Therapeutic Angiogenesis for Vascular Diseases (eBook)

Molecular Mechanisms and Targeted Clinical Approaches for the Treatment of Angiogenic Disease

Mark Slevin (Herausgeber)

eBook Download: PDF

2010 | 2011
XVI, 430 Seiten
Springer Netherland (Verlag)
978-90-481-9495-7 (ISBN)

Infos

Angiogenesis is the growth of new blood vessels and is a key process which occurs during pathological disease progression. Excessive and damaging angiogenesis occurs in diseases such as cancer, diabetic retinopathies, age-related macular degeneration and atherosclerosis. In other diseases such as stroke and myocardial infarction, insufficient or improper angiogenesis results in tissue loss and ultimately higher morbidity and mortality. In this book we will begin by providing the reader with an overview of the process of angiogenesis including normal embryological development of blood vessels. The following chapters will each focus on a key angiogenic disease incorporating current scientific knowledge concerning the causes of activation of the 'angiogenic switch', pathological consequences, current treatment options and future perspectives. Where appropriate, results from pre-clinical trials, novel imaging modalities and nanotechnological approaches will be incorporated into these sections. Finally, since it is now believed that the process of angiogenesis operated via different signalling mechanisms in different vascular beds, we will discuss our current understanding of this phenomenon. The target audience for this book would include researchers in all the basic sciences; post-graduate students at Universities and Institutes; pharmaceutical industries; clinicians working in vascular biology or tissue imaging; pathologists; neurologists; tumour biologists; ophthalmologists and cardiologists.

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Angiogenesis is the growth of new blood vessels and is a key process which occurs during pathological disease progression. Excessive and damaging angiogenesis occurs in diseases such as cancer, diabetic retinopathies, age-related macular degeneration and atherosclerosis. In other diseases such as stroke and myocardial infarction, insufficient or improper angiogenesis results in tissue loss and ultimately higher morbidity and mortality. In this book we will begin by providing the reader with an overview of the process of angiogenesis including normal embryological development of blood vessels. The following chapters will each focus on a key angiogenic disease incorporating current scientific knowledge concerning the causes of activation of the "e;angiogenic switch"e;, pathological consequences, current treatment options and future perspectives. Where appropriate, results from pre-clinical trials, novel imaging modalities and nanotechnological approaches will be incorporated into these sections. Finally, since it is now believed that the process of angiogenesis operated via different signalling mechanisms in different vascular beds, we will discuss our current understanding of this phenomenon. The target audience for this book would include researchers in all the basic sciences; post-graduate students at Universities and Institutes; pharmaceutical industries; clinicians working in vascular biology or tissue imaging; pathologists; neurologists; tumour biologists; ophthalmologists and cardiologists.

