Medical Physiology Commons^™

Mechanisms Of Post-Hemorrhagic Hydrocephalus After Germinal Matrix Hemorrhage, Damon William Klebe

Loma Linda University Electronic Theses, Dissertations & Projects

The inherently fragile vasculature of the germinal matrix is susceptible to rupture, possibly as a result of hemodynamic and cardiorespiratory instability associated with prematurity. Germinal matrix hemorrhage is a leading cause of morbidity and mortality in preterm and/or very low birthweight infants, and post-hemorrhagic hydrocephalus is major consequence of severe grade hemorrhages. Chronic post-hemorrhagic hydrocephalus treatment involves surgical insertion of shunts, which are costly and prone to complications. Thus, a safe non-invasive therapeutic approach towards post-hemorrhagic hydrocephalus clinical management would significantly improve the quality of life for this patient population. Thrombin, cerebroventricular blood clots, and iron have been identified as …

There Is Relief For Constipated Patients Taking Opioids., Ahmad Mohammadieh, James Choi, Md, Chelsea Gonzalez, Do, Diyanah Elyaman, Md

Clinical Research in Practice: The Journal of Team Hippocrates

A critical appraisal and clinical application of Tack J, Lappalainen J, Diva U, Tummala R, Sostek M. Efficacy and safety of naloxegol in patients with opioid-induced constipation and laxative-inadequate response. United European Gastroenterol J. 2015 Oct;3(5):471-80. doi: 10.1177/2050640615604543

Synapse Formation In Monosynaptic Sensory–Motor Connections Is Regulated By Presynaptic Rho Gtpase Cdc42, Fumiyasu Imai, David R. Ladle, Jennifer R. Leslie, Xin Duan, Tilat A. Rizvi, Georgianne M. Ciraolo, Yi Zheng, Yutaka Yoshida

Neuroscience, Cell Biology & Physiology Faculty Publications

Spinal reflex circuit development requires the precise regulation of axon trajectories, synaptic specificity, and synapse formation. Of these three crucial steps, the molecular mechanisms underlying synapse formation between group Ia proprioceptive sensory neurons and motor neurons is the least understood. Here, we show that the Rho GTPase Cdc42 controls synapse formation in monosynaptic sensory–motor connections in presynaptic, but not postsynaptic, neurons. In mice lacking Cdc42 in presynaptic sensory neurons, proprioceptive sensory axons appropriately reach the ventral spinal cord, but significantly fewer synapses are formed with motor neurons compared with wild-type mice. Concordantly, electrophysiological analyses show diminished EPSP amplitudes in monosynaptic …

White Blood Cell Count Versus Temperature As Predictors Of Pediatric Bacteremia, Ashley Ashby, Loren Moscinski

Physician Assistant Capstones, 2016 to 2019

Introduction: Although the prevalence of bacteremia has largely declined with the development of the Haemophilus Influenza Type b (Hib) and pneumococcal vaccines, it continues to be a leading cause of morbidity and mortality in children. Thus, it is crucial to differentiate bacteremia from other illnesses via the clinical picture and laboratory test results. Objective: The purpose of this research was to determine whether there is a clinically significant difference between temperature and white blood cell (WBC) count as determinants of bacteremia in the pediatric population. Methods: A PubMed search was conducted utilizing the following terms and filters: temperature, WBC, pediatrics, …

Role Of Chemokine Rantes In The Regulation Of Perivascular Inflammation, T-Cell Accumulation, And Vascular Dysfunction In Hypertension., Tomasz P Mikolajczyk, Ryszard Nosalski, Piotr Szczepaniak, Klaudia Budzyn, Grzegorz Osmenda, Paul J. Marvar, +10 Additional Authors

