Tobacco Documents Online

42 ~ TR HN 0 11577

I . I I I I r m m 1 THE COUNCII, FOR TOQACCO RFSEARCII - U.9.A. r

~. : Organizatipn and Policy r ~ TAe CoundJ for Tobacoo R.eseuth-U.S.A. ia the sponsoring agency df protpram ot re.eares Into questSoos of tobacoo use and health. It was :a', organbxd e" (a 1954 by repres~eetatlTa of tobacco maoufacturcn, I;!•' vvwers and warcbotreeea. Rres..rck h.npported through a program of r '.' A 1ci.etl6c Ad.boq dovd to The Couocll adminiaten this grantF b-aW pc>tr.m. The Board cvrteotty consisu of eight ncientl.ta and doctors 1•So .ralotaln tbcir respect).e Inathutbnal amdatlo.n. A list of the Bovd memben appean oa a.ub.equent page. ~ The Scientific Ad.isory Board has full n`.ponslbiihy for rrse.rrb po1ky and prtgnmminf. As a Board It dod not directly engage in research for The Counci), nor does The Council Ft.elf operate any research facility. dnntsin-ald for research are m.de by the Board to Independent ocl- eati.b who are assured ccxnpkte scientific freedom in conducting their ft.earch. Urantoes alone are responsible for reporting or publishing their Mdinp In the accepted scientific m.nner-throuRh medical and scientific /ootnab aad societies. or.nts by the Board through 1965 have been mack to 280 scientists In d t 100 h l i' Th T i i d h awar s mtrtut,cxu. se 6ran a e wsprt , u.n rexarc era r..% o+rer Te*s t , an 4 .i' . . e..e.trA t! 7M (Wl ' . . i,.,,,, - .... - .- ..... F..,,- ...jrF,,,..,.. .,y .- ............ .. ...~..,..~.. ... -rV Ihi. Report. Also Included are abstracts of 64 research paptn, acknowicdR- InR Council .upport, that ha.e ppeared In scientific journals since the ~ 1964-65 Report .nd through [)ecember 1965. A total of 465 such pqxro ~ have been published by Stant recipients. T1M(YT1fT V. ItARTTftt7T W. T. HOTT (balrvn.e F:arcullvr 1)Im lor T11E Cl)IIN(:11. FOR TORAC(:O RF.9F.AR(:11-1/.9.A. 633 Tbird Avrnu., New York, N. Y. 1()n1T i y I ANNIIAI, RI':1'(1RT of the SCIENTIFIC I11RF,(:T(1R CLARF.NCF. C(/(IK I.ITTIE, S...1).

SctENTtFtc AtrVtS(1tiY tlOArlt/ to 1 hc ('nuncil for 1 nhacco Rccc:rrch U S A KI NNF 111 Ml RRII L LYNCII, M I) , Sc 1) , I I. I) ,( hnnmarn ( hunr rl4+r anA I'rofrtior Emrrrlut u( !'othnluRv Medical College of South Carolina, ('harlcztrm, Stiuth ('ar~rlina '1'Altl.N: oF <:I /N'I'f:N'I'ti e HOWnRh fl ANpFRVnN1', S(' D. ScirntilSr Frfnor, The Journal of the National ('ancer Inaotutc NethesJa, M aryland I RI(IIARI) 1 IIIN(7, M h I f'ro/rrtnr ond ('hoirmon, Ikl+artmcnt nf MrJr(inc Wayne Statc llniversity ('ollcRc of MeJrcirK, I)ctroit, Mi(hrgan I I I InlnKluctirrn S hc Prtrrrctt anJ 1'1;rmtinl; ttf Rccc:uch K le.h.v;rctt nf Rcl><,rt. 26 M< KFFN CA 1"i hLL, Pn D, M 1) ~ I'rn/rr)rv Fmrrilut oJ Phormot nlnRy P.ychu Phyiitdngical SluJic% . 27 ('orrxll llniversity MeJical ('rdlrRc, New Ynrk, New York I ~ ( arJitivatcuLu Studies . 29 l.hON 0 IA('OI1SON, M 1) I)ran of thr I)rvivnn of Rrnlnqn of Sr rrnr rr ('arcinrrgc•ncvia SluJica 40 RrRrnrrrin 1'rn/rnor nf irl 1, rrn, rr I l lnivcraity nf ( hiciRrr Studic. ;rt thc ('cllular I cvcl . 41 !)i.rrrrn, ArRirnne ( antt'r RctrmiIr Itivtpii.il ('hicaRo, Illinoit I IriJt miuhrry . . . 44 ('I.ARFN( 1((x)K I 11 1 I I. G I) , I 1 I) . I rr t U I'ulnurn;rry Phy-,iuhrRy . 46 .Grrnrrfir Ihrrrtar, Ihc ( rruncit hn Ir~het( n Kc•t•.nch I SA f)irr((nr Fnvrur.r, Ruu'trc I( )acksun Mt•nurnal I aMuatury I ( hcmi.Lry nnJ Ninchcmi.try . 49 lfar Flartx,r, Maine I i SrANLFY P RFIMANN, M I) , Sc 1) ' Pharrnacuh,Ry anJ P.ychn t'IcrrmactrhoKy SI anccr Reccarch f)irrr m. Frnrrifut, 1 hc Inalitutc /ur ( OIltt•r StuJit'% . S7 Philadclphia, Pennsylvania I WII LIAM F RIFNFIOFF, la , M I) I I'rn/rfror Fmrrirur of SurRrrv )nhnt Hnpkint l)niversity SchtKd rif lvlcJitinc, ttaltirntrrc, K1aryl;mJ Rct'ilticnlc nf Gr;rnl% SV R(Hlhf(1 (' II(K Kf 1 1, f'rt I) I MrtHRISUN I11(AI)Y, M I) A rroa iolr S rrnrr/rr I)r.r( nrr f t r,-, mnr .Ir vnrr/r, I)nrr hor r

Int.roduction l 7 ...3. .f.. t 1 L.~ ~ <r, d ~ a, t1 ~ In the 19(,4-hS Report it was mentioned that over the yCars er<reri- + mental and clinical evidence to support the thesis that cigarette smoke ercr- ciaes a direct carcinosenic cffect on man has not been forthcrrminR After reviewing another year of research this slatement still eppresaec the state f of uar tcicntific knnwlcdRek fivcn fat•d'a-1ed or cprecled epidc•mittktFicr+l evidence whic'h the ciga rctle carcint+Fcncsis hypothesis rcyuires, such ac a narrowing trt thc gap In•twccn dr.Hh ralca from (unR cancer in the sexcc, owing to the Rrc:rt increaac in amtrkinR among womcn, has failcd to maleriali?c. Indead of appearing at increasingly earlier aRca fnlhrwinR an increacc in smoking among younger people, the peak age of incidence t+f lung cancer shaws, if anythinR, a shifl toward oldcr age Rroupc in recent dc•cadca I In addilittn, a numher of studics throw doubt ulxm file accuracy or diagnosis of primary cancer of the lung in a siRnilicant fx•rccnt:rRc of caaea• ac refittrtcd on death ccrtificales. Thccc ctudics ahuw that aa high ac IR-211'S, nf rcctxded c:nKera of the lung are actually metaataaes rrf cancer from t»hcr txr:rna •'1 hcse eludics highlight the need for widespread and concerted effort to cstahlieh more accurate and more uniform methods nf tccording thc incidence of lung cancer. Recording of this sort chtwld he a haaic Iwhlic he:rhh recla,naihility Similar prr+hkmc with respect to accuracy trf diaRmraia are encnumercd in the study uf the other constitutional di.c:nec which have been rcptxlcd to he associated staliatically with eifarclte Sm<tkinR Such Lrnhlcme are marked in file caec nf file chronic reapiratnry diacaas where lirm clinical atandards and dea'riplinn have slill nn/ Ix•cn dcvchqx•d It ia obvious that reliable cpidcmicrhrRy mual fx• Irrcmiacd tm rcliahlc diacacc incidcncc and mortality data. Ac mtne and more medical men and I:Jwtraltrry rca•:trih wtnkcra rcc riFnirc :tnd Lcctrnrc familiar with the ctrmplcnity c.f hurnan Fcnctiia. o muth mtrre reatiatie :rttilude k LcinR dcvc6qa•d hrwird file nct•J of huther anJ nurre rctincd atudiea in this ficld lht•rc ia inirc:rainR rccr+Rnr/itm Ihal in thc dt•vt•Inprnt•nl rr/ tmn.trru tirtnal dr.r:raca, auch aa IunR eanccr, inJivitlu.rl Kcnctri tli/firentt a.ric irulaut:urt I hc iJr•a th.rl thc pcnctii ha•ia rrf di.ra.c t riltin nru.r I•c .1 vml4h• Mt n dch:rn I ht nunrrmm Icra Itmr, ht•t•n nhatrlctr, hul Ihc :rb.urJ. 4imrnr id thi, S

unat,hhiatrcalcd tt,nccpl nl Rcnctics h.ra IK•rn Painfully tlt,w antl t,F.alrutlivc It, a rmxc rcalialic undcralinJinR td Iht• cnml+lct n:tturc trf Ihc yrnrtic crtilc and prt.ccs. I ach t,rr:,n tyttcm and tiacuc r,f any inrliviJual h:rt itt t,wn '•Lvill in•' level ttf atucnFth anJ of wcakncss, t+( autccrluhihty t.r t,f rrai.t:,ncc u, thc rhallcnrct t+r the cnvirnnmcnt, tM,lh from cxtcrnal fatttns anJ frrtrn imrrrctl unh:,lantct r,( function. (•t,mpirativcly few people •re sn cnnstilutt•d th:rt :, ttm,l'lcrc intcrnal halancc hclwrrn diflcrcnt r,rRan aytlrmt and lia.uca ia m.tinl:,inrtl Grr nine t.r Icn tlct'atlcs r,f aginR tt, that they c't,mt• In Ihc rnrl nf Ihrir Irlc ":,II at nntc" and at a fhal:mcrd unil S.,me ty.trrna, Irkc Ihe rrltrtKltativc, arr Iim,IcA hy Ihrir inhrrrnl n:rtutc Irt a thrntrr Iw ritr.l t+l activity than art• tHhcrs Hut trll aytlcma cvrmually .httw the cti(-ttc t+/ the wcar and Icar t.f lifc And il it Ihc t,rdcr in which. anJ t•.Irnl tr, whith, thc v;,rittua tnRan ay.tcntt and liaaut•a aKc atttl aht,w aip,n rd dnnin iahinr, irrcRnlaf tv ahnr,rmal luntut,n, that reflecla the Rcnetic pallern with whith the intlividuil it cntk,wrd Vcry cvitlcnlly thctc cai.tt a vaat numl.cr t.f, ia yct, htllr un.lrr.trwxl tyht•s and drrreea rd imenel.,tirmalul e Iytwren r,rFln .yatcma and t.etwccn thcir ct+nrl-ncnt liaaur. Ihcw tornldrt.rlt- iny tlter :rnJ "au:u/•ht Iinc" rclitiunahrf, IK Iwr cn Ilhc /tm. Il,.rl nntlt rht' nrr:tn ttr (rtCUC I4ttl'lltJallll(•4 and Ihcir fni,Prt.avc JcvcLy,nn nt ,nJ .nlln.tmtnt rn tfu• tt~mfdt. :mil th:,n~ inR ct,amtn ur Ihc ,ttthvitlr,:,l't Iwuly Ilut Ihc hral .Icl• townrtl Iht• cvcnlual an:dycic anrl wiac utiWititm nf rhr •rtuanra, n lu rcttq'.ntic 111.11 it t•ai.la the in,linl phaset t,f the t,rRaniralitm of mtnc cttcn.ive anJ rntcnaivc rcac~rth in thia hclJ arc umkrw:,y fhy I hc ('t,uncd In I,l:,nninl! Ihn ftrtrFr:,rn. consultation with thncc nr,w active in this type nf rescarch h:n hcc n cstah- lithcd and will t.c continued I he rcrsiatcnt slrikinR e.ccts r,/ IunF c:mccr in m:rlrt inJie,tcs II,:,t (nrlhcr knowlcdRr of cnJt,c'rinc cttnthtit,ns which accr,mpany Ihal diccaac is tkairahk Not nnly thc Ronida hul Ihc pituit:ny, :ulrcnnla antl IKrhal,a rtthcr cndt- crinc p.Iantla may, if rnnrc carcfully c.:,mincJ :,t aulrq,ty antl tltning thc ItrtKt•+t rd aFcinF. Rivc hiattq+atht,LoPical cluct lu hcll, in Ihr an:,lyaa t,f the t,h.crvcd ua dillcrcnce in lung canccr int'itlcncc I hc tlutly r,f r•nth.crinc lvnclit,n :,fqdica nrtt nnly It, the tlwly of Irmy cantcr F.ut tt, tNhrr Ir.rma uf tantt'r antl tt, certthnva•crrl.u rliu.ra a:,. wt 11 N1rnh rrnnc infnrm:rtittn ia nrct)ttl t,n II,t• trtrnlr:,r:,livt• h,.l rlr:rlhutnyy ttf v:,ruruc nrR.,n v.tcmt and Ua.uct whrtl, n,.,y Iw th.vattt•ri.tit ur Iht•.c tlr. r.ra a m Iwrth .. tr. antl •t drllt rt•nl .rt•r. t In auc•h alutlics we arc again faced wilh painslaking, lirnc cr,nwminR retcarch, hut the sountlncss nf cflorts tt+ ohlain as ncar ly a cunydclc /,icttnr uf dtc intcrnal hnrmnnal funcliun as is I+r,ssihic cannut fx yucstioncJ '1 he infr,rmatit,n Ihus ohlaincd will incrca.c uur recaFnitiun r,t Ihc cnmplettity r,f Ihcse tliscascc, make clear thc J:mRcr uf ovcrcml,hasis t,n any single fac•Inr in their etiology anJyhus dcvclt,p a rational and cr,n.trutUvc st•nse of scienlilic and lay persrectivc ca+nccrninR their utrgin, dcvchq,ment anJ evenurally their prntfa,ncmcnt or prevention. / hc past year has been charactcr'vcd by an especially inlensive cflorl tn analy>'c langress during Ihc (ast thirteen years of I hc (•ouncil's f,rr,gram ('rilit•al gal,s in knt,wlrJRe slill rcmain which nccdctl ttr l,e t'Icarly Jchncd, anJ cr,ntcntraICJ hlanninR has been umkrlakcn tn tlcvclt,p mcthtwl. wluth may fill w.h Raps and prnvitk murc dkcisivc au.wers to Ix•rarslcni kcy queslions. 7 h

