequency of the power spectral density (MNF decreased at the 4th lap for all muscles. These findings suggest the occurrence of fatigue at the beginning of the 2nd lap in the 200m breaststroke trial, characterized by changes in kinematic parameters and selective changes in upper limb muscle action. There was a trend towards a non-linear fatigue state.

  9. Inhibition of (prorenin Receptor Contributes to Renoprotective Effects of Angiotensin II Type 1 Receptor Blockade in Diabetic Nephropathy

    Directory of Open Access Journals (Sweden)

    Lin Zhang

    2017-10-01

    Full Text Available Aims: Renal renin-angiotensin system (RAS plays a pivotal role in the development of diabetic nephropathy (DN. Angiotensin II (Ang II type 1 receptor (AT1R blockade elevates (prorenin, which may bind to (prorenin receptor (PRR and exert receptor-mediated, angiotensin-independent profibrotic effects. We therefore investigated whether PRR activation leads to the limited anti-fibrotic effects of AT1R blockade on DN, and whether PRR inhibition might ameliorate progression of DN.Methods: To address the issue, the expression of RAS components was tested in different stages of streptozotocin (STZ-induced diabetic rats (6, 12, and 24 weeks and 6-week AT1R blockade (losartan treated diabetic rats. Using the blocker for PRR, the handle region peptide (HRP of prorenin, the effects of PRR on high glucose or Ang II-induced proliferative and profibrotic actions were evaluated by measurement of cell proliferation, matrix metalloproteinase-2 (MMP-2 activity, activation of extracellular signal-regulated kinase 1/2 (ERK1/2 and transforming growth factor-β1 (TGF-β1 expression in rat mesangial cells (MCs.Results: PRR was downregulated in the kidneys of different stages of diabetic rats (6, 12, and 24 weeks. Moreover, 6-week losartan treatment further suppressed PRR expression via upregulating AT2R, and ameliorated diabetic renal injury. HRP inhibited high glucose and Ang II-induced proliferative and profibrotic effects in MCs through suppressing TGF-β1 expression and activating MMP-2. Meanwhile, HRP enhanced losartan's anti-fibrotic effects through further inhibiting phosphorylation of ERK1/2 and TGF-β1 expression. Moreover, the inhibitive effect of HRP on Ang II-induced TGF-β1 expression depended on the regulation of PRR expression by AT2R.Conclusions: Our findings suggest that inhibition of PRR contributes to renoprotection against diabetic nephropathy by AT1R blockade.

  10. STEAL PHENOMENON AFTER LUMBAR AND THORACIC SYMPATHETIC GANGLION BLOCKADE IN DOGS1 THE INFLUENCE OF INTRAVASCULAR VOLUME

    OpenAIRE

    Marunaka, Shu; Hashizume, Keiji; Yamagami, Hiroaki; MIYATA, Yoshihisa; Furuya, Hitoshi

    2000-01-01

    The steal phenomenon between the bilateral sides following unilateral sympathetic denervation can be influenced by intravascular blood volume. We studied the changes in skin temperature as an indicator of this phenomenon induced by unilateral lumbar or thoracic sympathetic ganglion blockade in dogs under various hemodynamics. Each of 30 dogs in lumbar and thoracic experiments, which were divided into three groups according to mean right atrial pressure (RAP, mmHg) as hypovolemic (RAP<3 ; n=10...

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

    Science.gov (United States)

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

    2012-01-01

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

  12. [Ropivacaine (naropin), local anesthetic of choice for epidural blockade].

    Science.gov (United States)

    Ovechkin, A M; Gnezdilov, A V; Syrovegin, A V; Kukushkin, M L; Gasanov, I N

    2001-01-01

    The purpose of this study, carried out in 132 patients with intense acute radicular pain, was search for an optimal local anesthetic to be used in combination with a steroid for therapeutic epidural blockade. Comparative analysis of analgesia attained by epidural injections of 5 ml 2% lidocaine, 4 ml 0.5% bupivacaine, and 4 ml 1% ropivacaine showed the advantages of the latter drug in stable arrest of radicular pain immediately after injection. The duration of analgesia after blockade was 1.4 +/- 0.5, 3.1 +/- 0.3, and 9.5 +/- 1.2 h, respectively. Use of ropivacaine eliminated the main shortcoming of epidural blockade in the treatment of patients with radicular pain, consisting in temporary pain relapse after discontinuation of the local anesthetic effect before development of antiinflammatory effect of the steroid.

  13. CD27 Agonism Plus PD-1 Blockade Recapitulates CD4+ T-cell Help in Therapeutic Anticancer Vaccination.

    Science.gov (United States)

    Ahrends, Tomasz; Bąbała, Nikolina; Xiao, Yanling; Yagita, Hideo; van Eenennaam, Hans; Borst, Jannie

    2016-05-15

    While showing promise, vaccination strategies to treat cancer require further optimization. Likely barriers to efficacy involve cancer-associated immunosuppression and peripheral tolerance, which limit the generation of effective vaccine-specific cytotoxic T lymphocytes (CTL). Because CD4(+) T cells improve CTL responsiveness, next-generation vaccines include helper epitopes. Here, we demonstrate in mice how CD4(+) T-cell help optimizes the CTL response to a clinically relevant DNA vaccine engineered to combat human papillomavirus-expressing tumors. Inclusion of tumor-unrelated helper epitopes greatly increased CTL priming, effector, and memory T-cell programming. CD4(+) T-cell help optimized the CTL response in all these aspects via CD27/CD70 costimulation. Notably, administration of an agonistic CD27 antibody could largely replace helper epitopes in promoting primary and memory CTL responses, acting directly on CD8(+) T cells. CD27 agonism improved efficacy of the vaccine without helper epitopes, more so than combined PD-1 and CTLA-4 blockade. Combining CD27 agonism with CTLA-4 blockade improved vaccine-induced CTL priming and tumor infiltration, but only combination with PD-1 blockade was effective at eradicating tumors, thereby fully recapitulating the effect of CD4(+) T-cell help on vaccine efficacy. PD-1 blockade alone did not affect CTL priming or tumor infiltration, so these results implied that it cooperated with CD4(+) T-cell help by alleviating immune suppression against CTL in the tumor. Helper epitope inclusion or CD27 agonism did not stimulate regulatory T cells, and vaccine efficacy was also improved by CD27 agonism in the presence of CD4(+) T-cell help. Our findings provide a preclinical rationale to apply CD27 agonist antibodies, either alone or combined with PD-1 blockade, to improve the therapeutic efficacy of cancer vaccines and immunotherapy generally. Cancer Res; 76(10); 2921-31. ©2016 AACR. ©2016 American Association for Cancer Research.

  14. Effects of Neuromuscular Fatigue on Quadriceps Strength and Activation and Knee Biomechanics in Individuals Post-Anterior Cruciate Ligament Reconstruction and Healthy Adults.

    Science.gov (United States)

    Thomas, Abbey C; Lepley, Lindsey K; Wojtys, Edward M; McLean, Scott G; Palmieri-Smith, Riann M

    2015-12-01

    Laboratory-based experiment using a pretest/posttest design. To determine the effects of neuromuscular fatigue on quadriceps strength and activation and sagittal and frontal plane knee biomechanics during dynamic landing following anterior cruciate ligament reconstruction (ACLR). Impaired quadriceps central activation occurs post-ACLR, likely altering lower extremity biomechanics. Neuromuscular fatigue similarly reduces volitional muscle activation and impairs neuromuscular control. Upon return to full activity post-ACLR, individuals likely concurrently experience quadriceps central activation deficits and neuromuscular fatigue, though the effects of fatigue on muscle strength and activation and biomechanics post-ACLR are unknown. Seventeen individuals 7 to 10 months post-ACLR and 16 controls participated. Quadriceps strength and central activation ratio were recorded prefatigue and postfatigue, which was induced via sets of double-leg squats. Knee biomechanics were recorded during a dynamic landing activity prefatigue and postfatigue. Both groups demonstrated smaller knee flexion (initial contact, P = .017; peak, P = .004) and abduction (initial contact, P = .005; peak, P = .009) angles postfatigue. The ACLR group had smaller peak knee flexion angles (Pbiomechanics were present postfatigue in both groups, suggesting that neuromuscular fatigue may increase noncontact ACL injury risk. However, these changes were not exaggerated in those post-ACLR, likely because they already demonstrated a stiff-legged landing strategy prefatigue.

  15. Multibit CkNOT quantum gates via Rydberg blockade

    DEFF Research Database (Denmark)

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

    2011-01-01

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

  16. 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.

  17. 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.

  18. PD-1 Blockade Expands Intratumoral Memory T Cells

    DEFF Research Database (Denmark)

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

    2016-01-01

    Tumor responses to programmed cell death protein 1 (PD-1) blockade therapy are mediated by T cells, which we characterized in 102 tumor biopsies obtained from 53 patients treated with pembrolizumab, an antibody to PD-1. Biopsies were dissociated, and single-cell infiltrates were analyzed by multi...... with regressing melanoma. In conclusion, PD-1 blockade increases the frequency of T cells, B cells, and myeloid-derived suppressor cells in tumors, with the CD8+ effector memory T-cell subset being the major T-cell phenotype expanded in patients with a response to therapy....

  19. Genome Editing of Monogenic Neuromuscular Diseases: A Systematic Review.

    Science.gov (United States)

    Long, Chengzu; Amoasii, Leonela; Bassel-Duby, Rhonda; Olson, Eric N

    2016-11-01

    Muscle weakness, the most common symptom of neuromuscular disease, may result from muscle dysfunction or may be caused indirectly by neuronal and neuromuscular junction abnormalities. To date, more than 780 monogenic neuromuscular diseases, linked to 417 different genes, have been identified in humans. Genome-editing methods, especially the CRISPR (clustered regularly interspaced short palindromic repeats)-Cas9 (CRISPR-associated protein 9) system, hold clinical potential for curing many monogenic disorders, including neuromuscular diseases such as Duchenne muscular dystrophy, spinal muscular atrophy, amyotrophic lateral sclerosis, and myotonic dystrophy type 1. To provide an overview of genome-editing approaches; to summarize published reports on the feasibility, efficacy, and safety of current genome-editing methods as they relate to the potential correction of monogenic neuromuscular diseases; and to highlight scientific and clinical opportunities and obstacles toward permanent correction of disease-causing mutations responsible for monogenic neuromuscular diseases by genome editing. PubMed and Google Scholar were searched for articles published from June 30, 1989, through June 9, 2016, using the following keywords: genome editing, CRISPR-Cas9, neuromuscular disease, Duchenne muscular dystrophy, spinal muscular atrophy, amyotrophic lateral sclerosis, and myotonic dystrophy type 1. The following sources were reviewed: 341 articles describing different approaches to edit mammalian genomes; 330 articles describing CRISPR-Cas9-mediated genome editing in cell culture lines (in vitro) and animal models (in vivo); 16 websites used to generate single-guide RNA; 4 websites for off-target effects; and 382 articles describing viral and nonviral delivery systems. Articles describing neuromuscular diseases, including Duchenne muscular dystrophy, spinal muscular atrophy, amyotrophic lateral sclerosis, and myotonic dystrophy type 1, were also reviewed. Multiple proof

  20. 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.