Pharmacology and Physiology Faculty Publications

Recent studies have emphasized the role of perivascular inflammation in cardiovascular disease. We studied mechanisms of perivascular leukocyte infiltration in angiotensin II (Ang II)-induced hypertension and their links to vascular dysfunction. Chronic Ang II infusion in mice increased immune cell content of T cells (255 ± 130 to 1664 ± 349 cells/mg; P < 0.01), M1 and M2 macrophages, and dendritic cells in perivascular adipose tissue. In particular, the content of T lymphocytes bearing CC chemokine receptor (CCR) 1, CCR3, and CCR5 receptors for RANTES chemokine was increased by Ang II (CCR1, 15.6 ± 1.5% vs. 31 ± 5%; P < 0.01). Hypertension was associated with an increase in perivascular adipose tissue expression of the chemokine RANTES (relative quantification, 1.2 ± 0.2 vs. 3.5 ± 1.1; P < 0.05), which induced T-cell chemotaxis and vascular accumulation of T cells expressing the chemokine receptors CCR1, CCR3, and CCR5. Mechanistically, RANTES(-/-) knockout protected against vascular leukocyte, and in particular T lymphocyte infiltration (26 ± 5% in wild type Ang II vs. 15 ± 4% in RANTES(-/-)), which was associated with protection from endothelial dysfunction induced by Ang II. This effect was linked with diminished infiltration of IFN-γ-producing CD8(+) and double-negative CD3(+)CD4(-)CD8(-) T cells in perivascular space and reduced vascular oxidative stress while FoxP3(+) T-regulatory cells were unaltered. IFN-γ ex vivo caused significant endothelial dysfunction, which was reduced by superoxide anion scavenging. In a human cohort, a significant inverse correlation was observed between circulating RANTES levels as a biomarker and vascular function measured as flow-mediated dilatation (R = -0.3, P < 0.01) or endothelial injury marker von Willebrand factor (R = +0.3; P < 0.01). Thus, chemokine RANTES is important in the regulation of vascular dysfunction through modulation of perivascular inflammation.-Mikolajczyk, T. P., Nosalski, R., Szczepaniak, P., Budzyn, K., Osmenda, G., Skiba, D., Sagan, A., Wu, J., Vinh, A., Marvar, P. J., Guzik, B., Podolec, J., Drummond, G., Lob, H. E., Harrison, D. G., Guzik, T. J. Role of chemokine RANTES in the regulation of perivascular inflammation, T-cell accumulation, and vascular dysfunction in hypertension.

The Influence Of Mir-99a On Mtor Signaling Regulation In Colorectal Cancer Cell Lines., Jonathan Rice

Electronic Theses and Dissertations

Colorectal cancer (CRC) is the third most common cancer worldwide and the fourth most common cause of death. These are staggering statistics for a disease that can essentially be cured if caught early and the pathology is favorable to therapeutic intervention. There is currently a drastic decrease in five year survival as the cancer stage increases from locally confined disease to metastatic disease. These statistics suggest that although some strides have been made with colon cancer screening and early intervention, there is still much room for improvement in both screening and treatment of CRC. One of the pathways that have …

Na/K-Atpase Amplification Of Oxidant Stress; A Universal But Unrecognized Clinical Target?, Zijian Xie, Phd, Joseph I. Shapiro, Md

Marshall Journal of Medicine

The Na/K-ATPase has a signaling function which appears to be separate from its ion pumping function. This signaling function refers to the transduction of conformational changes in the Na/K-ATPase alpha1 subunit into activating Src’s tyrosine kinase activity, triggering a cascade which generates reactive oxygen species (ROS), modulates other signaling pathways, and causes many physiological and pathophysiological effects. We have recently observed that ROS themselves as well as cardiotonic steroids can actually initiate the signal by directly inducing conformational changes in alpha1. It therefore appears that the Na/K-ATPase signal cascade can serve as a feed forward amplification for ROS with circulating …

Ablation Of Matrix Metalloproteinase-9 Prevents Cardiomyocytes Contractile Dysfunction In Diabetics., Priyanka Prathipati, Naira Metreveli, Shyam Sundar Nandi, Suresh C. Tyagi, Paras K. Mishra

