Serotonin reuptake inhibitors and cardiovascular disease

Selective serotonin re-uptake inhibiting drugs (SSRIs) are widely used for endogenous depression. In addition to depleting the nerve terminals of serotonin they also lower blood platelet serotonin levels. Platelet aggregation is a major component of acute coronary syndromes, including sudden death, and also of limb ischaemia. Platelet-released serotonin causes constriction of diseased blood vessels. The recent literature has revealed a number of reports of association between the treatment of depression with SSRIs and reduced events caused by intra-arterial thrombosis. The effects of serotonin and serotonin depletion upon intracoronary thrombosis, diseased blood vessels, blood platelets and bleeding are discussed with recommendations for future research into the potential cardiovascular benefits of SSRIs and serotonin 5HT2A antagonists

Coronary vessel supersensitivity to noradrenaline in the presence of chronic sympathetic denervation.

It is well known that there is usually super-sensitivity to the normal neurotransmitter in chronically denervated organs. The present consensus of opinion is that there is no super-sensitivity of response of myocardial arteriolar resistance vessels to nor-adrenaline after chronic sympathetic denervation; this opinion was tested. We re-analysed the data in the literature on innervated myocardium, plus the effect of chronic sympathetic myocardial denervation induced by surgery plus phenol application. We found that the opinion is based on studies of isolated epicardial arteries. Studies of resistance vessels mostly ignore an important confounding factor, in that myocardial blood flow (MBF) within myocardium is heterogeneous under all circumstances. This heterogeneity is partly related to similar heterogeneity in myocardial oxygen consumption (MVO2), and partly to heterogeneity in local noradrenaline, as assessed by 11C-hydroxyephidrine positron emission tomography. The local volume of distribution of 11C-hydroxyephedrine in innervated myocardium was inversely correlated to local MBF, at the same perfusion pressure, i.e., increasing vasoconstriction with increasing tissue noradrenaline. In chronically denervated myocardium, local MBF was lower for any given amount of noradrenaline, showing the existence of supersensitivity of the resistance vessels. This factor may have a deletereous effect in diabetic patients with cardiac autonomic neuropathy

