Holick Vitamin D

Physiology, Molecular Biology, and Clinical Applications
2. Auflage 2010
ISBN: 978-1-60327-303-9
Verlag: Humana Press
Format: PDF
Kopierschutz: 1 - PDF Watermark

E-Book, Englisch, 1160 Seiten

Reihe: Nutrition and Health

In Vitamin D: Physiology, Molecular Biology, and Clinical Applications, Second Edition, leading researchers provide a comprehensive, highly readable overview of the biological functions and clinical applications of vitamin D and its metabolites. Topics range from the most recent recommendations for vitamin D intake to new approaches for the treatment and prevention of vitamin D deficiency and the development of active vitamin D drugs to treat psoriasis and cancer. The book demonstrates the significant role that vitamin D has in maintaining good bone health and the prevention of osteoporosis, an important health problem for adults over the age of fifty. In addition, it authoritatively reviews the relationship between sunlight exposure, vitamin D, and increased risk of colon and breast cancer; how vitamin D is made in the skin; and the sequence of events that leads to its activation by the kidney. Also examined are the biological functions of 1,25-dihydrovitamin D3 on the intestine and bone, as well as other tissues, such as skin, the immune system, prostate, and breast, and vitamin D's molecular mechanism of action on the cell membrane and nucleus. The first edition of Vitamin D: Physiology, Molecular Biology and Clinical Applications was the benchmark in the field when published in 1999. This new and expanded volume continues to include extensive, in-depth chapters covering the most important aspects of the complex interactions between vitamin D and other dietary components, the ongoing debate concerning the best indicator of optimal vitamin D status and its nutrient requirements, and the impact of less than optimal status on disease risk. Vitamin D: Physiology, Molecular Biology, and Clinical Applications, Second Edition is designed and organized not only to be an up-to-date review on the subject, but also to provide medical students, graduate students, health care professionals and even the lay public with a reference source for the most up-to-date information about the vitamin D deficiency pandemic and its clinical implications for health and disease.

Autoren/Hrsg.

Holick, Michael F.

Inhaltsverzeichnis

1;Dedication;5
2;In Memoriam;7
3;Series Editor Introduction;9
4;Preface;13
4.1;ACKNOWLEDGMENTS;14
5;Contents;15
6;Contributors;21
7;Part I Introduction and Basic Biology;27
7.1;1 Vitamin D and Health: Evolution, Biologic Functions,and Recommended Dietary Intakes for Vitamin D;28
7.1.1;1 Evolutionary Perspective;29
7.1.1.1;1.1 The Calcium Connection;29
7.1.1.2;1.2 Photosynthesis of Vitamin D in the Skin;31
7.1.1.3;1.3 Metabolism of Vitamin D;31
7.1.2;2 Vitamin D Deficiency And Sources Of Vitamin D;31
7.1.2.1;2.1 Consequences of Vitamin D Deficiency on Skeletal Health;31
7.1.2.2;2.2 Sources of Vitamin D;33
7.1.2.3;2.3 Definition of Vitamin D Deficiency, Insufficiency, and Sufficiency;35
7.1.2.4;2.4 The Vitamin D Deficiency Pandemic;37
7.1.3;3 Recommended Adequate Dietary Intake Of Vitamin D;39
7.1.3.1;3.1 Birth to 6 Months;39
7.1.3.2;3.2 Ages 6--12 Months;41
7.1.3.3;3.3 Ages 1--8 Years;42
7.1.3.4;3.4 Ages 9--18 Years;42
7.1.3.5;3.5 Ages 19--50 Years;43
7.1.3.6;3.6 Ages 51--70 Years;43
7.1.3.7;3.7 Age 71 Years and Older;44
7.1.3.8;3.8 Pregnancy;45
7.1.3.9;3.9 Lactation;45
7.1.3.10;3.10 Tolerable Upper Intake Levels;46
7.1.4;4 Causes Of And Treatment Strategies For Vitamin D Deficiency;46
7.1.4.1;4.1 Causes;46
7.1.4.2;4.2 Strategies for Preventing and Treating Vitamin D Deficiency;46
7.1.5;5 Myths;51
7.1.5.1;5.1 Vitamin D Treatment Will Worsen Hypercalcemia in Hyperparathyroid Patients;51
7.1.5.2;5.2 Treatment with Vitamin D Will Increase Risk of Kidney Stones;52
7.1.5.3;5.3 Patients with Chronic Kidney Disease Do Not Need to Be Treated with Vitamin D Since They Cannot Activate It;52
7.1.5.4;5.4 Treatment with 50,000 IU of Vitamin D Long-Term Will Cause Vitamin D Intoxication;53
7.1.6;6 Conclusion;53
7.1.7;Acknowledgments;54
7.2;References;54
7.3;2 Photobiology of Vitamin D;59
7.3.1;1 Introduction;1
7.3.2;2 Historical Perspective;60
7.3.3;3 Vitamin D Fortification In Milk;61
7.3.4;4 Photosynthesis Of Previtamin D 3 In The Skin;63
7.3.4.1;4.1 Photoconversion of 7-DHC to Previtamin D 3 ;63
7.3.4.2;4.2 Conversion of Previtamin D 3 to Vitamin D 3 ;66
7.3.4.3;4.3 Translocation of Vitamin D 3 from the Skin into the Circulation;67
7.3.4.4;4.4 Photodegradation of Vitamin D 3 ;68
7.3.4.5;4.5 Photoisomers of Vitamin D 3 ;68
7.3.5;5 Regulation Of The Cutaneous Synthesis Of Previtamin D 3 ;68
7.3.5.1;5.1 Role of Melanin Pigmentation;68
7.3.5.2;5.2 Influence of Altitude, Latitude, Time of Day, and Weather Conditions on Previtamin D 3 Production;70
7.3.5.3;5.3 Effect of Aging on the Cutaneous Production of Previtamin D 3 ;74
7.3.5.4;5.4 Effect of Sunscreen Use and Clothing on Previtamin D 3 Formation;75
7.3.5.5;5.5 Influence of Season on 25(OH)D Levels in Nursing Home and Home Care Elderly;77
7.3.5.6;5.6 Tanning Bed Irradiation Enhances Vitamin D Status and Bone Mineral Density;78
7.3.6;6 SUMMARY;79
7.3.7;Acknowledgments;80
7.4;References;80
7.5;3 The Functional Metabolism and Molecular Biology of Vitamin D Action;85
7.5.1;1 Introduction;85
7.5.2;2 Overall Role Of The Vitamin D Hormone In Calcium And Phosphorus Homeostasis;86
7.5.3;3 Functional Metabolism;87
7.5.4;4 Regulation Of The Production And Catabolism Of 1,25(OH) 2 D ;90
7.5.5;5 Molecular Mechanism Of Vitamin D Action;94
7.5.6;6 Analogs: Mechanisms Of Action;96
7.5.7;7 Function Of Vitamin D Not Related To Calcium And Phosphate Homeostasis;96
7.5.8;8 Vitamin D In Public Health;100
7.6;Bibliography;106
7.7;4 Metabolism and Catabolism of Vitamin D, Its Metabolites and Clinically Relevant Analogs;122
7.7.1;1 Metabolism Of Vitamin D 3 AND 25(OH)D 3 ;122
7.7.1.1;1.1 25- and 1-Hydroxylation;123
7.7.1.2;1.2 24-Hydroxylation;126