  1. Galectin-3 blockade inhibits cardiac inflammation and fibrosis in experimental hyperaldosteronism and hypertension.

    Science.gov (United States)

    Martínez-Martínez, Ernesto; Calvier, Laurent; Fernández-Celis, Amaya; Rousseau, Elodie; Jurado-López, Raquel; Rossoni, Luciana V; Jaisser, Frederic; Zannad, Faiez; Rossignol, Patrick; Cachofeiro, Victoria; López-Andrés, Natalia

    2015-10-01

    Hypertensive cardiac remodeling is accompanied by molecular inflammation and fibrosis, 2 mechanisms that finally affect cardiac function. At cardiac level, aldosterone promotes inflammation and fibrosis, although the precise mechanisms are still unclear. Galectin-3 (Gal-3), a β-galactoside-binding lectin, is associated with inflammation and fibrosis in the cardiovascular system. We herein investigated whether Gal-3 inhibition could block aldosterone-induced cardiac inflammation and fibrosis and its potential role in cardiac damage associated with hypertension. Aldosterone-salt-treated rats presented hypertension, cardiac inflammation, and fibrosis that were prevented by the pharmacological inhibition of Gal-3 with modified citrus pectin. Cardiac inflammation and fibrosis presented in spontaneously hypertensive rats were prevented by modified citrus pectin treatment, whereas Gal-3 blockade did not modify blood pressure levels. In the absence of blood pressure modifications, Gal-3 knockout mice were resistant to aldosterone-induced cardiac inflammation. In human cardiac fibroblasts, aldosterone increased Gal-3 expression via its mineralocorticoid receptor. Gal-3 and aldosterone enhanced proinflammatory and profibrotic markers, as well as metalloproteinase activities in human cardiac fibroblasts, effects that were not observed in Gal-3-silenced cells treated with aldosterone. In experimental hyperaldosteronism, the increase in Gal-3 expression was associated with cardiac inflammation and fibrosis, alterations that were prevented by Gal-3 blockade independently of blood pressure levels. These data suggest that Gal-3 could be a new molecular mechanism linking cardiac inflammation and fibrosis in situations with high-aldosterone levels, such as hypertension. © 2015 American Heart Association, Inc.

  2. Prolonged neuromuscular block in a preeclamptic patient induced ...

    African Journals Online (AJOL)

    Recent large use of magnesium in the obstetric population should incite anesthesiologists to control its side effects and drugs interactions. We report a case of a 30-year-old woman, with severe preeclampsia and HELLP syndrome, receiving sulfate magnesium and nicardipine, who underwent a cesarean section under ...

  3. Caenorhabditis elegans neuromuscular junction: GABA receptors and ivermectin action.

    Directory of Open Access Journals (Sweden)

    Guillermina Hernando

    Full Text Available The prevalence of human and animal helminth infections remains staggeringly high, thus urging the need for concerted efforts towards this area of research. GABA receptors, encoded by the unc-49 gene, mediate body muscle inhibition in Caenorhabditis elegans and parasitic nematodes and are targets of anthelmintic drugs. Thus, the characterization of nematode GABA receptors provides a foundation for rational anti-parasitic drug design. We therefore explored UNC-49 channels from C. elegans muscle cultured cells of the first larval stage at the electrophysiological and behavioral levels. Whole-cell recordings reveal that GABA, muscimol and the anthelmintic piperazine elicit macroscopic currents from UNC-49 receptors that decay in their sustained presence, indicating full desensitization. Single-channel recordings show that all drugs elicit openings of ∼2.5 pA (+100 mV, which appear either as brief isolated events or in short bursts. The comparison of the lowest concentration required for detectable channel opening, the frequency of openings and the amplitude of macroscopic currents suggest that piperazine is the least efficacious of the three drugs. Macroscopic and single-channel GABA-activated currents are profoundly and apparently irreversibly inhibited by ivermectin. To gain further insight into ivermectin action at C. elegans muscle, we analyzed its effect on single-channel activity of the levamisol-sensitive nicotinic receptor (L-AChR, the excitatory receptor involved in neuromuscular transmission. Ivermectin produces a profound inhibition of the frequency of channel opening without significant changes in channel properties. By revealing that ivermectin inhibits C. elegans muscle GABA and L-AChR receptors, our study adds two receptors to the already known ivermectin targets, thus contributing to the elucidation of its pleiotropic effects. Behavioral assays in worms show that ivermectin potentiates piperazine-induced paralysis, thus suggesting

  4. Neuromuscular consequences of an extreme mountain ultra-marathon.

    Directory of Open Access Journals (Sweden)

    Guillaume Y Millet

    Full Text Available We investigated the physiological consequences of one of the most extreme exercises realized by humans in race conditions: a 166-km mountain ultra-marathon (MUM with 9500 m of positive and negative elevation change. For this purpose, (i the fatigue induced by the MUM and (ii the recovery processes over two weeks were assessed. Evaluation of neuromuscular function (NMF and blood markers of muscle damage and inflammation were performed before and immediately following (n = 22, and 2, 5, 9 and 16 days after the MUM (n = 11 in experienced ultra-marathon runners. Large maximal voluntary contraction decreases occurred after MUM (-35% [95% CI: -28 to -42%] and -39% [95% CI: -32 to -46%] for KE and PF, respectively, with alteration of maximal voluntary activation, mainly for KE (-19% [95% CI: -7 to -32%]. Significant modifications in markers of muscle damage and inflammation were observed after the MUM as suggested by the large changes in creatine kinase (from 144 ± 94 to 13,633 ± 12,626 UI L(-1, myoglobin (from 32 ± 22 to 1,432 ± 1,209 µg L(-1, and C-Reactive Protein (from <2.0 to 37.7 ± 26.5 mg L(-1. Moderate to large reductions in maximal compound muscle action potential amplitude, high-frequency doublet force, and low frequency fatigue (index of excitation-contraction coupling alteration were also observed for both muscle groups. Sixteen days after MUM, NMF had returned to initial values, with most of the recovery process occurring within 9 days of the race. These findings suggest that the large alterations in NMF after an ultra-marathon race are multi-factorial, including failure of excitation-contraction coupling, which has never been described after prolonged running. It is also concluded that as early as two weeks after such an extreme running exercise, maximal force capacities have returned to baseline.

  5. Pharmacokinetic studies of neuromuscular blocking agents: Good Clinical Research Practice (GCRP)

    DEFF Research Database (Denmark)

    Viby-Mogensen, J.; Østergaard, D.; Donati, F.

    2000-01-01

    Good Clinical Research Practice (GCRP), neuromuscular blocking agents, pharmacokinetics, pharmacokinetic/pharmacodynamic modeling, population pharmacokinetics, statistics, study design......Good Clinical Research Practice (GCRP), neuromuscular blocking agents, pharmacokinetics, pharmacokinetic/pharmacodynamic modeling, population pharmacokinetics, statistics, study design...

  6. Respiratory motor training and neuromuscular plasticity in patients with chronic obstructive pulmonary disease: A pilot study.

    Science.gov (United States)

    Ovechkin, Alexander V; Sayenko, Dimitry G; Ovechkina, Elena N; Aslan, Sevda C; Pitts, Teresa; Folz, Rodney J

    2016-07-15

    The objective of this study was to examine the feasibility of a full-scale investigation of the neurophysiological mechanisms of COPD-induced respiratory neuromuscular control deficits. Characterization of respiratory single- and multi-muscle activation patterns using surface electromyography (sEMG) were assessed along with functional measures at baseline and following 21±2 (mean±SD) sessions of respiratory motor training (RMT) performed during a one-month period in four patients with GOLD stage II or III COPD. Pre-training, the individuals with COPD showed significantly increased (prespiratory muscle activity and disorganized multi-muscle activation patterns in association with lowered spirometrical measures and decreased fast- and slow-twitch fiber activity as compared to healthy controls (N=4). Following RMT, functional and respiratory sEMG activation outcomes during quite breathing and forced expiratory efforts were improved suggesting that functional improvements, induced by task-specific RMT, are evidence respiratory neuromuscular networks re-organization. Published by Elsevier B.V.

  7. Vertebral column resection in children with neuromuscular spine deformity.

    Science.gov (United States)

    Sponseller, Paul D; Jain, Amit; Lenke, Lawrence G; Shah, Suken A; Sucato, Daniel J; Emans, John B; Newton, Peter O

    2012-05-15

    Retrospective analysis. To determine, in pediatric patients with neuromuscular deformity undergoing vertebral column resection (VCR), the (1) characteristics of the surgery performed; (2) amount of pelvic obliquity restoration, and coronal and sagittal correction achieved; (3) associated blood loss and complications; and (4) extent to which curve type and VCR approach influenced correction, blood loss, and complications. VCR allows for correction of severe, rigid spinal deformity. This technique has not been previously reported in children with neuromuscular disorders. We retrospectively reviewed the records of 23 children with neuromuscular disorders (mean age, 15 years) and spinal deformities (severe scoliosis, 9; global kyphosis or angular kyphosis, 4; kyphoscoliosis, 10) who underwent VCR. The Student t test was used to compare correction differences (statistical significance, P deformity. However, this challenging procedure involves the potential for major complications.

  8. A neuromuscular test battery for osteoporotic women: a pilot study.

    Science.gov (United States)

    Kerschan-Schindl, K; Uher, E; Grampp, S; Kaider, A; Ghanem, A H; Fialka-Moser, V; Preisinger, E

    2001-05-01

    To examine the efficacy of a short neuromuscular test battery in elderly women suffering from osteoporosis in accordance with the World Health Organization criteria, with and without a history of fractures. Reduced bone mass and a high likelihood of falling increase the risk of osteoporotic fractures. There is a need for neuromuscular tests to identify individuals at risk for falls and fractures. The women were assessed twice. Forty-two women, with a mean age of 70.0 +/- 5.1 (SD) yr, completed the first assessment. The number of postmenopausal fractures and the women's history with regard to agility and falls were assessed. The women performed neuromuscular tests (one-leg stance, tandem walk, and body sway); bone mineral density of the spine and femoral neck were measured. For the follow-up assessment, 13.2 +/- 1.3 mo later, 39 women were studied. The same outcome measurements were obtained at both evaluations. During the observation period, five women fell once and one woman fell twice; there were only two vertebral fractures and no nonvertebral fracture. Neuromuscular performance did not change during this observation period. The median changes in bone mineral density between the two assessments were clinically not relevant. A comparison between patients suffering from established osteoporosis and osteoporotic patients without a history of postmenopausal fractures showed that both groups of patients did not differ with respect to age, neuromuscular performance, bone mineral density, and fear of falling. This neuromuscular test battery is a feasible and practical tool because it is brief and economical to perform. However, its efficacy as a predictor of fractures must be tested in additional studies with a long-term follow-up and a larger group of subjects.

