Encyclopedia of Vitamins New Research (4 Volume Set) 9781536156942, 1536156949

Table of contents :
Contents
Preface
Chapter 1
Liquid Chromatography for the Determination of Tocopherols and Tocotrienols (Vitamin E) in Food of Plant Origin
Abstract
Introduction
Sample Preparation
Chromatographic Determination of Tocopherols and Tocotrienols
Conclusions
References
Chapter 2
Differentiation Signaling Induced by Retinoic Acid and Vitamin D3
Abstract
Introduction
Genomic Control
1. Nuclear Receptors
2. Target Genes
2.1. ATRA Target Genes
2.2. 1,25(OH)2D3 Target Genes
3. Cell Cycle Regulatory Molecules
Intracellular Signaling Pathways
1. Raf-MEK-ERK
2. Protein Kinase (PKC) Isoforms
3. Phosphatidylinositol 3-Kinase (PI3-K)-AKT Pathway
Summary
References
Chapter 3
Suicide Risk Factors: Vitamin D Levels
Abstract
Introduction
Vitamin D
Excretion
UVB induced synthesis of active vitamin D (1,25 (OH)2D3) in the
skin and its significance
Mechanisms of action of vitamin D
Functions of vitamin D
Measuring vitamin D nutritional status
Risk factors for vitamin D deficiency
Consequences of vitamin D deficiency
Genetic and environmental triggers related to vitamin D and suicide
Chronic medical illness
Autoimmune diseases
Fibromyalgia
Cancer
Psychiatric disorders
Mood and anxiety disorders
Schizophrenia
Suicide
Adequate intake of vitamin D
Conclusions
Acknowledgments
References
APPENDIX
Chapter 4
Role of Ultraviolet-B Irradiance and Vitamin D in Reducing Risk of Cancer
1Sunlight, Nutrition and Health Research Center,
San Francisco, California, US
2School of Arts and Sciences, American University in Dubai
Dubai, UAE
Abstract
Introduction
Evidence That Ultraviolet-B Irradiance
and Vitamin D Reduce the Risk of Cancer
Case–Control Studies of 25(OH)D Level and Cancer Incidence Rates
Nested Case–Control Studies of 25(OH)D Level and Cancer Incidence Rates
Bladder Cancer
Ovarian Cancer
Prostate Cancer
Cancer Survival with Respect to Serum 25(OH)D Level
Racial Disparities in Cancer Survival
Randomized Controlled Trials
Occupation in Nordic Countries
Night-Shift Work
Vitamin D Mechanisms in Cancer Biology
Proliferation and Telomerase
Cell Cycle Control Mechanisms and Apoptosis
Cellular Stress, DNA Damage and Repair
Alterations in Cellular Microenvironment (E.G., Hypoxia) Promoting Angiogenesis and Metastasis
Interactions with Growth Factors That Mediate Transformation, Cell Adhesion, Invasion, and Metastasis
Inflammation and Cancer
Causality Using Hill’s Criteria
References
Chapter 5
HPLC Analysis of Vitamin B1, B2, B3, B6, B9, B12 and Vitamin C in Various Food Matrices
Abstract
Introduction
Vitamin B1 (Thiamine)
Generic Description and Structures – Vitamin B1
Nutritional/Physiological Importance and Dietary Sources – Vitamin B1
Assay Methodology for Vitamin B1 (Vitamins B2, B3 and B6) – General
HPLC Assay Methodology for Vitamin B1
Vitamin B2 (Riboflavin)
Generic Description and Structures – Vitamin B2
Nutritional/Physiological Importance and Dietary Sources – Vitamin B2
Assay Methodology for Vitamin B2 – General
HPLC Assay Methodology for Vitamin B2
Vitamin B3 (Niacin)
Generic Description and Structures – Vitamin B3
Nutritional/Physiological Importance and Dietary Sources – Vitamin B3
HPLC Assay Methodology for Vitamin B3
Vitamin B6 (Pyridoxine)
Generic Description and Structures – Vitamin B6
Nutritional/Physiological Importance and Dietary Sources – Vitamin B6
HPLC Assay Methodology for Vitamin B6
Improvements and Recent Developments: Vitamin B6 Methods
Vitamin B9 (Folate)
Generic Description and Structures – Vitamin B9
Nutritional/Physiological Importance – Vitamin B9
Dietary Sources – Vitamin B9
Assay Methodology for Vitamin B9 – General
HPLC Assay Methodology for Vitamin B9
Improvements and Recent Developments – Vitamin B9 Methods
Vitamin B12 (Cyanocobalamin)
Generic Description and Structures – Vitamin B12
Nutritional/Physiological Importance – Vitamin B12
Dietary Sources – Vitamin B12
Assay Methodology for Vitamin B12 – General
HPLC Assay Methodology for Vitamin B12
Improvements and Recent Developments – Vitamin B12 Methods
Vitamin C (Ascorbic Acid)
Generic Description and Structures – Vitamin C
Nutritional/Physiological Importance and Dietary Sources
Assay Methodology for Vitamin C – General
HPLC Assay Methodology for Vitamin C
References
Chapter 6
Vitamin E Isoforms: Multiple Mechanisms of Action against Carcinogenesis
Abstract
Abbreviations
Introduction
Diet Plays a Role in Cancer Risk
Vitamin E Compounds Other than Alpha Tocopherol are Physiologically Relevant
Vitamin E has Antioxidant Properites BUT Also Plays a Role in Signal Transduction Modulation
The Biology of Vitamin E
Vitamin E is at Least Eight Structurally Related Compounds
Synthetic Vitamin E is Not Identical to Natural Vitamin E
Vitamin E Transport and Metabolism Occur in the Liver with Different Reaction Kinetics Depending Upon Various Conditions
Vitamin E Interactions
The Role of Vitamin E Isoforms on Apoptosis
Natural Vitamin E Isoforms are Effective Apoptotic Modulators in Cancer Cell Lines
Apoptotic Induction by Natural Tocopherols and Tocotrienols Occurs in Animal Models
Natural Tocotrienols Need not be Purified to Demonstrate Apoptotic Activity
Synthetic Forms of Vitamin E Result in Apoptosis of Cancer Cells
Anticancer Effects of Synthetic Vitamin E Analogues Using Apoptosis as an Endpoint
The Influence of Vitamin E Isoforms on Cell Cycle, Cell Proliferation, and Tumor Burden
a-VES Modulates the Cell Cycle
Cell Cycle Modulation is Also Regulated by Tocotrienols
Cell Cycle Intervention by Vitamin E Isoforms in Animal Models
Non-Alpha-Tocopherol Forms of Vitamin E Reduce Tumor Burden in Animal Models
Vitamin E Inhibits Radiation-Induced Genotoxicity
Epidemiological Evidence that Multiple Forms of Vitamin E, Rather than Alpha Tocopherol Alone May be Chemopreventive
Vitamin e’s role in Oxidative Stress and Cancer
Vitamin E and Aberrant Crypt Foci
Some Vitamin E Isoforms May Exert Anticancer Effects by Non-Redox Mechanisms
The Potential for Vitamin E Isoforms to be Used as Adjuvant Chemotherapy
Some Vitamin E Isoforms Demonstrate an Ability to Enhance the Antiproliferative Effects of Chemotherapy in Cancer Cell Lines
Some Vitamin E Isoforms Reduce the Harmful Side Effects of Chemotherapeutic Agents
Vitamin E Isoforms Modulate Major Regulatory Elements Involved in Inflammation
Vitamin E Isoforms Modulate Pathways Involved in Metastasis
Vitamin E Isoforms Modulate Ras Levels Resulting in Cell Cycle Arrest and Apoptosis
Vitamin E Modulates the Master Fat Regulatory Element, Peroxisome Proliferator Activator Receptor, (PPAR)
Receptor Tyrosine Kinase Activity is Modulated by Redox Silent Forms of Vitamin E as Well as Naturally occuring Vitamin E forms
Vitamin E Compounds Modulate Proteins Involved in the Sphingolipid and Cholesterol Metabolism
Conclusion
References
Chapter 7
Thiol Metabolic Changes Induced by Oxidative Stress and Possible Role of B-Vitamins Supplements in Esophageal Cancer Patients
Abstract
Introduction
1. The Cell-Hormetic Responses to Oxidative Stress
2. The Role of Antioxidant Defenses
2.1. Sulfur-Containing Antioxidants
2.2. Glutathione Functions
2.3. Glutathione Modulation
3. Esophageal Cancer
3.1. Nutritional Risk-Factors
Objectives
Methods
Results
Discussion
Conclusion
Acknowledgment
References
Chapter 8
Vitamin B12 Modulates AM-Coagulation
Abstract
Introduction
Material and Methods
Results and Discussion
References
Chapter 9
The Relations between Water-Soluble
B Vitamins and Indoleamines
Abstract
1. Introduction
2. Thiamine (Vitamin B1)
2.1. Thiamine Deficiency in Animals
2.3. Thiamine Deficiency in Humans
2.3.1. Wernicke-Korsakoff Syndrome
2.3.2. Other Neural Diseases
3. Vitamin B9 (Folate)
3.1. Folate Deficiency in Animals
3.2. Folate Administration in Animals
3.3. Folate Deficiency in Humans
3.3.1. Neuropsychiatric Disorders in Adults
3.4. Folate Administration in Humans
4. Vitamin B6 (Pyridoxine)
4.1. Background
4.2. Vitamin B6 Deficiency in Animals
4.3. Vitamin B6 Administration in Animals
4.4. Vitamin B6 Deficiency in Humans
4.4. Vitamin B6 Administration in Human Subjects
5. Vitamin B12 (Cobalamin)
5.1. Background
5.2. Vitamin B12 Deficiency in Animals
5.3. Vitamin B12 Administration in Animals
5.4. Vitamin B12 Deficiency In Humans
5.5. Vitamin B12 Administration in Humans
Conclusion
References
Chapter 10
Sun Exposure and Protection Habits and Vitamin D Levels in Children and Adolescents With a History of Malignancy
Abstract
Abbreviations
Sun Exposure and Skin Cancer
Recommendations of Sun Protection Behaviors
Sources of Vitamin D
Sun Exposure
Food
Daily Vitamin D Requirements
Recommendations for 25OHD Levels
Prevalence of Vitamin D Deficiency
Vitamin D Roles
Skeletal
Extra-Skeletal
Sun Exposure and Non-Skin Cancer
Vitamin D and Cancer Risk, Morbidity and Mortality
Vitamin D Levels in Pediatric Patients with Malignancy
Childhood Cancer Survivors and Sun Exposure
Conclusion - Balancing Risks and Benefits of Sun Exposure
References
Chapter 11
The Effects of B Vitamins on Behavior and Neurochemistry
University of Rouen, Dept Psychology, ICONES Laboratory EA 4699, 76821 Mont-Saint-Aignan France
Abstract
1. Introduction
2. Thiamine (Vitamin B1)
2.1. Background
2.2. Thiamine Deficiency in Animals
2.2.1. Neurochemistry
2.2.2. Behavior
2.3. Thiamine Deficiency in Humans
2.3.1. Wernicke-Korsakoff syndrome
2.3.2. Other neurodegenerative diseases
2.3.2.1. Neurochemistry
2.3.2.2. Behavior
2.4. Thiamine Supplements in the Normal Population
3. Vitamin B9 (Folate)
3.1. Background
3.2. Folate Deficiency in Animals
3.2.1. Neurochemistry
3.2.2. Behavior
3.3. Folate Administration In Animals
3.4. Folate Deficiency in Humans
3.4.1. Neuropsychiatric disorders in adults
3.4.2. Neuropsychiatric disorders in children
3.4.3. Dementia
3.4.4. Normal aging
3.4.5. Young adults or chilren
3.5. Folate Supplements in Children and Adults
4. Vitamin B6 (Pyridoxine)
4.1. Background
4.2. Vitamin B6 Deficiency in Animals
4.3. Vitamin B6 Deficiency in Humans
4.4. Vitamin B6 Supplements in Normal Adults and Children
5. Vitamin B12
5.1. Background
5.2. Vitamin B12 Deficiency in Animals
5.3. Vitamin B12 Deficiency in Humans
5.3.1. Neurologic cases
5.3.2. Depression
5.3.3. Dementia
5.3.4. Normal aging
5.3.5. Neurologic syndromes in children
5.3.6. Normal children or adolescents
5.4. Vitamin B12 Supplements in Humans
5.4.1. Neuropsychiatric cases
5.4.2. Dementia and normal aging
6. Multiple B Vitamins
6.1. Vitamin B-Deficient Diets in Animals
6.2. Multiple B Vitamins in Humans
6.2.1. Stroke and dementia
6.2.2. Normal aging
6.2.3. Normal young adults
6.2.4. Normal children
7. Future Directions
7.1. Myelin
7.2. Optimal Vitamin Doses
References
Chapter 12
Development of Vitamin D Deficiency in Obese Individuals Undergoing Bariatric Surgery
Abstract
Growing International Prevalence of Obesity
Surgical Treatment of Obesity
Overview of the Physiology of Vitamin D
Vitamin D and Obesity
Vitamin D and Bariatric Surgery
Proposed Mechanisms of Vitamin D Deficiency After Bariatric Surgery
Vitamin D Deficiency and Small Intestinal Bacterial Overgrowth
Screening for Vitamin D Deficiency
Management of Vitamin D Deficiency After Bariatric Surgery
Conclusion
References
Chapter 13
Vitamins and Minerals as Alternative or Complementary Therapies in Depression
Abstract
Introduction
Vitamins
Vitamin D
Vitamin E
Vitamin C
Folic Acid
Other Vitamin B
Minerals
Zinc
Magnesium
Chrome
Selenium
Conclusion
References
Chapter 14
Vitamin B12 Importance for
the Proper Body Condition
Abstract
Introduction [1]
Prevalence of Vitamin B12 Deficiency [2]
Causes of Vitamin B12 Deficiency [3]
Clinical Manifestations of Vitamin B12 Deficiency
Diagnosis of Vitamin B12 Deficiency
Case Report
Discussion [3, 9-11, 13]
Conclusion
References
Chapter 15
Association between Vitamin D and Anti-Mullerian Hormone
Abstract
Introduction
Vitamin D and AMH Gene
a) AMH Gene
b) Serum AMH Protein Level
Vitamin D and AMH in Women with PCOS
Conclusion
Questions
References
Chapter 16
Impact of Vitamin D System on Ventricular Remodeling
Abstract
Introduction
Metabolism of Vitamin D
Vitamin D receptor
Vitamin D Circulating Levels and Cardiovascular Disease: Clinical Evidences
Vitamin D Pathway and Cardiac Hypertrophy
Conclusion
References
Chapter 17
Dexamethasone Suppresses Neurosteroid Biosynthesis in Human Glial Cells
via Cross-Talk with Vitamins A and D
Abstract
Introduction
Vitamin A and D Enhance Neurosteroid Synthesis in Human Glioma GI-1 Cells
Effect of Dex on the Steroidogenic Gene Expression in GI-1 Cells
Effects of Dex on Vitamin-Induced Steroidogenic Gene Expression in GI-1 Cells
Dex Reduces de novo Biosynthesis of Neurosteroids in GI-1 Cells
Regulation of 11-Hydroxysteroid Dehydrogenase (HSD11B) Gene Expression by Cross-Talk between GC and RA Receptors in GI-1 Cells
Conclusion
Acknowledgments
Competing Interests
References
Chapter 18
Vitamins and Supplements in Alcoholic Liver Disease
Abstract
Introduction
Water Soluble Vitamins
Vitamin B1 (Thiamine)
Vitamin B2 (Riboflavin)
Vitamin B3 (Niacin)
Vitamin B6 (Pyridoxine)
Vitamin B9 (Folic Acid/Folate)
Vitamin B12 (Cobalamin)
Vitamin C (Ascorbic Acid)
Fat Soluble Vitamins
Vitamin A (Retinol)
Vitamin E (Tocopherol)
Vitamin D
Minerals and Trace Elements
Iron
Calcium and Magnesium
Zinc
References
Chapter 19
A Comparative Study of Liposoluble Vitamin Effects in Decapod Crustacean with Emphasis in Argentine Shrimp Species
1Instituto de Investigaciones Marinas y Costeras,
Facultad de Ciencias Exactas y Naturales,
Universidad Nacional de Mar del Plata-Consejo Nacional
de Investigaciones Científicas y Técnicas, Mar del Plata, Argentina
2Museo Municipal de Ciencias Naturales Lorenzo Scaglia,
Municipalidad de General Pueyrredón,
Mar del Plata, Argentina
Abstract
Introduction
Argentine Shrimp Species
Vitamin a and Carotenoids
Vitamin D
Vitamin E
Vitamin K
Conclusion
Reviewed By
References
Chapter 20
Antioxidant Vitamins and the Heart
Abstract
Introduction
Effects of Vitamins in Cardiovascular Diseases
Individual Vitamins and Minerals
Vitamin A and C
Vitamin E and Selenium
β-Carotene and Folic Acid
Acknowledgments
References
Chapter 21
Antioxidant Vitamins and Oxidative Stress in Chronic Heart Failure
Abstract
Introduction
Subjects and Methods
Study Design
Laboratory Data
Statistical Analysis
Results
Discussion
Acknowledgments
References
Chapter 22
Hypoxia and Oxidative Stress: Cell Signaling Mechanisms and Protective Role of Vitamin C and Cilnidipine
Abstract
Introduction
Hypoxia: An Overview
Hypoxia and Oxidative Stress – Molecular Interactions
Hypoxia, Oxidative Stress, Antioxidants
Conclusion
Acknowledgment
References
Chapter 23
Vitamins, Minerals, Herbal Supplements and Other Dietary Supplements as Complementary and Alternative Therapies in Cancer Care
Abstract
Introduction
Literature search
Eligibility criteria
Selection process, data abstraction and analysis
Findings
Of the 20 eligible studies, 15 evaluated herbal supplements (8-22), 4 evaluated dietary supplements (23-26), 2 evaluated vitamins (8, 27), and two evaluated minerals (in combination with herbal supplements) (13, 14) (see Table 1). Four enrolled patien...
Therapies treating side-effects
Two independent studies investigated the efficacy of Goshajinkigan (GJG), a traditional Japanese medicine, in treating chemotherapy-induced neurotoxicity and found promising results. Abe and colleagues compared GJG with Mecobalamin (vitamin B12) as tr...
Therapies for disease management
A total of 5 studies primarily assessed the efficacy of complementary and alternative therapies on disease management (9, 12, 16, 25, 26).
Discussion
Conclusion
The use of VMHD in the treatment of cancer and traditional treatment side effects appears potentially promising. Many of the studies included in our scoping review were unique in their treatment condition and reported outcomes, making comparisons acro...
References
Chapter 24
Vitamin D and Cognitive Impairment: An Update
Abstract
Introduction
Vitamin D: Overview
Vitamin D Physiology
Vitamin D Deficiency: Definition
Prevalence of Vitamin D Deficiency
Vitamin D Deficiency: Causes and Risk Factors
Vitamin D and the Elderly
Clinical Consequences of VD Deficiency
Vitamin D Status and Cognition
Vitamin D and the Brain
Dementia and Cognitive impairment: Concepts and Epidemiology
Cognitive Decline and Dementia Risk Associated to Hypovitaminosis D
VD Status and Neuropsychological Profile
VD Status and Alzheimer’s Disease
VD Status and Lewy Body Disorders
VD Status and Vascular Dementia
VD Status and Mild Cognitive Impairment
VD Status and Attention Deficit Hyperactivity Disorder
Vitamin D and Neuroimaging
Screening and Treatment of VD Deficiency
Conclusion
References
Chapter 25
The Effects of Valproate and Levetiracetam as a Monotherapy on Vitamin D Status in Epileptic Children
Abstract
Introduction
Methods
Participants
Clinical Information and Anthropometry
Biochemical Analysis
Statystical Analysis
Results
Discussion
References
Biographical Sketch
Chapter 26
Photochemistry of Riboflavin (Vitamin B2) and Related Compounds
Abstract
1. Introduction
2. Anaerobic Photoreactions
3. Aerobic Photoreactions
4. Types of Photochemical Reactions
4.1. Photoreduction
4.1.1. Intramolecular Photoreduction
4.1.2. Intermolecular Photoreduction
4.2. Photodealkylation
4.3. Photoaddition Reactions
4.4. Photooxidation
4.5. Photosenstization Reactions
4.6. Photostabilisation Reactions
4.7. Factors Affecting Photochemical Reactions of RF
4.7.1. Radiation Source
4.7.2. pH Effect
4.7.3. Buffer Effect
4.7.4. Effect of Complexing Agents
4.7.5. Effect of Quenchers
4.7.6. Effect of Solvent
4.7.7. Effect of Ionic Strength
4.7.8. Effect of Metal Ion
4.7.9. Effect of Formulation
Conclusion
References
Chapter 27
Vitamin D and Multiple Sclerosis
Abstract
Introduction
Vitamin D: Production and Biological Effects
Vitamin D Deficiency and MS: Environmental Exposure vs. Genetic Predisposition
Role of Vitamin D Levels in MS Management
Conclusion
References
Chapter 28
The Use of Vitamins, Minerals, Herbal Supplements, and Other Dietary Supplements as Complementary and Alternative Therapies in Cancer Care: A Literature Review
Abstract
Introduction
Methods
Eligibility criteria
Selection process, data abstraction and analysis
Results
Therapies treating side-effects
Therapies for disease management
Discussion
Conclusion
Conflict of interest
Acknowledgments
References
Chapter 29
Immunomodulators and Postoperative Pain: Immunonutrition and Topical Vitamin E
Abstract
Immunonutrition
Components of Immunonutrition
Effects of Inmmunonutrition on Postoperative Pain After Bariatric Surgery
Topical Vitamin E
Conclusion
References
Chapter 30
Micronutrients and Periodontal Disease: The Potential Role of Vitamins
Abstract
1. Introduction
2. Relationship between Vitamins and Periodontal Disease - A Contemporary Review
3. Physiological Function of Vitamins
3.1. Vitamin A
3.2. Vitamin B
3.3. Vitamin C
3.4. Vitamin D
3.5. Vitamin E
3.6. Vitamin K
4. Effects of Vitamins Supplementation on Periodontal Disease
4.1. Animal Studies
4.2. Human Studies
Discussion
Conclusion and Recommendations
References
Chapter 31
Vitamin E: Nutritional Recommendation and Biofortified Foods
Abstract
Introduction
Function
Metabolism of Vitamin E
Absorption
Transport and Distribution of Vitamin E
Nutrition Recommendation
Biofortification
Vitamin E and Biofortification of Plant Crops
Biosynthesis of Vitamin E
Biofortification of Plants with Vitamin E by Transgenic Approach
Biofortification of Plants with Vitamin E by Conventional Breeding
Vitamin E in Foods of Animal Origin and the Importance of Biofortification
Eggs
Fish
Chicken, Pork, Lamb and Beef
Milk
Conflict of Interest
References
Chapter 32
Occurrence and Health Benefits of Alkaloids and Vitamins and Their Affinities to Plasma Proteins
Abstract
Abbereviations
1. Introduction
2. Occurance, Structure and Health Benefits of Alkaloids and Vitamins
2.1. Alkaloids
2.2. Vitamins
3. Spectroscopic and Electrochemical Investigations
3.1. Affinity of Alkaloids to Plasma Proteins
3.2. Binding Characteristics of Interactions of Vitamins with Blood Proteins
Conclusion
References
Chapter 33
Vitamin C Supplementation: Favorable or Noxious?
Abstract
1. Introduction
2. Physiological Concentrations of Vitamin C
2.1. Dietary Reference Intake (DRI) of Vitamin C
2.2. Dietary Sources and Bioavailability of Vitamin C
2.3. Pharmacokinetics of Vitamin C
3. Effects of Vitamin C on Health
4. Antioxidant and Pro-oxidant Effect of Vitamin C
5. Mutagenicity and Antimutagenicity of the Vitamin C
5.1. Effects of Vitamin C Over Transition Metals
5.2. Effects of Vitamin C Over Alkylating Agents
5.3. Effects of Vitamin C in Diabetes
5.4. Effects of Vitamin C in Obesity
5.5. Vitamin C and Cardiovascular Disease Risk Factors
5.6. Effects of Vitamin C in Amfepramone Treatment
5.7.Vitamin C and Nicotine
Conclusion
Acknowledgments/Revision
References
Chapter 34
An Overview of the Analytical Methods to Determine Ascorbic Acid in Foodstuffs
Abstract
1. Introduction
2. Extraction Procedures of Ascorbic Acid From Foods
3. Analytical Techniques
3.1. High Performance Liquid Chromatography (HPLC)
3.1.1. Ultrahigh-Performance Liquid Chromatographic (UPLC)
3.2. Gas Chromatography (GC)
3.3. Capillary Electrophoresis
3.4. Spectrophotometric and Spectrofluorimetric Methods
3.5. Other Methods
4. Conclusion
Acknowledgments/Revision
References
Chapter 35
Vitamin C Daily Supplements and Its Ameliorative Effects
Abstract
Introduction
1. Recommended Supplementation
2. Basis of Vitamin C Role
3. Hepatic Effects
4. Renal Effects
5. Cardiovascular Effects
6. Respiratory Effects
7. Anti-Cancer Effects
8. Ophthalmological Effects
9. Gynaecological and Obstetrical Effects
10. Toxicological Effects
11. Dermatological Effects
12. Endocrine Effects
13. Psychological Effects
14. Neuropsychiatric Effects
15. Anti-Infective and Immunity Effects
16. Physical Performance Effects
17. Vitamin C and Minerals
18. Vitamin C and Stem Cells
19. Vitamin C and Laboratory Investigations
20. Miscellaneous Effects
Conclusion
References
Chapter 36
Ionizing Radiation Effects on Vitamin C
Abstract
1. Introduction
2. Effects of Radiation on Food
3. Gamma Irradiation on Vitamin C
Conclusion
Acknowledgments/Revision
References
Chapter 37
Vitamin C in Marine and Freshwater Teleosts
Abstract
1. Introduction
2. Vitamin C Requirement in Marine Teleosts
2.1. Materials and Methods
2.1.1. Experimental Semipurified Diets
2.1.2. Experimental Diet, Fish and Feeding Trails
Experiment 1 (Korean Rockfish 3.1± 0.02 g)
Experiment 2 (Korean Rockfish 7.12 ± 0.02 g)
Experiment 3 (Korean Rockfish 12.6 ± 0.02 g)
Experiment 4 (Olive Flounder 3± 0.06 g)
Experiment 5 (Parrot Fish 3.9 ± 0.06 g)
2.1.3. Sample Collection and Analyses
2.2. Results
Experiment 1 (Korean Rockfish 3.1 ± 0.02 g)
Experiment 2 (Korean Rockfish 7.12 ± 0.02 g)
Experiment 3 (Korean Rockfish 12.6 ± 0.02 g)
Experiment 4 (Olive Flounder 3 ± 0.06 g)
Experiment 5 (Parrot Fish 3.9 ± 0.06 g)
2.3. Discussion
3. Vitamin C Requirement in Freshwater Teleosts
3.1. Materials and Methods
3.1.1. Experimental Semipurified Diets
3.1.2. Experimental Diet, Fish & Feeding Trail
3.1.3. Sample Collection and Analyses
3.2. Results
3.3. Discussion
4. General Discussion and Summary
Conclusion
Acknowledgments/Revision
References
Chapter 38
Effects of Ascorbic Acid on Immunity
and Low Grade Systemic Inflammation
1Department of Food Industry, Polythecnic Institute of Viseu, Portugal
2Institute for Biomedical Imaging and Life Sciences (IBILI), Faculty of Medicine, University of Coimbra, Portugal
3Faculty of Medicine, University of Coimbra, Portugal
4Educational Technologies and Health Study Center
Quinta da Alagoa, Estrada de Nelas, Viseu, Portugal
Abstract
1. Introduction
2. General Aspects of the Inflammatory
Process and the Role of Vitamin C
2.1. Actions of Vitamin C in the Innate Immune System
2.1.1. Immunobiological Relevance of the Antioxidant Capacity of Vitamin C
2.1.2. Immunobiological Relevance of Vitamin C by Its Involvement in the Carnitine Synthesis
2.1.3. Influence on the Synthesis of Tetrahydrobiopterin and Nitric Oxide
2.2. Chronic Inflammation
3. Vitamin C and Low Grade
Systemic Inflammatory Diseases
3.1. Atherosclerosis
3.2. Type 2 Diabetes Mellitus
3.3. Cancer
3.4. Aging
4. Pharmacological Approach of Vitamin C
4.1. Vitamin C Concentration in Humans As a Function of Dose
4.2. Vitamin C: Use As a Pro-Drug and Safe Profile Evidences
Conclusion
Acknowledgments
References
Chapter 39
Vitamin C Deficiency Enhances Disruption of Adrenal Non-Enzymatic Antioxidant Defense Systems in ODS Rats with Water-Immersion
Restraint Stress
Department of Chemistry, Fujita Health University
School of Medicine, Toyoake, Japan
Abstract
1. Introduction
2. Materials and Methods
2.1. Materials
2.2. Animals
2.3. Induction of WIRS
2.4. Assays of Adrenal and Serum Components
2.5. Statistical Analysis
3. Results
4. Discussion
Conclusion
Acknowledgments
References
Chapter 40
Vitamin C and Erythrocytes
Abstract
1. Introduction
2. Erythrocytes and Oxidative Stress
3. Vitamin C and Erythrocytes: Observations in Animals and Humans
3.1. Vitamin C and Storage of Human Erythrocytes
3.2. Vitamin C and Erythrocyte Diseases
Conclusion
Acknowledgments/Revision
References
Chapter 41
Vitamin C: Loss through Cooking
and Conservation Methods and
Symptoms of Deficiency
School of Nutrition Director, Faculty of Health Sciences,
Maimonides University, Buenos Aires City, Argentina
Abstract
1. Introduction
2. Vitamin C: Loss through Cooking
and Conservation Methods and
Symptoms of Deficiency
2.1. Sources of Vitamin C
2.2. Function
2.3.1. Potential for Maintaining Levels Found in the Fresh Produce
2.3.2. Effects of Processing
2.3.3. Industrial Processing
2.3.4. Losses during Storage
2.3.5. Conservation and Domestic Cooking
2.4. Symptoms of Deficiency of Vitamin C
2.4.1. Evidence on Dental Health and Vitamin C
2.4.2. Vitamins and the Treatment of Oral and Dental Diseases
Conclusion
Acknowledgments
References
Chapter 42
Pharmacological Effects of Ascorbic Acid
Departments of Pharmaceutics and Pharmaceutical Chemistry, Institute of Pharmaceutical Sciences, Baqai Medical University, Karachi, Pakistan
Abstract
1. Introduction
2. Pharmacological Utilization of AA
2.1. Scurvy
2.2. Osteoarthritis
2.3. Common Cold
2.4. Heart Diseases
2.5. Hypertension
2.6. Cancer
2.7. Diabetes Mellitus
2.8. Asthma
2.9. Pregnancy
2.10. Wound Healing
2.11. Gout
2.12. Cataracts and Glaucoma
2.13. Depression
2.14. Parkinsonism
2.15. Schizophrenia
2.16. Alzheimer Disease
2.17. Urinary Tract Infections
3. Adverse Effects and Contraindications
3.1. Kidney Stones
3.2. Other Complications
3.3. Contraindications
Conclusion
Acknowledgments
References
Chapter 43
Contradictions and Ambivalences of Vitamin C Consumption on Human Health: A Review of the Literature
Abstract
1. Introduction
2. Beneficial Effects of Vitamin C in Human Health
3. Action of Vitamin C As a Pro-oxidant
4. The Hypervitaminosis C
5. Considerations on the Effects of Vitamin C, Its Consumption and the Establishment of Nutritional Recommendations for Populations
Conclusion
References
Chapter 44
Vitamin C Role in Human Health, Disease and Sport
Abstract
1. Introduction
2. Vitamin C in Human Health and Disease
2.1. Vitamin C and Diabetes
2.2. Vitamin C and Cancer
2.3. Vitamin C and Cardiovascular Disease
2.4. Vitamin C and Age-Related Macular Degeneration and Cataracts
2.5. Vitamin C and Immune Function
2.6. Vitamin C and Tobacco Usage
2.7. Health Risks from Excessive Vitamin C Intake
3. Vitamin C and Sports
3.1. Vitamine C as Ergogenic Aid in Sport
3.2. Potential Action of Vitamine C in Sports Injuries and Muscle Recovery
Conclusion
Acknowledgments/Revision
References
Chapter 45
Variability in the Vitamin C Content of Baobab (Adansonia digitata L.) Fruit Pulp from Three African Sahelian Countries
Abstract
1. Introduction
2. The Baobab Tree
2.1. Description and Geographical Distribution
2.2. Importance of the Baobab (Adansonia digitata L) Tree
3. Regional Variability of Baobab Fruits Content in Vitamin C
Conclusion
Acknowledgments/Revision
References
Chapter 46
Vitamin A and Other Biochemical Markers in Obese Patients with Biliopancreatic Bypass
Abstract
Introduction
Material and Methods
Study Desing
Analytical Instrumentation
Statistical Analysis
Results
Conclusion
References
Chapter 47
Dietary Vitamin E Intake by Older
Japanese Adults
Abstract
Introduction
Methods
Study Design and Participants
Interview
Food Frequency Questionnaire
Statistical Analysis
Results
Discussion
Appendix. Vitamin E content of foods from Japanese Food Composition Tables [12]
References
Chapter 48
Vitamin A: Dietary Sources and Health Consequences
Abstract
1. Introduction
1. Daily Requirements
1.1. Toxicity
1.2. Factors Affecting Requirements
2. Dietary Sources
3. Symptoms of Deficiency
3.1. Clinical Signs and Symptoms of Vitamin A Deficiency
3.2. Age and Sex
3.3. Morbidity and Mortality
References
Chapter 49
Vitamin E and its Role in Dementia
Declaration
Abstract
Introduction
Conclusion
References
Chapter 50
Indigeneous Vegetables:
An Excellent Source of Vitamin A
Abstract
1.1. Introduction
1.2. Nutrition and Vitamin A Deficiency
1.3. Role of Indigenous Vegetables in
VAD Alleviation
1.4. Preservation of Indigenous Vegetables
1.5. The Future of Indigenous Vegetables
in Africa
References
Chapter 51
Medicinal and Dietary Aspects of Vitamin E
Abstract
1. Biosynthesis
2. Vitamin E Activity
2.1 Mechanism of Antioxidant Activity
2.2 Application of the Antioxidant Activity of Vitamin E
3. Absorption of Vitamin E
4. Current Medical Applications of Vitamin E in Cancer Cell Treatments
5. Vitamin E Deficiency
5.1 Genetic Defect of α-Tocopherol Transfer Protein
5.2 Insufficient Lipids Absorption
5.3 Malnutrition or Improper Diet
6. Daily Requirements
7. Dietary Sources of Vitamin E
Conclusions and Future Vitamin E Research
References
Chapter 52
Vitamin E: Daily Requirements, Dietary Sources, Symptoms of Deficiency and Recent Use in Clinical Studies
Abstract
Abbreviations
Introduction
Sources of Vitamin E
Biochemical and Physiological Functions of Vitamin E
Absorption, Transport, Metabolism and Excretion of Vitamin E
Daily Requirement of Vitamin E
Symptoms Deficiency in Vitamin E
Sign and Symptoms of Toxicity
Recent Research in Vitamin E
Vitamin E and diabetes mellitus
Vitamin E and Asthma
Vitamin E and Non-alcoholic Fatty Liver Disease
Vitamin E and Skin Disorders
Vitamin E and Pregnancy
Conclusion
References
Chapter 53
Vitamin D in the Immune System and Role of its Deficiency in Rheumatic Diseases
Abstract
Introduction
Vitamin D Role in Immune System
Vitamin D Role in Autoimmunity
Role of Vitamin D Deficiency in Rheumatic Diseases
Rheumatoid Arthritis
Systemic Lupus Erythematosus
Antiphospholipid Syndrome
Systemic Sclerosis
Systemic Vasculitis
Behcet’s Disease
Undifferentiated Connective Tissue Disease
Psoriatic Arthritis
Spondyloarthropathies
Juvenile Idiopathic Arthritis
Conclusion
References
Chapter 54
Genetic and Epigenetic Changes
of Vitamin D-Related Genes in Cancer
Abstract
Introduction
1.1. Vitamin D Metabolism
1.2. Anticancer Activity of Vitamin D
1.3. Vitamin D Related Genes
2. Genetic Changes in Vitamin D Related Genes
2.1. VDR Gene Polymorphisms
EcoRV (rs4516035)
FokI (rs2228570)
BsmI (rs1544410)
ApaI (rs7975232)
TaqI (rs731236)
BsmI-ApaI-TaqI Haplotype Block
Cdx-2 (rs11568820)
Poly A (rs2544038)
2.2. CYP27A1 Gene Polymorphisms
2.3. CYP27B1 Gene Polymorphisms
2.4. CYP24A1 Gene Polymorphisms
3. Epigenetic Changes in Vitamin D Related Genes
3.1. DNA Methylation and Vitamin D-Related Genes in Cancer
3.2. Histone Modifications and Vitamin D-Related Genes in Cancer
3.3. MicroRNAs and Vitamin D-Related Genes in Cancer
Conclusion
References
Chapter 55
Vitamin D and Ageing in Adults and the Elderly: Literature Review and Future Research Implications
Abstract
Introduction
Vitamin D and Brain Development
Epidemiological Studies
Possible Mechanism
Conclusion
References
Chapter 56
The Importance of Some Analytical Aspects and Confounding Factors in Relation to Clinical Interpretation of Results
Abstract
Introduction
Vitamin D: 25(OH)D and 1,25(OH)2D
Preanalytical Issues in the 25(OH)D Estimation
Analytical Issues in the 25(OH)D Estimation and External QualityASsessment (EQA) Schemes
Latitude, Season, Age and Sex Influences
Genetic Aspects Affecting 25(OH)D Levels
Reference Intervals for 25(OH)D
Conclusion
Acknowledgments
References
Chapter 57
Hypovitaminosis D and Cardiovascular Disease
Abstract
References
Chapter 58
Evidence for Positive Effects
of Vitamin D Supplementation
on Disease Conditions beyond Bone Health in Adults:
A Review of the Recent Literature
Abstract
Introduction
Methods
Study Identification
Review Methods
Results
Discussion
Fractures
Muscle Strength and Falls
Cardiovascular Disease and Mortality
Diabetes
Current recommendations for Vitamin D
Conclusion
References
Chapter 59
Hypovitaminosis D and Osteopenia/Osteoporosis in a Haemophilia Population: A Study in HCV and HCV/HIV Infected Patients
Introduction
Patients and Methods
Results
Discussion
References
Chapter 60
Vitamin D: Do We Know Everything?
Abstract
Introduction
Vitamin D Deficiency
Vitamin D Metabolism
Vitamin D Action
Bones
Muscle
Cancer
Heart
Autoimmune
Infections
Asthma
Neurons
Mortality
Fertility
Pregnancy
Supplemental and Treatment Doses
Summary
References
Chapter 61
Vitamin D Beyond Skeletal Health: Implications for Muscle Function and Physical Performance
Abstract
Introduction
Vitamin D Metabolism
Vitamin D Status
Roles of Vitamin D
Insulin Resistance
Low-Grade Systemic Inflammation
Vitamin D and Skeletal Muscle Function
Observational Studies
Muscular Strength and Power
Mobility and Balance
Supplementation Studies
Lean Mass Accumulation and Muscle Morphology
Muscular Strength and Physical Performance
Vitamin D supplementation during Exercise Training
Conclusion
References
Chapter 62
The History and Modern Controversies of Vitamin D Fortification and Supplementation
Abstract
Introduction
First Observations of Rickets
Finding the Cause of Rickets – Early Observations with Light and Cod Liver Oil
Isolation of the Anti-Rachitic Factor
Development of Fortification
Isolation of Vitamin D Metabolites
The Light-er ER Side of Vitamin D
Into the 21st Century
Determing How Much Vitamin D We Need –
What Does Vitamin D Do?
Serum Testing and Goals
Supplement Options
A Variety of Supplementation Recommendations
A Variety of Replacement Regimens
Conclusion
Referneces
Index
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Citation preview

NUTRITION AND DIET RESEARCH PROGRESS

ENCYCLOPEDIA OF VITAMINS NEW RESEARCH (4 VOLUME SET) VOLUME 1

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NUTRITION AND DIET RESEARCH PROGRESS Additional books and e-books in this series can be found on Nova’s website under the Series tab.

NUTRITION AND DIET RESEARCH PROGRESS

ENCYCLOPEDIA OF VITAMINS NEW RESEARCH (4 VOLUME SET) VOLUME 1 LINDSEY VALDEZ EDITOR

Copyright © 2019 by Nova Science Publishers, Inc.

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Library of Congress Cataloging-in-Publication Data ISBN: HERRN Library of Congress Control Number:2019943456

Published by Nova Science Publishers, Inc. † New York

CONTENTS Preface

xi VOLUME 1

Chapter 1

Liquid Chromatography for the Determination of Tocopherols and Tocotrienols (Vitamin E) in Food of Plant Origin Emmanouil D. Tsochatzis and Maria Papageorgiou

1

Chapter 2

Differentiation Signaling Induced by Retinoic Acid and Vitamin D3 Xiaotang Hu and Graham Shaw

17

Chapter 3

Suicide Risk Factors: Vitamin D Levels Tzvetelina Dimitrova, Elizabeth Streeten, Muhammad M Tariq and Teodor T Postolache

43

Chapter 4

Role of Ultraviolet-B Irradiance and Vitamin D in Reducing Risk of Cancer William B. Grant and Meis Moukayed

61

HPLC Analysis of Vitamin B1, B2, B3, B6, B9, B12 and Vitamin C in Various Food Matrices Jessy van Wyk, Larry Dolley and Ndumiso Mshicileli

93

Chapter 5

Chapter 6

Chapter 7

Chapter 8

Vitamin E Isoforms: Multiple Mechanisms of Action against Carcinogenesis Sharon E. Campbell, Aashish S. Morani, William L. Stone, Koyamangalath Krishnan and Victoria E. Palau Thiol Metabolic Changes Induced by Oxidative Stress and Possible Role of B-Vitamins Supplements in Esophageal Cancer Patients Roberto Carlos Burini, Vânia Cristina Lamônica, Fernando Moreto, Yong-Ming Yu and Maria Aparecida Coelho Arruda Henry Vitamin B12 Modulates AM-Coagulation Thomas Stief

151

213

239

vi

Contents

Chapter 9

The Relations between Water-Soluble B Vitamins and Indoleamines Robert Lalonde

Chapter 10

Sun Exposure and Protection Habits and Vitamin D Levels in Children and Adolescents With a History of Malignancy Yael Levy-Shraga and Dalit Modan-Moses

Chapter 11

The Effects of B Vitamins on Behavior and Neurochemistry Robert Lalonde

Chapter 12

Development of Vitamin D Deficiency in Obese Individuals Undergoing Bariatric Surgery William Hsueh, Bikram S. Bal, Timothy R. Shope and Timothy R. Koch

251

265 283

325

VOLUME 2 Chapter 13

Vitamins and Minerals as Alternative or Complementary Therapies in Depression Morgana Moretti, Luana M. Manosso and Ana Lúcia S. Rodrigues

341

Chapter 14

Vitamin B12 Importance for the Proper Body Condition José Luis Cabrerizo-García and Begoña Zalba-Etayo

377

Chapter 15

Association between Vitamin D and Anti-Mullerian Hormone Mohamad Irani and Zaher Merhi

385

Chapter 16

Impact of Vitamin D System on Ventricular Remodeling Claudia Kusmic, Nicoletta Vesentini and Cristina Barsanti

395

Chapter 17

Dexamethasone Suppresses Neurosteroid Biosynthesis in Human Glial Cells via Cross-Talk with Vitamins A and D Hiroomi Tamura

Chapter 18

Vitamins and Supplements in Alcoholic Liver Disease Katelyn R. Richards

Chapter 19

A Comparative Study of Liposoluble Vitamin Effects in Decapod Crustacean with Emphasis in Argentine Shrimp Species Nair de los Angeles Pereira, María Victoria Sarasa and Analia Fernández-Gimenez

409 421

433

Chapter 20

Antioxidant Vitamins and the Heart Teodora Handjieva-Darlenska, Krasimira Hristova and Ram B Singh

451

Chapter 21

Antioxidant Vitamins and Oxidative Stress in Chronic Heart Failure Ram B. Singh, Krasimira Hristova, Jan Fedacko, Shantanu Singhal, Shairy Khan, Douglas W. Wilson, Toru Takahashi and Zubin Sharma

459

Contents Chapter 22

Chapter 23

vii

Hypoxia and Oxidative Stress: Cell Signaling Mechanisms and Protective Role of Vitamin C and Cilnidipine Kusal K. Das, Swastika N. Das and Jeevan G. Ambekar

471

Vitamins, Minerals, Herbal Supplements and Other Dietary Supplements as Complementary and Alternative Therapies in Cancer Care Nicholas Lao, Madeleine Lao, Michael Lam, Arnav Agarwal, Edward Chow and Blair Henry

485

Chapter 24

Vitamin D and Cognitive Impairment: An Update Waleska Berríos and Angel Golimstok

Chapter 25

The Effects of Valproate and Levetiracetam as a Monotherapy on Vitamin D Status in Epileptic Children Teodoro Durá-Travé, Fidel Gallinas-Victoriano, María Urretavizcaya-García, Lotfi Ahmed-Mohamed, Sergio Aguilera-Albesa and María Eugenia Yoldi-Petri

497

529

Chapter 26

Photochemistry of Riboflavin (Vitamin B2) and Related Compounds Zubair Anwar and Iqbal Ahmad

543

Chapter 27

Vitamin D and Multiple Sclerosis Victor Kieu and Nikki Thaker

569

Chapter 28

The Use of Vitamins, Minerals, Herbal Supplements, and Other Dietary Supplements as Complementary and Alternative Therapies in Cancer Care: A Literature Review Nicholas Lao, Madeleine Lao, Michael Lam, Arnav Agarwal, Edward Chow and Blair Henry

575

Immunomodulators and Postoperative Pain: Immunonutrition and Topical Vitamin E Jaime Ruiz-Tovar and Carolina Llavero

587

Micronutrients and Periodontal Disease: The Potential Role of Vitamins Guat Syin Lau and Lum Peng Lim

595

Chapter 29

Chapter 30

Chapter 31

Vitamin E: Nutritional Recommendation and Biofortified Foods Paula L. Takeuchi, Karina Pfrimer, Márcia S. V. Salles and Hélio Vannucchi

609

VOLUME 3 Chapter 32

Occurrence and Health Benefits of Alkaloids and Vitamins and Their Affinities to Plasma Proteins Jaldappagari Seetharamappa, Sandhya Balakrishnan, Nagappa L. Teradal and Noboru Motohashi

635

viii

Contents

Chapter 33

Vitamin C Supplementation: Favorable or Noxious? Juliana da Silva, Daniel Prá, Vivian Kahl, Marisa Nunes, Roberta Nunes, Vanessa Andrade, Daniela Leffa and Silvia Isabel Rech Franke

Chapter 34

An Overview of the Analytical Methods to Determine Ascorbic Acid in Foodstuffs Julia López-Hernández and Ana Rodríguez-Bernaldo de Quirós

693

723

Chapter 35

Vitamin C Daily Supplements and Its Ameliorative Effects Said Said Elshama, Ayman EL-Meghawry EL-Kenawy and Hosam Eldin Osman

739

Chapter 36

Ionizing Radiation Effects on Vitamin C Marcia N. C. Harder, Valter Arthur, Suely S. H. Franco and Paula B. Arthur

755

Chapter 37

Vitamin C in Marine and Freshwater Teleosts Sungchul C. Bai, Kumar Katya and Hyeonho Yun

771

Chapter 38

Effects of Ascorbic Acid on Immunity and Low Grade Systemic Inflammation Edite Teixeira de Lemos, Luís Pedro Teixeira de Lemos and Maria João Reis Lima

Chapter 39

Vitamin C Deficiency Enhances Disruption of Adrenal Non-Enzymatic Antioxidant Defense Systems in ODS Rats with Water-Immersion Restraint Stress Yoshiji Ohta and Koji Yashiro

Chapter 40

Vitamin C and Erythrocytes Sambe Asha Devi and Challaghatta Seenappa Shiva Shankar Reddy

Chapter 41

Vitamin C: Loss through Cooking and Conservation Methods and Symptoms of Deficiency Marcela A. Leal and Ivana Lavanda

Chapter 42

Pharmacological Effects of Ascorbic Acid Muhammad Ali Sheraz, Marium Fatima Khan, Sofia Ahmed and Iqbal Ahmad

Chapter 43

Contradictions and Ambivalences of Vitamin C Consumption on Human Health: A Review of the Literature Vanessa A. Ferreira, Ivy S. C. Pires and Milton C. Ribeiro

Chapter 44

Vitamin C Role in Human Health, Disease and Sport Goreti Botelho and Marco Aguiar

799

831 847

861 881

899 915

Contents Chapter 45

Variability in the Vitamin C Content of Baobab (Adansonia digitata L.) Fruit Pulp from Three African Sahelian Countries Charles Parkouda, Jan Svejgaard Jensen and Bréhima Diawara

ix

949

VOLUME 4 Chapter 46

Vitamin A and Other Biochemical Markers in Obese Patients with Biliopancreatic Bypass María Ortiz-Espejo, Ricardo Batanero Maguregui, Juan Antonio Gómez Gerique and María Dolores Fernández González

957

Chapter 47

Dietary Vitamin E Intake by Older Japanese Adults Fumi Hirayama, Andy H. Lee and Keiji Yasukawa

969

Chapter 48

Vitamin A: Dietary Sources and Health Consequences Ediane Maria Gomes Ribeiro, Lucia Maria Jaeger de Carvalho, Lara de Azevedo Sarmet Smiderle and Gisela Maria Dellamora Ortiz

979

Chapter 49

Vitamin E and its Role in Dementia Arianna Vignini, Alessia Giulietti, Francesca Raffaelli, Simona Luzzi, Giulia Sforza, Leandro Provinciali, Laura Mazzanti and Laura Nanetti

995

Chapter 50

Indigeneous Vegetables: An Excellent Source of Vitamin A Hudson Nyambaka and Mildred Nawiri

1003

Chapter 51

Medicinal and Dietary Aspects of Vitamin E Danuta Siluk, Ewa Bartosińska, Dorota Bartusik, David Aebisher and Boguslaw Tomanek

1017

Chapter 52

Vitamin E: Daily Requirements, Dietary Sources, Symptoms of Deficiency and Recent Use in Clinical Studies Lunawati L. Bennett and Pamela Howell

1055

Vitamin D in the Immune System and Role of its Deficiency in Rheumatic Diseases N. Maruotti and F. P. Cantatore

1079

Genetic and Epigenetic Changes of Vitamin D-Related Genes in Cancer Katarina Zeljic, Gordana Supic and Zvonko Magic

1099

Vitamin D and Ageing in Adults and the Elderly: Literature Review and Future Research Implications Ivy Shiue

1117

Chapter 53

Chapter 54

Chapter 55

x Chapter 56

Contents The Importance of Some Analytical Aspects and Confounding Factors in Relation to Clinical Interpretation of Results Cristina Vassalle and Faustino R. Pérez-López

Chapter 57

Hypovitaminosis D and Cardiovascular Disease M. Saad Khan Sikanderkhel and Seth I. Sokol

Chapter 58

Evidence for Positive Effects of Vitamin D Supplementation on Disease Conditions beyond Bone Health in Adults: A Review of the Recent Literature Susan Whiting, Charity Evans and Leng Huat Foo

Chapter 59

Hypovitaminosis D and Osteopenia/Osteoporosis in a Haemophilia Population: A Study in HCV and HCV/HIV Infected Patients Daniela Melchiorre, Marco Matucci-Cerinic, Massimo Morfini and Silvia Linari

1127 1145

1151

1163

Chapter 60

Vitamin D: Do We Know Everything? Hanna Danielewicz

Chapter 61

Vitamin D Beyond Skeletal Health: Implications for Muscle Function and Physical Performance Andres E. Carrillo and Edward J. Ryan

1191

The History and Modern Controversies of Vitamin D Fortification and Supplementation Sara S. Oberhelman and Tom D. Thacher

1207

Chapter 62

1173

Index

1235

Related Nova Publications

1273

PREFACE This 4 volume set covers a wide range of topics, including: · liquid chromatography · vitamins · vegetables · cardiovascular disease · skeletal health Chapter 1 - During the past decade, a number of foodstuff have been the focus of scientific research since epidemiological and clinical studies showed their effect against chronic diseases such as cancer, cardiovascular disease and leukoplakia, skin damage and aging –related eye disease. Tocopherols and Tocotrienols, which are grouped as Tocols, are constituted Vitamin E. They are composed of a polar chromanol ring linked to an isoprenoid-derived hydrocarbon side chain with different saturation. There are four isomers in both Tocopherols (α-, β-, γ-, δ-) and Tocotrienols (α-, β-, γ-, δ-) based on the methyl groups of the chromanol ring. Tocols are very important phytochemical compounds and the level and relative composition of the eight isomers are considerably varied between different plant matrices. Regarding the analysis and determination of tocols, an interesting field of research is the application of Liquid Chromatography to separate the eight isomers. The two main techniques are Normal Phase (NP-) and Reversed Phase (RP-) High Performance Liquid Chromatography (HPLC). The eight isomers could be separated easily with NP-HPLC in contrast with RP-HPLC where in most cases the β- and γ- isomers of both Tocopherols and Tocotrienols are co-eluted. Relative research is targeting in isomers’ separation with simple RP-HPLC techniques, which have the advantages of reproducible chromatographic peak characteristics, stability, easy equilibration and low volatile mobile phases. Another research field regarding tocols separation and analysis are the different extraction methods used to isolate them from the different edible plant matrices with the highest possible yields. Chapter 2 - All-trans retinoic acid (ATRA) and 1, 25-dihydroxyvitamin D3 (1,25(OH)2D3) are involved in a variety of important physiological processes, among which their role in the induction of differentiation of leukemia cells has attracted particular attention in recent years. Acute myeloid leukemia (AML) cells can be stimulated to differentiate to granulocyte-like cells

xii

Emmanouil D. Tsochatzis and Maria Papageorgiou

by ATRA and to monocytes by 1,25(OH)2D3. The biological effects of these two molecules are mainly mediated by the nuclear retinoid acid (RAR) and vitamin D receptors (VDR), respectively. In each case, following ligand binding, the RARs and VDR form a heterodimer complex with retinoid X receptors (RXRs). These heterodimeric complexes regulate DNA transcription by binding to the promoter regions of various target genes in the presence of coactivators. In the absence of ligand, RAR-RXR or VDR-RXA heterodimers bind to corepressors and are not capable of inducing transcription of these target genes. Acute promyelocytic leukemia (APL) is a rare subtype of AML, which is characterized by the presence of an abnormal PML-RAR fusion protein. ATRA is able to disrupt the PML/RARαRXR complex and restore the RARα-RXR signaling. Several transcription factors, such as FOXO3A and c-Myc, have been reported to participate in ATRA-induced differentiation in AML and other blood cells and many ATRA and 1,25(OH)2D3 target genes including UBE1L, UBE2D3, C/EBPs, TRAIL, FOXOs, CAMPs, OLFM4, and c-Myc, have been identified in recent years. There is now accumulating evidence that a number of cell cycle regulatory molecules and multiple intracellular signal pathways/molecules, such as Raf-ERK, PKC isoforms, and PI3-K-AKT, may also regulate ATRA and 1,25(OH)2D3 induced differentiation of the leukemia cells. However, many questions remain to be answered: What is the degree of cross-talk between genomic regulation and intracellular signaling pathways? Which gene(s) or signal molecule(s) play a key role in determining the differentiation of AML cells into granulocytes or monocytes? Chapter 3 - There is a growing evidence that established risk factors (worsening depression, anxiety, psychosis, and certain medical conditions) for suicidal self-directed violence are associated with low 25(OH)vitamin D (25(OH)D) levels. Very low 25(OH)D levels were very recently found to be associated with suicide. Moreover, suicidal behavior follows a seasonal pattern peaking in late spring. 25(OH)D levels are lower at the end of winter as a result of the lower production in the skin due to decreased surface exposure and duration of sun exposure, as well as low heat index and solar radiation. We hereby present a brief summary of the recently published peer-reviewed literature on the effects of vitamin D deficiency and its potential association with risk factors for suicide. Chapter 4 - The evidence that ultraviolet-B irradiance and vitamin D reduce the risk of cancer comes from many types of studies. The UVB-vitamin D-cancer hypothesis was developed based on finding an inverse correlation between annual sunlight doses and colon cancer mortality rates in the United States. Subsequent single-country geographical ecological studies extended the hypothesis to nearly 20 types of cancer. Observational studies have provided some support for the hypothesis, especially for breast and colorectal cancer. One problem with observational studies is that when nested case-control studies are derived from cohort studies, serum 25-hydroxyvitamin D levels at the time of enrollment are used. Since serum 25(OH)D levels change with time, studies with long follow-up times tend to underestimate the effect of vitamin D. Studies of cancer survival with respect to serum 25(OH)D level at time of diagnosis have provided good evidence of beneficial effects for a number of cancer types. Randomized controlled trials have not been conducted properly to test the hypothesis. Two of the most prominent studies used vitamin D and calcium supplementation, making it difficult to separate the effects of the two substances. The mechanisms whereby vitamin D reduces the risk of cancer incidence, progression and metastasis have been studied extensively. Such studies have investigated cell cycle control mechanisms and apoptosis, cellular stress, DNA damage and repair, proliferation and

Preface

xiii

telomerase, alterations in cellular microenvironment promoting angiogenesis and metastasis, interactions with growth factors that mediate transformation, cell adhesion, invasion and metastasis, and inflammation. The scientific evidence regarding whether vitamin D can be considered a causal factor in reducing risk of cancer can be evaluated using Hill’s criteria for causality in a biological system. The important criteria include strength of association, consistent findings in different populations, biological gradient, plausibility (e.g., mechanisms), experiment (e.g., randomized controlled trial), and analogy. The evidence to date largely satisfies these criteria for several types of cancer. Ongoing research will undoubtedly strengthen the evidence in the near future. Chapter 5 - Various methods had been described for the analysis of vitamins in food matrices, with more and more of these including the use of HPLC to measure the levels of these micronutrients in foodstuffs. The renewed interest in rapid and accurate quantification of micronutrients in foodstuffs is due to more stringent requirements by food regulatory agencies around the world. Legislation now demands that the nutrition information displayed on food labels be backed up by reliable results obtained using validated analyses. Three challenges are common in terms of quantifying vitamins in food matrices: 1) extraction techniques that are sufficiently effective to liberate the various forms of the vitamin from each unique matrix, 2) ensuring that labile forms of the vitamin are protected against degeneration by light and/or air (oxygen) for a sufficiently long period to afford accurate quantification and 3) obtaining an analytical method with sufficient sensitivity, selectivity, accuracy and precision, with cost and time also being considerations. The chapter dealt with these aspects concerning vitamin B1, B2, B3, B6, B9, B12 and vitamin C. Extraction procedures were described, as well as typical HPLC methods and recent improvements in this field. Chapter 6 - Cancer is the second leading cause of death in the United States and is expected to become the primary cause of disease-related death within the next decade. There are significant country-to-country variations in cancer incidence, which suggests that nutrition and dietary factors are important to the carcinogenesis process. An increased risk of cancer is associated with obesity and a high body mass index demonstrating that nutrition has a central role in the promotion of cancer. Healthy eating habits protect against cancer, while unhealthy eating habits increase the risk of cancer. Mediterranean societies have a lower risk for many cancers than those of northern Europe and the Americas. Mediterranean diets consist of a high consumption of fruits, vegetables, grains, beans, nuts, and seeds, with olive oil as an important source of monounsaturated fat. These foods are rich in lipid soluble antioxidants such as vitamin E. Vitamin E may prevent cancer by decreasing the formation of mutagens arising from the oxidation of lipids, decreasing oxidative stress in the epithelial cells as well as modulating molecular mechanisms that influence cell death, cell cycle, and transcriptional events. Vitamin E is a major fat-soluble antioxidant and it occurs naturally as eight compounds (alpha-, beta-, gamma-, and delta-tocopherol or alpha-, beta-, gamma-, and delta-tocotrienol). Since the recognition of vitamin E in 1922 as an essential nutrient for reproduction, alpha-tocopherol has been considered the major form of vitamin E. It has the highest concentration in the plasma and has been studied more in epidemiological and clinical studies than any other form of vitamin E. Recent data suggests that other isoforms of vitamin E may be important in the control of cancer. These isoforms of vitamin E have varying anti-carcinogenic potencies. Data indicate that gamma-tocopherol may be a more effective anti-cancer agent than alpha-tocopherol. Our laboratories and others have demonstrated that tocotrienols are even more effective than tocopherols at inhibiting cell proliferation in cancer cells. Differences in apoptotic induction

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among the various vitamin E isoforms are reflective of different avenues of apoptotic signaling and may be tissue specific. Dietary fat has been linked to an increase in a number of cancers including colon, prostate, and breast cancer. Vitamin E modulates a number of molecular mechanisms involved in fat metabolism. These include: the peroxisome proliferator activator receptor (PPAR), arachidonic acid metabolism, de novo sphingolipid metabolism, and cholesterol metabolism. Vitamin E family members have demonstrated the potential to activate pathways involved in cell proliferation, differentiation, apoptosis, and cell cycle. This chapter reviews data that identify the molecular targets of vitamin E action against the development of cancer. Chapter 7 - Rationale: Reduction-oxidation reactions determine cell homeostasis and freeradicals productions are invariable components of the aerobic metabolism processes. The cells have an elaborate defense against free-radicals and the imbalance resulting in excessive accumulation of free-radicals, defined as oxidative stress which plays a key role in promotion of pathological processes including cancer. Hence physiological levels of free-radicals mediate crucial intracellular signaling pathways and are essential for cell survival whereas excess generates cell damage and death. Thereby, “hormetic” responses to free-radicals are resulting from the constant ongoing battle between the production of oxidants and the antioxidants defenses. Among the oxidative stress-dependent compounds are the thiol-antioxidants having glutathione (GSH) as its major representative intracellularly. Alterations in GSH levels are associated with human diseases including cancer where it has “double-edge sword” actions by protecting non-tumor cells against oxidative stress and by removal and detoxification of carcinogens. However, at the other end of the scale GSH protects tumor cells from apoptosis by increasing the resistance to cancer chemotherapeutic agents. By its physiological importance GSH levels can be controlled endogenous and exogenously by changing its biosynthesis with nutrients such as amino acids and vitamins. Almost none has been found in the available literature about B vitamin related-GSH metabolism in esophageal cancer. Nutritional deficits in fresh fruits, vegetables and dietary fiber are commonly referred as associated with the presence of esophagus cancer (EC). Moreover heavy consumption of alcoholic beverages and tobacco might interfere with vitamins and dietary components with potential anti-carcinogenic effects. To our understanding the adequacy of B-vitamins would allow the full effects of the sulfur-containing antioxidative defenses. Methods: Twenty-six patients with EC (58.4 ± 11.8 years) and a control group of 20 healthy subjects (27 ± 8.4 years) were assessed for nutritional and biochemical markers at baseline (Mo). The EC patients were distributed in two groups G1/G2 to be either supplemented with placebo or vitamins B2, B6, B12 and folate during 15 days (M1) followed by cross-over for the same period (M2). The results were statistically analyzed. Results: The EC patients were predominantly males addict to smoke and alcoholism, diagnosed with squamous-cell carcinoma, stage IV. Their food intake was inappropriate, particularly energy resulting in 46% with Body Mass Index (BMI) 70 years 90 75 2,000 Females 9-13 years 45 39 1,200 14-18 years 65 56 1,800 19-30 years 75 60 2,000 31-50 years 75 60 2,000 51-70 years 75 60 2,000 > 70 years 75 60 2,000 Pregnancy ≤ 18 years 80 66 1,800 19-30 years 85 70 2,000 31-50 years 85 70 2,000 Lactation ≤ 18 years 115 96 1,800 19-30 years 120 100 2,000 31-50 years 120 100 2,000 RDA: Recommended Dietary Allowance; AI: Adequate Intake; EAR: Estimated Average Requirement; UL: Tolerable Upper Intake Level; NA: not available. Source: IOM (2000a).

