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Full-Text Articles in Physiology

Methylglyoxal Requires Ac1 And Trpa1 To Produce Pain And Spinal Neuron Activation, Ryan B. Griggs, Don E. Laird, Renee R. Donahue, Weisi Fu, Bradley K. Taylor Dec 2017

Methylglyoxal Requires Ac1 And Trpa1 To Produce Pain And Spinal Neuron Activation, Ryan B. Griggs, Don E. Laird, Renee R. Donahue, Weisi Fu, Bradley K. Taylor

Physiology Faculty Publications

Methylglyoxal (MG) is a metabolite of glucose that may contribute to peripheral neuropathy and pain in diabetic patients. MG increases intracellular calcium in sensory neurons and produces behavioral nociception via the cation channel transient receptor potential ankyrin 1 (TRPA1). However, rigorous characterization of an animal model of methylglyoxal-evoked pain is needed, including testing whether methylglyoxal promotes negative pain affect. Furthermore, it remains unknown whether methylglyoxal is sufficient to activate neurons in the spinal cord dorsal horn, whether this requires TRPA1, and if the calcium-sensitive adenylyl cyclase 1 isoform (AC1) contributes to MG-evoked pain. We administered intraplantar methylglyoxal and then evaluated …


Hyperhomocysteinemia-Induced Gene Expression Changes In The Cell Types Of The Brain, Erica M. Weekman, Abigail E. Woolums, Tiffany L. Sudduth, Donna M. Wilcock Dec 2017

Hyperhomocysteinemia-Induced Gene Expression Changes In The Cell Types Of The Brain, Erica M. Weekman, Abigail E. Woolums, Tiffany L. Sudduth, Donna M. Wilcock

Sanders-Brown Center on Aging Faculty Publications

High plasma levels of homocysteine, termed hyperhomocysteinemia, are a risk factor for vascular cognitive impairment and dementia, which is the second leading cause of dementia. While hyperhomocysteinemia induces microhemorrhages and cognitive decline in mice, the specific effect of hyperhomocysteinemia on each cell type remains unknown. We took separate cultures of astrocytes, microglia, endothelial cells, and neuronal cells and treated each with moderate levels of homocysteine for 24, 48, 72, and 96 hr. We then determined the gene expression changes for cell-specific markers and neuroinflammatory markers including the matrix metalloproteinase 9 system. Astrocytes had decreased levels of several astrocytic end feet …


Sustained Sensitizing Effects Of Tumor Necrosis Factor Alpha On Sensory Nerves In Lung And Airways, Ruei-Lung Lin, Qihai Gu, Mehdi Khosravi, Lu-Yuan Lee Dec 2017

Sustained Sensitizing Effects Of Tumor Necrosis Factor Alpha On Sensory Nerves In Lung And Airways, Ruei-Lung Lin, Qihai Gu, Mehdi Khosravi, Lu-Yuan Lee

Physiology Faculty Publications

Tumor necrosis factor alpha (TNFα) plays a significant role in the pathogenesis of airway inflammatory diseases. Inhalation of aerosolized TNFα induced airway hyperresponsiveness accompanied by airway inflammation in healthy human subjects, but the underlying mechanism is not fully understood. We recently reported a series of studies aimed to investigate if TNFα elevates the sensitivity of vagal bronchopulmonary sensory nerves in a mouse model; these studies are summarized in this mini-review. Our results showed that intratracheal instillation of TNFα induced pronounced airway inflammation 24 hours later, as illustrated by infiltration of eosinophils and neutrophils and the release of inflammatory mediators and …


Physiological And Biomechanical Responses Of Highly Trained Distance Runners To Lower-Body Positive Pressure Treadmill Running, Kyle Barnes, Jessica N. Janecke Nov 2017

Physiological And Biomechanical Responses Of Highly Trained Distance Runners To Lower-Body Positive Pressure Treadmill Running, Kyle Barnes, Jessica N. Janecke

Funded Articles

Background: As a way to train at faster running speeds, add training volume, prevent injury, or rehabilitate after an injury, lower-body positive pressure treadmills (LBPPT) have become increasingly commonplace among athletes. However, there are conflicting evidence and a paucity of data describing the physiological and biomechanical responses to LBPPT running in highly trained or elite caliber runners at the running speeds they habitually train at, which are considerably faster than those of recreational runners. Furthermore, data is lacking regarding female runners’ responses to LBPPT running. Therefore, this study was designed to evaluate the physiological and biomechanical responses to LBPPT …


