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B Vitamins and Folate

Chemistry, Analysis, Function and Effects
View Online
Food and Nutritional Components in Focus
Series Editor:
Professor Victor R. Preedy, School of Medicine, King’s College London, UK
Titles in the Series:

1: Vitamin A and Carotenoids: Chemistry, Analysis, Function and Effects
2: Caffeine: Chemistry, Analysis, Function and Effects
3: Dietary Sugars: Chemistry, Analysis, Function and Effects
4: B Vitamins and Folate: Chemistry, Analysis, Function and Effects
How to obtain future titles on publication:

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B Vitamins and Folate

Chemistry, Analysis, Function and Effects
Edited by
Victor R. Preedy
School of Medicine, King’s College London, UK
View Online
Food and Nutritional Components in Focus No. 4

ISBN: 978-1-84973-369-4
ISSN: 2045-1695
A catalogue record for this book is available from the British Library
r The Royal Society of Chemistry 2013
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Preface
In the past three decades there have been major advances in our under-
standing of the chemistry and function of nutritional components. This has
been enhanced by rapid developments in analytical techniques and instru-
mentation. Chemists, food scientists and nutritionists are, however, separated
by divergent skills and professional disciplines. Hitherto this transdisciplinary

divide has been difficult to bridge.
The series Food and Nutritional Components in Focus aims to cover in a single
volume the chemistry, analysis, function and effects of single components in the
diet or its food matrix. Its aim is to embrace scientific disciplines so that
information becomes more meaningful and applicable to health in general.
The series Food and Nutritional Components in Focus covers the latest
knowledge base and has a structured format.
B Vitamins and Folate has four major sections namely:
B Vitamins and Folate in Context

Chemistry and Biochemistry
Analysis
Function and Effects.
Coverage includes B vitamins and folate in the context of a historical

background, disease, cardiovascular effects and the importance of vitamins in
biochemistry as illustrated by a single vitamin. Thereafter there are chapters on
the chemistry and biochemistry of thiamine, riboflavin, niacin, pantothenic
acid, pyridoxine, biotin, folate and cobalamin. Methodical aspects include
characterization and assays of B vitamins and folate in foods of all kinds,
dietary supplements, biological fluids and tissues. The techniques cover solid-
phase extraction, spectrofluorimetry, mass spectrometry, HPLC, enzymatic
assay, biosensor and chemiluminescence. In terms of function and effects or

B Vitamins and Folate: Chemistry, Analysis, Function and Effects
Edited by Victor R. Preedy
Published by the Royal Society of Chemistry, www.rsc.org
v
View Online
vi Preface
health and disease, there are both overviews and focused chapters covering
such topics such as cardiovascular disease, stroke, cognitive decline, dementia,
epilepsy, micronutrient interventions, Wernicke’s encephalopathy, neuronal
calcium, obesity, diabetes, gene expression, beta-oxidation, lipoprotein dis-
orders, pellagra, energy metabolism, immunity, kidney disease and many other
areas.
Each chapter transcends the intellectual divide with a novel cohort of fea-
tures namely by containing:
an Abstract (appears in the eBook only)

Key Facts (areas of focus explained for the lay person)
Definitions of Words and Terms
Summary Points.
B Vitamins and Folate is designed for chemists, food scientist and nutri-
tionists, as well as health care workers and research scientists. Contributions
are from leading national and international experts including contributions

from world renowned institutions.
Professor Victor R. Preedy,

King’s College London
Contents
B Vitamins and Folate in Context
Chapter 1 Historical Context of Vitamin B 3
Hideyuki Hayashi
1.1 Evidence for the Presence of Unidentified

Factors Essential for Life 3

1.2 Establishment of the Concept of Vitamins 4
1.3 Resolution of Vitamin B 6
1.4 Discovery that Vitamins act as Coenzymes 6
1.5 Influence on the Research into other Vitamins 8
1.6 Microbial Nutritional Factors and Vitamins 9
1.7 Vitamin B6 10
1.8 Anaemia and Vitamins 12
1.9 Concluding Remarks 14
Summary Points 15
Key Facts about Beriberi in the Russo-Japanese War (1905) 15
List of Abbreviations 16
References 16
Chapter 2 B Vitamins and Disease 21

Jutta Dierkes and Ottar Nygård
2.1 Introduction 21
2.2 The Role of Different Study Types 22
2.3 Treatment of Deficiency or Supplementation without
Reference to Vitamin Status 23
2.4 Mechanisms 24
2.5 Cardiovascular Disease 25
2.5.1 Folic acid, Vitamin B12 and Vitamin B6 25
2.5.2 Niacin in Cholesterol Reduction 26
B Vitamins and Folate: Chemistry, Analysis, Function and Effects
Edited by Victor R. Preedy
Published by the Royal Society of Chemistry, www.rsc.org
vii
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viii Contents
2.6 Cancer 27
2.7 Prevention of Age-related Cognitive
Decline or Dementia 28
2.8 Renal Disease 28
Summary Points 30
References 31
Chapter 3 Vitamins and Folate Fortification in the Context

of Cardiovascular Disease Prevention 35
Alexios S. Antonopoulos, Cheerag Shirodaria and
Charalambos Antoniades
3.1 Introduction 35
3.2 Homocysteinaemia as a Risk Factor for

Atherosclerosis 36
3.2.1 Mechanisms of Homocysteine-mediated
Vascular Disease 36
3.2.2 Epidemiological Evidence on Homocysteine as
a Cardiovascular Risk Factor 37
3.3 Cardiovascular Effects of Folic Acid, B6 and B12:
Any Need for Folate Fortification? 37
3.3.1 B Vitamins as Homocysteine Lowering Agents 37
3.3.2 Effects on Proinflammatory Mechanisms 39
3.3.3 Effects on Endothelial Function 39
3.3.4 Further Mechanistic Insights in Human
Vessels 40
3.3.5 Effects on Atheroma Progression 40
3.4 Folate and B Vitamins in Cardiovascular Disease:
Insights from Clinical Trials and Folate Fortification
Programme 42
3.4.1 Homocysteine Lowering and Cardiovascular
Disease Prevention 42
3.4.2 Criticism of Randomized Clinical Trials 43
3.4.3 Is Folate Fortification and B Vitamins
Administration Safe? 46
Summary Points 47
Key Facts about B Vitamins as Therapeutic Agents in
Cardiovascular Disease 48
Definitions of Words and Terms 48
References 50
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Contents ix
Chapter 4 The Importance of Vitamins in Biochemistry and Disease as
Illustrated by Thiamine Diphosphate (ThDP) Dependent
Enzymes 55
Shinya Fushinobu and Ryuichiro Suzuki
4.1 Reactions of ThDP-dependent Enzymes 55

4.1.1 General Mechanism 55
4.1.2 Pyruvate-processing Enzymes 57
4.1.3 Transketolase and Phosphoketolase 59
4.2 Structures and Classification 61
4.2.1 Structures of TK and PK 61
4.2.2 Structures of Other ThDP-Dependent
Enzymes 62
4.2.3 Classification of ThDP-Dependent Enzyme
Families 62
Summary Points 63
Key Facts 64
Key Facts about the History of Structural and
Functional Studies on ThDP-dependent Enzymes 64
Key Facts about Metabolic Pathways Involving
ThDP-dependent Enzymes 64
References 66
Chemistry and Biochemistry
Chapter 5 The Chemistry, Biochemistry and Metabolism

of Thiamin (Vitamin B1) 71
Lucien Bettendorff
5.1 Introduction 71
5.2 Chemical Properties of Thiamin 72
5.3 Thiamin Biosynthesis and Degradation 77
5.4 Riboswitches 77
5.5 Thiamin Transport 78
5.5.1 Thiamin Transporters in Mammalian Cells 78
5.5.2 Mitochondrial Transport of Thiamin
Diphosphate 79
5.6 Distribution of Thiamin Derivatives in Living
Organisms 79
5.6.1 Occurrence of ThDP 80
5.6.2 Occurrence of ThTP 80
5.6.3 Occurrence of Adenylated Thiamin
Derivatives 81
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x Contents
5.7 Metabolism of Thiamin Phosphates 81
5.7.1 Free and Bound ThDP Pools Coexist in the
Same Cell 81
5.7.2 Synthesis of Thiamin Diphosphate 83
5.7.3 Synthesis of ThTP 84
5.7.4 Synthesis of AThTP 84

5.7.5 Hydrolysis of ThMP 84
5.7.6 Hydrolysis of ThDP 85
5.7.7 Hydrolysis of ThTP 85
5.7.8 Thiamin-binding Proteins 86
Summary Points 87
Key Facts about Thiamin-related Diseases in Humans 88
References 89
Chapter 6 Chemistry and Biochemistry of Riboflavin and

Related Compounds 93
Mariana C. Monteiro and Daniel Perrone
6.1 Chemistry of Riboflavin 93

6.1.1 Structure and General Properties 93
6.1.2 Modes of Degradation and Stability in Foods 95
6.2 Biochemistry of Riboflavin 97
6.2.1 Digestion, Bioavailability, Absorption and
Transport 97
6.2.2 Metabolism, Storage and Excretion 100
6.2.3 Biological Functions 101
6.2.4 Requirements and Intakes 101
Summary Points 103
Key Facts about Digestion and Absorption 103
References 105
Chapter 7 The Chemistry and Biochemistry of Niacin (B3) 108

Asdrubal Aguilera-Meńdez, Cynthia Fernández-Lainez,
Isabel Ibarra-González and Cristina Fernandez-Mejia
7.1 Introduction 108