'I'lic I'rc~bress and . Malltllllg of ~~CSC~Ii'(l~l "The Council has consistently placcd cmphasis urnn direct studies of the respiratory systcm tisstxs, both in animal rrx~kls and in human patients Sincr ncnplastic druaxs of these tisnucs and partit ularly in t1rc• IunR are of sf+eeial errncern, prtrhkms enncerninR the etiohrRy ol (+ulrrxin.ry carKCrs havc received malor attention Inlurl~ctt(rn Stu~li(~s Ulnervatinrn of the consequences of exfrrsinR the lunRs rrf eafx•rinuntal animals tn whrrlc frcth ciRucttc smr+t.r have tn•cn a significant Part of lhc ('auncil's f~rc~gram aincc its carlrcct t+cRinninRs Such stuJits art Ntill being cnntinucd, cnlarRrrl and rrhnrrl Icn ycars of I~t•rsi.tcnt wr+rk by several independent ( uuncil clarnaurcd rnvr.trR;dra. and rnany rrthcrs, h:r.•c srr f:rr failed to dcmr+n~tratc the tkvchrhmr nt r+f clridcrnuud I uln>,rnary tumnrs in a variety of animal species following .uttr dnett etlwrwre trr ciRarene smuke by thc inhalatirnr route. Smrrk~ Conden.atYa in tlr~ Lung 1 hcse whole smoke inhalation cxrerimcnts have been snrplemented by nthers of a nMre e><treme and kst "phylioh,gical" nature in which rrrn• Acnrnrcr nf cigarette srsx>ke were inlrrxluccd inlratracheally into the IunRs of scvcral sf+ccics in various kinds r>f sotutions, su.f.cnsiom or cmulsions, both by ('ouncil sf.rmsored investiRatnrs and by rHhers While thcse exl.eri- ments do not rescmhle any situatiun normally cncrruntered by human~, they sre of scicnlilic interest in that they have not Irrrwluced cancera of the IunR, nnr have lung cancers been produced by snwrke crrndensates dehvered to either intact nr damaged IunRs by the inlravenrrua rrrute On the nthcr hand, carcinrryrrnic ~rlynutlr.rr hydrrrcartwvrs such a mcthvlchrrlanrhrcnc and hcnypyrcnc have I+rrrJuccJ canccr% when intrrrluccd into thc Itunl-. rrf Ir.rnnlcrs nr rlut'ks in simil:rr srdutirrrta rrt emul.ron~, and alcn ..hcn nrt~ttrrl urlritrnrru.ly into r:rtc wrth infarctcd IunKs I I I J Cnrn/te ('.rrr.lrruntrt ore nnt SmoltP 11 mn.t l.c• crnlrhatiirctl that cumlcnsatcc nf ciFarcltc smrrkc arc nrd cquivalcnt to wlurtc fresh tmnke in cithcr phy.ical or chcmical (trrqK rtics ( hcmical inrl f'hy.ic;J altcratirms lakc place. .umc ral+idly, in snurkc Irrl Irrwinp it% furnr:uurn antl Ihcx crrntinuc in the contknsatc altcr cnllcctirrn Nrrt only Jrr such crrndcnsalcs lack all of the Ras hhase inRrcdicnts rrf smr+kc hut alur arm(• nf its nnrmal val+ru constitucntt. Shur1-lived caml+rrncnts r,l hc%h smrrkc may not survivc rnntknsatinn and sturaRc, while thc Idrysical %tale of thc smnkc acrn%nl is nhvinusly quite diflcrcnt from that af a cnn dentatc I hc ncRative results of thcse etpc'rimcnta with smrrkc crrndcnaate uc nevcrthcrca% intcrestinR scit•mirrcany sirxe stmx uf thc cvtmlwrncnlc nf srnokc, includrnR :rny It:rccs nf fvdymKlcar hydrocarl>,ros, arc Frcatly con ccntralcd in Ihc cnntkna~tcs so that the tknaRe uf thcsc is greatly incrcasc•d whcn condcncatcs arc uu•d I)iflr•renr. Rrhrrrn Skin an.I Re.pirntory Trnr•t T'i..ur. The skin is ohvipusly a very diflcrcnl ticaue frrrm thc mucu% crr:ncd ti.cucs of thc• rcapiratory syslcm and would f.c cr<la•c/cd to -hrrw rhllcrcnl rccltirnccs to cnntacl aFcnts. Such diffcrcnccs h:wc rccc//1Iy IMCrI Jrmon aUatt•d, for crtamhlc, by exl.crimcnls shnwinR th:rt thc mucu. mcmhram% nf thc oral cavity in mitc arc much mnrc resistant to Ix•nil+yrcnc Ihan Ihcir skins whr n M,th li..uc% are Irt•atcd unJcr parallel crrnditirrnl wnh idcntic:J tlrraca rrf thic anh.t:mcc ( iycuctlc .nwrkc cunt/cnsah•s h:rvc l;ulctl :rltrrl•cther tn Intnluce canccra in thc oral eavitic% nf the camc Strain nf micc :n any drr.apc cn far attained Mnrcrrvcr, hcalthy intact rtxlcnts have failed to tlcvclrrr Luhnon;uy Iumurc whcn suhjcclt•d Irr tln• inhalalian of Iturc funx•c of mcthyh hnLrnt!ucoc ur IK•nrl.yrcnc, althnuph thc•ac tuhslanccs arc I+rNCnt muu.c .kin c;rr.inrrl-cn. Sut'h dirct•t rrh.crvatirms dcmrrnstratinR dram:Nic ditfcrcntcs in .ut cchtihility Ix Iwccn .kin and recpircNrny Ir:rct tiawcs hr c.ut innl•cnic ;p•rott place acvcrc linrit:uiuns nn the uccfulncss a( akin cilr rirncnt. in thc stuJy of lung cancer ctirrlrryY T'he 11ca.rrrr•m.•nt nJ LnnR T'iaxnr E;x/.rr>,rrr.• trr 4nrr.h.~ I)urinp thrw rrn rrr mrnc yc;na rif /vrai.trnt .turly uf tr~h:utir rnnkr inh:rLrtirm hy arunrel., many inytrrrvcmcntc in tcclmiyuc h.rvc Ircn nr.rJc hy a numltr of invc.tir:rtrna Ncvcrthclc.c. a majrrr rlrllirully hcrclulonr ha, been Ihr' I:rtk r f:rnv qu:mtil.rlivc 0hµ•ttivc mc:nrnr• nf Ihc acrual ctlrnurc 9 R

of lung surfaces to smr•ke, esf+cciatly to the parriculatc phasc, in cithcr ani- mals tit humans 1 his lack has prevented rkvrk+l+mcnt tit ar)cquatc infrx- matinn on dr+se response relationship In thc case of human cpidcmioh+Rical studre•s, dcf.endcncc has generally been placed on data derived from qucstionnairrs, fxrth as to the claily levcl and kind of smoking and as to subjective impressir,na of the cxtenl of inhala- tion of smoke A recent Council-suM+cxted study, not yet Puhlishcd, has shown the very pcwir reliability of such recall data by comparing the results of sevcral succcssive interviews with the same subjects at intervala A sepa- rate ('ouncil spnnscsred study has suMesled a suhatantial role nf psychn- kgical attitu<ks in modifying replies to questinns ahout smoke inhalation Practices I hese fmdinRt further empha.i?e the rneed for an nhicclive hir+chemieal methrxl of estimstrnR smoke e.fxnurr of Ihe lungs ('onfcrcnret on mcthrr- drrkrRy have t.ccn hcld, s dcxrrhrd in earlier Annual Rcfxxtt, and uveral r.(+L.ratnry studics have been set up Gime fanRrcts in mcthrx3rdoRy haa been made in Ihc case tit human suhjccla, who quitc uniformly inhalc anw+kc, if they d+r, frum the oral cavity with admiuurr tit trn tr+h+rty vr+lumc• tit air taken in thrrnrFh the nasal fras- saRes Since h+rnun suhlcctt can rcy-md to afv+kcn inclructinns. the hhxxl levclt of carM+cyhcmrrRh+hrn can hr rrlatrd tit al+c•cific numhers of inhaled or uninhalcd (,uf1a, taken t dclrrmrucd intrrvals I his may acrvc as a nxa- sure of Ihr dcRrrc r+f cnnt.cl of alvcr+lar aurfaccc with Ihc fis Phaac rrf anKtkc If the usual mannrr of human amr+krnR maintaina a rclitrvcly fircJ ratio between particulate matlrr and Ris f+haac cnm/wmenls of the amr+ke until they reach the alvre.li, the e.Prnure of IunR surfices to /+arliculate matter couW also he estimated as a fust apprnximatinn, from blood carhrtayhemo- Rlohin kvcls. It still remains, howcver, to apply this and other objective analytical methods that have been under development to a auhstantial laof.ulatinn rd human smokers to assess the variatinna in actual lung ea(xraure to particu- latcs, as a check aRaintt questinnnairc infnrmation I he cnmparativc IunR er<fxnures among typieal ciRarctrc amr+kcrs on the one hand and the •:mrrkers nf Pifus and ciRars, nn the othcr, still rCmaln to tic exl.hued aa Ihcy may he aRected by the various puffing and inhalatinn ptaclicca of individuuls within thcac Rrnufn With animsls, the I+ruhlcm has t+rr+vcn Ir+ ln- rur+rc ditfiruh tKralltc nf their Orncral f.raclicc r+f inhiling tnu+kc thrr+uph the nacal I+aa.,rfca Irn rtr dr•nla, thccr I+acsapr. liltcr srunc fM+rrn+n r+f thc I+:rrtic-ulate maller a+ Ihat the (ati++ tx,wcrn I+.nt++vletca :rnJ F.rt Id+.r.r cr+mlM+nrntt rd Ihc stnr+ke is moxli r t fied in rassaRc and the ratio as it actually reaches the lung is unknown Mnrersver, tbc ability of rodents to suspend respiration for considerable peri.xls of time is a complicating factor. C'arhn><yhemnglobin levels have been measured in the bloa.d of mice following vari<ws smoke inhalation procedures, and the levels have been shown to indicate substantial contact of lung tissue with Ras-ples-vaf+nr phase ingredients. The presence of nicotine, an ingredient chiefly of the particulate phase, has also been denfonstrated in the lung following such srnnke inhalation 1 hese measurements shdw that stnoke has reached the IunRs in substantial amounts Nevertheless. quantitative estimalir+n uf the particulate phase esposure from earbor<yhcmo6lobin levels in the bkxxl will not he justified unless the ratio between particulate matter and Ras-plus vapor phase as the smoke impinRes on lung surfaces, can he determined by snme objective method. (:on/er.nce on TKhni7rrea for Bxl.oarrre of F,xp.rirrrentnl Anirnale to (':iRnrette Smoke Inlsolation On April 21, 1965. a conference was held to consider the improvement of techniques for ex fxnure of experimenlal animals to cigarette srnnkc in- halation Participants included several recipients of ('ouncil Rrarus who have been involved in cnnduetin6 animal inhalation esreriments Iksides memhers of 'I he Council slaff and Scientific Advisory Hoard, several chem ists from tobacco processing companies were present to provide technical in- formation afx)ut the chemical and physical properties of tohaccn smoke Sev- eral guest scicntists representing the fieWs of engineering, pulmonary physi- ology, pulmonary pathology and other rekvant disciPlinec ako anended: 1'a.riripanr. (other than Roard and sta0) Or. Ilollis (iG liuren, 1)irector, Trudeau Found:uinn, Inc 1)r. Young ('hu, Research PhysinHrRist, Philadcll+hia (:cncral IL+.I+ilal 1)r. Arthur Fursl, Uirector, Institute of ('hemical flirrh.Py. ttniverehy ul San Francisco 1)r Ircnc PGrddrinR, Ik'Partmcnl of SurRcry. Allrrt l inacin ( rrllrpc of Medicinc. Yeshiva llniveraity I)r. I crmar+l (irccnhurR, I)cparuncnt (+f 1'rcvcntivc anJ Fnvirrrnmcntal Medicine, AIlK•rl 1•instcin ( r+IlcFc of Mrrhr rnr, Yeahiva l/nivrraity 11r F Itr.mhurRcr, 1'reaidcnt, llir+ Rcat•arclr lnditutc, Inc 1)r Cccrlic I curhtcntk•rycr, I)cl+iruncnt of ('ytr+.hcmr.try, Swi.a Inali tulc Irrr I xIKtrmrmal ('anccr kc.carch • II 1()

11r IlarnhlN Maclarland,Scmrrr Inucr~lr~~r.t,lla~lcttut I ~lwrratnrict, Inc 1)r hnrdc A Mclvcr, Atttnratc Prrdcttur tit 1'ethrtluRy, Mrtlhcal (•rt1 kRc of Sr)Uth ( irohna 1)r, Martin S PrtrVCl, ( hicf, 1)cl.artmcnt td Oral I'athttlrrRy, Ncwark (•ity llrrtpital Ur. Robert 1 Ryan. Department of Surgery, T ulanc l tnivcrttty Schrxtl of Medicine T)r C f larold Stefrce, PathoM6itt, C-af.c f car Vallcy ITtt%rital T)r. flernard Teah, Asuxiatc Oircctot, I rthund I.afxxattuy. University of Noire T)ame Mr Richard Wallon, ('onsullinR FnRincer, Ilmton Dr. Russctl W. Welkr, T)ircctor nf LaTxrratnrict, Menntrral Iltnl+ital ttf ('hctter (•ounty !)r. William W Nates, Jr , T)irector of Rcscarch, I.iRReu & Mycrs 7 ohacco Company Mr Robert (-arpenter, ('oordinator fnr Biological Research, Philip Morris, Inc. I)r. Ti S llarlow, Astittant ManaRinR f)ircclor-Rescarch and Ikvclopnxnt, 1 he Amerr(an I uhaccn (•tanpany 1)r lamcs 1) Mold, Atti%tinl Ihrcclrrr tit Retcarch. I itrRctt & Mycrt I nb.ccn Cnmltiny I)r II II I'.rmclc, Vrtt. 1'rt'r-L nt 1' I r,rrlLuJ l nntLanV. Inc I)r Murr.ty Scnkut, Itucttru r,t kr.r.u, Ir Il I Ittyn.4J. Ttrhactn ('nmltany 1 rnnt thc drtcutwunt, ccrt.trn I+r rnt rpit ~ tit t.tmc tlc:tr I Mechanically generated ciRarette srrntke mutt lie hrtxlucerl under conditinns clntcly rctcmblinR thutc in human srnttkinR if it is to apprnttimate tht phytical and chentical prttqxrtict of the trrxrke as it is in halcd hy humant lhis teyuirct intcrmittcnt huflinR at tuit:thlc inlcrvalt with rcRulation of puR volunx, duratinn, frcyucnt y, and lcngth of hult left unburned 2 CiRarrtle smoke, aftrr Reneratiun, chanFet rapidly with tinu in cer- tain prnf.erties, ntttohly p:vUClc ti?e, :tnd tht+rt hvcd irtFrt•dicnlt 3 Tn aPprmimate the conditions of human Imrtkinf. Ihe smoke must hc• diluted with an appropriate volume of air before contact with the bronchi and IunRs. Fxtreme conditions of exfxtturc, as to undilutcd snxtke, may he justified fnr cerlain laboratory exT+crimenlt hut, in such cases, cnnclusinnt with respect to normal human experience obviously cannot he based upon such observations. 4. Smoke produced by blowing air through the burning rone tnward the hun end is of essentially the same compotiliun as that produced by drawing the puff from the bult cnd, provided that free burning is allowed between puRs, and that the volume, duration and spacing of pulls is nm mtxlificd S To better approaimale the ratio between particulatc matter and Ras- plus-vapor components of smoke encountered by human lung sur- faces in ordinary smokinR, eufxrimental animals should he induced to inhale through the mouth rather than through the nose. 6. To maintain the conditions described in 2 and 3 above, animalt should he exposcd individually rather than in groups. Suhscyuent to this eonferersce, new and improved mechanical devices fnr e>lfxninR animals to smoke inhalation under conditions more closely approaching those set forth above, have been developed •T hey are currently under trial and adjustment. A solulion to the mouth inhalation problem in mice appears to be imminent and tome prnRtcss in the quantitative meacuremcnt of lung ex• rnture to Parliculates under standatdiYed eondiliont has been achieved Smoke inhalatinn e>trcrimcnts sfx.nsored by The ('ouncil in the futurc ahould have the advantaRe of slandardi?ed cquipment and rnethrxhrlnRy where this is dctirahle for Purrotes of comParahility. Cnuncil studies of the eflecls of inhaling the gas plus-vapor phase of tmnke free from any particulate phase are in proRress for crmqpariwn with the efiectt tit whole smoke inhalation Such invctliRatitmt are Ix•inR cxtendcd to compariamt of smnke inhaled from cigarette tobacco miRlures with those frunt typical ciRars or (.ire lnhacco rnialures, in (rrder tu attett tlrlTereniet rd any kind that may hc ohterved in hinlnRical ataivily. may disappear lhercftxc, rrtt•charut-.tlly ycra•r:ucd tmr+kc mu.l lie dclivtrcd to Ihe aplartpriate tittue tit the c.IX-nmcntal :tnim;ra witltin a carefully enn- I'rr'(lisll(r.eirtg 1'if('t(/rs irT I,urrg (:rrr(•inr,gr'nr'siS trrrltctl tirnc IKtind hdhtwinR formalitut irt thc hnrrtinR 'Prrnc Ihi% can Itc ' ~ adjnttcd by rcPulalirm tit thc drUancc In•twccn thc huntinF nmc antl thc 1he rctkt:tncc ttf heahhy inlact nxlcnts ttt inhalcd /unrct rrf Irurc car ~ anintal with al ltrnl ti.ttr crrntrrrl rrf Ilrrw r:trc and n.c rrl :t cy.tcrn that cinnycnit• hydrtKarlarnt, tuch at mcthylchul:uttlucnc and IK nilryrcnr, 11.1, m m tn a.r,t1k .rPlnr r.. t,l, t"rr rl•n.ttmm .,r r r:tl•InnF n( Ir:ntit ularct crt tuutc hcen mcmirrncd Ilrtwcvcr, intrtaluUinn uf tuth hyJrrK'arhrrnt unJcr trrnrli 13 e 12