Inhalt

Foreword 5
Preface 7
Contents 10
Contributors 12
1 Modified 3D-Fibrin Matrices in Tissue Engineeringfor Stimulation of Angiogenesis and Wound Healing 16
1.1 Introduction 17
1.2 Endothelial Cells and Their Functions in the Vascular System 18
1.2.1 Importance of Appropriate Extra-Cellular Matrix-Contacts for Endothelial Cells 20
1.2.2 The Importance of avß3 Integrin for Endothelial CellSurvival, Induction and Maintenance of Angiogenesis 21
1.2.3 Further Functions of avß3-integrin in AngiogenicEndothelial Cells: Co-operation with Growth FactorReceptors and Association with Matrix Metalloproteases 23
1.3 Hydrogels May be used as Substitutes for Native Extra-Cellular Matrix in Tissue Engineering 25
1.3.1 Fibrin Hydrogel Matrices for Increasing Angiogenesis and Improvement of Wound Healing 26
1.3.2 Modified 3D-Fibrin Matrices to Induce Angiogenesis 27
1.3.3 Fibrin Matrices as Combined Scaffold- and Drug Release Systems 27
1.3.4 3D-Fibrin Matrices Containing Homogeneously-Distributed and Gradients of Cell Guidance Cues 29
1.4 Conclusions and Outlook 29
References 32
2 Ocular Retinopathies and Clinical Control of Angiogenesis 42
2.1 Introduction of Ocular Neovascular Disorders 43
2.1.1 General Features of Ocular Neovascular Disorders 43
2.1.2 Corneal Neovascularization 47
2.1.3 Age-Related Macular Degeneration 49
2.1.4 Diabetic Retinopathy 50
2.1.5 Other Retinal Neovascular Diseases 52
2.2 Proangiogenic Factors in Ocular Neovascularization 53
2.2.1 General Features of Pro-Angiogenic Factors 53
2.2.2 Vascular Endothelial Cell Growth Factor 53
2.2.3 Insulin Growth Factor-1 56
2.2.4 Erythropoietin 57
2.3 Anti-Angiogenic Factors in the Eye 58
2.3.1 General Features of Anti-Angiogenic Factors 58
2.3.2 Pigment Epithelium-Derived Factor 59
2.3.3 Thrombospondin 61
2.3.4 Angiostatin 62
2.3.5 Kallikrein-binding Protein 62
2.4 Pathogenic Roles of the Wnt Pathway in Age-Related Macular Degeneration, Retinopathy of Prematurity and Diabetic Retinopathy 63
2.4.1 The Wnt Pathway 63
2.4.2 Mutations of Wnt Related Proteins in Neovascular Diseases in the Eye 65
2.4.3 Wnt Signaling Plays a Pathogenic Role in Ocular NV 65
2.4.4 The Wnt Pathway and Pro- and Anti-Angiogenic Factors 66
2.4.5 The Wnt Pathway, a New Drug Target for the Treatment of Ocular NV 67
References 67
3 Angiogenic Gene Therapy for the Treatment of Retinopathies 81
3.1 Introduction 82
3.2 Gene Therapy: Basic Principles 83
3.2.1 Gene Delivery Techniques and Vector Design 83
3.2.2 Target Selection and Strategic Considerations 84
3.2.3 siRNA and Cell-Based Approaches 87
3.3 Ocular Gene Therapy for Non-Neovascular Retinal Disease: Early Successes and Difficulties in a Fledgling Enterprise 87
3.4 Investigative Strategies for Angiogenic Gene Therapy of Neovascular Retinopathies 89
3.5 Ad Pigment Epithelial-Derived Factor for Choroidal Neovascularization in Macular Degeneration: The First Angiogenic Gene Therapy Trial for a Neovascular Retinopathy 90
3.6 Summary and Future Directions 90
References 91
4 Angiogenesis in Tumour Development and Metastasis 95
4.1 Initiation of Tumour Angiogenesis 96
4.1.1 Initiation of Angiogenesis 96
4.1.2 VEGF and VEGF Receptors 97
4.1.3 Cellular Action of VEGF 97
4.1.4 Endothelial Tip and Stalk Cells 98
4.1.5 Notch Pathway 98
4.1.6 Dll4 and Notch in Tumour Angiogenesis 100
4.2 Progression of Tumour Angiogenesis 101
4.2.1 Physiological Vessel Maturation 101
4.2.2 Tumour Vessel Maturation 101
4.3 Metastasis 102
4.3.1 Angiogenesis and the Pre-metastatic Niche 102
4.3.2 Angiogenesis and Cancer Cell Transit: Intravasation and Extravasation 102
