These are not the final page numbersMol. Nutr. Food Res. 2011, 55, 1–11 9Cytokine expression <strong>le</strong>vels (A.U)IL 12 p40IL 81.41.2 a1.2a,b aa1.01.00.8b a,b0.8b0.6 b0.60.40.40.20.20.00.0IL 1βIL 61.21.21.2aa1.0a,b1.0a,b1.0a0.8b b 0.8b,c0.80.60.6c0.60.40.40.40.20.20.20.0 0.00.0Control DON FB DON+FB Control DON FB DON+FB ControlAnimal treatm<strong>en</strong>tsMIP 1βaaFBbDON+FBFigure 4. Individual and<strong>co</strong>mbined effects of DON andFB on sp<strong>le</strong>nic mRNA expressionof cytokines. Pigs receiveda <strong>co</strong>ntrol diet (&), or a DON<strong>co</strong>ntaminateddiet ( ), or anFB-<strong>co</strong>ntaminated diet ( )oradiet <strong>co</strong>ntaminated with bothtoxins (&). Quantification ofthe relative cytokine mRNA<strong>le</strong>vel for each samp<strong>le</strong> isexpressed in arbitrary <strong>un</strong>its(A.U). Values are mean7SEMfor five animals.DON may increase the absorption of FB, my<strong>co</strong>toxins alreadyknown to be poorly absorbed [7, 9].The main objective of this study was to investigate theeffect of low doses of DON or FB ingested separately or in<strong>co</strong>mbination on the imm<strong>un</strong>e response of pig<strong>le</strong>ts. As inprevious experim<strong>en</strong>ts, it was observed that at low doses,my<strong>co</strong>toxins have litt<strong>le</strong> or no effect on the total non-specificimm<strong>un</strong>e responses as measured by lymphocyte proliferationupon mitog<strong>en</strong>ic stimulation and the plasmatic <strong>co</strong>nc<strong>en</strong>trationof imm<strong>un</strong>oglobulin classes. Imm<strong>un</strong>ization proto<strong>co</strong>ls,as already described, were needed to observe an effect of lowdoses of my<strong>co</strong>toxins, fed either alone or in <strong>co</strong>mbination onthe imm<strong>un</strong>e responses [14, 26, 38].A very low proliferative index, close to the one observedin <strong>un</strong>stimulated cells, was obtained in cells isolated fromanimals fed either DON-, FB- or DON1FB-<strong>co</strong>ntaminateddiets. This alteration of lymphocyte proliferation might bedue to an effect of these toxins on antig<strong>en</strong>-pres<strong>en</strong>ting cells(APC) as suggested by rec<strong>en</strong>t in vitro studies on monocytederivedAPC treated with DON [39, 40] or in vivo studieswith pig<strong>le</strong>ts acutely exposed to FB [27].Interestingly, the diet <strong>co</strong>-<strong>co</strong>ntaminated with DON and FBappeared to be ab<strong>le</strong> to <strong>co</strong><strong>un</strong>teract the increased <strong>le</strong>vel ofspecific IgA observed in the animal receiving only the DON<strong>co</strong>ntaminateddiet. Indeed, <strong>co</strong>nsumption of theDON-<strong>co</strong>ntaminated diet increased the <strong>le</strong>vel of specific IgA inthe plasma [11, 14] whereas ingestion of diet <strong>co</strong>ntaminatedwith both DON and FB did not alter the plasma <strong>le</strong>vel of thisimm<strong>un</strong>oglobulin isotype. We can hypothesize that FBinterfere with the DON-induced IgA e<strong>le</strong>vation at theintestinal <strong>le</strong>vel through its action on sphingolipids. Indeed,FB are known to disrupt the sphingolipid metabolism<strong>le</strong>ading to dep<strong>le</strong>tion of ceramide and all ceramide-derived<strong>co</strong>mp<strong>le</strong>x sphingolipids, such as sphingomyelin [41, 42]. Thislatter <strong>co</strong>mpo<strong>un</strong>d has be<strong>en</strong> rec<strong>en</strong>tly reported to <strong>co</strong>ntrol theamo<strong>un</strong>t of IgA in the large intestine [43].Dep<strong>en</strong>ding on the my<strong>co</strong>toxin, DON or FB significantlyimpaired