SNhunt151: An explosive event inside a dense cocoon

Indexación: Scopus.We thank S. Spiro, R. Rekola, A. Harutyunyan, and M. L. Graham for their help with the observations. We are grateful to the collaboration of Massimo Conti, Giacomo Guerrini, Paolo Rosi, and Luz Marina Tinjaca Ramirez from the Osservatorio Astronomico Provinciale di Montarrenti. The staffs at the different observatories provided excellent assistance with the observations.The research leading to these results has received funding from the European Union Seventh Framework Programme (FP7/2007-2013) under grant agreement No. 267251, ‘Astronomy Fellowships in Italy’ (AstroFIt)’. NE-R acknowledges financial support from MIUR PRIN 2010-2011, ‘The Dark Universe and the Cosmic Evolution of Baryons: From Current Surveys to Euclid’. NE-R, AP, SB, LT, MT, and GP are partially supported by the PRIN-INAF 2014 (project ‘Transient Universe: Unveiling New Types of Stellar Explosions with PESSTO’). GP acknowledges support provided by the Millennium Institute of Astrophysics (MAS) through grant IC120009 of the Programa Iniciativa Cientíifica Milenio del Ministerio de Economía, Fomento y Turismo de Chile. TK acknowledges financial support from the Emil Aaltonen Foundation. CRTS was supported by the NSF grants AST-0909182, AST-1313422, and AST-1413600. AVF is grateful for generous financial assistance from the Christopher R. Redlich Fund, the TABASGO Foundation, the Miller Institute for Basic Research in Science (UC Berkeley), and NASA/HST grant GO-14668 from the Space Telescope Science Institute, which is operated by AURA, Inc. under NASA contract NAS5-26555. The work of AVF was conducted in part at the Aspen Center for Physics, which is supported by NSF grantPHY-1607611; he thanks the Center for its hospitality during the neutron stars workshop in June and July 2017. NE-R acknowledges the hospitality of the ‘Institut de Ciències de l'Espai (CSIC), where this work was completed.This research is based on observations made with the Nordic Optical Telescope, operated by the Nordic Optical Telescope Scientific Association at the Observatorio del Roque de los Muchachos, La Palma, Spain, of the Instituto de Astrofísica de Canarias; the Gran Telescopio Canarias (GTC), installed in the Spanish Observatorio del Roque de los Muchachos of the Instituto de Astrofísica de Canarias, on the island of La Palma; the Italian Telescopio Nazionale Galileo (TNG), operated on the island of La Palma by the Fundaci Galileo Galilei of the INAF (Istituto Nazionale di Astrofisica) at the Spanish Observatorio del Roque de los Muchachos of the Instituto de Astrofísica de Canarias; the Liverpool Telescope, operated on the island of La Palma by Liverpool John Moores University in the Spanish Observatorio del Roque de los Muchachos of the Instituto de Astrofísica de Canarias with financial support from the UK Science and Technology Facilities Council; the 1.82-m Copernico Telescope and the Schmidt 67/92 cm of INAF-Asiago Observatory; the Catalina Real Time Survey (CRTS) Catalina Sky Survey (CSS) 0.7-m Schmidt Telescope; and the Las Cumbres Observatory (LCO) network. This work is also based in part on archival data obtained with the NASA/ESA Hubble Space Telescope, obtained from the Data Archive at the Space Telescope Science Institute (STScI), which is operated by the Association of Universities for Research in Astronomy (AURA), Inc., under NASA contract NAS5-26555; the Spitzer Space Telescope, which is operated by the Jet Propulsion Laboratory, California Institute of Technology, under a contract with NASA (support was provided by NASA through an award issued by JPL/Caltech); and the Swift telescope.This work has made use of the NASA/IPAC Extragalactic Database (NED), which is operated by the Jet Propulsion Laboratory, California Institute of Technology, under contract with NASA.SNhunt151 was initially classified as a supernova (SN) impostor (nonterminal outburst of a massive star). It exhibited a slow increase in luminosity, lasting about 450 d, followed by a major brightening that reaches M V ≈ -18 mag. No source is detected to M V ≳ -13 mag in archival images at the position of SNhunt151 before the slow rise. Low-to-mid-resolution optical spectra obtained during the pronounced brightening show very little evolution, being dominated at all times by multicomponent Balmer emission lines, a signature of interaction between the material ejected in the new outburst and the pre-existing circumstellar medium. We also analysed mid-infrared images from the Spitzer Space Telescope, detecting a source at the transient position in 2014 and 2015. Overall, SNhunt151 is spectroscopically a Type IIn SN, somewhat similar to SN 2009ip. However, there are also some differences, such as a slow pre-discovery rise, a relatively broad light-curve peak showing a longer rise time (~50 d), and a slower decline, along with a negligible change in the temperature around the peak (T ≤ 10 4 K). We suggest that SNhunt151 is the result of an outburst, or an SN explosion, within a dense circumstellar nebula, similar to those embedding some luminous blue variables like η Carinae and originating from past mass-loss events. © 2017 The Author(s).https://academic.oup.com/mnras/article/475/2/2614/479530

A serendipitous all sky survey for bright objects in the outer solar system

We use seven yearʼs worth of observations from the Catalina Sky Survey and the Siding Spring Survey covering most of the northern and southern hemisphere at galactic latitudes higher than 20° to search for serendipitously imaged moving objects in the outer solar system. These slowly moving objects would appear as stationary transients in these fast cadence asteroids surveys, so we develop methods to discover objects in the outer solar system using individual observations spaced by months, rather than spaced by hours, as is typically done. While we independently discover eight known bright objects in the outer solar system, the faintest having $V=19.8\pm 0.1,$ no new objects are discovered. We find that the survey is nearly 100% efficient at detecting objects beyond 25 AU for $V\lesssim 19.1$ ($V\lesssim 18.6$ in the southern hemisphere) and that the probability that there is one or more remaining outer solar system object of this brightness left to be discovered in the unsurveyed regions of the galactic plane is approximately 32%

