DOCSLIB.ORG

Detoxification of Glutathione and Nitrosoglutathione by Thioredoxin System of Mycobacterium Tuberculosis

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Detoxification of Glutathione and Nitrosoglutathione by Thioredoxin System of Mycobacterium Tuberculosis DETOXIFICATION OF GLUTATHIONE AND NITROSOGLUTATHIONE BY THIOREDOXIN SYSTEM OF MYCOBACTERIUM TUBERCULOSIS by RODGOUN ATTARIAN B.Sc., Tehran Azad University, 2002 A THESIS SUBMITTED IN PARTIAL FULLFILMENT OF THE REQUIREMENTS FOR THE DEGREE OF MASTER OF SCIENCE in THE FACULTY OF GRADUATE STUDIES (Experimental Medicine) THE UNIVERSITY OF BRITISH COLUMBIA (Vancouver) July 2009 © Rodgoun Attarian, 2009 ABSTRACT Tuberculosis is the leading cause of mortality due to a single pathogenic infection. Its etiological agent, Mycobacterium tuberculosis infects, resides and multiplies within human alveolar macrophages. It is exposed to reactive oxygen intermediates and reactive nitrogen intermediates (RNI) such as nitric oxide (NO) produced within phagosomes and granulomas against invading pathogens. Therefore, proliferation of M. tuberculosis within the host depends on its strategies to counteract the onslaught of these intermediates. One example is recruitment of the thioredoxin system as one of the most proficient pathways for protection against oxidative stress, since it dominates peroxide detoxification pathways. A burst of NO within macrophages parallels the production of glutathione (GSH) to protect the host against NO toxicity. The macrophage GSH pool reduces NO to S- nitrosoglutathione (GSNO). Both glutathione disulphide (GSSG) and GSNO possess mycobactericidal activities in vitro. This thesis is focused on characterizing the role of M. tuberculosis thioredoxin system in detoxification of antimycobacterial compounds produced within the host such as GSSG and GSNO, due to the intrinsic capacity of the system to universally reduce disulfide bonds and reduce GSNO in humans. By performing NADPH oxidation assays and HPLC analysis we demonstrate that M. tuberculosis thioredoxin redox cascade is a general reduction system able to efficiently reduce the low molecular weight disulfides GSSG and MSSM, and dissimilate GSNO. We also investigated the cellular pathways in which thioredoxin of M. tuberculosis participates. Here, we present an analysis of the thioredoxin-linked M. tuberculosis proteome by using a substrate trapping assay and mass spectrometry. We have identified eleven proteins associated with TrxC, implicating the involvement of thioredoxin in distinct cellular processes in this pathogen. The findings described in this thesis elucidate a novel function for the thioredoxin system of M. tuberculosis. We demonstrate that this system serves as a detoxification pathway against mycobactericidal compounds such as GSSG and GSNO. Overall, the data presented here establishes that M. tuberculosis thioredoxin has pleiotropic roles and is involved in a spectrum of processes from metabolic pathways to gene expression and signal transduction. ii Table of Contents Abstract ........................................................................................................................ ii Table of Contents .........................................................................................................iii List of Tables................................................................................................................. v List of Figures .............................................................................................................. vi List of Abbreviations................................................................................................... vii Acknowledgements....................................................................................................... ix Dedication...................................................................................................................... x Chapter One: Introduction........................................................................................... 1 1.1 Tuberculosis: Past, Present, Future ..................................................................... 1 1.2 M. tuberculosis: A Successful Human Pathogen................................................. 3 1.3 Host Defense Mechanisms ................................................................................. 4 1.4 Redox Control Strategies in Mycobacteria.......................................................... 7 1.5 Low-molecular-weight Thiols ............................................................................ 8 1.5.1 Mycothiol: The Unique Mycobacterial Anti-oxidant............................... 10 1.6 Thioredoxins ................................................................................................... 11 1.7 Thioredoxin Systems in Mycobacteria.............................................................. 