The autonomic nervous system and renal physiology

Research in resistant hypertension has again focused on autonomic nervous system denervation – 50 years after it had been stopped due to postural hypotension and availability of newer drugs. These (ganglionic blockers) drugs have all been similarly stopped, due to postural hypotension and yet newer antihypertensive agents. Recent demonstration of the feasibility of limited regional transcatheter sympathetic denervation has excited clinicians due to potential therapeutic implications. Standard use of ambulatory blood pressure recording equipment may alter our understanding of the diagnosis, potential treatment strategies, and health care outcomes – when faced with patients whose office blood pressure remains in the hypertensive range – while under treatment with three antihypertensive drugs at the highest tolerable doses, plus a diuretic. We review herein clinical relationships between autonomic function, resistant hypertension, current treatment strategies, and reflect upon the possibility of changes in our approach to resistant hypertension

Genomewide association study of acute anterior uveitis identifies new susceptibility loci

Acknowledgments The authors thank all participating subjects with AS and healthy individuals who provided the DNA and clinical information necessary for this study. We would like to acknowledge the contributions of Anna Deminger, Sahlgrenska Academy at University of Gothenburg, and Urban Hellman, Umeå University, for their assistance in case recruitment and assessment and handling biological samples Funding Information: The survey was conducted by NatCen and the genomewide scan data were analyzed and deposited by the Wellcome Trust Sanger Institute. Information on how to access the data can be found on the Understanding Society website https: www. understandingsociety.ac.uk/ . We acknowledge and thank the TCRA AS Group for their support in recruiting patients for the study. M.A.B. is funded by a National Health and Medical Research Council (Australia) Senior Principal Research Fellowship, and support for this study was received from a National Health and Medical Research Council (Australia) program Grant (566938) and project Grant (569829), and from the Australian Cancer Research Foundation and Rebecca Cooper Medical Research Foundation. We are also very grateful for the invaluable support received from the National Ankylosing Spondylitis Society (UK) and Spondyloarthritis Association of America in case recruitment. Additional financial and technical support for patient recruitment was provided by the National Institute for Health Research Oxford Musculoskeletal Biomedical Research Unit and NIHR Thames Valley Comprehensive Local Research and an unrestricted educational grant from Abbott Laboratories. The authors acknowledge the sharing of data and samples by the BSRBR-AS Register in Aberdeen. Chief Investigator, Prof Gary Macfarlane and Dr Gareth Jones, Deputy Chief Investigator, created the BSRBR-AS study, which was commissioned by the British Society for Rheumatology, funded in part by Abbvie, Pfizer, and UCB. We are grateful to every patient, past and present staff of the BSRBR-AS register team, and to all clinical staff who recruited patients, followed them up and entered data – details here: https://www.abdn.ac.uk/iahs/research/ epidemiology/spondyloarthritis.php#panel1011. Funding was also received from the Swedish Research Council and The Swedish state under the agreement between the Swedish government and the county councils, the ALF agreement. The Irish data was derived from participants in ASRI – The Ankylosing Spondylitis Registry of Ireland, which is funded by unrestricted grants from Abbvie and Pfizer. Funding bodies involved played no role in the study design, performance, or preparation of this manuscript. Funding Information: X.F.H. was funded by the National Natural Science Foundation of China (31771390). The TASC study was funded by the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) grants P01-052915, R01-AR046208. Funding was also received from the University of Texas Health Science Center at Houston CTSA grant UL1RR02418, Cedars-Sinai GCRC grant MO1-RR00425, Intramural Research Program, NIAMS/NIH, and Rebecca Cooper Foundation (Australia). This study was funded, in part, by Arthritis Research UK (Grants 19536 and 18797), by the Wellcome Trust (Grant number 076113), and by the Oxford Comprehensive Biomedical Research Centre ankylosing spondylitis chronic disease cohort (Theme Code: A91202). The New Zealand data was derived from participants in the Spondyloarthritis Genetics and the Environment Study (SAGE) and was funded by The Health Research Council, New Zealand. H.X. was funded by the National Natural Science Foundation of China Grant 81020108029 and 30872339. French sample collection was performed by the Groupe Française d’Etude Génétique des Spondylarthrites, coordinated by Professor Maxime Breban, and funded by the Agence Nationale de Recherche GEMISA grant reference ANR-10-MIDI-0002. We acknowledge the Understanding Society: The UK Household Longitudinal Study. This is led by the Institute for Social and Economic Research at the University of Essex and funded by the Economic and Social Research Council. Publisher Copyright: © 2020 Association for Research in Vision and Ophthalmology Inc.. All rights reserved.Peer reviewedPublisher PD

