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Sample records for blocker ro 40-5967

  1. The structurally novel Ca sup 2+ channel blocker Ro 40-5967, which binds to the ( sup 3 H) desmethoxyverapamil receptor, is devoid of the negative inotropic effects of verapamil in normal and failing rat hearts

    SciTech Connect

    Clozel, J.P.; Veniant, M.; Osterrieder, W. )

    1990-06-01

    Ro 40-5967 is a structurally novel Ca{sup 2+} channel blocker that binds to the verapamil-type receptor of cardiac membranes but that has been shown in isolated guinea-pig hearts to be about ten times less potent a negative inotropic agent than verapamil. The goals of the present study were to confirm these findings in vitro in isolated perfused rat hearts as well as in vivo in conscious rats and to compare Ro 40-5967 to verapamil. The effects of Ro 40-5967 and verapamil were tested not only in normal rats, but also in rats with heart failure induced by chronic myocardial infarction. In isolated Langendorff hearts (without heart failure), no decrease of contractility was observed with Ro 40-5967 up to complete AV block. In contrast, verapamil decreased contractility with an IC50 of 100 nM. In isolated, electrically stimulated rat papillary muscles, the IC50 values for the decrease of contractile force were 15,000 and 440 nM for Ro 40-5967 and verapamil, respectively. In vivo, Ro 40-5967 did not decrease left ventricular contractility (as assessed by changes of dP/dt max +) in rats without and with heart failure. In contrast, verapamil was markedly negative inotropic in both conditions.

  2. Novel mode of action of the calcium antagonist mibefradil (Ro 40-5967): potent immunosuppression by inhibition of T-cell infiltration through allogeneic endothelium.

    PubMed Central

    Blaheta, R A; Hailer, N P; Brude, N; Wittig, B; Oppermann, E; Leckel, K; Harder, S; Scholz, M; Weber, S; Encke, A; Markus, B H

    1998-01-01

    Cyclosporin A reduces the mitotic activity of allosensitized lymphocytes, but fails to limit emigration of these cells into the donor organ. However, the modulation of both lymphocyte proliferation and infiltration are desirable characteristics of immunosuppressive therapy. The calcium-channel blocker, verapamil, has recently been shown to effectively prevent the transmigration of CD4+ and CD8+ T cells through allogeneic endothelium. Mibefradil (Ro 40-5967) represents a new generation of calcium antagonists with high potency and long-term activity. To evaluate the immunosuppressive potential of this drug, the influence of mibefradil on lymphocyte adhesion to, horizontal locomotion along, and penetration through allogeneic endothelium (HUVEC) was performed. When lymphocytes were prestimulated for 24 hr with mibefradil, adhesion and penetration were dose-dependently reduced. The adhesion ID50 values were 3.4 microM (CD4+ T cells) versus 9.2 microM (CD8+ T cells) and 2.1 microM (CD4+ T cells) versus 3.9 microM (CD8+ T cells) with regard to penetration. Mibefradil also effectively blocked horizontal locomotion. Specific down-regulation of T-cell binding to the P-selection receptor (ID50: CD4+ T cells, 0.8 microM: CD8+ T cells, 1.2 microM) and to the intracellular adhesion molecule-1 (ICAM-1) receptor (ID50: CD4+ T cells, 1.9 microM; CD8+ T cells, 1.5 microM) by mibefradil seems to be responsible for the decreased adhesion and penetration rates. Reduction of intracellular F-actin in T lymphocytes could diminish cell locomotion. In conclusion, the potent suppressive properties of mibefradil support its use as a co-medication in cyclosporin A-based immunosuppressive therapy. PMID:9741343

  3. H2 blockers

    MedlinePlus

    Peptic ulcer disease - H2 blockers; PUD - H2 blockers; Gastroesophageal reflux - H2 blockers ... H2 blockers are used to: Relieve symptoms of acid reflux, or gastroesophageal reflux disease (GERD). This is a ...

  4. Calcium channel blocker overdose

    MedlinePlus

    ... this page: //medlineplus.gov/ency/article/002580.htm Calcium channel blocker overdose To use the sharing features on this page, please enable JavaScript. Calcium channel blockers are a type of medicine used ...

  5. β-Adrenergic blockers.

    PubMed

    Frishman, William H; Saunders, Elijah

    2011-09-01

    KEY POINTS AND PRACTICAL RECOMMENDATIONS: •  β-Blockers are appropriate treatment for patients with hypertension and those who have concomitant ischemic heart disease, heart failure, obstructive cardiomyopathy, or certain arrhythmias. •  β-Blockers can be used in combination with other antihypertensive drugs to achieve maximal blood pressure control. Labetalol can be used in hypertensive emergencies and urgencies. •  β-Blockers may be useful in patients having hyperkinetic circulation (palpitations, tachycardia, hypertension, and anxiety), migraine headache, and essential tremor. •  β-Blockers are highly heterogeneous with respect to various pharmacologic effects: degree of intrinsic sympathomimetic activity, membrane-stabilizing activity, β(1) selectivity, α(1) -adrenergic-blocking effect, tissue solubility, routes of systemic elimination, potencies and duration of action, and specific effects may be important in the selection of a drug for clinical use. •  β-Blocker usage to reduce perioperative ischemia and cardiovascular complications may not benefit as many patients as was once hoped and may actually cause harm in some individuals. Currently the best evidence supports β-blocker use in two patient groups: patients undergoing vascular surgery with known ischemic heart disease or multiple risk factors for it and for patients already receiving β-blockers for known cardiovascular conditions. PMID:21896144

  6. H2 blockers

    MedlinePlus

    H2 blockers are medicines that work by reducing the amount of stomach acid secreted by glands in the lining of your stomach. ... symptoms of acid reflux, or gastroesophageal reflux disease ... from the mouth to the stomach). Treat a peptic or stomach ulcer.

  7. [Beta blockers in migraine prophylaxis].

    PubMed

    Shimizu, Toshihiko

    2009-10-01

    Beta blockers (beta-adrenoceptor blockers) are known to be used for the prophylactic treatment of migraine. The improvement of migraine in the patients who recieved propranolol for angina pectoris revealed the effectiveness of propranolol in migraine prophylaxis. Many clinical trials have confirmed that propranolol is effective in the prophylactic treatment of migraine. Other beta-blocking drugs, namely nadolol, metoprolol, atenolol, timolol and bisoprolol, have also been demonstrated to be effective in the prophylaxis of migraine. In contrast, several beta blockers with intrinsic sympathetic activity (ISA), such as alprenolol, oxprenolol, pindolol and acebutolol, have not been demonstrated to be effective in migraine prophylaxis. In this review, we have descrived the pharmacologic background and pharmacokinetics of the beta blockers that demonstrated a prophylactic effect for migraine will be described. We have also reviewed the results of clinical trials of beta-blocking drugs for migraine. PMID:19882938

  8. Calcium channel blockers and dementia

    PubMed Central

    Nimmrich, V; Eckert, A

    2013-01-01

    Degenerative dementia is mainly caused by Alzheimer's disease and/or cerebrovascular abnormalities. Disturbance of the intracellular calcium homeostasis is central to the pathophysiology of neurodegeneration. In Alzheimer's disease, enhanced calcium load may be brought about by extracellular accumulation of amyloid-β. Recent studies suggest that soluble forms facilitate influx through calcium-conducting ion channels in the plasma membrane, leading to excitotoxic neurodegeneration. Calcium channel blockade attenuates amyloid-β-induced neuronal decline in vitro and is neuroprotective in animal models. Vascular dementia, on the other hand, is caused by cerebral hypoperfusion and may benefit from calcium channel blockade due to relaxation of the cerebral vasculature. Several calcium channel blockers have been tested in clinical trials of dementia and the outcome is heterogeneous. Nimodipine as well as nilvadipine prevent cognitive decline in some trials, whereas other calcium channel blockers failed. In trials with a positive outcome, BP reduction did not seem to play a role in preventing dementia, indicating a direct protecting effect on neurons. An optimization of calcium channel blockers for the treatment of dementia may involve an increase of selectivity for presynaptic calcium channels and an improvement of the affinity to the inactivated state. Novel low molecular weight compounds suitable for proof-of-concept studies are now available. PMID:23638877

  9. Topical beta-blocker treatment for migraine.

    PubMed

    Chiam, Patrick J T

    2012-02-01

    Beta-blockers are a well-known prophylactic treatment for migraine; however, treatment by the ocular route has not been widely considered. This case illustrates the resolution of a visual field defect associated with migraine and improvement of symptoms possibly due to administration of a topical beta-blocker. This novel method of treatment especially when visual field defects are present may have a place in the management of migraine. PMID:22278763

  10. Management of a mixed overdose of calcium channel blockers, β-blockers and statins

    PubMed Central

    Thakrar, Reena; Shulman, Rob; Bellingan, Geoff; Singer, Mervyn

    2014-01-01

    We describe a case of extreme mixed overdose of calcium channel blockers, β-blockers and statins. The patient was successfully treated with aggressive resuscitation including cardiac pacing and multiorgan support, glucagon and high-dose insulin for toxicity related to calcium channel blockade and β-blockade, and ubiquinone for treating severe presumed statin-induced rhabdomyolysis and muscle weakness. PMID:24907219

  11. Misperceptions About β-Blockers and Diuretics

    PubMed Central

    Ubel, Peter A; Jepson, Christopher; Asch, David A

    2003-01-01

    BACKGROUND Based on a series of clinical trials showing no difference in the effectiveness or tolerability of most major classes of antihypertensive medications, the Joint National Commission on High Blood Pressure Treatment recommends that physicians prescribe β-blockers or diuretics as initial hypertensive therapy unless there are compelling indications for another type of medication. Nevertheless, many physicians continue to favor more expensive medications like angiotensin-converting enzyme (ACE) inhibitors and calcium channel blockers as first line agents. The persistent use of these agents raises questions as to whether physicians perceive ACE inhibitors and calcium channel blockers to be better than β-blockers and diuretics. METHODS We surveyed 1,200 primary care physicians in 1997, and another 500 primary care physicians in 2000, and asked them to estimate the relative effectiveness and side effects of 4 classes of medication in treating a hypothetical patient with uncomplicated hypertension: ACE inhibitors, β-blockers, calcium channel blockers, and diuretics. In addition, we asked them to indicate whether they ever provided free samples of hypertension medications to their patients. RESULTS Perceptions of the relative effectiveness and side effects of the 4 classes of hypertension medications did not significantly change over the 3 years, nor did prescription recommendations. Physicians perceive that diuretics are less effective at lowering blood pressure than the other 3 classes (P < .001). They also perceive that β-blockers are less tolerated than the other 3 classes (P < .001). In a multivariate model, perceptions of effectiveness and tolerability displayed significant associations with prescription preference independent of background variables. The only other variable to contribute significantly to the model was provision of free medication samples to patients. CONCLUSIONS Despite numerous clinical trials showing no difference in the effectiveness

  12. 46 CFR 111.105-40 - Additional requirements for RO/RO vessels.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... RO/RO vessels. (a) Each RO/RO vessel must meet ABS Steel Vessel Rules (incorporated by reference; see 46 CFR 110.10-1), section 4-8-4/27.3.2. (b) Each item of installed electrical equipment must meet the... 1 hazardous location. (c) Where the ventilation requirement of ABS Steel Vessel Rules section...

  13. [Beta-adrenergic receptor blocker poisoning].

    PubMed

    Reingardiene, Dagmara

    2007-01-01

    Beta-adrenergic receptor blocking drugs are used in the treatment of hypertension, angina, myocardial infarction, cardiac dysrhythmia, cardiomyopathy, migraine headache, thyrotoxicosis, and glaucoma. beta-adrenergic receptor blocking agents are competitive antagonist at beta(1), beta(2), or both types of adrenergic receptors. Overdoses of beta-adrenergic receptor blockers are uncommon, but are associated with significant morbidity and mortality. This review article discusses the properties of beta-adrenergic receptor blockers, presents the doses of these drugs causing toxicity and doses, after ingestion of which, referral to an emergency department is recommended. Clinical presentation of overdose (the cardiovascular, neurologic manifestations, pulmonary and other complications), diagnosis, and treatment (gastrointestinal decontamination; the usage of atropine, phosphodiesterase inhibitors, glucagon, insulin; indications for cardiac pacing, extracorporeal procedures of drug removal, etc.) are analyzed. In addition, this article focuses on clinical course and prognosis of beta-blocker overdose. PMID:17768375

  14. β-Blocker Continuation After Noncardiac Surgery

    PubMed Central

    Kwon, Steve; Thompson, Rachel; Florence, Michael; Maier, Ronald; McIntyre, Lisa; Rogers, Terry; Farrohki, Ellen; Whiteford, Mark; Flum, David R.

    2014-01-01

    Background Despite limited evidence of effect, β-blocker continuation has become a national quality improvement metric. Objective To determine the effect of β-blocker continuation on outcomes in patients undergoing elective noncardiac surgery. Design, Setting, and Patients The Surgical Care and Outcomes Assessment Program is a Washington quality improvement benchmarking initiative based on clinical data from more than 55 hospitals. Linking Surgical Care and Outcomes Assessment Program data to Washington’s hospital admission and vital status registries, we studied patients undergoing elective colorectal and bariatric surgical procedures at 38 hospitals between January 1, 2008, and December 31, 2009. Main Outcome Measures Mortality, cardiac events, and the combined adverse event of cardiac events and/or mortality. Results Of 8431 patients, 23.5% were taking β-blockers prior to surgery (mean [SD] age, 61.9 [13.7] years; 63.1% were women). Treatment with β-blockers was continued on the day of surgery and during the postoperative period in 66.0% of patients. Continuation of β-blockers both on the day of surgery and postoperatively improved from 57.2% in the first quarter of 2008 to 71.3% in the fourth quarter of 2009 (P value <.001). After adjusting for risk characteristics, failure to continue β-blocker treatment was associated with a nearly 2-fold risk of 90-day combined adverse event (odds ratio, 1.97; 95% CI, 1.19-3.26). The odds were even greater among patients with higher cardiac risk (odds ratio, 5.91; 95% CI, 1.40-25.00). The odds of combined adverse events continued to be elevated 1 year postoperatively (odds ratio, 1.66; 95% CI, 1.08-2.55). Conclusions β-Blocker continuation on the day of and after surgery was associated with fewer cardiac events and lower 90-day mortality. A focus on β-blocker continuation is a worthwhile quality improvement target and should improve patient outcomes. PMID:22249847

  15. How Do Beta Blocker Drugs Affect Exercise?

    MedlinePlus

    ... American Heart area Search by State SELECT YOUR LANGUAGE Español (Spanish) 简体中文 (Traditional Chinese) 繁体中文 (Simplified Chinese) ... used because beta blockers affect everyone differently. The second way to monitor your intensity is simpler: making ...

  16. Cardiovascular drug class specificity: beta-blockers.

    PubMed

    Reiter, Michael J

    2004-01-01

    Beta-adrenergic blockers are one of the most frequently prescribed cardiovascular drugs. Numerous beta-blockers are available for clinical use. Although these agents differ substantially, it is not clear whether (and which) differences are clinically relevant. Most of the important differences among agents reflect the relative specificity for beta1-, beta2-, and alpha-adrenergic receptors. Selection of a particular agent and target dose is probably best guided by available trial data, even though data are limited. Nonselective agents (with or without alpha-blocking properties) devoid of intrinsic sympathetic activity (ISA) are most appropriate postinfarction. Evidence exists demonstrating a mortality benefit postinfarction for propranolol, timolol, metoprolol, and, in the presence of left ventricular dysfunction, carvedilol. In the setting of heart failure, the selective agents metoprolol and bisoprolol as well as the nonselective agent carvedilol (which possesses alpha-blocking properties) have a demonstrated mortality benefit. Not all tolerated beta-blockers are associated with a survival benefit and it is probably not advisable to extrapolate benefits to all drugs with similar (although probably not identical) properties. Carvedilol may possess advantages over other beta-blockers and a possible survival advantage, suggested by the recent Carvedilol or Metoprolol European Trial (COMET), although these findings are not universally accepted. Ultimately, selection of a specific agent avoids obvious contraindications and uses trial data to guide selection and dose as long as side effects are absent or tolerable. PMID:15517513

  17. Beta blocker eye drops for treatment of acute migraine.

    PubMed

    Migliazzo, Carl V; Hagan, John C

    2014-01-01

    We report seven cases of successful treatment of acute migraine symptoms using beta blocker eye drops. The literature on beta blockers for acute migraine is reviewed. Oral beta blocker medication is not effective for acute migraine treatment. This is likely due to a relatively slow rate of achieving therapeutic plasma levels when taken orally. Topical beta blocker eye drops achieve therapeutic plasma levels within minutes of ocular administration which may explain their apparent effectiveness in relief of acute migraine symptoms. PMID:25211851

  18. [AT1-blockers in the treatment of hypertension: summary].

    PubMed

    Jr, Jiří Widimský

    2016-02-01

    Angiotensin receptor antagonists (AT(1)-blockers) are considered as one of the major classes of antihypertensive drugs suitable for monotherapy as well as for combination treatment. AT(1)-blockers have comparable antihypertensive efficacy with other major classes of antihypertensive drugs. AT(1)-blockers are considered by current guidelines of Czech society of hypertension altogether with ACE-inhibitors and calcium channel blockers as universal antihypertensive drug class. AT(1)-blockers has the lowest profile of side-effects among all antihypertensive drug classes and thus very high persistence to therapy. Mechanisms of antihypertensive effects of AT(1)-blockers are discussed altogether with the results of large clinical trials and indications in the treatment of hypertension. PMID:27172437

  19. 29 CFR 1918.86 - Roll-on roll-off (Ro-Ro) operations (see also § 1918.2, Ro-Ro operations, and § 1918.25).

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 29 Labor 7 2012-07-01 2012-07-01 false Roll-on roll-off (Ro-Ro) operations (see also § 1918.2, Ro-Ro operations, and § 1918.25). 1918.86 Section 1918.86 Labor Regulations Relating to Labor... REGULATIONS FOR LONGSHORING Handling Cargo § 1918.86 Roll-on roll-off (Ro-Ro) operations (see also §...

  20. 29 CFR 1918.86 - Roll-on roll-off (Ro-Ro) operations (see also § 1918.2, Ro-Ro operations, and § 1918.25).

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 29 Labor 7 2014-07-01 2014-07-01 false Roll-on roll-off (Ro-Ro) operations (see also § 1918.2, Ro-Ro operations, and § 1918.25). 1918.86 Section 1918.86 Labor Regulations Relating to Labor... REGULATIONS FOR LONGSHORING Handling Cargo § 1918.86 Roll-on roll-off (Ro-Ro) operations (see also §...

  1. 29 CFR 1918.86 - Roll-on roll-off (Ro-Ro) operations (see also § 1918.2, Ro-Ro operations, and § 1918.25).

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 29 Labor 7 2013-07-01 2013-07-01 false Roll-on roll-off (Ro-Ro) operations (see also § 1918.2, Ro-Ro operations, and § 1918.25). 1918.86 Section 1918.86 Labor Regulations Relating to Labor... REGULATIONS FOR LONGSHORING Handling Cargo § 1918.86 Roll-on roll-off (Ro-Ro) operations (see also §...

  2. 29 CFR 1918.86 - Roll-on roll-off (Ro-Ro) operations (see also § 1918.2, Ro-Ro operations, and § 1918.25).

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 29 Labor 7 2011-07-01 2011-07-01 false Roll-on roll-off (Ro-Ro) operations (see also § 1918.2, Ro-Ro operations, and § 1918.25). 1918.86 Section 1918.86 Labor Regulations Relating to Labor... REGULATIONS FOR LONGSHORING Handling Cargo § 1918.86 Roll-on roll-off (Ro-Ro) operations (see also §...

  3. Proteinase inhibitor homologues as potassium channel blockers.

    PubMed

    Lancelin, J M; Foray, M F; Poncin, M; Hollecker, M; Marion, D

    1994-04-01

    We report here the NMR structure of dendrotoxin I, a powerful potassium channel blocker from the venom of the African Elapidae snake Dendroaspis polylepis polylepis (black mamba), calculated from an experimentally-derived set of 719 geometric restraints. The backbone of the toxin superimposes on bovine pancreatic trypsin inhibitor (BPTI) with a root-mean-square deviation of < 1.7 A. The surface electrostatic potential calculated for dendrotoxin I and BPTI, reveal an important difference which might account for the differences in function of the two proteins. These proteins may provide examples of adaptation for specific and diverse biological functions while at the same time maintaining the overall three-dimensional structure of a common ancestor. PMID:7544683

  4. Management of calcium channel blocker overdoses.

    PubMed

    Shenoy, Sundeep; Lankala, Shilpa; Adigopula, Sasikanth

    2014-10-01

    Calcium channel blockers (CCBs) are some of the most commonly used medications in clinical practice to treat hypertension, angina, cardiac arrhythmias, and some cases of heart failure. Recent data show that CCBs are the most common of the cardiovascular medications noted in intentional or unintentional overdoses.(1) Novel treatment approaches in the form of glucagon, high-dose insulin therapy, and intravenous lipid emulsion therapies have been tried and have been successful. However, the evidence for these are limited to case reports and case series. We take this opportunity to review the various treatment options in the management of CCB overdoses with a special focus on high-dose insulin therapy as the emerging choice for initial therapy in severe overdoses. PMID:25066023

  5. High-dose insulin therapy in beta-blocker and calcium channel-blocker poisoning.

    PubMed

    Engebretsen, Kristin M; Kaczmarek, Kathleen M; Morgan, Jenifer; Holger, Joel S

    2011-04-01

    INTRODUCTION. High-dose insulin therapy, along with glucose supplementation, has emerged as an effective treatment for severe beta-blocker and calcium channel-blocker poisoning. We review the experimental data and clinical experience that suggests high-dose insulin is superior to conventional therapies for these poisonings. PRESENTATION AND GENERAL MANAGEMENT. Hypotension, bradycardia, decreased systemic vascular resistance (SVR), and cardiogenic shock are characteristic features of beta-blocker and calcium-channel blocker poisoning. Initial treatment is primarily supportive and includes saline fluid resuscitation which is essential to correct vasodilation and low cardiac filling pressures. Conventional therapies such as atropine, glucagon and calcium often fail to improve hemodynamic status in severely poisoned patients. Catecholamines can increase blood pressure and heart rate, but they also increase SVR which may result in decreases in cardiac output and perfusion of vascular beds. The increased myocardial oxygen demand that results from catecholamines and vasopressors may be deleterious in the setting of hypotension and decreased coronary perfusion. METHODS. The Medline, Embase, Toxnet, and Google Scholar databases were searched for the years 1975-2010 using the terms: high-dose insulin, hyperinsulinemia-euglycemia, beta-blocker, calcium-channel blocker, toxicology, poisoning, antidote, toxin-induced cardiovascular shock, and overdose. In addition, a manual search of the Abstracts of the North American Congress of Clinical Toxicology and the Congress of the European Association of Poisons Centres and Clinical Toxicologists published in Clinical Toxicology for the years 1996-2010 was undertaken. These searches identified 485 articles of which 72 were considered relevant. MECHANISMS OF HIGH-DOSE INSULIN BENEFIT. There are three main mechanisms of benefit: increased inotropy, increased intracellular glucose transport, and vascular dilatation. EFFICACY OF HIGH

  6. A comparison of hypotension and bradycardia following spinal anesthesia in patients on calcium channel blockers and β-blockers

    PubMed Central

    Kaimar, Padmanabha; Sanji, Narendranath; Upadya, Madhusudan; Mohammed, K. Riaz

    2012-01-01

    Objectives: Hypotension is a common complication of spinal anesthesia and is frequent in patients with hypertension. Antihypertensive agents decrease this effect by controlling blood pressure. There are conflicting reports on the continuation of antihypertensive drugs on the day of surgery in patients undergoing spinal anesthesia. Sudden hypotension could have detrimental effect on the organ systems. This study was undertaken to compare the variation in blood pressure in hypertensive patients on β-blockers and calcium channel blockers undergoing spinal anesthesia. Materials and Methods: Ninety patients were enrolled for the study, 30 each in the control, β-blocker and the calcium channel blocker groups. Results: The incidence of hypotension was not different among the three groups. However, the number of times mephentermine used to treat hypotension was significant in the patients receiving calcium channel blockers while incidence of bradycardia in patients treated with β-blockers was significant (P<0.001). Conclusion: The incidence of hypotension following spinal anesthesia is not different in patients receiving β-blockers and calcium channel blockers among the three groups. PMID:22529474

  7. AstRoMap European Astrobiology Roadmap

    PubMed Central

    Horneck, Gerda; Westall, Frances; Grenfell, John Lee; Martin, William F.; Gomez, Felipe; Leuko, Stefan; Lee, Natuschka; Onofri, Silvano; Tsiganis, Kleomenis; Saladino, Raffaele; Pilat-Lohinger, Elke; Palomba, Ernesto; Harrison, Jesse; Rull, Fernando; Muller, Christian; Strazzulla, Giovanni; Brucato, John R.; Rettberg, Petra; Capria, Maria Teresa

    2016-01-01

    Abstract The European AstRoMap project (supported by the European Commission Seventh Framework Programme) surveyed the state of the art of astrobiology in Europe and beyond and produced the first European roadmap for astrobiology research. In the context of this roadmap, astrobiology is understood as the study of the origin, evolution, and distribution of life in the context of cosmic evolution; this includes habitability in the Solar System and beyond. The AstRoMap Roadmap identifies five research topics, specifies several key scientific objectives for each topic, and suggests ways to achieve all the objectives. The five AstRoMap Research Topics are • Research Topic 1: Origin and Evolution of Planetary Systems• Research Topic 2: Origins of Organic Compounds in Space• Research Topic 3: Rock-Water-Carbon Interactions, Organic Synthesis on Earth, and Steps to Life• Research Topic 4: Life and Habitability• Research Topic 5: Biosignatures as Facilitating Life Detection It is strongly recommended that steps be taken towards the definition and implementation of a European Astrobiology Platform (or Institute) to streamline and optimize the scientific return by using a coordinated infrastructure and funding system. Key Words: Astrobiology roadmap—Europe—Origin and evolution of life—Habitability—Life detection—Life in extreme environments. Astrobiology 16, 201–243. PMID:27003862

  8. AstRoMap European Astrobiology Roadmap.

    PubMed

    Horneck, Gerda; Walter, Nicolas; Westall, Frances; Grenfell, John Lee; Martin, William F; Gomez, Felipe; Leuko, Stefan; Lee, Natuschka; Onofri, Silvano; Tsiganis, Kleomenis; Saladino, Raffaele; Pilat-Lohinger, Elke; Palomba, Ernesto; Harrison, Jesse; Rull, Fernando; Muller, Christian; Strazzulla, Giovanni; Brucato, John R; Rettberg, Petra; Capria, Maria Teresa

    2016-03-01

    The European AstRoMap project (supported by the European Commission Seventh Framework Programme) surveyed the state of the art of astrobiology in Europe and beyond and produced the first European roadmap for astrobiology research. In the context of this roadmap, astrobiology is understood as the study of the origin, evolution, and distribution of life in the context of cosmic evolution; this includes habitability in the Solar System and beyond. The AstRoMap Roadmap identifies five research topics, specifies several key scientific objectives for each topic, and suggests ways to achieve all the objectives. The five AstRoMap Research Topics are • Research Topic 1: Origin and Evolution of Planetary Systems • Research Topic 2: Origins of Organic Compounds in Space • Research Topic 3: Rock-Water-Carbon Interactions, Organic Synthesis on Earth, and Steps to Life • Research Topic 4: Life and Habitability • Research Topic 5: Biosignatures as Facilitating Life Detection It is strongly recommended that steps be taken towards the definition and implementation of a European Astrobiology Platform (or Institute) to streamline and optimize the scientific return by using a coordinated infrastructure and funding system. PMID:27003862

  9. Characterisation of RO fouling in an integrated MBR/RO system for wastewater reuse.

    PubMed

    Moreno, J; Monclús, H; Stefani, M; Cortada, E; Aumatell, J; Adroer, N; De Lamo-Castellví, S; Comas, J

    2013-01-01

    Membrane filtration has gradually gained acceptance as the preferred pre-treatment for reverse osmosis (RO). In this paper, an integrated membrane bioreactor (MBR)/RO system for wastewater reuse treating real sewage water has been evaluated and the RO fouling has been characterised. The MBR achieved low values of organic matter, total nitrogen, PO(4)(3-), total organic carbon, turbidity and conductivity. Filtration with two different RO commercial membranes was performed after the MBR pre-treatment and the same average fouling rate (0.08 bar day(-1)) was noted. These results gained from the characterisation of the high quality MBR/RO permeate show its potential for water reuse. Inorganic precipitation appears to be the predominant form of fouling in the RO membranes. Calcium phosphate and alumino-silicates were identified by a scanning electron microscope combined with an energy dispersive X-ray and polysaccharides, amide and aliphatic structures were detected with attenuated total reflection infrared microspectroscopy. PMID:23306255

  10. Refractory anaphylactoid shock potentiated by beta-blockers.

    PubMed

    Javeed, N; Javeed, H; Javeed, S; Moussa, G; Wong, P; Rezai, F

    1996-12-01

    Allergic reactions, including anaphylactoid shock due to contrast material, are not uncommon. However, persistent anaphylactoid shock refractory to conventional therapy is rare. We present a case of refractory anaphylactoid shock during coronary angiography unresponsive to aggressive standard therapy in a patient on beta-blockers. Significant clinical improvement was noted upon administration of glucagon. Since beta-blockers are commonly used in patients with coronary artery disease, this potentially life-threatening complication has to be kept in mind with any procedure involving contrast media in patients on beta-blockers. Immediate access to glucagon by keeping it in the procedure room may be lifesaving in these situations. PMID:8958428

  11. Type 2 Diabetes and ADP Receptor Blocker Therapy

    PubMed Central

    Samoš, Matej; Fedor, Marián; Kovář, František; Mokáň, Michal; Bolek, Tomáš; Galajda, Peter; Kubisz, Peter; Mokáň, Marián

    2016-01-01

    Type 2 diabetes (T2D) is associated with several abnormalities in haemostasis predisposing to thrombosis. Moreover, T2D was recently connected with a failure in antiplatelet response to clopidogrel, the most commonly used ADP receptor blocker in clinical practice. Clopidogrel high on-treatment platelet reactivity (HTPR) was repeatedly associated with the risk of ischemic adverse events. Patients with T2D show significantly higher residual platelet reactivity on ADP receptor blocker therapy and are more frequently represented in the group of patients with HTPR. This paper reviews the current knowledge about possible interactions between T2D and ADP receptor blocker therapy. PMID:26824047

  12. Beta-Blockers: Current State of Knowledge and Perspectives.

    PubMed

    Ogrodowczyk, Magdalena; Dettlaff, Katarzyna; Jelinska, Anna

    2016-01-01

    It has been over half a century since propranolol, the first beta-blocker, was developed for medical treatment. Since that time a large number of compounds from this group have been synthesised and many are now in clinical use. The structure, function, pharmacokinetics, and mechanism of beta-blockers have been established. The possibilities for their use in treating different conditions continue to evolve. Since the discovery of later generation beta-blockers, such as carvedilol and nebivolol, the search for new compounds continues, and may include known substances with beta-blocking properties which could extend their therapeutic potential. PMID:26471965

  13. α-Blocker Therapy: Current Update

    PubMed Central

    Kaplan, Steven A

    2005-01-01

    α-Blockade is the predominant form of medical therapy for the treatment of symptomatic bladder outlet obstruction due to benign prostatic hyperplasia (BPH). Recent research has shown that there is a series of α1 receptor subtypes present in humans and that the α1A subtype appears to play a primary role in mediating prostatic smooth muscle contraction. Recent interest has therefore focussed on the development of agents specific to this α1A receptor subtype. The approval by the Food and Drug Administration of tamsulosin, an α1A-specific antagonist, offers physicians in the United States the opportunity to prescribe a selective α1-blocker for the treatment of BPH. Tamsulosin offers a pharmacologic means to better target α-blockade specifically to the prostatic smooth muscle and spare the vascular smooth muscle. Use of this agent has resulted in a lower incidence of clinically relevant effects on blood pressure or heart rate and minimal cardiovascular adverse effects. PMID:16985889

  14. [Therapy of heart failure with beta-blockers?].

    PubMed

    Osterziel, K J; Dietz, R

    1997-01-01

    In heart failure the chronic sympathetic stimulation alters the cardiac beta-adrenergic pathway. This alteration leads to a diminished contractile response to stimulation of the cardiac beta 1 receptor. A blockade of the beta 1 receptor partly restores the physiologic response to sympathetic stimulation at rest and during exercise. Several mechanisms resulting from the competitive blockade of the beta 1 receptor may be important. The major effect of beta-blockers seems to be triggered by a reduction of the heart rate at rest resulting in an increase of the left ventricular ejection fraction on the average by 7-8%. Patients with heart failure who are treated with a beta-blocker experience initially a slight decrease of the left ventricular function. beta-blocker therapy should therefore be initiated only in patients with stable heart failure. The starting dose of the beta-blocker has to be very small, e.g, 5 mg Metoprolol, 1.25 mg Bisoprolol or 3.125 mg Carvedilol. In a stepwise fashion the dose has to be increased to a full beta blocking effect over a period of 4-8 weeks. Despite a careful dose titration only 90% of the patients tolerate this regimen. Patients with high resting heart rates and/or dilated cardiomyopathy will have the greatest benefit. The two main reasons for withdrawal of the beta-blocker are deterioration of heart failure or symptomatic hypotension. Symptomatic improvement and a significant increase of exercise capacity appear gradually and can be measured only after more than 1 month duration of therapy. Three multicenter studies (MDC. CIBIS I, Carvedilol) evaluated the influence of beta-blockers on prognosis of heart failure. The MDC trial demonstrated a slower progression of heart failure with Metoprolol. The MDC and the CIBIS I trial could not show a significant improvement of prognosis. The larger trial with carvedilol was the first study to demonstrate a decreased mortality in patients who initially tolerate the beta-blocker therapy. One

  15. Systematic review of use of β-blockers in sepsis

    PubMed Central

    Chacko, Cyril Jacob; Gopal, Shameer

    2015-01-01

    Background and Aims: We proposed a review of present literature and systematic analysis of present literature to summarize the evidence on the use of β-blockers on the outcome of a patient with severe sepsis and septic shock. Material and Methods: Medline, EMBASE, Cochrane Library were searched from 1946 to December 2013. The bibliography of all relevant articles was hand searched. Full-text search of the grey literature was done through the medical institution database. The database search identified a total of 1241 possible studies. The citation list was hand searched by both the authors. A total of 9 studies were identified. Results: Most studies found a benefit from β-blocker administration in sepsis. This included improved heart rate (HR) control, decreased mortality and improvement in acid-base parameters. Chronic β-blocker usage in sepsis was also associated with improved mortality. The administration of β-blockers during sepsis was associated with better control of HR. The methodological quality of all the included studies, however, was poor. Conclusion: There is insufficient evidence to justify the routine use of β-blockers in sepsis. A large adequately powered multi-centered randomized controlled clinical trial is required to address the question on the efficacy of β-blocker usage in sepsis. This trial should also consider a number of important questions including the choice of β-blocker used, optimal dosing, timing of intervention, duration of intervention and discontinuation of the drug. Until such time based on the available evidence, there is no place for the use of β-blockers in sepsis in current clinical practice. PMID:26702201

  16. Effects of (−)-RO363 at human atrial β-adrenoceptor subtypes, the human cloned β3-adrenoceptor and rodent intestinal β3-adrenoceptors

    PubMed Central

    Molenaar, Peter; Sarsero, Doreen; Arch, Jonathan R S; Kelly, John; Henson, Sian M; Kaumann, Alberto J

    1997-01-01

    Chronic treatment of patients with β-blockers causes atrial inotropic hyperresponsiveness through β2-adrenoceptors, 5-HT4 receptors and H2-receptors but apparently not through β1-adrenoceptors despite data claiming an increased β1-adrenoceptor density from homogenate binding studies. We have addressed the question of β1-adrenoceptor sensitivity by determining the inotropic potency and intrinsic activity of the β1-adrenoceptor selective partial agonist (−)-RO363 and by carrying out both homogenate binding and quantitative β-adrenoceptor autoradiography in atria obtained from patients treated or not treated with β-blockers. In the course of the experiments it became apparent that (−)-RO363 also may cause agonistic effects through the third atrial β-adrenoceptor. To assess whether (−)-RO363 also caused agonistic effects through β3-adrenoceptors we studied its relaxant effects in rat colon and guinea-pig ileum, as well as receptor binding and adenylyl cyclase stimulation of chinese hamster ovary (CHO) cells expressing human β3-adrenoceptors. β-Adrenoceptors were labelled with (−)-[125I]-cyanopindolol. The density of both β1- and β2-adrenoceptors was unchanged in the 2 groups, as assessed with both quantitative receptor autoradiography and homogenate binding. The affinities of (−)-RO363 for β1-adrenoceptors (pKi=8.0–7.7) and β2-adrenoceptors (pKi=6.1–5.8) were not significantly different in the two groups. (−)-RO363 increased atrial force with a pEC50 of 8.2 (β-blocker treated) and 8.0 (non-β-blocker treated) and intrinsic activity with respect to (−)-isoprenaline of 0.80 (β-blocker treated) and 0.54 (non-β-blocker treated) (P<0.001) and with respect to Ca2+ (7 mM) of 0.65 (β-blocker treated) and 0.45 (non-β-blocker treated) (P<0.01). The effects of (−)-RO363 were resistant to antagonism by the β2-adrenoceptor antagonist, ICI 118,551 (50 nM). The effects of 0.3–10 nM (−)-RO363 were antagonized by 3–10 nM of the

  17. 29 CFR 1918.86 - Roll-on roll-off (Ro-Ro) operations (see also § 1918.2, Ro-Ro operations, and § 1918.25).

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... clearly marked and barricaded. (f) Air brake connections. Each tractor shall have all air lines connected... weight of the cargo. (i) Tractors. Tractors used in Ro-Ro operations shall have: (1) Sufficient power...

  18. β Blockers in heart failure: a comparison of a vasodilating β blocker with metoprolol

    PubMed Central

    Sanderson, J; Chan, S; Yu, C; Yeung, L; Chan, W; Raymond, K; Chan, K; Woo, K

    1998-01-01

    Objective—To determine whether a third generation vasodilating β blocker (celiprolol) has long term clinical advantages over metoprolol in patients with chronic heart failure.
Design—A double blind placebo controlled randomised trial.
Setting—University teaching Hospital.
Patients—50 patients with stable chronic heart failure (NYHA class II-IV) due to idiopathic dilated, ischaemic, or hypertensive cardiomyopathy, with left ventricular ejection fraction < 0.45.
Interventions—Celiprolol 200 mg daily (n = 21), metoprolol 50 mg twice daily (n = 19), or placebo (n = 10) for three months with a four week dose titration period. After the double blind period, patients entered an open label study (with placebo group receiving β blockers) and were assessed after one year.
Main outcome measures—Clinical response, efficacy, and tolerance were assessed by the Minnesota heart failure symptom questionnaire, six minute walk test, Doppler echocardiography (systolic and diastolic function), radionuclide ventriculography, and atrial and brain natriuretic peptides measured at baseline and after three months. 
Results—In the metoprolol group at 12 weeks v baseline there was a 47% reduction in symptom score (p < 0.001), improvement of NYHA class (mean (SEM), 2.6 (0.12) to 1.9 (0.13), p = 0.001), exercise distance (1246 (54) to 1402 (52) feet, p < 0.001), and left ventricular ejection fraction (26.9(3.1)% to 31(3.0)%, p = 0.016), and a fall in heart rate (resting, 79 (3) to 62 (3) beats/min, p < 0.001). In the celiprolol group there was a 38% reduction in symptom score (p = 0.02), less improvement in exercise distance (1191 (55) to 1256 (61) feet, p = 0.05), and no significant changes in NYHA class, left ventricular ejection fraction, or heart rate. Mortality at one year was 11% in metoprolol and 19% in the celiprolol group, and symptomatic improvement was maintained in the survivors.
Conclusions—Both drugs were well

  19. Angiotensin II Receptor Blockers and Cancer Risk

    PubMed Central

    Zhao, Yun-Tao; Li, Peng-Yang; Zhang, Jian-Qiang; Wang, Lei; Yi, Zhong

    2016-01-01

    Abstract Angiotensin II receptor blockers (ARB) are widely used drugs that are proven to reduce cardiovascular disease events; however, several recent meta-analyses yielded conflicting conclusions regarding the relationship between ARB and cancer incidence, especially when ARB are combined with angiotensin-converting enzyme inhibitors (ACEI). We investigated the risk of cancer associated with ARB at different background ACEI levels. Search of PubMed and EMBASE (1966 to December 17, 2015) without language restriction. Randomized, controlled trials (RCTs) had at least 12 months of follow-up data and reported cancer incidence was included. Study characteristics, quality, and risk of bias were assessed by 2 reviewers independently. Nineteen RCTs including 148,334 patients were included in this study. Random-effects model meta-analyses were used to estimate the risk ratio (RR) of cancer risk. No excessive cancer risk was observed in our analyses of ARB alone versus placebo alone without background ACEI use (risk ratio [RR] 1.08, 95% confidence interval [CI] 1.00–1.18, P = 0.05); ARB alone versus ACEI alone (RR 1.03, 95%CI 0.94–1.14, P = 0.50); ARB plus partial use of ACEI versus placebo plus partial use of ACEI (RR 0.97, 95%CI 0.90–1.04, P = 0.33); and ARB plus ACEI versus ACEI (RR 0.99, 95%CI 0.79–1.24, P = 0.95). Lack of long-term data, inadequate reporting of safety data, significant heterogeneity in underlying study populations, and treatment regimens. ARB have a neutral effect on cancer incidence in randomized trials. We observed no significant differences in cancer incidence when we compared ARB alone with placebo alone, ARB alone with ACEI alone, ARB plus partial use of ACEI with placebo plus partial use of ACEI, or ARB plus ACEI combination with ACEI. PMID:27149494

  20. Inhibition of in vivo [(3)H]MK-801 binding by NMDA receptor open channel blockers and GluN2B antagonists in rats and mice.

    PubMed

    Fernandes, Alda; Wojcik, Trevor; Baireddy, Praveena; Pieschl, Rick; Newton, Amy; Tian, Yuan; Hong, Yang; Bristow, Linda; Li, Yu-Wen

    2015-11-01

    N-methyl-D-aspartate (NMDA) receptor antagonists, including open channel blockers and GluN2B receptor subtype selective antagonists, have been developed for the treatment of depression. The current study investigated effects of systemically administered NMDA channel blockers and GluN2B receptor antagonists on NMDA receptor activity in rodents using in vivo [(3)H]MK-801 binding. The receptor occupancy of GluN2B antagonists was measured using ex vivo [(3)H]Ro 25-6981 binding. Ketamine, a NMDA receptor channel blocker, produced a dose/exposure- and time-dependent inhibition of in vivo [(3)H]MK-801 binding that was maximal at ~100%. The complete inhibition of in vivo [(3)H]MK-801 binding was also observed with NMDA receptor channel blockers, AZD6765 (Lanicemine) and MK-801 (Dizocilpine). CP-101,606 (Traxoprodil), a GluN2B antagonist, produced a dose/exposure- and time-dependent inhibition of in vivo [(3)H]MK-801 binding that was maximal at ~60%. Partial inhibition was also observed with other GluN2B antagonists including MK-0657 (CERC-301), EVT-101, Ro 25-6981 and radiprodil. For all GluN2B antagonists tested, partial [(3)H]MK-801 binding inhibition was achieved at doses saturating GluN2B receptor occupancy. Combined treatment with ketamine (10mg/kg, i.p.) and Ro 25-6981(10mg/kg, i.p.) produced a level of inhibition of in vivo [(3)H]MK-801 binding that was similar to treatment with either agent alone. In conclusion, this in vivo [(3)H]MK-801 binding study shows that NMDA receptor activity in the rodent forebrain can be inhibited completely by channel blockers, but only partially (~60%) by GluN2B receptor antagonists. At doses effective in preclinical models of depression, ketamine may preferentially inhibit the same population of NMDA receptors as Ro 25-6981, namely those containing the GluN2B subunit. PMID:26325093

  1. Beta-blockers: friend or foe in asthma?

    PubMed Central

    Arboe, Bente; Ulrik, Charlotte Suppli

    2013-01-01

    Background and aim Recently, β-blockers have been suggested as a potential maintenance treatment option for asthma. The aim of this review is to provide an overview of the current knowledge of the potential benefits and risks of β-blocker therapy for asthma. Method Systematic literature review. Results No significant increase in the number of patients requiring rescue oral corticosteroid for an exacerbation of asthma has been observed after initiation of β-blocker treatment. Patients with mild to moderate reactive airway disease, probably both asthma and chronic obstructive pulmonary disease, may have a limited fall in forced expiratory volume in 1 second (FEV1) following single-dose administration of β-blocker, whereas no change in FEV1 has been reported following long-term administration. In a murine model of asthma, long-term administration of β-blockers resulted in a decrease in airway hyperresponsiveness, suggesting an anti-inflammatory effect. In keeping with this, long-term administration of a nonselective β-blocker to steroid-naïve asthma patients has shown a dose-dependent improvement in airway hyperresponsiveness, and either an asymptomatic fall in FEV1 or no significant change in FEV1. Furthermore, available studies show that bronchoconstriction induced by inhaled methacholine is reversed by salbutamol in patients on regular therapy with a β-blocker. On the other hand, a recent placebo-controlled trial of propranolol and tiotropium bromide added to inhaled corticosteroids revealed no effect on airway hyperresponsiveness and a small, not statistically significant, fall in FEV1 in patients classified as having mild to moderate asthma. Conclusion The available, although limited, evidence suggests that a dose-escalating model of β-blocker therapy to patients with asthma is well tolerated, does not induce acute bronchoconstriction, and, not least, may have beneficial effects on airway inflammation and airway hyperresponsiveness in some patients with

  2. T-type Calcium Channel Blockers as Neuroprotective Agents

    PubMed Central

    Kopecky, Benjamin J.; Liang, Ruqiang; Bao, Jianxin

    2014-01-01

    T-type calcium channels are expressed in many diverse tissues, including neuronal, cardiovascular, and endocrine. T-type calcium channels are known to play roles in the development, maintenance, and repair of these tissues but have also been implicated in disease when not properly regulated. Calcium channel blockers have been developed to treat various diseases and their use clinically is widespread due to both their efficacy as well as their safety. Aside from their established clinical applications, recent studies have suggested neuroprotective effects of T-type calcium channels blockers. Many of the current T-type calcium channel blockers could act on other molecular targets besides T-type calcium channels making it uncertain whether their neuroprotective effects are solely due to blocking of T-type calcium channels. In this review, we discuss these drugs as well as newly developed chemical compounds that are designed to be more selective for T-type calcium channels. We review in vitro and in vivo evidence of neuroprotective effects by these T-type calcium channel blockers. We conclude by discussing possible molecular mechanisms underlying neuroprotective effects by T-type calcium channel blockers. PMID:24563219

  3. An innovative way to reinsert dislodged Arndt blocker using urological glide wire

    PubMed Central

    Pillai, Rahul; Ancheri, Sneha Ann; Dharmalingam, Sathish Kumar; Sahajanandan, Raj

    2016-01-01

    The Arndt blocker is positioned in the desired bronchus using a wire loop which couples the blocker with a fiberoptic bronchoscope (FOB). The wire loop once removed cannot be reinserted in 5F and 7F blockers making repositioning of the blocker difficult. A 34-year-old female was to undergo left thoracotomy followed by laparoscopic cholecystectomy. The left lung was isolated with a 7F Arndt bronchial blocker. During one-lung ventilation, the wire loop was removed for oxygen insufflation. There was loss of lung isolation during the procedure and dislodgement of the blocker was confirmed by FOB. The initial attempts to reintroduce the blocker into the left main bronchus failed. An alternative technique using a glide wire was attempted which resulted in successful reintroduction of the Arndt blocker. The 0.032 inch zebra glide wire may be effectively used to reposition a dislodged Arndt blocker if the wire loop has been removed. PMID:27052085

  4. Alpha Blockers for the Treatment of Benign Prostatic Hyperplasia

    PubMed Central

    Lepor, Herbert

    2007-01-01

    The evolution of alpha blocker therapy for benign prostatic hyperplasia (BPH) has focused on improving convenience and tolerability. Indications for treating BPH include reversing signs and symptoms or preventing progression of the disease. The indication that most commonly drives the need for intervention is relief of lower urinary tract symptoms (LUTS) with the intent of improving quality of life. Alpha blockers are the most effective, least costly, and best tolerated of the drugs for relieving LUTS. Four long-acting alpha 1 blockers are approved by the Food and Drug Administration for treatment of symptomatic LUTS/BPH: terazosin, doxazosin, tamsulosin, and alfuzosin. All are well tolerated and have comparable dose-dependent effectiveness. Tamsulosin and alfuzosin SR do not require dose titration. Alfuzosin, terazosin, and doxazosin have all been shown to be effective in relieving LUTS/BPH independent of prostate size. PMID:18231614

  5. Influence of alpha stimulants and beta blockers on yohimbine toxicity.

    PubMed

    Bourin, M; Malinge, M; Colombel, M C; Larousse, C

    1988-01-01

    1. Potentiation of yohimbine-induced sublethality has been largely used to predict antidepressant action. 2. Several products were tested in order to understand the mechanism of this toxicity better: an alpha-1 central stimulant (adrafinil); an alpha-2 central stimulant (clonidine); and 4 beta-blockers (propranolol, atenolol, penbutolol and metoprolol). 3. It was found that atenolol and adrafinil could not antagonize toxicity, whereas clonidine and the other 3 beta-blockers could. 4. It is suggested that a central beta-origin toxicity exists since only beta-blockers which cross the blood-brain barrier are capable of antagonizing this activity. 5. The fact that clonidine also antagonized this toxicity may be explained by the beta-antagonist action of this substance at the high doses used. PMID:2906156

  6. [Alternatives to beta blockers in preventive migraine treatment].

    PubMed

    Evers, S

    2008-10-01

    Drug prevention of migraine is recommended if more than three attacks occur per month, acute drug treatment is insufficient, or very severe attacks with aura are the main problem. Besides beta blockers, a variety of substances have proved efficacious in migraine prevention. Thus individualised treatment of migraine patients is possible. When choosing the appropriate preventive drug, the potential side effects are considered. Drugs of first choice, besides beta blockers, are flunarizine, valproic acid, and topiramate. Second-choice drugs with lower efficacy or less well published evidence include amitriptyline, venlafaxine, gabapentin, naproxen, acetylsalicylic acid, butterbur root, vitamin B2, and magnesium. Flunarizine or propranolol are recommended for children. PMID:18806984

  7. BLOCKER: A block diagram editing utility, release notes

    SciTech Connect

    Anderson, R.

    1986-10-09

    The BLOCKER block diagram utility was written in the interest of promoting better software documentation. It allows the user to easily create block diagrams which can be stored within software source text files and printed out with standard line printing devices. In this way, sketches which are often drawn on paper during software coding can be kept in an organized manner for later reference. BLOCKER is written in the PRAXIS programming language; it runs on VT-100-compatible terminals under version 4.3 of the VMS operating system on VAX computers. 9 refs.

  8. Pharmacokinetics and pharmacodynamics of beta blockers in heart failure.

    PubMed

    Talbert, Robert L

    2004-04-01

    Although beta-blockers have been used for nearly three decades in the management of heart failure, only recent randomized clinical trials have demonstrated substantial benefit in reducing morbidity and mortality. Carvedilol, metoprolol succinate and bisprolol have evidence supporting their use in heart failure while other beta blockers either lack evidence supporting their use or have not been shown to be useful in heart failure. The only currently approved beta-blockers in the U.S. for heart failure are metoprolol succinate and carvedilol.Beta-blockers differ in their pharmacokinetic and pharmacodynamic properties. It should not be assumed that potential benefit in heart failure is a class effect since differences in the half-life, volume of distribution, protein binding, and route of elimination may give rise to differences in duration of beta blockade and potential drug interactions. Furthermore, pharmacodynamic differences exist because of selectivity for beta(1), beta(2) or alpha(1) adrenoreceptor blockade among the beta-blockers. Receptor kinetics also differ among the beta-blockers and this may influence the extent and duration of beta and alpha blockade across the category. Carvedilol is an inherently long-acting beta-blocker while the duration of beta blockade for metoprolol is dependent on the salt and formulation, which is used. Metoprolol tartrate is a short-acting form of metoprolol while metoprolol succinate is a longer acting salt and the commercially available product is designed as a once daily formulation. A recently published trial, the Carvedilol or Metoprolol European Trial (COMET) tested carvedilol given twice daily versus metoprolol tartrate given twice daily in patients with chronic heart failure. Although carvedilol reduced all cause mortality when compared with metoprolol tartrate, extrapolation to similar findings with metoprolol succinate are not possible since the pharmacokinetic and pharmacodynamic effects of these two formulations are

  9. Role of calcium entry blockers in the prophylaxis of migraine.

    PubMed

    Olesen, J

    1986-01-01

    Published double-blind studies of the effectiveness of Ca2+ entry blockers in migraine prophylaxis are critically reviewed. The evidence in case of flunarizine is satisfactory, and the drug exerts few and minor side effects. Nimodipine also seems to be effective, but the evidence is not quite satisfactory. The interpretation of two studies with verapamil is hampered by serious methodological problems, and the evidence is clearly insufficient to recommend the use of verapamil in migraine prophylaxis. Mechanisms of action are understandable in classic migraine, but still completely unknown in common migraine. Ca2+ entry blockers open up new and fascinating aspects of migraine research. PMID:3530775

  10. Review of topical beta blockers as treatment for infantile hemangiomas.

    PubMed

    Painter, Sally L; Hildebrand, Göran Darius

    2016-01-01

    The treatment of infantile hemangiomas changed from the use of oral corticosteroids to oral propranolol on the serendipitous discovery of propanolol's clinical effectiveness in 2008. Since then, clinicians have begun to use topical beta blockers--in particular, timolol maleate 0.5% gel forming solution--with good effect. Topical beta blockers are now used for lesions with both deep and superficial components and those that are amblyogenic. When initiated in the proliferative phase of the lesion, the effectiveness of the treatment can be seen within days. There is no consensus on dosing, treatment bioavailability, or clinical assessment of lesions, but these are topics for future research. PMID:26408055

  11. Combination treatment with a calcium channel blocker and an angiotensin blocker in a rat systolic heart failure model with hypertension.

    PubMed

    Namba, Masashi; Kim, Shokei; Zhan, Yumei; Nakao, Takafumi; Iwao, Hiroshi

    2002-05-01

    The mechanism and treatment of hypertensive systolic heart failure are not well defined. We compared the effect of an angiotensin-converting enzyme inhibitor (cilazapril, 10 mg/kg), an angiotensin receptor blocker (candesartan, 3 mg/kg), a calcium channel blocker (benidipine, 1, 3 or 6 mg/kg), and the same calcium channel blocker combined with renin-angiotensin blockers on systolic heart failure in Dahl salt-sensitive (DS) rats. DS rats were fed an 8% Na diet from 6 weeks of age and then subjected to the above drug treatments. Benidipine (1 mg/kg), cilazapril, and candesartan had compatible hypotensive effects and similar beneficial effects on cardiac hypertrophy, gene expression, and survival rate. The combination of benidipine with cilazapril or candesartan was found to have no additional beneficial effects on the above parameters, with the exception of a reduction in atrial natriuretic polypeptide gene expression. On the other hand, candesartan normalized serum creatinine, but serum creatinine was unaffected by either benidipine at 1 or 3 mg/kg or cilazapril. Further, the combined use of benidipine and either candesartan or cilazapril resulted in an additional reduction of urinary albumin excretion in DS rats. Thus systolic heart failure in DS rats is mainly mediated by hypertension, while renal dysfunction of DS rats is due to both hypertension and the AT1 receptor itself. These findings suggest that the combination of a calcium channel blocker with an AT1 receptor blocker or ACE inhibitor may be more effective in treating the renal dysfunction associated with systolic heart failure than monotherapy with either agent alone. However, further studies will be needed before reaching any definitive conclusion on the efficacy of this combination therapy in patients with heart failure. PMID:12135327

  12. The role of beta-blockers in septic patients.

    PubMed

    Hamzaoui, O; Teboul, J L

    2015-03-01

    β-blockers are widely used to treat cardiovascular diseases and in the peri-operative period in selected patients. The main benefit in terms of morbidity and/or mortality of their use is believed to be linked to specific effects on myocardial oxygen supply/demand balance, to anti-arrhythmic effects and anti-inflammatory effects. Use of β-blockers in severe sepsis is still under debate and if any, their appropriate indications remain unclear. In this article, we analyze the recent literature addressing the metabolic, immuno-modulatory and hemodynamic effects of non cardio-selective and of cardio-selective β-blockers in experimental and human sepsis in order to help clarifying the potential place of these drugs in patients with severe sepsis. From this analysis, it appears that β-adrenoceptor blocking agents may represent a therapeutic approach in patients with severe sepsis, in whom catecholaminergic hyperactivity including excessive tachycardia is supposed to play an aggravating role. However, many questions about effectiveness, safety and cardio-selectivity of the drugs and about the appropriate target population remain partially unanswered. Recently, esmolol, a short-time acting β1-adrenoceptor blocker titrated to decrease heart rate below 95 beats/min was shown to exert beneficial effects in a monocentric randomized clinical trial including selected septic patients. Further large multicenter randomized trials are required to confirm the potential benefit of such a therapy in patients with severe sepsis. PMID:24941896

  13. beta-Blockers in sepsis: reexamining the evidence.

    PubMed

    Novotny, Nathan M; Lahm, Tim; Markel, Troy A; Crisostomo, Paul R; Wang, Meijing; Wang, Yue; Ray, Rinki; Tan, Jiangning; Al-Azzawi, Dalia; Meldrum, Daniel R

    2009-02-01

    Sepsis remains the leading cause for noncardiac intensive care unit deaths in the United States. Despite recent advances in the treatment of this devastating condition, mortality and morbidity remain unacceptably high. Sepsis is characterized by a multitude of pathophysiological changes that include inflammation, metabolic derangements, hemodynamic alterations, and multiorgan dysfunction. Unfortunately, several studies of treatment modalities aimed at correcting one or more of the underlying derangements have led to disappointing results. New treatment modalities are needed. beta-Receptor blockers have long been used for a variety of conditions such as coronary artery disease, congestive heart failure, and arterial hypertension. Recent data suggest that beta-blocker effects on metabolism, glucose homeostasis, cytokine expression, and myocardial function may be beneficial in the setting of sepsis. Although treating a potentially hypotensive condition with a drug with antihypertensive properties may initially seem counterintuitive, the metabolic and immunomodulatory properties of beta-blockers may be of benefit. It is the purpose of this review to discuss the effects of beta-blockers on the following: (1) metabolism, (2) glucose regulation, (3) the inflammatory response, (4) cardiac function, and (5) mortality in sepsis. PMID:18636043

  14. Peptide toxins and small-molecule blockers of BK channels.

    PubMed

    Yu, Mu; Liu, San-ling; Sun, Pei-bei; Pan, Hao; Tian, Chang-lin; Zhang, Long-hua

    2016-01-01

    Large conductance, Ca(2+)-activated potassium (BK) channels play important roles in the regulation of neuronal excitability and the control of smooth muscle contractions. BK channels can be activated by changes in both the membrane potential and intracellular Ca(2+) concentrations. Here, we provide an overview of the structural and pharmacological properties of BK channel blockers. First, the properties of different venom peptide toxins from scorpions and snakes are described, with a focus on their characteristic structural motifs, including their disulfide bond formation pattern, the binding interface between the toxin and BK channel, and the functional consequence of the blockage of BK channels by these toxins. Then, some representative non-peptide blockers of BK channels are also described, including their molecular formula and pharmacological effects on BK channels. The detailed categorization and descriptions of these BK channel blockers will provide mechanistic insights into the blockade of BK channels. The structures of peptide toxins and non-peptide compounds could provide templates for the design of new channel blockers, and facilitate the optimization of lead compounds for further therapeutic applications in neurological disorders or cardiovascular diseases. PMID:26725735

  15. Peptide toxins and small-molecule blockers of BK channels

    PubMed Central

    Yu, Mu; Liu, San-ling; Sun, Pei-bei; Pan, Hao; Tian, Chang-lin; Zhang, Long-hua

    2016-01-01

    Large conductance, Ca2+-activated potassium (BK) channels play important roles in the regulation of neuronal excitability and the control of smooth muscle contractions. BK channels can be activated by changes in both the membrane potential and intracellular Ca2+ concentrations. Here, we provide an overview of the structural and pharmacological properties of BK channel blockers. First, the properties of different venom peptide toxins from scorpions and snakes are described, with a focus on their characteristic structural motifs, including their disulfide bond formation pattern, the binding interface between the toxin and BK channel, and the functional consequence of the blockage of BK channels by these toxins. Then, some representative non-peptide blockers of BK channels are also described, including their molecular formula and pharmacological effects on BK channels. The detailed categorization and descriptions of these BK channel blockers will provide mechanistic insights into the blockade of BK channels. The structures of peptide toxins and non-peptide compounds could provide templates for the design of new channel blockers, and facilitate the optimization of lead compounds for further therapeutic applications in neurological disorders or cardiovascular diseases. PMID:26725735

  16. Beta-Blockers and Nitrates: Pharmacotherapy and Indications.

    PubMed

    Facchini, Emanuela; Degiovanni, Anna; Cavallino, Chiara; Lupi, Alessandro; Rognoni, Andrea; Bongo, Angelo S

    2015-01-01

    Many clinically important differences exist between beta blockers. B1-selectivity is of clinical interest because at clinically used doses, b1- selective agents block cardiac b-receptors while having minor effects on bronchial and vascular b-receptors. Beta-adrenergic blocking agents significantly decrease the frequency and duration of angina pectoris, instead the prognostic benefit of beta-blockers in stable angina has been extrapolated from studies of post myocardial infarction but has not yet been documented without left ventricular disfunction or previous myocardial infarction. Organic nitrates are among the oldest drugs, but they still remain a widely used adjuvant in the treatment of symptomatic coronary artery disease. While their efficacy in relieving angina pectoris symptoms in acute settings and in preventing angina before physical or emotional stress is undisputed, the chronic use of nitrates has been associated with potentially important side effects such as tolerance and endothelial dysfunction. B-blockers are the firstline anti-anginal therapy in stable stable angina patients without contraindications, while nitrates are the secondline anti-anginal therapy. Despite 150 years of clinical practice, they remain fascinating drugs, which in a chronic setting still deserve investigation. This review evaluated pharmacotherapy and indications of Beta-blockers and nitrates in stable angina. PMID:25544116

  17. Beta-blocker therapy: identification and management of side effects.

    PubMed

    Dennis, K E; Froman, D; Morrison, A S; Holmes, K D; Howes, D G

    1991-09-01

    The purpose of this study was to develop and test a new beta-Blocker Visual Analog Scale designed to identify and quantify the impact that the side effects of beta-blocker therapy have on people's lives, and the self-management practices people use to mediate their influence. Instruments included the 20-item beta-Blocker Visual Analog Scale and the Profile of Mood States. Subjects had hypertension; 51 men were involved in a larger study involving antihypertensive medications and exercise, and 19 men and women were receiving beta-blocker therapy as first-line drug of choice. Estimates of internal consistency reliability, content validity, and concurrent and discriminant validity were moderately strong. The most problematic side effects were related to lack of sleep, vivid or active dreams, lack of energy and pep, diminished interest in sexual activity, and changes in vision. Among self-management practices used to mediate side effects were planning rest and activity periods, thinking carefully before reacting, and seeking out others for support. PMID:1680114

  18. Photochemical fate of beta-blockers in NOM enriched waters.

    PubMed

    Wang, Ling; Xu, Haomin; Cooper, William J; Song, Weihua

    2012-06-01

    Beta-blockers, prescribed for the treatment of high blood pressure and for long-term use after a heart attack, have been detected in surface and ground waters. This study examines the photochemical fate of three beta-blockers, atenolol, metoprolol, and nadolol. Hydrolysis accounted for minor losses of these beta-blockers in the pH range 4-10. The rate of direct photolysis at pH 7 in a solar simulator varied from 6.1 to 8.9h(-1) at pH 7. However, the addition of a natural organic matter (NOM) isolate enhanced the photochemical loss of all three compounds. Indirect photochemical fate, generally described by reactions with hydroxyl radical (OH) and singlet oxygen ((1)ΔO(2)), and, the direct reaction with the triplet excited state, (3)NOM(⁎), also varied but collectively appeared to be the major loss factor. Bimolecular reaction rate constants of the three beta-blockers with (1)ΔO(2) and OH were measured and accounted for 0.02-0.04% and 7.2-38.9% of their loss, respectively. These data suggest that the (3)NOM(⁎) contributed 50.6-85.4%. Experiments with various (3)NOM(⁎) quenchers supported the hypothesis that it was singly the most important reaction. Atenolol was chosen for more detailed investigation, with the photoproducts identified by LC-MS analysis. The results suggested that electron-transfer could be an important mechanism in photochemical fate of beta-blockers in the presence of NOM. PMID:22503673

  19. Probing an open CFTR pore with organic anion blockers.

    PubMed

    Zhou, Zhen; Hu, Shenghui; Hwang, Tzyh-Chang

    2002-11-01

    The cystic fibrosis transmembrane conductance regulator (CFTR) is an ion channel that conducts Cl- current. We explored the CFTR pore by studying voltage-dependent blockade of the channel by two organic anions: glibenclamide and isethionate. To simplify the kinetic analysis, a CFTR mutant, K1250A-CFTR, was used because this mutant channel, once opened, can remain open for minutes. Dose-response relationships of both blockers follow a simple Michaelis-Menten function with K(d) values that differ by three orders of magnitude. Glibenclamide blocks CFTR from the intracellular side of the membrane with slow kinetics. Both the on and off rates of glibenclamide block are voltage dependent. Removing external Cl- increases affinity of glibenclamide due to a decrease of the off rate and an increase of the on rate, suggesting the presence of a Cl- binding site external to the glibenclamide binding site. Isethionate blocks the channel from the cytoplasmic side with fast kinetics, but has no measurable effect when applied extracellularly. Increasing the internal Cl- concentration reduces isethionate block without affecting its voltage dependence, suggesting that Cl- and isethionate compete for a binding site in the pore. The voltage dependence and external Cl- concentration dependence of isethionate block are nearly identical to those of glibenclamide block, suggesting that these two blockers may bind to a common binding site, an idea further supported by kinetic studies of blocking with glibenclamide/isethionate mixtures. By comparing the physical and chemical natures of these two blockers, we propose that CFTR channel has an asymmetric pore with a wide internal entrance and a deeply embedded blocker binding site where local charges as well as hydrophobic components determine the affinity of the blockers. PMID:12407077

  20. Probing an Open CFTR Pore with Organic Anion Blockers

    PubMed Central

    Zhou, Zhen; Hu, Shenghui; Hwang, Tzyh-Chang

    2002-01-01

    The cystic fibrosis transmembrane conductance regulator (CFTR) is an ion channel that conducts Cl− current. We explored the CFTR pore by studying voltage-dependent blockade of the channel by two organic anions: glibenclamide and isethionate. To simplify the kinetic analysis, a CFTR mutant, K1250A-CFTR, was used because this mutant channel, once opened, can remain open for minutes. Dose–response relationships of both blockers follow a simple Michaelis-Menten function with Kd values that differ by three orders of magnitude. Glibenclamide blocks CFTR from the intracellular side of the membrane with slow kinetics. Both the on and off rates of glibenclamide block are voltage dependent. Removing external Cl− increases affinity of glibenclamide due to a decrease of the off rate and an increase of the on rate, suggesting the presence of a Cl− binding site external to the glibenclamide binding site. Isethionate blocks the channel from the cytoplasmic side with fast kinetics, but has no measurable effect when applied extracellularly. Increasing the internal Cl− concentration reduces isethionate block without affecting its voltage dependence, suggesting that Cl− and isethionate compete for a binding site in the pore. The voltage dependence and external Cl− concentration dependence of isethionate block are nearly identical to those of glibenclamide block, suggesting that these two blockers may bind to a common binding site, an idea further supported by kinetic studies of blocking with glibenclamide/isethionate mixtures. By comparing the physical and chemical natures of these two blockers, we propose that CFTR channel has an asymmetric pore with a wide internal entrance and a deeply embedded blocker binding site where local charges as well as hydrophobic components determine the affinity of the blockers. PMID:12407077

  1. SyRoTek--Distance Teaching of Mobile Robotics

    ERIC Educational Resources Information Center

    Kulich, M.; Chudoba, J.; Kosnar, K.; Krajnik, T.; Faigl, J.; Preucil, L.

    2013-01-01

    E-learning is a modern and effective approach for training in various areas and at different levels of education. This paper gives an overview of SyRoTek, an e-learning platform for mobile robotics, artificial intelligence, control engineering, and related domains. SyRoTek provides remote access to a set of fully autonomous mobile robots placed in…

  2. RoMPS concept review automatic control of space robot

    NASA Technical Reports Server (NTRS)

    1991-01-01

    The Robot operated Material Processing in Space (RoMPS) experiment is being performed to explore the marriage of two emerging space commercialization technologies: materials processing in microgravity and robotics. This concept review presents engineering drawings and limited technical descriptions of the RoMPS programs' electrical and software systems.

  3. Effect of β-blockers on platelet aggregation: a systematic review and meta-analysis

    PubMed Central

    Bonten, Tobias N; Plaizier, Chiara E I; Snoep, Jaap-Jan D; Stijnen, Theo; Dekkers, Olaf M; van der Bom, Johanna G

    2014-01-01

    Aims Platelets play an important role in cardiovascular disease, and β-blockers are often prescribed for cardiovascular disease prevention. β-Blockers may directly affect platelet aggregation, because β-adrenergic receptors are present on platelets. There is uncertainty about the existence and magnitude of an effect of β-blockers on platelet aggregation. The aim of this study was to perform a systematic review and meta-analysis of the effect of β-blockers on platelet aggregation. Methods MEDLINE and EMBASE were searched until April 2014. Two reviewers independently performed data extraction and risk of bias assessment. Type of β-blocker, population, treatment duration and platelet aggregation were extracted. Standardized mean differences were calculated for each study and pooled in a random-effects meta-analysis. Results We retrieved 31 studies (28 clinical trials and three observational studies). β-Blockers decreased platelet aggregation (standardized mean difference −0.54, 95% confidence interval −0.85 to −0.24, P < 0.0001). This corresponds to a reduction of 13% (95% confidence interval 8–17%). Nonselective lipophilic β-blockers decreased platelet aggregation more than selective nonlipophilic β-blockers. Conclusions Clinically used β-blockers significantly reduce platelet aggregation. Nonselective lipophilic β-blockers seem to reduce platelet aggregation more effectively than selective nonlipophilic β-blockers. These findings may help to explain why some β-blockers are more effective than others in preventing cardiovascular disease. PMID:24730697

  4. Ro/SSA inhibits the autologous mixed lymphocyte reaction.

    PubMed Central

    Karsh, J; Harley, J B; Goldstein, R; Lazarovits, A I

    1993-01-01

    To test the hypothesis that the Ro/SSA autoantigen can be recognized as antigenic by the human immune system, lymphocytes obtained from normal volunteers were used in in vitro assays evaluating the ability of Ro/SSA (mol. wt 60 kD) to induce B and/or T cell responses. Bovine Ro/SSA strongly inhibited the autologous mixed lymphocyte reaction in a dose-dependent manner without similar effects on concurrently performed allogeneic mixed lymphocyte reactions or T cell proliferation induced by phytohaemagglutinin. Using three colour FACS analysis, Ro/SSA was found to decrease the percentage of CD4+CD45+RA+ T cells in the proliferative, S+(G2+M), phase of the cell cycle. Associated with the decrease in the percentage of suppressor-inducer cells, was the finding that Ro/SSA was able to augment RF production in pokeweed mitogen stimulated cultures of peripheral blood lymphocytes. PMID:7678209

  5. [Beta-blockers in septic shock: a review].

    PubMed

    Vela-Vásquez, R S; Grigorov-Tzenkov, I; Aguilar, J L

    2015-02-01

    In septic shock, high adrenergic stress is associated with cardiovascular and systemic adverse effects, which can negatively affect the results. Beta-adrenergic receptor block has been shown to be effective in controlling the disproportionate increase in heart rate, maintaining a favorable hemodynamic profile and apparently improving the efficiency of the cardiovascular system in order to maintain tissue perfusion. They have also been shown to modulate favorably catecholamine-induced immunosuppression and to decrease insulin resistance, protein catabolism, and proinflammatory cytokine expression associated with cardiovascular dysfunction. Selective beta-1 blockers appear to provide better results than non-selective blockers, even suggesting a positive impact on mortality. Future clinical trials are still needed to confirm these findings and define the scope of their benefits. PMID:25152109

  6. Photochromic Potassium Channel Blockers: Design and Electrophysiological Characterization

    PubMed Central

    Mourot, Alexandre; Fehrentz, Timm; Kramer, Richard H.

    2016-01-01

    Voltage-gated potassium (Kv) channels are membrane proteins that open a selective pore upon membrane depolarization, allowing K+ ions to flow down their electrochemical gradient. In neurons, Kv channels play a key role in repolarizing the membrane potential during the falling phase of the action potential, often resulting in an after hyperpolarization. Opening of Kv channels results in a decrease of cellular excitability, whereas closing (or pharmacological block) has the opposite effect, increased excitability. We have developed a series of photosensitive blockers for Kv channels that enable reversible, optical regulation of potassium ion flow. Such molecules can be used for remote control of neuronal excitability using light as an on/off switch. Here we describe the design and electrophysiological characterization of photochromic blockers of ion channels. Our focus is on Kv channels but in principle, the techniques described here can be applied to other ion channels and signaling proteins. PMID:23494374

  7. Mechanism of Proarrhythmic Effects of Potassium Channel Blockers.

    PubMed

    Skibsbye, Lasse; Ravens, Ursula

    2016-06-01

    Any disturbance of electrical impulse formation in the heart and of impulse conduction or action potential (AP) repolarization can lead to rhythm disorders. Potassium (K(+)) channels play a prominent role in the AP repolarization process. In this review we describe the causes and mechanisms of proarrhythmic effects that arise as a response to blockers of cardiac K(+) channels. The largest and chemically most diverse groups of compound targets are Kv11.1 (hERG) and Kv7.1 (KvLQT1) channels. Finally, the proarrhythmic propensity of atrial-selective K(+) blockers inhibiting Kv1.5, Kir3.1/3.4, SK, and K2P channels is discussed. PMID:27261830

  8. Classification of CoRoT Exoplanet Light Curves

    NASA Astrophysics Data System (ADS)

    Sarro, L. M.; Debosscher, J.; Aerts, C.

    2006-11-01

    We describe the methodology developed for the classification of the exoplanet light curves to be assembled by the CoRoT space mission. A supervised classification method will be used to deliver the N3 data products to the CoRoT Additional Programme community. Unsupervised classification will also be performed, but at a later stage of the mission. In the current paper, we provide the class definitions and attributes under consideration for the fast supervised classification. These definitions and attributes will be improved after each long run of CoRoT.

  9. Use of Calcium Ion Entry Blockers in Family Practice

    PubMed Central

    Tanser, Paul H.

    1983-01-01

    Verapamil, nifedipine, and diltiazem are drugs which decrease intracellular calcium in cardiac muscle, smooth muscle, and nodal cardiac cells. Unlike B-blockers, each drug acts at a different site on the cell membrane and has an important difference in overall action. Verapamil is used to treat angina, systemic hypertension, hypertrophic cardiomyopathy, and supraventricular and junctional tachyarrhythmias. Nifedipine is useful in angina, vasospastic disorders, and hypertension. A specific role for diltiazem is now being defined. PMID:21283319

  10. Add-on therapy in epilepsy with calcium entry blockers.

    PubMed

    Overweg, J; Ashton, D; de Beukelaar, F; Binnie, C D; Wauquier, A; van Wieringen, A

    1986-01-01

    In view of the known role of Ca2+ in the paroxysmal depolarization shifts of epileptic neurones, the possibility arises that certain Ca2+ entry blockers possess antiepileptic activity. The only drug of the class which readily passes the blood-brain barrier is flunarizine. This is effective in experimental models of epilepsy and produced significant seizure reduction in two therapeutic trials in therapy-resistant patients. It has few and mild side effects at therapeutic blood levels. PMID:3530778

  11. alpha(1)-blockers for BPH: are there differences?

    PubMed

    de Mey, C

    1999-01-01

    alpha(1)-blockers are well established for the treatment of lower urinary tract symptoms (LUTS) suggestive of benign prostatic obstruction (BPO), previously referred to as benign prostatic hyperplasia (BPH). The various available alpha(1)-blockers do not differ in terms of their clinical efficacy, but there are several indications that alpha(1)-blockers differ qualitatively with regard to their cardiovascular safety and tolerability, albeit the quantification of these differences is subject to several constraints and pitfalls. Clinical selectivity, i.e. the capacity of separating between desired urological and undesired (actually redundant) cardiovascular alpha(1)-blockade is not unlikely to relate to pharmacological selectivity (the relative preference to block the alpha(1A)- and alpha(1D)-adrenoceptor subtypes in vitro, whilst hardly blocking alpha(1B)-adrenoceptors). On the other hand, both clinical and pharmacological selectivity are not unequivocally reflected by experiments on so-called functional selectivity (in vivo experiments that differentiate urological and cardiovascular effects). Generally, alpha(1)-blockers that are efficacious in hypertension (doxazosin, terazosin, alfuzosin) are more likely to impair safety-relevant, physiological blood pressure control in normotensives with LUTS than tamsulosin, which does not reduce elevated blood pressure in comparison with placebo and has little effect on orthostatic blood pressure control. However, clinical selectivity and cardiovascular safety are also defined by the treatment regimen (dose, dosage interval, formulation, step-up dose-increments for treatment initiation, etc.) and by relevant patient-treatment interactions (co-morbidity and co-medication in particular). On the basis of the available information, tamsulosin administered once daily at a dose of 0.4 mg after breakfast (without step-up increments) can be accepted as a highly convenient and efficacious way to treat LUTS with a low cardiovascular

  12. Aldosterone receptor blockers spironolactone and canrenone: two multivalent drugs.

    PubMed

    Armanini, Decio; Sabbadin, Chiara; Donà, Gabriella; Clari, Giulio; Bordin, Luciana

    2014-05-01

    Canrenone is a derivative of spironolactone with lower antiandrogen activity. The drug is used only in few countries and can block all the side effects of aldosterone (ALDO). The drug is effective even in the presence of normal concentrations of ALDO. Mineralcorticoid receptor antagonists block the inflammatory activity of ALDO at the level of target tissues as heart, vessels and mononuclear leukocytes. Canrenone reduces the progression of insulin resistance and of microalbuminuria in type 2 diabetes and other related diseases. Both canrenone and hydrochlorothiazide can enhance the effect of treatment with ACE inhibitors and angiotensin II receptor blockers on microalbuminuria, but ALDO receptor blockers are more active. This different action is due to the fact that only canrenone blocks mineralocorticoid receptors. Serum potassium and renal function should be monitored before and during the treatment. ALDO receptor blockers are recommended in addition to polytherapy for resistant hypertension, but there are no studies on the effect of the drug as first-choice therapy. PMID:24617854

  13. Assuring the Legacy of the CoRoT Planets

    NASA Astrophysics Data System (ADS)

    Deeg, H. J.; Klagyivik, P.; Alonso, R.; Hoyer, S.

    2015-09-01

    For the long-lasting impact of CoRoT's planet findings, precise knowledge of the times of their transits is of vital importance for any future observing campaigns. Here we give the motivation and first results of a systematic revisit of the transits of most CoRoT planets to refine their ephemeris. As secondary objectives, more precise planet characterisations, from period or transit shape variations on/and from use of a well-defined passband may be obtained.

  14. GCM simulated geopotential heights compared to GPS RO data

    NASA Astrophysics Data System (ADS)

    Molodtsov, S.; Kirilenko, A.; Olsen, D.

    2012-12-01

    Accurate, high-quality, global coverage data is required for global climate monitoring. It also provides possibility of additional validation of the general circulation models (GCMs). GPS Radio occultation (GPS RO) measurements have potential of becoming a new benchmark in data acquisition, providing new high-quality profiles of the parameters of the atmosphere, such as the temperature, water vapor pressure, and geopotential heights. In our study we use GPS RO data with a purpose to test global circulation models (GCMs). We study how climate change signal emerges in the GPS RO data and how these signals are reflected in GCM simulations. We use temperature and geopotential height profiles from 2001-2006 CHAMP and 2006-2011 COMIC acquisitions to validate the output from twelve IPCC AR4 GCMs run under A1B SRES scenario. We found that the 2001-2011 trends of the temperature and geopotential height derived from the IPCC AR4 GCMs show the same pattern with trends derived from GPS RO data - warming of the upper troposphere (UT) and cooling of the lower stratosphere (LS). There is some discrepancy between trends in lower troposphere (LT) between models and GPS RO data: some GCMs show decreasing temperature and geopotential height trends while the GPS RO trends are positive. The statistical analysis of these trends will be reported.

  15. Treatment for calcium channel blocker poisoning: A systematic review

    PubMed Central

    Dubé, P.-A.; Gosselin, S.; Guimont, C.; Godwin, J.; Archambault, P. M.; Chauny, J.-M.; Frenette, A. J.; Darveau, M.; Le sage, N.; Poitras, J.; Provencher, J.; Juurlink, D. N.; Blais, R.

    2014-01-01

    Context Calcium channel blocker poisoning is a common and sometimes life-threatening ingestion. Objective To evaluate the reported effects of treatments for calcium channel blocker poisoning. The primary outcomes of interest were mortality and hemodynamic parameters. The secondary outcomes included length of stay in hospital, length of stay in intensive care unit, duration of vasopressor use, functional outcomes, and serum calcium channel blocker concentrations. Methods Medline/Ovid, PubMed, EMBASE, Cochrane Library, TOXLINE, International pharmaceutical abstracts, Google Scholar, and the gray literature up to December 31, 2013 were searched without time restriction to identify all types of studies that examined effects of various treatments for calcium channel blocker poisoning for the outcomes of interest. The search strategy included the following Keywords: [calcium channel blockers OR calcium channel antagonist OR calcium channel blocking agent OR (amlodipine or bencyclane or bepridil or cinnarizine or felodipine or fendiline or flunarizine or gallopamil or isradipine or lidoflazine or mibefradil or nicardipine or nifedipine or nimodipine or nisoldipine or nitrendipine or prenylamine or verapamil or diltiazem)] AND [overdose OR medication errors OR poisoning OR intoxication OR toxicity OR adverse effect]. Two reviewers independently selected studies and a group of reviewers abstracted all relevant data using a pilot-tested form. A second group analyzed the risk of bias and overall quality using the STROBE (STrengthening the Reporting of OBservational studies in Epidemiology) checklist and the Thomas tool for observational studies, the Institute of Health Economics tool for Quality of Case Series, the ARRIVE (Animal Research: Reporting In Vivo Experiments) guidelines, and the modified NRCNA (National Research Council for the National Academies) list for animal studies. Qualitative synthesis was used to summarize the evidence. Of 15,577 citations identified in

  16. Anti-ENA profiles related with anti-SS-A/Ro. The detection of Ro52 and Ro60 according to the presence of SS-B/La, and ANA pattern and titer.

    PubMed

    González, D Almeida; Rodríguez, C Casañas; Armas, L Magdalena; Varela, A Roces; Rodríguez, I Marcelino; Duarte, M Troche; de León, A Cabrera

    2014-09-01

    Anti-Ro52 (Ro52) and anti-Ro60 (Ro60) antibodies are associated with different clinical entities. We investigated their relationship with the presence of anti-SS-B/La (SSB) antibody, the pattern and titer of antinuclear antibody (ANA), and the variations in antibody profiles related with anti-SS-A/Ro (SSA) positivity. Our aim was to develop a strategy to increase the efficiency of anti-extractable nuclear antigen (ENA) determinations. Statistical analyses were based on the Chi-squared test for categorical variables, the Mann-Whitney U test to compare profiles, and the odds ratio (OR) and 95% confidence interval (95% CI) to estimate the risk of variability. We analyzed 800 SSA-positive samples with Ro52 or Ro60 reactivity. The most frequent profiles were Ro52+Ro60+SSB (n=349, 43.6%); Ro52+Ro60 (n=126, 15.8%); Ro52 (n=121, 15.1%) and Ro60 (n=71, 8.9%). In samples positive only for SSA and an ANA titer ≤1:640, the most likely profile was positivity for either Ro52 or Ro60, whereas when the ANA titer was >1:640, positivity for both Ro52 and Ro60 simultaneously was more likely (p<0.001). In samples positive for both SSA and SSB, the most likely profile was Ro52+Ro60+SSB regardless of the ANA titer (p=0.001). When only SSA was positive and the ANA staining pattern was nucleolar, centromeric or cytoplasmic, Ro52 positivity was most likely (p<0.001). When both SSA and SSB were positive, both Ro52 and Ro60 were likely to be positive regardless of the ANA staining pattern. In 28.7% of the patients the profile was variable. Variability was significantly greater in those with the SSA profile (23/67) than with the SSA+SSB profile (15/105; OR=1.9, 95% CI=1.1-3.3; p=0.025), and the difference in variability was greatest between the Ro52+Ro60 profile (8/23) and the Ro52+Ro60+SSB profile (8/68; OR=4.2, 95% CI=1.9-9.5; p<0.001). We conclude that to increase efficiency in the immunology laboratory, positivity for Ro52 and Ro60 individually or simultaneously can be deduced from SSB

  17. Stellar cycles from photometric data: CoRoT stars

    NASA Astrophysics Data System (ADS)

    Ferreira Lopes, C. E.; Leão, I. C.; de Freitas, D. B.; Canto Martins, B. L.; Catelan, M.; De Medeiros, J. R.

