Studies on Angiotensin Converting Enzyme Inhibitors

A range of studies are described examining the responses to blockade of the renin angiotensin system with angiotensin converting enzyme inhibition in patients with heart failure and normal volunteers. The common theme of the studies is the definition of response at low doses of drug and differentiation of effects between agents or over time on first administration. First dose response to ACE Inhibitors in heart failure (a) Oral doses of placebo, captopril 6.25mg, enalapril 2.5mg and perindopril 2mg were given in a randomised double blind parallel group study of 48 elderly patients with stable heart failure. Despite diuretic withdrawal considerable falls in supine blood pressure and heart rate were noted with captopril and enalapril. Compared to placebo perindopril produced no significant fall in pressure. Enalapril and perindopril produced similar plasma ACE inhibition. No patient experienced adverse symptoms. (b) Intravenous doses, by slow (6hr) constant rate infusion, of placebo (saline), enalaprilat (1.5mg) or perindoprilat (1mg) were given in a randomised, double blind, parallel group study of 36 elderly patients with stable heart failure. Both diacid ACE inhibitors caused falls in blood pressure and similar though greater inhibition of plasma ACE activity compared to the oral treatments. Five infusions were terminated on a priori criteria because of the degree of blood pressure fall. Termination of infusion effectively controlled the blood pressure fall. Two patients on active treatment had asymptomatic deterioration in biochemical indices of renal function necessitating withdrawal of maintenance ACE inhibitor treatment. Studies of the response to ACE inhibition in volunteers (a) The transpulmonary extraction of perindoprilat (1mg; by constant rate infusion into a peripheral vein over 20minutes) was examined in a novel study in 10 patients undergoing diagnostic cardiac catheterisation predominantly for symptoms suggestive of ischaemic heart disease. A co-infusion strategy employing concurrent indocyanine green as an intravascular marker was used. Concurrent sampling in the ascending aorta and the pulmonary trunk failed to show any significant first pass uptake of the drug into the pulmonary circulation. Pharmacokinetic models designed to incorporate elements describing simple nonlinear kinetics based on "tissue" distribution were not found to be applicable. A variety of procedural problems may have been responsible for the failure of this study to document tissue distribution. (b) Protracted low dose constant rate infusion of perindoprilat (1mg) over 1, 3 or 6hrs or placebo (saline over 3hr) was conducted in a single (subject) blinded randomised study in 10 healthy male volunteers. This predominantly pharmacokinetic study confirmed a blood pressure fall despite the low doses employed in normal volunteers. Despite higher peak drug concentrations the plasma ACE inhibition profile summarised by the area under the curve was greatest following the 6hr infusion where peak drug concentration was lowest. Drug concentration time profiles showed a clear sigmoid accumulation profile during drug infusion. Pharmacokinetic modelling of individual profiles confirmed that from a hierarchy of systems a non linear model with terms to represent tissue and plasma binding of drug provided the best fit to the observed data. (c) A model of activation of the renin angiotensin system was outlined in a double blind randomised study of low dose oral enalapril (5mg) in eight healthy salt depleted normal volunteers. A system of modest dietary salt restriction (40mmol per day) and diuretic therapy (40mg Frusemide BDS) over three prestudy days produced a reliable activation of the renin angiotensin system. Baseline and reactive elevation of renin activity was recorded in response to enalapril with an associated significant fall in supine and erect blood pressure. Conclusions Differential effects on blood pressure are evident between similar ACE inhibitors (enalapril and perindopril) but not with their respective diacid metabolites despite similar circulating enzyme inhibition in controlled circumstances. This may relate to a differential interaction with the tissue based elements of the renin angiotensin system. Although the transpulmonary study did not reveal significant extraction of the diacid ACE inhibitor perindoprilat into the lungs, the subsequent pharmacokinetic studies with low dose infusions of the same drug indicate that an indirect index of the tissue based system may be possible. Studies in heart failure patients may be usefully extended in volunteers whose renin system is activated using the salt depletion protocol as described

Dramatic level analysis for interactive narrative

In interactive 3D narratives, a user’s narrative emerges through interactions with the system and embodied agencies (characters) mediated through the 3D environment. We present a methodology that identifies and measures four factors in interactive narrative where agency is present. We describe a technique for measuring drama, agency and engagement and compare the centrality of a designed interactive narrative with the emergent participatory narrative. This methodology has application as an analytic device for any interactive narrative where agency is fundamental. The adoption of the FrameNet semantic resource and the interpretation of interaction in narrative, situate this work in the domain of 3D interactive narratives, mixed and augmented realities and polymorphic narratives that cross forms of media