  9. Neuromuscular electrical stimulation for mobility support of elderly

    Directory of Open Access Journals (Sweden)

    Winfried Mayr

    2015-10-01

    Full Text Available The stimulator for neuromuscular electrical stimulation for mobility support of elderly is not very complicated, but for application within "MOBIL" we have some additional demands to fulfill. First we have specific safety issues for this user group. A powerful compliance management system is crucial not only to guide daily application, but for creating hard data for the scientific outcome. We also need to assure easy handling of the stimulator, because the subjects are generally not able to cope with too difficult and complex motor skills. So, we developed five generations of stimulators and optimizing solutions after field tests. We are already planning the sixth generation with wireless control of the stimulation units by the central main handheld control unit. In a prototype, we have implemented a newly available high capacity memory, a breakthrough in “compliance data storage” as they offer the necessary high storage capacity and fast data handling for an affordable prize. The circuit also contains a 3D accelerometer sensor which acts as a further important safety features: if the control unit drops, this event is detected automatically by the sensor and activates an emergency switch-off that disables the stimulation to avoid associated risks. Further, we have implemented a hardware emergence shutdown and other safety measures. Finally, in the last example muscle torque measurements are referenced with compliance data. In the study normalized maximum voluntary contraction (MVC and maximum stimulation induced contraction (MSC were assessed in regular check-ups along the training period. With additional consideration of adjusted stimulation intensity for training out of the compliance data records we are able to estimate the induced contraction strength, which turned out to amount in average 11% of MVC. This value may seem on a first sight rather low, and ought to be considered in relation to the results at the end of the training period

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

    DEFF Research Database (Denmark)

    Miroshnychenko, Yevhen; Browaeys, Antoine; Evellin, Charles

    2011-01-01

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

  11. 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

  12. 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 ...

  13. Combination Approaches with Immune-Checkpoint Blockade in Cancer Therapy

    NARCIS (Netherlands)

    Swart, M.; Verbrugge, I.; Beltman, J.B.

    2016-01-01

    In healthy individuals, immune-checkpoint molecules prevent autoimmune responses and limit immune cell-mediated tissue damage. Tumors frequently exploit these molecules to evade eradication by the immune system. Over the past years, immune-checkpoint blockade of cytotoxic T lymphocyte antigen-4 and

  14. 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....

  15. Anisotropic Pauli spin blockade in hole quantum dots

    NARCIS (Netherlands)

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

    2016-01-01

    We present measurements on gate-defined double quantum dots in Ge-Si core-shell nanowires, which we tune to a regime with visible shell filling in both dots. We observe a Pauli spin blockade and can assign the measured leakage current at low magnetic fields to spin-flip cotunneling, for which we

  16. Coulomb blockade and superuniversality of the theta angle

    NARCIS (Netherlands)

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

    2008-01-01

    Based on the Ambegaokar-Eckern-Schön approach to the Coulomb blockade, we develop a complete quantum theory of the single electron transistor. We identify a previously unrecognized physical observable in the problem that, unlike the usual average charge on the island, is robustly quantized for any

  17. A mean field approach to Coulomb blockade for a disordered ...

    Indian Academy of Sciences (India)

    The Coulomb blockade (CB) in quantum dots (QDs) is by now well documented. It has been used to guide the fabrication of single electron transistors. Even the most sophisticated techniques for synthesizing QDs (e.g. MOCVD/MBE) result in an assembly in which a certain amount of disorder is inevitable. On the other hand, ...

  18. 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...

  19. 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...

  20. Potential protective effects of l-carnitine against neuromuscular ischemia-reperfusion injury: From experimental data to potential clinical applications.

    Science.gov (United States)

    Moghaddas, Azadeh; Dashti-Khavidaki, Simin

    2016-08-01

    Ischemia-reperfusion (I/R) injury plays important role in morbidity and mortality in several pathologies, including myocardial infarction, ischemic stroke, acute kidney injury, trauma, and circulatory arrest. An imbalance in metabolic supply and tissue's demand during ischemia results in profound tissue hypoxia and microvascular dysfunction. Subsequently, reperfusion further results in activation of immune responses and cell death programs. l-carnitine and its derivatives have been administered to improve tolerance against I/R injury in various tissues. Anti-ischemic properties of l-carnitine and its derivative in neuromuscular organs will be reviewed here at the light of pertinent results from basic and clinical researches. All available in vitro and in vivo studies, patents, clinical trials, and meeting abstracts in English language that examined the protective effects of l-carnitine against I/R induced injury in neuromuscular organs were reviewed. Materials were obtained by searching ELSEVIER, web of knowledge, PubMed, Scopus, clinical trials, and Cochrane database of systematic reviews. Although animal studies on central nervous system and some human studies on muscular system were in favors of effects of l-carnitine against I/R injury, however, more clinical trials are needed to clarify the clinical importance of l-carnitine as a treatment option to manage I/R-induced injury of neuromuscular system. Copyright © 2015 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.

  1. Efectos del vendaje neuromuscular sobre la flexibilidad del raquis lumbar

    OpenAIRE

    A.M. Labrador-Cerrato; P. Ortega Sánchez-Diezma; G. Lanzas Melendo; C. Gutiérrez-Ortega

    2015-01-01

    Introducción: El vendaje neuromuscular es una técnica que produce una estimulación muy selectiva sobre la piel a través de la aplicación de unas vendas elásticas especiales con el fin de lograr cambios propioceptivos, aumento o inhibición del tono muscular y mitigación de algias, entre otros. Objetivos: Comprobar si la aplicación del vendaje neuromuscular permite aumentar la flexión del raquis lumbar comparándola con otras técnicas de vendaje placebo (esparadrapo rígido convencional; Omniplas...

  2. Miller Fisher syndrome with presynaptic neuromuscular transmission disorder.

    Science.gov (United States)

    Ehler, Edvard; Latta, Jan

    2014-11-01

    Miller Fisher syndrome is defined by a triad of symptoms, namely areflexia, ataxia, and ophthalmoparesis. The ophthalmoparesis is mostly severe, undulating weakness of eye movements with ptosis and increased fatigability resembling a neuromuscular transmission disorder. We present a 52-year-old man with severe Miller Fisher syndrome with a high level of anti-GQ1b antibodies and a presynaptic type of neuromuscular transmission disorder. The diagnosis was confirmed by stimulated single-fiber electromyography with the use of a concentric needle electrode and various stimulation rates. Copyright © 2014 Elsevier Ltd. All rights reserved.

  3. Exercise Therapy in Spinobulbar Muscular Atrophy and Other Neuromuscular Disorders

    DEFF Research Database (Denmark)

    Dahlqvist, Julia Rebecka; Vissing, John

    2016-01-01

    There is no curative treatment for most neuromuscular disorders. Exercise, as a treatment for these diseases, has therefore received growing attention. When executed properly, exercise can maintain and improve health and reduce the risk of cardiovascular disease, obesity, and diabetes. In persons...... in patients with neuromuscular diseases associated with weakness and wasting. We review studies that have investigated different types of exercise in both myopathies and motor neuron diseases, with particular emphasis on training of persons affected by spinobulbar muscular atrophy (SBMA). Finally, we provide...

  4. Neuromuscular Activity and Knee Kinematics in Adolescents with Patellofemoral Pain

    DEFF Research Database (Denmark)

    Rathleff, Michael Skovdal; Samani, Afshin; Olesen, Jens L

    2013-01-01

    This study aimed to investigate the neuromuscular control of the knee during stair descent among female adolescents with patellofemoral pain (PFP) and to report its association with self-reported clinical status assessed by the Knee Injury and Osteoarthritis Outcome Score (KOOS).......This study aimed to investigate the neuromuscular control of the knee during stair descent among female adolescents with patellofemoral pain (PFP) and to report its association with self-reported clinical status assessed by the Knee Injury and Osteoarthritis Outcome Score (KOOS)....

  5. Neuromuscular function and fatigue resistance of the plantar flexors following short-term cycling endurance training.

    Science.gov (United States)

    Behrens, Martin; Weippert, Matthias; Wassermann, Franziska; Bader, Rainer; Bruhn, Sven; Mau-Moeller, Anett

    2015-01-01

    Previously published studies on the effect of short-term endurance training on neuromuscular function of the plantar flexors have shown that the H-reflex elicited at rest and during weak voluntary contractions was increased following the training regime. However, these studies did not test H-reflex modulation during isometric maximum voluntary contraction (iMVC) and did not incorporate a control group in their study design to compare the results of the endurance training group to individuals without the endurance training stimulus. Therefore, this randomized controlled study was directed to investigate the neuromuscular function of the plantar flexors at rest and during iMVC before and after 8 weeks of cycling endurance training. Twenty-two young adults were randomly assigned to an intervention group and a control group. During neuromuscular testing, rate of torque development, isometric maximum voluntary torque and muscle activation were measured. Triceps surae muscle activation and tibialis anterior muscle co-activation were assessed by normalized root mean square of the EMG signal during the initial phase of contraction (0-100, 100-200 ms) and iMVC of the plantar flexors. Furthermore, evoked spinal reflex responses of the soleus muscle (H-reflex evoked at rest and during iMVC, V-wave), peak twitch torques induced by electrical stimulation of the posterior tibial nerve at rest and fatigue resistance were evaluated. The results indicate that cycling endurance training did not lead to a significant change in any variable of interest. Data of the present study conflict with the outcome of previously published studies that have found an increase in H-reflex excitability after endurance training. However, these studies had not included a control group in their study design as was the case here. It is concluded that short-term cycling endurance training does not necessarily enhance H-reflex responses and fatigue resistance.

  6. Neuromuscular function and fatigue resistance of the plantar flexors following short-term cycling endurance training

    Directory of Open Access Journals (Sweden)

    Martin eBehrens

    2015-05-01

    Full Text Available Previously published studies on the effect of short-term endurance training on the neuromuscular function of the plantar flexors have shown that the H-reflex elicited at rest and during weak voluntary contractions was increased following the training regime. However, these studies did not test H-reflex modulation during isometric maximum voluntary contraction (iMVC and did not incorporate a control group in their study design to compare the results of the endurance training group to individuals without the endurance training stimulus. Therefore, this randomized controlled study was directed to investigate the neuromuscular function of the plantar flexors at rest and during iMVC before and after eight weeks of cycling endurance training. Twenty-two young adults were randomly assigned to an intervention group and a control group. During neuromuscular testing, rate of torque development, isometric maximum voluntary torque and muscle activation were measured. Triceps surae muscle activation and tibialis anterior muscle co-activation were assessed by normalized root mean square of the EMG signal during the initial phase of contraction (0-100, 100-200 ms and isometric maximum voluntary contraction of the plantar flexors. Furthermore, evoked spinal reflex responses of the soleus muscle (H-reflex evoked at rest and during iMVC, V-wave, peak twitch torques induced by electrical stimulation of the posterior tibial nerve at rest and fatigue resistance were evaluated. The results indicate that the endurance training did not lead to a significant change in any variable of interest. Data of the present study conflict with the outcome of previously published studies that have found an increase in H-reflex excitability after endurance training. However, these studies had not included a control group in their study design as was the case here. It is concluded that short-term cycling endurance training does not necessarily enhance H-reflex responses and fatigue

  7. Spinal Muscular Atrophy: From Defective Chaperoning of snRNP Assembly to Neuromuscular Dysfunction

    Directory of Open Access Journals (Sweden)

    Maia Lanfranco

    2017-06-01

    Full Text Available Spinal Muscular Atrophy (SMA is a neuromuscular disorder that results from decreased levels of the survival motor neuron (SMN protein. SMN is part of a multiprotein complex that also includes Gemins 2–8 and Unrip. The SMN-Gemins complex cooperates with the protein arginine methyltransferase 5 (PRMT5 complex, whose constituents include WD45, PRMT5 and pICln. Both complexes function as molecular chaperones, interacting with and assisting in the assembly of an Sm protein core onto small nuclear RNAs (snRNAs to generate small nuclear ribonucleoproteins (snRNPs, which are the operating components of the spliceosome. Molecular and structural studies have refined our knowledge of the key events taking place within the crowded environment of cells and the numerous precautions undertaken to ensure the faithful assembly of snRNPs. Nonetheless, it remains unclear whether a loss of chaperoning in snRNP assembly, considered as a “housekeeping” activity, is responsible for the selective neuromuscular phenotype in SMA. This review thus shines light on in vivo studies that point toward disturbances in snRNP assembly and the consequential transcriptome abnormalities as the primary drivers of the progressive neuromuscular degeneration underpinning the disease. Disruption of U1 snRNP or snRNP assembly factors other than SMN induces phenotypes that mirror aspects of SMN deficiency, and splicing defects, described in numerous SMA models, can lead to a DNA damage and stress response that compromises the survival of the motor system. Restoring the correct chaperoning of snRNP assembly is therefore predicted to enhance the benefit of SMA therapeutic modalities based on augmenting SMN expression.