2.2. Dietary Sources and Bioavailability of Vitamin C Fruits and vegetables are the richest sources of vitamin C, including several fruits such as berries and citrus fruits, followed by raw green leafy vegetables (Table 1.2). The content of vitamin C in vegetables depends on the maturity, the plant part, the seasons, and the geographic areas where they are produced (Nunes et al., 2011). Some processed or frozen foods marketed

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close to their source can have greater vitamin C content than unprocessed foods that travel long distances (Franke et al., 2004; Mahan et al., 2011; Peluzio & de Oliveira, 2008). Vitamin C is the most unstable of vitamins and can be easily lost by heat, oxidation, drying, storage, alkalinity, light exposure, as well as by the interaction with transition metals. As it is water soluble, vitamin C is easily extracted and discarded in the cooking water. Sodium bicarbonate (alkaline pH), added to preserve and improve the color of cooked vegetables, also destroys vitamin C (Franke et al., 2004; Mahan et al., 2011; Peluzio & de Oliveira, 2008). The vitamin C content of food is commonly reported as the sum of the ascorbate and its oxidized form DHA. The bioavailability of vitamin C naturally present in food and that added as supplement is the same. Some substances such as aspirin and the phenolic compound as quercetin can limit vitamin absorption (Wilson, 2005). Table 1.2. Vitamin C level in selected fruits, fruit juices and beverages, vegetables, and spices and herbs Food, type, portion size Fruit Acerola (West Indian Cherry), ½ cup Apple, 1 medium Avocado, cubes, ½ cup Banana, 1 medium Blackcurrants, ½ cup Blueberries, ½ cup Cherries, ½ cup Grapefruit, ½ medium fruit Guava, 1 medium fruit Grapes, ½ cup Kiwi fruit, 1 medium fruit Lemon, 1 medium fruit Mango, ½ cup Melon, cantaloupe, ¼ medium fruit Melon, honeydew, ⅛ medium fruit Orange, 1 medium fruit Papaya, cubes, ½ cup Pineapple, raw, ½ cup Strawberries, ½ cup Tangerine or tangelos, 1 medium fruit Watermelon, 1 cup Food, type, portion size Juice (not added vitamin C) Apple, ½ cup Grape, ½ cup Grapefruit, ½ cup Lime, ½ cup Orange, ½ cup Tomato, ½ cup

mg of vitamin C 820 8 8 10 100 7 5 40 126 2 72 31 23 51 40 70 43 28 48 25 15 mg of vitamin C 2 0.2 47 36 50 22

Vitamin C Supplementation: Favorable or Noxious? Food, type, portion size Beverages Cranberry juice cocktail, ½ cup Vegetable juice cocktail, ½ cup Vegetables Asparagus, cooked, ½ cup Broccoli, cooked, ½ cup Brussels sprouts, cooked, ½ cup Purple cabbage, raw, chopped, ½ cup Green cabbage, raw, chopped, ½ cup Cauliflower, raw or cooked, ½ cup Kale, cooked, ½ cup Mustard greens, cooked, ½ cup Onion, chopped, ½ cup Pepper, red or green, raw, ½ cup Plantains, sliced, cooked, 1 cup Potato, baked, 1 medium Radish, raw, ½ cup Snow peas, frozen, cooked, ½ cup Spinach, cooked, ½ cup Sweet potato, backed, 1 medium Tomato, raw, 1 medium Kohlrabi, cooked, ½ cup Edible pod peas, cooked, ½ cup Spices and Herbs Parsley, raw, 1 tablespoon Coriander leaf, dried, 1 tablespoon Source: U.S. Department of Agriculture (2012).

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mg of vitamin C 45 34 10 51 50 20 10 25 55 22 6 65 15 25 9 20 9 30 17 45 38 5 10

2.3. Pharmacokinetics of Vitamin C Vitamin C has 2 hydroxyl groups at positions 2 and 3 that ionize with pK values of 4.17 and 11.57. Therefore, reduced vitamin C exists predominantly as the ascorbate anion in most body fluids. DHA also occurs in biological systems. Biological systems can interconvert DHA to ascorbate and their metabolism is equivalent (Wilson, 2005). Serum and plasma concentrations reflect the recent intake of vitamin C, while the leukocytes concentration reflects the organic reserve of the vitamin. Normal plasma concentration of vitamin C ranges from 0.8-1.4 mg/dL, whereas the leukocytes concentration ranges from 20-40 µg/108 cells (Tomita, 2006). The absorption of vitamin C occurs in the intestine by facilitated diffusion and active mechanisms, several times in shared pathways with glucose (Wilson, 2005). At lower concentrations, the active transport is the predominant. At higher concentration, when the active mechanism is saturated, facilitated diffusion also occurs. The absorption of DHA is faster (about 10 times) than ascorbic acid either for intestinal or blood cells. Ascorbate absorption is downregulated by glucose transport and DHA is not. After DHA is absorbed, it is rapidly

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reduced to ascorbate within the intestinal cells. Due to this process, intracellular DHA is rarely found (Malo and Wilson, 2000; Tomita, 2006). Levine et al. (1996) tested 30 to 2500 mg vitamin C in healthy volunteers and observed that no vitamin C was excreted in urine of six of seven volunteers until the 100 mg dose. At single doses of 500 mg daily and higher, bioavailability declined and the absorbed amount was excreted. Bioavailability was complete for 200 mg per day of vitamin C as a single dose. But, when vitamin C is fractionated during the day a higher absorption can occur (Tomita, 2006). Ascorbate and DHA transport varies extensively between different cells (Tomita, 2006). Many cells have been shown to be capable of using extracellular DHA to produce intracellular ascorbate, including adipocytes, astrocytes, endothelial cells, erythrocytes, granulosa cells, hepatocytes, neutrophils, osteoblasts and smooth muscle cells. The interplay between DHA and glucose transport is not yet elucidated in biological system and deserves further attention (Wilson, 2005). Table 1.3 presents the concentration of vitamin C in key tissue and fluids. Table 1.3. Concentration of vitamin C in key tissues and fluids Tissue/ fluid Pituitary gland Adrenal gland Leukocytes Eye (crystalline) Brain Liver Spleen and pancreas Kidney Heart Semen Lungs Skeletal muscle Testicles Cerebrospinal fluid Thyroid gland Plasma Saliva Source: Tomita (2006).

Concentration (mg vitamin C per 100 g) 40-50 30-40 7-140 25-31 13-15 10-16 10-15 5-15 5-15 3-10 7 3 3 2-4 2 0.3-1 0.09

There is relatively little research on how vitamin C is transported out of cells (Franke et al., 2005a; 2005b).The excretion of ascorbate and DHA is performed by the kidneys, which maintain the homeostasis of vitamin C, but only occurs at high serum concentrations. Vitamin C is eliminated with an elimination half-life of 10 h (Malo and Wilson, 2000; Tomita, 2006).

3. EFFECTS OF VITAMIN C ON HEALTH Vitamin C is essential to health, it plays a fundamental role in the development and regeneration of muscles, skin, teeth and bones, collagen formation, body temperature

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regulation, production of various hormones and metabolism in general (Gardener et al., 2000). The lack of this vitamin in the organism increases the propensity for several diseases. When the deficiency is severe the body becomes vulnerable to more serious illnesses such as scurvy. However, when consumed in high doses it may cause adverse effects such as diarrhea, abdominal pain and kidney calculus in genetically predisposed individuals (Gardener et al., 2000). Epidemiological studies show that diets high in fruits and vegetables are associated with lower risk of cardiovascular and neurodegenerative diseases, stroke and several types of cancer (Fenech & Ferguson, 2001; Padayatty et al., 2003). The potential anticarcinogenic effects of vitamin C are related to its ability to neutralize carcinogenic substances and their antioxidant activity (Ferraz et al., 2010). The antimutagenic and anticarcinogenic mechanisms of vitamin C include bioantimutagenics and desmutagenic activities, as well as the regulation of DNA repair enzymes. In the desmutagenesis, protective agents, or antimutagenic, act directly on the compounds which induce DNA mutations, inactivating them chemically or enzymatically, inhibiting the metabolic activation of promutagenic or abducting reactive molecules. In bioantimutagenesis the antimutagenics act upon the process that leads to the induction of mutations, or repairing injuries caused to the DNA (Antunes & Araújo, 2000). The antioxidant action mechanism attributed to vitamin C is due for its direct reaction with O2•-, OH•, O21, in addition to regenerate E vitamin. It also maintains thiols enzymes in their reduced states and spares glutathione peroxidase, which is an important intracellular antioxidant and enzyme cofactor (Carr & Frei, 1999). Oxidant damage might cause or exacerbate common human diseases, and due to antioxidant effect, vitamin C has been described with a protective effect (Table 1.4). In breast carcinogenesis, ascorbic acid has its action based on the antioxidant defense (Willet, 2001). Studies have demonstrated an inverse relation between vitamin C intake and relative risk of this neoplasm kind (Gandini et al., 2000). In gastric inflammation caused by Helicobacter pylori, a bacterium with carcinogenic potential, vitamin C has shown an interrelation with this microorganism being capable to affect directly its growth and virulence (Correa et al., 1998; Zhang & Farthing, 2005). However, the prevention of gastric cancer does not occur only by this fact, but due to the major mechanism of vitamin C, which is the inhibition of the N-nitroso compounds and reactive oxygen metabolites inside the stomach (Bingham et al., 2002, Zhang & Farthing, 2005). The function of vitamin C in the prevention of cardiovascular diseases is currently well documented. It is believed that vitamin C protects against lipid peroxidation, besides interfering on other factors related to cardiovascular risk, such as vascular tissue integrity, vascular tone, lipid metabolism and blood pressure. Whereas ascorbic acid is an essential cofactor in collagen molecular formation and may therefore interfere in the elasticity and structural integrity of the vascular matrix. It also seems to exert a vasodilator and anticoagulant effect through relocation of prostacyclin production and other prostaglandins (Jacob, 1998). A study conducted with 15 patients from 9 to 20 years, with familiar hypercholesterolemia (LDL > 130mg/dL) used vitamin E supplements (400 UI/day) and C (500 mg/day) for six weeks. The authors observed the restoration of endothelial function in dyslipidemic children with the medicated supplementation and concluded that supplementing is essential for children with dyslipidemia, since only 20% of them consume five or more servings of fruits and vegetables per day (Engler et al., 2003).

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Health condition Cigarette smoking Wound healing Asthma

Cardiovascular disease

Type of research Controlled clinical trial; single oral dose (2 g) Controlled clinical trials; oral supplementation (0.5-3 g) Double-blind, controlled trial; single oral dose (2 g) Controlled clinical trial; oral supplementation (2 g/day) Observational study within elderly population

Neurodegenerative disorders

Cancer

Double-blind, randomized, controlled, 2-waycross over trial; intraarterial administration (24 mg/min for 110 min). In vitro study; various concentrations added to human plasma Cross-sectional and prospective study; vitamin C end vitamin E supplementation Mouse behavioral models; intraperitoneal injection (60 and 120 mg) In vitro study; dose concentration studies and pharmacokinetic modeling In vitro human lymphoma cell study

Case-control prospective study

In vitro B16 murine melanoma cell study Diabetes mellitus Cataract

Controlled trial; intraarterial infusion(G) polymorphisms in tobacco farmers. Environmental Molecular Mutagenesis, 53, 525-534. Dizdaroglu, M.; Jaruga, P.; Birincioglu, M. & Rodriguez, H. (2002). Free radical-induced damage to DNA: mechanisms and measurement. Free Radic Biol Med.;32(11), 1102-15. Domitrovic, R. (2006). Vitamin C in disease prevention and therapy. Biochemia Medica, 16, 89–228. Eikelis, N.; Schlaich, M.; Aggarwal, A.; Kaye, D. & Esler, M. (2003). Interactions between leptin and the human sympathetic nervous system. Hypertension, 41, 1072–1079. Eichholzer, M.; Luthy, J.; Gutzwiller, F & Stahelin, H. (2001). The role of folate, antioxidant vitamins and other constituents in fruit and vegetables in the prevention of cardiovascular disease: the epidemiological evidence. International Journal for Vitamin and Nutrition Research, 71, 5-17. Engler, M. M.; Engler, M. B.; Malloy, M. J.; Chiu, E. Y.; Scholoetter, M. C.; Paul, S. M.; Stuehlinger, M.; Lin, K.; Cooke, J.; Morrow, J.; Ridker, P.; Rifai, N.; Miller, E.; Witztum, J. & Mietus-Snyder, M. (2003). Antioxidant vitamins C and E improve endothelial function in children with hyperlipidemia: Endothelial Assessment of Risk from Lipids in Youth (EARLY) Trial. Circulation, 108, 1059-63. Fadupin, G. T.; Akpoghor, A. U. & Okunade, K. A. (2007). A comparative study of serum ascorbic acid level in people with and without type 2 diabetes in Ibadan, Nigeria. African Journal of Medicine and Medical Sciences, 36, 335-339. Fenech, M. & Ferguson, L. R. (2001). Vitamins/minerals and genomic stability in humans. Mutation Research, 18, 1-6. Fenech, M. & Bonassi, S. (2011). The effect of age, gender, diet and lifestyle on DNA damage measured using micronucleus frequency in human peripheral blood lymphocytes. Mutagenesis, 26, 43-49. Ferraz, C. M.; Steluti, J. & Marchioni, D. M. L. (2010). As vitaminas e minerais relacionados à estabilidade genômica e a proteção ao câncer. Revista da Sociedade Brasileira de Alimentação e Nutrição, São Paulo, 35, 181-199. Fletcher, R. H. & Fairfield, K. M. (2002). Vitamins for chronic disease prevention in adults: clinical applications. JAMA: The Journal of the American Medical Association, 287, 31273129.

716

Juliana da Silva, Daniel Prá, Vivian Kahl et al.

Flood, J. E.; Roe, L. S. & Rolls, B. J. (2006). The effect of increased beverage portion size on energy intake at a meal. Journal of the American Dietetic Association, 106, 1984–1990. Franke, S. I. R.; Ckless, K.; Silveira, J. D.; Rubensam, G.; Brendel, M.; Erdtmann, B. & Henriques, J. A. P. (2004). Study of antioxidant and mutagenic activity of different orange juices. Food Chemistry, 88, 45-55. Franke, S. I. R.; Pra, D.; da Silva, J.; Erdtmann, B. & Henriques, J. A. (2005a). Possible repair action of Vitamin C on DNA damage induced by methyl methanesulfonate, cyclophosphamide, FeSO4 and CuSO4 in mouse blood cells in vivo. Mutation Research, 583, 75-84. Franke, S. I. R.; Pra, D.; Erdtmann, B.; Henriques, J. A. & da Silva, J. (2005b). Influence of orange juice over the genotoxicity induced by alkylating agents: an in vivo analysis. Mutagenesis, 20, 279-283. Franke, S. I. R. (2006). Suco de laranja e vitamina C: efeito sobre a estabilidade genômica. Tese de doutorado. Programa de Pós-Graduação em Biologia Celular e Molecular, Universidade Federal do Rio Grande do Sul (UFRGS) [Orange juice and vitamin C: effect on genomic stability. Doctoral thesis. Postgraduate Program in Cellular and Molecular Biology, Federal University of Rio Grande do Sul (UFRGS)]. Porto Alegre, RS: UFRGS. Frei, B.; England, L. & Ames, B. N. (1989). Ascorbate is an outstanding antioxidant in human blood plasma. Proceedings of the National Academy of Sciences of the United States of America, 86, 6377–6381. Gandini, S.; Merzenich, H.; Robertson, C. & Boyle, P. (2000). Meta-analysis of studies on breast cancer risk and diet: the role of fruit and vegetable consumption and intake of associated micronutrients. European Journal of Cancer, 36, 636-646. Gardener, P. T.; White T. A. C.; McPhail, D. B. & Duthie, G. G. (2000). The relative contributions of vitamin C, carotenoids and phenolics to the antioxidant potential of fruit juices. Food Chemistry, 68, 471-474. Ghaskadbi, S.; Rajmachikar, S.; Agate, C.; Kapadi, A. H. & Vaidya, VG. (1992). Modulation of cyclophosphamide mutagenicity by vitamin C in the in vivo rodent micronucleus assay. Teratogenesis, Carcinogenesis, and Mutagenesis, 12, 11-17. Gey, K. F. (1995). Ten-year retrospective on the antioxidant hypothesis of arteriosclerosis: Threshold plasma levels of antioxidant micronutrients related to minimum cardiovascular risk. The Journal of Nutritional Biochemistry, 6, 206–236. Goldman, R. & Shields, P. G. (2003). Food mutagens. Journal of Nutrition,133, 965S-973S. Grinberg-Funes, R. A.; Singh, V. N.; Perera, F. P.; Bell, D. A.; Young, T. L.; Dickey, C.; Wang, L.W & Santella, R. M. (1994). Polycyclic aromatic hydrocarbon-DNA adducts in smvokers and their relationship to micronutrient levels and the glutathione- S-transferase M1 genotype, Carcinogenesis, 15, 2449-2454. Guarnieri, S.; Loft, S.; Riso, P.; Porrini, M.; Risom, L.; Poulsen, H. E. & Dragsted, P. (2008). DNA repair phenotype and dietary antioxidant supplementation, The British Journal of Nutrition, 99, 1018–1024. Gurbuz, N.; Ozkul, A. & Burgaz, S. (2009). Effects of vitamin C and N-acetylcysteine against cyclophosphamide-induced genotoxicity in exfoliated bladder cells of mice in vivo. Journal of B.U.ON. : Official Journal of the Balkan Union of Oncology, 14, 647-652. Halliwell, B. (2001). Vitamin C and genomic stability. Mutation Research, 475, 29–35. Halliwell, B. (1996). Antioxidants in human health and disease. Annual Review of Nutrition, 16, 33–50.

Vitamin C Supplementation: Favorable or Noxious?

717

Halliwell, B. & Guterridge, J. M. C. (2000). Free radicals in biology and medicine. New York, NY: Oxford University Press. Hara, S.; Mizukami, H.; Mukai, T.; Kurosaki, K.; Kuriiwa, F. & Endo, T. (2009). Involvement of extracellular ascorbate and iron in hydroxyl radical generation in rat striatum in carbon monoxide poisoning. Toxicology, 264, 69-73. Harreus, U.; Baumeister, P.; Zieger, S. & Matthias, C. (2005). The influence of high doses of vitamin C and zinc on oxidative DNA damage. Mutation Research, 681, 51-67. Hemilä, H. & Louhiala, P. Vitamin C for preventing and treating pneumonia. Cochrane Database of Systematic Reviews. 2007. Available from: http://dx.doi.org/10.1002/ 14651858.CD005532.pub2. Hemilä, H. & Chalker, E. Vitamin C for preventing and treating the common cold. Cochrane Database of Systematic Reviews. 2007. Available from: http://onlinelibrary.wiley.com/ doi/10.1002/14651858.CD000980.pub4. Huang, H.Y.; Helzlsouer, J. & Appel, L. J. (2000). The Effects of Vitamin C and Vitamin E on Oxidative DNA Damage: Results from a Randomized Controlled Trial. Cancer Epidemiology, Biomarkers & Prevention, 9, 647-652. Iannitti, T. & Palmieri, B. (2009). Antioxidant therapy effectiveness: an up to date. European Review for Medical and Pharmacological Sciences, 13, 245-278. Imai, H. & Nakagawa, Y. (2003). Biological significance of phospholipid hydroperoxide glutathione peroxidase (PHGPx, GPx4) in mammalian cells. Free Radical in Biology and Medicine, 34, 145-169. IOM (2000a). Institute of Medicine. Dietary Reference Intakes for Vitamin C, Vitamin E, Selenium, and Carotenoids. Food and Nutrition Board. Washington, DC: National Academy Press. IOM (2000b). Institute of Medicine. Dietary Reference Intakes: Applications in Dietary Assessment. Food and Nutrition Board. Washington, DC: National Academy Press. IOM (2003). Institute of Medicine. Dietary Reference Intake: Applications in Dietary Planning. Food and Nutritional Board. Washington, DC: National Academy Press. Jacobson, J. S.; Begg, M. D.; Wang, L. W.; Wang, Q.; Agarwal, M.; Norkus, E.; Singh, V. N.; Young, E. L.; Yang, D. & Santella, R. M. (2000). Effects of a 6-month vitamin intervention on DNA damage in heavy smokers. Cancer Epidemiology, Biomarkers & Prevention, 9, 1303-1311. Kagan, V. E.; Serbinova, E. A. & Packer, L. (1990). Generation and recycling of radicals from phenolic antioxidants. Archiv Biochem. Biophys., 280(1), 33-39. Kahl, V. F. S.; Reyes, J. M.; Sarmento, M. S. & da Silva, J. (2012). Mitigation by vitamin C of the genotoxic effects of nicotine in mice, assessed by the comet assay and micronucleus induction. Mutation Research, 744, 140-144. Kliemann, M.; Prá, D.; Müller, L. L.; Hermes, L.; Horta, J. A.; Reckziegel, M. B.; Burgos, M. S.; Maluf S. W.; Franke, S. I. R. & Silva, J. D. (2012). DNA damage in children and adolescents with cardiovascular disease risk factors. Anais da Academia Brasileira de Ciências, 84:833-40. Kloppel, G.; Lohr, M.; Habich, K.; Oberholzer, M. & Heitz P. U. (1985). Islet pathology and the pathogenesis of type 1 and type 2 diabetes mellitus revisited. Survey and Synthesis of Pathology Research, 4, 110-125. Krone, C.A. & Ely, J. T .A. (2004). Ascorbic acid, glycation, glycohemoglobin an aging. Medical Hypotheses, 62, 275-279.

718

Juliana da Silva, Daniel Prá, Vivian Kahl et al.

Ledikwe, J. H.; Blanck, H. M.; Khan, L. K.; Serdula, M. K.; Seymour, J. D.; Tohill, B. C. & Rolls, B. J. (2005). Dietary energy density determined by eight calculation methods in a nationally representative United States population. Journal of Nutrition, 135, 273–278. Lee, K. W.; Lee, H. J.; Surh, Y. J. & Lee, C. Y. (2003). Vitamin C and cancer chemoprevention: reappraisal. The American Journal of Clinical Nutrition, 78, 1074-1078. Leete, E. (1983). Biosynthesis and metabolism of the tobacco alkaloids. In S. W. Pelletier (Ed.), Alkaloids Chemical and Biological Perspectives (1st edition, 96-139). New York, NY: John Wiley and Sons. Levine, M.; Conry-Cantilena, C.; Wang, Y.; Welch, R. W.; Washko, P. W.; Dhariwal, K. R.; Park, J. B.; Lazarev, A.; Graumlich, J. F.; King, J. & Cantilena, L. R. (1996). Vitamin C pharmacokinetics in healthy volunteers: evidence for a recommended dietary allowance. Proceedings of the National Academy of Sciences of the United States of America, 93, 3704-3709. Linder, M. C. (2001). Copper and genomic stability in mammals. Mutation Research, 475, 141152. Lloyd-Jones, D. M.; Larson, M. B.; & Levy, D. (1999). Lifetime risk of developing coronary heart disease. Lancet, 353, 89-92. Loureiro, A. P.; Marques, S. A.; Garcia, C. M.; Di Mascio, P. & Medeiros, M. H. G. (2002). Development of an on-line liquid chromatography-electrospray tandem mass spectrometry assay to quantitatively determine 1,N2-etheno-2'-deoxyguanosine in DNA. Chemical Research in Toxicology, 15, 1302-1308. Lunec, J.; Holloway, K. A.; Cooke, M. S.; Faux, S.; Griffiths, H. R. & Evans, M. D. (2002). Urinary 8-oxo-2-deoxyguanosine: redox regulation of DNA repair in vivo. Free Radical Biology & Medicine, 33, 875–885. Machlin, L. J. (1995). Critical assessment of the epidemiological data concerning the impact of antioxidant nutrients on cancer and cardiovascular disease. Critical reviews in food science and nutrition, 35, 41-50. Mahan, L. K.; Escott-Stump, S. & Raymond, J. L. (2011). Krause's Food & the Nutrition Care Process. Portland, Or: Elsevier Health Sciences. Mahan, M. L. & Scott-Stump, S. E. (2005). Alimentos, nutrição & dietoterapia [Food, nutrition & diet therapy] (11st ed.) São Paulo, SP: Roca. Malo, C.; Wilson, J. X. (2000). Glucose modulates vitamin C transport in adult human small intestinal brush border membrane vesicles. The Journal of Nutrition, 130, 63-69. Maxwell, S. R. & Lip, G. Y. (1997). Free radicals and antioxidants in cardiovascular disease. British Journal of Clinical Pharmacology, 44, 307-317. Messner, B.; Frotsching, S.; Steinacher-Nigisch, A.; Winter, B.; Eichmair, E.; Gebetsberger, J.; Schwaiger, S.; Ploner, C.; Laufer, G. & Bernhard, D. Apoptosis and necrosis: two different outcomes of cigarette smoke condensate-induced endothelialcell death. 2012. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3542598/pdf/cddis2012 162a.pdf. Munzner, R. & Renner, H. W. (1989). Genotoxic investigations of tobacco protein using microbial and mammalian test systems. Zeitschrift für Ernährungswissenschaft, 28, 300309. Muralikrishnan, G.; Amalan Stanley, V. & Sadasivan Pillai, K. (2001). Dual role of vitamin C on lipid profile and combined application of cyclophosphamide, methotrexate and 5fluorouracil treatment in fibrosarcoma-bearing rats. Cancer Letters, 169, 115-120.

Vitamin C Supplementation: Favorable or Noxious?

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Murphy, S. P. & Poos, M. I. (2002). Dietary Reference Intakes: summary of applications in dietary assessment. Public Health Nutrition, 5, 843-849. Nakajima, M.; Yamamoto, T.; Nunoya, K.; Yokoi, T.; Nagashima, K.; Inoue, K.; Funae, Y.; Shimada, N.; Kamataki, T. & Kuroiwa Y. (1996). Role of human cytochrome P4502A6 in C-oxidation of nicotine. Drug Metabolism and Disposition, 24, 1212-1217. Naska, A.; Orfanos, P.; Trichopoulou, A.; May, A. M.; Overvad, K.; Jakobsen, M. U.; Tjønneland, A.; Halkjær, J.; Fagherazzi, G.; Clavel-Chapelon, F.; Boutron-Ruault, M. C.; Rohrmann, S.; Hermann, S.; Steffen, A.; Haubrock, J.; Oikonomou, E.; Dilis, V.; Katsoulis, M.; Sacerdote, C.; Sieri, S.; Masala, G.; Tumino, R.; Mattiello, A.; Bueno-de-Mesquita, H. B.; Skeie, G.; Engeset, D.; Barricarte, A.; Rodríguez, L.; Dorronsoro, M.; Sánchez, M. J.; Chirlaque, M. D,.; Agudo, A.; Manjer, J.; Wirfält, E.; Hellström, V.; Shungin, D.; Khaw, K. T.; Wareham, N. J.; Spencer, E. A.; Freisling, H.; Slimani, N.; Vergnaud, A. C.; Mouw, T.; Romaguera, D.; Odysseos, A.; & Peeters, P. H. (2011). Eating out, weight and weight gain. A cross-sectional and prospective analysis in the context of the EPIC-PANACEA study. International Journal of Obesity, 35, 416–426. Nelson, J. L.; Bernstein, P. S.; Schmidt, M. C.; Von Tress, M. S. & Askew, E. W. (2003). Dietary modification and moderate antioxidant supplementation differentially affect serum carotenoids, antioxidant levels and markers of oxidative stress in older humans. Journal of Nutrition, 133, 3117-3123. Nunes, M. (2011). Avaliação da Mutagenicidade de Pacientes em Tratamento com Anfepramona através do Teste de Micronúcleos em Mucosa Oral. Dissertação de Mestrado, PPGBioSaúde, ULBRA. Canoas, RS: ULBRA [Evaluation of Mutagenicity of Patients in Treatment with Amfepramone through the Oral Mucosa Micronucleus Test. Master Thesis, PPGBioSaúde, ULBRA. Canoas, RS: ULBRA]. Nunes, R. S.; Kahl, V. F. S.; Sarmento, M. S.; Richter, M. F.; Costa-Lotufo, L. V.; Rodrigues, F. A. R.; Abin-Carriquiry, J. A.; Martinez, M. M.; Ferronatto, S.; Ferraz, A. B. F. & Da Silva, J. (2011). Antigenotoxicity and antioxidant activity of acerola fruit (Malpighia glabra L.) at two stages of ripeness. Plant Foods for Human Nutrition, 66, 129-135. Obrenovich, M.; Li, Y.; Parvathaneni K.; Yendluri, B.; Palacios, H.; Leszek, J & Aliev, G. (2011). Antioxidants in health, disease and aging. CNS & Neurological Disorders Drug Targets, 10, 192-207. Ong, Z. Y.; Wanasuria, A. F.; Lin, M. Z.; Hiscock, J. & Muhlhausler, B. S. (2013). Chronic intake of a cafeteria diet and subsequent abstinence. Sex-specific effects on gene expression in the mesolimbic reward system. Appetite, 65, 189-199. Padayatty, S. J. & Levine, M. (2001). New insights into the physiology and pharmacology of vitamin C. CMAJ: Canadian Medical Association Journal, 164, 353-355. Padayatty, S. J.; Katz, A.; Wang, Y.; Eck, P.; Kwon, O.; Lee, J. H.; Chen, S.; Corpe, C.; Dutta, A.; Dutta, S. K. & Levine, M. (2003). Vitamin C as an antioxidant: evaluation of its role in disease prevention. Journal of the American College of Nutrition, 22, 18-35. Pallàs, M.C. (2002). Importancia de la nutrición en la persona de edad avanzada [Importance of nutrition in the elderly]. Barcelona: Novartis Consumer Health S.A. Paoloni-Giacobino, A.; Grimble, R. & Pichard, C. (2003). Genomic interactions with disease and nutrition. Clinical Nutrition, 6, 507-14. Paolisso, G.; D’Amore, A.; Galzerano, D.; Balbi, V.; Giugliano, D.; Varricchio, M. & D’Onofrio, F. (1993). Daily vitamin E supplements improve metabolic control but not insulin secretion in elderly type II diabetic patients. Diabetes Care, 16, 1433–1437.

720

Juliana da Silva, Daniel Prá, Vivian Kahl et al.

Peluzio, M. C. G. & de Oliveira, V. P. (2008). Vitaminas. In: N. M. B. Costa & M. C. G. Peluzio (Eds.), Nutrição e metabolismo (1st edition, 209-262). Viçosa, MG: Editora UFV. Da Silva, J.; Erdtmann, B.; Henriques, J. A. P.; Picada, J. N., Kern A. L.; Ramos, A. L. L. P. & Saffi, J. (2003). O estresse oxidativo e as defesas antioxidante [Oxidative stress and antioxidant defenses]. In: J. Da Silva; B. Erdtmann & J. A. Henriques (Eds.), Genética Toxicológica (1st edition, 251-264). Porto Alegre, RS: Alcance. Planeta, C. S. & De Lucia, R. (1998). Involvement of dopamine receptors in diethylpropioninduced conditioning place preference. Brazilian Journal of Medical and Biology Research, 31, 561-564. Poulsen, H. (2005). Oxidative DNA modifications. Experimental and Toxicologic Pathology, 57, 161-169. Premkumar, K.; Min, K.; Alkan, Z.; Hawkes, W. C.; Ebeler, S. & Bowlus, C. L. (2007). The potentiating and protective effects of ascorbate on oxidative stress depend upon the concentration of dietary iron fed C3H mice. The Journal of Nutritional Biochemistry, 18, 272-278. Quandt, S.A.; Arcury, T.A.; Preisser, J.S.; Norton, D. & Austin, C. (2000). Migrant farmworkers and green tobacco sickness: new issues for an understudied disease. American Journal of Industrial Medicine, 37, 307-315. Rahman, K. (2007). Studies on free radicals, antioxidants, and co-factors. Clinical Interventions and Aging, 2, 219-36. Riemersma, R. A. (1994). Epidemiology and the role of antioxidants in preventing coronary heart disease: a brief overview. The Proceedings of the Nutrition Society, 53, 59-65. Riso, P.; Martini, D.; Moller, P.; Loft, S.; Bonacina, M.; Moro, M. & Porrini, M. (2010). DNA damage and repair activity after broccoli intake in young healthy smokers. Mutagenesis, 25, 595-602. Risom, L.; Moller, P. & Loft, S. (2005). Oxidative stress-induced DNA damage by particulate air pollution. Mutation Research, 592, 119-137. Rutkowski, M. & Grzegorczyk, K. (2012). Adverse effects of antioxidative vitamins. International Journal of Occupational Medicine and Environmental Health, 25, 105-121. Saffi, J. & Henriques, J. A. P. (2003). Reparação de DNA em células eucarióticas [Repair of DNA in eukaryotic cells]. In: J. Da Silva; B. Erdtmann & J. A. Henriques (Eds.), Genética Toxicológica (1st edition, 183-205). Porto Alegre, RS: Alcance. Samarin, R. & Garattini, S. (1993). Neurochemical mechanism of action of anoretic drugs. Pharmacology & Toxicology, 73, 63-68. Samocha-Bonet, D.; Lichtenberg, D. & Pinchuk, I. (2005). Kinetic studies of copper-induced oxidation of urate, ascorbate and their mixtures. Journal of Inorganic Biochemistry, 99, 1963-1972. Schneider, M.; Diemer, K.; Engelhart, K.; Zanki, H.; Trommer, W. E. & Biesalski, H. K. (2001). Protective effects of vitamins C and E on the number of micronuclei in lymphocytes in smokers and their role in ascorbate free radical formation in plasma. Free Radical Research, 34, 209–219. Selvaraju, V.; Joshi, M.; Suresh, S.; Sanchez, J. A.; Maulik, N.; Maulik, G. (2012). Diabetes, oxidative stress, molecular mechanism, and cardiovascular disease--an overview. Toxicology Mechanisms and Methods, 22, 330-335.

Vitamin C Supplementation: Favorable or Noxious?

721

Shen, J.; Gammon, M. D.; Terry, M. B.; Wang, Q.; Bradshaw, P.; Teitelbaum, S. L.; Neugut, A. I. & Santella, R. M. (2009). Telomere length, oxidative damage, antioxidants and breast cancer risk. International Journal of Cancer, 124, 1637-1643. Sies, H. (1997). Oxidative stress: oxidants and antioxidants. Experimental Physiology, 82, 291– 295. Sies, H. (1993). Strategies of antioxidant defense. European Journal of Biochemistry, 215, 213219. Simon, J. (1992). Vitamin-C and Cardiovascular-Disease Review. Journal of the American College of Nutrition, 11, 107-125. Slupphaug, G.; Kavli, B.; & Krokan, H. E. (2003). The interacting pathways for prevention and repair of oxidative DNA damage. Mutation Research, 531, 231-51. Snyder, R. D. (2009). An update on the genotoxicity and carcinogenicity of marketed pharmaceuticals with reference to in silico predictivity. Environmental and Molecular Mutagenesis, 50, 435–450. Snyder, R. D. (2010). Possible Structural and Functional Determinants Contributing to the Clastogenicity of Pharmaceuticals. Environmental and Molecular Mutagenesis, 51, 800814. Spada, P. D. S.; Souza, G. G. N.; Bortolini, G. V.; Henriques, J. A. P.; Salvador, M. (2008). Antioxidant, mutagenic, and antimutagenic activity of frozen fruits. Journal of Medicinal Food, 11, 144-151. Sram, R. J.; Binkova, B.; Rossner Jr, P. (2012). Vitamin C for DNA damage prevention. Mutation Research, 733, 39-49. Sweetman, S. F.; Strain, J. J. & McKelvey-Martin, V. J. (1997). Effect of antioxidant vitamin supplementation on DNA damage and repair in human lymphoblastoid cells. Nutrition and Cancer, 27, 122-130. Thomas, P.; Hecker, J.; Faunt, J. & Fenech. M. (2007). Buccal micronucleus cytome biomarkers may be associated with Alzheimer’s disease. Mutagenesis, 22, 371–379. Tohamy, A. A.; Abdel Azeem, A. A.; Shafaa, M. W. & Mahmoud, W. S. (2012). Alleviation of genotoxic effects of cyclophosphamide using encapsulation into liposomes in the absence or presence of vitamin C. General Physiology and Biophysics, 31, 85-91. Tomita, L. Y. (2006). Vitamina C. In: M. A. Cardoso (Ed.), Nutrição e Metabolismo: Nutrição Humana (1st edition, 198-215). Rio de Janeiro, RJ: Guanabara Koogan. Tricker, A. R. (2003). Nicotine metabolism, human drug metabolism polymorphisms, and smoking behavior. Toxicology, 183, 151-173. USDA. USDA National Nutrient Database for Standard Reference, Release 18: U.S. Department of Agriculture, Agricultural Research Service, Nutrient Data Laboratory. 2005. Available from: http://www.nal.usda.gov/fnic/foodcomp. Valko, M.; Morris, H. & Cronin, M. T. (2005). Metals, toxicity and oxidative stress. Current Medicine Chemistry, 12, 1161–208. Von Zglinick, T. (2002). Oxidative stress shortens telomeres. Trends in Biochemical Sciences, 27, 339-344. Washi, S. A. & Ageib, M. B. (2010). Poor diet quality and food habits are related to impaired nutritional status in 13- to 18-year-old adolescents in Jeddah. Nutrition Research, 30, 527– 534. Wattanapitayakul, S. & Bauer, J. (2001). Oxidative pathways in cardiovascular disease: roles, mechanisms, and therapeutic implications. Pharmacology & Therapeutics, 89, 187-206.

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Weber, C.; Wolfgang, E.; Weber, K. & Weber, P. C. (1996). Increased adhesiveness of isolated monocytes to endothelium is prevented by vitamin C intake in smokers. Circulation, 93, 1488–1492. Willett, W.C. (2001). Diet and cancer: one view at the start of the millennium. Cancer Epidemiology, Biomarkers & Prevention, 10, 3-8. Wild, S.; Roglic, G.; Green, A.; Sicree, R. & King, H. (2004). Global prevalence of diabetes: estimates for the year 2000 and projections for 2030. Diabetes Care, 27, 1047-1053. Wilson, J. X. (2005). Regulation of vitamin C transport. Annual Review of Nutrition, 25, 105125. Wu, L. (1999). Review of risk factors for cardiovascular diseases. Annals of Clinical Laboratory Science, 29, 127-133. Yin, J. J.; Fu, P. P.; Lutterodt, H.; Zhou, Y. T.; Antholine, W. E.; Wamer, W. (2012). Dual role of selected antioxidants found in dietary supplements: crossover between anti- and prooxidant activities in the presence of copper. Journal of Agricultural and Food Chemistry, 60, 2554-2561. WHO.World Health Organization. Guidelines on food fortification with micronutrients. (2006). Available from: http://www.who.int/nutritionpublications/guide_food_ fortification_ micronutrients.pdf. Zhang, Z. W. & Farthing, M. J. (2005). The roles of vitamin C in Helicobacter pylori associated gastric carcinogenesis. Chinese Journal of Digestive Diseases, 6, 53-58.

In: Encyclopedia of Vitamins: New Research (4 Volume Set) ISBN: 978-1-53615-693-5 Editor: Lindsey Valdez © 2019 Nova Science Publishers, Inc.

Chapter 34

AN OVERVIEW OF THE ANALYTICAL METHODS TO DETERMINE ASCORBIC ACID IN FOODSTUFFS Julia López-Hernández* and Ana Rodríguez-Bernaldo de Quirós† Department of Analytical Chemistry, Nutrition and Food Science, University of Santiago de Compostela, Santiago de Compostela, Spain

ABSTRACT Ascorbic acid is a natural antioxidant widely distributed in fruits and vegetables. It is well known its participation in different biological processes such as, collagen formation, iron absorption and its involvement in neurotransmission and in immune responses. In addition is employed as additive to prevent food deterioration. Numerous analytical techniques have been developed for the determination of ascorbic acid in foods, including colorimetric, spectrophotometric, potentiometric, spectrofluorimetric, chromatographic and so on. The present work intends to provide an updated review on the analytical methods for the analysis of ascorbic acid in foodstuffs. The analytical conditions, the advantages and the drawbacks and the method validation characteristics are commented on. Moreover, the extraction procedures of the antioxidant from the food matrix are reviewed.

1. INTRODUCTION Ascorbic acid is a natural antioxidant widely distributed in vegetables and fruits, mainly citrus and tropical fruits. It is involved in different biochemical processes such as collagen formation, iron absorption and physiological functions including its involvement in neurotransmission and in immune responses (Spínola, et al. 2012; Martínez, 1998; Fenoll, et al. 2011; Pisoschi, et al. 2011). The ascorbic acid is not synthesized by the organism so it should be provided by the diet. The lack of the ascorbic acid can cause diseases such as scurvy. However, high levels of ascorbic acid in the human body could cause adverse effects. *, Corresponding Author’s E-mail: [email protected]. † E-mail: [email protected].

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In addition, it is used as a food additive by the industry in different food items including, fruit juices, jams and dairy products among others, in order to avoid the oxidation (Adam, et al. 2012). The study of the ascorbic acid has attracted the interest of the scientists in different fields; food science, pharmaceutical and clinical analysis. Therefore, sensitive and reliable methods to determine the antioxidant in different matrix are required. Several analytical techniques have been employed for its determination; including spectrophotometric, potentiometric, spectrofluorimetric, titrimetric, and chromatographic methods among others. The last ones are preferred because of their advantages of simplicity, short analysis time and sensitivity. Recently, ultra-high-performance liquid chromatography (UHPLC) has been successfully applied to determine the ascorbic acid as an excellent alternative to the conventional liquid chromatography. Regarding the detection systems; UV-Vis, fluorescence (FLD), electrochemical and mass spectrometry have been generally used. For fluorescence detection a derivatization step is necessary after treatment of the sample to obtain a fluorescent derivative of ascorbic acid. Mass spectrometry provides an excellent sensitivity and selectivity but its use become very expensive and it is not realistic for the routine analysis (Nováková et al. 2008). The present chapter is focused on the methods of analysis of ascorbic acid particularly chromatography, although are also presented spectrophotometric, electrophoresis, voltametric and potentiometric.

2. EXTRACTION PROCEDURES OF ASCORBIC ACID FROM FOODS The extraction of ascorbic acid from foods generally involves a treatment with an aqueous acidic solution; followed by a homogenization or centrifugation. A derivation step is essential when fluorescence is used as a detection system. In Table 2.1 some of the commonly used extraction procedures of ascorbic acid from foods are summarized.

3. ANALYTICAL TECHNIQUES 3.1. High Performance Liquid Chromatography (HPLC) Liquid chromatography coupled to different detection systems such as UV-Vis, electrochemical, fluorescence or mass spectrometry have been commonly employed to determine ascorbic acid. The separation of the vitamin was usually performed on a reversed stationary phase and employing a mobile phase at an acidic pH.

Table 2.1. Extraction procedures of ascorbic acid from foods. Food matrix Fruits (passion fruits papayas, strawberries lemons) and vegetables (broccoli and green and red peppers).

Extraction solvent 3% metaphosphoric acid–8% acetic acid– 1 mM ethylendiaminetetraacetic acid disodium salt (EDTA).

Treatments References Homogenization and centrifugation (10,000 rpm, Spínola et al. (2012). 10 min). Total ascorbic acid was determined after conversion of dehydroascorbic to L-ascorbic by using Tris buffer containing DL-1,4-dithiothreitol (DTT) at a concentration of 20mM; the reaction was stop by adding 0.4 M H2SO4. Edible whey protein films. Phosphoric acid solution (pH 2.0). Homogenization and centrifugation (300 rpm for Janjarasskul et al. (2011). 1.5 min). Tomato paste. 2.5% m-phosphoric acid. Vortex and centrifugation (4000 × g for 20 min). Koh et al. (2012). DL-1,4-Dithiothreital was used to convert dehydroascorbic to L-ascorbic. Ultra pure water; NaOH 2M and 12.5mL Homogenization and solubilization. Honey. Ciulu et al. (2011). of phosphate buffer 1M (pH = 5.5). Citrus fruits (Clementine mandarins Water and 3%meta phosphoric acid. Homogenization and mixed. Uckoo et al. (2011). and Meyer lemons). Different enriched food products. 2% (w/v) metaphosphoric acid solution. Sonication and centrifugation (4100 g for 15 min). Engel et al. (2010). Aqueous solution of 10% meta-phosphoric Vortex-mixed and centrifugation (2500 g for 10 Khan and Iqbal (2011). Biological matrices. acid (ascorbic acid). Aqueous solution of min). tris(2-carboxyethyl)phosphine solution in 0.05% trifluoroacetic acid . Tomato, kiwi, and mango. Methanol + a mixture of meta-phosphoric Homogenization. Garrido Frenich et al. (2005). acid 3% and acetic acid 8%. Tropical fruits (banana, papaya, Two solvents extraction: Homogenization and centrifugation (9000 g for 20 Hernández et al. (2006). mango, and pineapple). -3% metaphosphoric acid- 8% acetic acid. min). -0.1% oxalic acid. Exotic fruits (mango, papaya, passion 10% (v/v) perchloric acid and 1% (w/v) Vortex (1min) and dilution. Valente et al. (2011). fruit, etc.). metaphosphoric acid Homogenization and centrifugation (22,100g for 15 Odriozola-Serrano et al. (2007). Strawberries, tomatoes and apples. 4.5% metaphosphoric solution. min). Pepper, tomato, orange and lemon. 0.05% (w/v) EDTA (Ethylendiami- Homogenization and centrifugation (10000g for 10 Fenoll et al. (2011). netetraacetic acid disodium salt dehyd- min). rate).

Table 2.1. (Continued) Food matrix Green beans (Phaseolus vulgaris L.).

Extraction solvent 3% metaphosphoric acid with 8% acetic acid

Treatments References Magnetic stirring. Ascorbic acid was oxidized to Sánchez-Mata et al. (2000). dehydroascorbic acid. Derivatization with o-phenylenediamine.

Fruit juices, soft drinks and isotonic No extraction only sample dilution when Direct analysis. beverages. necessary. Alpine food plant (Phyteuma orbiculare 5% metaphosphoric acid. Mixed in a mortar. L.) Sea urchin (Paracentrotus lividus, L). 4.5% metaphosphoric acid. Vortex (2 min) and centrifugation (5 min, 1100 rpm).

Rodríguez-Bernaldo de Quirós et al. (2009). Abbet et al. (2013). Rodríguez-Bernaldo de Quirós et al. (2001). Tang and Wu (2005).

Orange juice, apple juice and orange drink Samples were diluted with double-distilled water. Centrifugation (5 min, 10 x 103 x g). concentrate. Beverages. Sampled were diluted with water or with the Sonication (10 min). Law et al. (2005). running buffer. Fruits (lemon, Sunkist, and pineapple) and 1 mM EDTA/0.2 M KH2PO4/0.474 M 27 mL Homogenization and centrifugation (30 000 x g, 5 min). Liao et al. (2001). spinach. H3PO4 (pH 2). 1 mM EDTA/3.0% methaphosphoric acid. Food (Grapefruit juice, orange juice, 1% (w/v) Methaphosphoric acid. Milk samples: Homogenization. Milk samples: centrifugation (4000 Burini (2007). apples, kiwi fruits, tomatoes, milk, endive, 20% trichloroacetic acid. rpm, 10 min). etc.) Wine samples. Direct analysis. Direct analysis. Lopes et al. (2006). Fruit juices (orange, pear, and mango), Fruit juices: 6.25% m-phosphoric acid (MPA), Fruit juices: dilution. Barros et al. (2010). ground chestnuts. 2.5 mM Tris(2-carboxyethyl) phosphine Ground chestnuts: centrifugation (3,000 × g, 5 min). hydrochloride (TCEP), and 2.5 mM EDTA. Ground chestnuts: 5% MPA, 2 mM TCEP, and 2 mM EDTA. Pharmaceutical preparation and energy Aqueous organic buffer containing 200 mg/L Dilution and sonication (10 min). Karatapanis et al. (2009). drink. double-distilled water.

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An isocratic and reversed-high-performance liquid chromatographic method to analyze ascorbic acid is reported by Janjarasskul et al. (2011). A C18 column, (25 cm x 4.6 mm i.d., 5 μm particles) (Supelco, Bellefonte, PA), with a C18 guard column (5 μm, Supelco) was employed as a stationary phase and an aqueous solution of phosphoric acid (pH 2.0) as the mobile phase. The flow rate was 1.0 mL/min. The wavelength was set at 245 nm. More recently, Koh et al. (2012) developed a method to determine ascorbic acid in tomato paste; in the analysis they used an Agilent Zorbax Eclipse XDBC18 column (4.6 × 250 mm, 5 μm) protected with a guard column (4.6 × 12.5 mm, 5 μm) of the same stationary phase and 0.05 mol L−1 KH2PO4 (pH 2.6) at a flow rate of 1.0 mL/ min as mobile phase. Chromatograms were recorded at a wavelength of 245 nm. Ciuli et al. (2011) proposed a reversed-phase high-performance liquid chromatographic with UV-Vis detection method for the simultaneous determination of hidrosoluble vitamins including ascorbic acid in honey samples. A binary solvent gradient consisting of solvent (A) aqueous solution of trifluoroacetic acid (0.025%, v/v), and solvent (B) acetonitrile at a flow rate of 1.0 mL/min was employed. An Alltima C18 column (250 mm ×4.6 mm, 5m particle size (Alltech, Sedriano, Italy) equipped with a guard cartridge of the same material was used for the separation of the water-soluble vitamins. With respect to performance characteristics, satisfactory limit of detection and quantification 0.10 mg/kg and 0.30 mg/kg, respectively, were achieved. Regarding the repeatability and reproducibility, appropriate values were obtained 7.3 and 3.3%, respectively (CV% exp, r.). Recovery values were around 104%. Uckoo et al. (2011) proposed an isocratic method to determine amines and organic acids in citrus fruits. 3 mM phosphoric acid was used at a flow rate of 1.0 mL/min was used as a mobile phase. In the study they tested three stationary phases: Xbridge C18 (3.5 m, 4.6 mm × 150 mm i.d.) from Waters; Gemini C18 (5m, 250 mm ×4.6 mm i.d.) from Phenomenex; and Luna C18 (5 m, 250 mm × 4.6 mm i.d.) from Phenomenex. Ascorbic acid was detected at 254 nm. The limit of detection and quantification obtained were 5 and 9.8 ng, respectively. For ascorbic acid the recovery percentage ranged from 84.01 and 92.71%. depending on the sample spiked. A gradient system consisted of (A) 0.1% (v/v %) formic acid in water (pH 2.55) and (B) 0.1% (v/v %) formic acid in methanol at a flow rate of 0.5 mL/min and a Restek Ultra Aqueous reverse phase C18 column (5 m, 150 x 3.2 mm) equipped with a guard column was used to analyze free forms of B group vitamins and ascorbic acid in various fortified food products; detection was performed at wavelength of 266 nm (Engel et al. 2010). A limit of detection of 6 ng/mL for ascorbic acid was obtained. Hernández et al. (2006) compared a titrimetic method and a reversed-phase highperformance liquid chromatographic method for the determination of ascorbic acid in tropical fruits. The chromatographic separation was performed on a Shodex RSpak KC- 811 column (250 x 4.6 mm i.d. 5 m particle size) and using 0.2% orthophosphoric acid at a flow rate of 1.2 mL/min as mobile phase. The column temperature was set at 25 ºC. Ascorbic acid was detected at 245 nm. Under these conditions the detection limit was 0.1 mg/L. The method presented a good linearity within the 0.5-50 mg/L range with a r2 of 0.999. A reversed-phase high-performance liquid chromatography method with photodiode array detection to determine ascorbic acid in exotic fruits was proposed by Valente et al. (2011). The chromatographic conditions were as follows: the stationary was a Phenomenex, Synergi™Hydro-RP (150 × 4.6 mm i.d., 4.0 μm particle size) protected by a guard cartridge

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AQ C18 (40 × 2.0 mm i.d., 5 μm particle size), the column was thermostatted at 30 ºC; a mobile phase composed by 20 mM ammonium dihydrogen phosphate, pH 3.5 (adjusted with orthophosphoric acid 85%), and containing 0.015% (w/v) of metaphosphoric acid was used. The flow rate and the injection volume were 0.6 mL/min and 20 L, respectively. The detection was done at 254 nm. Appropriate limits of detection (0.035 g/mL) and quantification (0.09 g/mL) were achieved. Two chromatographic methods with UV detection were compared in a study conducted by Odriozola-Serrano et al. (2007). In the first method a reverse phase C18 Spherisorb ODS2 stainless steel column (250 x 4.6 mm, 5 m) and an isocratic mobile phase consisting of a 0.01% solution of sulphuric acid adjusted to pH 2.6 were employed. In the second one the stationary phase was a NH2-Spherisorb S5 Column (250 x 4.6 mm, 5 m) and 10 mM potassium dihydrogen phosphate buffer adjusted to pH 3.5 and acetonitrile (60:40 v/v) as the mobile phase were used. In both methods the flow rate was set at 1.0 mL/min. Chromatograms were monitored at 245 nm. Two reducing agents, DL-1,4-dithiotreitol and 2,3-dimercapto-1propanol to convert dehydroascorbic to ascorbic acid were also compared. Both methods showed good sensibility with limits of detection and quantification ranging from 0.08 to 0.18 mg/100g and from 0.27 to 0.61 mg/100g, respectively. Recovery values were higher than 93.6% for both methods. Rodríguez-Bernaldo de Quirós et al. (2009) proposed a simple and rapid method to determine ascorbic acid in fruit juices and soft drinks. The samples were analyzed directly without a previous treatment; dilution when necessary. A novel stationary Teknokroma, Tr-010065 Mediterranea sea18 phase (15 x 0.4 cm, i.d., 3 m) based on perfectly spherical particles of ultra-pure silica with a very low metal content were used to carried out the analysis; Milli-Q water (0.1% v/v formic acid) at a flow rate of 0.8 mL/min was employed as the mobile phase. Chromatograms were recorded at 245 nm. The method showed a extraordinary sensibility with a limit of detection of 0.01 mg/L. The withinday repeatability calculated as the relative standard deviation (R.S.D.) was lower than 2%. Ferraces-Casais et al. (2012) in another study evaluated the ascorbic acid contents in fresh seaweed using a Kinetex C18 (150 × 4.6 mm, 2.6 μm; Phenomenex®, USA) column thermostatted at 30 ºC as stationary phase and a mobile phase consisting of acetic acid–MilliQ water (0.1% v/v) at a flow rate of 0.7 mL/min. Detection was performed at  245 nm. A gradient of two eluents, (A) water containing 1.03 g/L of n-hexane sodium sulfonic acid (pH adjusted to 2.6 with 40% H3PO4) and (B) and acetonitrile–water (8:2 v/v) was used for the determination of ascorbic acid in an Alpine food plant. The flow rate was 1 mL/min and the injection volume 10 L. A EC Nucleosil C18 column (250 x 4.0 mm i.d., 100–5 m) protected by a guard column (8.0 x 4.0 mm i.d.) packed with the same material was used as stationary phase and thermostatted at 25 ºC. The wavelength was set at 241 nm. The limits of detection and quantification obtained were 0.5 mg/100g and 2.0 mg/100g, respectively (Abbet et al., 2013). A polymeric stationary phase PLRP-S 100Å (5 m) column (150 mm×4.6 mm) was used to analyze ascorbic in wine samples. A gradient of two eluents (A) water-trifluoroacetic (99:1, v/v) and (B) acetonitrile-eluent A (80: 20 v/v) at a flow rate of 1 mL/min was used as mobile phase. The injection volume was 20 L. Chromatograms were monitored at 243 nm. Under these analytical conditions detection and quantification limits were 1 and 5 mg/L, respectively; and recoveries were higher than 90% (Lopes et al. 2006).

