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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. 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

  4. 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

  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. 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

  5. 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

  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. 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

  8. 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

  9. 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

  10. 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.

  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. 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

  13. 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

  14. 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

  15. 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

  16. 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

  17. 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

  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. 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

  2. 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…

  3. 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.

  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. 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

  6. 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

  7. [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

  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. 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

  10. 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

  11. 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

  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. 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

  15. 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.

  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. 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

  19. 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.

  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. 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...

  9. 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.

  10. 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.

  11. 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

  12. 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

  13. 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.

  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. 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

  17. 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

  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. 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

  1. 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

  2. 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

  3. 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.

  4. 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.

  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

    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.

  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. 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

  15. 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

  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. 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.

  20. 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, ...).

  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. 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.

  5. 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

  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. 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

  10. 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.

  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. 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

  14. 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

  15. 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

  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. 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

  19. 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

  20. 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

  1. 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

  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. 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

  9. 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

  10. 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

  11. 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

  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. 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

  15. [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

  16. 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

  17. 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

  18. 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

  19. 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

  20. 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

  1. 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

  2. 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

  3. 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

  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. 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

  3. 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

  4. 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).

  5. 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

  6. 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

  7. 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

  8. 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

  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. 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

  14. 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

  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. 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

  20. 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

  1. 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

  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. 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

  4. 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

  5. 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

  6. 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.

  7. 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

  8. 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

  9. 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

  10. 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

  11. 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

  12. [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

  13. 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

  14. 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

  15. 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

  16. 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.

  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. 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

  3. 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.

  4. 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

  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. 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

  12. 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

  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. 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

  5. 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.

  6. 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

  7. 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

  8. 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

  9. 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

  10. 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