Current Research And Statistical Practices In Sport Science And A Need For Change, Jake R. Bernards, Kimitake Sato, G. Gregory Haff, Caleb D. Bazyler Nov 2017

Current Research And Statistical Practices In Sport Science And A Need For Change, Jake R. Bernards, Kimitake Sato, G. Gregory Haff, Caleb D. Bazyler

ETSU Faculty Works

Current research ideologies in sport science allow for the possibility of investigators producing statistically significant results to help fit the outcome into a predetermined theory. Additionally, under the current Neyman-Pearson statistical structure, some argue that null hypothesis significant testing (NHST) under the frequentist approach is flawed, regardless. For example, a p-value is unable to measure the probability that the studied hypothesis is true, unable to measure the size of an effect or the importance of a result, and unable to provide a good measure of evidence regarding a model or hypothesis. Many of these downfalls are key questions researchers strive …


Primary Upper Urinary Tract Small Cell Carcinoma: A Case Series And Literature Review, Patrick J. Hensley, Amul A. Bhalodi, Shubham Gupta Nov 2017

Primary Upper Urinary Tract Small Cell Carcinoma: A Case Series And Literature Review, Patrick J. Hensley, Amul A. Bhalodi, Shubham Gupta

Urology Faculty Publications

Background: Primary upper urinary tract small cell carcinoma (SCC) is exceedingly rare with < 30 cases reported in the literature. Little is known about the incidence, diagnosis, treatment, and outcomes in these patients. We present a series of three patients with primary upper tract SCC.

Case Presentation: Patient 1 is an 89-year-old Caucasian male who presented with hydroureteronephrosis and a mass in the proximal right ureter. Biopsy revealed SCC. Without further intervention, the patient died 2 months after his diagnosis. Patient 2 is a 67-year-old Caucasian female who underwent left laparoscopic nephroureterectomy for primary distal ureteral SCC, pT4N1M0. She developed lymphadenopathy and completed external beam radiation to the pelvis and four courses of cisplatin-based chemotherapy. She died from metastatic disease 7 months after diagnosis. Patient 3 is a 45-year-old female who underwent …


Calpain Inhibition Attenuates Adipose Tissue Inflammation And Fibrosis In Diet-Induced Obese Mice, Latha Muniappan, Aida Javidan, Weihua Jiang, Shayan Mohammadmoradi, Jessica J. Moorleghen, Wendy S. Katz, Anju Balakrishnan, Deborah A. Howatt, Venkateswaran Subramanian Oct 2017

Calpain Inhibition Attenuates Adipose Tissue Inflammation And Fibrosis In Diet-Induced Obese Mice, Latha Muniappan, Aida Javidan, Weihua Jiang, Shayan Mohammadmoradi, Jessica J. Moorleghen, Wendy S. Katz, Anju Balakrishnan, Deborah A. Howatt, Venkateswaran Subramanian

Saha Cardiovascular Research Center Faculty Publications

Adipose tissue macrophages have been proposed as a link between obesity and insulin resistance. However, the mechanisms underlying these processes are not completely defined. Calpains are calcium-dependent neutral cysteine proteases that modulate cellular function and have been implicated in various inflammatory diseases. To define whether activated calpains influence diet-induced obesity and adipose tissue macrophage accumulation, mice that were either wild type (WT) or overexpressing calpastatin (CAST Tg), the endogenous inhibitor of calpains were fed with high (60% kcal) fat diet for 16 weeks. CAST overexpression did not influence high fat diet-induced body weight and fat mass gain throughout the study. …


Functional Neuroplasticity In The Nucleus Tractus Solitarius And Increased Risk Of Sudden Death In Mice With Acquired Temporal Lobe Epilepsy, Isabel D. Derera, Brian P. Delisle, Bret N. Smith Oct 2017

Functional Neuroplasticity In The Nucleus Tractus Solitarius And Increased Risk Of Sudden Death In Mice With Acquired Temporal Lobe Epilepsy, Isabel D. Derera, Brian P. Delisle, Bret N. Smith

Physiology Faculty Publications

Sudden unexpected death in epilepsy (SUDEP) is the leading cause of death in individuals with refractory acquired epilepsy. Cardiorespiratory failure is the most likely cause in most cases, and central autonomic dysfunction has been implicated as a contributing factor to SUDEP. Neurons of the nucleus tractus solitarius (NTS) in the brainstem vagal complex receive and integrate vagally mediated information regarding cardiorespiratory and other autonomic functions, and GABAergic inhibitory NTS neurons play an essential role in modulating autonomic output. We assessed the activity of GABAergic NTS neurons as a function of epilepsy development in the pilocarpine-induced status epilepticus (SE) model of …