Data challenges of time domain astronomy

Astronomy has been at the forefront of the development of the techniques and methodologies of data intensive science for over a decade with large sky surveys and distributed efforts such as the Virtual Observatory. However, it faces a new data deluge with the next generation of synoptic sky surveys which are opening up the time domain for discovery and exploration. This brings both new scientific opportunities and fresh challenges, in terms of data rates from robotic telescopes and exponential complexity in linked data, but also for data mining algorithms used in classification and decision making. In this paper, we describe how an informatics-based approach-part of the so-called "fourth paradigm" of scientific discovery-is emerging to deal with these. We review our experiences with the Palomar-Quest and Catalina Real-Time Transient Sky Surveys; in particular, addressing the issue of the heterogeneity of data associated with transient astronomical events (and other sensor networks) and how to manage and analyze it.Comment: 15 pages, 3 figures, to appear in special issue of Distributed and Parallel Databases on Data Intensive eScienc

A mathematical framework for critical transitions: normal forms, variance and applications

Critical transitions occur in a wide variety of applications including mathematical biology, climate change, human physiology and economics. Therefore it is highly desirable to find early-warning signs. We show that it is possible to classify critical transitions by using bifurcation theory and normal forms in the singular limit. Based on this elementary classification, we analyze stochastic fluctuations and calculate scaling laws of the variance of stochastic sample paths near critical transitions for fast subsystem bifurcations up to codimension two. The theory is applied to several models: the Stommel-Cessi box model for the thermohaline circulation from geoscience, an epidemic-spreading model on an adaptive network, an activator-inhibitor switch from systems biology, a predator-prey system from ecology and to the Euler buckling problem from classical mechanics. For the Stommel-Cessi model we compare different detrending techniques to calculate early-warning signs. In the epidemics model we show that link densities could be better variables for prediction than population densities. The activator-inhibitor switch demonstrates effects in three time-scale systems and points out that excitable cells and molecular units have information for subthreshold prediction. In the predator-prey model explosive population growth near a codimension two bifurcation is investigated and we show that early-warnings from normal forms can be misleading in this context. In the biomechanical model we demonstrate that early-warning signs for buckling depend crucially on the control strategy near the instability which illustrates the effect of multiplicative noise.Comment: minor corrections to previous versio

Temporin L and aurein 2.5 have identical conformations but subtly distinct membrane and antibacterial activities

Frogs such as Rana temporaria and Litoria aurea secrete numerous closely related antimicrobial peptides (AMPs) as an effective chemical dermal defence. Damage or penetration of the bacterial plasma membrane is considered essential for AMP activity and such properties are commonly ascribed to their ability to form secondary amphipathic, α-helix conformations in membrane mimicking milieu. Nevertheless, despite the high similarity in physical properties and preference for adopting such conformations, the spectrum of activity and potency of AMPs often varies considerably. Hence distinguishing apparently similar AMPs according to their behaviour in, and effects on, model membranes will inform understanding of primary-sequence-specific antimicrobial mechanisms. Here we use a combination of molecular dynamics simulations, circular dichroism and patch-clamp to investigate the basis for differing anti-bacterial activities in representative AMPs from each species; temporin L and aurein 2.5. Despite adopting near identical, α-helix conformations in the steady-state in a variety of membrane models, these two AMPs can be distinguished both in vitro and in silico based on their dynamic interactions with model membranes, notably their differing conformational flexibility at the N-terminus, ability to form higher order aggregates and the characteristics of induced ion conductance. Taken together, these differences provide an explanation of the greater potency and broader antibacterial spectrum of activity of temporin L over aurein 2.5. Consequently, while the secondary amphipathic, α-helix conformation is a key determinant of the ability of a cationic AMP to penetrate and disrupt the bacterial plasma membrane, the exact mechanism, potency and spectrum of activity is determined by precise structural and dynamic contributions from specific residues in each AMP sequence