  8. Immune Checkpoint Blockade in Cancer Treatment: A Double-Edged Sword Cross-Targeting the Host as an “Innocent Bystander”

    Directory of Open Access Journals (Sweden)

    Lucia Gelao

    2014-03-01

    Full Text Available Targeted immune checkpoint blockade augments anti-tumor immunity and induces durable responses in patients with melanoma and other solid tumors. It also induces specific “immune-related adverse events” (irAEs. IrAEs mainly include gastrointestinal, dermatological, hepatic and endocrinological toxicities. Off-target effects that arise appear to account for much of the toxicity of the immune checkpoint blockade. These unique “innocent bystander” effects are likely a direct result of breaking immune tolerance upon immune check point blockade and require specific treatment guidelines that include symptomatic therapies or systemic corticosteroids. What do we need going forward to limit immune checkpoint blockade-induced toxicity? Most importantly, we need a better understanding of the roles played by these agents in normal tissues, so that we can begin to predict potentially problematic side effects on the basis of their selectivity profile. Second, we need to focus on the predictive factors of the response and toxicity of the host rather than serially focusing on individual agents. Third, rigorous biomarker-driven clinical trials are needed to further elucidate the mechanisms of both the benefit and toxicity. We will summarize the double-edged sword effect of immunotherapeutics in cancer treatment.

  9. PD-1/PD-L1 blockade together with vaccine therapy facilitates effector T-cell infiltration into pancreatic tumors.

    Science.gov (United States)

    Soares, Kevin C; Rucki, Agnieszka A; Wu, Annie A; Olino, Kelly; Xiao, Qian; Chai, Yi; Wamwea, Anthony; Bigelow, Elaine; Lutz, Eric; Liu, Linda; Yao, Sheng; Anders, Robert A; Laheru, Daniel; Wolfgang, Christopher L; Edil, Barish H; Schulick, Richard D; Jaffee, Elizabeth M; Zheng, Lei

    2015-01-01

    Pancreatic ductal adenocarcinoma (PDA) has a poor prognosis due to late detection and resistance to conventional therapies. Published studies show that the PDA tumor microenvironment is predominantly infiltrated with immune suppressive cells and signals that if altered, would allow effective immunotherapy. However, single-agent checkpoint inhibitors including agents that alter immune suppressive signals in other human cancers such as cytotoxic T-lymphocyte antigen 4 (CTLA-4), programmed death 1 (PD-1), and its ligand PD-L1, have failed to demonstrate objective responses when given as single agents to PDA patients. We recently reported that inhibition of the CTLA-4 pathway when given together with a T cell inducing vaccine gives objective responses in metastatic PDA patients. In this study, we evaluated blockade of the PD-1/PD-L1 pathway. We found that PD-L1 is weakly expressed at a low frequency in untreated human and murine PDAs but treatment with a granulocyte macrophage colony-stimulating factor secreting PDA vaccine (GVAX) significantly upregulates PD-L1 membranous expression after treatment of tumor-bearing mice. In addition, combination therapy with vaccine and PD-1 antibody blockade improved murine survival compared with PD-1 antibody monotherapy or GVAX therapy alone. Furthermore, PD-1 blockade increased effector CD8 T lymphocytes and tumor-specific interferon-γ production of CD8 T cells in the tumor microenvironment. Immunosuppressive pathways, including regulatory T cells and CTLA-4 expression on T cells were overcome by the addition of vaccine and low-dose cyclophosphamide to PD-1 blockade. Collectively, our study supports combining PD-1 or PD-L1 antibody therapy with a T cell inducing agent for PDA treatment.

  10. Induced Cavities for Photonic Quantum Gates

    Science.gov (United States)

    Lahad, Ohr; Firstenberg, Ofer

    2017-09-01

    Effective cavities can be optically induced in atomic media and employed to strengthen optical nonlinearities. Here we study the integration of induced cavities with a photonic quantum gate based on Rydberg blockade. Accounting for loss in the atomic medium, we calculate the corresponding finesse and gate infidelity. Our analysis shows that the conventional limits imposed by the blockade optical depth are mitigated by the induced cavity in long media, thus establishing the total optical depth of the medium as a complementary resource.

  11. Efeitos neuromusculares in vitro e in vivo do atracúrio e do rocurônio em ratos submetidos a tratamento de sete dias com carbamazepina Efectos neuromusculares in vitro e in vivo del atracurio y del rocuronio en ratones sometidos a tratamiento de siete días con carbamazepina In vitro and in vivo neuromuscular effects of atracurium and rocuronium in rats treated with carbamazepine for seven days

    Directory of Open Access Journals (Sweden)

    Caroline Coutinho de Barcelos

    2008-04-01

    neuromuscular producido por el rocuronio y atracurio en ratones tratados con carbamazepina y determinó las concentraciones de citocromo P450 y b5 reductasis en microsomas hepáticos. MÉTODO: Ratones fueron tratados por siete días con carbamazepina (CBZ - 40 mg.kg-1 a través de una sonda y sacrificados al octavo día bajo anestesia con uretana. Las preparaciones in vitro e in vivo fueron montadas de acuerdo con las técnicas de Bulbring y de Leeuwin y Wolters, respectivamente. Las concentraciones y dosis utilizadas de los bloqueadores en las preparaciones in vitro e in vivo fueron, respectivamente, 20 µg.mL-1 y 0,5 mg.kg-1 para atracurio (ATC; 4 µg.mL-1 y 0,6 mg.kg-1 para rocuronio (ROC. Cada protocolo tuvo un n = 5 y las respuestas fueron observadas por 60 minutos. Los efectos del ATC y ROC fueron evaluados en las preparaciones de ratones tratados (Cbz t y comparados a los observados en los de ratones no tratados (CBZst. Las concentraciones de citocromo P450 y b5 reductasis fueron determinadas en microsomas aislados de hígados de ratones tratados (CBZt y comparadas con las obtenidas en ratones no tratados (CBZst RESULTADOS: La carbamazepina no alteró la amplitud de las respuestas musculares; in vitro y in vivo, no hubo diferencia entre el bloqueo neuromuscular producido por el atracurio en las preparaciones CBZt versus CBZst; el bloqueo neuromuscular producido por el Rocuronio en las preparaciones CBZt fue potenciado in vitro. La carbamazepina no alteró las concentraciones de citocromo P450 y b5. CONCLUSIONES: El tratamiento por siete días con carbamazepina, no influenció en el bloqueo producido por el atracurio, y alteró in vitro los efectos del rocuronio. El tiempo de tratamiento no fue suficiente para causar la inducción enzimática y disminuir la sensibilidad al rocuronio.BACKGROUND AND OBJECTIVES: This experimental study investigated the in vitro and in vivo neuromuscular blockade of rocuronium and atracurium in rats treated with carbamazepine and determined

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

    Directory of Open Access Journals (Sweden)

    Matthew E Hardee

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

  13. Pancreatic Digestive Enzyme Blockade in the Intestine Increases Survival After Experimental Shock

    Science.gov (United States)

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

    2015-01-01

    Shock, sepsis, and multiorgan failure are associated with inflammation, morbidity, and high mortality. The underlying pathophysiological mechanism is unknown, but evidence suggests that pancreatic enzymes in the intestinal lumen autodigest the intestine and generate systemic inflammation. Blocking these enzymes in the intestine reduces inflammation and multiorgan dysfunction. We investigated whether enzymatic blockade also reduces mortality after shock. Three rat shock models were used here: hemorrhagic shock, peritonitis shock induced by placement of cecal material into the peritoneum, and endotoxin shock. One hour after initiation of hemorrhagic, peritonitis, or endotoxin shock, animals were administered one of three different pancreatic enzyme inhibitors—6-amidino-2-naphtyl p-guanidinobenzoate di-methanesulfate, tranexamic acid, or aprotinin—into the lumen of the small intestine. In all forms of shock, blockade of digestive proteases with protease inhibitor attenuated entry of digestive enzymes into the wall of the intestine and subsequent autodigestion and morphological damage to the intestine, lung, and heart. Animals treated with protease inhibitors also survived in larger numbers than untreated controls over a period of 12 weeks. Surviving animals recovered completely and returned to normal weight within 14 days after shock. The results suggest that the active and concentrated digestive enzymes in the lumen of the intestine play a central role in shock and multi-organ failure, which can be treated with protease inhibitors that are currently available for use in the clinic. PMID:23345609

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

    Directory of Open Access Journals (Sweden)

    Joanne O Davidson

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

  15. 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

  16. Blockade of NMDA receptors prevents analgesic tolerance to repeated transcutaneous electrical nerve stimulation (TENS) in rats

    Science.gov (United States)

    Hingne, Priyanka M.; Sluka, Kathleen A.

    2008-01-01

    Repeated daily application transcutaneous electrical nerve stimulation (TENS) results in tolerance, at spinal opioid receptors, to the anti-hyperalgesia produced by TENS. Since N-Methyl-D-Aspartate (NMDA) receptor antagonists prevent analgesic tolerance to opioid agonists we hypothesized that blockade of NMDA receptors will prevent tolerance to TENS. In rats with knee joint inflammation, TENS was applied for 20 minute daily at high frequency (100 Hz), low frequency (4 Hz), or sham TENS. Rats were treated with the NMDA antagonist MK-801 (0.01 mg/kg-0.1 mg/kg) or vehicle daily before TENS. Paw withdrawal thresholds were tested before and after inflammation, and before and after TENS treatment for 4 days. On day 1 TENS reversed the decreased mechanical withdrawal threshold induced by joint inflammation. On day 4 TENS had no effect on the decreased withdrawal threshold in the group treated with vehicle demonstrating development of tolerance. However, in the group treated with 0.1 mg/kg MK-801, TENS significantly reversed the mechanical withdrawal thresholds on day 4 demonstrating that tolerance did not develop. Vehicle treated animals developed cross-tolerance at spinal opioid receptors. Treatment with MK-801 reversed this cross-tolerance at spinal opioid receptors. In summary, blockade of NMDA receptors prevents analgesic tolerance to daily TENS by preventing tolerance at spinal opioid receptors. Perspective Tolerance observed to the clinical treatment of TENS could be prevented by administration of pharmaceutical agents with NMDA receptors activity such as ketamine or dextromethorphan. PMID:18061543

  17. Immune Checkpoint Blockade to Improve Tumor Infiltrating Lymphocytes for Adoptive Cell Therapy.

    Science.gov (United States)

    Kodumudi, Krithika N; Siegel, Jessica; Weber, Amy M; Scott, Ellen; Sarnaik, Amod A; Pilon-Thomas, Shari

    2016-01-01

    Tumor-infiltrating lymphocytes (TIL) has been associated with improved survival in cancer patients. Within the tumor microenvironment, regulatory cells and expression of co-inhibitory immune checkpoint molecules can lead to the inactivation of TIL. Hence, there is a need to develop strategies that disrupt these negative regulators to achieve robust anti-tumor immune responses. We evaluated the blockade of immune checkpoints and their effect on T cell infiltration and function. We examined the ability of TIL to induce tumor-specific immune responses in vitro and in vivo. TIL isolated from tumor bearing mice were tumor-specific and expressed co-inhibitory immune checkpoint molecules. Administration of monoclonal antibodies against immune checkpoints led to a significant delay in tumor growth. However, anti-PD-L1 antibody treated mice had a significant increase in T cell infiltration and IFN-γ production compared to other groups. Adoptive transfer of in vitro expanded TIL from tumors of anti-PD-L1 antibody treated mice led to a significant delay in tumor growth. Blockade of co-inhibitory immune checkpoints could be an effective strategy to improve TIL infiltration and function.