    2015-11-01

    Context. Until a few years ago, the amplitude variation in the photometric data had been explored to a limited extent mainly because of time resolution and photometric sensitivity limitations. This investigation is now possible thanks to the Kepler and CoRoT databases which provide a unique set of data for studying the nature of stellar variability cycles. Aims: The present study characterizes the amplitude variation in a sample of main-sequence stars with light curves collected using CoRoT exofield CCDs. Methods: We analyze potential stellar activity cycles by studying the variability amplitude over small boxes. The cycle periods and amplitudes were computed based on the Lomb-Scargle periodogram, harmonic fits, and visual inspection. As a first application of our approach, we considered the photometric data for 16 CoRoT FGK main sequence stars, revisited during the IRa01, LRa01 and LRa06 CoRoT runs. Results: The 16 CoRoT stars appear to follow the empirical relations between activity cycle periods (Pcyc) and the rotation period (Prot) found by previous works. In addition to the so-called A (active) and I (inactive) sequences previously identified, there is a possible third sequence, here named S (short-cycles) sequence. However, recovery fractions estimated from simulations suggest that only a half of our sample has confident cycle measurements. Therefore, more study is needed to verify our results, and Kepler data will clearly be useful for such a study. Overall, our procedure provides a key tool for exploring the CoRoT and Kepler databases to identify and characterize stellar cycle variability. The CoRoT space mission was developed and is operated by the French space agency CNES, with the participation of ESA's RSSD and Science Programmes, Austria, Belgium, Brazil, Germany, and Spain.

  18. CoRoT data reduction by example

    NASA Astrophysics Data System (ADS)

    Weingrill, J.

    2015-02-01

    Data reduction techniques published so far for the CoRoT N2 data product were targeted primarily on the detection of extrasolar planets. Since the whole dataset has been released, specific algorithms are required to process the lightcurves from CoRoT correctly. Though only unflagged datapoints must be chosen for scientific processing, some flags might be reconsidered. The reduction of data along with improving the signal-to-noise ratio can be achieved by applying a one dimensional drizzle algorithm. Gaps can be filled by linear interpolated data without harming the frequency spectrum. Magnitudes derived from the CoRoT color channels might be used to derive additional information about the targets. Depending on the needs, various filters in the frequency domain remove either the red noise background or high frequency noise. The autocorrelation function or the least squares periodogram are appropriate methods to identify periodic signals. The methods described here are not strictly limited to CoRoT data but may also be applied on Kepler data or the upcoming PLATO mission. The CoRoT space mission, launched on 2006 December 27, has been developed and is operated by CNES, with the contribution of Austria, Belgium, Brazil, ESA (RSSD and Science Programme), Germany and Spain.

  19. Other important applications for beta-blockers in high-risk patients.

    PubMed

    Egan, Brent M; Chilton, Robert J

    2003-12-01

    Beta-blockers suppress the adverse effects of chronic activation of the sympathetic nervous system-which plays an important role in the progression of cardiovascular disease- and the drugs are also recommended as primary therapy in other diverse medical conditions that present treatment problems. For many patients with atrial fibrillation, a common condition that poses a high risk of stroke, heart rate control with beta-blockers is increasingly seen as a critical therapeutic component. Similarly, perioperative beta-blocker use provides clinical benefits in patients undergoing noncardiac surgery who are at risk of cardiac events. In migraine therapy, beta-blockers are well established as effective agents for prophylaxis, and beta-blockers may reduce levels of C-reactive protein, a sensitive marker of inflammation in cardiovascular disease. Reviewing the role of beta-blockers in several ancillary conditions should help illuminate various aspects of the complex progression of cardiovascular disease and clarify the drugs' various therapeutic benefits. PMID:19667668

  20. Clinical treatment of epilepsy with calcium entry blockers.

    PubMed

    Overweg, J; Binnie, C D

    1986-01-01

    In view of the known role of Ca2+ in the paroxysmal depolarisation shifts of epileptic neurons, the possibility arises that certain Ca2+ entry blockers possess antiepileptic activity. The only drug of the class which readily passes blood-brain barrier is flunarizine. This is effective in experimental models of epilepsy and produced significant seizure reduction in two trials in therapy-resistant patients. Efficacy was maintained without development of tolerance. The safety of the drug has already been established in a great number of subjects treated for a long time for other diseases. It has few and mild side effects at therapeutic blood levels. PMID:3609880

  1. Calcium entry blockers in the treatment of vertebrobasilar insufficiency.

    PubMed

    Hofferberth, B

    1986-01-01

    The influence of different calcium entry blockers on the vestibular system was investigated. The paper reports results from animal experiments and also from clinical studies with flunarizine and nimodipine. An animal experimental model of vertebrobasilar insufficiency was developed. The effect of the two drugs on the vestibular nystagmus was studied in Alsatian dogs before and after occluding one vertebral artery. In order to analyze the influence of the drugs on the vestibular nystagmus and on the clinical symptoms in patients with vertebrobasilar insufficiency, different open and double-blind studies were performed. PMID:3530776

  2. Evaluation of RO modules for the SSP ETC/LSS.

    NASA Technical Reports Server (NTRS)

    Jasionowski, W. J.; Bambenek, R. A.

    1973-01-01

    During the past eight years the NASA Manned Spacecraft Center has supported the development of an Integrated Water and Waste Management System for use in the Space Station Prototype (SSP) Environmental Thermal Control/Life-Support System (ETC/LSS). This system includes the reverse osmosis (RO) process for recycling wash water and the compression distillation process for recovering useable water from urine, urinal flush water, humidity condensate, commode flush water and the wash water concentrated by RO. This paper summarizes the experimental work performed during the past four years to select the best commercially available RO module for this system and to also define which surfactants and germicides are most compatible with the selected module.

  3. X-ray scatter correction for cone-beam CT using moving blocker array

    NASA Astrophysics Data System (ADS)

    Zhu, Lei; Strobel, Norbert; Fahrig, Rebecca

    2005-04-01

    Scatter correction is an active research topic in cone beam computed tomography (CBCT) because CBCT (especially flat-panel detector (FPD) based) systems have large scatter-to-primary ratios. Scatter produces artifact and contrast reduction, and is difficult to model accurately. Direct measurement using a beam blocker array provides accurate scatter estimates. However, since the blocker array also blocks primary radiation, imaging requires a second (or subsequent) scan without the blocker array in place. This approach is inefficient in terms of scanning time and patient dose. To combine accurate scatter estimation and reconstruction into one single scan, a new approach based on an array of moving blockers has been developed. The blocker array moves from projection to projection, such that every detector pixel is not consecutively blocked during the data acquisition, and the missing primary data in the blocker shadows are estimated by interpolation. Using different blocker array trajectories, the algorithm has been evaluated through software phantom studies using Monte Carlo simulations and image processing techniques. Results show that this approach is able to greatly reduce the effect of scatter in the reconstruction. By properly choosing blocker distance and primary data interpolation method, the mean square error of the reconstructed image decreases from 32.3% to 1.13%, and the induced visual artifacts are significantly reduced when a raster-scanning blocker array trajectory is used. Further analysis also shows that artifact arises mostly due to inaccurate scatter estimates, rather than due to interpolation of the primary data.

  4. New Insight into Effects of β-Blockers on Arterial Functions

    PubMed Central

    Eguchi, Kazuo

    2016-01-01

    The effects of β-blockers on arterial properties are not well investigated. In our recent study, we compared the effects of the two β-blockers celiprolol and bisoprolol on blood pressure, baroreflex sensitivity (BRS), flow-mediated vasodilatation, and vascular stiffness. We found that bisoprolol achieved a greater reduction in the pulse rate and improved BRS and vascular stiffness, whereas celiprolol reduced the central blood pressure level. In this review, the mechanisms of different types of β-blockers and their effects on arteries are discussed, and the appropriate use of β-blockers in hypertensive subjects will be proposed. PMID:27195240

  5. Calcium channel blockers intake and psoriasis: a case-control study.

    PubMed

    Cohen, A D; Kagen, M; Friger, M; Halevy, S

    2001-01-01

    In vitro evidence suggests that intracellular calcium metabolism influences keratinocyte differentiation. However, only a few reports have described exacerbation of psoriasis or psoriasiform eruptions due to intake of calcium channel blockers. We conducted a case-control study to evaluate the association between exposure to calcium channel blockers and psoriasis. Data were obtained through a retrospective assessment of the files of 150 patients hospitalized for psoriasis or psoriasiform eruptions and 150 matched control patients. Exposure to calcium channel blockers was recorded in case and control patients. It was found that 13/150 patients hospitalized for psoriasis consumed calcium channel blockers. Calcium channel blockers were associated with precipitation of new-onset psoriasis (n = 2), as well as with the exacerbation of psoriasis (n = 11). The calcium channel blockers were as follows: nifedipine (n = 10), felodipine (n = 2) and amlodipine (n = 1). The median latent period between the beginning of intake of calcium channel blockers and precipitation or exacerbation of psoriasis was 28 months (range 4-143 months). A stepwise multivariate logistic regression analysis demonstrated that intake of calcium channel blockers was significantly associated with psoriasis, as compared to the control group (p = 0.018). Our study implies a possible role of calcium channel blockers as precipitating or exacerbating factors in patients with psoriasis. PMID:11800142

  6. Metaflumizone is a novel sodium channel blocker insecticide.

    PubMed

    Salgado, V L; Hayashi, J H

    2007-12-15

    Metaflumizone is a novel semicarbazone insecticide, derived chemically from the pyrazoline sodium channel blocker insecticides (SCBIs) discovered at Philips-Duphar in the early 1970s, but with greatly improved mammalian safety. This paper describes studies confirming that the insecticidal action of metaflumizone is due to the state-dependent blockage of sodium channels. Larvae of the moth Spodoptera eridania injected with metaflumizone became paralyzed, concomitant with blockage of all nerve activity. Furthermore, tonic firing of abdominal stretch receptor organs from Spodoptera frugiperda was blocked by metaflumizone applied in the bath, consistent with the block of voltage-dependent sodium channels. Studies on native sodium channels, in primary-cultured neurons isolated from the CNS of the larvae of the moth Manduca sexta and on Para/TipE sodium channels heterologously expressed in Xenopus (African clawed frog) oocytes, confirmed that metaflumizone blocks sodium channels by binding selectively to the slow-inactivated state, which is characteristic of the SCBIs. The results confirm that metaflumizone is a novel sodium channel blocker insecticide. PMID:17959312

  7. Extracellular magnesium and calcium blockers modulate macrophage activity.

    PubMed

    Libako, Patrycja; Nowacki, Wojciech; Castiglioni, Sara; Mazur, Andrzej; Maier, Jeanette A M

    2016-03-01

    Magnesium (Mg) possesses anti-inflammatory properties, partly because it antagonizes calcium (Ca) and inhibits L-type Ca channels. Our aim was to determine the effects of different concentrations of extracellular Mg, with or without Ca-channel blockers, in macrophages. A macrophage-like cell line J774.E was cultured in different concentrations of extracellular Mg and exposed to i) the phorbol ester PMA to induce the production of reactive oxygen species ii) lipopolysaccharide to induce the production of pro-inflammatory cytokines, or iii) ovalbumin to study endocytosis. The Ca antagonists verapamil and/or TMB-8 were used to interfere with Ca homeostasis. Different concentrations of extracellular Mg did not impact on endocytosis, while Ca antagonists markedly decreased it. Low extracellular Mg exacerbated, whereas Ca antagonists inhibited, PMA-induced production of free radicals. Ca blockers prevented lipopolysaccharide-induced transcription and release of IL-1β, IL-6 and TNF-α, while extracellular Mg had only a marginal effect. Ca channel inhibitors markedly reduced the activity of J774.E cells, thus underscoring the critical role of Ca in the non-specific immune response, a role which was, in some instances, also modulated by extracellular Mg. PMID:27160489

  8. Treatment of RO brine-towards sustainable water reclamation practice.

    PubMed

    Ng, H Y; Lee, L Y; Ong, S L; Tao, G; Viawanath, B; Kekre, K; Lay, W; Seah, H

    2008-01-01

    Treatment and disposal of RO brine is an important part in sustaining the water reclamation practice. RO brine generated from water reclamation contains high concentration of organic and inorganic compounds. Cost-effective technologies for treatment of RO brine are still relatively unexplored. Thus, this study aim to determine a feasible treatment process for removal of both organic and inorganic compounds in RO brine generated from NEWater production. The proposed treatment consists of biological activated carbon (BAC) column followed by capacitive deionization (CDI) process for organic and inorganic removals, respectively. Preliminary bench-scale study demonstrated about 20% TOC removal efficiency was achieved using BAC at 40 mins empty bed contact time (EBCT) while the CDI process was able to remove more than 90% conductivity reducing it from 2.19 mS/cm to only about 164 microS/cm. More than 90% cations and anions in the BAC effluent were removed using CDI process. In addition, TOC and TN removals of 78% and 91%, respectively were also attained through this process. About 90% water recovery was achieved. This process shows the potential of increased water recovery in the reclamation process while volume for disposal can be further minimized. Further studies on the sustainable operation and process optimization are ongoing. PMID:18776632

  9. Removing Arsenic with a Softening/RO Combo

    EPA Science Inventory

    This paper provides a very short summary of the arsenic demonstration program and the limited test results from the point-of-use (POU), reverse osmosis (RO) project in Homedale, ID. Preformance data is presented on the effectiveness of the POU treatment system to remove arseni...

  10. AmeriFlux US-Ro3 Rosemount- G19

    SciTech Connect

    Baker, John; Griffis, Tim

    2016-01-01

    This is the AmeriFlux version of the carbon flux data for the site US-Ro3 Rosemount- G19. Site Description - This tower is located in a farm field farmed in accordance with the cominant farming practice in the region: a corn/soybean rotation with chisel plow tillage in the fall following corn harvest and in the spring following soybeans.

  11. AmeriFlux US-Ro1 Rosemount- G21

    SciTech Connect

    Baker, John; Griffis, Tim; Griffis, Timothy

    2016-01-01

    This is the AmeriFlux version of the carbon flux data for the site US-Ro1 Rosemount- G21. Site Description - This tower is located in a farm field farmed in accordance with the dominant farming practice in the region: a corn/soybean rotation with chisel plow tillage in the fall following corn harvest and in the spring following soybeans.

  12. Asteroseismology of OB stars with CoRoT

    NASA Astrophysics Data System (ADS)

    Degroote, P.; Aerts, C.; Samadi, R.; Miglio, A.; Briquet, M.; Auvergne, M.; Baglin, A.; Baudin, F.; Catala, C.; Michel, E.

    2010-12-01

    The CoRoT satellite is revolutionizing the photometric study of massive O-type and B-type stars. During its long runs, CoRoT observed the entire main sequence B star domain, from typical hot β Cep stars, via cooler hybrid p- and g-mode pulsators to the SPB stars near the edge of the instability strip. CoRoT lowers the sensitivity barrier from the typical mmag-precision reached from the ground, to the μmag-level reached from space. Within the wealth of detected and identified pulsation modes, relations have been found in the form of multiplets, combination of frequencies, and frequency- and period spacings. This wealth of observational evidence is finally providing strong constraints to test current models of the internal structure and pulsations of hot stars. Aside from the expected opacity driven modes with infinite lifetime, other unexpected types of variability are detected in massive stars, such as modes of stochastic nature. The simultaneous observation of all these light curve characteristics implies a challenge for both observational asteroseismology and stellar modelling. The CoRoT space mission was developed and is operated by the French space agency CNES, with participation of ESA's RSSD and Science Programmes, Austria, Belgium, Brazil, Germany, and Spain.

  13. Is ultraviolet radiation on haemodialysis RO water beneficial?

    PubMed

    Stragier, A

    2005-01-01

    The quality of dialysis fluids has become increasingly important in the treatment of HD patients. Purified water represents over 95% of its volume. Bacterial and endotoxin content of Reverse Osmosis (RO) water is usually kept under control by bacterial filters, inserted in the distribution departure loop, and by monthly disinfection of the distribution circuit; the simpler the circuit, the better. This paper reports 12 years experience during which Ultraviolet Irradiation (UV) has replaced bacterial filters. To keep the bacterial growth under control in a complex RO water circuit (including a tank and multiple loops) a simple UV lamp was inserted in the departure line. It proved sufficient to keep bacterial count within AAMI norms. Failure of the UV lamp was associated with a rise of up to 500 cfu/ml in the last (fourth week) before routine disinfection. Normal levels were again obtained after replacement of the UV lamp. Six years later, a second UV lamp was added on the return loop. Bacterial counts and endotoxin levels in RO water promptly fell to <1 cfu/ml and <0.125 EU, till today. It is concluded that UV lamps should be favoured over bacterial filters in systems that are not disinfected daily, such as the RO water circuit. The principle of UV irradiation is explained and its advantage over bacterial filters is discussed. Future possible applications of UV are presented. PMID:16551024

  14. Symmetric Kv1.5 Blockers Discovered by Focused Screening

    PubMed Central

    2012-01-01

    Guided by computational methods, a set of 1920 compounds were selected from the AstraZeneca corporate collection and screened for Kv1.5 activity. To facilitate rapid generation of structure–activity relationships, special attention was given to selecting subsets of structurally similar molecules by using a maximum common substructure similarity-based procedure. The focused screen hit rate was relatively high (12%). More importantly, a structural series featured by the symmetric 1,2-diphenylethane-1,2-diamine substructure was identified as potent Kv.1.5 blockers. The property profile for the series is shown to meet stringent lead-optimization criteria, providing a springboard for the development of a new and safe treatment for atrial fibrillation. PMID:24900546

  15. Beta-blockers in the environment: part II. Ecotoxicity study.

    PubMed

    Maszkowska, Joanna; Stolte, Stefan; Kumirska, Jolanta; Łukaszewicz, Paulina; Mioduszewska, Katarzyna; Puckowski, Alan; Caban, Magda; Wagil, Marta; Stepnowski, Piotr; Białk-Bielińska, Anna

    2014-09-15

    The increasing consumption of beta-blockers (BB) has caused their presence in the environment to become more noticeable. Even though BB are safe for human and veterinary usage, ecosystems may be exposed to these substances. In this study, three selected BB: propranolol, metoprolol and nadolol were subjected to ecotoxicity study. Ecotoxicity evaluation was based on a flexible ecotoxicological test battery including organisms, representing different trophic levels and complexity: marine bacteria (Vibrio fischeri), soil/sediment bacteria (Arthrobacter globiformis), green algae (Scenedesmus vacuolatus) and duckweed (Lemna minor). All the ecotoxicological studies were supported by instrumental analysis to measure deviation between nominal and real test concentrations. Based on toxicological data from the green algae test (S. vacuolatus) propranolol and metoprolol can be considered to be harmful to aquatic organisms. However, sorption explicitly inhibits the hazardous effects of BB, therefore the risks posed by these compounds for the environment are of minor importance. PMID:24975494

  16. Detection of Blotted Proteins: Not All Blockers Are Created Equal.

    PubMed

    Kothari, Vishal; Mathews, Suresh T

    2015-01-01

    Western blotting is a standard analytical technique for detection of proteins. It is dependent on a number of components; from the specificity of the primary antibody to the reduction of competing biomolecules present in the assay. Blocking agents are a critical component for western blotting protocols as these diminish nonspecific binding by blocking off-target sites on the membrane. A variety of blocking agents are available and these are selected in an empirical manner, as no single blocker is compatible with every system. The best blocking agent and method for any particular assay will be an optimized but not absolute choice. Here, we describe characteristics of the most common blocking agents used in western blotting and discuss their advantages and disadvantages. PMID:26139251

  17. Effect of alpha1-blockers on stentless ureteroscopic lithotripsy

    PubMed Central

    Zhu, Jianguo; Liang, Yuxiang; Chen, Weihong; Xu, Shuxiong; Wang, Yuanlin; Hu, Jianxing; He, Hui-chan; Zhong, Wei-de; Sun, Zhaolin

    2016-01-01

    ABSTRACT Objective To evaluate the clinical efficiency of alpha1-adrenergic antagonists on stentless ureteroscopic lithotripsy treating uncomplicated lower ureteral stones. Materials and Methods From January 2007 to January 2013, 84 patients who have uncomplicated lower ureteral stones treated by ureteroscopic intracorporeal lithotripsy with the holmium laser were analyzed. The patients were divided into two groups, group A (44 patients received indwelled double-J stents) and group B (40 patients were treated by alpha1-adrenergic antagonists without stents). All cases of group B were treated with alpha1 blocker for 1 week. Results The mean operative time of group A was significantly longer than group B. The incidences of hematuria, flank/abdominal pain, frequency/urgency after surgery were statistically different between both groups. The stone-free rate of each group was 100%. Conclusions The effect of alpha1-adrenergic antagonists is more significant than indwelling stent after ureteroscopic lithotripsy in treating uncomplicated lower ureteral stones. PMID:27136474

  18. The Evolution of Alpha-Blockers for the Treatment of Benign Prostatic Hyperplasia

    PubMed Central

    Lepor, Herbert

    2006-01-01

    Alpha-blockers have been evaluated for the treatment of benign prostatic hyperplasia (BPH) for 30 years, from early trials with the nonselective α-inhibitor phenoxybenzamine to short-acting (prazosin) then long-acting (terazosin, doxazosin, tamsulosin, alfuzosin) selective α1-antagonists. All of the α-blockers evaluated have demonstrated comparable effectiveness, and the evolution of α-blocker therapy for BPH has therefore focused primarily on improving convenience and tolerability. Although all of the long-acting α1-blockers are well tolerated, only tamsulosin and alfuzosin SR are administered without the requirement for dose titration. Alfuzosin has the additional advantage over tamsulosin of a lower incidence of ejaculatory dysfunction. Studies of subtype-selective α1-antagonists have not demonstrated superior efficacy or improved tolerability over the existing long-acting α1-blockers. PMID:17215999

  19. Skin prick testing in patients using beta-blockers: a retrospective analysis

    PubMed Central

    2010-01-01

    Rationale The use of beta-blockers is a relative contraindication in allergen skin testing yet there is a paucity of literature on adverse events in this circumstance. We examined a population of skin tested patients on beta-blockers to look for any adverse effects. Methods Charts from 2004-2008 in a single allergy clinic were reviewed for any patients taking a beta-blocker when skin tested. Data was examined for skin test reactivity, type of skin test, concomitant asthma diagnosis, allergens tested, and adverse events. Results One hundred and ninety-one patients were taking beta-blockers when skin testing occurred. Seventy-two patients had positive skin tests. No tests resulted in an adverse event. Conclusions This data demonstrates the relative safety of administrating of skin prick tests to patients on beta-blocker treatment. Larger prospective studies are needed to substantiate the findings of this study. PMID:20298514

  20. Alpha-adrenergic blocker mediated osteoblastic stem cell differentiation

    SciTech Connect

    Choi, Yoon Jung; Lee, Jue Yeon; Lee, Seung Jin; Chung, Chong-Pyoung; Park, Yoon Jeong

    2011-12-16

    Highlights: Black-Right-Pointing-Pointer Doxazocin directly up-regulated bone metabolism at a low dose. Black-Right-Pointing-Pointer Doxazocin induced osteoblastic stem cell differentiation without affecting cell proliferation. Black-Right-Pointing-Pointer This osteogenic stem cell differentiation is mediated by ERK-signal dependent pathway. -- Abstract: Recent researches have indicated a role for antihypertensive drugs including alpha- or beta-blockers in the prevention of bone loss. Some epidemiological studies reported the protective effects of those agents on fracture risk. However, there is limited information on the association with those agents especially at the mechanism of action. In the present study, we investigated the effects of doxazosin, an alpha-blocker that is clinically used for the treatment of benign prostatic hyperplasia (BPH) along with antihypertensive medication, on the osteogenic stem cell differentiation. We found that doxazosin increased osteogenic differentiation of human mesenchymal stem cells, detected by Alizarin red S staining and calcein. Doxazosin not only induced expression of alkaline phosphatase, type I collagen, osteopontin, and osteocalcin, it also resulted in increased phosphorylation of extracellular signal-regulated kinase (ERK1/2), a MAP kinase involved in osteoblastic differentiation. Treatment with U0126, a MAP kinase inhibitor, significantly blocked doxazosin-induced osteoblastic differentiation. Unrelated to activation of osteogenic differentiation by doxazosin, we found that there were no significant changes in adipogenic differentiation or in the expression of adipose-specific genes, including peroxisome proliferator-activated receptor {gamma}, aP2, or LPL. In this report, we suggest that doxazosin has the ability to increase osteogenic cell differentiation via ERK1/2 activation in osteogenic differentiation of adult stem cells, which supports the protective effects of antihypertensive drug on fracture risk and

  1. Calcium-channel blockers in the treatment of migraine.

    PubMed

    Gelmers, H J

    1985-01-25

    According to classic theory, a migraine attack is initiated by cerebrovascular spasm followed by extracranial vasodilatation. Results of recent studies support this theory and suggest that cerebral blood flow during the initial phase of migraine symptoms is, in fact, decreased and this decrease probably leads to ischemia and hypoxia. Cellular hypoxia, in turn, can cause an increase in the flow of calcium from the extracellular fluid to the intracellular space, resulting in calcium overload and cellular dysfunction. Because calcium-channel blockers selectively inhibit the intracellular influx of calcium ions, investigators have begun evaluating the efficacy of these agents for migraine prophylaxis. Nimodipine, a calcium-channel blocker that exhibits selective effects on cerebral vessels, seems to offer protection against the cerebral ischemia and hypoxia presumed to be operative during migraine attacks. In a double-blind, placebo-controlled study, nimodipine decreased the frequency and duration of migraine attacks by at least half in 69% of patients treated with this agent. Comparable reductions in migraine frequency and duration were attained in 58, 51, 41 and 52% of patients treated with methysergide maleate, pizotifen, clonidine hydrochloride and propranolol, respectively. The piperazine derivative flunarizine also has calcium-channel blocking properties. This agent prevents vasospasm in cerebral arteries and protects against cerebral hypoxia. Results of double-blind studies of migraine prophylaxis with flunarizine demonstrate the beneficial effects of this agent, particularly in younger patients. Flunarizine proved to be superior to pizotifen in decreasing the severity of migraine attacks and comparable to pizotifen in decreasing their frequency.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:3881906

  2. Cold molecules: Formation, ro-vibrational cooling and electronic conversion

    NASA Astrophysics Data System (ADS)

    Horchani, R.

    2016-05-01

    The possibility of controlling all the motion as well as the internal quantum state of a sample of molecules is a long term goal in the cold molecules field. Although many different techniques have been used to produce ultra-cold molecules, in this paper, we will concentrate on the optical pumping technique successfully used to achieve rotational and vibrational cooling of Cs2 molecules. We will review the different photo-association schemes for molecule formation, the detection schemes through photoionization, the ro-vibrational cooling into a single level and finally the electronic conversion. In addition, we will present a theoretical model for both ro-vibrational cooling and electronic conversion that can be used for the preparation of different experiments.

  3. Validation of Robotic Surgery Simulator (RoSS).

    PubMed

    Kesavadas, Thenkurussi; Stegemann, Andrew; Sathyaseelan, Gughan; Chowriappa, Ashirwad; Srimathveeravalli, Govindarajan; Seixas-Mikelus, Stéfanie; Chandrasekhar, Rameella; Wilding, Gregory; Guru, Khurshid

    2011-01-01

    Recent growth of daVinci Robotic Surgical System as a minimally invasive surgery tool has led to a call for better training of future surgeons. In this paper, a new virtual reality simulator, called RoSS is presented. Initial results from two studies - face and content validity, are very encouraging. 90% of the cohort of expert robotic surgeons felt that the simulator was excellent or somewhat close to the touch and feel of the daVinci console. Content validity of the simulator received 90% approval in some cases. These studies demonstrate that RoSS has the potential of becoming an important training tool for the daVinci surgical robot. PMID:21335803

  4. THE MASS OF CoRoT-7b

    SciTech Connect

    Hatzes, Artie P.; Wuchterl, Guenther; Fridlund, Malcolm; Gandolfi, Davide; Nachmani, Gil; Mazeh, Tsevi; Valencia, Diana; Hebrard, Guillaume; Borde, Pascal; Carone, Ludmila; Paetzold, Martin; Udry, Stephane; Bouchy, Francois; Deleuil, Magali; Moutou, Claire; Barge, Pierre; Deeg, Hans; Tingley, Brandon; Dvorak, Rudolf; Ferraz-Mello, Sylvio E-mail: malcolm.fridlund@esa.int; and others

    2011-12-10

    The mass of CoRoT-7b, the first transiting super-Earth exoplanet, is still a subject of debate. A wide range of masses have been reported in the literature ranging from as high as 8 M{sub Circled-Plus} to as low as 2.3 M{sub Circled-Plus }. This range in mass is largely due to the activity level of the star that contributes a significant amount of radial velocity (RV) 'jitter' and how the various methods correct this jitter. Although most mass determinations give a density consistent with a rocky planet, the lower value permits a bulk composition that can be up to 50% water. We present an analysis of the CoRoT-7b RV measurements that uses very few and simple assumptions in treating the activity signal. By analyzing those RV data for which multiple measurements were made in a given night, we remove the activity related RV contribution without any a priori model. We argue that the contribution of activity to the final RV curve is negligible and that the K-amplitude due to the planet is well constrained. This yields a mass of 7.42 {+-} 1.21 M{sub Circled-Plus} and a mean density of {rho} = 10.4 {+-} 1.8 gm cm{sup -3}. CoRoT-7b is similar in mass and radius to the second rocky planet to be discovered, Kepler-10b, and within the errors they have identical bulk densities-they are virtual twins. These bulk densities lie close to the density-radius relationship for terrestrial planets similar to what is seen for Mercury. CoRoT-7b and Kepler-10b may have an internal structure more like Mercury than the Earth.

  5. CoRoT space photometry of seven Cepheids

    NASA Astrophysics Data System (ADS)

    Poretti, E.; Le Borgne, J. F.; Rainer, M.; Baglin, A.; Benkő, J. M.; Debosscher, J.; Weiss, W. W.

    2015-11-01

    A few Galactic classical Cepheids were observed in the programmes of space missions as Coriolis, MOST, and Kepler. An appealing opportunity was to detect additional non-radial modes, thus opening the possibility to perform asteroseismic studies and making the pulsational content of Galactic Cepheids more similar to that of Magellanic Clouds ones. However, only hints of cycle-to-cycle variations were found, without any strict periodicity. In this context the potential of the CoRoT exoplanetary data base was not fully exploited despite the wide area covered on the Galactic plane. Therefore, we investigated all the candidate Cepheids pointed out by the automatic classification of the CoRoT curves. At the end, we could identify seven bona fide Cepheids. The light curves were investigated to remove some instrumental effects. The frequency analysis was particularly delicate since these small effects can be enhanced by the large amplitude, resulting in the presence of significant, but spurious, peaks in the power spectrum. Indeed, the careful evaluation of a very attracting peak in the spectra of CoRoT 0102618121 allowed us to certify its spurious origin. Once that the instrumental effects were properly removed, no additional mode was detected. On the other hand, cycle-to-cycle variations of the Fourier parameters were observed, but very small and always within ±3σ. Among the seven Cepheids, there are two Pop. I first-overtone pulsators, four Pop. I fundamental mode pulsators, and one Pop. II star. The CoRoT colours allowed us to measure that times of maximum brightness occur a little earlier (about 0.01 period) at short wavelengths than at long ones.

  6. The Mass of CoRoT-7b

    NASA Astrophysics Data System (ADS)

    Hatzes, Artie P.; Fridlund, Malcolm; Nachmani, Gil; Mazeh, Tsevi; Valencia, Diana; Hébrard, Guillaume; Carone, Ludmila; Pätzold, Martin; Udry, Stephane; Bouchy, Francois; Deleuil, Magali; Moutou, Claire; Barge, Pierre; Bordé, Pascal; Deeg, Hans; Tingley, Brandon; Dvorak, Rudolf; Gandolfi, Davide; Ferraz-Mello, Sylvio; Wuchterl, Günther; Guenther, Eike; Guillot, Tristan; Rauer, Heike; Erikson, Anders; Cabrera, Juan; Csizmadia, Szilard; Léger, Alain; Lammer, Helmut; Weingrill, Jörg; Queloz, Didier; Alonso, Roi; Rouan, Daniel; Schneider, Jean

    2011-12-01

    The mass of CoRoT-7b, the first transiting super-Earth exoplanet, is still a subject of debate. A wide range of masses have been reported in the literature ranging from as high as 8 M ⊕ to as low as 2.3 M ⊕. This range in mass is largely due to the activity level of the star that contributes a significant amount of radial velocity (RV) "jitter" and how the various methods correct this jitter. Although most mass determinations give a density consistent with a rocky planet, the lower value permits a bulk composition that can be up to 50% water. We present an analysis of the CoRoT-7b RV measurements that uses very few and simple assumptions in treating the activity signal. By analyzing those RV data for which multiple measurements were made in a given night, we remove the activity related RV contribution without any a priori model. We argue that the contribution of activity to the final RV curve is negligible and that the K-amplitude due to the planet is well constrained. This yields a mass of 7.42 ± 1.21 M ⊕ and a mean density of ρ = 10.4 ± 1.8 gm cm-3. CoRoT-7b is similar in mass and radius to the second rocky planet to be discovered, Kepler-10b, and within the errors they have identical bulk densities—they are virtual twins. These bulk densities lie close to the density-radius relationship for terrestrial planets similar to what is seen for Mercury. CoRoT-7b and Kepler-10b may have an internal structure more like Mercury than the Earth.

  7. Submillimeter Astronomy from the South Pole (AST/RO)

    NASA Astrophysics Data System (ADS)

    Stark, Antony A.

    2013-01-01

    The Antarctic Submillimeter Telescope and Remote Observatory (AST/RO), a 1.7 m diameter offset Gregorian telescope for astronomy and aeronomy studies at wavelengths between 200 and 2000 μm, saw first light in 1995 and operated until 2005. It was the first radio telescope to operate continuously throughout the winter on the Antarctic Plateau. It served as a site testing instrument and prototype for later instruments, as well as executing a wide variety of scientific programs that resulted in six doctoral theses and more than one hundred scientific publications. The South Pole environment is unique among observatory sites for unusually low wind speeds, low absolute humidity, and the consistent clarity of the submillimeter sky. Especially significant are the exceptionally low values of sky noise found at this site, a result of the small water vapor content of the atmosphere. Multiple submillimeter-wave and Terahertz detector systems were in operation on AST/RO, including heterodyne and bolometric arrays. AST/RO's legacy includes comprehensive submillimeter-wave site testing of the South Pole, spectroscopic studies of 492 GHz and 809 GHz neutral atomic carbon and 460 GHz and 806 GHz carbon monoxide in the Milky Way and Magellanic Clouds, and the first detection of the 1.46 THz [N II] line from a ground-based observatory.

  8. Discoveries in the Atmospheres of roAp Stars

    NASA Astrophysics Data System (ADS)

    Kurtz, D. W.; Freyhammer, L. M.; Elkin, V. G.; Mathys, G.

    2007-11-01

    We have obtained a large amount of data on over 40 roAp stars and potential roAp stars with the Ultraviolet and Visual Echelle Spectrograph (UVES) on the VLT with time resolution typically around 1 min and radial velocity precision as high as 1 m s-1. Abundance stratification caused by atomic diffusion in the presence of strong global magnetic fields gives promise of three-dimensional maps of the pulsation amplitude and phase, and of the abundance distributions of many ions that may provide the strongest observational tests of atomic diffusion theory. Studies of individual spectral lines and of line profile variability sample the observable atmospheres of roAp stars from continuum optical depth τ5000~1 to as high as τ5000~10-5, revealing fascinating new pulsational behaviour not observed in other types of pulsating stars, including, inter alia, line profile variability in rare earth elements lines interpreted by as evidence for shock waves in the high atmosphere of these stars, an intriguing range of line bisector shapes, and a new pulsational diagnostic for resolved Zeeman components for the most strongly magnetic stars.

  9. VizieR Online Data Catalog: CoRoT/Exoplanet fields with MATISSE (Gazzano+, 2010)

    NASA Astrophysics Data System (ADS)

    Gazzano, J.-C.; de Laverny, P.; Deleuil, M.; Recio-Blanco, A.; Bouchy, F.; Moutou, C.; Bijaoui, A.; Ordenovic, C.; Gandoli, D.; Loeillet, B.

    2010-11-01

    Atomic data modifications from VALD initial request, atmospheric parameters for 1227 CoRoT targets, radial velocity for 1534 CoRoT targets, and Vsini for 1604 CoRoT targets in three CoRoT/Exoplanet fields LRa01, LRc01, and SRc01. The reported uncertainties are only internal errors. (6 data files).

  10. Discovery of Potent and Orally Active p53-MDM2 Inhibitors RO5353 and RO2468 for Potential Clinical Development

    PubMed Central

    2013-01-01

    The development of small-molecule MDM2 inhibitors to restore dysfunctional p53 activities represents a novel approach for cancer treatment. In a previous communication, the efforts leading to the identification of a non-imidazoline MDM2 inhibitor, RG7388, was disclosed and revealed the desirable in vitro and in vivo pharmacological properties that this class of pyrrolidine-based inhibitors possesses. Given this richness and the critical need for a wide variety of chemical structures to ensure success in the clinic, research was expanded to evaluate additional derivatives. Here we report two new potent, selective, and orally active p53-MDM2 antagonists, RO5353 and RO2468, as follow-ups with promising potential for clinical development. PMID:24900784

  11. Discovery of Potent and Orally Active p53-MDM2 Inhibitors RO5353 and RO2468 for Potential Clinical Development.

    PubMed

    Zhang, Zhuming; Chu, Xin-Jie; Liu, Jin-Jun; Ding, Qingjie; Zhang, Jing; Bartkovitz, David; Jiang, Nan; Karnachi, Prabha; So, Sung-Sau; Tovar, Christian; Filipovic, Zoran M; Higgins, Brian; Glenn, Kelli; Packman, Kathryn; Vassilev, Lyubomir; Graves, Bradford

    2014-02-13

    The development of small-molecule MDM2 inhibitors to restore dysfunctional p53 activities represents a novel approach for cancer treatment. In a previous communication, the efforts leading to the identification of a non-imidazoline MDM2 inhibitor, RG7388, was disclosed and revealed the desirable in vitro and in vivo pharmacological properties that this class of pyrrolidine-based inhibitors possesses. Given this richness and the critical need for a wide variety of chemical structures to ensure success in the clinic, research was expanded to evaluate additional derivatives. Here we report two new potent, selective, and orally active p53-MDM2 antagonists, RO5353 and RO2468, as follow-ups with promising potential for clinical development. PMID:24900784

  12. Antioxidative properties of ginsenoside Ro against UV-B-induced oxidative stress in human dermal fibroblasts.

    PubMed

    Kang, Hyun Ji; Oh, Yuri; Lee, Sihyeong; Ryu, In Wang; Kim, Kyunghoon; Lim, Chang-Jin

    2015-01-01

    Ginsenoside Ro (Ro), an oleanolic acid-type ginsenoside, exhibited suppressive activities on reactive oxygen species (ROS) and matrix metalloproteinase-2 (MMP-2) elevation in UV-B-irradiated fibroblasts. Ro could overcome the reduction of the total glutathione (GSH) contents in UV-B-irradiated fibroblasts. Ro could not interfere with cell viabilities in UV-B-irradiated fibroblasts. Collectively, Ro possesses a potential skin anti-photoaging property against UV-B radiation in fibroblasts. PMID:26214051

  13. Radiosensitivity of CD45RO{sup +} memory and CD45RO{sup {minus}} naive T cells in culture

    SciTech Connect

    Uzawa, Akiko; Suzuki, Gen; Nakata, Yukiko; Akashi, Makoto; Ohyama, Harumi; Akanuma, Atsuo

    1994-01-01

    Radiosensitivities of various human T-cell subsets were investigated by a proliferation assay and by a single-cell gel electrophoresis assay. Each T-cell subset was purified using a cell sorter and was induced to proliferate by ionomycin and interleukin 2. Unsorted T cells showed biphasic dose-survival curves, indicating the heterogeneity of T cells in terms of radiosensitivity. Purified CD4{sup +} helper and CD8{sup +} killer T cells showed similar biphasic dose-survival curves. Hence both T-cell subsets were composed of cells of different radiosensitivity. The T-cell subsets belonging to different activation stages such as CD45RO{sup +} memory and CD45RO{sup {minus}} naive T cells had different dose-survival curves. The former was more radiosensitive than the latter. The high radiosensitivity of CD45RO{sup +} cells was also demonstrated by single-cell gel electrophoresis after irradiation. This is the first demonstration that a particular cell surface marker on T cells is correlated with greater radiosensitivity. 27 refs., 7 figs., 1 tab.

  14. Clinical Impact of Selective and Non-selective Beta Blockers on Survival in Ovarian Cancer Patients

    PubMed Central

    Watkins, Jack L.; Thaker, Premal H.; Nick, Alpa M.; Ramondetta, Lois M.; Kumar, Sanjeev; Urbauer, Diana L.; Matsuo, Koji; Squires, Kathryn; Lutgendorf, Susan K.; Ramirez, Pedro T.; Sood, Anil K.

    2015-01-01

    BACKGROUND Preclinical evidence suggests that sustained adrenergic activation can promote ovarian cancer growth and metastasis. We examined the impact of beta-adrenergic blockade on clinical outcome of women with epithelial ovarian, primary peritoneal or fallopian tube cancers (collectively, EOC). METHODS A multicenter review of 1,425 women with histopathologically confirmed EOC was performed. Comparisons were made between patients with documented beta blocker use during chemotherapy and those without beta blocker use. RESULTS The median age of patients in this study was 63 years (range, 21–93 years). The sample included 269 patients who received beta blockers. Of those, 193 (71.7%) were receiving beta-1 adrenergic receptor (ADRB1) selective agents, and the remaining patients were receiving non-selective beta antagonists. The primary indication for beta blocker use was hypertension but also included arrhythmia and post-myocardial infarction management. For patients receiving any beta blocker, the median overall survival (OS) was 47.8 months versus42 months (P = 0.04) for non-users. The median OS based on beta blocker receptor selectivity was 94.9 months for those receiving non-selective beta blockers versus 38 months for those receiving ADRB1 selective agents (P < 0.001). Hypertension was associated with decreased OS compared to no hypertension across all groups. However, even in patients with hypertension, users of a non-selective beta blocker had a longer median OS than non-users observed (38.2 vs 90 months, P < 0.001). CONCLUSION Use of non-selective beta blockers in epithelial ovarian cancer patients was associated with longer OS. These findings may have implications for new therapeutic approaches. PMID:26301456

  15. Comparison of Early Versus Delayed Oral β Blockers in Acute Coronary Syndromes and Effect on Outcomes.

    PubMed

    Bugiardini, Raffaele; Cenko, Edina; Ricci, Beatrice; Vasiljevic, Zorana; Dorobantu, Maria; Kedev, Sasko; Vavlukis, Marija; Kalpak, Oliver; Puddu, Paolo Emilio; Gustiene, Olivija; Trninic, Dijana; Knežević, Božidarka; Miličić, Davor; Gale, Christopher P; Manfrini, Olivia; Koller, Akos; Badimon, Lina

    2016-03-01

    The aim of this study was to determine if earlier administration of oral β ​blocker therapy in patients with acute coronary syndromes (ACSs) is associated with an increased short-term survival rate and improved left ventricular (LV) function. We studied 11,581 patients enrolled in the International Survey of Acute Coronary Syndromes in Transitional Countries registry from January 2010 to June 2014. Of these patients, 6,117 were excluded as they received intravenous β blockers or remained free of any β ​blocker treatment during hospital stay, 23 as timing of oral β ​blocker administration was unknown, and 182 patients because they died before oral β blockers could be given. The final study population comprised 5,259 patients. The primary outcome was the incidence of in-hospital mortality. The secondary outcome was the incidence of severe LV dysfunction defined as an ejection fraction <40% at hospital discharge. Oral β blockers were administered soon (≤24 hours) after hospital admission in 1,377 patients and later (>24 hours) during hospital stay in the remaining 3,882 patients. Early β ​blocker therapy was significantly associated with reduced in-hospital mortality (odds ratio 0.41, 95% CI 0.21 to 0.80) and reduced incidence of severe LV dysfunction (odds ratio 0.57, 95% CI 0.42 to 0.78). Significant mortality benefits with early β ​blocker therapy disappeared when patients with Killip class III/IV were included as dummy variables. The results were confirmed by propensity score-matched analyses. In conclusion, in patients with ACSs, earlier administration of oral β ​blocker therapy should be a priority with a greater probability of improving LV function and in-hospital survival rate. Patients presenting with acute pulmonary edema or cardiogenic shock should be excluded from this early treatment regimen. PMID:26778165

  16. Prognostic Value for Incidental Antihypertensive Therapy With β-Blockers in Metastatic Colorectal Cancer

    PubMed Central

    Giampieri, Riccardo; Scartozzi, Mario; Del Prete, Michela; Faloppi, Luca; Bianconi, Maristella; Ridolfi, Francesca; Cascinu, Stefano

    2015-01-01

    Abstract Previous studies suggested that the incidental use of β-blockers might influence clinical outcome in solid tumors. We assessed the correlation between the incidental use of β-blockers and clinical outcome in colorectal cancer patients treated with first-line chemotherapy alone or in combination with bevacizumab in metastatic colorectal cancer patients. We collected data from 235 metastatic colorectal cancer patients treated with first-line chemotherapy alone (128 patients) or with bevacizumab (107 patients). Patients were stratified for clinical factors such as β-blockers use, age, sex, and site of metastases, previous adjuvant chemotherapy and ECOG performance status. In the chemotherapy alone group patients receiving β-blockers showed an improved overall survival (median OS 41.3 vs 25.7 months, P = 0.03, HR: 2.26, 95% CI: 1.05–3.24). A significant relationship with improved response rate was also evident for B-blocker users (P = 0.044). On the contrary in the β-blockers users group treated with chemotherapy in combination with bevacizumab we observed a trend toward a worse overall survival although nonstatistically significant (median OS 18.5 vs 23.6 months, HR: 0. 89, 95% CI: 0.38–2.03, P = 0.77). Our analysis confirmed a potential prognostic role for the use of β-blockers in colorectal cancer patients treated with chemotherapy. Our findings also suggest a potential worse outcome for patients on β-blockers receiving bevacizumab. Future prospective studies should include the incidental use of β-blockers as stratification factor for clinical outcome.

  17. Type of Beta-blocker Use Among Patients with Versus without Diabetes after Myocardial Infarction

    PubMed Central

    Arnold, Suzanne V.; Spertus, John A.; Lipska, Kasia J.; Lanfear, David E.; Tang, Fengming; Grodzinsky, Anna; McGuire, Darren K.; Gore, M. Odette; Goyal, Abhinav; Maddox, Thomas M.; Kosiborod, Mikhail

    2014-01-01

    Background Discharge beta-blocker prescription after myocardial infarction (MI) is recommended for all eligible patients. Numerous beta-blocker choices are presently available with variable glycometabolic effects, which could be an important consideration in patients with diabetes mellitus (DM). Whether patients with DM preferentially receive beta-blockers with favorable metabolic effects after MI and if this choice is associated with better glycemic control post-discharge is unknown. Methods Among patients from 24 US hospitals enrolled in an MI registry (2005–08), we investigated the frequency of “DM-friendly” beta-blocker prescription at discharge by DM status. Beta-blockers were classified as DM-friendly (e.g., carvedilol, labetalol), or non-DM-friendly (e.g., metoprolol, atenolol), based on their effects on glycemic control. Hierarchical, multivariable logistic regression examined the association of DM with DM-friendly beta-blocker use. Among DM patients, we examined the association of DM-friendly beta-blockers with worsened glycemic control at 6 months after MI. Results Of 4031 MI patients, 1382 (34%) had DM. Beta-blockers were prescribed at discharge in 93% of patients. DM-friendly beta-blocker use was low regardless of DM status, although patients with DM were more likely to be discharged on a DM-friendly beta-blocker compared with patients without DM (13.5% vs. 10.3%, p=0.003), an association that remained after multivariable adjustment (OR 1.41, 95% CI 1.13–1.77). There was a trend toward a lower risk of worsened glucose control at 6 months in DM patients prescribed DM-friendly vs. non-friendly beta-blockers (RR 0.80, 95% CI 0.60–1.08). Conclusion The vast majority of DM patients were prescribed non-DM friendly beta-blockers—a practice that was associated with a trend towards worse glycemic control post-discharge. While in need of further confirmation in larger studies, our findings highlight an opportunity to improve current practices of beta-blockers

  18. Dispersion and nonlinear effects in OFDM-RoF system

    NASA Astrophysics Data System (ADS)

    Alhasson, Bader H.; Bloul, Albe M.; Matin, M.

    2010-08-01

    The radio-over-fiber (RoF) network has been a proven technology to be the best candidate for the wireless-access technology, and the orthogonal frequency division multiplexing (OFDM) technique has been established as the core technology in the physical layer of next generation wireless communication system, as a result OFDM-RoF has drawn attentions worldwide and raised many new research topics recently. At the present time, the trend of information industry is towards mobile, wireless, digital and broadband. The next generation network (NGN) has motivated researchers to study higher-speed wider-band multimedia communication to transmit (voice, data, and all sorts of media such as video) at a higher speed. The NGN would offer services that would necessitate broadband networks with bandwidth higher than 2Mbit/s per radio channel. Many new services emerged, such as Internet Protocol TV (IPTV), High Definition TV (HDTV), mobile multimedia and video stream media. Both speed and capacity have been the key objectives in transmission. In the meantime, the demand for transmission bandwidth increased at a very quick pace. The coming of 4G and 5G era will provide faster data transmission and higher bit rate and bandwidth. Taking advantages of both optical communication and wireless communication, OFDM Radio over Fiber (OFDM-RoF) system is characterized by its high speed, large capacity and high spectral efficiency. However, up to the present there are some problems to be solved, such as dispersion and nonlinearity effects. In this paper we will study the dispersion and nonlinearity effects and their elimination in OFDM-radio-over-fiber system.

  19. The driving mechanism of roAp stars

    NASA Astrophysics Data System (ADS)

    Dupret, M.-A.; Théado, S.; Noels, A.

    2008-10-01

    We analyse in detail the driving mechanism of roAp stars and present the theoretical instability strip predicted by our models with solar metallicity. A particular attention is given to the interpretation of the role played by the different eigenfunctions in the stabilization of the modes at the red edge of the instability strip. The gradient of temperature in the HI opacity bump appears to play a major role in this context. We also consider the particular and complex role played by the shape of the eigenfunctions (location of the nodes, ...).

  20. Long period oscillations in roAp stars

    NASA Astrophysics Data System (ADS)

    Riley, J. D.; Kurtz, D. W.; Cunha, M. S.

    2004-12-01

    We present the results of observations made over three weeks using the UCT CCD Photometer on the 0.75-m telescope at the South African Astronomical Observatory. Candidate long period roAp stars were identified from their positions on the H-R diagram and observed for a typical period of 4 hr to test for the existence of pulsations, with particular emphasis on pulsations with periods in excess of 15 min. Although 13 stars were successfully observed, none exhibited significant pulsations.

  1. Beta blockers, norepinephrine, and cancer: an epidemiological viewpoint.

    PubMed

    Fitzgerald, Paul J

    2012-01-01

    There is growing evidence that the neurotransmitter norepinephrine (NE) and its sister molecule epinephrine (EPI) (adrenaline) affect some types of cancer. Several recent epidemiological studies have shown that chronic use of beta blocking drugs (which antagonize NE/EPI receptors) results in lower recurrence, progression, or mortality of breast cancer and malignant melanoma. Preclinical studies have shown that manipulation of the levels or receptors of NE and EPI with drugs affects experimentally induced cancers. Psychological stress may play an etiological role in some cases of cancer (which has been shown epidemiologically), and this could be partly mediated by NE and EPI released by the sympathetic nervous system as part of the body's "fight or flight" response. A less well-appreciated phenomenon is that the genetic tone of NE/EPI may play a role in cancer. NE and EPI may affect cancer by interacting with molecular pathways already implicated in abnormal cellular replication, such as the P38/MAPK pathway, or via oxidative stress. NE/EPI-based drugs other than beta blockers also may prevent or treat various types of cancer, as may cholinesterase inhibitors that inhibit the sympathetic nervous system, which could be tested epidemiologically. PMID:22807646

  2. Use of β-Blockers, Angiotensin-Converting Enzyme Inhibitors, Angiotensin II Receptor Blockers, and Risk of Breast Cancer Recurrence: A Danish Nationwide Prospective Cohort Study

    PubMed Central

    Sørensen, Gitte Vrelits; Ganz, Patricia A.; Cole, Steven W.; Pedersen, Lars A.; Toft Sørensen, Henrik; Cronin-Fenton, Deirdre P.; Peter Garne, Jens; Christiansen, Peer M.; Lash, Timothy L.; Ahern, Thomas P.

    2013-01-01

    Purpose To estimate associations between use of β-blockers, angiotensin-converting enzyme (ACE) inhibitors, or angiotensin receptor blockers (ARBs) and breast cancer recurrence in a large Danish cohort. Patients and Methods We enrolled 18,733 women diagnosed with nonmetastatic breast cancer between 1996 and 2003. Patient, treatment, and 10-year recurrence data were ascertained from the Danish Breast Cancer Cooperative Group registry. Prescription and medical histories were ascertained by linkage to the National Prescription Registry and Registry of Patients, respectively. β-Blocker exposure was defined in aggregate and according to solubility, receptor selectivity, and individual drugs. ACE inhibitor and ARB exposures were defined in aggregate. Recurrence associations were estimated with multivariable Cox regression models in which time-varying drug exposures were lagged by 1 year. Results Compared with never users, users of any β-blocker had a lower recurrence hazard in unadjusted models (unadjusted hazard ratio [HR] = 0.91; 95% CI, 0.81 to 1.0) and a slightly higher recurrence hazard in adjusted models (adjusted HR = 1.3; 95% CI, 1.1 to 1.5). Associations were similar for exposures defined by receptor selectivity and solubility. Although most individual β-blockers showed no association with recurrence, metoprolol and sotalol were associated with increased recurrence rates (adjusted metoprolol HR = 1.5, 95% CI, 1.2 to 1.8; adjusted sotalol HR = 2.0, 95% CI, 0.99 to 4.0). ACE inhibitors were associated with a slightly increased recurrence hazard, whereas ARBs were not associated with recurrence (adjusted ACE inhibitor HR = 1.2, 95% CI, 0.97 to 1.4; adjusted ARBs HR = 1.1, 95% CI, 0.85 to 1.3). Conclusion Our data do not support the hypothesis that β-blockers attenuate breast cancer recurrence risk. PMID:23650417

  3. Comparison of antibody assays for detection of autoantibodies to Ro 52, Ro 60 and La associated with primary Sjögren's syndrome.

    PubMed

    Trier, Nicole Hartwig; Nielsen, Inger Ødum; Friis, Tina; Houen, Gunnar; Theander, Elke

    2016-06-01

    Anti-Ro(52/60) and anti-La constitute the hallmark autoantibodies in primary Sjögren's syndrome, being present in 40-70% of sera. Several anti-Ro/La assays exist, but antibody detection appears to be assay-specific, thus the aim of this study was to compare several anti-Ro/La assays. In total, 96 sera from individuals with primary Sjögren's syndrome and 114 healthy controls were tested for anti-Ro 52/60 and anti-La in 17 immunoassays. Especially the immunoassays used for detection of anti-Ro 52 differed in their sensitivity (48-79%), while only small differences in sensitivities were observed for the anti-Ro 60 (69-77%) anti-La (39-44%) assays. Concordances of 65%, 79% and 73% for the anti-Ro 52, anti-Ro 60 and anti-La assays were found, respectively. The majority of the assays yielded high specificities, primarily ranging from 97 to 100%, except from a single anti-Ro 60 assay, which yielded a specificity of 79%. Occasionally, reactivity levels were increased in a few assays, indicating that false-positive results can be obtained when applying assays of reduced specificity. In general, the commercial assays appeared to perform better than the in-house analyses. When correcting the in-house assays for background reactivity, sensitivities were reduced by approximately 7%, 17%, and 19% for anti-Ro 52, anti-Ro 60 and anti-La assays, respectively, illustrating the pitfalls when applying immunoassays for detection of autoantibodies, which in theory may apply to commercial assays as well. Finally, increased total sensitivities were obtained when combining assays. These studies contribute to clarify the clinical utility of immunoassays for detection of autoantibodies of Ro 52, Ro 60 and La and illustrate that the most efficient strategy to maximize antibody sensitivity is to combine several assays. PMID:26956184

  4. Virus removal and integrity in aged RO membranes.

    PubMed

    Pype, Marie-Laure; Donose, Bogdan C; Martí, Llucia; Patureau, Dominique; Wery, Nathalie; Gernjak, Wolfgang

    2016-03-01

    Membrane ageing reduces the quality of the filtered water. Therefore, in order to warrant public health, monitoring membrane performances are of utmost importance. Reverse osmosis (RO) membranes are generally used to remove viruses and salt. However, there is no detailed study demonstrating the impact of aged membrane on the rejection of viruses and of membrane integrity indicators. In this paper, the impact of hypochlorite induced RO ageing on the rejection of a virus surrogate (MS2 phage) and four membrane integrity indicators (salt, dissolved organic matter, rhodamine WT and sulphate) was evaluated. Hypochlorite exposure was either active (under filtration) or passive (soaking), and the changes of the membrane surface chemistry were characterised using several autopsy techniques. Under this accelerated ageing condition, the introduction of chlorine in the membrane chemistry and the breakage of amide bonds caused an increase of the water permeability and a decrease of the virus surrogate's and indicators' rejection. Ageing resulted in a more negatively charged membrane and also in a higher hydrophobicity, which lead to the adsorption of MS2 phage. Despite severe physical membrane damage leading to a reduction of salt rejection to 1.2 log (94%), the minimum rejection of MS2 phage stayed on or above 4 log. PMID:26724450

  5. Removal of organic contaminants by RO and NF membranes

    NASA Technical Reports Server (NTRS)

    Yoon, Yeomin; Lueptow, Richard M.

    2005-01-01

    Rejection characteristics of organic and inorganic compounds were examined for six reverse osmosis (RO) membranes and two nanofiltration (NF) membranes that are commercially available. A batch stirred-cell was employed to determine the membrane flux and the solute rejection for solutions at various concentrations and different pH conditions. The results show that for ionic solutes the degree of separation is influenced mainly by electrostatic exclusion, while for organic solutes the removal depends mainly upon the solute radius and molecular structure. In order to provide a better understanding of rejection mechanisms for the RO and NF membranes, the ratio of solute radius (r(i,s)) to effective membrane pore radius (r(p)) was employed to compare rejections. An empirical relation for the dependence of the rejection of organic compounds on the ratio r(i,s)/r(p) is presented. The rejection for organic compounds is over 75% when r(i,s)/r(p) is greater than 0.8. In addition, the rejection of organic compounds is examined using the extended Nernst-Planck equation coupled with a steric hindrance model. The transport of organic solutes is controlled mainly by diffusion for the compounds that have a high r(i,s)/r(p) ratio, while convection is dominant for compounds that have a small r(i,s)/r(p) ratio. c2005 Elsevier B.V. All rights reserved.

  6. Modeling of the Binding of Peptide Blockers to Voltage-Gated Potassium Channels: Approaches and Evidence

    PubMed Central

    Novoseletsky, V. N.; Volyntseva, A. D.; Shaitan, K. V.; Kirpichnikov, M. P.; Feofanov, A. V.

    2016-01-01

    Modeling of the structure of voltage-gated potassium (KV) channels bound to peptide blockers aims to identify the key amino acid residues dictating affinity and provide insights into the toxin-channel interface. Computational approaches open up possibilities for in silico rational design of selective blockers, new molecular tools to study the cellular distribution and functional roles of potassium channels. It is anticipated that optimized blockers will advance the development of drugs that reduce over activation of potassium channels and attenuate the associated malfunction. Starting with an overview of the recent advances in computational simulation strategies to predict the bound state orientations of peptide pore blockers relative to KV-channels, we go on to review algorithms for the analysis of intermolecular interactions, and then take a look at the results of their application. PMID:27437138

  7. The current status of beta blockers' use in the management of hypertension.

    PubMed

    Akbar, Shahid; Alorainy, Mohammad S

    2014-11-01

    The invention of beta (β)-blockers culminated in a new era in the treatment of cardiovascular diseases (CD), and changed the course of pharmacology research for years to come. Since the introduction of propranolol into clinical practice in 1964, β-blockers enjoyed a special place in the clinicians' armamentarium against CDs, especially for patients with ischemic heart diseases, and are still one of the most extensively used therapeutic drugs in both cardiac and non-cardiac ailments. Current uses of β-blockers in CDs include ischemic heart diseases, hypertension, cardiac arrhythmias, and heart failure. Other substantial non-cardiac uses include glaucoma, migraine, situational anxiety, benign essential tremors, and cardiac symptoms of thyrotoxicosis. This review covers some of the evolutionary changes of clinical uses of β-blockers, the rationale for their use, some recent controversies surrounding their use for treatment of hypertension, and advantages of newer additions to the group.  PMID:25399206

  8. Defining the optimal murine models to investigate immune checkpoint blockers and their combination with other immunotherapies.

    PubMed

    Sanmamed, M F; Chester, C; Melero, I; Kohrt, H

    2016-07-01

    The recent success of checkpoint blockers to treat cancer has demonstrated that the immune system is a critical player in the war against cancer. Historically, anticancer therapeutics have been tested in syngeneic mouse models (with a fully murine immune system) or in immunodeficient mice that allow the engraftment of human xenografts. Animal models with functioning human immune systems are critically needed to more accurately recapitulate the complexity of the human tumor microenvironment. Such models are integral to better predict tumor responses to both immunomodulatory agents and directly antineoplastic therapies. In this regard, the development of humanized models is a promising, novel strategy that offers the possibility of testing checkpoint blockers' capacity and their combination with other antitumor drugs. In this review, we discuss the strengths and weaknesses of the available animal models regarding their capacity to evaluate checkpoint blockers and checkpoint blocker-based combination immunotherapy. PMID:26912558

  9. A novel hypothesis for the binding mode of HERG channel blockers

    SciTech Connect

    Choe, Han . E-mail: hchoe@amc.seoul.kr; Nah, Kwang Hoon; Lee, Soo Nam; Lee, Han Sam; Lee, Hui Sun; Jo, Su Hyun; Leem, Chae Hun; Jang, Yeon Jin

    2006-05-26

    We present a new docking model for HERG channel blockade. Our new model suggests three key interactions such that (1) a protonated nitrogen of the channel blocker forms a hydrogen bond with the carbonyl oxygen of HERG residue T623; (2) an aromatic moiety of the channel blocker makes a {pi}-{pi} interaction with the aromatic ring of HERG residue Y652; and (3) a hydrophobic group of the channel blocker forms a hydrophobic interaction with the benzene ring of HERG residue F656. The previous model assumes two interactions such that (1) a protonated nitrogen of the channel blocker forms a cation-{pi} interaction with the aromatic ring of HERG residue Y652; and (2) a hydrophobic group of the channel blocker forms a hydrophobic interaction with the benzene ring of HERG residue F656. To test these models, we classified 69 known HERG channel blockers into eight binding types based on their plausible binding modes, and further categorized them into two groups based on the number of interactions our model would predict with the HERG channel (two or three). We then compared the pIC{sub 5} value distributions between these two groups. If the old hypothesis is correct, the distributions should not differ between the two groups (i.e., both groups show only two binding interactions). If our novel hypothesis is correct, the distributions should differ between Groups 1 and 2. Consistent with our hypothesis, the two groups differed with regard to pIC{sub 5}, and the group having more predicted interactions with the HERG channel had a higher mean pIC{sub 5} value. Although additional work will be required to further validate our hypothesis, this improved understanding of the HERG channel blocker binding mode may help promote the development of in silico predictions methods for identifying potential HERG channel blockers.

  10. Interaction between positive allosteric modulators and trapping blockers of the NMDA receptor channel

    PubMed Central

    Emnett, Christine M; Eisenman, Lawrence N; Mohan, Jayaram; Taylor, Amanda A; Doherty, James J; Paul, Steven M; Zorumski, Charles F; Mennerick, Steven

    2015-01-01

    Background and Purpose Memantine and ketamine are clinically used, open-channel blockers of NMDA receptors exhibiting remarkable pharmacodynamic similarities despite strikingly different clinical profiles. Although NMDA channel gating constitutes an important difference between memantine and ketamine, it is unclear how positive allosteric modulators (PAMs) might affect the pharmacodynamics of these NMDA blockers. Experimental Approach We used two different PAMs: SGE-201, an analogue of an endogenous oxysterol, 24S-hydroxycholesterol, along with pregnenolone sulphate (PS), to test on memantine and ketamine responses in single cells (oocytes and cultured neurons) and networks (hippocampal slices), using standard electrophysiological techniques. Key Results SGE-201 and PS had no effect on steady-state block or voltage dependence of a channel blocker. However, both PAMs increased the actions of memantine and ketamine on phasic excitatory post-synaptic currents, but neither revealed underlying pharmacodynamic differences. SGE-201 accelerated the re-equilibration of blockers during voltage jumps. SGE-201 also unmasked differences among the blockers in neuronal networks – measured either by suppression of activity in multi-electrode arrays or by neuroprotection against a mild excitotoxic insult. Either potentiating NMDA receptors while maintaining the basal activity level or increasing activity/depolarization without potentiating NMDA receptor function is sufficient to expose pharmacodynamic blocker differences in suppressing network function and in neuroprotection. Conclusions and Implications Positive modulation revealed no pharmacodynamic differences between NMDA receptor blockers at a constant voltage, but did expose differences during spontaneous network activity. Endogenous modulator tone of NMDA receptors in different brain regions may underlie differences in the effects of NMDA receptor blockers on behaviour. PMID:25377730

  11. Effects of Beta-Blocker Withdrawal in Acute Decompensated Heart Failure

    PubMed Central

    Prins, Kurt W.; Neill, John M.; Tyler, John O.; Eckman, Peter M.; Duval, Sue

    2015-01-01

    OBJECTIVES This study sought to evaluate the effects of beta-blocker withdrawal in acute decompensated heart failure (ADHF). BACKGROUND Published reports showed trends for either no harm or increased risk of in-hospital mortality, short-term mortality, and rehospitalization rates in patients admitted for ADHF that discontinued beta-blockers; however, a comprehensive analysis has not been conducted. METHODS Relevant studies from January 2000 through January 2015 were identified in the PubMed, EMBASE, and COCHRANE electronic databases. Where appropriate data were available, weighted relative risks were estimated using random-effects meta-analysis techniques. RESULTS Five observational studies and 1 randomized clinical trial (n = 2,704 patients who continued beta-blocker therapy and n = 439 patients who discontinued beta-blocker therapy) that reported the short-term effects of beta-blocker withdrawal in ADHF were included in the analyses. In 2 studies, beta-blocker withdrawal significantly increased risk of in-hospital mortality (risk ratio: 3.72; 95% confidence interval [CI]: 1.51 to 9.14). Short-term mortality (relative risk: 1.61; 95% CI: 1.04 to 2.49; 4 studies) and combined short-term rehospitalization or death (relative risk: 1.59; 95% CI: 1.03 to 2.45; 4 studies) were also significantly increased. CONCLUSIONS Discontinuation of beta-blockers in patients admitted with ADHF was associated with significantly increased in-hospital mortality, short-term mortality, and the combined endpoint of short-term rehospitalization or mortality. These data suggest beta-blockers should be continued in ADHF patients if their clinical picture allows. PMID:26251094

  12. Pseudosaccharin amines as potent and selective KV1.5 blockers.

    PubMed

    Lloyd, John; Finlay, Heather J; Kover, Alexander; Johnson, James; Pi, Zulan; Jiang, Ji; Neels, James; Cavallaro, Cullen; Wexler, Ruth; Conder, Mary Lee; Shi, Hong; Li, Danshi; Sun, Huabin; Chimalakonda, Anjaneya; Huang, Christine; Salvati, Mark; Levesque, Paul

    2015-11-01

    Phenethyl aminoheterocycles like compound 1 were known to be potent I(Kur) blockers although they lacked potency in vivo. Modification of the heterocycle led to the design and synthesis of pseudosaccharin amines. Compounds such as 14, 17d and 21c were found to be potent K(V)1.5 blockers and selective over other cardiac ion channels. These compounds had potent pharmacodynamic activity, however, they also showed off-target activities such as hemodynamic effects. PMID:25801931

  13. Nebivolol: a novel beta-blocker with nitric oxide-induced vasodilatation.

    PubMed

    Weiss, Robert

    2006-01-01

    Nebivolol is a novel beta1-blocker with a greater degree of selectivity for beta1-adrenergic receptors than other agents in this class and a nitric oxide (NO)-potentiating, vasodilatory effect that is unique among beta-blockers currently available to clinicians (nebivolol is approved in Europe and is currently under review in the US). A NO-potentiating agent such as nebivolol may have an important role in hypertensive populations with reduced endothelial function such as diabetics, African-Americans and those with vascular disease. Nebivolol is a racemic mixture with beta-blocker activity residing in the d-isomer; in contrast, l-nebivolol is far more potent in facilitating NO release. Nebivolol is unique among beta-blockers in that, at doses < 10 mg, it does not inhibit the increase in heart rate normally seen with exercise. The efficacy ofnebivolol has been tested successfully in clinical trials against other agents including other beta-blockers, angiotensin-converting enzyme-inhibitors and calcium channel antagonists in patients with hypertension, angina, and congestive heart failure. The tolerability of nebivolol has been shown to be superior to that of atenolol and metoprolol. In controlled clinical trials, nebivolol has a side effect profile that is similar to placebo, in particular as it relates to fatigue and sexual dysfunction. This article will review published clinical data regarding this cardioselective beta-blocker. PMID:17326335

  14. β-Blockers in hypertension: studies and meta-analyses over the years.

    PubMed

    Larochelle, Pierre; Tobe, Sheldon W; Lacourcière, Yves

    2014-05-01

    β-Blockers are among the most commonly used medications in the treatment of hypertension. However, 45 years after their initial indication for that treatment, their place in the treatment of hypertensive patients is under evaluation and their usefulness has been questioned based on evidence from meta-analyses of clinical trials. The β-blocker class consists of various agents with diverse pharmacokinetic and pharmacodynamic properties including lipo- and hydrophilicity, duration of action, intrinsic sympathomimetic activity, vasodilation, and metabolism linked to genetic polymorphisms. Because of their various properties, some β-blockers are indicated for cardiovascular conditions such as angina, rate control of atrial fibrillation, chronic heart failure, and after myocardial infarction, and other indications such as migraine and essential tremor. There have been more than 17 large trials influencing the recommendations on the use of these agents in the treatment of hypertension. The results of these trials initially led to the widespread recommendation for the use of β-blockers in the management of hypertension. However, the recent multiple meta-analyses using these trials have raised a controversy on their place in that treatment. The Canadian Hypertension Education Program recommendations have included β-blockers as a first-line treatment option for patients younger than 60 years of age based on the evidence from these large trials, and this has been supported by 2 of the meta-analyses. This article reviews these studies to help clinicians better understand the role of β-blockers in managing hypertension. PMID:24750978

  15. The case for beta-blockers as first-line antihypertensive therapy.

    PubMed

    Cruickshank, J M

    1992-06-01

    REASON FOR TREATMENT: In patients with asymptomatic high blood pressure, antihypertensive treatment is initiated for only one reason, to prevent the hypertensive sequelae of myocardial infarction, stroke and heart failure. MORBIDITY, MORTALITY AND SURROGATE ENDPOINTS: Only diuretics and beta-blockers have been shown to benefit hypertensive patients in terms of the hard endpoints morbidity and mortality. beta-Blockers and diuretics are cheaper than newer drugs and thus represent good value for money. It is not acceptable to use drug effects on plasma lipids or insulin resistance as measures of the effects on coronary heart disease, since dihydropyridine calcium antagonists improve these parameters while significantly increasing coronary heart disease events in the acute and chronic ischaemic situation. PATIENT PROFILING: Diuretics. Diuretics appear particularly suited to elderly hypertensives, especially those with isolated systolic hypertension, but they may increase cardiac events in younger and middle-aged diabetic and non-diabetic hypertensives. Angiotensin converting enzyme (ACE) inhibitors. ACE inhibitors are undoubtedly valuable in the presence of left ventricular dysfunction, and possibly in the diabetic in maintaining good renal function. beta-Blockers. beta-Blockers are particularly well suited to younger and middle-aged hypertensives at all blood pressure levels, especially white males; where ischaemia and/or stress is a factor, beta-blockers can significantly reduce the incidence of myocardial infarction and strokes. beta-Blockers benefit elderly hypertensives by preventing strokes and may prevent coronary heart disease if prescribed with a diuretic. PMID:1353111

  16. Renin-angiotensin system blockers regulate the metabolism of isolated fat cells in vitro.

    PubMed

    Caminhotto, R de O; Sertié, R A L; Andreotti, S; Campaãa, A B; Lima, F B

    2016-07-28

    Due to the presence of the renin-angiotensin system (RAS) in tissues and its specific influence on white adipose tissue, fat cells are possible targets of pharmacological RAS blockers commonly used as anti-hypertensive drugs. In the present study, we investigated the effects of different RAS blockers on fat cell metabolism, more specifically on lipolysis, lipogenesis and oxidation of energy substrates. Isolated primary adipocytes were incubated with different RAS blockers (aliskiren, captopril and losartan) in vitro for 24 h and lipolysis, lipogenesis and glucose oxidation capacities were determined in dose-response assays to a β-adrenergic agonist and to insulin. Although no change was found in lipolytic capacity, the RAS blockers modulated lipogenesis and glucose oxidation in a different way. While captopril decreased insulin-stimulated lipogenesis (-19% of maximal response and -60% of insulin responsiveness) due to reduced glucose derived glycerol synthesis (-19% of maximal response and 64% of insulin responsiveness), aliskiren increased insulin-stimulated glucose oxidation (+49% of maximal response and +292% of insulin responsiveness) in fat cells. Our experiments demonstrate that RAS blockers can differentially induce metabolic alterations in adipocyte metabolism, characterized by a reduction in lipogenic responsiveness or an increase in glucose oxidation. The impact of RAS blockers on adipocyte metabolism may have beneficial implications on metabolic disorders during their therapeutic use in hypertensive patients. PMID:27487419

  17. Renin-angiotensin system blockers regulate the metabolism of isolated fat cells in vitro

    PubMed Central

    Caminhotto, R de O.; Sertié, R.A.L.; Andreotti, S.; Campaãa, A.B.; Lima, F.B.

    2016-01-01

    Due to the presence of the renin-angiotensin system (RAS) in tissues and its specific influence on white adipose tissue, fat cells are possible targets of pharmacological RAS blockers commonly used as anti-hypertensive drugs. In the present study, we investigated the effects of different RAS blockers on fat cell metabolism, more specifically on lipolysis, lipogenesis and oxidation of energy substrates. Isolated primary adipocytes were incubated with different RAS blockers (aliskiren, captopril and losartan) in vitro for 24 h and lipolysis, lipogenesis and glucose oxidation capacities were determined in dose-response assays to a β-adrenergic agonist and to insulin. Although no change was found in lipolytic capacity, the RAS blockers modulated lipogenesis and glucose oxidation in a different way. While captopril decreased insulin-stimulated lipogenesis (−19% of maximal response and −60% of insulin responsiveness) due to reduced glucose derived glycerol synthesis (−19% of maximal response and 64% of insulin responsiveness), aliskiren increased insulin-stimulated glucose oxidation (+49% of maximal response and +292% of insulin responsiveness) in fat cells. Our experiments demonstrate that RAS blockers can differentially induce metabolic alterations in adipocyte metabolism, characterized by a reduction in lipogenic responsiveness or an increase in glucose oxidation. The impact of RAS blockers on adipocyte metabolism may have beneficial implications on metabolic disorders during their therapeutic use in hypertensive patients. PMID:27487419

  18. The CoRoT transit candidate catalog

    NASA Astrophysics Data System (ADS)

    Aigrain, S.; Deleuil, M.

    2013-09-01

    We present a full catalog of all the candidate transiting planets identified by the CoRoT space mission during its first 5 years of operations, including homogeneously derived transit parameters, validation diagnostics and a summary of the outcome of follow-up observations, where available.The catalog includes confirmed planets, clear false alarms (mainly blended or grazing eclipsing binaries), but also dozens of unconfirmed cases, where the follow-up was either inconclusive (hot stars, fast rotators) or incomplete (owing to limited telescope time and the relatively faint nature of the CoRoT targets). The catalog is intended primarily as a resource for the community, for example as a starting point for completeness and population studies. The candidate detection and selection processes have evolved significantly over the course of the mission. Several teams independently analyse the light curves from each observing run, searching for transits and providing ranked candidate lists, which are subsequently merged and ranked manually. This enables the use of some specialist methods, which are better suited to the detection of only certain types of transits, but makes it difficult to provide an overall assessment of the sensitivity of the mission to transits of different depths and periods. However, we note the transit search methods used by the different teams have gradually converged since launch, and there are now fewer teams actively involved in the transit search, with more overlap between the resulting candidate lists. For each CoRoT observing run, one team member coordinates the selection of candidates for followup, with input from the other team members. The set of criteria used to perform this selection have also evolved over the years, becoming more homogeneous. In particular, the light curve fitting tools used to produce the transit parameters and other diagnostics, which are included in the present catalog, are now routinely used to validate candidates and

  19. Angiotensin receptor blocker telmisartan suppresses renal gluconeogenesis during starvation.

    PubMed

    Tojo, Akihiro; Hatakeyama, Saaya; Kinugasa, Satoshi; Nangaku, Masaomi

    2015-01-01

    The kidney plays an important role in gluconeogenesis during starvation. To clarify the anti-diabetic action of angiotensin receptor blockers, we examined the effects of telmisartan on the sodium-glucose co-transporters (SGLT) and the pathways of renal gluconeogenesis in streptozotocin-induced diabetes mellitus (DM) rats. At 4 weeks, the DM rats treated with/without telmisartan for 2 weeks and normal control rats were used for the study after a 24-hour fast. SGLT2 expressed on the brush border membrane of the proximal convoluted tubules increased in the DM rats, but decreased in the rats treated with telmisartan. The expression of restriction enzymes of gluconeogenesis, glucose-6-phosphatase, and phosphoenolpyruvate carboxykinase increased in the proximal tubules in the DM rats, whereas these enzymes decreased in the kidneys of the rats treated with telmisartan. The elevated cytoplasmic glucose-6-phosphate and glucose levels in the kidney of DM rats significantly decreased in those treated with telmisartan, whereas those levels in the liver did not show significant change. Meanwhile, the high plasma glucose levels in the DM rats during the intravenous insulin tolerance tests were ameliorated by telmisartan. The increased fasting plasma glucose levels after 24 hours of starvation in the DM rats thus returned to the control levels by telmisartan treatment. In conclusion, the increased renal SGLT2 expression, elevated renal gluconeogenesis enzymes and extent of insulin-resistance in the DM rats were ameliorated by telmisartan therapy, thus resulting in decreased plasma glucose levels after 24 hours of fasting. PMID:25709483

  20. New advances in beta-blocker therapy in heart failure

    PubMed Central

    Barrese, Vincenzo; Taglialatela, Maurizio

    2013-01-01

    The use of β-blockers (BB) in heart failure (HF) has been considered a contradiction for many years. Considering HF simply as a state of inadequate systolic function, BB were contraindicated because of their negative effects on myocardial contractility. Nevertheless, evidence collected in the past years have suggested that additional mechanisms, such as compensatory neuro-humoral hyperactivation or inflammation, could participate in the pathogenesis of this complex disease. Indeed, chronic activation of the sympathetic nervous system, although initially compensating the reduced cardiac output from the failing heart, increases myocardial oxygen demand, ischemia and oxidative stress; moreover, high catecholamine levels induce peripheral vasoconstriction and increase both cardiac pre- and after-load, thus determining additional stress to the cardiac muscle (1). As a consequence of such a different view of the pathogenic mechanisms of HF, the efficacy of BB in the treatment of HF has been investigated in numerous clinical trials. Results from these trials highlighted BB as valid therapeutic tools in HF, providing rational basis for their inclusion in many HF treatment guidelines. However, controversy still exists about their use, in particular with regards to the selection of specific molecules, since BB differ in terms of adrenergic β-receptors selectivity, adjunctive effects on α-receptors, and effects on reactive oxygen species and inflammatory cytokines production. Further concerns about the heterogeneity in the response to BB, as well as the use in specific patients, are matter of debate among clinicians. In this review, we will recapitulate the pharmacological properties and the classification of BB, and the alteration of the adrenergic system occurring during HF that provide a rationale for their use; we will also focus on the possible molecular mechanisms, such as genetic polymorphisms, underlying the different efficacy of molecules belonging to this class

  1. The effect of angiotensin II receptor blockers on hyperuricemia

    PubMed Central

    Wolff, Marissa L.; Cruz, Jennifer L.; Vanderman, Adam J.; Brown, Jamie N.

    2015-01-01

    The objective of this review was to explore the efficacy of angiotensin II receptor blockers (ARBs) for the treatment of hyperuricemia in individuals diagnosed with gout or hyperuricemia defined as ⩾7 mg/dl at baseline. A literature search of MEDLINE (1946 to June 2015) and EMBASE (1947 to June 2015) was conducted. The following search terms were used: ‘uric acid’, ‘urate transporter’, ‘gout’, ‘angiotensin II receptor blockers’, ‘hyperuricemia’ and the names for individual ARBs, as well as any combinations of these terms. Studies were excluded that did not explore fractional excretion or serum uric acid as an endpoint, if patients did not have a diagnosis of gout or hyperuricemia at baseline, or if they were non-English language. A total of eight studies met the inclusion criteria. Of the eight studies identified, six explored ARB monotherapy and two studies investigated ARBs as adjunct therapy. Losartan demonstrated statistically significant reductions in serum uric acid levels or increases in fractional excretion of uric acid in all studies, whereas no other ARB reached statistical benefit. The effect of ARBs on the occurrence of gout attacks or other clinical outcomes were not represented. Four studies evaluated safety effects of these agents indicating abnormalities such as minor changes in lab values. In conclusion, losartan is the only ARB that has consistently demonstrated a significant reduction in serum uric acid levels, although the significance of impacting clinical outcomes remains unknown. Losartan appears to be a safe and efficacious agent to lower serum uric acid levels in patients with hyperuricemia. PMID:26568810

  2. Statin, Calcium Channel Blocker and Beta Blocker Therapy May Decrease the Incidence of Tuberculosis Infection in Elderly Taiwanese Patients with Type 2 Diabetes

    PubMed Central

    Lee, Mei-Yueh; Lin, Kun-Der; Hsu, Wei-Hao; Chang, Hsiu-Ling; Yang, Yi-Hsin; Hsiao, Pi-Jung; Shin, Shyi-Jang

    2015-01-01

    Background: It is well known that diabetes mellitus impairs immunity and therefore is an independent risk factor for tuberculosis. However, the influence of associated metabolic factors, such as hypertension, dyslipidemia and gout has yet to be confirmed. This study aimed to investigate whether the strong association between tuberculosis and diabetes mellitus is independent from the influence of hypertension and dyslipidemia, and its treatment in elderly Taiwanese patients. Methods: A total of 27,958 patients aged more than 65 years were identified from the National Health Insurance Research Database (NIHRD) in 1997 and were followed from 1998 to 2009. The demographic characteristics between the patients with and without diabetes were analyzed using the χ2 test. A total of 13,981 patients with type 2 diabetes were included in this study. Cox proportional hazard regression models were used to determine the independent effects of diabetes on the risk of tuberculosis. Results: After adjusting for age, sex, other co-morbidities and medications, calcium channel blocker, beta blocker and statin users had a lower independent association, with risk ratios of 0.76 (95% CI, 0.58–0.98), 0.72 (95% CI, 0.58–0.91) and 0.76 (95% CI, 0.60–0.97), respectively. Conclusion: Calcium channel blocker, beta blocker and statin therapy may decrease the incidence of tuberculosis infection in elderly Taiwanese patients with type 2 diabetes. PMID:25993300

  3. Intracellular calcium changes induced by the endozepine triakontatetraneuropeptide in human polymorphonuclear leukocytes: role of protein kinase C and effect of calcium channel blockers

    PubMed Central

    Marino, Franca; Cosentino, Marco; Ferrari, Marco; Cattaneo, Simona; Frigo, Giuseppina; Fietta, Anna M; Lecchini, Sergio; Frigo, Gian Mario

    2004-01-01

    Background The endozepine triakontatetraneuropeptide (TTN) induces intracellular calcium ([Ca++]i) changes followed by activation in human polymorphonuclear leukocytes (PMNs). The present study was undertaken to investigate the role of protein kinase (PK) C in the modulation of the response to TTN by human PMNs, and to examine the pharmacology of TTN-induced Ca++ entry through the plasma membrane of these cells. Results The PKC activator 12-O-tetradecanoylphorbol-13-acetate (PMA) concentration-dependently inhibited TTN-induced [Ca++]i rise, and this effect was reverted by the PKC inhibitors rottlerin (partially) and Ro 32-0432 (completely). PMA also inhibited TTN-induced IL-8 mRNA expression. In the absence of PMA, however, rottlerin (but not Ro 32-0432) per se partially inhibited TTN-induced [Ca++]i rise. The response of [Ca++]i to TTN was also sensitive to mibefradil and flunarizine (T-type Ca++-channel blockers), but not to nifedipine, verapamil (L-type) or ω-conotoxin GVIA (N-type). In agreement with this observation, PCR analysis showed the expression in human PMNs of the mRNA for all the α1 subunits of T-type Ca++ channels (namely, α1G, α1H, and α1I). Conclusions In human PMNs TTN activates PKC-modulated pathways leading to Ca++ entry possibly through T-type Ca++ channels. PMID:15228623

  4. Transiting exoplanets from the CoRoT space mission. XXVI. CoRoT-24: a transiting multiplanet system

    NASA Astrophysics Data System (ADS)

    Alonso, R.; Moutou, C.; Endl, M.; Almenara, J.-M.; Guenther, E. W.; Deleuil, M.; Hatzes, A.; Aigrain, S.; Auvergne, M.; Baglin, A.; Barge, P.; Bonomo, A. S.; Bordé, P.; Bouchy, F.; Cavarroc, C.; Cabrera, J.; Carpano, S.; Csizmadia, Sz.; Cochran, W. D.; Deeg, H. J.; Díaz, R. F.; Dvorak, R.; Erikson, A.; Ferraz-Mello, S.; Fridlund, M.; Fruth, T.; Gandolfi, D.; Gillon, M.; Grziwa, S.; Guillot, T.; Hébrard, G.; Jorda, L.; Léger, A.; Lammer, H.; Lovis, C.; MacQueen, P. J.; Mazeh, T.; Ofir, A.; Ollivier, M.; Pasternacki, T.; Pätzold, M.; Queloz, D.; Rauer, H.; Rouan, D.; Santerne, A.; Schneider, J.; Tadeu dos Santos, M.; Tingley, B.; Titz-Weider, R.; Weingrill, J.; Wuchterl, G.

