Medical genetics Books

Book Synopsis

Read more less

Book SynopsisA basic understanding of human genetics is vital for all those working in the field of assisted human reproduction. Genetic makeup can hamper reproduction and insight into this is making genetic diagnosis and counselling increasingly important. This fully updated textbook continues the clear structure of the original edition, beginning with a chapter on the basics of genetics and cytogenetics. Genetic causes of infertility and the effect of epigenetics and transposons on fertility are discussed in detail. Several new chapters are included in this edition, reflecting the advances of the field, including preconception genetic analysis and screening in IVF and mitochondrial genetics. Combining genetics, reproductive biology and medicine, this is an essential text for practitioners in reproductive medicine and geneticists involved in the field looking to improve their knowledge of the subject and provide outstanding patient care.Trade Review'Recommended.' D. Schulman, ChoiceTable of Contents1. Basic genetics and cytogenetics: a brief reminder Karen Sermon; 2. Application of whole-genome technologies to ART Elia Fernandez Gallardo, Thomas Lefevre, Koen Theunis, and Thierry Voet; 3. Meiosis: how to get a good start in life Ursula Eichenlaub-Ritter; 4. Chromosomes in early human embryo development: incidence of chromosomal abnormalities, underlying mechanisms, and consequences for development Esther B. Baart, Effrosyni Chavli, and Diane Van Opstal; 5. DNA is not the whole story: transgenerational epigenesis and imprinting Ashwini Balakrishnan and J. Richard Challiet; 6. Genes are not the whole story: retrotransposons as new determinants of male fertility Patricia Fauque and Deborah Bourc'his; 7. Chromosomal causes of infertility: the story continues Svetlana A. Yatsenko and Aleksandar Rajkovic; 8. Genetics of human male infertility Stephane Viville and Ozlem Okutman; 9. Genetics of human female infertility Svetlana A. Yatsenko and Aleksandar Rajkovic; 10. Preconception genetics analysis and screening in IVF Juan Jose Guillen and Rita Vassena; 11. Genetic counseling in ART Christine De Die-Smulders and Ron van Golde; 12. Mitochondrial genetics in reproductive medicine Claudia Spits and Filippo Zambelli; 13. Preimplantation genetic diagnosis Jan Traeger-Synodinos and Carmen Rubio Lluesa; 14. Epigenetics and ART Aafke P. A. van Montfoort; 15. Ethical considerations in human reproductive genetics Guido de Vert and Wybo Dondorp.

Read more less

Book SynopsisSCN2A encodes a voltage-gated sodium channel (designated NaV1.2) vital for generating neuronal action potentials. Pathogenic SCN2A variants are associated with a diverse array of neurodevelopmental disorders featuring neonatal or infantile onset epilepsy, developmental delay, autism, intellectual disability and movement disorders. SCN2A is a high confidence risk gene for autism spectrum disorder and a commonly discovered cause of neonatal onset epilepsy. This remarkable clinical heterogeneity is mirrored by extensive allelic heterogeneity and complex genotype-phenotype relationships partially explained by divergent functional consequences of pathogenic variants. Emerging therapeutic strategies targeted to specific patterns of NaV1.2 dysfunction offer hope to improving the lives of individuals affected by SCN2A-related disorders. This Element provides a review of the clinical features, genetic basis, pathophysiology, pharmacology and treatment of these genetic conditions authored by leading experts in the field and accompanied by perspectives shared by affected families. This title is also available as Open Access on Cambridge Core.

Read more less

Book Synopsis

Read more less

Book SynopsisDNA testing and its forensic analysis are recognized as the gold standard in forensic identification science methods. However, there is a great need for a hands-on step-by-step guide to teach the forensic DNA community how to interpret DNA mixtures, how to assign a likelihood ratio, and how to use the subsequent likelihood ratio when reporting interpretation conclusions.Forensic DNA Profiling: A Practical Guide to Assigning Likelihood Ratios will provide a roadmap for labs all over the world and the next generation of analysts who need this foundational understanding. The techniques used in forensic DNA analysis are based upon the accepted principles of molecular biology. The interpretation of a good-quality DNA profile generated from a crime scene stain from a single-source donor provides an unambiguous result when using the most modern forensic DNA methods. Unfortunately, many crime scene profiles are not single source. They are described as mixedTable of Contents1: An Introduction and Review of DNA Profile Interpretation2: An Introduction to Statistics and Proposition Setting3: Assigning the LR: Single-Source Examples Population Genetics Models4: Application of the Binary LR for Mixtures5: LRs Considering Relatives as Alternate Contributors6: Probabilistic Genotyping: Semicontinuous Models7: Probabilistic Genotyping: Continuous Models8: Considerations on Validation of Probabilistic Genotyping SoftwareAppendix 1: Allele FrequenciesAppendix 2: Model Answers

Read more less

Book SynopsisGenomic technologies provide the means of diagnosis and management of many human diseases. Without insights from cytogenetics, correct interpretation of modern high-throughput results is difficult, if not impossible. This book summarizes applications of cytogenetics and molecular cytogenetics for students, clinicians and researchers in genetics, genomics and diagnostics. The book combines the state-of-the-art knowledge and practical expertise from leading researchers and clinicians and provides a comprehensive overview of current medical and research applications of many of these technologies.KEY FEATURES Provides clear summaries of fluorescence in situ hybridization technologies and others Comprehensively covers established and emerging methods Chapters from an international team of leading researchers Useful for students, researchers and cliniciansTable of ContentsSeries Preface. Preface. Acknowledgements. Editor. List of Contributors. Chapter 1 Cytogenetics and Chromosomics. Chapter 2 Banding Cytogenetics. Chapter 3 Generation of Microdissection-Derived Painting Probes from Single Copy Chromosomes. Chapter 4 FISH—An Overview. Chapter 5 FISH—Microscopy and Evaluation. Chapter 6 FISH—in Routine Diagnostic Settings. Chapter 7 FISH—in Leukemia Diagnostics. Chapter 8 FISH—in Tissues. Chapter 9 FISH—in Human Sperm and Infertility. Chapter 10 FISH—in Spontaneously Aborted Products of Conception. Chapter 11 FISH—Characterization of Chromosomal Alterations, Recombination, and Outcomes after Segregation. Chapter 12 Multicolor-FISH—Methods and Applications. Chapter 13 FISH—Centromere- and Heterochromatin-Specific Multicolor Probe Sets. Chapter 14 FISH—Detection of Individual Radio Sensitivity. Chapter 15 FISH—Detection of CNVs. Chapter 16 FISH—Interphase Applications Including Detection of Chromosome Instability (CIN). Chapter 17 FISH—Determination of Telomere Length (Q-FISH/CO-FISH). Chapter 18 FISH—in Three Dimensions—3D-FISH. Chapter 19 FISH—On Fibers. Chapter 20 FISH—and Single-Cell Gel Electrophoresis Assay (Comet Assay). Chapter 21 Molecular Karyotyping. Chapter 22 FISH—Mitochondrial DNA. Chapter 23 FISH—in Birds. Chapter 24 FISH—in Fish Chromosomes. Chapter 25 FISH—and the Characterization of Synaptonemal Complex. Chapter 26 RNA-FISH—on Lampbrush Chromosomes: Visualization of Individual Transcription Units. Chapter 27 FISH—in Insect Chromosomes. Chapter 28 FISH—in Plant Chromosomes. Chapter 29 FISH—and CRISPR/CAS9. Index.

Read more less

Book SynopsisThis volume is the first of a new series dedicated to the historical developments in topics that are central to gynecological cancers. The six essays on ovarian cancer contained here provide context from the perspective of experts in the field, illustrating what is required for the development and realization of medical innovation: time consuming, decades-long basic research of the tumor genome and cancer cell biology, which may then set the basis for dramatic accelerations of recent therapeutic options; and the diligent assessment and fine-tuning of surgical techniques and concepts of patient prehabilitation and rehabilitation.

Read more less

Book SynopsisThis innovative and engaging book argues that because our genetic information is directly linked to the genetic information of others, it is impossible to assert a right to privacy' in the same way that we can in other areas of life. This position throws up questions around access to sensitive data. It suggests that we may have to abandon certain intuitions about who may access our genetic information; and it raises concerns about discrimination against people with certain genetic characteristics. But the author asserts that regulating access to genetic information requires a more nuanced perspective that does not rely on the familiar language of rights. The book proposes new ways in which we may think about who has access to what genetic information, and on what basis they do so. Conceptually challenging, the book will prove engaging reading for scholars and students interested in the area of bioethics and medical law, as well as policy makers working with these presTable of ContentsIntroduction. Part I: Presumptions and Foundations. 1.Genes and Information Sharing. 2.What is Privacy? Part II: A Sceptic’s Tour of Genetic Privacy Rights. 3.Rights to know and Duties no to. 4.What is a Privacy Right? 5.Other Ways to Think about Privacy Rights. 6.Privacy and Reasons to Disclose. Part III: Rebuilding Genetic Privacy Rights. 7.Reinventing Privacy. 8.Reinvention and Regulation.

Read more less

Book SynopsisThe new edition of Gene Control, for the first time, provides extensive coverage on prokaryotic gene regulation, which makes it the only textbook offering a complete and detailed account of gene control for both prokaryotic and eukaryotic organisms. The core objective of this edition is to educate students about the fundamental principles and mechanisms governing gene expression, regulation, and function. To reinforce these ideas, each chapter now includes discussion questions to promote critical thinking. There are also multiple choice questions and animations for students, and a large question bank and figure slides for instructors. The textbook also emphasizes the vital role of scientific experiments and evidence in shaping our current understanding of gene control and provides comprehensive coverage of essential gene expression techniques and methodologies throughout the book.This extensively updated edition of the renowned textbook Gene Control will remain a valuable resource for students, instructors, researchers, and medical professionals exploring various aspects of gene control, ranging from the regulation of genes in infectious diseases to embryonic development across different organisms, from bacteria to humans.

Read more less

Book SynopsisThis concise text examines the contribution of genetic research to clinical practice in colorectal cancer. It delves into the underlying molecular mechanisms and the genetic and environmental factors contributing to colorectal cancer, as well as into advances in personalized therapies, targeted interventions, and biomarker-based approaches. By providing a comprehensive overview of the subject, the book aims to bridge the gap between scientific research and clinical practice, offering valuable insights to researchers, clinicians, and healthcare professionals dedicated to combating colorectal cancer and improving patient outcomes. Unites scientific discovery to clinical practice Offers a practical resource for the multidisciplinary team treating colorectal cancer patients Presents the state of the art in clinical management

Read more less

Book SynopsisThis volume explores the latest techniques used by researchers to study directed evolution (DE) at each stage of the Design-Build-Test-Learn cycle.Table of ContentsPreface…Table of Contents…Contributing Authors…1. Designing Overlap Extension PCR Primers for Protein Mutagenesis: A Programmatic ApproachXiaofang Huang, Liangting Xu, Chuyun Bi, Zhao Lili, Zhang Limei, Xuanyang Chen, Shiqian Qi, and Shiqiang Lin2. Recombination of Single Beneficial Substitutions Obtained from Protein Engineering by Computer-Assisted Recombination (CompassR)Haiyang Cui, Mehdi D. Davari, and Ulrich Schwaneberg3. Non-Degenerate Saturation Mutagenesis: Library Construction and Analysis via MAX and ProxiMAX RandomizationAnupama Chembath, Ben P.G. Wagstaffe, Mohammed Ashraf, Marta M. Ferreira Amaral, Laura Frigotto, and Anna V. Hine4. Antha-Guided Automation of Darwin Assembly for the Construction of Bespoke Gene LibrariesP. Handal-Marquez, M. Koch, D. Kestemont, S. Arangundy-Franklin, and V.B. Pinheiro5. SpeedyGenesXL An Automated, High-Throughput Platform for the Preparation of Bespoke Ultra-Large Variant Libraries for Directed EvolutionJoanna C. Sadler, Neil Swainston, Mark S. Dunstan, Andrew Currin, and Douglas B. Kell6. Facile Assembly of Combinatorial Mutagenesis Libraries using Nicking MutagenesisMonica B. Kirby and Timothy A. Whitehead7. GeneORator: An Efficient Method for the Systematic Mutagenesis of Entire GenesLucy Green, Nigel S. Scrutton, and Andrew Currin8. Rapid Cloning of Random Mutagenesis Libraries using PTO-QuickStepPawel Jajesniak, Kang Lan Tee, and Tuck Seng Wong9. Construction of Strong Promoters by Assembling Sigma Factor Binding MotifsYonglin Zhang, Yang Wang, Jianghua Li, Chao Wang, Guocheng Du, and Zhen Kang10. Application of Restriction Free (RF) Cloning in Circular PermutationBoudhayan Bandyopadhyay and Yoav Peleg11. Site-Directed Mutagenesis Method Mediated by Cas9Wanping Chen, Wenwen She, Aitao Li, Chao Zhai, and Lixin Ma12. Directed Evolution of Transcription Factor-Based Biosensors for Altered Effector SpecificityLeopoldo Ferreira Marques Machado and Neil Dixon13. A Screening Method for P450 BM3 Mutant Libraries using Multiplexed Capillary Electrophoresis for Detection of Enzymatically Converted CompoundsAnna Gärtner, Gustavo de Almeida Santos, Anna Joëlle Ruff, and Ulrich Schwaneberg14. Directed Evolution of Glycosyltransferases by a Single-Cell Ultrahigh-Throughput FACS-Based Screening MethodYumeng Tan, Xue Zhang, Yan Feng, and Guangyu Yang15. Learning Strategies in Protein Directed EvolutionXavier F. Cadet, Jean Christophe Gelly, Aster van Noord, Frédéric Cadet, and Carlos G. Acevedo-RochaSubject Index List…

Read more less

Book SynopsisThis book discusses principles, methodology, and applications of microbiological laboratory techniques . It lays special emphasis on the use of various automated machines that are essential for medical microbiology and diagnostic labs. The book contains eleven major chapters. The first chapter describes the good lab practices which should be followed by the students in all biological, chemistry or microbiology laboratories. The next chapter describes manual and automated characterization of antibiotic resistant microbes, followed by a chapter on genomics based tools and techniques that are integral to research. Further chapters deal with other important techniques like immunology based techniques, spectrophotometry and its various types, MALDI-TOFF and microarrays, each with illustrations and detailed description of the protocols and applications. The book also gives certain important guidelines to the students about the planning the experiment and interpreting results. Table of Contents

Read more less

Book SynopsisThis Open Access volume provides comprehensive reviews and describes the latest techniques to study eukaryotic ribosome biogenesis. For more than 50 years ribosomes are a major research topic. Our knowledge about ribosome biogenesis and function such as   transcription, mRNA modification, and translation was the sine qua non for developing the powerful RNA-based vaccines against RNA-viruses causing the world-threatening Covid-19 pandemia. The chapters in this book are organized into six parts. Part One discusses a comparative survey about the unity and diversity of ribosome biogenesis in pro- and eukaryotic cells. Part Two deals with the genomic organization of eukaryotic rDNA and the role of RNA polymerase I in ribosomal RNA transcription. Part Three explores in vitro methods to study RNA polymerase I structure and its function, and Part Four analyzes the nucleo-cytoplasmic transport of assembled ribosomes and RNP complexes. Part Five covers modifications that increase Table of ContentsDedication……Acknowledgments…Preface…Table of Contents…Contributing Authors…Part I Ribosome Biogenesis1. A Comparative Perspective on Ribosome Biogenesis: Unity and Diversity across the Tree of LifeMichael Jüttner and Sébastien Ferreira-CercaPart II Genomic Organization2. Establishment and Maintenance of Open Ribosomal RNA Gene Chromatin States in EukaryotesChristopher Schächner, Philipp E. Merkl, Michael Pilsl, Katrin Schwank, Kristin Hergert, Sebastian Kruse, Philipp Milkereit, Herbert Tschochner, and Joachim Griesenbeck3. Analysis of Yeast RNAP I Transcription of Nucleosomal Templates In VitroPhilipp E. Merkl, Christopher Schächner, Michael Pilsl, Katrin Schwank, Kristin Hergert, Gernot Längst, Philipp Milkereit, Joachim Griesenbeck, and Herbert TschochnerPart III RNA Polymerases4. Specialization of RNA Polymerase I in Comparison to Other Nuclear RNA Polymerases of Saccharomyces cerevisiaePhilipp E. Merkl, Christopher Schächner, Michael Pilsl, Katrin Schwank, Catharina Schmid, Gernot Längst, Philipp Milkereit, Joachim Griesenbeck, and Herbert Tschochner5. Structural Studies of Eukaryotic RNA Polymerase I using Cryo-Electron MicroscopyMichael Pilsl and Christoph Engel6. Preparation of RNA Polymerase Complexes for their Analysis by Single Particle Cryo-Electron MicroscopyMichael Pilsl, Florian B. Heiss, Gisela Pöll, Mona Höcherl, Philipp Milkereit, and Christoph EngelPart IV Ribosome Assembly, Transport and RNP Complexes7. Eukaryotic Ribosome Assembly and Nucleo-Cytoplasmic TransportMichaela Oborská-Oplová, Ute Fischer, Martin Altvater, and Vikram Govind Panse8. Tethered MNase Structure Probing as Versatile Technique for Analyzing RNPs using Tagging Cassettes for Homologous Recombination in Saccharomyces cerevisiae Fabian Teubl, Katrin Schwank, Uli Ohmayer, Joachim Griesenbeck, Herbert Tschochner, and Philipp MilkereitPart V RNA Modification9. Chemical Modifications of Ribosomal RNASunny Sharma and Karl-Dieter Entian10. In Vitro Selection of Deoxyribozymes for the Detection of RNA ModificationsAnam Liaqat, Maksim V. Sednev, and Claudia Höbartner11. Mapping of the Chemical Modifications of rRNAs Jun Yang, Peter Watzinger, and Sunny Sharma12. Non-Radioactive In Vivo Labelling of RNA with 4-thio-uracilChristina Braun, Robert Knüppel, Jorge Perez-Fernandez, and Sébastien Ferreira-CercaPart VI Translation13. Translation Phases in EukaryotesSandra Blanchet and Namit Ranjan14. Differential Translation Activity using Bio-Orthogonal Non-Canonical Amino Acids Tagging (BONCAT) in ArchaeaMichael Kern and Sébastien Ferreira-Cerca15. Thermofluor-Based Analysis of Protein Integrity and Ligand Interactions Sophia Pinz, Eva Doskocil, and Wolfgang Seufert16. In Vitro Assembly of a Fully Reconstituted Yeast Translation System for Studies of Initiation and Elongation Phases of Protein SynthesisSandra Blancher and Namit Ranjan

Read more less

Book SynopsisThis volume offers readers an opportunity to learn about how genomes are sequenced, what discoveries have so far come out of this scientific revolution, and about the ethical dimensions of this advancing technology.Table of ContentsForeward: Still, The Genomic Revolution ix Acknowledgments xi Introduction: Welcome Back to the Genome xiii 1 From Mendel to Molecules 1 2 The Building Blocks of Gene Sequencing 31 3 Sequencing the Genome 47 4 The Next Generation 65 5 Making the Genome Safe 81 6 The Meanings of Genetic Diversity: Part I 121 7 The Meanings of Genetic Diversity: Part II 143 8 The Tree of Life: 4 Billion Years of Divergence 161 9 Sequencing the Small and Infamous: A Look at Metagenomics and Microbiomes 195 10 The World to Come: Agriculture 213 Conclusion: Don’t Believe the Hype (Including Ours) 245 Index 249