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

    Science.gov (United States)

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

    2016-07-01

    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. 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 and function of tumor

  19. Pivoting neuromuscular control and proprioception in females and males.

    Science.gov (United States)

    Lee, Song Joo; Ren, Yupeng; Kang, Sang Hoon; Geiger, François; Zhang, Li-Qun

    2015-04-01

    Noncontact ACL injuries occur most commonly in pivoting sports and are much more frequent in females than in males. However, information on sex differences in proprioceptive acuity under weight-bearing and leg neuromuscular control in pivoting is scarce. The objective of this study was to investigate sex differences in pivoting neuromuscular control during strenuous stepping tasks and proprioceptive acuity under weight-bearing. 21 male and 22 female subjects were recruited to evaluate pivoting proprioceptive acuity under weight-bearing, and pivoting neuromuscular control (in terms of leg pivoting instability, stiffness, maximum internal and external pivoting angles, and entropy of time-to-peak EMG in lower limb muscles) during strenuous stepping tasks performed on a novel offaxis elliptical trainer. Compared to males, females had significantly lower proprioceptive acuity under weight-bearing in both internal and external pivoting directions, higher pivoting instability, larger maximum internal pivoting angle, lower leg pivoting stiffness, and higher entropy of time-to-peak EMG in the gastrocnemius muscles during strenuous stepping tasks with internal and external pivoting perturbations. Results of this study may help us better understand factors contributing to ACL injuries in females and males, develop training strategies to improve pivoting neuromuscular control and proprioceptive acuity, and potentially reduce ACL and lower-limb musculoskeletal injuries.

  20. Roles of neuro-exocytotic proteins at the neuromuscular junction

    NARCIS (Netherlands)

    Sons-Michel, Michèle S.

    2011-01-01

    The aim of the studies described in the thesis was to elucidate the roles of several neuro-exocytotic proteins at the motor nerve terminal in neuromuscular synaptic transmission, making use of genetic knockout (KO) mice, each missing one (or more) neuro-exocytotic proteins. In addition, it was

  1. [Neuro-muscular apparatus state in lumbosacral radiculopathy in miners].

    Science.gov (United States)

    Battakova, Sh B; Amanbekov, U A; Otarbaeva, M B; Fazylova, M D; Sraĭmanov, K S; Miianova, G A; Kozhakhmetova, K M

    2008-01-01

    Based on clinical and electrophysiologic studies, the authors analysed neuro-muscular apparatus of "spinal center--periphery" axis for miners with radicular pain caused by occupational lumbosacral radiculopathy. Findings are that constantly irritated receptors in lumbar motor segment during occupational activities alter habitual motor stereotype and cause specific compensatory muscular reactions, rearrangement of motor activity in segmental apparatus.

  2. Imaging of respiratory muscles in neuromuscular disease: A review.

    Science.gov (United States)

    Harlaar, L; Ciet, P; van der Ploeg, A T; Brusse, E; van der Beek, N A M E; Wielopolski, P A; de Bruijne, M; Tiddens, H A W M; van Doorn, P A

    2017-11-24

    Respiratory muscle weakness frequently occurs in patients with neuromuscular disease. Measuring respiratory function with standard pulmonary function tests provides information about the contribution of all respiratory muscles, the lungs and airways. Imaging potentially enables the study of different respiratory muscles, including the diaphragm, separately. In this review, we provide an overview of imaging techniques used to study respiratory muscles in neuromuscular disease. We identified 26 studies which included a total of 573 patients with neuromuscular disease. Imaging of respiratory muscles was divided into static and dynamic techniques. Static techniques comprise chest radiography, B-mode (brightness mode) ultrasound, CT and MRI, and are used to assess the position and thickness of the diaphragm and the other respiratory muscles. Dynamic techniques include fluoroscopy, M-mode (motion mode) ultrasound and MRI, used to assess diaphragm motion in one or more directions. We discuss how these imaging techniques relate with spirometric values and whether these can be used to study the contribution of the different respiratory muscles in patients with neuromuscular disease. Copyright © 2017. Published by Elsevier B.V.

  3. Neuromuscular stimulation after stroke: from technology to clinical deployment

    NARCIS (Netherlands)

    IJzerman, Maarten Joost; Renzenbrink, Gerbert J.; Geurts, Alexander C.H.

    2009-01-01

    Since the early 1960s, electrical or neuromuscular electrical stimulation (NMES) has been used to support the rehabilitation of stroke patients. One of the earliest applications of NMES included the use of external muscle stimulation to correct drop-foot after stroke. During the last few decades

  4. Neuromuscular stimulation after stroke: from technology to clinical deployment.

    NARCIS (Netherlands)

    IJzerman, M.J.; Renzenbrink, G.J.; Geurts, A.C.H.

    2009-01-01

    Since the early 1960s, electrical or neuromuscular electrical stimulation (NMES) has been used to support the rehabilitation of stroke patients. One of the earliest applications of NMES included the use of external muscle stimulation to correct drop-foot after stroke. During the last few decades

  5. [New surgical treatment of late-stage neuromuscular ureteral dysplasia].

    Science.gov (United States)

    Lopatkin, N A; Zhitnikova, L H; Berestennikov, K A

    1999-01-01

    A surgical treatment of neuromuscular ureteral, dysplasia (NUD) is proposed which provides development of restenosis in vesicoureteral anastomosis and vesicoureteral reflux in maintenance of normal urodynamics of the upper urinary tracts. This organ-saving method can be applied at late disease. Multichannel impedance ureterography proved useful in definition of the operation's scope.

  6. Intraorbital neuromuscular choristoma adjacent to the optic nerve

    Directory of Open Access Journals (Sweden)

    Arie Perry, M.D.

    2017-03-01

    Full Text Available Neuromuscular choristoma is a rare tumor that incorporates mature skeletal muscle within fascicles of peripheral nerve. The etiology is poorly understood, yet most present in large nerves of children, with a tight link to post-operative fibromatosis recently appreciated. Herein, we report an exceptional intra-orbital example in a 53-year-old man with optic nerve compression.

  7. Comparison of the Effect of Neuromuscular Electrical Stimulation ...

    African Journals Online (AJOL)

    Children with cerebral palsy (CP) often demonstrate poor hand function due to spasticity. Thus spasticity in the wrist and finger flexors poses a great deal of functional limitations. This study was therefore designed to compare the effectiveness of Cryotherapy and Neuromuscular Electrical Stimulation (NMES) on spasticity ...

  8. Neuromuscular and mitochondrial disorders: what is relevant to the anaesthesiologist?

    NARCIS (Netherlands)

    Driessen, J.J.

    2008-01-01

    PURPOSE OF REVIEW: The review provides an up-to-date information to the anaesthesiologist about the more frequent and important neuromuscular disorders for which new basic insights or clinical implications have been reported. RECENT FINDINGS: The findings include the mechanisms of the hyperkalemia

  9. Neuromuscular function during stair descent in meniscectomized patients and controls

    DEFF Research Database (Denmark)

    Thorlund, Jonas Bloch; Roos, Ewa M; Aagaard, Per

    2011-01-01

    The aim of this study was to identify differences in knee range of motion (ROM), movement speed, ground reaction forces (GRF) profile, neuromuscular activity, and muscle coactivation during the transition between stair descent and level walking in meniscectomized patients at high risk of knee...

  10. Silent ischemia and beta-blockade

    DEFF Research Database (Denmark)

    Egstrup, K

    1991-01-01

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

  11. Photon-photon interactions via Rydberg blockade.

    Science.gov (United States)

    Gorshkov, Alexey V; Otterbach, Johannes; Fleischhauer, Michael; Pohl, Thomas; Lukin, Mikhail D

    2011-09-23

    We develop the theory of light propagation under the conditions of electromagnetically induced transparency in systems involving strongly interacting Rydberg states. Taking into account the quantum nature and the spatial propagation of light, we analyze interactions involving few-photon pulses. We show that this system can be used for the generation of nonclassical states of light including trains of single photons with an avoided volume between them, for implementing photon-photon gates, as well as for studying many-body phenomena with strongly correlated photons.

  12. Prime-boost using separate oncolytic viruses in combination with checkpoint blockade improves anti-tumour therapy.

    Science.gov (United States)

    Ilett, E; Kottke, T; Thompson, J; Rajani, K; Zaidi, S; Evgin, L; Coffey, M; Ralph, C; Diaz, R; Pandha, H; Harrington, K; Selby, P; Bram, R; Melcher, A; Vile, R

    2017-01-01

    The anti-tumour effects associated with oncolytic virus therapy are mediated significantly through immune-mediated mechanisms, which depend both on the type of virus and the route of delivery. Here, we show that intra-tumoral oncolysis by Reovirus induced the priming of a CD8+, Th1-type anti-tumour response. By contrast, systemically delivered Vesicular Stomatitis Virus expressing a cDNA library of melanoma antigens (VSV-ASMEL) promoted a potent anti-tumour CD4+ Th17 response. Therefore, we hypothesised that combining the Reovirus-induced CD8+ T cell response, with the VSV-ASMEL CD4+ Th17 helper response, would produce enhanced anti-tumour activity. Consistent with this, priming with intra-tumoral Reovirus, followed by an intra-venous VSV-ASMEL Th17 boost, significantly improved survival of mice bearing established subcutaneous B16 melanoma tumours. We also show that combination of either therapy alone with anti-PD-1 immune checkpoint blockade augmented both the Th1 response induced by systemically delivered Reovirus in combination with GM-CSF, and also the Th17 response induced by VSV-ASMEL. Significantly, anti-PD-1 also uncovered an anti-tumour Th1 response following VSV-ASMEL treatment that was not seen in the absence of checkpoint blockade. Finally, the combination of all three treatments (priming with systemically delivered Reovirus, followed by double boosting with systemic VSV-ASMEL and anti-PD-1) significantly enhanced survival, with long-term cures, compared to any individual, or double, combination therapies, associated with strong Th1 and Th17 responses to tumour antigens. Our data show that it is possible to generate fully systemic, highly effective anti-tumour immunovirotherapy by combining oncolytic viruses, along with immune checkpoint blockade, to induce complementary mechanisms of anti-tumour immune responses.

