Contents -- Contributors -- Foreword Francis S. Collins and Alan E. Guttmacher -- Acknowledgments -- Introduction . . .The Journey Inward Betty S. Pace -- PART I: THE HUMAN GENOME ERA, A HISTORIC PERSPECTIVE -- 1. Sickle Cell Disease: Demystifying the Beginnings Clarice Reid and Griffin Rodgers -- The Precursors -- The National Sickle Cell Disease Program -- Clinical Advances -- Summary -- References -- 2. Sponsorship of Sickle Cell Disease Research by the National Institutes of Health: A Brief History and Projections for the Future Gregory L. Evans and David G. Badman -- Introduction -- Sickle Cell Disease -- The National Institutes of Health -- The National Heart, Lung, and Blood Institute (NHLBI) -- The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) -- NHLBI Funding of Sickle Cell Disease Research -- Clinical Care Guidelines -- Clinical Research - Multicenter Clinical Trials -- The New NHLBI SCD Clinical Research Network -- NHLBI-Supported Translational SCD Research - Pulmonary Complications of SCD, and Programs of Excellence in Gene Therapy -- Translational Research - NHLBI Comprehensive Sickle Cell Centers -- Structure and Main Purpose -- Clinical Research - Change in Focus Toward Multicenter Clinical Trials -- Training Programs -- Basic Research -- Other NIH RFAs and Program Announcements -- National Heart, Lung, and Blood Institute -- National Institute of Diabetes and Digestive and Kidney Diseases -- National Human Genome Research Institute -- Investigator-Initiated Grants -- Joint Efforts between NHGRI, NHLBI, NIDDK, and other NIH Institutes and Centers - 2003 Conference -- TheFuture -- 3. The Human Genome Project Betty S. Pace -- Introduction -- The Pre-Genomic Era -- DNA: The Molecule of Heredity -- The National Institutes of Health (NIH) -- The Department of Energy (DOE).

Birth of the Human Genome Project -- The First FiveYears: 1990-1994 -- The International Human Genome Sequencing Consortium -- Goals of First FiveYears -- Budget Allocations -- A New Five-Year Plan: 1993-1998 -- Goals of the Extended Period -- The Final Phase of the Human Genome Project: 1998-2003 -- Goals for the Last Phase -- The Human Genome Draft Sequence -- Technological Advances -- The Genome Era -- The Human Genome -- Model Organisms -- The National Center for Biotechnology Information (NCBI) -- AVision for theFuture -- The Impact of Genome Era Research in Health and Disease -- DNA Variations Related to Human Disease -- Human Diseases and Haplotypes -- The International HapMap Project -- Pharmacogenomics -- Renaissance of Sickle Cell Disease Research in the Genome Era -- The Genome Era -- References -- PART II: CLINICAL RESEARCH PERSPECTIVES -- 4. Sickle Cell Disease: A Phenotypic Patchwork Kim Smith-Whitley and Betty S. Pace -- Introduction -- Origin of Sickle Gene -- SickleMutation -- Malaria -- Classification of Sickle Hemoglobin Syndromes -- Hemoglobin Genes -- Hemoglobin Disorders -- Diagnosis of Sickle Cell Disease -- Protein-Based Techniques -- Solubility Test -- Molecular-Based Techniques -- Genome Era Techniques -- Pathophysiology of Sickle Cell Disease (SCD) -- Cooperative Study of Sickle Cell Disease (CSSCD) -- Painful Episodes -- Globin Gene Effects -- Exacerbation of Anemia -- Acute Chest Syndrome -- Central Nervous System -- "Silent" Central Nervous System (CNS) Infarcts -- Priapism -- Other Complications -- Growth and Development -- Genetic Disease Modifiers -- Predictors of Disease-Severity -- Newborn Cohort -- Treatment Strategies -- Hydroxyurea -- Transfusions Therapy -- Alloimmunization and Delayed Hemolytic Transfusion Reactions -- Health Maintenance -- Medical Home -- Health Maintenance -- Family and Patient Education.

Transition to Adult Care -- SickleCellTrait -- Future Perspectives -- References -- 5. Preventive Care and Advances in the Treatment of Sickle Cell Disease Charles T. Quinn and George R. Buchanan -- Introduction -- Bacterial Infection -- Newborn Screening (NBS) -- Routine Health Maintenance -- Acute Vaso-Occlusive Complications -- Painful Episodes -- Acute Chest Syndrome -- Acute "Hematologic" Crises -- Priapism -- Stroke -- Specific Pharmacotherapy of Sickle Cell Disease -- ClinicalTrials -- Summary -- References -- 6. Sickle Cell Disease in Adults Johnson Haynes, Jr. and Ardie Pack-Mabien -- Introduction -- Medical Complications -- Long-term Survival -- Vaso-Occlusive Episodes -- Acute Pain -- Chronic Pain -- Acute Chest Syndrome -- Etiology of Acute Chest Syndrome -- Treatment -- Sickle-RBC Pulmonary Vascular Interactions -- Sickle Chronic Lung Disease -- Pulmonary Artery Hypertension -- Lactate Dehydrogenase -- Endothelial Dysfunction -- Sildenafil -- Arginine -- Stroke -- Stroke Treatment -- Avascular Necrosis -- Renal Failure -- Retinopathy -- Other Clinical Complications -- Infections -- Cardiovascular -- Priapism -- Liver and Gallbladder -- Skin Ulcers -- Genetic Counseling and Pregnancy -- Hemoglobin-SC Disease -- Hydroxyurea -- Other Treatments -- Preventive Health Maintenance -- Adult Healthcare Maintenance -- Adult Comprehensive Clinic Components -- Unmet Needs -- Quality of Life -- Education and Employment -- Social and Psychosocial Needs -- Workshop on Adults with Sickle Cell Diseases: Meeting Unmet Needs -- Sickle Cell Adult Provider Network (SCAPN) -- A Sickle Cell Disease Clinical Research Network -- FutureDirections -- References -- 7. Pain in Sickle Cell Disease: A Multidimensional Construct Lennette J. Benjamin and Richard Payne -- Introduction -- The Nature of Pain in Sickle Cell Disease (SCD).

