Vitamin D (eBook)

Dedication 5
In Memoriam 7
Series Editor Introduction 9
Preface 13
ACKNOWLEDGMENTS 14
Contents 15
Contributors 21
Part I Introduction and Basic Biology 27
1 Vitamin D and Health: Evolution, Biologic Functions,and Recommended Dietary Intakes for Vitamin D 28
1 Evolutionary Perspective 29
1.1 The Calcium Connection 29
1.2 Photosynthesis of Vitamin D in the Skin 31
1.3 Metabolism of Vitamin D 31
2 Vitamin D Deficiency And Sources Of Vitamin D 31
2.1 Consequences of Vitamin D Deficiency on Skeletal Health 31
2.2 Sources of Vitamin D 33
2.3 Definition of Vitamin D Deficiency, Insufficiency, and Sufficiency 35
2.4 The Vitamin D Deficiency Pandemic 37
3 Recommended Adequate Dietary Intake Of Vitamin D 39
3.1 Birth to 6 Months 39
3.2 Ages 6--12 Months 41
3.3 Ages 1--8 Years 42
3.4 Ages 9--18 Years 42
3.5 Ages 19--50 Years 43
3.6 Ages 51--70 Years 43
3.7 Age 71 Years and Older 44
3.8 Pregnancy 45
3.9 Lactation 45
3.10 Tolerable Upper Intake Levels 46
4 Causes Of And Treatment Strategies For Vitamin D Deficiency 46
4.1 Causes 46
4.2 Strategies for Preventing and Treating Vitamin D Deficiency 46
5 Myths 51
5.1 Vitamin D Treatment Will Worsen Hypercalcemia in Hyperparathyroid Patients 51
5.2 Treatment with Vitamin D Will Increase Risk of Kidney Stones 52
5.3 Patients with Chronic Kidney Disease Do Not Need to Be Treated with Vitamin D Since They Cannot Activate It 52
5.4 Treatment with 50,000 IU of Vitamin D Long-Term Will Cause Vitamin D Intoxication 53
6 Conclusion 53
Acknowledgments 54
References 54
2 Photobiology of Vitamin D 59
1 Introduction 1
2 Historical Perspective 60
3 Vitamin D Fortification In Milk 61
4 Photosynthesis Of Previtamin D 3 In The Skin 63
4.1 Photoconversion of 7-DHC to Previtamin D 3 63
4.2 Conversion of Previtamin D 3 to Vitamin D 3 66
4.3 Translocation of Vitamin D 3 from the Skin into the Circulation 67
4.4 Photodegradation of Vitamin D 3 68
4.5 Photoisomers of Vitamin D 3 68
5 Regulation Of The Cutaneous Synthesis Of Previtamin D 3 68
5.1 Role of Melanin Pigmentation 68
5.2 Influence of Altitude, Latitude, Time of Day, and Weather Conditions on Previtamin D 3 Production 70
5.3 Effect of Aging on the Cutaneous Production of Previtamin D 3 74
5.4 Effect of Sunscreen Use and Clothing on Previtamin D 3 Formation 75
5.5 Influence of Season on 25(OH)D Levels in Nursing Home and Home Care Elderly 77
5.6 Tanning Bed Irradiation Enhances Vitamin D Status and Bone Mineral Density 78
6 SUMMARY 79
Acknowledgments 80
References 80
3 The Functional Metabolism and Molecular Biology of Vitamin D Action 85
1 Introduction 85
2 Overall Role Of The Vitamin D Hormone In Calcium And Phosphorus Homeostasis 86
3 Functional Metabolism 87
4 Regulation Of The Production And Catabolism Of 1,25(OH) 2 D 90
5 Molecular Mechanism Of Vitamin D Action 94
6 Analogs: Mechanisms Of Action 96
7 Function Of Vitamin D Not Related To Calcium And Phosphate Homeostasis 96
8 Vitamin D In Public Health 100
Bibliography 106
4 Metabolism and Catabolism of Vitamin D, Its Metabolites and Clinically Relevant Analogs 122
1 Metabolism Of Vitamin D 3 AND 25(OH)D 3 122
1.1 25- and 1-Hydroxylation 123
1.2 24-Hydroxylation 126
1.3 26-Hydroxylation and 26,23-Lactone Formation 127
2 CATABOLISM of 1,25(OH)2D3 127
2.1 C-24 Oxidation Pathway to Calcitroic Acid 127
3 Metabolism And Catabolism Of The Analogs Of Vitamin D 130
3.1 Activation of Prodrugs 130
3.2 Vitamin D 2 130
3.2.1 Dihydrotachysterol 131
3.2.2 1(OH)D2 and 1(OH)D 3 132
3.3 Metabolism-Sensitive Analogs 134
3.3.1 Cyclopropane Ring Containing Analogs of Vitamin D 134
3.3.2 Oxa-Group-Containing Analogs 137
3.4 Metabolism-Resistant Analogs 140
3.4.1 F 6 -1,25-(OH) 2 D 140
3.4.2 Unsaturated Analogs 141
4 Important Implications Derived From Metabolism Studies 143
4.1 Relative Importance of Metabolism in the Mechanism of Action of Vitamin D Analogs 143
4.2 Future Directions 146
4.2.1 Structural Aspects of Vitamin D-Related Cytochrome P450s 146
4.2.2 Hydroxylase Gene Knockouts 147
4.2.3 Future Vitamin D Analog Design and Development 147
Acknowledgements 148
References 148
5 The Molecular Biology of the Vitamin D Receptor 158
1 INTRODUCTION 158
2 The Vitamin D Receptor Gene 159
3 Molecular Analysis Of The Functional Domains Of The Vdr 162
3.1 The DNA-Binding Domain (DBD) 162
3.2 The Multifunctional C-terminal Domain 164
4 Molecular Mechanism Of Transcriptional Control By Vdr 166
4.1 VDR Interaction with Vitamin D-Responsive Elements 166
4.1.1 Vitamin D-Responsive Elements 166
4.1.2 A R ole for the 1,25(OH) 2 D L igand 167
4.1.3 Gene Regulation Through Negative Response Elements 168
4.1.4 A Role for the Unliganded VDR in Transcriptional Regulation 168
4.2 Communication Between VDR and the Transcriptional Machinery 169
REFERENCES 171
6 VDR and RXR Subcellular Trafficking 176
1 Significance Of Receptor Localization 176