Read more less

Book SynopsisGenetic Analysis of Complex Diseases An up-to-date and complete treatment of the strategies, designs and analysis methods for studying complex genetic disease in human beings In the newly revised Third Edition of Genetic Analysis of Complex Diseases, a team of distinguished geneticists delivers a comprehensive introduction to the most relevant strategies, designs and methods of analysis for the study of complex genetic disease in humans. The book focuses on concepts and designs, thereby offering readers a broad understanding of common problems and solutions in the field based on successful applications in the design and execution of genetic studies. This edited volume contains contributions from some of the leading voices in the area and presents new chapters on high-throughput genomic sequencing, copy-number variant analysis and epigenetic studies. Providing clear and easily referenced overviews of the considerations involved in genetic analysis of compTable of ContentsList of Contributors xv Foreword xvii 1 Designing a Study for Identifying Genes in Complex Traits 1 William K. Scott, Marylyn D. Ritchie, Jonathan L. Haines,and Margaret A. Pericak-Vance Introduction 1 Components of a Disease Gene Discovery Study 3 Define Disease Phenotype 4 Clinical Definition 4 Determining that a Trait Has a Genetic Component 5 Identification of Datasets 5 Develop Study Design 5 Family-Based Studies 6 Population-Based Studies 6 Approaches for Gene Discovery 7 Analysis 7 Genomic Analysis 7 Statistical Analysis 8 Bioinformatics 8 Follow-up 8 Variant Detection 8 Replication 9 Functional Studies 9 Keys to a Successful Study 10 Foster Interaction of Necessary Expertise 10 Develop Careful Study Design 11 References 11 2 Basic Concepts in Genetics 13 Kayla Fourzali, Abigail Deppen, and Elizabeth Heise Introduction 13 Historical Contributions 13 Segregation and Linkage Analysis 13 Hardy–Weinberg Equilibrium 14 DNA, Genes, and Chromosomes 17 Structure of DNA 17 Genes and Alleles 19 Genes and Chromosomes 20 Genes, Mitosis, and Meiosis 22 When Genes and Chromosomes Segregate Abnormally 25 Inheritance Patterns in Mendelian Disease 25 Autosomal Recessive 25 Autosomal Dominant 25 X-linked Inheritance 28 Mitochondrial Inheritance 29 Y-linked 29 Genetic Changes Associated with Disease/ Trait Phenotypes 29 Mutations Versus Polymorphisms 29 Point Mutations 30 Sickle Cell Anemia 30 Achondroplasia 30 Deletion/Insertion Mutations 31 Duchenne and Becker Muscular Dystrophy 31 Cystic Fibrosis 31 Charcot-Marie- Tooth Disease 31 Nucleotide Repeat Disorders 32 Susceptibility Versus Causative Genes 32 Summary 34 References 34 3 Determining the Genetic Component of a Disease 36 Allison Ashley Koch and Evadnie Rampersaud Introduction 36 Study Design 37 Selecting a Study Population 37 Population-Based 38 Clinic-Based 38 Ascertainment 38 Single Affected Individual 39 Relative Pairs 40 Extended Families 40 Healthy or Unaffected Controls 41 Ascertainment Bias 42 Approaches to Determining the Genetic Component of a Disease 44 Co-segregation with Chromosomal Abnormalities and Other Genetic Disorders 44 Familial Aggregation 44 Family History Approach 44 Example of Calculating Attributable Fraction 46 Correlation Coefficients 46 Twin and Adoption Studies 47 Recurrence Risk in Relatives of Affected Individuals 48 Heritability 49 Example Using Correlation Coefficients to Calculate Heritability 50 Segregation Analysis 51 Summary 52 References 53 4 Study Design for Genetic Studies 58 Dana C. Crawford and Logan Dumitrescu Introduction 58 Selecting a Study Population 58 Family- Based Studies (Linkage) 59 Family- Based Studies (Association) 60 Studies of Unrelated Individuals (Association) 61 Cohort Studies 61 Cross- Sectional Studies 66 Case– Control Studies 66 Other Study Designs 68 Biobanks 69 Other Biobanks 71 Biospecimens for Biobanks 72 Summary 73 References 74 5 Responsible Conduct of Research in Genetic Studies 79 Susan Estabrooks Hahn, Adam Buchanan, Chantelle Wolpert,and Susan H. Blanton Introduction 79 Research Regulations and Genetics Research 80 Addressing Pertinent ELSI in Genetic Research 83 Genetic Discrimination 83 Privacy and Confidentiality 84 Certificate of Confidentiality 85 Coding Data and Samples 85 Secondary Subjects 86 Future Use of Samples/Data Sharing 87 Handling of Research Results 88 CLIA Regulations: Separation of Research and Clinical Laboratories 89 Releasing Children’s Genetic Research Results 90 DNA Ownership 90 DNA Banking 90 Family Coercion 91 Practical Methods for Efficient High-Quality Genetic Research Services 91 The Investigator as the Genetic Study Coordinator 92 Time Spent 92 Recruitment 93 Support Groups and Organizations 93 Referrals from Health Care Providers 93 Research Databases and the Internet 94 Institution Databases 94 Medical Clinics 94 Recruitment by Family Members 95 Informed Consent 95 Vulnerable Populations 96 Minors 97 Persons with Cognitive Impairment 97 Data and Sample Collection 97 Sample Collection 97 Confirmation of Diagnosis 98 The Art of Field Studies 99 Referring for Additional Medical Services 99 Maintaining Contact with Participants 100 Future Considerations 100 References 100 6 Linkage Analysis 105 Susan H. Blanton Disease Gene Discovery 107 Ability to Detect Linkage 116 Real World Example of LOD Score Calculation and Interpretation 117 Disease Gene Localization 120 Multipoint Analysis 121 Effects of Misspecified Model Parameters in LOD Score Analysis 124 Impact of Incorrect Disease Allele Frequency 124 Impact of Incorrect Mode of Inheritance 125 Impact of Incorrect Disease Penetrance 125 Impact of Incorrect Marker Allele Frequency 126 Control of Scoring Errors 127 Genetic Heterogeneity 128 Practical Approach for Model-Based Linkage Analysis of Complex Traits 131 Nonparametric Linkage Analysis 133 Identity by State and Identity by Descent 134 Methods for Nonparametric Linkage Analysis 136 Tests for Linkage Using Affected Sibling Pairs (ASP) 137 Test Based on Identity by State 137 Tests Based on Identity by Descent in ASPs 138 Simple Tests 138 Tests Applicable When IBD Status Cannot Be Determined 139 Multipoint Affected Sib-Pair Methods 141 Handling Sibships with More Than 2 Affected Siblings 142 Methods Incorporating Affected Relative Pairs 142 NPL Analysis 143 Fitting Population Parameters 145 Power Analysis and Experimental Design Considerations for Qualitative Traits 147 Factors Influencing Power of Sib-pair Methods 147 The Example of Testicular Cancer 148 Examples of Sib-Pair Methods for Mapping Complex Traits 150 Mapping Quantitative Traits 151 Measuring Genetic Effects in Quantitative Traits 152 Study Design for Quantitative Trait Linkage Analysis 154 Haseman–Elston Regression 155 Variance Components Linkage Analysis 156 Nonparametric Methods 158 The Future 159 Software Available 160 References 160 7 Data Management 169 Stephen D. Turner and William S. Bush Developing a Data Organization Strategy 170 A Brief Overview of Data Normalization 170 Database Management System (DBMS) and Structured Query Language (SQL) 172 Partitioning Data by Type 173 Sequence-Level Data 174 Sample-Level Data 174 Database Implementation 175 Hardware and Software Requirements 175 Implementation and Performance Tuning 175 Interacting with the Database Directly 176 Security 177 Other Tools for Data Management and Manipulation 177 R 177 PLINK 178 SAMtools 178 Workflow Management and Cloud Computing 178 Conclusion 179 References 179 8 Linkage Disequilibrium and Association Analysis 182 Eden R. Martin and Ren-HuaChung Introduction 182 Linkage Disequilibrium 182 Measures of Allelic Association 183 Causes of Allelic Association 184 Mapping Genes Using Linkage Disequilibrium 186 Tests of Association 187 Case–Control Tests 188 Test Statistics 188 Measures of Disease Association and Impact 189 Assessing Confounding Bias 191 Family-Based Tests of Association 192 The Transmission/Disequilibrium Test 192 Tests Using Unaffected Sibling Controls 194 Tests Using Extended Pedigrees 195 Regression and Likelihood-Based Methods 196 Association Tests with Quantitative Traits 197 Analysis of Haplotype Data 197 Genome-Wide Association Studies (GWAS) 198 Special Populations 199 HapMap 200 1000 Genomes Project 200 Summary 201 References 201 9 Genome-Wide Association Studies 205 Jacob L. McCauley, Yogasudha Veturi, Shefali Setia Verma, and Marylyn D. Ritchie Introduction 205 Definition of GWAS 206 Purpose of GWAS 206 Design 206 Technologies for High-Density Genotyping 206 Discrete and Quantitative Trait Analysis 208 Case–Control, Family-Based, and Cohort Study Designs 209 Statistical Power for Association and Correction for Testing Multiple Hypotheses 211 Data Analysis 212 Quality Control on Genotyping Call Data 212 Initial Genotyping Quality Control 213 Sample-Level Quality Control 214 SNP-Level Quality Control 215 Software Programs for Quality Control 215 Population Structure 216 Imputation 219 Genetic Association Testing 220 Meta-Analysis and “Mega-Analysis” 221 Whole-Genome Regression-Based GWAS 222 Conclusion 222 References 222 10 Bioinformatics of Human Genetic Disease Studies 228 Dale J. Hedges Introduction 228 Common Threads Genome Analysis 229 A Brief Note on Study Design 229 Data Format Manipulation 229 Planning for Adequate Computational Resources 230 Storage 231 Processing and Memory 232 Networking 232 Genomics in the Cloud 232 Processing and Analysis of Genomic Data 233 Array-Based Data 233 DNA Arrays and High-Throughput Genotyping 233 Preprocessing and Initial Quality Control 234 Genotype Calling 234 Call Efficiency 235 Data Cleaning and Additional Quality Control 236 Inferring Structural Variation From SNP-based Array Data 236 A Note on Statistical Analysis and Interpretation of Results 236 Array-Based Analysis of Gene Expression 237 Batch Effects and Data Normalization 237 Differential Expression 238 Classification and Clustering Methods 239 Visualization of Expression Data 240 Pathway and Network Analyses 240 Direct Counting and Other Expression Assay Procedures 241 Additional Uses for Oligonucleotide Arrays 242 High-Throughput Sequencing Methods for Genomics 243 Introduction 243 High-Throughput Sequencing for Genotype Inference 244 Expression Analysis from High-Throughput Sequencing Data – RNA-Seq 252 ChIP-Seq and Methylation-based Sequences 255 Bioinformatics Resources 256 Annotation of Genomic Data 257 Genome Browsers as Versatile Tools 258 Bioinformatics Frameworks and Workflows 259 Crowdsourcing and Troubleshooting 260 Data Sharing 260 References 261 11 Complex Genetic Interactions/Data Mining/Dimensionality Reduction 265 William S. Bush and Stephen D. Turner Human Diseases Are Complex 265 Complexity of Biological Systems 266 Genetic Heterogeneity 267 Statistical and Mathematical Concepts of Complex Genetic Models 268 Analytic Approaches to the Detection of Complex Interactions 270 Linkage Analysis/Genomic Sharing 270 Association Analysis 270 Genome‐Wide Association Analysis 272 Conclusion 273 References 273 12 Sample Size, Power, and Data Simulation 278 Sarah A. Pendergrass and Marylyn D. Ritchie Introduction 278 Sample Size and Power 279 Power Calculations and Simulation 282 Power Studies for Association Analysis 282 Software for Calculating Power for Association Studies, Family- or Population-Based 283 PGA: Power for Genetic Association Analyses 283 Fine-Mapping Power Calculator 284 Quanto 284 PAWE: Power for Association with Errors 284 PAWE-3D 284 GPC: Genetic Power Calculator 284 CaTS 284 INPower 284 Software for Calculating Power for Transmission Disequilibrium Testing (TDT) and Affected Sib-Pair Testing (ASP) 284 GPC: Genetic Power Calculator 284 TDT-PC: Transmission Disequilibrium Test Power Calculator 284 TDTASP 285 TDTPOWER 285 ASP/ASPSHARE 285 Simulation Software for Association Study Power Assessment 285 Backward and Forward Model Simulations 285 Coalescent Model Simulation – Short Genetic Sequences 286 Larger Coalescent Simulated Models 286 Forward Model Simulations – Short Genetic Sequences 286 Forward Model Simulations – Large Genetic Sequences 286 Resampling Simulation Tools 287 Software for Simulation of Phenotypic Data 287 Power Simulations for Linkage Analysis 288 Definitions for Power Assessments for Linkage Analysis 288 Computer Simulation Methods for Linkage Analysis of Mendelian Disease 289 SIMLINK 289 SLINK: Simulation Program for Linkage Analysis 289 SUP: Slink Utility Program 290 ALLEGRO 290 MERLIN: Multipoint Engine for Rapid Likelihood Inference 290 SimPED 290 Power Studies for Linkage Analysis – Complex Disease 290 Inclusion of Unaffected Siblings 291 Affected Relative Pairs of Other Types 291 Other Considerations 291 Genomic Screening Strategies: One-Stage versus Two-Stage Designs 291 Software for Designing Linkage Analysis Studies of Complex Disease 292 SIMLA 292 Quantitative Traits 292 Extreme Discordant Pairs 292 Sampling Consideration for the Variance Component Method 293 Software for Designing Linkage Analysis Studies for Quantitative Traits 294 SOLAR: Sequential Oligogenic Linkage Analysis Routines 294 MERLIN: Multipoint Engine for Rapid Likelihood Inference 294 SimuPOP 294 Summary 294 References 294 Index 298

Read more less

Book SynopsisWith a focus on estimating the success probability of an experiment, this book provides an introduction to the various statistical techniques involved in medical research and drug development addressing the theoretical and practical aspects of the topic.Table of ContentsPreface xv Acknowledgments xvii Acronyms xix Introduction xxi I.1 Overview of clinical trials xxii I.2 Success rates of clinical trials xxiv I.3 Success probability xxv I.4 Starting from practice xxvii PART I SUCCESS PROBABILITY ESTIMATION IN PLANNING AND ANALYZING CLINICAL TRIALS 1 Basic statistical tools 3 1.1 Pointwise estimation 4 1.2 Confidence interval estimation, conservative estimation 6 1.3 The statistical hypotheses, the statistical test and the type I error for one-tailed tests 10 1.4 The power function and the type II error 11 1.5 The p-value 14 1.6 The success probability and its estimation 17 1.7 Basic statistical tools for two tailed tests 19 1.8 Other statistical hypotheses and tests 23 2 Reproducibility Probability Estimation 25 2.1 Pointwise RP estimation 26 2.2 RP-testing 29 2.3 The RP estimate and the p-value 32 2.4 Statistical lower bounds for the RP 35 2.5 The stability criterion for statistical significance 37 2.6 Other stability criteria for statistical significance 40 2.7 Comparing stability criteria 43 2.8 Regulatory agencies and the single study 45 2.9 The RP for two-tailed tests 46 2.10 Discussing Situation I in Section I.4.1 49 3 Sample Size Estimation 51 3.1 The classical paradigm of sample size determination 52 3.2 SP estimation for adapting the sample size 55 3.3 Launching the trial in practice 57 3.4 Practical aspects of SSE 60 3.5 Frequentist conservative SSE 67 3.6 Optimal frequentist CSSE 70 3.7 Bayesian CSSE 75 3.8 A comparison of CSSE strategies 80 3.9 Discussing Situations I and II in Section I.4 83 3.10 Sample size estimation for the two-tailed setting 85 4 Robustness and Corrections in Sample Size Estimation 89 4.1 CSSE strategies with different effect sizes in phases II and III 90 4.2 Comparing CSSE strategies in different Scenarios 91 4.3 Corrections for CSSE strategies 94 4.4 A comparison among Corrected CSSE strategies 97 PART II SUCCESS PROBABILITY ESTIMATION FOR SOME WIDELY USED STATISTICAL TESTS 5 General parametric SP estimation 105 5.1 The parametric model 105 5.2 Power, SP and noncentrality parameter estimation 106 5.3 RP estimation and testing 107 5.4 Sample size estimation 108 5.5 Statistical tests included in the model 109 6 SP estimation for Student’s t statistical tests 113 6.1 Test for two means equal variances 114 6.1.1 Power and RP estimation 114 6.2 Test for two means unequal variances 117 6.3 On Student’s t RP estimates 120 7 SP estimation for Gaussian distributed test statistics 123 7.1 Test for two proportions 123 7.2 Test for survival: the log-rank test 127 8 SP estimation for Chi-square statistical tests 133 8.1 Test for two multinomial distributions: 2 x C comparative trial 133 8.2 Test for S couples of binomial distributions: the Mantel-Haenszel test 137 8.3 On χ2 RP estimates 141 9 General nonparametric SP estimation with - applications to the Wilcoxon test 143 9.1 The nonparametric model 144 9.2 General nonparametric SP estimation 145 9.3 The Wilcoxon rank-sum test 146 A Tables of quantiles 161 B Tables of RP estimates for the one-tailed Z test 169 References 179 Topic index 185 Author index 193

Read more less

Book SynopsisPain Genetics: Basic to Translational Scienceis a timely synthesis of the key areas of research informing our understanding of the genetic basis of pain. The book opens with foundational information on basic genetic mechanisms underlying pain perception and progresses recently discovered complex concepts facing the field. The coverage is wide-ranging and will serves as an excellent entry point into understating the genetics of pain as well as providing a single resource for established researchers looking for a better understanding of the diverse strands of research going on in the area. With contributors painstakingly selected to provide a broad range of perspectives and research,Pain Geneticswill be a valuable resource for geneticists, neuroscientists, and biomedical professionals alike.Table of ContentsEditors’ Biographies xi Contributors xiii 1 How Do Pain Genes Affect Pain Experience? 1 Marshall Devor Introduction 2 Heritability of Pain: Historical Roots 2 Why is Pain Genetics Interesting and Potentially Useful? 4 What Are Pain Genes? 8 How Do Pain Genes Affect Pain Experience? 9 Disease Susceptibility Genes Versus Pain Susceptibility Genes 12 Perspective 13 Acknowledgments 13 2 Conservation of Pain Genes Across Evolution 15 Thang Manh Khuong and G. Greg Neely Introduction 15 Anatomical Organization of Nociception Apparatus in Mammals and Drosophila 16 Acute Heat Pain in Mammals 16 Acute Heat Nociception in Drosophila 18 Mechanical Pain in Mammals 19 Mechanical Nociception in Drosophila 19 Chemical Nociception in Mammals 21 Chemical Nociception in Drosophila 21 Inflammatory Pain in Mammals 22 Persistent Pain in Drosophila 22 Neuropathic Pain in Mammals 25 Structural Reorganizations of Nerve Fibers in Neuropathic Pain 25 Mammalian Neuropathic Pain Genes That Are Conserved in Drosophila 25 Long-Term Potentiation and Long-Term Depression in Neuropathic Pain in Mammals 28 Neuropathic Pain in Drosophila 30 Conclusions 30 3 Defining Human Pain Phenotypes for Genetic Association Studies 37 Christopher Sivert Nielsen Introduction 37 What is a Pain Phenotype? 38 Pain Scaling 39 Heritability 40 Genotype–Phenotype Matching 41 Reliability and Temporal Stability 41 Clinical Phenotypes 43 Designing Clinical Pain Genetic Studies 43 The Heritability of Specific Clinical Pain Conditions 45 Experimental Phenotypes 45 The Heritability of Experimental Phenotypes 46 Extended Phenotypes 47 Practical Concerns 47 Conclusions 48 Conflict of Interest Statement 48 4 Genetic Contributions to Pain and Analgesia: Interactions with Sex and Stress 51 Roger B. Fillingim and Jeffrey S. Mogil Introduction 51 Brief Overview of Sex and Gender Differences in Pain and Analgesia 52 Brief Overview of Stress and Pain/Analgesia 52 Sex X Gene Interactions in Pain and Analgesia 53 Summary 57 5 Abnormal Pain Conditions in Humans Related to Genetic Mutations 61 Christopher Geoffrey Woods Introduction to SCN9A, NTRK1, and NGF and the Roles They Play in Pain 61 Introduction to SCN9A and Its Omnipotent Role in Pain Sensing 62 Introduction to NTRK1 and Its Role in Development and Function in the Pain and Sympathetic Nervous Systems 69 Introduction to NGF, the First Nerve Growth Factor to Be Found and Studied 72 6 Alternative Pre-mRNA Splicing of Mu Opioid Receptor Gene: Molecular Mechanisms Underlying the Complex Actions of Mu Opioids 79 Ying-Xian Pan Introduction 79 Evolution of OPRM1 Gene 80 OPRM1 Gene: Chromosomal Location and Gene Structure 82 Alternative Promoters 82 Alternative Pre-mRNA Splicing of the OPRM1 Gene 83 Expression and Function of the OPRM1 Splice Variants 90 Conclusion 94 7 Discovering Multilocus Associations with Complex Pain Phenotypes 99 Chia-Ling Kuo, Luda Diatchenko, and Dmitri Zaykin Introduction 99 Approaches Based on Testing Individual Genetic Variants Within a Region 100 Approaches That Combine Association Signals Across Genetic Variants 101 Methods for Testing Joint Effects of Multiple Genetic Variants 102 Multilocus Analysis of Mu Opioid Receptor Haplotypes 103 Two-Stage Multilocus Association Analysis: Collapsing SNPs with Adjustment for Effect Directions 104 Two-Stage Approach: Simulations 107 Two-Stage Approach: Results 108 Discussion 111 Acknowledgments 113 8 Overlapping Phenotypes: Genetic Contribution to Nausea and Pain 115 Charles C. Horn Introduction 115 What is the Functional Role of Nausea and Vomiting? 117 Pain Syndromes with Significant Nausea 118 The Neuropharmacology of Nausea and Emesis 119 Emetic and Antiemetic Action of Opioids 121 Preclinical Studies of Nausea and Vomiting 122 Heritability of Nausea and Vomiting Phenotypes 123 Human Genetic Sequence Variants Associated with Nausea and Vomiting 124 Summary and Future Directions 125 9 A Counterpart to Pain: Itch 131 Adam P. Kardon and Sarah E. Ross Introduction 131 Why Do We Scratch? 132 The Basics of Itch 132 So How is Itch Coded? 133 Measuring Itch in Mice 134 Genetic Models of Itch 135 A Key Role for the Skin in Itch 141 A Shift in the Balance of Pain and Itch 141 Genetic Variation and Itch in Humans – Challenges for the Future 143 Acknowledgments 143 10 Translating Genetic Knowledge into Clinical Practice for Musculoskeletal Pain Conditions 147 Luda Diatchenko, Shad B. Smith, and William Maixner Introduction 147 Results of Human Association Studies 148 Gene Sequencing 150 Development of New Therapeutics 150 Understanding of Interactions 155 In Summary 156 11 The Human Chronic Pain Phenome: Mapping Nongenetic Modifiers of the Heritable Risk 161 Ze’ev Seltzer, Scott R. Diehl, Hance Clarke, and Joel Katz The Current Crisis in Pain Medicine 162 The Importance of Estimating Risk of Chronic Neuropathic Pain (CNP) 162 Modification of the Heritable Risk for CNP 163 The Natural History of CNP 165 Modification of Heritable Risk for CNP In Utero 166 Modifications of the Heritable Risk for CNP Across Generations 167 Postnatal Modifications of the Heritable Risk for CNP 168 Modifications of the Heritable Risk for CNP by Childhood Adverse Experiences 168 Modifications of the Heritable Risk for CNP by Prior Chronic Pain Epochs 169 Modification of the Heritable Risk for CNP by Certain Personality Traits 172 Modification of the Heritable Risk for CNP by Social Factors 172 Modification of the Heritable Risk for CNP by Diet, Medications, Smoking, and Alcohol Intake Consumed Preoperatively 174 Modification of the Heritable Risk for CNP by Climate 175 Modification of the Heritable Risk for CNP by Lifestyle 175 Modifications of the Heritable Risk for Chronic Pain by Other Diseases 176 Modifications of the Heritable Risk for CNP by Nongenetic Factors Occurring Just Prior and During the Inciting Event 176 Summary 177 Appendix: List of Abbreviations 183 Index 185 Color insert found between pages 114 and 115

Read more less

Book SynopsisNeurodevelopmental disorders arise from disturbances to various processes of brain development, which can manifest in diverse ways. They encompass many rare genetic syndromes as well as common, heritable conditions such as intellectual disability, autism, ADHD, schizophrenia and many types of epilepsy.Table of ContentsList of Contributors vii ForewordKevin J. Mitchell ix 1 The Genetic Architecture of Neurodevelopmental Disorders 1Kevin J. Mitchell 2 Overlapping Etiology of Neurodevelopmental Disorders 29Eric Kelleher and Aiden Corvin 3 The Mutational Spectrum of Neurodevelopmental Disorders 49Nancy D. Merner, Patrick A. Dion, and Guy A. Rouleau 4 The Role of Genetic Interactions in Neurodevelopmental Disorders 69Jason H. Moore and Kevin J. Mitchell 5 Developmental Instability, Mutation Load, and Neurodevelopmental Disorders 81Ronald A. Yeo and Steven W. Gangestad 6 Environmental Factors and Gene–Environment Interactions 111John McGrath 7 The Genetics of Brain Malformations 129M. Chiara Manzini and Christopher A. Walsh 8 Disorders of Axon Guidance 155Heike Blockus and Alain Chédotal 9 Synaptic Disorders 195Catalina Betancur and Kevin J. Mitchell 10 Human Stem Cell Models of Neurodevelopmental Disorders 239Peter Kirwan and Frederick J. Livesey 11 Animal Models for Neurodevelopmental Disorders 261Hala Harony-Nicolas and Joseph D. Buxbaum 12 Cascading Genetic and Environmental Effects on Development: Implications for Intervention 275Esha Massand and Annette Karmiloff-Smith 13 Human Genetics and Clinical Aspects of Neurodevelopmental Disorders 289Gholson J. Lyon and Jason O'Rawe 14 Progress Toward Therapies and Interventions for Neurodevelopmental Disorders 319Ayokunmi Ajetunmobi and Daniela Tropea Subject Index 345 Gene Index 353

