簡介：中文中文4465字出處出處JOURNALOFMAGNETISMANDMAGNETICMATERIALS,2014,3491520畢業(yè)論文外文資料翻譯畢業(yè)論文外文資料翻譯題目TPH/FE3O4磁性復(fù)合微球的制備以及寬頻微波吸收性質(zhì)的研究學(xué)院化學(xué)化工學(xué)院專業(yè)高分子材料與工程二〇一四年三月十日2根據(jù)文獻，在大分子/FE3O4磁性復(fù)合微球的形成過程中，微球性能取決于類型和分子結(jié)構(gòu)中有機物的種類。不同種類的大分子與FE3O4組合具有不同的結(jié)構(gòu)和形態(tài)，導(dǎo)致微波吸收性能的不同。據(jù)報道，以酞菁為基礎(chǔ)的大分子/FE3O4磁性復(fù)合材料結(jié)合獨特的屬性通過現(xiàn)有的酞菁聚合物物質(zhì)的性質(zhì)包埋FE3O4微球，由于源自它們之間的交互影響的協(xié)同效應(yīng)使其展現(xiàn)出新穎的微波吸收特性12,13。在這，通過簡單有效的溶解熱的結(jié)晶路線，一種新型的TPH大分子用磁性物質(zhì)（FE3O4）設(shè)計和制造磁性聚合物微球。它可以發(fā)現(xiàn)TPH/FE3O4磁性復(fù)合微球具有規(guī)則的小粒度、良好的飽和磁化強度（5816EMUG1）和特殊強烈的反射損失（RL）寬頻率取得了預(yù)期效果。這種新磁性復(fù)合材料由于具有寬頻率的微波吸收特性一直被視為在微波領(lǐng)域的吸收有潛力應(yīng)用。2實驗部分21材料TPH是在我們實驗室制備的14。N甲基2吡咯烷酮，F(xiàn)ECL36H2O，乙二醇，聚乙二醇和三水合醋酸鈉都從中國成都科華試劑有限公司購買。在使用前TPH與無水乙醇一起提取。沒有使用的其他化學(xué)藥品和試劑進一步純化。22制備TPH/FE3O4磁性復(fù)合微球典型的復(fù)合微球在FECL36H2O和乙二醇共存的三水合醋酸鈉、聚乙烯2000和TPH中通過與減少溶解熱路線的一步法進行合成制備。這個過程根據(jù)REF的小修改第一步，F(xiàn)ECL36H2O在常溫下溶解于乙二醇中，然后加入聚乙烯2000和TPH在超聲波清洗器中形成橙色。第二步，把三水合醋酸鈉緩慢加入，同時大力攪拌30分鐘，然后密封于聚四氟乙烯襯里的高壓釜中。第三步，高壓蒸汽被加熱和維持在200℃15個小時。最后，產(chǎn)品過濾后用乙醇和蒸餾水洗滌數(shù)次，在60℃干燥數(shù)小時。第一步，通過調(diào)整加入混合溶液中TPH的含量，可以得到TPH含量不同的磁性復(fù)合微球。在這個操作中制備三個樣品并貼上S1、S2、S3，對應(yīng)的分別加入175G、35G和525G不同含量的混合溶液。23鑒定產(chǎn)品被掃描電子顯微鏡，通過一個溴化鉀顆粒用紅外光譜和X射線衍射表征。磁性研究由震動樣品磁強計檢測。把其他樣品和蠟按質(zhì)量比31用電磁測量計測

簡介：畢業(yè)設(shè)計外文資料翻譯學(xué)院學(xué)院（系）系）建筑工程系專業(yè)業(yè)土木工程姓名名學(xué)號號外文出處外文出處BUILDINGANDENVIRONMENT382003291295附件件1外文資料翻譯譯文；2外文原文。指導(dǎo)教師評語簽名用外文寫附件附件1外文資料翻譯譯文外文資料翻譯譯文作墻體和隔墻的磷石膏粉煤灰空心磚作墻體和隔墻的磷石膏粉煤灰空心磚摘要摘要在建造行業(yè)里，磷石膏粉煤灰空心磚FALG是最佳替代傳統(tǒng)的粘土空心磚或混凝土空心磚空心磚是空心、重量輕、保溫的，可用于建筑物本文的研究結(jié)果依據(jù)實驗調(diào)查FALG空心磚的抗壓強度、重量和吸水量而確定的。在這篇文章中也提出了，這些磚的耐久性方面的抗壓強度損失。它指出FALG空心磚有足夠的強度用于一般建筑物。關(guān)鍵詞關(guān)鍵詞建筑物；耐久性；環(huán)境；粉煤灰；磷石膏；廢棄物管理1介紹介紹目前是一個很好的時機去放眼未來,去提高公眾意識。因為能源、資源、生態(tài)問題不受工業(yè)增長的阻礙，不能視為理所當然。今后,在負責選擇工程材料時，將考慮全面的社會責任,不僅要有工程特性及生態(tài)環(huán)保,還要有工程材料的成本。磷石膏和粉煤灰主要分別來自下游的磷酸肥料工業(yè)廢水和熱電廠。在印度，平均每年生產(chǎn)磷石膏和粉煤灰是500萬噸和5億噸。這兩個問題所造成的廢料處理的環(huán)境惡化，以及自然原因所造成的空氣和水污染大。磷石膏使用的范圍有限,而作為建材其存在諸如五氧化二磷、氟化物、堿等不良的有機物雜質(zhì)。在水泥工業(yè)中，經(jīng)過適當?shù)奶幚砗?，磷石膏可用來替代作為天然石膏。但?面對如何對待磷石膏非常昂貴的問題,因此其在水泥業(yè)中越來越多的使用，尚未普及。雖有少部分的波特蘭粉煤灰、黏土水泥灰、灰磚等應(yīng)用于生產(chǎn)，但仍未有大量的粉煤灰被使用。在印度僅有約3的粉煤灰用做商業(yè)用途。在建筑業(yè)中，磷石膏、粉煤灰及石灰的組合使得這些數(shù)量龐大的工業(yè)廢物再次利用。在許多方面，磷石膏、粉煤灰、石灰是可以相互結(jié)合的。如果這些物質(zhì)可以用來制造具有足夠強度的磚和空心磚,以節(jié)約替代粘土燒磚、空心磚、以及那種殉葬用的燒結(jié)空心磚等。無論是從礦產(chǎn)資源，還是工業(yè)廢物，或者購買的乙炔石灰、紙制品、石灰污泥肥料,工業(yè)廢物都是石灰的來源。磷石膏粉煤灰FALG的廣泛應(yīng)用于建筑材料，如磚和混凝土結(jié)構(gòu)。在早期進

簡介：中文中文2900字二○一三屆畢業(yè)論文外文翻譯學(xué)院院工程機械學(xué)院工程機械學(xué)院專業(yè)業(yè)機械設(shè)計制造及其自動化機械設(shè)計制造及其自動化姓名名學(xué)號號指導(dǎo)教師指導(dǎo)教師完成時間完成時間2013年3月27日摘要摘要一般來說，行走式行星齒輪減速齒輪是由多重行星齒輪階段組成，并且在齒輪減速器末級有空心太陽齒輪。在設(shè)計減速器齒輪中，準確估計太陽齒輪的牙齒根處的彎曲應(yīng)力非常重要，因為太陽齒輪是減速器系統(tǒng)中的薄弱環(huán)節(jié)。雖然使用標準齒輪代碼可以輕易計算彎曲應(yīng)力,比如美國設(shè)備制造商協(xié)會AGMA和國際標準化組織ISO6336系列幾乎所有的齒輪，但是精確計算需要空心太陽齒輪有低備份比率輪緣厚度除以輪齒高度和相對大的根圓角半徑。在這項研究中,應(yīng)用一個有限元分析FEA研究輪緣厚度和根圓角半徑對空心太陽齒輪齒根彎曲應(yīng)力的影響。在標準規(guī)范下，牙齒根處彎曲應(yīng)力的線性計算的常數(shù)坡備份比低于12。然而，在行星齒輪系統(tǒng)中，輪緣處彎曲應(yīng)力的影響則更為復(fù)雜。同時比較了在各種備份比和根圓角半徑下應(yīng)用FEA計算彎曲應(yīng)力和應(yīng)用標準規(guī)定計算彎曲應(yīng)力。關(guān)鍵字關(guān)鍵字AGMA；備份比率；彎曲應(yīng)力；齒根圓角半徑；空心太陽齒輪；ISO；齒緣厚度

簡介：JOURNALOFINDUSTRIALMICROBIOLOGYPACKINGMACHINESMOULDSPORESPENICILLIUMHUMIDITYINTRODUCTIONHUMIDITYWOULDBEANOPTIONFORTHEDECONTAMINATIONOFPACKINGMATERIALSWHERETHEMAINREASONFORCONCERNISTHECONSUMERSAREMOREANDMOREDEMANDINGWITHRESPECTTOPRESENCEOFMOULDSTHEQUALITYOFFOODPRODUCTSTHEREFORE,PRODUCTSAREOFTENSPORESOFPENICILLIUMSPECIESAREFREQUENTLYFOUNDONPRESERVEDBYINLINESHORTTIMEHIGHTEMPERATURETREATPACKINGMATERIALSEVENAFTERTHERMOFORMINGFORTHISREASONMENTSTOPREVENTREINFECTION,THEPRODUCTTHENISANDBECAUSEOFAVAILABILITYANDEASEOFCULTIVATION,SPORESPACKEDASEPTICALLYOFPENICILLIUMROQUEFORTIIWEREUSEDTHEMICROBIALLOADOFTHEPACKINGMATERIALMUSTBELOWENOUGHTOASSURETHATTHEACCEPTABLERATEOFCONTAMINATIONISNOTEXCEEDED1DEPENDINGONTHEMICROBIOLOGICALQUALITY,ITMAYBENECESSARYTOREDUCETHENUMBEROFMICROMATERIALSANDMETHODSORGANISMSONTHEPACKINGMATERIALBEFOREUSETHISMAYBEACHIEVEDUSINGHYDROGENPEROXIDE,HEAT,ULTRAVIOLETLIGHT,MATERIALSOROTHERTREATMENTS,EITHERINDIVIDUALLYORINCOMBINATIONTHEPACKINGMATERIALCOMPRISEDRECTANGULARDISCSTREATMENTWITHHYDROGENPEROXIDEATELEVATEDTEMPERATURES3545MMMADEFROMASHEETOF550?MTHICKNESSISBYFARTHEMOSTCOMMONTECHNOLOGYUSEDRESIDUESOF55?MOFPOLYESTERPETGAND495?MOFPOLYSTYRENEHYDROGENPEROXIDE,HOWEVER,AREUNDESIRABLETHEACCEPTFROMCOBELPLAST,LOKEREN,BELGIUMTHEFUNGALSPORESABLERESIDUALCONCENTRATIONINTHEPRODUCTPACKEDISVERYWEREPENICILLIUMROQUEFORTITYPECB2,OBTAINEDFROMLOW?5MGKG?1INMOSTCOUNTRIESTHEUSEOFHYDROGENWIESBYNIEBU¨LL,GERMANY,LOT735263THETALCWASPEROXIDEALSOREQUIRESSAFETYMEASURESTOPROTECTPERSONNELHYDROUSMAGNESIUMSILICATE,OBTAINEDFROMLAMERSSTIRRINGBARBEPREFERABLEDIAMETER8MM,LENGTH50MMFORPRODUCTSTHATDONOTALLOWTHEGROWTHOFBACTERIA,SUCHASMANYACIDPRODUCTSANDPRODUCTSWITHALOWWATERACTIVITY,ITISOFTENSUFFICIENTTOINACTIVATEMOULDSANDMEDIAYEASTSMOULDSANDYEASTS,HOWEVER,CANBEINACTIVATEDBYTHEDILUTEDMALTEXTRACTAGARCONTAINEDAGARDIFCO20G,TEMPERATURESBELOW100°CPROVIDEDTHEWATERACTIVITYISMALTEXTRACTOXOIDCM5720G,DISTILLEDWATER1000MLHIGHENOUGHTHEMEDIUMWASAUTOCLAVEDAT115°CFOR15MINTHEPEPTHEOBJECTIVEOFTHEWORKREPORTEDHEREWASTODETERMINETONESALTSOLUTIONCONTAINEDPEPTONESALTOXOIDCM733WHETHERTHEUSEOFHEATINCOMBINATIONWITHENHANCED95G,OFWHICHPEPTONEMADEUP10GANDNACLMADEUP85G,DISTILLEDWATER1000MLTHESOLUTIONWASAUTOCLAVEDAT120°CFOR20MINTHEMALTEXTRACTBROTHCONTAINEDMALTCORRESPONDENCEHLMLELIEVELD,UNILEVERRESEARCHLABORATORIUMEXTRACTOXOIDCM57200G,OFWHICHMALTEXTRACTMADEVLAARDINGEN,POBOX1143130AC,VLAARDINGEN,THENETHERLANDSUP17GANDMYCOLOGICALPEPTONEMADEUP30G,DISTILLED2CURRENTADDRESSASEPT,RUEDESDOCTEURSCALMETTEETGUE′RIN,BP49WATER1000MLTHEBROTHWASAUTOCLAVEDAT115°CFOR53020,LAVALCEDEX,FRANCERECEIVED9SEPTEMBER1996ACCEPTED31JANUARY199710MINDECONTAMINATIONOFFOODPACKINGMATERIALDRAYNAUDANDHLMLELIEVELD328TABLE1INACTIVATIONOFSPORESOFPROQUEFORTIIUNDERVARIOUSCONDITIONSATREATMENTRESULTSTEMPERATUREINSIDERELATIVEHUMIDITYTEMPERATUREOFTIMEBETWEENNONRNO/NLOGRMEANSTERILIZATIONCHAMBERHEATINGPLATESHEATINGPLATESS°C°C4910060114102640?15250074600?1571007011410986140115250042700126210080114108981604352500135503813060?9?3402275870016603567100850306031991775870030401911400?1?140035055300115028731009001400?1?14003335530019291014410?5?88239855000?3?18333761009504410?3?14703485500012458315660?1?566039153300?5?10660771008805660?1?566037653300?9?592230100340403050130114560183025321203036826003890021NOTMEASURED40403001327150317582600832994560?3?152018180340482600?4?20650AINALLTESTSWITH100HUMIDITYTHETOTALTREATMENTTIMEWASSLIGHTLYLESSTHAN3SVALUESOFNAREAVERAGESOFCFUCOUNTSOFTHREEIDENTICALEXPERIMENTS,USINGDISCSOFEQUALINITIALCONTAMINATIONLOGRWASCALCULATEDAFTERAVERAGINGTHEVALUESOFRFROMIDENTICALEXPERIMENTSTHE‘?’SIGNSHAVEBEENIGNOREDTHUSTHELOGRVALUESMAYBEMINIMUMVALUESFIGURE3THEREDUCTIONINNUMBEROFVIABLESPORESOFPROQUEFORTIASAFUNCTIONOFTHETEMPERATUREATHIGHAANDLOWBRELATIVEHUMIDITY???T1S???T0S???T1S,RH?40

簡介：MATERIALSSCIENCEANDENGINEERINGA413–4142005545–549GROWTHRATEANDIMPURITYDISTRIBUTIONINMULTICRYSTALLINESILICONFORSOLARCELLSRANNVEIGKVANDE?,?YVINDMJ?S,BIRGITRYNINGENNORWEGIANUNIVERSITYOFSCIENCEANDTECHNOLOGY,DEPARTMENTOFMATERIALSSCIENCEANDENGINEERING,ALFREDGETSVEI2,7491TRONDHEIM,NORWAYRECEIVEDINREVISEDFORM1JULY2005ABSTRACTTHESOLIDIFICATIONRATEOFMULTICRYSTALLINESILICONMADEBYDIRECTIONALSOLIDIFICATIONHASBEENDETERMINEDBYINSITUMEASUREMENTSOFTHESOLID/LIQUIDINTERFACEPOSITIONINAPILOTSCALEFURNACETWOEXPERIMENTSWERECONDUCTEDWHERESILICONWASSOLIDIFIEDVERTICALLYFROMTHEBOTTOMWITHANEARLYPLANARINTERFACEANDCOOLEDAFTERSOLIDIFICATIONATTWODIFFERENTRATESTHEAVERAGESOLIDIFICATIONRATEWASFOUNDTOBE410?6M/S,WHICHFITSWELLCOMPAREDTOVALUESCALCULATEDFROMTEMPERATUREMEASUREMENTSBENEATHTHECRUCIBLETHESOLIDIFIEDSILICONWASEXAMINEDTODETERMINETHECARBONANDOXYGENDISTRIBUTIONANDTHEELECTRONLIFETIMEVERTICALLYINTHEINGOTSTHECARBONDISTRIBUTIONWASQUITESIMILARINBOTHINGOTSWITHACONCENTRATIONOFABOUT4PPMAINTHEMIDDLEOFTHEINGOTSAHIGHEROXYGENCONCENTRATIONWASFOUNDINTHEINGOTWITHSLOWCOOLINGTHISWASARESULTOFPOORCOATINGWHICHINCREASEDOXYGENDIFFUSIONFROMTHECRUCIBLETHEELECTRONLIFETIMEWASFOUNDTOBEABOUT10?SINTHEMATERIALWITHFASTCOOLING,WHEREASTHEMATERIALWITHSLOWCOOLINGHADANELECTRONLIFETIMEOF2?SMOREDIFFUSIONOFIRONFROMTHECRUCIBLEMAYBETHEREASONFORTHELOWLIFETIMEINTHEMATERIALWITHSLOWCOOLING?2005ELSEVIERBVALLRIGHTSRESERVEDKEYWORDSDIRECTIONALSOLIDIFICATIONMULTICRYSTALLINESILICONSOLIDIFICATIONRATEIMPURITYDISTRIBUTIONELECTRONLIFETIME1INTRODUCTIONMULTICRYSTALLINESILICONISTHEMOSTUSEDMATERIALINSOLARCELLSWITHASHAREOFMORETHAN50OFTHESHIPPEDPVMODULESWORLDWIDE1DIRECTIONALSOLIDIFICATIONISACOMMONMETHODTOCASTMULTICRYSTALLINESILICONFORUSEINSOLARCELLSHERE,THESILICONISMELTEDANDSOLIDIFIEDFROMBELOWBYEXTRACTIONOFHEATTHROUGHTHECRUCIBLEBOTTOM,RESULTINGINANEARLYPLANARSOLID/LIQUIDINTERFACEMOSTIMPURITIESARESEGREGATEDTOWARDSTHETOP,ANDTHEFINALCRYSTALSTRUCTUREISDOMINATEDBYLARGECOLUMNARGRAINSPARALLELTOTHESOLIDIFICATIONDIRECTIONTHESOLARENERGYCONVERSIONEFFICIENCYOFMULTICRYSTALLINESOLARCELLSISTYPICALLYINTHERANGEOF12–15THEEFFICIENCYISMAINLYLIMITEDBYMINORITYCARRIERRECOMBINATIONATDISLOCATIONSANDINTRAGRANULARDEFECTSSUCHASIMPURITIES,SMALLCLUSTERSOFATOMS,ORPRECIPITATES2SINCERECOMBINATIONATPUREDISLOCATIONSISKNOWNTOBERELATIVELYWEAK,ITHASBEENSUGGESTED?CORRESPONDINGAUTHORTEL4773596867FAX4773550203EMAILADDRESSRANNVEIGKVANDEMATERIALNTNUNORKVANDETHATTHEDECORATIONWITHMETALLICIMPURITIESORPRECIPITATESISRESPONSIBLEFORTHEENHANCEDRECOMBINATIONINTHESEREGIONS3–5ITISWELLKNOWNTHATTHESOLIDIFICATIONPROCESSSTRONGLYAFFECTSTHEEFFICIENCYTHESOLIDIFICATIONCONTROLSTHESTRUCTUREOFTHEMATERIAL,WHILEPOSTSOLIDIFICATIONCOOLINGISBELIEVEDTOAFFECTTHEDISLOCATIONDENSITYTHECURVATUREOFTHESOLIDIFIEDINTERFACEMAYAFFECTTHECRYSTALMORPHOLOGYANDTHELOCATIONOFIMPURITIESINTHESOLIDIFIEDMATERIALCARBONANDOXYGENARE,BESIDESNITROGEN,THEMAINIMPURITIESINMULTICRYSTALLINESILICON,WHERECARBONORIGINATESPRIMARILYFROMINSULATIONANDHEATINGELEMENTSINTHEFURNACE,WHILEOXYGENDIFFUSESINTOTHEMELTFROMTHEQUARTZCRUCIBLETHEPRESENTPAPERDESCRIBESEXPERIMENTSMADEINORDERTODETERMINETHEGROWTHRATEOFSILICONDURINGDIRECTIONALSOLIDIFICATIONINAPILOTSCALEBRIDGMANFURNACE,ANDTOESTABLISHTHEINFLUENCEOFCOOLINGRATEONTHEMINORITYCARRIERLIFETIMEWHICHISAFFECTEDBYTHEDISLOCATIONDENSITYTHEGROWTHRATEISALSOCALCULATEDFROMTEMPERATUREMEASUREMENTSINTHEPEDESTALBENEATHTHECRUCIBLETHEMATERIALFROMBOTHEXPERIMENTSWASCHARACTERIZEDTODETERMINETHECARBONANDOXYGENDISTRIBUTIONVERTICALLYINTHEINGOTS09215093/–SEEFRONTMATTER?2005ELSEVIERBVALLRIGHTSRESERVEDDOI101016/JMSEA200509035RKVANDEETAL/MATERIALSSCIENCEANDENGINEERINGA413–4142005545–549547FIG3MEASUREDANDCALCULATEDSOLIDIFICATIONLENGTHASFUNCTIONOFTIMECOMBININGEQS1–3ANDASSUMINGQSI,SQCRQGQ,GIVESTHEFOLLOWINGEXPRESSIONQATM?TPTGKGTSI,SKSI,STCRKCR4THETHERMALCONDUCTIVITYCOEFFICIENTSAREASSUMEDCONSTANTDURINGSOLIDIFICATIONTHEPEDESTALTEMPERATURETPISMEASUREDBYATHERMOCOUPLEDURINGSOLIDIFICATIONHEATTRANSFERTHROUGHTHESOLIDIFIEDSILICONCANBEEXPRESSEDASQSI,SQHEATFROMREACTIONQHEATFROMLIQUID?HSIΡSIMSIVAAKSI,LΔTSH?TM5?HSIISTHELATENTHEATFORSILICON,ΡSITHESILICONDENSITY,MSITHEMOLARMASSFORSILICON,ANDVISTHEGROWTHRATEBYSETTINGEQ4EQ5THEFOLLOWINGEQUATIONWASDERIVEDFORTHEGROWTHRATEVMSIΡSI?HSI??TM?TPTSI,SKSI,STCRKCRTGKG?KSI,LIQΔTSH?TM??6EQ6ISSIMPLIFIEDBYNEGLECTINGTHESECONDTERMUNDERTHEASSUMPTIONOFNOMELTSUPERHEAT,TSH0THETHERMALCONDUCTIVITYOFTHEQUARTZCRUCIBLEISUNCERTAINANDTHECONSTANTKCRINEQ6INCLUDESALSOINREALITYTHETHERMALCONDUCTIVITYOFTHECOATING,WHICHISDEPENDENTOFTHICKNESSANDDENSITYOFTHECOATINGITISTHEREFOREDIFFICULTTOQUANTIFYKCRANDTHEGROWTHRATEISCALCULATEDATTWODIFFERENTCONDUCTIVITIESTHECALCULATEDSOLIDIFICATIONLENGTHCORRESPONDSWELLWITHTHEMEASUREDVALUESWHENASSUMINGTHETHERMALCONDUCTIVITYOFTHECRUCIBLETOBE12W/MK,ASSHOWNINFIG3THEMEASUREDSOLIDIFICATIONLENGTHASFUNCTIONOFTIMEWASVERYSIMILARINTHETWOEXPERIMENTS,INDICATINGSTABLEANDREPRODUCIBLETHERMALCONDITIONSANAVERAGEGROWTHRATEOF410?6M/SISCALCULATEDFROMTHEMEASUREDVALUESTHECURVATUREOFTHEINTERFACEDURINGSOLIDIFICATIONWASINBOTHEXPERIMENTSSLIGHTLYCONVEXWITHANAPPROXIMATELYHEIGHTDIFFERENCEOF5MMBETWEENCENTREANDHALFWAYOUTTOTHESIDESFIG4CARBONCONTENTASFUNCTIONOFVERTICALPOSITIONININGOT,MEASUREDANDCALCULATEDFROMSCHEILEQUATION32CARBONANDOXYGENCONTENTTHECARBONCONTENT,SHOWNINFIG4,INCREASESINVERTICALDIRECTIONASARESULTOFSEGREGATIONANDEXCEEDSTHESOLUBILITYLIMITATTHEENDOFSOLIDIFICATIONTHISRESULTSINPRECIPITATIONOFSIC,ANDTHELASTMEASUREMENTFORBOTHINGOTSWILLTHEREFOREDEVIATEFROMTHEREALCARBONCONTENTSINCEFTIRCANONLYMEASURESUBSTITUTIONALCARBONTHECARBONDISTRIBUTIONINTHETWOINGOTSWASQUITESIMILARWITHACONCENTRATIONOFABOUT4PPMAINTHEMIDDLEOFTHEINGOTSTHECARBONCONTENTWASALSOCALCULATEDBYSCHEILEQUATIONUSINGADISTRIBUTIONCOEFFICIENTOF005810THESTARTCONCENTRATIONWASSETTO17PPMATHEMEASUREDCARBONCONCENTRATIONSFITWELLWITHTHECONCENTRATIONPROFILECALCULATEDFROMSCHEILEQUATIONTHEOXYGENPROFILERESULTSFROMTHECOMPETITIONOFTHREEMECHANISMSDIFFUSIONFROMTHECRUCIBLE,SOLIDIFICATIONREJECTION,ANDEVAPORATIONFROMTHEMELTSURFACETHEOXYGENCONCENTRATIONISPARTICULARLYHIGHATTHEBOTTOMFORBOTHINGOTSANDDECREASESFROMBOTTOMTOTOPASSHOWNINFIG5THEHIGHCONCENTRATIONINTHELOWERPARTISARESULTOFOXYGENDIFFUSIONINTOTHEMELTFROMTHEQUARTZCRUCIBLETHECONTACTAREABETWEENMELTANDCRUCIBLEREDUCESASSOLIDIFICATIONPROCEEDSANDTHISFIG5OXYGENCONTENTASFUNCTIONOFVERTICALPOSITIONININGOT

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簡介：ODMATRICESESTIMATIONFROMLINKFLOWSBYNEURALNETWORKSANDPCALORENZOMUSSONE1,MATTEOMATTEUCCI21DEPARTMENTOFBUILDINGENVIRONMENTSCIENCETECHNOLOGY,POLITECNICODIMILANO,ITALYMUSSONEPOLIMIIT,VIABONARDI,9,20123MILANO2DEPARTMENTOFELECTRONICANDINFORMATION,POLITECNICODIMILANO,ITALYMATTEUCCELETPOLIMIIT,VIAPONZIO,34/5,20123MILANOABSTRACTTHEPAPERTACKLESODMATRIXESTIMATIONSTARTINGFROMTHEMEASURESOFFLOWONROADNETWORKLINKSANDPROPOSESTHEAPPLICATIONOFSOFTCOMPUTINGTECHNIQUESTHEAPPLICATIONSCENARIOSARETWOATRIALNETWORKANDTHEREALRURALNETWORKOFTHEPROVINCEOFNAPLESBOTHSIMULATEDBYAMICROSIMULATORDYNAMICALLYASSIGNINGKNOWNODMATRICESAPCAPRINCIPALCOMPONENTANALYSISTECHNIQUEWASALSOUSEDTOREDUCETHEINPUTSPACEOFVARIABLESINORDERTOACHIEVEBETTERSIGNIFICANCEFORINPUTDATAANDTOSTUDYTHEPOSSIBLEEIGENGRAPHSOFTHEROADNETWORKSCOPYRIGHT?2006IFACKEYWORDSODESTIMATION,NEURALNETWORKS,PCA,LINKFLOWMEASURES,VARIANCESTABILIZATION1INTRODUCTIONTHEANALYSISOFURBANNETWORKSWASORGANICALLYANDSIGNIFICANTLYDEVELOPEDSINCETHEMIDDLEOF80SINORDERTOSOLVEPROBLEMSRELATEDTOROADCIRCULATIONMANYPLANNINGANDCONTROLMETHODOLOGIESBOTHWITHEQUILIBRIUMANDDYNAMICAPPROACHESAREBASEDONTHEUSEOFANORIGINDESTINATIONMATRIXODFIELDSURVEYNECESSARYTOBUILDTHISMATRIXISEXPENSIVEANDCANNOTBEREPEATEDWITHAHIGHFREQUENCYFORTHISREASON,METHODOLOGICALANDOPERATINGALTERNATIVESHAVEBEENEXPERIMENTEDSINCEMANYYEARSANDTHEYAIMATBUILDINGTHEODMATRIXBYUSINGLINKFLOWSTHATGENERALLYCOSTLESSTOBEMEASUREDINORDERTOSOLVETHEPROBLEMOFODESTIMATIONMANYAPPROACHESHAVEBEENDEVELOPEDSOMEAREBASEDONENTROPYMAXIMIZATIONTHATISONTHEMAXIMIZATIONOFTRIPDISTRIBUTIONDISPERSIONONALLAVAILABLEPATHSINSOMECASESTHEBUILTMODELREFERSTOANODMATRIXOBJECTIVEWITHOUTREFERRINGINDEEDTOESTIMATIONERRORS,ORTOSTATISTICESTIMATIONINDEXESORTOLIKELIHOODFUNCTIONSVANZUYLENANDWILLUMSEN,1980THISMODELWASLATEREXTENDEDTOCONGESTEDNETWORKSBYFORMULATINGANOPTIMIZATIONPROBLEMWITHVARIATIONALDISEQUALITYCONSTRAINTSLEADINGTOABILEVELPROGRAMMETHEBILEVELAPPROACHPRESENTSSOMEDIFFICULTIESTOFINDTHEOPTIMALSOLUTIONBECAUSEOFNONCONVEXANDNONDIFFERENTIALFORMULATIONFLORIANANDCHEN1995FORMULATEDAHEURISTICAPPROACHOFGAUSSSEIDELTYPECAPABLEOFCONVERGINGTOOPTIMALSOLUTIONBYLIMITINGTHEOBJECTIVETOTHECORRECTIONOFO/DMATRIXOTHERAPPROACHESAREBASEDONMODELSTHATUSETHESTATISTICALPROPERTIESOFOBSERVEDVARIABLESFORINSTANCEMAHER1983PROPOSEDABAYESIANESTIMATIONBYMEANSOFANORMALMULTIVARIATEDISTRIBUTIONBOTHFORMATRIXDISTRIBUTIONANDFORLINKFLOWCASCETTA1984USEDANESTIMATIONBASEDONGENERALIZEDLEASTSQUARESGLSANOVERVIEWOFSTATISTICALMETHODSFORESTIMATINGODMATRIXCANBEFOUNDINCASCETTAANDNGUYEN1988ITREGARDSGENERALIZEDANDCONSTRAINEDLEASTSQUARESANDESTIMATIONOFLIKELIHOODANDBAYESIANTYPETHEMOSTOFTHESESTUDIESASSUMESAFIXEDPERCENTAGEOFLINKORPATHCHOICECALCULATEDBYADETERMINISTICUSEREQUILIBRIUMASSIGNMENTMODELTHISCANCAUSESOMEINCONSISTENCYBETWEENFLOWSANDTHEODMATRIXESPECIALLYWHENTHENETWORKISHIGHLYCONGESTEDINORDERTOOVERTAKETHISLIMITATION,CASCETTA1989PROPOSEDTOINTERPRETLINKANDPATHFLOWSLIKESTOCHASTICVARIABLESAND,THEREFORE,VALUESOBTAINEDBYASUEASSIGNMENTLIKETHEAVERAGEVALUESOFTHESEVARIABLESONTHESAMELINETHEREAREOTHERPAPERSSUCHASYANGETAL1992,ANDINASUCCESSIVEIMPROVEMENTINYANGETAL,2001LOETAL1996PROPOSEDAUNIFIEDSTATISTICALAPPROACHFORTHEESTIMATIONOFODMATRIXUSINGSIMULTANEOUSLYLINKFLOWDATAANDINFORMATIONABOUTLINKCHOICEPERCENTAGEGONG1998USESAHOPFIELDNEURALNETWORKASATOOLFORSOLVINGANOPTIMALPROBLEM,COMPONENTSINTHEFOLLOWINGPLOTS,ARCSWITHAHIGHERCONTRIBUTIONARETHICKERANDTHEIRCOLORISREDIFTHEYHAVEAPOSITIVECONTRIBUTIONOTHERWISEISBLUETHEVISUALIZATIONOFEIGENFLOWS,IE,THEPRODUCTOFTHEFLOWMATRIXANDTHEEIGENGRAPHS,SHOWNINTHENEXTCHAPTERS,ISTHEPROJECTIONOFTRAFFICFLOWSONTOTHEEIGENGRAPHSPACEINTHESAMEWAYASBEFORE,ARCSWITHAHIGHERCONTRIBUTIONTOFLOWARETHICKERANDTHEIRCOLORISREDIFTHEYHAVEAPOSITIVECONTRIBUTIONOTHERWISETHEIRCOLORISBLUE3APPLICATIONSCENARIOS31THESIMULATORTHESCENARIOSREFERREDTODURINGEXPERIMENTATIONSAREPRODUCEDBYASIMULATIONENVIRONMENTFORROADNETWORKSDEVELOPEDBYTHETRANSPORTSECTIONOFTHEUNIVERSITYOFNAPLESTHISSIMULATORISABLETOREPRODUCEDYNAMICVEHICULARFLOWSTARTINGFROMAGENERICTRANSPORTDEMANDSETTINGUPTHEEXPERIMENTSREQUIRESTHEDEFINITIONOFTHETRANSPORTSYSTEM,DEMANDANDSUPPLY,BYWHICHEVERYMODELANDPROCEDURESMUSTBECALIBRATEDFORTHISREASON,ATRIALNETWORKWITH6NODESAMONGWHICHTHEREARE3