2 Spatial And Temporal Control Of Nuclear Receptor Functions 178
3 Nuclear Import Mechanisms For Vdr And Rxr 182
4 Nuclear Export Mechanisms For Vdr And Rxr 186
5 Intranuclear Trafficking Of Vdr And Rxr 189
6 Summary And Conclusion 191
REFERENCES 192
7 Mechanism of Action of 1,25-Dihydroxyvitamin D3 on IntestinalCalcium Absorption and Renal Calcium Transport 197
1 Introduction 197
2 Intestinal Calcium Absorption 198
2.1 Overview 198
2.2 Effect of 1,25-Dihydroxyvitamin D 3 on Saturable, Transcellular Intestinal Calcium Absorption 198
2.2.1 Role of 1,25(OH) 2 D on the Entry of Calcium Across the Brush Border Membrane 199
2.2.2 Role of 1,25(OH) 2 D on Transcellular Movement of Calcium 200
2.2.3 Role of 1,25(OH) 2 D on Calcium Extrusion from the Intestinal Cell 200
2.3 Other Models of Intestinal Calcium Transport -- Nonsaturable, Paracellular Intestinal Calcium Absorption 201
2.4 1,25(OH) 2 D and Intestinal Phosphorus Absorption 201
3 Renal Calcium Transport 201
3.1 Overview 201
3.2 Effect of 1,25(OH) 2 D on Renal Calcium Transport 203
3.2.1 Current Understanding of the Role of 1,25(OH) 2 D 203
3.2.2 Role of Vitamin D-Dependent Calcium-Binding Proteins and TRPV5 in Renal Calcium Transport 204
3.2.3 Role of the Plasma Membrane Calcium Pump and the Na + /Ca 2+ Exchanger 204
3.3 Other Effects of 1,25(OH) 2 D in the Kidney 205
4 Summary 205
References 206
8 Biological and Molecular Effects of Vitamin D on Bone 210
1 Introduction 210
2 A Spectrum of Cellular Activities of 1,25(OH) 2 D Contributing to Bone Formation 211
2.1 Bone Tissue Organization, Vitamin D, and Osteoblasts 211
2.2 Skeletal Development 213
2.3 Vitamin D3 Promotes Cell Differentiation at Multiple Levels 214
3 The Role of Vitamin D in Coupling Osteoblast Activity to Osteoclast Differentiation for Bone Resorption 216
4 Vitamin D Regulation of Gene Expression During Bone Formation 218
4.1 Components of Vitamin D-Dependent Regulatory Complexes 218
4.2 Vitamin D-Mediated Gene Expression Within the Three-Dimensional Context of Nuclear Structure in Bone Cells 220
4.3 Vitamin D Receptor Coregulatory Factors Provide Gene-Specific Regulation 221
5 Conclusions and Future Directions 224
Acknowledgments 225
References 225
9 Biological and Molecular Effects of Vitamin D on the Kidney 231
1 The Kidney, The Vitamin D Endocrine System, And Disease Prevention 231
2 Essential Role Of The Kidney In Vitamin D Biological Actions 233
2.1 Renal Regulation of Systemic Calcitriol 233
2.1.1 Calcitriol Synthesis 233
2.1.2 Calcitriol Catabolism 235
2.2 Abnormal Calcitriol Production in CKD 235
3 Renal Uptake Of 25(Oh)D: Relevance In The Maintenance Of Normal Vitamin D Status 235
3.1 Essential Contribution of Megalin-Mediated Endocytosis to Calcitriol Production 235
3.2 Abnormal Uptake of 25(OH)D in CKD 236
3.3 Abnormal Renal 25(OH)D Uptake in CKD Contributes to Impaired Extrarenal Calcitriol Production 238
4 Renal Regulation Of Vdr Expression And Function 239
4.1 Calcitriol Regulation of VDR Expression 239
4.2 Abnormal Regulation of VDR Expression and Function in CKD 240
4.3 Impaired VDR Function in CKD 240
5 Vitamin D Regulation Of Kidney Function 241
5.1 Mineral Homeostasis 241
5.1.1 Calcitriol/VDR Regulation of Calcitriol Homeostasis 241
5.1.2 Calcitriol/VDR Control of Renal Handling of Calcium and Phosphate 242
5.2 Renal Calcitriol/VDR Actions Affecting the Cardiovascular System 243
5.3 Calcitriol/VDR Renoprotective Actions 244
Acknowledgments 248
References 248
10 Vitamin D and the Parathyroids 255
1 INTRODUCTION 255
2 THE PARATHYROID HORMONE GENE 256
2.1 The PTH Gene 256
2.2 The PTH mRNA 256
3 DEVELOPMENT OF THE PARATHYROID AND TISSUE-SPECIFIC EXPRESSION OF THE PTH GENE 256
4 PROMOTER SEQUENCES 257
5 REGULATION OF PTH GENE EXPRESSION 258
5.1 1,25-Dihydroxyvitamin D 258
5.1.1 Calreticulin and the Action of 1,25(OH)2D on the PTH Gene 260
5.1.2 Studies on Mice with VDR Gene Deletion 262
5.2 Calcium 263
5.2.1 Mechanisms of Regulation of PTH mRNA by Caclium 263
5.3 Phosphate 265
5.3.1Phosphate Regulates the Parathyroid Independently of Calcium and 1,25(OH)2D 265
5.4 Protein--PTH mRNA Interactions Determine the Regulation of PTH Gene Expression by Serum Calcium and Phosphate 266
5.4.1 Identification of the PTH mRNA 30 -UTR-Binding Proteins that Determine PTH mRNA Stability 266
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
6 FIBROBLAST GROWTH FACTOR 23 AND THE PARATHYROID 268
7 SUMMARY 269
Acknowledgments 269
References 269
11 Diversity of Vitamin D Target Genes 275
1 INTRODUCTION 276
2 VDR IS A NUCLEAR RECEPTOR 276
2.1 The Nuclear Receptor Superfamily 276
2.2 Modular Structure of Nuclear Receptors 277
2.3 The VDR 277
3 VDR-BINDING SITES 277
3.1 DR3-Type VDREs 277
3.2 Other Types of VDREs 279
3.3 Chromatin and Co-factors 279
3.4 VDREs in the Chromatin Context 280
3.5 Negative VDREs 282
4 VDR TARGET GENES 283