Read more less

Book SynopsisThe Handbook of Behavioral Genetics and Phenotyping represents an integrative approach to neurobehavioural genetics; worldwide experts in their field will review all chapters. Advanced overviews of neurobehavioural characteristics will add immense value to the investigation of animal mutants and provide unique information about the genetics and behavioural understanding of animal models, under both normal and pathological conditions. Cross-species comparisons of neurobehavioural phenotypes will pave the way for an evolutionary understanding of behaviour. Moreover, while biological sciences are progressing towards a holistic approach to investigate the complexity of organisms (i.e., systems biology approach), an integrated analysis of behavioural phenotyping is still lacking. The Handbook of Behavioral Genetics and Phenotyping strengthens the cross-talk within disciplines that investigate the fundamental basis of behaviour and genetics. This will be the first volume in which traditioTable of ContentsList of Contributors xix Preface xxv 1 Genetic Screens in Neurodegeneration 1Abraham Acevedo Arozena and Silvia Corrochano Introduction 1 The Genetics of Neurodegenerative Disorders 2 Neurodegeneration Disease Models 4 Genetic Approaches to Discover New Genes Related to Neurodegeneration Using Disease Models 5 Saccharomyces cerevisiae 6 Caenorhabditis elegans 8 Drosophila melanogaster 9 Danio rerio 10 Mus musculus 11 Human Cellular Models and Post-mortem Material 14 The Future 14 Acknowledgments 15 References 15 2 Computational Epigenomics 19Mattia Pelizzola Background 19 Profiling and Analyzing the Methylation of Genomic DNA 19 Experimental Methods 20 Data Analysis 20 Array-based Methods 20 Sequencing-based Methods 20 Profiling and Analyzing Histone Marks 26 Experimental Methods 26 Data Analysis 27 Issues of Array-based Methods 27 Issues of NGS-based Methods 27 Integration with Other Omics Data 31 Chromatin States 32 Unraveling the Cross-talk Between Epigenetic Layers 33 References 33 3 Behavioral Phenotyping in Zebrafish: The First Models of Alcohol Induced Abnormalities 37Robert Gerlai Introduction 37 Alcohol Related Human Disorders: A Growing Unmet Medical Need 37 Unraveling Alcohol Related Mechanisms: The Importance of Animal Models 38 Face Validity: The First Step in Modeling a Human Disorder 39 Acute Effects of Alcohol in Zebrafish: A Range of Behavioral Responses 39 Chronic Alcohol Exposure Induced Behavioral Responses in Zebrafish 41 Effects of Embryonic Alcohol Exposure 42 Behavioral Phenotyping: Are We There Yet? 46 Assembling the Behavioral Test Battery 49 Concluding Remarks 50 References 50 4 How does Stress Affect Energy Balance? 53Maria Razzoli, Cheryl Cero, and Alessandro Bartolomucci Introduction 53 Stress 54 Energy Balance and Metabolic Disorders 55 Pro-adipogenic Stress Mediators 57 Pro-lipolytic Effect of Stress Mediators 57 How does Stress Affect Energy Balance? 57 Animal Models of Chronic Stress and their Impact on Energy Balance 58 Physical and Psychological (non-social) Chronic Stress Models 58 Mild Chronic Pain Models – Mild Tail Pinch, Foot Shock 58 Thermal Models – Cold and Heat Stress 64 Chronic Mild Stress Models: Chronic Mild Stress, Chronic Variable Stress, etc. 64 Restraint or Immobilization 65 Chronic Social Stress Models 66 Social Isolation, Individual Housing 66 Unstable Social Settings 66 Visible Burrow System 67 Intermittent Social Defeat (Resident/Intruder Procedure) 67 Chronic Psychosocial Stress, Sensory Contact, and Chronic Defeat stress 68 Stress, Recovery, and Maintenance: Insights on Adaptive and Maladaptive Effects of Stress 69 Molecular Mechanisms of Stress-Induced Negative and Positive Energy Balance 70 Serotonin (5-hydroxytryptamine, 5HT) 71 Orexin 71 Neuropeptide Y (NPY) 72 Ghrelin and Growth Hormone Secretagogue Receptor (GHSR) 72 Glucagon like Peptide 1 (GLP1) 73 Leptin 73 Amylin 74 Norepinephrine and β3-Adrenergic Receptor 74 Conclusion 74 References 75 5 Interactions of Experience-Dependent Plasticity and LTP in the Hippocampus During Associative Learning 91Agnès Gruart, Noelia Madroñal, María Teresa Jurado-Parras, and José María Delgado-García Introduction: Study of Learning and Memory Processes in Alert Behaving Mammals 91 Changes in Synaptic Strength During Learning and Memory 92 Classical Conditioning 92 Instrumental Conditioning 95 Changes in Synaptic Strength Evoked by Actual Learning can be Modified by Experimentally Evoked Long-term Potentiation 96 Other Experimental Constraints on the Study of the Physiological Basis of Learning Processes 100 Factors Modifying Synaptic Strength (Environment, Aging, and Brain Degenerative Diseases) 101 Different Genetic and Pharmacological Manipulations Able to Modify Synaptic Strength 103 Functional Relationships Between Experimentally Evoked LTP and Associative Learning Tasks 106 Future Perspectives 108 Context and Environmental Constraints 108 Other Forms of Learning and Memory Processes 109 Cortical Circuits and Functional States During Associative Learning 109 References 110 6 The Genetics of Cognition in Schizophrenia: Combining Mouse and Human Studies 115Diego Scheggia and Francesco Papaleo Background 115 Genetics of Schizophrenia 116 Cognitive (dys)functions in Schizophrenia 117 Translating Cognitive Symptoms in Animal Models 119 Executive Control 120 Performance in Schizophrenia 122 Animal Models 124 Working Memory 125 Performance in Schizophrenia 126 Animal Models 127 Control of Attention 128 Performance in Schizophrenia 130 Animal Models 130 Concluding Remarks 131 References 132 7 The Biological Basis of Economic Choice 143David Freestone and Fuat Balci Introduction 143 Translating from Animals to Humans 144 Reinforcement Learning in the Brain 145 Subjective Value 146 The Midbrain Dopamine System Updates Value 147 From Stimulus Value to Action Value 150 Model Based Learning 150 The Prefrontal Cortex Encodes Value 152 The Basal Ganglia Selects Actions 153 Optimal Decisions: Benchmarks for the Analysis of Choice Behavior 155 The Drift Diffusion Model 157 Temporal Risk Assessment 158 Timed-response Inhibition for Reward-rate Maximization 160 Timed Response Switching 163 Temporal Bisection 164 Numerical Risk Assessment 166 Rodent Version of Balloon Analog Risk Task 167 Conclusion 167 Acknowledgments 168 References 168 8 Interval-timing Protocols and Their Relevancy to the Study of Temporal Cognition and Neurobehavioral Genetics 179Bin Yin, Nicholas A. Lusk, and Warren H. Meck Introduction 179 Application of a Timing, Immersive Memory, and Emotional Regulation (Timer) Test Battery 190 Neural Basis of Interval Timing 191 What Makes a Mutant Mouse “Tick”? 193 Proposal of a TIMER Test Battery and Its Application in Reverse Genetics 199 Behavioral Test Battery Applications in Forward Genetics 202 Order of Behavioral Tasks 205 Location and Time of Behavioral Testing 205 Summary 205 References 206 Appendix I 226 Limitations of the individual-trials analysis for data obtained in the peak-interval (PI) procedure 226 9 Toolkits for Cognition: From Core Knowledge to Genes 229Giorgio Vallortigara and Orsola Rosa Salva Introduction 229 Core Knowledge: The Domestic Chick as a System Model 230 Numerical Competence 230 Physical Properties 230 Geometry of Space 232 Animate Agents 232 A Comparative Perspective on the Genetic and Evolutionary Bases of Social Behavior 236 From Social Experience to Genes 239 From Genes to Social Behavior 241 Future Directions 243 Conserved Mechanisms for Social Core Knowledge 243 Interactions Between Experience and Genomic Information 243 Neurogenetic Basis of Social Predispositions 243 Epigenetics and the Development of the Social Brain 244 Spatial Cognition, Another Promising Core-knowledge Domain 244 References 245 10 Quantitative Genetics of Behavioral Phenotypes 253Elzbieta Kostrzewa and Martien J.H. Kas Human Studies of Quantitative Traits 253 Mouse Studies of Quantitative Traits 254 Classical Inbred Mice 254 Quantitative Trait Loci (QTL) Analysis 254 Knock-out (KO) Mouse Lines 256 Use of Mice as Animal Model for Complex Human Traits 257 Comparative Genomic Approaches 257 Evolutionarily Conserved Behavioral Phenotypes 257 Physical Activity – Definitions and Methods of Phenotypic Measurement 258 Current Results of Quantitative Genetic Basis of PA in Humans 259 Current Results of Quantitative Genetic Basis of PA in Mice 260 KO Studies 260 QTL Studies 261 An Overlap of Genetic Findings Between the Species 261 Conclusions 265 References 265 11 Behavioral Phenotyping in Genetic Mouse Models of Autism Spectrum Disorders: A Translational Outlook 271Maria Luisa Scattoni, Caterina Michetti, Angela Caruso, and Laura Ricceri Introduction 271 Measuring Social behavior in ASD Mouse Models 272 Social Interaction Tests 272 Male-female 277 Female-female 278 Male-male 278 Social-approach 279 Sociability Test Phase 280 Social Novelty 280 Social Recognition 280 Repetitive Behavior 281 Motor Stereotypies 281 Restricted Interests 281 Behavioral Inflexibility 282 Behavioral Tests Targeting other ASD Symptoms 282 Anxiety 282 Epilepsy 283 Behavioral Phenotyping in ASD Mouse Pups 283 Future Directions: ASD Mouse Models as a Resource for Gene-environment Interaction Studies 284 Acknowledgments 285 References 285 12 Genetics of Human Sleep and Sleep Disorders 295Birgitte Rahbek Kornum The Mystery of Human Sleep 295 Sleep is Essential for Mammalian Life 295 The Function of Sleep 296 Extended Wakefulness Induces Sleep 296 Homeostatic and Circadian Regulation of Sleep and Wake 297 Adenosine and Sleep Homeostasis 298 Resistance to Sleep Loss is a Stable Phenotype 299 Genetic Markers of Response to Sleep Loss 299 A Unique Activity Pattern Characterizes the Sleeping Brain 300 Sleep Stages and Sleep Cycles 300 Genetics of the Human Sleep Electroencephalography 301 Normal Sleep Architecture is Lost in Fatal Familial Insomnia 303 Circadian Regulation of Sleep and Associated Disorders 304 Circadian Regulation of Sleep 304 Molecular Regulation of the Circadian Clock 305 The Central Circadian Clock is Entrained By Light 306 Circadian Rhythm Sleep Disorders 307 Advanced Sleep Phase Syndromes 307 Delayed Sleep Phase Syndromes 308 Short Sleep Times in Healthy Individuals 308 Destabilization of Sleep States and Narcolepsy 309 Normal Regulation of Sleep Architecture 309 Wakefulness is Associated with Cortical Activation 309 The Preoptic Area Contains Sleep-promoting Neurons 309 Mutual Inhibition Regulates Transitions Between Wake and Sleep 310 Regulation of REM Sleep 311 Narcolepsy, A Disorder of Wakefulness and REM Sleep 311 Narcolepsy with Cataplexy is Caused By Hypocretin Deficiency 312 Autoimmunity Toward Hypocretin Neurons 312 Genetic Evidence Supports the Autoimmune Hypothesis of Narcolepsy 313 Restless Legs Syndrome, A Developmental Sleep Disorder 314 Restless Legs Syndrome, A Mysterious Urge to Move 314 Restless Legs Syndrome and Dopamine Disturbances 315 Iron Deficiency Exacerbates RLS Symptoms 315 Genetic Studies Suggest Developmental Defects 316 Unresolved Issues and Future Perspectives 316 What is the Molecular and Neuroanatomical Basis for the Ultradian Rhythm of NREM-REM Sleep? 317 What is the Genetic Basis for Individual Variation in Complex Sleep Features such as Sleep Spindles and K-Complexes? 317 What is the Basis for the Individual Differences in Resistance to Sleep Loss? 317 Are Homeostatic and Circadian Mechanisms Genuinely Independent or Are They Intimately Linked? 318 What Controls the Molecular and Anatomical Diversity of Sleep Regulatory Networks Across Species? 318 References 319 13 The Endocannabinoid System in the Control of Behavior 323Edgar Soria-Gomez, Mathilde Metna, Luigi Bellocchio, Arnau Busquets-Garcia, and Giovanni Marsicano Introduction 323 Cannabinoid Effects and Endocannabinoid Functions 324 Role of the ECS in Memory Processes 325 Memory: General Background 325 Role of the ECS in Synaptic Plasticity 325 Memory Impairment Produced by Exogenous Cannabinoids 326 Cannabinoid Regulation of Memory: Neurobiological Mechanisms 327 Role of the ECS in Fear Processes 329 Fear: General Background 329 The ECS as an Endogenous Regulator of Fear Responses 331 Cannabinoid Regulation of Fear: Neurobiological Mechanisms 332 Implication of the ECS in Fear Coping Behaviors 333 Role of the ECS in Feeding Behavior 336 Feeding Behavior: General Background 336 The ECS as an Endogenous Regulator of Feeding Behavior 337 The ECS and Food Reward Circuits 338 The ECS in the Hypothalamic Appetite Network 338 The ECS in the Caudal Brainstem and Gastrointestinal Tract 340 Bimodal Control of Stimulated Food Intake by the ECS in the Brain 341 Paraventricular Hypothalamus Versus Ventral Striatum in Hypophagia induced by the ECS 342 The Olfactory Bulb and the Hyperphagic Action of the ECS 342 Conclusions 343 References 344 14 Epigenetics in Brain Development and Disease 357Elisabeth J. Radford, Anne C. Ferguson-Smith, and Sacri R. Ferrón Introduction 357 Epigenetics and Neurodevelopment 358 Histone Modifications 358 DNA Methylation 361 Hydroxymethylation 364 Genomic Imprinting 364 Non-coding RNAs 365 Neurodevelopmental Disorders with an Epigenetic Basis 366 Rett Syndrome 366 Coffin–Lowry Syndrome 367 Rubinstein–Taybi Syndrome 367 Alpha-thalassemia Mental Retardation Syndrome 367 Imprinted Neurodevelopmental Disorders 368 Trinucleotide Repeat Disorders 368 Fragile X Syndrome 370 Friedreich’s Ataxia 370 Myotonic Dystrophy 371 Huntington’s Disease (HD) 371 Epigenetics of Neurodegenerative Disorders 372 Parkinson´s Disease (PD) 372 Alzheimer´s Disease (AD) 373 The Impact of the Environment on the Epigenome 374 Epigenetic Therapy in Neurodevelopment 375 Untargeted Treatment 375 Targeted Epigenetic Modulation 377 Concluding Remarks 377 Acknowledgments 377 References 378 15 Impact of Postnatal Manipulations on Offspring Development in Rodents 395Diego Oddi, Alessandra Luchetti, and Francesca Romana D’Amato Introduction 395 Early Postnatal Environment in Laboratory Altricial Rodents 396 Rodents’ Responses to Postnatal Environment and Early Manipulations 397 Assessing Pups’ Responses to Postnatal Environment and Early Manipulation 397 Neonatal Ultrasonic Calls: Isolation-induced Vocalizations and Maternal Potentiation 397 Searching for Social Contact: Homing and Huddling Behaviors 398 Early-life Environment and Stress-Response 398 Separation from the Mother 399 Mother’s Stress 400 The Cross-fostering Paradigm 401 Repeated Cross-fostering as a Model of Early Maternal Environment Instability 403 Environmental Enrichment 405 Conclusions 406 References 407 16 Exploring the Roles of Genetics and the Epigenetic Mechanism DNA Methylation in Honey Bee (Apis Mellifera) Behavior 417Christina M. Burden and Jonathan E. Bobek Introduction 417 Genetics of Adult Honey Bee Biology and Behavior 418 Nurse to Forager Transition 418 Forager Preference 420 Techniques for Investigating the Genetic Bases of Behavior 420 QTL Mapping 421 RNA Techniques 421 Microarrays 421 RNA Sequencing 422 Experimentally Modulating the Genes Correlated with Specific Behaviors to Test Causality 422 DNA Methylation and Honey Bee Behavior 423 Honey Bee DNA Methylation Machinery and Genome-Wide Patterns 423 DNA Methylation and Task Specialization 424 DNA Methylation and Memory Consolidation 425 Techniques for Detecting and Assaying DNA Methylation 426 The Technological Bases for Most DNA Methylation Assays 426 Methylation-specific Restriction Endonucleases 426 Protein-mediated Precipitation of Methylated DNA 428 Bisulfite Conversion 428 Assaying Single CpGs, Short Sequences, and Target Regions 429 Analyzing Genome-wide DNA Methylation Patterns: Microarray-based Methodologies 431 Analyzing Genome-wide DNA Methylation Patterns: Sequencing-based Methodologies 432 Techniques for Manipulating DNA Methylation 434 Pharmacological Manipulation of DNA Methylation 434 RNA Interference as a DNMT Blockade 434 Concluding Remarks and Future Perspectives 435 References 436 17 Genetics and Neuroepigenetics of Sleep 443Glenda Lassi and Federico Tinarelli Defining Sleep 443 Sleep is Genetically Determined 445 EEG and Heritable Traits 445 Sleep Disorders and Genes 446 Sleep and Gene Expression 447 Epigenetics 448 DNA Methylation 450 Posttranslational Modifications (PTMs) 450 RNA interference 452 Neuroepigenetics 453 Two Neurodevelopmental Disorders with Opposing Imprinting Profiles and Opposing Sleep Phenotypes 453 Neuroepigenetics of Sleep 454 Fruit Fly 454 Rodent Models 454 Human Beings 456 Sleep and Parent-of-origin Effects 458 Conclusions 460 References 460 18 Behavioral Phenotyping Using Optogenetic Technology 469Stephen Glasgow, Carolina Gutierrez Herrera, and Antoine Adamantidis Introduction 469 Microbial Opsins 470 Fast Excitation Using Channelrhodopsin-2 and Its Variants 470 Fast Optical Silencing 474 Alternative strategies for cell-type specific modulation of neural activity 476 Targeting systems 476 Light Delivery in the Animal Brain 478 Recording Light-evoked Neuronal Activity 479 Behavioral Phenotyping 479 In-vivo Optogenetics: Defining Circuits 480 Perspectives 484 Acknowledgments 484 References 484 19 Phenotyping Sleep: Beyond EEG 489Sibah Hasan, Russell G. Foster, and Stuart N. Peirson Sleep Research 489 Phenotyping Sleep in Humans 490 Introduction 490 Actigraphy 490 Cardiorespiratory Signals 491 EEG 492 Phenotyping Sleep in Animal Models 494 Introduction 494 EEG 494 Introduction 494 Tethered EEG 496 Telemetered EEG 496 NeuroLogger EEG 498 Beyond EEG 498 Infrared Beam Break 499 Movement Based on Implanted Magnets 499 Piezo-electric Sensors 499 Video Tracking 500 Future Perspectives 501 Acknowledgements 502 References 502 20 A Cognitive Neurogenetics Screening System with a Data-Analysis Toolbox 507C.R. Gallistel, Fuat Balci, David Freestone, Aaron Kheifets, and Adam King Introduction 507 Mechanisms, Not Procedures 508 Functional Specificity 508 No Group Averages 509 Physiologically Meaningful Measures 509 Importance of Large-scale Screening and Minimal Handling 511 Utilizable Archived Data with Intact Data Trails 511 The System 512 The Toolbox 513 Core Commands 516 Powerful Graphics Commands 517 Results 518 Summary 523 References 524 21 Mapping the Connectional Architecture of the Rodent Brain with fMRI 527Adam J. Schwarz and Alessandro Gozzi Introduction 527 MRI Mapping of Functional Connectivity in the Rodent Brain 528 Networks of Functional Covariance 528 Connectivity of Neurotransmitter Systems 529 The Dopaminergic System 529 The Serotonergic System 531 Resting State BOLD fMRI 532 Connectivity Networks of the Rodent Brain 533 Do Rodent Brains have a Default Mode Network? 536 Use of Anesthesia and Other Methodological Considerations 539 Transgenic Models: Genetic Manipulation of Functional Connectivity Patterns 541 Future Perspectives 543 References 545 22 Cutting Edge Approaches for the Identification and the Functional Investigation of miRNAs in Brain Science 553Emanuela de Luca, Federica Marinaro, Francesco Niola, and Davide De Pietri Tonelli Introduction 553 History 553 Biology and Functions in the Brain 553 Identification of Novel MicroRNAs in the Brain 555 miRNA Extraction and Purification 556 miRNA Cloning 556 Computational Identification of Novel miRNAs 557 RNA Sequencing (RNA-Seq) 558 miRNA expression analysis in the brain 559 miRNA profiling 559 Analysis of miRNA Expression in Tissue 559 Target Identification 560 Computational Identification of Targets 561 Proteomics 561 RISC-associated miRNA Targets 562 RNomics 563 miRNA Manipulation/Target Validation 565 miRNA Inhibition 565 miRNA Over-expression 566 Target Validation 567 New Frontiers in Small RNA-based Technologies to Cure Nervous System Deficits 567 Use of miRNAs in Gene Therapy 567 Use of miRNAs in Gene Therapy in the Brain Requires Improved Delivery Strategies 571 Conclusion and Perspectives 572 Are Circulating miRNAs Novel Biomarkers for Brain Diseases? 572 Use of miRNAs in Cell Reprogramming Technology 573 Are miRNAs Just the “Tip of the Iceberg”? Emerging Classes of Noncoding RNAs and Novel Scenarios 574 Acknowledgments 575 Competing Financial Interests 575 References 575 Index 585

Read more less

Book SynopsisMolecular Neuroendocrinology: From Genome to Physiology, provides researchers and students with a critical examination of the steps being taken to decipher genome complexity in the context of the expression, regulation and physiological functions of genes in neuroendocrine systems. The 19 chapters are divided into four sectors: A) describes and explores the genome, its evolution, expression and the mechanisms that contribute to protein, and hence biological, diversity. B) discusses the mechanisms that enhance peptide and protein diversity beyond what is encoded in the genome through post-translational modification. C) considers the molecular tools that today's neuroendocrinologists can use to study the regulation and function of neuroendocrine genes within the context of the intact organism. D) presents a range of case studies that exemplify the state-of-the-art application of genomic technologies in physiological and behavioural experiments that seek to better understTable of ContentsList of Contributors, vii Series Preface, xi About the Companion Website, xiii Introduction 1 David Murphy and Harold Gainer Part A Genome and Genome Expression 1 Evolutionary Aspects of Physiological Function and Molecular Diversity of the Oxytocin/Vasopressin Signaling System 5 Zita Liutkevicǐūtė and Christian W. Gruber 2 The Neuroendocrine Genome: Neuropeptides and Related Signaling Peptides 25 J. Peter H. Burbach 3 Transcriptome Dynamics 57 David A. Carter, Steven L. Coon, Yoav Gothilf , Charles K. Hwang, Leming Shi, P. Michael Iuvone, Stephen Hartley, James C. Mullikin, Peter Munson, Cong Fu, Samuel J. Clokie, and David C. Klein 4 New Players in the Neuroendocrine System: A Journey Through the Non‐coding RNA World 75 Yongping Wang, Edward A. Mead, Austin P. Thekkumthala, and Andrzej Z. Pietrzykowski 5 Transcription Factors Regulating Neuroendocrine Development, Function, and Oncogenesis 97 Judy M. Coulson and Matthew Concannon 6 Epigenetics 121 Chris Murgatroyd Part B Proteins, Posttranslational Mechanisms, and Receptors 7 Proteome and Peptidome Dynamics 141 Lloyd D. Fricker 8 Neuropeptidomics: The Characterization of Neuropeptides and Hormones in the Nervous and Neuroendocrine Systems 155 Ning Yang, Samuel J. Irving, Elena V. Romanova, Jennifer W. Mitchell, Martha U. Gillette, and Jonathan V. Sweedler 9 Posttranslational Processing of Secretory Proteins 171 Nabil G. Seidah and Johann Guillemot 10 Neuropeptide Receptors 195 Stephen J. Lolait, James A. Roper, Georgina G.J. Hazell, Yunfei Li, Fiona J. Thomson, and Anne‐Marie O’Carroll Part C The Tool Kit 11 Germline Transgenesis 219 Jim Pickel 12 Somatic Transgenesis (Viral Vectors) 243 Valery Grinevich, H. Sophie Knobloch‐Bollmann, Lena C. Roth, Ferdinand Althammer, Andrii Domanskyi, Ilya A. Vinnikov, Marina Eliava, Megan Stanifer, and Steeve Boulant 13 Optogenetics Enables Selective Control of Cellular Electrical Activity 275 Ryuichi Nakajima, Sachiko Tsuda, Jinsook Kim, and George J. Augustine 14 Non‐Mammalian Models for Neurohypophysial Peptides 301 Einav Wircer, Shifra Ben‐Dor, and Gil Levkowitz Part D Case Studies – Integration and Translation 15 Osmoregulation 331 David Murphy, Jose Antunes‐Rodrigues, and Harold Gainer 16 Food Intake, Circuitry, and Energy Metabolism 355 Giles S.H. Yeo 17 Stress Adaptation and the Hypothalamic‐Pituitary‐Adrenal Axis 375 Greti Aguilera 18 Neuroendocrine Control of Female Puberty: Genetic and Epigenetic Regulation 405 Alejandro Lomniczi and Sergio R. Ojeda 19 Oxytocin, Vasopressin, and Diversity in Social Behavior 423 Lanikea B. King and Larry J. Young Glossary 443 Index 459