Deletion Of The Nr4a Nuclear Receptor Nor1 In Hematopoietic Stem Cells Reduces Inflammation But Not Abdominal Aortic Aneurysm Formation, Hua Qing, Karrie L. Jones, Elizabeth B. Heywood, Hong Lu, Alan Daugherty, Dennis Bruemmer Oct 2017

Deletion Of The Nr4a Nuclear Receptor Nor1 In Hematopoietic Stem Cells Reduces Inflammation But Not Abdominal Aortic Aneurysm Formation, Hua Qing, Karrie L. Jones, Elizabeth B. Heywood, Hong Lu, Alan Daugherty, Dennis Bruemmer

Pharmacology and Nutritional Sciences Faculty Publications

Background: The NR4A3 orphan nuclear hormone receptor, NOR1, functions as a constitutively active transcription factor to regulate inflammation, proliferation, and cell survival during pathological vascular remodeling. Inflammatory processes represent key mechanisms leading to abdominal aortic aneurysm (AAA) formation. However, a role of NOR1 in AAA formation has not been investigated previously.

Methods: Inflammatory gene expression was analyzed in bone marrow-derived macrophages isolated from NOR1-deficient mice. Low-density lipoprotein receptor-deficient (LDLr−/−) mice were irradiated and reconstituted with hematopoietic stem cells obtained from NOR1−/− or wild-type littermate mice. Animals were infused with angiotensin II and fed a diet enriched in saturated …


No Difference In Myosin Kinetics And Spatial Distribution Of The Lever Arm In The Left And Right Ventricles Of Human Hearts, Divya Duggal, S. Requena, Janhavi Nagwekar, Sangram Raut, Ryan Rich, Hriday Das, Vipul Patel, Ignacy Gryczynski, Rafal Fudala, Zygmunt Gryczynski, Cheavar Blair, Kenneth S. Campbell, Julian Borejdo Oct 2017

No Difference In Myosin Kinetics And Spatial Distribution Of The Lever Arm In The Left And Right Ventricles Of Human Hearts, Divya Duggal, S. Requena, Janhavi Nagwekar, Sangram Raut, Ryan Rich, Hriday Das, Vipul Patel, Ignacy Gryczynski, Rafal Fudala, Zygmunt Gryczynski, Cheavar Blair, Kenneth S. Campbell, Julian Borejdo

Physiology Faculty Publications

The systemic circulation offers larger resistance to the blood flow than the pulmonary system. Consequently, the left ventricle (LV) must pump blood with more force than the right ventricle (RV). The question arises whether the stronger pumping action of the LV is due to a more efficient action of left ventricular myosin, or whether it is due to the morphological differences between ventricles. Such a question cannot be answered by studying the entire ventricles or myocytes because any observed differences would be wiped out by averaging the information obtained from trillions of myosin molecules present in a ventricle or myocyte. …


Maximum Strength, Rate Of Force Development, Jump Height, And Peak Power Alterations In Weightlifters Across Five Months Of Training, W. Guy Hornsby, Jeremy A. Gentles, Christopher J. Macdonald, Satoshi Mizuguchi, Michael W. Ramsey, Michael H. Stone Oct 2017

Maximum Strength, Rate Of Force Development, Jump Height, And Peak Power Alterations In Weightlifters Across Five Months Of Training, W. Guy Hornsby, Jeremy A. Gentles, Christopher J. Macdonald, Satoshi Mizuguchi, Michael W. Ramsey, Michael H. Stone

ETSU Faculty Works

The purpose of this monitoring study was to investigate how alterations in training affect changes in force-related characteristics and weightlifting performance. Subjects: Seven competitive weightlifters participated in the study. Methods: The weightlifters performed a block style periodized plan across 20 weeks. Force plate data from the isometric mid-thigh pull and static jumps with 0 kg, 11 kg, and 20 kg were collected near the end of each training block (weeks 1, 6, 10, 13, 17, and 20). Weightlifting performance was measured at weeks 0, 7, 11, and 20. Results: Very strong correlations were noted between weightlifting performances and isometric rate …


Adipose Tissue As A Site Of Toxin Accumulation, Erin Jackson, Robin C. Shoemaker, Nika Larian, Lisa A. Cassis Oct 2017

Adipose Tissue As A Site Of Toxin Accumulation, Erin Jackson, Robin C. Shoemaker, Nika Larian, Lisa A. Cassis

