Influence of cardiac autonomic neuropathy on cardiac repolarisation during incremental adrenaline infusion in type 1 diabetes

Aims/hypothesis We examined the effect of a standardised sympathetic stimulus, incremental adrenaline (epinephrine) infusion on cardiac repolarisation in individuals with type 1 diabetes with normal autonomic function, subclinical autonomic neuropathy and established autonomic neuropathy. Methods Ten individuals with normal autonomic function and baroreceptor sensitivity tests (NAF), seven with subclinical autonomic neuropathy (SAN; normal standard autonomic function tests and abnormal baroreceptor sensitivity tests); and five with established cardiac autonomic neuropathy (CAN; abnormal standard autonomic function and baroreceptor tests) underwent an incremental adrenaline infusion. Saline (0.9% NaCl) was infused for the first hour followed by 0.01 μg kg−1 min−1 and 0.03 μg kg−1 min−1 adrenaline for the second and third hours, respectively, and 0.06 μg kg−1 min−1 for the final 30 min. High resolution ECG monitoring for QTc duration, ventricular repolarisation parameters (T wave amplitude, T wave area symmetry ratio) and blood sampling for potassium and catecholamines was performed every 30 min. Results Baseline heart rate was 68 (95% CI 60, 76) bpm for the NAF group, 73 (59, 87) bpm for the SAN group and 84 (78, 91) bpm for the CAN group. During adrenaline infusion the heart rate increased differently across the groups (p = 0.01). The maximum increase from baseline (95% CI) in the CAN group was 22 (13, 32) bpm compared with 11 (7, 15) bpm in the NAF and 10 (3, 18) bpm in the SAN groups. Baseline QTc was 382 (95% CI 374, 390) ms in the NAF, 378 (363, 393) ms in the SAN and 392 (367, 417) ms in the CAN groups (p = 0.31). QTc in all groups lengthened comparably with adrenaline infusion. The longest QTc was 444 (422, 463) ms (NAF), 422 (402, 437) ms (SAN) and 470 (402, 519) ms (CAN) (p = 0.09). T wave amplitude and T wave symmetry ratio decreased and the maximum decrease occurred earlier, at lower infused adrenaline concentrations in the CAN group compared with NAF and SAN groups. AUC for the symmetry ratio was different across the groups and was lowest in the CAN group (p = 0.04). Plasma adrenaline rose and potassium fell comparably in all groups. Conclusions/interpretation Participants with CAN showed abnormal repolarisation in some measures at lower adrenaline concentrations. This may be due to denervation adrenergic hypersensitivity. Such individuals may be at greater risk of cardiac arrhythmias in response to physiological sympathoadrenal challenges such as stress or hypoglycaemia

A transferable force-field for alkali metal nitrates

We present a new rigid-ion force-field for the alkali metal nitrates that is suitable for simulating solution chemistry, crystallisation and polymorphism. We show that it gives a good representation of the crystal structures, lattice energies, elastic and dielectric properties of these compounds over a wide range of temperatures. Since all the alkali metal nitrates are fitted together using a common model for the nitrate anion, the force-field is also suitable for simulating solid solutions. We use the popular Joung and Cheatham model for the interactions of the alkali metal cations with water and obtain the interaction of the nitrate ion with water by fitting to a hydrate

Cardiac autonomic regulation and repolarization during acute experimental hypoglycemia in Type 2 diabetes

Hypoglycemia is associated with increased cardiovascular mortality in trials of intensive therapy in type 2 diabetes (T2DM). We previously observed an increase in arrhythmias during spontaneous prolonged hypoglycemia in T2DM patients. Our aim was to examine changes in cardiac autonomic function and repolarization during sustained experimental hypoglycemia. Twelve adults with T2DM and eleven age, BMI-matched nondiabetic controls underwent paired hyperinsulinemic clamps separated by 4 weeks. Glucose was maintained at euglycemia (6.0mmol/L) or hypoglycemia (2.5mmol/L) for one hour. Heart rate, blood pressure, heart rate variability were assessed every thirty minutes and corrected QT (QTc) and T wave morphology every 60 minutes. Heart rate initially increased in T2DM participants but then fell towards baseline despite maintained hypoglycemia at 1 hour, accompanied by reactivation of vagal tone. In nondiabetic participants, vagal tone remained depressed during sustained hypoglycemia. Diabetic participants exhibited greater heterogeneity of repolarization during hypoglycemia as demonstrated by T wave symmetry and Principal Component Analysis (PCA) ratio compared with the nondiabetic group. Epinephrine levels during hypoglycemia were similar between groups. Cardiac autonomic regulation during hypoglycemia appears time-dependent. T2DM individuals demonstrate greater repolarization abnormalities for a given hypoglycemic stimulus despite comparable sympathoadrenal responses. These mechanisms could contribute to arrhythmias during clinical hypoglycemic episodes

Electrophiles modulate glutathione reductase activity via alkylation and upregulation of glutathione biosynthesis