.. 3. .a:r. 0 ~"d\ '..°; a, tn !D ... © rinns that insure pcrsistencc nf cnntac't havc o-r,mctimcs f.ccn f0h•wctl by afi/a•arance of canccrs Snme of Ihc%c Iciltniyuc% havc alctr invr,Lcd varir,us tkRrecs (if tissue tlamaRc nr Lrauma lhcae e.l,crimrntal finJntK% have Rivcn risc tn sreculatirnta cnncerninR the rnles that may t.c Id:tycd rrwne pcnerally in IunR cancer Rrnesis by factnrs that influcnce the efTic'icncy of the mamil IunR• ckansinR mrchanisms or by lung damagc ft,llrtwctl by rrRencrative ac- • Irvity Such sfa•culatinns have been extentlcd ill cttmidcratitm nf the lung cancer problem in man I he esisfence of rretlisf+cning factors to human lung carcinr,m:. is cug Rcded by many cf,idcmioltrRical tth.crvatir+ns nf thc human situatir,n 1740 or atl, it is nntahk that only a minnrity trf rcrsnns eR f+ericncinR crtrnparahle rw fatsurrs In varir+us envirmnmcntal eRt•nts tkvchtl, cancer nf the IunR Set drlTerences in int-itlince td the di.case suggesl a rttle hy hnrmrtn:tl aectelirtns in faedisfanitirtn Othcr enek+crine deficirneics or exccascs are supRccicd by stuJics of lunp canicr paticnls at autt+psy ( hrt,nic nr refK•litivc lung infee- tit.ns• f.ctsiVCnt ta't tilt virnve, damage ttt the liver, ehanRee in the efficicncy t f Ih r It• rh „ ' t a ~ c c tt rntlthcGal syatrm, nutruunel statns, altcratitrn rn mutus ct,mfwxitinn. aIlctp,c rcat lirtnc, an,l innrrtncr:rhlc r,thrr fac,tus inc Iudinp cven I+aytht,b,pical chiractrri%hcv, hivc tvtn f.rrq-cJ aa I,reJicpo,-,inR tn cancer ttf the lung 1 hc invc lir.tti„n t,f f., tmn (,r, J,y.,.rnp rn t.ut m„rn:t nf thc IunF his Ihm Ix-cr,mc fn intI-ntant 1,.irl „I I h, I r,nn, iI ti f,r„/•r:un In animil c.l,eri mcnt%• thc t'firttt t,f nrcth.rnt.al lunp 1re,nna im1 ,ir vunc infrcunrtt :rre al rcady undir stndy irt cnml,in.rtn,n ..nlt mh.tl.rth,m t,f .mnkc trr ntItcr :tpcnrs In humans, a new irtveatipati„n uf ht,rrn„nal /acl„ra in Itulmnn:rry cartin<tma has t.ecn initiatcd, which will cr,mhnc rn ht,Khcrnic:J t+h'.crvatir,ns with f,ntr rn,nlem e tamrnation of cndrrcrine gland riasuct frtr hylK•rUry,hy, attt.Phy or other chanRcs ,Inimnl AfrrtleLt for LrrnR Cnrrln(IFrltrArt/ Ctlltrrr'1 A truly adcquate ecf+crimcntil :rl,l,rnith In Ihc hrrt:rJ Itrt,hlem ttf /trc dislw+.inG factnrs, httwcvcr, wt,uld al,f,c:tr ill rcyuirc .clcttn,n nf anint:tl mrKlch suit:thk fur use in sy.lcnt:tuc. Ntcp hy vcl,• a/q+r:u.al uf numt•rttus intrimtc and c%trin.ic factrns that m.ty int'IC:r%c t,r thcri:r.c au•ccl,trhility Aoatiof:wnry animal tntNkl 0unA,l /,rnvitlt ntc:uts t,f In,.,ln.irya hi% t„In/•it.tfly I,ulm„n:rry tntn„r :tt i nuntrnt:rlly.uh.l;n,tt.tl an,l rc I,rralut il,Ir It a I I+rcli r;thly rn .ivrr.r) thllt•rinl .tt.tin% :uul %I,it ic. A h;cJ an,l " t,ht .,I,L •,•h ,r, nl In•n ill ,t tn Itl~ ,I .11 a tr,tl.d,lr IrtiI in i mentinR or diminishing eficcts of superimposed singlc facttrr mttdificatinns Once adrtptcd, such a test system should, of coursc• hc maintaincd with out basic change throughout a long series of screening tesrs in order to maintain comparability. lhesc facts make selcclion of the screening system a rather enacting choice. Several fxnsibk systcros are presently undcr evalu ation or trial ffints and leads deriving from the use of such animal models in system- atic testing must then he employed to suggest ohservatinns that can altprt.- rriately he af plied to the human siluatinn on a clinical basis In turn, such ohurvations might suggest additionll qucstions that can Le explrtrcd with anim:.l m<xfels. • 1,rrng (:IenrRnrt' Phertorrrrmr Among the factors that influence the rates of clearance (tf fnreign matter from the resltiratnry tree is the activity of the cilia which prrtfxl the mucus hlankct with its normal hurdcn of inhalcd dehris out of Ihc lung 1 frc (•uuncil is participating through granls fnr the basic study uf rhis clearance phennm enon and the factors that inerease nr tkerease its eQit;iency In such studies investigators have employed a variety nf animal prepa- rations, including ertcised frog ncsuphaRus, elams, etc. Whilc thcse studies have been scientifically infnrmative, they nced to be su/rrk•mrnted by further ohservatinns conducted under more physiological eondilions in intact mammals. One hyrothesis suggcsts that ikpressittn nf the ralc ttf mucus Iluw may allow inhaled agents from any uwree to remain Innger in cttntacl with IunR tissues and therefore increase their opportunity for action I his hYlxNhesis is slill untestcd as a pnssible factor in careinnRenesis. A dirccl test rniRhl he ptrssihle with an animal modcl ttf flte kind previuusly mcntittned It such a mrxkl systcm, tinder hasie eondilinns, could prtwlut•c a bistnhrpically al+• priate lung lumnr at a reprtalucihle Icvel, the effccl uf influcnccs /lctt dclness or slimulate ciliary activity and mucus flow mipht hc testcd ill htnR ternt etrt'rimcnts with whole animals Such studies w.ndd alai require the ute r,f improved inhahNit,n and mnnitnring tet'hnirluct if rcatrlls were ill fK• inrcr rretahle in tctma rd th,ae and reslwrrt.e I'rtrgrev- in tlcvclrrl.inr .urh Icch niques may rcrndrr Iwnsihle a hcl/cr rv:rhrtlinn nf thc r„li of mnr u. flr,w ac a th'fcn.c : pain.t the atlir,n ill inhalyd npt•nts As mt•nti„nid ill Inevi„us ( rtunttl rt•la,rta I I'!61 64 ). rht• nru, u% II„w is rtrily r,nc :tF•cnry invr,lvcd in thc clr:uanic r,f c%tr.minu. nr:rnrr frnm Ihc InnP Scvrt:rl invi lilat„ra in Ihic IirIJ :t..iFn r,nly :tla,nt It"3. „f Ihr t"d.r) tlcar:nnc attnrlv t„ thr tih.r mutu..y.lcnt. :t~rrrl.in/• :t f.u Lnt•ir r,Intivi IS

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

It was ft,unJ that thc ratr of changc nf thc cstt.rtut,n r.tti,,,,f ruln,Jtum H4 in the i.rdalcJ 1'ctfuuJ Jt,R hcatl ind in rnan w.,c nt,l :r11cr,J wrlh thinPc. in (h,w I hc /hnJrnR that mut,Flyccnn incrcascs ncc cnr„n.u y IdtM,J Ih,w rn I,itirnte wrthtnn ct,rr,niry atlcry lit.catc whtlc rleereavnR it tn I+.rttcnta wrth c,ntmary artrry rh.t'acc was innlhrmrJ Ofhrr Rrnnt..r.: 11 S Puhlic Ileallh Scrvicc, MichrR;tn Ilcart A~ctxiatir,n• the Ilurrt,uglrc "'cllcnrnc I nnd, A M A. Fduc:rnnn anJ Rcu arch I t,unJa- tit,n, tnJ tlte Jnltn A IlirtlnrJ Foundation "I'IIASI(' 1)IMI NSIONAI. ('lIAN(i1:S IN I III I 1-I 1 VI N I RI('1 1: " fly Pctrr 1 S.,Irshury (Jtct•ascJ Nnvrmhcr (h, 1964 1. ( ctrl I ( tr,at, altd P Andre Rincorn, SI Jt,acph IInsl,ilal, Ilurh.,nk, (':,Irlnrnrj Ar,Jrnrt Inrrr n.ninnnfrt dr I'ht,inlrrcrr rt dr llrn.lrrmrr 71'2 IRN 21)R, I'!(ht 1( r,ntinu ing Rr.ntre ( rns./ Cnrnl.rchrnsivc Icfl vt•niriculzir mcaturcmcnts wcrc matlr fn 41 .ncslhc- lirrd tW,r,t JurinR varying c.lvcrimcntal condtut,ns in orJcr ht Iratn mrrre of thc rcmarkahly IirRc chanrcs of Icll vcntritlr (I V 1 Jimcntir,n• anJ the LrantGamattnn of ita chal+c JurinR the iso.nlumic rr.c t,f vcnlrit ul;tr prresnre 1 hr Jata show Ihat it was an asynt hrnnnua shtntcnrnR of thc 1 V inflr,w trnt I whnh ratsrd I V prrssurr anrl rlnny.itcJ othrr Jrnncncitxn Jntrn` thc i.r,vr,l umrc rnntrat tu,n phaut of I V systr,lc Ourtnr thr t.r,v.+lumrt I~n..rl Ihi t InsrJ rniu:tl vilvr mnsl hivc t><'cn "IiIICJ ' tnw.trt) thr afti't anJ tht' st I-t"m Itnnt t rclauvcly lit, tl hirnPc Iw,nt1 cltnc lnthr rtwN nf thc i,nta ( . rd I V,lum n.ronc :tntl I,rt..utt's dnnn/• the isnvt,l,tmrc 1•h.) sc ntuat t,nt t.,,n t.,,r.r,l I, trm.rnly (,y r.tl•nl h,utrnrnr of Lalnllar y m„,. I r s antl rnnr r Lrit rs ..1 I V w. ll I V t rr, rrn,lt Ir nt t' :tnJ nulflt,w trict Irn/th thr,rtcnrrl rlt,nnr tht cl,ttnnt I,h.ta• (1tlher Rrnnrr,r: Nmir,nal Ilcirt Instrtutc "UNI)O111I•l Inl. ('IIAN(iFS 1'ROI)ll('1 I) RY AS(Y)RIII(' A('ll) 1)f! I('l1 Nl Y IN (:IIINI:A PI(iS" Ity Ira Gnrc, MI), lak,t, I ujinanti, N11), enJ lcurannhu Shirahanti, N11), llrtivcrsity Ift,.f,ital. Ilt,.lnn Ilnivt'r sily Mc4ical ("cntcr, Mass Arrlvrrr n( )'ruhnlnKv N(/ 4 171 176. Octuht'r (VbS ((lrantrc: (3nre) 1Vith scurvy in Ruinra I,iFs, Ifhc arutic cntlnlhclium. ccamint•J with rn /nrr I,rcparatit,na, Jisltliys rcdutcJ silvcr ct:tin:thilily t,f thc Ic'mrnt lincs anJ an int.rc:neJ ineidcnct• nf sttth nuclcnt ahm,nnalitics as vecut,lii:ui,m, swcllinP. Jiclnrtinn, anJ I,yknnsic lhe tlcfrcicnt tliet is nt,l :rsstKiatcd with i th:tnrc tn thr hl,r,n„Iytic nclivily t,( the t•rnlnthcliunt I hia Jiy,l.tyctl a Kt,uhrnt wlutlt in, rc.,sctl Irr,ru thc art h tt, tht• ahth,minal scrrncnt r,l thc tntt.r Ilcttrr.n mit rt,tcry,y rlrsld.,ycrl scI':n:rtinn rf r-n,lullh,li:J t, II•. ,r, .r ursy :ts tht I rcvrn,l,lnr cautt• of I. .tk.t/•c 1 Itrtc :t tlrl,lt tr.ni ,d •.nl„ ntL, tht I,.,I tn.nitl a t, tlu( lu n n( t v!nlQ.r.nnt .•rl .rnrllr. llrt..r 8..rnr... ,"'. - 0 t, i11.- .I 11. 011, • r "Al)RTIC A('ll) MI1CnPnLYSA(Y'l1ARInrS ANI) (-OI I.AG1:N IN S('OR111I11( GIIINVA PI(iS"Ily Ira Gtnc, Yukin Ian,tka, lak:u, I'uli nimi and M:tx I( ira,tlmrn, 1)cparlrncnt of Pa/hr,lugy, 1 tnivrnily Ilt,sl-it;tl, (lnclnn Ilniversity Mcdical ('entcr, Mass. lmuwl of Nntritir,n 97 3 lI l• 31(., Nt,vemlxr 19GS ((irantce: Gore) After Itrur wccks nl rccciving an ascorhie aeiJ dclicicncy Jict. nlhcrwise hrallhy young Ruinci I,igs displayed an incrca.c of tnlal aortic acid ntutr, FvdysacchariJc%, csst•ntially thc result u( increacetl hyaluronic aciJ ct,ntrnl and a dccrcau rof :tnrtic collagen mcasurcd ac hydrnuypralinc 'I hc'sc t h:rnrcs ire similar tn lhrtse t,hscrvcJ in these animals in wtarnd repair tlurinF scurvy, allhnuFh thcy are (uintitativc•ly less ('ullaKcn in (Irc aartic wall woc rnetalw,li- carly mt+re activt• than it was in other MKIy structurra (hh.r Rrnnror: II S Public IIe.Ith Service. "PRIMARY IIYPI'RiFNSI(1N SttRV1iY OF 7111i SIIRVIVAL OF F'Al 11:N I S W11/1 FSiADLISIII:I) I)IAS1O1.1(' IIYPI'R I FNSION A1 I VR I F:N YI ARSOF MF1)I('A1. ANI) St)RGI('AI.'TRUAI MFN I" Ily Jr,t,cph II Ildkcncchicl, MI) (now at Sandt,? Pharmaceutical., S:tn Fran eisco, ('al ), 1 1: Schmillhenner, MI), and Ii A I):nrRht•rly, MI), with the lechnit:al assistancc u/ 1 I) Ncnt]cy. MI), ('ardiac ('linic :tmJ Mcdical Serv• icc "It". I ankcnau IInspital, Philatklphia, Pa .Irnrrirun lrrnrnrd of ('nrdi. nhrRV 1(. I hl-h6, luly 1965. ((irantce: Flafkenschicl/ Rccenl aJv;tnccv in renal artery reconatruelir,n and newer kntrwlcJFc nf quantitating Ihc Rathological physinluFy ol thc adrenal Rland in mcm havc rt•JnccJ rltc nurnfx•r nf Ratients tliagnust•J as having Primary hyl,crtt•ncinn 1 hc Purlxnc nl Ihts rcrt,rt is Itr lacscnt cvitknce frurn nnc clinic'a cR rt•ricncc suppestinR that Ihc cstimate rd I1/ ycar survival tt/ men Irc:tted mcJic:tlly ( 1R^.• )(trt cvahli.hcJ Jiaslnlic hyrt•rlcncitrn ( Smithwick Rrt,ul,c 1 anJ 4 1 it hctlcr Ucrn tlt;d of mcn trcatcJ stnRically (•)(1^J, ). I hic is cncntrr:tginR anJ I,rt,v/x:ative I,aticnts ll,twcvcr, Ihc cclimatcs are hascJ on the ctirc•rit•ncc nf Itxt few to makt• the Jillcrt•ncc st-mimically rcli:thlc in (wtn nf mcdic:J Irt•atnu'n/ All I,:uicnts with hltwxl prc.ct.uc con.istcmly r,vcr I S(1 9(/ nun I Ig sht,ultl Ir• ctutht•J carcfutly tu Jctcrminc whclhcr tht•y have an c.t:rhhthcJ Jia.ttdic Itylx'rtcnsitm, antl if sn, whether dria is sccunJbry t,r I,rimary hylx'rtcn.it,n (Ithrr Frnnfrrr.: N;dir,n:d I It•art Inctilulc 12 ) anJ thc ('t,rnunhtrc t,n 1'rt,h Icros td Alt'uhtd t,f Ihc N;ttirmal AcaJcmy nf Scicnit•s N,tirur;tl Itc.c:uth ('t,unc•il "S1'SI(11 I(' MIIRh1tIR 1)1'VI'l O1'ING Af 11: R MYO('AItI)Inl IC( III I\11A OI( INI AI(( I I( IN " Fly I);rviJ 11 IIt,Ilnway Ir , MI) Itr-hrrt 1: Wh;tlcn, MI1 anrl Ihrnry /1 Mtlntr,sh, MI1, ('artlinv;rstul.n I.,Iwn.d,ny, U( 'I+:utnu•nt rd K1, tht mr I)nkr I lruv( rsity Mrdicnl ( rrttt r, I1urh:un N(' /..rnrrrd rrf tlrr• .4 rnrrn rnt Rfrrhr rrf .I,tr,, rrnnar IV 1 I I HHH H')!, f\1:utft I S I'1t,5 ( ( ir.rnlrc Mt Int,,.h I A.y.lr,ht munnur i..r,rnrltmt's hr:utl Inr Iht' tir.t tintt altrr ao rl,r. ,tlr 15