Pharmacology and Nutritional Sciences Faculty Publications

We examine the role of adipose tissue, typically considered an energy storage site, as a potential site of toxicant accumulation. Although the production of most persistent organic pollutants (POPs) was banned years ago, these toxicants persist in the environment due to their resistance to biodegradation and widespread distribution in various environmental forms (e.g., vapor, sediment, and water). As a result, human exposure to these toxicants is inevitable. Largely due to their lipophilicity, POPs bioaccumulate in adipose tissue, resulting in greater body burdens of these environmental toxicants with obesity. POPs of major concern include polychlorinated biphenyls (PCBs), polychlorinated dibenzo‐p‐dioxins and furans …


Brain Injury-Induced Synaptic Reorganization In Hilar Inhibitory Neurons Is Differentially Suppressed By Rapamycin, Corwin R. Butler, Jeffery A. Boychuk, Bret N. Smith Sep 2017

Brain Injury-Induced Synaptic Reorganization In Hilar Inhibitory Neurons Is Differentially Suppressed By Rapamycin, Corwin R. Butler, Jeffery A. Boychuk, Bret N. Smith

Physiology Faculty Publications

Following traumatic brain injury (TBI), treatment with rapamycin suppresses mammalian (mechanistic) target of rapamycin (mTOR) activity and specific components of hippocampal synaptic reorganization associated with altered cortical excitability and seizure susceptibility. Reemergence of seizures after cessation of rapamycin treatment suggests, however, an incomplete suppression of epileptogenesis. Hilar inhibitory interneurons regulate dentate granule cell (DGC) activity, and de novo synaptic input from both DGCs and CA3 pyramidal cells after TBI increases their excitability but effects of rapamycin treatment on the injury-induced plasticity of interneurons is only partially described. Using transgenic mice in which enhanced green fluorescent protein (eGFP) is expressed in …


Stress Increases Peripheral Axon Growth And Regeneration Through Glucocorticoid Receptor-Dependent Transcriptional Programs, Jessica K. Lerch, Jessica K. Alexander, Kathryn M. Madalena, Dario Motti, Tam Quach, Akhil Dhamija, Alicia Zha, John C. Gensel, Jeanette Webster Marketon, Vance P. Lemmon, John L. Bixby, Phillip G. Popovich Aug 2017

Stress Increases Peripheral Axon Growth And Regeneration Through Glucocorticoid Receptor-Dependent Transcriptional Programs, Jessica K. Lerch, Jessica K. Alexander, Kathryn M. Madalena, Dario Motti, Tam Quach, Akhil Dhamija, Alicia Zha, John C. Gensel, Jeanette Webster Marketon, Vance P. Lemmon, John L. Bixby, Phillip G. Popovich

Physiology Faculty Publications

Stress and glucocorticoid (GC) release are common behavioral and hormonal responses to injury or disease. In the brain, stress/GCs can alter neuron structure and function leading to cognitive impairment. Stress and GCs also exacerbate pain, but whether a corresponding change occurs in structural plasticity of sensory neurons is unknown. Here, we show that in female mice (Mus musculus) basal GC receptor (Nr3c1, also known as GR) expression in dorsal root ganglion (DRG) sensory neurons is 15-fold higher than in neurons in canonical stress-responsive brain regions (M. musculus). In response to stress or GCs, adult …


Body Size Predicts Cardiac And Vascular Resistance Effects On Men's And Women's Blood Pressure, Joyce M. Evans, Siqi Wang, Christopher Greb, Vladimir Kostas, Charles F. Knapp, Qingguang Zhang, Eric S. Roemmele, Michael B. Stenger, David C. Randall Aug 2017

Body Size Predicts Cardiac And Vascular Resistance Effects On Men's And Women's Blood Pressure, Joyce M. Evans, Siqi Wang, Christopher Greb, Vladimir Kostas, Charles F. Knapp, Qingguang Zhang, Eric S. Roemmele, Michael B. Stenger, David C. Randall

Biomedical Engineering Faculty Publications

Key Points Summary

  • We report how blood pressure, cardiac output and vascular resistance are related to height, weight, body surface area (BSA), and body mass index (BMI) in healthy young adults at supine rest and standing.
  • Much inter-subject variability in young adult's blood pressure, currently attributed to health status, may actually result from inter-individual body size differences.
  • Each cardiovascular variable is linearly related to height, weight and/or BSA (more than to BMI).
  • When supine, cardiac output is positively related, while vascular resistance is negatively related, to body size. Upon standing, the change in vascular resistance is positively related to size. …