7.7.1.3;1.3 26-Hydroxylation and 26,23-Lactone Formation;127
7.7.2;2 CATABOLISM of 1,25(OH)2D3 ;127
7.7.2.1;2.1 C-24 Oxidation Pathway to Calcitroic Acid;127
7.7.3;3 Metabolism And Catabolism Of The Analogs Of Vitamin D;130
7.7.3.1;3.1 Activation of Prodrugs;130
7.7.3.2;3.2 Vitamin D 2 ;130
7.7.3.2.1;3.2.1 Dihydrotachysterol;131
7.7.3.2.2;3.2.2 1(OH)D2 and 1(OH)D 3 ;132
7.7.3.3;3.3 Metabolism-Sensitive Analogs;134
7.7.3.3.1;3.3.1 Cyclopropane Ring Containing Analogs of Vitamin D;134
7.7.3.3.2;3.3.2 Oxa-Group-Containing Analogs;137
7.7.3.4;3.4 Metabolism-Resistant Analogs;140
7.7.3.4.1;3.4.1 F 6 -1,25-(OH) 2 D;140
7.7.3.4.2;3.4.2 Unsaturated Analogs;141
7.7.4;4 Important Implications Derived From Metabolism Studies;143
7.7.4.1;4.1 Relative Importance of Metabolism in the Mechanism of Action of Vitamin D Analogs;143
7.7.4.2;4.2 Future Directions;146
7.7.4.2.1;4.2.1 Structural Aspects of Vitamin D-Related Cytochrome P450s;146
7.7.4.2.2;4.2.2 Hydroxylase Gene Knockouts;147
7.7.4.2.3;4.2.3 Future Vitamin D Analog Design and Development;147
7.7.5;Acknowledgements;148
7.8;References;148
7.9;5 The Molecular Biology of the Vitamin D Receptor;158
7.9.1;1 INTRODUCTION;158
7.9.2;2 The Vitamin D Receptor Gene;159
7.9.3;3 Molecular Analysis Of The Functional Domains Of The Vdr;162
7.9.3.1;3.1 The DNA-Binding Domain (DBD);162
7.9.3.2;3.2 The Multifunctional C-terminal Domain;164
7.9.4;4 Molecular Mechanism Of Transcriptional Control By Vdr;166
7.9.4.1;4.1 VDR Interaction with Vitamin D-Responsive Elements;166
7.9.4.1.1;4.1.1 Vitamin D-Responsive Elements;166
7.9.4.1.2;4.1.2 A R ole for the 1,25(OH) 2 D L igand ;167
7.9.4.1.3;4.1.3 Gene Regulation Through Negative Response Elements ;168
7.9.4.1.4;4.1.4 A Role for the Unliganded VDR in Transcriptional Regulation ;168
7.9.4.2;4.2 Communication Between VDR and the Transcriptional Machinery;169
7.10;REFERENCES;171
7.11;6 VDR and RXR Subcellular Trafficking;176
7.11.1;1 Significance Of Receptor Localization;176
7.11.2;2 Spatial And Temporal Control Of Nuclear Receptor Functions;178
7.11.3;3 Nuclear Import Mechanisms For Vdr And Rxr;182
7.11.4;4 Nuclear Export Mechanisms For Vdr And Rxr;186
7.11.5;5 Intranuclear Trafficking Of Vdr And Rxr;189
7.11.6;6 Summary And Conclusion;191
7.12;REFERENCES;192
7.13;7 Mechanism of Action of 1,25-Dihydroxyvitamin D3 on IntestinalCalcium Absorption and Renal Calcium Transport;197
7.13.1;1 Introduction;197
7.13.2;2 Intestinal Calcium Absorption;198
7.13.2.1;2.1 Overview;198
7.13.2.2;2.2 Effect of 1,25-Dihydroxyvitamin D 3 on Saturable, Transcellular Intestinal Calcium Absorption;198
7.13.2.2.1;2.2.1 Role of 1,25(OH) 2 D on the Entry of Calcium Across the Brush Border Membrane;199
7.13.2.2.2;2.2.2 Role of 1,25(OH) 2 D on Transcellular Movement of Calcium;200
7.13.2.2.3;2.2.3 Role of 1,25(OH) 2 D on Calcium Extrusion from the Intestinal Cell;200
7.13.2.3;2.3 Other Models of Intestinal Calcium Transport -- Nonsaturable, Paracellular Intestinal Calcium Absorption;201
7.13.2.4;2.4 1,25(OH) 2 D and Intestinal Phosphorus Absorption;201
7.13.3;3 Renal Calcium Transport;201
7.13.3.1;3.1 Overview;201
7.13.3.2;3.2 Effect of 1,25(OH) 2 D on Renal Calcium Transport;203
7.13.3.2.1;3.2.1 Current Understanding of the Role of 1,25(OH) 2 D;203
7.13.3.2.2;3.2.2 Role of Vitamin D-Dependent Calcium-Binding Proteins and TRPV5 in Renal Calcium Transport;204
7.13.3.2.3;3.2.3 Role of the Plasma Membrane Calcium Pump and the Na + /Ca 2+ Exchanger;204
7.13.3.3;3.3 Other Effects of 1,25(OH) 2 D in the Kidney;205
7.13.4;4 Summary;205
7.14;References;206
7.15;8 Biological and Molecular Effects of Vitamin D on Bone;210
7.15.1;1 Introduction;210
7.15.2;2 A Spectrum of Cellular Activities of 1,25(OH) 2 D Contributing to Bone Formation ;211
7.15.2.1;2.1 Bone Tissue Organization, Vitamin D, and Osteoblasts;211
7.15.2.2;2.2 Skeletal Development;213
7.15.2.3;2.3 Vitamin D3 Promotes Cell Differentiation at Multiple Levels;214
7.15.3;3 The Role of Vitamin D in Coupling Osteoblast Activity to Osteoclast Differentiation for Bone Resorption;216
7.15.4;4 Vitamin D Regulation of Gene Expression During Bone Formation;218
7.15.4.1;4.1 Components of Vitamin D-Dependent Regulatory Complexes;218
7.15.4.2;4.2 Vitamin D-Mediated Gene Expression Within the Three-Dimensional Context of Nuclear Structure in Bone Cells;220
7.15.4.3;4.3 Vitamin D Receptor Coregulatory Factors Provide Gene-Specific Regulation;221
7.15.5;5 Conclusions and Future Directions;224
7.15.6;Acknowledgments;225
7.16;References;225
7.17;9 Biological and Molecular Effects of Vitamin D on the Kidney;231
7.17.1;1 The Kidney, The Vitamin D Endocrine System, And Disease Prevention;231
7.17.2;2 Essential Role Of The Kidney In Vitamin D Biological Actions;233
7.17.2.1;2.1 Renal Regulation of Systemic Calcitriol;233
7.17.2.1.1;2.1.1 Calcitriol Synthesis;233
7.17.2.1.2;2.1.2 Calcitriol Catabolism;235
7.17.2.2;2.2 Abnormal Calcitriol Production in CKD;235
7.17.3;3 Renal Uptake Of 25(Oh)D: Relevance In The Maintenance Of Normal Vitamin D Status;235
7.17.3.1;3.1 Essential Contribution of Megalin-Mediated Endocytosis to Calcitriol Production;235
7.17.3.2;3.2 Abnormal Uptake of 25(OH)D in CKD;236
7.17.3.3;3.3 Abnormal Renal 25(OH)D Uptake in CKD Contributes to Impaired Extrarenal Calcitriol Production;238
7.17.4;4 Renal Regulation Of Vdr Expression And Function;239
7.17.4.1;4.1 Calcitriol Regulation of VDR Expression;239
7.17.4.2;4.2 Abnormal Regulation of VDR Expression and Function in CKD;240
7.17.4.3;4.3 Impaired VDR Function in CKD;240
7.17.5;5 Vitamin D Regulation Of Kidney Function;241
7.17.5.1;5.1 Mineral Homeostasis;241
7.17.5.1.1;5.1.1 Calcitriol/VDR Regulation of Calcitriol Homeostasis;241
7.17.5.1.2;5.1.2 Calcitriol/VDR Control of Renal Handling of Calcium and Phosphate;242
7.17.5.2;5.2 Renal Calcitriol/VDR Actions Affecting the Cardiovascular System;243
7.17.5.3;5.3 Calcitriol/VDR Renoprotective Actions;244
7.17.6;Acknowledgments;248
7.18;References;248
7.19;10 Vitamin D and the Parathyroids;255
7.19.1;1 INTRODUCTION;255
7.19.2;2 THE PARATHYROID HORMONE GENE;256