    2014-07-01

    We present the discovery of a candidate multiply transiting system, the first one found in the CoRoT mission. Two transit-like features with periods of 5.11 and 11.76 d are detected in the CoRoT light curve around a main sequence K1V star of r = 15.1. If the features are due to transiting planets around the same star, these would correspond to objects of 3.7 ± 0.4 and 5.0 ± 0.5 R⊕ , respectively. Several radial velocities serve to provide an upper limit of 5.7 M⊕ for the 5.11 d signal and to tentatively measure a mass of 28+11-11 M⊕ for the object transiting with a 11.76 d period. These measurements imply low density objects, with a significant gaseous envelope. The detailed analysis of the photometric and spectroscopic data serves to estimate the probability that the observations are caused by transiting Neptune-sized planets as much as over 26 times higher than a blend scenario involving only one transiting planet and as much as over 900 times higher than a scenario involving two blends and no planets. The radial velocities show a long-term modulation that might be attributed to a 1.5 MJup planet orbiting at 1.8 AU from the host, but more data are required to determine the precise orbital parameters of this companion. The CoRoT space mission, launched on 27 December 2006, has been developed and is operated by the CNES, with the contribution of Austria, Belgium, Brazil, ESA (RSSD and Science Program), Germany, and Spain. Some of the observations were made with the HARPS spectrograph at ESO La Silla Observatory (184.C-0639) and with the HIRES spectrograph at the Keck Telescope (N035Hr, N143Hr 260 and N095Hr). Partly based on observations obtained at ESO Paranal Observatory, Chile (086.C-0235(A) and B).Tables 2-4 and Fig. 12 are available in electronic form at http://www.aanda.org

  5. The driving mechanism of roAp stars : effects of global metallicity

    NASA Astrophysics Data System (ADS)

    Theado, S.; Dupret, M.-A.; Noels, A.

    2008-12-01

    We have investigated the influence of global metallicity on the excitation mechanism of roAp star pulsations. Our computations show that the opacity in the driving region of the roAp modes is strongly sensitive to the metal content but surprisingly the roAp theoretical instability strip is only weakly affected by metallicity changes.

  6. The driving mechanism of roAp stars : effects of local metallicity enhancement

    NASA Astrophysics Data System (ADS)

    Théado, S.; Dupret, M.-A.; Noels, A.

    2009-07-01

    We have investigated the influence of a local metallicity enhancement on the excitation mechanism of roAp star pulsations. Our computations show that such accumulations poorly affect the position of the theoretical roAp star instability strip although the opacity in the driving region of roAp modes is affected by metal accumulation.

  7. Comparison of HERG channel blocking effects of various beta-blockers-- implication for clinical strategy.

    PubMed

    Kawakami, Kazunobu; Nagatomo, Toshihisa; Abe, Haruhiko; Kikuchi, Kan; Takemasa, Hiroko; Anson, Blake D; Delisle, Brian P; January, Craig T; Nakashima, Yasuhide

    2006-03-01

    beta-Blockers are widely used in the treatment of cardiovascular diseases. However, their effects on HERG channels at comparable conditions remain to be defined. We investigated the direct acute effects of beta-blockers on HERG current and the molecular basis of drug binding to HERG channels with mutations of putative common binding site (Y652A and F656C). beta-Blockers were selected based on the receptor subtype. Wild-type, Y652A and F656C mutants of HERG channel were stably expressed in HEK293 cells, and the current was recorded by using whole-cell patch-clamp technique (23 degrees C). Carvedilol (nonselective), propranolol (nonselective) and ICI 118551 (beta(2)-selective) inhibited HERG current in a concentration-dependent manner (IC(50) 0.51, 3.9 and 9.2 microM, respectively). The IC(50) value for carvedilol was a clinically relevant concentration. High metoprolol (beta(1)-selective) concentrations were required for blockade (IC(50) 145 microM), and atenolol (beta(1)-selective) did not inhibit the HERG current. Inhibition of HERG current by carvedilol, propranolol and ICI 118551 was partially but significantly attenuated in Y652A and F656C mutant channels. Affinities of metoprolol to Y652A and F656C mutant channels were not different compared with the wild-type. HERG current block by all beta-blockers was not frequency-dependent. Drug affinities to HERG channels were different in beta-blockers. Our results provide additional strategies for clinical usage of beta-blockers. Atenolol and metoprolol may be preferable for patients with type 1 and 2 long QT syndrome. Carvedilol has a class III antiarrhythmic effect, which may provide the rationale for a favourable clinical outcome compared with other beta-blockers as suggested in the recent COMET (Carvedilol Or Metoprolol European Trial) substudy. PMID:16314852

  8. The Ro60 Autoantigen Binds Endogenous Retroelements and Regulates Inflammatory Gene Expression

    PubMed Central

    Hung, T.; Pratt, G.; Sundararaman, B.; Townsend, M. J.; Chaivorapol, C.; Bhangale, T.; Graham, R. R.; Ortmann, W.; Criswell, L. A.; Yeo, G.; Behrens, T. W.

    2015-01-01

    Autoantibodies target the RNA binding protein Ro60 in systemic lupus erythematosus (SLE) and Sjögren’s syndrome. However, whether Ro60 and its associated RNAs contribute to disease pathogenesis is unclear. We catalogued the Ro60-associated RNAs in human cell lines and found that among other RNAs, Ro60 bound an RNA motif derived from endogenous Alu retroelements. Alu transcripts were induced by type I interferon and stimulated proinflammatory cytokine secretion by human peripheral blood cells. Ro60 deletion resulted in enhanced expression of Alu RNAs and interferon-regulated genes. Anti-Ro60 positive SLE immune complexes contained Alu RNAs, and Alu transcripts were upregulated in SLE whole blood samples compared to controls. These findings establish a link between the lupus autoantigen Ro60, Alu retroelements and type I interferon. PMID:26382853

  9. The Ro60 autoantigen binds endogenous retroelements and regulates inflammatory gene expression.

    PubMed

    Hung, T; Pratt, G A; Sundararaman, B; Townsend, M J; Chaivorapol, C; Bhangale, T; Graham, R R; Ortmann, W; Criswell, L A; Yeo, G W; Behrens, T W

    2015-10-23

    Autoantibodies target the RNA binding protein Ro60 in systemic lupus erythematosus (SLE) and Sjögren's syndrome. However, it is unclear whether Ro60 and its associated RNAs contribute to disease pathogenesis. We catalogued the Ro60-associated RNAs in human cell lines and found that among other RNAs, Ro60 bound an RNA motif derived from endogenous Alu retroelements. Alu transcripts were induced by type I interferon and stimulated proinflammatory cytokine secretion by human peripheral blood cells. Ro60 deletion resulted in enhanced expression of Alu RNAs and interferon-regulated genes. Anti-Ro60-positive SLE immune complexes contained Alu RNAs, and Alu transcripts were up-regulated in SLE whole blood samples relative to controls. These findings establish a link among the lupus autoantigen Ro60, Alu retroelements, and type I interferon. PMID:26382853

  10. High performance RO membranes for desalination and wastewater reclamation and their operation results.

    PubMed

    Henmi, M; Fusaoka, Y; Tomioka, H; Kurihara, M

    2010-01-01

    Reverse osmosis (RO) membrane is one of the most powerful tools for solving the global water crisis, and is used in a variety of water treatment scenes such as drinking water purification, waste-water treatment, boiler feed water production, ultra pure water production for semiconductor industry, etc. The desired performance of RO membrane varies according to quality of feed water being treated, and Toray has been developing RO membranes with suitable characteristic for each operating condition. RO membranes for seawater desalination and wastewater reclamation are especially regarded as most promising targets. Recently, high boron removal and energy saving RO membrane for seawater desalination and low fouling RO membrane for wastewater reclamation have been developed. In this paper, the prospect of attaining these renovative RO membrane, and furthermore, job references will be discussed. PMID:21045342

  11. Prevention of stroke and myocardial infarction by amlodipine and Angiotensin receptor blockers: a quantitative overview.

    PubMed

    Wang, Ji-Guang; Li, Yan; Franklin, Stanley S; Safar, Michel

    2007-07-01

    In the present quantitative overview of outcome trials, we investigated the efficacy of amlodipine or angiotensin receptor blockers in the prevention of stroke and myocardial infarction in patients with hypertension, coronary artery disease, or diabetic nephropathy. The analysis included 12 trials of 94 338 patients. The analysis of trials involving an amlodipine group showed that amlodipine provided more protection against stroke and myocardial infarction than other antihypertensive drugs, including angiotensin receptor blockers (-19%, P<0.0001 and -7%, P=0.03) and placebo (-37%, P=0.06 and -29%, P=0.04). The analysis of trials involving an angiotensin receptor blocker group showed contrasting results between trials versus amlodipine and trials versus other antihypertensive drugs for stroke (+19% versus -25%; P<0.0001) and myocardial infarction (+21% versus +1%; P=0.03). The results of 3 trials comparing an angiotensin receptor blocker with placebo were neutral (P> or =0.14). The within-trial between-group difference in achieved systolic pressure ranged from -1.1 to +4.7 mm Hg for trials involving an amlodipine group and from -2.8 to +4.0 mm Hg for trials involving an angiotensin receptor blocker group. The metaregression analysis correlating odds ratios with blood pressure differences showed a negative relationship (regression coefficients: -3% to -8%), which reached statistical significance (regression coefficient: -6%; P=0.01) for stroke in trials involving an amlodipine group. In conclusion, blood pressure differences largely accounted for cardiovascular outcome. PMID:17502490

  12. Potassium channel blockers from the venom of the Brazilian scorpion Tityus serrulatus ().

    PubMed

    Martin-Eauclaire, Marie-France; Pimenta, Adriano M C; Bougis, Pierre E; De Lima, Maria-Elena

    2016-09-01

    Potassium (K(+)) channels are trans-membrane proteins, which play a key role in cellular excitability and signal transduction pathways. Scorpion toxins blocking the ion-conducting pore from the external side have been invaluable probes to elucidate the structural, functional, and physio-pathological characteristics of these ion channels. This review will focus on the interaction between K(+) channels and their peptide blockers isolated from the venom of the scorpion Tityus serrulatus, which is considered as the most dangerous scorpion in Brazil, in particular in Minas-Gerais State, where many casualties are described each year. The primary mechanisms of action of these K(+) blockers will be discussed in correlation with their structure, very often non-canonical compared to those of other well known K(+) channels blockers purified from other scorpion venoms. Also, special attention will be brought to the most recent data obtained by proteomic and transcriptomic analyses on Tityus serrulatus venoms and venom glands. PMID:27349167

  13. The prevention of migraine: a critical review with special emphasis on beta-adrenoceptor blockers.

    PubMed

    Limmroth, V; Michel, M C

    2001-09-01

    Migraine is one of the most frequent neurological disorders affecting up to 15% of the general population. Many patients require not only management of individual migraine episodes but also prophylactic treatment. beta-adrenoceptor blockers, flunarizine and valproic acid have been established as first-line agents for the prophylaxis of migraine attacks. Among the beta-adrenoceptor blockers propranolol and metoprolol are best documented and hence deserve preferential use. On the other hand, it appears that other beta-adrenoceptor blockers, perhaps with the exception of those with intrinsic sympathomimetic activity, can be equally effective. Uncertainties regarding the relative merits of various treatment modalities are largely caused by lack of adherence to specific requirements for clinical trials on migraine prophylaxis. Therefore, this article reviews internationally recommended conditions for reliable studies on migraine prophylaxis and appraises individual agents in the light of these criteria. PMID:11560555

  14. [Beta-blockers usage in cardio-vascular diseases co-existing with COPD].

    PubMed

    Walczak, Dorota; Kowal, Aneta; Jankowska, Renata

    2012-12-01

    Chronic obstructive pulmonary disease (COPD) is one of the most frequent chronic diseases. Slightly reversable and progressive decrease in airflow through the airways is characteristic for the disease. It has been brought up last years that COPD course influences not only pulmonary system status but also many co-existing diseases in the eldery, especially cardio-vascular diseases, such as: ischaemic heart disease, hypertension, heart arrythmias, heart infarction. Wide usage and established position in the treatment of cardio-vascular diseases have the antagonists of beta-adrenergic receptors (beta-blockers). The aim of this work was the combination of the studies results quoted in the literature about the usage of beta-blockers in cardiovascular diseases co-existing with COPD. Conclusions. Nowadays there are no unambiguous recommendations for the usage of beta-blocker in patients with COPD and the decision about including them into treatment depends on the individually estimated risk of complications. PMID:23437704

  15. Beta-blockers in heart failure: are pharmacological differences clinically important?

    PubMed

    Metra, Marco; Cas, Livio Dei; di Lenarda, Andrea; Poole-Wilson, Philip

    2004-04-01

    Beta-blockers are not an homogeneous group of agents. Only three beta-blockers, carvedilol, bisoprolol and metoprolol succinate, have had favorable effects on prognosis in controlled clinical trials in the patients with chronic heart failure. However, pharmacological differences exist between them. Metoprolol and bisoprolol are selective for beta(1)-adrenergic receptors while carvedilol blocks also beta(2)-, and alpha(1)- adrenergic receptors, and has associated antioxidant, anti-endothelin and antiproliferative properties. In COMET carvedilol was associated with a significant reduction in mortality compared to metoprolol tartrate further showing that different beta-blockers may have different effects on the outcome. These differences may be related to the ancillary properties of carvedilol or to its broader antiadrenergic profile. However, also more effective and prolonged blockade of beta1 adrenergic receptors may occur with carvedilol compared to metoprolol. PMID:15516860

  16. A novel series of pyrazolylpiperidine N-type calcium channel blockers.

    PubMed

    Subasinghe, Nalin L; Wall, Mark J; Winters, Michael P; Qin, Ning; Lubin, Mary Lou; Finley, Michael F A; Brandt, Michael R; Neeper, Michael P; Schneider, Craig R; Colburn, Raymond W; Flores, Christopher M; Sui, Zhihua

    2012-06-15

    Selective blockers of the N-type calcium channel have proven to be effective in animal models of chronic pain. However, even though intrathecally delivered synthetic ω-conotoxin MVIIA from Conus magnus (ziconotide [Prialt®]) has been approved for the treatment of chronic pain in humans, its mode of delivery and narrow therapeutic window have limited its usefulness. Therefore, the identification of orally active, small-molecule N-type calcium channel blockers would represent a significant advancement in the treatment of chronic pain. A novel series of pyrazole-based N-type calcium channel blockers was identified by structural modification of a high-throughput screening hit and further optimized to improve potency and metabolic stability. In vivo efficacy in rat models of inflammatory and neuropathic pain was demonstrated by a representative compound from this series. PMID:22608964

  17. The prevention of migraine: a critical review with special emphasis on β-adrenoceptor blockers

    PubMed Central

    Limmroth, Volker; Michel, Martin C

    2001-01-01

    Migraine is one of the most frequent neurological disorders affecting up to 15% of the general population. Many patients require not only management of individual migraine episodes but also prophylactic treatment. β-adrenoceptor blockers, flunarizine and valproic acid have been established as first-line agents for the prophylaxis of migraine attacks. Among the β-adrenoceptor blockers propranolol and metoprolol are best documented and hence deserve preferential use. On the other hand, it appears that other β-adrenoceptor blockers, perhaps with the exception of those with intrinsic sympathomimetic activity, can be equally effective. Uncertainties regarding the relative merits of various treatment modalities are largely caused by lack of adherence to specific requirements for clinical trials on migraine prophylaxis. Therefore, this article reviews internationally recommended conditions for reliable studies on migraine prophylaxis and appraises individual agents in the light of these criteria. PMID:11560555

  18. CD45RO enriches for activated, highly mutated human germinal center B cells

    PubMed Central

    Jackson, Stephen M.; Harp, Natessa; Patel, Darshna; Zhang, Jeffrey; Willson, Savannah; Kim, Yoon J.; Clanton, Christian

    2007-01-01

    To date, there is no consensus regarding the influence of different CD45 isoforms during peripheral B-cell development. Examining correlations between surface CD45RO expression and various physiologic processes ongoing during the germinal center (GC) reaction, we hypothesized that GC B cells, like T cells, that up-regulate surface RO should progressively acquire phenotypes commonly associated with activated, differentiating lymphocytes. GC B cells (IgD−CD38+) were subdivided into 3 surface CD45RO fractions: RO−, RO+/−, and RO+. We show here that the average number of mutations per IgVH transcript increased in direct correlation with surface RO levels. Conjunctional use of RO and CD69 further delineated low/moderately and highly mutated fractions. Activation-induced cytidine deaminase (AID) mRNA was slightly reduced among RO+ GC B cells, suggesting that higher mutation averages are unlikely due to elevated somatic mutation activity. Instead, RO+ GC B cells were negative for Annexin V, comprised mostly (93%) of CD77− centrocytes, and were enriched for CD69+ cells. Collectively, RO+ GC B cells occupy what seems to be a specialized niche comprised mostly of centrocytes that may be in transition between activation states. These findings are among the first to sort GC B cells into populations enriched for live mutated cells solely using a single extracellular marker. PMID:17644737

  19. Calcium Binding by Ro 60 Multiple Antigenic Peptides on PVDF Membrane.

    PubMed

    Kurien, Biji T; Bachmann, Michael P

    2015-01-01

    Antibodies directed against ribonucleoprotein (RNP) particles are observed in systemic lupus erythematosus. Ro RNP particle is one such target. It is composed of a 60 kDa protein (Ro 60 or SS-A) that is non-covalently associated with at least one of the four short uridine-rich RNAs (the hY RNAs). Previously, we showed that multiple antigenic peptides (MAPs) made from the sequence of the Ro 60 autoantigen could be used, using double-immunodiffusion studies, enzyme-linked immunosorbant assay, affinity chromatography, and surface plasmon resonance, to show intramolecular and intermolecular protein-protein interaction within the Ro 60 RNP particle. We also observed that calcium is important in mediating this interaction. We hypothesized, therefore, that 60 kDa Ro is a calcium-binding protein. To investigate this, we electrophoresed 60 kDa Ro MAPs, transferred them to PVDF membrane, and assayed calcium binding using the Quin-2 system. Several Ro 60 MAPs were found to bind calcium using this assay, as well as bovine serum albumin, another calcium-binding protein. However, a MAP constructed from the Sm autoantigen did not bind to calcium. These data, along with our observation regarding the involvement of calcium in protein-protein interaction occurring between Ro 60 antigen and Ro 60 MAPs, makes us propose that Ro 60 antigen is a calcium-binding protein. PMID:26139264

  20. Management of drug interactions with beta-blockers: continuing education has a short-term impact

    PubMed Central

    Driesen, Annelies; Simoens, Steven; Laekeman, Gert

    There is a lack of clear guidelines regarding the management of drug-drug interactions. Objective To assess the impact of an educational intervention on the management of drug interactions with beta-blockers. Methods The study had a controlled before-and-after design. The intervention group (n=10 pharmacies) received a continuing education course and guidelines on the management of drug interactions with beta-blockers. The control group (n=10 pharmacies) received no intervention. Pharmacy students and staff of internship pharmacies participated in this study. Before and after the intervention, students registered interactions with beta-blockers during two weeks. Information was obtained on drug information of the beta-blocker and the interacting drug, patient’s demographics, and the mode of transaction. Results A total number of 288 interactions were detected during both study periods. Most beta-blockers causing an interaction were prescribed for hypertension, and interacted with hypoglycemic agents, NSAIDs, or beta2-agonists. Pharmacists’ intervention rate was low (14% in the pre-test compared to 39% in the post-test), but increased significantly in the post-test in the intervention group. Reasons for overriding the interaction included limited clinical relevance, refill prescriptions, not being aware of the interaction, and communication problems with the prescriber. Conclusion An interactive continuing education course, during which practice-oriented guidelines were offered, affected pharmacists’ short-term behavior at the counter in dealing with interactions of beta-blockers. Continuing education plays a role in raising pharmacists’ awareness and responsibility towards the detection and management of drug interactions in the pharmacy. PMID:25214902

  1. The evolving role of β-adrenergic receptor blockers in managing hypertension.

    PubMed

    Poirier, Luc; Lacourcière, Yves

    2012-05-01

    β-Adrenergic blocking agents (or β-blockers) have been widely used for the treatment of hypertension for the past 50 years, and continue to be recommended as a mainstay of therapy in many national guidelines. They have also been used in a variety of cardiovascular conditions commonly complicating hypertension, including angina pectoris, myocardial infarction (MI), acute and chronic heart failure, as well as conditions like essential tremor and migraine. Moreover, they have played a primary role in controlling blood pressure in patients with these specific comorbidities and in reducing cardiovascular risk with regard to the composite outcome of death, stroke, and MI among patients younger than 60 years of age. However, in patients 60 years of age or older, β-blockers were not associated with significantly lower rates of MI, heart failure or death, and demonstrated higher rates of stroke compared with other first-line therapies. Consequently, the Canadian Hypertension Education Program recommends the use of β-blockers as first-line therapy in hypertensive patients younger than 60 years of age but not for those age 60 and older, with the exception of patients with concomitant β-blocker-requiring cardiac diseases. Several reports suggest that the lack of consistent outcome data may relate to the use of traditional β-blockers such as atenolol and their ability only to reduce cardiac output, without beneficial effect on peripheral vascular resistance. The present report will describe the clinically relevant mechanisms of action of β-blockers, their pharmacological differences, their metabolic effects, and their usefulness in patients with hypertension. PMID:22595449

  2. Levosimendan vs. dobutamine: outcomes for acute heart failure patients on β-blockers in SURVIVE†

    PubMed Central

    Mebazaa, Alexandre; Nieminen, Markku S.; Filippatos, Gerasimos S.; Cleland, John G.; Salon, Jeffrey E.; Thakkar, Roopal; Padley, Robert J.; Huang, Bidan; Cohen-Solal, Alain

    2009-01-01

    Aims Many chronic heart failure (CHF) patients take β-blockers. When such patients are hospitalized for decompensation, it remains unclear how ongoing β-blocker treatment will affect outcomes of acute inotrope therapy. We aimed to assess outcomes of SURVIVE patients who were on β-blocker therapy before receiving a single intravenous infusion of levosimendan or dobutamine. Methods and results Cox proportional hazard regression revealed all-cause mortality benefits of levosimendan treatment over dobutamine when the SURVIVE population was stratified according to baseline presence/absence of CHF history and use/non-use of β-blocker treatment at baseline. All-cause mortality was lower in the CHF/levosimendan group than in the CHF/dobutamine group, showing treatment differences by hazard ratio (HR) at days 5 (3.4 vs. 5.8%; HR, 0.58, CI 0.33–1.01, P = 0.05) and 14 (7.0 vs. 10.3%; HR, 0.67, CI 0.45–0.99, P = 0.045). For patients who used β-blockers (n = 669), mortality was significantly lower for levosimendan than dobutamine at day 5 (1.5 vs. 5.1% deaths; HR, 0.29; CI 0.11–0.78, P = 0.01). Conclusion Levosimendan may be better than dobutamine for treating patients with a history of CHF or those on β-blocker therapy when they are hospitalized with acute decompensations. These findings are preliminary but important for planning future studies. PMID:19158152

  3. β-Blocker Dialyzability and Mortality in Older Patients Receiving Hemodialysis

    PubMed Central

    Dixon, Stephanie N.; Fleet, Jamie L.; Roberts, Matthew A.; Hackam, Daniel G.; Oliver, Matthew J.; Suri, Rita S.; Quinn, Robert R.; Ozair, Sundus; Beyea, Michael M.; Kitchlu, Abhijat; Garg, Amit X.

    2015-01-01

    Some β-blockers are efficiently removed from the circulation by hemodialysis (“high dialyzability”) whereas others are not (“low dialyzability”). This characteristic may influence the effectiveness of the β-blockers among patients receiving long-term hemodialysis. To determine whether new use of a high-dialyzability β-blocker compared with a low-dialyzability β-blocker associates with a higher rate of mortality in patients older than age 66 years receiving long-term hemodialysis, we conducted a propensity-matched population-based retrospective cohort study using the linked healthcare databases of Ontario, Canada. The high-dialyzability group (n=3294) included patients initiating atenolol, acebutolol, or metoprolol. The low-dialyzability group (n=3294) included patients initiating bisoprolol or propranolol. Initiation of a high- versus low-dialyzability β-blocker was associated with a higher risk of death in the following 180 days (relative risk, 1.4; 95% confidence interval, 1.1 to 1.8; P<0.01). Supporting this finding, we repeated the primary analysis in a cohort of patients not receiving hemodialysis and found no significant association between dialyzability and the risk of death (relative risk, 1.0; 95% confidence interval, 0.9 to 1.3; P=0.71). β-Blocker exposure was not randomly allocated in this study, so a causal relationship between dialyzability and mortality cannot be determined. However, our findings should raise awareness of this potentially important drug characteristic and prompt further study. PMID:25359874

  4. SS-A/Ro52 promotes apoptosis by regulating Bcl-2 production

    SciTech Connect

    Jauharoh, Siti Nur Aisyah; Saegusa, Jun; Sugimoto, Takeshi; Ardianto, Bambang; Kasagi, Shimpei; Sugiyama, Daisuke; Kurimoto, Chiyo; Tokuno, Osamu; Nakamachi, Yuji; Kumagai, Shunichi; Kawano, Seiji

    2012-01-06

    Highlights: Black-Right-Pointing-Pointer Ro52{sup low} HeLa cells are resistant to apoptosis upon various stimulations. Black-Right-Pointing-Pointer Ro52 is upregulated by IFN-{alpha}, etoposide, or IFN-{gamma} and anti-Fas Ab. Black-Right-Pointing-Pointer Ro52-mediated apoptosis is independent of p53. Black-Right-Pointing-Pointer Ro52 selectively regulates Bcl-2 expression. -- Abstract: SS-A/Ro52 (Ro52), an autoantigen in systemic autoimmune diseases such as systemic lupus erythematosus and Sjoegren's syndrome, has E3 ligase activity to ubiquitinate proteins that protect against viral infection. To investigate Ro52's role during stress, we transiently knocked it down in HeLa cells by siRo52 transfection. We found that Ro52{sup low} HeLa cells were significantly more resistant to apoptosis than wild-type HeLa cells when stimulated by H{sub 2}O{sub 2}- or diamide-induced oxidative stress, IFN-{alpha}, IFN-{gamma} and anti-Fas antibody, etoposide, or {gamma}-irradiation. Furthermore, Ro52-mediated apoptosis was not influenced by p53 protein level in HeLa cells. Depleting Ro52 in HeLa cells caused Bcl-2, but not other Bcl-2 family molecules, to be upregulated. Taken together, our data showed that Ro52 is a universal proapoptotic molecule, and that its proapoptotic effect does not depend on p53, but is exerted through negative regulation of the anti-apoptotic protein Bcl-2. These findings shed light on a new physiological role for Ro52 that is important to intracellular immunity.

  5. Why do hypertensive patients of African ancestry respond better to calcium blockers and diuretics than to ACE inhibitors and β-adrenergic blockers? A systematic review

    PubMed Central

    2013-01-01

    Background Clinicians are encouraged to take an individualized approach when treating hypertension in patients of African ancestry, but little is known about why the individual patient may respond well to calcium blockers and diuretics, but generally has an attenuated response to drugs inhibiting the renin-angiotensin system and to β-adrenergic blockers. Therefore, we systematically reviewed the factors associated with the differential drug response of patients of African ancestry to antihypertensive drug therapy. Methods Using the methodology of the systematic reviews narrative synthesis approach, we sought for published or unpublished studies that could explain the differential clinical efficacy of antihypertensive drugs in patients of African ancestry. PUBMED, EMBASE, LILACS, African Index Medicus and the Food and Drug Administration and European Medicines Agency databases were searched without language restriction from their inception through June 2012. Results We retrieved 3,763 papers, and included 72 reports that mainly considered the 4 major classes of antihypertensive drugs, calcium blockers, diuretics, drugs that interfere with the renin-angiotensin system and β-adrenergic blockers. Pharmacokinetics, plasma renin and genetic polymorphisms did not well predict the response of patients of African ancestry to antihypertensive drugs. An emerging view that low nitric oxide and high creatine kinase may explain individual responses to antihypertensive drugs unites previous observations, but currently clinical data are very limited. Conclusion Available data are inconclusive regarding why patients of African ancestry display the typical response to antihypertensive drugs. In lieu of biochemical or pharmacogenomic parameters, self-defined African ancestry seems the best available predictor of individual responses to antihypertensive drugs. PMID:23721258

  6. Association of β-blocker therapy with long-term clinical outcomes in patients with coronary chronic total occlusion.

    PubMed

    Hwang, Jin Kyung; Yang, Jeong Hoon; Hwang, Ji-Won; Jang, Woo Jin; Song, Young Bin; Hahn, Joo-Yong; Choi, Jin-Ho; Lee, Sang Hoon; Gwon, Hyeon-Cheol; Choi, Seung-Hyuk

    2016-07-01

    There are limited data regarding the efficacy of β-blockers for secondary prevention in patients with coronary chronic total occlusion (CTO). Therefore, we investigated the association of β-blocker therapy with long-term clinical outcomes in CTO patients. From March 2003 to February 2012, a total of 2024 CTO patients treated with either medical therapy alone or revascularization were enrolled in the study. We assessed 1596 patients with stable ischemic heart disease and divided them into the β-blocker group (n = 932) and the no-β-blocker group (n = 664). The primary outcome was all-cause death. The median follow-up duration was 3.9 (interquartile range: 2.0-6.2) years. All-cause death occurred in 11.6% patients in the β-blocker group and 13.6% patients in the no-β-blocker group (hazard ratio [HR]: 0.81, 95% confidence interval [CI]: 0.61-1.08; P = 0.15). In the propensity score-matched population (570 pairs), all-cause death occurred in 12.3% patients in the β-blocker group and 12.8% patients in the no-β-blocker group (HR: 0.93, 95% CI: 0.67-1.29; P = 0.66). In subgroup analysis, β-blocker therapy was associated with better outcome, in terms of all-cause death, in patients with CTO of the left anterior descending coronary artery and Synergy Between PCI with Taxus and Cardiac Surgery (SYNTAX) score ≥23 (P for interaction = 0.01 and 0.02, respectively). In conclusion, β-blocker therapy was not associated with favorable long-term clinical outcomes in stable CTO patients, regardless of treatment strategy. However, β-blocker therapy might be beneficial in a highly selective group of CTO patients with a high ischemic burden. PMID:27472704

  7. Initiation or maintenance of beta-blocker therapy in patients hospitalized for acute heart failure.

    PubMed

    Passos, Luiz Carlos; Oliveira, Márcio Galvão; Duraes, Andre Rodrigues; Trindade, Thiago Moreira; Barbosa, Andréa Cristina Costa

    2016-08-01

    Background Beta-blockers have been recommended for patients with heart failure and reduced ejection fraction for their long-term benefits. However, the tolerance to betablockers in patients hospitalized with acute heart failure should be evaluated. Objective To estimate the proportion of patients hospitalized with acute heart failure who can tolerate these agents in clinical practice and compare the clinical outcomes of patients who can and cannot tolerate treatment with beta-blockers. Setting Two reference hospitals in cardiology. Methods Retrospective cohort study of consecutive patients hospitalized for acute heart failure between September 2008 and May 2012. Population-based sample. During the study period, 325 patients were admitted consecutively, including 194 individuals with an acute heart failure diagnosis and systolic left ventricular dysfunction and ejection fraction ≤45 %, who were candidates for the initiation or continuation of beta-blockers. Main outcome measure The percentage of patients intolerant to beta-blockers and the clinical characteristics of patients. Results On admission, 61.8 % of patients were already using beta-blockers, and 73.2 % were using beta-blockers on discharge. During hospitalization, 85 % of patients used these agents for some period. The main reasons for not using betablockers were low cardiac output syndrome (24.4 %), bradycardia (24.4 %), severe hypotension or shock (17.8 %), and chronic obstructive pulmonary disease (13.3 %). Patients who were intolerant or did not use a beta-blocker had a longer hospital stay (18.3 vs. 11.0 days; p < .001), greater use of vasoactive drugs (41.5 vs. 16.3 %; p < .001, CI 1.80-7.35), sepsis and septic shock (RR = 3.02; CI 95 % 1.59-5.75), and higher mortality rate during hospitalization (22.6 vs. 2.9 %; p < .001; CI 3.05-32.26). Conclusion Beta-blockers could be used in 73.2 % of patients hospitalized for acute heart failure. Patients who can not tolerate BB presented

  8. The Cohen flexitip endobronchial blocker: an alternative to a double lumen tube.

    PubMed

    Cohen, Edmond

    2005-12-01

    One-lung ventilation (OLV) is usually achieved by the use of a double-lumen tubes (DLTs). With increasing need for use of OLV for video-assisted thoracoscopic procedures, the limitations of traditional DLT's, including difficult insertion and positioning, have become evident. This has led to renewed interest in devising alternative methods of achieving lung separation, such as the Univent tube or Arndt endobronchial blocker. This report describes the technical features and clinical use of a new tip-deflecting endobronchial blocker. PMID:16301278

  9. Ro15-4513 antagonizes depression of open-field horizontal activity by ethanol in rats.

    PubMed

    June, H L; Johnson, L T; Lewis, M J

    1989-01-01

    The imidazobenzodiazepine, Ro15-4513, has been shown to antagonize some of the behavioral effects of ethanol (ETOH). In rats having relatively little experience in the open field, the actions of ETOH (0.75 g/kg IP), Ro15-4513 (1.25 mg/kg and 2.5 mg/kg, IP), and Ro15-4513 in combination with ETOH were measured on horizontal activity. Rats receiving ETOH showed a significant depression in horizontal activity. Doses of Ro15-4513 given alone produced no significant differences in activity from baseline levels. Rats pretreated with Ro15-4513 prior to receiving ETOH, however, showed a significant attenuation of the ETOH induced depression of activity. These results indicate that Ro15-4513 is effective in attenuating the depressive effects of ETOH in the open field in rats having little experience in the apparatus. PMID:2765204

  10. Gas-Phase Ozonolysis of Cycloalkenes: Formation of Highly Oxidized RO2 Radicals and Their Reactions with NO, NO2, SO2, and Other RO2 Radicals.

    PubMed

    Berndt, Torsten; Richters, Stefanie; Kaethner, Ralf; Voigtländer, Jens; Stratmann, Frank; Sipilä, Mikko; Kulmala, Markku; Herrmann, Hartmut

    2015-10-15

    The gas-phase reaction of ozone with C5-C8 cycloalkenes has been investigated in a free-jet flow system at atmospheric pressure and a temperature of 297 ± 1 K. Highly oxidized RO2 radicals bearing at least 5 O atoms in the molecule and their subsequent reaction products were detected in most cases by means of nitrate-CI-APi-TOF mass spectrometry. Starting from a Criegee intermediate after splitting-off an OH-radical, the formation of these RO2 radicals can be explained via an autoxidation mechanism, meaning RO2 isomerization (ROO → QOOH) and subsequently O2 addition (QOOH + O2 → R'OO). Time-dependent RO2 radical measurements concerning the ozonolysis of cyclohexene indicate rate coefficients of the intramolecular H-shifts, ROO → QOOH, higher than 1 s(-1). The total molar yield of highly oxidized products (predominantly RO2 radicals) from C5-C8 cycloalkenes in air is 4.8-6.0% affected with a calibration uncertainty by a factor of about two. For the most abundant RO2 radical from cyclohexene ozonolysis, O,O-C6H7(OOH)2O2 ("O,O" stands for two O atoms arising from the ozone attack), the determination of the rate coefficients of the reaction with NO2, NO, and SO2 yielded (1.6 ± 0.5) × 10(-12), (3.4 ± 0.9) × 10(-11), and <10(-14) cm(3) molecule(-1) s(-1), respectively. The reaction of highly oxidized RO2 radicals with other peroxy radicals (R'O2) leads to detectable accretion products, RO2 + R'O2 → ROOR' + O2, which allows to acquire information on peroxy radicals not directly measurable with the nitrate ionization technique applied here. Additional experiments using acetate as the charger ion confirm conclusively the existence of highly oxidized RO2 radicals and closed-shell products. Other reaction products, detectable with this ionization technique, give a deeper insight in the reaction mechanism of cyclohexene ozonolysis. PMID:26392132

  11. RoBlock: a prototype autonomous manufacturing cell

    NASA Astrophysics Data System (ADS)

    Baekdal, Lars K.; Balslev, Ivar; Eriksen, Rene D.; Jensen, Soren P.; Jorgensen, Bo N.; Kirstein, Brian; Kristensen, Bent B.; Olsen, Martin M.; Perram, John W.; Petersen, Henrik G.; Petersen, Morten L.; Ruhoff, Peter T.; Skjolstrup, Carl E.; Sorensen, Anders S.; Wagenaar, Jeroen M.

    2000-10-01

    RoBlock is the first phase of an internally financed project at the Institute aimed at building a system in which two industrial robots suspended from a gantry, as shown below, cooperate to perform a task specified by an external user, in this case, assembling an unstructured collection of colored wooden blocks into a specified 3D pattern. The blocks are identified and localized using computer vision and grasped with a suction cup mechanism. Future phases of the project will involve other processes such as grasping and lifting, as well as other types of robot such as autonomous vehicles or variable geometry trusses. Innovative features of the control software system include: The use of an advanced trajectory planning system which ensures collision avoidance based on a generalization of the method of artificial potential fields, the use of a generic model-based controller which learns the values of parameters, including static and kinetic friction, of a detailed mechanical model of itself by comparing actual with planned movements, the use of fast, flexible, and robust pattern recognition and 3D-interpretation strategies, integration of trajectory planning and control with the sensor systems in a distributed Java application running on a network of PC's attached to the individual physical components. In designing this first stage, the aim was to build in the minimum complexity necessary to make the system non-trivially autonomous and to minimize the technological risks. The aims of this project, which is planned to be operational during 2000, are as follows: To provide a platform for carrying out experimental research in multi-agent systems and autonomous manufacturing systems, to test the interdisciplinary cooperation architecture of the Maersk Institute, in which researchers in the fields of applied mathematics (modeling the physical world), software engineering (modeling the system) and sensor/actuator technology (relating the virtual and real worlds) could

  12. Planetary transit candidates in the CoRoT LRa01 field

    NASA Astrophysics Data System (ADS)

    Carone, L.; Gandolfi, D.; Cabrera, J.; Hatzes, A. P.; Deeg, H. J.; Csizmadia, Sz.; Pätzold, M.; Weingrill, J.; Aigrain, S.; Alonso, R.; Alapini, A.; Almenara, J.-M.; Auvergne, M.; Baglin, A.; Barge, P.; Bonomo, A. S.; Bordé, P.; Bouchy, F.; Bruntt, H.; Carpano, S.; Cochran, W. D.; Deleuil, M.; Díaz, R. F.; Dreizler, S.; Dvorak, R.; Eislöffel, J.; Eigmüller, P.; Endl, M.; Erikson, A.; Ferraz-Mello, S.; Fridlund, M.; Gazzano, J.-C.; Gibson, N.; Gillon, M.; Gondoin, P.; Grziwa, S.; Günther, E. W.; Guillot, T.; Hartmann, M.; Havel, M.; Hébrard, G.; Jorda, L.; Kabath, P.; Léger, A.; Llebaria, A.; Lammer, H.; Lovis, C.; MacQueen, P. J.; Mayor, M.; Mazeh, T.; Moutou, C.; Nortmann, L.; Ofir, A.; Ollivier, M.; Parviainen, H.; Pepe, F.; Pont, F.; Queloz, D.; Rabus, M.; Rauer, H.; Régulo, C.; Renner, S.; de La Reza, R.; Rouan, D.; Santerne, A.; Samuel, B.; Schneider, J.; Shporer, A.; Stecklum, B.; Tal-Or, L.; Tingley, B.; Udry, S.; Wuchterl, G.

    2012-02-01

    Context. CoRoT is a pioneering space mission whose primary goals are stellar seismology and extrasolar planets search. Its surveys of large stellar fields generate numerous planetary candidates whose lightcurves have transit-like features. An extensive analytical and observational follow-up effort is undertaken to classify these candidates. Aims: We present the list of planetary transit candidates from the CoRoT LRa01 star field in the Monoceros constellation toward the Galactic anti-center direction. The CoRoT observations of LRa01 lasted from 24 October 2007 to 3 March 2008. Methods: We acquired and analyzed 7470 chromatic and 3938 monochromatic lightcurves. Instrumental noise and stellar variability were treated with several filtering tools by different teams from the CoRoT community. Different transit search algorithms were applied to the lightcurves. Results: Fifty-one stars were classified as planetary transit candidates in LRa01. Thirty-seven (i.e., 73% of all candidates) are "good" planetary candidates based on photometric analysis only. Thirty-two (i.e., 87% of the "good" candidates) have been followed-up. At the time of writing twenty-two cases were solved and five planets were discovered: three transiting hot-Jupiters (CoRoT-5b, CoRoT-12b, and CoRoT-21b), the first terrestrial transiting planet (CoRoT-7b), and another planet in the same system (CoRoT-7c, detected by radial velocity survey only). Evidence of another non-transiting planet in the CoRoT-7 system, namely CoRoT-7d, was recently found as well. The CoRoT space mission, launched on December 27, 2006, has been developed and is operated by CNES, with contributions of Austria, Belgium, Brazil, ESA (RSSD and Science Program), Germany and Spain.

  13. PRE-DISCOVERY OBSERVATIONS OF CoRoT-1b AND CoRoT-2b WITH THE BEST SURVEY

    SciTech Connect

    Rauer, H.; Erikson, A.; Kabath, P.; Hedelt, P.; Csizmadia, Sz.; Paris, P. v.; Renner, S.; Titz, R.; Voss, H.; Boer, M.; Tournois, G.; Carone, L.; Eigmueller, P.

    2010-01-15

    The Berlin Exoplanet Search Telescope (BEST) wide-angle telescope installed at the Observatoire de Haute-Provence and operated in remote control from Berlin by the Institut fuer Planetenforschung, DLR, has observed the CoRoT target fields prior to the mission. The resulting archive of stellar photometric light curves is used to search for deep transit events announced during CoRoT's alarm mode to aid in fast photometric confirmation of these events. The 'initial run' field of CoRoT (IRa01) was observed with BEST in 2006 November and December for 12 nights. The first 'long run' field (LRc01) was observed from 2005 June to September for 35 nights. After standard CCD data reduction, aperture photometry has been performed using the ISIS image subtraction method. About 30,000 light curves were obtained in each field. Transits of the first detected planets by the CoRoT mission, CoRoT-1b and CoRoT-2b, were found in archived data of the BEST survey and their light curves are presented here. Such detections provide useful information at the early stage of the organization of follow-up observations of satellite alarm-mode planet candidates. In addition, no period change was found over {approx}4 years between the first BEST observation and last available transit observations.

  14. Experience of hemostasis in tracheal bleeding very close to the carina by the bronchial blocker: a case report

    PubMed Central

    Son, MinKi; Lee, Sangjun; Lee, Sang Hyun; Lee, Soo Kyung; Lee, Kook Hyun

    2016-01-01

    Massive hemoptysis is respiratory compromise which should be managed as a life-threatening condition. In our case, the bronchial blocker played a role in hemostasis of tracheal bleeding very close to the carina and prevented further spillage into the contralateral lung. Right-sided one-lung isolation in an 87-year-old female, who received cardiopulmonary resuscitation due to myocardial infarction, was requested due to hemoptysis. Right-sided bronchial bleeding was suspected on auscultation, but esophageal and tracheal bleeding due to violent intubation with a stylet was also considered. We attempted one-lung isolation with the bronchial blocker. The bronchial blocker was inadvertently advanced to the left mainstem bronchus, but the inflated balloon of the bronchial blocker compressed the site of bleeding, which was within 1 cm proximal and left posterior to the carina. Tracheal bleeding stopped, and we confirmed that hemostasis was achieved with the balloon of the bronchial blocker using a fiberoptic bronchoscope. PMID:27274373

  15. Experience of hemostasis in tracheal bleeding very close to the carina by the bronchial blocker: a case report.

    PubMed

    Son, MinKi; Lee, Sangjun; Lee, Sang Hyun; Lim, Taewan; Lee, Soo Kyung; Lee, Kook Hyun

    2016-06-01

    Massive hemoptysis is respiratory compromise which should be managed as a life-threatening condition. In our case, the bronchial blocker played a role in hemostasis of tracheal bleeding very close to the carina and prevented further spillage into the contralateral lung. Right-sided one-lung isolation in an 87-year-old female, who received cardiopulmonary resuscitation due to myocardial infarction, was requested due to hemoptysis. Right-sided bronchial bleeding was suspected on auscultation, but esophageal and tracheal bleeding due to violent intubation with a stylet was also considered. We attempted one-lung isolation with the bronchial blocker. The bronchial blocker was inadvertently advanced to the left mainstem bronchus, but the inflated balloon of the bronchial blocker compressed the site of bleeding, which was within 1 cm proximal and left posterior to the carina. Tracheal bleeding stopped, and we confirmed that hemostasis was achieved with the balloon of the bronchial blocker using a fiberoptic bronchoscope. PMID:27274373

  16. Beta-Blockers and the Kidney: Implications for Renal Function and Renin Release.

    ERIC Educational Resources Information Center

    Epstein, Murray; And Others

    1985-01-01

    Reviews and discusses current information on the human renal response as related to beta-blockers (antihypertension agents). Topic areas considered include cardioselectivity, renal hemodynamics, systemic hemodynamics, changes with acute and chronic administration, influence of dose, and others. Implications and an 11-item multiple-choice self-quiz…

  17. Systemic delivery of β-blockers via transdermal route for hypertension

    PubMed Central

    Ahad, Abdul; Al-Jenoobi, Fahad I.; Al-Mohizea, Abdullah M.; Akhtar, Naseem; Raish, Mohammad; Aqil, Mohd.

    2014-01-01

    Hypertension is the most common cardiovascular disease worldwide. Moreover, management of hypertension requires long-term treatment that may result in poor patient compliance with conventional dosage forms due to greater frequency of drug administration. Although there is availability of a plethora of therapeutically effective antihypertensive molecules, inadequate patient welfare is observed; this arguably presents an opportunity to deliver antihypertensive agents through a different route. Ever since the transdermal drug delivery came into existence, it has offered great advantages including non-invasiveness, prolonged therapeutic effect, reduced side effects, improved bioavailability, better patient compliance and easy termination of drug therapy. Attempts were made to develop the transdermal therapeutic system for various antihypertensive agents, including β-blockers, an important antihypertensive class. β-blockers are potent, highly effective in the management of hypertension and other heart ailments by blocking the effects of normal amounts of adrenaline in the heart and blood vessels. The shortcomings associated with β-blockers such as more frequent dose administration, extensive first pass metabolism and variable bioavailability, make them an ideal candidate for transdermal therapeutic systems. The present article gives a brief view of different β-blockers formulated as transdermal therapeutic system in detail to enhance the bioavailability as well as to improve patient compliance. Constant improvement in this field holds promise for the long-term success in technologically advanced transdermal dosage forms being commercialized sooner rather than later. PMID:26702253

  18. Dissociation of POMC Peptides after Self-Injury Predicts Responses To Centrally Acting Opiate Blockers.

    ERIC Educational Resources Information Center

    Sandman, Curt A.; Hetrick, William; Taylor, Derek V.; Chicz-DeMet, Aleksandra

    1997-01-01

    This study investigated whether blood plasma levels of pro-opiomelanocortin-derived (POMC) peptides, beta-endorphin-like activity, adrenocorticotrophic hormone, and adrenal cortisol immediately after self injurious behavior (SIB) episodes predicted subsequent response to an opiate blocker in 10 patients with mental retardation. Results suggest…

  19. Thiazide-like/calcium channel blocker agents: a major combination for hypertension management.

    PubMed

    Safar, M E; Blacher, J

    2014-12-01

    In recent years, treatment strategies for hypertension have often focused on combination therapies that include diuretics and renin angiotensin aldosterone system blockers such as angiotensin-converting enzyme inhibitors or angiotensin receptor blockers. However, in clinical practice, a significant number of patients do not respond completely to these combination treatments, and long-term reduction of cardiovascular risk remains insufficient. The particularly high residual cardiovascular risk of hypertensive patients, even when adequately treated with strategies based on renin angiotensin aldosterone system blockers, speaks in favor of new, innovative strategies. Thus, it has become relevant to consider whether it is always necessary to block plasma renin activation and whether other guideline-approved combinations should be considered routinely. Diuretic/calcium channel blocker combinations, which are supported by significant long-term evidence, are put forth as a preferred combination in the main guidelines, but are still underused by physicians who do not yet have easy access to such treatments. Fixed-dose indapamide sustained release/amlodipine is the first such single-pill combination to become available. Complementary mechanisms of action of these two molecules are expected to lead to greater and longer-term reductions in systolic blood pressure and pulse pressure and potentially to the reduction of cardiovascular risk. PMID:25163857

  20. Comparison of beta blocker and digoxin alone and in combination for management of patients with atrial fibrillation and heart failure.

    PubMed

    Fauchier, Laurent; Grimard, Caroline; Pierre, Bertrand; Nonin, Emilie; Gorin, Laurent; Rauzy, Bruno; Cosnay, Pierre; Babuty, Dominique; Charbonnier, Bernard

    2009-01-15

    In patients with atrial fibrillation (AF) and heart failure (HF), beta blockers and digoxin reduce the ventricular rate, but controversy exists concerning how these drugs affect prognosis in this setting. This study compared the effects of beta blocker and digoxin on mortality in patients with both AF and HF. In a single-center institution, patients with AF and HF seen between January 2000 and January 2004 were identified and followed until September 2007. Of 1,269 consecutive patients with both AF and HF, 260 were treated with a beta blocker alone, 189 with beta blocker plus digoxin, 402 with digoxin alone, and 418 without beta blocker or digoxin (control group). During a follow-up of 881+/-859 days, 247 patients died. Compared with the control group, treatment with beta blocker was associated with a decreased mortality (relative risk=0.58, 95% confidence interval 0.40 to 0.85, p=0.005 for beta blocker alone and 0.59, 95% confidence interval 0.40 to 0.87, p=0.008 for beta blocker plus digoxin). By contrast, treatment with digoxin alone was not associated with a better survival (relative risk=0.97, 95% confidence interval 0.73 to 1.30, p=NS). Results remained significant after adjustment for potential confounders and similar when we considered, separately, HF with permanent or nonpermanent AF, presence or absence of coronary disease, and patients with decreased or preserved systolic function. In conclusion, in unselected patients with AF and HF, treatments with beta blocker alone or with beta blocker plus digoxin are associated with a similar decrease in the risk of death. Digoxin alone is associated with a worse survival chance, similar to that of patients without any rate control treatment. PMID:19121446

  1. Effect of β-Blockers on the Risk of Atrial Fibrillation in Patients with Acute Myocardial Infarction

    PubMed Central

    Pesaro, Antonio Eduardo; de Matos Soeiro, Alexandre; Serrano, Carlos Vicente; Giraldez, Roberto Rocha; Ladeira, Renata Teixeira; Nicolau, José Carlos

    2010-01-01

    INTRODUCTION: Oral β-blockers improve the prognosis of patients with acute myocardial infarction, while atrial fibrillation worsens the prognosis of this population. The reduction of atrial fibrillation incidence in patients treated with β-blockers could at least in part explain the benefits of this drug. OBJECTIVE: To investigate the effect of β-blockers on the incidence of atrial fibrillation in patients with acute myocardial infarction. METHODS: We analyzed 1401 patients with acute myocardial infarction and evaluated the occurrence or absence of atrial fibrillation, the use of oral β-blockers and mortality during the first 24 hours. RESULTS: a) The use of β-blockers was inversely correlated with the presence of atrial fibrillation (ρ = 0.004; OR = 0.54). b) Correlations with mortality were as follows: 31.5% in patients with atrial fibrillation, 9.2% in those without atrial fibrillation (ρ < 0.001; Odds Ratio = 4.52), and 17.5% in patients not treated with β-blockers and 6.7% in those who received the drug (ρ < 0.001; OR = 0.34). c) Adjusted Models: The presence of atrial fibrillation was independently correlated with mortality (OR = 2.48, ρ = 0.002). The use of β-blockers was inversely and independently correlated with mortality (OR = 0.53; ρ = 0.002). The patients who used β-blockers showed a lower risk of atrial fibrillation (OR = 0.59; ρ = 0.029) in the adjusted model. CONCLUSION: The presence of atrial fibrillation and the absence of oral β-blockers increased in-hospital mortality in patients with acute myocardial infarction. Oral β-blockers reduced the incidence of atrial fibrillation, which might be at least partially responsible for the drug’s benefit. PMID:20360916

  2. VizieR Online Data Catalog: CoRoT observation log (N2-4.4) (CoRoT 2016)

    NASA Astrophysics Data System (ADS)

    COROT Team

    2014-03-01

    CoRoT, a space astronomy mission, has measured photometric micro-variability of stars from minutes to months (up to 150 days) with a high duty cycle (more than 90%). The mission was led by CNES in association with four French laboratories and 7 participating countries and agencies (Austria, Belgium, Brazil, Germany, Spain, and the ESA Science Programme). The satellite was composed of a PROTEUS platform (the 3rd in the series) and a unique instrument: a stellar rapid photometer. It was launched on December 27th 2006 by a Soyuz Rocket, from Bakonour. The mission has lasted almost 6 years (the nominal 3-year duration and a 3-year extension) and has observed more than 160 000 stars. It stopped sending data on November 2nd 2012. Two regions of the sky were accessible for long period of time: circles of 10 degrees centered on the equator around alpha=06:50 and alpha=18:50. They were called the CoRoT eyes: the "anticenter" and the "center eye" (as they are approximately in these directions). Each pointing covers 1.4x2.8 square degrees within one of those CoRoT eyes. The original scientific objectives were focussed on the study of stellar pulsations (asteroseismology) to probe the internal structure of stars, and the detection of small exoplanets through their "transit" in front of their host star, and the measurement of their size. This lead to introduce two modes of observations, working simultaneously: - The "bright star" mode dedicated to very precise seismology of a small sample of bright and closeby stars - The "faint star" mode, observing a very large number of stars at the same time, to detect transits, which are rare events, as they imply the alignment of the star, the planet and the observer. The large amount of data gathered in this mode turned out to be extremely fruitful for many topics of stellar physics. Beyond these two initial objectives, CoRoT data revealed stellar variability associated with various other phenomena: granulation, rotational modulation by

  3. VizieR Online Data Catalog: CoRoT observation log (N2-4.4) (CoRoT 2016)

    NASA Astrophysics Data System (ADS)

    COROT Team

    2014-03-01

    CoRoT, a space astronomy mission, has measured photometric micro-variability of stars from minutes to months (up to 150 days) with a high duty cycle (more than 90%). The mission was led by CNES in association with four French laboratories and 7 participating countries and agencies (Austria, Belgium, Brazil, Germany, Spain, and the ESA Science Programme). The satellite was composed of a PROTEUS platform (the 3rd in the series) and a unique instrument: a stellar rapid photometer. It was launched on December 27th 2006 by a Soyuz Rocket, from Bakonour. The mission has lasted almost 6 years (the nominal 3-year duration and a 3-year extension) and has observed more than 160 000 stars. It stopped sending data on November 2nd 2012. Two regions of the sky were accessible for long period of time: circles of 10 degrees centered on the equator around alpha=06:50 and alpha=18:50. They were called the CoRoT eyes: the "anticenter" and the "center eye" (as they are approximately in these directions). Each pointing covers 1.4x2.8 square degrees within one of those CoRoT eyes. The original scientific objectives were focussed on the study of stellar pulsations (asteroseismology) to probe the internal structure of stars, and the detection of small exoplanets through their "transit” in front of their host star, and the measurement of their size. This lead to introduce two modes of observations, working simultaneously: - The “bright star” mode dedicated to very precise seismology of a small sample of bright and closeby stars - The “faint star” mode, observing a very large number of stars at the same time, to detect transits, which are rare events, as they imply the alignment of the star, the planet and the observer. The large amount of data gathered in this mode turned out to be extremely fruitful for many topics of stellar physics. Beyond these two initial objectives, CoRoT data revealed stellar variability associated

  4. β-Blockers Reduce Breast Cancer Recurrence and Breast Cancer Death: A Meta-Analysis.

    PubMed

    Childers, W Kurtis; Hollenbeak, Christopher S; Cheriyath, Pramil

    2015-12-01

    The normal physiologic stress mechanism, mediated by the sympathetic nervous system, causes a release of the neurotransmitters epinephrine and norepinephrine. Preclinical data have demonstrated an effect on tumor progression and metastasis via the sympathetic nervous system mediated primarily through the β-adrenergic receptor (β-AR) pathway. In vitro data have shown an increase in tumor growth, migration, tumor angiogenesis, and metastatic spread in breast cancer through activation of the β-AR. Retrospective cohort studies on the clinical outcomes of β-blockers in breast cancer outcomes showed no clear consensus. The purpose of this study was to perform a systematic review and meta-analysis of the effect of β-blockers on breast cancer outcomes. A systematic review was performed using the Cochrane library and PubMed. Publications between the dates of January 2010 and December 2013 were identified. Available hazard ratios (HRs) were extracted for breast cancer recurrence, breast cancer death, and all-cause mortality and pooled using a random effects meta-analysis. A total of 7 studies contained results for at least 1 of the outcomes of breast cancer recurrence, breast cancer death, or all-cause mortality in breast cancer patients receiving β-blockers. In the 5 studies that contained results for breast cancer recurrence, there was no statistically significant risk reduction (HR, 0.67; 95% confidence interval [CI], 0.39-1.13). Breast cancer death results were contained in 4 studies, which also suggested a significant reduction in risk (HR, 0.50; 95% CI, 0.32-0.80). Among the 4 studies that reported all-cause mortality, there was no significant effect of β-blockers on risk (HR, 1.02; 95% CI, 0.75-1.37). Results of this systematic review and meta-analysis suggest that the use of β-blockers significantly reduced risk of breast cancer death among women with breast cancer. PMID:26516037

  5. The Impact of Treatment with Beta-Blockers upon Mortality in Chronic Heart Failure Patients

    PubMed Central

    Taneva, Borjanka; Caparoska, Daniela

    2016-01-01

    BACKGROUND: Besides the conventional therapy for heart failure, the diuretics, cardiac glycosides and ACE-inhibitors, current pharmacotherapy includes beta-blockers, mainly because of their pathophysiological mechanisms upon heart remodeling. AIM: The study objective was to assess the cardiovascular mortality in the beta-blocker therapy group and to correlate it with the mortality in the control group as well as to correlate the combined outcome of death and/or hospitalization for cardiovascular reason between the two groups. MATERIALS AND METHODS: The study included 113 chronic heart failure patients followed up for a period of 18 months. The therapy group received conventional therapy plus the target dose of beta blockers, and the control group received the conventional therapy only. The therapy group was divided in three separate subgroups in terms of the type of beta-blocker (Metoprolol subgroup, Bisoprolol and Carvedilol subgroup). To compare the mortality and the combined outcome, the RRR (relative risk reduction) and NNT (number needed to treat) were used, as well as the survival analysis by Kaplan-Meier. RESULTS: The results showed the following: in regards of the cardiovascular mortality, the relative risk for death in the therapy group was 34%, which, though statistically not significant, is of great clinical significance. In regards of the combined outcome (death and/or number of hospitalizations) the results showed a RRR of 40% in the therapy group compared to the control group, which is statistically highly significant. CONCLUSION: The study confirmed that patients with stable chronic heart failure, treated with optimal doses of beta-blockers, show a significant reduction of the risk from death as well as combined outcome (death and/or number of hospitalizations).

  6. MONNA, a potent and selective blocker for transmembrane protein with unknown function 16/anoctamin-1.

    PubMed

    Oh, Soo-Jin; Hwang, Seok Jin; Jung, Jonghoon; Yu, Kuai; Kim, Jeongyeon; Choi, Jung Yoon; Hartzell, H Criss; Roh, Eun Joo; Lee, C Justin

    2013-11-01

    Transmembrane protein with unknown function 16/anoctamin-1 (ANO1) is a protein widely expressed in mammalian tissues, and it has the properties of the classic calcium-activated chloride channel (CaCC). This protein has been implicated in numerous major physiological functions. However, the lack of effective and selective blockers has hindered a detailed study of the physiological functions of this channel. In this study, we have developed a potent and selective blocker for endogenous ANO1 in Xenopus laevis oocytes (xANO1) using a drug screening method we previously established (Oh et al., 2008). We have synthesized a number of anthranilic acid derivatives and have determined the correlation between biological activity and the nature and position of substituents in these derived compounds. A structure-activity relationship revealed novel chemical classes of xANO1 blockers. The derivatives contain a --NO₂ group on position 5 of a naphthyl group-substituted anthranilic acid, and they fully blocked xANO1 chloride currents with an IC₅₀ < 10 μM. The most potent blocker, N-((4-methoxy)-2-naphthyl)-5-nitroanthranilic acid (MONNA), had an IC₅₀ of 0.08 μM for xANO1. Selectivity tests revealed that other chloride channels such as bestrophin-1, chloride channel protein 2, and cystic fibrosis transmembrane conductance regulator were not appreciably blocked by 10∼30 μM MONNA. The potent and selective blockers for ANO1 identified here should permit pharmacological dissection of ANO1/CaCC function and serve as potential candidates for drug therapy of related diseases such as hypertension, cystic fibrosis, bronchitis, asthma, and hyperalgesia. PMID:23997117

  7. MONNA, a Potent and Selective Blocker for Transmembrane Protein with Unknown Function 16/Anoctamin-1

    PubMed Central

    Oh, Soo-Jin; Hwang, Seok Jin; Jung, Jonghoon; Yu, Kuai; Kim, Jeongyeon; Choi, Jung Yoon; Hartzell, H. Criss

    2013-01-01

    Transmembrane protein with unknown function 16/anoctamin-1 (ANO1) is a protein widely expressed in mammalian tissues, and it has the properties of the classic calcium-activated chloride channel (CaCC). This protein has been implicated in numerous major physiological functions. However, the lack of effective and selective blockers has hindered a detailed study of the physiological functions of this channel. In this study, we have developed a potent and selective blocker for endogenous ANO1 in Xenopus laevis oocytes (xANO1) using a drug screening method we previously established (Oh et al., 2008). We have synthesized a number of anthranilic acid derivatives and have determined the correlation between biological activity and the nature and position of substituents in these derived compounds. A structure-activity relationship revealed novel chemical classes of xANO1 blockers. The derivatives contain a −NO2 group on position 5 of a naphthyl group-substituted anthranilic acid, and they fully blocked xANO1 chloride currents with an IC50 < 10 μM. The most potent blocker, N-((4-methoxy)-2-naphthyl)-5-nitroanthranilic acid (MONNA), had an IC50 of 0.08 μM for xANO1. Selectivity tests revealed that other chloride channels such as bestrophin-1, chloride channel protein 2, and cystic fibrosis transmembrane conductance regulator were not appreciably blocked by 10∼30 μM MONNA. The potent and selective blockers for ANO1 identified here should permit pharmacological dissection of ANO1/CaCC function and serve as potential candidates for drug therapy of related diseases such as hypertension, cystic fibrosis, bronchitis, asthma, and hyperalgesia. PMID:23997117

  8. Effects of β-blocker therapy on electrocardiographic and echocardiographic characteristics of left ventricular noncompaction.

    PubMed

    Li, Jin; Franke, Jennifer; Pribe-Wolferts, Regina; Meder, Benjamin; Ehlermann, Philipp; Mereles, Derliz; Andre, Florian; Abdelrazek, Mohamed Assem; Merten, Constanze; Schweizer, Patrick A; Becker, Rüdiger; Katus, Hugo A; Thomas, Dierk

    2015-03-01

    Left ventricular noncompaction (LVNC) is a cardiomyopathy with hypertrabeculation of the LV, often complicated by heart failure, arrhythmia and thromboembolic events. The features of LVNC are still incompletely characterized due to its late recognition as clinically relevant condition. The aims of this study were to describe echocardiographic and electrophysiologic characteristics of LVNC patients and to assess the effects of chronic β-blocker treatment. Study patients (n = 20; 42.5 [36.3; 52.5] years; 12 men) exhibited reduced LV ejection fraction (median LVEF = 32 %) and an increased LV mass of 210 g. Sinus rhythm was present in 19 patients, whereas one patient was in atrial fibrillation. Baseline heart rate was 77.5 beats per minute. Left bundle branch block was detected in five cases. In a subgroup of patients receiving β-blocker therapy (n = 17), LV mass was reduced from 226 [178; 306] g to 220 [169; 254] g (p = 0.007) at 13 ± 6 months follow-up. By contrast, a subgroup of three patients that were not treated with an anti-β-adrenergic agent showed LV mass increase from 180 [169; 197] g to 199 [185; 213] g (p = 0.023). LVEF and electrocardiographic parameters were not significantly modulated during chronic β-blocker treatment. There was no sustained symptomatic ventricular tachyarrhythmia, thromboembolic event or death in either group. In conclusion, this study reveals reduction of LV mass among LVNC patients during β-blocker therapy. Effects of β-blocker treatment in LVNC require validation in prospective controlled studies. PMID:25331160

  9. Regulation of Histone H4 Lys16 Acetylation by Predicted Alternative Secondary Structures in roX Noncoding RNAs▿ †

    PubMed Central

    Park, Seung-Won; Kuroda, Mitzi I.; Park, Yongkyu

    2008-01-01

    Despite differences in size and sequence, the two noncoding roX1 and roX2 RNAs are functionally redundant for dosage compensation of the Drosophila melanogaster male X chromosome. Consistent with functional conservation, we found that roX RNAs of distant Drosophila species could complement D. melanogaster roX mutants despite low homology. Deletion of a conserved predicted stem-loop structure in roX2, containing a short GUb (GUUNUACG box) in its 3′ stem, resulted in a defect in histone H4K16 acetylation on the X chromosome in spite of apparently normal localization of the MSL complex. Two copies of the GUb sequence, newly termed the “roX box,” were functionally redundant in roX2, as mutants in a single roX box had no phenotype, but double mutants showed reduced H4K16 acetylation. Interestingly, mutation of two of three roX boxes in the 3′ end of roX1 RNA also reduced H4K16 acetylation. Finally, fusion of roX1 sequences containing a roX box restored function to a roX2 deletion RNA lacking its cognate roX box. These results support a model in which the functional redundancy between roX1 and roX2 RNAs is based, at least in part, on short GUUNUACG sequences that regulate the activity of the MSL complex. PMID:18541664

  10. Regulation of histone H4 Lys16 acetylation by predicted alternative secondary structures in roX noncoding RNAs.

    PubMed

    Park, Seung-Won; Kuroda, Mitzi I; Park, Yongkyu

    2008-08-01

    Despite differences in size and sequence, the two noncoding roX1 and roX2 RNAs are functionally redundant for dosage compensation of the Drosophila melanogaster male X chromosome. Consistent with functional conservation, we found that roX RNAs of distant Drosophila species could complement D. melanogaster roX mutants despite low homology. Deletion of a conserved predicted stem-loop structure in roX2, containing a short GUb (GUUNUACG box) in its 3' stem, resulted in a defect in histone H4K16 acetylation on the X chromosome in spite of apparently normal localization of the MSL complex. Two copies of the GUb sequence, newly termed the "roX box," were functionally redundant in roX2, as mutants in a single roX box had no phenotype, but double mutants showed reduced H4K16 acetylation. Interestingly, mutation of two of three roX boxes in the 3' end of roX1 RNA also reduced H4K16 acetylation. Finally, fusion of roX1 sequences containing a roX box restored function to a roX2 deletion RNA lacking its cognate roX box. These results support a model in which the functional redundancy between roX1 and roX2 RNAs is based, at least in part, on short GUUNUACG sequences that regulate the activity of the MSL complex. PMID:18541664

  11. Cytotoxicity of Ro-07-0582; enhancement by hyperthermia and protection by cysteamine.

    PubMed Central

    Hall, E. J.; Astor, M.; Geard, C.; Biaglow, J.

    1977-01-01

    The selective cytotoxicity which Ro-07-0582 exhibits towards hypoxic cells is strongly temperature-dependent. This cytotoxicity is reduced by the radical scavenger cysteamine, suggesting that nitro radicals or nitroso intermediates are involved in cell killing by the drug. Chromosome aberrations are not induced by Ro-07-0582 even when the surviving fraction is reduced to 0-01. PMID:871368

  12. WARM SPITZER PHOTOMETRY OF THE TRANSITING EXOPLANETS CoRoT-1 AND CoRoT-2 AT SECONDARY ECLIPSE

    SciTech Connect

    Deming, Drake; Knutson, Heather; Agol, Eric; Cowan, Nicolas B.; Desert, Jean-Michel; Charbonneau, David; Burrows, Adam; Fortney, Jonathan J.; Laughlin, Gregory; Langton, Jonathan; Showman, Adam P.; Lewis, Nikole K.

    2011-01-10

    We measure secondary eclipses of the hot giant exoplanets CoRoT-1 at 3.6 and 4.5 {mu}m, and CoRoT-2 at 3.6 {mu}m, both using Warm Spitzer. We find that the Warm Spitzer mission is working very well for exoplanet science. For consistency of our analysis we also re-analyze archival cryogenic Spitzer data for secondary eclipses of CoRoT-2 at 4.5 and 8 {mu}m. We compare the total data for both planets, including optical eclipse measurements by the CoRoT mission, and ground-based eclipse measurements at 2 {mu}m, to existing models. Both planets exhibit stronger eclipses at 4.5 than at 3.6 {mu}m, which is often indicative of an atmospheric temperature inversion. The spectrum of CoRoT-1 is best reproduced by a 2460 K blackbody, due either to a high altitude layer that strongly absorbs stellar irradiance, or an isothermal region in the planetary atmosphere. The spectrum of CoRoT-2 is unusual because the 8 {mu}m contrast is anomalously low. Non-inverted atmospheres could potentially produce the CoRoT-2 spectrum if the planet exhibits line emission from CO at 4.5 {mu}m, caused by tidal-induced mass loss. However, the viability of that hypothesis is questionable because the emitting region cannot be more than about 30% larger than the planet's transit radius, based on the ingress and egress times at eclipse. An alternative possibility to account for the spectrum of CoRoT-2 is an additional opacity source that acts strongly at wavelengths less than 5 {mu}m, heating the upper atmosphere while allowing the deeper atmosphere seen at 8 {mu}m to remain cooler. We obtain a similar result as Gillon et al. for the phase of the secondary eclipse of CoRoT-2, implying an eccentric orbit with e cos({omega}) = -0.0030 {+-} 0.0004.

  13. Combination therapy of angiotensin II receptor blocker and calcium channel blocker exerts pleiotropic therapeutic effects in addition to blood pressure lowering: amlodipine and candesartan trial in Yokohama (ACTY).

    PubMed

    Maeda, Akinobu; Tamura, Kouichi; Kanaoka, Tomohiko; Ohsawa, Masato; Haku, Sona; Azushima, Kengo; Dejima, Toru; Wakui, Hiromichi; Yanagi, Mai; Okano, Yasuko; Fujikawa, Tetsuya; Toya, Yoshiyuki; Mizushima, Shunsaku; Tochikubo, Osamu; Umemura, Satoshi

    2012-01-01

    Recent guidelines recommend combination antihypertensive therapy to achieve the target blood pressure (BP) and to suppress target organ damage. This study aimed to examine the beneficial effects of combination therapy with candesartan and amlodipine on BP control and markers of target organ function in Japanese essential hypertensive patients (N = 20) who did not achieve the target BP level during the monotherapy period with either candesartan or amlodipine. After the monotherapy period, for patients already being treated with amlodipine, a once-daily 8 mg dose of candesartan was added on during the combination therapy period (angiotensin II receptor blocker [ARB] add-on group, N = 10), and a once-daily 5 mg dose of amlodipine was added on for those already being treated with candesartan (calcium channel blocker [CCB] add-on group, N = 10). Combination therapy with candesartan and amlodipine for 12 weeks significantly decreased clinic and home systolic blood pressure (SBP) and diastolic blood pressure (DBP). In addition, the combination therapy was able to significantly reduce urine albumin excretion without decrease in estimated glomerular filtration ratio and resulted in significant improvements in brachial-ankle pulse wave velocity, central SBP, and insulin sensitivity. Furthermore, the CCB add-on group showed a significantly greater decrease in clinic and home DBP than the ARB add-on group. The calcium channel blocker add-on group also exhibited better improvements in vascular functional parameters than the ARB add-on group. These results suggest that combination therapy with candesartan and amlodipine is an efficient therapeutic strategy for hypertension with pleiotropic benefits. PMID:22571446

  14. Rationale for triple fixed-dose combination therapy with an angiotensin II receptor blocker, a calcium channel blocker, and a thiazide diuretic

    PubMed Central

    Volpe, Massimo; Tocci, Giuliano

    2012-01-01

    Hypertension is a growing global health problem, and is predicted to affect 1.56 billion people by 2025. Treatment remains suboptimal, with control of blood pressure achieved in only 20%–35% of patients, and the majority requiring two or more antihypertensive drugs to achieve recommended blood pressure goals. To improve blood pressure control, the European hypertension guidelines recommend that angiotensin II receptor blockers (ARBs) or angiotensin-converting enzyme inhibitors (ACEIs) are combined with calcium channel blockers (CCBs) and/or thiazide diuretics. The rationale for this strategy is based, in part, on their different effects on the renin-angiotensin system, which improves antihypertensive efficacy. Data from a large number of trials support the efficacy of ACEIs or ARBs in combination with CCBs and/or hydrochlorothiazide (HCTZ). Combining two different classes of antihypertensive drugs has an additive effect on lowering of blood pressure, and does not increase adverse events, with the ARBs showing a tolerability advantage over the ACEIs. Among the different ARBs, olmesartan medoxomil is available as a dual fixed-dose combination with either amlodipine or HCTZ, and the increased blood pressure-lowering efficacy of these two combinations is proven. Triple therapy is required in 15%–20% of treated uncontrolled hypertensive patients, with a renin-angiotensin system blocker, CCB, and thiazide diuretic considered to be a rational combination according to the European guidelines. Olmesartan, amlodipine, and HCTZ are available as a triple fixed-dose combination, and significant blood pressure reductions have been observed with this regimen compared with the possible dual combinations. The availability of these fixed-dose combinations should lead to improvement in blood pressure control and aid compliance with long-term therapy, optimizing the management of this chronic condition. PMID:22745561

  15. Ro small cytoplasmic ribonucleoproteins are a subclass of La ribonucleoproteins: Further characterization of the Ro and La small ribonucleoproteins from uninfected mammalian cells

    SciTech Connect

    Hendrick, J.P.; Wolin, S.L.; Rinke, J.; Lerner, M.R.; Steitz, J.A.

    1981-12-01

    Small ribonucleic acid (RNA)-protein complexes precipitated by anti-Ro and anti-La antibodies from lupus patients have been examined with emphasis on their RNA components. In both ribonucleoprotein (RNP) classes, the numbers of different RNA molecules and their sequences vary between mouse and human cells. The complex mixtures of La RNAs include two previously sequenced 4.5S RNAs from mouse cells and 5S ribosomal RNA-like molecules from both mouse and human cells. All Ro and La RNAs possess 5'-triphosphates. Some La RNAs have internal modifications typical of transfer RNAs. The RoRNPs are quite stable and are localized by immunofluorescence in the cell cytoplasm, whereas the majority of the La RNPs turn over rapidly and reside in the nucleus. Despite these differences, reconstitution experiments show that the Ro particles carry the La as well as the Ro determinant. Studies using a nuclear transcription system demonstrate that most of the La RNAs are synthesized by RNA polymerase III. The possibility that the La protein(s) functions in the transcription or maturation of all RNA polymerase III transcripts is discussed.

  16. RO brine treatment and recovery by biological activated carbon and capacitive deionization process.

    PubMed

    Tao, Guihe; Viswanath, Bala; Kekre, Kiran; Lee, Lai Yoke; Ng, How Yong; Ong, Say Leong; Seah, Harry

    2011-01-01

    The generation of brine solutions from dense membrane (reverse osmosis, RO or nanofiltration, NF) water reclamation systems has been increasing worldwide, and the lack of cost effective disposal options is becoming a critical water resources management issue. In Singapore, NEWater is the product of a multiple barrier water reclamation process from secondary treated domestic effluent using MF/UF-RO and UV technologies. The RO brine (concentrates) accounts for more than 20% of the total flow treated. To increase the water recovery and treat the RO brine, a CDI based process with BAC as pretreatment was tested. The results show that ion concentrations in CDI product were low except SiO2 when compared with RO feed water. CDI product was passed through a RO and the RO permeate was of better quality including low SiO2 as compared to NEWater quality. It could be beneficial to use a dedicated RO operated at optimum conditions with better performance to recover the water. BAC was able to achieve 15-27% TOC removal of RO brine. CDI had been tested at a water recovery ranging from 71.6 to 92.3%. CDI based RO brine treatment could improve overall water recovery of NEWater production over 90%. It was found that calcium phosphate scaling and organic fouling was the major cause of CDI pressure increase. Ozone disinfection and sodium bisulfite dosing were able to reduce CDI fouling rate. For sustainable operation of CDI organic fouling control and effective organic fouling cleaning should be further studied. PMID:22053461

  17. β-Blocker use and mortality in cancer patients: systematic review and meta-analysis of observational studies.

    PubMed

    Zhong, Shanliang; Yu, Dandan; Zhang, Xiaohui; Chen, Xiu; Yang, Sujin; Tang, Jinhai; Zhao, Jianhua; Wang, Shukui

    2016-09-01

    A number of epidemiologic studies have attempted to link the use of β blockers to mortality in cancer patients, but their findings have been inconclusive. A meta-analysis was carried out to derive a more precise estimation. Relevant studies were identified by searching PubMed and EMBASE to May 2015. We calculated the summary hazard ratios (HRs) and 95% confidence intervals (CIs) using random-effects models. Twenty cohort studies and four case-control studies involving 76 538 participants were included. The overall results showed that patients who used β blockers after diagnosis had an HR of 0.89 (95% CI 0.81-0.98) for all-cause mortality compared with nonusers. Those who used β blockers after diagnosis (vs. nonusers) had an HR of 0.89 (95% CI 0.79-0.99) for cancer-specific mortality. Prediagnostic use of β blockers showed no beneficial effect on all-cause mortality or cancer-specific mortality. Stratifying by cancer type, only breast cancer patients who used β blockers after diagnosis had a prolonged overall survival. A linear but nonsignificant trend was found between postdiagnostic β-blocker use and mortality of cancer patients. In conclusion, the average effect of β-blocker use after diagnosis but not before diagnosis is beneficial for the survival of cancer patients. PMID:26340056

  18. Combination and triple therapy in patients with stable angina pectoris not adequately controlled by optimal β-blocker therapy

    PubMed Central

    Kok, W.E.M.; Visser, F.C.; Visser, C.A.

    2002-01-01

    In 60 to 80% of patients with stable angina pectoris at low risk for future coronary events, monotherapy with a β-blocker is an effective treatment. When patients with stable angina pectoris and low risk for events do not respond adequately to optimal β-blocker monotherapy, combination therapy or even triple therapy is may be recommended, but little is known of the actual benefit of such a strategy. We reviewed the evidence from the literature on the effectiveness of combination and triple therapy. Combination therapy with a calcium antagonist or nitrate was found to be more effective than β-blocker monotherapy in the majority of studies, but only an estimated 30% of patients objectively benefit from these combination therapies. Direct comparison shows that combination therapy of a β-blocker with a calcium antagonist is more effective than the combination of a β-blocker with a nitrate. An inadequate response to β-blocker monotherapy is more effectively improved by addition of a calcium antagonist than by alternative use of a calcium antagonist. The use of triple therapy is controversial and not recommended in patients with mild angina pectoris, while for patients with severe angina pectoris not responding to combination therapy of a β-blocker with a nitrate, triple therapy may be of advantage, although the number of patients studied has been small. PMID:25696045

  19. Modeling the Effects of β1-Adrenergic Receptor Blockers and Polymorphisms on Cardiac Myocyte Ca2+ Handling

    PubMed Central

    Amanfu, Robert K.

    2014-01-01

    β-Adrenergic receptor blockers (β-blockers) are commonly used to treat heart failure, but the biologic mechanisms governing their efficacy are still poorly understood. The complexity of β-adrenergic signaling coupled with the influence of receptor polymorphisms makes it difficult to intuit the effect of β-blockers on cardiac physiology. While some studies indicate that β-blockers are efficacious by inhibiting β-adrenergic signaling, other studies suggest that they work by maintaining β-adrenergic responsiveness. Here, we use a systems pharmacology approach to test the hypothesis that in ventricular myocytes, these two apparently conflicting mechanisms for β-blocker efficacy can occur concurrently. We extended a computational model of the β1-adrenergic pathway and excitation-contraction coupling to include detailed receptor interactions for 19 ligands. Model predictions, validated with Ca2+ and Förster resonance energy transfer imaging of adult rat ventricular myocytes, surprisingly suggest that β-blockers can both inhibit and maintain signaling depending on the magnitude of receptor stimulation. The balance of inhibition and maintenance of β1-adrenergic signaling is predicted to depend on the specific β-blocker (with greater responsiveness for metoprolol than carvedilol) and β1-adrenergic receptor Arg389Gly polymorphisms. PMID:24867460

  20. Isolated rat cardiac myocytes as an experimental model to study calcium overload: the effect of calcium-entry blockers.