Increases In Variation Of Barbell Kinematics Are Observed With Increasing Intensity In A Graded Back Squat Test, Kevin M. Carroll, Kimitake Sato, Caleb D. Bazyler, N. Travis Triplett, Michael H. Stone Jul 2017

Increases In Variation Of Barbell Kinematics Are Observed With Increasing Intensity In A Graded Back Squat Test, Kevin M. Carroll, Kimitake Sato, Caleb D. Bazyler, N. Travis Triplett, Michael H. Stone

ETSU Faculty Works

The purpose of the current study was two-fold: (1) To examine the variation in velocity and power with increasing intensity in the back squat among subjects; and (2) To explore individual subject characteristics as possible explanations for variations of velocity in the back squat. Fourteen recreationally trained male subjects with experience in the back squat agreed to participate in the study (age = 25.0 ± 2.6 years, height = 178.9 ± 8.1 cm, body mass = 88.2 ± 15.8 kg). One-repetition maximums (1RM) were performed for each subject on force platforms with four linear position transducers attached to the barbell. …


Temperature As A Circadian Marker In Older Human Subjects: Relationship To Metabolic Syndrome And Diabetes, Brianna D. Harfmann, Elizabeth A. Schroder, Jonathan H. England, Natalie J. Senn, Philip M. Westgate, Karyn A. Esser, Philip A. Kern Jul 2017

Temperature As A Circadian Marker In Older Human Subjects: Relationship To Metabolic Syndrome And Diabetes, Brianna D. Harfmann, Elizabeth A. Schroder, Jonathan H. England, Natalie J. Senn, Philip M. Westgate, Karyn A. Esser, Philip A. Kern

Internal Medicine Faculty Publications

Background: Circadian rhythms are characterized by approximate 24-hour oscillations in physiological and behavioral processes. Disruptions in these endogenous rhythms, most commonly associated with shift work and/or lifestyle, are recognized to be detrimental to health. Several studies have demonstrated a high correlation between disrupted circadian rhythms and metabolic disease. The aim of this study was to determine which metabolic parameters correlate with physiological measures of circadian temperature amplitude (TempAmp) and stability (TempStab).

Methods: Wrist skin temperature was measured in 34 subjects (ages 50 to 70, including lean, obese, and diabetic subjects) every 10 minutes for 7 consecutive days. Anthropometric measures and …


The Validity Of Submaximal Exercise Testing In Obese Women, Gabrielle Ringenberg Jun 2017

The Validity Of Submaximal Exercise Testing In Obese Women, Gabrielle Ringenberg

Mahurin Honors College Capstone Experience/Thesis Projects

Background: Submaximal exercise tests use heart rate responses to low-to-moderate intensity activity in order to predict cardiorespiratory fitness (VO2max). Currently used tests may be inappropriate for obese populations as obese women have altered heart rate responses to exercise. The purpose of this project is to test the validity of the Modified Bruce Protocol submaximal treadmill test in obese women. Methods: Normal-weight (NWG) and obese women (OBG) completed the Modified Bruce submaximal treadmill test (to predict VO2max using previously validated equations) and a maximal graded exercise test on a treadmill using the Standard Bruce Protocol (to obtain an …


Outcomes Of Spatially Fractionated Radiotherapy (Grid) For Bulky Soft Tissue Sarcomas In A Large Animal Model, Michael W. Nolan, Tracy L. Gieger, Alexander A. Karakashian, Mariana N. Nikolova‑Karakashian, Lysa P. Posner, Donald M. Roback, Judith N. Rivera, Sha Chang Jun 2017

Outcomes Of Spatially Fractionated Radiotherapy (Grid) For Bulky Soft Tissue Sarcomas In A Large Animal Model, Michael W. Nolan, Tracy L. Gieger, Alexander A. Karakashian, Mariana N. Nikolova‑Karakashian, Lysa P. Posner, Donald M. Roback, Judith N. Rivera, Sha Chang

Physiology Faculty Publications

GRID directs alternating regions of high- and low-dose radiation at tumors. A large animal model mimicking the geometries of human treatments is needed to complement existing rodent systems (eg, microbeam) and clarify the physical and biological attributes of GRID. A pilot study was undertaken in pet dogs with spontaneous soft tissue sarcomas to characterize responses to GRID. Subjects were treated with either 20 Gy (3 dogs) or 25 Gy (3 dogs), delivered using 6 MV X-rays and a commercial GRID collimator. Acute toxicity and tumor responses were assessed 2, 4, and 6 weeks later. Acute Radiation Therapy Oncology Group grade …