7.19.2.1;2.1 The PTH Gene;256
7.19.2.2;2.2 The PTH mRNA;256
7.19.3;3 DEVELOPMENT OF THE PARATHYROID AND TISSUE-SPECIFIC EXPRESSION OF THE PTH GENE;256
7.19.4;4 PROMOTER SEQUENCES;257
7.19.5;5 REGULATION OF PTH GENE EXPRESSION;258
7.19.5.1;5.1 1,25-Dihydroxyvitamin D;258
7.19.5.1.1;5.1.1 Calreticulin and the Action of 1,25(OH)2D on the PTH Gene ;260
7.19.5.1.2;5.1.2 Studies on Mice with VDR Gene Deletion ;262
7.19.5.2;5.2 Calcium;263
7.19.5.2.1;5.2.1 Mechanisms of Regulation of PTH mRNA by Caclium ;263
7.19.5.3;5.3 Phosphate;265
7.19.5.3.1;5.3.1Phosphate Regulates the Parathyroid Independently of Calcium and 1,25(OH)2D ;265
7.19.5.4;5.4 Protein--PTH mRNA Interactions Determine the Regulation of PTH Gene Expression by Serum Calcium and Phosphate;266
7.19.5.4.1;5.4.1 Identification of the PTH mRNA 30 -UTR-Binding Proteins that Determine PTH mRNA Stability ;266
7.19.5.4.2;5.4.2 A Conserved Sequence in the PTH m RNA 30-UTR Binds Parathyroid Cytosolic Proteins and Determines m RNA Stability in Response to Changes in Calcium and Phosphate;268
7.19.6;6 FIBROBLAST GROWTH FACTOR 23 AND THE PARATHYROID;268
7.19.7;7 SUMMARY;269
7.19.8;Acknowledgments;269
7.20;References;269
7.21;11 Diversity of Vitamin D Target Genes;275
7.21.1;1 INTRODUCTION;276
7.21.2;2 VDR IS A NUCLEAR RECEPTOR;276
7.21.2.1;2.1 The Nuclear Receptor Superfamily;276
7.21.2.2;2.2 Modular Structure of Nuclear Receptors;277
7.21.2.3;2.3 The VDR;277
7.21.3;3 VDR-BINDING SITES;277
7.21.3.1;3.1 DR3-Type VDREs;277
7.21.3.2;3.2 Other Types of VDREs;279
7.21.3.3;3.3 Chromatin and Co-factors;279
7.21.3.4;3.4 VDREs in the Chromatin Context;280
7.21.3.5;3.5 Negative VDREs;282
7.21.4;4 VDR TARGET GENES;283
7.21.4.1;4.1 Classical VDR Targets;283
7.21.4.2;4.2 VDR Targets in Cell Cycle Regulation;283
7.21.4.3;4.3 Relative Expression of VDR Target Genes;284
7.21.5;5 VDR TARGET GENE ANALYSIS;285
7.21.5.1;5.1 Transcriptome Analysis;285
7.21.5.2;5.2 ChIP Analysis;285
7.21.5.3;5.3 ChIP-Chip Assays;286
7.21.5.4;5.4 In Silico Screening of VDREs;287
7.21.6;6 CONCLUSIONS;288
7.21.7;Acknowledgments;289
7.22;REFERENCES;289
8;Part II Non-skeletal/Functions of Vitamin D;295
8.1;12Extrarenal Synthesis of 1,25-Dihydroxyvitamin D and Its Health Implications;296
8.1.1;1 INTRODUCTION;296
8.1.2;2 TISSUE DISTRIBUTION OF CYP27B1;297
8.1.3;3 REGULATION OF EXTRARENAL CYP27 b 1 EXPRESSION;301
8.1.4;4 FUNCTION OF EXTRARENAL CYP27B1;303
8.1.4.1;4.1 Regulation of Proliferation and Differentiation;303
8.1.4.2;4.2 Regulation of Hormone Secretion;305
8.1.4.3;4.3 Regulation of Immune Function;306
8.1.5;5 SUMMARY;308
8.2;REFERENCES;308
8.3;13 Vitamin D and the Innate Immunity;315
8.3.1;1 TUBERCULOSIS;315
8.3.1.1;1.1 Tuberculosis Overview;315
8.3.1.1.1;1.1.1 Innate Immunity;316
8.3.1.1.2;1.1.2 Toll-Like Receptors ;316
8.3.1.1.3;1.1.3 Immunoactivity of 1,25-Dihydroxyvitamin D ;317
8.3.1.1.4;1.1.4 Antimicrobial Peptides ;318
8.3.1.2;1.2 Vitamin D Pathway and Tuberculosis;319
8.3.1.2.1;1.2.1 Role of 25-HydroxyvitaminD on the Innate Immune Response ;320
8.3.1.2.2;1.2.2 History of Vitamin D, Sunshine, and Tuberculosis ;322
8.3.1.2.3;1.2.3 Treatment of Tuberculosis with Vitamin D ;322
8.4;REFERENCES;323
8.5;14 Vitamin D and Colon Cancer;329
8.5.1;1 INTRODUCTION;329
8.5.1.1;1.1 Colorectal Cancer Prevention by Vitamin D and Calcium: Molecular and Cellular Mechanisms;330
8.5.2;2 RELEVANCE OF ENDOGENOUS 1,25(OH)2 D SYNTHESIS FOR GROWTH CONTROL OF NORMAL AND NEOPLASTIC COLON EPITHELIAL CELLS ;331
8.5.3;3 EXPRESSION OF CYP27B1 DURING INFLAMMATION AND TUMOR PROGRESSION ;332
8.5.4;4 REGULATION OF VITAMIN D HYDROXYLASES, CYP27B1 AND CYP24A1 ;333
8.5.4.1;4.1 Regulation of Vitamin D Metabolism in the Gut Mucosa by Calcium;333
8.5.4.2;4.2 Regulation of the Vitamin D System by Estrogenic Compounds;334
8.5.4.3;4.3 Effect of Folate on CYP24A1 Expression;335
8.5.4.4;4.4 Epigenetic Regulation of CYP24A1 and CYP27B1 Activity;335
8.5.4.5;4.5 Regulation of CYP24A1 and CYP27B1 and Prevention of Colon Cancer;338
8.6;REFERENCES;338
8.7;15Mechanisms of Resistance to Vitamin D Action in Human Cancer Cells;342
8.7.1; Acknowledgments;349
8.8;REFERENCES;349
8.9;16Vitamin D and the Brain: A Neuropsychiatric Perspective;352
8.9.1;1 INTRODUCTION;352
8.9.2;2 Vitamin D And Brain Development;353
8.9.3;3 Brain Development In The Developmental Vitamin D (Dvd)-Deficient Rodent;354
8.9.4;4 Behaviour In The Dvd-Deficient Rat And Mouse;355
8.9.5;5 Vitamin D And Neuropsychiatric Disorders: Clues From Epidemiology;356
8.9.6;6 CONCLUSIONS;358
8.10;REFERENCES;358
8.11;17 Vitamin D Modulation of Adipocyte Function;362
8.11.1;1 INTRODUCTION;362
8.11.2;2 Ca2+ SIGNALING ;363
8.11.3;3 Role Of The Nuclear Vitamin D Receptor;364
8.11.4;4 Calcitriol Regulation Of Adipocyte Apoptosis;365
8.11.5;5 Calcitriol Modulation Of Adipocyte Glucocorticoid Production;366
8.11.6;6 Calcitriol Regulation Of Cross Talk Between Adipocyte And Skeletal Muscle In Energy Metabolism;367
8.11.7;7 Calcitriol Regulation Of Adipocyte Oxidative Stress;369
8.11.8;8 Calcitriol Regulation Of Adipocyte Inflammatory Cytokine Production;369
8.11.9;9 Calcitriol Regulation Of AdipocyteMacrophage Cross Talk In Inflammation;370
8.11.10;10 CONCLUSION;371
8.12;REFERENCES;371
9;Part III Vitamin D Status Global Analysis;376
9.1;18 Determinants of Vitamin D Intake;377
9.1.1;1 INTRODUCTION;377
9.1.2;2 Dietary Guidelines: Past, Present, And Future Considerations ;378
9.1.3;3 History And Use Of Dietary Reference Intakes For Vitamin D;379
9.1.4;4 The Tolerable Upper Intake Level;383
9.1.5;5 Estimated Vitamin D Intakes In Canada And The United States;383
9.1.6;6 Food Patterns And Dietary Sources Of Vitamin D;385
9.1.7;7 Vitamin D Fortification Of Food;389
9.1.8;8 Vitamin D Supplementation;393
9.1.9;9 Considerations For Public Health Action;394
9.2;REFERENCES;394
9.3;19 25-Hydroxyvitamin D Assays and Their Clinical Utility;399
9.3.1;1 INTRODUCTION;399
9.3.2;2 Vitamin D Physiology;399
9.3.3;3 Currently Available 25(Oh)D Assays;401
9.3.3.1;3.1 Chromatographic Assays;401
9.3.3.2;3.2 Immunochemical and Competitive Protein Binding Assays (CPBA);405
