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Sample records for amiodarone destabilizes intracellular

  1. Treatment with Amiodaron

    DEFF Research Database (Denmark)

    Adelborg, Kasper; Ebbehøj, Eva; Nielsen, Jens Cosedis

    2014-01-01

    Amiodarone is an effective antiarrhythmic drug for supra-ven-tri-cular and ventricular arrhythmias. A majority of patients treated with amiodarone suffer from mild adverse events, however, serious life-threatening adverse events caused by amiodarone are also seen. This review describes the pharma...

  2. Acute amiodarone promotes drift and early termination of spiral wave re-entry.

    Science.gov (United States)

    Nakagawa, Harumichi; Honjo, Haruo; Ishiguro, Yuko S; Yamazaki, Masatoshi; Okuno, Yusuke; Harada, Masahide; Takanari, Hiroki; Sakuma, Ichiro; Kamiya, Kaichiro; Kodama, Itsuo

    2010-07-01

    Intravenous application of amiodarone is commonly used in the treatment of life-threatening arrhythmias, but the underlying mechanism is not fully understood. The purpose of the present study is to investigate the acute effects of amiodarone on spiral wave (SW) re-entry, the primary organization machinery of ventricular tachycardia/fibrillation (VT/VF), in comparison with lidocaine. A two-dimensional ventricular myocardial layer was obtained from 24 Langendorff-perfused rabbit hearts, and epicardial excitations were analyzed by high-resolution optical mapping. During basic stimulation, amiodarone (5 microM) caused prolongation of action potential duration (APD) by 5.6%-9.1%, whereas lidocaine (15 microM) caused APD shortening by 5.0%-6.4%. Amiodarone and lidocaine reduced conduction velocity similarly. Ventricular tachycardias induced by DC stimulation in the presence of amiodarone were of shorter duration (sustained-VTs >30 s/total VTs: 2/58, amiodarone vs 13/52, control), whereas those with lidocaine were of longer duration (22/73, lidocaine vs 14/58, control). Amiodarone caused prolongation of VT cycle length and destabilization of SW re-entry, which is characterized by marked prolongation of functional block lines, frequent wavefront-tail interactions near the rotation center, and considerable drift, leading to its early annihilation via collision with anatomical boundaries. Spiral wave re-entry in the presence of lidocaine was more stabilized than in control. In the anisotropic ventricular myocardium, amiodarone destabilizes SW re-entry facilitating its early termination. Lidocaine, in contrast, stabilizes SW re-entry resulting in its persistence.

  3. Amiodarone for the treatment and prevention of ventricular fibrillation and ventricular tachycardia

    Directory of Open Access Journals (Sweden)

    Hugo Van Herendael

    2010-06-01

    Full Text Available Hugo Van Herendael, Paul DorianDivision of Cardiology, St. Michael’s Hospital, University of Toronto, Toronto, CanadaAbstract: Amiodarone has emerged as the leading antiarrhythmic therapy for termination and prevention of ventricular arrhythmia in different clinical settings because of its proven efficacy and safety. In patients with shock refractory out-of-hospital cardiac arrest and hemodynamically destabilizing ventricular arrhythmia, amiodarone is the most effective drug available to assist in resuscitation. Although the superiority of the transvenous implantable cardioverter defibrillator (ICD over amiodarone has been well established in the preventive treatment of patients at high risk of life-threatening ventricular arrhythmias, amiodarone (if used with a beta-blocker is the most effective antiarrhythmic drug to prevent ICD shocks and treat electrical storm. Both the pharmacokinetics and the electrophysiologic profile of amiodarone are complex, and its optimal and safe use requires careful patient surveillance with respect to potential adverse effects.Keywords: amiodarone, ventricular fibrillation, unstable ventricular tachycardia

  4. A Chimeric Cetuximab-Functionalized Corona as a Potent Delivery System for Microtubule-Destabilizing Nanocomplexes to Hepatocellular Carcinoma Cells: A Focus on EGFR and Tubulin Intracellular Dynamics.

    Science.gov (United States)

    Poojari, Radhika; Kini, Sudarshan; Srivastava, Rohit; Panda, Dulal

    2015-11-01

    In this study, we have developed microtubule destabilizing agents combretastatin A4 (CA4) or 2-methoxyestradiol (2ME) encapsulated poly(d,l-lactide-co-glycolide)-b-poly(ethylene glycol) (PLGA-b-PEG) nanocomplexes for targeted delivery to human hepatocellular carcinoma (HCC) cells. An epidermal growth factor receptor (EGFR) is known to be overexpressed in HCC cells. Therefore, the targeting moiety cetuximab (Cet), an anti-EGFR chimeric monoclonal antibody, is functionalized on the surface of these diblock copolymeric coronas. Cetuximab is associated with the extracellular domain of the EGFR; therefore, the uptake of the cetuximab conjugated nanocomplexes occurred efficiently in EGFR overexpressing HCC cells indicating potent internalization of the complex. The cetuximab targeted-PLGA-b-PEG nanocomplexes encapsulating CA4 or 2ME strongly inhibited phospho-EGFR expression, depolymerized microtubules, produced spindle abnormalities, stalled mitosis, and induced apoptosis in Huh7 cells compared to the free drugs, CA4 or 2ME. Further, the combinatorial strategy of targeted nanocomplexes, Cet-PLGA-b-PEG-CA4 NP and Cet-PLGA-b-PEG-2ME NP, significantly reduced the migration of Huh7 cells, and markedly enhanced the anticancer effects of the microtubule-targeted drugs in Huh7 cells compared to the free drugs, CA4 or 2ME. The results indicated that EGFR receptor-mediated internalization via cetuximab facilitated enhanced uptake of the nanocomplexes leading to potent anticancer efficacy in Huh7 cells. Cetuximab-functionalized PLGA-b-PEG nanocomplexes possess a strong potential for the targeted delivery of CA4 or 2ME in EGFR overexpressed HCC cells, and the strategy may be useful for selectively targeting microtubules in these cells.

  5. Amiodaron: Unersetzliches Rhythmusmittel oder "Teufelszeug"?

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    Meinertz T

    2015-01-01

    Full Text Available Die Probleme der Amiodaron-Therapie beruhen auf Handhabungsfehlern. Bei korrekter Handhabung (niedrige Dosierung, engmaschige Überwachung des Patienten ist die Häufigkeit schwerwiegender Nebenwirkungen gering. Wichtig ist die Kontrolle der Schild drü senfunktion, von Hautveränderungen, Augenveränderungen, Leberfunktionsstörungen, neuromuskulären Nebenwirkungen sowie Lungenschäden. Hauptindikation für Amiodaron sind therapierefraktäres Vorhofflimmern sowie maligne ventrikuläre Herzrhythmusstörungen, die zu häufigen ICD-Entladungen führen.

  6. Bronchiolitis obliterans organizing pneumonia during low-dose amiodarone therapy

    NARCIS (Netherlands)

    Jessurun, GAJ; Hoogenberg, K; Crijns, HJGM

    1997-01-01

    Two cases of amiodarone-induced pulmonary toxicity during a relatively short period of low-dose amiodarone treatment are reported. The toxicity risk of amiodarone is determined by cumulative factors in individual patients.

  7. Amiodarone -- waxed and waned and waxed again.

    Science.gov (United States)

    Doggrell, S A

    2001-11-01

    Amiodarone has been used as an anti-arrhythmic drug since the 1970s and has an established role in the treatment of ventricular tachyarrhythmias. Although considered to be a class III anti-arrhythmic, amiodarone also has class I, II and IV actions, which gives it a unique pharmacological and anti-arrhythmic profile. Amiodarone is a structural analogue of thyroid hormone and some of its anti-arrhythmic properties and toxicity may be attributable to interactions with nuclear thyroid hormone receptors. The lipid solubility of amiodarone gives it an exceptionally long half-life. Oral amiodarone takes days to work in ventricular tachyarrhythmias, but iv. amiodarone has immediate effect and can be used in life threatening ventricular arrhythmias. Intravenous amiodarone administered after out-of-hospital cardiac arrest due to ventricular fibrillation improves survival to hospital admission. Many survivors of myocardial infarction (MI) die during the subsequent year, probably due to ventricular arrhythmia. Amiodarone reduces sudden death after MI and this benefit is predominantly observed in patients with preserved cardiac function. Sudden cardiac death, predominantly due to ventricular arrhythmias, is also commonly seen in patients with heart failure. The Grupo de Estudio de la Sobrevida en lsuficiencia Cardiaca en Argentina (GESICA) and Estudio Piloto Argentino de Muerte Subita y Amiodarona (EPAMSA) trials showed survival benefit of amiodarone in heart failure, whereas Congestive Heart Failure-Survival Trial of Anti-arrhythmic Therapy (CHF-STAT) did not. Subsequent meta-analysis established a survival benefit of amiodarone in heart failure. Implanted Cardioverter Def ibrillators (ICDs) also give survival benefit to patients at risk of sudden death. In patients with a history of ventricular fibrillation or haemodynamically-compromising ventricular tachycardia, ICDs have been shown to be superior to anti-arrhythmic drugs, principally amiodarone. Further analysis has been

  8. Acute pancreatitis and amiodarone: A case report

    Institute of Scientific and Technical Information of China (English)

    Yen-Yuan Chen; Ching-Yu Chen; Kai-Kuen Leung

    2007-01-01

    Amiodarone, a class m antiarrhythmic drug, is one of the most effective drugs used in the treatment of ventricular and paroxysmal supraventricular tachyarrhythmia. Adverse effects of amiodarone including pulmonary toxicity, hepatotoxicity, aggravation of arrhythmia, and thyroid diseases are well understood. A 66-year old woman with acute pancreatitis was admitted to our hospital with the complaint of epigastralgia radiating to both flanks for two months. Her symptoms and elevation of pancreatic enzymes did not respond to conventional medical treatment of pancreatitis for 18 d. No known causal factors for pancreatitis such as biliary tract stone, hypertriglyceridemia and alcohol consumption could be identified. Under the suspicion of amiodarone-induced acute pancreatitis, amiodarone was substituted by propafenone. Her symptoms soon alleviated and serum lipase level declined. Three months after hospital discharge, the abdominal pain did not recur. Amiodarone was approved to treat recurrent ventricular fibrillation or sustained ventricular tachyarrhythmia that has been resistant to other medications since 1986. Pancreatitis is a very rare adverse effect associated with the use of amiodarone, and only four cases of amiodarone-induced pancreatitis have been reported in literature. We report a patient who developed acute pancreatitis during amiodarone therapy.

  9. Anticonvulsant and hypnotic effects of amiodarone

    Institute of Scientific and Technical Information of China (English)

    Gunnur OZBAKIS-DENGIZ; Aysegul BAKIRCI

    2009-01-01

    Amiodarone hydrochloride is a potent anti-arrhythmic agent, known as a multiple ion-channel blocker in the heart.Although it has been detected in the rat brain, there are no data related to its central nervous system (CNS) effects. In this study, we evaluated anticonvulsant and hypnotic effects of amiodarone. Convulsions were induced by phentylenetetrazole (PTZ) (100 mg/kg) or caffeine (300 mg/kg) in mice. In both models, amiodarone prolonged both latency period and time to death, and acted as an anticonvulsant drug. It was found to be more effective in the PTZ model than in the caffeine model; none of the animals treated with 150 mg/kg dose amiodarone had died in the PTZ model. For hypnotic effect, sleeping was induced with pentobarbital (35 mg/kg) in rats. Amiodarone dose-dependently increased the sleeping time (677.7%~725.9%). In the sleeping test, all rats in 200 mg/kg amiodarone group died. In conclusion, anticonvulsant and hypnotic effects of amiodarone have shown the depressant effects on CNS. These effects may be dependent on its pharmacological properties.

  10. Amiodaron: Effektivität und Sicherheit

    Directory of Open Access Journals (Sweden)

    Hofmann R

    2009-01-01

    Full Text Available Aufgrund neutraler Nettoeffekte auf Herz-Kreislaufparameter hat sich Amiodaron wie kein konventionelles oder neu entwickeltes Antiarrhythmikum zur Behandlung verschiedener Tachyarrhythmien bewährt. Intravenöses Amiodaron ist guidelinekonform das Antiarrhythmikum der Wahl zur Behandlung von bedrohlichen ventrikulären Tachyarrhythmien. Patienten mit hoher Ventrikelfrequenz bei Vorhofflimmern profitieren von einer unmittelbaren Frequenzkontrolle sowie einem Potenzial zur Kardioversion ohne wesentliche Kompromittierung der Hämodynamik. Orales Amiodaron hat eine symptomatische Bedeutung bei Patienten mit ventrikulären Arrhythmien, eine Beeinflussung der Prognose konnte nicht nachgewiesen werden. Bei Patienten mit nichtpermanentem Vorhofflimmern ist Amiodaron das wirksamste Antiarrhythmikum und vor allem bei bestehender Herzinsuffizienz die einzige medikamentöse Option. Die Inzidenz klinisch relevanter Nebenwirkungen wurde historisch überbewertet und reduziert sich abgesehen von Einzelfällen auf Haut- und funktionelle Schilddrüsenveränderungen.

  11. Compound list: amiodarone [Open TG-GATEs

    Lifescience Database Archive (English)

    Full Text Available amiodarone AM 00033 ftp://ftp.biosciencedbc.jp/archive/open-tggates/LATEST/Human/in_vitro/amio...darone.Human.in_vitro.Liver.zip ftp://ftp.biosciencedbc.jp/archive/open-tggates/LATEST/Rat/in_vitro/amio...darone.Rat.in_vitro.Liver.zip ftp://ftp.biosciencedbc.jp/archive/open-tggates/LATEST/Rat/in_vivo/Liver/Single/amio...ve/open-tggates/LATEST/Rat/in_vivo/Liver/Repeat/amiodarone.Rat.in_vivo.Liver.Repeat.zip ...

  12. Amiodarone

    Science.gov (United States)

    ... nervousness irritability intolerance to heat or cold thinning hair excessive sweating changes in menstrual cycle swelling in ... to your pharmacist or contact your local garbage/recycling department to learn about take-back programs in ...

  13. Amiodarone Induced Morphological Changes in Rabbit Pneumocytes

    Directory of Open Access Journals (Sweden)

    Fereshteh Mehraein

    2009-01-01

    Full Text Available Objective: Amiodarone as an iodinated benzofuran derivative is a potent antiarrhythmicagent currently used for the treatment of ventricular arrhythmias. Pulmonary toxicityis one of the complications of Amiodarone therapy. The aim of this study was todetermine the toxicity of Amiodarone for pneumocytes.Materials and Methods: 14 male white New Zealand rabbits were divided in a controlgroup and an experimental group. The experimental group was subjected to intraperitoneal injection with a single daily dose of 80 mg/kg Amiodarone for two weeks.The control group received only normal saline. At the end of the injection period, thetwo groups were anesthetized and perfused with Karnovsky fixative. The lung tissuewas removed and fixed, then prepared for light and electron microscope studies.Morphometric studies were made on sections to find nucleus profile dimensions.Results: Light microscope observation showed acute changes in the alveolus includingcongestion of alveolar capillaries and infiltration of red blood cells (RBCs intothe lumen of the alveoli. Electron microscope study of lung tissue revealed abnormalinclusion bodies within type ΙΙ & Ι pneumocytes. The micrographs also showedthe presence of vacuoles in 5% of the type ΙΙ pneumocytes. Morphometric studiesshowed that the nucleus of the cells in the experimental group were smaller than inthe control group (p<0.01.Conclusion: These results indicate that Amiodarone administration can cause damageto pnuemocytes and the alveolus of rabbit lung, so the effectiveness of Amiodaronein long term treatment of heart failure patients is limited because of the developmentof lung toxicity.

  14. Amiodarone for ACLS: a critical evaluation.

    Science.gov (United States)

    Stewart, C E

    2001-09-01

    Years ago, William Osler taught physicians, "Be not the first nor the last to adopt a therapy." This continues to be sage advice. Clinicians should be cautious in considering the use of amiodarone in a field setting for cardiac arrest until studies clearly show a benefit over drugs currently in use. The endpoint of the only cardiac arrest study available shows improved survival when amiodarone is combined with other drugs over placebo until the patient gets to the emergency department, but is not a comparison with other current drugs nor had any effect on long-term survival or functioning neurologic status. As previously cited, amiodarone was comparable with bretylium in treating recurrent VT/VF in one controlled study. Further study of this and other ACLS drugs is imperative. In summary, amiodarone should be reclassified as either a class indeterminate agent when used alone ("no harm but no benefit ... evidence insufficient to support final class decision") or a class IIb agent ("acceptable and useful ... supported by fair to good evidence") when used in addition to other therapies in the treatment of ventricular fibrillation and pulseless ventricular tachycardia. There is not sufficient evidence to move amiodarone to first-line therapy in the "out-of-hospital" cardiac arrest. This evidence may be available in the future and would then change this recommendation.

  15. Geometrical Destabilization of Inflation

    Science.gov (United States)

    Renaux-Petel, Sébastien; Turzyński, Krzysztof

    2016-09-01

    We show the existence of a general mechanism by which heavy scalar fields can be destabilized during inflation, relying on the fact that the curvature of the field space manifold can dominate the stabilizing force from the potential and destabilize inflationary trajectories. We describe a simple and rather universal setup in which higher-order operators suppressed by a large energy scale trigger this instability. This phenomenon can prematurely end inflation, thereby leading to important observational consequences and sometimes excluding models that would otherwise perfectly fit the data. More generally, it modifies the interpretation of cosmological constraints in terms of fundamental physics. We also explain how the geometrical destabilization can lead to powerful selection criteria on the field space curvature of inflationary models.

  16. Continuous vs episodic prophylactic treatment with amiodarone for the prevention of atrial fibrillation : a randomized trial

    NARCIS (Netherlands)

    Ahmed, Sheba; Rienstra, Michiel; Crijns, Harry J. G. M.; Links, Thera P.; Wiesfeld, Ans C. P.; Hillege, Hans L.; Bosker, Hans A.; Lok, Dirk J. A.; Van Veldhuisen, Dirk J.; Van Gelder, Isabelle C.

    2008-01-01

    Context Amiodarone effectively suppresses atrial fibrillation but causes many adverse events. Objective To compare major events in patients randomized to receive episodic amiodarone treatment with those who received continuous amiodarone treatment while still aiming to prevent atrial fibrillation. D

  17. Vorhofflimmern und Herzinsuffizienz - Die Rolle von Amiodaron

    Directory of Open Access Journals (Sweden)

    Scherr D

    2015-01-01

    Full Text Available Vorhofflimmern (VHF und Herzinsuffizienz (HI sind häufige kardiale Erkrankungen mit jeweils prognostischen Implikationen und gegenseitiger Beeinflussung/Verstärkung. Bei Patienten mit VHF und HI ist in den meisten Fällen die Frequenzkontrolle die Therapie der Wahl des VHF, jedoch bei ausgeprägter Symptomatik durch VHF, Zunahme der HI durch VHF oder bei Vorliegen einer Tachykardiomyopathie kann der Versuch der Rhythmisierung (Sinusrhythmus, SR angestrebt werden. In diesem Fall ist Amiodaron bei HI-Patienten das Antiarrhythmikum der Wahl zur Rezidivprophylaxe des VHF. Einer 45%igen 5-Jahres-Rate des SR-Erhalts bei Patienten mit VHF unter Amiodaron steht eine ca. 20%ige Nebenwirkungsrate gegenüber. Aber auch bei einer Strategie der Frequenzkontrolle des VHF ist Amiodaron bei HI-Patienten eine Second-line- Therapieoption. Zudem ist Amiodaron i. v. eine medikamentöse Therapieoption im Rahmen der akuten Rhythmuskontrolle (Kardioversion wie auch im Rahmen der akuten Frequenzkontrolle (tachykardes VHF bei HI-Patienten.

  18. Amiodaron-induced pulmonary toxicity with fatal outcome

    Energy Technology Data Exchange (ETDEWEB)

    Brachtel, D.; Krischel, W.

    1984-12-01

    Three month after initiation of amiodarone treatment wih 1000 mg daily a 62 years old man with refractory ventricular tachycardia developed increasing dyspnea. Chest X-ray findings consisted of patchy alveolar infiltrates and interstitial changes. Despite withdrawal of amiodarone and institution of prednisolone treatment the patient died of cardiorespiratory failure. Chest X-ray examinations at frequent intervals should be performed during the first year of high dose amiodarone therapy to detect early signs of pulmonary toxicity.

  19. Amiodarone supplants lidocaine in ACLS and CPR protocols.

    Science.gov (United States)

    Mizzi, Anna; Tran, Thanh; Mangar, Devanand; Camporesi, Enrico M

    2011-09-01

    Amiodarone is an antiarrhythmic medication used to treat and prevent certain types of serious, life-threatening ventricular arrhythmias. Amiodarone gained slow acceptance outside the specialized field of cardiac antiarrhythmic surgery because the side-effects are significant. Recent adoption of amiodarone in the ACLS (Advanced Cardiac Life Support) protocol has somewhat popularized this class of antiarrhythmics. Its use is slowly expanding in the acute medicine setting of anesthetics. This article summarizes the use of Amiodarone by anesthesiologists in the operating room and during cardiopulmonary resuscitation.

  20. The Incidence and Risk of Inducing Hyperthyroidism Following Amiodarone Treatment

    Directory of Open Access Journals (Sweden)

    Cozlea D L

    2013-06-01

    Full Text Available Introduction: Amiodarone, a frequently used antiarrhythmic drug in cardiology, is very efficient in the treatment of ventricular and supraventricular tachiarrithmyas. The iodine content of amiodarone is 39%. Its chemical structure is similar to tyrosine. It is estimated that 1-23% of patients treated with amiodarone can develop hyperthyroidism. The purpose of this study is to assess and monitor the incidence of hyperthyroidism induced by amiodarone in patients admitted for various types of cardiac dysrhythmias, considering that most of the patients included in the study came from an endemic goitre area.

  1. Drug induced lung disease - amiodarone in focus

    Directory of Open Access Journals (Sweden)

    Vasić Nada R.

    2014-01-01

    Full Text Available More than 380 medications are known to cause pulmonary toxicity. Selected drugs that are important causes of pulmonary toxicity fall into the following classes: cytotoxic, cardiovascular, anti-inflammatory, antimicrobial, illicit drugs, miscellaneous. The adverse reactions can involve the pulmonary parenchyma, pleura, the airways, pulmonary vascular system, and mediastinum. Drug-induced lung diseases have no pathognomonic clinical, laboratory, physical, radiographic or histological findings. A drug-induced lung disease is usually considered a diagnosis of exclusion of other diseases. The diagnosis of drug-mediated pulmonary toxicity is usually made based on clinical findings. In general, laboratory analyses do not help in establishing the diagnosis. High-resolution computed tomography scanning is more sensitive than chest radiography for defining radiographic abnormalities. The treatment of drug-induced lung disease consists of immediate discontinuation of the offending drug and appropriate management of the pulmonary symptoms. Glucocorticoids have been associated with rapid improvement in gas exchange and reversal of radiographic abnormalities. Before starting any medication, patients should be educated about the potential adverse effects of the drug. Amiodarone is an antiarrhythmic agent used in the treatment of many types of tachyarrhythmia. Amiodarone-caused pulmonary toxicity is a well-known side effect (complication of this medication. The incidence of amiodarone-induced lung disease is approximately 5-7%.

  2. CT aspects of amiodarone intoxication; Computertomographische Aspekte der Amiodaronintoxikation

    Energy Technology Data Exchange (ETDEWEB)

    Pitton, M. B. [Klinik mit Poliklinik fuer Radiologie, Universitaet Mainz (Germany); Schweden, F. [Klinik mit Poliklinik fuer Radiologie, Universitaet Mainz (Germany); Lenci, G. [3. Medizinische Klinik, Abteilung Pneumologie, Universitaet Mainz (Germany)

    1995-07-01

    Amiodarone, an antiarrhythmic drug, may cause pulmonary toxicity with typical high-attenuation-pleuro-parenchymal lesions and increased attentuation of liver and spleen. Characteristic CT findings are diagnositically significant. (orig.) [Deutsch] Amiodaron ist ein sehr potentes Antiarrhythmikum. Eine Intoxikation fuehrt fedoch zu entzuendlichen Lungengewebsveraenderungen mit hyperdensen Parenchymkonsolidierungen und typischen Dichteanhebungen in den parenchymatoesen Oberbauchorgan. Das computertomographische Erscheinungsbild ist fuer die Differentialdiagnose hilfreich. (orig.)

  3. Amiodarone-induced acute lung toxicity in an ICU setting.

    Science.gov (United States)

    Skroubis, G; Skroubis, T; Galiatsou, E; Metafratzi, Z; Karahaliou, A; Kitsakos, A; Nakos, G

    2005-04-01

    Amiodarone is a highly effective antiarrhythmic drug, albeit notorious for its serious pulmonary toxicity. The incidence of amiodarone-induced pulmonary toxicity (APT) appears to be 1% per year (1). We report a case of very acute APT in a man suffering from postoperative atrial fibrillation.

  4. Chronic amiodarone remodels expression of ion channel transcripts in the mouse heart

    Institute of Scientific and Technical Information of China (English)

    S.LEBOUTER; A.ELHARCHI; C.MARIONNEAU; C.BELLOCQ; A.CHAMBELLAN; K.LEQUANG; JCBELLOCQ; JCCHEVALIER; GLANDE; JJLEGER; FCHARPENTIER; DESCANDE; SDEMOLOMBE

    2004-01-01

    AIM: The basis for the unique effectiveness of chronic amiodarone on cardiac arrhythmias is incompletely understood. The present study investigated the pharmacogenomics profile of amiodarone on genes encoding ion channel subunits. METHODS AND RESULTS: Adult male mice were treated for 6 weeks with vehicle or oral amiodarone at 30,90,or 180 mg·kg-1·d-1, Plasma and myocardial levels of amiodarone and n-desethyl-amiodarone in

  5. Increased Density of the Liver and Amiodarone-Associated Phospholipidosis

    Directory of Open Access Journals (Sweden)

    Sunao Kojima

    2009-01-01

    Full Text Available This is a case report in which a 60-year-old man who suffered from ventricular tachycardia with dilated cardiomyopathy was prescribed amiodarone. After taking amiodarone, liver enzymes were increased and computed tomographic (CT scanning of the abdomen showed a significant increase in the density of the liver without contrast medium. He was suspected as hemochromatosis and liver biopsy was performed. An abnormal high density of liver tissue may be observed in an unenhanced CT in patients treated with amiodarone and we suggest that periodic monitoring of liver function and/or liver biopsy is warranted before an irreversible stage is reached.

  6. Amiodarone-Induced Thyrotoxic Thyroiditis: A Diagnostic and Therapeutic Challenge

    Directory of Open Access Journals (Sweden)

    Umang Barvalia

    2014-01-01

    Full Text Available Amiodarone is an iodine-based, potent antiarrhythmic drug bearing a structural resemblance to thyroxine (T4. It is known to produce thyroid abnormalities ranging from abnormal thyroid function testing to overt hypothyroidism or hyperthyroidism. These adverse effects may occur in patients with or without preexisting thyroid disease. Amiodarone-induced thyrotoxicosis (AIT is a clinically recognized condition commonly due to iodine-induced excessive synthesis of thyroid, also known as type 1 AIT. In rare instances, AIT is caused by amiodarone-induced inflammation of thyroid tissue, resulting in release of preformed thyroid hormones and a hyperthyroid state, known as type 2 AIT. Distinguishing between the two states is important, as both conditions have different treatment implications; however, a mixed presentation is not uncommon, posing diagnostic and treatment challenges. We describe a case of a patient with amiodarone-induced type 2 hyperthyroidism and review the current literature on the best practices for diagnostic and treatment approaches.

  7. Moduli destabilization via gravitational collapse

    Energy Technology Data Exchange (ETDEWEB)

    Hwang, Dong-il [Sogang Univ., Seoul (Korea, Republic of). Center for Quantum Spacetime; Pedro, Francisco G. [Deutsches Elektronen-Synchrotron DESY, Hamburg (Germany). Theory Group; Yeom, Dong-han [Sogang Univ., Seoul (Korea, Republic of). Center for Quantum Spacetime; Kyoto Univ. (Japan). Yukawa Inst. for Theoretical Physics

    2013-06-15

    We examine the interplay between gravitational collapse and moduli stability in the context of black hole formation. We perform numerical simulations of the collapse using the double null formalism and show that the very dense regions one expects to find in the process of black hole formation are able to destabilize the volume modulus. We establish that the effects of the destabilization will be visible to an observer at infinity, opening up a window to a region in spacetime where standard model's couplings and masses can differ significantly from their background values.

  8. Amiodarone-induced pulmonary toxicity - Predisposing factors, clinical symptoms and treatment

    NARCIS (Netherlands)

    Jessurun, GAJ; Boersma, WG; Crijns, HJGM

    1998-01-01

    Amiodarone is frequently used for the treatment of cardiac arrhythmias. Although the therapeutic efficacy of amiodarone has been established, its use is limited by its safety profile. Amiodarone-induced pulmonary toxicity is one of the most life-threatening complications of this therapy. It is a rel

  9. Amiodarone: Effects on thyroid function and the peripheral metabolism of the thyroid hormones

    Energy Technology Data Exchange (ETDEWEB)

    Braverman, L.E.; Safran, M.; Bambini, G.; Pinchera, A.; Martino, E.

    1985-11-01

    In addition to the effects of Amiodarone on the peripheral metabolism of the thyroid hormones and on pituitary TSH secretion, a major complication of therapy is the relatively high frequency of iodide-induced thyroid dysfunction. The mean T/sub 4/ and T/sub 3/ concentration following Amiodarone application was measured in euthyroid, hypothyroid and hyperthyroid patients and in control patients with and without cardiac disorders. Furthermore, the serum TSH was determined in euthyroid Amiodarone-treated euthyroid patients. /sup 131/I uptake was studied in patients with Amiodarone-associated thyrotoxicosis. The difficulties of the therapy of Amiodarone-induced hyperthyroidism are outlined. Preliminary studied of the effect of Amiodarone and its analogues on the metabolism of thyroid hormones in the rat indicate that Amiodarone may act as a thyroid hormone agonist in the pituitary. (MG).

  10. Cholinergic Manipulations Bidirectionally Regulate Object Memory Destabilization

    Science.gov (United States)

    Stiver, Mikaela L.; Jacklin, Derek L.; Mitchnick, Krista A.; Vicic, Nevena; Carlin, Justine; O'Hara, Matthew; Winters, Boyer D.

    2015-01-01

    Consolidated memories can become destabilized and open to modification upon retrieval. Destabilization is most reliably prompted when novel information is present during memory reactivation. We hypothesized that the neurotransmitter acetylcholine (ACh) plays an important role in novelty-induced memory destabilization because of its established…

  11. Amiodarone-Induced Pulmonary Toxicity – A Frequently Missed Complication

    Science.gov (United States)

    Sweidan, Alexander J.; Singh, Navneet K.; Dang, Natasha; Lam, Vinh; Datta, Jyoti

    2016-01-01

    INTRODUCTION Amiodarone is often used in the suppression of tachyarrhythmias. One of the more serious adverse effects includes amiodarone pulmonary toxicity (APT). Several pulmonary diseases can manifest including interstitial pneumonitis, organizing pneumonia, acute respiratory distress syndrome, diffuse alveolar hemorrhage, pulmonary nodules or masses, and pleural effusion. Incidence of APT varies from 5–15% and is correlated to dosage, age of the patient, and preexisting lung disease. DESCRIPTION A 56-year-old male with a past medical history of coronary artery disease and chronic obstructive pulmonary disease was admitted for a coronary artery bypass graft. Post-operatively, the patient was admitted to the ICU for ventilator management and continued to receive his home dose of amiodarone 400 mg orally twice daily, which he had been taking for the past 3 months. The patient was found to be hypoxemic with a PaO2 52 mmHg and bilateral infiltrates on chest x-ray. Patient also complained of new onset dyspnea. Physical exam found bilateral rhonchi with bibasilar crackles and subcutaneous emphysema along the left anterior chest wall. Daily chest x-rays showed worsening of bilateral interstitial infiltrates and pleural effusions. A chest high-resolution computed tomography on post-operative day 3 showed extensive and severe bilateral ground glass opacities. APT was suspected and amiodarone was discontinued. A course of oral prednisone without antibiotics was initiated, and after one week of treatment the chest film cleared, the PaO2 value normalized and dyspnea resolved. DISCUSSION APT occurs via cytotoxic T cells and indirectly by immunological reaction. Typically the lungs manifest a diffuse interstitial pneumonitis with varying degrees of fibrosis. Infiltrates with a ‘ground-glass’ appearance appreciated on HRCT are more definitive than chest x-ray. Pulmonary nodules can be seen, frequently in the upper lobes. These are postulated to be accumulations of

  12. Dronedarone and Amiodarone Induce Dyslipidemia and Thyroid Dysfunction in Rats

    Directory of Open Access Journals (Sweden)

    Li-Qin Jiang

    2016-05-01

    Full Text Available Background/Aims: Amiodarone, a thyroid hormone-like molecule, can induce dyslipidemia and thyroid dysfunction. However, the effects of dronedarone on lipid metabolism and of both dronedarone and amiodarone on thyroid function and lipid metabolism remain unknown. Methods: Fifty male Sprague-Dawley rats were randomly divided into 5 groups (10 in each group: normal control (NC, amiodarone-treated (AMT, dronedarone-treated (DRT, rats treated with amiodarone combined with polyene phosphatidylcholine (AC, and rats treated with dronedarone combined with polyene phosphatidylcholine (DC. Rats were given amiodarone (120 mg/kg/d, dronedarone (120 mg/kg/d, and polyene phosphatidylcholine (200 mg/kg/d for 13 weeks. At the end of weeks 4, 8, 12, and 13, plasma-free triiodothyronine (FT3, free thyroxine (FT4, triglycerides (TG, total cholesterol (TC, low-density lipoprotein cholesterol (LDL-c, and high-density lipoprotein cholesterol (HDL-c were determined. At the end of this protocol, rats were sacrificed and the thyroid glands were isolated, weighed, and examined histopathologically. The protein expression of Bcl-2 was measured by immunochemical staining. The mRNA expression of thyroglobulin (Tg, type-1 deiodinase (D1, and thyroid peroxidase (TPO were detected by polymerase chain reaction (PCR. Results: Compared with the NC group, FT3 and FT4 levels in the DRT and DC groups significantly increased at week 4 but declined thereafter. The AMT and AC groups had lower FT3 levels but comparable FT4 levels. The levels of TG, LDL-c, and HDL-c in the NC group were lower than those in the other groups whereas the LDL-c/HDL-c ratio was lowest in the AMT group. Bcl-2 expression significantly increased in the DRT group. The mRNA expression of Tg increased whereas the mRNA expression of D1 decreased. Dronedarone induced hyperthyroidism at the early stage and hypothyroidism at the late stage whereas amiodarone only caused hypothyroidism. Conclusion: Both dronedarone and

  13. Herb-drug interaction of Fucus vesiculosus extract and amiodarone in rats: a potential risk for reduced bioavailability of amiodarone in clinical practice.

    Science.gov (United States)

    Rodrigues, Márcio; Alves, Gilberto; Abrantes, João; Falcão, Amílcar

    2013-02-01

    Fucus vesiculosus is a seaweed claimed to be useful for obesity management. Therefore, considering the relationship between obesity and cardiovascular diseases, this work aimed to assess the potential for an herb-drug interaction among a standardized F. vesiculosus extract (GMP certificate) and amiodarone (a narrow therapeutic index drug) in rats. In a first pharmacokinetic study, rats were simultaneously co-administered with a single-dose of F. vesiculosus (575 mg/kg, p.o.) and amiodarone (50 mg/kg, p.o.); in a second study, rats were pre-treated during 14 days with F. vesiculosus (575 mg/kg/day, p.o.) and received amiodarone (50 mg/kg, p.o.) on the 15th day. Rats of the control groups received the corresponding volume of vehicle. After analysis of the pharmacokinetic data it deserves to be highlighted the significant decrease in the peak plasma concentration of amiodarone (55.4%) as well as the reduction of systemic exposure to the parent drug (~30%) following the simultaneous co-administration of F. vesiculosus extract and amiodarone. This paper reports, for the first time, the herb-drug interaction between F. vesiculosus and amiodarone, which determined a considerable decrease on amiodarone bioavailability in rats. Therefore, the therapeutic efficacy of amiodarone may be compromised by the concurrent administration of herbal slimming medicines/dietary supplements containing F. vesiculosus.

  14. Effects of amiodarone on the pharmacokinetics and toxicity of digoxin in laboratory animals.

    Science.gov (United States)

    Staneva-Stoytcheva, D; Kristeva, E

    1992-04-01

    Some pharmacokinetic interactions between digoxin and amiodarone were studied in experiments on rabbits. An increase of digoxin serum levels was established in amiodarone-treated rabbits (amiodarone 30 mg/kg s.c. for five days alone or together with digoxin). The calculated elimination half-life (t 1/2) and the area under the curve (AUC) of digoxin were increased and the digoxin clearance was decreased, being most pronounced in animals receiving amiodarone-digoxin combination for five days. There were no changes either in digoxin toxicity in amiodarone-treated guinea pigs or in serum levels of T4, T3 and TTH. The possible mechanisms of digoxin-amiodarone interactions are discussed.

  15. Antiproliferative, Ultrastructural, and Physiological Effects of Amiodarone on Promastigote and Amastigote Forms of Leishmania amazonensis

    Directory of Open Access Journals (Sweden)

    Sara Teixeira de Macedo-Silva

    2011-01-01

    Full Text Available Amiodarone (AMIO, the most frequently antiarrhythmic drug used for the symptomatic treatment of chronic Chagas' disease patients with cardiac compromise, has recently been shown to have also specific activity against fungi, Trypanosoma cruzi and Leishmania. In this work, we characterized the effects of AMIO on proliferation, mitochondrial physiology, and ultrastructure of Leishmania amazonensis promastigotes and intracellular amastigotes. The IC50 values were 4.21 and 0.46 μM against promastigotes and intracellular amastigotes, respectively, indicating high selectivity for the clinically relevant stage. We also found that treatment with AMIO leads to a collapse of the mitochondrial membrane potential (ΔΨm and to an increase in the production of reactive oxygen species, in a dose-dependent manner. Fluorescence microscopy of cells labeled with JC-1, a marker for mitochondrial energization, and transmission electron microscopy confirmed severe alterations of the mitochondrion, including intense swelling and modification of its membranes. Other ultrastructural alterations included (1 presence of numerous lipid-storage bodies, (2 presence of large autophagosomes containing part of the cytoplasm and membrane profiles, sometimes in close association with the mitochondrion and endoplasmic reticulum, and (3 alterations in the chromatin condensation and plasma membrane integrity. Taken together, our results indicate that AMIO is a potent inhibitor of L. amazonensis growth, acting through irreversible alterations in the mitochondrial structure and function, which lead to cell death by necrosis, apoptosis and/or autophagy.

  16. [Intravenous amiodarone in the therapy of paroxysmal supraventricular tachycardias].

    Science.gov (United States)

    Storelli, A; Andriulo, C; Chisena, A; De Giorgi, M; De Giorgio, N A; Gallone, V; Guadalupi, M; Lupis, O; Nadovezza, S; Tarentini, A

    1985-03-01

    The Authors evaluated the effectiveness and the tolerance of intravenous Amiodarone in 50 cases of recent onset paroxysmal supraventricular tachyarrhythmias. Fifty consecutive patients, aged 17 to 84 (mean 52 years), presenting with paroxysmal supraventricular tachycardia (PSVT, 33 cases) or atrial flutter (11 cases) or atrial fibrillation (6 cases), were given 300 mg of Amiodarone intravenously within 2 min, followed in 4 patients by 150 mg after 15 min. All patients were monitored for 1 hour; ECG and blood pressure were recorded at fixed times. Within 15 min sinus rhythm was restored in 88% of PSVT, in 27% of atrial flutter and in 17% of atrial fibrillation cases; the other cases of atrial flutter and fibrillation always showed a 48-81% reduction of the average heart rate within 15 min. We have evidenced neither significant modifications of blood pressure and ECG parameters (P-Q, QRS and Q-T duration) nor particular side effects, except for 2 cases in which brief hot flushes were reported. The Authors believe Amiodarone to be an effective and well tolerated drug for the above mentioned arrhythmias, particularly promptly acting in PSVT cases, in whom sinus rhythm was restored within 15 min in 88% and within 1 hour in 100% of the cases.

  17. Treatment of Amiodarone-Induced Thyrotoxicosis Type 2 : A Randomized Clinical Trial

    NARCIS (Netherlands)

    Eskes, Silvia A.; Endert, Erik; Fliers, Eric; Geskus, Ronald B.; Dullaart, Robin P. F.; Links, Thera P.; Wiersinga, Wilmar M.

    2012-01-01

    Context: Amiodarone-induced thyrotoxicosis (AIT) type 2 is self-limiting in nature, but most physicians are reluctant to continue amiodarone. When prednisone fails to restore euthyroidism, possibly due to mixed cases of AIT type 1 and 2, perchlorate (ClO4) might be useful because ClO4 reduces the cy

  18. Interactions of amiodarone with model membranes and amiodarone-photoinduced peroxidation of lipids.

    Science.gov (United States)

    Sautereau, A M; Tournaire, C; Suares, M; Tocanne, J F; Paillous, N

    1992-06-23

    The potent antiarrhythmic drug, amiodarone (AMIO) exhibits phototoxicity, which is thought to be related to its interaction with biological membranes. We report here a spectroscopic study of the interactions of this drug with phosphatidylglycerol (PG) and phosphatidylcholine (PC) liposomes used as membrane model systems. A linear increase in absorbance at 300 nm was observed with increasing addition of AMIO to dimyristoyl-DL-PC (DMPC) liposomes over all the drugs-lipid molar ratio (Ri)s tested. In contrast, in the dimyristoyl-DL-PG (DMPG) liposomes, there was a dramatic increase in absorbance at values of Ri above unity. Light scattering by DMPG liposomes at 350 nm increased with increasing AMIO concentration up to a Ri = 1, and then decreased with increasing drug concentration. Such changes were not observed with the DMPC liposomes. Moreover, addition of AMIO changed the fluorescence polarization rate of 1,6-diphenyl 1,3,5-hexatriene embedded in these liposomes. It reduced the rate below the phase transition temperature (Tt) of the lipid, but increased it above this temperature. These effects on the lipidic phases observed at low Ri were more pronounced on the DMPG than on the DMPC liposomes. The strong interactions of AMIO with phospholipids, especially the acidic ones, were confirmed by liposome size determinations. All these data strongly suggest that the drug was incorporated in the core of the lipid bilayers. Such a penetration would favor a drug-photoinduced peroxidation of lipids. Indeed, UV irradiation of AMIO-DOPG mixtures led to the disappearance of the unsaturated fatty acids of phospholipids, checked by gas chromatography measurements, which was correlated with the amount of oxygen consumed. This showed that AMIO did photosensitize phospholipid peroxidation.

  19. Effect of amiodarone therapy on mortality in patients with left ventricular dysfunction and asymptomatic complex ventricular arrhythmias: Argentine Pilot Study of Sudden Death and Amiodarone (EPAMSA).

    Science.gov (United States)

    Garguichevich, J J; Ramos, J L; Gambarte, A; Gentile, A; Hauad, S; Scapin, O; Sirena, J; Tibaldi, M; Toplikar, J

    1995-09-01

    The efficiency of prophylactic antiarrhythmic treatment with amiodarone in reducing 1-year mortality in patients with reduced left ventricular ejection fraction ( < 35%) and asymptomatic ventricular arrhythmias (Lown classes 2 and 4) was investigated in a prospective, multicenter, randomized, controlled study. Among 127 patients who entered the study, 61 were assigned to no antiarrhythmic therapy (control group [CG] and 66 to amiodarone treatment (amiodarone group [AG]). Amiodarone was administered at a dosage of 800 mg/day for 2 weeks followed by 400 mg/day thereafter. A 12-month follow-up was completed for 106 patients (57 in the AG and 49 in the CG). Amiodarone reduced the overall mortality rate, which was 10.5% in the AG versus 28.6% in the CG (odds ratio [OR] 0.29; 95% confidence interval [CI] 0.10 to 0.84; log-rank test 0.02) and sudden death rate, which was 7.0% in the AG versus 20.4% in the CG (OR 0.29; 95% CI 0.08 to 1.00; log-rank test 0.04). Side effects were rare, and in only three patients did amiodarone treatment have to be discontinued.

  20. Amiodarone and metabolite MDEA inhibit Ebola virus infection by interfering with the viral entry process.

    Science.gov (United States)

    Salata, Cristiano; Baritussio, Aldo; Munegato, Denis; Calistri, Arianna; Ha, Huy Riem; Bigler, Laurent; Fabris, Fabrizio; Parolin, Cristina; Palù, Giorgio; Mirazimi, Ali

    2015-07-01

    Ebola virus disease (EVD) is one of the most lethal transmissible infections characterized by a high fatality rate, and a treatment has not been developed yet. Recently, it has been shown that cationic amphiphiles, among them the antiarrhythmic drug amiodarone, inhibit filovirus infection. In the present work, we investigated how amiodarone interferes with Ebola virus infection. Wild-type Sudan ebolavirus and recombinant vesicular stomatitis virus, pseudotyped with the Zaire ebolavirus glycoprotein, were used to gain further insight into the ability of amiodarone to affect Ebola virus infection. We show that amiodarone decreases Ebola virus infection at concentrations close to those found in the sera of patients treated for arrhythmias. The drug acts by interfering with the fusion of the viral envelope with the endosomal membrane. We also show that MDEA, the main amiodarone metabolite, contributes to the antiviral activity. Finally, studies with amiodarone analogues indicate that the antiviral activity is correlated with drug ability to accumulate into and interfere with the endocytic pathway. Considering that it is well tolerated, especially in the acute setting, amiodarone appears to deserve consideration for clinical use in EVD.

  1. Dantrolene versus amiodarone for cardiopulmonary resuscitation: a randomized, double-blinded experimental study

    Science.gov (United States)

    Wiesmann, Thomas; Freitag, Dennik; Dersch, Wolfgang; Eschbach, Daphne; Irqsusi, Marc; Steinfeldt, Thorsten; Wulf, Hinnerk; Feldmann, Carsten

    2017-01-01

    Dantrolene was introduced for treatment of malignant hyperthermia. It also has antiarrhythmic properties and may thus be an alternative to amiodarone for the treatment of ventricular fibrillation (VF). Aim of this study was to compare the return of spontaneous circulation (ROSC) with dantrolene and amiodarone in a pig model of cardiac arrest. VF was induced in anesthetized pigs. After 8 min of untreated VF, chest compressions and ventilation were started and one of the drugs (amiodarone 5 mg kg−1, dantrolene 2.5 mg kg−1 or saline) was applied. After 4 min of initial CPR, defibrillation was attempted. ROSC rates, hemodynamics and cerebral perfusion measurements were measured. Initial ROSC rates were 7 of 14 animals in the dantrolene group vs. 5 of 14 for amiodarone, and 3 of 10 for saline). ROSC persisted for the 120 min follow-up in 6 animals in the dantrolene group, 4 after amiodarone and 2 in the saline group (n.s.). Hemodynamics were comparable in both dantrolene group amiodarone group after obtaining ROSC. Dantrolene and amiodarone had similar outcomes in our model of prolonged cardiac arrest, However, hemodynamic stability was not significantly improved using dantrolene. Dantrolene might be an alternative drug for resuscitation and should be further investigated. PMID:28098197

  2. Effects of Combination Therapy of Amiodarone and Bisoprolol in Patients With Paroxysmal Atrial Fibrillation

    Institute of Scientific and Technical Information of China (English)

    Rong-qiang YAN; Fang-sheng ZHENG; Qing-hai ZHANG

    2009-01-01

    Objectives To examine the long-term efficacy of combination therapy of amiodarone and bisoprolol in patients with paroxysmal atrial fibrillation (P-AF). Methods Eighty-eight patients with P-AF were divided into two groups: 44 pa-tients treated with bisoprolol and amiodarone were enrolled in group A; 44 patients treated with amiodarone alone were enrolled in group B. Survival rates, rates of conversing to permanent atrial fibrillation (AF), subjective symptom im-provement rates and secondary bradyarrhythmia rates of the two groups were measured and analyzed. Results At 12 and 24 months, the survival rates for patients free from atrial fibrillation recurrence were 75 % and 59. 1% in group A, and 54.5 % and 36.4 % in group B (P0.05, group A vs. Group B). Conclusions In patients with P-AF, bisoprolol appears to enhance the efficacy of amiodarone therapy in maintaining sinus rhythm and improving subjective symptoms.

  3. Effects of amiodarone and thoracic epidural analgesia on atrial fibrillation after coronary artery bypass grafting

    DEFF Research Database (Denmark)

    Nygård, Eigil; Sørensen, Lars H; Hviid, Lamia B;

    2004-01-01

    OBJECTIVE: This study was designed to assess the effects of a perioperative dosing regimen of amiodarone administration, high thoracic epidural anesthesia (TEA), or a combination of the 2 regimens on atrial fibrillation (AF) after coronary artery bypass grafting (CABG). DESIGN AND SETTING......: The study was prospective, controlled, and randomized and was performed in a tertiary health care center associated with a university. PARTICIPANTS: One hundred sixty-three patients scheduled for coronary artery bypass graft surgery. INTERVENTIONS: In this 2 x 2 factorial-designed study the patients were...... randomized to 1 of 4 regimens in which group E had perioperative TEA, group E+A had TEA and amiodarone, group A had amiodarone, and group C served as control. The epidural catheter was inserted at T1-3 the day before surgery. TEA groups received TEA for 96 hours. The amiodarone regimen consisted of a single...

  4. Acute Amiodarone Pulmonary Toxicity after Drug Holiday: A Case Report and Review of the Literature

    Directory of Open Access Journals (Sweden)

    Ahmed Abuzaid

    2015-01-01

    Full Text Available Amiodarone is reported to cause a wide continuum of serious clinical effects. It is often challenging to detect Amiodarone-induced pulmonary toxicity (AIPT. Typically, the diagnosis is made based on the clinical settings and may be supported by histopathology results, if available. We describe a 57-year-old patient who developed severe rapidly progressive respiratory failure secondary to AIPT with acute bilateral infiltrates and nodular opacities on chest imaging. Interestingly, Amiodarone was discontinued 3 weeks prior to his presentation. He had normal cardiac filling pressures confirmed by echocardiography. To our knowledge, this is the first case of isolated acute lung injury induced by Amiodarone, three weeks after therapy cessation, with adequate clinical improvement after supportive management and high dose steroid therapy.

  5. Ameliorative effect of grapefruit juice on amiodarone-induced cytogenetic and testicular damage in albino rats

    Institute of Scientific and Technical Information of China (English)

    Saber Abdelruhman Sakr; Mohamed El-said Zoil; Samraa Samy El-shafey

    2013-01-01

    Objective:To evaluate the ameliorative role of grapefruit juice on the cytogenetic and testicular damage induced by the antiarrythmic drug amiodarone in albino rats. Methods: Animals were divided into four groups. Group I was considered as control. Group II was given grapefruit juice at a dose level of 27 mL/kg body weight. Group III was orally administered amiodarone (18 mg/kg body weight) daily for 5 weeks. Animals were sacrificed after 5 weeks of treatment. Bone marrow was collected from the femurs for analysis of chromosomal aberrations and mitotic indices. Testes were removed and stained with H&E for histological examination. Sperms were collected from epidedymis for detection of sperm head abnormalities. Comet assay was used to detect DNA damage. Results: Amiodarone treatment caused a significant increase in the percentage of chromosomal aberrations, decreased the mitotic index and increased DNA damage. The testis showed many histopathological alterations, inhibition of spermatogenesis and morphometric changes. The number of sperm head abnormalities was increased. Treating animals with amiodarone and grapefruit juice caused a reduction in chromosomal aberrations, mitotic index, DNA damage and testicular alterations caused by amiodarone. Conclusions:The results of this study indicated that grapefruit juice ameliorates the cytotoxicty and testicular alterations induced by amiodarone in albino rats and this is may be due to the potent antioxidant effects of its components.

  6. Acute lung affection in an endurance-trained man under amiodarone medication

    Directory of Open Access Journals (Sweden)

    Saurbier, Bernward

    2005-06-01

    Full Text Available Patients undergoing treatment with amiodarone can develop severe pulmonary side effects. This effect, which is often highly underestimated, can lead to dyspnea, pneumonitis, and further fibrosis. A recent change in the labeling of amdiodarone by the American Food and Drug Administration (FDA supports this suspicion. Tracing the symptoms back to the causing agent can be difficult, as shown in our report. The subject of this case report is an endurance-trained 65 year old male marathon runner who appeared with atrial fibrillation during a routine check up in autumn 2003. After medical cardioversion with flecainide a complaint free interval of 8 months was followed by a relapse, which resulted in a change of medication to amiodarone. Due to misunderstandings the patient kept on taking the amiodarone loading dose for six weeks and returned with severe dyspnea on exertion. Losses in CO diffusing capacity, a lowered macrophages count and a positive lymphocyte transformation test were the only first hand clinical evidence of amiodarone intoxication, despite the sensation of dyspnea. This case shows that special care has to be taken in treatment with amiodarone. Side effects can be hard to trace and do not evidently show a clear connection to amiodarone.

  7. Herb-Drug Interaction of Paullinia cupana (Guarana) Seed Extract on the Pharmacokinetics of Amiodarone in Rats

    Science.gov (United States)

    Rodrigues, Márcio; Alves, Gilberto; Lourenço, Nulita; Falcão, Amílcar

    2012-01-01

    Paullinia cupana is used in weight-loss programs as a constituent of medicinal/dietary supplements. This study aimed to assess a potential herb-drug interaction among a standardized (certified) Paullinia cupana extract and amiodarone (narrow therapeutic index drug) in rats. In a first pharmacokinetic study rats were simultaneously coadministered with a single dose of Paullinia cupana (821 mg/kg, p.o.) and amiodarone (50 mg/kg, p.o.), and in a second study rats were pretreated during 14 days with Paullinia cupana (821 mg/kg/day, p.o.) receiving amiodarone (50 mg/kg, p.o.) on the 15th day. Rats of the control groups received the corresponding volume of vehicle. Blood samples were collected at several time points after amiodarone dosing, and several tissues were harvested at the end of the experiments (24 h after dose). Plasma and tissue concentrations of amiodarone and its major metabolite (mono-N-desethylamiodarone) were measured and analysed. A significant reduction in the peak plasma concentration (73.2%) and in the extent of systemic exposure (57.8%) to amiodarone was found in rats simultaneously treated with Paullinia cupana and amiodarone; a decrease in tissue concentrations was also observed. This paper reports for the first time an herb-drug interaction between Paullinia cupana extract and amiodarone, which determined a great decrease on amiodarone bioavailability in rats. PMID:23304200

  8. Herb-Drug Interaction of Paullinia cupana (Guarana Seed Extract on the Pharmacokinetics of Amiodarone in Rats

    Directory of Open Access Journals (Sweden)

    Márcio Rodrigues

    2012-01-01

    Full Text Available Paullinia cupana is used in weight-loss programs as a constituent of medicinal/dietary supplements. This study aimed to assess a potential herb-drug interaction among a standardized (certified Paullinia cupana extract and amiodarone (narrow therapeutic index drug in rats. In a first pharmacokinetic study rats were simultaneously coadministered with a single dose of Paullinia cupana (821 mg/kg, p.o. and amiodarone (50 mg/kg, p.o., and in a second study rats were pretreated during 14 days with Paullinia cupana (821 mg/kg/day, p.o. receiving amiodarone (50 mg/kg, p.o. on the 15th day. Rats of the control groups received the corresponding volume of vehicle. Blood samples were collected at several time points after amiodarone dosing, and several tissues were harvested at the end of the experiments (24 h after dose. Plasma and tissue concentrations of amiodarone and its major metabolite (mono-N-desethylamiodarone were measured and analysed. A significant reduction in the peak plasma concentration (73.2% and in the extent of systemic exposure (57.8% to amiodarone was found in rats simultaneously treated with Paullinia cupana and amiodarone; a decrease in tissue concentrations was also observed. This paper reports for the first time an herb-drug interaction between Paullinia cupana extract and amiodarone, which determined a great decrease on amiodarone bioavailability in rats.

  9. Revisiting the flocculation kinetics of destabilized asphaltenes.

    Science.gov (United States)

    Vilas Bôas Fávero, Cláudio; Maqbool, Tabish; Hoepfner, Michael; Haji-Akbari, Nasim; Fogler, H Scott

    2016-07-07

    A comprehensive review of the recently published work on asphaltene destabilization and flocculation kinetics is presented. Four different experimental techniques were used to study asphaltenes undergoing flocculation process in crude oils and model oils. The asphaltenes were destabilized by different n-alkanes and a geometric population balance with the Smoluchowski collision kernel was used to model the asphaltene aggregation process. Additionally, by postulating a relation between the aggregation collision efficiency and the solubility parameter of asphaltenes and the solution, a unified model of asphaltene aggregation model was developed. When the aggregation model is applied to the experimental data obtained from several different crude oil and model oils, the detection time curves collapsed onto a universal single line, indicating that the model successfully captures the underlying physics of the observed process.

  10. Destabilization of free convection by weak rotation

    CERN Document Server

    Gelfgat, Alexander

    2011-01-01

    This study offers an explanation of a recently observed effect of destabilization of free convective flows by weak rotation. After studying several models where flows are driven by a simultaneous action of convection and rotation, it is concluded that the destabilization is observed in the cases where centrifugal force acts against main convective circulation. At relatively low Prandtl numbers this counter action can split the main vortex into two counter rotating vortices, where the interaction leads to instability. At larger Prandtl numbers, the counter action of the centrifugal force steepens an unstable thermal stratification, which triggers Rayleigh-B\\'enard instability mechanism. Both cases can be enhanced by advection of azimuthal velocity disturbances towards the axis, where they grow and excite perturbations of the radial velocity. The effect was studied considering a combined convective/rotating flow in a cylinder with a rotating lid and a parabolic temperature profile at the sidewall. Next, explana...

  11. The Characteristics of Amiodarone-induced Thyrotoxicosis in a Moderate Iodine Deficit Area

    Directory of Open Access Journals (Sweden)

    Ancuța-Elena Cota

    2013-08-01

    Full Text Available Introduction: Amiodarone (AMI, a class III anti-arrhythmic drug, is associated with a number of side effects, including thyroid dysfunction (both hypo- and hyperthyroidism, which is due to amiodarone's high iodine content and its direct toxic effect on the thyroid. Objective: To evaluate the incidence of Amiodarone induced thyrotoxicosis (AIT (type, rate of occurrence and to identify the risk factors involved in its occurrence. Material and method: We examined patients treated with amiodarone, between January 2002 and December 2011, who presented to our Department of Endocrinology Târgu Mures for thyroid dysfunctions. Results: The retrospective study included 87 patients with thyroid dysfunctions; 58 (66.7% patients had AIT and 29 (33.3% had Amiodarone induced hypothyroidism (AIH. In the AIT group: 35 were women (60.3%, 23 were men (39.7%; the average age was 61.60 ± 12.39 years. Risk factors identified for the AIT group were male gender (RR = OR = 3.8; Chi-squer = 5.7, p = 0.004 and pre-existing thyroid abnormalities (RR = 2.5, Chi-square = 4.1, p = 0.005. The thyroid dysfunction occurrence was heterogeneous (0.2-183 months. The patients with previous thyroid abnormalities developed earlier thyroid dysfunction compared to those with an apparently normal thyroid gland (22.25 ± 4.14 months versus 32.09 ± 7.69 months, p = 0.02, T test. Conclusion: In the context of the specific iodine geoclimatic intake and the area of origin, amiodarone - induced thyroid dysfunction spectrum is dominated by thyrotoxicosis. Screening and monitoring of thyroid function for patiens under chronic amiodarone treatment is necessary

  12. Comparative efficacy of amiodarone with ivabradin combination or amiodarone with bisoprolol combination in the prevention of atrial fibrillation recurrence in pa- tients with left ventricular diastolic dysfunction

    Directory of Open Access Journals (Sweden)

    K. G. Adamyan

    2015-11-01

    Full Text Available Aim. To study the efficacy of use of amiodarone with ivabradine combination or amiodarone with bisoprolol combination in the prevention of atrial fibrillation (AF recurrence in patients (pts with left ventricular diastolic dysfunction (LVDD after conversion to sinus rhythm. Material and methods. 65 patients (40 males, 25 females aged 53±8 years with persistent AF and LVDD were included into the study and randomized into 3 groups to receive ivabradine and amiodarone (22 pts, bisoprolol and amiodarone (22 pts or amiodarone alone (21 pts. Left atrium (LA volume indices, LA longitudinal strain rate (LASR in systole, LV mass index, mean heart rate (HR, 24-hour HR variability and the incidence of AF by 96 h ECG monitoring were measured after the titration period, and after 3 and 6 months of follow-up. Results. After 6 months of follow-up group 1 revealed significantly lower maximum LA volume index (21.3±2.4 vs 25.2±3.0 and 28.7±3.6 ml/m2 in the 2nd and control groups, respectively, P-wave LA volume index (15.3±3.5 versus 18.1±3.8 and 20.4±4.0 ml/m2 in the 2nd and control groups, respectively, and LA systolic volume index (7.3±1.2 versus 9.4±1.6 and 9.6±1.7 ml/m2 in 2nd and control groups, respectively. The incidence of side effects in group 1 was significantly less than that in group 2 and was not different compared with control group. Conclusion. Ivabradine and amiodarone combination provides better prevention of AF recurrence and less side-effects in pts with LVDD and persistent AF after sinus rhythm restoration as compared with bisoprolol and amiodarone combination, it also reduces LA maximum, conduit and systolic volumes, and increases LASR.

  13. Comparative efficacy of amiodarone with ivabradin combination or amiodarone with bisoprolol combination in the prevention of atrial fibrillation recurrence in pa- tients with left ventricular diastolic dysfunction

    Directory of Open Access Journals (Sweden)

    K. G. Adamyan

    2015-01-01

    Full Text Available Aim. To study the efficacy of use of amiodarone with ivabradine combination or amiodarone with bisoprolol combination in the prevention of atrial fibrillation (AF recurrence in patients (pts with left ventricular diastolic dysfunction (LVDD after conversion to sinus rhythm. Material and methods. 65 patients (40 males, 25 females aged 53±8 years with persistent AF and LVDD were included into the study and randomized into 3 groups to receive ivabradine and amiodarone (22 pts, bisoprolol and amiodarone (22 pts or amiodarone alone (21 pts. Left atrium (LA volume indices, LA longitudinal strain rate (LASR in systole, LV mass index, mean heart rate (HR, 24-hour HR variability and the incidence of AF by 96 h ECG monitoring were measured after the titration period, and after 3 and 6 months of follow-up. Results. After 6 months of follow-up group 1 revealed significantly lower maximum LA volume index (21.3±2.4 vs 25.2±3.0 and 28.7±3.6 ml/m2 in the 2nd and control groups, respectively, P-wave LA volume index (15.3±3.5 versus 18.1±3.8 and 20.4±4.0 ml/m2 in the 2nd and control groups, respectively, and LA systolic volume index (7.3±1.2 versus 9.4±1.6 and 9.6±1.7 ml/m2 in 2nd and control groups, respectively. The incidence of side effects in group 1 was significantly less than that in group 2 and was not different compared with control group. Conclusion. Ivabradine and amiodarone combination provides better prevention of AF recurrence and less side-effects in pts with LVDD and persistent AF after sinus rhythm restoration as compared with bisoprolol and amiodarone combination, it also reduces LA maximum, conduit and systolic volumes, and increases LASR.

  14. SEVERE AMIODARONE-INDUCED BRADICARDIA CONCEALES SICK SINUS SYNDROME: CASE REPORT.

    Science.gov (United States)

    Crăcană, Irina; Vasilcu, T F; Mardare, Alexandra; Alexa, Ioana Dana; Marcu, D T M

    2016-01-01

    Sinus node dysfunction is one of the most common arrhythmias in elderly patients; it is usually associated with intermittent and variable symptoms, thus making it difficult to diagnose. We present the case of an elderly female patient with a personal history of atrial fibrillation treated for the last three years with amiodarone; she was admitted to the Geriatric Clinic for non-specific symptoms with onset two months previously for which she had already sought care in different medical services. Clinical examination showed severe bradycardia; ECG and Holter ECG on admission confirmed severe bradycardia, with a heart rate between 29 and 50 beats/min (bpm). Given her long-term treatment with amiodarone we looked for and found hyperthyroidism; the endocrine examination led to the diagnosis of mixed type Amiodarone-induced thyrotoxicosis and initiation of corticosteroid and antithyroid treatment. The evolution of cardiac arrhythmia was monitored with the help of several Holter ECGs performed after amiodarone washout and return to the euthyroid state, which revealed a tachycardia-bradycardia syndrome initially masked by the side effects of the unsupervised therapy with amiodarone, and properly treated by the implantation of a pacemaker.

  15. AMIODARONE INDUCES THE SYNTHESIS OF HSPS IN SACCHAROMYCES CEREVISIAE AND ARABIDOPSIS THALIANA CELLS

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    Pyatrikas D.V.

    2012-08-01

    Full Text Available Many biotic and abiotic stresses cause an increase of cytosolic Ca2+ level in cells. Calcium is one of the most important second messengers, regulating many various activities in the cell and was known to affect expression of stress activated genes. Mild heat shock induces the expression of heat shock proteins (Hsps which protect cell from drastic heat shock exposure. There are some literature data permitting to suggest that transient elevation of cytosolic Ca2+ level in plant cells is important for activation of Hsps expression. On the other hand mitochondria are known to regulate the intracellular calcium and reactive oxygen species signaling. It has been shown recently that mild heat shock induces hyperpolarization of inner mitochondrial membrane in plant and yeast cells and this event is critically important for activation of Hsps expression. To reveal the relationship between mitochondrial activity, intracellular calcium homeostasis and Hsps expression an antiarrhythmic drug amiodarone (AMD have been used. AMD is known to cause transient increase of cytosolic Ca2+ level in Saccharomyces cerevisiae. Obtained results have showed that AMD treatment induced the synthesis of Hsp104p in S. cerevisiae cells and Hsp101p in A. thaliana cell culture. Induction of Hsp104p synthesis leads to enhanced yeast capability to survive lethal heat shock exposure. Development of S. cerevisiae thermotolerance depended significantly on the presence of Hsp104p. Elevation of Hsp104p level in the result of AMD treatment was shown to be governed by activity of Msn2p and Msn4p transcription factors. Deletion of the MSN2 and MSN4 genes abrogated the AMD ability to induce Hsp104p synthesis. Mild heat shock and AMD treatment induced the hyperpolarization of the inner mitochondrial membrane in yeast and Arabidopsis cells which accompanied by HSP synthesis and development of thermotolerance. It was suggested that increase of cytosolic Ca2+ level after AMD treatment

  16. [Population pressure: a factor of political destabilization].

    Science.gov (United States)

    Tallon, F

    1993-04-01

    Political stability throughout the world appears to be greater in countries with slowly growing populations than in those with rapid growth. Population is not the only influence on political stability, however. The relationship between political stability and development is strong. The rich countries with the slowest growth are the most stable, while poor developing countries with rapid growth suffer from chronic instability. Demographic pressure and density are not the same thing and must be distinguished. A fragile environment like that of the Sahel will experience demographic pressure despite low density. Japan has a greater population density than Rwanda and little cultivable land, but the population has a high standard of living. demographic pressure is not comparable in Japan and Rwanda because Japan has slow population growth and stable democratic political institutions. The rate of growth seems to be a more important element in destabilization than density. Rapid growth creates enormous political tensions especially when profound ethnic divisions exist, and it complicates problems of government by encouraging rapid urbanization. The unbalanced age structures resulting from rapid growth hinder the satisfaction of employment, educational, and health care needs for the ever-increasing masses of young people. 49% of Rwanda's population is under 15 and 66% is under 25. Rwanda is already densely populated, with around 300 inhabitants/sq km, and its population is projected to double in 20 years. 95% of the population is dependent on agriculture, but by 1988 the average landholding per family was only 1.25 hectares and 58% of families did not grown sufficient food for household needs. Further reduction in the size of holdings or a growing landless population will have multiple consequences. Urban migration will inevitably increase, bringing with it all the problems so evident in other poor countries where the process is more advanced than in Rwanda. Chaotic

  17. Hyperacute drug-induced hepatitis with intravenous amiodarone: case report and review of the literature.

    Science.gov (United States)

    Nasser, Mohammad; Larsen, Timothy R; Waanbah, Barryton; Sidiqi, Ibrahim; McCullough, Peter A

    2013-01-01

    Amiodarone is a benzofuran class III antiarrhythmic drug used to treat a wide spectrum of ventricular tachyarrhythmias. The parenteral formulation is prepared in polysorbate 80 diluent. We report an unusual case of acute elevation of aminotransaminase concentrations after the initiation of intravenous amiodarone. An 88-year-old Caucasian female developed acute hepatitis and renal failure after initiating intravenous amiodarone for atrial fibrillation with a rapid ventricular response in the setting of acutely decompensated heart failure and hepatic congestion. Liver transaminases returned to baseline within 7 days after discontinuing the drug. Researchers hypothesized that this type of injury is related to liver ischemia with possible superimposed direct drug toxicity. The CIOMS/RUCAM scale identifies our patient's acute hepatitis as a highly probable adverse drug reaction. Future research is needed to understand the mechanisms by which hyperacute drug toxicity occurs in the setting of impaired hepatic perfusion and venous congestion.

  18. Development and X-ray morphology of amiodarone pneumopathy. Die Entwicklung und Roentgenmorphologie der Amiodaronpneumopathie

    Energy Technology Data Exchange (ETDEWEB)

    Billmann, P. (Kreiskrankenhaus Lahr (Germany, F.R.). Radiologisches Inst.); Fleischmann, D. (Kreiskrankenhaus Lahr (Germany, F.R.). Kardiologische Klinik); Baumeister, L. (Sankt-Josefs-Krankenhaus, Offenburg am Main (Germany, F.R.). Radiologische Abt.)

    1991-04-01

    Besides general extracardiac physical side effects, the antiarrhythmic amiodarone hydrochloride gives rise to morphologically manifest organ changes. Pneumopathy has been reported in up to 8% of the patients treated with this preparation. Radiologically and histologically, the clinical picture can resemble that of exogenous allergic alveolitis. When the course is protracted there is interstitial fibrotic degeneration of the pulmonary parenchyma with a corresponding morphological correlate in the X-ray. The extent to which the changes observed result from dose-dependent toxicity of amiodarone has not been completely elucidated even now, since pulmonary changes suggestive of an immune process can occur even at low doses. When there is reason suspect the presence of amiodarone pneumopathy, the preparation should be discontinued. Radiological and clinical findings generally regress with cortisone treatment. (orig.).

  19. Acutely Onset Amiodarone-Induced Angioedema in a Patient with New Atrial Fibrillation

    Directory of Open Access Journals (Sweden)

    Hossein Vakili

    2014-01-01

    Full Text Available A 50-year-old man was admitted to our emergency department due to new episode of palpitation. He had history of angioplasty of right coronary artery (RCA with drug eluting stent 2 years ago. His electrocardiogram revealed atrial fibrillation (AF. Intravenous amiodarone 150 mg during 10 minutes and then 1 mg/min infusion were started to achieve rate control and pharmacologic conversion to sinus rhythm. After 60 minutes of starting amiodarone infusion, he developed swelling of the skin around his mouth and eyes, and also mucosa of the mouth, eyes and tongue. To conclude, angioedema should be considered a rare side effect of amiodarone which is used broadly in cardiovascular field.

  20. Drug-induced lupus: simvastatin or amiodarone? A case report in elderly

    Directory of Open Access Journals (Sweden)

    Mauro Turrin

    2013-03-01

    Full Text Available Reports of systemic lupus erythematosus (SLE seen during treatment with amiodarone are rare in the literature. SLE or immunological abnormalities induced by treatment with statins are more frequent. In this issue we report a case of a 81-year-old male who, after a 2-year therapy with amiodarone, developed a clinical and serologic picture of drug-induced SLE (DILE. He was admitted for congestive heart failure in mechanical aortic valve prosthesis, permanent atrial fibrillation (anticoagulation with warfarin, hypercholesterolaemia, and hypothyroidism. Amiodarone was started two years earlier for polymorphic ventricular tachycardia, statin and L-thyroxine the following year. At admission he presented pleuro-pericardical effusion detected by CT-scan (also indicative of interstitial lung involvement and echocardiography. Serological main indicative findings were: elevation of inflammatory markers, ANA (Anti-Nuclear Antibodies titers = 1:320 (indirect immune-fluorescence – IIF – assay on HEp-2, homogeneous/fine speckled pattern, anti-dsDNA titers = 1:80 (IIF on Crithidia luciliae, negative ENA (Extractable Nuclear Antigens and antibodies anti-citrulline, rheumatoid factor = 253 KU/l, normal C3-C4, negative HbsAg and anti-HCV, negative anticardiolipin antibodies IgG and IgM, negative anti-beta2GPI IgG and IgM. Amiodarone was discontinued and methylprednisolone was started, since the patient was severely ill. At discharge, after a month, the patient was better and pleuro-pericardical effusion was reduced. Readmitted few weeks later for bradyarithmia and worsening of dyspnoea, pericardial effusion was further reduced but he died for refractory congestive heart failure and pneumonia. Clinical picture (sierositis, neither skin nor kidney involvement, other typical side effects of amiodarone (hypothyroidism and lung interstitial pathology and serological findings are suggestive of amiodarone-induced SLE.

  1. Rhythminotropic Reactions of Human Myocardium in Ischemic and Rheumatic Heart Diseases against the Background of Amiodarone

    Directory of Open Access Journals (Sweden)

    Boris N. Kozlov, PhD, ScD

    2012-03-01

    Full Text Available In human heart failure, Ca2+ homeostasis gets disturbed due to a decrease in the function of the sarcoplasmic reticulum (SR. We studied the differences in the SR function in patients with rheumatic and coronary heart disease, against the background of amiodarone. Cardiac preparations from the atrium of 21 patients with coronary artery disease (CAD and 14 patients with rheumatic heart disease (RHD were used in this study. Myocardial strips perfused with oxygenated Krebs-Henzelait solution without and with amiodarone (1 mM/l at 37°C. The steady state stimulation rate of the muscle strips was 0.5 Hz. The single extraordinary impulse was given as 0.2-1.5 sec after the steady state beat. Then, the first beat after a 4- to 60-sec rest period was evaluated. The extrasystoles of the myocardium in both groups, after long intervals, were decreased after amiodarone treatment. The amplitude of post extrasystoles of amiodarone-treated myocardium showed differences only after long intervals in both groups. Two types of inotropic responses of a failing myocardium after rest periods were observed. Type I post-rest contractions maintained the steady state amplitude after all rests. However, type II was characterized by a reduction in the amplitude of the contractions. Amiodarone treatment of the myocardium showing type I reactions led to an increase in the potentiation after rests, but showed no effect on the reaction of the muscle with the type II response. The results suggested that SR dysfunction was different in CAD and RHD. The realization of the therapeutic effect of amiodarone was found to be dependent on the functional activity of the SR.

  2. In vitro kinetics of amiodarone and its major metabolite in two human liver cell models after acute and repeated treatments.

    Science.gov (United States)

    Pomponio, Giuliana; Savary, Camille C; Parmentier, Céline; Bois, Frederic; Guillouzo, André; Romanelli, Luca; Richert, Lysiane; Di Consiglio, Emma; Testai, Emanuela

    2015-12-25

    The limited value of in vitro toxicity data for the in vivo extrapolation has been often attributed to the lack of kinetic data. Here the in vitro kinetics of amiodarone (AMI) and its mono-N-desethyl (MDEA) metabolite was determined and modelled in primary human hepatocytes (PHH) and HepaRG cells, after single and repeated administration of clinically relevant concentrations. AMI bioavailability was influenced by adsorption to the plastic and the presence of protein in the medium (e.g. 10% serum protein reduced the uptake by half in HepaRG cells). The cell uptake was quick (within 3h), AMI metabolism was efficient and a dynamic equilibrium was reached in about a week after multiple dosing. In HepaRG cells the metabolic clearance was higher than in PHH and increased over time, as well as CYP3A4. The interindividual variability in MDEA production in PHHs was not proportional to the differences in CYP3A4 activities, suggesting the involvement of other CYPs and/or AMI-related CYP inhibition. After repeated treatment AMI showed a slight potential for bioaccumulation, whereas much higher intracellular MDEA levels accumulated over time, especially in the HepaRG cells, associated with occurrence of phospholipidosis. The knowledge of in vitro biokinetics is important to transform an actual in vitro concentration-effect into an in vivo dose-effect relationship by using appropriate modelling, thus improving the in vitro-to-in vivo extrapolation.

  3. Effect of Lidocaine and Amiodarone on Transmural Heterogeneityricular Repolarization in Isolated Rabbit Hearts Model of Sustained Global Ischemia

    Institute of Scientific and Technical Information of China (English)

    YOU Binquan; PU Jun; LIU Nian; YU Ronghui; RUAN Yanfei; LI Yang; WANG Lin

    2005-01-01

    To study the effect of of lidocaine and amiodarone on the transmural heterogeneity of ventricular repolarization in isolated rabbit hearts model of sustained global ischemia and to explore the mechanisms underlying the antiarrhythmic activity of lidocaine and amiodarone, rabbits were randomly divided into 4 groups: control group, ischemia group, lidocaine group and amiodarone group. By the monophasic action potential (MAP) recording technique, MAPs of recorded across the left ventricular free wall in rabbit hearts perfused transmural dispersion of repolarization (TDR) and arrhythmic induced by ischemia. Our results showed that TDR of three myocardial layers in ischemia group were significantly lengthened after ischemia. TDR was increased from 17.5±3.9 ms to 31.2±4.6 ms at the time that concided with the onset of sustained ventricle arrhythmic. Amiodarone could decrease TDR, but lidocaine could increase TDR at initial ischemia, and no significant difference was found at other ischemia time points. 5 cases had ventriclar arrhythmia in ischemia group (62.5 %), but no case in lidocaine group (P<0.01) and only 1 case in amiodarone group had ventrilar arrhythmia (P< 0.01). No significant difference was found between amiodarone group and lidocaine group. It is concluded that TDR of of three myocardial layers increases significantly at ischemia and it is closely associated with development of ventricular arrhythmia, and amiodarone could decrease TDR, but lidocaine could increase TDR at initial ischemia and has no effects at other ischemia time points.

  4. Comparison of Ventricular Electrophysiological Effects of Amiodarone in Canine Models With Congestive Heart Failure and Normal Dogs

    Institute of Scientific and Technical Information of China (English)

    Shuxian Zhou; Yuling Zhang; Juan Lei; Wei Wu; Xuming Zhang

    2008-01-01

    Objectives This study compared the effects of amiodarone on ventricular electrophysiological properties in normal dogs and CHF dogs.Methods Dogs(n=44) were randomized into four groups:Group 1(n=10)was the control.Group 2(n=10) was given amiodarone orally 300 mg·d-1 for4 to 5 weeks.Group 3(n=12)was the congestive heart failure(CHF)models induced by right ventricular rapid pacing(240 pulses·rain-1 for 4 to 5 weeks).Group 4 (n=12) was the CHF models given amiodarone orally 300 mg·d-1 for 4 to 5 weeks.The ventricular electrophysiological variables were evaluated by standard electric stimulation and monophasic action potential(MAP)recording.Results Amiodarone prolonged sinus cycle length(SCL),intra-ventricular conduction time(IVCT),MAP duration(MAPD90),ventricular effective period(VERP),ventricular activation time(VAT)and ventficular recovery time(VRT)without significant effects on the ratio of VERP to MAPD90 (VERP/MAPD90),ventricular fibrillation threshold(VFT),the dispersion of VRT(VRTD),and ventricular late repolarization duration(VLRD)in normal dogs.However,amiodarone did not further prolong the prolonged SCL,MAPD90,VERP,VAT and VRT,but further prolonged IVCT in CHF dogs.Amiodarone normalized the abnormal ventficular electrophysiological properties in CHF dogs as manifested by increasing the decreased VERP/MAPD90 and VFT,shortening the prolonged VLRD,and decreasing the increased VRTD.Amiodarone did not worsen the hemodynamic parameters in normal and CHF dogs.Conclusions Amiodarone had different effects on ventricular electrophysiological properties in normal and CHF dogs.The favorable effects of amiodarone in normalizing some abnormal cardiac electrophysiological properties in CHF models may have potential value on the prevention and treatment of ventricular arrhythmias and sudden cardiac death in CHF.

  5. Thermodynamics of protein destabilization in live cells.

    Science.gov (United States)

    Danielsson, Jens; Mu, Xin; Lang, Lisa; Wang, Huabing; Binolfi, Andres; Theillet, François-Xavier; Bekei, Beata; Logan, Derek T; Selenko, Philipp; Wennerström, Håkan; Oliveberg, Mikael

    2015-10-06

    Although protein folding and stability have been well explored under simplified conditions in vitro, it is yet unclear how these basic self-organization events are modulated by the crowded interior of live cells. To find out, we use here in-cell NMR to follow at atomic resolution the thermal unfolding of a β-barrel protein inside mammalian and bacterial cells. Challenging the view from in vitro crowding effects, we find that the cells destabilize the protein at 37 °C but with a conspicuous twist: While the melting temperature goes down the cold unfolding moves into the physiological regime, coupled to an augmented heat-capacity change. The effect seems induced by transient, sequence-specific, interactions with the cellular components, acting preferentially on the unfolded ensemble. This points to a model where the in vivo influence on protein behavior is case specific, determined by the individual protein's interplay with the functionally optimized "interaction landscape" of the cellular interior.