the specific IgG <strong>co</strong>nc<strong>en</strong>tration and the <strong>le</strong>vel ofcytokine expression. Nonethe<strong>le</strong>ss, the diet <strong>co</strong>-<strong>co</strong>ntaminatedwith DON and FB <strong>le</strong>d to a strong decrease of specific IgG<strong>co</strong>nc<strong>en</strong>tration, greater than the one observed in animalsreceiving only one toxin. Similar effects were observed forthe five cytokines investigated, where the impact of the <strong>co</strong><strong>co</strong>ntaminateddiet was higher than either of the mono<strong>co</strong>ntaminateddiets. Several studies investigated cytokineexpression during chronic exposure to my<strong>co</strong>toxins [14, 15,25, 27], but none of them <strong>co</strong>ncern the <strong>co</strong>-<strong>co</strong>ntamination.Cytokines are important mediators in the imm<strong>un</strong>eresponse. Expressions of IL-8 and MIP-1b, which areinvolved in cell chemotaxis, were significantly inhibited inanimals fed the <strong>co</strong>-<strong>co</strong>ntaminated diet, and it can be anticipatedthat in these animals, recruitm<strong>en</strong>t and migration ofAPC to peripheral lymphoid tissue were reduced. Similarly,the decreased mRNA <strong>le</strong>vels of IL-1b and IL-6 mRNA inpig<strong>le</strong>ts receiving the <strong>co</strong>-<strong>co</strong>ntaminated diet may <strong>le</strong>ad to adefective antig<strong>en</strong> pres<strong>en</strong>tation and an impaired activation oflymphocytes and may explain the decreased IgG responseobserved in this study.Find a mechanism that explains the observed effects afterthe <strong>co</strong>mbination of both toxins is not easy, but at the cellular<strong>le</strong>vel, it might be hypothesized that MAPK activation <strong>co</strong>uldbe involved. Indeed, both DON and FB have be<strong>en</strong> shown toactivate MAPKs [12, 44], and these kinases are well known tomodulate numerous physiological processes, such as cellgrowth, apoptosis or imm<strong>un</strong>e response [45].In <strong>co</strong>nclusion, chronic exposure to low doses of DON orFB, either alone or in <strong>co</strong>mbination did not elicit importantclinical signs (body weight gain, hematology, biochemistry),but induced micros<strong>co</strong>pic <strong>le</strong>sions and altered the imm<strong>un</strong>eresponse, especially wh<strong>en</strong> the my<strong>co</strong>toxins were fed in<strong>co</strong>mbination. The modulation of the imm<strong>un</strong>e response wasonly observed wh<strong>en</strong> the imm<strong>un</strong>e system was activated.Considering (i) that vaccination or infection by pathog<strong>en</strong>s isa <strong>co</strong>mmon situation <strong>en</strong><strong>co</strong><strong>un</strong>tered in animal husbandry and(ii) the natural occurr<strong>en</strong>ce of these my<strong>co</strong>toxins in feedstuffs,the pres<strong>en</strong>t experim<strong>en</strong>t suggests a significant disruption in& 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheimwww.mnf-journal.<strong>co</strong>m
These are not the final page numbers10 B. Gr<strong>en</strong>ier et al. Mol. Nutr. Food Res. 2011, 55, 1–11the establishm<strong>en</strong>t of an appropriate specific response inanimals receiving my<strong>co</strong>toxin-<strong>co</strong>ntaminated diets. This studyalso highlights the <strong>co</strong>mp<strong>le</strong>xity of my<strong>co</strong>toxin interactions;some effects are not <strong>en</strong>hanced by the <strong>co</strong>mbination of toxins(biochemistry, l<strong>un</strong>g and kidney <strong>le</strong>sions, specific IgA<strong>co</strong>nt<strong>en</strong>t), whi<strong>le</strong> others are (specific