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rnlc tn Ihc mocr,y+hapcs n('nnncil tf+,+na+rcrl Om1y whit h mc:,.urr•rl „vcr•rll ratca nf clcirincc r,f rndir,:,ctivc rlu.l% frc.m tht• lunF,c uf int•rtt r:,h/+itt Ir:r, rc/a,rtcd thal inh:tlalir+n of cipart•Itc 'rnr,kc h.,J n„ mc:rwrahlr , Ifr t I r,n Ir,l:rl clr•arintc .f•rcrl Ihis resull hat tn•cn in,lrl+rnrltvilly cnnlnmcd I,y ;1 aimilar slurly tt,nrlncted unrlcr other ausrices Ihc imrlicilinn of thcsc studics cccros 1„ fw• tt,at if clcarancc of .uch tapped Ju~ls hy mucus flr,w was dcpresacd by smt,kc inhal:uir,n, aanc c.thcr mechanism such aa the activity of the macrnph:rpcs must have Lccn 1t'cclcr- ateJ Neincrt stuJy, hnwcver, included uhjectivc mcasurcnxnt nf vnr,kc ctf-nurc Rcf.ctiri„ns with nwne refined Icchniyucs ntay hc indit itcd Meanwhik, however, lhc ('ouncil has untkrtaken tn sfv,n.nr a rlircct slwly nf the cflccts of Ir,hnccn smr,kc nn thc macr,q,hapcs. Intlurhnp fMNh fa,.cihlc c(Trtls r,n their nw,hili?alinn and on the ataivuy nf snmc nl thcir eniymcs Slrerial Prohhrrt.s The (kveL,rmcnt nl hcttcr tcchn6tnc% for inh:rlalinn ~turlics in animals ant/ imfanvcmcnl of mrthrwls for mc:,s„rrnp cxtinl r,f lunp hctuc cc(w,wres are e crectcd m ficrlitilc trdntrnn r.f :r nnnd,cr of tht h:rsre rescarch lar+hlcros that havt ari.rn Itut rnrinwhrlc, .Irci,rt f+rnMrm. :,riac Ih:rl rrquire cr,n sitScratinn apart from thi~ sytlrmant, loop tcrm I+rr,prirn Scvcral invc~ti gatnrs have nflcrcJ sf.rcul;rtive tuppcainns frnm Irmc• tn limc Ihat vant,us suhslances present nr faxsihly prctcnl in tnhnctn mq•ht play .runc rnlc in the rathnpenesis of lung cincer Among Ihe apcPls ~upreocJ hite been arsenie. nic-kel, f+r+lr,ninm"", nitrrnamincs, frce r:ahcala antl tnxins /,rrxluccd by such mnlds as Aaf.crRillus niRcr and the Altcrnaria lhe Reneral lack of succe~s in prrxlucinR lunp tumors in e.lserirnental anirnals by IrniR tcrm inhal:rlinn nf tmr,kc fYnm standard cnmmcrc-ial ciFa rettcs I,urchascJ on the open markct tcnds to tliminish materially the inrf.act r,f n11 these suppcstinns Nevcrthclces- Ihc (-r,unt'il has undcrt:rken invicetipa- lir,nc nf the factrrrs listed SG,mc nf Ihcsa• stutliea h:rvt• In•cn cnml,lctcrl, ar,mc :,rc wctl atlv:rnccd, s,+mc art• in (,tt,prc.-. :rnd w,nrr :crc aill in a, livc f,1,rn ninp ~tapcv At prctcrV, nnnc nf Ihc %upt-c.tcd altitrtrt' thcmit'il uuh.t:rncc. apfrars likely tr, rrnvitk an c.(d:maw,n uf the rclw,rncd hurnan cf,rdrmir, I„pit:d d.,ti with rc•I+cct It, cip;rrcttc vm„kinp :,nd nrv,l,l:r.tit N,-vcr Ihc t+.., t,+ml+h It .,n,1 rh r r.ivr infr,rn,.,t,r,n r. I. ml• .,,ul•Fhl I ltc ( r+un, il t,+ntcrn „v, r Iht' nt tt'•tily „I ,hrctt .luthr'. I„ tlca rrl,t• the cfTrtl~ rd tr.v„ 1„ (rc.h n,nrn.rl trt•.urtlc .m,+lc ralhrr IFhan In , ,,..,t, . 1„- I- „ .1 .1,41 1 1,14 .,I+ Jty I I,,. t„n+, rn I,.,. I+cr n I+r+,ht .rh,l urnn Ilre fact Ihat smtike itself has M,th chemic:J anJ (,hy.ic:d prr,l.c•rtics drflcrinR aipnilhcantly from those uf cnndensatcs Onc such Jrllcrcnce is the presentc (if unstahlc free raJicals in fresh smukc ('crlain (rce radicals rersist hrr some time in conJcnsatcs, hut at a lower levcl, and thnsc that rcrsist arc of a rclativcly mt,re stablc character than thasc that Jisapf,car from smnkc within sccnnds or (ractions of a sccunJ after formation in the burning ?orx. On purely theoretical grourttls, it can he speculatetl that free radicals, especially certain lypcs, might have carcinogenic prof+crfies, yet dircct con- firmation of this hyprHhesis has been totally lacking. 7 wu ('ouncil hrojccts have been undertaken in the hopc• of closing gaps in knowkdpe A tcam sfutly involving collaboration uf chcmisls arul biulu- gisls has been sf+r,nuxcJ with the object of preparing a number of diflcrent tyres (if synthelic free raJicals, of various degrees of stahility, and of hr,nging thcse into cnntact with the lissues of sclcctcd animal srrains unJcr corurullcd contlitiuns of dosage. l his study ckres not involve tobacco dircctly hut Ins a general traring on the free radical problem. 1 he other study is a purely dcscriptive physical-chcmical ctudy of (rcc radicals in tt+hacco smoke by elrctron spin resnnancc sfx•ctrrncupy 11 is aimctl at tktermining the kint/s, amounts and degree (if Lcrsi+tence of para ,.ragnclic species derivable from various tnhaccos from scvc•ral snurccs, and at JiscovcrinR the general nature and fxnsrhle origin of tlresc q,ccics In par ticular, it is hoped that a diffcrcntialion can be nrade IK•twccn thr,.e nl ut ganic and inorganic origin. T7ie Irtr/estigatirrn (>'f' 1'(rrllul(>'gical (:/t(rrrges in t/r(r I,IrrrE,r -1 he irnprnvement of techniqucs for regulating antl qu:rntitatinR acn,.nl exrosures to the lungs of exrerirrxntal animals will furthcr cmrha%itc thc need for prurc•r interpretation nf such hiur,pathr,h,Fic:rl clr:rnltc% as may hc acse><'iated with these exf.r,sures. 'Ihe Feneral failurc of cip:ncne cnu,ke ex fanures in ammal% tr, Lrrwluce IunR lumnrs imf,t,ws Ihc prt,hlcm uf rlr:rwing cnrrccl infcrenccv flt,m ttrc presencc of any suth Ii..uc :Jlrr:,u,urs .ra rnay r><'t'ur Murcnvcr, if J„sc resf+r,nsc rcl:nir,n0hil,s :nt• rr, IK• drduccd, .r,rur kind cd scmi quantrtativc mcthtwl uf c+timaling Jcprcrs 411 th.rnpc rnu%t IM' drvchq,cd a nrt cml+lnyrd I hcsc Irrr,hlcm% :y,lr'ar It) inv„lvc f.uth -cncudar :turl rnnrcl+lu:J ,hfler cnccs :rnump I,:ulu,lr,pi.l. Wt• lind 1.11 Ihc onc hand, thc tt,nc,'I+t Ilr.q hyl,cr plas,ia, mctaq+t.r.i:r, :dyl+it:rl rncl.rl,l:t.i:r :uul "c;ut rrn,ncr in .nu :nc I„ f,c 17 i ~+

regarJctl at sequential (hanprs in a prngrct.n,n ht•twccn nrnm:rl tclit antl cart inr+ma On thc cHhcr h.rntl, thcre rt a t'r+ntcl+t tlcrt 1hc th.rnKc lrum nr+r- mality tr+ maliRnancy in a tcll txcur. tudJcnly antl invi.ihly ur :rny Krvcn ccll withuut inlcrmctliatc tlapct that arc hitlr+Ir+Rically rctr+pni'ahlc Ac- cr+rdinR to Ihis crrncrfH, thc hyfK'rl+litrat, mcral+la.i;rs and atyl+r:rt Ih.rt are vcry wulcly f.rcva/rnt in the IunRs (+f most adult inrl m.rny yr+unR human paticnrt, are to l+c rcgartkd as ••ntamal•' rctla+n.cs trt challcn)•rs trf many kindt VariOus t.htrrvatit+ns have hccn prntluccd that t+car ula+n thrtr quct- tit+ns wit)rnut tcltlinR thrnt contlutivcly I rn cR any+lc, Ihc Jcu rrl+trvc tludy r+f human lung rath<dr+Ry inauRuratcd hy Ihit ( t+uncd and r.IcnJ+ d unJcr nther ausl+icct• hat shnwn th.t mttalditiat wcrc nW mrnr Lrcv;rlcnt in Ihc lunps nf I+ulrnr.nnry carcinoma paticntt than in tuhlcctt without IunR canccr If inetal+lmia were a rraRr in cancer devck+(+ment, une wouhl exl.ccl a diller ent (+iclure (•nuncil tfx+nv+red ttudiet nf f+r+ttihle synerRistic efleclt Letwecn inOn rn?a in(rctinnt in mice and the inhalatiun rd crRarctte snu+kc havc nut re sultcd in cpr+krmrud t'arcrnnma rd dir IunR, thr+uRh evitJcntct rd tyncrRitm in pmlileraUvr rllrttt wcre tccn I hctc t+htcrvatu+nt tland dctl+ne rclK•titUve cRl.rrimrntt with prt+prcttivclv inrl+r++.t•d tcthruyuct lhcrc it nn I+rescnl evidcncc that ( iR.rcttr