  6. Effects of Amiodarone plus Losartan on Electrical Remodeling in Rapid Atrial Pacing in Rabbits

    Institute of Scientific and Technical Information of China (English)

    Liye Wei; Yue Xia; Guoqing Qi; Qingwen Zhang

    2008-01-01

    Objectives To investigate the electrical remodeling and the effects of amiodarone and losartan on electrical remode-ling in rapid atrial pacing on rabbit model. Methods 40 normal rabbits were randomly divided into 4 groups: the sa-line group (control group), amiodarone group, losartan group, ami + los group. All rabbits were raised drugs in a week. The atrial effective refractory period (AERP) was measured. Then, take a rapid atrial pacing (600 bpm) and the AERP was measured after 0. 5, 1, 2, 4, 6 and 8 hours pacing and 30 minutes after the termination of rapid pacing. Results ① In control group, after 8 hours rapid pacing, AERP 200 and AERP 150 were significantly shortened 16. 11%± 3. 1% (P <0. 01) and 9. 99%±4. 2% (P <0. 01). And the degree of AERP shortening induced by rapid pacing was greater at basic cycle lengths of 200 ms (BCL200) than that at BCL150. The AERP of amiodarone, losartan group and anti + los group were not shortened during rapid pacing.② In the control group, after the termination of rapid pacing, the AERP gradually increased. The AERP at all of the BCLS examined recovered to almost the 95.78% and 96. 76% of baseline values within the first 10 minutes and recovered to almost the 99. 07% and 99. 39% of baseline values within the first 30 minutes. Condusions Short-term atrial rapid pacing can induce the atrial electrical remodeling. Amiodarone and losartan can prevent the electrical remodeling.

  7. Hyperacute drug-induced hepatitis with intravenous amiodarone: case report and review of the literature

    Directory of Open Access Journals (Sweden)

    Nasser M

    2013-09-01

    Full Text Available Mohammad Nasser, Timothy R Larsen, Barryton Waanbah, Ibrahim Sidiqi, Peter A McCullough Providence Hospitals and Medical Centers, Department of Medicine, Division of Cardiology, Southfield and Novi, MI, USA Abstract: Amiodarone is a benzofuran class III antiarrhythmic drug used to treat a wide spectrum of ventricular tachyarrhythmias. The parenteral formulation is prepared in polysorbate 80 diluent. We report an unusual case of acute elevation of aminotransaminase concentrations after the initiation of intravenous amiodarone. An 88-year-old Caucasian female developed acute hepatitis and renal failure after initiating intravenous amiodarone for atrial fibrillation with a rapid ventricular response in the setting of acutely decompensated heart failure and hepatic congestion. Liver transaminases returned to baseline within 7 days after discontinuing the drug. Researchers hypothesized that this type of injury is related to liver ischemia with possible superimposed direct drug toxicity. The CIOMS/RUCAM scale identifies our patient’s acute hepatitis as a highly probable adverse drug reaction. Future research is needed to understand the mechanisms by which hyperacute drug toxicity occurs in the setting of impaired hepatic perfusion and venous congestion. Keywords: intravenous amiodarone, acute hepatotoxicity, liver transaminases, drug-induced liver toxicity

  8. Amiodarone is a cost-neutral way of preventing atrial fibrillation after surgery for lung cancer

    DEFF Research Database (Denmark)

    Riber, Lars P; Christensen, Thomas D; Pilegaard, Hans K

    2013-01-01

    OBJECTIVES: Our aim was to estimate the costs and health benefits of routinely administered postoperative amiodarone as a prophylactic agent in reducing the risk of atrial fibrillation in patients undergoing surgery for lung cancer. METHODS: This was a cost-effectiveness study, based on the rando......OBJECTIVES: Our aim was to estimate the costs and health benefits of routinely administered postoperative amiodarone as a prophylactic agent in reducing the risk of atrial fibrillation in patients undergoing surgery for lung cancer. METHODS: This was a cost-effectiveness study, based...... on the randomized, controlled, double-blinded PASCART study, using avoidance of atrial fibrillation as the measure of benefit. Two hundred and fifty-four eligible, consecutively enrolled patients, undergoing surgery for lung cancer at the department of Cardiothoracic and Vascular Surgery, Aarhus University Hospital.......23). There were no signs of adverse developments referable to amiodarone in this prophylactic regime. CONCLUSIONS: For patients undergoing surgery for lung cancer, routine use of postoperative prophylactic intravenous bolus and five subsequent days of oral amiodarone therapy reduces the risk of atrial...

  9. Effect of prophylactic amiodarone in patients with rheumatic valve disease undergoing valve replacement surgery

    Directory of Open Access Journals (Sweden)

    Kar Sandeep

    2011-01-01

    Full Text Available The study was carried out to evaluate the effect of prophylactic single-dose intravenous amiodarone in patients undergoing valve replacement surgery. Maintenance of sinus rhythm is better than maintenance of fixed ventricular rate in atrial fibrillation (AF especially in the presence of irritable left or right atrium because of enlargement. Fifty-six patients with valvular heart disease with or without AF were randomly divided into two groups. Group I or the amiodarone group (n=28 received amiodarone (3 mg/kg in 100 ml normal saline and group II or the control group received same volume of normal saline. The standardized protocol for cardiopulmonary bypass was maintained for all the patients. AF occurred in 7.14% patients in group I, and in group II, 28.57% (P=0.035; ventricular tachycardia/fibrillation was observed in 21.43% patients in group I and 46.43% patients in group II (P=0.089 after release of aortic clamp. Most of the patients in group I (92.86% maintained sinus rhythm without cardioversion or defibrillation after release of aortic cross clamp (P=0.002. Defibrillation or cardio version was needed in 7.14% patients in group I and 28.57% patients in group II (P=0.078. A single prophylactic intraoperative dose of intravenous amiodarone decreased post bypass arrhythmia in this study in comparison to the control group. Single dose of intraoperative amiodarone may be used to decrease postoperative arrhythmia in open heart surgery.

  10. Acceleration of ventricular rate by amiodarone in atrial fibrillation associated with the Wolff-Parkinson-White syndrome

    Science.gov (United States)

    Sheinman, Bryan D; Evans, Tom

    1982-01-01

    Amiodarone has proved to be a valuable drug in atrial fibrillation associated with the Wolff-Parkinson-White syndrome. When it was administered to a patient with this syndrome in atrial fibrillation, who had previously suffered an inferior myocardial infarction, the ventricular rate accelerated from 170 to 230 beats/minute. This unusual case emphasises the need for full electrophysiological assessment of patients with the Wolff-Parkinson-White syndrome for whom amiodarone treatment is being considered. Imagesp1000-a PMID:6812745

  11. Amiodarone inhibits the mitochondrial beta-oxidation of fatty acids and produces microvesicular steatosis of the liver in mice

    Energy Technology Data Exchange (ETDEWEB)

    Fromenty, B.; Fisch, C.; Labbe, G.; Degott, C.; Deschamps, D.; Berson, A.; Letteron, P.; Pessayre, D. (Institut National de la Sante et de la Recherche Medicale U24, Clichy (France))

    1990-12-01

    Amiodarone has been shown to produce microvesicular steatosis of the liver in some recipients. We have determined the effects of amiodarone on the mitochondrial oxidation of fatty acids in mice. In vitro, the formation of 14C-acid-soluble beta-oxidation products from (U-14C)palmitic acid by mouse liver mitochondria was decreased by 92% in the presence of 125 microM amiodarone and by 94% in the presence of 125 microM N-desethylamiodarone. Inhibition due to 100 or 150 microM amiodarone persisted in the presence of 5 mM acetoacetate, whereas acetoacetate totally relieved inhibition due to 15 microM rotenone. In vivo, exhalation of (14C)CO2 from (U-14C)palmitic acid was decreased by 31, 40, 58 and 78%, respectively, in mice receiving 19, 25, 50 and 100 mg.kg-1 of amiodarone hydrochloride 1 hr before the administration of (U-14C)palmitic acid. One hour after 100 mg.kg-1, the exhalation of (14C)CO2 from (1-14C)palmitic acid, (1-14C)octanoic acid or (1-14C)butyric acid was decreased by 78, 72 and 53%, respectively. Exhalation of (14C)CO2 from (1-14C)palmitic acid was normal between 6 and 9 hr after administration of 100 mg.kg-1 of amiodarone hydrochloride, but was still inhibited by 71 and 37%, 24 and 48 hr after 600 mg.kg-1. Twenty four hours after the latter dose of amiodarone, hepatic triglycerides were increased by 150%, and there was microvesicular steatosis of the liver. We conclude that amiodarone inhibits the mitochondrial beta-oxidation of fatty acids and produces microvesicular steatosis of the liver in mice.

  12. Is the Preoperative Administration of Amiodarone or Metoprolol More Effective in Reducing Atrial Fibrillation: After Coronary Bypass Surgery?

    Science.gov (United States)

    Onk, Oruc Alper; Erkut, Bilgehan

    2015-10-01

    This study examined the influence of preoperative administration of amiodarone and metoprolol in preventing postoperative atrial fibrillation (AF) after coronary artery bypass grafting (CABG) surgery.The study comprised 251 patients who underwent CABG surgery at our hospital between January 2012 and May 2014. The patients were randomly divided into 2 groups: amiodarone therapy group (n = 122 patients) and metoprolol therapy group (n = 129 patients).In the amiodarone group, the patients received amiodarone tablet orally 1 week before coronary bypass surgery and during the postoperative period. In the metoprolol group, the patients received metoprolol tablet orally 1 week before surgery and during the postoperative period. The AF development rate was retrospectively evaluated between the first 3 days and 4 weeks after surgery.AF developed in 14 patients in the amiodarone group and 16 patients in the metoprolol group 4 weeks after the operation (P = 0.612).No significant difference was observed between the groups in terms of intensive care unit and hospital stay. Furthermore, hospital charges were similar in both groups (P = 0.741).The results of the logistic regression analysis showed age, left ventricular ejection fraction, left atrial diameter, and aortic cross-clamping time to be predictors for postoperative AF.This study demonstrates that amiodarone and metoprolol have similar effects in prevention of AF after cardiac surgery. However, larger-scale studies need to be conducted to substantiate these findings.

  13. The effect of beta-naphthoflavone on the metabolism of amiodarone by hepatic and extra-hepatic microsomes.

    Science.gov (United States)

    Elsherbiny, Marwa E; El-Kadi, Ayman O S; Brocks, Dion R

    2010-06-02

    Amiodarone is a potent antiarrhythmic drug with several limiting side effects, some of which have been correlated with increased levels of its more toxic metabolite, desethylamiodarone. Elevated serum desethylamiodarone to amiodarone ratios are associated with a risk of amiodarone-induced pulmonary toxicity. Polycyclic aromatic hydrocarbons such as beta-naphthoflavone are known to increase desethylamiodarone levels in rat in vivo. In this article we investigated if this increase was solely due to increased formation as a result of cytochrome P450 (CYP) 1A1 and 1A2 induction in different rat hepatic and extra-hepatic tissues. Additionally, the effect of amiodarone treatment on CYP1A1 and 1A2 gene expression and activity was investigated. In rats, beta-naphthoflavone was found to increase desethylamiodarone forming activity in lung and kidney microsomes. Amiodarone increased beta-naphthoflavone mediated induction of CYP1A1 gene expression in liver, lung and kidney. However, there was no significant change in CYP1A activity. As expected, the data indicated that the increase in desethylamiodarone levels in vivo was partly due to increased formation through CYP1A1 induction, although increased formation was only evident in some extra-hepatic tissues. Amiodarone treatment did not affect basal or induced CYP1A activity.

  14. [Total thyroidectomy in patients with amiodarone-induced hyperthyroidism: when does the risk of conservative treatment exceed the risk of surgery?].

    Science.gov (United States)

    Meerwein, C; Vital, D; Greutmann, M; Schmid, C; Huber, G F

    2014-02-01

    Amiodarone plays a pivotal role in the treatment of ventricular and supraventricular arrhythmias. However, amiodarone-induced hyperthyroidism (AIH) is one of the most feared complications, which necessitates interdisciplinary treatment and careful balancing of the risks of conservative treatment against those of total thyroidectomy. In this article we discuss the pharmacological aspects of amiodarone and its diverse effects on the thyroid. Furthermore, we present diagnostic and therapeutic strategies and report our positive experiences with total thyroidectomy in patients with AIH. Particularly in patients for whom continuation of amiodarone treatment is compulsory, a well-timed total thyroidectomy is a reliable therapeutic option, with minimal complication rates and immediate amelioration of symptoms.

  15. Amiodarone cost effectiveness in preventing atrial fibrillation after coronary artery bypass graft surgery

    DEFF Research Database (Denmark)

    Zebis, Lars R; Christensen, Thomas D; Hjortdal, Vibeke E

    2008-01-01

    BACKGROUND: The purpose of this study was to estimate the costs and health benefits of routinely administered postoperative amiodarone as prevention of atrial fibrillation for patients undergoing coronary artery bypass grafting (CABG) for stable angina. METHODS: This cost-effectiveness study...... was based on a randomized, controlled, double-blind trial (the RASCABG study) using avoidance of atrial fibrillation as the measure of benefit at the Department of Cardiothoracic and Vascular Surgery, Aarhus University Hospital, Skejby, Denmark. Two hundred and fifty eligible consecutively enrolled CABG...... of atrial fibrillation compared with 32 in the control group (p cost per patient was 7,639 euros in the amiodarone group and 7,814 euros in the placebo group (p

  16. Interaction of rivaroxaban with amiodarone, verapamil and diltiazem in patients with atrial fibrillation: terra incognita

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    S. N. Bel'diev

    2016-01-01

    Full Text Available Currently there are no generally accepted guidelines for the use of rivaroxaban together with amiodarone, verapamil or diltiazem in patients with creatinine clearance (CrCl<80 ml/min. Some researchers suggest that in renal failure amiodarone, verapamil and diltiazem contribute to a significant increase in plasma concentrations of rivaroxaban that is accompanied by increased risk of bleeding. According to preliminary calculations, it seems rational to reduce the dose of rivaroxaban when co-administered with these drugs: to 15 mg/day in patients with ClCr 50-79 ml/min and to 10 mg/day in patients with ClCr<50 ml/min.

  17. Comparative in vitro and in vivo evaluation of three tablet formulations of amiodarone in healthy subjects

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    J Emami

    2010-09-01

    Full Text Available "nBackground and the purpose of the study:The relative in vivo bioavailability and in vitro dissolution studies of three chemically equivalent amiodarone generic products in healthy volunteers was evaluated in three separate occasions. The possibility of a correlation between in vitro and in vivo performances of these tablet formulations was also evaluated. "nMethods: The bioequivalence studies were conducted based on a single dose, two-sequence, cross over randomized design. The bioavailability was compared using AUC0-72, AUC0-∞, Cmax and Tmax. Similarity factor, dissolution efficiency (DE, and mean dissolution time (MDT was used to compare the dissolution profiles. Polynomial linear correlation models were tested using either MDT vs mean residence time (MRT or fraction of the drug dissolved (FRD vs fraction of the drug absorbed (FRA. "nResults: Significant differences were found in the dissolution performances of the tested formulations and therefore they were included in the development of the correlation. The 90% confidence intervals of the log-transformed AUC0-72, AUC0-∞, and Cmax of each two formulations in each bioequivalence studies were within the acceptable range of 80-125%. Differences were not observed between the untransformed Tmax values. Poor correlation was found between MRT and MDT of the products. A point-to-point correlation which is essential for a reliable correlation was not obtained between pooled FRD and FRA. The dissolution condition which was used for amiodarone tablets failed for formulations which were bioequivalent in vivo and significant difference between the dissolution characteristics of products (f2<50 did not reflect their in vivo properties. Major conclusions: Bioequivalence studies should be considered as the only acceptable way to ensure the interchangeability and in vivo equivalence of amiodarone generic drug products. The dissolution conditions used of the present study could be used for routine and in

  18. Trastornos tiroideos por amiodarona The effects of amiodarone on the thyroid

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    M. Toni

    2009-12-01

    (59% vs 41%, lo que puede estar justificado por ser Navarra una comunidad con déficit de yodo. Es necesario el seguimiento de la función tiroidea durante al menos 2-3 años después del inicio del tratamiento con amiodarona.Background. Amiodarone is a drug widely used for the treatment of arrhythmias. In 16% of amiodarone-treated patients it causes changes in the thyroid function. The aim of this study was to determine the importance of amiodarone-induced thyroid dysfunction in the population of Navarre, studied between 2001 and 2007. Methods. We present a retrospective study that considers the characteristics of 182 amiodarone-treated patients with thyroid dysfunction who had been referred to our Institute. We determined a series of biochemical and instrumental investigations (measurement of thyrotrophin, free thyroid hormones and thyroid autoantibodies; thyroid sonography and thyroid scintigraphy uptake. Results. Screening of the thyroid function, recommended before starting amiodarone treatment, was carried out in only 20.9 % of the patients. Forty-one percent of patients developed amiodarone induced hypothyroidism; in 76% of them the drug was withdrawn. Hypothyroidism appears after 21 (± 12 months of amiodarone treatment. Forty-eight point six developed permanent hypothyroidism. This group of patients had higher serum levels of TSH (thyrotropin and were treated for less time with amiodarone. Fifty-nine percent of patients developed amiodarone induced thyrotoxicosis; 59.4 % were diagnosed with thyrotoxicosis (AIT type 1, 30.6% AIT type 2 and the remaining 10 % were diagnosed with mixed thyrotoxicosis. Thyrotoxicosis appears after 29.5 (± 17 months of amiodarone treatment. The serum levels of free thyroxine were significantly higher in the AIT type 2 than in the AIT type1. All patients were treated with antithyroid drugs and/or corticoids. Some patients were admitted to hospital due to the severity of their illness. Conclusions. In our study, amiodarone induced

  19. In vitro study of lovastatin interactions with amiodarone and with carbon tetrachloride in isolated rat hepatocytes

    Institute of Scientific and Technical Information of China (English)

    AZ Krasteva; MK Mitcheva; MS Kondeva-Burdina; VA Descatoire

    2007-01-01

    AIM: To investigate the interactions at a metabolic level between lovastatin, amiodarone and carbon tetrachloride in isolated rat hepatocytes.METHODS: For cell isolation two-step collagenase liver perfusion was performed. Lovastatin was administered alone in increasing concentrations (1 μmol/L, 3 μmol/L,5 μmol/L and 10 μmol/L) and in combination with CCl4 (86 μmol/L). The cells were also pretreated with 14 μmol/Lamiodarone and then the other two compounds were added.RESULTS: Lovastatin promoted concentration-dependent significant toxicity estimated by decrease in cell viability and GSH level by 45% and 84%, respectively. LDH-activity increased by 114% and TBARS content by 90%. CCl4 induced the expected severe damage on the examined parameters. CCl4 induced toxicity was attenuated after lovastatin pretreatment, which was expressed in less increased values of LDH activity and TBARS levels, as well as in less decreased cell viability and GSH concentrations. However, the pretreatment of hepatocytes with amiodarone abolished the protective effect of lovastatin.CONCLUSION: We suggest that the observed cytoprotective effect was due to interactions between lovastatin,CCl4 and amiodarone at a metabolic level.

  20. Catalytic Adsorptive Stripping Voltammetry at a Carbon Paste Electrode for the Determination of Amiodarone

    Institute of Scientific and Technical Information of China (English)

    LIU Ning; GAO Wei; SONG Jun-Feng

    2006-01-01

    Voltammetry using solid electrodes usually suffers from the contamination due to the deposition of the redox products of analytes on the electrode surface. The contamination has resulted in poor reproducibility and overelaborate operation procedures. The use of the chemical catalysis of oxidant on the reduction product of analyte not only can eliminate the contamination of analyte to solid electrodes but also can improve the faradaic response of analyte. This work introduced both the catalysis of oxidant K2S2O8 and the enhancement of surfactant Triton X-100 on the faraday response of amiodarone into an adsorptive stripping voltammetry at a carbon paste electrode for the determination of amiodarone. The method exhibits high sensitivity, good reproducibility and simple operation procedure. In 0.2 mol·L-1 HOAc-NaOAc buffer (pH=5.3) containing 2.2 × 10-2 mol·L-1 K2S2O8 and 0.002% Triton X-100, the 2.5th-order derivative stripping peak current of the catalytic wave at 0.3 V (vs. Ag/AgCl) is rectilinear to amiodarone concentration in the range of 2.0× 10-10-2.3× 10-8 mol·L-1 with a detection limit of 1.5× l0-10 mol·L-1 after accumulation at 0 V for 30 s.

  1. Effect of Stem Cell Therapy on Amiodarone Induced Fibrosing Interstitial Lung Disease in Albino Rat

    Science.gov (United States)

    Zaglool, Somaya Saad; Zickri, Maha Baligh; Abd El Aziz, Dalia Hussein; Mabrouk, Doaa; Metwally, Hala Gabr

    2011-01-01

    Background and Objectives: The fibrosing forms of interstitial lung disease (ILD) are associated with significant morbidity and mortality. ILD may be idiopathic, secondary to occupational, infection, complicate rheumatic diseases or drug induced. Efficacy of antifibrotic agents is as far as, limited and uncertain. No effective treatment was confirmed for pulmonary fibrosis except lung transplantation. The present study aimed at investigating the possible effect of human cord blood mesenchymal stem cell (MSC) therapy on fibrosing ILD. This was accomplished by using amiodarone as a model of induced lung damage in albino rat. Methods and Results: Seventeen adult male albino rats were divided into 3 groups. Rats of amiodarone group were given 30 mg/kg of amiodarone orally 6 days/ week for 6 weeks. Rats of stem cell therapy group were injected with stem cells in the tail vein following confirmation of lung damage and left for 4 weeks before sacrifice. Obstructed bronchioles, thickened interalveolar septa and thickened wall of pulmonary vessels were found and proved morphometrically. Reduced type I pneumocytes and increased area% of collagen fibers were recorded. All findings regressed on stem cell therapy. Conclusions: Cord blood MSC therapy proved definite amelioration of fibrosing interstitial lung disease provided therapy starts early in the development of the pathogenesis. PMID:24298346

  2. Temporally remote destabilization of prediction after rare breaches of expectancy.

    Science.gov (United States)

    Kühn, Anne B; Schubotz, Ricarda I

    2012-08-01

    While neural signatures of breaches of expectancy and their immediate effects have been investigated, thus far, temporally more remote effects have been neglected. The present fMRI study explored neural correlates of temporally remote destabilization of prediction following rare breaches of expectancy with a mean delay of 14 s. We hypothesized temporally remote destabilization to be reflected either in an attenuation of areas related to long-term memory or in an increase of lateral fronto-parietal loops related to the encoding of new stimuli. Monitoring a deterministic 24-digit sequence, subjects were asked to indicate occasional sequential omissions by key press. Temporally remote destabilization of prediction was expected to be revealed by contrasting sequential events whose equivalent was omitted in the preceding sequential run n-1 (destabilized events) with sequential events without such history (nondestabilized events). Temporally remote destabilization of prediction was reflected in an attenuation of activity in the dorsal frontomedian cortex (Brodmann Area (BA) 9) bilaterally. Moreover, activation of the left medial BA 9 was enhanced by contrasting nondestabilized events with breaches. The decrease of dorsal frontomedian activation in the case of destabilized events might be interpreted as a top-down modulation on perception causing a less expectation-restricted encoding of the current stimulus and hence enabling the adaptation of expectation and prediction in the long run.

  3. Correlation of Biomicroscopic Findings with Confocal Microscopy in Eyes with Amiodarone-Induced Cornea Verticillata

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    Emine Kaya

    2014-01-01

    Full Text Available Objectives: To investigate the correlation between biomicroscopic and confocal microscopic findings in eyes with amiodarone-induced cornea verticillata. Materials and Methods: Sixteen eyes of 8 patients with amiodarone-induced cornea verticillata were evaluated. Eyes with keratopathy were staged according to Orlando slit-lamp microscopy classification. Confocal laser-scanning microscopy was performed by Rostock cornea modulated to HRT II (Heidelberg Engineering GmbH, Heidelberg, Germany, and staging was done according to Falke’s classification that is based on the degree of epithelial basal cell deposit accumulation. The relation between biomicroscopic staging and corneal involvement detected on confocal microscopy was assessed by Spearman correlation analysis. Results: The mean age of the 8 patients (5 male, 3 female was 63.1±7.2 (50 to 69 years. The mean duration of drug treatment was 12.1±11.8 (3 to 36 months, and the mean drug treatment dose was 312.5±223.2 (100 to 800 mg/day. At the time of examination, 50% of the patients had already given up the treatment at a mean of 29.5±15.8 (6 to 40 months ago, whereas the other 50% were still on amiodarone therapy. Hyper-reflecting deposits were observed in the basal epithelium, anterior-, mid-and deep-stroma, and in the endothelium on confocal microscopic examination. Correlation was detected between biomicroscopic and confocal microscopic stages (r=0.770, p<0.001. Frequency of detecting deposits in the stroma and endothelium was found to be increasing as the biomicroscopic stage increased (r=0.844; p<0.001 and r=0.551; p<0.01, respectively. Conclusion: In amiodarone-induced cornea verticillata, correlated results were detected between biomicroscopic and confocal microscopic staging. Therefore, in clinics where confocal microscopy is not available, biomicroscopic staging can be used as a guiding parameter in eyes with amiodarone-induced cornea verticillata. (Turk J Ophthalmol 2014; 44: 63-67

  4. A randomized active-controlled study comparing the efficacy and safety of vernakalant to amiodarone in recent-onset atrial fibrillation

    DEFF Research Database (Denmark)

    Camm, A John; Capucci, Alessandro; Hohnloser, Stefan H;

    2011-01-01

    with 32.8% of amiodarone patients; p = 0.0012). Serious adverse events or events leading to discontinuation of study drug were uncommon. There were no cases of torsades de pointes, ventricular fibrillation, or polymorphic or sustained ventricular tachycardia. Conclusions Vernakalant demonstrated efficacy......Objectives This randomized double-blind study compared the efficacy and safety of intravenous vernakalant and amiodarone for the acute conversion of recent-onset atrial fibrillation (AF). Background Intravenous vernakalant has effectively converted recent-onset AF and was well tolerated in placebo...... superior to amiodarone for acute conversion of recent-onset AF. Both vernakalant and amiodarone were safe and well tolerated in this study. (A Phase III Superiority Study of Vernakalant vs Amiodarone in Subjects With Recent Onset Atrial Fibrillation...

  5. Stabilizing versus destabilizing the microtubules: a double-edge sword for an effective cancer treatment option?

    Science.gov (United States)

    Fanale, Daniele; Bronte, Giuseppe; Passiglia, Francesco; Calò, Valentina; Castiglia, Marta; Di Piazza, Florinda; Barraco, Nadia; Cangemi, Antonina; Catarella, Maria Teresa; Insalaco, Lavinia; Listì, Angela; Maragliano, Rossella; Massihnia, Daniela; Perez, Alessandro; Toia, Francesca; Cicero, Giuseppe; Bazan, Viviana

    2015-01-01

    Microtubules are dynamic and structural cellular components involved in several cell functions, including cell shape, motility, and intracellular trafficking. In proliferating cells, they are essential components in the division process through the formation of the mitotic spindle. As a result of these functions, tubulin and microtubules are targets for anticancer agents. Microtubule-targeting agents can be divided into two groups: microtubule-stabilizing, and microtubule-destabilizing agents. The former bind to the tubulin polymer and stabilize microtubules, while the latter bind to the tubulin dimers and destabilize microtubules. Alteration of tubulin-microtubule equilibrium determines the disruption of the mitotic spindle, halting the cell cycle at the metaphase-anaphase transition and, eventually, resulting in cell death. Clinical application of earlier microtubule inhibitors, however, unfortunately showed several limits, such as neurological and bone marrow toxicity and the emergence of drug-resistant tumor cells. Here we review several natural and synthetic microtubule-targeting agents, which showed antitumor activity and increased efficacy in comparison to traditional drugs in various preclinical and clinical studies. Cryptophycins, combretastatins, ombrabulin, soblidotin, D-24851, epothilones and discodermolide were used in clinical trials. Some of them showed antiangiogenic and antivascular activity and others showed the ability to overcome multidrug resistance, supporting their possible use in chemotherapy.

  6. Stabilizing versus Destabilizing the Microtubules: A Double-Edge Sword for an Effective Cancer Treatment Option?

    Science.gov (United States)

    Fanale, Daniele; Bronte, Giuseppe; Passiglia, Francesco; Calò, Valentina; Castiglia, Marta; Di Piazza, Florinda; Barraco, Nadia; Cangemi, Antonina; Catarella, Maria Teresa; Insalaco, Lavinia; Listì, Angela; Maragliano, Rossella; Massihnia, Daniela; Perez, Alessandro; Toia, Francesca; Cicero, Giuseppe; Bazan, Viviana

    2015-01-01

    Microtubules are dynamic and structural cellular components involved in several cell functions, including cell shape, motility, and intracellular trafficking. In proliferating cells, they are essential components in the division process through the formation of the mitotic spindle. As a result of these functions, tubulin and microtubules are targets for anticancer agents. Microtubule-targeting agents can be divided into two groups: microtubule-stabilizing, and microtubule-destabilizing agents. The former bind to the tubulin polymer and stabilize microtubules, while the latter bind to the tubulin dimers and destabilize microtubules. Alteration of tubulin-microtubule equilibrium determines the disruption of the mitotic spindle, halting the cell cycle at the metaphase-anaphase transition and, eventually, resulting in cell death. Clinical application of earlier microtubule inhibitors, however, unfortunately showed several limits, such as neurological and bone marrow toxicity and the emergence of drug-resistant tumor cells. Here we review several natural and synthetic microtubule-targeting agents, which showed antitumor activity and increased efficacy in comparison to traditional drugs in various preclinical and clinical studies. Cryptophycins, combretastatins, ombrabulin, soblidotin, D-24851, epothilones and discodermolide were used in clinical trials. Some of them showed antiangiogenic and antivascular activity and others showed the ability to overcome multidrug resistance, supporting their possible use in chemotherapy. PMID:26484003

  7. Stabilizing versus Destabilizing the Microtubules: A Double-Edge Sword for an Effective Cancer Treatment Option?

    Directory of Open Access Journals (Sweden)

    Daniele Fanale

    2015-01-01

    Full Text Available Microtubules are dynamic and structural cellular components involved in several cell functions, including cell shape, motility, and intracellular trafficking. In proliferating cells, they are essential components in the division process through the formation of the mitotic spindle. As a result of these functions, tubulin and microtubules are targets for anticancer agents. Microtubule-targeting agents can be divided into two groups: microtubule-stabilizing, and microtubule-destabilizing agents. The former bind to the tubulin polymer and stabilize microtubules, while the latter bind to the tubulin dimers and destabilize microtubules. Alteration of tubulin-microtubule equilibrium determines the disruption of the mitotic spindle, halting the cell cycle at the metaphase-anaphase transition and, eventually, resulting in cell death. Clinical application of earlier microtubule inhibitors, however, unfortunately showed several limits, such as neurological and bone marrow toxicity and the emergence of drug-resistant tumor cells. Here we review several natural and synthetic microtubule-targeting agents, which showed antitumor activity and increased efficacy in comparison to traditional drugs in various preclinical and clinical studies. Cryptophycins, combretastatins, ombrabulin, soblidotin, D-24851, epothilones and discodermolide were used in clinical trials. Some of them showed antiangiogenic and antivascular activity and others showed the ability to overcome multidrug resistance, supporting their possible use in chemotherapy.

  8. Microscopia confocal in vivo nos depósitos corneanos por amiodarona In vivo confocal microscopy in amiodarone corneal deposits

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    Gustavo Victor

    2007-02-01

    Full Text Available OBJETIVO: Descrever os achados da microscopia confocal in vivo em pacientes nos diversos estágios de ceratopatia induzida por amiodarona, e correlacionar o estadiamento biomicroscópico com o estadiamento confocal. MÉTODOS: Vinte olhos de 10 pacientes (6 homens e 4 mulheres em tratamento com amiodarona, que apresentavam ceratopatia induzida pela droga, foram selecionados para o estudo, com a microscopia confocal (MC. RESULTADOS: A média de idade foi 58 ± 6,2 anos (50-66 anos e o tempo de uso da droga foi de 6 ± 3,2 anos (2-11 anos. Todos pacientes tinham acuidade visual com correção melhor ou igual a 20/40. A biomicroscopia evidenciou ceratopatia por amiodarona: dois pacientes no estágio 1, quatro no estágio 2 e quatro no estágio 3. Todas as córneas apresentaram inclusões intracelulares brilhantes e de alta refletividade na camada epitelial basal. A partir dos estágios 2 e 3, foram encontrados microdepósitos em todas camadas corneanas. Foram observados afilamento e aumento da tortuosidade dos nervos corneanos nos estágios 2 e 3 da ceratopatia. A contagem endotelial média foi de 2.524 ± 150,3 células/mm². CONCLUSÃO: O epitélio basal foi o mais acometido nos diferentes estágios da ceratopatia. Nos pacientes do estágio 1 a biomicroscopia, os microdepósitos subepiteliais são restritos ao epitélio superficial e basal, ao passo que nos pacientes dos estágios 2 e 3, os microdepósitos afetam todas camadas corneanas. À medida que a ceratopatia avança, os nervos corneanos ficam mais afilados e tortuosos.PURPOSE: To describe in vivo confocal microscopy findings in patients with different stages of amiodarone-induced keratopathy, and correlate biomicroscopy stages with confocal stages. METHODS: Twenty eyes of 10 patients (6 men and 4 women, who receive treatment with amiodarone were selected for the study with confocal microscopy (MC. RESULTS: The average age was 58 ± 6.2 years (50-66 years and time of use of the drug was 6

  9. Destabilization and intracranial fragmentation of a full metal jacket bullet.

    Science.gov (United States)

    Farrugia, A; Raul, J S; Geraut, A; Tortel, M C; Ludes, B

    2009-10-01

    We report a case with an atypical entrance wound as a result of a destabilized full metal jacket bullet penetration. The destabilized bullet by an impact with the dorsal hand experiences a yawing to tumbling motion in flight. The large angle of yaw induces a larger presenting profile upon impact that contributes, associated to a rapid deceleration, to a greater mechanical force on the projectile structure and a fragmentation into core and jacket. Forensic pathologists have to be aware that the metal jacket bullet could tend to break up outside or inside the body particularly after a shooting through a target. This phenomenon induces atypical entrance wounds and atypical X-ray presentation.

  10. Dysfunction of the thyroid gland during amiodarone therapy: a study of 297 cases

    Directory of Open Access Journals (Sweden)

    Czarnywojtek A

    2016-04-01

    Full Text Available Agata Czarnywojtek,1,2,* Maria Teresa Płazińska,3,* Małgorzata Zgorzalewicz-Stachowiak,4 Kosma Woliński,1 Adam Stangierski,1 Izabela Miechowicz,5 Joanna Waligórska-Stachura,1 Paweł Gut,1 Leszek Królicki,3 Maja Zioncheck,6 Marek Ruchała1 1Department of Endocrinology, Metabolism and Internal Medicine, 2Department of Pharmacology, Poznan University of Medical Sciences, Poznan, 3Nuclear Medicine Department, Medical University of Warsaw, Warsaw, 4Department of Health Prophylaxis, Laboratory of Medical Electrodiagnostics, 5Department of Computer Science and Statistics, 6Poznan University of Medical Sciences, Poznan, Poland *These authors contributed equally to this work Aim: This study aims to explore and compare the efficacy of radioiodine treatment (RIT in hyperthyroid and euthyroid patients who have been treated with amiodarone (AM in the past or are currently undergoing AM treatment. Clinical observation of a group of patients with amiodarone-induced hypothyroidism during a 12-month follow-up period was used for comparison.Design: This was a observational, two-centered study. Patients were assessed at baseline and at 2 months, 6 months, 8 months, and 12 months after RIT.Patients: Group A: At baseline (61 males [M] and 17 females [F], mean age 50±19 years, there were 78 euthyroid patients with cardiac arrhythmias, who were treated with AM and developed amiodarone-induced thyrotoxicosis, and currently require retreatment with AM. Group B: Hyperthyroid patients (92 M and 26 F, mean age 72±11.8 years after AM therapy in the past. Group C: Hyperthyroid patients (66 M and 13 F, mean age 63.9±13.2 years currently treated by AM. Group D: Hypothyroid patients (6 M and 16 F, mean age 61.4±10.4 years after AM therapy. The patients from Groups A, B, and C were retreated with AM after ~3–6 weeks of RIT.Results: In Group A, after 12 months of RIT therapy, recurrent thyrotoxicosis was observed in six (7.7% cases, and persistent

  11. Amiodarona y disfunción tiroidea Amiodarone and thyroid dysfunction

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    Leonardo F. L. Rizzo

    2012-02-01

    Full Text Available La amiodarona es un análogo estructural de la hormona tiroidea, y algunas de sus propiedades antiarrítmicas como así también su toxicidad son atribuibles a su interacción con los receptores nucleares de las hormonas tiroideas. Por ser muy lipofílica, la amiodarona se concentra en muchos tejidos y se elimina, por consecuencia, muy lentamente. Se emplea preferentemente para el tratamiento de arritmias graves tales como fibrilación y taquicardia ventriculares. Otras indicaciones incluyen la fibrilación auricular y el aleteo, la insuficiencia cardíaca congestiva grave, la prevención de la fibrilación auricular recurrente y situaciones de emergencia médica como la prevención de muerte súbita cardiaca¹. Nuestro objetivo es proporcionar un enfoque actualizado sobre la amiodarona y su influencia sobre la fisiología tiroidea y discutir y analizar en profundidad sus potenciales efectos adversos como el hipotiroidismo y la tirotoxicosis.Amiodarone is a structural analogue of thyroid hormone, and some of its anti-arrhythmic actions and toxicity are attributable to its interaction with nuclear receptors of thyroid hormones. Being highly lipophilic, amiodarone is concentrated in many tissues and is eliminated, consequently, very slowly. It is preferably employed to manage life-threatening arrhythmias, including ventricular fibrillation and unstable ventricular tachycardia. Other indications include atrial fibrillation and flutter, severe congestive heart failure, prevention of atrial fibrillation recurrence, and even in emergency medical situations to prevent sudden cardiac death. The aim of this review is to provide an updated approach on amiodarone and its influence on thyroid physiology and to discuss and analyze in depth its potential and not infrequent thyroidal adverse effects such as hypothyroidism and thyrotoxicosis.

  12. Effects of amiodarone therapy on thyroid iodine content as measured by x-ray fluorescence

    Energy Technology Data Exchange (ETDEWEB)

    Fragu, P.; Schlumberger, M.; Davy, J.M.; Slama, M.; Berdeaux, A.

    1988-04-01

    Thyroid iodine content (TIC) was measured by x-ray fluorescence in 68 patients who had received amiodarone treatment for varying intervals (1 g/week for 1-120 months). Thirty-six patients were euthyroid; the mean TIC of the patients (n = 15), who had been treated for less than 12 months was 30 +/- 19 (+/- SD) mg, twice the normal mean value (14.6 +/- 5.0 mg), and it was 39 +/- 17 mg in those (n = 16) who had been treated for 12-60 months and 29 +/- 6 mg in those (n = 5) who had been treated longer (greater than 60 months). Nineteen patients were hyperthyroid and had elevated TIC values. Of them, 6 patients had a goiter; their TIC (50 +/- 19 mg) was not significantly different from that of the hyperthyroid patients with no goiter (55 +/- 29 mg), but they became hyperthyroid more rapidly. Thirteen patients were hypothyroid; none had TIC values above the normal range, and it was below 2.5 mg in 5 patients. A sequential study was undertaken in 11 euthyroid patients who had no detectable antithyroid antibodies. TIC did not increase during treatment in 2 patients; both developed hypothyroidism, which was transient in 1 despite continuation of amiodarone treatment. The TIC initially increased during amiodarone treatment in the other 9 patients, leveling off at the end of the first year. The TIC rose well above the upper limit of the normal range in 4 patients, of whom 2 became hyperthyroid during the second year of treatment. TIC remained within the normal range in the other 5 patients, of whom 3 became hypothyroid after 12-24 months of treatment (1 subclinical, 2 overt). Although the TIC was significantly higher in the patients with hyperthyroidism than in the patients who remained euthyroid, the TIC test cannot be used to predict the occurrence of hyperthyroidism.

  13. Cardiac arrest provoked by itraconazole and amiodarone interaction: a case report

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    Betrosian Alex

    2011-07-01

    Full Text Available Abstract Introduction Azoles, and specifically itraconazole, are often prescribed for the treatment of fungal diseases or empirically for persistent sepsis in patients who are neutropenic or in intensive care. Occasional cardiovascular adverse events have been associated with itraconazole use, and are usually attributed to the interaction of itraconazole with cisapride, terfenadine or digoxin. Its interaction with amiodarone has not been previously described. Case presentation A 65-year-old Caucasian man was admitted to the Intensive Care Unit at our facility for an extensive ischemic stroke associated with atrial fibrillation. Due to rapid ventricular response he was started on intravenous amiodarone and few days later itraconazole was also prescribed for presumed candidemia. After receiving the first dose our patient became profoundly hypotensive but responded rapidly to fluids and adrenaline. Then, two months later, itraconazole was again prescribed for confirmed fungemia. After receiving the first dose via a central venous catheter our patient became hypotensive and subsequently arrested. He was resuscitated successfully, and as no other cause was identified the arrest was attributed to septic shock and his antifungal treatment was changed to caspofungin. When sensitivity test results became available, antifungal treatment was down-staged to itraconazole and immediately after drug administration our patient suffered another arrest and was once again resuscitated successfully. This time the arrest was related to itraconazole, which was discontinued, and from then on our patient remained stable until his discharge to our neurology ward. Conclusions Itraconazole and amiodarone coadministration can lead to serious cardiovascular adverse events in patients who are critically ill. Intensivists, pharmacists and medical physicians should be aware of the interaction of these two commonly used drugs.

  14. How frequently should a patient taking amiodarone be screened for thyroid dysfunction?

    Directory of Open Access Journals (Sweden)

    A. Pazin-Filho

    2009-08-01

    Full Text Available Amiodarone-induced thyroid dysfunction (AITD is a common complication of amiodarone therapy and its prevalence varies according to iodine intake, subclinical thyroid disorders and the definition of AITD. There is no consensus about the frequency of screening for this condition. We evaluated 121 patients on chronic regular intake of amiodarone (mean intake = 248.5 ± 89 mg; duration of treatment = 5.3 ± 3.9 years, range = 0.57-17 years and with stable baseline cardiac condition. Those with no AITD were followed up for a median period of 3.2 years (range: 0.6-6.7 and the incidence rate of AITD, defined by clinical and laboratorial findings as proposed by international guidelines, was obtained (62.8 per 1000 patients/year. We applied the Cox proportional hazard model to adjust for potential confounding factors and used sensitivity analysis to identify the best screening time for follow-up. We detected thyroid dysfunction in 59 (48.7% of the 121 patients, amiodarone-induced hypothyroidism in 50 (41.3% and hyperthyroidism in 9 (7.5%. Compared with patients without AITD, there was no difference regarding dosage or duration of therapy, heart rhythm disorder or baseline cardiac condition. During the follow-up of the 62 patients without AITD at baseline evaluation, 11 developed AITD (interquartile range, IR: 62.8 (95%CI: 31.3-112.3 cases per 1000 patients/year, 9 of them with hypothyroidism - IR: 11.4 (95%CI: 1.38-41.2, and 2 hyperthyroidism - IR: 51.3 (95%CI: 23.4-97.5. Age, gender, dose, and duration of treatment were not significant after adjustment. During the first 6 months of follow-up the incidence rate for AITD was 39.3 (9.2-61.9 cases per 1000 patients/year. These data show that AITD is quite common, and support the need for screening at 6-month intervals, unless clinical follow-up dictates otherwise or further information regarding the prognosis of untreated subclinical AITD is available.

  15. A CASE REPORT OF AMIODARONE INDUCED MYOPATHY IN A PATIENT OF VENTRICULAR ARRHYTHMIA

    Directory of Open Access Journals (Sweden)

    Rajat

    2014-09-01

    Full Text Available Myopathies are disorders with structural changes or functional impairment of muscle. Voluntary muscle is subject to a range of hereditary and acquired disorders affecting either its structure, or the biochemical processes which convert the chemical energy derived from cell metabolism into mechanical energy in a controlled manner. These disorders present in a limited number of ways, most commonly a symmetrical weakness of the large, power-generating proximal muscles. Drug induced myopathy comes under acquired causes of myopathy. Here we shall be presenting a case of Amiodarone induced myopathy in a 40 years old male patient of ventricular arrhythmia. We shall also discuss the further management of this presentation.

  16. Uninhibited thyroidal uptake of radioiodine despite iodine excess in amiodarone-induced hypothyroidism

    Energy Technology Data Exchange (ETDEWEB)

    Wiersinga, W.M.; Touber, J.L.; Trip, M.D.; van Royen, E.A.

    1986-08-01

    Iodine excess is associated with a low thyroidal radioiodine uptake due to dilution of the radioisotope by the increased stable iodide pool. We studied thyroidal uptake of radioisotopes in cardiac patients with iodine excess due to amiodarone treatment. /sup 99m/Tc-pertechnetate scintigraphy was performed in 13 patients receiving long term amiodarone therapy. Five patients had a clearly visible thyroid gland, and 8 patients had no or a very faint thyroid image. All patients with positive scans had an increased plasma TSH level, whereas all patients with negative scans had a normal or absent TSH response to TRH. Thyroidal uptake and discharge of 123I were studied in 30 other patients. Group I (n = 11) had normal plasma TSH responses to TRH and no iodine excess, group II (n = 7) had normal TSH responses to TRH and excess iodine from metrizoate angiography in the previous month, group III (n = 7) had normal or decreased TSH responses to TRH while receiving long term amiodarone therapy, and group IV (n = 5) had increased TSH responses to TRH while receiving long term amiodarone therapy. The mean radioiodine uptake value in group I (5.4 +/- 0.8% (+/- SE) at 60 min) was higher than those in group II (2.3 +/- 0.7%; P = 0.009) and group III (0.8 +/- 0.3%; P = 0.0005), but not different from that in group IV (5.3 +/- 1.2%; P = NS). Radioiodine discharge after perchlorate (expressed as a percentage of the 60 min uptake) in group I (10.1 +/- 2.2%) was lower than those in group II (24.9 +/- 10.6%; P = 0.05) and group III (28.8 +/- 5.3%; P less than 0.005), whereas discharge in group IV (58.0 +/- 6.1%) was greater than those in group II (P less than 0.05) and group III (P less than 0.01). In conclusion, 1) thyroid visualization by /sup 99m/Tc-pertechnetate and thyroid radioiodine uptake during iodine excess are decreased in euthyroid and hyperthyroid patients, but preserved in hypothyroid patients.

  17. Hepatic and renal failure associated with amiodarone infusion in a patient with hereditary fructose intolerance.

    Science.gov (United States)

    Curran, B J; Havill, J H

    2002-06-01

    Hereditary fructose intolerance is a rare inherited metabolic disorder. Although fructose intolerance usually presents in the paediatric age group, individuals can survive into adulthood by self.manipulation of diet. Hospitalisation can become a high.risk environment for these individuals because of loss of control of their strict dietary constraints and the added danger of administration of medications containing fructose, sucrose and sorbitol. We report a case of hereditary fructose intolerance in an adult presenting with hepatic and renal failure associated with an amiodarone infusion and explore the possibility of polysorbate 80 as a cause of this patient's hepatic and renal failure.

  18. Effect of single intraoperative dose of amiodarone in patients with rheumatic valvular heart disease and atrial fibrillation undergoing valve replacement surgery

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    Selvaraj Thiruvenkadam

    2009-01-01

    Full Text Available Maintenance of sinus rhythm (SR is superior to rate control in atrial fibrillation (AF. In order to achieve SR, we administered single-dose intravenous amiodarone intraoperatively and evaluated its effect on conversion of rheumatic AF to SR in patients undergoing valvular heart surgery. Patients were randomly assigned to amiodarone ( n = 42 or control ( n = 40 group in a double blind manner. The amiodarone group received amiodarone (3 mg/kg intravenously prior to the institution of cardiopulmonary bypass and the control group received the same volume of normal saline. In the amiodarone group, the initial rhythm after the release of aortic cross clamp was noted to be AF in 14.3% ( n = 6 and remained so in 9.5% ( n = 4 of patients till the end of surgery. In the control group, the rhythm soon after the release of aortic cross clamp was AF in 37.5% ( n = 15 ( p = 0.035 and remained so in 32.5% ( n = 13 of patients till the end of surgery ( p = 0.01. At the end of first post-operative day 21.4% ( n = 9 of patients in amiodarone group and 55% ( n = 22 of patients in control group were in AF ( p = 0.002. The requirement of cardioversion/defibrillation was 1.5 (±0.54 in amiodarone group and 2.26 (±0.73 in the control group ( p = 0.014, and the energy needed was 22.5 (±8.86 joules in the amiodarone group and 40.53 (±16.5 in the control group ( p = 0.008. A single intraoperative dose of intravenous amiodarone increased the conversion rate of AF to normal sinus rhythm, reduced the need and energy required for cardioversion/defibrillation and reduced the recurrence of AF within one day.

  19. How Do Amateur Soccer Referees Destabilize a Match?

    Science.gov (United States)

    Fruchart, Eric; Carton, Annie

    2012-01-01

    The refereeing system in amateur football is not without weakness. Some referees could be deliberately led to destabilize a match in order to demonstrate their skills in regulating a situation of potential conflict. This has posed an ethical problem to soccer institutions. Our study proposes to focus on this phenomenon by questioning seventy four…

  20. Destabilizing DNA during Rejoining Enhances Fidelity of Repair.

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    Richard Robinson

    2015-08-01

    Full Text Available A new study shows that during repair of DNA, the effect of a single-strand annealing protein is to destabilize DNA duplex formation so that annealing only occurs between perfectly matched strands; the protein then clamps the strands together for repair. Read the Research Article.

  1. Comparative Study of Nifekalant Versus Amiodarone for Shock-Resistant Ventricular Fibrillation in Out-of-Hospital Cardiopulmonary Arrest Patients

    NARCIS (Netherlands)

    M. Amino; K. Yoshioka; T. Opthof; S. Morita; S. Uemura; K. Tamura; T. Fukushima; S. Higami; H. Otsuka; K. Akieda; M. Shima; D. Fujibayashi; T. Hashida; S. Inokuchi; I. Kodama; T. Tanabe

    2010-01-01

    Background: In Japan, intravenous nifekalant ( NIF) was often used for direct current cardioversion-resistant ventricular fibrillation (VF), until the use of intravenous amiodarone (AMD) was approved in 2007. The defibrillatory efficacy of NIF and AMD has thus far not been compared for resuscitation

  2. Protective Effect of Wenxin Granula on Heart from Myocardial Infarction through Regulating Intracellular Ca2+

    Institute of Scientific and Technical Information of China (English)

    LI Xiao-xue; YANG Bao-feng; LI Xue-lian; CHU Wen-feng; CAI Rui-jun; SHI Yong-fang; XU Chao-qian; SHAN Hong-li; WANG Xing-yang; LU Yan-jie

    2011-01-01

    Objective To assess the anti-arrhythmic activity and cardioprotective effects of Wenxin Granula, a traditional Chinese formula (consisting of Salviae Miltiorrhizae Radix, Polygonati Rhizoma, Notoginseng Radix et Rhizoma, Nardostachyos Radix et Rhizoma, Angelicae Sinensis Radix, and Succinum), on heart in ischemic-induced myocardial infarction (MI) rats and compare with those of Amiodarone which have been demonstrated in clinic. Methods Rats were randomly divided into Sham-operated (control), Ml + Amiodarone [5 mg/(kg·d)] (MI), and MI + Wenxin Granula [10 mg/(kg·d)] groups and left anterior descending coronary artery was occluded in each group. After left anterior descending for 12 h, standard lead Ⅱ of administration electrocardiogram was recorded in order to analyze the occurrence of arrhythmia. After one month, the size of the infarct area of heart was evaluated by TTC staining method and haemodynamic function was assessed to detect the heart function. Laser scanning confocal microscope and the technique of patch clamp were used to detect the intracellular Ca2+ ([Ca2+]j) and L-type calcium current (ICa-L), respectively. Results Both Wenxin Granula [10 mg/(kg·d)] and Amiodarone [5 mg/(kg·d)] could markedly decrease the incidence of arrhythmia in heart of rats which were subjected to ischemic injury. After one month, Wenxin Granula could significantly decrease mortality to 22.22% and reduce the infarct area (P < 0.05), but Amiodarone did not. The mechanism may involve that Wenxin Granula attenuated [Ca2+]j decreasing in MI rats. Additionally, Wenxin Granula could obviously ameliorate the impaired heart function of MI rats by decreasing the elevated left ventricular end-diastolic pressure and increasing the attenuated maximum change velocity of left ventricular pressure in the isovolumic contraction or relaxation period. On the other hand, electrophysiological experiment results revealed that Wenxin Granula administration one month later also increased the

  3. Characterization of lysosome-destabilizing DOPE/PLGA nanoparticles designed for cytoplasmic drug release.

    Science.gov (United States)

    Chhabra, Resham; Grabrucker, Andreas M; Veratti, Patrizia; Belletti, Daniela; Boeckers, Tobias M; Vandelli, Maria Angela; Forni, Flavio; Tosi, Giovanni; Ruozi, Barbara

    2014-08-25

    Polymeric nanoparticles (NPs) offer a promising approach for therapeutic intracellular delivery of proteins, conventionally hampered by short half-lives, instability and immunogenicity. Remarkably, NPs uptake occurs via endocytic internalization leading to NPs content's release within lysosomes. To overcome lysosomal degradation and achieve NPs and/or loaded proteins release into cytosol, we propose the formulation of hybrid NPs by adding 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE) as pH sensitive component in the formulation of poly-lactide-co-glycolide (PLGA) NPs. Hybrid NPs, featured by different DOPE/PLGA ratios, were characterized in terms of structure, stability and lipid organization within the polymeric matrix. Experiments on NIH cells and rat primary neuronal cultures highlighted the safety profile of hybrid NPs. Moreover, after internalization, NPs are able to transiently destabilize the integrity of lysosomes in which they are taken up, speeding their escape and favoring cytoplasmatic localization. Thus, these DOPE/PLGA-NPs configure themselves as promising carriers for intracellular protein delivery.

  4. Intracellular Bacteria in Protozoa

    Science.gov (United States)

    Görtz, Hans-Dieter; Brigge, Theo

    Intracellular bacteria in humans are typically detrimental, and such infections are regarded by the patients as accidental and abnormal. In protozoa it seems obvious that many bacteria have coevolved with their hosts and are well adapted to the intracellular way of life. Manifold interactions between hosts and intracellular bacteria are found, and examples of antibacterial resistance of unknown mechanisms are observed. The wide diversity of intracellular bacteria in protozoa has become particularly obvious since they have begun to be classified by molecular techniques. Some of the bacteria are closely related to pathogens; others are responsible for the production of toxins.

  5. Amiodarone-induced pulmonary toxicity. Immunoallergologic tests and bronchoalveolar lavage phospholipid content.

    Science.gov (United States)

    Nicolet-Chatelain, G; Prevost, M C; Escamilla, R; Migueres, J

    1991-02-01

    Amiodarone (A) is a widely-used antiarrhythmic drug. Pulmonary toxicity is the most serious adverse effect with an estimated mortality of 1 to 33 percent. In order to determine an element helpful for diagnosis, we examined four patients with amiodarone-induced pulmonary toxicity, three patients treated with A, without evidence of pulmonary toxicity but with a main underlying pulmonary disease, and four healthy volunteers. Daily and cumulative doses or duration of treatment were similar in the first two groups. Pulmonary function tests (spirometry, CO-diffusing capacity, arterial blood gases), roentgenographic examinations, pulmonary biopsies or immunoallergologic tests (skin reaction, lymphoblastic transformation test and human basophile degranulation test) did not provide any discriminatory element. In APT+, we observed an increased cellularity of the bronchoalveolar lavage. Neither the differential cell count nor the presence of foamy macrophages were distinguishable between APT+ and APT-. The phospholipid composition of BAL fluid showed a decreased total phospholipid and phospholipid/protein ratio in all patients compared to normal subjects. These changes reflect more the severity of pulmonary disease than the specificity of the causative agent. However, we observed that the unique PL which decreases in APT- and remains normal in APT+ is phosphatidyl-serine + phosphatidylinositol (PS + PI). This has to be confirmed and should be evaluated at different stages of the disease to determine an eventual specific element. We conclude that there are no data currently available to establish the diagnosis of APT except perhaps for the analysis of BAL PL content.

  6. Block of inactivated sodium channels and of depolarization-induced automaticity in guinea pig papillary muscle by amiodarone.

    Science.gov (United States)

    Mason, J W; Hondeghem, L M; Katzung, B G

    1984-09-01

    The electrophysiological effects of amiodarone were studied in guinea pig papillary muscle by means of the single sucrose gap voltage clamp technique. The first time derivative of the upstroke of the action potential was measured as an indicator of the sodium current. The preparations were not voltage clamped during the action potential upstroke. Acute effects of amiodarone (4.4 X 10(-5) M and 8.8 X 10(-5) M; six experiments each) and effects of chronic administration at a single dose level (nine experimental vs. eight control animals) were studied. Results were qualitatively the same for all experimental conditions, and concentration dependent in the acute studies. Amiodarone caused marked use-dependent depression of the first time derivative of the upstroke of the action potential during stimulus trains. For example, at normal resting potential, chronic amiodarone treatment reduced the first time derivative of the upstroke of the action potential of the 16th beat of trains of cycle length 300 msec to 70 +/- 15% (mean +/- SD) of the initial value. This blocking effect was accentuated at more depolarized holding potentials and reduced at hyperpolarized holding potentials. Reduction of the first time derivative of the upstroke of the action potential was found to depend upon sodium channel inactivation. For all experiments, the mean normalized first time derivative of the upstroke of the action potential following a 1-second clamp in the -20 to +20 mV range was 0.92 +/- 0.08 in the control condition and 0.66 +/- 0.20 in the presence of amiodarone (less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

  7. Antiarrhythmic effect of the Ca(2+)-activated K(+) (SK) channel inhibitor ICA combined with either amiodarone or dofetilide in an isolated heart model of atrial fibrillation

    DEFF Research Database (Denmark)

    Kirchhoff, Jeppe Egedal; Diness, Jonas Goldin; Abildgaard, Lea;

    2016-01-01

    whether a combination of the SK channel blocker N-(pyridin-2-yl)-4-(pyridin-2-yl)thiazol-2-amine (ICA) together with either dofetilide or amiodarone provided a synergistic effect. The duration of AF was reduced with otherwise subefficacious concentrations of either dofetilide or amiodarone when combined......Dose is an important parameter in terms of both efficacy and adverse effects in pharmacological treatment of atrial fibrillation (AF). Both of the class III antiarrhythmics dofetilide and amiodarone have documented anti-AF effects. While dofetilide has dose-related ventricular side effects......, amiodarone primarily has adverse non-cardiac effects. Pharmacological inhibition of small conductance Ca(2+)-activated K(+) (SK) channels has recently been reported to be antiarrhythmic in a number of animal AF models. In a Langendorff model of acutely induced AF on guinea pig hearts, it was investigated...

  8. Antiarrhythmic effect of the Ca(2+)-activated K(+) (SK) channel inhibitor ICA combined with either amiodarone or dofetilide in an isolated heart model of atrial fibrillation

    DEFF Research Database (Denmark)

    Kirchhoff, Jeppe Egedal; Diness, Jonas Goldin; Abildgaard, Lea;

    2016-01-01

    Dose is an important parameter in terms of both efficacy and adverse effects in pharmacological treatment of atrial fibrillation (AF). Both of the class III antiarrhythmics dofetilide and amiodarone have documented anti-AF effects. While dofetilide has dose-related ventricular side effects...... that combination of subefficacious concentrations of an SK channel blocker and either dofetilide or amiodarone can maintain anti-AF properties, while the risk of ventricular arrhythmias is reduced....

  9. The protective effect of amiodarone in lung tissue of cecal ligation and puncture-induced septic rats: a perspective from inflammatory cytokine release and oxidative stress.

    Science.gov (United States)

    Polat, Beyzagul; Cadirci, Elif; Halici, Zekai; Bayir, Yasin; Unal, Deniz; Bilgin, Bulent Caglar; Yuksel, Tugba Nurcan; Vancelik, Serhat

    2013-07-01

    Sepsis is a serious medical condition that is characterized by a whole-body inflammatory state and the presence of a known or suspected infection. Amiodarone is a class III antiarrhythmic agent, a multichannel blocker (Ca++, Na+, and K+), and a noncompetitive α- and β-adrenergic blocker in cardiac cells. The present study aimed to determine whether amiodarone was protective against experimentally induced cecal ligation and puncture sepsis in rat lung tissue. The relationship between its probable protective effect and antioxidant/anticytokine action biochemically and histopathologically was also examined. Five groups of rats were used, each composed of 20 rats: (1) the sham-operated control group; (2) the CLP group; (3) the 25-mg/kg amiodarone-treated control healthy group; (4) the 50-mg/kg amiodarone-treated CLP group; and (5) the 50-mg/kg amiodarone-treated CLP group. A CLP polymicrobial sepsis model was applied to the rats. All groups were sacrificed 16 h later, and lung and blood samples were analyzed histopathologically and biochemically. Twenty-five and 50 mg/kg amiodarone decreased the level of interleukin (IL)-1β, IL-6, and tumor necrosis factor-α in serum and 8-iso-prostaglandin F2α level in lung tissue. They increased the activities of superoxide dismutase and levels of total glutathione in lung tissues of rats. Histopathological scores and examinations were in accordance with the biochemical results. Histopathological analysis revealed significant differences in inflammation scores between the sepsis group and the other groups. The CLP + amiodarone 50 mg/kg group had the lowest inflammation score among CLP groups. Our results indicate that administration of amiodarone prevented oxidative stress and cytokine action and protected lung tissue during sepsis cascade.

  10. Analysis of specific mRNA destabilization during Dictyostelium development.

    Science.gov (United States)

    Mangiarotti, G; Bulfone, S; Giorda, R; Morandini, P; Ceccarelli, A; Hames, B D

    1989-07-01

    A number of specific mRNAs are destabilized upon disaggregation of developing Dictyostelium discoideum cells. Analysis of a family of cloned genes indicates that only prespore-enriched mRNAs are affected; constitutive mRNAs that are expressed throughout development and mRNAs that accumulate preferentially in prestalk cells are stable under these conditions. The decay of sensitive prespore mRNAs can be halted by allowing the cells to reaggregate, indicating that destabilization occurs by the progressive selection of individual molecules rather than on all members of an mRNA subpopulation at the time of disaggregation. Individual molecules of the sensitive mRNA species remain engaged in protein synthesis in the disaggregated cells until selected. Destabilization of sensitive mRNAs is induced by cell dissociation even in the presence of concentrations of nogalamycin that inhibit RNA synthesis. The reported prevention of disaggregation-induced mRNA decay by actinomycin D and daunomycin is therefore probably a secondary effect unrelated to the inhibition of transcription.

  11. Atherosclerotic Plaque Destabilization in Mice: A Comparative Study.

    Directory of Open Access Journals (Sweden)

    Helene Hartwig

    Full Text Available Atherosclerosis-associated diseases are the main cause of mortality and morbidity in western societies. The progression of atherosclerosis is a dynamic process evolving from early to advanced lesions that may become rupture-prone vulnerable plaques. Acute coronary syndromes are the clinical manifestation of life-threatening thrombotic events associated with high-risk vulnerable plaques. Hyperlipidemic mouse models have been extensively used in studying the mechanisms controlling initiation and progression of atherosclerosis. However, the understanding of mechanisms leading to atherosclerotic plaque destabilization has been hampered by the lack of proper animal models mimicking this process. Although various mouse models generate atherosclerotic plaques with histological features of human advanced lesions, a consensus model to study atherosclerotic plaque destabilization is still lacking. Hence, we studied the degree and features of plaque vulnerability in different mouse models of atherosclerotic plaque destabilization and find that the model based on the placement of a shear stress modifier in combination with hypercholesterolemia represent with high incidence the most human like lesions compared to the other models.

  12. Randomised trial of low-dose amiodarone in severe congestive heart failure. Grupo de Estudio de la Sobrevida en la Insuficiencia Cardiaca en Argentina (GESICA)

    Science.gov (United States)

    Doval, H C; Nul, D R; Grancelli, H O; Perrone, S V; Bortman, G R; Curiel, R

    1994-08-20

    In severe heart failure many deaths are sudden and are presumed to be due to ventricular arrhythmias. The GESICA trial evaluated the effect of low-dose amiodarone on two-year mortality in patients with severe heart failure. Our prospective multicentre trial included 516 patients on optimal standard treatment for heart failure. Patients were randomised to 300 mg/day amiodarone (260) or to standard treatment (256). Intention-to-treat analysis showed 87 deaths in the amiodarone group (33.5%) compared with 106 in the control group (41.4%) (risk reduction 28%; 95% CI 4%-45%; log rank test p = 0.024). There were reductions in both sudden death (risk reduction 27%; p = 0.16) and death due to progressive heart failure (risk reduction 23%; p = 0.16). Fewer patients in the amiodarone group died or were admitted to hospital due to worsening heart failure (119 versus 149 in the control group; risk reduction 31%; 95% CI 13-46%; p = 0.0024). The decrease in mortality and hospital admission was present in all subgroups examined and independent of the presence of non-sustained ventricular tachycardia. Side-effects were reported in 17 patients (6.1%); amiodarone was withdrawn in 12. Low-dose amiodarone proved to be an effective and reliable treatment, reducing mortality and hospital admission in patients with severe heart failure independently of the presence of complex ventricular arrhythmias.

  13. Risk assessment of mountain infrastructure destabilization in the French Alps

    Science.gov (United States)

    Duvillard, Pierre-Allain; Ravanel, Ludovic; Deline, Philip

    2015-04-01

    In the current context of imbalance of geosystems in connection with the rising air temperature for several decades, high mountain environments are especially affected by the shrinkage of glaciers and the permafrost degradation which can trigger slope movements in the rock slopes (rockfall, rock avalanches) or in superficial deposits (slides, rock glacier rupture, thermokarst). These processes generate a risk of direct destabilization for high mountain infrastructure (huts, cable-cars...) in addition to indirect risks for people and infrastructure located on the path of moving rock masses. We here focus on the direct risk of infrastructure destabilization due to permafrost degradation and/or glacier shrinkage in the French Alps. To help preventing these risks, an inventory of all the infrastructure was carried out with a GIS using different data layers among which the Alpine Permafrost Index Map and inventories of the French Alps glaciers in 2006-2009, 1967-1971 and at the end of the Little Ice Age. 1769 infrastructures have been identified in areas likely characterized by permafrost and/or possibly affected by glacier shrinkage. An index of risk of destabilization has been built to identify and to rank infrastructure at risk. This theoretical risk index includes a characterization of hazards and a diagnosis of the vulnerability. The value of hazard is dependent on passive factors (topography, lithology, geomorphological context...) and on so-considered active factors (thermal state of the permafrost, and changing constraints on slopes related to glacier shrinkage). The diagnosis of vulnerability has meanwhile been established by combining the level of potential damage to the exposed elements with their operational and financial values. The combination of hazard and vulnerability determines a degree of risk of infrastructure destabilization (from low to very high). Field work and several inventories of infrastructure damages were used to validate it. The

  14. Twenty-four hour radioactive iodine uptake in 35 patients with amiodarone associated thyrotoxicosis

    Energy Technology Data Exchange (ETDEWEB)

    Martino, E.; Aghini-Lombardi, F.; Lippi, F.; Baschieri, L.; Safran, M.; Braverman, L.E.; Pinchera, A.

    1985-12-01

    Amiodarone associated thyrotoxicosis (AAT) occurs in approximately 10% of patients treated with this iodine rich drug in areas of mild iodine deficiency. The thyroid radioactive iodine uptake (RAIU) is usually undetectable or very low in iodine-induced thyrotoxicosis. In the present study, 35 patients with AAT were evaluated. Twelve patients had no thyroid abnormalities by physical exam and all had 24-hr RAIU less than or equal to 4%. In contrast, nine of 11 patients with AAT and diffuse goiters and eight of 12 patients with AAT and nodular goiters had RAIU values greater than 8%. In patients with AAT and goiter it appears possible that the thyroid fails to adapt normally to the excess iodide load, resulting in an inappropriately high RAIU in the presence of excess plasma iodine.

  15. Concurrent Chagas’ disease and borderline disseminated cutaneous leishmaniasis: The role of amiodarone as an antitrypanosomatidae drug

    Directory of Open Access Journals (Sweden)

    Alberto E Paniz-Mondolfi

    2008-06-01

    Full Text Available Alberto E Paniz-Mondolfi1,4, Alexandra M Pérez-Álvarez1, Oscar Reyes-Jaimes2, Gustavo Socorro1, Olga Zerpa3, Denisa Slova4, Juan L Concepción51Laboratorio de Estudio de Antígenos, Instituto de Biomedicina, “Hospital José Gregório Hernández”, Instituto Venezolano de los Seguros Sociales, Caracas, Venezuela; 2Departamento de Dermopatología, Instituto de Biomedicina, 3Sección de Leishmaniasis, Instituto de Biomedicina, Caracas, Venezuela; 4Department of Pathology and Laboratory Medicine, St. Luke’s – Roosevelt - Beth Israel Medical Center, University Hospital of Columbia University College of Physicians and Surgeons, New York, USA; 5Laboratorio de Enzimología de Parásitos, Facultad de Ciencias, Universidad de Los Andes, Mérida, VenezuelaAbstract: The occurrence of mixed infections of Trypanosoma cruzi and Leishmania spp. is becoming a common feature in Central and South America due to overlapping endemic areas. Unfortunately, the possibilities for treating flagellated kinetoplastid infections are still very limited and most of the available drugs exhibit severe side effects. Although the development of new drugs for Leishmania has markedly improved in the last years, the tendency is still to employ antimonial compounds. On the other hand, treatment for Chagas’ disease is only available for the acute phase with no effective therapeutical options for chronic stage disease. The following case report substantiates the recently discovered effect of amiodarone as a nonconventional antiparasitic drug, particularly against Leishmania, breaching a new perspective in the therapeutic management of these important infectious parasitic diseases.Keywords: Chagas’ disease, leishmaniasis, chemotherapy, amiodarone

  16. A model predicting fluindione dose requirement in elderly inpatients including genotypes, body weight, and amiodarone.

    Science.gov (United States)

    Moreau, Caroline; Pautas, Eric; Duverlie, Charlotte; Berndt, Celia; Andro, Marion; Mahé, Isabelle; Emmerich, Joseph; Lacut, Karine; Le Gal, Grégoire; Peyron, Isabelle; Gouin-Thibault, Isabelle; Golmard, Jean-Louis; Loriot, Marie-Anne; Siguret, Virginie

    2014-04-01

    Indandione VKAs have been widely used for decades, especially in Eastern Europe and France. Contrary to coumarin VKAs, the relative contribution of individual factors to the indandione-VKA response is poorly known. In the present multicentre study, we sought to develop and validate a model including genetic and non-genetic factors to predict the daily fluindione dose requirement in elderly patients in whom VKA dosing is challenging. We prospectively recorded clinical and therapeutic data in 230 Caucasian inpatients mean aged 85 ± 6 years, who had reached international normalized ratio stabilisation (range 2.0-3.0) on fluindione. In the derivation cohort (n=156), we analysed 13 polymorphisms in seven genes potentially involved in the pharmacological effect or vitamin-K cycle (VKORC1, CYP4F2, EPHX1) and fluindione metabolism/transport (CYP2C9, CYP2C19, CYP3A5, ABCB1). We built a regression model incorporating non-genetic and genetic data and evaluated the model performances in a separate cohort (n=74).Body-weight, amiodarone intake, VKORC1, CYP4F2, ABCB1 genotypes were retained in the final model, accounting for 31.5% of dose variability. None influence of CYP2C9 was observed. Our final model showed good performances: in 83.3% of the validation cohort patients, the dose was accurately predicted within 5 mg, i.e.the usual step used for adjusting fluindione dosage. In conclusion, in addition to body-weight and amiodarone-intake, pharmacogenetic factors (VKORC1, CYP4F2, ABCB1) related to the pharmacodynamic effect and transport of fluindione significantly influenced the dose requirement in elderly patients while CYP2C9 did not. Studies are required to know whether fluindione could be an alternative VKA in carriers of polymorphic CYP2C9 alleles, hypersensitive to coumarins.

  17. Long-term use of amiodarone before heart transplantation significantly reduces early post-transplant atrial fibrillation and is not associated with increased mortality after heart transplantation

    Directory of Open Access Journals (Sweden)

    Rivinius R

    2016-02-01

    Full Text Available Rasmus Rivinius,1 Matthias Helmschrott,1 Arjang Ruhparwar,2 Bastian Schmack,2 Christian Erbel,1 Christian A Gleissner,1 Mohammadreza Akhavanpoor,1 Lutz Frankenstein,1 Fabrice F Darche,1 Patrick A Schweizer,1 Dierk Thomas,1 Philipp Ehlermann,1 Tom Bruckner,3 Hugo A Katus,1 Andreas O Doesch1 1Department of Cardiology, Angiology and Pneumology, 2Department of Cardiac Surgery, Heidelberg University Hospital, 3Institute for Medical Biometry and Informatics, University of Heidelberg, Heidelberg, Germany Background: Amiodarone is a frequently used antiarrhythmic drug in patients with end-stage heart failure. Given its long half-life, pre-transplant use of amiodarone has been controversially discussed, with divergent results regarding morbidity and mortality after heart transplantation (HTX.Aim: The aim of this study was to investigate the effects of long-term use of amiodarone before HTX on early post-transplant atrial fibrillation (AF and mortality after HTX.Methods: Five hundred and thirty patients (age ≥18 years receiving HTX between June 1989 and December 2012 were included in this retrospective single-center study. Patients with long-term use of amiodarone before HTX (≥1 year were compared to those without long-term use (none or <1 year of amiodarone. Primary outcomes were early post-transplant AF and mortality after HTX. The Kaplan–Meier estimator using log-rank tests was applied for freedom from early post-transplant AF and survival.Results: Of the 530 patients, 74 (14.0% received long-term amiodarone therapy, with a mean duration of 32.3±26.3 months. Mean daily dose was 223.0±75.0 mg. Indications included AF, Wolff–Parkinson–White syndrome, ventricular tachycardia, and ventricular fibrillation. Patients with long-term use of amiodarone before HTX had significantly lower rates of early post-transplant AF (P=0.0105. Further, Kaplan–Meier analysis of freedom from early post-transplant AF showed significantly lower rates of AF in this

  18. Unfolding Ubiquitin by force: water mediated H-bond destabilization

    Directory of Open Access Journals (Sweden)

    Germán Pabón

    2012-12-01

    Full Text Available Using the “pull and wait” (PNW simulation protocol at 300 K, we studied the unfolding by force of an ubiquitin molecule. PNW was implemented in the CHARMM program using an integration time step of 1 fs and a uniform dielectric constant of 1. The ubiquitin molecule, initially solvated, was put under mechanical stress, exerting forces from different directions. The rupture of five hydrogen bonds between parallel strands β1 and β5 takes place during the extension from 13 to 15 Å, defines a mechanical barrier for unfolding and dominates the point of maximum unfolding force. The simulations described here show that given adequate time, a small applied force can destabilize those five H-bonds relative to the bonds that can be created to water molecules; allowing the formation of stable H-bonds between a single water molecule and the donor and acceptor groups of the interstrand H-bonds. Thus, simulations run with PNW show that the force is not responsible for “ripping apart” the backbone H-bonds; it merely destabilizes them making them less stable than the H-bonds they can make with water. Additional simulations show that the force necessary to destabilize the H-bonds and allow them to be replaced by H-bonds to water molecules depends strongly on the pulling direction. By using a simulation protocol that allows equilibration at each extension we have been able to observe the details of the events leading to the unfolding of ubiquitin by mechanical force.

  19. A Case of Type 2 Amiodarone-Induced Thyrotoxicosis That Underwent Total Thyroidectomy under High-Dose Steroid Administration

    Directory of Open Access Journals (Sweden)

    Koshi Hashimoto

    2015-01-01

    Full Text Available Amiodarone is used commonly and effectively in the treatment of arrhythmia; however, it may cause thyrotoxicosis categorized into two types: iodine-induced hyperthyroidism (type 1 amiodarone-induced thyrotoxicosis (AIT and destructive thyroiditis (type 2 AIT. We experienced a case of type 2 AIT, in which high-dose steroid was administered intravenously, and we finally decided to perform total thyroidectomy, resulting in a complete cure of the AIT. Even though steroid had been administered to the patient (maximum 80 mg of prednisolone, the operation was performed safely and no acute adrenal crisis as steroid withdrawal syndrome was found after the operation. Few cases of type 2 AIT that underwent total thyroidectomy with high-dose steroid administration have been reported. The current case suggests that total thyroidectomy should be taken into consideration for patients with AIT who cannot be controlled by medical treatment and even in those under high-dose steroid administration.

  20. Trapped particle destabilization of the internal kink mode

    Energy Technology Data Exchange (ETDEWEB)

    White, R.B.; Chen, L.; Romanelli, F.; Hay, R.

    1984-06-01

    The internal kink mode is destabilized by trapped high energy particles, leading to a new branch of the internal kink dispersion relation with a real frequency near the average trapped particle precession frequency and a growth rate of the same magnitude. This trapped particle branch of the dispersion relation is investigated numerically for a variety of particle distributions. Mode growth rate and frequency are found as a function of plasma ..beta.., density, and trapped particle energy and distribution. The high energy trapped particle sources considered are neutral beam injection, ion cyclotron heating, and fusion alpha particles. Relevance for various plasma heating schemes is discussed.

  1. Simultaneous determination of amiodarone and its metabolite desethylamiodarone by high-performance liquid chromatography with chemiluminescent detection

    Energy Technology Data Exchange (ETDEWEB)

    Perez-Ruiz, Tomas [Department of Analytical Chemistry, Faculty of Chemistry, University of Murcia, 30071 Murcia (Spain)], E-mail: tpr@um.es; Martinez-Lozano, Carmen; Garcia-Martinez, Maria Dolores [Department of Analytical Chemistry, Faculty of Chemistry, University of Murcia, 30071 Murcia (Spain)

    2008-08-08

    A novel method was developed for the determination of amiodarone and desethylamiodarone by high-performance liquid chromatography (HPLC) coupled with chemiluminescent (CL) detection. The procedure is based on the post-column photolysis of the analytes into photoproducts which are active in the tris(2,2'-bipyridyl)ruthenium(III) [Ru(bpy){sub 3}{sup 3+}] CL system. Ru(bpy){sub 3}{sup 3+} was on-line generated by photo-oxidation of the Ru(II) complex in the presence of peroxydisulfate. The separation was carried out on a Mediterranea C{sub 18} column with isocratic elution using a mixture of methanol and 0.017 mol L{sup -1} ammonium sulfate buffer of pH 6.8. Under the optimum conditions, analytical curves, based on standard solutions, were linear over the range 0.1-50 {mu}g mL{sup -1} for amiodarone and 0.5-25 {mu}g mL{sup -1} for desethylamiodarone. The detection limits of amiodarone and desethylamiodarone were 0.02 and 0.11 {mu}g mL{sup -1}, respectively. Intra- and inter-day precision values of 0.9% relative standard deviation (R.S.D.) (n = 10) and 1.6% R.S.D. (n = 15), respectively, were obtained. The method was applied successfully to the determination of these compounds in serum and pharmaceutical formulations.

  2. New viewpoint of clinical treatment of amiodarone%胺碘酮临床治疗的新观点

    Institute of Scientific and Technical Information of China (English)

    朱彩玲

    2015-01-01

    Amiodarone is widely used in clinical.It has an important role in the treatment of arrhythmia and anti angina pectoris and so on.It has good treatment effect,at the same time,amiodarone also has more adverse reactions,which should arouse the attention of clinicians.In this paper,the author briefly introduces the new viewpoint of clinical treatment of amiodarone,to provide study for clinical.%胺碘酮在临床有着广泛的应用,其在治疗心律失常和抗心绞痛等方面有着重要的作用.在发挥较好治疗作用的同时,胺碘酮也有着较多的不良反应,应引起临床医生的注意.本文简要介绍胺碘酮临床治疗的新观点,为临床提供依据.

  3. 静注胺碘酮治疗心律失常%Static note Amiodarone Treatment of Arrhythmia

    Institute of Scientific and Technical Information of China (English)

    陈淑华

    2014-01-01

    胺碘酮是一种广谱抗心律失常药物,具有许多独立的药理特性,虽属III类抗心律失常药,但它对多个离子通道均有阻断作用,同时具有 I及IV类抗心律失常药性质。近年来静脉注射胺碘酮治疗难治性室上性心律失常、顽固性室性心动过速,室颤疗效甚佳。本文对本科30例心律失常患者使用静脉注射胺碘酮。现将其治疗结果记录如下。%Amiodarone is a broad-spectrum anti-arrhythmic drugs,has many pharmacological characteristics of independent,although department class III anti-arrhythmic drugs,but its effect on multiple ion channels are blocked ,at the same time is in the nature of class I and IV anti -arrhythmic drugs.In recent years the in-travenous amiodarone be well in treatment of refractory room on cardiac arrhythmia,refractory ventricular tachycardia,ventricular fibrillation in good curative effect.In this paper,the undergraduate course of 30 patients with arrhythmia intravenous amiodarone.It is presently as follows the treatment result record.

  4. Dramatic destabilization of the Ru(0001) surface upon oxygen adsorption

    Science.gov (United States)

    Reuter, K.; Ganduglia-Pirovano, M. V.; Scheffler, M.; Stampfl, C.

    2000-03-01

    Under high oxygen pressures, where most other transition metal surfaces typically form inert surface oxides, Ru(0001) displays the highest rates for oxidation reactions. This unusual behavior has been attributed to the fact that Ru can exist in different oxidation states and to the ease with which its surface can be loaded with high concentrations of subsurface oxygen. Yet, recent experiments have also indicated that high oxygen loads in the subsurface region destabilize Ru(0001) and lead to the emission of RuOx (xA. Böttcher, H. Conrad and H. Niehus, J. Chem. Phys. (submitted).). We perform density functional theory calculations to gain a fundamental understanding of the O-Ru bond in on-surface as well as subsurface oxygen phases. After completion of a full monolayer coverage on the surface, Ru(0001) is found to strongly bind even up to another full monolayer in the sites directly below the first substrate layer. In agreement with the experimental findings, this highly loaded O-Ru-O fringe is then relatively instable against lift-off, which might lead to either RuOx fragmentation or restructuring. The relation between charge transfer towards the oxygen and bond formation, as well as substrate destabilization is discussed.