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Adam et al. (2012) determine ascorbic acid in beverages by using High-PerformanceLiquid Chromatography-UV detection. The extraction of the vitamin from the drinks involves a microextraction by packed sorbent (MEPS). Concerning the chromatographic conditions, a LiChrospher 100 RP-18e (250 x 4 mm i.d., sorbent size 5 m) protected by a guard column LiChrospher 100 RP-18e (4 x 4 mm i.d., sorbent size 5 m) was used as a stationary phase. The mobile phase consisted of water acidified with acetic acid pH 2.94 and methanol (B). The analysis was performed under isocratic conditions with 80% (A) and 20% (B) at a flow rate of 1mL/min. The wavelength used was 265 nm. The limits of detection and quantification of the method were 7.2 g/mL and 24 g/mL, respectively. Two high-performance-liquid chromatographic methods with UV-Vis and fluorescence detection were compared for the determination of ascorbic acid in sea urchin samples. Direct determination of ascorbic acid at 245 nm was done with the UV-Vis detector; the HPLC-FLD method involves a oxidation of ascorbic acid to dehydroascorbic acid, followed by a derivatization with 1,2-phenylenediamine in order to obtain a fluorescence product (em 430 nm ex 350 nm). The stationary phase was the same in both methods a Kromasil (25 x 0.4 cm),100, C18 5 Teknokroma. The mobile phase was Milli-Q water adjusted to pH 2.2 with metaphosphoric acid, for the HPLC-UV method and methanol-0.1% metaphosphoric acid (7:3 v/v) for the HPLC-FLD method. The flow rate and injection volume were 1 mL/min and 20 L, respectively. The authors found that the HPLC-FLD showed better sensitivity (LOD: 0.082 g/mL) than the HPLC-UV (LOD: 0.19 g/mL) (Rodríguez Bernaldo de Quirós, et al. 2001). In a study carried out by Sánchez-Mata et al. (2000) a spectrofluorimetric assay and a chromatographic method were compared to determine ascorbic acid in green beans. The chromatographic method involves the use of Sphereclone ODS 2, 5 m (Phenomenex) as a stationary phase and 1.8 mM H2SO4 in distilled water (pH 2.6) as the mobile phase. The flow rate was 0.9 mL/min and the injection volume was 20 L. The detection was done with a UVvisible detector at 245 nm. Regarding the method validation parameters, a suitable sensibility (Detection Limit: 0.0097 mg/100 mL and Quantification Limit: 0.0323 mg/100 mL) were achieved. Coefficients of variation of repeatability were lower than 4.474% and coefficients of variation of reproducibility were 6.400% for ascorbic acid and 7.087% for Total Ascorbic Acid. The values of recovery ranged from 89.379% to 93.269%. Liquid chromatography with fluorescence detection was used to determine total ascorbic acid in foods (Burini, 2007). The method involves the reaction of ascorbic acid with peroxyl radical generated in situ by thermal decomposition of an azo-compound, 2,2’- azobis(2amidinopropane) dihydrochloride to produce dehydroasorbic followed by a derivatization to form a fluorescence derivative. The separation was performed on a Nova-Pak C18 (150mm×3.9mm i.d., 4m particle size) column and using phosphate buffered solution (pH = 7.8) containing 16% MeOH (v/v) at a flow-rate of 0.8 mL/min as mobile phase. Detection was performed at λex = 365 nm and λem = 425 nm. With regard to the sensibility, a limit of detection of 0.27 g/mL was obtained. A novel method for the determination of L-ascorbic acid, aminothiols, and methionine in biological matrices by ion-pairing reversed-phase high performance liquid-chromatographyelectrochemical detection was reported by Khan and Iqbal (2011). The analyses were performed on a Supelco Discovery® HS C18 (250 mm x 4.6 mm, 5 m; Bellefonte, USA) analytical column equipped with a

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Perkin Elmer C18 (30 mm x 4.6 mm, 10 m; Norwalk, USA) pre-column guard cartridge and using a isocratic mobile phase composed by methanol–aqueous solution of 0.05% trifluoroacetic acid (5:95, v/v), containing 0.1 mM 1-octane sulphonic acid as the ion-pairing agent. The flow rate was 1.5 mL/min. Regarding sensitivity, a limit of detection of 60 pg/mL was obtained for ascorbic acid. High-performance liquid chromatography coupled to mass spectrometry (HPLC-MS) was used to determine simultaneously ascorbic acid, dehydroascorbic acid and 2,3-diketogulonic acid in a model juice system. In this study a gradient of two eluents, (A) water-acetonitrileformic acid (95:5:0.95; v/v/v) adjusted to pH 1.8 and (B) acetonitrile at a flow rate of 1 mL/min was used. The separation was performed on a reverse phase/cation exchange column (Primesep-D, 4.6mm x150mm, particle size 5 μm) (Tikekar et al. 2011). An isocratic method to determine ascorbic acid in vegetables and fruits by highperformance liquid chromatography coupled to mass spectrometry was developed by Garrido Frenich et al. (2005). Two coupled columns a Symmetry C18 (75 x 4.6 mm i.d. 3.5 m) and then an Atlantis dC18 (150 x 2.0 mm i.d. 5 m) were used to perform the analyses. The columns were thermostatted at 30 ºC. The mobile phase consists of 70% methanol (0.005% acetic acid) and 30% acetic acid 0.05%. The injection volume was 10 L. MS data were acquired in negative mode with electrospray ionization (ESI). The developed method was validated in terms of linearity, limits of detection and quantification, recovery and repeatability. The method showed an excellent sensitivity, with a limit of detection and quantification of 10 and 50 g/L, respectively. The value obtained for the repeatability expressed as R.S.D.% was 8.7% and regarding the recovery a 85% was achieved. Ascorbic and dehydroascorbic acids were determined in fruits and vegetables by LCMS/MS using electrospray ionization (ESI) in the negative mode (Fenoll, et al. 2011). The analyses were performed on a Prontosil C18 analytical column (250 x 3 mm, 3 m particle size). The column temperature was 20 ºC. 0.2% (v/v) formic acid at a flow rate of 0.4 mL/min was used as mobile phase. The injection volume was 20 L. The limits of detection were 13 and 11 ng/mL and the limits of quantification were 44 and 38 ng/mL for ascorbic and dehydroascorbic acids, respectively. Recoveries higher than 80% were obtained for both analytes. Hydrophilic interaction chromatography (HILIC) has been used by Barros et al. (2010) to determine ascorbic and isoascorbic acids in different foods. The analyses were performed on a TSKgel Amide-80 (4.6 i.d. × 100 mm, 5 μm, Tosoh Bioscience, Japan) column thermostatted at 20 ºC and using a gradient elution system consisted of (A) acetonitrile and (B) aqueous 0.1% trifluoroacetic acid (90:10, v/v) at a flow rate of 0.7 mL/min as mobile phase. The detection was done at 244 nm. A quantification limit of 1.5 mg/L was obtained for ascorbic acid. Drivelos et al. (2010) tested several HILIC columns to analyze ascorbic and isoascorbic acids in fish tissue. APS-2 Hypersil (2.1 i.d.×50 mm, 3 μm, Thermo) was selected as the stationary phase and acetonitrile– ammonium acetate (90:10, v/v) at a flow rate of 0.4 mL/min as the mobile phase to carry out the analyses. The injection volume was 20μL and the optimum wavelength was 240 nm. Karatapanis et al. (2009) used a HILIC-diol column to separate several water-soluble vitamins including ascorbic acid. The analytical conditions were as follows: HILIC Inertsil, diol column (150 mm x 4.6 mm, 5 m particle size); the mobile phase was composed by ACN– H2O (90:10 v/v), containing ammonium acetate 10 mM, triethylamine 20 mM, pH 5.0; flow

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rate 0.8 mL/min and the ascorbic acid detection wavelength was 267 nm. Under these conditions a limit of detection of 0.3 g/mL was obtained for ascorbic acid. Hydrophilic interaction liquid chromatography coupled to a diode array detector (DAD) was employed to determine ascorbic acid (Nováková, 2008). The separation was carried out on a ZIC HILIC (150 x 2.1 mm, 3.5 m) column; the mobile phase consisted of acetonitrile and 50 mM ammonium acetate buffer pH 6.8 (78:22 v/v); the flow rate was 0.30 mL/min and the injection volume 5 L. The column temperature was 23 ºC and the wavelength used 268 nm.

3.1.1. Ultrahigh-Performance Liquid Chromatographic (UPLC) Lately, the ultrahigh-performance liquid chromatography has been used in the food analysis field due to its advantages in comparison with the conventional liquid chromatography, such as higher resolution and shorter analysis time, among others. An UPLC-PAD method for the determination of L-ascorbic acid was reported by Spínola et al. (2012). The separation was performed on a Acquity HSS T3 analytical column (100 × 2.1 mm, 1.8 μm particle size) and using a mobile phase composed by an aqueous 0.1% (v/v) formic acid solution at a flow rate of 250 μL/min. The detection was done at 245 nm. Under these conditions the analysis was completed within 3 minutes. Regarding the method validation, an appropriate sensitivity (LOD: 22 ng/mL; LOQ: 67 ng/mL), good precision (R.S.D.  4%) and satisfactory recoveries (96.6 ± 4.4% for L-ascorbic acid and 103.1 ± 4.8% for total ascorbic acid) were achieved. The method proposed by these authors is rapid, sensitive and environmental friendly when compared with conventional HPLC. More recently, the same authors applied the UPLC-PAD method for the determination of ascorbic acid in different fruits and vegetables from Madeira. The chromatographic conditions employed were the same as previously reported (Spínola et al. 2013).

3.2. Gas Chromatography (GC) In a study conducted by Silva (2005) a gas chromatographic method with flame ionization detector (FID) to determine total ascorbic acid in fresh squeezed orange juice was developed. The method involves the use of a Chrompack (Middelburg, Netherlands) (CP-Sil-5, 15 mm x 0.32 mm I.D., 0.25 m film thickness) column as a stationary phase. Operating conditions were as follows: the injection port and detector temperatures were set at 300 ºC, the ramp temperature was initially set at 150 ºC for 1 min, then increased at 20 ºC/min until 320 ºC and held for 3 min. Injection was performed in the split mode with a split ratio of 100:1. A limit of detection of 4 mg/100 mL was obtained. Vecci & Kaiser (1967) determined ascorbic acid by gas chromatography coupled to mass spectrometry as its trimethylsilylether derivative.

3.3. Capillary Electrophoresis CE appears as an alternative to chromatographic methods for the determination of food components such as a vitamin’s organic acids and so on. CE has been successfully applied for

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the determination of ascorbic acid in different food items (Cheung et al. 2007). This technique provides good sensitivity and high resolution. Tang and Wu (2005) developed a simple and rapid capillary zone electrophoresis (CZE) method to determine ascorbic acid and sorbic acid in fruit juices. The analytes were separated under the follow conditions: 80 mmol/L boric acid–5 mmol/L borax (pH = 8.0) and a 75mi.d., 360 m-o.d. fused-silica capillary tube with a length of 55 cm. The detection was performed with a UV detector; the wavelength selected was 270 nm. For ascorbic acid the method showed a good linearity within 2.54–352.00 mg/L range. The limit of detection obtained was 1.70 mg/L. Choi and Jo (1997) determined ascorbic acid in different foods including, ascorbic acid fortified biscuit, candy, chocolate and balanced nutrition biscuit, by capillary zone electrophoresis coupled to a diode array detector; the analysis was completed within two minutes. The wavelengths used were 245 and 265 nm. The separation was carried out on untreated fused-silica capillary of 27 cm of length x 57 m I.D. and using a sodium borate buffer. Under these conditions the limits of detection and quantification achieved were 0.06 and 0.25 g/mL, respectively. Recoveries higher than 95% were obtained. A comparison of conventional capillary electrophoresis and microchip electrophoresis with capacitively coupled contactless conductivity detection for the determination of ascorbic acid in beverages is reported by Law et al. (2005). For the conventional capillary electrophoresis method a fused-silica Capillaries (50 m ID and 360 m OD) with a length of 60 cm and buffer of 10mM histidine/ 0.135mM tartaric acid, 0.1mM CTAB, and 0.25% hydroxypropyl--CD (HP--CD) were used whereas for the microchip electrophoresis method PMMA microchips with dimensions of 90 x 16mm and histidine/tartrate buffer at pH 6.5, with 0.06% HP--CD and 0.25mM CTAB were employed. The limit of detection obtained with the conventional CE method was 3 mg/L and with the microchip 10 mg/L. But however, the analysis time was shorter with the microchip method. Capillary zone electrophoresis has also been used by Liao et al. (2001) to quantify ascorbic acid in fruits and vegetables. The analyses were performed on an uncoated fused silica capillary tubing (57 cm length, 75 m inner diameter) and using 0.2 M borate buffer (pH 9.0) as running buffer. The detection was done at wavelength of 265 nm. Recoveries ranged between 95% and 105%. Three soluble vitamins including ascorbic acid were separated by means of poly(dimethylsiloxane) microchannel electrophoresis with electrochemical detection. 20 mM borate solution (pH 8.5) was used as a carrier buffer. The proposed method showed a good sensibility with a limit of detection of 1.0 M, and appropriate recoveries ranging from 86.6 to 112.3% (Li et al. 2007).

3.4. Spectrophotometric and Spectrofluorimetric Methods Spectrophotometric methods have been widely used to determine ascorbic acid in different matrices such as biological samples and pharmaceutical preparations among others. These methods are fast and simple (Arya et al. 1998).

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Nejati-Yazdinejad (2007) developed a spectrophotometric method for the determination of ascorbic acid. Cu (II) was used as ascorbic acid oxidant, once the reaction was completed the excess of Cu (II) was determined by complexation with alizarin red s (ARS). The method showed a good sensibility with a limit of detection of 0.35 ppm and satisfactory recoveries (> 97%). A spectrophotometric method that involves the use of iron (III), and pcarboxyphenylfluorone in a cationic surfactant micellar medium to analyze vitamin C in pharmaceutical preparations has been proposed by Fujita et al. (2001). Spectrofluorimetry technique was applied to determine ascorbic acid, in green beans, after the oxidation to dehydroascorbic acid and derivatization with o-phenylenediamine. The wavelengths used were ex 350 nm and em 430 nm, respectively. With regard to the method sensibility, a limit of quantification of 0.0998 mg/100 mL and a limit of detection of 0.0299 mg/100 mL, were obtained (Sánchez-Mata et al. 2000).

3.5. Other Methods In this section other methods such as voltametric and potentiometric are commented on. A voltametric determination of ascorbic acid in fruit juice samples has been reported by Romão Sartori and Fatibello-Filho (2012). The determination was performed using a glassy carbon electrode modified with functionalized multiwalled carbon nanotubes within a poly(allylaminehydrochloride) film. Calibration curves were constructed within the 5.0 to 200.0 M range and a limit of detection of 3.0 M was obtained. Differential pulse voltammetry and using a chitosan-graphene modified electrode was employed for the determination of ascorbic acid together with other analytes (Han et al. 2010). The linearity of the method was evaluated within a concentration range 50-1200 M. The detection and quantification limits achieved were 50 and 166 M, respectively. Differential pulse voltammetry was also employed to determine ascorbic acid in fruit juices and wine samples in a method described by Pisoschi et al. (2011). The analyses were performed at Pt and carbon paste electrodes. Baś et al. (2011) reported a method that involves a voltammetric determination of several vitamins including ascorbic acid, for that they used a silver liquid amalgam film–modified silver solid amalgam annular band electrode (AgLAF–AgSAE). The method showed a good linearity within the concentration range studied (0.05-12 mg/L) with a correlation coefficient of 0.9998, and an extraordinary sensitivity with a limit of detection of 0.02 mg/L. A potentiometric sensor based on molecularly imprinted polypyrrole to determine ascorbic acid was developed by Tonelli et al. (2011). The sensor was successfully used to analyze ascorbic acid in food and pharmaceutical samples. Llamas et al. (2011) used a flow injection spectrophotometric method (FIA) to determine ascorbic acid in fruit juices. The wavelength used to detect ascorbic acid was 300 nm. The method showed a good linearity within the concentration range (4.18-20.8 mg/L) studied (R2 0.9914). Detection and quantification limits were 2.26 and 7.5 mg/L, respectively. Appropriate recoveries were achieved (> 96%).

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4. CONCLUSION Different techniques including, spectrophotometry, spectrofluorometry, voltammetry, potentiometry, titrimetric methods, chromatography and electrophoresis among others have been applied to determine ascorbic acid in foods. Chromatographic techniques present several advantages such as simplicity, short analysis time and sensitivity. In this chapter an overview of the methods to determine ascorbic acid, particularly chromatography, is presented. The last trends in chromatographic techniques, such as ultra-high performance liquid chromatography (UPLC) are also included and commented on.

ACKNOWLEDGMENTS/REVISION The present chapter has been reviewed by:   

Aida Moreira da Silva (PhD), Departamento de Ciência e Tecnología Alimentar, Escola Superior Agrária de Coimbra, Instituto Politécnico de Coimbra, Portugal. Ana I.R.N.A. Barros (PhD), Departamento de Química, Escola de Ciências da Vida e do Ambiente, Universidade de Tras-os-Montes e Alto Douro, Portugal. Mª José González Castro (PhD), Department of Analytical Chemistry, University of A Coruña, Spain.

REFERENCES Abbet, C.; Slacanin, I.; Hamburger, M. & Potterat, O. (2013). Comprehensive analysis of Phyteuma orbiculare L., a wild Alpine food plant. Food Chemistry, 136, 595-603. Adam, M.; Pavlíková, P.; Čížková, A.; Bajerová, P.& Ventura, K. (2012). Microextraction by packed sorbent (MEPS) as a suitable selective method for L-ascorbic acid determination in beverages. Food Chemistry, 135, 1613–1618. Arya S. P.; Mahajan, M. & Jain. P. (1998). Photometric methods for the determination of vitamin C. Analytical Sciences, 14, 889-895. Barros, A. I. R. N. A.; Silva, A. P.; Gonçalves, B. & Nunes, F. M. (2010). A fast, simple, and reliable hydrophilic interaction liquid chromatography method for the determination of ascorbic and isoascorbic acids. Analytical and Bioanalytical Chemistry, 396, 1863-1875. Baś, B.; Jakubowska, M. & Górski, L. (2011). Application of renewable silver amalgam annular band electrode to voltammetric determination of vitamins C, B1 and B2. Talanta, 84, 1032-1037. Burini, G. (2007). Development of a quantitative method for the analysis of total l-ascorbic acid in foods by high-performance liquid chromatography. Journal of Chromatography A, 1154, 97-102. Cheung, R. H. F.; Marriott, P. J. & Small, D. M. (2007). CE methods applied to the analysis of micronutrients in foods. Electrophoresis, 28, 3390–3413. Choi, O. K. & Jo, J. S. (1997). Determination of L-ascorbic acid in foods by capillary zone electrophoresis. Journal of Chromatography A, 781, 435-443.

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Ciulu, M.; Solinas, S.; Floris, I.; Panzanelli, A.; Pilo, M. I.; Piu, P. C.; Spano, N. & Sanna, G. (2011). RP-HPLC determination of water-soluble vitamins in honey. Talanta, 83, 924-929. Drivelos, S.; Dasenaki, M. E. & Thomaidis, N. S. (2010). Determination of isoascorbic acid in fish tissue by hydrophilic interaction liquid chromatography–ultraviolet detection. Analytical and Bioanalytical Chemistry, 397, 2199-2210. Engel, R.; Stefanovits-Bányai, E. & Abranko, L. (2010). LC simultaneous determination of the free forms of B group vitamins and vitamin C in various fortified food products. Chromatographia,71, 1069-1074. Fenoll, J.; Martínez, A.; Hellín, P. & Flores, P.(2011). Simultaneous determination of ascorbic and dehydroascorbic acids in vegetables and fruits by liquid chromatography with tandemmass spectrometry. Food Chemistry, 127, 340-344. Ferraces-Casais, P.; Lage-Yusty, M. A.; Rodríguez-Bernaldo de Quirós, A. & LópezHernández, J. (2012). Evaluation of Bioactive Compounds in Fresh Edible Seaweeds. Food Analytical Methods, 5, 828-834. Fujita, Y.; Mori, I.; Yamaguchi, T.; Hoshino, M.; Shigemura, Y. & Shimano, M. (2001). Spectrophotometric determination of ascorbic acid with iron (III) and pcarboxyphenylfluorone in a cationic surfactant micellar medium. Analytical Sciences, 17, 853-857. Garrido Frenich, A.; Hernández Torres, M. E.; Belmonte Vega, A.; Martínez Vidal, J. L. & Plaza Bolaños, P. (2005). Determination of ascorbic acid and carotenoids in food commodities by liquid chromatography with mass spectrometry detection. Journal of Agricultural and Food Chemistry, 53, 7371-7376. Han, D.; Han, T.; Shan, C.; Ivaska, A. & Niu, L. (2010). Simultaneous Determination of ascorbic Acid, dopamine and uric acid with chitosan-graphene modified electrode. Electroanalysis, 22, 2001-2008. Hernádez, Y.; Lobo, M.G. & González, M. (2006). Determination of vitamin C in tropical fruits: A comparative evaluation of methods. Food Chemistry, 96, 654-664. Janjarasskul, T.; Min, S. C. & Krochta, J. M. (2011). Storage stability of ascorbic acid incorporated in edible whey protein films. Journal of Agricultural and Food Chemistry, 59, 12428-12432. Karatapanis, A. E.; Fiamegos, Y. C. & Stalikas, C. D. (2009). HILIC separation and quantitation of water-soluble vitamins using diol column. Journal of Separation Science, 32, 909-917. Khan, M. I. & Iqbal Z. (2011). Simultaneous determination of ascorbic acid, aminothiols, and methionine in biological matrices using ion-pairing RP-HPLC coupled with electrochemical detector. Journal of Chromatography B, 879, 2567– 2575. Koh, E.; Charoenprasert, S. & Mitchell, A. E. (2012). Effects of industrial tomato paste processing on ascorbic acid, flavonoids and carotenoids and their stability over one-year storage. Journal of the Science of Food and Agriculture, 92, 23-28. Law, W. S.; Kubáň, P.; Zhao, J. H.; Li, S. F. Y. & Hauser, P. C. (2005). Determination of vitamin C and preservatives in beverages by conventional capillary electrophoresis and microchip electrophoresis with capacitively coupled contactless conductivity detection. Electrophoresis, 26, 4648–4655. Li, X. Y.; Zhang, Q. L.; Lian, H. Z.; Xu, J. J. & Chen, H. Y. (2007). Separation of three watersoluble vitamins by poly(dimethylsiloxane) microchannel electrophoresis with electrochemical detection. Journal of Separation Science, 30, 2320-2325.

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Liao, T.; Jiang, C. M.; Wu, M. C.; Hwang, J. Y. & Chang, H. M. (2001). Quantification of Lascorbic acid and total ascorbic acid in fruits and spinach bycapillaryzone electrophoresis. Electrophoresis, 22, 1484–1488. Llamas, N. E.; Di Nezio, M. S.& Fernández Band, B. S. (2011). Flow-injection spectrophotometric method with on-line photodegradation for determination of ascorbic acid and total sugars in fruit juices. Journal of Food Composition and Analysis, 24, 127130. Lopes, P.; Drinkine, J.; Saucier, C. & Glories, Y. (2006). Determination of l-ascorbic acid in wines by direct injection liquid chromatography using a polymeric column. Analytica Chimica Acta, 555, 242–245. Martínez, J. A. (1998). Fundamentos teórico-prácticos de Nutrición y dietética [Theoreticalpractical foundations of Nutrition and Dietetics]. España: McGraw-Hill, Interamericana. Nejati-Yazdinejad, M. (2007). Indirect determination of ascorbic acid (vitamin C) by spectrophotometric method. International Journal of Food Science and Technology, 42, 1402–1407. Nováková, L.; Solichová, D.; Pavlovičová, S. & Solich, P. (2008). Hydrophilic interaction liquid chromatography method for the determination of ascorbic acid. Journal of Separation Science, 31, 1634-1644. Nováková, L.; Solich, P. & Solichová, D. (2008). HPLC methods for simultaneous determination of ascorbic and dehydroascorbic acids. Trends in Analytical Chemistry, 27, 942-958. Odriozola-Serrano, I.; Hernádez-Jover, T. & Martín-Belloso, O. (2007). Comparative evaluation of UV-HPLC methods and reducing agents to determine vitamin C in fruits. Food Chemistry, 105, 1151-1158. Pisoschi, A. M.; Pop, A.; Negulescu, G. P. & Pisoschi, A. (2011). Determination of ascorbic acid content of some fruit juices and wine by voltammetry performed at Pt and carbon paste electrodes. Molecules, 16, 1349-1365. Rodríguez-Bernaldo de Quirós, A.; Lopez-Hernandez, J. & SirnaI-Lozano, J. (2001). Determination of Vitamin C in Sea Urchin: Comparison of Two HPLC Methods. Chromatographia, 53, Suppl, S246-S249. Rodríguez-Bernaldo de Quirós, A.; Fernández-Arias, M. & López-Hernández, J. (2009). A screening method for the determination of ascorbic acid in fruit juices and soft drinks. Food Chemistry, 116, 509-512. Romão Sartori, E. & Fatibello-Filho, O. (2012). Simultaneous voltammetric determination of ascorbic acid and sulfite in beverages employing a glassy carbon electrode modified with carbon nanotubes within a poly(allylamine hydrochloride) film. Electroanalysis, 24, 627634. Sánchez-Mata, M.; C.; Cámara-Hurtado, M.; Díez-Marqués, C. & Torija-Isasa, M. E. (2000). Comparison of high-performance liquid chromatography and spectrofluorimetry for vitamin C analysis of green beans (Phaseolus vulgaris L.). European Food Research and Technology, 210, 220-225. Silva, F. O. (2005). Total ascorbic acid determination in fresh squeezed orange juice by gas chromatography. Food Control, 16, 55–58. Spínola, V.; Mendes, B.; Câmara, J. S.;& Castilho, P. (2012). An improved and fast UHPLCPDA methodology for determination of L-ascorbic and dehydroascorbic acids in fruits and

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vegetables. Evaluation of degradation rate during storage. Analytical and Bioanalytical Chemistry, 403, 1049-1058. Spínola, V.; Mendes, B.; Câmara, J. S. & Castilho, P. C. (2013). Effect of time and temperature on vitamin C stability in horticultural extracts. UHPLC-PDA vs iodometric titration as analytical methods. LWT - Food Science and Technology, 50, 489-495. Tang, Y. & Wu, M. (2005). A quick method for the simultaneous determination of ascorbic acid and sorbic acid in fruit juices by capillary zone electrophoresis. Talanta, 65, 794-798. Tikekar, R. V.; Anantheswaran, R. C.; Elias, R. J. & LaBorde, L. F. (2011). Ultraviolet-Induced oxidation of ascorbic acid in a model juice system: identification of degradation products. Journal of Agricultural and Food Chemistry, 59, 8244-8248. Tonelli, D.; Ballarin, B.; Guadagnini, L.; Mignani, A. & Scavetta, E. (2011). A novel potentiometric sensor for l-ascorbic acid based on molecularly imprinted polypyrrole. Electrochimica Acta, 56, 7149– 7154. Uckoo, R. M.; Jayaprakasha, G. K.; Nelson, S.D. & Patil, B. S. (2011). Rapid simultaneous determination of amines and organic acids in citrus using high-performance liquid chromatography. Talanta, 83, 948-954. Valente, A.; Gonçalves Albuquerque, T.; Sanches-Silva, A. & Costa, H. S. (2011). Ascorbic acid content in exotic fruits: A contribution to produce quality data for food composition databases. Food Research International, 44, 2237-2242. Vecci, M. & Kaiser, K. (1967). Gas chromatographic determination of ascorbic acid in form of its trimethylsilyl ether derivative. Journal of Chromatography, 26, 22-29.

In: Encyclopedia of Vitamins: New Research (4 Volume Set) ISBN: 978-1-53615-693-5 Editor: Lindsey Valdez © 2019 Nova Science Publishers, Inc.

Chapter 35

VITAMIN C DAILY SUPPLEMENTS AND ITS AMELIORATIVE EFFECTS Said Said Elshama, Ayman EL-Meghawry EL-Kenawy and Hosam Eldin Osman 1

Department of Forensic Medicine and Clinical Toxicology - College of Medicine Suez Canal University, Ismailia, Egypt 2 Department of Molecular biology, Genetic Engineering and Biotechnology Inst., University of Menofia, Sadat city, Egypt 3 Department of Anatomy, faculty of medicine, Al Azhar University, Cairo, Egypt

ABSTRACT Daily food supplementation rich by vitamin C is an important issue for our body. There is an individual difference of daily intake of dietary vitamin C depending on the age. Preventive and therapeutic doses of vitamin c range from 500 to 1000 mg per day. It is a recommended dose to prevent or treat many of disorders induced by vitamin C deficiency. It is used by the body to form cartilage, tendons, ligaments, skin and blood vessels. Vitamin c acts as an antioxidant by protecting the body against oxidative stress. It is a powerful reducing agent capable of rapidly scavenging a number of reactive oxygen species (ROS). The risk of developing some of diseases is reduced by recommended daily intake of dietary vitamin C according to recent studies. But taking vitamin C supplements will not prevent any of these conditions. Role of vitamin C for prevention or treatment of cancer is still controversial among different studies.

INTRODUCTION Daily intake of vitamin C is an essential need for our body; it isn’t stored in the body because it is a water-soluble vitamin. We should be depended on the daily food supplementation 

Corresponding Author’s E-mail:[email protected].

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rich by vitamin c such as citrus fruits, broccoli, and tomatoes. Orange, spinach, red and green peppers, watermelon, papaya, grapefruit, cantaloupe, strawberries, kiwi, mango, Brussels sprouts, cauliflower, pineapple, potatoes and cabbage. Every person should eat these fruits and vegetables raw or lightly cooked because Vitamin C is sensitive to light, air and heat. Daily of dietary vitamin C intake should be calculated according to content of vitamin in every food such as one cup of Cantaloupe (59 mg), one cup of Orange juice (97 mg), one cup of cooked Broccoli (74 mg), one cup of Red cabbage(80 mg), one cup of Tomato juice (45 mg), one Kiwi (70 mg) and one cup of Green pepper (120 mg). Synthetic vitamin C is available in a variety of forms such as tablets, capsules, powdered crystalline, effervescent, liquid and chewable forms. The best way to take vitamin C supplements is 2 - 3 times per day, with meals, depending on the dosage, adults should take 250 - 500 mg twice per day as seen by Michaels & Frei (2012).

1. RECOMMENDED SUPPLEMENTATION According to the National Academy of Sciences (NAS), daily intake of dietary vitamin C is different from person to another depending on his age. Newborn and infant up to 6 months should be taken 40 mg per day and raise to 50 mg per day until 12 months. Child of 1-3 years needs less daily intake around 15 mg and raise to 25 mg until 8 years and then 45 mg by end 13 years. Adolescent boys of 18 years need 75 mg per day but Adolescent girls of the same age need less daily intake around 65 mg. Pregnant women should be taken 80 – 85 mg per day but daily intake of Breastfeeding women ranges from 115- 120mg per day. Smoking depletes approximately 35 mg of vitamin C per day. The preventive and therapeutic dose of vitamin C ranges from 500 to 1000 mg per day. It is a recommended dose to prevent or treat many of disorders induced by vitamin C deficiency. Depending on antioxidants and health effects of vitamin C, recommended dietary allowance for vitamin C is 60 mg/day for healthy, nonsmoking adults. It is determined by the rate of turnover and rate of depletion of an initial body pool of 1500 mg vitamin C and an assumed absorption of 85% of the vitamin at usual intakes. This amount provides an adequate margin of safety. Vitamin C is safe because our body gets rid of non-used vitamin C. But, high dose (more than 2000 mg per day) is limited for some persons because it causes diarrhea or git upset. Some patients of inherited diseases such as hemochromatosis should not take vitamin C supplements because it increases the amount of iron absorbed from foods as seen by McGregor & Biesalski (2006).

2. BASIS OF VITAMIN C ROLE Collagen formation depends on the presence of vitamin C. It is used in the formation of cartilage, tendons, ligaments, skin and blood vessels and then Vitamin c plays an imperative role for healing wounds, repairing bones and teeth. Deficiency signs of vitamin C represent as gingivitis, bleeding gums, dry & scaly skin and defective healing wound but scurvy is the severe form of vitamin C deficiency. Oxidative stress means that free radicals (reactive oxygen species "ROS") in the body more than antioxidants. The oxidative process damages the important biological macromolecules such as DNA, proteins and lipids. The free radicals lead to aging process and development of some health conditions such as cancer, heart disease, and arthritis.

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Vitamin C acts as an antioxidant by protecting the body against oxidative stress. It is a powerful reducing agent capable of rapidly scavenging a number of reactive oxygen species (ROS). There are many controversial studies on role of vitamin C in the body. Is its role preventive or treatable for many diseases? Some studies conducted to conclusive answer that diet contained enough vitamin C lead to reduction the risk of developing some of diseases. But taking vitamin C supplements will not prevent any of these conditions as seen by Padayatty et al., (2003).

3. HEPATIC EFFECTS The liver is the second largest organ in the human body and it is one of the five vital organs. The liver conducts several hundreds of functions; it metabolizes nutrients and substances. It also stores many vitamins and minerals. With liver diseases, Vitamin requirements increase for tissue repair and compensation of reduced storage capacity. The dietary intake of vitamin is often decreased because of git upset symptoms such as vomiting. It is known that vitamin C is involved in corticosteroid and cholesterol metabolism, electron transport processes and conversion of folic acid to folinic acid. This vitamin is considered the most potent antioxidant for liver because it protects hepatic cells from any chemical induced toxic effect. It antagonises the released free radicals of hepatic detoxification process. According to the above mentioned knowledge, some researchers searched about role for vitamin C in treatment of liver diseases. Ersöz et al. (2005) confirmed that Vitamin C with E is effective treatment option in patients with fatty liver disease in comparison with ursodeoxycholic acid as other therapeutic option for the same disease. Claudia et al. (2003) discovered that Vitamin C inhibits the development of experimental liver steatosis induced by choline-deficient diet in contrast to vitamin E which had not the same action for the same disease. The University of Michigan, Medical School had many studies on relation of vitamin C and liver diseases especially alcoholic cirrhosis and fatty liver diseases. It was conducted that this vitamin can prevent or treat liver diseases depending on its dose ranging from 500 - 5000 mg/day according to type of hepatic disease and tolerance of the body to vitamin C. Ascorbic acid is considered as liver detox because it helps liver to detoxify any toxin and neutralizes any free radical release. Acute viral hepatitis (hepatitis A), chronic hepatitis (hepatitis B) and non-A non-B hepatitis respond well to very large doses of vitamin C and B-complex vitamins. Myoglobinuria produce hepatic failure by oxidative reactions. It is induced by rhabdomyolysis (skeletal muscle injury). Sabzevarizadeh & Najafzadeh, (2012) discovered that myoglobinuric hepatic failure is modulated of by vitamin C administration is better than silymarin administration. Cisplatin is one of chemotherapy for cancer but it has a major side effect for liver because it reacts with hepatic vital compounds such as proteins or DNA. Liver degeneration and cell death is the end result of cisplatin use as therapeutic agent for cancer. Some researchers suggested that combination of spirulina and vitamin C can be given before and during chemotherapy cycles to reduce the risk of liver damage or renal failure with Cisplatin.

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4. RENAL EFFECTS The kidney is an excretory organ; it filters the blood except red blood cells and protein. Kidney maintains acid-base balance, recycles water and minerals and excretes waste products in the urine. Vitamin C is filtered and wasted through the kidneys, where vitamin C does not cause kidney problems but it prevents them from dysfunction as seen by (Sebastian et al. 2003). It stops the formation of oxalate stones and dissolves phosphate kidney stones. Ascorbic acid acidifies the urine and then dissolving phosphate stones and preventing their formation. Acidic urine dissolves also magnesium ammonium phosphate stones which require surgical removal. Both the urinary tract infections and stone are easily cured with large doses of vitamin C. Daily consumption of greater amounts than recommended of ascorbic acid prevent nearly 100% the urinary tract infections and stone. Ascorbate increases the body's production of oxalate but it does not increase oxalate stone formation. Vitamin C in the urine binds calcium and decreases its free form. This means less chance of occurrence of calcium oxalate stones formation. The diuretic effect of vitamin C reduces the static conditions which are necessary for stone formation. Dialysis is only and an important therapeutic option in cases of renal failure. Therefore, during dialysis, the water soluble vitamins such as B-complex and C are lost from the blood. Supplementation of these vitamins in these times is an essential issue. Deicher (2003) referred that 300 mg parenteral ascorbate is recommended for chronic kidney disease and hemodialysis patients because ascorbate represents one of the most prominent antioxidants both in plasma as well as intracellular, exerting beneficial effects by an inhibition of lipid peroxidation and reduction of endothelial dysfunction and then it decreases the accelerated atherosclerosis of chronic kidney disease patients. Reactive oxygen species is a fundamental issue in pathogenesis of chronic renal failure causing protein, lipid and DNA damage. Supplementation with antioxidants such as vitamin C prevents oxidative stress such as lipid peroxidation and then chronic renal failure and its complications as seen by (Ratna & Vasudha 2009). Rhabdomyolysis is one of the most important causes of acute renal failure. Free radicals have a vital role in pathogenesis of myoglobinuric acute renal failure. Thus Vitamin C has ability to prevent this disease because it is a major antioxidant. Ustundag et al. (2008) confirmed that 20 mg/kg of vitamin C may be beneficial for better functional and morphological recovery in rhabdomyolysis-induced acute renal failure.

5. CARDIOVASCULAR EFFECTS There is an inverse relationship between blood ascorbate concentration and cardiovascular mortality in old age patients. It showed protective effects of vitamin C for cardiovascular diseases as seen by Cook et al. (2007). Vitamin C slows down the progression of atherosclerosis by prevention of plaques formation on arterial walls and keeps flexibility of arteries as seen by (Lonn, 2001; Langlois et al. 2001). Patients of low levels of vitamin C may be more likely to have a heart attack or peripheral artery disease such as atherosclerosis. Physicians recommended that foods rich in antioxidants such as vitamin C for patients of hypertension because it lowers risk of high blood pressure depending on population based studies. Oxidative stress and sympathetic activity are main issues for pathogenesis of essential hypertension. Reactive oxygen species can modulate sympathetic nerve activity. Vitamin C has a clear effect

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on sympathetic activity of muscle and sensitivity of baroreflex in hypertensive patients as seen by (Shinke et al. 2007).

6. RESPIRATORY EFFECTS Ascorbic acid plays an important role for lung health especially if it suffers from serious effects of smoking. Clinical study confirmed that vitamin C may prevent symptoms of airway diseases such as cystic fibrosis and chronic obstructive lung diseases. Vitamin C maintains hydration of airway passages. So any shortage of vitamin C supplementation leads to dryness of airway passages and participation of respiratory infection. Other studies referred to importance of higher daily intake of vitamin C for good lung function. Recent studies showed that vitamin C reversed oxidative damage of proteins and lipids which were induced by cigarette smoke provided that discontinuation of cigarette smokes exposure as seen by Lykkesfeldt et al. (2000). Relationship between lack of vitamin C and many respiratory disorders is well established by many studies in the last years. Enough daily intake of vitamin C for pregnant woman is essential for maturation of lung of premature baby. Number of recent studies indicated to importance of this vitamin for decreasing harmful effects of nicotine on fetal lung tissues as seen by Kompauer et al. (2006). Some studies confirmed that vitamin C doesn’t cure the common cold but regular daily intake of vitamin C leads to reduction of common cold duration. Until now, other studies still referred to the prevention role of vitamin C for common cold as seen by (Douglas et al. 2000; Braun et al. 2000; and Audera et al. 2001). Depending on population based studies, patients of bronchial asthma have low levels of vitamin C and then it reduces the risk of asthma especially exercise-induced asthma as seen by Ram et al. (2004).

7. ANTI-CANCER EFFECTS According to some studies, antioxidants such as vitamin C reduce incidence of some cancers such as skin, breast and cervical cancer Rock et al. (2000) but there is one urgent question for this manner, is taking large doses of vitamin C by cancerous patient to help the cure from this disease? As seen by Padayatty & Levine (2000). Other studies have the answer for the previous question and confirmed that it is impossible that vitamin C has protection role against cancer and referred to large doses of antioxidants interfere with chemotherapy medications. Furthermore, new studies referred that vitamin C enhances chemotherapy drugs action because of its ability to modulate the expression of transcription factor hypoxia inducible factor 1 (HIF-1) which is responsible for basic cell metabolism and controls cellular response to hypoxia. HIF-1 regulates many genes, enzymes and proteins coding involved in glycolysis and angiogenesis which is related to tumor growth. The above mentioned results support the use of intravenous administration of vitamin C as an adjuvant treatment for cancer as seen by (Heaney et al. 2008 & Gaziano et al. 2009).

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8. OPHTHALMOLOGICAL EFFECTS The leading cause of blindness in the United States is a macular degeneration. Combination of many antioxidants such as Vitamin C, zinc, beta-carotene and vitamin E protect the eyes against developing macular degeneration. Retinopathy of diabetes is one of common causes of blindness. Researchers showed that oxidative stress is responsible for pathogenesis of this condition. Lipid peroxidation and other biomarkers of oxidative stress such as malondialdehyde, superoxide dismutase and glutathione peroxidase are reduced by administration of antioxidants such as vitamin C and then severity and progression of this condition were reversed as seen by Taylor et al. (2002). Other population based studies observed that daily intake of vitamin C reduces incidence of cataract. These studies discovered that vitamin C supplementation for at least 10 years prevent occurrence of cataract as seen by (Head, 2001 & Mare-Perlman et al. 2000).

9. GYNAECOLOGICAL AND OBSTETRICAL EFFECTS Some obstetricians suggested that vitamin C and vitamin E lowers occurrence of preeclampsia in high risk women. In contrast, some studies don’t agree. There is a relationship between overdose of vitamin C and abortion, 12 gm per day regularly is effective to induce abortion. In the majority of cases the fetus dies within 5 days of taking Vitamin C. Ascorbic acid decreases the response of uterus to progesterone which is necessary for pregnancy as seen by (Sharma & Mittal 2004; Chappell et al. 2002). Based on other studies, vitamin C is recommended for bacterial vaginosis of women in the first trimester of pregnancy because some topical antibiotics are contra-indicated. Vaginal vitamin C increases local acidification and decreases hydrogen peroxide which results from reduction of number of lactobacilli in vagina. Vitamin C reduces side effects of oral contraceptives by reduction of oxidative biomarkers and lipid peroxidation (potential cardiovascular risk factor) in receiving oral contraceptive pills as seen by Petersen et al. (2011).

10. TOXICOLOGICAL EFFECTS This vitamin is one natural antidote and supplementation for many toxicological cases. Vitamin C enhances detoxification process and then reduces bio-accumulation of toxins and toxic minerals in body. It has essential role for modulation the toxicity of many agents and every day we discover a new use of vitamin C in the clinical toxicology field. Vitamin C modulates toxicity of some agents such as organophosphorous pesticides, aflatoxin induced liver cancer and monosodium glutamate induced hepatotoxicity as seen by EL-Meghawry et al. (2013). It abolishes chromosome damage resulted from the effect of toxic substances and help to protect the body against pollutants. Vitamin C reduces toxic effects of lindane poisoning on liver and brain because it overcomes oxidative stress induced by lindane. It has been demonstrated to be highly effective in neutralizing the toxic nature of mercury in all of its chemical forms. There are many medical reports about role of vitamin C as antidote of snake bite especially it is administrated by intravenous route. But its role as antivenin is still

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controversial until now. Food allergy can lead to anaphylactic shock for some persons according to degree of his sensitivity to this food. This condition is a life-threatening and requires urgent intervention. Vitamin C is a powerful antioxidant that can help to support immune system and kill free radicals that can lead to food sensitivities and produce symptoms similar to allergy reactions. Vitamin C should be given with antihistamines. Vitamin c supplements have capacity to relief mental and physical symptoms of some occupational diseases such as lead poisoning. It has a protective effect against arsenic, benzene and other chemicals, as well as such organic poisons as botulism, spider and scorpion bites. Met hemoglobin is a type of hemoglobin that contains ferric iron and has a decreased ability to bind oxygen. Methemoglobinemia is abnormal condition characterized by the presence of a higher level of met hemoglobin in the blood. The ascorbic acid dosage is 200-500 mg/day can reduce cyanosis associated with chronic methemoglobinemia but long term oral therapy should be avoided because it can cause the formation of sodium oxalate stones as seen by Daniel & Nawarskas 2000; Bano & Bhatt 2010).

11. DERMATOLOGICAL EFFECTS There is relationship between skin aging and low intake of vitamin C. A recent study including 4,025 women aged 40-74, found that higher vitamin C intake is associated with a lower incidence of a wrinkled appearance, dryness of the skin and a less skin-aging appearance. Vitamin C is responsible for collagen formation which makes skin elastic and reduces the risk of sunburn. It has an advantage for treatment of some dermatological disorders. Acne is one of these dermatological disorders which affect hair follicles and sebaceous glands. It is caused by the lack of collagen in the body. Vitamin C is the most important vitamin for treatment of acne because it is essential for collagen production. It also removes and prevents the toxins that damage skin cells. Vitamin C also reduces acne scars of severe cases and helps in their healing. Every day, there is a new fact about therapeutically benefits of vitamin C. New study revealed that vitamin C can relieve neurological pain and other dermatological symptoms of herpes zoster if it is administrated by intravenous route. It improves general fatigue and impaired concentration. It strengths the immunity and act as antiviral agent in the same time as seen by Masaki (2010).

12. ENDOCRINE EFFECTS Vitamin C has many healthy effects which provide more viability for the body. It is involved in biosynthesis of hormone. It helps hormone to be potent action and decreases undesirable actions of hormone. Functions of neurotransmitter need vitamin C to induce more effective actions. Vitamin C has a relation for balance of some hormones in the body such as thyroxin hormone. The thyroid gland needs vitamin C to keep its healthy condition. Negative feedback of thyroxin level in the body causes the thyroid gland to secrete too much hormone to compensate this deficiency. There is an increase of thyroid stimulating hormone concentration, thyroid lipo-peroxidation and the thyroid gland weight. These changes of above mentioned parameters are modulated by pretreatment with vitamin C due to its antioxidant

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properties. Overactive thyroid needs extra vitamin C which is actually drained from the tissues of the body as seen by (Padayatty et al. 2007 & Suleiman et al. 2011). Vitamin C is one of alternative medicine for obesity. It is a cofactor for burning of fat. Many researches confirmed that eating enough amount of food containing vitamin C which increases fat burn in the body during exercise by 25% more than people with low blood levels of vitamin C. It has anti- fatigue effect because it decreases heart rate, perception of fatigue and exertion during exercises. Other recent studies confirmed that obesity is associated with reduced growth hormone secretion and vitamin C levels are also reduced in obesity. Researchers discovered that dietary vitamin C intake has role for the regulation of growth hormone secretion and then the increasing vitamin C concentrations in obese will increase growth hormone secretion as seen by (Canoy et al. 2005; Furukawa et al. 2004 & Flora, 2007).

13. PSYCHOLOGICAL EFFECTS Stress lowers levels of vitamin C in the body because it is one of the nutrients sensitive to stress. It weakens immune system and enough daily intake of vitamin C improves condition of immune system. Some studies discovered that vitamin C decreases physical and psychological impact of stress. Patients of high levels of vitamin C have not any mental and physical signs of stress in acute psychological challenges. Vitamin C decreases secretion of cortisol in animals which is released by the adrenal glands in response to stress. Vitamin C is considered as an essential part of stress management by researchers (Levine et al., 2006).

14. NEUROPSYCHIATRIC EFFECTS Psychiatric diseases such as vascular dementia, schizophrenia and Alzheimer have more benefit from using vitamin C as one of therapeutic option for these diseases because it is protective and improve cognitive function. Researchers observed that prevalence and incidence of Alzheimer are reduced among patients who received combination of vitamin C and E. According to recent experimental studies, vitamin C improves learning and memory in both sex but with different degree because of its antioxidants effects. Vitamin C may indirectly improve sleeping schedule and energy levels of daytime. According to the Mayo Clinic, it may improve iron absorption. Some people suffer from anemia due to poor iron absorption, which inhibits the ability to produce red blood cells and transport oxygen throughout the body. This can lead to feeling of fatigue and difficult sleep as seen by (David et al. 2010; Harrison, 2012). So far, the relationship between vitamin c and brain function is not established although it’s high concentration in the brain. Vitamin C improves cognition, alertness, language skills and increases IQ scores in normal and Down's. There are many studies about role of vitamin c for treatment of autism. We can use high doses of vitamin C for treatment of autism but by intravenous route to overcome its high dose side effects such as diarrhea. There is a link between autism in many children and vitamin C deficiency but this link is not well established because some autistic children have normal levels of vitamin C. It has a positive effect for change of behavior and improvement of autism symptoms such as oversensitivity to touch,

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light, or sound, aggression and difficulty with social interactions because it has a signaling effect on the brain, like a dopamine effect and then it is a cofactor for dopamine production. Some studies confirm that oxidative stress and free radicals play role for autism and then antioxidant property of vitamin c helps as alternative therapy line for autism. Vitamin C is not used as only one of autism treatment but it is added to vitamin mixtures. Autistic child with low level of vitamin C usually has a normal level after three months of oral supplementation with vitamin C as seen by (McGinnis, 2004 & Lisa, 2008). Some studies suggest that vitamin C has high efficacy for treatment of some neurological disorders such as Parkinsonism. Tyrosine hydroxylase is responsible enzyme of dopamine biosynthesis. Vitamin C administration helps for regulation and increasing of this enzyme. Nurr1 gene is highly expressed in brain, midbrain dopaminergic cell development and survival. Vitamin C can increase Nurr1 protein expression. The progressive loss of dopaminergic neuron leads to motor function defect which is the cause of Parkinsonism. Status epilepticus is a neurologic disorder associated high mortality rate. It is characterized by alterations of normal brain function and cognitive state. Neurochemical and enzymatic activities studies suggest that status epilepticus can change free radical metabolism in brain. The oxidative stress has been associated with neuronal damage induced by seizures. The membrane lipid peroxidation can be produced by increase in free radicals levels and decrease in activities of antioxidant defense. The brain is a target for the peroxidative process because it has a high content of polyunsaturated fatty acids. Vitamin C is an exogenous antioxidant able to face the brain oxidative stress. According to experimental studies, vitamin C administration affects on latency of first seizures, percentage of seizures, mortality rate, lipid peroxidation levels and hippocampal catalase activity after seizures and status epilepticus as seen by Masaki et al. (2000).

15. ANTI-INFECTIVE AND IMMUNITY EFFECTS Vitamin C is not an instant cure of whooping cough but it leads to significant decrease in cough severity because of neutralization of its toxin by this vitamin. Every breastfeeding mother should keep high levels of vitamin C in her body within 24 hours to relief whooping cough of her baby rapidly. Vitamin C is not antibacterial agent but it strengthens immune system by mobilization of neutrophils and phagocytes. There are other functions of vitamin C to keep the body against other toxins induced infectious diseases such as strengthening cellular and vascular collagen bonds, detoxifying the body and keeping mitochondria running properly. Clinical researches confirmed that large doses of vitamin C lead to therapeutic advantage for bums, injuries, surgical operations and infections. Phagocytosis and microbicidal activity of leukocytes are one of the major defense mechanisms of the host against infection. Vitamin C affects oxidative metabolism which causes an increase in hexose monophosphate shunt (HMS) activity. The process of phagocytosis by human polymorph nuclear leukocytes (PMN) is associated with changes of oxidative metabolism. HMS activity of leukocytes has an important role for the bactericidal activity of PMN. Although some recommends 2 grams or more of vitamin C for an adult as daily intake, but the use of vitamin C massive dose is still a controversial issue as seen by Azad et al. (2007).

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A vaccination is a controversial issue because parents usually are unsatisfied about its side effects. Adverse effects and outcomes of vaccines result from allergic reactions depending on negative interaction with compromised immune systems. Any toxic effect or allergic reaction leads to oxidation of vital bio-molecules. Vitamin C is nonspecific antidote to any toxin or excess oxidative stress because its antioxidant effect. It should be included as part of any vaccination protocol for infants because of two reasons, the first it blocks the toxicity or side effects of vaccine and the second reason, it increases the antibody response of the immune system and then it improves efficacy of vaccine. Some studies demonstrated a protective role for vitamin C to decrease mortality rate of vaccinated infants if it is given before or after vaccinations as seen by (Amakye-Anim et al. 2000; Lauridsen& Jensen,2005; Cornford-Nairns 2012).

16. PHYSICAL PERFORMANCE EFFECTS Vitamin C is useful for exercise metabolism and the health of exercising individuals because it is involved in some biochemical pathways. Some studies investigate requirement of vitamin C with exercise based on dietary vitamin C intakes. It assesses the response of body to supplementation of vitamin C and its changes of concentration in plasma, serum and leukocyte following both acute exercise and regular training. Exercise usually causes a transient increase in circulating ascorbic acid in the hours following exercise, but it declines below pre-exercise levels in the days after prolonged exercise. These changes are associated with increased exercise-induced oxidative stress. But it is still many questions so far on the role of regular exercise on increase metabolism of vitamin C. Some indicated that regular exercise does not increase the requirement of vitamin C in athletes. Others noticed a new finding such as attenuated levels of cortisol post-exercise after high doses of vitamin c. Athletes often take vitamin C supplements because severe muscular contractile activity results in oxidative stress. It is investigated by changes of glutathione concentrations in muscle and blood with increase in protein, DNA and lipid peroxidation. Oral administration of vitamin C decreases muscle mitochondrial biogenesis and training efficiency because it prevents some cellular adaptations to exercise. On the contrary other studies demonstrated that consuming 2 gram per day of vitamin C through five or more servings of fruit and vegetables may be sufficient to reduce oxidative stress and provide other health benefits without impairing training adaptations as indicated by Gandini et al. (2000).

17. VITAMIN C AND MINERALS Vitamin C has a synergistic or parallel action with some minerals such as calcium. This action represents as alteration of cell permeability, decrease of nerve irritability, increase of blood coagulation, inhibition of allergic reactions, participation in tooth and bone growth, detoxification on heavy metals and arsenic. Vitamin C increases calcium absorption if it is taken with calcium supplements at the same time. Vitamin C and zinc have many health advantages such as potentiating of immunity; reducing the risk of age-related eye diseases and helping wounds heal. It helps the absorption of iron while zinc is required for the body to

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synthesize DNA and for cell division. The oral administration of the antioxidant vitamin C improves the performance of the iodine retention mechanism and treats defective cellular transport mechanism for iodine as seen by Morton et al. (2001); Maggini et al.(2012).

18. VITAMIN C AND STEM CELLS In the last years, researchers discovered that vitamin C is capable of generation of embryonic-like stem cells from adult cells by turning on set of genes. Adult cells are reprogrammed into cells with characteristics similar to embryonic stem cells. The reprogrammed cells (induced pluripotent stem cells “iPSCs”) are potential for regeneration. Production of reactive oxygen species occurs during reprogramming. There is a potential link between high ROS and low reprogramming efficiency. Vitamin C is an essential antioxidant, so it enhances iPSC generation from both mouse and human cells. Vitamin C accelerated gene expression changes but other antioxidants do not have the same effect. Effect of Vitamin C on reprogramming is considered a reversal of the aging process at the cellular level. So it has antiaging effects as seen by (Khaw et al. 2001 & Wei et al. 2012).

19. VITAMIN C AND LABORATORY INVESTIGATIONS Vitamin C has an unwanted effect on laboratory investigations inducing false results and misdiagnosis. It reacts with chemical reagents of some tests and then it influences the results of tests. For example, Vitamin C blocks relevant chemical reactions, which may lead to false low blood glucose value. Two grams of vitamin C per day cause a positive result of urinary sugar test although glucose is not present, but it produces a negative result when glucose is present. Vitamin C affects other used tests such as enzymes activity assessment, uric acid and bilirubin. So physician should advise patient to stop taking the vitamins for two to three days prior to test. Vitamin C supplementation is recommended in haemodialysis patients because of diet limitations and losses with dialysis, (Luciak, 2004) but vitamin C affects on results of laboratory tests in haemodialysis patients. The lowest dose vitamin C leads to a false positive result whereas higher doses produce a false negative interference. Besides, there is a decrease in uric acid level with the high doses of vitamin C as seen by (Freemantle et al. 1994; Laight et al. 2000).

20. MISCELLANEOUS EFFECTS Vitamin C has many ameliorative effects such as improving vision for uveitis, maintaining healthy gums, treating allergy conditions (eczema and allergic rhinitis) (Nurmatov et al. 2011), lowering of blood sugar in diabetic patients (Afkhami-Ardekani et al. 2007), strengthening of immune system and then high dose of vitamin C acts as antiviral agents. It exerts protective role against acute ultraviolet B-rays (Sunburn). Ascorbic acid has a prophylactic or therapeutic effect for some chronic diseases. Daily consumption of 1000 mg of vitamin C decreases blood glucose and lipids in patients of diabetes and thus reducing the risk of complications as seen by

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Tofler et al. (2000). Vitamin C is a new modern therapeutic line for fatty liver disease also. Increased vitamin C intake could prevent nephrotoxic effect. It assists in the prevention of blood clotting and bruising. It strengthens the walls of the capillaries. Vitamin C helps to reduce cholesterol levels and preventing atherosclerosis as seen by Kurowska et al. (2000). Vitamin C lowers risk of developing gout if it is taken regularly. It significantly lowered serum uric acid. According to results of previous studies, every 500 mg increase in vitamin C intake leads to decrease of risk for gout by 17% as seen by (Choi et al., 2009). Any joint consists of two covered bone with cartilage. Collagen is an essential part of cartilage. Vitamin C helps the body to form collagen. Destruction of this cartilage is called osteoarthritis. Some studies indicated to free radicals may be involved in destruction of cartilage. Incidence of this disease is reduced for persons who eat foods rich in vitamin C. Nonsteroidal anti-inflammatory drugs are the first choice for treatment of osteoarthritis but it reduces levels of vitamin C. So taking of these drugs for osteoarthritis is associated with vitamin C supplement (Canter et al. 2007). It protects susceptible cells from genotoxicity associated with antiestrogen metabolite-4hydroxyl tamoxifen (4-OH tom) and inhibit DNA adduct induced by tamoxifen. Update study discovered that electromagnetic field of cell phone affects testes by increase of seminiferous tubules diameter with disorganization of sperm cycle. Effects of electromagnetic field were caused by oxidative stress. This study revealed that vitamin C can counter theses effects and restore the testes to normal condition.