    PubMed

    Donck, L V; Pauwels, P J; Vandeplassche, G; Borgers, M

    1986-03-01

    Calcium overload and the effect of a series of calcium-entry blockers were studied in isolated adult cardiac myocytes from the rat challenged with veratrine. The isolation procedure resulted in a high yield of individual rod shaped, calcium tolerant myocytes. After incubation with veratrine, an alkaloid which induces both sodium and calcium influx, 93% of the myocytes became calcium intolerant: the quiescent rod shaped cells vigorously contracted after 30 sec of contact with veratrine and contracture (round cells) ensued within 1 min. Exposure for 30 min to various doses of calcium-entry blockers prior to veratrine addition resulted in the prevention of contracture, the degree of protection depending on the type and the concentration of calcium-entry blocker. Among the different calcium-entry blockers tested, the diarylalkylpiperazines lidoflazine, cinnarizine and flunarizine were protective from the 10(-7) M concentration onwards. Nicardipine was protective at the 10(-6) M and 10(-5) M concentrations, verapamil at 10(-5)M only while other blockers of the "slow channel" type (diltiazem and nifedipine) were not protective in the concentration range tested. This study shows that isolated myocytes represent a valid model for pharmacological investigations. The results with the calcium-entry blockers stress the heterogeneity of the different series of calcium-entry blockers. PMID:3951332

  1. Primary prevention of atrial fibrillation with beta-blockers in patients with end-stage renal disease undergoing dialysis

    PubMed Central

    Lin, Ting-Tse; Chiang, Jiun-Yang; Liao, Min-Tsun; Tsai, Chia-Ti; Hwang, Juey Jen; Chiang, Fu-Tien; Lin, Jiunn-Lee; Lin, Lian-Yu

    2015-01-01

    Current evidence suggests that beta-blocker lower the risk of development of atrial fibrillation (AF) and in-hospital stroke after cardiac surgery. This study was to assess whether beta-blockers could decrease incidence of new-onset AF in patients with end stage renal disease (ESRD). We identified patients from a nation-wide database called Registry for Catastrophic Illness, which encompassed almost 100% of the patients receiving dialysis therapy in Taiwan from 1995 to 2008. Propensity score matching and Cox’s proportional hazards regression model were used to estimate hazard ratios (HRs) for new-onset AF. Among 100066 patients, 41.7% received beta-blockers. After a median follow-up of 1500 days, the incidence of new-onset AF significantly decreased in patients treated with beta-blockers (HR = 0.483, 95% confidence interval = 0.437-0.534). The prevention of new-onset AF was significantly better in patients taking longer duration of beta-blockers therapy (P for time trend <0.001). The AF prevention effect remains robust in subgroup analyses. In conclusion, beta-blockers seem effective in the primary prevention of AF in ESRD patients. Hence, beta-blockers may be the target about upstream treatment of AF. PMID:26643783

  2. Antiproliferative effects of β-blockers on human colorectal cancer cells.

    PubMed

    Coelho, M; Moz, M; Correia, G; Teixeira, A; Medeiros, R; Ribeiro, L

    2015-05-01

    Colon cancer is the fourth and third most common cancer, respectively in men and women worldwide and its incidence is on the increase. Stress response has been associated with the incidence and development of cancer. The catecholamines (CA), adrenaline (AD) and noradrenaline (NA), are crucial mediators of stress response, exerting their effects through interaction with α- and β-adrenergic receptors (AR). Colon cancer cells express β-AR, and their activation has been implicated in carcinogenesis and tumor progression. Interest concerning the efficacy of β-AR blockers as possible additions to cancer treatment has increased. The aim of this study was to investigate the effect of several AR agonists and β-blockers following cell proliferation of HT-29 cells, a human colon adenocarcinoma cell line. For this purpose, HT-29 cells were incubated in the absence (control) or in the presence of the AR-agonists, AD, NA and isoprenaline (ISO) (0.1-100 µM) for 12 or 24 h. The tested AR agonists revealed proliferative effects on HT-29 cells. In order to study the effect of several β-blockers following proliferation induced by AR activation, the cells were treated with propranolol (PRO; 50 µM), carvedilol (CAR; 5 µM), atenolol (ATE; 50 µM), or ICI 118,551 (ICI; 5 µM) for 45 min prior, and simultaneously, to incubation with each of the AR agonists, AD and ISO, both at 1 and 10 µM. The results suggested that adrenergic activation plays an important role in colon cancer cell proliferation, most probably through β-AR. The β-blockers under study were able to reverse the proliferation induced by AD and ISO, and some of these blockers significantly decreased the proliferation of HT-29 cells. The elucidation of the intracellular pathways involved in CA-induced proliferation of colon cancer cells, and in the reversion of this effect by β-blockers, may contribute to identifying promising strategies in cancer treatment. PMID:25812650

  3. Transiting exoplanets from the CoRoT space mission . VI. CoRoT-Exo-3b: the first secure inhabitant of the brown-dwarf desert

    NASA Astrophysics Data System (ADS)

    Deleuil, M.; Deeg, H. J.; Alonso, R.; Bouchy, F.; Rouan, D.; Auvergne, M.; Baglin, A.; Aigrain, S.; Almenara, J. M.; Barbieri, M.; Barge, P.; Bruntt, H.; Bordé, P.; Collier Cameron, A.; Csizmadia, Sz.; de La Reza, R.; Dvorak, R.; Erikson, A.; Fridlund, M.; Gandolfi, D.; Gillon, M.; Guenther, E.; Guillot, T.; Hatzes, A.; Hébrard, G.; Jorda, L.; Lammer, H.; Léger, A.; Llebaria, A.; Loeillet, B.; Mayor, M.; Mazeh, T.; Moutou, C.; Ollivier, M.; Pätzold, M.; Pont, F.; Queloz, D.; Rauer, H.; Schneider, J.; Shporer, A.; Wuchterl, G.; Zucker, S.

    2008-12-01

    Context: The CoRoT space mission routinely provides high-precision photometric measurements of thousands of stars that have been continuously observed for months. Aims: The discovery and characterization of the first very massive transiting planetary companion with a short orbital period is reported. Methods: A series of 34 transits was detected in the CoRoT light curve of an F3V star, observed from May to October 2007 for 152 days. The radius was accurately determined and the mass derived for this new transiting, thanks to the combined analysis of the light curve and complementary ground-based observations: high-precision radial-velocity measurements, on-off photometry, and high signal-to-noise spectroscopic observations. Results: CoRoT-Exo-3b has a radius of 1.01 ± 0.07 R_Jup and transits around its F3-type primary every 4.26 days in a synchronous orbit. Its mass of 21.66 ± 1.0 M_Jup, density of 26.4 ± 5.6 g cm-3, and surface gravity of logg = 4.72 clearly distinguish it from the regular close-in planet population, making it the most intriguing transiting substellar object discovered so far. Conclusions: With the current data, the nature of CoRoT-Exo-3b is ambiguous, as it could either be a low-mass brown-dwarf or a member of a new class of “superplanets”. Its discovery may help constrain the evolution of close-in planets and brown-dwarfs better. Finally, CoRoT-Exo-3b confirms the trend that massive transiting giant planets (M ≥ 4 M_Jup) are found preferentially around more massive stars than the Sun. The CoRoT space mission, launched on December 27th 2006, has been developed and is operating by CNES, with the contribution of Austria, Belgium, Brasil, ESA, Germany and Spain. The first CoRoT data will be available to the public in February 2009 from the CoRoT archive: http://idoc-corot.ias.u-psud.fr/ Table of the COROT photometry is only available in electronic form at the CDS via anonymous ftp to cdsarc.u-strasbg.fr (130.79.128.5) or via http://cdsweb

  4. Transiting exoplanets from the CoRoT space mission. XXV. CoRoT-27b: a massive and dense planet on a short-period orbit

    NASA Astrophysics Data System (ADS)

    Parviainen, H.; Gandolfi, D.; Deleuil, M.; Moutou, C.; Deeg, H. J.; Ferraz-Mello, S.; Samuel, B.; Csizmadia, Sz.; Pasternacki, T.; Wuchterl, G.; Havel, M.; Fridlund, M.; Angus, R.; Tingley, B.; Grziwa, S.; Korth, J.; Aigrain, S.; Almenara, J. M.; Alonso, R.; Baglin, A.; Barros, S. C. C.; Bordé, P.; Bouchy, F.; Cabrera, J.; Díaz, R. F.; Dvorak, R.; Erikson, A.; Guillot, T.; Hatzes, A.; Hébrard, G.; Mazeh, T.; Montagnier, G.; Ofir, A.; Ollivier, M.; Pätzold, M.; Rauer, H.; Rouan, D.; Santerne, A.; Schneider, J.

    2014-02-01

    Aims: We report the discovery of a massive and dense transiting planet CoRoT-27b on a 3.58-day orbit around a 4.2 Gyr-old G2 star. The planet candidate was identified from the CoRoT photometry, and was confirmed as a planet with ground-based spectroscopy. Methods: The confirmation of the planet candidate is based on radial velocity observations combined with imaging to rule out blends. The characterisation of the planet and its host star was carried out using a Bayesian approach where all the data (CoRoT photometry, radial velocities, and spectroscopic characterisation of the star) are used jointly. The Bayesian analysis included a study whether the assumption of white normally distributed noise holds for the CoRoT photometry and whether the use of a non-normal noise distribution offers advantages in parameter estimation and model selection. Results: CoRoT-27b has a mass of 10.39 ± 0.55MJup, a radius of 1.01 ± 0.04RJup, a mean density of 12.6-1.67+1.92g cm-3, and an effective temperature of 1500 ± 130 K. The planet orbits around its host star, a 4.2 Gyr-old G2-star with a mass M⋆ = 1.06M⊙ and a radius R⋆ = 1.05R⊙, on a 0.048 ± 0.007 AU orbit of 3.58 days. The radial velocity observations allow us to exclude highly eccentric orbits, namely, e < 0.065 with 99% confidence. Given its high mass and density, theoretical modelling of CoRoT-27b is demanding. We identify two solutions with heavy element mass fractions of 0.11 ± 0.08M⊕ and 0.07 ± 0.06M⊕, but even solutions void of heavy elements cannot be excluded. We carry out a secondary eclipse search from the CoRoT photometry using a method based on Bayesian model selection, but conclude that the noise level is too high to detect eclipses shallower than 9% of the transit depth. Using a non-normal noise model was shown not to affect the parameter estimation results, but led to significant improvement in the sensitivity of the model selection process. The CoRoT space mission, launched on December 27, 2006

  5. The high-energy environment in the super-Earth system CoRoT-7

    NASA Astrophysics Data System (ADS)

    Poppenhaeger, K.; Czesla, S.; Schröter, S.; Lalitha, S.; Kashyap, V.; Schmitt, J. H. M. M.

    2012-05-01

    High-energy irradiation of exoplanets has been identified to be a key influence on the stability of these planets' atmospheres. So far, irradiation-driven mass-loss has been observed only in two Hot Jupiters, and the observational data remain even more sparse in the super-Earth regime. We present an investigation of the high-energy emission in the CoRoT-7 system, which hosts the first known transiting super-Earth. To characterize the high-energy XUV radiation field into which the rocky planets CoRoT-7b and CoRoT-7c are immersed, we analyzed a 25 ks XMM-Newton observation of the host star. Our analysis yields the first clear (3.5σ) X-ray detection of CoRoT-7. We determine a coronal temperature of ≈ 3 MK and an X-ray luminosity of 3 × 1028 erg s-1. The level of XUV irradiation on CoRoT-7b amounts to ≈37 000 erg cm-2 s-1. Current theories for planetary evaporation can only provide an order-of-magnitude estimate for the planetary mass loss; assuming that CoRoT-7b has formed as a rocky planet, we estimate that CoRoT-7b evaporates at a rate of about 1.3 × 1011 g s-1 and has lost ≈4-10 earth masses in total.

  6. Experimental results from RO-PRO: a next generation system for low-energy desalination.

    PubMed

    Achilli, Andrea; Prante, Jeri L; Hancock, Nathan T; Maxwell, Eric B; Childress, Amy E

    2014-06-01

    A pilot system was designed and constructed to evaluate reverse osmosis (RO) energy reduction that can be achieved using pressure-retarded osmosis (PRO). The RO-PRO experimental system is the first known system to utilize energy from a volume of water transferred from atmospheric pressure to elevated pressure across a semipermeable membrane to prepressurize RO feedwater. In other words, the system demonstrated that pressure could be exchanged between PRO and RO subsystems. Additionally, the first experimental power density data for a RO-PRO system is now available. Average experimental power densities for the RO-PRO system ranged from 1.1 to 2.3 W/m2. This is higher than previous river-to-sea PRO pilot systems (1.5 W/m2) and closer to the goal of 5 W/m2 that would make PRO an economically feasible technology. Furthermore, isolated PRO system testing was performed to evaluate PRO element performance with higher cross-flow velocities and power densities exceeding 8 W/m2 were achieved with a 28 g/L NaCl draw solution. From this empirical data, inferences for future system performance can be drawn that indicate future RO-PRO systems may reduce the specific energy requirements for desalination by ∼1 kWh/m3. PMID:24798068

  7. Rapid field assessment of RO desalination of brackish agricultural drainage water.

    PubMed

    Thompson, John; Rahardianto, Anditya; Gu, Han; Uchymiak, Michal; Bartman, Alex; Hedrick, Marcos; Lara, David; Cooper, Jim; Faria, Jose; Christofides, Panagiotis D; Cohen, Yoram

    2013-05-15

    Rapid field evaluation of RO feed filtration requirements, selection of effective antiscalant type and dose, and estimation of suitable scale-free RO recovery level were demonstrated using a novel approach based on direct observation of mineral scaling and flux decline measurements, utilizing an automated Membrane Monitor (MeMo). The MeMo, operated in a stand-alone single-pass desalting mode, enabled rapid assessment of the adequacy of feed filtration by enabling direct observation of particulate deposition on the membrane surface. The diagnostic field study with RO feed water of high mineral scaling propensity revealed (via direct MeMo observation) that suspended particulates (even for feed water of turbidity <1 NTU) could serve as seeds for promoting surface crystal nucleation. With feed filtration optimized, a suitable maximum RO water recovery, with complete mineral scale suppression facilitated by an effective antiscalant dose, can be systematically and directly identified (via MeMo) in the field for a given feed water quality. Scale-free operating conditions, determined via standalone MeMo rapid diagnostic tests, were shown to be applicable to spiral-would RO system as validated via both flux decline measurements and ex-situ RO plant membrane scale monitoring. It was shown that the present approach is suitable for rapid field assessment of RO operability and it is particularly advantageous when evaluating water sources of composition that may vary both temporally and across the regions of interest. PMID:23538039

  8. Use of beta-blockers, angiotensin-converting enzyme inhibitors and angiotensin receptor blockers and breast cancer survival: Systematic review and meta-analysis.

    PubMed

    Raimondi, Sara; Botteri, Edoardo; Munzone, Elisabetta; Cipolla, Carlo; Rotmensz, Nicole; DeCensi, Andrea; Gandini, Sara

    2016-07-01

    Breast cancer (BC) is the second leading cause of cancer death among women in Western Countries. Beta-blocker (BB) drugs, angiotensin-converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARB) were suggested to have a favorable role in the development and progression of BC. We have performed a meta-analysis to clarify the potential benefits of these drugs on BC survival. A total number of 46 265 BC patients from eleven papers were included, ten independent studies on BB use and seven on ACEi/ARB use. The summary hazard ratio (SHR) was estimated by pooling the study-specific estimates with random effects models and maximum likelihood estimation. We assessed the homogeneity of the effects across studies and evaluated between-study heterogeneity by meta-regression and sensitivity analyses. We found a significant improvement in BC specific survival for patients treated with BB drugs at the time of BC diagnosis (SHR: 0.44; 95%CI: 0.26-0.73 with I(2)  = 78%). We also observed a borderline significant improvement in disease free survival for subjects treated with BB (SHR: 0.71, 95%CI: 0.19-1.03). No association of ACEi/ARB use with disease free and overall survival was found. In conclusion, we report epidemiological evidence that BB improve BC-specific survival. Clinical trials addressing this hypothesis are warranted. PMID:26916107

  9. Comparison of Alpha Blockers in Treatment of Premature Ejaculation: A Pilot Clinical Trial

    PubMed Central

    Akin, Yigit; Gulmez, Hakan; Ates, Mutlu; Bozkurt, Aliseydi; Nuhoglu, Baris

    2013-01-01

    Background: Premature ejaculation (PE) is the most common sexual disorder in men and studies reported prevalence up to 30% (1, 2). PE is not a life-threatening medical condition but it influences the quality of life (QoL). Objectives: The aim of this study was to compare the efficiency, and safety of alpha blocker drugs in the treatment of patients with premature ejaculation (PE). Additionally we investigated the quality of life (QoL) in patients with PE who were treated with alpha blocker drugs. Materials and Methods: This study was a pilot clinical trial. Prospectively documented 108 patients with PE were treated and were followed-up in urology outpatient clinic. All patients were divided into 5 groups according to used alpha blocker agents which were determined by simple randomization. Silodosin 4mg (Group 1, n = 21), tamsulosin hydrochloride 0.4mg (Group 2, n = 23), alfuzosin 10mg (Group 3, n = 22), terazosin 5mg (Group 4, n = 21), doksazosin mesylate 4mg (Group5, n = 21), were used for treatment. The demographic parameters of patients, pre and post treatment intravaginal ejaculation latency time (IELT), PE Profile (PEP), and QoL index were recorded and evaluated. Effectiveness of treatment was evaluated by measuring IELT. Additionally, side effects of drugs were recorded. P < 0.05 was considered statistically significant. Results: All alpha blocker drugs were statistically effective for preventing PE. Notably, silodosin seemed to be more effective for preventing PE than other alpha blockers (P < 0.05). However all alpha blockers provided development in QoL scores, silodosin was a little better than other drugs in statistical analyses. Furthermore statistical increase in IELT and decrease in PEP were provided more in Group 1 than other groups (P < 0.05). Conclusions: Silodosin seems to be able to even more prevent PE. Silodosin may provide development in QoL than other alpha blocker agents. Additionally, lower systemic adverse events and more effectivity are

  10. [Current topic of next generation of angiotensin II type 1 receptor blockers].

    PubMed

    Mogi, Masaki; Horiuchi, Masatsugu

    2012-09-01

    Angiotensin receptor blockers(ARBs) are used as the first-choice anti-hypertensives for prevention of multiple organ damage. Recently, the next-generation ARBs have been expected to have more preventive effect for cardiovascular diseases. For example, metabosartans which have a partial agonistic effect of peroxisome proliferator-activated receptor gamma induce an improvement of metabolism compared with ordinary ARBs. Moreover, LCZ696, ARB with a neprilysin inhibitor which increases natriuretic peptides has a significant reduction in blood pressure compared with ARB. Furthermore, ARBs with nitric oxide donor or endothelin receptor blocker have been reported to have a benefit beyond ordinary ARBs. Dual action in the next multi-functional ARBs may be a strong therapeutic contributor for patients with multiple organ dysfunction. PMID:23012813

  11. Evolution of β-blockers: from anti-anginal drugs to ligand-directed signalling.

    PubMed

    Baker, Jillian G; Hill, Stephen J; Summers, Roger J

    2011-04-01

    Sir James Black developed β-blockers, one of the most useful groups of drugs in use today. Not only are they being used for their original purpose to treat angina and cardiac arrhythmias, but they are also effective therapeutics for hypertension, cardiac failure, glaucoma, migraine and anxiety. Recent studies suggest that they might also prove useful in diseases as diverse as osteoporosis, cancer and malaria. They have also provided some of the most useful tools for pharmacological research that have underpinned the development of concepts such as receptor subtype selectivity, agonism and inverse agonism, and ligand-directed signalling bias. This article examines how β-blockers have evolved and indicates how they might be used in the future. PMID:21429598

  12. Perioperative beta-blockers for preventing surgery-related mortality and morbidity.

    PubMed

    Bolton, Nerys

    2016-03-01

    For many patients any type of surgical invention can increase their stress response which can make the body vulnerable to untoward outcomes. An extreme consequence of the stress response is death with other responses including heart attacks and stroke, to impacting on the patients' postoperative reviver such as their psychological status and pain recovery. Therefore there is a need to consider the attenuation of the perioperative stress response through the use of drugs such as beta-blockers. These drugs have been shown to reduce the heart rate and lower the patients' blood pressure. Although this is a desired result in trying to eliminate the effects of the stress response it can also have the opposite effect on reducing the patients' blood pressure and pulse to a point where the patients suffers ill effects such as stroke or death. Therefore it is vital to understand the influence of beta-blockers and their ability to influence perioperative cardiovascular morbidity and mortality. PMID:27149829

  13. Xestospongins: potent membrane permeable blockers of the inositol 1,4,5-trisphosphate receptor.

    PubMed

    Gafni, J; Munsch, J A; Lam, T H; Catlin, M C; Costa, L G; Molinski, T F; Pessah, I N

    1997-09-01

    Xestospongins (Xe's) A, C, D, araguspongine B, and demethylxestospongin B, a group of macrocyclic bis-1-oxaquinolizidines isolated from the Australian sponge, Xestospongia species, are shown to be potent blockers of IP3-mediated Ca2+ release from endoplasmic reticulum vesicles of rabbit cerebellum. XeC blocks IP3-induced Ca2+ release (IC50 = 358 nM) without interacting with the IP3-binding site, suggesting a mechanism that is independent of the IP3 effector site. Analysis of Pheochromocytoma cells and primary astrocytes loaded with Ca2+-sensitive dye reveals that XeC selectively blocks bradykinin- and carbamylcholine-induced Ca2+ efflux from endoplasmic reticulum stores. Xe's represent a new class of potent, membrane permeable IP3 receptor blockers exhibiting a high selectivity over ryanodine receptors. Xe's are a valuable tool for investigating the structure and function of IP3 receptors and Ca2+ signaling in neuronal and nonneuronal cells. PMID:9331361

  14. Beta-blockers in heart failure. The 'new wave' of clinical trials.

    PubMed

    Krum, H

    1999-08-01

    There is now considerable clinical trial data to support the use of beta-blockers in patients with congestive heart failure (CHF) due to systolic left ventricular dysfunction. A substantial database has accumulated over the last 20 years supporting the benefits of these agents on ventricular function and clinical status. In addition, morbidity and mortality benefits have been suggested, specifically with the non-selective vasodilating agent, carvedilol. More recently, a "new wave" of clinical trials have been conducted to definitively determine the mortality benefits of beta-blockers in patients with mild to moderate CHF as well as addressing other important clinical questions. These questions include whether the beneficial effects of carvedilol on survival can be reproduced by other agents in prospective, adequately powered studies; whether the benefits of carvedilol in systolic heart failure are due to its beta-blocking properties alone or to a combination of the beta-blocking and ancillary effects of the drug; whether beta-blockers are of benefit in patients with severe New York Heart Association (NYHA) Class IIIB-IV CHF; and, whether beta-blockers are of benefit (additional to ACE inhibitors) in patients with evidence of systolic ventricular dysfunction when commenced in the immediate post-myocardial infarction period. Major studies are currently being undertaken to address the above questions. Most are still underway but 3 studies have recently reported their results: the second Cardiac Insufficiency Bisoprolol Study (CIBIS II), the Research in Left Ventricular Dysfunction Study (RESOLVD), and the Metoprolol CR/XL Randomised Intervention Trial in Heart Failure (MERIT-HF) study. These studies have demonstrated that blockade with beta1-selective, non-vasodilating agents (i.e. bisoprolol and metoprolol) improve survival in patients with CHE Comparison of relative risk reduction in these recent studies with the earlier carvedilol studies raises mechanistic

  15. 2-Ethynylbenzenealkanamines: a new class of calcium entry blockers with potential antihypertensive and antianginal properties

    SciTech Connect

    Brannan, M.D.; Carson, J.R.; Gill, A.; Keely, S.L.; Flaim, S.F.; Sit, S.P.; Damiano, B.P.; Carmosin, R.R.J.; Gleason, M.M.; Ludovici, D.W.; Pitis, P.M.

    1986-03-05

    2-Ethynylbenzenealkanamines represent a newly discovered class of calcium channel blockers in that they inhibited KCl-stimulated /sup 45/Ca influx and isometric tension development in isolated vascular smooth muscle and prolonged AV-nodal conduction time in canine hearts. Testing revealed optimal activity in the following structure where R1 is aryl, R2 and R4 are methyl, R3 is aralkyl and X is methoxy: compounds in this group lowered arterial pressures in conscious spontaneously hypertensive rats and renal hypertensive dogs following either oral or parenteral administration, and thus are potential antihypertensive agents. These compounds also caused coronary vasodilation at concentrations which did not affect rate or force of contraction in the isolated, perfused guinea pig heart preparation, they increased coronary blood flow and decreased coronary vascular resistance in the anesthetized canine, and thus are potential antianginal agents. In summary, 2-ethynylbenzenealkanamines represent a new class of calcium entry blockers which have potential antihypertensive and antianginal properties.

  16. Facile diverted synthesis of pyrrolidinyl triazoles using organotrifluoroborate: discovery of potential mPTP blockers.

    PubMed

    Jung, Sun hwa; Choi, Kihang; Pae, Ae Nim; Lee, Jae Kyun; Choo, Hyunah; Keum, Gyochang; Cho, Yong Seo; Min, Sun-Joon

    2014-12-21

    This article describes the rapid and diversified synthesis of pyrrolidinyl triazoles for the discovery of mitochondrial permeability transition pore (mPTP) blockers. The 1,3-dipolar cycloaddition of ethynyl trifluoroborate with azidopyrrolidine produced a key intermediate, triazolyl trifluoroborate 4, which subsequently underwent a Suzuki-Miyaura coupling reaction to afford a series of 1,4-disubstituted triazoles 2. Subsequent biological evaluation of these derivatives indicated 2ag and 2aj as the most potent mPTP blockers exhibiting excellent cytochrome P450 (CYP) stability when compared to the previously reported oxime analogue 1. The present work clearly demonstrates that a 1,2,3-triazole can be used as a stable oxime surrogate. Furthermore, it suggests that late-stage diversification through coupling reactions of organotrifluoroborates is suitable for the rapid discovery of biologically active molecules. PMID:25348904

  17. Pharmacological correction of obesity-induced autophagy arrest using calcium channel blockers

    PubMed Central

    Park, Hwan-Woo; Park, Haeli; Semple, Ian A.; Jang, Insook; Ro, Seung-Hyun; Kim, Myungjin; Cazares, Victor A.; Stuenkel, Edward L.; Kim, Jung-Jae; Kim, Jeong Sig; Lee, Jun Hee

    2014-01-01

    Autophagy deregulation during obesity contributes to the pathogenesis of diverse metabolic disorders. However, without understanding the molecular mechanism of obesity interference in autophagy, development of therapeutic strategies for correcting such defects in obese individuals is challenging. Here we show that chronic increase of cytosolic calcium concentration in hepatocytes upon obesity and lipotoxicity attenuates autophagic flux by preventing the fusion between autophagosomes and lysosomes. As a pharmacological approach to restore cytosolic calcium homeostasis in vivo, we administered the clinically approved calcium channel blocker verapamil to obese mice. Such treatment successfully increases autophagosome-lysosome fusion in liver, preventing accumulation of protein inclusions and lipid droplets and suppressing inflammation and insulin resistance. As calcium channel blockers have been safely used in clinics for the treatment of hypertension for more than thirty years, our results suggest they may be a safe therapeutic option for restoring autophagic flux and treating metabolic pathologies in obese patients. PMID:25189398

  18. Long-term effect of β-blocker in ST-segment elevation myocardial infarction in patients with preserved left ventricular systolic function: a propensity analysis.

    PubMed

    Konishi, Hirokazu; Miyauchi, Katsumi; Kasai, Takatoshi; Tsuboi, Shuta; Ogita, Manabu; Naito, Ryo; Nishizaki, Yuji; Okai, Iwao; Tamura, Hiroshi; Okazaki, Shinya; Isoda, Kikuo; Daida, Hiroyuki

    2016-04-01

    The current guidelines for acute myocardial infarction (AMI) recommended that β-blocker should be used in patients with decreased left ventricular (LV) systolic function for long-term period. However, the effect of β-blocker in AMI patients with preserved LV systolic function is uncertain. We sought to assess the long-term effect of β-blocker in AMI patients with preserved LV systolic function. During the follow-up period (1997-2011), total 3508 patients were performed percutaneous coronary intervention (PCI). Of these patients, 424 AMI patients with preserved LV systolic function [ejection fraction (EF) > 40 %] were analyzed. Median follow-up period was 4.7 years. Then, patients were divided into two groups (β-blocker group 197 patients and no-β-blocker group 227 patients). However, there are substantial differences in baseline characteristics between two groups. Therefore, we calculated propensity score to match the patients in β-blocker and no-β-blocker groups. After post-match patients (N = 206, 103 matched pair), β-blocker therapy significantly reduced cardiac death compared with no-β-blocker [hazard ratio (HR) 0.40, p = 0.04], whereas β-blocker therapy was not associated with major adverse cardiac events (MACE) and all-cause death. β-Blocker is an effective treatment for AMI patients who underwent PCI with preserved LV systolic function. PMID:25573259

  19. Expected Performance of the CoRoT Planet Search from Light Curve Beauty Contests

    NASA Astrophysics Data System (ADS)

    Moutou, C.; Aigrain, S.; Almenara, J.; Alonso, R.; Auvergne, M.; Barge, P.; Blouin, D.; Borde, P.; Cabrera, J.; Carone, L.; Cautain, R.; Deeg, H.; Erikson, A.; Fressin, F.; Guis, V.; Leger, A.; Guterman, P.; Irwin, M.; Kabath, P.; Lanza, A.; Maceroni, C.; Mazeh, T.; Ollivier, M.; Pont, F.; Paetzold, M.; Queloz, D.; Rauer, H.; Rouan, D.; Schneider, J.; Tamuz, O.; Voss, H.; Zucker, S.

    2007-07-01

    The CoRoT space mission, scheduled for launch in December 2006, has two primary science goals: asteroseismology and the detection of planetary transits, the latter being the subject of this contribution. Given its expected photometric performance and its 150 day observing window, CoRoT will detect planets with periods up to 75 days and radii down to 2 Earth radii. To prepare for the data analysis and evaluate the detection limits of the mission, a number of blind exercises to detect planets in simulated light curves have been carried out within the CoRoT exoplanet community, and their results to date are summarized here.

  20. Transiting exoplanets from the CoRoT space mission. XXIV. CoRoT-25b and CoRoT-26b: two low-density giant planets

    NASA Astrophysics Data System (ADS)

    Almenara, J. M.; Bouchy, F.; Gaulme, P.; Deleuil, M.; Havel, M.; Gandolfi, D.; Deeg, H. J.; Wuchterl, G.; Guillot, T.; Gardes, B.; Pasternacki, T.; Aigrain, S.; Alonso, R.; Auvergne, M.; Baglin, A.; Bonomo, A. S.; Bordé, P.; Cabrera, J.; Carpano, S.; Cochran, W. D.; Csizmadia, Sz.; Damiani, C.; Diaz, R. F.; Dvorak, R.; Endl, M.; Erikson, A.; Ferraz-Mello, S.; Fridlund, M.; Hébrard, G.; Gillon, M.; Guenther, E.; Hatzes, A.; Léger, A.; Lammer, H.; MacQueen, P. J.; Mazeh, T.; Moutou, C.; Ollivier, M.; Ofir, A.; Pätzold, M.; Parviainen, H.; Queloz, D.; Rauer, H.; Rouan, D.; Santerne, A.; Samuel, B.; Schneider, J.; Tal-Or, L.; Tingley, B.; Weingrill, J.

    2013-07-01

    We report the discovery of two transiting exoplanets, CoRoT-25b and CoRoT-26b, both of low density, one of which is in the Saturn mass-regime. For each star, ground-based complementary observations through optical photometry and radial velocity measurements secured the planetary nature of the transiting body and allowed us to fully characterize them. For CoRoT-25b we found a planetary mass of 0.27 ± 0.04 MJup, a radius of 1.08-0.10+0.3 RJup and hence a mean density of 0.15-0.06+0.15 g cm-3. The planet orbits an F9 main-sequence star in a 4.86-day period, that has a V magnitude of 15.0, solar metallicity, and an age of 4.5-2.0+1.8-Gyr. CoRoT-26b orbits a slightly evolved G5 star of 9.06 ± 1.5-Gyr age in a 4.20-day period that hassolar metallicity and a V magnitude of 15.8. With a mass of 0.52 ± 0.05 MJup, a radius of 1.26-0.07+0.13 RJup, and a mean density of 0.28-0.07+0.09 g cm-3, it belongs to the low-mass hot-Jupiter population. Planetary evolution models allowed us to estimate a core mass of a few tens of Earth mass for the two planets with heavy-element mass fractions of 0.52-0.15+0.08 and 0.26-0.08+0.05, respectively, assuming that a small fraction of the incoming flux is dissipated at the center of the planet. In addition, these models indicate that CoRoT-26b is anomalously large compared with what standard models could account for, indicating that dissipation from stellar heating could cause this size. The CoRoT space mission, launched on December 27th 2006, has been developed and is operated by CNES, with the contribution of Austria, Belgium, Brazil, ESA (RSSD and Science Programme), Germany and Spain. Partly based on observations obtained at the European Southern Observatory at Paranal and La Silla, Chile in programs 083.C-0690(A), 184.C-0639.

  1. Individual patient data meta-analysis of beta-blockers in heart failure: rationale and design

    PubMed Central

    2013-01-01

    Abstract The Beta-Blockers in Heart Failure Collaborative Group (BB-HF) was formed to obtain and analyze individual patient data from the major randomized controlled trials of beta-blockers in heart failure. Even though beta-blockers are an established treatment for heart failure, uptake is still sub-optimal. Further, the balance of efficacy and safety remains uncertain for common groups including older persons, women, those with impaired renal function and diabetes. Our aim is to provide clinicians with a thorough and definitive evidence-based assessment of these agents. We have identified 11 large randomized trials of beta-blockers versus placebo in heart failure and plan to meta-analyze the data on an individual patient level. In total, these trials have enrolled 18,630 patients. Uniquely, the BB-HF group has secured access to the individual data for all of these trials, with the participation of key investigators and pharmaceutical companies. Our principal objectives include deriving an overall estimate of efficacy for all-cause mortality and cardiovascular hospitalization. Importantly, we propose a statistically-robust sub-group assessment according to age, gender, diabetes and other key factors; analyses which are only achievable using an individual patient data meta-analysis. Further, we aim to provide an assessment of economic benefit and develop a risk model for the prognosis of patients with chronic heart failure. This paper outlines inclusion criteria, search strategies, outcome measures and planned statistical analyses. Trial registration Clinical trial registration information: http://clinicaltrials.gov/ct2/show/NCT00832442 PMID:23327629

  2. Calcium balance in pea root statocytes under both clinorotation and Ca2+ channel blockers' influence

    NASA Astrophysics Data System (ADS)

    Belyavskaya, Ninel A.; Tsarik, Nina P.

    We have previously demonstrated that space flight and clinorotation conditions increase cytoplasmic Ca^2+ level in pea root statocytes. A rise in [Ca^2+]_i may be a serious problem for plants in microgravity environment. It is hypothesized that involvement of Ca^2+ channel blockers in the growth medium may rescue a plant from abundance of Ca^2+ ions. Indeed, combination of clinorotation (2 rpm, 5 days) and any Ca^2+ channel blocker (1 μm D600 or nicardipine, 12 hr) causes decreasing the Ca^2+ concentration in pea root statocytes in comparison with clinorotation alone. Redistribution of Ca^2+-ATPase activities observed under clinorotation comes to normal after D600 application whereas following by nicardipine action the pattern of the cytochemical staining is intermediate between those in stationary control and under clinorotation. Our data support the hypothesis that Ca^2+ channel blockers may act as protectors for plants against rise in [Ca^2+]i. The role for Ca^2+ channels in graviperception and in microgravity effects as well as ways for stabilization of Ca^2+ balance in plant cells in space flights are discussed.

  3. Angiotensin II receptor blockers: a new possible treatment for chronic migraine?

    PubMed

    Disco, Caterina; Maggioni, Ferdinando; Zanchin, Giorgio

    2015-08-01

    The objective is to suggest a possible role of different angiotensin receptor blockers in the treatment of chronic migraine, especially in hypertensive subjects. Chronic migraine is a highly disabling disorder affecting between 1.4 and 2.2 % of the general population. Despite many pharmacological and non-pharmacological treatments proposed, the results are rather discouraging. Therefore, we believe that should be highlighted all the possible therapies that may lead to an improvement of the symptomatology. Particularly, data available on efficacy of ARBs in preventing chronic migraine are poor. Methods include case reports, literature review and discussion. We report three cases recently treated with angiotensin II receptor blockers that showed a significant improvement, never previously presented with more conventional treatments, including beta blockers. In all three cases, we obtained the reversibility from a chronic migraine to an episodic. Taking a cue from this observation, we consider desirable large controlled, randomized trials to assess the effectiveness of ARBs both in CM hypertensive patients and in patients who do not require anti-hypertensive therapy; furthermore are desirable comparative studies between the various ARB inhibitors to assay any intermolecular differences in efficacy. PMID:25917398

  4. How Administration of the Beta-Blocker Propranolol Before Extinction can Prevent the Return of Fear.

    PubMed

    Kroes, Marijn C W; Tona, Klodiana-Daphne; den Ouden, Hanneke E M; Vogel, Susanne; van Wingen, Guido A; Fernández, Guillén

    2016-05-01

    Combining beta-blockers with exposure therapy has been advocated to reduce fear, yet experimental studies combining beta-blockers with memory reactivation have had contradictory results. We explored how beta-blockade might affect the course of safety learning and the subsequent return of fear in a double-blind placebo-controlled functional magnetic resonance imaging study in humans (N=46). A single dose of propranolol before extinction learning caused a loss of conditioned fear responses, and prevented the subsequent return of fear and decreased explicit memory for the fearful events in the absence of drug. Fear-related neural responses were persistently attenuated in the dorsal medial prefrontal cortex (dmPFC), increased in the hippocampus 24 h later, and correlated with individual behavioral indices of fear. Prediction error-related responses in the ventral striatum persisted during beta-blockade. We suggest that this pattern of results is most consistent with a model where beta-blockade can prevent the return of fear by (i) reducing retrieval of fear memory, via the dmPFC and (ii) increasing contextual safety learning, via the hippocampus. Our findings suggest that retrieval of fear memory and contextual safety learning form potential mnemonic target mechanisms to optimize exposure-based therapy with beta-blockers. PMID:26462618

  5. Effects of calcium channel blockers on gastric emptying and acid secretion of the rat in vivo.

    PubMed Central

    Brage, R.; Cortijo, J.; Esplugues, J.; Esplugues, J. V.; Martí-Bonmatí, E.; Rodriguez, C.

    1986-01-01

    Experiments were designed to evaluate the effects of three calcium channel blockers (verapamil, diltiazem and cinnarizine) on gastric emptying and secretion in the rat. Pretreatment with the calcium blockers delayed gastric emptying of phenol red in a dose-dependent manner. Verapamil was the most effective of the agents tested. Verapamil and diltiazem inhibited gastric acid secretion in the pylorus-ligated rat without affecting pepsin output. Cinnarizine was ineffective in this model. When the perfused lumen of the anaesthetized rat was used, verapamil was found to inhibit responses to carbachol or histamine more than those to pentagastrin. Further, we found a greater sensitivity to verapamil for basal compared with vagal-stimulated (2-deoxy-D-glucose) acid secretion. Neither diltiazem nor cinnarizine modified gastric acid secretion in this experimental model. These findings are discussed in relation to the role of extracellular calcium in gastric motility and secretion, and the existence of a regional and functional selectivity for calcium blockers is proposed. PMID:3814903

  6. α-Blockers for the Treatment of Chronic Prostatitis/Chronic Pelvic Pain Syndrome: An Update on Current Clinical Evidence

    PubMed Central

    Nickel, J. Curtis; Touma, Naji

    2012-01-01

    The pathogenesis of chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is multifactorial, making its treatment difficult. Multimodal therapy including α-adrenergic antagonists (α-blockers), anti-inflammatory agents, and other pain treatments may provide optimal management for CP/CPPS. Although α-blockers are the most prescribed drugs for patients with CP/CPPS, not all studies support their efficacy. A recent meta-analysis of small trials suggested that treatment with α-blockers, possibly in combination with antibacterial agents, is efficacious in relieving symptoms. Third-generation α1A blockers (silodosin, tamsulosin) may provide efficacy as well as reduced cardiovascular side effects. Future research should aim to identify potential biomarkers associated with treatment response. PMID:23526487

  7. Transiting exoplanets from the CoRoT space mission. VIII. CoRoT-7b: the first super-Earth with measured radius

    NASA Astrophysics Data System (ADS)

    Léger, A.; Rouan, D.; Schneider, J.; Barge, P.; Fridlund, M.; Samuel, B.; Ollivier, M.; Guenther, E.; Deleuil, M.; Deeg, H. J.; Auvergne, M.; Alonso, R.; Aigrain, S.; Alapini, A.; Almenara, J. M.; Baglin, A.; Barbieri, M.; Bruntt, H.; Bordé, P.; Bouchy, F.; Cabrera, J.; Catala, C.; Carone, L.; Carpano, S.; Csizmadia, Sz.; Dvorak, R.; Erikson, A.; Ferraz-Mello, S.; Foing, B.; Fressin, F.; Gandolfi, D.; Gillon, M.; Gondoin, Ph.; Grasset, O.; Guillot, T.; Hatzes, A.; Hébrard, G.; Jorda, L.; Lammer, H.; Llebaria, A.; Loeillet, B.; Mayor, M.; Mazeh, T.; Moutou, C.; Pätzold, M.; Pont, F.; Queloz, D.; Rauer, H.; Renner, S.; Samadi, R.; Shporer, A.; Sotin, Ch.; Tingley, B.; Wuchterl, G.; Adda, M.; Agogu, P.; Appourchaux, T.; Ballans, H.; Baron, P.; Beaufort, T.; Bellenger, R.; Berlin, R.; Bernardi, P.; Blouin, D.; Baudin, F.; Bodin, P.; Boisnard, L.; Boit, L.; Bonneau, F.; Borzeix, S.; Briet, R.; Buey, J.-T.; Butler, B.; Cailleau, D.; Cautain, R.; Chabaud, P.-Y.; Chaintreuil, S.; Chiavassa, F.; Costes, V.; Cuna Parrho, V.; de Oliveira Fialho, F.; Decaudin, M.; Defise, J.-M.; Djalal, S.; Epstein, G.; Exil, G.-E.; Fauré, C.; Fenouillet, T.; Gaboriaud, A.; Gallic, A.; Gamet, P.; Gavalda, P.; Grolleau, E.; Gruneisen, R.; Gueguen, L.; Guis, V.; Guivarc'h, V.; Guterman, P.; Hallouard, D.; Hasiba, J.; Heuripeau, F.; Huntzinger, G.; Hustaix, H.; Imad, C.; Imbert, C.; Johlander, B.; Jouret, M.; Journoud, P.; Karioty, F.; Kerjean, L.; Lafaille, V.; Lafond, L.; Lam-Trong, T.; Landiech, P.; Lapeyrere, V.; Larqué, T.; Laudet, P.; Lautier, N.; Lecann, H.; Lefevre, L.; Leruyet, B.; Levacher, P.; Magnan, A.; Mazy, E.; Mertens, F.; Mesnager, J.-M.; Meunier, J.-C.; Michel, J.-P.; Monjoin, W.; Naudet, D.; Nguyen-Kim, K.; Orcesi, J.-L.; Ottacher, H.; Perez, R.; Peter, G.; Plasson, P.; Plesseria, J.-Y.; Pontet, B.; Pradines, A.; Quentin, C.; Reynaud, J.-L.; Rolland, G.; Rollenhagen, F.; Romagnan, R.; Russ, N.; Schmidt, R.; Schwartz, N.; Sebbag, I.; Sedes, G.; Smit, H.; Steller, M. B.; Sunter, W.; Surace, C.; Tello, M.; Tiphène, D.; Toulouse, P.; Ulmer, B.; Vandermarcq, O.; Vergnault, E.; Vuillemin, A.; Zanatta, P.

    2009-10-01

    Aims: We report the discovery of very shallow (Δ F/F ≈ 3.4× 10-4), periodic dips in the light curve of an active V = 11.7 G9V star observed by the CoRoT satellite, which we interpret as caused by a transiting companion. We describe the 3-colour CoRoT data and complementary ground-based observations that support the planetary nature of the companion. Methods: We used CoRoT colours information, good angular resolution ground-based photometric observations in- and out- of transit, adaptive optics imaging, near-infrared spectroscopy, and preliminary results from radial velocity measurements, to test the diluted eclipsing binary scenarios. The parameters of the host star were derived from optical spectra, which were then combined with the CoRoT light curve to derive parameters of the companion. Results: We examined all conceivable cases of false positives carefully, and all the tests support the planetary hypothesis. Blends with separation >0.40´´or triple systems are almost excluded with a 8 × 10-4 risk left. We conclude that, inasmuch we have been exhaustive, we have discovered a planetary companion, named CoRoT-7b, for which we derive a period of 0.853 59 ± 3 × 10-5 day and a radius of Rp = 1.68 ± 0.09 R_Earth. Analysis of preliminary radial velocity data yields an upper limit of 21 M_Earth for the companion mass, supporting the finding. Conclusions: CoRoT-7b is very likely the first Super-Earth with a measured radius. This object illustrates what will probably become a common situation with missions such as Kepler, namely the need to establish the planetary origin of transits in the absence of a firm radial velocity detection and mass measurement. The composition of CoRoT-7b remains loosely constrained without a precise mass. A very high surface temperature on its irradiated face, ≈1800-2600 K at the substellar point, and a very low one, ≈50 K, on its dark face assuming no atmosphere, have been derived. The CoRoT space mission, launched on 27

  8. Influence of beta-blockers on the myocardial mRNA expressions of circadian clock- and metabolism-related genes.

    PubMed

    Ushijima, Kentarou; Maekawa, Tomohiro; Ishikawa-Kobayashi, Eiko; Ando, Hitoshi; Shiga, Tsuyoshi; Fujimura, Akio

    2013-01-01

    Daily rhythms are regulated by a master clock-system in the suprachiasmatic nucleus and by a peripheral clock-system in each organ. Because norepinephrine is one of the timekeepers for the myocardial circadian clock that influences cardiac metabolism, it is speculated that a beta-blocker may affect the circadian clock and metabolism in heart tissue. In this study, thirty mg/kg/day of propranolol (a lipophilic beta-blocker) or atenolol (a hydrophilic beta-blocker) was given orally to Wistar rats for 4 weeks. The mRNA expressions of Bmal1 and E4BP4 in heart tissue were suppressed by the beta-blockers. However, the mRNA expressions of these clock genes in the suprachiasmatic nucleus were unchanged. Myocardial mRNA expressions of lactate dehydrogenase a and pyruvate dehydrogenase kinase 4 were also suppressed by the beta-blockers. In addition, ATP content in heart tissue was significantly elevated by the beta-blockers throughout 24 hours. The effects of propranolol and atenolol did not differ significantly. This study showed for the first time that a beta-blocker affects myocardial clock gene expression. Propranolol and atenolol increased ATP content in heart tissue throughout 24 hours. The influences of beta-blockers may be negligible on the SCN, and may be independent of lipid solubility on heart tissue. It is well known that these drugs exert a protective effect against myocardial ischemia, which may be mediated by an increase in the preservation of myocardial ATP. PMID:23394803

  9. Quality of life in functional rhinoplasty: rhinoplasty outcomes evaluation German version (ROE-D).

    PubMed

    Bulut, Olcay Cem; Plinkert, Peter K; Wallner, Frank; Baumann, Ingo

    2016-09-01

    The aim of this study was to validate a German version of the rhinoplasty outcomes evaluation (ROE) questionnaire. A prospective study was conducted and a German translated ROE (ROE-D) questionnaire administered to 100 patients preoperatively, 6 and 12 months postoperatively. The translation was performed according to internationally accepted guidelines. To validate this instrument, we evaluated its reliability, validity and sensitivity. ROE-D was completed by 54 patients after 6 months and by 69 patients 1 year after functional rhinoplasty. Cronbach's α indicated good internal consistency. Reliability was tested with a split-half-reliability, showing significant correlation. Discrimination validity was demonstrated by a comparison with healthy controls. Sensitivity to change showed medium to large effects. ROE-D is a reliable, validated and sensitive German instrument for measuring health-related quality of life in patients after rhinoplasty. The ROE-D focuses mainly on the aesthetic aspects of the rhinoplasty surgery. PMID:26864439

  10. Micro-Electro-Mechanical-Systems-Based Micro-Ro-Boat Utilizing Steam as Propulsion Power

    NASA Astrophysics Data System (ADS)

    Choi, Ju Chan; Choi, Young Chan; Kyoo Lee, June; Kong, Seong Ho

    2012-06-01

    We report the design and fabrication of a micro-electro-mechanical-systems (MEMS)-based microactuator, that floats on the surface of water and is driven by steam. We named the actuator “micro-Ro-boat”, a compound word created from the words “robot” and “boat”. The MEMS-based micro-Ro-boat utilizes steam as the propulsion power, giving it a high speed and long lifetime. A hydrophobic surface has been utilized for the wing of the actuator to enhance the buoyancy. Instead of using gas or fuel, the proposed micro-Ro-boat utilizes steam form electrically heated water. The velocity of the micro-Ro-boat is in the range of 0.5-2 cm/s and the maximum loading capability for a device size of 10 ×10 mm2 is 0.4 g.

  11. The influence of antiscalants on biofouling of RO membranes in seawater desalination.

    PubMed

    Sweity, Amer; Oren, Yoram; Ronen, Zeev; Herzberg, Moshe

    2013-06-15

    Antiscalants are surface active polyelectrolyte compounds commonly used in reverse osmosis (RO) desalination processes to avoid membrane scaling. In spite of the significant roles of antiscalants in preventing membrane scaling, they are prone to enhance biofilm growth on RO membranes by either altering membrane surface properties or by serving as nutritional source for microorganisms. In this study, the contribution of antiscalants to membrane biofouling in seawater desalination was investigated. The effects of two commonly used antiscalants, polyphosphonate- and polyacrylate-based, were tested. The effects of RO membrane (DOW-Filmtec SW30 HRLE-400) exposure to antiscalants on its physico-chemical properties were studied, including the consequent effects on initial deposition and growth of the sessile microorganisms on the RO membrane surface. The effects of antiscalants on membrane physico-chemical properties were investigated by filtration of seawater supplemented with the antiscalants through flat-sheet RO membrane and changes in surface zeta potential and hydrophobicity were delineated. Adsorption of antiscalants to polyamide surfaces simulating RO membrane's polyamide layer and their effects on the consequent bacterial adhesion was tested using a quartz crystal microbalance with dissipation monitoring technology (QCM-D) and direct fluorescent microscopy. A significant increase in biofilm formation rate on RO membranes surface was observed in the presence of both types of antiscalants. Polyacrylate-based antiscalant was shown to enhance initial cell attachment as observed with the QCM-D and a parallel plate flow cell, due to rendering the polyamide surface more hydrophobic. Polyphosphonate-based antiscalants also increased biofilm formation rate, most likely by serving as an additional source of phosphorous to the seawater microbial population. A thicker biofilm layer was formed on the RO membrane when the polyacrylate-based antiscalant was used. Following

  12. Two tarantula venom peptides as potent and differential Na(V) channels blockers.

    PubMed

    Cherki, Ronit S; Kolb, Ela; Langut, Yael; Tsveyer, Lior; Bajayo, Nissim; Meir, Alon

    2014-01-01

    Voltage dependent sodium (Na(V)) channels are large membrane spanning proteins which lie in the basis of action potential generation and propagation in excitable cells and hence are essential mediators of neuronal signaling. Inhibition of Na(V) channel activity is one of the core mechanisms to treat conditions related to neuronal hyperexcitability, such as epilepsy in the clinic. Na(V) channel blockers are also extensively used to locally inhibit action potential generation and related pain perceptions in the form of local anesthetics. Here we describe the isolation, biochemical characterization, synthesis and in vitro characterization of two potent Na(V) channel blockers from the venom of the Paraphysa scrofa (Phrixotrichus auratus) tarantula spider. Both Voltage sensor toxin 3 (VSTx-3, κ-theraphotoxin-Gr4a) and GTx1-15 (Toxin Gtx1-15), were originally isolated from the venom of the related tarantula Grammostola rosea and described as K(V) and Ca(V) channel blockers, respectively. In our hands, GTx1-15 was shown to be a potent inhibitor of tetrodotoxin (TTX)-sensitive channels (IC₅₀ 0.007 μM for hNa(V)1.7 and 0.12 μM for hNa(V)1.3 channels), with very little effect on TTX-resistant (Na(V)1.5 and NaV1.8) channels. VSTx-3 was demonstrated to be a potent, TTX-sensitive sodium channel blocker and especially, potent blocker of Na(V)1.8 channels (IC₅₀ 0.19 μM for hNa(V)1.3, 0.43 μM for hNa(V)1.7 and 0.77 μM for hNa(V)1.8 channels). Such potent inhibitors with differential selectivity among Na(V) channel isoforms may be used as tools to study the roles of the different channels in processes related to hyperexcitability and as lead compounds to treat pathological pain conditions. PMID:24211312

  13. CoRoT-7b: SUPER-EARTH OR SUPER-Io?

    SciTech Connect

    Barnes, Rory; Kaib, Nathan A.; Raymond, Sean N.; Greenberg, Richard; Jackson, Brian

    2010-02-01

    CoRoT-7b, a planet about 70% larger than the Earth orbiting a Sun-like star, is the first-discovered rocky exoplanet, and hence has been dubbed a 'super-Earth'. Some initial studies suggested that since the planet is so close to its host star, it receives enough insolation to partially melt its surface. However, these past studies failed to take into consideration the role that tides may play in this system. Even if the planet's eccentricity has always been zero, we show that tidal decay of the semimajor axis could have been large enough that the planet formed on a wider orbit which received less insolation. Moreover, CoRoT-7b could be tidally heated at a rate that dominates its geophysics and drives extreme volcanism. In this case, CoRoT-7b is a 'super-Io' that, like Jupiter's volcanic moon, is dominated by volcanism and rapid resurfacing. Such heating could occur with an eccentricity of just 10{sup -5}. This small value could be driven by CoRoT-7c if its own eccentricity is larger than {approx}10{sup -4}. CoRoT-7b may be the first of a class of planetary super-Ios likely to be revealed by the CoRoT and Kepler spacecraft.

  14. Planets and Stellar Activity: Hide and Seek in the CoRoT-7 system

    NASA Astrophysics Data System (ADS)

    Haywood, R. D.; Cameron, A. C.; Queloz, D.; Barros, S. C. C.; Deleuil, M.; Fares, R.; Gillon, M.; Hatzes, A.; Lanza, A. F.; Lovis, C.; Moutou, C.; Pepe, F.; Pollacco, D.; Santerne, A.; Ségransan, D.; Unruh, Y.

    2014-01-01

    Since the discovery of the transiting Super-Earth CoRoT-7b, several investigations have been made of the number and precise masses of planets present in the system, but they all yield different results, owing to the star's high level of activity. Radial velocity (RV) variations induced by stellar activity therefore need to be modelled and removed to allow a reliable detection of all planets in the system. We re-observed CoRoT-7 in January 2012 with both HARPS and the CoRoT satellite, so that we now have the benefit of simultaneous RV and photometric data. We fitted the off-transit variations in the CoRoT lightcurve using a harmonic decomposition similar to that implemented in Queloz et al. (2009). This fit was then used to model the stellar RV contribution, according to the methods described by Aigrain et al. (2011). This model was incorporated into a Monte Carlo Markov Chain in order to make a precise determination of the orbits of CoRoT-7b and CoRoT-7c. We also assess the evidence for the presence of one or two additional planetary companions.

  15. CoRoT-7b: Super-Earth or Super-Io?

    NASA Astrophysics Data System (ADS)

    Barnes, Rory; Raymond, Sean N.; Greenberg, Richard; Jackson, Brian; Kaib, Nathan A.

    2010-02-01

    CoRoT-7b, a planet about 70% larger than the Earth orbiting a Sun-like star, is the first-discovered rocky exoplanet, and hence has been dubbed a "super-Earth." Some initial studies suggested that since the planet is so close to its host star, it receives enough insolation to partially melt its surface. However, these past studies failed to take into consideration the role that tides may play in this system. Even if the planet's eccentricity has always been zero, we show that tidal decay of the semimajor axis could have been large enough that the planet formed on a wider orbit which received less insolation. Moreover, CoRoT-7b could be tidally heated at a rate that dominates its geophysics and drives extreme volcanism. In this case, CoRoT-7b is a "super-Io" that, like Jupiter's volcanic moon, is dominated by volcanism and rapid resurfacing. Such heating could occur with an eccentricity of just 10-5. This small value could be driven by CoRoT-7c if its own eccentricity is larger than ~10-4. CoRoT-7b may be the first of a class of planetary super-Ios likely to be revealed by the CoRoT and Kepler spacecraft.

  16. Transiting exoplanets from the CoRoT space mission. XXVII. CoRoT-28b, a planet orbiting an evolved star, and CoRoT-29b, a planet showing an asymmetric transit

    NASA Astrophysics Data System (ADS)

    Cabrera, J.; Csizmadia, Sz.; Montagnier, G.; Fridlund, M.; Ammler-von Eiff, M.; Chaintreuil, S.; Damiani, C.; Deleuil, M.; Ferraz-Mello, S.; Ferrigno, A.; Gandolfi, D.; Guillot, T.; Guenther, E. W.; Hatzes, A.; Hébrard, G.; Klagyivik, P.; Parviainen, H.; Pasternacki, Th.; Pätzold, M.; Sebastian, D.; Tadeu dos Santos, M.; Wuchterl, G.; Aigrain, S.; Alonso, R.; Almenara, J.-M.; Armstrong, J. D.; Auvergne, M.; Baglin, A.; Barge, P.; Barros, S. C. C.; Bonomo, A. S.; Bordé, P.; Bouchy, F.; Carpano, S.; Chaffey, C.; Deeg, H. J.; Díaz, R. F.; Dvorak, R.; Erikson, A.; Grziwa, S.; Korth, J.; Lammer, H.; Lindsay, C.; Mazeh, T.; Moutou, C.; Ofir, A.; Ollivier, M.; Pallé, E.; Rauer, H.; Rouan, D.; Samuel, B.; Santerne, A.; Schneider, J.

    2015-07-01

    Context. We present the discovery of two transiting extrasolar planets by the satellite CoRoT. Aims: We aim at a characterization of the planetary bulk parameters, which allow us to further investigate the formation and evolution of the planetary systems and the main properties of the host stars. Methods: We used the transit light curve to characterize the planetary parameters relative to the stellar parameters. The analysis of HARPS spectra established the planetary nature of the detections, providing their masses. Further photometric and spectroscopic ground-based observations provided stellar parameters (log g, Teff, v sin i) to characterize the host stars. Our model takes the geometry of the transit to constrain the stellar density into account, which when linked to stellar evolutionary models, determines the bulk parameters of the star. Because of the asymmetric shape of the light curve of one of the planets, we had to include the possibility in our model that the stellar surface was not strictly spherical. Results: We present the planetary parameters of CoRoT-28b, a Jupiter-sized planet (mass 0.484 ± 0.087 MJup; radius 0.955 ± 0.066 RJup) orbiting an evolved star with an orbital period of 5.208 51 ± 0.000 38 days, and CoRoT-29b, another Jupiter-sized planet (mass 0.85 ± 0.20 MJup; radius 0.90 ± 0.16 RJup) orbiting an oblate star with an orbital period of 2.850 570 ± 0.000 006 days. The reason behind the asymmetry of the transit shape is not understood at this point. Conclusions: These two new planetary systems have very interesting properties and deserve further study, particularly in the case of the star CoRoT-29. The CoRoT space mission, launched on December 27th 2006, was developed and is operated by CNES, with the contribution of Austria, Belgium, Brazil, ESA (RSSD and Science Programme), Germany, and Spain. Based on observations obtained with the Nordic Optical Telescope, operated on the island of La Palma jointly by Denmark, Finland, Iceland

  17. Interactions between dendrotoxin, a blocker of voltage-dependent potassium channels, and charybdotoxin, a blocker of calcium-activated potassium channels, at binding sites on neuronal membranes.

    PubMed

    Harvey, A L; Marshall, D L; De-Allie, F A; Strong, P N

    1989-08-30

    Dendrotoxin I (DpI) from black mamba venom (Dendroaspis polylepis) has high affinity binding sites on rat brain synaptic membranes. Native DpI displaced [125I]-DpI binding with a Ki of 1 x 10(-10) M, and over 90% of specific binding was displaceable. Charybdotoxin isolated from the Israeli scorpion venom (Leiurus quinquestriatus hebraeus), also displaced [125I]-DpI binding, with a Ki of approximately 3 x 10(-9) M, although the displacement curve was shallower than with native DpI. Both toxins are thought to be high affinity blockers of specific K+ currents. Charybdotoxin selectively blocks some types of Ca2+-activated K+ channels, whereas dendrotoxins only block certain voltage-dependent K+ channels. The interaction between the two types of toxin at the DpI binding site is unexpected and may suggest the presence of related binding sites on different K+ channel proteins. PMID:2476127

  18. Implications of Plasma Protein Binding for Pharmacokinetics and Pharmacodynamics of the γ-Secretase Inhibitor RO4929097

    PubMed Central

    Wu, Jianmei; LoRusso, Patricia M.; Matherly, Larry H.; Li, Jing

    2013-01-01

    Purpose Understanding of plasma protein binding will provide mechanistic insights into drug interactions or unusual pharmacokinetic properties. This study investigated RO4929097 binding in plasma and its implications for the pharmacokinetics and pharmacodynamics of this compound. Experimental Design RO4929097 binding to plasma proteins was determined using a validated equilibrium dialysis method. Pharmacokinetics of total and unbound RO4929097 was evaluated in eight patients with breast cancer receiving RO4929097 alone and in combination with the Hedgehog inhibitor GDC-0449. The impact of protein binding on RO4929097 pharmacodynamics was assessed using an in vitro Notch cellular assay. Results RO4929097 was extensively bound in human plasma, with the total binding constant of 1.0 × 106 and 1.8 × 104 L/mol for α1-acid glycoprotein (AAG) and albumin, respectively. GDC-0449 competitively inhibited RO4929097 binding to AAG. In patients, RO4929097 fraction unbound (Fu) exhibited large intra- and interindividual variability; GDC-0449 increased RO4929097 Fu by an average of 3.7-fold. Concomitant GDC-0449 significantly decreased total (but not unbound) RO4929097 exposure. RO4929097 Fu was strongly correlated with the total drug exposure. Binding to AAG abrogated RO4929097 in vitro Notch-inhibitory activity. Conclusions RO4929097 is highly bound in human plasma with high affinity to AAG. Changes in plasma protein binding caused by concomitant drug (e.g., GDC-0449) or disease states (e.g., ↑AAG level in cancer) can alter total (but not unbound) RO4929097 exposure. Unbound RO4929097 is pharmacologically active. Monitoring of unbound RO4929097 plasma concentration is recommended to avoid misleading conclusions on the basis of the total drug levels. PMID:22351688

  19. Transiting exoplanets from the CoRoT space mission. XVIII. CoRoT-18b: a massive hot Jupiter on a prograde, nearly aligned orbit

    NASA Astrophysics Data System (ADS)

    Hébrard, G.; Evans, T. M.; Alonso, R.; Fridlund, M.; Ofir, A.; Aigrain, S.; Guillot, T.; Almenara, J. M.; Auvergne, M.; Baglin, A.; Barge, P.; Bonomo, A. S.; Bordé, P.; Bouchy, F.; Cabrera, J.; Carone, L.; Carpano, S.; Cavarroc, C.; Csizmadia, Sz.; Deeg, H. J.; Deleuil, M.; Díaz, R. F.; Dvorak, R.; Erikson, A.; Ferraz-Mello, S.; Gandolfi, D.; Gibson, N.; Gillon, M.; Guenther, E.; Hatzes, A.; Havel, M.; Jorda, L.; Lammer, H.; Léger, A.; Llebaria, A.; Mazeh, T.; Moutou, C.; Ollivier, M.; Parviainen, H.; Pätzold, M.; Queloz, D.; Rauer, H.; Rouan, D.; Santerne, A.; Schneider, J.; Tingley, B.; Wuchterl, G.

    2011-09-01

    We report the detection of CoRoT-18b, a massive hot Jupiter transiting in front of its host star with a period of 1.9000693 ± 0.0000028 days. This planet was discovered thanks to photometric data secured with the CoRoT satellite combined with spectroscopic and photometric ground-based follow-up observations. The planet has a mass Mp = 3.47 ± 0.38 MJup, a radius Rp = 1.31 ± 0.18 RJup, and a density ρp = 2.2 ± 0.8 g cm-3. It orbits a G9V star with a mass M⋆ = 0.95 ± 0.15 M⊙, a radius R⋆ = 1.00 ± 0.13 R⊙, and arotation period Prot = 5.4 ± 0.4 days. The age of the system remains uncertain, with stellar evolution models pointing either to a few tens Ma or several Ga, while gyrochronology and lithium abundance point towards ages of a few hundred Ma. This mismatch potentially points to a problem in our understanding of the evolution of young stars, with possibly significant implications for stellar physics and the interpretation of inferred sizes of exoplanets around young stars. We detected the Rossiter-McLaughlin anomaly in the CoRoT-18 system thanks to the spectroscopic observation of a transit. We measured the obliquity ψ = 20° ± 20° (sky-projected value λ = -10° ± 20°), indicating that the planet orbits in the same way as the star is rotating and that this prograde orbit is nearly aligned with the stellar equator. The CoRoT space mission, launched on 2006 December 27, has been developed and is operated by CNES, with the contribution of Austria, Belgium, Brazil, ESA (RSSD and Science Programme), Germany and Spain.Table 2 is available in electronic form at http://www.aanda.org

  20. Transiting exoplanets from the CoRoT space mission. XXIII. CoRoT-21b: a doomed large Jupiter around a faint subgiant star

    NASA Astrophysics Data System (ADS)

    Pätzold, M.; Endl, M.; Csizmadia, Sz.; Gandolfi, D.; Jorda, L.; Grziwa, S.; Carone, L.; Pasternacki, T.; Aigrain, S.; Almenara, J. M.; Alonso, R.; Auvergne, M.; Baglin, A.; Barge, P.; Bonomo, A. S.; Bordé, P.; Bouchy, F.; Cabrera, J.; Cavarroc, C.; Cochran, W. B.; Deleuil, M.; Deeg, H. J.; Díaz, R.; Dvorak, R.; Erikson, A.; Ferraz-Mello, S.; Fridlund, M.; Gillon, M.; Guillot, T.; Hatzes, A.; Hébrard, G.; Léger, A.; Llebaria, A.; Lammer, H.; MacQueen, P. J.; Mazeh, T.; Moutou, C.; Ofir, A.; Ollivier, M.; Parviainen, H.; Queloz, D.; Rauer, H.; Rouan, D.; Santerne, A.; Schneider, J.; Tingley, B.; Weingrill, J.; Wuchterl, G.

    2012-09-01

    CoRoT-21, a F8IV star of magnitude V = 16 mag, was observed by the space telescope CoRoT during the Long Run 01 (LRa01) in the first winter field (constellation Monoceros) from October 2007 to March 2008. Transits were discovered during the light curve processing. Radial velocity follow-up observations, however, were performed mainly by the 10-m Keck telescope in January 2010. The companion CoRoT-21b is a Jupiter-like planet of 2.26 ± 0.33 Jupiter masses and 1.30 ± 0.14 Jupiter radii in an circular orbit of semi-major axis 0.0417 ± 0.0011 AU and an orbital period of 2.72474 ± 0.00014 days. The planetary bulk density is (1.36 ± 0.48) × 103 kg m-3, very similar to the bulk density of Jupiter, and follows an M1/3 - R relation like Jupiter. The F8IV star is a sub-giant star of 1.29 ± 0.09 solar masses and 1.95 ± 0.2 solar radii. The star and the planet exchange extremetidal forces that will lead to orbital decay and extreme spin-up of the stellar rotation within 800 Myr if the stellar dissipation is Q∗/k2∗ ≤ 107. The CoRoT space mission, launched on December 27th 2006, has been developed and is operated by CNES, with the contribution of Austria, Belgium, Brazil, ESA (RSSD and Science Programme), Germany and Spain.

  1. Transiting exoplanets from the CoRoT space mission. XX. CoRoT-20b: A very high density, high eccentricity transiting giant planet

    NASA Astrophysics Data System (ADS)

    Deleuil, M.; Bonomo, A. S.; Ferraz-Mello, S.; Erikson, A.; Bouchy, F.; Havel, M.; Aigrain, S.; Almenara, J.-M.; Alonso, R.; Auvergne, M.; Baglin, A.; Barge, P.; Bordé, P.; Bruntt, H.; Cabrera, J.; Carpano, S.; Cavarroc, C.; Csizmadia, Sz.; Damiani, C.; Deeg, H. J.; Dvorak, R.; Fridlund, M.; Hébrard, G.; Gandolfi, D.; Gillon, M.; Guenther, E.; Guillot, T.; Hatzes, A.; Jorda, L.; Léger, A.; Lammer, H.; Mazeh, T.; Moutou, C.; Ollivier, M.; Ofir, A.; Parviainen, H.; Queloz, D.; Rauer, H.; Rodríguez, A.; Rouan, D.; Santerne, A.; Schneider, J.; Tal-Or, L.; Tingley, B.; Weingrill, J.; Wuchterl, G.

    2012-02-01

    We report the discovery by the CoRoT space mission of a new giant planet, CoRoT-20b. The planet has a mass of 4.24 ± 0.23 MJup and a radius of 0.84 ± 0.04 RJup. With a mean density of 8.87 ± 1.10 g cm-3, it is among the most compact planets known so far. Evolutionary models for the planet suggest a mass of heavy elements of the order of 800 M⊕ if embedded in a central core, requiring a revision either of the planet formation models or both planet evolution and structure models. We note however that smaller amounts of heavy elements are expected by more realistic models in which they are mixed throughout the envelope. The planet orbits a G-type star with an orbital period of 9.24 days and an eccentricity of 0.56.The star's projected rotational velocity is vsini = 4.5 ± 1.0 km s-1, corresponding to a spin period of 11.5 ± 3.1 days if its axis of rotation is perpendicular to the orbital plane. In the framework of Darwinian theories and neglecting stellar magnetic breaking, we calculate the tidal evolution of the system and show that CoRoT-20b is presently one of the very few Darwin-stable planets that is evolving toward a triple synchronous state with equality of the orbital, planetary and stellar spin periods. The CoRoT space mission, launched on December 27th 2006, has been developed and is operated by CNES, with the contribution of Austria, Belgium, Brazil, ESA (RSSD and Science Programme), Germany, and Spain.

  2. Benefits of β blockers in patients with heart failure and reduced ejection fraction: network meta-analysis

    PubMed Central

    Biondi-Zoccai, Giuseppe; Abbate, Antonio; D’Ascenzo, Fabrizio; Castagno, Davide; Van Tassell, Benjamin; Mukherjee, Debabrata; Lichstein, Edgar

    2013-01-01

    Objective To clarify whether any particular β blocker is superior in patients with heart failure and reduced ejection fraction or whether the benefits of these agents are mainly due to a class effect. Design Systematic review and network meta-analysis of efficacy of different β blockers in heart failure. Data sources CINAHL(1982-2011), Cochrane Collaboration Central Register of Controlled Trials (-2011), Embase (1980-2011), Medline/PubMed (1966-2011), and Web of Science (1965-2011). Study selection Randomized trials comparing β blockers with other β blockers or other treatments. Data extraction The primary endpoint was all cause death at the longest available follow-up, assessed with odds ratios and Bayesian random effect 95% credible intervals, with independent extraction by observers. Results 21 trials were included, focusing on atenolol, bisoprolol, bucindolol, carvedilol, metoprolol, and nebivolol. As expected, in the overall analysis, β blockers provided credible mortality benefits in comparison with placebo or standard treatment after a median of 12 months (odds ratio 0.69, 0.56 to 0.80). However, no obvious differences were found when comparing the different β blockers head to head for the risk of death, sudden cardiac death, death due to pump failure, or drug discontinuation. Accordingly, improvements in left ventricular ejection fraction were also similar irrespective of the individual study drug. Conclusion The benefits of β blockers in patients with heart failure with reduced ejection fraction seem to be mainly due to a class effect, as no statistical evidence from current trials supports the superiority of any single agent over the others. PMID:23325883

  3. Differential Effects of Voltage-Gated Calcium Channel Blockers on Calcium Channel Alpha-2-Delta-1 Subunit Protein Mediated Nociception

    PubMed Central

    Chang, E.; Chen, X.; Kim, M.; Gong, N.; Bhatia, S.; Luo, Z.D.

    2014-01-01

    Background Overexpression of the voltage gated calcium channel (VGCC) alpha-2-delta1 subunit protein (Cavα2δ1) has been shown to cause pain states. However, whether VGCC are involved in pain states driven by abnormal Cavα2δ1 expression is not known. Methods Intrathecal injection of N-, P/Q-, and L-type VGCC blockers were tested in two models: a transgenic neuronal Cavα2δ1 overexpression (TG) model with behavioral hypersensitivity and a spinal nerve ligation (SNL) model with Cavα2δ1 overexpression in sensory pathways and neuropathy pain states. Results The nociceptive response to mechanical stimuli was significantly attenuated in both models with ω-conotoxin GVIA (an N-type VGCC blocker) and nifedipine (a L-type VGCC blocker), in which ω-conotoxin GVIA appeared more potent than nifedipine. Treatments with ω-agatoxin IVA (P-VGCC blocker), but not ω-conotoxin MVIIC (Q-VGCC blocker) had similar potency in the TG model as the N-type VGCC blocker, while both ω-agatoxin IVA and ω-conotoxin MVIIC had minimal effects in the SNL model compared to controls. Conclusion These findings suggest that, at the spinal level, N- and L-type VGCC are likely involved in behavioral hypersensitivity states driven by Cavα2δ1 overexpression. Q-type VGCC have minimal effects in both models. The anti-nociceptive effects of P-type VGCC blocker in the Cavα2δ1 TG mice, but minimally at the SNL model with presynaptic Cavα2δ1 upregulation, suggest that its potential action site(s) is at the post-synaptic and/or supraspinal level. These findings support that N-, L- and P/Q-type VGCC have differential contributions to behavioral hypersensitivity modulated by Cavα2δ1 dysregulation at the spinal cord level. PMID:25158907

  4. Pro-survival function of MEF2 in cardiomyocytes is enhanced by β-blockers

    PubMed Central

    Hashemi, S; Salma, J; Wales, S; McDermott, JC

    2015-01-01

    β1-Adrenergic receptor (β1-AR) stimulation increases apoptosis in cardiomyocytes through activation of cAMP/protein kinase A (PKA) signaling. The myocyte enhancer factor 2 (MEF2) proteins function as important regulators of myocardial gene expression. Previously, we reported that PKA signaling directly represses MEF2 activity. We determined whether (a) MEF2 has a pro-survival function in cardiomyocytes, and (b) whether β-adrenergic/PKA signaling modulates MEF2 function in cardiomyocytes. Initially, we observed that siRNA-mediated gene silencing of MEF2 induces cardiomyocyte apoptosis as indicated by flow cytometry. β1-AR activation by isoproterenol represses MEF2 activity and promotes apoptosis in cultured neonatal cardiomyocytes. Importantly, β1-AR mediated apoptosis was abrogated in cardiomyocytes expressing a PKA-resistant form of MEF2D (S121/190A). We also observed that a β1-blocker, Atenolol, antagonizes isoproterenol-induced apoptosis while concomitantly enhancing MEF2 transcriptional activity. β-AR stimulation modulated MEF2 cellular localization in cardiomyocytes and this effect was reversed by β-blocker treatment. Furthermore, Kruppel-like factor 6, a MEF2 target gene in the heart, functions as a downstream pro-survival factor in cardiomyocytes. Collectively, these data indicate that (a) MEF2 has an important pro-survival role in cardiomyocytes, and (b) β-adrenergic signaling antagonizes the pro-survival function of MEF2 in cardiomyocytes and β-blockers promote it. These observations have important clinical implications that may contribute to novel strategies for preventing cardiomyocyte apoptosis associated with heart pathology. PMID:27551452

  5. SU-E-I-08: Investigation of Deconvolution Methods for Blocker-Based CBCT Scatter Estimation

    SciTech Connect

    Zhao, C; Jin, M; Ouyang, L; Wang, J

    2015-06-15

    Purpose: To investigate whether deconvolution methods can improve the scatter estimation under different blurring and noise conditions for blocker-based scatter correction methods for cone-beam X-ray computed tomography (CBCT). Methods: An “ideal” projection image with scatter was first simulated for blocker-based CBCT data acquisition by assuming no blurring effect and no noise. The ideal image was then convolved with long-tail point spread functions (PSF) with different widths to mimic the blurring effect from the finite focal spot and detector response. Different levels of noise were also added. Three deconvolution Methods: 1) inverse filtering; 2) Wiener; and 3) Richardson-Lucy, were used to recover the scatter signal in the blocked region. The root mean square error (RMSE) of estimated scatter serves as a quantitative measure for the performance of different methods under different blurring and noise conditions. Results: Due to the blurring effect, the scatter signal in the blocked region is contaminated by the primary signal in the unblocked region. The direct use of the signal in the blocked region to estimate scatter (“direct method”) leads to large RMSE values, which increase with the increased width of PSF and increased noise. The inverse filtering is very sensitive to noise and practically useless. The Wiener and Richardson-Lucy deconvolution methods significantly improve scatter estimation compared to the direct method. For a typical medium PSF and medium noise condition, both methods (∼20 RMSE) can achieve 4-fold improvement over the direct method (∼80 RMSE). The Wiener method deals better with large noise and Richardson-Lucy works better on wide PSF. Conclusion: We investigated several deconvolution methods to recover the scatter signal in the blocked region for blocker-based scatter correction for CBCT. Our simulation results demonstrate that Wiener and Richardson-Lucy deconvolution can significantly improve the scatter estimation

  6. Electrically enhanced microextraction for highly selective transport of three β-blocker drugs.

    PubMed

    Seidi, Shahram; Yamini, Yadollah; Rezazadeh, Maryam

    2011-12-15

    Facilitated transport of three β-blocker drugs including atenolol (ATE), betaxolol (BET) and propranolol (PRO) was investigated under electrical field across a supported liquid membrane (SLM) using phosphoric acid derivatives as selective ion carriers, dissolved in 2-nitro phenyl octyl ether (NPOE). In the presence of di-(2-ethylhexyl) phosphate (DEHP) and tris-(2-ethylhexyl) phosphate (TEHP) in the membrane phase, the three β-blockers showed completely different transport behaviors which enabled highly selective separation of the drugs. Each β-blocker migrated from 3 mL of sample solutions, through a thin layer of specific organic solvent immobilized in the pores of a porous hollow fiber, and into a 15 μL acidic aqueous acceptor solution present inside the lumen of the fiber. The influences of fundamental parameters affecting the transport of target drugs including type of ion carrier for selective separation of each drug and its concentration in the membrane phase, extraction voltage, time of transport, pH of donor and acceptor phases, stirring speed of donor phase and salt effect were studied and optimized. After microextraction process, the extracts were analyzed by high-performance liquid chromatography with ultraviolet detection. Under optimal conditions, ATE was selectively extracted from different saliva samples with recovery of 37%, which corresponded to preconcentration factor of 74. A good linearity was achieved for calibration curve with a coefficient of determination higher than 0.997. Limits of detection and intra-day precision (n=3) were less than 2 μg L(-1) and 8.8%, respectively. PMID:21856103

  7. Cystic fibrosis transmembrane conductance regulator chloride channel blockers: Pharmacological, biophysical and physiological relevance

    PubMed Central

    Linsdell, Paul

    2014-01-01

    Dysfunction of the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel causes cystic fibrosis, while inappropriate activity of this channel occurs in secretory diarrhea and polycystic kidney disease. Drugs that interact directly with CFTR are therefore of interest in the treatment of a number of disease states. This review focuses on one class of small molecules that interacts directly with CFTR, namely inhibitors that act by directly blocking chloride movement through the open channel pore. In theory such compounds could be of use in the treatment of diarrhea and polycystic kidney disease, however in practice all known substances acting by this mechanism to inhibit CFTR function lack either the potency or specificity for in vivo use. Nevertheless, this theoretical pharmacological usefulness set the scene for the development of more potent, specific CFTR inhibitors. Biophysically, open channel blockers have proven most useful as experimental probes of the structure and function of the CFTR chloride channel pore. Most importantly, the use of these blockers has been fundamental in developing a functional model of the pore that includes a wide inner vestibule that uses positively charged amino acid side chains to attract both permeant and blocking anions from the cell cytoplasm. CFTR channels are also subject to this kind of blocking action by endogenous anions present in the cell cytoplasm, and recently this blocking effect has been suggested to play a role in the physiological control of CFTR channel function, in particular as a novel mechanism linking CFTR function dynamically to the composition of epithelial cell secretions. It has also been suggested that future drugs could target this same pathway as a way of pharmacologically increasing CFTR activity in cystic fibrosis. Studying open channel blockers and their mechanisms of action has resulted in significant advances in our understanding of CFTR as a pharmacological target in disease

  8. Cystic fibrosis transmembrane conductance regulator chloride channel blockers: Pharmacological, biophysical and physiological relevance.

    PubMed

    Linsdell, Paul

    2014-02-26

    Dysfunction of the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel causes cystic fibrosis, while inappropriate activity of this channel occurs in secretory diarrhea and polycystic kidney disease. Drugs that interact directly with CFTR are therefore of interest in the treatment of a number of disease states. This review focuses on one class of small molecules that interacts directly with CFTR, namely inhibitors that act by directly blocking chloride movement through the open channel pore. In theory such compounds could be of use in the treatment of diarrhea and polycystic kidney disease, however in practice all known substances acting by this mechanism to inhibit CFTR function lack either the potency or specificity for in vivo use. Nevertheless, this theoretical pharmacological usefulness set the scene for the development of more potent, specific CFTR inhibitors. Biophysically, open channel blockers have proven most useful as experimental probes of the structure and function of the CFTR chloride channel pore. Most importantly, the use of these blockers has been fundamental in developing a functional model of the pore that includes a wide inner vestibule that uses positively charged amino acid side chains to attract both permeant and blocking anions from the cell cytoplasm. CFTR channels are also subject to this kind of blocking action by endogenous anions present in the cell cytoplasm, and recently this blocking effect has been suggested to play a role in the physiological control of CFTR channel function, in particular as a novel mechanism linking CFTR function dynamically to the composition of epithelial cell secretions. It has also been suggested that future drugs could target this same pathway as a way of pharmacologically increasing CFTR activity in cystic fibrosis. Studying open channel blockers and their mechanisms of action has resulted in significant advances in our understanding of CFTR as a pharmacological target in disease

  9. Amino Acid Derivatives as Bitter Taste Receptor (T2R) Blockers*

    PubMed Central

    Pydi, Sai P.; Sobotkiewicz, Tyler; Billakanti, Rohini; Bhullar, Rajinder P.; Loewen, Michele C.; Chelikani, Prashen

    2014-01-01

    In humans, the 25 bitter taste receptors (T2Rs) are activated by hundreds of structurally diverse bitter compounds. However, only five antagonists or bitter blockers are known. In this study, using molecular modeling guided site-directed mutagenesis, we elucidated the ligand-binding pocket of T2R4. We found seven amino acids located in the extracellular side of transmembrane 3 (TM3), TM4, extracellular loop 2 (ECL2), and ECL3 to be involved in T2R4 binding to its agonist quinine. ECL2 residues Asn-173 and Thr-174 are essential for quinine binding. Guided by a molecular model of T2R4, a number of amino acid derivatives were screened for their ability to bind to T2R4. These predictions were tested by calcium imaging assays that led to identification of γ-aminobutryic acid (GABA) and Nα,Nα-bis(carboxymethyl)-l-lysine (BCML) as competitive inhibitors of quinine-activated T2R4 with an IC50 of 3.2 ± 0.3 μm and 59 ± 18 nm, respectively. Interestingly, pharmacological characterization using a constitutively active mutant of T2R4 reveals that GABA acts as an antagonist, whereas BCML acts as an inverse agonist on T2R4. Site-directed mutagenesis confirms that the two novel bitter blockers share the same orthosteric site as the agonist quinine. The signature residues Ala-90 and Lys-270 play important roles in interacting with BCML and GABA, respectively. This is the first report to characterize a T2R endogenous antagonist and an inverse agonist. The novel bitter blockers will facilitate physiological studies focused on understanding the roles of T2Rs in extraoral tissues. PMID:25059668

  10. Comparative effects of sodium channel blockers in short term rat whole embryo culture

    SciTech Connect

    Nilsson, Mats F; Sköld, Anna-Carin; Ericson, Ann-Christin; Annas, Anita; Villar, Rodrigo Palma; Cebers, Gvido; Hellmold, Heike; Gustafson, Anne-Lee; Webster, William S

    2013-10-15

    This study was undertaken to examine the effect on the rat embryonic heart of two experimental drugs (AZA and AZB) which are known to block the sodium channel Nav1.5, the hERG potassium channel and the L-type calcium channel. The sodium channel blockers bupivacaine, lidocaine, and the L-type calcium channel blocker nifedipine were used as reference substances. The experimental model was the gestational day (GD) 13 rat embryo cultured in vitro. In this model the embryonic heart activity can be directly observed, recorded and analyzed using computer assisted image analysis as it responds to the addition of test drugs. The effect on the heart was studied for a range of concentrations and for a duration up to 3 h. The results showed that AZA and AZB caused a concentration-dependent bradycardia of the embryonic heart and at high concentrations heart block. These effects were reversible on washout. In terms of potency to cause bradycardia the compounds were ranked AZB > bupivacaine > AZA > lidocaine > nifedipine. Comparison with results from previous studies with more specific ion channel blockers suggests that the primary effect of AZA and AZB was sodium channel blockage. The study shows that the short-term rat whole embryo culture (WEC) is a suitable system to detect substances hazardous to the embryonic heart. - Highlights: • Study of the effect of sodium channel blocking drugs on embryonic heart function • We used a modified method rat whole embryo culture with image analysis. • The drugs tested caused a concentration dependent bradycardia and heart block. • The effect of drugs acting on multiple ion channels is difficult to predict. • This method may be used to detect cardiotoxicity in prenatal development.