Disulfide High Mobility Group Box-1 Causes Bladder Pain Through Bladder Toll-Like Receptor 4, Fei Ma, Dimitrios E. Kouzoukas, Katherine L. Meyer-Siegler, Karin N. Westlund, David E. Hunt, Pedro L. Vera May 2017

Disulfide High Mobility Group Box-1 Causes Bladder Pain Through Bladder Toll-Like Receptor 4, Fei Ma, Dimitrios E. Kouzoukas, Katherine L. Meyer-Siegler, Karin N. Westlund, David E. Hunt, Pedro L. Vera

Physiology Faculty Publications

Background: Bladder pain is a prominent symptom in several urological conditions (e.g. infection, painful bladder syndrome/interstitial cystitis, cancer). Understanding the mechanism of bladder pain is important, particularly when the pain is not accompanied by bladder pathology. Stimulation of protease activated receptor 4 (PAR4) in the urothelium results in bladder pain through release of urothelial high mobility group box-1 (HMGB1). HGMB1 has two functionally active redox states (disulfide and all-thiol) and it is not known which form elicits bladder pain. Therefore, we investigated whether intravesical administration of specific HMGB1 redox forms caused abdominal mechanical hypersensitivity, micturition changes, and bladder inflammation in …


Optimal Nutrition For Endurance Exercise: A Systematic Review, Sarah E. Andrus Ms, Bruce W. Andrus Md Ms May 2017

Optimal Nutrition For Endurance Exercise: A Systematic Review, Sarah E. Andrus Ms, Bruce W. Andrus Md Ms

Dartmouth Scholarship

Introduction

As fatigue in endurance events correlates with depletion of muscle glycogen, the traditional approach to nutritional support has been carbohydrate loading. However, there has been recent interest in improving athletic endurance performance by novel diets in the days to weeks prior to endurance events, the pre-event meal, and during exercise.

Methods

We searched PubMed and SCOPUS for randomized trials published from 1992-2017 with a primary endpoint of endurance performance. We identified 407 citations which were examined against our inclusion criteria of randomization or crossover allocation to diet and for which a primary outcome was endurance performance.

Results

Twenty full …


Qt Prolongation Is Associated With Increased Mortality In End Stage Liver Disease, Sun Moon Kim, Bennet George, Diego Alcivar-Franco, Charles L. Campbell, Richard Charnigo, Brian P. Delisle, Jonathan Hundley, Yousef Darrat, Gustavo Morales, Samy-Claude Elayi, Alison L. Bailey Apr 2017

Qt Prolongation Is Associated With Increased Mortality In End Stage Liver Disease, Sun Moon Kim, Bennet George, Diego Alcivar-Franco, Charles L. Campbell, Richard Charnigo, Brian P. Delisle, Jonathan Hundley, Yousef Darrat, Gustavo Morales, Samy-Claude Elayi, Alison L. Bailey

Internal Medicine Faculty Publications

AIM

To determine the prevalence of QT prolongation in a large series of end stage liver disease (ESLD) patients and its association to clinical variables and mortality.

METHODS

The QT interval was measured and corrected for heart rate for each patient, with a prolonged QT cutoff defined as QT > 450 ms for males and QT > 470 ms for females. Multiple clinical variables were evaluated including sex, age, serum sodium, international normalized ratio, creatinine, total bilirubin, beta-blocker use, Model for End-Stage Liver Disease (MELD), MELD-Na, and etiology of liver disease.

RESULTS

Among 406 ESLD patients analyzed, 207 (51.0%) had QT prolongation. …


Pharmacology, Pharmacokinetics, And Metabolism Of The Dna-Decoy Ayx1 For The Prevention Of Acute And Chronic Post-Surgical Pain, Julien Mamet, Scott Harris, Michael Klukinov, David C. Yeomans, Renee R. Donahue, Bradley K. Taylor, Kelly Eddinger, Tony Yaksh, Donald C. Manning Apr 2017

Pharmacology, Pharmacokinetics, And Metabolism Of The Dna-Decoy Ayx1 For The Prevention Of Acute And Chronic Post-Surgical Pain, Julien Mamet, Scott Harris, Michael Klukinov, David C. Yeomans, Renee R. Donahue, Bradley K. Taylor, Kelly Eddinger, Tony Yaksh, Donald C. Manning

Physiology Faculty Publications

Background: AYX1 is an unmodified DNA-decoy designed to reduce acute post-surgical pain and its chronification with a single intrathecal dose at the time of surgery. AYX1 inhibits the transcription factor early growth response protein 1, which is transiently induced at the time of injury and triggers gene regulation in the dorsal root ganglia and spinal cord that leads to long-term sensitization and pain. This work characterizes the AYX1 dose-response profile in rats and the link to AYX1 pharmacokinetics and metabolism in the cerebrospinal fluid, dorsal root ganglia, and spinal cord.

