trans

More documents

Recommendations

Info

DRUG RESISTANCE IN KINETOPLASTID PARASITES 413 are possible. For example antifolates are not useful against this parasite, but the sequence of the C. parvum DHFR active site contains novel residues at several positions analogous to those at which point mutations have been shown to produce antifolate resistance in other parasite DHFRs. DRUG RESISTANCE IN KINETOPLASTID PARASITES Leishmania and chemotherapy Leishmania is a significant cause of morbidity and mortality, with a disease prevalence of 12 million cases and a worldwide annual incidence of 1.5–2 million cases. Leishmania manifestations range, depending on the species, from self-healing cutaneous lesions to lifethreatening visceral infections. Although several experimental approaches (killed parasites BCG; subunit vaccines; DNA vaccines; attenuated organisms) have been used as vaccination strategies against Leishmania, chemotherapy is still the only effective way to control all forms of diseases. The first agents with a favorable therapeutic index, the pentavalent antimonials (SbV), were introduced in the 1940s, and despite the need for prolonged parenteral administration are still the mainstay of therapy for all forms of leishmaniasis. Formulations available include sodium stibogluconate (Pentostam) in which antimony is complexed with gluconic acid, and meglumine antimonate (Glucantime) where antimony is complexed with the sugar meglumine (Figure 16.5). Although antimonials are likely to remain the pillar of anti-leishmanial therapy for the foreseeable future, we remain uncertain of the mechanism of action or even the biologically active component of the most commonly utilized formulations. Over the years, in face of slowly developing clinical resistance in the 1970s and 1980s, both the daily dose of SbV and the duration of treatment were increased to maintain satisfactory levels of efficacy. Resistance to SbV is now endemic with more than 50% resistance rate in the state of Bihar, India. Undertreatment and noncompliance are likely to have contributed to SbV resistance, but in India anthroponotic <strong>trans</strong>mission is possibly a determining factor in disseminating SbV resistance. Second-line drugs against Leishmania infections include pentamidine and lipid forms of amphotericin B (AmB), as well as a number of other drugs with more specific indications. Pentavalent antimonials Clinical unresponsiveness to SbV has been attributed to several factors, but resistant parasites have now been formally documented in the laboratory and contribute to treatment failure in several endemic regions. A strong correlation between clinical response and SbV sensitivity in vitro was observed only when strains were assessed as intracellular amastigotes, while no correlation with clinical response was found using extracellular promastigotes. This complicates the testing of resistance in the laboratory, as measuring and evaluating intracellular Leishmania is laborious. However, recent advances using Leishmania expressing reporter genes, such as firefly luciferase, may facilitate susceptibility testing within macrophages. It is also possible to grow amastigotes in axenic culture, and these could possibly be used for drug testing, although several species are refractory to axenization and it is possible that intracellular parasites will be required for drug testing. The rate of appearance of resistance to SbV in the field has been slow, which suggests that resistance, as discussed for chloroquine resistance in Plasmodium, is the consequence of MEDICAL APPLICATIONS
414 DRUG RESISTANCE FIGURE 16.5 Structure of the main drugs used against kinetoplastid parasites. (A) Pentostam; (B) pentamidine; (C) amphotericin B; (D) miltefosine; (E) melarsoprol; (F) eflornithine; (G) suramin; (H) benznidazole; (I) nifurtimox; (J) metronidazole. MEDICAL APPLICATIONS
Page 2 and 3:
Molecular Medical Parasitology
Page 4 and 5:
Molecular Medical Parasitology Edit
Page 6 and 7:
Contents List of contributors Prefa
Page 8 and 9:
List of contributors Mark Blaxter,
Page 10 and 11:
LIST OF CONTRIBUTORS ix Richard. J.
Page 12 and 13:
Preface Parasitology was born as th
Page 14 and 15:
S E C T I O N I MOLECULAR BIOLOGY
Page 16 and 17:
C H A P T E R 1 Parasite genomics M
Page 18 and 19:
TABLE 1.1 Parasite genomes: genome
Page 20 and 21:
GENERATING GENOMICS DATA 7 differen
Page 22 and 23:
GENERATING GENOMICS DATA 9 TABLE 1.