7.2 Niacin Chemistry 109
7.3 Niacin Daily Requirement, Food Sources and Niacin
Deficiency 110
7.4 Factors and Diseases Affecting Niacin Requirement 110
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Contents xi
7.5 Metabolism 111
7.5.1 Niacin de novo Synthesis from Tryptophan 111
7.5.2 NAD Biosynthesis 113
7.5.3 NADP Biosynthesis 114
7.5.4 NAD Recycling 114
7.6 NAD/NAPD Chemical and Structural Proprieties 115

7.7 NAD/NADP Metabolic Actions 115
7.7.1 Energy Metabolism and Oxidation Processes 115
7.7.2 Protective Action of NADP 118
7.7.3 Non-redox Adenosine Diphosphate
(ADP)-Ribose Transfer Reactions 119
Summary Points 122
Key Facts about Niacin History 122
Acknowledgments 124
References 124
Chapter 8 The Chemistry of Pantothenic Acid (Vitamin B5) 127

Katsumi Shibata and Tsutomu Fukuwatari

8.2 Chemical Structure of Pantothenic Acid and its
Related Compounds 127
8.3 Stereoisomers of Pantothenic Acid 128
8.4 Characteristic Properties of D-(þ)-Pantothenic Acid 129
8.5 Stability of D-(þ)-Pantothenic Acid 130
8.6 Analogues of Pantothenic Acid 130
8.6.1 Panthenol 130
8.6.2 Pantetheine 131
8.6.3 Pantethine 131
8.6.4 Coenzyme A (CoA) 132
8.6.5 Iso-coenzyme A (Iso-CoA) 132
Summary Points 132
Key Facts 133
References 134
Chapter 9 The Chemistry and Biochemistry of Vitamin B6: Synthesis of

Novel Analogues of Vitamin B6 135
Dajana Gasˇo Sokacˇ, Spomenka Kovacˇ, Valentina Busˇic´,
Colin R. Martin and Jasna Vorkapic´ Furacˇ

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xii Contents
9.2 Discovery of Vitamin B6 136
9.3 Function of Vitamin B6 138
9.4 Diversity of Vitamin B6 Derivatives 140
Summary Points 142
Key facts about Antidotes and Oxidative Stress 142

References 143
Chapter 10 Biochemistry of Biotin 146

Janos Zempleni, Wei Kay Eng, Mahendra P. Singh and
Scott Baier

10.1.1 History 146
10.1.2 Biosynthesis 147
10.2 Catabolism of Biotin 147

10.3 Biochemistry of Biotin 148
10.3.1 Biotin-dependent Carboxylases 148
10.3.2 Biotinylation of Histones 150
10.3.3 HLCS 151
10.3.4 Biotinidase 152
10.3.5 Cell Signalling 152
10.4 Biotin–Drug Interactions 153
Summary Points 153
Key Facts about Histones 154
Acknowledgments 154
References 155
Chapter 11 The Chemistry of Folate 158

Abalo Chango

11.2 Chemistry 158
11.2.1 Extraction and Isolation 159
11.2.2 Structure 160
11.2.3 Physicochemical Properties 160
11.3 Analysis 160
Summary Points 162
Key Facts 162
Acknowledgements 162
References 163
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Contents xiii
Chapter 12 The Chemistry of Cobalamins 164
Alexios S. Antonopoulos and Charalambos Antoniades

12.2 Chemical Structure of Cobalamins 164
12.3 Natural Forms of Cobalamins 166

12.4 Biochemistry of Cobalamins 166
12.4.1 Methionine Synthase 167
12.4.2 Methylmalonyl-CoA Mutase 167
Summary Points 168
Key Facts about the Chemistry of Cobalamins 168
References 170
Analysis
Chapter 13 Assay of B Vitamins and other Water-soluble Vitamins
in Honey 173
Marco Ciulu, Nadia Spano, Severyn Salis, Maria I. Pilo,
Ignazio Floris, Luca Pireddu and Gavino Sanna
13.1 Honey 173

13.2 Vitamins in Honey 174
13.2.1 B Group Vitamins in Honey 177
13.2.2 Vitamin C: Ascorbic Acid 180
13.3 Assay of Water-soluble Vitamins in Honey 180
13.3.1 Assay of B Group Vitamins in Honey 180
13.3.2 Assay of Vitamin C in Honey 182
13.4 Validation 183
13.4.1 LoD and LoQ 184
13.4.2 Linearity 184
13.4.3 Precision 186
13.4.4 Trueness 186
Summary Points 187
Key Facts 187
Key Facts about Honey 187
Key Facts about the Vitamins in Honey 188
Key Facts about Assaying Water-soluble
Vitamins in Honey 188
Key Facts about Assaying B Group Vitamins in Honey 188
Key Facts about Assaying Vitamin C in Honey 188
Key Facts about Validation Protocols 188
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xiv Contents
References 191
Chapter 14 Analytical Trends in the Simultaneous Determination

of Vitamins B1, B6 and B12 in Food Products
and Dietary Supplements 195
Anna Lebiedzińska and Marcin L. Marszałł

14.2 Analysis of B Vitamins in Food Products and
Dietary Supplements 197
14.3 Simultaneous Analysis of Vitamins B in Food
Supplements and Food Products by HPLC 199
14.4 Simultaneous Analysis of Vitamins B6 and B12 in
Seafood Products 200

Summary Points 205
Key Facts about Electrochemical Detection 205
References 207
Chapter 15 Spectrofluorimetric Analysis of Vitamin B1 in

Pharmaceutical Preparations, Bio-fluid and
Food Samples 210
Sang Hak Lee, Mohammad Kamruzzaman and
Al-Mahmnur Alam

15.2 Fluorescence Determination of Vitamin B1 using
Various Catalysts 211
15.3 Extraction-based Determination 215
15.4 Nanomaterial-based Determination of Vitamin B1 217
15.5 Flow Injection and Other Techniques 217
Summary Points 219
Key Facts 220
Key Facts about Spectrofluorimetry 220
Key Facts about Nanomaterials 220
Key Facts about Oxidation 220
References 222
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Contents xv
Chapter 16 Measurement of Thiamine Levels in Human Tissue 227
Natalie M. Zahr, Mary E. Lough, Young-Chul Jung
and Edith V. Sullivan

16.2 Thiamine Measurements in Human Urine 228

16.3 Thiamine Measurements in Human Blood 230
16.3.1 Erythrocyte Transketolase Activation
and the TDP Effect 230
16.3.2 High Performance Liquid Chromatography
Methods 233
16.4 Thiamine Measurements in Other Human Tissue 234
16.4.1 Thiamine Measurements in Human Heart,
Liver, and Other Organs 234
16.4.2 Thiamine Measurements in Human
Cerebrospinal Fluid 239
16.4.3 Thiamine Measurements in Human Brain 240

Summary Points 241
Key Facts 241
Key Facts about High Performance Liquid
Chromatography (HPLC) 241
Key Facts about Thiamine Diphosphate (TDP) 242
Key Facts about Wernicke–Korsakoff Syndrome
(WKS) 242
Definition of Words and Terms 243
References 244
Chapter 17 The Assay of Thiamine in Food 252

Henryk Zieliński and Juana Frias
17.1 Food as a Source of Thiamine 252

17.2 The Recommended Dietary Allowance for Thiamine 253
17.3 Overview of Analytical Methods 254
17.4 Analysis of Thiamine in Food 255
17.4.1 Extraction Procedures 255
17.4.2 Microbiological Methods for Thiamine
Analysis 256
17.4.3 Chemical Methods of Thiamine Analysis 257
17.4.4 Electrochemical Methods 264
17.4.5 Animal Assays (Biological Methods) 264
Summary Points 265
Key Facts 265
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xvi Contents
References 267
Chapter 18 Assays of Riboflavin in Food using Solid-phase Extraction 271

Marcela A. Segundo, Marcelo V. Osório, Hugo M. Oliveira,
Luı´sa Barreiros and Luı´s M. Magalhães

18.2 Batch Solid-phase Extraction Methods 273
18.3 Automatic Flow Based Solid-phase Extraction
Methods 274
18.3.1 Off-line Method 275
18.3.2 On-line Methods 276
Summary Points 281
Key Facts 281

Key Facts about Solid-phase Extraction 281
Key Facts about Flow Injection Analysis 282
References 283
Chapter 19 Isotope Dilution Mass Spectrometry for Niacin in Food 285

Robert J. Goldschmidt and Wayne R. Wolf

19.2 Methodological Considerations 287
19.2.1 Equilibration Requirement in IDMS 287
19.2.2 Sample Preparation and Analysis 287
19.3 IDMS Calculations 289
19.4 Isotopic Effect in Fragmentation of Nicotinic Acid 290
19.5 Illustrative Results for Food Samples 290
Summary Points 296
Key Facts about Isotope Dilution Mass Spectrometry 296
References 300
Chapter 20 Analysis of Pantothenic Acid (Vitamin B5) 302

Tsutomu Fukuwatari and Katsumi Shibata

20.2 Extraction for Measurement 303
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Contents xvii
20.3 Analytical Methods 304
20.3.1 Microbiological Assay 304
20.3.2 Radioimmunoassay (RIA) and Enzyme-
linked Immunosorbent Assay (ELISA) 307
20.3.3 High-performance Liquid Chromatography
(HPLC) 307
20.3.4 Mass Spectrometry (MS) 310
20.3.5 Optical Biosensor-based Immunoassay 311
Summary Points 312
Key Facts about AOAC International 312
References 314
Chapter 21 High-performance Liquid Chromatography Mass