Results: The effects of ascending dose-levels of AYX1 on mechanical …


Vestibular Activation Habituates The Vasovagal Response In The Rat, Bernard Cohen, Giorgio P. Martinelli, Yongqing Xiang, Theodore Raphan, Sergei B. Yakushin Mar 2017

Vestibular Activation Habituates The Vasovagal Response In The Rat, Bernard Cohen, Giorgio P. Martinelli, Yongqing Xiang, Theodore Raphan, Sergei B. Yakushin

Publications and Research

Vasovagal syncope is a significant medical problem without effective therapy, postulated to be related to a collapse of baroreflex function. While some studies have shown that repeated static tilts can block vasovagal syncope, this was not found in other studies. Using anesthetized, male Long–Evans rats that were highly susceptible to generation of vasovagal responses, we found that repeated activation of the vestibulosympathetic reflex (VSR) with ±2 and ±3 mA, 0.025 Hz sinusoidal galvanic vestibular stimulation (sGVS) caused incremental changes in blood pressure (BP) and heart rate (HR) that blocked further generation of vasovagal responses. Initially, BP and HR fell ≈20–50 …


Apolipoprotein E4 And Insulin Resistance Interact To Impair Cognition And Alter The Epigenome And Metabolome, Lance A. Johnson, Eileen Ruth S. Torres, Soren Impey, Jan F. Stevens, Jacob Raber Mar 2017

Apolipoprotein E4 And Insulin Resistance Interact To Impair Cognition And Alter The Epigenome And Metabolome, Lance A. Johnson, Eileen Ruth S. Torres, Soren Impey, Jan F. Stevens, Jacob Raber

Physiology Faculty Publications

Apolipoprotein E4 (E4) and type 2 diabetes are major risk factors for cognitive decline and late onset Alzheimer’s disease (AD). E4-associated phenotypes and insulin resistance (IR) share several features and appear to interact in driving cognitive dysfunction. However, shared mechanisms that could explain their overlapping pathophysiology have yet to be found. We hypothesized that, compared to E3 mice, E4 mice would be more susceptible to the harmful cognitive effects of high fat diet (HFD)-induced IR due to apoE isoform-specific differences in brain metabolism. While both E3 and E4 mice fed HFD displayed impairments in peripheral metabolism and cognition, deficits in …


Pre-Training Muscle Characteristics Of Subjects Who Are Obese Determine How Well Exercise Training Will Improve Their Insulin Responsiveness, Charles A. Stuart, Michelle L. Lee, Mark A. South, Mary E. A. Howell, Brian M. Cartwright, Michael W. Ramsey, Michael H. Stone Mar 2017

Pre-Training Muscle Characteristics Of Subjects Who Are Obese Determine How Well Exercise Training Will Improve Their Insulin Responsiveness, Charles A. Stuart, Michelle L. Lee, Mark A. South, Mary E. A. Howell, Brian M. Cartwright, Michael W. Ramsey, Michael H. Stone

ETSU Faculty Works

Pre-training muscle characteristics of subjects who are obese determine how well exercise training will improve their insulin responsiveness. J Strength Cond Res 31(3): 798–808, 2017—Only half of prediabetic subjects who are obese who underwent exercise training without weight loss increased their insulin responsiveness. We hypothesized that those who improved their insulin responsiveness might have pretraining characteristics favoring a positive response to exercise training. Thirty nondiabetic subjects who were obese volunteered for 8 weeks of either strength training or endurance training. During training, subjects increased their caloric intake to prevent weight loss. Insulin responsiveness by euglycemic clamps and muscle fiber composition, …


Myocardial Relaxation Is Accelerated By Fast Stretch, Not Reduced Afterload, Charles S. Chung, Charles W. Hoopes, Kenneth S. Campbell Feb 2017

Myocardial Relaxation Is Accelerated By Fast Stretch, Not Reduced Afterload, Charles S. Chung, Charles W. Hoopes, Kenneth S. Campbell