Pathophysiology of Sickle-Related Pain -- Appraisal of Risk Factors -- Pain Mechanisms and Biopsychosocial Integration -- Nociceptive Pain -- Neuropathic Pain -- Biopsychosocial Integration -- Treatment-Related Issues -- Assessment of Pain and Symptom Management -- Access to Quality Care -- Home Care -- Outpatient Day Hospital and Day Care Centers -- Disease-Specific Therapy -- Disparities in Access to Care -- Inadequate Pain Treatment: A Major Public Health Problem -- Physiological and Pharmacological Consequences -- Pain Under Treatment and Pseudoaddiction -- Opioid-Induced Hyperalgesia: An Emerging Neurotoxicity Syndrome -- NMDA and Opioid Receptor Interactions -- Physical Dependence and OpioidWithdrawal-Related Pain -- Pharmacologic Tolerance and Tolerance-Associated Hyperalgesia -- NMDA Receptor Antagonists -- OpioidRotation -- Fentanyl or Sufentanil -- Combine Opioid Rotation and NMDA Receptor Antagonist Therapy -- Methadone -- Caution in the Use of Methadone -- Practical Matters: Post Script -- Summary -- References -- 8. Transfusion Therapy in Sickle Cell Disease Carolyn Hoppe, Robert Adams and Elliot Vichinsky -- Introduction -- Stroke in Sickle Cell Disease -- Epidemiology of Stroke -- Diagnosis of Stroke -- Neurocognitive Functioning and Silent Infarction -- Pathophysiology of Stroke -- Risk Factors for Ischemic Stroke -- Primary Prevention of Ischemic Stroke in Children -- Prevention of Recurrent Stroke -- Alternative Treatments for Stroke -- Advances in Transfusion Medicine -- Transfusion-Transmitted Infection -- Alloimmunization -- Iron Overload -- Erythrocytapheresis -- Summary -- References -- PART III: BASIC RESEARCH PERSPECTIVES -- 9. Hemoglobin S Polymerization, Just the Beginning Frank A. Ferrone -- Introduction -- Equilibrium -- Hemoglobin Function -- Polymer Structure -- Polymer Stability -- pH and Ionic Dependences.

Hemoglobin Mixtures -- Fiber andGelRigidity -- Kinetics -- Mechanism of Hemoglobin S Polymerization -- The Thermodynamic Control of Nucleation -- Kinetics of HbF Mixtures -- Depolymerization -- Inhibition by Design -- Drugs -- Hemoglobin -- References -- 10. Damage to the Red Blood Cell Membrane in Sickle Cell Disease Steven R. Goodman and Clinton Joiner -- Introduction -- The RBC Surface and Vaso-Occlusion -- Altered Phospholipid Asymmetry in the RBC Membrane -- Membrane Transport and Volume Regulation in Sickle RBC Membrane Transport -- CellVolumeRegulation -- Consequences of Sickle RBC Dehydration -- Mechanisms of Sickle RBC Dehydration -- Sickling-Induced Cation Pathway -- Gardos Pathway -- KCl Cotransport -- CationUptakePathways -- Interaction of Cation Transport Pathways and the Kinetics of Cellular Dehydration -- Beyond Dehydration-Pathological Rehydration in Sickle RBCs -- Pharmacological Intervention in Dehydrated Sickle RBCs -- The Membrane Skeleton and ISC Formation -- The Proteomics of the Sickle RBC Membrane -- References -- 11. Fetal Hemoglobin for What Ails Sickle Hemoglobin Solomon F. Ofori-Acquah and Betty S. Pace -- Introduction -- Developmental Expression and Cellular Distribution of HbF -- Composition of Fetal Hemoglobin -- Interactions between Hemoglobin F and S -- Globin Gene Regulation: The Locus Control Region -- β-Globin Cluster Restriction Fragment Length Polymorphisms -- The Role of HS2 Polymorphisms in HbF Synthesis -- Regulation of γ-Globin Gene Expression -- Hereditary Persistence of Fetal Hemoglobin -- Deletional HPFH -- Non-deletional HPFH -- Emerging Cell Signaling Mechanisms for Drug-Mediated HbF Induction -- Mitogen Activated Protein Kinase Signaling Pathway -- Signal Transducer and Activators of Transcription (STAT) Signaling Pathways -- Nitric Oxide and Cyclic Guanosine Monophosphate (cGMP) Signaling Pathways.

Pharmacological Fetal Hemoglobin Induction.