t+l myr.cartlial iKhcmia of the rKturrcntc of a nry,x:rrth:rl inf,rrct,nn Ihia murrnur rniy t+c tluc to the ru/+Unc ,+r :+ I+a1+rll.1ry mualc, thc rul+turr of Ilrc inlcrvrntricular aclHnm, papillary muulc tlyclunUUrn, t+r actutr Iclt vcnrric ular drlalinn Srncc cr.rrcctive surRcry rc Ihrrnctically larccihlc /,+r Il+c hrcl two crvrditir+m, a rlrccicc functir,nal anJ anetrrmit'aI JriRn,+cis churdJ )+t• mat)c in f+aticnts wh,+ Jcvclr+p cuch a murmur so that thc m,+U ctTcctivC long Irrrn thcrafiy may f.e inctitutrd (-crtain features of the hrctrny and /+hycical cRami natit+n hclf+ in the ddlerential diaRrx+sis, but it ic frt•yuently nrcessary to resort to cardiac cathcriration to estahlish the corrcct draRnucis (Ith.r Rr.ntnr.r Natinnal Ileatt Instilute, Nnrth ('art+lina Ilcart Asstx'ia. tinn, and American f Icart Asscxiation. "(-ARI)I(1VAS('Ul AR AND III (K/1) (7AS RI:SPONSI S 1O IIYI'1?R IIARI(' ()XY( il•NA 11()N " 11y Rulr•rl F Whakn, MI), Flcrtx•rt A Saltu rnan, MI), 1lavid 11 IInllnway )r . MI), Ilenry I) Mclnh+ch, MI), Ilerl+ert (1 Siekrr, MI), and Ivan W. Iltown lr , MI), Ikpartmcnls of Mediernr anti SurRcry, I)ukr I)nivcrsity Medical (•cnler, f)urham, N('. ,lmrritan Irrurnal of ( ardi•rbrRr 15 '5 R)R 645. May 1965 (Grantcc McImosh) i cn normal suhjects were sunlrcd while thcy hrc:rthcd air and IIXI^Jo aryRen at I and 1 04 atrrx+ef+hcrec (ItyRcn inhalation al 1114 atmr+cl+hrres was acct+ciatctl with a siRndicant incrr.%ct• in artcri:ri and vcnnua 1,(/. nnd O, content Ilcm<+Rlr+hin in thr venr+uc tutul:rn,+n wac c,rmf+lrrt'ly saturatrtl irt R nf Il) cuhjctra OtyRen inhal.tu+n at 1114 atm,+y,hrrec Lr,+tlutcrl a amall hut ciFni/icant incrricc in vcm+uc I+( () , fvc.um.rhly tlue tu thc Incc r+f tlrr huffcrinp cfftct of retfuccrl hcm,•Rb,hin Ileart ratc n nJ t'arJriC nutl+nt Icll crrnil,t.rrrrly wnJr IinIC th:utf-,c in ctrukc vnlumc durinR usyRcn rnh:J:uu+n .rl 1114 ,,trnu.l+hcrcc imlrc:rtrn)• that the dccrcacc in cardric t+utl+ut w;tc r:dc J, It ndrnt I hcrc w:n Irrrlr t h.rn/•c in ntcan irrcrial luccvrrc hut an incrr•:rcc in c.dtul:rlt'd f+cnl+hcr:rl rc•iclant'r durinR t+tyRcn inhil:ninn at 111.( atrn,t.l+hcrcc Iwr+ cuhjr•t'Ic wh,+ tlcm,m slratcd siRns of acutC myRcn inlnticatit+n ditl nut thtlcr cipmlicantJy flr+m Ihc group as a whole either in Irrms of hlrwxl R:rs valucs or paltt•rns of hcnxr- dynamic reslxtnu Othrr Rr.n(nr.: Natinnal Fleart Imtitute ( 1), North ('arr+linn Ilcart Aasn eialion, and Ameri( an Hear1 Acsrxi:rlit+n i "INVIINf)IFlU1.AR Pill M(1N1('S1 VN(1SIS t)I11: IO A 1'I RI('ARI)IAI- IIANI) " fly Wilh:rm 11 WcRliiki, MI), lamcs 1: I cc, MI), Ivan W I(rnwn lr , MI). antl Rr+f+erl li Whalen, MI), Cardi,+vacrut.u I atHnalruy. 1)Clr:ul mcul t+( MCdicinc and Ihe I)ivi.ir+n t+f Ihuracic SurRt•ry, Uukc llnivrrcily Mrdical ('t•nter. I)urham, N(' ,4mrrr, an Ir+rrrrrul ,+f ('ardr,duRv 11,.'2 2I+2 ]hr,,AuruU I')r•S ((;ranrre Mclnt,+.h) Irnucn.rl rttrnnal anatrnnic rclatr,+nchiln h.rvt- IKrn chnwn t,+ rr.ull in ,+hcrrntlr,m r+l Ihc ,+utfluw tratl of thc rrPlu vcnlntlr :rntl vnr,datr inlrac:n tlr:x I+nlrn,•nn 0, n,+•rc Sut h i rrn,hup w.,% .,'tn I„ )w IuccCnt rn a I~ vr:v ,+I,I Iw+y wh- h.r,l rht tY/•, .rl cyrul•r unc, vl•n. rnrl It, m,alyn.rnut of . t intracardiic inlundihular pulmnnic stenncis hut at curRery was /ruunrt tu havc ul.drucriun to t+utfh+w due ttt a calcified I+ericardial hantl On G11inF thr han,l frr+m the wrfacC (+f the heart at the time of surRery, a 45 rnm drop in riRht vcntric'ular prccture was noted lhis patient was tmiyue in that the f+Cricar tlial cr+nclrictinR Iccir.n was present without a previous hislury of pcricartlial diccasc or rcricardiil surgery. ()thrr Rrnnrnr: National Ileart Institule. "POSTPUR1('ARI)IOrOMY SYNnROMF: IN A PAl-If?NT W11l1 A RIilA1Nf I) IURF1GN Il(1I)Y" Ny Fluward 1. 7c(t, MI), and Ilcnry 1) Mclnta+sh, MI), ('ardiovascular I.atr)ratnry, I)uke Ilniver.ity Mrdic:rl ('en tt•r, 1)urham, N(' A mrrit an Juurnof of ('ordinhrRy I(,/4 :5V)-547, Uclyda•r 1965 ((;rantee: Mclntosh) A patient is tkscrifrcd in whom the pnslpericartlinlttmy symhnmc devel tqx•d secondaty,tn a RunshtN wound tn the chest with the retainetl missilc in clocc prnximity tu the rericardium. Steroid therapy prtxluced a prompt antl suctained clinical rcnussittn l'he literature is reviewed, and it ic cuRFccrcd that retained foreign txxlies in or near the (+cricardium are still annlhcr prccipitatinR caucc• nf the (xnlTx•ricarditNnmy syndrt+rnc 1'rrs.ihlC ctirdrrPic mechanisms, the rulc of corticoctcroids in therapy, antl indicatitrnc /ur aurRcty arc diccussrd. Ot6rr Rrnntor: National Ileart Instilute. "IIYI rR11ARI(' (1XYGFNATION IN )'alf: 7RIWTMFNr (11' AC1111? ('ORONARY ARIfiRY FMIfU1.I7A11ON IN IRK;S•' fly 1lavid if. Ilulhrway )r , Rnl+crt I' . Whalcn, Ilcnccrl A Saluman, and Ilrnry I) Mt In Insh, 1)nrlram, N(' Inurnal nf l.nhrnar.rry and (Tinical Afcda inr hb/4 SVA- (.Q1,(klttfx'r IV(+S ((;rantce: Mcinlosh) 1 he left circurttfk>a coronary artery wat sclt•t'tively cmhr+li~rd with micrn.l+hcres in 30 tM,Rs. 'I hese were divided into three Rrtrurs nf I(/ th+Re each. (iroup I was emhtdi?ed while breathing room air at I atnuwf+hrrc (irnup II was emlydiyed while h/ea(hinR I(K) per cent oRyltcn at 2 aunnc- phcrec, and (7rou1+ 111 was emholired while hrcalhinR 1(K1 lx•r cent r+eyycn at 3 atmnsphcres (irnurs 11 and I11 remained under hylx•rh:uic c•nndrtit+ne fur 2 hours aftcr rmht+liyaliun 1'ararnetcrs tklerminetl fx•ftue and afler cmlwrli7atiun includrd. cicc(rtkardiogram, artcrial prrccurc, carth:rc r+utl+ut, c'alculaled reril+hrril resistance, arlerial and venuue p11, I+('( ), I+( ), and calculatcd t)><yKcn cnntcnt I fle dnf!t wele t+lhcr•rved until dcath nr sacri/icd at 2 wrcMe In all threc Rrnuf+c, alter emhdrtari,tn. Iherr was a m:nkrd (all in mcan :ulerial (+rrc.urc. a deerrace in t'ard,:tc uull+ul, a widt•nCJ A V(1. tlitlert•ntt•, and :r hi)•Ir rnru Inlily ralr Nn I+nrtc,tivr r•11rC1 rd hyfK'rh:nic urryRt'n:rUr+n tr•uld fr• drm,rn clrarcd after aclrctivic emlwdi-alirm (+f tfhc Ic•fl cirt'um/hR tnrnn.uy :utcry wilh mit'rncrhere. Otftrr Rrnnfnr.: Natinn:tl Ilt'art Inctitutc, ( 1), Nurth (':v,dioa Ifr:ul A..,• cialir+n, and Amcric:rn Itt•art Acaaxiitir+n „ )h 17 ~P