  5. Destabilization of confined granular packings due to fluid flow

    Science.gov (United States)

    Monloubou, Martin; Sandnes, Bjørnar

    2016-04-01

    Fluid flow through granular materials can cause fluidization when fluid drag exceeds the frictional stress within the packing. Fluid driven failure of granular packings is observed in both natural and engineered settings, e.g. soil liquefaction and flowback of proppants during hydraulic fracturing operations. We study experimentally the destabilization and flow of an unconsolidated granular packing subjected to a point source fluid withdrawal using a model system consisting of a vertical Hele-Shaw cell containing a water-grain mixture. The fluid is withdrawn from the cell at a constant rate, and the emerging flow patterns are imaged in time-lapse mode. Using Particle Image Velocimetry (PIV), we show that the granular flow gets localized in a narrow channel down the center of the cell, and adopts a Gaussian velocity profile similar to those observed in dry grain flows in silos. We investigate the effects of the experimental parameters (flow rate, grain size, grain shape, fluid viscosity) on the packing destabilization, and identify the physical mechanisms responsible for the observed complex flow behaviour.

  6. Intracellular drug release nanosystems

    Directory of Open Access Journals (Sweden)

    Fenghua Meng

    2012-10-01

    Full Text Available In order to elicit therapeutic effects, many drugs including small molecule anticancer drugs, proteins, siRNA, and DNA have to be delivered and released into the specific cellular compartments typically the cytoplasm or nucleus of target cells. Intracellular environment-responsive nanosystems that exhibit good extracellular stability while rapidly releasing drugs inside cancer cells have been actively pursued for effective cancer therapy. Here, we highlight novel designs of smart nanosystems that release drugs in response to an intracellular biological signal of cancer cells such as acidic pH in endo/lysosomal compartments, enzymes in lysosomes, and redox potential in cytoplasm and the cell nucleus.

  7. Development of nanoparticles incorporating a novel liposomal membrane destabilization peptide for efficient release of cargos into cancer cells.

    Directory of Open Access Journals (Sweden)

    Shoko Itakura

    Full Text Available In anti-cancer therapy mediated by a nanoparticle-based drug delivery system (DDS, overall efficacy depends on the release efficiency of cargos from the nanoparticles in the cancer cells as well as the specificity of delivery to tumor tissue. However, conventional liposome-based DDS have no mechanism for specifically releasing the encapsulated cargos inside the cancer cells. To overcome this barrier, we developed nanoparticles containing a novel liposomal membrane destabilization peptide (LMDP that can destabilize membranes by cleavage with intramembranous proteases on/in cancer cells. Calcein encapsulated in liposomes modified with LMDP (LMDP-lipo was effectively released in the presence of a membrane fraction containing an LMDP-cleavable protease. The release was inhibited by a protease inhibitor, suggesting that LMDP-lipo could effectively release its cargo into cells in response to a cancer-specific protease. Moreover, when LMDP-lipo contained fusogenic lipids, the release of cargo was accelerated, suggesting that the fusion of LMDP-lipo with cellular membranes was the initial step in the intracellular delivery. Time-lapse microscopic observations showed that the release of cargo from LMDP-lipo occurred immediately after association of LMDP-lipo with target cells. Consequently, LMDP-lipo could be a useful nanoparticle capable of effective release of cargos specifically into targeted cancer cells.

  8. Effects of Amiodarone on Transmural Dispersion of Ventricular Effective Refractory Periods across Myocardial Layers in the Normal and Hypertrophic Canine Heart

    Institute of Scientific and Technical Information of China (English)

    WANG Lan; L(U) Jiagao; ZHANG Fanzhi; BAI Rong; WANG Lin

    2006-01-01

    The effects of amiodarone on transmural dispersion of ventricular effective refractory periods (ERPs) in the normal and hypertrophic canine heart were investigated in vivo. By using the programmed stimulation protocol, the ERPs of epicardium (Epi), midmyocardium (Mid) and endocardium (Endo) were measured by inserting specially-designed electrodes into the three myocardial layers before and after mainlining of amiodarone. No significant ERPs-dispersion was observed in the three layers before and after mainlining of amiodarone in the normal group. In contrast, ERPs of all the three layers were prolonged in the hypertrophic heart, while the ERPs-dispersion was reduced significantly after mainlining of amiodarone. The ERPs-dispersion was significantly increased in the hypertrophic heart but not in the normal heart using "long-short" and "short-long" interval stimulation technique. It was concluded that (1) the differences in ERPs-dispersion among the three layers were significant in hypertrophic heart, and differences were not significant in normal canine heart;(2) ERPs of each three-myocardial layers were significantly prolonged after using amiodarone, but the ERPs-dispersion decreased in hypertrophic heart and (3) the programmed extrastimulus technique of "long-short" and "short-long" intervals increased the transmural ERPs-dispersion in the hypertrophic heart.

  9. Efficacy and safety in pharmacological cardioversion of recent-onset atrial fibrillation: a propensity score matching to compare amiodarone vs class IC antiarrhythmic drugs.

    Science.gov (United States)

    Bonora, Antonio; Turcato, Gianni; Franchi, Elena; Taioli, Gabriele; Dilda, Alice; Zerman, Germana; Maccagnani, Antonio; Pistorelli, Claudio; Olivieri, Oliviero

    2016-07-06

    The acute management of recent-onset (IC antidysrhythmic agents vs amiodarone in a propensity score matched series of patients acutely treated for AF in the emergency department. During a 3-year period, we retrospectively evaluated all episodes of recent-onset (IC group in terms of efficacy and safety that is conversion to sinus rhythm rates within 12 and 48 h after starting treatment, time to conversion, and adverse drug effects. An overall number of 817 episodes of recent-onset AF were collected (amiodarone group = 406, class IC group = 411). After matching, we obtained 358 episodes equally divided (amiodarone group = 179 and class IC group = 179). Conversion rates within 12 h were 139 (53.1 %) in amiodarone group and 95 (72.6 %) in class IC group (p IC group (p IC agents, when compared with amiodarone, proved to be more rapid and effective, and equally safe in the acute management of recent-onset AF.

  10. A mechanism for dust-induced destabilization of glacial climates

    Directory of Open Access Journals (Sweden)

    B. F. Farrell

    2012-05-01

    Full Text Available Abrupt transitions between cold/dry stadial and warm/wet interstadial states occurred during glacial periods in the absence of any known external forcing. The climate record preserved in polar glaciers, mountain glaciers, and widespread cave deposits reveals that these events were global in extent with temporal distribution implying an underlying memoryless process with millennial time scale. Here a theory is advanced implicating feedback between atmospheric dust and the hydrological cycle in producing these abrupt transitions. Calculations are performed using a radiative-convective model that includes the interaction of aerosols with radiation to reveal the mechanism of this dust/precipitation interaction feedback process and a Langevin equation is used to illustrate qualitatively glacial climate destabilization by this mechanism. This theory explains the observed abrupt, bimodal, and memoryless nature of these transitions as well as their intrinsic connection with the hydrological cycle.

  11. A mechanism for dust-induced destabilization of glacial climates

    Directory of Open Access Journals (Sweden)

    B. F. Farrell

    2012-12-01

    Full Text Available Abrupt transitions between cold/dry stadial and warm/wet interstadial states occurred during glacial periods in the absence of any known external forcing. The climate record preserved in polar glaciers, mountain glaciers, and widespread cave deposits reveals that these events were global in extent with temporal distribution implying an underlying memoryless process with millennial time scale. Here a theory is advanced implicating feedback between atmospheric dust and the hydrological cycle in producing these abrupt transitions. Calculations are performed using a radiative-convective model that includes the interaction of aerosols with radiation to reveal the mechanism of this dust/precipitation interaction feedback process and a Langevin equation is used to illustrate glacial climate destabilization by this mechanism. This theory explains the observed abrupt, bimodal, and memoryless nature of these transitions as well as their intrinsic connection with the hydrological cycle.

  12. Destabilizing Tachyonic Vacua at or above the BF Bound

    CERN Document Server

    Kanno, Sugumi; Soda, Jiro

    2012-01-01

    It is well known that tachyonic vacua in an asymptotically Anti-de Sitter (AdS) space-time are classically stable if the mass squared is at or above the Breitenlohner and Freedman (BF) bound. We study the quantum stability of these tachyonic vacua in terms of instantons. We find a series of exact instanton solutions destabilizing tachyonic state at or above the BF bound in asymptotically AdS space. We also give an analytic formula for the decay rate and show that it is finite. Comparing our result with the well-known algebraic condition for the stability, we discuss stability conditions of tachyonic vacua at or above the BF bound.

  13. Nutrient flows between ecosystems can destabilize simple food chains.

    Science.gov (United States)

    Marleau, Justin N; Guichard, Frédéric; Mallard, François; Loreau, Michel

    2010-09-07

    Dispersal of organisms has large effects on the dynamics and stability of populations and communities. However, current metacommunity theory largely ignores how the flows of limiting nutrients across ecosystems can influence communities. We studied a meta-ecosystem model where two autotroph-consumer communities are spatially coupled through the diffusion of the limiting nutrient. We analyzed regional and local stability, as well as spatial and temporal synchrony to elucidate the impacts of nutrient recycling and diffusion on trophic dynamics. We show that nutrient diffusion is capable of inducing asynchronous local destabilization of biotic compartments through a diffusion-induced spatiotemporal bifurcation. Nutrient recycling interacts with nutrient diffusion and influences the susceptibility of the meta-ecosystem to diffusion-induced instabilities. This interaction between nutrient recycling and transport is further shown to depend on ecosystem enrichment. It more generally emphasizes the importance of meta-ecosystem theory for predicting species persistence and distribution in managed ecosystems.

  14. Low-dose amiodarone for the prevention of atrial fibrillation after coronary artery bypass grafting in patients older than 70 years

    Institute of Scientific and Technical Information of China (English)

    GU Song; SU Pi-xiong; LIU Yan; YAN Jun; ZHANG Xi-tao; WANG Tian-you

    2009-01-01

    Background Atrial fibrillation (AF) is one of the most common arrhythmia after coronary artery bypass grafting (CABG), which not only increases the suffering of the patients, but also prolongs hospital stay and enhances cost of care, especially for patients older than 70 years. This study was designed to evaluate the efficacy and safety of low-dose amiodarone in the prevention of AF after CABG, especially for the elderly.Methods Two hundred and ten senile patients undergoing off-pump CABG were included in this prospective, randomized, double-blind and placebo controlled study. Patients were given 10 mg/kg of amiodarone (low-dose amiodarone group, n=100) or placebo (control group, n=110) daily for 7 days before surgery and followed by 200 mg of amiodarone or placebo daily for 10 days postoperatively.Results Postoperative AF occurred in 16 patients (16%) receiving amiodarone and in 36 (37.7%) patients receiving placebo (P=0.006). AF occurred at (58.13±16.63) hours after CABG in the low-dose amiodarone group and at (45.03±17.40) hours in the control group (P=0.018). The maximum ventricular rate during AF was significantly slower in the low-dose amiodarone group ((121.42±28.91) beats/min) than in the control group ((134.11 ±30.57) beats/min, P=0.036). The duration of AF was (10.92±9.56) hours for the low-dose amiodarone group compared with (14.81 ±10.37) hours for the control group (P=0.002). The postoperative left ventricular ejection fraction (LVEF) was significantly improved in the low-dose amiodarone group (from (59.9 ±10.3)% to (63.4±11.4)%, P=0.001), and significantly higher compared with the control group ((58.5±10.7)%, P=0.002). Both groups had a similar incidence of complication other than rhythm disturbances (12.0% vs 16.4%, P=0.368). The low-dose amiodarone group patients had shorter hospital stays ((11.8±3.2) days vs (13.8±4.7) days, P=0.001) and lower cost of care (RMB (79 115±16 673) Yuan vs RMB (84 997±21 587) Yuan, P=0.031) than that of

  15. 胺碘酮长期应用致间质性肺炎%Interstitial pneumonitis due to long-term amiodarone use

    Institute of Scientific and Technical Information of China (English)

    任晓蕾; 贺真; 李玉珍

    2011-01-01

    1例62岁女性患者,因心房颤动服用胺碘酮300mg/d,4年后出现咳嗽、咯痰、发热。胸部CT检查示双肺间质弥漫性病变。考虑为药物性间质性肺炎,与胺碘酮有关。停用胺碘酮,给予泼尼松治疗。患者病情逐渐好转。%A 62-year-old woman presented with cough, expectoration, and fever after receiving amiodarone 300 mg/d for 4 yearsfor atria] fibrillation. A chest CT scan revealed bilateral pulmonary diffuse interstitial infiltrations. Drug-induced interstitial pneumonitiswas considered to be related to amiodarone. Amiodarone was discontinued, and prednisone was given. Her condition graduallyimproved.

  16. Comparative effect of amiodarone and amiodarone combined with other drugs in treatment of atrial fibrillation%胺碘酮与胺碘酮联合用药治疗心房纤颤疗效的比较

    Institute of Scientific and Technical Information of China (English)

    陈士良; 辛卫鹏; 高谊

    2011-01-01

    AIM: To compare the effect of amiodarone alone and amiodarone combined with other drugs in treatment of atrial fibrillation ( AF). METHODS: A total of 119 patients with AF were divided into single drug group ( n = 54) and multiple drug group ( n = 65 ). The single drug group received amiodarone treatment, whereas the multiple drug group received treatment of amiodarone together with glucose-insulin-potassium and diuretics. The recovery rate of AF and the maintenance rate of sinus rhythm were observed and compared after 6 months treatment. RESULTS: A significant increase in the recovery rate (from 80% vs. 94% ) and a significant decrease in the recovery duration of sinus rhythm from (55 ± 19) h to (39 ±15) h were observed in the multiple drug group. The maintenance rate increased from 81% to 95% , left atrial diameter decreased from (46 ±6) mm to (42 ±6) mm and the left ventricular diastolic diameter decreased from (52 ±7) mm to (45 ±6) mm in the multiple drug group. However, these phenomena were not seen in the single drug group. CONCLUSION: Compared with amiodarone alone, amiodarone combined with other drugs significantly increases the recovery rate and the maintenance rate in patients with AF.%目的:观察单纯用药与联合用药对心房纤颤(房颤)治疗效果.方法:选择119例房颤患者随机分为2组:单纯用药组54例,给予静脉胺碘酮150~300 mg后,继之以口服胺碘酮维持;联合用药组65例,使用极化液、硝酸甘油和小剂量利尿剂、胺碘酮,胺碘酮使用的剂量与方法同单纯用药组.观察两组房颤转复率和窦性维持率.结果:联合用药组的房颤转复率较单纯组明显提高(80% vs.94%,P<0.05),复律时间减少[(55±19)vs.(39±15)s,P<0.05],追踪复律半年后的维持率,联合用药组明显高于单纯用药组(81% vs.95%,P<0.05).复查B超显示:联合用药后,左心房内经明显缩小,从[(46±6)mm减少到(42±6)mm,P<0.05],左心

  17. Treatment of Atrial Fibrillation with Amiodarone Combined with Simvastatin and Amiodarone: A Meta-analysis%胺碘酮联合辛伐他汀与单用胺碘酮治疗心房颤动的Meta分析

    Institute of Scientific and Technical Information of China (English)

    易欣; 黎明江

    2012-01-01

    目的 评价胺碘酮联合辛伐他汀与单用胺碘酮治疗心房颤动(房颤)的疗效.方法 计算机检索Cochrane图书馆、EMBASE及万方医学数据库等1990~2011年收录的文献,对其中胺碘酮联合辛伐他汀(试验组)与单用胺碘酮(对照组)治疗房颤的随机对照试验进行Meta分析.结果 共纳入12篇文献954例.经异质性检验发现各研究结果具有同质性(P=1.0,I2=0%),故选择固定效应模型合并进行两组疗效的Meta分析,求得OR=2.98,95%CI(2.21,4.02),对总体效应进行假设检验得Z=7.18,P<0.00001,提示试验组治疗房颤的效果较对照组好.漏斗图分析结果显示两组疗效Meta分析结果存在偏倚的可能性较小.Meta分析结果示两组治疗房颤不良反应发生率比较差异无统计学意义.结论 胺碘酮联合辛伐他汀治疗房颤较单用胺碘酮效果好.%Objective To evaluate the effectiveness of Amiodarone combined with Simvastatin and Amiodarone in treating atrial fibrillation. Methods We retrieved the literature of Cochrane Library, EMBASE and Wangfang medical Databases, etc, which were published during 1990 to 2011. A Meta-analysis was conducted on the outcomes of randomized controlled trials (RCT) of Amiodarone with simvastatin (experimental group) and Amiodarone (control group) in treating atrial fibrillation. Results We included 954 cases of 12 records in the analysis. The test for heterogeneity in all studies showed that various research results were of heterogeneity (P = 1.0,I2 =0% ) , so a fixed effect model of Meta-analysis was conducted. The total odds ratio was 2.95, 95% confidence interval (95% CI) was from 2.21 to 4.02. The test of hypothesis for overall effects: Z =7. 18, P < 0.00001. The results in treatment of atrial fibrillation were better in experimental group than in control group. There was little deflective possibility in Meta-analysis result of treatment effectiveness from infundibular schema in the two groups. Mela

  18. Screening of herbal components for attenuating amiodarone-induced hepatotoxicity on gel-entrapped rat hepatocytes.

    Science.gov (United States)

    Deng, Xudong; Shen, Chong; Meng, Qin

    2014-01-01

    Amiodarone (AMD) is a hepatotoxic drug that has been widely used as a class III antiarrhythmic drug. Because, to date, only a few kinds of protectants are able to reduce AMD hepatotoxicity, this article utilized gel-entrapped rat hepatocytes to screen effective protectants from a series of herbal compounds for their effects against AMD-induced toxicity. Herbal compounds, including matrine, silibinin, glycyrrhizic acid, schisandrin B, epigallocatechin gallate and anisodamine, were cotreated with AMD to assess their protective effect, whereas vitamin E, which has been shown to be protective in rats, was selected as a control. It was found that vitamin E, as with its function in rats, provided the best protection in gel-entrapped rat hepatocytes, whereas silibinin, a major component of silymarin, could largely reduce AMD-induced hepatotoxicity, performing a similar function as silymarin in rats. The results illustrated that gel-entrapped hepatocytes may reflect the protective effects of drugs and serve as a reliable model for screening hepatoprotectants. Moreover, matrine, a widely used monomer of the traditional Chinese medicine, Sophora flavescens, for treatment of arrhythmia, was evidenced to show some effective protections against AMD hepatotoxicity. Taken together, gel-entrapped rat hepatocytes may provide a platform for screening effective candidates from the herbal component library.

  19. EFFICACY AND SAFETY OF SINUS RHYTHM RESTORATION WITH AMIODARONE AND PROPAFENONE IN OUTPATIENTS, ECONOMIC ASPECTS (BASED ON DATA OF N.A. SEMASHKO NORTHERN MEDICAL CLINICAL CENTER

    Directory of Open Access Journals (Sweden)

    T. A. Istomina

    2010-01-01

    Full Text Available Aim. To study efficacy and safey of sinus rhythm restoration with amiodarone and propafenone in outpatients with recurrent atrial fibrillation (AF, and to estimate pharmacoeconomic efficiency of such cardioversion in comparison with hospital treatment.Material and methods. Patients (n=199; aged 59.2±1.36 with paroxysmal (73.9% or persistent (26.1% AF were included into the multicenter prospective study. Follow-up period was 13.14 months (min 1 month, max 36 months. Patients with arrhythmia relapse <48 h received outpatient cardioversion with amiodarone or propafenone orally. Daily outpatient examination, including ECG and blood pressure monitoring every 30-60 min, was carried out to evaluate efficacy of cardioversion and hemodynamics. Phone contact with patients was available. Patients with unstable hemodynamics received cardioversion in hospital. Patients received propafenone in cumulative dose of 600 mg (150-300 mg every hour, and amiodarone 600-800 mg daily. The cost/effectiveness ratio (CER was estimated. This ratio shows the cost of one unit of effect.Results. Outpatient cardioversion with amiodarone was started 24 h earlier (p=0.029 and with propafenone — 4.5 h earlier (p=0.002 than that in hospital. The average dose of amiodarone in ambulatory cardioversion was 1.3 times less (713.7±84,62 mg, p=0.345 than that in hospital cardioversion. Outpatient treatment with amiodarone restored sinus rhythm 8.7 h earlier, and with propafenone - 3.5 h earlier than the same treatments in hospital. Efficiency of hospital cardioversion with amiodarone was 70%, with propafenone - 80%, and efficiency of outpatient cardioversion — 96,1% and 98,4%, respectively. Outpatient treatment did not cause any severe side effects. Expenses for outpatient cardioversion made up 143 724.25 rubles, and for hospital cardioversion — 92 870.47 rubles. Average treatment costs for one patient in hospital was 6 times greater than for an outpatient. Outpatient

  20. Involvement of Protein Phosphatases in the Destabilization of Methamphetamine-Associated Contextual Memory

    Science.gov (United States)

    Yu, Yang-Jung; Huang, Chien-Hsuan; Chang, Chih-Hua; Gean, Po-Wu

    2016-01-01

    Destabilization refers to a memory that becomes unstable when reactivated and is susceptible to disruption by amnestic agents. Here we delineated the cellular mechanism underlying the destabilization of drug memory. Mice were conditioned with methamphetamine (MeAM) for 3 d, and drug memory was assessed with a conditioned place preference (CPP)…

  1. Acoustic emissions in granular structures under gravitational destabilization

    Science.gov (United States)

    Thirot, J.-L.; Le Gonidec, Y.; Kergosien, B.

    2012-05-01

    In this work, we perform experiments in an acoustic tank to record acoustic emissions (AEs) occurring when a granular medium is submitted to a gravitational destabilization. The granular medium is composed of monodisperse glass beads filling a box which can be inclined from α=0° up to the avalanche threshold angle α0=28°. To respect quasi-static conditions, the angle increases by steps less than 3°/mn. An omnidirectional hydrophone records the continuous acoustic field in the bead structure until the avalanche occurs. We compare the results for different experimental configurations, in particular for dry and water saturated granular media, but also for different bead diameters (d=8, 3 and 0.3 mm) in order to span the viscosity range of the granular structure. We show that the AE signatures strongly depend on the viscosity parameter, which can be related to the Stokes number and the fluid/solid density ratio. The transition from a viscous to an inertial dynamic of the granular structure is discussed, based on these experimental results.

  2. Destabilization of Surfactant-Dispersed Carbon Nanotubes by Anions

    Science.gov (United States)

    Hirano, Atsushi; Gao, Weilu; He, Xiaowei; Kono, Junichiro

    2017-01-01

    The colloidal stability of surfactant-dispersed single-wall carbon nanotubes (SWCNTs) is determined by microscopic physicochemical processes, such as association, partitioning, and adsorption propensities. These processes can be controlled by the addition of solutes. While the effects of cations on the colloidal stability of SWCNTs are relatively well understood, little is known about the effects of anions. In this study, we examined the effects of anions on the stability of SWCNTs dispersed by sodium dodecyl sulfate (SDS) using sodium salts, such as NaCl and NaSCN. We observed that the intensity of the radial breathing mode Raman peaks rapidly decreased as the salts were added, even at concentrations less than 25 mM, indicating the association of SWCNTs. The effect was stronger with NaSCN than NaCl. We propose that the association of SWCNTs was caused by thermodynamic destabilization of SDS assemblies on SWCNT surfaces by these salts, which was confirmed through SWCNT separation experiments using aqueous two-phase extraction and gel chromatography. These results demonstrate that neutral salts can be used to control the colloidal stability of surfactant-dispersed SWCNTs.

  3. Microfluidic destabilization of viscous stratifications: Interfacial waves and droplets

    Science.gov (United States)

    Hu, Xiaoyi; Cubaud, Thomas

    2016-11-01

    Microfluidic two-fluid flows with large differences in viscosity are experimentally investigated to examine the role of fluid properties on hydrodynamic destabilization processes at the small scale. Two- and three-layer flow configurations are systematically studied in straight square microchannels using miscible and immiscible fluid pairs. We focus our attention on symmetric three-layer stratifications with a fast central stream made of low-viscosity fluid and a slow sheath flow composed of high-viscosity fluid. We quantify the influence of the capillary and the Reynolds numbers on the formation and evolution of droplets and wavy stratifications. Several functional relationships are developed for the morphology and dynamics of droplets and interfacial waves including size, celerity and frequency. In the wavy stratification regime, the formation and entrainment of thin viscous ligaments from wave crests display a rich variety of dynamics either in the presence or in the absence of interfacial tension between liquids. This work is supported by NSF (CBET-1150389).

  4. Dlic1 deficiency impairs ciliogenesis of photoreceptors by destabilizing dynein

    Institute of Scientific and Technical Information of China (English)

    Shanshan Kong; Xinrong Du; Chao Peng; Yiming Wu; Huirong Li; Xi Jin; Ling Hou

    2013-01-01

    Cytoplasmic dynein 1 is fundamentally important for transporting a variety of essential cargoes along microtubules within eukaryotic cells.However,in mammals,few mutants are available for studying the effects of defects in dynein-controlled processes in the context of the whole organism.Here,we deleted mouse Dlic1 gene encoding DLIC1,a subunit of the dynein complex.Dlic1-/-mice are viable,but display severe photoreceptor degeneration.Ablation of Dlic1 results in ectopic accumulation of outer segment (OS) proteins,and impairs OS growth and ciliogenesis of photoreceptors by interfering with Rabll-vesicle trafficking and blocking efficient OS protein transport from Golgi to the basal body.Our studies show that Dlic1 deficiency partially blocks vesicle export from endoplasmic reticulum (ER),but seems not to affect vesicle transport from the ER to Golgi.Further mechanistic study reveals that lack of Dlic1 destabilizes dynein subunits and alters the normal subcellular distribution of dynein in photoreceptors,probably due to the impaired transport function of dynein.Our results demonstrate that Dlic1 plays important roles in ciliogenesis and protein transport to the OS,and is required for photoreceptor development and survival.The Dlic1-/-mice also provide a new mouse model to study human retinal degeneration.

  5. Evolution of intracellular compartmentalization.

    Science.gov (United States)

    Diekmann, Yoan; Pereira-Leal, José B

    2013-01-15

    Cells compartmentalize their biochemical functions in a variety of ways, notably by creating physical barriers that separate a compartment via membranes or proteins. Eukaryotes have a wide diversity of membrane-based compartments, many that are lineage- or tissue-specific. In recent years, it has become increasingly evident that membrane-based compartmentalization of the cytosolic space is observed in multiple prokaryotic lineages, giving rise to several types of distinct prokaryotic organelles. Endosymbionts, previously believed to be a hallmark of eukaryotes, have been described in several bacteria. Protein-based compartments, frequent in bacteria, are also found in eukaryotes. In the present review, we focus on selected intracellular compartments from each of these three categories, membrane-based, endosymbiotic and protein-based, in both prokaryotes and eukaryotes. We review their diversity and the current theories and controversies regarding the evolutionary origins. Furthermore, we discuss the evolutionary processes acting on the genetic basis of intracellular compartments and how those differ across the domains of life. We conclude that the distinction between eukaryotes and prokaryotes no longer lies in the existence of a compartmentalized cell plan, but rather in its complexity.

  6. Amiodarone use after acute myocardial infarction complicated by heart failure and/or left ventricular dysfunction may be associated with excess mortality

    DEFF Research Database (Denmark)

    Thomas, Kevin L; Al-Khatib, Sana M; Lokhnygina, Yuliya;

    2008-01-01

    BACKGROUND: We sought to assess the association of amiodarone use with mortality during consecutive periods in patients with post-acute myocardial infarction with left ventricular systolic dysfunction and/or HF treated with a contemporary medical regimen. METHODS: This study used data from VALIAN...

  7. The microtubule destabilizing protein stathmin controls the transition from dividing neuronal precursors to postmitotic neurons during adult hippocampal neurogenesis.

    Science.gov (United States)

    Boekhoorn, Karin; van Dis, Vera; Goedknegt, Erika; Sobel, André; Lucassen, Paul J; Hoogenraad, Casper C

    2014-12-01

    The hippocampus is one of the two areas in the mammalian brain where adult neurogenesis occurs. Adult neurogenesis is well known to be involved in hippocampal physiological functions as well as pathophysiological conditions. Microtubules (MTs), providing intracellular transport, stability, and transmitting force, are indispensable for neurogenesis by facilitating cell division, migration, growth, and differentiation. Although there are several examples of MT-stabilizing proteins regulating different aspects of adult neurogenesis, relatively little is known about the function of MT-destabilizing proteins. Stathmin is such a MT-destabilizing protein largely restricted to the CNS, and in contrast to its developmental family members, stathmin is also expressed at significant levels in the adult brain, notably in areas involved in adult neurogenesis. Here, we show an important role for stathmin during adult neurogenesis in the subgranular zone of the mouse hippocampus. After carefully mapping stathmin expression in the adult dentate gyrus (DG), we investigated its role in hippocampal neurogenesis making use of stathmin knockout mice. Although hippocampus development appears normal in these animals, different aspects of adult neurogenesis are affected. First, the number of proliferating Ki-67+ cells is decreased in stathmin knockout mice, as well as the expression of the immature markers Nestin and PSA-NCAM. However, newborn cells that do survive express more frequently the adult marker NeuN and have a more mature morphology. Furthermore, our data suggest that migration in the DG might be affected. We propose a model in which stathmin controls the transition from neuronal precursors to early postmitotic neurons.

  8. Long-term efficacy of empirical chronic amiodarone therapy in patients with sustained ventricular tachyarrhythmia and structural heart disease.

    Science.gov (United States)

    Aiba, Takeshi; Kurita, Takashi; Taguchi, Atsushi; Shimizu, Wataru; Suyama, Kazuhiro; Aihara, Naohiko; Kamakura, Shiro

    2002-04-01

    The efficacy of empirical chronic oral amiodarone therapy in 129 patients with sustained ventricular tachyarrhythmia (VTNVF) and structural heart disease is evaluated. Twenty-nine patients were treated with class I drugs and monitored by electrophysiological study (EPS) and Holter electrocardiogram (ECG) (class I). The remaining 100 non-responders to the class I drugs were treated with oral amiodarone, of whom 70 were tolerant (AMD+) and 30 were intolerant (AMD-). Patients were followed up to 36 months. The primary and secondary end-points were recurrence of VT/VF and hypothetical death, respectively; whereby, hypothetical death was defined as actual death and the event of rapid VT.VF (heart rate >240beats/min) in patients with an implantable cardioverter defibrillator. Class I and AMD+ patients showed a better prognosis than AMD- patients. The VT/VF event free at 36 months in class I (64.8%) and AMD+ (56.1%) patients were significantly higher than that in AMD- (27.2%) (pAMD+ (83.6%) patients were significantly higher than that in AMD- (57.0%) (pdisease.

  9. Cognitive Fatigue Destabilizes Economic Decision Making Preferences and Strategies.

    Directory of Open Access Journals (Sweden)

    O'Dhaniel A Mullette-Gillman

    Full Text Available It is common for individuals to engage in taxing cognitive activity for prolonged periods of time, resulting in cognitive fatigue that has the potential to produce significant effects in behaviour and decision making. We sought to examine whether cognitive fatigue modulates economic decision making.We employed a between-subject manipulation design, inducing fatigue through 60 to 90 minutes of taxing cognitive engagement against a control group that watched relaxing videos for a matched period of time. Both before and after the manipulation, participants engaged in two economic decision making tasks (one for gains and one for losses. The analyses focused on two areas of economic decision making--preferences and choice strategies. Uncertainty preferences (risk and ambiguity were quantified as premium values, defined as the degree and direction in which participants alter the valuation of the gamble in comparison to the certain option. The strategies that each participant engaged in were quantified through a choice strategy metric, which contrasts the degree to which choice behaviour relies upon available satisficing or maximizing information. We separately examined these metrics for alterations within both the gains and losses domains, through the two choice tasks.The fatigue manipulation resulted in significantly greater levels of reported subjective fatigue, with correspondingly higher levels of reported effort during the cognitively taxing activity. Cognitive fatigue did not alter uncertainty preferences (risk or ambiguity or informational strategies, in either the gains or losses domains. Rather, cognitive fatigue resulted in greater test-retest variability across most of our economic measures. These results indicate that cognitive fatigue destabilizes economic decision making, resulting in inconsistent preferences and informational strategies that may significantly reduce decision quality.

  10. 普罗帕酮联合胺碘酮使用对混合性心律失常控制的临床观察%Propafenone Joint Amiodarone Use of Mixed Arrhythmia Controlled Clinical Observation

    Institute of Scientific and Technical Information of China (English)

    连献杰

    2015-01-01

    Objective Observation of propafenone joint amiodarone use and separate use of amiodarone on mixed arrhythmia converting the curative effect of contrast. Methods Wil exist more than two kinds of new 34 cases of arrhythmia patients were randomly divided into into propafenone joint amiodarone group (19 cases) and amiodarone group (15 cases), the selected cases not including slow arrhythmia. Propafenone joint amiodarone group was given propafenone 35~70 mg (5~10 min after injection) intravenous injection, if invalid, 20 min after repeated 1 time, rhythm control give amiodarone after 1 mg/min to the micro pump pumping control; Amiodarone group, give amiodarone 150 mg of diluted intravenous glucose injection (10~15 min after injection), if the invalid 10~15 min after repeated injections, rhythm control give amiodarone after 1 mg/min to the micro pump pumping control. If two groups patients 3 consecutive load intravenous drug can not control the rhythm of the heart, it wil give amiodarone to the micro pump pumping 1 mg/min.Results Propafenone group joint amiodarone amiodarone and converting efficiency were 95% (18/19) and 73% (11/15) (P<0.05); Propafenone joint amiodarone group average converting time (1.2 h), amiodarone group average converting time (3.5 h). Conclusion Propafenone joint amiodarone use on converting mixed arrhythmia in curative effect is better than the separate use of amiodarone.%目的 观察普罗帕酮联合胺碘酮使用与单独使用胺碘酮对混合性心律失常转复的疗效对比.方法 将同时存在有2种以上新发心律失常的患者34例随机分为成普罗帕酮联合胺碘酮组(19例)和胺碘酮组(15例)(此次所选病例不包括缓慢型心律失常).普罗帕酮联合胺碘酮组给予普罗帕酮35~70 mg(5~10 min注完)静脉注射,若无效,20 min后重复1次,心律控制后给予胺碘酮1 mg/min持继微量泵泵入控制;胺碘酮组,给予胺碘酮150 mg以葡萄糖注射液稀释后静脉注射(10~15 min

  11. Amiodarone therapy in chronic heart failure and myocardial infarction: a review of the mortality trials with special attention to STAT-CHF and the GESICA trials. Grupo de Estudio de la Sobrevida en la Insuficiencia Cardiaca en Argentina.

    Science.gov (United States)

    Pinto, J V; Ramani, K; Neelagaru, S; Kown, M; Gheorghiade, M

    1997-01-01

    Amiodarone appears to reduce sudden death in patients with left ventricular dysfunction resulting from an acute MI or a primary dilated cardiomyopathy, particularly if complex ventricular arrhythmias are present. Amiodarone's beneficial effect on mortality in these patients could be unrelated to its antiarrhythmic effects. Multiple factors could account for the improvement in mortality such as the drug's antiischemic effects, neuromodulating effects, its effect on left ventricular function and on heart rate. Moreover, patients with LV dysfunction who have survived an episode of sudden death would potentially benefit from amiodarone therapy. Future trials are needed to determine the precise subsets(s) of patients who would benefit from the drug and the most efficacious dosing regimen for the drug. Based on available data, amiodarone is the only antiarrhythmic agent which has not been shown to increase mortality in patients with chronic heart failure.

  12. Mechanisms governing the reactivation-dependent destabilization of memories and their role in extinction

    OpenAIRE

    Charlotte Rachael Flavell; Elliot eLambert; Winters, Boyer D.; Bredy, Timothy W.

    2013-01-01

    The extinction of learned associations has traditionally been considered to involve new learning, which competes with the original memory for control over behaviour. However, a recent resurgence of interest in reactivation-dependent amnesia has revealed that the retrieval of fear-related memory (with what is essentially a brief extinction session) can result in it’s destabilization. This review discusses some of the cellular and molecular mechanisms that are involved in the destabilization of...

  13. LKB1 destabilizes microtubules in myoblasts and contributes to myoblast differentiation.

    Directory of Open Access Journals (Sweden)

    Isma Mian

    Full Text Available BACKGROUND: Skeletal muscle myoblast differentiation and fusion into multinucleate myotubes is associated with dramatic cytoskeletal changes. We find that microtubules in differentiated myotubes are highly stabilized, but premature microtubule stabilization blocks differentiation. Factors responsible for microtubule destabilization in myoblasts have not been identified. FINDINGS: We find that a transient decrease in microtubule stabilization early during myoblast differentiation precedes the ultimate microtubule stabilization seen in differentiated myotubes. We report a role for the serine-threonine kinase LKB1 in both microtubule destabilization and myoblast differentiation. LKB1 overexpression reduced microtubule elongation in a Nocodazole washout assay, and LKB1 RNAi increased it, showing LKB1 destabilizes microtubule assembly in myoblasts. LKB1 levels and activity increased during myoblast differentiation, along with activation of the known LKB1 substrates AMP-activated protein kinase (AMPK and microtubule affinity regulating kinases (MARKs. LKB1 overexpression accelerated differentiation, whereas RNAi impaired it. CONCLUSIONS: Reduced microtubule stability precedes myoblast differentiation and the associated ultimate microtubule stabilization seen in myotubes. LKB1 plays a positive role in microtubule destabilization in myoblasts and in myoblast differentiation. This work suggests a model by which LKB1-induced microtubule destabilization facilitates the cytoskeletal changes required for differentiation. Transient destabilization of microtubules might be a useful strategy for enhancing and/or synchronizing myoblast differentiation.

  14. Comparison of use and role of adrenaline and amiodarone in cardiac arrest:Case of emergency center in Kosovo

    Institute of Scientific and Technical Information of China (English)

    Basri Lenjani; Nehat Baftiu; Ilaz Bunjaku; Kadir Hyseni; Arianit Jakupi

    2013-01-01

    Objective: To investigate application of cardiopulmonary resuscitation (CPR) measures within the golden minutes in Europe. Methods: The collected data belong to the patients with cardiac arrest that have been recorded in patients’ protocol logbook at the Emergency Clinic. During the 2010-2011 in the Emergency Center of the CUCK in Prishtina have been treated a total of 269 patients with cardiac arrest, of whom 159 or 59.1% have been treated in 2010, and 110 patients or 40.9% in 2011. Cardiac arrest cases were present during all days of the week, but most frequently cases have been reported on Monday with 32.0% of cases, and on Friday with 24.5% of cases. All patients with cardiac arrest have been treated with physiological solution. Results: In 245 or 91.1% patients adrenaline has been applied; in 64 or 23.8% amiodarone has been applied; in 12 or 4.5% cases atropine has been applied, 11 or 4.1% of cases were treated with NaHCO3; 7 or 2.6% of cases were treated with lidocaine; and 6 or 2.2% of cases were treated with dopamine. All survivors from cardiac arrest have received appropriate medical assistance within 10 minutes from attack, which implies that if cardiac arrest occurs near an health care institution (with an opportunity to provide the emergent health care) the rate of survival is higher. Conclusions: Anti-arrhythmic drugs as with vasopressors, the evidence that anti-arrhythmic drugs are of benefit in cardiac is limited. No anti-arrhythmic drug given during human cardiac arrest has been shown to increase survival to hospital discharge, although amiodarone has been shown to increase survival to hospital admission after shock-refractory VF/VT. There are no data on the use of amiodarone for shock-refractory VF/VT when single shocks are used. Despite the lack of human long-term outcome data, the balance of evidence is in favour of the use of some anti-arrhythmic drugs for the management of arrhythmias in cardiac arrest.

  15. HER2 phosphorylates and destabilizes pro-apoptotic PUMA, leading to antagonized apoptosis in cancer cells.

    Science.gov (United States)

    Carpenter, Richard L; Han, Woody; Paw, Ivy; Lo, Hui-Wen

    2013-01-01

    HER2 is overexpressed in 15-20% of breast cancers. HER2 overexpression is known to reduce apoptosis but the underlying mechanisms for this association remain unclear. To elucidate the mechanisms for HER2-mediated survival, we investigated the relationship between HER2 and p53 upregulated modulator of apoptosis (PUMA), a potent apoptosis inducer. Our results showed that HER2 interacts with PUMA, which was independent of HER2 activation. In addition, we observed that HER2 interacted with PUMA in both mitochondrial and non-mitochondrial compartments. We next examined whether HER2 phosphorylates PUMA. Notably, PUMA tyrosine phosphorylation has never been reported. Using an intracellular assay, we found PUMA to be phosphorylated in breast cancer cells with activated HER2. Via cell-free HER2 kinase assay, we observed that PUMA was directly phosphorylated by HER2. Activation of HER2 decreased PUMA protein half-life. To identify which of the three tyrosines within PUMA are targeted by HER2, we generated three PUMA non-phosphorylation mutants each with a single Tyr→Phe substitution. Results indicated that each PUMA single mutant had lost some, but not all phosphorylation by HER2 indicating that HER2 targets all three tyrosines. Consequently, we created an additional PUMA mutant with all three tyrosines mutated (TM-PUMA) that could not be phosphorylated by HER2. Importantly, TM-PUMA was found to have a longer half-life than PUMA. An inverse association was observed between HER2 and PUMA in 93 invasive breast carcinoma samples. We further found that TM-PUMA suppressed growth of breast cancer cells to a greater degree than PUMA. Also, TM-PUMA had a stronger propensity to induce apoptosis than PUMA. Together, our results demonstrate, for the first time, that PUMA can be tyrosine phosphorylated and that HER2-mediated phosphorylation destabilizes PUMA protein. The HER2-PUMA interplay represents a novel mechanism by which PUMA is regulated and a new molecular basis for HER2

  16. Combined etiology of anaphylactic cardiogenic shock: Amiodarone, epinephrine, cardioverter defibrillator, left ventricular assist devices and the Kounis syndrome

    Directory of Open Access Journals (Sweden)

    Nicholas G Kounis

    2015-01-01

    Full Text Available Anaphylactic shock is a life-threatening condition which needs detailed and mediculous clinical assessment and thoughtful treatment. Several causes can join forces in order to degranulate mast cells. Amiodarone which is an iodine-containing highly lipophilic benzofuran can induce allergic reactions and anaphylactic shock in sensitized patients. Epinephrine is a life saving drug, but in sulfite allergic patients it should be given with caution due its metabisulfite preservative. Metals covering cardiac defibrillators and pacemakers can act as antigens attached to serum proteins and induce allergic reactions. In anaphylactic shock, myocardial involvement due to vasospasm-induced coronary blood flow reduction manifesting as Kounis syndrome should be always considered. Clinically, combined treatment targeting the primary cause of anaphylaxis together with protection of cardiac tissue seems to be of paramount importance.

  17. The safety assessment of saffron (Crocus sativus L.) on sympathovagal balance and heart rate variability; a comparison with amiodarone.

    Science.gov (United States)

    Joukar, Siyavash; Dehesh, Mohammad-Moein

    2015-12-01

    Dry stigmas of the Crocus sativus L. (Saffron) are well known in world as a popular flavouring and therapeutic agent. The anxiolytic, antidepressant, anticonvulsant and antiarrhythmic effects of saffron suggest that it may affect the autonomic control of the heart. This study assessed its safety on cardiac sympathovagal balance and heart rate variability in rat. Experimental groups were control, Saf50, Saf100, Saf200 (received saffron at dosages of 50 and 100 and 200 mg/kg/d, orally, respectively) and Amio (received 30 mg/mL/kg/d of amiodarone, orally, for 7 days) groups. On day 8, the frequency domain and time domain indices of animals' electrocardiograms were calculated. The heart rate decreased and RR interval increased in Saf200 and Amio groups (Psaffron not only has no harmful effect on activity of cardiac autonomic nervous system, but it may improve the stability of heart sympathovagal balance in normal rat.

  18. Slurry Erosion Behavior of Destabilized and Deep Cryogenically Treated Cr-Mn-Cu White Cast Irons

    Directory of Open Access Journals (Sweden)

    S. Gupta

    2016-12-01

    Full Text Available The effects of destabilization treatment and destabilization followed by cryogenic treatment have been evaluated on the microstructural evolution and sand-water slurry erosion behavior of Cr-Mn-Cu white cast irons. The phase transformations after the destabilization and cryotreatment have been characterized by bulk hardness measurement, optical and scanning electron microscopy, x-ray diffraction analysis. The static corrosion rate has been measured in tap water (with pH=7 and the erosion-corrosion behavior has been studied by slurry pot tester using sand-water slurry. The test results indicate that the cryogenic treatment has a significant effect in minimizing the as-cast retained austenite content and transforming into martensitic and bainitic matrix embedded with ultra-fine M7C3 alloy carbides. In contrast, by conventional destabilization treatment retained austenite in the matrix are not fully eliminated. The slurry erosive wear resistance has been compared with reference to destabilized and cryotreated high chromium iron samples which are commonly employed for such applications. The cryotreated Cr-Mn-Cu irons have exhibited a comparable erosive wear performance to those of high chromium irons. Higher hardness combined with improved corrosion resistance result in better slurry erosion resistance.

  19. Pattern destabilization and emotional processing in cognitive therapy for personality disorders

    Directory of Open Access Journals (Sweden)

    Adele M. Hayes

    2015-02-01

    Full Text Available Clinical trials of treatments for personality disorders can provide a medium for studying the process of therapeutic change with particularly entrenched and self-perpetuating systems and might reveal important principles of system transition. We examined the extent to which maladaptive personality patterns were destabilized in a trial of cognitive therapy personality disorders (CT-PD and how destabilization was associated with emotional processing and treatment outcomes. Dynamic systems theory was used as a theoretical framework for studying change. Method: Participants were 27 patients diagnosed with Avoidant or Obsessive Compulsive Personality Disorder, who completed an open trial of CT-PD. Raters coded treatment sessions using a coding system that operationalizes emotional processing, as well as cognitive, affective, behavioral, and somatic components of pathological (negative and more adaptive (positive patterns of functioning. Pattern destabilization (dispersion scores during the early phase of treatment (phase 1: session 1-10 and the schema-focused phase (phase 2: session 11-34 were calculated using a program called GridWare. Results: More pattern destabilization and emotional processing in the schema-focused phase of CT-PD predicted more improvement in personality disorder symptoms and positive pattern strength at the end of treatment, whereas these variables in phase 1 did not predict outcome. Conclusions: In addition to illustrating a quantitative method for studying destabilization and change of patterns of psychopathology, we present findings that are consistent with recent updates of emotional processing theory and with principles from dynamic systems theory.

  20. Destabilization analysis of overlapping underground chambers induced by blasting vibration with catastrophe theory

    Institute of Scientific and Technical Information of China (English)

    YAN Chang-bin; XU Guo-yuan; ZUO Yu-jun

    2006-01-01

    According to the main characters of overlapping underground chambers, the roof (floor) of two adjacent underground chambers is simplified to the mechanical model that is the beam with build-in ends. And vibration load due to blasting is simplified to harmonic wave. The catastrophic model of double cusp for underground chambers destabilization induced by blasting vibration has been established under the circumstances of considering deadweight of the beam, and the condition of destabilization has been worked out. The critical safety thickness of the roof (floor) of underground chambers has been confirmed according to the destabilization condition. The influence of amplitude and frequency of blasting vibration load on the critical safety thickness has been analyzed, and the quantitative relation between velocity, frequency of blasting vibration and critical safety thickness has been determined. Research results show that the destabilization of underground chambers is not only dependent on the amplitude and frequency of blasting vibration load, but also related to deadweight load and intrinsic attribute. It is accordant to testing results and some related latest research results of blasting seismic effect. With increasing amplitude, the critical safety thickness of underground chambers decreases gradually. And the possibility of underground chambers destabilization increases. When the frequency of blasting vibration is equal to or very close to the frequency of beam, resonance effect will take place in the system. Then the critical safety thickness will turn to zero, underground chambers will be damaged severely, and its loading capacity will lose on the whole.

  1. EMC1-dependent stabilization drives membrane penetration of a partially destabilized non-enveloped virus

    Science.gov (United States)

    Bagchi, Parikshit; Inoue, Takamasa; Tsai, Billy

    2016-01-01

    Destabilization of a non-enveloped virus generates a membrane transport-competent viral particle. Here we probe polyomavirus SV40 endoplasmic reticulum (ER)-to-cytosol membrane transport, a decisive infection step where destabilization initiates this non-enveloped virus for membrane penetration. We find that a member of the ER membrane protein complex (EMC) called EMC1 promotes SV40 ER membrane transport and infection. Surprisingly, EMC1 does so by using its predicted transmembrane residue D961 to bind to and stabilize the membrane-embedded partially destabilized SV40, thereby preventing premature viral disassembly. EMC1-dependent stabilization enables SV40 to engage a cytosolic extraction complex that ejects the virus into the cytosol. Thus EMC1 acts as a molecular chaperone, bracing the destabilized SV40 in a transport-competent state. Our findings reveal the novel principle that coordinated destabilization-stabilization drives membrane transport of a non-enveloped virus. DOI: http://dx.doi.org/10.7554/eLife.21470.001 PMID:28012275

  2. Functional genomics of intracellular bacteria.

    Science.gov (United States)

    de Barsy, Marie; Greub, Gilbert

    2013-07-01

    During the genomic era, a large amount of whole-genome sequences accumulated, which identified many hypothetical proteins of unknown function. Rapidly, functional genomics, which is the research domain that assign a function to a given gene product, has thus been developed. Functional genomics of intracellular pathogenic bacteria exhibit specific peculiarities due to the fastidious growth of most of these intracellular micro-organisms, due to the close interaction with the host cell, due to the risk of contamination of experiments with host cell proteins and, for some strict intracellular bacteria such as Chlamydia, due to the absence of simple genetic system to manipulate the bacterial genome. To identify virulence factors of intracellular pathogenic bacteria, functional genomics often rely on bioinformatic analyses compared with model organisms such as Escherichia coli and Bacillus subtilis. The use of heterologous expression is another common approach. Given the intracellular lifestyle and the many effectors that are used by the intracellular bacteria to corrupt host cell functions, functional genomics is also often targeting the identification of new effectors such as those of the T4SS of Brucella and Legionella.

  3. Adaptation of the QT interval to heart rate changes in isolated perfused guinea pig heart: influence of amiodarone and D-sotalol.

    Science.gov (United States)

    Padrini, R; Speranza, G; Nollo, G; Bova, S; Piovan, D; Antolini, R; Ferrari, M

    1997-05-01

    The inadequacy of the QT interval to shorten following heart rate increase is a feature of the inherited long QT syndrome and may have a role in the genesis of the typical arrhythmias associated with this syndrome (torsade des pointes). The aim of our study was to evaluate whether drugs that prolong the QT interval, such as amiodarone and D-sotalol, may also impair the ability of the QT interval to adapt to sudden heart rate changes. Experiments were carried out on isolated perfused guinea pig hearts (Langendorff preparation). Driving frequency was changed, in steps, every two minutes (Hz: 2.5-3-2.5-3.75-2.5-5-2.5), while epicardial ECG was continuously recorded on magnetic tape. QT interval was automatically measured by means of a beat-by-beat analysis program. D-sotalol was added to the perfusion medium at a concentration of 4 micrograms ml-1, while amiodarone was administered, before in vitro evaluation, for seven days (50 mg kg-1 per day, intraperitoneally). In control experiments two phases of QT adaptation were identified: an abrupt QT shortening at the first beat after frequency change (QT1), followed by a gradual, exponential QT shortening that reached a new steady state in about 1 min (half life: 13 sec). The electrical restitution curve (the relation between QT1 and the corresponding diastolic interval) had a rate constant of 57 +/- 8 ms. Neither drug changed the slow component of QT adaptation. However, both drugs increased the ability of QT to shorten upon premature stimulation: D-sotalol by increasing the rate constant of the restitution curve and amiodarone by decreasing the y-intercept. Our results indicate that D-sotalol and amiodarone do not impair QT shortening during tachycardia but, on the contrary, they may favour QT adaptation, thus reducing the likelihood of the potentially lethal 'R on T phenomenon'. This may be an additional mechanism by which these drugs can exert their antifibrillatory action.

  4. Electromagnetic waves destabilized by runaway electrons in near-critical electric fields

    CERN Document Server

    Kómár, A; Fülöp, T

    2013-01-01

    Runaway electron distributions are strongly anisotropic in velocity space. This anisotropy is a source of free energy that may destabilize electromagnetic waves through a resonant interaction between the waves and the energetic electrons. In this work we investigate the high-frequency electromagnetic waves that are destabilized by runaway electron beams when the electric field is close to the critical field for runaway acceleration. Using a runaway electron distribution appropriate for the near-critical case we calculate the linear instability growth rate of these waves and conclude that the obliquely propagating whistler waves are most unstable. We show that the frequencies, wave numbers and propagation angles of the most unstable waves depend strongly on the magnetic field. Taking into account collisional and convective damping of the waves, we determine the number density of runaways that is required to destabilize the waves and show its parametric dependences.

  5. Mechanisms governing the reactivation-dependent destabilization of memories and their role in extinction

    Directory of Open Access Journals (Sweden)

    Charlotte Rachael Flavell

    2013-12-01

    Full Text Available The extinction of learned associations has traditionally been considered to involve new learning, which competes with the original memory for control over behaviour. However, a recent resurgence of interest in reactivation-dependent amnesia has revealed that the retrieval of fear-related memory (with what is essentially a brief extinction session can result in it’s destabilization. This review discusses some of the cellular and molecular mechanisms that are involved in the destabilization of a memory following it’s reactivation and/or extinction, and investigates the evidence that extinction may involve both new learning as well as a partial destabilization-induced erasure of the original memory trace.

  6. Recent changes to the Gulf Stream causing widespread gas hydrate destabilization.

    Science.gov (United States)

    Phrampus, Benjamin J; Hornbach, Matthew J

    2012-10-25

    The Gulf Stream is an ocean current that modulates climate in the Northern Hemisphere by transporting warm waters from the Gulf of Mexico into the North Atlantic and Arctic oceans. A changing Gulf Stream has the potential to thaw and convert hundreds of gigatonnes of frozen methane hydrate trapped below the sea floor into methane gas, increasing the risk of slope failure and methane release. How the Gulf Stream changes with time and what effect these changes have on methane hydrate stability is unclear. Here, using seismic data combined with thermal models, we show that recent changes in intermediate-depth ocean temperature associated with the Gulf Stream are rapidly destabilizing methane hydrate along a broad swathe of the North American margin. The area of active hydrate destabilization covers at least 10,000 square kilometres of the United States eastern margin, and occurs in a region prone to kilometre-scale slope failures. Previous hypothetical studies postulated that an increase of five degrees Celsius in intermediate-depth ocean temperatures could release enough methane to explain extreme global warming events like the Palaeocene-Eocene thermal maximum (PETM) and trigger widespread ocean acidification. Our analysis suggests that changes in Gulf Stream flow or temperature within the past 5,000 years or so are warming the western North Atlantic margin by up to eight degrees Celsius and are now triggering the destabilization of 2.5 gigatonnes of methane hydrate (about 0.2 per cent of that required to cause the PETM). This destabilization extends along hundreds of kilometres of the margin and may continue for centuries. It is unlikely that the western North Atlantic margin is the only area experiencing changing ocean currents; our estimate of 2.5 gigatonnes of destabilizing methane hydrate may therefore represent only a fraction of the methane hydrate currently destabilizing globally. The transport from ocean to atmosphere of any methane released--and thus its

  7. Destabilization and recovery of a yeast prion after mild heat shock.

    Science.gov (United States)

    Newnam, Gary P; Birchmore, Jennifer L; Chernoff, Yury O

    2011-05-06

    Yeast prion [PSI(+)] is a self-perpetuating amyloid of the translational termination factor Sup35. Although [PSI(+)] propagation is modulated by heat shock proteins (Hsps), high temperature was previously reported to have little or no effect on [PSI(+)]. Our results show that short-term exposure of exponentially growing yeast culture to mild heat shock, followed by immediate resumption of growth, leads to [PSI(+)] destabilization, sometimes persisting for several cell divisions after heat shock. Prion loss occurring in the first division after heat shock is preferentially detected in a daughter cell, indicating the impairment of prion segregation that results in asymmetric prion distribution between a mother cell and a bud. Longer heat shock or prolonged incubation in the absence of nutrients after heat shock led to [PSI(+)] recovery. Both prion destabilization and recovery during heat shock depend on protein synthesis. Maximal prion destabilization coincides with maximal imbalance between Hsp104 and other Hsps such as Hsp70-Ssa. Deletions of individual SSA genes increase prion destabilization and/or counteract recovery. The dynamics of prion aggregation during destabilization and recovery are consistent with the notion that efficient prion fragmentation and segregation require a proper balance between Hsp104 and other (e.g., Hsp70-Ssa) chaperones. In contrast to heat shock, [PSI(+)] destabilization by osmotic stressors does not always depend on cell proliferation and/or protein synthesis, indicating that different stresses may impact the prion via different mechanisms. Our data demonstrate that heat stress causes asymmetric prion distribution in a cell division and confirm that the effects of Hsps on prions are physiologically relevant.

  8. Destabilization of fast particle stabilized sawteeth in ASDEX Upgrade with electron cyclotron current drive

    DEFF Research Database (Denmark)

    Igochine, V.; Chapman, I.T.; Bobkov, V.;

    2011-01-01

    It is often observed that large sawteeth trigger the neoclassical tearing mode well below the usual threshold for this instability. At the same time, fast particles in the plasma core stabilize sawteeth and provide these large crashes. The paper presents results of first experiments in ASDEX...... Upgrade for destabilization of fast particle stabilized sawteeth with electron cyclotron current drive (ECCD). It is shown that moderate ECCD from a single gyrotron is able to destabilize the fast particle stabilized sawteeth. A reduction in sawtooth period by about 40% was achieved in first experiments...

  9. 胺碘酮联用缬沙坦治疗阵发性房颤临床观察%Effect of amiodarone combined with valsartan in treating paroxysmal atrial fibrillation

    Institute of Scientific and Technical Information of China (English)

    王会玖; 王智斌; 杨迅

    2011-01-01

    目的 观察口服胺碘酮联合应用血管紧张素Ⅱ受体拮抗剂(ARB)缬沙坦在阵发性心房颤动(简称房颤)复律后维持窦律的疗效及对左心房功能的影响.方法 将68例阵发性房颤患者分为单纯口服胺碘酮组(对照组,34例)和胺碘酮加缬沙坦组(治疗组,34例),疗效观察12个月.结果 共66例完成治疗,随访12个月,治疗1、3个月后两组左心房内径比较差异无统计学意义,但6、12个月后两组差异有统计学意义(P<0.05),窦性心律维持6、12个月后比较差异有统计学意义(P<0.05).结论 胺碘酮与缬沙坦联合治疗阵发性房颤维持窦性心律的疗效优于单用胺碘酮,并能延缓左心房扩大.%Objective To investigate the efficacy of amiodarone combined with angiotensin Ⅱ receptor antagonist(ARB)valsartan on paroxysmal atrial fibrillation and left atrial function.Methods A total of 68 patients with paroxysmal atrial fibrillation were randomly divided into two groups:simple amiodarone group(control group,34 cases),amiodarone + valsartan group(stydy group,34 cases),they were treated for 12 months,following-up for 12 months.Results Totally 66 cases completed the treatment.The left atrium in simple amiodarone group was significantly higher than that in amiodarone + valsartan group 6-12 months after treatment(P < 0.05); the maintenance rates of 6 months,12 months of sinus rhythm in amiodarone + valsartan group were significantly higher than those in simple amiodarone group(P < 0.05).Conclusions Amiodarone combined with valsartan can reverse expansion of left atrium,and is more effective for transfer and maintain sinus rhythm compared with simple amiodarone treatment in patients with paroxysmal atrial fibrillation.

  10. Metallochaperones regulate intracellular copper levels.

    Directory of Open Access Journals (Sweden)

    W Lee Pang

    Full Text Available Copper (Cu is an important enzyme co-factor that is also extremely toxic at high intracellular concentrations, making active efflux mechanisms essential for preventing Cu accumulation. Here, we have investigated the mechanistic role of metallochaperones in regulating Cu efflux. We have constructed a computational model of Cu trafficking and efflux based on systems analysis of the Cu stress response of Halobacterium salinarum. We have validated several model predictions via assays of transcriptional dynamics and intracellular Cu levels, discovering a completely novel function for metallochaperones. We demonstrate that in addition to trafficking Cu ions, metallochaperones also function as buffers to modulate the transcriptional responsiveness and efficacy of Cu efflux. This buffering function of metallochaperones ultimately sets the upper limit for intracellular Cu levels and provides a mechanistic explanation for previously observed Cu metallochaperone mutation phenotypes.

  11. Preparation of liposomal amiodarone and investigation of its cardiomyocyte-targeting ability in cardiac radiofrequency ablation rat model

    Directory of Open Access Journals (Sweden)

    Zhuge Y

    2016-05-01

    Full Text Available Ying Zhuge,1,* Zhi-Feng Zheng,1,* Mu-Qing Xie,2 Lin Li,2 Fang Wang,1 Feng Gao2,3 1Department of Cardiology, Shanghai First People’s Hospital of Nanjing Medical University, 2Department of Pharmaceutics, School of Pharmacy, 3Shanghai Key Laboratory of Functional Materials Chemistry, East China University of Science and Technology, Shanghai, People’s Republic of China*These authors contributed equally to this workAbstract: The objective of this study was to develop an amiodarone hydrochloride (ADHC-loaded liposome (ADHC-L formulation and investigate its potential for cardiomyocyte targeting after cardiac radiofrequency ablation (CA in vivo. The ADHC-L was prepared by thin-film method combined with ultrasonication and extrusion. The preparation process was optimized by Box–Behnken design with encapsulation efficiency as the main evaluation index. The optimum formulation was quantitatively obtained with a diameter of 99.9±0.4 nm, a zeta potential of 35.1±10.9 mV, and an encapsulation efficiency of 99.5%±13.3%. Transmission electron microscopy showed that the liposomes were spherical particles with integrated bilayers and well dispersed with high colloidal stability. Pharmacokinetic studies were investigated in rats after intravenous administration, which revealed that compared with free ADHC treatment, ADHC-L treatment showed a 5.1-fold increase in the area under the plasma drug concentration–time curve over a period of 24 hours (AUC0–24 h and an 8.5-fold increase in mean residence time, suggesting that ADHC-L could facilitate drug release in a more stable and sustained manner while increasing the circulation time of ADHC, especially in the blood. Biodistribution studies of ADHC-L demonstrated that ADHC concentration in the heart was 4.1 times higher after ADHC-L treatment in CA rat model compared with ADHC-L sham-operated treatment at 20 minutes postinjection. Fluorescence imaging studies further proved that the heart

  12. Amygdala Dopamine Receptors Are Required for the Destabilization of a Reconsolidating Appetitive Memory(1,2).

    Science.gov (United States)

    Merlo, Emiliano; Ratano, Patrizia; Ilioi, Elena C; Robbins, Miranda A L S; Everitt, Barry J; Milton, Amy L

    2015-01-01

    Disrupting maladaptive memories may provide a novel form of treatment for neuropsychiatric disorders, but little is known about the neurochemical mechanisms underlying the induction of lability, or destabilization, of a retrieved consolidated memory. Destabilization has been theoretically linked to the violation of expectations during memory retrieval, which, in turn, has been suggested to correlate with prediction error (PE). It is well-established that PE correlates with dopaminergic signaling in limbic forebrain structures that are critical for emotional learning. The basolateral amygdala is a key neural substrate for the reconsolidation of pavlovian reward-related memories, but the involvement of dopaminergic mechanisms in inducing lability of amygdala-dependent memories has not been investigated. Therefore, we tested the hypothesis that dopaminergic signaling within the basolateral amygdala is required for the destabilization of appetitive pavlovian memories by investigating the effects dopaminergic and protein synthesis manipulations on appetitive memory reconsolidation in rats. Intra-amygdala administration of either the D1-selective dopamine receptor antagonist SCH23390 or the D2-selective dopamine receptor antagonist raclopride prevented memory destabilization at retrieval, thereby protecting the memory from the effects of an amnestic agent, the protein synthesis inhibitor anisomycin. These data show that dopaminergic transmission within the basolateral amygdala is required for memory labilization during appetitive memory reconsolidation.

  13. Thermal Destabilization of Collagen Matrix Hierarchical Structure by Freeze/Thaw.

    Directory of Open Access Journals (Sweden)

    Altug Ozcelikkale

    Full Text Available This study aims to characterize and understand the effects of freezing on collagen structures and functionality. Specifically, thermodynamic destabilization of collagen at molecular- and fibril-levels by combination of low temperatures and freezing were experimentally characterized using modulated differential scanning calorimetry. In order to delineate the effects of sub-zero temperature and water-ice phase change, we hypothesized that the extent of destabilization can be determined based on post-thaw heat induced thermal denaturation of collagen. It is found that thermal denaturation temperature of collagen in hydrogel decreases by 1.4-1.6°C after freeze/thaw while no such decrease is observed in the case of molecular solution. The destabilization is predominantly due to ice formation. Exposure to low temperatures in the absence of ice has only minimal effect. Calorimetry measurements combined with morphological examination of collagen matrices by scanning electron microscopy suggest that freezing results in destabilization of collagen fibrils due to expansion of intrafibrillar space by ice formation. This fibril-level damage can be alleviated by use of cryoprotectant DMSO at concentrations as low as 0.5 M. A theoretical model explaining the change in collagen post-thaw thermal stability by freezing-induced fibril expansion is also proposed.

  14. Methane seeps, methane hydrate destabilization, and the late Neoproterozoic postglacial cap carbonates

    Institute of Scientific and Technical Information of China (English)

    JIANG Ganqing; SHI Xiaoying; ZHANG Shihong

    2006-01-01

    Methane hydrates constitute the largest pool of readily exchangeable carbon at the Earth's sedimentary carapace and may destabilize, in some cases catastrophically, during times of global-scale warming and/or sea level changes. Given the extreme cold during Neoproterozoic ice ages, the aftermath of such events is perhaps amongst the most likely intervals in Earth history to witness a methane hydrate destabilization event. The coincidence of localized but widespread methane seep-like structures and textures, methane-derived isotopic signal,low sulfate concentration, marine barites, and a prominent, short-lived carbon isotope excursion (δ13C≤-5‰) from the post-Marinoan cap carbonates (~635 Ma) provides strong evidence for a methane hydrate destabilization event during the late Neoproterozoic postglacial warming and transgression. Methane release from hydrates could cause a positive feedback to global warming and oxidation of methane could result in ocean anoxia and fluctuation of atmospheric oxygen, providing an environmental force for the early animal evolution in the latest Neoproterozoic. The issues that remain to be clarified for this event include the trigger of methane hydrate destabilization, the time of initial methane release, the predicted ocean anoxia event and its relationship with the biological innovation, additional geochemical signals in response to methane release, and the regional and global synchrony of cap carbonate precipitation. The Doushantuo cap carbonate in South China provides one of the best examples of its age for a better understanding of these issues.

  15. Stabilization and destabilization effects of the electric field on stochastic precipitate pattern formation

    NARCIS (Netherlands)

    Lagzi, István; Izsák, Ferenc

    2004-01-01

    Stabilization and destabilization effects of an applied electric field on the Liesegang pattern formation in low concentration gradient were studied with numerical model simulations. In the absence of an electric field pattern formation exhibits increasingly stochastic behaviour as the initial conce

  16. E-cadherin destabilization accounts for the pathogenicity of missense mutations in hereditary diffuse gastric cancer.

    Directory of Open Access Journals (Sweden)

    Joana Simões-Correia

    Full Text Available E-cadherin is critical for the maintenance of tissue architecture due to its role in cell-cell adhesion. E-cadherin mutations are the genetic cause of Hereditary Diffuse Gastric Cancer (HDGC and missense mutations represent a clinical burden, due to the uncertainty of their pathogenic role. In vitro and in vivo, most mutations lead to loss-of-function, although the causal factor is unknown for the majority. We hypothesized that destabilization could account for the pathogenicity of E-cadherin missense mutations in HDGC, and tested our hypothesis using in silico and in vitro tools. FoldX algorithm was used to calculate the impact of each mutation in E-cadherin native-state stability, and the analysis was complemented with evolutionary conservation, by SIFT. Interestingly, HDGC patients harbouring germline E-cadherin destabilizing mutants present a younger age at diagnosis or death, suggesting that the loss of native-state stability of E-cadherin accounts for the disease phenotype. To elucidate the biological relevance of E-cadherin destabilization in HDGC, we investigated a group of newly identified HDGC-associated mutations (E185V, S232C and L583R, of which L583R is predicted to be destabilizing. We show that this mutation is not functional in vitro, exhibits shorter half-life and is unable to mature, due to premature proteasome-dependent degradation, a phenotype reverted by stabilization with the artificial mutation L583I (structurally tolerated. Herein we report E-cadherin structural models suitable to predict the impact of the majority of cancer-associated missense mutations and we show that E-cadherin destabilization leads to loss-of-function in vitro and increased pathogenicity in vivo.

  17. Molecular mechanisms for the destabilization and restabilization of reactivated spatial memory in the Morris water maze

    Directory of Open Access Journals (Sweden)

    Kim Ryang

    2011-02-01

    Full Text Available Abstract Background Memory retrieval is not a passive process. Recent studies have shown that reactivated memory is destabilized and then restabilized through gene expression-dependent reconsolidation. Molecular studies on the regulation of memory stability after retrieval have focused almost exclusively on fear memory, especially on the restabilization process of the reactivated fear memory. We previously showed that, similarly with fear memories, reactivated spatial memory undergoes reconsolidation in the Morris water maze. However, the underlying molecular mechanisms by which reactivated spatial memory is destabilized and restabilized remain poorly understood. In this study, we investigated the molecular mechanism that regulates the stability of the reactivated spatial memory. Results We first showed that pharmacological inactivation of the N-methyl-D-aspartate glutamate receptor (NMDAR in the hippocampus or genetic inhibition of cAMP-responsible element binding protein (CREB-mediated transcription disrupted reactivated spatial memory. Finally, we showed that pharmacological inhibition of cannabinoid receptor 1 (CB1 and L-type voltage gated calcium channels (LVGCCs in the hippocampus blocked the disruption of the reactivated spatial memory by the inhibition of protein synthesis. Conclusions Our findings indicated that the reactivated spatial memory is destabilized through the activation of CB1 and LVGCCs and then restabilized through the activation of NMDAR- and CREB-mediated transcription. We also suggest that the reactivated spatial memory undergoes destabilization and restabilization in the hippocampus, through similar molecular processes as those for reactivated contextual fear memories, which require CB1 and LVGCCs for destabilization and NMDAR and CREB for restabilization.

  18. Time-dependent loss of mitochondrial function precedes progressive histologic cartilage degeneration in a rabbit meniscal destabilization model.

    Science.gov (United States)

    Goetz, Jessica E; Coleman, Mitchell C; Fredericks, Douglas C; Petersen, Emily; Martin, James A; McKinley, Todd O; Tochigi, Yuki

    2017-03-01

    The goals of this work were to characterize progression of osteoarthritic cartilage degeneration in a rabbit medial meniscus destabilization (MMD) model and then to use the model to identify pre-histologic disruptions in chondrocyte metabolism under chronically elevated joint contact stresses in vivo. To characterize PTOA progression, 24 rabbits received either MMD or sham surgery. Limb loading was analyzed preoperatively and at regular postoperative intervals using a Tekscan pressure-sensitive walkway. Animals were euthanized 8 (n = 8 MMD; n = 8 sham) or 26 weeks (n = 8 MMD) postoperatively for histological cartilage evaluation by an objective, semi-automated Mankin scoring routine. To examine pre-histologic pathology, MMD was performed on an additional 20 rabbits, euthanized 1 (n = 9) or 4 weeks (n = 10) postoperatively. Chondrocytes were harvested fresh for measurement of mitochondrial function, an intracellular indicator of pathology after mechanical injury. Both MMD and sham surgery caused slight decreases in limb loading which returned to preoperative levels after 2 weeks. Histologically apparent cartilage damage progressed from 8 to 26 weeks after MMD. Changes in chondrocyte respiration were variable at 1 week, but by 4 weeks postoperatively chondrocyte mitochondrial function was significantly reduced. Many human injuries that lead to PTOA are relatively mild, and the cell-level mechanisms leading to disease remain unclear. We have documented PTOA progression in an animal model of subtle joint injury under continued use, and demonstrated that this model provides a realistic environment for investigation of multi-stage cellular pathology that develops prior to overt tissue degeneration and which could be targeted for disease modifying treatments. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:590-599, 2017.

  19. 胺碘酮与西地兰控制快速心房颤动的疗效观察%Clinical effect of Amiodarone and Cedilanid in the patients with rapid atrial fibrilation

    Institute of Scientific and Technical Information of China (English)

    廖祖发

    2013-01-01

    Objective: Observe clinical effect of Amiodarone and Cedilanid in the patients with rapid atrial fibrilation.Methods: 70 patients with rapid atrial fibrilation patients were randomly divided into two groups,35 cases in each group, amiodarone and Cedilanid was used respectively in two groups.Result: atrial fibrilation cardioversion success rate of Amiodarone group (74.3%) was significantly higher than Cedilanid group (48.6%), the cardioversion successful time on amiodarone group (6.3± 1.4h) was significantly shorter than Cedilanid group(9.7 ± 3.5h), the difference was statisticaly significant. Conclusion: Intravenous bolus amiodarone in clinical efficacy to control rapid ventricular rate of AF significantly better than Cedilanid. Conclusion: Intravenous bolus amiodarone in clinical efficacy to control rapid ventricular rate of atrial fibrilation significantly better than Cedilanid.%  目的:观察胺碘酮与西地兰在控制快速心房颤动心室率上的临床疗效。方法:将70例快速房颤患者随机分组,每组35例,分别行胺碘酮和西地兰治疗。结果:胺碘酮组的房颤转复成功率(74.3%)显著高于西地兰组(48.6%),转复成功时间上,胺碘酮组(6.3±1.4h)明显短于西地兰组(9.7±3.5h),差异具有统计意义。结论:静脉推注胺碘酮在控制快速房颤心室率的临床疗效上显著优于西地兰。

  20. Liver cirrhosis induced by long-term administration of a daily low dose of amiodarone: A case report

    Institute of Scientific and Technical Information of China (English)

    Hiroki Oikawa; Kazuyuki Suzuki; Tomoyuki Masuda; Chihaya Maesawa; Ryo Sato; Kanta Oikawa; Hiroyuki Yamada; Seizo Oriso; Sadahide Ono; Akiko Yashima-Abo; Koji Kotani

    2005-01-01

    The anti-arrhythmic agent amiodarone (AD) is associated with numerous adverse effects, but serious liver disease is rare. The improved safety of administration of daily low doses of AD has already been established and this regimen is used for long-term medication. Nevertheless,asymptomatic continuous liver injury by AD may increase the risk of step-wise progression of non-alcoholic fatty liver disease. We present an autopsy case of AD-induced liver cirrhosis in a patient who had been treated with a low dose of AD (200 mg/d) daily for 84 mo. The patient was a 85-year-old male with a history of ischemic heart disease.Seven years after initiation of treatment with AD, he was admitted with cardiac congestion. The total dose of AD was 528 g. Mild elevation of serum aminotransferase and hepatomegaly were present. Liver biopsy specimens revealed cirrhosis, and under electron microscopy numerous lysosomes with electron-dense, whorled, lamellar inclusions characteristic of a secondary phospholipidosis were observed. Initially, withdrawal of AD led to a slight improvement of serum aminotransferase levels, but unfortunately his general condition deteriorated and he died from complications of pneumonia and renal failure.Long-term administration of daily low doses of AD carries the risk of progression to irreversible liver injury. Therefore,periodic examination of liver function and/or liver biopsy is required for the management of patients receiving long-term treatment with AD.

  1. Ground state destabilization by anionic nucleophiles contributes to the activity of phosphoryl transfer enzymes.

    Directory of Open Access Journals (Sweden)

    Logan D Andrews

    2013-07-01

    Full Text Available Enzymes stabilize transition states of reactions while limiting binding to ground states, as is generally required for any catalyst. Alkaline Phosphatase (AP and other nonspecific phosphatases are some of Nature's most impressive catalysts, achieving preferential transition state over ground state stabilization of more than 10²²-fold while utilizing interactions with only the five atoms attached to the transferred phosphorus. We tested a model that AP achieves a portion of this preference by destabilizing ground state binding via charge repulsion between the anionic active site nucleophile, Ser102, and the negatively charged phosphate monoester substrate. Removal of the Ser102 alkoxide by mutation to glycine or alanine increases the observed Pi affinity by orders of magnitude at pH 8.0. To allow precise and quantitative comparisons, the ionic form of bound P(i was determined from pH dependencies of the binding of Pi and tungstate, a P(i analog lacking titratable protons over the pH range of 5-11, and from the ³¹P chemical shift of bound P(i. The results show that the Pi trianion binds with an exceptionally strong femtomolar affinity in the absence of Ser102, show that its binding is destabilized by ≥10⁸-fold by the Ser102 alkoxide, and provide direct evidence for ground state destabilization. Comparisons of X-ray crystal structures of AP with and without Ser102 reveal the same active site and P(i binding geometry upon removal of Ser102, suggesting that the destabilization does not result from a major structural rearrangement upon mutation of Ser102. Analogous Pi binding measurements with a protein tyrosine phosphatase suggest the generality of this ground state destabilization mechanism. Our results have uncovered an important contribution of anionic nucleophiles to phosphoryl transfer catalysis via ground state electrostatic destabilization and an enormous capacity of the AP active site for specific and strong recognition of the

  2. Stochastic models of intracellular transport

    KAUST Repository

    Bressloff, Paul C.

    2013-01-09

    The interior of a living cell is a crowded, heterogenuous, fluctuating environment. Hence, a major challenge in modeling intracellular transport is to analyze stochastic processes within complex environments. Broadly speaking, there are two basic mechanisms for intracellular transport: passive diffusion and motor-driven active transport. Diffusive transport can be formulated in terms of the motion of an overdamped Brownian particle. On the other hand, active transport requires chemical energy, usually in the form of adenosine triphosphate hydrolysis, and can be direction specific, allowing biomolecules to be transported long distances; this is particularly important in neurons due to their complex geometry. In this review a wide range of analytical methods and models of intracellular transport is presented. In the case of diffusive transport, narrow escape problems, diffusion to a small target, confined and single-file diffusion, homogenization theory, and fractional diffusion are considered. In the case of active transport, Brownian ratchets, random walk models, exclusion processes, random intermittent search processes, quasi-steady-state reduction methods, and mean-field approximations are considered. Applications include receptor trafficking, axonal transport, membrane diffusion, nuclear transport, protein-DNA interactions, virus trafficking, and the self-organization of subcellular structures. © 2013 American Physical Society.

  3. Clinical observation of amiodarone in the treatment of atrial fibril ation%胺碘酮在心房颤动治疗中的疗效观察

    Institute of Scientific and Technical Information of China (English)

    陈思光

    2013-01-01

    Objective Comparative Study on efficacy of amiodarone and digitalis drug treatment of atrial fibril ation to control ventricular rate.Methods October 2009 to October 2011, 110 cases of hospitalization of patients with atrial fibril ation in hospital medicine as a research object,The patients were randomly divided into 2 groups,Amiodarone group 54 cases,Digitalis group of 56 cases, Intravenous administration.Results Amiodarone group the total effective rate was 85.2%(46/54),Digitalis group, the total effective rate was 57.1%(32/56),Two groups of patients with total efficiency,Statistical y significant difference(P<0.05).Conclusion Intravenous bolus of amiodarone in the treatment of atrial fibril ation effective than digitalis drugs,Superior to digitalis drugs in the control of ventricular rate.%目的对比研究胺碘酮与洋地黄类药物治疗房颤控制心室率的疗效。方法以2009年10月至2011年10月在本院内科住院110例房颤患者为研究对象,患者随机分成2组,胺碘酮组54例,洋地黄组56例,分别静脉给药胺碘酮和毛花苷C。结果胺碘酮组的总有效率为85.2%(46/54),洋地黄组的总有效率为57.1%(32/56),两组患者的总有效率比较,差异具有统计学意义(P<0.05)。结论静脉推注胺碘酮治疗房颤的疗效优于洋地黄类药物,在控制心室率方面也优于洋地黄类药物。

  4. Dispersal-induced destabilization of metapopulations and oscillatory Turing patterns in ecological networks

    Science.gov (United States)

    Hata, Shigefumi; Nakao, Hiroya; Mikhailov, Alexander S.

    2014-01-01

    As shown by Alan Turing in 1952, differential diffusion may destabilize uniform distributions of reacting species and lead to emergence of patterns. While stationary Turing patterns are broadly known, the oscillatory instability, leading to traveling waves in continuous media and sometimes called the wave bifurcation, remains less investigated. Here, we extend the original analysis by Turing to networks and apply it to ecological metapopulations with dispersal connections between habitats. Remarkably, the oscillatory Turing instability does not lead to wave patterns in networks, but to spontaneous development of heterogeneous oscillations and possible extinction of species. We find such oscillatory instabilities for all possible food webs with three predator or prey species, under various assumptions about the mobility of individual species and nonlinear interactions between them. Hence, the oscillatory Turing instability should be generic and must play a fundamental role in metapopulation dynamics, providing a common mechanism for dispersal-induced destabilization of ecosystems.