CONCLUSION Vitamin C (L-ascorbic acid) is an essential nutrient for humans. It scavenges reactive oxygen species and may, thereby, prevent oxidative damage to the important biological macromolecules, and could reduce aflatoxin induced liver cancer. Moreover, vitamin C abolishes chromosome damage resulting from the effect of toxic molecules, and help to protect the body against pollutants. Vitamin C is a biological reducing agent; it is also linked to the prevention of degenerative diseases such as cataracts, certain cancers and cardiovascular diseases. Increased vitamin C intake could possibly reduce and the prevent nephrotoxic effect. It assists in the prevention of blood clotting and bruising. It also strengthens the walls of the capillaries and in addition, it is well documented that vitamin C helps to reduce cholesterol levels, high blood pressure and prevent atherosclerosis. Vitamin C is absorbed by the intestine using a sodium-ion dependent channel, transported through the intestine via both glucosesensitive and glucose-insensitive mechanisms. The presence of large quantities of sugar either in the intestines or in the blood can slow absorption. The richest natural sources are fruits, vegetables and some cuts of meat, especially liver. Plants are generally a good source of vitamin C, the amount in foods of plant origin depends on the precise variety of the plant, the soil condition, the climate in which it grew the length of time since it was picked, the storage conditions and the method of preparation. While in animals, vitamin C is most present in liver, muscle, mother's milk and in a lower amount in raw cow's milk, with pasteurized milk containing only trace amount. All excess vitamin C is disposed of through the urinary system. Moreover, during the cooking of food decomposes vitamin C chemically. The concentrations

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of various food substances decrease with time in proportion to the temperature they are stored at and cooking can reduce the vitamin C content of vegetables by around 60%.

REFERENCES Afkhami-Ardekani M, Shojaoddiny-Ardekani A. Effect of vitamin C on blood glucose, serum lipids & serum insulin in type 2 diabetes patients (2007). Indian J. Med. Res.; 126(5):4714. Amakye-Anim, J., T. Lin, P. Hester, D. Thiagarajan, B. A. Watkins, and C. C. Wu. (2000). Ascorbic acid supplementation improved antibody response to infectious bursal disease vaccination in chickens. Poultry Science 79:680-688. Audera C, Patulny RV, Sander BH, Douglas RM (2001). Mega-dose vitamin C in treatment of the common cold: a randomized controlled trial. Med. J. Aust.; 175(7):359-362. Azad, I., J. Dayal, M. Poornima, and S. Ali. (2007). Supra dietary levels of vitamins C and E enhance antibody production and immune memory in juvenile milkfish, chanos (Forsskal) to formalin-killed Vibrio vulnificus. Fish & Shellfish Immunology 23:154-163. Bano M, Bhatt DK. (2010). Ameliorative effect of a combination of vitamin E, vitamin C, alpha-lipoid acid and stilbene resveratrol on lindane induced toxicity in mice olfactory lobe and cerebrum. Indian J. Exp. Biol.; 48(2):150-8. Braun BL, Fowles JB, Solberg L, Kind E, Healey M, Anderson R (2000). Patient beliefs about the characteristics, causes, and care of the common cold: an update. J. Fam. Pract.; 49(2):153-156. Canoy D, Wareham N, Welch A, Bingham S, Luben R, Day N & Khaw KT. (2005). Plasma ascorbic acid concentrations and fat distribution in 19,068 British men and women in the European Prospective Investigation into Cancer and Nutrition Norfolk cohort study. American Journal of Clinical Nutrition 82; 1203–1209. Canter PH, Wider B, Ernst E. (2007). The antioxidant vitamins A, C, E and selenium in the treatment of arthritis: a systematic review of randomized clinical trials. Rheumatology. 46(8):1223-33. Chappell LC, Seed PT, Kelly FJ, Briley A, Hunt BJ, Charnock-Jones DS, et al. (2002).Vitamin C and E supplementation in women at risk of pre-eclampsia is associated with changes in indices of oxidative stress and placental function. Am. J. Obstet. Gynecol; 187(3):777–84. Choi HK, Goa X, Curhan G. Vitamin C intake and the risk of gout in men. Arch. Intern. Med 2009; 169:502-7. Claudia PMS Oliveira, Luiz Carlos da Costa Gayotto, Caroline Tatai, Bianca Ishimoto Della Nina, Emerson S Lima, Dulcinéia SP Abdulla, Fabio P Lopasso, Francisco RM Laurindo, and Deicher R, Hörl WH. (2003). Vitamin C in chronic kidney disease and hemodialysis patients. Kidney Blood Press Res.; 26(2):100-6. Cornford-Nairns, R. (2012). “Construction and Preliminary Immunobiological Characterization of a Novel, Non-Reverting, Intranasal Live Attenuated Whooping Cough Vaccine Candidate.” J. Microbiol. Biotechnol. 22(6), 856–865. Cook NR, Albert CM, Gaziano JM, Zaharris E, MacFadyen J, Danielson E, Buring JE, Manson JE. (2007). a randomized factorial trial of vitamins C and E and beta carotene in the

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secondary prevention of cardiovascular events in women: results from the Women's Antioxidant Cardiovascular Study. Arch. Intern. Med.; 167(15):1610-8. Daniel TA, Nawarskas JJ. (2000). Vitamin C in the prevention of nitrate tolerance. Ann. Pharacother.; 34(10):1193-1197. David O. Kennedy, Rachel Veasey, Anthony Watson, Fiona Dodd, Emma Jones, Silvia Maggini, and Crystal F. Haskell. (2010). Effects of high-dose B vitamin complex with vitamin C and minerals on subjective mood and performance in healthy males. Psychopharmacology (Berl). 211(1): 55–68. Douglas RM, Chalker EB, Treacy B. (2000). Vitamin C for preventing and treating the common cold. Cochrane Database Syst. Rev. (2):CD000980. EL-Meghawry EL-Kenawy Ayman, Hosam Eldin Hussein Osman, Maha Hasan Daghestani (2013). The effect of vitamin C administration on monosodium glutamate induced liver injury. An experimental study. Exp. Toxicol. Pathology, in press. Ersöz G, Günşar F, Karasu Z, Akay S, Batur Y, Akarca US. (2005). Management of fatty liver disease with vitamin E and C compared to ursodeoxycholic acid treatment, Turk J. Gastroenterol., 16(3):124-8. Flora SJ. (2007). Role of free radicals and antioxidants in health and disease. Cellular and Molecular Biology 53; 1–2. Freemantle J, Freemantle MJ, Badrick T. (1994). Ascorbate interferences in common clinical assays performed on three analyzers. Clin. Chem; 40: 950–951. Furukawa S, Fujita T, Shimabukuro M, Iwaki M, Yamada Y, Nakajima Y, Nakayama O, Makishima M, Matsuda M & Shimomura I. (2004). Increased oxidative stress in obesity and its impact on metabolic syndrome. Journal of Clinical Investigation 114; 1752–1761. Gandini S, Merzenich H, Robertson C, Boyle P. (2000). Meta-analysis of studies on breast cancer risk and diet: the role of fruit and vegetable consumption and the intake of associated micronutrients. Eur. J. Cancer.; 36:636-646. Gaziano JM, Glynn RJ, and Christen WG, et al. Vitamins E and C in the prevention of prostate total cancer in men: the physicians' health study II randomized controlled trial. JAMA 2009; 301:52-62. Harrison FE. (2012). A critical review of vitamin C for the prevention of age-related cognitive decline and Alzheimer's disease. J Alzheimer’s Dis. 29(4):711-26. Head KA. (2001) Natural therapies for ocular disorders, part two: cataracts and glaucoma. Altern Med Rev.; 6(2):141-66. Heaney ML, Gardner JR, Karasavvas N, et al. (2008).Vitamin C antagonizes the cytotoxic effects of antineoplastic drugs. Cancer Res; 68:8031-8. Kompauer I, Heinrich J, Wolfram G, Linseisen J. (2006) Association of carotenoids, tocopherols, and vitamin C in plasma with allergic rhinitis and allergic sensitization in adults. Public Health Nutr.; 9:472-9. Khaw KT, Bingham S, Welch A, Luben R, Wareham N, Oakes S. & Day N. (2001). Relation between plasma ascorbic acid and mortality in men and women in EPIC-Norfolk prospective study: a prospective population study. European Prospective Investigation into Cancer and Nutrition. Lancet. 3; 357(9257):657-63. Kurowska EM, Spence JD, Jordan J, Wetmore S, Freeman DJ, Piche LA, Serratore P. (2000). HDL-cholesterol-raising effect of orange juice in subjects with hypercholesterolemia. Am J. Clin. Nutr.72 (5):1095-1100.

Vitamin C Daily Supplements and Its Ameliorative Effects

753

Laight DW, Carrier MJ, Anggard EE. (2000). Antioxidants, diabetes and endothelial dysfunction. Cardiovasc. Res.; 47:457-464. Langlois M, Duprez D, Delanghe J, De Buyzere M, Clement DL. (2001). Serum vitamin C concentration is low in peripheral arterial disease and is associated with inflammation and severity of atherosclerosis. Circulation, 103(14):1863-1868. Lauridsen, C. & Jensen S. (2005). Influence of supplementation of all-rac-alpha-tocopheryl acetate pre weaning and vitamin C post weaning on alpha-tocopherol and immune responses in piglets. Journal of Animal Science 83:1274-1286. Lisa A. Kurtz. (2008). “Understanding Controversial Therapies for Children with Autism, Attention Deficit Disorder, and Other Learning Disabilities: A Guide to Complementary and Alternative Medicine”; Jessica Kingsley Publishers. Lon E. (2001). Do antioxidant vitamins protect against atherosclerosis? The proof is still lacking. J. Am. Coll. Cardio.; 38:1795-8. Luciak M (2004). Antioxidants in the treatment of patients with renal failure Roczniki Akademii Medycznej w Bialymstoku 49: 135- 260. Annales Academiae Medicae Bialostocensis. Lykkesfeldt J, Christen S, Wallock LM, Chang HH, Jacob RA, Ames BN. (2000). Ascorbate is depleted by smoking and repleted by moderate supplementation: a study in male smokers and nonsmokers with matched dietary antioxidant intakes. Am. J. Clin. Nutr., 71(2):530536. Maggini S, Beveridge S. & Suter M. (2012). A combination of high-dose vitamin C plus zinc for the common cold. J Int Med Res. 40(1):28-42. Masaki H. (2010). Role of antioxidants in the skin: anti-aging effects. J. Dermatol. Sci. 2010; 58(2):85-90. Epub Mar 17. Masaki KH, Losonczy KG, Izmirlian G. (2000). Association of vitamin E and C supplement use with cognitive function and dementia in elderly men. Neurology. 54:1265-1272. Mares-Perlman JA, Lyle BJ, Klein R, et al. (2000). Vitamin supplements use and incident cataracts in a population-based study. Arch. Ophthalmol.118:1556-63. Michaels A, Frei B. (2012). "Vitamin C". In Caudill MA, Rogers M. Biochemical, Physiological, and Molecular Aspects of Human Nutrition (3 Ed.). Philadelphia: Saunders. pp. 627–654. McGregor GP, Biesalski HK. (2006). "Rationale and impact of vitamin C in clinical nutrition". Curr. Opin. Clin. Nutr. Metab. Care 9 (6): 697–703. McGinnis WR. (2004).Oxidative stress in autism. Altern Ther Health Med; 10(6):22-36; 37, 92. Morton DJ, Barrett-Connor EL. & Schneider DL. (2001). Vitamin C supplement use and bone mineral density in postmenopausal women. J. Bone Miner. Res., 16(1):135-40. Nurmatov U, Devereux G, Sheikh A. (2011). Nutrients and foods for the primary prevention of asthma and allergy: systematic review and meta-analysis. J. Allergy Clin. Immunol; 127(3):724-33.e1-30. Padayatty SJ, Doppman JL, Chang R, Wang Y, Gill J, Papanicolaou DA, Levine M. (2007). Human adrenal glands secrete vitamin C in response to adrenocorticotrophic hormone. Am. J. Clin. Nutr.; 86(1):145-9. Padayatty SJ, Katz A, Wang Y, Eck P, Kwon O, Lee JH, Chen S, Corpe C, Dutta A, Dutta SK, Levine M. (2003). "Vitamin C as an antioxidant: evaluation of its role in disease prevention". J. Am. Coll. Nutr 22 (1): 18–35. Padayatty SJ, Levine M. (2000). Reevaluation of ascorbate in cancer treatment: emerging evidence, open minds and serendipity. J. Am. Coll. Nutr. 19(4):423-425.

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Petersen EE, Genet M, Caserini M, Palmieri R. (2011). Efficacy of vitamin C vaginal tablets in the treatment of bacterial vaginosis: a randomized, double blind, placebo controlled clinical trial. Arzneimittelforschung, 61(4):260-5. Ram FS, Rowe BH, Kaur B. (2004). Vitamin C supplementation for asthma. Cochrane Database Syst Rev. (3):CD000993. Ratna Priya and Vasudha K. C. (2009). Antioxidant vitamins in chronic renal failure. Biomedical Research 2009; 20 (1): 67-70. Rock CL, Michael CW, Reynolds RK, Ruffin MT. (2000). Prevention of cervix cancer. Crit Rev. Oncol. Hematol. 33(3):169-185. Sabzevarizadeh M. & Najafzadeh H. (2012). Comparison Effect of Silymarin and Vitamin C on Liver Function in Myoglobinuric Status in Rats. World Applied Sciences Journal 17 (2): 228-232. Sebastian J. Padayatty, Yaohui Wang, Oran Kwon (2003).Vitamin C as an Antioxidant: Evaluation of Its Role in Disease Prevention. Journal of the American College of Nutrition, 22, No. 1, 18–35. Sharma JB, Mittal S. (2004). Oxidative stress and pre-eclampsia. Obstet. Gynaecol. Today; 9:551– 4. Shinke T, Shite J, Takaoka H, Hata K, Inoue N, Yoshikawa R, Matsumoto H, Masai H, Watanabe S, Ozawa T, Otake H, Matsumoto D, Hirata K, Yokoyama M. (2007). Vitamin C restores the contractile response to dobutamine and improves myocardial efficiency in patients with HF. Amer Heart J.154 (4):645.1-8. Suleiman F. Ambali, Chinedu Orieji, Woziri O. Abubakar, Muftau Shittu, and Mohammed U. Kawu. (2011).Ameliorative Effect of Vitamin C on Alterations in Thyroid Hormones Concentrations Induced by Sub chronic Co administration of Chlorpyrifos and Lead in Wistar Rats. Journal of Thyroid Research, 2; 1-6. Taylor A, Jacques PF, Chylack LT Jr, et al. (2002). Long-term intake of vitamins and carotenoids and odds of early age-related cortical and posterior sub capsular lens opacities. Am. J. Clin. Nutr. 75(3):540-549. Tofler GH, Stec JJ, Stubbe I, Beadle J, Feng D, Lipinska I, Taylor A. (2000).The effect of vitamin C supplementation on coagulability and lipid levels in healthy male subjects. Thromb. Res. 100(1):35-41. Ustundag S, Yalcin O, Sen S, Cukur Z, Ciftci S, Demirkan B. (2008). Experimental myoglobinuric acute renal failure: the effect of vitamin C. Ren. Fail.;30(7):727-35. Wei F, Qu C, Song T, Ding G, Fan Z, Liu D, Liu Y, Zhang C, Shi S. & Wang S. (2012). Vitamin C treatment promotes mesenchymal stem cell sheet formation and tissue regeneration by elevating telomerase activity. J. Cell. Physiol.; 227(9):3216-24.

Reviewed by El-kott A. F. (phD), Department of biology, Faculty of Science, Damanhour University, Damanhour, Egypt Metwally El-Sayed Metwally (PhD), Forensic Medicine and clinical Toxicology Department, College of Medicine, Suez Canal University, Ismailia, Egypt

In: Encyclopedia of Vitamins: New Research (4 Volume Set) ISBN: 978-1-53615-693-5 Editor: Lindsey Valdez © 2019 Nova Science Publishers, Inc.

Chapter 36

IONIZING RADIATION EFFECTS ON VITAMIN C Marcia N. C. Harder1,, Valter Arthur2,, Suely S. H. Franco2,† and Paula B. Arthur2,‡ 1

Department of Agroindustry, Technology College of Piracicaba “Dep. Roque Trevisan”, FATEC Piracicaba, Santa Rosa, Piracicaba, Brazil 2 Department of Radiobiology and Enviroment, Center of Nuclear Energy in Agriculture, University of São Paulo, CENA/USP, São Judas, Piracicaba, Brazil

ABSTRACT The irradiation process has been the subject of increasing attention during the last decades because of the distinct advantages it offers over conventional methods of food processing: food can be processed after packaging; can be preserved in fresh state and perishable can be kept longer without quality loss. For fruits; fruit juices and vegetables are the most promising treatment is the combination of radiation and other treatments for sterilization. With irradiation alone, it may require higher doses of radiation and consequently promote enzyme´s inactivation, wich are responsible for sensory changes during storage of these products. Food irradiation is not a new technology. The lethal effects of ionizing radiation on organisms are observed and reported since 1898 and techniques for using radiation in order to kill bacteria in food have been tested since 1916. The amounts of scientific data generated by various countries and international partnership programs during the past 50 years and together with research outweigh any other techniques for food processing. The percentage of vitaminis lost in food production will depend on: irradiation dose; food composition food temperature to be irradiated and the presence or absence of oxygen. Vitamins are more susceptible to irradiation in the presence of oxygen at temperatures above freezing. Generally the higher the radiation dose greatest is the loss of vitamins. Lost vitamins to food treated with irradiation below 1 kGy are 

Corresponding Author’s E-mail: [email protected]. E-mail: [email protected]. † E-mail: [email protected]. ‡ E-mail: [email protected]. 

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Marcia N. C. Harder, Valter Arthur, Suely S. H. Franco et al. minimum compatible with the loss in regards to heating foods treated and stored for long periods of time. Already doses above 10 kGy are likely to degrade these substances; however researchers indicated that these losses can be minimized by irradiation in oxygenfree packaging (cans or flexible packaging) or at cryogenic temperatures ranging from 20°C to -40°C. Aqueous solutions of vitamins are more vulnerable to destruction by irradiation than those in the matrix of dehydrated food or food. The objective of this study was to conduct a literature review pointing out studies that assessed changes in vitamin C caused by the action of ionizing radiation.

1. INTRODUCTION The irradiation process has been the subject of increasing attention during the last decades due to the distinct advantages it offers over conventional methods of food processing: food can be processed after packaging; can be preserved in the fresh state; and perishable can be kept longer without quality loss. For fruits; fruit juices and vegetables, the most promising treatment is the combination of radiation and other treatments because the sterilization with irradiation alone may require high doses of radiation and consequently promote enzyme inactivation responsible for sensory changes during storage of these products. The fruits and vegetables treatment with ionizing radiation whose main purpose is to ensure its preservation, i.e., increase shelf life of food. This process may involve the inactivation of microorganisms (mainly fungi, bacteria and yeast); delay ripening and disinfestations among other mechanisms (Iemma et al, 1999). Like other food processing techniques the irradiation can cause changes in the chemical composition and nutritional value. The nature and extent of these changes depends essentially of the type; variety and composition of the food; the radiation dose received and the environmental conditions during and after irradiation (Wiendl, 1984). The ascorbic acid is known as a promoter of numerous chemical; biochemical and physiological characteristics, both in animals and in plants. It performs many functions in the body related to the immune system; collagen formation; iron absorption; inhibition of nitrosamines formation and antioxidant activity. Its contents can be influenced by soil type; cultivation; climatic conditions; agricultural procedures for harvesting and storage. Furthermore, the ascorbic acid in its pure form is very unstable and is easily destroyed by oxidation, particularly in high temperature; light; humidity; alkalinity; metal catalysts and physical damage (O'Keefe, 2001; Silva et al, 2004; Lima et al, 2009). Studies have shown that among the water-soluble vitamins, the vitamin C is the most sensitive to radiation (Josephson, 1978). However, is necessary to remember that, the vitamin C as a relatively labile vitamin and similar results occur in its destruction treatments food by use of heat (Wiendl, 1984).

2. EFFECTS OF RADIATION ON FOOD The food irradiation is not a new technology. The lethal effects of ionizing radiation on organisms are being observed and reported since 1898 and techniques for using radiation to kill

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bacteria in food have been tested since 1916. The amount of scientific data generated by various countries and international partnership programs during the past 50 years, the research outweighs any other technique for food processing (Mollins et al., 2001). The Board of Experts on Food Irradiation Committee, formed by UN (United Nations) agencies (IAEA, WHO, among others) suggests that the process of food irradiation which is used gamma radiation from radionuclide originated Cobalto-60; Césio-137; and X-rays with energy up to 5MeV or electrons with energy up to 10MeV (Diehl, 1992; FAO/IAEA 1982). In general, the irradiation process at recommended doses causes little chemical changes in foods (Diehl et al., 1994, Al-Masri, 2003) however when inadequate doses are applied in food, they might have flavor or level components changed, making it unsuitable for consumption (ICGFI, 1999). According to Diehl (1992a, 1992b, 1995) at doses up to 1kGy the nutritional losses are considered insignificant and not known changes found in irradiated foods are harmful or dangerous being within the limits, normally found in foods (Satin, 1993; Delincee et al. 1998). For higher doses (over 10kGy) which are used for sterilization control and dangerous pathogens; nutritional losses are evaluated as lower or comparable with those arising from the cooking and cooling process (Grolinchova et al., 2004). Radiation in proteins is able to induce changes in their configuration by the breaks through on the original connections as hydrogen bonds and SS bonds which stabilize their secondary and tertiary structures. With this change, its features can be compromised. It is important to note that these changes are related to pure chemicals compounds, when these elements are irradiated in complex mixtures (foods) there may be a variation in the sensitivity to the radiation (Grolinchova et al. 2004). Fats are classified as one of the components most sensitive to ionizing radiation which can induce many hydrolytic reactions and auto-oxidant leading to undesirable organoleptic changes and loss of essential fatty acids. The range and nature of the changes caused by some radiation doses depend upon the material composition that is being irradiated; the type of fat and the unsaturated fatty acids content (Grolinchova et al. 2004). Moreover, carbohydrates and minerals in foods are relatively radiation stable until 10kGy (Roberts & Weese, 2006). The electromagnetic radiation absorption by biological tissues is the food, constitute is a function of the constituent molecules electron excitation. In the case of gamma radiation, the electronic excitation produced is sufficient to eject electrons from their respective orbitals resulting in the molecular ionization. One of the most important free radicals induced by radiation is the hydroxyl radical (HO-) formation that is involved in reactions of initiation and propagation of the chain reaction responsible for the effects of radiation (Riley, 1994). The percentage of lost vitamins in food production will depend on: irradiation dose; food composition; food temperature to be irradiated; and presence or absence of oxygen. Vitamins are more susceptible to irradiation in the presence of oxygen at temperatures above freezing. Generally higher radiation dose causes higher losses of vitamins. A Committee formed by the FAO (Food and Agriculture Organization); WHO (World Health Organization) and IAEA (International Atomic Energy Agency) indicated that loss of vitamins to food treated with irradiation below 1kGy are minimum and are compatible losses in foods heating treated and stored for long periods of time (Roberts & Weese, 2006). Already doses above 10kGy can degrade these substances; however, researchers indicated that these losses can be minimized by irradiation in oxygen-free packaging (cans or flexible packaging) or at cryogenic temperatures ranging from -20°C to -40°C. Aqueous solutions of vitamins are more vulnerable to destruction by irradiation than those in the food matrix or the dehydrated food. Then the

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extrapolation of the nutritional losses of aqueous solutions is inappropriate for solid food (SCF, 2003). Although there is a minimal vitamin losses associated to irradiation, especially some more sensitive as vitamins: B1; C and E, it is extremely unlikely that there are vitamins deficiencies due to consumption of irradiated foods (GAO, 2000). All other vitamins tend to be relatively stable to irradiation under 5kGy (Roberts & Weese, 2006). In 1962 the WHO and the American Medical Association reported that irradiated food was produced according to good manufacturing practices (GMP) and should be considered safe and nutritionally adequate, because the radiation: a) does not induce a change in the composition of the food, which the toxicological point of view, that could lead to adverse effects on human health; b) does not induce changes in the food microflora, which could increase the microbiological risk to the consumer and; c) does not lead to nutrient losses, which could impose adverse effects to the individual or population state nutritional (Spolaore et al., 2003). The Joint Expert Committee on Food Irradiation (JECFI), formed by FAO; WHO and IAEA in 1980 granted the 10kGy dose to irradiated foods as a safety condition: "any food irradiated to a dose of 10kGy did not caused toxicological problems, so toxicology tests with this kind of food are not necessary anymore". Moreover, the JECFI declared that food irradiation to a dose of 10kGy does not induce nutritional or microbiological problems. From these findings the Codex Alimentarius Commission, in association with the International Recommended Code of Practice for the Operation of Radiation Facilities used for the Treatment of Food presented in 1983 a General Standard for Irradiated Food. These codes were followed by many countries in the 80´s and 90´s thereafter initiated the procedures for this technology adoption for various irradiation applications. Currently 40 countries have radiating at least one or more products and 29 countries are already applying the irradiation process on a commercial basis (Kooij, [n/d]). In 1997 the WHO together with FAO and IAEA held a meeting of experts to examine issues related to irradiation at doses above 10kGy and concluded that: "The food irradiated to any dose needs to have an appropriate dose to achieve the intended technological objective and both safe when to consume are nutritionally adequate" (GAO, 2000; Mollins et al., 2001). Irradiation doses above 10kGy are used for animal origin and very moist food; full meals for patients on immunotherapy; astronauts; military; and individuals in special activities outdoors and for decontamination of low moisture herbs and dried vegetables (SCF, 2003).

3. GAMMA IRRADIATION ON VITAMIN C As any thermal treatment, loss of nutrients in foods from animal and plant sources occurs with irradiation, and nutrient loss increases with radiation´s dose. According to the World Health Organization, thiamin (vitamin B1), vitamin C, and the tocopherols (vitamin E) are extremely radiation sensitive. Much of the change in nutrient composition is a result of irradiation unexplainable-loss of certain nutrients is different for different foods. The most radiation-sensitive, fat-soluble vitamin is vitamin E, and then Carotene, vitamin A, vitamin D, and vitamin K follows in decreasing order of sensitivity. Vitamin B1 is the most radiationsensitive, water-soluble vitamin, and then vitamin C, vitamin B6, vitamin B2, folate and niacin,

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and vitamin B12 follow in decreasing order of sensitivity (FAP/IAEA/WHO, 1999; Keller, 2013). The organic and inorganic molecules and atoms, that contain one or more unpaired electrons, with independent existence, can be classified as free radicals (Halliwell, 1994). This configuration makes the free radicals highly unstable molecules with very short half-life and chemically very reactive (Bianchi & Antunes, 1999). The continuous production of free radicals during the metabolic processes turns the development of many antioxidant defense mechanisms to limit the intracellular levels and prevent damage induction (Sies, 1993). Antioxidants are agents responsible for the inhibition and reduction of injuries caused by free radicals in cells (Bianchi & Antunes, 1999). A broader definition of antioxidant is: "any substance that when present in low concentrations compared to oxidizable substrate delays or inhibits oxidation of the substrate effectively" (Stahl & Sies, 1997; Bianchi & Antunes, 1999). These agents that protects cells against the effects of free radicals can be classified into antioxidants enzymatic or non-enzymatic (Sies, 1993). Vitamin C, for example, operates in the aqueous phase as an excellent antioxidant on free radicals, but it is not able to act on lipophilic compartments to inhibit the lipid peroxidation. Furthermore, in vitro studies showed that this vitamin in the presence of transition metals such as iron can act as a pro-oxidant molecule and generate OH and H2O2 radicals. Generally these metals are available in very limited quantities and the antioxidant properties of this vitamin predominates in vivo (Odin, 1997; Bianchi & Antunes, 1999). The vitamin C (ascorbic acid) is usually consumed in large doses by humans, being added to many food products for inhibiting the formation of nitro carcinogenic metabolites. The vitamin C diet is absorbed quickly and efficiently by an energy-dependent process. Consumption of high doses can lead to increased concentration of this vitamin in the tissues and blood plasma (Bianchi & Antunes, 1999). The benefits obtained in the vitamin C therapeutic use in biological assays with animals include a protective effect against damage caused by exposure to radiation and drugs (AmaraMokrane et al., 1996). Epidemiological studies also attribute this vitamin as a possible protective role in the development of tumors in humans (Lupulescu, 1993; Duthie et al., 1996; Bianchi & Antunes, 1999). However, the recommendation of this vitamin supplementation should be evaluated specifically for each case where there are many organic and inorganic components in cells that can modulate the activity of vitamin C, affecting their antioxidant activity (Bianchi & Antunes, 1999). According to Graham & Stevenson (1997) the vitamin C content four varieties of strawberry and it was determined before and after treatment with ionizing radiation at doses of 1, 2 or 3 kGy and after storage for 5 and 10 days at 6°C, and also in potatoes which having been allowed a period of one month to recover from the effects of post-harvest stress, were irradiated at a sprout inhibition dose of 0•15 kGy, followed by storage and cooking. Total ascorbic acid (TAA), ascorbic acid (AA) and dehydroascorbic acid (DHAA) concentrations were measured using the technique of ion-exclusion high-performance liquid chromatography. Results from analysis of strawberry samples showed the DHAA content increased immediately following irradiation and must, therefore, be take into account when reporting vitamin C levels in irradiated produce. In addition, it was observed that whilst irradiation did affect the vitamin C concentration in all varieties of strawberry, the change was small in comparison with the large

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variations observed between varieties. With regard to potatoes results showed that, whilst irradiation, storage and cooking all had the effect of reducing vitamin C concentration, irradiated samples stored for 5 months had similar or marginally higher levels than their nonirradiated counterparts. Cooking did not markedly reduce TAA content of irradiated potatoes compared to non-irradiated potatoes and it was also noted that microwave cooking was more destructive than boiling in lightly salted water (Dionísio et al., 2009). As seen, the ascorbic acid is one of the vitamins more sensitive font the irradiation. According to Proctor & Goldblith (1949), there are many fruits in which the level of ascorbic acid is not reduced significantly in a dose that fruit may tolerate (Maxie et al. 1964). These doses used to irradiate orange juice are above the tolerance level and the results showed a decrease in ascorbic acid with increasing radiation dose, reaching a lower value with the highest 7.5kGy dose (Spoto, 1988). These results are in agreement with those find by Munhoz-Burgos (1985) who observed a decrease in the vitamin C content with increasing radiation dose in orange juice; tangerine; tomato and passion fruit, being the orange and tangerine juices the most sensitive to radiation. Wilska-Jeszka & Skorupinska (1975) also observed an ascorbic acid drastic decrease in tomato juices and blackcurrant and red syrups irradiated in relation to pasteurization by heating. This fact was also observed by Hussain & Maxie (1974) who observed losses of up to 70% of vitamin C in orange juice irradiated with doses of 2.5 to 10kGy. Although there are some disagreement about the effects of radiation on the ascorbic acid content in citrus fruits, the results reported by the majority jobs shows unanimous in saying this lost in minimal when samples are irradiated with doses up to 1.0kGy. Exposure to doses higher than 1.0kGy can cause the destruction of this vitamin at a rate that increases proportionally with increasing doses of radiation to cite the work of: Romani et al., 1963; Ahmed et al., 1968; Ahmed, 1977; Guerrero et al., 1967; Dennison, 1968; Macfarlane and Roberts, 1968; Maxie et. al., 1964; Maxie et al., 1969; Kurosaki & Ogatta, 1971; Moshonas and Shaw 1984; Shaw and Moshonas, 1991. Minimum ascorbic acid values found by Monseline & Khan (1966) arrived around 84% compared to controls and the differences were significant only in green fruit over ripe fruit. Josephson et al. (1978) observed that the retention of ascorbic acid in oranges; tangerines; tomatoes and papayas had a range of 73% to 100% when they were irradiated with doses from 0.4 to 3.0kGy. Spoto (1988) found a higher ascorbic acid loss when juices were heated at 50ºC compared to 25ºC irradiation temperature being lower than the variation between doses at that same temperature. Authors like Hussain & Maxie (1974); Dharkar (1964) reported that there is a higher ascorbic acid loss only by the irradiation than when compared to the combined treatment of irradiation and heating. Munhoz-Burgos (1985) gave a better retention of acid ascorbic in tangerine juice irradiated, previously pasteurized as compared to only irradiated with a dose of 1.0kGy. Much more pronounced than the effects of radiation dose and temperature of irradiation according to Spoto (1988) were the temperatures and storage periods which is consistent with the work of Wilska-Jeszka & Skorupinska (1975) that observed that the ascorbic acid losses percentage showed a variation of 15 to 23% in the juice irradiated with different doses of radiation over the pasteurized juice which was 76 to 80% during the storage period.

According to Dionísio et al. (2009):

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These are reports describing gradual loss of ascorbic acid in apples (Pyrus malus L.) irradiated with more than 2 kGy (Saito & Igarashi, 1970; Chunyao et al., 1993; Lastarria-Tapia & Sequeiros, 1985). However, after six months of storage at 0ºC, no alterations in the ascorbic acid content of the fruits were observed (Saito & Igarashi, 1970). Destruction of vitamin C is a consequence of alteration of fruits metabolic oxidation pathways by radiation, which can convert vitamin C into dehydro-ascorbic acid, which can still be metabolized as vitamin C (Snauwart, 1973). Papaya and mango rot caused by fungi is a major problem during the storage and marketing. Gamma irradiation treatment was studied to determine its effect on the quality of papaya and mango irradiated at 0.5 to 0.95 kGy. The content of vitamin C was not significantly affected by the irradiation (Lacroix et al., 1990). Star fruit, mango, papaya, rambutan, and lichia were irradiated with 0.75 kGy and evaluated the vitamin C retention. Only star fruit presented significant vitamin C loss (Moy & Wong, 2002). Capsicums (green and red), cucumbers, custard apples, lemons, lychees, mandarins, mangoes, nectarines, papayas, peaches, persimmons, and zucchinis were irradiated at 0, 75, or 300 Gy. Commodities were analyzed shortly after the irradiation and again after 3 to 4 weeks of storage at 1-7ºC for some parameters, such as vitamin C and dehydroascorbic acid. Significant (p < 0.05) small changes were recorded in some variables for some commodities. However, storage effects were higher than irradiation effects (Mitchell et al, 1992). Strawberries (Shasta variety, Fragaria sp.) presented minute, non-significant decrease in vitamin C levels when submitted to 1.0-2.0 kGy doses, during two and 11 days of storage at 5ºC (Maxie et al., 1964). Similar observations were reported by Lopez et al. (1967). A study using higher radiation doses (3.0 and 4.0 kGy), resulted in 62 and 81% losses of ascorbic acid, respectively (Clark, 1959). However, 1.0-2.0 kGy doses are deemed enough to extend the shelf life of the fruits. Fruits irradiated with 2.0 kGy doses presented immediate increase in niacin contents, while thiamin was unaltered (Maxie & Sommer, 1968). A study with Selekta and Parafit varieties irradiated with 2 kGy doses, showed non-significant differences in riboflavin, thiamin and niacin contents, evaluated after 24 h. of exposure to the treatment (Beyers et al., 1979). In strawberry, vitamin C content was significantly affected by original content or the variety rather than treatments such as irradiation, heating or microwave. These results indicated that the losses of water-soluble vitamins, especially thiamin or vitamin C, were affected by the food temperature during the irradiation process (Chung & Yook, 2003). Irradiation can be an alternative for quarantining the papayas. Hot water treatment (immersion of fruits in water at 46 ºC) can be used for the fruits smaller than 0.7 kg. However, it can harm fruit quality. It is not advisable to submit the mangos heavier than 0.7 kg to hot water treatment because of lack of efficiency and intolerance of the product to the binomial time/temperature, which increases according to the fruit size (Hallman, 1999). Mangos and papayas irradiated with 2.0 kGy doses showed no loss of carotenoid; however, papayas stored at low temperatures without any kind of ionizing energy treatment showed large losses of these nutrients (Beyers & Thomas, 1979).

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Lycium, a popular fruit from China, was exposed to severe doses of gamma radiation (2-14 kGy), and decontaminating efficiency, changes in chemical composition and sensory characteristics were evaluated. Increasing the radiation dosage gradually decreased the fruits vitamin C concentration, but no alterations in β-carotene and riboflavin contents were registered (Wen et al., 2006). Reduction of vitamin C contents in irradiated Lycium is not a significant problem because this fruit is ordinarily used in traditional Chinese medicine for vision treatments, as an essential source of βcarotene and not vitamin C (Hsu et al., 1994). The importance of physiological state on vitamin loss was demonstrated with Early Park nº 7 tomato fruits irradiated with 4.0 kGy doses at the green-ripe stage. After ripening, tomatoes presented 8.6% loss of ascorbic acid, while ripe fruits irradiated with 3.0 kGy showed 20.4% loss. However, because ripe fruits contained almost twice as much ascorbic acid, even after high destruction percentage of vitamin C by irradiation, still contained 5mg/100g more vitamin C than the control, harvested at green-ripe stage (Maxie & Sommer, 1968).

The loss of vitamin C of fresh-cutted lettuce irradiated with 1.0kGy was significantly (a = 0.05) lower than non-irradiated. The best treatment of maintaining quality of fresh-cutted lettuce appeared to be 1.0kGy irradiation (Zhang et al, 2006). Adequate doses for insect disinfestations showed non-significant effects in vitamin C contents of citric fruits (Fan & Mattheis, 2001). Non significant losses of ascorbic acid were observed in the oranges irradiated and stored at 0ºC during 100 days. However, reduction of ascorbic acid content was observed in the lemons irradiated and stored at 15ºC during one month (Maxie et al., 1964). Grapefruit Rio Red variety (Citrus paradisi Macf.) in different maturation stages, were irradiated to evaluate the influence of dose and storage period, showed the loss of some bioactive components and fruit quality. Fruit's response to irradiation depended on its maturation stage. Low irradiation doses (60 yrs 74.8* >65 yrs >65 yrs 65± 0.9 (mean± SE)

Children Children

45 (number of subjects with 320 nm) wavelengths curative [12]. With Unger, they also demonstrated that UV exposure to one arm produced x-ray evidence of bilateral wrist improvements (via epiphyses calcification) of previously rachitic children [14]. In 1919 Winkler used medium soft tube x-rays to treat the craniotabes (skull abnormalities from rickets). X-ray findings post-treatment showed lime salt deposition on the radius, indicative of rickets healing [7]. Shortly after World War I, Dr. Harriette Chick analyzed both cod liver oil and light effects at the Kinderklinik in Vienna. Rachitic infants and children were divided into groups receiving varying diets and sunlight exposures. Staff completed careful records of intake, exposure, and clinical outcomes. The six children administered cod liver oil as part of their diet showed radiographic evidence of healing in two to four weeks. The seven children treated with mercury vapor quartz lamp exposure (increasing taper to 30 minutes of exposure three to four times per week) healed in two to four weeks (two to five total hours of UV exposure) with radiographic findings indistinguishable from the children treated with cod liver oil. She observed that the healing occurred regardless of whether a single limb, half of the body or the entire body received the UV exposure. The twelve children taken out on the sunny balcony (with various levels of direct sunlight, shade, and clothing) also improved but the ones who also received cod liver oil healed the most rapidly. Children with no sunlight exposure, mercury vapor quartz lamp treatment, or cod liver oil supplementation healed slowly after May; no one developed rickets during the summer [15 13,16].

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ISOLATION OF THE ANTI-RACHITIC FACTOR Native Kansan, Elmer McCollum began his nutritional research at the Wisconsin College of Agriculture. He bought twelve albino rats from a pet dealer with six of his own dollars to develop his first rat colony [17]. For years, he studied the clinical implications of nutritional deficiencies by feeding rats various restricted diets. In 1917 he joined the faculty at Johns Hopkins and began collaborating with fellow chemists Nina Simmonds and Helen Parsons, pediatrician John Howland and orthopedic histopathologists Edward Park and Paul Shipley. Combining their collective expertise, the group developed a diet that consistently induced clinical and histopathological findings of rickets in rats. They further demonstrated that these rachitic changes would heal with the addition of cod liver oil and concluded that a deficiency in fat soluble A, calcium or a similar metabolite was to blame. They also developed the “line test”, deposition of lime salts in the cartilage of the metaphysis junction, as a marker of rachitic healing [2, 18, 19, 20 21] English physician Edward Mellanby induced rickets in puppies by utilizing this diet. He then introduced a single food to observe the clinical impact on the rickets symptoms. Yeast and orange juice provided no improvement whereas cod liver oil, butter and whole milk did. He concluded that “the cause of rickets is a diminished intake of an antirachitic factor which is either fat-soluble A or has a somewhat similar distribution to fat-soluble A.” [2, 22] His work was noted by the British Medical Research Committee and they publically committed to the theory that a deficiency of “an antirachitic factor” caused rickets [7]. Both Mellanby and McCollum’s groups sought to determine if the anti-rachitic factor was indeed vitamin A or a distinct other element. Mellanby oxidized butter fat and cod liver oil to destroy the vitamin A and found that the oxidized cod liver oil maintained its anti-rachitic effect on puppies but that the oxidized butter did not. He queried whether the calcium of milk played a role in this observed difference [7]. Similarly, McCollum’s group found that oxidized cod liver oil maintained anti-rachitic properties while losing anti-xerophthalmic properties [23]. They concluded that the anti-rachitic factor was indeed separate from vitamin A. As this was the fourth nutritional factor identified it was named “vitamin D.” [2] (Vitamins A, B and C had already been discovered as impacting sight, pellagra and beriberi and scurvy, respectively.)

DEVELOPMENT OF FORTIFICATION While Mellanby and McCollum’s works identified the nutritional source of rickets protection, the question as to why sunlight seemed to also play a role in rickets had not yet been determined. In 1922 Alfred Hess, Lester Unger and Alwin Pappenheimer (Columbia University) irradiated rats with UV light shone through window glass and found that this method failed to protect the animals from rickets [24]. The next year Hume and Smith performed experiments irradiating rats (outside of their cages) or irradiating the glass jars in which the rats lived (without the rats present during the irradiation). Both groups of rats showed improvement in rickets compared to control animals (neither the animal nor its glass jar received irradiation). Webster and Hill tried to replicate this experiment but did not show rachitic improvement in the non-irradiated rats living in the irradiated cages. It was later realized that the latter experiment replaced the cage bedding after irradiation. Although not

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understood at the time, some irradiated organic products like rat bedding can synthesize vitamin D when exposed to UV light. Rats ingesting even small amounts of the irradiated bedding likely lead to the difference in outcomes between the two studies [16]. Back at the University of Wisconsin, Harry Steenbock built on these findings. Son of a Wisconsin dairy farmer and student of Edward McCollum, Steenbock earned both his bachelors and doctoral degrees from the University of Wisconsin and remained on as faculty in the Department of Agricultural Chemistry. His experiments fed two rats living in the same cage the previously discovered rickets-inducing -diet. Once both rats had developed clinical manifestations of rickets, one of the rats would be temporarily removed from the cage for UV irradiation and then replaced. Both the irradiated rat and its non-irradiated cage mate improved in terms of their rachitic symptoms. However, if the rats were placed in separate cages in near vicinity to each other, the non-irradiated rat did not improve. Hypothesizing that the nonirradiated rat may have been consuming the irradiated rat’s excrement, they repeated the experiments but included a screen floor through which excrement would pass. Both the irradiated and non-irradiated cage-mate still improved. Once they then began cleaning or replacing the screen after the single rat was irradiated, the cage-mate no longer improved. They hypothesized that the non-irradiated rat consumed either residual excrement on the screen floor (via exposure on paws and subsequent cleaning rituals) or irradiated bedding. Wondering if the rachitic-protective factor was being imparted onto previously vitamin D-deficient substances via irradiation, Steenbock irradiated hog millet and added it to the rat feed. These rats, too, improved, showing that vitamin D could be imparted into previously deficient foods [16, 25, 26, 27]. Although Alfred Hess was and Mildred Weinstock were finding similar results at Columbia University by irradiating cottonseed and linseed oil by mercury vapor lamp [24], Steenbock was the first to patent the process. Early on, he realized the potential commercial implications of the discovery that the anti-rachitic properties could be generated in certain food products (containing appropriate sterols) with UV irradiation. His university president denied funding for a patent, so Steenbock filed for the patent with his own $300. As one of the first university professors to obtain a patent, Steenbock was publically criticized, but he astutely argued that other professors received royalties from their books. Realizing that managing a patent was beyond the abilities of the university and learning from the successes of other universities’ patent management boards (namely Columbia, the University of Minnesota and the University of Toronto), Steenbock and the University of Wisconsin administration created the Wisconsin Alumni Research Foundation (WARF). In 1927 Steenbock sold the patent to the foundation for $10. [17] The foundation licensed the process of fortification to Quaker Oats for breakfast cereals. Believing the fortification process should only include nutritional foods, they refused licenses to manufacturers of chewing gum, tobacco, lipstick, beer, and soft drinks. Addition of irradiated yeast provided an easy way to fortify cereals but laws at the time prevented the addition of anything (including chocolate or vitamins) to milk. Located in dairy farmland, the University recognized the potential impacts of milk fortification and created a process of directly irradiating flowing milk [28]. The milk was fortified to 400 IU per liter because that was the amount found in one teaspoon of cod liver oil [12, 17]. In addition to the license to Quaker Oats, the WARF licensed the vitamin D development process to pharmaceutical companies which developed Viosterol, the first medicinal vitamin D preparation [28]. Thus, vitamin D supplements and fortified foods were born.

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A workaholic bachelor, Steenbock accepted no royalties initially. In order to set a precedent for future scientists who may need the salary boost, he eventually agreed to receive 15%; however he only accepted a fraction of this as the earnings became larger and larger. The profits from this patent funded the University’s research endeavors not only through the great depression but for decades to come [17].

ISOLATION OF VITAMIN D METABOLITES For almost four decades, vitamin D was recognized only as a single entity. However, in 1964 a group also from the University of Wisconsin identified five distinct metabolites. They administered radio-labeled vitamin D either orally or by intraperitoneal injection to rats and identified five separate peaks on chromatography of extracts from the intestine and kidney. Only one of these peaks was identical to the parent vitamin D compound administered to these animals [29]. Morii and colleagues administered one of these metabolites to calcium-deficient rats and noted stimulation of intestinal calcium transport, an increase in serum calcium, and improvement in rickets symptoms. Additional studies further elucidated that the more-polar metabolite existed in the chromatin fraction of chick intestine and that the radio-labeled vitamin D metabolite would not be taken up animals previously fed vitamin D rich diets or supplements [30]. Using ultraviolet spectra, gas-liquid partition chromatography and mass spectrometric and nuclear magnetic resonance spectrometric analyses, Blunt and his colleagues at the University of Wisconsin identified the structure of the metabolite, 25-hydroxycholecalciferol (25(OH)D), in hog serum and found its ability to cure rickets 1.4 times stronger than the parent vitamin D compound [31]. Noting the incidence of bony diseases in patients with advanced liver disease, University of Wisconsin researchers (Ponchon, Kennan and DeLuca) hypothesized the liver as the site of 25OH-hydroxylation. By studying rats after surgical ligation of the hepatic artery and bile duct (effectively eliminating all hepatic function), they found no further production of the 25(OH)D metabolite and deduced that the liver was the site of this conversion [32]. Although initially it was thought that 25(OH)D was the final product in vitamin D metabolism, Lawson and his Cambridge colleagues identified a yet more-polar metabolite. They also found that regardless of the dose of cholecalciferol administered to a chick, the concentration of this more-polar substance did not exceed one nanogram per gram of chick intestine tissue. Additionally, this metabolite seemed to have a rapid half-life with full clearance from the blood or adipose within 16 hours of the original cholecalciferol administration. [33, 34]. In an attempt to localize the source of this metabolite’s production, liver, adrenal, parathyroid, thyroid, ultimobranchial body, thymus, bone, and blood samples were incubated with 25(OH)D but no subsequent extra-polar metabolite was produced. Additionally, observational studies conducted in this same Cambridge lab continued to note this metabolite’s production even after surgical removal of the gut, pancreas, spleen, thyroid, parathyroid, ultimobranchial bodies, adrenals or thymus [35]. This was confirmed by Anthony Norman and his colleagues at the University of California [36]. Finally, two studies identified the kidney as the production location. First, the more-polar metabolite in question was produced by in-vitro kidney tissues exposed to 25(OH)D. Additionally, post-nephrectomy rats were found to produce 25(OH)D but not the more-polar metabolite [35]. In the early 1970s it was found that

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this kidney-produced, more-polar compound was superior to the precursor vitamin D metabolites in increasing calcium absorption in the gut. In 1971, all three labs (University of Wisconsin, Cambridge University and the University of California) concurrently and independently identified the structure of this most-polar metabolite as 1,25-dihydroxycholecalciferol (1,25(OH)2D) by utilizing mass spectrometry, ultraviolet absorption spectrophotometry and chemical reactions [37-40]. Injecting radiolabeled 1,25(OH)2D into vitamin D deficient rats identified 1,25(OH)2D receptors in the nuclei of the gut (duodenal, jejunal, ileal and colonic luminal and crypt epithelium), kidney (nuclei of distal tubule epithelium and glomeruli podocytes), epidermis, stomach, pituitary and parathyroid [41]. Since its location of action was distant from its location of production, the 1,25(OH)2D metabolite was reclassified as a hormone and not a true vitamin. Subsequent work allowed scientists to chemically synthesize 1,25(OH)2D and in the 1970s Dr. Uskovick developed the ability to produce synthetic 1,25(OH)2D for commercial use in renal osteodystrophy patients [42].

THE LIGHT-ER ER SIDE OF VITAMIN D All of this work successfully isolated vitamin D as the nutritional factor able to heal rickets as well as identified the sun’s role in imparting vitamin D to food. Historical observation studies of children and complex research projects on animals had shown rickets healing with exposure to UV but the mechanism had not been established. Back during the 1920 experiments that showed that UV-irradiated foods could develophad rickets-healing effects, Hess and Weinstock had also fed irradiated human and calf skin to rachitic rats and found that the rat’s rachitic clinical features healed. It was hypothesized that the skin, like the rat feed, could synthesize vitamin D with UV exposure [43]. The role of the skin was not fully identifiedcharacterized, though, for almost sixty years. University of Wisconsin Medical School graduate, Michael Holick, and his colleagues at Massachusetts General Hospital identified 7-dehydrocholesterol and previtamin D compounds within rat skin after UV exposure [44] Subsequent studies using human cadaver skin, human subjects and rats identified that the 7-dehydrocholesterol (sometimes called provitamin D) was converted to previtamin D in the epidermis with exposure to UV light. Over the course of about three days, warm (i.e., physiologic) temperatures promoted previtamin D conversion to vitamin D3 in a light-independent mechanism [45 46].

INTO THE 21ST CENTURY With Steenbock’s development of vitamin D fortification, the days of rickets were thought to be numbered. However, even with our modern understanding of vitamin D’s role in skeletal health and the ability to impart vitamin D into our diet, rickets and hypovitaminosis D continue to be prevalent worldwide with estimates of six to nine cases of rickets per million children in the US and over one billion cases of vitamin D deficiency worldwide [47-51]. An estimated 9% of children, 24% of adolescents, 32-36% of young adults, 47.8% of lactating women, 2557% of adults and 40-100% of elderly adults in the US are deficient have insufficient vitamin D status (30 ng/mL 25(OH)D serum concentrations ≥30 ng/mL and defined sufficiency as such. Their guidelines recommend 4001,000 IU of vitamin D per day for children under one year, 600-1,000 IU daily for children over the age of one year, and 1,500-2,000 IU per day for adults over the age of 19, including pregnant women. Tolerable upper intake levels of daily vitamin D ingestion were set at 2,000 IU for infants under one year, 4,000 IU for children and adolescents ages 1-18 years, and 10,000 IU for adults. These guidelines also recommend that obese children and adults and individuals on certain medications (i.e., anticonvulsants, glucocorticoids, antifungals, HAART) be given two to three times the recommended supplementation dose. The task force did recommend prescribing vitamin D for fall prevention but did not recommend supplementation to improve cardiovascular disease, all-cause mortality or quality of life. The committee also recommends screening patients at higher risk of deficiency including those with rickets, osteomalacia, osteoporosis, chronic kidney disease, malabsorptive syndromes (cystic fibrosis, inflammatory bowel disease, Crohn’s disease, history of bariatric surgery, radiation enteritis), hyperparathyroidism, use of certain medications (antiseizure medications, glucocorticoids, HAART, antifungals, and cholestyramine), African American or Hispanic ethnicity, pregnancy, lactation, a history of falls or nontraumatic fractures in older adults, BMI >30 kg/m2, granuloma-forming disorders (sarcoidosis, tuberculosis, histoplasmosis, coccidiomycosis, berylliosis) and lymphoma, but not the general population [67,149]. The United States Preventative Services Task Force updated their calcium and vitamin D recommendations in 2013. For fracture prevention in post-menopausal, noninstitutionalized women, they found insufficient evidence for daily supplementation with more than 400 IU vitamin D and 1200 mg calcium (I statement) and recommended against daily supplementation with less than 400 IU vitamin D and 1200 mg calcium (Grade B recommendation).

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Additionally, the task force found insufficient evidence to assess vitamin D and calcium supplementation to prevent fractures in premenopausal women and men (I statement). These recommendations only assess fracture- related evidence and no other potential health outcomes. They also do not apply to higher risk groups such as persons with a history of fractures or osteoporosis. 150 Additionally, although not part of the USPSTF’s assessment, they did recognizeacknowledged a meta-analysis published after their review which concluded that fractures may be reduced in individuals taking higher doses of vitamin D – 30% lower incidence of hip fracture with doses 792-2,000 IU vitamin D per day and no reduction in hip fractures at doses less than 792 IU daily [143,150,151] Of note, the task force had previously recommended vitamin D supplementation – along with exercise or physical therapy – to prevent falls in community dwelling adults over the age of 65 (Grade B recommendation). The Task Force did not specify a dosing regimen, recognizing that the data included a variety of supplementation regimens (median dose of 800 IU vitamin D daily for a median of 12 months) but did cite IOM’s recommendations of 600 IU vitamin D per day for adults 51-70 and 800 IU per day for adults over the age of 70 years and the American Geriatric Society’s recommendation of 800 IU daily for persons at increased risk of falls [69]. Like the IOM recommendations in 2010, these new 2013 USPSTF recommendations were met with quite a bit of controversy, not only among proponents of higher supplementation doses that were surprised by the IOM recommendations but by those who had accepted the IOM guidelines as well. Editorials abounded but reminded critics that these assessments were limited – the IOM only considered skeletal impacts and the newest USPSTF recommendations only assessed fracture risk [143]. Additionally, none of the aforementioned guidelines consider any outcome other than skeletal health, falls and fractures. Neither the IOM nor the US Endocrine Society recommends any additional supplementation for pregnant or lactating women beyond the doses recommended for all adults. The American College of Obstetricians and Gynecologists’ (ACOG) Committee Opinion concluded that insufficient evidence exists to recommend routine screening for vitamin D deficiency during pregnancy or to routinely supplement vitamin D beyond that which is contained within a prenatal vitamin. ACOG recognized that vitamin D deficiency is likely common during pregnancy and that maternal status impacts the infant’s vitamin D status at birth. They acknowledged that new data has suggested a role for vitamin D supplementation to prevent preterm birth and preeclampsia but found the evidence insufficient to date. They did state that if vitamin D deficiency is identified, 1,000-2,000 IU of vitamin D per day is safe during pregnancy [152]. The United Kingdom’s National Institute for Health and Clinical Excellence recommends counseling pregnant and breastfeeding women to take 400 IU vitamin D daily (the amount contained in most US prenatal vitamins) [153]. The World Health Organization Food and Agriculture Organization of the United Nations (WHO/FAO) set the recommended nutrient intake (RNI) at 200 IU of vitamin D per day for pregnant women. The WHO’s 2012 guidelines regarding vitamin D supplementation in pregnant women recommended against vitamin D supplementation during pregnancy to prevent pre-eclampsia (strong recommendation) or as a routine practice to improve maternal or infant health (conditional recommendation) with the latter recommendation being due to lack of evidence to fully assess potential benefits and harms [154]. In line with the IOM’s AI and EAR but below the IOM’s RDA and the US Endocrine Society’s recommendations, the American Academy of Pediatrics (AAP) also recommends

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vitamin D supplementation for children. The AAP based their original 2003 recommendations on the IOM’s 1997 vitamin D recommendation of 200 IU per day. Although pediatric reference ranges did not exist, adult sufficiency was later defined as serum concentrations of 20-30 ng/mL, and the daily 200 IU supplementation failed to achieve this in infants. Breastfed infants receiving 400 IU of vitamin D daily supplementation did achieve serum concentrations of 25(OH)D greater than 20 ng/mL. In terms of convenience, the AAP noted that the only commercially available liquid infant preparation of supplemental vitamin D came in 400 IU drops. Also recognizing that rickets continued to exist within Western society, especially among exclusively breastfed and/or darker pigmented infants, in 2008 the AAP published updated their recommendations to supplement infants within days of birth, and children and adolescents with 400 IU of vitamin D daily. In addition to rickets prevention, the AAP based this new recommended dose on studies that had confirmed safety at of 400 IU per day as well as early evidence for a role of vitamin D in innate immunity and disease prevention (including diabetes and cancer). The World Health Organization has stated that vitamin D supplementation in children may prevent rickets (Category 2 intervention), but actual guidelines have yet to be developed [155]. Daily consumption of 32 ounces of vitamin D fortified milk would provide a child with the 400 IU of vitamin D recommended; however, the AAP recognizes that most children and adolescents do not consume the necessary dietary amounts of vitamin D fortified products. From the 1970s to the 1990s milk consumption decreased by 36% in adolescent girls. Thus, the AAP recommends universal daily vitamin D supplementation with 400 IU for children and adolescents [55]. Although dietary sources are often not considered a reliable source of sufficient vitamin D, formula fed infants usually do receive enough vitamin D from their diet. Since the 1980 Infant Formula Act established the vitamin D fortification mandate, infant formula has included substantial vitamin D. [156]. Presently, the Food and Drug Administration has set a requirement of 40-100 IU vitamin D per 100 kcal of formula. Standard infant formulas are 20 kcal per ounce which means that they would contain 258-266 IU of vitamin D per liter of formula [157]. Most commercially available infant formulas in the US advertise 400-500 IU vitamin D per liter; therefore, consumption of one liter of infant formula provides an infant with the recommended 400 IU of vitamin D. By one month of age, most formula-fed infants are consuming at least one liter of formula daily and, therefore, do not require additional vitamin D supplementation. Infants consuming less than one liter of formula per day should, per the AAP recommendation, receive an additional 400 IU of supplemental vitamin D per day. [55] Breastfeeding is encouraged as a healthy practice for most infants. HealthyPeople 2010 set the goal for that 75% of infants breastfeed for the first six months of their lives [158]. However, human milk is universally vitamin D deficient with an average of 15.9 +/- 8.6 IU/L [67] which is why the AAP recommends universal vitamin D supplementation for breastfed infants [55]. Some find all of these recommendations too conservative and suggest much higher dosing regimens. While the concern of hypervitaminosis D is legitimate; hypercalcemia has only been reported with serum concentrations of 25(OH)D exceeding 150 ng/mL. Models have suggested that to achieve that concentration would require daily oral supplementation of 40,000 IU of vitamin D. [51]. Although cautiously, given concerns for skin cancer and the recommendations against it, some do suggest limited but regular sunlight exposure to meet physiologic needs. Full body

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exposure to UVB in an adult with fair complexion produces about 20,000 IU of vitamin D in 30 minutes [61]. With the rapidly changing recommendations and varying guidelines, it’s no surprise that compliance with these recommendations is poor. Studies of supplementation rates in exclusively breastfed infants (per the AAP guidelines) have been shown to be as low as 5-16%. [159,160]. Evaluation of elderly individuals with hip fractures revealed that only 24% complied with the vitamin D and calcium supplementation recommendations [52].