Page 24 and 25:
GENERATING GENOMICS DATA 11 called
Page 26 and 27:
GENERATING GENOMICS DATA 13 200 000
Page 28 and 29:
BIOINFORMATICS AND THE ANALYSIS OF
Page 30 and 31:
THE POST-GENOMICS ERA, AND THE OTHE
Page 32 and 33:
THE PARASITES AND THEIR GENOMES 19
Page 34 and 35:
Page 36 and 37:
Page 38 and 39:
Page 40 and 41:
FURTHER READING 27 treated with a d
Page 42 and 43:
C H A P T E R 2 RNA processing in p
Page 44 and 45:
TRANS-SPLICING 31 cis trans Exon 1
Page 46 and 47:
TRANS-SPLICING 33 snRNPs (small nuc
Page 48 and 49:
TRANS-SPLICING 35 trans cis U2AF35
Page 50 and 51:
RNA EDITING 37 P AAAA... AAAA... AA
Page 52 and 53:
RNA EDITING 39 entire transcript re
Page 54 and 55:
RNA EDITING 41 5 Editing block C Ed
Page 56 and 57:
RNA EDITING 43 microscopy) approach
Page 58 and 59:
FURTHER READING 45 Nilsen, T.W. (19
Page 60 and 61:
C H A P T E R 3 Transcription Arthu
Page 62 and 63:
UNUSUAL MODES OF TRANSCRIPTION IN T
Page 64 and 65:
CLASS I TRANSCRIPTION IN TRYPANOSOM
Page 66 and 67:
Page 68 and 69:
Page 70 and 71:
CLASS II TRANSCRIPTION OF PROTEIN C
Page 72 and 73:
SL RNA AND U snRNA GENE TRANSCRIPTI
Page 74 and 75:
Page 76 and 77:
Page 78 and 79:
FURTHER READING 65 and switching in
Page 80 and 81:
C H A P T E R 4 Post-transcriptiona
Page 82 and 83:
POST-TRANSCRIPTIONAL REGULATION IN
Page 84 and 85:
Page 86 and 87:
Page 88 and 89:
Page 90 and 91:
Page 92 and 93:
Page 94 and 95:
Page 96 and 97:
Page 98 and 99:
Page 100 and 101:
FURTHER READING 87 inhibition, it m
Page 102 and 103:
C H A P T E R 5 Antigenic variation
Page 104 and 105:
ANTIGENIC VARIATION AT THE STRUCTUR
Page 106 and 107:
ANTIGENIC VARIATION AT THE STRUCTUR
Page 108 and 109:
VSG Signal sequence Amino-terminal
Page 110 and 111:
GENETICS OF ANTIGENIC VARIATION 97
Page 112 and 113:
Page 114 and 115:
Page 116 and 117:
IMMUNE RESPONSES TO TRYPANOSOME INF
Page 118 and 119:
INNATE RESISTANCE, HUMAN SUSCEPTIBI
Page 120 and 121:
ANTIGENIC VARIATION IN MALARIA 107
Page 122 and 123:
FURTHER READING 109 ACKNOWLEDGEMENT
Page 124 and 125:
C H A P T E R 6 Genetic and genomic
Page 126 and 127:
‘FORWARD’ VS. ‘REVERSE’ GEN
Page 128 and 129:
EXAMPLES OF ‘FORWARD’ GENETIC A
Page 130 and 131:
EXAMPLES OF ‘FORWARD’ GENETIC A
Page 132 and 133:
REVERSE GENETICS AND LEISHMANIA VIR
Page 134 and 135:
VALIDATION OF CANDIDATE VIRULENCE G
Page 136 and 137:
S E C T I O N II BIOCHEMISTRY AND C
Page 138 and 139:
C H A P T E R 7 Energy metabolism P
Page 140 and 141:
SUBCELLULAR ORGANIZATION OF AMITOCH
Page 142 and 143:
CELL MEMBRANE Fructose [b] Glucose
Page 144 and 145:
STEPS OF AMITOCHONDRIATE CORE METAB