  5. Calcium signaling and mitochondrial destabilization in the triggering of the NLRP3 inflammasome.

    Science.gov (United States)

    Horng, Tiffany

    2014-06-01

    The NLRP3 inflammasome is a cytosolic complex that activates Caspase-1, leading to maturation of interleukin-1β (IL-1β) and IL-18 and induction of proinflammatory cell death in sentinel cells of the innate immune system. Diverse stimuli have been shown to activate the NLRP3 inflammasome during infection and metabolic diseases, implicating the pathway in triggering both adaptive and maladaptive inflammation in various clinically important settings. Here I discuss the emerging model that signals associated with mitochondrial destabilization may critically activate the NLRP3 inflammasome. Together with studies indicating an important role for Ca2+ signaling, these findings suggest that many stimuli engage Ca2+ signaling as an intermediate step to trigger mitochondrial destabilization, generating the mitochondrion-associated ligands that activate the NLRP3 inflammasome.

  6. Chaos in temporarily destabilized regular systems with the slow passage effect

    Energy Technology Data Exchange (ETDEWEB)

    Perc, Matjaz [Department of Physics, Faculty of Education, University of Maribor, Koroska cesta 160, SI-2000 Maribor (Slovenia)] e-mail: matjaz.perc@uni-mb.si; Marhl, Marko [Department of Physics, Faculty of Education, University of Maribor, Koroska cesta 160, SI-2000 Maribor (Slovenia)

    2006-01-01

    We provide evidences for chaotic behaviour in temporarily destabilized regular systems. In particular, we focus on time-continuous systems with the slow passage effect. The extreme sensitivity of the slow passage phase enables the existence of long chaotic transients induced by random pulsatile perturbations, thereby evoking chaotic behaviour in an initially regular system. We confirm the chaotic behaviour of the temporarily destabilized system by calculating the largest Lyapunov exponent. Moreover, we show that the newly obtained unstable periodic orbits can be easily controlled with conventional chaos control techniques, thereby guaranteeing a rich diversity of accessible dynamical states that is usually expected only in intrinsically chaotic systems. Additionally, we discuss the biological importance of presented results.

  7. A disorder-induced domino-like destabilization mechanism governs the folding and functional dynamics of the repeat protein IκBα.

    Directory of Open Access Journals (Sweden)

    Srinivasan Sivanandan

    Full Text Available The stability of the repeat protein IκBα, a transcriptional inhibitor in mammalian cells, is critical in the functioning of the NF-κB signaling module implicated in an array of cellular processes, including cell growth, disease, immunity and apoptosis. Structurally, IκBα is complex, with both ordered and disordered regions, thus posing a challenge to the available computational protocols to model its conformational behavior. Here, we introduce a simple procedure to model disorder in systems that undergo binding-induced folding that involves modulation of the contact map guided by equilibrium experimental observables in combination with an Ising-like Wako-Saitô-Muñoz-Eaton model. This one-step procedure alone is able to reproduce a variety of experimental observables, including ensemble thermodynamics (scanning calorimetry, pre-transitions, m-values and kinetics (roll-over in chevron plot, intermediates and their identity, and is consistent with hydrogen-deuterium exchange measurements. We further capture the intricate distance-dynamics between the domains as measured by single-molecule FRET by combining the model predictions with simple polymer physics arguments. Our results reveal a unique mechanism at work in IκBα folding, wherein disorder in one domain initiates a domino-like effect partially destabilizing neighboring domains, thus highlighting the effect of symmetry-breaking at the level of primary sequences. The offshoot is a multi-state and a dynamic conformational landscape that is populated by increasingly partially folded ensembles upon destabilization. Our results provide, in a straightforward fashion, a rationale to the promiscuous binding and short intracellular half-life of IκBα evolutionarily engineered into it through repeats with variable stabilities and expand the functional repertoire of disordered regions in proteins.

  8. Destabilization kinetics of polyvinylpyrrolidone-iodine in a field of low frequency impacts

    Science.gov (United States)

    Fadeev, G. N.; Ermolaeva, V. I.; Boldyrev, V. S.; Sinkevich, V. V.

    2016-09-01

    Experimental results on the destabilization kinetics of compounds with chelate structure (polyvinylpyrrolidone-iodine) in the field of the impact of low-frequency vibrations (from 2 to 45 Hz) are presented. The optimum frequencies at which the process rate is greatest are found for different impact modes. Based on the experimental data, conclusions are drawn as to the effect the energy of low-frequency impacts has on the studied clathrate and chelate structures.

  9. Critical thinking of destabilizing interpretations of events and phenomena: the role of economic sciences

    Directory of Open Access Journals (Sweden)

    Тетяна Андріївна Непокупна

    2015-03-01

    Full Text Available This article analyzes the global transformations and their impact on the main society life; the specifics of modern interpretations of events and phenomena, their destabilizing effects on behavior, health and life of humans; the role of economic sciences in the formation of critical thinking as a means of combating ignorance and propaganda, formation of an objective world view that grounded on knowledge

  10. Destabilization and recovery of a yeast prion after mild heat shock

    OpenAIRE

    Newnam, Gary P.; Birchmore, Jennifer L.; Chernoff, Yury O.

    2011-01-01

    Yeast prion [PSI+] is a self-perpetuating amyloid of the translational termination factor Sup35. Although [PSI+] propagation is modulated by heat shock proteins (Hsps), high temperature was previously reported to have little or no effect on [PSI+]. Our results show that short-term exposure of exponentially growing yeast culture to mild heat shock, followed by immediate resumption of growth, leads to [PSI+] destabilization, sometimes persisting for several cell divisions after heat shock. Prio...

  11. Study of nonlinear behaviors and modal reductions for friction destabilized systems. Application to an elastic layer

    Science.gov (United States)

    Loyer, A.; Sinou, J.-J.; Chiello, O.; Lorang, X.

    2012-02-01

    As noise reduction tends to be part of environmental directives, predicting squeal noise generated by disc brakes is an important industrial issue. It involves both the transient and stationary nonlinear dynamics of self-excited systems with frictional contact. Time simulation of the phenomenon is an attractive option for reducing experiment costs. However, since such computations using full finite element models of industrial disc brake systems is time-consuming, model reduction has to be performed. In this paper, both the transient and stationary nonlinear behaviors of the friction destabilized system and the effect of dynamical reduction on the nonlinear response of a simple friction destabilized system are carried out. The first part provides a description of the general modeling retained for friction destabilized systems. Then, discretization and solving processes for the stability analysis and the temporal evolution are presented. The third part presents an analysis of a sliding elastic layer for different operating conditions, in order to better understand the nonlinear behavior of such systems. Finally, spatial model reduction is performed with different kinds of reduction bases in order to analyze the different effects of modal reductions. This clearly shows the necessity of including static modes in the reduction basis and that nonlinear interactions between unstable modes are very difficult to represent with reduced bases. Finally, the proposed model and the associated studies are intended to be the benchmark cases for future comparison.

  12. Posturographic destabilization in eating disorders in female patients exposed to body image related phobic stimuli.

    Science.gov (United States)

    Forghieri, M; Monzani, D; Mackinnon, A; Ferrari, S; Gherpelli, C; Galeazzi, G M

    2016-08-26

    Human postural control is dependent on the central integration of vestibular, visual and proprioceptive inputs. Psychological states can affect balance control: anxiety, in particular, has been shown to influence balance mediated by visual stimuli. We hypothesized that patients with eating disorders would show postural destabilization when exposed to their image in a mirror and to the image of a fashion model representing their body ideal in comparison to body neutral stimuli. Seventeen females patients attending a day centre for the treatment of eating disorders were administered psychometric measures of body dissatisfaction, anxiety, depression and underwent posturographic measures with their eyes closed, open, watching a neutral stimulus, while exposed to a full length mirror and to an image of a fashion model corresponding to their body image. Results were compared to those obtained by eighteen healthy subjects. Eating disordered patients showed higher levels of body dissatisfaction and higher postural destabilization than controls, but this was limited to the conditions in which they were exposed to their mirror image or a fashion model image. Postural destabilization under these conditions correlated with measures of body dissatisfaction. In eating disordered patients, body related stimuli seem to act as phobic stimuli in the posturographic paradigm used. If confirmed, this has the potential to be developed for diagnostic and therapeutic purposes.

  13. Dynamic destabilization analysis based on AE experiment of deep-seated, steep-inclined and extra-thick coal seam

    Institute of Scientific and Technical Information of China (English)

    Fenhua Ren; Xingping Lai; Meifeng Cai

    2008-01-01

    No. 5 coal seam in Huating Coal Mine is a deep-seated, steep-inclined extra-thick coal seam where excavation disturbance is quite frequent. The maximum and minimum principal stresses differ widely. During mining, dynamical destabilization happens frequently and induce tragedies. Based on the comparison between the acoustic emission (AE) experiment on dynamical destabilization of coal rock and the related in situ testing results, this article provides comprehensive analysis on the regular quantificational AE patterns (energy rate, total events) of coal rock destabilization in complex-variable environment. The comparison parameters include dynamic tension energy rate, deformation resistance to compression, and shear stress.

  14. Intracardiac intracellular angiotensin system in diabetes.

    NARCIS (Netherlands)

    Kumar, R.; Yong, Q.C.; Thomas, C.M.G.; Baker, K.M.

    2012-01-01

    The renin-angiotensin system (RAS) has mainly been categorized as a circulating and a local tissue RAS. A new component of the local system, known as the intracellular RAS, has recently been described. The intracellular RAS is defined as synthesis and action of ANG II intracellularly. This RAS appea

  15. Study on Transport Mechanism of Amiodarone and Effect of Atorvastatin on Transport of Amiodarone by Caco-2 Cell Monolayer Model%采用Caco-2细胞转运模型研究胺碘酮转运机制及阿托伐他汀对其转运的影响

    Institute of Scientific and Technical Information of China (English)

    孔令提; 刘冬; 宋春丽; 朱裕林

    2016-01-01

    OBJECTIVE:To probe into the intestinal absorption characteristics of amiodarone , and to evaluate the effects of combination of atorvastatin on intestinal absorption of amiodarone .METHODS: The apparent permeability coefficients(Papp) of amiodarone in both the apical-to-basolateral(AP→BL) and the basolateral-to-apical(BL→AP) direction were studied by using the Caco-2 cell monolayer model , the transport mechanism of membrane-disrupting were also evaluated .And the effects of verapamil and atorvastatin on the Papp value was determined .RESULTS:The bilateral transfer capacity of amiodarone increased with the ascent of concentration (10μmol/L, 20μmol/L, 40μmol/L) . There was no significant difference in Papp values of different concentrations ( P>0.05) , and the outside ratio were all less than 1.5.There was no obvious effects on Papp values with verapamil or atorvastatin (P>0.05), which indicated that the transport mechanism of intestinal absorption of amiodarone was passive diffusion .CONCLUSIONS:The passive diffusion is the main transport mechanism of intestinal absorption of amiodarone , and combination of atorvastatin does not affect the intestinal absorption of amiodarone .%目的:探讨胺碘酮的肠吸收特性,评价联合应用阿托伐他汀是否影响胺碘酮的肠吸收。方法:采用Caco-2细胞转运模型,研究胺碘酮在不同浓度下从绒毛面(apical,AP)侧到基底面(basolateral,BL)侧,以及从BL侧到AP侧2个方向的转运过程,计算表观渗透系数(apparent permeability coefficient ,Papp),考察其跨膜转运机制,同时考察维拉帕米、阿托伐他汀对其Papp值的影响。结果:不同浓度(10、20、40μmol/L)胺碘酮的双侧转运量均随浓度增高而相应增大;不同浓度胺碘酮双向转运Papp值的差异无统计学意义(P>0.05),且外排比率均<1.5;加入维拉帕米或阿托伐他汀对胺碘酮的 Papp值无显著影响(P>0.05);

  16. Validated HPLC and Ultra-HPLC Methods for Determination of Dronedarone and Amiodarone Application for Counterfeit Drug Analysis.

    Science.gov (United States)

    El-Bagary, Ramzia I; Elkady, Ehab F; Mowaka, Shereen; Attallah, Maria

    2015-01-01

    Two simple, accurate, and precise chromatographic methods have been developed and validated for the determination of dronedarone (DRO) HCl and amiodarone (AMI) HCl either alone or in binary mixtures due to the possibility of using AMI as a counterfeit of DRO because of its lower price. First, an RP-HPLC method is described for the simultaneous determination of DRO and AMI. Chromatographic separation was achieved on a BDS Hypersil C18 column (150×4.6 mm, 5 μm). Isocratic elution based on potassium dihydrogen phosphate buffer with 0.1% triethylamine pH 6-methanol (10+90, v/v) at a flow rate of 2 mL/min with UV detection at 254 nm was performed. The second method is RP ultra-HPLC in which the chromatographic separation was achieved on an AcclaimTM RSLC 120 C18 column (100×2.1 mm, 2.2 μm) using isocratic elution with potassium dihydrogen phosphate buffer with 0.1% triethylamine pH 6-methanol (5+95, v/v) at a flow rate of 1 mL/min with UV detection at 254 nm. Linearity, accuracy, and precision of the two methods were found to be acceptable over the concentration ranges of 5-80 μg/mL for both DRO and AMI. The results were statistically compared using one-way analysis of variance. The optimized methods were validated and proved to be specific, robust, precise, and accurate for the QC of the drugs in their pharmaceutical preparations.

  17. Real-time monitoring of oxygen uptake in hepatic bioreactor shows CYP450-independent mitochondrial toxicity of acetaminophen and amiodarone.

    Science.gov (United States)

    Prill, Sebastian; Bavli, Danny; Levy, Gahl; Ezra, Elishai; Schmälzlin, Elmar; Jaeger, Magnus S; Schwarz, Michael; Duschl, Claus; Cohen, Merav; Nahmias, Yaakov

    2016-05-01

    Prediction of drug-induced toxicity is complicated by the failure of animal models to extrapolate human response, especially during assessment of repeated dose toxicity for cosmetic or chronic drug treatments. In this work, we present a 3D microreactor capable of maintaining metabolically active HepG2/C3A spheroids for over 28 days in vitro under stable oxygen gradients mimicking the in vivo microenvironment. Mitochondrial respiration was monitored using two-frequency phase modulation of phosphorescent microprobes embedded in the tissue. Phase modulation is focus independent and unaffected by cell death or migration. This sensitive measurement of oxygen dynamics revealed important information on the drug mechanism of action and transient subthreshold effects. Specifically, exposure to antiarrhythmic agent, amiodarone, showed that both respiration and the time to onset of mitochondrial damage were dose dependent showing a TC50 of 425 μm. Analysis showed significant induction of both phospholipidosis and microvesicular steatosis during long-term exposure. Importantly, exposure to widely used analgesic, acetaminophen, caused an immediate, reversible, dose-dependent loss of oxygen uptake followed by a slow, irreversible, dose-independent death, with a TC50 of 12.3 mM. Transient loss of mitochondrial respiration was also detected below the threshold of acetaminophen toxicity. The phenomenon was repeated in HeLa cells that lack CYP2E1 and 3A4, and was blocked by preincubation with ascorbate and TMPD. These results mark the importance of tracing toxicity effects over time, suggesting a NAPQI-independent targeting of mitochondrial complex III might be responsible for acetaminophen toxicity in extrahepatic tissues.

  18. Rational design and synthesis of water-compatible molecularly imprinted polymers for selective solid phase extraction of amiodarone.

    Science.gov (United States)

    Muhammad, Turghun; Cui, Liu; Jide, Wang; Piletska, Elena V; Guerreiro, Antonio R; Piletsky, Sergey A

    2012-01-04

    Novel water-compatible molecularly imprinted polymers (MIPs) selective for amiodarone (AD) were designed via a new methodology which relies on screening library of non-imprinted polymers (NIPs). The NIP library consisted of eighteen cross-linked co-polymers synthesized from monomers commonly used in molecular imprinting. The binding capacity of each polymer in the library was analyzed in two different solvents. Binding in water was used to assess non-specific (hydrophobic) interactions and binding in an appropriate organic solvent was used to assess specific interactions. A good correlation was found between the screening tests and modeling of monomer-template interactions performed using computational approach. Additionally, analysis of template-monomer interactions was performed using UV-vis spectroscopy. As the result, 4-vinylpyridine (4-VP) was selected as the best monomer for developing MIP for AD. The 4-VP-based polymers demonstrated imprinting factor equal 3.9. The polymers performance in SPE was evaluated using AD and its structural analogues. The recovery of AD was as high as 96% when extracted from spiked phosphate buffer (pH 4.5) solution and 82.1% from spiked serum samples. The developed MIP shown as a material with specific binding to AD, comparing to its structural analogues, 1-(2-diethylaminoethoxy)-2,6-diiodo-4-nitrobenzene and lidocaine, which shown 9.9% and 25.4% of recovery from the buffer solution, correspondingly. We believe that the screening of NIP library could be proposed as an alternative to commonly used computational and combinatorial approaches.

  19. Treatment of 200 cases with atrial fibrillation by Shensong Yangxin capsules compared with amiodarone%参松养心胶囊对比胺碘酮治疗心房纤颤200例

    Institute of Scientific and Technical Information of China (English)

    马军

    2015-01-01

    目的:对比参松养心胶囊和胺碘酮治疗心房纤颤的疗效和安全性。方法:100例心房纤颤患者随机分为参松养心胶囊组和胺碘酮组。结果:参松养心胶囊组和胺碘酮组治疗心房纤颤总有效率分别为55%、60%,统计学处理无明显差异(P>0.05)。结论:参松养心胶囊和胺碘酮治疗心房纤颤疗效相当,但参松养心胶囊不良反应更少。%Objective:To compare the clinical effects and safety of Shensong Yangxin capsules and amiodarone in the treatment of atrial fibrillation.Methods:100 cases with atrial fibrillation were divided into Shensong Yangxin capsule group and amiodarone group. Results: Shensong Yangxin capsule group and amiodarone group the total effective rate was 55% and 60% respectively in the treatment of atrial fibrillation, statistically no significant difference (P> 0.05).Conclusion:The therapeutic effects of Shensong Yangxin capsule and amiodarone in the treatment of atrial fibrillation are equal,but Shensong Yangxin capsule with less adverse reactions.

  20. 冠心病快速心律失常应用胺碘酮治疗的临床效果分析%The Clinical Effect of Coronary Heart Disease Tachyarrhythmia Analysis Amiodarone Therapy

    Institute of Scientific and Technical Information of China (English)

    陈铸雄

    2014-01-01

    Objective Clinical efficacy in patients with coronary heart disease tachyarrhythmia amiodarone therapy. Methods In our hospital from January 2012 to January 2014 were treated 60 cases of coronary heart disease complicated by tachyarrhythmias in patients of all emergency patients were given amiodarone therapy, and efficacy determination. Results The group of 60 patients after amiodarone total effective rate of 90.0%, adverse reactions were mild and no serious adverse events. Conclusions Amiodarone in the treatment of coronary artery disease in patients with tachyarrhythmia safe and effective.%目的:冠心病快速心律失常患者应用胺碘酮治疗的临床疗效。方法选取我院在2012年1月至2014年1月收治的冠心病并发快速心律失常患者60例,对所有患者均急诊给予胺碘酮治疗,并对疗效进行判定。结果本组60例患者经过胺碘酮治疗总有效率达90.0%,不良反应均较轻微,无严重不良反应发生。结论胺碘酮在冠心病快速心律失常患者的治疗中安全、有效。

  1. 胺碘酮治疗心衰伴心律失常的临床分析%Therapeutic effects of amiodarone on chronic heart failure complicated by arrhythmia

    Institute of Scientific and Technical Information of China (English)

    周兰珠

    2010-01-01

    目的 评价胺碘酮治疗心力衰竭(HF)伴心律失常的疗效.方法 选择心力衰竭合并心律失常患者96例,在抗心衰治疗同时给予口服胺碘酮6周.结果 治疗6周后观察总有效率91.9%.结论 胺碘酮治疗HF伴心律失常安全、有效.%Objective To evaluate the the therapeutic effects of amiodarone on chronic heart failure complicated by arrhythmia. Methods From 2006 to 2008,96 chronic congestive heart failure patients with arrhythmia were enrolled. All patients were given standard medical treatment according to the current practice guidelines with a β-blocker, an angiotensin-converting enzyme(ACE) inhibitor, and diuretics. At the same time,they were also given oral amiodarone for six weeks. Results After 6 weeks' treatment with amiodarone,the total effective therapeutic effects was 91.9 percent. Conclusion For patients with chronic congestive heart failure complicated by with arrhythmia, amiodarone treatment for six weeks is safe and effective.

  2. The amiodarone derivative 2-methyl-3-(3,5-diiodo-4-carboxymethoxybenzyl)benzofuran (KB130015) opens large-conductance Ca2+-activated K+ channels and relaxes vascular smooth muscle.

    Science.gov (United States)

    Gessner, Guido; Heller, Regine; Hoshi, Toshinori; Heinemann, Stefan H

    2007-01-26

    2-methyl-3-(3,5-diiodo-4-carboxymethoxybenzyl)benzofuran (KB130015) has been developed to retain the antiarrhythmic properties of the parent molecule amiodarone but to eliminate its undesired side effects. In patch-clamp experiments, KB130015 activated large-conductance, Ca2+-activated BK(Ca) channels formed by hSlo1 (alpha) subunits in HEK 293 cells. Channels were reversibly activated by shifting the open-probability/voltage (P(o)/V) relationship by about -60 mV in 3 muM intracellular free Ca2+ ([Ca2+]in). No effect on the single-channel conductance was observed. KB130015-mediated activation of BK(Ca) channels was half-maximal at 20 microM with a Hill coefficient of 2.8. BK(Ca) activation by KB130015 did not require the presence of Ca2+ and still occurred with saturating (100 microM) [Ca2+]in. Effects of the prototypic BK(Ca) activator NS1619 (1,3-dihydro-1-[2-hydroxy-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-2H-benzimidazol-2-one) and those of KB130015 were not additive suggesting that both activators may at least partially share a common mechanism of action. KB130015-mediated activation was observed also for BK(Ca) channels from insects and for human BK(Ca) channels with already profoundly left-shifted voltage-dependence. In contrast, human intermediate conductance Ca2+-activated channels were inhibited by KB130015. Using segments of porcine pulmonary arteries, KB130015 induced endothelium-independent vasorelaxation, half-maximal at 43 microM KB130015. Relaxation was inhibited by 1 mM tetraethylammonium, suggesting that KB130015 can activate vascular smooth muscle type BK(Ca) channels under physiological conditions. Interestingly, the shift in the P(o)/V relationship was considerably stronger (-90 mV in 3 microM [Ca2+]in) for BK(Ca) channels containing Slo-beta1 subunits. Thus, KB130015 belongs to a novel class of BK(Ca) channel openers that exert an effect depending on the subunit composition of the channel complex.

  3. The destabilizing effect of external damping: Singular utter boundary for the Pfluger column with vanishing external dissipation

    CERN Document Server

    Tommasini, Mirko; Misseroni, Diego; Bigoni, Davide

    2016-01-01

    Elastic structures loaded by nonconservative positional forces are prone to instabilities induced by dissipation: it is well-known in fact that internal viscous damping destabilizes the marginally stable Ziegler's pendulum and Pfluger column (of which the Beck's column is a special case), two structures loaded by a tangential follower force. The result is the so-called 'destabilization paradox', where the critical force for flutter instability decreases by an order of magnitude when the coefficient of internal damping becomes infinitesimally small. Until now external damping, such as that related to air drag, is believed to provide only a stabilizing effect, as one would intuitively expect. Contrary to this belief, it will be shown that the effect of external damping is qualitatively the same as the effect of internal damping, yielding a pronounced destabilization paradox. Previous results relative to destabilization by external damping of the Ziegler's and Pfluger's elastic structures are corrected in a defi...

  4. DNA-Destabilizing Agents as an Alternative Approach for Targeting DNA: Mechanisms of Action and Cellular Consequences

    Directory of Open Access Journals (Sweden)

    Gaëlle Lenglet

    2010-01-01

    Full Text Available DNA targeting drugs represent a large proportion of the actual anticancer drug pharmacopeia, both in terms of drug brands and prescription volumes. Small DNA-interacting molecules share the ability of certain proteins to change the DNA helix's overall organization and geometrical orientation via tilt, roll, twist, slip, and flip effects. In this ocean of DNA-interacting compounds, most stabilize both DNA strands and very few display helix-destabilizing properties. These types of DNA-destabilizing effect are observed with certain mono- or bis-intercalators and DNA alkylating agents (some of which have been or are being developed as cancer drugs. The formation of locally destabilized DNA portions could interfere with protein/DNA recognition and potentially affect several crucial cellular processes, such as DNA repair, replication, and transcription. The present paper describes the molecular basis of DNA destabilization, the cellular impact on protein recognition, and DNA repair processes and the latter's relationships with antitumour efficacy.

  5. Effect of Processing Conditions on the Crystallization behavior and Destabilization Kinetics of Oil-in-Water Emulsions

    OpenAIRE

    Martini, Silvana; Tippetts, Megan

    2008-01-01

    The objective of this research was to systematically study the effect of processing conditions on the crystallization behavior and destabilization mechanisms of oil-in-water emulsions. The effect of crystallization temperature (T c) and homogenization conditions on both thermal behavior and destabilization mechanisms were analyzed. Results show that the crystallization of lipids present in the emulsions was inhibited when compared with bulk lipids as evidenced by a lower onset and peak temper...

  6. Amiodarona causa vasodilatação dependente do endotélio em artérias coronárias caninas Amiodarone causes endothelium-dependent vasodilation in canine coronary arteries

    Directory of Open Access Journals (Sweden)

    Alfredo José Rodrigues

    2005-03-01

    Full Text Available OBJETIVO: Avaliar os efeitos vasodilatadores da amiodarona em artérias coronárias caninas empregando soluções de amiodarona dissolvida em polisorbato 80 ou em água. MÉTODOS: Anéis de artéria coronária, com e sem o endotélio íntegro, foram imersos em solução de krebs e conectadas a um transdutor para aferição de força isométrica promovida por contração vascular. As artérias foram expostas a concentrações crescentes de polisorbato 80, amiodarona dissolvida em água, amiodarona dissolvida em polisorbato 80 e uma apresentação comercial da amiodarona (Cordarone®. Os experimentos foram conduzidos na presença e na ausência dos seguintes bloqueadores enzimáticos: apenas indometacina, Nômega-nitro-L-arginina associada à indometacina e apenas Nômega-nitro-L-arginina. RESULTADOS: O polisorbato 80 causou pequeno relaxamento não dependente do endotélio. O Cordarone®, a amiodarona dissolvida em água e em polisorbato 80 promoveram relaxamento dependente do endotélio, que foi de maior magnitude para a amiodarona dissolvida em polisorbato e para o Cordarone®. Apenas a associação de indometacina com a Nômega-nitro-L-arginina foi capaz de abolir o relaxamento dependente do endotélio provocado pela amiodarona dissolvida em polisorbato 80. CONCLUSÃO: Os resultados obtidos indicam que a vasodilatação promovida pela amiodarona em artérias coronárias caninas é causada principalmente pela estimulação da liberação de óxido nítrico e fatores endoteliais relaxantes dependentes das ciclo-oxigenases.OBJECTIVE: To assess the vasodilating effects of amiodarone on canine coronary arteries by using solutions of amiodarone dissolved in polysorbate 80 or water. METHODS: Rings of coronary arteries, with or without intact endothelium, were immersed in Krebs solution and connected to a transducer for measuring the isometric force promoted by a vascular contraction. The arteries were exposed to increasing concentrations of

  7. 厄贝沙坦联合胺碘酮治疗阵发性房颤的临床疗效%Effects of the irbesartan combined with amiodarone in the treatment of paroxysmal atrial fibrillation

    Institute of Scientific and Technical Information of China (English)

    邹丽芳; 张光君; 陈士良

    2012-01-01

    目的 评价胺碘酮联合厄贝沙坦治疗阵发性房颤的临床疗效.方法 78例阵发性房颤的患者随机分为治疗组(胺碘酮+厄贝沙坦)和对照组(胺碘酮),口服给药,疗程均为1年.比较治疗后2组窦性心律维持率和左心房内径的变化.结果 治疗组窦性心率维持率明显高于对照组(P<0.05),左心房内径亦有显著性缩小(P<0.05).结论 胺碘酮联合厄贝沙坦治疗阵发性心房颤动维持窦性心率的疗效优于单用胺碘酮,且能抑制左心房扩大.%Objective To observe clinical efficacy of amiodarone and irbesartan in the treatment of paroxysmal atrial fibrillation. Methods Seventy - eight cases of paroxysmal atrial fibrillation were randomly divided into treatment group ( amiodarone + irbesartan ) and the control group ( single with amiodarone ) . Taking drugs were by orally and the course was a year. Compared the change of sinus rhythm maintenance rate and left atrial diameter after the treatment in two groups. Results Compared with control group, the sinus rhythm maintenance rate in the treatment group was significantly higher than the control group (P < 0. 05 ) , the left atrial diameter in the treatment group also significantly reduced than the control group ( P < 0. 05 ).Conclusion Effects of amiodarone and irbesartan in the treatment of paroxysmal atrial fibrillation to maintain sinus rhythm has better than single amiodarone , and it can inhibit left atrial enlargement.

  8. Clinical study on the efficacy and safety of Amiodarone for treating atrial fibrillation in old patients%胺碘酮治疗老年心房纤颤的疗效及安全性观察

    Institute of Scientific and Technical Information of China (English)

    曹丹阳; 曹晶晶; 周冬翠; 武云涛; 陈艳梅; 毕磊

    2011-01-01

    Objective To study the efficacy and safety of Amiodarone for treating atrial fibrillation in old patients. Methods We retrospectively reviewed 40 elderly cases of atrial fibrillation, amiodarone was administered 0.6 g/day initially, then gradually reduced to 0.2 g/day for maintainance, the curative effect and the side effects of amiodarone in treatment of atrial fibrillation was observed. Results The efficiency of amiodarone treatment was 55%, laseris 32.5%, inefficient to 12. 5%. Simultaneous hypothyroidism occurred in 7 cases, thyroid function in hyperthyroidism, pulmonary fibrosis, pigmentation did not happen in all cases. Conclusions Amiodarone for treating atrial fibrillation in old patients is effective and safe.%目的 探讨胺碘酮对老年阵发性房颤治疗的效果和安全性.方法 观察分析40例老年阵发性房颤患者胺碘酮治疗的效果和药物副作用.结果 胺碘酮治疗显效率为55 0%,有效率为32 5%,无效率为12 5%;发生甲状腺功能减退 7例,未发生甲状腺功能亢进、肺纤维化、色素沉着.结论 胺碘酮应用于老年人房颤有效、安全,但需密切观察甲状腺功能和对肺的毒性作用.

  9. Long-term efficacy and safety of very-low-dose amiodarone treatment for the maintenance of sinus rhythm in patients with chronic atrial fibrillation after successful direct-current cardioversion

    Institute of Scientific and Technical Information of China (English)

    JONG Gwo-ping; CHANG Mu-hsin; CHANG Ting-chuan; CHOU Pesus; FU Chong-yau; TIEN Li-yun; CHEN Chung-yin; MA Tso-chiang

    2006-01-01

    Background Long-term maintenance of sinus rhythm after successful conversion of chronic atrial fibrillation (CAF), often ameliorates patients' symptoms, reduces the risk of ischemic stroke and improves cardiovascular hemodynamics. This prospective study aims to evaluate the long-term efficacy and safety of very low-dose amiodarone (100 mg daily) for the maintenance of sinus rhythm after successful direct-current (DC)cardioversion in patients with CAF and rheumatic heart disease (RHD) post intervention.Methods This study was a randomized prospective trial. One day after successful DC cardioversion (remained normal sinus rhythm) in patients with CAF and RHD post intervention for more than six months and adequate anticoagulation, all were randomly administered either amiodarone 200 mg daily in group A or amiodarone 100mg daily in group B.Results A total of 76 patients (40 men and 36 women) were examined from February 1998 to December 1999.The mean age of the patients was (66±10) years, and the mean follow-up was (67±8) months (range 61 to 84months). Actuarial rates of the maintenance of sinus rhythm were similar in the two groups after 5 years of follow-up. Four patients (11%) in group A but none in group B experienced significant adverse effects that necessitated withdrawal of amiodarone. No death occurred during the study period.Conclusion A very low dose of amiodarone results in adequate long-term efficacy and is safe for maintaining sinus rhythm in patients with CAF and RHD post intervention after successful DC cardioversion.

  10. 胺碘酮急诊治疗快速性心律失常的疗效观察%THE EFFICACY OBSERVATION OF AMIODARONE IN EMERGENCY TREATMENT OF TACHYARRHYTHMIA

    Institute of Scientific and Technical Information of China (English)

    武彦秋; 王燕; 孙鹏; 胥冬梅

    2011-01-01

    [Objective]To discuss the curaliveeffect and the safety of amiodarone treatment of pediatric tachyarrhythmia (supraventricular SVT, ventricular VT).[Methods]Divided 60 infants into 2 groups according to SVT and VT.Each group was randomly divided into treatment group and control group.[Results]The converting rates in SVT group with amiodarone treatment was 94.4%, 40.9% in SVT group with rytmonorm treatment, the converting rates in VT group with amiodarone treatment was 88.2% , that in VT group with lidocaine treatment was 35% , and the adverse reaction rate due to amiodarone was 3.3%.[Conclusion]The successful converting rate of the amiodarone in treating pediatric tachyarrhythmia has high performance and the safety is high.It can be used in clinic preferentially.%[目的]探讨胺碘酮治疗小儿快速性心律失常(室上性SVT、室性VT)的疗效及安全性.[方法]将60例患儿按病种(SVT、VT)分为2组,每组再随机分为治疗组(胺碘酮)、对照组(心律平、利多卡因)治疗.[结果]SVT组胺碘酮转复率为94.4%,心律平组40.9%;对VT成功复律率为88.2%,利多卡因组35%,胺碘酮不良反应发生率3.3%.[结论]胺碘酮治疗小儿快速性心律失常转复成功率高,起效快,安全性高,在临床上可优先使用.

  11. The Clinical Analysis of 24 Cases of Patients with Amiodarone Ventricular Tachycardia%胺碘酮室性心动过速24例临床分析

    Institute of Scientific and Technical Information of China (English)

    宋雪莲

    2014-01-01

    目的:探讨静脉注射胺碘酮治疗室性心动过速疗效。方法自2012年2月~2013年12月对24例室性心动过速患者应用胺碘酮临床治疗资料进行分析。结果经治疗室性心动过速成功复律21例,占87.5%。结论室速发生较多者可用胺碘酮,胺碘酮应采取小剂量负荷,胺碘酮治疗较为安全,维持量亦可相应减少,可提高疗效,提高生活质量。%Objective The effect of intravenous amiodarone treatment of ventricular tachycardia to be investigated. Methods Analyzing clinical treatment data selected from 24 cases of patients with ventricular tachycardia who are given intravenous amiodarone treatment from February 2012 to December 2013. Results With intravenous amiodarone treatment, 21 cases of patients with ventricular tachycardia are cured which make up 87.5 percent of the whole. Conclusions The patients with ventricular tachycardia are suggested to take intravenous amiodarone, but with smal amount of dosage;since the intravenous amiodarone treatment is comparative safe, the dosage can be reduced gradual y with improving the effect and quality of life.

  12. Palladium-mediated intracellular chemistry

    Science.gov (United States)

    Yusop, Rahimi M.; Unciti-Broceta, Asier; Johansson, Emma M. V.; Sánchez-Martín, Rosario M.; Bradley, Mark

    2011-03-01

    Many important intracellular biochemical reactions are modulated by transition metals, typically in the form of metalloproteins. The ability to carry out selective transformations inside a cell would allow researchers to manipulate or interrogate innumerable biological processes. Here, we show that palladium nanoparticles trapped within polystyrene microspheres can enter cells and mediate a variety of Pd0-catalysed reactions, such as allylcarbamate cleavage and Suzuki-Miyaura cross-coupling. The work provides the basis for the customization of heterogeneous unnatural catalysts as tools to carry out artificial chemistries within cells. Such in cellulo synthesis has potential for a plethora of applications ranging from cellular labelling to synthesis of modulators or inhibitors of cell function.

  13. Destabilizing Effects of Pore-Scale Disorder on Capillary Invasion in Partially-Wettable Porous Media

    CERN Document Server

    Holtzman, Ran

    2016-01-01

    We present a systematic, quantitative assessment of the impact of pore size disorder and its interplay with flow rates and the wettability on immiscible fluid displacement. Pore-scale simulations and micromodel experiments show that increasing disorder destabilizes the displacement, reducing the its efficiency and increasing the fluid-fluid interfacial area, by enhancing trapping at low rates, and fingering at high rates. Lowering disorder enhances the effect of the underlying lattice. Increasing wettability of the invading fluid (contact angle) stabilizes the invasion, smoothing the interface and inhibiting trapping--effects which are suppressed at low disorder and high rates.

  14. Mephisto - Research equipment for the study of solid/liquid interface destabilization in metal alloys

    Science.gov (United States)

    Favier, J. J.; Malmejac, Y.; Praizey, J. P.; Cambon, G.; Barillot, R.; Changeart, F. J.

    1982-09-01

    Preliminary results of a feasiblity study of space apparatus intended for solid/liquid destabilization in metal alloys, the Mephisto project, are presented. The phenomena that Mephisto will observe, the parameters it will measure, and the scientific studies that it will perform are stated. A general description is given of the instrument, its experimental tubes, and the experiment process. The environmental and thermal constraints, electrical characteristics, and the characteristics of the different signals are outlined. Finally, the requirements of the payload interfaces on which the equipment will be mounted are set forth, including mechanical/geometrical interfaces, thermal interfaces, and electrical interfaces.

  15. Substrate Phosphorylation and Feedback Regulation in JFK-promoted p53 Destabilization*

    OpenAIRE

    Sun, Luyang; SHI, LEI; Wang, Feng; Huangyang, Peiwei; Si, Wenzhe; Yang, Jie; Yao, Zhi; Shang, Yongfeng

    2010-01-01

    The p53 tumor suppressor plays a central role in integrating cellular responses to various stresses. Tight regulation of p53 is thus essential for the maintenance of genome integrity and normal cell proliferation. Previously, we reported that JFK, the only Kelch domain-containing F-box protein in human, promotes ubiquitination and degradation of p53 and that unlike the other E3 ligases for p53, all of which possess an intrinsic ubiquitin ligase activity, JFK destabilizes p53 through the assem...

  16. Thermodynamically destabilized hydride formation in "bulk" Mg-AlTi multilayers for hydrogen storage.

    Science.gov (United States)

    Kalisvaart, Peter; Shalchi-Amirkhiz, Babak; Zahiri, Ramin; Zahiri, Beniamin; Tan, XueHai; Danaie, Mohsen; Botton, Gianluigi; Mitlin, David

    2013-10-21

    Thermodynamic destabilization of MgH2 formation through interfacial interactions in free-standing Mg-AlTi multilayers of overall "bulk" (0.5 μm) dimensions with a hydrogen capacity of up to 5.5 wt% is demonstrated. The interfacial energies of Mg-AlTi and Mg-Ti (examined as a baseline) are calculated to be 0.81 and 0.44 J m(-2). The enhanced interfacial energy of AlTi opens the possibility of creating ultrathin alloy interlayers that provide further thermodynamic improvements in metal hydrides.

  17. Efficacy Observation of Amiodarone in the Treatment of Atrial Fibrillation Cardioversion with Intravenous Administration%静脉应用胺碘酮治疗心房颤动复律的疗效观察

    Institute of Scientific and Technical Information of China (English)

    张景富; 尹春元

    2011-01-01

    OBJECTIVE: To observe clinical efficacy of amiodarone in the treatment of atrial fibrillation cardioversion with intravenous administration. METHODS: 172 patients with atrial fibrillation were randomly divided into amiodarone group and placebo group. Amiodarone group (n=87) received amiodarone 5 mg·kg-1 intravenously, and then followed by continuous infusion of 0.9% Sodium chloride injection with amiodarone at 10~20 mg·kg-1· d-1 until sinus rhythm was restored. Placebo group (n=85)received0.9% Sodium chloride injection with intravenous push and intravenous infusion, and ventricular rate control treatment. Successful rate and time of rhythm control of 2 groups were observed. RESULTS: 74 patients (85.1%) in amiodarone group returned into sinus rhythm. 68 patients (80.0%) in placebo group also returned into sinus rhythm (P>0.05). The duration of atrial fibrillation in amiodarone group was shorter than in placebo group (P<0.01). One patient suffered from sinus bradycardia in amiodarone group. CONCLUSION: Intravenous administration of amiodarone can not improve the successful rate of rhythm control but can shorten the duration of atrial fibrillation.%目的:观察静脉应用胺碘酮对心房颤动复律的临床疗效.方法:将172例心房颤动患者随机分为胺碘酮组和安慰剂组.胺碘酮组(n=87)静脉推注胺碘酮5mg·kg-1,再以胺碘酮10~20mg·kg-1·d-1加入0.9%氯化钠注射液中持续静脉滴注,维持直至恢复为窦性节律;安慰剂组(n=85)静脉推注和静脉滴注0.9%氯化钠注射液,并给予控制心室率治疗.观察2组复律成功率和复律时间.结果:胺碘酮组有74例(85.1%)恢复为窦性节律,安慰剂组有68例(80.0%)恢复为窦性节律,2组比较差异无统计学意义(P>0.05).胺碘酮组心房颤动持续时间短于安慰剂组(P<0.01).胺碘酮组1例患者出现窦性心动过缓,停药后恢复.结论:胺碘酮静脉应用不能提高复律率,但能缩短心房颤动持续时间.

  18. 伊布利特和胺碘酮转复心房扑动及心房颤动的临床观察%Efficacy of ibutilide and amiodarone for termination of atrial fibrillation and flutter

    Institute of Scientific and Technical Information of China (English)

    王磊

    2011-01-01

    目的 观察新一代Ⅲ类抗心律失常药物伊布利特和经典Ⅲ类抗心律失常药物胺碘酮转复心房颤动(房颤)和心房扑动(房扑)的成功率及安全性.方法 选择40 ~ 75岁,持续时间≤90 d的房颤和房扑患者38例,按入院顺序随机分为伊布利特组19例和胺碘酮组19例,伊布利特组体质量≥60 kg者首剂1 mg、体质量<60 kg者首剂0.01 mg/kg,如无效10 min后再给予1 mg或0.01 mg/kg;胺碘酮组首剂150 mg,如无效10 min后再给予150 mg,观察转复率和转复时间,记录不良反应.结果 伊布利特和胺碘酮组4h内转复窦律分别为78.9%和31.5%,24 h内转复窦律分别为84.2%和52.6%,平均转复时间分别为(19±12)min和(48 ±17)min (P<0.01).两组均未发生致命性不良反应.结论 伊布利特与胺碘酮均能终止房颤和房扑,伊布利特转复房颤、房扑的疗效高于胺碘酮,转复时间短于胺碘酮,但须在严格监控下进行.%Objective To investigate the efficacy,safety and tolerance of intravenous ibutilide and amiodarone for conversion of atrial fibrillation( AF) and flutter( AFL) to normal sinus rhythm.Methods Thirty - eight consecutive patients aged 40 - 75 years with AF/AFL were included.The duration of arrhythmia were less than 90 days (ranged from 3 hours to 90 days),and ventricular rate(VR) were more than 60 beats/min.Two groups were assigned randomly.Patients in the ibutilide group( 19 cases) received ibutilide 1 mg if body weight ≥60 kg or 0.01 mg/kg if body weight < 60 kg; Treatment was repeated if atrial fibrillation or flutter was not converted after 10 min of the first dosage.Patients in the amiodarone group( 19 cases) received amiodarone 150 mg,followed by amiodarone 150 mg if atrial fibrillation or flutter persisted after 10 min of the first dosage.Results In 4 hours AF/AFL were converted in 15 of 19 patients(78.9% )in ibutilide group and in 6 of 19 patients(31.5% )in amiodarone group (P < 0.05),and in 24

  19. Optimizing and slope determination of final wall for Maiduk Mine with consideration of destabilizer factors

    Institute of Scientific and Technical Information of China (English)

    Shamsoddin Saeed Masoud; Maarefvand Parviz; Yaaghubi Ebrahim

    2016-01-01

    In this research, determination of final slope for Maiduk copper mine of Kerman is investigated according to destabilizing factors of the mine. The development of the Maiduk Mine caused the extension of the mine area and also withdrawal of its wall. So, optimizing possibility of mine slope is essential. Finally, the magnitude of optimized slopes for different walls of the mine in association with executive com-mands with better factors of safety is provided. The results show that the most important destabilizer factors are the presence of water and pore pressure in the faults and the main joints. With the omission of pore pressure, mine wall for the designed depth is quite stable. This requires a drainage pattern in the lifetime of the mine. In an optimistic point of view, the minimum factor of safety of the wall will be 2.81 even without drainage. This conclusion allows optimizing the slope to its maximum magnitude of 51 degree. With the pessimistic engineering judgment and with the higher SF, the magnitude of the slope is optimized to 47 degree.

  20. Use of mixtures containing nonionic surfactants in the destabilization of petroleum emulsions

    Energy Technology Data Exchange (ETDEWEB)

    Mansur, Claudia R.E.; Mauro, Aparecida C.; Aquino, Aline S.; Lechuga, Fernanda C.; Gonzalez, Gaspar; Lucas, Elizabete F. [Universidade Federal do Rio de Janeiro (UFRJ), RJ (Brazil). Inst. de Macromoleculas; Gonzalez, Gaspar [PETROBRAS, Rio de Janeiro, RJ (Brazil). Centro de Pesquisas (CENPES)

    2004-07-01

    During the petroleum dehydration process, it is necessary to used chemical demulsifiers in order to break the w/o emulsions that are formed in the oil field. These demulsifiers products are, in many cases, surfactants based poly(ethylene oxide-propylene oxide) block copolymers (PEO-PPO), with different EO/PO molar ratio. In this work were correlate the structure and the properties of PEO-PPO block copolymers with their performance as petroleum emulsion-destabilizing agent. Moreover, it was used an additive in the formulations, known as hydrotrope, in order to increase the solubility of these copolymers in aqueous solution. The results showed that the copolymer branched, whose hydrophilic segments (PEO and OH) are in an external adjacent position, present the higher solubility, in spite of to own EO/PO ratio similar to the others copolymers and the highest molar mass. Moreover, this copolymer presented the best efficiency in the emulsion destabilization. The addition of the hydrotrope NaBMGS to the PEO-PPO copolymers aqueous solutions caused the solubility increasing of these compounds in water. Such additive being used in the demulsifier formulation provoked an efficiency improving on the emulsion breaking process. (author)

  1. State-dependent effect of dopamine D₁/D₅ receptors inactivation on memory destabilization and reconsolidation.

    Science.gov (United States)

    Rossato, Janine I; Köhler, Cristiano A; Radiske, Andressa; Lima, Ramón H; Bevilaqua, Lia R M; Cammarota, Martín

    2015-05-15

    Object recognition memories (ORM) can incorporate new information upon reactivation. This update initially involves destabilization of the original memory, which is followed by restabilization of the upgraded engram through a reconsolidation process that requires gene expression and protein synthesis in the hippocampus. We found that when given in dorsal CA1 either immediately after training or 15 min before ORM reactivation in the presence of a novel object, the dopamine D1/D5 receptor antagonist SCH23390 did not affect ORM consolidation, expression or retention but impeded the amnesia caused by the post-retrieval administration of the mRNA synthesis inhibitor α-amanitin or the protein synthesis blocker anisomycin. This anti-amnesic effect was not observed when SCH23390 was given immediately after training and again 15 min before memory reactivation. Our results demonstrate that hippocampal D1/D5 receptors are not needed for formation, retrieval or post-retrieval restabilization of the ORM trace but are essential for its destabilization when reactivation occurs together with the incorporation of new information into the original memory. Importantly, they also suggest that reenactment of the animal's post-learning neurochemical milieu at the moment of memory reactivation can be a boundary condition for reconsolidation.

  2. URGENT DESTABILIZERS OF PUBLIC AND STATE SECURITY, TACTICS OF COUNTERACTION TO IT

    Directory of Open Access Journals (Sweden)

    D. N. Marinkin

    2016-01-01

    Full Text Available At creation of civil society in any constitutional state there is a crime counteraction problem. In the modern Russian Federation safety problems from the negative social phenomena and processes force scientists, public agents and ordinary citizens to investigate constantly such determinants and the reasons (destabilizers of safety of society and the constitutional state, to eliminate their consequences. Such problems as are urgent now: increase in information on ways and consequences of violence in the mass media (MM, the Internet, computer games, traditional physical abuse. The number of questions and assessment by citizens of consequences of the conducted terrorist attacks and infringement of life of citizens causes. The accounting of the specified problems and versions of decisions in law-enforcement practice, will allow to promote as a result efficiency of prevention of offenses and crimes and will bring closer modern Russia to ideal model of the constitutional state with real civil society. In article the author designates a number of the legal and social destabilizers of safety existing now in the Russian society and the state, proposes the solution of their negative impact on society within tactics of crime control.

  3. Transformation and destabilization of graphene oxide in reducing aqueous solutions containing sulfide.

    Science.gov (United States)

    Fu, Heyun; Qu, Xiaolei; Chen, Wei; Zhu, Dongqiang

    2014-12-01

    The colloidal stability of carbon nanomaterials is a key factor controlling their fate and bioavailability in natural aquatic systems. The authors report that graphene oxide nanoparticles could be destabilized in reducing aqueous solutions containing a low concentration (0.5 mM) of sulfide, a naturally occurring reductant. Spectroscopic characterization using combined X-ray photoelectron, Fourier-transform infrared, X-ray diffraction, and Raman analyses revealed that the surface oxygen-containing groups (mainly epoxy groups) of graphene oxide were significantly reduced after reacting with sodium sulfide. The destabilization of graphene oxide was likely caused by the enhanced surface hydrophobicity of the reduced graphene oxide, whereas electrostatic repulsion played a minimal role. Solution pH was found to affect both the deoxygenation process and the aggregation behavior of graphene oxide. Coexisting humic acid reduced the reaction efficiency and stabilized graphene oxide through steric hindrance. These findings suggest for the first time that the colloidal behavior of carbon nanomaterials might change drastically when they enter natural reducing environments containing sulfide such as anaerobic aquifers and sediments.

  4. Prediction of protein-destabilizing polymorphisms by manual curation with protein structure.

    Directory of Open Access Journals (Sweden)

    Craig Alan Gough

    Full Text Available The relationship between sequence polymorphisms and human disease has been studied mostly in terms of effects of single nucleotide polymorphisms (SNPs leading to single amino acid substitutions that change protein structure and function. However, less attention has been paid to more drastic sequence polymorphisms which cause premature termination of a protein's sequence or large changes, insertions, or deletions in the sequence. We have analyzed a large set (n = 512 of insertions and deletions (indels and single nucleotide polymorphisms causing premature termination of translation in disease-related genes. Prediction of protein-destabilization effects was performed by graphical presentation of the locations of polymorphisms in the protein structure, using the Genomes TO Protein (GTOP database, and manual annotation with a set of specific criteria. Protein-destabilization was predicted for 44.4% of the nonsense SNPs, 32.4% of the frameshifting indels, and 9.1% of the non-frameshifting indels. A prediction of nonsense-mediated decay allowed to infer which truncated proteins would actually be translated as defective proteins. These cases included the proteins linked to diseases inherited dominantly, suggesting a relation between these diseases and toxic aggregation. Our approach would be useful in identifying potentially aggregation-inducing polymorphisms that may have pathological effects.

  5. On the destabilizing effect of damping on discrete and continuous circulatory systems

    Science.gov (United States)

    Luongo, Angelo; D`Annibale, Francesco

    2014-12-01

    The 'Ziegler paradox', concerning the destabilizing effect of damping on elastic systems loaded by nonconservative positional forces, is addressed. The paper aims to look at the phenomenon in a new perspective, according to which no surprising discontinuities in the critical load exist between undamped and damped systems. To show that the actual critical load is found as an (infinitesimal) perturbation of one of the infinitely many sub-critically loaded undamped systems. A series expansion of the damped eigenvalues around the distinct purely imaginary undamped eigenvalues is performed, with the load kept as a fixed, although unknown, parameter. The first sensitivity of the eigenvalues, which is found to be real, is zeroed, so that an implicit expression for the critical load multiplier is found, which only depends on the 'shape' of damping, being independent of its magnitude. An interpretation is given of the destabilization paradox, by referring to the concept of 'modal damping', according to which the sign of the projection of the damping force on the eigenvector of the dual basis, and not on the eigenvector itself, is the true responsible for stability. The whole procedure is explained in detail for discrete systems, and successively extended to continuous systems. Two sample structures are studied for illustrative purposes: the classical reverse double-pendulum under a follower force and a linear visco-elastic beam under a follower force and a dead load.

  6. Thermodynamic and kinetic destabilization of magnesium hydride using Mg-In solid solution alloys.

    Science.gov (United States)

    Zhou, Chengshang; Fang, Zhigang Zak; Lu, Jun; Zhang, Xiaoyi

    2013-07-31

    Efforts to thermodynamically destabilize magnesium hydride (MgH2), so that it can be used for practical hydrogen storage applications, have been a difficult challenge that has eluded scientists for decades. This letter reports that MgH2 can indeed be destabilized by forming solid solution alloys of magnesium with group III and IVB elements, such as indium. Results of this research showed that the equilibrium hydrogen pressure of a Mg-0.1In alloy is 70% higher than that of pure MgH2. The temperature at 1 bar hydrogen pressure (T1bar) of Mg-0.1In alloy was reduced to 262.9 °C from 278.9 °C, which is the T1bar of pure MgH2. Furthermore, the kinetic rates of dehydrogenation of Mg-0.1In alloy hydride doped with a titanium intermetallic (TiMn2) catalyst were also significantly improved compared with those of MgH2.

  7. MTOR-Driven Metabolic Reprogramming Regulates Legionella pneumophila Intracellular Niche Homeostasis

    Science.gov (United States)

    Abshire, Camille F.; Roy, Craig R.

    2016-01-01

    Vacuolar bacterial pathogens are sheltered within unique membrane-bound organelles that expand over time to support bacterial replication. These compartments sequester bacterial molecules away from host cytosolic immunosurveillance pathways that induce antimicrobial responses. The mechanisms by which the human pulmonary pathogen Legionella pneumophila maintains niche homeostasis are poorly understood. We uncovered that the Legionella-containing vacuole (LCV) required a sustained supply of host lipids during expansion. Lipids shortage resulted in LCV rupture and initiation of a host cell death response, whereas excess of host lipids increased LCVs size and housing capacity. We found that lipids uptake from serum and de novo lipogenesis are distinct redundant supply mechanisms for membrane biogenesis in Legionella-infected macrophages. During infection, the metabolic checkpoint kinase Mechanistic Target of Rapamycin (MTOR) controlled lipogenesis through the Serum Response Element Binding Protein 1 and 2 (SREBP1/2) transcription factors. In Legionella-infected macrophages a host-driven response that required the Toll-like receptors (TLRs) adaptor protein Myeloid differentiation primary response gene 88 (Myd88) dampened MTOR signaling which in turn destabilized LCVs under serum starvation. Inactivation of the host MTOR-suppression pathway revealed that L. pneumophila sustained MTOR signaling throughout its intracellular infection cycle by a process that required the upstream regulator Phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) and one or more Dot/Icm effector proteins. Legionella-sustained MTOR signaling facilitated LCV expansion and inhibition of the PI3K-MTOR-SREPB1/2 axis through pharmacological or genetic interference or by activation of the host MTOR-suppression response destabilized expanding LCVs, which in turn triggered cell death of infected macrophages. Our work identified a host metabolic requirement for LCV homeostasis and demonstrated that L

  8. 急性心肌梗死急诊诊断与治疗分析%Clinical effect of intravenous injection of amiodarone in treatment of acute heart failure with rapid atrial fibrillation

    Institute of Scientific and Technical Information of China (English)

    许敏

    2013-01-01

    目的:分析研究AMI(急性心肌梗死)的临床诊断以及治疗效果。方法抽取近年来在我院收治的80例患有急性心肌梗塞的患者,随机分为实验组和对照组,每组各40例患者,其中实验组对患者采取尿激酶溶栓治疗,对照组对患者采取传统常规治疗。结果实验组患者的临床治疗效果明显优于对照组患者,两组间差异具有统计学意义(P<0.05)。结论采取及时有效的临床干预以及治疗对治疗急性心肌梗塞的患者起到至关重要的作用,具有临床推广价值应用。%Objective To investigate the clinical effect of intravenous injection of amiodarone in the treatment of acute heart failure with rapid atrial fibrillation.Methods A total of 172 patients with acute heart failure and rapid atrial fibrillation who were admitted to our hospital from October 2011 to July 2013 were randomly divided into heart failure and atrial fibrillation group and amiodarone group. The heart failure and atrial fibrillation group received conventional treatment, while the amiodarone group received conventional treatment plus injection of amiodarone. The treatment outcomes of the two groups were compared.Results After 7 d of treatment, the amiodarone group had a significant more improvement in cardiac function, a significantly better heart rate control, and a significantly lower mortality rate, as compared with the heart failure and atrial fibrillation group (P<0.05 for all comparisons). ConclusionConventional treatment plus injection of amiodarone can improve cardiac function and control heart rate in the treatment of heart failure.

  9. Influence of puncture site and methods for phlebitis caused by amiodarone%穿刺部位及方法对胺碘酮致静脉炎的影响

    Institute of Scientific and Technical Information of China (English)

    曹利芸

    2011-01-01

    Objective To study the correlation between the different puncture site and methods and of the incidence of phlebitis caused by amiodarone. Methods 90 patients treated with amiodarone were selected as research object. The incidence of phlebitis caused by amiodarone at different puncture site and methods, concentration of amiodarone, injection time were analyzed. Results The incidence of phlebitis of upper limbs vein was lower than that of the other position.The incidence of phlebitis of central venous was lower than that of peripheral vein. The incidence of phlebitis of micropump was higher than that of the other methods. The incidence of phlebitis injected with longer time was higher than that of the shorter. The incidence of phlebitis at high-concentration amiodarone was higher than that of lower-concentration amiodarone. Conclusion The different puncture site and methods are related to the incidence of phlebitis.%目的 探讨不同穿刺部位及方法与胺碘酮致静脉炎的发生率的相关性.方法 选取胺酮进行治疗的90例患者为研究对象,将穿刺部位、穿刺方法及胺碘酮浓度、注射时间不同时静脉炎的发生率进行统计和比较.结果 颈外静脉炎发生率较其他部位要低,微泵注药静脉炎发生率高于其他方式,注药时间长者静脉炎发生率高于短者,胺碘酮浓度高者静脉炎发生率高于低浓度者,经比较,差异均有显著性(均P<0.05).结论 不同穿刺部位及方法与胺碘酮致静脉炎的发生率相关性较大,应引起重视,以预防静脉炎的发生.

  10. Amiodarone-induced ADR reports in Anhui from 2005~2009%安徽省2005~2010年胺碘酮药品不良反应报告分析

    Institute of Scientific and Technical Information of China (English)

    张树强; 叶根深

    2012-01-01

    Objective To study the condition and analyze the related factors of amiodarone-induced adverse drug reactions( ADR ) in An-hui province. Methods Amiodarone-related ADR reports reported in Anhui province from Jan 1,2005 to Nov 31,2010 were searched, from which a total of 120 qualified amiodarone-induced ADR reports were screened out and analyzed statistically. Results Amiodarone-induced ADR occurred more in males, aged from 40 to 80, most of which were not serious. They were majorly induced by oral administration, and majorly occurred within 1 to 7 days. They might involve multi-organs or systems, and their clinical manifestations were chiefly nausea,vomiting or constipation. Most were relatively mild,and subsided after amiodarone withdrawal. Conclusion Medical staffs should pay much attention to amiodarone -induced ADR,and ADR monitoring should be more strengthened.%目的 调查安徽省胺碘酮致药品不良反应(ADR)情况并分析相关因素.方法 检索安徽省2005年1月1日~2010年11月31日呈报的与胺碘酮相关的ADR报告表,筛选合格报告表120例,进行统计分析.结果 ADR多发生在40~80岁,男性多于女性;以一般不良反应居多.主要由口服途径给药引起,多发生于给药后1~7 d内;可累及多个系统/器官,多为恶心、呕吐或便秘;多数较轻微,停药或/和对症处理后可好转、治愈.结论 医务人员应重视胺碘酮所致ADR,并进一步加强ADR监测.

  11. Clinical analysis of low-dose amiodarone therapy in the management of ventricular arrhythmias%小剂量胺碘酮治疗室性心律失常56例临床分析

    Institute of Scientific and Technical Information of China (English)

    王珍

    2001-01-01

    Objective:To evaluate the efficacy and safety of low-dose amiodarone therapy in the management of ventricular arrhythmias.Methods:56 patients with symptomatic drug refractory managed with low-dose oral amiodarone therapy over 5-year period was analyzed retrospec tively. Loading dose of amiodarone 800 mg daily for 1 week, 400 mg daily for anoth er week, then, 100-200 mg daily as maintenance daily.Mean treatment duration was 29±8 months.Results:The efficacy of amiodarone was 81% in the management of ventricular arrhymias. The cumulative incidence of amiodarone related adverse effects was 9%. 1 patient had thyroid dysfunction, and 1 developed pulmonary int erstitial fibrosis.Conclusion:The higer efficacy and acceptable side effect profile of low amiodarone therapy in the management of ventricular arrhythmias.%目的:观察小剂量胺碘酮长期治疗室性心律失常的疗效和安全性。方法:回顾性分析了我院5年来收治的经其它药物治疗无效的室性心律失常的患者56例,给以胺碘酮负荷量800 mg/日,一周后400 mg/日,一周后100~200 mg/日维持,平均给药时间29±8月。结果:胺碘酮治疗室性心律失常有效率81%。与胺碘酮有关的副作用累计发生率为9%,引起甲状腺功能异常和肺间质纤维化各1例。结论:小剂量胺碘酮治疗室性心律失常是安全有效的。

  12. Thiol-responsive gemini poly(ethylene glycol)-poly(lactide) with a cystine disulfide spacer as an intracellular drug delivery nanocarrier.

    Science.gov (United States)

    Kim, Hyun-Chul; Kim, Eunjoo; Ha, Tae-Lin; Jeong, Sang Won; Lee, Se Guen; Lee, Sung Jun; Lee, Boram

    2015-03-01

    Thiol-responsive gemini micelles consisting of hydrophilic poly(ethylene glycol) (PEG) blocks and hydrophobic polylactide (PLA) blocks with a cystine disulfide spacer were reported as effective intracellular nanocarriers of drugs. In the presence of cellular glutathione (GSH) as a reducing agent, gemini micelles gradually destabilize into monomeric micelles through cleavage of the cystine linkage. This destabilization of the gemini micelles changed their size distribution, with the appearance of small aggregates, and led to the enhanced release of encapsulated doxorubicin (DOX). The results obtained from cell culture via confocal laser scanning microscopy (CLSM) for cellular uptake, as well as cell viability measurements for anticancer efficacy suggest the potential of disulfide-based gemini polymeric micelles as controlled drug delivery carriers.

  13. Hydrophilic fluorescent nanogel thermometer for intracellular thermometry.

    Science.gov (United States)

    Gota, Chie; Okabe, Kohki; Funatsu, Takashi; Harada, Yoshie; Uchiyama, Seiichi

    2009-03-01

    The first methodology to measure intracellular temperature is described. A highly hydrophilic fluorescent nanogel thermometer developed for this purpose stays in the cytoplasm and emits stronger fluorescence at a higher temperature. Thus, intracellular temperature variations associated with biological processes can be monitored by this novel thermometer with a temperature resolution of better than 0.5 degrees C.

  14. Disfunção tireoidiana e conduta dos cardiologistas em pacientes usando amiodarona Thyroid dysfunction and cardiological management in patients receiving amiodarone

    Directory of Open Access Journals (Sweden)

    Anna Gabriela Fuks

    2004-06-01

    Full Text Available OBJETIVO: Determinar a prevalência de disfunção tireoidiana em pacientes usando amiodarona e os possíveis fatores associados. Verificar através de questionário aplicado a cardiologistas, a importância do fármaco causar alterações na função tireoidiana. MÉTODO: Avaliados 56 pacientes em uso crônico (> 3 meses de amiodarona com dosagens séricas de TSH, T4 livre, T3 total e Anti-TPO e definidos como portadores de disfunção tireoidiana (DT pacientes com TSH alterado. RESULTADOS: A prevalência de disfunção tireoidiana foi de 33,9%. Não houve diferença entre este grupo e os pacientes sem disfunção, exceto em relação à prevalência de anti-TPO positivo maior nos pacientes com DT (p=0,02. Hipotireoidismo subclínico foi diagnosticado em 10 (17,9% pacientes e hipotireoidismo clínico em 6 (10,7%. A prevalência de hipertireoidismo subclínico foi de 3,6% e de hipertireoidismo clínico de 1,8%. Anticorpos anti-TPO foram positivos em 5 (8% pacientes (dos quais 4 apresentavam disfunção. Quando comparados aos doentes sem anti-TPO positivo este grupo teve maior prevalência de disfunção (80% vs 29,4%; p=0,04. Verificado que apenas 49,2% dos cardiologistas faziam acompanhamento da função tireoidiana rotineiramente e a prevalência de disfunção referida na experiência da maioria era de 1 a 10%. CONCLUSÃO: A prevalência de disfunção tireoidiana na nossa população foi elevada, mostrando a necessidade de implementação de uma rotina laboratorial. Houve grande divergência entre os cardiologistas em relação ao tipo de acompanhamento utilizado nos pacientes em uso de amiodarona.OBJECTIVE: To determine the prevalence of thyroid dysfunction in patients receiving amiodarone, and the possible associated factors. The study also aimed at assessing the effect of amiodarone on thyroid function through the application of a questionnaire to cardiologists. METHOD: Fifty-six patients chronically (> 3 months receiving amiodarone were

  15. Use of Intravenous Amiodarone in the Treatment of Nifekalant-Resistant Arrhythmia: A Review of 11 Consecutive Cases with Severe Heart Failure

    Science.gov (United States)

    Nakagawa, Koji; Nakamura, Kazufumi; Kusano, Kengo Fukushima; Nagase, Satoshi; Tada, Takeshi; Murakami, Masato; Hata, Yoshiki; Morita, Hiroshi; Kohno, Kunihisa; Hina, Kazumasa; Ujihira, Tohru; Ohe, Tohru; Ito, Hiroshi

    2011-01-01

    Background: Both nifekalant hydrochloride (NIF), a selective IKr blocker, and intravenous amiodarone (AMD), a multi-channel (including IKr blocking) blocker, have been reported to be efficacious for refractory arrhythmias. However, the optimal use of those antiarrhythmic drugs for refractory arrhythmia with severe heart failure has not been established. Intravenous AMD might be effective for arrhythmias refractory to NIF in patients with severe heart failure. Here, we report that intravenous amiodarone was effective in the treatment of nifekalant-resistant in a group of arrhythmia patients with severe heart failure. Methods: Eleven severe heart failure patients who had received intravenous AMD for treatment of NIF-resistant arrhythmias were included in this study, and retrospective analysis was performed. Clinical efficacy (terminative and preventive effects on arrhythmia) of intravenous AMD was evaluated. Results: All cases were emergent cases and had depressed left ventricular ejection fraction (30 ± 13%). Clinical arrhythmias were ventricular fibrillation (VF) in four patients, ventricular tachycardia (VT) in six patients, and atrial fibrillation (AF) in one patient. NIF was administered to all patients by intravenous injection. After administration of NIF, VT/VF/AF was terminated in seven of the 10 patients, but a preventive effect was not obtained in any of the patients (NIF-resistance). Intravenous AMD (maintenance dose: 484 ± 166 mg/day) was effective both in termination (80%) and in prevention (80%) of VT/VF events in those patients. It was also effective in termination (80%) and prevention (60%) of AF events refractory to NIF. During continuous AMD administration, no significant adverse effects or proarrhythmic effects were observed in any of the patients. Five patients died within one month, but there was no arrhythmic deaths. Conclusions: Intravenous AMD was effective in NIF-resistant lethal arrhythmias and was relatively safe in emergent cases with

  16. Transmission stabilization and destabilization involving Kerr and Raman effects in broadband soliton-based fiber optics systems

    CERN Document Server

    Peleg, Avner; Tran, Thinh P

    2015-01-01

    We study stabilization and destabilization of propagating soliton sequences in broadband fiber optics systems with $N$ frequency channels, taking into account second-order dispersion, Kerr nonlinearity, delayed Raman response, and linear gain-loss. We employ a propagation model consisting of a system of $N$ coupled nonlinear Schr\\"odinger (NLS) equations and a reduced $N$-dimensional predator-prey model for amplitude dynamics. Numerical simulations with the coupled-NLS model with $2 \\le N \\le 4$ show stable oscillatory dynamics of soliton amplitudes at short-to-intermediate distances, in agreement with predictions of the predator-prey model. Furthermore, the main destabilizing mechanism at long distances is due to generation of radiative sidebands, where the sidebands for a given channel form at the frequencies of solitons in the neighboring channels. This destabilizing process can be partially mitigated by employing frequency dependent linear gain-loss. Moreover, significant enhancement of transmission stabi...

  17. Intracellular structure and nucleocytoplasmic transport.

    Science.gov (United States)

    Agutter, P S

    1995-01-01

    Intracellular movement of any solute or particle accords with one of two general schemes: either it takes place predominantly in the solution phase or it occurs by dynamic interactions with solid-state structures. If nucleocytoplasmic exchanges of macromolecules and complexes are predominantly solution-phase processes, i.e., if the former ("diffusionist") perspective applies, then the only significant structures in nucleocytoplasmic transport are the pore complexes. However, if such exchanges accord with the latter ("solid-state") perspective, then the roles of the nucleoskeleton and cytoskeleton in nucleocytoplasmic transport are potentially, at least, as important as that of the pore complexes. The role of the nucleoskeleton in mRNA transport is more difficult to evaluate than that of the cytoskeleton because it is less well characterized, and current evidence does not exclude either perspective. However, the balance of evidence favors a solid-state scheme. It is argued that ribosomal subunits are also more likely to migrate by a solid-state rather than a diffusionist mechanism, though the opposite is true of proteins and tRNAs. Moreover, recent data on the effects of viral proteins on intranuclear RNA processing and migration accord with the solid-state perspective. In view of this balance of evidence, three possible solid-state mechanisms for nucleocytoplasmic mRNA transport are described and evaluated. The explanatory advantage of solid-state models is contrasted with the heuristic advantage of diffusion theory, but it is argued that diffusion theory itself, even aided by modern computational techniques and numerical and graphical approaches, cannot account for data describing the movements of materials within the cell. Therefore, the mechanisms envisaged in a diffusionist perspective cannot be confined to diffusion alone, but must include other processes such as bulk fluid flow.

  18. Engineering FKBP-Based Destabilizing Domains to Build Sophisticated Protein Regulation Systems.

    Directory of Open Access Journals (Sweden)

    Wenlin An

    Full Text Available Targeting protein stability with small molecules has emerged as an effective tool to control protein abundance in a fast, scalable and reversible manner. The technique involves tagging a protein of interest (POI with a destabilizing domain (DD specifically controlled by a small molecule. The successful construction of such fusion proteins may, however, be limited by functional interference of the DD epitope with electrostatic interactions required for full biological function of proteins. Another drawback of this approach is the remaining endogenous protein. Here, we combined the Cre-LoxP system with an advanced DD and generated a protein regulation system in which the loss of an endogenous protein, in our case the tumor suppressor PTEN, can be coupled directly with a conditionally fine-tunable DD-PTEN. This new system will consolidate and extend the use of DD-technology to control protein function precisely in living cells and animal models.

  19. Four-Rod Stabilization of Severely Destabilized Lumbar Spine Caused by Metastatic Tumor

    Directory of Open Access Journals (Sweden)

    Isao Shibuya

    2013-01-01

    Full Text Available We report a case of a 67-year-old female with severely destabilized lumbar spine caused by metastatic malignant tumor. The primary lesion was a thyroid follicular adenocarcinoma. Complete destruction of the L3, L4, and L5 vertebrae had resulted in severe instability, which left the patient with severe back pain and bed-ridden. Since the vertebrae were so severely damaged at 3 levels, 4 rods were used to stabilize the spine. Following stabilization, the pain was alleviated and the patient’s quality of life improved. We introduce here the 4-rod technique to stabilize the spine over 3 vertebral levels following severe destruction by metastatic tumor.

  20. Formation and Destabilization of the Particle Band on the Fluid-Fluid Interface

    Science.gov (United States)

    Kim, Jungchul; Xu, Feng; Lee, Sungyon

    2017-02-01

    An inclusion of particles in a Newtonian liquid can fundamentally change the interfacial dynamics and even cause interfacial instabilities. For instance, viscous fingering can arise even in the absence of the destabilizing viscosity ratio between invading and defending phases, when particles are added to the viscous invading fluid inside a Hele-Shaw cell. In the same flow configuration, the formation and breakup of a dense particle band are observed on the interface, only when the particle diameter d becomes comparable to the channel gap thickness h . We experimentally characterize the evolution of the fluid-fluid interface in this new physical regime and propose a simple model for the particle band that successfully captures the fingering onset as a function of the particle concentration and h /d .

  1. A Destabilized Case of Stable Effort Angina Pectoris Induced by Low-dose Adenosine Triphosphate

    Science.gov (United States)

    Sueta, Daisuke; Kojima, Sunao; Izumiya, Yasuhiro; Yamamuro, Megumi; Kaikita, Koichi; Hokimoto, Seiji; Ogawa, Hisao

    2016-01-01

    A 79-year-old man was diagnosed with sudden deafness. He had previously experienced a suspected episode of angina pectoris. At a local hospital, after 500 mg of hydrocortisone and 80 mg adenosine triphosphate (ATP) were administered, he became aware of chest discomfort. An electrocardiogram revealed serious ST-segment depressions. He was diagnosed with a non-ST elevated myocardial infarction (NSTEMI). Emergency coronary angiography revealed triple vessel disease, and the lesion was successfully stented. The mechanisms whereby the stable effort angina pectoris destabilized in this case were thought to include a reduction of the local blood flow because of an ATP product and probable thrombus formation in response to the administered steroids. PMID:27853071

  2. Numerical studies of gravity destabilized percolation in 2D porous media

    Science.gov (United States)

    Bo, Z.; Loggia, D.; Xiaorong, L.; Vasseur, G.; Ping, H.

    2006-04-01

    Two dimensional simulations of percolation are realized on square networks of pore throats with a random capillary pressure distribution. We analyse the influence of a destabilizing gravity field (g) and of the standard deviation of the distribution of the capillary pressure thresholds (Wt). The fragmentation process is not taken into account in this study. For an increase of g or/and when Wt decreases, two transitions are analyzed with three different regimes displacement patterns: Invasion percolation, invasion percolation in a gradient, and invasion in a pure gradient. The transitions are controlled both by the ratio g/Wt and by the sample size (L). A scaling law between the saturation at the percolation threshold and g/Wt allows delineating the three regimes in agreement with theoretical argument of the percolation in a gradient.

  3. The mass media destabilizes the cultural homogenous regime in Axelrod's model

    Energy Technology Data Exchange (ETDEWEB)

    Peres, Lucas R; Fontanari, Jose F [Instituto de Fisica de Sao Carlos, Universidade de Sao Paulo, Caixa Postal 369, 13560-970 Sao Carlos SP (Brazil)

    2010-02-05

    An important feature of Axelrod's model for culture dissemination or social influence is the emergence of many multicultural absorbing states, despite the fact that the local rules that specify the agents interactions are explicitly designed to decrease the cultural differences between agents. Here we re-examine the problem of introducing an external, global interaction-the mass media-in the rules of Axelrod's model: in addition to their nearest neighbors, each agent has a certain probability p to interact with a virtual neighbor whose cultural features are fixed from the outset. Most surprisingly, this apparently homogenizing effect actually increases the cultural diversity of the population. We show that, contrary to previous claims in the literature, even a vanishingly small value of p is sufficient to destabilize the homogeneous regime for very large lattice sizes.

  4. Mechanism for the catastrophe-promoting activity of the microtubule destabilizer Op18/stathmin.

    Science.gov (United States)

    Gupta, Kamlesh K; Li, Chunlei; Duan, Aranda; Alberico, Emily O; Kim, Oleg V; Alber, Mark S; Goodson, Holly V

    2013-12-17

    Regulation of microtubule dynamic instability is crucial for cellular processes, ranging from mitosis to membrane transport. Stathmin (also known as oncoprotein 18/Op18) is a prominent microtubule destabilizer that acts preferentially on microtubule minus ends. Stathmin has been studied intensively because of its association with multiple types of cancer, but its mechanism of action remains controversial. Two models have been proposed. One model is that stathmin promotes microtubule catastrophe indirectly, and does so by sequestering tubulin; the other holds that stathmin alters microtubule dynamics by directly destabilizing growing microtubules. Stathmin's sequestration activity is well established, but the mechanism of any direct action is mysterious because stathmin binds to microtubules very weakly. To address these issues, we have studied interactions between stathmin and varied tubulin polymers. We show that stathmin binds tightly to Dolastatin-10 tubulin rings, which mimic curved tubulin protofilaments, and that stathmin depolymerizes stabilized protofilament-rich polymers. These observations lead us to propose that stathmin promotes catastrophe by binding to and acting upon protofilaments exposed at the tips of growing microtubules. Moreover, we suggest that stathmin's minus-end preference results from interactions between stathmin's N terminus and the surface of α-tubulin that is exposed only at the minus end. Using computational modeling of microtubule dynamics, we show that these mechanisms could account for stathmin's observed activities in vitro, but that both the direct and sequestering activities are likely to be relevant in a cellular context. Taken together, our results suggest that stathmin can promote catastrophe by direct action on protofilament structure and interactions.

  5. Evidence of sheared sills related to flank destabilization in a basaltic volcano

    Science.gov (United States)

    Berthod, C.; Famin, V.; Bascou, J.; Michon, L.; Ildefonse, B.; Monié, P.

    2016-04-01

    Piton des Neiges basaltic volcano (La Réunion) has been deeply dissected by erosion, exposing large volumes of debris avalanche deposits. To shed light on the factors that led to volcano flank destabilizations, we studied the structure, the crystallographic and magnetic fabrics of the substratum of a debris avalanche unit. This substratum is a complex of > 50 seaward-dipping sills that has been exposed by the avalanche. Structural observations show that the sill plane in contact with the avalanche is one of the latest intrusions in the sill complex. In this uppermost sill, the anisotropy of magnetic susceptibility (AMS) is correlated to the crystallographic preferred orientation of magmatic silicate minerals, allowing us to use AMS as a proxy to infer the magmatic flow. The AMS fabric across the intrusion is strongly asymmetric, which reveals that the contact sill was emplaced with a normal shear displacement of its hanging wall. The shear displacement and the magma flow in the intrusion are both directed toward the NNE, i.e. toward the sea, which is also the direction of the slope and of the debris avalanche runout. Because all the sills in the intrusion complex have a similar dip and dip direction, it is likely that several of them also underwent a cointrusive slip toward the NNE. We conclude that this cointrusive normal slip, repeated over many intrusions of the sill complex, increased the flank instability of the volcano. This incremental instability may have ended up into the observed debris avalanche deposit. At Piton de la Fournaise, the active volcano of La Réunion, sill intrusion and cointrusive flank displacement have been inferred from geophysical studies for the April 2007 eruption. By providing direct evidence of sheared sills, our study substantiates the idea that repeated sill intrusions may eventually trigger flank destabilizations in basaltic volcanoes.

  6. Destabilizing protein polymorphisms in the genetic background direct phenotypic expression of mutant SOD1 toxicity.

    Directory of Open Access Journals (Sweden)

    Tali Gidalevitz

    2009-03-01

    Full Text Available Genetic background exerts a strong modulatory effect on the toxicity of aggregation-prone proteins in conformational diseases. In addition to influencing the misfolding and aggregation behavior of the mutant proteins, polymorphisms in putative modifier genes may affect the molecular processes leading to the disease phenotype. Mutations in SOD1 in a subset of familial amyotrophic lateral sclerosis (ALS cases confer dominant but clinically variable toxicity, thought to be mediated by misfolding and aggregation of mutant SOD1 protein. While the mechanism of toxicity remains unknown, both the nature of the SOD1 mutation and the genetic background in which it is expressed appear important. To address this, we established a Caenorhabditis elegans model to systematically examine the aggregation behavior and genetic interactions of mutant forms of SOD1. Expression of three structurally distinct SOD1 mutants in C. elegans muscle cells resulted in the appearance of heterogeneous populations of aggregates and was associated with only mild cellular dysfunction. However, introduction of destabilizing temperature-sensitive mutations into the genetic background strongly enhanced the toxicity of SOD1 mutants, resulting in exposure of several deleterious phenotypes at permissive conditions in a manner dependent on the specific SOD1 mutation. The nature of the observed phenotype was dependent on the temperature-sensitive mutation present, while its penetrance reflected the specific combination of temperature-sensitive and SOD1 mutations. Thus, the specific toxic phenotypes of conformational disease may not be simply due to misfolding/aggregation toxicity of the causative mutant proteins, but may be defined by their genetic interactions with cellular pathways harboring mildly destabilizing missense alleles.