9.3.3.3;3.3 Specimen Stability;406
9.3.3.4;3.4 Proficiency Testing and Assay Quality;406
9.3.3.5;3.5 Current Status of 25(OH)D Result Agreement;408
9.3.3.6;3.6 25(OH)D Variability;410
9.3.3.7;3.7 Definition of Low Vitamin D Status/Reporting of Circulating 25(OH)D Results;411
9.3.3.8;3.8 When Should 25(OH)D Be Measured?;412
9.3.4;4 CLINICAL UTILITY of 25(OH)D MEASUREMENT;413
9.3.5;5 CONCLUSIONS;413
9.4;REFERENCES;413
9.5;20 Health Disparities and Vitamin D;416
9.5.1;1 Introduction;416
9.5.2;2 Infant Mortality;419
9.5.3;3 Cardiovascular Disease;425
9.5.4;4 Cancer;428
9.5.5;5 Total Mortality;432
9.5.6;6 Diabetes;434
9.5.7;7 Tuberculosis;434
9.5.8;8 HIV/AIDS;435
9.5.9;9 Conclusion;435
9.6;ReferenceS;436
9.7;21 Vitamin D Deficiency in Canada;440
9.7.1;1 INTRODUCTION;440
9.7.2;2 Dietary Studies Of Vitamin D In Canadians;441
9.7.3;3 Studies Of Canadians Utilizing Measurements Of Serum 25(OH)D;442
9.7.3.1;3.1 Healthy Ambulatory Adults;442
9.7.3.2;3.2 Children;444
9.7.3.3;3.3 Aboriginal (First Nations and Inuit) Peoples;445
9.7.4;4 CONCLUSIONS;446
9.8;REFERENCES;446
9.9;22 Vitamin D Deficiency and Its Health Consequences in Northern Europe;449
9.9.1;1 INTRODUCTION;449
9.9.2;2 DEFINITION OF VITAMIN D INSUFFICIENCY AND DEFICIENCY;450
9.9.3;3 GEOGRAPHY AND SOLAR UV RADIATION;450
9.9.4;4 OVERVIEW OF VITAMIN D STATUS IN EUROPE;452
9.9.5;5 WHAT IS THE EFFECT OF LATITUDE ON VITAMIN D STATUS IN EUROPE?;452
9.9.6;6 NATIONAL NUTRITIONAL RECOMMENDATIONS AND DIET;453
9.9.7;7 FORTIFICATION POLICY IN NORTHERN EUROPE;454
9.9.8;8 SUPPLEMENTATION;460
9.9.9;9 INDIVIDUAL LIFESTYLE FACTORS;460
9.9.10;10 VITAMIN D INTAKES;461
9.9.11;11 PREVALENCE OF VITAMIN D INSUFFICIENCY;461
9.9.12;12 VITAMIN D STATUS IN DENMARK;461
9.9.13;13 CONCLUSION;462
9.10;REFERENCES;463
9.11;23 Vitamin D Deficiency and Consequences for the Health of People in Mediterranean Countries;466
9.11.1;1 INTRODUCTION;466
9.11.2;2 VITAMIN D STATUS IN MEDITERRANEAN POPULATIONS IN SPAIN AND OTHER EUROPEAN COUNTRIES;470
9.11.3;3 VITAMIN D STATUS IN MEDITERRANEAN POPULATIONS OF THE MIDDLE EAST AND NORTH AFRICAN COUNTRIES;473
9.12;REFERENCES ;478
9.13;24 Vitamin D Deficiency in the Middle East and Its Health Consequences;481
9.13.1;1 INTRODUCTION;482
9.13.2;2 Nutritional Rickets;483
9.13.2.1;2.1 Nutritional Rickets in the Middle East;484
9.13.2.2;2.2 Non-skeletal Manifestations of Nutritional Rickets;486
9.13.2.3;2.3 Rickets in Immigrants from Middle East;487
9.13.3;3 Hypovitaminosis D;487
9.13.3.1;3.1 Mothers--Neonates--Infants;487
9.13.3.2;3.2 Children and Adolescents;495
9.13.3.3;3.3 Adults;496
9.13.3.4;3.4 Immigrants from Middle East;497
9.13.3.5;3.5 Impact of Hypovitaminosis D on Musculoskeletal Outcomes;497
9.13.4;4 Recommendations For Treatment;498
9.13.4.1;4.1 Rickets;498
9.13.4.2;4.2 Hypovitaminosis D;500
9.13.5;5 Conclusion;501
9.13.6;Acknowledgments;502
9.14;References;502
9.15;25Vitamin D Deficiency in the Middle East and Its Health Consequencesfor Adults;507
9.15.1;1 Introduction;507
9.15.2;2 Epidemiology;507
9.15.3;3 Etiology;510
9.15.4;4 Conclusions;513
9.16;References;513
9.17;26 Vitamin D Deficiency and Its Health Consequences in Africa;516
9.17.1;1 Introduction;516
9.17.2;2 The Continent Of Africa;517
9.17.2.1;2.1 Geography, Topography, Climate;517
9.17.2.2;2.2 Demography;518
9.17.2.3;2.3 Ultraviolet Radiation and Skin Pigmentation;518
9.17.2.4;2.4 Diet and Foodstuffs;519
9.17.3;3 Indicators Of Health And Burden Of Disease In Africa Which May Affect Or Be Affected By Vitamin D Status;522
9.17.3.1;3.1 Malnutrition;522
9.17.3.2;3.2 Vitamin D Intake;522
9.17.3.3;3.3 Low Calcium Intake;522
9.17.3.4;3.4 Fluorosis;523
9.17.3.5;3.5 Tropical Enteropathy;523
9.17.3.6;3.6 Malaria;523
9.17.3.7;3.7 HIV/AIDS;524
9.17.3.8;3.8 Tuberculosis;524
9.17.3.9;3.9 Non-communicable Disease;524
9.17.4;4 Health Consequences Of Poor Vitamin D Status In Africa;524
9.17.4.1;4.1 Rickets and Osteomalacia;525
9.17.4.2;4.2 Tuberculosis;525
9.17.4.3;4.3 HIV/AIDS;526
9.17.5;5 Studies Of Vitamin D Status In Africa;527
9.17.6;6 Conclusions;527
9.18;REFERENCES;534
9.19;27 Vitamin D Deficiency and Its Health Consequences in India;540
9.19.1;1 Introduction;540
9.19.2;2 Historical Background;541
9.19.3;3 Vitamin D Status In Adults;541
9.19.3.1;3.1 Vitamin D Deficiency and Bone Mineral Density;543
9.19.4;4 Vitamin D Status In Pregnancy And Lactation;544
9.19.5;5 Vitamin D Status In Neonates And Infants;545
9.19.6;6 Vitamin D Status In Indian Children;546
9.19.6.1;6.1 Clinical Evidence of Rickets;547
9.19.7;7 Serum 25(Oh)D Levels;547
9.19.7.1;7.1 Vitamin D Deficiency and Bone Mineral Density;548
9.19.7.2;7.2 Do We Have Protective Bioadaptation to Vitamin D Deficiency?;549
9.19.7.3;7.3 How to Tackle Vitamin D Deficiency;549
9.19.8;8 Conclusion;550
9.20;References;550
9.21;28 Vitamin D Deficiency, Rickets, and Fluorosis in India;554
9.21.1;1 Vitamin D Deficiency In India;554
9.21.2;2 Nutritional Rickets In India;562
9.21.2.1;2.1 Skeletal Fluorosis in India: An Endemic Disease;567
9.21.3;3 Pathogenesis Of Fluorotoxic Bone Disease;568
9.21.4;4 Calcium Vitamin DFluoride Interactions;569
9.22;REFERENCES;569
9.23;29 Vitamin D in Asia;573
9.23.1;1 Vitamin D In Asia;573
9.23.2;2 Northern Asia;573
9.23.2.1;2.1 Vitamin D Status;574
9.23.2.2;2.2 Consequences;574
9.23.2.3;2.3 Causes of Vitamin D Deficiency;577
9.23.3;3 Middle East;579
9.23.3.1;3.1 Vitamin D Status;579
9.23.3.2;3.2 Consequences;582
9.23.3.3;3.3 Causes of Vitamin D Deficiency;583
9.23.4;4 Southern Asia;584
9.23.4.1;4.1 Vitamin D Status;584
9.23.4.2;4.2 Consequences;584
9.23.4.3;4.3 Causes of Vitamin D Deficiency;590
9.23.5;5 Strategies To Improve Vitamin D Status;590
9.23.6;6 CONCLUSION;591
9.24;References;592
9.25;30 Vitamin D Deficiency and Its Health Consequences in New Zealand;598
9.25.1;1 INTRODUCTION;598
9.25.2;2 New Zealand Location, Climate, And Uv Exposure;599
9.25.3;3 Prevalence Of Low 25(Oh)D Levels;599
9.25.4;4 Determinants Of 25(Oh)D Levels;601
9.25.5;5 The Effects Of Seasonal Variation Of 25(Oh)D And Fat Mass On The Diagnosis Of Vitamin D Sufficiency;604
