Effect of Bromocriptine-QR (a Quick-Release Formulation of Bromocriptine Mesylate) on Major Adverse Cardiovascular Events in Type 2 Diabetes Subjects

Background: Bromocriptine-QR (a quick-release formulation of bromocriptine mesylate), a dopamine D2 receptor agonist, is a US Food and Drug Administrration–approved treatment for type 2 diabetes mellitus (T2DM). A 3070-subject randomized trial demonstrated a significant, 40% reduction in relative risk among bromocriptine-QR-treated subjects in a prespecified composite cardiovascular (CV) end point that included ischemic-related (myocardial infarction and stroke) and nonischemic-related (hospitalization for unstable angina, congestive heart failure [CHF], or revascularization surgery) end points, but did not include cardiovascular death as a component of this composite. The present investigation was undertaken to more critically evaluate the impact of bromocriptine-QR on cardiovascular outcomes in this study subject population by (1) including CV death in the above-described original composite analysis and then stratifying this new analysis on the basis of multiple demographic subgroups and (2) analyzing the influence of this intervention on only the “hard” CV end points of myocardial infarction, stroke, and CV death (major adverse cardiovascular events [MACEs]). Methods and Results: Three thousand seventy T2DM subjects on stable doses of ≤2 antidiabetes medications (including insulin) with HbA1c ≤10.0 (average baseline HbA1c=7.0) were randomized 2:1 to bromocriptine-QR (1.6 to 4.8 mg/day) or placebo for a 52-week treatment period. Subjects with heart failure (New York Heart Classes I and II) and precedent myocardial infarction or revascularization surgery were allowed to participate in the trial. Study outcomes included time to first event for each of the 2 CV composite end points described above. The relative risk comparing bromocriptine-QR with the control for the cardiovascular outcomes was estimated as a hazard ratio with 95% confidence interval on the basis of Cox proportional hazards regression. The statistical significance of any between-group difference in the cumulative percentage of CV events over time (derived from a Kaplan–Meier curve) was determined by a log-rank test on the intention-to-treat population. Study subjects were in reasonable metabolic control, with an average baseline HbA1c of 7.0±1.1, blood pressure of 128/76±14/9, and total and LDL cholesterol of 179±42 and 98±32, respectively, with 88%, 77%, and 69% of subjects being treated with antidiabetic, antihypertensive, and antihyperlipidemic agents, respectively. Ninety-one percent of the expected person-year outcome ascertainment was obtained in this study. Respecting the CV-inclusive composite cardiovascular end point, there were 39 events (1.9%) among 2054 bromocriptine-QR-treated subjects versus 33 events (3.2%) among 1016 placebo subjects, yielding a significant, 39% reduction in relative risk in this end point with bromocriptine-QR exposure (P=0.0346; log-rank test) that was not influenced by age, sex, race, body mass index, duration of diabetes, or preexisting cardiovascular disease. In addition, regarding the MACE end point, there were 14 events (0.7%) among 2054 bromocriptine-QR-treated subjects and 15 events (1.5%) among 1016 placebo-treated subjects, yielding a significant, 52% reduction in relative risk in this end point with bromocriptine-QR exposure (P<0.05; log-rank test). Conclusions: These findings reaffirm and extend the original observation of relative risk reduction in cardiovascular adverse events among type 2 diabetes subjects treated with bromocriptine-QR and suggest that further investigation into this impact of bromocriptine-QR is warranted

Discovery of a Variable Star Population in NGC 2808

We have applied the image subtraction method to images of the peculiar, bimodal-horizontal branch globular cluster NGC 2808, taken over a total of six nights over a range of five months. As a result, we have found, for the first time, a sizeable population of variable stars in the crowded inner regions of the cluster, thus raising the known RR Lyrae population in the cluster to a total of 18 stars. In addition, an eclipsing binary and two other variables with periods longer than 1 day were also found. Periods, positions and (differential) light curves are provided for all the detected variables. The Oosterhoff classification of NGC 2808, which has recently been associated with a previously unknown dwarf galaxy in Canis Major, is briefly discussed.Comment: 8 pages, 4 figures. A&A, in pres

Dynamical analysis and constraints for the HD 196885 system

The HD\,196885 system is composed of a binary star and a planet orbiting the primary. The orbit of the binary is fully constrained by astrometry, but for the planet the inclination with respect to the plane of the sky and the longitude of the node are unknown. Here we perform a full analysis of the HD\,196885 system by exploring the two free parameters of the planet and choosing different sets of angular variables. We find that the most likely configurations for the planet is either nearly coplanar orbits (prograde and retrograde), or highly inclined orbits near the Lidov-Kozai equilibrium points, i = 44^{\circ} or i = 137^{\circ} . Among coplanar orbits, the retrograde ones appear to be less chaotic, while for the orbits near the Lidov-Kozai equilibria, those around \omega= 270^{\circ} are more reliable, where \omega_k is the argument of pericenter of the planet's orbit with respect to the binary's orbit. From the observer's point of view (plane of the sky) stable areas are restricted to (I1, \Omega_1) \sim (65^{\circ}, 80^{\circ}), (65^{\circ},260^{\circ}), (115^{\circ},80^{\circ}), and (115^{\circ},260^{\circ}), where I1 is the inclination of the planet and \Omega_1 is the longitude of ascending node.Comment: 10 pages, 7 figures. A&A Accepte

Radial stability of a family of anisotropic Hernquist models with and without a supermassive black hole