Spectrometry Analysis of Pantothenic Acid (Vitamin B5) in
Multivitamin Dietary Supplements 317
Pei Chen

21.1.1 Pantothenic Acid Supplementation: Aims
and Problems 318
21.1.2 Chemical Properties of Pantothenic
Acid 318
21.1.3 History of Analysis of Pantothenic
Acid 318
21.2 Review of Analysis of Pantothenic Acid Using
High-performance Liquid Chromatography 319
21.2.1 Introduction to High-performance Liquid
Chromatography 319
21.2.2 Earlier HPLC Method for Pantothenic Acid
Analysis 319
21.2.3 Common Detection Techniques for HPLC 320
21.3 Analysis of Pantothenic Acid Using Liquid
Chromatography Mass Spectrometry 320
21.3.1 LC-MS Interfaces 320
21.3.2 Ion Suppression 320
21.3.3 Mass Analysers 321
21.3.4 Stable Isotope Dilution Mass Spectrometry 322
21.3.5 Mobile Phases for LC-MS 322
21.4 Analysis of Pantothenic Acid Using LC/MS in
Multivitamin Dietary Supplements 322
21.4.1 Reference Standard 322
21.4.2 Sample Preparation 322
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xviii Contents
21.4.3 Chromatography 323
21.4.4 LC-MS Analysis 325
Summary Points 326
Key Facts 327
Key Facts about the National Institute of Standards
and Technology 327

Key Facts about Standard Reference Material
(SRM) 3280 327
References 332
Chapter 22 Enzymatic HPLC Assay for all Six

Vitamin B6 Forms 335
Toshiharu Yagi
22.1 Current Status and Challenges of Vitamin B6

Analysis 335
22.2 Enzymatic Reactions for Conversion of
Vitamin B6 Forms and PNG into 4-PLA 337
22.3 Materials and Methods 338
22.3.1 Materials 338
22.3.2 Enzyme Activity Determination 338
22.3.3 HPLC System 339
22.3.4 Enzymatic Conversion into 4-PLA and
Calculation 339
22.4 Chromatograms from Analyses of Standard
4-PLA and Pistachio Nuts, and Contents of
Vitamin B6 Forms and PNG in the Sample
and Human Urine 342
22.4.1 Chromatographic Analyses of Standard
4-PLA, Vitamin B6 Forms and PNG 342
22.4.2 Analysis of all Vitamin B6 Forms and PNG
in Pistachio Nuts 342
22.4.3 Analysis of Vitamin B6 Forms and PNG in
Human Urine 348
Summary Points 349
Key Facts 349
Key Facts about Vitamin B6 349
Key Facts about Enzymes 350
References 351
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Contents xix
Chapter 23 Analysis of Biotin (Vitamin B7) and Folic Acid (Vitamin B9):
A Focus on Immunosensor Development with Liposomal
Amplification 353
Ja-an Annie Ho, Yu-Hsuan Lai, Li-Chen Wu,
Shen-Huan Liang, Song-Ling Wong and Jr-Jiun Liou

23.2 Current Available Analytical Methods for Biotin and
Folate 355
23.2.1 Analytical Methods for Biotin 355
23.2.2 Analytical Methods for Folic Acid 357
23.3 Application of Liposome in the Development of New
Immunosensing Systems for Biotin and Folic Acid 358
23.3.1 Immunosensors for Biotin 358
23.3.2 Immunosensors for Folic Acid 364
Summary Points 369

Key Facts about Immunosensors 369
References 372
Chapter 24 Biotin Analysis in Dairy Products 377

David C. Woollard and Harvey E. Indyk

24.2 Microbiological Methods 379
24.3 Biological Methods 380
24.4 Chromatographic and Physicochemical Methods 381
24.5 Ligand-binding Methods 385
24.5.1 Labelled Techniques 385
24.5.2 Non-Labelled Techniques 387
24.6 Biotin Forms and Concentration in Milk and
Dairy Products 389
Summary Points 391
Key Facts 391
References 393
Chapter 25 Quantitation of Folates by Stable Isotope Dilution Assays 396

Michael Rychlik
25.1 Folates 396

25.2 Current Methods for the Analysis of Folates 398
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xx Contents
25.2.1 Microbiological Assays 398
25.2.2 Binding Assays 399
25.2.3 Chromatography 399
25.3 Stable Isotope Dilution Assays 399
25.4 Benefits and Limitations of Folate SIDAs 401
25.4.1 Benefits 401

25.4.2 Limitations 401
25.5 Application of SIDAs to Folate Analysis 403
25.5.1 Stable Isotopologues of Folates 403
25.5.2 SIDAs in Food Folate Analysis 405
25.5.3 Tracer Folates and SIDAs in Folate
Analysis of Clinical Samples 405
25.6 Method Comparisons 407
25.6.1 Folates in Blood Plasma 408
25.6.2 Comparisons of Folates Analyses
in Foods 410
25.7 Perspectives 412

Summary Points 412
Key Facts 413
Acknowledgment 414
References 414
Chapter 26 Analysis of Cobalamins (Vitamin B12) in Human Samples:

An Overview of Methodology 419
Dorte L. Lildballe and Ebba Nexo

26.2 Cobalamins in Humans 420
26.2.1 Cobalamins in Human Serum 420
26.3 Analysis of Cobalamins in Human Serum 421
26.3.2 Calibrators 424
26.3.3 Analytical Principles 425
26.3.4 Choice of Method 430
Summary Points 432
Key Facts 433
Key Facts about Assay Validation 433
Key Facts about Cobalamin Analysis in Human
Samples 434
References 436
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Contents xxi
Chapter 27 Assay by Biosensor and Chemiluminescence for Vitamin B12 439
M.S. Thakur and L. Sagaya Selva Kumar
27.1 Introduction to Biosensors 439

27.2 Biosensor-based Assay for Vitamin B12 440
27.3 Chemiluminescence 442

27.3.1 Enzyme-based Enhanced CL 443
27.3.2 Chemiluminescence of Luminol 443
27.3.3 Chemiluminescence of the Dioxetane,
CDP-Star 443
27.3.4 Chemiluminescence of Acridans 444
27.3.5 Electrochemiluminescence 445
27.4 Chemiluminescence Analysis of Vitamin B12 445
27.4.1 Acridium Ester Based Chemiluminescence 445
27.4.2 Luminol Based Chemiluminescence 445
27.4.3 Chemiluminescence Work at CFTRI 447

Summary Points 452
Key Facts 453
References 455
Chapter 28 The Diagnostic Value of Measuring Holotranscobalamin

(Active Vitamin B12) in Human Serum: A Clinical
Biochemistry Viewpoint 458
Fabrizia Bamonti and Cristina Novembrino

28.2 HoloTC Analytical Performance 461
28.2.1 Pre-analytical Phase 461
28.2.2 Analytic Phase 462
28.2.3 Post-analytical Phase: Clinical Studies 464
28.3 Clinical Significance and Utility 469
28.3.1 Vitamin B12 Status of Elderly People 469
28.3.2 Vitamin B12 Status of Vegetarians and Vegans 470
28.3.3 Vitamin B12 Status in Different Countries
and Ethnic Groups 471
28.3.4 HoloTC in Subjects with Renal Failure 471
28.3.5 Vitamin B12 Status in Pregnancy 471
28.4 Discussion 471
28.4.1 Asymptomatic Subjects’ HoloTC
Concentrations 472
28.4.2 Asymptomatic Subjects’ ‘Hcy Panel’ 474
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xxii Contents
Summary Points 474
Key Facts about Cobalamin Deficiency 475
Definitions of Key Terms 475
References 476
Function and Effects

Chapter 29 B Vitamins (Folate, B6 and B12) in Relation to Stroke and its
Cognitive Decline 481
Concepción Sánchez-Moreno and Antonio Jimeńez-Escrig

29.2 B Vitamins: Folate, B12, B6 484
29.3 Homocysteine 494
Summary Points 495

Key Facts 496
Key Features of B Vitamins: Folate, Vitamin B6 and
Vitamin B12 496
Key Features of Stroke 496
References 498
Chapter 30 Epilepsy and B Vitamins 504

Terje Apeland, Roald E. Strandjord and
Mohammad Azam Mansoor

30.2 Infrequent B Vitamin Disorders may Induce Epilepsy 504
30.2.1 Vitamin B6 505
30.2.2 Folate 506
30.2.3 Thiamine 507
30.2.4 Vitamin B12 508
30.3 Antiepileptic Drugs and B Vitamins 508
30.3.1 AEDs and Folate 509
30.3.2 AEDs and Vitamin B6 513
30.3.5 AEDs and Vitamin B7 (Biotin) 515
30.4 AEDs and Vitamin Supplementation 516
30.4.1 Folic Acid Supplements 517
30.4.2 Supplements with Vitamins B1, B2, B6, B7
and B12 517
View Online
Contents xxiii
Summary Points 518
Key Facts 518
Key Features about Epilepsy 518
Key Facts about Epilepsy Treatment 519
Key Facts about the C677T Polymorphism of
MTHFR 519
References 521
Chapter 31 B Vitamins and Folate in Multiple Micronutrient

Intervention: Function and Effects 524
Faruk Ahmed

31.2 Functions of B Vitamins 525
31.3 Effect of Supplementation 526

31.3.1 Haemoglobin Concentration 526
31.3.2 Micronutrient Status 527
31.3.3 Growth in Children 528
31.3.4 Morbidity in Children 528
31.3.5 Birth Outcomes 529
31.3.6 Cognitive Function 531
31.3.7 Cardiovascular Disease 532
Summary Points 533
Key Facts 533
Key Facts about Multiple Micronutrient
Intervention 533
Key Facts about Anaemia (Low Haemoglobin
in Blood) 534
Key Facts about Homocysteine 534
References 535
Chapter 32 Wernicke’s Encephalopathy caused by Thiamine (Vitamin B1)