A VARIETY OF REPLACEMENT REGIMENS Although controversy exists regarding whether or not to supplement a healthy individual, most are in agreement that an individual with vitamin D deficiency needs replacement. The best route, schedule, and dose remain to be determined, though. Oral and intramuscular routes are both used. Schedules include administration twice daily, daily, twice weekly, weekly, monthly, quarterly or even annually. A chart review at an Atlanta Veterans Administration (VA) identified 36 different vitamin D replacement regimens [161]. Recent assessment has suggested that either intermittent high dose replacement for two months or regular lower dose supplementation schedules are both acceptable [145]. Oral doses of 400-50,000 IU per day for six weeks to several years, 8,400-100,000 IU per week, and 300,000 IU quarterly have all been used. Additional regimens include intramuscular administration of 300,000 IU quarterly or 600,000 IU annually [136,145 144]. The most commonly prescribed regimens at the aforementioned VA included oral vitamin D 50,000 IU weekly for four weeks followed by monthly administration for five months; oral 50,000 IU monthly for six months; and oral 50,000 IU three times weekly for six weeks. Although all of the VA’s regimens improved vitamin D status, only the 50,000 IU monthly dose for six months achieved a serum concentration exceeding 30 ng/mL in greater than half of recipients (82% compared to 38 and 42%, respectively) [161]. The US Endocrine Society recommends treatment of vitamin D deficiency with either 2,000 IU per day or 50,000 IU per week for infants and children from birth to the age of 18 years; 6,000 IU per day or 50,000 IU per week for adults; and 6,000-10,000 IU per day for at risk individuals (including those with obesity or malabsorptive syndromes). Once high dose treatment had achieved a serum concentration of greater than 30 ng/mL (or the person had completed six weeks of treatment for children or eight weeks of treatment in adults), long term maintenance therapy was suggested with daily supplementation of 400-1,000 IU for infants less than one year of age, 600-1,000 IU for children and adolescents ages 1-18, 1,500-2,000 IU for adults, and 3,000-6,000 IU for at-risk individuals [67]. The United Kingdom’s National Osteoporosis Society recommends oral replacement therapy with either fixed loading doses or just maintenance therapy for vitamin D deficient individuals. Suggested loading doses included 50,000 IU weekly for six weeks, 20,000 IU twice weekly for seven weeks or 4,000 IU daily for 10 weeks. Maintenance therapy recommendations included 800-2,000 IU daily [141]. Micromedex® currently recommends treatment of dietary vitamin D deficiency with 1,000 IU daily or 100,000 IU quarterly [162].

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CONCLUSION From the first observations of rachitic findings in ancient times to the initial studies of rickets in the 1600s to the discovery of vitamin D in the early 20th century to modern investigations of its role in the genome, vitamin D has already created a rich and complex history. Over the years controversies have abounded – the etiology of rickets, the ethics of a professor or university holding and profiting from a patent, what products to fortify, the definition as vitamin or hormone, the role outside of the skeleton, whether to recommend UV exposure, whether to test, how to define sufficiency, whether to supplement, how to treat deficiencies and what to study next. Although there may be lack of consensus regarding supplementation doses or replacement regimens, most agree that we need to learn more. Organized by the National Institute of Child Health and Human Development and the National Institutes of Health Office of Dietary Supplements, the 2003 “Vitamin D and Health in the 21st Century: Bone and Beyond” conference included more than 200 attendees representing multiple national institute health offices, the US Department of Health and Human Services, the CDC, the Department of Agriculture and the National Dairy Council. They concluded that a number of topics needed to be better addressed including defining adequacy and sufficiency, establishing a qualitative measurement for UV exposure, exploring more thoroughly the benefits versus harms of UV exposure, determining bony and non-bony outcomes based on vitamin D status, reevaluating daily reference intake, providing the public with better information regarding vitamin D (and avoiding the mixed messages that can easily occur, especially with breastfeeding and UV exposure), studying genetic polymorphisms, improving prevalence estimates, determining what type of surveillance high risk groups may need, better explaining the relationship between vitamin D and obesity, and establishing more complete data for vitamin D in food [163]. Similarly, the attendees of IOM’s 2011 “A Vitamin D Expert Panel Meeting” (including representatives from the CDC, AAP, academics, government agencies and laboratories) suggested that future recommendations should consider health effects other than rickets and identified the need for more long term studies [48]. Within their most recent guidelines, the IOM also concluded that additional research and better understandings are urgently needed [60, 148, 164]. While some of these ambitions set forth by these conferences have already been and continue to be explored, the fact that each of these conferences developed lists of additional research needs is quite telling of our still elementary understanding of vitamin D. As we look back on the insightful observations and ground-breaking experiments of scientists such as Francis Glisson, Theobald Palm, Harriette Chick, Elmer McCollum, Edward Mellanby, and Harry Steenbock (just to name a very select few), one can only wonder what the next century will bring for the sunshine vitamin.

REFERNECES [1] [2]

Foote JA. Evidence of rickets prior to 1650. Am. J. Dis. Child. 1927:45-61. Rajakumar K. Vitamin D, cod-liver oil, sunlight, and rickets: a historical perspective. Pediatrics 2003;112:e132-5.

1226 [3] [4]

[5] [6] [7] [8] [9]

[10] [11] [12] [13] [14] [15]

[16] [17] [18]

[19] [20]

[21]

[22] [23]

[24]

Sara S. Oberhelman and Tom D. Thacher O'Riordan JL. Rickets in the 17th century. J. Bone Miner. Res. 2006;21:1506-10. Whistler D. Inaugural Medical Disputation on the Children's Disease of the English which the inhabitants idiomatically call The Rickets. Journal of the History of Medicine reprinted Autumn 1950:401-15. Smerdon GT. Daniel Whistler and the English disease: a translation and biographical note. Journal of the History of Medicine 1950:397-415. Cheadle W. A discussion on rickets. Brit. Med. J. November 24, 1888;II:1145-8. Park EA. The etiology of rickets. Physiol. Rev. 1923:106-63. Findlay L. The Etiology of Rickets: A Clinical and Experimental Study. Br. Med. J. 1908;2:13-7. Thacher TD, Fischer PR, Pettifor JM. Rickets: vitamin D and calcium deficiency. J. Bone Miner. Res. Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research 2007;22:638; author reply 9. Guy R. The history of cod liver oil as a remedy. Am. J. Dis. Child. 1923;26:112-6. Mayer J. Armand Trousseau and the arrow of time. Nutr. Rev. 1957;15:321-3. Chesney RW. Theobald palm and his remarkable observation: how the sunshine vitamin came to be recognized. Nutrients 2012;4:42-51. O'Riordan JL. Rickets, from history to molecular biology, from monkeys to YACS. The Journal of eJ. Endocrinol.ogy 1997;154 Suppl:S3-13. Hess A, Unger L. The cure of Infantile Rickets by Sunlight. The Journal of the American Medical Association JAMA 1921;77:39. Chick H, Dalyell, E., Hume, M., Mackay, H.M.M., Henderson Smith, H. The aetiology of rickets in infants: prophylactic and curative observations at the Vienna University Kinderklinik. Lancet 1922:7-11. Carpenter KJ, Zhao L. Forgotten Mysteries in the Early History of Vitamin D. J. Nutr. 1999:923-7. Schneider HA. Harry Steenbock (1886-1967)--a biographical sketch. J. Nutr. 1973;103:1233-47. McCollum E, Simmonds N, Parsons H, Shipley P, Park E. Studies on Experimental Rickets: The Production of Rachitis and Similar Diseases is the Rat of Deficient Diets. J. Biol. Chem. 1921;45:333-41. McCollum EV, Simmonds, N., Becker, Shipley, P.G. and Park, E.A. The production of rickets by diets low in phosphorus and fat-solube vitamin A. J. Biol. Chem. 1921:507-28. McCollum EV, Simmonds, N., Shipley, P.G. and Park, E.A. A delicate biological test for calcium-depositing substances. J. Biol. Chem. Journal of Biological Chemistry 1922;51:41-50. Shipley P, Park E, McCollum E, Simmonds N, Parsons H. Studies on Experimental Rickets: The Effect of Cod Liver Oil Administered to Rats with Experimental Rickets. J. Biol. Chem. 1921;45. Mellanby E. An experimental investigation on rickets. The Lancet 1919;2:407-12. McCollum EV, Simmonds, N., Becker, E. and Shipley, P.G. An experimental demonstration of a vitamin which promotes calcium deposition. J. Biol. Chem. 1922:293312. Hess AFW, Weinstock M. A study of light waves in their relation to rickets. JAMA 1925;80:687-90.

The History and Modern Controversies of Vitamin D …

1227

[25] Steenbock H. The Induction of Growth Promoting and Calcifying Properties in a Ration by Exposure to Light. Science 1924;60:224-5. [26] Steenbock H. The induction of growth promoting and calcifying properties in a ration by exposure to ultraviolet light. J. Biol. Chem. Journal of Biological Chemistry 1924.;61:405-22. [27] Steenbock H. The induction of calcifying properties in rickets-producing ration by radiant energy. J. Biol. Chem. Journal of Biological Chemistry 1924;62. [28] Wisconsin Alumni Research Foundation. Steenbock and WARF's Founding. (Accessed 2012 at http://www.warf.org/about/index.jsp?cid=26&scid=33.) [29] Norman AW, Lund J, Deluca HF. Biologically Active Forms of Vitamin D3 in Kidney and Intestine. Arch. Biochem. Biophys. 1964;108:12-21. [30] Haussler MR, Myrtle, James F. and Norman, Anthony W. The association of a metabolite of vitamin D3 with intestinal mucosa chromatin in vivo. J. Biol. Chem. 1967;243:405564. [31] Blunt JW, DeLuca HF, Schnoes HK. 25-hydroxycholecalciferol. A biologically active metabolite of vitamin D3. Biochemistry 1968;7:3317-22. [32] Ponchon G, Kennan AL, DeLuca HF. "Activation" of vitamin D by the liver. J. Clin. Invest 1969;48:2032-7. [33] Lawson DE, Wilson PW, Kodicek E. Metabolism of vitamin D. A new cholecalciferol metabolite, involving loss of hydrogen at C-1, in chick intestinal nuclei. Biochem. J. 1969;115:269-77. [34] Lawson DE, Wilson PW, Kodicek E. New vitamin D metabolite localized in intestinal cell nuclei. Nature 1969;222:171-2. [35] Fraser DR, Kodicek E. Unique biosynthesis by kidney of a biological active vitamin D metabolite. Nature 1970;228:764-6. [36] Norman AW, Midgett RJ, Myrtle JF, Nowicki HG. Studies on calciferol metabolism. I. Production of vitamin D metabolite 4B from 25-OH-cholecalciferol by kidney homogenates. Biochem. Biophys. Res. Commun. 1971;42:1082-7. [37] Macintyre I, Evans IM, Larkins RG. Vitamin D. Clin. Endocrinol. (Oxf) 1977;6:65-79. [38] Holick MF, Schnoes HK, DeLuca HF, Suda T, Cousins RJ. Isolation and identification of 1,25-dihydroxycholecalciferol. A metabolite of vitamin D active in intestine. Biochemistry 1971;10:2799-804. [39] Lawson DE, Fraser DR, Kodicek E, Morris HR, Williams DH. Identification of 1,25dihydroxycholecalciferol, a new kidney hormone controlling calcium metabolism. Nature 1971;230:228-30. [40] Norman AW, Myrtle JF, Midgett RJ, Nowicki HG, Williams V, Popjak G. 1,25dihydroxycholecalciferol: identification of the proposed active form of vitamin D3 in the intestine. Science 1971;173:51-4. [41] Stumpf WE, Sar M, Reid FA, Tanaka Y, DeLuca HF. Target cells for 1,25dihydroxyvitamin D3 in intestinal tract, stomach, kidney, skin, pituitary, and parathyroid. Science 1979;206:1188-90. [42] Holick MF. Vitamin D: A millenium perspective. Journal of Cellular BiochemistryJ. Cell. Biochem. 2003;88:296-307. [43] Hess AFW, Mildred. The antirachitic value of irradiated cholesterol and phytosterol. J. Biol. Chem. 1925;64:181-91.

1228

Sara S. Oberhelman and Tom D. Thacher

[44] Holick MF, Frommer JE, McNeill SC, Richtand NM, Henley JW, Potts JT, Jr. Photometabolism of 7-dehydrocholesterol to previtamin D3 in skin. Biochem. Biophys. Res. Commun. 1977;76:107-14. [45] Holick MF, Richtand NM, McNeill SC, et al. Isolation and identification of previtamin D3 from the skin of rats exposed to ultraviolet irradiation. Biochemistry 1979;18:10038. [46] Holick MF, MacLaughlin JA, Clark MB, et al. Photosynthesis of previtamin D3 in human skin and the physiologic consequences. Science 1980;210:203-5. [47] Center for Disease Control. Severe malnutrition among young children - Georgia, January 1997-June 1999. MMWR Morb. Mortal. Wkly. Rep.Morbidity and Morality Weekly Report 2001;50:224-7. [48] Scanlon KS. Vitamin D Expert Panel Meeting. 2001. [49] Holick MF. Vitamin D deficiency. N. Engl. J. Med. 2007;357:266-81. [50] Bell DS. Protean manifestations of vitamin D deficiency, part 1: the epidemic of deficiency. South. Med. J. 2011;104:331-4. [51] Makariou S, Liberopoulos EN, Elisaf M, Challa A. Novel roles of vitamin D in disease: what is new in 2011? Eur. J. Intern. Med. 2011;22:355-62. [52] Holick MF. High prevalence of vitamin D inadequacy and implications for health. Mayo Clin.ic Proc.eedings 2006;81:353-73. [53] Office of Dietary Supplements. Dietary Supplement Fact Sheet: Vitamin D. June 24, 2011. (Accessed 2013, at http://ods.od/nih.gov/factsheets/VitaminD-HealthProfessiona/) [54] American Academy of Dermatology. Position Statement on Vitamin D; 2009. [55] Wagner CL, Greer FR. Prevention of rickets and vitamin D deficiency in infants, children, and adolescents. Pediatrics 2008;122:1142-52. [56] Moyer VA. Behavioral counseling to prevent skin cancer: U.S. Preventive Services Task Force recommendation statement. Ann. Intern. Med. 2012;157:59-65. [57] Holick MF, Chen TC. Vitamin D deficiency: a worldwide problem with health consequences. American Journal of Clinical NutritionAm. J. Clin. Nutr. 2008;87:1080S6S. [58] Highwood EJ, Kinnersley RP. When smoke gets in our eyes: the multiple impacts of atmospheric black carbon on climate, air quality and health. Environment International 2006;32:560-6. [59] Mims FM. Significant reduction of UVB caused by smoke from biomass burning in Brazil. Photochemistry and Photobiology 1996;64:814-6. [60] Aloia JF. Clinical Review: The 2011 report on dietary reference intake for vitamin D: where do we go from here? J. Clin. Endocrinol. Metab. 2011;96:2987-96. [61] Cannell JJ, Hollis BW. Use of vitamin D in clinical practice. Altern. Med. Rev. 2008;13:620. [62] MacLaughlin J, Holick MF. Aging decreases the capacity of human skin to produce vitamin D3. J. Clin. Invest. 1985;76:1536-8. [63] Holick MF, Shao Q, Liu WW, Chen TC. The vitamin D content of fortified milk and infant formula. N. Engl. J. Med. 1992;326:1178-81. [64] Macdonald HM. Contributions of sunlight and diet to vitamin D status. Calcif. Tissue Int. 2013;92:163-76. [65] Holick MF. McCollum Award Lecture, 1994: vitamin D--new horizons for the 21st century. American Journal of Clinical Nutrition Am. J. Clin. Nutr. 1994;60:619-30.

The History and Modern Controversies of Vitamin D …

1229

[66] Tsiaras WG, Weinstock MA. Factors influencing vitamin D status. Acta Derm. Venereol. 2011;91:115-24. [67] Holick MF, Binkley NC, Bischoff-Ferrari HA, et al. Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline. Journal of Clinical Endocrinology and Metabolism J. Clin. Endocrinol. Metab. 2011;96:1911-30. [68] Haussler MR, Whitfield GK, Kaneko I, et al. Molecular mechanisms of vitamin D action. Calcif. Tissue Int. 2013;92:77-98. [69] Moyer VA. Prevention of falls in community-dwelling older adults: U.S. Preventive Services Task Force recommendation statement. Ann. Intern. Med. 2012;157:197-204. [70] Thacher TD, Clarke BL. Vitamin D insufficiency. Mayo Clin.ic Proc.eedings 2011;86:50-60. [71] Dawson-Hughes B, Mithal A, Bonjour JP, et al. IOF position statement: vitamin D recommendations for older adults. Osteoporosis Int.ernational 2010;21:1151-4. [72] Bischoff-Ferrari HA, Dawson-Hughes B, Staehelin HB, et al. Fall prevention with supplemental and active forms of vitamin D: a meta-analysis of randomised controlled trials. BMJ 2009;339:b3692. [73] Broe KE, Chen TC, Weinberg J, Bischoff-Ferrari HA, Holick MF, Kiel DP. A higher dose of vitamin d reduces the risk of falls in nursing home residents: a randomized, multiple-dose study. J. Am. Geriatr. Soc. 2007;55:234-9. [74] Murad MH, Elamin KB, Abu Elnour NO, et al. Clinical review: The effect of vitamin D on falls: a systematic review and meta-analysis. J. Clin. Endocrinol. Metab. 2011;96:2997-3006. [75] Mason RS, Sequeira VB, Gordon-Thomson C. Vitamin D: the light side of sunshine. Eur. J. Clin. Nutr. 2011;65:986-93. [76] Bischoff-Ferrari HA, Dietrich T, Orav EJ, et al. Higher 25-hydroxyvitamin D concentrations are associated with better lower-extremity function in both active and inactive persons aged > or =60 y. Am. J. Clin. Nutr. 2004;80:752-8. [77] Visser M, Deeg DJ, Lips P. Low vitamin D and high parathyroid hormone levels as determinants of loss of muscle strength and muscle mass (sarcopenia): the Longitudinal Aging Study Amsterdam. J. Clin. Endocrinol. Metab. 2003;88:5766-72. [78] Plotnikoff GA, Quigley JM. Prevalence of severe hypovitaminosis D in patients with persistent, nonspecific musculoskeletal pain. Mayo Clin.ic Proc.eedings 2003;78:146370. [79] Zittermann A, Iodice S, Pilz S, Grant WB, Bagnardi V, Gandini S. Vitamin D deficiency and mortality risk in the general population: a meta-analysis of prospective cohort studies. American Journal of Clinical Nutrition Am. J. Clin. Nutr. 2012;95:91-100. [80] Ginde AA, Scragg R, Schwartz RS, Camargo CA, Jr. Prospective study of serum 25hydroxyvitamin D level, cardiovascular disease mortality, and all-cause mortality in older U.S. adults. J. Am. Geriatr. Soc. 2009;57:1595-603. [81] Bjelakovic G, Gluud LL, Nikolova D, et al. Vitamin D supplementation for prevention of mortality in adults. Cochrane Database Syst Rev 2011:CD007470. [82] Nadir MA, Szwejkowski BR, Witham MD. Vitamin D and cardiovascular prevention. Cardiovascular therapeutics 2010;28:e5-12. [83] Autier P, Gandini S. Vitamin D supplementation and total mortality: a meta-analysis of randomized controlled trials. Arch. Intern. Med. 2007;167:1730-7.

1230

Sara S. Oberhelman and Tom D. Thacher

[84] Scragg R, Sowers M, Bell C. Serum 25-hydroxyvitamin D, ethnicity, and blood pressure in the Third National Health and Nutrition Examination Survey. American journal of hypertensionAm. J. Hypertens. 2007;20:713-9. [85] Forman JP, Giovannucci E, Holmes MD, et al. Plasma 25-hydroxyvitamin D levels and risk of incident hypertension. Hypertension 2007;49:1063-9. [86] Lind L, Hanni A, Lithell H, Hvarfner A, Sorensen OH, Ljunghall S. Vitamin D is related to blood pressure and other cardiovascular risk factors in middle-aged men. Am. J. Hypertens. American journal of hypertension 1995;8:894-901. [87] Reis JP, von Muhlen D, Miller ER, 3rd, Michos ED, Appel LJ. Vitamin D status and cardiometabolic risk factors in the United States adolescent population. Pediatrics 2009;124:e371-9. [88] Judd SE, Raiser SN, Kumari M, Tangpricha V. 1,25-dihydroxyvitamin D3 reduces systolic blood pressure in hypertensive adults: a pilot feasibility study. J. Steroid Biochem. Mol. Biol. 2010;121:445-7. [89] Pfeifer M, Begerow B, Minne HW, Nachtigall D, Hansen C. Effects of a short-term vitamin D(3) and calcium supplementation on blood pressure and parathyroid hormone levels in elderly women. J. Clin. Endocrinol. Metab. 2001;86:1633-7. [90] Islam T, Peiris P, Copeland RJ, El Zoghby M, Peiris AN. Vitamin D: Lessons from the veterans population. J. Am. Med. Dir. Assoc. 2011;12:257-62. [91] Witham MD, Nadir MA, Struthers AD. Effect of vitamin D on blood pressure: a systematic review and meta-analysis. Journal of HypertensionJ. Hypertens. 2009;27:1948-54. [92] Margolis KL, Ray RM, Van Horn L, et al. Effect of calcium and vitamin D supplementation on blood pressure: the Women's Health Initiative Randomized Trial. Hypertension 2008;52:847-55. [93] Krause R, Buhring M, Hopfenmuller W, Holick MF, Sharma AM. Ultraviolet B and blood pressure. Lancet 1998;352:709-10. [94] Martins D, Wolf M, Pan D, et al. Prevalence of cardiovascular risk factors and the serum levels of 25-hydroxyvitamin D in the United States: data from the Third National Health and Nutrition Examination Survey. Arch. Intern. Med. 2007;167:1159-65. [95] Hypponen E, Boucher BJ, Berry DJ, Power C. 25-hydroxyvitamin D, IGF-1, and metabolic syndrome at 45 years of age: a cross-sectional study in the 1958 British Birth Cohort. Diabetes 2008;57:298-305. [96] Carbone LD, Rosenberg EW, Tolley EA, et al. 25-Hydroxyvitamin D, cholesterol, and ultraviolet irradiation. Metabolism: clinical and experimental 2008;57:741-8. [97] Ford ES, Ajani UA, McGuire LC, Liu S. Concentrations of serum vitamin D and the metabolic syndrome among U.S. adults. Diabetes Care 2005;28:1228-30. [98] Cannell JJ, Vieth R, Umhau JC, et al. Epidemic influenza and vitamin D. Epidemiol.ogy and Infect.ion 2006;134:1129-40. [99] Laaksi I, Ruohola JP, Tuohimaa P, et al. An association of serum vitamin D concentrations < 40 nmol/L with acute respiratory tract infection in young Finnish men. American Journal of Clinical Nutrition Am. J. Clin. Nutr. 2007;86:714-7. [100] Urashima M, Segawa T, Okazaki M, Kurihara M, Wada Y, Ida H. Randomized trial of vitamin D supplementation to prevent seasonal influenza A in schoolchildren. Am. J. Clin. Nutr. American Journal of Clinical Nutrition 2010;91:1255-60.

The History and Modern Controversies of Vitamin D …

1231

[101] Hypponen E, Laara E, Reunanen A, Jarvelin MR, Virtanen SM. Intake of vitamin D and risk of type 1 diabetes: a birth-cohort study. Lancet 2001;358:1500-3. [102] Zipitis CS, Akobeng AK. Vitamin D supplementation in early childhood and risk of type 1 diabetes: a systematic review and meta-analysis. Arch.ives of Dis.ease in Child.hood 2008;93:512-7. [103] McGrath J, Saari K, Hakko H, et al. Vitamin D supplementation during the first year of life and risk of schizophrenia: a Finnish birth cohort study. Schizophrenia Research 2004;67:237-45. [104] Bodnar LM, Catov JM, Simhan HN, Holick MF, Powers RW, Roberts JM. Maternal vitamin D deficiency increases the risk of preeclampsia. Journal of Clinical Endocrinology and MetabolismJ. Clin. Endocrol. Metab. 2007;92:3517-22. [105] Kendrick J, Targher G, Smits G, Chonchol M. 25-Hydroxyvitamin D deficiency is independently associated with cardiovascular disease in the Third National Health and Nutrition Examination Survey. Atherosclerosis 2009;205:255-60. [106] Kim DH, Sabour S, Sagar UN, Adams S, Whellan DJ. Prevalence of hypovitaminosis D in cardiovascular diseases (from the National Health and Nutrition Examination Survey 2001 to 2004). The American journal of cardiology Am. J. Cardiol. 2008;102:1540-4. [107] Pilz S, Dobnig H, Fischer JE, et al. Low vitamin d levels predict stroke in patients referred to coronary angiography. Stroke 2008;39:2611-3. [108] Grandi NC, Breitling LP, Brenner H. Vitamin D and cardiovascular disease: systematic review and meta-analysis of prospective studies. Prev. Med.entive medicine 2010;51:228-33. [109] Temmerman JC. Vitamin D and cardiovascular disease. J. Am. Coll. Nutr. 2011;30:16770. [110] Pittas AG, Dawson-Hughes B, Li T, et al. Vitamin D and calcium intake in relation to type 2 diabetes in women. Diabetes Care 2006;29:650-6. [111] Gannage-Yared MH, Chedid R, Khalife S, Azzi E, Zoghbi F, Halaby G. Vitamin D in relation to metabolic risk factors, insulin sensitivity and adiponectin in a young MiddleEastern population. Eur. J. Endocrinol. 2009;160:965-71. [112] Pilz S, Iodice S, Zittermann A, Grant WB, Gandini S. Vitamin D status and mortality risk in CKD: a meta-analysis of prospective studies. American Journal of Kidney DiseasesAm. J. Kidney Dis. 2011;58:374-82. [113] de Boer IH, Ioannou GN, Kestenbaum B, Brunzell JD, Weiss NS. 25-Hydroxyvitamin D levels and albuminuria in the Third National Health and Nutrition Examination Survey (NHANES III). Am. J. Kidney Dis. 2007;50:69-77. [114] Agarwal R, Acharya M, Tian J, et al. Antiproteinuric effect of oral paricalcitol in chronic kidney disease. Kidney Int. international 2005;68:2823-8. [115] Alborzi P, Patel NA, Peterson C, et al. Paricalcitol reduces albuminuria and inflammation in chronic kidney disease: a randomized double-blind pilot trial. Hypertension 2008;52:249-55. [116] Munger KL, Zhang SM, O'Reilly E, et al. Vitamin D intake and incidence of multiple sclerosis. Neurology 2004;62:60-5. [117] Munger KL, Levin LI, Hollis BW, Howard NS, Ascherio A. Serum 25-hydroxyvitamin D levels and risk of multiple sclerosis. JAMA 2006;296:2832-8. [118] VanAmerongen BM, Dijkstra CD, Lips P, Polman CH. Multiple sclerosis and vitamin D: an update. Eur. J. Clin. Nutr. 2004;58:1095-109.

1232

Sara S. Oberhelman and Tom D. Thacher

[119] Kimball SM, Ursell MR, O'Connor P, Vieth R. Safety of vitamin D3 in adults with multiple sclerosis. Am. J. Clin. Nutr. 2007;86:645-51. [120] Bertone-Johnson ER. Vitamin D and the occurrence of depression: causal association or circumstantial evidence? Nutr. Rev. 2009;67:481-92. [121] Jorde R, Sneve M, Figenschau Y, Svartberg J, Waterloo K. Effects of vitamin D supplementation on symptoms of depression in overweight and obese subjects: randomized double blind trial. Journal of Internal MedicineJ. Intern. Med. 2008;264:599-609. [122] Chen P, Hu P, Xie D, Qin Y, Wang F, Wang H. Meta-analysis of vitamin D, calcium and the prevention of breast cancer. Breast Cancer Res Treat 2010;121:469-77. [123] Garland CF, Gorham ED, Mohr SB, et al. Vitamin D and prevention of breast cancer: pooled analysis. J. Steroid Biochem. Mol. Biol. 2007;103:708-11. [124] World Health Organization International Agency for Research on Cancer. Vitamin D and Cancer. 2008. [125] Gissel T, Rejnmark L, Mosekilde L, Vestergaard P. Intake of vitamin D and risk of breast cancer--a meta-analysis. J. Steroid Biochem. Mol. Biol. 2008;111:195-9. [126] Grant WB. Relation between prediagnostic serum 25-hydroxyvitamin D level and incidence of breast, colorectal, and other cancers. Journal of photochemistry and photobiology B, Biology J. Photochem. Photobiol. B 2010;101:130-6. [127] Fedirko V, Bostick RM, Goodman M, Flanders WD, Gross MD. Blood 25hydroxyvitamin D3 concentrations and incident sporadic colorectal adenoma risk: a pooled case-control study. American journal of epidemiology Am. J. Epidemiol. 2010;172:489-500. [128] Gandini S, Boniol M, Haukka J, et al. Meta-analysis of observational studies of serum 25-hydroxyvitamin D levels and colorectal, breast and prostate cancer and colorectal adenoma. Int. J. Cancer 2011;128:1414-24. [129] Gorham ED, Garland CF, Garland FC, et al. Vitamin D and prevention of colorectal cancer. J. Steroid Biochem. Mol. Biol. Journal of Steroid Biochemistry and Molecular Biology 2005;97:179-94. [130] Gorham ED, Garland CF, Garland FC, et al. Optimal vitamin D status for colorectal cancer prevention: a quantitative meta analysis. Am. J. Prev. Med. 2007;32:210-6. [131] Lee JE, Li H, Chan AT, et al. Circulating levels of vitamin D and colon and rectal cancer: the Physicians' Health Study and a meta-analysis of prospective studies. Cancer Prev. Res. (Phila) 2011;4:735-43. [132] Ma Y, Zhang P, Wang F, Yang J, Liu Z, Qin H. Association between vitamin D and risk of colorectal cancer: a systematic review of prospective studies. Journal of clinical oncology : official journal of the American Society of Clinical OncologyJ. Clin. Oncol. 2011;29:3775-82. [133] Wei MY, Garland CF, Gorham ED, Mohr SB, Giovannucci E. Vitamin D and prevention of colorectal adenoma: a meta-analysis. Cancer Epidemiol. Biomarkers Prev. 2008;17:2958-69. [134] Yin L, Grandi N, Raum E, Haug U, Arndt V, Brenner H. Meta-analysis: Serum vitamin D and colorectal adenoma risk. Preventive medicine Prev. Med. 2011;53:10-6. [135] Yin L, Grandi N, Raum E, Haug U, Arndt V, Brenner H. Meta-analysis: longitudinal studies of serum vitamin D and colorectal cancer risk. Alimentary Pharmacology and Therapeutics Aliment. Pharmacol. Ther. 2009;30:113-25.

The History and Modern Controversies of Vitamin D …

1233

[136] Mayo Clinic. Vitamin D. 2012. (Accessed 2013, at http://www.mayoclinic.com/health/ vitamin-d/NS_patient-vitamind) [137] Dawson-Hughes B. What is the optimal dietary intake of vitamin D for reducing fracture risk? Calcif. Tissue Int. 2013;92:184-90. [138] Lee JH, O'Keefe JH, Bell D, Hensrud DD, Holick MF. Vitamin D deficiency an important, common, and easily treatable cardiovascular risk factor? J. Am. Coll. Cardiol. 2008;52:1949-56. [139] Heaney RP. Functional indices of vitamin D status and ramifications of vitamin D deficiency. American Journal of Clinical NutritionAm. J. Clin. Nutr. 2004;80:1706S-9S. [140] Heaney RP. What is vitamin D insufficiency? And does it matter? Calcif Tissue Int. 2013;92:177-83. [141] National Osteoporosis Society. Vitamin D and Bone Health: A Practical Clinical Guideline for Patient Management. United Kingdom; 2013. [142] National Osteoporosis Foundation. Bone Basics Alert; November 2010. [143] Dore R. Should healthy people take calcium and vitamin D to prevent fractures? What the US Preventive Service Task Force and others say. Cleveland Clinic Journal of MedicineCleve. Clin. J. Med. 2013;80:341-4. [144] Henry HL, Bouillon R, Norman AW, et al. 14th Vitamin D Workshop consensus on vitamin D nutritional guidelines. J. Steroid Biochem. Mol. Biol. 2010;121:4-6. [145] Sinha A, Cheetham TD, Pearce SH. Prevention and treatment of vitamin D deficiency. Calcif. Tissue Int. 2013;92:207-15. [146] Management of osteoporosis in postmenopausal women: 2010 position statement of The North American Menopause Society. Menopause 2010;17:25-54; quiz 5-6. [147] Institute of Medicine’s Food and Nutritional Board’s Standing Committee on the Scientific Evaluation of Dietary Reference Intakes. Dietary Reference Intakes for Caclium, Phosophorus, Magnesium, Vitamin D and Flouride. Washington DC: National Academy Press; 1997. [148] Institute of Medicine’s Committee to Review Dietary Reference Intakes for Vitamin D and Calcium. Dietary reference intakes for calcium and vitamin D. Washington DC:National Academies Press; 2011. [149] Pramyothin P, Holick MF. Vitamin D supplementation: guidelines and evidence for subclinical deficiency. Curr. Opin. Gastroenterol. 2012;28:139-50. [150] Moyer VA. Vitamin D and calcium supplementation to prevent fractures in adults: U.S. Preventive Services Task Force recommendation statement. Ann. Intern. Med. 2013;158:691-6. [151] Bischoff-Ferrari HA, Willett WC, Orav EJ, et al. A pooled analysis of vitamin D dose requirements for fracture prevention. N. Engl. J. Med. 2012;367:40-9. [152] American College of Obstetricians and Gynecologists. Vitamin D: Screening and Supplementation During Pregnancy. Committee Opinion Number 495; July 2011. [153] National Institute for Health and Clinical Excellence. Improving the nutrition of pregnant and breastfeeding mothers and children in low income households. London: Public health guidance; 2008. [154] World Health Organization. Vitamin D supplementation in pregnant women. Geneva: World Health Organization; 2012. [155] World Health Organization. Vitamin D supplementation in infants. September 23, 2012. (Accessed 2013, at http://www.who.int/elena/titles/vitamind_infants/en/index.html.)

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[156] Greer FR. Issues in establishing vitamin D recommendations for infants and children. Am. J. Clin. Nutr. 2004;80:1759S-62S. [157] Yetley EA. Assessing the vitamin D status of the US population. Am. J. Clin. Nutr. American Journal of Clinical Nutrition 2008;88:558S-64S. [158] US Department of Health. HealthyPeople 2010. 2000. [159] Taylor JA, Geyer LJ, Feldman KW. Use of supplemental vitamin d among infants breastfed for prolonged periods. Pediatrics 2010;125:105-11. [160] Perrine CG, Sharma AJ, Jefferds ME, Serdula MK, Scanlon KS. Adherence to vitamin D recommendations among US infants. Pediatrics 2010;125:627-32. [161] Pepper KJ, Judd SE, Nanes MS, Tangpricha V. Evaluation of vitamin D repletion regimens to correct vitamin D status in adults. Endocrine practice : official journal of the American College of Endocrinology and the American Association of Clinical EndocrinologistsEndocr. Pract. 2009;15:95-103. [162] Cholecalfierol. 2013. (Online search accessed 2013 at http://www.micromedex solutions.com/micromedex2/librarian/ND_T/evidencexpert/ND_PR/evidencexpert/CS/ E6DCB8/ND_AppProduct/evidencexpert/DUPLICATIONSHIELDSYNC/FE6461/ND _PG/evidencexpert/ND_B/evidencexpert/ND_P/evidencexpert/PFActionId/evidencexp ert.DisplayDrugpointDocument?docId=922242&contentSetId=100&title=Cholecalcifer ol&servicesTitle=Cholecalciferol&topicId=dosingAndIndicationsSection&subtopicId= adultDosingSection.) [163] Raiten DJ, Picciano MF. Vitamin D and health in the 21st century: bone and beyond. Executive summary. Am. J. Clin. Nutr. American Journal of Clinical Nutrition 2004;80:1673S-7S. [164] Ross AC, Manson JE, Abrams SA, et al. The 2011 Dietary Reference Intakes for Calcium and Vitamin D: what dietetics practitioners need to know. J. Am. Diet. Assoc. 2011;111:524-7.

INDEX A absorption spectra, 657, 660, 661, 666, 672 absorption spectroscopy, 641, 658, 660, 661, 676, 678, 679, 959 abstraction, 487, 545, 552, 577 access, 68, 73, 86, 328, 333, 614, 620, 800, 834, 985, 1031, 1063, 1080 acetic acid, 8, 102, 103, 119, 124, 126, 128, 130, 132, 133, 252, 286, 413, 415, 547, 551, 559, 564, 725, 726, 728, 729, 730, 867 acetone, 119, 249, 559 acetonitrile, 5, 9, 11, 101, 103, 104, 111, 117, 120, 123, 124, 125, 127, 128, 129, 130, 132, 133, 135, 550, 560, 727, 728, 730, 731 acetylation, 20, 1108, 1109, 1115, 1176 acetylcholinesterase, 285, 514 acetylcholinesterase inhibitor, 514 acidic, xxvii, 119, 545, 553, 556, 639, 678, 694, 724, 847 acidity, 546, 764, 769 ACL, 932 ACL injury, 932 acne, 653, 745 acquired immunity, 801 acrosome, 1181 activation complex, 79 active compound, 928, 1015 active transport, 296, 444, 498, 699, 814, 815, 916 acupuncture, 486, 576 acute lymphoblastic leukemia, 279, 280, 1022 acute myelogenous leukemia, 35, 1025 acute promyelocytic leukemia, 31, 32, 34, 35, 36, 37, 38, 39, 40, 41, 1048 adaptation, xx, 83, 195, 223, 224, 471, 481, 482, 628, 805, 857, 870 adaptive immune responses, 502 adaptive immunity, 605, 802, 803, 1182

additives, 438, 562, 567, 640, 670, 1012, 1024 adenine, 99, 101, 102, 422, 423, 854, 864, 932 adenocarcinoma, 32, 153, 160, 161, 166, 195, 198, 225, 238, 894, 1023 adenoma, 76, 84, 1128, 1232 adenomatous polyposis coli, 197 adenosine, 372, 853, 1058 adenosine triphosphate, 1058 adhesion, xiii, 61, 74, 78, 79, 90, 210, 342, 461, 685, 802, 807, 813, 1042, 1101, 1148, 1179 adipose, 200, 329, 593, 611, 612, 621, 708, 802, 809, 1023, 1060, 1133, 1139, 1214, 1217 adjunctive therapy, 261, 345, 348, 368 adjustment, xx, 67, 74, 460, 462, 463, 464, 504, 510, 875, 924, 997, 1128, 1146 adolescents, xvi, xxxv, 44, 50, 55, 58, 265, 269, 272, 274, 275, 276, 277, 297, 318, 320, 331, 343, 355, 365, 500, 537, 538, 539, 540, 569, 627, 709, 717, 721, 858, 905, 910, 1077, 1133, 1134, 1141, 1142, 1143, 1159, 1162, 1164, 1174, 1184, 1189, 1215, 1216, 1221, 1223, 1224, 1228 adrenal gland, 411, 477, 746, 753, 832, 833, 834, 835, 836, 838, 841, 842, 843, 844, 845, 846, 1060 adrenaline, 833, 841 adrenocorticotropic hormone, 833 adsorption, xxxiv, 119, 667, 669, 671, 1163 adulthood, xxii, 55, 300, 349, 511, 569, 1177, 1181, 1187 adverse conditions, 848 adverse effects, xx, xxviii, 273, 278, 429, 451, 452, 455, 490, 491, 515, 535, 579, 582, 591, 618, 696, 701, 723, 758, 881, 888, 900, 909, 913, 986, 1038, 1062 adverse event, 220, 490, 491, 492, 577, 579, 582, 583, 888, 1220 aerodigestive tract, 70, 71, 85, 205, 279, 1026, 1045 aetiology, xxii, 529, 530, 531, 532, 534, 1226 affective disorder, 51, 58, 362, 370, 895 aflatoxin, 744, 750

1236 aging population, 182, 970, 976 aging process, 703, 740, 749, 797, 812, 902 aging society, 978 agonist, 253, 413, 810, 841 AIDS, 141, 820, 918, 1015, 1172 air temperature, 906 albumin, xiv, 214, 218, 223, 228, 231, 399, 427, 641, 663, 664, 669, 671, 675, 676, 916, 959, 962, 966, 1166, 1167, 1169, 1170 albuminuria, 462, 1183, 1189, 1231 alcohol abuse, 423, 424, 428, 431 alcohol consumption, 82, 233, 422, 427, 429, 430, 710, 803, 1028 alcohol dependence, 430 alcoholic liver disease, 422, 423, 424, 425, 426, 427, 428, 429, 430 alcoholics, xix, 228, 260, 286, 304, 379, 421, 422, 423, 424, 425, 427, 428, 430 alcoholism, xiv, 50, 53, 57, 59, 214, 252, 259, 284, 304, 364, 422, 428, 430, 1031 alcohols, 545 aldehydes, 545, 547, 705 aldosterone, 461, 465, 1146 alertness, 508, 645, 746 alfalfa, 655 algae, 443, 615 algorithm, 822 alkaline, xxvii, 4, 94, 98, 116, 129, 330, 336, 440, 444, 445, 448, 449, 450, 532, 533, 545, 546, 554, 556, 557, 562, 566, 567, 605, 698, 706, 786, 847, 1166 alkaline hydrolysis, 94, 556, 567 alkaline phosphatase, 330, 336, 440, 444, 445, 448, 450, 532, 533, 605, 786, 1166 alkalinity, 698, 756 alkaloids, vii, xxiv, 635, 638, 639, 642, 644, 648, 650, 657, 659, 660, 662, 669, 670, 682, 683, 687, 688, 689, 718 allele, 63, 506, 507, 1026, 1084, 1085, 1086, 1093, 1103, 1105, 1106, 1111, 1120 allergens, 1181 allergic inflammation, 801 allergic reaction, 748, 1028 allergic rhinitis, 749, 752, 936, 1180 allergy, 647, 745, 749, 753, 926, 1075, 1180, 1187, 1202 allylamine, 736 almonds, xxii, 351, 466, 543 alpha-tocopherol, xiii, 151, 152, 154, 155, 156, 157, 158, 159, 160, 161, 162, 166, 168, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 194, 195, 196, 202, 203, 204, 205, 207, 208, 210, 356, 366, 468, 599, 603, 623, 624, 625, 629, 632,

Index 714, 753, 889, 896, 907, 908, 1000, 1001, 1025, 1026, 1042, 1044, 1045, 1046, 1047, 1048, 1049, 1050, 1052, 1053, 1069, 1070, 1071, 1073, 1074, 1077 alternative, vi, vii, xvii, xxi, xxiii, 33, 231, 266, 341, 428, 485, 486, 488, 489, 491, 492, 493, 575, 576, 578, 580, 581, 582, 584, 616, 622, 638, 647, 724, 731, 746, 747, 753, 761, 766, 818, 857, 871, 895, 938, 958, 1045, 1096, 1201 alternative hypothesis, 266 alternative medicine, xxi, xxiii, 485, 486, 488, 493, 575, 576, 580, 584, 746, 818, 895 alternative therapy, 486, 492, 576, 582, 747 alters, xxi, 59, 196, 208, 217, 253, 260, 287, 306, 321, 373, 374, 392, 472, 476, 477, 1106 alveolar macrophage, 1049, 1088 amalgam, 733, 734 American Heart Association, 457, 469, 1149 American Psychiatric Association, 520 amine, 111, 260, 305, 640, 679 amines, 287, 630, 640, 727, 737, 833, 845, 846 amino acids, xiv, xv, xix, 100, 214, 221, 222, 226, 227, 228, 231, 232, 233, 256, 262, 302, 303, 421, 464, 466, 552, 554, 598, 626, 641, 675, 680, 1006, 1066, 1103 ammonium, 100, 102, 104, 123, 126, 127, 128, 129, 133, 135, 680, 728, 730, 731, 742 amnesia, 95, 303, 304 amylase, 97, 99, 110, 111, 120, 121, 122, 124, 130, 131, 132, 133, 143, 145 amyotrophic lateral sclerosis, 902, 998, 1001 anabolism, xxxii, 223, 1099 anaerobic bacteria, 333 analgesic, 592, 639, 644, 647 androgen, 77, 161, 162, 163, 164, 389, 393, 921, 944, 1113 anemia, xviii, xxvii, 22, 185, 255, 293, 313, 377, 379, 380, 381, 382, 383, 444, 490, 579, 641, 652, 653, 655, 746, 847, 855, 882, 900, 966, 970, 1028, 1031, 1044, 1049, 1062, 1074 anesthesiologist, 592 angiogenesis, xiii, xx, 61, 74, 77, 79, 88, 91, 188, 191, 210, 237, 471, 472, 481, 673, 743, 810, 811, 825, 1101, 1110, 1176, 1179, 1218 angiogram, 1035 angiography, 1129, 1231 angiotensin converting enzyme, 460, 1063 angiotensin II, 402, 461, 465, 808 ankles, 1166 ankylosing spondylitis, 1083, 1087, 1091 annihilation, 552 anorexia, 232, 289, 651, 653, 654, 778, 782, 783, 785, 790, 984

Index anterior cruciate, 686, 935, 938, 944, 945 anterograde amnesia, xvi, 283, 285, 286, 296 antibody, 185, 379, 598, 647, 671, 688, 748, 751, 803, 875, 1091, 1132, 1177 anti-cancer, xiii, xvi, 19, 152, 155, 156, 157, 265, 270, 645, 1129, 1186 antidepressant, xvii, 261, 307, 341, 342, 344, 345, 346, 347, 348, 349, 350, 351, 352, 353, 354, 357, 359, 360, 361, 362, 363, 365, 366, 367, 368, 370, 371, 372, 373, 374, 375, 376, 890 antidepressants, 342, 343, 345, 348, 350, 351, 360, 363, 370, 371, 372, 373, 886 antiepileptic drugs, xxii, 500, 529, 530, 531, 534, 537, 538 antigen, 570, 824, 1081, 1082, 1089, 1092, 1096 anti-inflammatory drugs, 750, 827 antioxidative activity, 647, 936 antitumor, 77, 79, 88, 185, 209, 494, 559, 584, 647, 688, 893 anxiety, xii, 43, 44, 47, 49, 50, 51, 58, 252, 288, 352, 353, 355, 362, 363, 364, 367, 370, 373, 374, 375, 506, 651, 886, 892 anxiety disorder, 43, 47, 49, 50, 51, 58, 367, 892 apathy, 288, 506, 998 apnea, 648 apoptogenic activity, 162 apoptosis, xii, xiv, xxxii, 18, 19, 22, 23, 25, 27, 28, 31, 32, 35, 36, 37, 39, 40, 41, 61, 74, 75, 76, 78, 86, 152, 158, 159, 160, 161, 162, 163, 165, 183, 184, 185, 186, 189, 190, 191, 192, 195, 196, 197, 198, 199, 200, 208, 209, 210, 211, 212, 214, 217, 220, 221, 232, 235, 321, 349, 386, 403, 442, 460, 465, 478, 702, 706, 715, 808, 821, 826, 828, 848, 890, 895, 904, 922, 1021, 1023, 1025, 1027, 1035, 1040, 1041, 1047, 1099, 1101, 1108, 1109, 1128, 1165, 1176, 1218 apoptotic mechanisms, 1179 apoptotic pathways, 158 appetite, 353, 439, 441, 491, 579, 651, 710 apples, 725, 726, 761, 766, 769, 920, 938, 1070 Arabidopsis thaliana, 618, 628 arabinoside, 34 arginine, 241, 242, 243, 244, 245, 246, 247, 248, 588, 590, 593, 677, 805, 1061 arrest, 22, 25, 26, 32, 33, 36, 37, 40, 75, 76, 160, 163, 165, 167, 183, 197, 198, 200, 208, 223, 1025, 1108 arrow of time, 1226 arsenic, 745, 748 Artemesia longinaris, xix, 433, 434, 437, 438, 445, 447, 449 arterial hypertension, 1179 arteriosclerosis, 343, 648, 716

1237 artery, 463, 646, 687, 742, 1047, 1214 arthritis, 740, 751, 805, 882, 890, 900, 1082, 1083, 1084, 1086, 1087, 1092, 1094, 1095, 1097, 1164 asbestos, 454, 455 asparagus, 651, 653, 655, 800 aspartate, 342, 357, 427, 1066 assessment, xx, xxxiii, 59, 146, 305, 382, 422, 435, 459, 465, 468, 490, 504, 505, 512, 524, 536, 578, 595, 718, 719, 749, 874, 957, 959, 1026, 1033, 1072, 1117, 1120, 1127, 1129, 1130, 1132, 1137, 1140, 1146, 1194, 1197, 1222, 1224 assessment tools, xxxiii, 1117, 1120 asthma, xxviii, xxxii, 639, 702, 743, 753, 754, 881, 885, 889, 892, 893, 896, 897, 898, 902, 1028, 1040, 1053, 1055, 1077, 1082, 1093, 1180, 1181, 1187, 1218 asthmatic children, 1065, 1077 asymptomatic, 308, 310, 506, 512, 513, 1028, 1031, 1143 ataxia, 114, 144, 253, 258, 286, 289, 290, 305, 310, 381, 984, 1028, 1029, 1031, 1034, 1041, 1043, 1048, 1050, 1051, 1053, 1061, 1062, 1073 atherogenesis, xxviii, 452, 899 atherosclerosis, xix, xxvi, xxix, 234, 401, 451, 452, 456, 457, 468, 473, 526, 653, 703, 742, 750, 753, 799, 801, 802, 805, 807, 808, 809, 812, 818, 819, 822, 826, 827, 849, 902, 906, 911, 915, 922, 923, 935, 970, 1063, 1094 atherosclerotic plaque, 709, 808 athletes, 703, 748, 928, 929, 930, 935, 946, 1200 atmosphere, 270, 871, 1011, 1046 atomic force, 555, 857 atoms, 217, 676, 759 atopic dermatitis, 1067, 1078, 1180 at-risk populations, 526 atrophy, xviii, xxxvi, 253, 254, 255, 258, 286, 290, 291, 297, 299, 308, 309, 310, 312, 322, 377, 381, 383, 500, 506, 511, 512, 786, 933, 937, 988, 1191, 1192, 1201 Attention Deficit/Hyperactivity Disorder (ADHD), 525 auditory evoked potentials, 316 autoimmune disease, xxii, xxxv, 47, 48, 49, 275, 379, 518, 569, 570, 572, 811, 1082, 1083, 1087, 1088, 1090, 1093, 1095, 1096, 1173, 1174, 1186, 1201, 1203, 1218 autoimmunity, 707, 825, 1083, 1088, 1090, 1092, 1096, 1144 automation, 4 autosomal dominant, 506, 998 autosomal recessive, 294, 317, 1029, 1061 avoidance, xv, 265, 269, 273, 285, 286, 288, 303, 1174, 1216

1238

Index

awareness, 272, 1005, 1012 axonal degeneration, 381

B B12 and C., 93 B2, v, vii, xiii, xiv, 93, 97, 98, 99, 100, 122, 135, 147, 214, 226, 227, 230, 231, 298, 346, 349, 369, 422, 543, 565, 566, 598, 636, 651, 656, 675, 676, 677, 692, 734, 758 B3, v, xiii, 93, 97, 101, 122, 135, 423, 598, 651, 656 B6, v, xiii, xiv, xv, xvi, 93, 95, 97, 102, 103, 104, 106, 122, 123, 134, 135, 143, 144, 147, 153, 214, 222, 226, 227, 230, 231, 251, 253, 255, 256, 257, 258, 259, 262, 283, 284, 287, 292, 293, 294, 295, 298, 299, 300, 301, 311, 312, 313, 316, 317, 322, 323,346, 348, 349, 357, 367, 368, 369, 423, 429, 431, 489, 490, 559, 566, 578, 581, 597, 598, 636, 638, 640, 652, 656, 678, 684, 692, 758, 797, 891, 937, 942, 1061 B9, v, xiii, xvi, 93, 95, 104, 105, 106, 107, 108, 109, 112, 122, 134, 135, 147, 251, 253, 257, 283, 284, 287, 295, 298, 299, 300, 424, 636, 653, 656, 679, 680 babesiosis, 687 baby boomers, 978 back pain, 335 bacteremia, 593 bacteria, xvii, xxv, 23, 241, 333, 340, 377, 378, 599, 605, 615, 639, 755, 756, 757, 804, 816, 818, 887, 890, 1195 bacterial infection, 23, 37, 118, 379, 1128, 1180 bacteriostatic, 818, 823 bariatric surgery, xvii, xxiii, 325, 326, 327, 328, 329, 330, 331, 332, 333, 334, 335, 336, 337, 338, 339, 340, 387, 391, 587, 589, 590, 592, 593, 958, 962, 965, 966, 967, 1221 barriers, 99, 273, 802, 824, 989 basal cell carcinoma, 73, 266, 281 basal ganglia, 256, 284, 294 basal lamina, 188, 445 base, xxvii, 215, 223, 234, 442, 546, 640, 688, 704, 742, 847, 926, 950, 1109 base catalysis, 546 basement membrane, 216, 808 baths, 1211 bedding, 1212, 1213 beef, 621, 627, 628, 630, 973, 976, 1045, 1051, 1216 beer, 97, 100, 147, 353, 1213 behaviors, xv, xix, 265, 267, 268, 272, 273, 275, 409, 410, 413, 659 bending, xxxv, 1173, 1178

benign, 78, 170, 171, 178, 200, 201, 590, 1110, 1112, 1113, 1128 benign prostatic hyperplasia, 1112 benzo(a)pyrene, 1027, 1040 benzodiazepine, 410 beriberi, 252, 284, 651, 1210, 1212 berylliosis, 1221 beta-carotene, 202, 203, 204, 207, 425, 452, 464, 465, 466, 600, 608, 629, 744, 854, 858, 878, 907, 921, 923, 924, 925, 937, 946, 981, 1007, 1008, 1009, 1011, 1012, 1013, 1015, 1016, 1037, 1050, 1075, 1077 beverages, xiv, 104, 118, 132, 141, 147, 214, 225, 226, 563, 645, 694, 698, 708, 726, 729, 732, 734, 735, 736, 952, 971 bias, 65, 80, 168, 492, 493, 583, 602, 703, 975, 1132, 1137 bicarbonate, 698 bilateral, 318, 381, 508, 894, 1211 bile, 219, 327, 328, 329, 333, 378, 612, 646, 924, 1022, 1043, 1058, 1062, 1071, 1214, 1217 bile acids, 328, 333, 924 bile duct, 646, 1214 biliary cirrhosis, 1060 bilirubin, 552, 567, 749, 916 bioavailability, xxxii, 107, 115, 137, 139, 141, 149, 157, 468, 629, 631, 696, 698, 700, 773, 786, 792, 793, 801, 815, 816, 822, 878, 906, 981, 982, 990, 991, 1004, 1007, 1008, 1009, 1013, 1014, 1015, 1016, 1018, 1035, 1037, 1047, 1049, 1060, 1072, 1133, 1202 biocatalytic process, 640 biochemical processes, 723 biochemistry, 157, 516, 682, 1202, 1203, 1204 bioconversion, 965, 981, 1008, 1010, 1016 biofortified food, 609, 614, 620 biological activities, 639, 642, 796, 882, 1045, 1057 biological activity, xxxi, 2, 94, 108, 398, 399, 436, 441, 618, 640, 642, 1006, 1017, 1046, 1057 biological processes, xxv, xxxii, 386, 507, 673, 723, 1087, 1099, 1101 biological roles, xxxi, xxxii, 705, 995, 1055, 1057 biological samples, 94, 108, 116, 143, 468, 688, 732 biological systems, 205, 699, 703, 1049 biomarkers, xx, 278, 309, 449, 460, 462, 464, 491, 522, 523, 524, 525, 582, 705, 715, 721, 744, 806, 810, 819, 909, 919, 921, 938, 946, 1016, 1106, 1109, 1124, 1142, 1162, 1195, 1202 biomolecules, 94, 640, 695, 903 biopsy, 227, 337, 381, 611, 1065, 1066, 1077 biosynthesis, xiv, xix, xxviii, xxix, 2, 28, 214, 215, 221, 223, 232, 346, 391, 409, 411, 412, 413, 415, 416, 417, 418, 419, 443, 446, 478, 615, 616, 617,

Index 623, 624, 625, 626, 629, 631, 695, 745, 747, 795, 803, 826, 864, 882, 895, 899, 900, 915, 931, 1018, 1041, 1050, 1118, 1136, 1147, 1227 biotechnology, 614, 618, 682 biotin, 259, 301, 636, 640, 652, 656, 775 bipolar disorder, 51, 57, 58, 114, 145, 353, 501 birth weight, 540, 1031, 1046, 1060, 1067, 1182 bladder cancer, 67, 68, 74, 83, 200, 203, 270, 884, 946 bleeding, xxviii, 119, 426, 596, 599, 601, 614, 653, 655, 740, 800, 861, 875, 876, 882, 1062, 1170 blindness, xxxi, 86, 425, 428, 654, 744, 986, 988, 991, 1003, 1004, 1005, 1061 blood circulation, 398 blood clot, 443, 597, 599, 655, 750 blood flow, 512, 589, 808, 827, 854 blood plasma, xxiv, 205, 603, 609, 641, 716, 759, 846, 884, 939, 1035 blood pressure, 380, 402, 456, 467, 510, 644, 645, 647, 648, 696, 701, 833, 891, 893, 895, 910, 1129, 1147, 1149, 1154, 1157, 1158, 1160, 1161, 1183, 1189, 1218, 1230 blood pressure reduction, 1157 blood stream, 188, 216, 674, 1022 blood supply, 802 blood vessels, xxv, xxvii, 77, 119, 739, 740, 806, 861, 1158 blood-brain barrier, 410, 519 bloodstream, 188, 410, 1058, 1063, 1100, 1217 body composition, 231, 280, 430, 531, 534, 538, 1193, 1202 body fat, 269, 452, 457, 709, 1133, 1194 body mass index, xiii, xvii, xx, 151, 266, 271, 325, 326, 328, 337, 338, 460, 462, 463, 464, 874, 958, 971, 972, 1133, 1165, 1168 body weight, xxvi, xxx, 185, 186, 228, 427, 462, 590, 713, 771, 775, 776, 777, 778, 779, 781, 782, 783, 787, 836, 841, 845, 852, 927, 979, 1005 bonding, 559, 564, 662, 670, 672, 675, 680, 681 bone cells, 1080, 1097 bone form, 329, 428, 570, 597, 604, 655, 873, 1165, 1166, 1208 bone growth, 46, 654, 748, 1164 bone marrow, 19, 24, 105, 337, 340, 381, 594, 708, 713, 848, 851, 1025, 1088 bone marrow aspiration, 381 bone marrow transplant, 594 bone mass, 269, 279, 280, 332, 538, 1164, 1177, 1178, 1186 bone mineral content, 535, 539 bone resorption, 46, 47, 535, 570, 597, 604, 606, 1164, 1165, 1166, 1172

1239 bones, xxvii, xxxv, 119, 329, 500, 654, 700, 740, 861, 882, 984, 988, 1164, 1178, 1192, 1194, 1210 boric acid, 732, 889 bowel, xvii, 295, 340, 377, 379, 490, 518, 579, 1031, 1086 bradyarrhythmia, 644 brain abnormalities, 53 brain damage, 96, 114, 141, 295, 309, 1016 brain functions, xix, 409, 415, 812 Brazil, 213, 225, 341, 353, 435, 500, 592, 609, 693, 710, 712, 713, 755, 765, 769, 770, 874, 905, 920, 979, 986, 1077, 1086, 1228 breakdown, 220, 221, 222, 223, 224, 379, 425, 442, 546, 600, 652, 875, 939, 1007, 1198 breast carcinoma, 32 breast feeding, 1182 breast milk, xxxv, 1031, 1067, 1164 breastfeeding, xxx, 747, 979, 1188, 1221, 1222, 1225, 1233 breeding, 3, 614, 618, 626, 645, 1013 bronchial asthma, 648, 743, 893, 906 bronchial hyperresponsiveness, 1077 bronchoconstriction, 885, 898 bronchodilator, 648 Burkina Faso, xxix, 949, 950, 953, 954, 955, 956 B-vitamin supplementation in esophageal cancer, 214 by-products, 15