"illt ASS(K IAiI(1N Of N(X'III RNAI AN(iINA I'I('I() RIC \V1111 1)RI M11N(i •' Ity ) It N,rwbn, INI) W(i Irnycr lr. , MI), \V S( r+lltnc MI), (i Srh'crm.m, f`11), (• R Nrtht,lc, fNl), II 1) MtInttnh, MI), I'A( I', 1 11 FOct )r , fNl1, FA( 1, anJ M I) IIuRJtm,tfl, MI/, I A( I', Utl+.vtmcnts td MeJtcinc anJ I'sythlitry. I1uke l!ntvertity MtJit:il ( cnter. I)ulhent N(' Annnlt r+/ Inrrrnal AfrArtrnr 61 h.11)41/_1O4M1, I)ecemtn•r IVhS ((itan /cc' Mclnttnh ) frntr Itiricntt with a hittray of cucrtional anJ nrxlurnal anpini f.cttnric, all of whrmt haJ c'linical IinJinRs o( coronary hcart Jrcea.c, wcre nx,nitnrcJ IhtnuRh ccvcr:J tull niRhts of sleep with cttntinurruc rccrntlings of clcclrtt encelthalttRral,luc palternt, eleelrr.carJirtRramc, eye nxtvcmcntt, and alsn rct/titatnry I+atlcrnt A ItNaI nf 19 cltitrxkt t+f ntKturnal anyin.t wirh tirnili eant S 1«rmcnt Jc(+restinnt rtn Ihe electr(x'arJn,Pr arn wcrc m'tcJ, nf which 32 were asstx'iatcJ with I+critxlc af ra/+id eye rrtr,vemcnl attivity Ra/liJ eye nxtvemenl rcritxlt have heen hrt'vit+utly sh,+wn ill cr+rrelatc well with tlream activity In two paucnts, the astr+ciatir+n lirlwccn raf.iJ eye mt•vcmcnt at tivity and eleclrr.carJit,praphic chinRc wat /nunJ tn I~c ttatitti cally tiRnllht'anl tt+ a probability 1cvCI t,f F• (/ (IS 1 ht scyucntc r+f cvcnlc wac Gnmtlltt 1.c clrch that nnscl rif ra/,iJ cyc (nnvcntcnl activlty prc'ccJt•J that of the ekclrr.cardir+Prif.hie ehanRee IFtts sut•Ret1c thit Ihe Jreantinp. s1:ue UiR• Rcrs the tkvelt,rrncnt t.f thr nt.tturn:tl inFina crttrxk 1 hcrc wic no cviJcnce in tltete tftlJrct Ihal the revrree miPlu tx• Iruc NI+ atlctnl,t w.c matlt• ill In%c Iht I,aricnts rccitc thc Jrc:un cr,ntcrt( ulx+n wakcttinr wit)t ntxturnal chcv f'.+irt hut Iht•y wt rt' ync.ut,ncJ f4 ,r :tny tllt•ant rccill in Ihc nxtnnny I hf t)rt :unt It mlt J It, fetl i++tt, Iwn )•cncr;tl c.ltt/•t+ricc: trrt'nunut f,hytit.tl xlivily, an,l ft.tr, r, „1 Iru.rr.rln,n AII Ihr It,ttirnt, wcrc awarc „f t hctl I,ain ill tut It Jrr tnt. l)th.r Rrnnlnr.: Nitit,n:tl Inttint,ct t,l Ilt.lllh 121 anJ i\rnrric:tn Ilc:trt ASQKiatitln "IIlI1 R(;VR'S hlS/'ASW IN ISRA1 1." Ily RichilJ M G( Jnctn, MI), fnrnxrly at lt+hna Ilul,kinc tlnivcrstty Sthrxtl nl fklcJicrnc, IS:Jtimtnc• MJ , n(.w at (lhitt Ctatc t/nivcrsily ( ttllcEc r,/ Mcditine• ('tdumhut; Ilraur(t• I li:tn, N11), Mark Mn7ct, h11), anJ Vit'tla 1)iutsch, MI), IcI Ila.hrtrncr Ilrttl,ital, Ramm Gan, Itracl lnrrrrrtrn ltorrrrnl tr( M11erhtrrrr 19'4 (,O1 (,IS, (klt+lx'r I')h5 ((irantrc 1)r Vittl+r A Mtknsick, Italtimore, MJ 1 I iFhty cast't r,f IlucrPcr'. J/tr.t~c wclc tnwhctl antnnl. , the varirmt ctl+nic Rrnultt in lsricl, incluJing 11( rncn anJ twtn wuntcn Of Ilrc 71) ill fcwc, h2 mcn anJ t+nc wuman wcrc A.hkrn:vtrn mt,aly t,f ( irnrn,nt I't,lr.h Itus tlan I,ripin, m:+ny r,l whont tf,rc:tJ It, IFhc Amrrn .r., 17 nn'n antl t,nr wt,man wcte Scl,ltartlnt nf Slvmith 1'trrlul•uctc rnl)•in, wht, •I+It'aJ t„ 1(.rlkan and Nnrth Alritavt :ucat, antl thrcc nlcrt wt•rt• (r,•m A,+e kltnnt 1l,r+r w:t, t,nc Arah m:+lt ir+ Ihr Pr,+uf. A t tmtrul prt,ul, t,/ 7 7 Irwr.Fh mnlr I.++ nt% wiltutut fx•ril,ht•I :+I va.+ ril.u rh.raw~, rn.rtt I+t tl 1„r :+/•t.+uJ , tlunt tu,t•,n .. nt, IF+r .1u,ly anJ a/•Innl, nl 4 1)rwl.h r».rh I,.+r+. nl. willt •nl, rtu.t It tu.r. nhlltrt.tn. Nl~ll' .,I", 0lt/!1. 11 Ilir I++t'I n, r„t,.,h ntr „I Ilrn,t•~,. ,li•.~ n•~ .+nn,n!• Ilr,,\.!iArn.vittt it ttaticlically 6Pnihcanl Ihc mean aRc r+f rmtcl ill the Ji.casc was afx+ul 111 ycarc, ctanlmncJ tt+ 47 ycarc in cascs (d artcriusclcnrtic r+hlrlcr:lnc I hc avcr aRe numlx•r uf cigaretles snx+keJ daily in the three Rrtwla was as frPubws: SmolrnR II.Lurt ((-ilimrnrt I flurrRrr•s I)nea st Atrrritnclrnttvt I) b1+1r rem (unttah Never Imetked 2 0 25 ' ( kcaciunal trnt,kcr 1 2 (+ li pack daily 8 1 14 t I pack daily 25 1) 2(/ I' i I+acks J;tily 24) 12 9 2 (tacks daily 2 2 3 Mlrre than 2 I+a(kt Jaily 10 4 11 lulal 79 34 77 I One male I,aticnt wilh anset of Uuerger's Jisease at age 25 hatl ncver smnkcJ; Iwo tt-1tcJ they had begun smokinR after the (+nscl td thc Jrscase, twu occacittnally smttkeJ a pipe in aJJiut,n to eigarettes. O1 Iht• two wl+nx•n, nnc smoked rmly tx:casiunally and thc ulhcr ahuul one (tack of ciK:trcuc< daily. lhe diflcrence between the smoking hahits td thl+te with ItucrRer's Jiscacc or arteri<xclcrosic ohlitcrant as eomparctl to Ihttse ill Ihc crtnlrol gtltu/t withltul )x•rila•ral vatcular Jiccasc is highly ciynilit'ant ct:rUstiiatly, thcrc is no cil;nihcanl difference in the quantity sntuked lK•twccn Ihc Ifuctl;cr and artcrincclernsic Rrmrln Vrturtccn nf Ihc 79 Hucrgcr's diseace palienls had ctultltcJ sn(r+kinR fur less thatt nne year and 33 for a year t.r rtxae of Ihe L'rllcr, 211 cu(dJ ohserve nn chartgc ill Iheir cttnJilion, 11/ c1a1eJ they had iml+rtrveJ, anJ 1 raticnls ntdcJ I,roFressiun in their symlHoms with eecsatit,n t+l trnr+kinp In Ihtnc whn h:td s(nl'Ix•J smtrkinR nnc ycar or kss, a11 statcJ thcy ca+u1J not Jctccl any imprnvcmcnt in thcir ennJitirtn, ac was Ihe t'ast• will aIl thucc whtt haJ not Vrqtlx'J emrtking I here was a ciRnilicanl Jilfercrtcc IK•Iwccn Ihc 12 IluctRcr rnticnts whr, crmtinucd ill smttkc and whlt mHCJ nn inqnnvt mcnl in syml+lrrmc anJ thc 11 who haJ aoplx•J srntrkinR for mt+rc than nnc yc:u. u( whtrrn 111 haJ sfutwn tkfinilc imrirovcmcnl. Allhttul•h thc etiology trf HucrFcr'c Jiccasc ttill Icm:tins ttt I,c t I.urht'J (thtcrvatiam rcl..:trtlrrtg latnily aKKrcgatit,n 14 f:tnulicsl anJ I„t.rtnr a'ttun I:ttcR tcclc ( 17":, td :JI t'ascsl may I.e hcll+lul in lutllhcr Jt-hnr.ttnnt ttl Ihc havic hittrqt:+lh„h,pical ahct:ttinn in Ihis Ji.catc, wha Ih 11.1. rn.ury t It.+r,,t tcrittics lu t1t.linPut.h it Ironr arterit,st Icrtrsis uhhrh•r.tnc llthrr Rrnnt..rr Anlcrit'an Ilcarl Aatxiatirrn ••1111: I I fl ('IC O1- SMOKINIi (1N I111; ( AI(I)IA(' O111I'll l AI Ill SI ANI) It1IRIN(: I X11(( ISI' IN 1'AIII NIS \VII11 111 AI 1 1) NI1'ICARI)IAl INI AR( I I()N." Ily Wrlli:un S I r.lnkl N11). \lrllr.rnt I Witttcrt, N111, antl I r,uic A S,tln!1, h111, I)tl+:ulmcnl td (\lctlunlc; I)rtr.inn 19 t`l

I I I „/ ( ar.lr. d, ,J•y .rntl rFtc (.ntln,vea rnl.rr Itc., .ut h( t nr, r, I cnrl'It 1'nca r.rty ftlitlhi.rl ((•nltr, I'hrL.rtJtll,hr.r, I•.r I rrrnhrlnur 1I 1 42 JJ• Janu:uy I'/ht I(ir:rnlcc StJt,(II Smr,lli(nr r,f rwr, cl:mdard ciictl hltcr lil) u(•,ncttc. /n I1/ mrmrlt.• wrlh inh:rleur,n. hy crfthl I,.rhtnlc a/'t'd 4M In M) yc.rr. wrflr Irr .rl, 11 nrv,N.:uth:rl inl.utln,n I.rrlctl lr, f•rtNlucc Ihc .trrArnK rncrca.cc in t:uJiac r,ull,ul .rrNt cllukt• tnlrnnc witnrc.t (/ V•v Ihc authl,rc antl rahcrt in nrnru.rt hc:rllhy Wnrn/• h,nhrtu.rl tnu,t,rr. Ohr thc t,nct r han,1, the heart rnrc wa% tntrc:rcrA m thr Ir:rlrrnt )•rt,rrl,, ;rt rl Irarl nr Ihc (u•ehhy tuhit'clt A tJr..r,tr:rut,n INrwtcn hcarl ralc anll clrulc vr,InnN• h;rJ al.,, hl-cn nr,ri tl irn the hc.rlthy y„ung hahFlu.d cml,kt't. 1r(•alct/ wrlh Flutt,.c 1•t G,rc fhc am„krnr Ictlc Iht'tt' J.u:r ir,tlit:t/c Ilh.rl intrcatc in hi:ut r:,lt rt rtxrh.rlctl f.y Jrll,'rt'nl f:lcfrrrc Ih:,n tIrncc Ih:N int rcav' atrnkc vr,lun/c and t.utfi.lc t,vll,ul I hl• I.nlurr Ir, I,rrNhrtc .1 nct• rn cirtfh,rt t,trlfau :mJ ctrr,kt' vnIunN• nt fhr I,:rlrcnl (~rt rrl, tl.K't nnl :rl•fti•ar In It• rt•l.rtrtl tn Ihc tna,krnR h.rl.r1 vntc tw„ ld Ita' IaLLrclnrc Icttcrl wrrt• nrm cnr„kcrt Ihll,uhlnhctl d.tta irn rhit I.rlw,ratrny culy-ccf 111.11 Ihc c:rlrt ht,l.rnrrnc (nnccn/r.rlu,n nl hc:trlc in the rdllcr pr„ul, r,l p:nicntc rn:ry nr,l th/lcr crl•niht antly Irt,m Ihal rn Ihc yr•tmgrr Lt'rurn wifh hcart tli.c:nc (llh.r (rrnnrnr: II S Pubirc IICJIIh Ccrvice "('Akl)I/\(' I1111I'1)1 AI /tI S l /\NI) 1)IIRIN(i IX I It( ISI IN Pn111 NIS WIIII III AI I 1) M1"(N AI(1)IAI INI AH( 11(IN"Ily Wit lianl S I rtnkl, MI), w'rilrant I Nrnlcrv, MI1, .rn,l I r,ruc A Snlnll, M/), IcmJ,li Ilnivcrtrty Mt'tlrt:rl ( rnttr, I'Inl.ultll,ln.r, 1':r .Irnrrrrnn l,•rnrrul n/ llre Alnlrr nl 1, vnr r, :4') b I.)I• hH I, Imrr' I'!At ((:r.mlct' Sulull I I1rc c:rrth.lc nullml :11 rt'tt .1ml tlhrrrnv t'ttrtra w.r..luthrrl m 11 p•rlrcnf, a}•t•tl •12 trr 7(1 yc.rrc wifh dtN unrrnlt tl hr.rlyd myr•t erdr:rl rrnf ert 111,11 1 hrcr I,atit'nlc cht,wctl a motkcd rinl•t' r,l t Irnrt:rl llrc.rl,rlny / lnly •1 wt rt' Il'.. Ihan :rKc 51/ (lur II.V:r rr.t•:,Ictl Ihel Ihw.r p.,licnlc wnlr n„ .yny•rtrnr., (rn rngirr.r IK'tltliit ilt,nc, /:rnr1 a nrnm:rl hcarl vir tan In' ctrt tICl1 Ir, h:rvc n„ rml,.r(r m. nl t,f cartliut' mulf,ut al rcct t,r m rc.INmcc It, ctrrt rcc Iht,cc p.rticntc wilh •yrnptt,mc in adllilir,n lu :rngin;r :rnJ winc t:ntlit, mcr:tly tan tx• cttN'c(cd ttr h:cvc iny'aircll c:tnli:tc mullwl :rl rccl :rnll in rct/a+ncc Itl ctcrcicc It it (,t+ctihlc Ihat facll,rc actr,('ialctl wrlh :rp'rng, :rc wcll ac milra) valvc inclrmllclcntc. m.rv a/a, Idny I r+,lc rn Ihc th:rnrct cct•n in Ihi. I:lltcr Rrt,up in adtJrtwn Ir, Ih:u if Ihc untlrrlying itthcntic hc,ut dr.cacc I I Uthrr Rrmrrnr.: 1 I S Prrhlic I Ir,r11h tirrvitc antl Grcati r I l:ricllr,n 11c;u1 Accr.t i:rlir,n 1 III. f:rrrr'in(rKr r(.•.ia Slrrrlir•t ' "I•Irl A1tINnItY 1 I'~ IONC (N CYIt1,1N (i(/I 111 N IInMCl1 I(S i t/1 1lIWIN(i INI I('tI(1N 1V1111 INI I Irl N/ \ VI(tlI\' Ily trs - I' /~"Irl rrnl; .unl I'lulh/r r -rl- /. 1)t•p.rrlnrrrrl r~l \rrr(•r ry :nr,l \rrr(•rt.rl I.rl rel .ry 4.1 (, Ihrl,,r I'hv•,n.l. yy i\IIN r1 I iu.r, rn („Ilr f`1, tht rnr. .nrJ 11 1•.utrnr nl r.f \nrf•~ rv. \'t r, rnnt A,Innni.lr,rti,•n II~•.I•rl.rl 1lrnnt. Nrw \.rrl I rh' t, " n., , 1 II II rI I 14.1 Innr~ I'rr.t 1(:r.rnr~r I -•I•tr1 It h.rc l,t•cn tlrmrrnctralctl that a mrtucc atlal+tcd clrain t,f rnllulni.r viru., I ylv' A, cfrain I'R K, it c:rpahlc uf rnnlucing Ilrc c:rrnc ccyucntc trf hivlr,l,:rthrdl,l itil ch:mpcc in the IunRc of wcanling Syrian hnrn.lrrc at it tlrN•c in fcrrclc :rnd nncc, hnl wilJwu( accrtml,anyinK t'littical linttinp< Ilri virnc wac nnl It IIcJ It, :uty t,f Ihc wc;rnling :rnintalc to infcctcd AIlht,uFh Ihc acurc I,hatr t,l Ihc hi.luhathldt,l ical t'hanFcc wac rrver twit wcckc after infrt'li„n, minr,r hut IN•rcicIcnl hmp th:rnpcc were act•rt in arntt• :tnim:dt ac h,nF at nnr yc:u :tflcr int,tuLrtiun Nurtc rd Ihc IunR clt:rnl;cc wat uhct'rvctl in Ihc cunlrr,lc "1RANti1OI(MA 11ON INI)11('11) IIY F'R K INIIUI:N/A VIR(/C IN 1•ItIMA/tY ( 111 I III(I S(W MOIISF: K11)NI Y ANI) ItFtON("IlllS'• ANI/ I•/t( q)11('II(/N (11 MAI IIiNANI KII)NI?Y IIIMORS IN MI( I 111' SIt1I('111 I I IRI S" Ily ('ccilic I ctKhlcntx•rKcr, Rudul( I curltlt•nl,t•rl•cr, 1hrtMh,r Ilrunncr, 1)urtnfry Ntnlin, and Sylvia Wcitt, I)c/,:n/ntcnl l,f ( ytr, t'hcmiary, Swict In.lilulc frtr Urlx•rintcnlal ('anccr Rcu:trch. I.nrcannt•, Switvcrland l'rr,, r,-rlrnt'l rr/ Ihr Nrni.rnu! .4r urlrnev n/ Xt u•nl et S 1 1 694. 7111, M:uth It)(,S ((;ranlcc ('. l.cuchtcnla•rl;cr) ('ultutcc flt,m kitlncy antl hrnnthuc rtf Srk'll't dw:u( ntit C, wlrcn inft•t Icrl wilh PR K influcnra viruc, thttwc(1 ccacrttially Iltt• cantc ct•tlucncc t,f cyttdrrgi. c:d antl tylr,( hcmic:J :nccr:nit'nc :n Ih,tct• nhct'rvcd in hrtint hi and Iurrh. t,l ( I, micc :rllcr nr r nvr, infcilitrn wilh I'R K inllucnin viruc In athlilinn, fhcrc t•tt urrrJ trt Ihc inlct'ICtI liccuc cullurct l;ianl hiiarrcly ch:y,.•tI t clic rc.crnhlin•' clmt'ly 1h„cc tlcckrilk'd fr,r cc11v frnm hum:rn kidncy cullaric inlcttcJ whh SV J(1 viruc (Shcin, II M h Fndcrv, I U , 1'rtN; N:d. Acatl Sti 4K 1104, 11162) Whilr laim:ny cnl(trrcc irtfct/ctl wilh PR R influcn?a viruc whco inlctlctl 1r111111t'wlN,rll nl/(i Ihll rttll l,ry/(hltl' (tlmllr5, :IfIMNII! /hl' IICwIN,trl nntt' I/ltt'(It'II :.4 /nrnditc I,rctirnr.ly with tuhcrdlurcc frurn PR H infcclyd ctl,l:mtc t,t kitlni y antl l.runthuc, 4 micc (kvchrrt'tl kitlncy tunnrnc (c:trct,rttac 1 11 Ihut alqw'arc that PR K inOtn'n1a vituc it anl,tJtcr rcq•ir:rlt,ry "infcc lir,uc" vinrm whith, un/h•r ct'rf:tin cnndilit,nt, i. ca(•ahlc t,( clicilinl• m.dipn.tnt Irtncftnncnit,n t,i ccllt, at hat ht•en d'mt,natr:dcd fl,r huntcm ,rtlrnt, viruc lylrt 12 anJ I R I I rrnlin, Y. Y cl it , St'icncc 117 X15. 1•ln? 1 I hic hnthn/• nt/1 ttnly (•ivt•c furlhcr cuPlaat trr the n~nccl,l Ihal inllucniu vtrum tn.ry lit implit';ttrtl ac a cr,f:nltrr in Ihc th'vt'hy,mcrtt t,f hrt,uth,qtcnit l.nlinnnr.r f.ut it irnlNlcc. c:rulit,n r,n Ihc >(ricl acrar:rlitnt Ih'Iwctn "Ium„r" vrnra'c antl "infrtlir,nt" virucct Ilrh.•r Rrnnhlr: ('ih:r, H:t.cl, SwiVcrl.tntl "I11()1 (Hil('AI \I(:NII I( r\N( 1OI I r\( 1(11(C INI 1 111 Nt INIi 1111 IN( 11)I N( 1; ()1 t\1AMMA)(1' (/\N( I It IN Mll I" Ily \1'dlr.rm \ Alrrr r.ry. Srnit.n Sl:rlf C,nnri.l, Ihr I.rlka,n I.AN,r.rltny, 11.11 Il.rrh„r. NLnn. /nrn n,rt lr/ Ilrr Nuu~nr,d ( ulrr . r lrrtnftulr 1 1 I: 1 4 1, J.rmr.u y I Vr,\ I tlcn.ivr rl.~l.r „n Ihr hlr hr.hnn . nl rhr fhrcr,lrn1• .rn,J n„n I•rr r Jrnr• nr rr•.r I• ( ul., Icm:tlct ul I,rur rnlarrl rn,~rr.r •r,N k• .rml Ini rtlr rnrrt 111.01 41

