Spinal neuromodulation mitigates myocardial ischemia-induced sympathoexcitation by suppressing the intermediolateral nucleus hyperactivity and spinal neural synchrony

IntroductionMyocardial ischemia disrupts the cardio-spinal neural network that controls the cardiac sympathetic preganglionic neurons, leading to sympathoexcitation and ventricular tachyarrhythmias (VTs). Spinal cord stimulation (SCS) is capable of suppressing the sympathoexcitation caused by myocardial ischemia. However, how SCS modulates the spinal neural network is not fully known.MethodsIn this pre-clinical study, we investigated the impact of SCS on the spinal neural network in mitigating myocardial ischemia-induced sympathoexcitation and arrhythmogenicity. Ten Yorkshire pigs with left circumflex coronary artery (LCX) occlusion-induced chronic myocardial infarction (MI) were anesthetized and underwent laminectomy and a sternotomy at 4−5 weeks post-MI. The activation recovery interval (ARI) and dispersion of repolarization (DOR) were analyzed to evaluate the extent of sympathoexcitation and arrhythmogenicity during the left anterior descending coronary artery (LAD) ischemia. Extracellular in vivo and in situ spinal dorsal horn (DH) and intermediolateral column (IML) neural recordings were performed using a multichannel microelectrode array inserted at the T2-T3 segment of the spinal cord. SCS was performed for 30 min at 1 kHz, 0.03 ms, 90% motor threshold. LAD ischemia was induced pre- and 1 min post-SCS to investigate how SCS modulates spinal neural network processing of myocardial ischemia. DH and IML neural interactions, including neuronal synchrony as well as cardiac sympathoexcitation and arrhythmogenicity markers were evaluated during myocardial ischemia pre- vs. post-SCS.ResultsARI shortening in the ischemic region and global DOR augmentation due to LAD ischemia was mitigated by SCS. Neural firing response of ischemia-sensitive neurons during LAD ischemia and reperfusion was blunted by SCS. Further, SCS showed a similar effect in suppressing the firing response of IML and DH neurons during LAD ischemia. SCS exhibited a similar suppressive impact on the mechanical, nociceptive and multimodal ischemia sensitive neurons. The LAD ischemia and reperfusion-induced augmentation in neuronal synchrony between DH-DH and DH-IML pairs of neurons were mitigated by the SCS.DiscussionThese results suggest that SCS is decreasing the sympathoexcitation and arrhythmogenicity by suppressing the interactions between the spinal DH and IML neurons and activity of IML preganglionic sympathetic neurons

Hubble Space Telescope Spectroscopy of the Balmer lines in Sirius B

Sirius B is the nearest and brightest of all white dwarfs, but it is very difficult to observe at visible wavelengths due to the overwhelming scattered light contribution from Sirius A. However, from space we can take advantage of the superb spatial resolution of the Hubble Space Telescope to resolve the A and B components. Since the closest approach in 1993, the separation between the two stars has become increasingly favourable and we have recently been able to obtain a spectrum of the complete Balmer line series for Sirius B using HST?s Space Telescope Imaging Spectrograph (STIS). The quality of the STIS spectra greatly exceed that of previous ground-based spectra, and can be used to provide an important determination of the stellar temperature (Teff = 25193K) and gravity (log g = 8.556). In addition we have obtained a new, more accurate, gravitational red-shift of 80.42 +/- 4.83 km s-1 for Sirius B. Combining these results with the photometric data and the Hipparcos parallax we obtain new determinations of the stellar mass for comparison with the theoretical mass-radius relation. However, there are some disparities between the results obtained independently from log g and the gravitational redshift which may arise from flux losses in the narrow 50x0.2arcsec slit. Combining our measurements of Teff and log g with the Wood (1995) evolutionary mass-radius relation we get a best estimate for the white dwarf mass of 0.978 M. Within the overall uncertainties, this is in agreement with a mass of 1.02 M obtained by matching our new gravitational red-shift to the theoretical M/R relation.Comment: 11 pages, 6 figures, accepted for publication in the Monthly Notices of the Royal Astronomical Societ

Spinal Anesthesia Reduces Myocardial Ischemia-triggered Ventricular Arrhythmias by Suppressing Spinal Cord Neuronal Network Interactions in Pigs