C C reactive protein, 589, 591 Ca2+, 27, 374, 403, 418, 448, 473, 480, 483, 560, 675, 1100, 1101 cabbage, xxviii, xxx, 107, 110, 653, 654, 655, 699, 740, 763, 800, 861, 862, 973, 976, 979, 985 cacao, 648 cachexia, 465 cadaver, 1215 cadmium, 891 caesarean section, 1182 caffeine, 558, 561, 567, 636, 645, 649, 662, 663, 686, 689 calcification, 655, 888, 984, 1129, 1146, 1148, 1211 calcitriol, xxxiv, xxxvi, 45, 88, 271, 386, 388, 392, 396, 403, 570, 571, 823, 1080, 1090, 1096, 1100, 1101, 1105, 1107, 1108, 1109, 1110, 1118, 1121, 1146, 1163, 1191, 1192, 1217 calcium carbonate, 337, 514 calcium channel blocker, xxi, 472, 473, 476, 478, 479, 648 calculus, 701, 876 calibration, 1140

1240 caloric intake, 958 caloric restriction, 206 calorie, 590, 592, 593, 958, 966 calorimetric measurements, 668 calorimetric method, 665 calorimetry, 638, 641 cancer cells, xiii, 2, 22, 32, 47, 64, 75, 77, 78, 87, 88, 152, 158, 159, 161, 162, 163, 165, 166, 183, 184, 186, 187, 188, 189, 190, 209, 211, 215, 216, 220, 221, 223, 236, 687, 702, 811, 817, 820, 893, 901, 921, 936, 1021, 1023, 1026, 1041, 1107, 1109, 1176 cancer therapy, 19, 91, 193, 208, 479, 483, 811, 896, 943, 1023, 1114 cancerous cells, 1025 candidates, 590, 818, 965, 967 capillary, 5, 12, 14, 97, 100, 115, 641, 686, 732, 734, 735, 737, 802 capsule, 514 carbamazepine, 535, 538, 539 carbohydrate, 235, 353, 375, 435, 947, 1209 carbon, xxvii, xxix, 13, 15, 105, 124, 138, 146, 155, 156, 157, 183, 184, 206, 253, 287, 346, 367, 549, 554, 610, 639, 641, 664, 667, 676, 681, 686, 688, 690, 692, 694, 717, 733, 736, 786, 800, 847, 848, 849, 915, 1228 carbon dioxide, xxvii, 13, 15, 138, 549, 641, 847, 848 carbon monoxide, 717 carbon nanotubes, 736 carbon tetrachloride, 206 carcinogen, 200, 706, 1025, 1216 carcinogenesis, xiii, xxviii, xxxii, 76, 89, 151, 154, 158, 163, 164, 166, 167, 181, 183, 188, 189, 190, 192, 198, 200, 206, 215, 216, 225, 234, 235, 701, 722, 810, 884, 899, 940, 1024, 1027, 1040, 1099, 1102, 1103 cardiac arrhythmia, 646 cardiovascular diseases, xix, 105, 451, 460, 466, 701, 708, 713, 722, 742, 750, 883, 919, 935, 944, 978, 1145, 1149, 1179, 1231 cardiovascular morbidity, 1129 cardiovascular risk, xxxiv, 363, 701, 712, 716, 744, 920, 937, 1064, 1076, 1129, 1138, 1141, 1145, 1146, 1150, 1179, 1230, 1233 cardiovascular system, 655, 1139 cartilage, xxv, xxvii, 739, 740, 750, 861, 882, 1183, 1189, 1212 case study, xx, 452, 459, 768, 1014 catabolism, xxxii, xxxv, 45, 196, 221, 435, 499, 924, 1022, 1080, 1099, 1101, 1102, 1164, 1165, 1218 cataract, xxviii, 64, 702, 744, 848, 881, 886, 890, 893, 894, 896, 924, 934, 941

Index catecholamines, 709, 803, 864 catfish, 140, 621, 623, 773, 784, 785, 786, 791, 793, 794, 795, 796, 798, 1052 Catharanthus roseus, 648 cation, 351, 567, 730, 858 cattle, 621, 624, 629, 1051 Caucasian population, 82, 1106 Caucasians, 49, 1085, 1104, 1113 causal relationship, 106, 571, 1146 causality, xiii, 62, 64, 80, 91, 297, 402, 1128, 1133, 1139, 1153 causation, 65, 91, 401, 1121 cell culture, 188, 270, 404, 559, 818, 904, 1024, 1082, 1195 cell cycle, xii, xiii, 17, 18, 19, 24, 25, 26, 30, 32, 36, 37, 40, 61, 74, 75, 76, 78, 151, 154, 160, 163, 164, 165, 166, 167, 183, 184, 189, 190, 191, 197, 198, 199, 208, 220, 221, 232, 403 cell death, xiii, xx, 18, 22, 37, 87, 151, 154, 158, 163, 184, 190, 191, 198, 208, 217, 220, 284, 471, 478, 741, 808, 817, 851, 903, 1023, 1045, 1049, 1108 cell differentiation, 19, 21, 23, 25, 26, 27, 28, 29, 31, 34, 35, 37, 39, 40, 41, 46, 217, 271, 400, 570, 904, 1081, 1086, 1090, 1101, 1115, 1158 cell membranes, xxxi, 452, 599, 610, 619, 855, 858, 933, 1007, 1017, 1021, 1028, 1061 cell metabolism, 475, 743, 1071 cell oxidation -reduction homeostasis, 214 cell signaling, 217, 220, 475, 479, 522, 610, 903, 1028 cell surface, 18, 26, 188, 850 cellular signaling pathway, 216, 472, 474 cellulose, 774, 775, 776, 787 central nervous system, 46, 49, 253, 287, 307, 317, 318, 343, 345, 346, 349, 370, 410, 418, 477, 501, 530, 536, 569, 644, 645, 648, 653, 903, 984, 1028, 1030, 1058 ceramide, 192, 212 cerebellum, 252, 285, 305, 353, 418, 1039 cerebral blood flow, 512, 526 cerebral cortex, 349, 353 cerebrospinal fluid, 253, 260, 261, 305, 307, 310, 318, 525, 819, 887, 892, 984, 988 cerebrovascular disease, 308, 509, 510, 511, 526, 918 challenges, xiii, xxxi, 93, 94, 99, 100, 101, 746, 1003, 1004, 1009 cheese, xxii, xxxvi, 543, 632, 985, 1174, 1176 chemical, xxiv, xxix, 2, 16, 76, 94, 115, 136, 228, 248, 343, 353, 396, 519, 567, 635, 639, 640, 652, 687, 693, 704, 741, 744, 749, 756, 757, 762, 765,

Index 766, 768, 769, 770, 800, 846, 878, 879, 915, 916, 956, 1020, 1069, 1211, 1215 chemicals, 19, 554, 638, 640, 745, 757, 834 chemiluminescence, 100, 108, 115, 228, 685 chemokine receptor, 806 chemokines, 186, 235, 806, 811 chemometrics, 691 chemoprevention, 87, 206, 718, 898, 911, 1027, 1049 chemopreventive agents, 1025 chemotherapy, 78, 184, 185, 186, 208, 221, 234, 236, 237, 271, 272, 280, 319, 489, 490, 491, 493, 494, 495, 577, 578, 579, 581, 582, 584, 585, 741, 743, 1021, 1022, 1024, 1025, 1026, 1027, 1038, 1040, 1042, 1043, 1049, 1051, 1052, 1104 chicken, 110, 147, 621, 627, 628, 766, 767, 856, 973, 977, 985 child mortality, 991, 1187 childhood cancer, xv, 265, 271, 272, 273, 280, 281 chimera, 41 Chinese medicine, 486, 576, 646, 762 cholecalciferol, xxxiv, 45, 268, 336, 343, 386, 396, 397, 398, 426, 439, 498, 570, 637, 654, 656, 1079, 1090, 1097, 1100, 1102, 1130, 1133, 1159, 1163, 1189, 1192, 1214, 1217, 1219, 1227, 1234 cholestasis, 425, 530, 1074 cholesterol, xiv, xxiv, 2, 12, 28, 45, 48, 152, 171, 192, 214, 228, 231, 343, 344, 410, 412, 418, 467, 468, 598, 611, 629, 652, 653, 693, 741, 750, 752, 797, 874, 907, 920, 924, 959, 960, 965, 966, 1031, 1034, 1047, 1063, 1071, 1130, 1136, 1158, 1179, 1192, 1218, 1227, 1230 choline, 257, 259, 295, 301, 605, 741, 775, 1072 chromatography, 4, 12, 94, 98, 111, 117, 139, 140, 143, 641, 724, 729, 730, 731, 734, 736, 1041, 1066, 1131, 1132, 1214, 1218 chromium, 353, 354, 361, 375, 919 chromosome, 75, 317, 507, 715, 744, 750, 890, 1061, 1073, 1101, 1102, 1113 chronic diseases, xi, xxvi, 1, 47, 94, 105, 114, 343, 351, 452, 468, 530, 614, 696, 708, 749, 799, 801, 802, 806, 901, 907, 908, 913, 920, 921, 975, 1031, 1193 chronic kidney disease, 401, 742, 751, 856, 1171, 1218, 1221, 1231 chronic lymphocytic leukemia, 71, 85, 278, 279 chronic obstructive pulmonary disease, 646, 805, 902 chronic renal failure, 461, 742, 754, 937, 938, 939, 940, 943, 944, 946, 947 cigarette smoke, 167, 219, 718, 743, 939, 1049 circadian rhythm, 74, 263, 452

1241 circulation, xxvii, 378, 398, 399, 644, 801, 802, 847, 848, 849, 1022, 1024, 1034, 1058, 1130, 1152, 1192 cirrhosis, 422, 427, 429, 1065, 1165 classes, xx, xxxii, 22, 35, 379, 459, 461, 663, 664, 671, 1055, 1056 classification, 73, 231, 531, 532, 538, 540, 603, 955, 1172 cleavage, 35, 159, 160, 162, 410, 418, 544, 556, 567, 811, 849, 1007 cleavages, 162 climate, 44, 750, 1007, 1008, 1057, 1209, 1228 clinical application, xxviii, 602, 715, 881, 1138, 1139, 1201 clinical symptoms, xxviii, 337, 461, 509, 881, 900, 904, 986, 1031 clinical trial(s), xvi, xxiii, xxxi, xxxii, xxxiii, 19, 51, 56, 86, 181, 192, 265, 270, 297, 335, 346, 348, 365, 366, 371, 430, 453, 455, 495, 514, 515, 522, 585, 586, 590, 595, 596, 599, 600, 602, 606, 607, 696, 702, 703, 751, 754, 809, 814, 818, 822, 827, 854, 885, 890, 892, 917, 921, 922, 924, 925, 933, 934, 995, 996, 997, 998, 999, 1000, 1001, 1034, 1055, 1061, 1066, 1068, 1077, 1084, 1117, 1120, 1121, 1139, 1183, 1185, 1186, 1188 clothing, 44, 267, 268, 500, 1133, 1152, 1211 clusters, 802 coagulopathy, 426 coal, 1211 cobalamin, xv, xvi, xvii, 105, 113, 114, 116, 133, 135, 137, 138, 144, 227, 239, 240, 241, 242, 251, 257, 260, 263, 283, 284, 295, 296, 297, 306, 309, 314, 317, 318, 320, 322, 323, 377, 378, 381, 382, 383, 384, 424, 425, 428 cobalt, xv, 113, 186, 239, 241, 483 coenzyme, 28, 95, 96, 101, 241, 252, 284, 346, 381, 423, 452, 456, 461, 463, 464, 468, 598, 684, 937, 945, 1136 coffee, 645, 952 cognition, xvi, xxxi, xxxiii, 261, 283, 284, 289, 292, 299, 300, 305, 309, 311, 312, 313, 314, 320, 321, 322, 323, 324, 364, 501, 513, 514, 515, 519, 520, 521, 522, 526, 527, 746, 996, 1095, 1117, 1118, 1119, 1120, 1121, 1122, 1125, 1187 cognitive abilities, xvi, 283, 291, 296, 299, 619, 1119 cognitive development, 262, 291, 297, 314, 316, 324, 1004, 1031 cognitive domains, 291, 502, 506 cognitive dysfunction, 304, 370, 382, 417, 503 cognitive function, xvi, xxxiii, xxxv, 283, 289, 292, 298, 301, 305, 310, 312, 313, 314, 315, 319, 320, 321, 322, 323, 363, 369, 382, 384, 410, 419, 503,

1242 504, 505, 514, 521, 522, 527, 746, 753, 890, 996, 997, 1095, 1117, 1118, 1120, 1122, 1123, 1124, 1125, 1173, 1174 cognitive impairment, xxi, xxii, 289, 290, 299, 304, 306, 310, 311, 312, 313, 314, 319, 321, 322, 380, 382, 384, 497, 498, 501, 502, 503, 504, 508, 509, 510, 511, 515, 520, 522, 523, 524, 525, 527, 996, 997, 999, 1000, 1119, 1120, 1121, 1123, 1124, 1181 cognitive level, 298 cognitive performance, xxi, 286, 291, 294, 297, 301, 308, 312, 313, 320, 323, 324, 364, 497, 503, 504, 505, 514, 521, 999, 1000, 1121, 1122, 1123, 1124 collagen, xxiii, xxv, xxvi, xxvii, xxviii, xxix, 46, 118, 119, 345, 403, 425, 588, 595, 598, 600, 606, 695, 700, 701, 723, 745, 747, 750, 756, 772, 799, 801, 808, 826, 861, 864, 873, 882, 885, 899, 900, 915, 931, 934, 1084, 1097, 1177, 1178 colorectal cancer, xii, 49, 61, 62, 64, 65, 68, 71, 72, 76, 80, 82, 84, 85, 90, 106, 143, 162, 168, 182, 194, 197, 198, 201, 204, 211, 270, 279, 489, 491, 493, 580, 582, 584, 942, 1041, 1102, 1103, 1104, 1112, 1113, 1128, 1232 combined effect, 2, 224, 589, 850, 851, 1200 commercial, 110, 112, 132, 147, 150, 435, 445, 632, 647, 758, 773, 774, 867, 872, 995, 1007, 1213, 1215 community, 53, 57, 170, 171, 172, 173, 175, 176, 178, 313, 314, 319, 322, 323, 345, 355, 365, 366, 373, 378, 506, 513, 517, 522, 603, 891, 938, 970, 975, 989, 1010, 1101, 1119, 1123, 1142, 1149, 1154, 1156, 1188, 1197, 1205, 1221, 1222, 1229 complexity, 95, 108, 113, 396, 773, 920, 1010 compliance, 94, 272, 274, 339, 383, 602, 834, 1037, 1224 complications, 225, 330, 332, 427, 428, 429, 452, 456, 466, 490, 494, 579, 585, 588, 589, 593, 707, 742, 749, 885, 898, 916, 918, 919, 920, 935, 941, 958, 965, 966, 1042, 1058, 1061, 1063, 1075, 1154, 1159 condensation, 158, 162, 616, 1108 conditionally essential, 221 conductivity, 732, 735, 852 conference, 446, 1219, 1225 configuration, 757, 759, 1057 confounding variables, 510, 922, 924 congestive heart failure, 468, 655, 826, 1159, 1162 connective tissue, xxvi, xxxii, 119, 152, 210, 435, 441, 605, 799, 801, 812, 864, 1079, 1083, 1086, 1087, 1090, 1097 consensus, xxxv, xxxvi, 46, 54, 147, 512, 1004, 1137, 1146, 1156, 1164, 1174, 1181, 1200, 1219, 1225, 1233

Index Consensus, 228, 1034, 1039 consent, 532, 971 conservation, 223, 439, 768, 866, 867, 868, 869, 870, 955, 1013 conserving, 224 constipation, 508, 653, 1006 constituents, xviii, 223, 395, 434, 439, 684, 705, 715, 813, 1013, 1014, 1042, 1209 construction, 328, 867, 1062, 1178 consumption patterns, 146 content analysis, 356, 357, 359, 360, 361 control group, xiv, xxii, xxix, 51, 168, 214, 227, 229, 231, 232, 233, 272, 343, 352, 360, 443, 454, 465, 490, 491, 492, 514, 529, 530, 531, 532, 533, 534, 535, 577, 579, 582, 583, 622, 708, 710, 809, 875, 925, 957, 960, 961, 962, 963, 964, 987 control measures, 602 controlled studies, 301, 925, 1087 controlled trials, xii, xxix, xxxiv, 61, 63, 72, 86, 299, 301, 323, 344, 348, 356, 357, 370, 390, 594, 600, 893, 907, 915, 923, 925, 935, 1064, 1087, 1088, 1129, 1145, 1147, 1161, 1186, 1229 controversial, xxi, xxiv, xxv, xxix, xxxi, 387, 497, 512, 694, 705, 739, 741, 745, 747, 748, 828, 901, 902, 907, 915, 995, 998, 1084, 1085, 1129, 1164, 1180 controversies, 709, 934, 1175, 1208, 1221, 1225 cooking, 140, 147, 354, 698, 750, 757, 759, 766, 767, 801, 862, 866, 869, 870, 871, 872, 873, 878, 879, 919, 1007, 1009, 1069 cooling, 98, 111, 122, 125, 130, 131, 757 cooling process, 757 coordination, 96, 288, 298, 307, 321, 564 copper, 122, 141, 371, 472, 695, 705, 706, 720, 722, 859, 864, 893, 906, 925, 928 coronary artery bypass graft, 687, 890 coronary artery disease, 383, 451, 456, 460, 461, 467, 702, 822, 851, 1035, 1149, 1179 coronary heart disease, 467, 696, 718, 720, 897, 909, 910, 911, 913, 918, 922, 923, 941, 943, 948, 1037, 1038, 1044, 1045, 1050, 1159 correlation, xii, xxii, xxiii, xxvii, xxix, 27, 50, 52, 53, 61, 62, 65, 66, 67, 68, 71, 112, 179, 220, 254, 288, 290, 297, 317, 345, 348, 350, 354, 356, 359, 382, 387, 388, 402, 505, 510, 512, 530, 532, 534, 569, 571, 589, 593, 702, 705, 707, 733, 785, 817, 831, 875,884, 886, 887, 949, 953, 997, 1027, 1044, 1065, 1084, 1119, 1164, 1182 correlations, 62, 66, 68, 71, 168, 323, 349, 359, 919, 954, 1030, 1172 cortex, 259, 262, 303, 342, 349, 351, 410, 501, 512, 832, 846 cortical neurons, 520

Index cortisol, 374, 465, 746, 748, 833, 841 cost, xiii, 73, 93, 95, 101, 113, 383, 614, 620, 639, 682, 703, 765, 774, 854, 874, 1063, 1067 covering, xxxvii, 273, 572, 703, 1175, 1207 creatinine, 228, 233, 249, 490, 578, 1166, 1167, 1169, 1170 cross-sectional study, 48, 297, 343, 344, 348, 373, 388, 503, 505, 524, 531, 536, 537, 539, 822, 970, 1124, 1230 cultivars, 13, 16, 140, 614, 623, 871, 1012, 1038 cultivation, 2, 3, 12, 756 culture, xix, 19, 31, 157, 166, 187, 189, 191, 211, 399, 403, 411, 413, 414, 415, 433, 435, 449, 519, 597, 604, 773, 854, 955, 1025, 1180 culture conditions, xix, 433, 854 culture medium, 411, 413, 414, 415, 1026 curcumin, 197 cure, 647, 703, 743, 747, 881, 1056, 1180, 1210, 1211, 1214, 1226 cures, xxxvii, 315, 983, 1006, 1181, 1207, 1211 cyclooxygenase, 152, 155, 186, 194, 197, 206, 210, 302, 475, 480, 806, 813, 1081, 1121 cyclophosphamide, 706, 707, 716, 718, 721 cysteine, 207, 217, 218, 222, 233, 236, 237, 255, 292, 366, 826, 937 cystic fibrosis, 217, 655, 743, 1031, 1034, 1039, 1040, 1043, 1060, 1061, 1074, 1217, 1218, 1221 cytochrome, xxxii, 45, 76, 158, 160, 196, 215, 217, 241, 396, 398, 410, 412, 418, 426, 481, 535, 710, 719, 803, 1099, 1100, 1101, 1102, 1107 cytochrome P450 hydroxylases, 398 cytokines, xx, xxiii, xxxii, 24, 186, 209, 224, 225, 232, 305, 342, 350, 371, 456, 460, 461, 464, 466, 468, 474, 507, 570, 587, 599, 600, 610, 802, 806, 811, 884, 932, 937, 1040, 1079, 1080, 1081, 1082, 1089, 1128, 1146, 1147, 1148, 1165, 1195, 1204 cytotoxicity, 195, 197, 198, 221, 236, 428, 475, 559, 704, 884, 891, 1041, 1048, 1049

D daily requirements, xxx, xxxi, xxxii, 257, 295, 378, 909, 913, 936, 979, 980, 1017, 1032, 1055 data collection, 536, 602, 975 deacetylation, 1108, 1114 death rate, 453 deaths, 216, 326, 452, 455, 920, 923, 988, 1005, 1013, 1146, 1210, 1216 decomposition, 225, 553, 824, 942 decontamination, 758 defecation, 490, 579

1243 defects, 25, 94, 105, 138, 139, 146, 149, 158, 262, 288, 290, 310, 396, 653, 1067, 1073 defence, 601, 687, 769, 770, 970 defense mechanisms, 76, 216, 333, 747, 759, 802, 938, 1022 deficiencies, xvi, 95, 96, 113, 146, 153, 193, 224, 225, 232, 251, 257, 261, 283, 284, 295, 299, 300, 307, 308, 315, 318, 328, 330, 333, 336, 338, 339, 379, 422, 435, 445, 587, 620, 713, 758, 876, 958, 960, 965, 966, 967, 978, 982, 986, 1004, 1012, 1038, 1061, 1066, 1067, 1210, 1211, 1225 deficit, xviii, 47, 288, 294, 307, 317, 348, 358, 377, 380, 511, 525, 539, 540, 965, 986, 988, 997, 1000 deflate, 50 deformability, 854, 856, 858 deformation, 772 degenerate, xv, 251 degenerative dementia, 526 degradation, xxii, 22, 35, 45, 79, 94, 105, 110, 116, 119, 188, 189, 255, 292, 423, 441, 473, 477, 481, 543, 545, 546, 547, 554, 555, 556, 557, 563, 566, 567, 568, 571, 605, 606, 616, 737, 763, 764, 765, 855, 859, 870, 871, 879, 916, 942, 952, 1011, 1036, 1061, 1109,1110, 1131, 1205 degradation rate, 546, 737 dehydrate, 725 dehydration, xxxi, 654, 866, 867, 872, 876, 1003, 1011, 1012 dementia, ix, xvi, xviii, xxi, xxii, xxxi, xxxv, 94, 106, 114, 283, 290, 292, 296, 297, 298, 310, 311, 312, 315, 319, 320, 321, 322, 377, 380, 382, 384, 411, 497, 502, 503, 504, 505, 506, 507, 508, 509, 510, 511, 512, 513, 514, 515, 520, 521, 522, 523, 524, 525, 526, 651, 653, 746, 753, 805, 848, 891, 892, 894, 902, 910, 970, 995, 996, 997, 998, 1000, 1029, 1117, 1118, 1119, 1120, 1125, 1173, 1174, 1181, 1187 demographic characteristics, 231 demyelinating disease, 569 demyelination, 114, 263, 289, 295, 308, 317, 380, 381 dendritic cell, xxxii, 507, 599, 810, 812, 1079, 1080, 1081, 1082, 1085, 1086, 1089, 1091, 1092, 1093, 1095, 1097, 1176, 1180 deoxyribonucleic acid, 33, 684, 686, 864 deoxyribose, 241 Department of Agriculture, 1035, 1072, 1225 Department of Defense, 54 deposition, 403, 438, 443, 444, 808, 817, 885, 988, 1164, 1211, 1212, 1226 depression, xii, xv, xvii, xxviii, 43, 47, 49, 50, 51, 52, 53, 56, 57, 58, 106, 114, 119, 251, 254, 255, 257, 258, 261, 263, 289, 292, 293, 294, 296, 307,

1244 309, 312, 315, 317, 318, 335, 341, 342, 343, 344, 345, 346, 347, 348, 349, 350, 351, 352, 353, 354, 355, 356, 357, 358, 359, 360, 361, 362, 363, 364, 365, 366, 367, 368, 369, 370, 371, 372, 373, 374, 375, 380, 382, 384, 411, 417, 501, 506, 509, 510, 519, 651, 652, 653, 654, 655, 805, 881, 886, 890, 892, 970, 998, 1214, 1218, 1232 depressive symptoms, 51, 254, 255, 257, 289, 317, 319, 323, 342, 343, 344, 345, 346, 347, 348, 349, 350, 351, 353, 354, 355, 356, 357, 358, 359, 360, 361, 362, 363, 364, 365, 366, 367, 368, 369, 371, 376, 382, 1120, 1124 deprivation, 226, 302, 372, 376 derivatives, 104, 105, 113, 148, 397, 554, 556, 559, 563, 564, 639, 644, 670, 691, 773, 786, 787, 791, 792, 793, 802, 1208 dermatitis, 255, 293, 651, 652, 918, 1067, 1181 dermatology, 58, 177, 274, 275, 276, 1078 destruction, xxv, xxxii, 4, 554, 595, 600, 608, 750, 756, 757, 760, 762, 764, 882, 926, 1055, 1176 detection, 2, 5, 6, 12, 13, 14, 27, 47, 94, 97, 98, 99, 100, 102, 104, 108, 109, 111, 113, 116, 117, 120, 122, 123, 124, 125, 129, 134, 136, 138, 140, 141, 142, 143, 144, 148, 149, 210, 430, 468, 523, 553, 664, 667, 683, 724, 727, 728, 729, 730, 731, 732, 733, 735,835, 856, 981, 990, 1041, 1109, 1115 detection system, 5, 6, 102, 724, 1041 detoxification, xiv, xxiv, 194, 214, 218, 219, 220, 221, 343, 651, 665, 694, 696, 741, 744, 748, 793, 803, 1118 developed countries, 96, 614, 984, 985 developing countries, xxxi, 286, 298, 300, 499, 516, 614, 707, 987, 990, 992, 1003, 1004, 1005, 1008, 1010, 1011, 1063, 1067, 1072 developmental factors, 44, 51 diabetic patients, 719, 749, 852, 856, 884, 886, 894, 896, 919, 920, 946, 1042, 1063, 1149, 1183, 1189, 1203 diabetic retinopathy, 884 Diagnostic and Statistical Manual of Mental Disorders, 520 dialysis, 641, 669, 742, 749, 817, 923, 936, 1203 diarrhea, xxviii, 332, 333, 379, 427, 491, 579, 614, 640, 644, 645, 652, 696, 701, 740, 746, 817, 888, 900, 904, 927, 984, 986, 987, 989, 990, 1005, 1013, 1062, 1209 diastolic blood pressure, 883, 1158 dietary intake, xix, xxx, xxxv, 47, 168, 238, 277, 320, 328, 339, 344, 345, 351, 356, 360, 421, 422, 423, 424, 425, 426, 427, 465, 489, 491, 494, 503, 507, 513, 514, 522, 579, 581, 585, 600, 602, 607, 696, 712, 713, 741, 813, 874, 921, 924, 969, 986, 997, 998, 999, 1008, 1029, 1057, 1059, 1065,

Index 1072, 1078, 1118, 1123, 1130, 1133, 1164, 1185, 1216, 1233 dietary risk factors for esophageal cancer, 214 dietary sources, xxvii, xxviii, xxx, xxxi, 45, 96, 101, 108, 115, 268, 273, 379, 386, 612, 696, 851, 861, 899, 900, 909, 913, 969, 970, 975, 1017, 1043, 1055, 1100, 1220, 1223 dietary supplementation, 180, 236, 345, 621, 632, 791, 1159 dietary supplements, xxi, xxiii, xxvii, 94, 97, 104, 113, 137, 263, 316, 317, 343, 397, 455, 457, 485, 486, 487, 488, 575, 576, 577, 578, 722, 806, 812, 847, 897, 975, 1040, 1043, 1078 dietary supply, 772, 793 differential scanning, 638, 641, 658 differential scanning calorimetry, 638, 641 diffusion, 553, 611, 681, 699, 814, 918, 1132 digestibility, 438, 449 digestion, 94, 101, 125, 327, 435, 619, 788, 980 digestive enzymes, 435 dilated cardiomyopathy, 461, 462 dimerization, 553, 1100 dimethylformamide, 122 direct measure, 659, 1086 disability, xvii, 341, 342, 362, 514, 530, 569, 572, 713, 805, 998, 1000, 1029, 1086, 1096, 1204 disclosure, 900 discomfort, 592, 602, 614, 653 discrimination, 157, 285, 286, 1052, 1070 disease activity, 53, 1083, 1084, 1085, 1086, 1087, 1088, 1089, 1090, 1092, 1093, 1094, 1095, 1096, 1097 disease progression, 382, 401, 491, 582, 596, 601, 1030, 1078, 1106 disorder, xvii, 44, 49, 50, 51, 52, 53, 292, 294, 341, 343, 344, 355, 366, 379, 418, 448, 490, 502, 508, 510, 511, 524, 525, 539, 540, 579, 595, 646, 747, 1000, 1028, 1052, 1061, 1073, 1095, 1164, 1170 displacement, 658, 666, 668 dissociation, 25, 88, 670, 855 dissolved oxygen, 775, 776, 777 distilled water, xxvii, 560, 726, 729, 831, 834 distribution, xxiv, xxix, 55, 81, 157, 180, 208, 211, 229, 230, 259, 338, 346, 435, 448, 450, 532, 534, 546, 605, 612, 620, 626, 635, 639, 640, 641, 642, 657, 669, 704, 751, 801, 814, 862, 908, 950, 957, 960, 965, 985, 1010, 1014, 1031, 1045, 1057, 1059, 1070, 1110, 1176, 1212 DNA damage, xii, xxiv, 61, 74, 75, 76, 87, 106, 153, 159, 166, 167, 186, 193, 198, 215, 216, 234, 235, 564, 686, 694, 703, 704, 706, 707, 708, 709, 710, 711, 712, 713, 714, 715, 716, 717, 720, 721, 742,

Index 766, 819, 887, 892, 909, 916, 928, 938, 996, 1038, 1069 DNA repair, xxiv, 48, 74, 76, 160, 163, 166, 167, 184, 215, 220, 694, 701, 706, 710, 711, 712, 716, 718, 817, 1111, 1177 DNA strand breaks, 706, 904 docetaxel, 490, 493, 577, 584 docosahexaenoic acid, 588 dopamine, 51, 58, 253, 254, 256, 262, 287, 294, 303, 345, 346, 352, 502, 687, 720, 735, 747, 864 dopaminergic, 260, 306, 343, 345, 354, 366, 501, 508, 747, 864 dosage, xxii, xxxii, 382, 529, 530, 531, 532, 561, 645, 710, 740, 745, 762, 763, 810, 975, 1062, 1075, 1079, 1087, 1088, 1153, 1199 dose-response relationship, 272, 1129 dosing, 512, 811, 816, 1032, 1155, 1221, 1222, 1223 double blind study, 316 down-regulation, 23, 29, 40, 86, 163, 199, 209, 318, 415, 501, 684, 811, 814, 895, 1195 drug delivery, 641, 707, 1028 drug discovery, 363, 642, 682 drug metabolism, 721 drug resistance, 219, 236, 639, 1047 drug therapy, 468, 535, 537 drugs, xxiv, 28, 167, 190, 220, 233, 345, 351, 352, 353, 361, 363, 373, 409, 489, 490, 493, 538, 555, 578, 580, 584, 591, 635, 639, 641, 642, 657, 669, 679, 683, 685, 706, 710, 720, 743, 750, 752, 759, 813, 887, 888, 1024, 1027, 1063, 1109 duality, xv, 265 duodenum, 378, 427, 1062, 1152 dysarthria, 509, 1029, 1031 dyslipidemia, 506, 701, 919, 920, 939, 958, 1065, 1179 dysphagia, 226, 228, 231, 509 dysthymic disorder, 353, 361, 375

E ecology, 1008 economic status, 603, 1008 ecotoxicological, 440 editors, 235, 259, 302, 307, 429, 1051, 1160 education, 275, 291, 386, 965, 970, 971, 976, 997, 1005 egg, xxx, 44, 106, 109, 115, 148, 353, 386, 620, 626, 767, 973, 976, 979, 984, 985, 1216 elaboration, 867, 868, 869, 982 elderly population, xvi, xx, 260, 283, 306, 312, 319, 451, 510, 514, 515, 521, 702, 970, 1123 elders, 312, 317, 521, 522, 822, 891, 1072, 1123 electricity, 1011

1245 electrocardiogram, 461 electrochemical behavior, 664, 681 electrochemical impedance, 667 electrochemistry, 685 electrode surface, 676, 681 electromagnetic, 750, 757 electron, 94, 100, 101, 215, 443, 446, 472, 475, 545, 546, 548, 552, 553, 554, 555, 560, 562, 564, 568, 616, 660, 662, 667, 681, 694, 695, 741, 757, 805, 864, 919, 1021 electron paramagnetic resonance, 662 electrophoresis, 97, 100, 115, 641, 686, 724, 732, 734, 735, 736, 737 emission, 5, 7, 8, 9, 10, 11, 98, 111, 121, 122, 129, 134, 512, 628, 661, 665, 666, 667, 672, 675, 681 emotion, 284 emotional problems, 292, 297 encephalomyelitis, 47, 48, 1083, 1094 encephalopathy, 259, 286, 301, 302, 304, 422, 428, 431, 897 encoding, 20, 22, 215, 217, 221, 402, 403, 418, 474, 606, 619, 625, 1018, 1029, 1031, 1081, 1136 encouragement, 417, 479 endocrine, xxxiv, 190, 389, 396, 398, 399, 498, 531, 552, 805, 812, 1071, 1138, 1148, 1151, 1152, 1158, 1182 endocrinology, 275, 276, 277, 279, 516, 518, 525 endogenous depression, 358 endogenous synthesis, 396, 398, 498, 499 endothelial cells, 77, 88, 153, 188, 483, 501, 598, 700, 711, 802, 808, 809, 826, 849, 1047, 1108, 1110, 1145, 1148, 1179 endothelial dysfunction, 703, 742, 753, 808, 821, 823, 909, 919, 936, 1147 endothelium, 236, 702, 722, 802, 808, 900, 922, 1146, 1147, 1179 energy, xiv, xxvii, 115, 147, 149, 214, 228, 230, 231, 232, 252, 284, 352, 358, 452, 474, 536, 549, 550, 553, 596, 598, 640, 645, 651, 652, 657, 658, 659, 661, 662, 663, 664, 665, 666, 667, 668, 669, 671, 672, 673, 675, 676, 677, 678, 680, 681, 716, 718, 726, 746, 757, 759, 761, 764, 765, 774, 776, 787, 804, 847, 859, 918, 929, 930, 950, 986, 989, 1004, 1006, 1171, 1172, 1198, 1227 energy transfer, 115, 149, 553, 657, 658, 659, 661, 662, 663, 664, 665, 666, 667, 668, 669, 671, 672, 673, 675, 676, 677, 678, 680, 681 enlargement, xx, xxxv, 411, 459, 461, 948, 1173, 1178 enrollment, xii, 61, 65, 67, 71 entropy, 559, 658, 659, 660, 661, 664, 665, 678 environment, 13, 18, 48, 91, 224, 353, 427, 434, 439, 445, 554, 557, 563, 667, 668, 669, 672, 675, 704,

1246 874, 903, 944, 991, 1009, 1106, 1110, 1117, 1137, 1141, 1210 environmental change, 435, 638, 1210 environmental conditions, 553, 756, 1209 environmental factors, xxii, 47, 52, 58, 569, 570, 572, 573, 763, 812, 1063, 1104, 1106, 1143, 1192 environmental protection, 1065 environments, 12, 300, 800, 925, 926 enzymatic activity, 289, 344, 440 enzymes, xix, xx, xxiv, xxxii, xxxvi, 22, 76, 87, 94, 96, 97, 101, 102, 103, 110, 111, 113, 118, 119, 138, 158, 166, 183, 190, 191, 192, 207, 215, 216, 217, 218, 221, 223, 255, 259, 260, 292, 301, 303, 306, 333, 349, 378, 398, 409, 415, 418, 419, 425, 442, 449, 464, 471, 478, 489, 491, 494, 535, 581, 582, 585, 588, 589, 597, 616, 625, 629, 693, 695, 701, 704, 710, 743, 749, 802, 804, 849, 850, 853, 854, 855, 859, 864, 866, 870, 871, 903, 904, 926, 931, 936, 946, 947, 1007, 1022, 1077, 1099, 1100, 1102, 1107, 1110, 1158, 1191, 1198 eosinophilic granuloma, 1086 epidemic, 460, 466, 708, 1093, 1185, 1201, 1217, 1228 epidemiologic, 266, 275, 362, 531, 714, 806, 810, 901, 913, 919, 920, 947, 1037, 1158 epidemiologic studies, 531, 806, 810, 901, 913, 919, 920, 947, 1158 epidemiology, xxiii, 91, 145, 200, 278, 518, 524, 538, 569, 571, 904, 1044, 1232 epidermis, 45, 901, 1215, 1217 epigenetic modification, 1107, 1109, 1176 epilepsy, xxii, 48, 148, 253, 286, 294, 310, 317, 349, 529, 530, 531, 532, 534, 535, 536, 537, 538, 539, 540 epinephrine, 864 epiphyses, xxxv, 1173, 1178, 1211 episodic memory, 304, 505, 506, 508 epithelial cells, xiii, 23, 26, 77, 78, 79, 87, 88, 89, 151, 154, 159, 183, 187, 190, 191, 194, 196, 208, 211, 392, 399, 598, 605, 1023, 1058, 1081, 1097, 1193 epithelial ovarian cancer, 194, 209, 829 epithelium, 435, 437, 448, 873, 988, 1215 equilibrium, 3, 218, 219, 442, 641, 659, 663, 667, 669, 681, 856 ergocalciferol, xxxiv, 44, 45, 268, 336, 337, 343, 386, 396, 397, 398, 426, 439, 498, 570, 1079, 1100, 1156, 1163, 1180, 1192, 1217, 1219 erythrocyte membranes, 205, 610, 859, 1028 erythrocytes, xxvii, 18, 105, 158, 195, 209, 240, 352, 358, 361, 380, 477, 482, 610, 700, 708, 847, 848, 849, 850, 851, 852, 853, 854, 855, 856, 857, 858, 859, 860, 908, 919, 928, 936, 1023, 1027

Index erythroid cells, 854 erythropoietin, 474, 477 esophageal cancer, xiv, 202, 214, 225, 226, 227, 237, 238, 490, 494, 579, 585, 912, 946 esophagitis, 490, 579 esophagus, xiv, 74, 180, 202, 214, 225, 226, 228, 231, 238, 901, 921 essential fatty acids, 757, 1056, 1060, 1074 ester, 19, 36, 39, 152, 157, 162, 192, 980, 989, 1026, 1048 estrogen, 77, 159, 161, 165, 185, 198, 391 ethanol, 111, 119, 429, 430, 559, 560, 787, 1026 ethers, 156 ethical standards, 532 ethnic groups, 72, 226, 1088, 1106 ethnicity, xxxvii, 52, 225, 389, 537, 1115, 1148, 1207, 1221, 1230 ethyl acetate, 3, 8, 9, 11, 411, 560, 1011 etiology, xvii, xxii, 225, 238, 341, 343, 392, 461, 502, 506, 569, 704, 886, 922, 924, 1057, 1068, 1164, 1209, 1225, 1226 Europe, xiii, xxix, xxxv, 11, 69, 71, 151, 499, 500, 516, 644, 949, 1029, 1032, 1090, 1134, 1141, 1146, 1173, 1174, 1176, 1184, 1192, 1209, 1211 evil, 1209 evoked potential, 317 evolution, 233, 520, 540, 676, 703, 801, 958, 959, 1175 excess body weight, 331, 540 excision, 706 excitability, 347, 530 excitation, 5, 7, 8, 9, 10, 11, 98, 111, 121, 122, 129, 134, 648, 662, 670, 677, 757 exciton, 674 excretion, xxiv, xxxii, 195, 196, 252, 253, 260, 284, 330, 336, 424, 425, 427, 428, 612, 635, 640, 688, 700, 801, 815, 816, 826, 927, 935, 945, 990, 1032, 1047, 1055, 1059, 1179 executive function, 291, 292, 293, 294, 296, 297, 309, 505, 510, 514, 1119, 1123 executive functions, 291, 292, 293, 294, 296, 297, 514, 1119 exercise performance, 929, 931, 932 exercises, 703, 746 exertion, 746, 931 exons, xxxii, 1099, 1101, 1102 exophthalmia, 778, 779, 793 experimental autoimmune encephalomyelitis, 570, 1083, 1090 experimental condition, 440, 442, 772, 784, 787, 792 expertise, 1212 exploitation, 95, 955 extensor, 380, 938, 1157

Index extracellular matrix, 79, 152, 188, 189, 216, 402 extracts, 14, 15, 16, 110, 111, 117, 128, 132, 146, 443, 490, 491, 579, 582, 737, 797, 856, 920, 1214

F fabrication, 1024 false negative, 749 families, 154, 155, 851, 1005, 1040, 1048, 1208, 1209 family history, 44, 201, 225, 278, 921 family meals, 714 family members, xiv, 23, 152, 154, 188, 190 family physician, 526 fasting, 228, 333, 476, 532, 707, 810, 1154, 1158, 1194 fasting glucose, 810, 1154, 1158, 1194 fat intake, 204, 944, 945 fat soluble, xix, xxxiv, 328, 421, 426, 441, 443, 455, 570, 572, 764, 966, 982, 1163, 1212 fatty acids, xxiii, 197, 257, 295, 301, 364, 371, 441, 442, 464, 466, 587, 588, 590, 592, 598, 599, 610, 611, 612, 624, 628, 641, 652, 757, 804, 805, 889, 897, 919, 999, 1025, 1062 fermentation, 149, 333, 952, 955, 956, 1011, 1209 ferric ion, 110 ferritin, xxx, 803, 957, 959, 964 fertility, 154, 354, 391, 618, 1007, 1181, 1188 fertilization, 388, 390 fetal growth, 1067, 1078, 1188 fetus, 391, 744, 885 fever, 453, 645, 647, 653, 683, 849, 925 fiber, 7, 13, 202, 708, 820, 952, 1048, 1050, 1158, 1198, 1200 fibers, xxxvi, 1128, 1191, 1192, 1196, 1198, 1200 fibrinogen, xxx, 249, 806, 957, 959, 960, 1159 fibroblast growth factor, 152, 188, 396, 398, 811, 1080, 1217 fibroblasts, 26, 403, 477, 606, 713, 1026, 1204 fibromyalgia, 47, 49, 56, 355, 364, 1084, 1092 fibrosarcoma, 707, 718 fibrosis, 337, 340, 402, 403, 423, 425, 427, 428, 590, 1031, 1042, 1074, 1086 film thickness, 731 films, 667, 725, 735 filtration, 98, 102, 112, 123, 125, 127, 130, 228, 233, 1166, 1172 financial, 855, 970, 995 fish, xxiv, xxvi, xxxvi, 44, 45, 107, 124, 148, 268, 342, 349, 354, 364, 378, 386, 397, 434, 442, 443, 444, 448, 449, 536, 570, 597, 619, 620, 621, 626, 631, 653, 693, 730, 735, 771, 772, 773, 774, 775, 776, 777, 778, 779, 780, 781, 782, 783, 784, 785,

1247 786, 787, 788, 789, 790, 791, 792, 793, 795, 796, 797, 798, 800, 974, 977, 984, 999, 1036, 1100, 1149, 1174, 1176, 1216 fish oil, 442, 448 fission, 551 fitness, 276 fixation, 868 flame, 4, 731 flatulence, 333, 614, 653, 655, 1062 flavonoids, 158, 196, 464, 466, 615, 638, 704, 735, 795, 797, 906, 919, 1071 flavor, 380, 757, 870 flavour, 638, 768, 952 flaws, 365, 1146 flexibility, 505, 742, 1109 flowers, 950 fluctuations, 387, 435, 445, 508 fluid, 3, 4, 16, 110, 286, 305, 307, 308, 328, 366, 388, 460, 478, 653, 700, 820, 871, 933, 936, 1041, 1049, 1064 fluid extract, 3, 4, 16 fluorescence, xxiv, 2, 5, 12, 13, 94, 98, 99, 100, 104, 109, 111, 113, 115, 128, 136, 138, 140, 144, 147, 149, 553, 554, 557, 559, 565, 635, 641, 642, 657, 658, 659, 660, 661, 662, 664, 665, 666, 667, 668, 669, 670, 671, 672, 673, 674, 675, 676, 677, 678, 679, 680, 681, 689, 690, 691, 724, 729, 1041 fluorophores, 675 fluoxetine, 345, 346, 347, 357, 367, 368, 895 folic acid, xx, xxx, 99, 104, 112, 136, 138, 139, 142, 143, 145, 148, 153, 227, 238, 254, 260, 261, 288, 301, 305, 306, 307, 308, 309, 310, 312, 313, 314, 315, 318, 319, 320, 321, 322, 323, 336, 346, 347, 349, 357, 362, 368, 380, 424, 451, 452, 453, 601, 603, 606, 607, 608, 636, 653, 656, 679, 680, 692, 741, 775, 852, 874, 929, 957, 958, 959, 960, 962, 966, 1024, 1049 follicle, xviii, 385, 387, 388, 392 follicles, 387, 388, 389, 988 food additive, 724, 800, 812, 1036 Food and Drug Administration, 1223 food habits, 721 food industry, 900 food intake, xiv, 214, 232, 710, 714, 845, 971, 975, 982, 1176 food production, xxv, 755, 757 food products, xxii, xxviii, 96, 100, 103, 104, 116, 119, 138, 140, 142, 143, 144, 150, 543, 630, 725, 727, 735, 759, 766, 861, 866, 868, 869, 870, 900, 1011, 1213 food security, xxxi, 1003, 1005 football, 933

1248

Index

force, 513, 657, 661, 663, 665, 669, 672, 673, 679, 680, 940, 972, 1197, 1221, 1222 Ford, 205, 299, 323, 370, 375, 457, 520, 884, 891, 919, 939, 947, 1047, 1201, 1230 forebrain, 286, 303, 415, 1039 formula, xxxvi, 44, 127, 131, 132, 136, 144, 147, 240, 516, 593, 1174, 1176, 1223, 1228 fractures, xxxiv, 278, 329, 513, 517, 535, 655, 1128, 1138, 1152, 1154, 1157, 1161, 1162, 1171, 1178, 1198, 1204, 1221, 1222, 1233 fragility, 72, 73, 517, 853, 854, 1028, 1045, 1062, 1138 fragments, 849 frameshift mutation, 1030 France, 62, 63, 81, 200, 251, 283, 453, 626, 797, 1120, 1138, 1174, 1179 free energy, 660, 661 free radicals, xx, xxvii, xxviii, xxxi, xxxii, 119, 153, 156, 167, 184, 205, 215, 216, 218, 219, 221, 225, 226, 345, 426, 427, 441, 443, 471, 472, 475, 478, 480, 481, 482, 588, 599, 601, 610, 611, 612, 695, 704, 714, 720, 740, 741, 745, 747, 750, 752, 757, 759, 806, 810, 819, 847, 848, 858, 882, 899, 900, 902, 903, 916, 919, 926, 929, 931, 933, 938, 996, 999, 1017, 1021, 1022, 1055, 1057, 1061, 1064, 1065, 1068 freezing, xxv, 112, 755, 757, 765, 866, 867, 868, 869, 870, 871, 872, 876, 879, 906, 1010 reshwater, xxvi, 434, 446, 563, 771, 772, 774, 790, 792, 793 freshwater species, 772 fruits, xiii, xiv, xxiv, xxv, xxviii, 2, 7, 13, 134, 137, 140, 142, 144, 148, 151, 201, 214, 226, 342, 345, 354, 378, 460, 464, 466, 467, 597, 599, 607, 615, 623, 629, 638, 639, 654, 685, 693, 697, 698, 701, 705, 708, 711, 712, 721, 723, 725, 726, 727, 730, 731,732, 735, 736, 737, 740, 750, 755, 756, 760, 761, 762, 765, 767, 768, 770, 800, 810, 861, 862, 863, 865, 866, 867, 871, 872, 874, 877, 879, 882, 883, 884, 899, 900, 901, 903, 905, 906, 907, 911, 917, 920, 922, 946, 949, 950, 952, 953, 954, 955, 956, 980, 984, 1004, 1005, 1007, 1011, 1012, 1014, 1016, 1035, 1036, 1040, 1050 functional food, 87, 142, 820 fungi, xvii, 23, 343, 377, 615, 639, 756, 761, 931 fusion, xii, 17, 19, 20, 32, 37

G gadolinium, 235 gait, 252, 284, 294, 1155, 1158, 1161, 1197, 1204, 1205 gallbladder, 62, 73, 80, 179, 1129

gamma glutamyl transpeptidase, 502 gamma radiation, 757, 762, 763, 764, 767, 768, 769 gamma rays, 767 gamma-tocopherol, xiii, 152, 154, 155, 157, 158, 159, 160, 161, 163, 164, 165, 166, 167, 168, 180, 181, 182, 183, 186, 187, 189, 190, 191, 194, 195, 196, 198, 200, 205, 206, 207, 208, 594, 628 gastrectomy, xvii, 325, 328, 329, 330, 331, 332, 336, 337, 339, 340, 379, 490, 494, 579, 585, 589, 593, 1031, 1052, 1062, 1074 gastric mucosa, 832, 834, 845, 846 gastric ulcer, 832, 845 gastritis, 296, 379, 381 gastroenteritis, 541, 984 gastroesophageal reflux, 225, 894 gastrointestinal tract, 333, 429, 646, 704, 801, 906, 927, 1033, 1059, 1217 gastroliths, 439 gel, 5, 7, 10, 28, 117, 456, 468, 600, 606, 683, 1131, 1140 gender differences, 1133 gene expression, xviii, xix, xx, xxxi, xxxii, xxxvi, 23, 41, 46, 58, 76, 78, 79, 88, 189, 199, 216, 219, 223, 253, 287, 372, 385, 388, 395, 398, 399, 400, 409, 411, 413, 414, 416, 417, 419, 442, 471, 477, 478, 482, 501, 590, 597, 605, 610, 628, 630, 704, 719, 749, 801, 823, 827, 845, 864, 904, 986, 995, 1068, 1094, 1097, 1099, 1106, 1107, 1108, 1109, 1114, 1115, 1176, 1177, 1191, 1195, 1196, 1204 gene promoter, xxxvi, 402, 403, 475, 1103, 1107, 1109, 1191 gene regulation, 48, 401, 474, 1107 genes, xii, xxxii, xxxiii, xxxv, 17, 20, 21, 22, 23, 25, 30, 37, 38, 48, 76, 77, 79, 89, 90, 105, 138, 148, 186, 188, 189, 190, 215, 217, 220, 221, 344, 386, 392, 399, 401, 403, 412, 413, 414, 415, 416, 418, 419, 428, 474, 475, 477, 502, 506, 507, 518, 590, 615, 626, 629, 632, 710, 743, 749, 904, 1062, 1068, 1080, 1099, 1100, 1101, 1102, 1106, 1107, 1108, 1109, 1111, 1112, 1113, 1114, 1115, 1128, 1136, 1137, 1141, 1173, 1177, 1182, 1193, 1217 genetic alteration, 188 genetic background, 192 genetic engineering, 614 genetic factors, 507, 1100, 1134, 1136, 1137 genetic marker, 1068, 1113, 1133 genetic predisposition, xxiii, 47, 569, 571, 708, 809, 958, 1111 genome, xxiv, 91, 163, 220, 478, 628, 694, 712, 1136, 1137, 1144, 1217, 1225 genomic stability, 87, 715, 716, 718, 910 genotype, 2, 14, 51, 58, 82, 195, 292, 311, 315, 367, 507, 710, 716, 997, 1030, 1045, 1064, 1076,

Index 1077, 1084, 1085, 1086, 1093, 1095, 1103, 1104, 1106, 1110, 1113, 1147, 1201, 1203 geometry, xix, 395, 401, 402, 663 Germany, 64, 69, 71, 111, 185, 228, 238, 239, 241, 480, 487, 489, 500, 521, 577, 581, 777, 828, 920, 1119, 1120, 1123, 1174, 1209 gestation, 287, 293, 298, 299, 300, 314, 355, 612, 1034, 1042, 1067 gestational diabetes, 1182, 1184, 1188 gill, 777, 781, 783, 785 ginger, 490, 492, 579, 583 gingival, 596, 600, 601, 603, 606, 607, 713 gingival overgrowth, 601, 606, 607 gingivitis, 596, 600, 603, 606, 607, 654, 740 gland, 48, 90, 174, 203, 254, 257, 263, 399, 411, 435, 436, 437, 438, 439, 440, 441, 443, 444, 445, 446, 536, 700, 745, 832, 833, 834, 835, 836, 838, 841, 842, 843, 844, 846, 917, 1071, 1177 glaucoma, xxviii, 752, 881, 886, 889, 894, 898 glial cells, 343, 410, 412, 501, 519, 864 glucocorticoid, xxxvi, 271, 410, 411, 415, 416, 418, 419, 841, 844, 1174 glucocorticoid receptor, 410, 418, 841 glucocorticoids, xix, 269, 409, 411, 415, 418, 419, 530, 531, 1221 gluconeogenesis, 478 glucose tolerance, 477, 478, 809, 1032, 1154, 1158, 1202 glucose tolerance test, 1154 glutamate, xv, 105, 130, 147, 149, 214, 222, 233, 236, 284, 285, 293, 295, 303, 304, 342, 351, 352, 363, 374, 410, 424, 443, 481, 501, 502, 519, 520 glutathione, xiv, xxvii, 77, 100, 183, 194, 207, 214, 217, 218, 219, 222, 226, 230, 234, 235, 236, 350, 354, 372, 422, 423, 428, 460, 477, 478, 559, 566, 588, 701, 704, 716, 717, 744, 748, 810, 817, 831, 832, 846, 849, 850, 851, 853, 854, 855, 856, 857, 858, 859, 864, 865, 891, 903, 909, 912, 916, 1022, 1027, 1041, 1066, 1077, 1118 glycine, 105, 217, 219, 222, 309, 706, 864 gout, xxviii, 750, 751, 881, 885, 890, 897, 1210 gouty arthritis, 686 government policy, 773 governments, 94, 1005, 1220 grass, 444, 448, 796, 797 growth arrest, 26, 32, 33, 40, 78, 165, 210 growth factor, xiii, 24, 26, 61, 75, 77, 78, 88, 89, 152, 188, 189, 191, 210, 216, 224, 225, 295, 318, 391, 473, 474, 597, 807, 811, 1023, 1041, 1080, 1095, 1182, 1193, 1201 growth hormone, 746 growth rate, 777, 787, 788 guanine, 941

1249 guidelines, xxxi, 46, 54, 82, 267, 268, 336, 337, 340, 431, 531, 601, 632, 687, 712, 975, 1017, 1034, 1059, 1131, 1134, 1166, 1188, 1220, 1221, 1222, 1223, 1224, 1225, 1233

H haemocytic infiltration, 438 hair, 255, 293, 652, 654, 745, 882, 950 hair follicle, 745, 882 hair loss, 255, 293, 652, 654 half-life, 64, 241, 386, 398, 399, 700, 704, 759, 816, 870, 1058, 1101, 1131, 1214, 1218 hallucinations, 295, 382, 506, 508 halogens, 216 hamstring, 948 haplotypes, 1104, 1106, 1112, 1113 haptoglobin, 1063, 1076, 1077 harmful effects, xxiv, 442, 694, 743, 907, 931, 999 harvesting, 756, 801, 862, 867, 1007 Hawaii, 203, 204, 768, 1043 head and neck cancer, 49, 56, 71, 84, 184, 648, 1038, 1106, 1114 headache, 640, 646, 652, 654, 983, 984 healing, xxix, 399, 486, 576, 595, 596, 597, 598, 600, 601, 604, 607, 702, 707, 740, 745, 808, 874, 875, 885, 891, 894, 915, 1209, 1210, 1211, 1212, 1215 health benefits, xxiv, xxvi, xxx, 537, 635, 642, 644, 651, 682, 684, 748, 799, 903, 917, 920, 942, 969, 1044 health care, 336, 342, 493, 584, 970 health care professionals, 336, 493, 584 health condition, 702, 740, 916, 918, 970, 982, 1193 health effects, 62, 268, 457, 606, 686, 714, 740, 910, 927, 936, 986, 1225 health problems, 1170 health promotion, 105, 106, 900, 906, 912, 970, 976 heart disease, xxviii, xxxi, 94, 215, 451, 461, 462, 467, 469, 473, 476, 521, 641, 654, 696, 718, 720, 740, 881, 883, 884, 888, 897, 909, 910, 911, 913, 918, 922, 923, 927, 941, 943, 948, 1003, 1006, 1032, 1035, 1037, 1038, 1044, 1045, 1050, 1069, 1092, 1149, 1159, 1195 heart failure, xviii, xix, xx, 395, 401, 402, 403, 452, 456, 459, 460, 462, 463, 464, 465, 466, 468, 483, 655, 805, 826, 883, 892, 896, 1048, 1053, 1159, 1162 heart rate, 380, 403, 462, 465, 645, 746, 931 height, 227, 337, 462, 463, 540, 950, 959, 1065, 1165 helicity, 660, 662, 668, 670, 681 Helicobacter pylori, 701, 722

1250 hematocrit, 380, 779, 781, 783, 959, 962 hematopoietic stem cells, 848, 854 heme, 183, 217, 241, 346, 477, 478, 643, 704, 848, 1063, 1076 heme oxygenase, 217, 346, 477 hemodialysis, 309, 350, 359, 371, 742, 751, 906, 923, 924, 936, 937, 939, 940, 943, 947, 1031, 1062, 1074, 1129, 1195 hemoglobin, xxx, 103, 380, 477, 638, 707, 745, 777, 779, 783, 853, 854, 856, 857, 957, 959, 960, 962, 1015, 1063, 1074, 1076, 1154 hemorrhage, 481, 646, 779, 782, 786, 793, 854 hemorrhagic stroke, 454, 510 hepatic encephalopathy, 428, 429 hepatitis, 345, 426, 428, 430, 590, 646, 741, 818, 821, 1165, 1180 hepatitis a, 590 hepatitis d, 426 hepatocarcinogenesis, 87, 1025 hepatocellular carcinoma, 153, 185, 424, 494, 585 hepatorenal syndrome, 206 herbal medicine, 494, 585, 644, 657 herbal supplements, xxi, xxiii, 485, 486, 487, 488, 490, 575, 576, 577, 578, 579 herbicide, 448 herbs, 486, 576, 638, 639, 644, 648, 683, 698, 699, 758 heterogeneity, 278, 317, 367, 504, 505, 507, 510, 975, 1040, 1106 hexane, 3, 4, 5, 7, 8, 9, 122, 248, 728 high blood pressure, 647, 742, 750, 1156 high density lipoprotein, 153, 192, 467, 920, 947, 1022, 1056, 1058, 1071, 1158 highly active antiretroviral therapy, 1168 hip fractures, xxxiv, 47, 454, 1154, 1156, 1163, 1178, 1201, 1222, 1224 hippocampus, 49, 55, 284, 303, 342, 349, 351, 352, 360, 372, 373, 410, 501, 502, 999 histamine, 262, 379, 802, 845, 926, 936 histidine, 105, 262, 732 histological changes, 435, 437, 445 histology, 440, 441, 592 histone, xxxii, 21, 27, 152, 167, 197, 1099, 1107, 1108, 1109, 1114, 1115 history, xvi, xxxvi, 64, 73, 81, 168, 228, 265, 266, 270, 271, 272, 273, 274, 278, 357, 358, 363, 379, 389, 463, 493, 509, 512, 584, 647, 683, 785, 791, 793, 884, 923, 966, 1068, 1076, 1084, 1088, 1168, 1174, 1181, 1208, 1217, 1221, 1222, 1225, 1226 homeostasis, xiv, xviii, xxi, xxiv, xxxii, xxxiii, xxxv, 19, 55, 157, 158, 166, 193, 213, 214, 215, 223, 224, 225, 237, 269, 279, 343, 386, 395, 396, 398,