  7. Hydrazine borane-induced destabilization of ammonia borane, and vice versa

    Energy Technology Data Exchange (ETDEWEB)

    Petit, Jean-Fabien; Moussa, Georges [IEM (Institut Europeen des Membranes), UMR 5635 (CNRS-ENSCM-UM2), Universite Montpellier 2, Place E. Bataillon, F-34095 Montpellier (France); Demirci, Umit B., E-mail: umit.demirci@um2.fr [IEM (Institut Europeen des Membranes), UMR 5635 (CNRS-ENSCM-UM2), Universite Montpellier 2, Place E. Bataillon, F-34095 Montpellier (France); Toche, François; Chiriac, Rodica [Université Lyon 1, CNRS, UMR 5615, Laboratoire des Multimatériaux et Interfaces, 43 boulevard du 11 Novembre 1918, F-69622 Villeurbanne (France); Miele, Philippe [IEM (Institut Europeen des Membranes), UMR 5635 (CNRS-ENSCM-UM2), Universite Montpellier 2, Place E. Bataillon, F-34095 Montpellier (France)

    2014-08-15

    Graphical abstract: - Highlights: • Hydrazine borane and ammoniaborane (mole ratio 1:1) destabilize each other. • This is characterized by a melting point at ∼30 °C and decomposition into hydrazine. • Also, some hydrogen H{sub 2} is “explosively” liberated at around 90 °C. • The mixture can be however stabilized into a potential hydrogen storage material. • This hydrogen storage material dehydrogenates up to 300 °C to form boron nitride. - Abstract: In the field of solid-state chemical hydrogen storage, ammonia borane NH{sub 3}BH{sub 3} has been widely studied while hydrazine borane N{sub 2}H{sub 4}BH{sub 3} can be considered as a “novel” material. In the present work, we investigated the behaviour of these boranes when mixed together in a mole ratio of 1:1. Hydrazine borane and ammonia borane destabilize each other. Though stable at 20–25 °C, the mixture melts at ∼30 °C and then undergoes significant decomposition, with desorption of hydrogen H{sub 2} and hydrazine N{sub 2}H{sub 4} from 67 °C. This is explained by the fact that the presence of hydrazine borane disrupts the H{sup δ+}⋯H{sup δ−} network of ammonia borane, and vice versa; the mixture is then much less stable than the pristine boranes. The mixture can nevertheless be stabilized (by heat- or vacuum-treatment and thus extraction of evolving hydrogen and hydrazine), making the as-obtained solid a potential chemical hydrogen storage material. Over the range 25–300 °C, it is able to release ca. 11.4 wt% of almost pure H{sub 2}. Furthermore forms boron nitride as the solid residue, at temperatures as low as 300 °C.

  8. Stochastic resonance in an intracellular genetic perceptron

    Science.gov (United States)

    Bates, Russell; Blyuss, Oleg; Zaikin, Alexey

    2014-03-01

    Intracellular genetic networks are more intelligent than was first assumed due to their ability to learn. One of the manifestations of this intelligence is the ability to learn associations of two stimuli within gene-regulating circuitry: Hebbian-type learning within the cellular life. However, gene expression is an intrinsically noisy process; hence, we investigate the effect of intrinsic and extrinsic noise on this kind of intracellular intelligence. We report a stochastic resonance in an intracellular associative genetic perceptron, a noise-induced phenomenon, which manifests itself in noise-induced increase of response in efficiency after the learning event under the conditions of optimal stochasticity.

  9. 胺碘酮对急性心肌梗死并发室性心动过速的治疗分析%Clinical analysis on intravenous Amiodarone for continuous ventricular tachycardia in patients with acute myocardial infarction

    Institute of Scientific and Technical Information of China (English)

    阎晋华; 齐守罡

    2012-01-01

      目的观察静脉注射胺碘酮治疗急性心肌梗死并发室性心动过速的疗效。方法将30例急性心肌梗死患者分为2组,每组15例,分别给予静脉注射利多卡因、胺碘酮治疗,观察2组临床疗效。结果胺碘酮组15例患者中,13例患者室性心动过速得到控制,对照组有8例患者室性心动过速得到控制,胺碘酮组有效率高于对照组。结论静脉注射胺碘酮治疗急性心肌梗死并发室性心动过速安全有效,可提高急性心肌梗死的抢救成功率。%  Objective To investigate the effect of amiodarone to continuous ventricular tachycardia in patients with acute myocardial infarction.Methods 30 cases of acute myocardial infarction patients were divided into 2 groups, 15 cases in each group, were given intravenous lidocaine, amiodarone treatment, observation of clinical curative effect of 2 sets.Results Among 15 cases in the observation group, 13 patients with ventricular tachycardia were under control, in the control group, 8 patients with ventricular tachycardia got controlled heartbeat, amiodarone group was higher than that of control group.Conclusion Intravenous amiodarone is more effective and safer than lidocaine in treating continuous ventricular tachycardia in patients with AMI.

  10. Clinical observation of amiodarone in treatment of pulmonary tachyarrhythmia complicated with respiratory failure%胺碘酮治疗呼吸衰竭并快速肺源性心律失常的临床观察

    Institute of Scientific and Technical Information of China (English)

    张淑立; 王毅

    2012-01-01

    Objective To observe the effect of amiodarone in the treatment of pulmonary tachyarrhythmia complicated with respiratory failure. Methods Multifocal atrial tachycardia, atrial fibrillation, atrial flutter and rapid ventricular arrhythmia were observed in 20 patients with acute exacerbation of chronic respiratory failure in our ICU receiving electrocardiography custody. Amiodarone was first injected intravenously followed by infusion pumps, and then orally. Results After amiodarone being administrated, all kinds of arrhythmia in the 19 patients were greatly reduced or disappeared, while only 1 patient with atrial flutter remained. Serious side effect was not detected during the therapy. Conclusions Amiodarone can be used in the patients with pulmonary tachyarrhythmia complicated with respiratory failure safely and effectively.%目的 观察胺碘酮对呼吸衰竭伴快速肺源性心律失常的疗效.方法 20例慢性呼吸衰竭病人,在监护病房持续心电监护,呼吸衰竭急性加重期出现紊乱性房性心律失常、房颤、房扑以及快速室性心律失常,予胺碘酮先静脉推注、静脉泵入,后序贯为口服.结果 用胺碘酮后19例病人各种心律失常明显减少或消失,1例房扑病人无转复.用药过程中未发现明显副作用.结论 胺碘酮对呼吸衰竭伴快速肺源性快速心律失常安全、有效.

  11. Discuss the Treatment of Amiodarone Combined With Metoprolol in Coronary Heart Disease in Elderly Patients%胺碘酮联合美托洛尔治疗老年冠心病

    Institute of Scientific and Technical Information of China (English)

    王勇; 李连鑫

    2015-01-01

    目的:探讨胺碘酮联合美托洛尔治疗老年冠心病的临床效果。方法将我院于2013年1月~2014年1月收治的156例老年冠心病患者列为研究对象,将其随机平分,观察组给予常规药物加胺碘酮联合美托洛尔口服;对照组给予常规药物加胺碘酮口服,6个月后对较分析其心绞痛、心律失常的改善情况。结果观察组室性心绞痛、心律失常的治疗有效率均明显大于对照组,差异显著(P<0.05),具有统计学意义。结论胺碘酮联合美托洛尔治疗老年冠心病效果比单用胺碘酮疗效好,差异显著。%ObjectiveDiscuss the clinical effect of Amiodarone combined with metoprolol in Coronary heart disease in elderly.Method Selected 156 cases of coronary heart disease in elderly admitted in our hospital, divided them into two groups. Observation group received conventional drugs and oral amiodarone combined with metoprolol, control group received conventional drugs and oral amiodarone, compared their improvement of angina and arrhythmias six months later.Results Observation group' room angina, arrhythmia treatment effective rate was signiifcantly greater than control group, the difference was signiifcant (P<0.05), with statistical significance.Conclusion Amiodarone combined with metoprolol have a better efifcacy in coronary heart disease in elderly patients..

  12. 利多卡因混合制剂湿敷治疗胺碘酮所致静脉炎%Lidocaine mixture wet compress therapy with amiodarone induced phlebitis

    Institute of Scientific and Technical Information of China (English)

    陈秀红

    2012-01-01

      Objective:To investigate the loss and treatment with amiodarone induced phlebitis method. Methods:Using 2%lidocaine, 75%ethanol, dexamethasone, vitamin B12 four kinds of drugs into the mixture wet compress therapy with amiodarone induced phlebitis. 60 patients with amiodarone induced phlebitis were randomly divided into the experimental group 32 cases, 28 cases of the control group. The experimental group used lidocaine mixture wet compress therapy, the control group with 75%alcohol wet compress therapy.Results:in the experimental group were significantly better than the control group, treatment effect.Conclusion:intravenous infusion of amiodarone induced peripheral phlebitis, application of lidocaine mixture wet compress remarkable curative effect, safety and Reliability, no adverse reaction.%  目的:探讨减轻及治疗胺碘酮所致静脉炎的方法。方法:采用2%利多卡因、75%乙醇、地塞米松、维生素B12等四种药物配伍成混合制剂湿敷治疗胺碘酮所致静脉炎。将60例盐酸胺碘酮所致静脉炎患者随机分为实验组32例,对照组28例。实验组用利多卡因混合制剂湿敷治疗,对照组用75%乙醇湿敷治疗。结果:实验组治疗效果显著优于对照组。结论:对于胺碘酮静脉滴注所致的外周静脉炎,应用利多卡因混合制剂湿敷疗效显著,安全可靠,无不良反应。

  13. 去乙基胺碘酮--容易被忽视的影响胺碘酮临床使用质量的因素%Desethylamiodarone-an Neglected Factor Affecting the Clinical Use of Amiodarone

    Institute of Scientific and Technical Information of China (English)

    谭蓉; 杨继红; 孙为民

    2014-01-01

    Drugs could affect the activity of CYP450 isoenzyme, which would influence drug safety and efficacy of the substrates of CYP450 isoenzyme. Desethylamiodarone, an in vivo metabolite of amiodarone, not only contributes to its therapeutic effect, at the same time, also plays great role in the side effects of amiodarone by influencing the CYP450 isoenzyme system. Therefore, neglecting the influence factors of desethylamiodarone will affect the safety and efficacy evaluation of amiodarone.%药物可通过CYP450同工酶途径影响其底物药物临床使用的安全性和有效性。胺碘酮体内代谢产物去乙基胺碘酮不仅对其治疗作用贡献较大,同时,对CYP450同工酶系的影响也较为广泛,作用也更强。因此,对胺碘酮临床使用的评估,忽视去乙基胺碘酮的影响因素,将影响胺碘酮临床使用的安全性和有效性。

  14. 胺碘酮治疗老年冠心病心律不齐的临床疗效观察%Clinical Efficacy of Amiodarone for Elderly Patients With Coronary Heart Disease Combined With Arrhythmia

    Institute of Scientific and Technical Information of China (English)

    张洪莲

    2016-01-01

    Objective To investigate the efficacy of amiodarone in the treatment of CHD combined with Arrhythmia for elderly patients.Methods We divided 80 patients into two groups,the control group used conventional therapy,and observation group used amiodarone treatment.Results The efficiency and incidence of adverse reactions of observation group were significantly better than control group(P<0.05).ConclusionThe effect of of amiodarone in the treatment of CHD combined with Arrhythmia is ideal.%目的:观察胺碘酮治疗老年冠心病心律不齐的效果。方法随机将我院收治的80例冠心病心律不齐老年患者平均分为两组,对照组行常规治疗,观察组行胺碘酮治疗。结果观察组总有效率、不良反应发生率等优于对照组(P<0.05)。结论胺碘酮治疗老年冠心病心律不齐效果理想。

  15. The Clinical Research of Amiodarone in the Treatment of Patients With Heart Failure Combined With Arrhythmia%胺碘酮治疗心衰合并心律失常患者的临床研究

    Institute of Scientific and Technical Information of China (English)

    许波

    2015-01-01

    目的:分析胺碘酮治疗心衰合并心律失常的效果。方法选取心衰合并心律失常患者42例,均给予胺碘酮治疗。结果42例患者总有效率95.2%,用药后心功能较用药前明显改善,无严重不良反应,仅2例胃肠道不适,经对症处理后好转。结论胺碘酮治疗心衰合并心律失常效果显著。%Objective To analysis the effect of amiodarone in the treatment of heart failure combined with arrhythmia. Methods 42 cases of patients with heart failure combined with arrhythmia were selected and all patients were given amiodarone treatment. Results After treatment,the total effective rate was 95.2%in 42 cases. The cardiac function of patients were significantly improved than before treatment. There was no serious adverse reaction. Only 2 patients had gastrointestinal discomfort and they were cured after symptomatic treatment. Conclusion The effect of amiodarone in treatment of heart failure combined with arrhythmia is significantly.

  16. Validation of merocyanine 540 staining as a technique for assessing capacitation-related membrane destabilization of fresh dog sperm

    NARCIS (Netherlands)

    Steckler, D; Stout, T A E; Durandt, C; Nöthling, J O

    2015-01-01

    The aim of this study was to determine whether flow cytometric evaluation of combined merocyanine 540 and Yo-Pro 1 (M540-YP) staining would identify viable dog sperm that had undergone membrane stabilization known to be associated with capacitation in other species, and whether such destabilization

  17. The Francisella intracellular life cycle: towards molecular mechanisms of intracellular survival and proliferation

    Directory of Open Access Journals (Sweden)

    Audrey eChong

    2010-12-01

    Full Text Available The tularemia-causing bacterium Francisella tularensis is a facultative intracellular organism with a complex intracellular lifecycle that ensures its survival and proliferation in a variety of mammalian cell types, including professional phagocytes. Because this cycle is essential to Francisella pathogenesis and virulence, much research has focused on deciphering the mechanisms of its intracellular survival and replication and characterizing both bacterial and host determinants of the bacterium’s intracellular cycle. Studies of various strains and host cell models have led to the consensual paradigm of Francisella as a cytosolic pathogen, but also to some controversy about its intracellular cycle. In this review, we will detail major findings that have advanced our knowledge of Francisella intracellular survival strategies and also attempt to reconcile discrepancies that exist in our molecular understanding of the Francisella-phagocyte interaction.

  18. 胺碘酮治疗心房颤动23例的临床体会%Clinical Experience of 23 Cases of Atrial Fibrillation Treated with Amiodarone

    Institute of Scientific and Technical Information of China (English)

    赵文霞; 刘成涛

    2015-01-01

    Objective To investigate the amiodarone treatment the clinical curative ef ect of new onset atrial fibril ation.Methods Our hospital from May 2011 to May 2015 were 23 cases of amiodarone treatment for atrial fibril ation patients as the research object. In the strong heart diuresis expansion blood vessel, etc on the basis of routine therapy and amiodarone treatment. Results 23 cases, 13 cases were markedly improved (57%), 7 cases (30%), ef ective invalid in 3 patients (22%), the total ef ective rate was 87%. The group were markedly improved in 1 case because of gastrointestinal symptoms and recur ence after the drug was stopped, take amiodarone after converting. Conclusion Amiodarone compared with other anti-arrhythmic drugs, can more safely and ef ectively control and prevent the occur ence of ventricular ar hythmias, atrial fibril ation and does not af ect heart function.%目的:探讨胺碘酮治疗新发心房纤颤的临床疗效。方法选取本院自2011年5月~2015年5月收治的23例胺碘酮治疗心房房颤动患者作为研究对象。在强心利尿扩血管等常规治疗的基础上采用胺碘酮治疗。结果23例中显效13例(57%),有效7例(30%),无效3例(22%),总有效率87%。其中的显效组中1例因出现胃肠道症状而自行停药后复发,续服胺碘酮后转复。结论胺碘酮与其他抗心律失常药相比,能更安全有效地防治房颤和预防室性心律失常的发生,且不影响心功能。

  19. 胺碘酮联合美托洛尔静注治疗快速心律失常的临床观察%Clinical observation of amiodarone combined with metoprolol injection in the treatment of rapid arrhythmia

    Institute of Scientific and Technical Information of China (English)

    戴志刚

    2014-01-01

    目的:探讨胺碘酮联合美托洛尔静脉注射治疗快速心律失常的临床疗效。方法:2009年1月-2013年8月收治快速心律失常患者60例,对照组给予胺碘酮治疗,研究组给予胺碘酮联合美托洛尔静注治疗。结果:研究组临床治疗效果明显优于对照组,两组差异具有统计学意义(P<0.05);研究组与对照组均未发生严重的不良反应,两组差异不具备统计学意义(P>0.05)。结论:研究胺碘酮联合美托洛尔静脉注射治疗快速心律失常的临床疗效好于单用胺碘酮治疗,安全性、有效性较高,值得在临床治疗中推广使用。%Objective:To investigate the clinical efficacy of amiodarone combined with metoprolol injection in the treatment of rapid arrhythmia.Methods:60 patients with rapid arrhythmia were selected from January 2009 to August 2013.The control group received the treatment of amiodarone,while the research group were treated with amiodarone combined with metoprolol injection therapy.Results:The clinical effect of the treatment group was better than that of the control group,and the difference was statistically significant between two groups(P0.05).Conclusion:The therapeutic effect of amiodarone combined with metoprolol injection is better than single amiodarone in the treatment of rapid arrhythmia.This treatment has high safety,and it also effective,so it worth to be popularized in clinical treatment.

  20. 胺碘酮在临床使用中如何预防静脉炎的发生%In clinical use of amiodarone on prevention of phlebitis

    Institute of Scientific and Technical Information of China (English)

    李小英

    2016-01-01

    objective:Study of infusion of amiodarone causing phlebitis main reason and prevention measures.Methods:the hospital treated 120 ca-ses of intravenous amiodarone in the treatment of arrhythmias in patients with clinical data analysis,detailed study amiodarone intravenous drip or phlebitis after peripheral intravenous injection causes and ways to prevent phlebitis.Results:78 cases of Ⅰ - Ⅱ stage nursing care of patients with phlebitis after 3-7d cured,12 cases of grade ⅲ local induration at the injection site for magnesium sulfate wet packing of 72h is not valid.Conclusion:proper use hydrochloric acid amiodarone and effective nursing intervention on prevention of phlebitis induced by amiodarone hydrochloride controlled and vesting has an extremely important role.%目的:研究输注胺碘酮导致静脉炎发生的主要原因及预防措施。方法:对我院收治的120例静脉应用胺碘酮治疗心律失常患者的临床资料进行分析,详细探讨盐酸胺碘酮静脉滴注或外周静脉推注后致静脉炎的原因和预防静脉炎发生的方法。结果:78例Ⅰ-Ⅱ级静脉炎患者经过3-7d 的护理治疗痊愈,12例Ⅲ级的注射部位局部硬结给予硫酸镁湿敷72h 无效。结论:正确合理的使用盐酸胺碘酮和积极有效的护理措施对盐酸胺碘酮所致静脉炎的预防控制及转归有极其重要的作用。

  1. 盐酸胺碘酮治疗儿童难治性持续性心动过速%Treatment of intractable incessant tachycardia in children with Amiodarone

    Institute of Scientific and Technical Information of China (English)

    李筠; 周爱卿; 杨健萍; 朱敏; 张海燕

    2009-01-01

    目的 提高对盐酸胺碘酮治疗儿童难治性持续性心动过速的认识.方法 对2006年1月-2007年12月80例应用盐酸胺碘酮治疗的难治性心动过速患儿的资料进行总结.其中男52例,女38例;年龄1个月~14岁(平均2.5岁).结果 盐酸胺碘酮具有良好的控制心室率的作用,总有效率为90%左右;同时它有不同程度转复窦性心律的作用,房性心动过速67%,阵发性室上性心动过速92%,交界逸搏性心动过速89%、室性心动过速56%;小剂量β受体阻滞剂具有协同盐酸胺碘酮抗心动过速的作用.治疗过程中7例出现低血压,4例出现心动过缓.结论 Ⅲ类抗心律失常药盐酸胺碘酮具有广泛的抗心律失常作用,它对治疗血流动力学相对稳定的小儿难治性持续性心动过速是安全有效的.%Objective To improve the understanding of Amiodarone in the treatment of intractable incessant tachycardia in children. Methods Data of 80 patients with intractable incessant tachycardia treated by Amiodarone were summarized. Among them 52 were male, 38 were female, and average age was 2.5 years old. Results Amiodarone reduced heart rate effectively, with about 90% effective. Simultaneously, it could convert tachycardia into sinus rhythm and succeeded 67% in atrial tachycardia, 92% in paroxysmal supraventricular tachycardia, 89% in junctional ectopic tachycardia, 56% in ventricular tachycardia respectively. Use of small dosage of β-receptor blocker together with Amiodarone showed synergy. Hypotension and bradycardia are the main side effects. Conclusions Too rapid and sustained tachycardia can lead, to hemodynamic disorders and cause heart failure, it requires urgent and adequate treatment. Amiodarone can be used to treat different kinds of intractable incessant tachycardia, and is safe and effective in patients with relatively stable hemodynamis.

  2. Inhibition of AmpC beta-lactamase through a destabilizing interaction in the active site

    Energy Technology Data Exchange (ETDEWEB)

    Trehan, I.; Beadle, B.M.; Shoichet, B.K. (NWU)

    2010-03-08

    {beta}-Lactamases hydrolyze {beta}-lactam antibiotics, including penicillins and cephalosporins; these enzymes are the most widespread resistance mechanism to these drugs and pose a growing threat to public health. {beta}-Lactams that contain a bulky 6(7){alpha} substituent, such as imipenem and moxalactam, actually inhibit serine {beta}-lactamases and are widely used for this reason. Although mutant serine {beta}-lactamases have arisen that hydrolyze {beta}-lactamase resistant {beta}-lactams (e.g., ceftazidime) or avoid mechanism-based inhibitors (e.g., clavulanate), mutant serine {beta}-lactamases have not yet arisen in the clinic with imipenemase or moxalactamase activity. Structural and thermodynamic studies suggest that the 6(7){alpha} substituents of these inhibitors form destabilizing contacts within the covalent adduct with the conserved Asn152 in class C {beta}-lactamases (Asn132 in class A {beta}-lactamases). This unfavorable interaction may be crucial to inhibition. To test this destabilization hypothesis, we replaced Asn152 with Ala in the class C {beta}-lactamase AmpC from Escherichia coli and examined the mutant enzyme's thermodynamic stability in complex with imipenem and moxalactam. Consistent with the hypothesis, the Asn152 {yields} Ala substitution relieved 0.44 and 1.10 kcal/mol of strain introduced by imipenem and moxalactam, respectively, relative to the wild-type complexes. However, the kinetic efficiency of AmpC N152A was reduced by 6300-fold relative to that of the wild-type enzyme. To further investigate the inhibitor's interaction with the mutant enzyme, the X-ray crystal structure of moxalactam in complex with N152A was determined to a resolution of 1.83 {angstrom}. Moxalactam in the mutant complex is significantly displaced from its orientation in the wild-type complex; however, moxalactam does not adopt an orientation that would restore competence for hydrolysis. Although Asn152 forces {beta}-lactams with 6(7){alpha

  3. 胺碘酮联合肉毒素A治疗面肌痉挛的临床疗效观察%Clinical efficacy of amiodarone combined with botulinum toxin A in hemifacial spasm

    Institute of Scientific and Technical Information of China (English)

    冯建钦; 张鹏飞

    2016-01-01

    Objective To observe the clinical efficacy of amiodarone combined with botulinum toxin A in the treatment of hemifacial spasm.Methods Sixty-five patients with hemifacial spasm were randomly divided into amiodarone(n=33)and control(n=32)group.In the amiodarone group,oral amiodarone and local intramuscular injection of botulinum toxin A were administered.In the control group,only local intramuscular injections of botulinum toxin A was performed.The clinical efficacy was evaluated according to the Cohen rating on the 1st,4th,16th,32nd week.Results The Cohen rating in amiodarone group was significantly better than control group on 4th,16th,32nd week(P<0.05).The complete remission in amiodarone group was significantly higher than control group on 4th,16th,32nd week(75.8% vs.43.8%,81.8% vs.12.5%,81.8% vs.6.2%,all P <0.05).The total effective rate in amiodarone group was significantly higher than control group on 16th,32nd week(97.0%vs.75.0%,93.9% vs.65.6%,all P<0.05). There was one case of recurrence in control group on 4th week,while there was no recurrence in amiodarone group.The recurrence in control group on 16th,32nd week was higher than amiodarone group(56.3 % vs.0.0 %,65.6% vs.12.1%,all P<0.05).There was no signigicant difference in adverse reactions between amiodarone group and control group(24.2%vs.18.8%).Conclusion Combination of amiodarone and botulinum toxin A is more effective than botulinum toxin A alone in the treatment of hemifacial spasm.%目的:探讨胺碘酮( amiodarone)与肉毒素A( botulinum toxin A)联合治疗面肌痉挛的临床疗效。方法65例面肌痉挛患者,随机分为胺碘酮组(33例,胺碘酮联合肉毒素A治疗)和对照组(32例,单纯肉毒素A治疗)。2组治疗前及治疗1、4、16、32周时依据Cohen痉挛强度分级标准进行功能分级及疗效判定。结果治疗4、16、32周时,胺碘酮组Cohen分级明显优于对照组( P<0.05)。治疗4、16和32周时,胺碘酮组的完

  4. 静脉用胺碘酮致急性严重肝损害七例分析%Clinical analysis of seven cases of acute severe hepatic injury induced by intravenous infusion with amiodarone

    Institute of Scientific and Technical Information of China (English)

    衣桂燕; 张彩云; 张萱; 彦青

    2013-01-01

    目的 探讨短时(12 h内)静脉滴注胺碘酮致急性严重肝功能损害的临床特点.方法 收集我院2000年1月至2011年12月12 h内静脉用胺碘酮患者908例的临床表现进行回顾性分析.结果 908例患者中发生急性严重肝损害者7例,发生率为0.8%,病毒性肝炎指标均未见异常.静脉使用胺碘酮时间为1.0~10.0 h,平均使用时间(6±4)h;胺碘酮使用总剂量为210± 1150 mg,平均(733±312)mg.静脉使用胺碘酮前有5例患者肝功能正常,2例轻度升高,ALT为15 ~ 78 U/L,平均(39±21) U/L,AST为22~ 65 U/L,平均(37±15)U/L.用胺碘酮后次日ALT为820~ 4845 U/L,平均(2604±1295) U/L,AST为758~3962U/L,平均(2069±1091) U/L.肝功能恢复时间为7~15 d,平均(10±3)d.肝功能恢复后继续随访至少3个月,未再出现肝损害.结论 短时静脉滴注胺碘酮可导致急性严重肝损害,其发生较早,及时停用胺碘酮后可较快恢复.在静脉用胺碘酮过程中应监测肝功能,尽量避免或及时治疗肝损害.%Objective To analyze the clinical feature and possible mechanism of acute severe hepatic injury induced by intravenous infusion with amiodarone within 12 hours.Methods The clinical diagnoses,medication and characteristics of hepatic injury induced by intravenous infusion with amiodarone within 12 hours were analyzed in 908 cases from 2000 to 2011.Results There were 7 cases of acute severe hepatic injury in 908 cases of intravenous infusion with amiodarone(the rate of 0.8%).The average time of intravenous infusion with amiodarone was (6 ± 4) h.The average accumulated dosage of amiodarone was (733 ± 312) mg,ranging from 210 mg to 1150 mg.The peak of alanine aminotransferase(ALT) was (2604 ± 1295) U/L,ranging from 820 U/L to 4845 U/L,and the aspartate aminotransferase (AST) was (2069 ± 1091) U/L,ranging from 758 U/L to 3962 U/L.The liver enzyme levels returned to baseline values within (10 ± 3)d after hepatoprotection therapy,ranging from 7 d to

  5. LFA-1 binding destabilizes the JAM-A homophilic interaction during leukocyte transmigration.

    Science.gov (United States)

    Wojcikiewicz, Ewa P; Koenen, Rory R; Fraemohs, Line; Minkiewicz, Julia; Azad, Hashem; Weber, Christian; Moy, Vincent T

    2009-01-01

    Leukocyte transendothelial migration into inflamed areas is regulated by the integrity of endothelial cell junctions and is stabilized by adhesion molecules including junctional adhesion molecule-A (JAM-A). JAM-A has been shown to participate in homophilic interactions with itself and in heterophilic interactions with leukocyte function-associated antigen-1 (LFA-1) via its first and second immunoglobulin domains, respectively. Using competitive binding assays in conjunction with atomic force microscopy adhesion measurements, we provide compelling evidence that the second domain of JAM-A stabilizes the homophilic interaction because its deletion suppresses the dynamic strength of the JAM-A homophilic interaction. Moreover, binding of the LFA-1 inserted domain to the second domain of JAM-A reduces the dynamic strength of the JAM-A homophilic interaction to the level measured with the JAM-A domain 2 deletion mutant. This finding suggests that LFA-1 binding cancels the stabilizing effects of the second immunoglobulin domain of JAM-A. Finally, our atomic force microscopy measurements reveal that the interaction of JAM-A with LFA-1 is stronger than the JAM-A homophilic interaction. Taken together, these results suggest that LFA-1 binding to JAM-A destabilizes the JAM-A homophilic interaction. In turn, the greater strength of the LFA-1/JAM-A complex permits it to support the tension needed to disrupt the JAM-A homophilic interaction, thus allowing transendothelial migration to proceed.

  6. Comparative analysis of the plant mRNA-destabilizing element, DST, in mammalian and tobacco cells.

    Science.gov (United States)

    Feldbrügge, M; Arizti, P; Sullivan, M L; Zamore, P D; Belasco, J G; Green, P J

    2002-05-01

    The labile SAUR transcripts from higher plants contain a conserved DST sequence in their 3'-untranslated regions. Two copies of a DST sequence from soybean are sufficient to destabilize reporter transcripts in cultured tobacco cells whereas variants bearing mutations in the conserved ATAGAT or GTA regions are inactive. To investigate the potential for conserved recognition components in mammalian and plant cells, we examined the function of this instability determinant in mouse NIH3T3 fibroblasts and tobacco BY2 cells. In fibroblasts, a tetrameric DST element from soybean accelerated deadenylation and decay of a reporter transcript. However, a version mutated in the ATAGAT region was equally effective in this regard, and a tetrameric DST element from Arabidopsis was inactive. In contrast, the soybean DST element was more active as an mRNA instability element than the mutant version and the Arabidopsis element, when tested as tetramers in tobacco cells. Hence, the plant DST element is not recognized in animal cells with the same sequence requirements as in plant cells. Therefore, its mode of recognition appears to be plant-specific.

  7. Space geodetic monitoring of engineered structures: The ongoing destabilization of the Mosul dam, Iraq

    Science.gov (United States)

    Milillo, Pietro; Bürgmann, Roland; Lundgren, Paul; Salzer, Jacqueline; Perissin, Daniele; Fielding, Eric; Biondi, Filippo; Milillo, Giovanni

    2016-12-01

    We present a detailed survey of the ongoing destabilization process of the Mosul dam. The dam is located on the Tigris river and is the biggest hydraulic structure in Iraq. From a geological point of view the dam foundation is poor due to a site geology formed by alternating strata of highly soluble materials including gypsum, anhydrite, marl and limestone. Here we present the first multi-sensor cumulative deformation map for the dam generated from space-based interferometric synthetic aperture radar measurements from the Italian constellation COSMO-SkyMed and the European sensor Sentinel-1a over the period 2014-2016 that we compare to an older dataset spanning 2004-2010 acquired with the European Envisat satellite. We found that deformation was rapid during 2004-2010, slowed in 2012-2014 and increased since August 2014 when grouting operations stopped due to the temporary capture of the dam by the self proclaimed Islamic State. We model the inferred deformation using a Markov chain Monte Carlo approach to solve for change in volume for simple tensile dislocations. Results from recent and historical geodetic datasets suggests that the volume dissolution rate remains constant when the equivalent volume of total concrete injected during re-grouting operations is included in the calculations.

  8. Mode competition and destabilization of microfluidic channel flows by the Coriolis force

    Science.gov (United States)

    Sengupta, Saunak; Saha, Sandeep; Chakraborty, Suman

    2016-11-01

    Understanding flow stability in inertial microfluidics is very important due to its increased application in medical and chemical engineering. On a steady rotating platform centrifugal actuation drives fluid flow but Coriolis force can destabilize the flow and enhance mixing in a short span. We investigate the role of Coriolis force in micro-mixing and the structure of the roll-cells formed in rotating channel flow using linear stability theory. We conduct a parametric study at different rotation numbers, Reynolds number, axial and spanwise wavenumbers. Our results reveal existence of multiple competing unstable modes (Types I to IV) due to Coriolis force: Types I and II have been reported in literature and are responsible for the formation of evenly-spaced roll-cells. We find new instabilities (Types III and IV) which contribute to the formation of twisted roll cells. The existence of the instabilities is clearly demarcated on a regime map to assist future experiments to identify them. The kinetic energy budget has been analyzed to gain insight into the mechanism of energy transfer by Coriolis force from the mean flow to the perturbations. We make a qualitative comparison of roll-cells predicted by linear stability with previously reported experiments.

  9. Cortisol and testosterone increase financial risk taking and may destabilize markets

    Science.gov (United States)

    Cueva, Carlos; Roberts, R. Edward; Spencer, Tom; Rani, Nisha; Tempest, Michelle; Tobler, Philippe N.; Herbert, Joe; Rustichini, Aldo

    2015-01-01

    It is widely known that financial markets can become dangerously unstable, yet it is unclear why. Recent research has highlighted the possibility that endogenous hormones, in particular testosterone and cortisol, may critically influence traders’ financial decision making. Here we show that cortisol, a hormone that modulates the response to physical or psychological stress, predicts instability in financial markets. Specifically, we recorded salivary levels of cortisol and testosterone in people participating in an experimental asset market (N = 142) and found that individual and aggregate levels of endogenous cortisol predict subsequent risk-taking and price instability. We then administered either cortisol (single oral dose of 100 mg hydrocortisone, N = 34) or testosterone (three doses of 10 g transdermal 1% testosterone gel over 48 hours, N = 41) to young males before they played an asset trading game. We found that both cortisol and testosterone shifted investment towards riskier assets. Cortisol appears to affect risk preferences directly, whereas testosterone operates by inducing increased optimism about future price changes. Our results suggest that changes in both cortisol and testosterone could play a destabilizing role in financial markets through increased risk taking behaviour, acting via different behavioural pathways. PMID:26135946

  10. Entropic (de)stabilization of surface-bound peptides conjugated with polymers.

    Science.gov (United States)

    Carmichael, Scott P; Shell, M Scott

    2015-12-28

    In many emerging biotechnologies, functional proteins must maintain their native structures on or near interfaces (e.g., tethered peptide arrays, protein coated nanoparticles, and amphiphilic peptide micelles). Because the presence of a surface is known to dramatically alter the thermostability of tethered proteins, strategies to stabilize surface-bound proteins are highly sought. Here, we show that polymer conjugation allows for significant control over the secondary structure and thermostability of a model surface-tethered peptide. We use molecular dynamics simulations to examine the folding behavior of a coarse-grained helical peptide that is conjugated to polymers of various lengths and at various conjugation sites. These polymer variations reveal surprisingly diverse behavior, with some stabilizing and some destabilizing the native helical fold. We show that ideal-chain polymer entropies explain these varied effects and can quantitatively predict shifts in folding temperature. We then develop a generic theoretical model, based on ideal-chain entropies, that predicts critical lengths for conjugated polymers to effect changes in the folding of a surface-bound protein. These results may inform new design strategies for the stabilization of surface-associated proteins important for a range technological applications.

  11. A Mutation Identified in Neonatal Microcephaly Destabilizes Zika Virus NS1 Assembly in Vitro

    Science.gov (United States)

    Wang, Deping; Chen, Cheng; Liu, Shengnan; Zhou, Han; Yang, Kailin; Zhao, Qi; Ji, Xiaoyun; Chen, Chen; Xie, Wei; Wang, Zefang; Mi, Li-Zhi; Yang, Haitao

    2017-01-01

    An unprecedented epidemic of Zika virus (ZIKV) infection had spread to South and Central America. ZIKV infection was recently confirmed by CDC (the Centers for Disease Control and Prevention) to cause neonatal microcephaly, which posed a significant public health emergency of international concern. No specific vaccines or drugs are currently available to fight ZIKV infection. ZIKV nonstructural protein 1 (NS1) plays an essential role in viral replication and immune evasion. We determined the crystal structure of ZIKV NS1172–352, which forms a head-to-head, symmetric dimer with a unique 14-stranded β-ladder conserved among flaviviruses. The assembly of the β-ladder dimer is concentration dependent. Strikingly, one pathogenic mutation T233A (NCBI accession no. KU527068), found in the brain tissue of infected fetus with neonatal microcephaly, is located at the dimer interface. Thr233, a unique residue found in ZIKV but not in other flaviviruses, organizes a central hydrogen bonding network at NS1 dimer interface. Mutation of Thr233 to Ala disrupts this elaborated interaction network, and destabilizes the NS1 dimeric assembly in vitro. In addition, our structural comparison of epitopes for protective antibody 22NS1, targeting West Nile Virus NS1, could potentially be valuable in understanding its anti-virus specificities and in the development of antibodies against ZIKV. PMID:28198446

  12. Entropic (de)stabilization of surface-bound peptides conjugated with polymers

    Science.gov (United States)

    Carmichael, Scott P.; Shell, M. Scott

    2015-12-01

    In many emerging biotechnologies, functional proteins must maintain their native structures on or near interfaces (e.g., tethered peptide arrays, protein coated nanoparticles, and amphiphilic peptide micelles). Because the presence of a surface is known to dramatically alter the thermostability of tethered proteins, strategies to stabilize surface-bound proteins are highly sought. Here, we show that polymer conjugation allows for significant control over the secondary structure and thermostability of a model surface-tethered peptide. We use molecular dynamics simulations to examine the folding behavior of a coarse-grained helical peptide that is conjugated to polymers of various lengths and at various conjugation sites. These polymer variations reveal surprisingly diverse behavior, with some stabilizing and some destabilizing the native helical fold. We show that ideal-chain polymer entropies explain these varied effects and can quantitatively predict shifts in folding temperature. We then develop a generic theoretical model, based on ideal-chain entropies, that predicts critical lengths for conjugated polymers to effect changes in the folding of a surface-bound protein. These results may inform new design strategies for the stabilization of surface-associated proteins important for a range technological applications.

  13. De-stabilization of the positive vago-vagal reflex in bulimia nervosa.

    Science.gov (United States)

    Faris, Patricia L; Hofbauer, Randall D; Daughters, Randall; Vandenlangenberg, Erin; Iversen, Laureen; Goodale, Robert L; Maxwell, Robert; Eckert, Elke D; Hartman, Boyd K

    2008-04-22

    Bulimia nervosa is characterized by consuming large amounts of food over a defined period with a loss of control over the eating. This is followed by a compensatory behavior directed at eliminating the consumed calories, usually vomiting. Current treatments include antidepressants and/or behavioral therapies. Consensus exists that these treatments are not very effective and are associated with high relapse rates. We review evidence from literature and present original data to evaluate the hypothesis that bulimia involves alterations in vago-vagal function. Evidence in support of this include (1) laboratory studies consistently illustrate deficits in meal size, meal termination, and satiety in bulimia; (2) basic science studies indicate that meal size and satiation are under vagal influences; (3) anatomical, behavioral and physiological data suggest that achieving satiety and the initiation of emesis involve common neural substrates; (4) abnormal vagal and vago-vagal reflexive functions extend to non-eating activational stimuli; and (5) studies from our laboratory modulating vagal activation have shown significant effects on binge/vomit frequencies and suggest a return of normal satiation. We propose a model for the pathophysiology of bulimia based upon de-stabilization of a bi-stable positive vago-vagal feedback loop. This model is not meant to be complete, but rather to stimulate anatomical, psychobiological, and translational neuroscience experiments aimed at elucidating the pathophysiology of bulimia and developing novel treatment strategies.

  14. EDTA-induced Membrane Fluidization and Destabilization: Biophysical Studies on Artificial Lipid Membranes

    Institute of Scientific and Technical Information of China (English)

    Virapong PRACHAYASITTIKUL; Chartchalerm ISARANKURA-NA-AYUDHYA; Tanawut TANTIMONGCOLWAT; Chanin NANTASENAMAT; Hans-Joachim GALLA

    2007-01-01

    The molecular mechanism of ethylenediaminetetraacetic acid (EDTA)-induced membrane destabilization has been studied using a combination of four biophysical techniques on artificial lipid membranes.Data from Langmuir film balance and epifluorescence microscopy revealed the fluidization and expansion effect of EDTA on phase behavior of monolayers of either 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) or mixtures of DPPC and metal-chelating lipids, such as Nα,Nα-Bis[carboxymethyl]-Nε-[(dioctadecylamino)succinyl]-L-lysine or 1,2-dioleoyl-sn-glycero-3-[N-(5-amino- 1-carboxypentyl iminodiacetic acid) succinyl]. A plausible explanation could be drawn from the electrostatic interaction between negatively charged groups of EDTA and the positively charged choline head group of DPPC.Intercalation of EDTA into the lipid membrane induced membrane curvature as elucidated by atomic force microscopy. Growth in size and shape of the membrane protrusion was found to be time-dependent upon exposure to EDTA. Further loss of material from the lipid membrane surface was monitored in real time using a quartz crystal microbalance. This indicates membrane restabilization by exclusion of the protrusions from the surface. Loss of lipid components facilitates membrane instability, leading to membrane permeabilization and lysis.

  15. Cortisol and testosterone increase financial risk taking and may destabilize markets.

    Science.gov (United States)

    Cueva, Carlos; Roberts, R Edward; Spencer, Tom; Rani, Nisha; Tempest, Michelle; Tobler, Philippe N; Herbert, Joe; Rustichini, Aldo

    2015-07-02

    It is widely known that financial markets can become dangerously unstable, yet it is unclear why. Recent research has highlighted the possibility that endogenous hormones, in particular testosterone and cortisol, may critically influence traders' financial decision making. Here we show that cortisol, a hormone that modulates the response to physical or psychological stress, predicts instability in financial markets. Specifically, we recorded salivary levels of cortisol and testosterone in people participating in an experimental asset market (N = 142) and found that individual and aggregate levels of endogenous cortisol predict subsequent risk-taking and price instability. We then administered either cortisol (single oral dose of 100 mg hydrocortisone, N = 34) or testosterone (three doses of 10 g transdermal 1% testosterone gel over 48 hours, N = 41) to young males before they played an asset trading game. We found that both cortisol and testosterone shifted investment towards riskier assets. Cortisol appears to affect risk preferences directly, whereas testosterone operates by inducing increased optimism about future price changes. Our results suggest that changes in both cortisol and testosterone could play a destabilizing role in financial markets through increased risk taking behaviour, acting via different behavioural pathways.

  16. A mechanistic study on the destabilization of whole inactivated influenza virus vaccine in gastric environment.

    Directory of Open Access Journals (Sweden)

    Hyo-Jick Choi

    Full Text Available Oral immunization using whole inactivated influenza virus vaccine promises an efficient vaccination strategy. While oral vaccination was hampered by harsh gastric environment, a systematic understanding about vaccine destabilization mechanisms was not performed. Here, we investigated the separate and combined effects of temperature, retention time, pH, and osmotic stress on the stability of influenza vaccine by monitoring the time-dependent morphological change using stopped-flow light scattering. When exposed to osmotic stress, clustering of vaccine particles was enhanced in an acidic medium (pH 2.0 at ≥25°C. Fluorescence spectroscopic studies showed that hyper-osmotic stress at pH 2.0 and 37°C caused a considerable increase in conformational change of antigenic proteins compared to that in acidic iso-osmotic medium. A structural integrity of membrane was destroyed upon exposure to hyper-osmotic stress, leading to irreversible morphological change, as observed by undulation in stopped-flow light scattering intensity and transmission electron microscopy. Consistent with these analyses, hemagglutination activity decreased more significantly with an increasing magnitude of hyper-osmotic stress than in the presence of the hypo- and iso-osmotic stresses. This study shows that the magnitude and direction of the osmotic gradient has a substantial impact on the stability of orally administrated influenza vaccine.

  17. Experimental Branch Retinal Vein Occlusion Induces Upstream Pericyte Loss and Vascular Destabilization.

    Directory of Open Access Journals (Sweden)

    Elisa Dominguez

    Full Text Available Branch retinal vein occlusion (BRVO leads to extensive vascular remodeling and is important cause of visual impairment. Although the vascular morphological changes following experimental vein occlusion have been described in a variety of models using angiography, the underlying cellular events are ill defined.We here show that laser-induced experimental BRVO in mice leads to a wave of TUNEL-positive endothelial cell (EC apoptosis in the upstream vascular network associated with a transient edema and hemorrhages. Subsequently, we observe an induction of EC proliferation within the dilated vein and capillaries, detected by EdU incorporation, and the edema resolves. However, the pericytes of the upstream capillaries are severely reduced, which was associated with continuing EC apoptosis and proliferation. The vascular remodeling was associated with increased expression of TGFβ, TSP-1, but also FGF2 expression. Exposure of the experimental animals to hypoxia, when pericyte (PC dropout had occurred, led to a dramatic increase in endothelial cell proliferation, confirming the vascular instability induced by the experimental BRVO.Experimental BRVO leads to acute endothelial cells apoptosis and increased permeability. Subsequently the upstream vascular network remains destabilized, characterized by pericyte dropout, un-physiologically high endothelial cells turnover and sensitivity to hypoxia. These early changes might pave the way for capillary loss and subsequent chronic ischemia and edema that characterize the late stage disease.

  18. Isoflurane reversibly destabilizes hippocampal dendritic spines by an actin-dependent mechanism.

    Directory of Open Access Journals (Sweden)

    Jimcy Platholi

    Full Text Available General anesthetics produce a reversible coma-like state through modulation of excitatory and inhibitory synaptic transmission. Recent evidence suggests that anesthetic exposure can also lead to sustained cognitive dysfunction. However, the subcellular effects of anesthetics on the structure of established synapses are not known. We investigated effects of the widely used volatile anesthetic isoflurane on the structural stability of hippocampal dendritic spines, a postsynaptic structure critical to excitatory synaptic transmission in learning and memory. Exposure to clinical concentrations of isoflurane induced rapid and non-uniform shrinkage and loss of dendritic spines in mature cultured rat hippocampal neurons. Spine shrinkage was associated with a reduction in spine F-actin concentration. Spine loss was prevented by either jasplakinolide or cytochalasin D, drugs that prevent F-actin disassembly. Isoflurane-induced spine shrinkage and loss were reversible upon isoflurane elimination. Thus, isoflurane destabilizes spine F-actin, resulting in changes to dendritic spine morphology and number. These findings support an actin-based mechanism for isoflurane-induced alterations of synaptic structure in the hippocampus. These reversible alterations in dendritic spine structure have important implications for acute anesthetic effects on excitatory synaptic transmission and synaptic stability in the hippocampus, a locus for anesthetic-induced amnesia, and have important implications for anesthetic effects on synaptic plasticity.

  19. Space geodetic monitoring of engineered structures: The ongoing destabilization of the Mosul dam, Iraq.

    Science.gov (United States)

    Milillo, Pietro; Bürgmann, Roland; Lundgren, Paul; Salzer, Jacqueline; Perissin, Daniele; Fielding, Eric; Biondi, Filippo; Milillo, Giovanni

    2016-12-06

    We present a detailed survey of the ongoing destabilization process of the Mosul dam. The dam is located on the Tigris river and is the biggest hydraulic structure in Iraq. From a geological point of view the dam foundation is poor due to a site geology formed by alternating strata of highly soluble materials including gypsum, anhydrite, marl and limestone. Here we present the first multi-sensor cumulative deformation map for the dam generated from space-based interferometric synthetic aperture radar measurements from the Italian constellation COSMO-SkyMed and the European sensor Sentinel-1a over the period 2014-2016 that we compare to an older dataset spanning 2004-2010 acquired with the European Envisat satellite. We found that deformation was rapid during 2004-2010, slowed in 2012-2014 and increased since August 2014 when grouting operations stopped due to the temporary capture of the dam by the self proclaimed Islamic State. We model the inferred deformation using a Markov chain Monte Carlo approach to solve for change in volume for simple tensile dislocations. Results from recent and historical geodetic datasets suggests that the volume dissolution rate remains constant when the equivalent volume of total concrete injected during re-grouting operations is included in the calculations.

  20. EDTA-induced membrane fluidization and destabilization: biophysical studies on artificial lipid membranes.

    Science.gov (United States)

    Prachayasittikul, Virapong; Isarankura-Na-Ayudhya, Chartchalerm; Tantimongcolwat, Tanawut; Nantasenamat, Chanin; Galla, Hans-Joachim

    2007-11-01

    The molecular mechanism of ethylenediaminetetraacetic acid (EDTA)-induced membrane destabilization has been studied using a combination of four biophysical techniques on artificial lipid membranes. Data from Langmuir film balance and epifluorescence microscopy revealed the fluidization and expansion effect of EDTA on phase behavior of monolayers of either 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) or mixtures of DPPC and metal-chelating lipids, such as N(alpha),N(alpha)-Bis[carboxymethyl]-N(epsilon)-[(dioctadecylamino)succinyl]-L-lysine or 1,2-dioleoyl-sn-glycero-3-[N-(5-amino-1-carboxypentyl iminodiacetic acid) succinyl]. A plausible explanation could be drawn from the electrostatic interaction between negatively charged groups of EDTA and the positively charged choline head group of DPPC. Intercalation of EDTA into the lipid membrane induced membrane curvature as elucidated by atomic force microscopy. Growth in size and shape of the membrane protrusion was found to be time-dependent upon exposure to EDTA. Further loss of material from the lipid membrane surface was monitored in real time using a quartz crystal microbalance. This indicates membrane restabilization by exclusion of the protrusions from the surface. Loss of lipid components facilitates membrane instability, leading to membrane permeabilization and lysis.

  1. Substrate phosphorylation and feedback regulation in JFK-promoted p53 destabilization.

    Science.gov (United States)

    Sun, Luyang; Shi, Lei; Wang, Feng; Huangyang, Peiwei; Si, Wenzhe; Yang, Jie; Yao, Zhi; Shang, Yongfeng

    2011-02-11

    The p53 tumor suppressor plays a central role in integrating cellular responses to various stresses. Tight regulation of p53 is thus essential for the maintenance of genome integrity and normal cell proliferation. Previously, we reported that JFK, the only Kelch domain-containing F-box protein in human, promotes ubiquitination and degradation of p53 and that unlike the other E3 ligases for p53, all of which possess an intrinsic ubiquitin ligase activity, JFK destabilizes p53 through the assembly of a Skp1-Cul1-F-box complex. Here, we report that the substrate recognition by JFK requires phosphorylation of p53 in its central core region by CSN (COP9 signalosome)-associated kinase. Significantly, inhibition of CSN-associated kinase activity or knockdown of CSN5 impairs JFK-promoted p53 degradation, enhances p53-dependent transcription, and promotes cell growth suppression, G(1) arrest, and apoptosis. Moreover, we showed that JFK is transcriptionally regulated by p53 and forms an auto-regulatory negative feedback loop with p53. These data may shed new light on the functional connection between CSN, Skp1-Cul1-F-box ubiquitin ligase, and p53 and provide a molecular mechanism for the regulation of JFK-promoted p53 degradation.

  2. The destabilization of the French electricity supply industry nascent competition in an open environment

    Energy Technology Data Exchange (ETDEWEB)

    Finon, D

    2001-06-01

    In February 2000 France, compelled by the 1996 European Directive 96/92, undertook a minimal reform of the organisation of its electricity industry, while preserving the boundaries of the incumbent company. The aim of this paper is to analyse the conditions of destabilization of the industrial organisation of the French ESI, by identifying the economic factors of endogenous and exogenous erosion. Firstly, after setting out the main elements of the French reform, which is aimed at making the electricity market contestable, the effectiveness of the ''contestability'' of the French power market is discussed. Secondly in order to test the stability of the new institutional arrangements, an institutional prospect is developed, on the basis of economic factors of instability and resistance, to produce two contrasting scenarios: one in which the particularly French model is retained (limited contestability market scenario); another in which there is movement towards a de-integrated competitive model (contamination by competition scenario). Thirdly the author concludes on the basis of recent elements, that the future would be a mix of these two trajectories which will come within in the progressive integration of the national markets in continental Europe. (A.L.B.)

  3. Allosteric Inhibition via R-state Destabilization in ATP Sulfurylase from Penicillium chrysogenum

    Energy Technology Data Exchange (ETDEWEB)

    MacRae, I. J.

    2002-01-01

    The structure of the cooperative hexameric enzyme ATP sulfurylase from Penicillium chrysogenum bound to its allosteric inhibitor, 3'-phosphoadenosine-5'-phosphosulfate (PAPS), was determined to 2.6 {angstrom} resolution. This structure represents the low substrate-affinity T-state conformation of the enzyme. Comparison with the high substrate-affinity R-state structure reveals that a large rotational rearrangement of domains occurs as a result of the R-to-T transition. The rearrangement is accompanied by the 17 {angstrom} movement of a 10-residue loop out of the active site region, resulting in an open, product release-like structure of the catalytic domain. Binding of PAPS is proposed to induce the allosteric transition by destabilizing an R-state-specific salt linkage between Asp 111 in an N-terminal domain of one subunit and Arg 515 in the allosteric domain of a trans-triad subunit. Disrupting this salt linkage by site-directed mutagenesis induces cooperative inhibition behavior in the absence of an allosteric effector, confirming the role of these two residues.

  4. Destabilization of long-wavelength Love and Stoneley waves in slow sliding

    CERN Document Server

    Ranjith, K

    2008-01-01

    Love waves are dispersive interfacial waves that are a mode of response for anti-plane motions of an elastic layer bonded to an elastic half-space. Similarly, Stoneley waves are interfacial waves in bonded contact of dissimilar elastic half-spaces, when the displacements are in the plane of the solids. It is shown that in slow sliding, long wavelength Love and Stoneley waves are destabilized by friction. Friction is assumed to have a positive instantaneous logarithmic dependence on slip rate and a logarithmic rate weakening behavior at steady-state. Long wavelength instabilities occur generically in sliding with rate- and state-dependent friction, even when an interfacial wave does not exist. For slip at low rates, such instabilities are quasi-static in nature, i.e., the phase velocity is negligibly small in comparison to a shear wave speed. The existence of an interfacial wave in bonded contact permits an instability to propagate with a speed of the order of a shear wave speed even in slow sliding, indicatin...

  5. SLAP displays tumour suppressor functions in colorectal cancer via destabilization of the SRC substrate EPHA2

    Science.gov (United States)

    Naudin, Cécile; Sirvent, Audrey; Leroy, Cédric; Larive, Romain; Simon, Valérie; Pannequin, Julie; Bourgaux, Jean-François; Pierre, Josiane; Robert, Bruno; Hollande, Frédéric; Roche, Serge

    2014-01-01

    The adaptor SLAP is a negative regulator of receptor signalling in immune cells but its role in human cancer is ill defined. Here we report that SLAP is abundantly expressed in healthy epithelial intestine but strongly downregulated in 50% of colorectal cancer. SLAP overexpression suppresses cell tumorigenicity and invasiveness while SLAP silencing enhances these transforming properties. Mechanistically, SLAP controls SRC/EPHA2/AKT signalling via destabilization of the SRC substrate and receptor tyrosine kinase EPHA2. This activity is independent from CBL but requires SLAP SH3 interaction with the ubiquitination factor UBE4A and SLAP SH2 interaction with pTyr594-EPHA2. SRC phosphorylates EPHA2 on Tyr594, thus creating a feedback loop that promotes EPHA2 destruction and thereby self-regulates its transforming potential. SLAP silencing enhances SRC oncogenicity and sensitizes colorectal tumour cells to SRC inhibitors. Collectively, these data establish a tumour-suppressive role for SLAP in colorectal cancer and a mechanism of SRC oncogenic induction through stabilization of its cognate substrates.

  6. Internal affairs: investigating the Brucella intracellular lifestyle.

    Science.gov (United States)

    von Bargen, Kristine; Gorvel, Jean-Pierre; Salcedo, Suzana P

    2012-05-01

    Bacteria of the genus Brucella are Gram-negative pathogens of several animal species that cause a zoonotic disease in humans known as brucellosis or Malta fever. Within their hosts, brucellae reside within different cell types where they establish a replicative niche and remain protected from the immune response. The aim of this article is to discuss recent advances in the field in the specific context of the Brucella intracellular 'lifestyle'. We initially discuss the different host cell targets and their relevance during infection. As it represents the key to intracellular replication, the focus is then set on the maturation of the Brucella phagosome, with particular emphasis on the Brucella factors that are directly implicated in intracellular trafficking and modulation of host cell signalling pathways. Recent data on the role of the type IV secretion system are discussed, novel effector molecules identified and how some of them impact on trafficking events. Current knowledge on Brucella gene regulation and control of host cell death are summarized, as they directly affect intracellular persistence. Understanding how Brucella molecules interplay with their host cell targets to modulate cellular functions and establish the intracellular niche will help unravel how this pathogen causes disease.

  7. Efficient intracellular delivery and improved biocompatibility of colloidal silver nanoparticles towards intracellular SERS immuno-sensing.

    Science.gov (United States)

    Bhardwaj, Vinay; Srinivasan, Supriya; McGoron, Anthony J

    2015-06-21

    High throughput intracellular delivery strategies, electroporation, passive and TATHA2 facilitated diffusion of colloidal silver nanoparticles (AgNPs) are investigated for cellular toxicity and uptake using state-of-art analytical techniques. The TATHA2 facilitated approach efficiently delivered high payload with no toxicity, pre-requisites for intracellular applications of plasmonic metal nanoparticles (PMNPs) in sensing and therapeutics.

  8. GTPases in intracellular trafficking: an overview.

    Science.gov (United States)

    Segev, Nava

    2011-02-01

    Small GTPases that belong to the ras sub-families of Rab, Arf, and Rho, and the large GTPase dynamin, regulate intracellular trafficking. This issue of Seminars of Cell and Developmental Biology highlights topics regarding mechanisms by which these GTPases regulate the different steps of vesicular transport: vesicle formation, scission, targeting and fusion. In addition, the emerging roles of GTPases in coordination of individual transport steps as well as coordination of intracellular trafficking with other cellular processes are reviewed. Finally, common structures and mechanisms underlying the function of the ras-like GTPases and the importance of their function to human health and disease are discussed.

  9. Methanolic extract of Moringa oleifera leaf and low doses of gamma radiation alleviated amiodarone-induced lung toxicity in albino rats

    Directory of Open Access Journals (Sweden)

    Hasan Hesham F.

    2016-01-01

    Full Text Available This study aimed to evaluate the effects of methanolic extract of Moringa oleifera (MO and/or low doses of gamma radiation (LDR on amiodarone (AMD-induced lung toxicity in rats. AMD administered to female albino rats (100 mg/kg body weight for 10 consecutive days. Rats received methanolic extract of MO (250 mg/kg bwt for 15 successive days and/or were exposed to whole body LDR (0.25Gy on the 1st and 10th days, up to a total dose of 0.5Gy. MO administration induced a significant decrease in serum tumor necrosis factor-alpha (TNF-α and transforming growth factor-beta (TGF-β levels as well as lactate dehydrogenase (LDH activity. Also, the content of malondialdehyde (MDA and hydroxyproline (HYP was significantly decreased in lung tissue. Furthermore, MO significantly increased reduced glutathione (GSH content in lung tissue as compared with AMD. The histopathological investigation of lung tissue revealed the appearance of interstitial pneumonia in rats treated with AMD. The oral administration of MO and/or exposure to LDR reversed the biochemical and histopathological alterations induced by AMD. It can be posited that MO and LDR might have a considerable role in the prevention of lung toxicity induced by AMD.

  10. Comparison of the Frequency-dependent Effects of Amiodarone on Ventricular Electrophysiology in Congestive Heart Failure Canine Models and Normal Dogs

    Institute of Scientific and Technical Information of China (English)

    Zhou Shuxian; Zhang Yuling; Lei Juan; Wu Wei; Zhang Xuming

    2007-01-01

    Objectives To compare the frequency-dependent effects of amiodarone (Ami) on ventricular electrophysiology in right ventricular rapid pacing-induced congestive heart failure (CHF) canine models.Methods Thirty-two dogs were randomized into four groups: the control group, the Ami group in which the normal dogs were given Ami orally 300 mg a day for 4~5 weeks, the CHF group induced by right ventricular rapid pacing ( 240 pulses. min -1 for 4 ~ 5 weeks), and the group of CHF dogs fed with Ami orally 300 mg a day for 4 ~ 5 weeks. The techniques of electrical stimulation and monophasic action potential (MAP) recording were used in the electrophysiology studies. Results The effects of Ami on ventricular MAP duration(MAPD90) and effective refractory period (VERP)were not frequency-dependent in CHF dogs. There was also no frequency-dependent effect on the increase in the ratio of VERP to MAPD90 (VERP/MAPD90). The prolongation of ventricular conduction time was frequencydependent. Conclusions The frequency-dependent effects of Ami on ventricular electrophysiology in CHF dogs were similar to that in normal dogs.

  11. A transcriptomics-based hepatotoxicity comparison between the zebrafish embryo and established human and rodent in vitro and in vivo models using cyclosporine A, amiodarone and acetaminophen.

    Science.gov (United States)

    Driessen, Marja; Vitins, Alexa P; Pennings, Jeroen L A; Kienhuis, Anne S; Water, Bob van de; van der Ven, Leo T M

    2015-01-22

    The zebrafish embryo (ZFE) is a promising alternative, non-rodent model in toxicology, which has an advantage over the traditionally used models as it contains complete biological complexity and provides a medium to high-throughput setting. Here, we assess how the ZFE compares to the traditionally used models for liver toxicity testing, i.e., in vivo mouse and rat liver, in vitro mouse and rat hepatocytes, and primary human hepatocytes. For this comparison, we analyzed gene expression changes induced by three model compounds for cholestasis, steatosis, and necrosis. The three compounds, cyclosporine A, amiodarone, and acetaminophen, were chosen because of their relevance to human toxicity and these compounds displayed hepatotoxic-specific changes in the mouse in vivo data. Compound induced expression changes in the ZFE model shared similarity with both in vivo and in vitro. Comparison on single gene level revealed the presence of model specific changes and no clear concordance across models. However, concordance was identified on the pathway level. Specifically, the pathway "regulation of metabolism - bile acids regulation of glucose and lipid metabolism via FXR" was affected across all models and compounds. In conclusion, our study with three hepatotoxic model compounds shows that the ZFE model is at least as comparable to traditional models in identifying hepatotoxic activity and has the potential for use as a pre-screen to determine the hepatotoxic potential of compounds.

  12. Does sex-selective predation stabilize or destabilize predator-prey dynamics?

    Directory of Open Access Journals (Sweden)

    David S Boukal

    Full Text Available BACKGROUND: Little is known about the impact of prey sexual dimorphism on predator-prey dynamics and the impact of sex-selective harvesting and trophy hunting on long-term stability of exploited populations. METHODOLOGY AND PRINCIPAL FINDINGS: We review the quantitative evidence for sex-selective predation and study its long-term consequences using several simple predator-prey models. These models can be also interpreted in terms of feedback between harvesting effort and population size of the harvested species under open-access exploitation. Among the 81 predator-prey pairs found in the literature, male bias in predation is 2.3 times as common as female bias. We show that long-term effects of sex-selective predation depend on the interplay of predation bias and prey mating system. Predation on the 'less limiting' prey sex can yield a stable predator-prey equilibrium, while predation on the other sex usually destabilizes the dynamics and promotes population collapses. For prey mating systems that we consider, males are less limiting except for polyandry and polyandrogyny, and male-biased predation alone on such prey can stabilize otherwise unstable dynamics. On the contrary, our results suggest that female-biased predation on polygynous, polygynandrous or monogamous prey requires other stabilizing mechanisms to persist. CONCLUSIONS AND SIGNIFICANCE: Our modelling results suggest that the observed skew towards male-biased predation might reflect, in addition to sexual selection, the evolutionary history of predator-prey interactions. More focus on these phenomena can yield additional and interesting insights as to which mechanisms maintain the persistence of predator-prey pairs over ecological and evolutionary timescales. Our results can also have implications for long-term sustainability of harvesting and trophy hunting of sexually dimorphic species.

  13. MDMA induces cardiac contractile dysfunction through autophagy upregulation and lysosome destabilization in rats.

    Science.gov (United States)

    Shintani-ishida, Kaori; Saka, Kanju; Yamaguchi, Koji; Hayashida, Makiko; Nagai, Hisashi; Takemura, Genzou; Yoshida, Ken-ichi

    2014-05-01

    The underlying mechanisms of cardiotoxicity of 3,4-methylenedioxymethylamphetamine (MDMA, "ecstasy") abuse are unclear. Autophagy exerts either adaptive or maladaptive effects on cardiac function in various pathological settings, but nothing is known on the role of autophagy in the MDMA cardiotoxicity. Here, we investigated the mechanism through which autophagy may be involved in MDMA-induced cardiac contractile dysfunction. Rats were injected intraperitoneally with MDMA (20mg/kg) or saline. Left ventricular (LV) echocardiography and LV pressure measurement demonstrated reduction of LV systolic contractility 24h after MDMA administration. Western blot analysis showed a time-dependent increase in the levels of microtubule-associated protein light chain 3-II (LC3-II) and cathepsin-D after MDMA administration. Electron microscopy showed the presence of autophagic vacuoles in cardiomyocytes. MDMA upregulated phosphorylation of adenosine monophosphate-activated protein kinase (AMPK) at Thr172, mammalian target of rapamycin (mTOR) at Thr2446, Raptor at Ser792, and Unc51-like kinase (ULK1) at Ser555, suggesting activation of autophagy through the AMPK-mTOR pathway. The effects of autophagic inhibitors 3-methyladenine (3-MA) and chloroquine (CQ) on LC3-II levels indicated that MDMA enhanced autophagosome formation, but attenuated autophagosome clearance. MDMA also induced release of cathepsins into cytosol, and western blotting and electron microscopy showed cardiac troponin I (cTnI) degradation and myofibril damage, respectively. 3-MA, CQ, and a lysosomal inhibitor, E64c, inhibited cTnI proteolysis and improved contractile dysfunction after MDMA administration. In conclusion, MDMA causes lysosome destabilization following activation of the autophagy-lysosomal pathway, through which released lysosomal proteases damage myofibrils and induce LV systolic dysfunction in rat heart.

  14. The developmental outcomes of P0-mediated ARGONAUTE destabilization in tomato.

    Science.gov (United States)

    Hendelman, Anat; Kravchik, Michael; Stav, Ran; Zik, Moriyah; Lugassi, Nitsan; Arazi, Tzahi

    2013-01-01

    The plant protein ARGONAUTE1 (AGO1) functions in multiple RNA-silencing pathways, including those of microRNAs, key regulators of growth and development. Genetic analysis of ago1 mutants with informative defects has provided valuable insights into AGO1's biological functions. Tomato encodes two AGO1 homologs (SlAGO1s), but mutants have not been described to date. To analyze SlAGO1s' involvement in development, we confirmed that both undergo decay in the presence of the Polerovirus silencing suppressor P0 and produce a transgenic responder line (OP:P0HA) that, upon transactivation, expresses P0 C-terminally fused to a hemagglutinin (HA) tag (P0HA) and destabilizes SlAGO1s at the site of expression. By crossing OP:P0HA with a battery of driver lines, constitutive as well as organ- and stage-specific SlAGO1 downregulation was induced in the F1 progeny. Activated plants exhibited various developmental phenotypes that partially overlapped with those of Arabidopsis ago1 mutants. Plants that constitutively expressed P0HA had reduced SlAGO1 levels and increased accumulation of miRNA targets, indicating compromised SlAGO1-mediated silencing. Consistent with this, they exhibited pleiotropic morphological defects and their growth was arrested post-germination. Transactivation of P0HA in young leaf and floral organ primordia dramatically modified corresponding organ morphology, including the radialization of leaflets, petals and anthers, suggesting that SlAGO1s' activities are required for normal lateral organ development and polarity. Overall, our results suggest that the OP:P0HA responder line can serve as a valuable tool to suppress SlAGO1 silencing pathways in tomato. The suppression of additional SlAGOs by P0HA and its contribution to the observed phenotypes awaits investigation.

  15. An Archaean heavy bombardment from a destabilized extension of the asteroid belt.

    Science.gov (United States)

    Bottke, William F; Vokrouhlický, David; Minton, David; Nesvorný, David; Morbidelli, Alessandro; Brasser, Ramon; Simonson, Bruce; Levison, Harold F

    2012-05-03

    The barrage of comets and asteroids that produced many young lunar basins (craters over 300 kilometres in diameter) has frequently been called the Late Heavy Bombardment (LHB). Many assume the LHB ended about 3.7 to 3.8 billion years (Gyr) ago with the formation of Orientale basin. Evidence for LHB-sized blasts on Earth, however, extend into the Archaean and early Proterozoic eons, in the form of impact spherule beds: globally distributed ejecta layers created by Chicxulub-sized or larger cratering events4. At least seven spherule beds have been found that formed between 3.23 and 3.47 Gyr ago, four between 2.49 and 2.63 Gyr ago, and one between 1.7 and 2.1 Gyr ago. Here we report that the LHB lasted much longer than previously thought, with most late impactors coming from the E belt, an extended and now largely extinct portion of the asteroid belt between 1.7 and 2.1 astronomical units from Earth. This region was destabilized by late giant planet migration. E-belt survivors now make up the high-inclination Hungaria asteroids. Scaling from the observed Hungaria asteroids, we find that E-belt projectiles made about ten lunar basins between 3.7 and 4.1 Gyr ago. They also produced about 15 terrestrial basins between 2.5 and 3.7 Gyr ago, as well as around 70 and four Chicxulub-sized or larger craters on the Earth and Moon, respectively, between 1.7 and 3.7 Gyr ago. These rates reproduce impact spherule bed and lunar crater constraints.

  16. Enhanced North Atlantic deep convection preceding Heinrich 1 glacial ice sheet destabilization

    Science.gov (United States)

    Seidenkrantz, Marit-Solveig; Kuijpers, Antoon; Lindgreen, Holger

    2015-04-01

    The Labrador Sea is a crucial center of action for North Atlantic meridional overturning circulation. This region is characterized in winter by strong cold and dry winds from land or ice surfaces inducing large heat and moisture fluxes at the ocean-atmosphere interface. Particularly in late winter these conditions favor deep-convection processes leading to the formation of a relatively homogeneous and oxygen-rich intermediate water mass (Labrador Sea Water, LSW) spreading to other parts of the North Atlantic at water depths between about 1,000 and 2,000 m. Sedimentary records from the Labrador Sea have previously indicated here the presence of North Atlantic Deep Water during periods in between glacial ('Heinrich') ice-rafting events. The present sediment core investigation based on clay mineralogical analysis and study of the benthic foraminiferal fauna shows a significant oxygenation event at 18000 cal.yrs BP recorded both in the Labrador Sea and at the northern margin of Rockall Trough at 2381 m and 1286 m water depth, respectively. We conclude this ventilation pulse to be related to a period of enhanced deep convection and formation of glacial North Atlantic Intermediate Water occupying those parts of the water column presently affected under conditions of strong LSW formation. This ventilation event implies an early, significant re-activation of North Atlantic meridional overturning circulation after the Last Glacial Maximum immediately prior to Heinrich 1 large-scale ice-sheet destabilization. This scenario points to an oceanic trigger mechanism for large-scale glacial iceberg surges around the northern North Atlantic, which involves enhanced northward ocean (sub)surface heat transport and subsequent enhanced bottom melting of floating outlet glaciers and ice shelves.

  17. Protein tyrosine phosphatase receptor delta acts as a neuroblastoma tumor suppressor by destabilizing the aurora kinase a oncogene

    Directory of Open Access Journals (Sweden)

    Meehan Maria

    2012-02-01

    Full Text Available Abstract Background Protein tyrosine phosphatase receptor delta (PTPRD is a member of a large family of protein tyrosine phosphatases which negatively regulate tyrosine phosphorylation. Neuroblastoma is a major childhood cancer arising from precursor cells of the sympathetic nervous system which is known to acquire deletions and alterations in the expression patterns of PTPRD, indicating a potential tumor suppressor function for this gene. The molecular mechanism, however, by which PTPRD renders a tumor suppressor effect in neuroblastoma is unknown. Results As a molecular mechanism, we demonstrate that PTPRD interacts with aurora kinase A (AURKA, an oncogenic protein that is over-expressed in multiple forms of cancer, including neuroblastoma. Ectopic up-regulation of PTPRD in neuroblastoma dephosphorylates tyrosine residues in AURKA resulting in a destabilization of this protein culminating in interfering with one of AURKA's primary functions in neuroblastoma, the stabilization of MYCN protein, the gene of which is amplified in approximately 25 to 30% of high risk neuroblastoma. Conclusions PTPRD has a tumor suppressor function in neuroblastoma through AURKA dephosphorylation and destabilization and a downstream destabilization of MYCN protein, representing a novel mechanism for the function of PTPRD in neuroblastoma.

  18. Protein tyrosine phosphatase receptor delta acts as a neuroblastoma tumor suppressor by destabilizing the aurora kinase a oncogene

    LENUS (Irish Health Repository)

    Meehan, Maria

    2012-02-05

    Abstract Background Protein tyrosine phosphatase receptor delta (PTPRD) is a member of a large family of protein tyrosine phosphatases which negatively regulate tyrosine phosphorylation. Neuroblastoma is a major childhood cancer arising from precursor cells of the sympathetic nervous system which is known to acquire deletions and alterations in the expression patterns of PTPRD, indicating a potential tumor suppressor function for this gene. The molecular mechanism, however, by which PTPRD renders a tumor suppressor effect in neuroblastoma is unknown. Results As a molecular mechanism, we demonstrate that PTPRD interacts with aurora kinase A (AURKA), an oncogenic protein that is over-expressed in multiple forms of cancer, including neuroblastoma. Ectopic up-regulation of PTPRD in neuroblastoma dephosphorylates tyrosine residues in AURKA resulting in a destabilization of this protein culminating in interfering with one of AURKA\\'s primary functions in neuroblastoma, the stabilization of MYCN protein, the gene of which is amplified in approximately 25 to 30% of high risk neuroblastoma. Conclusions PTPRD has a tumor suppressor function in neuroblastoma through AURKA dephosphorylation and destabilization and a downstream destabilization of MYCN protein, representing a novel mechanism for the function of PTPRD in neuroblastoma.

  19. Poliovirus-associated protein kinase: Destabilization of the virus capsid and stimulation of the phosphorylation reaction by Zn sup 2+

    Energy Technology Data Exchange (ETDEWEB)

    Ratka, M.; Lackmann, M.; Ueckermann, C.; Karlins, U.; Koch, G. (Univ. of Hamburg (West Germany))

    1989-09-01

    The previously described poliovirus-associated protein kinase activity phosphorylates viral proteins VP0 and VP2 as well as exogenous proteins in the presence of Mg{sup 2+}. In this paper, the effect of Zn{sup 2+} on the phosphorylation reaction and the stability of the poliovirus capsid has been studied in detail and compared to that of Mg{sup 2+}. In the presence of Zn{sup 2+}, phosphorylation of capsid proteins VP2 and VP4 is significantly higher while phosphorylation of VP0 and exogenous phosphate acceptor proteins is not detected. The results indicate the activation of more than one virus-associated protein kinase by Zn{sup 2+}. The ion-dependent behavior of the enzyme activities is observed independently of whether the virus was obtained from HeLa or green monkey kidney cells. The poliovirus capsid is destabilized by Zn{sup 2+}. This alteration of the poliovirus capsid structure is a prerequisite for effective phosphorylation of viral capsid proteins. The increased level of phosphorylation of viral capsid proteins results in further destabilization of the viral capsid. As a result of the conformational changes, poliovirus-associated protein kinase activities dissociate from the virus particle. The authors suggest that the destabilizing effect of phosphorylation on the viral capsid plays a role in uncoating of poliovirus.

  20. Nano-engineering approach to destabilization of magnesium hydride (MgH2) by solid-state reaction with Si.

    Science.gov (United States)

    Bystrzycki, J; Polanski, M; Plocinski, T

    2009-06-01

    We studied a possibility of destabilization of MgH2 by chemical reaction with Si by using a nano-engineering method for reducing diffusion distances and increasing surface area. The structure, morphology, chemical composition and dehydriding properties were investigated by XRD, SEM, EDS, DTA-TG and the volumetric Sievert method. The commercial MgH2 and Si powder mixture corresponded to the stoichiometry of the ideal Mg2Si intermetallic compound was ball-milled under argon atmosphere to reach a nanocrystalline composite structure (MgH2-Si mixture leads to the formation only a small amount of the Mg2Si compound. Microstructural studies showed that Si after ball-milling is heterogeneously distributed on the surface of MgH2 particles and incorporated in the nanocrystalline MgH2 matrix, forming a nanocomposite structure. The sluggish destabilization of MgH2 by solid-state reaction with Si forming the Mg2Si intermetallic compound was observed at 250 degrees C. The XRD and EDS analysis confirmed that the Mg2Si compound is formed after the dehydrogenation of the synthesized MgH2-Si composite. The activation energy of the destabilization reaction for the investigated composite significantly decreased (162 kJ/mol) as compared with unmilled MgH2-Si powder mixture (213 kJ/mol).

  1. [Magnetic nanoparticles and intracellular delivery of biopolymers].

    Science.gov (United States)

    Kornev, A A; Dubina, M V

    2014-03-01

    The basic methods of intracellular delivery of biopolymers are present in this review. The structure and synthesis of magnetic nanoparticles, their stabilizing surfactants are described. The examples of the interaction of nanoparticles with biopolymers such as nucleic acids and proteins are considered. The final part of the review is devoted to problems physiology and biocompatibility of magnetic nanoparticles.

  2. 厄贝沙坦联合胺碘酮对阵发性房颤复律后维持窦性心律的效果%Maintenance of sinus rhythm by lrbesartan combined with amiodarone after cardioversion in patients with paroxysmal atrial fibrillation

    Institute of Scientific and Technical Information of China (English)

    闫晓英; 林小凤

    2012-01-01

    目的:观察厄贝沙坦联合胺碘酮对阵发性心房颤动复律后维持窦性心律的临床效果及其对左心房内径的影响.方法:选择阵发性心房颤动患者89例,分为胺碘酮治疗组(44例,单纯服用胺碘酮),联合治疗组(45例,服用胺碘酮及厄贝沙坦),随访12个月,观察两组患者治疗前后窦性心律维持率,左房内径的变化,并进行比较分析.结果:治疗12个月后,与胺碘酮组比较,联合治疗组窦性心律维持率明显提高(64.3%比81.4%),左房内径明显减小[ (40.12±10.6) mm比(34.10±10.11)mm],P均<0.05.结论:厄贝沙坦联合胺碘酮对阵发性心房颤动复律后维持窦性心律的作用明显优于单用胺碘酮,且明显抑制左房扩大,无明显不良反应.%Objective: To study maintenance of sinus rhythm by irbesartan combined with amiodarone after cardioversion in patients with paroxysmal atrial fibrillation (PAF) and its influence on left atrial diameter. Methods: A total of 89 PAF patients were divided into amiodarone treatment group (n = 44, only received amiodarone) and combination therapy group (n = 45. received amiodarone and irbesartan). All patients were followed up for 12 months. Changes of maintenance rate of sinus rhythm and left atrial diameter before and after treatment were observed and compared between the two groups. Results: Compared with amiodarone group after 12 months, there was significant increase in maintenance rate of sinus rhythm (64.3% vs. 81.4%) and significant decrease in left atrial diameter [ (40.12 ± 10.6) mm vs. (34.10 ± 10.11) mm] in combination therapy group, P<0.05 both. Conclusion: Maintenance of sinus rhythm by irbesartan combined with amiodarone after cardioversion in patients with paroxysmal atrial fibrillation is significantly better than that of single amiodarone treatment, and irbesartan combined with amiodarone significantly inhibits left atrial enlargement without significant adverse reactions.

  3. 胺碘酮治疗老年冠心病心律不齐的临床研究%Clinical Research on Amiodarone for the Treatment of Senile Coronary Heart Disease and Arrhythmia

    Institute of Scientific and Technical Information of China (English)

    程红伟

    2015-01-01

    目的:研究分析胺碘酮应用于老年冠心病心律不齐患者的临床治疗中所取得的效果。方法选择本院76例冠心病心律不齐老年患者,选择胺碘酮以及普罗帕酮对患者实施分组治疗,对比两组患者的临床疗效。结果采用胺碘酮的观察组总治疗有效率为95.6%,明显优于对照组(采用普罗帕酮)的76.5%,两组患者临床治疗有效率比较存在明显差异,具有统计学意义(P<0.05);观察组患者的不良反应发生率明显低于对照组患者(P<0.05)。结论针对老年冠心病心律不齐患者,采用胺碘酮进行治疗能够取得明显疗效,建议推广应用。%Objective To study the clinical application of amiodarone treatment in elderly patients with coronary heart disease arrhythmia in multi effect has been achieved. Methods 76 cases of elderly patients with coronary heart disease arrhythmia amiodarone and propafenone in our hospital, choice of implementation of grouping treatment of patients, the clinical efficacy were compared between two groups. Results The effective rate of observation group with amiodarone total treatment was 95.6%, significantly better than the control group (using propafenone) 76.5% (P<0.05). Conclusion In elderly coronary heart disease patients with amiodarone for the treatment of arrhythmia, can obtain obvious effect, application suggestions.

  4. Clinical Experience of Amiodarone Combined with Wenxinkeli in Treating New Atrial Fibrillation%胺碘酮联合稳心颗粒治疗新发心房纤颤的临床体会

    Institute of Scientific and Technical Information of China (English)

    李晓渝

    2014-01-01

    Objective To analyze the clinical efficacy of amiodarone combined with Wenxinkeli in treating new atrial fibrillation. Methods A total of 46 patients with new atrial fibrillation in our hospital from April 2O1O to March 2O14 were se-lected,and then they were divided into control group(23 cases)and observation group(23 cases). The control group was treated with amiodarone combined with verapamil,the observation group was treated with amiodarone combined with Wenxinkeli. Clinical efficacy of two groups were compared. Results The total effective rate of the observation group was higher than that of control group,the difference was statistically significant( PAmiodarone combined with Wenxinkeli has significant clinical efficacy in treating new atrial fibrillation,which,can improve patients'physical fitness and quality of life.%目的:探讨胺碘酮联合稳心颗粒治疗新发心房纤颤的临床疗效。方法选取2O1O年4月-2O14年3月于本院接受治疗的新发心房纤颤患者46例作为研究对象。将其分成对照组及观察组,各23例。对照组给予盐酸胺碘酮联合维拉帕米治疗;观察组给予胺碘酮及稳心颗粒的联合治疗。比较两组患者的临床疗效。结果观察组临床治疗的总有效率高于对照组,差异有统计学意义( P

  5. Efficacy and safety of small dose of amiodarone in treatment of arrhythmia%小剂量胺碘酮在心律失常治疗中的疗效及安全性

    Institute of Scientific and Technical Information of China (English)

    冯杰

    2015-01-01

    目的:探讨小剂量胺碘酮在心律失常治疗中的疗效和安全性。方法将该院2013年10月—2014年9月医治的54例心律失常患者随机分为常规组与观察组。两组患者在常规治疗基础上分别使用普鲁帕酮与小剂量的胺碘酮进行治疗。比较两组患者不同药物治疗后总有效率和不良反应情况。结果在治疗后,观察组、对照组总有效率分别为88.89%(24/27)、59.26%(16/27),观察组疗效优于对照组(P<0.05);观察组不良反应情况明显低于对照组(P<0.05)。结论使用小剂量胺碘酮治疗室性心律失常,治疗效果明显,安全、有效,值得推广。%Objective To investigate the efficacy and safety of small dose of amiodarone in treatment of arrhythmia. Methods 54 patients with arrhythmia were divided into control group and observation group randomly. Two groups of patients were given propafenone and small dose of amiodarone on the basis of conventional treatment. the clinical efficacy and adverse reactions of propafenone situation with a small dose of amiodarone. Results after treatment, the observation group, the control group total effectiveness respectively is 88.89% (24/27), 59.26% (16/27), the effect of observation group is better than control group (P <0.05); the adverse reactions observed was significantly lower than control group (P < 0.05). Conclusion the use of small dose amiodarone in therapeutic room, arrhythmia, obvious curative effect, safety, effective, worthy of promotion.