CENTROIDSAND12LINKSWASFIRSTLYUSEDFIGURE1FIG1THESIMPLIFIEDNETWORKFORFIRSTEXPERIMENTSFIG2SCHEMATICNETWORKUSEDFORTHERURALROADNETWORKOFTHEPROVINCEOFNAPLESTHEN,WITHTHEAIMATMAKINGMORELIKELYTHEAPPLICATIONSCENERY,AREALLANDSYSTEMHASBEENSURVEYEDBOTHWITHITSDEMOGRAPHICCHARACTERISTICSANDACTIVITYLOCATIONS,ANDACTUALTRANSPORTSUPPLYTHETERRITORIALCONTEXTISTHEWHOLEPROVINCEOFNAPLESFROMWHICHTHERURALROADNETWORKHASBEENEXTRACTEDFIGURE2THISNETWORKHAS994NODESAMONGWHICHTHEREARE45CENTROIDSAND1363LINKSREDUCEDTO1190AFTERDISCHARGINGLINKSWITHNOFLOW32DEMANDANDVEHICULARFLOWONLINKSDEMANDISCHARACTERIZEDBYWITHINDAYANDDAYTODAYDYNAMICANDITISUPDATEDEACH15MINUTESFLOWSONLINKAREDETECTEDEACHFIVEMINUTESFORTHETRIALNETWORK,DEMANDISDESCRIBEDBYA3X3MATRIXANDTHENODES1AND6AREORIGINCENTROIDSTHENODES1,4AND6AREDESTINATIONCENTROIDSFORATOTALOFFOURNONEMPTYCELLSSIMULATIONDAYSARE15FORTHENETWORKOFNAPLESPROVINCETHEFINALNETWORKTHESCENERYISMORECOMPLEXDEMANDISDESCRIBEDBYA48X48WITH1004NONEMPTYCELLSOUTOF2304ANDWITHASTRUCTUREHIGHLYVARIABLEDURINGTHEDAYBESIDESTHEHIGHVARIABILITYOFDEMANDITMUSTBEUNDERLINEDTHATNONEMPTYCELLSSETSINTHE15MINUTEINTERVALSAREGENERALLYNOTOVERLAPPINGCELLSWITHLESSTHAN10VEHICLESPERHOURARECANCELLEDFORTWOMAINREASONSFIRSTLYTOREDUCEDATADISPERSIONANDSECONDLYBECAUSEITISVERYDIFFICULTTHATTHESELOWVALUESHAVEASTATISTICALSIGNIFICANCEWHILEITISLIKELYTHEYDON’TGIVEAREALINFORMATIONTHEFINALMATRIXHASTHEREFORE726NONEMPTYCELLSABOUTTHE31OFTHETOTALWITHAREDUCTIONOFTHENUMBEROFNONEMPTYCELLSOFABOUT28,BUTWITHREDUCTIONOFDEMANDOFONLYABOUT88SIMULATIONDAYSARE15ALSOFORTHISSCENARIOBUTOBVIOUSLYTHEAMOUNTOFDATATOBEUSEDISMORETHANTENTIMESHIGHERTOTALDEMANDIS41,488,230VEH/HFORBOTHNETWORKSTHENUMBEROFRECORDSIS1440FORODDEMANDAND4320FORLINKFLOWSFORTHISREASONEACHROWOFODDEMAND15MINUTEINTERVALISRELATEDTOTHETHREEROWSOFFLOWOFTHESAME15INTERVAL,LEADINGTO4320RECORDSBOTHFORODDEMANDANDLINKFLOWSBYUSINGTHEDATASETUNDEREXAMINATIONANDOBSERVINGTHEPLOTOFSEASONALITY,WECANARGUETHATPROCESSVARIANCEISLOWWHENTHESEASONALITYVALUEISLOWAND,CONVERSELY,ITISHIGHWHENTHESEASONALITYVALUEISHIGHASSUMINGTHIS,ITISREASONABLETOLOOKFORTHEEXISTENCEOFANANALYTICALRELATIONSHIPBETWEENSEASONALITYBASICALLYAMEANANDVARIANCETHEEXISTENCEOFARELATIONSHIPBETWEENTHESETWOVARIABLESPLOTTEDINFIGURE3CONFIRMSTHATTHEPROCESSISNOTSTATIONARYFROMTHISFIGUREITCANBEEASYARGUEDTHATVARIANCEANDAVERAGEARERELATEDBYANONLINEARRELATIONSHIP,SPECIFICALLYAQUADRATICONEINTHISSITUATIONAPOSSIBLETECHNIQUETOSTABILIZETHEVARIANCEISTOAPPLYALOGARITHMICTRANSFORMATIONTHEFOLLOWINGRESULTSSHOWTHATTHISTRANSFORMATIONREALLYALLOWSUSTOIMPROVEPERFORMANCEOFABOUTSOMEPERCENTAGEPOINTSFORTHERMSEINDEXWITHRESPECTTORESULTSOBTAINEDWITHOUTSTABILIZATIONHOWEVER,ITMUSTBEUNDERLINEDTHATTHISRESULTISNOTGENERALTHOUGHINTRANSPORTAPPLICATIONITISRATHERFREQUENT

簡介：SILVERSTAININGDNAINPOLYACRYLAMIDEGELSBRANTJBASSAM1DOI101038/NPROT2007330THISPROTOCOLDESCRIBESASIMPLESILVERSTAININGMETHODUSEDTOVISUALIZEDNAFRAGMENTSANDOTHERORGANICMOLECULESWITHUNSURPASSEDDETAILFOLLOWINGTRADITIONALPOLYACRYLAMIDEGELELECTROPHORESISPAGESENSITIVITYRIVALSRADIOISOTOPICMETHODSANDDNAINTHEPICOGRAMRANGECANBERELIABLYDETECTEDTHEDESCRIBEDPROTOCOLISFASTB1HANDISIMPLEMENTEDUSINGREADILYAVAILABLECHEMICALSANDMATERIALSTOACHIEVETHESENSITIVITYANDVISUALCLARITYEXPECTED,QUALITYREAGENTSANDCLEANHANDLINGAREIMPORTANTTHEUPDATEDPROTOCOLDESCRIBEDHEREISBASEDONTHEWIDELYUSEDMETHODOFBASSAMETAL1991,BUTPROVIDESIMPROVEDIMAGECONTRASTANDLESSRISKOFSTAININGARTEFACTSINTRODUCTIONTHESEPARATIONOFCOMPLEXDNASAMPLESANDOTHERBIOLOGICALMOLECULESWITHHIGHRESOLUTIONBYPOLYACRYLAMIDEGELELECTROPHORESISPAGEHASBROADAPPLICATIONHOWEVER,TOREALIZETHEPOTENTIALOFPAGE,AVISUALIZATIONMETHODOFFERINGSUPERIORCLARITYANDSENSITIVITYISALSOREQUIREDTHESILVERSTAININGMETHODDESCRIBEDHEREHASPROVENVERYEFFECTIVEINTHISREGARDASAMETHOD,SILVERSTAININGWASORIGINALLYDEVELOPEDTODETECTPROTEINSSEPARATEDBYPAGE1–3ITWASFURTHEROPTIMIZEDANDAPPLIEDTOVISUALIZEOTHERBIOLOGICALMOLECULES,FOREXAMPLE,NUCLEICACIDS4,5,LIPOPOLYSACCHARIDES6,GLYCOPROTEINSANDPOLYSACCHARIDES7THESEEARLIERPROTOCOLSWERE,HOWEVER,COMPARATIVELYTEDIOUSANDOFFEREDLIMITEDSENSITIVITYTHEDEVELOPMENTOFDNAAMPLIFICATIONFINGERPRINTINGDAFBYCAETANOANOLLE′SETAL8REQUIREDASUPERIORPROTOCOLTOADEQUATELYRESOLVEANDVISUALIZECOMPLEXDNAPROFILESTHESEREQUIREMENTSLEDDIRECTLYTOTHECODEVELOPMENTOFASUCCESSFULCOMBINATIONOFPOLYESTERBACKEDPAGEGELSANDDNASILVERSTAININGTHESILVERSTAINPROTOCOLDEVELOPEDFORDAFWASDESCRIBEDSEPARATELYBYBASSAMETAL,9ANDHASSINCEGAINEDWIDEACCEPTANCEINCLUDINGCOMMERCIALIZATIONEG,INTHEGENEPRINTSTRSYSTEMSANDSILVERSEQUENCEPRODUCTSFROMPROMEGACORPORATION,USASILVERSTAININGOFDNAANDOTHERBIOLOGICALSAMPLESHASSEVERALADVANTAGES?IMAGEDEVELOPMENTANDVISUALIZATIONISDONEUNDERNORMALAMBIENTLIGHTTHUS,THEPROCEDURECANBEPERFORMEDENTIRELYATTHELABORATORYBENCHWITHOUTTHENEEDFORDARKROOMORUVILLUMINATIONFACILITIES?THEIMAGEISRESOLVEDWITHTHEBESTPOSSIBLESENSITIVITYANDDETAIL,BECAUSESILVERISDEPOSITEDDIRECTLYONTHEMOLECULESWITHINTHETRANSPARENTGELMATRIXTHUSVISUALIZATIONISFROMTHEPRIMARYSOURCEANDDOESNOTSUFFERANYDEGRADATIONORBLURRINGTHATCANACCOMPANYSECONDARYIMAGINGDEVICESWHICHINVOLVEFLUORESCENCE,AUTORADIOGRAPHY,FOCUSINGLENSES,FILMDEVELOPMENTORDIGITALIMAGEPROCESSING?SILVERSTAININGOFFERSSIMILARSENSITIVITYTOAUTORADIOGRAPHY,BUTAVOIDSRADIOACTIVEHANDLING,DELAYSFROMDEVELOPMENTTIMESANDWASTEDISPOSALISSUES?ASAPREFERREDOPTION,GELSCANBEDRIEDONTOASEMIRIGIDPLASTICBACKINGFILMSUCHASGELBONDPAGFILM,CREATINGAPERMANENTRECORDOFTHEORIGINALMATERIAL8SEEREF10FORAREVISEDPROTOCOLAIRDRIEDGELSARERESILIENT,PRESERVINGACONCENTRATEDANDCONTRASTINTENSIFIEDIMAGETHEYCANALSOBESTOREDINDEFINITELYWITHOUTDISTORTION,OBVIATINGTHENEEDANDADDEDEXPENSEOFPHOTOGRAPHYANDPRINTINGINADDITION,THEPRESERVEDGELISA‘MOLECULARARCHIVE’,ASSTAINEDDNABANDSARE‘REAL’DNATHATCANBEEXTRACTED,AMPLIFIED,CLONEDANDDNASEQUENCEDWHILETHEPROTOCOLDESCRIBEDHEREFOCUSESONTHEVISUALIZATIONOFDNABYPAGE,THEMETHODCANBEUSEDWITHOUTMODIFICATIONTOVISUALIZEAWIDERANGEOFBIOLOGICALMOLECULESINCLUDINGRNA,POLYSACCHARIDES,LIPOPOLYSACCHARIDES,PROTEINSANDPOLYPEPTIDESINPOLYACRYLAMIDEGELSDATANOTSHOWNALTHOUGHTHISISANADVANTAGEINTERMSOFSCOPE,ITNEVERTHELESSMEANSTHATTHEPROTOCOLMUSTBEAPPLIEDWITHDUECARESTRAYHUMANFINGERPRINTSONTHEGELSURFACESTAINWITHPERFECTDETAILASWILLALMOSTANYOTHERBIOLOGICALIMPURITYINCORPORATEDINTOORONTOTHEGELMATRIXITISTHUSIMPORTANTTOUSEDUSTFREEREAGENTSOFTHEBESTANALYTICALGRADE,INCLUDINGTHEPURESTWATERAVAILABLEMATERIALSREAGENTSACETICACID,GLACIAL,ARSELECTACSCH3COOHEG,MALLINCKRODT,CATNOV193MCRITICALFORBESTRESULTS,MUSTBEOFHIGHPURITYSILVERNITRATECRYSTAL,ARACSAGNO3EG,MALINCKRODT,CATNO2169SEEREAGENTSETUPMCRITICALFORBESTRESULTS,MUSTBEOFHIGHPURITYFORMALDEHYDESOLUTION,ARACSHCHOEG,MALINCKRODT,CATNO5016SEEREAGENTSETUPMCRITICALFORBESTRESULTS,MUSTBEOFHIGHPURITYSODIUMTHIOSULFATENA2S2O3EG,SIGMA,CATNOS7026SEEREAGENTSETUPMCRITICALFORBESTRESULTS,MUSTBEOFHIGHPURITYSODIUMCARBONATEPOWDER,Z995,ACSREAGENTNA2CO3EG,SIGMAALDRICH,CATNO223530MCRITICALFORBESTRESULTS,MUSTBEOFHIGHPURITYETHANOLPOLYACRYLAMIDEGELFIXERSOLUTIONSEEREAGENTSETUPDEVELOPERSOLUTIONSEEREAGENTSETUPDEVELOPERSTOPSOLUTIONSEEREAGENTSETUPEQUIPMENTPLASTICSTORAGECARBOYSWITHSPIGOTFROMANYGENERALLABORATORYSUPPLIERPUORGGNIHSILBUPERUTAN7002?NATUREPROTOCOLS/MOCERUTANWWW//PTTHNATUREPROTOCOLS|VOL2NO11|2007|2649PROTOCOL11|TOWASHTHEGEL,POURSUFFICIENTDEIONIZEDWATERINTOTHESTAININGTRAYTOCOVERTHEGELTOADEPTHOFB5MM12|ROCKTHESTAININGTRAYCONTINUOUSLYONAPLATFORMROCKERFOR2MINLONGERTIMESMAYBENEEDEDIFGELSTHICKERTHANB1MMAREUSEDIFTHEGELISWASHEDFORTOOLONGOVERB20MIN,THENSTAININGMAYBECOMPROMISED,ANDFAINTERBANDSWILLRESULT13|ATTHEENDOFTHEWASH,CAREFULLYDECANTTHEWASHSOLUTIONASDESCRIBEDINSTEP1014|REPEATTHEWASHSTEPSTWOTIMESMOREFORATOTALOFTHREEWASHESINDEIONIZEDWATERMCRITICALSTEPWASHINGTHEGELISIMPORTANTITREMOVESACIDANDOTHERTRACESUBSTANCESTHATINTERFEREWITHSTAINING,ANDPROVIDESACLEAR,BLEMISHFREEBACKGROUNDTOTHEFINALSTAINFORMALDEHYDEPRETREATMENT15|ADDSUFFICIENTFORMALDEHYDESOLUTIONTOCOVERTHEGELINTHESTAININGTRAYTOADEPTHOFB5MMGENTLYROCKTHESTAININGTRAYCONTINUOUSLYONAPLATFORMROCKERFORTYPICALMINIGELSOFB1MMTHICKNESS,AMINIMUMOF5MINFORMALDEHYDEPRETREATMENTISREQUIREDWHILEB10MINPROVIDESOPTIMUMCONTRASTLONGERTIMESMAYBENEEDEDIFTHICKERGELSAREUSEDTHISSTEPMAYCONTINUEFORUPTOB30MINASANALTERNATIVE,FORMALDEHYDEPRETREATMENTSTEP15ANDSILVERIMPREGNATIONSTEP17CANBECOMBINEDASPERTHEORIGINALBASSAMETAL9PROTOCOLSEEANTICIPATEDRESULTSTOVIEWANEXAMPLEGELPROCESSEDUSINGTHISALTERNATIVEMCRITICALSTEPFORMALDEHYDEPRETREATMENTISIMPORTANTFORSTAINSENSITIVITYANDMAXIMUMIMAGECONTRAST16|FOLLOWINGTHEFORMALDEHYDEPRETREATMENT,CAREFULLYDECANTTHESOLUTION,TAKINGCARENOTTODAMAGETHEGELORTOUCHTHEGELSURFACEALTERNATIVELY,USEAWATERPOWEREDVENTURIPUMPTOVACUUMTHEFIXERSOLUTIONAWAYANDDOWNTHESINKSILVERIMPREGNATION17|ADDSUFFICIENTSILVERSOLUTIONTOCOVERTHEGELINTHESTAININGTRAYTOADEPTHOFB5MM18|GENTLYROCKTHESTAININGTRAYCONTINUOUSLYONAPLATFORMROCKERFORTYPICALMINIGELSOFB1MMTHICKNESS,A20MINIMPREGNATIONTIMEISUSUALLYOPTIMALMCRITICALSTEPTHERECOMMENDEDSILVERCONCENTRATIONCANNOTBEREDUCEDWITHOUTAFFECTINGSENSITIVITYANDCONTRASTACAREFULEXAMINATIONOFSILVERIMPREGNATIONTIMESSHOWEDTHATOPTIMALSTAININGWASACHIEVEDAFTERB20MINHOWEVER,ASLITTLEAS10MINISSUFFICIENTFORHIGHQUALITYSTAININGWITHOUTSIGNIFICANTLOSSOFSENSITIVITYIMPREGNATIONTIMESCANBEINCREASEDUPTOB60MIN,BUTGREATERTHANB90MINCANCAUSESEVEREIMAGELOSS19|FOLLOWINGSILVERIMPREGNATION,CAREFULLYDECANTTHESOLUTION,TAKINGCARENOTTODAMAGETHEGELORTOUCHTHEGELSURFACECAUTIONTHESILVERSOLUTIONISTOXICANDSHOULDBEDISPOSEDOFWITHCAREAVOIDSPILLINGTHESOLUTION,ASITWILLPERMANENTLYSTAINMOSTSURFACESWEPRECIPITATETHESILVERFROMUSEDSILVERSOLUTIONWITHNACLINGLASSWINCHESTERBOTTLES,ANDACCUMULATEITFORRECYCLINGITSHOULDTURNMILKYINTHEBOTTLEASTHESILVERPRECIPITATES20|BRIEFLYRINSERESIDUALSILVERSOLUTIONFROMTHESURFACEOFTHEGELBYRINSINGWITHB100MLOFDEIONIZEDWATERFOR5–10SDONOTRINSETHEGELLONGERTHANB15S,ASTHISSTEPREMOVESSILVERFROMTHEGELIMAGEDEVELOPMENT21|CHECKWHETHERTHEDEVELOPERISCOLDITSHOULDBEBETWEEN4AND101CADDSUFFICIENTDEVELOPERSOLUTIONTOCOVERTHEGELINTHESTAININGTRAYTOADEPTHOFB5MMAGITATETHESTAININGTRAYTHROUGHOUTIMAGEDEVELOPMENTSOTHEDEVELOPERSOLUTIONISNOTSTAGNANTIMAGEDEVELOPMENTBEGINSASSOONASTHEDEVELOPERSOLUTIONISADDEDTHEDEVELOPERSOLUTIONISKEPTCOLDTOCONTROLTHERATEOFIMAGEDEVELOPMENT,SINCEDEVELOPMENTISUSUALLYTOOFASTTOCONTROLIFDONEATTEMPERATURESABOVE101CIMAGEDEVELOPMENTTYPICALLYTAKESABOUT3MINDEPENDINGONGELTHICKNESS,THEREAGENTSUSEDANDTHETEMPERATUREOFTHEREAGENTSALTERNATIVELY,YOUCANADD600MLOFFORMALDEHYDESOLUTIONPER100MLOFFINALDEVELOPERSOLUTIONASPERTHEORIGINALMETHOD9THISMAYIMPROVEIMAGECONTRAST,BUTUSUALLYALSOINCREASESTHEBACKGROUNDANDEDGESTAININGARTEFACTSSEEANTICIPATEDRESULTSTOVIEWANEXAMPLEGELPROCESSEDUSINGTHISALTERNATIVEROOMTEMPERATUREDEVELOPMENTISPOSSIBLEFORTHINGELSLESSTHANB1MMINTHICKNESSSEEANTICIPATEDRESULTSTOVIEWANEXAMPLEGELPROCESSEDUSINGROOMTEMPERATUREREAGENTALTERNATIVESMCRITICALSTEPDECREASINGNA2CO3CONCENTRATIONBELOWTHERECOMMENDEDLEVELSCAUSESHIGHERBACKGROUNDSTAININGANDPOORIMAGECONTRASTPOORSTAININGCANALSORESULTFROMTHEUSEOFLOWQUALITYOROLDSTALEREAGENTSSTOPPINGTHEREACTION22|DECANTTHEDEVELOPERSOLUTIONCAREFULLY,AVOIDINGDAMAGETOTHEGELORTOUCHINGTHEGELSURFACE23|CHECKWHETHERTHEDEVELOPERSTOPSOLUTIONISCOLDITSHOULDBESTOREDREFRIGERATEDAT41CADDSUFFICIENTDEVELOPERSTOPSOLUTIONTOCOVERTHEGELINTHESTAININGTRAYTOADEPTHOFB5MMASANALTERNATIVE,DEVELOPERSTOPSOLUTIONKEPTATROOMTEMPERATURECANBEUSEDFORTHINGELSO1MMINTHICKNESSHOWEVER,THISALTERNATIVEREQUIRESSOMEPRACTICEASTHEPUORGGNIHSILBUPERUTAN7002?NATUREPROTOCOLS/MOCERUTANWWW//PTTHNATUREPROTOCOLS|VOL2NO11|2007|2651PROTOCOL

簡介：BIODRUGS20082213744NOVELTHERAPEUTICSTRATEGIES11738804/08/00010037/4800/0?2008ADISDATAINFORMATIONBVALLRIGHTSRESERVEDFIBROBLASTGROWTHFACTOR21ASATHERAPEUTICAGENTFORMETABOLICDISEASESALEXEIKHARITONENKOVANDARMENBSHANAFELTBIOTECHOLOGYDISCOVERYRESEARCH,LILLYRESEARCHLABORATORIES,LILLYCORPORATECENTER,INDIANAPOLIS,INDIANA,USACONTENTSABSTRACT371THEROLEOFFIBROBLASTGROWTHFACTORSFGFSINTHEREGULATIONOFMETABOLICPROCESSES372OVERVIEWOFFGF21ANDITSINVITROEFFECTS383FGF21INVIVOPHARMACOLOGY394INSIGHTSINTOFGF21MECHANISMOFACTION405CONCLUSION43FIBROBLASTGROWTHFACTORFGF21ISAUNIQUEMEMBEROFTHEFGFFAMILY,WITHSEVERALMOLECULARCHARACTERISABSTRACTTICSTHATDIFFERFROMCLASSICALFGFSANDEXHIBITINGAPHARMACOLOGICPROFILETHATINCLUDESAVARIETYOFMETABOLICRESPONSESINVITROANDWHENTESTEDINVIVOINANIMALMODELSFGF21REPRESENTSANOVELANDATTRACTIVETHERAPEUTICAGENTFORTYPE2DIABETESMELLITUS,BECAUSEOFITSABILITYTOMODULATEDISEASEPHENOTYPEINPRECLINICALSETTINGSWITHOUTINDUCINGANYAPPARENTADVERSEEFFECTSALTHOUGHFGF21WASDISCOVEREDRELATIVELYRECENTLY,THEUNDERSTANDINGOFITSBIOLOGYANDTHERAPEUTICUTILITYISRAPIDLYEVOLVINGANUMBEROFKEYMETABOLICALLYLINKEDMOLECULESANDPATHWAYSHAVEBEENSUGGESTEDTOBEINVOLVEDINTHEMECHANISMOFACTIONOFFGF21,DEPENDINGONTHESPECIFICTARGETTISSUE/ORGANFURTHERRESEARCHINTOTHESEMECHANISMSSHOULDLEADTOIMPORTANTADVANCESINTHEUNDERSTANDINGOFFGF21BIOLOGYANDPAVETHEWAYFORNOVELTHERAPEUTICSTRATEGIESTHESPECIFICSOFFGF21ACTIVITIESBOTHINCELLCULTUREANDINVIVO,ITSPOTENTIALASATARGETFORDIABETES,ANDINSIGHTSINTOTHEMOLECULARMECHANISMSOFFGF21METABOLICACTIONSWILLBEDISCUSSEDINTHISREVIEW1THEROLEOFFIBROBLASTGROWTHFACTORSFGFSINRODENTS,RESPECTIVELY8,9WHENTESTEDINMICE,FGF19PROVIDESTHEREGULATIONOFMETABOLICPROCESSESRESISTANCETOOBESITYANDINSULINDESENSITIZATION10,11ANOTHERMEMBEROFTHEFGFFAMILY,FGF23,ISAKEYPLAYERINTHEREGULAFIBROBLASTGROWTHFACTORSFGFSANDTHEIRCORRESPONDINGRETIONOFPHOSPHATEANDCALCIUMMETABOLISM12,13LIKEWISE,THECEPTORSFGFRSHAVEBEENPRIMARILYASSOCIATEDWITHTHEPROCESSESOFDEVELOPMENT,TRANSFORMATION,ANDANGIOGENESIS14HOWOVEREXPRESSIONOFADOMINANTNEGATIVEFORMOFFGFR1INPANCREEVER,OVERTHELASTDECADE,NEWDATAHAVEEMERGEDSHOWINGTHATATICΒCELLSLEADSTODIABETESMELLITUSINMICE14FGFR2APPEARSTOFGF/FGFRMEDIATEDPATHWAYSMAYPLAYIMPORTANTROLESINDEFINBEAKEYMOLECULEINTHEPROCESSOFPANCREATICDEVELOPMENT1517INGANDREGULATINGFUNCTIONSOFENDOCRINERELEVANTTISSUESANDFGFR3ISACRITICALPLAYERINBONE,18WHEREASFGFR4HASBEENORGANS,ASWELLASMODULATINGVARIOUSMETABOLICPROCESSESFORIMPLICATEDINCHOLESTEROLMETABOLISMANDBILEACIDSYNTHESIS19EXAMPLE,FGF10ANDFGF16PLAYIMPORTANTROLESINADIPOCYTEANDTHEMETABOLICROLESOFFGF/FGFRARESTILLNOTPRECISELYDEFINEDPANCREATICBIOLOGY,57ANDFGF19ANDITSMOUSEORTHOLOGFGF15,REGULATECHOLESTEROLANDBILEACIDMETABOLISMINHUMANSANDANDARECURRENTLYUNDERINTENSEINVESTIGATIONFGF21ANDMETABOLICDISEASES39INDUCESUPREGULATIONOFPPARΓPROTEINALTHOUGHITISCURRENTLYINCIDENCEOFHEPATOCELLULARCARCINOMASINFGF21TRANSGENICMICEUNCLEARWHATPARTICULARIMPACTEACHOFTHESEEFFECTSHASONGLUCOSEAT12MONTHSOFAGEWASSIMILARTOTHATINCONTROLANIMALSTHUS,IFTRANSPORT,THESEDATAREVEALPOTENTIALSYNERGYINTHEACTIONSBEFGF21NEGATIVELYREGULATESCHEMICALLYINDUCEDHEPATOCARCITWEENTHESETWOREGULATORSOFGLUCOSEHOMEOSTASIS,FGF21ANDNOGENESIS,ITISLIKELYTOINTERFEREWITHDISEASEPROGRESSIONATITSPPARΓ31EARLYSTAGES24RECENTLY,ANOTHERLINEOFFGF21TRANSGENICMICEONAC57BL/6JBACKGROUNDHASBEENDESCRIBED26THESEANIMALSHAD50–1503FGF21INVIVOPHARMACOLOGYTIMESHIGHERLEVELSOFFGF21MRNAINTHELIVERTHANCONTROLANIMALS,ANDHADLOWEREDLEVELSOFSERUMCHOLESTEROL,TRITHEINVIVOBIOACTIVITYOFFGF21HASBEENOBSERVEDUSINGGLYCERIDES,GLUCOSEANDINSULININDICATIVEOFTHEIMPROVEDLIPIDNUMEROUSBIOMARKERSTHATILLUSTRATETHEEFFECTSOFFGF21ACTIONSANDGLYCEMICMETABOLISM,ANDAMELIORATEDINSULINRESISTANCE,INABROADRANGEOFANIMALSTUDIESCOVERINGAVARIETYOFDISEASECONSISTENTWITHPREVIOUSLYPUBLISHEDDATA20FGF21TRANSGENICMODELS20,2326,35MICEWEREALSOFOUNDTOHAVEELEVATEDSERUMLEVELSOFΒHYDROXYTHECONSEQUENCESOFENFORCEDEXPRESSIONOFHUMAN20ANDBUTYRATE,SUGGESTINGTHEINDUCTIONOFKETOGENESIS,ASWELLASHAVMOUSEFGF2123,26HAVEBEENEVALUATEDINTRANSGENICMICE20,24,26INGADIPOCYTESOFSMALLERSIZE,INCREASEDLIPASEEXPRESSIONINWHITEFGF21TRANSGENICANIMALSAPPEARVIABLE,NORMALATBIRTH,ANDADIPOSETISSUEANDELEVATEDSERUMLEVELSOFFREEFATTYACIDS,ALLESSENTIALLYINDISTINGUISHABLEFROMTHEIRWILDTYPELITTERMATESNOEVOCATIVEOFTHEINDUCTIONOFLYPOLYSIS26IMPORTANTLY,ASURINETICEABLY,THEYDONOTPOSSESSSIGNSOFNEOPLASIA,TUMORS,ORANYCONCENTRATIONSOFADRENALINEANDNORADRENALINEWEREREDUCEDINOTHEROVERTABNORMALITIESTHROUGHOUTTHEIRLIFESPAN,ASDEMONSTRAFGF21TRANSGENICANIMALS,FGF21DOESNOTAPPEARTOSTIMULATETEDBYEXTENSIVEMORPHOLOGICANDHISTOLOGICANALYSES20,23THUS,LIPOLYSISTHROUGHASYSTEMICINCREASEINCATECHOLAMINES26SURPROLONGEDEXPOSUREOFMICETOFGF21DOESNOTLEADTOCARCINOGENPRISINGLY,THESEFGF21TRANSGENICMICEWEREALSOREPORTEDTOHAVEICEVENTSNEVERTHELESS,ASPECIFICPHENOTYPEOFFGF21TRANSGENIC1–2oCLOWERCOREBODYTEMPERATURES,REDUCEDLOCOMOTORACTIVITY,MICEWASREVEALEDUPONAVARIETYOFCHALLENGESANDENHANCEDTORPORDURING24HOURFASTINGCOMPAREDWITHTHEIRC57BL/6MICEOVEREXPRESSINGHUMANFGF21FROMTHELIVERCONTROLLITTERMATES26ALTHOUGHINTRIGUING,THELATTEROBSERVATIONSCIRCULATINGLEVELSOF70–150NG/MLWEREEVALUATEDFORCHANGESHAVENOTBEENREPORTEDBYOTHERS20,24AND,THEREFORE,NEEDTOBEINMETABOLICPARAMETERS20WHENFEDAHIGHFAT,HIGHCARBOHYEXPLOREDFURTHERDRATEHFHCDIETFOR15WEEKS,FGF21TRANSGENICMICEWEREADENOVIRUSMEDIATEDKNOCKDOWNOFFGF21WITHSHORTHAIRPINRESISTANTTOWEIGHTGAINANDFATACCUMULATION,DESPITEANINCREASEDRNASHFGF21INMICELEDTOASUBSTANTIALDECREASEINCIRCULATCALORICINTAKECONSISTENTWITHLOWADIPOSITY,THELEVELSOFLEPTININGFGF21LEVELSANDRESULTEDINSERIOUSMETABOLICABNORMALITIES,WERENOTICEABLYREDUCED,ASWELLASTHOSEOFGLUCAGONIMPORTANTSUCHASFATTYLIVER,SEVEREHYPERTRIGLYCERIDEMIAPREDOMINANTLYASLY,THESEEFFECTSWERENOTASSOCIATEDONLYWITHTHEHFHCDIET,ASARESULTOFTHEINCREASEINCHYLOMICRON/VERYLOWDENSITYLIPOTHEYWEREALSOOBSERVEDINAGEDFGF21TRANSGENICMICEONAPROTEINFRACTION,ASIGNIFICANTELEVATIONINSERUMFREEFATTYACIDSNORMALCHOWDIETAT9MONTHSOFAGE,THEYWEIGHEDSIGNIFICANTLYANDTOTALCHOLESTEROL,ANDAREDUCTIONINSERUMKETONES23IMPORLESS,HADLOWERFASTINGGLUCOSELEVELS,LESSTOTALANDLIVERFAT,MORETANTLY,THESECHANGESWEREAPPARENTONLYINANIMALSFEDAHIGHFATBROWNADIPOCYTES,ANDSHOWEDIMPROVEDGLUCOSECLEARANCEANDDIETANDNOTONANORMALCHOWDIETTHISCORRELATESWITHADRAMATICINSULINSENSITIVITYCOMPAREDWITHCONTROLANIMALS20ELEVATIONINTHEENDOGENOUSEXPRESSIONOFFGF21INANIMALSONAANALYSISOFFVBMICEWITHLIVERSPECIFICOVEREXPRESSIONOFKETOGENICDIET,ANDPROVIDESFURTHEREVIDENCETHATTHEOUTCOMESOFMOUSEFGF21CONFIRMEDTHEABSENCEOFNEOPLASIASORTUMORS24SHFGF21EXPERIMENTSAREINDEEDARESULTOFADIRECTATTENUATIONOFMOREOVER,WHENCOMPAREDWITHCONTROLANIMALS,NOCHANGEWASENDOGENOUSFGF21EXPRESSION/FUNCTION23OBSERVEDINTHEINCORPORATIONOFBROMODEOXYURIDINEBRDUINTOTHELIVERSOFFGF21TRANSGENICMICEAFTERPARTIALHEPATECTOMYORSYSTEMICADMINISTRATIONOFFGF21INRODENTSVIASUBCUTANEOUSCCL4INSULT,SUGGESTINGTHATFGF21ISUNLIKELYTOPLAYAROLEINAINJECTIONSORTHROUGHCONSTANTINFUSIONLEADSTOAVARIETYOFMETACOMPENSATORYLIVERRESTORATIONPROCESSUNEXPECTEDLY,FORCEDEXBOLICCONSEQUENCESFGF21EFFECTIVELYLOWERSFEDANDFASTEDPRESSIONOFFGF21MARKEDLYREDUCESTUMORINCIDENCE,MEASUREDPLASMAGLUCOSELEVELS,STIMULATESGLUCOSEDISPOSAL,ANDINCREASESBYTHEFREQUENCYOFDIETHYLNITROSAMINEINDUCEDADENOMASANDTHEINSULINSENSITIVITYINORALGLUCOSETOLERANCETESTS20IMPORTANTLY,TIMINGOFTHEIRFIRSTAPPEARANCE24HOWEVER,ALTHOUGHFGF21THEFGF21GLUCOSELOWERINGEFFECTSARELONGLASTING,ASTHEYAPPEARSTODELAYTHEPROCESSOFTUMORINITIATIONINTHELIVER,THEPERSISTFORATLEAST24HOURSFOLLOWINGTHECESSATIONOFFGF21?2008ADISDATAINFORMATIONBVALLRIGHTSRESERVEDBIODRUGS2008221

簡介：CEFOSELISCFSL,AFOURTHGENERATIONPARENTERALCEPHALOSPORIN,HASBEENMARKETEDINJAPANSINCESEPTEMBER1998INDECEMBER1998,WARNINGSOFCENTRALNERVOUSSYSTEMCNSADVERSEEFFECTSSUCHASSEIZURESANDCONFUSIONALSTATESWEREADDEDTOTHELABELINGOFCFSLINMANYCASES,THESEADVERSEEFFECTSWEREOBSERVEDINPATIENTSWHOWEREELDERLYAND/ORHADRENALFAILURETHEREFORERENALFAILUREISCONSIDEREDASONEOFTHERISKFACTORSFORNEUROTOXICITYOFCFSLSINCECFSLISMAINLYELIMINATEDBYRENALEXCRETION,1RENALFAILUREWOULDBEASSOCIATEDWITHINCREASEDSERUMCONCENTRATIONSOFCFSLONTHEOTHERHAND,ITISSTILLUNKNOWNWHETHERRENALFAILURECANALTERTHEPHARMACODYNAMICSOFCFSLINDUCEDSEIZURESDRUGADMINISTRATIONCANBEDIVIDEDINTOTWOPHASESAPHARMACOKINETICPHASEINWHICHDOSE,DOSAGEFORM,FREQUENCY,ANDROUTEOFADMINISTRATIONARERELATEDTODRUGCONCENTRATION–TIMERELATIONSHIPSINTHEBODYANDAPHARMACODYNAMICPHASEINWHICHTHECONCENTRATIONOFDRUGATTHESITESOFACTIONISRELATEDTOTHEMAGNITUDESOFTHEEFFECTSPRODUCED2THEPATHOPHYSIOLOGICSTATUSOFPATIENTSCANAFFECTBOTHTHEPHARMACOKINETICSANDTHEPHARMACODYNAMICSOFADRUGOURKNOWLEDGEOFTHEEFFECTSOFDISEASEONTHEPHARMACOKINETICSOFADRUGCANNOTBEUSEDTOOPTIMIZETHEDRUGDOSAGEOFAPATIENTWITHOUTINFORMATIONONDISEASEEFFECTSONTHEPHARMACODYNAMICS3THEREFOREITISIMPORTANTTODISTINGUISHTHEEFFECTSOFDISEASEONTHEPHARMACOKINETICSFROMTHOSEONTHEPHARMACODYNAMICSDANHOFANDLEVY3REPORTEDANEXPERIMENTALSTRATEGYTOASSESSTHEEFFECTSOFDISEASEANDOTHERVARIABLESONTHEPHARMACODYNAMICSOFDRUGSWITHCNSACTIVITYTHEEFFECTSOFEXPERIMENTALRENALFAILUREONTHEPHARMACODYNAMICSOFCNSSTIMULANTDRUGSSUCHASTHEOPHYLLINE,4PENTYLENTETRAZOLE,5ANDCIMETIDINE6WEREINVESTIGATEDPREVIOUSLYTHEREHAVEBEENCLINICALCASEREPORTSOFSEIZURESCAUSEDBYVARIOUSBLACTAMANTIBIOTICSSUCHASPENICILLIN,7CEFAZOLINE,8AMPICILLIN,9ANDIMIPENEM10HOWEVER,TOOURKNOWLEDGE,THEREHAVEBEENNOREPORTSTHATCLARIFIEDTHEEFFECTOFRENALFAILUREONTHEPHARMACODYNAMICSOFBLACTAMANTIBIOTICINDUCEDSEIZURESTOASSURESAFEANDEFFECTIVEANTIBIOTICDRUGTHERAPY,ITMUSTBEDETERMINEDIFRENALFAILURECANCHANGETHERELATIONSHIPBETWEENTHECONCENTRATIONANDINTENSITYOFPHARMACOLOGICACTIVITYOFDRUGSTHEPRESENTSTUDYWASDESIGNEDTODETERMINE1THESUITABILITYOFTHERATASANANIMALMODELOFCFSLINDUCEDSEIZURES2THESAMPLINGSITEWHERECFSLCONCENTRATIONSREFLECTTHEDRUGCONCENTRATIONATTHESITEOFNEUROTOXICACTIONAND3THEEFFECTOFRENALFAILUREONTHEPHARMACODYNAMICSOFCFSLINDUCEDSEIZURESMATERIALSANDMETHODSANIMALSMALEWISTARRATSWEIGHING240TO300GWEREUSEDINTHISINVESTIGATIONTHERATSHADANINDWELLINGCANNULAIMPLANTEDINTHELEFTJUGLARVEINUNDERLIGHTETHERANESTHESIAONEDAYBEFORETHEEXPERIMENTANDTHEYWEREFASTEDUNTILTHECFSLINFUSIONBEGANCHEMICALSCFSLSULFATEWINCEF?FORINFUSIONUSEDFORANIMALEXPERIMENTSWASOBTAINEDFROMFUJISAWAPHARMACEUTICALCO,LTDCEFPIROMESULFATEBROACT?INJECTIONUSEDASANINTERNALSTANDARDWASOBTAINEDFROMSHIONOGICO,LTDALLOTHERCHEMICALSWEREPURCHASEDFROMCOMMERCIALSOURCESANDUSEDWITHOUTFURTHERPURIFICATIONEFFECTOFINFUSIONRATEONTHECONCENTRATIONSOFCFSLINSERUM,BRAIN,ANDCSFATONSETOFMAXIMALSEIZURESCFSLWASINFUSEDTHROUGHTHECANNULAATONEOFTHREEDIFFERENTRATES14,29,OR58G/HINRATSTHEINFUSIONWASSTOPPEDIMMEDIATELYATTHEONSETOFMAXIMALSEIZURESTHERATSWERETHENLIGHTLYANESTHETIZEDWITHETHER,ANDSAMPLESOFCSF,BLOOD,ANDBRAINWEREOBTAINED,INTHATORDERCSFWASOBTAINEDBYCISTERNALPUNCTUREBLOODWASOBTAINEDFROMTHEABDOMINALAORTAANDCENTRIFUGEDTOOBTAINSERUMTHEWHOLEBRAINWASREMOVEDANDTHERIGHTHALFOFTHECEREBRUMWASUSEDFORDRUGASSAYSEPTEMBER2001BIOLPHARMBULL2491049105220011049?TOWHOMCORRESPONDENCESHOULDBEADDRESSEDEMAILYASUHARAMPHAMEDTMDACJP?2001PHARMACEUTICALSOCIETYOFJAPANEFFECTOFEXPERIMENTALRENALFAILUREONTHEPHARMACODYNAMICSOFCEFOSELISINDUCEDSEIZURESINRATSMASASHINAGATAANDMASATOYASUHARADEPARTMENTOFHOSPITALPHARMACY,SCHOOLOFMEDICINE,TOKYOMEDICALANDDENTALUNIVERSITY,1–5–45YUSHIMA,BUNKYOKU,TOKYO113–8519,JAPANRECEIVEDAPRIL17,2001ACCEPTEDJUNE12,2001WEINVESTIGATEDTHEEFFECTOFINFUSIONRATEANDEXPERIMENTALRENALFAILUREONTHEPHARMACODYNAMICSOFCEFOSELISCFSLINDUCEDSEIZURESASANANIMALMODELOFCFSLINDUCEDSEIZURES,MALEWISTARRATSRECEIVEDANINTRAVENOUSINFUSIONOFCFSLATONEOFTHREEDIFFERENTRATES1458G/H/RATUNTILTHEONSETOFMAXIMALSEIZURESWHICHOCCURREDAFTER80TO360MINOFINFUSIONSAMPLESOFCEREBROSPINALFLUIDCSF,BLOODFORSERUM,ANDBRAINWEREOBTAINEDIMMEDIATELYAFTERSTOPPINGINFUSIONOFCSFLTHESERUMCONCENTRATIONOFCFSLATTHEONSETOFSEIZURESINCREASEDWITHINCREASINGINFUSIONRATE,BUTBRAINANDCSFCONCENTRATIONSOFCFSLATTHEONSETOFSEIZURESWERENOTAFFECTEDBYTHEINFUSIONRATEURETERLIGATEDULANDCONTROLRATSRECEIVEDANINTRAVENOUSINFUSIONOFCFSLAT14G/H/RATUNTILTHEONSETOFSEIZURESTHENTHESAMEPROCEDUREASUSEDTODETERMINETHEEFFECTOFINFUSIONRATEONTHECONCENTRATIONSOFCFSLWASCARRIEDOUTRENALFAILUREWASASSOCIATEDWITHASIGNIFICANTDECREASEINTHEAMOUNTOFCFSLREQUIREDTOINDUCESEIZURESSERUM,BRAIN,ANDCSFCONCENTRATIONSOFCFSLINULRATSWERESIGNIFICANTLYLOWERTHANTHOSEINCONTROLRATSTHESERESULTSINDICATETHATTHEEXPERIMENTALSTRATEGYANDANIMALMODELINTHISINVESTIGATIONWOULDBEUSEFULTOASSESSTHEEFFECTSOFDISEASESANDOTHERVARIABLESONTHEPHARMACODYNAMICSOFCFSLINDUCEDSEIZURESANDTHATRENALFAILUREISONEOFTHERISKFACTORSFORNEUROTOXICITYOFCFSLKEYWORDSCEFOSELISRENALFAILURESEIZUREPHARMACODYNAMICSDISCUSSIONDRUGSTHATACTDIRECTLYANDREVERSIBLY,HAVENOPHARMACOLOGICALLYACTIVEMETABOLITES,ANDARENOTSUBJECTTOTHEDEVE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簡介：THEMEDSECTIONVECTORDESIGNANDDRUGDELIVERYREVIEWTWENTYYEARSOFCELLPENETRATINGPEPTIDESFROMMOLECULARMECHANISMSTOTHERAPEUTICSFREDERICHEITZ,MAYCATHERINEMORRISANDGILLESDIVITACENTREDERECHERCHESDEBIOCHIMIEMACROMOLéCULAIRE,UMR5237,CNRS,UM1,UM2,CRBMDEPARTMENTOFMOLECULARBIOPHYSICSANDTHERAPEUTICS,1919ROUTEDEMENDE,MONTPELLIER,FRANCETHERECENTDISCOVERYOFNEWPOTENTTHERAPEUTICMOLECULESTHATDONOTREACHTHECLINICDUETOPOORDELIVERYANDLOWBIOAVAILABILITYHAVEMADEOFDELIVERYAKEYSTONEINTHERAPEUTICDEVELOPMENTSEVERALTECHNOLOGIESHAVEBEENDESIGNEDTOIMPROVECELLULARUPTAKEOFTHERAPEUTICMOLECULES,INCLUDINGCELLPENETRATINGPEPTIDESCPPSCPPSWEREFIRSTDISCOVEREDBASEDONTHEPOTENCYOFSEVERALPROTEINSTOENTERCELLSNUMEROUSCPPSHAVEBEENDESCRIBEDSOFAR,WHICHCANBEGROUPEDINTOTWOMAJORCLASSES,THEFIRSTREQUIRINGCHEMICALLINKAGEWITHTHEDRUGFORCELLULARINTERNALIZATIONANDTHESECONDINVOLVINGFORMATIONOFSTABLE,NONCOVALENTCOMPLEXESWITHDRUGSNOWADAYS,CPPSCONSTITUTEVERYPROMISINGTOOLSFORNONINVASIVECELLULARIMPORTOFCARGOANDHAVEBEENSUCCESSFULLYAPPLIEDFORINVITROANDINVIVODELIVERYOFTHERAPEUTICMOLECULESVARYINGFROMSMALLCHEMICALMOLECULE,NUCLEICACIDS,PROTEINS,PEPTIDES,LIPOSOMESANDPARTICLESTHISREVIEWWILLFOCUSONTHESTRUCTURE/FUNCTIONANDCELLULARUPTAKEMECHANISMOFCPPSINTHEGENERALCONTEXTOFDRUGDELIVERYWEWILLALSOHIGHLIGHTTHEAPPLICATIONOFPEPTIDECARRIERSFORTHEDELIVERYOFTHERAPEUTICMOLECULESANDPROVIDEANUPDATEOFTHEIRCLINICALEVALUATIONBRITISHJOURNALOFPHARMACOLOGY2009157,195–206DOI101111/J14765381200800057XPUBLISHEDONLINE20MARCH2009THISARTICLEISPARTOFATHEMEDSECTIONONVECTORDESIGNANDDRUGDELIVERYFORALISTOFALLARTICLESINTHISSECTIONSEETHEENDOFTHISPAPER,ORVISITHTTP//WWW3INTERSCIENCEWILEYCOM/JOURNAL/121548564/ISSUEYEARYEAR2009KEYWORDSCELLPENETRATINGPEPTIDENONCOVALENTDELIVERYSYSTEMSIRNANANOPARTICLEDRUGDELIVERYMOLECULARMECHANISMSTHERAPEUTICSABBREVIATIONSCPP,CELLPENETRATINGPEPTIDEGAG,GLUCOSAMINOGLYCANNLS,NUCLEARLOCALIZATIONSEQUENCEPMO,PHOSPHORODIAMIDATEMORPHOLINOOLIGOMERPNA,PEPTIDENUCLEICACIDPTD,PROTEINTRANSDUCTIONDOMAINSINTRODUCTIONCHALLENGESINDRUGDELIVERYOVERTHEPAST10YEARS,INORDERTOCIRCUMVENTLIMITATIONSOFSMALLMOLECULEANDGENEBASEDTHERAPIES,WEHAVEWITNESSEDADRAMATICACCELERATIONINTHEPRODUCTIONOFNEWLARGETHERAPEUTICMOLECULES,WHICHDONOTFOLLOWLIPINSKI’SRULES,SUCHASPROTEINS,PEPTIDESANDNUCLEICACIDTHERAPEUTICSHOWEVER,THEIRDEVELOPMENTISRESTRICTEDBYVERYSPECIFICISSUESINCLUDINGPOORSTABILITYINVIVO,LACKOFCELLULARUPTAKEANDINSUFFICIENTCAPABILITYTOREACHTARGETSTHISISASSOCIATEDWITHTHECOMPLETELOSSOFPHARMACEUTICALPOTENCYORATLEASTWITHTHEREQUIREMENTFORHIGHDOSESANDRISKOFMAJORSIDEEFFECTSTHEREFORE,DELIVERYCONSTITUTESAMAJORPIECEOFTHETHERAPEUTICPUZZLE,ANDTHEREISAREALDEMANDFORNEWANDMOREEFFICIENTDRUGDELIVERYSYSTEMSMAJORRULESHAVETOBESATISFIED,INPARTICULARIDELIVERYEFFICIENCYINDIFFERENTANDCHALLENGINGCELLLINESIIRAPIDENDOSOMALRELEASEIIIABILITYTOREACHTHETARGETIVACTIVITYATLOWDOSESVLACKOFTOXICITYANDVIFACILITYOFTHERAPEUTICAPPLICATIONSUBSTANTIALPROGRESSHASBEENMADEINTHEDESIGNOFNEWTECHNOLOGIESTOIMPROVECELLULARUPTAKEOFTHERAPEUTICCOMPOUNDSOPALINSKAANDGEWIRTZ,2002J?RVERANDLANGEL,2004GLOVERETAL,2005TORCHILIN,2005DEFOUGEROLLESETAL,2007KONGANDMOONEY,2007ANUMBEROFNONVIRALSTRATEGIESHAVEBEENPROPOSEDINCLUDINGLIPID,POLYCATIONIC,NANOPARTICLEANDPEPTIDEBASEDFORMULATIONSASREPORTEDINTHISSPECIALISSUEMORRISETAL,2000OGRISANDWAGNER,2002J?RVERANDLANGEL,2004TORCHILIN,2005,BUTONLYASUBSETOFTHESETECHNOLOGIESAREEFFICIENTLYAPPLIEDINVIVOATEITHERPRECLINICALORCLINICALLEVELSPROTEINTRANSDUCTIONDOMAINSPTDSORCELLPENETRATINGPEPTIDESCPPSCORRESPONDTOSHORT30RESIDUESYNTHETICPEPTIDESANDAREPARTOFTHEMOSTPROMISINGSTRATEGYTOOVERCOMEBOTHEXTRACELLULARANDINTRACELLULARLIMITATIONSOFVARIOUSBIOMOLECULESOFINCLUDINGPLASMIDDNA,CORRESPONDENCEGILLESDIVITA,CENTREDERECHERCHESDEBIOCHIMIEMACROMOLéCULAIRE,UMR5237,CNRS,UM1,UM2,CRBMDEPARTMENTOFMOLECULARBIOPHYSICSANDTHERAPEUTICS,1919ROUTEDEMENDE,34293MONTPELLIER,FRANCEEMAILGILLESDIVITACRBMCNRSFRRECEIVED14JULY2008REVISED7OCTOBER2008ACCEPTED20OCTOBER2008BRITISHJOURNALOFPHARMACOLOGY2009,157,195–206?2009THEAUTHORSJOURNALCOMPILATION?2009THEBRITISHPHARMACOLOGICALSOCIETYALLRIGHTSRESERVED00071188/09WWWBRJPHARMACOLORGCOVALENTSTRATEGYCELLPENETRATINGPEPTIDEBASEDTECHNOLOGIESDESCRIBEDSOFARMAINLYINVOLVETHEFORMATIONOFACOVALENTCONJUGATEBETWEENTHECARGOANDTHECARRIERPEPTIDE,WHICHISACHIEVEDBYCHEMICALCROSSLINKINGORBYCLONINGFOLLOWEDBYEXPRESSIONOFACPPFUSIONPROTEINNAGAHARAETAL,1998GAIT,2003MOULTONANDMOULTON,2004ZATSEPINETAL,2005MOSTOFTHEWORKHASBEENREPORTEDFORPEPTIDESDERIVEDFROMTATFAWELLETAL,1994VIVESETAL,1997FRANKELANDPABO,1988,PENETRATINDEROSSIETAL,1994,POLYARGININEPEPTIDEARG8SEQUENCEWENDERETAL,2000FUTAKIETAL,2001ANDTRANSPORTAN,POOGAETAL,1998OTHERPROTEINDERIVEDPEPTIDESSUCHASVP22PROTEINFROMHERPESSIMPLEXVIRUSELLIOTTANDO’HARE,1997,PVECELMQUISTETAL,2001,CALCITONINDERIVEDPEPTIDESSCHMIDTETAL,1998KRAUSSETAL,2004,ANTIMICROBIALPEPTIDESBUFORINIANDSYNBPARKETAL,1998PARKETAL,2000,ASWELLASPOLYPROLINESWEETARROWPEPTIDEPUJALSETAL,2006HAVEALSOBEENSUCCESSFULLYUSEDTOIMPROVETHEDELIVERYOFCOVALENTLYLINKEDCARGOSJOLIOTANDPROCHIANTZ,2004ELANDALOUSSIETAL,2005MURRIELANDDOWDY,2006MORERECENTLY,NEWGENERATIONSOFCPPS,COMBININGDIFFERENTTRANSDUCTIONMOTIFSABESETAL,2007ORTRANSDUCTIONDOMAINSINTANDEMWITHPROTEINOROLIGONUCLEOTIDEBINDINGDOMAINSMEADEANDDOWDY,2007HAVEBEENPROPOSEDDIFFERENTCHEMISTRIESHAVEBEENPROPOSEDFORSTABLEORCLEAVABLECONJUGATIONINVOLVINGMAINLYDISULFIDEORTHIOESTERSLINKAGESACCORDINGTOTHESTABILITYANDEFFICIENCYOFTHECARGO,SEVERALPARAMETERSNEEDTOBECONSIDEREDINCLUDINGTHETYPEOFLINKAGECHEMISTRY,THENATUREOFTHESPACERGAIT,2003ZATSEPINETAL,2005COVALENTSTRATEGIESHAVEBEENMAINLYREPORTEDFORTHEDELIVERYOFDNAMIMICMOLECULESORSTERICBLOCKOLIGONUCLEOTIDES,INCLUDINGPNAKOPPELHUSETAL,2002FABANIETAL,2008,PHOSPHORODIAMIDATEMORPHOLINOOLIGOMERPMOABESETAL,2006LEBLEUETAL,2008MOULTONANDMOULTON,2008,PEPTIDEANDPROTEINSNYDERANDDOWDY,2005CONJUGATIONMETHODSOFFERSEVERALADVANTAGESFORINVIVOAPPLICATIONSINCLUDINGRATIONALIZATION,REPRODUCIBILITYOFTHEPROCEDURE,TOGETHERWITHTHECONTROLOFTHESTOECHIOMETRYOFTHECPPCARGOHOWEVER,THECOVALENTCPPTECHNOLOGYISLIMITEDFROMACHEMICALPOINTOFVIEWANDRISKSALTERINGTHEBIOLOGICALACTIVITYOFTHECARGOTHISISPARTICULARLYTRUE,INTHECASEOFCHARGEDOLIGONUCLEOTIDEORSIRNA,FORWHICHCPPCOUPLINGHASLEDTORESTRICTEDBIOLOGICALACTIVITIESJULIANOETAL,2008,NONCOVALENTSTRATEGIESTHEREBYAPPEARINGMOREAPPROPRIATENONCOVALENTSTRATEGYTHISSTRATEGYISMAINLYBASEDONSHORTAMPHIPATHICPEPTIDECARRIERSCONSISTINGOFTWODOMAINSAHYDROPHILICPOLARDOMAINANDAHYDROPHOBICNONPOLARDOMAINTABLE1THEAMPHIPATHICCHARACTERMAYARISEFROMEITHERTHEPRIMARYSTRUCTUREORTHESECONDARYSTRUCTUREPRIMARYAMPHIPATHICPEPTIDESCANBEDEFINEDASTHESEQUENTIALASSEMBLYOFADOMAINOFHYDROPHOBICRESIDUESWITHADOMAINOFHYDROPHILICRESIDUESSECONDARYAMPHIPATHICPEPTIDESAREGENERATEDBYTHECONFORMATIONALSTATETHATALLOWSPOSITIONINGOFHYDROPHOBICANDHYDROPHILICRESIDUESONOPPOSITESIDESOFTHEMOLECULEDESHAYESETAL,2005SEVERALCPPSHAVEBEENREPORTEDTOFORMNONCOVALENTCOMPLEXESWITHBIOMOLECULESANDTOIMPROVETHEIRDELIVERYINTOMAMMALIANCELLSMORRISETAL,2008NONCOVALENTAPPROACHWASORIGINALLYDEVELOPEDFORGENEDELIVERYSEVERALPEPTIDESABLETOCONDENSEDNAASSOCIATEDWITHPEPTIDESTHATFAVOURENDOSOMALESCAPEINCLUDINGFUSIONPEPTIDEOFHA2SUBUNITOFINFLUENZAHEMAGLUTININHAVEBEENDESCRIBEDLEARANDDEGRADO,1987PARENTEETAL,1990SYNTHETICPEPTIDESANALOGSGALA,KALA,JTS1GOTTSCHALKETAL,1996WYMANETAL,1997,PPTG1RITTNERETAL,2002,MPGMORRISETAL,1999ANDHISTIDINERICHPEPTIDESMIDOUXETAL,1998KICHLERETAL,2003WEREALSOREPORTEDASPOTENTGENEDELIVERYSYSTEMSIN2001,WEDEMONSTRATEDTHATTHEAMPHIPATHICPEPTIDEPEP1COULDBESUCCESSFULLYAPPLIEDTOTHEDELIVERYOFSMALLPEPTIDESANDPROTEINSINANONCOVALENTAPPROACHMORRISETAL,2001IN2003,ANONCOVALENTSTRATEGYBASEDONMPGWASSHOWNTOEFFICIENTLYDELIVERSIRNAINTOCULTUREDCELLLINESSIMEONIETAL,2003PEP1ANDMPGAREPRIMARYAMPHIPATHICPEPTIDESCONTAININGAHYDROPHILICLYSINERICHDOMAINDERIVEDFROMTHENUCLEARLOCALIZATIONSEQUENCENLSOFSV40LARGETANTIGENKKKRKV,ANDAVARIABLENTERMINALHYDROPHOBICMOIETYDERIVEDFORMTHEFUSIONSEQUENCEOFTHEHIVPROTEINGP41GALFLGFLGAAGSTMGAFORMPG,ANDFROMATRYPTOPHANRICHCLUSTERKETWWETWWTEWFORPEP1,SEPARATEDBYALINKERDOMAIN,WHICHIMPROVESTHEFLEXIBILITYANDTHEINTEGRITYOFBOTHTHEHYDROPHOBICANDHYDROPHILICDOMAINSMORRISETAL,1997MORRISETAL,1999SIMEONIETAL,2003MPGANDPEP1FORMSTABLECOMPLEXESWITHTHEIRRESPECTIVECARGOOLIGONUCLEOTIDEORPROTEIN/PEPTIDETHROUGHNONCOVALENTELECTROSTATICANDHYDROPHOBICINTERACTIONSMORRISETAL,199719992001SIMEONIETAL,2003GROSETAL,2006MUNOZMORRISETAL,2007NONCOVALENTSTRATEGIESFORPROTEINANDOLIGONUCLEOTIDEDELIVERYHAVEBEENRECENTLYBEENEXTENDEDTOOTHERCPPS,INCLUDINGTATMEADEANDDOWDY,2007,POLYARGININEKIMETAL,2006KUMARETAL,2007ANDTRANSPORTANDERIVEDPEPTIDESPOOGAETAL,2001LUNDBERGETAL,2007CELLULARUPTAKEMECHANISMOFCELLPENETRATINGPEPTIDESTHECELLULARUPTAKEMECHANISMOFCPPSISANESSENTIALPIECEOFTHEPUZZLEFORTHEDEVELOPMENTANDOPTIMIZATIONOFAPPROPRIATESTRATEGIESFORINVIVOTHERAPEUTICAPPLICATIONSALTHOUGHCELLULARINTERNALIZATIONOFCPPSWASREPORTEDINAWIDEVARIETYOFCELLTYPES,THEIRMECHANISMOFINTERNALIZATIONREMAINED‘MYSTERIOUS’FORALONGTIME,ASBEINGINDEPENDENTOFENDOCYTOSIS,OFENERGYANDOFSPECIFICRECEPTORINTHELAST5YEARS,THECPPFIELDHASSUFFEREDANDLEARNTFROMTECHNICALARTIFACTSASSUCH,IN2003,LEBLEUANDCOLLEAGUES,PROPOSEDAREVISEDCELLULARUPTAKEMECHANISMFORCPPS,ESSENTIALLYASSOCIATEDWITHTHEENDOSOMALPATHWAYRICHARDETAL,2003EVERSINCE,THEMECHANISMOFMANYCPPSHASREEXAMINEDANDREPORTEDTOBEMEDIATEDBYENDOCYTOSISLUNDBERGANDJOHANSSON,2001NAKASEETAL,2004WADIAETAL,2004FISCHERETAL,2005RICHARDETAL,2005MURRIELANDDOWDY,2006HOWEVER,FORMOSTCPPS,THECELLULARUPTAKEMECHANISMSTILLNEEDSTOBECONFIRMEDANDREMAINSCONTROVERSIAL,PARTLYDUETOTHEFACTTHATDIFFERENTMETHODS,WHICHARENOTCOMPARABLEFROMONELABPEPTIDEBASEDDRUGDELIVERYTECHNOLOGYFHEITZETAL197BRITISHJOURNALOFPHARMACOLOGY2009157195–206

簡介：1ABSTRACTTHECOMBUSTIONSYSTEMOFCIRCULATINGFLUIDIZEDBEDBOILERCFBBISACOMPLEXOBJECTWITHMULTIVARIABLE,LARGEDELAY,TIGHTLYCOUPLING,NONLINEARANDSLOWTIMEVARYINGITISDIFFICULTTOBUILDTHEPRECISEMATHEMATICMODELOFTHEOBJECTANDTOACCURATELYCONTROLTHEOBJECTWITHTHETRADITIONALCONTROLMETHODSINTHISPAPER,THEOBJECTISDYNAMICALLYDECOUPLEDBYAFEEDFORWARDCOMPENSATORTHEN,THEOBJECTISRESPECTIVELYCONTROLLEDBYTHREECONTROLLERS,PIDCONTROLLER,FUZZYCONTROLLERANDSELFTUNINGPARAMETERFUZZY–PIDCONTROLLERTHESIMULATIONEXPERIMENTSARECARRIEDOUTTHROUGHCONTRASTWITHFORMERCONTROLLERSINMATLABSIMULATIONENVIRONMENTTHESIMULATIONRESULTSSHOWTHATTHESELFTUNINGPARAMETERFUZZYPIDCONTROLLERISSUPERIORTOTHEGENERALPIDCONTROLLERANDTHEGENERALFUZZYCONTROLLERINSPEEDINESS,STABILITY,ADAPTABILITY,ROBUSTNESSANDABILITYOFANTIDISTURBANCEINDEXTERMSCIRCULATINGFLUIDIZEDBEDBOILERDECOUPLINGFUZZYCONTROLMULTIVARIABLESELFTUNINGPARAMETERFUZZYPIDCONTROLI．