Journal Articles: Cellular & Integrative Physiology

Elevated expression and activity of matrix metalloproteinase-9 (MMP9) and decreased contractility of cardiomyocytes are documented in diabetic hearts. However, it is unclear whether MMP is involved in the regulation of contractility of cardiomyocytes in diabetic hearts. In the present study, we tested the hypothesis that MMP9 regulates contractility of cardiomyocytes in diabetic hearts, and ablation of MMP9 prevents impaired contractility of cardiomyocytes in diabetic hearts. To determine the specific role of MMP9 in cardiomyocyte contractility, we used 12-14 week male WT (normoglycemic sibling of Akita), Akita, and Ins(2+∕-)/MMP9(-∕-) (DKO) mice. DKO mice were generated by cross-breeding male Ins2(+∕-) Akita (T1D) …

Role Of Slit2 In Reducing Complications After Surgical Brain Injury, Prativa Sherchan

Loma Linda University Electronic Theses, Dissertations & Projects

Surgical brain injury (SBI) is the inadvertent injury to brain tissue at the perisurgical site which occurs due to neurosurgical maneuvers such as incision, retraction, and electrocoagulation that can result in post-operative complications. Blood brain barrier (BBB) disruption and neuroinflammation are major pathophysiological consequences after neurosurgical injury. Blood brain barrier dysfunction leads to increased influx of water and plasma proteins as well as peripheral immune cell infiltration into the brain parenchyma that further potentiates brain edema and worsens post-operative neurological function. Activated resident immune cells and infiltrated peripheral immune cells release inflammatory mediators and promote oxidative stress and cell death …

Mitogenic Activation And Proliferation Of T Lymphocytes In Trpm7 Kinase-Dead Mutant Mice, Pavani Beesetty, Masayuki Matsushita, J. Ashot Kozak

Neuroscience, Cell Biology & Physiology Faculty Publications

Calcium and magnesium ions have been implicated in T lymphocyte proliferation in response to antigen recognition. Specifically, it is believed that calcium and magnesium elevations in the cytoplasm are necessary for efficient T cell proliferation. Research over the past two decades has focused on identifying the plasma membrane ion channels responsible for governing Ca2+ influx in lymphocytes and Orai-STIM, Kv1.3 and KCa3.1 channels were shown to be crucial for persistent calcium mobilization. Pharmacologic or genetic suppression of calcium influx gives rise to lymphoproliferative defects. In addition to Ca2+, several studies have demonstrated that Mg2+ influx positively regulates proliferation. TRPM7 is …

Reversible Recruitment Of A Homeostatic Reserve Pool Of Synaptic Vesicles Underlies Rapid Homeostatic Plasticity Of Quantal Content, Xueyong Wang, Martin J. Pinter, Mark M. Rich

Neuroscience, Cell Biology & Physiology Faculty Publications

Homeostatic regulation is essential for the maintenance of synaptic strength within the physiological range. The current study is the first to demonstrate that both induction and reversal of homeostatic upregulation of synaptic vesicle release can occur within seconds of blocking or unblocking acetylcholine receptors at the mouse neuromuscular junction. Our data suggest that the homeostatic upregulation of release is due to Ca²⁺-dependent increase in the size of the readily releasable pool (RRP). Blocking vesicle refilling prevented upregulation of quantal content (QC), while leaving baseline release relatively unaffected. This suggested that the upregulation of QC was due to mobilization …

Structure Of The Polyisoprenyl-Phosphate Glycosyltransferase Gtrb And Insights Into The Mechanism Of Catalysis, Chiara Ardiccioni, Oliver B. Clarke, David Tomasek, Habon A. Issa, Desiree C. Von Alpen, Heather L. Pond, M. Chiara Manzini, +11 Additional Authors