Dramatic flow in interactive 3D narrative

The concept of dramatic level is crucial for a model of dramatic flow. We present a framework to maintain optimal dramatic flow in an interactive 3D environment where both linear and emergent narratives co-exist. Unlike all other interactive narrative prototypes the framework advanced focuses on the optimal dramatic flow of the emerging user narrative so that although fragmented, it can be engaging and make sense. Using a sample narrative from Ovid’s Metamorphoses [18] we demonstrate a method to evaluate dramatic levels as plot points so that movement across narratives retains a strong dramatic flow. Although users may never choose to explore any given linear narrative in its entirety, the result is an engaging and rich narrative experience

Self-lensing flares from black hole binaries III: general-relativistic ray tracing of circumbinary accretion simulations

Self-lensing flares (SLFs) are expected to be produced once or twice per orbit by an accreting massive black hole binary (MBHB), if the eclipsing MBHBs are observed close to edge-on. SLFs can provide valuable electromagnetic (EM) signatures to accompany the gravitational waves (GWs) detectable by the upcoming Laser Interferometer Space Antenna (LISA). EM follow-ups are crucial for, e.g., sky-localization, and constraining the Hubble constant and the graviton mass. We use high-resolution two-dimensional viscous hydrodynamical simulations of a circumbinary disk (CBD) embedding a MBHB. We then use very high-cadence output of these hydrodynamical simulation inputs for a general-relativistic ray-tracing code to produce synthetic spectra and phase-folded light curves. Our main results show a significant periodic amplification of the flux with the characteristic shape of a sharp flare with a central dip, as the foreground black hole (BH) transits across the minidisk and shadow of the background BH, respectively. These corroborate previous conclusions based on the microlensing approximation and analytical toy models of the emission geometry. We also find that at lower inclinations, without some occlusion of the minidisk emission by the CBD, shocks from quasi-periodic mass-trading between the minidisks can produce bright flares which can mimic SLFs and could hinder their identification.Comment: 14 pages, 11 figures, submitted to journal, split Fig. 1 by frequency, fixed some typo

An interaction framework for scenario-based three dimensional environments

Although popular and engaging, three dimensional environments are rarely deployed to depict strong narratives involving complex characters engaged in reasoning. The design of three dimensional environments rich in narrative and character depth can be facilitated with a detailed representation of interactions between characters. However, the representation of interaction in current 3D development environments such as game engines is quite basic. This work advances a scheme for representing interactions that integrates a representation of semantics from linguistics called FrameNet with conceptualizations of drama and narrative by Georges Polti and Joseph Campbell. The resulting interaction frame facilitates the design of 3D environments by providing designers rich, yet standard elements that include spatial and temporal data, with which to represent complex interactions in 3D environments. This has application for the authoring of dynamically generated interactive narrative environments.E

Disappearing thermal X-ray emission as a tell-tale signature of merging massive black hole binaries

The upcoming Laser Interferometer Space Antenna (LISA) is expected to detect gravitational waves (GWs) from massive black hole binaries (MBHB). Finding the electromagnetic (EM) counterparts for these GW events will be crucial for understanding how and where MBHBs merge, measuring their redshifts, constraining the Hubble constant and the graviton mass, and for other novel science applications. However, due to poor GW sky localisation, multi-wavelength, time-dependent electromagnetic (EM) models are needed to identify the right host galaxy among many candidates. We studied merging MBHBs embedded in a circumbinary disc using high-resolution two-dimensional simulations, with a $\Gamma$-law equation of state, incorporating viscous heating, shock heating, and radiative cooling. We simulate the binary from large separation until after merger, allowing us to model the decoupling of the binary from the circumbinary disc (CBD). We compute the EM signatures and identify distinct features before, during, and after the merger. Our main result is a multi-band EM signature: we find that the MBHB produces strong thermal X-ray emission until 1-2 days prior to the merger. However, as the binary decouples from the CBD, the X-ray-bright minidiscs rapidly shrink in size, become disrupted, and the accretion rate drops precipitously. As a result, the thermal X-ray luminosity drops by orders of magnitude, and the source remains X-ray dark for several days after the merger, regardless of any post-merger effects such as GW recoil or mass loss. Looking for the abrupt spectral change where the thermal X-ray disappears is a tell-tale EM signature of LISA mergers that does not require extensive pre-merger monitoring.Comment: 14 pages, 16 figures, 1 table, submitted to journa

Revealing the High-Redshift Star Formation Rate with Gamma-Ray Bursts

While the high-z frontier of star formation rate (SFR) studies has advanced rapidly, direct measurements beyond z ~ 4 remain difficult, as shown by significant disagreements among different results. Gamma-ray bursts, owing to their brightness and association with massive stars, offer hope of clarifying this situation, provided that the GRB rate can be properly related to the SFR. The Swift GRB data reveal an increasing evolution in the GRB rate relative to the SFR at intermediate z; taking this into account, we use the highest-z GRB data to make a new determination of the SFR at z = 4-7. Our results exceed the lowest direct SFR measurements, and imply that no steep drop exists in the SFR up to at least z ~ 6.5. We discuss the implications of our result for cosmic reionization, the efficiency of the universe in producing stellar-mass black holes, and ``GRB feedback'' in star-forming hosts.Comment: 4 pages, 2 figures; ApJ Letters, in pres