Models of classroom assessment for course-based research experiences

Course-based research pedagogy involves positioning students as contributors to authentic research projects as part of an engaging educational experience that promotes their learning and persistence in science. To develop a model for assessing and grading students engaged in this type of learning experience, the assessment aims and practices of a community of experienced course-based research instructors were collected and analyzed. This approach defines four aims of course-based research assessment—(1) Assessing Laboratory Work and Scientific Thinking; (2) Evaluating Mastery of Concepts, Quantitative Thinking and Skills; (3) Appraising Forms of Scientific Communication; and (4) Metacognition of Learning—along with a set of practices for each aim. These aims and practices of assessment were then integrated with previously developed models of course-based research instruction to reveal an assessment program in which instructors provide extensive feedback to support productive student engagement in research while grading those aspects of research that are necessary for the student to succeed. Assessment conducted in this way delicately balances the need to facilitate students’ ongoing research with the requirement of a final grade without undercutting the important aims of a CRE education

Broadband Multi-wavelength Properties of M87 during the 2017 Event Horizon Telescope Campaign

Abstract: In 2017, the Event Horizon Telescope (EHT) Collaboration succeeded in capturing the first direct image of the center of the M87 galaxy. The asymmetric ring morphology and size are consistent with theoretical expectations for a weakly accreting supermassive black hole of mass ∼6.5 × 109 M ⊙. The EHTC also partnered with several international facilities in space and on the ground, to arrange an extensive, quasi-simultaneous multi-wavelength campaign. This Letter presents the results and analysis of this campaign, as well as the multi-wavelength data as a legacy data repository. We captured M87 in a historically low state, and the core flux dominates over HST-1 at high energies, making it possible to combine core flux constraints with the more spatially precise very long baseline interferometry data. We present the most complete simultaneous multi-wavelength spectrum of the active nucleus to date, and discuss the complexity and caveats of combining data from different spatial scales into one broadband spectrum. We apply two heuristic, isotropic leptonic single-zone models to provide insight into the basic source properties, but conclude that a structured jet is necessary to explain M87’s spectrum. We can exclude that the simultaneous γ-ray emission is produced via inverse Compton emission in the same region producing the EHT mm-band emission, and further conclude that the γ-rays can only be produced in the inner jets (inward of HST-1) if there are strongly particle-dominated regions. Direct synchrotron emission from accelerated protons and secondaries cannot yet be excluded

Lipid Toxicity in the Cardiovascular-Kidney-Metabolic Syndrome (CKMS)

Recent studies of Cardiovascular-Kidney-Metabolic Syndrome (CKMS) indicate that elevated concentrations of derivatives of phospholipids (ceramide, sphingosine), oxidized LDL, and lipoproteins (a, b) are toxic to kidney and heart function. Energy production for renal proximal tubule resorption of critical fuels and electrolytes is required for homeostasis. Cardiac energy for ventricular contraction/relaxation is preferentially supplied by long chain fatty acids. Metabolism of long chain fatty acids is accomplished within the cardiomyocyte cytoplasm and mitochondria by means of the glycolytic, tricarboxylic acid, and electron transport cycles. Toxic lipids and excessive lipid concentrations may inhibit cardiac function. Cardiac contraction requires calcium movement from the sarcoplasmic reticulum from a high to a low concentration at relatively low energy cost. Cardiac relaxation involves calcium return to the sarcoplasmic reticulum from a lower to a higher concentration and requires more energy consumption. Diastolic cardiac dysfunction occurs when cardiomyocyte energy conversion is inadequate. Diastolic dysfunction from diminished ATP availability occurs in the presence of inadequate blood pressure, glycemia, or lipid control and may lead to heart failure. Similar disruption of renal proximal tubular resorption of fuels/electrolytes has been found to be associated with phospholipid (sphingolipid) accumulation. Elevated concentrations of tissue oxidized low-density lipoprotein cholesterols are associated with loss of filtration efficiency at the level of the renal glomerular podocyte. Macroscopically excessive deposits of epicardial and intra-nephric adipose are associated with vascular pathology, fibrosis, and inhibition of essential functions in both heart and kidney. Chronic triglyceride accumulation is associated with fibrosis of the liver, cardiac and renal structures. Successful liver, kidney, or cardiac allograft of these vital organs does not eliminate the risk of lipid toxicity. Lipid lowering therapy may assist in protecting vital organ function before and after allograft transplantation