9.25.6;6 CONCLUSION;609
9.26;References ;609
9.27;31 Toxicity of Vitamin D;611
9.27.1;1 Signs And Symptoms;612
9.27.2;2 Treatment;612
9.27.3;3 Mechanisms Of Toxicity;613
9.27.3.1;3.1 Hypersensitivity to Vitamin D;614
9.27.4;4 Mandated Safety Levels;614
9.27.5;5 Theoretical Noncalcemic Risks Of Vitamin D;616
9.27.6;6 Conclusion;617
9.28;References;618
10;Part IV Health Consequences of Vitamin D Deficiency and Resistance on Musculoskeletal Health;621
10.1;32 Vitamin D Deficiency in Pregnancy and Lactation and Health Consequences;622
10.1.1;1 Introduction;622
10.1.2;2 Maternal/Infant Calcium Homeostasis In Pregnancy;623
10.1.3;3 Contemporary Maternal Vitamin D Status In Pregnancy;623
10.1.4;4 Clinical Trials Of Vitamin D Supplementation In Pregnancy;624
10.1.5;5 Vitamin D And Fetal Development;627
10.1.6;6 Fetal Vitamin D Exposure And Immune Function;627
10.1.7;7 Fetal Vitamin D Exposure And Cardiac Development;628
10.1.8;8 Vitamin D And Pregnancy Health;628
10.1.9;9 Vitamin D Requirements For Mother And Infant During Lactation;629
10.1.10;10 The Mechanism Of Vitamin D In Human Milk;629
10.1.11;11 Maternal Vitamin D Supplementation During Lactation;630
10.1.12;12 Infant Vitamin D Supplementation During Lactation;631
10.1.13;13 Consequences Of Infant Vitamin D Status;631
10.1.14;14 Conclusion;632
10.2;References;633
10.3;33 Vitamin D Deficiency in Children and Its Health Consequences;639
10.3.1;1 Introduction;639
10.3.2;2 Prevalence Data;640
10.3.2.1;2.1 Newborns, Infants, and Toddlers;641
10.3.2.2;2.2 Older Children and Adolescents;641
10.3.2.3;2.3 Factors Influencing Vitamin D Status Throughout Childhood;642
10.3.3;3 Prevalence Of Vitamin D Deficiency In At-Risk Groups;643
10.3.3.1;3.1 Overweight;643
10.3.3.2;3.2 Epilepsy and Other Neurological Disorders;644
10.3.3.3;3.3 Inflammatory Bowel Disease, Celiac Disease, and Cystic Fibrosis;645
10.3.3.4;3.4 Hereditary Predisposition;645
10.3.4;4 Assessment Of Vitamin D Status;646
10.3.5;5 Supplementation;647
10.3.5.1;5.1 Supplementation in Infants;647
10.3.5.2;5.2 Supplementation in Children and Adolescents;649
10.3.6;6 Treatment;650
10.3.7;7 Conclusions;651
10.4;REFERENCES;651
10.5;34Dietary Calcium Deficiency and Rickets;657
10.5.1;1 INTRODUCTION;657
10.5.2;2 Calcium Homeostasis;658
10.5.3;3 Dietary Calcium Deficiency Rickets;661
10.5.3.1;3.1 Dietary Calcium Intakes;663
10.5.3.2;3.2 Intestinal Calcium Absorption;665
10.5.3.3;3.3 Vitamin D Requirements;666
10.5.3.4;3.4 Possible Genetic Influences;667
10.5.4;4 CONCLUSIONS;669
10.6;REFERENCES;670
10.7;35 Vitamin D in Fracture Prevention and Muscle Function and Fall Prevention;674
10.7.1;1 Introduction;674
10.7.2;2 Vitamin D: Its Role In Muscle Health;675
10.7.3;3 Desirable 25-Hydroxyvitamin D Status For Better Function And Lower Risk Of Sarcopenia;675
10.7.4;4 Vitamin D And Muscle Weakness;676
10.7.5;5 Vitamin D And Fall Prevention;676
10.7.6;6 Desirable 25-Hydroxyvitamin D Status For Better Bone Health;677
10.7.7;7 Importance Of Dose In Anti-Fracture Efficacy With Vitamin D;678
10.7.8;8 Summary;680
10.8;REFERENCES;680
10.9;36 Inherited Defects of Vitamin D Metabolism;683
10.9.1;1 Introduction;683
10.9.2;2 Pseudovitamin D Deficiency Rickets;684
10.9.3;3 Hereditary Vitamin D-Resistant Rickets;688
10.9.4;4 25-Hydroxylase Deficiency;690
10.10;REFERENCES;691
10.11;37Molecular Defects in the Vitamin D Receptor Associatedwith Hereditary 1,25-Dihydroxyvitamin D-Resistant Rickets (HVDRR);694
10.11.1;1 Introduction;694
10.11.2;2 Hereditary 1,25-Dihydroxyvitamin D-Resistant Rickets (Hvdrr);695
10.11.3;3 The Vitamin D Receptor;696
10.11.4;4 Cellular Basis Of Hvdrr;697
10.11.5;5 Molecular Basis For Hvdrr;698
10.11.5.1;5.1 Mutations in the VDR DNA-Binding Domain (DBD);698
10.11.5.2;5.2 Mutations Causing Premature Termination of the VDR;701
10.11.5.2.1;5.2.1 Premature Stop Mutations ;701
10.11.5.2.2;5.2.2 Splicing Mutations ;702
10.11.5.3;5.3 Mutations in the VDR Ligand-Binding Domain (LBD);702
10.11.5.3.1;5.3.1 Mutations That Affect 1,25(OH)2D Binding ;702
10.11.5.3.2;5.3.2 Mutations That Affect VDR0RXR Heterodimerization ;704
10.11.5.3.3;5.3.3 Mutations That Affect Coactivator Binding ;704
10.11.5.4;5.4 Compound Heterozygous Mutations in the VDR;705
10.11.5.5;5.5 Other Mutations in the VDR;706
10.11.6;6 Therapy Of Hvdrr;706
10.11.6.1;6.1 General;706
10.11.6.2;6.2 Treatment with Vitamin D;707
10.11.6.3;6.3 Calcium Therapy;708
10.11.6.4;6.4 Lessons from the Therapy of HVDRR Cases;709
10.11.7;7 Alopecia;709
10.11.8;8 Concluding Remarks;710
10.12;References;711
10.13;38Receptor-Independent Vitamin D Resistance in Subhumanand Human Primates;718
10.13.1;1 Early Primate Evolution;718
10.13.2;2 Simian Bone Disease;720
10.13.3;3 Steroid Hormone Resistance In New World Primates;721
10.13.4;4 Outbreak Of Rickets in The New World Primate Colonies of the Los Angeles Zoo;722
10.13.5;5 Investigating the Biochemical Nature of Vitamin D Resistance in New World Primates;723
10.13.6;6 Vitamin D Response Element-Binding Protein;725
10.13.7;7 hn RNPC-Related Proteins as Multifunctional Regulators of Gene Expression: Beyond Transcription;726
10.13.8;8 Intracellular Vitamin D-Binding Protein;728
10.13.9;9 Summary;729
10.13.10;Acknowledgments;729
10.14;References;729
10.15;3925-Hydroxyvitamin D-1-Hydroxylase: Studies in Mouse Modelsand Implications for Human Disease;732
10.15.1;1 Introduction;732
10.15.2;2 Skeletal and Mineral Modulating Actions of 25-Hydroxyvitamin D 3 -1 -Hydroxylase as Determined by Genetic Mouse Models;734
10.15.2.1;2.1 Regulation of Calcium Absorption;735
10.15.2.2;2.2 Regulation of the 1(OH)ase and of the 24(OH)ase Enzymes;735
10.15.2.3;2.3 Parathyroid Gland Function;736
10.15.2.4;2.4 Development of the Cartilaginous Growth Plate;736
10.15.2.5;2.5 Bone and Cartilage Remodeling;737
10.15.2.6;2.6 Mineralization of Bone;738
10.15.2.7;2.7 1,25 Dihydroxyvitamin D as a Bone Anabolic Agent;738
10.15.2.7.1;2.7.1 1anabolic Effects in Older Animals ;738
10.15.2.7.2;2.7.2 Anabolic Effects in Neonatal Animals ;738