15 1.8 Glutathione and S-nitrosoglutathione are Toxic to Mycobacteria...................... 17 Chapter Two: Working Hypothesis and Specific Aims............................................. 19 2.1 Hypothesis ....................................................................................................... 20 2.2 Specific Aims................................................................................................... 20 Chapter Three: Experimental .................................................................................... 21 3.1 Materials .......................................................................................................... 21 3.2 Methods ........................................................................................................... 23 3.2.1 Gene Cloning ......................................................................................... 23 3.2.2 Site-directed Mutagenesis....................................................................... 24 3.2.3 Protein Production.................................................................................. 25 3.2.4 NADPH Oxidation Assays ..................................................................... 26 3.2.5 HPLC Analysis....................................................................................... 29 iii 3.2.6 Determination of Kinetic Parameters ...................................................... 31 3.2.7 Proteomic Analysis................................................................................. 31 3.2.7.1 Substrate Trapping Assay............................................................ 31 3.2.7.2 Silver Staining ............................................................................ 33 3.2.7.3 In-Gel Trypsin Digestion ............................................................ 33 3.2.7.4 Mass Spectrometry Analysis ....................................................... 34 Chapter Four: Results ................................................................................................ 36 4.1 Generation of a Catalytic Defective TrxC......................................................... 36 4.2 Purification of Recombinant Proteins ............................................................... 37 4.3 Reductase Activity of Mycobacterial Thioredoxin System................................ 38 4.3.1 NADPH Oxidation ................................................................................ 38 4.3.2 Analysis of Product Formation by HPLC................................................ 41 4.4 Enzyme Kinetic Studies.................................................................................... 47 4.5 Thioredoxin-Associated M. tuberculosis Proteome........................................... 51 Chapter Five: Discussion ............................................................................................ 55 Chapter Six: Future Work ......................................................................................... 63 Bibliography................................................................................................................ 67 iv LIST OF TABLES Table 1 Plasmids and Oligonucleotides Used in This Work ...................................... 21 Table 2 PCR Program for Site-directed Mutagenesis ................................................. 24 Table 3 NADPH Oxidation by Thioredoxin System Towards H2O2 and DTNB ......... 40 Table 4 Reductase Activity of Thioredoxin System Towards Candidate Substrates.... 41 Table 5 Steady-State Kinetic Parameters of Substrate Conversion ............................. 50 Table 6 Identification of Thioredoxin Targets in M. tuberculosis Lysates Using Substrate Trapping Procedure ....................................................................... 53 Table 7 Determination of Predicted Peptides According to Masses Obtained from MS Analysis ................................................................................................. 54 Table 8 Comparison of Kinetic Parameters of Different Thioredoxin Systems........... 59 v LIST OF FIGURES Figure 1 ROIs and RNIs Generation in Intracellular Milieu of Macrophages ............. 5 Figure 2 Major LMW Thiols Serving as Intracellular Redox Buffer ........................... 9 Figure 3 Mycothiol: The Major LMW Thiol in Actinomycetes.................................. 10 Figure 4 General Oxidoreductase Activities of the Thioredoxin System.................... 13 Figure 5 Genomic Context of trxB2 (Rv3913) and trxC (Rv3914).............................. 15 Figure 6 Plasmid Maps of Expression Vectors Used in This Work .......................... 23 Figure 7 NADPH-driven Route of H2O2 and DTNB Reduction in Redox Cascade.... 27 Figure 8 Proposed Route of NADPH-dependent Reduction of LMW Thiols............. 28 Figure 9 GS-mB Calibration Curve .........................................................................