Read more less

Book SynopsisThe analysis and interpretation of data is fundamental to the subject of genetics and forms a compulsory part of the undergraduate genetics curriculum.Table of ContentsPreface ix Acknowledgements xi How to Use this Book xiii Section 1: Introductory 1.1 Grandma’s Secret 3 1.2 Tiger! Tiger! 7 1.3 Anticipation 13 1.4 Budgie Hell 17 1.5 Friends Reunited 21 1.6 The Footballer, his Wife, their Kids and her Lover 25 1.7 Give Peas a Chance 29 1.8 Noah’s ARC 35 1.9 The Mysterious Disappearance of Midnight 39 1.10 RANCID 45 Section 2: Intermediate 2.1 Otto’s Finger 51 2.2 The Mystery of Muckle Morag 57 2.3 Drosophila hogwashii 63 2.4 The Curse of Lilyrot 69 2.5 Strawberry Fields Forever 75 2.6 The Mystery of Trypton Fell 81 2.7 Sir Henry’s Enormous Chest 89 2.8 Pandemonium 93 2.9 My Imperfect Cousin 101 2.10 The Curse of the WERE Rabbits 107 Section 3: Advanced 3.1 The Legend of Neptune’s Cutlass 117 3.2 The Devil’s Pumpkin 129 3.3 Gravity 141 3.4 Kate and William, a Love Story 151 3.5 The Titanians 163 3.6 Once Bitten, Twice Shy 175 3.7 Red‐Crested Dragons of Mythological Island 185 3.8 I Scream! 197 3.9 The Nuns of Gaborone 209 3.10 Poissons Sans Yeux 221 Answers 233 List of Figures 361

Read more less

Book SynopsisA comprehensive and authoritative compilation of up-to-date developments in stem cell research and its use in toxicology and medicine Presented by internationally recognized investigators in this exciting field of scientific researchProvides an insight into the current trends and future directions of research in this rapidly developing new fieldA valuable and excellent source of authoritative and up-to-date information for researchers, toxicologists, drug industry, risk assessors and regulators in academia, industry and governmentTable of ContentsList of Contributors xx Preface xxvi Acknowledgements xxvii PART I 1 1 Introduction 3 Saura C. Sahu References 4 2 Application of Stem Cells and iPS Cells in Toxicology 5 Maria Virginia Caballero, Ramon A. Espinoza‐Lewis, and Manila Candiracci 2.1 Introduction 5 2.2 Significance 6 2.3 Stem Cell (SC) Classification 7 2.4 Stem Cells and Pharmacotoxicological Screenings 8 2.5 Industrial Utilization Showcases Stem Cell Technology as a Research Tool 8 2.6 Multipotent Stem Cells (Adult Stem Cells) Characteristics and Current Uses 9 2.7 Mesenchymal Stem Cells (Adult Stem Cells) 10 2.8 Hematopoietic Stem Cells (Adult Stem Cells) 11 2.9 Cardiotoxicity 12 2.10 Hepatotoxicity 15 2.11 Epigenetic Profile 17 2.12 Use of SC and iPSC in Drug Safety 18 2.13 Conclusions and Future Applications 19 Acknowledgments 19 References 19 3 Stem Cells: A Potential Source for High Throughput Screening in Toxicology 26 Harish K Handral, Gopu Sriram, and Tong Cao 3.1 Introduction 26 3.2 Stem Cells 27 3.3 High Throughput Screening (HTS) 31 3.4 Need for a Stem Cell Approach in High Throughput Toxicity Studies 37 3.5 Role of Stem Cells in High Throughput Screening for Toxicity Prediction 38 3.6 Conclusion 40 Acknowledgement 41 Disclosure Statement 41 Author’s Contribution 41 References 41 4 Human Pluripotent Stem Cells for Toxicological Screening 50 Lili Du and Dunjin Chen 4.1 Introduction 50 4.2 The Biological Characteristics of hPSCs 51 4.3 Screening of Embryotoxic Effects using hPSCs 52 4.4 The Potential of hPSC‐Derived Neural Lineages in Neurotoxicology 55 4.5 The Potential of hPSC ‐Derived Cardiomyocytes in Cardiotoxicity 60 4.6 The Potential of hPSC‐Derived Hepatocytes in Hepatotoxicity 62 4.7 Future Challenges and Perspectives for Embryotoxicity and Developmental Toxicity Studies using hPSCs 65 Acknowledgments 66 References 67 5 Effects of Culture Conditions on Maturation of Stem Cell‐Derived Cardiomyocytes 71 Deborah K. Hansen, Amy L. Inselman, and Xi Yang 5.1 Introduction 71 5.2 Lengthening Culture Time 75 5.3 Substrate Stiffness 76 5.4 Structured Substrates 78 5.5 Conclusions 82 Disclaimer 82 References 83 6 Human Stem Cell‐Derived Cardiomyocyte In Vitro Models for Cardiotoxicity Screening 85 Tracy Walker, Kate Harris, Evie Maifoshie, and Khuram Chaudhary 6.1 Introduction 85 6.2 Overview of hPSC‐Derived Cardiomyocytes 88 6.3 Human PSC‐CM Models for Cardiotoxicity Investigations 90 6.4 Conclusions and Future Direction 112 References 112 7 Disease‐Specific Stem Cell Models for Toxicological Screenings and Drug Development 122 Matthias Jung, Juliane‐Susanne Jung, Jovita Schiller, and Insa S. Schroeder 7.1 Evidence for Stem Cell‐Based Drug Development and Toxicological Screenings in Psychiatric Diseases, Cardiovascular Diseases and Diabetes 122 7.2 Disease‐Specific Stem Cell Models for Drug Development in Psychiatric Disorders 127 7.3 Stem Cell Models for Cardiotoxicity and Cardiovascular Disorders 132 7.4 Stem Cell Models for Toxicological Screenings of EDCs 133 References 135 8 Three‐Dimensional Culture Systems and Humanized Liver Models Using Hepatic Stem Cells for Enhanced Toxicity Assessment 145 Ran‐Ran Zhang, Yun‐Wen Zheng, and Hideki Taniguchi 8.1 Introduction 145 8.2 Hepatic Cell Lines and Primary Human Hepatocytes 146 8.3 Embryonic Stem Cells and Induced Pluripotent Stem‐Cell Derived Hepatocytes 147 8.4 Ex Vivo: Three‐Dimensional and Multiple‐Cell Culture System 148 8.5 In Vivo: Humanized Liver Models 149 8.6 Summary 150 Acknowledgments 150 References 150 9 Utilization of In Vitro Neurotoxicity Models in Pre‐Clinical Toxicity Assessment 155 Karin Staflin, Dinah Misner, and Donna Dambach 9.1 Introduction 155 9.2 Current Models of Drug‐Related Clinical Neuropathies and Effects on Electrophysiological Function 159 9.3 Cell Types that Can Potentially Be Used for In Vitro Neurotoxicity Assessment in Drug Development 162 9.4 Utility of iPSC Derived Neurons in In Vitro Safety Assessment 167 9.5 Summary of Key Points for Consideration in Neurotoxicity Assay Development 170 9.6 Concluding Remarks 172 References 172 10 A Human Stem Cell Model for Creating Placental Syncytiotrophoblast, the Major Cellular Barrier that Limits Fetal Exposure to Xenobiotics 179 R. Michael Roberts, Shinichiro Yabe, Ying Yang, and Toshihiko Ezashi 10.1 Introduction 179 10.2 General Features of Placental Structure 180 10.3 The Human Placenta 180 10.4 Human Placental Cells in Toxicology Research 182 10.5 Placental Trophoblast Derived from hESC 183 10.6 Isolation of Syncytial Areas from BAP‐Treated H1 ESC Colonies 185 10.7 Developmental Regulation of Genes Encoding Proteins Potentially Involved in Metabolism of Xenobiotics 185 10.8 Concluding Remarks 191 Acknowledgments 192 References 192 11 The Effects of Endocrine Disruptors on Mesenchymal Stem Cells 196 Marjorie E. Bateman, Amy L. Strong, John McLachlan, Matthew E. Burow, and Bruce A. Bunnell 11.1 Mesenchymal Stem Cells 196 11.2 Endocrine Disruptors 198 11.3 Pesticides 201 11.4 Alkyl Phenols and Derivatives 206 11.5 Bisphenol A 211 11.6 Polychlorinated Biphenyls 216 11.7 Phthalates 221 11.8 Areas for Future Research 225 11.9 Conclusions 226 Abbreviations 226 References 228 12 Epigenetic Landscape in Embryonic Stem Cells 238 Xiaonan Sun, Nicholas Spellmon, Joshua Holcomb, Wen Xue, Chunying Li, and Zhe Yang 12.1 Introduction 238 12.2 DNA Methylation in ESCs 239 12.3 Histone Methylation in ESCs 240 12.4 Chromatin Remodeling and ESCs Regulation 241 12.5 Concluding Remarks 242 Acknowledgements 243 References 243 PART II 247 13 The Effect of Human Pluripotent Stem Cell Platforms on Preclinical Drug Development 249 Kevin G. Chen 13.1 Introduction 249 13.2 Core Signaling Pathways Underlying hPSC Stemness and Differentiation 250 13.3 Basic Components of In Vitro and Ex Vivo hPSC Platforms 251 13.4 Diverse hPSC Culture Platforms for Drug Discovery 252 13.5 Representative Analyses of hPSC‐Based Drug Discovery 255 13.6 Current Challenges and Future Considerations 257 13.7 Concluding Remarks 260 Acknowledgments 260 References 260 14 Generation and Application of 3D Culture Systems in Human Drug Discovery and Medicine 265 H. Rashidi and D.C. Hay 14.1 Introduction 265 14.2 Traditional Scaffold‐Based Tissue Engineering 266 14.3 Scaffold‐Free 3D Culture Systems 269 14.4 Modular Biofabrication 270 14.5 3D Bioprinting 270 14.6 Tissue Modelling and Regenerative Medicine Applications of Pluripotent Stem Cells 272 14.7 Applications in Drug Discovery and Toxicity 275 14.8 Conclusions 278 References 278 15 Characterization and Therapeutic Uses of Adult Mesenchymal Stem Cells 288 Juliann G. Kiang 15.1 Introduction 288 15.2 MSC Characterization 289 15.3 MSCs and Tissue or Organ Therapy 293 15.4 Conclusions 298 Acknowledgments 298 References 298 16 Stem Cell Therapeutics for Cardiovascular Diseases 303 Yuning Hou, Xiaoqing Guan, Shukkur M. Farooq, Xiaonan Sun, Peijun Wang, Zhe Yang, and Chunying Li 16.1 Introduction 303 16.2 Types of Stem/Progenitor Cell‐Derived Endothelial Cells 304 16.3 EPC and Other Stem/Progenitor Cell Therapy in CVDs 306 16.4 Strategies and Approaches for Enhancing EPC Therapy in CVDs 306 16.5 Concluding Remarks 315 Acknowledgments 316 References 316 17 Stem‐Cell‐Based Therapies for Vascular Regeneration in Peripheral Artery Diseases 324 David M Smadja and Jean‐Sébastien Silvestre 17.1 Sources of Stem Cells for Vascular Regeneration 325 17.2 Canonic Mechanisms Governing Vascular Stem Cells Therapeutic Potential 329 17.3 Stem‐Cell‐Based Therapies in Patients with Peripheral Artery Disease 333 References 337 18 Gene Modified Stem/Progenitor‐Cell Therapy for Ischemic Stroke 347 Yaning Li, Guo‐Yuan Yang, and Yongting Wang 18.1 Introduction 347 18.2 Gene Modified Stem Cells for Ischemic Stroke 348 18.3 Gene Transfer Vectors 354 18.4 Unsolved Issues for Gene‐Modified Stem Cells in Ischemic Stroke 356 18.5 Conclusion 356 Abbreviations 356 Acknowledgments 357 References 357 19 Role of Stem Cells in the Gastrointestinal Tract and in the Development of Cancer 363 Pengyu Huang, Bin Li, and Yun‐Wen Zheng 19.1 Introduction 363 19.2 GI Development and Regeneration 365 19.3 GI Tumorigenesis and Stemness Gene Expression 367 19.4 Toxicants and Other Stress Trigger Epigenetic Changes, Dedifferentiation, and Carcinogenesis 368 19.5 Summary and Perspective 369 Acknowledgments 369 References 370 20 Cancer Stem Cells: Concept, Significance, and Management 375 Haseeb Zubair, Shafquat Azim, Sanjeev K. Srivastava, Arun Bhardwaj, Saravanakumar Marimuthu, Mary C. Patton, Seema Singh, and Ajay P. Singh 20.1 Introduction 375 20.2 Stem Cells and Cancer: Historical Perspective 376 20.3 Cancer Stem Cells 377 20.4 Identification and Isolation of CSCs 382 20.5 Pathological Significance of Cancer Stem Cells 388 20.6 Pathways Regulating Cancer Stem Cells 389 20.7 Therapeutic Strategies Targeting Cancer Stem Cells 394 20.8 Conclusion and Future Directions 399 References 400 21 Stem Cell Signaling in the Heterogeneous Development of Medulloblastoma 414 Joanna Triscott and Sandra E. Dunn 21.1 Brain Tumor Cancer Stem Cells 414 21.2 Medulloblastoma 416 21.3 Hijacking Cerebellar Development 417 21.4 Molecular Classification of MB 420 21.5 Mouse Models and Cell of Origin 424 21.6 Additional Drivers of MB 425 21.7 Repurposing Off‐Patent Drugs 426 21.8 Emerging Therapies for MB 428 21.9 Conclusion 429 Acknowledgments 429 References 429 22 Induced Pluripotent Stem Cell‐Derived Outer-Blood‐Retinal Barrier for Disease Modeling and Drug Discovery 436 Jun Jeon, Nathan Hotaling, and Kapil Bharti 22.1 Introduction 436 22.2 The Outer Blood‐Retinal Barrier 437 22.3 iPSC‐Based Model of the Outer-Blood‐Retinal-Barrier 439 22.4 iPSC Based OBRB Disease Models 442 22.5 Applications of iPSC‐Based Ocular Disease Models for Drug Discovery 448 22.6 Conclusion and Future Directions 451 References 451 23 Important Considerations in the Therapeutic Application of Stem Cells in Bone Healing and Regeneration 458 Hoda Elkhenany, Shawn Bourdo, Alexandru Biris, David Anderson, and Madhu Dhar 23.1 Introduction 458 23.2 Stem Cells, Progenitor Cells, Mesenchymal Stem Cells 459 23.3 Scaffolds 461 23.4 Animal Models in Bone Healing and Regeneration 464 23.5 Conclusions and Future Directions 472 References 472 24 Stem Cells from Human Dental Tissue for Regenerative Medicine 481 Junjun Liu and Shangfeng Liu 24.1 Introduction 481 24.2 Dental Stem Cells 482 24.3 Potential Clinical Applications 488 24.4 Safety 492 24.5 Dental Stem Cell Banking 493 24.6 Conclusions and Perspective 494 References 495 25 Stem Cells in the Skin 502 Hongwei Wang, Zhonglan Su, Shiyu Song, Ting Su, Mengyuan Niu, Yaqi Sun, and Hui Xu 25.1 Introduction 502 25.2 Stem Cells in the Skin 503 25.3 Isolation and the Biological Markers of Skin Stem Cells 506 25.4 Skin Stem Cell Niches 508 25.5 Signaling Control of Stem Cell Differentiation 510 25.6 Stem Cells in Skin Aging 514 25.7 Stem Cells in Skin Cancer 516 25.8 Medical Applications of Skin Stem Cells 518 25.9 Conclusions and Future Directions 520 References 521 Author Index 527 Subject Index 529