Deficiency 538
Alan S. Hazell

32.2 Neuroanatomical Damage in Wernicke’s
Encephalopathy and Thiamine Deficiency 539
32.3 Thiamine-dependent Enzymes 539
32.4 Pathophysiology of Thiamine Deficiency 540
32.5 Glucose Utilization in Thiamine Deficiency 541
32.6 Excitotoxicity and Thiamine Deficiency 542
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xxiv Contents
32.7 Oxidative Stress and Thiamine Deficiency 544
32.8 Inflammation in Thiamine Deficiency and
Wernicke’s Encephalopathy 544
32.9 Blood–Brain Barrier in Thiamine Deficiency 545
32.10 Neurodegenerative Disease and Thiamine Deficiency 545
32.11 Relative Contributions of Thiamine Deficiency and

Alcohol to Wernicke’s Encephalopathy 546
Summary Points 547
Key Facts about Wernicke’s Encephalopathy 548
References 550
Chapter 33 Disturbances in Acetyl-CoA Metabolism: A Key Factor

in Preclinical and Overt Thiamine Deficiency

Encephalopathy 553
Andrzej Szutowicz, Agnieszka Jankowska-Kulawy and
Hanna Bielarczyk

33.2 Sources of Neuronal Susceptibility to Thiamine
Diphosphate Deficiency 555
33.3 Brain Thiamine Diphosphate Levels and
Encephalopathy 557
33.4 Transmitter Systems in Thiamine Deficiency
Encephalopathy 557
33.4.1 Glutamate 558
33.4.2 Acetylcholine 559
33.5 Acetyl-CoA Metabolism a Primary Target for TDP
Deficiency 560
33.5.1 Sources of Acetyl-CoA in the Brain 560
33.5.2 Acetyl-CoA Compartmentalization in Brain
Cells 562
33.5.3 Redistribution of Acetyl-CoA in Brain
Subcellular Compartments in Pathological
Conditions 563
33.6 Alcoholism and Subclinical Thiamine Deficiency 564
33.7 Screening for Minimal or Asymptomatic Thiamine
Deficiency 565
Summary Points 566
Key Facts 566
View Online
Contents xxv
References 569
Chapter 34 Thiamine Deficiency and Neuronal Calcium
Homeostasis 572
Zunji Ke and Jia Luo

34.2 Thiamine Deficiency Disrupts Homeostasis
of Intracellular Ca21 574
34.3 Consequences of TD-induced Disruption
of Ca21 Homeostasis 575
Summary Points 576
Key Facts about Glutamate Receptors 576
References 578
Chapter 35 Role of Thiamine in Obesity-related Diabetes:

Modification of the Gene Expression 580
Yuka Kohda, Takao Tanaka and
Hitoshi Matsumura

35.2 Does Thiamine Intervention Decrease the Extent of
Weight Gain? 581
35.3 Thiamine Intervention Decreases not only Body
Weight but also Visceral Fat Mass and Adipocyte Size 581
35.4 Thiamine Decreases Hepatic Triglyceride
Accumulation and Modulates PDH Activity 584
35.5 Thiamine Differentially Modifies Transcript Expression
Levels of Genes Involved in Carbohydrate Metabolism,
Lipid Metabolism, Vascular Physiology and
Carcinogenesis in the Liver 585
Summary Points 587
Key Facts 588
Key Features of Otsuka Long–Evans Tokushima
Fatty Rats 588
Key Features of Thiamine Intervention in OLETF Rats 588
Key Features of Obesity Worldwide 588
Key Features of Microarray Analysis 589
References 590
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xxvi Contents
Chapter 36 Riboflavin Uptake 592
Magdalena Zielińska-Dawidziak

36.2 Recognized Mechanisms of Riboflavin Transport 594
36.2.1 Passive Diffusion 594

36.2.2 Carrier-mediated Transport 594
36.2.3 Receptor-mediated Endocytosis 594
36.3 Absorption and Transport of Riboflavin 595
36.3.1 Small Intestine 595
36.3.2 Large Intestine 598
36.3.3 Blood 602
36.3.4 Liver cells 602
36.3.5 Brain 603
36.3.6 Placenta 604
36.3.7 Kidneys 604
36.3.8 Ocular System 605

Summary Points 606
Key Facts about Enterocytes 606
References 607
Chapter 37 Riboflavin and b-oxidation Flavoenzymes 611

Bárbara J. Henriques, João V. Rodrigues and
Cláudio M. Gomes
37.1 Riboflavin Metabolism and Chemistry 611

37.1.1 Riboflavin Metabolism 612
37.1.2 Flavin Chemistry and Flavoproteins 613
37.2 Mitochondrial b-oxidation Flavoenzymes 613
37.2.1 Overview of Mitochondrial b-oxidation 614
37.2.2 The Flavoprotein Enzymatic Machinery 615
37.3 Riboflavin Effects in Defective b-oxidation
Flavoenzymes 621
37.3.1 Proteomics Responses to Riboflavin
Supplementation 622
37.3.2 Molecular Basis for Effects of ETF
Flavinylation 623
Summary Points 626
Key Facts 627
Key Facts about Flavoproteins 627
Key Facts about Inborn Errors of Fatty Acid
Oxidation 628
View Online
Contents xxvii
References 630
Chapter 38 Function and Effects of Niacin (Niacinamide, Vitamin B3) 633

Ahmed A. Megan, Said O. Muhidin, Mahir A. Hamad
and Mohamed H Ahmed
38.1 Food Sources of Niacin 633

38.2 Absorption, Excretion and Clinical Features of
Niacin Deficiency 634
38.3 Niacin Overdose 634
38.4 Cellular Function and Effects of Niacin 634
38.4.1 Niacin and Cellular Lipid Metabolism 636
38.4.2 Non-oxidative and Reduction Reactions
involving Niacin (NAD Substrate) 636

38.4.3 DNA Repair 637
38.4.4 Apoptosis and Necrosis 637
38.5 Metabolic Effects of Niacin 638
38.5.1 Niacin and Lipid Metabolism and
Atherosclerosis 638
38.5.2 Effect of Niacin on Atherosclerosis,
Inflammation and Vascular Reactivity 641
38.5.3 Niacin and Dyslipidaemia and Hyper-
phosphatemia with Chronic Kidney Disease 643
38.5.4 Effect of Niacin on Insulin Sensitivity and
Glucose Metabolism 645
38.5.5 Niacin and Cardiovascular Disease 646
Summary Points 648
Key Facts 649
References 651
Chapter 39 Pharmacological Use of Niacin for Lipoprotein Disorders 660

John R. Guyton, Wanda C. Lakey, Kristen B. Campbell and
Nicole G. Greyshock

39.2 Mechanisms of Action 661
39.2.1 Role of the Niacin Receptor (GPR109A) in
Inhibiting Non-esterified Fatty Acid Release
from Adipocytes 661
39.2.2 Effects on Apolipoprotein B-containing
Lipoproteins 662
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xxviii Contents
39.2.3 Niacin-Related Mechanisms to Increase
HDL and Reverse Cholesterol Transport 662
39.2.4 Niacin-Induced Cutaneous Flushing 663
39.2.5 Niacin-Induced Reduction in Inflammation
and Oxidative Stress 663
39.3 Lipoprotein Effects of Niacin 663

39.4 Adverse Effects and Drug Administration 664
39.4.1 Flushing 664
39.4.2 Hepatotoxicity 664
39.4.3 Myopathy 665
39.4.4 Insulin Resistance and Hyperglycemia 665
39.5 Randomized Trials with Cardiovascular and Clinical
Endpoints 665
39.5.1 Coronary Drug Project, the Only Large
Monotherapy Trial 665
39.5.2 Smaller Randomized Trials with Anatomic
Endpoints 667
39.5.3 The AIM-HIGH Study 667
Summary Points 668
Key Facts 669
Key Facts about Mechanisms in Niacin
Pharmacology 669
Key Facts about Niacin’s Effects on Lipoproteins 669
Key Facts about Niacin and Atherosclerosis
Prevention 669
References 671
Chapter 40 Pellagra: Psychiatric Manifestations 675

Ravi Prakash, Priyanka Rastogi and Suprakash Choudhary

40.2 Common Early Psychiatric Features 676
40.3 Cognitive Deficits in Pellagra 676
40.4 Psychotic Spectrum Features in Pellagra 677
40.5 Case Vignette: A Unique case of Pellagra Delusional
Parasitosis 678
40.6 Neurophysiological Mechanisms of
Pellagra–Psychiatric Features 680
Summary Points 681
Key Facts 681
Key Facts about Pellagra 681
Key Facts about Neuropathophysiological
Understanding of Pellagra 682
View Online
Contents xxix
References 683
Chapter 41 Pantetheine and Pantetheinase: From Energy Metabolism

to Immunity 685
Takeaki Nitto
41.1 The Synthesis and Metabolism of Coenzyme A 685

41.2 Enzymatic Features of Pantetheinase 686
41.3 Pantetheinase Gene Family 687
41.3.1 Pantetheinase/Vanin-1/VNN1 687
41.3.2 GPI-80/VNN2 688
41.3.3 Vanin-3/VNN3 689
41.4 Role of Pantetheinase in vivo: Regulation of
Inflammation rather than CoA Metabolism? 690
41.4.1 Vanin-1 Deficient Mice 690