  6. Application Effect of Amiodarone on Patients With Congestive Heart Failure and Arrhythmias%心力衰竭并心律失常患者胺碘酮的应用效果观察

    Institute of Scientific and Technical Information of China (English)

    雷娜

    2015-01-01

    目的 研究探讨对心力衰竭合并心律失常患者应用胺碘酮的临床疗效.方法 选择我院心内科自2013年1月~2015年1月收治的80例心力衰竭合并心律失常的患者作为研究对象,所有患者均予以胺碘酮进行治疗,对其临床效果进行回顾性分析.结果 经胺碘酮治疗研究患者的总有效率为90.0%,不良反应发生率为8.7%,且心脏功能较治疗前改善(P<0.05),差异具有统计学意义.结论 在临床中应用胺碘酮治疗心力衰竭合并心律失常患者具有有效率高及不良反应率低等优点,并且可显著改善患者的心脏功能.%Objective To investigate the clinical efifcacy in patients with heart failure, arrhythmia amiodarone. Methods Hospital Cardiology from 80 cases of patients with heart failure with cardiac arrhythmia from January 2013 to January 2015 admitted to the study, all patients were to be treated with amiodarone were retrospectively analyzed clinical Results . Results Amiodarone therapy in patients with total effective rate was 90.0% incidence of adverse reactions was 8.7%, and heart function was significantly improved compared with before treatment (P < 0.05), a statistically significant difference. Conclusion The clinical application of amiodarone treatment of heart arrhythmia the patient has high efficiency and low adverse reaction rate, etc., and can significantly improve the patient's cardiac function.

  7. 普罗帕酮和胺碘酮治疗阵发性室上性心动过速的临床分析%Clinical analysis of propafenone and amiodarone in the treatment of paroxysmal suproventricular tachycardia

    Institute of Scientific and Technical Information of China (English)

    税小波; 高建军; 邹玉刚; 税朝东; 税朝莲

    2015-01-01

    目的:探讨分别运用普罗帕酮和胺碘酮治疗阵发性室上性心动过速的临床效果。方法:2010年11月-2014年7月收治阵发性室上性心动过速患者64例,随机分为观察组和对照组,各32例。对照组和观察组分别采用普罗帕酮和胺碘酮进行治疗,比较两组的治疗效果。结果:观察组转复时间明显长于对照组,不良反应率明显低于对照组,组间比较差异均具有统计学意义(P<0.05)。观察组临床总有效率(87.50%)同对照组(90.63%)相比差异无统计学意义(P>0.05)。结论:在阵发性室上性心动过速的临床治疗中,普罗帕酮和胺碘酮均有良好的治疗效果,但普罗帕酮起效更快,胺碘酮的安全性更高。%Objective:To explore the clinical effect of propafenone and amiodarone used respectively in the treatment of paroxysmal suproventricular tachycardia.Methods: 64 cases of paroxysmal suproventricular tachycardia were selected from November 2010 to July 2014.They were divided into the observation group and the control group with 32 cases in each.The control group and the observation group were treated with propafenone and amiodarone respectively.We compared the therapeutic effect of the two groups.Results:The converting time of the observation group was obviously higher than that of the control group,and the adverse reaction rate was significantly lower than that of the control group.The differences between the two groups were statistically significant(P0.05).Conclusion:Propafenone and amiodarone in the treatment of paroxysmal suproventricular tachycardia had good treatment effect,but amiodarone had faster effect and higher safety.

  8. 胺碘酮致飞行员甲状腺功能异常二例并文献复习%Two cases of pilots with amiodarone-induced thyroid dysfunction and literature review

    Institute of Scientific and Technical Information of China (English)

    杨彩哲; 于亚静; 徐先荣; 郑军; 刘红巾; 付兆君; 崔丽; 关小宏; 王建昌

    2015-01-01

    目的 总结飞行人员因心律失常服用胺碘酮而引起甲状腺功能异常的临床特征、诊断、分型、治疗及预后,为以后类似疾病的诊治及航空医学鉴定提供经验. 方法 通过回顾性分析2例飞行员因心房颤动服用胺碘酮而引起甲状腺功能异常的过程,结合文献复习,总结胺碘酮诱发甲状腺功能异常的临床特征、诊断、分型、治疗及转归. 结果 例1飞行员在服用胺碘酮7个月后停药,停药1个月后出现“低T3综合征”.停药2年后再次服用胺碘酮,1个月后出现碘诱导2型甲状腺毒症;停用胺碘酮3个月,甲状腺功能恢复正常.例2飞行员间断服用胺碘酮9年后诊断为碘诱导甲状腺功能减退,停用胺碘酮,并口服左甲状腺素钠75 μg,1次/d,补充治疗,5个月后甲状腺功能恢复正常.应用左甲状腺素钠2年后停药,甲状腺功能完全恢复正常.两例飞行员鉴定结论为暂时飞行不合格. 结论 飞行人员应用胺碘酮前,应完善相关检查.在治疗过程中、停药后6~9月甚至更长时间内,应定期检查甲状腺功能.对服用胺碘酮的飞行员要定期随访,尤其对既往存在甲状腺疾病和存在危险因素者.胺碘酮所引起的甲状腺功能异常有可能恢复正常.鉴定结论要结合心律失常和甲状腺功能情况综合判断.%Objective To summarize the clinic feature,diagnosis,treatment,and prognosis of amiodarone-induced thyroid dysfunction in the pilots with arrhythmia and gather the experiences on treatment and aviation medical assessment.Methods Retrospective analysis was done on the process of 2 cases with amiodarone induced abnormal thyroid function in pilots with atrial fibrillation and on the literatures to summary the clinic feature,diagnosis,treatment,and prognosis were reviewed.Results Case 1 had taken amiodarone for 7 months and low T3 syndrome was diagnosed 1 month later.Two years later,he took amiodarone again for 1 month and was

  9. L-arginine destabilizes oral multi-species biofilm communities developed in human saliva.

    Science.gov (United States)

    Kolderman, Ethan; Bettampadi, Deepti; Samarian, Derek; Dowd, Scot E; Foxman, Betsy; Jakubovics, Nicholas S; Rickard, Alexander H

    2015-01-01

    The amino acid L-arginine inhibits bacterial coaggregation, is involved in cell-cell signaling, and alters bacterial metabolism in a broad range of species present in the human oral cavity. Given the range of effects of L-arginine on bacteria, we hypothesized that L-arginine might alter multi-species oral biofilm development and cause developed multi-species biofilms to disassemble. Because of these potential biofilm-destabilizing effects, we also hypothesized that L-arginine might enhance the efficacy of antimicrobials that normally cannot rapidly penetrate biofilms. A static microplate biofilm system and a controlled-flow microfluidic system were used to develop multi-species oral biofilms derived from pooled unfiltered cell-containing saliva (CCS) in pooled filter-sterilized cell-free saliva (CFS) at 37° C. The addition of pH neutral L-arginine monohydrochloride (LAHCl) to CFS was found to exert negligible antimicrobial effects but significantly altered biofilm architecture in a concentration-dependent manner. Under controlled flow, the biovolume of biofilms (μm(3)/μm(2)) developed in saliva containing 100-500 mM LAHCl were up to two orders of magnitude less than when developed without LAHCI. Culture-independent community analysis demonstrated that 500 mM LAHCl substantially altered biofilm species composition: the proportion of Streptococcus and Veillonella species increased and the proportion of Gram-negative bacteria such as Neisseria and Aggregatibacter species was reduced. Adding LAHCl to pre-formed biofilms also reduced biovolume, presumably by altering cell-cell interactions and causing cell detachment. Furthermore, supplementing 0.01% cetylpyridinium chloride (CPC), an antimicrobial commonly used for the treatment of dental plaque, with 500 mM LAHCl resulted in greater penetration of CPC into the biofilms and significantly greater killing compared to a non-supplemented 0.01% CPC solution. Collectively, this work demonstrates that LAHCl moderates multi

  10. Salt bridges destabilize a leucine zipper designed for maximized ion pairing between helices.

    Science.gov (United States)

    Phelan, Paul; Gorfe, Alemayehu A; Jelesarov, Ilian; Marti, Daniel N; Warwicker, James; Bosshard, Hans Rudolf

    2002-03-05

    Interhelical salt bridges are common in leucine zippers and are thought to stabilize the coiled coil conformation. Here we present a detailed thermodynamic investigation of the designed, disulfide-linked leucine zipper AB(SS) whose high-resolution NMR structure shows six interhelical ion pairs between heptad positions g of one helix and e' of the other helix but no ion pairing within single helices. The average pK(a) value of the Glu side chain carboxyl groups of AB(SS) is slightly higher than the pK(a) of a freely accessible Glu in an unfolded peptide [Marti, D. N., Jelesarov, I., and Bosshard, H. R. (2000) Biochemistry 39, 12804-12818]. This indicates that the salt bridges are destabilizing, a prediction we now have confirmed by determining the pH +/- stability profile of AB(SS). Circular dichroism-monitored unfolding by urea and by heating and differential scanning calorimetry show that the coiled coil conformation is approximately 5 kJ/mol more stable when salt bridges are broken by protonation of the carboxyl side chains. Using guanidinium chloride as the denaturant, the increase in the free energy of unfolding on protonation of the carboxyl side chains is larger, approximately 17 kJ/mol. The discrepancy between urea and guanidinium chloride unfolding can be ascribed to the ionic nature of guanidinium chloride, which screens charge-charge interactions. This work demonstrates the difficulty of predicting the energetic contribution of salt bridges from structural data alone even in a case where the ion pairs are seen in high-resolution NMR structures. The reason is that the contribution to stability results from a fine balance between energetically favorable Coulombic attractions and unfavorable desolvation of charges and conformational constraints of the residues involved in ion pairing. The apparent discrepancy between the results presented here and mutational studies indicating stabilization by salt bridges is discussed and resolved. An explanation is

  11. L-arginine destabilizes oral multi-species biofilm communities developed in human saliva.

    Directory of Open Access Journals (Sweden)

    Ethan Kolderman

    Full Text Available The amino acid L-arginine inhibits bacterial coaggregation, is involved in cell-cell signaling, and alters bacterial metabolism in a broad range of species present in the human oral cavity. Given the range of effects of L-arginine on bacteria, we hypothesized that L-arginine might alter multi-species oral biofilm development and cause developed multi-species biofilms to disassemble. Because of these potential biofilm-destabilizing effects, we also hypothesized that L-arginine might enhance the efficacy of antimicrobials that normally cannot rapidly penetrate biofilms. A static microplate biofilm system and a controlled-flow microfluidic system were used to develop multi-species oral biofilms derived from pooled unfiltered cell-containing saliva (CCS in pooled filter-sterilized cell-free saliva (CFS at 37° C. The addition of pH neutral L-arginine monohydrochloride (LAHCl to CFS was found to exert negligible antimicrobial effects but significantly altered biofilm architecture in a concentration-dependent manner. Under controlled flow, the biovolume of biofilms (μm(3/μm(2 developed in saliva containing 100-500 mM LAHCl were up to two orders of magnitude less than when developed without LAHCI. Culture-independent community analysis demonstrated that 500 mM LAHCl substantially altered biofilm species composition: the proportion of Streptococcus and Veillonella species increased and the proportion of Gram-negative bacteria such as Neisseria and Aggregatibacter species was reduced. Adding LAHCl to pre-formed biofilms also reduced biovolume, presumably by altering cell-cell interactions and causing cell detachment. Furthermore, supplementing 0.01% cetylpyridinium chloride (CPC, an antimicrobial commonly used for the treatment of dental plaque, with 500 mM LAHCl resulted in greater penetration of CPC into the biofilms and significantly greater killing compared to a non-supplemented 0.01% CPC solution. Collectively, this work demonstrates that LAHCl

  12. Eicosanoid release is increased by membrane destabilization and CFTR inhibition in Calu-3 cells.

    Science.gov (United States)

    Borot, Florence; Vieu, Diane-Lore; Faure, Grazyna; Fritsch, Janine; Colas, Julien; Moriceau, Sandra; Baudouin-Legros, Maryvonne; Brouillard, Franck; Ayala-Sanmartin, Jesus; Touqui, Lhousseine; Chanson, Marc; Edelman, Aleksander; Ollero, Mario

    2009-10-22

    The antiinflammatory protein annexin-1 (ANXA1) and the adaptor S100A10 (p11), inhibit cytosolic phospholipase A2 (cPLA2alpha) by direct interaction. Since the latter is responsible for the cleavage of arachidonic acid at membrane phospholipids, all three proteins modulate eicosanoid production. We have previously shown the association of ANXA1 expression with that of CFTR, the multifactorial protein mutated in cystic fibrosis. This could in part account for the abnormal inflammatory status characteristic of this disease. We postulated that CFTR participates in the regulation of eicosanoid release by direct interaction with a complex containing ANXA1, p11 and cPLA2alpha. We first analyzed by plasmon surface resonance the in vitro binding of CFTR to the three proteins. A significant interaction between p11 and the NBD1 domain of CFTR was found. We observed in Calu-3 cells a rapid and partial redistribution of all four proteins in detergent resistant membranes (DRM) induced by TNF-alpha. This was concomitant with increased IL-8 synthesis and cPLA2alpha activation, ultimately resulting in eicosanoid (PGE2 and LTB4) overproduction. DRM destabilizing agent methyl-beta-cyclodextrin induced further cPLA2alpha activation and eicosanoid release, but inhibited IL-8 synthesis. We tested in parallel the effect of short exposure of cells to CFTR inhibitors Inh172 and Gly-101. Both inhibitors induced a rapid increase in eicosanoid production. Longer exposure to Inh172 did not increase further eicosanoid release, but inhibited TNF-alpha-induced relocalization to DRM. These results show that (i) CFTR may form a complex with cPLA2alpha and ANXA1 via interaction with p11, (ii) CFTR inhibition and DRM disruption induce eicosanoid synthesis, and (iii) suggest that the putative cPLA2/ANXA1/p11/CFTR complex may participate in the modulation of the TNF-alpha-induced production of eicosanoids, pointing to the importance of membrane composition and CFTR function in the regulation of

  13. Eicosanoid release is increased by membrane destabilization and CFTR inhibition in Calu-3 cells.

    Directory of Open Access Journals (Sweden)

    Florence Borot

    Full Text Available The antiinflammatory protein annexin-1 (ANXA1 and the adaptor S100A10 (p11, inhibit cytosolic phospholipase A2 (cPLA2alpha by direct interaction. Since the latter is responsible for the cleavage of arachidonic acid at membrane phospholipids, all three proteins modulate eicosanoid production. We have previously shown the association of ANXA1 expression with that of CFTR, the multifactorial protein mutated in cystic fibrosis. This could in part account for the abnormal inflammatory status characteristic of this disease. We postulated that CFTR participates in the regulation of eicosanoid release by direct interaction with a complex containing ANXA1, p11 and cPLA2alpha. We first analyzed by plasmon surface resonance the in vitro binding of CFTR to the three proteins. A significant interaction between p11 and the NBD1 domain of CFTR was found. We observed in Calu-3 cells a rapid and partial redistribution of all four proteins in detergent resistant membranes (DRM induced by TNF-alpha. This was concomitant with increased IL-8 synthesis and cPLA2alpha activation, ultimately resulting in eicosanoid (PGE2 and LTB4 overproduction. DRM destabilizing agent methyl-beta-cyclodextrin induced further cPLA2alpha activation and eicosanoid release, but inhibited IL-8 synthesis. We tested in parallel the effect of short exposure of cells to CFTR inhibitors Inh172 and Gly-101. Both inhibitors induced a rapid increase in eicosanoid production. Longer exposure to Inh172 did not increase further eicosanoid release, but inhibited TNF-alpha-induced relocalization to DRM. These results show that (i CFTR may form a complex with cPLA2alpha and ANXA1 via interaction with p11, (ii CFTR inhibition and DRM disruption induce eicosanoid synthesis, and (iii suggest that the putative cPLA2/ANXA1/p11/CFTR complex may participate in the modulation of the TNF-alpha-induced production of eicosanoids, pointing to the importance of membrane composition and CFTR function in the

  14. Dynamics of gradient formation by intracellular shuttling

    Energy Technology Data Exchange (ETDEWEB)

    Berezhkovskii, Alexander M. [Mathematical and Statistical Computing Laboratory, Division of Computational Bioscience, Center for Information Technology, National Institutes of Health, Bethesda, Maryland 20892 (United States); Shvartsman, Stanislav Y. [Department of Chemical and Biological Engineering and Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, New Jersey 08544 (United States)

    2015-08-21

    A number of important cellular functions rely on the formation of intracellular protein concentration gradients. Experimental studies discovered a number of mechanisms for the formation of such gradients. One of the mechanisms relies on the intracellular shuttling of a protein that interconverts between the two states with different diffusivities, under the action of two enzymes, one of which is localized to the plasma membrane, whereas the second is uniformly distributed in the cytoplasm. Recent work reported an analytical solution for the steady state gradient in this mechanism, obtained in the framework of a one-dimensional reaction-diffusion model. Here, we study the dynamics in this model and derive analytical expressions for the Laplace transforms of the time-dependent concentration profiles in terms of elementary transcendental functions. Inverting these transforms numerically, one can obtain time-dependent concentration profiles of the two forms of the protein.

  15. Comparison of amiodarone plus irbesartan regimen versus amiodarone alone on maintaining sinus rhythm in rheumatic heart disease patients with persistent atrial fibrillation post valve replacement and cordioversion%厄贝沙坦与胺碘酮联合对风湿性心脏病持续性心房颤动转复患者的窦性心律维持作用

    Institute of Scientific and Technical Information of China (English)

    丁平; 李莉; 张浩; 陈良金; 邓学军; 袁义强

    2009-01-01

    Objective To compare the efficacy of combined amiodamne and irbesartan use versus amiodarone alone on maintaining sinus rhythm in rheumatic heart disease patients with persistent atrial fibrillation(AF)post valve replacement and cardioversion.nethods Patients were randomly divided into amiodarone group(A,n=31)and amiodarone plus irbesartan group(AI,n=32)and all patients received Warfarin(INR 2.0-3.0).For patients in group A,intravenous amiodarone(600 mg/d)was applied for 10 days and oral amiodarone(200 mg,b.I.d.)was given on the 7th day for 3 days.For patients in group AI,irhesartan(150 mg/d)was added on top of amiodarone at the study begin.Electric cardioversion was performed for patients still with AF on day 10.Amiodarone(200 mg,b.I.d.for 1 week,then 200 mg,q.d.till study end) with or without irbesartan(150 me/d)was continued thereafter.Patients were followed up for 12 months after sinus rhythm recovery.The primary end points are first recurrence of symptomatic and asymptomatic AF.Results Twelve months post therapy,number of patients on sinus rhythm was significantly higher(68.7%vs.41.9%,P<0.05)and left atrium diameter(LAD)was significantly smaller[(48.6±4.6)mm vs.(51.5±4.2)mm,P<0.05]in group AI than those in group A.LAD(OR 1.242)and use of irbesartan(OR 0.226)are associated with the AF recurrence.Conclusion Combined amiodarone and irbesartan use is superior to amiodarone alone for maintaining sinus rhythm in rheumatic heart disease patients with persistent AF post valve replacement and cardioversion.%目的 研究风湿性心脏病持续性心房颤动(房颤)应用厄贝沙坦联合胺碘酮的窦性心律(窦律)维持作用及复发的危险因素.方法 选择住院准备房颤复律且符合入选标准风湿性心脏病(风心病)瓣膜置换术后持续性房颤患者63例.随机分为对照组(31例)和试验组(32例).对照组给予胺碘酮,试验组用胺碘酮+厄贝沙坦.入选患者转复为窦律后即为试验起始

  16. Biology and intracellular life of chlamydia

    Directory of Open Access Journals (Sweden)

    Ranin Lazar

    2011-01-01

    Full Text Available Introduction. Chlamydiae are Gram-negative obligate intracellular bacteria. The developmental cycle of Chlamydiae is specific and different from other bacteria. The elementary body is the infectious form of the organism, responsible for attaching to the target host cell and promoting its entry. The reticulate body is the larger, metabolically active form of the organism, synthesizing deoxyribonucleic acid, ribonucleic acid and proteins. The elementary body and reticulate body represent evolutionary adaptations to extracellular and intracellular environments. Intracellular persistence of Chlamydia. Predisposition of Chlamydia to persist within the host cell has been recognized as a major factor in the pathogenesis of chlamydial disease. The persistence implies a long-term association between chlamydiae and their host cell that may not manifest as clinically recognizable disease. The ability of chlamydia to remain within one morphological state for a long time in response to exogenous factors suggests an innate ability of these organisms to persist intracellulary in a unique developmental form. Chlamydiae induce interferon γ and exhibit growth inhibition in their presence. While the high levels of interferon γ completely restrict the development of chlamydia, its low levels induce the development of morphologically aberrant intracellular forms. The persistent forms contain reduced levels of major outer membrane protein but high levels of chlamydial heat shock protein. Conclusion. Immunopathogenesis of chlamydial infection is one of the main focal points of current research into Chlamydia. Chlamydial infections are highly prevalent, usually asymptomatic and associated with serious sequelae. Screening programmes are the most important in the prevention of a long-term sequele.

  17. Detection of intracellular phosphatidylserine in living cells.

    Science.gov (United States)

    Calderon, Frances; Kim, Hee-Yong

    2008-03-01

    To demonstrate the intracellular phosphatidylserine (PS) distribution in neuronal cells, neuroblastoma cells and hippocampal neurons expressing green fluorescence protein (GFP)-AnnexinV were stimulated with a calcium ionophore and localization of GFP-AnnexinV was monitored by fluorescence microscopy. Initially, GFP-AnnexinV distributed evenly in the cytosol and nucleus. Raising the intracellular calcium level with ionomycin-induced translocation of cytoplasmic GFP-AnnexinV to the plasma membrane but not to the nuclear membrane, indicating that PS distributes in the cytoplasmic side of the plasma membrane. Nuclear GFP-AnnexinV subsequently translocated to the nuclear membrane, indicating PS localization in the nuclear envelope. GFP-AnnexinV also localized in a juxtanuclear organelle that was identified as the recycling endosome. However, minimal fluorescence was detected in any other subcellular organelles including mitochondria, endoplasmic reticulum, Golgi complex, and lysosomes, strongly suggesting that PS distribution in the cytoplasmic face in these organelles is negligible. Similarly, in hippocampal primary neurons PS distributed in the inner leaflet of plasma membranes of cell body and dendrites, and in the nuclear envelope. To our knowledge, this is the first demonstration of intracellular PS localization in living cells, providing an insight for specific sites of PS interaction with soluble proteins involved in signaling processes.

  18. Invasion and intracellular survival by protozoan parasites.

    Science.gov (United States)

    Sibley, L David

    2011-03-01

    Intracellular parasitism has arisen only a few times during the long ancestry of protozoan parasites including in diverse groups such as microsporidians, kinetoplastids, and apicomplexans. Strategies used to gain entry differ widely from injection (e.g. microsporidians), active penetration of the host cell (e.g. Toxoplasma), recruitment of lysosomes to a plasma membrane wound (e.g. Trypanosoma cruzi), to host cell-mediated phagocytosis (e.g. Leishmania). The resulting range of intracellular niches is equally diverse ranging from cytosolic (e.g. T. cruzi) to residing within a non-fusigenic vacuole (e.g. Toxoplasma, Encephalitozoon) or a modified phagolysosome (e.g. Leishmania). These lifestyle choices influence access to nutrients, interaction with host cell signaling pathways, and detection by pathogen recognition systems. As such, intracellular life requires a repertoire of adaptations to assure entry-exit from the cell, as well as to thwart innate immune mechanisms and prevent clearance. Elucidating these pathways at the cellular and molecular level may identify key steps that can be targeted to reduce parasite survival or augment immunologic responses and thereby prevent disease.

  19. Fluorescent nanoparticles for intracellular sensing: A review

    Energy Technology Data Exchange (ETDEWEB)

    Ruedas-Rama, Maria J., E-mail: mjruedas@ugr.esmailto [Department of Physical Chemistry, Faculty of Pharmacy, University of Granada, Campus Cartuja, 18071, Granada (Spain); Walters, Jamie D. [Department of Chemical Engineering and Biotechnology, University of Cambridge, Tennis Court Road, Cambridge, UK CB2 1QT (United Kingdom); Orte, Angel [Department of Physical Chemistry, Faculty of Pharmacy, University of Granada, Campus Cartuja, 18071, Granada (Spain); Hall, Elizabeth A.H., E-mail: lisa.hall@biotech.cam.ac.uk [Department of Chemical Engineering and Biotechnology, University of Cambridge, Tennis Court Road, Cambridge, CB2 1QT (United Kingdom)

    2012-11-02

    Highlights: Black-Right-Pointing-Pointer Analytical applications of fluorescent nanoparticles (NPs) in intracellular sensing. Black-Right-Pointing-Pointer Critical review on performance of QDots, metal NPs, silica NPs, and polymer NPs. Black-Right-Pointing-Pointer Highlighted potential of fluorescence lifetime imaging microscopy (FLIM). - Abstract: Fluorescent nanoparticles (NPs), including semiconductor NPs (Quantum Dots), metal NPs, silica NPs, polymer NPs, etc., have been a major focus of research and development during the past decade. The fluorescent nanoparticles show unique chemical and optical properties, such as brighter fluorescence, higher photostability and higher biocompatibility, compared to classical fluorescent organic dyes. Moreover, the nanoparticles can also act as multivalent scaffolds for the realization of supramolecular assemblies, since their high surface to volume ratio allow distinct spatial domains to be functionalized, which can provide a versatile synthetic platform for the implementation of different sensing schemes. Their excellent properties make them one of the most useful tools that chemistry has supplied to biomedical research, enabling the intracellular monitoring of many different species for medical and biological purposes. In this review, we focus on the developments and analytical applications of fluorescent nanoparticles in chemical and biological sensing within the intracellular environment. The review also points out the great potential of fluorescent NPs for fluorescence lifetime imaging microscopy (FLIM). Finally, we also give an overview of the current methods for delivering of fluorescent NPs into cells, where critically examine the benefits and liabilities of each strategy.

  20. Combinatorial release of dexamethasone and amiodarone from a nano-structured parylene-C film to reduce perioperative inflammation and atrial fibrillation

    Science.gov (United States)

    Robinson, Erik; Kaushal, Sunjay; Alaboson, Justice; Sharma, Sudhish; Belagodu, Amogh; Watkins, Claire; Walker, Brandon; Webster, Gregory; McCarthy, Patrick; Ho, Dean

    2016-02-01

    Suppressing perioperative inflammation and post-operative atrial fibrillation requires effective drug delivery platforms (DDP). Localized anti-inflammatory and anti-arrhythmic agent release may be more effective than intravenous treatment to improve patient outcomes. This study utilized a dexamethasone (DEX) and amiodarone (AMIO)-loaded Parylene-C (PPX) nano-structured film to inhibit inflammation and atrial fibrillation. The PPX film was tested in an established pericardial adhesion rabbit model. Following sternotomy, the anterior pericardium was resected and the epicardium was abraded. Rabbits were randomly assigned to five treatment groups: control, oxidized PPX (PPX-Oxd), PPX-Oxd infused with DEX (PPX-Oxd[DEX]), native PPX (PPX), and PPX infused with DEX and AMIO (PPX[AMIO, DEX]). 4 weeks post-sternotomy, pericardial adhesions were evaluated for gross adhesions using a 4-point grading system and histological evaluation for epicardial neotissue fibrosis (NTF). Atrial fibrillation duration and time per induction were measured. The PPX[AMIO, DEX] group had a significant reduction in mean adhesion score compared with the control group (control 2.75 +/- 0.42 vs. PPX[AMIO, DEX] 0.25 +/- 0.42, P films compared to control (9.5 +/- 6.8 s vs. 187.6 +/- 174.7 s, p = 0.003). Time of atrial fibrillation per successful induction decreased among PPX[AMIO, DEX] films compared to control (2.8 +/- 1.2 s vs. 103.2 +/- 178 s, p = 0.004). DEX/AMIO-loaded PPX films are associated with reduced perioperative inflammation and a diminished atrial fibrillation duration. Epicardial application of AMIO, DEX films is a promising strategy to prevent post-operative cardiac complications.Suppressing perioperative inflammation and post-operative atrial fibrillation requires effective drug delivery platforms (DDP). Localized anti-inflammatory and anti-arrhythmic agent release may be more effective than intravenous treatment to improve patient outcomes. This study utilized a dexamethasone (DEX

  1. ErbB3/HER3 intracellular domain is competent to bind ATP and catalyze autophosphorylation

    Energy Technology Data Exchange (ETDEWEB)

    Shi, Fumin; Telesco, Shannon E.; Liu, Yingting; Radhakrishnan, Ravi; Lemmon, Mark A. (UPENN); (UPENN-MED)

    2010-06-21

    ErbB3/HER3 is one of four members of the human epidermal growth factor receptor (EGFR/HER) or ErbB receptor tyrosine kinase family. ErbB3 binds neuregulins via its extracellular region and signals primarily by heterodimerizing with ErbB2/HER2/Neu. A recently appreciated role for ErbB3 in resistance of tumor cells to EGFR/ErbB2-targeted therapeutics has made it a focus of attention. However, efforts to inactivate ErbB3 therapeutically in parallel with other ErbB receptors are challenging because its intracellular kinase domain is thought to be an inactive pseudokinase that lacks several key conserved (and catalytically important) residues - including the catalytic base aspartate. We report here that, despite these sequence alterations, ErbB3 retains sufficient kinase activity to robustly trans-autophosphorylate its intracellular region - although it is substantially less active than EGFR and does not phosphorylate exogenous peptides. The ErbB3 kinase domain binds ATP with a K{sub d} of approximately 1.1 {micro}M. We describe a crystal structure of ErbB3 kinase bound to an ATP analogue, which resembles the inactive EGFR and ErbB4 kinase domains (but with a shortened {alpha}C-helix). Whereas mutations that destabilize this configuration activate EGFR and ErbB4 (and promote EGFR-dependent lung cancers), a similar mutation conversely inactivates ErbB3. Using quantum mechanics/molecular mechanics simulations, we delineate a reaction pathway for ErbB3-catalyzed phosphoryl transfer that does not require the conserved catalytic base and can be catalyzed by the 'inactive-like'configuration observed crystallographically. These findings suggest that ErbB3 kinase activity within receptor dimers may be crucial for signaling and could represent an important therapeutic target.

  2. Strategies to improve intracellular drug delivery by targeted liposomes

    NARCIS (Netherlands)

    Fretz, M.M.

    2007-01-01

    Biotechnological advances increased the number of novel macromolecular drugs and new drug targets. The latter are mostly found intracellular. Unfortunately, most of the new macromolecular drugs rely on drug delivery tools for their intracellular delivery because their unfavourable physicochemical pr

  3. Early vessel destabilization mediated by Angiopoietin-2 and subsequent vessel maturation via Angiopoietin-1 induce functional neovasculature after ischemia.

    Directory of Open Access Journals (Sweden)

    Di Qin

    Full Text Available BACKGROUND: We assessed whether Angiopoietin-2 (Ang2, a Tie2 ligand and partial antagonist of Angiopoietin-1 (Ang1, is required for early vessel destabilization during postischemic angiogenesis, when combined with vascular growth factors. METHODS: In vitro, matrigel co-cultures assessed endothelial-cell tube formation and pericyte recruitment after stimulation of VEGF-A, Apelin (APLN, Ang1 with or without Ang2. In a murine hindlimb ischemia model, adeno-associated virus (rAAV, 3×10(12 virusparticles transduction of VEGF-A, APLN and Ang1 with or without Ang2 (continuous or early expression d0-3 was performed intramuscularly (d-14. Femoral artery ligation was performed at d0, followed by laser doppler perfusion meassurements (LDI 7 and 14. At d7 (early timepoint and d14 (late timepoint, histological analysis of capillary/muscle fiber ratio (CMF-R, PECAM-1 and pericyte/capillary ratio (PC-R, NG2 was performed. RESULTS: In vitro, VEGF-A, APLN and Ang1 induced ring formation, but only APLN and Ang1 recruited pericytes. Ang2 did not affect tube formation by APLN, but reduced pericyte recruitment after APLN or Ang1 overexpression. In vivo, rAAV.VEGF-A did not alter LDI-perfusion at d14, consistent with an impaired PC-R despite a rise in CMF-R. rAAV.APLN improved perfusion at d14, with or without continuous Ang2, increasing CMF-R and PC-R. rAAV.Ang1 improved perfusion at d14, when combined with rAAV.Ang2 (d0-3, accompanied by an increased CMF-R and PC-R. CONCLUSION: The combination of early vessel destabilization (Ang2 d0-3 and continuous Ang1 overexpression improves hindlimb perfusion, pointing to the importance of early vessel destabilization and subsequent vessel maturation for enhanced therapeutic neovascularization.

  4. Extracellular α-synuclein leads to microtubule destabilization via GSK-3β-dependent Tau phosphorylation in PC12 cells.

    Directory of Open Access Journals (Sweden)

    Magdalena Gąssowska

    Full Text Available α-Synuclein (ASN plays an important role in pathogenesis of Parkinson's disease (PD and other neurodegenerative disorders. Novel and most interesting data showed elevated tauopathy in PD and suggested relationship between ASN and Tau protein. However, the mechanism of ASN-evoked Tau protein modification is not fully elucidated. In this study we investigated the role of extracellular ASN in Tau hyperphosphorylation in rat pheochromocytoma (PC12 cells and the involvement of glycogen synthase kinase-3β (GSK-3β and cyclin-dependent kinase 5 (CDK5 in ASN-dependent Tau modification. Our results indicated that exogenously added ASN increases Tau phosphorylation at Ser396. Accordingly, the GSK-3β inhibitor (SB-216763 prevented ASN-evoked Tau hyperphosphorylation, but the CDK5 inhibitor had no effect. Moreover, western blot analysis showed that ASN affected GSK-3β via increasing of protein level and activation of this enzyme. GSK-3β activity evaluated by its phosphorylation status assay showed that ASN significantly increased the phosphorylation of this enzyme at Tyr216 with parallel decrease in phosphorylation at Ser9, indicative of stimulation of GSK-3β activity. Moreover, the effect of ASN on microtubule (MT destabilization and cell death with simultaneous the involvement of GSK-3β in these processes were analyzed. ASN treatment increased the amount of free tubulin and concomitantly reduced the amount of polymerized tubulin and SB-216763 suppressed these ASN-induced changes in tubulin, indicating that GSK-3β is involved in ASN-evoked MT destabilization. ASN-induced apoptotic processes lead to decrease in PC12 cells viability and SB-216763 protected those cells against ASN-evoked cytotoxicity. Concluding, extracellular ASN is involved in GSK-3β-dependent Tau hyperphosphorylation, which leads to microtubule destabilization. GSK-3β inhibition may be an effective strategy for protecting against ASN-induced cytotoxicity.

  5. Destabilization of survival factor MEF2D mRNA by neurotoxin in models of Parkinson's disease.

    Science.gov (United States)

    Wang, Bao; Cai, Zhibiao; Lu, Fangfang; Li, Chen; Zhu, Xiaofei; Su, Linna; Gao, Guodong; Yang, Qian

    2014-09-01

    Progressive loss of dopaminergic (DA) neurons in the substantial nigra pars compacta (SNc) is an important pathological feature in Parkinson's disease (PD). Loss of transcription factor myocyte enhancer factor 2D (MEF2D), a key neuronal survival factor, has been shown to underlie the loss of DA neurons in SNc and the pathogenic process of PD. It is known that PD-associated neurotoxins reduce the level of MEF2D protein to trigger neuronal death. Although neurotoxins clearly destabilize MEF2D by post-translational mechanisms, it is not known whether regulation of MEF2D mRNA contributes to neurotoxin-induced decrease in MEF2D protein. In this work, we showed that MPP(+), the toxic metabolite of MPTP, caused a significant decrease in the half-life and total level of MEF2D mRNA in a DA neuronal cell line, SN4741 cells. Quantitative PCR analysis of the SNc DA neurons captured by immune-laser capture microdissection showed that exposure to MPTP led to a marked reduction in the level of MEF2D mRNA in SNc DA neurons compared to controls. Down-regulation of MEF2D mRNA alone reduced the viability of SN4741 cells and sensitized the cells to MPP(+)-induced toxicity. These results suggest that destabilization and reduction in MEF2D mRNA is in part responsible for neurotoxin-induced decrease in MEF2D protein and neuronal viability. Myocyte enhancer factor 2D (MEF2D) plays an important role in neuronal survival. How MEF2D mRNA is deregulated under toxic stress is unclear. We found that PD-associated neurotoxins destabilize MEF2D mRNA and reduce its level in vitro and in vivo. Reduction in MEF2D mRNA is sufficient to sensitize model cells to neurotoxin-induced toxicity, suggesting that destabilization of MEF2D mRNA is part of the mechanism by which neurotoxins trigger deregulation of neuronal survival.

  6. Warm, salty surface water incursions and destabilization of the Cordilleran Ice Sheet

    Science.gov (United States)

    Taylor, M.; Hendy, I. L.; Pak, D. K.

    2012-12-01

    Ocean temperature change has the potential to destabilize tide-water glaciers and ice shelves. Here we investigate the potential impact of changing North Pacific sea surface temperatures (SST) on the stability of the Cordilleran Ice Sheet during the last deglaciation. Stable isotope values and trace metal ratios were generated on the planktonic foraminifera Neogloboquadrina pachyderma and Globigerina bulloides from core MD02-2496, (1243 m water depth; 48°58N, 127°02W), British Columbia. The site is located where the North Pacific Current bifurcates in the modern climate system, transporting water northward into the Alaskan Gyre and southward to the California Current system. In addition as the site is ~35 km from the coast of Vancouver Island, it is ideally located to detect changes in Cordilleran Ice Sheet behavior. The region is also affected by plumes from the Columbia River deflected north by the Coriolis effect, making it possible to monitor Glacial Lake Missoula Outburst Flooding. The high-resolution (50-200cm kyr-1) reconstruction of SST and δ18Oseawater (salinity) reveals cool (4-7°C), relatively fresh and stratified surface waters occupied the region between 20 and 16.5 ka. Frequent incursions of warm (>10°C), relatively saline water on decadal to centennial timescales began ~18.8 kyr, persisting until ~14.7 kyr. Reconstructed warm and salty waters from 18.5-17.9 kyr are associated with cyclic (~80 year) sedimentation of terrigenous organic carbon-rich, >300 Ma shale-like sediments, which may be evidence of Lake Missoula outburst floodwaters. These sediments contrast with the typical ~100 Ma volcanic sediments typically deposited during deglaciation. A step-wise warming of ~2-4°C occurs at ~16.6 ka and both planktonic foraminiferal species record identical SSTs until ~14.7 ka. During this interval the Vancouver Margin surface waters were relatively more saline and very well mixed. The warmest (14.5-16°C) incursion of saline water occurs at ~16.5 ka

  7. Intracellular ethanol accumulation in Saccharomyces cerevisiae during fermentation.

    OpenAIRE

    D'Amore, T; C.J. Panchal; Stewart, G G

    1988-01-01

    An intracellular accumulation of ethanol in Saccharomyces cerevisiae was observed during the early stages of fermentation (3 h). However, after 12 h of fermentation, the intracellular and extracellular ethanol concentrations were similar. Increasing the osmotic pressure of the medium caused an increase in the ratio of intracellular to extracellular ethanol concentrations at 3 h of fermentation. As in the previous case, the intracellular and extracellular ethanol concentrations were similar af...

  8. Phospholipidosis in rats treated with amiodarone: serum biochemistry and whole genome micro-array analysis supporting the lipid traffic jam hypothesis and the subsequent rise of the biomarker BMP.

    Science.gov (United States)

    Mesens, Natalie; Desmidt, Miek; Verheyen, Geert R; Starckx, Sofie; Damsch, Siegrid; De Vries, Ronald; Verhemeldonck, Marc; Van Gompel, Jacky; Lampo, Ann; Lammens, Lieve

    2012-04-01

    To provide mechanistic insight in the induction of phospholipidosis and the appearance of the proposed biomarker di-docosahexaenoyl (C22:6)-bis(monoacylglycerol) phosphate (BMP), rats were treated with 150 mg/kg amiodarone for 12 consecutive days and analyzed at three different time points (day 4, 9, and 12). Biochemical analysis of the serum revealed a significant increase in cholesterol and phospholipids at the three time points. Bio-analysis on the serum and urine detected a time-dependent increase in BMP, as high as 10-fold compared to vehicle-treated animals on day 12. Paralleling these increases, micro-array analysis on the liver of treated rats identified cholesterol biosynthesis and glycerophospholipid metabolism as highly modulated pathways. This modulation indicates that during phospholipidosis-induction interactions take place between the cationic amphiphilic drug and phospholipids at the level of BMP-rich internal membranes of endosomes, impeding cholesterol sorting and leading to an accumulation of internal membranes, converting into multilamellar bodies. This process shows analogy to Niemann-Pick disease type C (NPC). Whereas the NPC-induced lipid traffic jam is situated at the cholesterol sorting proteins NPC1 and NPC2, the amiodarone-induced traffic jam is thought to be located at the BMP level, demonstrating its role in the mechanism of phospholipidosis-induction and its significance for use as a biomarker.

  9. Die zukünftige Rolle von Amiodaron bei Hochrisikopatienten. Aktuelle Schlußfolgerungen aus den Ergebnissen früherer und jüngst veröffentlichter Studien zur Problematik des plötzlichen Herztodes.

    Directory of Open Access Journals (Sweden)

    Pürerfellner H

    2004-01-01

    Full Text Available Der plötzliche Herztod (PHT stellt heute nach wie vor ein epidemiologisch bedeutendes und medizinisch ungelöstes Problem in der westlichen Welt dar. Die häufigsten Grunderkrankungen finden sich dabei in der ischämischen und nichtischämischen Kardiomyopathie. Hochrisikopatienten sind im besonderen durch eine eingeschränkte Pumpfunktion und die symptomatische Herzinsuffizienz charakterisiert. Noch vor wenigen Jahren war der Nutzen implantierbarer Geräte (implantierbarer Kardioverter-Defibrillator, ICD zur Behandlung von lebensbedrohlichen ventrikulären Arrhythmien im Vergleich zur Standardtherapie mit antiarrhythmisch wirksamen Medikamenten (im besonderen mit Amiodaron unklar. Der folgende Artikel gibt einen Überblick über die Entwicklung der Rhythmustherapie in der Primär- und Sekundärprophylaxe zur Verhinderung des PHT anhand von Ergebnissen der in den letzten 15 Jahren erschienen großen randomisierten, kontrollierten Studien. Zusätzlich wird der zukünftige Stellenwert von Amiodaron bei Hochrisikopatienten beleuchtet.

  10. The treatment effect and relapse prevention of cardioversion of atrial fibrillation with Wenxin granules and amiodarone%稳心颗粒与胺碘酮联合转复心房颤动及预防复发的疗效观察

    Institute of Scientific and Technical Information of China (English)

    张玉榕; 史继利; 贾荣波

    2011-01-01

    目的 观察稳心颗粒联合胺碘酮转复及预防心房颤动复发的疗效.方法 选择慢性心房颤动患者共60例,随机分为稳心颗粒联合胺碘酮组(A组)及单纯胺碘酮组(B组)各30例,所有患者入院后静脉应用胺碘酮24 h同时口服胺碘酮由600 mg/d逐渐减量至200 mg/d维持,另外A组同时给予口服步长稳心颗粒(9 g,3次/d)共4周.观察2组患者4周内转复窦性心律情况及半年内复发情况.结果 第2、3、4周内累积转复窦性心律例数A组显著高于B组(分别是73.3%与43.3%,x2=5.55:83.3%与63.3%,x2=3.07;90.0%与66.7%,x2=4.81;P均<0.05),半年内复发B组有高于A组的趋势.结论 稳心颗粒联合应用胺碘酮转复心房颤动疗效优于单纯应用胺碘酮,并且半年内复发率可能更低.%Objective To observe the treatment effect and relapse prevention of cardioversion of atrial fibrillation with Wenxin granules and amiodarone. Methods Sixty patients of chronic atrial fibrillation were divided randomly into treatment of Wenxin granules and amiodarone group (group A) and treatment of simple amiodarone gorup(group B),Thirty cases in each group. All cases were treated with amiodarone by intravenous drip along with oral amiodarone. Thirty cases in group A were treated with Wenxin granules (9 grams,per day) additionally for 4 weeks. Results Patients in group A resumed normal sinus rhythm significantly higher than that in group B. The increasing relapse tendency of atrial fibrillation was higher in group B within 6 months. Conclusion Drug combination with Wenxin granules and amiodarone has better effect than simple amiodarone in the relapse prevention of cardioversion of atrial fibrillation.

  11. 胺碘酮联合β受体阻断药治疗冠脉搭桥术后早期新发房颤%The Effect of Amiodarone and β Blockers on 102 Cases of the Early Arrhythmia after Coronary Artery Bypass Grafting

    Institute of Scientific and Technical Information of China (English)

    陈雪; 唐泓波; 胡大清; 曾宁

    2012-01-01

    [目的]:观察胺碘酮联合β受体阻断药治疗冠状动脉搭桥(CABG)术后早期新发房颤(AF)的效果和不良反应.[方法]:102例CABG术后早期发生快室率房颤患者随机分为对照组48例和治疗组54例,对照组给予胺碘酮注射液静脉泵入,治疗组在对照组基础上加用艾司洛尔注射液或美托洛尔注射液.观察心电监护、心电图及24h动态心电图心率变化,比较两组1周内转复为窦性心律的有效率和不良反应发生率.[结果]:两组有效率分别为79.1%和94.4%,差异有统计学意义(P<0.05).两组不良反应发生率比较,差异无统计学意义(P>0.05).[结论]:胺碘酮联合艾司洛尔或美托洛尔转复CABG术后早期新发房颤效果优于单用胺碘酮.不良反应少,安全性高,值得临床推荐.%Objective:To investigate the effect and side effect of Amiodarone and β blockers on the arrhythmia after Coronary artery bypass grafting( CABG). Methods; 102 AF patients after CABG were randomly divided into two groups; Amiodarone group and Amiodarone and β blockers combined group. There were 48 cases with Amiodarone alone, 54 cases with Amiodarone and β blockers. The heart rale of ambulatory Holter monitor,electrocardiogram ( ECG) and dynamic electrocardiogram were recorded. The effective rate and complication rate of the two groups whose heart rate turned to sinus rhythm in one week were recorded. Results:The effective rate of combined group was superior to the Amiodarone group, 94.4% to 79.1 % (P 0.05). Conclusion: Using combined group on AF patients after CABG can achieve better results comparing to the Amiodarone group. Side effect is low and the combination drug therapy is worth to clinical recommenclation.

  12. Analysis on curative effect of metoprolol combined with amiodarone in patients with congestive heart failure and taehyarrhythmia%胺碘酮联合美托洛尔治疗充血性心力衰竭患者快速型室性心律失常的临床效果分析

    Institute of Scientific and Technical Information of China (English)

    邓志元

    2014-01-01

    目的:观察美托洛尔联合胺碘酮治疗充血性心力衰竭并快速性心律失常的治疗效果。方法:选择慢性心功能不全合并室性心律失常43例。心功能按NYHA分级为Ⅱ~Ⅳ级,随机分为胺碘酮治疗组、胺碘酮+美托洛尔治疗组。结果:胺碘酮+美托洛尔治疗组临床有效率90%(18/20),胺碘酮治疗组的总有效率60.87%(14/23)。2组差异有统计学意义(P<0.05)。结论:联合应用胺碘酮及美托洛尔治疗慢性心功能不全合并室性心律失常疗效明显优于单用胺碘酮或美托洛尔,不良反应无增加。%Objective:To investigate the curative effect of metoprolol combined with amiodarone in patients with congestive heart failure and taehyarrhythmia .Methods:A total of 43 NYHA classⅡ-Ⅳpatients with CHF complicated by ventricular arrhythmia were randomly divided into amiodarone group and amiodarone +metoprolol group .The therapeutic effects were evaluated .Results:The clinical effective rate was 90%(18/20)in amiodarone+metoprolol group,while that was 60.87%(14/23)in amiodarone group,the difference was statisti-cally significant(P<0.05).Conclusion:The combination of amiodarone and metoprolol could produce better effect than amiodarone alone in the treatment of CHF complicated by ventricular arrhythmia .

  13. Intracellular pH in sperm physiology.

    Science.gov (United States)

    Nishigaki, Takuya; José, Omar; González-Cota, Ana Laura; Romero, Francisco; Treviño, Claudia L; Darszon, Alberto

    2014-08-01

    Intracellular pH (pHi) regulation is essential for cell function. Notably, several unique sperm ion transporters and enzymes whose elimination causes infertility are either pHi dependent or somehow related to pHi regulation. Amongst them are: CatSper, a Ca(2+) channel; Slo3, a K(+) channel; the sperm-specific Na(+)/H(+) exchanger and the soluble adenylyl cyclase. It is thus clear that pHi regulation is of the utmost importance for sperm physiology. This review briefly summarizes the key components involved in pHi regulation, their characteristics and participation in fundamental sperm functions such as motility, maturation and the acrosome reaction.

  14. A cypovirus VP5 displays the RNA chaperone-like activity that destabilizes RNA helices and accelerates strand annealing.

    Science.gov (United States)

    Yang, Jie; Cheng, Zhenyun; Zhang, Songliu; Xiong, Wei; Xia, Hongjie; Qiu, Yang; Wang, Zhaowei; Wu, Feige; Qin, Cheng-Feng; Yin, Lei; Hu, Yuanyang; Zhou, Xi

    2014-02-01

    For double-stranded RNA (dsRNA) viruses in the family Reoviridae, their inner capsids function as the machinery for viral RNA (vRNA) replication. Unlike other multishelled reoviruses, cypovirus has a single-layered capsid, thereby representing a simplified model for studying vRNA replication of reoviruses. VP5 is one of the three major cypovirus capsid proteins and functions as a clamp protein to stabilize cypovirus capsid. Here, we expressed VP5 from type 5 Helicoverpa armigera cypovirus (HaCPV-5) in a eukaryotic system and determined that this VP5 possesses RNA chaperone-like activity, which destabilizes RNA helices and accelerates strand annealing independent of ATP. Our further characterization of VP5 revealed that its helix-destabilizing activity is RNA specific, lacks directionality and could be inhibited by divalent ions, such as Mg(2+), Mn(2+), Ca(2+) or Zn(2+), to varying degrees. Furthermore, we found that HaCPV-5 VP5 facilitates the replication initiation of an alternative polymerase (i.e. reverse transcriptase) through a panhandle-structured RNA template, which mimics the 5'-3' cyclization of cypoviral positive-stranded RNA. Given that the replication of negative-stranded vRNA on the positive-stranded vRNA template necessitates the dissociation of the 5'-3' panhandle, the RNA chaperone activity of VP5 may play a direct role in the initiation of reoviral dsRNA synthesis.

  15. A cellular model of memory reconsolidation involves reactivation-induced destabilization and restabilization at the sensorimotor synapse in Aplysia.

    Science.gov (United States)

    Lee, Sue-Hyun; Kwak, Chuljung; Shim, Jaehoon; Kim, Jung-Eun; Choi, Sun-Lim; Kim, Hyoung F; Jang, Deok-Jin; Lee, Jin-A; Lee, Kyungmin; Lee, Chi-Hoon; Lee, Young-Don; Miniaci, Maria Concetta; Bailey, Craig H; Kandel, Eric R; Kaang, Bong-Kiun

    2012-08-28

    The memory reconsolidation hypothesis suggests that a memory trace becomes labile after retrieval and needs to be reconsolidated before it can be stabilized. However, it is unclear from earlier studies whether the same synapses involved in encoding the memory trace are those that are destabilized and restabilized after the synaptic reactivation that accompanies memory retrieval, or whether new and different synapses are recruited. To address this issue, we studied a simple nonassociative form of memory, long-term sensitization of the gill- and siphon-withdrawal reflex in Aplysia, and its cellular analog, long-term facilitation at the sensory-to-motor neuron synapse. We found that after memory retrieval, behavioral long-term sensitization in Aplysia becomes labile via ubiquitin/proteasome-dependent protein degradation and is reconsolidated by means of de novo protein synthesis. In parallel, we found that on the cellular level, long-term facilitation at the sensory-to-motor neuron synapse that mediates long-term sensitization is also destabilized by protein degradation and is restabilized by protein synthesis after synaptic reactivation, a procedure that parallels memory retrieval or retraining evident on the behavioral level. These results provide direct evidence that the same synapses that store the long-term memory trace encoded by changes in the strength of synaptic connections critical for sensitization are disrupted and reconstructed after signal retrieval.

  16. Dimethyl Sulfoxide Induced Destabilization and Disassembly of Various Structural Variants of Insulin Fibrils Monitored by Vibrational Circular Dichroism.

    Science.gov (United States)

    Zhang, Ge; Babenko, Viktoria; Dzwolak, Wojciech; Keiderling, Timothy A

    2015-12-15

    Dimethyl sulfoxide (DMSO) induced destabilization of insulin fibrils has been previously studied by Fourier transform infrared spectroscopy and interpreted in terms of secondary structural changes. The variation of this process for fibrils with different types of higher-order morphological structures remained unclear. Here, we utilize vibrational circular dichroism (VCD), which has been reported to provide a useful biophysical probe of the supramolecular chirality of amyloid fibrils, to characterize changes in the macroscopic chirality following DMSO-induced disassembly for two types of insulin fibrils formed under different conditions, at different reduced pH values with and without added salt and agitation. We confirm that very high concentrations of DMSO can disaggregate both types of insulin fibrils, which initially maintained a β-sheet conformation and eventually changed their secondary structure to a disordered form. The two types responded to varying concentrations of DMSO, and disaggregation followed different mechanisms. Interconversion of specific insulin fibril morphological types also occurred during the destabilization process as monitored by VCD. With transmission electron microscopy, we were able to correlate the changes in VCD sign patterns to alteration of morphology of the insulin fibrils.

  17. Gene Therapy for HIV Infections: Intracellular Immunization

    Directory of Open Access Journals (Sweden)

    Alain Piché

    1999-01-01

    Full Text Available Despite significant advances in the treatment of human immunodeficiency virus (HIV infection in the past 10 years, it remains an incurable disease. The inability of traditional drug-based therapies to inhibit HIV replication effectively for extended periods of time has stimulated intense research to develop novel approaches for this disease. Current understanding of HIV molecular biology and pathogenesis has opened the way for the development of gene therapy strategies for HIV infections. In this context, a number of intracellular immunization-based strategies have been evaluated, and some of them have reached the stage of phase I/II human clinical trials. These strategies include the use of single-chain antibodies, capsid-targeted viral inactivation, transdominant negative mutants, ribozymes, antisense oligonucleotides and RNA decoys. While a number of issues remain to be studied before intracellular immunization can be applied to the treatment of HIV infections, the significant progress already made in this field is likely to lead to clinical applications.

  18. Stochastic models of intracellular calcium signals

    Energy Technology Data Exchange (ETDEWEB)

    Rüdiger, Sten, E-mail: sten.ruediger@physik.hu-berlin.de

    2014-01-10

    Cellular signaling operates in a noisy environment shaped by low molecular concentrations and cellular heterogeneity. For calcium release through intracellular channels–one of the most important cellular signaling mechanisms–feedback by liberated calcium endows fluctuations with critical functions in signal generation and formation. In this review it is first described, under which general conditions the environment makes stochasticity relevant, and which conditions allow approximating or deterministic equations. This analysis provides a framework, in which one can deduce an efficient hybrid description combining stochastic and deterministic evolution laws. Within the hybrid approach, Markov chains model gating of channels, while the concentrations of calcium and calcium binding molecules (buffers) are described by reaction–diffusion equations. The article further focuses on the spatial representation of subcellular calcium domains related to intracellular calcium channels. It presents analysis for single channels and clusters of channels and reviews the effects of buffers on the calcium release. For clustered channels, we discuss the application and validity of coarse-graining as well as approaches based on continuous gating variables (Fokker–Planck and chemical Langevin equations). Comparison with recent experiments substantiates the stochastic and spatial approach, identifies minimal requirements for a realistic modeling, and facilitates an understanding of collective channel behavior. At the end of the review, implications of stochastic and local modeling for the generation and properties of cell-wide release and the integration of calcium dynamics into cellular signaling models are discussed.

  19. Mucolipins: Intracellular TRPML1-3 channels.

    Science.gov (United States)

    Cheng, Xiping; Shen, Dongbiao; Samie, Mohammad; Xu, Haoxing

    2010-05-17

    The mucolipin family of Transient Receptor Potential (TRPML) proteins is predicted to encode ion channels expressed in intracellular endosomes and lysosomes. Loss-of-function mutations of human TRPML1 cause type IV mucolipidosis (ML4), a childhood neurodegenerative disease. Meanwhile, gain-of-function mutations in the mouse TRPML3 result in the varitint-waddler (Va) phenotype with hearing and pigmentation defects. The broad spectrum phenotypes of ML4 and Va appear to result from certain aspects of endosomal/lysosomal dysfunction. Lysosomes, traditionally believed to be the terminal "recycling center" for biological "garbage", are now known to play indispensable roles in intracellular signal transduction and membrane trafficking. Studies employing animal models and cell lines in which TRPML genes have been genetically disrupted or depleted have uncovered roles of TRPMLs in multiple cellular functions including membrane trafficking, signal transduction, and organellar ion homeostasis. Physiological assays of mammalian cell lines in which TRPMLs are heterologously overexpressed have revealed the channel properties of TRPMLs in mediating cation (Ca(2+)/Fe(2+)) efflux from endosomes and lysosomes in response to unidentified cellular cues. This review aims to summarize these recent advances in the TRPML field and to correlate the channel properties of endolysosomal TRPMLs with their biological functions. We will also discuss the potential cellular mechanisms by which TRPML deficiency leads to neurodegeneration.

  20. Mechanisms of cellular invasion by intracellular parasites.

    Science.gov (United States)

    Walker, Dawn M; Oghumu, Steve; Gupta, Gaurav; McGwire, Bradford S; Drew, Mark E; Satoskar, Abhay R

    2014-04-01

    Numerous disease-causing parasites must invade host cells in order to prosper. Collectively, such pathogens are responsible for a staggering amount of human sickness and death throughout the world. Leishmaniasis, Chagas disease, toxoplasmosis, and malaria are neglected diseases and therefore are linked to socio-economical and geographical factors, affecting well-over half the world's population. Such obligate intracellular parasites have co-evolved with humans to establish a complexity of specific molecular parasite-host cell interactions, forming the basis of the parasite's cellular tropism. They make use of such interactions to invade host cells as a means to migrate through various tissues, to evade the host immune system, and to undergo intracellular replication. These cellular migration and invasion events are absolutely essential for the completion of the lifecycles of these parasites and lead to their for disease pathogenesis. This review is an overview of the molecular mechanisms of protozoan parasite invasion of host cells and discussion of therapeutic strategies, which could be developed by targeting these invasion pathways. Specifically, we focus on four species of protozoan parasites Leishmania, Trypanosoma cruzi, Plasmodium, and Toxoplasma, which are responsible for significant morbidity and mortality.

  1. Site-selective probing of cTAR destabilization highlights the necessary plasticity of the HIV-1 nucleocapsid protein to chaperone the first strand transfer

    Science.gov (United States)

    Godet, Julien; Kenfack, Cyril; Przybilla, Frédéric; Richert, Ludovic; Duportail, Guy; Mély, Yves

    2013-01-01

    The HIV-1 nucleocapsid protein (NCp7) is a nucleic acid chaperone required during reverse transcription. During the first strand transfer, NCp7 is thought to destabilize cTAR, the (−)DNA copy of the TAR RNA hairpin, and subsequently direct the TAR/cTAR annealing through the zipping of their destabilized stem ends. To further characterize the destabilizing activity of NCp7, we locally probe the structure and dynamics of cTAR by steady-state and time resolved fluorescence spectroscopy. NC(11–55), a truncated NCp7 version corresponding to its zinc-finger domain, was found to bind all over the sequence and to preferentially destabilize the penultimate double-stranded segment in the lower part of the cTAR stem. This destabilization is achieved through zinc-finger–dependent binding of NC to the G10 and G50 residues. Sequence comparison further revealed that C•A mismatches close to the two G residues were critical for fine tuning the stability of the lower part of the cTAR stem and conferring to G10 and G50 the appropriate mobility and accessibility for specific recognition by NC. Our data also highlight the necessary plasticity of NCp7 to adapt to the sequence and structure variability of cTAR to chaperone its annealing with TAR through a specific pathway. PMID:23511968

  2. Intracellular signaling by diffusion: can waves of hydrogen peroxide transmit intracellular information in plant cells?

    DEFF Research Database (Denmark)

    Vestergaard, Christian L.; Flyvbjerg, Henrik; Møller, Ian Max

    2012-01-01

    Amplitude- and frequency-modulated waves of Ca(2+) ions transmit information inside cells. Reactive Oxygen Species (ROS), specifically hydrogen peroxide, have been proposed to have a similar role in plant cells. We consider the feasibility of such an intracellular communication system in view...

  3. Attenuation of amiodarone induced lung fibrosis and phospholipidosis in hamsters, by treatment with the platelet activating factor receptor antagonist, WEB 2086

    Directory of Open Access Journals (Sweden)

    S. N. Giri

    1993-01-01

    Full Text Available Therapeutic use of amiodarone (AMD, a Class III antiarrhythmic drug is complicated by the development of lung fibrosis (LF and phospholipidosis (PL. In the present study, the effectiveness of a PAF antagonist, WEB 2086, against AMD induced LF and PL has been tested in hamsters. The animals were randomly divided into four groups: (1 saline + H2O; (2 WEB + H2O; (3 saline + AMD; and (4 WEB + AMD. Saline or WEB (10 mg/kg i.p. was given 2 days prior to intratracheal instillation of water or AMD (1.5 μmol/0.25 ml/100 g BW and thereafter daily throughout the study. Twenty-eight days after intratracheal instillation, the animals were killed and the lungs processed for various assays. The amount of lung hydroxyproline, an index of LF, in saline + H2O, WEB + H2O, saline + AMD, and WEB + AMD groups were 959 ± 46, 1035 ± 51, 1605 ± 85 and 1374 ± 69 μg/lung, respectively. Total lung PL, an index of phospholipidosis, in the corresponding groups were 8.4 ± 0.4, 8.3 ± 0.3, 11.7 ± 0.3 and 9.9 μg/lung. Lung malondialdehyde, an index of lipid peroxidation and superoxide dismutase activity in saline + H2O WEB + H2O, saline + AMD, and WEB + AMD were 93.0 ± 4.3, 93.0 ± 2.7, 138.9 ± 6.0 and 109.0 ± 3.8 nmol/lung and 359.7 ± 13.9, 394.0 ± 22.8, 497.5 ± 19.7 and 425.5 ± 4.9 units/lung, respectively. Administration of AMD alone caused significant increases in all the above indexes of lung toxicity, and treatment with WEB 2086 minimized the AMD induced toxicity as reflected by significant decreases in these indexes. Histopathological studies revealed a marked reduction in the extent and severity of lung lesions in the WEB + AMD group compared with the saline + AMD group. Treatment with WEB 2086 also reduced the acute mortality from 35% in saline + AMD group to 22% in WEB + AMD group. It was concluded that PAF is involved in the AMD induced lung fibrosis and phospholipidosis and that the PAF receptor antagonist may, therefore, be potentially useful in

  4. Acquisition of a novel eleven amino acid insertion directly N-terminal to a tetrabasic cleavage site confers intracellular cleavage of an H7N7 influenza virus hemagglutinin

    Energy Technology Data Exchange (ETDEWEB)

    Hamilton, Brian S.; Sun, Xiangjie; Chung, Changik [Department of Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca NY 14853 (United States); New York Center of Excellence for Influenza Research and Surveillance, University of Rochester Medical Center, Rochester NY 14627 (United States); Whittaker, Gary R., E-mail: grw7@cornell.edu [Department of Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca NY 14853 (United States); New York Center of Excellence for Influenza Research and Surveillance, University of Rochester Medical Center, Rochester NY 14627 (United States)

    2012-12-05

    A critical feature of highly pathogenic avian influenza viruses (H5N1 and H7N7) is the efficient intracellular cleavage of the hemagglutinin (HA) protein. H7N7 viruses also exist in equine species, and a unique feature of the equine H7N7 HA is the presence of an eleven amino acid insertion directly N-terminal to a tetrabasic cleavage site. Here, we show that three histidine residues within the unique insertion of the equine H7N7 HA are essential for intracellular cleavage. An asparagine residue within the insertion-derived glycosylation site was also found to be essential for intracellular cleavage. The presence of the histidine residues also appear to be involved in triggering fusion, since mutation of the histidine residues resulted in a destabilizing effect. Importantly, the addition of a tetrabasic site and the eleven amino acid insertion conferred efficient intracellular cleavage to the HA of an H7N3 low pathogenicity avian influenza virus. Our studies show that acquisition of the eleven amino acid insertion offers an alternative mechanism for intracellular cleavage of influenza HA.

  5. Comparison of the efficacy and safety of propafenone and amiodarone in the treatment of paroxysmal supraventricular tachycardia%普罗帕酮和胺碘酮治疗阵发性室上性心动过速疗效与安全性比较

    Institute of Scientific and Technical Information of China (English)

    曾益华; 张世杰; 胡爱民

    2011-01-01

    Objective To evaluate the efficacy and safety of propafenone and amiodarone in the treatment of paroxysmal supraventricular tachycardia(PSVT). Methods Total 86 cases of PSVT were randomly divided into propafenone group and amiodarone group. Propafenone group had intravenously injected 70 mg propafenone. The intravenous injections lasted 5 minutes. Amiodarone group were intravenously infused amiodarone(5-7 mg/kg) (the intravenous infusion lasted 30 minutes). Results The termination rate of PSVT was 93.2% in propafenone group and 88.1% in amiodarone group respectively. Cardioversion time showed as follows: propafenone group(12.4 ±7.8 min) was significantly shorter than amiodarone group (30.7 ± 10.3) min (P < 0.01). Side reaction showed that propafenone group(29.5%) was significantly higher than amiodarone group (11.9%) (P < 0.05). Conclusions The effective cardioversion rates of propafenone and amiodarone in treating PSVT are high in emergency department.Propafenone shows faster effect and higher side effects but better outcome for patients without serious organic heart diseases than Amiodarone which is better for patients with serious organic heart diseases.%目的 比较普罗帕酮和胺碘酮静脉用于急诊转复阵发性室上性心动过速的疗效及不良反应.方法 将急诊阵发性室上性心动过速患者86例完全随机分成普罗帕酮组(44例)和胺碘酮组(42例),普罗帕酮组给予普罗帕酮70 mg静脉注射(5 min注完),若无效,20min后重复1次;胺碘酮组给予胺碘酮5~7 mg/kg加入100 ml 5%葡萄糖或0.9%氯化钠注射液中静脉滴注,30 min滴完,继之以1 mg/min的速度持续静脉滴注.观察2组的治疗效果和不良反应发生情况.结果 普罗帕酮组和胺碘酮组转复有效率分别为93.2%(41/44)和88.1%(37/42)(P>0.05);平均转复时间普罗帕酮组[(12.4±7.8)min]明显短于胺碘酮组[(30.7±10.3)min](P<0.01);不良反应发生率普罗帕酮组为[29.5%(13/44)]明显高

  6. 雷米普利和替米沙坦与胺碘酮联用治疗阵发性心房颤动的临床观察%Clinical observations of ramipril and telmisartan combined with amiodarone in patients with paroxysmal atrial fibrillation

    Institute of Scientific and Technical Information of China (English)

    赵美丽; 刘大钧

    2010-01-01

    目的 探讨雷米普利和替米沙坦与小剂量胺碘酮联用对心功能正常的阵发性心房颤动(房颤)维持窦性心律的长期疗效.方法 将180例阵发性房颤患者完全随机分为胺碘酮组(A组,61例)、胺碘酮+雷米普利组(B组,59例)、胺碘酮+替米沙坦组(C组,60例),随访2年,比较3组治疗后6、12、18、24个月的窦性心律维持率以及治疗前、后的左心房内径.结果 治疗12个月后,A组左心房内径大于B、C组(P<0.05),A组窦性心律维持率明显低于B、C组(P<0.05).试验终点时,A组的窦性心律维持率为58.62%,B组为77.78%,C组为78.57%(P<0.05).结论 胺碘酮分别与雷米普利和替米沙坦配伍治疗阵发性房颤维持窦性心律具有相同的疗效,但优于单用胺碘酮,并能抑制左心房的扩大.%Objective To evaluate the clinical efficacy of ramipril and telmisartan combined with amioda-rone on maintenance of sinus rhythm in patients with idiopathic paroxysmal atrial fibrillation(PAF). Methods One hundred and eighty patients with idiopathic PAF were included in the study and randomly divided into three groups: group A (Amiodarone group, n=61) was treated with amiodarone alone; group B (Amiodarone plus Ramipril, n=59) was treated with amiodarone combined with Ramipril;group C(Amiodarone plus telmisartan group,n=60)was trea-ted with amiodarone combined with telmisartan. The left atrial diameter(LAD) was measured with transthoracic echo-cardiogram before and 6,12,18 and 24 month after treatment. The follow-up was up to 2 years and the primary end point of the study was the first recurrence of AF. Results During the 6 months follow-up, there was no difference in LAD among three groups. After 12 months, LAD in group A was significantly larger than that in group B and group C(P<0.05). At the end of 12 months, the sinus rhythm maintenance of group A was lower significantly than that of group B and group C. At the end of the study, the maintenance of sinus rhythm in

  7. Estudo prospectivo dos efeitos da amiodarona na função tiroidiana de pacientes chagásicos em área de deficiência de iodo Prospective study of amiodarone effects on thyroid function of chagasic patients in an iodine deficient area

    Directory of Open Access Journals (Sweden)

    Maria Aparecida Enes de Barros

    1994-09-01

    Full Text Available Com o objetivo de avaliar a junção tiroidiana após uso crônico da amiodarona, em área de deficiência de iodo e endemia chagásica, 24 pacientes foram analisados antes e após três e nove meses de uso da droga. A avaliação constou de exame clínico, dosagem sérica de T4, T3, rT3, TSH, anticorpo antitiroglobulina e TSH 30 minutos após infusão venosa de uma ampola de 200µg de TRH. A captação do iodo radioativo 131 e a cintilografia datiróide foram realizadas antes e aos 9 meses após tratamento. Disfunção tiroidiana ocorreu em 20,8% dos pacientes sendo 12,5% de hipertiroidismo e 8,3% de hipotiroidismo, com anticorpos antitiroglobulina negativos. Captação do iodo radioativo 131 foi positiva em um paciente hipertiroideo com bócio. O diagnóstico de hipertiroidismo foi melhor evidenciado pela resposta reduzida ou bloqueada do TSH ao TRH e não pela concentração do T3 no soro e o de hipotiroidismo pela concentração elevada do TSH. O TSH elevado desde o início do tratamento pode predispor ao aparecimento de bócio. Concluímos que o uso da amiodarona em nossa região deve serjudiciosamente analisado, sendo a função tiroidiana cuidadosamente monitorizada antes e durante o tratamento.In order to evaluate the development of thyroid dysfunction during chronic amiodarone treatment in an area deficient in iodine and endemic for Chagas 'disease, a group of 24patients wasprospectively studied. Clinical examination and measurement of serum T4, T3, rT3, TSH and antithyroglobulin antibodies were performed before and at 3 and 9 months of use of amiodarone. A TSH response 30 minutes after IV injection of 200µg of TRH was also compared to TSH basal levels before and during amiodarone treatment. Thyroid radioative uptake and scan were obtained before and nine months after amiodarone was started. Elevated rT3 concentrations were unexpectedly found in two thirds of the patients before treatment. Thyroid dysfunction developed during

  8. [Measurement of intracellular pH].

    Science.gov (United States)

    Hanaoka, K; Imai, M; Yoshitomi, K

    1992-09-01

    Since various cellular processes depend on changes in pH, the regulation of intracellular pH (pHi) is important both for the individual cell and for the organism. The mechanisms of the regulation of pHi can be investigated by monitoring pHi. In this report, we discuss the four major techniques available for measuring pHi, which are 1) Distribution of weak acids and bases, 2) pH-sensitive microelectrodes, 3) pH-sensitive dyes, and 4) Nuclear magnetic resonance. Among four techniques, the advantage of the microelectrode approach is that it can monitor membrane potential at the same time and be applied to a single cell. The dye technique is a relative new developing technique, which has lots of advantages. It is easy to use, and is capable of monitoring rapid pHi changes, and being applied to a smaller cell, or a single cell.

  9. Cytoskeletal network morphology regulates intracellular transport dynamics

    CERN Document Server

    Ando, David; Huang, Kerwyn Casey; Gopinathan, Ajay

    2016-01-01

    Intracellular transport is essential for maintaining proper cellular function in most eukaryotic cells, with perturbations in active transport resulting in several types of disease. Efficient delivery of critical cargos to specific locations is accomplished through a combination of passive diffusion and active transport by molecular motors that ballistically move along a network of cytoskeletal filaments. Although motor-based transport is known to be necessary to overcome cytoplasmic crowding and the limited range of diffusion within reasonable time scales, the topological features of the cytoskeletal network that regulate transport efficiency and robustness have not been established. Using a continuum diffusion model, we observed that the time required for cellular transport was minimized when the network was localized near the nucleus. In simulations that explicitly incorporated network spatial architectures, total filament mass was the primary driver of network transit times. However, filament traps that r...

  10. 胺碘酮联合磷酸肌酸钠对心肺复苏后心肌的保护作用%Protective effects of amiodarone combined with creatine phosphate sodium on myocardium after cardiopulmonary resuscitation in rabbits

    Institute of Scientific and Technical Information of China (English)

    王芳; 周雨; 许铁

    2013-01-01

    目的 研究胺碘酮联合磷酸肌酸钠对兔心肺复苏(CPR)后心肌的保护作用.方法 用窒息法制作CPR模型.选取健康日本长耳大白兔40只,随机分为A组(假手术组)、B组(生理盐水组)、C组(胺碘酮组)、D组(磷酸肌酸钠组)、E组(胺碘酮联合磷酸肌酸钠组),每组8只,动态监测HR、MAP及血浆CK、CK-MB含量.复苏后6 h处死兔,光镜下观察心肌组织病理学变化.结果 B组、C组、D组和E组兔的HR、MAP比较差异无统计学意义(P>0.05).与A组比较,CPR后B组、C组、D组和E组兔血浆CK、CK-MB含量均增高,差异有统计学意义(P 0.05). Compared with group A, the levels of plasma CK, CK - MB were significantly higher in group B, group C, group D and group E after CPR (P 0.05). In group B, group C, group D and group E, the levels of plasma CK, CK - MB increased gradually after CPR( P < 0. 05 ). Correlation analysis showed that there was significantly postitive relation between the levels of plasma CK, CK - MB and the time after CPR in group B, group C, group D and group E (P < 0. 05 ) . Results of pathology showed that myocardial injury were more seriously in group B than in group C and group D, and myocardial injury were more seriously in group C and group D than in group E. Conclusion Treatment with amiodarone, creatine phosphate sodium, amiodarone combined with creatine phosphate sodium can alleviate myocardial injury after CPR in rabbits, the protective effects of amiodarone combined with creatine phosphate sodium were the best.

  11. A tomografia computadorizada de alta resolução na avaliação da toxicidade pulmonar por amiodarona High-resolution computed tomography of amiodarone pulmonary toxicity

    Directory of Open Access Journals (Sweden)

    Daniela Peixoto Consídera

    2006-04-01

    Full Text Available OBJETIVO: Avaliar as principais alterações identificadas na tomografia computadorizada de alta resolução do tórax em pacientes com toxicidade pulmonar pela amiodarona. MATERIAIS E MÉTODOS: Foram avaliadas dez tomografias computadorizadas de alta resolução de tórax de pacientes com pneumonite pela amiodarona, seis desses pacientes do sexo masculino e quatro do sexo feminino, com idade média de 73,5 anos. RESULTADOS: Os achados tomográficos mais relevantes foram opacidades lineares ou reticulares em seis casos (60%, pequenos nódulos com densidade elevada em seis casos (60%, consolidações densas em três casos (30% e aumento da densidade do parênquima hepático em cinco de oito casos em que havia estudo tomográfico do abdome superior (62,5%. CONCLUSÃO: A tomografia computadorizada de alta resolução é um exame importante na avaliação de pacientes com toxicidade pulmonar pela amiodarona, devendo ser realizada sempre que houver suspeita deste diagnóstico. O achado de espessamento de septos interlobulares associado a lesões com aumento de densidade é altamente sugestivo deste diagnóstico.OBJECTIVE: To evaluate the main findings of chest high-resolution computed tomography in patients with amiodarone pulmonary toxicity. MATERIALS AND METHODS: Ten patients - six male and four female, average age of 73.5 years - with amiodarone-induced pneumonitis have undergone chest high-resolution computed tomography. RESULTS: The most relevant tomographic findings were linear or reticular opacities in six cases (60%, small high density nodules in six cases (60%, dense consolidations in three cases (30% and increased density in the hepatic parenchyma in five of eight cases in which there was a superior abdomen CT scan (62.5%. CONCLUSION: The high-resolution computed tomography is a valuable non-invasive test for evaluating patients with amiodarone pulmonary toxicity and should always be performed when one suspects of the presence of this

  12. Mechanistic modeling of fingering, nonmonotonicity, fragmentation, and pulsation within gravity/buoyant destabilized two-phase/unsaturated flow

    Science.gov (United States)

    Glass, Robert J.; Yarrington, Lane

    2003-03-01

    Fingering, nonmonotonicity, fragmentation, and pulsation within gravity/buoyant destabilized two-phase/unsaturated flow systems has been widely observed with examples in homogeneous to heterogeneous porous media, in single fractures to fracture networks, and for both wetting and nonwetting invasion. To model this phenomena, we consider a mechanistic approach based on forms of modified invasion percolation (MIP) that include gravity, the influence of the local interfacial curvature along the phase-phase interface, and the simultaneous invasion and reinvasion of both wetting and nonwetting fluids. We present example simulations and compare them to experimental data for three very different situations: (1) downward gravity-driven fingering of water into a dry, homogeneous, water-wettable, porous medium; (2) upward buoyancy-driven migration of gas within a water saturated, heterogeneous, water-wettable, porous medium; and (3) downward gravity-driven fingering of water into a dry, water-wettable, rough-walled fracture.

  13. On resonant destabilization of toroidal Alfven eigenmodes by circulating and trapped energetic ions/alpha particles in tokamaks

    Energy Technology Data Exchange (ETDEWEB)

    Biglari, H.; Zonca, F.; Chen, L.

    1991-10-01

    Toroidal Alfven eigenmodes are shown to be resonantly destabilized by both circulating and trapped energetic ions/alpha particles. In particular, the energetic circulating ions are shown to resonate with the mode not only at the Alfven speed ({upsilon}{sub A}), but also one-third of this speed, while resonances exist between trapped energetic ions and the wave when {upsilon} = {upsilon}{sub A}/21{epsilon}{sup {1/2}} (l=integer, {epsilon}=r/R is the local inverse aspect ratio), although the instability becomes weaker for resonances other than the fundamental. The oft-quoted criterion that instability requires super-Alfvenic ion velocities is thus sufficient but not necessary. 14 refs.

  14. Geomorphic consequences of two large glacier and rock glacier destabilizations in the Central and northern Chilean Andes

    Science.gov (United States)

    Iribarren Anacona, Pablo; Bodin, Xavier

    2010-05-01

    Mountain areas are occasionaly affected by complex mass movements of high magnitude and large extent, which generally involve water, snow, rock and ice in variable proportions. Those events can take the form of rock avalanche, landslide, debris flow, glacier collapse or a combination of these phenomenons. In the Central Andes of Chile, they affect hardly accessible regions with low population, explaining the scarcity of previous studies. Nevertheless, during the last 30 years, some documented examples of such events in this region have shown that the volume of material involved is in the order of several millions of m³, the areas affected can reach several tenth of km² and the velocity of the movement can exceed several tenths of m/s. In this context, this study intends i) to inventory and to describe the main characteristics of events previously documented in the Central Andes of Chile, and ii) analyse in detail two recent events (2005-2007) never described before which have affected in one case a glacier and in another case a rock glacier. With the objectives of determining the possible chain of triggering factors and interpreting the event's significance in terms of geomorphic, cryogenic and climatic dynamics, we used air photographs, satellite imagery (Landsat TM & ETM+; Quick Bird when available in Google Earth 5.0), data from the closest meteorological stations, glacier mass balance data and seismic records to investigate the collapse of a rock glacier occurred in 2006 on the west-facing flank of the Cerro Las Tórtolas (6160 m asl; 29°58' S. - 69°55' W.), in the arid North of Chile, and the collapse of a glacier that occurred during austral summer 2006-2007 on the South side of the Tinguiririca Volcano (4075 m asl; 34°48' S. - 70°21' W.). The rock glacier collapse of the Cerro Las Tórtolas West flank occurred during the spring of 2006, but signs of destabilization were already observable since the end of 2005. The deposit of the collapsed mass of the

  15. Traffic jams II: an update of diseases of intracellular transport.

    Science.gov (United States)

    Aridor, Meir; Hannan, Lisa A

    2002-11-01

    As more details emerge on the mechanisms that mediate and control intracellular transport, the molecular basis for variety of human diseases has been revealed. In turn, disease pathology and physiology shed light on the intricate controls that regulate intracellular transport to assure proper cellular and tissue function and homeostasis. We previously listed a number of diseases that are the result of defects in intracellular transport, or cause defects in intracellular transport. (Aridor M, Hannan LA. Traffic Jam: A compendium of human diseases that affect intracellular transport processes. Traffic 2000; 1: 836-851). This Toolbox updates the previous list to include additional disorders that were recently identified to be related to intracellular trafficking. In the time since we have published our first list there have been significant advances in understanding of the molecular basis of these defects. Such advances will pave the way to future effective therapeutics.