Read more less

Book SynopsisThis book provides a comprehensive foundation for the contemporary application of pharmacokinetics and pharmacodynamics. The second edition updates and strengthens existing chapters and adds new topics to address current needs including physiologically based pharmacokinetic modeling, pharmacogenomics and predicting drug-drug interactions.Table of ContentsPreface xix Contributors xxi 1 Introduction to Pharmacokinetics and Pharmacodynamics 1Sara E. Rosenbaum 1.1 Introduction: Drugs and Doses 2 1.2 Introduction to Pharmacodynamics 3 1.2.1 Drug Effects at the Site of Action 3 1.2.2 Agonists, Antagonists, and Concentration–Response Relationships 6 1.3 Introduction to Pharmacokinetics 9 1.3.1 Plasma Concentration of Drugs 9 1.3.2 Processes in Pharmacokinetics 11 1.4 Dose–Response Relationships 12 1.5 Therapeutic Range 14 1.5.1 Determination of the Therapeutic Range 15 1.6 Summary 18 Reference 18 2 Passage of Drugs Through Membranes 19Sara E. Rosenbaum 2.1 Introduction 20 2.2 Structure and Properties of Membranes 20 2.3 Passive Diffusion 21 2.3.1 Transcellular Passive Diffusion 23 2.3.2 Paracellular Passive Diffusion 25 2.4 Carrier-Mediated Processes: Transport Proteins 26 2.4.1 Uptake Transporters: SLC Superfamily 27 2.4.2 Efflux Transporters: ABC Superfamily 29 2.4.3 Characteristics of Transporter Systems 31 2.4.4 Simulation Exercise 32 2.4.5 Clinical Examples of Transporter Involvement in Drug Response 32 References 33 3 Drug Administration and Drug Absorption 35Steven C. Sutton 3.1 Introduction: Local and Systemic Drug Administration 36 3.2 Routes of Drug Administration 37 3.2.1 Common Routes of Local Drug Administration 37 3.2.2 Common Routes of Systemic Drug Administration 38 3.3 Overview of Oral Absorption 41 3.3.1 Anatomy and Physiology of the Oral-Gastric-Intestinal Tract and Transit Time 41 3.4 Extent of Drug Absorption 44 3.4.1 Bioavailability Factor 44 3.4.2 Individual Bioavailability Factors 45 3.5 Determinants of the Fraction of the Dose Absorbed (F) 46 3.5.1 Disintegration 46 3.5.2 Dissolution 46 3.5.3 Formulation Excipients 50 3.5.4 Adverse Events within the Gastrointestinal Lumen 50 3.5.5 Transcellular Passive Diffusion 53 3.5.6 Particulate Uptake 53 3.5.7 Paracellular Passive Diffusion 53 3.5.8 Uptake and Efflux Transporters 54 3.5.9 Presystemic Intestinal Metabolism or Extraction 58 3.5.10 Presystemic Hepatic Metabolism or Extraction 60 3.6 Factors Controlling the Rate of Drug Absorption 61 3.6.1 Dissolution-Controlled Absorption 63 3.6.2 Membrane Penetration-Controlled Absorption 63 3.6.3 Overall Rate of Drug Absorption 63 3.7 Biopharmaceutics Classification System 64 3.7.1 Intestinal Reserve Length 64 3.7.2 Biopharmaceutics Classification System (BCS) 64 3.7.3 Biopharmaceutics Drug Disposition Classification System (BDDCS) 65 3.8 Food Effects 65 Problems 66 References 67 4 Drug Distribution 71Sara E. Rosenbaum 4.1 Introduction 72 4.2 Extent of Drug Distribution 72 4.2.1 Distribution Volumes 74 4.2.2 Tissue Binding Plasma Protein Binding and Partitioning: Concentrating Effects 75 4.2.3 Assessment of the Extent of Drug Distribution: Apparent Volume of Distribution 76 4.2.4 Plasma Protein Binding 82 4.3 Rate of Drug Distribution 89 4.3.1 Perfusion-Controlled Drug Distribution 90 4.3.2 Diffusion or Permeability-Controlled Drug Distribution 93 4.4 Distribution of Drugs to the Central Nervous System 93 Problems 96 References 98 5 Drug Elimination and Clearance 99Sara E. Rosenbaum 5.1 Introduction 100 5.1.1 First-Order Elimination 101 5.1.2 Determinants of the Elimination Rate Constant and the Half-Life 102 5.2 Clearance 102 5.2.1 Definition and Determinants of Clearance 102 5.2.2 Total Clearance, Renal Clearance, and Hepatic Clearance 104 5.2.3 Relationships among Clearance, Volume of Distribution, Elimination Rate Constant, and Half-Life 105 5.2.4 Primary and Secondary Parameters 106 5.2.5 Measurement of Total Body Clearance 106 5.3 Renal Clearance 108 5.3.1 Glomerular Filtration 109 5.3.2 Tubular Secretion 110 5.3.3 Tubular Reabsorption 113 5.3.4 Putting Meaning into the Value of Renal Clearance 114 5.3.5 Measurement of Renal Clearance 115 5.3.6 Fraction of the Dose Excreted Unchanged 118 5.4 Hepatic Elimination and Clearance 119 5.4.1 Phase I and Phase II Metabolism 120 5.4.2 The Cytochrome P450 Enzyme System 121 5.4.3 Glucuronidation 122 5.4.4 Metabolism-Based Drug–Drug Interactions 122 5.4.5 Hepatic Drug Transporters and Drug–Drug Interactions 125 5.4.6 Kinetics of Drug Metabolism 127 5.4.7 Hepatic Clearance and Related Parameters 128 Problems 139 References 142 6 Compartmental Models in Pharmacokinetics 145Sara E. Rosenbaum 6.1 Introduction 146 6.2 Expressions for Component Parts of the Dose–Plasma Concentration Relationship 146 6.2.1 Effective Dose 146 6.2.2 Rate of Drug Absorption 147 6.2.3 Rate of Drug Elimination 148 6.2.4 Rate of Drug Distribution 148 6.3 Putting Everything Together: Compartments and Models 149 6.3.1 One-Compartment Model 149 6.3.2 Two-Compartment Model 150 6.3.3 Three-Compartment Model 150 6.4 Examples of Complete Compartment Models 152 6.4.1 Intravenous Bolus Injection in a One-Compartment Model with First-Order Elimination 152 6.4.2 Intravenous Bolus Injection in a Two-Compartment Model with First-Order Elimination 153 6.4.3 First-Order Absorption in a Two-Compartment Model with First-Order Elimination 154 6.5 Use of Compartmental Models to Study Metabolite Pharmacokinetics 155 6.6 Selecting and Applying Models 156 Problems 157 Suggested Readings 157 7 Pharmacokinetics of an Intravenous Bolus Injection in a One-Compartment Model 159Sara E. Rosenbaum 7.1 Introduction 160 7.2 One-Compartment Model 160 7.3 Pharmacokinetic Equations 162 7.3.1 Basic Equation 162 7.3.2 Half-Life 163 7.3.3 Time to Eliminate a Dose 163 7.4 Simulation Exercise 163 7.5 Application of the Model 165 7.5.1 Predicting Plasma Concentrations 165 7.5.2 Duration of Action 166 7.5.3 Value of a Dose to Give a Desired Initial Plasma Concentration 167 7.5.4 Intravenous Loading Dose 167 7.6 Determination of Pharmacokinetic Parameters Experimentally 168 7.6.1 Study Design for the Determination of Parameters 168 7.6.2 Pharmacokinetic Analysis 169 7.7 Pharmacokinetic Analysis in Clinical Practice 173 Problems 174 Suggested Reading 176 8 Pharmacokinetics of an Intravenous Bolus Injection in a Two-Compartment Model 177Sara E. Rosenbaum 8.1 Introduction 178 8.2 Tissue and Compartmental Distribution of a Drug 179 8.2.1 Drug Distribution to the Tissues 179 8.2.2 Compartmental Distribution of a Drug 180 8.3 Basic Equation 181 8.3.1 Distribution: A, α, and the Distribution t1/2 182 8.3.2 Elimination: B, β, and the β t1/2 182 8.4 Relationship Between Macro and Micro Rate Constants 183 8.5 Primary Pharmacokinetic Parameters 183 8.5.1 Clearance 184 8.5.2 Distribution Clearance 184 8.5.3 Volume of Distribution 186 8.6 Simulation Exercise 188 8.7 Determination of the Pharmacokinetic Parameters of the Two-Compartment Model 191 8.7.1 Determination of Intercepts and Macro Rate Constants 191 8.7.2 Determination of the Micro Rate Constants: k12 k21 and k10 193 8.7.3 Determination of the Primary Pharmacokinetic Parameters 193 8.8 Clinical Application of the Two-Compartment Model 194 8.8.1 Measurement of the Elimination Half-Life in the Postdistribution Phase 194 8.8.2 Determination of the Loading Dose 195 8.8.3 Evaluation of a Dose: Monitoring Plasma Concentrations and Patient Response 197 Problems 197 Suggested Readings 199 9 Pharmacokinetics of Extravascular Drug Administration 201Dr. Steven C. Sutton 9.1 Introduction 202 9.2 First-Order Absorption in a One-Compartment Model 203 9.2.1 Model and Equations 203 9.2.2 Parameter Determination 205 9.2.3 Absorption Lag Time 210 9.2.4 Flip-Flop Model and Sustained-Release Preparations 212 9.2.5 Determinants of Tmax and Cmax 212 9.3 Modified Release and Gastric Retention Formulations 214 9.3.1 Impact of the Stomach 214 9.3.2 Moisture in the Gastrointestinal Tract 215 9.4 Bioavailability 215 9.4.1 Bioavailability Parameters 215 9.4.2 Absolute Bioavailability 217 9.4.3 Relative Bioavailability 217 9.4.4 Bioequivalence 217 9.4.5 Single-Dose Crossover Parallel and Steady-State Study Designs 219 9.4.6 Example Bioavailability Analysis 219 9.5 In Vitro-In Vivo Correlation 219 9.5.1 Definitions 219 9.5.2 Assumptions 220 9.5.3 Utility 220 9.5.4 Immediate Release IVIVC 220 9.5.5 Modified Release IVIVC 221 9.6 Simulation Exercise 222 Problems 223 References 224 10 Introduction to Noncompartmental Analysis 225Sara E. Rosenbaum 10.1 Introduction 225 10.2 Mean Residence Time 226 10.3 Determination of Other Important Pharmacokinetic Parameters 229 10.4 Different Routes of Administration 231 10.5 Application of Noncompartmental Analysis to Clinical Studies 232 Problems 234 11 Pharmacokinetics of Intravenous Infusion in a One-Compartment Model 237Sara E. Rosenbaum 11.1 Introduction 238 11.2 Model and Equations 239 11.2.1 Basic Equation 239 11.2.2 Application of the Basic Equation 241 11.2.3 Simulation Exercise: Part 1 241 11.3 Steady-State Plasma Concentration 242 11.3.1 Equation for Steady-State Plasma Concentrations 242 11.3.2 Application of the Equation 242 11.3.3 Basic Formula Revisited 243 11.3.4 Factors Controlling Steady-State Plasma Concentration 243 11.3.5 Time to Steady State 244 11.3.6 Simulation Exercise: Part 2 245 11.4 Loading Dose 246 11.4.1 Loading-Dose Equation 246 11.4.2 Simulation Exercise: Part 3 248 11.5 Termination of Infusion 248 11.5.1 Equations for Termination Before and After Steady State 248 11.5.2 Simulation Exercise: Part 4 249 11.6 Individualization of Dosing Regimens 249 11.6.1 Initial Doses 249 11.6.2 Monitoring and Individualizing Therapy 250 Problems 252 12 Multiple Intravenous Bolus Injections in the One-Compartment Model 255Sara E. Rosenbaum 12.1 Introduction 256 12.2 Terms and Symbols Used in Multiple-Dosing Equations 257 12.3 Monoexponential Decay During a Dosing Interval 259 12.3.1 Calculation of Dosing Interval to Give Specific Steady-State Peaks and Troughs 260 12.4 Basic Pharmacokinetic Equations for Multiple Doses 260 12.4.1 Principle of Superposition 260 12.4.2 Equations that Apply Before Steady State 261 12.5 Steady State 262 12.5.1 Steady-State Equations 263 12.5.2 Average Plasma Concentration at Steady State 264 12.5.3 Fluctuation 267 12.5.4 Accumulation 267 12.5.5 Time to Reach Steady State 269 12.5.6 Loading Dose 270 12.6 Basic Formula Revisited 270 12.7 Pharmacokinetic-Guided Dosing Regimen Design 270 12.7.1 General Considerations for Selection of the Dosing Interval 270 12.7.2 Protocols for Pharmacokinetic-Guided Dosing Regimens 272 12.8 Simulation Exercise 276 Problems 277 Reference 278 13 Multiple Intermittent Infusions 279Sara E. Rosenbaum 13.1 Introduction 279 13.2 Steady-State Equations for Multiple Intermittent Infusions 281 13.3 Monoexponential Decay During a Dosing Interval: Determination of Peaks Troughs and Elimination Half-Life 284 13.3.1 Determination of Half-Life 284 13.3.2 Determination of Peaks and Troughs 286 13.4 Determination of the Volume of Distribution 286 13.5 Individualization of Dosing Regimens 289 13.6 Simulation 289 Problems 290 14 Multiple Oral Doses 293Sara E. Rosenbaum 14.1 Introduction 293 14.2 Steady-State Equations 294 14.2.1 Time to Peak Steady-State Plasma Concentration 295 14.2.2 Maximum Steady-State Plasma Concentration 296 14.2.3 Minimum Steady-State Plasma Concentration 296 14.2.4 Average Steady-State Plasma Concentration 296 14.2.5 Overall Effect of Absorption Parameters on a Steady-State Dosing Interval 297 14.3 Equations Used Clinically to Individualize Oral Doses 298 14.3.1 Protocol to Select an Appropriate Equation 298 14.4 Simulation Exercise 300 References 301 15 Nonlinear Pharmacokinetics 303Sara E. Rosenbaum 15.1 Linear Pharmacokinetics 304 15.2 Nonlinear Processes in Absorption, Distribution, Metabolism, and Elimination 306 15.3 Pharmacokinetics of Capacity-Limited Metabolism 307 15.3.1 Kinetics of Enzymatic Processes 307 15.3.2 Plasma Concentration–Time Profile 309 15.4 Phenytoin 310 15.4.1 Basic Equation for Steady State 311 15.4.2 Estimation of Doses and Plasma Concentrations 313 15.4.3 Influence of Km and Vmax and Factors That Affect These Parameters 314 15.4.4 Time to Eliminate the Drug 316 15.4.5 Time to Reach Steady State 317 15.4.6 Individualization of Doses of Phenytoin 318 Problems 321 References 322 16 Introduction to Pharmacogenetics 323Dr. Daniel Brazeau 16.1 Introduction 324 16.2 Genetics Primer 324 16.2.1 Basic Terminology: Genes Alleles Loci and Polymorphism 324 16.2.2 Population Genetics: Allele and Genotype Frequencies 326 16.2.3 Quantitative Genetics and Complex Traits 327 16.3 Pharmacogenetics 328 16.3.1 Pharmacogenetics of Drug-Metabolizing Enzymes 330 16.3.2 Pharmacogenetics of Drug Transporters 333 16.4 Genetics and Pharmacodynamics 334 16.4.1 Drug Target Pharmacogenetics 334 16.5 Summary 335 Reference 335 Suggested Readings 335 17 Models Used to Predict Drug–Drug Interactions for Orally Administered Drugs 337Sara E. Rosenbaum 17.1 Introduction 338 17.2 Mathematical Models for Inhibitors and Inducers of Drug Metabolism Based on In Vitro Data 340 17.2.1 Reversible Inhibition 340 17.2.2 Time-Dependent Inhibition 341 17.2.3 Induction 345 17.3 Surrogate In Vivo Values for the Unbound Concentration of the Perpetrator at the Site of Action 345 17.3.1 Surrogate Measures of Hepatic Inhibitor and Inducer Concentrations 346 17.3.2 Surrogate Measures of Intestinal Inhibitor and Inducer Concentrations 346 17.4 Models Used to Predict DDIs In Vivo 347 17.4.1 Introduction 347 17.4.2 Basic Predictive Models: R Values 348 17.4.3 Predictive Models Incorporating Parallel Pathways of Elimination (fm) 350 17.4.4 Models Incorporating Intestinal Extraction 354 17.4.5 Models Combining Multiple Actions of Perpetrators 358 17.5 Predictive Models for Transporter-Based DDIs 359 17.5.1 Kinetics of Drug Transporters 359 17.6 Application of Physiologically Based Pharmacokinetic Models to DDI Prediction: The Dynamic Approach 362 17.7 Conclusion 362 Problems 363 References 364 18 Introduction to Physiologically Based Pharmacokinetic Modeling 367Sara E. Rosenbaum 18.1 Introduction 368 18.2 Components of PBPK Models 369 18.3 Equations for PBPK Models 369 18.4 Building a PBPK Model 373 18.5 Simulations 377 18.6 Estimation of Human Drug-Specific Parameters 378 18.6.1 Tissue Plasma Partition Coefficient 379 18.6.2 Volume of Distribution 379 18.6.3 Clearance 380 18.7 More Detailed PBPK Models 381 18.7.1 Permeability-Limited Distribution 381 18.7.2 Drug Transporters 383 18.7.3 Models for Oral Absorption 386 18.7.4 Reduced Models 387 18.8 Application of PBPK Models 387 References 388 19 Introduction to Pharmacodynamic Models and Integrated Pharmacokinetic–Pharmacodynamic Models 391Drs. Diane Mould and Paul Hutson 19.1 Introduction 392 19.2 Classic Pharmacodynamic Models Based on Receptor Theory 393 19.2.1 Receptor Binding 394 19.2.2 Concentration-Response Models 395 19.3 Direct Effect Pharmacodynamic Models 402 19.3.1 Emax and Sigmoidal Emax Models 402 19.3.2 Inhibitory Imax and Sigmoidal Imax Models 404 19.3.3 Linear Adaptations of the Emax and Imax Model 404 19.4 Integrated PK–PD Models: Intravenous Bolus Injection in the One-Compartment Model and the Sigmoidal Emax Model 406 19.4.1 Simulation Exercise 409 19.5 Pharmacodynamic Drug–Drug Interactions 410 19.5.1 Simulation Exercise 410 Problems 411 References 412 20 Semimechanistic Pharmacokinetic–Pharmacodynamic Models 413Drs. Diane Mould and Paul Hutson 20.1 Introduction 414 20.2 Hysteresis and the Effect Compartment 416 20.2.1 Simulation Exercise 419 20.3 Physiological Turnover Models and Their Characteristics 419 20.3.1 Points of Drug Action 421 20.3.2 System Recovery After Change in Baseline Value 421 20.4 Indirect Effect Models 422 20.4.1 Introduction 422 20.4.2 Characteristics of Indirect Effect Drug Responses 424 20.4.3 Characteristics of Indirect Effect Models Illustrated Using Model I 426 20.5 Other Indirect Effect Models 432 20.5.1 Transit Compartment Models 435 20.5.2 Model for Hematological Toxicity of Anticancer Drugs 439 20.5.3 Alternate Parameterizations of Transit Models 442 20.6 Models of Tolerance 442 20.6.1 Introduction to Pharmacologic Tolerance 442 20.6.2 Counter-Regulatory Force Tolerance Model 444 20.6.3 Precursor Pool Model of Tolerance 447 20.7 Irreversible Drug Effects 450 20.7.1 Application of the Turnover Model to Irreversible Drug Action 450 20.8 Disease Progression Models 452 20.8.1 Drug Pharmacokinetics 452 20.8.2 Pharmacodynamics 452 20.8.3 Disease Activity Models 453 20.8.4 Disease Progression Models 453 Problems 459 References 465 Appendix A Review of Exponents and Logarithms 469Sara E. Rosenbaum A.1 Exponents 469 A.2 Logarithms: Log and Ln 470 A.3 Performing Calculations in the Logarithmic Domain 471 A.3.1 Multiplication 471 A.3.2 Division 472 A.3.3 Reciprocals 472 A.3.4 Exponents 472 A.4 Calculations Using Exponential Expressions and Logarithms 472 A.5 Decay Function: e−kt 474 A.6 Growth Function: 1 − e−kt 475 A.7 Decay Function in Pharmacokinetics 475 Problems 476 Appendix B Rates of Processes 479Sara E. Rosenbaum B.1 Introduction 479 B.2 Order of a Rate Process 480 B.3 Zero-Order Processes 480 B.3.1 Equation for Zero-Order Filling 480 B.3.2 Equation for Zero-Order Emptying 481 B.3.3 Time for Zero-Order Emptying to Go to 50% Completion 481 B.4 First-Order Processes 482 B.4.1 Equation for a First-Order Process 482 B.4.2 Time for 50% Completion: the Half-Life 483 B.5 Comparison of Zero- and First-Order Processes 484 B.6 Detailed Example of First-Order Decay in Pharmacokinetics 484 B.6.1 Equations and Semilogarithmic Plots 484 B.6.2 Half-Life 485 B.6.3 Fraction or Percent Completion of a First-Order Process Using First-Order Elimination as an Example 485 B.7 Examples of the Application of First-Order Kinetics to Pharmacokinetics 487 Appendix C Creation of Excel Worksheets for Pharmacokinetic Analysis 489Sara E. Rosenbaum C.1 Measurement of AUC and Clearance 489 C.1.1 Trapezoidal Rule 490 C.1.2 Excel Spreadsheet to Determine AUC0→∞ and Clearance 491 C.2 Analysis of Data from an Intravenous Bolus Injection in a One-Compartment Model 494 C.3 Analysis of Data from an Intravenous Bolus Injection in a Two-Compartment Model 496 C.4 Analysis of Oral Data in a One-Compartment Model 498 C.5 Noncompartmental Analysis of Oral Data 501 Appendix D Derivation of Equations for Multiple Intravenous Bolus Injections 505Sara E. Rosenbaum D.1 Assumptions 505 D.2 Basic Equation for Plasma Concentration After Multiple Intravenous Bolus Injections 505 D.3 Steady-State Equations 508 Appendix E Enzyme Kinetics: Michaelis–Menten Equation and Models for Inhibitors and Inducers of Drug Metabolism 509Sara E. Rosenbaum and Roberta S. King E.1 Kinetics of Drug Metabolism: The Michaelis–Menten Model 510 E.1.1 Overview 510 E.1.2 Assumptions for Validity of Michaelis–Menten Model 510 E.1.3 Km and Vmax 511 E.1.4 Derivation of the Michaelis–Menten Equation 511 E.1.5 Summary, Practical Considerations, and Interpretations 513 E.1.6 Relationship Between Intrinsic Clearance and the Michaelis–Menten Parameters 514 E.2 Effect of Perpetrators of DDI on Enzyme Kinetics and Intrinsic Clearance 515 E.2.1 Reversible Inhibition 515 E.2.2 Time-Dependent Inhibition 518 E.2.3 Enzyme Induction 524 References 526 Appendix F Summary of the Properties of the Fictitious Drugs Used in the Text 527Sara E. Rosenbaum Appendix G Computer Simulation Models 529Sara E. Rosenbaum Glossary of Terms 531 Index 537