Page 146 and 147:
ENZYMATIC DIFFERENCES BETWEEN AMITO
Page 148 and 149:
ACTION OF NITROIMIDAZOLE DRUGS 135
Page 150 and 151:
ENVOI 137 unambiguously reflect the
Page 152 and 153:
FURTHER READING 139 Saavedra-Lira,
Page 154 and 155:
THE EMBDEN-MEYERHOF-PARNAS (EMP) PA
Page 156 and 157:
Page 158 and 159:
Page 160 and 161:
Page 162 and 163:
Page 164 and 165:
WHY DO TRYPANOSOMATIDAE HAVE GLYCOS
Page 166 and 167:
FURTHER READING 153 for use in agri
Page 168:
CARBOHYDRATE METABOLISM 155 as a hu
Page 171 and 172:
158 ENERGY METABOLISM - APICOMPLEXA
Page 173 and 174:
Page 175 and 176:
Page 177 and 178:
Page 179 and 180:
Page 181 and 182:
Page 183 and 184:
This Page Intentionally Left Blank
Page 185 and 186:
172 PROTEIN METABOLISM PROTEINS (1)
Page 187 and 188:
174 PROTEIN METABOLISM the C-termin
Page 189 and 190:
176 PROTEIN METABOLISM and also, to
Page 191 and 192:
178 PROTEIN METABOLISM values rangi
Page 193 and 194:
180 PROTEIN METABOLISM of the plasm
Page 195 and 196:
182 PROTEIN METABOLISM in vivo, in
Page 197 and 198:
184 PROTEIN METABOLISM PROLINE Poly
Page 199 and 200:
186 PROTEIN METABOLISM CO 2 Dec-SAM
Page 201 and 202:
188 PROTEIN METABOLISM a cMDH has b
Page 203 and 204:
190 PROTEIN METABOLISM Urea ARGININ
Page 205 and 206:
192 PROTEIN METABOLISM been describ
Page 207 and 208:
194 PROTEIN METABOLISM absence of g
Page 209 and 210:
Page 211 and 212:
198 PURINES AND PYRIMIDINES enable
Page 213 and 214:
200 PURINES AND PYRIMIDINES provide
Page 215 and 216:
202 PURINES AND PYRIMIDINES activit
Page 217 and 218:
204 PURINES AND PYRIMIDINES physiol
Page 219 and 220:
206 PURINES AND PYRIMIDINES Amitoch
Page 221 and 222:
208 PURINES AND PYRIMIDINES their a
Page 223 and 224:
210 PURINES AND PYRIMIDINES FIGURE
Page 225 and 226:
Page 227 and 228:
214 PURINES AND PYRIMIDINES protein
Page 229 and 230:
Page 231 and 232:
Page 233 and 234:
220 PURINES AND PYRIMIDINES in Plas
Page 235 and 236:
222 PURINES AND PYRIMIDINES whereas
Page 237 and 238:
Page 239 and 240:
226 TRYPANOSOMATID CARBOHYDRATES AF
Page 241 and 242:
228 TRYPANOSOMATID CARBOHYDRATES In
Page 243 and 244:
230 TRYPANOSOMATID CARBOHYDRATES po
Page 245 and 246:
232 TRYPANOSOMATID CARBOHYDRATES LP
Page 247 and 248:
234 TRYPANOSOMATID CARBOHYDRATES re
Page 249 and 250:
236 TRYPANOSOMATID CARBOHYDRATES sc
Page 251 and 252:
A. sAP COOH [T][T](S/T)(S/T)(S/T)SS
Page 253 and 254:
240 TRYPANOSOMATID CARBOHYDRATES Cr
Page 255 and 256:
242 INTRACELLULAR SIGNALING protein
Page 257 and 258:
244 INTRACELLULAR SIGNALING FIGURE
Page 259 and 260:
246 INTRACELLULAR SIGNALING 212.5 2
Page 261 and 262:
248 INTRACELLULAR SIGNALING cycle.
Page 263 and 264:
250 INTRACELLULAR SIGNALING V-H -A
Page 265 and 266:
252 INTRACELLULAR SIGNALING domain)
Page 267 and 268:
254 INTRACELLULAR SIGNALING the kno
Page 269 and 270:
256 INTRACELLULAR SIGNALING from in
Page 271 and 272:
258 INTRACELLULAR SIGNALING FIGURE
Page 273 and 274:
260 INTRACELLULAR SIGNALING ESAG4 (
Page 275 and 276:
262 INTRACELLULAR SIGNALING and ind
Page 277 and 278:
264 INTRACELLULAR SIGNALING ATPase
Page 279 and 280:
266 INTRACELLULAR SIGNALING G11XG
Page 281 and 282:
268 INTRACELLULAR SIGNALING a diffe
Page 283 and 284:
270 INTRACELLULAR SIGNALING rapid l
Page 285 and 286:
272 INTRACELLULAR SIGNALING cells w
Page 287 and 288:
274 INTRACELLULAR SIGNALING PfPPJ i
Page 289 and 290:
276 INTRACELLULAR SIGNALING is cont
Page 291 and 292:
278 PLASTIDS, MITOCHONDRIA, AND HYD
Page 293 and 294:
Page 295 and 296:
Page 297 and 298:
Page 299 and 300:
Page 301 and 302:
Page 303 and 304:
Page 305 and 306:
Page 307 and 308:
Page 309 and 310:
Page 311 and 312:
298 HELMINTH SURFACES Important exc
Page 313 and 314:
300 HELMINTH SURFACES protease inhi
Page 315 and 316:
302 HELMINTH SURFACES volume, there
Page 317 and 318:
304 HELMINTH SURFACES projecting si
Page 319 and 320:
306 HELMINTH SURFACES schistosome t
Page 321 and 322:
308 HELMINTH SURFACES re-establish
Page 323 and 324:
310 HELMINTH SURFACES hepatic cells
Page 325 and 326:
312 HELMINTH SURFACES lungs. Larvae
Page 327 and 328:
314 HELMINTH SURFACES cuticle, whic
Page 329 and 330:
316 HELMINTH SURFACES cuticle in th
Page 331 and 332:
318 HELMINTH SURFACES mec-8 or sym-
Page 333 and 334:
320 HELMINTH SURFACES current, when
Page 335 and 336:
322 HELMINTH SURFACES The cuticle-h
Page 337 and 338:
324 HELMINTH SURFACES are typically
Page 339 and 340:
326 HELMINTH SURFACES or carrier pr
Page 341 and 342:
328 HELMINTH SURFACES of tyrosine-b
Page 343 and 344:
330 HELMINTH SURFACES blood. The ge
Page 345 and 346:
332 HELMINTH SURFACES Mutations in
Page 347 and 348:
334 HELMINTH SURFACES in the hypode
Page 349 and 350:
336 HELMINTH SURFACES (including H-
Page 351 and 352:
338 HELMINTH SURFACES Blaxter, M.L.
Page 353 and 354:
340 ENERGY METABOLISM IN HELMINTHS
Page 355 and 356:
Page 357 and 358:
Page 359 and 360:
Page 361 and 362:
Page 363 and 364:
Page 365 and 366:
Page 367 and 368:
Page 369 and 370:
Page 371 and 372:
Page 373 and 374:
360 NEUROTRANSMITTERS CO 2 H NH 2 G
Page 375 and 376: 362 NEUROTRANSMITTERS TABLE 15.1 An
Page 377 and 378: 364 NEUROTRANSMITTERS more arms tha
Page 379 and 380: 366 NEUROTRANSMITTERS the surroundi
Page 381 and 382: 368 NEUROTRANSMITTERS proteins requ
Page 383 and 384: 370 NEUROTRANSMITTERS FIGURE 15.11
Page 385 and 386: 372 NEUROTRANSMITTERS FIGURE 15.13
Page 387 and 388: 374 NEUROTRANSMITTERS sensitivity t
Page 389 and 390: 376 NEUROTRANSMITTERS TABLE 15.3 Cl
Page 391 and 392: 378 NEUROTRANSMITTERS crossed the c
Page 393 and 394: 380 NEUROTRANSMITTERS have been tes