tmwkc t.tn furni.h thc .ct++nJ.uy th.rllcnFc wlrith h:rt been wRyrttrrt at ct+ntrivahly t:rl+:+hlc rd Ir;rn.inrnrinp I+ruh/cralrnR lung cpithclium intr, tyuarntrut (cll t:utrnnma An tihvir+us ncrJ cwittt (rn Ihc rtrrmir+n r+f .uth rifx•rrrncntt Mt+rc tlcfrnitivc infr»matinn mirht I+c prt+tluccd hy ttuJrrt in wluth c1+rthch.rl l+rn lifcralir+n in the tunR wat fhrtt ttimulatcd by a unrtiry fattnr tuth a• a virm infection nr a nnn tf+t•cific irritanl, h+llnwcd by yuantitatcd trc,rtmrnt with known individual carcint+p,cnt (rathrr Ihan ct+ml+Icx and v;uiahlc mitturct) intrtKluced at mcaturrd Ievelt into thc retpiratrrry Iree Mt•anwhilc their hat ht•cn a resurrcncc td intcrctt in virutct as Iwtttihlc sr+lc agcntt in cartint+Rcncsis In a ( r+until tlx+n.urctl trntly, :rn i tllucn7a virut was cultivatctl in a mr+usc litsuc ( ulturc :mJ mrxlifictl tcll% thcn Irant ldantcd hack intn hosl anim:rls I nrntas alq+t•arcJ I lhit c+h.crvatu+n hat cm I+hatin-d the ncceaity of rulinR r+ut ct+nt.uninutir,n by rtthcr vlru.rt, ctlN•t1ally h+lynma, that miRht have played a rr+lt• in Ihit tumrn Fcnctit tiut h Inntihlc ct+ntaminantt erc hcinR carcfully clhct kcd by tayt•cJ :u+tdw+Jy ctlw•rirucnrt Tianre• (:rrlturp Srrtdi.a I itwc tulturc &tudict arc alt,+ IK inR crnl+l++yt+l in rlir+rlt at an ctutida riom r+f Ihc yut•Srr"m la,%rd hy r~h.rrv.rtrnn nl (. Ihr+hr)•i.:rl Ih:rnF~ct rn Ilrc t lung One htttihle nulhcxl of tlelcctinR •'mali(tnanl Iransfrnmalit+n•• in cui turcd cclls it Itt plant them back into husl animals and rrt+sc•rvc dircctly Ihcir l.r,tcntial G+r Rruwth, invasion and nKtaqasis A study rtf this kind Iras Inen inauguratcd Its r+hjcct is tn dclcrmine whclhcr hislrltrKicat clranRcs inJuccd by vari<rus uc:+tmcnts of lung tissuc in culture and analolt+us in al+ln•arantc lo Ihatc frwnd in human lungs at autnltsy arc actually "prccanccrnu<•• that is• carahlc uf f+ntgrestian ta cancer without furlhcr mtxlilicatittn by eRtern.rl facaas 'Ifhc dcvch+rnKnt uf culture techniyucs suilahk for such a purlK+cc is crvnrplicated by the etrcricnce of F.arle and Sanford whct rertxted that snnx nnrriarrd cell cultures after in vinn cultivation for scvcral Rencratiunt. grew into malignant IunNns followinR rNranaplanl into animah A( rruncil Rrant is pruvidinR ft,r rcfa•lilion (+f this work with special attention trt the e>iclusinn nf virus contaminations that miRht have pruduccd such a resull, as the cited authors rtnlulatcd might have oceurred. Another new study slvttnsnrcd by 1hc (•ountil will ohscrvc slxtifically the chanRes induced in in rirrn eulturct of human lissucs by varittus vrrut infcctions. (;(tncer of llte Illaul(Irr Dcspitc rcf+nrtctf asst.ciations hctween ciRarette smt,kinR and carxer of Ihc hladdcr in man, animal cxlrtimcnls involving hmR-Irrrn cal+rrsures In ciRarette smoke condcnsales have failed to prrnluce carxcrs r,f the hladdcr A project has nuw been authnrintl to invcstipale, among other facaxt, the Ixtssihlc rt+le of ahnnrmal IrylHuphan mt•tal>t+lism in thc rtinluFy af Ihis tli.casc in human suhjccts with arnsitkratittn of any cffccls nicrHinc ntay pnaluec u/Hrn the mclalarlic pathways I neal facUtrs ant•ttinR Ivt•rtistcnte or dcsrtuctir+n uf Iryptnl+han tm•taM+litcs in Ihe hladth•r will al.rr rcccivr attention The I'alllogertesis of I nfirr(•1 ion 1 hc ( rnmcil't stut/ict nn cflrcls uf nictdinc ur cmr+kinF r+n thc c:nrhnvis culat syttcrn havr Lccn dcscriht•d rathcr fully in rrcvirtut Rcla+rlt 1 I')t+1 64 anJ 19(+4 /+t 1 Nr+ htrn cvitlcnce t+f +uly tiy.nilit'ant t't+ntrihutir+n I.v .mr+ktnp r+r nicr+tint• to cau.atian tu :rf-rrav•ttiun td any c:utlir+v:r.tul•u rlr.ca.c th•rt cnnlril.utrs imlMtrtantty tr+ nu+rl:tlity h•rs at+ far rmcrFcd 1hr+rq•h vnr+krnt• hat IK•crr rcfii+rtcJ tn IurKlucc :ut r lrvatir+n in frcc fatty :rciJt in thc I+h+r+J « rum, the imldicatirmt rd Ihit cllt•tt with rc%lt•tl In any influcn.c t+n :rthcrt+ Rrnt•-.is are in tlitl+ute Flcvatirm r+f ~crum free f:rtty icitls is a rnum;rl I+hy.inlrq•it:rl rcy+nn.c tn ttrcts, :+nd cvirlcntc t+f avtr:tl krnd. Ir++m.tudict Iwrth by I hr ('nnnt rl and 19 IR

I reFartlcd as scyucntial cllanFcs in a Pn/Frct.inn tx'twccn nilrmal tcllt and can in"ma On the nthcr h.rntl• tlhcrc r% a tvmtcht th.u nce ch.lnpt• Irtmt nnr. mality In maliRn;lncy in a t't'll tKCUr% suthlcnly :1nJ invi.ihly ln any Kivin ccll withrlut intcrrnediite ataFes th:n are hiattdr+Rically retrlpnitahle Ac cnrdinR ttt this cnncchl, the hylK•rrlasras, mt•tapla.i;ls and alypr,ls Ih:lt art• very wrdily prcvaknt in Ihe IunRs t.f mt+sl adult antl ni.iny ytrunR huntan l/aticnts, are tn Ir rcgartkd as "ntumal" resfaln.cs ttl ch:dlcnFts nf ntany kinds Various ohscrvatit/ns have hecn pr(xluccd tflat l.car ufa,n thcsc yuca- ti(+ns withnul acltlinR thcnt ctlnt1usivcly I or caarnldc. the trr.trtptrvc study nf human lung pathohlRy inaugurated hy this ('tluncil and cittt•nJitl untkr other ausflit'ea, has sMlwn that nxlaf.litias were ntN mnrr prcvalcnt in the IunRs nf pulrntmnry carcinoma palicnts than in suhjct'Is without IunR canccr If nxtaplatia were a vaitc in cancer Jcveklpment, ane wot/ld ewf.ecl a difler- cnt picture ('rnrncil sf+t.nvlrcd atudies nf fvltsihle synerRistic cflccts between influ en?a infcc'tinns in mice and the inhalation of cigarette smoke hive nut re sultctl in cpitkrmrnd carernnma r+l tllc IunR• thnuRh eviJcnccs uf cynerRiim in prolifcraUvc cflccts were «cn 1 hctc nhacrvititlns ttand dcshile rclrtilwe elif+erimeMs with pr11Rre«ivcly inlla l.cd tcthrurluca Ihcrt• is no prescnl cvit)cncc that ciParcrtc snurlc c.n lurni.h thc wtnntLuy th.lllcnpc whitft h:r. Leen suRRcstrtt as cnnccivahly tallahlc n/ trnn.fmntinK hrrrllfcr:lfinR IunR cpithclium intn uluarnt/us tcll tirt'innma An ohvitlus nccd cti~ts frrr thc cttt•nmtln td suth clfYrlrltclll( More dcfinilive infnrmatinn might be (+rutlurctl by autlics in whit h clIithclr.d flrn- lifcratinn in the hinR was hrst ~timuliled by a urut:uy fatrllr wth a•. a viru% inkctiun nr a nnn specific irrilant, fnllnwcd by quantit:rtctl Ircatrncnt with known individual carcintlRcns (rather than ctlmldct and variahlc mistures) introduced at mcasured Icvels into the respiratnry Iree Meanwhile thcrc has ht•cn a resnrFcnce of inacrest in viruses as Iwlssihlc snlt• agcnts in carcinnRcncsis In a( rluncil vfalnancJ audy, an i rllni nra virus was cultivalcd in a mrnrsc liatLC tulturc :tntl mtHlilit'tl tcll+ thcn Irans plantccl hack intn ho.t anirnalt I nmru. alqu•arcJ I his nh.crvati"n hac cm /lha~i~rd the nct'raily nf ruhnR nut ct nleminatiun I+y ntllcr vrru~t ., i~l~ t ially (rllyoma, that miRh1 have f/layt•d a rt4c in Ihi. tunuIr Fcnc.is Sut h IMt%sildc cnnlaminants are being earefully tllctlcd by taYf•rJ :1nuMrJy cn1w•rnncnta Tim1ur Crrl/urr Srrrrlira l iswc ( ultnrc ktudic% are als,l hcinR crnpl„yt tl in ellrnt., al an clutitla li ln nf thc yuco-m Ia,vrJ hy id"rrv.wwn ul I.ith luli.al th:lnFc% in the IR : lung One frxsihk method of detecting "malignant tran-~fnrmalit.n" in cui turcd