Load more

Recommended publications
  • RR5211-Front Cover-TB.Pmd
    Morbidity and Mortality Weekly Report Recommendations and Reports June 20, 2003 / Vol. 52 / No. RR-11 Treatment of Tuberculosis American Thoracic Society, CDC, and Infectious Diseases Society of America INSIDE: Continuing Education Examination department of health and human services Centers for Disease Control and Prevention MMWR CONTENTS The MMWR series of publications is published by the Purpose ............................................................................... 1 Epidemiology Program Office, Centers for Disease What’s New In This Document ............................................. 1 Control and Prevention (CDC), U.S. Department of Health and Human Services, Atlanta, GA 30333. Summary ............................................................................. 1 1. Introduction and Background ......................................... 13 SUGGESTED CITATION 2. Organization and Supervision of Treatment ................... 15 Centers for Disease Control and Prevention. 3. Drugs in Current Use ..................................................... 19 Treatment of Tuberculosis, American Thoracic 4. Principles of Antituberculosis Chemotherapy .................. 32 Society, CDC, and Infectious Diseases Society of America. MMWR 2003;52(No. RR-11):[inclusive 5. Recommended Treatment Regimens .............................. 36 page numbers]. 6. Practical Aspects of Treatment........................................ 42 7. Drug Interactions ........................................................... 45 8. Treatment in Special Situations
    [Show full text]
  • D-Cycloserine
    D-Cycloserine Catalog Numbers: C6880, C3909, C7670 Storage Temperature –20°C CAS #: 68-41-7 Reagents Synonyms: D-4-amino-3-isoxazolidone, D-oxamycin, These products are supplied as powders. Seromycin, K300, NJ-21 C7670 is convenience packaged for use in molecular Product Description biology; it is pre-weighed in quantities to give typical Appearance: White powder working concentrations when the entire package is Molecular Formula: C3H6N2O2 added to 1 L of agar preparations (for 50 plates of 20 ml Molecular Weight: 102.09 per plate). Furthermore, C 7670 is g-irradiated for E 1% = 402 (226 nm) sterility and septum-capped for ease in injecting sterile 23 1 [a]D = +115° (c=1.0%, water) diluent. C 7670 is also USP tested for potency following g-irradiation to assure full biological activity. D-Cycloserine, a structural analog of D-alanine, is a broad spectrum antibiotic produced by certain strains of Preparation Instructions Streptomyces orchidaceus or S. garphalus.1-5 D-cyclo- D-cycloserine is soluble in deionized water up to serine (at 100-200 mg/ml) inhibits the synthesis of 100 mg/ml. A solution of 50 mg/ml cycloserine in water bacterial cell walls (involving peptidoglycan synthesis) is clear and colorless or very faintly yellow. by preventing formation of D-alanine from L-alanine and D-cycloserine is also soluble at 1 in 50 parts of 96% hence the formation of peptide bonds involving ethanol, but practically insoluble in chloroform and D-alanine.4 D-cycloserine has antibiotic activity in vitro ether. It is also slightly soluble in methanol or propylene against growth phase Gram-negative bacteria including glycol.
    [Show full text]
  • The Impact of D-Cycloserine and Sarcosine on in Vivo Frontal Neural
    Yao et al. BMC Psychiatry (2019) 19:314 https://doi.org/10.1186/s12888-019-2306-1 RESEARCH ARTICLE Open Access The impact of D-cycloserine and sarcosine on in vivo frontal neural activity in a schizophrenia-like model Lulu Yao1, Zongliang Wang1, Di Deng1, Rongzhen Yan1, Jun Ju1 and Qiang Zhou1,2* Abstract Background: N-methyl-D-aspartate receptor (NMDAR) hypofunction has been proposed to underlie the pathogenesis of schizophrenia. Specifically, reduced function of NMDARs leads to altered balance between excitation and inhibition which further drives neural network malfunctions. Clinical studies suggested that NMDAR modulators (glycine, D-serine, D-cycloserine and glycine transporter inhibitors) may be beneficial in treating schizophrenia patients. Preclinical evidence also suggested that these NMDAR modulators may enhance synaptic NMDAR function and synaptic plasticity in brain slices. However, an important issue that has not been addressed is whether these NMDAR modulators modulate neural activity/spiking in vivo. Methods: By using in vivo calcium imaging and single unit recording, we tested the effect of D-cycloserine, sarcosine (glycine transporter 1 inhibitor) and glycine, on schizophrenia-like model mice. Results: In vivo neural activity is significantly higher in the schizophrenia-like model mice, compared to control mice. D-cycloserine and sarcosine showed no significant effect on neural activity in the schizophrenia-like model mice. Glycine induced a large reduction in movement in home cage and reduced in vivo brain activity in control mice which prevented further analysis of its effect in schizophrenia-like model mice. Conclusions: We conclude that there is no significant impact of the tested NMDAR modulators on neural spiking in the schizophrenia-like model mice.