41.4.2 Cysteamine: A Key Player in Inflammation
and Host Defence 691
41.5 Panetetheinase Family Genes and Proteins as
Indicators of Human Diseases 692
41.6 Studies on Pantetheinase in Future 692
Summary Points 693
Key Facts 693
Key Facts about Neutrophils 693
Key Facts about Cysteamine 694
References 695
Chapter 42 Function and Effects of Pyridoxine (Vitamin B6):

An Epidemiological Review of Evidence 699
Junko Ishihara and Hiroyasu Iso
42.1 Overall Characteristics and Function 699

42.2 Current Recommended Intake and Chronic Diseases 701
42.3 Epidemiologic Evidence of Vitamin B6 and Vascular
Disease 702
42.3.1 Findings on Dietary Intake in Prospective
Observational Studies 702
42.3.2 Findings on Blood Level in Prospective
Observational Studies 703
42.3.3 Findings from Clinical Trials 703
42.3.4 Current Knowledge of the Effect on
Vascular Disease 704
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disciplinarians until all are wearied out in turn, and all too late
conclude that the case is one for a doctor or perhaps an asylum. At
the evolution of the sexual power and at its decadence, during
menstruation, pregnancy, childbirth, lactation, especially after fevers,
blows injuring the brain, and cerebral disease or disorders of any
kind, are the periods of especial danger, as more general mental
disease is then developed with seemingly trivial exciting causes. The
friends observe that the sufferers do not seem entirely natural. They
imagine and suspect a great deal, rather than possess real
delusions. They often say that their heads are not quite right, and
manifest an evidently diminished capacity for mental work, which
tires them or makes them irritable. Modest girls become indelicate,
the truthful lie, the delicate use profane and obscene language, the
mild-mannered destroy furniture and clothing, the peaceful quarrel,
the gentle storm and rave; and yet there is a standard of virtue and
right, often a high one, on which they theorize, and up to which they
often think that they live. They take strong dislikes to those with
whom they are brought in contact, especially their nearest relatives.
They often lose the capacity to do work, and now and then become
spendthrifts or drunkards. As a rule, there are frequent periods of
quiet, amounting to depression, but rarely reaching the condition of
melancholia. Alternation or periodicity in the symptoms is the rule.
After threatening and even endangering the lives of those nearest to
them, insulting and indelicate conduct in public, perhaps frequent
arrests, a dozen times outwitting those who wish to confine them in
asylums, where they belong, their minds being alert enough to
attribute their conduct to drink or some cause for which they receive
slight punishment, and to argue their own cases so as to convince
almost any jury of their sanity, the rule is that their doubts,
imaginations, and suspicions deepen into active insane delusions,
their mental impairment advances to noticeable dementia, their
moral deterioration goes on to such a degree of depravity that every
body wonders why they had not been seen to be insane long ago,
and they are secluded in an asylum or elsewhere. A not uncommon
but unfortunate end is when they kill themselves before anybody but
a few specialists recognize their irresponsibility. Their recklessness
and want of judgment are often the cause of fatal illnesses and
accidents. Clouston reports the case of a lady who by a series of
extraordinary misrepresentations and clever impostures raised large
sums of money on no security whatever, and spent them as
recklessly; imposed on jewellers, so that they trusted her with goods
worth hundreds of pounds; furnished grand houses at the expense of
trusting upholsterers; introduced herself by open impudence to one
great nobleman after another, and then introduced her dupes, who,
on the faith of these distinguished social connections, at once
disgorged money. To one person she was a great literary character;
to another of royal descent; to another she had immense
expectations; to another she was a stern religionist. At last all this
lying, cheating, scheming, and imposture developed into marked
insanity and brain disease, of which she soon died; and it was seen
that all these people had been the dupes of a lunatic whose very
boldness, cunning, and mendacity had been the direct result of her
insanity.
S. K. Towle has reported the case of a man whom he had under his
care at the Soldiers' Home near Milwaukee, Wis., as follows: “He
had been a lieutenant in a volunteer regiment, and I gave him rather
more privileges on that account, but after a time I found that he was
more nearly an example of total depravity than I had ever seen.
There was no truth in him, and he was intelligent enough to make his
lies often seem plausible to me as well as to others. By his writing
and talking and conduct generally he kept the patients and their
friends in a ferment, and gave me more trouble than the whole
hospital besides. He had a small scar about the middle of his
forehead, which he said was due to a slight flesh wound from a
glancing ball in battle. While he was under my care an older brother
came to see him, and he told me that up to the time his brother, my
patient, who so tried my patience, entered the army he was almost a
model young man, amiable and affectionate, the pet of the whole
family and intimate friends; ‘But,’ said he, ‘ever since he came back
he has been possessed of a devil if ever any one was.’ After a time,
much to my delight, he asked for a transfer to the Soldiers' Home at
Dayton, Ohio, which I got for him with commendable alacrity; and he
went there. His conduct at Dayton was the same as with me, but
after a few months he quite suddenly died, when an autopsy was
made. In sawing open the skull, at the point of the small scar on his
forehead the saw came directly upon the butt end of a conical bullet,
two-thirds of which projected through the skull, piercing the
membranes and into the brain. The internal table of the skull had
been considerably splintered by the ball, the pieces not being
entirely separated, and there was evidence of severe chronic
inflammation all around, and quite a collection of pus in the brain
where the ball projected into it. Here was the devil that had
possessed the poor fellow—that not only took his life, but destroyed
his character, lost him the love and esteem of his friends, and
doomed him for half a dozen years to do things he would most have
hated and despised when he was himself. Dunlap, the assistant
surgeon at Dayton, told me that he found in this man's trunk letters
from several—half a dozen, I think, at least—women in various
places, from which it appeared that he was engaged to be married to
each one of them. The letters were neatly tied up in packages, each
one's separately, in several instances with photographs supposed to
be of the writers, and the date of reception and reply was noted on
many of the letters in a business-like way.”
As Westphal well says15 of such persons, “They often think correctly

and logically, and show reflection and deliberation to a certain
degree; but there is a certain something lacking, and there are some
general conceptions, general processes of thought and judgment, of
which they are incapable. Their mentality stops short on a certain
plane, especially in matters of judgment where every even
uneducated person easily succeeds. They sometimes act as if they
had good judgment and common sense, of which they are really
destitute, particularly in regard to the proprieties of life and their
proper social relations and duties. Certain of the finer feelings are
absolutely impossible of development in them. Through their various
nets, perverted by their mental defect, the patients often seem
perverse (bösartig), passionate (leidenschaftlich), although of true
sustained passion they are incapable. What seems passion is a
sudden idea or fitful impulse to which they yield at once. Moral
insanity is a defect in the affective sphere, but also an intellectual
defect of a peculiar kind, which is often concealed under the mask of
a perverted moral sense, and which requires time and practice on
the part of the physician for its detection.”
15 Berl. klin. Wochenchrift, 1878, No. 15.
Moral insanity is quite certain to pursue a downward course,

although something can be done by training, general hygiene, simple
diet, mental discipline, avoiding overwork, a judicious choice of the
few occupations of which the moral insane are capable, and a
constant steadying hand to help them try to keep their balance.
IMPULSIVE INSANITY is perhaps more properly called instinctive

monomania, as the morbid impulse is usually shown in only one
insane propensity at a time. Like moral insanity, its manifestations
are commonly periodic, or at least alternating. Under the name of
emotional insanity it furnishes sympathetic juries with an excuse for
finding not guilty of murder women who kill their betrayers and
husbands who shoot a wife's seducer. It is a not uncommon
symptom in a considerable proportion of the persons suffering from
the various forms of insanity. As a separate disease it is quite rare,
and includes those persons whose insanity is manifested, as Marc
says, by what they do rather than by what they say. The insane
impulse does not come from any logical process. It is rarely
provoked by or associated with a criminal motive, except in an
analogous way to the production by excitement of an epileptic attack,
to which, indeed, it offers some points of similarity. There would be
reason to doubt the existence of the disease unless other indications
of mental degeneration were present, especially where there is proof
of a criminal motive or where the criminal act and the prisoner's
statements are the sole evidence of unsoundness of mind.
Unconsciousness, even temporary, and loss of memory, are not
symptoms of instinctive monomania. On the contrary, the mind is
quite clear, and resists successfully the insane impulse so long that
the person affected with it has often gained confidence that he will
never yield to it; and he soon learns the fact that, there being in
circumstances external to himself no reason for the crime suggested
to the mind with such force, temptations do not occur to the act.
While the impulse lasts a great variety of distressing mental
symptoms accompany it, so intense that the impulse often cannot be
resisted, and then the terrible brain-tension is relieved. I doubt
whether hallucinations of hearing are found in impulsive insanity, and
incline to think that all the reported cases where crimes of impulse
have been committed in obedience to a voice commanding the
individual to do this or that act of violence are more properly
classified under other forms of mental disease. One kind of
instinctive monomania sometimes disappears to be replaced by
another. In developing boys and girls there is not seldom a
pathological mental state during which lying, stealing, running away
from home, etc. are common for several months or a few years; but
this is a curable condition, and does not by any means necessarily
end in instinctive monomania.
Suicidal insanity is probably the most common form of instinctive