  13. Potential interests and limits of magnetic and electrical stimulation techniques to assess neuromuscular fatigue.

    Science.gov (United States)

    Millet, G Y; Bachasson, D; Temesi, J; Wuyam, B; Féasson, L; Vergès, S; Lévy, P

    2012-12-01

    Neuromuscular function can change under different conditions such as ageing, training/detraining, long-term spaceflight, environmental conditions (e.g. hypoxia, hyperthermia), disease, therapy/retraining programs and also with the appearance of fatigue. Neuromuscular fatigue can be defined as any decrease in maximal voluntary strength or power. There is no standardized method to induce fatigue and various protocols involving different contraction patterns (such as sustained or intermittent submaximal isometric or dynamic contractions on isokinetic or custom chairs) have been used. Probably due to lack of motivation/cooperation, results of fatigue resistance protocols are more variable in patients than in healthy subjects. Magnetic and electrical stimulation techniques allow non-invasive assessment of central and peripheral origins of fatigue. They also allow investigation of different types of muscle fatigue when combining various types of stimulation with force/surface EMG measurements. Since maximal electrical stimuli may be uncomfortable or even sometimes painful, several alternative methods have been recently proposed: submaximal muscle stimulation, low/high-frequency paired pulses instead of tetanic stimuli and the use of magnetic stimulation at the peripheral level. Copyright © 2012 Elsevier B.V. All rights reserved.

  14. Sport-specific functional movement can simulate aspects of neuromuscular fatigue occurring in team sports.

    Science.gov (United States)

    Wilke, Jan; Fleckenstein, Johannes; Krause, Frieder; Vogt, Lutz; Banzer, Winfried

    2016-06-01

    Fatigue protocols have been used over the years to examine muscular exhaustion. As an alternative to approaches in laboratory settings, functional agility protocols claiming to mimic the multifaceted loads of athletic activity have been proposed. This study aimed to examine the effects of a functional agility short-term fatigue protocol (FAST-FP) on neuromuscular function. Twenty-eight healthy sports students (15 males, aged 24.3 ± 2.4 years) completed the FAST-FP, which consists of four components: three counter-movement jumps (90% of individual maximum), a 20-s bout of step-ups, three bodyweight squats and an agility run. Tasks were repeated until the participants no longer achieved the required jump height in two consecutive sets. Outcomes (pre-post) encompassed subjective exhaustion (visual analogue scale [VAS]), maximum isometric voluntary force of the knee extensors (MIVF), reactive strength index (RSI), mean power frequency (MPF, measured using surface electromyography) and maximum knee range of motion (ROM). Post-intervention, VAS (+54 mm) increased significantly, while MIVF (-6.1%), RSI (-10.7%) and MPF (-4.1%) were reduced (p  0.05). The FAST-FP induces small-to-moderate impairments in neuromuscular function and considerable self-perceived fatigue. Current evidence on exhaustion developing in team sports suggests that this magnitude of fatigue is similar. The protocol might thus be valuable in the evaluation of treatments counteracting post-match fatigue in team sports.

  15. Stunted PFC activity during neuromuscular control under stress with obesity.

    Science.gov (United States)

    Mehta, Ranjana K

    2016-02-01

    Obesity is an established risk factor for impaired cognition, which is primarily regulated by the prefrontal cortex (PFC). However, very little is known about the neural pathways that underlie obesity-related declines in neuromuscular control, particularly under stress. The purpose of this study was to determine the role of the PFC on neuromuscular control during handgrip exertions under stress with obesity. Twenty non-obese and obese young adults performed submaximal handgrip exertions in the absence and presence of a concurrent stressful task. Primary dependent measures included oxygenated hemoglobin (HbO2: a measure of PFC activity) and force fluctuations (an indicator of neuromuscular control). Higher HbO2 levels in the PFC were observed in the non-obese compared to the obese group (P = 0.009). In addition, higher HbO2 levels were observed in the stress compared to the control condition in the non-obese group; however, this trend was reversed in the obese group (P = 0.043). In general, force fluctuations increased by 26% in the stress when compared to the control condition (P = 0.001) and obesity was associated with 39% greater force fluctuation (P = 0.024). Finally, while not significant, obesity-related decrements in force fluctuations were magnified under stress (P = 0.063). The current study provides the first evidence that neuromuscular decrements with obesity were associated with impaired PFC activity and this relationship was augmented in stress conditions. These findings are important because they provide new information on obesity-specific changes in brain function associated with neuromuscular control since the knowledge previously focused largely on obesity-specific changes in peripheral muscle capacity.

  16. Neuromuscular and perceptual fatigue responses to consecutive tag football matches.

    Science.gov (United States)

    Hogarth, Luke W; Burkett, Brendan J; McKean, Mark R

    2015-07-01

    To examine the neuromuscular and perceptual fatigue responses to consecutive tag football matches played on the same day and determine the relationship between fatigue and match running performance. Neuromuscular and perceptual fatigue responses of 15 national tag football players were assessed before and during the 2014 State of Origin tournament. Global positioning systems (GPS) provided data on players' match running performance, and a vertical-jump test and subjective questionnaire were used to assess players' neuromuscular and perceptual fatigue, respectively. There were small to moderate reductions in the majority of match-running-performance variables over consecutive matches, including distance (ES=-0.81), high-speed-running (HSR) distance (ES=-0.51), HSR efforts (ES=-0.64), and maximal accelerations (ES=-0.76). Prematch vertical jump was initially below baseline values before the first match (ES=0.68-0.88). There were no substantial reductions in vertical-jump performance from baseline values over consecutive matches, although there was a small decline from after match 2 to after match 3 (3.3%; ES=-0.45±0.62). There were progressive reductions in perceived well-being scores after matches 1 (ES=-0.38), 2 (ES=-0.70), and 3 (ES=-1.14). There were small to moderate associations between changes in fatigue measures and match running performance. Perceptual fatigue accumulates over consecutive tag football matches, although there were only marginal increases in neuromuscular fatigue. However, both neuromuscular and perceptual fatigue measures were found to contribute to reduced match running performance in the final match.

  17. Adrenergic blockade in diabetic and uninephrectomized rats

    DEFF Research Database (Denmark)

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

    1999-01-01

    The present study reports on the effects of adrenergic blocking agents on the renal growth and on the renal content and urinary excretion of epidermal growth factor (EGF) in streptozotocin-induced diabetic or uninephrectomized rats. Diabetic and uninephrectomized rats were allocated to groups...... an increase of 33% in kidney weight when compared to controls. The adrenergic antagonist treated diabetic groups had a significantly lower increase of 15%. Postnephrectomized renal growth was not affected by adrenergic antagonists. The total renal content of EGF was comparable in the saline-treated diabetic...... was not affected by adrenergic blocking agents. These results provide evidence for fundamental differences between diabetes-related renal growth and that observed in compensation to nephrectomy and suggest a connection between adrenergic activity, renal growth, and EGF in diabetes....

  18. Heterologous immunity triggered by a single, latent virus in Mus musculus: combined costimulation- and adhesion- blockade decrease rejection.

    Directory of Open Access Journals (Sweden)

    Jonathan M Beus

    Full Text Available The mechanisms underlying latent-virus-mediated heterologous immunity, and subsequent transplant rejection, especially in the setting of T cell costimulation blockade, remain undetermined. To address this, we have utilized MHV68 to develop a rodent model of latent virus-induced heterologous alloimmunity. MHV68 infection was correlated with multimodal immune deviation, which included increased secretion of CXCL9 and CXCL10, and with the expansion of a CD8(dim T cell population. CD8(dim T cells exhibited decreased expression of multiple costimulation molecules and increased expression of two adhesion molecules, LFA-1 and VLA-4. In the setting of MHV68 latency, recipients demonstrated accelerated costimulation blockade-resistant rejection of skin allografts compared to non-infected animals (MST 13.5 d in infected animals vs 22 d in non-infected animals, p100 d for both, p100 d. Graft acceptance was significantly impaired when CTLA-4-Ig alone (no anti-CD154 was combined with adhesion blockade (MST 41 d. These results suggest that in the setting of MHV68 infection, synergy occurs predominantly between adhesion pathways and CD154-based costimulation, and that combined targeting of both pathways may be required to overcome the increased risk of rejection that occurs in the setting of latent-virus-mediated immune deviation.

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

    Science.gov (United States)

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

    2016-06-01

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

  20. Single-photon source based on Rydberg exciton blockade

    Science.gov (United States)

    Khazali, Mohammadsadegh; Heshami, Khabat; Simon, Christoph

    2017-11-01

    Bound states of electron–hole pairs in semiconductors demonstrate a hydrogen-like behavior in their high-lying excited states that are also known as Rydberg exciton states. The strong interaction between excitons in levels with high principal quantum numbers prevents the creation of more than one exciton in a small crystal; resulting in the Rydberg blockade effect. Here, we propose a new kind of solid-state single-photon source based on the recently observed Rydberg blockade effect for excitons in cuprous oxide. Our quantitative estimates based on single and double excitation probability dynamics indicate that GHz rates and values of the second-order correlation function {g}2(0) below the percent level can be simultaneously achievable. These results should pave the way to explore applications of Rydberg excitons in photonic quantum information processing.

  1. Effect of Early Physical Activity Programs on Motor Performance and Neuromuscular Development in Infants Born Preterm: A Randomized Clinical Trial

    Directory of Open Access Journals (Sweden)

    Leila Valizadeh

    2017-03-01

    Full Text Available Introduction: Although the survival rate of infants born preterm has increased, the prevalence of developmental problems and motor disorders among this population of infants remains the same. This study investigated the effect of physical activity programs in and out of water on motor performance and neuromuscular development of infants born preterm and had induced immobility by mechanical ventilation.Methods: This study was carried out in Al-Zahra hospital, Tabriz. 76 premature infants were randomly assigned into four groups. One group received daily passive range of motion to all extremities based on the Moyer-Mileur protocol. Hydrotherapy group received exercises for shoulders and pelvic area in water every other day. A combination group received physical activity programs in and out of water on alternating days. Infants in a containment group were held in a fetal position. Duration of study was two weeks ‘from 32 through 33 weeks post menstrual age (PMA. Motor outcomes were measured by the Test of Infant Motor Performance. Neuromuscular developmental was assessed by New Ballard scale and leg recoil and Ankle dorsiflexion items from Dubowitz scale. Data were analyzed using SPSS version 13.Results: TIMP and neuromuscular scores improved in all groups. Motor performance did not differ between groups at 34 weeks PMA. Postural tone of leg recoil was significantly higher in physical activity groups post intervention.Conclusion: Physical activities and containment didn’t have different effects on motor performance in infants born preterm. Leg recoil of neuromuscular development items was affected by physical activity programs.

  2. Blockade of gap junction hemichannel suppresses disease progression in mouse models of amyotrophic lateral sclerosis and Alzheimer's disease.

    Directory of Open Access Journals (Sweden)

    Hideyuki Takeuchi

    Full Text Available Glutamate released by activated microglia induces excitotoxic neuronal death, which likely contributes to non-cell autonomous neuronal death in neurodegenerative diseases, including amyotrophic lateral sclerosis and Alzheimer's disease. Although both blockade of glutamate receptors and inhibition of microglial activation are the therapeutic candidates for these neurodegenerative diseases, glutamate receptor blockers also perturbed physiological and essential glutamate signals, and inhibitors of microglial activation suppressed both neurotoxic/neuroprotective roles of microglia and hardly affected disease progression. We previously demonstrated that activated microglia release a large amount of glutamate specifically through gap junction hemichannel. Hence, blockade of gap junction hemichannel may be potentially beneficial in treatment of neurodegenerative diseases.In this study, we generated a novel blood-brain barrier permeable gap junction hemichannel blocker based on glycyrrhetinic acid. We found that pharmacologic blockade of gap junction hemichannel inhibited excessive glutamate release from activated microglia in vitro and in vivo without producing notable toxicity. Blocking gap junction hemichannel significantly suppressed neuronal loss of the spinal cord and extended survival in transgenic mice carrying human superoxide dismutase 1 with G93A or G37R mutation as an amyotrophic lateral sclerosis mouse model. Moreover, blockade of gap junction hemichannel also significantly improved memory impairments without altering amyloid β deposition in double transgenic mice expressing human amyloid precursor protein with K595N and M596L mutations and presenilin 1 with A264E mutation as an Alzheimer's disease mouse model.Our results suggest that gap junction hemichannel blockers may represent a new therapeutic strategy to target neurotoxic microglia specifically and prevent microglia-mediated neuronal death in various neurodegenerative diseases.

