A randomized, double-blind, placebo-controlled trial to assess safety and tolerability during treatment of type 2 diabetes with usual diabetes therapy and either Cycloset™ or placebo

Background: Cycloset™ is a quick-release formulation of bromocriptine mesylate, a dopamine agonist, which in animal models of insulin resistance and type 2 diabetes acts centrally to reduce resistance to insulin- mediated suppression of hepatic glucose output and tissue glucose disposal. In such animals, bromocriptine also reduces hepatic triglyceride synthesis and free fatty acid mobilization, manifesting decreases in both plasma triglycerides and free fatty acids. In clinical trials, morning administration of Cycloset™ either as monotherapy or adjunctive therapy to sulfonylurea or insulin reduces HbA1c levels relative to placebo by 0.55–1.2. Cycloset™ therapy also reduces plasma triglycerides and free fatty acid by approximately 25% and 20%, respectively, among those also receiving sulfonylurea therapies. The effects of once-daily morning Cycloset™ therapy on glycemic control and plasma lipids are demonstrable throughout the diurnal portion of the day (7 a.m. to 7 p.m.) across postprandial time points. Methods/Design: 3,095 individuals were randomized in a 2:1 ratio into a one year trial aimed to assess the safety and efficacy of Cycloset™ compared to placebo among individuals receiving a variety of treatments for type 2 diabetes. Eligibility criteria for this randomized placebo controlled trial included: age 30–80, HbA1c ≤ 10%, diabetes therapeutic regimen consisting of diet or no more than two hypoglycemic agents or insulin with or without one additional oral agent (usual diabetes therapy; UDT). The primary safety endpoint will test the hypothesis that the rate of all-cause serious adverse events after one year of usual diabetes therapy (UDT) plus Cycloset™ is not greater than that for UDT plus placebo by more than an acceptable margin defined as a hazard ratio of 1.5 with a secondary endpoint analysis of the difference in the rate of serious cardiovascular events, (myocardial infarction, stroke, coronary revascularization or hospitalization for or angina or congestive heart failure). Efficacy analyses will evaluate effects of Cycloset™ versus placebo on change from baseline in HbA1c, fasting glucose, body weight, waist circumference, blood pressure and plasma lipids. Discussion: This study will extend the current data on Cycloset™ safety, tolerability and efficacy in individuals with type 2 diabetes to include its effects in combination with thiazolodinediones, insulin secretagogues, metformin, alpha-glucosidase inhibitors and exogenous insulin regimens. Trial registration: clinical trials.gov NCT0037767

NIMASTEP: a software to modelize, study and analyze the dynamics of various small objects orbiting specific bodies

NIMASTEP is a dedicated numerical software developed by us, which allows one to integrate the osculating motion (using cartesian coordinates) in a Newtonian approach of an object considered as a point-mass orbiting a homogeneous central body that rotates with a constant rate around its axis of smallest inertia. The code can be applied to objects such as particles, artificial or natural satellites or space debris. The central body can be either any terrestrial planet of the solar system, any dwarf-planet, or even an asteroid. In addition, very many perturbations can be taken into account, such as the combined third-body attraction of the Sun, the Moon, or the planets, the direct solar radiation pressure (with the central body shadow), the non-homogeneous gravitational field caused by the non-sphericity of the central body, and even some thrust forces. The simulations were performed using different integration algorithms. Two additional tools were integrated in the software package; the indicator of chaos MEGNO and the frequency analysis NAFF. NIMASTEP is designed in a flexible modular style and allows one to (de)select very many options without compromising the performance. It also allows one to easily add other possibilities of use. The code has been validated through several tests such as comparisons with numerical integrations made with other softwares or with semi-analytical and analytical studies. The various possibilities of NIMASTEP are described and explained and some tests of astrophysical interest are presented. At present, the code is proprietary but it will be released for use by the community in the near future. Information for contacting its authors and (in the near future) for obtaining the software are available on the web site http://www.fundp.ac.be/en/research/projects/page_view/10278201/Comment: Astronomy & Astrophysics - Received: 25 November 2011 / Accepted: 27 February 2012 -- 14 pages, 4 figure

The production of Tsallis entropy in the limit of weak chaos and a new indicator of chaoticity