Pharmacology and Physiology Faculty Publications

The attachment of a sugar to a hydrophobic polyisoprenyl carrier is the first step for all extracellular glycosylation processes. The enzymes that perform these reactions, polyisoprenyl-glycosyltransferases (PI-GTs) include dolichol phosphate mannose synthase (DPMS), which generates the mannose donor for glycosylation in the endoplasmic reticulum. Here we report the 3.0Å resolution crystal structure of GtrB, a glucose-specific PI-GT from Synechocystis, showing a tetramer in which each protomer contributes two helices to a membrane-spanning bundle. The active site is 15 Å from the membrane, raising the question of how water-soluble and membrane-embedded substrates are brought into apposition for catalysis. A conserved …

Treatment Of Men For “Low Testosterone”: A Systematic Review, Samantha Huo, Anthony R. Scialli, Sean Mcgarvey, Elizabeth Hill, Buğra Tügertimur, Alycia Hogenmiller, Alessandra I. Hirsch, Adriane Fugh-Berman

Pharmacology and Physiology Faculty Publications

Testosterone products are recommended by some prescribers in response to a diagnosis or presumption of “low testosterone” (low-T) for cardiovascular health, sexual function, muscle weakness or wasting, mood and behavior, and cognition. We performed a systematic review of 156 eligible randomized controlled trials in which testosterone was compared to placebo for one or more of these conditions. We included studies in bibliographic databases between January 1, 1950 and April 9, 2016, and excluded studies involving bodybuilding, contraceptive effectiveness, or treatment of any condition in women or children. Studies with multiple relevant endpoints were included in all relevant tables. Testosterone supplementation …

Brain Responses To Biological Motion Predict Treatment Outcome In Young Children With Autism, D. Yang, Kevin Pelphrey, D. Sukholdolsky, M. Crowley, E. Dayan, +6 Additional Authors

Pharmacology and Physiology Faculty Publications

Autism spectrum disorders (ASDs) are common yet complex neurodevelopmental disorders, characterized by social, communication and behavioral deficits. Behavioral interventions have shown favorable results—however, the promise of precision medicine in ASD is hampered by a lack of sensitive, objective neurobiological markers (neurobiomarkers) to identify subgroups of young children likely to respond to specific treatments. Such neurobiomarkers are essential because early childhood provides a sensitive window of opportunity for intervention, while unsuccessful intervention is costly to children, families and society. In young children with ASD, we show that functional magnetic resonance imaging-based stratification neurobiomarkers accurately predict responses to an evidence-based behavioral treatment—pivotal …

Sensory Hypo-Excitability In A Rat Model Of Fetal Development In Fragile X Syndrome, Julia Berzhanskaya, Marnie Phillips, Jing Shen, Matthew Colonnese

Pharmacology and Physiology Faculty Publications

Fragile X syndrome (FXS) is characterized by sensory hyper-sensitivity, and animal models suggest that neuronal hyper-excitability contributes to this phenotype. To understand how sensory dysfunction develops in FXS, we used the rat model (FMR-KO) to quantify the maturation of cortical visual responses from the onset of responsiveness prior to eye-opening, through age equivalents of human juveniles. Rather than hyper-excitability, visual responses before eye-opening had reduced spike rates and an absence of early gamma oscillations, a marker for normal thalamic function at this age. Despite early hypo-excitability, the developmental trajectory of visual responses in FMR-KO rats was normal, and showed the …

Ovarian Tumour Growth Is Characterized By Mevalonate Pathway Gene Signature In An Orthotopic, Syngeneic Model Of Epithelial Ovarian Cancer, Daniel B. Hardy

Physiology and Pharmacology Publications

Epithelial ovarian cancer (EOC) is the most lethal gynecological cancer and often is not detected until late stages when cancer cells transcoelomically metastasize to the abdomen and typically become resistant to therapy resulting in very low survival rates. We utilize an orthotopic, syngeneic mouse model to study late stage disease and have discovered that the tumor cells within the abdominal ascites are irreversibly re-programmed, with an increased tumorigenicity and resistance to apoptosis. The goal of this study was to characterize the reprogramming that occurred in the aggressive ascites-derived cells (28-2 cells) compared to the original cell line used for tumor …