4.3.3 Angiogenesis and the Transition from Micro- to Macrometastases 103
4.4 Tumour Lymphangiogenesis 103
4.4.1 VEGF-C and VEGFR-3 104
4.4.2 VEGFR-3 in Tumour Biology 104
References 104
5 Cancer Therapy by Targeting Vascular Endothelial Cell Growth Factor- and Non-Vascular Endothelial Cell Growth Factor-Mediated Angiogenesis 108
5.1 Multiple Factors Contribute to the Angiogenic Switch in Tumors 109
5.2 Spatiotemporal Interaction Between Vascular Endothelial Cell Growth Factor and Other Factors 110
5.3 Reciprocal Interplay Between Fibroblast Growth Factor-2 and Platelet-Derived Growth Factor-B 114
5.4 Hypoxia Induces a Shift of Functional Interplay Between Growth Factors 116
5.5 Therapeutic Implications and Drug Resistance 117
5.6 Perspectives 121
References 122
6 Molecular Mechanisms of Post-Ischemic Angiogenesis in the Brain 127
6.1 Angiogenesis After Cerebral Ischemia 128
6.2 Temporal Course of Post-Ischemic Angiogenesis in the Brain 128
6.3 Gene Expression Studies Following Stroke 130
6.3.1 Hypoxia Inducible Factor-1 130
6.3.2 Hypoxia Inducible Factor-2 Alpha 131
6.3.3 Vascular Endothelial Growth Factor 131
6.3.4 Vascular Endothelial Growth Factor Receptors 133
6.3.4.1 Neuropilins 134
6.3.4.2 Tie Receptor System 134
6.3.4.3 Angiopoietins 135
6.4 Endothelial Progenitor Cells and Their Involvement in Post-Ischemic Angiogenesis 137
6.5 Therapeutic Angiogenesis and Vasculogenesis 138
6.6 Pharmacological Approach to Enhance Angiogenesis 139
6.7 Physical Activity to Increase Post-Ischemic Angiogenesis 144
6.8 Cellular Approach to Increase Post-Ischemic Angiogenesis 144
6.9 Remarks 146
References 146
7 Angiogenesis, the Neurovascular Niche and Neuronal Reintegration After Injury 156
7.1 Introduction 157
7.2 Structure/Composition/Functions of the Neurovascular Niches 158
7.3 In Vitro Models of the Neurovascular Niche 160
7.4 Coupled Angiogenesis and Neurogenesis in the Neurovascular Niche Following Central Nervous System (CNS) Injury: In Vivo and In Vitro Models of the Neurovascular Niche Potential Usefulness for Mechanistic Studies, Therapeutic Screens and Therapy 166
7.5 Conclusions Future Directions 171
References 172
8 Safe and Effective Vascular Endothelial Cell Growth Factor (VEGF)-based Therapeutic Angiogenesis for Ischemic Stroke: Insights from Preclinical Trials 179
8.1 Challenges of Treatments for Ischemic Stroke 181
8.1.1 Epidemiology of Stroke 181
8.1.2 Limitations of Current Treatments for Ischemic Stroke 182
8.2 Vascular Endothelial Cell Growth Factor, Neuroprotection and Vascular Endothelial Cell Growth Factor-Based Therapeutic Angiogenesis for Ischemic Stroke 183
8.2.1 Neuroprotection as a New Treatment for Ischemic Stroke 183
8.2.2 Therapeutic Angiogenesis as a Treatment for Ischemic Stroke 184
8.2.3 Basics of Vascular Endothelial Cell Growth Factor 185
8.2.4 Potential Clinical Benefits of Vascular Endothelial Cell Growth Factor-based Therapeutic Angiogenesis 186
8.2.5 Potential Adverse Effects of Vascular Endothelial Cell Growth Factor-based Therapeutic Angiogenesis 187
8.3 Gaps in Knowledge Regarding Safety and Efficacy of Vascular Endothelial Cell Growth Factor-based Therapeutic Angiogenesis for Ischemic Stroke 188
8.3.1 Does Vascular Endothelial Cell Growth Factor-based Therapeutic Angiogenesis Promote or Hinder Neuroprotection of Ischemic Nervous Tissue, and Does the Induced Angiogenesis Damage the Microanatomy of Normal (Non-ischemic) Tissue? 188
8.3.2 Do Doses of Vascular Endothelial Cell Growth Factor That Appear to be Neuroprotective at the Light Microscopy Level Cause Clinically-significant Ultrastructural Alterations of the Neurovascular Unit? 189