4.1 Classical VDR Targets 283
4.2 VDR Targets in Cell Cycle Regulation 283
4.3 Relative Expression of VDR Target Genes 284
5 VDR TARGET GENE ANALYSIS 285
5.1 Transcriptome Analysis 285
5.2 ChIP Analysis 285
5.3 ChIP-Chip Assays 286
5.4 In Silico Screening of VDREs 287
6 CONCLUSIONS 288
Acknowledgments 289
REFERENCES 289
Part II Non-skeletal/Functions of Vitamin D 295
12Extrarenal Synthesis of 1,25-Dihydroxyvitamin D and Its Health Implications 296
1 INTRODUCTION 296
2 TISSUE DISTRIBUTION OF CYP27B1 297
3 REGULATION OF EXTRARENAL CYP27 b 1 EXPRESSION 301
4 FUNCTION OF EXTRARENAL CYP27B1 303
4.1 Regulation of Proliferation and Differentiation 303
4.2 Regulation of Hormone Secretion 305
4.3 Regulation of Immune Function 306
5 SUMMARY 308
REFERENCES 308
13 Vitamin D and the Innate Immunity 315
1 TUBERCULOSIS 315
1.1 Tuberculosis Overview 315
1.1.1 Innate Immunity 316
1.1.2 Toll-Like Receptors 316
1.1.3 Immunoactivity of 1,25-Dihydroxyvitamin D 317
1.1.4 Antimicrobial Peptides 318
1.2 Vitamin D Pathway and Tuberculosis 319
1.2.1 Role of 25-HydroxyvitaminD on the Innate Immune Response 320
1.2.2 History of Vitamin D, Sunshine, and Tuberculosis 322
1.2.3 Treatment of Tuberculosis with Vitamin D 322
REFERENCES 323
14 Vitamin D and Colon Cancer 329
1 INTRODUCTION 329
1.1 Colorectal Cancer Prevention by Vitamin D and Calcium: Molecular and Cellular Mechanisms 330
2 RELEVANCE OF ENDOGENOUS 1,25(OH)2 D SYNTHESIS FOR GROWTH CONTROL OF NORMAL AND NEOPLASTIC COLON EPITHELIAL CELLS 331
3 EXPRESSION OF CYP27B1 DURING INFLAMMATION AND TUMOR PROGRESSION 332
4 REGULATION OF VITAMIN D HYDROXYLASES, CYP27B1 AND CYP24A1 333
4.1 Regulation of Vitamin D Metabolism in the Gut Mucosa by Calcium 333
4.2 Regulation of the Vitamin D System by Estrogenic Compounds 334
4.3 Effect of Folate on CYP24A1 Expression 335
4.4 Epigenetic Regulation of CYP24A1 and CYP27B1 Activity 335
4.5 Regulation of CYP24A1 and CYP27B1 and Prevention of Colon Cancer 338
REFERENCES 338
15Mechanisms of Resistance to Vitamin D Action in Human Cancer Cells 342
Acknowledgments 349
REFERENCES 349
16Vitamin D and the Brain: A Neuropsychiatric Perspective 352
1 INTRODUCTION 352
2 Vitamin D And Brain Development 353
3 Brain Development In The Developmental Vitamin D (Dvd)-Deficient Rodent 354
4 Behaviour In The Dvd-Deficient Rat And Mouse 355
5 Vitamin D And Neuropsychiatric Disorders: Clues From Epidemiology 356
6 CONCLUSIONS 358
REFERENCES 358
17 Vitamin D Modulation of Adipocyte Function 362
1 INTRODUCTION 362
2 Ca2+ SIGNALING 363
3 Role Of The Nuclear Vitamin D Receptor 364
4 Calcitriol Regulation Of Adipocyte Apoptosis 365
5 Calcitriol Modulation Of Adipocyte Glucocorticoid Production 366
6 Calcitriol Regulation Of Cross Talk Between Adipocyte And Skeletal Muscle In Energy Metabolism 367
7 Calcitriol Regulation Of Adipocyte Oxidative Stress 369
8 Calcitriol Regulation Of Adipocyte Inflammatory Cytokine Production 369
9 Calcitriol Regulation Of AdipocyteMacrophage Cross Talk In Inflammation 370
10 CONCLUSION 371
REFERENCES 371
Part III Vitamin D Status Global Analysis 376
18 Determinants of Vitamin D Intake 377
1 INTRODUCTION 377
2 Dietary Guidelines: Past, Present, And Future Considerations 378
3 History And Use Of Dietary Reference Intakes For Vitamin D 379
4 The Tolerable Upper Intake Level 383
5 Estimated Vitamin D Intakes In Canada And The United States 383
6 Food Patterns And Dietary Sources Of Vitamin D 385
7 Vitamin D Fortification Of Food 389
8 Vitamin D Supplementation 393
9 Considerations For Public Health Action 394
REFERENCES 394
19 25-Hydroxyvitamin D Assays and Their Clinical Utility 399
1 INTRODUCTION 399
2 Vitamin D Physiology 399
3 Currently Available 25(Oh)D Assays 401
3.1 Chromatographic Assays 401
3.2 Immunochemical and Competitive Protein Binding Assays (CPBA) 405
3.3 Specimen Stability 406
3.4 Proficiency Testing and Assay Quality 406
3.5 Current Status of 25(OH)D Result Agreement 408
3.6 25(OH)D Variability 410
3.7 Definition of Low Vitamin D Status/Reporting of Circulating 25(OH)D Results 411
3.8 When Should 25(OH)D Be Measured? 412
4 CLINICAL UTILITY of 25(OH)D MEASUREMENT 413
5 CONCLUSIONS 413
REFERENCES 413
20 Health Disparities and Vitamin D 416
1 Introduction 416
2 Infant Mortality 419
3 Cardiovascular Disease 425
4 Cancer 428
5 Total Mortality 432
6 Diabetes 434
7 Tuberculosis 434
8 HIV/AIDS 435
9 Conclusion 435
ReferenceS 436
21 Vitamin D Deficiency in Canada 440
1 INTRODUCTION 440
2 Dietary Studies Of Vitamin D In Canadians 441
3 Studies Of Canadians Utilizing Measurements Of Serum 25(OH)D 442
3.1 Healthy Ambulatory Adults 442
3.2 Children 444
3.3 Aboriginal (First Nations and Inuit) Peoples 445
4 CONCLUSIONS 446
REFERENCES 446
22 Vitamin D Deficiency and Its Health Consequences in Northern Europe 449
1 INTRODUCTION 449
2 DEFINITION OF VITAMIN D INSUFFICIENCY AND DEFICIENCY 450