  11. Modeling the binding modes of Kv1.5 potassium channel and blockers.

    PubMed

    Yang, Qian; Du, Lupei; Wang, Xiaojian; Li, Minyong; You, Qidong

    2008-09-01

    The ultra-rapid delayed rectifier potassium current (I(Kur)), encoded by Kv1.5 gene, is the critical determinant of Phase I repolarization of action potential duration (APD). The evidences that Kv1.5 gene expresses more extensively in human atrial myocytes than in ventricle and the I(Kur) currents has not been recorded in the human ventricle, suggest Kv1.5 potassium channel as a selective target for the treatment of atrial fibrillation (AF). Recent mutagenesis studies have provided us some evidences that are useful in designing Kv1.5 blockers. In order to further evaluate these molecular biological information, the homology model of Kv1.5 potassium channel was established based on the Kv1.2 crystal structure (PDB entry: 2A79) using MODELLER 9v2 program. After the molecular dynamics refinement, the optimized homology model was assessed as a reliable structure by PROCHECK, ERRAT, WHAT-IF, PROSA2003 and DOPE graph. The results of molecular docking studies on different Kv1.5 inhibitors are in agreement with the published mutagenesis data. Based on the docking conformations, a pharmacophore model was developed by HipHop algorithm in order to probe the common features of blockers. By analyzing the results, active site architecture, certain key residues and pharmacophore common-features that are responsible for substrate specificity were identified on the Kv1.5 potassium channel, which would be very helpful in understanding the blockade mechanism of Kv1.5 potassium channel and providing insights into rational design of novel Kv1.5 blockers. PMID:18485768

  12. Pharmacodynamics of beta-blockers in heart failure: lessons from the carvedilol or metoprolol European trial.

    PubMed

    Bauman, Jerry L; Talbert, Robert L

    2004-06-01

    Heart failure is a growing public health problem in the United States, and the approach to the treatment of heart failure has undergone a radical transformation in the past decade. The use of beta-blocker therapy in heart failure patients is now widely recommended, based on evidence from large-scale clinical trials demonstrating that bisoprolol, carvedilol, and extended-release metoprolol succinate significantly reduce morbidity and mortality in patients with heart failure. Although these agents appear to provide similar benefits, the question remains whether pharmacologic differences among them could translate to differences in clinical outcomes. The Carvedilol Or Metoprolol European Trial (COMET) compared nonselective blockade of the beta1-/beta2-/alpha1-adrenergic receptors with carvedilol versus selective beta1-blockade with immediate-release metoprolol tartrate in patients with chronic heart failure. The trial found that carvedilol significantly reduced all-cause mortality compared with immediate-release metoprolol tartrate, although there were no differences in hospitalizations. Herein we review the pharmacokinetics and pharmacodynamics of metoprolol and carvedilol. In doing so, several issues regarding the design of COMET are identified that could alter the interpretation of the results of this trial. These include the choice of dose and dosage regimen of immediate-release metoprolol tartrate, a dosage form that has never been shown to reduce mortality in patients with heart failure. Additional studies are needed to fully understand whether there are any advantages of selective versus nonselective adrenergic blockade and whether there are any clinically meaningful differences in effectiveness between beta-blockers with proven benefit in the management of chronic heart failure. The results of COMET demonstrate that all beta-blockers and dosage forms are not interchangeable when prescribed for heart failure. Clinicians should choose only those agents (and

  13. FIXED DOSE COMBINATIONS WITH SELECTIVE BETA-BLOCKERS: QUANTITATIVE DETERMINATION IN BIOLOGICAL FLUIDS.

    PubMed

    Mahu, Ştefania Corina; Hăncianu, Monica; Agoroaei, Luminiţa; Grigoriu, Ioana Cezara; Strugaru, Anca Monica; Butnaru, Elena

    2015-01-01

    Hypertension is one of the most common causes of death, a complex and incompletely controlled disease for millions of patients. Metoprolol, bisoprolol, nebivolol and atenolol are selective beta-blockers frequently used in the management of arterial hypertension, alone or in fixed combination with other substances. This study presents the most used analytical methods for simultaneous determination in biological fluids of fixed combinations containing selective beta-blockers. Articles in Pub-Med, Science Direct and Wiley Journals databases published between years 2004-2014 were reviewed. Methods such as liquid chromatography--mass spectrometry--mass spectrometry (LC-MS/MS), high performance liquid chromatography (HPLC) or high performance liquid chromatography--mass spectrometry (HPLC-MS) were used for determination of fixed combination with beta-blockers in human plasma, rat plasma and human breast milk. LC-MS/MS method was used for simultaneous determination of fixed combinations of metoprolol with simvastatin, hydrochlorothiazide or ramipril, combinations of nebivolol and valsartan, or atenolol and amlodipine. Biological samples were processed by protein precipitation techniques or by liquid-liquid extraction. For the determination of fixed dose combinations of felodipine and metoprolol in rat plasma liquid chromatography--electrospray ionization--mass spectrometry (LC-ESI-MS/MS) was applied, using phenacetin as internal standard. HPLC-MS method was applied for the determination of bisoprolol and hydrochlorothiazide in human plasma. For the determination of atenolol and chlorthalidone from human breast milk and human plasma the HPLC method was used. The analytical methods were validated according to the specialized guidelines, and were applied to biological samples, thing that confirms the permanent concern of researchers in this field. PMID:26204671

  14. Effects of calcium entry blockers on calcium-dependent contractions of rat portal vein.

    PubMed Central

    Dacquet, C.; Mironneau, C.; Mironneau, J.

    1987-01-01

    1 The effects of six calcium entry blockers belonging to the dihydropyridine (isradipine or PN 200-110, nifedipine, nicardipine), verapamil (D888 or desmethoxyverapamil, D600 or gallopamil) and diltiazem classes were investigated on isometric spontaneous contractions and contractions induced by high-K+ solutions, noradrenaline, acetylcholine and caffeine. 2 The rank order of potency was PN 200-110 greater than nicardipine = nifedipine = D888 greater than D600 greater than diltiazem from experiments on spontaneous contractions and high-K+ induced contractions. With depolarized preparations, the concentration-response curves for nicardipine, PN 200-110, nifedipine and D600 were significantly shifted to the left indicating that the calcium entry blockers show voltage-dependent inhibitory properties. This effect was not significant with D888 and diltiazem. 3 All the calcium entry blockers strongly reduced the noradrenaline (NA)- and acetylcholine (ACh)-induced contractions at concentrations which produced complete inhibition of spontaneous contractions. They had a slight effect on caffeine-induced contractions. 4 In Ca2+-free, EGTA-containing solutions, both ACh, NA and caffeine produced transient contractions, the amplitude of which could be taken as a measurement of the amount of internal calcium present in a drug-sensitive calcium store. The filling of the calcium store was maximal after 10-12 min of calcium loading in 2.1 mM Ca2+, while the depletion was complete after 4-6 min of perfusion in Ca2+-free solution. 5 At concentrations which abolished spontaneous contractions, PN 200-110, nifedipine, D888 and D600 had no appreciable effect on contractions evoked in Ca2+-free solutions by ACh, NA and caffeine.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:2959345

  15. Effect of RAAS blockers on adverse clinical outcomes in high CVD risk subjects with atrial fibrillation

    PubMed Central

    Chaugai, Sandip; Sherpa, Lhamo Yanchang; Sepehry, Amir A.; Arima, Hisatomi; Wang, Dao Wen

    2016-01-01

    Abstract Recent studies have demonstrated that atrial fibrillation significantly increases the risk of adverse clinical outcomes in high cardiovascular disease risk subjects. Application of renin–angiotensin–aldosterone system blockers for prevention of recurrence of atrial fibrillation and adverse clinical outcomes in subjects with atrial fibrillation is a theoretically appealing concept. However, results of clinical trials evaluating the effect of renin–angiotensin–aldosterone blockers on adverse clinical outcomes in high cardiovascular disease risk subjects with atrial fibrillation remain inconclusive. A pooled study of 6 randomized controlled trials assessing the efficacy of renin–angiotensin–aldosterone blockers on subjects with atrial fibrillation was performed. A total of 6 randomized controlled trials enrolled a total of 53,510 patients followed for 1 to 5 years. RAAS blockade therapy was associated with 14% reduction in the incidence of heart failure (OR: 0.86, [95%CI: 0.76– 0.97], P=0.018) and 17% reduction in the incidence of CVE (OR: 0.83, [95%CI: 0.70–0.99], P = 0.038). The corresponding decline in absolute risk against heart failure (ARR: 1.4%, [95%CI: 0.2–2.6%], P = 0.018) and CVE (ARR: 3.5%, [95%CI: 0.0–6.9%], P = 0.045) in the AF group was much higher than the non-AF group for heart failure (ARR: 0.4%, [95%CI: 0.0–0.7%], P = 0.057) and CVE (ARR: 1.6%, [95%CI: –0.1% to 3.3%], P = 0.071). No significant effect was noted on all-cause or cardiovascular mortality, stroke, or myocardial infarction. This study suggests that RAAS blockade offers protection against heart failure and cardiovascular events in high cardiovascular disease risk subjects with atrial fibrillation. PMID:27368043

  16. Enantiomeric selectivity in adsorption of chiral β-blockers on sludge.

    PubMed

    Sanganyado, Edmond; Fu, Qiuguo; Gan, Jay

    2016-07-01

    Adsorption of weakly basic compounds by sludge is poorly understood, although it has important implications on the distribution and fate of such micropollutants in wastewater effluent and sludge. Additionally, many of these compounds are chiral, and it is likely that their interactions with sludge is stereoselective and that the process may be further modified by surfactants that coexist in these systems. Adsorption of (R) and (S)-enantiomers of five commonly used β-blockers, i.e., acebutolol, atenolol, metoprolol, pindolol and propranolol, on sludge was characterized through batch experiments. Stereoselectivity in adsorption increased with decreases in hydrophobicity of the β-blockers. The enantiomeric fraction (EF) of the amount of acebutolol, atenolol and metoprolol sorbed on sludge were 0.27, 0.55 and 0.32, respectively. Thus, Kd values of the (S)-enantiomers of acebutolol and metoprolol were approximately twice that of the (R)-enantiomer, that is, 109 ± 11 and 57 ± 8 L/kg compared to 52 ± 13 and 22 ± 8 L/kg, respectively. There was no statistically significant difference in Kd values of the enantiomers of pindolol and propranolol, suggesting stereoselectivity in adsorption was likely driven by specific polar interactions rather than hydrophobic interactions. The EF value of atenolol decreased from 0.55 ± 0.03 to 0.44 ± 0.04 after modifying the sludge with Triton X 100. These results suggested that surfactants altered adsorption of β-blockers to sludge, likely by forming ion pair complexes that promote hydrophobic interactions with the solid surfaces. PMID:27155096

  17. Data Analysis Provenance: Use Case for Exoplanet Search in CoRoT Database

    NASA Astrophysics Data System (ADS)

    de Souza, L.; Salete Marcon Gomes Vaz, M.; Emílio, M.; Ferreira da Rocha, J. C.; Janot Pacheco, E.; Carlos Boufleur, R.

    2012-09-01

    CoRoT (COnvection Rotation and Planetary Transits) is a mission led by the French national space agency CNES, in collaboration with Austria, Spain, Germany, Belgium and Brazil. The mission priority is dedicated to exoplanet search and stellar seismology. CoRoT light curves database became public after one year of their delivery to the CoRoT Co-Is, following the CoRoT data policy. The CoRoT archive contains thousands of light curves in FITS format. Several exoplanet search algorithms require detrend algorithms to remove both stellar and instrumental signal, improving the chance to detect a transit. Different detrend and transit detection algorithms can be applied to the same database. Tracking the origin of the information and how the data was derived in each level in the data analysis process is essential to allow sharing, reuse, reprocessing and further analysis. This work aims at applying a formalized and codified knowledge model by means of domain ontology. It allows to enrich the data analysis with semantic and standardization. It holds the provenance information in the database for a posteriori recovers by humans or software agents.

  18. Abnormal clinical pharmacokinetics of the developmental radiosensitizers pimonidazole (Ro 03-8799) and etanidazole (SR 2508)

    SciTech Connect

    Maughan, T.S.; Newman, H.F.; Bleehen, N.M.; Ward, R.; Workman, P. )

    1990-05-01

    The hypoxic cell radiosensitizers Ro 03-8799 (pimonidazole) and SR 2508 (etanidazole) are under evaluation as single agents (Phase III) and in combination (Phase I). Ro 03-8799 produces an acute, transient central nervous system syndrome, whereas SR 2508 causes cumulative, peripheral neurotoxicity; both effects are dose-limiting. Pharmacokinetic studies have shown the importance of area under the plasma drug concentration versus time curve (AUC) in predicting the risk of peripheral neuropathy. Most patients have very similar pharmacokinetic parameters. This study reports 2/25 patients receiving 0.75 g/m2 Ro 03-8799 plus 2.0 g/m2 SR 2508 who showed significant discrepancies in drug handling. One patient exhibited a markedly elevated AUC and prolonged t1/2 beta for SR 2508 and this was associated with an unusually rapid onset of peripheral neuropathy. A second patient showed normal handling of SR 2508 but prolonged values for both t1/2 alpha and t1/2 beta for Ro 03-8799 and unusually low levels of its N-oxide metabolite. In addition a low peak Ro 03-8799 concentration combined with a very high volume of distribution was found in this patient, leading to a normal AUC value and toxicity profile. Both patients exhibited a relatively low creatinine clearance. The mechanisms which may underlie these findings are discussed, and the importance of pharmacokinetic monitoring in the use of these agents is emphasized.

  19. Revisiting the transits of CoRoT-7b at a lower activity level

    NASA Astrophysics Data System (ADS)

    Barros, S. C. C.; Almenara, J. M.; Deleuil, M.; Diaz, R. F.; Csizmadia, Sz.; Cabrera, J.; Chaintreuil, S.; Collier Cameron, A.; Hatzes, A.; Haywood, R.; Lanza, A. F.; Aigrain, S.; Alonso, R.; Bordé, P.; Bouchy, F.; Deeg, H. J.; Erikson, A.; Fridlund, M.; Grziwa, S.; Gandolfi, D.; Guillot, T.; Guenther, E.; Leger, A.; Moutou, C.; Ollivier, M.; Pasternacki, T.; Pätzold, M.; Rauer, H.; Rouan, D.; Santerne, A.; Schneider, J.; Wuchterl, G.

    2014-09-01

    The first super-Earth with measured radius discovered was CoRoT-7b and it has opened the new field of rocky exoplanet characterisation. To better understand this interesting system, new observations were taken with the CoRoT satellite. During this run 90 new transits were obtained in the imagette mode. These were analysed together with the previous 151 transits obtained in the discovery run and HARPS radial velocity observations to derive accurate system parameters. A difference is found in the posterior probability distribution of the transit parameters between the previous CoRoT run (LRa01) and the new run (LRa06). We propose that this is due to an extra noise component in the previous CoRoT run suspected of being transit spot occultation events. These lead to the mean transit shape becoming V-shaped. We show that the extra noise component is dominant at low stellar flux levels and reject these transits in the final analysis. We obtained a planetary radius, Rp = 1.585 ± 0.064 R⊕ , in agreement with previous estimates. Combining the planetary radius with the new mass estimates results in a planetary density of 1.19 ± 0.27 ρ⊕ which is consistent with a rocky composition. The CoRoT-7 system remains an excellent test bed for the effects of activity in the derivation of planetary parameters in the shallow transit regime.

  20. Two functionally distinct subsites for the binding of internal blockers to the pore of voltage-activated K+ channels

    PubMed Central

    Baukrowitz, Thomas; Yellen, Gary

    1996-01-01

    Many blockers of Na+ and K+ channels act by blocking the pore from the intracellular side. For Shaker K+ channels, such intracellular blockers vary in their functional effect on slow (C-type) inactivation: Some blockers interfere with C-type inactivation, whereas others do not. These functional differences can be explained by supposing that there are two overlapping “subsites” for blocker binding, only one of which inhibits C-type inactivation through an allosteric effect. We find that the ability to bind to these subsites depends on specific structural characteristics of the blockers, and correlates with the effect of mutations in two distinct regions of the channel protein. These interactions are important because they affect the ability of blockers to produce use-dependent inhibition. PMID:8917595

  1. The angiotensin II type 1 receptor blocker candesartan suppresses proliferation and fibrosis in gastric cancer.

    PubMed

    Okazaki, Mitsuyoshi; Fushida, Sachio; Harada, Shinichi; Tsukada, Tomoya; Kinoshita, Jun; Oyama, Katsunobu; Tajima, Hidehiro; Ninomiya, Itasu; Fujimura, Takashi; Ohta, Tetsuo

    2014-12-01

    Gastric cancer with peritoneal dissemination has poor clinical prognosis because of the presence of rich stromal fibrosis and acquired drug resistance. Recently, Angiotensin II type I receptor blockers such as candesartan have attracted attention for their potential anti-fibrotic activity. We examined whether candesartan could attenuate tumor proliferation and fibrosis through the interaction between gastric cancer cell line (MKN45) cells and human peritoneal mesothelial cells. Candesartan significantly reduced TGF-β1 expression and epithelial-to-mesenchymal transition-like change, while tumor proliferation and stromal fibrosis were impaired. Targeting the Angiotensin II signaling pathway may therefore be an efficient strategy for treatment of tumor proliferation and fibrosis. PMID:25224569

  2. Intraoperative Extracorporeal Carbon Dioxide Removal During Apneic Oxygenation with an EZ-Blocker in Tracheal Surgery.

    PubMed

    Rispoli, Marco; Nespoli, Moana Rossella; Mattiacci, Dario Maria; Esposito, Marianna; Corcione, Antonio; Buono, Salvatore

    2016-06-01

    Tracheal surgery requires continued innovation to manage the anesthetic during an open airway phase. A common approach is apneic oxygenation with continuous oxygen flow, but the lack of effective ventilation causes hypercapnia, with respiratory acidosis. We used extracorporeal carbon dioxide removal for intraoperative decapneization during apneic oxygenation in a 64-year-old woman who was scheduled for tracheal surgery because of tracheal stenosis caused by long-term intubation. Our findings demonstrate that even after 40 minutes of total apnea, using an EZ-blocker for oxygenation and external decapneization, hemodynamic and gas exchange variables never demonstrated any dangerous alterations. PMID:27075426

  3. Complications of cataract surgery in patients with BPH treated with alpha 1A-blockers

    PubMed Central

    Dobrowolski, Dariusz; Wylegala, Edward

    2011-01-01

    The prevalence of benign prostate hyperplasia (BPH) and cataract increases with age. Both diseases may develop concomitantly and may affect almost 50% of elderly men as comorbidities. Cataract is treated surgically and it has been reported that there may be an association between use of alpha-blockers for BPH, particularly alpha1A-adrenergic receptor selective drugs, and complications of cataract surgery known as Intraoperative Floppy Iris Syndrome (IFIS). The article reviews literature published on this topic and provides recommendations on how to reduce incidence of iatrogenic IFIS or its severity and outcomes in patients with BPH. PMID:24578865

  4. Extraction of a Large Central Airway Foreign Body Using Flexible Bronchoscopy Combined with an Endobronchial Blocker

    PubMed Central

    2016-01-01

    Adult foreign body (FB) aspiration is an uncommon but potentially fatal event. Options for extraction include flexible bronchoscopy (FLXB), rigid bronchoscopy (RB), and surgical extraction. We report the case of a large, smooth aspirated rock causing airway obstruction in an elderly male. RB is generally the preferred approach for extraction of a large complex FB; however, due to its size, the FB had to be removed using FLXB combined with an endobronchial blocker. In this report, we describe the anesthetic and surgical considerations and the novel technique used to extract the FB. PMID:27274879

  5. Prophylaxis of migraine attacks with a calcium-channel blocker: flunarizine versus methysergide.

    PubMed

    Steardo, L; Marano, E; Barone, P; Denman, D W; Monteleone, P; Cardone, G

    1986-01-01

    In this study, flunarizine, a selective calcium-channel blocker, was employed in the prophylactic treatment of headache and was compared with methysergide in terms of efficacy. The trial was conducted with 104 patients (53 treated with flunarizine and 51 treated with methysergide) and lasted six months--one month of pretreatment and five months of therapy. Patients in both groups experienced a highly significant reduction in the number and duration of migraine attacks. Unlike those in the methysergide group, patients treated with flunarizine achieved a significant reduction in the intensity of attacks with very negligible side effects. PMID:3531248

  6. Antitussive profile of the NOP agonist Ro-64-6198 in the guinea pig.

    PubMed

    McLeod, Robbie L; Jia, Yanlin; Fernandez, Xiomara; Parra, Leonard E; Wang, Xin; Tulshian, Deen B; Kiselgof, Eugenia J; Tan, Zheng; Fawzi, Ahmad B; Smith-Torhan, April; Zhang, Hongtao; Hey, John A

    2004-07-01

    We have previously shown that N/OFQ, the endogenous peptide ligand for the 'opioid-like' NOP receptor, inhibits cough in guinea pigs and cats. In the present study we sought to continue our characterization of the cough-suppressant effects of NOP stimulation by profiling the pulmonary and antitussive effects of a novel non-peptide NOP agonist, Ro-64-6198, in guinea pigs. In receptor-binding assays, we confirmed that Ro-64-6198 selectively binds to NOP receptors over other opioid receptors. The Ki values for Ro-64-6198 at NOP, MOP, KOP and DOP receptors was 0.3, 36, 214 and 3,787 nmol/l, respectively. In GTPgammaS-binding assays, Ro-64-6198 displayed >900-fold functional selectivity at NOP relative to MOP receptors. We evaluated the effects of Ro-64-6198 (3 and 10 micromol/l) in isolated guinea pig nodose ganglia cells on the increases in intracellular Ca2+ concentration evoked by capsaicin stimulation (1 x 10(-8)-1 x 10(-6) mol/l). Similar to previously reported data with N/OFQ, Ro-64-6198 (3 and 10 micromol/l) significantly attenuated Ca2+ responses in nodose ganglia cells produced by exposure to capsaicin. The effect of Ro-64-6198 (3 micromol/l) on capsaicin-induced intracellular Ca2+ responses was blocked by the NOP antagonist, J113397 (3 micromol/l). In guinea pig in vivo studies, aerosolized capsaicin (10-300 micromol/l) produced a dose-dependent increase in cough number. Ro-64-6198 given i.p. significantly inhibited cough due to capsaicin (300 micromol/l) exposure. In a duration study we found that the maximum antitussive effect (42 +/- 8% inhibition) of Ro-64-6198 (3 mg/kg) was observed at 1 h after i.p. administration. Also at 1 h after administration, Ro-64-6198 (0.003-3.0 mg/kg, i.p.) produced a dose-dependent inhibition of cough. The antitussive effect of Ro-64-6198 (3 mg/kg, i.p.) was blocked by J113397 (12 mg/kg, i.p.) but not by the classical opioid antagonist naltrexone (10 mg/kg, i.p.). Although the antitussive action of Ro-64-6198 may be mediated

  7. Research and development of Ro-boat: an autonomous river cleaning robot

    NASA Astrophysics Data System (ADS)

    Sinha, Aakash; Bhardwaj, Prashant; Vaibhav, Bipul; Mohommad, Noor

    2013-12-01

    Ro-Boat is an autonomous river cleaning intelligent robot incorporating mechanical design and computer vision algorithm to achieve autonomous river cleaning and provide a sustainable environment. Ro-boat is designed in a modular fashion with design details such as mechanical structural design, hydrodynamic design and vibrational analysis. It is incorporated with a stable mechanical system with air and water propulsion, robotic arms and solar energy source and it is proceed to become autonomous by using computer vision. Both "HSV Color Space" and "SURF" are proposed to use for measurements in Kalman Filter resulting in extremely robust pollutant tracking. The system has been tested with successful results in the Yamuna River in New Delhi. We foresee that a system of Ro-boats working autonomously 24x7 can clean a major river in a city on about six months time, which is unmatched by alternative methods of river cleaning.

  8. Identification of the Ro and La antigens in the endoribonuclease VII--ribonucleoprotein complex.

    PubMed Central

    Bachmann, M; Mayet, W J; Schröder, H C; Pfeifer, K; Meyer zum Büschenfelde, K H; Müller, W E

    1987-01-01

    45 S RNP (ribonucleoprotein) particles from calf thymus or L5178y mouse lymphoma cells contain the poly(A)-modulated and oligo(U)-binding endoribonuclease VII [Bachmann, Zahn & Müller (1983) J. Biol. Chem. 258, 7033-7040]. From these particles a 4.5 S RNA was isolated that possesses an oligo(U) sequence. By using monospecific and non-cross-reacting antibodies directed against the La or Ro antigen, both proteins were identified in the endoribonuclease VII-RNP complex after phosphorylation in vitro. In a second approach, endoribonuclease VII activity was identified in immunoaffinity-purified Ro RNPs after preparative isoelectric focusing. Therefore we conclude that the 4.5 S RNA belongs to the Ro RNAs. The results indicate a possible function of endoribonuclease VII in activating stored mRNAs. Images Fig. 1. Fig. 3. PMID:2440423

  9. PAPR reduction based on improved Nyquist pulse shaping technology in OFDM-RoF systems

    NASA Astrophysics Data System (ADS)

    Liu, Jian-fei; Li, Ning; Lu, Jia; Zeng, Xiang-ye; Li, Jie; Wang, Meng-jun

    2013-01-01

    High peak-to-average power ratio (PAPR) is the main disadvantage in orthogonal frequency-division multiplexing (OFDM) communication systems, which also exists in OFDM-radio over fiber (RoF) systems. In this paper, we firstly analyze the impact of high PAPR on a 40 GHz OFDM-RoF system, and then describe the theory of Nyquist pulse shaping technology for reducing PAPR. To suppress PAPR further, an improved Nyquist pulse shaping technology is proposed, in which the distribution of original-data amplitude is changed by properly selecting the time-limited waveforms of the different subcarriers. We firstly apply the improved Nyquist pulse shaping technology to an OFDM-RoF system. The simulation results show that PAPR is effectively reduced by more than 2 dB with the bit error rate (BER) declining by about 0.125%.

  10. Removal of bisphenol A (BPA) from water by various nanofiltration (NF) and reverse osmosis (RO) membranes.

    PubMed

    Yüksel, Suna; Kabay, Nalan; Yüksel, Mithat

    2013-12-15

    The removal of an endocrine disrupting compound, bisphenol A (BPA), from model solutions by selected nanofiltration (NF) and reverse osmosis (RO) membranes was studied. The commercially available membranes NF 90, NF 270, XLE BWRO, BW 30 (Dow FilmTech), CE BWRO and AD SWRO (GE Osmonics) were used to compare their performances for BPA removal. The water permeability coefficients, rejection of BPA and permeate flux values were calculated for all membranes used. No significant changes in their BPA removal were observed for all tight polyamide based NF and RO membranes tested except for loose NF 270 membrane. The polyamide based membranes exhibited much better performance than cellulose acetate membrane for BPA removal. Almost a complete rejection (≥ 98%) for BPA was obtained with three polyamide based RO membranes (BW 30, XLE BWRO and AD SWRO). But cellulose acetate based CE BWRO membrane offered a low and variable (10-40%) rejection for BPA. PMID:23731784

  11. Validation of the smallest CoRoT candidates using PASTIS

    NASA Astrophysics Data System (ADS)

    Díaz, R. F.; Almenara, J. M.; Santerne, A.; Moutou, C.; Lethuillier, A.; Deleuil, M.; Bouchy, F.; Hébrard, G.; Montagnier, G.

    2013-09-01

    The majority of the smallest transiting planet candidates detected by CoRoT could not be directly confirmed by a dynamical measurement of their mass. This is due mainly to the faintness of the typical stars observed by CoRoT and to the small reflex motion induced by low-mass planets on their host stars. These candidates have traditionally being labeled as "unresolved", and virtually forgotten in the hope that the new generation of ultra-precise spectrographs installed in large telescopes would permit their confirmation. A way out of this problem is to statistically validate these candidates. In this talk, I will present PASTIS, the validation tool developed in Marseille that is being used to study the CoRoT unresolved candidates.

  12. Effect of Perioperative β-Blockers on Pulmonary Complications among Patients with Chronic Obstructive Pulmonary Disease Undergoing Lung Resection Surgery

    PubMed Central

    Kamath, A.; Stover, D. E.; Hemdan, A.; Belinskaya, I.; Steingart, R. M.; Taur, Y.; Feinstein, M. B.

    2015-01-01

    The aim of this study is to determine if COPD patients undergoing lung resection with perioperative β-blocker use are more likely to suffer postoperative COPD exacerbations than those that did not receive perioperative β-blockers. Methods. A historical cohort study of COPD patients, undergoing lung resection surgery at Memorial Sloan-Kettering Cancer Center between 2002 and 2006. Primary outcomes were the rate of postoperative COPD exacerbations, defined as any initiation or increase of glucocorticoids for documented bronchospasm. Results. 520 patients with COPD were identified who underwent lung resection. Of these, 205 (39%) received perioperative β-blockers and 315 (61%) did not. COPD was mild among 361 patients (69% of all patients), moderate in 117 patients (23%), and severe in 42 patients (8%). COPD exacerbations occurred among 11 (5.4%) patients who received perioperative β-blockers and among 20 (6.3%) patients who did not. Secondary outcomes, which included respiratory failure, 30-day mortality, and the presence or absence of any cardiovascular complication, ICU transfer, cardiovascular complication, or readmission within 30 days, did not differ in prevalence between the two groups. Conclusions. This study implies that perioperative β-blockers use among COPD patients undergoing lung resection surgery does not impact the rate of exacerbations. PMID:26421192

  13. [Are the theoretical drawbacks of beta-blocker treatment in pregnancy being confirmed? A review of the literature].

    PubMed

    Tcherdakoff, P; Goupil-Colliard, M

    1983-01-01

    The use of beta-blocking drugs in the treatment of hypertension during pregnancy has been the subject of controversies on the basis of theoretical hazards due to the pharmacology and pharmacokinetic characteristics of these drugs. A review of the literature on the subject shows that: The danger of premature contractions, abortion or premature delivery does not seem to increase with the use of beta-blockers. The blood supply is not more impaired with beta-blockers than with other antihypertensive drugs according to fetal growth, birth-weight, frequency of perinatal deaths or APGAR score. Although beta-blocking drugs pass into fetal circulation, neonatal bradycardia, respiratory distress or hypoglycemia do not seem more frequent with beta-blockers. Beta-blockers pass from maternal plasma into milk but the 24 hour dose brought to the newborn by maternal feeding is so slight as to be negligible. Thus, the cumulative data and the favorable opinions of many authors, the greater efficiency of beta-blockers authorizes the use of these drugs in the treatment of hypertension in pregnancy, where it seems to improve the outcome of the pregnancy and the state of the fetus at birth. PMID:6138464

  14. Planets and stellar activity: hide and seek in the CoRoT-7 system

    NASA Astrophysics Data System (ADS)

    Haywood, R. D.; Collier Cameron, A.; Queloz, D.; Barros, S. C. C.; Deleuil, M.; Fares, R.; Gillon, M.; Lanza, A. F.; Lovis, C.; Moutou, C.; Pepe, F.; Pollacco, D.; Santerne, A.; Ségransan, D.; Unruh, Y. C.

    2014-09-01

    Since the discovery of the transiting super-Earth CoRoT-7b, several investigations have yielded different results for the number and masses of planets present in the system, mainly owing to the star's high level of activity. We re-observed CoRoT-7 in 2012 January with both HARPS and CoRoT, so that we now have the benefit of simultaneous radial-velocity and photometric data. This allows us to use the off-transit variations in the star's light curve to estimate the radial-velocity variations induced by the suppression of convective blueshift and the flux blocked by starspots. To account for activity-related effects in the radial velocities which do not have a photometric signature, we also include an additional activity term in the radial-velocity model, which we treat as a Gaussian process with the same covariance properties (and hence the same frequency structure) as the light curve. Our model was incorporated into a Monte Carlo Markov Chain in order to make a precise determination of the orbits of CoRoT-7b and CoRoT-7c. We measure the masses of planets b and c to be 4.73 ± 0.95 and 13.56 ± 1.08 M⊕, respectively. The density of CoRoT-7b is (6.61 ± 1.72)(Rp/1.58 R⊕)-3 g cm-3, which is compatible with a rocky composition. We search for evidence of an additional planet d, identified by previous authors with a period close to 9 d. We are not able to confirm the existence of a planet with this orbital period, which is close to the second harmonic of the stellar rotation at ˜7.9 d. Using Bayesian model selection, we find that a model with two planets plus activity-induced variations is most favoured.

  15. Planetary transit candidates in the CoRoT-SRc01 field

    NASA Astrophysics Data System (ADS)

    Erikson, A.; Santerne, A.; Renner, S.; Barge, P.; Aigrain, S.; Alapini, A.; Almenara, J.-M.; Alonso, R.; Auvergne, M.; Baglin, A.; Benz, W.; Bonomo, A. S.; Bordé, P.; Bouchy, F.; Bruntt, H.; Cabrera, J.; Carone, L.; Carpano, S.; Csizmadia, Sz.; Deleuil, M.; Deeg, H. J.; Díaz, R. F.; Dvorak, R.; Ferraz-Mello, S.; Fridlund, M.; Gandolfi, D.; Gazzano, J.-C.; Gillon, M.; Guenther, E. W.; Guillot, T.; Hatzes, A.; Hébrard, G.; Jorda, L.; Lammer, H.; Léger, A.; Llebaria, A.; Mayor, M.; Mazeh, T.; Moutou, C.; Ollivier, M.; Ofir, A.; Pätzold, M.; Pepe, F.; Pont, F.; Queloz, D.; Rabus, M.; Rauer, H.; Régulo, C.; Rouan, D.; Samuel, B.; Schneider, J.; Shporer, A.; Tingley, B.; Udry, S.; Wuchterl, G.

    2012-03-01

    Context. The space mission CoRoT is devoted to the analysis of stellar variability and the photometric detection of extrasolar planets. Aims: We present the list of planetary transit candidates detected in the first short run observed by CoRoT that targeted SRc01, towards the Galactic center in the direction of Aquila, which lasted from April to May 2007. Methods: Among the acquired data, we analyzed those for 1269 sources in the chromatic bands and 5705 in the monochromatic band. Instrumental noise and the stellar variability were treated with several detrending tools, to which several transit-search algorithms were subsequently applied. Results: Fifty-one sources were classified as planetary transit candidates and 26 were followed up with ground-based observations. Until now, no planet has been detected in the CoRoT data from the SRc01 field. The CoRoT space mission, launched on December 27th 2006, has been developed and is operated by CNES, with contributions from Austria, Belgium, Brazil, ESA, Germany, and Spain. The CoRoT data are available to the community from the CoRoT archive: http://idoc-corot.ias.u-psud.frBased in part on observations made with the 1.93-m telescope at Observatoire de Haute Provence (CNRS), France (SOPHIE Program 08A.PNP.MOUT).Based in part on observations made with the ESO-3.60-m telescope at La Silla Observatory (ESO), Chile (HARPS Program ESO - 081.C-0388) and with the ESO-VLT telescope at Paranal Observatory (ESO), Chile (FLAMES Program ESO - 081.C-0413).

  16. Meta-analysis of the efficacy and safety of adding an angiotensin receptor blocker (ARB) to a calcium channel blocker (CCB) following ineffective CCB monotherapy

    PubMed Central

    Ma, Jin; Wang, Xiao-Yan; Hu, Zhi-De; Zhou, Zhi-Rui; Schoenhagen, Paul

    2015-01-01

    Background We conducted this meta-analysis to systematically review and analyze the clinical benefits of angiotensin receptor blocker (ARB) combined with calcium channel blocker (CCB) following ineffective CCB monotherapy. Methods PubMed was searched for articles published until August 2015. Randomized controlled trials (RCTs) evaluating the clinical benefits of ARB combined with CCB following ineffective CCB monotherapy were included. The primary efficacy endpoint of the studies was normal rate of blood pressure, the secondary efficacy endpoints were the response rate and change in blood pressure from baseline. The safety endpoint of the studies was incidence of adverse events. Differences are expressed as relative risks (RRs) with 95% confidence intervals (CIs) for dichotomous outcomes and weighted mean differences (WMDs) with 95% CIs for continuous outcomes. Heterogeneity across studies was tested by using the I2 statistic. Results Seven RCTs were included and had sample sizes ranging from 185 to 1,183 subjects (total: 3,909 subjects). The pooled analysis showed that the on-target rate of hypertension treatment was significantly higher in the amlodipine + ARB group than in the amlodipine monotherapy group (RR =1.59; 95% CI, 1.31–1.91; P<0.01). The response rate of systolic blood pressure (SBP) (RR =1.28; 95% CI, 1.04–1.58; P<0.01) and diastolic blood pressure (DBP) (RR =1.27; 95% CI, 1.12–1.44; P=0.04) were significantly higher in the amlodipine + ARB group than in the amlodipine monotherapy group. The change in SBP (RR =−3.56; 95% CI, −7.76–0.63; P=0.10) and DBP (RR =−3.03; 95% CI, −6.51–0.45; P=0.09) were higher in hypertensive patients receiving amlodipine + ARB but the difference did not reach statistical significance. ARB + amlodipine treatment carried a lower risk of adverse events relative to amlodipine monotherapy (RR =0.88; 95% CI, 0.80-0.96; P<0.01). Conclusions The results of our meta-analysis demonstrate that adding an ARB to CCB

  17. The legacy of CoRoT and Kepler on the physics of stellar evolution

    NASA Astrophysics Data System (ADS)

    Chaplin, William

    2015-08-01

    It is a golden era for stellar astrophysics studies, driven by new satellite observations of unprecedented quality and scope. In this talk I will review advances in our understanding that have followed from asteroseismic studies with CoRoT and Kepler data, not only for stellar evolution theory but also in respect of the legacy for exoplanet and Galactic stellar population studies. I will also highlight the huge amount of work that remains to be performed to fully exploit the CoRoT and Kepler databases, and look to ongoing studies with K2, and the future promise of the NASA TESS and ESA PLATO Missions.

  18. Multiple star systems observed with CoRoT and Kepler

    NASA Astrophysics Data System (ADS)

    Southworth, John

    2015-09-01

    The CoRoT and Kepler satellites were the first space platforms designed to perform high-precision photometry for a large number of stars. Multiple systems display a wide variety of photometric variability, making them natural benefactors of these missions. I review the work arising from CoRoT and Kepler observations of multiple systems, with particular emphasis on eclipsing binaries containing giant stars, pulsators, triple eclipses and/or low-mass stars. Many more results remain untapped in the data archives of these missions, and the future holds the promise of K2, TESS and PLATO.

  19. How to separate the low amplitude delta Scuti variation in CoRoT data unambigousely?

    NASA Astrophysics Data System (ADS)

    Benko, Jozsef M.; Paparo, Margit

    2015-08-01

    Rich regular frequency patterns were found in the Fourier spectra of low-amplitude Delta Scuti stars observed by CoRoT satellite. The CoRoT observations are, however, influenced by the disturbing effect of the SAA. The effect is marginal for high amplitude variable stars but it could be dangerous in the case of low amplitude variables, especially if the frequency range of the intrinsic variation overlaps the instrumental frequencies. Systematic tests were carried out both on synthetic and real data. Our aim was to determine a limit amplitude above which we were sure that the frequency pattern belonged to the stars.

  20. AST/RO: Lessons from a Decade of Sub-mm Astronomy at the South Pole

    NASA Astrophysics Data System (ADS)

    Tothill, N. F. H.

    AST/RO spent over a decade at the South Pole, observing submillimetre-wave emission from the interstellar medium. We outline some of the lessons learned and experience gained that may be relevant to future Antarctic projects. Small submillimetre-wave telescopes, on the excellent sites provided by the Antarctic plateau, have very strong large-area mapping capabilities, together with the potential for ground-based THz observations. Highlighted technical aspects include AST/RO's lack of icing problems and availability of warm space.

  1. Characterization of novel cannabinoid based T-type calcium channel blockers with analgesic effects.

    PubMed

    Bladen, Chris; McDaniel, Steven W; Gadotti, Vinicius M; Petrov, Ravil R; Berger, N Daniel; Diaz, Philippe; Zamponi, Gerald W

    2015-02-18

    Low-voltage-activated (T-type) calcium channels are important regulators of the transmission of nociceptive information in the primary afferent pathway and finding ligands that modulate these channels is a key focus of the drug discovery field. Recently, we characterized a set of novel compounds with mixed cannabinoid receptor/T-type channel blocking activity and examined their analgesic effects in animal models of pain. Here, we have built on these previous findings and synthesized a new series of small organic compounds. We then screened them using whole-cell voltage clamp techniques to identify the most potent T-type calcium channel inhibitors. The two most potent blockers (compounds 9 and 10) were then characterized using radioligand binding assays to determine their affinity for CB1 and CB2 receptors. The structure-activity relationship and optimization studies have led to the discovery of a new T-type calcium channel blocker, compound 9. Compound 9 was efficacious in mediating analgesia in mouse models of acute inflammatory pain and in reducing tactile allodynia in the partial nerve ligation model. This compound was shown to be ineffective in Cav3.2 T-type calcium channel null mice at therapeutically relevant concentrations, and it caused no significant motor deficits in open field tests. Taken together, our data reveal a novel class of compounds whose physiological and therapeutic actions are mediated through block of Cav3.2 calcium channels. PMID:25314588

  2. Anticonvulsant effects of some calcium entry blockers in DBA/2 mice.

    PubMed Central

    De Sarro, G. B.; Meldrum, B. S.; Nisticó, G.

    1988-01-01

    1. The behavioural and anticonvulsant effects of several drugs acting by various mechanisms on calcium-channels or affecting intracellular Ca2+ concentrations were studied after both systemic and intracerebroventricular administration in DBA/2 mice, a strain genetically susceptible to sound-induced seizures. 2. The anticonvulsant effects were evaluated on seizures evoked by means of auditory stimulation (109 dB) in animals placed singly under a perspex dome. 3. Flunarizine and dihydropyridine derivatives, belonging to class I of calcium entry blockers, administered intraperitoneally, were the most potent compounds. 4. Diltiazem, a benzothiazepine derivative belonging to class III, and HA 1004, a calcium antagonist, acting by inhibiting Ca2+ mobilization from intracellular stores, injected intraperitoneally, were 3-7.6 fold and 5.8-10.7 fold less potent than flunarizine respectively. 5. Verapamil and methoxyverapamil, two phenylalkylamine derivatives, given intraperitoneally, were completely ineffective in preventing sound-induced seizures in DBA/2 mice. In addition, high doses of verapamil and its methoxyderivative occasionally produced spontaneous tonic-clonic seizures. 6. After intracerebroventricular administration of the hydrosoluble calcium entry blockers, belonging to different classes, the anticonvulsant effects were similar to those observed after systemic administration. 7. The systemic administration of Bay K 8644, a dihydropyridine analogue, having the ability to stimulate calcium entry into cells produced a dose-dependent increase in clonic and tonic convulsions and other neurological side effects. 8. The present results strongly support the idea that some Ca2+ antagonists may be useful in human epilepsy. PMID:3359104

  3. A new cardiopulmonary exercise testing prognosticating algorithm for heart failure patients treated with beta-blockers.

    PubMed

    Corrà, Ugo; Mezzani, Alessandro; Giordano, Andrea; Caruso, Roberto; Giannuzzi, Pantaleo

    2012-04-01

    In 2004, a cardiopulmonary exercise testing (CPET) prognosticating algorithm for heart failure (HF) patients was proposed. The algorithm employed a stepwise assessment of peak oxygen consumption (VO2), slope of regression relating minute ventilation to carbon dioxide output (VE/VCO2) and peak respiratory exchange ratio (RER), and was proposed as an alternative to the traditional strategy of using a single CPET parameter to describe prognosis. Since its initial proposal, the prognosticating algorithm has not been reassessed, although a re-evaluation is in order given the fact that new HF therapies, such as beta-blocker therapy, have significantly improved survival in HF. The present review, based on a critical examination of CPET outcome studies in HF patients regularly treated with beta-blockers, suggests a new prognosticating algorithm. The algorithm comprises four CPET parameters: peak RER, exertional oscillatory ventilation (EOV), peak VO2 and peak systolic blood pressure (SBP). Compared to previous proposals, the present preliminary attempt includes EOV instead of VE/VCO2 slope as ventilatory CPET parameter, and peak SBP as hemodynamic-derived index. PMID:21450608

  4. Substituted Indazoles as Nav1.7 Blockers for the Treatment of Pain.

    PubMed

    Frost, Jennifer M; DeGoey, David A; Shi, Lei; Gum, Rebecca J; Fricano, Meagan M; Lundgaard, Greta L; El-Kouhen, Odile F; Hsieh, Gin C; Neelands, Torben; Matulenko, Mark A; Daanen, Jerome F; Pai, Madhavi; Ghoreishi-Haack, Nayereh; Zhan, Cenchen; Zhang, Xu-Feng; Kort, Michael E

    2016-04-14

    The genetic validation for the role of the Nav1.7 voltage-gated ion channel in pain signaling pathways makes it an appealing target for the potential development of new pain drugs. The utility of nonselective Nav blockers is often limited due to adverse cardiovascular and CNS side effects. We sought more selective Nav1.7 blockers with oral activity, improved selectivity, and good druglike properties. The work described herein focused on a series of 3- and 4-substituted indazoles. SAR studies of 3-substituted indazoles yielded analog 7 which demonstrated good in vitro and in vivo activity but poor rat pharmacokinetics. Optimization of 4-substituted indazoles yielded two compounds, 27 and 48, that exhibited good in vitro and in vivo activity with improved rat pharmacokinetic profiles. Both 27 and 48 demonstrated robust activity in the acute rat monoiodoacetate-induced osteoarthritis model of pain, and subchronic dosing of 48 showed a shift to a lower EC50 over 7 days. PMID:27015369

  5. Inhibition of Peripheral Nerve Scarring by Calcium Antagonists, Also Known as Calcium Channel Blockers.

    PubMed

    Xue, Jin-Wei; Jiao, Jian-Bao; Liu, Xiao-Feng; Jiang, Yuan-Tao; Yang, Guang; Li, Chun-Yu; Yin, Wei-Tian; Ling, Li

    2016-05-01

    The aim of this research was to investigate the impact of calcium channel blockers (verapamil) on the formation of scars in the sciatic nerve anastomosis after peripheral nerve injury. One hundred twenty healthy, male Sprague-Dawley rats were selected and prepared with right sciatic nerve injury for this study. Samples were selected at the fourth and 12th weeks, respectively, after treatment and observations were made on the nerve anastomosis healing and diameter. Image analysis and statistical processing were carried out relating to the results of the study. The diameter of the anastomosis of the treatment group at weeks 4 and 12 was noticeably smaller than the control group (P < 0.05). In the treatment group at week 4, there were many vesicles observed in the fibroblasts' cytosol and in the control group, the fibroblasts exhibited high number of rough endoplasmic reticulum. The collagen content of the nerve scarring at week 12 in the treatment group was apparently less than the control group (P < 0.01). The calcium channel blocker (verapamil) reduced the axon resistance through the anastomosis during nerve regeneration. It can effectively inhibit the formation of scarring from nerve injury. It also provided an excellent microenvironment for the regeneration of nerve fibers. PMID:26488333

  6. Characterization of Novel Cannabinoid Based T-Type Calcium Channel Blockers with Analgesic Effects

    PubMed Central

    2015-01-01

    Low-voltage-activated (T-type) calcium channels are important regulators of the transmission of nociceptive information in the primary afferent pathway and finding ligands that modulate these channels is a key focus of the drug discovery field. Recently, we characterized a set of novel compounds with mixed cannabinoid receptor/T-type channel blocking activity and examined their analgesic effects in animal models of pain. Here, we have built on these previous findings and synthesized a new series of small organic compounds. We then screened them using whole-cell voltage clamp techniques to identify the most potent T-type calcium channel inhibitors. The two most potent blockers (compounds 9 and 10) were then characterized using radioligand binding assays to determine their affinity for CB1 and CB2 receptors. The structure–activity relationship and optimization studies have led to the discovery of a new T-type calcium channel blocker, compound 9. Compound 9 was efficacious in mediating analgesia in mouse models of acute inflammatory pain and in reducing tactile allodynia in the partial nerve ligation model. This compound was shown to be ineffective in Cav3.2 T-type calcium channel null mice at therapeutically relevant concentrations, and it caused no significant motor deficits in open field tests. Taken together, our data reveal a novel class of compounds whose physiological and therapeutic actions are mediated through block of Cav3.2 calcium channels. PMID:25314588

  7. Computational investigations of hERG channel blockers: New insights and current predictive models.

    PubMed

    Villoutreix, Bruno O; Taboureau, Olivier

    2015-06-23

    Identification of potential human Ether-a-go-go Related-Gene (hERG) potassium channel blockers is an essential part of the drug development and drug safety process in pharmaceutical industries or academic drug discovery centers, as they may lead to drug-induced QT prolongation, arrhythmia and Torsade de Pointes. Recent reports also suggest starting to address such issues at the hit selection stage. In order to prioritize molecules during the early drug discovery phase and to reduce the risk of drug attrition due to cardiotoxicity during pre-clinical and clinical stages, computational approaches have been developed to predict the potential hERG blockage of new drug candidates. In this review, we will describe the current in silico methods developed and applied to predict and to understand the mechanism of actions of hERG blockers, including ligand-based and structure-based approaches. We then discuss ongoing research on other ion channels and hERG polymorphism susceptible to be involved in LQTS and how systemic approaches can help in the drug safety decision. PMID:25770776

  8. Triazine-based vanilloid 1 receptor open channel blockers: design, synthesis, evaluation, and SAR analysis.

    PubMed

    Vidal-Mosquera, Miquel; Fernández-Carvajal, Asia; Moure, Alejandra; Valente, Pierluigi; Planells-Cases, Rosa; González-Ros, José M; Bujons, Jordi; Ferrer-Montiel, Antonio; Messeguer, Angel

    2011-11-10

    The thermosensory transient receptor potential vanilloid 1 channel (TRPV1) is a polymodal receptor activated by physical and chemical stimuli. TRPV1 activity is drastically potentiated by proinflammatory agents released upon tissue damage. Given the pivotal role of TRPV1 in human pain, there is pressing need for improved TRPV1 antagonists, the development of which will require identification of new pharmacophore scaffolds. Uncompetitive antagonists acting as open-channel blockers might serve as activity-dependent blockers that preferentially modulate the activity of overactive channels, thus displaying fewer side effects than their competitive counterparts. Herein we report the design, synthesis, biological evaluation, and SAR analysis of a family of triazine-based compounds acting as TRPV1 uncompetitive antagonists. We identified the triazine 8aA as a potent, pure antagonist that inhibits TRPV1 channel activity with nanomolar efficacy and strong voltage dependency. It represents a new class of activity-dependent TRPV1 antagonists and may serve as the basis for lead optimization in the development of new analgesics. PMID:21950613

  9. Ineffectiveness of organic calcium channel blockers in antagonizing long-term potentiation.

    PubMed

    Taube, J S; Schwartzkroin, P A

    1986-08-01

    Evidence has accumulated suggesting that the presence of calcium is critical for development of hippocampal long-term potentiation (LTP). However, there is a paucity of information about whether calcium's role in LTP is pre- or postsynaptic. In the present study, we examined the effectiveness of nitrendipine, verapamil, flunarizine and the benzodiazepine diazepam in: blocking voltage-dependent calcium channels; blocking synaptic transmission; and preventing development of LTP. Using the in vitro slice preparation, we obtained intracellular and extracellular recordings from guinea pig hippocampal CA1 pyramidal cells. At the cellular level, all 4 drugs were ineffective in blocking voltage-dependent calcium spikes (TTX resistant) and the calcium-dependent afterhyperpolarization. Verapamil and diazepam appeared to antagonize synaptic transmission, as reflected in smaller population spike amplitudes. Development of long-term potentiation was not affected by the presence of verapamil, flunarizine and diazepam. Nitrendipine appeared to reduce the percentage of slices exhibiting LTP; however, ethanol, the vehicle used to dissolve nitrendipine, was shown in separate experiments to reduce the percentage of slices exhibiting LTP. These results suggest that neither the organic calcium channel blockers--nitrendipine, verapamil, and flunarizine--nor micromolar concentrations of diazepam are potent blockers of extrasynaptic voltage-sensitive calcium channels in hippocampus. They thus cannot be used to demonstrate a specific pre- or postsynaptic calcium role in LTP. PMID:3017511

  10. Modulation of ischemic-induced damage to cerebral adenylate cyclase in gerbils by calcium channel blockers.

    PubMed

    Christie-Pope, B C; Palmer, G C

    1986-12-01

    It has been previously established that prolonged bilateral carotid occlusion followed by recirculation produces damage to the synaptic enzyme adenylate cyclase in the frontal cortex of the gerbil. Since calcium entrance into the brain may account in part for the deleterious consequences of stroke, the present study examined whether pretreatment with calcium channel blockers would modify the effects of 60 min of bilateral ischemia plus 40 min of reflow on various parameters of cortical adenylate cyclase activation. In this context activation of cerebral homogenates by norepinephrine with or without 5'-guanylyl imidodiphosphate was preserved by pretreatment of ischemic gerbils with verapamil but worsened by flunarizine. In contrast, in particulate fractions (treated with EGTA to reduce metallic ion levels) the damage to the Mn2+-sensitive catalytic site of adenylate cyclase was prevented only by flunarizine. Pretreatment with the two calcium channel blockers resulted in an elevated basal activity of the enzyme, thereby reducing the response in the homogenate preparation to forskolin. Gerbils pretreated with verapamil tended to have an increased ability for survival resulting from the ischemic episode. Under in vitro conditions the enzyme preparations were not markedly influenced by either drug. PMID:3508245

  11. Chemoenzymatic Route for the Synthesis of (S)-Moprolol, a Potential β-Blocker.

    PubMed

    Ghosh, Saptarshi; Bhaumik, Jayeeta; Banoth, Linga; Banesh, Sooram; Banerjee, Uttam Chand

    2016-04-01

    A biocatalytic route for the synthesis of a potential β-blocker, (S)-moprolol is reported here. Enantiopure synthesis of moprolol is mainly dependent on the chiral intermediate, 3-(2-methoxyphenoxy)-propane-1,2-diol. Various commercial lipases were screened for the enantioselective resolution of (RS)-3-(2-methoxyphenoxy)propane-1,2-diol to produce the desired enantiomer. Among them, Aspergillus niger lipase (ANL) was selected on the basis of both stereo- and regioselectivity. The optimized values of various reaction parameters were determined such as enzyme (15 mg/mL), substrate concentration (10 mM), organic solvent (toluene), reaction temperature (30 °C), and time (18 h).The optimized conditions led to achieving >49% yield with high enantiomeric excess of (S)-3-(2-methoxyphenoxy)propane-1,2-diol. The lipase-mediated catalysis showed regioselective acylation with dual stereoselectivity. Further, the enantiopure intermediate was used for the synthesis of (S)-moprolol, which afforded the desired β-blocker. Chirality 28:313-318, 2016. © 2016 Wiley Periodicals, Inc. PMID:26821612

  12. [The effect of calcium channel blockers in experimental myocardial infarct in rats].

    PubMed

    Kuzelová, M; Svec, P

    1993-06-01

    The effect of the blockers of calcium channels on the development of myocardial ischaemia in rats with an occlusion of the coronary artery was examined. An occlusion of the coronary artery was carried out in rats anaesthetized with pentobarbital by tightening the ends of the ligature freely placed under the left coronary artery - ramus interventricularis seven days prior to ligation. The ischaemia-induced changes in the R-wave and ST-segment were recorded using ECG. The occlusion of the coronary artery produced arrhythmias, a significant elevation of the ST-segment and a slight increase in the heart rate. The blockers of calcium channels with different pharmacological properties - verapamil, nifedipine and diltiazem influenced the ischaemia-induced changes with different intensity. Nifedipine (0.02 mg.kg-1, i.v., 30 min prior to occlusion), verapamil (0.2 mg.kg-1, i.v., 10 mins prior to ischaemia), and diltiazem (0.3 mg.kg-1, i.v., 10 mins prior to ischemia) significantly reduced the increased elevation of the ST-segment. The highest effect on the above-mentioned model was shown by verapamil. PMID:8402964

  13. Transiting exoplanets from the CoRoT space mission . XIX. CoRoT-23b: a dense hot Jupiter on an eccentric orbit

    NASA Astrophysics Data System (ADS)

    Rouan, D.; Parviainen, H.; Moutou, C.; Deleuil, M.; Fridlund, M.; Ofir, A.; Havel, M.; Aigrain, S.; Alonso, R.; Auvergne, M.; Baglin, A.; Barge, P.; Bonomo, A. S.; Bordé, P.; Bouchy, F.; Cabrera, J.; Cavarroc, C.; Csizmadia, Sz.; Deeg, H. J.; Diaz, R. F.; Dvorak, R.; Erikson, A.; Ferraz-Mello, S.; Gandolfi, D.; Gillon, M.; Guillot, T.; Hatzes, A.; Hébrard, G.; Jorda, L.; Léger, A.; Llebaria, A.; Lammer, H.; Lovis, C.; Mazeh, T.; Ollivier, M.; Pätzold, M.; Queloz, D.; Rauer, H.; Samuel, B.; Santerne, A.; Schneider, J.; Tingley, B.; Wuchterl, G.

    2012-01-01

    We report the detection of CoRoT-23b, a hot Jupiter transiting in front of its host star with a period of 3.6314 ± 0.0001 days. This planet was discovered thanks to photometric data secured with the CoRoT satellite, combined with spectroscopic radial velocity (RV) measurements. A photometric search for possible background eclipsing binaries conducted at CFHT and OGS concluded with a very low risk of false positives. The usual techniques of combining RV and transit data simultaneously were used to derive stellar and planetary parameters. The planet has a mass of Mp = 2.8 ± 0.3 MJup, a radius of Rpl= 1.05 ± 0.13RJup, a density of ≈ 3 g cm-3. RV data also clearly reveal a nonzero eccentricity of e = 0.16 ± 0.02. The planet orbits a mature G0 main sequence star of V = 15.5 mag, with a mass M⋆ = 1.14 ± 0.08 M⊙, a radius R ⋆ = 1. 61 ± 0.18 R⊙ and quasi-solarabundances. The age of the system is evaluated to be 7 Gyr, not far from the transition to subgiant, in agreement with the rather large stellar radius. The two features of a significant eccentricity of the orbit and of a fairly high density are fairly uncommon for a hot Jupiter. The high density is, however, consistent with a model of contraction of a planet at this mass, given the age of the system. On the other hand, at such an age, circularization is expected to be completed. In fact, we show that for this planetary mass and orbital distance, any initial eccentricity should not totally vanish after 7 Gyr, as long as the tidal quality factor Qp is more than a few 105, a value that is the lower bound of the usually expected range. Even if CoRoT-23b features a density and an eccentricity that are atypical of a hot Jupiter, it is thus not an enigmatic object. The CoRoT space mission, launched on 27 December 2006, has been developed and is operated by CNES, with the contribution of Austria, Belgium, Brazil, ESA, Germany, and Spain. First CoRoT data are available to the public from the CoRoT archive: http

  14. A Meta-Analysis of Long- Versus Short-Acting Phosphodiesterase 5 Inhibitors: Comparing Combination Use With α-Blockers and α-Blocker Monotherapy for Lower Urinary Tract Symptoms and Erectile Dysfunction

    PubMed Central

    Kim, Hyun Jung; Bae, Jae Hyun; Kim, Jae Heon; Moon, Du Geon; Cheon, Jun

    2015-01-01

    Purpose: Combination therapy with an α-1-adrenergic blocker and phosphodiesterase type 5 inhibitors (PDE5Is) has shown improvements in lower urinary tract symptoms (LUTS) with negligible side effects. Nonetheless, decisive advantages in symptom improvement were insufficient, and there were no clinical differences between long- or short-acting PDE5Is in combination with combination medication. Methods: To review the studies on α-1-adrenergic blocker monotherapy and combination therapy with long vs. short-acting PDE5Is in their use in LUTS and erectile dysfunction (ED). A search of the MEDLINE, Embase, Cochrane Library, and KoreaMed databases was conducted from 2000 to 2014 using combinations of the relevant terms. Among the 323 relevant references discovered, 10 were selected for meta-analysis. The data showed that 616 men received combination therapy (PDE5Is with α-1-adrenergic blockers) or α-1-adrenergic blocker monotherapy. Results: Meta-analysis of the combination therapy showed it was more effective than α-blockers in improving symptoms, with a mean International Prostrate Symptom Score change difference of –1.93 while those of the long- vs. short-acting PDE5I were –2.12 vs. –1.70. Compared to maximum flow rate (Qmax) value with monotherapy, the Qmax increased more with the combination therapy (mean difference of 0.71) while change values were 0.14 and 1.13 for the long- and short-acting PDE5Is, respectively. Residual urine decreased more with the combination therapy than it did with α-1-adrenergic blocker monotherapy with a mean difference of –7.09 while the mean residual urine change values for long- vs. short-acting PDE5Is were –18.83 vs. –5.93. The International Index of Erectile Function value increased by 3.99, 2.85, and 4.85 following combination therapy, and therapy with long- and short-acting PDE5Is. Conclusions: Our meta-analysis suggests that PDE5Is can significantly improve LUTS in men with benign prostatic hyperplasia

  15. Transiting exoplanets from the CoRoT space mission. XVII. The hot Jupiter CoRoT-17b: a very old planet

    NASA Astrophysics Data System (ADS)

    Csizmadia, Sz.; Moutou, C.; Deleuil, M.; Cabrera, J.; Fridlund, M.; Gandolfi, D.; Aigrain, S.; Alonso, R.; Almenara, J.-M.; Auvergne, M.; Baglin, A.; Barge, P.; Bonomo, A. S.; Bordé, P.; Bouchy, F.; Bruntt, H.; Carone, L.; Carpano, S.; Cavarroc, C.; Cochran, W.; Deeg, H. J.; Díaz, R. F.; Dvorak, R.; Endl, M.; Erikson, A.; Ferraz-Mello, S.; Fruth, Th.; Gazzano, J.-C.; Gillon, M.; Guenther, E. W.; Guillot, T.; Hatzes, A.; Havel, M.; Hébrard, G.; Jehin, E.; Jorda, L.; Léger, A.; Llebaria, A.; Lammer, H.; Lovis, C.; MacQueen, P. J.; Mazeh, T.; Ollivier, M.; Pätzold, M.; Queloz, D.; Rauer, H.; Rouan, D.; Santerne, A.; Schneider, J.; Tingley, B.; Titz-Weider, R.; Wuchterl, G.

    2011-07-01

    We report on the discovery of a hot Jupiter-type exoplanet, CoRoT-17b, detected by the CoRoT satellite. It has a mass of 2.43 ± 0.30 MJup and a radius of 1.02 ± 0.07 RJup, while its mean density is 2.82 ± 0.38 g/cm3. CoRoT-17b is in a circular orbit with a period of 3.7681 ± 0.0003 days. The host star is an old (10.7 ± 1.0 Gyr) main-sequence star, which makes it an intriguing object for planetary evolution studies. The planet's internal composition is not well constrained and can range from pure H/He to one that can contain ~380 earth masses of heavier elements. The CoRoT space mission, launched on December 27th 2006, has been developed and is operated by CNES, with the contribution of Austria, Belgium, Brazil, ESA (RSSD and Science Programme), Germany and Spain. Part of the observations were obtained at the Canada-France-Hawaii Telescope (CFHT) which is operated by the National Research Council of Canada, the Institut National des Sciences de l'Univers of the Centre National de la Recherche Scientifique of France, and the University of Hawaii. Based on observations made with HARPS spectrograph on the 3.6-m European Organisation for Astronomical Research in the Southern Hemisphere telescope at La Silla Observatory, Chile (ESO program 184.C-0639). Based on observations made with the IAC80 telescope operated on the island of Tenerife by the Instituto de Astrofísica de Canarias in the Spanish Observatorio del Teide. Part of the data presented herein were obtained at the W.M. Keck Observatory, which is operated as a scientific partnership among the California Institute of Technology, the University of California and the National Aeronautics and Space Administration. The Observatory was made possible by the generous financial support of the W.M. Keck Foundation.

  16. Thyroid Storm with Heart Failure Treated with a Short-acting Beta-adrenoreceptor Blocker, Landiolol Hydrochloride.

    PubMed

    Yamashita, Yugo; Iguchi, Moritake; Nakatani, Rieko; Usui, Takeshi; Takagi, Daisuke; Hamatani, Yasuhiro; Unoki, Takashi; Ishii, Mitsuru; Ogawa, Hisashi; Masunaga, Nobutoyo; Abe, Mitsuru; Akao, Masaharu

    2015-01-01

    Beta-adrenoreceptor blockers are essential in controlling the peripheral actions of thyroid hormones and a rapid heart rate in patients with thyroid storm, although they should be used with great caution when there is the potential for heart failure. A 67-year-old woman was diagnosed as having thyroid storm in addition to marked tachycardia with atrial fibrillation and heart failure associated with a reduced left ventricular function. The administration of an oral beta blocker, bisoprolol fumarate, induced hypotension and was not tolerable for the patient, whereas landiolol hydrochloride, a short-acting intravenous beta-adrenoreceptor blocker with high cardioselectivity and a short elimination half-life, was useful for controlling the patient's tachycardia and heart failure without causing hemodynamic deterioration. PMID:26134196

  17. Inhibition of collagen synthesis by select calcium and sodium channel blockers can be mitigated by ascorbic acid and ascorbyl palmitate

    PubMed Central

    Ivanov, Vadim; Ivanova, Svetlana; Kalinovsky, Tatiana; Niedzwiecki, Aleksandra; Rath, Matthias

    2016-01-01

    Calcium, sodium and potassium channel blockers are widely prescribed medications for a variety of health problems, most frequently for cardiac arrhythmias, hypertension, angina pectoris and other disorders. However, chronic application of channel blockers is associated with numerous side effects, including worsening cardiac pathology. For example, nifedipine, a calcium-channel blocker was found to be associated with increased mortality and increased risk for myocardial infarction. In addition to the side effects mentioned above by different channel blockers, these drugs can cause arterial wall damage, thereby contributing to vascular wall structure destabilization and promoting events facilitating rupture of plaques. Collagen synthesis is regulated by ascorbic acid, which is also essential for its optimum structure as a cofactor in lysine and proline hydroxylation, a precondition for optimum crosslinking of collagen and elastin. Therefore, the main objective in this study was to evaluate effects of various types of channel blockers on intracellular accumulation and cellular functions of ascorbate, specifically in relation to formation and extracellular deposition of major collagen types relevant for vascular function. Effects of select Na- and Ca- channel blockers on collagen synthesis and deposition were evaluated in cultured human dermal fibroblasts and aortic smooth muscle cells by immunoassay. All channel blockers tested demonstrated inhibitory effects on collagen type I deposition to the ECM by fibroblasts, each to a different degree. Ascorbic acid significantly increased collagen I ECM deposition. Nifedipine (50 µM), a representative of channel blockers tested, significantly reduced ascorbic acid and ascorbyl palmitate-dependent ECM deposition of collagen type l and collagen type lV by cultured aortic smooth muscle cells. In addition, nifedipine (50 µM) significantly reduced ascorbate-dependent collagen type l and type lV synthesis by cultured aortic smooth

  18. Combined therapy for migraine prevention? Clinical experience with a beta-blocker plus sodium valproate in 52 resistant migraine patients.

    PubMed

    Pascual, J; Leira, R; Láinez, J M

    2003-12-01

    The aim was to explore whether combining a beta-blocker and sodium valproate could lead to an advantage in efficacy in patients with migraine previously resistant to the two medications in monotherapy. Fifty-two patients (43 women) with a history of episodic migraine with or without aura, and previously unresponsive to beta-blockers and sodium valproate in monotherapy, were treated with a combination of propranolol or nadolol and sodium valproate in an open-label fashion. Eight patients (15%) discontinued due to adverse events. Fifteen (29%) did not respond. The remaining 29 cases (56%) showed response (> 50% reduction in migraine days). The response was excellent in nine (17%). From this open trial, combination therapy with a beta-blocker and sodium valproate appears to be a good migraine preventative in some previously resistant migraine cases. Controlled trials are now necessary to determine the true advantage in efficacy of this combination in difficult to treat migraineurs. PMID:14984228

  19. Inhibition of collagen synthesis by select calcium and sodium channel blockers can be mitigated by ascorbic acid and ascorbyl palmitate.

    PubMed

    Ivanov, Vadim; Ivanova, Svetlana; Kalinovsky, Tatiana; Niedzwiecki, Aleksandra; Rath, Matthias

    2016-01-01

    Calcium, sodium and potassium channel blockers are widely prescribed medications for a variety of health problems, most frequently for cardiac arrhythmias, hypertension, angina pectoris and other disorders. However, chronic application of channel blockers is associated with numerous side effects, including worsening cardiac pathology. For example, nifedipine, a calcium-channel blocker was found to be associated with increased mortality and increased risk for myocardial infarction. In addition to the side effects mentioned above by different channel blockers, these drugs can cause arterial wall damage, thereby contributing to vascular wall structure destabilization and promoting events facilitating rupture of plaques. Collagen synthesis is regulated by ascorbic acid, which is also essential for its optimum structure as a cofactor in lysine and proline hydroxylation, a precondition for optimum crosslinking of collagen and elastin. Therefore, the main objective in this study was to evaluate effects of various types of channel blockers on intracellular accumulation and cellular functions of ascorbate, specifically in relation to formation and extracellular deposition of major collagen types relevant for vascular function. Effects of select Na- and Ca- channel blockers on collagen synthesis and deposition were evaluated in cultured human dermal fibroblasts and aortic smooth muscle cells by immunoassay. All channel blockers tested demonstrated inhibitory effects on collagen type I deposition to the ECM by fibroblasts, each to a different degree. Ascorbic acid significantly increased collagen I ECM deposition. Nifedipine (50 µM), a representative of channel blockers tested, significantly reduced ascorbic acid and ascorbyl palmitate-dependent ECM deposition of collagen type l and collagen type lV by cultured aortic smooth muscle cells. In addition, nifedipine (50 µM) significantly reduced ascorbate-dependent collagen type l and type lV synthesis by cultured aortic smooth

  20. Effects of extracellular calcium and of the calcium entry blockers flunarizine and nimodipine on contractile responses in human temporal arteries.

    PubMed

    Jansen, I; Edvinsson, L

    1986-12-01

    Contraction induced by 124 mM potassium followed the depolarization of smooth-muscle cells and activation of potential-operated calcium channels in human temporal arteries. The contraction elicited consisted of two phases, one rapid and one slowly developing stable phase; both were affected by the two calcium entry blockers flunarizine and nimodipine but at significantly different concentrations. In calcium-free medium 124 mM potassium resulted in a weak contraction. Addition of calcium caused a concentration-dependent contraction that was attenuated by the calcium entry blockers at concentrations comparable to those inhibiting the second phase. The results suggested that in human temporal arteries flunarizine and nimodipine act as calcium entry blockers; there was good correlation with the therapeutic plasma concentration for nimodipine but not for flunarizine. PMID:3802190

  1. [The present status and prospects of therapeutic use of beta-blockers in diseases of the cardiovascular system].

    PubMed

    Kuzelová, M; Svec, P

    1998-02-01

    Beta-blockers are being revived as effective, safe, reasonably priced and well-tolerated drugs. Differences in the pharmacodynamic and pharmacokinetic properties of beta-blockers now make it possible to select for the therapy of the individual diseases from a wide range of available beta-blockers the most effective drug with the minimal undesirable effects. It is made possible by the progress in the development of this ATS group and particularly by the third generation of these compounds. A proof of the prospects of these drugs is provided by their extended indications as the first-choice drugs (myocardial infarction) as well as the generally extended possibilities of their therapeutic use (therapy of heart failure). PMID:9600149

  2. Beta-blocker drug therapy reduces secondary cancer formation in breast cancer and improves cancer specific survival.

    PubMed

    Powe, Desmond G; Voss, Melanie J; Zänker, Kurt S; Habashy, Hany O; Green, Andrew R; Ellis, Ian O; Entschladen, Frank

    2010-11-01

    Laboratory models show that the beta-blocker, propranolol, can inhibit norepinephrine-induced breast cancer cell migration. We hypothesised that breast cancer patients receiving beta-blockers for hypertension would show reduced metastasis and improved clinical outcome. Three patient subgroups were identified from the medical records of 466 consecutive female patients (median age 57, range 28-71) with operable breast cancer and follow-up (>10 years). Two subgroups comprised 43 and 49 hypertensive patients treated with beta-blockers or other antihypertensives respectively, prior to cancer diagnosis. 374 patients formed a non-hypertensive control group. Metastasis development, disease free interval, tumour recurrence and hazards risk were statistically compared between groups. Kaplan-Meier plots were used to model survival and DM. Beta-blocker treated patients showed a significant reduction in metastasis development (p=0.026), tumour recurrence (p=0.001), and longer disease free interval (p=0.01). In addition, there was a 57% reduced risk of metastasis (Hazards ratio=0.430; 95% CI=0.200-0.926, p=0.031), and a 71% reduction in breast cancer mortality after 10 years (Hazards ratio=0.291; 95% CI=0.119-0.715, p=0.007). This proof-of-principle study showed beta-blocker therapy significantly reduces distant metastases, cancer recurrence, and cancer-specific mortality in breast cancer patients suggesting a novel role for beta-blocker therapy. A larger epidemiological study leading to randomised clinical trials is needed for breast and other cancer types including colon, prostate and ovary. PMID:21317458

  3. Impact of oral beta-blocker therapy on mortality after primary percutaneous coronary intervention for Killip class 1 myocardial infarction.

    PubMed

    Hioki, Hirofumi; Motoki, Hirohiko; Izawa, Atsushi; Kashima, Yuichirou; Miura, Takashi; Ebisawa, Souichirou; Tomita, Takeshi; Miyashita, Yusuke; Koyama, Jun; Ikeda, Uichi

    2016-05-01

    The use of beta-blockers therapy has been recommended to reduce mortality in patients with left ventricular dysfunction after acute myocardial infarction (AMI). Primary percutaneous coronary intervention (PCI), which has become the mainstay of treatment for AMI, is associated with a lower mortality than fibrinolysis. The benefits of beta-blockers after primary PCI in AMI patients without pump failure are unclear. We hypothesized that oral beta-blocker therapy after primary PCI might reduce the mortality in AMI patients without pump failure. The assessment of lipophilic vs. hydrophilic statin therapy in acute myocardial infarction (ALPS-AMI) study was a multi-center study that enrolled 508 AMI patients to compare the efficacy of hydrophilic and lipophilic statins in secondary prevention after myocardial infarction. We prospectively tracked cardiovascular events for 3 years in 444 ALPS-AMI patients (median age 66 years; 18.2 % women) who had Killip class 1 on admission and were discharged alive. The primary endpoint was all-cause mortality. The 3-year follow-up was completed in 413 patients (93.0 %). During this follow-up, 21 patients (4.7 %) died. In Kaplan-Meier analysis, patients on beta-blockers had a significantly lower incidence of all-cause mortality (2.7 vs. 7.3 %, log-rank p = 0.025). After adjusting for the calculated propensity score for using beta-blockers, their use remained an independent predictor of all-cause mortality (hazard ratio 0.309; 95 % confidence interval 0.116-0.824; p = 0.019). In the statin era, the use of beta-blocker therapy after primary PCI is associated with lower mortality in AMI patients with Killip class 1 on admission. PMID:25863805

  4. Increasing RO efficiency by chemical-free ion-exchange and Donnan dialysis: Principles and practical implications.

    PubMed

    Vanoppen, Marjolein; Stoffels, Griet; Demuytere, Célestin; Bleyaert, Wouter; Verliefde, Arne R D

    2015-09-01

    Ion-exchange (IEX) and Donnan dialysis (DD) are techniques which can selectively remove cations, limiting scaling in reverse osmosis (RO). If the RO concentrate could be recycled for regeneration of these pre-treatment techniques, RO recovery could be largely increased without the need for chemical addition or additional technologies. In this study, two different RO feed streams (treated industrial waste water and simple tap water) were tested in the envisioned IEX-RO and DD-RO hybrids including RO concentrate recycling. The efficiency of multivalent cation removal depends mainly on the ratio of monovalent to multivalent cations in the feed stream, influencing the ion-exchange efficiency in both IEX and DD. Since the mono-to-multivalent ratio was very high in the waste water, the RO recovery could potentially be increased to 92%. For the tap water, these high RO recoveries could only be reached by adding additional NaCl, because of the low initial monovalent to multivalent ratio in the feed. In both cases, the IEX-RO hybrid proved to be most cost-efficient, due to the high current cost of the membranes used in DD. The membrane cost would have to decrease from ±300 €/m² to 10-30 €/m² - comparable to current reverse osmosis membranes - to achieve a comparable cost. In conclusion, the recycling of RO concentrate to regenerate ion exchange pre-treatment techniques for RO is an interesting option to increase RO recovery without addition of chemicals, but only at high monovalent/multivalent cation-ratios in the feed stream. PMID:25996753

  5. Draft Genome Sequence of the Xylella fastidiosa CoDiRO Strain.

    PubMed

    Giampetruzzi, Annalisa; Chiumenti, Michela; Saponari, Maria; Donvito, Giacinto; Italiano, Alessandro; Loconsole, Giuliana; Boscia, Donato; Cariddi, Corrado; Martelli, Giovanni Paolo; Saldarelli, Pasquale

    2015-01-01

    We determined the draft genome sequence of the Xylella fastidiosa CoDiRO strain, which has been isolated from olive plants in southern Italy (Apulia). It is associated with olive quick decline syndrome (OQDS) and characterized by extensive scorching and desiccation of leaves and twigs. PMID:25676759

  6. Jean Vigo's "Zéro De Conduite" and the Spaces of Revolt

    ERIC Educational Resources Information Center

    Vanobbergen, Bruno; Grosvenor, Ian; Simon, Frank

    2014-01-01

    In this article we will contribute to the contemporary theoretical debate about film by considering, from a history-of-education perspective, the film "Zéro de conduite" by Jean Vigo (1905--1934). This film is classified under the umbrella of "poetic realism": a product of "cinéma de gauche" and an avant-gardist,…

  7. Highly Oxidized RO2 Radicals and Consecutive Products from the Ozonolysis of Three Sesquiterpenes.

    PubMed

    Richters, Stefanie; Herrmann, Hartmut; Berndt, Torsten

    2016-03-01

    The formation of highly oxidized multifunctional organic compounds (HOMs) from the ozonolysis of three sesquiterpenes, α-cedrene, β-caryophyllene, and α-humulene, was investigated for the first time. Sesquiterpenes contribute 2.4% to the global carbon emission of biogenic volatile organic compounds (BVOCs) and can be responsible for up to 70% of the regional BVOC emissions. HOMs were detected with chemical ionization-atmospheric pressure interface-time-of-flight mass spectrometry and nitrate and acetate ionization. Acetate ions were more sensitive toward highly oxidized RO2 radicals containing a single hydroperoxide moiety. Under the chosen reaction conditions, product formation was dominated by highly oxidized RO2 radicals which react with NO, NO2, HO2, and other RO2 radicals under atmospheric conditions. The ozonolysis of sesquiterpenes resulted in molar HOM yields of 0.6% for α-cedrene (acetate), 1.8% for β-caryophyllene (acetate), and 1.4% for α-humulene (nitrate) afflicted with an uncertainty factor of 2. Molar yields of highly oxidized RO2 radicals were identical with HOM yields measuring the corresponding closed-shell products. HOM formation from ozonolysis of α-cedrene was explained by an autoxidation mechanism initiated by ozone attack at the double bond similar to that found in the ozonolysis of cyclohexene and limonene. PMID:26830670

  8. Proposal of adaptive wireless cell configuration for RoF-DAS over WDM-PON system

    NASA Astrophysics Data System (ADS)

    Iwakuni, Tatsuhiko; Miyamoto, Kenji; Higashino, Takeshi; Tsukamoto, Katsutoshi; Komaki, Shozo; Tashiro, Takayoshi; Fukada, Youichi; Kani, Jun-ichi; Yoshimoto, Naoto; Iwatsuki, Katsumi

    2013-01-01

    Radio on fiber (RoF) - distributed antenna system (DAS) over wavelength division multiplexing - passive optical network (WDM-PON) with multiple - input multiple - output (MIMO) has been proposed as a next generation radio access network (RAN). This system employs optical time division multiplexing (OTDM) over one WDM channel to multiplex and transmit various types of wireless interfaces such as 3.9G, Wireless LAN and WiMAX. A combination of star and bus topologies has employed to cover a wider service area. The optical transmission loss is caused notably at remote base stations (RBSs) quipped on a WDM bus link. The loss is relatively small, but at the RBS far from the center station (CS), the RBS suffers the large accumulated loss, so the reduction of cell size provides the increasing of the number of RBSs, causes the degradation of the SNR of RoF link. This paper addresses this trade-off problem, and considers the application to the actual service area by the channel capacity investigation of RoF-DAS over WDM-PON with computer simulation. Then, this paper focuses on the flexibility of RoF-DAS over WDM-PON, considers the adaptive wireless cell configuration according to population fluctuations of day and night, or densely populated areas and sparsely populated areas, respectively.

  9. HD 12098 a new far-northern roAp star

    NASA Astrophysics Data System (ADS)

    Girish, V.; Joshi, S.; Seetha, S.; Ashoka, B. N.; Martinez, P.; Chaubey, U. S.; Gupta, S. K.; Kurtz, D. W.; Sagar, R.

    2001-09-01

    The rapidly oscillating Ap (roAp) stars are cool, magnetic, chemically peculiar stars which pulsate in non-radial p-modes in the period range 4-16 min and have Johnson B amplitudes less than 8 mmag. "The NainiTal-Cape survey" to search for and study new roAp stars in the northern hemisphere was initiated in 1998 in collaboration between ISAC & UPSO from India and SAAO & UCT from South Africa. HD12098 is the first roAp star discovered in this survey and also the first far northern hemisphere roAp star. During the initial observations the star showed modulation in the pulsation amplitude indicating the multi-periodicity of pulsations. The multi-periodicity may be either due to the excitation of different modes or due to the rotation of the star. In order to resolve these frequencies HD12098 was observed extensively in October 2000. The preliminary results of these observations are presented here.

  10. Bidirectional hybrid PM-based RoF and VCSEL-based VLLC system.

    PubMed

    Li, Chung-Yi; Lu, Hai-Han; Chang, Ching-Hung; Lin, Chun-Yu; Wu, Po-Yi; Zheng, Jun-Ren; Lin, Chia-Rung

    2014-06-30

    A bidirectional hybrid phase modulation (PM)-based radio-over-fiber (RoF) and vertical cavity surface emitting laser (VCSEL)-based visible laser light communication (VLLC) systems employing injection-locked VCSEL-based PM-to-intensity modulation (IM) converters and optical interleavers (ILs) is proposed and demonstrated. To be the first one of using injection-locked VCSEL-based PM-to-IM converters and optical ILs in such bidirectional hybrid RoF and VLLC systems, the downstream light is successfully phase-remodulated with RoF signal for up-link transmission. Through a serious investigation in systems, bit error rate (BER) and eye diagram perform brilliantly over a 40-km single-mode fiber (SMF) transport and a 12-m free-space transmission. Such a bidirectional hybrid RoF and VLLC system would be very attractive for the integration of fiber backbone and in-door networks to provide broadband integrated services, including Internet and telecommunication services. PMID:24977870

  11. RoMPS concept review automatic control of space robot, volume 2

    NASA Technical Reports Server (NTRS)

    Dobbs, M. E.

    1991-01-01

    Topics related to robot operated materials processing in space (RoMPS) are presented in view graph form and include: (1) system concept; (2) Hitchhiker Interface Requirements; (3) robot axis control concepts; (4) Autonomous Experiment Management System; (5) Zymate Robot Controller; (6) Southwest SC-4 Computer; (7) oven control housekeeping data; and (8) power distribution.

  12. Spectral characterization and differential rotation study of active CoRoT stars

    NASA Astrophysics Data System (ADS)

    Nagel, E.; Czesla, S.; Schmitt, J. H. M. M.

    2016-05-01

    The CoRoT space telescope observed nearly 160 000 light curves. Among the most outstanding is that of the young, active planet host star CoRoT-2A. In addition to deep planetary transits, the light curve of CoRoT-2A shows strong rotational variability and a superimposed beating pattern. To study the stars that produce such an intriguing pattern of photometric variability, we identified a sample of eight stars with rotation periods between 0.8 and 11 days and photometric variability amplitudes of up to 7.5%, showing a similar CoRoT light curve. We also obtained high-resolution follow-up spectroscopy with TNG/SARG and carried out a spectral analysis with SME and MOOG. We find that the color dependence of the light curves is consistent with rotational modulation due to starspots and that latitudinal differential rotation provides a viable explanation for the light curves, although starspot evolution is also expected to play an important role. Our MOOG and SME spectral analyses provide consistent results, showing that the targets are dwarf stars with spectral types between F and mid-K. Detectable Li i absorption in four of the targets confirms a low age of 100-400 Myr also deduced from gyrochronology. Our study indicates that the photometric beating phenomenon is likely attributable to differential rotation in fast-rotating stars with outer convection zones.