  16. The MitCHAP-60 disease is due to entropic destabilization of the human mitochondrial Hsp60 oligomer.

    Science.gov (United States)

    Parnas, Avital; Nadler, Michal; Nisemblat, Shahar; Horovitz, Amnon; Mandel, Hanna; Azem, Abdussalam

    2009-10-01

    The 60-kDa heat shock protein (mHsp60) is a vital cellular complex that mediates the folding of many of the mitochondrial proteins. Its function is executed in cooperation with the co-chaperonin, mHsp10, and requires ATP. Recently, the discovery of a new mHsp60-associated neurodegenerative disorder, MitCHAP-60 disease, has been reported. The disease is caused by a point mutation at position 3 (D3G) of the mature mitochondrial Hsp60 protein, which renders it unable to complement the deletion of the homologous bacterial protein in Escherichia coli (Magen, D., Georgopoulos, C., Bross, P., Ang, D., Segev, Y., Goldsher, D., Nemirovski, A., Shahar, E., Ravid, S., Luder, A., Heno, B., Gershoni-Baruch, R., Skorecki, K., and Mandel, H. (2008) Am. J. Hum. Genet. 83, 30-42). The molecular basis of the MitCHAP-60 disease is still unknown. In this study, we present an in vitro structural and functional analysis of the purified wild-type human mHsp60 and the MitCHAP-60 mutant. We show that the D3G mutation leads to destabilization of the mHsp60 oligomer and causes its disassembly at low protein concentrations. We also show that the mutant protein has impaired protein folding and ATPase activities. An additional mutant that lacks the first three amino acids (N-del), including Asp-3, is similarly impaired in refolding activity. Surprisingly, however, this mutant exhibits profound stabilization of its oligomeric structure. These results suggest that the D3G mutation leads to entropic destabilization of the mHsp60 oligomer, which severely impairs its chaperone function, thereby causing the disease.

  17. Thermodynamic Destabilization of Ti-O Solid Solution by H2 and Deoxygenation of Ti Using Mg.

    Science.gov (United States)

    Zhang, Ying; Fang, Zhigang Zak; Sun, Pei; Zhang, Tuoyang; Xia, Yang; Zhou, Chengshang; Huang, Zhe

    2016-06-08

    Reactive metals including Ti, Zr, Hf, and V, among others, have a strong chemical affinity to oxygen, which makes them difficult to produce and costly to use. It is especially challenging to produce pure or metal alloy powders of these elements when extremely low oxygen content is required, because they have high solubility for oxygen, and the solid solution of these metals with oxygen is often more stable thermodynamically than their oxides. We report a novel thermochemical approach to destabilize Ti(O) solid solutions using hydrogen, thus enabling deoxygenation of Ti powder using Mg, which has not been possible before because of the thermodynamic stability of Ti(O) solid solutions relative to MgO. The work on Ti serves as an example for other reactive metals. Both analytical modeling and experimental results show that hydrogen can indeed increase the oxygen potential of Ti-O solid solution alloys; in other words, the stability of Ti-O solid solutions is effectively decreased, thus increasing the thermodynamic driving force for Mg to react with oxygen in Ti. Because hydrogen can be easily removed from Ti by a simple heat treatment, it is used only as a temporary alloying element to destabilize the Ti-O systems. The thermodynamic approach described here is a breakthrough and is applicable to a range of different materials. This work is expected to provide an enabling solution to overcome one of the key scientific and technological hurdles to the additive manufacturing of metals, which is emerging rapidly as the future of the manufacturing industry.

  18. Intracellular Environment-Responsive Stabilization of Polymer Vesicles Formed from Head-Tail Type Polycations Composed of a Polyamidoamine Dendron and Poly(L-lysine

    Directory of Open Access Journals (Sweden)

    Kenji Kono

    2013-09-01

    Full Text Available For the development of effective drug carriers, nanocapsules that respond to micro-environmental changes including a decrease in pH and a reductive environment were prepared by the stabilization of polymer vesicles formed from head-tail type polycations, composed of a polyamidoamine dendron head and a poly(L-lysine tail (PAMAM dendron-PLL, through the introduction of disulfide bonds between the PLL tails. Disulfide bonds were successfully introduced through the reaction of Lys residues in the PAMAM dendron-PLL polymer vesicles with 2-iminothiolane. The stabilization of PAMAM dendron-PLL polymer vesicles was confirmed by dynamic light scattering measurements. In acid-base titration experiments, nanocapsules cross-linked by disulfide bonds had a buffering effect during the cellular uptake process. The PAMAM dendron-PLL nanocapsules were used to incorporate the fluorescent dyes rhodamine 6G and fluorescein as a drug model. Cationic rhodamine 6G was generally not released from the nanocapsules because of the electrostatic barrier of the PLL membrane. However, the nanocapsules were destabilized at high glutathione concentrations corresponding to intracellular concentrations. Rhodamine 6G was immediately released from the nanocapsules because of destabilization upon the cleavage of disulfide bonds. This release of rhodamine 6G from the nanocapsules was also observed in HeLa cells by laser confocal microscopy.

  19. 文献对胺碘酮、利多卡因治疗阵发性室性心动过速预后差异的Meta分析%Research Document of Amiodarone, Lidocaine Treatment of Paroxysmal Supraventricular Tachycardia Meta-analysis of Differences in Prognosis

    Institute of Scientific and Technical Information of China (English)

    陈阵; 刘亚凤; 胡念丹; 苏薇薇; 李文强

    2012-01-01

    目的 评价相关文献中关于使用胺碘酮和利多卡因治疗阵发性室性心动过速(paroxysmal ventricular tachycardia,PVT)的预后差异.方法 检索Cochrane图书馆、EMbase、Pubmed及Medline 1996~ 2011年中采用随机对照试验(RCT)中关于使用胺碘酮、利多卡因治疗PVT预后差异的文献,对纳入文献质量进行评价和资料提取,并进行Meta分析.结果 本研究共纳入5篇文献,均表明使用胺碘酮治疗PVT较利多卡因预后好,差异有统计学意义(P<0.05);两药治疗PVT在复律失败人数、死亡人数、药物不良反应等方面比较差异均有统计学意义(P<0.05).结论 使用胺碘酮治疗PVT可降低患者住院次数,且未增加不良反应,故当PVT症状不严重时,胺碘酮可作为治疗的首选.%Objective To evaluate the pertinent literature of amiodarone, lidocaine treatment in the prognosis of paroxysmal ventricular tachycardia ( PVT). Methods The papers from Cochrane Library, EM base, Pubmed were searched, Medline for RCT of paroxysmal ventricular tachycardia treatment using amiodarone or lidocaine was randomly evalvated, an assessment for the methodology after screening and selecting all the papers with the help of the software of Review manager 5.0 was made, and Meta analysis was conducted. Results A total of 5 literatures were included, all of which results showed that amiodarone had a better prognosis than lidocaine, and the difference was significant (P < 0.05 ) ; the number of successful cardio version, adverse reactions and the number of deaths related to the RCT docamented significant differences between the Amiodarone and Lidocaine treatment of PVT (P <0.05). Conclusion The use of PVT Amiodarone treatment can reduce the rate of hospitalization, without increasing the incidence rate of other adverse reactions. Therefore, in minor cases of PVT, Amiodarone can be the preferred treatment method.

  20. Intracellular signaling by diffusion: can waves of hydrogen peroxide transmit intracellular information in plant cells?

    DEFF Research Database (Denmark)

    Vestergaard, Christian L.; Flyvbjerg, Henrik; Møller, Ian Max

    2012-01-01

    Amplitude- and frequency-modulated waves of Ca(2+) ions transmit information inside cells. Reactive Oxygen Species (ROS), specifically hydrogen peroxide, have been proposed to have a similar role in plant cells. We consider the feasibility of such an intracellular communication system in view...... of the physical and biochemical conditions in plant cells. As model system, we use a H(2)O(2) signal originating at the plasma membrane (PM) and spreading through the cytosol. We consider two maximally simple types of signals, isolated pulses and harmonic oscillations. First we consider the basic limits...... which diffusion-mediated signaling is possible. We show that purely diffusive transmission of intracellular information by H(2)O(2) over a distance of 1 μm (typical distance between organelles, which may function as relay stations) is possible at frequencies well above 1 Hz, which is the highest...

  1. Intracellular signaling by diffusion: can waves of hydrogen peroxide transmit intracellular information in plant cells?

    DEFF Research Database (Denmark)

    Vestergaard, Christian Lyngby; Flyvbjerg, Henrik; Møller, Ian Max

    2012-01-01

    Amplitude- and frequency-modulated waves of Ca2+ ions transmit information inside cells. Reactive Oxygen Species (ROS), specifically hydrogen peroxide, have been proposed to have a similar role in plant cells. We consider the feasibility of such an intracellular communication system in view...... of the physical and biochemical conditions in plant cells. As model system, we use a H2O2 signal originating at the plasma membrane (PM) and spreading through the cytosol. We consider two maximally simple types of signals, isolated pulses and harmonic oscillations. First we consider the basic limits...... diffusion-mediated signaling is possible. We show that purely diffusive transmission of intracellular information by H2O2 over a distance of 1 μm (typical distance between organelles, which may function as relay stations) is possible at frequencies well above 1 Hz, which is the highest frequency observed...

  2. Strategies of Intracellular Pathogens for Obtaining Iron from the Environment

    Directory of Open Access Journals (Sweden)

    Nidia Leon-Sicairos

    2015-01-01

    Full Text Available Most microorganisms are destroyed by the host tissues through processes that usually involve phagocytosis and lysosomal disruption. However, some organisms, called intracellular pathogens, are capable of avoiding destruction by growing inside macrophages or other cells. During infection with intracellular pathogenic microorganisms, the element iron is required by both the host cell and the pathogen that inhabits the host cell. This minireview focuses on how intracellular pathogens use multiple strategies to obtain nutritional iron from the intracellular environment in order to use this element for replication. Additionally, the implications of these mechanisms for iron acquisition in the pathogen-host relationship are discussed.

  3. Comparison on Effect of Amiodarone and Propafenone Treating Paroxysmal Supraventricular Tachycardia%胺碘酮和普罗帕酮治疗阵发性室上性心动过速的效果比较

    Institute of Scientific and Technical Information of China (English)

    赵敏

    2014-01-01

    目的:比较胺碘酮和普罗帕酮治疗阵发性室上性心动过速的疗效。方法将88例阵发性室上性心动过速患者随机分为两组,A 组44例患者给予胺碘酮治疗,B 组44例患者给予普罗帕酮治疗。结果两组复律成功率比较,差异无统计学意义(P >0.05);A 组复律时间长于 B 组,复律时间分布较 B 组差,不良反应发生率低于 B 组,差异均有统计学意义(P <0.05)。结论胺碘酮和普罗帕酮对阵发性室上性心动过速的治疗各有利弊,普罗帕酮见效快、患者耐受差,适用于无严重器质性心脏病及心功能正常者;而胺碘酮见效较慢、不良反应少、适应证广,适用于器质性心脏病及心功能不全患者。%Objective To compare the efficacy of amiodarone and propafenone treating paroxysmal supraventricular tachycardia. Methods 88 cases with paroxysmal supraventricular tachycardia were selected and divided into two groups randomly. The A group for 44 cases were treated with amiodarone, and the B group for 44 cases were treated with propafenone. Results The difference for the successful rate of cardioversion between two groups had no statistical significance(P>0.05). The cardioversion time of A group was longer than that of B group, and the cardioversion time distribution of A group was worse than that of B group, the incidence rate of adverse reactions in A group was lower than that of B group ,which had statistical significance (P<0.05). Conclusion Propafenone and propafenone treating paroxysmal supraventricular tachycardia has advantages and disadvantages. Amiodarone has the advantages that the effect is fast, the patients have poor tolerance and it is applied to the patients with normal cardiac function and without organic heart disease, and amiodarone has the advantages that the effect is slow, there are few adverse reactions, there are wide range of indications, and it is applied to patients with organic heart disease

  4. 胺碘酮对冠心病心律失常心率变异性的影响%Influnce of amiodarone on coronary heart arrhythmia heart rate variability

    Institute of Scientific and Technical Information of China (English)

    贺桂彬

    2012-01-01

    Objective To observe the effect of amiodarone on clinical treatment of coronary heart disease,analysis of the drug on arrhythmia heart rate variability. Methods From May 2009 to October 2010 our hospital 80 patients with coronary heart arrhythmia patients were randomly divided into treatment group (40 cases) and control group (40 cases) ,the expansion of the control group with conventional coronary artery and anti - arrhythmic drugs,while the experimental group was given amiodarone weekly decline. The two groups were compared the efficiency of treatment and related indicators of the efficacy of amiodarone in the treatment of coronary heart disease arrhythmias. Results The treatment rate was 80% ,higher than 65% ,respectively,compared with a statistically significant difference ( P < 0.01). Two groups of patients did not occur during treatment reduced heart function,liver function abnormalities,interstitial pneumonia,thyroid dysfunction and nerve,cornea and other adverse reactions. Conclusions Amiodarone in patients with coronary heart arrhythmia efficacy,low cost,convenient route of administration,security,it is worth promoting and applications.%目的 观察胺碘酮对冠心病的临床治疗作用,分析该药对心律失常心率变异性的影响.方法 收取2009年5月至2010年10月本院治疗的80例冠心病心率失常患者,按照随机原则分为治疗组(40例)和对照组(40例),对照组采用常规扩张冠状动脉和抗心律失常药物,而实验组则每周递减给予胺碘酮治疗.比较两组患者的治疗有效率及相关指标,探讨胺碘酮治疗冠心病心律失常的疗效.结果 治疗组的治疗有效率为80%,高于对照组的65%,两组相比具有明显统计学差异(P<0.01).两组患者在治疗过程中未发生心功能减低、肝功能异常、间质性肺炎、甲状腺功能异常及神经、眼角膜等不良反应.结论 胺碘酮对冠心病心律失常的患者疗效明显,价格低廉,用药途径方便

  5. The microtubule destabilizing protein stathmin controls the transition from dividing neuronal precursors to postmitotic neurons during adult hippocampal neurogenesis

    NARCIS (Netherlands)

    Boekhoorn, K.; van Dis, V.; Goedknegt, E.; Sobel, A.; Lucassen, P.J.; Hoogenraad, C.C.

    2014-01-01

    The hippocampus is one of the two areas in the mammalian brain where adult neurogenesis occurs. Adult neurogenesis is well known to be involved in hippocampal physiological functions as well as pathophysiological conditions. Microtubules (MTs), providing intracellular transport, stability, and trans

  6. Clinical Analysis of Emergency Application of Amiodarone in Acute Myocardial Infarction Patients with Malignant Ventricular Arrhythmia%急性心肌梗死伴恶性室性心律失常急诊胺碘酮的应用

    Institute of Scientific and Technical Information of China (English)

    杨华; 王月权; 李宁

    2015-01-01

    39 cases of acute myocardial infarction (AMI) with malignant ventricular ar hythmia, frequent ventricular premature beat (hereinafter refer ed to as premature ventricular) in 16 cases, 17 cases of ventricular tachycardia (vt), ventricular fibril ation (ventricular fibril ation) 6 cases. Give room early and ventricular tachycardia patients after intravenous amiodarone, rectified ventricular ar hythmia, ventricular fibril ation, 6 cases of patients with first give cardioerter, success in 4 cases, 2 cases after fails to give amiodarone, defibril ation success again. 38 cases of successful rescue, 1 case died of brain death. Rescue winners are transfer ed to medical ward for treatment.%39例急性心肌梗死(AMI)伴恶性室性心律失常,频发室性早搏(简称室早)16例,室性心动过速(简称室速)17例,心室颤动(简称室颤)6例。对室早及室速的患者给予静脉胺碘酮后,室性心律失常得以纠正,对室颤6例患者先给予电复律,4例除颤成功,2例不成功者给予胺碘酮后,再次除颤成功。抢救成功38例,1例死于脑死亡。抢救成功者均转入内科病房治疗。

  7. Duodenal Intracellular Bicarbonate and the 'CF Paradox'

    Directory of Open Access Journals (Sweden)

    Kaunitz JD

    2001-07-01

    Full Text Available HCO(3(- secretion, which is believed to neutralize acid within the mucus gel, is the most studied duodenal defense mechanism. In general, HCO(3(- secretion rate and mucosal injury susceptibility correlate closely. Recent studies suggest that luminal acid can lower intracellular pH (pH(i of duodenal epithelial cells and that HCO(3(- secretion is unchanged during acid stress. Furthermore, peptic ulcers are rare in cystic fibrosis (CF, although, with impaired HCO(3(- secretion, increased ulcer prevalence is predicted, giving rise to the 'CF Paradox'. We thus tested the hypothesis that duodenal epithelial cell protection occurs as the result of pH(i regulation rather than by neutralization of acid by HCO(3(- in the pre-epithelial mucus. Cellular acidification during luminal acid perfusion, and unchanged HCO(3(- secretion during acid stress are inconsistent with pre-epithelial acid neutralization by secreted HCO(3(-. Furthermore, inhibition of HCO(3(- secretion by 5-nitro-2-(3-phenylpropylamino benzoic acid (NPPB despite preservation of pH(i and protection from acid-induced injury further question the pre-epithelial acid neutralization hypothesis. This decoupling of HCO(3(- secretion and injury susceptibility by NPPB (and possibly by CF further suggest that cellular buffering, rather than HCO(3(- exit into the mucus, is of primary importance for duodenal mucosal protection, and may account for the lack of peptic ulceration in CF patients.

  8. Intracellular Signals of T Cell Costimulation

    Institute of Scientific and Technical Information of China (English)

    Jianxun Song; Fengyang Tylan Lei; Xiaofang Xiong; Rizwanul Haque

    2008-01-01

    Ligation of T cell receptor (TCR) alone is insufficient to induce full activation of T lymphocytes. Additional ligand-receptor interactions (costimulation) on antigen presenting cells (APCs) and T cells are required. T cell costimulation has been shown to be essential for eliciting efficient T cell responses, involving all phases during T cell development. However, the mechanisms by which costimulation affects the function of T cells still need to be elucidated. In recent years, advances have been made in studies of costimulation as potential therapies in cancer, infectious disease as well as autoimmune disease. In this review, we discussed intracellular costimulation signals that regulate T cell proliferation, cell cycle progression, cytokine production, survival, and memory development. In general, the pathway of phosphoinositide-3 kinase (PBK)/protein kinase B (PKB, also known as Akt)/nuclear factor κB (NF-κB) might be central to many costimulatory effects. Through these pathways, costimulation controls T-cell expansion and proliferation by maintenance of survivin and aurora B expression, and sustains long-term T-cell survival and memory development by regulating the expression of bci-2 family members. Cellular & Molecular Immunology.2008;5(4):239-247.

  9. On the Computing Potential of Intracellular Vesicles.

    Science.gov (United States)

    Mayne, Richard; Adamatzky, Andrew

    2015-01-01

    Collision-based computing (CBC) is a form of unconventional computing in which travelling localisations represent data and conditional routing of signals determines the output state; collisions between localisations represent logical operations. We investigated patterns of Ca2+-containing vesicle distribution within a live organism, slime mould Physarum polycephalum, with confocal microscopy and observed them colliding regularly. Vesicles travel down cytoskeletal 'circuitry' and their collisions may result in reflection, fusion or annihilation. We demonstrate through experimental observations that naturally-occurring vesicle dynamics may be characterised as a computationally-universal set of Boolean logical operations and present a 'vesicle modification' of the archetypal CBC 'billiard ball model' of computation. We proceed to discuss the viability of intracellular vesicles as an unconventional computing substrate in which we delineate practical considerations for reliable vesicle 'programming' in both in vivo and in vitro vesicle computing architectures and present optimised designs for both single logical gates and combinatorial logic circuits based on cytoskeletal network conformations. The results presented here demonstrate the first characterisation of intracelluar phenomena as collision-based computing and hence the viability of biological substrates for computing.

  10. Catechins and Procyanidins of Ginkgo biloba Show Potent Activities towards the Inhibition of β-Amyloid Peptide Aggregation and Destabilization of Preformed Fibrils

    Directory of Open Access Journals (Sweden)

    Haiyan Xie

    2014-04-01

    Full Text Available Catechins and procyanidins, together with flavonoid glycosides and terpene trilactones, are three important categories of components in the standard extract of Ginkgo biloba leaves (EGb761. In this research, catechins and proanthocyanidins were found to exist in both the extract of Ginkgo leaves and Ginkgo products. By comparing with reference compounds, six of them were identified as (+-catechin, (−-epicatechin, (−-gallocatechin, (−-epigallocatechin and procyanidins B1 and B3. The activities of these polyphenols in the inhibition of Aβ42 aggregation and the destabilization of preformed fibrils were evaluated using biochemical assays, which showed that all six of the polyphenols, as well as a fraction of the extract of Ginkgo biloba leaves (EGb containing catechins and procyanidins, exerted potent inhibitory activities towards Aβ42 aggregation and could also destabilize the performed fibrils. Catechins and procyanidins can therefore be regarded as the potent active constituents of EGb761 in terms of their inhibition of Aβ42 aggregation and destabilization of the fibrils. Although quantitative mass spectroscopic analysis revealed that the catechins and procyanidins are only present in low concentrations in EGb761, these components should be studied in greater detail because of their potent inhibitory effects towards Aβ42 aggregation and their ability to destabilize preformed fibrils, especially during the quality control of Ginkgo leaves and the manufacture of Ginkgo products.

  11. Catechins and procyanidins of Ginkgo biloba show potent activities towards the inhibition of β-amyloid peptide aggregation and destabilization of preformed fibrils.

    Science.gov (United States)

    Xie, Haiyan; Wang, Jing-Rong; Yau, Lee-Fong; Liu, Yong; Liu, Liang; Han, Quan-Bin; Zhao, Zhongzhen; Jiang, Zhi-Hong

    2014-04-22

    Catechins and procyanidins, together with flavonoid glycosides and terpene trilactones, are three important categories of components in the standard extract of Ginkgo biloba leaves (EGb761). In this research, catechins and proanthocyanidins were found to exist in both the extract of Ginkgo leaves and Ginkgo products. By comparing with reference compounds, six of them were identified as (+)-catechin, (-)-epicatechin, (-)-gallocatechin, (-)-epigallocatechin and procyanidins B1 and B3. The activities of these polyphenols in the inhibition of Aβ42 aggregation and the destabilization of preformed fibrils were evaluated using biochemical assays, which showed that all six of the polyphenols, as well as a fraction of the extract of Ginkgo biloba leaves (EGb) containing catechins and procyanidins, exerted potent inhibitory activities towards Aβ42 aggregation and could also destabilize the performed fibrils. Catechins and procyanidins can therefore be regarded as the potent active constituents of EGb761 in terms of their inhibition of Aβ42 aggregation and destabilization of the fibrils. Although quantitative mass spectroscopic analysis revealed that the catechins and procyanidins are only present in low concentrations in EGb761, these components should be studied in greater detail because of their potent inhibitory effects towards Aβ42 aggregation and their ability to destabilize preformed fibrils, especially during the quality control of Ginkgo leaves and the manufacture of Ginkgo products.

  12. Destabilization and fusion of zwitterionic large unilamellar lipid vesicles induced by a beta-type structure of the HIV-1 fusion peptide

    NARCIS (Netherlands)

    Nieva, JL; Nir, S; Wilschut, J

    1998-01-01

    The peptide HIVarg, corresponding to a sequence of 23 amino acid residues at the N-terminus of HIV-1 gp41, has the capacity to induce fusion of large unilamellar vesicles (LUV) consisting of negatively charged or zwitterionic phospholipids. In the present study, we further characterize this destabil

  13. Clinical observation of amiodarone combined with metoprolol intravenous injection in the treatment of tachyarrhythmia%胺碘酮联合美托洛尔静脉注射治疗快速心律失常的临床观察

    Institute of Scientific and Technical Information of China (English)

    周斌

    2016-01-01

    目的:探讨胺碘酮联合美托洛尔治疗快速心律失常的临床效果。方法:收治快速心律失常患者62例,随机分为对照组和试验组,对照组采用胺碘酮治疗,试验组采用胺碘酮联合美托洛尔治疗,比较两组治疗效果。结果:治疗后,试验组的有效率、心率和收缩压均明显优于对照组(P<0.05)。两组不良反应发生率差异无统计学意义(P>0.05)。结论:胺碘酮联合美托洛尔治疗快速心律失常的临床效果显著。%Objective:To explore the clinical effect of amiodarone combined with metoprolol intravenous injection in the treatment of tachyarrhythmia.Methods:62 patients with tachyarrhythmia were selected.They were randomly divided into the control group and the experimental group.The control group was treated with amiodarone,and the experimental group was treated with amiodarone combined with metoprolol.We compared the treatment effect of two groups.Results:After treatment,the effective rate, heart rate and systolic blood pressure of the experimental group were significantly better than those of the control group(P0.05).Conclusion:The clinical effect of amiodarone combined with metoprolol intravenous injection in the treatment of tachyarrhythmia was significant.

  14. Clinical Observation of Amiodarone Combined With Wenxin Granule in the Treatment of Heart Failure Complicated With Arrhythmia%胺碘酮联合稳心颗粒治疗心衰合并心律失常的临床观察

    Institute of Scientific and Technical Information of China (English)

    高尚

    2015-01-01

    Objective To explore the clinical effect of amiodarone combined with Wenxin Granule in the treatment of heart failure complicated with arrhythmia. Methods 80 cases of patients with heart failure combined with arrhythmia were randomly divided into observation group and control group, respectively treated with amiodarone and amiodarone combined with Wenxin Granule treatment. Results Observation of curative effect, the patient's heart rate, QT interval, LVEF improvement was superior to the control group, the incidence of adverse reaction was lower than the control group (P<0.05). Conclusion Amiodarone combined with Wenxin Granule in the treatment of heart failure complicated with arrythmia curative effect, worthy of clinical application.%目的:探讨胺碘酮联合稳心颗粒治疗心衰合并心律失常的临床效果。方法将80例心衰合并心律失常患者随机分为观察组和对照组,分别给予胺碘酮治疗和胺碘酮联合稳心颗粒治疗。结果观察组疗效、患者心率、QT间期、LVEF改善情况均优于对照组,不良反应发生率明显低于对照组(P<0.05)。结论胺碘酮联合稳心颗粒治疗心衰合并心律失常疗效确切,值得临床应用推广。

  15. Clinical Analysis of the Treatment of Arrhythmia in Patients with Coronary Heart Disease Combined with the Stability of the Core Particles and Amiodarone%稳心颗粒联合胺碘酮治疗冠心病心律失常疗效分析

    Institute of Scientific and Technical Information of China (English)

    冯宝连

    2016-01-01

    Objective To observe the metacentre grain joint amiodarone treatment of arrhythmia in coronary heart disease clinical curative effect. Methods From October 2009 to October 2009 treatment of 90 cases of patients with arrhythmia in coronary heart disease, were randomly divided into two groups, treatment group 45 cases, on the basis of conventional treatment of oral metacentric particles and amiodarone; Control group 45 cases, on the basis of conventional treatment taking amiodarone, course of six weeks. Look before and after using patients electrocardiogram (ecg) and the improvement of clinical symptoms. Results The curative effect of treatment group is better than that of control group ( < 0.05). Conclusion metacentric particles joint amiodarone has good curative effect of treatment of coronary heart disease (CHD).%目的观察稳心颗粒联合胺碘酮治疗冠心病心律失常的临床疗效.方法选取我院2009年10月~2015年10月治疗的冠心病心律失常患者90例,随机分为两组,治疗组45例,在常规治疗基础上口服稳心颗粒和胺碘酮;对照组45例,在常规治疗基础上服用胺碘酮,疗程6w.观察用药前/后患者心电图及临床症状的改善程度.结果治疗组疗效优于对照组(<0.05).结论稳心颗粒联合胺碘酮治疗冠心病心律失常具有良好的疗效.

  16. Imaging and controlling intracellular reactions: Lysosome transport as a function of diameter and the intracellular synthesis of conducting polymers

    Science.gov (United States)

    Payne, Christine

    2014-03-01

    Eukaryotic cells are the ultimate complex environment with intracellular chemical reactions regulated by the local cellular environment. For example, reactants are sequestered into specific organelles to control local concentration and pH, motor proteins transport reactants within the cell, and intracellular vesicles undergo fusion to bring reactants together. Current research in the Payne Lab in the School of Chemistry and Biochemistry at Georgia Tech is aimed at understanding and utilizing this complex environment to control intracellular chemical reactions. This will be illustrated using two examples, intracellular transport as a function of organelle diameter and the intracellular synthesis of conducting polymers. Using single particle tracking fluorescence microscopy, we measured the intracellular transport of lysosomes, membrane-bound organelles, as a function of diameter as they underwent transport in living cells. Both ATP-dependent active transport and diffusion were examined. As expected, diffusion scales with the diameter of the lysosome. However, active transport is unaffected suggesting that motor proteins are insensitive to cytosolic drag. In a second example, we utilize intracellular complexity, specifically the distinct micro-environments of different organelles, to carry out chemical reactions. We show that catalase, found in the peroxisomes of cells, can be used to catalyze the polymerization of the conducting polymer PEDOT:PSS. More importantly, we have found that a range of iron-containing biomolecules are suitable catalysts with different iron-containing biomolecules leading to different polymer properties. These experiments illustrate the advantage of intracellular complexity for the synthesis of novel materials.

  17. The Clinic Alapplication Value of Amiodarone in the Treatment of Chronic Heart Failure Complicated With Arrhythmia%胺碘酮治疗慢性心力衰竭并发心律失常的临床应用价值

    Institute of Scientific and Technical Information of China (English)

    姜桂菊

    2015-01-01

    目的:讨论胺碘酮治疗慢性心力衰竭衰并发心律失常的临床应用价值。方法对照组采用抗心衰的治疗,研讨组在此基础上联合应用胺碘酮进行治疗。结果研讨组治疗效果、并发症等方面均优于对照组。结论在常规抗心衰的治疗基础上采用胺碘酮治疗心衰并发心律失常安全、有效。%ObjectiveTo investigate the clinic application value of amiodarone in the treatment of chronic heart failure complicated with arrhythmia. Methods The research group was treated with anti heart failure. The research group based on the combined application of amiodarone for the treatment.Results Research group of the treatment effect, complications were better than those of control group. ConclusionOn the basis of routine anti heart failure treatment on the use of amiodarone in the treatment of heart failure complicated with arrhythmia safe, effective.

  18. Destabilization of acrosome and elastase influence mediate the release of secretory phospholipase A2 from human spermatozoa

    Institute of Scientific and Technical Information of China (English)

    Jacqueline Leβig; Uta Reibetanz; Jürgen Arnhold; Hans-Jürgen Glander

    2008-01-01

    Aim: To determine the cellular distribution of secretory phospholipase A2 (sPLA2) in dependence on the acrosomal state and under the action of elastase released under inflammatory processes from leukocytes. Methods: Acrosome reaction of spermatozoa was triggered by calcimycin. Human leukocyte elastase was used to simulate in flammatory conditions. To visualize the distribution of sPLA2 and to determine the acrosomal state, immunofluorescence tech-niques and lectin binding combined with confocal laser scanning fluorescence microscopy and flow cytometry were used. Results: Although sPLA2 was detected at the acrosome and tail regions in intact spermatozoa, it disappearedfrom the head region after triggering the acrosome reaction. This release of sPLA2 was associated with enhanced binding of annexin V-fluoroscein isothiocyanate (FITC) to spermatozoa surfaces, intercalation of ethidium-homodimer L and bnding of FITC-iabelled concanavalin A at the acrosomal region. Spermatozoa from healthy subjects treated with elastase were characterized by release of sPLA2, disturbance of acrosome structure, and loss of vitality. Conclusion:The ability of spermatozoa to release secretory phospholipase A2 is related to the acrosomal state. Premature destabi-lization of the acrosome and loss of sPLA2 can occur during silent inflammations in the male genital tract. The distribution pattern of sPLA2 in intact spermatozoa might be an additional parameter for evaluating sperm quality.

  19. Decrease in pH destabilizes individual vault nanocages by weakening the inter-protein lateral interaction

    Science.gov (United States)

    Llauró, Aida; Guerra, Pablo; Kant, Ravi; Bothner, Brian; Verdaguer, Núria; de Pablo, Pedro J.

    2016-10-01

    Vault particles are naturally occurring proteinaceous cages with promising application as molecular containers. The use of vaults as functional transporters requires a profound understanding of their structural stability to guarantee the protection and controlled payload delivery. Previous results performed with bulk techniques or at non-physiological conditions have suggested pH as a parameter to control vault dynamics. Here we use Atomic Force Microscopy (AFM) to monitor the structural evolution of individual vault particles while changing the pH in real time. Our experiments show that decreasing the pH of the solution destabilize the barrel region, the central part of vault particles, and leads to the aggregation of the cages. Additional analyses using Quartz-Crystal Microbalance (QCM) and Differential Scanning Fluorimetry (DSF) are consistent with our single molecule AFM experiments. The observed topographical defects suggest that low pH weakens the bonds between adjacent proteins. We hypothesize that the observed effects are related to the strong polar character of the protein-protein lateral interactions. Overall, our study unveils the mechanism for the influence of a biologically relevant range of pHs on the stability and dynamics of vault particles.

  20. Microtubule Destabilizer KIF2A Undergoes Distinct Site-Specific Phosphorylation Cascades that Differentially Affect Neuronal Morphogenesis

    Directory of Open Access Journals (Sweden)

    Tadayuki Ogawa

    2015-09-01

    Full Text Available Neurons exhibit dynamic structural changes in response to extracellular stimuli. Microtubules (MTs provide rapid and dramatic cytoskeletal changes within the structural framework. However, the molecular mechanisms and signaling networks underlying MT dynamics remain unknown. Here, we have applied a comprehensive and quantitative phospho-analysis of the MT destabilizer KIF2A to elucidate the regulatory mechanisms of MT dynamics within neurons in response to extracellular signals. Interestingly, we identified two different sets of KIF2A phosphorylation profiles that accelerate (A-type and brake (B-type the MT depolymerization activity of KIF2A. Brain-derived neurotrophic factor (BDNF stimulates PAK1 and CDK5 kinases, which decrease the MT depolymerizing activity of KIF2A through B-type phosphorylation, resulting in enhanced outgrowth of neural processes. In contrast, lysophosphatidic acid (LPA induces ROCK2 kinase, which suppresses neurite outgrowth from round cells via A-type phosphorylation. We propose that these two mutually exclusive forms of KIF2A phosphorylation differentially regulate neuronal morphogenesis during development.

  1. Electrostatic transition state stabilization rather than reactant destabilization provides the chemical basis for efficient chorismate mutase catalysis.

    Science.gov (United States)

    Burschowsky, Daniel; van Eerde, André; Ökvist, Mats; Kienhöfer, Alexander; Kast, Peter; Hilvert, Donald; Krengel, Ute

    2014-12-09

    For more than half a century, transition state theory has provided a useful framework for understanding the origins of enzyme catalysis. As proposed by Pauling, enzymes accelerate chemical reactions by binding transition states tighter than substrates, thereby lowering the activation energy compared with that of the corresponding uncatalyzed process. This paradigm has been challenged for chorismate mutase (CM), a well-characterized metabolic enzyme that catalyzes the rearrangement of chorismate to prephenate. Calculations have predicted the decisive factor in CM catalysis to be ground state destabilization rather than transition state stabilization. Using X-ray crystallography, we show, in contrast, that a sluggish variant of Bacillus subtilis CM, in which a cationic active-site arginine was replaced by a neutral citrulline, is a poor catalyst even though it effectively preorganizes chorismate for the reaction. A series of high-resolution molecular snapshots of the reaction coordinate, including the apo enzyme, and complexes with substrate, transition state analog and product, demonstrate that an active site, which is only complementary in shape to a reactive substrate conformer, is insufficient for effective catalysis. Instead, as with other enzymes, electrostatic stabilization of the CM transition state appears to be crucial for achieving high reaction rates.

  2. Establishing a High-content Analysis Method for Tubulin Polymerization to Evaluate Both the Stabilizing and Destabilizing Activities of Compounds.

    Science.gov (United States)

    Sum, Chi Shing; Nickischer, Debra; Lei, Ming; Weston, Andrea; Zhang, Litao; Schweizer, Liang

    2014-01-01

    Microtubules are important components of the cellular cytoskeleton that play roles in various cellular processes such as vesicular transport and spindle formation during mitosis. They are formed by an ordered organization of α-tubulin and β-tubulin hetero-polymers. Altering microtubule polymerization has been known to be the mechanism of action for a number of therapeutically important drugs including taxanes and epothilones. Traditional cell-based assays for tubulin-interacting compounds rely on their indirect effects on cell cycle and/or cell proliferation. Direct monitoring of compound effects on microtubules is required to dissect detailed mechanisms of action in a cellular setting. Here we report a high-content assay platform to monitor tubulin polymerization status by directly measuring the acute effects of drug candidates on the cellular tubulin network with the capability to dissect the mechanisms of action. This high-content analysis distinguishes in a quantitative manner between compounds that act as tubulin stabilizers versus those that are tubulin destabilizers. In addition, using a multiplex approach, we expanded this analysis to simultaneously monitor physiological cellular responses and associated cellular phenotypes.

  3. Intracellular acidosis enhances the excitability of working muscle.

    Science.gov (United States)

    Pedersen, Thomas H; Nielsen, Ole B; Lamb, Graham D; Stephenson, D George

    2004-08-20

    Intracellular acidification of skeletal muscles is commonly thought to contribute to muscle fatigue. However, intracellular acidosis also acts to preserve muscle excitability when muscles become depolarized, which occurs with working muscles. Here, we show that this process may be mediated by decreased chloride permeability, which enables action potentials to still be propagated along the internal network of tubules in a muscle fiber (the T system) despite muscle depolarization. These results implicate chloride ion channels in muscle function and emphasize that intracellular acidosis of muscle has protective effects during muscle fatigue.

  4. New perspective in the assessment of total intracellular magnesium

    Directory of Open Access Journals (Sweden)

    Azzurra Sargenti

    2014-01-01

    Full Text Available Magnesium (Mg is essential for biological processes, but its cellular homeostasis has not been thoroughly elucidated, mainly because of the inadequacy of the available techniques to map intracellular Mg distribution. Recently, particular interest has been raised by a new family of fluorescent probes, diaza-18-crown-hydroxyquinoline (DCHQ, that shows remarkably high affinity and specificity for Mg, thus permitting the detection of the total intracellular Mg. The data obtained by fluori- metric and cytofluorimetric assays performed with DCHQ5 are in good agreement with atomic absorption spectroscopy, confirming that DCHQ5 probe allows both qualitative and quantitative determination of total intracellular Mg.

  5. Human neutrophils dump Candida glabrata after intracellular killing.

    Science.gov (United States)

    Essig, Fabian; Hünniger, Kerstin; Dietrich, Stefanie; Figge, Marc Thilo; Kurzai, Oliver

    2015-11-01

    Interaction between fungal pathogens and human phagocytes can lead to remarkably variable outcomes, ranging from intracellular killing to prolonged survival and replication of the pathogen in the host cell. Using live cell imaging we observed primary human neutrophils that release phagocytosed Candida glabrata yeast cells after intracellular killing. This process, for which we propose the name "dumping", adds a new outcome to phagocyte-fungus interaction which may be of potential immunological importance as it allows professional antigen presenting cells to take up and process neutrophil-inactivated pathogens that in their viable state are able to evade intracellular degradation in these cells.

  6. Comparison of short-term efficacy and safety between amiodarone and esmolol treatment in elderly patients with acute myocardial infarction complicated with ventricular arrhythmia%胺碘酮与艾司洛尔治疗老年患者急性心肌梗死合并室性心律失常的短期疗效与安全性比较

    Institute of Scientific and Technical Information of China (English)

    邹德玲; 刘兴利; 方悦; 陈艳丽; 耿宁; 庞文跃

    2014-01-01

    目的 比较老年急性心肌梗死(AMI)合并严重室性心律失常患者静脉应用胺碘酮或艾司洛尔48 h内疗效及不良反应,为临床安全用药提供依据. 方法 2009年1月至2013年6月在中国医科大学附属盛京医院心脏内科连续住院治疗的老年AMI合并严重室性心律失常患者纳入研究,分为胺碘酮组与艾司洛尔组.胺碘酮组患者在10 min内静脉注射胺碘酮150 mg+ 5%葡萄糖注射液20 ml后经微量注射泵静脉输注胺碘酮1 mg/min共6h,减量至0.5 mg/min静脉输注24~48 h,之后口服胺碘酮0.2g,3次/d,共7d.艾司洛尔组患者在1 min内静脉注射艾司洛尔注射液0.5 mg/kg后经微量注射泵静脉输注艾司洛尔0.1 mg/(kg·min)共6h,减量至0.05 mg/(kg·min)静脉输注24 ~ 48 h,之后口服美托洛尔25 mg,2次/d,共7d.胺碘酮组和艾司洛尔组静脉应用胺碘酮或艾司洛尔6h后仍有室速发作者,分别加用上述艾司洛尔或胺碘酮治疗方案.比较2组患者治疗48 h内有效率和不良反应发生率. 结果 胺碘酮组和艾司洛尔组48 h内有效率分别为92.1%(35/38)和75.0%(27/36),组间差异有统计学意义(P=0.046);不良反应发生率分别为39.5%(15/38)和19.4%(7/36),组间差异无统计学意义(P =0.060).胺碘酮组2例伴有心力衰竭患者静脉用药24 h后出现急性肝损伤,停药并对症治疗2周后肝功能恢复正常. 结论 静脉应用胺碘酮治疗老年患者AMI合并严重室性心律失常有效率优于艾司洛尔.胺碘酮与艾司洛尔均较安全.高龄AMI且伴心力衰竭者静脉应用胺碘酮时需密切监测肝功能,出现肝损伤需立即停药并给予对症治疗.%Objective To compare the efficacy and safety of intravenous application of amiodarone or esmolol in elderly patients with ventricular arrhythmia following acute myocardial infarction (AMI) within 48 hours,and provide reference for safe use of medication in clinical practice.Methods Elderly hospitalized

  7. Structural fold, conservation and Fe(II) binding of the intracellular domain of prokaryote FeoB

    Energy Technology Data Exchange (ETDEWEB)

    Hung, Kuo-Wei; Chang, Yi-Wei; Eng, Edward T.; Chen, Jai-Hui; Chen, Yi-Chung; Sun, Yuh-Ju; Hsiao, Chwan-Deng; Dong, Gang; Spasov, Krasimir A.; Unger, Vinzenz M.; Huang, Tai-huang (Yale-MED); (Perutz Lab); (AS); (NTHU-Taiwan)

    2010-09-17

    FeoB is a G-protein coupled membrane protein essential for Fe(II) uptake in prokaryotes. Here, we report the crystal structures of the intracellular domain of FeoB (NFeoB) from Klebsiella pneumoniae (KpNFeoB) and Pyrococcus furiosus (PfNFeoB) with and without bound ligands. In the structures, a canonical G-protein domain (G domain) is followed by a helical bundle domain (S-domain), which despite its lack of sequence similarity between species is structurally conserved. In the nucleotide-free state, the G-domain's two switch regions point away from the binding site. This gives rise to an open binding pocket whose shallowness is likely to be responsible for the low nucleotide-binding affinity. Nucleotide binding induced significant conformational changes in the G5 motif which in the case of GMPPNP binding was accompanied by destabilization of the switch I region. In addition to the structural data, we demonstrate that Fe(II)-induced foot printing cleaves the protein close to a putative Fe(II)-binding site at the tip of switch I, and we identify functionally important regions within the S-domain. Moreover, we show that NFeoB exists as a monomer in solution, and that its two constituent domains can undergo large conformational changes. The data show that the S-domain plays important roles in FeoB function.

  8. 炙甘草汤加减配合胺碘酮治疗慢性心力衰竭312例疗效观察%Curative effect observation of Zhi Gan Cao decoction adjusted with amiodarone in the treatment of 312 cases of chronic cardiac failure

    Institute of Scientific and Technical Information of China (English)

    李玉红; 王立娜; 崔骞

    2014-01-01

    目的:观察炙甘草汤加减配合胺碘酮治疗慢性心力衰竭情况。方法:将慢性心力衰竭患者312例按随机数字表法分为观察组160例(炙甘草汤加减配合胺碘酮组)与对照组152例(胺碘酮组)。随访6个月,观察两组总有效率和复发率情况。结果:观察组总有效率98%,复发率10.22%;对照组总有效率82%,复发率32.9%。两者差异有统计学意义(P<0.05)。结论:在预防慢性心力衰竭的复发方面,炙甘草汤加减配合胺碘酮优于单纯应用胺碘酮,值得在临床中推广应用。%Objective:To observe Zhi Gan Cao decoction adjusted with amiodarone in the preventment of recurrence of chronic cardiac failure.Methods:According to random number table method,312 patients with chronic cardiac failure were divided into the observation group in 160 cases(Zhi Gan Cao decoction adjusted with amiodarone group)and the control group in 152 cases(amiodarone group).After 6 months of follow up,the recurrence rates of premature beat in the two groups were observed. Results:In the observation group,the total effective rate was 98%,and the recurrence rate was 10.22%.In the control group, the total effective rate was 82%, and the recurrence rate was 32.9%.The difference was statistically significant(P<0.05).Conclusion:In the preventment of recurrence of chronic cardiac failure,Zhi Gan Cao decoction adjusted with amiodarone is better than the simple application of amiodarone.It is worth of popularization and application in clinical.

  9. 盐酸胺碘酮联合步长稳心颗粒治疗阵发性快速房颤疗效观察%The Clinical Observation of amiodarone with Wenxinkeli in Treatment of rapid atrial fibrillation in patients with paroxysmal efficacy

    Institute of Scientific and Technical Information of China (English)

    严新美

    2013-01-01

    目的:评价胺碘酮联合步长稳心颗粒治疗阵发性快速房颤的疗效。方法将80例阵发性快速房颤患者随机分为治疗组和对照组,两组均予以吸氧、心电监护、胺碘酮治疗,治疗组加服步长稳心颗粒,共观察6个月。结果观察6个月后,治疗组在有效改善症状、复律时间、及胺碘酮用量方面明显优于对照组,差异有统计学意义(P<0.01)。结论胺碘酮与步长稳心颗粒合用治疗阵发性房颤,能有效改善症状,提高治疗效果且可减少胺碘酮用量,缩短复律时间,有一定的临床应用价值。%Objective Evaluation of amiodarone the joint step Wenxinkeli rapid atrial fibrillation in patients with paroxysmal efficacy. Methods 80 patients with paroxysmal rapid atrial fibrillation were randomly divided into a treatment group and a control group, and both groups are oxygen, ECG, amiodarone,The treatment group took Buchangwenxin particles were observed 6 months. Results Observed after 6 months, the treatment group was effective in improving symptoms, time of cardioversion and amiodarone dosage was significantly better than the control group, the difference was statistically significant (P <0.01). Conclusion the particle combination therapy of paroxysmal atrial fibrillation, amiodarone and Buchangwenxin improve symptoms, improve treatment and reduce amiodarone dosage and shorten the time of cardioversion clinical application value.

  10. 胺碘酮配合中药对慢性心力衰竭并室性早搏的临床干预%Clinical intervention of amiodarone with Traditional Chinese Medicine on chronic heart failure and premature ventricular contractions

    Institute of Scientific and Technical Information of China (English)

    于瑞玲; 宗燕

    2014-01-01

    Objective:T o observe the effect of amiodarone with Traditional Chinese Medicine on prev enting the re currence of chronic h eart failure and p remature ventr icular contractions. Me thods:78 cases with ch ronic heart failur e were randomized into a group given amiodarone with Traditional Chinese Medicine( the treatment group with 40 cases) and a group given amiodarone( the control group with 38 cases) .Followed up for six months, the recurrence r ates of premature w ere observ ed . Results:Th e treatment groups:the t otal effective r ate was 98%, th e re currence ra te w as 10.22%; the control group: the to tal effective rat e was 82%, the re currence rate was 32.9%. The dif ference was st atistically sign ificant ( P<0 .05). C onclusions:In the aspect of prevention of chronic h eart fa ilure and premature ventricular contractions, amiodarone with Traditional Chinese Medicine is better than amiodarone and it is worth y of promotion in clinical applications.%目的:观察中药联合胺碘酮预防慢性心力衰竭并室性早搏复发情况。方法:慢性心力衰竭室性早搏病人78例,随机分为中药联合胺碘酮组(治疗组40例)与胺碘酮组(对照组38例)。随访6个月,观察两组早搏复发率情况。结果:治疗组:总有效率分别为98%,复发率10.22%;对照组:总有效率82%,复发率32.9%。两者有显著性差异(P<0.05)。结论:在预防慢性心力衰竭并室性早搏的复发方面中药联合胺碘酮优于单纯应用胺碘酮,值得在临床中推广应用。

  11. Intracellular concentrations determine the cytotoxicity of adefovir, cidofovir and tenofovir.

    Science.gov (United States)

    Zhang, Xun; Wang, Ruduan; Piotrowski, Mary; Zhang, Hui; Leach, Karen L

    2015-02-01

    Lack of in vitro to in vivo translation is a major challenge in safety prediction during early drug discovery.One of the most common in vitro assays to evaluate the probability of a compound to cause adverse effects is a cytotoxicity assay. Cytotoxicity of a compound is often measured by dose–response curves assuming the administered doses and intracellular exposures are equal at the time of measurement.However, this may not be true for compounds with low membrane permeability or those which are substrates for drug transporters as intracellular concentrations are determined both by passive permeability and active uptake through drug transporters. We show here that three antiviral drugs, adefovir, cidofovir and tenofovir exhibit significantly increased cytotoxicity in HEK293 cells transfected with organic anion transporter (OAT) 1 and 3 compared to a lack of cytotoxicity in HEK293 wildtype cells. A further look at the media and intracellular drug concentrations showed that 24 h after dosing, all three drugs had higher intracellular drug concentrations than that of media in the HEK-OAT1 cells whereas the intracellular drug concentrations in the wildtype cells were much lower than the administered doses. Comparing cytotoxicity IC(50) values of adefovir, cidofovir and tenofovir based on administered doses and measured intracellular concentrations in HEK-OAT1 cells revealed that intracellular drug concentrations have significant impact on calculated IC(50) values. Tenofovir showed much less intrinsic cytotoxicity than adefovir and cidofovir using intracellular concentrations rather than media concentration. Our data suggest that for low permeable drugs or drugs that are substrates for drug transporters, the choice of cellular model is critical for providing an accurate determination of cytotoxicity.

  12. Study of neurotoxic intracellular calcium signalling triggered by amyloids.

    Science.gov (United States)

    Villalobos, Carlos; Caballero, Erica; Sanz-Blasco, Sara; Núñez, Lucía

    2012-01-01

    Neurotoxicity in Alzheimer's disease (AD) is associated to dishomeostasis of intracellular Ca(2+) induced by amyloid β peptide (Aβ) species. Understanding of the effects of Aβ on intracellular Ca(2+) homeostasis requires preparation of the different Aβ assemblies including oligomers and fibrils and the testing of their effects on cytosolic and mitochondrial Ca(2+) in neurons. Procedures for cerebellar granule cell culture, preparation of Aβ species as well as fluorescence and bioluminescence imaging of cytosolic and mitochondrial Ca(2+) in neurons are described.

  13. In vivo metabolite compartmentalization probed using intracellular GdDTPA

    DEFF Research Database (Denmark)

    Peters, David Alberg; Rowland, Ian

    Fast trans-membrane water exchange enables in- tracellular relaxation enhancement of water by contrast agents in the extracellular space. For me- tabolites not in fast exchange across membranes, intracellular metabolite relaxation enhancement will only occur if the contrast agent and metabolite a...... are in the same compartment. Extracellular contrast has utilized electroporation methods to deliver GdDTPA into the cytosol of rat muscle in vivo in order to probe the intracellular compart- mentalization of MR-visible metabolites....

  14. Comparison of clinical effect between amiodarone and propafenone in prehospital treatment of paroxysmal supraventricular tachycardia%胺碘酮与盐酸普罗帕酮在院前急救中治疗阵发性室上性心动过速的疗效比较

    Institute of Scientific and Technical Information of China (English)

    胡远扬; 洪建芳; 赫英春; 林志华

    2016-01-01

    目的:研究院前急救中选择胺碘酮与盐酸普罗帕酮治疗阵发性室上性心动过速(paroxysmal supraventricular tachycardia,PSVT)的临床疗效。方法选取2008-01至2016-02福建省某急救指挥中心院前急救PSVT患者78例,随机分成胺碘酮组(n=39)和盐酸普罗帕酮组(n=39),给予相应药物治疗,观察两组患者治疗后PSVT转复有效率、转复时间及药物不良反应。结果经胺碘酮治疗组的转复有效率略优于盐酸普罗帕酮组,但差异无统计学意义;盐酸普罗帕酮组转复所用时间明显短于胺碘酮组[(13.1±3.2)vs(24.8±5.3) h],差异有统计学意义(t=2.07,P=0.003);胺碘酮组不良反应发生率(5.13%)低于盐酸普罗帕酮组(20.51%),差异有统计学意义(P<0.05)。结论院前急救选择胺碘酮与盐酸普罗帕酮转复PSVT均可获得明显疗效,胺碘酮的治疗效果略优于盐酸普罗帕酮,且不良反应较少,但转复时间较长。%Objective To compare clinical efficacy between amiodarone and propafenone in prehospital treatment of paroxysmal supraventricular tachycardia.Methods 78 cases of an emergency command center in PSVT prehospital emergency patients from 2008, January to 2016, February in Fujian province were selected and randomly divided into amiodarone group (n=39) and propafenone group (n=39) treated by corresponding methods, PSVT cardioversion rate, cardioversion time and adverse drug reaction after treatment ,of the two groups were observed.Results The effective cardioversion rate of amiodarone group is slightly higher than that of propafenone hydrochloride group, but there was no significant difference; cardioversion time of the patients in the hydrochloride group was significantly shorter than that in the amiodarone group [(13.1±3.2)vs(24.8±5.3)h ], and the difference was statistically significant (t=2.07,P=0.003); the incidence of adverse reaction in the amiodarone group (5

  15. The clinical effect of amiodarone versus lidocaine on the myocardial infarction patients complicated with ventricular tachycardia: A Meta-analysis%胺碘酮与利多卡因治疗急性心肌梗死并室性心动过速疗效及安全性的Meta分析

    Institute of Scientific and Technical Information of China (English)

    党松; 王晞; 胡娟; 王鑫

    2012-01-01

    Objective To retrospectively compare the therapeutic effectiveness of amiodarone and lidocaine in the treatment of ventricular arrhythmia after acute myocardial infarction. Methods PubMed, Cochrane, EMBASE, MEDLINE, CNKI, Wanfang data were searched from the time of self-build library to December 2011 for randomized clinical trials( RCT ) of amiodarone vs. Lidocaine on the myocardial infarction patients complicated with ventricular tachycardia. Two investigators independently screened these data. Pooled estimates were calculate with usage of RevMan 5. 0 software. Results Ten trials were included in the analysis ( 1381 patients ). ( 1 )The effective rate in amiodarone group was higher than that in lidocaine group ( RR = 1. 27 , 95% CI 1. 12 ~ 1.44, P =0.0002 ). ( 2 ) Regardless of the effect of other medicines, the side effects of amiodarone was similar as lidocaine ( RR = 0. 79, 95% CI 0. 42 ~ 1. 48, P = 0. 46 ). ( 3 )The mortality rate in amiodarone group was higher than that in lidocaine group ( RR = 0.48, 95% CI 0. 27 ~ 0. 85, P =0.01). Conclusion The results of this Meta-analysis provide strong evidence that preferable effective of amiodarone therapy on the myocardial infarction patients complicated with ventricular arrhythmia, amiodarone can significantly decrease the incidence of ventricular tachycardia without increase the side effects, and decrease the mortality rate.%目的 运用Meta 分析比较胺碘酮和利多卡因对急性心肌梗死合并室性心动过速的疗效.方法 计算机检索PubMed、Cochrane、EMBASE、MEDLINE、中国知网(CNKI)数据库、万方数据库,查找自建库以来至2011年12月公开发表的比较胺碘酮和利多卡因治疗心肌梗死合并室性心动过速临床随机对照试验(RCT),按纳入排除标准进行RCT 的筛选、资料提取和质量评价,使用RevMan 5.0软件进行数据统计学分析.结果 共纳入10项研究、1381例患者.(1)胺碘酮组治疗有效率显著高于利多卡因组(RR=1

  16. Alta dose de amiodarona em curto período reduz incidência de fibrilação atrial e flutter atrial no pós-operatório de cirurgia de revascularização miocárdica High dose of amiodarone in a short-term period reduces the incidence of postoperative atrial fibrillation and atrial flutter

    Directory of Open Access Journals (Sweden)

    Rafael Vieira Alcalde

    2006-09-01

    Full Text Available OBJETIVOS: Avaliar se a administração de amiodarona, em doses altas e curso rápido, reduz a incidência de fibrilação ou flutter atrial, após cirurgia de revascularização miocárdica e se reduz, também, o tempo de internação hospitalar. MÉTODOS: A amostra se constituiu de 93 pacientes randomizados, em estudo duplo-cego, para receberem amiodarona (46 pacientes ou placebo (47 pacientes. A terapia consistia na aplicação de 600mg de amiodarona, três vezes ao dia, iniciada no mínimo 30 horas e no máximo 56 horas antes da cirurgia. RESULTADOS: Fibrilação ou flutter atrial no pós-operatório ocorreu em 8 dos 46 pacientes no grupo amiodarona (17,4% e em 19 dos 47 pacientes no grupo placebo (40,4% (p=0,027. A dose média de amiodarona foi de 2,8g. Os pacientes do grupo amiodarona ficaram hospitalizados por 8,9±3,1 dias, enquanto a internação dos pacientes do grupo placebo foi de 11,4± 8,7 dias (p=0,07. O tempo de internação foi significativamente prolongado nos pacientes que desenvolveram fibrilação ou flutter atrial após a cirurgia, independente do grupo randomizado. CONCLUSÃO: Esta nova alternativa de administração de amiodarona em alta dose e por um curto período, antes da cirurgia de revascularização miocárdica, reduz a incidência de fibrilação ou flutter atrial no pós-operatório desta cirurgia.OBJECTIVE: To investigate wheter oral amiodarone administered before surgery for a short period in high dose would reduce the incidence of postoperative atrial fibrillation or atrial flutter and reduces the lenght of hospital stay. METHODS: In the double-blind, randomized study, 93 patients were given either oral amiodarone (46 patients or placebo (47 patients. Therapy consisted of 600mg of amiodarone three times a day, started at mininum 30 hours and at maximum 56 hours before surgery. RESULTS: Postoperative atrial fibrillation or atrial flutter occurred in 8 of 46 patients in the amiodarone group (17.4% and 19 of the

  17. Key Role for Intracellular K+ and Protein Kinases Sat4/Hal4 and Hal5 in the Plasma Membrane Stabilization of Yeast Nutrient Transporters▿

    Science.gov (United States)

    Pérez-Valle, Jorge; Jenkins, Huw; Merchan, Stephanie; Montiel, Vera; Ramos, José; Sharma, Sukesh; Serrano, Ramón; Yenush, Lynne

    2007-01-01

    K+ transport in living cells must be tightly controlled because it affects basic physiological parameters such as turgor, membrane potential, ionic strength, and pH. In yeast, the major high-affinity K+ transporter, Trk1, is inhibited by high intracellular K+ levels and positively regulated by two redundant “halotolerance” protein kinases, Sat4/Hal4 and Hal5. Here we show that these kinases are not required for Trk1 activity; rather, they stabilize the transporter at the plasma membrane under low K+ conditions, preventing its endocytosis and vacuolar degradation. High concentrations (0.2 M) of K+, but not Na+ or sorbitol, transported by undefined low-affinity systems, maintain Trk1 at the plasma membrane in the hal4 hal5 mutant. Other nutrient transporters, such as Can1 (arginine permease), Fur4 (uracil permease), and Hxt1 (low-affinity glucose permease), are also destabilized in the hal4 hal5 mutant under low K+ conditions and, in the case of Can1, are stabilized by high K+ concentrations. Other plasma membrane proteins such as Pma1 (H+-pumping ATPase) and Sur7 (an eisosomal protein) are not regulated by halotolerance kinases or by high K+ levels. This novel regulatory mechanism of nutrient transporters may participate in the quiescence/growth transition and could result from effects of intracellular K+ and halotolerance kinases on membrane trafficking and/or on the transporters themselves. PMID:17548466

  18. Polycyclic aromatic hydrocarbon body residues and lysosomal membrane destabilization in mussels exposed to the Dubai Star bunker fuel oil (intermediate fuel oil 380) spill in San Francisco Bay.

    Science.gov (United States)

    Hwang, Hyun-Min; Stanton, Beckye; McBride, Toby; Anderson, Michael J

    2014-05-01

    Following the spill of bunker fuel oil (intermediate fuel oil 380, approximately 1500-3000 L) into San Francisco Bay in October 2009, polycyclic aromatic hydrocarbon (PAH) concentrations in mussels from moderately oiled areas increased up to 87 554 ng/g (dry wt) and, 3 mo later, decreased to concentrations found in mussels collected prior to oiling, with a biological half-life of approximately 16 d. Lysosomal membrane destabilization increased in mussels with higher PAH body burdens.

  19. Analysis of Alfvén eigenmode destabilization by energetic particles in Large Helical Device using a Landau-closure model

    Science.gov (United States)

    Varela, J.; Spong, D. A.; Garcia, L.

    2017-04-01

    Energetic particle populations in nuclear fusion experiments can destabilize the Alfvén Eigenmodes through inverse Landau damping and couplings with gap modes in the shear Alfvén continua. We use the reduced MHD equations to describe the linear evolution of the poloidal flux and the toroidal component of the vorticity in a full 3D system, coupled with equations of density and parallel velocity moments for the energetic particles. We add the Landau damping and resonant destabilization effects using a closure relation. We apply the model to study the Alfvén mode stability in the inward-shifted configurations of the Large Helical Device (LHD), performing a parametric analysis of the energetic particle β ({βf} ) in a range of realistic values, the ratios of the energetic particle thermal/Alfvén velocities ({{V}\\text{th}}/{{V}A0} ), the magnetic Lundquist numbers (S) and the toroidal modes (n). The n  =  1 and n  =  2 TAEs are destabilized, although the n  =  3 and n  =  4 TAEs are weakly perturbed. The most unstable configurations are associated with the density gradients of energetic particles in the plasma core: the TAEs are destabilized, even for small energetic particle populations, if their thermal velocity is lower than 0.4 times the Alfvén velocity. The frequency range of MHD bursts measured in the LHD are 50–70 kHz for the n  =  1 and 60–80 kHz for the n  =  2 TAE, which is consistent with the model predictions. ).

  20. Nutrient/serum starvation derived TRIP-Br3 down-regulation accelerates apoptosis by destabilizing XIAP

    Science.gov (United States)

    Lee, Soonduck; Jeong, Dongjun; Yang, Young; Kim, Keun-Il; Lim, Jong-Seok; Cheon, Chung-Il; Kim, Changjin; Kang, Young-Sook; Lee, Myeong-Sok

    2015-01-01

    TRIP-Br3 and TRIP-Br1 have shown to have important biological functions. However, the function of TRIP-Br3 in tumorigenesis is not well characterized compared to oncogenic TRIP-Br1. Here, we investigated the function of TRIP-Br3 in tumorigenesis by comparing with that of TRIP-Br1. Under nutrient/serum starvation, TRIP-Br3 expression was down-regulated slightly in cancer cells and significantly in normal cells. Unexpectedly, TRIP-Br1 expression was greatly up-regulated in cancer cells but not in normal cells. Moreover, TRIP-Br3 activated autophagy while TRIP-Br1 inactivated it under serum starvation. In spite of different expression and roles of TRIP-Br3 and TRIP-Br1, both of them alleviate cell death by directly binding to and stabilizing XIAP, a potent apoptosis inhibitor, through blocking its ubiquitination. Taken together, we propose that TRIP-Br3 primarily activates the autophagy and suppresses apoptosis in nutrient sufficient condition. However, the prolonged extreme stressful condition of nutrient starvation causes a dramatic decrease of TRIP-Br3, which in turn induces apoptosis by destabilizing XIAP. Up-regulated TRIP-Br1 in cancer cells compensates this effect and delays apoptosis. This can be explained by the competitive alternative binding of TRIP-Br3 and TRIP-Br1 to the BIR2 domain of XIAP. In an extended study, our immunohistochemical analysis revealed a markedly lower level of TRIP-Br3 protein in human carcinoma tissues compared to normal epithelial tissues, implying the role of TRIP-Br3 as a tumor suppressor rather than onco-protein. PMID:25691055

  1. Bile Acids Function Synergistically To Repress Invasion Gene Expression in Salmonella by Destabilizing the Invasion Regulator HilD.

    Science.gov (United States)

    Eade, Colleen R; Hung, Chien-Che; Bullard, Brian; Gonzalez-Escobedo, Geoffrey; Gunn, John S; Altier, Craig

    2016-08-01

    Salmonella spp. are carried by and can acutely infect agricultural animals and humans. After ingestion, salmonellae traverse the upper digestive tract and initiate tissue invasion of the distal ileum, a virulence process carried out by the type III secretion system encoded within Salmonella pathogenicity island 1 (SPI-1). Salmonellae coordinate SPI-1 expression with anatomical location via environmental cues, one of which is bile, a complex digestive fluid that causes potent repression of SPI-1 genes. The individual components of bile responsible for SPI-1 repression have not been previously characterized, nor have the bacterial signaling processes that modulate their effects been determined. Here, we characterize the mechanism by which bile represses SPI-1 expression. Individual bile acids exhibit repressive activity on SPI-1-regulated genes that requires neither passive diffusion nor OmpF-mediated entry. By using genetic methods, the effects of bile and bile acids were shown to require the invasion gene transcriptional activator hilD and to function independently of known upstream signaling pathways. Protein analysis techniques showed that SPI-1 repression by bile acids is mediated by posttranslational destabilization of HilD. Finally, we found that bile acids function synergistically to achieve the overall repressive activity of bile. These studies demonstrate a common mechanism by which diverse environmental cues (e.g., certain short-chain fatty acids and bile acids) inhibit SPI-1 expression. These data provide information relevant to Salmonella pathogenesis during acute infection in the intestine and during chronic infection of the gallbladder and inform the basis for development of therapeutics to inhibit invasion as a means of repressing Salmonella pathogenicity.

  2. Protein homeostasis disorders of key enzymes of amino acids metabolism: mutation-induced protein kinetic destabilization and new therapeutic strategies.

    Science.gov (United States)

    Pey, Angel L

    2013-12-01

    Many inborn errors of amino acids metabolism are caused by single point mutations affecting the ability of proteins to fold properly (i.e., protein homeostasis), thus leading to enzyme loss-of-function. Mutations may affect protein homeostasis by altering intrinsic physical properties of the polypeptide (folding thermodynamics, and rates of folding/unfolding/misfolding) as well as the interaction of partially folded states with elements of the protein homeostasis network (such as molecular chaperones and proteolytic machineries). Understanding these mutational effects on protein homeostasis is required to develop new therapeutic strategies aimed to target specific features of the mutant polypeptide. Here, I review recent work in three different diseases of protein homeostasis associated to inborn errors of amino acids metabolism: phenylketonuria, inherited homocystinuria and primary hyperoxaluria type I. These three different genetic disorders involve proteins operating in different cell organelles and displaying different structural complexities. Mutations often decrease protein kinetic stability of the native state (i.e., its half-life for irreversible denaturation), which can be studied using simple kinetic models amenable to biophysical and biochemical characterization. Natural ligands and pharmacological chaperones are shown to stabilize mutant enzymes, thus supporting their therapeutic application to overcome protein kinetic destabilization. The role of molecular chaperones in protein folding and misfolding is also discussed as well as their potential pharmacological modulation as promising new therapeutic approaches. Since current available treatments for these diseases are either burdening or only successful in a fraction of patients, alternative treatments must be considered covering studies from protein structure and biophysics to studies in animal models and patients.

  3. Destabilized bioluminescent proteins

    Science.gov (United States)

    Allen, Michael S.; Rakesh, Gupta; Gary, Sayler S.

    2007-07-31

    Purified nucleic acids, vectors and cells containing a gene cassette encoding at least one modified bioluminescent protein, wherein the modification includes the addition of a peptide sequence. The duration of bioluminescence emitted by the modified bioluminescent protein is shorter than the duration of bioluminescence emitted by an unmodified form of the bioluminescent protein.

  4. The Influence of Oblique Angle Forced Exercise in Surgically Destabilized Stifle Joints Is Synergistic with Bone, but Antagonistic with Cartilage in an Ovine Model of Osteoarthritis.

    Science.gov (United States)

    Hill, Rachel J; Mason, Holly M; Yeip, Gavin; Merchant, Samer S; Olsen, Aaron L; Stott, Rusty D; Van Wettere, Arnaud J; Bressel, Eadric; Mason, Jeffrey B

    2017-01-01

    Large animal models of osteoarthritis are a necessary testing ground for FDA approval of human medicine applications. Sheep models have advantages over other available large animals, but development and progression of osteoarthritis in sheep is exceedingly slow, which handicaps progress in development of potential treatments. We combined oblique angle forced exercise to increase stress on the stifle, with surgical destabilization to hasten the development of osteoarthritis in ewes. Methods for early detection of clinical signs included radiography, urine, and serum biomarker assays and gait analysis and ex vivo we used microcomputed tomography and macroscopic joint analysis. Our model was able to produce clinically detectable signs of osteoarthritis in a relatively short period (14 weeks). Changes in bone were highly correlated between microcomputed tomography and radiographic analysis and changes in cartilage correlated well between urinary glycosaminoglycan levels and serum aggrecanase analyses. Exercise improved the negative effects of destabilization in bone but exacerbated the negative effects of destabilization in cartilage. These observations suggest that we may need to consider treatments for bone and cartilage separately. These results represent an improved large animal model of osteoarthritis with rapid onset of disease and superior detection of bone and soft tissue changes.

  5. Effects of undiluted and diluted amiodarone on defibrillation and haemodynamics in a ventricular fibrillation pig model%胺碘酮原液和稀释液对心室颤动转复作用及血流动力学的影响

    Institute of Scientific and Technical Information of China (English)

    武军元; 李春盛; 王胜奇

    2010-01-01

    Objective Amiodarone was diluted to release the side effect of hypotension in clinic, but this maybe unsuitable during cardiopulmonary resuscitation (CPR). This study was designed to observe the effects of undiluted amiodarone, diluted amiodarone, and CPR alone on ventricular fibrillation (VF) in a pig model. Methods VF was induced in 21 pigs. The animals were randomly (random mumber) divided into 3 groups after VF 3 min.① CPR group ( n= 7): standard CPR; ② undiluted amiodarone group ( n= 7): undiluted amiodarone (5 mg/kg)bolus within 3 s, then 20 mL saline flush into the peripheral vein, CPR was started after observed 30 s; ③ diluted amiodarone group ( n = 7): amiodarone was dissolved in 20 mL saline and bolus with 30 s. Defibrillation was attempted at VF 5 min. Results The restoration of spontaneous circulation (ROSC) of CPR and undiluted amiodarone groups were higher than diluted group (85.7% vs. 71.4% vs. 42.9%), but the differences were not significant (all P >0.05). The defibrillation energy and times of CPR group were higher than that of undiluted amiodarone (P= 0.009) and diluted group ( P = 0. 170). The mean arterial pressure of undiluted amiodarone were lower than diluted and CPR groups at ROSC 10 min (all P <0.05), but the differences of undiluted and diluted groups were not significant after ROSC 0.5 h. Conclusions In this study, undiluted amiodaronecan effectively reduced the defibrillation times and energy. Although diluted amiodaronecan release the side effect of hypotension which was transient, it didn't significantly improved cardiac electric activity and delayed to start CPR.%目的 通过猪心室颤动(VF)模型,观察胺碘酮原液、稀释液以及单纯标准CPR对心肺复苏效果的影响.方法 21头北京长白猪,应用程控刺激仪诱导VF,VF 3 min后,将动物随机(随机数字法)分为3组.①单纯CPR组:只进行单纯标准CPR;②胺碘酮原液组:予胺碘酮原液5 mg/kg快速(<3 s)静推,生理盐水20 m

  6. Intracellular calcium levels can regulate Importin-dependent nuclear import

    Energy Technology Data Exchange (ETDEWEB)

    Kaur, Gurpreet; Ly-Huynh, Jennifer D.; Jans, David A., E-mail: David.Jans@monash.edu

    2014-07-18

    Highlights: • High intracellular calcium inhibits Impα/β1- or Impβ1-dependent nuclear protein import. • The effect of Ca{sup 2+} on nuclear import does not relate to changes in the nuclear pore. • High intracellular calcium can result in mislocalisation of Impβ1, Ran and RCC1. - Abstract: We previously showed that increased intracellular calcium can modulate Importin (Imp)β1-dependent nuclear import of SRY-related chromatin remodeling proteins. Here we extend this work to show for the first time that high intracellular calcium inhibits Impα/β1- or Impβ1-dependent nuclear protein import generally. The basis of this relates to the mislocalisation of the transport factors Impβ1 and Ran, which show significantly higher nuclear localization in contrast to various other factors, and RCC1, which shows altered subnuclear localisation. The results here establish for the first time that intracellular calcium modulates conventional nuclear import through direct effects on the nuclear transport machinery.

  7. Intracellular Ca-carbonate biomineralization is widespread in cyanobacteria.

    Science.gov (United States)

    Benzerara, Karim; Skouri-Panet, Feriel; Li, Jinhua; Férard, Céline; Gugger, Muriel; Laurent, Thierry; Couradeau, Estelle; Ragon, Marie; Cosmidis, Julie; Menguy, Nicolas; Margaret-Oliver, Isabel; Tavera, Rosaluz; López-García, Purificación; Moreira, David

    2014-07-29

    Cyanobacteria have played a significant role in the formation of past and modern carbonate deposits at the surface of the Earth using a biomineralization process that has been almost systematically considered induced and extracellular. Recently, a deep-branching cyanobacterial species, Candidatus Gloeomargarita lithophora, was reported to form intracellular amorphous Ca-rich carbonates. However, the significance and diversity of the cyanobacteria in which intracellular biomineralization occurs remain unknown. Here, we searched for intracellular Ca-carbonate inclusions in 68 cyanobacterial strains distributed throughout the phylogenetic tree of cyanobacteria. We discovered that diverse unicellular cyanobacterial taxa form intracellular amorphous Ca-carbonates with at least two different distribution patterns, suggesting the existence of at least two distinct mechanisms of biomineralization: (i) one with Ca-carbonate inclusions scattered within the cell cytoplasm such as in Ca. G. lithophora, and (ii) another one observed in strains belonging to the Thermosynechococcus elongatus BP-1 lineage, in which Ca-carbonate inclusions lie at the cell poles. This pattern seems to be linked with the nucleation of the inclusions at the septum of the cells, showing an intricate and original connection between cell division and biomineralization. These findings indicate that intracellular Ca-carbonate biomineralization by cyanobacteria has been overlooked by past studies and open new perspectives on the mechanisms and the evolutionary history of intra- and extracellular Ca-carbonate biomineralization by cyanobacteria.

  8. Intracellular Ca-carbonate biomineralization is widespread in cyanobacteria

    Science.gov (United States)

    Benzerara, Karim; Skouri-Panet, Feriel; Li, Jinhua; Férard, Céline; Gugger, Muriel; Laurent, Thierry; Couradeau, Estelle; Ragon, Marie; Cosmidis, Julie; Menguy, Nicolas; Margaret-Oliver, Isabel; Tavera, Rosaluz; López-García, Purificación; Moreira, David

    2014-07-01

    Cyanobacteria have played a significant role in the formation of past and modern carbonate deposits at the surface of the Earth using a biomineralization process that has been almost systematically considered induced and extracellular. Recently, a deep-branching cyanobacterial species, Candidatus Gloeomargarita lithophora, was reported to form intracellular amorphous Ca-rich carbonates. However, the significance and diversity of the cyanobacteria in which intracellular biomineralization occurs remain unknown. Here, we searched for intracellular Ca-carbonate inclusions in 68 cyanobacterial strains distributed throughout the phylogenetic tree of cyanobacteria. We discovered that diverse unicellular cyanobacterial taxa form intracellular amorphous Ca-carbonates with at least two different distribution patterns, suggesting the existence of at least two distinct mechanisms of biomineralization: (i) one with Ca-carbonate inclusions scattered within the cell cytoplasm such as in Ca. G. lithophora, and (ii) another one observed in strains belonging to the Thermosynechococcus elongatus BP-1 lineage, in which Ca-carbonate inclusions lie at the cell poles. This pattern seems to be linked with the nucleation of the inclusions at the septum of the cells, showing an intricate and original connection between cell division and biomineralization. These findings indicate that intracellular Ca-carbonate biomineralization by cyanobacteria has been overlooked by past studies and open new perspectives on the mechanisms and the evolutionary history of intra- and extracellular Ca-carbonate biomineralization by cyanobacteria.

  9. Advances in genetic manipulation of obligate intracellular bacterial pathogens

    Directory of Open Access Journals (Sweden)

    Paul eBeare

    2011-05-01

    Full Text Available Infections by obligate intracellular bacterial pathogens result in significant morbidity and mortality worldwide. These bacteria include Chlamydia spp., which causes millions of cases of sexually transmitted disease and blinding trachoma annually, and members of the α-proteobacterial genera Anaplasma, Ehrlichia, Orientia and Rickettsia, agents of serious human illnesses including epidemic typhus. Coxiella burnetii, the agent of human Q fever, has also been considered a prototypical obligate intracellular bacterium, but recent host cell-free (axenic growth has rescued it from obligatism. The historic genetic intractability of obligate intracellular bacteria has severely limited molecular dissection of their unique lifestyles and virulence factors involved in pathogenesis. Host cell restricted growth is a significant barrier to genetic transformation that can make simple procedures for free-living bacteria, such as cloning, exceedingly difficult. Low transformation efficiency requiring long term culture in host cells to expand small transformant populations is another obstacle. Despite numerous technical limitations, the last decade has witnessed significant gains in genetic manipulation of obligate intracellular bacteria including allelic exchange. Continued development of genetic tools should soon enable routine mutation and complementation strategies for virulence factor discovery and stimulate renewed interest in these refractory pathogens. In this review, we discuss the technical challenges associated with genetic transformation of obligate intracellular bacteria and highlight advances made with individual genera.

  10. Exploring anti-bacterial compounds against intracellular Legionella.

    Directory of Open Access Journals (Sweden)

    Christopher F Harrison

    Full Text Available Legionella pneumophila is a ubiquitous fresh-water bacterium which reproduces within its erstwhile predators, environmental amoeba, by subverting the normal pathway of phagocytosis and degradation. The molecular mechanisms which confer resistance to amoeba are apparently conserved and also allow replication within macrophages. Thus, L. pneumophila can act as an 'accidental' human pathogen and cause a severe pneumonia known as Legionnaires' disease. The intracellular localisation of L. pneumophila protects it from some antibiotics, and this fact must be taken into account to develop new anti-bacterial compounds. In addition, the intracellular lifestyle of L. pneumophila may render the bacteria susceptible to compounds diminishing bacterial virulence and decreasing intracellular survival and replication of this pathogen. The development of a single infection cycle intracellular replication assay using GFP-producing L. pneumophila and Acanthamoebacastellanii amoeba is reported here. This fluorescence-based assay allows for continuous monitoring of intracellular replication rates, revealing the effect of bacterial gene deletions or drug treatment. To examine how perturbations of the host cell affect L. pneumophila replication, several known host-targeting compounds were tested, including modulators of cytoskeletal dynamics, vesicle scission and Ras GTPase localisation. Our results reveal a hitherto unrealized potential antibiotic property of the β-lactone-based Ras depalmitoylation inhibitor palmostatin M, but not the closely related inhibitor palmostatin B. Further characterisation indicated that this compound caused specific growth inhibition of Legionella and Mycobacterium species, suggesting that it may act on a common bacterial target.

  11. 乙胺碘肤酮用作甲亢术前准备的临床观察%Clinical Observation of Amiodarone Used in the Preoperative Preperation in Grave's Disease

    Institute of Scientific and Technical Information of China (English)

    曾毅克; 黎绍基; 吕诗寿

    2000-01-01

    目的:初步探讨乙胺碘肤酮(Amiodarone)用于甲亢术前准备的可行性.方法:12名患者非随机分为两组,以使其平均年龄、甲亢的严重程度和甲状腺肿大程度相匹配,分别使用Lugol液和Amiodarone作术前准备,比较两组患者切除的腺体质量(m),术中出血量(V),甲状腺组织的碘含量(mI).结果:Amiodarone组m=(89.81±51.41)g,V=(128.16±30.92)ml,mI=(0.033±0.017)%;Lugol液组m=(81.28±39.81)g,V=(194.97±57.77)ml,mI=(0.034±0.013)%;两组对比在切除腺体质量相当时,Amiodarone组的术中出血量较少(t检验P0.05).结论:乙胺碘肤酮用于甲亢术前准备对甲亢控制良好,能达到常规Lugol液的准备效果,而且口服无刺激,较Lugol液优越.