African cassava whitefly, Bemisia tabaci, cassava colonization preferences and control implications

Cassava is a staple food for people across sub-Saharan Africa. Over the last 20 years, there has been an increased frequency of outbreaks and crop damage in this region caused by the cassava-adapted Bemisia tabaci putative species. Little is known about when and why B. tabaci adults move and colonize new cassava crops, especially in farming systems that contain a mixture of cultivar types and plant ages. Here, we assessed experimentally whether the age and variety of cassava affected the density of B. tabaci. We also tested whether the age and variety of the source cassava field affected the variety preference of B. tabaci when they colonized new cassava plants. We placed uninfested potted “sentinel” plants of three cassava varieties (Nam 130, Nase 14, and Njule Red) in source fields containing one of two varieties (Nam 130 or Nase 14) and one of three age classes (young, medium, or old). After two weeks, the numbers of nymphs on the sentinel plants were used as a measure of colonization. Molecular identification revealed that the B. tabaci species was sub-Saharan Africa 1 (SSA1). We found a positive correlation between the density of nymphs on sentinel plants and the density of adults in the source field. The density of nymphs on the sentinels was not significantly related to the age of the source field. Bemisia tabaci adults did not preferentially colonize the sentinel plant of the same variety as the source field. There was a significant interactive effect, however, between the source and sentinel variety that may indicate variability in colonization. We conclude that managing cassava source fields to reduce B. tabaci abundance will be more effective than manipulating nearby varieties. We also suggest that planting a “whitefly sink” variety is unlikely to reduce B. tabaci SSA1 populations unless fields are managed to reduce B. tabaci densities using other integrative approaches

Relationship of C-reactive protein reduction to cardiovascular event reduction following treatment with canakinumab: a secondary analysis from the CANTOS randomised controlled trial

Canakinumab, a monoclonal antibody targeting interleukin-1β, reduces inflammation and cardiovascular event rates with no effect on lipid concentrations. However, it is uncertain which patient groups benefit the most from treatment and whether reductions in the inflammatory biomarker high-sensitivity C-reactive protein (hsCRP) correlate with clinical benefits for individual patients.The Canakinumab Anti-Inflammatory Thrombosis Outcomes Study (CANTOS) used computer-generated codes to randomly allocate 10 061 men and women with a history of myocardial infarction to placebo or one of three doses of canakinumab (50 mg, 150 mg, or 300 mg) given subcutaneously once every 3 months. In a prespecified secondary analysis designed to address the relationship of hsCRP reduction to event reduction in CANTOS, we evaluated the effects of canakinumab on rates of major adverse cardiovascular events, cardiovascular mortality, and all-cause mortality according to on-treatment concentrations of hsCRP. We used multivariable modelling to adjust for baseline factors associated with achieved hsCRP and multiple sensitivity analyses to address the magnitude of residual confounding. The median follow-up was 3·7 years. The trial is registered with ClinicalTrials.gov, number NCT01327846.Baseline clinical characteristics did not define patient groups with greater or lesser cardiovascular benefits when treated with canakinumab. However, trial participants allocated to canakinumab who achieved hsCRP concentrations less than 2 mg/L had a 25% reduction in major adverse cardiovascular events (multivariable adjusted hazard ratio [HRadj]=0·75, 95% CI 0·66-0·85, p<0·0001), whereas no significant benefit was observed among those with on-treatment hsCRP concentrations of 2 mg/L or above (HRadj=0·90, 0·79-1·02, p=0·11). For those treated with canakinumab who achieved on-treatment hsCRP concentrations less than 2 mg/L, cardiovascular mortality (HRadj=0·69, 95% CI 0·56-0·85, p=0·0004) and all-cause mortality (HRadj=0·69, 0·58-0·81, p<0·0001) were both reduced by 31%, whereas no significant reduction in these endpoints was observed among those treated with canakinumab who achieved hsCRP concentrations of 2 mg/L or above. Similar differential effects were found in analyses of the trial prespecified secondary cardiovascular endpoint (which additionally included hospitalisation for unstable angina requiring unplanned revascularisation) and in sensitivity analyses alternatively based on median reductions in hsCRP, on 50% or greater reductions in hsCRP, on the median percent reduction in hsCRP, in dose-specific analyses, and in analyses using a causal inference approach to estimate the effect of treatment among individuals who would achieve a targeted hsCRP concentration.The magnitude of hsCRP reduction following a single dose of canakinumab might provide a simple clinical method to identify individuals most likely to accrue the largest benefit from continued treatment. These data further suggest that lower is better for inflammation reduction with canakinumab.Novartis Pharmaceuticals