Background: Cardiac sympathoexcitation leads to ventricular arrhythmias. Spinal anesthesia modulates sympathetic output and can be cardioprotective. However, its effect on the cardio-spinal reflexes and network interactions in the dorsal horn cardiac afferent neurons and the intermediolateral nucleus sympathetic neurons that regulate sympathetic output is not known. The authors hypothesize that spinal bupivacaine reduces cardiac neuronal firing and network interactions in the dorsal horn–dorsal horn and dorsal horn–intermediolateral nucleus that produce sympathoexcitation during myocardial ischemia, attenuating ventricular arrhythmogenesis. Methods: Extracellular neuronal signals from the dorsal horn and intermediolateral nucleus neurons were simultaneously recorded in Yorkshire pigs (n = 9) using a 64-channel high-density penetrating microarray electrode inserted at the T2 spinal cord. Dorsal horn and intermediolateral nucleus neural interactions and known markers of cardiac arrhythmogenesis were evaluated during myocardial ischemia and cardiac load–dependent perturbations with intrathecal bupivacaine. Results: Cardiac spinal neurons were identified based on their response to myocardial ischemia and cardiac load–dependent perturbations. Spinal bupivacaine did not change the basal activity of cardiac neurons in the dorsal horn or intermediolateral nucleus. After bupivacaine administration, the percentage of cardiac neurons that increased their activity in response to myocardial ischemia was decreased. Myocardial ischemia and cardiac load–dependent stress increased the short-term interactions between the dorsal horn and dorsal horn (324 to 931 correlated pairs out of 1,189 pairs, P \u3c 0.0001), and dorsal horn and intermediolateral nucleus neurons (11 to 69 correlated pairs out of 1,135 pairs, P \u3c 0.0001). Bupivacaine reduced this network response and augmentation in the interactions between dorsal horn–dorsal horn (931 to 38 correlated pairs out of 1,189 pairs, P \u3c 0.0001) and intermediolateral nucleus–dorsal horn neurons (69 to 1 correlated pairs out of 1,135 pairs, P \u3c 0.0001). Spinal bupivacaine reduced shortening of ventricular activation recovery interval and dispersion of repolarization, with decreased ventricular arrhythmogenesis during acute ischemia. Conclusions: Spinal anesthesia reduces network interactions between dorsal horn–dorsal horn and dorsal horn–intermediolateral nucleus cardiac neurons in the spinal cord during myocardial ischemia. Blocking short-term coordination between local afferent–efferent cardiac neurons in the spinal cord contributes to a decrease in cardiac sympathoexcitation and reduction of ventricular arrhythmogenesis

Examination of psychological risk factors for chronic pain following cardiac surgery: protocol for a prospective observational study

© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ. INTRODUCTION: Approximately 400 000 Americans and 36 000 Canadians undergo cardiac surgery annually, and up to 56% will develop chronic postsurgical pain (CPSP). The primary aim of this study is to explore the association of pain-related beliefs and gender-based pain expectations on the development of CPSP. Secondary goals are to: (A) explore risk factors for poor functional status and patient-level cost of illness from a societal perspective up to 12 months following cardiac surgery; and (B) determine the impact of CPSP on quality-adjusted life years (QALYs) borne by cardiac surgery, in addition to the incremental cost for one additional QALY gained, among those who develop CPSP compared with those who do not. METHODS AND ANALYSES: In this prospective cohort study, 1250 adults undergoing cardiac surgery, including coronary artery bypass grafting and open-heart procedures, will be recruited over a 3-year period. Putative risk factors for CPSP will be captured prior to surgery, at postoperative day 3 (in hospital) and day 30 (at home). Outcome data will be collected via telephone interview at 6-month and 12-month follow-up. We will employ generalised estimating equations to model the primary (CPSP) and secondary outcomes (function and cost) while adjusting for prespecified model covariates. QALYs will be estimated by converting data from the Short Form-12 (version 2) to a utility score. ETHICS AND DISSEMINATION: This protocol has been approved by the responsible bodies at each of the hospital sites, and study enrolment began May 2015. We will disseminate our results through CardiacPain.Net, a web-based knowledge dissemination platform, presentation at international conferences and publications in scientific journals. TRIAL REGISTRATION NUMBER: NCT01842568

Structure-Based Design of Non-Natural Amino Acid Inhibitors of Amyloid Fibrillation