IgG <strong>co</strong>nt<strong>en</strong>t, cytokinesexpression, liver <strong>le</strong>sions). These results may have someimpact on the curr<strong>en</strong>t regulation/re<strong>co</strong>mm<strong>en</strong>dation that onlytakes into ac<strong>co</strong><strong>un</strong>t individual my<strong>co</strong>toxins and not multimy<strong>co</strong>toxin<strong>co</strong>ntamination.B.G. was supported by a doctoral fellowship (CIFRE 065/2007), jointly financed by the Biomin <strong>co</strong>mpany, ANRT (AssociationNationa<strong>le</strong> de la Recherche Technique) and INRA(Institut National de la Recherche Agronomique). This studywas supported in part by a CAPES/COFECUB Grant (No.593/08) and a CNDT Grant (No. 472048/2008-2). Theauthors thank M. Kainz and E. Pich<strong>le</strong>r from Quantas AnalytikGmbH and M. Sulyok from IFA-Tulln for my<strong>co</strong>toxin analysis,G. H.aubl and G. Ja<strong>un</strong>ecker from Biopure (Romer Labs) formy<strong>co</strong>toxin production, G. Guil<strong>le</strong>mois from INRA R<strong>en</strong>nes for hisassistance with feed manufacture, P. Pinton, J. Laffitte,R. Solinhac and M. Gallois for technical assistance during theanimal experim<strong>en</strong>ts and Dr. Mike Watkins for his help with theEnglish text.The authors have declared no <strong>co</strong>nflict of interest.5 Refer<strong>en</strong>ces[1] CAST, Co<strong>un</strong>cil for Agricultural Sci<strong>en</strong>ce and Technology,My<strong>co</strong>toxins, Risks in Plant, Animal, and Human System,Task Force Report 139, Ames Iowa 2003.[2] Oswald, I. P., Comera, C., Imm<strong>un</strong>otoxicity of my<strong>co</strong>toxins.Rev. Med. Vet. 1998, 149, 585–590.[3] Binder, E. M., Tan, L. M., Chin, L. J., Handl, J., Richard, J.,Worldwide occurr<strong>en</strong>ce of my<strong>co</strong>toxins in <strong>co</strong>mmodities,feeds and feed ingredi<strong>en</strong>ts. Anim. Feed Sci. Technol. 2007,137, 265–282.[4] Placinta, C. M., D’Mello, J. P. F., Macdonald, A. M. C.,A review of worldwide <strong>co</strong>ntamination of cereal grains andanimal feed with Fusarium my<strong>co</strong>toxins. Anim. Feed Sci.Technol. 1999, 78, 21–37.[5] Schothorst, R. C., van Egmond, H. P., Report from SCOOPtask 3.2.10 ‘‘<strong>co</strong>l<strong>le</strong>ction of occurr<strong>en</strong>ce data of Fusariumtoxins in food and assessm<strong>en</strong>t of dietary intake by thepopulation of EU member states’’ – Subtask: trichothec<strong>en</strong>es.Toxi<strong>co</strong>l. Lett. 2004, 153, 133–143.[6] Monbaliu, S., Van Poucke, C., Detavernier, C., Dumoulin, F.et al., Occurr<strong>en</strong>ce of my<strong>co</strong>toxins in feed as analyzed by amulti-my<strong>co</strong>toxin LC-MS/MS method. J. Agric. Food Chem.2010, 58, 66–71.[7] Voss, K. A., Smith, G. W., Haschek, W. M., Fumonisins:toxi<strong>co</strong>kinetics, mechanism of action and toxicity. Anim.Feed Sci. Technol. 2007, 137, 299–325.[8] Halloy, D. J., Gustin, P. G., Bouhet, S., Oswald, I. P., Ora<strong>le</strong>xposure to culture material extract <strong>co</strong>ntaining fumonisinspredisposes swine to the developm<strong>en</strong>t of pneumonitiscaused by Pasteurella multocida. Toxi<strong>co</strong>logy 2005, 213,34–44.[9] Haschek, W. M., Gumprecht, L. A., Smith, G., Tumb<strong>le</strong>son,M. E., Constab<strong>le</strong>, P. D., Fumonisin toxi<strong>co</strong>sis in swine: anoverview of porcine pulmonary edema and curr<strong>en</strong>tperspectives. Environ. Health Perspect. 2001, 109, 251–257.[10] Oswald, I. P., Desautels, C., Laffitte, J., Fournout, S. et al.,My<strong>co</strong>toxin fumonisin B-1 increases intestinal <strong>co</strong>lonizationby pathog<strong>en</strong>ic Escherichia <strong>co</strong>li in pigs. Appl. Environ.Microbiol. 