We study the connection between the appearance of a `metastable' behavior of weakly chaotic orbits, characterized by a constant rate of increase of the Tsallis q-entropy (Tsallis 1988), and the solutions of the variational equations of motion for the same orbits. We demonstrate that the variational equations yield transient solutions, lasting for long time intervals, during which the length of deviation vectors of nearby orbits grows in time almost as a power-law. The associated power exponent can be simply related to the entropic exponent for which the q-entropy exhibits a constant rate of increase. This analysis leads to the definition of a new sensitive indicator distinguishing regular from weakly chaotic orbits, that we call `Average Power Law Exponent' (APLE). We compare the APLE with other established indicators of the literature. In particular, we give examples of application of the APLE in a) a thin separatrix layer of the standard map, b) the stickiness region around an island of stability in the same map, and c) the web of resonances of a 4D symplectic map. In all these cases we identify weakly chaotic orbits exhibiting the `metastable' behavior associated with the Tsallis q-entropy.Comment: 19 pages, 12 figures, accepted for publication by Physica

Symplectic integration of space debris motion considering several Earth's shadowing models

In this work, we present a symplectic integration scheme to numerically compute space debris motion. Such an integrator is particularly suitable to obtain reliable trajectories of objects lying on high orbits, especially geostationary ones. Indeed, it has already been demonstrated that such objects could stay there for hundreds of years. Our model takes into account the Earth's gravitational potential, luni-solar and planetary gravitational perturbations and direct solar radiation pressure. Based on the analysis of the energy conservation and on a comparison with a high order non-symplectic integrator, we show that our algorithm allows us to use large time steps and keep accurate results. We also propose an innovative method to model Earth's shadow crossings by means of a smooth shadow function. In the particular framework of symplectic integration, such a function needs to be included analytically in the equations of motion in order to prevent numerical drifts of the energy. For the sake of completeness, both cylindrical shadows and penumbra transitions models are considered. We show that both models are not equivalent and that big discrepancies actually appear between associated orbits, especially for high area-to-mass ratios

Fingerprinting the impacts of global change on tropical forests

Recent observations of widespread changes in mature tropical forests such as increasing tree growth, recruitment and mortality rates and increasing above-ground biomass suggest that 'global change' agents may be causing predictable changes in tropical forests. However, consensus over both the robustness of these changes and the environmental drivers that may be causing them is yet to emerge. This paper focuses on the second part of this debate. We review (i) the evidence that the physical, chemical and biological environment that tropical trees grow in has been altered over recent decades across large areas of the tropics, and (ii) the theoretical, experimental and observational evidence regarding the most likely effects of each of these changes on tropical forests. Ten potential widespread drivers of environmental change were identified: temperature, precipitation, solar radiation, climatic extremes (including El Niño Southern Oscillation events), atmospheric CO2 concentrations, nutrient deposition, O3/acid depositions, hunting, land-use change and increasing liana numbers. We note that each of these environmental changes is expected to leave a unique 'fingerprint' in tropical forests, as drivers directly force different processes, have different distributions in space and time and may affect some forests more than others (e.g. depending on soil fertility). Thus, in the third part of the paper we present testable a priori predictions of forest responses to assist ecologists in attributing particular changes in forests to particular causes across multiple datasets. Finally, we discuss how these drivers may change in the future and the possible consequences for tropical forests

Soil Aggregates as a Source of Dissolved Organic Carbon to Streams: An Experimental Study on the Effect of Solution Chemistry on Water Extractable Carbon

Over the past two decades, headwater streams of the northern hemisphere have shown increased amounts of dissolved organic carbon (DOC), coinciding with decreased acid deposition. The exact nature of the mechanistic link between precipitation composition and stream water DOC is still widely debated in the literature. We hypothesize that soil aggregates are the main source of stream water DOC and that DOC release is greater in organic rich, riparian soils vs. hillslope soils. To test these hypotheses, we collected soils from two main landscape positions (hillslope and riparian zones) from the acid-impacted Sleepers River Research Watershed in northeastern Vermont. We performed aqueous soil extracts with solutions of different ionic strength (IS) and composition to simulate changes in soil solution. We monitored dynamic changes in soil particle size, aggregate architecture and composition, leachate DOC concentrations, dissolved organic matter (DOM) characteristics by fluorescence spectroscopy and trends in bioavailability. In low IS solutions, extractable DOC concentrations were significantly higher, particle size (by laser diffraction) was significantly smaller and organic material was separated from mineral particles in scanning electron microscope observations. Furthermore, higher DOC concentrations were found in Na+ compared to Ca2+ solutions of the same IS. These effects are attributed to aggregate dispersion due to expanding diffuse double layers in decreased IS solutions and to decreased bridging by divalent cations. Landscape position impacted quality but not quantity of released DOC. Overall, these results indicate that soil aggregates might be one important link between Critical Zone inputs (i.e., precipitation) and exports in streams

Does stream water composition at sleepers river in vermont reflect dynamic changes in soils during recovery from acidification?