Many globular and natively disordered proteins can convert into amyloid fibers. These fibers are associated with numerous pathologies1 as well as with normal cellular functions2,3, and frequently form during protein denaturation4,5. Inhibitors of pathological amyloid fibers could serve as leads for therapeutics, provided the inhibitors were specific enough to avoid interfering with normal processes. Here we show that computer-aided, structure-based design can yield highly specific peptide inhibitors of amyloid formation. Using known atomic structures of segments of amyloid fibers as templates, we have designed and characterized an all D-amino acid inhibitor of fibrillation of the tau protein found in Alzheimer’s disease, and a non-natural L-amino acid inhibitor of an amyloid fiber that enhances sexual transmission of HIV. Our results indicate that peptides from structure-based designs can disrupt the fibrillation of full-length proteins, including those like tau that lack fully ordered native structures.We thank M.I. Ivanova, J. Corn, T. Kortemme, D. Anderson, M.R. Sawaya, M. Phillips, S. Sambashivan, J. Park, M. Landau, Q. Zhang, R. Clubb, F. Guo, T. Yeates, J. Nowick, J. Zheng, and M.J. Thompson for discussions, HHMI, NIH, NSF, the GATES foundation, and the Joint Center for Translational Medicine for support, R. Peterson for help with NMR experiments, E. Mandelkow for providing tau constructs, R. Riek for providing amyloid beta, J. Stroud for amyloid beta preparation. Support for JK was from the Damon Runyon Cancer Research Foundation, for HWC by the Ruth L. Kirschstein National Research Service Award, for JM from the programme for junior-professors by the ministry of science, Baden-Württemberg, and for SAS by a UCLA-IGERT bioinformatics traineeship

Pseudo-nitzschia physiological ecology, phylogeny, toxicity, monitoring and impacts on ecosystem health

This paper is not subject to U.S. copyright. The definitive version was published in Harmful Algae 14 (2012): 271-300, doi:10.1016/j.hal.2011.10.025.Over the last decade, our understanding of the environmental controls on Pseudo-nitzschia blooms and domoic acid (DA) production has matured. Pseudo-nitzschia have been found along most of the world's coastlines, while the impacts of its toxin, DA, are most persistent and detrimental in upwelling systems. However, Pseudo-nitzschia and DA have recently been detected in the open ocean's high-nitrate, low-chlorophyll regions, in addition to fjords, gulfs and bays, showing their presence in diverse environments. The toxin has been measured in zooplankton, shellfish, crustaceans, echinoderms, worms, marine mammals and birds, as well as in sediments, demonstrating its stable transfer through the marine food web and abiotically to the benthos. The linkage of DA production to nitrogenous nutrient physiology, trace metal acquisition, and even salinity, suggests that the control of toxin production is complex and likely influenced by a suite of environmental factors that may be unique to a particular region. Advances in our knowledge of Pseudo-nitzschia sexual reproduction, also in field populations, illustrate its importance in bloom dynamics and toxicity. The combination of careful taxonomy and powerful new molecular methods now allow for the complete characterization of Pseudo-nitzschia populations and how they respond to environmental changes. Here we summarize research that represents our increased knowledge over the last decade of Pseudo-nitzschia and its production of DA, including changes in worldwide range, phylogeny, physiology, ecology, monitoring and public health impacts

Three Dimensional Speckle Tracking Based Strain Imaging Identifies Alterations in Dynamic Left Ventricular Function after Cardiac Surgery

Three-dimensional (3D) echocardiography based strain imaging is an emerging modality to assess dynamic left ventricular function in patients undergoing cardiac surgery. Adult patients undergoing cardiac surgery (n=182) were prospectively imaged with 3D transthoracic echocardiograms (TTE) pre- and post-operatively and analyzed for left ventricular 3D; ejection fraction (EF), global peak systolic area (GAS), longitudinal (GLS), circumferential (GCS), and radial (GRS) strain. 3D strain correlated well with 3D EF. Receiver operating curves identified 3D GAS as the best indicator for ventricular function, with a normal cutoff of -25%. Pre-operative 3D strain was an independent predictor of ICU stay and inotrope score, increasing predictive value of known pre-operative risk factor models, especially in patients with reduced ventricular function. Demonstrating that after cardiac surgery, there is an acute reduction in post-operative left ventricular function that can be accurately measured with 3D speckle tracking strain imaging and strain measures may be predictive of post-operative outcomes