3 GEOGRAPHY AND SOLAR UV RADIATION 450
4 OVERVIEW OF VITAMIN D STATUS IN EUROPE 452
5 WHAT IS THE EFFECT OF LATITUDE ON VITAMIN D STATUS IN EUROPE? 452
6 NATIONAL NUTRITIONAL RECOMMENDATIONS AND DIET 453
7 FORTIFICATION POLICY IN NORTHERN EUROPE 454
8 SUPPLEMENTATION 460
9 INDIVIDUAL LIFESTYLE FACTORS 460
10 VITAMIN D INTAKES 461
11 PREVALENCE OF VITAMIN D INSUFFICIENCY 461
12 VITAMIN D STATUS IN DENMARK 461
13 CONCLUSION 462
REFERENCES 463
23 Vitamin D Deficiency and Consequences for the Health of People in Mediterranean Countries 466
1 INTRODUCTION 466
2 VITAMIN D STATUS IN MEDITERRANEAN POPULATIONS IN SPAIN AND OTHER EUROPEAN COUNTRIES 470
3 VITAMIN D STATUS IN MEDITERRANEAN POPULATIONS OF THE MIDDLE EAST AND NORTH AFRICAN COUNTRIES 473
REFERENCES 478
24 Vitamin D Deficiency in the Middle East and Its Health Consequences 481
1 INTRODUCTION 482
2 Nutritional Rickets 483
2.1 Nutritional Rickets in the Middle East 484
2.2 Non-skeletal Manifestations of Nutritional Rickets 486
2.3 Rickets in Immigrants from Middle East 487
3 Hypovitaminosis D 487
3.1 Mothers--Neonates--Infants 487
3.2 Children and Adolescents 495
3.3 Adults 496
3.4 Immigrants from Middle East 497
3.5 Impact of Hypovitaminosis D on Musculoskeletal Outcomes 497
4 Recommendations For Treatment 498
4.1 Rickets 498
4.2 Hypovitaminosis D 500
5 Conclusion 501
Acknowledgments 502
References 502
25Vitamin D Deficiency in the Middle East and Its Health Consequencesfor Adults 507
1 Introduction 507
2 Epidemiology 507
3 Etiology 510
4 Conclusions 513
References 513
26 Vitamin D Deficiency and Its Health Consequences in Africa 516
1 Introduction 516
2 The Continent Of Africa 517
2.1 Geography, Topography, Climate 517
2.2 Demography 518
2.3 Ultraviolet Radiation and Skin Pigmentation 518
2.4 Diet and Foodstuffs 519
3 Indicators Of Health And Burden Of Disease In Africa Which May Affect Or Be Affected By Vitamin D Status 522
3.1 Malnutrition 522
3.2 Vitamin D Intake 522
3.3 Low Calcium Intake 522
3.4 Fluorosis 523
3.5 Tropical Enteropathy 523
3.6 Malaria 523
3.7 HIV/AIDS 524
3.8 Tuberculosis 524
3.9 Non-communicable Disease 524
4 Health Consequences Of Poor Vitamin D Status In Africa 524
4.1 Rickets and Osteomalacia 525
4.2 Tuberculosis 525
4.3 HIV/AIDS 526
5 Studies Of Vitamin D Status In Africa 527
6 Conclusions 527
REFERENCES 534
27 Vitamin D Deficiency and Its Health Consequences in India 540
1 Introduction 540
2 Historical Background 541
3 Vitamin D Status In Adults 541
3.1 Vitamin D Deficiency and Bone Mineral Density 543
4 Vitamin D Status In Pregnancy And Lactation 544
5 Vitamin D Status In Neonates And Infants 545
6 Vitamin D Status In Indian Children 546
6.1 Clinical Evidence of Rickets 547
7 Serum 25(Oh)D Levels 547
7.1 Vitamin D Deficiency and Bone Mineral Density 548
7.2 Do We Have Protective Bioadaptation to Vitamin D Deficiency? 549
7.3 How to Tackle Vitamin D Deficiency 549
8 Conclusion 550
References 550
28 Vitamin D Deficiency, Rickets, and Fluorosis in India 554
1 Vitamin D Deficiency In India 554
2 Nutritional Rickets In India 562
2.1 Skeletal Fluorosis in India: An Endemic Disease 567
3 Pathogenesis Of Fluorotoxic Bone Disease 568
4 Calcium Vitamin DFluoride Interactions 569
REFERENCES 569
29 Vitamin D in Asia 573
1 Vitamin D In Asia 573
2 Northern Asia 573
2.1 Vitamin D Status 574
2.2 Consequences 574
2.3 Causes of Vitamin D Deficiency 577
3 Middle East 579
3.1 Vitamin D Status 579
3.2 Consequences 582
3.3 Causes of Vitamin D Deficiency 583
4 Southern Asia 584
4.1 Vitamin D Status 584
4.2 Consequences 584
4.3 Causes of Vitamin D Deficiency 590
5 Strategies To Improve Vitamin D Status 590
6 CONCLUSION 591
References 592
30 Vitamin D Deficiency and Its Health Consequences in New Zealand 598
1 INTRODUCTION 598
2 New Zealand Location, Climate, And Uv Exposure 599
3 Prevalence Of Low 25(Oh)D Levels 599
4 Determinants Of 25(Oh)D Levels 601
5 The Effects Of Seasonal Variation Of 25(Oh)D And Fat Mass On The Diagnosis Of Vitamin D Sufficiency 604
6 CONCLUSION 609
References 609
31 Toxicity of Vitamin D 611
1 Signs And Symptoms 612
2 Treatment 612
3 Mechanisms Of Toxicity 613
3.1 Hypersensitivity to Vitamin D 614
4 Mandated Safety Levels 614
5 Theoretical Noncalcemic Risks Of Vitamin D 616
6 Conclusion 617
References 618
Part IV Health Consequences of Vitamin D Deficiency and Resistance on Musculoskeletal Health 621
32 Vitamin D Deficiency in Pregnancy and Lactation and Health Consequences 622
1 Introduction 622
2 Maternal/Infant Calcium Homeostasis In Pregnancy 623
3 Contemporary Maternal Vitamin D Status In Pregnancy 623
4 Clinical Trials Of Vitamin D Supplementation In Pregnancy 624
5 Vitamin D And Fetal Development 627
6 Fetal Vitamin D Exposure And Immune Function 627
7 Fetal Vitamin D Exposure And Cardiac Development 628
8 Vitamin D And Pregnancy Health 628