  3. Clinical utility of sympathetic blockade in cardiovascular disease management.

    Science.gov (United States)

    Park, Chan Soon; Lee, Hae-Young

    2017-04-01

    A dysregulated sympathetic nervous system is a major factor in the development and progression of cardiovascular disease; thus, understanding the mechanism and function of the sympathetic nervous system and appropriately regulating sympathetic activity to treat various cardiovascular diseases are crucial. Areas covered: This review focused on previous studies in managing hypertension, atrial fibrillation, coronary artery disease, heart failure, and perioperative management with sympathetic blockade. We reviewed both pharmacological and non-pharmacological management. Expert commentary: Chronic sympathetic nervous system activation is related to several cardiovascular diseases mediated by various pathways. Advancement in measuring sympathetic activity makes visualizing noninvasively and evaluating the activation level even in single fibers possible. Evidence suggests that sympathetic blockade still has a role in managing hypertension and controlling the heart rate in atrial fibrillation. For ischemic heart disease, beta-adrenergic receptor antagonists have been considered a milestone drug to control symptoms and prevent long-term adverse effects, although its clinical implication has become less potent in the era of successful revascularization. Owing to pathologic involvement of sympathetic nervous system activation in heart failure progression, sympathetic blockade has proved its value in improving the clinical course of patients with heart failure.

  4. Pathophysiology and Etiology of Nerve Injury Following Peripheral Nerve Blockade.

    Science.gov (United States)

    Brull, Richard; Hadzic, Admir; Reina, Miguel A; Barrington, Michael J

    2015-01-01

    This review synthesizes anatomical, anesthetic, surgical, and patient factors that may contribute to neurologic complications associated with peripheral nerve blockade. Peripheral nerves have anatomical features unique to a given location that may influence risk of injury. Peripheral nerve blockade-related peripheral nerve injury (PNI) is most severe with intrafascicular injection. Surgery and its associated requirements such as positioning and tourniquet have specific risks. Patients with preexisting neuropathy may be at an increased risk of postoperative neurologic dysfunction. Distinguishing potential causes of PNI require clinical assessment and investigation; a definitive diagnosis, however, is not always possible. Fortunately, most postoperative neurologic dysfunction appears to resolve with time, and the incidence of serious long-term nerve injury directly attributable to peripheral nerve blockade is relatively uncommon. Nonetheless, despite the use of ultrasound guidance, the risk of block-related PNI remains unchanged. Since the 2008 Practice Advisory, new information has been published, furthering our understanding of the microanatomy of peripheral nerves, mechanisms of peripheral nerve injection injury, toxicity of local anesthetics, the etiology of and monitoring methods, and technologies that may decrease the risk of nerve block-related peripheral nerve injury.

  5. Mismatch Repair Deficiency and Response to Immune Checkpoint Blockade

    Science.gov (United States)

    Lee, Valerie; Murphy, Adrian; Le, Dung T.

    2016-01-01

    More than 1.6 million new cases of cancer will be diagnosed in the U.S. in 2016, resulting in more than 500,000 deaths. Although chemotherapy has been the mainstay of treatment in advanced cancers, immunotherapy development, particularly with PD-1 inhibitors, has changed the face of treatment for a number of tumor types. One example is the subset of tumors characterized by mismatch repair deficiency and microsatellite instability that are highly sensitive to PD-1 blockade. Hereditary forms of cancer have been noted for more than a century, but the molecular changes underlying mismatch repair-deficient tumors and subsequent microsatellite unstable tumors was not known until the early 1990s. In this review article, we discuss the history and pathophysiology of mismatch repair, the process of testing for mismatch repair deficiency and microsatellite instability, and the role of immunotherapy in this subset of cancers. Implications for Practice: Mismatch repair deficiency has contributed to our understanding of carcinogenesis for the past 2 decades and now identifies a subgroup of traditionally chemotherapy-insensitive solid tumors as sensitive to PD-1 blockade. This article seeks to educate oncologists regarding the nature of mismatch repair deficiency, its impact in multiple tumor types, and its implications for predicting the responsiveness of solid tumors to immune checkpoint blockade. PMID:27412392

  6. Histochemical and immunohistological approach to comparative neuromuscular diseases.

    Directory of Open Access Journals (Sweden)

    Serenella Papparella

    2009-12-01

    Full Text Available The broad category of neuromuscular diseases covers conditions that involve the weakness or wasting of the body muscles. These problems may occur in the spinal cord, the peripheral nerves or the muscle fibers. Some may be hereditary, while others are acquired. Commonly recognized conditions fall into the categories of myopathies, which are diseases of the muscle like muscular dystrophy, disorders of the junction where the nerve impulses are transmitted to the muscle like myasthenia gravis, and neuropathies, which are diseases of the peripheral nervous system. The diagnosis of most neuromuscular diseases rest on careful clinical evaluation of the patient, electromyography, the muscle biopsy, and in some instances, molecular genetic studies. Muscle biopsy, associated to histochemical and immunohistological techniques, plays a key role in diagnosis of many neuromuscular disorders. A number of morphological abnormalities of muscle can be recognized on histological stains such as haematoxylin and eosin and Engel trichrome. Histochemical techniques are essential for the study of muscle biopsies for four main reasons. First, they demonstrate the non-uniform nature of the muscle highlighting the different biochemical properties of specific fibre type and their selective involvement in certain disease processes. Second, they may show an absences of a particular enzyme. Third, an excess of a particular substrate can be demonstrated. Fourth, they may show structural changes in the muscle which would not be apparent with routine histological stains, such as the enzyme-deficient cores in central core disease "mouth-eaten" fibers, and abnormalities in the distribution of mitochondria. In some neuromuscular disorders there could be only non-specific myopathological features. However, a number of proteins, including sarcolemmal, sarcomeric, and nuclear proteins as well as enzymes with defects responsible for neuromuscular disorders, have been identified during

  7. Orexin-1 receptor blockade dysregulates REM sleep in the presence of orexin-2 receptor antagonism

    Directory of Open Access Journals (Sweden)

    Christine eDugovic

    2014-02-01

    Full Text Available In accordance with the prominent role of orexins in the maintenance of wakefulness via activation of orexin-1 (OX1R and orexin-2 (OX2R receptors, various dual OX1/2R antagonists have been shown to promote sleep in animals and humans. While selective blockade of OX2R seems to be sufficient to initiate and prolong sleep, the beneficial effect of additional inhibition of OX1R remains controversial. The relative contribution of OX1R and OX2R to the sleep effects induced by a dual OX1/2R antagonist was further investigated in the rat, and specifically on rapid eye movement (REM sleep since a deficiency of the orexin system is associated with narcolepsy/cataplexy based on clinical and pre-clinical data. As expected, the dual OX1/2R antagonist SB-649868 was effective in promoting non-REM (NREM and REM sleep following oral dosing (10 and 30 mg/kg at the onset of the dark phase. However, a disruption of REM sleep was evidenced by a more pronounced reduction in the onset of REM as compared to NREM sleep, a marked enhancement of the REM/total sleep ratio, and the occurrence of a few episodes of direct wake to REM sleep transitions (REM intrusion. When administered subcutaneously, the OX2R antagonist JNJ-10397049 (10 mg/kg increased NREM duration whereas the OX1R antagonist GSK-1059865 (10 mg/kg did not alter sleep. REM sleep was not affected either by OX2R or OX1R blockade alone, but administration of the OX1R antagonist in combination with the OX2R antagonist induced a significant reduction in REM sleep latency and an increase in REM sleep duration at the expense of the time spent in NREM sleep. These results indicate that additional blockade of OX1R to OX2R antagonism elicits a dysregulation of REM sleep by shifting the balance in favor of REM sleep at the expense of NREM sleep that may increase the risk of adverse events. Translation of this hypothesis remains to be tested in the clinic.

  8. DOSE-RESPONSE RELATION, NEUROMUSCULAR BLOCKING ACTION, INTUBATION CONDITIONS, AND CARDIOVASCULAR EFFECTS OF ORG-9273, A NEW NEUROMUSCULAR BLOCKING-AGENT

    NARCIS (Netherlands)

    VANDENBROEK, L; LAMBALK, LM; RICHARDSON, FJ; WIERDA, JMKH

    The ED50 and the ED90, the time-course of the neuromuscular block, the intubation conditions, and the cardiovascular effects of Org 9273, a new steroidal nondepolarizing neuromuscular blocking agent, have been evaluated in 41 anesthetized patients. From cumulative dose-response curves the ED50 and

  9. Blockade of immunosuppressive cytokines restores NK cell antiviral function in chronic hepatitis B virus infection.

    Directory of Open Access Journals (Sweden)

    Dimitra Peppa

    2010-12-01

    Full Text Available NK cells are enriched in the liver, constituting around a third of intrahepatic lymphocytes. We have previously demonstrated that they upregulate the death ligand TRAIL in patients with chronic hepatitis B virus infection (CHB, allowing them to kill hepatocytes bearing TRAIL receptors. In this study we investigated whether, in addition to their pathogenic role, NK cells have antiviral potential in CHB. We characterised NK cell subsets and effector function in 64 patients with CHB compared to 31 healthy controls. We found that, in contrast to their upregulated TRAIL expression and maintenance of cytolytic function, NK cells had a markedly impaired capacity to produce IFN-γ in CHB. This functional dichotomy of NK cells could be recapitulated in vitro by exposure to the immunosuppressive cytokine IL-10, which was induced in patients with active CHB. IL-10 selectively suppressed NK cell IFN-γ production without altering cytotoxicity or death ligand expression. Potent antiviral therapy reduced TRAIL-expressing CD56(bright NK cells, consistent with the reduction in liver inflammation it induced; however, it was not able to normalise IL-10 levels or the capacity of NK cells to produce the antiviral cytokine IFN-γ. Blockade of IL-10 +/- TGF-β restored the capacity of NK cells from both the periphery and liver of patients with CHB to produce IFN-γ, thereby enhancing their non-cytolytic antiviral capacity. In conclusion, NK cells may be driven to a state of partial functional tolerance by the immunosuppressive cytokine environment in CHB. Their defective capacity to produce the antiviral cytokine IFN-γ persists in patients on antiviral therapy but can be corrected in vitro by IL-10+/- TGF-β blockade.

  10. Autoregulation of Neuromuscular Transmission by Nerve Terminals.

    Science.gov (United States)

    1985-09-01

    chlorpromazine (CPZ) and trifluoperazine (TFP), with known anti-calmodulin activity’l induced a decrease in FC via indirect, but not direct muscle...release ACh synthesis by motor nerve terminals requires an adequate supply of its precusor, choline. We have found that diisopropyl1fluorophosphate (DFP...inhibits choline efflux from the isolated hemidiaphragm and futher suggest that, by limiting the availability of choline for ACh synthesis , DFP reduces the

  11. [Electromyography (EMG) and neurography in patients with severe neuromuscular diseases].