lit+na -lrr ucctl Ir, illuclrllc Ihr cnntclH rh.+t thc nt,n rnannrr.uy c'.rntrrt,na -vninl:tlt in aut tt lw,l+ut:rlit,nc tlrt• wnlt .nr unfulhllrrl Irrttlcnt y tr, tlivt h,l, Ltc•aat ttnnt,ra Analyait rtf Ihc t•u+tcrnu\ ct'}tnrentc t,( thccc Ir,1,nLrtint c, un tht• Rrtnrnd thet Ihcy are rcl-rcct nt,+livr t,f Ihc n„r trn:+l It ralcnt rtc t,f Ihc ctt,tkc whcn rcarcd unJc•r tnr,rc ttadr„Ilcd tnnthtit,nc, frulhcr rlluarr.ttcc Ihat matnntary tumtn incidincc in cath t,f then) ia lhc rccnll r,( a rnml,lcc vyntlrnmc invttlvrng varyinK dcpccc uf ItltyciulaFit .rl rctcl,liv+ly It+ nurni rt,tr. ct,n+hinarit,nc t,( viral :tntl hnrnrunal ctimuli (/(hrr Rrnnrnr.: Natit,nal (';tncer InatittltC antl A1nt'nt;ul (•:Int'cr %,Krcty "(•AR('IN(1(',1 N INI)1/('1'I) 1O1 I RAN(T 10 II(1MUI/tAN%1'I AN I A I I( /N " Ily Ih'n)ar»in A Ruhin, !'h1), ft,rmt'rly :tt llayh,r I Initrrtrly ('t+lltpt' n/ Mctllcinc, Ilnuchtn, IcAs aa, nnw al Wyt-rh I.Itwnaltrttic, Inc , ftatlnr,r, ('a I hapIrr in Vulumc 5•'l'rnjerr+t rn I I(rrrrrrrr•nrnl I rrnrrrr /lrvrrr. h'" It ul,lrahctl 1964. hby S Knrpcr, Il,tccl Ncw Yt,rk 217-2tt2 A(ICr micc havc I'.t•cn Ircalctl with (rolytyclic hytlrtK:ulatn t arcin„~rnc, they ahr,w i thmrn+chctl ciratFly Irt rcptt ht,rnt+Prillc t,( n•nmal antl lururn liacucc, a p(hcmm+rntrrt whith m:ty (w'rat.t rur tht•ir cntirc hfc y:rn Cn.ccl,ti hrhly It, Ihia tirtrm,l•cn cfhtt vernt wrlh thlTrrcrvt cU:tint of rnuc anJ ttt•Irmlc t,n crvir.il trtcativc pcnt t,c in i m.rnnt r arnul:tr It, Ihc I-t nclirc t,f circrnogcnrc cuctrl•trf.+(hty Ou.urtrt.ruvc tt,ml,.ar.nnt trl a tinuler t'llrtl (irt•tlutcd f.y rn.tny tcl.Httl h)Jrrr:ul,r,n. ahr,w :+ .trnnp ct,ntl.+rirm with t'arcinogcnicic Allhr,uph thc'rc n nr.nLril rnL~l~~i~~~n •4 In.nn,t.~ ih cralt'd tlitrt'itc rn fturnntel .~nt~l..,lt I„rr~r ru•,n ~. J, t, ~ r,I,I, ~\ t.,u, ty nl t/udrec intlit:ilc Ih.tl an attrtt rnrnrnm~l..r•r. ~I l~rrrr., nr~t~.rt~,l /,v r.u, ur.•/•rn trcalntcnl ic rCtlttirctl tr, c•1.+14r.tr .+ l-nrn ••I r•J, r.rn, r Nlw h r nn I,tIr.rn. /crtctl paccivcly I hc mt•t h.rnr.m nl tlr,, r II,, 1 r, rrttt r l,rt rrJ r. an :+nlr, intmunt• I,hcnt,ntcnt+n Suth i hylv,lhc.ia ic cu(,(>„rlctl f,y n+:+ny ctndicc atlcctinp tt, Ihr ability t+( carcint,pcnc to ftnm pndcin cnny~lrtca, ;tnd +hcrt• ic cvitlintc th;tl curh tnrnl+lcwcc wrll :,Itct anliFcnic clx•trltt ity In (act• it het Itccn tt;ucd Ihat fl+c ahility In ftntm cuch liccuc cr+ntldctcc ic rttrruird tu t':trt'int,pcnccic, :tnJ that Ihcrc ic a cltxt• yu;+nritativc rcLVit,nthip Itclwccn Ihc ahilily to ft+rm tt,m- (dcRCS with Ivt,tcinc nntl unct,rcrtic cipatily If circinnFcm acl lo intcr(crc with Ihc ht,rno)•rall rcatlinn hy mcnnc of tuch :+nlil'.•n t't,m(dca•~, it thnuld f,c• Ix,c.rhlc lu cnh.rncc Iht• cf)cct Ly crc:d in/• :r ailu;dir,n in whith liccttc ttattplri fr,rrn.llit,n rni/•ht Iti• (aciFit:+1rA Ihit w•+t :+(qp:ttcntiy atlticvctl by Ihc adtlitiun td Iyrq,htlvitl luntt,r antl nurrnal liacut• htnnt,Fcnatit tn Ific carcinr,rtn trtatr»int I)ru(•c Ith.tl cnhantt• imnunw rtal.rmac r.ntrcnartl thc Irvt•1 t,f t.ntrnn)•tn inrlnttrl Ir,lir.,ntr• cvcn Ihr•nrlr t.rl,.rhlt' u/ .,rr t I• r.rlinl• rtaft rcict lir,n wl+r n/•rvcn .r6•n, ( t,nvrr., ry. nnmu nn.nlyrria..u+t. n+.tv ,nrcrfcrc w+lh t:rrtinr,)•rn atlivrly (Ilh.•r ( .rnr tr In.trtutr .nrrl •\rn~ rri .ur ( :,ntt•r Ci,( iilv / f 1 1V. Slurlii's nl fhr' (:rllttlrrr l.rri'1 "( I1R(tMOSt)MAI ( IIANGI C 1:(11 1OWINfi SIt/tGI KY AN1) RAI)I O1111 IZAI'Y IN I'A I II'N I S W1111 /'I 1 VI(' (•AN( I IZ '• Ity Anthtnty P Amalt,at•, 1'hl), anJ Ik,n.+ltl II I1:ttlcr, MI1, I)cPar(rm•nl rtf Ohalt-tri(--. anJ (iynccttit,ry :rnt( 1), f,:utrrtcnt u( Radu+lt,gy, Iltc AIh•tny I1lrtht•:tl ('nllc(•t• uf IIninn Ilnivcrcily, Alh;+ny, N Y(lhttr•(rir t and (:ynrruGrlv 25 6 929 K41, )unc IVhS (Grantrc' Ant:urnt•) Si> wt,mcn wilh fovlvic canrt•r wcrc t'hncrn (tu Ihic ctutly, which w.1c tlrvi.ctl tn :ultl It, thc inatdlicicnt knr.wlt•tll;c alunn Ihc rllccl r,f rc/,c:uctl .nt:rll dr+.ct t,l Ihct:y+t•uuc r:uG;qitnt Iu Ir:tt'littns uf Ihc Iwtily IShanl c;mq,lcc (ur cnllurc wirc nldaincd, whcnt•vt•r Iwtttihlc. Ivrinr lu (rcutntcnt, al Itntctl irdcr val. Jurinr, Ihc tht•ra(+y, antl n(ICr Ihc ct,ml,lclion t,f radittlhcral,y 1'alrcnlt Itcalit7 nnly wilh vrrpcry hatl bltKnl wilhtlr•rwn ptc•nntl Iw,clnltctanvcly Mrcrtratr,l,rc it•unm.Niun ul Ihc• ccll ctthurt•t ahr+wctl ytc•nttit:Nivc anJ yu.+hlant: t hrt,rnr,.,,ntal tl.rmapC which tcauhctl in cclk t'ttnl:rnunl• a tlcvi.t tir,n Irt+m Ihc ntnm:tt ct,ml,,ucnl td 40, Pt,ttirradi:dit,n h•v.•I% hrl•:m to ri.r hul JrJ ntN rc•rth I,rcltca/nk•nl ct+uula. Ihc (rctlucncy :Intl Itt•raiatcncc t,( tcaitlu:d :+hnt,rnt.tl trllc hm11 :dtcr IFtc cnntl,lclitm td Ihcr:r),y au/•/•tcl. Ihi t rti.tcnic nl tlt'm tt II. willh tluumr,amtal tLrnt:tgc 1 hcrr alryr :u. Itr ly cnrnr Fcnrrd valitlity in rullin)• Guaattl ac a wr,rk ml• Irylw,thca.. antl nr,l ac a rnt•rc cr+nlccltrrt'. Ihc (t,llnwin(. tlatt rnrnl A la,tcil,lr ttntrl.rti„tt nr.ty cti.l in a tanccr I,:nit•ru tR•Iwcirn Iltc Ificra.rtl 111%. tlrl,riaau,n t,f Fvrttl,htM ytc• willt Ilrt• nntntal cnml+lcntcnl yd 46 tlhrt.rm, .t,rnvc Iw hnc and Jurmc lhrnq,y• Ilrc rcl:+hlichtttcnI nf :I I,I.rtran wilh nt, aipruhtanl th:rncc in tlh. nunthct nl cr11% with mntc tu icac 1h:tn •I(6 thrt,nu+ urnrc. thr trtrlJu,d t,l tut•a+ntcnl, and :r "frutlralctl•' rcunn nf Ihr mrnrl.cr t+f ttlla wlll+ -Itr thtt,rnt,.tm+c. to Il+c I,rclrtalminl atatc. f Itlrrr grnutnr; Anrit ii:rn (•untt r Snt icly "RAI'I11k1 M(tVAI ()1 II%CIII'('III IttItI: Mt1NOI.AYI'RSItY('OI I tII)It)N IOR CI111C1 t)111 NI SIAININ(i•' Ily )t+hn I' Mant,.. 11,p:u1 tucnl t,( Mitlul,itdury, Mcdit:d ( tdlryc t+l Starth (•:ut+lin:+, ( It.uh•ctun \trnrr Irrhrtrdrrt!t•411 2 7S 77, I4(,S An irnlnuvcJ ntrtn,wl Itn rrrnt,c:tl td li.cur t•ulum• iill. fYr,rn tt,llcr Inlt.c Ik•ft,rc at:rinirr/• rctlutc. Irtnn ac nruth :IC 1( ht+ur. lu :d.nut 1 ht,ur /hc timc invtdvcd itn (at l,arinp crll. 1,+/ ttaininp. clintin.tt: c dtc th:rnt i nf t.un Ir,ct, :md Iwrntilc Ihr I+n•/+•nalittn 4.1 ccvcla) clitlt•c /rt,nt Ihc c.rmr t'ulturc Ir•nnlltin/' Il+c u.c o1 ntnrc Ihcut t,nc .t•nn antl Iltuc Irrm1•in(• nut tlrllrrrnl tcllul:u clcmi nlt r,f intcrctt Iltc tcll. :uc Ir.r,l rrr trnr, tl,hytlr:urtl. :mtl rt,vrrctl ttHh tnllr.Jrnn Iru III minutcc I hi t r•11t,t1am r. I,tnrritl 4.11. Ihi flurtl tc.+Joi hnu+r Ua lula :,Ilr,wt tl tr, tiry Itn Itl mrnulr.. nntl Iht• tulr i. hllttl wrtl+ 1.11, w.+lrr 111, , r•1 Inrhtrn t a.1 1 rrnt.nnir./• Ihc t t II. t. Ir+r,a n, tl :ntt1 rt•ntnw tl• t ut mlt, Ir rt,. I Lrt t d nrt chJr. .mJ ld,•I/rJ rnlr, Inm t onl.n I I Ilr t trlL,Juut r. Ih, rt J• In dr.utJ mtl tlraa,4trl wrlh .rl,.r•ltnr ,Jtr,lu,l Irlh,wrtl hy :t I 1 nrrclnrr r•I :ritt,hnt aml t lhcr I hr .Ir,h. t.nt Iln n Ir. r, hytlr•11t.1 .rnJ ~LUn, tl l'v tr•n., n lir,n:11 n1t'Ihtul. 41,