9 Vitamin D Requirements For Mother And Infant During Lactation 629
10 The Mechanism Of Vitamin D In Human Milk 629
11 Maternal Vitamin D Supplementation During Lactation 630
12 Infant Vitamin D Supplementation During Lactation 631
13 Consequences Of Infant Vitamin D Status 631
14 Conclusion 632
References 633
33 Vitamin D Deficiency in Children and Its Health Consequences 639
1 Introduction 639
2 Prevalence Data 640
2.1 Newborns, Infants, and Toddlers 641
2.2 Older Children and Adolescents 641
2.3 Factors Influencing Vitamin D Status Throughout Childhood 642
3 Prevalence Of Vitamin D Deficiency In At-Risk Groups 643
3.1 Overweight 643
3.2 Epilepsy and Other Neurological Disorders 644
3.3 Inflammatory Bowel Disease, Celiac Disease, and Cystic Fibrosis 645
3.4 Hereditary Predisposition 645
4 Assessment Of Vitamin D Status 646
5 Supplementation 647
5.1 Supplementation in Infants 647
5.2 Supplementation in Children and Adolescents 649
6 Treatment 650
7 Conclusions 651
REFERENCES 651
34Dietary Calcium Deficiency and Rickets 657
1 INTRODUCTION 657
2 Calcium Homeostasis 658
3 Dietary Calcium Deficiency Rickets 661
3.1 Dietary Calcium Intakes 663
3.2 Intestinal Calcium Absorption 665
3.3 Vitamin D Requirements 666
3.4 Possible Genetic Influences 667
4 CONCLUSIONS 669
REFERENCES 670
35 Vitamin D in Fracture Prevention and Muscle Function and Fall Prevention 674
1 Introduction 674
2 Vitamin D: Its Role In Muscle Health 675
3 Desirable 25-Hydroxyvitamin D Status For Better Function And Lower Risk Of Sarcopenia 675
4 Vitamin D And Muscle Weakness 676
5 Vitamin D And Fall Prevention 676
6 Desirable 25-Hydroxyvitamin D Status For Better Bone Health 677
7 Importance Of Dose In Anti-Fracture Efficacy With Vitamin D 678
8 Summary 680
REFERENCES 680
36 Inherited Defects of Vitamin D Metabolism 683
1 Introduction 683
2 Pseudovitamin D Deficiency Rickets 684
3 Hereditary Vitamin D-Resistant Rickets 688
4 25-Hydroxylase Deficiency 690
REFERENCES 691
37Molecular Defects in the Vitamin D Receptor Associatedwith Hereditary 1,25-Dihydroxyvitamin D-Resistant Rickets (HVDRR) 694
1 Introduction 694
2 Hereditary 1,25-Dihydroxyvitamin D-Resistant Rickets (Hvdrr) 695
3 The Vitamin D Receptor 696
4 Cellular Basis Of Hvdrr 697
5 Molecular Basis For Hvdrr 698
5.1 Mutations in the VDR DNA-Binding Domain (DBD) 698
5.2 Mutations Causing Premature Termination of the VDR 701
5.2.1 Premature Stop Mutations 701
5.2.2 Splicing Mutations 702
5.3 Mutations in the VDR Ligand-Binding Domain (LBD) 702
5.3.1 Mutations That Affect 1,25(OH)2D Binding 702
5.3.2 Mutations That Affect VDR0RXR Heterodimerization 704
5.3.3 Mutations That Affect Coactivator Binding 704
5.4 Compound Heterozygous Mutations in the VDR 705
5.5 Other Mutations in the VDR 706
6 Therapy Of Hvdrr 706
6.1 General 706
6.2 Treatment with Vitamin D 707
6.3 Calcium Therapy 708
6.4 Lessons from the Therapy of HVDRR Cases 709
7 Alopecia 709
8 Concluding Remarks 710
References 711
38Receptor-Independent Vitamin D Resistance in Subhumanand Human Primates 718
1 Early Primate Evolution 718
2 Simian Bone Disease 720
3 Steroid Hormone Resistance In New World Primates 721
4 Outbreak Of Rickets in The New World Primate Colonies of the Los Angeles Zoo 722
5 Investigating the Biochemical Nature of Vitamin D Resistance in New World Primates 723
6 Vitamin D Response Element-Binding Protein 725
7 hn RNPC-Related Proteins as Multifunctional Regulators of Gene Expression: Beyond Transcription 726
8 Intracellular Vitamin D-Binding Protein 728
9 Summary 729
Acknowledgments 729
References 729
3925-Hydroxyvitamin D-1-Hydroxylase: Studies in Mouse Modelsand Implications for Human Disease 732
1 Introduction 732
2 Skeletal and Mineral Modulating Actions of 25-Hydroxyvitamin D 3 -1 -Hydroxylase as Determined by Genetic Mouse Models 734
2.1 Regulation of Calcium Absorption 735
2.2 Regulation of the 1(OH)ase and of the 24(OH)ase Enzymes 735
2.3 Parathyroid Gland Function 736
2.4 Development of the Cartilaginous Growth Plate 736
2.5 Bone and Cartilage Remodeling 737
2.6 Mineralization of Bone 738
2.7 1,25 Dihydroxyvitamin D as a Bone Anabolic Agent 738
2.7.1 1anabolic Effects in Older Animals 738
2.7.2 Anabolic Effects in Neonatal Animals 738
2.7.3 Anabolic Effects of Exogenous 1, 25(OH)2D 739
2.7.4 Interaction of Exogenous PTH and Endogenous 1,25(OH)2D in Exerting a Bone Anabolic Effect 740
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
Acknowledgments 742
References 742
Part V Sunlight, Vitamin D and Cancer 746
40The Health Benefits of Solar Irradiance and Vitamin Dand the Consequences of Their Deprivation 747
1 Introduction 747
2 Scientific Methods Utilized 748
3 Application to Specific Health Conditions 750
3.1 Bone Health 750
3.2 Cancer 750
3.3 Infectious Diseases 753
3.4 Autoimmune Diseases 755
3.5 Metabolic Diseases 756
3.6 Cardiovascular Diseases 756
3.7 Alzheimer's Disease 757