  12. Manuseio peri-operatório do paciente em uso de amiodarona Manoseo peri-operatorio del paciente en uso de amiodarona Peri-operative management of amiodarone patients

    Directory of Open Access Journals (Sweden)

    Gilson Ramos

    2004-08-01

    principales efectos de la amiodarona y asociarlos a la práctica clínica del anestesista. CONTENIDO: Se trató de las principales propiedades de la amiodarona, su uso clínico, bien como los más importantes efectos adversos que pueden aumentar el riesgo quirúrgico de los pacientes en uso de este antidisrítmico. CONCLUSIONES: La amiodarona, a pesar de habitualmente segura y eficiente, puede presentar efectos adversos exacerbados, especialmente para el aparato cardiovascular, durante procedimientos anestésico-cirúgicos. Esto se debe posiblemente a las interacciones entre ese fármaco y agentes anestésicos, asociados principalmente a la anestesia general. Hay relatos de bradicárdias graves y resistentes a la terapéutica, bien como bloqueo atrioventricular (BAV en grados variados. El paciente debe ser rigurosamente monitorizado, especialmente en los procedimientos de grande porte, y el anestesista debe estar amparado en el peri-operatorio con drogas vasoactivas (isoproterenol y marcapaso cardíaco artificial temporario, que pueden ser fundamentales durante el procedimiento.BACKGROUND AND OBJECTIVES: Amiodarone is quite an effective anti-arrhythmic drug indicated for controlling ventricular and supra-ventricular arrhythmias, and it is being widely administered in clinical practice. However, its chronic use may be associated to severe side effects which may be worsened by anesthetic-surgical acts, thus increasing the risk of such procedures. This study aimed at reviewing major amiodarone effects and relating them to anesthetic procedures. CONTENTS: The study covers major amiodarone properties, its clinical use, as well as major adverse effects, which may increase patient's surgical risk. CONCLUSIONS: Amiodarone, although normally safe and effective, may present adverse effects, especially on cardiovascular system, during anesthetic-surgical procedures. This is possibly due to interactions between this drug and anesthetic agents mainly related to general anesthesia. There

  13. Modulation of mammalian apoptotic pathways by intracellular protozoan parasites.

    Science.gov (United States)

    Rodrigues, V; Cordeiro-da-Silva, A; Laforge, M; Ouaissi, A; Silvestre, R; Estaquier, J

    2012-03-01

    During intracellular parasitic infections, pathogens and host cells take part in a complex web of events that are crucial for the outcome of the infection. Modulation of host cell apoptosis by pathogens attracted the attention of scientists during the last decade. Apoptosis is an efficient mechanism used by the host to control infection and limit pathogen multiplication and dissemination. In order to ensure completion of their complex life cycles and to guarantee transmission between different hosts, intracellular parasites have developed mechanisms to block apoptosis and sustain the viability of their host cells. Here, we review how some of the most prominent intracellular protozoan parasites modulate the main mammalian apoptotic pathways by emphasizing the advances from the last decade, which have begun to dissect this dynamic and complex interaction.

  14. Connecting extracellular metabolomic measurements to intracellular flux states in yeast

    Directory of Open Access Journals (Sweden)

    Herrgård Markus J

    2009-03-01

    Full Text Available Abstract Background Metabolomics has emerged as a powerful tool in the quantitative identification of physiological and disease-induced biological states. Extracellular metabolome or metabolic profiling data, in particular, can provide an insightful view of intracellular physiological states in a noninvasive manner. Results We used an updated genome-scale metabolic network model of Saccharomyces cerevisiae, iMM904, to investigate how changes in the extracellular metabolome can be used to study systemic changes in intracellular metabolic states. The iMM904 metabolic network was reconstructed based on an existing genome-scale network, iND750, and includes 904 genes and 1,412 reactions. The network model was first validated by comparing 2,888 in silico single-gene deletion strain growth phenotype predictions to published experimental data. Extracellular metabolome data measured in response to environmental and genetic perturbations of ammonium assimilation pathways was then integrated with the iMM904 network in the form of relative overflow secretion constraints and a flux sampling approach was used to characterize candidate flux distributions allowed by these constraints. Predicted intracellular flux changes were consistent with published measurements on intracellular metabolite levels and fluxes. Patterns of predicted intracellular flux changes could also be used to correctly identify the regions of the metabolic network that were perturbed. Conclusion Our results indicate that integrating quantitative extracellular metabolomic profiles in a constraint-based framework enables inferring changes in intracellular metabolic flux states. Similar methods could potentially be applied towards analyzing biofluid metabolome variations related to human physiological and disease states.

  15. Cadmium induces transcription independently of intracellular calcium mobilization.

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    Brooke E Tvermoes

    Full Text Available BACKGROUND: Exposure to cadmium is associated with human pathologies and altered gene expression. The molecular mechanisms by which cadmium affects transcription remain unclear. It has been proposed that cadmium activates transcription by altering intracellular calcium concentration ([Ca(2+](i and disrupting calcium-mediated intracellular signaling processes. This hypothesis is based on several studies that may be technically problematic; including the use of BAPTA chelators, BAPTA-based fluorescent sensors, and cytotoxic concentrations of metal. METHODOLOGY/PRINCIPAL FINDING: In the present report, the effects of cadmium on [Ca(2+](i under non-cytotoxic and cytotoxic conditions was monitored using the protein-based calcium sensor yellow cameleon (YC3.60, which was stably expressed in HEK293 cells. In HEK293 constitutively expressing YC3.60, this calcium sensor was found to be insensitive to cadmium. Exposing HEK293::YC3.60 cells to non-cytotoxic cadmium concentrations was sufficient to induce transcription of cadmium-responsive genes but did not affect [Ca(2+](i mobilization or increase steady-state mRNA levels of calcium-responsive genes. In contrast, exposure to cytotoxic concentrations of cadmium significantly reduced intracellular calcium stores and altered calcium-responsive gene expression. CONCLUSIONS/SIGNIFICANCE: These data indicate that at low levels, cadmium induces transcription independently of intracellular calcium mobilization. The results also support a model whereby cytotoxic levels of cadmium activate calcium-responsive transcription as a general response to metal-induced intracellular damage and not via a specific mechanism. Thus, the modulation of intracellular calcium may not be a primary mechanism by which cadmium regulates transcription.

  16. Autophagic clearance of bacterial pathogens: molecular recognition of intracellular microorganisms.

    Science.gov (United States)

    Pareja, Maria Eugenia Mansilla; Colombo, Maria I

    2013-01-01

    Autophagy is involved in several physiological and pathological processes. One of the key roles of the autophagic pathway is to participate in the first line of defense against the invasion of pathogens, as part of the innate immune response. Targeting of intracellular bacteria by the autophagic machinery, either in the cytoplasm or within vacuolar compartments, helps to control bacterial proliferation in the host cell, controlling also the spreading of the infection. In this review we will describe the means used by diverse bacterial pathogens to survive intracellularly and how they are recognized by the autophagic molecular machinery, as well as the mechanisms used to avoid autophagic clearance.

  17. In vitro and ex vivo strategies for intracellular delivery

    Science.gov (United States)

    Stewart, Martin P.; Sharei, Armon; Ding, Xiaoyun; Sahay, Gaurav; Langer, Robert; Jensen, Klavs F.

    2016-10-01

    Intracellular delivery of materials has become a critical component of genome-editing approaches, ex vivo cell-based therapies, and a diversity of fundamental research applications. Limitations of current technologies motivate development of next-generation systems that can deliver a broad variety of cargo to diverse cell types. Here we review in vitro and ex vivo intracellular delivery approaches with a focus on mechanisms, challenges and opportunities. In particular, we emphasize membrane-disruption-based delivery methods and the transformative role of nanotechnology, microfluidics and laboratory-on-chip technology in advancing the field.

  18. Role of intracellular calcium in contraction of internal anal sphincter

    Institute of Scientific and Technical Information of China (English)

    1999-01-01

    @@ INTRODUCTION Internal anal sphincter (IAS) is a continuation of the smooth circular muscle layer thickened at the rectum, innervated by vegetative nerve. IAS is a special smooth muscle, which is different from colonic smooth muscle in physiology and pharmaology[1]. It was found that contraction of gastric smooth muscle depends on the influx of extracellular calcium and release of intracellular calcium[2]. In present study, we observed and compared the effects of extra- and intracellular calcium on the contraction of IAS and colonic smooth muscle.

  19. 静脉注射胺碘酮与普罗帕酮治疗阵发性室上性心动过速疗效的Meta分析%A meta-analysis of amiodarone and propafenone treatment of supraventricular tachycardia

    Institute of Scientific and Technical Information of China (English)

    王少波; 梁锦军; 黄从新

    2013-01-01

    Objective To evaluate the efficacy and safety of intravenous amiodarone and propafenone in treating par-oxysmal supraventricular tachycardia with the meta analysis. Methods Randomized controlled trials ( RCT ) included written in Chinese and English concerned using amiodarone and propafenone in treatment of paroxysmal supraventricular tachycardia were collected from 1999 to 2012 in a meta-analysis. The RevMan 5. 1 software of Cochrane Coordination Net was used for sta-tistical analysis. Results The therapy of amiodarone group and propafenone group in the treatment of paroxysmal supraventric-ular tachycardia effect analysis were: integrated test results was( OR = 1.45, 95% CIO.83 -2.51, P > 0. 05 ). The funnel plot analysis showed no significant bias. The adverse reaction analysis of amiodarone group and propafenone group therapy in the treatment of paroxysmal supraventricular tachycardia as follows: integrated test results was( OR =0.47, 95% CI 0. 29~ 0.77, P >0. 05 ). The funnel plot analysis showed no significant bias. Conclusion The amiodarone group and propafenone group therapy in the treatment of paroxysmal supraventricular tachycardia were showed no obvious differences. The incidence of adverse reactions of the amiodarone were lower than the propafenone.%目的 系统评价静脉注射胺碘酮与普罗帕酮治疗阵发性室上性心动过速的疗效与安全性.方法 计算机检索1999-2012年中英文电子文献数据库,收集有关胺碘酮和普罗帕酮治疗阵发性室上性心动过速的随机对照试验(RCT),应用Cochrane协作网提供的RevMan 5.1软件进行系统评价.结果 最终纳入5篇文献,(1)静脉注射胺碘酮组与普罗帕酮组治疗阵发性室上性心动过速疗效:两药差异无统计学意义(OR=1.45,95%CI 0.83~2.51,P>0.05);漏斗图分析结果未发现显著偏倚.(2)静脉注射胺碘酮组与普罗帕酮组治疗阵发性室上性心动过速不良反应:胺碘酮组不良反应发

  20. The cystic-fibrosis-associated ΔF508 mutation confers post-transcriptional destabilization on the C. elegans ABC transporter PGP-3

    Directory of Open Access Journals (Sweden)

    Liping He

    2012-11-01

    Membrane proteins make up ∼30% of the proteome. During the early stages of maturation, this class of proteins can experience localized misfolding in distinct cellular compartments, such as the cytoplasm, endoplasmic reticulum (ER lumen and ER membrane. ER quality control (ERQC mechanisms monitor folding and determine whether a membrane protein is appropriately folded or is misfolded and warrants degradation. ERQC plays crucial roles in human diseases, such as cystic fibrosis, in which deletion of a single amino acid (F508 results in the misfolding and degradation of the cystic fibrosis transmembrane conductance regulator (CFTR Cl– channel. We introduced the ΔF508 mutation into Caenorhabditis elegans PGP-3, a 12-transmembrane ABC transporter with 15% identity to CFTR. When expressed in intestinal epithelial cells, PGP-3wt was stable and efficiently trafficked to the apical plasma membrane through a COPII-dependent mechanism. However, PGP-3ΔF508 was post-transcriptionally destabilized, resulting in reduced total and apical membrane protein levels. Genetic or physiological activation of the osmotic stress response pathway, which causes accumulation of the chemical chaperone glycerol, stabilized PGP-3ΔF508. Efficient degradation of PGP-3ΔF508 required the function of several C. elegans ER-associated degradation (ERAD homologs, suggesting that destabilization occurs through an ERAD-type mechanism. Our studies show that the ΔF508 mutation causes post-transcriptional destabilization and degradation of PGP-3 in C. elegans epithelial cells. This model, combined with the power of C. elegans genetics, provides a new opportunity to genetically dissect metazoan ERQC.

  1. Analysis on efficacy and safety of amiodarone combined with dabigatran etexilate in treatment of non-valvular atrial fi-brillation%胺碘酮联合达比加群酯治疗非瓣膜性心房颤动的疗效和安全性分析

    Institute of Scientific and Technical Information of China (English)

    李玲; 罗晓丽; 王红勇

    2015-01-01

    Objective To investigate the efficacy and safety of amiodarone combined with dabigatran etexilate in the treatment of non-valvular atrial fibrillation.Methods 76 cases of non-valvular atrial fibrillation in our hospital from January to July 2014 were randomly divided into the treatment group and the control group.The treatment group was treated with amiodarone combined with dabigatran etexilate,while the control group was treated with ami-odarone combined with warfarin.The changes of electrocardiogram(EKG),blood coagulation indexes and biochemical indexes,and adverse reactions were observed in the two groups.Results Compared with before treatment,PT, APTT,INR and TT after treatment in the two groups were increased (P 0.05),the heart rate in the two groups was signif-icantly decreased (P 0.05).9 cases (23.7%) of gastrointestinal reactions occurred in the treatment group,which were higher than 5.3% in the control group (P 0.05),两组患者心率明显降低(P 0.05)。治疗组发生消化道反应9例(23.7%),高于对照组的5.3%(P <0.05)。而治疗组栓塞或血栓以及出血的发生率均低于对照组(P <0.05)。结论胺碘酮联合达比加群酯治疗非瓣膜性心房颤动安全有效,值得在临床推广。

  2. Biochemical and ultrastructural studies suggest that the effects of thapsigargin on human platelets are mediated by changes in intracellular calcium but not by intracellular histamine

    DEFF Research Database (Denmark)

    Saxena, S P; McNicol, A; Becker, A B;

    1992-01-01

    The involvement of intracellular histamine in thapsigargin (Tg)-induced platelet aggregation was studied. Platelet aggregation induced by 0.25 and 0.5 microM Tg was not accompanied by a rise in intracellular histamine but a significant (p <0.01) increase in the level of intracellular histamine wa...

  3. 胺碘酮治疗应用于冠心病急性心肌梗死伴高危快速型心律失常的临床疗效观察%Clinical effect of amiodarone in the treatment of acute myocardial infarction with high risk and rapid arrhythmia

    Institute of Scientific and Technical Information of China (English)

    许雪

    2015-01-01

    目的:研究分析胺碘酮应用于冠心病急性心肌梗死伴高危快速型心律失常的临床疗效.方法:收集我院2013年1月至2014年12月收治的80例冠心病急性心肌梗死伴高危快速型心律失常的患者,将80例患者平均分为观察组与对照组,两组患者均为40例,观察组采用胺碘酮对患者进行治疗,对照组采用利多卡因进行治疗,对两组患者的临床疗效进行对照分析.结果:观察组患者总有效率明显高于对照组(P<0.05).结论:对急性心肌梗死伴高危快速型心律失常的患者静脉注射胺碘酮能有效控制患者病情,胺碘酮治疗急性心肌梗死伴高危快速性心律失常具有良好的疗效,值得在临床上进行推广.%Objective: To study the clinical effect of amiodarone used in coronary heart disease (CHD) with high risk and rapid arrhythmia acute myocardial infarction. Methods: 80 cases of patients with acute myocardial infarction, coronary heart disease associated with high risk of fast arrhythmia patients were collected in our hospital during January 2013 to December 2013. The 80 patients were divided into an observation group and a control group with 40 cases in each group. The observation group was treated with amiodarone and the control group was treated with lidocaine. Analysis on comparison of the clinical curative effect of two groups of patients was conducted. Results: The total effective rate in the observation group was significantly higher than that of the control group (P< 0.05). Conclusion: For the acute myocardial infarction patients with high risk and rapid arrhythmia intravenous, amiodarone is effective to control the patient's condition. Amiodarone in treatment of acute myocardial infarction with high risk and rapid arrhythmia has good curative effect and it is worthy of application in clinical treatment.

  4. CONTRIBUTIONS OF INTRACELLULAR IONS TO Kv CHANNEL VOLTAGE SENSOR DYNAMICS.

    Directory of Open Access Journals (Sweden)

    Samuel eGoodchild

    2012-06-01

    Full Text Available Voltage sensing domains of Kv channels control ionic conductance through coupling of the movement of charged residues in the S4 segment to conformational changes at the cytoplasmic region of the pore domain, that allow K+ ions to flow. Conformational transitions within the voltage sensing domain caused by changes in the applied voltage across the membrane field are coupled to the conducting pore region and the gating of ionic conductance. However, several other factors not directly linked to the voltage dependent movement of charged residues within the voltage sensor impact the dynamics of the voltage sensor, such as inactivation, ionic conductance, intracellular ion identity and block of the channel by intracellular ligands. The effect of intracellular ions on voltage sensor dynamics is of importance in the interpretation of gating current measurements and the physiology of pore/voltage sensor coupling. There is a significant amount of variability in the reported kinetics of voltage sensor deactivation kinetics of Kv channels attributed to different mechanisms such as open state stabilization, immobilization and relaxation processes of the voltage sensor. Here we separate these factors and focus on the causal role that intracellular ions can play in allosterically modulating the dynamics of Kv voltage sensor deactivation kinetics. These considerations are of critical importance in understanding the molecular determinants of the complete channel gating cycle from activation to deactivation.

  5. Monitoring intracellular oxidative events using dynamic spectral unmixing microscopy

    Science.gov (United States)

    There is increasing interest in using live-cell imaging to monitor not just individual intracellular endpoints, but to investigate the interplay between multiple molecular events as they unfold in real time within the cell. A major impediment to simultaneous acquisition of multip...

  6. Nutrient salvaging and metabolism by the intracellular pathogen Legionella pneumophila.

    Science.gov (United States)

    Fonseca, Maris V; Swanson, Michele S

    2014-01-01

    The Gram-negative bacterium Legionella pneumophila is ubiquitous in freshwater environments as a free-swimming organism, resident of biofilms, or parasite of protozoa. If the bacterium is aerosolized and inhaled by a susceptible human host, it can infect alveolar macrophages and cause a severe pneumonia known as Legionnaires' disease. A sophisticated cell differentiation program equips L. pneumophila to persist in both extracellular and intracellular niches. During its life cycle, L. pneumophila alternates between at least two distinct forms: a transmissive form equipped to infect host cells and evade lysosomal degradation, and a replicative form that multiplies within a phagosomal compartment that it has retooled to its advantage. The efficient changeover between transmissive and replicative states is fundamental to L. pneumophila's fitness as an intracellular pathogen. The transmission and replication programs of L. pneumophila are governed by a number of metabolic cues that signal whether conditions are favorable for replication or instead trigger escape from a spent host. Several lines of experimental evidence gathered over the past decade establish strong links between metabolism, cellular differentiation, and virulence of L. pneumophila. Herein, we focus on current knowledge of the metabolic components employed by intracellular L. pneumophila for cell differentiation, nutrient salvaging and utilization of host factors. Specifically, we highlight the metabolic cues that are coupled to bacterial differentiation, nutrient acquisition systems, and the strategies utilized by L. pneumophila to exploit host metabolites for intracellular replication.

  7. The outcome of Cryptococcus neoformans intracellular pathogenesis in human monocytes

    Directory of Open Access Journals (Sweden)

    Pirofski Liise-anne

    2009-03-01

    Full Text Available Abstract Background Cryptococcus neoformans is an encapsulated yeast that is a facultative intracellular pathogen. The interaction between macrophages and C. neoformans is critical for extrapulmonary dissemination of this pathogenic yeast. C. neoformans can either lyse macrophages or escape from within them through a process known as phagosomal extrusion. However, most studies of intracellular pathogenesis have been made with mouse cells and their relevance to human infection is uncertain. In this study we extended studies of C. neoformans-macrophage cellular interaction/s to human peripheral blood monocytes. Results This study demonstrated that C. neoformans can shed polysaccharide within human monocytes, spread from cell to cell, and be extruded from them. Furthermore, human monocytes responded to ingestion of C. neoformans with cell cycle progression from G1 to S. Conclusion Similarities between mouse and human cells support the suitability of mouse cells for the study of intracellular pathogenesis mechanisms. Given that these hosts diverged over 70 million years ago, the similar pathogenic strategies for C. neoformans in murine and human cells supports the hypothesis that the mechanism that underlies the mammalian intracellular pathogenesis of C. neoformans originated from interactions with a third host, possibly soil amoeboid predators, before the mammalian radiation.

  8. Cell-penetrating antimicrobial peptides - prospectives for targeting intracellular infections

    DEFF Research Database (Denmark)

    Bahnsen, Jesper S; Franzyk, Henrik; Sayers, Edward J;

    2015-01-01

    . TPk showed the highest antibacterial activity. SA-3 exhibited selective disruption of liposomes mimicking Gram-positive and Gram-negative membranes. CONCLUSION: PK-12-KKP is an unlikely candidate for targeting intracellular bacteria, as the eukaryotic cell-penetrating ability is poor. SA-3, affected...

  9. Biomineralization Patterns of Intracellular Carbonatogenesis in Cyanobacteria: Molecular Hypotheses

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    Jinhua Li

    2016-02-01

    Full Text Available The recent discovery of intracellular carbonatogenesis in several cyanobacteria species has challenged the traditional view that this process was extracellular and not controlled. However, a detailed analysis of the size distribution, chemical composition and 3-D-arrangement of carbonates in these cyanobacteria is lacking. Here, we characterized these features in Candidatus Gloeomargarita lithophora C7 and Candidatus Synechococcus calcipolaris G9 by conventional transmission electron microscopy, tomography, ultramicrotomy, and scanning transmission X-ray microscopy (STXM. Both Ca. G. lithophora C7 and Ca. S. calcipolaris G9 formed numerous polyphosphate granules adjacent or engulfing Ca-carbonate inclusions when grown in phosphate-rich solutions. Ca-carbonates were scattered within Ca. G. lithophora C7 cells under these conditions, but sometimes arranged in one or several chains. In contrast, Ca-carbonates formed at cell septa in Ca. S. calcipolaris G9 and were segregated equally between daughter cells after cell division, arranging as distorted disks at cell poles. The size distribution of carbonates evolved from a positively to a negatively skewed distribution as particles grew. Conventional ultramicrotomy did not preserve Ca-carbonates explaining partly why intracellular calcification has been overlooked in the past. All these new observations allow discussing with unprecedented insight some nucleation and growth processes occurring in intracellularly calcifying cyanobacteria with a particular emphasis on the possible involvement of intracellular compartments and cytoskeleton.

  10. Novel Waddlia Intracellular Bacterium in Artibeus intermedius Fruit Bats, Mexico.

    Science.gov (United States)

    Pierlé, Sebastián Aguilar; Morales, Cirani Obregón; Martínez, Leonardo Perea; Ceballos, Nidia Aréchiga; Rivero, Juan José Pérez; Díaz, Osvaldo López; Brayton, Kelly A; Setién, Alvaro Aguilar

    2015-12-01

    An intracellular bacterium was isolated from fruit bats (Artibeus intermedius) in Cocoyoc, Mexico. The bacterium caused severe lesions in the lungs and spleens of bats and intracytoplasmic vacuoles in cell cultures. Sequence analyses showed it is related to Waddlia spp. (order Chlamydiales). We propose to call this bacterium Waddlia cocoyoc.

  11. Imaging atrial arrhythmic intracellular calcium in intact heart.

    Science.gov (United States)

    Xie, Wenjun; Santulli, Gaetano; Guo, Xiaoxiao; Gao, Melanie; Chen, Bi-Xing; Marks, Andrew R

    2013-11-01

    Abnormalities in intracellular Ca(2+) signaling have been proposed to play an essential role in the pathophysiology of atrial arrhythmias. However, a direct observation of intracellular Ca(2+) in atrial myocytes during atrial arrhythmias is lacking. Here, we have developed an ex vivo model of simultaneous Ca(2+) imaging and electrocardiographic recording in cardiac atria. Using this system we were able to record atrial arrhythmic intracellular Ca(2+) activities. Our results indicate that atrial arrhythmias can be tightly linked to intracellular Ca(2+) waves and Ca(2+) alternans. Moreover, we applied this strategy to analyze Ca(2+) signals in the hearts of WT and knock-in mice harboring a 'leaky' type 2 ryanodine receptor (RyR2-R2474S). We showed that sarcoplasmic reticulum (SR) Ca(2+) leak increases the susceptibility to Ca(2+) alternans and Ca(2+) waves increasing the incidence of atrial arrhythmias. Reduction of SR Ca(2+) leak via RyR2 by acute treatment with S107 reduced both Ca(2+) alternans and Ca(2+) waves, and prevented atrial arrhythmias.

  12. Intracellular localization of VAMP-1 protein in human neutrophils.

    Science.gov (United States)

    Nabokina, S M

    2001-02-01

    We studied the intracellular localization of vesicle-associated membrane protein VAMP-1 in human neutrophils. VAMP-1 was associated with membranes of gelatinase and specific secretory granules rapidly mobilized during exocytosis. VAMP-1 probably acts as a component of the SNARE complex during exocytosis of gelatinase and specific granules in human neutrophils.

  13. Intracellular pH measurements using perfluorocarbon nanoemulsions.

    Science.gov (United States)

    Patrick, Michael J; Janjic, Jelena M; Teng, Haibing; O'Hear, Meredith R; Brown, Cortlyn W; Stokum, Jesse A; Schmidt, Brigitte F; Ahrens, Eric T; Waggoner, Alan S

    2013-12-11

    We report the synthesis and formulation of unique perfluorocarbon (PFC) nanoemulsions enabling intracellular pH measurements in living cells via fluorescent microscopy and flow cytometry. These nanoemulsions are formulated to readily enter cells upon coincubation and contain two cyanine-based fluorescent reporters covalently bound to the PFC molecules, specifically Cy3-PFC and CypHer5-PFC conjugates. The spectral and pH-sensing properties of the nanoemulsions were characterized in vitro and showed the unaltered spectral behavior of dyes after formulation. In rat 9L glioma cells loaded with nanoemulsion, the local pH of nanoemulsions was longitudinally quantified using optical microscopy and flow cytometry and displayed a steady decrease in pH to a level of 5.5 over 3 h, indicating rapid uptake of nanoemulsion to acidic compartments. Overall, these reagents enable real-time optical detection of intracellular pH in living cells in response to pharmacological manipulations. Moreover, recent approaches for in vivo cell tracking using magnetic resonance imaging (MRI) employ intracellular PFC nanoemulsion probes to track cells using (19)F MRI. However, the intracellular fate of these imaging probes is poorly understood. The pH-sensing nanoemulsions allow the study of the fate of the PFC tracer inside the labeled cell, which is important for understanding the PFC cell loading dynamics, nanoemulsion stability and cell viability over time.

  14. Deciphering the Intracellular Fate of Propionibacterium acnes in Macrophages

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    Natalie Fischer

    2013-01-01

    Full Text Available Propionibacterium acnes is a Gram-positive bacterium that colonizes various niches of the human body, particularly the sebaceous follicles of the skin. Over the last years a role of this common skin bacterium as an opportunistic pathogen has been explored. Persistence of P. acnes in host tissue has been associated with chronic inflammation and disease development, for example, in prostate pathologies. This study investigated the intracellular fate of P. acnes in macrophages after phagocytosis. In a mouse model of P. acnes-induced chronic prostatic inflammation, the bacterium could be detected in prostate-infiltrating macrophages at 2 weeks postinfection. Further studies performed in the human macrophage cell line THP-1 revealed intracellular survival and persistence of P. acnes but no intracellular replication or escape from the host cell. Confocal analyses of phagosome acidification and maturation were performed. Acidification of P. acnes-containing phagosomes was observed at 6 h postinfection but then lost again, indicative of cytosolic escape of P. acnes or intraphagosomal pH neutralization. No colocalization with the lysosomal markers LAMP1 and cathepsin D was observed, implying that the P. acnes-containing phagosome does not fuse with lysosomes. Our findings give first insights into the intracellular fate of P. acnes; its persistency is likely to be important for the development of P. acnes-associated inflammatory diseases.

  15. Intracellular pH gradients in migrating cells

    DEFF Research Database (Denmark)

    Martin, Christine; Pedersen, Stine Helene Falsig; Schwab, Albrecht;

    2011-01-01

    might function as such unevenly distributed regulators as they modulate the interaction of focal adhesion proteins and components of the cytoskeleton in vitro. However, an intracellular pH (pH(i)) gradient reflecting a spatial asymmetry of protons has not been shown so far. One major regulator of p...

  16. Galectin-3 guides intracellular trafficking of some human serotransferrin glycoforms

    DEFF Research Database (Denmark)

    Carlsson, Carl Michael; Bengtson, Per; Cucak, Helena

    2013-01-01

    these transferrin glycoforms differently after preloading with exogenously added galectin-3. In all, this study provides the first evidence of a functional role for transferrin glycans, in intracellular trafficking after uptake. Moreover, the galectin-3 bound glycoform increased in cancer, suggesting...

  17. Intracellular particle tracking as a tool for tumor cell characterization

    NARCIS (Netherlands)

    Li, Yixuan; Duits, Michel H.G.; Schnekenburger, Jürgen

    2009-01-01

    We studied the dynamics of two types of intracellular probe particles, ballistically injected latex spheres and endogenous granules, in tumor cell lines of differerent metastatic potential: breast tumor cells (MCF-7 malignant, MCF-10A benign) and pancreas adenocarcinoma (PaTu8988T malignant, PaTu898

  18. Bioresponsive poly(amidoamine)s designed for intracellular protein delivery

    NARCIS (Netherlands)

    Coue, G.M.J.P.C.; Freese, C.; Unger, R.E.; Kirkpatrick, C.J.; Engbersen, J.F.J.

    2013-01-01

    Poly(amidoamine)s with bioreducible disulfide linkages in the main chain (SS-PAAs) and pH-responsive, negatively charged citraconate groups in the sidechain have been designed for effective intracellular delivery and release of proteins with a net positive charge at neutral pH. Using lysozyme as a c

  19. Environmental and intracellular regulation of Francisella tularensis ripA

    Directory of Open Access Journals (Sweden)

    Taft-Benz Sharon

    2009-10-01

    Full Text Available Abstract Background Francisella tularensis is a highly virulent, facultative intracellular pathogen and the etiologic agent of the zoonotic disease Tularemia. RipA is a cytoplasmic membrane protein that is conserved among Francisella species and is required for intracellular growth. F. tularensis ripA deletion mutants escape the phagosome of infected cells, but unlike wild type organisms fail to replicate in the host cell cytoplasm. Results Further analysis of ripA with respect to environmental effects on the growth of mutant strains and expression levels revealed that RipA is required for optimal growth at pH 7.5 but not pH 6.5. Using a combination of RT-PCR, ripA-lacZ transcriptional and translational fusions, and a RipA-tetracysteine tag fusion protein we found that both ripA transcription and RipA protein levels were elevated in organisms grown at pH 7.5 as compared to organisms grown at pH 5.5. A number of genes, including iglA, that are required for intracellular growth are regulated by the transcriptional regulators MglA and SspA, and are induced upon infection of host cells. We quantified ripA and iglA expression at different stages of intracellular growth and found that the expression of each increased between 1 and 6 hours post infection. Given the similar intracellular expression patterns of ripA and iglA and that MglA and SspA are positive regulators of iglA we tested the impact of mglA and sspA deletions on ripA and iglA expression. In the deletion mutant strains iglA expression was reduced dramatically as expected, however ripA expression was increased over 2-fold. Conclusion Expression of ripA is required for growth at neutral pH, is pH sensitive, and is responsive to the intracellular environment. The intracellular expression pattern of ripA coincided with iglA, which is positively regulated by MglA and SspA. However, in contrast to their positive impact on iglA expression, MglA and SspA negatively impacted ripA expression in

  20. Legionella pneumophila transcriptome during intracellular multiplication in human macrophages

    Directory of Open Access Journals (Sweden)

    Sebastien P Faucher

    2011-04-01

    Full Text Available Legionella pneumophila is the causative agent of Legionnaires’ disease, an acute pulmonary infection. L. pneumophila is able to infect and multiply in both phagocytic protozoa, such as Acanthamoeba castellanii, and mammalian professional phagocytes. The best-known L. pneumophila virulence determinant is the Icm/Dot Type IVB secretion system (TFBSS, which is used to translocate more than 150 effector proteins to host cells. While the transcriptional response of Legionella to the intracellular environment of A. castellanii has been investigated, much less is known about the Legionella transcriptional response inside human macrophages. In this study, the transcriptome of L. pneumophila was monitored during exponential and post-exponential phase in rich AYE broth as well as during infection of human cultured macrophages. This was accomplished with microarrays and an RNA amplification procedure called SCOTS to detect small amounts of mRNA from low numbers of intracellular bacteria. Among the genes induced intracellularly are those involved in amino acid biosynthetic pathways leading to L-arginine, L-histidine and L-proline as well as many transport systems involved in amino acid and iron uptake. Gene involved in catabolism of glycerol is also induced during intracellular growth and could be used as a carbon source. The genes encoding the Icm/Dot system are not differentially expressed inside cells compared to control bacteria grown in rich broth, but the genes encoding several translocated effectors are strongly induced. Moreover, we used the transcriptome data to predict previously unrecognized Icm/Dot effector genes based on their expression pattern and confirmed translocation for three candidates. This study provides a comprehensive view of how L. pneumophila responds to the human macrophage intracellular environment.

  1. Modulation of intracellular calcium levels by calcium lactate affects colon cancer cell motility through calcium-dependent calpain.

    Directory of Open Access Journals (Sweden)

    Pasupathi Sundaramoorthy

    Full Text Available Cancer cell motility is a key phenomenon regulating invasion and metastasis. Focal adhesion kinase (FAK plays a major role in cellular adhesion and metastasis of various cancers. The relationship between dietary supplementation of calcium and colon cancer has been extensively investigated. However, the effect of calcium (Ca2+ supplementation on calpain-FAK-motility is not clearly understood. We sought to identify the mechanism of FAK cleavage through Ca2+ bound lactate (CaLa, its downstream signaling and role in the motility of human colon cancer cells. We found that treating HCT116 and HT-29 cells with CaLa immediately increased the intracellular Ca2+ (iCa2+ levels for a prolonged period of time. Ca2+ influx induced cleavage of FAK into an N-terminal FAK (FERM domain in a dose-dependent manner. Phosphorylated FAK (p-FAK was also cleaved in to its p-N-terminal FAK. CaLa increased colon cancer cells motility. Calpeptin, a calpain inhibitor, reversed the effects of CaLa on FAK and pFAK cleavage in both cancer cell lines. The cleaved FAK translocates into the nucleus and modulates p53 stability through MDM2-associated ubiquitination. CaLa-induced Ca2+ influx increased the motility of colon cancer cells was mediated by calpain activity through FAK and pFAK protein destabilization. In conclusion, these results suggest that careful consideration may be given in deciding dietary Ca2+ supplementation to patient undergoing treatment for metastatic cancer.

  2. Genomic analysis suggests that mRNA destabilization by the microprocessor is specialized for the auto-regulation of Dgcr8.

    Directory of Open Access Journals (Sweden)

    Archana Shenoy

    Full Text Available BACKGROUND: The Microprocessor, containing the RNA binding protein Dgcr8 and RNase III enzyme Drosha, is responsible for processing primary microRNAs to precursor microRNAs. The Microprocessor regulates its own levels by cleaving hairpins in the 5'UTR and coding region of the Dgcr8 mRNA, thereby destabilizing the mature transcript. METHODOLOGY/PRINCIPAL FINDINGS: To determine whether the Microprocessor has a broader role in directly regulating other coding mRNA levels, we integrated results from expression profiling and ultra high-throughput deep sequencing of small RNAs. Expression analysis of mRNAs in wild-type, Dgcr8 knockout, and Dicer knockout mouse embryonic stem (ES cells uncovered mRNAs that were specifically upregulated in the Dgcr8 null background. A number of these transcripts had evolutionarily conserved predicted hairpin targets for the Microprocessor. However, analysis of deep sequencing data of 18 to 200nt small RNAs in mouse ES, HeLa, and HepG2 indicates that exonic sequence reads that map in a pattern consistent with Microprocessor activity are unique to Dgcr8. CONCLUSION/SIGNIFICANCE: We conclude that the Microprocessor's role in directly destabilizing coding mRNAs is likely specifically targeted to Dgcr8 itself, suggesting a specialized cellular mechanism for gene auto-regulation.

  3. Relative contribution of structural inheritance and glacial morphology on the post-glacial slope destabilization. The Séchilienne slope case study (French western Alps).

    Science.gov (United States)

    Schwartz, Stéphane; Zerathe, Swann; Audin, Laurence; Dumont, Thierry; Jarre, Raphael; Jongmans, Denis; Carcaillet, Julien; Dubois, Laurent

    2016-04-01

    In the main Alpine valleys, the chronological constraints about the onset of the slope movements following glacial retreat are scarse. The southern part of the Belledonne massif (French western Alps) along the Romanche valley is affected by numerous slope destabilizations. A detailed geomorphological study using a high resolution LIDAR digital model elevation, allows to characterize the structural framework, the evolution of the glacial retreat and the distribution of the gravitational instabilities. The systematic survey of (i) the main fracturing and (ii) the glacial and gravity morphological witness along the slopes of the Romanche valley coupled with (iii) cosmogenic 10Be dating provides a regional view of the dynamics of slope destabilisation in this area. The proposed scenario allows to evaluate the relative influence of different triggering factors such as seismo-tectonic stresses and climatic changes. These data also allow to propose a consistent dynamic destabilization model of a major lanslide (> 100×106 m3) in relation with the last episode of glacial retreat ~ 21ka ago.

  4. Destabilization of PDK1 by Hsp90 inactivation suppresses hepatitis C virus replication through inhibition of PRK2-mediated viral RNA polymerase phosphorylation.

    Science.gov (United States)

    Kim, Mi-Gyeong; Moon, Jae-Su; Kim, Eun-Jung; Lee, Seung-Hoon; Oh, Jong-Won

    2012-04-27

    Heat shock protein 90 (Hsp90), which chaperones multiple client proteins, has been shown to be implicated in HCV replication. Pharmacological inhibitors of Hsp90 display an anti-HCV activity. However, little is known about the mechanisms of regulation of HCV replication by Hsp90. Here, we show that Hsp90 inhibition by 17-(dimethylaminoethylamino)-17-demethoxygeldanamycin (17-DMAG) destabilizes phosphoinositide-dependent kinase-1 (PDK1), an upstream kinase of the protein kinase C-related kinase 2 (PRK2) responsible for phosphorylation of HCV RNA polymerase, through the proteosome pathway. Destabilization of PDK1 led to inhibition of phosphorylation of the viral RNA polymerase through a decrease in the abundance of active form PRK2 level. Consequently, Hsp90 inhibition resulted in suppression of HCV replication both in human hepatoma Huh7 cells harboring an HCV subgenomic replicon and in HCV-infected cells. 17-DMAG treatment did not interfere with HCV internal ribosome entry site-mediated translation and the cell cycle in Huh7 cells. Co-treatment of 17-DMAG with interferon-α or HA1077, an inhibitor of PRK2, enhanced the anti-HCV activity of 17-DMAG. Taken together, these findings suggest that Hsp90 plays a critical role in the regulation of HCV RNA polymerase phosphorylation via the PDK1-PRK2 signaling pathway.

  5. Task Repetition and Noticing as a Route to Semester-long Destabilization: A Cross-sectional Study of Iranian EFL Learners’ Oral Output

    Directory of Open Access Journals (Sweden)

    Ali Eliasi

    2013-05-01

    Full Text Available Tackling learners’ erroneous oral output has always been a substantial issue for both language teachers and researchers. Taking Swain’s output hypothesis and Schmidt’s noticing hypothesis into account, this study aims at investigating the effect of task- initiated noticing along with task repetition sessions as a route to destabilization of learner errors. The participants of the study were thirty two Iranian upper-intermediate learners.  The participants were divided into two groups, an experimental and a control group.  Both groups’ voices were recorded while delivering a prepared speech. The participants in experimental group were given the recorded presentation to be transcribed and compared with the original text they used while the control group didn’t receive feedback of any kind. The experimental group submitted a draft to their teacher who checked the papers and later asked them to prepare themselves for another prepared speech in the future. There was a pre-test, a treatment and a post-test. The comparison of the erroneous utterances in both groups lent support to the effectiveness of task repetition and noticing on destabilization of learners’ oral output. Keywords: fossilization, noticing, task repetition, output

  6. Enhanced intracellular delivery and antibacterial efficacy of enrofloxacin-loaded docosanoic acid solid lipid nanoparticles against intracellular Salmonella

    Science.gov (United States)

    Xie, Shuyu; Yang, Fei; Tao, Yanfei; Chen, Dongmei; Qu, Wei; Huang, Lingli; Liu, Zhenli; Pan, Yuanhu; Yuan, Zonghui

    2017-01-01

    Enrofloxacin-loaded docosanoic acid solid lipid nanoparticles (SLNs) with different physicochemical properties were developed to enhance activity against intracellular Salmonella. Their cellular uptake, intracellular elimination and antibacterial activity were studied in RAW 264.7 cells. During the experimental period, SLN-encapsulated enrofloxacin accumulated in the cells approximately 27.06–37.71 times more efficiently than free drugs at the same extracellular concentration. After incubation for 0.5 h, the intracellular enrofloxacin was enhanced from 0.336 to 1.147 μg/mg of protein as the sizes of nanoparticles were increased from 150 to 605 nm, and from 0.960 to 1.147 μg/mg of protein when the charge was improved from −8.1 to −24.9 mv. The cellular uptake was more significantly influenced by the size than it was by the charge, and was not affected by whether the charge was positive or negative. The elimination of optimal SLN-encapsulated enrofloxacin from the cells was significantly slower than that of free enrofloxacin after removing extracellular drug. The inhibition effect against intracellular Salmonella CVCC541 of 0.24 and 0.06 μg/mL encapsulated enrofloxacin was stronger than 0.6 μg/mL free drug after all of the incubation periods and at 48 h, respectively. Docosanoic acid SLNs are thus considered as a promising carrier for intracellular bacterial treatment. PMID:28112240

  7. Analysing intracellular deformation of polymer capsules using structured illumination microscopy

    Science.gov (United States)

    Chen, Xi; Cui, Jiwei; Sun, Huanli; Müllner, Markus; Yan, Yan; Noi, Ka Fung; Ping, Yuan; Caruso, Frank

    2016-06-01

    Understanding the behaviour of therapeutic carriers is important in elucidating their mechanism of action and how they are processed inside cells. Herein we examine the intracellular deformation of layer-by-layer assembled polymer capsules using super-resolution structured illumination microscopy (SIM). Spherical- and cylindrical-shaped capsules were studied in three different cell lines, namely HeLa (human epithelial cell line), RAW264.7 (mouse macrophage cell line) and differentiated THP-1 (human monocyte-derived macrophage cell line). We observed that the deformation of capsules was dependent on cell line, but independent of capsule shape. This suggests that the mechanical forces, which induce capsule deformation during cell uptake, vary between cell lines, indicating that the capsules are exposed to higher mechanical forces in HeLa cells, followed by RAW264.7 and then differentiated THP-1 cells. Our study demonstrates the use of super-resolution SIM in analysing intracellular capsule deformation, offering important insights into the cellular processing of drug carriers in cells and providing fundamental knowledge of intracellular mechanobiology. Furthermore, this study may aid in the design of novel drug carriers that are sensitive to deformation for enhanced drug release properties.Understanding the behaviour of therapeutic carriers is important in elucidating their mechanism of action and how they are processed inside cells. Herein we examine the intracellular deformation of layer-by-layer assembled polymer capsules using super-resolution structured illumination microscopy (SIM). Spherical- and cylindrical-shaped capsules were studied in three different cell lines, namely HeLa (human epithelial cell line), RAW264.7 (mouse macrophage cell line) and differentiated THP-1 (human monocyte-derived macrophage cell line). We observed that the deformation of capsules was dependent on cell line, but independent of capsule shape. This suggests that the mechanical forces

  8. Influence of amiodarone on cardiac function in patients with arrhythmia%探讨胺碘酮对冠心病心律不齐患者心功能的影响

    Institute of Scientific and Technical Information of China (English)

    张春茹; 吕健; 郝丹

    2016-01-01

    Objective To investigate the influence of amiodarone on cardiac function and adverse events in elderly patients with arrhythmia. Methods A total of 78 elderly patients with arrhythmia who were diagnosed and treated in our hospital from March 2015 to March 2016 were enrolled and randomly divided into control group with 40 patients and observation group with 38 patients. Both groups were given conventional drugs for the treatment of coronary heart disease. The patients in the control group were given oral mexiletine treatment in addition, and those in the observation group were given oral amiodarone and long-term maintenance treatment in addition. The clinical effect and adverse events were compared between the two groups after one course of the treatment (14 days). Results The observation group had a significantly higher overall response rate than the control group (89.47% vs 65.0%, P0.05); after treatment, the observation group had significantly lower serum levels of hs-CRP and NT-proBNP and a significantly longer 6-minute walking distance compared with the control group (P<0.05). Six patients in the control group (15.0%) and 2 in the observation group (5.26%) experienced adverse events such as vomiting and nausea. The patients in both group achieved remission of symptoms after drug withdrawal. Among the patients in the control group, 3 (7.89%) experienced sinus bradycardia and a normal cardiac rhythm after the dose was reduced. Conclusion As for elderly patients with arrhythmia, amiodarone treatment has a significant clinical effect and few adverse effects and can significantly improve patients' cardiac function and relieve their signs. Clinical practice shows that this drug has a long half-life and needs few times of administration,which helps to guarantee safety. Therefore, it holds promise for clinical application.%目的:探讨胺碘酮对老年冠心病心律不齐患者心功能与不良反应的影响。方法选取2015年3月-2016年3

  9. Pico gauges for minimally invasive intracellular hydrostatic pressure measurements.

    Science.gov (United States)

    Knoblauch, Jan; Mullendore, Daniel L; Jensen, Kaare H; Knoblauch, Michael

    2014-11-01

    Intracellular pressure has a multitude of functions in cells surrounded by a cell wall or similar matrix in all kingdoms of life. The functions include cell growth, nastic movements, and penetration of tissue by parasites. The precise measurement of intracellular pressure in the majority of cells, however, remains difficult or impossible due to their small size and/or sensitivity to manipulation. Here, we report on a method that allows precise measurements in basically any cell type over all ranges of pressure. It is based on the compression of nanoliter and picoliter volumes of oil entrapped in the tip of microcapillaries, which we call pico gauges. The production of pico gauges can be accomplished with standard laboratory equipment, and measurements are comparably easy to conduct. Example pressure measurements are performed on cells that are difficult or impossible to measure with other methods.

  10. Intracellular transport proteins: classification, structure and function of kinesins

    Directory of Open Access Journals (Sweden)

    Agnieszka Chudy

    2011-09-01

    Full Text Available Correct cell functioning, division and morphogenesis rely on efficient intracellular transport. Apart from dyneins and myosins, kinesins are the main proteins responsible for intracellular movement. Kinesins are a large, diverse group of motor proteins, which based on phylogenetic similarity were classified into fourteen families. Among these families, due to the location of their motor domains, three groups have been characterized: N-, C- and M-kinesin. As molecular motors, kinesins transport various molecules and vesicles mainly towards the microtubule plus end (from the cell body participating in anterograde transport, although there are also kinesins involved in retrograde transport (C-kinesins. Kinesins are also involved in spindle formation, chromosome segregation, and spermatogenesis. Because of their great importance for the correct functioning of cells, mutations in kinesin coding genes may lead to such neurodegenerative diseases as dominant hereditary spastic paraplegia or Charcot-Marie-Tooth disease.

  11. An Intracellular Calcium Oscillations Model Including Mitochondrial Calcium Cycling

    Institute of Scientific and Technical Information of China (English)

    SHI Xiao-Min; LIU Zeng-Rong

    2005-01-01

    @@ Calcium is a ubiquitous second messenger. Mitochondria contributes significantly to intracellular Ca2+ dynamics.The experiment of Kaftan et al. [J. Biol. Chem. 275(2000) 25465] demonstrated that inhibiting mitochondrial Ca2+ uptake can reduce the frequency of cytosolic Ca2+ concentration oscillations of gonadotropes. By considering the mitochondrial Ca2+ cycling we develop a three-variable model of intracellular Ca2+ oscillations based on the models of Atri et al. [Biophys. J. 65 (1993) 1727] and Falcke et al. [Biophys. J. 77 (1999) 37]. The model reproduces the fact that mitochondrial Ca2+ cycling increases the frequency of cytosolic Ca2+ oscillations, which accords with Kaftan's results. Moreover the model predicts that when the mitochondria overload with Ca2+, the cytosolic Ca2+ oscillations vanish, which may trigger apoptosis.

  12. Intracellular transport driven by cytoskeletal motors: General mechanisms and defects

    CERN Document Server

    Appert-Rolland, Cecile; Santen, Ludger

    2015-01-01

    Cells are strongly out-of-equilibrium systems driven by continuous energy supply. They carry out many vital functions requiring active transport of various ingredients and organelles, some being small, others being large. The cytoskeleton, composed of three types of filaments, determines the shape of the cell and plays a role in cell motion. It also serves as a road network for the so-called cytoskeletal motors. These molecules can attach to a cytoskeletal filament, perform directed motion, possibly carrying along some cargo, and then detach. It is a central issue to understand how intracellular transport driven by molecular motors is regulated, in particular because its breakdown is one of the signatures of some neuronal diseases like the Alzheimer. We give a survey of the current knowledge on microtubule based intracellular transport. We first review some biological facts obtained from experiments, and present some modeling attempts based on cellular automata. We start with background knowledge on the origi...

  13. Non-contact intracellular binding of chloroplasts in vivo

    Science.gov (United States)

    Li, Yuchao; Xin, Hongbao; Liu, Xiaoshuai; Li, Baojun

    2015-06-01

    Non-contact intracellular binding and controllable manipulation of chloroplasts in vivo was demonstrated using an optical fiber probe. Launching a 980-nm laser beam into a fiber, which was placed about 3 μm above the surface of a living plant (Hydrilla verticillata) leaf, enabled stable binding of different numbers of chloroplasts, as well as their arrangement into one-dimensional chains and two-dimensional arrays inside the leaf without damaging the chloroplasts. Additionally, the formed chloroplast chains were controllably transported inside the living cells. The optical force exerted on the chloroplasts was calculated to explain the experimental results. This method provides a flexible method for studying intracellular organelle interaction with highly organized organelle-organelle contact in vivo in a non-contact manner.

  14. Monitoring the intracellular calcium response to a dynamic hypertonic environment

    Science.gov (United States)

    Huang, Xiaowen; Yue, Wanqing; Liu, Dandan; Yue, Jianbo; Li, Jiaqian; Sun, Dong; Yang, Mengsu; Wang, Zuankai

    2016-03-01

    The profiling of physiological response of cells to external stimuli at the single cell level is of importance. Traditional approaches to study cell responses are often limited by ensemble measurement, which is challenging to reveal the complex single cell behaviors under a dynamic environment. Here we report the development of a simple microfluidic device to investigate intracellular calcium response to dynamic hypertonic conditions at the single cell level in real-time. Interestingly, a dramatic elevation in the intracellular calcium signaling is found in both suspension cells (human leukemic cell line, HL-60) and adherent cells (lung cancer cell line, A549), which is ascribed to the exposure of cells to the hydrodynamic stress. We also demonstrate that the calcium response exhibits distinct single cell heterogeneity as well as cell-type-dependent responses to the same stimuli. Our study opens up a new tool for tracking cellular activity at the single cell level in real time for high throughput drug screening.

  15. Efficient intracellular retrotransposition of an exogenous primate retrovirus genome

    OpenAIRE

    Heinkelein, Martin; Pietschmann, Thomas; Jármy, Gergely; Dressler, Marco; Imrich, Horst; Thurow, Jana; Lindemann, Dirk,; Bock, Michael; Moebes, Astrid; Roy, Jacqueline; Herchenröder, Ottmar; Rethwilm, Axel

    2000-01-01

    The foamy virus (FV) subgroup of Retroviridae reverse transcribe their RNA (pre-)genome late in the replication cycle before leaving an infected cell. We studied whether a marker gene-transducing FV vector is able to shuttle to the nucleus and integrate into host cell genomic DNA. While a potential intracellular retrotransposition of vectors derived from other retroviruses was below the detection limit of our assay, we found that up to 5% of cells transfected with the FV vector were stably tr...

  16. Mycobacterium intracellulare infection in a capybara (Hydrochoerus hydrochaeris).

    Science.gov (United States)

    Pezzone, Natalia; Eberhardt, Ayelen T; Fernández, Analia; Garbaccio, Sergio; Zumárraga, Martín; Gioffré, Andrea; Magni, Carolina; Beldomenico, Pablo M; Marini, M Rocío; Canal, Ana M

    2013-12-01

    This report describes the first case of Mycobacterium intracellulare infection with typical granulomatous lesions of mycobacteriosis in a capybara (Hydrochoerus hydrochaeris). The individual was a captive-bred young female, part of the control group of an experimental study on stress. Multiple granulomatous lesions were detected in a mesenteric lymph node of this young female. Mycobacterial infection was confirmed by bacteriologic culture and molecular identification methods. Clinical lesions were characterized by histopathology.

  17. Effect of mycobacteriophage to intracellular mycobateria in vitro

    Institute of Scientific and Technical Information of China (English)

    2006-01-01

    @@ Mycobacterium tuberculosis (M. tuberculosis) is a pathogen associated with the deaths of millions of people worldwide annually. Although tuberculosis is a treatable disease, the emergence and increasing prevalence of multi-drug resistant bacterial pathogens emphasizes the need for new and innovative anti-microbial strategies. Effective therapeutic regimens, which have existed, are limited by the emergence of drug resistance and the inability of antibiotics to kill dormant or intracellular organisms.

  18. Molecular evolution, intracellular organization, and the quinary structure of proteins.

    OpenAIRE

    McConkey, E H

    1982-01-01

    High-resolution two-dimensional polyacrylamide gel electrophoresis shows that at least half of 370 denatured polypeptides from hamster cells and human cells are indistinguishable in terms of isoelectric points and molecular weights. Molecular evolution may have been more conservative for this set of proteins than sequence studies on soluble proteins have implied. This may be a consequence of complexities of intracellular organization and the numerous macromolecular interactions in which most ...

  19. NAD+-Glycohydrolase Promotes Intracellular Survival of Group A Streptococcus.

    Directory of Open Access Journals (Sweden)

    Onkar Sharma

    2016-03-01

    Full Text Available A global increase in invasive infections due to group A Streptococcus (S. pyogenes or GAS has been observed since the 1980s, associated with emergence of a clonal group of strains of the M1T1 serotype. Among other virulence attributes, the M1T1 clone secretes NAD+-glycohydrolase (NADase. When GAS binds to epithelial cells in vitro, NADase is translocated into the cytosol in a process mediated by streptolysin O (SLO, and expression of these two toxins is associated with enhanced GAS intracellular survival. Because SLO is required for NADase translocation, it has been difficult to distinguish pathogenic effects of NADase from those of SLO. To resolve the effects of the two proteins, we made use of anthrax toxin as an alternative means to deliver NADase to host cells, independently of SLO. We developed a novel method for purification of enzymatically active NADase fused to an amino-terminal fragment of anthrax toxin lethal factor (LFn-NADase that exploits the avid, reversible binding of NADase to its endogenous inhibitor. LFn-NADase was translocated across a synthetic lipid bilayer in vitro in the presence of anthrax toxin protective antigen in a pH-dependent manner. Exposure of human oropharyngeal keratinocytes to LFn-NADase in the presence of protective antigen resulted in cytosolic delivery of NADase activity, inhibition of protein synthesis, and cell death, whereas a similar construct of an enzymatically inactive point mutant had no effect. Anthrax toxin-mediated delivery of NADase in an amount comparable to that observed during in vitro infection with live GAS rescued the defective intracellular survival of NADase-deficient GAS and increased the survival of SLO-deficient GAS. Confocal microscopy demonstrated that delivery of LFn-NADase prevented intracellular trafficking of NADase-deficient GAS to lysosomes. We conclude that NADase mediates cytotoxicity and promotes intracellular survival of GAS in host cells.

  20. Dual Readout BRET/FRET Sensors for Measuring Intracellular Zinc

    Science.gov (United States)

    2016-01-01

    Genetically encoded FRET-based sensor proteins have significantly contributed to our current understanding of the intracellular functions of Zn2+. However, the external excitation required for these fluorescent sensors can give rise to photobleaching and phototoxicity during long-term imaging, limits applications that suffer from autofluorescence and light scattering, and is not compatible with light-sensitive cells. For these applications, sensor proteins based on Bioluminescence Resonance Energy Transfer (BRET) would provide an attractive alternative. In this work, we used the bright and stable luciferase NanoLuc to create the first genetically encoded BRET sensors for measuring intracellular Zn2+. Using a new sensor approach, the NanoLuc domain was fused to the Cerulean donor domain of two previously developed FRET sensors, eCALWY and eZinCh-2. In addition to preserving the excellent Zn2+ affinity and specificity of their predecessors, these newly developed sensors enable both BRET- and FRET-based detection. While the dynamic range of the BRET signal for the eCALWY-based BLCALWY-1 sensor was limited by the presence of two competing BRET pathways, BRET/FRET sensors based on the eZinCh-2 scaffold (BLZinCh-1 and -2) yielded robust 25–30% changes in BRET ratio. In addition, introduction of a chromophore-silencing mutation resulted in a BRET-only sensor (BLZinCh-3) with increased BRET response (50%) and an unexpected 10-fold increase in Zn2+ affinity. The combination of robust ratiometric response, physiologically relevant Zn2+ affinities, and stable and bright luminescence signal offered by the BLZinCh sensors allowed monitoring of intracellular Zn2+ in plate-based assays as well as intracellular BRET-based imaging in single living cells in real time. PMID:27547982

  1. Increasing intracellular bioavailable copper selectively targets prostate cancer cells.

    Science.gov (United States)

    Cater, Michael A; Pearson, Helen B; Wolyniec, Kamil; Klaver, Paul; Bilandzic, Maree; Paterson, Brett M; Bush, Ashley I; Humbert, Patrick O; La Fontaine, Sharon; Donnelly, Paul S; Haupt, Ygal

    2013-07-19

    The therapeutic efficacy of two bis(thiosemicarbazonato) copper complexes, glyoxalbis[N4-methylthiosemicarbazonato]Cu(II) [Cu(II)(gtsm)] and diacetylbis[N4-methylthiosemicarbazonato]Cu(II) [Cu(II)(atsm)], for the treatment of prostate cancer was assessed in cell culture and animal models. Distinctively, copper dissociates intracellularly from Cu(II)(gtsm) but is retained by Cu(II)(atsm). We further demonstrated that intracellular H2gtsm [reduced Cu(II)(gtsm)] continues to redistribute copper into a bioavailable (exchangeable) pool. Both Cu(II)(gtsm) and Cu(II)(atsm) selectively kill transformed (hyperplastic and carcinoma) prostate cell lines but, importantly, do not affect the viability of primary prostate epithelial cells. Increasing extracellular copper concentrations enhanced the therapeutic capacity of both Cu(II)(gtsm) and Cu(II)(atsm), and their ligands (H2gtsm and H2atsm) were toxic only toward cancerous prostate cells when combined with copper. Treatment of the Transgenic Adenocarcinoma of Mouse Prostate (TRAMP) model with Cu(II)(gtsm) (2.5 mg/kg) significantly reduced prostate cancer burden (∼70%) and severity (grade), while treatment with Cu(II)(atsm) (30 mg/kg) was ineffective at the given dose. However, Cu(II)(gtsm) caused mild kidney toxicity in the mice, associated primarily with interstitial nephritis and luminal distention. Mechanistically, we demonstrated that Cu(II)(gtsm) inhibits proteasomal chymotrypsin-like activity, a feature further established as being common to copper-ionophores that increase intracellular bioavailable copper. We have demonstrated that increasing intracellular bioavailable copper can selectively kill cancerous prostate cells in vitro and in vivo and have revealed the potential for bis(thiosemicarbazone) copper complexes to be developed as therapeutics for prostate cancer.

  2. Novel intracellular proteins associated with cellular vitamin D action.

    Science.gov (United States)

    Angelo, Giana; Wood, Richard J; Mayer, Jean

    2002-07-01

    Work with vitamin D-resistant New World primates has revealed novel cellular proteins involved in vitamin D action. An "intracellular vitamin D-binding protein" functions to bind vitamin D metabolites in the cell and enhances vitamin D action. By contrast, a "vitamin D response element-binding protein" inhibits vitamin D receptor binding to the DNA and is responsible for vitamin D resistance in New World primates.

  3. ApoHRP-based Assay to Measure Intracellular Regulatory Heme

    Science.gov (United States)

    Atamna, Hani; Brahmbhatt, Marmik; Atamna, Wafa; Shanower, Gregory A.; Dhahbi, Joseph M.

    2015-01-01

    The majority of the heme-binding proteins possess a “heme-pocket” that stably binds with heme. Usually known as housekeeping heme-proteins, they participate in a variety of metabolic reactions (e.g., catalase). Heme also binds with lower affinity to the “Heme-Regulatory Motifs” (HRM) in specific regulatory proteins. This type of heme binding is known as exchangeable or regulatory heme (RH). Heme binding to HRM proteins regulates their function (e.g., Bach1). Although there are well-established methods for assaying total cellular heme (e.g., heme-proteins plus RH), currently there is no method available for measuring RH independently from the total heme (TH). The current study describes and validates a new method to measure intracellular RH. The method is based on the reconstitution of apo-horseradish peroxidase (apoHRP) with heme to form holoHRP. The resulting holoHRP activity is then measured with a colorimetric substrate. The results show that apoHRP specifically binds RH but not with heme from housekeeping heme-proteins. The RH assay detects intracellular RH. Furthermore, using conditions that create positive (hemin) or negative (N-methyl protoporphyrin IX) controls for heme in normal human fibroblasts (IMR90), the RH assay shows that RH is dynamic and independent from TH. We also demonstrated that short-term exposure to subcytotoxic concentrations of lead (Pb), mercury (Hg), or amyloid-β(Aβ) significantly alters intracellular RH with little effect on TH. In conclusion the RH assay is an effective assay to investigate intracellular RH concentration and demonstrates that RH represents ~6% of total heme in IMR90 cells. PMID:25525887

  4. Fatty Acid Signaling: The New Function of Intracellular Lipases

    Directory of Open Access Journals (Sweden)

    Zuzana Papackova

    2015-02-01

    Full Text Available Until recently, intracellular triacylglycerols (TAG stored in the form of cytoplasmic lipid droplets have been considered to be only passive “energy conserves”. Nevertheless, degradation of TAG gives rise to a pleiotropic spectrum of bioactive intermediates, which may function as potent co-factors of transcription factors or enzymes and contribute to the regulation of numerous cellular processes. From this point of view, the process of lipolysis not only provides energy-rich equivalents but also acquires a new regulatory function. In this review, we will concentrate on the role that fatty acids liberated from intracellular TAG stores play as signaling molecules. The first part provides an overview of the transcription factors, which are regulated by fatty acids derived from intracellular stores. The second part is devoted to the role of fatty acid signaling in different organs/tissues. The specific contribution of free fatty acids released by particular lipases, hormone-sensitive lipase, adipose triacylglycerol lipase and lysosomal lipase will also be discussed.

  5. Modulation of lipoprotein receptor functions by intracellular adaptor proteins.

    Science.gov (United States)

    Stolt, Peggy C; Bock, Hans H

    2006-10-01

    Members of the low density lipoprotein (LDL) receptor gene family are critically involved in a wide range of physiological processes including lipid and vitamin homeostasis, cellular migration, neurodevelopment, and synaptic plasticity, to name a few. Lipoprotein receptors exert these diverse biological functions by acting as cellular uptake receptors or by inducing intracellular signaling cascades. It was discovered that a short sequence in the intracellular region of all lipoprotein receptors, Asn-Pro-X-Tyr (NPXY) is important for mediating either endocytosis or signal transduction events, and that this motif serves as a binding site for phosphotyrosine-binding (PTB) domain containing scaffold proteins. These molecular adaptors connect the transmembrane receptors with the endocytosis machinery and regulate cellular trafficking, or function as assembly sites for dynamic multi-protein signaling complexes. Whereas the LDL receptor represents the archetype of an endocytic lipoprotein receptor, the structurally closely related apolipoprotein E receptor 2 (apoER2) and very low density lipoprotein (VLDL) receptor activate a kinase-dependent intracellular signaling cascade after binding to the neuronal signaling molecule Reelin. This review focuses on two related PTB domain containing adaptor proteins that mediate these divergent lipoprotein receptor responses, ARH (autosomal recessive hypercholesterolemia protein) and Dab1 (disabled-1), and discusses the structural and molecular basis of this different behaviour.

  6. Intracellular Trafficking Network of Protein Nanocapsules: Endocytosis, Exocytosis and Autophagy

    Science.gov (United States)

    Zhang, Jinxie; Zhang, Xudong; Liu, Gan; Chang, Danfeng; Liang, Xin; Zhu, Xianbing; Tao, Wei; Mei, Lin

    2016-01-01

    The inner membrane vesicle system is a complex transport system that includes endocytosis, exocytosis and autophagy. However, the details of the intracellular trafficking pathway of nanoparticles in cells have been poorly investigated. Here, we investigate in detail the intracellular trafficking pathway of protein nanocapsules using more than 30 Rab proteins as markers of multiple trafficking vesicles in endocytosis, exocytosis and autophagy. We observed that FITC-labeled protein nanoparticles were internalized by the cells mainly through Arf6-dependent endocytosis and Rab34-mediated micropinocytosis. In addition to this classic pathway: early endosome (EEs)/late endosome (LEs) to lysosome, we identified two novel transport pathways: micropinocytosis (Rab34 positive)-LEs (Rab7 positive)-lysosome pathway and EEs-liposome (Rab18 positive)-lysosome pathway. Moreover, the cells use slow endocytosis recycling pathway (Rab11 and Rab35 positive vesicles) and GLUT4 exocytosis vesicles (Rab8 and Rab10 positive) transport the protein nanocapsules out of the cells. In addition, protein nanoparticles are observed in autophagosomes, which receive protein nanocapsules through multiple endocytosis vesicles. Using autophagy inhibitor to block these transport pathways could prevent the degradation of nanoparticles through lysosomes. Using Rab proteins as vesicle markers to investigation the detail intracellular trafficking of the protein nanocapsules, will provide new targets to interfere the cellular behaver of the nanoparticles, and improve the therapeutic effect of nanomedicine. PMID:27698943

  7. Forced resurgence and targeting of intracellular uropathogenic Escherichia coli reservoirs.

    Directory of Open Access Journals (Sweden)

    Matthew G Blango

    Full Text Available Intracellular quiescent reservoirs of uropathogenic Escherichia coli (UPEC, which can seed the bladder mucosa during the acute phase of a urinary tract infection (UTI, are protected from antibiotic treatments and are extremely difficult to eliminate. These reservoirs are a potential source for recurrent UTIs that affect millions annually. Here, using murine infection models and the bladder cell exfoliant chitosan, we demonstrate that intracellular UPEC populations shift within the stratified layers of the urothelium during the course of a UTI. Following invasion of the terminally differentiated superficial layer of epithelial cells that line the bladder lumen, UPEC can multiply and disseminate, eventually establishing reservoirs within underlying immature host cells. If given access, UPEC can invade the superficial and immature bladder cells equally well. As infected immature host cells differentiate and migrate towards the apical surface of the bladder, UPEC can reinitiate growth and discharge into the bladder lumen. By inducing the exfoliation of the superficial layers of the urothelium, chitosan stimulates rapid regenerative processes and the reactivation and efflux of quiescent intracellular UPEC reservoirs. When combined with antibiotics, chitosan treatment significantly reduces bacterial loads within the bladder and may therefore be of therapeutic value to individuals with chronic, recurrent UTIs.

  8. Effects of Propafenone, Amiodarone and Dilthiazem on the potassium channel of c-Type Kv1.4△N%普罗帕酮、胺碘酮、地尔硫卓对Kv1.4△N钾通道的作用

    Institute of Scientific and Technical Information of China (English)

    王智泉; 蒋学俊; 王世敏; 徐林; 王能; 张冬

    2011-01-01

    目的 探讨不同类别抗心律失常药物普罗帕酮、胺碘酮和地尔硫卓对去N端Kv1.4通道(Kv1.4△N)的作用方式,以及这些作用的差异性.方法 将Kv1.4△N的mRNA注射入非洲爪蟾卵母细胞并使用双电极钳制法(two electrodes voltage clamp,TEV),运用Clampfit 9.0软件分别观察三种药物对KV1..4△N电生理特性的影响.结果 三种药物对ELvl.4△N通道的作用都具有浓度、频率和电压依赖性.在亲和力方面,propafenone的IC50最小,dilthiazem次之,amiodarone的IC50最大(P=0.031);在频率抑制性方面,propafenone组达到稳态时为对照组的41%,amiodarone为32%左右,dilthiazem为21%左右(P=0.045);在电压抑制性方面,100μMpropafenone,500μM amiodarone、350μM dilthjazem在+50 mV电压下分别能使fKv1.4△N通道电流抑制到对照组的(54.6±1.9)%,(46.3±3.5)%和(52.8±2.8)%(P=0.046).结论 三者都是fKv1.4△N通道的开放通道阻滞剂,对fKv1.4△N通道的作用和机制既有相同之处,又有不同特点,这可能是三者抗心律失常的机制之一.%Objective To study the effects of the antiarrhythmic drugs of propafenone, amiodarone and dilthiazem on c-type Kv1. 4 channels in Xenopus laevis oocytes with two-electrode voltage-clamp technique. Methods Defolliculated oocytes ( stage Ⅴ - Ⅵ) had transcribed cRNAs of ferret Kv1. 4△N channels injected. The oocytes were continuously perfused with control solution or propafenone, amiodarone and dilthiazem under monitoring of software of Clampfit v 9. 0. Results All of the three drugs blocked ferret Kv1. 4△N channel in voltage-, frequency- and concentration-dependent manners. The values of IC50 (50%inhibiting concentration ) of propafenone, amiodarone and dilthiazem were ( 103.4± 2. 2 ) μ mol/L,(501.22 +5.9) μmol/L and (353.62 +9.9) μmol/L, respectively. The currents under the actions of propafenone , amiodarone and dilthiazem were decreased to 41%, 32% and 21% of control group, respectively. Propafenone

  9. Intracellular diffusion restrictions in isolated cardiomyocytes from rainbow trout

    Directory of Open Access Journals (Sweden)

    Birkedal Rikke

    2009-12-01

    Full Text Available Abstract Background Restriction of intracellular diffusion of adenine nucleotides has been studied intensively on adult rat cardiomyocytes. However, their cause and role in vivo is still uncertain. Intracellular membrane structures have been suggested to play a role. We therefore chose to study cardiomyocytes from rainbow trout (Oncorhynchus mykiss, which are thinner and have fewer intracellular membrane structures than adult rat cardiomyocytes. Previous studies suggest that trout permeabilized cardiac fibers also have diffusion restrictions. However, results from fibers may be affected by incomplete separation of the cells. This is avoided when studying permeabilized, isolated cardiomyocytes. The aim of this study was to verify the existence of diffusion restrictions in trout cardiomyocytes by comparing ADP-kinetics of mitochondrial respiration in permeabilized fibers, permeabilized cardiomyocytes and isolated mitochondria from rainbow trout heart. Experiments were performed at 10, 15 and 20°C in the absence and presence of creatine. Results Trout cardiomyocytes hypercontracted in the solutions used for mammalian cardiomyocytes. We developed a new solution in which they retained their shape and showed stable steady state respiration rates throughout an experiment. The apparent ADP-affinity of permeabilized cardiomyocytes was different from that of fibers. It was higher, independent of temperature and not increased by creatine. However, it was still about ten times lower than in isolated mitochondria. Conclusions The differences between fibers and cardiomyocytes suggest that results from trout heart fibers were affected by incomplete separation of the cells. However, the lower ADP-affinity of cardiomyocytes compared to isolated mitochondria indicate that intracellular diffusion restrictions are still present in trout cardiomyocytes despite their lower density of intracellular membrane structures. The lack of a creatine effect indicates that

  10. DMPD: Intracellular NOD-like receptors in host defense and disease. [Dynamic Macrophage Pathway CSML Database

    Lifescience Database Archive (English)

    Full Text Available 17967410 Intracellular NOD-like receptors in host defense and disease. Kanneganti T...D-like receptors in host defense and disease. PubmedID 17967410 Title Intracellular NOD-like receptors in host defense and dise

  11. Intracellular angiotensin II elicits Ca2+ increases in A7r5 vascular smooth muscle cells

    NARCIS (Netherlands)

    Filipeanu, CM; Brailoiu, E; Kok, JW; Henning, RH; De Zeeuw, D; Nelemans, SA

    2001-01-01

    Recent studies show that angiotensin II can act within the cell, possibly via intracellular receptors pharmacologically different from typical plasma membrane angiotensin II receptors. The signal transduction of intracellular angiotensin LI is unclear. Therefore. we investigated the effects of intra

  12. Destabilization emulsion of oil by means of additives based on silicones polyethers; Desestabilizacao de emulsoes de petroleo por meio de aditivos a base de silicones polieteres

    Energy Technology Data Exchange (ETDEWEB)

    Jarque, Erika A.; Mansur, Claudia R.E. [Universidade Federal do Rio de Janeiro (IMA/UFRJ), RJ (Brazil). Inst. de Macromoleculas Professora Eloisa Mano], e-mails: alegrio@ima.ufrj.br, celias@ima.ufrj.br

    2011-07-01

    The process of demulsification has great importance in the petroleum industry, since the formation of emulsions is a natural phenomenon in this sector. Several polymers have been used commercially as additives emulsion destabilizing, among them are the block copolymers of poly (ethylene oxide)-poly (propylene oxide) (PEO-PPO). This work aims to study the efficiency of five additives based on silicones polyethers, which have structures in their chains of poly (ethylene oxide) (PEO) or PEO-PPO copolymers. The results show that the addition of these additives in the water / oil reduced the values of interfacial tension of systems. From the testing of gravitational separation water / oil was observed that all the additives promoted the breakdown of water / oil, but those who hold in their structures the chains of block copolymers of PEO-PPO were the most efficient, and that the caused a smaller reduction in the interfacial tensions of these systems. (author)

  13. Gravity destabilized non-wetting phase invasion in macro-heterogeneous porous media: Near pore scale macro modified invasion percolation simulation of experiments

    Energy Technology Data Exchange (ETDEWEB)

    GLASS JR.,ROBERT J.; CONRAD,STEPHEN H.; YARRINGTON,LANE

    2000-03-08

    The authors reconceptualize macro modified invasion percolation (MMIP) at the near pore (NP) scale and apply it to simulate the non-wetting phase invasion experiments of Glass et al [in review] conducted in macro-heterogeneous porous media. For experiments where viscous forces were non-negligible, they redefine the total pore filling pressure to include viscous losses within the invading phase as well as the viscous influence to decrease randomness imposed by capillary forces at the front. NP-MMIP exhibits the complex invasion order seen experimentally with characteristic alternations between periods of gravity stabilized and destabilized invasion growth controlled by capillary barriers. The breaching of these barriers and subsequent pore scale fingering of the non-wetting phase is represented extremely well as is the saturation field evolution, and total volume invaded.

  14. Structures of Highly Twisted Amides Relevant to Amide N-C Cross-Coupling: Evidence for Ground-State Amide Destabilization.

    Science.gov (United States)

    Pace, Vittorio; Holzer, Wolfgang; Meng, Guangrong; Shi, Shicheng; Lalancette, Roger; Szostak, Roman; Szostak, Michal

    2016-10-04

    Herein, we show that acyclic amides that have recently enabled a series of elusive transition-metal-catalyzed N-C activation/cross-coupling reactions are highly twisted around the N-C(O) axis by a new destabilization mechanism of the amide bond. A unique effect of the N-glutarimide substituent, leading to uniformly high twist (ca. 90°) irrespective of the steric effect at the carbon side of the amide bond has been found. This represents the first example of a twisted amide that does not bear significant steric hindrance at the α-carbon atom. The (15) N NMR data show linear correlations between electron density at nitrogen and amide bond twist. This study strongly supports the concept of amide bond ground-state twist as a blueprint for activation of amides toward N-C bond cleavage. The new mechanism offers considerable opportunities for organic synthesis and biological processes involving non-planar amide bonds.

  15. Methane release from the East-Siberian Arctic Shelf and its connection with permafrost and hydrate destabilization: First results and potential future developments

    Science.gov (United States)

    Shakhova, N.; Semiletov, I.

    2012-04-01

    The East Siberian Arctic Shelf (ESAS) is home to the world's largest hydrocarbon stocks, which consist of natural gas, coal bed methane (CH4), and shallow Arctic hydrates. Until recently, the ESAS was not considered a CH4 source due to the supposed impermeability of sub-sea permafrost, which was thought to completely isolate the CH4 beneath from modern biogeochemical cycles. However, the ESAS represents an enormous potential CH4 source that could be responsive to ongoing global warming. Such response could occur in substantially shorter time than that of terrestrial Arctic ecosystems, because sub-sea permafrost has experienced long-lasting destabilization initiated by its inundation during the Holocene ocean transgression. ESAS permafrost stability and integrity is key to whether sequestered ancient carbon escapes as the potent greenhouse gas CH4. Recent data suggest the sub-sea permafrost is currently experiencing significant changes in its thermal regime. For example, our recent data obtained in the ESAS during the drilling expedition of 2011 showed no frozen sediments at all within the 53 m long drilling core at water temperatures varying from -0.6°C to -1.3°C. Unfrozen sediments provide multiple potential CH4 migration pathways. We suggest that open taliks have formed beneath the areas underlain or influenced by the nearby occurrence of fault zones, under paleo-valleys, and beneath thaw lakes submerged several thousand years ago during the ocean transgression. Temporary gas migration pathways might occur subsequent to seismic and tectonic activity in an area, due to sediment settlement and subsidence; hydrates could destabilize due to development of thermokarst-related features or ice-scouring. Recently obtained geophysical data identified numerous gas seeps, mostly above prominent reflectors, and the ubiquitous occurrence of shallow gas-charged sediments containing numerous gas chimneys, underscoring the likelihood that the ability of sub-sea permafrost to

  16. Effects of Ti-Based Additives on the Hydrogen Storage Properties of a LiBH4/CaH2 Destabilized System

    Directory of Open Access Journals (Sweden)

    Hongwei Yang

    2010-01-01

    Full Text Available The hydrogen storage properties of a destabilized LiBH4/CaH2 system ball-milled with TiCl3, TiF3, and TiO2 additives have been investigated. It is found that the system with TiCl3 additive has a lower dehydrogenation temperature than the ones with other additives. Further study shows that a higher amount of TiCl3 is more effective in reducing the desorption temperature of the LiBH4/CaH2 system, since it leads to a lower activation energy of dehydrogenation. The activations energies for mixtures containing 4, 10, and 25 mol% of TiCl3 are 141, 126, and 110 kJ/mol, respectively. However, the benefits of higher amounts of TiCl3 are offset by a larger reduction in hydrogen capacity of the mixtures.

  17. DMPD: Intracellular DNA sensors in immunity. [Dynamic Macrophage Pathway CSML Database

    Lifescience Database Archive (English)

    Full Text Available 18573338 Intracellular DNA sensors in immunity. Takeshita F, Ishii KJ. Curr Opin Im...munol. 2008 Aug;20(4):383-8. Epub 2008 Jun 23. (.png) (.svg) (.html) (.csml) Show Intracellular DNA sensors ...in immunity. PubmedID 18573338 Title Intracellular DNA sensors in immunity. Authors Takeshita F, Ishii KJ. P

  18. DMPD: NOD-like receptors (NLRs): bona fide intracellular microbial sensors. [Dynamic Macrophage Pathway CSML Database

    Lifescience Database Archive (English)

    Full Text Available 18585455 NOD-like receptors (NLRs): bona fide intracellular microbial sensors. Shaw...tml) (.csml) Show NOD-like receptors (NLRs): bona fide intracellular microbial sensors. PubmedID 18585455 Ti...tle NOD-like receptors (NLRs): bona fide intracellular microbial sensors. Authors

  19. Intracellular lipophilic inclusions of mycobacteria in vitro and in sputum.

    Science.gov (United States)

    Garton, Natalie J; Christensen, Henriette; Minnikin, David E; Adegbola, Richard A; Barer, Michael R

    2002-10-01

    Although most mycobacterial lipids are thought to be associated with the cell envelope, the authors previously observed substantial deposits of intracellular lipophilic material. A Nile-red-based cytological assay was used to determine factors which affect the presence and natural history of intracellular lipophilic inclusions (ILIs) in Mycobacterium smegmatis. Development of ILIs was associated with stationary-phase cultures in broth and with aged (6 days) colonies on agar. Using variants of Youmans' defined medium, the frequency and size of ILIs was observed to be minimal in carbon-poor medium. ILIs were observed to form within 15 min after provision of fatty acids to the medium and after a period of several days in nitrogen-poor medium. Analysis of the non-polar lipid extracts of ILI-rich and -poor preparations indicated that the triacylglycerols (TAGs) were a major component of the inclusions. The acyl substituents of the TAGs varied according to whether they were formed in Middlebrook 7H9 broth, in low-nitrogen Youmans' broth or rapidly after oleic acid supplementation of Youmans' broth. These studies support a storage function for TAGs in mycobacteria in addition to their previously suggested occurrence as components of the cell envelope. To assess a possible role for ILIs in Mycobacterium tuberculosis, a combined acid-fast (Auramine)/Nile red assay was applied to heavily positive sputum samples from patients with tuberculosis. Strong intracellular Nile red signals were obtained from acid-fast cells, indicating that ILI occur in M. tuberculosis in vivo. This may reflect a distinct physiological state of these cells, which it has not been possible to reproduce in vitro. These findings indicate that the uptake of long-chain fatty acids and TAG biosynthetic and degradative pathways are important aspects of mycobacterial lipid metabolism, meriting further investigation.