t:c•lls ia tn plant them hack into hu.l animals and uhst•rvc directly Ihcir fwltt•ntial for Rrnwlh, invasion and mclaslasis. A slutly tlf this kind ha% been inauguratcd Ils object is In dcltrrmine whctlKr hislr/1uKical chanRcs induccd by varinus Ircatments of lung tissuc in culture and analol;aus in allllcarance to thoce frn,nd in human lungs at aWnpsy nrc actually "prceant:ert/ut" that is, capable of Ilrugression to cancer without furlhcr mtKlilicatitln by eslern,.t factors 'I hc tlcvclnpment nf culture techniyucs suilahlc ftrr such a purlwne is cnmplicated by the eitfrcrienee of F.ark and Sanford who rel.arled that snmc rrnr.rarnl cell culluret after in vinn cultivation for several gent•raliuns, grew into malignant lumors following retranaplanl into animals. A('uunc'il grant is providing for rcpe•lilinn of this work with special cutentitsn trt the e><clusion of virus conlaminaliont that might have produced such a result, as the cited authors fvxlulated might have occurred. Another new sludy sfltlnsored by 7he Council will nhscrve q,ccifically the chanRes induced in in ritrrr euhures of human tissues by varitlus vuus infections. (:fincer of the Bladder Ikspitc reported associatinns hetween cigarette smtlkinR and cancer of thc hlatldcr in man, animal eapcrimenls involving InnR-term e>tfwltures In cigarette smr+ke cnndcnsalcs have failcd to prtxluce canccrt of lhc hladder. A pmjcct has now been authtai?cd to invesligate, an>,+nR olhcr factnrs. the possihlc rnlc of ahnnrmal tryptophan mclalwdism in the etiology of this diuwsc in human suhjccls with ctlnsitkralion of any cffccls nicntine may prtltlucc ulwln the nx'latxdic (+:uhways I rlcal faclnrs afTcctinR f.crsiucnce ur tJrstruction uf tryllluphan rnctaMllitcs in lhe hladdcr will alal rcccivc attcntinn. The 1'atltngenesis or I nl /'irr(•1 iort T hc ('nuncil's atutlica (in cffccts of nicrlline nr cmtlkinF r/n thc c:utlinvas cul:n sy-,tem have het•n dcserilx'd r:uher lully in previuus Rtywlrt. 1 I1)nl 64 nnd I9t,4 (.S I No hnn cvitlcncc of nny sifrnilit'ant t'rlntril.utitm hy .mllknlp ttr nit'ntint' ttl c:tn":dian t/r :yyrav.uitm td any t':udinv:r.tul;tr th.iaw Ilt.lt cnntrihutcs imlwut:tntly lit n>,lrt:rlity It,lc arl (:u cmcrFcd Ihuul•Il .nurkin)• ha. IK•en rcfxntt•d to prrwlucc an t lcv;ltiun in frcc futly ucid% in Illl' I1lINNI ccrrmr, lhc irnhlit'alinns 411 Ilris t'llrt t wilh rcv/K•t:t Itt :uly influt•nrc tnr atln'rtl Rcnt•vis are in dialalte Flevalir/n tlf .crunt free fally acitls is a nrnntal flhy.inlrq•ic:r1 rc.laln.e In slrtss, and cvidinrc nf cvcr:d kinJ. /rtlm.tudica Iwrlh by 1 hr ('"nncrl anJ 19

many t+ther arcncirc have herct+)hac failctl to chnw any cnnuihuti++n by smoking to the prnRress (+f athcrtrctlirucic thc chief (d thccc have hccn as ftrlluws 1 I he fatlurc of chrnnic nict+tinc at)minictraunn to accclcrate athcrn. sclerosis in anirnale fed on atherogenie thets 2 1 he relatively low incidcnce of earditrvaccular tliccasrs amttnR smokers of t iRars and f+ires, who are believed tn absorb nrctrline in amnunts similar to those absorbed by cip,arcrle smt,ketc 1 Several routine autt,lny e>taminatinns (if ctrrttnary arterirc chrtwiny no significant difference in the deRrce of sclertxis Ixrwecn snn+kerc and non smokers 4 ihe inditatittns (if efitkmitrlnRical atudicc that smokcrs tlcvelop angina Irt turis no more often or earlier than non smokcrc lhcce findings aPrcarcd to t.c sufficicnlly convincing to suggest that the fulure prnRram td 1he Cnuncil ehttultl he cancrn,rated more It:trlicularly trn annthcr aSlKct nf the iuhcmic hcart disease frrthlcm, nanx•ly invcsliRa tion of (acrnrs that precipitate acute "hrart atracks" For want of any Ix-11er Icrminnlt+Ry, thic /icltl hac been callctl "thc mcchinicmc of Ihrtrmlxt.ic and (if infarctinn" hor the purlx+ct- (if taking ct,xk td the aate (if knt,wlcdre and crrncitlcr inR such nSw trhjct tive., as well ;ts Iw+ccihlc tcchniyvec fr+r attiming them, a ('rrn(rrrnrt nn 1h.+r.nAmrr and Inhrrr rnnn - I'.rdrtl+nun~ ( trndunmt, I'rr tiprrnrinR Farrort nnd RLwrd ('uaRulanon I'hrntrnrrna ot 11hrv Afrrv Rrhur ru thr ('hnir al F.tvrrt. was hcld nn lunc 10. 1966 lleeides memhen of the staR antl Scienlific Advicnry Rt+ard, six reci/ti ents (if Rrants in ficldc related to the Itrhic and live Rnest «icntists partit:ihatetl 1)r Ira (iorc, Professnr of f athttluRy, btrclun llnivcrsily Schtxt/ of Medicine f)r. Kenneth A Moscr, Assictant Professor (if Metlicine, Cenrpcttrwn I Iniversity Medical Schtxd 1)r Ftlnxond A hlurl+hy, Sthtx+l i+f Mcdiiint'. Ihc luhnc Ilnl+kinc ltniversity I)r llctathrl SantllterR. Radiiri.rdnl+c antl ( r+.ipularum tir+Unm, 1)ivicitrn ttf ( ardirdtr/y, 1'Infatlt lldrur (it nrr.tl llrnltrtel m v+ I)r Iouic A Crrh+ff, Prnfecatrr t+f ( hniutl Mt rht inc. I crtn/+le I Inivcrcrty Mrdit.1I ( cntcr r-. © I)r Robert I Whulvrn, n.cixi:ttc I'rnlccct+r r+l Mtthcinr. A•~i•tant © llircttm t+l tlic (:uJinvacr iil,ir I ahtndtt+ry, I)ukc llnivcraiy m ~ Mcdht.tll , ntcr ?tt r. I f)r Marin Ilaldini, Pawtucket Memorial Ilncpital I1r Kenneth M Ilrinkhous, St:h(wl of Medicinc, ltnivcrcity (if North Cartrhna I)r Ilyman fnRclhcrR, ('cdars of I,ebanon Itnspilal 1)ivicitrn, ('ctlarc Sinai Mcdical ('cnter I)r f-hcrhard Mammen, Wayne State University ('nllcgc (if Mcdicinc I)r. Ira SinFcr, Assistant [)ireclor of Medical Research, Anrerican Mcdit:al nsvaialion A full day of discussion elicited a number of practical suRRcslitms for rclevant investip,ations. It seemed to he the ennsensus that while atherrnekroeis Icnds in general to rrcdisrnce to inlarclion, there are many cases of advanced atheroulerosis in which infarctinn is never ohurved, while arnversely infarctitm may take place in cases where relatively little atheroselerosis is present Morenvcr, infarcliun often occurs without evidence of Ihrombus formation and vice versa. l he hope of pinpointing any pnssibk contributory effcct of nicntine or other specific agent thus seems dependent upon hettcr elucidation (if Ihe mechanisms by which infarcti(xt eventuates. One new study of thrombus formation in vitro has suhccqucnlly been approved, another is under eonsidcratavn, nd additional suggcstions are still being received. Sufnequenl to the conference on the pathogenesis of infarclinn, a pre liminary report was released from a nine-year Council•aupfxorled study to determine whether the degree of arterial sclerosis found on autopcy of acci- tknt viclirns would show any correlation with their smoking pracliccs. A positive correlation was reported. Snxtkcrc and nnn-srnokers, however, are knnwni to differ significantly in their relative practice of alher life habits that might influence arterittcclern sis 7 hey are also strongly suspected of differing significantly in ctmetilutinnal makeup and hasic physiology. 1 he new findinR thus apl+eare tn impose the need for ctill hulhcr t+har vatinns antl exlx•rimentc in which all perlirxnl (actnrc can Ix• cnnlndled and h:tlancetl timOkirrg, Irrrs(r:rt(rlify, .tirylr (rf /,ir(r (rrl(I I,n1,grriry Sint'e the lirct I+nhlicalinn (if rytidcmitdtrRical studicc crvrclatml' ti/,.t rcllc cntt+kinp wilJt mt+rtality frnm «•vcral tliseau•c, a h;nit rlnccunn 11.0% trt,uhlcd many ctienu.te arlcmlainK tt, ascccs the mcaninp td thcsc ttmcl.r 21