monomania. The force, or even presence, of the suicidal impulse is
largely dependent upon the general tone of the system. The suicidal
idea is common; it occurs to the minds of a vast number of sane
people at one time or another under adverse circumstances.
Hysterical women talk a lot of nonsense on the subject. Self-
destruction due to self-depreciation, weariness of life, and general
gloom is not uncommon in the insane temperament. It is also a
refuge to proud and sensitive people who have sacrificed their honor.
But this is quite different from suicidal insanity, in which the impulse
is often strongest at a time when there are the most reasons for
living and the greatest happiness in life if the tormenting demon
urging to self-murder could be excluded. Such people finally kill
themselves, in spite of their best resolutions and efforts to the
contrary, if the various faculties of the mind become more and more
involved as the disease goes on and the power of self-control is
progressively weakened. More general insanity of the degenerative
type is sometimes developed from suicidal insanity.
Homicidal insanity is fortunately still rarer than the last-mentioned

form, although motiveless homicidal ideas occur to husbands and
wives and parents with reference to those dearest to them, under
conditions of prolonged mental strain or exhaustion, during
pregnancy and the puerperal state, and at the climacterium. In
suspected crimes the evidence of homicidal insanity should be clear
and should rest upon the general signs of the degenerative mental
state. Homicidal impulses are common enough among the insane.
Just as there are persons who do not dare to have sharp instruments
in their rooms for fear of killing themselves, so there are others to
whose minds axes, knives, and razors suggest imperative
conceptions of plans for killing another. It is difficult in either case for
the physician to satisfy himself at what point real insanity begins.
Seclusion under the morbid influences of an asylum is very bad
treatment for the individual, and symptoms which seem very serious
often disappear by restoring the general health. In a recent case,16
where a youth of nineteen was acquitted of the murder of his mother
on the ground of homicidal insanity, he knew that the act was wrong,
realized that he had committed a crime, and was full of grief for it, as
occurs in all such cases. It is the rule, too, that there is some
condition of mental defect or degeneration out of which the homicidal
insanity is developed.
16 Quarterly Journal of Mental Science, October, 1883, p. 387.
Dipsomania, a rare manifestation of impulsive insanity, differs

entirely from the acquired alcohol habit, drunkenness, acute or
chronic alcoholism, delirium tremens, or habitual intoxication, all of
which conditions are also more readily developed in the neuro-
psychopathic constitution than in persons with healthy brains, and
may reach a point constituting insanity. Dipsomania is periodic,
uncontrollable, and associated with other evidences of the insane
diathesis. The prognosis is unfavorable. The treatment is to improve
the general nervous tone and to seclude the patient during his
attacks.
Pyromania and kleptomania are not rare as symptoms of insanity of

the marked forms which are observed in asylums. As manifestations
of impulsive insanity—that is, as constituting a form of insanity—they
are associated with other evidences of mental defect or
degeneration. Burning and stealing alone are not indications of
insanity. As such, they are without sane motive, and directed to
objects in burning or stealing which there is no gain to the person
and usually no gratification except the sense of relief which comes
from yielding to the impulse, and of distressing mental symptoms if
the impulse is resisted.
Nymphomania in the female, satyriasis in the male, and the various

perverse and degrading methods of gratification of the sexual
instinct, may, when joined with other evidences of mental or nervous
disorder, constitute one form of impulsive insanity. Erotomania, an
ideal attachment without erotic feeling, is a more common mental
disease, but the other evidences of insane conduct are quite striking.
The same statement holds true of the many perverted instincts
which, according to circumstances, are or are not manifestations of
the defective brain-inhibition of disease. Animal impulse as a form of
impulsive insanity I had been inclined to doubt until I recently saw
two cases of as extreme mental suffering as I ever witnessed, in two
refined ladies who had suffered also from some cerebral symptoms,
occasional dizziness, and suicidal insanity, but who had no other
symptoms of cerebral disorder than those which are grouped under
the head of insane diathesis, and they not marked. It is not
associated with any erotic feeling or with particular persons. There is
more rapid wasting in flesh and strength and loss of sleep than in the
other forms of impulsive insanity, and, in my experience, greater
dread of yielding to the demon of unrest.
The perverted sexual instinct, with a feeling of repugnance to the

opposite sex, has thus far been observed chiefly in persons who
have been addicted to masturbation. It is marked by a passion for
some individual of the same sex, by other evidences of the
neuropathic condition, and commonly by a grotesque imitation of the
habits or dress of the opposite sex.
The indications for treatment in impulsive insanity are cod-liver oil,

the bromides, simple non-stimulating diet, open-air life, judiciously
regulated exercise, mental occupation so far as is possible, and
removal from suggestive surroundings and associations. The
prognosis is not favorable as to the final result. If the symptoms
disappear on restoration of the general health, other marked
indications of cerebro-mental disorder are pretty certain to appear
sooner or later.
HYSTERICAL INSANITY is one of the states of mental degeneration,

much less common among men than among women, arising from
the further development of a neurosis, hysteria, and probably to a
great extent due to bad training. Hysterical symptoms, quite marked,
are very common among young persons and in single women of all
ages in simple mania. They are not uncommon in simple
melancholia and in other forms of mental disease. They add
somewhat to the gravity of the prognosis in these cases. They
constitute a group of symptoms which I suppose to be understood by
those authors who speak of hysterical insanity as a disease in which
the cure-rate is high. But hysterical insanity, as quite distinct from
other psychoses, is quite a different matter. It is characterized by
extreme and rapid mobility of the mental symptoms—amnesia,
exhilaration, melancholic depression, theatrical display, suspicion,
distrust, prejudice, a curious combination of truth and more or less
unconscious deception, with periods of mental clearness and sound
judgment which are often of greater degree than is common in their
families; sleeplessness, distressing and grotesque hallucinations of
sight, distortion and perversion of facts rather than definite delusions,
visions, hyperæsthesias, anæsthesias, paræsthesias, exceeding
sensitiveness to light, touch, and sound, morbid attachments, fanciful
beliefs, an unhealthy imagination, abortive or sensational suicidal
manœuvres, occasional outbursts of violence, a curious combination
of unspeakable wretchedness alternating with joy, generosity, and
selfishness—of gifts and graces on the one hand and exactions on
the other. The mental instability is like a vane veered by every
zephyr. The most trifling causes start a mental whirlwind. There is no
disease giving rise to more genuine suffering or appealing more
strongly for the sympathy which, freely given, only does harm. One
such person in the house wears out and outlives one after another
every healthy member of the family who is unwisely allowed to
devote herself with conscientious zeal to the invalid.
The PROGNOSIS is unfavorable. While the symptoms may be

alleviated and a nominal cure may be effected, a relapse or the
development of some other troublesome form of insanity or neurosis
is the rule, to which the exceptions occur for the most part in women
in whom there is also some serious curable uterine disease or a
state of excessive physical prostration which can be relieved.
The TREATMENT of hysterical insanity demands tact and educating

power which will tax to the utmost the ingenuity of the wisest
physician. Sympathetic friends, and sympathy in general, are useful
in moderation, but they oftener do great harm, because they are
excessive; and the care which does good is that which, while being
kind and firm, tends to develop strength and character. The will and
the imagination are so extraordinarily powerful that their wise
direction and government constitute the most important part of
successful treatment. Diversion, occupation, and the development of
self-control, with careful attention to the general laws of health, are
quite important. The temptation to use drugs is, like the fascination of
being pitied and petted, very great, as alcohol, chloral, or opium
often acts like magic for the time being, and there is generally a
craving for one or all of them. But they are utterly demoralizing in the
end. The habitual use of stimulants and narcotics in such cases only
increases the evil. The fact must be recognized that the hysterical
insane are often least responsible where they seem most so, and
that they must be treated with unending patience, kindness, gentle
firmness, and a wise ignoring of most of the symptoms. Simple
palliative sedatives which cannot do harm must sometimes be used,
but the general rule, the less active treatment the better, is safest. In
the few cases where benefit has been got from removal of the
ovaries, healthy or diseased, the improvement, if it shall prove to be
lasting, will probably be attributable to the great physiological shock
from the operation rather than to any relation of the ovaries to the
disease. Removal from home is usually advisable for a time at least
—often it is necessary; and if residence in an asylum is not thought
to be wise, properly-selected hydropathic establishments or private
asylums are useful. Living in a judicious physician's home is
desirable when a suitable one can be found. In an asylum a rational
letting-alone treatment is found to be the most successful. If the
patient remains at home, hired nurses should be in charge of the
patient, or at least not members of the family. Safe seclusion will be
found necessary for the few who will not otherwise be prevented
from committing crimes and offences of startling ingenuity or
conspicuous publicity.
EPILEPTIC INSANITY arises from a neurosis, epilepsy, which almost

inevitably ends in mental deterioration of greater or less degree, from
scarcely noticeable impairment to complete dementia. The insanity
may be a continuous state; it may be subsequent to the epileptic
attack, or precede it, or take the place of it. Epileptic dementia is
more nearly allied to idiocy than dementia following other mental
diseases, and it is associated with a degree of moral perversion and
brutality which is quite uncommon in other dementia. The insanity
following or preceding the epileptic attack is attended with stupor,
delusions of persecution, confusion, transitory fury, or a condition
quite analogous to somnambulism or cerebral automatism; and the
same may be said of insanity replacing the epileptic attack, except
that the most common condition in it is a violent maniacal fury, with
unconsciousness, and subsequent nearly if not quite complete
amnesia. The forms of mental impairment are progressive in the vast
majority of cases. The other forms are more amenable to the usual
treatment of epilepsy, and sometimes diminish in severity as the
disease advances and the mind becomes weakened. In the fury
which takes the place of the epileptic convulsion there is in nearly
every case—I am inclined to think in all cases—an intellectual aura,
a slight change of action, observable early enough to give warning of
the approaching storm, which can always be mitigated, and often
entirely prevented, by absolute rest in bed and the use of chloral and
the bromides.
Although some few epileptics become well without treatment, and a