2003, 69, 5870–5874.[11] Pestka, J. J., Smolinski, A. T., Deoxyniva<strong>le</strong>nol: toxi<strong>co</strong>logyand pot<strong>en</strong>tial effects on humans. J. Toxi<strong>co</strong>l. Env. HealthCrit. Rev. 2005, 8, 39–69.[12] Zhou, H. R., Islam, Z., Pestka, J. J., Rapid, sequ<strong>en</strong>tial activationof mitog<strong>en</strong>-activated protein kinases and transcriptionfactors precedes proinflammatory cytokine mRNAexpression in sp<strong>le</strong><strong>en</strong>s of mice exposed to the trichothec<strong>en</strong>evomitoxin. Toxi<strong>co</strong>l. Sci. 2003, 72, 130–142.[13] Pestka, J. J., Zhou, H. R., Moon, Y., Ch<strong>un</strong>g, Y. J., Cellularand mo<strong>le</strong>cular mechanisms for imm<strong>un</strong>e modulation bydeoxyniva<strong>le</strong>nol and other trichothec<strong>en</strong>es: <strong>un</strong>raveling aparadox. Toxi<strong>co</strong>l. Lett. 2004, 153, 61–73.[14] Pinton, P., Acc<strong>en</strong>si, F., Beauchamp, E., Cossalter, A. M.et al., Ingestion of deoxyniva<strong>le</strong>nol (DON) <strong>co</strong>ntaminated feedalters the pig vaccinal imm<strong>un</strong>e responses. Toxi<strong>co</strong>l. Lett.2008, 177, 215–222.[15] Acc<strong>en</strong>si, F., Pinton, P., Callu, P., Abella-Bourges, N. et al.,Ingestion of low doses of deoxyniva<strong>le</strong>nol does not affecthematological, biochemical, or imm<strong>un</strong>e responses ofpig<strong>le</strong>ts. J. Anim. Sci. 2006, 84, 1935–1942.[16] Kouadio, J. H., Dano, S. D., Moukha, S., Mobio, T. A.,Creppy, E. E., Effects of <strong>co</strong>mbinations of Fusarium my<strong>co</strong>toxinson the inhibition of macromo<strong>le</strong>cular synthesis,malondialdehyde <strong>le</strong>vels, DNA methylation and fragm<strong>en</strong>tation,and viability in Ca<strong>co</strong>-2 cells. Toxi<strong>co</strong>n 2007, 49,306–317.[17] Marzoc<strong>co</strong>, S., Russo, R., Bian<strong>co</strong>, G., Autore, G., Severino, L.,Pro-apoptotic effects of niva<strong>le</strong>nol and deoxyniva<strong>le</strong>noltrichothec<strong>en</strong>es in J774A.1 murine macrophages. Toxi<strong>co</strong>l.Lett. 2009, 189, 21–26.[18] Harvey, R. B., Edrington, T. S., Kub<strong>en</strong>a, L. F., Elissalde, M. H.et al., Effects of dietary fumonisin B-1-<strong>co</strong>ntaining culturematerial, deoxyniva<strong>le</strong>nol-<strong>co</strong>ntaminated wheat, or their<strong>co</strong>mbination on growing barrows. Am. J. Vet. Res. 1996, 57,1790–1794.[19] Kub<strong>en</strong>a, L. F., Edrington, T. S., Harvey, R. B., Buck<strong>le</strong>y, S. A.et al., Individual and <strong>co</strong>mbined effects of fumonisin B1pres<strong>en</strong>t in Fusarium moniliforme culture material and T-2toxin or deoxyniva<strong>le</strong>nol in broi<strong>le</strong>r chicks. Poult. Sci. 1997,76, 1239–1247.[20] Marin, D. E., Taranu, I., Pasca<strong>le</strong>, F., Lionide, A. et al., Sexrelateddiffer<strong>en</strong>ces in the imm<strong>un</strong>e response of weanlingpig<strong>le</strong>ts exposed to low doses of fumonisin extract. Br.J. Nutr. 2006, 95, 1185–1192.& 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheimwww.mnf-journal.<strong>co</strong>m
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AUTEUR : Bertrand GRENIERTITRE : Ef
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REMERCIEMENTSLe travail ici présen
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J’ai une pensée particulière po
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Grenier, B., Loureiro-Bracarense, A
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TABLE DES MATIERES ................