3.8 Life Expectancy 757
3.9 Historical Review 757
4 Summary and Conclusion 758
References 759
41 Vitamin D Status, Solar Radiation and Cancer Prognosis 767
1 INTRODUCTION 767
2 skin synthesis and activation of vitamin d 768
3 Calculation Of Seasonal And Latitudinal Variations In Vitamin D Status 769
4 Serum Measurements Of Vitamin D Metabolites 770
5 Epidemiological Investigations Of Relative Risk Of Death From Breast, Colon And Prostate Cancer 772
6 Anti-Neoplastic Mechanisms Of Action 773
7 Summary 774
References 774
42 The Epidemiology of Vitamin D and Cancer Risk 778
1 Introduction 778
2 Colorectal Cancer 779
2.1 25(OH)D Level 779
2.2 Predicted 25(OH)D Level 782
2.3 Dietary Intake 783
2.4 Sun Exposure 783
2.5 Randomized Controlled Trial 783
3 Prostate Cancer 784
3.1 25(OH)Vitamin D 784
3.2 Predicted 25(OH)D Level 784
3.3 Vitamin D Intake 785
3.4 Sun Exposure 785
4 Breast Cancer 786
4.1 25(OH)Vitamin D 786
4.2 Vitamin D Intake 786
4.3 Sun Exposure 787
5 Pancreatic Cancer 787
5.1 25(OH)D Level 787
5.2 Predicted 25(OH)D 788
5.3 Vitamin D Intake 788
6 Esophageal And Gastric Cancers 788
6.1 25(OH)D Level 788
7 Ovarian Cancer 789
7.1 25(OH)D 789
7.2 Sun Exposure 789
8 Non-Hodgkin's Lymphoma (NHL) 789
8.1 Sun Exposure 789
9 Total Cancer 790
9.1 Circulating 25(OH)D 790
9.2 Predicted 25(OH)D 790
9.3 Randomized Trials (RCT) 791
10 Synthesis And Summary 791
REFERENCES 793
43 Vitamin D Deficiency and the Epidemiology of Prostate Cancer 797
1 INTRODUCTION 797
2 Prostate Cancer, Clinical Considerations 797
3 Synthesis Of Vitamin D Metabolites 798
4 Prostate Cancer And The Vitamin D Hypothesis 798
5 1,25(OH) 2 D Is Synthesized By Normal Prostate Cells 800
6 PROSTATE CANCER CELLS EXPRESS VDR BUT LOSE EXPRESSION OF 1 -OH ase 801
7 Vdr Polymorphisms 803
8 Serological Studies Of The Vitamin D Deficiency Hypothesis 803
9 Epidemiologic Studies Of Solar Exposure 804
10 Vitamin D Deficiency And Prostate Cancer: Potential Mechanisms 806
11 Serum Calcium And Prostate Cancer Risk 807
REFERENCES 808
44Vitamin D for Cancer Prevention and Survival 812
1 Introduction 812
2 Serum 25-Hydroxyvitamin D and Risk of Breast Cancer 813
3 Serum 25-Hydroxyvitamin D and Risk of Colon Cancer 818
4 Latitude, Ultraviolet B, Serum 25-Hydroxyvitamin D and Risk of Cancer of the Ovary 820
5 Vitamin D and Cancer of Other Sites 820
6 Randomized Trials 821
7 Future Potential For Cancer Prevention 823
8 Serum 25-Hydroxyvitamin D And Cancer Survival 824
9 Vitamin D And Global Cancer Prevention 824
10 DisjunctionNatural SelectionInvasion (Dni) Model 826
10.1 Natural Selection: Basis of Pathogenesis 826
10.2 Invasion 828
10.3 Role of Calcium and Dietary Factors 829
10.4 Implications for Cancer Treatment 831
11 Safety of Vitamin D for Cancer Prevention and As an Adjunct to Treatment 831
12 Geographic Distribution of Cancer and Environmental Factors 832
13 Summary 833
Acknowledgments 833
References 833
45 The Anti-cancer Effect of Vitamin D: What Do the Randomized Trials Show? 840
1 INTRODUCTION 840
2 Potential Mechanism Of Vitamin D Anti-Cancer Effects 841
3 Vitamin D And Calcium In Prevention Of Cancer 843
4 Randomized Trials Of Vitamin D Supplementation And Cancer 843
5 Levels Of 25(Oh)d For Cancer Prevention 845
6 Doses Of Vitamin D Supplementation For Cancer Prevention 845
7 SUMMARY 846
REFERENCES 847
46 Sunlight, Skin Cancer, and Vitamin D 850
1 The Most Important Negative Health Effect Of Solar Uv Exposure: Induction Of Skin Cancer 851
1.1 Non-melanoma Skin Cancer, Malignant Melanoma, and Solar UV Exposure 851
1.2 Photocarcinogenesis of Skin Cancer 851
2 Recommendations For Sun Protection In Skin Cancer Prevention Campaigns 856
3 A Challenging Perspective: Understanding And Fighting Vitamin D Deficiency 856
3.1 Vitamin D Deficiency -- A Serious and Underappreciated Health Problem 856
3.2 Consequent Sun Protection Increases the Risk of Vitamin D Deficiency 858
3.3 How Much Vitamin D Do We Need? 859
4 Conclusions 859
References 861
Part VI Vitamin D Deficiency and Chronic Disease 864
47 Vitamin D and the Risk of Type 1 Diabetes 865
1 MECHANISMS 865
2 Ecological Correlations 866
3 Animal Experiments 868
4 Studies In Humans 870
5 Genetic Studies 872
6 Conclusions 873
References 873
48 Vitamin D and Multiple Sclerosis 878
1 Introduction 878
2 Ms Epidemiology 879
3 Sun Exposure, Vitamin D, And Ms Risk 880
3.1 Database Analyses 881
3.2 Case--Control Studies 881
3.3 Longitudinal Studies 883
4 Seasonal Variations In Birth Patterns 886
5 Vitamin D And Ms Progression 886
6 Summary 887
REFERENCES 887
49 Vitamin D and Type 2 Diabetes 891
1 Epidemiology And Burden Of Type 2 Diabetes 891
2 Vitamin D Metabolism 892
3 Potential Mechanisms Of Action Of Vitamin D On Glucose Metabolism 892
3.1 Vitamin D and Pancreatic Beta-Cell Function/Insulin Secretion 892
3.2 Vitamin D and Insulin Sensitivity 894