Physiology Faculty Publications

Fast relaxation of cross-bridge generated force in the myocardium facilitates efficient diastolic function. Recently published research studying mechanisms that modulate the relaxation rate has focused on molecular factors. Mechanical factors have received less attention since the 1980s when seminal work established the theory that reducing afterload accelerates the relaxation rate. Clinical trials using afterload reducing drugs, partially based on this theory, have thus far failed to improve outcomes for patients with diastolic dysfunction. Therefore, we reevaluated the protocols that suggest reducing afterload accelerates the relaxation rate and identified that myocardial relengthening was a potential confounding factor. We hypothesized that the …


Omecamtiv Mecarbil Enhances The Duty Ratio Of Human Β-Cardiac Myosin Resulting In Increased Calcium Sensitivity And Slowed Force Development In Cardiac Muscle, Anja M. Swenson, Wanjian Tang, Cheavar A. Blair, Christopher M. Fetrow, William C. Unrath, Michael J. Previs, Kenneth S. Campbell, Christopher M. Yengo Jan 2017

Omecamtiv Mecarbil Enhances The Duty Ratio Of Human Β-Cardiac Myosin Resulting In Increased Calcium Sensitivity And Slowed Force Development In Cardiac Muscle, Anja M. Swenson, Wanjian Tang, Cheavar A. Blair, Christopher M. Fetrow, William C. Unrath, Michael J. Previs, Kenneth S. Campbell, Christopher M. Yengo

Physiology Faculty Publications

The small molecule drug omecamtiv mecarbil (OM) specifically targets cardiac muscle myosin and is known to enhance cardiac muscle performance, yet its impact on human cardiac myosin motor function is unclear. We expressed and purified human β-cardiac myosin subfragment 1 (M2β-S1) containing a C-terminal Avi tag. We demonstrate that the maximum actin-activated ATPase activity of M2β-S1 is slowed more than 4-fold in the presence of OM, whereas the actin concentration required for half-maximal ATPase was reduced dramatically (30-fold). We find OM does not change the overall actin affinity. Transient kinetic experiments suggest that there are …


Predictive Screening Of M1 And M2 Macrophages Reveals The Immunomodulatory Effectiveness Of Post Spinal Cord Injury Azithromycin Treatment, John C. Gensel, Timothy J. Kopper, Bei Zhang, Michael B. Orr, William M. Bailey Jan 2017

Predictive Screening Of M1 And M2 Macrophages Reveals The Immunomodulatory Effectiveness Of Post Spinal Cord Injury Azithromycin Treatment, John C. Gensel, Timothy J. Kopper, Bei Zhang, Michael B. Orr, William M. Bailey

Spinal Cord and Brain Injury Research Center Faculty Publications

Spinal cord injury (SCI) triggers a heterogeneous macrophage response that when experimentally polarized toward alternative forms of activation (M2 macrophages) promotes tissue and functional recovery. There are limited pharmacological therapies that can drive this reparative inflammatory state. In the current study, we used in vitrosystems to comprehensively defined markers of macrophages with known pathological (M1) and reparative (M2) properties in SCI. We then used these markers to objectively define the macrophage activation states after SCI in response to delayed azithromycin treatment. Mice were subjected to moderate-severe thoracic contusion SCI. Azithromycin or vehicle was administered beginning 30 minutes post-SCI and …


Cell Free Dna As A Marker Of Training Status In Weightlifters, Jeremy A. Gentles, William G. Hornsby, Christine L. Coniglio, Andy R. Dotterweich, Jon A. Miller, Charles A. Stuart, Michael H. Stone Jan 2017

Cell Free Dna As A Marker Of Training Status In Weightlifters, Jeremy A. Gentles, William G. Hornsby, Christine L. Coniglio, Andy R. Dotterweich, Jon A. Miller, Charles A. Stuart, Michael H. Stone

ETSU Faculty Works

The purpose of this investigation was to elucidate the changes in cf-DNA as it relates to fluctuations in resistance training workloads and intensities. The relationship between cell free DNA (cf-DNA), C-reactive protein (CRP), creatine kinase (CK), testosterone (T), cortisol (C), testosterone-cortisol ratio (T:C), body mass and body composition were also examined. Eight weightlifters (5 males and 3 females, age = 25 ± 3.5 yr, body mass = 88.3 ± 22.7 kg, height = 173.8 ±8.4 cm) volunteered to participate in this study. Venous blood samples, body mass and body composition were taken six times, each corresponding to the end of …