INTRODUCTIONHECIRCULATINGFLUIDIZEDBEDBOILERCFBBHASBEENWIDELYUSEDASACLEANCOALCOMBUSTIONTECHNIQUEFORITSHIGHCOMBUSTIONEFFICIENCY,WIDEADAPTABILITYTOCOALRANKS,LOADADJUSTINGPERFORMANCEANDLOWPOLLUTION14HOWEVER,DUETOITSSPECIALSTRUCTUREANDTHECOMPLEXITYOFCOMBUSTIONMECHANISM,THECOMBUSTIONPROCESSHASCOMPLEXFEATURES,SUCHASHIGHLYNONLINEAR,TIMEVARYING,LARGEDELAYANDMULTIVARIABLEDECOUPLING,ETCITISVERYDIFFICULTTOESTABLISHITSPRECISEMATHEMATICALMODEL58,ANDTOCONTROLTHEOBJECTWITHTHETRADITIONALCONTROLMETHODSATPRESENT,THECOMMONCONTROLMETHODISTHATTHEMAINSTEAMPRESSUREISFOCALLYCONTROLLED,MEANWHILE,THEPRIMARYAIRFLOWISADJUSTEDACCORDINGTOTHEBESTAIRCOALRATIO,ANDTHEBEDTEMPERATUREISCONTROLLEDINTHEREQUIREDRANGE9THEMETHODCAN’TMAINTAINTHEBEDTEMPERATUREINTHEBESTRANGEWHILEKEEPINGTHEMAINSTEAMPRESSUREINTHISPAPER,ONTHEBASISOFDECOUPLINGMODELOFTHEMAINSTEAMPRESSUREANDTHEBEDTEMPERATURE10,THESELFTUNINGFUZZYPIDCONTROLLER1118WHICHHASBETTERADAPTABILITYANDTHISWORKWASSUPPORTEDBYLEADINGACADEMICDISCIPLINEPROJECTOFSHANGHAIMUNICIPALEDUCATIONCOMMISSIONPROJECTNUMBERJ51301ANDNATURESCIENCEKEYFOUNDATIONOFSHANGHAIMUNICIPALEDUCATIONCOMMISSIONPROJECTNUMBER06ZZ69ALLOFTHEAUTHORSAREWITHCOLLEGEOFELECTRICPOWERANDAUTOMATION,SHANGHAIUNIVERSITYOFELECTRICPOWER,YANGPUDISTRICT,SHANGHAI,200090,CHINAEMAILCHENGQIMINGSINACOMBETTERROBUSTNESS,ISUSEDTOCONTROLTHESTEAMPRESSUREANDTHEBEDTEMPERATURETOGETTHEBETTERCONTROLEFFECTSII．THECHARACTERISTICSOFCFBBANDTHESTRUCTUREOFTHEDECOUPLEDCONTROLSYSTEMOFCFBBTHEKEYREASONSTHATCFBBCOMBUSTIONSYSTEMISDIFFICULTTOCONTROL,ARETHESTRONGCOUPLINGRELATIONSBETWEENMULTIINPUTSCOAL,PRIMARYAIR,SECONDARYAIR,DRAWINGWIND,RECYCLEMATERIALANDMULTIOUTPUTSBEDTEMPERATURE,MAINSTEAMPRESSURE,THEFURNACENEGATIVEPRESSURE,OXYGENCONTENT,THEMOSTIMPORTANTRELATIONINTHESECOUPLINGRELATIONSISTHECOUPLINGRELATIONBETWEENBEDTEMPERATUREANDMAINSTEAMPRESSURE56INCHINA,CFBBAREUSUALLYDESIGNEDWITHOUTEXTERNALHEATEXCHANGERTOENSURESIMPLESTRUCTUREANDLOWCOSTTHEMAINSTEAMPRESSUREANDTHEBEDTEMPERATUREWITHSTRONGLYCOUPLEDRELATIONARECONTROLLEDBYREGULATINGTHECOALAMOUNTANDTHEPRIMARYAIRAMOUNTTHISCONTROLMETHODISWIDELYUSEDTOTHEACTUALCONTROLOFCFBBCOMBUSTIONSYSTEMINCHINA12THEREFORE,INTHISPAPER,THEBEDTEMPERATUREISCONTROLLEDBYTHEPRIMARYAIRAMOUNT,ANDTHEMAINSTEAMPRESSUREISREGULATEDBYTHECOALAMOUNTINTHISPAPER,THEDOMESTIC75T/HCFBBISSELECTEDASTHEOBJECTOFSIMULATIONEXPERIMENTSTHETRANSFERFUNCTIONMATRIXOFTHESYSTEMATTHELOADRANGEOF70TO100ISGOTTEN16???????????????????????????????????????12602230212221121101160036012600066011638767811803860QBSESSESQBSGSGSGSGPTSSB1WHERETB,P0ARERESPECTIVELYBEDTEMPERATUREANDMAINSTEAMPRESSUREB,Q1ARERESPECTIVELYCOALAMOUNTANDPRIMARYAIRAMOUNTG11,G12G21,G22ARERESPECTIVELYINPUTOUTPUTTRANSFERFUNCTIONSOFBTB,BP0,Q1TBANDQ1P0FROMEQ1TOSEE,THATTIMEDELAYSEXISTINBOTHCOALMAINSTEAMPRESSURELOOPANDCOALBEDTEMPERATURELOOPANDTHEREARESERIOUSLYCOUPLINGRELATIONSINCFBBSYSTEMTHEREFORE,DYNAMICFEEDFORWARDCOMPENSATIONISNEEDEDFORDYNAMICDECOUPLINGSYSTEMTOCONTROLTHESYSTEMBETTERDYNAMICFEEDFORWARDCOMPENSATIONISCOMMONLYUSEDFORSYSTEMDECOUPLING10FIG1ISTHESTRUCTUREOFTHERESEARCHONMULTIVARIABLEDECOUPLINGCONTROLSYSTEMFORCOMBUSTIONSYSTEMOFCIRCULATINGFLUIDIZEDBEDBOILERQIMINGCHENG,RUIQINGGUO,ANDXUFENGDUT3TRIALANDERRORMETHODIV．THEDESIGNOFSELFTUNINGFUZZYPIDCONTROLLERFORCOMBUSTIONCONTROLSYSTEMOFCFBBATHESTRUCTUREOFCONTROLSYSTEMTHEPIDCONTROLLERHASMANYADVANTAGES,SUCHASSIMPLESTRUCTURE,MATURETHEORETICALBASIS,WIDEAPPLICABILITY,CONVENIENTPARAMETERTUNING,MUCHENGINEERINGAPPLICATIONTHEREFORE,THEPIDCONTROLLEROCCUPIESADOMINANTPOSITIONINTHEACTUALCONTROLSYSTEMBUTTHELINEARCHARACTERISTICSOFTHECONVENTIONALPIDCONTROLLERWITHFIXEDCONTROLPARAMETERSHAVEGOODCONTROLPERFORMANCEONLYWHENWORKINGNEAROPERATINGPOINTWHENTHESYSTEMISFARTHEROUTOFTHEOPERATINGPOINT,NONLINEARCONTROLCHARACTERISTICSOFTHEOBJECTISDIFFICULTTOMAINTAINTHEDYNAMICQUALITYOFPIDCONTROLTHEREFORE,FUZZYREASONINGISINTRODUCEDTOSOLVEDTHEPROBLEM,THEPARAMETERSOFPIDCONTROLLERBASEDONTHEINITIALPIDCONTROLPARAMETERSARECORRECTEDWITHADDINGFUZZYREASONINGTOIMPROVETHESYSTEMDYNAMICPERFORMANCEINSELFTUNINGFUZZYPIDCONTROLLER1618,THECONDITIONSANDTHEOPERATIONSOFCONTROLRULESAREEXPRESSEDBYFUZZYSETONTHEBASISOFPIDCONTROL,ANDTHESEFUZZYCONTROLRULESASWELLASOTHERINFORMATIONARESTOREDINTOCOMPUTERKNOWLEDGEBASES,THEN,ACCORDINGTOACTUALRESPONSEOFTHECONTROLSYSTEM,FUZZYREASONINGISCARRIEDOUTBYCOMPUTERTOACHIEVEBESTADJUSTMENTOFPIDCONTROLTHESTRUCTUREOFSELFTUNINGPARAMETERFUZZYPIDCONTROLSYSTEMISSHOWNINFIG5FIRSTLY,THESELFTUNINGFUZZYPIDCONTROLLERISDESIGNEDTOFINDTHEFUZZYRELATIONSBETWEENTHETHREECONTROLPARAMETERSNAMELY,PROPORTIONALCOEFFICIENTKP,DIFFERENTIALCOEFFICIENTKDANDINTEGRALCOEFFICIENTKIANDTHETWOSYSTEMVARIABLESTHATIS,ERRORE,ERRORDEVIATIONECTHEN,ΔKP,ΔKI,ΔKD,THECHANGESOFKP,KI,KDPIDCONTROLPARAMETERSAREONLINEAMENDEDONFUZZYTHEORYWITHMEASURINGEANDECDURINGTHESYSTEMOPERATIONFINALLY,THECONTROLSYSTEMHASGOODDYNAMICANDSTATICPERFORMANCETHEDIGITALPIDCONTROLLERUSUALLYCANBEEXPRESSEDASUKKPEKKIΣEIKDECK（4）INFUZZYREASONING,THEINPUTVARIABLESAREEANDEC,ANDTHEOUTPUTVARIABLESAREΔKP,ΔKI,ΔKDTHEPIDCONTROLPARAMETERSAREGIVENASKPKP0ΔKP，KIKI0ΔKI，KDKD0ΔKD（5）WHERE,KP0,KI0,KD0ARETHEINITIALSETTINGVALUESOFKD,KI,KDPIDCONTROLPARAMETERSBTHERULETABLESOFFUZZYCONTROLFROMTHECHARACTERISTICSOFPIDCONTROLTOKNOW,THESTRONGINTEGRALACTIONILEADSTOBIGOVERSHOOT,FASTRESPONSETHESTRONGDERIVATIVEACTIONDHASGOODSTABILITY,SMALLOVERSHOOT,SMALLABILITYOFANTIINTERFERENCEACCORDINGTOEANDECATDIFFERENTSTAGES,THESETTINGPRINCIPLEOFPIDCONTROLPARAMETERSAREGIVEN11,181WHENTHECONTROLLEDVARIABLESARECLOSETOSETTINGVALUES,THEINTEGRALACTIONWITHTHESAMESIGNASECCANAVOIDSOVERSHOOTANDOSCILLATION,ANDISBENEFICIALTOTHECONTROLWHENTHECONTROLLEDVARIABLESAREFARFROMSETTINGVALUES,THEINTEGRALACTIONWITHTHEOPPOSITESIGNASECANREDUCEOVERSHOOTANDAVOIDOSCILLATION2ATINITIALSTAGEOFPIDPARAMETERADJUSTMENT,ITCANAVOIDOVERSHOOTANDINCREASERESPONSESPEEDTHATKPISPROPERLYLARGEANDKIISSMALLORZEROATMIDDLESTAGE,LETTHEVALUESOFKPANDKIBEMODERATEWHILETAKINGACCOUNTTOSTABILITYANDCONTROLPRECISIONATLASTSTAGE,ITCANELIMINATETHEERRORSANDREDUCEOVERSHOOTTHATKPISREDUCEDANDKIISINCREASEDPROPERLY3DIFFERENTIALCOEFFICIENTKDCANINHIBITCHANGEOFCONTROLLEDVARIABLE,SHORTENSTEADYTIME,REDUCESTEADYSTATEERRORITISASUPPLEMENTTOKP,KITHEFUZZYSUBSETSOFINPUTANDOUTPUTVARIABLESOFFUZZYCONTROLLERARERESPECTIVELYE,EC,ΔKP,ΔKI,ΔKDTHELANGUAGEVALUESOFTHESEFUZZYVARIABLESAREIN{NB,NM,NS,ZO,PS,PM,PB},ANDTHEMEMBERSHIPFUNCTIONSOFTHESEFUZZYVARIABLESAREALLSENSITIVELYTRIGONOMETRICFUNCTIONSWITHTHEVALUEFIELDIN3,3BYFUZZYREASONINGANDTESTMODIFICATIONBASEDONTHEABOVESETTINGPRINCIPLE,THEFUZZYCONTROLRULESOFTHESELFTUNINGPARAMETERFUZZYPIDCONTROLSYSTEMAREOBTAINEDANDSHOWNINTABLEIIITALLEIIFUZZYCONTROLRULESOFBP0CONTROLLOOPFIG5THESTRUCTUREOFSELFTUNINGFUZZYPIDCONTROLLER

簡介：APPLIEDSOFTCOMPUTING112011103–110CONTENTSLISTSAVAILABLEATSCIENCEDIRECTAPPLIEDSOFTCOMPUTINGJOURNALHOMEPAGEWWWELSEVIERCOM/LOCATE/ASOCMODELINGANDSIMULATIONOFCHAOTICPHENOMENAINELECTRICALPOWERSYSTEMSDEEPAKKUMARLAL,KSSWARUP?DEPARTMENTOFELECTRICALENGINEERING,INDIANINSTITUTEOFTECHNOLOGY,MADRAS,CHENNAI600036,INDIAARTICLEINFOARTICLEHISTORYRECEIVED23DECEMBER2007RECEIVEDINREVISEDFORM30OCTOBER2009ACCEPTED15NOVEMBER2009AVAILABLEONLINE18NOVEMBER2009KEYWORDSNONLINEARSYSTEMCHAOSHOFFBIFURCATIONDOUBLESCROLLEQUATIONDYNAMICALSYSTEMLIMITSETSPOWERSYSTEMINSTABILITYABSTRACTMODELINGANDSIMULATIONOFNONLINEARSYSTEMSUNDERCHAOTICBEHAVIORISPRESENTEDNONLINEARSYSTEMSANDTHEIRRELATIONTOCHAOSASARESULTOFNONLINEARINTERACTIONOFDIFFERENTELEMENTSINTHESYSTEMAREPRESENTEDAPPLICATIONOFCHAOTICTHEORYFORPOWERSYSTEMSISDISCUSSEDTHROUGHSIMULATIONRESULTSSIMULATIONOFSOMEMATHEMATICALEQUATIONS,EGVANDERPOL’SEQUATION,LORENZ’SEQUATION,DUFFING’SEQUATIONANDDOUBLESCROLLEQUATIONSAREPRESENTEDTHEORETICALASPECTSOFDYNAMICALSYSTEMS,THEEXISTENCEOFCHAOSINPOWERSYSTEMANDTHEIRDEPENDENCYONSYSTEMPARAMETERSANDINITIALCONDITIONSUSINGCOMPUTERSIMULATIONSAREDISCUSSEDFROMTHERESULTSONECANEASILYUNDERSTANDTHESTRANGEATTRACTORANDTRANSIENTSTAGESTOVOLTAGECOLLAPSE,ANGLEINSTABILITYORVOLTAGECOLLAPSEANDANGLEDIVERGENCESIMULTANEOUSLYIMPORTANTSIMULATIONRESULTSOFCHAOSFORAMODELTHREEBUSSYSTEMAREPRESENTEDANDDISCUSSED?2009ELSEVIERBVALLRIGHTSRESERVED1INTRODUCTIONCHAOTICPHENOMENAHAVEBEENDRAWINGEXTENSIVEATTENTIONINVARIOUSFIELDSOFNATURALSCIENCE1RECENTDEVELOPMENTSINNONLINEARSYSTEMTHEORIESALLOWONETOUNDERSTANDANDANALYZESEVERALCOMPLEXBEHAVIORSINPOWERSYSTEMSNONLINEARPHENOMENASUCHASBIFURCATIONANDCHAOSINPOWERSYSTEMSHASBEENOBSERVEDINTHEPOWERSYSTEMNETWORKSDURINGTHEPASTFEWYEARS2DISTURBANCESINPOWERSYSTEMCAUSESCHANGEINPARAMETERSWHICHRESULTINTHESYSTEMEXHIBITINGCHAOTICBEHAVIORWHENCHAOSBREAKS,ITENTERSINTODIFFERENTINSTABILITYMODES,WHICHCAUSESTHEPOWERSYSTEMSTOEXHIBITINSTABILITYWHICHNEEDSTOBEAVOIDEDMOSTOFTHEPHYSICALSYSTEMSINNATUREARENONLINEARANDASARESULTPOWERFULMATHEMATICALTOOLSAREREQUIREDFORANALYSIS3,4ITISDESIRABLETOMAKELINEARASSUMPTIONSWHENEVERACOMPROMISECANBEOBTAINEDBETWEENTHESIMPLICITYOFANALYSISANDACCURACYOFRESULTSCHAOTICPHENOMENAAREONETYPEOFUNDETERMINISTICOSCILLATIONEXISTINGINDETERMINISTICSYSTEMSTHEYARERELATEDTORANDOM,CONTINUOUSANDBOUNDEDOSCILLATIONANDNOTDYNAMICALLYSTABLEANDMAYFACESERIOUSPROBLEMSFROMANOPERATIONVIEWPOINTTHEHOFFBIFURCATIONANDCHAOSLIMITTHELOADABILITYOFTHEPOWERSYSTEMANDAREUNWANTEDPHENOMENA5FORTHEIRCOMPLEXITY,MECHANISMOFCHAOTICPHENOMENAISVERYLITTLEKNOWNUPTONOWTHEREISNOGENERALLYACCEPTEDDEFINITIONOFCHAOSHENCEISCALLEDSTRANGE?CORRESPONDINGAUTHORATDEPARTMENTOFELECTRICALENGINEERING,INDIANINSTITUTEOFTECHNOLOGY,MADRAS,ELECTRICALSCIENCEBLOCKESB245D,CHENNAI600036,TAMILNADU,INDIATEL914422574440FAX914422574402EMAILADDRESSSWARUPEEIITMACINKSSWARUPATTRACTORDISCOVERYOFCHAOSENHANCESOURUNDERSTANDINGOFCOMPLEXANDUNPREDICTABLEBEHAVIORSARISINGFROMAWIDEVARIETYOFSYSTEMSINENGINEERINGANDSCIENCES,MAINLYINNONLINEARSYSTEMSRESEARCHALSO,STUDYONCHAOTICPHENOMENAISONEIMPORTANTPARTOFPOWERSYSTEMSTABILITYSTUDIES6,7INTHISPAPERTHENUMERICALSIMULATIONOFTHEMATHEMATICALRELATIONSFORCHAOSOCCURRINGINPOWERSYSTEMSHAVEBEENSIMULATEDTHEBEHAVIOROFTHESYSTEMUNDERVARIOUSOPERATINGCONDITIONSISPRESENTEDTHEPAPERISORGANIZEDASFOLLOWSTHEORETICALFORMULATIONANDMATHEMATICALREPRESENTATIONOFCHAOSISGIVENINSECTION2SECTION3PROVIDESTHESTEADYSTATEBEHAVIOROFNONLINEARSYSTEMSMODELINGOFCHAOTICBEHAVIORINPOWERSYSTEMSISDESCRIBEDINSECTION4SECTION5PROVIDESTHEIMPLEMENTATIONASPECTSOFTHECHAOSCHAOSANDINSTABILITYINPOWERSYSTEMSISPROVIDEDINSECTION6IMPORTANTCONCLUSIONSAREGIVENINSECTION72NONLINEARDYNAMICALSYSTEMSTHREETYPESOFDYNAMICALSYSTEMSAREPRESENTEDWITHSOMEUSEFULFACTSFROMTHETHEORYOFDIFFERENTIALEQUATIONS1,821AUTONOMOUSDYNAMICALSYSTEMSANNTHORDERAUTONOMOUSDYNAMICALSYSTEMISDEFINEDBYTHESTATEEQUATION˙XFXXT0X01WHERE˙XDY/DTANDXT∈?ARETHESTATEATTIMETANDF?