Prions and Mad Cow Disease

Foreword......Page 3
REFERENCES......Page 8
Preface......Page 9
Contents......Page 11
Contributors......Page 13
I. INTRODUCTION......Page 17
B. The 1950s......Page 18
C. The 1960s and 1970s......Page 19
D. The 1980s and 1990s......Page 21
A. Markers: PrPSc and Surrogates......Page 24
B. Diagnostic Problems with PrPSc—Spectrum of Conformations......Page 25
C. Issues Involving the Ratio of PrPSc to Infectivity......Page 26
IV. FURTHER MISCONCEPTIONS AFTER THE TARGET IS HIT......Page 27
V. THE FOCUS OF THIS BOOK......Page 29
REFERENCES......Page 30
I. INTRODUCTION......Page 37
A. Normal Science......Page 38
B. Crisis......Page 40
D. Paradigm Shift......Page 41
A. Accepted Paradigm......Page 43
C. Anomalies Arise......Page 45
III. CRISIS......Page 46
A. The Membrane Hypothesis......Page 47
B. The Virino Hypothesis......Page 48
C. The Protein Hypothesis......Page 49
D. Genetic Hypothesis......Page 50
A. New Directions......Page 51
B. Direct Evidence......Page 52
C. Indirect Evidence......Page 61
V. CONCLUSIONS......Page 64
NOTES......Page 66
REFERENCES......Page 69
I. INTRODUCTION......Page 77
II. MODEL DESCRIPTION AND BASE CASE ASSUMPTIONS......Page 78
A. Cattle Population Dynamics......Page 80
B. The Slaughter Process......Page 88
C. Rendering and Feed Production......Page 97
A. Hypothetical Introduction of BSE into the United States......Page 105
B. Sensitivity Analysis......Page 106
C. Evaluation of the Swiss BSE Outbreak......Page 108
IV. RESULTS......Page 112
A. Base Case Results......Page 124
B. Sensitivity Analyses......Page 126
C. Switzerland......Page 128
D. Summary......Page 129
APPENDIX A......Page 132
APPENDIX B......Page 134
REFERENCES......Page 136
I. INTRODUCTION......Page 141
II. HISTORY......Page 142
III. IMPORT PROHIBITIONS......Page 143
IV. DOMESTIC FEED PROHIBITIONS......Page 144
V. SURVEILLANCE......Page 145
VI. EMERGENCY RESPONSE PLANNING......Page 148
VIII. EVALUATION......Page 149
IX. SUMMARY......Page 150
REFERENCES......Page 151
I. RECOGNITION OF CHRONIC WASTING DISEASE IN DEER AND THEN IN ELK......Page 153
II. ATTEMPTS AT CONTROL OF CWD IN FREE-RANGING CERVIDS......Page 155
III. ATTEMPTS TO REGULATE CAPTIVE CERVIDS......Page 156
IV. REGULATION OF CAPTIVE CERVIDS IN SOUTH DAKOTA......Page 157
V. SUGGESTED MODEL FOR CWD ERADICATION IN CAPTIVE CERVIDS......Page 158
VI. CURRENT STATUS OF CWD IN CAPTIVE CERVIDS AND POTENTIAL TO ERADICATE......Page 162
VII. POTENTIAL TO ERADICATE CWD IN FREE-RANGING CERVIDS......Page 164
REFERENCES......Page 165
II. PROTEIN-ONLY HYPOTHESIS OF PRION REPLICATION......Page 167
III. SPECIES BARRIERS......Page 168
IV. SPECIES-BARRIER-INDEPENDENT PRION REPLICATION......Page 170
V. PRION STRAINS......Page 176
VI. BIOASSAYS IN WILD-TYPE MICE......Page 178
VII. STRAIN MUTATION......Page 180
VIII. BIOASSAYS IN TRANSGENIC MICE......Page 181
B. Hamster-Mouse PrP Chimeric Mouse Models......Page 182
C. Human PrP Transgenic Mouse Models......Page 183
D. Bovine PrP Transgenic Mouse Models......Page 184
E. BSE Transmission to Human PrP Transgenic Mouse Models......Page 186
G. Effect of Methionine 129 Homozygosity in Human PrP......Page 187
I. Testing of Potential Therapeutic Compounds by Bioassay......Page 188
REFERENCES......Page 190
II. BACKGROUND......Page 197
III. ETIOLOGY......Page 198
IV. THE DIAGNOSIS PROBLEM......Page 199
V. RATIONALE BEHIND PMCA......Page 201
VI. PMCA: PROOF-OF-CONCEPT STUDIES......Page 203
VII. SCIENTIFIC APPLICATIONS OF PMCA......Page 205
VIII. PRACTICAL APPLICATIONS OF PMCA......Page 207
GLOSSARY......Page 208
REFERENCES......Page 209
I. INTRODUCTION......Page 215
A. History of Transmissible Degenerate Encephalopathies (TDE)......Page 216
B. The Prion Protein—PrP......Page 217
C. Primary Sequence of the Prion Protein......Page 220
D. Prion Diseases—The Current Situation......Page 221
A. Screening Technology......Page 222
B. The Enfer TSE Assay—Effective as a Screening Assay?......Page 224
C. Overview of Test Method......Page 228
D. Assay Principle......Page 233
E. Assay Performance and Evaluation Work......Page 237