    [Show full text]
  • CYCLOSERINE Proposal for Revision of the International Pharmacopoeia (August 2012)
    Working document QAS/12.463 August 2012 RESTRICTED CYCLOSERINE Proposal for revision of The International Pharmacopoeia (August 2012) Draft for comment This document was provided by a quality control expert. Should you have any comments thereon, please send these to Dr Herbert Schmidt, Medicines Quality Assurance Programme, Quality Assurance and Safety: Medicines, World Health Organization, 1211 Geneva 27, Switzerland; fax: (+41 22) 791 4730 or e-mail: [email protected] with a copy to [email protected] by 17 September 2012. In order to speed up the process for receiving draft monographs and for sending comments, please let us have your e-mail address (to [email protected] ) and we will add it to our electronic mailing list. Please specify if you wish to receive monographs. © World Health Organization 2012 All rights reserved. This draft is intended for a restricted audience only, i.e. the individuals and organizations having received this draft. The draft may not be reviewed, abstracted, quoted, reproduced, transmitted, distributed, translated or adapted, in part or in whole, in any form or by any means outside these individuals and organizations (including the organizations' concerned staff and member organizations) without the permission of the World Health Organization. The draft should not be displayed on any web site. Please send any request for permission to: Dr Sabine Kopp, Medicines Quality Assurance Programme, Quality Assurance and Safety: Medicines, Department of Essential Medicines and Health Products , World Health Organization, CH-1211 Geneva 27, Switzerland. Fax: (41-22) 791 4730; e-mail: [email protected] . The designations employed and the presentation of the material in this draft do not imply the expression of any opinion whatsoever on the part of the World Health Organization concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries.
    [Show full text]
  • Estonian Statistics on Medicines 2016 1/41
    Estonian Statistics on Medicines 2016 ATC code ATC group / Active substance (rout of admin.) Quantity sold Unit DDD Unit DDD/1000/ day A ALIMENTARY TRACT AND METABOLISM 167,8985 A01 STOMATOLOGICAL PREPARATIONS 0,0738 A01A STOMATOLOGICAL PREPARATIONS 0,0738 A01AB Antiinfectives and antiseptics for local oral treatment 0,0738 A01AB09 Miconazole (O) 7088 g 0,2 g 0,0738 A01AB12 Hexetidine (O) 1951200 ml A01AB81 Neomycin+ Benzocaine (dental) 30200 pieces A01AB82 Demeclocycline+ Triamcinolone (dental) 680 g A01AC Corticosteroids for local oral treatment A01AC81 Dexamethasone+ Thymol (dental) 3094 ml A01AD Other agents for local oral treatment A01AD80 Lidocaine+ Cetylpyridinium chloride (gingival) 227150 g A01AD81 Lidocaine+ Cetrimide (O) 30900 g A01AD82 Choline salicylate (O) 864720 pieces A01AD83 Lidocaine+ Chamomille extract (O) 370080 g A01AD90 Lidocaine+ Paraformaldehyde (dental) 405 g A02 DRUGS FOR ACID RELATED DISORDERS 47,1312 A02A ANTACIDS 1,0133 Combinations and complexes of aluminium, calcium and A02AD 1,0133 magnesium compounds A02AD81 Aluminium hydroxide+ Magnesium hydroxide (O) 811120 pieces 10 pieces 0,1689 A02AD81 Aluminium hydroxide+ Magnesium hydroxide (O) 3101974 ml 50 ml 0,1292 A02AD83 Calcium carbonate+ Magnesium carbonate (O) 3434232 pieces 10 pieces 0,7152 DRUGS FOR PEPTIC ULCER AND GASTRO- A02B 46,1179 OESOPHAGEAL REFLUX DISEASE (GORD) A02BA H2-receptor antagonists 2,3855 A02BA02 Ranitidine (O) 340327,5 g 0,3 g 2,3624 A02BA02 Ranitidine (P) 3318,25 g 0,3 g 0,0230 A02BC Proton pump inhibitors 43,7324 A02BC01 Omeprazole
    [Show full text]
  • World Health Organization Model List of Essential Medicines, 21St List, 2019
    World Health Organizatio n Model List of Essential Medicines 21st List 2019 World Health Organizatio n Model List of Essential Medicines 21st List 2019 WHO/MVP/EMP/IAU/2019.06 © World Health Organization 2019 Some rights reserved. This work is available under the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 IGO licence (CC BY-NC-SA 3.0 IGO; https://creativecommons.org/licenses/by-nc-sa/3.0/igo). Under the terms of this licence, you may copy, redistribute and adapt the work for non-commercial purposes, provided the work is appropriately cited, as indicated below. In any use of this work, there should be no suggestion that WHO endorses any specific organization, products or services. The use of the WHO logo is not permitted. If you adapt the work, then you must license your work under the same or equivalent Creative Commons licence. If you create a translation of this work, you should add the following disclaimer along with the suggested citation: “This translation was not created by the World Health Organization (WHO). WHO is not responsible for the content or accuracy of this translation. The original English edition shall be the binding and authentic edition”. Any mediation relating to disputes arising under the licence shall be conducted in accordance with the mediation rules of the World Intellectual Property Organization. Suggested citation. World Health Organization Model List of Essential Medicines, 21st List, 2019. Geneva: World Health Organization; 2019. Licence: CC BY-NC-SA 3.0 IGO. Cataloguing-in-Publication (CIP) data. CIP data are available at http://apps.who.int/iris.