Utrnt I hit yucstirrn it, •'llrrw muth do smttkcrt anJ mm cmrtktra drllcr alt:ut Irnm Ilrcir snrtrkrnR PractitW" In any anima} ctutly, the enfvrimcntal and crrnutd Rrnul•c :nc r:mJrrm iYccl to halance all dillcrenccs ttthcr than the one factrrr whuce clTctls were trt Ix• astc•tacJ -(tn IrmRcvity t+r any othc•r trait Ilut this, (tf cnur.c, it nrtt the cau with the (thtervatic+ns on human groups Smokcrs and non .mrucrc tclctt Ihcmaclvcs on a hasis that is still esxntially unkntrwn 1hc m.rn who Irkcs to snxrkc cigarcttcs and elects to do so may dilicr in many ctrngcnit:rl Iraits from the man who tJ(xs txN core !n smnke, and may indulFe in ncrny ttthcr activitirt (.r rractices to a ditlrrcnl dcgrec ( r/,arcllc srmrkinp nr.ry therrforc lie a rc/fit nrrn n(  whnk tnnatcllrtit+n n/ t h.r;n trrituts whit It in turn larxlut c thflrrrnl hattcrna nf living 1 hcse tongrnrt.tl Ir,trt. anJ rlrllcnng Irlr ttylt's' may thrmtrlvrs influrnte krnRcvity and nuuhrdrty rtlvncntc I hr need ltrr rtrt( rihinR the heavy tn,.rkrr of ciRarrttcs, thc light cmrrkrr, the ciyar tnsttkrr nnJ the prrr anwrkrr• at well as the r>,rn un(.kcr, in rcrmc rrr Ihrir Iattcrnt of living and Irhavrn, anJ rtn a hrrtad hatit, f.ct't+mct intrcat rrrply imhrrlanl PLmt In c.pand tuth alahct aK untlcrway 1 hr ( nunt tl hat iIrratly alw.nt.rrt it a nur»}n r of invcctiFatitrnc inltr thc drflcrcn(cs t.ttwtrn.rn,Acrt anJ ntrn triwlt ta, nr tK•twt-cn hcivy tnrnl+ttl.rvc tmukcrs antl c.i n.tl •nurkrr, r.r h,lwr,n t•rl,r :urJ tq•.u .na,kcrt a~ crrm frlrcrl tn lr('.drt Itt' vn,4 t rt tu/•I•, •rr., Innltl tY r•.,,n.rirly. ctKial ha}rllt, (\rCC/ .r It t I ,n nr rrr I I•, L.„r rr J n , t~ ,Ir}t, r I rt t,.r. I. r.r txcn rclxtrtrd lhe ('nuntil it nrrw f~~nrr rt-erurp tn r L•rtt• tr tm •t... lv r,l /.itl,n% .ta Iht'y miy rrlatc to hrnFcvily in a ptqpulatu,n r,l ttttr.tn< «'Inlt' ncc I,rrnt.ny rc. scar(h it /trosPcctivc in nature antl will t.c ttf IrrnR rluralittn, a aut.vdary ttntly of rclrotlteclive character has Iren undcrt,ken in the hope of finrliny tlnet and RuitJclinct Five hunJred reccntly tlrtcascd suhjcc'It are IrcinR invc.ti Ratcd with resf.ec't to a large num)xr nf facttxt, irxluJinR tmnkinR, thnl mil•ht havc inllucnccd IcnFth of life Sirxr thc numhc•rs (tf faclrrrs that mipht Lc int'IuJed are excecdinRly numernus, it is htqvrl that Ihe Prt'liminiry curvcy may help sh(rw which t,ncs are nxnl likcly to t.c w(alhy of furthcr invcttif;t lit+n and re+carch An invcttiR:uinn of this charattcr will Ithvu11/\Iy 1rl.llc heavy drm:rntlv rtn ttnnlruter tet hniyurs in analytit 1 hc ( nuntil Fh:rt nculc a Rrant trt aiJ rlr vt l lrmt nl uf nrw anJ mr,re stq.hi%litalcd ctrnyrrrlrr frrrq•r.umnrnp ty.lcnta, inc IutlinR Ihc "t IutlcrinR ,cchniyuc'• lrr rrMnin in/rrrm:rlirrn, tul•Frt/urnt antl ruitl:tntt• frtnn ctl+c'rtt, a (nn Irrr nt t' ht Itl tut April h, 1'!hh (,.nlrrrrrr e rur ( "ntrhrurronuf I u, h'r t tit Rc(nrrd ro ltrtca.tc Recidcs stafl and the Scientific Advisory Itt,ard mcmlrrs, five grantcea and nine guests were present: l)r. RrrRer K I.aru>n, Chief of Medicine. 'The Fresno ('ounly Gcncral I lnsl.it al Mr. ('harlcs 1. Rose. ('rxordinatnr, Normative Aging Stutly, Vclcrans Administralinn Outpatient (7inic, tiosttrn Or. ('arI C Scll?cr, 1)cpartmenl of Nutritiun, Harvard University Schrxd of Public /lealth 1)r Sheldon ('. Sommers, Professor of Pathology, ('oltcge of Physicians and Surgertnc, ('rtlumhia Univcrtily Or ('ar(drnr Ilcdcll Ihomat, Asxrciate Prnfecsur of Meditinc, SchrKrl nf Mrdn inc, 1 he )uhnt Ilopkint University Mr Kurt Fmlcin, ('(tnsuttinR Ungineer on ('amputcr Systems, RrK hcttcr I)r Alvan R Fcinatcin, Associate Prtdcssrrr nf Mt•dicine. I)epartmcnt (if Internal Mcdicine, Yale University Sthord of Mctlicinc Dr John W. FcrtiR, Profesanr of (lioslalisiics. Sch(wrl of Public Ilcalth and Administrative Mcdicine, (•olun,bia univercity Mr Marco hiorentinn, )he University of le>tas-M 1) Andcrartn IlnsPital and I unxu Inctitute Mr I~tlward A I.cw, Vice President and Actuary. Mctrnlxtlitan I ife Inaurance ( •ontpany Mits Annic M. I.ylc, formerly Actuary. lhe Prudential I ife Inturanrc Company Misc FIcannr 1 MacdonaW, f-Pidemird(tRist,1'he I/nivercity of fcxaa M 1) Antkrsnn 11tnPilat and 1 umor Inslilulc f)r. I hrtmas F. Mancucn, Recearch Prufcacor, I)clt:utmcnl tr/ (kcuPatinrnal Ifealth, Gra(luale Sch(wd of Puhlic Ilc:dth, l Inivcrtity nf Pittchurph hr. Ilcrnicc (' Sachc, Medical Stafr, Group Health (•linic, Scattlc FnllnwinR thic c(rnference, /(wr new studiet were inaugwaleJ and other promisinR fwxsihilitics were lucated for cnnsideratinn. Oral CRvity Rr?seRrrh As mentioncd Itrevinutly, ('auneil sludics of carcinnRcncsit in 1he oral cavilict of mice havc ahown thete ticsucs to Le far more reai.lant Irr txnr- pyrcne than the +kin While liver tlamaRc tuh.tantially ahtutt•ne thc inrluc titrn fwritKl hrr cantcr hrrwluttirrn hy Ihis hytlrtK'artwrn cithcr un mrru.c akin rrr nral mucut mcruhranc. Irrhaccrt smr+kc ctrnJcmalcs hnvc an far latlyd lit inJuce cancera ineide the ttral cavitiea rrf mice evt•n in Ihe Prcacncc rd %ut h liver imltairmcnt 1 he rect'mblance IK•twcen the (nal mucus memhranec and the ti.wre nf !hc lung w(tultl it,IK•ar ttt t.c mnth t'htarr than that IM-twccn tkin :mJ IrurK Since. mnrc(rvcr, thc rrlal tiauc•c arc rtLrtivcly murc actcctihlc tu rrh%crv:r ct, (T ~n 2 tn

ritrn than the IunR, an intemive sturly (if their rccf.nnce to variouti kinda (if challenRe would apf+eat In oflcr Prtimise (d ohacrvatimnc mrrrc rrlrvanl tn the lung than skin studies On (kt<Mt.er 16, IVhS, a cnnference was called fur consitkrinR the Rrde of Oral ('avity Rrtrarrh in the Srudy of Tobotrn I/lc and l/runcnn Nralth fle6dcs memhers of the s1aR and Seientifx Advisory Ik,ard, the following scicntists were prescnt, including three previous grant rccipicnts: f)r. E) Fichel, Director, Institute of Slomatological Research, Science Resourecs Foundation Dr. luli Meyer, AsxKiate Professor of Oral Pathohrgy, Ilnivcrsily of Illin<tis School of 1)entistry Dr. Martin S. Prtrlrel, Chief, Ikputmcnt of Oral PathullrRy. Newark City Ilosritul Dr. 11 Fl (-hauney, Profcsaor of Oral Pathology, Tufts llniversily School of Ikntal Medicine l)r Bernard K Forschet, Puhlicalions Scclion, Mayo (linic 1)r. Paul Gtddhaher, Asutciate Profesatr of PcrirxluntahlRy. Ilarvard llniversity School of lkntal Medicine 1)r. F. 1) (inldsmith, Prrfcsaor (if Ilickrh.Ry snd Research ('cwirdinatnr. New York llniversily Schrad of Iknlal Mcdieine Dr S Kre.hover, Asarxiate Ihrectrx, Natitrnal Institute of 1><ntal Rc rearch flr 11 M Mycr., Prr+fettinr r,l Oral 1lirrhrFy. l!nivrrsity rrf California Schrwrl of tltntittr y Mrs Rrtse Marie PanFIon, A«ktant I rwxl lethnttlrrRnt