  13. Possible role of anti-SSA/Ro antibodies in the pathogenesis of pulmonary hypertension

    PubMed Central

    Guerreso, Kelsey; Conner, Edward Alexander

    2016-01-01

    Introduction There are many different causes of pulmonary hypertension and the pathogenesis of the disease is still being elucidated. Although they are not the most common, autoimmunity and inflammation have been identified as possible causes. No one autoantibody has been identified as the definite cause of pulmonary hypertension. We present a rare association of anti-SSA/Ro antibodies and isolated pulmonary hypertension. Case presentation A 53 year old African American female presented with abdominal pain, nausea, weight loss, dyspnea and fatigue. Upon further exam she was found to have high titers of antinuclear antibodies and anti-SSA/Ro antibodies. This antibody profile would typically be suggestive of Sjögren's Syndrome, which is characterized by dry eyes and poor salivary gland function. However, since this patient did not have any symptoms consistent with the disease a diagnosis of Sjögren's Syndrome could not be made. A combination of laboratory, imaging and diagnostic studies were done that revealed a final diagnosis of pulmonary hypertension. Conclusion It is known that pulmonary hypertension has association with autoimmune diseases, however no clear markers yet exist. Anti-SSA/Ro antibodies have been rarely described in cases of pulmonary disease, and less so in pulmonary hypertension. This case describes a unique association between isolated pulmonary hypertension and anti-SSA/Ro antibody, thereby illustrating the need to investigate this autoantibody and others in the pathogenesis of autoimmune pulmonary hypertension.

  14. Uncovering the planets and stellar activity of CoRoT-7 using only radial velocities

    NASA Astrophysics Data System (ADS)

    Faria, J. P.; Haywood, R. D.; Brewer, B. J.; Figueira, P.; Oshagh, M.; Santerne, A.; Santos, N. C.

    2016-04-01

    Stellar activity can induce signals in the radial velocities of stars, complicating the detection of orbiting low-mass planets. We present a method to determine the number of planetary signals present in radial-velocity datasets of active stars, using only radial-velocity observations. Instead of considering separate fits with different number of planets, we use a birth-death Markov chain Monte Carlo algorithm to infer the posterior distribution for the number of planets in a single run. In a natural way, the marginal distributions for the orbital parameters of all planets are also inferred. This method is applied to HARPS data of CoRoT-7. We confidently recover the orbits of both CoRoT-7b and CoRoT-7c although the data show evidence for the presence of additional signals. All data and software presented in this article are available online at http://https://github.com/j-faria/exoBD-CoRoT7

  15. Association between β-blocker therapy and outcomes in patients hospitalised with acute exacerbations of chronic obstructive lung disease with underlying ischaemic heart disease, heart failure or hypertension

    PubMed Central

    Stefan, Mihaela S; Rothberg, Michael B; Priya, Aruna; Pekow, Penelope S; Au, David H; Lindenauer, Peter K

    2015-01-01

    Background β-Blocker therapy has been shown to improve survival among patients with ischaemic heart disease (IHD) and congestive heart failure (CHF) and is underused among patients with chronic obstructive pulmonary disease (COPD). Evidence regarding the optimal use of β-blocker therapy during an acute exacerbation of COPD is particularly weak. Methods We conducted a retrospective cohort study of patients aged ≥40 years with IHD, CHF or hypertension who were hospitalised for an acute exacerbation of COPD from 1 January 2006 to 1 December 2007 at 404 acute care hospitals throughout the USA. We examined the association between β-blocker therapy and in-hospital mortality, initiation of mechanical ventilation after day 2 of hospitalisation, 30-day all-cause readmission and length of stay. Results Of 35 082 patients who met the inclusion criteria, 29% were treated with β blockers in the first two hospital days, including 22% with β1-selective and 7% with non-selective β blockers. In a propensity-matched analysis, there was no association between β-blocker therapy and in-hospital mortality (OR 0.88, 95% CI 0.71 to 1.09), 30-day readmission (OR 0.96, 95% CI 0.89 to 1.03) or late mechanical ventilation (OR 0.98, 95% CI 0.77 to 1.24). However, when compared with β1 selective β blockers, receipt of non-selective β blockers was associated with an increased risk of 30-day readmission (OR 1.25, 95% CI 1.08 to 1.44). Conclusions Among patients with IHD, CHF or hypertension, continuing β1-selective β blockers during hospitalisation for COPD appears to be safe. Until additional evidence becomes available, β1-selective β blockers may be superior to treatment with a non-selective β blocker. PMID:22941975

  16. A New Method for Detecting and Monitoring Atmospheric Natural Hazards with GPS RO

    NASA Astrophysics Data System (ADS)

    Biondi, R.; Steiner, A. K.; Rieckh, T. M.; Kirchengast, G.

    2014-12-01

    Global Positioning System (GPS) Radio Occultation (RO) allows measurements in any meteorological condition, with global coverage, high vertical resolution, and high accuracy. With more than 13 years of data availability, RO also became a fundamental tool for studying climate change. We present here the application of RO for detecting and monitoring tropical cyclones (TCs), deep convective systems (CSs) and volcanic ash clouds (ACs).Deep CSs and TCs play a fundamental role in atmospheric circulation producing vertical transport, redistributing water vapor and trace gases, changing the thermal structure of the Upper Troposphere and Lower Stratosphere (UTLS) and affecting climate through overshooting into the stratosphere. Explosive volcanic eruptions produce large ACs dangerous for the aviation and they can impact climate when the ash is injected into the UTLS.The detection of cloud top height, the determination of cloud extent, the discrimination of ACs from CSs clouds and the detection of overshooting are main challenges for atmospheric natural hazards study. We created a reference atmosphere with a resolution of 5° in latitude and longitude, sampled on a 1° x 1° grid, and a vertical sampling of 100 m. We then compared RO profiles acquired during TCs, CSs and ACs to the reference atmosphere and computed anomaly profiles.CSs, TCs and the ACs leave a clear signature in the atmosphere which can be detected by RO. Using RO temperature and bending angle profiles we gain insight into the vertical thermal structure and developed a new method for detecting the cloud top altitude with high accuracy.We have characterized the TCs by ocean basins and intensities, showing that they have a different thermal structure and reach to different altitudes according to the basin. We provide statistics on overshooting frequency, achieving results consistent with patterns found in the literature and demonstrating that RO is well suited for this kind of study. We have analyzed the

  17. ACT‐ONE ‐ ACTION at last on cancer cachexia by adapting a novel action beta‐blocker

    PubMed Central

    Laviano, Alessandro

    2016-01-01

    Abstract Novel action beta‐blockers combine many different pharmacological effects. The espindolol exhibits effects through β and central 5‐HT1α receptors to demonstrate pro‐anabolic, anti‐catabolic, and appetite‐stimulating actions. In the ACT‐ONE trial, espindolol reversed weight loss and improved handgrip strength in patients with cachexia due to non‐small cell lung cancer or colorectal cancer. With this trial, another frontier of cachexia management is in sight. Nonetheless, more efficacy and safety data is needed before new therapeutic indications for novel action beta‐blockers can be endorsed. PMID:27625919

  18. Prediction of the effectiveness of long term β blocker treatment for dilated cardiomyopathy by signal averaged electrocardiography

    PubMed Central

    Yamada, T; Fukunami, M; Shimonagata, T; Kumagai, K; Kim, J; Sanada, S; Ogita, H; Hori, M; Hoki, N

    1998-01-01

    Objective—To determine whether the effectiveness of long term β blocker treatment for idiopathic dilated cardiomyopathy can be predicted by signal averaged electrocardiography (ECG).
Patients—31 patients with dilated cardiomyopathy and without bundle branch block were included in a retrospective study and 16 in a prospective study.
Methods—A signal averaged ECG was recorded before β blocker treatment, and three variables were measured from the vector magnitude: QRS duration, root mean square voltage for the last 40 ms (RMS40), and duration of the terminal low amplitude signals (< 40 µV) (LAS40). In the retrospective study, these variables were compared among good responders (showing ⩾ 0.10 increase in ejection fraction 12 months after start of β blocker treatment) and poor responders without such improvement. The validity of the signal averaged ECG criteria for prediction of the response to β blocker treatment was examined in the prospective study.
Results—In the retrospective study, good responders (n = 16) had a shorter QRS duration (mean (SD): 122.9 (11) v 138 (14.4) ms, p < 0.005) and LAS40 (33.1 (8.9) v 42.5 (7.8) ms, p < 0.005), and a higher RMS40 (31.6 (16.3) v 19.0 (10.3) µV, p < 0.02) than poor responders (n = 15). Signal averaged ECG criteria for good response were defined as two or more of the following: QRS duration < 130 ms, RMS40 > 20 µV, LAS40 < 40 ms (sensitivity 81%, specificity 73%). In the prospective study, six of seven patients who met these criteria showed a good response to the β blocker treatment, while eight of nine who did not showed a poor response (χ2 = 6.1, p < 0.02). The signal averaged ECG criteria gave a sensitivity of 86% and a specificity of 89% for predicting the effectiveness of β blocker treatment.
Conclusions—A signal averaged ECG might be useful in predicting the effectiveness of β blocker treatment for dilated cardiomyopathy.

 Keywords: signal

  19. The 52 000 MW Ro/SS-A autoantigen in Sjögren's syndrome/systemic lupus erythematosus (Ro52) is an interferon-gamma inducible tripartite motif protein associated with membrane proximal structures.

    PubMed

    Rhodes, Davd A; Ihrke, Gudrun; Reinicke, Anna T; Malcherek, Georg; Towey, Michael; Isenberg, David A; Trowsdale, John

    2002-06-01

    The 52 000 MW Ro/SS-A (Ro52) protein is a major target of autoantibodies in autoimmune conditions such as systemic lupus erythematosus and Sjögren's syndrome. Recent genomic and bioinformatic studies have shown that Ro52 belongs to a large family of related RING/Bbox/coiled-coil (RBCC) tripartite motif proteins sharing overall domain structure and 40-50% identity at the amino acid level. Ro52 also has a B30.2 domain at the C-terminus. Using the human genome draft sequence, the genomic organization of the Ro52 gene on human chromosome 11p15.5 has been deduced and related to the protein domain structure. We show that the steady-state levels of Ro52 mRNA are normally very low but are induced by cell activation with interferon-gamma. In transient transfection of HeLa cells, epitope-tagged Ro52 protein was localized to unidentified membrane proximal rod-like structures. Using in vitro coupled transcription/translation followed by immunoprecipitation, the autoimmune response to Ro52 protein was investigated and two distinct interactions were resolved. The Ro52 C-terminal B30.2 domain interacts with human immunoglobulin independently of antibody specificities. Sera derived from patients with Sjögren's syndrome and systemic lupus erythematosus, in addition, contained specific autoantibodies directed towards the rest of the Ro52 molecule. The majority of these autoimmune sera also immunoprecipitated the Ro52-related molecule RNF15. A possible role for Ro52 protein in alterations of plasma membranes during cellular activation or apoptosis is discussed. PMID:12047754

  20. PTEN regulates sensitivity of melanoma cells to RO4929097, the γ-secretase inhibitor.

    PubMed

    Nair, Jayasree S; Sheikh, Tahir; Ho, Alan L; Schwartz, Gary K

    2013-04-01

    De-regulated expression of components of the Notch signaling pathway is observed in malignant melanoma. This pathway is activated by catalytic cleavage of the Notch receptor by γ-secretase. Phase-I trials with RO4929097, a potent gamma secretase inhibitor (GSI), and other agents of this class have demonstrated clinical activity in patients with melanoma. An understanding of the mechanisms for de novo sensitivity and resistance to this class of drugs would be critical for future drug development. We treated a panel of Phosphatase and Tensin Homolog (PTEN)-null, -mutant and -wild-type human melanoma cell lines with RO4929097 and evaluated the efficacy alone and in combination with chemotherapy. Although cleaved Notch-1 formation was observed in all the cell lines, RO4929097-induced senescence or apoptosis was achieved only in PTEN-wild-type cell lines in which gamma-secretase inhibition with an induction of PTEN expression and decreased AKT/PKB (protein kinase B) phosphorylation in addition to transcriptional suppression at the Hairy and enhancer of split-1 (HES1) gene promoter. Overexpression of wild-type PTEN in PTEN-null and -mutant cell lines, and studies with isogenic breast cell lines that differ only in PTEN status, confirmed the importance of PTEN expression for conferring tumor cell susceptibility to RO4929097. Furthermore, in PTEN-expressing rapidly accelerated fibrosarcoma 1 (B-RAF)-mutant melanoma cells, RO4929097 enhanced the effect of temozolomide both in vitro and in vivo. These results indicate that tumor cell susceptibility to a GSI, whether alone or in combination with chemotherapy, are reliant upon reducing AKT phosphorylation and hence GSI in combination with chemotherapy may be useful as a new therapeutic approach in treating PTEN-wild-type melanoma. PMID:23564767

  1. Quantum Calculation of Inelastic CO Collisions with H. III. Rate Coefficients for Ro-vibrational Transitions

    NASA Astrophysics Data System (ADS)

    Song, L.; Balakrishnan, N.; Walker, K. M.; Stancil, P. C.; Thi, W. F.; Kamp, I.; van der Avoird, A.; Groenenboom, G. C.

    2015-11-01

    We present calculated rate coefficients for ro-vibrational transitions of CO in collisions with H atoms for a gas temperature range of 10 K ≤ T ≤ 3000 K, based on the recent three-dimensional ab initio H-CO interaction potential of Song et al. Rate coefficients for ro-vibrational v=1,j=0-30\\to v\\prime =0,j\\prime transitions were obtained from scattering cross sections previously computed with the close-coupling (CC) method by Song et al. Combining these with the rate coefficients for vibrational v=1-5\\to v\\prime \\lt v quenching obtained with the infinite-order sudden approximation, we propose a new extrapolation scheme that yields the rate coefficients for ro-vibrational v=2-5,j=0-30\\to v\\prime ,j\\prime de-excitation. Cross sections and rate coefficients for ro-vibrational v=2,j=0-30\\to v\\prime =1,j\\prime transitions calculated with the CC method confirm the effectiveness of this extrapolation scheme. Our calculated and extrapolated rates are very different from those that have been adopted in the modeling of many astrophysical environments. The current work provides the most comprehensive and accurate set of ro-vibrational de-excitation rate coefficients for the astrophysical modeling of the H-CO collision system. The application of the previously available and new data sets in astrophysical slab models shows that the line fluxes typically change by 20%-70% in high temperature environments (800 K) with an H/H2 ratio of 1; larger changes occur for lower temperatures.

  2. Colloidal interactions and fouling of NF and RO membranes: a review.

    PubMed

    Tang, Chuyang Y; Chong, T H; Fane, Anthony G

    2011-05-11

    Colloids are fine particles whose characteristic size falls within the rough size range of 1-1000 nm. In pressure-driven membrane systems, these fine particles have a strong tendency to foul the membranes, causing a significant loss in water permeability and often a deteriorated product water quality. There have been a large number of systematic studies on colloidal fouling of reverse osmosis (RO) and nanofiltration (NF) membranes in the last three decades, and the understanding of colloidal fouling has been significantly advanced. The current paper reviews the mechanisms and factors controlling colloidal fouling of both RO and NF membranes. Major colloidal foulants (including both rigid inorganic colloids and organic macromolecules) and their properties are summarized. The deposition of such colloidal particles on an RO or NF membrane forms a cake layer, which can adversely affect the membrane flux due to 1) the cake layer hydraulic resistance and/or 2) the cake-enhanced osmotic pressure. The effects of feedwater compositions, membrane properties, and hydrodynamic conditions are discussed in detail for inorganic colloids, natural organic matter, polysaccharides, and proteins. In general, these effects can be readily explained by considering the mass transfer near the membrane surface and the colloid-membrane (or colloid-colloid) interaction. The critical flux and limiting flux concepts, originally developed for colloidal fouling of porous membranes, are also applicable to RO and NF membranes. For small colloids (diameter≪100 nm), the limiting flux can result from two different mechanisms: 1) the diffusion-solubility (gel formation) controlled mechanism and 2) the surface interaction controlled mechanism. The former mechanism probably dominates for concentrated solutions, while the latter mechanism may be more important for dilute solutions. Future research needs on RO and NF colloidal fouling are also identified in the current paper. PMID:21094487

  3. Investigation of the mechanisms of neuroprotection mediated by Ro5-4864 in brain injury.

    PubMed

    Palzur, Eilam; Sharon, Aviram; Shehadeh, Mona; Soustiel, Jean Francois

    2016-08-01

    Increasing evidence has established the involvement of the 18-kDa translocator protein (TSPO) in the process of mitochondrial membrane permeabilization and subsequent apoptosis through modulation of the mitochondrial permeability transition pore. Recent studies have shown that treatment with Ro5-4864, a TSPO ligand, resulted in a neuroprotective effect in traumatic brain injury. Yet, the nature of this effect remained uncertain as mature neurons are considered to be lacking the TSPO protein. In order to investigate the mechanism of Ro5-4864-mediated neuroprotection, the neuro-inflammatory and neurosteroid response to cortical injury was tested in sham-operated, vehicle, cyclosporine A (CsA) and Ro5-4864-treated rats. As anticipated, the levels of interleukin 1β and tumor necrosis factor α, as well as the astrocyte and microglia cellular density in the injured area were all decreased by CsA in comparison with the vehicle group. By contrast, no visible effect could be observed in Ro5-4864-treated animals. None of the groups showed any significant difference with any other in respect with the expression of brain-derived neurotrophic factor. Double immunofluorescence staining with NeuN and TSPO confirmed the absence of TSPO in native neurons though showed clear evidence of co-localization of TSPO in the cytoplasm of NeuN-stained injured neurons. Altogether, this study shows that the neuronal protection mediated by Ro5-4864 in brain injury cannot be solely attributed to an indirect effect of the ligand on glial TSPO but may also represent the consequence of the modulation of upregulated TSPO in injured neurons. This observation may be of importance for future pharmacological research in neurotrauma. PMID:27223627

  4. BEER analysis of Kepler and CoRoT light curves. III. Spectroscopic confirmation of seventy new beaming binaries discovered in CoRoT light curves

    NASA Astrophysics Data System (ADS)

    Tal-Or, L.; Faigler, S.; Mazeh, T.

    2015-08-01

    Context. The BEER algorithm searches stellar light curves for the BEaming, Ellipsoidal, and Reflection photometric modulations that are caused by a short-period companion. These three effects are typically of very low amplitude and can mainly be detected in light curves from space-based photometers. Unlike eclipsing binaries, these effects are not limited to edge-on inclinations. Aims: Applying the algorithm to wide-field photometric surveys such as CoRoT and Kepler offers an opportunity to better understand the statistical properties of short-period binaries. It also widens the window for detecting intrinsically rare systems, such as short-period brown-dwarf and massive-planetary companions to main-sequence stars. Methods: Applying the search to the first five long-run center CoRoT fields, we identified 481 non-eclipsing candidates with periodic flux amplitudes of 0.5-87 mmag. Optimizing the Anglo-Australian-Telescope pointing coordinates and the AAOmega fiber-allocations with dedicated softwares, we acquired six spectra for 231 candidates and seven spectra for another 50 candidates in a seven-night campaign. Analysis of the red-arm AAOmega spectra, which covered the range of 8342-8842 Å, yielded a radial-velocity precision of ~1 km s-1. Spectra containing lines of more than one star were analyzed with the two-dimensional correlation algorithm TODCOR. Results: The measured radial velocities confirmed the binarity of seventy of the BEER candidates - 45 single-line binaries, 18 double-line binaries, and 7 diluted binaries. We show that red giants introduce a major source of false candidates and demonstrate a way to improve BEER's performance in extracting higher fidelity samples from future searches of CoRoT light curves. The periods of the confirmed binaries span a range of 0.3-10 days and show a rise in the number of binaries per ΔlogP toward longer periods. The estimated mass ratios of the double-line binaries and the mass ratios assigned to the single

  5. Mutation-induced Blocker Permeability and Multiion Block of the CFTR Chloride Channel Pore

    PubMed Central

    Gong, Xiandi; Linsdell, Paul

    2003-01-01

    Chloride permeation through the cystic fibrosis transmembrane conductance regulator (CFTR) Cl− channel is blocked by a broad range of anions that bind tightly within the pore. Here we show that the divalent anion Pt(NO2)42− acts as an impermeant voltage-dependent blocker of the CFTR pore when added to the intracellular face of excised membrane patches. Block was of modest affinity (apparent Kd 556 μM), kinetically fast, and weakened by extracellular Cl− ions. A mutation in the pore region that alters anion selectivity, F337A, but not another mutation at the same site that has no effect on selectivity (F337Y), had a complex effect on channel block by intracellular Pt(NO2)42− ions. Relative to wild-type, block of F337A-CFTR was weakened at depolarized voltages but strengthened at hyperpolarized voltages. Current in the presence of Pt(NO2)42− increased at very negative voltages in F337A but not wild-type or F337Y, apparently due to relief of block by permeation of Pt(NO2)42− ions to the extracellular solution. This “punchthrough” was prevented by extracellular Cl− ions, reminiscent of a “lock-in” effect. Relief of block in F337A by Pt(NO2)42− permeation was only observed for blocker concentrations above 300 μM; as a result, block at very negative voltages showed an anomalous concentration dependence, with an increase in blocker concentration causing a significant weakening of block and an increase in Cl− current. We interpret this effect as reflecting concentration-dependent permeability of Pt(NO2)42− in F337A, an apparent manifestation of an anomalous mole fraction effect. We suggest that the F337A mutation allows intracellular Pt(NO2)42− to enter deeply into the CFTR pore where it interacts with multiple binding sites, and that simultaneous binding of multiple Pt(NO2)42− ions within the pore promotes their permeation to the extracellular solution. PMID:14610019

  6. Mutation-induced blocker permeability and multiion block of the CFTR chloride channel pore.

    PubMed

    Gong, Xiandi; Linsdell, Paul

    2003-12-01

    Chloride permeation through the cystic fibrosis transmembrane conductance regulator (CFTR) Cl- channel is blocked by a broad range of anions that bind tightly within the pore. Here we show that the divalent anion Pt(NO2)42- acts as an impermeant voltage-dependent blocker of the CFTR pore when added to the intracellular face of excised membrane patches. Block was of modest affinity (apparent Kd 556 microM), kinetically fast, and weakened by extracellular Cl- ions. A mutation in the pore region that alters anion selectivity, F337A, but not another mutation at the same site that has no effect on selectivity (F337Y), had a complex effect on channel block by intracellular Pt(NO2)42- ions. Relative to wild-type, block of F337A-CFTR was weakened at depolarized voltages but strengthened at hyperpolarized voltages. Current in the presence of Pt(NO2)42- increased at very negative voltages in F337A but not wild-type or F337Y, apparently due to relief of block by permeation of Pt(NO2)42- ions to the extracellular solution. This "punchthrough" was prevented by extracellular Cl- ions, reminiscent of a "lock-in" effect. Relief of block in F337A by Pt(NO2)42- permeation was only observed for blocker concentrations above 300 microM; as a result, block at very negative voltages showed an anomalous concentration dependence, with an increase in blocker concentration causing a significant weakening of block and an increase in Cl- current. We interpret this effect as reflecting concentration-dependent permeability of Pt(NO2)42- in F337A, an apparent manifestation of an anomalous mole fraction effect. We suggest that the F337A mutation allows intracellular Pt(NO2)42- to enter deeply into the CFTR pore where it interacts with multiple binding sites, and that simultaneous binding of multiple Pt(NO2)42- ions within the pore promotes their permeation to the extracellular solution. PMID:14610019

  7. Otilonium: a potent blocker of neuronal nicotinic ACh receptors in bovine chromaffin cells.

    PubMed Central

    Gandía, L.; Villarroya, M.; Lara, B.; Olmos, V.; Gilabert, J. A.; López, M. G.; Martínez-Sierra, R.; Borges, R.; García, A. G.

    1996-01-01

    1. Otilonium, a clinically useful spasmolytic, behaves as a potent blocker of neuronal nicotinic acetylcholine receptors (AChR) as well as a mild wide-spectrum Ca2+ channel blocker in bovine adrenal chromaffin cells. 2. 45Ca2+ uptake into chromaffin cells stimulated with high K+ (70 mM, 1 min) was blocked by otilonium with an IC50 of 7.6 microM. The drug inhibited the 45Ca2+ uptake stimulated by the nicotinic AChR agonist, dimethylphenylpiperazinium (DMPP) with a 79 fold higher potency (IC50 = 0.096 microM). 3. Whole-cell Ba2+ currents (IBa) through Ca2+ channels of voltage-clamped chromaffin cells were blocked by otilonium with an IC50 of 6.4 microM, very close to that of K(+)-evoked 45Ca2+ uptake. Blockade developed in 10-20 s, almost as a single step and was rapidly and almost fully reversible. 4. Whole-cell nicotinic AChR-mediated currents (250 ms pulses of 100 microM DMPP) applied at 30 s intervals were blocked by otilonium in a concentration-dependent manner, showing an IC50 of 0.36 microM. Blockade was induced in a step-wise manner. Wash out of otilonium allowed a slow recovery of the current, also in discrete steps. 5. In experiments with recordings in the same cells of whole-cell IDMPP, Na+ currents (INa) and Ca2+ currents (ICa), 1 microM otilonium blocked 87% IDMPP, 7% INa and 13% ICa. 6. Otilonium inhibited the K(+)-evoked catecholamine secretory response of superfused bovine chromaffin cells with an IC50 of 10 microM, very close to the IC50 for blockade of K(+)-induced 45Ca2+ uptake and IBa. 7. Otilonium inhibited the secretory responses induced by 10 s pulses of 50 microM DMPP with an IC50 of 7.4 nM. Hexamethonium blocked the DMPP-evoked responses with an IC50 of 29.8 microM, 4,000 fold higher than that of otilonium. 8. In conclusion, otilonium is a potent blocker of nicotinic AChR-mediated responses. The drugs also blocked various subtypes of neuronal voltage-dependent Ca2+ channels at a considerably lower potency. Na+ channels were unaffected by

  8. Linc-RoR promotes c-Myc expression through hnRNP I and AUF1.

    PubMed

    Huang, Jianguo; Zhang, Ali; Ho, Tsui-Ting; Zhang, Ziqiang; Zhou, Nanjiang; Ding, Xianfeng; Zhang, Xu; Xu, Min; Mo, Yin-Yuan

    2016-04-20

    Linc-RoR was originally identified to be a regulator for induced pluripotent stem cells in humans and it has also been implicated in tumorigenesis. However, the underlying mechanism of Linc-RoR-mediated gene expression in cancer is poorly understood. The present study demonstrates that Linc-RoR plays an oncogenic role in part through regulation of c-Myc expression. Linc-RoR knockout (KO) suppresses cell proliferation and tumor growth. In particular, Linc-RoR KO causes a significant decrease in c-Myc whereas re-expression of Linc-RoR in the KO cells restores the level of c-Myc. Mechanistically, Linc-RoR interacts with heterogeneous nuclear ribonucleoprotein (hnRNP) I and AU-rich element RNA-binding protein 1 (AUF1), respectively, with an opposite consequence to their interaction with c-Myc mRNA. While Linc-RoR is required for hnRNP I to bind to c-Myc mRNA, interaction of Linc-RoR with AUF1 inhibits AUF1 to bind to c-Myc mRNA. As a result, Linc-RoR may contribute to the increased stability of c-Myc mRNA. Although hnRNP I and AUF1 can interact with many RNA species and regulate their functions, with involvement of Linc-RoR they would be able to selectively regulate mRNA stability of specific genes such as c-Myc. Together, these results support a role for Linc-RoR in c-Myc expression in part by specifically enhancing its mRNA stability, leading to cell proliferation and tumorigenesis. PMID:26656491

  9. VizieR Online Data Catalog: Fourier analysis of HD 49330 CoRoT light curve (Huat+, 2009)

    NASA Astrophysics Data System (ADS)

    Huat, A.-L.; Hubert, A.-M.; Baudin, F.; Floquet, M.; Neiner, C.; Fremat, Y.; Gutierrez-Soto, J.; Andrade, L.; de Batz, B.; Diago, P. D.; Emilio, M.; Espinosa, F. Lara; Fabregat, J.; Janot-Pacheco, E.; Leroy, B.; Martayan, C.; Semaan, T.; Suso, J.; Auvergne, M.; Catala, C.; Michel, E.; Samadi, R.

    2009-09-01

    This work analyses the high precision photometric light curve obtained for the CoRoT target HD49330 (B0.5 IVe) which was observed during 136.886 days with a sample of 32s. During the CoRoT run the star underwent an outburst often observed in hot Be star. The CoRoT light curve was analysed using Fourier methods and non-linear least square fitting. (5 data files).

  10. VizieR Online Data Catalog: Algorithm for correcting CoRoT raw light curves (Mislis+, 2010)

    NASA Astrophysics Data System (ADS)

    Mislis, D.; Schmitt, J. H. M. M.; Carone, L.; Guenther, E. W.; Patzold, M.

    2010-10-01

    Requirements : gfortran (or g77, ifort) compiler Input Files : The input files sould be raw CoRoT txt files (http://idoc-corot.ias.u-psud.fr/index.jsp) with names CoRoT*.txt Run the cda by typing C>: ./cda.csh (code and data sould be in the same directory) Output files : CDA creates one ascii output file with name - CoRoT*.R.cor for R filter (2 data files).

  11. Linc-RoR promotes c-Myc expression through hnRNP I and AUF1

    PubMed Central

    Huang, Jianguo; Zhang, Ali; Ho, Tsui-Ting; Zhang, Ziqiang; Zhou, Nanjiang; Ding, Xianfeng; Zhang, Xu; Xu, Min; Mo, Yin-Yuan

    2016-01-01

    Linc-RoR was originally identified to be a regulator for induced pluripotent stem cells in humans and it has also been implicated in tumorigenesis. However, the underlying mechanism of Linc-RoR-mediated gene expression in cancer is poorly understood. The present study demonstrates that Linc-RoR plays an oncogenic role in part through regulation of c-Myc expression. Linc-RoR knockout (KO) suppresses cell proliferation and tumor growth. In particular, Linc-RoR KO causes a significant decrease in c-Myc whereas re-expression of Linc-RoR in the KO cells restores the level of c-Myc. Mechanistically, Linc-RoR interacts with heterogeneous nuclear ribonucleoprotein (hnRNP) I and AU-rich element RNA-binding protein 1 (AUF1), respectively, with an opposite consequence to their interaction with c-Myc mRNA. While Linc-RoR is required for hnRNP I to bind to c-Myc mRNA, interaction of Linc-RoR with AUF1 inhibits AUF1 to bind to c-Myc mRNA. As a result, Linc-RoR may contribute to the increased stability of c-Myc mRNA. Although hnRNP I and AUF1 can interact with many RNA species and regulate their functions, with involvement of Linc-RoR they would be able to selectively regulate mRNA stability of specific genes such as c-Myc. Together, these results support a role for Linc-RoR in c-Myc expression in part by specifically enhancing its mRNA stability, leading to cell proliferation and tumorigenesis. PMID:26656491

  12. Effects of ATP-sensitive potassium channel blockers on vascular hyporeactivity, mesenteric blood flow, and survival in lipopolysaccharide-induced septic shock model.

    PubMed

    Boz, Mustafa; Atilla, Pergin; Iskit, Alper B; Ilhan, Mustafa

    2016-08-01

    In this study, the possible therapeutic effects of various ATP-sensitive potassium channel (KATP) blockers (glibenclamide, repaglinide, 5-HD, HMR-1098) have been tested in experimental septic shock model. Rats were given lipopolysaccharide (1 mg·kg(-1)) to create experimental shock model and 4 h later, under 400 mg·kg(-1) chloral hydrate anesthesia, parameters such as blood pressure, mesenteric blood flow, the response of mesenteric circulation to phenylephrine (vasoconstrictor stimulation), and organ and oxidative damage were analyzed. Also 75 mg·kg(-1) lethal dose of lipopolysaccharide was given to mice and effects of KATP blockers on survival have been tested. Non-selective blocker glibenclamide with sulphonylurea structure and sarcolemmal KATP channel blocker HMR-1098, which have the similar chemical structure, have improved the pathological parameters such as decrease in mesenteric blood flow, vascular hyporeactivity, but could not prevent the decrease in blood pressure, and oxidative and organ damage that were observed in the shock model. Also, both blockers have decreased the mortality rate from 80% to 40%-50%. Similar (preventive) therapeutic effects were not observed with non-selective blocker repaglinide and mitochondrial KATP channel blocker 5-HD, which were non-sulphonylurea structure. As a result, only KATP channel blockers that have sulphonylurea structure can be a new therapeutic approach in septic shock. PMID:27239899

  13. Monte Carlo method for predicting of cardiac toxicity: hERG blocker compounds.

    PubMed

    Gobbi, Marco; Beeg, Marten; Toropova, Mariya A; Toropov, Andrey A; Salmona, Mario

    2016-05-27

    The estimation of the cardiotoxicity of compounds is an important task for the drug discovery as well as for the risk assessment in ecological aspect. The experimental estimation of the above endpoint is complex and expensive. Hence, the theoretical computational methods are very attractive alternative of the direct experiment. A model for cardiac toxicity of 400 hERG blocker compounds (pIC50) is built up using the Monte Carlo method. Three different splits into the visible training set (in fact, the training set plus the calibration set) and invisible validation sets examined. The predictive potential is very good for all examined splits. The statistical characteristics for the external validation set are (i) the coefficient of determination r(2)=(0.90-0.93); and (ii) root-mean squared error s=(0.30-0.40). PMID:27067105

  14. Cadmium and calcium uptake in the mollusc donax rugosus and effect of a calcium channel blocker

    SciTech Connect

    Sidoumou, Z.; Gnassia-Barelli, M.; Romeo, M.

    1997-02-01

    Donax rugosus, a common bivalve mollusc in the coastal waters of Mauritania, has been studied for trace metal concentrations as a function of sampling site (from South of Mauritania to the North of this country) and of season. In this paper, the uptake of cadmium was experimentally studied in the different organs of D. rugosus. Since metals such as cadmium, copper and mercury may alter calcium homeostasis, calcium uptake was also studied in the animals treated with cadmium. Since calcium is taken up through specific channels, it appears that metals inhibit Ca uptake by interacting with these channels in the plasma membrane. Cadmium and calcium have very similar atomic radii, thus cadmium may be taken up through the calcium channels, particularly through voltage-dependent channels. The uptake of cadmium and calcium by D. Rugosus was therefore also studied in the presence of the calcium channel blocker verapamil. 13 refs., 3 figs., 1 tab.

  15. Antioxidant effect of T-type calcium channel blockers in gastric injury.

    PubMed

    Bilici, Dilek; Banoğlu, Z Nur; Kiziltunç, Ahmet; Avci, Bahattin; Ciftçioğlu, Akif; Bilici, Sefa

    2002-04-01

    It is known that calcium ion has an important role in the cellular function. For this reason, calcium channel blockers may have a protective action against gastric injury which is induced by various stimuli. In this study, the influence of mibefradil on ethanol-induced gastric injury was investigated in rats. Mibefradil was given at a dose 50 mg/kg intraperitoneally 30 min before administration of 1 ml absolute ethanol given by gavage. We compared this effect of mibefradil with that of omeprazol. Ethanol-induced mucosal damage was evaluated using three different approaches: analysis of biochemical parameters and pathologic and macroscopic investigation. It was found that pretreatment with mibefradil significantly reduced ethanol-induced macroscopic, pathologic, and biochemical changes in the gastric mucosa. In conclusion, it is speculated that this findings may prove important in the development of new and improved therapies for the treatment and prevention of gastric ulcers in humans. PMID:11991620

  16. Beta-blockers in the environment: part I. Mobility and hydrolysis study.

    PubMed

    Maszkowska, Joanna; Stolte, Stefan; Kumirska, Jolanta; Łukaszewicz, Paulina; Mioduszewska, Katarzyna; Puckowski, Alan; Caban, Magda; Wagil, Marta; Stepnowski, Piotr; Białk-Bielińska, Anna

    2014-09-15

    Beta-blockers (BB) are one of the most widely used pharmaceuticals whose presence in different environmental compartments has already been proven in concentrations of even up to a few μg L(-1). However, our knowledge of their fate in the environment is still scarce. To obtain a better understanding on the environmental behavior of three selected BB comprehensive laboratory experiments assessing their mobility and hydrolytic stability has been conducted. Propranolol, metoprolol and nadolol--the most commonly consumed and detected in environmental samples--were selected as representatives of this group of pharmaceuticals. The objectives of our research were: (i) evaluation of the sorption potential and an explanation of the sorption mechanisms of these compounds onto soil and clay mineral (kaolinite); and (ii) investigation of the hydrolytic stability of these BB according to OECD 111. This comprehensive study supports the Environmental Risk Assessment of these pharmaceuticals. PMID:25005235

  17. The effect of ions, ion channel blockers, and ionophores on uptake of vitellogenin into cockroach follicles.

    PubMed

    Kindle, H; Lanzrein, B; Kunkel, J G

    1990-12-01

    Since calcium plays an important role in vitellogenin binding and uptake in Nauphoeta cinerea and because calcium channels have been described in follicles of this species, we investigated the effect of various ions, ionophores, and ion channel blockers on vitellogenin uptake in vitro. Calcium significantly stimulated vitellogenin uptake; this effect could be substituted best by barium and less well by strontium and magnesium. The stimulatory effect of calcium, and to a certain extent also that of barium, was dependent on the vitellogenin concentration, whereas the effect of strontium and magnesium was not. In the presence of calcium, vitellogenin uptake was inhibited by barium, strontium, and magnesium as well as by the transition elements nickel, cobalt, and zinc, but not by manganese which had a stimulatory effect. Valinomycin, verapamil, tetraethylammonium, and atropine reduced vitellogenin uptake, while amiloride and ouabain were ineffective. Our results indicate that calcium inward (and possibly potassium outward) fluxes play an important role in vitellogenin uptake. PMID:2257971

  18. In vitro and in vivo evaluation of polymethylene tetraamine derivatives as NMDA receptor channel blockers.

    PubMed

    Saiki, Ryotaro; Yoshizawa, Yuki; Minarini, Anna; Milelli, Andrea; Marchetti, Chiara; Tumiatti, Vincenzo; Toida, Toshihiko; Kashiwagi, Keiko; Igarashi, Kazuei

    2013-07-01

    The biological activities of six symmetrically substituted 2-methoxy-benzyl polymethylene tetraamines (1-4) and diphenylethyl polymethylene tetraamines (5 and 6) as N-methyl-D-aspartate (NMDA) receptor channel blockers, were evaluated in vitro and in vivo. Although all compounds exhibited stronger channel block activities in comparison to memantine in Xenopus oocytes voltage clamped at -70 mV, only compound 2 (0.4 mg/kg intravenous injection) decreased the size of brain infarction in a photochemically induced thrombosis model mice at the same extent of memantine (10mg/kg intravenous injection). Other compounds (1, 3, 4, 5 and 6) did not decrease the size of brain infarction significantly due to the limited injection doses. The present study suggests that compound 2 could represent a valuable lead compound to design low toxicity polyamines for clinical use against stroke. PMID:23692871

  19. Non-vascular action of calcium blockers in migraine: pupillopharmacological study.

    PubMed

    Fanciullacci, M; Pietrini, U; Nicolodi, M; Sicuteri, F

    1986-01-01

    A pupillopharmacological study has been carried out to evaluate the influence of two calcium blockers (CBs), flunarizine and nimodipine, on iris neurotransmission in migraine patients. Pretreatment with an oral dose of flunarizine or nimodipine markedly decreased the mydriasis induced by instillation of tyramine, a noradrenaline releaser. On the contrary, both drugs did not change the mydriasis by conjunctival phenylephrine, a postsynaptic adrenoceptor stimulant. In addition, nimodipine abolished the miosis caused by echothiophate iodide eye drops, a putative releaser of substance P from trigeminal sensory nerve endings. These findings suggest the idea that CBs treatment in migraine syndromes acts at presynaptic level by attenuating calcium-dependent release of monoaminergic and peptidergic neurotransmitters. PMID:3038706

  20. [Comparative multicenter study of carteolol eyedrops with other beta blockers in 768 patients under normal conditions].

    PubMed

    Schnarr, K D

    1988-02-01

    In an open multi-center study involving 768 patients the efficacy and tolerability of Carteolol eye drops as compared to other beta blockers were investigated. The patients started to use the new medication without a prior washout period. In patients who were well stabilized (57%), IOP either did not change when the medication was switched to Carteolol (73%) or it actually decreased. In 78% of the patients who had not responded altogether satisfactorily to the pretreatment, Carteolol eye drops lowered IOP to a tolerable level of 21 mm Hg or less without using any comedication. IOP remained hypertonic under Carteolol in only 19% of the cases. Fewer systemic and local side effects were observed under Carteolol therapy. Patients had fewer problems going upstairs. Burning after installation decreased by 25% to 2%. Even fluorescein-positive corneal findings almost completely disappeared under Carteolol. PMID:2896266

  1. A deleterious gene-by-environment interaction imposed by calcium channel blockers in Marfan syndrome.

    PubMed

    Doyle, Jefferson J; Doyle, Alexander J; Wilson, Nicole K; Habashi, Jennifer P; Bedja, Djahida; Whitworth, Ryan E; Lindsay, Mark E; Schoenhoff, Florian; Myers, Loretha; Huso, Nick; Bachir, Suha; Squires, Oliver; Rusholme, Benjamin; Ehsan, Hamid; Huso, David; Thomas, Craig J; Caulfield, Mark J; Van Eyk, Jennifer E; Judge, Daniel P; Dietz, Harry C

    2015-01-01

    Calcium channel blockers (CCBs) are prescribed to patients with Marfan syndrome for prophylaxis against aortic aneurysm progression, despite limited evidence for their efficacy and safety in the disorder. Unexpectedly, Marfan mice treated with CCBs show accelerated aneurysm expansion, rupture, and premature lethality. This effect is both extracellular signal-regulated kinase (ERK1/2) dependent and angiotensin-II type 1 receptor (AT1R) dependent. We have identified protein kinase C beta (PKCβ) as a critical mediator of this pathway and demonstrate that the PKCβ inhibitor enzastaurin, and the clinically available anti-hypertensive agent hydralazine, both normalize aortic growth in Marfan mice, in association with reduced PKCβ and ERK1/2 activation. Furthermore, patients with Marfan syndrome and other forms of inherited thoracic aortic aneurysm taking CCBs display increased risk of aortic dissection and need for aortic surgery, compared to patients on other antihypertensive agents. PMID:26506064

  2. Noise properties of the CoRoT data. A planet-finding perspective

    NASA Astrophysics Data System (ADS)

    Aigrain, S.; Pont, F.; Fressin, F.; Alapini, A.; Alonso, R.; Auvergne, M.; Barbieri, M.; Barge, P.; Bordé, P.; Bouchy, F.; Deeg, H.; de La Reza, R.; Deleuil, M.; Dvorak, R.; Erikson, A.; Fridlund, M.; Gondoin, P.; Guterman, P.; Jorda, L.; Lammer, H.; Léger, A.; Llebaria, A.; Magain, P.; Mazeh, T.; Moutou, C.; Ollivier, M.; Pätzold, M.; Queloz, D.; Rauer, H.; Rouan, D.; Schneider, J.; Wuchter, G.; Zucker, S.

    2009-10-01

    In this short paper, we study the photometric precision of stellar light curves obtained by the CoRoT satellite in its planet-finding channel, with a particular emphasis on the time scales characteristic of planetary transits. Together with other articles in the same issue of this journal, it forms an attempt to provide the building blocks for a statistical interpretation of the CoRoT planet and eclipsing binary catch to date. After pre-processing the light curves so as to minimise long-term variations and outliers, we measure the scatter of the light curves in the first three CoRoT runs lasting more than 1 month, using an iterative non-linear filter to isolate signal on the time scales of interest. The behaviour of the noise on 2 h time scales is described well by a power-law with index 0.25 in R-magnitude, ranging from 0.1 mmag at R=11.5 to 1 mmag at R=16, which is close to the pre-launch specification, though still a factor 2-3 above the photon noise due to residual jitter noise and hot pixel events. There is evidence of slight degradation in the performance over time. We find clear evidence of enhanced variability on hour time scales (at the level of 0.5 mmag) in stars identified as likely giants from their R magnitude and B-V colour, which represent approximately 60 and 20% of the observed population in the directions of Aquila and Monoceros, respectively. On the other hand, median correlated noise levels over 2 h for dwarf stars are extremely low, reaching 0.05 mmag at the bright end. The CoRoT space mission, launched on December 27, 2006, has been developed and is operated by the CNES, with the contribution of Austria, Belgium, Brazil, ESA, Germany, and Spain. CoRoT data become publicly available one year after release to the Co-Is of the mission from the CoRoT archive: http://idoc-corot.ias.u-psud.fr/.

  3. Role of endothelial cells in antihyperalgesia induced by a triptan and β-blocker.

    PubMed

    Joseph, E K; Levine, J D

    2013-03-01

    While blood vessels have long been implicated in diverse pain syndromes (e.g., migraine headache, angina pectoris, vasculitis, and Raynaud's syndrome), underlying mechanisms remain to be elucidated. Recent evidence supports a contribution of the vascular endothelium in endothelin-1-induced hyperalgesia, and its enhancement by repeated mechanical stimulation; a phenomenon referred to as stimulus-induced enhancement of (endothelin) hyperalgesia (SIEH). SIEH is thought to be mediated by release of ATP from endothelial cells, to act on P2X3 receptors on nociceptors. In the present study we evaluated the ability of another vasoactive hyperalgesic agent, epinephrine, to induce endothelial cell-dependent hyperalgesia and SIEH. We found that epinephrine also produces hyperalgesia and SIEH. Both P2X3 receptor antagonists, A317491 and octoxynol-9, which attenuate endothelial cell function, eliminated SIEH without affecting epinephrine hyperalgesia. We further evaluated the hypothesis that members of two important classes of drugs used to treat migraine headache, whose receptors are present in endothelial cells - the triptans and β blockers - have a vascular component to their anti-hyperalgesic action. For this, we tested the effect of ICI-118,551, a β₂-adrenergic receptor antagonist and sumatriptan, an agonist at 5-HT1B and 5-HT₁D receptors, on nociceptive effects of endothelin and epinephrine. ICI-118,551 inhibited endothelin SIEH, and attenuated epinephrine hyperalgesia and SIEH. Sumatriptan inhibited epinephrine SIEH and inhibited endothelin hyperalgesia and SIEH, while having no effect on epinephrine hyperalgesia or the hyperalgesia induced by a prototypical direct-acting inflammatory mediator, prostaglandin E₂. These results support the suggestion that triptans and β-blockers interact with the endothelial cell component of the blood vessel to produce anti-hyperalgesia. PMID:23262231

  4. Role of Endothelial Cells in Antihyperalgesia Induced by a Triptan and β-blocker

    PubMed Central

    Joseph, Elizabeth K.; Levine, Jon D.

    2012-01-01

    While blood vessels have long been implicated in diverse pain syndromes (e.g., migraine headache, angina pectoris, vasculitis, and Raynaud’s syndrome), underlying mechanisms remain to be elucidated. Recent evidence supports a contribution of the vascular endothelium in endothelin-1 induced hyperalgesia, and its enhancement by repeated mechanical stimulation; a phenomenon referred to as stimulus-induced enhancement of (endothelin) hyperalgesia (SIEH). SIEH is thought to be mediated by release of ATP from endothelial cells, to act on P2X3 receptors on nociceptors. In the present study we evaluated the ability of another vasoactive hyperalgesic agent, epinephrine, to induce endothelial cell dependent hyperalgesia and SIEH. We found that epinephrine also produces hyperalgesia and SIEH. Both a P2X3 receptor antagonist, A317491 and octoxynol-9, which attenuate endothelial cell function, eliminated SIEH without affecting epinephrine hyperalgesia. We further evaluated the hypothesis that members of two important classes of drugs used to treat migraine headache, whose receptors are present in endothelial cells - the triptans and beta blockers - have a vascular component to their anti-hyperalgesic action. For this, we tested the effect of ICI-118,551, a β2-adrenergic receptor antagonist and sumatriptan, an agonist at 5-HT1B and 5-HT1D receptors, on nociceptive effects of endothelin and epinephrine. ICI-118,551 inhibited endothelin SIEH, and attenuated epinephrine hyperalgesia and SIEH. Sumatriptan inhibited epinephrine SIEH and inhibited endothelin hyperalgesia and SIEH, while having no effect on epinephrine hyperalgesia or the hyperalgesia induced by a prototypical direct-acting inflammatory mediator, prostaglandin E2. These results support the suggestion that triptans and beta-blockers interact with the endothelial cell component of the blood vessel to produce anti-hyperalgesia. PMID:23262231

  5. Effects of calcium entry blockers on tension development and calcium influx in rat uterus.

    PubMed Central

    Granger, S. E.; Hollingsworth, M.; Weston, A. H.

    1986-01-01

    Spontaneous and potassium chloride (KCl)-induced tension development of strips of whole uterus from the day-22 pregnant rat was reduced when the tissues were incubated in a calcium ion (Ca2+)-free medium. Strips of whole uterus, in an initially Ca2+-free medium, responded to the cumulative addition of Ca2+ with graded phasic tension development and associated rapid electrical discharges. The spasms were inhibited by gallopamil (100 nM) and diltiazem (1 microM). Strips of whole uterus in a depolarizing (40 mM K+) medium, which was initially Ca2+-free, responded to the cumulative addition of Ca2+ with graded tonic tension development without associated electrical discharges. These spasms were inhibited by calcium entry blockers with a rank order of potency of nifedipine = gallopamil greater than diltiazem greater than cinnarizine. KCl-induced tension development in endometrium-free uterine strips was antagonized by calcium entry blockers with a rank order of potency of nifedipine greater than gallopamil greater than diltiazem greater than cinnarizine. Ca2+ influx into endometrium-free uterine strips was assessed by means of the 'lanthanum method'. KCl induced a concentration-dependent increase in 45Ca2+ influx which was suppressed or abolished by nifedipine (2.5 nM), gallopamil (100 nM), diltiazem (500 nM) or cinnarizine (5 microM). It is concluded that spontaneous and KCl-induced tension development of rat uterus involves Ca2+ influx from the extracellular medium into the myometrial cell. These results support the hypothesis that nifedipine, gallopamil, diltiazem and cinnarizine inhibit Ca2+- and KCl-induced tension development of rat uterus by reduction of Ca2+ influx. PMID:3955298

  6. Effectiveness of β-blockers in physically active patients with hypertension: protocol of a systematic review

    PubMed Central

    Tučková, Dagmar; Klugar, Miloslav; Sovová, Eliška; Sovová, Markéta; Štégnerová, Lenka

    2016-01-01

    Introduction Based on more than 5 decades of epidemiological studies, it is now widely accepted that higher physical activity patterns and levels of cardiorespiratory fitness are associated with better health outcomes. Therefore, it is necessary to consider how treatment methods affect these two components. Clinically, one very important question concerns the influence of aerobic performance on patients being treated for hypertension. The administration of β-blockers can significantly reduce maximal—and especially submaximal—aerobic exercise capacity. The objective of this review is to determine, by comparison of existing mono and combination therapy, which β-blockers are less physically limiting for patients with hypertension who are physically active. Methods A three-step strategy will be adopted in the review, following the methods used by the Joanna Briggs Institute (JBI). The initial search will be conducted using the MEDLINE and EMBASE databases. The second search will involve the listed databases for the published literature (MEDLINE, Biomedica Czechoslovaca, Tripdatabase, Pedro, EMBASE, the Cochrane Central Register of Controlled Trials, Cinahl, WoS) and the unpublished literature (Open Grey, Current Controlled Trials, MedNar, ClinicalTrials.gov, Cos Conference Papers Index, the International Clinical Trials Registry Platform of the WHO). Following the JBI methodology, analysis of title/abstracts and full texts, critical appraisal and data extraction will be carried out on selected studies using the JBI tool, MAStARI. This will be performed by two independent reviewers. If possible, statistical meta-analysis will be pooled. Statistical heterogeneity will be assessed. Subgroup analysis will be used for different age and gender characteristics. Funnel plots, Begg's rank correlation and Egger's regression test will be used to detect or correct publication bias. Ethics and dissemination The results will be disseminated by publishing in a peer

  7. Curcumin: an orally bioavailable blocker of TNF and other pro-inflammatory biomarkers

    PubMed Central

    Aggarwal, Bharat B; Gupta, Subash C; Sung, Bokyung

    2013-01-01

    TNFs are major mediators of inflammation and inflammation-related diseases, hence, the United States Food and Drug Administration (FDA) has approved the use of blockers of the cytokine, TNF-α, for the treatment of osteoarthritis, inflammatory bowel disease, psoriasis and ankylosis. These drugs include the chimeric TNF antibody (infliximab), humanized TNF-α antibody (Humira) and soluble TNF receptor-II (Enbrel) and are associated with a total cumulative market value of more than $20 billion a year. As well as being expensive ($15 000–20 000 per person per year), these drugs have to be injected and have enough adverse effects to be given a black label warning by the FDA. In the current report, we describe an alternative, curcumin (diferuloylmethane), a component of turmeric (Curcuma longa) that is very inexpensive, orally bioavailable and highly safe in humans, yet can block TNF-α action and production in in vitro models, in animal models and in humans. In addition, we provide evidence for curcumin's activities against all of the diseases for which TNF blockers are currently being used. Mechanisms by which curcumin inhibits the production and the cell signalling pathways activated by this cytokine are also discussed. With health-care costs and safety being major issues today, this golden spice may help provide the solution. Linked Articles This article is part of a themed section on Emerging Therapeutic Aspects in Oncology. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2013.169.issue-8 PMID:23425071

  8. Protective activity of calcium entry blockers against ouabain intoxication in anesthetized guinea pigs.

    PubMed

    Jonkman, F A; Boddeke, H W; van Zwieten, P A

    1986-01-01

    Several studies have suggested a central role for calcium in the pathogenesis of digitalis-induced arrhythmias. To test this hypothesis, the effects on ouabain-induced arrhythmia of intraarterial pretreatment with the calcium entry blockers nifedipine, flunarizine, verapamil, diltiazem, and bepridil, the calcium entry promotor Bay K 8644, and CaCl2 were compared with those of the currently applied digitalis antidotes phenytoin and lidocaine in urethane-anesthetized (1.5 g/kg i.p.) guinea pigs. Pretreatment with nifedipine (0.03 and 0.1 mg/kg), flunarizine (1 and 3 mg/kg), and phenytoin (10 mg/kg) doubled the time (from 10-20 to 20-40 min) required to provoke toxic ECG changes. Verapamil, diltiazem, and bepridil caused a slight but significant reduction of ouabain toxicity. Pretreatment with CaCl2 (10 mg/kg) enhanced all toxic effects of ouabain. None of the above-mentioned pretreatments as such changed the ECG parameters. Bay k 8644 (0.03 and 0.1 mg/kg) enhanced the effects of ouabain on ventricular rhythm, but abolished the ouabain-induced impairment of AV conduction. Bay k 8644 as such increased heart rate (from 318 +/- 11 to 376 +/- 6 beats/min at 0.1 mg/kg) and shortened the PR interval. The negative inotropic effects of the calcium entry blockers were quantified in electrically paced (3 Hz) guinea pig isolated left atria 15 min after pretreatment with ouabain (3 X 10(-7) M). The rank order of potency for the negative inotropic effect was nifedipine greater than verapamil greater than bepridil greater than diltiazem greater than flunarizine. In conclusion, nifedipine, flunarizine, and phenytoin showed obvious and equally effective protection against ouabain-induced arrhythmia.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:2429073

  9. The action of calcium channel blockers on recombinant L-type calcium channel α1-subunits

    PubMed Central

    Morel, Nicole; Buryi, Vitali; Feron, Olivier; Gomez, Jean-Pierre; Christen, Marie-Odile; Godfraind, Théophile

    1998-01-01

    CHO cells expressing the α1C-a subunit (cardiac isoform) and the α1C-b subunit (vascular isoform) of the voltage-dependent L-type Ca2+ channel were used to investigate whether tissue selectivity of Ca2+ channel blockers could be related to different affinities for α1C isoforms.Inward current evoked by the transfected α1 subunit was recorded by the patch-clamp technique in the whole-cell configuration.Neutral dihydropyridines (nifedipine, nisoldipine, (+)-PN200-110) were more potent inhibitors of α1C-b-subunit than of α1C-a-subunit. This difference was more marked at a holding potential of −100 mV than at −50 mV. SDZ 207-180 (an ionized dihydropyridine) exhibited the same potency on the two isoforms.Pinaverium (ionized non-dihydropyridine derivative) was 2 and 4 fold more potent on α1C-a than on α1C-b subunit at Vh of −100 mV and −50 mV, respectively. Effects of verapamil were identical on the two isoforms at both voltages.[3H]-(+)-PN 200-110 binding experiments showed that neutral dihydropyridines had a higher affinity for the α1C-b than for the α1C-a subunit. SDZ 207-180 had the same affinity for the two isoforms and pinaverium had a higher affinity for the α1C-a subunit than for the α1C-b subunit.These results indicate marked differences among Ca2+ channel blockers in their selectivity for the α1C-a and α1C-b subunits of the Ca2+ channel. PMID:9846638

  10. The action of calcium channel blockers on recombinant L-type calcium channel alpha1-subunits.

    PubMed

    Morel, N; Buryi, V; Feron, O; Gomez, J P; Christen, M O; Godfraind, T

    1998-11-01

    1. CHO cells expressing the alpha(1C-a) subunit (cardiac isoform) and the alpha(1C-b) subunit (vascular isoform) of the voltage-dependent L-type Ca2+ channel were used to investigate whether tissue selectivity of Ca2+ channel blockers could be related to different affinities for alpha1C isoforms. 2. Inward current evoked by the transfected alpha1 subunit was recorded by the patch-clamp technique in the whole-cell configuration. 3. Neutral dihydropyridines (nifedipine, nisoldipine, (+)-PN200-110) were more potent inhibitors of alpha(1C-)b-subunit than of alpha(1C-a)-subunit. This difference was more marked at a holding potential of -100 mV than at -50 mV. SDZ 207-180 (an ionized dihydropyridine) exhibited the same potency on the two isoforms. 4. Pinaverium (ionized non-dihydropyridine derivative) was 2 and 4 fold more potent on alpha(1C-a) than on alpha(1C-b) subunit at Vh of -100 mV and -50 mV, respectively. Effects of verapamil were identical on the two isoforms at both voltages. 5. [3H]-(+)-PN 200-110 binding experiments showed that neutral dihydropyridines had a higher affinity for the alpha(1C-b) than for the alpha(1C-a) subunit. SDZ 207-180 had the same affinity for the two isoforms and pinaverium had a higher affinity for the alpha(1C-a) subunit than for the alpha(1C-b) subunit. 6. These results indicate marked differences among Ca2+ channel blockers in their selectivity for the alpha(1C-a) and alpha(1C-b) subunits of the Ca2+ channel. PMID:9846638

  11. CoRoT light curves of Blazhko RR Lyrae stars. Evidence of a strong correlation between phase and amplitude modulations of CoRoT ID 0105288363

    NASA Astrophysics Data System (ADS)

    Chadid, M.; Perini, C.; Bono, G.; Auvergne, M.; Baglin, A.; Weiss, W. W.; Deboscher, J.

    2011-03-01

    Context. The CoRoT - Convection Rotation and planetary Transits - space mission provides a unique opportunity to monitor RR Lyrae stars with excellent time-sampling, unprecedented photometric precision, and a long time base of 150 days. Aims: The pulsation characteristics of RR Lyrae stars rely on robust physics, but we still lack a firm quantitative understanding of the physical mechanisms driving the Blazhko modulation and the long-term changes in their pulsation behavior. We use the high-precision space data of an unknown RR Lyrae star CoRoT ID 0105288363 observed during a second long run centered on the Galaxy - LRc02 -, to improve our understanding of the pulsation properties of RR Lyrae stars. Methods: The CoRoT data were corrected using a jump and trend filtering code. We applied different period-finding techniques including Period04, MuFrAn, PDM, and SigSpec. Amplitude and phase modulation were investigated using an analytical function method as well as traditional O-C diagrams. Results: For the first time, we detect significant cycle-to-cycle changes in the Blazhko modulation, which appear to be analogous to those predicted by Stothers - owing to the suppression of turbulent convection - to explain this phenomenon. We discuss the clear correlations between the phase and the amplitude of the bump, and the skewness and acuteness of the light curve during different Blazhko cycles. We find that these quantities are strongly anticorrelated with the fundamental pulsation period. This provides a strong support to the slow convective cycle model suggested by Stothers. We also detect a long-term modulation period in the maximum brightness spectrum. A more extended coverage of the long-term modulation is required to constrain its period. Seventh-order side peaks of the pulsation multiplet structure are also visible with the left-side peak amplitudes being higher than those of the right. This has never previously been detected. Future theoretical investigations are

  12. Correlation between docetaxel-induced skin toxicity and the use of steroids and H₂ blockers: a multi-institution survey.

    PubMed

    Kawaguchi, K; Ishiguro, H; Morita, S; Nakamura, S; Ohno, S; Masuda, N; Iwata, H; Aogi, K; Kuroi, K; Toi, M

    2011-11-01

    Steroids and H(2) blockers are commonly used as supportive care for taxane-containing chemotherapy, but they also affect docetaxel's primary metabolizer, cytochrome P(450) 3A4. This retrospective observational study was performed to better understand the effects of these compounds on docetaxel-induced skin toxicities, specifically hand-foot syndrome (HFS) and facial erythema (FE), a relationship that is currently poorly understood. Member institutions of the Japan Breast Cancer Research Group were invited to complete a questionnaire on the occurrence of grade 2 or higher HFS and FE among patients treated between April 2007 and March 2008 with docetaxel as an adjuvant or neoadjuvant chemotherapeutic treatment for breast cancer. We obtained data for 993 patients from 20 institutions. Twenty percent received H(2) blockers, and all patients received dexamethasone. Univariate and multivariate analyses revealed that H(2) blockers are associated with a significantly higher incidence of both HFS and FE. The incidence of FE was significantly higher for the docetaxel + cyclophosphamide (TC) regimen than for non-TC regimens combined. Dexamethasone usage did not affect the incidence of either HFS or FE. In conclusion, use of H(2) blockers as premedication in breast cancer patients receiving docetaxel significantly increases the risk of both HFS and FE. PMID:21698408

  13. Effect of a calcium channel blocker on pituitary luteinizing hormone secretion in intact and castrated male and female rats

    SciTech Connect

    Babichev, V.N.; Sidneva, L.N.; Ozol', L.Yu.

    1987-08-01

    The authors study the effect of a calcium channel blocker on leuteinizing hormone (LH) secretion through experiments on rats. LH was determined by radioimmunoassay in two or three parallel tests and in two dilutions. The effect of verapamil on the LH level in rat blood serum and the pituitary gland is shown.

  14. β-Blockers in sepsis: protocol for a systematic review and meta-analysis of randomised control trials

    PubMed Central

    Duan, Erick H; Oczkowski, Simon J W; Belley-Cote, Emilie; Whitlock, Richard; Lamontagne, Francois; Devereaux, Phillip J; Cook, Deborah J

    2016-01-01

    Introduction Sepsis is a common and deadly complication of infection. As part of the host response, sympathetic stimulation can result in septic myocardial depression, and metabolic, haematological and immunological dysfunction. Administration of β-blockers may attenuate this pathophysiological response to infection, but the effects on clinical outcomes are unknown. The objective of this systematic review is to determine the efficacy and safety of β-blockers in adults with sepsis using data from randomised control trials. Methods and analysis We will identify randomised control trials comparing treatment with β-blockers, versus placebo or standard care in adults with sepsis. Data sources will include MEDLINE, EMBASE, CENTRAL, clinical trial registries and conference proceedings. Two reviewers will independently determine trial eligibility. For each included trial, we will conduct duplicate independent data extraction, risk of bias assessment and evaluation of the quality of the evidence using the GRADE approach. Ethics and dissemination Our systematic review will evaluate the effects of β-blockers in adults with sepsis, comprehensively summarising and appraising the available evidence from randomised control trials. The results of this systematic review will help clinicians treating patients with sepsis to understand the potential role of β-blockade, and inform future research on this topic. Our findings will be disseminated through conference presentation and publication in a peer-reviewed journal. Trial registration number CRD42016036933. PMID:27338886

  15. The L-type Ca(2+) Channel Blocker Nifedipine Inhibits Mycelial Growth, Sporulation, and Virulence of Phytophthora capsici.

    PubMed

    Liu, Peiqing; Gong, Jie; Ding, Xueling; Jiang, Yue; Chen, Guoliang; Li, Benjin; Weng, Qiyong; Chen, Qinghe

    2016-01-01

    The oomycete vegetable pathogen Phytophthora capsici causes significant losses of important vegetable crops worldwide. Calcium and other plant nutrients have been used in disease management of oomycete pathogens. Calcium homeostasis and signaling is essential for numerous biological processes, and Ca(2+) channel blockers prevent excessive Ca(2+) influx into the fungal cell. However, it is not known whether voltage-gated Ca(2+) channel blockers improve control over oomycete pathogens. In the present study, we compared the inhibitory effects of CaCl2 and the extracellular Ca(2+) chelator EDTA on mycelial growth and found that calcium assimilation plays a key role in P. capsici mycelial growth. Next, we involved the voltage-gated Ca(2+) channel blockers verapamil (VP) and nifedipine (NFD) to analyze the effect of Ca(2+) channel blockers on mycelial growth and sporulation; the results suggested that NFD, but not VP, caused significant inhibition. Ion rescue in an NFD-induced inhibition assay suggested that NFD-induced inhibition is calcium-dependent. In addition, NFD increased P. capsici sensitivity to H2O2 in a calcium-dependent manner, and extracellular calcium rescued it. Furthermore, NFD inhibited the virulence and gene expression related to its pathogenicity. These results suggest that NFD inhibits mycelial growth, sporulation, and virulence of P. capsici. PMID:27540377

  16. Implications of Dynamic Occupancy, Binding Kinetics, and Channel Gating Kinetics for hERG Blocker Safety Assessment and Mitigation.

    PubMed

    Pearlstein, Robert A; MacCannell, K Andrew; Erdemli, Gül; Yeola, Sarita; Helmlinger, Gabriel; Hu, Qi-Ying; Farid, Ramy; Egan, William; Whitebread, Steven; Springer, Clayton; Beck, Jeremy; Wang, Hao-Ran; Maciejewski, Mateusz; Urban, Laszlo; Duca, José S

    2016-01-01

    Blockade of the hERG potassium channel prolongs the ventricular action potential (AP) and QT interval, and triggers early after depolarizations (EADs) and torsade de pointes (TdP) arrhythmia. Opinions differ as to the causal relationship between hERG blockade and TdP, the relative weighting of other contributing factors, definitive metrics of preclinical proarrhythmicity, and the true safety margin in humans. Here, we have used in silico techniques to characterize the effects of channel gating and binding kinetics on hERG occupancy, and of blockade on the human ventricular AP. Gating effects differ for compounds that are sterically compatible with closed channels (becoming trapped in deactivated channels) versus those that are incompatible with the closed/closing state, and expelled during deactivation. Occupancies of trappable blockers build to equilibrium levels, whereas those of non-trappable blockers build and decay during each AP cycle. Occupancies of ~83% (non-trappable) versus ~63% (trappable) of open/inactive channels caused EADs in our AP simulations. Overall, we conclude that hERG occupancy at therapeutic exposure levels may be tolerated for nontrappable, but not trappable blockers capable of building to the proarrhythmic occupancy level. Furthermore, the widely used Redfern safety index may be biased toward trappable blockers, overestimating the exposure-IC50 separation in nontrappable cases. PMID:26975508

  17. Lanicemine: a low-trapping NMDA channel blocker produces sustained antidepressant efficacy with minimal psychotomimetic adverse effects.

    PubMed

    Sanacora, G; Smith, M A; Pathak, S; Su, H-L; Boeijinga, P H; McCarthy, D J; Quirk, M C

    2014-09-01

    Ketamine, an N-methyl-D-aspartate receptor (NMDAR) channel blocker, has been found to induce rapid and robust antidepressant-like effects in rodent models and in treatment-refractory depressed patients. However, the marked acute psychological side effects of ketamine complicate the interpretation of both preclinical and clinical data. Moreover, the lack of controlled data demonstrating the ability of ketamine to sustain the antidepressant response with repeated administration leaves the potential clinical utility of this class of drugs in question. Using quantitative electroencephalography (qEEG) to objectively align doses of a low-trapping NMDA channel blocker, AZD6765 (lanicemine), to that of ketamine, we demonstrate the potential for NMDA channel blockers to produce antidepressant efficacy without psychotomimetic and dissociative side effects. Furthermore, using placebo-controlled data, we show that the antidepressant response to NMDA channel blockers can be maintained with repeated and intermittent drug administration. Together, these data provide a path for the development of novel glutamatergic-based therapeutics for treatment-refractory mood disorders. PMID:24126931

  18. [Beta-blockers in cardiac insufficiency: should they always be considered in the therapeutic strategy? Arguments against].

    PubMed

    Ortigosa Aso, J; Silva Melchor, L; García, A; de Artaza Andrade, M

    1997-05-01

    The evidence supporting the use of beta-adrenergic blockers in the treatment of heart failure secondary to systolic dysfunction is reviewed. Up to date, seven controlled trials of carvedilol in patients with heart failure have been published. It has been concluded that the use of the non-selective, third generation beta-adrenergic blockers, with alpha-adrenergic (vasodilator) and antioxidant properties, carvedilol, is only justified in patients with mild or moderate heart failure without contraindications to beta-adrenergic blockers. There are not data to support the use of carvedilol in patients with severe or unstable heart failure. It seems logical to wait for the results of the ongoing trials (BEST Trial, CIBIS II Trial, COMET Trial, and MERIT Trial) to more precisely define the role that beta-adrenergic blockers should play in the treatment of patients with heart failure. The information presently available suggests that carvedilol should be considered a therapeutic agent for the prevention of progressive clinical heart failure rather than for the treatment of refractory heart failure. PMID:9281008

  19. Effect of different organic and inorganic blockers of calcium entry on the release of endogenous dopamine from tuberoinfundibular neurones.

    PubMed

    Annunziato, L; Amoroso, S; Taglialatela, M; De Natale, G; Di Renzo, G F

    1986-05-01

    In the present study the effect of different blockers of calcium entry belonging to different chemical classes on basal and K+-elicited release of endogenous dopamine (DA) from tuberoinfundibular dopaminergic neurones was studied in vitro. For this purpose fragments of hypothalamus containing arcuate-periventricular nuclei and median eminence were incubated in vitro and endogenous DA released into the medium was assayed by radioenzymatic assay. The organic blockers of calcium entry, nitrendipine, nimodipine, nifedipine, diltiazem and flunarizine did not modify basal or K+-evoked release of endogenous DA, unless very large concentrations (100 microM) of nifedipine or diltiazem were used. The phenylalkylamine methoxyverapamil (D-600) consistently inhibited K+-stimulated release of endogenous DA in concentrations of 50 and 100 microM. Cobalt and lanthanum, two ions with an ionic radius similar to that of calcium and which are known to inhibit calcium fluxes through nerve membranes, significantly blocked release of endogenous DA elicited by 35 mM K+. In summary, the results of the present study showed that calcium channels in the tuberoinfundibular dopaminergic system displayed a different sensitivity to various classes of blockers of calcium entry. Inorganic blockers of calcium entry, like lanthanum and cobalt, appeared to be the most effective in blocking Ca2+-dependent release of endogenous DA, whereas, among the organic calcium antagonists, phenylalkylamines seemed to possess a certain degree of effectiveness. PMID:3736788

  20. β-blockers and Angiotensin Converting Enzyme Inhibitors: Comparison of Effects on Aortic Growth in Pediatric Patients with Marfan Syndrome

    PubMed Central

    Phomakay, Venusa; Huett, Wilson G.; Gossett, Jeffrey M.; Tang, Xinyu; Bornemeier, Renee A.; Collins, R. Thomas

    2015-01-01

    Objectives Angiotensin converting enzyme inhibitors (ACEI) have been shown to decrease AGV in Marfan syndrome (MFS). We sought to compare the effect of β-blockers and ACEI on aortic growth velocity (AGV) in MFS. Study design We reviewed retrospectively all data from all patients with MFS seen at Arkansas Children’s Hospital between January 1, 1976 and January 1, 2013. Generalized least squares were used to evaluate AGV over time as a function of age, medication group, and the interaction between the two. A mixed model was used to compare AGV between medication groups as a function of age, medication group (none, β-blocker, ACEI), and the interaction between the two. Results A total of 67 patients with confirmed MFS were identified (34/67, 51% female). Mean age at first encounter was 13 ± 10 years, with mean follow-up of 7.6 ± 5.8 years. There were 839 patient encounters with a median of 10 (range 2–42) encounters per patient. AGV was nearly normal in the β-blocker group, and was less than either the ACEI or untreated groups. The AGV was higher than normal in ACEI and untreated groups (p<0.001 for both). Conclusions β-blocker therapy results in near-normalization of AGV in MFS. ACEI did not decrease AGV in a clinically significant manner. PMID:25109242

  1. The L-type Ca2+ Channel Blocker Nifedipine Inhibits Mycelial Growth, Sporulation, and Virulence of Phytophthora capsici

    PubMed Central

    Liu, Peiqing; Gong, Jie; Ding, Xueling; Jiang, Yue; Chen, Guoliang; Li, Benjin; Weng, Qiyong; Chen, Qinghe

    2016-01-01

    The oomycete vegetable pathogen Phytophthora capsici causes significant losses of important vegetable crops worldwide. Calcium and other plant nutrients have been used in disease management of oomycete pathogens. Calcium homeostasis and signaling is essential for numerous biological processes, and Ca2+ channel blockers prevent excessive Ca2+ influx into the fungal cell. However, it is not known whether voltage-gated Ca2+ channel blockers improve control over oomycete pathogens. In the present study, we compared the inhibitory effects of CaCl2 and the extracellular Ca2+ chelator EDTA on mycelial growth and found that calcium assimilation plays a key role in P. capsici mycelial growth. Next, we involved the voltage-gated Ca2+ channel blockers verapamil (VP) and nifedipine (NFD) to analyze the effect of Ca2+ channel blockers on mycelial growth and sporulation; the results suggested that NFD, but not VP, caused significant inhibition. Ion rescue in an NFD-induced inhibition assay suggested that NFD-induced inhibition is calcium-dependent. In addition, NFD increased P. capsici sensitivity to H2O2 in a calcium-dependent manner, and extracellular calcium rescued it. Furthermore, NFD inhibited the virulence and gene expression related to its pathogenicity. These results suggest that NFD inhibits mycelial growth, sporulation, and virulence of P. capsici. PMID:27540377

  2. Can a poison center overdose guideline safely reduce pediatric emergency department visits for unintentional β-blocker ingestions?

    PubMed

    Hickey, Colleen N; Mycyk, Mark B; Wahl, Michael S

    2012-09-01

    Poisoning is a leading cause cause for injury and death in pediatric patients. For this reason, β-blocker ingestion has been an indication for emergency department (ED) referral and evaluation in pediatric patients even though significant clinical effects are uncommonly reported. We sought to determine whether an evidence-based triage guideline developed jointly by the American Association of Poison Control Centers, American Academy of Clinical Toxicology, and American College of Medical Toxicology safely reduces unnecessary pediatric ED visits after unintentional small dose β-blocker overdose. This was a prospective study of patients aged 0-6 years with a β-blocker ingestion managed by a regional poison center pre and postimplementation of the triage guideline. One hundred fifty-three cases met inclusion criteria. Before implementation of an evidence-based triage guideline for out-of-hospital management, 52 (67%) cases were referred for ED evaluation, and 26 (33%) cases were recommended for home observation. After guideline implementation, 38 (51%) cases were referred for ED evaluation, and 37 (49%) were recommended for home observation. No deaths occurred in either group. The triage guideline was accurately followed by poison center staff in 96% of cases after implementation. An out-of-hospital triage guideline for pediatric β-blocker overdose was accurately followed by poison center staff and safely reduced unnecessary ED referrals with a 50% increase in home observation. PMID:21192245

  3. Factors affecting the development of adverse drug reactions to β-blockers in hospitalized cardiac patient population

    PubMed Central

    Mugoša, Snežana; Djordjević, Nataša; Djukanović, Nina; Protić, Dragana; Bukumirić, Zoran; Radosavljević, Ivan; Bošković, Aneta; Todorović, Zoran

    2016-01-01

    The aim of the present study was to undertake a study on the prevalence of cytochrome P450 2D6 (CYP2D6) poor metabolizer alleles (*3, *4, *5, and *6) on a Montenegrin population and its impact on developing adverse drug reactions (ADRs) of β-blockers in a hospitalized cardiac patient population. A prospective study was conducted in the Cardiology Center of the Clinical Center of Montenegro and included 138 patients who had received any β-blocker in their therapy. ADRs were collected using a specially designed questionnaire, based on the symptom list and any signs that could point to eventual ADRs. Data from patients’ medical charts, laboratory tests, and other available parameters were observed and combined with the data from the questionnaire. ADRs to β-blockers were observed in 15 (10.9%) patients. There was a statistically significant difference in the frequency of ADRs in relation to genetically determined enzymatic activity (P<0.001), with ADRs’ occurrence significantly correlating with slower CYP2D6 metabolism. Our study showed that the adverse reactions to β-blockers could be predicted by the length of hospitalization, CYP2D6 poor metabolizer phenotype, and the concomitant use of other CYP2D6-metabolizing drugs. Therefore, in hospitalized patients with polypharmacy CYP2D6 genotyping might be useful in detecting those at risk of ADRs. PMID:27536078

  4. Effects of calcium channel blockers on spontaneous electrical activity of freshly isolated three-day-old embryonic chick ventricle.

    PubMed

    Prakash, P; Meera, P; Tripathi, O

    1996-01-01

    The effects of four major types of organic Ca2+ channel blockers, verapamil, nifedipine, diltiazem and fendiline and of tetrodotoxin (TXX), a fast Na+ channel blocker, on the action potential (AP) of freshly isolated 3-day-old embryonic chick ventricle (3d ECV) were investigated to resolve the controversy about the ionic basis of upstroke. The APs were characterized by a maximum diastolic potential (MDP) of -60 mV, an overshoot (Eov) of 16 mV and a maximum upstroke velocity (+Vmax) of 42 V s-1. All four Ca2+ channel blockers (0.1-40 microM) and TTX (0.1-80 nM) produced a dose-dependent reduction in +Vmax and Eov. MDP was also reduced by Ca2+ channel blockers in a dose-dependent manner but was unaffected by TTX. A significant linear correlation between MDP and +Vmax was observed for verapamil (r = 0.99), nifedipine (r = 0.99), diltiazem (r = 0.96) and fendiline (r = 0.98). Surprisingly, all Ca2+ channel blockers produced a dose-dependent positive chronotropic effect leading to cessation of firing at high doses (20-40 microM). In preparations becoming quiescent with high doses of verapamil (20-40 microM), elevated extracellular concentrations of Ca2+ (up to 9.6 nM) and isoproterenol (0.5-40 microM) failed to restore spontaneous APs. Electrical stimulation also failed to elicit APs in preparations inhibited by verapamil, diltiazem and fendiline. The inhibition of +Vmax by TTX demonstrates that fast Na+ channels were involved in the upstroke of AP in 3d ECV. Voltage-dependent inactivation of fast Na+ channels during depolarization (reduction in MDP) by the Ca2+ channel blockers explains their inhibitory effect on +Vmax and indicates that L-type Ca2+ channels had no significant role in the upstroke. A positive chronotropic effect of the Ca2+ channel blockers further suggests that slow Ca2+ channels are not involved in automaticity in freshly isolated 3d ECV. PMID:8876052

  5. Effects of α-Blockers, Antimuscarinics, or Combination Therapy in Relieving Ureteral Stent-Related Symptoms: A Meta-Analysis

    PubMed Central

    Zhou, Liang; Cai, Xiang; Li, Hong

    2015-01-01

    Abstract Purpose: We evaluated the effects of α-blockers, antimuscarinics, or a combination of both in reducing ureteral stent-related symptoms. Methods: The relevant studies were identified by searching MEDLINE, EMBASE and Cochrane Library Database from January 2000 to May 2014. Randomized controlled trials evaluating effects of α-blocker, antimuscarinic, and combination therapy for stent-related symptoms were included. Two reviewers independently screened studies and extracted data. Results: A total of 13 articles were identified including 1408 patients. There were statistically significant differences in urinary symptom (−6.37; P<0.0001) and body pain index score (−7.03; P=0.0008) of the Ureteral Stent Symptom Questionnaire (USSQ), total International Prostate Symptom Score (IPSS) (−4.16; P=0.0006), Visual Analogue Pain Scale (VAPS) score (−2.48; P<0.00001), and quality of life (QoL) (−1.42; P=0.0009) in favor of the α-blocker group. Antimuscarinics alone vs the control group showed significant improvement in total IPSS (mean difference [MD]: −3.76; 95% confidence interval [CI], −5.08 to −2.43; P<0.00001) and QoL (MD: −0.82; 95% CI, −1.31 to −0.32; P=0.001). Compared with α-blockers monotherapy, combination therapy has significant lower total IPSS (MD: −3.74; 95% CI, −4.94 to −2.54; P<0.00001), VAPS (MD: −0.50; 95% CI, −0.89 to −0.11; P=0.01), and QoL (MD: −0.93; 95% CI, −1.30 to −0.55; P<0.00001). Conclusions: Our data showed the beneficial effect of α-blockers alone and antimuscarinics alone in reducing stent-related symptoms. Furthermore, we suggested significant advantages of combination therapy of α-blocker and antimuscarinic compared with α-blocker monotherapy. However, more high quality, randomized controlled trials are warranted to better address this issue, however. PMID:25491604

  6. Stellar parameters for stars of the CoRoT exoplanet field

    NASA Astrophysics Data System (ADS)

    Cortés, C.; Maciel, S. C.; Vieira, S.; Ferreira Lopes, C. E.; Leão, I. C.; de Oliveira, G. P.; Correia, C.; Canto Martins, B. L.; Catelan, M.; De Medeiros, J. R.

    2015-09-01

    Context. Spectroscopic observations represent a fundamental step in the physical characterization of stars and, in particular, in the precise location of stars in the HR diagram. Rotation is also a key parameter, impacting stellar properties and evolution, which modulates the interior and manifests itself on the surface of stars. To date, the lack of analysis based on large samples has prevented our understanding of the real impact of stellar parameters and rotation on the stellar evolution as well as on the behavior of surface abundances. The space missions, CoRoT and Kepler, are providing us with rotation periods for thousands of stars, thus enabling a robust assessment of the behavior of rotation for different populations and evolutionary stages. For these reasons, the follow-up programs are fundamental to increasing the returns of these space missions. An analysis that combines spectroscopic data and rotation/modulation periods obtained from these space missions provides the basis for establishing the evolutionary behavior of the angular momentum of solar-like stars at different evolutionary stages, and the relation of rotation with other relevant physical and chemical parameters. Aims: To support the computation and evolutionary interpretation of periods associated with the rotational modulation, oscillations, and variability of stars located in the CoRoT fields, we are conducting a spectroscopic survey for stars located in the fields already observed by the satellite. These observations allow us to compute physical and chemical parameters for our stellar sample. Methods: Using spectroscopic observations obtained with UVES/VLT and Hydra/Blanco, and based on standard analysis techniques, we computed physical and chemical parameters (Teff, log (g), [Fe/H], vmic, vrad, vsin (i), and A(Li)) for a large sample of CoRoT targets. Results: We provide physical and chemical parameters for a sample comprised of 138 CoRoT targets. Our analysis shows the stars in our

  7. Isolated anti-Ro/SSA thrombocytopenia: a rare feature of neonatal lupus

    PubMed Central

    Ayadi, Imene Dahmane; Hamida, Emira Ben; Boukhris, Mohamed Riadh; Bezzine, Ahlem; Chaouachi, Sihem; Marrakchi, Zahra

    2015-01-01

    We report a rare case of isolated thrombocytopenia related to anti-Ro/SSA antibodies. The mother was followed for unlabeled familial thrombocytopenia. The mother had positive anti-Ro/SSA antibodies. She was asymptomatic without skin lesions or other criteria neither of systemic lupus erythematosus nor other connective tissue disease. Pregnancy was uneventful. The postnatal examination was normal. On the first day of life, blood cells count showed thrombocytopenia at 40 x 109/L. Within the second day of life, platelet level dropped to 20 x 109/L. The management of thrombocytopenia included platelet transfusion and human immunoglobulin infusion. On the fifth day of life, there has been a drop in platelet count to 10 x 109/L requiring renewed platelet transfusion and human immunoglobulin infusion. On the 10th of life platelets rate was stable around 60 x 109/L. The infant had no evidence of cardiac, dermatologic or hepatobilary involvement initially or throughout follow up. PMID:26977221

  8. Thematic trip: "Save Roşia MontanÄă"

    NASA Astrophysics Data System (ADS)

    Eugenia, Marcu

    2015-04-01

    The name Roşia Montană, situated in Transylvania, became well known after a Romanian-Canadian company, Roşia Montană Gold Company (RMGC), obtained the concession license on exploitation for gold and silver minerals in the Roşia Montană area. The project consists of opening the largest surface gold mines in Europe using cyanide, which will include four open pits and a processing plant for gold and silver in The Roşia Valley and a tailings facility with an area of 367 hectares in the Corna Valley. One of the main fears is related to a possible ecological accident like the one in Baia Mare in 2000, when a tailing facility dam break led to cyanide pollution of Tisa and Danube rivers that resulted in the death of 1,200 tons of fish and contamination of water resources for 2 million people. This thematic trip is important for the scientific preparation of students and an opportunity to educate them in the spirit of environmental protection. The training and education of students will require assimilation and understanding, actively and consciously, using the knowledge acquired during the compulsory curriculum and training skills. REASON: The continuous degradation of the environment is a major crisis due to human intervention in nature, and the proposed Roşia Montană mining project will continue this trend. The company proposes to extract gold from mines by using the gold separation technique using cyanide, a process that involves destroying a total area of 16 km² which includes 5 mountains, 7 churches, 11 cemeteries and the ruins of Alburnus Maior Citadel, as well as creating pollution that would last for hundreds of years. The extraction of gold from low-grade ores using cyanide processes was estimated to result in a worldwide emission of 45,300 tons of hydrogen cyanide. Environmental education for a healthy life has children as target group, because they are the trustees and beneficiaries of tomorrow's natural resources and can influence the attitudes of

  9. VizieR Online Data Catalog: CoRoT 105906206 frequencies analysis (da Silva+, 2014)

    NASA Astrophysics Data System (ADS)

    da Silva, R.; Maceroni, C.; Gandolfi, D.; Lehmann, H.; Hatzes, A. P.

