Reactive Oxygen Species Insufficiency (ROSI) as the Basis for Disease Allowance and Coexistence: Extraordinary Support for an Extraordinary Theory VOLUME I (One) BY PROF. HON. RANDOLPH M. HOWES, M.D., Ph.D. Orthomolecular Surgical Scientist and Biochemist Contents of volumes I through III: Volume I (One) Pages 1-530 of original: pp 501 Sections 1.0-1.9.0.4 Volume II (Two) Pages 531-1018 of original: pp 505 Sections 1.9.0.5-11.1.3 Volume III (Three) Pages 1019-1564 of original: pp 562 Sections 11.1.4-20.0.0 Unauthorized use of any of this material, without author permission, is prohibited by law. © 2008, Randolph M. Howes, M.D., Ph.D. Reactive Oxygen Species Insufficiency (ROSI) as the Basis for Disease Allowance and Coexistent: Extraordinary Support for an Extraordinary Theory Relationships between CANCER, ATHEROSCLEROSIS, DIABETES, OBESITY, HYPERTENSION, ARTHRITIS & CATARACTS (EMOD Insufficiency Syndrome of Howes) (EMODs) Electronically Modified Oxygen Derivatives THE HOWES SELECTIVE WORLD LIBRARY OF OXYGEN METABOLISM [The seventh in a series and a companion book to the following: #1. U.T.O.P.I.A. © 2004 Unified Theory of Oxygen Participation In Aerobiosis; #2. The Medical and Scientific Significance of Oxygen Free Radical Metabolism © 2005; #3. Hydrogen Peroxide Monograph 1: Scientific, Medical and Biochemical Overview & #4. Antioxidant Vitamins A, C, & E Monograph 2: Equivocal Scientific Studies, © 2006; #5. Cardiovascular Disease and Oxygen Free Radical Mythology, © 2006; #6. Diabetes and Oxygen Free Radical Sophistry, © 2006] A Selective World Literature Review Available at www.thepundit.com BY PROF. HON. RANDOLPH M. HOWES, M.D., Ph.D. Orthomolecular Surgical Scientist and Biochemist Adjunct Assistant Professor of Plastic Surgery, The Johns Hopkins Hospital, Baltimore, MD USA Espaldon Professor of Plastic and Reconstructive Surgery, University of Santo Tomas, Manila, Philippines Adjunct Professor of Biological Sciences, Southeastern Louisiana University Professor of Surgery, Biophysics and Biochemistry, Louisiana University of Medical Sciences Vice Chancellor/Dean, Louisiana University of Medical Sciences (Also holds an Honorary Doctorate of Humanities, SLU) Copyright © 2008 Free Radical Publishing Co. ISBN:1-885458-06-1 © 2008 by Randolph M. Howes M.D., Ph.D. All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, recording, or otherwise, without the written prior permission of the author. Notice to users: 1. User agrees not to redistribute any electronic artifacts of this resource without prior written permission from Free Radical Publishing Co. 2. Except as permitted under the United States Copyright Act of 1976, no part of this publication may be reproduced or distributed in any form or by any means, or stored in a data base or retrieval system, without prior written permission of the publisher. 3. It is understood that medicine is an ever-changing science. As new research and clinical experience broaden our knowledge, changes in treatment and drug therapy are required. The author and the publisher of this work have checked with sources believed to be reliable in their efforts to provide information that is complete and generally in accord with the standards accepted at the time of publication. However in view of the possibility of human error or changes in the medical sciences, neither the authors nor the publisher nor any other party who has been involved in the preparation of publication of this work warrants that the information contained herein is in every respect accurate or complete, and they disclaim all responsibility to any errors or omissions or for the results obtained from use of the information contained in the work. Readers are encouraged to confirm the information contained herein with other sources. For example and in particular, readers are advised to check the product information sheet included in the package of each drug they plan to administer to be certain that the information contained in this work is accurate and that changes have not been made in the recommended dose or in the contraindications for administration. This recommendation is of particular importance in connection with new or infrequently used drugs. Reactive Oxygen Species Insufficiency (ROSI) as the Basis for Coexistent Diseases: Extraordinary Support for an Extraordinary Theory Relationships between CANCER, ATHEROSCLEROSIS, DIABETES, OBESITY, HYPERTENSION, ARTHRITIS & CATARACTS (EMOD Insufficiency Syndrome of Howes) (EMODs) Electronically Modified Oxygen Derivatives TABLE OF CONTENTS Unauthorized use of any of this material, without author permission, is prohibited by law. © 2008, Randolph M. Howes, M.D., Ph.D. The U.T.O.P.I.A. Institute and Free Radical Publishing Co. 1.0 The