We present a method to investigate the radial stability of a spherical anisotropic system that hosts a central supermassive black hole (SBH). Such systems have never been tested before for stability, although high anisotropies have been considered in the dynamical models that were used to estimate the masses of the central putative supermassive black holes. A family of analytical anisotropic spherical Hernquist models with and without a black hole were investigated by means of N-body simulations. A clear trend emerges that the supermassive black hole has a significant effect on the overall stability of the system, i.e. an SBH with a mass of a few percent of the total mass of the galaxy can prevent or reduce the bar instabilities in anisotropic systems. Its mass not only determines the strength of the instability reduction, but also the time in which this occurs. These effects are most significant for models with strong radial anisotropies. Furthermore, our analysis shows that unstable systems with similar SBH but with different anisotropy radii evolve differently: highly radial systems become oblate, while more isotropic models tend to form into prolate structures. In addition to this study, we also present a Monte-Carlo algorithm to generate particles in spherical anisotropic systems.Comment: 16 pages, 12 figures, accepted for publication in MNRAS (some figures have a lowered resolution

Killing Hypoxic Cell Populations in a 3D Tumor Model with EtNBS-PDT

An outstanding problem in cancer therapy is the battle against treatment-resistant disease. This is especially true for ovarian cancer, where the majority of patients eventually succumb to treatment-resistant metastatic carcinomatosis. Limited perfusion and diffusion, acidosis, and hypoxia play major roles in the development of resistance to the majority of front-line therapeutic regimens. To overcome these limitations and eliminate otherwise spared cancer cells, we utilized the cationic photosensitizer EtNBS to treat hypoxic regions deep inside in vitro 3D models of metastatic ovarian cancer. Unlike standard regimens that fail to penetrate beyond ∼150 µm, EtNBS was found to not only penetrate throughout the entirety of large (>200 µm) avascular nodules, but also concentrate into the nodules' acidic and hypoxic cores. Photodynamic therapy with EtNBS was observed to be highly effective against these hypoxic regions even at low therapeutic doses, and was capable of destroying both normoxic and hypoxic regions at higher treatment levels. Imaging studies utilizing multiphoton and confocal microscopies, as well as time-lapse optical coherence tomography (TL-OCT), revealed an inside-out pattern of cell death, with apoptosis being the primary mechanism of cell killing. Critically, EtNBS-based photodynamic therapy was found to be effective against the model tumor nodules even under severe hypoxia. The inherent ability of EtNBS photodynamic therapy to impart cytotoxicity across a wide range of tumoral oxygenation levels indicates its potential to eliminate treatment-resistant cell populations

Timing of birth for women with a twin pregnancy at term: a randomised controlled trial

<p>Abstract</p> <p>Background</p> <p>There is a well recognized risk of complications for both women and infants of a twin pregnancy, increasing beyond 37 weeks gestation. Preterm birth prior to 37 weeks gestation is a recognized complication of a twin pregnancy, however, up to 50% of twins will be born after this time.</p> <p>The aims of this randomised trial are to assess whether elective birth at 37 weeks gestation compared with standard care in women with a twin pregnancy affects the risk of perinatal death, and serious infant complications.</p> <p>Methods/Design</p> <p>Design: Multicentred randomised trial.</p> <p>Inclusion Criteria: women with a twin pregnancy at 36⁶weeks or more without contraindication to continuation of pregnancy.</p> <p>Trial Entry & Randomisation: Following written informed consent, eligible women will be randomised from 36⁺⁶weeks gestation. The randomisation schedule uses balanced variable blocks, with stratification for centre of birth and planned mode of birth. Women will be randomised to either elective birth or standard care.</p> <p>Treatment Schedules: Women allocated to the elective birth group will be planned for elective birth from 37 weeks gestation. Where the plan is for vaginal birth, this will involve induction of labour. Where the plan is for caesarean birth, this will involve elective caesarean section. For women allocated to standard care, birth will be planned for 38 weeks gestation or later. Where the plan is for vaginal birth, this will involve either awaiting the spontaneous onset of labour, or induction of labour if required. Where the plan is for caesarean birth, this will involve elective caesarean section (after 38 and as close to 39 weeks as possible).</p> <p>Primary Study Outcome: A composite of perinatal mortality or serious neonatal morbidity.</p> <p>Sample Size: 460 women with a twin pregnancy to show a reduction in the composite outcome from 16.3% to 6.7% with adjustment for the clustering of twin infants within mothers (p = 0.05, 80% power).</p> <p>Discussion</p> <p>This is a protocol for a randomised trial, the findings of which will contribute information about the optimal time of birth for women with an uncomplicated multiple pregnancy at and beyond 37 weeks gestation.</p> <p>Clinical Trial Registration</p> <p>Current Controlled Trials ISRCTN15761056</p

Stability of prograde and retrograde planets in circular binary systems

We investigate the stability of prograde versus retrograde planets in circular binary systems using numerical simulations. We show that retrograde planets are stable up to distances closer to the perturber than prograde planets. We develop an analytical model to compute the prograde and retrograde mean motion resonances' locations and separatrices. We show that instability is due to single resonance forcing, or caused by nearby resonances' overlap. We validate our results regarding the role of single resonances and resonances' overlap on orbit stability, by computing surfaces of section of the CR3BP. We conclude that the observed enhanced stability of retrograde planets with respect to prograde planets is due to essential differences between the phase-space topology of retrograde versus prograde resonances (at p/q mean motion ratio, prograde resonance is of order p - q while retrograde resonance is of order p + q).Comment: 13 pages, 10 figures; to appear in MNRA