10.15.2.7.3;2.7.3 Anabolic Effects of Exogenous 1, 25(OH)2D;739
10.15.2.7.4;2.7.4 Interaction of Exogenous PTH and Endogenous 1,25(OH)2D in Exerting a Bone Anabolic Effect ;740
10.15.3;3 Role of 25-Hydroxyvitamin D 3 -1 -Hydroxylase in Extra-Skeletal Actions of 1,25(OH) 2 D as Determined by Genetic Mouse Models;740
10.15.4;Acknowledgments;742
10.16;References;742
11;Part V Sunlight, Vitamin D and Cancer;746
11.1;40The Health Benefits of Solar Irradiance and Vitamin Dand the Consequences of Their Deprivation;747
11.1.1;1 Introduction;747
11.1.2;2 Scientific Methods Utilized;748
11.1.3;3 Application to Specific Health Conditions;750
11.1.3.1;3.1 Bone Health;750
11.1.3.2;3.2 Cancer;750
11.1.3.3;3.3 Infectious Diseases;753
11.1.3.4;3.4 Autoimmune Diseases;755
11.1.3.5;3.5 Metabolic Diseases;756
11.1.3.6;3.6 Cardiovascular Diseases;756
11.1.3.7;3.7 Alzheimer's Disease;757
11.1.3.8;3.8 Life Expectancy;757
11.1.3.9;3.9 Historical Review;757
11.1.4;4 Summary and Conclusion;758
11.2;References;759
11.3;41 Vitamin D Status, Solar Radiation and Cancer Prognosis;767
11.3.1;1 INTRODUCTION;767
11.3.2;2 skin synthesis and activation of vitamin d;768
11.3.3;3 Calculation Of Seasonal And Latitudinal Variations In Vitamin D Status;769
11.3.4;4 Serum Measurements Of Vitamin D Metabolites;770
11.3.5;5 Epidemiological Investigations Of Relative Risk Of Death From Breast, Colon And Prostate Cancer;772
11.3.6;6 Anti-Neoplastic Mechanisms Of Action;773
11.3.7;7 Summary;774
11.4;References;774
11.5;42 The Epidemiology of Vitamin D and Cancer Risk;778
11.5.1;1 Introduction;778
11.5.2;2 Colorectal Cancer;779
11.5.2.1;2.1 25(OH)D Level;779
11.5.2.2;2.2 Predicted 25(OH)D Level;782
11.5.2.3;2.3 Dietary Intake;783
11.5.2.4;2.4 Sun Exposure;783
11.5.2.5;2.5 Randomized Controlled Trial;783
11.5.3;3 Prostate Cancer;784
11.5.3.1;3.1 25(OH)Vitamin D;784
11.5.3.2;3.2 Predicted 25(OH)D Level;784
11.5.3.3;3.3 Vitamin D Intake;785
11.5.3.4;3.4 Sun Exposure;785
11.5.4;4 Breast Cancer;786
11.5.4.1;4.1 25(OH)Vitamin D;786
11.5.4.2;4.2 Vitamin D Intake;786
11.5.4.3;4.3 Sun Exposure;787
11.5.5;5 Pancreatic Cancer;787
11.5.5.1;5.1 25(OH)D Level;787
11.5.5.2;5.2 Predicted 25(OH)D;788
11.5.5.3;5.3 Vitamin D Intake;788
11.5.6;6 Esophageal And Gastric Cancers;788
11.5.6.1;6.1 25(OH)D Level;788
11.5.7;7 Ovarian Cancer;789
11.5.7.1;7.1 25(OH)D;789
11.5.7.2;7.2 Sun Exposure;789
11.5.8;8 Non-Hodgkin's Lymphoma (NHL);789
11.5.8.1;8.1 Sun Exposure;789
11.5.9;9 Total Cancer;790
11.5.9.1;9.1 Circulating 25(OH)D;790
11.5.9.2;9.2 Predicted 25(OH)D;790
11.5.9.3;9.3 Randomized Trials (RCT);791
11.5.10;10 Synthesis And Summary;791
11.6;REFERENCES;793
11.7;43 Vitamin D Deficiency and the Epidemiology of Prostate Cancer;797
11.7.1;1 INTRODUCTION;797
11.7.2;2 Prostate Cancer, Clinical Considerations;797
11.7.3;3 Synthesis Of Vitamin D Metabolites;798
11.7.4;4 Prostate Cancer And The Vitamin D Hypothesis;798
11.7.5;5 1,25(OH) 2 D Is Synthesized By Normal Prostate Cells;800
11.7.6;6 PROSTATE CANCER CELLS EXPRESS VDR BUT LOSE EXPRESSION OF 1 -OH ase ;801
11.7.7;7 Vdr Polymorphisms;803
11.7.8;8 Serological Studies Of The Vitamin D Deficiency Hypothesis;803
11.7.9;9 Epidemiologic Studies Of Solar Exposure;804
11.7.10;10 Vitamin D Deficiency And Prostate Cancer: Potential Mechanisms;806
11.7.11;11 Serum Calcium And Prostate Cancer Risk;807
11.8;REFERENCES;808
11.9;44Vitamin D for Cancer Prevention and Survival;812
11.9.1;1 Introduction;812
11.9.2;2 Serum 25-Hydroxyvitamin D and Risk of Breast Cancer;813
11.9.3;3 Serum 25-Hydroxyvitamin D and Risk of Colon Cancer;818
11.9.4;4 Latitude, Ultraviolet B, Serum 25-Hydroxyvitamin D and Risk of Cancer of the Ovary;820
11.9.5;5 Vitamin D and Cancer of Other Sites;820
11.9.6;6 Randomized Trials;821
11.9.7;7 Future Potential For Cancer Prevention;823
11.9.8;8 Serum 25-Hydroxyvitamin D And Cancer Survival;824
11.9.9;9 Vitamin D And Global Cancer Prevention;824
11.9.10;10 DisjunctionNatural SelectionInvasion (Dni) Model;826
11.9.10.1;10.1 Natural Selection: Basis of Pathogenesis;826
11.9.10.2;10.2 Invasion;828
11.9.10.3;10.3 Role of Calcium and Dietary Factors;829
11.9.10.4;10.4 Implications for Cancer Treatment;831
11.9.11;11 Safety of Vitamin D for Cancer Prevention and As an Adjunct to Treatment;831
11.9.12;12 Geographic Distribution of Cancer and Environmental Factors;832
11.9.13;13 Summary;833
11.9.14;Acknowledgments;833
11.10;References;833
11.11;45 The Anti-cancer Effect of Vitamin D: What Do the Randomized Trials Show?;840
11.11.1;1 INTRODUCTION;840
11.11.2;2 Potential Mechanism Of Vitamin D Anti-Cancer Effects;841
11.11.3;3 Vitamin D And Calcium In Prevention Of Cancer;843
11.11.4;4 Randomized Trials Of Vitamin D Supplementation And Cancer;843
11.11.5;5 Levels Of 25(Oh)d For Cancer Prevention;845
11.11.6;6 Doses Of Vitamin D Supplementation For Cancer Prevention;845
11.11.7;7 SUMMARY;846
11.12;REFERENCES;847
11.13;46 Sunlight, Skin Cancer, and Vitamin D;850
11.13.1;1 The Most Important Negative Health Effect Of Solar Uv Exposure: Induction Of Skin Cancer;851
11.13.1.1;1.1 Non-melanoma Skin Cancer, Malignant Melanoma, and Solar UV Exposure;851
11.13.1.2;1.2 Photocarcinogenesis of Skin Cancer;851
11.13.2;2 Recommendations For Sun Protection In Skin Cancer Prevention Campaigns;856
11.13.3;3 A Challenging Perspective: Understanding And Fighting Vitamin D Deficiency;856
11.13.3.1;3.1 Vitamin D Deficiency -- A Serious and Underappreciated Health Problem;856
11.13.3.2;3.2 Consequent Sun Protection Increases the Risk of Vitamin D Deficiency;858
11.13.3.3;3.3 How Much Vitamin D Do We Need?;859
11.13.4;4 Conclusions;859
11.14;References;861
12;Part VI Vitamin D Deficiency and Chronic Disease;864
12.1;47 Vitamin D and the Risk of Type 1 Diabetes;865
12.1.1;1 MECHANISMS;865
12.1.2;2 Ecological Correlations;866
12.1.3;3 Animal Experiments;868
12.1.4;4 Studies In Humans;870
12.1.5;5 Genetic Studies;872
12.1.6;6 Conclusions;873
12.2;References;873
12.3;48 Vitamin D and Multiple Sclerosis;878
12.3.1;1 Introduction;878
12.3.2;2 Ms Epidemiology;879
12.3.3;3 Sun Exposure, Vitamin D, And Ms Risk;880