Oxypocalypse 1.0.1 Prologue 1.0.2 Fundamental Value of Creative Ideas 1.0.3 DISCLOSURE AND DISCLAIMER 1.0.4 Introduction 1.0.4.1 The EMOD Insufficiency Syndrome of Howes or the ROSI Syndrome (Reactive Oxygen Species Insufficiency Syndrome) 1.0.4.2 Oxygen Factoids 1.0.5 Personal Introductory Comments: “Radical Planet” 1.0.6 Howes’ First Law 1.0.7 Howes’ Second Law 1.0.8 Howes’ Third Law 1.0.9 Howes’ Fourth Law 1.0.10 Howes’ Law of Cellular Biochemical Reactions 1.0.11 Howes’ Law of Risk of Infection 1.0.12 Howes’ Law of Common Chemistry 1.1.0 Antioxidant Vitamins, Free Radicals and Oxygen Myths 1.1.1 “Vitamine” History 1.1.2 The Antioxidant Myth: A Medical Fairy Tale – from New Scientist 1.1.3 Brief Primer on Oxygen Free Radicals: Current Misconceptions 1.1.3.1 Misconceptions Regarding SOD 1.1.3.2 Snapple’s New Antioxidant Water 1.1.4 Formation of Reactive Oxygen Species 1.1.5 Biological Effects of Reactive Oxygen 1.1.6 EMOD Production and Role 1.1.7 EMOD Sources and Control 1.1.8 Thomas L. Hesselink, MD: A Different Redox View 1.2.0 Most Biological Oxidants Arise from Superoxide 1.2.1.0 Superoxide the Evil 1.2.1.1 Antioxidant Enzyme 1.2.1.2 Low Molecular Weight Antioxidants 1.2.2.3 Superoxide the Good - 1.2.2.4 O2 Production by Phagocytes - 1.2.2.5 A Possible Antioxidant Activity of O2 Itself - 1.2.2.6 Regulation by O2 and H2O2 1.2.2.7 Conclusion 1.2.3.0 Oxygen Homeostasis 1.2.3.1 Heart Disease Predetermined by Oxygen Levels in the Womb 1.2.4.0 EMODs: General Information and Cardiovascular Disease 1.2.4.1 Producers and Destroyers of Reactive Oxygen Species 1.2.4.2 Xanthine Oxidoreductase 1.2.4.3 Nitric Oxide Synthase 1.2.4.4 Nitric Oxide Synthase, Nitrotyrosine Linked to Clustering of CVD and Other diseases 1.2.4.5 Superoxide Dismutases 1.2.4.6 Catalase 1.2.4.7 Glutathione Redox Cycle 1.2.4.8 ROS Scavengers 1.2.5.0 Arteries and Veins: A Comparison of Structure and Function 1.2.5.1 Vascular EMOD Metabolism 1.2.5.2 NADPH Oxidases 1.2.5.3 Xanthine Oxidase 1.2.5.4 NOS 1.2.5.5 SODs 1.2.5.6 So-called Oxidative Stress and Disease 1.2.5.7 Atherosclerosis 1.2.5.8 Hypertension 1.2.6.0 Three Mutations Control Hypertension 1.2.6.1 Novel Sources of EMODs in Humans 1.2.6.2 Functional Role of Nox and Duox EMOD Producers 1.2.6.3 EMOD Level Determines Brain Temperature Regulation/Fever 1.2.6.4 EMOD Producing Methylene Blue Fights Off Alzheimer’s 1.2.6.5 Methylene Blue Generates EMOD Hydrogen Peroxide and Hydroxyl Radical 1.2.6.6 EMODS and Cellular Regulation 1.2.6.7 Cellular Regulation by Hydrogen Peroxide 1.2.6.8 Vasodilation HYDROGEN PEROXIDE 1.2.7.0 Hydrogen Peroxide and the Peroxisome 1.2.7.1 Hydrogen Peroxide Produced by Lung Epithelial Cells 1.2.7.2 Hydrogen Peroxide Unexpectedly Benefits Airways 1.2.7.3 Inhibiting Stress Oxidant May Be New Therapy for COPD 1.2.7.4 More cellular Regulation by Hydrogen Peroxide 1.2.8.0 Hydrogen Peroxide and Endothelial Function 1.2.8.1 Sources of EMODs in Mammalian Cells 1.2.8.2 Questionable Role of Peroxide in Vascular Disease 1.2.8.3 Nitric Oxide and Natural Anti-cancer Activity 1.2.8.4 Insulin Stimulation also Induces the Production of Intracellular H2O2 1.2.8.5 Hydrogen Peroxide in Urine and Aqueous Humor 1.2.8.6 Ascorbate Autoxidation Produces H2O2 1.2.8.7 EMODs and Spermatozoa 1.2.8.8 Alleged Diseases Associated with EMODS VITAMINS 1.2.9.0 US Vitamin Sales 1.2.9.1 Vitamin Preferences 1.2.9.2 US Overview 1.2.9.3 Vitamin C as a Prooxidant 1.2.9.4 Vitamin C and Iron Co-supplementation Decrease LDL Oxidation and Platelet Aggregation 1.2.9.5 Antioxidant Vitamins May Raise LDL Levels 1.2.9.6 Meta-analysis of Vitamin C Heart Benefits 1.2.9.7 Vitamin E as a Prooxidant ANTIOXIDANTS 1.2.9.8 Superoxide Dismutase (SOD) as a Prooxidant 1.2.9.9 Impaired Antioxidant Defense System (SOD) of Colonic Tissue and Cancer Development in Dextran Sulfate Sodium-induced Colitis in Mice 1.3.0.0 Glutathione (GSH) as a Prooxidant 1.3.0.1 So-called Antioxidants (Polyphenolics) have Prooxidant Activity 1.3.0.2 Prooxidant Activity of Vitamins C, E, Carotenoids and Flavonoids 1.3.0.3 Prooxidant Activity of Polyphenolic Antioxidant (GSPE) Grape Seed Extract 1.3.0.4 Green Tea EGCG Activates Prooxidant-induced Apoptosis 1.3.0.5 Black Tea Antioxidants Show No Impact on Cardiovascular Risk Factors 1.3.1.0 Risks and Safety of Polyphenol Consumption: [Antioxidants: Isoflavones, Quercetin, Citrus Flavonoids, Resveratrol, Punicalagin (an Ellagitannin Present in Pomegranate Juice), Green Tea Catechins, Vitexin (a C-glycosylflavone), Proanthocyanidins (Condensed Tannins) and Ellagitannins, etc.] PROCEEDINGS OF THE 1ST INTERNATIONAL CONFERENCE ON POLYPHENOLS AND HEALTH 1.3.1.1 Immune Function and EMODs 1.3.1.2 Antioxidants 1.3.1.3 Comment of Balz Frei 1.3.1.4 Failed Antioxidant Studies of Brown et al.