8.3.3 Does Vascular Endothelial Cell Growth Factor Combination Therapy Provide Greater Neuroprotection over Vascular Endothelial Cell Growth Factor Monotherapy Without Increasing the Adverse Effects? 195
8.3.4 What is the Best Route, Timing and Duration for Administering Vascular Endothelial Cell Growth Factor, and How Do These Parameters Influence Inflammation? 197
8.3.5 What are the Relationships between Exogenous Vascular Endothelial Cell Growth Factor, Existing Tissue Injury, and Inflammation? 199
8.3.6 What is the Best Vascular Endothelial Cell Growth Factor Isoform for Therapeutic Angiogenesis, and How Does It Affect the Anatomy and Physiology of Other Organs? 199
8.3.7 Does Vascular Endothelial Cell Growth Factor-Based Therapeutic Angiogenesis Compromise Systemic Hemodynamics? 200
8.3.8 How Would the Beneficial and Adverse Outcomes of Vascular Endothelial Cell Growth Factor-based Therapeutic Angiogenesis Differ in Various Stroke Models, Particularly with Differences in Age, Gender or Coexisting Chronic Diseases? 202
8.3.8.1 Permanent and Transient Stroke Models 202
8.3.8.2 Different Animal Species 202
8.3.8.3 Short-Term and Long-Term Evaluations with Constant Physiology Monitoring 203
8.3.8.4 Gender-Based Stroke Models 204
8.3.8.5 Age-Based Stroke Models 204
8.3.8.6 Chronic Disease-Based Stroke Models 205
8.3.9 Are Gene Therapy and Stem Cells Beneficial for Vascular Endothelial Cell Growth Factor-based Therapeutic Angiogenesis for Stroke? 205
8.4 Conclusions 207
References 208
9 Atherosclerotic Plaque Angiogenesis as a Mechanism of Intraplaque Hemorrhage and Acute Coronary Rupture 223
9.1 The Vasa Vasorum as a Physiologic Structure of the Normal Vessel Wall 225
9.2 The Natural Progression of Human Atherosclerosis by Lesion Morphology 226
9.3 The Paradigm of Erythrocyte-Derived Cholesterol and Lesion Destabilization 228
9.4 Plaque NeovascularizationA Substantive Component of Atherosclerosis 229
9.5 Evidence for an Angiogenic Switch Hypothesis in Atherosclerotic Plaques 229
9.6 Hypoxia-Driven Neovascularization in Atherosclerosis 232
9.7 Extra-Pericellular Proteolysis, the Choreographers of Pathologic Angiogenesis 235
9.8 Rapid Endothelial Response Proteins Control of Angiogenesis and Permeability 236
9.9 Selective Factors Controlling Endothelial Permeability 237
9.9.1 Angiopoietin-Tie2 Signaling 237
9.9.2 The Bioactive Lipid, Sphingosine-1-Phosphate 237
9.10 The Role of Tissue Macrophages as Modifiers of Angiogenic Responses 238
9.11 The Concept of Normalization of Blood Vessels to Prevent Hemorrhagic Events in Plaques 239
9.12 Concluding Remarks and Future Perspectives 241
References 241
10 Neovascularization and Intra-plaque Hemorrhage: Role of Haptoglobin, Macrophages, and Heme-Oxygenase-1 Pathway 247
10.1 Introduction 248
10.2 Neovascularization as a Defense Mechanism 248
10.2.1 Response to Injury: Granulation Tissue 249
10.2.2 Neovascularization and Adventitial Remodeling 249
10.2.3 Neovascularization and Plaque Regression 251
10.3 Failure of Neovessels: Intraplaque Hemorrhage 252
10.3.1 Extravasation of Red Blood Cells and Lipid Deposition 254
10.3.2 Extracorpuscular Hemoglobin and Oxidative Stress 254
10.4 Haptoglobin 255
10.4.1 Haptoglobin Genotype and Protein Structure in Humans 255
10.4.2 Role of Haptoglobin Genotype in Human Atherosclerosis 256
10.4.2.1 Macrophage Activation and Infiltration 257
10.4.2.2 Iron Deposition in Plaque Tissue 258
10.4.2.3 Reverse Cholesterol Transport 258
10.5 The Macrophage Scavenger Receptor CD163 259
10.5.1 Downregulation of CD163 Gene and Protein Expression in Diabetes Mellitus 259
10.6 Heme Oxygenase-1 260