and I ccturer, l Inivcrsity of (-alrhrrnla 1)r. Shtdrrm Pearlman, Srcretary, ('rnrncil (,n I)cntal Rrsrarth, Amer- ican Dental Association 1)r. P. Perxm, ('hie(, Sfrcial Dental Rescarch I atwiratnry, Veterans Adminititualion Flnspital, hnK,klyn f)r Anthony Pieonl, I-t (ltl , 11 S Army Rescrve 1)ental (-rrrwc Dr Gurdrtn 11 Rnvelstad, 1)enlal Research Fatility, ll. S Naval 1'rain- inR Center, Great 1-akcs. Illinois Dr Sheldon Rovin, Asst.ciatc Prrtfcssor and (?rairman. I)rparlment rrr Oral ParhrrloEy, llniversity of Kentucky (bllere (if Ikntictry Dr Alf.erl 1. Russell, ( hicf, I Iri(icmioloRy & Fiiometry Branch. Na- linnal Inuitute of 1?ental Rc%rarch f)r Mrrrill G Whealt'rnfl, Asa(Kiale P,fc,or r,f PaUu lnpy, lhc llni ver6ty (if Ietas 1)ental 1lranth 1)r. 1 A Yacovone, (lrirf, 1)ivi%ion (if Ikntal 1'uhlit' Ilr:rlth, RhrK1c Itland Ikpartment of Health 1 Ilnwinp Ihr cnnfrrence. a nrw fnr+lrct w:r% inin`rrtatrd fm rsrtailrrl I ath d~ir.rl tturly r,f trrrnnn nal tit.urs in .rn.Arrt anrl mm imnkrrs ns wrll ~a aati ti :J rvaluatinn i,f ct,llrtlrll trcmil. ,f ~ur'h ctimin:Niim; An ..-l thi lin.~l rr.pmirt rrf •t-IN 4 1 ..nll"Ov I PnKluction in animals and humans in response ta tobacco vmr,kc ta smoke crtndcncate cxl.rttures was undertaken. Studies of possible eflccls (if trrhaccrr smtrkc on mctahdic processes in the oral ticsues were cuntinuctl Inviceliga tiun of liver damage as related to oral cavity earcinogenesis was intcnsilicd (:hrortic 1'ulrrt(ntary 1)ise(rses The study of chronic pulmonary diseascs such as the various forms of hrnnchitis, ssthma and emphysema is an important and growing part of 1 he ('ouncil's program because problems of differential clinical diagnusis, dcfini- rrnn and nomenclature have greatly eumPlicated ellorls in the past to con- dtrct nreanirrRful epidemiological and other studies aimed al discovery of clues in the etiology of these diseases. A long-tcrnr clinical study of chronic respiratory disease patients is being suProrted with the objects of improving clinical description by bio chemical tlata, function tests, drug reslxmse ohcervations and radiuingical techniyues -1lte course of developnxnl of the various diatinRui~hat,le syn dromes is heing followcd and in vivo data correlated with pott murrern eRaminalinns. Sludies of pulmonary surfaetant, its oriRin, naturr, functional tnlc snd rclatirtn to chronic dieeases are being sFxmsored in several Irrrrjrcls on a long range hasis, with correlated eleclron microscopic rrhservatiuns of nurmal and diseased tissucs. 1 he possihlc role of certain congenital en?yme deficicncies as a factrrr in cmlrhyscma lucdi.l.enitinn has been undertaken in a new study An e><Iduratiun into familial prcdisptrsition In cmPhy.crnj is being cnn ducled by clinical study (if siblings of chronic reshirah+ry di.ease palicnls in comparison with their marriage parlners as controls. Previous annual rrfxuts have described earlier ('yuncii sWdic~ un Irthaccrr smoke inhalation and the respiratory physiology o/ normal Lcnnns and (if patients. New srrics of controlled animal studies have hcen authrrriicd fnr furlher cxphnatitm rrf thc chn+nic cflccts uf long term cuntrrdlcd inh:d;ttrrrn Irf cinKlr F.:r.cs and yaa mntures, as they mly Ihrrrw IiFht un .uch rc.pualmy .h.r:rwN in m:vr (•larence ( rM'k I iltlc, Sr I) 1r rrnuF, l)rerr rrrt Rrrln•rt (' Ilrvkctt, I'h 1) Atlrrrrurr lrrrrurfl, Ibr.- r,,r 25 ~, , '

111rstracts of Ileports F'ach rrripirnt nl a Rrant in aid (rrrrn The ('mrncrl fnr Irihtctrr Rc- srarch - 1 1 S A it rcil•rnsrhlc fnr thc inrual prescntatnrn tu I+uhlhcatnrn crf the rrsults of his rrscarch at scrcntifrC mccthnRs or rn a(q,rnrrialc scicntihc jnurnals FollrrwinR are ah.tracts, approved by the authrvs, nf rc(MUts rrn ncw cuPcrirncntal rescarth acknowlcdRinR supfxxl from I lrr ( rruncil th;rt h:rvc alqKarrd in scicntrfic r+urnals since publication of thc 1964 65 Rclwat uf the Scientific 1)ircctnr 1 hrsc abslracts have hccn 6rnupcd untkr thr frdlrrwinR hrarlinRs I Psychr+ PhysiohrOical Studies, II ('ardurvascular Sturhrs, III ('arcrnrr Rrnrsrs Studics, IV Srudies at the ('rllular I evcl, V I/,rdcmirrhrRy, VI 1'ul mrrnary 1'hysiohrRy, VII Chcmistry and Hir.chemnrry, VIII F'harmatr+IoRy and Ptychu Pharmacolr,Ry, and IX Other Studics A numher of yrantres of I he ('ourxil (rir 1'ohacco Research - 1I S A ParticiPated in the 1-uurlh Annual Symposium nn lahxco Alkaloids and Rtlatcd ( rrmfxrunds, hcld at thc Wrmxr (irrn ('cntcr, Strrckhulm, Swrdcn, in Pehruary 1964. uunder the auaprccs nf the Mcdic'aI Adviaory ('(runt'it of the Swedrsh Tnhacco Crrnrpany anrl the Inhacco Rtsrarch (lrmmirtre of the Swcdish Medical Recc.rch ( munt rl 1 hr I'rrx'crrhnRs were puhhshcd hy I he Macmillan ( nmli:rny. New Ymk ( rry, in 190 the (rrllrrwinp (ialrrs acknnwlrJprnP (-IR 1ISA %ufywrrt arr rrvirws nf work larvinnsly rrj-rtrd 1•y Ihr .rurhr r.. :rnd al,pr.n rrn Ihr inrlit:rlctl PaRcs of thc (whli0hrd ('rrxcrrhngs "MFI)I('A1. (ISI'S OF 1OItA(Y 0 (1'ASI ANI) PRI:SI N I 1 " Itv /' .C l.artnn and H Sitvrttc ( I 11 ) "1)ISPOSI I ION ANI) FAl F OF NI('O1 INF IN ANIMAIS " fly I/rrh.rr M( Krnnir Jr. (S1 74) "MI TAIIO1 ISM OF NI('O1INF IN ANIMAI. 1ISSIIFS IN I'IIRrI ANI) IN !'IVO " Ily N Papadrqxrulns (Grantcc F. ( llo(J). 110 I IlW ) "1OIIA('('O AI KAIOIl)S ANI) ('FNIRAI NI: RVOT1S SYSIFM 1:11N( "1 IUNS " Ily I' S l arrrm and I I Silvcttc ( lllt 124 ) "SOk11 11111 nVORIAI. A("11()NS OI NI( ()I INF " fly I Jr.wd I 1b,nvnrr ( 145 Ihh) "IOItA('( (1 AI KAI OIUC ANI) ( II2( 1tI.A1I()N" 11y R I RrnR. A ('uhrn and G Itlurmc hrn ( 241 151 ) f ) `C()C\11: ( (tMPAI(AIIVf PIInRMA( ( )1 O(cl('AI A('tl()Nti OI: NIl OIINI , IItittl'II/ AI 11uM/ R, r\NI) RI I A II I)( t)h11'(r1 Nl>S" I1v I ih. n l l Ir"-- ( 1111 111) I. I'1yr•leo_I'hyeiuloRir•td Studi.'ra "1 OO1) PRI I:FRI N('fi ANI) SUNS11IV17 YOF I AS I F FOR Iit 1-11:R ('OMI'OI(NI)S " 11y 1)r F V(ilanvillc and 1)r. A. R Kaldan, I abnatnry of Mcrlical (icnctics, ('Icvcland Psychiatric Institute, Ohiu. Nurure 21)5: R51-R51, Fchru:rry 27, 1965. ((;rantec: Kaplan) Ihis Vudy fxuvidcs a new method of eslimalinR frxxl prcfercnccs and inwrlves a larger and uldcr study group Ilun prcviuus work by the authurs In (rther respccts, similar dila were rrhlained, in particular the relauvc tasle scrnitivities lo quinine and h n prt>rylduouracil (PROP). A yucstitrnnaire was devised which, in cflecl, nAcrs a choicc Fx•twecn mild, mtxlerate and strongly taslinR melhrhls of InerarinR sclctaed frxxls, in witlc hxa) use, hut which are crrrmmordy preparcd in a varicty nf forms I hc atudy Rroup incluJcd 51 maks and 116 femalcs aRcd 22 to 66. all uf liuropesn descent. lhere were hipFhly siRnificanl ).rtsilive cortelalions hclwcen high scrnrs on the GMx1 yucstirrnnaire (that is, a preference for strunRly lastinR frxxls) ancl high lastc thresholch (Ihat is, insentitive taue) of FxHh yuinine and PROP. llre data sulrf.rxt the conclusion that there is a fx.silive asaKialirrn t 1><Iween increasing number