12.3.3.1;3.1 Database Analyses;881
12.3.3.2;3.2 Case--Control Studies;881
12.3.3.3;3.3 Longitudinal Studies;883
12.3.4;4 Seasonal Variations In Birth Patterns;886
12.3.5;5 Vitamin D And Ms Progression;886
12.3.6;6 Summary;887
12.4;REFERENCES;887
12.5;49 Vitamin D and Type 2 Diabetes;891
12.5.1;1 Epidemiology And Burden Of Type 2 Diabetes;891
12.5.2;2 Vitamin D Metabolism;892
12.5.3;3 Potential Mechanisms Of Action Of Vitamin D On Glucose Metabolism;892
12.5.3.1;3.1 Vitamin D and Pancreatic Beta-Cell Function/Insulin Secretion;892
12.5.3.2;3.2 Vitamin D and Insulin Sensitivity;894
12.5.3.3;3.3 Vitamin D and Systemic Inflammation;895
12.5.4;4 Evidence From Observational Human Studies;895
12.5.4.1;4.1 Seasonal Variation and Type 2 Diabetes;895
12.5.4.2;4.2 Case--Control and Cross-Sectional Studies of Vitamin D and Type 2 Diabetes;895
12.5.4.3;4.3 Prospective Studies of Vitamin D and Type 2 Diabetes;900
12.5.4.4;4.4 The Role of Calcium Intake and Type 2 Diabetes or the Metabolic Syndrome;905
12.5.4.5;4.5 Summary of Evidence from Human Observational Studies;906
12.5.5;5 Evidence From Intervention Human Studies;906
12.5.5.1;5.1 Effect of Vitamin D Supplementation on Type 2 Diabetes;906
12.5.5.2;5.2 Effect of Combined Vitamin D and Calcium Supplementation on Type 2 Diabetes;906
12.5.5.3;5.3 Summary of Evidence from Intervention Studies;911
12.5.6;6 Limitations In The Study Of Vitamin D;911
12.5.7;7 Optimal Intake Of Vitamin D And Calcium In Relation To Type 2 Diabetes;911
12.5.8;8 Conclusions And Future Directions;912
12.6;REFERENCES;912
12.7;50 Role of Vitamin D for Cardiovascular Health;917
12.7.1;1 Historical Review;917
12.7.1.1;1.1 Adverse Cardiovascular Effects from Very High Intake of vitamin D;917
12.7.1.2;1.2 Early Epidemiological Studies;918
12.7.2;2 Ecological Studies;918
12.7.2.1;2.1 Hypothesis That Sunlight and vitamin D Protect Against Cardiovascular Disease;918
12.7.2.2;2.2 Winter Excess in Cardiovascular Disease;919
12.7.3;3 Recent Epidemiological Studies;920
12.7.3.1;3.1 Observational Studies;920
12.7.3.2;3.2 Experimental Studies;921
12.7.4;4 Possible Cardio-Preventive Mechanisms Of vitamin D;922
12.7.4.1;4.1 Cardiac Function;922
12.7.4.2;4.2 Blood Pressure;923
12.7.4.3;4.3 Inflammatory Factors;924
12.7.4.4;4.4 Summary of Possible Mechanisms;925
12.8;REFERENCES;925
12.9;51 Vitamin D, Renin, and Blood Pressure;933
12.9.1;1 Introduction;933
12.9.2;2 Vitamin D, Blood Pressure, and Cardiac Functions: Evidence for a Connection;934
12.9.2.1;2.1 Epidemiological Evidence;934
12.9.2.2;2.2 Clinical Evidence;936
12.9.3;3 The ReninAngiotensin System: A Central Regulator of Blood Pressure;937
12.9.3.1;3.1 The RAS Cascade and Its Functions;937
12.9.3.2;3.2 Renin, the Rate-Limiting Enzyme of the RAS Cascade;938
12.9.3.3;3.3 Pharmacological Inhibition of the Renin--Angiotensin System;939
12.9.4;4 Vitamin D Regulation of the ReninAngiotensin System: Mechanism for the Connection?;940
12.9.4.1;4.1 Vitamin D: Negative Endocrine Regulator of the Renin--Angiotensin System;941
12.9.4.2;4.2 Mechanism of Renin Suppression;942
12.9.4.3;4.3 Vitamin D Analogs as Novel Renin Inhibitors;943
12.9.5;5 Conclusion;944
12.9.6;Acknowledgments;944
12.10;References;944
12.11;52 Role of Vitamin D and Vitamin D Analogs for Bone Health and Survival in Chronic Kidney Disease;950
12.11.1;1 Vitamin D and Metabolic Changes of Chronic Kidney Disease;950
12.11.2;2 Bone Disease and Vitamin D in Ckd;951
12.11.3;3 Osteitis Fibrosa Cystica;951
12.11.4;4 Adynamic Bone Disease;952
12.11.5;5 Osteomalacia;953
12.11.6;6 Vitamin D and Survival;953
12.11.7;7 Potential Mechanisms of a Cardiovascular Survival Benefit;955
12.11.8;8 Infectious Disease Survival and Vitamin D;957
12.11.9;9 Summary;957
12.12;References;957
12.13;53 Role of Vitamin D and Ultraviolet Radiation in Chronic Kidney Disease;961
12.13.1;1 Vitamin D Status in Chronic Kidney Disease;961
12.13.2;2 Vitamin D Supplementation in Chronic Kidney Disease;962
12.13.3;3 Vitamin D and Uv Radiation in Chronic Kidney Disease Patients on Haemodialysis (Own Experiences and Data);962
12.13.4;4 Uv Trials With Patients on Haemodialysis;963
12.13.4.1;4.1 Whole-Body Irradiation;963
12.13.4.2;4.2 Partial-Body Irradiation;963
12.13.4.3;4.3 Vitamin D Metabolism During UVB Irradiation;966
12.13.4.4;4.4 Renal Osteodystrophy, Bone Mineral Density, and Bone Turnover;969
12.13.4.5;4.5 Physical Work Capacity and Blood Pressure;970
12.13.4.5.1;4.5.1 E rythropoiesis and UV R adiation in ESKD P atients ;971
12.13.4.6;4.6 Heart Rate Variability and UV Radiation in ESKD Patients;972
12.13.4.7;4.7 UVB Radiation in Clinical Routine of a Dialysis Unit;972
12.13.5;5 Vitamin D and Uv Exposure in Prevention and Treatment of Chronic Kidney Disease;974
12.14;References;974
12.15;54 Role of Vitamin D in Rheumatoid Arthritis;978
12.15.1;1 INTRODUCTION;978
12.15.2;2 Rheumatoid Arthritis Disease Mechanism;979
12.15.2.1;2.1 Genetic Involvement;979
12.15.2.2;2.2 Rheumatoid Arthritis Immune System Involvement;979
12.15.3;3 Vitamin D And Rheumatoid Arthritis;980
12.15.3.1;3.1 Background;980
12.15.3.1.1;3.1.1 Immune System Effects of Vitamin D and Rheumatoid Arthritis ;981
12.15.3.2;3.2 Joint Destruction in Rheumatoid Arthritis;982
12.15.3.3;3.3 Clinical, Animal, and Epidemiologic Studies of Vitamin D and Rheumatoid Arthritis;983
12.16;REFERENCES;985
12.17;55 Vitamin D, Respiratory Infections, and Obstructive Airway Diseases;989
12.17.1;1 Introduction;989
12.17.2;2 Respiratory Infections;991
12.17.3;3 Obstructive Airway Diseases;992
12.17.3.1;3.1 Asthma;992
12.17.3.2;3.2 Chronic Obstructive Pulmonary Disease;993
12.17.4;4 Childhood Wheezing;993
12.17.5;5 Vitamin D And Respiratory Infection;994
12.17.5.1;5.1 Tuberculosis;994
12.17.5.2;5.2 Epidemiologic Studies on Respiratory Infections;995
12.17.5.3;5.3 Preliminary Evidence from Interventional Trials;996
12.17.6;6 Vitamin D And Asthma;998
12.17.6.1;6.1 Asthma Pathogenesis;998
12.17.6.2;6.2 Asthma Control;999
12.17.6.3;6.3 Asthma Exacerbation;1000
12.17.7;7 Vitamin D And Copd;1000
12.17.7.1;7.1 COPD Pathogenesis;1000