Read more less

Book SynopsisLearn to implement effective control measures for mutagenic impurities in pharmaceutical development InMutagenic Impurities: Strategies for Identification and Control,distinguished chemist Andrew Teasdale deliversa thorough examinationof mutagenic impurities and their impact on the pharmaceutical industry. The book incorporates the adoption of the ICH M7 guideline and focuses on mutagenic impurities from both a toxicological and analytical perspective. The editor has created a primary reference for any professional or studentstudying or working with mutagenic impurities and offers readers a definitive narrative of applicable guidelines and practical, tested solutions. It demonstrates the development of effective control measures, including chapters onthe purge tool for risk assessment. The book incorporates a discussion of N-Nitrosamines which was arguably the largestmutagenic impurityissue ever faced by the pharmaceutical industry, resulting in thTable of ContentsList of Contributors xix Preface xxi Section 1 The Development of Regulatory Guidelines for Mutagenic/Genotoxic Impurities – Overall Process 1 1 Historical Perspective on the Development of the EMEA Guideline and Subsequent ICH M7 Guideline 3Andrew Teasdale 1.1 Introduction 3 1.1.1 CPMP – Position Paper on the Limits of Genotoxic Impurities –2002 4 1.1.1.1 Scope/Introduction 4 1.1.1.2 Toxicological Background 4 1.1.1.3 Pharmaceutical (Quality) Assessment 4 1.1.1.4 Toxicological Assessment 4 1.1.2 Guideline on the Limits of Genotoxic Impurities – Draft June 2004 5 1.1.3 PhRMA (Mueller) White Paper 6 1.1.4 Finalized EMA Guideline on the Limits of Genotoxic Impurities – June 2006 8 1.1.4.1 Issues Associated with Implementation 9 1.1.4.2 Control Expectations for Excipients 11 1.1.4.3 Control Expectations for Natural/Herbal Products 12 1.1.4.4 Identification of Potential Impurities 12 1.1.4.5 The Principle of Avoidance 12 1.1.4.6 The ALARP Principle 14 1.1.4.7 Overall 14 1.1.5 SWP Q&A Document 14 1.1.5.1 The Application of the Guideline in the Investigational Phase and Acceptable Limits for GIs Where Applied to Studies of Limited Duration 14 1.1.5.2 Application of the Guideline to Existing Products 15 1.1.5.3 Avoidance and ALARP 17 1.1.5.4 ICH Identification Threshold and its Relation to MI Assessment 17 1.1.6 FDA Draft Guideline 17 1.1.7 Other Relevant Guidance 17 1.1.7.1 Excipients 18 1.1.8 Herbals 18 1.1.9 ICH S9 18 1.1.10 Conclusions 19 References 19 2 ICH M7 – Assessment and Control of DNA Reactive (Mutagenic) Impurities in Pharmaceuticals to Limit Potential Carcinogenic Risk 21Andrew Teasdale and Raphael Nudelman 2.1 Introduction 21 2.2 ICH M7 22 2.2.1 Introduction 22 2.2.2 Scope 22 2.2.2.1 Established Products 22 2.2.2.2 Anticancer Treatments 23 2.2.2.3 Nature of Therapeutic Agent/Excipients 23 2.2.3 General Principles 24 2.2.4 Considerations for Marketed Products 25 2.2.4.1 Post-approval Changes to Drug Substance, Chemistry, and Manufacturing Controls 26 2.2.4.2 Post-approval Changes to Drug Product Chemistry, Manufacturing, and Controls 26 2.2.4.3 Changes to the Clinical Use of Drug Products 26 2.2.5 Other Considerations for Marketed Products 27 2.2.6 Drug Substance and Drug Product Impurity Assessment 27 2.2.6.1 Synthetic Impurities 28 2.2.6.2 Degradation Products 28 2.2.7 Hazard Assessment 29 2.2.8 Risk Characterization 32 2.2.8.1 Acceptable Intakes Based on Compound-specific Risk Assessments 32 2.2.8.2 Acceptable Intakes for Class 2 and Class 3 Compounds 33 2.2.8.3 Multiple Impurities 34 2.2.8.4 Exceptions and Flexibility in Approaches 35 2.2.9 Control Strategy 35 2.2.9.1 Considerations for Control Approaches 37 2.2.9.2 Considerations for Periodic Testing 37 2.2.9.3 Control of Degradation Products 38 2.2.10 Lifecycle Management 38 2.2.11 Documentation 38 2.2.11.1 Clinical Trail Applications 38 2.2.11.2 Common Technical Document (Marketing Application) 39 2.2.12 Other Aspects 39 2.2.12.1 Relationship Between ICH M7 and ICH Q3A 39 2.3 Conclusions 40 2.4 Commentary on ICH M7 Questions and Answers 40 2.4.1 Section 1 – Introduction 41 2.4.1.1 Question 1.1 41 2.4.1.2 Question 1.2 42 2.4.1.3 Question 1.3 42 2.4.1.4 Question 1.4 42 2.4.2 Section 2 – Scope 43 2.4.2.1 Question 2.1 43 2.4.3 Section 3 – General Principles 43 2.4.3.1 Question 3.1 44 2.4.3.2 Question 3.2 44 2.4.4 Section 4 – Considerations for Marketed Products 44 2.4.4.1 Question 4.1 45 2.4.5 Section 5 – Drug Substance and Drug Product Impurity Assessment 45 2.4.6 Section 6 – Hazard Assessment Elements 45 2.4.6.1 Question 6.1 45 2.4.6.2 Question 6.2 46 2.4.6.3 Question 6.3 47 2.4.6.4 Question 6.4 48 2.4.7 Section 7 – Risk Characterization 48 2.4.7.1 Question 7.1 48 2.4.7.2 Question 7.2 49 2.4.7.3 Question 7.3 49 2.4.7.4 Question 7.4 50 2.4.7.5 Question 7.5 51 2.4.8 Section 9 – Documentation 53 References 55 3 Control Strategies for Mutagenic Impurities 57Andrew Teasdale, Michael Burns, and Michael Urquhart 3.1 Introduction 57 3.2 Assessment Process 58 3.2.1 General 58 3.2.2 Step 1 – Evaluation of Drug Substance and Drug Product Processes for Sources of Potentially Mutagenic Impurities 60 3.2.3 Step 2 – Structural Assessment 61 3.2.4 Step 3 – Classification 61 3.2.5 Step 4 – Assessment of Risk of Potential Carryover of Impurities 63 3.2.6 Overall Quantification of Risk 63 3.2.6.1 Predicted Purge Factor 64 3.2.6.2 Required Purge Factor 65 3.2.6.3 Purge Ratio 66 3.2.6.4 High Predicted Purge 67 3.2.6.5 Moderate Predicted Purge 67 3.2.6.6 Low Predicted Purge 67 3.2.6.7 ICH M7 Control Option 1, 2, or 3 67 3.2.6.8 Step 5 – Further Evaluation 67 3.2.6.9 Safety Testing 67 3.2.7 Quantification of Level Present 68 3.3 Step 6 – Overall Risk Assessment 69 3.4 Further Evaluation of Risk – Purge (Spiking) Studies 70 3.5 Conclusion 70 3.6 Case Studies 71 3.6.1 Case Study 1 – GW641597X 71 3.6.1.1 Ethyl Bromoisobutyrate 2 73 3.6.1.2 Hydroxylamine 74 3.6.1.3 Alkyl Chloride 8 75 3.6.1.4 Additional Evidence for the Purging of Ethyl Bromoisobutyrate and Alkyl Chloride 8 76 3.6.2 Proposed ICH M7-aligned Potential Mutagenic Control Regulatory Discussion 78 3.6.3 Case Study 2 – Candesartan 78 References 84 Section 2 In Silico Assessment of Mutagenicity 87 4 Use of Structure–Activity Relationship (SAR) Evaluation as a Critical Tool in the Evaluation of the Genotoxic Potential of Impurities 89Catrin Hasselgren and Glenn Myatt 4.1 Introduction 89 4.2 (Q)SAR Assessment 90 4.2.1 Looking-up Experimental Data 90 4.2.2 (Q)SAR Methodologies 91 4.2.2.1 Overview 91 4.2.2.2 OECD Validation Principles 91 4.2.3 Expert Rule-Based Methodology 92 4.2.4 Statistical-Based Methodology 95 4.2.5 Applying (Q)SAR Models 97 4.2.6 Expert Review 98 4.2.6.1 Overview 98 4.2.6.2 Refuting a Statistical-Based Prediction 100 4.2.6.3 Mechanistic Assessment 101 4.2.6.4 Assessing Lack of Chemical Reactivity 101 4.2.7 Class Assignment 103 4.2.7.1 Overview 103 4.2.8 Documentation 109 4.3 Discussion 109 4.4 Conclusions 110 Acknowledgments 111 References 111 5 Evolution of Quantitative Structure–Activity Relationships ((Q)SAR) for Mutagenicity 115James Harvey and David Elder 5.1 Introduction 115 5.2 Pre ICH M7 Guideline 116 5.3 Post ICH M7 117 5.3.1 Evolution of (Q)SAR Platforms 117 5.3.2 Robust Negative In Silico (Q)SAR Predictions 118 5.3.3 Development of Composite (Q)SAR Models 119 5.3.4 Expansion of Training Data Sets to Enhance the Predictive Power of (Q)SAR Tools 120 5.3.5 Focused Data Sharing Initiatives on Specific Chemical Classes 120 5.3.5.1 Understanding In Vitro Mechanisms Leading to Mutagenicity 121 5.3.5.2 Shared Data, Shared Progress 122 5.3.6 Novel Data Mining Approaches 125 5.3.6.1 Case Study: Primary Aromatic Amines (PAAs) 125 5.3.6.2 Case Study: Aromatic N-oxides 125 5.4 Expert Knowledge 127 5.5 Future Direction 129 References 131 Section 3 Toxicological Perspective on Mutagenic Impurities 137 6 Toxicity Testing to Understand the Mutagenicity of Pharmaceutical Impurities 139Andrew Teasdale, John Nicolette, Joel P. Bercu, James Harvey, Stephen Dertinger, Michael O’Donovan, and Christine Mee 6.1 Introduction 139 6.2 In Vitro Genotoxicity Tests 141 6.2.1 Background 141 6.2.2 Bacterial Reverse Mutation or “Ames” Test 142 6.2.3 Modifications to the Standard Ames Test 145 6.2.3.1 Six-well Ames Assay 146 6.2.4 Test Strategy 146 6.3 In Vivo Mutation Assays 148 6.3.1 In Vivo Pig-a Gene Mutation Assay 148 6.3.2 Rodent Micronucleus Test 152 6.3.3 Rodent “Comet” Assay 155 6.3.4 Transgenic Rodent (TGR) Mutation Assay 155 6.4 Conclusions 158 Glossary 159 References 160 7 Compound-and Class-Specific Limits for Common Impurities in Pharmaceuticals 165Joel P. Bercu, Melisa J. Masuda-Herrera, Alejandra Trejo-Martin, David J. Snodin, Kevin P. Cross, George E. Johnson, James Harvey, Robert S. Foster, David J. Ponting, and Richard V. Williams 7.1 Introduction 165 7.2 Monograph Development 167 7.2.1 Exposure to the General Population 167 7.2.2 Mutagenicity/Genotoxicity 170 7.2.3 Noncarcinogenic Effects 170 7.2.4 Carcinogenic Effects 170 7.2.5 Mode of Action (MOA) and Assessment of Human Relevance 171 7.2.6 Toxicokinetics 171 7.2.7 Regulatory/Published Limits 171 7.3 Derivation of the Compound-specific Limit 171 7.3.1 PoD Selection 172 7.3.2 Limited Data Sets 172 7.3.3 PDE Development 172 7.3.4 AI Development 172 7.3.5 Class-specific Limit 173 7.3.6 Less than Lifetime (LTL) AIs 173 7.4 Examples of Published Compound-specific Limits 173 7.4.1 Mutagenic Carcinogens 173 7.4.2 Nonmutagenic Carcinogens 176 7.4.3 Mutagenic Noncarcinogens 176 7.4.4 Nonmutagenic Compounds 176 7.4.5 Mutagenic In vitro but not In vivo 176 7.4.6 Route of Administration-specific Limits 177 7.5 Class-specific Limits 177 7.5.1 Alkyl Chlorides 177 7.5.2 Alkyl Bromides 178 7.5.3 N-Nitrosamines 178 7.5.3.1 Regulatory Limits for N-Nitrosamines 178 7.5.3.2 Additional Proposed Limits for N-Nitrosamines 180 7.5.3.3 N-Nitrosamine Exposure in the General Population 181 7.5.3.4 Developing a Class-specific Limit for N-Nitrosamines 182 7.5.4 Arylboronic Acids and Esters 193 7.6 EMS Case Study and Updated Toxicity Analysis 196 7.6.1 Potential for Human Exposure 196 7.6.2 Mutagenicity/Genotoxicity 196 7.6.3 Noncarcinogenic Effects 198 7.6.4 Carcinogenicity 199 7.6.5 Regulatory and/or Published Limits 199 7.6.6 Permitted Daily Exposure 199 7.7 Extractables and Leachables 202 7.8 Lhasa AI/PDE Database for Impurities 203 7.9 Conclusions and Future Directions 203 Acknowledgments 204 References 204 8 Genotoxic Threshold Mechanisms and Points of Departure 213George E. Johnson, Shareen H. Doak, Gareth J.S. Jenkins, and Adam D. Thomas 8.1 Introduction to Genotoxic Dose Responses 213 8.1.1 The Linear Default Position for Genotoxic Carcinogens 213 8.1.2 Theoretical Evidence for Rejecting the Linear Approach 214 8.1.3 In Vitro Experimental Evidence for Threshold Mechanism 215 8.1.4 In Vivo Evidence for Genotoxic Thresholds 218 8.2 Threshold Mechanisms 221 8.2.1 Statistical Assessment of Dose Response Data Sets 224 8.2.2 Extrapolation from One Chemical to Another 224 8.2.3 Extrapolation of Threshold Mechanisms and PoDs to Populations 225 8.3 Conclusions 227 References 227 Section 4 Quality Perspective on Genotoxic Impurities 233 9 Mutagenic Impurities – Assessment of Fate and Control Options 235Michael W. Urquhart, Andrew Teasdale, and Michael Burns 9.1 Introduction/Background 235 9.2 Reactivity 236 9.2.1 Reactivity Classification 238 9.3 Solubility – Isolated Stages 238 9.4 Recrystallization 239 9.4.1 Solubility – Liquid/Liquid Partitioning 239 9.5 Volatility 241 9.6 Chromatography 241 9.7 Other Techniques 242 9.7.1 Activated Charcoal 242 9.7.2 Scavenger Resins 242 9.8 Overall Quantification of Risk 243 9.9 Alignment to ICH M7 – Control Options 244 9.10 Control Option Selection 247 9.10.1 Predicted Purge Factor 248 9.10.2 Required Purge Factor 249 9.10.3 Purge Ratio 249 9.10.4 High Predicted Purge 250 9.10.5 Moderate Predicted Purge 250 9.10.6 Low Predicted Purge 250 9.10.7 ICH M7 Control Option 1, 2, or 3 251 9.10.8 Representative Data to be Supplied in Regulatory Submission Under an ICH M7 Control Strategy 251 9.10.9 Summary of PMI Purging Across the Synthetic Route 251 9.10.10 Details of Individual Impurity Purging Through the Subsequent Downstream Chemistry 253 9.10.11 Development of a Knowledge Base Expert In Silico System 254 9.10.12 Experimental Work to Assess Reactivity 257 9.11 Utilizing Mirabilis for a Purge Calculation 259 9.11.1 Utility of In Silico Predictions 260 9.11.1.1 Case Study – Camicinal [38] 260 References 266 10 N-Nitrosamines 269Andrew Teasdale, Justin Moser, J. Gair Ford, and Jason Creasey 10.1 Background 269 10.2 Generation of N-Nitrosamines 270 10.3 Article 31 273 10.4 Further Issues – Cross Contamination and Ranitidine 275 10.4.1 Article 5(3) and Associated Q&A Document 276 10.5 How to Assess the Risk Posed in Pharmaceuticals 278 10.5.1 Drug Substance 278 10.5.1.1 Where do Nitrites Come Within Drug Substance Come From? 278 10.5.1.2 What Other Sources Are There? 278 10.5.1.3 Other Factors Associated with Drug Substance Synthesis 280 10.5.2 Process to Assess Drug Substance-Related Risk 280 10.5.3 Drug Product-Related Risk 282 10.5.3.1 Related Risks of Contamination and Formation in Drug Products 282 10.5.4 Container Closure Systems 289 10.5.5 Elastomeric Components 291 10.5.6 Nitrosamine Impurities in Biologics 293 10.5.6.1 Active Substance 293 10.5.6.2 The Water Used in Formulation Is Depleted in Nitrosating Agents 295 10.5.6.3 Bioconjugated or Chemically Modified Products 295 10.5.6.4 Excipients 296 10.6 Regulatory Guidance Pursuant to N-Nitrosamines and its Implications 297 10.6.1 Article 31 Process and Outcomes 297 10.6.1.1 Article 31 Request 297 10.6.2 Sartans Lessons Learnt Report 298 10.6.2.1 Reflection on the Initial Section of the EMA Report 299 10.6.3 Article 5(3) Report 299 10.6.3.1 Quality 299 10.6.3.2 Consideration for Analytical Method Development to Identify and Quantify N-Nitrosamines in Drug Substances and Medicinal Products 300 10.6.3.3 Safety 301 10.6.3.4 Conclusions 305 10.6.4 EMA Question and Answer Document [6] 305 10.6.4.1 Further Revision of the EMA Question and Answer Document 310 10.6.5 FDA Guideline 310 10.6.5.1 Introduction and Background 310 10.6.5.2 Recommendations 310 10.6.5.3 Acceptable Intakes (section III.A) 313 10.6.5.4 Quality/Chemistry and Controls 314 10.7 Way Forward 315 Acknowledgments 316 References 317 11 Conditions Potentially Leading to the Formation of Mutagenic Impurities 321Lucie Lovelle, Andrew Teasdale, Ian Ashworth, Adrian Clarke, and Alan Steven 11.1 Problematic Reagent Combinations per Structural Alert 323 11.1.1 N-Nitroso Compounds (COC) 323 11.1.1.1 Amines and Nitrosating Agents [10] 323 11.1.1.2 Amine Derivatives and Nitrosating Agents 324 11.1.1.3 Other 324 11.1.2 Alkyl-azoxy Compounds (COC) 325 11.1.2.1 Reduction [52–54] 325 11.1.2.2 Oxidation 325 11.1.2.3 Others 325 11.1.3 Other N-O Compounds 326 11.1.3.1 Reduction of Nitro Groups 326 11.1.3.2 Oxidation of Amines and Hydroxylamines 326 11.1.4 Nitration 326 11.1.5 Other N-N Compounds [59, 60] 326 11.1.6 Aflatoxin-like Compounds [62] (COC) 327 11.1.7 Dioxin-like Compounds (Including Polychlorinated Biphenyls = PCBs) [63] 327 11.1.8 Alkyl and Acyl Halides 327 11.1.8.1 ROH + HCl → RCl + H2O 327 11.1.8.2 Ether Opening with Halides 328 11.1.9 Methyl Sulfoxides and Pummerer Rearrangement 328 11.1.10 Acyl Chlorides Formation [82] 329 11.1.11 Halogenation of Unsaturated Compounds 329 11.1.12 Ammonium Salts (Hofmann Elimination) 329 11.1.12.1 Alkyl Sulfonates [90] 329 11.1.13 Epoxides and Aziridines [95–97] 330 11.2 Miscellaneous 331 11.2.1 B and P Based Compounds 331 11.2.2 Formation of N-Methylol 331 11.2.3 Acetamide 332 11.2.4 Quinones and Quinone Derivatives 332 11.2.5 Anilines [100] 332 11.2.6 Michael Acceptors 333 11.2.7 Others 333 11.3 Mechanism and Processing Factors Affecting the Formation of N-nitrosamines 333 11.3.1 Introduction 333 11.3.2 Mechanisms of Amine Nitrosation 333 11.3.2.1 Nitrosation of Secondary Amines 333 11.3.2.2 Aqueous Nitrosation 334 11.3.2.3 Nitrosation in Organic Solvents 336 11.3.3 Nitrosation of Tertiary Amines 337 11.3.3.1 Nitrosation of Quaternary Amines 337 11.3.3.2 Nitrosation of Amine Oxides 338 11.3.4 Sources of Nitrosating Agents 338 11.3.4.1 Process Water 338 11.3.4.2 Nitric Acid 339 11.3.4.3 Atmospheric Sources 339 11.3.4.4 Excipients Used in Drug Product Manufacture 340 11.3.4.5 Nitrocellulose 340 11.3.4.6 Nitrosating Agent Scavengers 340 11.3.4.7 Removal of Nitrosamines 341 11.4 Formation, Fate, and Purge of Impurities Arising from the Hydrogenation of Nitroarenes to Anilines 341 11.4.1 Primary Reaction Mechanism 341 11.4.2 Mass and Heat Transfer Effects 342 11.4.3 Condensation Chemistry 344 11.4.4 Factors Affecting Aryl Hydroxylamine Accumulation 346 11.4.5 Aryl Hydroxylamine Control 347 11.4.5.1 Use of Cocatalysts 347 11.4.5.2 Physical Adsorption 348 11.4.5.3 Kinetic Understanding Around Formation and Consumption 349 11.4.5.4 Holistic Control of Impurity Profile 349 11.4.6 Controlling Residual Nitroarene 351 11.4.7 Specific Considerations of Alkyl Nitro Reductions 353 11.4.8 Closing Comments on Hydrogenation of Nitroarenes to Anilines 353 11.5 Mechanism and Processing Parameters Affecting the Formation of Sulfonate Esters – Summary of the PQRI Studies 353 11.5.1 Introduction 353 11.5.2 Reaction Mechanism 355 11.5.3 Experimental Results 357 11.5.3.1 Experimental Results from Study of the Ethyl Methanesulfonate (EMS) System 357 11.5.3.2 Other Methanesulfonic Acid Systems 359 11.5.3.3 Experimental Results from Study of the Isopropyl Methanesulfonate (IMS) System 360 11.5.4 Experimental Results from Study of Toluenesulfonic (Tosic) Acid Systems 361 11.5.4.1 Experimental Results from Study of the Ethyl Tosylate (ETS) System 362 11.5.4.2 Kinetic Modeling 363 11.5.4.3 Key Learnings and Their Implications for Process Design 365 11.5.4.4 Processing Rules 366 11.5.5 What About Viracept™? 366 11.5.6 What About Other Sources of Sulfonate Esters? 367 11.5.7 Potential for Ester Formation in the Solid Phase 368 11.5.8 Conclusions 369 References 369 12 Strategic Approaches to the Chromatographic Analysis of Mutagenic Impurities 381Frank David, Gerd Vanhoenacker, Koen Sandra, Pat Sandra, Tony Bristow, and Mark Harrison 12.1 Introduction 381 12.2 Method Development and Validation 384 12.3 Analytical Equipment for Mutagenic Impurity Analysis 385 12.4 Alkyl Halides and Aryl Halides 388 12.4.1 Method Selection 388 12.4.2 Typical Conditions Used for Alkyl-and Aryl Halide Analysis by SHS-GC-MS and SPME-GC-MS 390 12.4.2.1 Sample Preparation 390 12.4.2.2 GC-MS Parameters 391 12.4.3 Typical Results Obtained for Alkyl-and Aryl Halide Analysis by SHS-GC-MS and SPME-GC-MS 391 12.5 Sulfonates 393 12.5.1 Method Selection 393 12.5.2 Typical Conditions Used for Sulfonate Analysis by Derivatization SHS-GC-MS 394 12.5.2.1 Sample Preparation 395 12.5.2.2 Synthesis of Deuterated Internal Standards 395 12.5.2.3 GC-MS Parameters 395 12.5.3 Typical Results Obtained Using Derivatization – SHS – GC-MS 395 12.5.4 Confirmation Analysis by PTV-GC-MS 396 12.6 S-and N-mustards 398 12.6.1 Method Selection 398 12.6.2 Typical Analytical Conditions for the Analysis of N-mustards by Derivatization – SPME-GC-MS 399 12.6.2.1 Sample Preparation 399 12.6.3 Typical Results for N-mustards by Derivatization – SPME-GC-MS 399 12.7 Michael Reaction Acceptors 400 12.7.1 Method Selection 400 12.7.2 Typical Analytical Conditions for Michael Reaction Acceptors 400 12.7.2.1 Sample Preparation 401 12.7.2.2 Parameters for SHS-GC-MS 401 12.7.2.3 Parameters for Liquid Injection and GC-MS with Back-flush 402 12.7.3 Typical Results Obtained for Trace Analysis of Michael Reaction Acceptors 402 12.7.3.1 SHS with PTV 402 12.7.3.2 Liquid Injection GC-MS 403 12.8 Epoxides 404 12.8.1 Method Selection 404 12.8.2 Typical Analytical Conditions for the Analysis of Volatile Epoxides by SHS-GC-MS 406 12.8.2.1 Sample Preparation 406 12.8.2.2 SHS-GC-MS Parameters 406 12.8.3 Typical Results Obtained for Volatile Epoxides Using SHS-GC-MS 407 12.9 Haloalcohols 407 12.9.1 Method Selection 407 12.9.2 Analytical Conditions for Trace Analysis of Halo-alcohols by Derivatization and Liquid Injection - 2DGC-MS 409 12.9.2.1 Sample Preparation 409 12.9.2.2 2D-GC-MS Parameters 410 12.9.3 Typical Results for Analysis of Halo-alcohols by Derivatization and Liquid Injection - 2DGC-MS 410 12.10 Aziridines 411 12.10.1 Method Selection 411 12.10.2 Typical Analytical Conditions for RPLC-MS and HILIC-MS Analysis of Aziridines 412 12.10.2.1 Sample Preparation 412 12.10.2.2 RPLC-MS Method Parameters 413 12.10.2.3 HILIC-MS Method Parameters 413 12.10.3 Typical Results Obtained for Aziridine Analysis Using RPLC and HILIC 413 12.11 Arylamines and Amino Pyridines 414 12.11.1 Method Selection 414 12.11.2 Typical Analytical Conditions for Arylamines and Aminopyridines by RPLC-MSD 415 12.11.2.1 Sample Preparation 415 12.11.2.2 HPLC-MS Parameters 416 12.11.3 Typical Results for Arylamines and Aminopyridines by RPLC-MSD 417 12.12 Hydrazines and Hydroxylamine 419 12.12.1 Method Selection 419 12.12.2 Analytical Conditions for the Analysis of Hydrazines Using Derivatization and HPLC-MS 420 12.12.2.1 Sample Preparation 421 12.12.2.2 HPLC-MS Parameters 421 12.12.3 Typical Results Obtained for Hydrazines Using Derivatization LC-MS 421 12.13 Aldehydes and Ketones 423 12.13.1 Method Selection 423 12.13.2 Typical Analytical Conditions for Analysis of Aldehydes and Ketones by DNPH Derivatization, Followed by LC-MS Analysis 423 12.13.2.1 Sample Preparation 424 12.13.2.2 Derivatization Reagent Solution 425 12.13.2.3 HPLC-MS Parameters 425 12.13.3 Typical Results Obtained for Aldehyde Analysis by DNPH Derivatization – LC-MS 426 12.14 Nitrosamines 426 12.14.1 Method Selection 426 12.14.2 Sample preparation for SHS-GC-MS Analysis (according to ref [85]) 428 12.14.2.1 SHS-GC-MS Analysis [85] Sample Preparation 428 12.14.2.2 GC-MS (HRAM-MS) Conditions 428 12.14.2.3 UHPLC-MS Analysis 429 12.14.2.4 Sample Preparation for Hydrophilic Samples (e.g. Metformin) 429 12.14.2.5 Sample Preparation for Hydrophobic Matrices 430 12.14.2.6 UHPLC Conditions 430 12.14.2.7 HRAM-MS and MS/MS Conditions 430 12.14.3 Typical Results Obtained for Volatile N-nitrosamines Using SHS-GC-MS 430 12.14.4 Typical Results Obtained for N-nitrosamines Using LC-MS 431 12.15 Nontarget Analysis of PMI/MIs 434 12.16 Conclusions 435 Acknowledgements 436 References 436 13 Analysis of Mutagenic Impurities by Nuclear Magnetic Resonance (NMR) Spectroscopy 439Andrew R. Phillips and Stephen Coombes 13.1 Introduction to NMR 439 13.2 Why Is NMR an Insensitive Technique? 439 13.2.1 Nuclear Spin 439 13.2.2 Boltzmann Distribution 440 13.3 How Could NMR Be Used for Trace Analysis? 440 13.3.1 Generating an NMR Spectrum 440 13.3.2 Chemical Shift 442 13.3.3 Scalar Coupling 443 13.3.4 The Quantitative Nature of NMR 444 13.3.5 Relaxation 445 13.3.6 Summary 446 13.4 What Can Be Done to Maximize Sensitivity? 446 13.4.1 System Performance 447 13.4.1.1 Field Strength 447 13.4.2 Probe Performance 447 13.4.2.1 Probe Design 447 13.4.2.2 Probe Diameter 448 13.4.2.3 Cryogenically Cooled Probes 448 13.4.3 Substrate Concentration 449 13.4.4 Molecular Weight Ratio 451 13.4.5 Acquisition Time and Signal Averaging 451 13.4.6 Number of Protons and Linewidth 453 13.4.7 Resolution 455 13.4.8 Dynamic Range 455 13.4.8.1 Selective Excitation 458 13.4.8.2 Shaped Pulses 458 13.4.8.3 Quantification Using Selective Pulses 460 13.4.8.4 Excitation Sculpting 461 13.4.9 Limit Tests 461 13.4.9.1 Method Development 462 13.4.9.2 Validation 463 13.4.9.3 Unresolved Signals 463 13.4.9.4 Rapid Analysis 464 13.4.10 Expanded Use of MI NMR Methodology 464 13.4.11 Summary 464 13.5 Case Studies 464 13.5.1 Case Study 1 – An Aldehyde Functionalized MI 464 13.5.2 Case Study 2 – Use of 19F NMR 466 13.5.3 Case Study 3 – Epoxide and Chlorohydrin MIs 468 13.5.4 Case Study 4 – Sulfonate Esters 469 13.5.5 Case Study 5 – Limit Test for Poorly Resolved Signals 470 13.5.6 Case Study 6 – Using NMR MI Methodology for Cleaning Validation 472 13.6 Conclusion 473 References 475 14 Addressing the Complex Problem of Degradation-Derived Mutagenic Impurities in Drug Substances and Products 477Steven W. Baertschi and Andrew Teasdale 14.1 Introduction 477 14.1.1 Background 477 14.2 Working Definitions 478 14.3 Challenges Associated with the Assessment of Risk Posed by (Potentially) Mutagenic Degradation Products 479 14.4 Risk Assessment Process for Mutagenic Degradants 479 14.4.1 Stability-Related MRA Process Overview 479 14.4.2 Stress Studies 480 14.4.3 Accelerated Stability Studies 480 14.4.4 Long-term ICH Stability Studies 481 14.4.5 Deciding Which Products to Include in the MRA 481 14.4.6 In Silico Tools for the Prediction of Potential Degradation Products 482 14.5 Using Stress Testing to Select Degradation Products for Identification 482 14.5.1 Approach 1: Criteria for Structure Identification After Observation in Accelerated and Long-term Stability Studies 483 14.5.2 Approach 2: Criteria for Structure Identification Through Use of an Algorithm in Stress Testing Studies 483 14.5.3 Approach 3: Structure Identification Through Use of Kinetic Equivalence and Scaled ICH Q3B Thresholds 485 14.5.3.1 Kinetic Equivalence 485 14.5.3.2 Scaled ICH Q3B Thresholds 486 14.6 Development Timeline Considerations 487 14.6.1 Drug Discovery Stage 487 14.6.2 Preclinical to Phases 1/2 487 14.6.3 Phase 3 to New Drug Application (NDA) Regulatory Submission 488 14.6.4 Post-marketing/Line Extensions 488 14.7 Developing Control Strategies for (Potential) Mutagenic Degradation Products 488 14.7.1 Determining Relevancy of Potential Degradation Products and Developing Control Strategies for Actual Degradation Products 488 14.7.2 Accelerated Stability (40 °C/75% RH Six months) or Kinetic Equivalent 489 14.7.3 Photostability Studies 489 14.7.4 Degradation Chemistry Knowledge 490 14.8 Risk Assessment Process Illustrated 491 14.8.1 Case Study #1: Molecule A 491 14.8.2 Case Study #2: Galunisertib 492 14.8.3 Case Study #3: Naloxegol 494 14.8.4 Case Study #4: Selumetinib Side Chain 496 14.9 Significance of the Risk of Forming Mutagenic Degradation Products 498 14.9.1 Frequency of Alerting Structures in Degradation Products 498 14.10 Degradation Reactions Leading to Alerting Structures in Degradation Products 499 14.10.1 Frequency of Alerting Structures Giving Rise to Ames Positive Tests 503 14.10.2 Mutagenic Degradation Products: Overall Predicted Frequency 503 14.11 N-Nitrosamines: Special Considerations 503 14.11.1 Evaluation of Potential Formation of N-Nitrosamines in Drug Product 504 14.12 Conclusions 506 References 507 Index 513

Read more less

Book SynopsisIn a field where even experts may find that years have elapsed since they last encountered a child with a given disorder, it is essential for the clinician to have a comprehensive source of practical and highly illustrated information covering the whole spectrum of metabolic disease to refer to.The content is divided into sections of related disorders, including disorders of amino acid metabolism, lipid storage disorders, and mitochondrial diseases for ease of reference, with an introductory outline where appropriate summarizing the biochemical features and general management issues. Within the sections, each chapter deals with an individual disease, opening with a useful summary of major phenotypic expression including clear and helpful biochemical pathways, identifying for the reader exactly where the defect occurs.Throughout the book, plentiful photographs, often showing extremely rare disorders, are an invaluable aid to diagnosis.Key Featuresâ Fully updated to incorporate all new developments in the fieldâ Brand new chapters cover methylmalonic aciduria of ACSF3 deficiency, branched chain keto acid dehydrogenase deficiency, serine deficiencies, purine nucleoside phosphorylase deficiency, antiquitin deficiency, and othersâ Excellent and detailed clinical descriptions, with numerous valuable hints and suggestions for managementâ Helpful explanatory algorithms and decision trees, and high-quality illustrative material including biochemical pathways and an unrivaled photographic collection, which enhance clinical applicabilityThe fourth edition of this highly regarded book, authored by two of the foremost authorities in pediatric metabolic medicine, continues to provide incomparable insight into the problems associated with metabolic diseases and remains invaluable to pediatricians, geneticists, and general clinicians worldwide.Trade Review"In the library of inherited metabolic diseases, it is a case sui generis in describing single disorders or groups of disorders concisely … in text, tables, graphs, references, and a unique collection of pictures"-Georg F. Hoffmann Univ.-Prof. Dr. med., Prof. h.c. mult. (RCH) Chairman/Department of Pediatrics, University of HeidelbergTable of ContentsPart 1: Organic Acidemias. Part 2: Disorders of Amino Acid Metabolism. Part 3: Hyperammonemia and Disorders of the Urea Cycle. Part 4: Disorders of Fatty Acid Oxidation. Part 5: The Lactic Acidemias and Mitochondrial Disease. Part 6: Disorders of Carbohydrate Metabolism. Part 7: Peroxisomal Disorders. Part 8: Disorders Of Purine And Pyridine Metabolism. Part 9: Mucopolysaccharidoses. Part 10: Mucolipidosis. Part 11: Disorders Of Cholesterol And Neutral Lipid Metabolism. Part 12: Lipid Storage Disorders. Part 13: Miscellaneous.