small number permanently recover under treatment, the PROGNOSIS is
even less favorable for the epileptic insane. The care of insane
epileptics should embrace, in the first place, safety to the community
by secluding those dangerous to it, and, second, the usual hygienic
and medical treatment of epilepsy.
Epileptic vertigo, analogous to petit mal, is a transitory mania, often

associated with passing delusions.
With regard to the responsibility of the epileptic insane—and, indeed,

all epileptics—the facts should be borne in mind that their mental
state is usually one of such instability that a slight irritation of any
kind is apt to induce a full or modified convulsion, and that under
provocation they commit partly volitional crimes, for which they are
not fully responsible.
HYPOCHONDRIACAL INSANITY differs only in degree from

hypochondriasis, described on a subsequent page. It is an incurable
manifestation of one type of the mental degenerations. It is slowly
progressive, and often ends in dementia. It differs from
hypochondriacal melancholia in being an evolution of mental defect
or degeneration, and in the fact that the mental depression, which is
usually of a mild, periodic, or impulsive form, is secondary to the
other symptoms, and not, as in hypochondriacal melancholia, the
mental condition out of which the hypochondriacal symptoms are
evolved.
The TREATMENT consists in attention to the general laws of health,

occupation, and a fattening diet. It is seldom successfully managed
without occasional recourse to an asylum at least, and oftenest a
permanent residence in hospitals, occasionally changing, is quite
necessary.
PERIODIC INSANITY, usually mania or melancholia, is marked by

attacks recurring at more or less regular intervals, with a partial but
not complete return to the previous mental health between them. It is
one of the incurable degenerative mental diseases. The seeming
recovery is only apparent, and the mental deterioration is
progressive, although quite slow. The form of insanity is also not
seldom a folie raisonnante (affective or moral insanity) with periods
of all sorts of excesses, destructive tendencies, tramp-life,
destructive acts, drunkenness, stealing, indecent exposure, etc. In
the intervals, which may be short or long, and which sometimes
correspond to certain seasons of the year, the mental condition is
still a pathological one, with the usual signs of mental degeneration,
thereby being differentiated from recurrent insanity, one of the
curable psychoneuroses, in which there is a state of mental health
between the successive attacks, but no sort of regularity or
periodicity in the recurrences. The prognosis is unfavorable, except
in so far as a quiet life in an asylum tends to prolong the intervals
between the periodic outbreaks, as well as to prevent annoyance to
the community during them.
CIRCULAR INSANITY (Alternating insanity, Folie circulaire, Folie à

double forme, Folie à formes alternes, Die cyclische Psychose, Das
circuläre Irresein) consists in a psycho-rhythm or succession, in
uniform order in each particular case, of (1) mental exaltation in all
degrees, from mild exhilaration or even gayness to acute mania, and
(2) mental depression of all conditions, torpor, or anergic stupor.
These two opposite mental conditions are separated in the vast
majority of cases by a shorter or longer interval of the normal mental
state, in which, however, there is soon observed some mental
impairment, however slight, rarely amounting to pronounced
dementia except in old age. Sometimes the three states shade off
into each other, so that it is difficult to say just where one begins and
the other ends; less often the transition is abrupt, sometimes during
sleep. The interval between the two opposite conditions of mind may
succeed either of the other mental stages, but the order once
established is maintained. The duration of the vicious circle varies in
succeeding attacks, sometimes becoming longer, sometimes shorter,
in the progress of the disease. The relative duration of the three
succeeding mental condition also varies, but the type of each
remains identical, or at least changes very gradually. The state of
mental exaltation often resembles moral insanity, with all sorts of
immoral impulses and tendencies, and may then properly be called
an insanity of action. The depression sometimes goes no farther
than sluggishness of will. The tendency of the disease is to shorten
life only slightly, if at all, except from the chance of suicide in the
depressed state and from exhaustion when the excited stage is one
of active mania. The shortest duration of the cycle in my experience
has been twenty-four hours, and the longest reported extends over
several years. It sometimes remains an affective insanity in its whole
course, without delusions and with little more dementia than might
happen from simply a corresponding advance in age without mental
disease.
During the period of excitement some supervision or control will

usually be desirable, and removal to some retreat or asylum will
often be necessary. In the depressed stage the indications are to
maintain the general health, to meet the chances of suicide, and if
there are delusions to obviate the risks of danger to other persons. If
the interval of comparative mental health is of considerable duration,
the ordinary occupation of the patient can commonly be followed at
that time for a number of years, rarely for life; but a better result may
be looked for if the patient's circumstances are such that he can give
up active and anxious work for some quiet occupation not involving
great care.
PRIMARY INSANITY (primäre Verrücktheit, primordiale Verrücktheit,

originäre Verrücktheit) is usually a further development of an
hereditary predisposition to mental disease. The term primary
monomania, although used as an equivalent for primäre
Verrücktheit, seems to me too narrow for a disease in which the
leading delusion may change so many times. Primary insanity is
sometimes congenital, and may be developed also by injury or by
disease involving the brain early in life or during the physiological
changes at puberty, possibly by self-abuse, in persons of an
unstable mental organization. It often develops so slowly with the
character as to almost seem part of it, until it reaches such a degree
of insane delusion of self-importance and expansive ideas as to be
unmistakable insanity. There are also delusions of persecution,
distrust, and suspicion, erotomania, and moral perversion, in spite of
high claims to superior character, and indeed in spite of a high
standard of life in some particulars. Perhaps the most striking
symptom of primary insanity is the great variety of imperative
conceptions (Zwangsvorstellungen) by virtue of which the individual
is impelled, by a force often irresistible, to commit various offences
against propriety and the laws, even to murder, as well as to perform
countless acts of unwisdom or folly. There are usually physical
indications of chronic or old cerebral disease, or of defect or
degeneration in the incomplete or asymmetrical development of the
brain, which, however, may be no more than are found in persons
who might not be classed as of unsound mind. Attacks of simple
mania (mental excitement) of short duration are quite common, and
there is a progressive impairment of the higher faculties of the brain
—those which come last in a high order of civilization—although
there may be acuteness of memory, perspicacity, and shrewdness
which seem altogether phenomenal as compared with the other
mental qualities. There is no form of mental disease which is better
expressed by the word craziness than primary insanity, no other in
which the victim is more thoroughly in the grasp of his malady, and
yet no other in which he is more likely to be held responsible for the
crazy acts which he may perform, because his inherent mental state,
out of which his generally deluded frame of mind is evolved, gives
rise to delusive ideas of such a character that they are not
universally recognized, even by physicians of experience in mental
disease, as insane delusions, but are considered by some of them
as the prevarications of a criminally-minded person. When these
persons commit crimes, too, they often do so with methods and
motives quite like those of the ordinary criminal.
The PROGNOSIS in primary insanity, after the disease is fully

developed, is in the highest degree unfavorable. It remains to be
seen how much can be done by moral training in childhood and
youth to correct the evil tendency. The education of those who get
into the courts and insane asylums, so far as my knowledge of such
cases goes, has been bad to the last degree, so that, in my opinion,
there has been a fair difference of opinion as to which of them the
law should treat as criminals and which as insane persons.
TREATMENT for the most part requires absolute control of the
individual, which there is usually no one in the family sound enough
to maintain. If begun early, training away from home may accomplish
much. Restraint in some institution is commonly called for, but the
vast majority of the primary insane are allowed to take their chances
in the world, and as many end in jails and prisons or on the scaffold
as in asylums.
The states of mental defect and degeneration, except in the case of

idiocy or marked imbecility, are not associated with such obvious
physical evidences of deviation from a normal mental standard as to
make them pathognomonic. While asymmetry and other cerebral
defects are frequently observed in them, it must be acknowledged
with Schüle that similar and as extensive gross intracranial
anomalies are found in persons who could not be called of unsound
mind, and that this statement holds true even of primary insanity, in
which some writers have laid so much stress upon the value of any
indication of imperfect or asymmetrical cerebral development. Any
defect in the brain, however, is far more common among persons of
unsound mind than among those of sound mind, and therefore in
doubtful cases it is of a certain value as corroborative evidence of
mental infirmity or impairment.
Spitzka places as signs of the insane constitution (1) atypical

asymmetry of the cerebral hemispheres as regards bulk; (2) atypical
asymmetry in the gyral development; (3) persistence of embryonic
features in the gyral arrangement; (4) defective development of the
great interhemispheric commissure; (5) irregular and defective
development of the great ganglia and of the conducting tracts; (6)
anomalies in the development of the minute elements of the brain;
(7) abnormal arrangement of the cerebral vascular channels,—at the
same time acknowledging that there are cases of insanity of
inherited origin in which cerebral defects are not discernible. It is too
early to estimate the value and importance of the finer or qualitative
cerebral defects as giving rise to insanity. Benedikt finds them also in
criminals.
With regard to responsibility before the law, the statutes of no
country provide for any criterion by which accountability is defined in
these cases; medical witnesses differ in opinion as to their
criminality, and the courts are obliged to interpret the law to suit
individual cases.
The states of mental defect and degeneration are not sharply

defined. They run more or less into one another. The fact should also
be kept in mind that isolated symptoms and groups of symptoms
belonging to them are repeatedly found in curable conditions of
physical and mental exhaustion in neurotic persons.
The degenerative mental states are thought to be increasing, to

furnish material for the increase in the otherwise curable insanities,
and to thus include much of that portion of the community which is
most filling up our institutions with incurable cases. It is probably in
the prevention of them, or at least in the proper training and
disposition of children affected with them or predisposed to them,
that the most can be done to stay the increase of insanity. Perhaps
at some time unwise marriages of passion and sentiment will be less
common than now, and the rights of children to a fair start in life
more considered.
Psychoneuroses.
AFFECTIVE MENTAL DISEASE is a folie raisonnante, one of the