Calcium Ion Channels: Roles in Infection and Sepsis Mechanisms of Calcium Channel Blocker Benefits in Immunocompromised Patients at Risk for Infection

Immunosuppression may occur for a number of reasons related to an individual’s frailty, debility, disease or from therapeutic iatrogenic intervention or misadventure. A large percentage of morbidity and mortality in immunodeficient populations is related to an inadequate response to infectious agents with slow response to antibiotics, enhancements of antibiotic resistance in populations, and markedly increased prevalence of acute inflammatory response, septic and infection related death. Given known relationships between intracellular calcium ion concentrations and cytotoxicity and cellular death, we looked at currently available data linking blockade of calcium ion channels and potential decrease in expression of sepsis among immunosuppressed patients. Notable are relationships between calcium, calcium channel, vitamin D mechanisms associated with sepsis and demonstration of antibiotic-resistant pathogens that may utilize channels sensitive to calcium channel blocker. We note that sepsis shock syndrome represents loss of regulation of inflammatory response to infection and that vitamin D, parathyroid hormone, fibroblast growth factor, and klotho interact with sepsis defense mechanisms in which movement of calcium and phosphorus are part of the process. Given these observations we consider that further investigation of the effect of relatively inexpensive calcium channel blockade agents of infections in immunosuppressed populations might be worthwhile

The Diabetic Cardiorenal Nexus

The end-stage of the clinical combination of heart failure and kidney disease has become known as cardiorenal syndrome. Adverse consequences related to diabetes, hyperlipidemia, obesity, hypertension and renal impairment on cardiovascular function, morbidity and mortality are well known. Guidelines for the treatment of these risk factors have led to the improved prognosis of patients with coronary artery disease and reduced ejection fraction. Heart failure hospital admissions and readmission often occur, however, in the presence of metabolic, renal dysfunction and relatively preserved systolic function. In this domain, few advances have been described. Diabetes, kidney and cardiac dysfunction act synergistically to magnify healthcare costs. Current therapy relies on improving hemodynamic factors destructive to both the heart and kidney. We consider that additional hemodynamic solutions may be limited without the use of animal models focusing on the cardiomyocyte, nephron and extracellular matrices. We review herein potential common pathophysiologic targets for treatment to prevent and ameliorate this syndrome

Sodium–glucose cotransporter-2 inhibition and acidosis in patients with type 2 diabetes: a review of US FDA data and possible conclusions

Objective: To evaluate whether adverse event reports to the US Food and Drug Administration on incidents of ketoacidosis from use of sodium glucose cotransport inhibitors (SGLT2 inhibitors) provide insight into ways this new class of drugs is being prescribed with other antihyperglycemic agents; to examine possible mechanisms to explain ketoacidosis. Design and methods Reports of adverse events concerned to SGLT2 inhibitors, namely, empagliflozin, dapagliflozin, and canagliflozin were obtained under the Freedom of Information Act for 5 years ending in August 31, 2015. The data were evaluated for incidents of ketoacidosis by looking for keywords such as diabetic ketoacidosis, ketoacidosis, lactic acidosis, acidosis, and metabolic acidosis. Results were tabulated individually for empagliflozin (n=260 adverse event reports), dapagliflozin (n=520), and canagliflozin (n=2159). Adverse events were categorized according to age, gender, and insulin use. Results: There were 46, 144, and 450 reports of ketoacidosis concerned with the use of empagliflozin, dapagliflozin, and canagliflozin, respectively. The use of SGLT2 inhibitors was not strictly limited to patients with type 2 diabetes but was cut across categories of insulin use, including a total of 172 cases of SGLT2-related ketoacidosis in individuals above the age of 40 who were not on insulin. Conclusion: Further studies should focus to detect pleiotropic effects of SGLT2 inhibitors, particularly with other oral antihyperglycemic drugs or insulin. A review of the literature suggests that patients with type 2 diabetes with low C-peptide level may be at increased risk of ketoacidosis, particularly if they are on statins and diuretics due to hypokalemia and impaired release of insulin. More studies are warranted to further clarify these mechanisms