Nicotine Directly Induces Endoplasmic Reticulum Stress Response In Rat Placental Trophoblast Giant Cells, Michael K. Wong, Alison Holloway C, Daniel B. Hardy

Physiology and Pharmacology Publications

Nicotine exposure during pregnancy leads to placental insufficiency impairing both fetal and neonatal development. Previous studies from our laboratory have demonstrated that in rats,nicotine augmented endoplasmic reticulum (ER) stress in association with placental insufficiency, however, the underlying mechanisms remain elusive. Therefore, we sought to investigate the possible direct effect of nicotine on ER stress in Rcho-1 rat placental trophoblastgiant (TG) cells during differentiation. Protein and/or mRNA expression of markers involved in ER stress (e.g., phosphorylated PERK, eIF2α, CHOP, BiP/GRP78) and trophoblast giant cell differentiation and function (e.g., Pl-1, Pgf, Hsd11b1, and Hsd11b2) were quantified via Western blot or …

Micrornas Are Involved In The Development Of Morphine-Induced Analgesic Tolerance And Regulate Functionally Relevant Changes In Serpini1., Jenica D. Tapocik, Kristin Ceniccola, Cheryl L. Mayo, Melanie L. Schwandt, Matthew Solomon, Bi-Dar Wang, Truong V. Luu, Jacqueline Olender, Thomas Harrigan, Thomas M. Maynard, Greg I. Elmer, Norman H. Lee

Pharmacology and Physiology Faculty Publications

Long-term opioid treatment results in reduced therapeutic efficacy and in turn leads to an increase in the dose required to produce equivalent pain relief and alleviate break-through or insurmountable pain. Altered gene expression is a likely means for inducing long-term neuroadaptations responsible for tolerance. Studies conducted by our laboratory (Tapocik et al., 2009) revealed a network of gene expression changes occurring in canonical pathways involved in neuroplasticity, and uncovered miRNA processing as a potential mechanism. In particular, the mRNA coding the protein responsible for processing miRNAs, Dicer1, was positively correlated with the development of analgesic tolerance. The …

Analysis Of Ca²⁺ Mobilization Of Nanosecond Pulses In Cells, Iurii Semenov

Bioelectrics Publications

Exposure to nanosecond electric pulses (nsEPs) evokes transient rise of cytosolic free Ca²⁺ concentration ([Ca²⁺]i) in the cells. We quantified the external Ca²⁺ uptake, intracellular Ca²⁺ release and uncover interplay of these processes for CHO-K1 cells upon exposure to single 60 ns pulse in the range of amplitudes from 0 to 30 kV/cm. NsEPs are distinguished by the ability to electroporate intracellular membranes. We studied how duration of nsEPs is related to efficiency of intracellular membranes electroporation comparing ability of single 300-, 60- and 10 ns pulses to recruit Ca²⁺ from endoplasmic reticulum (ER) in respect to the uptake of …

Faster Movement Speed Results In Greater Tendon Strain During The Loaded Squat Exercise, Jacob E. Earp, Robert U. Newton, Prue Cormie, Anthony J. Blazevich

Research outputs 2014 to 2021

Introduction:

Tendon dynamics influence movement performance and provide the stimulus for long-term tendon adaptation. As tendon strain increases with load magnitude and decreases with loading rate, changes in movement speed during exercise should influence tendon strain.

Methods:

Ten resistance-trained men [squat one repetition maximum (1RM) to body mass ratio: 1.65 ± 0.12] performed parallel-depth back squat lifts with 60% of 1RM load at three different speeds: slow fixed-tempo (TS: 2-s eccentric, 1-s pause, 2-s concentric), volitional-speed without a pause (VS) and maximum-speed jump (JS). In each condition joint kinetics, quadriceps tendon length (L_T), patellar tendon force (F_{T …}