A. Antibody Used in the Enfer Assay......Page 249
B. Increased Sensitivity Study......Page 253
REFERENCES......Page 258
A. Characteristics of the Problem......Page 263
C. PrPres, the Only Specific Biochemical Marker of Prion Diseases......Page 265
II. DETECTION OF PURIFIED AND CONCENTRATED PRPRES: THE CEA/BIO-RAD TEST......Page 266
A. Validation of the CEA/Bio-Rad Test by the European Community......Page 269
B. Screening of PreclinicalSamples with theCEA/Bio-Rad Test......Page 271
C. Limit of Detection of the CEA/Bio-Rad Test Corresponds to Sensitivity of the Bioassay in Laboratory Models......Page 273
D. Confirmation Test......Page 276
A. Optimal Sampling for BSE Detection by the CEA/Bio-Rad Test......Page 278
B. Performing the Test in the Field......Page 280
B. Detection of PrPres in Peripheral Organs......Page 281
C. The Particular Case of Muscle......Page 283
VI. DEVELOPMENT OF NEW TESTS......Page 285
REFERENCES......Page 287
I. INTRODUCTION......Page 293
II. TIME-RESOLVED FLUORESCENCE......Page 294
III. IMMUNOASSAY FOR PrP......Page 295
A. Reference Material......Page 297
IV. EARLY STUDIES ON TISSUE PREPARATION USING PROTEINASE K......Page 298
B. Interpretation......Page 299
V. THE DEVELOPMENT OF A DIFFERENTIAL EXTRACTION PROCEDURE......Page 302
A. Effect of Chaotrope Concentration on the Solubility of Insoluble PrP......Page 303
B. DELFIA Reagents......Page 305
F. Immunoassay......Page 306
G. Calculation......Page 307
VIII. EFFECT OF PK ON THE PROTEOLYTIC SUSCEPTIBILITY OF SOLUBLE AND INSOLUBLE PrP......Page 309
IX. MAPPING THE BRAIN DISTRIBUTION OF AGGREGATED PrP......Page 311
A. Application to Scrapie......Page 312
B. Application to CJD......Page 314
C. Effects of Autolysis and Sample Quality......Page 316
A. Labeling Antibodies with Europium......Page 319
B. Recombinant Bovine Standard......Page 320
XI. THE SECOND EUROPEAN EVALUATION IN JUNE 2001......Page 323
B. Immunoassay......Page 324
C. The Effects of Autolysis......Page 326
ACKNOWLEDGMENTS......Page 328
REFERENCES......Page 329
I. INTRODUCTION......Page 333
B. In Vivo Experiments......Page 335
F. Bovine Urine Samples......Page 337
III. RESULTS......Page 338
IV. DISCUSSION......Page 344
ACKNOWLEDGMENTS......Page 345
REFERENCES......Page 346
I. INTRODUCTION......Page 349
II. INSTRUMENTATION......Page 352
III. ANALYSIS TECHNIQUES......Page 356
IV. MEASUREMENTS OF PrP......Page 361
V. DISCUSSION AND FUTURE DIRECTIONS......Page 369
REFERENCES......Page 371
I. INTRODUCTION......Page 375
A. Solubilization and Extraction of the Prion Protein......Page 377
A. Labeling of Peptides......Page 379
A. Free-Zone Capillary Electrophoresis......Page 380
B. HPLC Size Exclusion......Page 382
IV. ASSAY SENSITIVITY......Page 383
V. BIOLOGICAL CORRELATIONS......Page 386
B. Correlation of Sheep That Are Positive on Lymphoid Biopsy......Page 387
VI. CONCLUSIONS......Page 389
REFERENCES......Page 390
A. General Pathogen Safety of Biological Products......Page 395
B. TSEs: Nonconventional Pathogens and the Safety of Human-Plasma-Derived Therapeutics......Page 396
II. COMPONENTS OF A TSE CLEARANCE STUDY......Page 399
A. Process Scale-Down Studies......Page 400
B. TSE Partitioning Studies......Page 401
A. TSE Infectivity: In Vivo Assays as Direct Measurements of Infectivity......Page 402
C. Bayer Corporation’s In Vitro Assay for PrP......Page 403
A. Source of the Spiking Material......Page 406
B. Preparation of the Spiking Material......Page 408
A. Bayer’s Plasma Fractionation Clearance Studies......Page 410
C. Independent Plasma Fractionation Steps vs. a Series of Coupled Steps......Page 416
D. Clearance Studies for Biological Products That Are Not Derived from Plasma......Page 417
E. Survey of Clearance Data......Page 418
VI. MODEL STUDIES......Page 419
VII. SUMMARY AND CONCLUSIONS......Page 420
REFERENCES......Page 422
A......Page 429
B......Page 430
C......Page 431
E......Page 433
F......Page 434
H......Page 435
M......Page 436
O......Page 437
P......Page 438
Q,R......Page 440
S......Page 441
T......Page 442
U......Page 443
X......Page 444