Read more less

Book SynopsisSolving intractable biotechnological questions of evolution, medicine, and genetics is now easier due to methods permitting the rapid analysis of molecular sequence data. These advances have exposed ethical and policy concerns. How would genomic information be used and by whom? Should individuals be able to make decisions regarding their own genomic data? How accurate are these genetic tests and how should they be regulated? These and other ethical conundrums are the subject of this book. Bioethicists, biomedical policy experts and lawyers, physicians, nursing and allied health students as well as science educators will find this book helpful and engaging in exploring the complexities of modern evolutionary, genetic and biomedical data.Table of ContentsA General Introduction. Ethics. The Bioethics of Genetics. Law and Bioethics. Genes and Patents. Genetic Bioengineering. Gene Editing. Ethico-Regulatory Trends. Conclusions and Perspectives.

Read more less

Book Synopsis

Read more less

Book SynopsisHow did an obscure academic idea pave the way to the Holocaust within just fifty years?Trade Review"A remarkable combination of intelligence, knowledge, insight and admirable political passion, on a serious moral problem in contemporary society." -- Carlo Rovelli, author of Seven Brief Lessons on Physics"A short, sharp, illuminating overview of the science, politics, uses and abuses of human gene editing" -- Tim Adams - Observer"Weighty and serious but accessible and perfectly pitched. The scholarship is astounding." -- Alice Roberts, author of Ancestors"A clear-sighted look at the past and present dangers of eugenics. Rutherford tells [the story] with great concision and with clarity, both scientific and moral. [He] condenses tricky concepts into smart and often witty prose, combining erudition with humility.… Honest, informed and humane." -- Philip Ball - Financial Times"Rutherford’s swift, well-written account of these fascinating scientific and moral issues is well worth a read." -- Emma Duncan - The Times"Control is persuasive, sensible and ultimately reassuring, but it is not complacent.… To know history is ‘to inoculate ourselves against its being repeated,’ Rutherford argues. From that perspective, this book is a shot worth having." -- Katy Guest - Guardian"[Rutherford’s] scientific demolition of the eugenic project is brilliantly illuminating and compelling. His book will be indispensable for anyone who wants to assess the wild claims and counter-claims surrounding new genetic technologies." -- John Gray - New Statesman"[A] stimulating critique of one of science’s most disgraceful chapters." -- Publishers Weekly

Read more less

Book SynopsisWritten by the successful author team of Sandy Primrose and Richard Twyman, Genomics: Applications in Human Biology is a topical book showing how the new science of genomics is adding impetus to the advances in human health provided by biotechnology. Written to provide the necessary overview of the subject, covering technological developments, applications and (where necessary) the ethical implications. Divided into three sections, the first section introduces the role of biotechnology and genomics in medicine and sets out some of the technological advances that have been the basis of recent medical breakthroughs. The second section takes a closer look at how biotechnology and genomics are influencing the prevention and treatment of different categories of disease. Finally the contribution of biotechnology and genomics to the development of different types of therapy is descriTrade Review"Genomics is the more specialised...but still manages to cover an impressive array of topics relevant to human biology, including infectious disease, cancer and biopharmaceuticals. Wherever possible, the authors have gone out of their way to link technology and biological application." Paul B. Rainey, Times Higher Education Supplement, March 2004Table of ContentsChapter One: Biotechnology And Genomics In Medicine. Introduction. Recombinant DNA Technology. From Recombinant DNA To Molecular Medicine. Gene Medicine. Disease Models. The Impact Of Genomics On Medicine. The New Molecular Medicine. Outline Of This Book. Further Reading. Chapter Two: An Overview Of Genomics. Introduction. A Review Of Progress: The Human Genome Project. The Future: Functional Genomics. Mutational Genomics. Further Reading. Chapter Three: Genomics And The Challenge Of Infectious Disease. Microorganisms Causing Disease. Where Do New Diseases Come From?. Identifying The Causative Agent Of A Disease. Molecular Epidemiology. Host Resistance To Infection. Understanding Bacterial Pathogenicity. Comparative Genomics And Genome Plasticity. Combating Infectious Disease. Further Reading. Chapter Four: Analyzing And Treating Genetic Diseases. Genetic Disease In Context. Detecting Single Gene Disorders. Treating Single Gene Disorders. Finding Genes For Monogenic Diseases And Determining Gene Function. Analysis Of Polygenic Disorders. Haplotypes. The Major Histocompatibility Complex (MHC). Individual Responses To Drugs (Pharmacogenomics). Further Reading. Chapter Five: Diagnosis And Treatment Of Cancer. Introduction. The Impact Of Genomics On Cancer Research. New Methods For The Diagnosis Of Cancer. New Approaches To Cancer Therapy. Further Reading. Chapter Six: The Large Scale Production Of Biopharmaceuticals. Overview. The Generation Of Monoclonal Antibodies. The Large Scale Culture Of Microorganisms. The Large Scale Culture Of Animal Cells. Expression Systems. Downstream Processing. Using Gene Manipulation To Facilitate Downstream Processing. Of Biopharmaceuticals. The Quality Of Biopharmaceuticals. Good Manufacturing Practice. Alternative Production Systems. Further Reading. Chapter Seven: Genomics And The Development Of New Chemical Entities. Introduction. How Drugs Are Developed. High-Throughput Screening. Target Validation And Animal Models. Combinatorial Chemistry. Dynamic Combinatorial Libraries. Virtual Screening. Combinatorial Biosynthesis And Chemobiosynthesis. Drug Metabolism. Toxicogenomics. Further Reading. Chapter Eight: Gene And Cell Therapies. Introduction. Gene Therapy. Nucleic Acids As Drugs. DNA Vaccines. Disease Models. Cell Therapy. Further Reading.

Read more less

Book SynopsisPromises to remodel the way cardiovascular medicine is practised * Written and edited by two pioneers in this area * Specially selected material for the practising clinician * Must-have reference to this developing field to ensure up-to-date patient care .Trade Review"An excellent guide for developing, reviewing, or updating a keen understanding of genetics and its future in medicine. The book should find wide readership." Doodys ReviewTable of ContentsContributors. Foreword. Introduction. 1 The gene in the twenty-first century. Choong-Chin Liew, Victor J. Dzau. Part I: Cardiovascular single gene disorders. 2 Monogenic hypercholesterolemia. Ruth McPherson. 3 Hypertrophic cardiomyopathy. Ali J. Marian. 4 Dilated cardiomyopathy and other cardiomyopathies. Mitra Esfandiarei, Robert Yanagawa, Bruce M. McManus. 5 The long QT syndrome. Sabina Kupershmidt, Kamilla Kelemen, Tadashi Nakajima. Part II: Cardiovascular polygenic disorders. 6 Atherosclerosis. Päivi Pajukanta, Kiat Tsong Tan, Choong-Chin Liew. 7 Heart failure. Markus Meyer, Peter VanBuren. 8 The implications of genes on the pathogenesis, diagnosis and therapeutics of hypertension. Kiat Tsong Tan, Choong-Chin Liew. Part III: Therapies and applications. 9 Gene therapy for cardiovascular disease: inserting new genes, regulating the expression of native genes, and correcting genetic defects. Ion S. Jovin, Frank J. Giordano. 10 Stem cell therapy for cardiovascular disease. Emerson C. Perin, Guilherme V. Silva. 11 Pharmacogenetics and personalized medicine. Julie A. Johnson, Issam Zineh. 12 The potential of blood-based gene profiling for disease assessment. Steve Mohr, Choong-Chin Liew. Index. Colour plates

Read more less

Book SynopsisAdopted at Cambridge University Essential Medical Genetics provides students, clinicians, counsellors and scientists with the up-to-date information they need regarding the basic principles underlying medical genetics. It also provides guidance on how to apply current knowledge in clinical contexts, covering a wide variety of topics: from genome structure and function to mutations, screening and risk assessment for inherited disorders. This sixth edition has been substantially updated to include, for instance, the latest information on the Human Genome Project as well as several new molecular genetic and chromosome analysis techniques.In full colour throughout, it includes a number of brand new features, including: a large number of self-assessment questions; ''Essentials'' chapter summaries; further reading suggestions; and case study scenarios introducing clinical situations. An invaluable new section gives illustrated practical advice regarding Trade Review“Essential Medical Genetics is the perfect resource for a course on medical genetics, and is now accompanied by a regularly updated website and the FREE enhanced Wiley Desktop Edition (upon purchase of the book) .” (MedReport, 9 October 2012) “I have watched this textbook from its first inception and was disappointed that there was no new edition for so many years. Having waited, the result now is excellent and it has overcome my preference for Emery's Elements as a basic human genetics text.” Emeritus Professor in Clinical Genetics "I find the reference to electronic resources particularly useful, especially for people who approach clinical genetics for the first time and are not familiar with these tools." Dr Sixto García-Miñaúr, Imperial College London, and Hospital Universitario La Paz, Madrid, Spain Reviews of the previous edition "This book is an easy to read, well illustrated introduction to medical genetics. It deals nicely with all the classical aspects of the subject..." Black Bag, Medical Students' Society of Bristol University "...a justifiably popular introductory text." The British Medical JournalTable of ContentsPreface vii Acknowledgements ix How to get the best out of your textbook x Part 1: Basic principles 1 1 Medical genetics in perspective 3 Scientific basis of medical genetics 5 Clinical applications of medical genetics 9 2 The human genome 13 Structure and organisation of the genome 14 Gene identification 14 Th e Human Genome Project 14 3 Nucleic acid structure and function 23 Nucleic acid structure 24 Nucleic acid function 26 Gene regulation 29 DNA replication 31 Mutation types, eff ects and nomenclature 32 4 DNA analysis 41 Basic methods 42 Mutation detection 43 Indirect mutant gene tracking 52 Analysis of DNA length polymorphisms 53 Analysis of single-nucleotide polymorphisms 54 5 Chromosomes 57 Chromosome structure 58 Chromosome analysis 59 Chromosome heteromorphisms 65 Chromosomes in other species 66 Mitochondrial chromosomes 68 Mitosis 69 6 Gametogenesis 73 Meiosis 74 Spermatogenesis 76 Oogenesis 78 Fertilisation 78 X-inactivation and dosage compensation 79 Sex chromosome aberrations 80 Sex determination and differentiation 83 Genomic imprinting (parental imprinting) 83 7 Chromosome aberrations 89 Numerical aberrations 90 Structural aberrations 92 Cytogenetic and molecular methods for the detection of chromosomal aberrations 100 Identification of the chromosomal origin of complex structural rearrangements 107 Other aberrations 111 8 Typical Mendelian inheritance 117 Introduction to autosomal single-gene inheritance 118 Autosomal dominant inheritance 118 Autosomal recessive inheritance 120 Introduction to sex-linked inheritance 123 X-linked recessive inheritance 125 X-linked dominant inheritance 127 Y-linked inheritance (holandric inheritance) 128 9 Atypical Mendelian inheritance 131 Genetic anticipation 132 Pseudoautosomal inheritance 134 Autosomal dominant inheritance with sex limitation 134 Pseudodominant inheritance 134 X-linked dominant inheritance with male lethality 135 Mosaicism 135 Modifi er genes and digenic inheritance 135 Uniparental disomy 136 Imprinting disorders 136 10 Non-Mendelian inheritance 141 Multifactorial disorders 142 Somatic cell genetic disorders 147 Mitochondrial disorders 147 11 Medical genetics in populations 151 Selection for single-gene disorders 152 Founder effect and genetic drift for single-gene disorders 153 Altered mutation rate for single-gene disorders 154 Linkage analysis and the International Hapmap Project 154 Human population evolution and migration 155 Part 2: Clinical applications 161 12 Genetic assessment, genetic counselling and reproductive options 163 Communication of advice 164 Special points in counselling 168 Prenatal diagnosis 170 Amniocentesis 170 Chorionic villus sampling 174 Cordocentesis, fetal skin biopsy and fetal liver biopsy 175 Ultrasonography 175 Fetal cells in the maternal circulation 175 Free fetal DNA and RNA detection 175 Preimplantation genetic diagnosis 176 13 Family history of cancer 179 General principles 180 Tumour suppressor genes 181 Genes involved in DNA repair mechanisms 187 Oncogenes 187 Other cancer-related genes 189 Genetic counselling aspects of cancer 189 Common familial cancer predisposition syndromes 189 14 Family history of common adult-onset disorder 199 General principles 200 Diabetes mellitus: common and monogenic forms 200 Dementia: Alzheimer disease, Huntington disease, prion diseases and other causes 202 15 Strong family history – typical Mendelian disease 209 Cystic fibrosis 210 Duchenne and Becker muscular dystrophies 212 Neurofi bromatosis type 1 214 16 Strong family history – other inheritance mechanisms 219 Myotonic dystrophy 220 Fragile X syndrome 221 Mitochondrial disorder 222 Imprinting-related disorder 223 Chromosomal translocation 224 17 Screening for disease and for carriers 229 Prenatal screening 230 Neonatal screening 233 Carrier detection in the adult population 234 Presymptomatic screening of adults 237 18 Family history of one or more congenital malformations 241 Aetiology 242 Chromosomal disorders 243 Neural tube defects 247 Teratogenic eff ects 250 Multiple malformation syndromes 253 Part 3: Electronic databases – a user's guide 265 19 Electronic databases – a user's guide 267 Finding information regarding specifi c conditions and names of associated genes 268 Laboratories undertaking genetic testing 270 Patient information and support groups 270 Gene- and protein-specifi c sequence, structure, function and expression information 272 Nucleotide sequences and human mutations 281 Automatic primer design tools 281 Displaying map data for genes and markers 287 Online missense mutation analysis tools 288 Computer-aided syndrome diagnosis 293 Professional genetics societies 297 Th e Human Genome Project: ethics and education 297 Self-assessment – answers 305 Appendix 1: Odds, probabilities and applications of Bayes’ theorem 312 Appendix 2: Calculation of the coeffi cients of relationship and inbreeding 314 Appendix 3: Population genetics of single-gene disorders 315 Appendix 4: Legal aspects 317 Glossary 318 Index 324

Read more less

Book SynopsisWith its unique combination of the latest research, expert advice, and compelling personal stories, this book gives previvors, survivors, and their family members the guidance they need to face the unique challenges of hereditary cancer.Trade ReviewA fine resource discussing the challenges of living in a high-risk body. Midwest Book Review An insightful and informative read. Nursing Times A top pick for any breast cancer collection. Midwest Book Review This book is an excellent resource for lay people trying to understand and deal with inherited breast and ovarian cancer. -- Judith Offman Journal of Family Planning and Reproductive HealthcareTable of ContentsForeword by Mark H. Greene, M.D.AcknowledgmentsIntroductionPart I: Understanding Cancer, Genetics, and Risk1. Breast and Ovarian Cancer BasicsMost Cancers Aren't HereditaryAn Introduction to Breast CancerAn Introduction to Ovarian CancerOther Hereditary Cancers2. A Peek Inside: Your Genes at WorkThe Evolution of Genetic Discovery: From Peas to BRCAYour Genetic ABCs . . . and a DMutations: Spelling Errors in Your DNA CookbookHow Mutations Lead to CancerWhat's So Special about BRCA?3. Defining RiskMaking Sense of StatisticsGetting Personal: Factors That Modify Your RiskIt's a Numbers Game4. Hereditary Cancer: What's Swimming in Your Gene Pool?Mutations from Mom or DadHidden Risk in the Family TreeHBOC and Other Hereditary Cancer SyndromesPlotting Your Genetic PedigreePart II: Assessing Your Risk5. Genetic CounselingThe Value of CounselingWhat to Expect from the ProcessWhy You Need an Expert to Unravel Your Genetic HistoryDeciding Who Should Test First6. Genetic Testing: Facing Your Hereditary HoroscopeWhich Test Is Right for You?Powerful, Yet ImperfectIssues for Survivors and Women in Treatment7. Decoding Your Test ResultsLife, Interrupted: It's PositiveGood News! You're a True NegativeWhen No Might Mean MaybeGenetic VariantsNow What? Implications for You and Your FamilyPart III: Managing Your Risk: Your DNA Doesn't Have to Be Your Destiny8. Early Detection StrategiesHigh-Risk Surveillance for Breast CancerHigh-Risk Surveillance for Ovarian CancerIs It Cancer?Screening for Other Hereditary Cancers9. ChemopreventionRisk-Reducing Medications for Breast CancerAlternatives under StudyChemoprevention for Ovarian Cancer10. Mastectomy for Risk Reduction and TreatmentReducing Cancer Risk by Removing the BreastsSkin-Sparing ProceduresTreating Breast Cancer with MastectomyWho Should Perform Your Surgery?Risks and Recovery11. Reconstruction: New Breasts after MastectomyDelaying Reconstruction to Complete Breast Cancer TreatmentLiving with a Flat ChestSaline and Silicone ImplantsOptions for Using Your Own TissueOptional Last Steps: Adding Nipples and AreolasGreat Expectations: Surgery and RecoveryChoosing the Right Surgeon12. Oophorectomy and Other Risk-Reducing Gynecologic SurgeriesOophorectomy ProceduresShould You Have a Hysterectomy Too?Oophorectomy, Mastectomy: Either, Neither, or Both?Issues for Breast Cancer Survivors13. Dealing with Menopause and Quality-of-Life IssuesSymptoms of Surgical MenopauseLong-Term Side EffectsShould You Take Hormones?Issues for Breast Cancer SurvivorsPart IV: Living with BRCA: Issues and Answers14. Managing Lifestyle ChoicesThe Three-Legged Stool: Nutrition, Weight, and Physical ActivityAlcohol: An Unwise ChoiceOther Lifestyle Risk Factors15. Sharing Information with Friends, Family, and CoworkersSharing Risk and Genetic Testing Information with FamilyIssues for Spouses, Partners, and People You DateWhat Should You Tell Employers and Coworkers?16. Young and at High RiskShould You Consider Testing Now?Diagnostic DifficultiesDealing with a Diagnosis before MenopausePlanning Your Family, Preserving Your FertilityOophorectomy in Young WomenSorting through Emotions17. How BRCA Affects MenMen Get Breast Cancer TooHigh Risk for Prostate CancerOther BRCA-Related Cancers18. Diagnosis: Hereditary CancerHow Important Is a Second Opinion?Treating Hereditary CancersMaking Breast Cancer Treatment DecisionsOvarian Cancer IssuesThe Importance of Clinical Trials19. Putting the Pieces Together to Make Difficult DecisionsStart at the Beginning: Should You Be Tested?Making Decisions to Reduce Your RiskMaking Decisions about TreatmentFrom Confused to Clear in Fifteen StepsNotesIndex

Read more less

Book SynopsisWith its unique combination of the latest research, expert advice, and compelling personal stories, this book gives previvors, survivors, and their family members the guidance they need to face the unique challenges of hereditary cancer.Trade ReviewA fine resource discussing the challenges of living in a high-risk body. Midwest Book Review An insightful and informative read. Nursing Times A top pick for any breast cancer collection. Midwest Book Review This book is an excellent resource for lay people trying to understand and deal with inherited breast and ovarian cancer. -- Judith Offman Journal of Family Planning and Reproductive HealthcareTable of ContentsForeword by Mark H. Greene, M.D.AcknowledgmentsIntroductionPart I: Understanding Cancer, Genetics, and Risk1. Breast and Ovarian Cancer BasicsMost Cancers Aren't HereditaryAn Introduction to Breast CancerAn Introduction to Ovarian CancerOther Hereditary Cancers2. A Peek Inside: Your Genes at WorkThe Evolution of Genetic Discovery: From Peas to BRCAYour Genetic ABCs . . . and a DMutations: Spelling Errors in Your DNA CookbookHow Mutations Lead to CancerWhat's So Special about BRCA?3. Defining RiskMaking Sense of StatisticsGetting Personal: Factors That Modify Your RiskIt's a Numbers Game4. Hereditary Cancer: What's Swimming in Your Gene Pool?Mutations from Mom or DadHidden Risk in the Family TreeHBOC and Other Hereditary Cancer SyndromesPlotting Your Genetic PedigreePart II: Assessing Your Risk5. Genetic CounselingThe Value of CounselingWhat to Expect from the ProcessWhy You Need an Expert to Unravel Your Genetic HistoryDeciding Who Should Test First6. Genetic Testing: Facing Your Hereditary HoroscopeWhich Test Is Right for You?Powerful, Yet ImperfectIssues for Survivors and Women in Treatment7. Decoding Your Test ResultsLife, Interrupted: It's PositiveGood News! You're a True NegativeWhen No Might Mean MaybeGenetic VariantsNow What? Implications for You and Your FamilyPart III: Managing Your Risk: Your DNA Doesn't Have to Be Your Destiny8. Early Detection StrategiesHigh-Risk Surveillance for Breast CancerHigh-Risk Surveillance for Ovarian CancerIs It Cancer?Screening for Other Hereditary Cancers9. ChemopreventionRisk-Reducing Medications for Breast CancerAlternatives under StudyChemoprevention for Ovarian Cancer10. Mastectomy for Risk Reduction and TreatmentReducing Cancer Risk by Removing the BreastsSkin-Sparing ProceduresTreating Breast Cancer with MastectomyWho Should Perform Your Surgery?Risks and Recovery11. Reconstruction: New Breasts after MastectomyDelaying Reconstruction to Complete Breast Cancer TreatmentLiving with a Flat ChestSaline and Silicone ImplantsOptions for Using Your Own TissueOptional Last Steps: Adding Nipples and AreolasGreat Expectations: Surgery and RecoveryChoosing the Right Surgeon12. Oophorectomy and Other Risk-Reducing Gynecologic SurgeriesOophorectomy ProceduresShould You Have a Hysterectomy Too?Oophorectomy, Mastectomy: Either, Neither, or Both?Issues for Breast Cancer Survivors13. Dealing with Menopause and Quality-of-Life IssuesSymptoms of Surgical MenopauseLong-Term Side EffectsShould You Take Hormones?Issues for Breast Cancer SurvivorsPart IV: Living with BRCA: Issues and Answers14. Managing Lifestyle ChoicesThe Three-Legged Stool: Nutrition, Weight, and Physical ActivityAlcohol: An Unwise ChoiceOther Lifestyle Risk Factors15. Sharing Information with Friends, Family, and CoworkersSharing Risk and Genetic Testing Information with FamilyIssues for Spouses, Partners, and People You DateWhat Should You Tell Employers and Coworkers?16. Young and at High RiskShould You Consider Testing Now?Diagnostic DifficultiesDealing with a Diagnosis before MenopausePlanning Your Family, Preserving Your FertilityOophorectomy in Young WomenSorting through Emotions17. How BRCA Affects MenMen Get Breast Cancer TooHigh Risk for Prostate CancerOther BRCA-Related Cancers18. Diagnosis: Hereditary CancerHow Important Is a Second Opinion?Treating Hereditary CancersMaking Breast Cancer Treatment DecisionsOvarian Cancer IssuesThe Importance of Clinical Trials19. Putting the Pieces Together to Make Difficult DecisionsStart at the Beginning: Should You Be Tested?Making Decisions to Reduce Your RiskMaking Decisions about TreatmentFrom Confused to Clear in Fifteen StepsNotesIndex