    [Show full text]
  • Frequently Asked Questions on The
    Frequently asked questions on the WHO treatment guidelines for isoniazid-resistant tuberculosis Version: 24 April 2018 The advice in this document has been prepared by the Global TB Programme of the World Health Organization (WHO) and is to be read alongside the WHO treatment guidelines for isoniazid-resistant tuberculosis and its online annexes. See Further reading ​ ​ at end for additional resources. Who are the new WHO treatment guidelines for isoniazid-resistant tuberculosis intended for ? ​ ​ The WHO treatment guidelines for isoniazid-resistant tuberculosis are targeted at health care ​ professionals (doctors, nurses) and other staff involved in TB care in both low and high resource settings. The possibility of drug-resistant disease now needs to be entertained whenever treating TB patients. These guidelines provide technical detail which is helpful in making the best-informed decision in clinical practice and programme management. The answers to the frequently asked questions (FAQ) in this document intend to help implementers with common, practical issues that arise when adopting the new guidance. This document complements the WHO guidelines by elaborating further on certain aspects of ​ implementation that were beyond the scope of the guideline itself. What are the main recommendations of these new guidelines ? The new guidelines recommend that patients with confirmed isoniazid-resistant and rifampicin susceptible tuberculosis (abbreviated to Hr-TB) are treated for 6 months with a regimen composed of ​ ​ rifampicin (R), ethambutol (E), pyrazinamide (Z) and levofloxacin (Lfx). The exclusion of rifampicin resistance ahead of start of this regimen is critical. It is further recommended not to add streptomycin (S) or other injectable agents to the treatment regimen.
    [Show full text]
  • An Alanine Permease Mutation Or Exposure to D-Cycloserine Increases the Susceptibility Of
    bioRxiv preprint doi: https://doi.org/10.1101/616920; this version posted June 22, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license. 1 An alanine permease mutation or exposure to D-cycloserine increases the susceptibility of 2 MRSA to -lactam antibiotics 3 4 Laura A. Gallagher1, Rebecca K. Shears2, Claire Fingleton1, Laura Alvarez3, Elaine M. 5 Waters1,2, Jenny Clarke2, Laura Bricio-Moreno2, Christopher Campbell1, Akhilesh K. Yadav3, 6 Fareha Razvi4, Eoghan O'Neill5, Alex J. O’Neill6, Felipe Cava3, Paul D. Fey4, Aras Kadioglu2 and 7 James P. O’Gara1* 8 9 1School of Natural Sciences, National University of Ireland, Galway, Ireland. 10 2Department of Clinical Infection, Microbiology and Immunology, Institute of Infection and 11 Global Health, University of Liverpool, UK. 12 3MIMS-Molecular Infection Medicine Sweden, Molecular Biology Department, Umeå 13 University, Umeå, Sweden. 14 4Department of Pathology and Microbiology, University of Nebraska Medical Center, 15 Omaha, Nebraska, USA. 16 5Department of Clinical Microbiology, Royal College of Surgeons in Ireland, Connolly 17 Hospital, Dublin 15, Ireland. 18 6Antimicrobial Research Centre, School of Molecular and Cellular Biology, Faculty of 19 Biological Sciences, University of Leeds, Leeds, UK. 20 21 22 23 *Correspondence: [email protected] 24 25 Running title: Re-sensitization of AMR pathogens to -lactams 26 27 1 bioRxiv preprint doi: https://doi.org/10.1101/616920; this version posted June 22, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.