Cells evolved robust homeostatic mechanisms to protect against oxidation or alkylation by electrophilic species. Glutathione (GSH) is the most abundant intracellular thiol, protects cellular components from oxidation and is maintained in a reduced state by glutathione reductase (GR). Nitro oleic acid (NO2-OA) is an electrophilic fatty acid formed under digestive and inflammatory conditions that both reacts with GSH and induces its synthesis upon activation of Nrf2 signaling. The effects of NO2-OA on intracellular GSH homeostasis were evaluated. In addition to upregulation of GSH biosynthesis, we observed that NO2-OA increased intracellular GSSG in an oxidative stress-independent manner. NO2-OA directly inhibited GR in vitro by covalent modification of the catalytic Cys61, with kon of (3.45±0.04)×103 M−1 s−1, koff of (4.4±0.4)×10−4 s−1, and Keq of (1.3±0.1)×10−7 M. Akin to NO2-OA, the electrophilic Nrf2 activators bardoxolone-imidazole (CDDO-Im), bardoxolone-methyl (CDDO-Me) and dimethyl fumarate (DMF) also upregulated GSH biosynthesis while promoting GSSG accumulation, but without directly inhibiting GR activity. In vitro assays in which GR was treated with increasing GSH concentrations and GSH depletion experiments in cells revealed that GR activity is finely regulated via product inhibition, an observation further supported by theoretical (kinetic modeling of cellular GSSG:GSH levels) approaches. Together, these results describe two independent mechanisms by which electrophiles modulate the GSH/GSSG couple, and provide a novel conceptual framework to interpret experimentally determined values of GSH and GSSG

Origins of the Ambient Solar Wind: Implications for Space Weather

The Sun's outer atmosphere is heated to temperatures of millions of degrees, and solar plasma flows out into interplanetary space at supersonic speeds. This paper reviews our current understanding of these interrelated problems: coronal heating and the acceleration of the ambient solar wind. We also discuss where the community stands in its ability to forecast how variations in the solar wind (i.e., fast and slow wind streams) impact the Earth. Although the last few decades have seen significant progress in observations and modeling, we still do not have a complete understanding of the relevant physical processes, nor do we have a quantitatively precise census of which coronal structures contribute to specific types of solar wind. Fast streams are known to be connected to the central regions of large coronal holes. Slow streams, however, appear to come from a wide range of sources, including streamers, pseudostreamers, coronal loops, active regions, and coronal hole boundaries. Complicating our understanding even more is the fact that processes such as turbulence, stream-stream interactions, and Coulomb collisions can make it difficult to unambiguously map a parcel measured at 1 AU back down to its coronal source. We also review recent progress -- in theoretical modeling, observational data analysis, and forecasting techniques that sit at the interface between data and theory -- that gives us hope that the above problems are indeed solvable.Comment: Accepted for publication in Space Science Reviews. Special issue connected with a 2016 ISSI workshop on "The Scientific Foundations of Space Weather." 44 pages, 9 figure

Evaluation of correlated studies using liquid cell‐ and cryo‐transmission electron microscopy : hydration of calcium sulfate and the phase transformation pathways of bassanite to gypsum

Insight into the nucleation, growth and phase transformations of calcium sulfate could improve the performance of construction materials, reduce scaling in industrial processes and aid understanding of its formation in the natural environment. Recent studies have suggested that the calcium sulfate pseudo polymorph, gypsum (CaSO4·2H2O) can form in aqueous solution via a bassanite (CaSO4·0.5H2O) intermediate. Some in situ experimental work has also suggested that the transformation of bassanite to gypsum can occur through an oriented assembly mechanism. In this work, we have exploited liquid cell transmission electron microscopy (LCTEM) to study the transformation of bassanite to gypsum in an undersaturated aqueous solution of calcium sulfate. This was benchmarked against cryogenic TEM (cryo-TEM) studies to validate internally the data obtained from the two microscopy techniques. When coupled with Raman spectroscopy, the real-time data generated by LCTEM, and structural data obtained from cryo-TEM show that bassanite can transform to gypsum via more than one pathway, the predominant one being dissolution/reprecipitation. Comparisons between LCTEM and cryo-TEM also show that the transformation is slower within the confined region of the liquid cell as compared to a bulk solution. This work highlights the important role of a correlated microscopy approach for the study of dynamic processes such as crystallisation from solution if we are to extract true mechanistic understanding

Review and assessment of latent and sensible heat flux accuracy over the global oceans