    2014-03-01

    The file frequenc.dat contains the table with 220 frequencies, amplitudes, and phases, together with their uncertainties, derived for the light curve of CoRoT 105906206 with pulsations only (after subtracting the best binary model). The uncertainties are the formal values computed using equations (4), (10), and (11) of Montgomery & O'Donoghue (1999DSSN...13...28M). (1 data file).

  10. Raman investigation of ro-vibrational modes of interstitial H2 in Si

    NASA Astrophysics Data System (ADS)

    Koch, S. G.; Lavrov, E. V.; Weber, J.

    2012-08-01

    A Raman scattering study of ro-vibrational transitions Q(J) of the interstitial H2 in Si is presented. It is shown that the Q(2) mode of para hydrogen is coupled to the TAX phonon of Si. The mode appears in the spectra at temperatures above 200 K. The results presented also suggest that the Q(3) transition of ortho hydrogen is resonantly coupled to the OΓ phonon.

  11. European landscape in astrobiology, results of the AstRoMap consultation

    NASA Astrophysics Data System (ADS)

    Horneck, Gerda; Rettberg, Petra; Walter, Nicolas; Gomez, Felipe

    2015-05-01

    Astrobiology is a multidisciplinary field of research, which encompasses scientists ranging from cosmology, astronomy, planetary sciences, physics, chemistry, geology, paleontology to biology. In order to map the existing astrobiological expertise in Europe a comprehensive community consultation has been performed within the AstRoMap (Astrobiology Road Mapping) project that is supported by the European Commission FP7 framework. From this information a data base of scientists (European and beyond) interested in astrobiology and planetary exploration (see:

  12. Antiscalant removal in accelerated desupersaturation of RO concentrate via chemically-enhanced seeded precipitation (CESP).

    PubMed

    McCool, Brian C; Rahardianto, Anditya; Cohen, Yoram

    2012-09-01

    An experimental study was carried out to demonstrate and quantify the feasibility of antiscalant (AS) removal from brackish water RO concentrate of high gypsum scaling propensity via lime treatment prior to seeded gypsum precipitation. Based on studies with model solutions, it was shown that sufficient AS removal (up to ∼90%) from RO concentrate is feasible via a lime treatment step (at a dose significantly lower than that required for conventional lime softening) to enable effective subsequent seeded gypsum precipitation. This two-step chemically-enhanced seeded precipitation (CESP) treatment of primary RO concentrate is suitable as an intermediate concentrate demineralization (ICD) stage for high recovery desalting employing secondary RO desalination. Analysis of gypsum precipitation and lime treatment kinetic data suggests that, after adequate CaCO(3) precipitation has been induced for effective AS scavenging, CaSO(4) desupersaturation can be achieved via seeded gypsum precipitation without retardation due to seed poisoning by AS. Also, the lime dose required to prevent seed poisoning during subsequent gypsum desupersaturation via seeded gypsum precipitation can be adequately assessed with a precipitation kinetics model that considers AS seed poisoning based on a Langmuir adsorption isotherm. The degree of AS removal after lime treatment increased linearly with the logarithm of the single lime dose additions. Staged lime dosing (i.e., multiple lime additions), however, removed a higher degree of AS relative to an equivalent single lime dose addition since a higher driving force for CaCO(3) precipitation could be maintained over the course of the lime treatment period. PMID:22673342

  13. 77 FR 47275 - Airworthiness Directives; HPH s. r.o. Sailplanes

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-08-08

    ...We are adopting a new airworthiness directive (AD) for all HPH s. r.o. Models 304C, 304CZ, and 304CZ-17 sailplanes. This AD results from mandatory continuing airworthiness information (MCAI) issued by an aviation authority of another country to identify and correct an unsafe condition on an aviation product. The MCAI describes the unsafe condition as the lack of a drain hole in the elevator......

  14. Learning to Improve E-mail Classification with numéro interactive

    NASA Astrophysics Data System (ADS)

    Jones, Dean M.

    This paper describes some of the ways in which we use artificial intelligence technologies in numéro interactive, a Customer Interaction Management system. In particular, we focus on the classification of e-mail messages into one of multiple business categories. We describe different features that are extracted from e-mail messages to help in this classification, and the improvement in the overall classification accuracy that results from the use of each kind of feature.

  15. Multiple dose study of the combined radiosensitizers Ro 03-8799 (pimonidazole) and SR 2508 (etanidazole)

    SciTech Connect

    Bleehen, N.M.; Newman, H.F.; Maughan, T.S.; Workman, P.

    1989-04-01

    The hypoxic cell radiosensitizers Ro 03-8799 and SR 2508 have different clinical toxicities. The former produces an acute but transient central nervous system syndrome, whereas the latter produces cumulative peripheral neuropathy. Following single dose studies, an escalating multiple dose schedule using both drugs in combination showed no unexpected adverse reactions at lower doses. This study identifies the clinical tolerance and pharmacokinetics when doses in the region of the maximal tolerated dose are given to 26 patients receiving infusions of 0.75 g/m2 Ro 03-8799 and 2 g/m2 SR 2508 three times per week. At 15 doses, 3/4 patients experienced WHO grade 2 peripheral neuropathy, whereas at 12 doses 1/9 developed grade 2 and 6/9 developed grade 1 neuropathies. This represents a lower dose of SR 2508 than can be given alone suggesting that some interaction between the two drugs does exist in terms of chronic peripheral neurotoxicity. Pharmacokinetic studies show no adverse interactions between the two drugs and minimal inter-patient variation. From bivariate analysis, cumulative AUC for Ro 03-8799 has the most significant correlation with the development of peripheral neuropathy. Tumor drug concentrations normalized to the administered dose show mean values of 34 micrograms/g Ro 03-8799 and 76 micrograms/g SR 2508 30 minutes after infusion. These could be expected to produce a single dose sensitizer enhancement ratio of 1.5. The combination of the two sensitizers at the maximum tolerable dose may be expected to give an increased therapeutic efficacy over either drug alone.

  16. THE FUTURE OF THE SUN: AN EVOLVED SOLAR TWIN REVEALED BY CoRoT

    SciTech Connect

    Do Nascimento, J.-D. Jr.; Da Costa, J. S.; Castro, M.; Takeda, Y.; Melendez, J.

    2013-07-10

    The question of whether the Sun is peculiar within the class of solar-type stars has been the subject of active investigation over the past three decades. Although several solar twins have been found with stellar parameters similar to those of the Sun (albeit in a range of Li abundances and with somewhat different compositions), their rotation periods are unknown, except for 18 Sco, which is younger than the Sun and with a rotation period shorter than solar. It is difficult to obtain rotation periods for stars of solar age from ground-based observations, as a low-activity level implies a shallow rotational modulation of their light curves. CoRoT has provided space-based long time series from which the rotation periods of solar twins as old as the Sun could be estimated. Based on high-signal-to-noise, high-resolution spectroscopic observations gathered at the Subaru Telescope, we show that the star CoRoT ID 102684698 is a somewhat evolved solar twin with a low Li abundance. Its rotation period is 29 {+-} 5 days, compatible with its age (6.7 Gyr) and low lithium content, A{sub Li} {approx}< 0.85 dex. Interestingly, our CoRoT solar twin seems to have enhanced abundances of the refractory elements with respect to the Sun, a typical characteristic of most nearby twins. With a magnitude V {approx_equal} 14.1, ID 102684698 is the first solar twin revealed by CoRoT, the farthest field solar twin so far known, and the only solar twin older than the Sun for which a rotation period has been determined.

  17. The Transit Detection Algorithm DST and its application to CoRoT and Kepler data

    NASA Astrophysics Data System (ADS)

    Cabrera, J.; Rauer, H.; Erikson, A.; Csizmadia, S.

    2011-10-01

    Transit detection algorithms are mathematical tools used to detect the presence of planets in the photometric data of transit surveys. Space missions are exploring the parameter space of transit surveys towards small planets where classical algorithms do not perform optimally, either due to the low signal to noise ratio of the signal or to its non-periodic characteristics. We present an algorithm addressing these challenges and its performance in an application to CoRoT and Kepler data.

  18. The Safety and Effects of the Beta-Blocker, Nadolol, in Mild Asthma; An Open-label Pilot Study

    PubMed Central

    Hanania, Nicola A; Singh, Supria; Eli-Wali, Rami; Flashner, Michael; Franklin, Amie E; Garner, William J; Dickey, Burton F; Parra, Sergio; Ruoss, Stephen J; Shardonofsky, Felix; O'Connor, Brian J; Page, Clive; Bond, Richard A

    2008-01-01

    Beta-blockers are currently contraindicated in asthma because their acute administration may be associated with worsening bronchospasm. However, their effects and safety with their chronic administration are not well evaluated. The rationale for this pilot study was based on the paradigm shift that was observed with the use of beta-blockers in congestive heart failure which once contraindicated because of their acute detrimental effects, have now been shown to reduce mortality with their chronic use. We hypothesized that certain beta-blockers may also be safe and useful in chronic asthma therapy. In this prospective, open-label, pilot study, we evaluated the safety and effects of escalating doses of the beta-blocker, nadolol, administered over 9 weeks to 10 subjects with mild asthma. Dose escalation was performed on a weekly basis based on pre-determined safety lung function, asthma control and hemodynamic parameters. The primary objective was to evaluate safety and secondary objectives were to evaluate effects on airway hyperresponsiveness, and indices of respiratory function. The escalating administration of nadolol was well tolerated. In 8 out of the 10 subjects, nine weeks of nadolol treatment produced a significant, dose-dependent increase in PC20 that reached 2.1 doubling doses at 40 mg (p < 0.0042). However, there was also a dose-independent 5% reduction in mean FEV1 over the study period (p < 0.01). We conclude that in most patients with mild asthma, the dose-escalating administration of the beta-blocker, nadolol, is well tolerated and may have beneficial effects on airway hyperresponsiveness. Our findings warrant further testing in future larger trials. PMID:17703976

  19. NVP-QBE170: an inhaled blocker of the epithelial sodium channel with a reduced potential to induce hyperkalaemia

    PubMed Central

    Coote, K J; Paisley, D; Czarnecki, S; Tweed, M; Watson, H; Young, A; Sugar, R; Vyas, M; Smith, N J; Baettig, U; Groot-Kormelink, P J; Gosling, M; Lock, R; Ethell, B; Williams, G; Schumacher, A; Harris, J; Abraham, W M; Sabater, J; Poll, C T; Faller, T; Collingwood, S P; Danahay, H

    2015-01-01

    Background and Purpose Inhaled amiloride, a blocker of the epithelial sodium channel (ENaC), enhances mucociliary clearance (MCC) in cystic fibrosis (CF) patients. However, the dose of amiloride is limited by the mechanism-based side effect of hyperkalaemia resulting from renal ENaC blockade. Inhaled ENaC blockers with a reduced potential to induce hyperkalaemia provide a therapeutic strategy to improve mucosal hydration and MCC in the lungs of CF patients. The present study describes the preclinical profile of a novel ENaC blocker, NVP-QBE170, designed for inhaled delivery, with a reduced potential to induce hyperkalaemia. Experimental Approach The in vitro potency and duration of action of NVP-QBE170 were compared with amiloride and a newer ENaC blocker, P552-02, in primary human bronchial epithelial cells (HBECs) by short-circuit current. In vivo efficacy and safety were assessed in guinea pig (tracheal potential difference/hyperkalaemia), rat (hyperkalaemia) and sheep (MCC). Key Results In vitro, NVP-QBE170 potently inhibited ENaC function in HBEC and showed a longer duration of action to comparator molecules. In vivo, intratracheal (i.t.) instillation of NVP-QBE170 attenuated ENaC activity in the guinea pig airways with greater potency and duration of action than that of amiloride without inducing hyperkalaemia in either guinea pig or rat. Dry powder inhalation of NVP-QBE170 by conscious sheep increased MCC and was better than inhaled hypertonic saline in terms of efficacy and duration of action. Conclusions and Implications NVP-QBE170 highlights the potential for inhaled ENaC blockers to exhibit efficacy in the airways with a reduced risk of hyperkalaemia, relative to existing compounds. PMID:25573195

  20. Cocaine self-administration produces pharmacodynamic tolerance: differential effects on the potency of dopamine transporter blockers, releasers, and methylphenidate.

    PubMed

    Ferris, Mark J; Calipari, Erin S; Mateo, Yolanda; Melchior, James R; Roberts, David C S; Jones, Sara R

    2012-06-01

    The dopamine transporter (DAT) is the primary site of action for psychostimulant drugs such as cocaine, methylphenidate, and amphetamine. Our previous work demonstrated a reduced ability of cocaine to inhibit the DAT following high-dose cocaine self-administration (SA), corresponding to a reduced ability of cocaine to increase extracellular dopamine. However, this effect had only been demonstrated for cocaine. Thus, the current investigations sought to understand the extent to which cocaine SA (1.5 mg/kg/inf × 40 inf/day × 5 days) altered the ability of different dopamine uptake blockers and releasers to inhibit dopamine uptake, measured using fast-scan cyclic voltammetry in rat brain slices. We demonstrated that, similar to cocaine, the DAT blockers nomifensine and bupropion were less effective at inhibiting dopamine uptake following cocaine SA. The potencies of amphetamine-like dopamine releasers such as 3,4-methylenedioxymethamphetamine, methamphetamine, amphetamine, and phentermine, as well as a non-amphetamine releaser, 4-benzylpiperidine, were all unaffected. Finally, methylphenidate, which blocks dopamine uptake like cocaine while being structurally similar to amphetamine, shared characteristics of both, resembling an uptake blocker at low concentrations and a releaser at high concentrations. Combined, these experiments demonstrate that after high-dose cocaine SA, there is cross-tolerance of the DAT to other uptake blockers, but not releasers. The reduced ability of psychostimulants to inhibit dopamine uptake following cocaine SA appears to be contingent upon their functional interaction with the DAT as a pure blocker or releaser rather than their structural similarity to cocaine. Further, methylphenidate's interaction with the DAT is unique and concentration-dependent. PMID:22395730

  1. SU-D-12A-07: Optimization of a Moving Blocker System for Cone-Beam Computed Tomography Scatter Correction

    SciTech Connect

    Ouyang, L; Yan, H; Jia, X; Jiang, S; Wang, J; Zhang, H

    2014-06-01

    Purpose: A moving blocker based strategy has shown promising results for scatter correction in cone-beam computed tomography (CBCT). Different parameters of the system design affect its performance in scatter estimation and image reconstruction accuracy. The goal of this work is to optimize the geometric design of the moving block system. Methods: In the moving blocker system, a blocker consisting of lead strips is inserted between the x-ray source and imaging object and moving back and forth along rotation axis during CBCT acquisition. CT image of an anthropomorphic pelvic phantom was used in the simulation study. Scatter signal was simulated by Monte Carlo calculation with various combinations of the lead strip width and the gap between neighboring lead strips, ranging from 4 mm to 80 mm (projected at the detector plane). Scatter signal in the unblocked region was estimated by cubic B-spline interpolation from the blocked region. Scatter estimation accuracy was quantified as relative root mean squared error by comparing the interpolated scatter to the Monte Carlo simulated scatter. CBCT was reconstructed by total variation minimization from the unblocked region, under various combinations of the lead strip width and gap. Reconstruction accuracy in each condition is quantified by CT number error as comparing to a CBCT reconstructed from unblocked full projection data. Results: Scatter estimation error varied from 0.5% to 2.6% as the lead strip width and the gap varied from 4mm to 80mm. CT number error in the reconstructed CBCT images varied from 12 to 44. Highest reconstruction accuracy is achieved when the blocker lead strip width is 8 mm and the gap is 48 mm. Conclusions: Accurate scatter estimation can be achieved in large range of combinations of lead strip width and gap. However, image reconstruction accuracy is greatly affected by the geometry design of the blocker.

  2. A theoretical perspective on the ultra-compact systems of CoRoT and Kepler

    NASA Astrophysics Data System (ADS)

    Wuchterl, G.

    2011-10-01

    CoRoT and Kepler discovered closely spaced short period planetary systems. We investigate into the physics of these systems by combining an approach that was developed for the CoRoT mission to determine the distributions of planetary masses and radii based on a minimum number of basic physical principles with the classical approach of Hill-exclusion volumes to estimate dynamical stability. We discuss to what extent the discovered systems can be understood as a random draw from the theoretical mass and/or radius distributions with Hill-exclusion stability as a constraint. We point to the bi-modality of the theoretical planetary mass-function as a key factor in shaping the architecture of the presently known systems. Given the first-time availability of new high-resolution epoch-of observation theoretical radius distributions for the entire present period sensitivity of CoRoT and Keplerreleases, we take the opportunity to confront the various radius anomalies — 'styrofoam' planets, inflated Jupiters and Neptunes — to our statistical approach.

  3. Quantum scattering calculations for ro-vibrational de-excitation of CO by hydrogen atoms

    SciTech Connect

    Song, Lei; Avoird, Ad van der; Karman, Tijs; Groenenboom, Gerrit C.; Balakrishnan, N.

    2015-05-28

    We present quantum-mechanical scattering calculations for ro-vibrational relaxation of carbon monoxide (CO) in collision with hydrogen atoms. Collisional cross sections of CO ro-vibrational transitions from v = 1, j = 0 − 30 to v′ = 0, j′ are calculated using the close coupling method for collision energies between 0.1 and 15 000 cm{sup −1} based on the three-dimensional potential energy surface of Song et al. [J. Phys. Chem. A 117, 7571 (2013)]. Cross sections of transitions from v = 1, j ≥ 3 to v′ = 0, j′ are reported for the first time at this level of theory. Also calculations by the more approximate coupled states and infinite order sudden (IOS) methods are performed in order to test the applicability of these methods to H–CO ro-vibrational inelastic scattering. Vibrational de-excitation rate coefficients of CO (v = 1) are presented for the temperature range from 100 K to 3000 K and are compared with the available experimental and theoretical data. All of these results and additional rate coefficients reported in a forthcoming paper are important for including the effects of H–CO collisions in astrophysical models.

  4. Special cascade LMS equalization scheme suitable for 60-GHz RoF transmission system.

    PubMed

    Liu, Siming; Shen, Guansheng; Kou, Yanbin; Tian, Huiping

    2016-05-16

    We design a specific cascade least mean square (LMS) equalizer and to the best of our knowledge, it is the first time this kind of equalizer has been employed for 60-GHz millimeter-wave (mm-wave) radio over fiber (RoF) system. The proposed cascade LMS equalizer consists of two sub-equalizers which are designated for optical and wireless channel compensations, respectively. We control the linear and nonlinear factors originated from optical link and wireless link separately. The cascade equalization scheme can keep the nonlinear distortions of the RoF system in a low degree. We theoretically and experimentally investigate the parameters of the two sub-equalizers to reach their best performances. The experiment results show that the cascade equalization scheme has a faster convergence speed. It needs a training sequence with a length of 10000 to reach its stable status, which is only half as long as the traditional LMS equalizer needs. With the utility of a proposed equalizer, the 60-GHz RoF system can successfully transmit 5-Gbps BPSK signal over 10-km fiber and 1.2-m wireless link under forward error correction (FEC) limit 10-3. An improvement of 4dBm and 1dBm in power sensitivity at BER 10-3 over traditional LMS equalizer can be observed when the signals are transmitted through Back-to-Back (BTB) and 10-km fiber 1.2-m wireless links, respectively. PMID:27409882

  5. THE CoRoT DISCOVERY OF A UNIQUE TRIPLE-MODE CEPHEID IN THE GALAXY

    SciTech Connect

    Poretti, E.; Baglin, A.; Weiss, W. W.

    2014-11-10

    The exploitation of the CoRoT treasure of stars observed in the exoplanetary field allowed the detection of a unusual triple-mode Cepheid in the Milky Way, CoRoT 0223989566. The two modes with the largest amplitudes and a period ratio of 0.80 are identified with the first (P {sub 1} = 1.29 days) and second (P {sub 2} = 1.03 days) radial overtones. The third period, which has the smallest amplitude but is able to produce combination terms with the other two, is the longest one (P {sub 3} = 1.89 days). The ratio of 0.68 between the first-overtone period and the third period is the unusual feature. Its identification with the fundamental radial or a nonradial mode is discussed with respect to similar cases in the Magellanic Clouds. In both cases, the period triplet and the respective ratios make the star unique in our Galaxy. The distance derived from the period-luminosity relation and the galactic coordinates put CoRoT 0223989566 in the metal-rich environment of the ''outer arm'' of the Milky Way.

  6. RoCoMAR: Robots' Controllable Mobility Aided Routing and Relay Architecture for Mobile Sensor Networks

    PubMed Central

    Van Le, Duc; Oh, Hoon; Yoon, Seokhoon

    2013-01-01

    In a practical deployment, mobile sensor network (MSN) suffers from a low performance due to high node mobility, time-varying wireless channel properties, and obstacles between communicating nodes. In order to tackle the problem of low network performance and provide a desired end-to-end data transfer quality, in this paper we propose a novel ad hoc routing and relaying architecture, namely RoCoMAR (Robots' Controllable Mobility Aided Routing) that uses robotic nodes' controllable mobility. RoCoMAR repeatedly performs link reinforcement process with the objective of maximizing the network throughput, in which the link with the lowest quality on the path is identified and replaced with high quality links by placing a robotic node as a relay at an optimal position. The robotic node resigns as a relay if the objective is achieved or no more gain can be obtained with a new relay. Once placed as a relay, the robotic node performs adaptive link maintenance by adjusting its position according to the movements of regular nodes. The simulation results show that RoCoMAR outperforms existing ad hoc routing protocols for MSN in terms of network throughput and end-to-end delay. PMID:23881134

  7. Water Quality of Hills Water, Supply Water and RO Water Machine at Ulu Yam Selangor

    NASA Astrophysics Data System (ADS)

    Ngadiman, N.; ‘I Bahari, N.; Kaamin, M.; Hamid, N. B.; Mokhtar, M.; Sahat, S.

    2016-07-01

    The rapid development resulted in the deterioration of the quality of drinking water in Malaysia. Recognizing the importance of water quality, new alternatives for drinking water such as mineral water processing from reverse osmosis (RO) machine become more popular. Hence, the demand for mineral water, natural spring water or water from the hills or mountains rose lately. More consumers believed the quality of these spring water better than other source of drinking water. However, the quality of all the drinking water sources is to meet the required quality standard. Therefore, this paper aims to measure the quality of the waters from hills, from RO machine and the water supply in Ulu Yam, Selangor Batang Kali, Malaysia. The water quality was determined based on following parameters: ammoniacal nitrogen (NH3), iron (Fe), turbidity (NTU) and pH. The results show that the water from hills has better quality compared to water supply and water from RO machine. The value of NH3 ranged from 0.03 mg/L- 0.67 mg/L; Fe was from 0.03mg/L - 0.12 mg/L, turbidity at 0.42 NTU - 0.88 NTU and pH is at 6.60 - 0.71. Based on the studied parameters, all three types of water are fit for drinking and have met the required national drinking water quality standard.

  8. Quantum scattering calculations for ro-vibrational de-excitation of CO by hydrogen atoms

    NASA Astrophysics Data System (ADS)

    Song, Lei; Balakrishnan, N.; van der Avoird, Ad; Karman, Tijs; Groenenboom, Gerrit C.

    2015-05-01

    We present quantum-mechanical scattering calculations for ro-vibrational relaxation of carbon monoxide (CO) in collision with hydrogen atoms. Collisional cross sections of CO ro-vibrational transitions from v = 1, j = 0 - 30 to v' = 0, j' are calculated using the close coupling method for collision energies between 0.1 and 15 000 cm-1 based on the three-dimensional potential energy surface of Song et al. [J. Phys. Chem. A 117, 7571 (2013)]. Cross sections of transitions from v = 1, j ≥ 3 to v' = 0, j' are reported for the first time at this level of theory. Also calculations by the more approximate coupled states and infinite order sudden (IOS) methods are performed in order to test the applicability of these methods to H-CO ro-vibrational inelastic scattering. Vibrational de-excitation rate coefficients of CO (v = 1) are presented for the temperature range from 100 K to 3000 K and are compared with the available experimental and theoretical data. All of these results and additional rate coefficients reported in a forthcoming paper are important for including the effects of H-CO collisions in astrophysical models.

  9. [Phase II study of recombinant leukocyte A interferon (Ro 22-8181) in hematological malignancies].

    PubMed

    1985-04-01

    A Phase II study of recombinant leukocyte A interferon (rIFN-alpha A, Ro 22-8181) was performed in 121 patients with hematological malignancies at 33 institutions from July, 1982 to May, 1984. Patients received Ro 22-8181 by intramuscular injection daily for more than 4 weeks. Daily doses were escalated from 3 X 10(6) to 6X, 9X, 18X, 36X and 50X 10(6) units every 3-7 days. Among 70 evaluable cases, complete or partial responses were observed in 15 patients (21.4%). One complete and 10 partial responses (22.4%) were noted in 49 cases of multiple myeloma, 2 partial remissions (18.2%) in 11 cases of malignant lymphoma and 2 partial remissions (25.0%) in 8 cases of leukemia. Side effects included fever (57.0%), anorexia (34.2%), nausea-vomiting (22.8%), malaise (19.0%), leukopenia (44.3%), thrombocytopenia (45.6%) and increase of GOT or GPT (26.6% or 22.8%). They were all not serious and disappeared quickly after the discontinuation of Ro 22-8181. PMID:3885864

  10. The CoRoT Discovery of a Unique Triple-mode Cepheid in the Galaxy

    NASA Astrophysics Data System (ADS)

    Poretti, E.; Baglin, A.; Weiss, W. W.

    2014-11-01

    The exploitation of the CoRoT treasure of stars observed in the exoplanetary field allowed the detection of a unusual triple-mode Cepheid in the Milky Way, CoRoT 0223989566. The two modes with the largest amplitudes and a period ratio of 0.80 are identified with the first (P 1 = 1.29 days) and second (P 2 = 1.03 days) radial overtones. The third period, which has the smallest amplitude but is able to produce combination terms with the other two, is the longest one (P 3 = 1.89 days). The ratio of 0.68 between the first-overtone period and the third period is the unusual feature. Its identification with the fundamental radial or a nonradial mode is discussed with respect to similar cases in the Magellanic Clouds. In both cases, the period triplet and the respective ratios make the star unique in our Galaxy. The distance derived from the period-luminosity relation and the galactic coordinates put CoRoT 0223989566 in the metal-rich environment of the "outer arm" of the Milky Way.

  11. Radiative accuracy assessment of CrIS upper level channels using COSMIC RO data

    NASA Astrophysics Data System (ADS)

    Qi, C.; Weng, F.; Han, Y.; Lin, L.; Chen, Y.; Wang, L.

    2012-12-01

    The Cross-track Infrared Sounder(CrIS) onboard Suomi National Polar-orbiting Partnership(NPP) satellite is designed to provide high vertical resolution information on the atmosphere's three-dimensional structure of temperature and water vapor. There are much work has been done to verify the observation accuracy of CrIS since its launch date of Oct. 28, 2011, such as SNO cross comparison with other hyper-spectral infrared instruments and forward simulation comparison using radiative transfer model based on numerical prediction background profiles. Radio occultation technique can provide profiles of the Earth's ionosphere and neutral atmosphere with high accuracy, high vertical resolution and global coverage. It has advantages of all-weather capability, low expense, long-term stability etc. Assessing CrIS radiative calibration accuracy was conducted by comparison between observation and Line-by-line simulation using COSMIC RO data. The main process technique include : (a) COSMIC RO data downloading and collocation with CrIS measurements through weighting function (wf) peak altitude dependent collocation method; (b) High spectral resolution of Line-by-line radiance simulation using collocated COSMIC RO profiles ; (c) Generation of CrIS channel radiance by FFT transform method; (d): Bias analysis . This absolute calibration accuracy assessing method verified a 0.3K around bias error of CrIS measurements.

  12. Constraints on the exosphere of CoRoT-7b

    NASA Astrophysics Data System (ADS)

    Guenther, E. W.; Cabrera, J.; Erikson, A.; Fridlund, M.; Lammer, H.; Mura, A.; Rauer, H.; Schneider, J.; Tulej, M.; von Paris, Ph.; Wurz, P.

    2011-01-01

    Context. The small radius and high density of CoRoT-7b implies that this transiting planet belongs to a different species than all transiting planets previously found. Current models suggest that this is the first transiting rocky planet found outside the solar system. Given that the planet orbits a solar-like star at a distance of only 4.5 R*, it is expected that material released from its surface may then form an exosphere. Aims: We constrain the properties of the exosphere by observing the planet in- and out-of-transit. Detecting the exosphere of CoRoT-7b would for the first time allow us to study the material originating in the surface of a rocky extrasolar planet. We scan the entire optical spectrum for any lines originating from the planet, focusing particularly on spectral lines such as those detected in Mercury and Io in our solar system. Methods: Since lines originating in the exosphere are expected to be narrow, we observed CoRoT-7b at high resolution with UVES on the VLT. By subtracting the two spectra from each other, we search for emission and absorption lines originating in the exosphere of CoRoT-7b. Results: In the first step, we focus on Ca I, Ca II, and Na, because these lines have been detected in Mercury. Since the signal-to-noise ratio (S/N) of the spectra is as high as 300, we derive firm upper limits for the flux-range between 1.6 × 10-18 and 3.2 × 10-18 W m-2. For CaO, we find an upper limit of 10-17 W m-2. We also search for emission lines originating in the plasma torus fed by volcanic activity and derive upper limits for these lines. In the whole spectrum we finally try to identify other lines originating in the planet. Conclusions: Except for CaO, the upper limits derived correspond to 2-6 × 10-6 L*, demonstrating the capability of UVES to detect very weak lines. Our observations certainly exclude the extreme interpretations of data for CoRoT-7b, such as an exosphere that emits 2000 times as brightly as Mercury. Based on observations

  13. Distribution of refractory and volatile elements in CoRoT exoplanet host stars

    NASA Astrophysics Data System (ADS)

    Chavero, C.; de La Reza, R.; Domingos, R. C.; Drake, N. A.; Pereira, C. B.; Winter, O. C.

    2010-07-01

    The relative distribution of abundances of refractory, intermediate, and volatile elements in stars with planets can be an important tool for investigating the internal migration of a giant planet. This migration can lead to the accretion of planetesimals and the selective enrichment of the star with these elements. We report on a spectroscopic determination of the atmospheric parameters and chemical abundances of the parent stars in transiting planets CoRoT-2b and CoRoT-4b. Adding data for CoRoT-3 and CoRoT-5 from the literature, we find a flat distribution of the relative abundances as a function of their condensation temperatures. For CoRoT-2, the relatively high lithium abundance and intensity of its Li i resonance line permit us to propose an age of 120 Myr, making this star one of the youngest stars with planets to date. We introduce a new methodology to investigate a relation between the abundances of these stars and the internal migration of their planets. By simulating the internal migration of a planet in a disk formed only by planetesimals, we are able, for the first time, to separate the stellar fractions of refractory, intermediate, and volatile rich planetesimals accreting onto the central star. Intermediate and volatile element fractions enriching the star are similar and much larger than those of pure refractory ones. This result is opposite to what has been considered in the literature for the accreting self-enrichment processes of stars with planets. We also show that these results are highly dependent on the model adopted for the disk distribution regions in terms of refractory, intermediate, and also volatile elements and other parameters considered. We note however, that this self-enrichment mechanism is only efficient during the first 20-30 Myr or later in the lifetime of the disk when the surface convection layers of the central star for the first time attain its minimum size configuration. Based on observations made with the 2.2 m telescope

  14. Study of HD 169392A observed by CoRoT and HARPS

    NASA Astrophysics Data System (ADS)

    Mathur, S.; Bruntt, H.; Catala, C.; Benomar, O.; Davies, G. R.; García, R. A.; Salabert, D.; Ballot, J.; Mosser, B.; Régulo, C.; Chaplin, W. J.; Elsworth, Y.; Handberg, R.; Hekker, S.; Mantegazza, L.; Michel, E.; Poretti, E.; Rainer, M.; Roxburgh, I. W.; Samadi, R.; Stȩślicki, M.; Uytterhoeven, K.; Verner, G. A.; Auvergne, M.; Baglin, A.; Barceló Forteza, S.; Baudin, F.; Roca Cortés, T.

    2013-01-01

    Context. The results obtained by asteroseismology with data from space missions such as CoRoT and Kepler are providing new insights into stellar evolution. After five years of observations, CoRoT is continuing to provide high-quality data and we here present an analysis of the CoRoT observations of the double star HD 169392, complemented by ground-based spectroscopic observations. Aims: This work aims at characterising the fundamental parameters of the two stars, their chemical composition, the acoustic-mode global parameters including their individual frequencies, and their dynamics. Methods: We analysed HARPS observations of the two stars to derive their chemical compositions. Several methods were used and compared to determine the global properties of stars' acoustic modes and their individual frequencies from the photometric data of CoRoT. Results: The new spectroscopic observations and archival astrometric values suggest that HD 169392 is a weakly bound wide binary system. We obtained spectroscopic parameters for both components which suggest that they originate from the same interstellar cloud. However, only the signature of oscillation modes of HD 169392 A was measured; the signal-to-noise ratio of the modes in HD 169392B is too low to allow any confident detection. For HD 169392 A we were able to extract parameters of modes for ℓ = 0, 1, 2, and 3. The analysis of splittings and inclination angle gives two possible solutions: one with with splittings and inclination angles of 0.4-1.0 μHz and 20 - 40°, the other with 0.2-0.5 μHz and 55-86°. Modelling this star using the Asteroseismic Modeling Portal (AMP) gives a mass of 1.15 ± 0.01 M⊙, a radius of 1.88 ± 0.02 R⊙, and an age of 4.33 ± 0.12 Gyr. The uncertainties come from estimated errors on the observables but do not include uncertainties on the surface layer correction or the physics of stellar models. The CoRoT space mission, launched on December 27 2006, has been developed and is operated by

  15. HD 50844: a new look at δ Scuti stars from CoRoT space photometry

    NASA Astrophysics Data System (ADS)

    Poretti, E.; Michel, E.; Garrido, R.; Lefèvre, L.; Mantegazza, L.; Rainer, M.; Rodríguez, E.; Uytterhoeven, K.; Amado, P. J.; Martín-Ruiz, S.; Moya, A.; Niemczura, E.; Suárez, J. C.; Zima, W.; Baglin, A.; Auvergne, M.; Baudin, F.; Catala, C.; Samadi, R.; Alvarez, M.; Mathias, P.; Paparò, M.; Pápics, P.; Plachy, E.

    2009-10-01

    Context: Aims: This work presents the results obtained by CoRoT on HD 50844, the only δ Sct star observed in the CoRoT initial run (57.6 d). The aim of these CoRoT observations was to investigate and characterize for the first time the pulsational behaviour of a δ Sct star, when observed at a level of precision and with a much better duty cycle than from the ground. Methods: The 140 016 datapoints were analysed using independent approaches (SigSpec software and different iterative sine-wave fittings) and several checks performed (splitting of the timeseries in different subsets, investigation of the residual light curves and spectra). A level of 10-5 mag was reached in the amplitude spectra of the CoRoT timeseries. The space monitoring was complemented by ground-based high-resolution spectroscopy, which allowed the mode identification of 30 terms. Results: The frequency analysis of the CoRoT timeseries revealed hundreds of terms in the frequency range 0-30 d-1. All the cross-checks confirmed this new result. The initial guess that δ Sct stars have a very rich frequency content is confirmed. The spectroscopic mode identification gives theoretical support since very high-degree modes (up to ℓ=14) are identified. We also prove that cancellation effects are not sufficient in removing the flux variations associated to these modes at the noise level of the CoRoT measurements. The ground-based observations indicate that HD 50844 is an evolved star that is slightly underabundant in heavy elements, located on the Terminal Age Main Sequence. Probably due to this unfavourable evolutionary status, no clear regular distribution is observed in the frequency set. The predominant term (f_1=6.92 d-1) has been identified as the fundamental radial mode combining ground-based photometric and spectroscopic data. Conclusions: The CoRoT space mission was developed and is operated by the French space agency CNES, with participation of ESA's RSSD and Science Programmes, Austria

  16. RoY peptide-modified chitosan-based hydrogel to improve angiogenesis and cardiac repair under hypoxia.

    PubMed

    Shu, Yao; Hao, Tong; Yao, Fanglian; Qian, Yufeng; Wang, Yan; Yang, Boguang; Li, Junjie; Wang, Changyong

    2015-04-01

    Myocardial infarction (MI) still represents the "Number One Killer" in the world. The lack of functional vasculature of the infracted myocardium under hypoxia is one of the main problems for cardiac repair. In this study, a thermosensitive chitosan chloride-RoY (CSCl-RoY) hydrogel was developed to improve angiogenesis under hypoxia after MI. First, RoY peptides were conjugated onto the CSCl chain via amide linkages, and our data show that the conjugation of RoY peptide to CSCl does not interfere with the temperature sensitivity. Then, the effect of CSCl-RoY hydrogels on vascularization in vitro under hypoxia was investigated using human umbilical vein endothelial cells (HUVECs). Results show that CSCl-RoY hydrogels can promote the survival, proliferation, migration and tube formation of HUVECs under hypoxia compared with CSCl hydrogel. Further investigations suggest that CSCl-RoY hydrogels can modulate the expression of membrane surface GRP78 receptor of HUVECs under hypoxia and then activate Akt and ERK1/2 signaling pathways related to cell survival/proliferation, thereby enhancing angiogenic activity of HUVECs under hypoxia. To assess its therapeutic properties in vivo, a MI model was induced in rats by the left anterior descending artery ligation. CSCl or CSCl-RoY hydrogels were injected into the border of infracted hearts. The results demonstrate that the introduction of RoY peptide can not only improve angiogenesis at MI region but also improve the cardiac functions. Overall, we conclude that the CSCl-RoY may represent an ideal scaffold material for injectable cardiac tissue engineering. PMID:25756853

  17. Cholesterol biosynthesis inhibitor RO 48-8071 suppresses growth of hormone-dependent and castration-resistant prostate cancer cells

    PubMed Central

    Liang, Yayun; Mafuvadze, Benford; Aebi, Johannes D; Hyder, Salman M

    2016-01-01

    Standard treatment for primary prostate cancer includes systemic exposure to chemotherapeutic drugs that target androgen receptor or antihormone therapy (chemical castration); however, drug-resistant cancer cells generally emerge during treatment, limiting the continued use of systemic chemotherapy. Patients are then treated with more toxic standard therapies. Therefore, there is an urgent need for novel and more effective treatments for prostate cancer. The cholesterol biosynthetic pathway is an attractive therapeutic target for treating endocrine-dependent cancers because cholesterol is an essential structural and functional component of cell membranes as well as the metabolic precursor of endogenous steroid hormones. In this study, we have examined the effects of RO 48-8071 (4′-[6-(allylmethylamino)hexyloxy]-4-bromo-2′-fluorobenzophenone fumarate; Roche Pharmaceuticals internal reference: RO0488071) (RO), which is an inhibitor of 2, 3-oxidosqualene cyclase (a key enzyme in the cholesterol biosynthetic pathway), on prostate cancer cells. Exposure of both hormone-dependent and castration-resistant human prostate cancer cells to RO reduced prostate cancer cell viability and induced apoptosis in vitro. RO treatment reduced androgen receptor protein expression in hormone-dependent prostate cancer cells and increased estrogen receptor β (ERβ) protein expression in both hormone-dependent and castration-resistant prostate cancer cell lines. Combining RO with an ERβ agonist increased its ability to reduce castration-resistant prostate cancer cell viability. In addition, RO effectively suppressed the growth of aggressive castration-resistant human prostate cancer cell xenografts in vivo without any signs of toxicity to experimental animals. Importantly, RO did not reduce the viability of normal prostate cells in vitro. Our study is the first to demonstrate that the cholesterol biosynthesis inhibitor RO effectively suppresses growth of human prostate cancer cells

  18. Repeated Melatonin Supplementation Improves Sleep in Hypertensive Patients Treated with Beta-Blockers: A Randomized Controlled Trial

    PubMed Central

    Scheer, Frank A.J.L.; Morris, Christopher J.; Garcia, Joanna I.; Smales, Carolina; Kelly, Erin E.; Marks, Jenny; Malhotra, Atul; Shea, Steven A.

    2012-01-01

    Study Objectives: In the United States alone, approximately 22 million people take beta-blockers chronically. These medications suppress endogenous nighttime melatonin secretion, which may explain a reported side effect of insomnia. Therefore, we tested whether nightly melatonin supplementation improves sleep in hypertensive patients treated with beta-blockers. Design: Randomized, double-blind, placebo-controlled, parallel-group design. Setting: Clinical and Translational Research Center at Brigham and Women’s Hospital, Boston. Patients: Sixteen hypertensive patients (age 45-64 yr; 9 women) treated with the beta-blockers atenolol or metoprolol. Interventions: Two 4-day in-laboratory admissions including polysomnographically recorded sleep. After the baseline assessment during the first admission, patients were randomized to 2.5 mg melatonin or placebo (nightly for 3 weeks), after which sleep was assessed again during the second 4-day admission. Baseline-adjusted values are reported. One patient was removed from analysis because of an unstable dose of prescription medication. Measurements and Results: In comparison with placebo, 3 weeks of melatonin supplementation significantly increased total sleep time (+36 min; P = 0.046), increased sleep efficiency (+7.6%; P = 0.046), and decreased sleep onset latency to Stage 2 (-14 min; P = 0.001) as assessed by polysomnography. Compared with placebo, melatonin significantly increased Stage 2 sleep (+41 min; P = 0.037) but did not significantly change the durations of other sleep stages. The sleep onset latency remained significantly shortened on the night after discontinuation of melatonin administration (-25 min; P = 0.001), suggesting a carryover effect. Conclusion: n hypertensive patients treated with beta-blockers, 3 weeks of nightly melatonin supplementation significantly improved sleep quality, without apparent tolerance and without rebound sleep disturbance during withdrawal of melatonin supplementation (in fact, a

  19. Comparison of COSMIC RO Data with European Digisondes and GPS TEC measurements

    NASA Astrophysics Data System (ADS)

    Zakharenkova, Irina; Krypiak-Gregorczyk, Anna; Shagimuratov, Irk; Krankowski, Andrzej; Lagovsky, Anatoly

    FormoSat-3/COSMIC now provides unprecedented global coverage of GPS occultations mea-surements, each of which yields the ionosphere electron density information with high vertical resolution. However systematic validation work is still needed before using the powerful RO technique for sounding the ionosphere on a routine basis. In the given study electron density profiles retrieved from the Formosat-3/COSMIC RO measurements were compared with differ-ent kinds of ground-based observations. We used the ionospheric data recorded by European digisondes of DIAS network (Rome, Ebro, Arenosillo, Athens, Chilton, Pruhonice and Julius-ruh) for temporal interval of 2007-2009 and compare these ground measured data with the GPS COSMIC RO ionospheric profiles. It was revealed that in general the form of COSMIC profile in the bottom side is in a good agreement with ionosonde profiles, the heights of the peak density value are also good comparable. Special attention was focused to the question of the topside part of electron density profile. Practically for all analyzed cases there are observed the understated values of electron density in the topside part of the ionosonde profiles in compare with RO profiles. As the topside ionosonde profile is obtained by fitting a model to the peak electron density value, the COSMIC radio occultation measurements can make an important contribution to the investigation of the topside part of the ionosphere. In order to assess the ac-curacy of the COSMIC ionospheric electron density retrievals, coincidences of ionosonde data with COSMIC NmF2 values have been examined. NmF2 was calculated from the observed critical plasma frequency foF2 of the F2 layer. Values of foF2 have been scaled manually from ionograms for all considered time-location cases to avoid the evident risks related with using of the autoscaled data. The created scatter plots show a high degree of correlation between two independent estimates of NmF2. Also it was analyzed the

  20. CoRoT-7b: Convection in a Tidally Locked Planet

    NASA Astrophysics Data System (ADS)

    Noack, Lena; Stamenkovic, Vlada; Wagner, Frank W.; Sohl, Frank; Breuer, Doris

    2010-05-01

    The number of terrestrial extrasolar planets found in the past few years is increasing rapidly. Some have masses ranging from 2 to 10 Earth masses, and the habitability of these planets is widely discussed in the planetary community. Due to observational limitations we will mostly be able to observe planets that are very close to its host star, resulting in a potentially tidally locked orbit. Our goal is to investigate if such planets can be habitable at all. But to do so, we first have to understand the convection behaviour of such planets. In this work we model the mantle convection of the recently discovered exoplanet CoRoT-7b [1], which is a planet believed to be tidally locked. The extreme intense insolation in the vicinity of its host star heats the day-side of CoRoT-7b, leading to surface temperatures about 2000 Kelvin higher than on the night-side [1]. CoRoT-7b is about 5 times more massive than the Earth and predominantly composed of dry silicate rock similar to Earth's Moon. A central iron core, if present, would be relatively small [2] with a core mass fraction of no more than 15 wt%. The mantle convection is modelled in a spherical shell [3] using a temperature- and pressure-dependent viscosity. We use a radioactive heat source density similar to present Earth. Coriolis forces are neglected and we assume that CoRoT-7b has no atmosphere. The results show that the lower mantle above the core-mantle boundary is in a more sluggish convection regime as a consequence of the viscosity increase with pressure. Depending on the strength of the viscosity increase, even a so-called low-lid [4] can form and conductive heat transport dominates from the core to the upper part of the mantle. The thermal state of such a deeply situated, conductive lower mantle of CoRoT-7b is not much influenced by the strongly laterally varying surface temperature. However, the temperatures of the upper convecting mantle are found to strongly vary from one side of the planet to the

  1. Nutrient removal by NF and RO membranes in a decentralized sanitation system.

    PubMed

    van Voorthuizen, Ellen M; Zwijnenburg, Arie; Wessling, Matthias

    2005-09-01

    Decentralized treatment of domestic wastewater offers the possibility of water and nutrient reuse. In a decentralized sanitation system the household wastewater streams are separated in a large diluted stream (gray water) and a small and concentrated stream (black water) containing important nutrients like ammonium and phosphate. Nanofiltration (NF) and reverse osmosis (RO) membranes might be used to recover the nutrients from anaerobically treated black water. The permeate might be used in a water reuse scheme. In case of water reuse the produced permeate should meet guidelines for potable water or meet new guidelines which might be applied in the future for intermediate quality of water, for example toilet flushwater; when this is not possible the permeate should meet guidelines for discharge. The most stringent guidelines apply for ammonium and phosphate. The focus of this paper is to test commercially available NF and RO membranes to remove nutrients from anaerobically treated black water in order to meet the Dutch guidelines. A large number of commercial tubular, capillary and flat sheet NF and RO membranes was tested on laboratory scale on their performance to meet the Dutch guidelines for ammonium and phosphate. The ammonium and phosphate concentrations used were based on the effluent composition of anaerobically treated black water. Ammonium and phosphate rejection were both measured in synthetic single salt and multi-ion mixtures and in anaerobic effluent. The rejection for ammonium (30-95%) is neither sufficient for discharge nor potable water use. The rejection of phosphate (74-99%) is in most cases almost sufficient to meet the standards for potable water. PMID:16054670

  2. Characteristics of atmospheric Kelvin waves during warm and cold ENSO phases observed with GPS RO

    NASA Astrophysics Data System (ADS)

    Scherllin-Pirscher, Barbara; Ladstädter, Florian; Steiner, Andrea; Kirchengast, Gottfried

    2015-04-01

    Inter-annual variability in the Earth's troposphere at low and middle latitudes is dominated by the El Niño-Southern Oscillation (ENSO) phenomenon. While ENSO emerges from an atmosphere-ocean interaction in the tropical Pacific, it has a significant impact on global weather and climate. Atmospheric wave dynamics plays a crucial role in this context. However, current understanding of this wave dynamics is mostly based on climate model output and reanalysis data. We use observational data from Global Positioning System (GPS) radio occultation (RO) measurements to investigate characteristics of atmospheric Kelvin waves during warm and cold ENSO phases. Due to their high accuracy and vertical resolution, RO data provide reliable and valuable information on wave-induced temperature oscillations with short vertical wavelengths of a few kilometers. After the launch of the six micro-satellites of the Formosat-3/COSMIC mission in April 2006, the number of RO measurements per day increased significantly compared to earlier time periods. With an appropriate binning strategy, the sampling is therefore sufficiently dense from mid-2006 onwards in order to capture the main characteristics of large-scale atmospheric waves. Frequencies and wavelengths of atmospheric Kelvin waves are extracted from space-time spectral analysis for overlapping 60-day time series centered on each month. In this study we focus on the northern hemisphere winter season DJF (December, January, February) using data from DJF 2006/07 to DJF 2011/12. Comparative results are presented for warm ENSO phases, which occurred in DJF 2006/07 and DJF 2009/10, and for cold ENSO phases in DJF 2007/08, DJF 2010/11, and DJF 2011/12.

  3. New RoF-PON architecture using polarization multiplexed wireless MIMO signals for NG-PON

    NASA Astrophysics Data System (ADS)

    Elmagzoub, M. A.; Mohammad, Abu Bakar; Shaddad, Redhwan Q.; Al-Gailani, Samir A.

    2015-06-01

    Next-generation access networks require provision of wireless services and high data rate to meet the huge demands for mobility and multiple services. Moreover, reusing the currently deployed optical distribution networks (ODNs) is highly beneficial and cost effective for providing the new high data rate wireless demands. In this paper, bidirectional radio over fiber passive optical network (RoF-PON) capable of handling multiple-input-multiple-output (MIMO) streams at low cost, high spectral efficiency and backward compatibility with currently deployed PON, is proposed. To the best of our knowledge, all the existing RoF MIMO solutions have not considered compatibility with currently deployed ODNs. Eight laser diodes (LDs) at the central office (CO) are enough for the whole system, instead of having LD or optical transmitter at each remote antenna unit (RAU), which makes a colorless and cost-effective RAU. Twenty four wavelengths are generated using optical comb technique. Each two 16-QAM MIMO signals that have the same carrier frequency in the downstream (DS) transmission are optically combined using polarization-division-multiplexing (PDM), where each two upstream (US) MIMO signals are time division multiplexed. The PDM configuration doubles spectral efficiency with a power penalty of only 1.5 dB. The proposed architecture is a bidirectional asymmetric RoF-PON with total 40/10 Gb/s for DS/US transmission. Even after transmission over 20 km SMF and splitting ratio of 32, acceptable transmission performance and widely separated constellation diagrams for the 16-QAM signals are achieved, with bit error rate (BER) of 10-6 for DS signals and 10-3 for the US signals which can be reduced down to 10-6 by using forward error correction (FEC).

  4. Variability in the CO ro-vibrational lines from HD163296

    NASA Astrophysics Data System (ADS)

    Hein Bertelsen, Rosina P.; Kamp, I.; van der Plas, G.; van den Ancker, M. E.; Waters, L. B. F. M.; Thi, W.-F.; Woitke, P.

    2016-05-01

    We present for the first time a direct comparison of multi-epoch (2001-2002 and 2012) CO ro-vibrational emission lines from HD 163296. We find that both the line shapes and the FWHM (full width at half-maximum) differ between these two epochs. The FWHM of the median observed line profiles are 10-25 km s-1 larger in the earlier epoch, and confirmed double peaks are only present in high J lines from 2001 to 2002. The line wings of individual transitions are similar in the two epochs making an additional central component in the later epoch a likely explanation for the single peaks and the lower FWHM. Variations in near-infrared brightness have been reported and could be linked to the observed variations. Additionally, we use the thermo-chemical disc code PRODIMO to compare for the first time the line shapes, peak separations, FWHM, and line fluxes, to those observed. The PRODIMO model reproduces the peak separations, and low and mid J line fluxes well. The FWHM however, are overpredicted and high J line fluxes are underpredicted. We propose that a variable non-Keplerian component of the CO ro-vibrational emission, such as a disc wind or an episodic accretion funnel, is causing the difference between the two data sets collected at different epochs, and between model and observations. Additional CO ro-vibrational line detections (with cryogenic high-resolution infrared echelle spectrograph/Very Large Telescope (VLT) or Near InfraRed SPECtrometer/Keck) or [Ne II] line observations with VLT Imager and Spectrometer for mid Infrared/VLT could help to clarify the cause of the variability.

  5. Animal pharmacokinetics and metabolism of the new antimalarial Ro 42-1611 (arteflene).

    PubMed

    Girometta, M A; Jauch, R; Ponelle, C; Guenzi, A; Wiegand-Chou, R C

    1994-09-01

    Ro 42-1611 (arteflene) is a new synthetic structural analogue of yingzhaosu, a Chinese traditional herbal drug, now under development for treatment of malaria. The in vivo activity of arteflene in a mouse animal model was 4-5 fold higher after parenteral than after oral administration. Pharmacokinetics of the drug were investigated in mice, rats, dogs, marmosets and cynomolgus monkeys. Plasma concentrations of arteflene were determined using a specific HPLC-UV method; the limit of quantification was 45 ng/ml using 0.5 ml plasma. The oral bioavailability was very low and variable (0.6% in mice, 4-5% in rats, 2.5 +/- 1% in dogs, < or = 0.5% in marmosets and < 0.5% in cynomolgus) as expected from the high metabolic clearance and the relative short apparent half-life (1.4-4.7 h). However, a metabolite (MA) was observed in plasma of all species indicating that drug was absorbed but underwent extensive first-pass metabolism. MA was also detected in samples of human plasma, collected during an oral tolerability study in healthy volunteers. After incubation of 14C-arteflene with liver microsomes of mice, rats, dogs and humans, the same major metabolite was detected and both samples were identical to Ro 47-6936 which was chemically synthesized as a reference compound. The in vitro activity of Ro 47-6936 was tested against Plasmodium falciparum and found to be about 1/4 that of the parent drug. Therefore, this metabolite makes a significant contribution to the biological activity in vivo, partially explaining the high activity of arteflene after oral administration in spite of its low bioavailability. Moreover, comparison of the metabolic patterns from human, rat and dog microsomes indicated that the dog is an appropriate species for toxicological evaluations. PMID:7899803

  6. Rotation period distribution of CoRoT and Kepler Sun-like stars

    NASA Astrophysics Data System (ADS)

    Leão, I. C.; Pasquini, L.; Ferreira Lopes, C. E.; Neves, V.; Valcarce, A. A. R.; de Oliveira, L. L. A.; Freire da Silva, D.; de Freitas, D. B.; Canto Martins, B. L.; Janot-Pacheco, E.; Baglin, A.; De Medeiros, J. R.

    2015-10-01

    Aims: We study the distribution of the photometric rotation period (Prot), which is a direct measurement of the surface rotation at active latitudes, for three subsamples of Sun-like stars: one from CoRoT data and two from Kepler data. For this purpose, we identify the main populations of these samples and interpret their main biases specifically for a comparison with the solar Prot. Methods: Prot and variability amplitude (A) measurements were obtained from public CoRoT and Kepler catalogs, which were combined with public data of physical parameters. Because these samples are subject to selection effects, we computed synthetic samples with simulated biases to compare with observations, particularly around the location of the Sun in the Hertzsprung-Russel (HR) diagram. Publicly available theoretical grids and empirical relations were used to combine physical parameters with Prot and A. Biases were simulated by performing cutoffs on the physical and rotational parameters in the same way as in each observed sample. A crucial cutoff is related with the detectability of the rotational modulation, which strongly depends on A. Results: The synthetic samples explain the observed Prot distributions of Sun-like stars as having two main populations: one of young objects (group I, with ages younger than ~1 Gyr) and another of main-sequence and evolved stars (group II, with ages older than ~1 Gyr). The proportions of groups I and II in relation to the total number of stars range within 64-84% and 16-36%, respectively. Hence, young objects abound in the distributions, producing the effect of observing a high number of short periods around the location of the Sun in the HR diagram. Differences in the Prot distributions between the CoRoT and Kepler Sun-like samples may be associated with different Galactic populations. Overall, the synthetic distribution around the solar period agrees with observations, which suggests that the solar rotation is normal with respect to Sun

  7. Discovery of potent and selective spiroindolinone MDM2 inhibitor, RO8994, for cancer therapy.

    PubMed

    Zhang, Zhuming; Ding, Qingjie; Liu, Jin-Jun; Zhang, Jing; Jiang, Nan; Chu, Xin-Jie; Bartkovitz, David; Luk, Kin-Chun; Janson, Cheryl; Tovar, Christian; Filipovic, Zoran M; Higgins, Brian; Glenn, Kelli; Packman, Kathryn; Vassilev, Lyubomir T; Graves, Bradford

    2014-08-01

    The field of small-molecule inhibitors of protein-protein interactions is rapidly advancing and the specific area of inhibitors of the p53/MDM2 interaction is a prime example. Several groups have published on this topic and multiple compounds are in various stages of clinical development. Building on the strength of the discovery of RG7112, a Nutlin imidazoline-based compound, and RG7388, a pyrrolidine-based compound, we have developed additional scaffolds that provide opportunities for future development. Here, we report the discovery and optimization of a highly potent and selective series of spiroindolinone small-molecule MDM2 inhibitors, culminating in RO8994. PMID:24997575

  8. Molecular line lists: The ro-vibrational spectra of NaF and KF

    NASA Astrophysics Data System (ADS)

    Frohman, Daniel J.; Bernath, Peter F.; Brooke, James S. A.

    2016-01-01

    Rotation-vibration line lists for 23Na19F, 39K19F, and 41K19F in their ground electronic states are presented. Experimental data previously collected for infrared transitions up to v=8 and v=9 for KF [1] and NaF [2], respectively, and for pure rotational transitions have been used to construct potential energy curves to yield ro-vibrational energy levels. Dipole moment functions were generated from ab initio calculations using the SA-CASSCF and ACPF methods. Full line lists and partition functions are made available as supplementary data.

  9. Full-Dimensional Potential Energy Surface and Ro-vibrational Levels of Dioxirane.

    PubMed

    Li, Jun; Guo, Hua

    2016-05-19

    A full-dimensional potential energy surface is developed for dioxirane based on a high-fidelity fit of ∼46,000 ab initio points at the CCSD(T)-F12a/AVTZ level. The ro-vibrational levels of dioxirane were computed using the MULTIMODE method on this potential energy surface, and the agreement with the available experimental microwave spectrum is quite satisfactory. In addition, dipole moment surfaces have been constructed from ab initio data, and they allow the prediction of the infrared (IR) spectrum. PMID:26422048

  10. Asteroid spectroscopy with FoReRo2 at BNAO Rozhen --- first results

    NASA Astrophysics Data System (ADS)

    Vchova Bebekovska, E.; Borisov, G.; Apostolovska, G.; Donchev, Z.

    2014-07-01

    The Bulgarian National Astronomical Observatory (BNAO) in Rozhen (071 Rozhen), with astrometric observations, has been already involved in the Gaia Follow-Up Network for Solar System Objects since the end of 2011. One of our aims is to develop a coordinated program of asteroid spectroscopy complementary to Gaia's observations. In this paper, the first results of asteroid spectroscopy at BNAO Rozhen are presented. In order to contribute to the compositional characterization of the main-belt asteroids, we performed low-dispersion asteroid spectroscopy with 2-Channel-Focal-Reducer Rozhen (FoReRo2) on the 2-m Ritchey-Chrétien-Coudé (RCC) telescope at BNAO. We obtained optical spectra of few MBAs using the 2-m RCC telescope equiped with the CCD VarsArray 1300B camera (pixel size 20 μ m or 0.736 arcsec/px) in the spectroscopic mode of FoReRo2 in its red channel [1]. The spectroscopic characteristics are: a low-dispersion grism Bausch & Lomb, working in the parallel beam of FoReRo2, with 300 lines/mm which gives 4.3 Å/px and 200 μ m width slit which corresponds to 2.6 arcsec. We determined spectral types of the asteroids [2] by the overall shapes of the spectra between 440 nm and 830 nm. For spectral analysis in our work, we use the public software tool M4AST [3]. It covers aspects related to taxonomy, curve matching with laboratory spectra, space weathering models, and mineralogical diagnosis. Most of the observed asteroids belong to some families and there are no published spectra. Besides their spectra, for some asteroids, best matches derived from a comparison with laboratory spectra are presented. We are planning to use a polarimetric mode of FoReRo2 and a Wollaston prism in order for the results to be confirmed by obtaining the degree of linear polarization around asteroid phase angles of 10° --- around the minimum of polarization in the phase curve, where the deviation for different taxonomic classes is best resolvable.

  11. Metabolism and pharmacokinetics of JM6 in mice: JM6 is not a prodrug for Ro-61-8048.

    PubMed

    Beconi, Maria G; Yates, Dawn; Lyons, Kathryn; Matthews, Kim; Clifton, Steve; Mead, Tania; Prime, Michael; Winkler, Dirk; O'Connell, Catherine; Walter, Daryl; Toledo-Sherman, Leticia; Munoz-Sanjuan, Ignacio; Dominguez, Celia

    2012-12-01

    Understanding whether regulation of tryptophan metabolites can ameliorate neurodegeneration is of high interest to investigators. A recent publication describes 3,4-dimethoxy-N-(4-(3-nitrophenyl)-5-(piperidin-1-ylmethyl)thiazol-2-yl)benzenesulfonamide (JM6) as a novel prodrug for the kynurenine 3-monooxygenase (KMO) inhibitor 3,4-dimethoxy-N-(4-(3-nitrophenyl)thiazol-2-yl)benzenesulfonamide (Ro-61-8048) that elicits therapeutic effects in mouse models of Huntington's and Alzheimer's diseases (Cell 145:863-874, 2011). Our evaluation of the metabolism and pharmacokinetics of JM6 and Ro-61-8048 indicate instead that Ro-61-8048 concentrations in mouse plasma after JM6 administration originate from a Ro-61-8048 impurity (<0.1%) in JM6. After a 0.05 mg/kg Ro-61-8048 oral dose alone or coadministered with 10 mg/kg JM6 to mice, the Ro-61-8048 areas under the concentration-time curves (AUCs) from 0 to infinity were similar (4300 and 4900 nM × h, respectively), indicating no detectable contributions of JM6 metabolism to the Ro-61-8048 AUCs. JM6 was stable in incubations under acidic conditions and Ro-61-8048 was not a product of JM6 metabolism in vitro (plasma, blood, or hepatic models). Species differences in the quantitative rate of oxidative metabolism indicate that major circulating JM6 metabolite(s) in mice are unlikely to be major in humans: JM6 is rapidly metabolized via the piperidyl moiety in mouse (forming an iminium ion reactive intermediate) but is slowly metabolized in human (in vitro), primarily via O-dealkylation at the phenyl ring. Our data indicate that JM6 is not a prodrug for Ro-61-8048 and is not a potent KMO inhibitor. PMID:22942319

  12. Characterization of the Discriminative Stimulus Effects of a NOP Receptor Agonist Ro 64-6198 in Rhesus Monkeys

    PubMed Central

    Zelenock, Kathy A.; Lindsey, Angela M.; Sulima, Agnieszka; Rice, Kenner C.; Prinssen, Eric P.; Wichmann, Jürgen; Woods, James H.

    2016-01-01

    Nociceptin/orphanin FQ receptor (NOP) agonists have been reported to produce antinociceptive effects in rhesus monkeys with comparable efficacy to μ-opioid receptor (MOP) agonists, but without their limiting side effects. There are also known to be species differences between rodents and nonhuman primates (NHPs) in the behavioral effects of NOP agonists. The aims of this study were the following: 1) to determine if the NOP agonist Ro 64-6198 could be trained as a discriminative stimulus; 2) to evaluate its pharmacological selectivity as a discriminative stimulus; and 3) to establish the order of potency with which Ro 64-6198 produces discriminative stimulus effects compared with analgesic effects in NHPs. Two groups of rhesus monkeys were trained to discriminate either fentanyl or Ro 64-6198 from vehicle. Four monkeys were trained in the warm-water tail-withdrawal procedure to measure antinociception. Ro 64-6198 produced discriminative stimulus effects that were blocked by the NOP antagonist J-113397 and not by naltrexone. The discriminative stimulus effects of Ro 64-6198 partially generalized to diazepam, but not to fentanyl, SNC 80, ketocyclazocine, buprenorphine, phencyclidine, or chlorpromazine. Fentanyl produced stimulus effects that were blocked by naltrexone and not by J-113397, and Ro 64-6198 did not produce fentanyl-appropriate responding in fentanyl-trained animals. In measures of antinociception, fentanyl, but not Ro 64-6198, produced dose-dependent increases in tail-withdrawal latency. Together, these results demonstrate that Ro 64-6198 produced stimulus effects in monkeys that are distinct from other opioid receptor agonists, but may be somewhat similar to diazepam. In contrast to previous findings, Ro 64-6198 did not produce antinociception in the majority of animals tested even at doses considerably greater than those that produced discriminative stimulus effects. PMID:26801398

  13. Non-coding roX RNAs prevent the binding of the MSL-complex to heterochromatic regions.

    PubMed

    Figueiredo, Margarida L A; Kim, Maria; Philip, Philge; Allgardsson, Anders; Stenberg, Per; Larsson, Jan

    2014-12-01

    Long non-coding RNAs contribute to dosage compensation in both mammals and Drosophila by inducing changes in the chromatin structure of the X-chromosome. In Drosophila melanogaster, roX1 and roX2 are long non-coding RNAs that together with proteins form the male-specific lethal (MSL) complex, which coats the entire male X-chromosome and mediates dosage compensation by increasing its transcriptional output. Studies on polytene chromosomes have demonstrated that when both roX1 and roX2 are absent, the MSL-complex becomes less abundant on the male X-chromosome and is relocated to the chromocenter and the 4th chromosome. Here we address the role of roX RNAs in MSL-complex targeting and the evolution of dosage compensation in Drosophila. We performed ChIP-seq experiments which showed that MSL-complex recruitment to high affinity sites (HAS) on the X-chromosome is independent of roX and that the HAS sequence motif is conserved in D. simulans. Additionally, a complete and enzymatically active MSL-complex is recruited to six specific genes on the 4th chromosome. Interestingly, our sequence analysis showed that in the absence of roX RNAs, the MSL-complex has an affinity for regions enriched in Hoppel transposable elements and repeats in general. We hypothesize that roX mutants reveal the ancient targeting of the MSL-complex and propose that the role of roX RNAs is to prevent the binding of the MSL-complex to heterochromatin. PMID:25501352

  14. Characterization of the Discriminative Stimulus Effects of a NOP Receptor Agonist Ro 64-6198 in Rhesus Monkeys.

    PubMed

    Saccone, Phillip A; Zelenock, Kathy A; Lindsey, Angela M; Sulima, Agnieszka; Rice, Kenner C; Prinssen, Eric P; Wichmann, Jürgen; Woods, James H

    2016-04-01

    Nociceptin/orphanin FQ receptor (NOP) agonists have been reported to produce antinociceptive effects in rhesus monkeys with comparable efficacy to μ-opioid receptor (MOP) agonists, but without their limiting side effects. There are also known to be species differences between rodents and nonhuman primates (NHPs) in the behavioral effects of NOP agonists. The aims of this study were the following: 1) to determine if the NOP agonist Ro 64-6198 could be trained as a discriminative stimulus; 2) to evaluate its pharmacological selectivity as a discriminative stimulus; and 3) to establish the order of potency with which Ro 64-6198 produces discriminative stimulus effects compared with analgesic effects in NHPs. Two groups of rhesus monkeys were trained to discriminate either fentanyl or Ro 64-6198 from vehicle. Four monkeys were trained in the warm-water tail-withdrawal procedure to measure antinociception. Ro 64-6198 produced discriminative stimulus effects that were blocked by the NOP antagonist J-113397 and not by naltrexone. The discriminative stimulus effects of Ro 64-6198 partially generalized to diazepam, but not to fentanyl, SNC 80, ketocyclazocine, buprenorphine, phencyclidine, or chlorpromazine. Fentanyl produced stimulus effects that were blocked by naltrexone and not by J-113397, and Ro 64-6198 did not produce fentanyl-appropriate responding in fentanyl-trained animals. In measures of antinociception, fentanyl, but not Ro 64-6198, produced dose-dependent increases in tail-withdrawal latency. Together, these results demonstrate that Ro 64-6198 produced stimulus effects in monkeys that are distinct from other opioid receptor agonists, but may be somewhat similar to diazepam. In contrast to previous findings, Ro 64-6198 did not produce antinociception in the majority of animals tested even at doses considerably greater than those that produced discriminative stimulus effects. PMID:26801398

  15. Impact of Angiotensin-II receptor blockers on vasogenic edema in glioblastoma patients.

    PubMed

    Kourilsky, Antoine; Bertrand, Guillaume; Ursu, Renata; Doridam, Jennifer; Barlog, Ciprian; Faillot, Thierry; Mandonnet, Emmanuel; Belin, Catherine; Levy, Christine; Carpentier, Antoine F

    2016-03-01

    Glioblastoma patients often require chronic administration of steroids due to peri-tumoral edema. Preliminary studies showed that treatment with Angiotensin-II Receptor Blockers (ARBs) for high blood pressure might be associated with reduced peri-tumoral edema. In this study, we aim to radiologically assess the effect of ARBs on peri-tumoral edema. We conducted a cross-sectional survey on patients with newly diagnosed GBM. Patients treated with ARBs for high blood pressure were paired to non ARB-treated patients based on similar age, tumor location and tumor size. Patients taking steroids at the time of pre-operative Magnetic Resonance Imaging were excluded from the study. In each pair of patients, we compared the volumes of peri-tumoral hyper T2-Fluid Attenuated Inversion Recovery (FLAIR) signal and the Apparent Diffusion Coefficient (ADC) in the same area. Eleven (11) ARB-treated patients were selected and paired to 11 non ARB-treated controls. Volumes of peri-tumoral hyper T2-FLAIR signal were significantly lower in the ARB-treated group than in the non ARB-treated group (p = 0.02). Additionally, peri-tumoral ADCs were also significantly lower in the treated group (p = 0.02), suggesting that the peri-tumoral area in this group had less edematous features. These results suggest that ARBs may reduce the volume of peri-tumoral hyper T2-FLAIR signal by decreasing edema. PMID:26754004

  16. Study of permeation and blocker binding in TMEM16A calcium-activated chloride channels.

    PubMed

    Reyes, J P; Huanosta-Gutiérrez, A; López-Rodríguez, A; Martínez-Torres, A

    2015-01-01

    We studied the effects of mutations of positively charged amino acid residues in the pore of X. tropicalis TMEM16A calcium-activated chloride channels: K613E, K628E, K630E; R646E and R761E. The activation and deactivation kinetics were not affected, and only K613E showed a lower current density. K628E and R761E affect anion selectivity without affecting Na(+) permeation, whereas K613E, R646E and the double mutant K613E + R646E affect anion selectivity and permeability to Na(+). Furthermore, altered blockade by the chloride channel blockers anthracene-9-carboxylic acid (A-9-C), 4, 4'-Diisothiocyano-2,2'-stilbenedisulfonic acid (DIDS) and T16inh-A01 was observed. These results suggest the existence of 2 binding sites for anions within the pore at electrical distances of 0.3 and 0.5. These sites are also relevant for anion permeation and blockade. PMID:25853341

  17. A deleterious gene-by-environment interaction imposed by calcium channel blockers in Marfan syndrome

    PubMed Central

    Doyle, Jefferson J; Doyle, Alexander J; Wilson, Nicole K; Habashi, Jennifer P; Bedja, Djahida; Whitworth, Ryan E; Lindsay, Mark E; Schoenhoff, Florian; Myers, Loretha; Huso, Nick; Bachir, Suha; Squires, Oliver; Rusholme, Benjamin; Ehsan, Hamid; Huso, David; Thomas, Craig J; Caulfield, Mark J; Van Eyk, Jennifer E; Judge, Daniel P; Dietz, Harry C; Farrar, Carrie; Dietz, Harry C

    2015-01-01

    Calcium channel blockers (CCBs) are prescribed to patients with Marfan syndrome for prophylaxis against aortic aneurysm progression, despite limited evidence for their efficacy and safety in the disorder. Unexpectedly, Marfan mice treated with CCBs show accelerated aneurysm expansion, rupture, and premature lethality. This effect is both extracellular signal-regulated kinase (ERK1/2) dependent and angiotensin-II type 1 receptor (AT1R) dependent. We have identified protein kinase C beta (PKCβ) as a critical mediator of this pathway and demonstrate that the PKCβ inhibitor enzastaurin, and the clinically available anti-hypertensive agent hydralazine, both normalize aortic growth in Marfan mice, in association with reduced PKCβ and ERK1/2 activation. Furthermore, patients with Marfan syndrome and other forms of inherited thoracic aortic aneurysm taking CCBs display increased risk of aortic dissection and need for aortic surgery, compared to patients on other antihypertensive agents. DOI: http://dx.doi.org/10.7554/eLife.08648.001 PMID:26506064

  18. Calcium Channel Blockers as Tocolytics: Principles of Their Actions, Adverse Effects and Therapeutic Combinations

    PubMed Central

    Gáspár, Róbert; Hajagos-Tóth, Judit

    2013-01-01

    Dihydropyridine Ca2+ channel blockers (CCBs) are widely accepted in the treatment of premature labour. Their mechanism of action in tocolysis involves the blockade of L-type Ca2+ channels, influenced by the Ca2+-activated K+ channels, beta-adrenergic receptors (β-ARs) and sexual hormones. In clinical practice, most experience has been gained with the use of nifedipine, whose efficacy is superior or comparable to those of β-agonists and oxytocin antagonists. Additionally, it has a favourable adverse effect profile as compared with the majority of other tocolytics. The most frequent and well-tolerated side-effects of CCBs are tachycardia, headache and hypotension. In tocolytic therapy efforts are currently being made to find combinations of tocolytic agents that yield better therapeutic action. The available human and animal studies suggest that the combination of CCBs with β-AR agonists is beneficial, although such combinations can pose risk of pulmonary oedema in multiple pregnancies and maternal cardiovascular diseases. Preclinical data indicate the potential benefit of combinations of CCBs and oxytocin antagonists. However, the combinations of CCBs with progesterone or cyclooxygenase inhibitors may decrease their efficacy. The CCBs are likely to remain one of the most important groups of drugs for the rapid inhibition of premature uterine contractions. Their significance may be magnified by further clinical studies on their combined use for tocolysis. PMID:24276256

  19. THE ROLE OF ALPHA-BLOCKERS IN THE MANAGEMENT OF PROSTATE CANCER

    PubMed Central

    Tahmatzopoulos, Anastasios; Rowland, Randall G.; Kyprianou, Natasha

    2008-01-01

    Prostate cancer is the second most common cause of cancer death in men in the United States. Patients with prostate cancer are initially treated with surgical resection, radiation or antiandrogen therapy. After an initial remission however, the majority of prostate tumors evolve into a highly aggressive, metastatic androgen-independent state for which successful therapy has not yet been established. During recent years, new perspectives have emerged towards the development of preventive and therapeutic approaches for prostate cancer. The quinazoline-based α1-blockers have been shown to have antitumor efficacy against prostate cancer cells via their potency to induce apoptosis and anoikis via an α1-adrenoceptor-independent mechanism. Specifically, doxazosin and terazosin can induce apoptosis, inhibit invasion and migration of prostate cancer cells and endothelial cells and reduce their adhesion potential to extracellular matrix components (ECM), thus enhancing their susceptibility to anoikis. In this review we discuss recent evidence suggesting the apoptotic efficacy of quinazoline-based α1 adrenoceptor antagonists, doxazosin and terazosin and we speculate on the therapeutic promise of these drugs as novel antitumor agents against prostate cancer. From a drug discovery perspective, separation of the effect of doxazosin on apoptosis in prostate cancer cells from its original pharmacological activity in normal prostate cells, will provide a molecular basis to develop a novel class of apoptosis-inducing agents through lead optimization. PMID:15163273

  20. Behavioral and biochemical adjustments of the zebrafish Danio rerio exposed to the β-blocker propranolol.

    PubMed

    Mitchell, Kimberly M; Moon, Thomas W

    2016-09-01

    Propranolol (PROP) is a β-blocker prescribed mainly to treat human cardiovascular diseases and as a result of its wide usage and persistence, it is reported in aquatic environments. This study examined whether PROP alters developmental patterns and catecholamine (CA)-regulated processes in the zebrafish (Danio rerio) and if exposure during early life alters the stress response and behaviors of adults. The calculated 48h larva LC50 was 21.6mg/L, well above reported environmental levels (0.01-0.59μg/L). Stressed and PROP-exposed adult zebrafish had reduced testosterone and estradiol levels and exhibited behaviors indicating less anxiety than control fish. Furthermore, adults previously PROP-exposed as embryos/larvae had decreased growth in terms of body length and mass. Finally, these adults showed increased cholesterol and a dose-dependent decrease in testosterone levels compared with unexposed zebrafish. Thus PROP-exposure of zebrafish embryos/larvae alters developmental patterns and CA-regulated processes that may affect normal behaviors and responses to stressors, and at least some of these changes persist in the adult zebrafish. PMID:26520238

  1. Stage fright in musicians: a model illustrating the effect of beta blockers.

    PubMed

    Neftel, K A; Adler, R H; Käppeli, L; Rossi, M; Dolder, M; Käser, H E; Bruggesser, H H; Vorkauf, H

    1982-11-01

    Stage fright was used to investigate the mode of action of beta blockers in acute anxiety and on the technical-motor performance of 22 performing string players. They received 100 mg of atenolol or placebo 6.5 hr before performing either in the presence or absence of an audience. Continuous heart rate, stage fright (especially devised rating scale), technical-motor performance (runs of fast notes, trills, vibratos), and urine catecholamine levels were assessed. Before an audience the placebo group showed a significant impairment of technical-motor performance (increase in the relative variance of repeated fast elements of movements: + 25.68%, p less than 0.01) as compared to performance with no audience present; there was a slight but not significant improvement under beta blockade (- 7.48%). Heart rate was significantly lower under beta blockade than under placebo (p less than 0.001). Urine catecholamine levels increased twice as much under beta blockade as under placebo before an audience (p less than 0.01). Beta blockade did not influence stage fright measured before performing, but reduced it (measured immediately after the concert) during the concert. We conclude that the drug was at least partially effective as shown by an improvement in technical-motor performance, and that the beneficial effects of beta blockade in stage fright only involve a peripheral site of action. PMID:6129674

  2. Biodegradation and cometabolic modeling of selected beta blockers during ammonia oxidation.

    PubMed

    Sathyamoorthy, Sandeep; Chandran, Kartik; Ramsburg, C Andrew

    2013-11-19

    Accurate prediction of pharmaceutical concentrations in wastewater effluents requires that the specific biochemical processes responsible for pharmaceutical biodegradation be elucidated and integrated within any modeling framework. The fate of three selected beta blockers-atenolol, metoprolol, and sotalol-was examined during nitrification using batch experiments to develop and evaluate a new cometabolic process-based (CPB) model. CPB model parameters describe biotransformation during and after ammonia oxidation for specific biomass populations and are designed to be integrated within the Activated Sludge Models framework. Metoprolol and sotalol were not biodegraded by the nitrification enrichment culture employed herein. Biodegradation of atenolol was observed and linked to the activity of ammonia-oxidizing bacteria (AOB) and heterotrophs but not nitrite-oxidizing bacteria. Results suggest that the role of AOB in atenolol degradation may be disproportionately more significant than is otherwise suggested by their lower relative abundance in typical biological treatment processes. Atenolol was observed to competitively inhibit AOB growth in our experiments, though model simulations suggest inhibition is most relevant at atenolol concentrations greater than approximately 200 ng·L(-1). CPB model parameters were found to be relatively insensitive to biokinetic parameter selection suggesting the model approach may hold utility for describing pharmaceutical biodegradation during biological wastewater treatment. PMID:24112027

  3. Efficacy of a New Blind Insertion Technique of Arndt Endobronchial Blocker for Lung Isolation

    PubMed Central

    Liang, Peng; Ni, Juan; Zhou, Cheng; Yu, Hai; Liu, Bin

    2016-01-01

    Abstract This study aimed to find other methods of blind insertion of Arndt endobronchial blocker (AEB) for lung isolation when a fiberoptic bronchoscope (FOB) is unavailable. We compared the effectiveness and safety of 3 insertion techniques of AEB: Gum elastic bougie (GEB)-, bougie combined with cricoid displacing (BCD)-, and fiberoptic bronchoscope (FOB)-guided insertion. Seventy-eight patients undergoing esophageal procedure and requiring left thoracotomy were randomly assigned to 1 of 3 groups: GEB group, BCD group, and FOB group. We recorded the successful placement of AEBs at first attempt, placement time, malposition of AEBs in supine and lateral decubitus position, the bronchus injury score, and other complications. The successful placement of AEB for the first attempt was 22/26, 25/26, and 26/26 patients in GEB, BCD, and FOB groups, respectively. The placement times in GEB and BCD groups were longer than those in the FOB group (P < 0.05). AEB malposition occurred in 1/26, 2/26, 1/26 patients after lateral decubitus position, and AEBs were repositioned in 5/26, 3/26, 1/26 patients by FOB due to poor lung isolation in GEB, BCD, and FOB groups, respectively. There was no difference for the bronchus injury scores and other complications among 3 groups (P > 0.05). Bougie and cricoid displacing-guided blind insertion of AEB seems to be a novel method, which is an effective and safe alternative when FOB was unavailable. PMID:27175708

  4. Effect of beta-blockers on arrhythmias during six weeks after suspected myocardial infarction.

    PubMed

    Roland, J M; Wilcox, R G; Banks, D C; Edwards, B; Fentem, P H; Hampton, J R

    1979-09-01

    Twenty-four-hour electrocardiographic tape-recording was used to investigate the incidence of arrhythmias in patients with suspected myocardial infarction who were receiving either propranolol, atenolol, or placebo. Recordings begun within 24 hours after admission to a coronary care unit showed that 76% of patients eventually found to have had a myocardial infarction had ventricular arrhythmias of a type generally regarded as serious, whereas of patients in whom myocardial infarction was not substantiated, only 24% had such arrhythmias. At one and six weeks after admission the incidence of arrhythmias ranged from 25% to 33% irrespective of diagnosis. Of patients monitored at both one and six weeks, however, only 5% had arrhythmias on each occasion. Patients treated with propranolol and atenolol showed a similar incidence of arrhythmias to those taking placebo. There was no difference in the incidence or type of arrhythmias recorded between patients who died and those who were still alive at six weeks.These results confirm that "serious" ventricular arrythmias occur in most patients during the acute phase of myocardial infarction and suggest that they do not constitute an independent risk factor. Beta-blockers showed little evidence of useful antiarrhythmic action in the dosage used, but increasing the dosage in suspected myocardial infarction is not practicable because of the risk of hypotension. The findings raise grave doubts about the value of studying arrhythmias to assess drugs intended to reduce mortality from myocardial infarction. PMID:387170

  5. Angiotensin II and angiotensin II receptor blocker modulate the arrhythmogenic activity of pulmonary veins

    PubMed Central

    Chen, Yi-Jen; Chen, Yao-Chang; Tai, Ching-Tai; Yeh, Hung-I; Lin, Cheng-I; Chen, Shih-Ann