    [Show full text]
  • Estonian Statistics on Medicines 2013 1/44
    Estonian Statistics on Medicines 2013 DDD/1000/ ATC code ATC group / INN (rout of admin.) Quantity sold Unit DDD Unit day A ALIMENTARY TRACT AND METABOLISM 146,8152 A01 STOMATOLOGICAL PREPARATIONS 0,0760 A01A STOMATOLOGICAL PREPARATIONS 0,0760 A01AB Antiinfectives and antiseptics for local oral treatment 0,0760 A01AB09 Miconazole(O) 7139,2 g 0,2 g 0,0760 A01AB12 Hexetidine(O) 1541120 ml A01AB81 Neomycin+Benzocaine(C) 23900 pieces A01AC Corticosteroids for local oral treatment A01AC81 Dexamethasone+Thymol(dental) 2639 ml A01AD Other agents for local oral treatment A01AD80 Lidocaine+Cetylpyridinium chloride(gingival) 179340 g A01AD81 Lidocaine+Cetrimide(O) 23565 g A01AD82 Choline salicylate(O) 824240 pieces A01AD83 Lidocaine+Chamomille extract(O) 317140 g A01AD86 Lidocaine+Eugenol(gingival) 1128 g A02 DRUGS FOR ACID RELATED DISORDERS 35,6598 A02A ANTACIDS 0,9596 Combinations and complexes of aluminium, calcium and A02AD 0,9596 magnesium compounds A02AD81 Aluminium hydroxide+Magnesium hydroxide(O) 591680 pieces 10 pieces 0,1261 A02AD81 Aluminium hydroxide+Magnesium hydroxide(O) 1998558 ml 50 ml 0,0852 A02AD82 Aluminium aminoacetate+Magnesium oxide(O) 463540 pieces 10 pieces 0,0988 A02AD83 Calcium carbonate+Magnesium carbonate(O) 3049560 pieces 10 pieces 0,6497 A02AF Antacids with antiflatulents Aluminium hydroxide+Magnesium A02AF80 1000790 ml hydroxide+Simeticone(O) DRUGS FOR PEPTIC ULCER AND GASTRO- A02B 34,7001 OESOPHAGEAL REFLUX DISEASE (GORD) A02BA H2-receptor antagonists 3,5364 A02BA02 Ranitidine(O) 494352,3 g 0,3 g 3,5106 A02BA02 Ranitidine(P)
    [Show full text]
  • An Investigation of D-Cycloserine As a Memory Enhancer Sabine Wilhelm
    May 23, 2016 An investigation of D-cycloserine as a memory enhancer Sabine Wilhelm, Ph.D. 1. Background and Significance BDD is defined as a preoccupation with an imagined defect in appearance; if a slight physical anomaly is present, the concern is markedly excessive (American Psychiatric Association [APA], 1994). Preoccupations may focus on any body area but commonly involve the face or head, most often the skin, hair, or nose (Phillips et al., 1993). These preoccupations have an obsessional quality, in that they occur frequently and are usually difficult to resist or control (Phillips et al., 1998). Additionally, more than 90% of BDD patients perform repetitive, compulsive behaviors (Phillips et al., 1998), such as frequent mirror checking (Alliez & Robin, 1969), excessive grooming (Vallat aet al., 1971), and skin picking (Phillips & Taub, 1995). Accordingly, a core component of Cognitive-Behavioral treatment for BDD is exposure and response prevention (ERP). Exposure and response prevention involves asking patients to gradually expose themselves to situations that make them anxious (e.g. talking to a stranger, going to a party) while refraining from engaging in any rituals (e.g. excessive grooming or camouflaging) or safety behaviors (e.g. avoiding eye contact). Rituals and safety behaviors are thought to maintain the fear response because they prevent the sufferer from staying in contact with the stimulus long enough for his or her anxiety to extinguish. By exposing the patient to the feared situation while preventing the rituals and safety behaviors, the patient’s anxiety is allowed to naturally extinguish and he is able to acquire a sense of safety in the presence of the feared stimulus.