Stream water pH and composition are widely used to monitor ongoing recovery from the deposition of strong anthropogenic acids in many forested headwater catchments in the northeastern United States. However, stream water composition is a function of highly complex and coupled processes, flowpaths, and variations in soil and bedrock composition. Spatial heterogeneity is especially pronounced in headwater catchments with steep topography, potentially limiting stream water composition as an indicator of changes in critical zone (CZ) dynamics during system recovery. To investigate the link between catchment characteristics, landscape position, and stream water composition we used long-term data (1991–2015) from the Sleepers River Research Watershed (SRRW) in northeastern Vermont. We investigated trends with time in stream water and trends with time, depth, and landscape position (upslope, midslope, and riparian zone) in groundwater (GW) and soil solution. We further determined soil elemental composition and mineralogy on archived (1996) and modern (2017) soil samples to assess changes in composition with time. SRRW is inherently well-buffered by calcite in bedrock and till, but soils had become acidified and are now recovering from acidification. Although base cations, especially Ca, decrease progressively with time in GW, riparian soils have become more enriched in Ca, due to a mixture of lateral and vertical transfers. At the same time stream water Ca fluxes increased over the past two decades, likely due to the leaching of (transient) legacy Ca from riparian zones and increased water fluxes. The stream water response therefore reflects the dynamic changes in soil chemistry, flow routing and water inputs

On the relevance of chaos for halo stars in the solar neighbourhood II

In a previous paper based on dark matter only simulations we show that, in the approximation of an analytic and static potential describing the strongly triaxial and cuspy shape of Milky Way-sized haloes, diffusion due to chaotic mixing in the neighbourhood of the Sun does not efficiently erase phase space signatures of past accretion events. In this second paper we further explore the effect of chaotic mixing using multicomponent Galactic potential models and solar neighbourhood-like volumes extracted from fully cosmological hydrodynamic simulations, thus naturally accounting for the gravitational potential associated with baryonic components, such as the bulge and disc. Despite the strong change in the global Galactic potentials with respect to those obtained in dark matter only simulations, our results confirm that a large fraction of halo particles evolving on chaotic orbits exhibit their chaotic behaviour after periods of time significantly larger than a Hubble time. In addition, significant diffusion in phase space is not observed on those particles that do exhibit chaotic behaviour within a Hubble time

Phytochemical constituents, antioxidant activity, and toxicity assessment of the aerial part extracts from the infraspecific taxa of Matthiola fruticulosa (Brassicaceae) endemic to Sicily

In a project designed to investigate the specific and infraspecific taxa of Matthiola endemic to Sicily (Italy) as new potential sources of bioactive compounds in this work, the infraspecific taxa of Matthiola fruticulosa were studied, namely, subsp. fruticulosa and subsp. coronopifolia. HPLC-PDA/ESI-MS and SPME-GC/MS analyses of hydroalcoholic extracts obtained from the aerial parts of the two subspecies led to the detection of 51 phenolics and 61 volatile components, highlighting a quite different qualitative-quantitative profile. The antioxidant properties of the extracts were explored through in vitro methods: 1,1-diphenyl-2-picrylhydrazyl (DPPH), reducing power and Fe2+ chelating activity assays. The results of the antioxidant tests showed that the extracts possess a different antioxidant ability: Particularly, the extract of M. fruticulosa subsp. fruticulosa exhibited higher radical scavenging activity than that of subsp. coronopifolia (IC50 = 1.25 ± 0.02 mg/mL and 2.86 ± 0.05 mg/mL), which in turn displayed better chelating properties (IC50 = 1.49 ± 0.01 mg/mL and 0.63 ± 0.01 mg/mL). Lastly, Artemia salina lethality bioassay was performed for toxicity assessment. The results of the bioassay showed lack of toxicity against brine shrimp larvae for both extracts. The data presented indicate the infraspecific taxa of M. fruticulosa as new and safe sources of antioxidant compounds