10.6.1 Increased HO-1 Protein in Plaques with Intraplaque Hemorrhage 261
10.6.2 Role of Heme Oxygenase-1 in Diabetes-Related Atherosclerosis 262
10.7 Summary 262
References 263
11 Angiogenic Approaches for Inhibition of Plaque Destabilization in Atherosclerosis 267
11.1 Introduction 268
11.2 Role of Neovascularization in Destabilization of the Vulnerable Plaque 268
11.3 Imaging Techniques of Vasa Vasorum 270
11.4 Therapeutic Approaches for Inhibition of Plaque Neovascularization 271
11.4.1 Systemic Anti-Neoangiogenetic Agents 272
11.4.2 Local Antiangiogenic Therapy 272
11.5 Future Directions 273
References 274
12 A Key Role of Angiogenic Control in Recovery from Ischaemic Heart Disease 276
12.1 Introduction 277
12.2 Challenges for Ischaemic Heart Disease: Myogenesis and Angiogenesis 278
12.3 Myocardial Plasticity/Regeneration 278
12.3.1 Evidence for Cardiomyocyte Repopulation in Postnatal Hearts 279
12.3.2 Sources of Cardiogenic Cells 281
12.3.2.1 Bone Marrow Derived Stem Cells 281
12.3.2.2 Resident Cardiac Stem Cells 282
12.3.2.3 Stem Cells in the Periphery and/or Circulation 284
12.3.2.4 Cell-Based Cardiac Repair with Exogenous Pluripotent Stem Cells 284
12.4 Myocardial Repair: The Burden of Remodelling 285
12.5 Angiogenesis 287
12.5.1 Principle 287
12.5.2 Mechanism of Angiogenesis 288
12.5.3 Sprouting and Non-sprouting Angiogenesis 289
12.5.4 Angiogenesis Post Myocardial Ischaemia 291
12.5.5 Role of Inflammation 291
12.5.6 Growth Factors, Cytokines and Angiogenesis 292
12.6 Therapeutic Potential of Angiogenesis 294
12.6.1 Cell Therapy for Therapeutic Angiogenesis: Experimental Evidence 294
12.6.2 Cell Therapy for Therapeutic Angiogenesis: Human Trials 295
12.6.3 Growth Factors and Cytokines for Therapeutic Angiogenesis 297
12.6.4 Vascular Endothelial Cell Growth Factor for Therapeutic Angiogenesis 297
12.6.5 Other Options for Therapeutic Angiogenesis 298
12.7 Conclusion 299
References 300
13 Angiogenic Mediators and the Pathogenesis of Alzheimer'sDisease 304
13.1 Introduction 305
13.2 Vascular Changes in Alzheimers Disease 306
13.2.1 Loss of Vascular Density 306
13.2.2 Amyloid Angiopathy 307
13.3 Angiogenic Mediators in the Brain Vasculature in Alzheimers Disease 308
13.3.1 Pro-Angiogenic Factors 310
13.3.2 Angiogenic Inhibitors 311
13.3.3 Angiogenic Signaling Mechanisms 312
13.4 Effects of Anti-Angiogenic Drugs in the Brain 313
13.5 Activated-Angiogenic Vasculature in AD: A New Paradigm of Disease Pathogenesis 314
13.6 Conclusions and Future Directions 316
References 316
14 Vascular Development, Stroke and Neurodegenerative Disease: A Place for Novel Clinical Interventions? 322
14.1 Introduction 323
14.2 Neurorepair: Plasticity, Neurogenesis and Angiogenesis 324
14.3 Significance of the Neurovascular Unit 325
14.4 Angiogenesis 326
14.4.1 Occurrence and Importance 326
14.4.2 Mechanisms of Angiogenesis After Stroke 326
14.4.2.1 Animal Models of Stroke 326
14.4.2.2 Human Studies 327
14.5 Stroke and Neurodegenerative Disease 328
14.5.1 Common Risk Factors 328
14.5.1.1 Genetic Risk Factors 329
14.5.2 Stroke and Vascular Dementia 331
14.5.3 Lacunar Stroke and Alzheimer's Disease 333
14.5.4 Lacunar Stroke and Vascular Cognitive Impairment 335
14.6 Therapeutic Potential of Angiogenesis 339
14.7 Conclusions and Perspectives 340
References 340
15 Peripheral Artery Disease and Angiogenesis: A Link Between Angiogenesis and Atherothrombosis 348
15.1 Introduction 349
15.2 Thrombogenesis and Atherogenesis in Peripheral Artery Disease 350
15.2.1 Thrombogenesis 350
15.2.2 Atherogenesis 352
15.3 Angiogenesis 355
15.3.1 Angiogenesis and Coagulation 357