→?ISCALLEDTHEVECTORFIELD15684946/–SEEFRONTMATTER?2009ELSEVIERBVALLRIGHTSRESERVEDDOI101016/JASOC200911001DKLAL,KSSWARUP/APPLIEDSOFTCOMPUTING112011103–110105FIG1LIMITCYCLEBEHAVIOROFANONLINEARSYSTEMAUNDERDAMPEDSYSTEMFOR|X|?1WITHSTABLELIMITCYCLEBOVERDAMPEDSYSTEM|X|?1WITHUNSTABLELIMITCYCLETHEPHASETRAJECTORIESFORTHISEQUATIONWILLBEDIVERGEDAWAYFROMLIMITCYCLE,ANDHENCEITWILLINDICATETHELIMITCYCLEWILLBEUNSTABLE33QUASIPERIODICSOLUTIONSAQUASIPERIODICSOLUTIONISONETHATCANBEWRITTENASASUMOFPERIODICFUNCTIONSXT?IHIT11WHEREHIHASMINIMALPERIODTIANDFREQUENCYFI1/TIFURTHERMORE,THEREEXISTAFINITESETOFBASEFREQUENCIES{F1,F2,F3,,FP}WITHTHEFOLLOWINGPROPERTIESIITISLINEARLYINDEPENDENTTHATIS,THEREDOESNOTEXISTANONZEROSETOFINTEGERS{K1,K2,K3,,KP}SUCHTHATK1F1K1F1K1F1KPFPIIITFORMSAFINITEINTEGRALBASEFORFITHATIS,FOREACHI,FIK1F1K1F1K1F1KPFPFORSOMEINTEGERS{K1,K2,K3,,KP}INOTHERWORDS,AQUASIPERIODICWAVEFORMISTHESUMOFPERIODICWAVEFORMSEACHOFWHOSEFREQUENCYISONEOFTHEVARIOUSSUMSANDDIFFERENCESOFAFINITESETOFBASEFREQUENCIESNOTETHATTHEBASEFREQUENCIESARENOTUNIQUELYDEFINED,BUTTHATPISAQUASIPERIODICSOLUTIONWITHPBASEFREQUENCIESISCALLEDPPERIODICFIG2TWODIMENSIONALTRAJECTORYOFCHAOSINLORENZSYSTEMFOR?10,?28,ˇ8/3ATWODIMENSIONALCORRESPONDINGTOX–YANDY–ZAXISBTWODIMENSIONALCORRESPONDINGTOX–ZAXISANDRANDOMWAVEFORMFEATUREOFCHAOS

簡介：INTENSIVECAREMED2007331162–1167DOI101007/S0013400706752ORIGINALHKALLELLHERGAFIMBAHLOULAHAKIMHDAMMAKHCHELLYCBENHAMIDAACHAARINREKIKMBOUAZIZSAFETYANDEFFICACYOFCOLISTINCOMPAREDWITHIMIPENEMINTHETREATMENTOFVENTILATORASSOCIATEDPNEUMONIAAMATCHEDCASE–CONTROLSTUDYRECEIVED26JULY2006ACCEPTED23APRIL2007PUBLISHEDONLINE25MAY2007?SPRINGERVERLAG2007HKALLELULHERGAFIMBAHLOULHDAMMAKHCHELLYCBHAMIDAACHAARINREKIKMBOUAZIZCHUHABIBBOURGUIBA,SERVICEDERéANIMATIONMéDICALE,ROUTEELAINKM1,3029SFAX,TUNISIAEMAILKALLELHATYAHOOFRTEL21698415299FAX21674243427AHAKIMFACULTéDEMéDECINEDESFAX,LABORATOIREDEPHARMACOLOGIE,ROUTEELAINKM1,3029SFAX,TUNISIAABSTRACTOBJECTIVEOURSTUDYAIMEDTODETERMINETHEEFFICACYANDSAFETYOFCOLISTININTHETREATMENTOFVENTILATORASSOCIATEDPNEUMONIAVAPCAUSEDBYPANDRUGRESISTANTPSEUDOMONASAERUGINOSAORACINETOBACTERBAUMANIIDESIGNPAIRWISE,RETROSPECTIVEEXPOSED–UNEXPOSEDSTUDYSETTINGCOMBINEDMEDICALANDSURGICALINTENSIVECAREUNITOFHABIBBOURGUIBAUNIVERSITYHOSPITALSFAX,TUNISIAPATIENTSSIXTYPATIENTSWITHVAPCAUSEDBYPANDRUGRESISTANTABAUMANIIORPAERUGINOSAMATCHEDTO60CONTROLSWITHVAPCAUSEDBYABAUMANIIORPAERUGINOSASUSCEPTIBLETOIMIPENEMALLPATIENTSHADNORMALRENALFUNCTIONATTHEONSETOFANTIBIOTICTHERAPYINTERVENTIONSCASEPATIENTSWERETREATEDBYCOLISTININTRAVENOUSLYANDCONTROLPATIENTSWERETREATEDBYIMIPENEMINTRAVENOUSLYMEASUREMENTSANDRESULTSBASELINECHARACTERISTICSWERESIMILARBETWEENTHECOLISTINANDIMIPENEMGROUPSTHEMEANDURATIONOFANTIBIOTICTHERAPYFORVAPWAS95±38DAYSRANGE5–22DAYSWITHCOLISTINAND89±28DAYSRANGE5–20DAYSWITHIMIPENEMP032AFAVORABLECLINICALRESPONSETOANTIBIOTICTHERAPYFORVAPOCCURREDIN45PATIENTS75INTHECOLISTINGROUPANDIN43PATIENTS717INTHEIMIPENEMGROUPP068THETIMETORESOLUTIONOFINFECTIOUSPARAMETERSAFTERTHEINITIATIONOFANTIBIOTICTHERAPYWASNOTSTATISTICALLYDIFFERENTBETWEENTHETWOGROUPSDURINGTHEANTIBIOTICCOURSE,NONEOFTHEPATIENTSINEITHERGROUPDEVELOPEDRENALFAILURECONCLUSIONSWECONCLUDETHATCOLISTINCANBEASAFEANDEFFECTIVEOPTIONINTHETREATMENTSOFVAPCAUSEDBYPANDRUGRESISTANTPAERUGINOSAORABAUMANIIKEYWORDSCOLISTINVENTILATORASSOCIATEDPNEUMONIANEPHROTOXICITYIMIPENEMINTRODUCTIONPANDRUGRESISTANTPDRGRAMNEGATIVEBACTERIAAREANIMPORTANTPROBLEMWORLDWIDE,ESPECIALLYINTHEINTENSIVECAREUNITICU1,2MULTIPLEDRUGRESISTANCEMAKESDIFFICULTTHECHOICEOFTHEEMPIRICANTIMICROBIALMOLECULEANDISRESPONSIBLEFORDELAYEDADAPTEDANTIMICROBIALTREATMENT3INTHERECENTLYPUBLISHEDLITERATURE,PSEUDOMONASAERUGINOSAANDACINETOBACTERBAUMANIIARETHETWOMOSTWIDELYDESCRIBEDMICROORGANISMSTOBERESISTANTTOTHEMOSTOFAVAILABLEANTIBIOTICS4FORTHISREASON,COLISTINHASBEENRECENTLYCONSIDEREDASALASTTHERAPEUTICOPTIONFORTHETREATMENTOFPATIENTSWITHINFECTIONSCAUSEDBYTHESEMICROORGANISMS4COLISTINISANOLDANTIBIOTICWHICHWASUSEDUNTILTHEEARLY1980STOTREATINFECTIONSCAUSEDBYGRAMNEGATIVERODSWHENGENTAMICINANDSECONDANDTHIRDGENERATIONCEPHALOSPORINSBECAMEAVAILABLE,COLISTINWASDROPPED,MAINLYBECAUSEOFITSNEUROANDNEPHROTOXICITY5–8THEINCREASINGPREVALENCEOFPDRGRAMNEGATIVEORGANISMS,1164TREATMENTREGIMENINTHECOLISTINGROUP,PATIENTSWERETREATEDWITHCOLISTINSULFOMETHATESODIUMBELLONRH?NEPOULENCRORERADMINISTEREDINTRAVENOUSLYTHEDOSAGEWAS6MILLIONUNITS≈100,000U/KGOFCOLISTINDAILY,DIVIDEDINTOTHREEDOSESINTHEIMIPENEMGROUP,PATIENTSWERETREATEDWITHIMIPENEMIMIPENEM/CILASTATINMSDADMINISTEREDINTRAVENOUSLYTHEDOSAGEWAS2GOFIMIPENEMDAILY,DIVIDEDINTOFOURDOSESINTHISSTUDY,ALLPATIENTSRECEIVEDCOLISTINORIMIPENEMONANEMPIRICALBASIS,WHICHMADETHEINITIALANTIBIOTICTREATMENTAPPROPRIATEINALLCASESSTATISTICALANALYSISCATEGORICALVARIABLESWEREEXPRESSEDASPERCENTAGESANDCONTINUOUSVARIABLESASMEANVALUESSDPERCENTAGESWERECOMPAREDUSINGTHECHISQUARETESTANDMEANSWITHTHETTESTTHEWILCOXONMATCHEDPAIRSTESTWASUSEDTOCOMPARETHEMATCHINGCRITERIAAGE,SAPSII,ANDPAO2/FIO2KAPLAN–MEIERCURVESWEREUSEDTOASSESSDIFFERENCESBETWEENTHECOLISTINGROUPANDTHEIMIPENEMGROUPIN1RESOLUTIONOFINFECTIOUSPARAMETERSAFTERTHEINITIATIONOFANTIBIOTICTHERAPYAND2MORTALITYAT28DAYSAFTERTHEONSETOFCOLISTINORIMIPENEMTHERAPYFORVAPCURVESWERECOMPAREDUSINGTHELOGRANKTESTAPVALUE≤005INATWOTAILEDTESTWASCONSIDEREDTOINDICATESTATISTICALSIGNIFICANCERESULTSDURINGTHESTUDYPERIOD,1,208PATIENTSWEREADMITTEDTOTHEUNITONETHOUSANDANDSEVENTYSIXOFTHEM891RETABLE1MATCHINGCRITERIAOFTHESTUDYPOPULATIONCOLISTINGROUPN60IMIPENEMGROUPN60PEFFECTIVENESSOFMATCHINGAGEYEARS434±188414±167060100SAPS352±123332±108035100PAO2/FIO2ONDAYOFINITIATIONOFANTIBIOTICS213±79215±81087100TABLE2BASELINECHARACTERISTICSOFTHESTUDYPOPULATIONCOLISTINGROUPN60IMIPENEMGROUPN60PREASONFORADMISSIONNACUTERESPIRATORYFAILURE71178133078COMA8133466022MULTIPLETRAUMA42704880020POSTOPERATIVERESUSCITATION3500024SEXRATIOMALE/FEMALE65445045SHOCKN183014233040ANTIBIOTICSN467673965016PAO2/FIO2ATADMISSION311±82313±8409UREANITROGENMMOL/L59±1964±20018SERUMCREATININEΜMOL/L797±178820±154046CEIVEDMECHANICALVENTILATIONAND123114DEVELOPEDVAPIN78634OFTHESEPATIENTSTHEVAPCAUSEDBYPDRABAUMANIIORPAERUGINOSAANDWASTREATEDWITHCOLISTINOFTHESE78PATIENTSPOTENTIALLYELIGIBLEASCASES,12WEREEXCLUDEDBECAUSEOFRENALFAILUREATTHEONSETOFCOLISTINTHERAPYOFTHE66REMAININGCASEPATIENTSENROLLEDINTHESTUDY,MATCHINGWASPOSSIBLEFORONLY60909ALLPATIENTSWEREMATCHEDFORAGE,SAPSII,ANDPAO2/FIO2ATTHEONSETOFANTIBIOTICTHERAPYFORVAPOVERALLSUCCESSOFMATCHINGWASACHIEVEDIN100OFTHEVARIABLESUSEDTABLE1BASELINECHARACTERISTICSOFTHESTUDYPOPULATIONARESHOWNINTABLE2INTHECOLISTINGROUP,517OFCASESOFVAPWERECAUSEDBYABAUMANIIAND484BYPAERUGINOSAINALLPATIENTSINTHISGROUP,ABAUMANIIANDPAERUGINOSAWEREPDRANDWERESUSCEPTIBLEONLYTOCOLISTININTHEIMIPENEMGROUP,617OFCASESOFVAPWERECAUSEDBYABAUMANIIAND383BYPAERUGINOSAINALLPATIENTSINTHISGROUP,ABAUMANIIANDPAERUGINOSAWERERESISTANTTOPENICILLINSANDTHIRDGENERATIONCEPHALOSPORINSANDSUSCEPTIBLETOIMIPENEMTHEMEANICUSTAYBEFORETHEINITIATIONOFANTIBIOTICTHERAPYFORTHEVAPWAS13±10DAYSRANGE5–43DAYSINTHECOLISTINGROUPAND11±9DAYSRANGE5–38DAYSANDTHEIMIPENEMGROUPP024THEMEANDURATIONOFANTIBIOTICTHERAPYFORVAPWAS95±38DAYSRANGE5–22DAYSAND89±28DAYSRANGE5–20DAYSRESPECTIVELYP032EIGHTPATIENTSINTHECOLISTINGROUPAND9PATIENTSINTHEIMIPENEMGROUPRECEIVEDANTIBIOTICSCOLISTINORIMIPENEMFORLESSTHAN10DAYSBECAUSETHEYDIEDDURINGTHECOURSEOFTHERAPYAFAVORABLECLINICALRESPONSETOANTIBIOTICTHERAPYFORVAPOCCURREDIN45PATIENTS75INTHECOLISTINGROUPANDIN43PATIENTS717INTHEIMIPENEMGROUPP068FIGURES1AND2SHOWTHERESOLUTIONOFINFECTIOUSPARAMETERSANDTHEEVOLUTIONOF