12.17.7.2;7.2 Acute Exacerbations of COPD;1001
12.17.8;8 Potential Mechanisms;1001
12.17.8.1;8.1 Vitamin D and Innate Immunity;1001
12.17.8.2;8.2 Vitamin D and Adaptive Immunity;1002
12.17.8.3;8.3 Vitamin D, Atopy, and Allergies;1003
12.17.9;9 Future Research on Vitamin D, Respiratory Infections, and OAD s ;1005
12.17.10;10 Conclusions;1007
12.17.11;Acknowledgments;1007
12.18;References;1008
13;Part VII Clinical Uses of Vitamin D Analogues;1014
13.1;56 Treatment of Immunomediated Diseases by Vitamin D Analogs;1015
13.1.1;1 INTRODUCTION;1015
13.1.2;2 ENHANCEMENT OF INNATE IMMUNE RESPONSES BY VDR AGONISTS;1016
13.1.3;3 MODULATION OF ADAPTIVE IMMUNE RESPONSES BY VDR AGONISTS;1017
13.1.3.1;3.1 Induction of Pro-tolerogenic Properties in Myeloid Dendritic Cells;1017
13.1.3.2;3.2 Modulation of Effector Lymphocytes;1018
13.1.3.3;3.3 Enhancement of Regulatory T Cells;1019
13.1.4;4 VITAMIN D DEFICIENCY IN AUTOIMMUNE AND OTHER IMMUNOMEDIATED DISEASES;1019
13.1.5;5 ANTI-INFLAMMATORY AND IMMUNOMODULATORY EFFECTS OF VDR AGONISTS IN AUTOIMMUNE AND IMMUNOMEDIATED DISEASES;1020
13.1.5.1;5.1 Rheumatoid Arthritis;1020
13.1.5.2;5.2 Systemic Lupus Erythematosus;1022
13.1.5.3;5.3 Type 1 Diabetes;1022
13.1.5.4;5.4 Experimental Allergic Encephalomyelitis;1023
13.1.5.5;5.5 Inflammatory Bowel Disease;1023
13.1.5.6;5.6 Immunomediated Prostatic Diseases;1024
13.1.6;6 DEVELOPMENT OF VDR AGONISTS FOR THE TREATMENT OF AUTOIMMUNE AND OTHER IMMUNOMEDIATED DISEASES;1025
13.2;REFERENCES;1026
13.3;57Clinical Utility of 1,25-Dihydroxyvitamin D3 and Its Analoguesfor the Treatment of Psoriasis;1032
13.3.1;1 THE VITAMIN D SYSTEM IN THE SKIN;1032
13.3.2;2 PSORIASIS: PATHOGENESIS, IMMUNOLOGY, AND HISTOLOGY OF SKIN LESIONS;1034
13.3.3;3 CLINICAL STUDIES OF VITAMIN D AND ANALOGUES IN PSORIASIS AND OTHER SKIN DISEASES;1035
13.3.3.1;3.1 Treatment of Scalp Psoriasis;1038
13.3.3.2;3.2 Treatment of Nail Psoriasis;1038
13.3.3.3;3.3 Treatment of Face and Flexures;1038
13.3.3.4;3.4 Treatment of Skin Lesions in Children;1039
13.3.3.5;3.5 Treatment of Psoriatic Lesions in HIV Patients;1039
13.3.3.6;3.6 Combination of Vitamin D Analogues with Other Therapies;1039
13.3.4;4 TREATMENT OF OTHER SKIN DISORDERS WITH VITAMIN D ANALOGUES;1040
13.3.4.1;4.1 Vitamin D and Ichthyosis;1040
13.3.4.2;4.2 Vitamin D and Scleroderma;1040
13.3.4.3;4.3 Vitamin D and Vitiligo;1040
13.3.4.4;4.4 Vitamin D and Skin Cancer;1041
13.3.4.5;4.5 Vitamin D and Other Skin Diseases;1041
13.3.5;5 BIOLOGICAL EFFECTS OF VITAMIN D AND ANALOGUES IN PSORIASIS;1041
13.3.6;6 PERSPECTIVES FOR THE EVALUATION OF NEW VITAMIN D ANALOGUES WITH LESS CALCEMIC ACTIVITY THAT CAN BE USED FOR THE TREATMENT OF HYPERPROLIFERATIVE SKIN DISORDERS;1043
13.4;REFERENCES;1045
13.5;58Affinity Alkylating Vitamin D Analogs as Molecular Probesand Therapeutic Agents;1050
13.5.1;1 Affinity And Photoaffinity Labeling Reagents as Molecular Probes of Enzymes and Receptors;1050
13.5.2;2 Affinity Alkylating Compounds as Therapeutic Agents;1051
13.5.3;3 Vitamin D and Its Metabolites: Biosynthesis, Properties, and Mechanism of Action;1052
13.5.4;4 Mineral Homeostatic and Cell-Regulatory Properties of 1,25(OH) 2 D;1053
13.5.5;5 Transcriptional Mechanism of 1,25(OH) 2 D;1054
13.5.6;6 Vdr and Its Ligand-Binding Domain (Vdr-Lbd);1055
13.5.7;7 Affinity Labeling of Vdr from Endogenous Sources;1055
13.5.8;8 Affinity Labeling of Recombinant Vdr and Identification of a Contact Point;1057
13.5.9;9 Vdr-Affinity Alkylating Derivatives of 1,25(OH) 2 D AND 25(OH)D As Potential Therapeutic Agents;1058
13.5.10;10 Pharmacokinetic Property of 1,25(OH) 2 D as it Relates to its Therapeutic Activity;1058
13.5.11;11 1,25(OH) 2 D-3-Be, A Derivative of 1,25(OH) 2 D, with a Potential of Less Catabolic Degradation: Our Hypothesis;1059
13.5.12;12 Kinetic And Stoichiometric Studies With 1,25(OH) 2 D-BE AND VDR;1059
13.5.13;13 Antiproliferative Effects Of 1,25(Oh) 2 D-Be In Various Cancer Cells;1060
13.5.14;14 Molecular Mechanisms Related To The Growth-Inhibitory Effect Of 1,25(OH) 2 D-3-Be;1062
13.5.14.1;14.1 VDR-Related Mechanisms;1062
13.5.14.2;14.2 Additional VDR-Related and VDR-Unrelated Mechanisms;1065
13.5.15;15 Therapeutic Potential Of 1,25(OH) 2 D-3-Be And Related Compounds In Cancer;1069
13.5.16;16 Summary;1071
13.5.17;Acknowledgment;1071
13.6;References;1072
13.7;59Anti-inflammatory Activity of Calcitriol That Contributesto Its Therapeutic and Chemopreventive Effects in Prostate Cancer;1076
13.7.1;1 INTRODUCTION;1076
13.7.2;2 CALCITRIOL AND PROSTATE CANCER;1077
13.7.2.1;2.1 Anti-proliferative Effects of Calcitriol in PCa Cells;1077
13.7.2.2;2.2 Tumor Inhibitory Effects of Calcitriol in Animal Models of PCa;1078
13.7.3;3 MECHANISMS OF THE ANTI-PROLIFERATIVE EFFECTS OF CALCITRIOL;1078
13.7.3.1;3.1 Growth Arrest;1078
13.7.3.2;3.2 Apoptosis;1078
13.7.3.3;3.3 Differentiation;1079
13.7.3.4;3.4 Modulation of Growth Factor Actions;1079
13.7.3.5;3.5 Inhibition of Invasion, Metastasis, and Angiogenesis;1079
13.7.3.6;3.6 Novel Molecular Pathways of Calcitriol Actions in PCa Cells;1080
13.7.4;4 ANTI-INFLAMMATORY EFFECTS OF CALCITRIOL IN PROSTATE CANCER;1080
13.7.4.1;4.1 Regulation of Prostaglandin Metabolism and Signaling;1080
13.7.4.1.1;4.1.1 COX-2 and Prostate Cancer ;1080
13.7.4.1.2;4.1.2 15-PGDH ;1081
13.7.4.1.3;4.1.3 PG Receptors ;1081
13.7.4.1.4;4.1.4 Calcitriol Effects on the PG Pathway in Prostate Cells ;1082
13.7.4.1.5;4.1.5 Combination of Calcitriol and Non-steroidal Anti-inflammatory Drugs (NSAIDs)as a Therapeutic Approach in Prostate Cancer ;1083
13.7.4.2;4.2 Induction of MKP5 and Inhibition of Stress-Activated Kinase Signaling;1084
13.7.4.3;4.3 Inhibition of NFB Activation and Signaling;1085
13.7.5;5 THE ROLE OF ANTI-INFLAMMATORY EFFECTS OF CALCITRIOL IN PROSTATE CANCER PREVENTION AND TREATMENT;1086
13.7.5.1;5.1 Inflammation and Prostate Cancer;1086
13.7.5.2;5.2 Calcitriol and Prostate Cancer Chemoprevention;1087
13.7.6;6 SUMMARY AND CONCLUSIONS;1087
13.7.6.1;REFERENCES;1088
14;Subject Index;1094
15;About the Editor;1146
16;About the Series Editor;1148