3.3 Vitamin D and Systemic Inflammation 895
4 Evidence From Observational Human Studies 895
4.1 Seasonal Variation and Type 2 Diabetes 895
4.2 Case--Control and Cross-Sectional Studies of Vitamin D and Type 2 Diabetes 895
4.3 Prospective Studies of Vitamin D and Type 2 Diabetes 900
4.4 The Role of Calcium Intake and Type 2 Diabetes or the Metabolic Syndrome 905
4.5 Summary of Evidence from Human Observational Studies 906
5 Evidence From Intervention Human Studies 906
5.1 Effect of Vitamin D Supplementation on Type 2 Diabetes 906
5.2 Effect of Combined Vitamin D and Calcium Supplementation on Type 2 Diabetes 906
5.3 Summary of Evidence from Intervention Studies 911
6 Limitations In The Study Of Vitamin D 911
7 Optimal Intake Of Vitamin D And Calcium In Relation To Type 2 Diabetes 911
8 Conclusions And Future Directions 912
REFERENCES 912
50 Role of Vitamin D for Cardiovascular Health 917
1 Historical Review 917
1.1 Adverse Cardiovascular Effects from Very High Intake of vitamin D 917
1.2 Early Epidemiological Studies 918
2 Ecological Studies 918
2.1 Hypothesis That Sunlight and vitamin D Protect Against Cardiovascular Disease 918
2.2 Winter Excess in Cardiovascular Disease 919
3 Recent Epidemiological Studies 920
3.1 Observational Studies 920
3.2 Experimental Studies 921
4 Possible Cardio-Preventive Mechanisms Of vitamin D 922
4.1 Cardiac Function 922
4.2 Blood Pressure 923
4.3 Inflammatory Factors 924
4.4 Summary of Possible Mechanisms 925
REFERENCES 925
51 Vitamin D, Renin, and Blood Pressure 933
1 Introduction 933
2 Vitamin D, Blood Pressure, and Cardiac Functions: Evidence for a Connection 934
2.1 Epidemiological Evidence 934
2.2 Clinical Evidence 936
3 The ReninAngiotensin System: A Central Regulator of Blood Pressure 937
3.1 The RAS Cascade and Its Functions 937
3.2 Renin, the Rate-Limiting Enzyme of the RAS Cascade 938
3.3 Pharmacological Inhibition of the Renin--Angiotensin System 939
4 Vitamin D Regulation of the ReninAngiotensin System: Mechanism for the Connection? 940
4.1 Vitamin D: Negative Endocrine Regulator of the Renin--Angiotensin System 941
4.2 Mechanism of Renin Suppression 942
4.3 Vitamin D Analogs as Novel Renin Inhibitors 943
5 Conclusion 944
Acknowledgments 944
References 944
52 Role of Vitamin D and Vitamin D Analogs for Bone Health and Survival in Chronic Kidney Disease 950
1 Vitamin D and Metabolic Changes of Chronic Kidney Disease 950
2 Bone Disease and Vitamin D in Ckd 951
3 Osteitis Fibrosa Cystica 951
4 Adynamic Bone Disease 952
5 Osteomalacia 953
6 Vitamin D and Survival 953
7 Potential Mechanisms of a Cardiovascular Survival Benefit 955
8 Infectious Disease Survival and Vitamin D 957
9 Summary 957
References 957
53 Role of Vitamin D and Ultraviolet Radiation in Chronic Kidney Disease 961
1 Vitamin D Status in Chronic Kidney Disease 961
2 Vitamin D Supplementation in Chronic Kidney Disease 962
3 Vitamin D and Uv Radiation in Chronic Kidney Disease Patients on Haemodialysis (Own Experiences and Data) 962
4 Uv Trials With Patients on Haemodialysis 963
4.1 Whole-Body Irradiation 963
4.2 Partial-Body Irradiation 963
4.3 Vitamin D Metabolism During UVB Irradiation 966
4.4 Renal Osteodystrophy, Bone Mineral Density, and Bone Turnover 969
4.5 Physical Work Capacity and Blood Pressure 970
4.5.1 E rythropoiesis and UV R adiation in ESKD P atients 971
4.6 Heart Rate Variability and UV Radiation in ESKD Patients 972
4.7 UVB Radiation in Clinical Routine of a Dialysis Unit 972
5 Vitamin D and Uv Exposure in Prevention and Treatment of Chronic Kidney Disease 974
References 974
54 Role of Vitamin D in Rheumatoid Arthritis 978
1 INTRODUCTION 978
2 Rheumatoid Arthritis Disease Mechanism 979
2.1 Genetic Involvement 979
2.2 Rheumatoid Arthritis Immune System Involvement 979
3 Vitamin D And Rheumatoid Arthritis 980
3.1 Background 980
3.1.1 Immune System Effects of Vitamin D and Rheumatoid Arthritis 981
3.2 Joint Destruction in Rheumatoid Arthritis 982
3.3 Clinical, Animal, and Epidemiologic Studies of Vitamin D and Rheumatoid Arthritis 983
REFERENCES 985
55 Vitamin D, Respiratory Infections, and Obstructive Airway Diseases 989
1 Introduction 989
2 Respiratory Infections 991
3 Obstructive Airway Diseases 992
3.1 Asthma 992
3.2 Chronic Obstructive Pulmonary Disease 993
4 Childhood Wheezing 993
5 Vitamin D And Respiratory Infection 994
5.1 Tuberculosis 994
5.2 Epidemiologic Studies on Respiratory Infections 995
5.3 Preliminary Evidence from Interventional Trials 996
6 Vitamin D And Asthma 998
6.1 Asthma Pathogenesis 998
6.2 Asthma Control 999
6.3 Asthma Exacerbation 1000
7 Vitamin D And Copd 1000
7.1 COPD Pathogenesis 1000
7.2 Acute Exacerbations of COPD 1001
8 Potential Mechanisms 1001
8.1 Vitamin D and Innate Immunity 1001
8.2 Vitamin D and Adaptive Immunity 1002
8.3 Vitamin D, Atopy, and Allergies 1003
9 Future Research on Vitamin D, Respiratory Infections, and OAD s 1005