Index 399, 402, 404, 427, 439, 471, 472, 473, 474, 476, 477, 478, 479, 481, 482, 497, 498, 501, 530, 572, 597, 694, 700, 801, 802, 803, 805, 1058, 1079, 1100, 1101, 1120, 1127, 1128, 1141, 1157, 1163, 1165, 1170, 1178, 1181, 1194, 1217 homocysteine, xv, xvi, 94, 95, 103, 105, 106, 113, 137, 143, 145, 147, 149, 214, 222, 233, 237, 241, 253, 254, 255, 257, 260, 263, 283, 287, 288, 289, 290, 291, 292, 293, 295, 298, 299, 305, 306, 307, 308, 309, 310, 311, 312, 313, 314, 317, 319, 321, 322, 323, 324, 346, 347, 364, 367, 369, 378, 380, 382, 383, 423, 424, 430, 598, 822, 959, 965 homogeneity, 228, 233 homovanillic acid, 254, 261 hormone, xviii, xix, xxxii, xxxiii, xxxv, 20, 30, 36, 41, 46, 48, 55, 78, 162, 166, 385, 386, 387, 390, 391, 392, 396, 397, 399, 403, 409, 417, 439, 474, 597, 640, 745, 746, 753, 833, 841, 844, 846, 864, 932, 1006, 1079, 1080, 1087, 1090, 1100, 1117, 1118, 1121, 1122, 1128, 1129, 1130, 1138, 1147, 1164, 1178, 1192, 1194, 1204, 1215, 1218, 1220, 1225, 1227 hormone levels, 48, 391, 392, 1129 hormones, xxxiii, 24, 77, 192, 396, 398, 399, 419, 424, 474, 652, 654, 695, 701, 745, 801, 803, 864, 931, 1117, 1118, 1148, 1165 horticultural crops, 879 hospitalization, 426, 461, 987 host, xv, 214, 238, 340, 591, 747, 802, 805, 809, 823, 865, 873, 876, 1008 household income, 1009 human behavior, 1117 human body, xxviii, xxxi, 241, 349, 640, 654, 676, 723, 741, 849, 899, 900, 917, 930, 983, 1017, 1100 human brain, xxi, 497, 519, 1121, 1187 human health, xxiv, xxviii, xxix, 274, 366, 375, 396, 418, 609, 622, 629, 638, 694, 711, 716, 758, 800, 899, 901, 907, 908, 915, 933, 943, 992, 1004, 1092, 1110, 1138, 1148, 1187 human immunodeficiency virus, 388, 1067, 1078 human milk, 143, 146, 696, 936, 981, 984, 1034, 1223 human neutrophils, 191, 211 human resources, 1132 human skin, 328, 1026, 1066, 1078, 1141, 1185, 1217, 1228 human subjects, 428, 468, 1215 Hunter, 261, 481, 615, 616, 626, 948, 1042, 1078, 1112, 1143, 1144, 1187 hydrocarbons, 547, 548 hydrocephaly, 988

Index hydrogen, 99, 122, 156, 194, 218, 221, 226, 235, 333, 334, 442, 472, 547, 548, 553, 559, 564, 566, 614, 639, 641, 658, 660, 662, 664, 670, 672, 673, 675, 680, 681, 694, 695, 702, 705, 712, 744, 757, 772, 814, 817, 820, 848, 849, 903, 916, 921, 928, 936, 1021, 1081, 1227 hydrogen atoms, 553, 694, 772 hydrogen bonds, 660, 664, 757 hydrogen peroxide, 99, 122, 194, 218, 221, 226, 442, 548, 553, 614, 695, 702, 705, 712, 744, 814, 817, 820, 848, 903, 916, 921, 928, 936, 1081 hydroperoxides, 225, 817, 824, 942, 946, 1061 hydroxyl, 154, 156, 157, 241, 442, 472, 547, 553, 677, 679, 699, 717, 750, 757, 832, 848, 864, 902, 903, 916, 928, 1021 hyperactivity, xxi, 26, 285, 294, 317, 471, 476, 511, 525, 539, 540 hyperactivity-impulsivity, 511 hypercalcemia, 47, 513, 1221, 1223 hypercholesterolemia, 28, 701, 752, 924 hyperglycemia, xx, xxi, 460, 471, 472, 477, 478, 714, 808, 809, 849, 891, 919, 920, 945, 947, 1063 hyperlipidemia, 328, 456, 715, 920, 947, 960, 984 hypermethylation, 1107, 1108, 1114 hyperparathyroidism, xxxv, 329, 331, 339, 355, 401, 500, 517, 532, 534, 966, 1119, 1131, 1143, 1164, 1173, 1177, 1178, 1194, 1205, 1221 hypertension, xix, xxiv, xxviii, xxix, 328, 351, 395, 401, 402, 452, 460, 461, 462, 465, 473, 476, 506, 518, 644, 647, 648, 654, 687, 693, 742, 812, 881, 883, 888, 891, 906, 957, 958, 960, 972, 1040, 1063, 1065, 1068, 1139, 1143, 1146, 1148, 1230 hypertrophy, xix, 395, 401, 402, 436, 438, 441, 444, 465, 900, 1146, 1148 hypothalamus, 48, 49, 343, 386, 833, 844 hypothesis, xii, 51, 52, 53, 61, 62, 64, 66, 68, 73, 74, 80, 81, 82, 155, 183, 186, 206, 221, 248, 297, 335, 342, 362, 451, 536, 589, 591, 706, 716, 913, 929, 932, 998, 1121, 1186 hypovitaminosis D, x, xxxiv, xxxvii, 56, 58, 83, 276, 339, 497, 499, 500, 503, 513, 515, 516, 522, 530, 532, 533, 534, 535, 537, 539, 1133, 1137, 1141, 1145, 1146, 1147, 1149, 1163, 1165, 1170, 1172, 1184, 1207, 1215, 1216, 1229, 1231 hypoxia, xx, xxi, 74, 77, 88, 167, 200, 443, 471, 472, 473, 474, 475, 476, 477, 478, 479, 480, 481, 482, 483, 743, 806, 828, 850, 853, 856

I identification, 14, 147, 386, 563, 612, 737, 1050, 1071, 1103, 1106, 1145, 1185, 1227, 1228

1251 idiopathic, xxii, 263, 461, 530, 531, 532, 534, 1083, 1087, 1094, 1095 ileum, 240, 241, 378, 1031 illumination, 554 imbalances, 291, 297, 809 immersion, xxvii, 761, 831, 832, 845, 846 immigrants, 52, 500, 1175 immobilization, 690, 833, 841, 845, 935, 989, 1164 immune function, xxvi, 269, 354, 428, 498, 587, 592, 799, 802, 806, 809, 820, 824, 828, 918, 932, 985, 1024, 1070, 1177, 1193 immune response, xxiii, xxv, xxxii, 218, 224, 448, 518, 530, 589, 591, 595, 605, 611, 629, 723, 753, 795, 796, 803, 804, 821, 824, 916, 1004, 1037, 1057, 1079, 1085, 1180 immunoglobulin, 570, 805, 824, 875, 1078, 1081, 1128 immunoglobulins, 695 immunomodulation, 590, 591, 1181 immunomodulator, 507, 1057, 1180 immunomodulatory, xxiii, xxviii, xxxvi, 502, 569, 570, 899, 1088, 1118, 1173, 1175 immunomodulatory effects, xxiii, 569, 570, 1118, 1175 immunonutrition, vii, xxiii, 587, 588, 592, 593, 594 immunosuppression, 386, 932, 935, 1087 immunosuppressive drugs, 688 impaired immune function, 425, 426 impairments, xxxvi, 48, 286, 288, 293, 296, 303, 304, 1191, 1192, 1195, 1200 imprinting, 685 improvements, xiii, 93, 300, 323, 331, 337, 434, 492, 582, 1147, 1194, 1196, 1198, 1199, 1211 impurities, 1133 inattention, 511 income, 226, 620, 920, 949, 997, 1233 incubation period, 443, 1195 India, xxxv, 57, 451, 459, 461, 465, 468, 471, 479, 480, 487, 489, 499, 577, 580, 635, 686, 794, 844, 847, 855, 896, 920, 1173, 1182 Indonesia, 301, 596, 875, 1014 inducer, 159, 519, 594, 860, 1097, 1195 inducible protein, 28, 153, 165 induction, xi, xiii, 17, 19, 23, 24, 25, 28, 29, 30, 37, 39, 76, 89, 90, 152, 160, 161, 162, 163, 164, 165, 167, 181, 186, 189, 191, 192, 197, 198, 200, 216, 217, 224, 412, 413, 414, 416, 418, 465, 482, 483, 535, 570, 614, 621, 701, 717, 759, 765, 1023, 1027, 1041,1082, 1083, 1097, 1108, 1227 inductor, 237 industrial processing, 139 industry, 434, 455, 620, 682, 724, 779, 786, 900 infancy, 47, 320

1252 infants, xxx, xxxii, xxxv, xxxvii, 51, 268, 286, 292, 297, 300, 307, 314, 316, 320, 540, 655, 696, 748, 927, 936, 979, 990, 993, 1008, 1031, 1033, 1034, 1046, 1055, 1068, 1125, 1164, 1175, 1176, 1177, 1178, 1180, 1183, 1185, 1189, 1208, 1210, 1211, 1216, 1220, 1221, 1223, 1224, 1226, 1228, 1233, 1234 infection, xxvii, xxxvi, 386, 501, 588, 589, 591, 592, 598, 647, 743, 747, 801, 803, 805, 820, 847, 875, 882, 932, 944, 989, 992, 1004, 1014, 1015, 1029, 1044, 1078, 1166, 1170, 1172, 1174, 1182, 1183, 1187, 1230 inferior vena cava, 835 infertility, 389, 390, 655, 713, 918, 1018, 1056 inflammasome, 468 inflammation, xiii, xviii, xx, xxvi, xxix, 27, 61, 79, 155, 181, 182, 186, 192, 206, 207, 210, 216, 221, 224, 225, 226, 232, 234, 237, 238, 298, 328, 343, 344, 363, 386, 395, 410, 459, 460, 462, 465, 466, 472, 483, 507, 519, 593, 594, 600, 601, 602, 604, 607, 608, 640, 684, 701, 753, 799, 801, 802, 805, 806, 807, 808, 809, 810, 811, 812, 818, 819, 821, 822, 823, 824, 825, 828, 849, 856, 857, 860, 884, 885, 895, 910, 915, 932, 935, 1041, 1065, 1146, 1147, 1149, 1159, 1180, 1194, 1195, 1200, 1203, 1231 inflammatory bowel disease, 501, 518, 1083, 1090, 1128, 1221 inflammatory cells, 224, 610, 801, 885, 1080 inflammatory disease, 473, 480, 601, 801, 807, 808, 813, 902, 912 inflammatory mediators, 465, 801, 802, 807 inflammatory responses, 49, 75, 79, 593, 802, 809, 1133 influenza, 925, 1089, 1230 information processing, xvi, 283, 287, 292, 294, 296, 300 information processing speed, 287, 292, 294, 296, 300 information retrieval, 510 informed consent, 241, 461, 1166 ingest, 227, 906, 927 ingestion, 226, 347, 427, 531, 534, 611, 919, 927, 928, 945, 947, 982, 984, 1070, 1084, 1192, 1216, 1217, 1218, 1221 inhibitor, 26, 28, 29, 76, 160, 197, 249, 252, 254, 284, 288, 310, 322, 482, 483, 535, 639, 645, 952, 997, 1108, 1109, 1168, 1195 initiation, 68, 76, 155, 166, 167, 215, 216, 220, 267, 270, 324, 337, 757, 806, 808, 809, 819, 1025, 1057, 1106 injury, xxiii, 216, 218, 224, 382, 422, 424, 426, 427, 428, 429, 430, 431, 465, 478, 483, 501, 588, 591,

Index 592, 609, 714, 741, 752, 801, 805, 808, 809, 812, 849, 852, 855, 894, 902, 904, 929, 937, 970, 1028, 1040, 1069, 1199, 1205 innate immune response, 599, 805, 809, 818, 1081, 1195 insecurity, xxxi, 1003, 1004, 1005, 1009 insulin, xxi, 46, 47, 56, 78, 88, 228, 351, 353, 375, 389, 390, 391, 393, 427, 439, 452, 456, 472, 473, 474, 476, 478, 480, 482, 506, 514, 527, 537, 707, 713, 719, 751, 805, 809, 810, 821, 823, 826, 884, 898, 901, 909, 918, 919, 936, 938, 996, 1032, 1041, 1063, 1065, 1066, 1075, 1124, 1129, 1154, 1158, 1159, 1161, 1162, 1176, 1179, 1182, 1183, 1186, 1189, 1193, 1194, 1200, 1201, 1202, 1203, 1205, 1218, 1231 insulin resistance, 56, 353, 375, 389, 390, 393, 427, 452, 456, 476, 478, 482, 805, 809, 821, 823, 901, 909, 918, 919, 936, 938, 1063, 1065, 1066, 1075, 1154, 1158, 1159, 1161, 1182, 1193, 1194, 1200, 1202, 1203, 1205 insulin sensitivity, 47, 477, 537, 809, 1162, 1179, 1183, 1186, 1189, 1194, 1202, 1203, 1231 integrity, xxx, xxxii, 76, 167, 328, 403, 436, 535, 589, 610, 701, 703, 713, 804, 872, 874, 901, 979, 980, 985, 1008, 1028, 1037, 1055 interactions, xiii, xxvi, 18, 19, 21, 29, 30, 31, 51, 61, 77, 79, 158, 194, 207, 242, 350, 429, 475, 480, 564, 566, 570, 602, 606, 610, 626, 635, 640, 642, 658, 659, 660, 661, 662, 664, 665, 666, 668, 670, 671, 672, 673, 674, 675, 676, 679, 680, 688, 689, 691, 704, 715, 719, 747, 799, 803, 820, 833, 846, 878, 930, 1039, 1049, 1106, 1109, 1112, 1118, 1165 intercellular adhesion molecule, 806 interface, 94, 102, 104, 122, 127, 659, 660, 832 interference, 22, 119, 555, 749, 1132 interferon, 153, 165, 184, 208, 572, 703, 1026, 1080, 1147, 1165 intervention, xiv, xx, xxix, 72, 165, 205, 214, 221, 233, 300, 301, 451, 452, 453, 454, 455, 465, 492, 507, 583, 604, 717, 745, 806, 809, 810, 818, 819, 904, 918, 923, 924, 946, 957, 958, 960, 962, 964, 965, 970, 993, 997, 998, 999, 1004, 1009, 1026, 1037, 1078, 1153,1156, 1170, 1180, 1181, 1198, 1199, 1202, 1223 intestinal tract, 115, 219, 253, 287, 328, 593, 1227 intestine, 46, 157, 327, 328, 329, 343, 378, 396, 398, 399, 422, 424, 498, 699, 750, 814, 904, 916, 918, 958, 1193, 1196, 1201, 1214, 1217, 1227 intracellular calcium, xxi, xxxvi, 401, 403, 404, 471, 476, 483, 849, 1191, 1196 intrauterine growth retardation, 1067 intravenously, 240, 811, 813, 818, 888

Index ionization, 4, 103, 112, 118, 140, 558, 641, 730, 731, 757 ionizing radiation, xxv, 217, 755, 756, 757, 759, 764, 765, 766, 767, 769, 770 ions, 27, 373, 450, 557, 560, 641, 657, 668, 672, 675, 679, 681, 692 iron, xxv, xxvii, xxx, 119, 153, 158, 189, 196, 218, 314, 315, 336, 427, 430, 472, 474, 483, 619, 630, 695, 704, 705, 706, 717, 720, 723, 733, 735, 740, 745, 746, 748, 756, 759, 803, 804, 817, 822, 847, 849, 859, 861, 864, 865, 878, 888, 900, 904, 927, 928, 930, 957, 958, 959, 960, 963, 965, 966, 982, 991, 1004, 1011, 1014, 1024, 1063, 1142 iron transport, 803 irradiation, xxv, 45, 186, 209, 220, 274, 545, 554, 555, 561, 564, 568, 676, 678, 755, 756, 757, 758, 759, 760, 761, 762, 763, 764, 765, 766, 767, 768, 769, 770, 1024, 1067, 1199, 1212, 1213, 1217 irrigation, 1015 irritability, xxviii, 380, 506, 652, 748, 861, 998 irritable bowel syndrome, 645 ischaemic heart disease, 521, 1032, 1044 ischemia, 465, 473, 501, 856, 912, 1016 isolation, 3, 639, 683, 850, 970, 999 isomers, xi, 1, 4, 5, 12, 13, 14, 155, 1018, 1051 isothermal calorimetry, xxiv, 635 issues, xxxiii, 80, 430, 539, 720, 742, 758, 876, 970, 975, 1099, 1130, 1140

J Japan, xxx, 62, 69, 71, 81, 345, 366, 369, 409, 417, 449, 459, 487, 488, 489, 492, 499, 500, 577, 580, 581, 583, 596, 635, 730, 775, 798, 831, 834, 835, 894, 920, 924, 969, 970, 971, 978, 1179, 1211 Japanese women, 348, 358 jejunum, 327, 378, 611, 814 joints, xxviii, xxxv, 653, 861, 882, 1084, 1164, 1170 juvenile diabetes, 1082, 1083

K keratinocytes, xxxii, 24, 45, 76, 87, 1079, 1080, 1097, 1176 keratosis, 882 kidney, xxviii, xxix, xxxv, 45, 73, 74, 110, 219, 270, 343, 396, 398, 399, 426, 474, 483, 498, 513, 570, 597, 610, 647, 701, 708, 742, 782, 785, 815, 816, 817, 821, 832, 884, 888, 889, 894, 897, 900, 901, 915, 927, 928, 937, 946, 988, 1041, 1060, 1062, 1063, 1080, 1100, 1102, 1130, 1164, 1177, 1193, 1214, 1215, 1217, 1227

1253 kidney stones, xxviii, 513, 742, 817, 888, 889, 897, 900, 901, 927, 928, 937, 946 kidney transplantation, 817 kidneys, 45, 106, 110, 386, 399, 517, 700, 742, 814, 1165, 1176, 1182, 1192 kill, xxv, 208, 220, 640, 745, 755, 756, 817, 820, 936 kinase activity, 31, 610 kinetics, 158, 403, 555, 560, 561, 563, 565, 1052, 1060, 1070 knees, 1166 Krebs cycle, 100

L labeling, 28, 1139, 1146 laboratory studies, xvi, 109, 265, 708 laboratory tests, 749 lactation, xxxii, xxxiv, 287, 293, 298, 304, 612, 630, 905, 993, 1008, 1055, 1068, 1078, 1151, 1182, 1221 lactic acid, 866, 1209 Lactobacillus, 108, 116, 147 lactose intolerance, 333 landscape, 155 language development, 286, 305 language impairment, 506 laparoscopic cholecystectomy, 589, 593 laparoscopic colectomy, 490, 579, 593 laparoscopic surgery, 589 laparoscopy, 328 larva, 448 larvae, 436, 444, 449 larynx, 180, 202, 921 latency, 303, 747 laws and regulations, 812 leaching, 434, 867, 873 learning, xvi, xxxiii, 283, 285, 286, 288, 290, 291, 292, 293, 300, 301, 302, 303, 304, 324, 746, 1000, 1117, 1121, 1125, 1213 learning process, 302 left ventricle, 402 legs, xxxv, 289, 309, 380, 1173, 1178 lens, 553, 754, 886, 894, 917, 924, 941 lesions, xvi, 2, 77, 166, 206, 215, 236, 252, 283, 284, 289, 300, 302, 303, 304, 308, 317, 318, 382, 491, 572, 579, 651, 652, 704, 808, 845, 846, 904, 928, 988, 1026, 1218 lethargy, 619, 778, 782, 785 leukemia, xi, 17, 18, 19, 21, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 39, 40, 70, 71, 75, 159, 161, 164, 186, 189, 191, 641, 1024, 1026, 1047, 1048

1254 leukocytes, 19, 23, 380, 573, 699, 703, 709, 747, 804, 806, 810, 946, 1095 life course, 342, 357, 367 lifetime, 51, 274, 341, 362, 455, 642, 1175 ligament, 327, 598, 599, 605, 606, 686, 932, 935, 938, 944, 945, 948 ligand, xii, 17, 20, 22, 26, 30, 31, 33, 37, 38, 113, 160, 162, 193, 198, 378, 399, 641, 658, 671, 672, 673, 674, 675, 1080, 1103, 1165 light, xiii, xxii, xxxv, 4, 5, 44, 45, 47, 51, 62, 67, 82, 93, 99, 102, 110, 111, 116, 118, 124, 125, 126, 132, 133, 162, 167, 186, 257, 258, 263, 271, 274, 285, 286, 396, 434, 514, 543, 544, 545, 546, 549, 551, 552, 553, 554, 555, 556, 558, 559, 561, 562, 563,564, 565, 566, 567, 568, 641, 676, 677, 698, 740, 747, 756, 763, 834, 954, 1007, 1066, 1131, 1133, 1149, 1163, 1211, 1213, 1215, 1226, 1227, 1229 light scattering, 5, 555, 641, 677 linear function, 560 linoleic acid, 491, 494, 579, 585, 624, 630, 919 lipid metabolism, 353, 480, 628, 701, 806, 939, 1071 lipid peroxidation, 106, 205, 206, 215, 221, 225, 350, 426, 441, 442, 443, 468, 473, 477, 610, 615, 621, 623, 627, 630, 701, 702, 704, 742, 744, 747, 748, 759, 806, 819, 842, 846, 849, 853, 859, 864, 889, 903, 916, 923, 926, 933, 936, 939, 940, 943, 947, 970, 1028, 1041, 1045, 1047, 1057, 1064, 1074 lipid peroxides, 845, 860, 919, 922, 924, 936 lipoproteins, xxix, 158, 195, 369, 903, 915, 940, 996, 1022, 1029, 1042, 1056, 1058, 1060, 1069, 1070, 1073 liposoluble, vi, xix, xxx, 433, 434, 445, 958, 979, 980 liquid chromatography, xi, 12, 13, 14, 16, 94, 109, 112, 119, 137, 139, 140, 141, 142, 143, 144, 145, 147, 149, 461, 468, 629, 641, 688, 718, 724, 727, 730, 731, 734, 735, 736, 737, 759, 787, 788, 835, 959, 1046, 1066, 1131, 1140, 1218 liver cancer, 220, 744, 750 liver damage, 233, 440, 651, 741 liver disease, xxxii, 423, 424, 425, 426, 427, 428, 429, 430, 592, 594, 623, 624, 627, 632, 741, 750, 752, 1031, 1055, 1065, 1073, 1077, 1142, 1165, 1214 liver enzymes, 589, 1142 liver failure, 286 living environment, 238 localization, 20, 23, 31, 35, 79, 216, 388, 448, 632, 1122, 1204 loci, 1136 locomotor, 316 locus, 1104

Index longitudinal study, 55, 313, 367, 521, 896, 1119, 1186 loss of appetite, 651, 652, 654, 1004 lovastatin, 192, 452, 457 low temperatures, 441, 615, 761, 869 low-density lipoprotein, 153, 192, 653, 864, 922, 1021 low-grade inflammation, 805, 806, 809 lumen, 328, 436, 437, 440, 441, 611, 814, 1023, 1058 luminescence, 567 lung cancer, 35, 62, 71, 73, 74, 85, 163, 165, 166, 168, 187, 189, 195, 202, 203, 204, 211, 234, 270, 431, 454, 455, 457, 480, 648, 884, 947, 978, 1028, 1037, 1041, 1043, 1102, 1103, 1104, 1111 lung disease, 902 lung function, 743, 1065, 1077, 1187 lupus erythematosus, 1083, 1085, 1087, 1088, 1090, 1092 lutein, 392, 637, 654, 980, 1007, 1015, 1016 luteinizing hormone, 392 lycopene, 203, 204, 559, 637, 654, 682, 1007 lymph, 185, 189, 1070, 1082 lymphocytes, 18, 47, 48, 157, 186, 195, 594, 597, 612, 647, 705, 707, 715, 720, 765, 766, 803, 811, 812, 815, 825, 926, 928, 938, 1025, 1042, 1057, 1069, 1080, 1093, 1165, 1176, 1180, 1193, 1217 lymphoid, 18, 80, 83, 1025 lymphoma, 63, 65, 70, 71, 72, 74, 84, 162, 186, 198, 235, 270, 278, 279, 280, 382, 648, 702, 884, 1221 lysine, 482, 598, 801, 803, 804, 864, 931, 1108, 1109

M machinery, 24, 163, 199, 269, 400, 587, 1108 macrocytosis, 313, 383 macromolecules, 215, 546, 565, 640, 642, 740, 750 macronutrients, 464, 596, 1004, 1034 macrophages, xxvii, xxxii, 18, 19, 23, 27, 30, 79, 187, 194, 195, 210, 216, 224, 225, 232, 237, 502, 599, 805, 808, 809, 810, 812, 823, 847, 848, 1026, 1063, 1079, 1080, 1081, 1084, 1088, 1094, 1124, 1165, 1176, 1180, 1203, 1217 macular degeneration, 105, 744, 902, 906, 918, 924, 934, 937, 938, 947 magnesium, xxx, 294, 317, 340, 351, 352, 354, 360, 361, 362, 370, 373, 374, 427, 450, 452, 457, 600, 654, 742, 919, 957, 959, 1001 magnetic resonance, 526, 534, 572 magnetic resonance imaging, 526, 534, 572 magnitude, 216, 642, 659, 669, 675, 681, 816, 817, 989

Index major depression, xv, 53, 57, 59, 251, 254, 255, 258, 261, 289, 292, 296, 300, 318, 344, 347, 349, 352, 355, 361, 364, 365, 368, 371, 374, 376 major depressive disorder, 43, 49, 51, 58, 362, 367, 370, 374 major histocompatibility complex, 507, 570 malabsorption, xvii, xix, xxxv, 325, 326, 328, 330, 332, 333, 335, 337, 379, 381, 421, 422, 426, 500, 513, 530, 958, 965, 986, 1029, 1032, 1034, 1060, 1061, 1062, 1072, 1074, 1075, 1086, 1164 malaria, xxvii, 639, 683, 847, 1004, 1013, 1029, 1044 malignancy, xvi, 74, 76, 77, 78, 79, 235, 265, 271, 272, 273, 280, 822, 824, 892 malignant cells, 19, 28, 75, 220 malignant hyperthermia, 1032 malignant melanoma, 168, 202, 204, 266, 274, 1111, 1112, 1113 malnutrition, xix, xx, xxxi, 228, 231, 232, 252, 259, 284, 304, 421, 422, 427, 430, 451, 465, 539, 592, 593, 619, 622, 800, 965, 966, 986, 988, 989, 1003, 1004, 1005, 1006, 1009, 1013, 1015, 1016, 1028, 1031, 1032, 1044, 1228 mammalian brain, 1000 mammals, xxix, xxxii, 118, 268, 375, 399, 440, 481, 605, 615, 646, 718, 791, 801, 858, 859, 915, 942, 1030, 1099, 1107 management, xvii, xxi, xxiii, 145, 238, 275, 276, 340, 341, 344, 429, 430, 460, 466, 468, 485, 491, 492, 493, 494, 506, 516, 523, 524, 536, 569, 575, 582, 584, 585, 594, 614, 624, 687, 806, 876, 886, 897, 920, 1004, 1016, 1073, 1075, 1121, 1171, 1172, 1213 marketing, 761, 862, 952, 1013 marrow, 279, 280, 848, 917, 1025 mass, xxxvi, 5, 12, 50, 53, 64, 94, 98, 100, 103, 104, 109, 112, 138, 139, 140, 141, 145, 149, 224, 228, 233, 326, 328, 332, 436, 641, 718, 724, 730, 731, 735, 808, 1066, 1131, 1132, 1133, 1140, 1164, 1191, 1193, 1198, 1201, 1214, 1215, 1218 mass spectrometry, 94, 100, 109, 112, 139, 140, 141, 149, 641, 718, 724, 730, 731, 735, 1066, 1131, 1132, 1140, 1215, 1218 mast cells, 18, 801, 806 matching-to-sample, 285, 286 materials, xxii, 45, 99, 109, 117, 543, 771, 859, 1011, 1132, 1140 matrix, xiii, xv, xxv, 3, 4, 89, 90, 93, 95, 97, 99, 102, 104, 107, 110, 115, 116, 119, 125, 153, 158, 188, 189, 195, 210, 235, 239, 240, 403, 489, 494, 535, 581, 585, 598, 599, 605, 641, 701, 723, 724, 725, 726, 756, 757, 802, 804, 864, 931, 982, 984, 1007, 1024, 1062, 1071, 1177, 1178, 1217

1255 matrix metalloproteinase, 89, 90, 153, 188, 210, 235, 403, 489, 494, 581, 585, 1062 matter, iv, 3, 289, 308, 324, 442, 511, 512, 530, 928, 1065, 1074, 1077, 1233 MCP, 807 MCP-1, 807 measles, 654, 986, 987, 989, 990, 1013 measurement, xxi, 80, 136, 146, 159, 168, 336, 355, 356, 357, 358, 359, 360, 380, 399, 431, 497, 499, 596, 713, 715, 762, 814, 844, 922, 1052, 1131, 1132, 1137, 1139, 1140, 1146, 1176, 1185, 1218, 1225 measurements, 56, 72, 228, 335, 380, 536, 561, 641, 671, 681, 874, 875, 986, 1096, 1129, 1131, 1157, 1218, 1219 meat, xxiv, 96, 101, 109, 115, 116, 131, 141, 144, 147, 148, 226, 257, 294, 342, 349, 353, 354, 378, 397, 609, 619, 620, 621, 622, 627, 628, 629, 653, 713, 750, 765, 918, 1036, 1046, 1210 media, 140, 191, 563, 854, 1208 median, 65, 66, 67, 69, 72, 169, 170, 171, 172, 174, 175, 176, 177, 490, 579, 921, 923, 982, 1065, 1135, 1155, 1166, 1168, 1169, 1222 mediation, 96 medical, xii, xxxiv, 43, 44, 48, 80, 221, 271, 273, 340, 342, 379, 516, 592, 601, 646, 744, 888, 958, 1059, 1076, 1151, 1166, 1208, 1209, 1211, 1221 medical history, 271, 273 medication, xxxiii, 253, 258, 309, 531, 817, 958, 1117, 1121, 1217 medicine, xxi, xxiii, xxiv, xxix, 216, 274, 275, 276, 277, 278, 307, 308, 309, 453, 480, 485, 486, 490, 493, 494, 517, 519, 520, 522, 523, 524, 525, 526, 575, 576, 577, 584, 585, 596, 635, 638, 639, 641, 642, 670, 683, 694, 710, 712, 717, 739, 818, 825, 929, 949, 950, 1014, 1069, 1072, 1140, 1201, 1202, 1203, 1204, 1205, 1231 Mediterranean, xiii, 151, 460, 464, 465, 467, 540, 645, 911, 1015, 1029, 1030, 1090, 1094, 1124, 1142 medulla, 476, 832, 846 melanoma, xv, 71, 72, 73, 74, 80, 85, 159, 177, 179, 189, 211, 220, 221, 236, 265, 266, 272, 274, 481, 702, 821, 884, 890, 1025, 1040, 1103, 1104, 1105, 1106, 1108, 1109, 1111, 1112, 1115, 1216 melatonin, 47, 65, 74, 78, 86, 252, 254, 256, 257, 258, 260, 263, 288, 306, 821, 857, 934, 943 mellitus, xxviii, 47, 328, 351, 460, 462, 463, 506, 513, 702, 714, 717, 809, 819, 821, 822, 827, 828, 856, 858, 881, 884, 891, 892, 901, 910, 916, 918, 919, 920, 933, 935, 939, 946, 1042, 1056, 1063, 1076, 1077, 1082, 1083, 1128, 1179, 1184, 1188, 1203, 1218

1256 membrane permeability, 218 membranes, 186, 351, 436, 441, 464, 610, 615, 616, 623, 631, 814, 871, 885, 896, 996, 999, 1021, 1029, 1067 memory, xvi, xxxiii, 259, 260, 283, 289, 291, 293, 294, 295, 296, 298, 299, 300, 301, 302, 303, 304, 307, 311, 313, 314, 315, 317, 373, 380, 382, 418, 505, 506, 508, 509, 510, 522, 524, 602, 746, 975, 997, 1000, 1081, 1117, 1118, 1119, 1125 memory function, xvi, 283, 307, 1119, 1125 memory performance, 314, 997 menadione, 443, 444, 449 menadione sodium bisulfite, 443 menstrual cycles, 389 mental development, 314, 1044 mental disorder, 52, 57, 58, 308, 362, 364, 887 mental retardation, 294, 310, 316, 531, 534 mental state, 319 mercury, 676, 681, 686, 744, 793, 796, 1211, 1213 meta-analysis, 49, 58, 64, 65, 66, 67, 84, 149, 194, 270, 292, 299, 323, 347, 365, 367, 375, 455, 457, 486, 498, 499, 501, 502, 504, 505, 506, 507, 509, 511, 514, 518, 519, 520, 521, 522, 523, 525, 576, 589, 607, 703, 714, 753, 822, 889, 893, 909, 910, 913, 923, 924, 935, 937, 946, 948, 991, 1001, 1068, 1093, 1094, 1105, 1113, 1136, 1149, 1153, 1154, 1156, 1159, 1161, 1162, 1178, 1179, 1181, 1186, 1187, 1189, 1193, 1199, 1205, 1222, 1229, 1230, 1231, 1232 Metabolic, v, 213, 232, 309, 336, 339, 340, 429, 624, metabolic pathways, xx, 26, 221, 222, 224, 298, 443, 471, 632, 929 metabolic syndrome, 271, 280, 327, 351, 352, 360, 401, 539, 708, 752, 805, 809, 901, 918, 919, 937, 938, 1077, 1129, 1139, 1143, 1182, 1201, 1230 metabolites, 21, 34, 46, 47, 50, 51, 85, 155, 158, 166, 199, 218, 231, 254, 256, 259, 260, 270, 293, 305, 313, 338, 380, 383, 396, 399, 401, 402, 426, 444, 535, 612, 621, 639, 641, 687, 688, 701, 706, 759, 895, 1028, 1058, 1059, 1066, 1071, 1072, 1092, 1101, 1140, 1204, 1214, 1215, 1218 metabolized, 45, 158, 222, 223, 233, 535, 612, 704, 710, 761, 1008, 1058, 1060, 1068 metabolizing, xxxii, 710, 859, 1055, 1110, 1158 metal ion, xxix, 110, 118, 560, 564, 657, 685, 704, 915, 928 metal ions, 110, 118, 560, 564, 657, 685, 704, 928 metals, 87, 234, 483, 568, 695, 705, 706, 712, 714, 759, 903, 912 metastasis, xii, 61, 68, 74, 75, 78, 79, 89, 188, 189, 198, 208, 216, 221, 224, 235, 686, 810, 890, 1047, 1103, 1104, 1115

Index methanol, 4, 5, 9, 10, 11, 98, 100, 102, 112, 117, 121, 122, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 144, 552, 554, 560, 727, 729, 730, 774, 784 methodology, xxxv, 95, 97, 145, 378, 736, 1120, 1140, 1146, 1164 methyl group, xi, xxxi, 1, 2, 113, 154, 155, 157, 159, 183, 260, 306, 1017, 1107, 1108 methylation, xxxii, 20, 90, 105, 113, 158, 222, 237, 248, 253, 254, 261, 287, 289, 295, 306, 309, 346, 423, 424, 616, 619, 714, 1099, 1107, 1108, 1109, 1114, 1115, 1137, 1176 micrograms, 378, 1026, 1027, 1219 micronucleus, 708, 709, 710, 711, 715, 716, 717, 721 micronutrients, xiii, xix, xxvi, xxxi, 93, 153, 200, 201, 202, 203, 204, 205, 208, 226, 301, 327, 339, 433, 446, 468, 596, 600, 602, 607, 614, 619, 625, 626, 673, 682, 709, 712, 714, 716, 722, 734, 752, 773, 792, 793, 799, 803, 809, 904, 905, 907, 933, 939, 940, 950, 958, 959, 965, 966, 978, 1003, 1004, 1023, 1048, 1145 microorganism, 701, 867, 868 microorganisms, 115, 377, 687, 756, 873, 887, 1011 microwave heating, 16, 110, 873 midgut, 435, 436, 437, 438, 439, 440, 441, 443, 444, 445, 446, 448 midgut gland, 435, 436, 437, 438, 439, 440, 441, 443, 444, 445, 446 migraine headache, 351, 651 migration, 58, 163, 191, 195, 645, 802, 808, 1026 Mild Cognitive Impairment, xxxi, 510, 520, 521, 995, 996 milligrams, 111, 640, 1020, 1033, 1059 mineralization, xxxiv, 47, 386, 396, 439, 498, 517, 599, 1100, 1101, 1118, 1128, 1137, 1163, 1164, 1177, 1178 mineralocorticoid, 410 Ministry of Education, 417, 978 mitochondria, 45, 160, 198, 219, 220, 410, 418, 460, 475, 478, 479, 483, 747, 803, 817, 848, 1100, 1128, 1138 mitochondrial DNA, 996 mitogen, xxxvi, 26, 32, 39, 40, 75, 77, 191, 343, 473, 627, 813, 1191, 1193 mitosis, 164, 645, 1122 mixing, 131, 327, 787 models, xix, xxiii, 50, 161, 165, 166, 167, 181, 206, 259, 260, 270, 284, 302, 306, 365, 373, 395, 396, 399, 402, 403, 404, 417, 427, 507, 534, 535, 569, 588, 589, 595, 702, 707, 809, 818, 845, 859, 879, 885, 997, 999, 1011, 1022, 1029, 1082, 1083, 1084, 1087, 1120, 1129, 1146, 1158, 1223 moderates, 590

Index modern society, 638 modifications, xxxii, 25, 97, 111, 117, 157, 215, 248, 327, 435, 704, 720, 763, 765, 827, 942, 988, 1099, 1107, 1108, 1109, 1136, 1176 moisture, 758, 777, 779, 781, 788, 952, 1010, 1011 molecular biology, 39, 278, 515, 516, 564, 1202, 1203, 1204, 1226 molecular dynamics, 559 molecular oxygen, 217, 472, 553, 554, 704, 855, 864, 916 molecular structure, xxiv, 240, 635, 694, 705 molecules, xii, 17, 18, 19, 21, 24, 25, 28, 29, 30, 78, 186, 190, 215, 216, 217, 222, 223, 224, 232, 240, 295, 370, 396, 412, 442, 461, 475, 507, 610, 612, 616, 638, 639, 641, 659, 660, 662, 663, 665, 667, 668, 672, 674, 675, 676, 680, 701, 704, 748, 750, 757, 759,802, 804, 806, 807, 813, 848, 902, 916, 978, 996, 1042, 1045, 1082, 1179, 1196 molybdenum, 923 mood disorder, xvii, 43, 54, 58, 254, 288, 341, 349, 355, 361, 362, 370, 382, 419, 936 mood states, 931 morbidity, xx, 51, 270, 271, 328, 401, 451, 518, 589, 920, 924, 982, 986, 988, 989, 990, 1050, 1063, 1066, 1172 morphine, 591, 639 morphology, 436, 444, 598, 667, 851, 1024, 1198 mortality rate, xii, xxxv, 61, 62, 63, 67, 68, 72, 73, 80, 81, 82, 270, 454, 491, 582, 589, 593, 747, 748, 1173 mortality risk, 518, 988, 1157, 1187, 1229, 1231 motor activity, 288, 293, 298, 645 motor system, 316 mucosa, 378, 381, 611, 711, 802, 832, 1201, 1227 mucous membrane, 654, 703, 989 multiple factors, 387 multiple sclerosis, xxii, 47, 48, 56, 57, 114, 143, 263, 269, 277, 317, 382, 409, 501, 518, 569, 570, 573, 654, 1082, 1083, 1091, 1094, 1096, 1128, 1218, 1219, 1231, 1232 multiwalled carbon nanotubes, 733 muscle contraction, xxxvi, 1191, 1196 muscle mass, xxxvi, 228, 1178, 1191, 1192, 1198, 1204, 1206, 1229 muscle strength, xxxiv, 1152, 1156, 1157, 1158, 1160, 1161, 1178, 1197, 1198, 1199, 1204, 1205, 1206, 1218, 1219, 1229 muscles, xxviii, xxxv, 21, 119, 621, 622, 651, 652, 700, 861, 1164, 1173, 1178 musculoskeletal, 500, 1138, 1144, 1157, 1172, 1200, 1204, 1205, 1218, 1229 mutagen, 155, 706 mutagenesis, 946

1257 mutant, 36, 160, 161, 165, 402, 624, 631, 796, 833, 845, 1050 mutations, 74, 76, 153, 158, 163, 166, 189, 215, 506, 701, 704, 1029, 1030, 1031, 1040, 1044, 1048, 1049, 1052, 1061, 1115 mycobacteria, 1186 myelin, xvi, 114, 257, 283, 287, 293, 295, 300, 306, 381, 572, 864, 1028 myelin basic protein, 306 myelodysplastic syndromes, 85 myeloid cells, 18, 19, 33, 37, 1091 myocardial infarction, 401, 402, 451, 453, 454, 455, 456, 457, 465, 467, 806, 883, 893, 922, 946, 1032, 1035, 1050, 1149 myocardium, xviii, 395, 399, 419, 464 myocyte, xix, 395, 402, 403, 404, 1029, 1148 myopathy, 970, 1029, 1043, 1050, 1052, 1062, 1075, 1198

N naming, 639 nanoparticles, 664, 667, 676, 681, 692, 1024, 1047, 1049 nanotube, 688 naphthalene, 449, 637, 669, 670, 675, 677 nasopharyngeal carcinoma, 235, 1103, 1112 nasopharynx, 1103 National Aeronautics and Space Administration, 270 National Health and Nutrition Examination Survey, xxxv, 58, 64, 277, 313, 329, 378, 503, 874, 897, 939, 947, 1000, 1036, 1077, 1148, 1149, 1164, 1216, 1230, 1231 National Health and Nutrition Examination Survey (NHANES), 1216 National Research Council, 448, 629, 796, 911, 956, 1072 natural compound, 1007 natural food, xxvii, 596, 847 natural killer (NK) cells, 1081 natural products, xxiv, 486, 576, 635, 639 natural resources, 682 nausea, 489, 490, 491, 494, 579, 581, 585, 614, 640, 652, 653, 654, 655, 904, 927, 983, 984, 1062 necrosis, 237, 318, 440, 441, 444, 464, 715, 718, 809, 890, 932, 939, 1029, 1032, 1052, 1165, 1203 negative consequences, 988 neocortex, 252, 284, 285, 294, 296, 310, 349 neonates, 1176, 1188 neoplasm, 80, 81, 382, 486, 576, 701, 1179 nephrectomy, 1214 nephritis, 1085 nephrolithiasis, 927, 939

1258 nerve, xv, 53, 114, 239, 240, 295, 351, 382, 479, 501, 519, 530, 651, 652, 742, 748, 1026, 1039, 1040, 1121, 1122 nerve growth factor, 53, 295, 501, 519, 1121, 1122 nervous system, 259, 260, 301, 306, 314, 364, 381, 383, 410, 417, 418, 501, 598, 651, 652, 801, 864, 1028, 1031, 1044, 1118, 1121, 1122 neuralgia, 647 neurobiology, 370 neuroblastoma, 37, 38, 153, 189, 211, 279 neurodegeneration, 252, 353, 502, 506, 909, 1120 neurodegenerative dementia, 508, 510 neurodegenerative diseases, 286, 417, 478, 508, 519, 701 neurodegenerative disorders, xxxi, 105, 217, 349, 686, 812, 893, 903, 995, 997, 999, 1041, 1073 neurofibrillary tangles, 506 neuroimaging, 509, 510, 512, 525 neurologic symptom, 254, 288, 290, 295, 297 neurological disease, 137, 308, 511, 515, 908, 999, 1038, 1068 neurological disorders, xvii, 259, 304, 377, 530, 747, 902, 1061, 1062, 1074 neurological rehabilitation, 510 neurons, xv, 251, 252, 253, 256, 258, 259, 260, 285, 287, 288, 293, 294, 302, 304, 306, 349, 410, 501, 864, 887, 996, 1025, 1061, 1118, 1120, 1121, 1122 neuropathic pain, 49, 56 neuropathy, xviii, 185, 208, 209, 308, 309, 316, 377, 381, 488, 489, 490, 493, 494, 578, 580, 581, 584, 585, 652, 1026, 1038, 1061, 1075 neuropeptides, 864, 931 neuropharmacology, 261, 315 neuroprotection, xxi, 48, 185, 209, 323, 372, 497, 501, 515, 827, 997 neuropsychiatry, 319 neuropsychological tests, 382, 502, 503, 505, 509 neuroscience, 520 neurotoxicity, xxi, xxiii, 185, 485, 488, 490, 492, 501, 519, 520, 575, 577, 580, 583, 1025 neurotransmission, xxv, 48, 345, 352, 366, 410, 502, 530, 723, 890 neurotransmitter, 53, 343, 410, 418, 423, 477, 745, 864, 931, 1118 neurotransmitters, xxviii, xxix, 114, 254, 263, 284, 295, 310, 354, 502, 507, 899, 915 neurotrophic factors, 501, 1118 neutral, 28, 545, 547, 552, 553, 555, 567, 639, 668 neutropenia, 490, 579 neutrophils, 18, 591, 598, 605, 622, 700, 747, 803, 804, 810, 815, 864, 918, 932, 1028

Index New England, 139, 274, 277, 447, 516, 624, 630, 822, 1044, 1046, 1050, 1051, 1053, 1153 niacin, 95, 97, 101, 102, 122, 124, 131, 133, 142, 153, 259, 301, 423, 429, 453, 598, 603, 636, 640, 651, 656, 758, 761, 767, 769, 775, 991, 1061 niacin deficiency, 95, 603 niacinamide, 122, 142, 636, 651, 656, 681 nickel, 480, 481, 483, 667, 690 nicotinamide, 99, 101, 102, 104, 123, 423, 692, 864, 889, 932 nicotine, xxiv, 636, 639, 646, 650, 665, 687, 690, 694, 710, 711, 712, 713, 717, 719, 743 nicotinic acid, 97, 101, 102, 104, 129, 430 nitric oxide, xx, 153, 183, 191, 212, 224, 302, 345, 352, 367, 393, 461, 471, 472, 473, 475, 482, 501, 502, 588, 704, 805, 806, 807, 808, 822, 828, 890, 895, 902, 922, 1081, 1118, 1120, 1121 nitric oxide synthase, 191, 224, 302, 461, 473, 588, 806, 807, 1081, 1118, 1121 nitrite, xx, 460, 462, 475, 478, 887, 890 nitrogen, 98, 100, 102, 111, 112, 123, 124, 126, 128, 154, 183, 194, 472, 478, 566, 588, 624, 639, 668, 670, 704, 769, 806, 864, 887, 902, 903, 918, 1056, 1057 nitrogen dioxide, 154, 194 nitrosamines, 225, 756, 901, 916 nitroso compounds, 226, 701 nitroxide, 864, 918 nitroxide radicals, 864, 918 nodules, 438 non-classical, 1128 non-enzymatic antioxidants, 704, 804, 832 non-Hodgkin’s lymphoma, 80, 270, 1129 non-institutionalized, 538, 601, 874 non-polar, 3, 117 non-radiation energy transfer, 658, 660, 669, 672, 675 non-steroidal anti-inflammatory drugs, 679 noradrenergic system, 261, 307, 345, 347, 368 norepinephrine, 302, 345, 346, 479, 695, 801, 864, 931 normal aging, xvi, 283, 290, 293, 296, 297, 502 normal development, 90, 654, 1046, 1164 North America, xxxvii, 82, 503, 516, 1029, 1092, 1207, 1221, 1233 nuclear magnetic resonance, 510, 641, 665, 670, 1214 nuclear receptors, 19, 20, 30, 38, 39, 399, 417, 429, 1058, 1109 nuclei, 46, 252, 441, 570, 1025, 1118, 1215, 1227 nucleic acid, xxiii, xxxii, 119, 142, 566, 587, 590, 884, 917, 1004, 1055, 1057 nucleosome, 715

Index nucleotides, 346, 552, 566, 588, 594, 1105 nucleus, xxxvi, 18, 20, 23, 24, 26, 27, 30, 160, 217, 262, 403, 437, 441, 498, 501, 545, 659, 841, 844, 848, 852, 1061, 1080, 1191, 1195, 1196, 1217 nursing, 47, 55, 320, 500, 514, 517, 527, 993, 1078, 1124, 1154, 1155, 1156, 1159, 1160, 1161, 1209, 1229 nursing home, 47, 55, 320, 500, 514, 517, 527, 1154, 1156, 1160, 1229 nutrients, xiv, xix, xxx, 144, 201, 203, 208, 214, 226, 248, 305, 314, 354, 421, 430, 433, 434, 438, 453, 454, 460, 464, 465, 466, 596, 600, 601, 602, 605, 614, 620, 622, 718, 741, 746, 758, 761, 765, 773, 791, 793, 797, 812, 813, 848, 866, 867, 869, 873, 874, 878,905, 906, 922, 926, 929, 938, 943, 944, 946, 952, 957, 958, 965, 982, 1004, 1005, 1072, 1078, 1171, 1220 nutrition assessment, 595, 874, 1072 nutritional assessment, 227, 991 Nutritional assessment Obesity Biliopancreatic bypass Vitamin A Bariatric surgery, 957 nutritional deficiencies, xxix, 226, 328, 337, 339, 340, 365, 430, 622, 876, 957, 958, 965, 966, 1067, 1068, 1212 nutritional status, 46, 231, 238, 297, 312, 320, 338, 369, 491, 494, 531, 534, 540, 579, 585, 713, 721, 784, 825, 862, 874, 905, 928, 929, 958, 959, 967, 1008, 1068, 1123, 1204, 1217, 1218

O obesity, xiii, xvii, 47, 147, 151, 325, 326, 327, 328, 329, 337, 338, 340, 386, 387, 390, 391, 392, 393, 460, 462, 465, 500, 506, 513, 518, 530, 539, 540, 646, 708, 709, 710, 712, 713, 714, 746, 752, 805, 809, 958, 959, 960, 961, 965, 966, 967, 1063, 1086, 1129, 1133, 1141, 1159, 1174, 1175, 1183, 1202, 1205, 1217, 1224, 1225 obstruction, 231, 232, 1062 obstructive lung disease, 743, 918, 970, 978 obstructive sleep apnea, 327, 958 occurrence, vii, xxiv, xxxi, 2, 180, 596, 623, 635, 642, 670, 682, 742, 744, 834, 842, 999, 1005, 1017, 1022, 1033, 1043, 1102, 1104, 1105, 1106, 1165, 1199, 1205, 1232 oesophageal, 237, 238, 884, 894, 1179 old age, 312, 320, 527, 742, 1124 oligodendrocytes, 300, 501 olive oil, xiii, 7, 151, 464, 624, 682, 1036, 1041 omega-3, 364, 464, 466, 588, 590, 592, 593, 632, 824, 889, 891, 897, 919, 1150 oncogenes, 189, 211, 215, 473, 1109 oncogenesis, 106

1259 oncoproteins, 35 oocyte, 388, 392, 438 oophorectomy, 593 operations, 747 opioids, 591 opportunities, 280, 639, 646 opthalmoplegia, 1061 optic nerve, xviii, 295, 377, 381, 383 optical activity, 668, 1018 optimization, xvii, 14, 341, 565, 900 oral cavity, 174, 178, 180, 876, 896, 901, 921 oral diseases, 877 oral health, 595, 874 orbit, 215 orchestration, 90 organ, 96, 105, 115, 118, 396, 435, 445, 589, 647, 741, 742, 1082, 1196 organelle, xx, 471 organic chemicals, 639 organic compounds, 435, 641 organic solvents, 3, 117, 559, 560, 562, 565, 889 organism, xxvii, 44, 108, 116, 396, 477, 591, 701, 723, 801, 804, 805, 812, 861, 862, 907, 980, 1006, 1028 organs, 100, 188, 386, 397, 444, 465, 481, 498, 515, 623, 741, 802, 817, 832, 845, 1026, 1036, 1039, 1059, 1060, 1063, 1100, 1179, 1209 originality, 1208 orthostatic hypotension, 508 ossification, 1209 osteoarthritis, xviii, xxviii, 269, 277, 395, 750, 881, 882, 892, 896, 897, 1164, 1183, 1189 osteodystrophy, 654 osteomalacia, xvii, xxxv, 47, 325, 326, 329, 330, 331, 337, 338, 343, 396, 500, 654, 1128, 1164, 1173, 1178, 1210, 1219, 1221 osteonectin, 599 osteoporosis, xvii, xxxiv, xxxv, 47, 56, 106, 114, 325, 326, 329, 330, 331, 337, 338, 343, 386, 426, 427, 500, 516, 517, 596, 654, 655, 805, 854, 856, 947, 1092, 1124, 1128, 1163, 1164, 1165, 1166, 1168, 1170, 1171, 1172, 1173, 1178, 1194, 1221, 1222, 1233 outpatients, 58, 352, 353, 360, 361, 531, 536, 1119 ovarian cancer, 64, 67, 68, 75, 80, 82, 83, 84, 86, 185, 203, 208, 319, 1025, 1042, 1103, 1104, 1112, 1113 ovarian tumor, 75, 185 ovaries, 386, 389, 1181 overlap, 64, 100, 101, 333, 508, 511, 1005 overweight, 326, 338, 343, 350, 355, 360, 365, 371, 393, 513, 540, 714, 912, 958, 1147, 1150, 1159, 1194, 1200, 1202, 1232

1260

Index

ovulation, xviii, 385, 388 ovulatory dysfunction, xviii, 385, 390 ox, 119, 920, 1047 oxalate, 742, 745, 817, 827, 888, 889, 895, 927, 947, 952 oxidation products, 136, 443, 694, 704, 864, 874, 894 oxidative damage, 76, 215, 216, 218, 226, 236, 298, 321, 346, 367, 478, 481, 611, 696, 705, 706, 721, 743, 750, 806, 816, 845, 853, 857, 858, 864, 886, 895, 916, 919, 922, 926, 928, 930, 996, 998, 1021, 1022, 1024, 1025, 1037, 1041, 1057, 1064, 1066, 1074 oxidative destruction, 873 oxidative reaction, 741 oxidative stress in cancer, 214 oxygen, xiii, xx, xxii, xxv, xxvii, xxviii, 93, 99, 110, 111, 118, 143, 219, 235, 441, 442, 471, 472, 473, 474, 476, 477, 478, 479, 480, 481, 482, 543, 545, 546, 548, 550, 552, 553, 554, 556, 559, 564, 565, 566, 567, 610, 639, 641, 652, 677, 695, 704, 714, 741, 742, 745, 746, 755, 757, 763, 765, 804, 806, 821, 847, 848, 849, 850, 851, 858, 859, 861, 864, 865, 894, 902, 903, 908, 918, 923, 928, 930, 931, 938, 940, 941, 1007, 1011, 1015, 1021, 1067 oxygen consumption, 482, 903 oysters, 125, 349 ozone, 62, 498, 918, 1066, 1077, 1192, 1216

P p53, 76, 78, 159, 160, 161, 162, 165, 166, 184, 192, 197, 198, 199, 219, 220, 893, 912, 1024, 1025, 1041 paclitaxel, 1024, 1038, 1043, 1048, 1049 paediatric patients, 280 pain, vii, xxiii, xxviii, 49, 56, 208, 255, 293, 333, 335, 491, 579, 587, 589, 590, 591, 592, 593, 644, 645, 648, 652, 654, 655, 701, 745, 861, 882, 906, 941, 1038, 1084, 1142, 1164, 1166, 1178, 1183, 1189, 1218, 1229 palm oil, xxx, 11, 161, 165, 183, 191, 198, 199, 207, 618, 979, 984, 1041, 1049 pancreas, 81, 110, 128, 147, 219, 248, 700, 901, 1032, 1100, 1128, 1214, 1217 pancreatic cancer, 32, 65, 66, 68, 74, 81, 83, 160, 162, 179, 191, 192, 198, 204, 819, 823, 884, 891, 1024 pancreatic insufficiency, 425, 426 pancreatitis, 902, 1039, 1060, 1217 parallel, xxxi, 103, 261, 301, 368, 427, 494, 585, 607, 748, 995 paralysis, 1044

parasitic infection, 992, 1004 parathyroid, 45, 46, 48, 51, 56, 57, 277, 329, 331, 336, 337, 338, 364, 386, 396, 427, 498, 513, 534, 536, 539, 570, 959, 1080, 1119, 1122, 1128, 1141, 1142, 1144, 1146, 1148, 1166, 1176, 1177, 1186, 1193, 1194, 1209, 1214, 1215, 1217, 1227, 1229, 1230 parathyroid hormone, 45, 46, 51, 57, 277, 329, 331, 336, 337, 364, 386, 427, 498, 513, 534, 539, 570, 959, 1080, 1119, 1122, 1128, 1141, 1142, 1144, 1146, 1148, 1166, 1186, 1193, 1217, 1229, 1230 participants, xxx, 51, 53, 66, 67, 72, 271, 272, 277, 344, 388, 455, 503, 504, 505, 531, 534, 602, 710, 714, 810, 874, 925, 943, 969, 970, 971, 972, 975, 1039, 1065, 1066, 1119, 1132, 1153, 1154, 1155, 1156, 1158, 1196, 1197, 1198, 1199, 1219 partition, 663, 858, 1214 pathogenesis, xix, xxxii, 37, 47, 52, 53, 79, 219, 225, 237, 266, 302, 392, 451, 460, 464, 508, 611, 717, 742, 744, 806, 809, 824, 829, 918, 919, 1028, 1068, 1076, 1079, 1082, 1083, 1087, 1100, 1115, 1128, 1145, 1165, 1172 pathogens, xxvii, 598, 605, 611, 638, 647, 757, 847, 1011 pathophysiological, xxxi, 473, 507, 995, 1129 pathophysiology, xxi, 343, 346, 363, 370, 373, 374, 389, 401, 402, 472, 502, 506, 508, 515, 887, 1066, 1171 peak expiratory flow rate, 1065, 1077 pediatrician, 1211, 1212 pellagra, 101, 423, 651, 1210, 1212 penaeoid, xix, 433, 434, 435, 440, 442, 445, 447 peptide, 33, 37, 403, 519, 599, 658, 662, 667, 695, 801, 802, 803, 849, 864, 893, 1000, 1081, 1084, 1091, 1096, 1097, 1177 peptides, 23, 507, 1128 percentile, 531, 813 pericytes, 519 perinatal, 300, 306, 827, 1078 periodontal disease, 596, 597, 599, 600, 601, 602, 603, 604, 606, 607, 608, 873, 875, 876, 877, 1128 periodontitis, 596, 600, 601, 602, 603, 604, 606, 607, 875, 877, 879 peripheral blood, 708, 715, 821, 1042, 1195 peripheral neuropathy, 114, 293, 294, 300, 380, 382, 383, 423, 489, 490, 492, 495, 577, 581, 583, 586, 652, 1026, 1028, 1031, 1038, 1062, 1075 permission, 327, 917, 930, 931, 932 peroxidation, 225, 442, 443, 706, 713, 714, 742, 744, 745, 747, 828, 853, 857, 908, 923, 926, 939, 940, 944, 946, 1027, 1039, 1057, 1064 peroxide, xxvii, 550, 817, 823, 827, 831, 832, 946, 1021, 1022