15.3.2 Angiogenesis and Atherogenesis 357
15.3.3 The Endothelium: A Link Between Angiogenesis, Atherogenesis and Thrombogenesis 360
15.4 Therapeutic Angiogenesis in Peripheral Vascular Disease 361
15.5 Conclusions 363
References 364
16 Role of Angiogenesis in the Pathogenesis of Arthritis: Potential Therapeutic Applications 369
16.1 Introduction 370
16.1.1 Causes, Symptoms, and Complications of Rheumatoid Arthritis 370
16.1.2 Treatment of Rheumatoid Arthritis 372
16.2 Angiogenesis: A Key Role in Rheumatoid Arthritis 373
16.2.1 Growth Factors Regulating Angiogenesis in Rheumatoid Arthritis 374
16.2.2 Hypoxia as a Trigger for Angiogenesis in Rheumatoid Arthritis 375
16.3 New Therapeutic Approaches in Rheumatoid Arthritis 377
16.3.1 Potential for Angiogenesis Inhibition in Rheumatoid Arthritis 377
16.3.2 Targeting Hypoxia in Rheumatoid Arthritis 379
16.4 Conclusions 383
References 383
17 Angiogenesis and Giant Cell Arteritis 391
17.1 Introduction: Giant Cell Arteritis 392
17.2 Angiogenesis in Giant Cell Arteritis 396
17.2.1 Angiogenesis in the Inflamed Artery of Giant Cell Arteritis 396
17.2.1.1 Inflammation and Hypoxia in GCA 396
17.2.1.2 Demonstration of Angiogenesis by Immunohistochemistry in GCA 397
17.2.1.3 Angiogenesis and Inflammatory Cell Recruitment 398
17.2.1.4 Angiogenesis and Intimal Hyperplasia 399
17.2.1.5 Functional Relevance of Endothelial Markers in Giant Cell Arteritis 399
17.2.2 Angiogenic Mediators in the Temporal Artery 400
17.2.2.1 Vascular Endothelial Cell Growth Factor 400
17.2.2.2 Platelet Derived Growth Factor 400
17.2.2.3 Monocyle Chemotactic Protein-1 401
17.2.2.4 Transforming Growth Factor- 401
17.2.2.5 iNOS 401
17.2.2.6 Other Possible Angiogenic Mediators in the Temporal Artery 401
17.2.3 Angiogenesis, Intimal Hyperplasia and Systemic Inflammation 402
17.2.3.1 Systemic Inflammatory Mediators and Angiogenesis in Ischaemic Organs 403
17.2.3.2 Hyperpermeability of Microvessels 404
17.3 Treatment of Giant Cell Arteritis and Angiogenesis 404
17.3.1 Steroids 404
17.3.2 Steroid-Sparing Agents 405
17.3.3 Selection of Therapies for Co-morbid Cardiovascular Diseases 405
17.4 Conclusions and Future Directions 406
References 406
18 Moyamoya Disease 411
18.1 Background 412
18.2 Epidemiology 412
18.3 Pathology and Pathophysiology 414
18.4 Clinical Features 415
18.5 Moyamoya Syndromes 417
18.6 Diagnosis 417
18.7 Treatment Options for Moyamoya Disease 420
References 422
19 Overview on Nanotechnology and Angiogenesis in Major Diseases Processes 425
19.1 State-of-Art: Angiogenesis and Nanotechnology 426
19.2 Nanotechnology 426
19.2.1 Overview on Nanomedicine 426
19.2.2 Nanosystems Applied to Medicine 426
19.2.3 Nano-Diagnosis and Medical Imaging 427
19.2.4 Nano-Based Drug Delivery Systems 427
19.2.5 Nano-Based Drug Delivery Systems Market 428
19.3 Nanomedicine Applications in Angiogenesis 428
19.3.1 Oncology 429
19.3.2 Cardiology 429
19.3.3 Ophthalmology 430
19.3.4 Imaging of Angiogenesis 430
19.4 Conclusions 431
References 431
Index 433

Produkt-Details

• Erscheint lt. Verlag: 11.10.2010
• Zusatzinfo: XVI, 430 p.
• Verlagsort: Dordrecht
• Sprache: englisch
• Themenwelt: Medizin / Pharmazie ► Medizinische Fachgebiete ► Onkologie
• Themenwelt: Studium ► 1. Studienabschnitt (Vorklinik) ► Biochemie / Molekularbiologie
• Themenwelt: Studium ► 2. Studienabschnitt (Klinik) ► Humangenetik
• Themenwelt: Naturwissenschaften ► Biologie ► Humanbiologie
• Themenwelt: Naturwissenschaften ► Biologie ► Zoologie
• Themenwelt: Technik
• Schlagworte: angiogenesis • Imaging • therapy
• ISBN-10: 90-481-9495-4 / 9048194954
• ISBN-13: 978-90-481-9495-7 / 9789048194957