Effectiveness of Metyrapone in Treating Cushing's Syndrome: A Retrospective Multicenter Study in 195 Patients

Background: Cushing's syndrome (CS) is a severe condition with excess mortality and significant morbidity necessitating control of hypercortisolemia. There are few data documenting use of the steroidogenesis inhibitor metyrapone for this purpose. Objective: The objective was to assess the effectiveness of metyrapone in controlling cortisol excess in a contemporary series of patients with CS. Design: This was designed as a retrospective, multicenter study. Setting: Thirteen University hospitals were studied. Patients: We studied a total of 195 patients with proven CS: 115 Cushing's disease, 37 ectopic ACTH syndrome, 43 ACTH-independent disease (adrenocortical carcinoma 10, adrenal adenoma 30, and ACTH-independent adrenal hyperplasia 3). Measurements: Measurements included biochemical parameters of activity of CS: mean serum cortisol “day-curve” (CDC) (target 150–300 nmol/L); 9 am serum cortisol; 24-hour urinary free cortisol (UFC). Results: A total of 164/195 received metyrapone monotherapy. Mean age was 49.6 ± 15.7 years; mean duration of therapy 8 months (median 3 mo, range 3 d to 11.6 y). There were significant improvements on metyrapone, first evaluation to last review: CDC (91 patients, 722.9 nmol/L [26.2 μg/dL] vs 348.6 nmol/L [12.6 μg/dL]; P < .0001); 9 am cortisol (123 patients, 882.9 nmol/L [32.0 μg/dL] vs 491.1 nmol/L [17.8 μg/dL]; P < .0001); and UFC (37 patients, 1483 nmol/24 h [537 μg/24 h] vs 452.6 nmol/24 h [164 μg/24 h]; P = .003). Overall, control at last review: 55%, 43%, 46%, and 76% of patients who had CDCs, UFCs, 9 am cortisol less than 331 nmol/L (12.0 μg/dL), and 9 am cortisol less than upper limit of normal/600 nmol/L (21.7 μg/dL). Median final dose: Cushing's disease 1375 mg; ectopic ACTH syndrome 1500 mg; benign adrenal disease 750 mg; and adrenocortical carcinoma 1250 mg. Adverse events occurred in 25% of patients, mostly mild gastrointestinal upset and dizziness, usually within 2 weeks of initiation or dose increase, all reversible. Conclusions: Metyrapone is effective therapy for short- and long-term control of hypercortisolemia in CS

The first ultracompact Roche lobe-filling hot subdwarf binary

We report the discovery of the first short period binary in which a hot subdwarf star (sdOB) fills its Roche lobe and started mass transfer to its companion. The object was discovered as part of a dedicated high-cadence survey of the Galactic Plane named the Zwicky Transient Facility and exhibits a period of Porb=39.3401(1) min, making it the most compact hot subdwarf binary currently known. Spectroscopic observations are consistent with an intermediate He-sdOB star with an effective temperature of Teff=42,400±300 K and a surface gravity of log(g)=5.77±0.05. A high-signal-to noise GTC+HiPERCAM light curve is dominated by the ellipsoidal deformation of the sdOB star and an eclipse of the sdOB by an accretion disk. We infer a low-mass hot subdwarf donor with a mass MsdOB=0.337±0.015 M⊙ and a white dwarf accretor with a mass MWD=0.545±0.020 M⊙. Theoretical binary modeling indicates the hot subdwarf formed during a common envelope phase when a 2.5−2.8 M⊙ star lost its envelope when crossing the Hertzsprung Gap. To match its current Porb, Teff, log(g), and masses, we estimate a post-common envelope period of Porb≈150 min, and find the sdOB star is currently undergoing hydrogen shell burning. We estimate that the hot subdwarf will become a white dwarf with a thick helium layer of ≈0.1 M⊙ and will merge with its carbon/oxygen white dwarf companion after ≈17 Myr and presumably explode as a thermonuclear supernova or form an R CrB star