of fiwxls disliked and inereasinR taste scnsirivily .1 he invcsliRation al%o reveals social influences on foaxl Irrefercnce antl dcrn- nnstratcd Ihc importance of perceptive faclors in this respect. (lrh.r /rren(or: National Inslitules of Ileahh (2). "I'ASIF. Sf~NSITIVIIY FOR RITTIiRNFSS: SOMF 11101 (X71('AI. ANI) ('I.INI('A1. IMI'l lCA 11ONS." fly Arnt+ld R. Ka1+L•rn, I'hl), and Ruland hischcr, ('hl). ('haptcr 21 in "Rrcent .LIr•unrrr nr llur6rKirr.l 1'rv- rlriarrv," Vrrl VII, IraRes 1R1-19h, ediled by ). Wnrtis, MI), Puhlislrcd 19h5 by Plenum 1'ress, New York ('ity. ((iranlee: Kaplan) 'This sludy is a review tif data prrvinusly re(xnlcd by the authors (see Report of the Scientific hireclor for 1964 65, pages 26 & 27 ). "('11M1/1.A1lVF I hFF(T OF A(iF. ANI) SMOKING ON 1'ACI 1? SUN SI I IVI I Y IN MAI IiS ANI) FFMAI.F.S" fly Arnold R Kalrlan, 1'hl), and Ftlward VGlanvillc, 1'hO, 1)cPartment tu( Mt'dical (:cnclics, ( IcvclanJ Psychiatric Inatitutr: anrl Ruland Fischer, Pirl), 1)clr;utments of 1'.ychi:ruy and F'hysinloRic;rl ('hcmistry, Ohia State University Mcdicad Schrxrl, ('rrlum hua lnr.rnrtlrrl (:rronroGoRV 20/);)14-137, lUly I9(.S ((ir:udre KapLrn) Nu siRnific;rnt ,pc rrlatrd di/lerenees in laste scmilivily frn quininc rrr frn (. n Pn,lrylthi,mr.u d( F'R( )1' ) were nhscrvcrl in a samfdc nf .'6R nrm smnkinR suhletls (R4 m.rks and IR4 femaks) f.rtwren lhe aRcs rrf ltr anrl SS Nrr ser< rliflrrrntc was alrharent AnxmR 127 suhjrcts 179 malcs anrl 4'1 fcmales) who smrrkrd 21) rrr nx+rc ciRarcltes Per day, a signiticant decrcasr in tave sensilivily w:rs alqiarcnl with increasing age. Within the It. Irr 111 year ay,c Rruup. the taste sensitivity rrf non smokrrs and heavy smr+kcrs Jul nrrt dilTcr, hut Irom this age rrnward a rhlTcrrncc apl.eared which Lec:rnK increasinRly mnre (xunrrunced I hus, aRinR within J ;h 27 r

Ihc 16. Ico ts ycir aRc span dicl ntrl srcm tn t,r a«cx'iatrd with a6)•nificnnt clclcrirtraln,n in taslc srnirlivrty unlttc tnmhincd with smt,kinF 1 hc sca drllrrcncc snnK•limcs rtt.%rrvcd in Ix,trul.tliun survcvs .c•rmcd to he an arti/:tt.t asstx iilcd wilh drflcrrntr:ll smukinF h:rhrts r,f mrn :Irul worncn Othrr Rrantarr National Institules o/ Ileallh (2 / "R1A A11UNS1111' c)F ORAI. FRItS1RA1ION VA('IURS WI111 III:AVY ( IGARVI 1F, SMOKIN(i IN MAI FS" Ry Martin A lacrrhs, Phl), f'etcr 11 Knal,P, MI), l.uken S. Anderson. Pht>, Nathaniel Karush, A11, Rosalie Mrissncr, M11, and Stephen I Richman, A11, 1)ivision of 1'syt'hi- alry, Ilcrstttn I Inivcrsily SchtH,) nf Mrdicinc, Mass I(Pnrnaf .r/ Nrrvrrur and Mrntal f)rtratr 141 '2 Ih1-171, AuRust 1965 ((iranlre Knal+p) lhis paper is a refw,rl r'f two studirs eksiRncd ttr test the hylw,lhrsis that heavy t iFarrllr smoking is in (•art a fune'tion of Ihe nced k, salisfy vicarutusly otal kvel nrede which were /rustuated elurinR early parent child relatictmhips flcavr snrnkinR ia defined as more than 25 cigarettes smokcJ daily '1 wtr qur.ut,nnaires were devchq.cd 1- the suhject's view on how his father and rrwtthrr hrhaved loward~ him when he was a child, each ilcro scnred htrnr O In 1 under thr eonecpls r+f f.rncvnlcnce, over cnnlrttl, r,vrr lut,tcctitrn, incfTcctivenrss. eoldness, antl harahne•ee 11 - an inventory trf the suhjccl's aUitudcs and npinutns, eath itrrn unrcd frnm l) lu 1 on I(M) itcros in the first, arxl (rt,m 11 /r, S r,n 62 itt ms in the i.rcnncl stutly. both cc,n.ttuc,rd tn int'lude ealeRories hY1x,Ihc67eJ I„ Ix• lar%cnl in heavy %.rntrkt•rs and their n(,fKKilct Six factnrs Ihcnri;'cd to hc rclcv.tnt wt•rr 1c1,•ctctl fcu ~litf%lical a11I,rais:J in M,Ih sludics rrtt.thrr scrn as ctrntrt4lrny, cnld, h:tr.h, nr:rl 1,rr trcnf,alit,ns; im(xtucrucncst; d.tnprr «ckinp. Jtltnnrr, am1 nturt,lic rmt,ut,n.,l Iahility In the firat ctutly 'I7 adult ntalrs wcrr t:rm(drtl, (ttm(,ri.iny m.trnlv cnik/•c cJucalctl rnichllc ctass individuals haviny hiRh cthctirn ~nht in Iht cltclrtnras intlustry In Ihr scrt,nd study I lh aJull m:rlrs wcrc ~amldrd, h.ivink c,n the avcraRc nn nx,re than hiRh schcxrl yducalicros, invc,lvcd in factc,ry Ixt,tluclic,n work witll rrlativcly Inw slatus Results c,f Ihc first study intlicalcd that heavy ciRareitc smt+kcrs evi tknce the hi`hest mcan scnres for live of the six relevant fyclc,rs, i e, for all cxccpt Ihr cnnccpt nf ttinprr scrkinp, Ihcrsc high mcan ccnres wcrc siRnificinlly greater th:tn thmc cvitlcnccd by nt,n srnc,kcrs e.crpt in thr inMance uf orality The srcnnd sludv ipain shnwctl that hr:rvy %mt,kcrs cvulcnccll tht• hi/hett ntean scorrs in all calcpt,rics ritr(H in rclx,rts uf ntitt•rn.d hch:tvhn, whrrc ntc>,Icrale smtrkr•rs shtrwcd thc hil'hcsl sctrrrs, :uld in the 11.111 t,f drltancc, c'nntriry kr thc first slutly, whith wj. rm tmvr~lrnt :rmnn)• thc v:ui nus .r»trkinp, nnn arnl ru .m"dinp Rrtnrl,t I ht- tltlfrrrnrcc Ix twrt'n Ihr Incl antl tccnntl %tutltr, are Ix'Icnti;tlly :rtlrthlrlaldt t., thrrc I.rt I"r% t h ml•c% in Iltc tlvr.Litrnnnirr, inlcntlttl 14, 0harl'rn Iht• ttmttllt% :mtl Itt (.t.rltl:rlr tonr I.Ittum ") Ilt, (-i,i~ tltlltrtnttt rrt Il,r I-y,irl.ui'm m.tnt)c.rt'J rn )~rr.rttl rcliu I intttn 11" r .i i"nd ..tml,lr ).tinil, I., I•r.r .~t~t tn(nrtU.rln,n .rlwnrl tmrt I parcnts; and lack nf significance of the cnnstrucls Lrof+rncd as et planaa,ry factors fur heavy ciRareltc snKtkinR. I Icmcnls trf Ihe nver-all concept thal early oral frustralicrn in chihlhrx>,I which facxlucc-, siRns of emotional distress and which is drfcnded aRain+l by imf.ctunus, danper «ckinR and rebellious behavior later in life were Prescnl in significantly mt,rc intense degrees in the rcPrtrts of heavy smukcrs, and in the rc•fxttts nf a cvtmhined Rrrtup nf mrKlerate In heavy smokers, than in the records of non smnkers, mild smokers, or former smokers. Certain asf.ects r,f the defensive cluster, such as rehcllinusness, may hc a function nf demographic faclors and nM intimately asscxiated with heavy snx,kinR in and of itself Other aspects are ennsistently manifested in hc,th studics Further work is necessary tro resolve the issue of the rclcvance r+/ the total constellation as an e.planatory concept. lhe c.planatictn rd heavy cigarette smoking as an outgrowth uf fx,th social reinforcement and inner untesolved oral bnRinRs and n>,xks of dealing with these longings seems congruent with the findings in these sludics, hul has not been ckrrHmstraled conclusively as yet. lhc hyfx,lhcsis is suplxuted that former srrwtkers are able 1n give up the hahit, when it appears apprnpriate In do so, hccausc they dt/ not evicknce a need to gratify previously (rustraled oral impulses, hul further work is required hcre, too, in order to establish the Renerality of this ohscrvation. "Sl llOIfS ON '1 FIE PSYCIInI-(X7ICAI. CIIARA("I1:RIST1('S UF MFt)I('AI. STlll)F.NTS. I. AN INI)t?X OF RORS('f1A('11 RI:SP( )N% _S," and "II AN INf)IiX UF RFSPONSFS'fn 1'f1E GROl/l' RORS('IIA('II TFSr" Ily ('aroline Hedcll lhomas, 1)onald C. Ross artd I;llcn S. hrced, Johns Ilopkins llniversily School of Medicine, Ilaltimore, Md Puhlished 1964 and 1965 by The Itrhnr llupkhet Prrrr. (Crrantee: lhontas) In these two volumes the (+rotocots of SRh sludenls who took the indi- vidual Rorschach test and of 568 swdcnts who tcKrk the group Rc,rschach test have been orRani7ed by means of the KWI(' Index computcr /accRrarn Through its use, the keywords of the Rorschach responses arr listed all.ha helically in cunteut, the resfxmscs thenrselves are lisred by arca, and the frequency of keywords is presented In all, more Ihan 4(/,INM) Rtnschach rea+onses are thus nnalyred lhe work is intendcd•lo serve as a lrame of reference for the fuller untkrstandinR by psychultrpical invcslipaltns of the Rorschach I,rotocnls of similar highly intelligent individu:rls rtr yruul's I lrc tests were artminlstered at a(rart of the hrlncll,al nuthta's hmR trtm sludy trf precursnrs (tf hypertension and coronary discase thhrr Rrantarr National Heart Instilutc 11. Crtrdionrrrrrrlrtr Shulir'a "Rf LFnSI: OF NORI P1NI PIIRINF VR(1M IS()! A 11 1) llt:n!