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LISTE DES ABREVIATIONSAFAflatoxineD
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FIGURES ET TABLEAUXFigure 1 : Mycot
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INTRODUCTION8
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INTRODUCTIONCONTEXTE DE L’ETUDELe
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INTRODUCTIONElle se présentait sou
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INTRODUCTIONl’utilisation de ce m
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INTRODUCTION1. Les mycotoxines : g
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INTRODUCTIONc) La zéaralénone (vo
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INTRODUCTIONleucoencéphalomalacies
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INTRODUCTIONMycotoxins co-contamina
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INTRODUCTIONINTRODUCTIONFood safety
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INTRODUCTIONCHARACTERIZATION OF THE
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Quail(140 d)AF-FBRabbit(21 d)AF-FBR
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INTRODUCTIONdue to the ingestion of
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Table 2 : Interaction between Aflat
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(49 d) - RW-L ↗- Ab SRBC ↘- RW-
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INTRODUCTIONb) effects AF and OTA o
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INTRODUCTIONThe depletion of lympho
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AF-T2Chicken 0.3 - 3.0(35 d)AF-T2Ra
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(30 d) 2AF-RUBGuinea pig 0.02 bw -(
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INTRODUCTIONbetween AF and CPA on t
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(21 day) - RBC, hemoglobin ↗- AST
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INTRODUCTIONII. INTERACTIONS BETWEE
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INTRODUCTIONwhereas in the experime
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INTRODUCTION2.2) TCT type A and BTw
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Table 6 : Interaction between Ochra
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T2-CPAChicken(28 d)T2-CPAChicken(21
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INTRODUCTIONexposed group (Brown et
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INTRODUCTION2.3) Interaction betwee
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INTRODUCTIONeffects in comparison t
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INTRODUCTION3. Procédés de décon
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INTRODUCTIONPhysical and chemical m
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INTRODUCTIONINTRODUCTIONConsumption
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INTRODUCTIONmm screen shows that fr
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INTRODUCTIONseparate the grain into
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Table 7 : toxicological evaluation
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TRAVAIL EXPERIMENTALb,cca,ba,b,da,d
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Figure 21 : Effet de l’exposition
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1,41,21,00,80,60,40,20,0IL‐8a,cc
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DISCUSSIONGENERALE160
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DISCUSSION GENERALEet al., 2008b).
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DISCUSSION GENERALE• une réactio
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DISCUSSION GENERALE2. Les systèmes
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DISCUSSION GENERALEMycoplasma agala
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CONCLUSIONS184
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REFERENCES BIBLIOGRAPHIQUESBHANDARI
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REFERENCES BIBLIOGRAPHIQUESCASADO,
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REFERENCES BIBLIOGRAPHIQUESDEGIRMEN
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REFERENCES BIBLIOGRAPHIQUESETIENNE,
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REFERENCES BIBLIOGRAPHIQUESGRENIER,
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REFERENCES BIBLIOGRAPHIQUESHERZALLA
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REFERENCES BIBLIOGRAPHIQUESKERKADI,
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REFERENCES BIBLIOGRAPHIQUESKUMAR, M
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REFERENCES BIBLIOGRAPHIQUESMARZOCCO
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REFERENCES BIBLIOGRAPHIQUESODHAV, B
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REFERENCES BIBLIOGRAPHIQUESPFOHL-LE
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