V. Epirht)rirrlr)Ry "nN I I'II)1 MIOI (Kill'AI SIItI)Y IN I lING ( nN( I It " 11y Ilrllx•rt I 1 nn.h•nJ, MI), NI'II, AfFllcllt• tn Ihc ( antrr kc•.c.nth In.nlntl, Niw I nrl.tntl Ui,ltr nrcc /lrtcl+ilal, Itnctl,n, Macc •( I,ncnll,rnl. (.Intir ( t+nUld PluFram, II S f'uhlfi Ilc•Illh Srrvice: I ntnn•r Urrctll+r. I)rviat+n nf ( antcr and OIhcr ( hrr,nlc 1)Liavt, Maccichuccttc Ucl+artrnrnt 1+1 I'uhtic Ili•11th, 111nton ( rntr.r IR I1/ I1111A )1M), OtlOhcr 1'!h5 Ihic rcfHrrl ic :t ctititlicul invcsliRalian Id Ihc tlictrrbulir+n nf vnrir+u. crnr+king f+t.ltllcct antl r:tllcrns and ccttain tllhcr cnvut+nnunl.tl f•rctnrc anlr+nR II/JI) tn:tlc anti 141 lcmalc InnR cancer I+alientt cccn at t'Irclid Mat- sathuccltc hucf+ltalt durinle t/tc Ix'rilxl 1942 In 1'!hd ilµluctve• tn cl+nll,:trictln wllh inv+king dela fnr c/+nLr+dt witlt/,ut carttcr Ihi hi.lnlic:ll ntithllJ wac rtnl,h+ycll in t)nc ttully It Iklvnll% t/fv+n thc na•rrtnry r,l Ihr inthvitlual rcRarJinr I,att t'vt•nft, hit wrllnynict In tllvulp- 1nll,rnl.Wt+n, .InJ Ihc ahilily rd a nl+n I+/accd curvcy/+t !n I+hl.lin Ihc factt A Iahulmnm td tlala fur mih• cantcr anll t'tmVnl cltl,lictt rrr+ulK•tl hy Ihc Ilfctrrnc nl/ml.cr nf f+itkc r,l tir.lrcllc. crnrrkcd chnwc Ihnl 1hr,.c whn nt•vt•r cm,+kcd tnntti1111i J I tt'': ,rl Ihr IIIJ(1 rn.tlc Ihlng t t/nct r f,.Iliinlc :rrtll 111 77^ 1,1 fhc 111.111 Itl;tlc tl.nu/,lc, .nlldcn 1+1 f+il,ic anJ•ur Ilcer. I+nly wcrc 4I,1^.• inrl 1411J^.• rt,(k'ttr.tly, anll').11.1'f• :Intl 7~ 14': rc.lac lively cmnkcrl (I)••IrNlcc II hr.lvy ,nu.krnc I. Ilrhnrtl :1. cmrlkml• '!.I?t nl mrnc rit kc nf t rpalt tlcc rn u II/, Inn, 1?S „r numi l,:n k'tl.ry y, •u. i c• 1 Ilack nt mrnc deily f++r 2~ yl ir., 2 1• n l c rrr nwrt /1.Irly flrr 1 11 i sr.rn, clt / thc I-t'rtcnl.lpc nf Iht• m•Ik Innl• r.rn„ r I..rll, nl. whr+ wrrc hravy tnlnkcr. wnulrl I+c M1 1f^S . tr+nll+•ncll I.r rar 1': r.l Ihl nr.rlr tr+n)r•,Ic Ilhc rttitt•J cml,kclt whn .nn.lc tl/•erc •nul I,r LIIk% in aJJrlinn In ciprctlct h:lvc a h+wct cl.tlr.ut.+l ri.k ++f lun)• t.mtrr Ill.ln Ihr trnukrtc Id ciF•trcttt'c nnly fnr cttual Icvl Ic nf lh/l limc t r) .Irr tlc .nlr,knll•. :InJ /crn.lli amnkcrc whr, smr,kc arnr+untt cinul.tr h, malcc h.wc a ct/ll Inwi1 ri'k /+f Innl~ c:tnccr• Ihc I:Ihulitit+nc chrlw lfhc I+ilv and/nr cicar crnr+kcr Ilac nnly :1 .li/•htly prl:ltcr rick t,f Iunl: cancct thin thc non tml+kcr nmtlnF nthcr fmdin/'c in Ihic imt.tip:ltiun :trc Iltc fnllrlwinl• Intlividual% with chrrlnic rr.l,irah,rv t+,nllltil+nc :nc mt,ri :Il+t Ir, tlrvcLq, lunf t inccr lll;tn Iltc nnrnt:d irnfividu.d Ihc ivcr;tpc aRc I+f Ihr nl•rlr lurt/. t'•Intrr indrellllc.d h•1. Inrrc:l.id hv alw+ul 2 yr:trt in Ihc I11 yc:lt inlt/t;ll Irr+nt I')t' 11+ 11)f,2 I hcrc al+lv'ire ttn ht' a c,rluleli.rn Iw+inl I if .ilH,clt S11 f,•u k rLrv ycar. i c. I I+;tck Il.uIy fr+t tl/ yc:tr., 2 I+.uI,' tl.tily Ir,r 'S yian. cft I hry.nltl wlt/.h tltc inctc:lcct) u.c nf til trcllr. tl,n c rlr.l r:u.r Ilp li.k :t/q+r, I i:J,)y 1 hr' II+iJr nnnlr+pv r~l lrrn/• t nn+rr ,. n..t r.~.nt.l.lr In .I.u~ ..( tllr rnartv tnn111hlnn.n. In Ihl• .II1.)tl1 M114 h.Ib,w Ih.il /1~. r. n.1 .Irnnl• 0Lr11.liC.Cl :I~~nl i.llinrl Iq'Nit'1, t1rn1• t Jnt rl :1nrl 111'.nl I11 .nl..l 111/'. Inr r.tlll•l~ (l' IIIIr,/111.1 tin.. r urr. nr. i4 :/nrl r.rt Iltu' / "Clltl CC, 1OIln( ('O, nNl) ( l)RONARY 1)ICI ASI IN NtIRIII AA11 Itll AN t'ItU11 SS1)NAL. GROlll'C" Ily Ilcnly I Ituc.ik. MI). Rn..ik I nunJ.uirm Inc , Stolcn Icl:md, N Y., antl St Il:rlrtall:rc Il,+yal.d Nrw Ynrk ( Fty /,nurud rr/ flrr .Irnrrirrrn Als-dnul ./tlraruru,n 1'J2 3 199 1114. Alail 19, I')hS A clnc•cy nf I I,RKI prtlfcctit+nal men in 14 tKCupatinn:d c:t1c(•nlit•c in thc mctlical, tJcnt:d• IcFal cmd cccuri/ics hclJc, which clicilcd 4.'1KI uc:lhlc rrl+licc Ill tltc yucctinnrt:luct• chnws a sltiking asulcialion of ctntlnary hcart Jl.cacc I,rcv:tlcuic with the rt•I:rlivc strescf111nccc (if nccull:Ninnal activilv Ilrcrc wac a mvkcd Rradirnl wilh aFc. Usahlc da/a tin snulking histnry, rcccivc•d Irltm 2•7R7 rcclxmtknlc, .howcd that smnkinR waa clrccc rcl:ncd and a:cn tl:lC/ctitally t'tnrcl:Hed with Ihc rclx+rlcd frct,ncncy Id i•cht•nne hcart Ili.cacc An crnircly utw•xpc•ctcd finding wus the hlghcr I+rcvalcncc nf t'/rrlmary hc:ul di.i act• amr/ng nnn•cnNlkcrt ((•.S4^•i• / Ihan ana,nR cR cnnikt•rc 12 14^: ), a I+:uarlnt whit.'h caclt tl4mhl ufxln Ihc allcrcd rtllc nf crnnkinr in Ihc• rt•nccic Id ctlrnnary heart diccace and adds furthcr emllhacic lo lhc Ilrlth:rhlc inllucncc I+f cmrlliun:J laclorc in ilc caucalinn. Rt•lativc cuctcfulncca rlf tlcculiatilmc in their rccllictlvc Iit'IIIc wat r:ucJ by R I+hycicianc, 7 dcnliclc, I I atnnrTCyc, and l/ sccuriticc c><Ix•rlc• :IC fnllr+wc RanlomR of 14 nccup>aionil.utrrt+rirt by drRrrn rd trrrc•futnr.. I nmry,.nc .Urc, rank /1lcdilint• ttrnrrctry 1 aw Srturrlrr. I cacl I)rrmatnlupy 1'Critahlnlia l':ttt'nt law Nrcl Ica.l I'•rthnhlFy (hthlah/nlia Var clM•ci:lllicc ~ nrcdvclc Ncu nw.l nncctht•cirllttFy O/al turrcty I ri:d law Mucl ( ictt I+raclicc ( icn rraclicc ( kn luncticc I r:ulrr. If .mnkinp ic cymf+lt+milic nf c/n/ltit/nal clrcct antl nt+l, t+l it.clf, an ctit+lnhical faclnr in curr+rt:uy hc:lrl diccacc. r•nc wlluld ctla'tt cm++kcrc and nr+n crnnkcrc wilhin t•ach "htrml+l:crn'Iw." t+t'cultalirrnal .trccc c:tlc(•I+ry lo havc .imil:u ct,rrntary div:Itc Incvalcncc r:dcc. 1nclcaJ. cl+run,ny I+r. v:Jcntc ic cihnitrcantly hil'hcr (rrr tmukcrc than fut rntmvnnkcr% tn coch 1,1 Ihc 14 I'ruul+t Whilc thic n/ihht :q,lt•ar tr/ indic:tlc thal crnrlking ic m+at• .trl+nl•Iy rclalctl trl icthtmic hc:ul tlicc:t.c Ihan tK.ullalirtn rcLrlctt clrcc., Ihc :q+l+,ucnl thll/ rrttt'rc in .Itt•nplh uf tclalil/nchih ct+uld In• dut• lu thr I'rc:ucl Ilrtcta prncily +,f thc Irccc yrt,ull ac ctlnq+atcJ with the rt•lalivc ht+nwl•cnilly r+( Ihc cnulkinp ftn,u/+c It ic tr-nt InIIrJ Irlmt Ihic clluly ( I 1 that cmr+linnal clricc urly ht• :nl unlNlr/an1 attt It•/:nuq. laclllr in :dhrrl+l'cnccit whrn Ihc tbcl ic lut'h in :Inirn•d 1•It. 121 111.11 .nu,kin/' II:nlctrtc in Ihc Intltvidtc/l „r fyl+ul+ m•ry Iu,,./Jr In inllrt I,y whn 11 rrrn.ulm•rl ti ncil+n. nlay l,t• rcl•rliv/ lyl:1\tl ~Al'II, ( I I III•11 wIr/I1• Illl .mnkinl r,f Ird,.atr+ nt:ly I+t• inllrht:llyd itt Iht I+tlhrq•cniac rd .,+rr+n.rly hcarl tlr.ca.r. Ihc /1 Llla,n.ltll, n n,+l a t L•ar nnc Nn ctl+l:lnalir+n r, el h.lnrl Irl a/trlnttl Ilrr Iht Inw (,Irv:Jt'ntc Id t+,lnna/y ht':ut Ili.racc :Int++rt/• I„ I.rrn. wlrn rlrttc .mrdr J I lnt unlinuart, c,+I III, cm.din)! Itahn m.1y t.mcc I r,lnl l. lr rcvt•rc:rl Ilf Ilrlrrrrl,+llc rllctl.:unl Il l.lllti °inunurnly.' Ill Llhtrtnt hr.rrl Ji. m a, 11 4t a. t,, .