( I S I11 A(T I YI ( II( )1 INV " Hy I-vanFclus I ArtRc•lalrrs untl I urutr lil-wmtyur.r. 11eparlrnrnt ul I'hy.ic,h,`y, Ihr.ltm (Inivrrsily Mt•thc:rl ( cntt•r, f.1.tt% .Irr 29

hn rt lrurrnrur,+rtnh't rlr 1'Irt vrrlntvr• rr dr Hrr„ hrrnrr 7 1' 1 1') 7 41/2, lunc ( ( ;r:tnlce AnRclakrts I I Ihc ciltu r,f atclylchnlrnc ( A ( hI t,n tJtc rt•Ic.r.c of talt•tlxrl.tnuncv frnnt Ihc i«+IatcJ I,tr/uvcJ yurnca prR hcart wat stuJrcJ II w;tS ft,untl Ihat A( h rclc:t«•a m+rcf+tncl+hrinc INI~) intn tltc I,rrlu.atc in Ihc unmcta/x,lvctl ftant Iluwcvcr thc t:rrthac slurrs td NV wcrt• .r/-nrh tanlly lufhcr Inlh,winr Ir•rfusir,n with A( h as cranl,:trcJ It+ Ihr+«' in hr.rrt% fx'rfuscJ wrth I trkc's «+hrlir,n alnnc No tklt•cl:rhlc :rmttunts n/ cl+rncl+hrrnc wt-rc ft+und to Le reka«•J hy A( h It is cMxlUlh'll Ihat fhe 1M+\rtltl' In+,trl+l,ic anJ thrunntrtq,ic cfl,'t'/s td A( h are due to Ihc rclcasc of NI: . cvt n thuu)-h Ihe•fe is n,+ Jcl+lctrun r.t NF tisaue slnres by A( h fl/hrr Rrnnfur: (1 S 1'uhlic Ilcallh Scrvicc "I I F VA11ON OI SI'R(IM ('IIUI I S 11=.R() I AI IFK AI)MINISI/2A 110 )N ()I NI( t) I IN1: " fly Alfred Krrshhaum, MI), Samucl Itrllcl, MI), and Rt+st.tm Kht,rsandran, MI), Urvisrnn of Cardit,h+Ry, I'hiladel/+hra (icn cral IItnl,ilal. I'a Arrvnr on Ilro.r /rn..nnl 6V,'2 1Uh-210, 1'chruary 1965 (Gr;rn,cc Ikllct) I wrnty atlull, hrahhy, mr,nprt I J+,Rs were IcstcJ for hasc Imc «rum chulcstcrr,l and urFlytcrrdc Icvcl, rn L.t%tutR vcnttus hhwxl samldcs l:tkcn daily ftu nne week Nute dr,Ps were yrvrn J.,rly IntfanlusculAf in)ections r+l nicr,Irnc hitartate in a rlycrrur Rtlaltn vtlutlc lur vq wccks at a dusr rate rtl 0 5 mR kR fur Inur wccks and I nip kR Irtr tw„ wcckt In five t1uRs, the Rlyccrin Rcl:uin vchitlc wrthrnrl nrtt,tiuc w,r% rrvt•n d.nly Inr (nur wccks In sL4 t1uRs nct inlcctn,ns werc prvcn tltnrnp Ihc X wctk I,t'nt+rt r,f tht• eR f+t'rirrtenls Ihc mran «•rurn c1u,ItVCrr,l IcvtI rt,vc Itr,m 144 ' 1I R nip Irr ccnt In 216 r IS timR Ir•r tcnt (SI/"3 I in Ihr• rntuttne ucatcd tltrRs Ihcrc waa no siFrtihc:un chanpr in triRlytt'ritlc Icvch JurnnR the atlmini.lratinn of rncr,tine the clcvatiun ttf thr+lcslcrt,l w.tc rn.untatnctl until niculinc a,lmrnrvu:uir,n stt,/+lx•d I hcrc wcrc nn siRnilrt'arrt th:+ngcs in either Rfrtu(v c,f cttnlrtd Jtq{s In Itvc r+l Ihc ninc th,ps rcccrvinR nrcnline, lirnh anJ chcsl Icad elcctrn- cardit,pams wcrc Iakcn wcckly, and the animals wcre sacrihccJ at the cnJ ld the t'tlK•rimcnt Scctit.ns l,l the arrrlic and uf the cnrtrnary and fernnral artcfics wcrc et:tminctl grr,s.ly antl micrtrccuf+ically Nu clet'(rrn'artlitrRral+hic ut I,:rthtdt+ric cvit/cncc of mytK'atlli:tl th•Ft•ncralittn ttt alhcrnsclcrnsis was tlclcclt'J in Ihcsc IIt+Fs llfhrr Rrnrrfnr r Nalir,nal Inctitutca r+/ IIcalth "('IR( 1i1 AI()1(Y ('IIANGI S IOI I()WIN(i P\('I HIMfNIAI MY- (N AIII)IAI INI AR('fIUN" Ity V I: Wcntlt, MI), It Il:tl,t,n, MI). I KrIK•ihnr.r, MI), an,1 1( 1 IlrnR. A11), I)cl+.irtmcnt r,/ Mcdrernc, Waync %Lttt• Ilnivcr6ty Sthrwd t,l fvlcttttinc, .nt1 Ihc Il.trl,cr lfu.l,it;tl, I)clt,ul, Ltnh ( l,:tl~trr 1.1 '~11r, r AA wnd 11v)nrrrn,rr,n "/,vhhthcd I'!l,S, (irunr & Ctr.tlturt .192 d'7H I(:ranrrc IlrnRl Iht,r r. prncrel aRrccrncnt r+n Ihc tirtulotmy cllt•tt~ +I ctl+rnncnt:tl nry„t ar,)i.,l rnl:trt li+,n 7 tlct rca« tl hlraal I,res.urr, tnr,utary hl,ral Itt+w, :tnJ Irnt,n.,ry vea+rl.,r r, rN.rnt+ (.crrh.u „utl+trt rl,thrtc% Lut IK•nl+hcrnl J vaccular rrsiatance either is unchanged or increases It is a1stv widely aRrrcJ that the hcmrKlynamic eflecls in shock ate at kast in part Jue ar a h,ss of funclirminR myrk'ardium, hut additional factors such at failure trf perilrheral vascular resistantc to comf+ensale for dccrcaseJ cardiac oulltut may be important Whcthcr this is under neuroRcnic or hurnural contrtrl is still nrtt known It is alsu believed that in duRs that do tkvclop shock thcre is an inhibition of va«K'nnstriclor reflexcs. 1 he role of other reflex mechanisms in the production of carditrRenic shcxk is slill somcwhat controversial On the basis of the present knnwlcJRe - though there is a markeJ initial tkcrease in coronary blood flow UtlltrwinR exPc•rimental my,xardial infarction, as determined by direct t:orrmary hhxnl fftrw measurt•ments, changes in ct+ronary vascular resislanee, and sckctivt• cotnnar,~{ anRinRraphy - it would appear that rcOcx vastxlilatatiun rathcr tha/l reneR vls/lttrasm lxcufs. I)rhrr Rrnnfnra: (I S Public Ilcalth Service, American 1leart Asstxiatitm. MichiRan Ift•arl Asstxiation, I.ife Insurarxe Medical Research Fund, Ihe Ilurrnughs-Wellcume Fund, and the John A. FlaftforJ Foundation "I:PI'F('T Of KF.IUNF. FfOhIF.S ON ('ARI)IA(' MFf-AFiOI.ISM." fly (? flaaenRe, V. 1=. WenJl, P. Schollmeyer, (i. Itlumchen, S(:udblarnastrn, anJ R. 1 Ffinlt, IkPartnxnt of Medicine, Wayne State liniversity SrhlKrl trf MeJicirte, anJ Ilarl,er I-fospilal, lh'troit, Mieh. .Imrriron lrrurnol nf l4rvri- t,lo4Y 211R/1. 162-16R, January 1965. ((Grantee: ffinR) 1 he cflcct t,f acetoacetate infusion at varying cutxentratittns ttn rnyu cardial mctahalism was studied in I) Jt>Rs. Aceluacelale was extuacted by the my(xardium at arlcrial kvck of from 1 to 54 mg'I(N) nil At attcrial levcls of :rM)ve h(1 mR! 1(1(1 ml, e><traclion of aceloacetatc by the hcart was very small ('nnsidcrahlc amtwnls uf the infused aectt+.x'ctatc were Irlllll'etI lo beta hydrutyhutyrale. Acetoacelate inhibited the utiliialian of free fauy acids by thc hearl, resulting in a ris,e in the respirattrry quotient ttf the ht•:ut An incrcase in the myocardial e><trataiun of lactate txcurrcJ at artcrial acctu:xctatc Icvcls of below 34 mg%1(K) ml. Rclwt•cn 14 and RI1 ntR IINI ntl of acctttacctalc Icvcls, myocardial Iaelale eRlrat'tinn JeclineJ, Ihc kctnnc Ixcame the pte(crred fuel td the myt+cardium •1 arleti.J ncett,atclatc kvcl% tx•Iwccn 14 anJ 54 nrR' Ilx) ml Arterial lFluctrsc Icvt•Is fail gr:rrlu:rlly Jurin(; Ihe exlx•rimenf, leading tn scvcrc hYlKtylycemia the ncR:nivc my,Kartli:rl halanct• nf pyruvate siRnificantly int'reaseJ throuRhout Ihe e.fxrimcnt l'rutr nary hlrxHl Ilnw, hc:nt ratc. left vcnlticular presstnc• mytK'ardi:d ct,nuat'littty. anJ I K(i wcrc m,t a(Icctt•J siy,nilicanlly by arterial acetuacetale IcvcIv t:rn/; ing (rr+ln I ttr RII ntK ' I(M) ntl llthrr RrnnL.r.: (t S 1'uMit' 1lcalth Scrvice• Mi(hrp:rn llc:rrt Ataurrau,+n, I ile In.urante Mrdital (lc«•arch I untl, the Ilurrnu/'hs Wc1tt„rnr I umt, rltc Arnctiean ('ant er Cta'icty, the A M A I'IlUtatrlHl anll /lfteflrt II 1 nurnl,tln+u and the lnlhn A I Iarlfrrnl F,wntlalinn i "IIUM(11)YNAk1I(' AN11 MI: IAHOI I(' ITl V('IS OI ('lIK(1N11' Ital,h.rrl I1.J+++n. A1.('OIIOt.1SM IN MAN " Ity V I: WcnJt, ('lydc Wu. ~,. „ tt) 11 tn ,~