For over a decade, several research groups have been developing air-sea heat flux information over the global ocean, including latent (LHF) and sensible (SHF) heat fluxes over the global ocean. This paper aims to provide new insight into the quality and error characteristics of turbulent heat flux estimates at various spatial and temporal scales (from daily upwards). The study is performed within the European Space Agency (ESA) Ocean Heat Flux (OHF) project. One of the main objectives of the OHF project is to meet the recommendations and requirements expressed by various international programs such as the World Research Climate Program (WCRP) and Climate and Ocean Variability, Predictability, and Change (CLIVAR), recognizing the need for better characterization of existing flux errors with respect to the input bulk variables (e.g. surface wind, air and sea surface temperatures, air and surface specific humidities), and to the atmospheric and oceanic conditions (e.g. wind conditions and sea state). The analysis is based on the use of daily averaged LHF and SHF and the asso- ciated bulk variables derived from major satellite-based and atmospheric reanalysis products. Inter-comparisons of heat flux products indicate that all of them exhibit similar space and time patterns. However, they also reveal significant differences in magnitude in some specific regions such as the western ocean boundaries during the Northern Hemisphere winter season, and the high southern latitudes. The differences tend to be closely related to large differences in surface wind speed and/or specific air humidity (for LHF) and to air and sea temperature differences (for SHF). Further quality investigations are performed through comprehensive comparisons with daily-averaged LHF and SHF estimated from moorings. The resulting statistics are used to assess the error of each OHF product. Consideration of error correlation between products and observations (e.g., by their assimilation) is also given. This reveals generally high noise variance in all products and a weak signal in common with in situ observations, with some products only slightly better than others. The OHF LHF and SHF products, and their associated error characteristics, are used to compute daily OHF multiproduct-ensemble (OHF/MPE) estimates of LHF and SHF over the ice-free global ocean on a 0.25° × 0.25° grid. The accuracy of this heat multiproduct, determined from comparisons with mooring data, is greater than for any individual product. It is used as a reference for the anomaly characterization of each individual OHF product

Studies of the Response of the Prototype CMS Hadron Calorimeter, Including Magnetic Field Effects, to Pion, Electron, and Muon Beams

We report on the response of a prototype CMS hadron calorimeter module to charged particle beams of pions, muons, and electrons with momenta up to 375 GeV/c. The data were taken at the H2 and H4 beamlines at CERN in 1995 and 1996. The prototype sampling calorimeter used copper absorber plates and scintillator tiles with wavelength shifting fibers for readout. The effects of a magnetic field of up to 3 Tesla on the response of the calorimeter to muons, electrons, and pions are presented, and the effects of an upstream lead tungstate crystal electromagnetic calorimeter on the linearity and energy resolution of the combined calorimetric system to hadrons are evaluated. The results are compared with Monte Carlo simulations and are used to optimize the choice of total absorber depth, sampling frequency, and longitudinal readout segmentation.Comment: 89 pages, 41 figures, to be published in NIM, corresponding author: P de Barbaro, [email protected]

Asteroseismology of red giants & galactic archaeology

Red-giant stars are low- to intermediate-mass ($M \lesssim 10$~M$_{\odot}$) stars that have exhausted hydrogen in the core. These extended, cool and hence red stars are key targets for stellar evolution studies as well as galactic studies for several reasons: a) many stars go through a red-giant phase; b) red giants are intrinsically bright; c) large stellar internal structure changes as well as changes in surface chemical abundances take place over relatively short time; d) red-giant stars exhibit global intrinsic oscillations. Due to their large number and intrinsic brightness it is possible to observe many of these stars up to large distances. Furthermore, the global intrinsic oscillations provide a means to discern red-giant stars in the pre-helium core burning from the ones in the helium core burning phase and provide an estimate of stellar ages, a key ingredient for galactic studies. In this lecture I will first discuss some physical phenomena that play a role in red-giant stars and several phases of red-giant evolution. Then, I will provide some details about asteroseismology -- the study of the internal structure of stars through their intrinsic oscillations -- of red-giant stars. I will conclude by discussing galactic archaeology -- the study of the formation and evolution of the Milky Way by reconstructing its past from its current constituents -- and the role red-giant stars can play in that.Comment: Lecture presented at the IVth Azores International Advanced School in Space Sciences on "Asteroseismology and Exoplanets: Listening to the Stars and Searching for New Worlds" (arXiv:1709.00645), which took place in Horta, Azores Islands, Portugal in July 201

Electron transparent nanotubes reveal crystallization pathways in confinement

The cylindrical pores of track-etched membranes offer excellent environments for studying the effects of confinement on crystallization as the pore diameter is readily varied and the anisotropic morphologies can direct crystal orientation. However, the inability to image individual crystals in situ within the pores in this system has prevented many of the underlying mechanisms from being characterized. Here, we study the crystallization of calcium sulfate within track-etched membranes and reveal that oriented gypsum forms in 200 nm diameter pores, bassanite in 25–100 nm pores and anhydrite in 10 nm pores. The crystallization pathways are then studied by coating the membranes with an amorphous titania layer prior to mineralization to create electron transparent nanotubes that protect fragile precursor materials. By visualizing the evolutionary pathways of the crystals within the pores we show that the product single crystals derive from multiple nucleation events and that orientation is determined at early reaction times. Finally, the transformation of bassanite to gypsum within the membrane pores is studied using experiment and potential mean force calculations and is shown to proceed by localized dissolution/reprecipitation. This work provides insight into the effects of confinement on crystallization processes, which is relevant to mineral formation in many real-world environments