reasoning insanities, sometimes called moral insanity, and very like
the moral insanity already described, except in the absence of signs
of mental degeneration and in the fact that it is a curable disorder. It
is an insanity of action, marked by scarcely noticeable mental
impairment. It often is the early stage of more serious mental
disease, and not seldom its symptoms remain, as simply change of
character, after the striking symptoms of extensive mental disorder
have disappeared. It also exists and is cured without the appearance
of more pronounced insanity. At the time of the climacteric it is a
form of mental disorder not uncommon among women, who,
however, usually fail to recognize it as such until they have
recovered. Maudsley includes under this head simple melancholia,
simple mania, and moral alienation, but it will be more convenient for
the present purpose to use the term affective mental disease as
indicating a curable moral alienation or change of character affecting
the intellect chiefly so far as the judgment and sense of propriety
only are concerned, and not dependent upon constitutional defect or
developed degenerative mental state. There is usually slight
exhilaration or depression, which alternates or varies from time to
time.
The PROGNOSIS is favorable.
The TREATMENT is brain-nutrition, with those general measures

already described.
HYPOCHONDRIASIS, as Flint17 well says, belongs in the list of disorders

of the mind, although the mental alienation is not regarded as
amounting to insanity. The mental state is one of morbid imagination
and apprehension rather than of definite delusion, and it consists in a
belief in the existence, present or to come, of maladies and diseased
conditions for which there is no foundation in fact, in spite of
sufficient proof of their unreality. There is usually, not always, mental
depression. Its causes lie in conditions, usually obscure, which lower
the tone of the general health, including hereditary weaknesses, or
depress the vitality of the brain either by physical wear or mental
worry, and the exhausting influence of functional disorders or of
organic diseases which may not be discovered before the autopsy.
Disappointment, bad habits, want of proper mental occupation are
often at fault.
17 Practice of Medicine, p. 854.
The physical symptoms of hypochondriasis are commonly those

associated with impaired digestion and nutrition—namely, anæmia,
dyspepsia, neurasthenia, constipation, flatulence, headache or a
feeling of discomfort after using the brain, less appetite, slight loss of
flesh, disordered sleep.
The mental indications are more or less melancholy, indisposition to

exertion, irritability, diminished power of self-control, and an inability
to cease except temporarily from interpreting signs, proved to be
trivial, as indicating grave maladies or as forewarnings of severe
disease to come. Sometimes the fixed idea is limited to a single false
conception, but oftener slight changes in physical symptoms or
differing phases of morbid introspection produce a complete
kaleidoscope of pictures of fancied misery. The whole catalogue of
diseases, or a large part of it, may be exhausted, with the help of
some of the many foolish treatises always ready for hypochondriacs
or from reading medical books and talking with charlatans, who are
consulted at rapid intervals, one after another, both by those who
wander from office to office and those who take to their beds. The
most common type of hypochondriasis arises, directly or indirectly, in
some form of unhealthy or false ideas regarding the sexual function,
and in the idea that some imagined or exaggerated abuse of it has
produced or will produce most serious evils; but there is not an organ
of the body which may not be the basis for the unwholesome
thoughts. Not seldom there is simply the delusion of especial
weakness or sensitiveness or delicacy.
Hypochondriasis may be only the early stage of more serious mental

disease. It may be one manifestation of an hereditary neurosis or
psychoneurosis, or it may arise from deterioration of the body's
vitality by organic disease, especially of the abdominal or pelvic
organs or through some incurable weakness or functional disorder.
In either of these cases its cause and duration will be determined by
the clinical history. As an uncomplicated psychoneurosis
hypochondria lasts from a few months to a number of years, with
very little change in its prominent symptoms, resulting in recovery for
the most part, becoming chronic in a moderate proportion of cases,
and rarely proving fatal except by some accidental complication,
including suicide.
The PATHOLOGY AND MORBID ANATOMY of the disease are unknown.
The differential DIAGNOSIS consists in the exclusion of other diseases.
The PROGNOSIS is favorable in uncomplicated cases.
TREATMENT consists in measures to improve the general health,

especially a full diet carefully selected, hydro-therapeutics, massage,
gymnastics, horseback riding, walking, rowing, abundant and
agreeable exercise in the open air, and the management of the
patient's surroundings so as to lighten the mind and relieve from
worry, perhaps by travel, sea-voyages, etc. Argument is commonly
worse than useless, but there should be a decided impression given
that the generally morbid state is due to ill-health. The risk of suicide
is so small that restrictions of liberty directed to its prevention do
more harm than good. It goes without saying that bad habits should
be reformed, narcotics should be avoided, and a healthy occupation
should be encouraged, or, if possible, insisted upon. The difficulties
in treatment are fully as great with the highly-educated superstitious
and credulous people whom we find in the literary and professional
circles as in the ignorant and weak-minded.
MELANCHOLIA (Die Melancholie, Schwermuth, Tiefsinn, Trübsinn,
Lypemanie, Mélaneolie, Aliénation partielle depressive, Monomanie
triste, Phrenalgie, Psychalgia) is one of the functional mental
diseases, in the sense that the pathological condition of the brain
upon which it depends is not yet known, although it is thought to
begin with disturbances in circulation and nutrition, which end, if not
resulting in cure, in atrophic, degenerative, and inflammatory states,
indicating, in the great majority of cases, extensive brain disease. As
a rule, melancholia first appears in a slight change of character; the
patient is said by his friends to be not quite like himself. After some
days or months, as the case may be, the symptoms develop into
settled gloom associated with mental pain—the state known as
Simple Melancholia (Mélancolie raisonnante), in which the events of

life are correctly observed, but, incorrectly interpreted, are the source
of constant apprehension, self-depreciation, depression, and
despondency. There are no delusions, properly speaking, and yet
there is a disposition to take the dark-side view even of
circumstances which promise favorably, which amounts to a
generally deluded state of mind. Commonly there is increased
irritability, now and then a genuine moral insanity, and occasionally in
neuropathic constitutions the state of mind already described under
the head of Impulsive Insanity, of which the suicidal impulse is the
least infrequent. Sometimes there are no physical indications of
disease, but as a rule there are headache, increased sensibility to
light and noise, sleeplessness, restlessness, impaired appetite and
digestion, gastro-intestinal catarrh, marked loss of flesh, diminished
or abolished sexual desire, and in women usually delayed
menstruation or amenorrhœa. A few persons are able to keep up, in
an irregular sort of way, their customary employment. In the majority
of cases it is impossible to concentrate the mind upon work, mental
occupation fatigues the brain, and the physical strength is too
impaired for steady labor. Suicide is thought of probably in nearly
every case, as it is by many sane people at some time in their lives,
but it is very seldom committed unless there are such disgraceful or
distressing acts performed or suffered by them as would tempt to

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B Vitamins and Folate Chemistry

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Isoflavones Chemistry Analysis Function and Effects 1st

Dietary Sugars Chemistry Analysis Function and Effects

Vitamin A and Carotenoids Chemistry Analysis Function

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Aging : Oxidative Stress and Dietary Antioxidants

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B Vitamins and Folate

Food and Nutritional Components in Focus

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B Vitamins and Folate

Food and Nutritional Components in Focus No. 4

r The Royal Society of Chemistry 2013

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Published by The Royal Society of Chemistry,

Registered Charity Number 207890

For further information see our web site at www.rsc.org

by divergent skills and professional disciplines. Hitherto this transdisciplinary

 B Vitamins and Folate in Context

Coverage includes B vitamins and folate in the context of a historical

Food and Nutritional Components in Focus No. 4

 an Abstract (appears in the eBook only)

are from leading national and international experts including contributions

Professor Victor R. Preedy,

1.1 Evidence for the Presence of Unidentiﬁed

Factors Essential for Life 3

Chapter 2 B Vitamins and Disease 21

Chapter 3 Vitamins and Folate Fortiﬁcation in the Context

3.2 Homocysteinaemia as a Risk Factor for

4.1 Reactions of ThDP-dependent Enzymes 55

Chemistry and Biochemistry

Chapter 5 The Chemistry, Biochemistry and Metabolism

5.7.4 Synthesis of AThTP 84

Chapter 6 Chemistry and Biochemistry of Riboﬂavin and

6.1 Chemistry of Riboﬂavin 93

Chapter 7 The Chemistry and Biochemistry of Niacin (B3) 108

7.1 Introduction 108

7.6 NAD/NAPD Chemical and Structural Proprieties 115

Chapter 8 The Chemistry of Pantothenic Acid (Vitamin B5) 127

8.1 Introduction 127

Chapter 9 The Chemistry and Biochemistry of Vitamin B6: Synthesis of

9.1 Introduction 135

Deﬁnitions of Words and Terms 143

Chapter 10 Biochemistry of Biotin 146

10.1 Introduction 146

10.2 Catabolism of Biotin 147

Chapter 11 The Chemistry of Folate 158

11.1 Introduction 158

12.1 Introduction 164

12.3 Natural Forms of Cobalamins 166

13.1 Honey 173

Chapter 14 Analytical Trends in the Simultaneous Determination

14.1 Introduction 195

Seafood Products 200

Chapter 15 Spectroﬂuorimetric Analysis of Vitamin B1 in

15.1 Introduction 210

16.1 Introduction 227

16.2 Thiamine Measurements in Human Urine 228

16.4.3 Thiamine Measurements in Human Brain 240

B Vitamins and Folate in Context

an Abstract (appears in the eBook only)