I I (iordnn Uoty, and R J flrnR, Wayne State Itnivcrcity Schrrd r,f Medit;ne, nrl Ilarrer IIr,spi(al, fkunit, Mith .Imnrran /r,urnuf rr( ('urdrnf qv IS.'j 174 184, f rhruary 1965 (Grantcc II;nR) A group of 14 men and 1 wnmen with histnries nf hcavy alcoholic inlake of I(1 to 30 years' duration was studied lhc hcmralynam;c IinJinRs shnw distinct diflerences among the cardinmynpathic and cirrhnl;c f,iticnls and Paticnts without liver or clinical heart discau 1 he consistcntly negative myncardial balances of isocittic dehydroRenacc and malic dchyJrnpenise would appear tn indicalc that intramittxhnndrial cnrymes are affcctcd by chronic alcohol;sm even in patients without clinical, hemodynamic or other biochemical evidences of heart disease. In patients with clinical alcoholic cardinmynpathy, evidence has f.een presented which Indicales hrnxxlynamic as wrll as myrxardi:d cytnldaamic and intramitnchnndrial mtlaMtlic alterations It wrtuld a/+pear, tht•rcGue. that frequent fK,ut1 of acule akohnlism might result in I,crrnanent atlcra- tittns of mclah.d;c pathways or altcratinns in m;trtthtmdrial mr•rnhrane rt•r- meaf.ility, the direction and maRnituck of which await further detailed investiRation Othrr Rrontnr.: 11 S Public fkalth Scrvicc, American Flcart naarx'iatinn, MichiRan Ilrarl nsar.ciatinn, I ife Inaurance Medical Reaearth I unJ, the Rurri,uRhs Welltr,me fttnd, and the Inltn A IlarlfnrJ Pnundal;nn "IMMIINOI (X:I(-AI I Y PRl)1)tl('1 1) I YMf'!1OP1 NIn " 11y (•hiyn ('hiha• M Rnacnhlitt, )irl, Yammn:,k.r I'.1ul IW.M. 1: It:rcarnrc. and R 1 fling. Wayne St:,tc I tn;.rrvty .d M'J„ mr :u, l Il.irl„ r llrrt(,it:J, f)elunit, Mich 4rrhrrrr ~'I Inlrrn,il 1/..Ir rrv I I< S ttH Sr.1, N1ey 1'/hS (Grantee ItinR) I.yml,ht,prnia was prrxlutrd In Jl,p, f,y nrlu mr an rtwr atite nf immunily aRa;nat their own lyml'hrr.rl tclla I hr.c lynrl,hoitt tl ll, wcrc matlc antigenic hy couplinR with humin y Rhrhuhn hy means nf a hiahamf,cnri• dine linkage Peripheral lymphorylc count dccrcaaed by 41r :, In 91)'S• of the enntrol values In sonx instarxes the lymphocyte count relurned tu, normal levels afler three In ten weeks flislnhrRica) e.aminal;nn nf aplccn and lymph nrxle showed a marked depletinn nf lymphoid cella I lumnral and cell Ir,untl antifanlics aRaina the animals' own lymphoid cclls were demnnalralc•d Oth.r Rrenfnr.r US Public Health Service, Michigan Ifcirt Aacocialir,n, Life Insurance Medical Rescarch Punt1, the RrnrnuFhs-Wcllcr,n.e Fund, American Cancer Society. A M A Ftlucation and Reaearch fnund:rtinn, and the Inhn A llartford Foundation "MYOSIN SYNIIIFSIS IN CIIRONI(• IIf:AR1' FAll I IRI " 11y (•. 1)c Sthryver and S Gudhjarnasnn, Ikf,arlment of Mcnctinc, W:,ync St:rte Itni versity Stluwd rd Medieitx, arrd Il:rr(x•r Itu.lrital. I)rurrit, Mt, h I'.,n rr•dlnK, nf rhr S,NIrrY for F rprrimrnrul lli„hrjev un,l Mnhr rrrr 111) 4'lb1 91,1, nuRuN Srl,trrnt.rt 1965 ((;rantrc R 1 11inR_) I t•ft hc.,rt Lnlurc waa I,rirrlucctl in r:thl itc hy t' rnatritlii,n f tht iaccntl 12 0 0 t 1 . rp anrta Intnrfvxation of Cyslinc-S"' into cardiac myna;n, watcr .rdulde cniymc., Idaam:r l,rnrcin and skcklal rnust•Ic lautcin w:n .tuJrcd I hcrc wcre no airniticant drtlt•rt•nccs hclwccn Ihc ralc of tynlhc.iv uf Iclt vt•ntricular rnyovn and Ihc othcr Prutcin (lactions ohlaincd ttntlcr cnntlitirrn% od heart failurc, a% cnrn/,ircJ to thc.•rmc protein fractions in the normal animll (hhrr Rrnnfnr.: 11 S Puhlic 11t•ilth Scrvicc, Michi)'nn Ilcarl A..rxiitinn, Ilwrrnrrhs Wr-Ih'nnx Fund, Arrt<rican ('anccr Stkit•ty, A M A I tluc:tlir,n :utd Rcsc:trth I nunJ:rtion, anJ the John A. IlartfnrJ Foundation "1111? IISF O1 POSI I RON f;MIT f FR IN I I11: . I)F.ff:RMINA 1ION Ot (•ORONAI(Y III (N)1) 11 OW IN MAN." 11r All.crlrt('rtht•n, MI), I dward 1 lalcaki. MI). I rtk hitlmar Luchs. MI), and Rich:ud 1 IIrnR, MI), Ih•/,art- ntt•nl nf Mcrhtinc. Waync Statc llnivercity Sthrwd of Mcditirtc, and llarl,t•r Iln.l,it:rl, IA•truit, Mit h/nrnrr.rf of Nut bnr Alydir rnr 6'! 651 hhh, Scl, Icml,t•r 1965 ((;ranlcc' Iling) 'I he cnnccl,la undcrlyinR a cr+incidcncc cnuntinR mc,hrx) hn thc mcas urcrncnt nr cnrnnary Lhxx) flow uainK -'Rh, a ptr.itur,n cm;tlcr, i% dc.crilK•d ('urun:uy 1,1tKxI flow ia calcuL•ucJ by Ihc IuF:uitlunic cslr:ynd:,tinn of Ihc myrx'attlial clt•arancc valuct n( "Rh In ?crtv limc At Ihis tirnc, Ihi myr,.:udi,rl cR(roctinn r:rlio ic unity. Ihc accuracy of the mrthrxl ha% hrcn c.t:ddi.hed in cuprrimcnts nn Ihc ianL•ucJ JuK hc:ut. All c:dtul:tlir+n% auc nhjccuvcly I><r- fnrmcd by a digital comrulcr. The resling cortmary hltNxl flnws in intlividucdc alrwc anrl Lt•hrw Ihc a(;c n( 4(1 :tnd in milcs and fcm:dcs wcrc not st:rli.lically ditfcrcnt In addition, /hcre wcrc no siynilicant ditfcrcnccc in the tt•aling ctnorruy hhwxl Ilows in I+aticnls with and withr+ul coronary artery diacase 1 lie r,hccrvitirm thal suhlingual adminitUation nf rtitrnFlyccrin ;ntrcaccs thc curunary hltw>,I flow in individu:da willxtut comnary artcry tli•c:r.c wlulc failinc tu incrca.c it in palicnts wilh coronaty arlcry dia':t.c h:rv Ix•cn n.cd as a diagnc,at;c Icar in the rcrnFnitirxt (if coronary :ulcry disc:r•c. (Irb.r Rrnntnr.: II.S Puhlic ffcalth Service, A M/1 Ftlucntit,n and Rcsearch I oundalinn, and the John A Ilartford houndatinn "lllf? QlInNlIlnf IVF n1i1FRMINA'11ON O1' ('ORONnl(Y 1:1 OW WI I II A 1'OSI11(()N VMl l I I R/R111111)Il1M 94 1 " Ity A(-t,hl•n, I I' (;:dlaFhcr, 1: I) 1 uchs, 7.. Varg:r, I Y:rmnnal :r. I' I 7ah al l. (; I1lulru hr n and R I It;nr, Ik~(ralmcnl yd McJ;rinc, W:rync St:rtc Itnivcr.ity tirhrrd rrl Mrdicinc. :1nr1 ttrc Il:rrfx•r Ilucf.ital, I)c(roit, Mirh ( uruLulorr t; ./ tllt, (r4'1,(hurM•t I9AS ((;ranlcc ISinr,) Art nhjct'trvc nx•IhrKl frrr Iht• yn:nNit:Nivc rncnaurcmtnt ul Ih,• trnrar.uv hlrwxl flow in nd tn;n u.inp a cr,irx iJtncc t'uunliut• .y.h m whlr rul,r,l,um N•t a Iwr.ittnn rrmlrr r, i% rlrauilK•rl I hc t,.rnnar y bl Nwl flnw we, c.rlr ul.rtrJ hy llte ctlrafn,l:rrir,n of Ihc clr:u:mct• v:rlut•. trr n•ro Irmc At Ihra lunr thr nryr, t•:uJial c.tr:rtta~n r.rrrrr ~d rul,;rlnnn R I i. un;ty :rnrl t Ir.u:urtr i. r~l~t.~l tn (I ~w l lrc at cur:n v~If Ihi. rnclh"Kl waa dtrrnrr~.tr:rlcrl rrn thc t• rLrtrJ I'r tlu.r l dog hcart 33