Index peroxisome proliferator activator receptor, xiv, 152, 153 pH, xxii, xxvii, 98, 101, 102, 109, 110, 111, 112, 117, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 134, 135, 241, 543, 545, 546, 547, 549, 552, 553, 554, 555, 556, 557, 558, 560, 561, 562, 565, 567, 568, 641, 657, 663, 666, 669, 670, 671, 678, 679, 692, 698, 724, 725, 726, 727, 728, 729, 730, 731, 732, 763, 764, 765, 777, 835, 847, 848, 849, 856, 865, 866, 867, 868, 872, 889, 890, 943 phagocytosis, 502, 605, 747, 804, 805, 816, 864, 932, 1180, 1181 pharmaceutical, xxii, xxxvii, 119, 145, 148, 288, 543, 559, 563, 639, 640, 641, 642, 659, 665, 682, 724, 732, 733, 882, 900, 935, 1033, 1036, 1207, 1213 pharmacogenetics, 827 pharmacokinetics, xxxii, 642, 718, 824, 827, 887, 895, 942, 944, 1018 pharmacology, 366, 374, 453, 518, 606, 682, 688, 719, 824, 826 phenol, 552, 554, 559, 1040 phenolic compounds, 564, 683, 684, 852 phenothiazines, 552, 568 phenotype, 39, 78, 197, 220, 221, 303, 347, 348, 402, 570, 605, 716, 814, 1030, 1048, 1073, 1075, 1076, 1081, 1128, 1136, 1202 phenytoin, 253, 254, 255, 286, 290, 305, 535, 538, 606, 607 phosphatase, 153, 191, 330, 336, 440, 444, 448, 449, 450, 532, 533, 605, 786, 1081, 1166, 1193 phosphatidylcholine, 287, 306, 555, 561, 858 phosphatidylserine, xxvii, 847, 858 phospholipids, 15, 114, 253, 257, 287, 293, 295, 610, 611, 853, 1031, 1062 phosphorus, xxix, xxxiii, xxxv, 269, 340, 343, 386, 439, 440, 444, 498, 500, 639, 654, 949, 950, 952, 1095, 1118, 1127, 1128, 1163, 1166, 1167, 1169, 1170, 1173, 1176, 1177, 1178, 1209, 1217, 1226 phosphorylation, 20, 23, 24, 25, 26, 29, 30, 31, 34, 37, 38, 39, 40, 78, 79, 164, 165, 190, 191, 197, 199, 211, 217, 346, 350, 351, 372, 376, 388, 440, 475, 477, 483, 1023, 1108 photoaddition, xxii, 543, 544, 546, 551, 552, 557, 558, 560 photobleaching, 545, 546, 555, 565, 566 photodegradation, xxii, 543, 544, 545, 549, 552, 553, 554, 555, 556, 557, 558, 559, 560, 561, 562, 563, 564, 566, 567, 736 photolysis, 544, 545, 546, 552, 554, 555, 556, 557, 558, 559, 560, 561, 562, 564, 567, 568

1261 photooxidation, 544, 546, 552, 553, 554, 563, 564, 565, 566, 568 photoreduction, xxii, 543, 544, 545, 546, 547, 548, 549, 552, 557, 558, 560, 564 photostability, 543, 555, 561, 564, 565, 889 photosynthesis, 338, 1035, 1138, 1185 phototoxicity, 676 physical activity, 276, 373, 513, 531, 534, 906, 1033, 1170, 1204 physical characteristics, 956 physical exercise, 201, 237, 703, 883, 925, 926, 931, 947 physicians, 269, 431, 453, 455, 752, 813, 911, 923, 943, 1192, 1209 physicochemical properties, xxviii, 899, 956 physiological factors, 290 physiology, 44, 188, 215, 223, 224, 328, 366, 370, 386, 391, 395, 434, 440, 445, 446, 450, 471, 480, 498, 515, 518, 623, 625, 626, 628, 630, 632, 683, 684, 714, 719, 721, 769, 794, 795, 819, 821, 824, 826, 845, 846, 855, 912, 1035, 1040, 1041, 1042, 1044, 1045, 1048, 1051, 1078, 1138, 1184 phytosterols, 611, 626 pigmentation, xxxiii, xxxvi, 66, 72, 267, 499, 500, 516, 530, 534, 1061, 1127, 1133, 1134, 1174, 1175 pigments, 436, 438 pigs, xxiv, xxix, 424, 428, 621, 693, 773, 786, 791, 795, 797, 798, 809, 811, 820, 852, 853, 856, 860, 915, 916, 940, 1028, 1029, 1032, 1044 piloerection, 252, 284 pilot study, 57, 367, 514, 527, 537, 593, 897, 1077, 1124, 1147 placenta, 253, 287, 399, 612, 1030, 1176, 1181, 1182, 1185, 1217 placental hormones, 1182 plants, xxiv, xxxii, xxxiv, 2, 15, 161, 222, 268, 343, 386, 443, 449, 599, 609, 614, 615, 616, 617, 618, 619, 623, 624, 625, 626, 628, 629, 630, 638, 639, 644, 646, 647, 648, 670, 683, 688, 694, 710, 756, 955, 984, 1018, 1035, 1042, 1044, 1048, 1055, 1056, 1100,1163, 1192, 1217 plaque, 602, 647, 823, 826, 875, 876, 895, 922 plasma levels, 157, 181, 191, 202, 231, 232, 258, 296, 298, 312, 344, 350, 396, 456, 467, 532, 589, 600, 696, 703, 711, 716, 810, 875, 906, 907, 1000, 1029, 1203 plasma membrane, 46, 343, 401, 673, 713, 1045 plasma proteins, xxiv, 635, 641 plasticity, 342, 362, 363, 502, 1109 platelets, 18, 157, 191, 194, 195, 380, 598, 814 plausibility, xiii, 62, 80, 402, 596, 1129, 1146, 1157 playing, 662

1262 pleasure, 341 pleiotropy, 812 Pleoticus muelleri, xix, 433, 434, 435, 436, 437, 438, 441, 442, 443, 444, 445, 446, 447, 449 pneumonia, 703, 717, 987, 1013 pneumonitis, 490, 579 point mutation, 38, 211, 1076 poison, 910 Poland, 920, 1017, 1119, 1173, 1174, 1188 polar, xi, 1, 4, 32, 117, 136, 535, 559, 564, 667, 669, 672, 674, 679, 1214, 1215 polar groups, 674, 679 polarity, 547, 559, 659, 660, 661, 662, 666, 670, 678, 681 polarization, 681, 1081, 1096 policy, 267, 275, 990 pollutants, 442, 449, 611, 744, 750, 1064, 1065 pollution, xxxvii, 434, 435, 442, 446, 498, 712, 720, 774, 1065, 1077, 1133, 1174, 1192, 1207, 1216 polyamines, 223 polycyclic aromatic hydrocarbon, 711 polymerase, 25, 38, 400, 418, 507 polymerase chain reaction, 418 polymers, 1024, 1043 polymorphism, 49, 51, 289, 290, 291, 309, 311, 312, 507, 509, 522, 536, 600, 1064, 1076, 1084, 1085, 1086, 1091, 1092, 1093, 1094, 1096, 1103, 1104, 1105, 1106, 1108, 1111, 1112, 1113, 1114, 1115, 1119, 1123, 1175, 1178, 1182, 1193 polymorphisms, xxxii, 57, 63, 82, 105, 137, 145, 149, 215, 309, 311, 402, 507, 509, 523, 524, 539, 571, 606, 619, 710, 711, 715, 721, 824, 1083, 1084, 1088, 1092, 1093, 1094, 1099, 1101, 1102, 1103, 1104, 1105, 1106, 1108, 1110, 1111, 1112, 1113, 1120, 1124, 1136, 1147, 1180, 1193, 1225 polyphenols, 134, 150, 559 polysaccharides, 94, 110 polyunsaturated fat, 207, 225, 442, 590, 593, 610, 612, 620, 747, 903, 1011, 1021, 1028, 1040, 1056, 1057, 1074 polyvinylidene fluoride, 121 population control, 169, 170, 171, 173, 174, 175, 176, 177 population density, 1015 population group, 96, 883, 1004 positive correlation, 233, 329, 350, 360, 388, 389, 441, 512, 785, 953, 1095, 1122 positive feedback, 40, 87 positive relationship, 46, 51, 1196, 1197, 1198 positron emission tomography, 262 postpartum depression, 348, 358, 365, 369, 376 post-transcriptional regulation, 1109

Index potassium, 98, 111, 121, 123, 127, 129, 346, 347, 353, 368, 375, 545, 559, 728, 800, 827, 855 potato, xxx, 614, 651, 652, 654, 699, 871, 877, 879, 973, 976, 979, 985 potential benefits, 278, 284, 490, 578, 602, 811, 1199, 1222 precipitation, xxix, 48, 101, 855, 869, 949, 953, 954 preeclampsia, 906, 943, 1067, 1068, 1078, 1222, 1231 prefrontal cortex, 53, 58, 342, 350, 366, 371 pregnancy, xxviii, xxx, xxxii, xxxiv, 52, 309, 315, 321, 343, 347, 354, 357, 361, 365, 367, 369, 376, 390, 391, 571, 600, 601, 603, 653, 655, 744, 813, 881, 885, 891, 896, 905, 979, 992, 993, 1008, 1055, 1067, 1068, 1078, 1151, 1175, 1177, 1178, 1179, 1180, 1182, 1184, 1186, 1187, 1188, 1221, 1222 premature infant, 935, 1028, 1046, 1060, 1209 premenstrual syndrome, 256, 263, 294, 317, 368 premolar, 874 preparation, iv, xxxi, 3, 4, 12, 98, 99, 103, 104, 110, 144, 561, 562, 726, 750, 877, 1003, 1010, 1014, 1213, 1223 preschool, 300, 986, 990, 993, 1009, 1015 preschool children, 300, 990, 993, 1009, 1015 preservation, 231, 403, 756, 765, 766, 770, 856, 868, 874, 1010, 1011, 1014 preservative, 900 president, 1213 primary hyperparathyroidism, 1119, 1203 primary prophylaxis, 1165 primary tumor, 188, 189, 216 principles, 97, 446, 685, 712, 1014 probability, 51, 661, 663, 664, 668, 675, 709, 712 progenitor cells, 18, 38, 186, 209, 419 progesterone, xix, 388, 409, 410, 412, 413, 414, 744 prognosis, xx, 78, 85, 279, 319, 459, 461, 811, 1112, 1113, 1114 programming, 48, 482, 828, 1177, 1185 pro-inflammatory, 218, 224, 232, 342, 344, 461, 464, 466, 507, 599, 806, 811, 812, 813, 1088, 1121, 1125, 1128, 1165, 1195, 1203, 1204 project, 267, 275, 604, 875, 877, 911 proliferation, xii, xiii, xxi, xxx, xxxii, 2, 18, 19, 22, 23, 25, 26, 27, 29, 31, 36, 47, 48, 61, 74, 75, 77, 79, 87, 90, 152, 160, 162, 163, 165, 182, 183, 184, 185, 188, 189, 190, 191, 192, 195, 196, 198, 199, 207, 210, 211, 216, 217, 219, 220, 223, 225, 269, 271, 363, 386, 388, 396, 403, 404, 488, 491, 493, 497, 498, 530, 536, 570, 580, 582, 584, 597, 598, 627, 644, 647, 673, 688, 808, 810, 827, 828, 979, 980, 1024, 1026, 1037, 1057, 1080, 1081, 1082, 1099, 1101, 1107, 1108, 1109, 1128, 1129,

Index 1146, 1148, 1157, 1176, 1179, 1180, 1193, 1196, 1217 proline, 598, 772, 801, 803, 864, 873 promoter, xii, xxxii, 17, 20, 21, 23, 88, 90, 198, 388, 389, 392, 399, 402, 468, 479, 507, 618, 619, 623, 756, 1080, 1097, 1099, 1101, 1102, 1105, 1107, 1108, 1109, 1111, 1114, 1201 propagation, xxxi, xxxii, 158, 757, 1017, 1055, 1064 prophylactic, 94, 106, 647, 703, 749, 896, 910, 925, 932, 1226 prophylaxis, 209, 242, 703, 876, 902, 1038, 1167, 1172 propylene, 254, 286 prostacyclins, 588 prostaglandin, 153, 187, 197, 206, 224, 473, 590, 1081 prostaglandins, 588, 695, 701, 802, 1121 prostate cancer, xviii, 37, 49, 62, 66, 68, 71, 74, 75, 76, 77, 78, 79, 80, 83, 84, 85, 86, 87, 88, 90, 91, 161, 162, 163, 164, 165, 168, 179, 180, 182, 185, 186, 187, 188, 190, 194, 198, 199, 203, 204, 205, 207, 209, 210, 211, 270, 385, 388, 392, 454, 455, 457, 493, 559, 584, 884, 921, 935, 937, 938, 939, 940, 942, 944, 945, 1013, 1044, 1047, 1097, 1103, 1104, 1105, 1106, 1108, 1110, 1111, 1112, 1113, 1114, 1115, 1128, 1129, 1139, 1232 prostate carcinoma, 199, 944 prostate gland, 182, 206 protection, xv, xxiii, 54, 99, 102, 182, 183, 186, 217, 218, 220, 226, 265, 267, 272, 273, 274, 275, 299, 438, 442, 443, 465, 478, 483, 513, 546, 564, 565, 570, 572, 609, 610, 615, 621, 705, 712, 743, 819, 824, 853, 859, 860, 864, 865, 900, 924, 931, 932, 996, 997, 998, 999, 1028, 1035, 1038, 1040, 1041, 1065, 1066, 1067, 1069, 1131, 1158, 1175, 1180, 1181, 1210, 1211, 1212 protective role, xvi, 78, 265, 507, 519, 610, 748, 749, 759, 793, 857, 859, 885, 893, 933, 991 protein family, xxxii, 41, 1099 protein kinase C, 31, 32, 34, 36, 37, 39, 153, 155, 186, 188, 190, 194, 211, 212, 217, 343 protein synthesis, xxxii, 223, 346, 473, 989, 1055 proteinuria, 1166 pro-vitamin A, 980, 981, 1006, 1007, 1008, 1009, 1015 proximal tubules, 814 psychiatric disorder, 44, 47, 48, 57, 324, 341, 357, 380, 525, 886 psychiatric disorders, 44, 47, 48, 324, 357, 380, 525, 886 psychiatric illness, 43, 106, 309, 368 psychological processes, 477 psychological stress, 832

1263 psychological stressors, 832 psychological well-being, 320 psychopathology, 53, 261, 309 psychosis, xii, 43, 253, 260, 304, 380, 382, 998 purification, 4, 111, 113, 141, 143 purines, 215 purity, 136, 639, 773, 787 pyridoxine, xvi, 94, 97, 99, 102, 103, 104, 106, 124, 142, 143, 150, 227, 251, 255, 256, 257, 261, 262, 263, 283, 284, 292, 294, 295, 316, 317, 348, 368, 369, 423, 424, 567, 598, 636, 652, 656, 775 pyrimidine, 105, 216, 637, 663 pyrophosphate, 95, 96

Q quality of life, 322, 344, 356, 365, 370, 490, 491, 493, 578, 579, 584, 591, 592, 811, 828, 958, 965, 966, 1005, 1040, 1074, 1087, 1221 quantification, xiii, 4, 6, 15, 16, 93, 94, 95, 97, 113, 140, 143, 148, 149, 727, 728, 729, 730, 732, 733, 1040 quantitative estimation, 774 questionnaire, xxx, 357, 358, 491, 493, 579, 584, 602, 969, 971, 975, 997, 1065

R race, 153, 156, 225, 271, 276, 386, 507, 924, 932, 1018, 1020, 1042, 1056, 1068 radiation, xii, xv, xxii, xxv, xxxvi, 43, 62, 73, 80, 81, 91, 153, 184, 186, 208, 209, 219, 221, 234, 265, 266, 270, 271, 272, 274, 275, 276, 278, 328, 343, 382, 397, 398, 439, 490, 543, 555, 561, 570, 571, 579, 661, 669, 673, 755, 756, 757, 758, 759, 760, 761, 762, 763, 764, 765, 766, 767, 768, 1038, 1042, 1048, 1066, 1067, 1079, 1091, 1095, 1152, 1174, 1175, 1176, 1179, 1185, 1191, 1192, 1193, 1217, 1221 radiation therapy, 184, 186, 208, 1038, 1048 radicals, xiv, 2, 87, 213, 214, 215, 216, 217, 226, 234, 235, 426, 442, 443, 472, 477, 478, 549, 552, 553, 568, 591, 601, 602, 610, 677, 679, 717, 718, 740, 742, 759, 766, 767, 769, 792, 804, 805, 826, 827, 849, 850, 851, 852, 902, 912, 916, 918, 919, 928, 929, 937, 1021, 1022, 1026, 1028, 1046, 1057, 1067, 1069, 1120 radio, 86, 1022, 1027, 1214, 1215 radiotherapy, 208, 233, 481, 490, 494, 579, 585, 828, 1027, 1039 rash, 492, 583, 653, 655, 1180 reactants, 589, 590, 591, 593

1264 reactive oxygen species, xx, xxiv, xxv, 2, 76, 106, 143, 153, 442, 461, 471, 472, 475, 477, 478, 479, 482, 483, 519, 553, 563, 566, 610, 615, 627, 677, 694, 704, 739, 740, 742, 749, 750, 802, 804, 821, 832, 848, 859, 862, 864, 884, 892, 902, 908, 916, 918, 921, 926, 932, 1028, 1035, 1056, 1057, 1121 reactivity, 241, 294, 472, 480, 556, 640, 1007, 1145 recognition, xiii, xxxiii, 151, 285, 286, 304, 858, 900, 1119, 1127, 1129 recurrence, 71, 79, 270, 271, 491, 579, 606, 829, 1183 recycling, 111, 194, 223, 605, 717, 816, 832, 851, 858, 906, 942, 1052, 1070 red blood cells, xxvii, xxx, 186, 205, 641, 652, 653, 655, 742, 746, 847, 857, 858, 859, 860, 995, 1035, 1062, 1063 regeneration, xxix, 233, 425, 700, 749, 754, 796, 873, 901, 915 regression, xx, xxii, 64, 65, 66, 68, 185, 310, 320, 388, 392, 460, 462, 463, 464, 516, 530, 532, 534, 790, 875, 991, 1027, 1042 regression analysis, xx, xxii, 66, 388, 460, 462, 463, 464, 516, 530, 790 rehabilitation, 303, 381, 510, 844, 935, 1199 rehabilitation program, 510 relevance, xv, xvii, 89, 251, 254, 258, 289, 290, 319, 341, 369, 418, 639, 676, 804, 805, 876, 1110, 1153 reliability, 111, 1129 relief, xxix, 644, 745, 747, 772, 915 remission, 49, 342, 362, 363, 489, 490, 579, 581, 1027 remyelination, 263, 289, 300, 317 renal calculi, 712 renal cell carcinoma, 77, 88, 1113 renal failure, 596, 741, 742, 753, 817, 1031, 1203 renin, xix, 395, 401, 402, 461, 465, 507, 1146, 1148, 1202, 1218 repair, xii, xxiv, xxix, 37, 61, 75, 76, 105, 167, 186, 234, 253, 263, 287, 317, 694, 695, 706, 707, 710, 712, 714, 716, 720, 721, 741, 801, 805, 819, 857, 873, 904, 915, 916, 934, 941, 1045, 1077 replication, 24, 54, 105, 167, 215, 821, 1107 repression, 21, 77, 410, 476, 482, 1090 reproduction, xiii, xviii, xxx, 151, 349, 385, 386, 390, 391, 435, 436, 610, 651, 654, 673, 979, 980, 986, 996, 1011, 1018, 1043, 1068 reproductive age, 58, 277, 988, 993 reproductive organs, xviii, 385, 386, 1181 requirement, xxvi, xxxi, 223, 240, 255, 268, 292, 382, 434, 439, 441, 442, 444, 447, 448, 449, 591, 594, 596, 600, 601, 657, 696, 748, 771, 772, 773, 774, 776, 778, 784, 785, 786, 790, 791, 792, 793,

Index 794, 795, 796, 797, 813, 814, 851, 929, 941, 975, 981, 982, 983, 996, 1017, 1032, 1043, 1052, 1059, 1060, 1068, 1072, 1183, 1202, 1223 researchers, xxv, xxxvii, 4, 110, 112, 116, 119, 535, 571, 602, 612, 712, 741, 746, 749, 756, 757, 900, 904, 922, 924, 998, 1009, 1067, 1120, 1207, 1214 resection, 257, 295, 328, 383, 490, 494, 579, 585 reserves, 435, 783, 785, 791, 900, 1034 Residential, 972 residue, 24, 132, 218, 641, 657, 659, 660, 665, 667, 669, 672, 675, 1061 resolution, 5, 95, 97, 98, 103, 116, 136, 147, 242, 328, 339, 672, 685, 731, 732, 959, 1043 resources, 445, 596, 956 respiration, 476, 644, 648, 868, 869, 871, 874 respiratory disorders, 743 respiratory rate, 645 responsiveness, 34, 351, 373, 393, 439, 809, 926, 936, 1053, 1076, 1107, 1203 restenosis, 809, 827 restless legs syndrome, 289 restoration, 701, 883 restriction enzyme, 1103 restrictions, 958, 1153 resveratrol, 682, 751 retail, 632 retardation, xxxv, 310, 1173, 1178 reticulum, 219, 616, 803 retina, 194, 218, 612 retinitis, 1039, 1050, 1051 retinitis pigmentosa, 1039, 1050, 1051 retinoblastoma, 153, 162, 163, 164, 199 retinol, xxx, 201, 202, 203, 204, 425, 436, 455, 552, 600, 627, 637, 654, 656, 671, 673, 674, 691, 896, 934, 938, 939, 945, 965, 979, 980, 981, 982, 983, 984, 986, 987, 989, 990, 992, 993, 1006, 1008, 1010, 1012, 1014, 1015, 1016 retinopathy, 707, 898, 1029, 1030, 1031, 1061, 1063 reverse transcriptase, 75, 86, 646, 1165, 1168 rewards, 966 rhabdomyolysis, 741, 742 rheumatic diseases, xxxii, 1079, 1087, 1088, 1090 rheumatic heart disease, 462 rheumatoid arthritis, xxxii, 48, 269, 277, 453, 596, 647, 655, 825, 848, 897, 902, 918, 1079, 1082, 1083, 1084, 1087, 1089, 1090, 1091, 1092, 1093, 1094, 1096, 1128 rheumatoid factor, 1084 riboflavin, vii, xxii, 94, 96, 97, 98, 99, 100, 101, 103, 120, 121, 122, 123, 124, 127, 129, 131, 132, 133, 135, 137, 138, 140, 142, 146, 150, 218, 227, 259, 301, 348, 357, 358, 362, 368, 369, 422, 429, 430, 431, 543, 561, 562, 563, 564, 565, 566, 567, 568,

Index 598, 636, 640, 651, 656, 675, 676, 677, 691, 692, 761, 762, 767, 769, 775, 889, 942, 991, 1061 ribonucleotide reductase, 219 ribose, 507, 545 ribosomes, 848 rickets, xviii, xxxvii, 47, 343, 386, 395, 396, 397, 500, 517, 654, 1100, 1128, 1164, 1175, 1186, 1192, 1201, 1207, 1208, 1209, 1210, 1211, 1212, 1213, 1214, 1215, 1219, 1220, 1221, 1223, 1225, 1226, 1227, 1228 righting, 252, 284 rights, iv rings, 545, 825 risk assessment, 516, 1044 risks, xvii, 52, 238, 273, 326, 338, 452, 602, 703, 709, 767, 902, 904, 913, 966, 1063, 1090, 1193 rodents, 404, 648, 706, 996, 1032 room temperature, 104, 766, 866, 868, 1131, 1140 root, 601, 607, 647, 812, 866, 872 roots, 615, 646, 648 routes, 223, 487, 577, 1022, 1224 rural counties, 63 rural people, 1013

S safety, xxi, xxiii, 47, 59, 374, 375, 485, 486, 535, 575, 576, 627, 740, 758, 768, 812, 827, 868, 935, 1037, 1038, 1075, 1188, 1202, 1223 salmon, xxxvi, 125, 268, 447, 597, 621, 625, 626, 628, 786, 790, 795, 1045, 1174, 1176, 1216 salt concentration, 659 salts, 148, 800, 827, 1058, 1209, 1212, 1217 sarcopenia, 805, 1128, 1193, 1195, 1201, 1229 saturation, xi, xxvi, 1, 427, 669, 674, 771, 775, 776, 777, 785, 792, 793, 815, 817, 906, 922, 927 schizophrenia, xxviii, 44, 47, 50, 51, 52, 53, 57, 58, 59, 289, 290, 298, 309, 315, 322, 364, 417, 501, 518, 519, 746, 881, 887, 889, 891, 892, 897, 1181, 1187, 1218, 1231 sclerosis, xxii, 48, 569, 1083, 1086, 1231 seasonality, xxxiii, 48, 83, 1127, 1133, 1134, 1180 secretion, 46, 47, 48, 77, 224, 260, 263, 288, 306, 328, 329, 335, 378, 389, 425, 435, 436, 441, 507, 536, 570, 719, 746, 809, 816, 841, 844, 864, 958, 996, 1022, 1023, 1032, 1041, 1062, 1071, 1073, 1081, 1119, 1129, 1142, 1179, 1195, 1203 seedlings, 615, 1035, 1036 seizure, xxii, 48, 294, 529, 531, 534, 1183 selective attention, 300 selective serotonin reuptake inhibitor, 56, 347

1265 selectivity, xiii, 4, 93, 95, 100, 104, 113, 117, 118, 157, 198, 639, 642, 664, 665, 724, 1007, 1026, 1061 selenium, xx, 168, 179, 182, 201, 203, 204, 205, 207, 353, 354, 361, 362, 375, 376, 442, 451, 453, 454, 457, 589, 600, 606, 629, 631, 751, 794, 890, 905, 911, 923, 939, 947, 997, 1024, 1027, 1041, 1045, 1047, 1049, 1051 self-esteem, 341 semantic memory, 505 semen, 864 semimembranosus, 622 seminiferous tubules, 750 senescence, 615, 623, 624, 625, 857 senile dementia, 106, 114 sensation, 381, 591, 652, 653 sensing, xx, 373, 471, 473, 475, 479, 480, 481, 482 sensitivity, xiii, xviii, 93, 94, 95, 98, 100, 101, 102, 104, 108, 109, 113, 117, 118, 136, 228, 230, 234, 259, 334, 380, 385, 388, 389, 390, 477, 557, 642, 724, 729, 730, 731, 732, 733, 734, 743, 745, 757, 758, 764, 765, 857, 869, 1109, 1129, 1186, 1195 sensitization, 78, 184, 209, 752, 1187 sensor, xxxi, 145, 146, 465, 474, 685, 733, 737, 995 sensor proteins, 465 sensors, 465 sensory perceptions, 1046 sepsis, 593, 610, 809, 1034, 1128 serine, 23, 24, 27, 105, 165, 190, 309, 849, 850 serotonin, 252, 254, 259, 260, 261, 262, 263, 302, 306, 315, 317, 345, 346, 352, 353, 369, 373, 375, 502, 803, 828 serum albumin, 638, 641, 659, 664, 671, 672, 674, 675, 676, 681, 685, 689, 690, 691, 692 services, iv, 521, 526, 624, 1140 settlements, 950 severe stress, 834 sex, xxix, 54, 388, 392, 513, 531, 534, 696, 746, 826, 957, 989, 1068, 1134, 1178 shade, 268, 273, 1008, 1011, 1211 shape, 558, 641, 662, 669, 672, 852, 871 shelf life, 621, 622, 627, 756, 761, 767, 870, 871, 1012 shellfish, 985, 1036 shock, xxvii, 461, 473, 847 showing, xvi, 2, 159, 265, 270, 343, 344, 345, 437, 438, 452, 555, 622, 852, 885, 898, 948, 951, 1010, 1157, 1180, 1210, 1213 shrimp, vi, xix, 433, 434, 435, 436, 438, 439, 440, 441, 442, 443, 444, 445, 446, 447, 448, 449, 772, 786, 796, 797, 985, 1049 sickle cell, xxvii, 847, 854, 1062 sickle cell anemia, xxvii, 847, 854, 1062

1266 side chain, xi, xxxi, 1, 2, 45, 113, 155, 163, 412, 545, 546, 547, 567, 610, 624, 670, 849, 864, 1017, 1018, 1056 side effects, xvii, xxi, xxiii, 76, 185, 256, 294, 341, 342, 485, 489, 490, 492, 575, 578, 579, 580, 581, 582, 583, 647, 652, 744, 746, 748, 818, 887, 897, 1022, 1059, 1170, 1221 signaling pathway, xii, xiv, 18, 26, 30, 78, 89, 160, 162, 181, 189, 199, 214, 215, 217, 236, 342, 343, 346, 351, 400, 401, 403, 404, 472, 475, 480, 483, 825, 1109, 1158 signals, 18, 19, 26, 78, 188, 191, 216, 224, 232, 388, 475, 926 signs, xviii, xxxii, 220, 286, 289, 290, 302, 348, 377, 381, 382, 383, 441, 460, 461, 508, 509, 517, 674, 740, 746, 778, 779, 783, 784, 786, 790, 793, 834, 862, 982, 986, 988, 989, 1025, 1029, 1032, 1055, 1210 skeletal remains, 1208 skeleton, 439, 1164, 1175, 1177, 1225 skin cancer, xv, xxxvii, 73, 74, 86, 204, 265, 266, 267, 270, 272, 273, 274, 275, 276, 280, 514, 1103, 1112, 1113, 1193, 1207, 1216, 1223, 1228 sleep apnea, 961 sleep disorders, 254, 288 small intestine, xvii, xix, 73, 326, 327, 328, 331, 333, 340, 386, 421, 422, 423, 424, 611, 814, 1061, 1062, 1217 smoking, 62, 73, 81, 82, 180, 202, 506, 601, 604, 608, 686, 697, 702, 710, 711, 721, 740, 743, 753, 803, 809, 858, 924, 926, 940, 971, 1011, 1028, 1164, 1186 smooth muscle, 46, 152, 188, 194, 210, 211, 475, 480, 482, 700, 808, 809, 827, 828, 1145, 1147, 1148, 1179, 1193 smooth muscle cells, 194, 211, 480, 482, 700, 808, 809, 1146, 1147, 1148 SNP, 507, 1103, 1104, 1106, 1114, 1120 SO42, 544, 546, 552, 557 social class, 620, 708 social group, 452 social interaction, 747 social interactions, 747 social stress, 713 society, 686, 900, 978, 1223 socioeconomic status, 56, 72, 344 sodium, 99, 116, 121, 122, 125, 131, 132, 134, 206, 443, 546, 554, 555, 559, 637, 669, 670, 671, 675, 677, 685, 708, 728, 732, 745, 750, 800, 814, 827, 833, 851, 874, 882, 918, 1027, 1108, 1115, 1148 sodium dodecyl sulfate, 546 sodium dodecyl sulfate (SDS), 546 software, 228, 788, 1064

Index soil type, 756 sol-gel, 894 solid matrix, 4 solid phase, 3, 111, 121, 462 solid state, 558, 568 solid tumors, 162 Solomon I, 140 solubility, 558, 559, 695, 869, 956 solution, 4, 10, 98, 102, 110, 119, 124, 127, 131, 227, 544, 545, 546, 553, 554, 555, 556, 557, 558, 559, 561, 562, 563, 566, 567, 568, 657, 660, 661, 662, 664, 669, 670, 671, 672, 673, 676, 678, 681, 724, 725, 727, 728, 729, 730, 731, 732, 770, 777, 823, 867, 868, 1024, 1219 solvents, 4, 99, 103, 117, 547, 559, 560, 562, 566, 725, 1132 South Africa, 93, 105, 136, 148, 630, 920, 952 South America, xix, xxxv, 433, 435, 500, 639, 1173 South Asia, 1203 Southeast Asia, 448 soybeans, 970 Spain, 7, 62, 81, 200, 204, 377, 435, 529, 531, 539, 540, 541, 587, 723, 734, 894, 920, 944, 957, 1043, 1088, 1127, 1134, 1174, 1179 spastic, xviii, 310, 377, 381 spatial learning, 285, 298, 307, 321 spatial memory, 307, 418 specialists, 848 specific surface, 1081 spectral techniques, 662 spectrophotometric method, 733, 736, 777 spectrophotometry, 657, 663, 734, 959, 1215 spectroscopic techniques, 679, 680 spectroscopy, 53, 100, 553, 554, 624, 641, 642, 658, 659, 663, 665, 666, 667, 673, 675, 676, 677, 678, 679, 681, 690, 691 spinal cord, xviii, 114, 289, 295, 300, 317, 318, 377, 381, 382, 384, 410, 1164 spinal cord injury, 1164 spine, xxxv, 340, 1061, 1154, 1173, 1178 spinocerebellar degeneration, 1074 spleen, 832, 1023, 1214 spondyloarthritis, 1091 spontaneity, 676, 677 spontaneous abortion, 1059 Sprague-Dawley rats, 161, 165, 688, 1198 Spring, 338, 339, 522, 533 sprue, 1009 sputum, 893 squamous cell, 49, 75, 79, 85, 89, 153, 192, 204, 208, 212, 225, 234, 266, 270, 279, 1113, 1114 squamous cell carcinoma, 49, 75, 79, 85, 89, 153, 192, 208, 212, 225, 234, 266, 279, 1113, 1114

Index stabilization, xxiv, xxvii, 142, 381, 473, 555, 562, 662, 674, 694, 826, 847 stabilizers, xxii, 543, 555, 561, 562 standard deviation, 228, 271, 532, 728, 835, 982, 1220 standard error, 953 standardization, 133, 512, 1184 starch, 109, 120, 131 starvation, 624, 834 statistics, xxxiv, 469, 532, 904, 971, 1027, 1149, 1163 status epilepticus, 747 steel, 728, 1012, 1015 stem cells, 18, 75, 186, 749, 1093 sterile, 591, 592, 805 steroids, xxxiv, 410, 411, 413, 478, 1100, 1163 stimulant, 443, 644, 645, 646, 648 stimulation, 23, 24, 26, 34, 189, 216, 224, 401, 410, 428, 597, 627, 714, 805, 812, 822, 849, 935, 1082, 1128, 1214 stimulus, 26, 217, 706 stoichiometry, 671, 674, 680 stomach, xxiv, 74, 202, 241, 327, 328, 329, 333, 378, 435, 439, 693, 701, 833, 901, 921, 1006, 1215, 1217, 1227 stress response, 235, 589, 623, 806, 833, 840, 844, 856, 1023 striatum, 253, 256, 287, 303, 349, 717 stroke, xxxi, 105, 289, 298, 311, 321, 348, 349, 351, 358, 369, 451, 454, 455, 469, 473, 478, 506, 509, 510, 512, 518, 524, 526, 638, 682, 701, 923, 927, 943, 970, 1003, 1006, 1063, 1064, 1149, 1159, 1179, 1183, 1189, 1198, 1201, 1231 style, 275, 460, 464, 465, 500, 773, 958, 1063, 1134 subacute, xviii, 289, 295, 300, 317, 377, 380, 381, 384 subacute combined spinal cord degeneration, xviii, 377, 384 subarachnoid hemorrhage, 646, 687 substitution, 110, 310, 1103, 1104 substrate, 25, 27, 40, 45, 187, 219, 221, 241, 255, 292, 388, 399, 500, 548, 549, 552, 587, 588, 616, 759, 814, 864, 917, 1080, 1136 substrates, 259, 302, 548, 588, 1061 sudden infant death syndrome, 307 suicidal behavior, xii, 43, 47, 48, 55, 352, 360 suicide, xii, xvii, 43, 44, 47, 48, 49, 50, 51, 52, 53, 54, 55, 57, 58, 59, 341, 342, 351, 352, 360, 362, 373 sulfate, 181, 206, 219, 351, 360, 546, 557, 773, 786, 787, 795, 797, 798 sulfur, xiv, 214, 217, 218, 221, 222, 226, 227, 231, 233, 236, 237, 639

1267 sulfur antioxidant pathway in esophageal cancer, 214 sulfuric acid, 119 sulphur, 1012 supervision, 1059 supplier, 112, 185 supply chain, 627 suppression, 39, 75, 89, 160, 165, 183, 185, 189, 191, 198, 207, 209, 216, 417, 481, 558, 570, 599, 841, 1004, 1005, 1023, 1051, 1081, 1082, 1090, 1108, 1179, 1218 surface area, 327, 328, 333, 865, 989, 1176 surfactant, 129, 733, 735, 1024 surfactants, 680, 1024 surgical removal, 742, 1214 surgical technique, 590, 965 surgical techniques, 590, 965 surveillance, 336, 505, 632, 1225 survival, xii, xiv, xvi, xix, xxxii, 31, 32, 34, 61, 68, 69, 70, 71, 72, 81, 82, 84, 85, 90, 155, 160, 165, 184, 185, 186, 190, 192, 194, 208, 210, 211, 214, 215, 216, 220, 221, 226, 233, 234, 266, 270, 271, 279, 342, 433, 434, 435, 436, 438, 439, 441, 444, 445, 447, 448, 467, 491, 515, 579, 582, 589, 747, 777, 778, 781, 782, 784, 787, 794, 811, 822, 825, 826, 827, 829, 884, 912, 916, 922, 1015, 1027, 1047, 1049, 1077, 1082, 1095, 1099, 1102, 1103, 1104, 1106, 1111, 1113, 1121, 1129, 1186 survival rate, 69, 71, 72, 81, 85, 184, 777, 781, 787, 1186 survivors, xv, 265, 271, 272, 273, 274, 276, 280, 281 susceptibility, xxxiii, 58, 182, 296, 506, 507, 509, 523, 570, 592, 627, 711, 715, 923, 924, 940, 988, 1004, 1028, 1085, 1092, 1093, 1096, 1100, 1102, 1103, 1104, 1105, 1106, 1111, 1113, 1177, 1185 sweat, 988 Sweden, 73, 202, 278, 510, 788, 901 swelling, 644, 900 Switzerland, 242, 538, 631, 1016 sympathetic nervous system, 465, 479, 508, 715 synapse, 342, 363 synaptic plasticity, 307, 363, 502 syndrome, xv, xxxv, 77, 251, 252, 253, 258, 259, 263, 284, 285, 289, 290, 302, 304, 309, 315, 316, 320, 332, 333, 335, 343, 355, 387, 389, 392, 393, 422, 430, 431, 651, 796, 820, 822, 902, 945, 961, 1028, 1029, 1031, 1034, 1039, 1060, 1061, 1074, 1083, 1085, 1086,1093, 1123, 1173, 1182, 1183, 1193, 1201, 1205, 1218 synergistic effect, 590, 852, 1024 synovial fluid, 948 synthetic analogues, 162 syphilis, 1209 syringomyelia, 382

1268

Index

systemic lupus erythematosus, xxxii, 48, 1079, 1083, 1084, 1085, 1087, 1088, 1089, 1090, 1092, 1093, 1094, 1095, 1096, 1097 systolic blood pressure, xxxiv, 402, 895, 1152, 1158, 1159, 1230

T T cell, xxiii, 56, 319, 498, 569, 570, 806, 811, 825, 829, 1057, 1080, 1081, 1082, 1086, 1089, 1090, 1093, 1095, 1096, 1097, 1180 T lymphocytes, 570, 805, 821, 825 Taiwan, 138, 487, 489, 577, 580, 581, 1065, 1123 tardive dyskinesia, 256, 262, 294, 316, 895 target, xii, xv, 17, 20, 21, 22, 23, 25, 27, 30, 32, 33, 35, 36, 38, 45, 46, 48, 49, 79, 91, 190, 191, 217, 236, 251, 252, 284, 342, 346, 367, 399, 401, 412, 415, 419, 452, 474, 477, 483, 514, 570, 572, 605, 641, 673, 681, 682, 696, 704, 706, 747, 817, 820, 919,925, 975, 1024, 1059, 1066, 1080, 1091, 1107, 1108, 1109, 1122, 1132, 1146, 1177, 1195, 1196, 1200 task demands, 303 Task Force, xxxvii, 136, 456, 457, 467, 513, 526, 1161, 1207, 1216, 1221, 1222, 1228, 1229, 1233 techniques, xi, xiii, xxv, 1, 3, 4, 5, 6, 12, 93, 94, 97, 100, 115, 118, 119, 140, 145, 434, 444, 486, 553, 576, 614, 641, 642, 658, 667, 671, 677, 681, 692, 723, 724, 734, 755, 756, 866, 867, 869, 908, 919, 981, 1011, 1014, 1028 technology, xxv, 100, 391, 755, 756, 758, 959 teeth, xxx, 119, 595, 654, 700, 740, 874, 882, 979, 980 temperament, 56 temperature, xxv, 4, 5, 97, 98, 102, 104, 111, 117, 123, 125, 131, 135, 563, 566, 628, 645, 663, 665, 666, 670, 671, 678, 679, 680, 681, 700, 710, 727, 730, 731, 737, 751, 755, 756, 757, 760, 761, 763, 764, 765, 775, 776, 777, 787, 834, 845, 865, 866, 867, 868, 869, 870, 872, 873, 876, 1131, 1175, 1217 temperature dependence, 670, 680 testing, xxii, xxxiv, 155, 182, 187, 192, 333, 336, 380, 512, 529, 531, 901, 1067, 1128, 1139, 1140, 1145, 1146 testis, 386, 411, 832, 1045, 1181 testosterone, 389, 390, 1166, 1167, 1169, 1170 tetrabutylammonium bromide, 638 tetracycline antibiotics, 647 thalamus, 252, 284, 285, 302, 501 thalassemia, xxvii, 847, 854, 1062 therapeutic agents, 76, 1022 therapeutic benefits, xxiii, 595, 600

therapeutic effect, xxiv, 343, 635, 642, 749, 813, 901, 1024, 1087 therapeutic effects, 343, 813, 1024, 1087 therapeutic interventions, 1171 therapeutic targets, 1107 therapeutic use, 606, 638, 759, 813, 817, 818, 883 therapeutics, 89, 235, 278, 806, 807, 1021, 1110, 1229 thermal decomposition, 729 thermal degradation, 867, 873 thermal treatment, 758, 867, 872 thermodynamic parameters, 666, 667, 670, 671, 672, 673, 675, 678, 680 thiamin, 138, 146, 259, 301, 303, 358, 362, 369, 636, 651, 758, 761, 766, 878 thiamin deficiency, 303, 358, 369 thrombin, xv, 239, 241, 242, 243, 244, 245, 246, 247, 248, 249, 474 thrombophlebitis, 1062 thrombosis, 242, 248, 653, 1085 thymus, 1209, 1214, 1217 thyroid, 41, 189, 203, 315, 354, 386, 391, 399, 647, 651, 745, 884, 1209, 1214 thyroid cancer, 884 thyroid gland, 399, 745 thyroid stimulating hormone, 745 tissue perfusion, 854 tissue remodelling, 810 TNF-α, xx, 24, 344, 460, 462, 463, 464, 491, 582, 589, 622, 802, 806, 808, 810, 811, 1081, 1082, 1084 tobacco, xiv, 83, 200, 214, 225, 226, 231, 241, 455, 618, 623, 628, 646, 686, 710, 715, 718, 720, 918, 1213 tobacco smoke, 241 tocopherols, xiii, xxiv, xxxi, xxxii, 2, 3, 4, 5, 7, 8, 10, 11, 12, 13, 14, 15, 16, 152, 154, 155, 157, 158, 159, 161, 162, 166, 180, 181, 195, 196, 200, 201, 204, 206, 207, 210, 344, 441, 559, 563, 599, 609, 610, 615, 616, 618, 619, 620, 623, 626, 629, 637, 655, 752, 758, 996, 997, 1017, 1018, 1033, 1035, 1036, 1037, 1039, 1040, 1041, 1045, 1048, 1051, 1052, 1055, 1056, 1068, 1069, 1070, 1071 toddlers, 47 tofu, 974, 977 Tonga, 326 tonometry, 1147 tooth, 596, 600, 601, 602, 603, 604, 607, 647, 654, 748, 874, 875, 900 total cholesterol, xxx, 229, 230, 451, 702, 810, 920, 957, 963, 1158 tourniquet, 894

Index toxic effect, 216, 426, 710, 741, 744, 748, 848, 855, 992 toxic substances, 744, 873 toxicology, 216, 744, 758 toxin, 647, 741, 747, 748 training, xxxi, 539, 704, 748, 929, 930, 933, 934, 935, 944, 948, 1003, 1012, 1198, 1199, 1202, 1206 transcription, xii, 17, 18, 20, 21, 22, 24, 25, 26, 27, 30, 31, 32, 35, 36, 37, 38, 39, 40, 46, 76, 77, 79, 86, 90, 152, 155, 159, 165, 166, 186, 194, 197, 198, 210, 216, 217, 219, 220, 344, 399, 401, 402, 403, 430, 436, 472, 473, 474, 476, 477, 478, 479, 480, 498, 610, 615, 743, 806, 904, 1080, 1082, 1101, 1105, 1107, 1108, 1133, 1152, 1177, 1178, 1195, 1217 transcription factors, xii, 17, 21, 22, 36, 37, 39, 40, 79, 198, 216, 219, 220, 401, 403, 430, 473, 610, 904, 1108, 1133, 1177 transduction, 36, 155, 184, 190 transferrin, xxx, 427, 803, 957, 959, 964 transformation, xiii, 30, 61, 74, 75, 76, 78, 79, 89, 184, 191, 221, 226, 632, 640, 658, 660, 805, 924, 1023, 1107 transformations, 191, 659, 1018 transforming growth factor, 78, 89, 153, 167, 190, 210, 387, 1082 transient ischemic attack, 512 transition metal, xxiv, 472, 474, 694, 698, 705, 706, 759, 903, 928 transition metal ions, 928 translation, 18, 77, 190, 400, 404, 591, 1226 translocation, 19, 31, 32, 35, 36, 38, 39, 41, 162, 191 transmembrane glycoprotein, 78 transplant recipients, 355, 364 transplantation, 270, 276, 279, 280, 343, 570, 825, 1203 transport, xxxii, xxxvi, 100, 105, 149, 186, 195, 379, 382, 410, 427, 436, 439, 444, 475, 536, 605, 612, 613, 641, 655, 665, 671, 673, 699, 700, 707, 714, 718, 722, 741, 746, 749, 801, 804, 814, 816, 826, 827, 828, 844, 858, 862, 918, 919, 931, 935, 944, 945, 980, 989, 1051, 1055, 1056, 1058, 1059, 1060, 1061, 1069, 1071, 1131, 1132, 1136, 1191, 1195, 1196, 1203, 1214 transport processes, 741 transportation, xxvii, 641, 764, 847, 856 transverse section, 437 trauma, 610 traumatic brain injury, 349 tremor, 508 tricarboxylic acid, 476 trichostatin A, 1115

1269 tricyclic antidepressant, 348, 349, 369 trifluoroacetic acid, 725, 727, 730 triggers, xv, 22, 31, 35, 47, 49, 77, 88, 232, 239, 242, 400, 476, 519, 553, 859, 1092 triglycerides, 231, 804, 920, 1031 trisomy, 315 trisomy 21, 315 trypsin, 378, 952 tryptophan, xv, 95, 251, 252, 256, 258, 262, 284, 293, 345, 353, 423, 553, 554, 567, 598, 637, 641, 657, 659, 660, 661, 665, 666, 667, 668, 669, 670, 671, 672, 673, 675, 676, 677, 678, 681, 685, 803 tuberculosis, 804, 1115, 1180, 1221 tumor cells, xiv, 22, 75, 79, 91, 165, 184, 197, 210, 214, 217, 221, 223, 224, 225, 232, 817, 901, 1025, 1038, 1128 tumor development, 78, 197, 206, 207, 216, 220, 221, 232, 810, 1106 tumor growth, 79, 162, 167, 188, 200, 216, 231, 237, 653, 743, 811, 820, 1025 tumor necrosis factor, 22, 37, 79, 162, 198, 209, 211, 224, 295, 318, 463, 473, 502, 802, 826, 942, 1080, 1128, 1195 tumor progression, xv, 77, 79, 91, 188, 211, 214, 220, 223, 224, 225, 232, 234, 1102 tumorigenesis, 25, 76, 79, 90, 91, 161, 165, 198, 200, 220 tumors, 77, 78, 89, 106, 166, 170, 171, 178, 182, 185, 186, 189, 216, 221, 223, 224, 231, 233, 392, 646, 759, 811, 820, 921, 1046, 1101, 1107, 1108, 1128 turnover, 157, 222, 253, 259, 280, 285, 304, 331, 339, 354, 366, 517, 535, 537, 598, 740, 791, 823, 855, 917, 926, 941, 1023, 1063, 1066, 1164, 1165, 1170, 1171, 1203 type 1 diabetes, 269, 277, 500, 518, 707, 714, 858, 1042, 1092, 1094, 1180, 1187, 1218, 1231 type 2 diabetes, xxxiv, xxxv, 269, 278, 351, 352, 360, 361, 373, 374, 460, 501, 513, 707, 713, 715, 717, 751, 805, 809, 819, 821, 822, 827, 884, 891, 892, 893, 894, 901, 909, 910, 918, 919, 920, 936, 944, 945, 946, 947, 1077, 1151, 1154, 1158, 1159, 1161, 1162, 1171, 1173, 1174, 1231 tyrosine, 26, 36, 190, 191, 211, 473, 554, 637, 661, 667, 669, 672, 676, 681, 695, 795, 801, 864, 1023

U ubiquitin, 22, 25, 33, 35, 223 ulcerative colitis, 902, 1083 ultrasound, 138, 676, 688 ultraviolet irradiation, 81, 1185, 1192, 1228, 1230 umbilical cord, 511

1270

Index

underlying mechanisms, 332, 536, 1185 universities, 1213 upper respiratory tract, 925, 926, 932, 1180 urban, 52, 82, 369, 452, 456, 530, 531, 534, 905, 952, 982 urea, 228, 231, 233, 637, 662, 669, 691 uric acid, 228, 559, 563, 735, 749, 750, 817, 823, 885, 892, 893, 898, 916, 927, 935, 1025, 1065, 1077 uric acid levels, 898 urinary tract, xxviii, 742, 881, 887, 890, 896, 988 urinary tract infection, xxviii, 742, 881, 887, 890, 896 urine, 158, 196, 215, 233, 240, 336, 378, 422, 612, 640, 645, 651, 700, 742, 800, 815, 816, 817, 827, 876, 887, 890, 925, 927, 943, 1166 urokinase, 79 uterus, 386, 744, 1046, 1217 UV irradiation, xxxvii, 76, 1130, 1199, 1207, 1213 UV light, xxxvii, 98, 99, 117, 167, 267, 514, 543, 678, 886, 1131, 1207, 1212, 1215 UV radiation, 267, 556, 1118, 1175, 1216

V vaccinations, 748 validation, xxv, 13, 14, 95, 104, 138, 139, 142, 147, 148, 723, 729, 731 valvular heart disease, 461 vapor, 1211, 1213 variables, 228, 229, 230, 233, 344, 462, 512, 534, 540, 608, 710, 761, 764, 938, 946, 1133, 1140 variations, xiii, xvii, 65, 66, 73, 109, 151, 330, 377, 401, 434, 498, 508, 536, 539, 603, 623, 632, 760, 802, 816, 832, 854, 989, 1101, 1113, 1128, 1136, 1152, 1193, 1199 varieties, xxix, 2, 3, 12, 13, 14, 15, 618, 619, 631, 646, 759, 761, 763, 949, 1007 vascular cell adhesion molecule, 810 vascular dementia, 290, 310, 311, 505, 509, 510, 524, 746, 892 vascular diseases, xxiv, 473, 648, 685, 694 vascular endothelial growth factor, 77, 88, 153, 188, 197, 235, 477 vascular endothelial growth factor (VEGF), 77, 188 vascular occlusion, 473 vasculature, 475 vasculitides, 1091 vasculitis, 1083, 1086 vasoconstriction, 474 vasodilation, 702, 883, 922 vasodilator, 514, 646, 648, 701, 891 vasopressin, 589, 803

vasospasm, 687 VCAM, 807 vegetable oil, xxxii, 12, 15, 344, 610, 612, 619, 1039, 1055, 1057, 1210 vegetables, xi, xiii, xiv, xxii, xxiv, xxv, xxviii, xxxi, 7, 13, 100, 102, 107, 112, 118, 119, 121, 126, 127, 128, 134, 139, 140, 144, 147, 148, 151, 201, 214, 222, 226, 342, 345, 351, 354, 460, 464, 466, 543, 604, 607, 610, 619, 638, 639, 652, 682, 693, 694, 697, 698, 701, 708, 711, 712, 715, 723, 725, 730, 731, 732, 735, 737, 740, 748, 750, 755, 756, 758, 763, 768, 800, 810, 820, 822, 861, 862, 863, 865, 866, 867, 868, 869, 870, 871, 872, 873, 874, 876, 877, 878, 879, 882, 883, 884, 899, 900, 901, 903, 905, 906, 907, 911, 917, 918, 920, 922, 937, 942, 946, 970, 973, 975, 976, 980, 982, 984, 991, 1003, 1004, 1005, 1006, 1007, 1008, 1009, 1010, 1011, 1012, 1013, 1014, 1015, 1016, 1036, 1040, 1050, 1057 vein, 153, 188, 248 velocity, 702, 816 verbal fluency, 289, 291, 293, 296, 297, 299, 508, 509 vertebrates, 436, 439, 443, 444, 648, 848, 851, 1030, 1192 very low density lipoprotein, 611, 920, 1052, 1056, 1058, 1070 vibration, 1061, 1200, 1206 victims, 351, 352, 360, 373 viral infection, xxviii, 118, 899, 900, 925, 1128 virus replication, 818 viscosity, xxii, 543, 557, 559, 562, 871 vision, xxx, 572, 597, 614, 651, 654, 655, 673, 749, 762, 924, 934, 979, 980, 985, 988, 1062 vitamin B12 deficiency, xv, xvi, xviii, 106, 113, 114, 119, 138, 251, 257, 258, 283, 295, 296, 297, 300, 313, 317, 319, 320, 369, 377, 378, 379, 380, 381, 382, 383, 384, 653 vitamin B2, 99, 100, 147, 565, 566, 692, 758 vitamin B3, 101, 656 vitamin B6, xvi, 95, 102, 103, 104, 106, 153, 222, 253, 255, 256, 258, 259, 262, 283, 287, 292, 293, 294, 298, 299, 300, 301, 311, 316, 317, 348, 357, 367, 559, 566, 597, 638, 640, 652, 656, 678, 684, 692, 758 vitamin B6 deficiency, xvi, 95, 255, 256, 283, 293, 294, 300, 316 vitamin C deficiency, xxv, 345, 598, 739, 740, 746, 772, 778, 783, 784, 786, 790, 796, 797, 803, 854, 875, 922, 1045 vitamin D receptor, xii, xviii, xxi, xxxii, xxxvi, 17, 20, 21, 33, 34, 35, 38, 40, 46, 47, 51, 55, 56, 57, 58, 75, 77, 82, 87, 88, 269, 270, 343, 364, 385,

Index

1271

386, 392, 395, 396, 399, 400, 402, 404, 418, 497, 519, 520, 522, 523, 524, 536, 570, 598, 1080, 1088, 1090, 1091, 1092, 1093, 1094, 1096, 1099, 1100, 1101, 1103, 1110, 1111, 1112, 1113, 1114, 1115, 1118, 1121, 1123, 1124, 1128, 1129, 1136, 1138, 1145, 1148, 1176, 1187, 1191, 1193, 1201, 1202, 1204, 1217 vitamin D responsive elements, 30, 399, 1217 vitamin K, xxx, 443, 444, 447, 449, 597, 599, 600, 606, 638, 681, 692, 758, 991, 995, 1062 vitamin requirements, 434, 435, 445, 446, 447, 741, 794, 797 vitamin supplementation, xv, 214, 227, 231, 233, 299, 321, 322, 324, 600, 601, 602, 721, 759, 818, 828, 894, 896, 930, 944, 1031, 1032, 1059 vitiligo, 1218 vocabulary, 291 vomiting, 332, 490, 579, 648, 652, 654, 741, 904, 983 vulnerability, 252, 285, 302, 304, 713, 872, 1004

white matter, 289, 295, 300, 303, 308, 311, 314, 382, 511, 512, 525 whooping cough, 747 wild type, 184, 1103, 1104, 1106 Wisconsin, xxxvii, 289, 1207, 1212, 1213, 1214, 1215, 1227 withdrawal, 423, 476 wool, 120, 1012, 1015, 1209 workers, 74, 454, 475, 600, 661, 663, 665, 676, 680, 809, 811, 814, 815, 816, 817, 851, 883, 884, 886, 888 working memory, 285, 292, 299, 304, 510, 514 World Health Organization, xxxvii, 227, 267, 342, 499, 516, 686, 694, 722, 757, 758, 879, 913, 986, 990, 991, 992, 993, 1016, 1050, 1053, 1207, 1219, 1222, 1223, 1232, 1233 World War I, 1211 wound healing, xx, xxiii, xxviii, 119, 471, 473, 479, 588, 595, 596, 601, 604, 607, 655, 702, 796, 861, 874, 877, 881, 882, 890, 893, 894

W

X

walking, 289, 322, 380, 1164, 1197 war, 1006 warts, 274, 1218 Washington, 43, 59, 168, 259, 301, 325, 340, 429, 448, 458, 520, 625, 630, 717, 765, 768, 796, 821, 911, 939, 941, 942, 943, 945, 947, 956, 1001, 1014, 1015, 1043, 1051, 1052, 1069, 1160, 1188, 1233 weakness, xxviii, xxxvi, 96, 289, 295, 500, 517, 614, 652, 655, 861, 882, 1029, 1061, 1062, 1178, 1191, 1192, 1193, 1205 wealth, 271 weapons, 592 wear, 73, 267, 273 weight gain, 436, 441, 444, 719, 777, 780, 783, 788, 789, 1218 weight loss, xiv, xvii, xxviii, xxix, 214, 225, 228, 231, 232, 233, 238, 252, 284, 325, 327, 330, 465, 590, 593, 651, 861, 957, 958, 960, 965, 966, 1149 well-being, xxiii, xxx, 358, 369, 595, 620, 645, 969, 975, 989 wellness, 455 Western Europe, 1174 wheat germ, xxxii, 9, 100, 619, 996, 999, 1036, 1055, 1056, 1057 wheeze, 896, 1180 wheezing, 653, 885, 1187 white blood cell count, 494, 585 white blood cells, 186, 570, 1177 White House, 896

xenografts, 77, 162, 167, 189, 821, 936 xenon, 556 xerophthalmia, xxx, 654, 979, 981, 986, 989, 991 xiphoid process, 834 x-rays, 1211

Y yeast, 96, 97, 100, 104, 107, 141, 353, 705, 756, 1209, 1213, 1217 yield, 4, 110, 112, 287, 555, 559, 670, 815, 818, 884, 1007, 1015 yolk, xxx, 106, 109, 115, 386, 620, 626, 979, 984, 1030, 1216 young adults, xxxii, 44, 55, 268, 272, 277, 287, 299, 318, 345, 356, 527, 822, 941, 1055, 1196, 1197, 1205, 1215 young women, 367, 393, 815, 816, 824, 942, 1013

Z zinc, xxx, 20, 153, 226, 235, 314, 315, 349, 350, 351, 354, 359, 360, 362, 370, 371, 372, 373, 428, 429, 452, 453, 457, 589, 619, 717, 744, 748, 753, 859, 886, 894, 905, 924, 925, 934, 947, 957, 958, 959, 960, 966, 967, 982, 986, 991, 992, 1004 zinc sulfate, 428 Zollinger-Ellison syndrome, 379