    2005-01-01

    Angiotensin II receptor blockers (AIIRBs) have been shown to prevent atrial fibrillation. The pulmonary veins (PVs) are the most important focus for the generation of atrial fibrillation. The aim of this study was to evaluate whether angiotensin II or AIIRB may change the arrhythmogenic activity of the PVs. Conventional microelectrodes and whole-cell patch clamps were used to investigate the action potentials (APs) and ionic currents in isolated rabbit PV tissue and single cardiomyocytes before and after administering angiotensin II or losartan (AIIRB). In the tissue preparations, angiotensin II induced delayed after-depolarizations (1, 10, and 100 nM) and accelerated the automatic rhythm (10 and 100 nM). Angiotensin II (100 nM) prolonged the AP duration and increased the contractile force (10 and 100 nM). Losartan (1 and 10 μM) inhibited the automatic rhythm. Losartan (10 μM) prolonged the AP duration and reduced the contractile force (1 and 10 μM). Angiotensin II reduced the transient outward potassium current (Ito) but increased the L-type calcium, delayed rectifier potassium (IK), transient inward (Iti), pacemaker, and Na+–Ca2+ exchanger (NCX) currents in the PV cardiomyocytes. Losartan decreased the Ito, IK, Iti, and NCX currents. In conclusion, angiotensin II and AIIRB modulate the PV electrical activity, which may play a role in the pathophysiology of atrial fibrillation. PMID:16273119

  6. A Pentasymmetric Open Channel Blocker for Cys-Loop Receptor Channels

    PubMed Central

    Baur, Roland; Puthenkalam, Roshan; Ernst, Margot; Trauner, Dirk; Sigel, Erwin

    2014-01-01

    γ-Aminobutyric acid type A receptors (GABAA receptors) are chloride ion channels composed of five subunits, mediating fast synaptic and tonic inhibition in the mammalian brain. These receptors show near five-fold symmetry that is most pronounced in the second trans-membrane domain M2 lining the Cl− ion channel. To take advantage of this inherent symmetry, we screened a variety of aromatic anions with matched symmetry and found an inhibitor, pentacyanocyclopentdienyl anion (PCCP−) that exhibited all characteristics of an open channel blocker. Inhibition was strongly dependent on the membrane potential. Through mutagenesis and covalent modification, we identified the region α1V256-α1T261 in the rat recombinant GABAA receptor to be important for PCCP− action. Introduction of positive charges into M2 increased the affinity for PCCP− while PCCP− prevented the access of a positively charged molecule into M2. Interestingly, other anion selective cys-loop receptors were also inhibited by PCCP−, among them the Drosophila RDL GABAA receptor carrying an insecticide resistance mutation, suggesting that PCCP− could serve as an insecticide. PMID:25184303

  7. Anti-Neuroinflammatory Effects of the Calcium Channel Blocker Nicardipine on Microglial Cells: Implications for Neuroprotection

    PubMed Central

    Huang, Bor-Ren; Chang, Pei-Chun; Yeh, Wei-Lan; Lee, Chih-Hao; Tsai, Cheng-Fang; Lin, Chingju; Lin, Hsiao-Yun; Liu, Yu-Shu; Wu, Caren Yu-Ju; Ko, Pei-Ying; Huang, Shiang-Suo; Hsu, Horng-Chaung; Lu, Dah-Yuu

    2014-01-01

    Background/Objective Nicardipine is a calcium channel blocker that has been widely used to control blood pressure in severe hypertension following events such as ischemic stroke, traumatic brain injury, and intracerebral hemorrhage. However, accumulating evidence suggests that inflammatory processes in the central nervous system that are mediated by microglial activation play important roles in neurodegeneration, and the effect of nicardipine on microglial activation remains unresolved. Methodology/Principal Findings In the present study, using murine BV-2 microglia, we demonstrated that nicardipine significantly inhibits microglia-related neuroinflammatory responses. Treatment with nicardipine inhibited microglial cell migration. Nicardipine also significantly inhibited LPS plus IFN-γ-induced release of nitric oxide (NO), and the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). Furthermore, nicardipine also inhibited microglial activation by peptidoglycan, the major component of the Gram-positive bacterium cell wall. Notably, nicardipine also showed significant anti-neuroinflammatory effects on microglial activation in mice in vivo. Conclusion/Significance The present study is the first to report a novel inhibitory role of nicardipine on neuroinflammation and provides a new candidate agent for the development of therapies for inflammation-related neurodegenerative diseases. PMID:24621589

  8. Effects of Angiotensin II Receptor Blockers on Metabolism of Arachidonic Acid via CYP2C8.

    PubMed

    Senda, Asuna; Mukai, Yuji; Toda, Takaki; Hayakawa, Toru; Yamashita, Miki; Eliasson, Erik; Rane, Anders; Inotsume, Nobuo

    2015-01-01

    Arachidonic acid (AA) is metabolized to epoxyeicosatrienoic acids (EETs) via cytochrome enzymes such as CYP 2C9, 2C8 and 2J2. EETs play a role in cardioprotection and regulation of blood pressure. Recently, adverse reactions such as sudden heart attack and fatal myocardial infarction were reported among patients taking angiotensin II receptor blockers (ARBs). As some ARBs have affinity for these CYP enzymes, metabolic inhibition of AA by ARBs is a possible cause for the increase in cardiovascular events. In this study, we quantitatively investigated the inhibitory effects of ARBs on the formation of EETs and further metabolites, dihydroxyeicosatrienoic acids (DHETs), from AA via CYP2C8. In incubations with recombinant CYP2C8 in vitro, the inhibitory effects were compared by measuring EETs and DHETs by HPLC-MS/MS. Inhibition of AA metabolism by ARBs was detected in a concentration-dependent manner with IC50 values of losartan (42.7 µM), telmisartan (49.5 µM), irbesartan (55.6 µM), olmesartan (66.2 µM), candesartan (108 µM), and valsartan (279 µM). Losartan, telmisartan and irbesartan, which reportedly accumulate in the liver and kidneys, have stronger inhibitory effects than other ARBs. The lower concentration of EETs leads to less protective action on the cardiovascular system and a higher incidence of adverse effects such as sudden heart attack and myocardial infarction in patients taking ARBs. PMID:26632190

  9. Removal of beta-blockers from aqueous media by adsorption onto graphene oxide.

    PubMed

    Kyzas, George Z; Koltsakidou, Anastasia; Nanaki, Stavroula G; Bikiaris, Dimitrios N; Lambropoulou, Dimitra A

    2015-12-15

    The aim of the present study is the evaluation of graphene oxide (GhO) as adsorbent material for the removal of beta-blockers (pharmaceutical compounds) in aqueous solutions. The composition and morphology of prepared materials were characterized by scanning electron microscopy (SEM) and Fourier transform infrared spectroscopy (FT-IR). Atenolol (ATL) and propranolol (PRO) were used as model drug molecules and their behavior were investigated in terms of GhO dosage, contact time, temperature and pH. Adsorption mechanisms were proposed and the pH-effect curves after adsorption were discussed. The kinetic behavior of GhO-drugs system was analyzed after fitting to pseudo-first and -second order equations. The adsorption equilibrium data were fitted to Langmuir, Freundlich and Langmuir-Freundlich model calculating the maximum adsorption capacity (67 and 116 mg/g for PRO and ATL (25 °C), respectively). The temperature effect on adsorption was tested carrying out the equilibrium adsorption experiments at three different temperatures (25, 45, 65 °C). Then, the thermodynamic parameters of enthalpy, free energy and entropy were calculated. Finally, the desorption of drugs from GhO was evaluated by using both aqueous eluants (pH2-10) and organic solvents. PMID:26282775

  10. Nonselective beta-blockers in cirrhotic patients with no or small varices: A meta-analysis

    PubMed Central

    Qi, Xing-Shun; Bao, Yong-Xin; Bai, Ming; Xu, Wen-Da; Dai, Jun-Na; Guo, Xiao-Zhong

    2015-01-01

    AIM: To explore effects of nonselective beta-blockers (NSBBs) in cirrhotic patients with no or small varices. METHODS: The PubMed, EMBASE, Science Direct, and Cochrane library databases were searched for relevant papers. A meta-analysis was performed using ORs with 95%CI as the effect sizes. Subgroup analysis was conducted according to the studies including patients without varices and those with small varices. RESULTS: Overall, 784 papers were initially retrieved from the database searches, of which six randomized controlled trials were included in the meta-analysis. The incidences of large varices development (OR = 1.05, 95%CI: 0.25-4.36; P = 0.95), first upper gastrointestinal bleeding (OR = 0.59, 95%CI: 0.24-1.47; P = 0.26), and death (OR = 0.70, 95%CI: 0.45-1.10; P = 0.12) were similar between NSBB and placebo groups. However, the incidence of adverse events was significantly higher in the NSBB group compared with the placebo group (OR = 3.47, 95%CI: 1.45-8.33; P = 0.005). The results of subgroup analyses were similar to those of overall analyses. CONCLUSION: The results of this meta-analysis indicate that NSBBs should not be recommended for cirrhotic patients with no or small varices. PMID:25780311

  11. Do calcium channel blockers increase the diagnosis of heart failure in patients with hypertension?

    PubMed

    Shibata, Marcelo C; León, Hernando; Chatterley, Trish; Dorgan, Marlene; Vandermeer, Ben

    2010-07-15

    Calcium channel blockers (CCBs) are widely used to control hypertension. Previous work suggested that their use could increase heart failure (HF), which is 1 of the consequences of uncontrolled hypertension. Information about the effect of CCBs on incident HF in patients with hypertension is scarce. A systematic review was conducted to evaluate patients with hypertension treated with CCBs and incident HF. An electronic search of publications was conducted using 8 major databases. Studies were eligible if they (1) were randomized clinical trials, (2) performed comparisons of CCBs versus active control, (3) randomized >200 patients, (4) had follow-up periods >6 months, and (5) provided data regarding incident HF. Trials of renal transplantation patients, placebo-controlled trials, and HF trials were excluded. A total of 156,766 patients were randomized to CCBs or control, with a total of 5,049 events. The analysis indicated a significant increase in the diagnosis of HF in patients allocated to CCBs (odds ratio 1.18, 95% confidence interval 1.07 to 1.31). The effect observed was independent of incident myocardial infarction. Subgroup analyses indicated that patients with diabetes were at higher risk for developing HF (odds ratio 1.71, 95% confidence interval 1.21 to 2.41). In conclusion, the results suggest that patients with hypertension treated with CCBs have increased incident HF. PMID:20599008

  12. A pentasymmetric open channel blocker for Cys-loop receptor channels.

    PubMed

    Carta, Valentina; Pangerl, Michael; Baur, Roland; Puthenkalam, Roshan; Ernst, Margot; Trauner, Dirk; Sigel, Erwin

    2014-01-01

    γ-Aminobutyric acid type A receptors (GABAA receptors) are chloride ion channels composed of five subunits, mediating fast synaptic and tonic inhibition in the mammalian brain. These receptors show near five-fold symmetry that is most pronounced in the second trans-membrane domain M2 lining the Cl- ion channel. To take advantage of this inherent symmetry, we screened a variety of aromatic anions with matched symmetry and found an inhibitor, pentacyanocyclopentdienyl anion (PCCP-) that exhibited all characteristics of an open channel blocker. Inhibition was strongly dependent on the membrane potential. Through mutagenesis and covalent modification, we identified the region α1V256-α1T261 in the rat recombinant GABAA receptor to be important for PCCP- action. Introduction of positive charges into M2 increased the affinity for PCCP- while PCCP- prevented the access of a positively charged molecule into M2. Interestingly, other anion selective cys-loop receptors were also inhibited by PCCP-, among them the Drosophila RDL GABAA receptor carrying an insecticide resistance mutation, suggesting that PCCP- could serve as an insecticide. PMID:25184303

  13. Degradation kinetics and pathways of three calcium channel blockers under UV irradiation.

    PubMed

    Zhu, Bing; Zonja, Bozo; Gonzalez, Oscar; Sans, Carme; Pérez, Sandra; Barceló, Damia; Esplugas, Santiago; Xu, Ke; Qiang, Zhimin

    2015-12-01

    Calcium channel blockers (CCBs) are a group of pharmaceuticals widely prescribed to lower blood pressure and treat heart diseases. They have been frequently detected in wastewater treatment plant (WWTP) effluents and downstream river waters, thus inducing a potential risk to aquatic ecosystems. However, little is known about the behavior and fate of CCBs under UV irradiation, which has been adopted as a primary disinfection method for WWTP effluents. This study investigated the degradation kinetics and pathways of three commonly-used CCBs, including amlodipine (AML), diltiazem (DIL), and verapamil (VER), under UV (254 nm) irradiation. The chemical structures of transformation byproducts (TBPs) were first identified to assess the potential ecological hazards. On that basis, a generic solid-phase extraction method, which simultaneously used four different cartridges, was adopted to extract and enrich the TBPs. Thereafter, the photo-degradation of target CCBs was performed under UV fluences typical for WWTP effluent disinfection. The degradation of all three CCBs conformed to the pseudo-first-order kinetics, with rate constants of 0.031, 0.044 and 0.011 min(-1) for AML, DIL and VER, respectively. By comparing the MS(2) fragments and the evolution (i.e., formation or decay) trends of identified TBPs, the degradation pathways were proposed. In the WWTP effluent, although the target CCBs could be degraded, several TBPs still contained the functional pharmacophores and reached peak concentrations under UV fluences of 40-100 mJ cm(-2). PMID:26003333

  14. The Role of Beta-Blocker in Heart Failure in Adults with Congenital Heart Disease.

    PubMed

    Norozi, Kambiz

    2014-01-01

    Thanks to the enormous progress in the field of cardiac surgery and paediatric cardiology since the mid of 20th century, more and more children with congenital heart defects reach the adulthood. This on the other hand encounter physician and patients various problems due to late complications after the heart surgery like congestive heart failure, arrhythmia and sudden death. One of the challenging area is the medical management of heart failure in these patients with complex anatomy and hemodynamics. The lack of evidence of the effectiveness of the anti congestive medications in this population in from of large randomized controlled trials, makes it difficult to establish universally accepted therapy guidelines. In this article we will review the evidence of the beta-blockers in heart failure in patients with congenital heart disease. Also we will discuss the mechanisms of heart failure in this patient's cohort and will review the literature with respect to the use of neurohormonal antagonists in congenital heart disease. There is an urgent need to initiate well-designed clinical trials to prove if the positive results of neurohormonal blockade in acquired heart failure in adults can be translated in patients with congenital heart disease. PMID:25198738

  15. Impact of anti-inflammatories, beta-blockers and antibiotics on leaf litter breakdown in freshwaters.

    PubMed

    Hughes, S R; Kay, P; Brown, L E

    2016-02-01

    Pharmaceuticals are now recognised as important pollutants in freshwater systems, but a shortcoming of effects studies is that they have focused on structural endpoints and impacts on ecosystem functioning are poorly understood. The decomposition of organic matter is an important functional process in aquatic systems, and it is known that this can be impacted by the presence of pollutants. Previous studies on leaf litter breakdown have only considered the effects of antibiotics and not other groups of drugs though. The current study investigated the effects of anti-inflammatories, a beta-blocker and an antibiotic on microbially mediated breakdown of leaf litter in the laboratory; colonisation of leaf packs by benthic macroinvertebrates when placed in a stream; and shredding of leaf litter by these organisms. Furthermore, the effects of single compounds relative to their mixture were assessed. It was found that exposure of leaf litter to the study compounds did not influence its breakdown by microbes in the laboratory or macroinvertebrates in a stream. Exposure of leaf litter to pharmaceuticals also had no effect on its colonisation by macroinvertebrates in this study. Many unknowns remain, however, and further studies of the effects of pharmaceuticals on structural and functional endpoints are needed to aid aquatic conservation. PMID:26635223

  16. Vincamine and vincanol are potent blockers of voltage-gated Na+ channels.

    PubMed

    Erdo, S A; Molnár, P; Lakics, V; Bence, J Z; Tömösközi, Z

    1996-10-24

    The effects of three vinca derivatives on [3H]batrachotoxin binding in rat cortical synaptosomes, on the inhibition of whole-cell Na+ currents evoked in voltage-clamped cortical neurones of the rat, on the protection against veratridine-induced cell death in cortical cultures and on the maximal electroshock-induced seizures in mice were compared. Vinpocetine, vincamine and vincanol reduced [3H]batrachotoxin binding with IC50 values of 0.34, 1.9 and 10.7 microM, blocked Na+ currents with IC50 values of 44.72 and 40 microM, and protected cortical against veratridine-induced cell death with IC50 values of 0.49, 26 and 33 microM, respectively. Upon i.p. administration, vinpocetine, vincamine and vincanol attenuated maximal electric shock-induced convulsions in a dose-dependent manner with ED50 values of 27, 15.4 and 14.6 mg/kg, respectively. The present findings indicate that the three vinca derivatives are potent blockers of voltage-gated Na+ channels, a mechanism that may contribute at least in part to the pharmacological/therapeutic benefit of these drugs. PMID:8957220

  17. Flunarizine, a calcium entry blocker, ameliorates ischemic brain damage in the rat.

    PubMed

    Deshpande, J K; Wieloch, T

    1986-02-01

    The effects of flunarizine, a calcium entry blocker, were evaluated in a long-term survival model of ischemia in rats. One group of animals received the drug orally at 24 and 4 h prior to the insult (40 mg X kg-1 X dose-1). Another group was given flunarizine following the insult, intravenously at 5 min (0.1 mg X kg-1), and orally at 8 and 24 h (40 mg X kg-1 X dose-1). A third group received the solvent for the oral suspension on the same schedule as the pretreated group. Six animals from each group were subjected to 9 min ischemia and recovery of 7 days, at which time the brains were harvested for histologic study. In another six animals from each group, cortical metabolites and fatty acids were determined during early recirculation. Local cerebral blood flow was measured at 60 min recirculation in a third set of animals. Flunarizine significantly improved histological outcome (fewer irreversibly damaged cells) in both treatment groups. This amelioration was not related to improvement of cerebral blood flow during the period of delayed hypoperfusion, nor the postischemic levels of high-energy phosphates or free fatty acids. PMID:3946808

  18. Prenatal exposure to H2 blockers and to proton pump inhibitors and asthma development in offspring.

    PubMed

    Yitshak-Sade, Maayan; Gorodischer, Rafael; Aviram, Micha; Novack, Lena

    2016-01-01

    Fetal exposure to H2 blockers (H2 Bs) or proton pump inhibitors (PPIs) has been reported to be associated with asthma in children. We evaluated the risk of asthma in offspring following prenatal H2 Bs. We enrolled 91 428 children and their mothers who resided in southern Israel during 1998-2011. The computerized medications database was linked with records from the district hospital. Of the eligible children, 11 227 developed asthma, and overall 5.5% had been exposed to H2 Bs or PPIs prenatally. The risk of developing asthma was slightly higher in the group exposed to H2 Bs or PPIs (RR, 1.09; P = .023). At greater risk were children whose mothers purchased these medications more than 3 times (RR, 1.22; P = .038) or exposed to >20 defined daily doses or prenatally exposed to lansoprazole. The statistical association was significant and depended on magnitude of exposure and specific medication, but the absolute risk was low. The association between maternal consumption of H2 Bs or PPIs and asthma and childhood remained statistically significant 2 years after delivery, raising the possibility of confounding by the indication phenomenon. In view of the findings, a causal relationship could not be ascertained, and an unidentified etiological factor could be operative. PMID:26096778

  19. Safety and efficacy of an ultrashort-acting β1-blocker on left ventricular dysfunction.

    PubMed

    Ito, Nobuhisa; Tashiro, Tadashi; Morishige, Noritsugu; Nishimi, Masaru; Hayashida, Yoshio; Minematsu, Noritoshi; Kuwahara, Go; Sukehiro, Yuta; Teratani, Hiromitsu

    2012-08-01

    Landiolol hydrochloride, an ultrashort-acting β1-selective blocker, is a highly regulated drug. This study evaluated the safety and efficacy of this drug for cases of coronary artery bypass grafting (CABG) with left ventricular dysfunction. Between September 2006 and August 2009, 32 patients with a left ventricular ejection fraction of <40% underwent CABG. Two groups of patients, a group administered landiolol hydrochloride and a control group not administered this drug, were compared. The administration of landiolol hydrochloride was initiated at 1 μg/kg per minute (γ) after cardiopulmonary bypass in on-pump cases and after completion of all the distal anastomoses in off-pump cases. We observed no significant differences between the groups with respect to preoperative patient background or incidences of complications, except for postoperative atrial fibrillation. The heart rate decreased significantly 30 minutes after landiolol hydrochloride administration, but no change was observed in arterial pressure. No change was observed in other parameters; the hemodynamics were stable. The occurrence of atrial fibrillation during the intensive care unit stay (during landiolol hydrochloride administration) was significantly lower in the administration group. The difference remained significant after multiple logistic regression analysis; landiolol hydrochloride was the sole inhibitory factor. PMID:22917822

  20. Chemokines and chemokine receptors blockers as new drugs for the treatment of chronic obstructive pulmonary disease.

    PubMed

    Caramori, G; Di Stefano, A; Casolari, P; Kirkham, P A; Padovani, A; Chung, K F; Papi, A; Adcock, I M

    2013-01-01

    Chronic obstructive pulmonary disease (COPD) is characterised by an abnormal inflammatory response of the lung to noxious particles or gases. The cellular inflammatory response in COPD is characterised by an increased number of inflammatory cells in the lungs. Although the molecular and cellular mechanisms responsible for the development of COPD are not well understood; several mediators are assumed to regulate the activation and recruitment of these inflammatory cells into the lung of COPD patients particularly those belonging to the chemokine family. Inhibitors or blockers of chemokine and chemokine receptors are therefore of great interest as potential novel therapies for COPD and many are now in clinical development. A high degree of redundancy exists in the chemokine network and inhibition of a single chemokine or receptor may not be sufficient to block the inflammatory response. Despite this, animal studies suggest a strong rationale for inhibiting the chemokine network in COPD. As such, every leading pharmaceutical company maintains a significant interest in developing agents that regulate leukocyte navigation as potential anti-inflammatory drugs. Drugs and antibodies targeting chemokines and their receptors are generally still in early stages of development and the results of clinical trial are awaited with great interest. These agents may not only provide improved management of COPD but also, importantly, indicate proof-of-concept to further clarify the role of chemokines in the pathophysiology of COPD. PMID:24059236

  1. Structure and function of μ-conotoxins, peptide-based sodium channel blockers with analgesic activity

    PubMed Central

    Green, Brad R; Bulaj, Grzegorz; Norton, Raymond S

    2015-01-01

    μ-Conotoxins block voltage-gated sodium channels (VGSCs) and compete with tetrodotoxin for binding to the sodium conductance pore. Early efforts identified μ-conotoxins that preferentially blocked the skeletal muscle subtype (NaV1.4). However, the last decade witnessed a significant increase in the number of μ-conotoxins and the range of VGSC subtypes inhibited (NaV1.2, NaV1.3 or NaV1.7). Twenty μ-conotoxin sequences have been identified to date and structure–activity relationship studies of several of these identified key residues responsible for interactions with VGSC subtypes. Efforts to engineer-in subtype specificity are driven by in vivo analgesic and neuromuscular blocking activities. This review summarizes structural and pharmacological studies of μ-conotoxins, which show promise for development of selective blockers of NaV1.2, and perhaps also NaV1.1,1.3 or 1.7. PMID:25406007

  2. Effects of vesicular acetylcholine uptake blockers on frequency augmentation-potentiation in frog neuromuscular transmission.

    PubMed

    Maeno, T; Enomoto, K

    1994-03-01

    Vesamicol inhibits the vesicular loading of acetylcholine molecules. The effects of vesamicol and similarly acting compounds on neuromuscular transmission in frogs were investigated to determine whether these inhibitors-inhibit the frequency augmentation-potentiation of transmitter release. Various vesicular acetylcholine transport blockers suppressed the stimulation frequency-related release parameter, k, in a dose-dependent manner. Artane, cetiedil, chloroquine, ethodin, quinacrine, vesamicol and its benzyl-analogue, 2-(4-benzylpiperidino)cyclohexanol, had strong effects, while those of aminacrine, chlorpromazine, fluphenazine, imipramine, pyrilamine and thioridazine were weak. A significant correlation was observed between the biochemically reported values of IC50 and the electrophysiological inhibitory potencies on k at 20 microM. Contrary to expectations from the biochemical data, however, vesamicol and its benzyl-analogue showed equipotent inhibitory actions on the electrophysiological frequency augmentation-potentiation relation. Low sensitivity and low selectivity of the frequency augmentation-potentiation for vesamicol and its benzyl-analogue lead us to conclude that the vesicular acetylcholine transporter is not the site of the electrophysiological action of vesamicol and similarly acting chemicals. PMID:8008203

  3. Calcium channel blockers and Alzheimer's disease: potential relevance in treatment strategies of metabolic syndrome.

    PubMed

    Goodison, William V; Frisardi, Vincenza; Kehoe, Patrick G

    2012-01-01

    Midlife hypertension is a risk factor for late onset Alzheimer's disease (AD) and it is one of the components of metabolic syndrome (MetS). Observational studies and some cardiovascular disease-related clinical trials suggest that antihypertensive treatment reduced the incidence and progression of AD. Calcium channel blockers (CCBs), one of the more commonly used treatments for hypertension, target voltage-gated calcium channels (VGCCs) which are found on neurons in the brain where calcium regulation is very important in both learning and memory. Amyloid-β (Aβ) peptide, one of the main pathological hallmarks of AD, causes increases to intracellular calcium via VGCCs, which in turn leads to further increases in Aβ production. Memantine, a current treatment used in AD, exerts some of its beneficial effects by blocking calcium entry into neurons. We explore the possibility of whether CCBs acting in the brain may delay the onset and progression of AD and thus may inform treatment regimes in people with MetS. PMID:22377784

  4. Synergistic Effect of Fluconazole and Calcium Channel Blockers against Resistant Candida albicans

    PubMed Central

    Liu, Shuyuan; Yue, Longtao; Gu, Wenrui; Li, Xiuyun; Zhang, Liuping; Sun, Shujuan

    2016-01-01

    Candidiasis has increased significantly recently that threatens patients with low immunity. However, the number of antifungal drugs on the market is limited in comparison to the number of available antibacterial drugs. This fact, coupled with the increased frequency of fungal resistance, makes it necessary to develop new therapeutic strategies. Combination drug therapy is one of the most widely used and effective strategy to alleviate this problem. In this paper, we were aimed to evaluate the combined antifungal effects of four CCBs (calcium channel blockers), amlodipine (AML), nifedipine (NIF), benidipine (BEN) and flunarizine (FNZ) with fluconazole against C. albicans by checkerboard and time-killing method. In addition, we determined gene (CCH1, MID1, CNA1, CNB1, YVC1, CDR1, CDR2 and MDR1) expression by quantitative PCR and investigated the efflux pump activity of resistant candida albicans by rhodamine 6G assay to reveal the potential mechanisms. Finally, we concluded that there was a synergy when fluconazole combined with the four tested CCBs against resistant strains, with fractional inhibitory concentration index (FICI) <0.5, but no interaction against sensitive strains (FICI = 0.56 ~ 2). The mechanism studies revealed that fluconazole plus amlodipine caused down-regulating of CNA1, CNB1 (encoding calcineurin) and YVC1 (encoding calcium channel protein in vacuole membrane). PMID:26986478

  5. Synergistic Effect of Fluconazole and Calcium Channel Blockers against Resistant Candida albicans.

    PubMed

    Liu, Shuyuan; Yue, Longtao; Gu, Wenrui; Li, Xiuyun; Zhang, Liuping; Sun, Shujuan

    2016-01-01

    Candidiasis has increased significantly recently that threatens patients with low immunity. However, the number of antifungal drugs on the market is limited in comparison to the number of available antibacterial drugs. This fact, coupled with the increased frequency of fungal resistance, makes it necessary to develop new therapeutic strategies. Combination drug therapy is one of the most widely used and effective strategy to alleviate this problem. In this paper, we were aimed to evaluate the combined antifungal effects of four CCBs (calcium channel blockers), amlodipine (AML), nifedipine (NIF), benidipine (BEN) and flunarizine (FNZ) with fluconazole against C. albicans by checkerboard and time-killing method. In addition, we determined gene (CCH1, MID1, CNA1, CNB1, YVC1, CDR1, CDR2 and MDR1) expression by quantitative PCR and investigated the efflux pump activity of resistant candida albicans by rhodamine 6G assay to reveal the potential mechanisms. Finally, we concluded that there was a synergy when fluconazole combined with the four tested CCBs against resistant strains, with fractional inhibitory concentration index (FICI) <0.5, but no interaction against sensitive strains (FICI = 0.56 ~ 2). The mechanism studies revealed that fluconazole plus amlodipine caused down-regulating of CNA1, CNB1 (encoding calcineurin) and YVC1 (encoding calcium channel protein in vacuole membrane). PMID:26986478

  6. Beta blocker effects on plasma homocysteine levels in patients with hypertension.

    PubMed

    Atar, Ilyas; Korkmaz, Mehmet Emin; Demircan, Senol; Atar, Inci Asli; Bozbaş, Hüseyin; Aydinalp, Alp; Ozin, Bülent; Yildirir, Aylin; Müderrisoğlu, Haldun

    2005-08-01

    Recent studies have shown that hyperhomocysteinemia might play a role in the pathogenesis of hypertension. The effects of antihypertensive agents on plasma homocysteine levels have not been tested extensively. We investigated the effects of beta-blocker therapy on homocysteine levels in patients with hypertension. In the study, 120 patients with newly diagnosed hypertension were enrolled. All patients received metoprolol succinate 100 mg/day initially. If blood pressure was above normal on the 15th day of follow-up, the metoprolol dosage was doubled. Before initiation of the antihypertensive medication and after the fourth month of treatment, homocysteine levels were measured. Of the 120 patients enrolled, 39 could not complete the study. Homocysteine levels decreased significantly by the end of the fourth month when compared with basal values (13.5+/-4.5 micromol/l versus 12.4+/-4.9 micromol/l; P = 0.001). There was no relation between homocysteine level and blood pressure control. There was a significant decrease in homocysteine levels in the women treated in this study (P = 0.001); however, this effect was absent in men (P = 0.185). We demonstrate that metoprolol succinate treatment significantly decreases plasma homocysteine levels in patients with hypertension, especially in women. PMID:16039296

  7. Suppression of rat carotid lesion development by the calcium channel blocker PN 200-110.

    PubMed Central

    Handley, D. A.; Van Valen, R. G.; Melden, M. K.; Saunders, R. N.

    1986-01-01

    Balloon catheter damage of the rat carotid artery endothelium results in an extensive and reproducible neointimal lesion composed of smooth muscle cells and connective matrix. The authors have examined two calcium channel blockers, PN 200-110 and PY 108-068, for their ability to inhibit neointimal lesion development in the rat carotid model. When given subcutaneously (1.0 mg/kg day) both compounds produced rapidly acting and long-lasting hypotension, reducing blood pressure 25-29%. At this dose given daily, PN 200-110 reduced lesion cross-sectional area by 44%, compared with only 25% seen by PY 108-068, which suggests that the antiatherosclerotic effect may not be related to lowering of blood pressure. Furthermore, PN 200-110 did not reduce the extent of platelet deposition (compared with controls) occurring at the denuded vessel surface 1 hour or 24 hours after balloon catheterization, which indicates that the inhibition of lesion development may not reflect an antiplatelet mechanism. The observed inhibition by PN 200-110 may relate to mitogen responses of the smooth muscle cell in the vessel wall (migration and proliferation) involved in lesion progression after endothelial damage. Images Figure 3 Figure 4 PMID:2942038

  8. Suppression of rat carotid lesion development by the calcium channel blocker PN 200-110.

    PubMed

    Handley, D A; Van Valen, R G; Melden, M K; Saunders, R N

    1986-07-01

    Balloon catheter damage of the rat carotid artery endothelium results in an extensive and reproducible neointimal lesion composed of smooth muscle cells and connective matrix. The authors have examined two calcium channel blockers, PN 200-110 and PY 108-068, for their ability to inhibit neointimal lesion development in the rat carotid model. When given subcutaneously (1.0 mg/kg day) both compounds produced rapidly acting and long-lasting hypotension, reducing blood pressure 25-29%. At this dose given daily, PN 200-110 reduced lesion cross-sectional area by 44%, compared with only 25% seen by PY 108-068, which suggests that the antiatherosclerotic effect may not be related to lowering of blood pressure. Furthermore, PN 200-110 did not reduce the extent of platelet deposition (compared with controls) occurring at the denuded vessel surface 1 hour or 24 hours after balloon catheterization, which indicates that the inhibition of lesion development may not reflect an antiplatelet mechanism. The observed inhibition by PN 200-110 may relate to mitogen responses of the smooth muscle cell in the vessel wall (migration and proliferation) involved in lesion progression after endothelial damage. PMID:2942038

  9. Comparison of electrophysiological effects of calcium channel blockers on cardiac repolarization

    PubMed Central

    Lee, Hyang-Ae; Hyun, Sung-Ae; Park, Sung-Gurl

    2016-01-01

    Dihydropyridine (DHP) calcium channel blockers (CCBs) have been widely used to treat of several cardiovascular diseases. An excessive shortening of action potential duration (APD) due to the reduction of Ca2+ channel current (ICa) might increase the risk of arrhythmia. In this study we investigated the electrophysiological effects of nicardipine (NIC), isradipine (ISR), and amlodipine (AML) on the cardiac APD in rabbit Purkinje fibers, voltage-gated K+ channel currents (IKr, IKs) and voltage-gated Na+ channel current (INa). The concentration-dependent inhibition of Ca2+ channel currents (ICa) was examined in rat cardiomyocytes; these CCBs have similar potency on ICa channel blocking with IC50 (the half-maximum inhibiting concentration) values of 0.142, 0.229, and 0.227 nM on NIC, ISR, and AML, respectively. However, ISR shortened both APD50 and APD90 already at 1 µM whereas NIC and AML shortened APD50 but not APD90 up to 30 µM. According to ion channel studies, NIC and AML concentration-dependently inhibited IKr and IKs while ISR had only partial inhibitory effects (<50% at 30 µM). Inhibition of INa was similarly observed in the three CCBs. Since the IKr and IKs mainly contribute to cardiac repolarization, their inhibition by NIC and AML could compensate for the AP shortening effects due to the block of ICa. PMID:26807031

  10. Kinetic Spectrofluorometric Determination of Certain Calcium Channel Blockers via Oxidation with Cerium (IV) in Pharmaceutical Preparations.

    PubMed

    Walash, M I; Belal, F; El-Enany, N; Abdelal, A A

    2009-06-01

    A simple and sensitive kinetic spectrofluorometric method was developed for the determination of some calcium channel blockers namely, verapamil hydrochloride, diltiazem hydrochloride, nicardipine hydrochloride and flunarizine. The method is based upon oxidation of the studied drugs with cerium (IV) ammonium sulphate in acidic medium. The fluorescence of the produced Ce (III) was measured at 365 nm after excitation at 255 nm. The different experimental parameters affecting the development and stability of the reaction product were carefully studied and optimized. The fluorescence-concentration plots were rectilinear for all the studied compounds over the concentration range of 0.01 to 0.12 μg mL(-1). The limits of detections for the studied compounds ranged from 2.93 × 10(-3) to 0.012 μg mL(-1) and limits of quantification from 9.76 × 10(-3) to 0.04 μg mL(-1) were obtained. The method was successfully applied to the analysis of commercial tablets. The results obtained were in good agreement with those obtained with reference methods. PMID:23675129

  11. Amelioration of light-induced retinal degeneration by a calcium overload blocker. Flunarizine.

    PubMed

    Edward, D P; Lam, T T; Shahinfar, S; Li, J; Tso, M O

    1991-04-01

    Although free radical formation and lipid peroxidation have been implicated in photoreceptor degeneration following continuous light exposure, recent evidence led us to hypothesize that excessive stimulation of the photoreceptor cells in prolonged light exposure may cause intracellular calcium overload and consequent photoreceptor cell injury. To test this hypothesis, we studied the effects of flunarizine hydrochloride, a calcium overload blocker that inhibits the inositol 1,4,5-triphosphate-induced release of intracellular stores of calcium, in an established rat model of light-induced retinal degeneration. Light and electron microscopic examination of the flunarizine-treated retinas revealed remarkable preservation of the retinal pigment epithelium, rod inner and outer segments, nuclei, and synapses of the photoreceptor cells at all phases of the recovery period. This observation was further supported by morphometric evaluation of the outer nuclear layer thickness, which revealed a greater preservation of the photoreceptor nuclei in the drug-treated animals at 6 and 14 days after exposure. In addition, the rhodopsin levels in the flunarizine-treated retinas were also significantly higher than in the controls in all phases of recovery. The ability of flunarizine to ameliorate light-induced retinal degeneration in the rat supports our hypothesis that elevated intracellular calcium may indeed play a role in light-induced photoreceptor degeneration. PMID:2012559

  12. Kinetic Spectrofluorometric Determination of Certain Calcium Channel Blockers via Oxidation with Cerium (IV) in Pharmaceutical Preparations

    PubMed Central

    Walash, M. I.; Belal, F.; El-Enany, N.; Abdelal, A. A.

    2009-01-01

    A simple and sensitive kinetic spectrofluorometric method was developed for the determination of some calcium channel blockers namely, verapamil hydrochloride, diltiazem hydrochloride, nicardipine hydrochloride and flunarizine. The method is based upon oxidation of the studied drugs with cerium (IV) ammonium sulphate in acidic medium. The fluorescence of the produced Ce (III) was measured at 365 nm after excitation at 255 nm. The different experimental parameters affecting the development and stability of the reaction product were carefully studied and optimized. The fluorescence-concentration plots were rectilinear for all the studied compounds over the concentration range of 0.01 to 0.12 μg mL-1. The limits of detections for the studied compounds ranged from 2.93 × 10-3 to 0.012 μg mL-1 and limits of quantification from 9.76 × 10-3 to 0.04 μg mL-1 were obtained. The method was successfully applied to the analysis of commercial tablets. The results obtained were in good agreement with those obtained with reference methods. PMID:23675129

  13. L-type calcium channel blockers, morphine and pain: Newer insights

    PubMed Central

    Kumar, Rakesh; Mehra, RD; Ray, S Basu

    2010-01-01

    Earlier, we had reported that co-administration of opioids and L-type calcium channel blockers (L-CCBs) like diltiazem could prove useful in the treatment of cancer pain. Much of this report was based upon earlier published work involving animal models of pain exposed to brief periods of noxious radiant heat without any tissue injury. However, pain in clinical situations usually result from tissue injury. Thus, the aim of the current investigation was to study the analgesic effect of this combination of drugs in the rat formalin test which is associated with actual tissue injury. Wistar rats (n=60) received either L-CCB (nifedipine/nimodipine/verapamil/diltiazem i.p.) or morphine (s.c.) or both drugs. The formalin test was done 30 min after morphine or placebo injection. The naloxone reversal test was also done. Administration of L-CCBs alone, particularly diltiazem, increased pain in the formalin test. In contrast, co-administration of these L-CCBs with morphine led to decreased pain response, though statistically significant decrease was noted only with nimodipine + morphine. Naloxone reversed this analgesic effect, indicating that it was primarily an opioid-mediated effect. The results show that administration of L-CCBs alone may prove counterproductive in the therapeutic management of pain (anti-analgesic effect). However, co-administration of both drugs (morphine and nimodipine) in quick succession could lead to adequate pain relief. PMID:20661350

  14. Calcium Channel Blockers, Progression to Dementia, and Effects on Amyloid Beta Peptide Production

    PubMed Central

    Lovell, Mark A.; Abner, Erin; Kryscio, Richard; Xu, Liou; Fister, Shuling X.; Lynn, Bert C.

    2015-01-01

    Previous epidemiologic studies suggest that antihypertensive drugs may be protective against cognitive decline. To determine if subjects enrolled in the University of Kentucky longitudinal aging study who used antihypertensive drugs showed diminished progression to dementia, we used a 3-parameter logistic regression model to compare the rate of progression to dementia for subjects who used any of the five common categories of antihypertensive drugs to those with similar demographic characteristics but who did not use antihypertensives. Regression modeling showed that subjects who used calcium channel blockers (CCBs) but not the other classes of antihypertensives showed a significant decrease in the rate of progression to dementia. Significantly, use of CCBs ameliorated the negative effects of the presence of APOE-4 alleles on cognitive decline. To determine if CCBs could minimize amyloid beta peptide (Aβ1–42) production, H4 neuroglioma cultures transfected to overexpress APP were treated with various CCBs and Aβ1–42 levels and levels of proteins involved in Aβ production were quantified. Results show that treatment with nifedipine led to a significant decrease in levels of Aβ1–42, with no significant decrease in cell viability. Collectively, these data suggest that use of CCBs significantly diminishes the rate of progression to dementia and may minimize formation of Aβ1–42. PMID:26221415

  15. Polyaniline-graphene oxide nanocomposite sensor for quantification of calcium channel blocker levamlodipine.

    PubMed

    Jain, Rajeev; Sinha, Ankita; Khan, Ab Lateef

    2016-08-01

    A novel polyaniline-graphene oxide nanocomposite (PANI/GO/GCE) sensor has been fabricated for quantification of a calcium channel blocker drug levamlodipine (LAMP). Fabricated sensor has been characterized by electrochemical impedance spectroscopy, square wave and cyclic voltammetry, Raman spectroscopy and Fourier transform infrared (FTIR) spectroscopy. The developed PANI/GO/GCE sensor has excellent analytical performance towards electrocatalytic oxidation as compared to PANI/GCE, GO/GCE and bare GCE. Under optimized experimental conditions, the fabricated sensor exhibits a linear response for LAMP for its oxidation over a concentration range from 1.25μgmL(-1) to 13.25μgmL(-1) with correlation coefficient of 0.9950 (r(2)), detection limit of 1.07ngmL(-1) and quantification limit of 3.57ngmL(-1). The sensor shows an excellent performance for detecting LAMP with reproducibility of 2.78% relative standard deviation (RSD). The proposed method has been successfully applied for LAMP determination in pharmaceutical formulation with a recovery from 99.88% to 101.75%. PMID:27157745

  16. Potassium channel blockers as an effective treatment to restore impulse conduction in injured axons.

    PubMed

    Shi, Riyi; Sun, Wenjing

    2011-02-01

    Most axons in the vertebral central nervous system are myelinated by oligodendrocytes. Myelin protects and insulates neuronal processes, enabling the fast, saltatory conduction unique to myelinated axons. Myelin disruption resulting from trauma and biochemical reaction is a common pathological event in spinal cord injury and chronic neurodegenerative diseases. Myelin damage-induced axonal conduction block is considered to be a significant contributor to the devastating neurological deficits resulting from trauma and illness. Potassium channels are believed to play an important role in axonal conduction failure in spinal cord injury and multiple sclerosis. Myelin damage has been shown to unmask potassium channels, creating aberrant potassium currents that inhibit conduction. Potassium channel blockade reduces this ionic leakage and improves conduction. The present review was mainly focused on the development of this technique of restoring axonal conduction and neurological function of demyelinated axons. The drug 4-aminopyridine has recently shown clinical success in treating multiple sclerosis symptoms. Further translational research has also identified several novel potassium channel blockers that may prove effective in restoring axonal conduction. PMID:21270902

  17. Effect of Channel Blockers on the Smooth Muscle of the Adult Crop of the Queen Blowfly, Phormia regina

    PubMed Central

    Stoffolano, John G.; Danai, Laura; Chambers, James

    2013-01-01

    Few studies have examined the various factors affecting the rate of contraction of the supercontractile muscles of the crop lobes of adult Phormia regina Meigen (Diptera: Calliphoridae). Using an in situ bioassay of the crop organ, various ion channel blockers were tested and it was demonstrated that in all cases the blockers (i.e., against the following conductances: Cl- , Ca2+ , Na+, and a FMRF-amide action) significantly reduced the contraction rates of the crop lobes, which were filled with 4.5 µL of 1.0 M sucrose containing 10 mM of the dye amaranth. Benzyltrimethylammonium chloride, never before reported for its effect on insect muscle, was as effective in suppressing crop muscle contraction as benzethonium chloride, which is a reported agonist of dromyosuppressin. PMID:24205919

  18. Perioperative management of tumor necrosis factor-alpha blocker-treated psoriatic patients: Case reports and review.

    PubMed

    Kawakami, Hiroshi; Matsumoto, Yuka; Abe, Namiko; Katori, Youich; Takahashi, Kousuke; Tsuboi, Ryoji; Okubo, Yukari

    2016-02-01

    Regarding appropriate timings of discontinuation and resumption of biologics for psoriasis patients before and after elective surgeries, an international consensus has yet to be reached. The Japanese Dermatological Association of Guideline and Safety Manual for the use of Biologic Agents in Psoriasis 2013 states that infliximab (IFX) and adalimumab (ADA) should be withheld at least 4 and 2 weeks, respectively, before surgery and can be restarted as neither postoperative infection nor delayed wound healing is recognized. We experienced three generalized pustular psoriasis (GPP) patients and one plaque-type psoriasis patient undergoing surgeries during tumor necrosis factor (TNF)-α blocker therapy. Three GPP cases experienced uneventful post-surgical course. One psoriasis vulgaris patient on IFX had a wound healing delay with deterioration of psoriatic plaques which was restored by restarting IFX. The timing of suspension and resumption of TNF-α blockers in all cases were determined following the Japanese guideline. PMID:26346621

  19. Cell differentiation and infectivity of Leishmania mexicana are inhibited in a strain resistant to an ABC-transporter blocker.

    PubMed

    Silva, N; Camacho, N; Figarella, K; Ponte-Sucre, A

    2004-06-01

    We analysed whether markers of cell differentiation and infectivity differed when compared to the parental sensitive strain [NR(Gs)] in an in vitro selected Leishmania strain [NR(Gr)] resistant to Glibenclamide, an ATP-binding-cassette (ABC)-transporter blocker. The data show that the cell body area was larger in NR(Gr) compared to NR(Gs) and that functional characters associated with an infective metacyclic phenotype, such as resistance to the lytic effect of the alternative complement pathway and expression of the Meta-1 protein, were reduced. The infectivity of NR(Gr) to J774.1 macrophages was also significantly reduced. These results suggest that resistance in Leishmania against Glibenclamide, a general blocker of P-glycoproteins, could produce functional modifications that may be relevant for Leishmania differentiation, infectivity and survival. PMID:15206465

  20. Understanding nuclear motions in molecules: Derivation of Eckart frame ro-vibrational Hamiltonian operators via a gateway Hamiltonian operator

    SciTech Connect

    Szalay, Viktor

    2015-05-07

    A new ro-vibrational Hamiltonian operator, named gateway Hamiltonian operator, with exact kinetic energy term, T-hat, is presented. It is in the Eckart frame and it is of the same form as Watson’s normal coordinate Hamiltonian. However, the vibrational coordinates employed are not normal coordinates. The new Hamiltonian is shown to provide easy access to Eckart frame ro-vibrational Hamiltonians with exact T-hat given in terms of any desired set of vibrational coordinates. A general expression of the Eckart frame ro-vibrational Hamiltonian operator is given and some of its properties are discussed.

  1. Effect of an imidazobenzodiazepine, Ro15-4513, on the incoordination and hypothermia produced by ethanol and pentobarbital.

    PubMed

    Hoffman, P L; Tabakoff, B; Szabó, G; Suzdak, P D; Paul, S M

    1987-08-01

    The imidazobenzodiazepine, Ro15-4513, which is a partial inverse agonist at brain benzodiazepine receptors, reversed the incoordinating effect of ethanol in mice, as measured on an accelerating Rotarod. This effect was blocked by benzodiazepine receptor antagonists. In contrast, Ro15-4513 had no effect on ethanol-induced hypothermia in mice. However, Ro15-4513 reversed the hypothermic effect of pentobarbital, and, at a higher dose, also reversed the incoordinating effect of pentobarbital in mice. The data support the hypothesis that certain of the pharmacological effects of ethanol are mediated by actions at the GABA-benzodiazepine receptor-coupled chloride channel. PMID:3600196

  2. VizieR Online Data Catalog: Planetary transit candidates in CoRoT LRa01 field (Carone+, 2012)

    NASA Astrophysics Data System (ADS)

    Carone, L.; Gandolfi, D.; Cabrera, J.; Hatzes, A. P.; Deeg, H. J.; Csizmadia, Sz.; Paetzold, M.; Weingrill, J.; Aigrain, S.; Alonso, R.; Alapini, A.; Almenara, J.-M.; Auvergne, M.; Baglin, A.; Barge, P.; Bonomo, A. S.; Borde, P.; Bouchy, F.; Bruntt, H.; Carpano, S.; Cochran, W. D.; Deleuil, M.; Diaz, R. F.; Dreizler, S.; Dvorak, R.; Eisloeffel, J.; Eigmueller, P.; Endl, M.; Erikson, A.; Ferraz-Mello, S.; Fridlund, M.; Gazzano, J.-C.; Gibson, N.; Gillon, M.; Gondoin, P.; Grziwa, S.; Guenther, E. W.; Guillot, T.; Hartmann, M.; Havel, M.; Hebrard, G.; Jorda, L.; Kabath, P.; Leger, A.; Llebaria, A.; Lammer, H.; Lovis, C.; MacQueen, P. J.; Mayor, M.; Mazeh, T.; Moutou, C.; Nortmann, L.; Ofir, A.; Ollivier, M.; Parviainen, H.; Pepe, F.; Pont, F.; Queloz, D.; Rabus, M.; Rauer, H.; Regulo, C.; Renner, S.; de La, Reza R.; Rouan, D.; Santerne, A.; Samuel, B.; Schneider, J.; Shporer, A.; Stecklum, B.; Tal-Or, L.; Tingley, B.; Udry, S.; Wuchterl, G.

    2012-04-01

    We present the list of planetary transit candidates from the CoRoT LRa01 star field in the Monoceros constellation toward the Galactic anti-center direction. The CoRoT observations of LRa01 lasted from 24 October 2007 to 3 March 2008. We acquired and analyzed 7470 chromatic and 3938 monochromatic lightcurves. Instrumental noise and stellar variability were treated with several filtering tools by different teams from the CoRoT community. Different transit search algorithms were applied to the lightcurves. (4 data files).

  3. Pleiotropic effects of the beta-adrenoceptor blocker carvedilol on calcium regulation during oxidative stress-induced apoptosis in cardiomyocytes.

    PubMed

    Wang, Ruijuan; Miura, Toshiro; Harada, Nozomu; Kametani, Ryosuke; Shibuya, Masaki; Fukagawa, Yasuhiro; Kawamura, Shuji; Ikeda, Yasuhiro; Hara, Masayuki; Matsuzaki, Masunori

    2006-07-01

    Carvedilol is a nonselective beta-adrenoceptor blocker with multiple pleiotropic actions. A recent clinical study suggested that carvedilol may be superior to other beta-adrenoceptor blockers in the treatment of heart failure. Despite numerous investigations, the underlying mechanisms of carvedilol on improving heart failure are yet to be fully established. The purpose of this study is to clarify the pleiotropic effect of carvedilol on cytosolic and mitochondrial calcium regulation during oxidative stress-induced apoptosis in cardiomyocytes. Carvedilol (10 microM), but not metoprolol (10 microM), reduced H2O2 (100 microM)-induced apoptosis in neonatal rat cardiomyocytes. During the process, changes in cytosolic calcium concentration ([Ca2+]i) and mitochondrial calcium concentration ([Ca2+]m) and mitochondrial membrane potential (DeltaPsim) were measured by fluorescent probes [Fluo-3/acetoxymethyl ester (AM), Rhod-2/AM, and tetramethylrhodamine ethyl ester, respectively] and imaged by laser confocal microscopy. The results showed that H2O2 caused [Ca2]m overload first, followed by [Ca2+]i overload, leading to DeltaPsim dissipation and the induction of apoptosis. Carvedilol (10 microM) significantly delayed these processes and reduced apoptosis. These effects were not observed with other beta-adrenoceptor blockers (metoprolol, atenolol, and propranolol) or with a combination of the alpha (phentolamine)- and the beta-adrenoceptor blocker. The antioxidant N-acetyl-L-cysteine (NAC, 5 mM) and the combination of NAC and propranolol (10 microM) showed an effect similar to that of carvedilol. Therefore, the effect of carvedilol on H2O2-induced changes in [Ca2+]m, [Ca2+]i, and DeltaPsi(m) is independent of alpha- and beta-adrenoceptors but is probably dependent on the antioxidant effect. PMID:16611853

  4. Arrachements des épines iliaques antéro-supérieures et antéro-inférieures chez l'adolescent sportifs: à propos de deux cas

    PubMed Central

    Louaste, Jamal; Cherrad, Taoufik; Rachid, Khalid

    2015-01-01

    Les arrachements des épines iliaques antéro-supérieures et antéro-inférieures sont des entités rares qui touchent surtout l'enfant et l'adolescent. Elles se voient généralement lors d'une activité sportive. Le tableau clinique est dominé par une douleur brutale et importante de la hanche de type mécanique. Alors que le diagnostic est confirmé par les examens radiologiques. Nous rapportons deux cas de fractures arrachement des épines iliaques l'une antéro-supérieure et l'autre antéro-inférieure. PMID:26985274

  5. Dramatic improvement of anti-SS-A/Ro-associated interstitial lung disease after immunosuppressive treatment.

    PubMed

    Paola, Caramaschi; Giuliana, Festi; Giovanni, Orsolini; Cristian, Caimmi; Domenico, Biasi

    2016-07-01

    The aim of the study was to report three patients affected by interstitial lung disease associated with positive anti-SS-A/Ro autoantibody who showed a dramatic improvement after immunosuppressive treatment. Medical charts were reviewed to obtain clinical data, laboratory parameters, lung function tests, high-resolution computed tomography results and response to immunosuppressive treatment. The three patients showed a clinical picture of a lung-dominant connective tissue disease characterized by a sudden onset with dyspnea, cough and subtle extrathoracic features together with positive anti-SS-A/Ro antibody and weak titer antinuclear antibodies. All three patients responded favorably to immunosuppressive therapy: Two cases were treated with a combination of corticosteroid and cyclophosphamide followed by mycophenolate mofetil; in the third patient, clinical benefit was obtained after rituximab was added to corticosteroid and immunosuppressant drug. In spite of an abrupt onset with significant lung function impairment, all three patients had a favorable clinical response to immunosuppressive therapy. This report may be useful in making therapeutic decisions in case of interstitial lung disease associated with anti-SS-A antibody. PMID:27021338

  6. New light on the driving mechanism in roAp stars. I. Effects of metallicity

    NASA Astrophysics Data System (ADS)

    Théado, S.; Dupret, M.-A.; Noels, A.; Ferguson, J. W.

    2009-01-01

    Context: Observations suggest that a relationship exists between the driving mechanism of roAp star pulsations and the heavy element distribution in these stars. Aims: We attempt to study the effects of local and global metallicity variations on the excitation mechanism of high order p-modes in A star models. Methods: We developed stellar evolutionary models to describe magnetic A stars with different global metallicity or local metal accumulation profiles. These models were computed with CLES (“Code Liègeois d'évolution stellaire”), and the stability of our models was assessed with the non-adiabatic oscillation code MAD. Results: Our models reproduce the blue edge of the roAp star instability strip, but generate a red edge hotter than the observed one, regardless of metallicity. Surprisingly, we find that an increase in opacity inside the driving region can produce a lower amount of driving, which we refer to as the “inverse κ-mechanism”.

  7. RO concentrate minimization by electrodialysis: techno-economic analysis and environmental concerns.

    PubMed

    Zhang, Yang; Ghyselbrecht, Karel; Vanherpe, Ruben; Meesschaert, Boudewijn; Pinoy, Luc; Van der Bruggen, Bart

    2012-09-30

    This paper presents a systematic techno-economical analysis and an environmental impact evaluation of a reverse osmosis (RO) concentrate treatment process using electrodialysis (ED) in view of environmental management of brine discharges. The concentrate originates from a secondary effluent treated by RO. Without any treatment, the concentrate would have to be discharged; this is compared in this study to the costs and benefits of an effective treatment method in a pilot scale ED plant. A technical analysis was done both on lab scale and pilot scale for the determination of operational and maintenance costs for the ED installation at the required conditions of process performance and safety. Subsequently, an economical analysis was done to calculate the cost of the different parts of the ED system. It was shown that an operational cost of 0.19 EUR m(-3) can be achieved, assuming that the ED concentrate is to decarbonated at pH 6.0 to prevent membrane scaling. Finally, environmental impact issues were calculated and discussed for the overall system. Results imply that if renewable energy is applied for the ED power source, CO(2) emission from membrane processes can be much less than from the conventional treatment methods. PMID:22579771

  8. Novel cost-effective PON-to-RoF photonic bridge for multigigabit access networks.

    PubMed

    Aldaya, Ivan; Campuzano, Gabriel; Castañón, Gerardo; Gosset, Christophe

    2013-12-30

    Telecommunication operators are investing significant resources in developing passive optical networks (PONs) to meet the increasing capacity requirements. Therefore, wireless transmission has become the bottleneck for the wireless broadband internet access due to the spectrum saturation. This issue can be solved taking advantage of the huge portions of unused spectrum at high-microwave / millimeter-wave (mm-wave) bands, but their generation is power consuming. Radio over fiber (RoF) is a cost-efficient solution for the distribution of high-frequency broadband signals to remote base stations. We present a novel photonic PON-to-RoF bridge based on heterodyning a PON signal with an unmodulated tone generated by an independent laser. The proposed scheme is transparent to modulation format and can generate RF signals in the entire microwave band. The feasibility of the bridge is experimentally shown converting a 2-Gbps orthogonal frequency division multiplexing PON signal using inexepensive distributed feedback lasers, whose phase noise is cancelled employing an envelope detection based mobile terminal. PMID:24514776

  9. Ab initio ro-vibronic spectroscopy of SiCCl (X{sup ~2}Π)

    SciTech Connect

    Brites, Vincent; Mitrushchenkov, Alexander O.; Léonard, Céline; Peterson, Kirk A.

    2014-07-21

    The full dimensional potential energy surfaces of the {sup 2}A{sup ′} and {sup 2}A{sup ′′} electronic components of X{sup ~2}Π SiCCl have been computed using the explicitly correlated coupled cluster method, UCCSD(T)-F12b, combined with a composite approach taking into account basis set incompleteness, core-valence correlation, scalar relativity, and higher order excitations. The spin-orbit and dipole moment surfaces have also been computed ab initio. The ro-vibronic energy levels and absorption spectrum at 5 K have been determined from variational calculations. The influence of each correction on the fundamental frequencies is discussed. An assignment is proposed for bands observed in the LIF experiment of Smith et al. [J. Chem. Phys. 117, 6446 (2002)]. The overall agreement between the experimental and calculated ro-vibronic levels is better than 7 cm{sup −1} which is comparable with the 10–20 cm{sup −1} resolution of the emission spectrum.

  10. Accuracy Assessments of ATMS Upper-Level Temperature Sounding Channels Using COSMIC RO Data

    NASA Astrophysics Data System (ADS)

    Lin, L.; Weng, F.; Zou, X.

    2012-12-01

    The Advanced Technology Microwave Sounder (ATMS) on board Suomi National Polar-orbiting Partnership (NPP) is a 22-channel passive microwave radiometer that can provide high-spatial-resolution data for generating temperature and moisture soundings in cloudy conditions. Global Positioning System (GPS) radio occultation (RO) data have high vertical resolution, are not affected by clouds, and are most accurate from 8 to 30 km, making them ideally suited for estimating the precision of ATMS measurements for upper level temperature sounding channels. In this study, Constellation Observing System for Meteorology, Ionosphere, and Climate (COSMIC) RO data are collocated with ATMS observation from December 10, 2011 to June 30, 2012. Compared with GPS simulations using the U.S. Joint Center of Satellite Data Assimilation (JCSDA) Community Radiative Transfer Model (CRTM), the global biases of brightness temperatures from ATMS measurements are within 0.5K for channels 6 to 13 for clear-sky data over ocean. This value is well within the pre-launch specification, indicating that the ATMS upper level temperature sounding channels have high accuracy. The monthly variation and angular dependence of ATMS bias are also examined.

  11. 3D atmospheric structure of the prototypical roAp star HD 24712 (HR1217)

    NASA Astrophysics Data System (ADS)

    Lüftinger, T.; Kochukhov, O.; Ryabchikova, T.; Piskunov, N.; Weiss, W. W.; Ilyin, I.

    2008-04-01

    The first analysis of the structure of the surface magnetic field of a rapidly oscillating Ap (roAp) star is presented. We obtain information about abundance distributions of a number of chemical elements on the surface of the prototypical roAp star HD 24712 and about magnetic field geometry. Inverting rotationally modulated spectra in Stokes parameters I and V obtained with the SOFIN spectropolarimeter attached to the NOT, we recover surface abundance structures of sixteen different chemical elements, including Mg, Ca, Sc, Ti, Cr, Fe, Co, Ni, Y, La, Ce, Pr, Nd, Gd, Tb, and Dy. Our analysis reveal a pure dipolar structure of the stellar magnetic field and surprising and unexpected correlations of the various elemental surface abundance structures to this field geometry. Stratification analysis at phases of both magnetic extrema enable us to obtain the vertical dimension in the atmosphere of HD 24712. High time resolved spectroscopic data and observations obtained with the MOST space photometer give us the possibility to compare (Lüftinger, 2007) our results to detailed pulsational analysis.

  12. Physical state of the deep interior of the CoRoT-7b exoplanet

    NASA Astrophysics Data System (ADS)

    Wagner, Frank W.; Sohl, Frank; Rückriemen, Tina; Rauer, Heike

    2011-11-01

    The present study takes the CoRoT-7b exoplanet as an analogue for massive terrestrial planets to investigate conditions, under which intrinsic magnetic fields could be sustained in liquid cores. We examine the effect of depth-dependent transport parameters (e.g., activation volume of mantle rock) on a planet's thermal structure and the related heat flux across the core mantle boundary. For terrestrial planets more massive than the Earth, our calculations suggest that a substantial part of the lowermost mantle is in a sluggish convective regime, primarily due to pressure effects on viscosity. Hence, we find substantially higher core temperatures than previously reported from parameterized convection models. We also discuss the effect of melting point depression in the presence of impurities (e.g., sulfur) in iron-rich cores and compare corresponding melting relations to the calculated thermal structure. Since impurity effects become less important at the elevated pressure and temperature conditions prevalent in the deep interior of CoRoT-7b, iron-rich cores are likely solid, implying that a self-sustained magnetic field would be absent.

  13. Heterochromatin dynamics during the differentiation process revealed by the DNA methylation reporter mouse, MethylRO.

    PubMed

    Ueda, Jun; Maehara, Kazumitsu; Mashiko, Daisuke; Ichinose, Takako; Yao, Tatsuma; Hori, Mayuko; Sato, Yuko; Kimura, Hiroshi; Ohkawa, Yasuyuki; Yamagata, Kazuo

    2014-06-01

    In mammals, DNA is methylated at CpG sites, which play pivotal roles in gene silencing and chromatin organization. Furthermore, DNA methylation undergoes dynamic changes during development, differentiation, and in pathological processes. The conventional methods represent snapshots; therefore, the dynamics of this marker within living organisms remains unclear. To track this dynamics, we made a knockin mouse that expresses a red fluorescent protein (RFP)-fused methyl-CpG-binding domain (MBD) protein from the ROSA26 locus ubiquitously; we named it MethylRO (methylation probe in ROSA26 locus). Using this mouse, we performed RFP-mediated methylated DNA immunoprecipitation sequencing (MeDIP-seq), whole-body section analysis, and live-cell imaging. We discovered that mobility and pattern of heterochromatin as well as DNA methylation signal intensity inside the nuclei can be markers for cellular differentiation status. Thus, the MethylRO mouse represents a powerful bioresource and technique for DNA methylation dynamics studies in developmental biology, stem cell biology, as well as in disease states. PMID:24936475

  14. MOST observations of the roAp stars HD 9289, HD 99563, and HD 134214

    NASA Astrophysics Data System (ADS)

    Gruberbauer, M.; Huber, D.; Kuschnig, R.; Weiss, W. W.; Guenther, D. B.; Matthews, J. M.; Moffat, A. F. J.; Rowe, J. F.; Rucinski, S. M.; Sasselov, D.; Fischer, M.

    2011-06-01

    We report on the analysis of high-precision space-based photometry of the roAp (rapidly oscillating Ap) stars HD 9289, HD 99563, and HD 134214. All three stars were observed by the MOST satellite for more than 25 days, allowing unprecedented views of their pulsation. We find previously unknown candidate frequencies in all three stars. We establish the rotation period of HD 9289 (8.5 d) for the first time and show that the star is pulsating in two modes that show different mode geometries. We present a detailed analysis of HD 99563's mode multiplet and find a new candidate frequency that appears to be independent of the previously known mode. Finally, we report on 11 detected pulsation frequencies in HD 134214, nine of which have never before been detected in photometry, and three of which are completely new detections. Thanks to the unprecedentedly small frequency uncertainties, the p-mode spectrum of HD 134214 can be seen to have a well-defined large frequency spacing similar to the well-studied roAp star HD 24712 (HR 1217). Based on data from the MOST satellite, a Canadian Space Agency mission, jointly operated by Dynacon Inc., the University of Toronto Institute for Aerospace Studies and the University of British Columbia, with the assistance of the University of Vienna.

  15. Heterochromatin Dynamics during the Differentiation Process Revealed by the DNA Methylation Reporter Mouse, MethylRO

    PubMed Central

    Ueda, Jun; Maehara, Kazumitsu; Mashiko, Daisuke; Ichinose, Takako; Yao, Tatsuma; Hori, Mayuko; Sato, Yuko; Kimura, Hiroshi; Ohkawa, Yasuyuki; Yamagata, Kazuo

    2014-01-01

    Summary In mammals, DNA is methylated at CpG sites, which play pivotal roles in gene silencing and chromatin organization. Furthermore, DNA methylation undergoes dynamic changes during development, differentiation, and in pathological processes. The conventional methods represent snapshots; therefore, the dynamics of this marker within living organisms remains unclear. To track this dynamics, we made a knockin mouse that expresses a red fluorescent protein (RFP)-fused methyl-CpG-binding domain (MBD) protein from the ROSA26 locus ubiquitously; we named it MethylRO (methylation probe in ROSA26 locus). Using this mouse, we performed RFP-mediated methylated DNA immunoprecipitation sequencing (MeDIP-seq), whole-body section analysis, and live-cell imaging. We discovered that mobility and pattern of heterochromatin as well as DNA methylation signal intensity inside the nuclei can be markers for cellular differentiation status. Thus, the MethylRO mouse represents a powerful bioresource and technique for DNA methylation dynamics studies in developmental biology, stem cell biology, as well as in disease states. PMID:24936475

  16. [Phase II study of recombinant leukocyte A interferon (Ro 22-8181) in skin malignant tumors].

    PubMed

    1985-04-01

    A clinical phase II study of recombinant human leukocyte interferon A (rIFN-alpha A, Ro 22-8181) for various skin malignant tumors was jointly conducted at nine medical institutes across the country in order to study its clinical effect and side effects. Patients received Ro 22-8181 alone in doses ranging from 3 X 10(6) U/day to 50 X 10(6) U/day either by intramuscular injection or by local injection. Good response was obtained in one (4.8%) of 21 patients treated by intramuscular injection and in 26 (72.2%) of 36 patients treated by local injection. The percentage of good responses achieved by local injection for individual diseases was 55.6% (5/9) for metastatic malignant skin melanoma, 100% (11/11) for cutaneous malignant lymphoma, 100% (5/5) for extramammary Paget's disease, 75% (3/4) for intraepidermal cancer and 50% (2/4) for metastatic skin cancer. Main side effects were fever, anorexia, general fatigue, chills, nausea and vomiting. Abnormal laboratory data included leukopenia, and elevation of GOT and GPT, although their incidence was lower with local injection than with intramuscular injection. Side effects were mostly improved by reduction of the dose or discontinuation of the treatment. PMID:2985007

  17. Tailoring the structure of thin film nanocomposite membranes to achieve seawater RO membrane performance.

    PubMed

    Lind, Mary Laura; Eumine Suk, Daniel; Nguyen, The-Vinh; Hoek, Eric M V

    2010-11-01

    Herein we report on the formation and characterization of pure polyamide thin film composite (TFC) and zeolite-polyamide thin film nanocomposite (TFN) reverse osmosis (RO) membranes. Four different physical-chemical post-treatment combinations were applied after the interfacial polymerization reaction to change the molecular structure of polyamide and zeolite-polyamide thin films. Both TFC and TFN hand-cast membranes were more permeable, hydrophilic, and rough than a commercial seawater RO membrane. Salt rejection by TFN membranes was consistently below that of hand-cast TFC membranes; however, two TFN membranes exhibited 32 g/L NaCl rejections above 99.4%, which was better than the commercial membrane under the test conditions employed. The nearly defect-free TFN films that produced such high rejections were achieved only with wet curing, regardless of other post-treatments. Polyamide films formed in the presence of zeolite nanoparticles were less cross-linked than similarly cast pure polyamide films. At the very low nanoparticle loadings evaluated, differences between pure polyamide and zeolite-polyamide membrane water and salt permeability correlated weakly with extent of cross-linking of the polyamide film, which suggests that defects and molecular-sieving largely govern transport through zeolite-polyamide thin film nanocomposite membranes. PMID:20942398

  18. How administration of the beta-blocker propranolol prior to extinction can prevent the return of fear

    PubMed Central

    Kroes, Marijn CW; Tona, Klodiana-Daphne; den Ouden, Hanneke EM; Vogel, Susanne; van Wingen, Guido A.; Fernández, Guillén

    2015-01-01

    Combining beta-blockers with exposure-therapy has been advocated to reduce fear, yet experimental studies combining beta-blockers with memory reactivation have had contradictory results. We explored how beta-blockade might affect the course of safety learning and the subsequent return of fear in a double-blind placebo-controlled functional magnetic resonance imaging study in humans (N=46). A single dose of propranolol prior to extinction learning caused a loss of conditioned fear responses, and prevented the subsequent return of fear and decreased explicit memory for the fearful events in the absence of drug. Fear-related neural responses were persistently attenuated in the dorsal medial prefrontal cortex (dmPFC), increased in the hippocampus 24h later, and correlated with individual behavioral indices of fear. Prediction error-related responses in the ventral striatum persisted during beta-blockade. We suggest that this pattern of results is most consistent with a model where beta-blockade can prevent the return of fear by i) reducing retrieval of fear memory, via the dmPFC and ii) increasing contextual safety learning, via the hippocampus. Our findings suggest that retrieval of fear memory and contextual safety learning form potential mnemonic target mechanisms to optimize exposure-based therapy with beta-blockers. PMID:26462618

  19. Lack of rebound during intermittent transdermal treatment with glyceryl trinitrate in patients with stable angina on background beta blocker.

    PubMed Central

    Holdright, D R; Katz, R J; Wright, C A; Sparrow, J L; Sullivan, A K; Cunningham, A D; Fox, K M

    1993-01-01

    OBJECTIVE--To assess whether intermittent transdermal treatment with glyceryl trinitrate causes clinically significant rebound in patients maintained on beta blockers for stable angina pectoris. DESIGN--Serial treadmill exercise testing in a double blind, randomised, placebo controlled cross over trial. Baseline exercise testing was performed at 0900 and 1100 at visit 1. Transdermal glyceryl trinitrate patches releasing 15 mg/24 h were applied at 2200 the evening before visits 2 and 3, and exercise testing was performed at 0900 the next morning. The patch was removed and replaced with either an identical patch or matching placebo and exercise tests were repeated two hours later. The alternative treatment was given at visit 3. SETTING--Tertiary referral centre. PATIENTS--14 patients with stable angina pectoris maintained on beta blocker treatment alone. MAIN OUTCOME MEASURES--Time to angina, 1 mm ST segment depression, and total time, together with heart rate, systolic blood pressure, and rate-pressure product. RESULTS--Active treatment improved treadmill performance at 0900 and 1100. Time to angina, time to 1 mm ST segment depression, and total time fell significantly on placebo compared with the 0900 exercise test on active treatment, but were not significantly different to the baseline exercise test either. CONCLUSIONS--Intermittent transdermal treatment with glyceryl trinitrate is not associated with the rebound phenomenon in patients maintained on beta blockers for stable angina pectoris. PMID:8096389

  20. Cardiovascular effects of alpha-blockers used for the treatment of symptomatic BPH: impact on safety and well-being.

    PubMed

    de Mey, C

    1998-01-01

    Alpha-adrenoceptor antagonists (alpha-blockers) are efficacious in treating lower urinary tract symptoms (LUTS) suggestive of benign prostatic obstruction (BPO), also termed symptomatic benign prostatic hyperplasia (BPH), causing bladder outlet obstruction (BOO). There is little difference among the various alpha-blockers in terms of efficacy in treating LUTS. However, conventional quinazoline derivatives such as terazosin, doxazosin and alfuzosin, originally developed for hypertension, have inherent cardiovascular extension effects, which influence the well being and safety of patients with LUTS by impairing physiological blood pressure (BP) control, even when their effect on unchallenged BP may be quite low. Preclinically, tamsulosin, a sulphonamide-substituted phenethylamine, has a relative selectivity for the alpha 1-adrenoceptors of the lower urinary tract. Clinically, this is associated with fewer cardiovascular extension effects with tamsulosin (modified release capsule) 0.4 mg once daily. This allows the use of convenient regimens of 0.4 mg tamsulosin administered once daily after breakfast from initiation of treatment without the need for 'step-up' increases of dose to avoid 'first-dose' hypotension. Extensive investigation, including multiple orthostatic stress testing (which otherwise is unusual in the characterization of alpha-blockers because of their inherent safety), confirms that tamsulosin 0.4 mg definitely carries a lower risk of impaired BP control. PMID:9732825

  1. Impact of β-blocker selectivity on long-term outcomes in congestive heart failure patients with chronic obstructive pulmonary disease

    PubMed Central

    Kubota, Yoshiaki; Asai, Kuniya; Furuse, Erito; Nakamura, Shunichi; Murai, Koji; Tsukada, Yayoi Tetsuou; Shimizu, Wataru

    2015-01-01

    Background Chronic obstructive pulmonary disease (COPD) is present in approximately one-third of all congestive heart failure (CHF) patients, and is a key cause of underprescription and underdosing of β-blockers, largely owing to concerns about precipitating respiratory deterioration. For these reasons, the aim of this study was to evaluate the impact of β-blockers on the long-term outcomes in CHF patients with COPD. In addition, we compared the effects of two different β-blockers, carvedilol and bisoprolol. Methods The study was a retrospective, non-randomized, single center trial. Acute decompensated HF patients with COPD were classified according to the oral drug used at discharge into β-blocker (n=86; carvedilol [n=52] or bisoprolol [n=34]) and non-β-blocker groups (n=46). The primary endpoint was all-cause mortality between the β-blocker and non-β-blocker groups during a mean clinical follow-up of 33.9 months. The secondary endpoints were the differences in all-cause mortality and the hospitalization rates for CHF and/or COPD exacerbation between patients receiving carvedilol and bisoprolol. Results The mortality rate was higher in patients without β-blockers compared with those taking β-blockers (log-rank P=0.039), and univariate analyses revealed that the use of β-blockers was the only factor significantly correlated with the mortality rate (hazard ratio: 0.41; 95% confidence interval: 0.17–0.99; P=0.047). Moreover, the rate of CHF and/or COPD exacerbation was higher in patients treated with carvedilol compared with bisoprolol (log-rank P=0.033). In the multivariate analysis, only a past history of COPD exacerbation significantly increased the risk of re-hospitalization due to CHF and/or COPD exacerbation (adjusted hazard ratio: 3.11; 95% confidence interval: 1.47–6.61; P=0.003). Conclusion These findings support the recommendations to use β-blockers in HF patients with COPD. Importantly, bisoprolol reduced the incidence of CHF and/or COPD

  2. Locating a Plausible Binding Site for an Open-Channel Blocker, GlyH-101, in the Pore of the Cystic Fibrosis Transmembrane Conductance RegulatorS⃞

    PubMed Central

    Ivetac, Anthony; Alexander, Christopher; O'Donnell, Nicolette; Frye, Leah; Sansom, Mark S. P.; Dawson, David C.

    2012-01-01

    High-throughput screening has led to the identification of small-molecule blockers of the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel, but the structural basis of blocker binding remains to be defined. We developed molecular models of the CFTR channel on the basis of homology to the bacterial transporter Sav1866, which could permit blocker binding to be analyzed in silico. The models accurately predicted the existence of a narrow region in the pore that is a likely candidate for the binding site of an open-channel pore blocker such as N-(2-naphthalenyl)-[(3,5-dibromo-2,4-dihydroxyphenyl)methylene]glycine hydrazide (GlyH-101), which is thought to act by entering the channel from the extracellular side. As a more-stringent test of predictions of the CFTR pore model, we applied induced-fit, virtual, ligand-docking techniques to identify potential binding sites for GlyH-101 within the CFTR pore. The highest-scoring docked position was near two pore-lining residues, Phe337 and Thr338, and the rates of reactions of anionic, thiol-directed reagents with cysteines substituted at these positions were slowed in the presence of the blocker, consistent with the predicted repulsive effect of the net negative charge on GlyH-101. When a bulky phenylalanine that forms part of the predicted binding pocket (Phe342) was replaced with alanine, the apparent affinity of the blocker was increased ∼200-fold. A molecular mechanics-generalized Born/surface area analysis of GlyH-101 binding predicted that substitution of Phe342 with alanine would substantially increase blocker affinity, primarily because of decreased intramolecular strain within the blocker-protein complex. This study suggests that GlyH-101 blocks the CFTR channel by binding within the pore bottleneck. PMID:22923500

  3. Effects of RO 60 0175, a 5-HT(2C) receptor agonist, in three animal models of anxiety.

    PubMed

    Kennett, G; Lightowler, S; Trail, B; Bright, F; Bromidge, S

    2000-01-10

    There is some controversy as to whether 5-HT(2C) receptor agonists are anxiogenic or anxiolytic. The effects of the novel 5-HT(2C) receptor agonist, (S)-2-chloro-5-fluoro-indol-1-yl)-1-methyl ethylamine fumarate (RO 60 0175), in three models of anxiety were therefore tested. RO 60 0175 was found to induce hypolocomotion in rats at doses greater than 0.5 mg/kg s.c., an effect reversed by the selective 5-HT(2C) receptor antagonist, SB-242084. RO 60 0175 did not elicit anxiolytic-like responses in the social interaction test under high light unfamiliar conditions, but suppressed both time spent in social interaction and locomotion at doses of 1 and 3 mg/kg s.c., suggesting a sedative response. In the Vogel conflict test, RO 60 0175 had no significant action on the number of shocks taken. In the Geller-Seifter test, RO 60 0175 (0.3 and 1 mg/kg s.c.) simultaneously reduced both unpunished and punished lever pressing, a profile consistent with sedation. Finally, RO 60 0175 was tested in a rat social interaction test under low light familiar conditions optimal for the detection of anxiogenic-like responses. At 1 and 3 mg/kg s.c., RO 60 0175 reduced both time spent in social interaction and concurrent locomotion, a profile more consistent with sedation than anxiogenesis. In conclusion, RO 60 0175 induced sedative-like responses via 5-HT(2C) receptor activation, but was neither anxiolytic, nor clearly anxiogenic at the doses tested. PMID:10650160

  4. Enzymatic cleaning of biofouled thin-film composite reverse osmosis (RO) membrane operated in a biofilm membrane reactor.

    PubMed

    Khan, Mohiuddin; Danielsen, Steffen; Johansen, Katja; Lorenz, Lindsey; Nelson, Sara; Camper, Anne

    2014-02-01

    Application of environmentally friendly enzymes to remove thin-film composite (TFC) reverse osmosis (RO) membrane biofoulants without changing the physico-chemical properties of the RO surface is a challenging and new concept. Eight enzymes from Novozyme A/S were tested using a commercially available biofouling-resistant TFC polyamide RO membrane (BW30, FilmTech Corporation, Dow Chemical Co.) without filtration in a rotating disk reactor system operated for 58 days. At the end of the operation, the accumulated biofoulants on the TFC RO surfaces were treated with the three best enzymes, Subtilisin protease and lipase; dextranase; and polygalacturonase (PG) based enzymes, at neutral pH (~7) and doses of 50, 100, and 150 ppm. Contact times were 18 and 36 h. Live/dead staining, epifluorescence microscopy measurements, and 5 μm thick cryo-sections of enzyme and physically treated biofouled membranes revealed that Subtilisin protease- and lipase-based enzymes at 100 ppm and 18 h contact time were optimal for removing most of the cells and proteins from the RO surface. Culturable cells inside the biofilm declined by more than five logs even at the lower dose (50 ppm) and shorter incubation period (18 h). Subtilisin protease- and lipase-based enzyme cleaning at 100 ppm and for 18 h contact time restored the hydrophobicity of the TFC RO surface to its virgin condition while physical cleaning alone resulted in a 50° increase in hydrophobicity. Moreover, at this optimum working condition, the Subtilisin protease- and lipase-based enzyme treatment of biofouled RO surface also restored the surface roughness measured with atomic force microscopy and the mass percentage of the chemical compositions on the TFC surface estimated with X-ray photoelectron spectroscopy to its virgin condition. This novel study will encourage the further development and application of enzymes to remove biofoulants on the RO surface without changing its surface properties. PMID:24329165

  5. The Roles of Tidal Evolution and Evaporative Mass Loss in the Origin of CoRoT-7 b

    NASA Technical Reports Server (NTRS)

    Jackson, Brian; Miller, Neil; Barnes, Rory; Raymond, Sean N.; Fortney, Jonathan J.; Greenberg, Richard

    2010-01-01

    CoRoT-7 b is the first confirmed rocky exoplanet, but, with an orbital semimajor axis of 0.0172 au, its origins may be unlike any rocky planet in our Solar System. In this study, we consider the roles of tidal evolution and evaporative mass loss in CoRoT-7 b's history, which together have modified the planet's mass and orbit. If CoRoT-7 b has always been a rocky body, evaporation may have driven off almost half its original mass, but the mass loss may depend sensitively on the extent of tidal decay of its orbit. As tides caused CoRoT-7 b's orbit to decay, they brought the planet closer to its host star, thereby enhancing the mass loss rate. Such a large mass loss also suggests the possibility that CoRoT-7 b began as a gas giant planet and had its original atmosphere completely evaporated. In this case, we find that CoRoT-7 b's original mass probably did not exceed 200 Earth masses (about two-third of a Jupiter mass). Tides raised on the host star by the planet may have significantly reduced the orbital semimajor axis, perhaps causing the planet to migrate through mean-motion resonances with the other planet in the system, CoRoT-7 c. The coupling between tidal evolution and mass loss may be important not only for CoRoT-7 b but also for other close-in exoplanets, and future studies of mass loss and orbital evolution may provide insight into the origin and fate of close-in planets, both rocky and gaseous.

  6. Sclera-Choroid-RPE Transport of Eight β-Blockers in Human, Bovine, Porcine, Rabbit, and Rat Models

    PubMed Central

    Kadam, Rajendra S.; Cheruvu, Narayan P. S.; Edelhauser, Henry F.

    2011-01-01

    Purpose. To determine the influence of drug lipophilicity, ocular pigmentation, and species differences on transscleral solute transport. Methods. The transport of eight β-blockers across excised sclera/sclera-choroid-RPE (SCRPE) of albino rabbit, pigmented rabbit, human, porcine, and bovine eyes was determined over 6 hours. The ex vivo transscleral β-blocker transport to the vitreous at the end of 6 hours was determined in euthanatized, pigmented Brown Norway rats. The thicknesses of the sclera and SCRPE and the melanin content in choroid-RPE (CRPE) were measured to determine whether species differences in drug transport can be explained on this basis. Results. Solute lipophilicity inversely correlated with the SCRPE cumulative percentage of transport in all species (R2 ≥ 0.80). The CRPE impeded the SCRPE transport of all β-blockers (51%–64% resistance in the rabbits; 84%–99.8% in the bovine and porcine eyes) more than the sclera, with the impedance increasing with lipophilicity. SCRPE transport followed the trend albino rabbit > pigmented rabbit > human > porcine > bovine, and a cross-species comparison showed good Spearman's rho correlation (R2 ≥ 0.85). Bovine (R2 = 0.84), porcine (R2 = 0.84), and human (R2 = 0.71) SCRPE transport was more predictive than that in the rabbit models (R2 = 0.60–0.61) of transscleral solute transport to the vitreous in rats. The CRPE concentrations were higher in pigmented rabbits than in albino rabbits. The melanin content of the CRPE exhibited the trend albino rabbit ≪ pigmented rabbit < porcine ∼ bovine < rat. Normalization to scleral thickness abolished the species differences in scleral transport. Normalization to SCRPE thickness and melanin content significantly reduced species differences in SCRPE transport. Conclusions. Owing to the presence of pigment and drug binding, choroid-RPE is the principal barrier to transscleral β-blocker transport, with the barrier being more significant for lipophilic β-blockers

  7. An Evolutionarily Conserved Domain of roX2 RNA Is Sufficient for Induction of H4-Lys16 Acetylation on the Drosophila X Chromosome

    PubMed Central

    Park, Seung-Won; Kang, Yool Ie; Sypula, Joanna G.; Choi, Jiyeon; Oh, Hyangyee; Park, Yongkyu

    2007-01-01

    The male-specific lethal (MSL) complex, which includes two noncoding RNA on X (roX)1 and roX2 RNAs, induces histone H4-Lys