10 Conclusions 1007
Acknowledgments 1007
References 1008
Part VII Clinical Uses of Vitamin D Analogues 1014
56 Treatment of Immunomediated Diseases by Vitamin D Analogs 1015
1 INTRODUCTION 1015
2 ENHANCEMENT OF INNATE IMMUNE RESPONSES BY VDR AGONISTS 1016
3 MODULATION OF ADAPTIVE IMMUNE RESPONSES BY VDR AGONISTS 1017
3.1 Induction of Pro-tolerogenic Properties in Myeloid Dendritic Cells 1017
3.2 Modulation of Effector Lymphocytes 1018
3.3 Enhancement of Regulatory T Cells 1019
4 VITAMIN D DEFICIENCY IN AUTOIMMUNE AND OTHER IMMUNOMEDIATED DISEASES 1019
5 ANTI-INFLAMMATORY AND IMMUNOMODULATORY EFFECTS OF VDR AGONISTS IN AUTOIMMUNE AND IMMUNOMEDIATED DISEASES 1020
5.1 Rheumatoid Arthritis 1020
5.2 Systemic Lupus Erythematosus 1022
5.3 Type 1 Diabetes 1022
5.4 Experimental Allergic Encephalomyelitis 1023
5.5 Inflammatory Bowel Disease 1023
5.6 Immunomediated Prostatic Diseases 1024
6 DEVELOPMENT OF VDR AGONISTS FOR THE TREATMENT OF AUTOIMMUNE AND OTHER IMMUNOMEDIATED DISEASES 1025
REFERENCES 1026
57Clinical Utility of 1,25-Dihydroxyvitamin D3 and Its Analoguesfor the Treatment of Psoriasis 1032
1 THE VITAMIN D SYSTEM IN THE SKIN 1032
2 PSORIASIS: PATHOGENESIS, IMMUNOLOGY, AND HISTOLOGY OF SKIN LESIONS 1034
3 CLINICAL STUDIES OF VITAMIN D AND ANALOGUES IN PSORIASIS AND OTHER SKIN DISEASES 1035
3.1 Treatment of Scalp Psoriasis 1038
3.2 Treatment of Nail Psoriasis 1038
3.3 Treatment of Face and Flexures 1038
3.4 Treatment of Skin Lesions in Children 1039
3.5 Treatment of Psoriatic Lesions in HIV Patients 1039
3.6 Combination of Vitamin D Analogues with Other Therapies 1039
4 TREATMENT OF OTHER SKIN DISORDERS WITH VITAMIN D ANALOGUES 1040
4.1 Vitamin D and Ichthyosis 1040
4.2 Vitamin D and Scleroderma 1040
4.3 Vitamin D and Vitiligo 1040
4.4 Vitamin D and Skin Cancer 1041
4.5 Vitamin D and Other Skin Diseases 1041
5 BIOLOGICAL EFFECTS OF VITAMIN D AND ANALOGUES IN PSORIASIS 1041
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
REFERENCES 1045
58Affinity Alkylating Vitamin D Analogs as Molecular Probesand Therapeutic Agents 1050
1 Affinity And Photoaffinity Labeling Reagents as Molecular Probes of Enzymes and Receptors 1050
2 Affinity Alkylating Compounds as Therapeutic Agents 1051
3 Vitamin D and Its Metabolites: Biosynthesis, Properties, and Mechanism of Action 1052
4 Mineral Homeostatic and Cell-Regulatory Properties of 1,25(OH) 2 D 1053
5 Transcriptional Mechanism of 1,25(OH) 2 D 1054
6 Vdr and Its Ligand-Binding Domain (Vdr-Lbd) 1055
7 Affinity Labeling of Vdr from Endogenous Sources 1055
8 Affinity Labeling of Recombinant Vdr and Identification of a Contact Point 1057
9 Vdr-Affinity Alkylating Derivatives of 1,25(OH) 2 D AND 25(OH)D As Potential Therapeutic Agents 1058
10 Pharmacokinetic Property of 1,25(OH) 2 D as it Relates to its Therapeutic Activity 1058
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
12 Kinetic And Stoichiometric Studies With 1,25(OH) 2 D-BE AND VDR 1059
13 Antiproliferative Effects Of 1,25(Oh) 2 D-Be In Various Cancer Cells 1060
14 Molecular Mechanisms Related To The Growth-Inhibitory Effect Of 1,25(OH) 2 D-3-Be 1062
14.1 VDR-Related Mechanisms 1062
14.2 Additional VDR-Related and VDR-Unrelated Mechanisms 1065
15 Therapeutic Potential Of 1,25(OH) 2 D-3-Be And Related Compounds In Cancer 1069
16 Summary 1071
Acknowledgment 1071
References 1072
59Anti-inflammatory Activity of Calcitriol That Contributesto Its Therapeutic and Chemopreventive Effects in Prostate Cancer 1076
1 INTRODUCTION 1076
2 CALCITRIOL AND PROSTATE CANCER 1077
2.1 Anti-proliferative Effects of Calcitriol in PCa Cells 1077
2.2 Tumor Inhibitory Effects of Calcitriol in Animal Models of PCa 1078
3 MECHANISMS OF THE ANTI-PROLIFERATIVE EFFECTS OF CALCITRIOL 1078
3.1 Growth Arrest 1078
3.2 Apoptosis 1078
3.3 Differentiation 1079
3.4 Modulation of Growth Factor Actions 1079
3.5 Inhibition of Invasion, Metastasis, and Angiogenesis 1079
3.6 Novel Molecular Pathways of Calcitriol Actions in PCa Cells 1080
4 ANTI-INFLAMMATORY EFFECTS OF CALCITRIOL IN PROSTATE CANCER 1080
4.1 Regulation of Prostaglandin Metabolism and Signaling 1080
4.1.1 COX-2 and Prostate Cancer 1080
4.1.2 15-PGDH 1081
4.1.3 PG Receptors 1081
4.1.4 Calcitriol Effects on the PG Pathway in Prostate Cells 1082
4.1.5 Combination of Calcitriol and Non-steroidal Anti-inflammatory Drugs (NSAIDs)as a Therapeutic Approach in Prostate Cancer 1083
4.2 Induction of MKP5 and Inhibition of Stress-Activated Kinase Signaling 1084
4.3 Inhibition of NFB Activation and Signaling 1085
5 THE ROLE OF ANTI-INFLAMMATORY EFFECTS OF CALCITRIOL IN PROSTATE CANCER PREVENTION AND TREATMENT 1086
5.1 Inflammation and Prostate Cancer 1086
5.2 Calcitriol and Prostate Cancer Chemoprevention 1087
6 SUMMARY AND CONCLUSIONS 1087
REFERENCES 1088
Subject Index 1094
About the Editor 1146
About the Series Editor 1148