    Science.gov (United States)

    Løseth, Sissel; Torbergsen, Torberg

    2013-01-22

    Many neuromuscular diseases are potentially severe, and EMG and neurography are methods used in the assessment of these conditions. The article is based on the authors' knowledge and experience, with special emphasis on the use of these methods in the assessment of severe diseases affecting striated muscle and peripheral nerves. A PubMed search was performed with the cut-off fifteen years back in time, and in addition a discretionary selection was made of articles known to the authors. EMG is the most valuable method for assessing myopathy, and neurography provides most information about neuropathy, but the methods are complementary. These examinations are the most sensitive for diagnosing some conditions (for example myasthaenia) A high level of expertise is necessary for diagnosing these conditions. EMG and neurography are important and often necessary means of assessing patients with severe neuromuscular disease.

  12. Effect of electrostimulation training-detraining on neuromuscular fatigue mechanisms.

    Science.gov (United States)

    Jubeau, Marc; Zory, Raphaël; Gondin, Julien; Martin, Alain; Maffiuletti, Nicola A

    2007-08-31

    The aim of this study was to evaluate the effects of neuromuscular electrical stimulation (NMES) training and subsequent detraining on neuromuscular fatigue mechanisms. Ten young healthy men completed one NMES fatigue protocol before and after a NMES training program of 4 weeks and again after 4 weeks of detraining. Muscle fatigue (maximal voluntary torque loss), central fatigue (activation failure), and peripheral fatigue (transmission failure and contractile failure) of the plantar flexor muscles were assessed by using a series of electrically evoked and voluntary contractions with concomitant electromyographic and torque recordings. At baseline, maximal voluntary torque decreased significantly with fatigue (Pmuscle activation after training and detraining was significantly lower compared to baseline values (Ptraining-detraining of the plantar flexor muscles significantly reduced the muscle fatigue associated to one single NMES exercise session. This was mainly attributable to a reduction in activation failure, i.e., lower central fatigue, probably as a result of subject's accommodation to pain and discomfort during NMES.

  13. [Neuromuscular disease: respiratory clinical assessment and follow-up].

    Science.gov (United States)

    Martínez Carrasco, C; Villa Asensi, J R; Luna Paredes, M C; Osona Rodríguez de Torres, F B; Peña Zarza, J A; Larramona Carrera, H; Costa Colomer, J

    2014-10-01

    Patients with neuromuscular disease are an important group at risk of frequently suffering acute or chronic respiratory failure, which is their main cause of death. They require follow-up by a pediatric respiratory medicine specialist from birth or diagnosis in order to confirm the diagnosis and treat any respiratory complications within a multidisciplinary context. The ventilatory support and the cough assistance have improved the quality of life and long-term survival for many of these patients. In this paper, the authors review the pathophysiology, respiratory function evaluation, sleep disorders, and the most frequent respiratory complications in neuromuscular diseases. The various treatments used, from a respiratory medicine point of view, will be analyzed in a next paper. Copyright © 2013 Asociación Española de Pediatría. Published by Elsevier Espana. All rights reserved.

  14. Early appearance and possible roles of non-neuromuscular cholinesterases.

    Directory of Open Access Journals (Sweden)

    Carla eFalugi

    2012-04-01

    Full Text Available The biological function of the cholinesterase (ChE enzymes is well known and has been studied since the beginning of the XXth century; in particular, acetylcholinesterase (AChE, E.C. 3.1.1.7 is an enzyme playing a key role in the modulation of neuromuscular impulse transmission. However, in the past decades, there has been increasing interest concerning its role in regulating non-neuromuscular cell-to-cell interactions mediated by intracellular ion concentration changes, like the ones occurring during gamete interaction and embryonic development. An understanding of the mechanisms of the cholinergic regulation of these events can help us foresee the possible impact on environmental and human health, including gamete efficiency and possible teratogenic effects on different models, and help elucidate the extent to which exposure to ChE inhibitors may affect human health.

  15. One clinic's experience with carbon fiber orthoses in neuromuscular disease.

    Science.gov (United States)

    Mnatsakanian, Ani; Kissel, John T; Terry, Philip; King, Wendy M

    2017-02-01

    The purpose of this study was to summarize our experience with off-the-shelf anterior shell carbon fiber ankle-foot orthoses (CFAFOs) prescribed to adult neuromuscular patients in an outpatient clinic. We studied ambulatory patients who were seen in Muscular Dystrophy Association or amyotrophic lateral sclerosis clinics between 2011 and 2014 and prescribed anterior shell CFAFOs. Charts were reviewed with attention to diagnosis, satisfaction with use, and reasons for acceptance or rejection. We included individuals who were currently using AFOs and those being prescribed AFOs for the first time. We were especially interested in reasons for acceptance or rejection of the orthosis. Two hundred eighty-three charts were reviewed. Of these, 109 of 123 (89%) patients were satisfied or extremely satisfied with the anterior shell CFAFOs, including 38 who had previously used other styles. Anterior shell CFAFOs should be considered for most neuromuscular patients with distal leg weakness. Muscle Nerve 55: 202-205, 2017. © 2016 Wiley Periodicals, Inc.

  16. Neuromuscular paralysis for newborn infants receiving mechanical ventilation.

    Science.gov (United States)

    Cools, F; Offringa, M

    2005-04-18

    Ventilated newborn infants breathing in asynchrony with the ventilator are at risk for complications during mechanical ventilation, such as pneumothorax or intraventricular hemorrhage, and are exposed to more severe barotrauma, which consequently could impair their clinical outcome. Neuromuscular paralysis, which eliminates spontaneous breathing efforts of the infant, has potential advantages in this respect. However, a number of complications have been reported with muscle relaxation in infants, so that concerns exist regarding the safety of prolonged neuromuscular paralysis in newborn infants. To determine whether routine neuromuscular paralysis of newborn infants receiving mechanical ventilation compared with no routine paralysis results in clinically important benefits or harms. The Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 1, 2004), MEDLINE (from 1966 to April 2004) and EMBASE (from 1988 to April 2004) were searched. References of review articles were hand searched. Language restriction was not imposed. All trials using random or quasi-random patient allocation, in which the routine use of neuromuscular blocking agents during mechanical ventilation was compared to no paralysis or selective paralysis in newborn infants. Methodological quality was assessed blindly and independently by the two authors. Data were abstracted using standard methods of the Cochrane Collaboration and its Neonatal Review Group, with independent evaluation of trial quality, and abstraction and synthesis of data by both authors. Treatment effect was analysed using relative risk, risk difference and weighted mean difference. Ten possibly eligible trials were identified, of which six were included in the review. All the included trials studied preterm infants ventilated for respiratory distress syndrome, and used pancuronium as the neuromuscular blocking agent. In the analysis of the results of all trials, no significant difference was found in

  17. [From joint to neuromuscular, from mechanics to electronics: the concept of neuromuscular compatibility].

    Science.gov (United States)

    Toubol, J P; Duret, F

    1989-06-01

    The development of devices to record the functional mandibular kinetics, has permitted the physiological analysis of the masticatory cycles. Therefore, it is possible to consider a functional integration of the corrections, by addition or subtraction to the occlusal surfaces of the teeth. For this purpose, we have established the conditions of a physiological concept of occlusion taking into account the efficiency of the masticatory apparatus through a velocity analysis. This is the N.M.C. concept or concept of Neuro-Muscular Compatibility. This concept has led us to define the ISCA (Intra-Cuspid Spatial Angle), represented by the angle defined in the three spatial planes, by the trajectory of the occlusal contact point of a cusp liding over its opposite, in any excursive opportunity. We have shortly reported the studies by Levin on the SIROGNATOGRAPH and the prospects resulting from these studies. Then, we have studied in greater details the Saphon VISI TRAINER III developed by HOBO and described the various potentials of its use in the GBM Laboratory in Vienna (France), with François DURET. We have also analyzed the specific points which seem to represent the weaknesses of this device and have outlined some solutions to this problem. This approach, within a clinical context, may at term give rise to a complex analyser-expert-system intends to facilitate the establishment of a reliable diagnosis and to control the physiological integration of our procedures. The establishment, at term, of parameters and constants of this function, will guide this progression towards success.

  18. Brain-controlled neuromuscular stimulation to drive neural plasticity and functional recovery.

    Science.gov (United States)

    Ethier, C; Gallego, J A; Miller, L E

    2015-08-01

    There is mounting evidence that appropriately timed neuromuscular stimulation can induce neural plasticity and generate functional recovery from motor disorders. This review addresses the idea that coordinating stimulation with a patient's voluntary effort might further enhance neurorehabilitation. Studies in cell cultures and behaving animals have delineated the rules underlying neural plasticity when single neurons are used as triggers. However, the rules governing more complex stimuli and larger networks are less well understood. We argue that functional recovery might be optimized if stimulation were modulated by a brain machine interface, to match the details of the patient's voluntary intent. The potential of this novel approach highlights the need for a better understanding of the complex rules underlying this form of plasticity. Copyright © 2015 Elsevier Ltd. All rights reserved.

  19. Reliability of a Test Battery Designed for Quickly and Safely Assessing Diverse Indices of Neuromuscular Function

    Science.gov (United States)

    Spiering, Barry A.; Lee, Stuart M. C.; Mulavara, Ajitkumar P.; Bentley, Jason, R.; Buxton, Roxanne E.; Lawrence, Emily L.; Sinka, Joseph; Guilliams, Mark E.; Ploutz-Snyder, Lori L.; Bloomberg, Jacob J.

    2010-01-01

    Spaceflight affects nearly every physiological system. Spaceflight-induced alterations in physiological function translate to decrements in functional performance. Purpose: To develop a test battery for quickly and safely assessing diverse indices of neuromuscular performance. I. Quickly: Battery of tests can be completed in approx.30-40 min. II. Safely: a) No eccentric muscle actions or impact forces. b) Tests present little challenge to postural stability. III. Diverse indices: a) Strength: Excellent reliability (ICC = 0.99) b) Central activation: Very good reliability (ICC = 0.87) c) Power: Excellent reliability (ICC = 0.99) d) Endurance: Total work has excellent reliability (ICC = 0.99) e) Force steadiness: Poor reliability (ICC = 0.20 - 0.60) National

  20. Neuromuscular Electrical Stimulation for Motor Restoration in Hemiplegia.

    Science.gov (United States)

    Knutson, Jayme S; Fu, Michael J; Sheffler, Lynne R; Chae, John

    2015-11-01

    This article reviews the most common therapeutic and neuroprosthetic applications of neuromuscular electrical stimulation (NMES) for upper and lower extremity stroke rehabilitation. Fundamental NMES principles and purposes in stroke rehabilitation are explained. NMES modalities used for upper and lower limb rehabilitation are described, and efficacy studies are summarized. The evidence for peripheral and central mechanisms of action is also summarized. Copyright © 2015 Elsevier Inc. All rights reserved.

  1. Thermal, circulatory, and neuromuscular responses to whole-body cryotherapy

    OpenAIRE

    Westerlund, T. (Tarja)

    2009-01-01

    Abstract The purpose of this study was to examine thermal (body temperature, thermal sensation and comfort ratings), circulatory (blood