    [Show full text]
  • Tuberculosis Drug Information Guide, 2Nd Edition
    Tuberculosis Drug Information Guide 2ND EDITION Edmund G. Brown Jr, Governor STATE OF CALIFORNIA Diana S. Dooley, Secretary CALIFORNIA HEALTH & HUMAN SERVICES AGENCY Ron Chapman, MD, MPH, Director DEPARTMENT OF PUBLIC HEALTH Tuberculosis Drug Information Guide 2ND EDITION Edmund G. Brown Jr, Governor STATE OF CALIFORNIA Diana S. Dooley, Secretary CALIFORNIA HEALTH & HUMAN SERVICES AGENCY Ron Chapman, MD, MPH, Director DEPARTMENT OF PUBLIC HEALTH DrugInfo_2ndEd_v9.indd 3 12/5/12 3:55 PM Tuberculosis Drug Information Guide, 2nd edition was created through a collaboration of the Curry International Tuberculosis Center (CITC) and the State of California Department of Public Health, Tuberculosis Control Branch (CDPH). CITC is a project of the University of California, San Francisco, funded by the Centers for Disease Control and Prevention (CDC). The development of this Guide was funded through CDC Cooperative Agreement U52 CCU 900454. Permission is granted for nonprofit educational use and library duplication and distribution. Suggested citation: Curry International Tuberculosis Center and California Department of Public Health, 2012: Tuberculosis Drug Information Guide, 2nd edition. This publication is available on the CITC website: http://www.currytbcenter.ucsf.edu/ tbdruginfo/ Design: Edi Berton Design DrugInfo_2ndEd_v9.indd 4 12/5/12 3:55 PM Contributors Acknowledgments Ann M. Loeffler, MD John S. Bradley, MD Pediatric Infectious Diseases Attending and Director of Pediatric Rady Children’s Hospital San Diego, San Diego, California Hospitalists at Randall Children’s Hospital at Legacy Emanuel, Daniel Deck, Pharm.D. Portland, Oregon Department of Pharmaceutical Services, Pediatric Tuberculosis Consultant, San Francisco General Hospital, California Curry International Tuberculosis Center, San Francisco, California David Forinash, RPh Randall Children’s Hospital at Legacy Emanuel, Portland, Oregon Charles A.
    [Show full text]
  • Nmda-Receptor-Glycine.Pdf
    Neuropharmacology 55 (2008) 1238–1250 Contents lists available at ScienceDirect Neuropharmacology journal homepage: www.elsevier.com/locate/neuropharm A NMDA receptor glycine site partial agonist, GLYX-13, simultaneously enhances LTP and reduces LTD at Schaffer collateral–CA1 synapses in hippocampus Xiao-lei Zhang a, John A. Sullivan a, Joseph R. Moskal b, Patric K. Stanton a,c,* a Department of Cell Biology & Anatomy, New York Medical College, Basic Sciences Building, Room 217, Valhalla, NY 10595, USA b The Falk Center for Molecular Therapeutics, Department of Biomedical Engineering, McCormick School of Engineering and Applied Sciences, Northwestern University, Evanston, IL 60201, USA c Department of Neurology, New York Medical College, Valhalla, NY 10595, USA article info abstract 2þ Article history: N-methyl-D-aspartate glutamate receptors (NMDARs) are a key route for Ca influx into neurons Received 13 June 2008 important to both activity-dependent synaptic plasticity and, when uncontrolled, triggering events that Received in revised form 18 July 2008 cause neuronal degeneration and death. Among regulatory binding sites on the NMDAR complex is Accepted 4 August 2008 a glycine binding site, distinct from the glutamate binding site, which must be co-activated for NMDAR channel opening. We developed a novel glycine site partial agonist, GLYX-13, which is both nootropic and Keywords: neuroprotective in vivo. Here, we assessed the effects of GLYX-13 on long-term synaptic plasticity and Glutamate receptor NMDAR transmission at Schaffer collateral–CA1 synapses in hippocampal slices in vitro.GLYX-13 Learning Memory simultaneously enhanced the magnitude of long-term potentiation (LTP) of synaptic transmission, while N-methyl-D-aspartate receptor reducing long-term depression (LTD).
    [Show full text]