Page 395 and 396: 382 NEUROTRANSMITTERS C-terminals a
Page 397 and 398: 384 NEUROTRANSMITTERS Davis and Str
Page 399 and 400: 386 NEUROTRANSMITTERS Cephalic gang
Page 401 and 402: 388 NEUROTRANSMITTERS myoexcitation
Page 403 and 404: 390 NEUROTRANSMITTERS is phosphoryl
Page 405 and 406: 392 NEUROTRANSMITTERS many other an
Page 407 and 408: This Page Intentionally Left Blank
Page 409 and 410: This Page Intentionally Left Blank
Page 411 and 412: 398 DRUG RESISTANCE of some of the
Page 413 and 414: 400 DRUG RESISTANCE It is now estim
Page 415 and 416: 402 DRUG RESISTANCE is again assume
Page 417 and 418: 404 DRUG RESISTANCE An alternative
Page 419 and 420: 406 DRUG RESISTANCE clinical eviden
Page 421 and 422: 408 DRUG RESISTANCE FIGURE 16.4 Fol
Page 423 and 424: 410 DRUG RESISTANCE Using similar s
Page 425: 412 DRUG RESISTANCE whether these r
Page 429 and 430: 416 DRUG RESISTANCE FIGURE 16.6 Try
Page 431 and 432: 418 DRUG RESISTANCE has permitted e
Page 433 and 434: 420 DRUG RESISTANCE FIGURE 16.7 Dru
Page 435 and 436: 422 DRUG RESISTANCE near future. Th
Page 437 and 438: 424 DRUG RESISTANCE million new inf
Page 439 and 440: 426 DRUG RESISTANCE some 50 million
Page 441 and 442: 428 DRUG RESISTANCE pharynx, the bo
Page 443 and 444: 430 DRUG RESISTANCE efforts for glo
Page 445 and 446: 432 DRUG RESISTANCE and resistance
Page 447 and 448: 434 MEDICAL IMPLICATIONS TABLE 17.1
Page 449 and 450: 436 MEDICAL IMPLICATIONS TABLE 17.1
Page 451 and 452: 438 MEDICAL IMPLICATIONS transmissi
Page 453 and 454: 440 MEDICAL IMPLICATIONS H 2 C H H
Page 455 and 456: 442 MEDICAL IMPLICATIONS parasites
Page 457 and 458: 444 MEDICAL IMPLICATIONS neuropsych
Page 459 and 460: 446 MEDICAL IMPLICATIONS of toxic f
Page 461 and 462: 448 MEDICAL IMPLICATIONS Future con
Page 463 and 464: 450 MEDICAL IMPLICATIONS Melarsopro
Page 465 and 466: 452 MEDICAL IMPLICATIONS prevention
Page 467 and 468: 454 MEDICAL IMPLICATIONS resulting
Page 469 and 470: 456 MEDICAL IMPLICATIONS for S. ste
Page 471 and 472: 458 MEDICAL IMPLICATIONS are though
Page 473 and 474: 460 MEDICAL IMPLICATIONS FIGURE 17.
Page 475 and 476: 462 MEDICAL IMPLICATIONS Marr, J.J.
Page 477 and 478:
464 INDEX Aldolase, 143 Plasmodium
Page 479 and 480:
466 INDEX Ascofuranone, 143 ASCUT-1
Page 481 and 482:
468 INDEX Cnidarians, RNA trans-spl
Page 483 and 484:
470 INDEX Entamoeba, 125 Ca 2 metab
Page 485 and 486:
472 INDEX Glucose-6-phosphate dehyd
Page 487 and 488:
474 INDEX Ivermectin, 398, 427, 455
Page 489 and 490:
476 INDEX Maduramicin, 412 Major va
Page 491 and 492:
478 INDEX Nitric oxide: neurotransm
Page 493 and 494:
480 INDEX calcium-binding proteins,
Page 495 and 496:
482 INDEX Pyrimidine transport, 200
Page 497 and 498:
484 INDEX Succinate:rhodoquinone ox
Page 499 and 500:
486 INDEX genome, 21 survey sequenc
Page 501:
488 INDEX U small nuclear RNA (snRN
show all

trans

You also want an ePaper? Increase the reach of your titles

Delete template?

Save as template?