Read more less

Book SynopsisShares experiences of living with genetic disorders. This title includes stories that illustrate the complexities involved in making decisions about genetic diseases: whether to be tested, who to tell, whether to have children, and whether and how to treat children medically, if treatment is available.Trade ReviewA compelling collection of essays that address the experiences of many who have genetically based illnesses... These pieces can comfort those in similar situations; inform friends, relatives, and caregivers; enlighten health providers; and help us all better understand how others experience the world in which we live. VERDICT Recommended for those who are touched by genetic disorders or are interested in health in the modern world. Library Journal If there were an All-Star Team for memoirists struggling with genetic misfortune... The Story Within would surely be it. -- Patrick Tracey PsychCentral Thought provoking, moving and extremely interesting. -- Jane Brown Nursing Times For those who have traveled a similar path and who have faced genetic illnesses, these stories can be a source of comfort. These stories can also help inform and educate and generate much needed dialogue about health and body norms. The narratives in The Story Within are a reminder that every life has value. -- Dena Hurst Metapsychology The Story Within is a true success of a collection. With joy, rigor, and respect, it strvies to reconcile something like the original (one-of-a-kind) and the originator (universal), the literal (DNA) and the literary (collected essays). Original review below -- Adrien Guignard Gesnerus The Story Within est un collectif reussi. Il s'efforce avec bonheur, rigueur et respect de concilier quelque chose comme l'orignal (singulier) et l'originaire (universel), le litteral (de l'ADN) et le litteraire (des textes reunis). -- Adrien Guignard Gesnerus When medical students really feel that they understand genetics... let them read The Story Within and be brought down to earth with a bang. I know I was. BioNewsTable of ContentsAcknowledgmentsIntroductionPart I: Finding Out: Genetics and Ideas of SelfChapter 1. UndiagnosedChapter 2. Driving NorthChapter 3. Collateral DamageChapter 4. In SamarraChapter 5. The UnnumberedPart II: Intervening: Living with Genetic DifferenceChapter 6. Of Helices, HIPAA, Hairballs . . . and HumansChapter 7. The Power of Two: Two Sisters, Two Genes, and Two New Chances at LifeChapter 8. Permission to Look: Documenting the BRCA MutationChapter 9. "Why Would You Be Wantin' to Know?" Not Talking about Schizophrenia in IrelandChapter 10. Help WantedChapter 11. Community and Other Ordinary MiraclesPart III: Passing Down: Genetics and FamilyChapter 12. String Theory, or How One Family Listens Through DeafnessChapter 13. What IfChapter 14. The Long ArmChapter 15. Lettuce and ShoesChapter 16. Dear Dr. Frankenstein: Creation Up CloseEpilogueNotesList of ContributorsIndex

Read more less

Book SynopsisThe questions it raises touch on ongoing controversies about newborn screening and what happens to blood samples collected at birth.Trade ReviewPaul and Brosco are to be congratulated on producing an extremely worthwhile, interesting and very readable book. I highly recommend it to geneticists, bioethicists, to those directly or indirectly involved in newborn screening, and to all others who wish to understand the basis for the current enthusiasm about the role of genetics and genetic screening in health and the prevention of disease. -- Harvey L. Levy Journal of Medical Genetics The PKU Paradox will be essential reading for anyone interested in the sociocultural, ethical and historical aspects of PKU and newborn screening more generally. -- Mara Buchbinder Social History of Medicine This book is a fascinating biography of this syndrome... enriched by illustrations from public health campaigns, advertising material for PKU-friendly supplements, and interviews with people who have lived with PKU and who have given first-hand accounts of their lived experience... The PKU Paradox is a useful and provoking addition to the Biographies of Disease series. -- Philippa Martyr Health and History The ability to illustrate a wide range of historical themes through a single, compelling case will make The PKU Paradox particularly useful for undergraduate teaching, as will the short, concisely written chapters. It is not an easy task to clearly portray the history of a subject as complex and elusive as disease, and Paul and Brosco have done an admirable job in this regard. The PKU Paradox will be essential reading for anyone interested in the sociocultural, ethical and historical aspects of PKU and newborn screening more generally. -- Mara Buchbinder Social History of Medicine Paul and Brosco are to be commended for reminding us all how central the PKU story has been to the development of genetics and medicine, the connection of genotype to phenotype to society, and to the way this society views people with intellectual disabilities. This is a book that should be read by all geneticists and physicians and people with an interest and concern about individuals for with intellectual impairments. -- John B. Jenkins Quarterly Review of Biology The PKU Paradox is a clearly and engagingly written book that provides an excellent introduction to the history of a disease and its broader implications in twentieth-century biomedicine. -- Soraya De Chadarevian Isis This is a deeply researched and most readable history of PKU from its discovery in 1930... up to the success story of the present day. -- Neil R. M. Buist Journal of Inherited Metabolic Disease Significant book for readers interested in understanding the many factors and intricacies involved in the history of diseases, in particular genetic diseases... Provides a compelling argument against the simplistic and persistent view that genetic diseases are fixed in the lab. Instead, it proposes a complex contextual history, not only a more persuasive one, but also one that provides a model for comprehensive study of other diseases, genetic or not. British Journal for the History of Science Paul and Brosco enable the reader to shift their gaze from PKU the paradigm to PKU the disease, in all its historical and biological complexity. For this reason, this book will be of interest to historians and practitioners of medicine alike. Moreover, it also serves as an excellent example of the constructive possibilities inherent in a collaboration between historians and physicians, and indeed, of the value of such an approach. University of Toronto Medical JournalTable of ContentsForeword, by Charles E. RosenbergPrefaceList of AbbreviationsIntroduction: Pearl Buck, PKU, and Mental Retardation1. The Discovery of PKU as a Metabolic Disorder2. PKU as a Form of Cognitive Impairment3. Testing and Treating Newborns, 1950–19624. The Campaign for Mandatory Testing5. Sources of Skepticism6. New Paradigms for PKU7. Living with PKU8. The Perplexing Problem of Maternal PKU9. Who Should Procreate? Perspectives on Reproductive Choice and Responsibility in Postwar America10. Newborn Screening ExpandsEpilogue: "The Government Has Your Baby's DNA": Contesting the Storage and Secondary Use of Residual Dried Blood SpotsAcknowledgmentsA Note on SourcesNotesIndex

Read more less

Book SynopsisThis guide is essential for health professionals seeking more information about this underdiagnosed disease.Trade ReviewThis book is an excellent basic overview of HHT. It describes the condition, the difficulties often found in diagnosis, current and potential future treatments, as well as emotional and social effects for both patients and their families along with coping strategies. Throughout, the ability to live well with knowledge and appropriate care is emphasized.—Jeffrey Pollak, MD, Katharine Henderson, MS, Department of Radiology and Biomedical Imaging, Yale School of Medicine, New Haven, CT, Journal of Radiology NursingTable of ContentsAcknowledgmentsIntroductionPart I1. Diagnosis2. The Trouble with Telangiectasias3. HHT's Hidden DangersPart II4. Taking Care of Yourself5. Taking Care of Your Family6. Beyond the FamilyPart III7. Frontiers in HHT ResearchNotesGlossaryResourcesIndex

Read more less

Book SynopsisThe most comprehensive guide available on hereditary cancers, from understanding risk, prevention, and genetic counseling and testing to treatment, quality of life, and more. Up to 10 percent of cancers are caused by inherited mutations in specific genes. Finding out that you or your loved ones may be at increased risk of developing cancer because of a genetic mutation raises a lot of questions: Is cancer inevitable? Is there anything I should do differently in my life? Will my children also be at higher risk of cancer? Should I have preemptive treatments or surgery? This comprehensive guide provides answers to these questions and more. Written by three passionate patient advocates, this book is a compilation of the trusted information and support provided for more than two decades by Facing Our Risk of Cancer Empowered (FORCE), the de facto voice of the hereditary cancer community. Combining the latest scientific research with national guidelines, expert advice, and compelling patieTable of ContentsList of TablesForeword, by Matthew Boland Yurgelun, MDIntroductionPart I. Understanding Cancer and Inherited Risk1. The Link between Genetics and CancerThe Basics of GeneticsGene Wear and Tear and Repair How Cancers Develop and Grow Most Cancers Aren't Caused by Inherited Mutations2. What's Swimming in Your Gene Pool?Hidden Risk in the Family TreePlotting Your Genetic Pedigree3. Signs of Hereditary CancerThe Value of Genetic Counseling Making Decisions about Testing Insurance CoveragePrivacy and Protection4. What Your Test Results Tell YouPositive, Negative, Maybe Making Sense of StatisticsYou Have a Mutation; Now What?Part II. Inherited Gene Mutations and the Cancers They Cause5. Introducing BRCA1 and BRCA2Who Inherits a BRCA Mutation?Signs of a BRCA MutationLevels of Risk6. Lynch Syndrome: Five Genes, One Hereditary SyndromeSigns of Lynch Syndrome in FamiliesLevels of Risk7. Other Genes That Are Linked to Inherited Cancer RiskLess Known, Less Studied Genes8. Breast Cancer BasicsSigns and SymptomsWhat Affects Breast Cancer Risk?Types of Breast Cancer9. Gynecologic CancersOvarian, Fallopian Tube, and Primary Peritoneal CancersEndometrial Cancers10. Gastrointestinal CancersColorectal CancerSmall Bowel CancerPancreatic CancerStomach CancerAnal Cancer11. Genitourinary CancersProstate CancerBladder, Ureter, and Renal Pelvis Cancers12. MelanomaMelanoma of the SkinOcular MelanomaPart III. Strategies for Risk Reduction and Early Detection13. Risk Management GuidelinesGuidelines for BRCA1 or BRCA2 Gene MutationsGuidelines for Lynch Syndrome Gene MutationsGuidelines for Mutations in Other Genes14. Early Detection Strategies for High-Risk PeopleThe Vocabulary of ScreeningSurveillance for Breast CancerSurveillance for Gynecologic CancersSurveillance for Gastrointestinal CancersSurveillance for Prostate and Other Genitourinary Cancers Surveillance for MelanomaScreening for Other Hereditary Cancers15. Medications That Reduce Cancer RiskRisk-Reducing Medications for Breast CancerRisk-Reducing Medications for Gynecologic CancersRisk-Reducing Medications for Colorectal Cancers16. Surgeries That Reduce Breast Cancer RiskMastectomy ProceduresBreast Reconstruction ChoicesSide Effects, Risks, and Recovery17. Surgeries That Reduce the Risk of Gynecologic CancersSalpingo-Oophorectomy to Reduce the Risk of Ovarian CancerHysterectomy to Reduce the Risk of Endometrial Cancer18. Surgeries That Reduce the Risk of Gastrointestinal CancersTotal and Segmental Colectomy to Reduce the Risk of Colon CancerTotal Gastrectomy to Reduce the Risk of Stomach Cancer19. Factors That Affect Cancer RiskNutrition, Weight, and Physical Activity Alcohol: An Unwise ChoiceSmoking and Tobacco ProductsOther Lifestyle and Behavioral Risk FactorsPart IV. Treatment Choices for Hereditary Cancers20. Identifying Tumor Characteristics That Inform Treatment ChoicesStaging and Grading CancerTargeted Approaches to TreatmentDNA Damage Repair Genes21. Treating Breast CancerCancer Type, Subtype, and StageBiomarker TestingGenetic TestingOptions for TreatmentFollow-Up Care22. Treating Gynecologic CancersOptions for Ovarian, Fallopian Tube, and Primary Peritoneal CancersOptions for Endometrial Cancer23. Treating Gastrointestinal CancersOptions for Colorectal CancerOptions for Pancreatic CancerOptions for Gastric Cancer24. Treating Genitourinary CancersOptions for Prostate CancerOptions for Bladder, Renal Pelvis, and Ureter Cancers25. Treating Melanoma Options for Melanoma in the SkinOptions for Ocular MelanomaPart V. Living with Inherited High Risk26. Regaining Sexual Health and IntimacyBody ImageCoping with PainReduced Sexual DesireErectile DysfunctionRebuilding Intimacy27. Effects of Prevention and Treatment on FertilityPreserving Fertility in WomenPreserving Fertility in MenOther Parenting Alternatives28. Managing MenopauseSymptoms of Early MenopauseReplacement HormonesLong-Term Side Effects29. Side Effects and Other Quality-of-Life IssuesSummarizing Side Effects by TreatmentManaging Immediate Side EffectsLong-Term Effects of Prevention and TreatmentPrevivorship, Survivorship, and Follow-Up CareEnd-of-Life Issues30. Making Difficult Decisions Start at the Beginning: Should You Be Tested?Decisions about Your Cancer RiskDecisions about TreatmentPrevention and Treatment Clinical TrialsDecision-Making in 15 Steps31. You Are Not AloneCreate a Support SystemFind Emotional StrengthPursue Financial ResourcesLook to the HorizonAcknowledgmentsGlossaryNotesResourcesIndex

Read more less

Book SynopsisThe most comprehensive guide available on hereditary cancers, from understanding risk, prevention, and genetic counseling and testing to treatment, quality of life, and more. Up to 10 percent of cancers are caused by inherited mutations in specific genes. Finding out that you or your loved ones may be at increased risk of developing cancer because of a genetic mutation raises a lot of questions: Is cancer inevitable? Is there anything I should do differently in my life? Will my children also be at higher risk of cancer? Should I have preemptive treatments or surgery? This comprehensive guide provides answers to these questions and more. Written by three passionate patient advocates, this book is a compilation of the trusted information and support provided for more than two decades by Facing Our Risk of Cancer Empowered (FORCE), the de facto voice of the hereditary cancer community. Combining the latest scientific research with national guidelines, expert advice, and compelling patieTable of ContentsList of TablesForeword, by Matthew Boland Yurgelun, MDIntroductionPart I. Understanding Cancer and Inherited Risk1. The Link between Genetics and CancerThe Basics of GeneticsGene Wear and Tear and Repair How Cancers Develop and Grow Most Cancers Aren't Caused by Inherited Mutations2. What's Swimming in Your Gene Pool?Hidden Risk in the Family TreePlotting Your Genetic Pedigree3. Signs of Hereditary CancerThe Value of Genetic Counseling Making Decisions about Testing Insurance CoveragePrivacy and Protection4. What Your Test Results Tell YouPositive, Negative, Maybe Making Sense of StatisticsYou Have a Mutation; Now What?Part II. Inherited Gene Mutations and the Cancers They Cause5. Introducing BRCA1 and BRCA2Who Inherits a BRCA Mutation?Signs of a BRCA MutationLevels of Risk6. Lynch Syndrome: Five Genes, One Hereditary SyndromeSigns of Lynch Syndrome in FamiliesLevels of Risk7. Other Genes That Are Linked to Inherited Cancer RiskLess Known, Less Studied Genes8. Breast Cancer BasicsSigns and SymptomsWhat Affects Breast Cancer Risk?Types of Breast Cancer9. Gynecologic CancersOvarian, Fallopian Tube, and Primary Peritoneal CancersEndometrial Cancers10. Gastrointestinal CancersColorectal CancerSmall Bowel CancerPancreatic CancerStomach CancerAnal Cancer11. Genitourinary CancersProstate CancerBladder, Ureter, and Renal Pelvis Cancers12. MelanomaMelanoma of the SkinOcular MelanomaPart III. Strategies for Risk Reduction and Early Detection13. Risk Management GuidelinesGuidelines for BRCA1 or BRCA2 Gene MutationsGuidelines for Lynch Syndrome Gene MutationsGuidelines for Mutations in Other Genes14. Early Detection Strategies for High-Risk PeopleThe Vocabulary of ScreeningSurveillance for Breast CancerSurveillance for Gynecologic CancersSurveillance for Gastrointestinal CancersSurveillance for Prostate and Other Genitourinary Cancers Surveillance for MelanomaScreening for Other Hereditary Cancers15. Medications That Reduce Cancer RiskRisk-Reducing Medications for Breast CancerRisk-Reducing Medications for Gynecologic CancersRisk-Reducing Medications for Colorectal Cancers16. Surgeries That Reduce Breast Cancer RiskMastectomy ProceduresBreast Reconstruction ChoicesSide Effects, Risks, and Recovery17. Surgeries That Reduce the Risk of Gynecologic CancersSalpingo-Oophorectomy to Reduce the Risk of Ovarian CancerHysterectomy to Reduce the Risk of Endometrial Cancer18. Surgeries That Reduce the Risk of Gastrointestinal CancersTotal and Segmental Colectomy to Reduce the Risk of Colon CancerTotal Gastrectomy to Reduce the Risk of Stomach Cancer19. Factors That Affect Cancer RiskNutrition, Weight, and Physical Activity Alcohol: An Unwise ChoiceSmoking and Tobacco ProductsOther Lifestyle and Behavioral Risk FactorsPart IV. Treatment Choices for Hereditary Cancers20. Identifying Tumor Characteristics That Inform Treatment ChoicesStaging and Grading CancerTargeted Approaches to TreatmentDNA Damage Repair Genes21. Treating Breast CancerCancer Type, Subtype, and StageBiomarker TestingGenetic TestingOptions for TreatmentFollow-Up Care22. Treating Gynecologic CancersOptions for Ovarian, Fallopian Tube, and Primary Peritoneal CancersOptions for Endometrial Cancer23. Treating Gastrointestinal CancersOptions for Colorectal CancerOptions for Pancreatic CancerOptions for Gastric Cancer24. Treating Genitourinary CancersOptions for Prostate CancerOptions for Bladder, Renal Pelvis, and Ureter Cancers25. Treating Melanoma Options for Melanoma in the SkinOptions for Ocular MelanomaPart V. Living with Inherited High Risk26. Regaining Sexual Health and IntimacyBody ImageCoping with PainReduced Sexual DesireErectile DysfunctionRebuilding Intimacy27. Effects of Prevention and Treatment on FertilityPreserving Fertility in WomenPreserving Fertility in MenOther Parenting Alternatives28. Managing MenopauseSymptoms of Early MenopauseReplacement HormonesLong-Term Side Effects29. Side Effects and Other Quality-of-Life IssuesSummarizing Side Effects by TreatmentManaging Immediate Side EffectsLong-Term Effects of Prevention and TreatmentPrevivorship, Survivorship, and Follow-Up CareEnd-of-Life Issues30. Making Difficult Decisions Start at the Beginning: Should You Be Tested?Decisions about Your Cancer RiskDecisions about TreatmentPrevention and Treatment Clinical TrialsDecision-Making in 15 Steps31. You Are Not AloneCreate a Support SystemFind Emotional StrengthPursue Financial ResourcesLook to the HorizonAcknowledgmentsGlossaryNotesResourcesIndex

Read more less

Book SynopsisThousands of methods have been developed in the various biomedical disciplines, and those covered in this book represent the basic, essential and most widely used methods in several different disciplines. Table of Contents1: Detection And Analysis Of Proteins A. Introduction B. Basic methods for protein analysis C. Characterization of primary, secondary, tertiary and quaternary structures of proteins 2: Detection And Analysis Of Nucleic Acids A. Introduction B. Basic methods for nucleic acid analysis C. DNA sequencing D. Detection and quantitation of RNA 3: Recombinant DNA Techniques: Cloning And Manipulation Of DNA A. Introduction B. Plasmid and viral vectors C. Libraries D. Site Directed Mutagenesis E. Polymerase chain reaction (PCR) F. Screening for differentially expressed genes (DEGs) G. Promoter-protein interactions H. Silencing gene expression I. Forensics and DNA technology 4: Antibody-Based Techniques A. Introduction B. Monoclonal antibodies C. Purification and use of antibodies D. Flow cytometry and fluorescence activated cell sorting (FACS) E. Other assays using antibodies 5: Microscopy: Imaging Of Biological Specimens A. Introduction B. Light microscopy C. Fluorescence and laser confocal microarray microscopy D. Electron Microscopy (EM) E. Magnetic resonance imaging (MRI) 6: The Derivation And Manipulation Of Experimental Animals In Biomedical Sciences A. Introduction B. Inbred strains of mice C. Congenic strains of mice D. Transgenic mice E. Targeted transgenes: 'knockout' and 'knockin' mice F. Other uses of mice in biomedical research References Some excellent methodology manuals Index

Read more less

Book SynopsisMedicine has recently discovered spectacular tools for human enhancement. Yet to date, it has failed to use them well, in part because of ethical objections. Meanwhile, covert attempts flourish to enhance with steroids, mind-enhancing drugs, and cosmetic surgeryall largely unstudied scientifically. The little success to date has been sporadic and financed privately. In How to Build a Better Human, prominent bioethicist Gregory E. Pence argues that people, if we are careful and ethical, can use genetics, biotechnology, and medicine to improve ourselves, and that we should publicly study what people are doing covertly. Pence believes that we need to transcend the two common frame stories of bioethics: bioconservative alarmism and uncritical enthusiasm, and that bioethics should become part of the solutionnot the problemin making better humans.Trade ReviewHuman enhancement is an important topic. However, too many authors dwell on improbable scenarios, such as genetic engineering of super-babies. By contrast, this book tackles the real ethical dilemmas that our society faces today. Is it wrong for healthy college students to boost academic performance with Ritalin and similar drugs? Is increased longevity a bane or a boon? How can simple interventions like good nutrition and vaccinations produce children who are not only healthier but smarter? Professor Gregory Pence uses science, logic, and ethics to analyze these and many other topics. Along the way, he explains why we need not fear designer babies and other Brave New World scenarios. Legislators and other policymakers should read this timely and fascinating book so that they will know what to regulate—and what to leave alone -- Kerry Lynn Macintosh, Santa Clara UniversityFrom Frankenstein to GATTACA innovative biomedical technologies have been portrayed as bogeymen and dystopias. Bringing commonsense to bear on subjects often misrepresented by enthusiasts and alarmists, bioethics professor Gregory Pence, author of Whose Afraid of Human Cloning, clarifies the science and dispels the hype and paranoia surrounding the bioethics of everyday life. He offered reasonable answers to such questions as: Should I use life extending medical or mind enhancing drugs? Is there anything wrong with extending peoples' lives? Should I vaccinate my children? Is it OK to take anti-depressants? Is there something to fear from the new genetics or from stem cell research? How to Build a Better Human provides astute and invaluable advice on these issues and is without a doubt the best "How To" book ever published in bioethics. -- Robert Baker, Union Graduate College, FiT PublishingGregory E. Pence has managed to wed nuance, rigor and wit in the service of one of the thorniest issues in bioethics. The debate over human enhancement is too often shaped by ideologues and zealots – and too infrequently informed by the kind of thoughtful and enjoyable analysis found in How to Build a Better Human. -- Kenneth W. Goodman, University of MiamiTable of ContentsPreface Part I—Competent Adults Chapter 1: What if Your Virtual Life Surpasses Your Real Life? Chapter 2: Lessons from Bioethics’ History Chapter 3: Expanding the Mind with Drugs Chapter 4: Building Better Female Bodies Chapter 5: Building Better Male Bodies Chapter 6: Is it Moral to Feel Better than Well? Chapter 7: Practical Ways to Build a Longer Life Chapter 8: Is It Wrong to Live to a Hundred? Chapter 9: Personalized Genomics: Caveat Emptor! Part II—Choosing Better, Future Children Chapter 10: Choosing a Better Embryo Chapter 11: Eugenic Abortions? Chapter 12: Building Better Fetuses in Utero Chapter 13: Building Better Kids at Birth: Vaccinations Chapter 14: Building Better Minds of Children: Ritalin and Adderal Part III—Changing Human Nature? Chapter 15: How Not to think about Genetic Enhancement Chapter 16: Human Enhancement; Six Psychosocial Objections Chapter 17: Overview: Cloning, Primordial Cells & Enhancement Chapter 18: Conclusions and Six Practical Proposals Acknowledgments

Read more less