.1 I- 7 .+... cacr r111crn;lllvrlv. Iftr if,ilitv In alnr vnnS.rnF nl.lv Inlldy :I rl•.Ih( nt In'r.rm a111y rc.Jxmac In atrc%t anJ Jrnlinnhc(I vulnrr.rlnhly tn athrrnl.cmt Inllncntr. "14kON( II(N;I NI(' ( nR('IN(1N1n A SI111)1' OI ('ACI'C Il2I nll l) Af //)IINS II(rl'I:INS II()SI'llnI I ROh1 1911 IO IvSli ' liv Wdll:)rn I Ricnhnfl 111, M11, J:Imrt 1. I aRx•tl, 1611), :InJ Sun/ncr Wl+rxl )r , A11) I>.-Lartnlcntt nf SvrY,r•ry :InJ P:nhulnRy, /nhnt Ilnl+kin. Ilnivcr.ify S(h(xd n/ Mc111ttrlt•, It:lltlmr+rc, MJ .Innulr n1.Curgrrv I1.1 S 674 (rKl. I\1ny 196" ((irintcc W(xx)) 1 he avthnra analy>'e elinical anJ paUlnlnrical laclnrc in I+;lurntc whh hrnnthnpcnit t art inllm•1 Ircalcd :,t Jnllnt Ilnl+krn. I Iny+i1.J tlurlnr :, 1S vrclr It•ntxl ( lnc hunJrct) anJ ntn( ly rtin(. rali(•nla Irt• .ch ( Ir(I wh., rrll rl /ht• fnllnwlnr, t'cilrr/i I) cnml+lrrc chrnt'.11 rrtnrlJa. 21 (Irllnllnr .t nr:+Uvr•" rc.rt tirrn, 11 I+nrFhnlnpit' m•Itcrr.,l evalt•Ihlc 1r,r rt.ln(ly, •,nrl •1 ) I,II.+w nl, tmul Jr•ath nr Inr a mlmnwrn nf S yr.ra I hcrr wtrr 1 17 I,nrulnrln( t Ir+mtr.. dh Inlx t rnrnlc%, 1? h/h+l. t Innlrct, and 4 acr~ nlcnt.J r+r wclJpt• rcact ti,mc I nnR Irrnl anrvival fnllnwlnr, nlx'ratinn ia rclatcJ to hi.lnL+pic lyl+c an(I hhxxl vcaa(I Invavnn In.lArw.r ,.l wl•r.,r V.,,el In...4•w 1..,.. h rn. a.. Rn.n(l,..d.,, rn,-.n. tlll I'R 17 t`t n/l 1 1 7 14 1'F ro.ln. /!41 Irr 74 Ar. T: II'IR 7-` 7• 1 11 tnll':. SQlan....r,.fll,.r( I.r.r,lr11 17At 17 /n 7{ll: 4r.!nll 7h7': II'Ir./.R of': rr,.•.r.l.lll.rc 1~.,.Ir111 147/ 4 I'J/ Ir7! . 111'IV 91 4 ': 1r/ 17a': 11n.hIIr1 Il.,rr,rltl .u( I!CI 71:v v1 t: 7r,.;7 V., 1. : I' NI1/'• (Inil.nfl I,ni.ll lt!II ,ar( 1111 11It II.I : IJrt4 tlMl': II IIMI': /1001 t,7: lV4 !" V: I I!IINV Nr. 7. ••11, 111 S(1":. An mdrtiai.c rrl~lil+nthll` ~I'Iw ira fx twccrl aurvlv:ll .In(1 /n+l.l.( nlrnl n( lyml,h n(xlrc ~nJ J rnilmal hrunthlal In;l+)•,In,.vc Id Ic.inn inll ty~x cf nlxla lion I hcrc ia nn r( Llliun.hiJ, Ix Iwrcn .urviv:ll ;1nJ ar., :1p', t.ltc nl Jur:llinn of syml+rnmc V 1. I'ttlrn(rnrrry 1'hyeinluRy "Itlt)N('ItOI'I11 MONARY Il IT(ASOW I()1lA(*(Y) ANI) tit I_A11'1) SllI4SIAN( VS I 11RON('II(K()NSIRI('llON ANI) Ifl(I)N( 1I(/1)I- 1 AIAIIIIN INI'l 111 N( 1OF I IIN(7 1)I NI ItVAI1ON II I11tUN ( tIIAI. AHIFRIA1. INII ('IIONC /)1 NI( ()IIN1 ANI) IIICIANIINV III A\ON I(1'11 I:XI-S I-I 1( 111 1) 1 ItOM 1111 VIS('I I(nI I'I 1(IRA SI'l)NSI S, IV IIItON( IIIAL VAS( (II.nR AN1111RON( III)MO1(/1( RI 111I 1f1 S(I(;(;I:SI1:I11)I l I.NCF I(IN('I ION " Ily 1)nlninpn A1 nvi.l(Lr• MI ), Mtlen S.Ilninrlo, 1N1), :+nlJ ( icr.11J W I'cakin, MI) I lr(I I,.,IIr l 1. I)rl+.lrl Inrnl nf 1'h.lrln:lr ulr+ry, St h(wd tit Mctll( inr, ( Intv( nFly ul 1'r nrr•ylvaui;r, I'llll.lrl,ll~hi,1 Irlhrrrl lr/ ln,n.rrrnrrrur111/rnhlr II 2 1.11 ISI, IS: 1S'/, Ihll Il,l, ,n„I 11.7 1)/. Au/•u.1 IVr,t ((;r•111t(c A vl.l(Ir11 I ln Ihr ~nl ah( url J J.,I• Ilr, .,In,un.ll.,lnm „I t I('.nl Ilr .Inr,kr ur / 1 nicotine aerv.anl In one IunR initialcd the follnwinR hil+ha.ic rcal,nmea: (a) Inith:ll lnnnthlx-unctriclinn invulvinR thc v:rgus nrrvr, anJ II,) wh.cyurnl hrunthrxhl:uau(+n invulvinR the synq,alhctic nt•rvnuc ay.trm 1 hc mrch:ur iarnc (nr Lrnnt h(x6lal;uinn h:lvc nnt Ixcn iJrnldlrJ hut rl r• rr:r%(+nutdc In suafn•t't Iht• rclt•:Lt' tit catr.hnlamincc (rnm thr adtcn.rl mcdulla anJ dnrcl .timulatinn of Ihc aynq,:dhclic Ranplla Onc f.rnnthtk't,n.lriclnt mrth.lm.m hat been iJt•n1/1irJ tnn.iclinK uf a vay:d rellrit inhiateJ (n+m Ihc airwaya 11 In the ant•alheti>'cJ JnR, thc hrnrx'hial :nterial injccti(,n (+1 ni(n1in- intn thc riFht lunp. rficitt Ihrce mcchaniamc: ( I ) hrtnxhl,cun.tri( linn tit 1he came tiJr whith ia nK•Jial(•J via llle p:uacymlarlhctic g:u11tILr in 1ht• airwavt anJ ic hhlt krJ hY hr~:mKthunium thl(,ritk; 12/ hn+nchtKtln+triiliun tnl Ihr nthcr .iJr whith ia rntirrly a rcllrt rurdi:rtcJ via lhc varua ncrvr; nnd I 1/ a JrliycJ hrnn(h(xI11a1:Hinn whith i% :Ilw.li.hc•J hy an adrencrrii bh+tkln-r Jrun fnr tl/c Itiml rcct•I+tnra which mrdialc hrnnchtNlil:rt:qi(+n Iliatanunc rhtila I anJ 2:ImJ it i. I,uqx,.rJ that hiat:rminc rclt•:r.r m:ty I+r thc ha%ic mccllaniam /nr thc Mnnchncnn.trictiun ntCCIlJllltnlt ;Irllvatt•J hy nicnline 111 1 he nlihlicalinn nf hictaminc and nicotine ct,lulit,n I(+ the vi.ccral pIcura of Ihc anctthcliicJ Jng clicitcJ Ihc fr+llnwing mccllani.mc: (a) rnrrr- Inhnr rnenJ rcflcx hrnnchncon.triclitm mcdiatcJ via intact vapuc; (11) brlrr• Irlher reflra hrnntf>,KOnslritliun. I,rnhahly art aRnn rt IIr. invnlvinR Iltc fx•riphcral prcFanglionic vagal lihcrs; and (c) irur,drrhur rrlliu hrnnchrx'nn- .Iriclinn, 1nt+hahly an ;nnn rrllcx invulving Ihc varal 1'anq'li:l in Ihc lung A11 Ilrrcc rcflcxc.. arc mcchanicma hltx'kcJ hy lhc Idrtn:J aJminoralinn tit hJlKainc. IV. lhc f<IrrrninR papcrs cttahli.hcJ the mcch:rni.ma fnr hrnrrchn rnnsthitlnr rccJxtmc tn cigarctlc vn>,+kc and nicl,tinc hul Jt) not :tccnunl ft+r the hrnnch(xhl:(Inr rcclx,n.c It, Mllh AlthouFh inhalalinn nl ci)•;trcllr tmnkc (I) and thc I+Innclu:d artrrial adminiclr:Uinn tit nit'nLlnt• 111 1 rtirilrJ :1 hil+hcnir rrqxrn.c tn hrnncht,t'rn).trictiun It+tlnwrJ hy hr(Inchn(hlat:rri(rn. 1hr Jrl:lycJ nn%ct t+f thc I:utcr rcnderrJ it diflicult t/. Jiflrrrnli.NC Ix•Iwrcn a hx.d Lulmnnary mcchani.m and a syctcntit' unc inw,IvinR climulatinn tit .yml+a Ihctic ganRlia anJ rclcaac of calccholamincc. Furlher e.fx•rirncnls ia,lalctl the tighl hrontfiial arlrry anJ cul+(+IirJ it with a I+cr(uaiun I,um), sy.ICm which Jrl:ryctl cntuy t+f :Iny catcrhnl.lnnnt•a rt'IraacJ fr(tnl Illc :IJrc•nal nx•dulla into Ihc hhwxl aul+ldy tit thr airwav• I hcy rc•uI1cJ in ( a ) hr(+nthtalilalalinn fnllnwinK inh:Jalinn tit clp:ucnr .nu+kr anJ t+rnnt'hial arlcri:ll injcttit.n (,f nit-rllinc; Ihl htr,nchial :trtrtial vnaxr+n.lric linn fntlnwinp 1)u .amc Iwn InIK'tJurec, anJ (c ) l+nlmnnal y reaxnn.ulctinn Ir/,m inh:J:llinn tit t iRmctte cmnkr and hrt.nchial rnlrclinn nl hi.t;uninr I lie hrnnt h(wlil:d:dlnn, likt' Ihr hrnnch(K'(+n.uirrinn, thrrrfl+lc 1% n+rJi I1cJ f+y n(•urnrcnit mrth;nn.mc in thc huly I ht• .ynll+n(hcur :I..+n rrlh .r. JI'nlnn.Lr:11cJ :nr (nnvdt•rrJ In fx' dc/rnar lan(Ilnn. whi,Ir 1(Ilnlr Ihr arnnunl nf .ul,.lan( r. aF+anrtx•J lrnnt Ihc hrnR :InJ lhua m.linl.nn .nl :nlr Ilualt• vcnlil:tli(ln I+tlJn.i(+n rafin "( AKI1OX YIII Mc1(;I O111N 111 111()I)YNAMI( ' nNI) It1 til'lltA IORY RI SI'()NCI S I() S't1Al I(()N('I NIILA I1ONS" Ily CI,Irhl n Tt1 ny,(a. 47

St:,nlry ( iiannr lh )r anrl Ruth (i Armctrr+np, I )i I+:,rlrut ntt ++( '';t rhrrnc anJ SurFrry, Sr Vnnrrtt'c II+n1+n.rl antl !tltrht.+l ( tntcr, rrntI Nt-w lnr4 Ilni vcrcity S.hr+a+l of MrtJtcrnc, New Yr+rk ( tty .Srrrrrrr 14').141 144, )uly 4, 19h5 ((irantrc Ayrrc) IlcmrKlynirnic end recpiratnrv rneacuremcntc were mmt1c nn I,rrrnanc hcfr,re and after inhalation nf tulht'icnt earlr+m monntnlc tr, r:rnce the car- tvnyhrmr+plnhin to f•ctwccn S and I(1 per ccnt of catur;ttirm Arlcrial and mitrd vcnmrc (ltypt•n tcncinns tkcrcaxd on avcrafr 7.1 :rutl I I i 1><•r ccnl, rccf.cctivcly Onc of livc suhjccts dcvclu(rCd cviJcntr• of milJ left vt•ruricular rlydunc(ion Othrr Rranrnr: Ifealth Rexareh Council of the (-ity of New York `('AIISfS ()1' ARIF:RIAI. IIYP(1)(FiMIA IN PAIIVNIS W1/I1 OII SIRII('IIVF I'III.MUNARY I:M/'IIYSI:.MA" fly Strl'hcn M Ayrcc, MI)• antl Slanl, y(iiinnclli Jr , MI), 1)cparamcnts t+f Mrdicinc anJ SurRcry, St Vrnccnt's 11r+tl+ital, New York ('ily, and New York t)nivcrcity SthrHd of Mcdicine .Imrriran Jrrurnnl n/ M1frJrrirv 19/3:422 42R, ScPtemlrr 1965. ((iranlr•c' Ayrcc) Arlcrial nxygen Irneir,n and alvt•nlar vcntilatinn were mcaeurcd In eiFhteen (+:rticnle with nhclructive pulmnn:rry cml,hyccma In tcr, of Ihcce paticntc Ihc tlctcrminanlc of artcrial hcmt+plr+f+in catur;,tinn were analylrd by a technic cr+mF+ininR Iht• rnricurcmcnl of alvc•r+l;n artcrial ntypcn Icntinn difTcrcnccc af twn Icvclc of mc/+irctl ntyKcn tcn.inn wilh thr dctrru,inalinn of the diRncinp c:+f+:,city r+f Ihc InnF f++r c:rtlwm mr+nnciJr Arlrrial rrtypcn tcntinn wac Ir+wcr Ih:,n nnrn+:rl rr, -III Iint twn ++f Ihc ci/-hlccn I+alp•rrtc It wat conclut)cr1 that hylrrtcmi;, in crnf+hyct m:, wa. Jnc In a tr+nrl+lrt intcrl+l:,y nf tcvcral (artnrt, parlic'ul.uly alctrJ.rr vcnriL.+linn, vcnt+ :ulcn:,l chuntin/' antl the tliclrihutirm nf alvr td;,r vcnlrl.di++n intl I+ulmr,n:uy t;rl rll:uy IK,fu cit+n: diflucir+n limitatinnc were m+t fnund to I+c a tirmfhc:tnl c:,u.c rd I,ylr+t crnia in rcctinp cuhjct-/c wilh cnq+hyccma Otlrrr Rrnnrnra: National Inclilutcc nf Ilr:,lth, and N:Nitmat I uhrrc,ducic Acct,ci:,litm Nrw Jertcy Mcdic.il Retearch and fr:,t'hinR Funtl "('I FARAN(T (1f- IIA('l1 R1A fly l1IF I UWf'R RFSI'IRA IORY 'I RA('T " fly (:uctavc A I aurcnii• )rncf+h )Onarncri, R:rul It I-nJripa and )uhn P ( arr-y, Sclr+n 11.01 ( nUcFr nf Mcdtcinc, /rrcc•y ('ity, N 1 Ir rrru r 142 I572 IS11, Ikct'ml+c•r 20. 1961 ((irantrc I aurcnii) Acrrrtnlt pt nrraletl frr,m a hnlfc•rcd cuc/x•ntir+n nf h:,clcria cl+r:,yt•tl fr+r 111 minutcc inlr, :, chimhcr h+dJrnl- 21N1 Swicc Wchttrr m:,lr mitr, whr+tr hu,Rt arc nrurn.rlly ttcrilr, dre:rlqa•mcd r:q'ully and I,rcJictalrly frnm /lht• lunr.c r+vcr an R hr+ur Lcrir+J hrllr,wrnl' cul>,r.urc Ihc cnnttant I+.rr/rrn of tlc•+r.+nt't• r+fTrrt .+n cclw rrn++ 111.11 cytrrnl 'rn wln+lh thw c/lctt, nf v.+nnnc r+m thu"n1 rr l, v:+nr I" r+.t+ir:ur+ry inl++ru+n t:,n Ir t.Um.+lrtl yn,u+tuallw ly Inl+.rl.+iinn +d t rl•.nt llc .nudc .+1 cul+I~+ti. tnncrnrr.ttwnc r+f rut++rnrc rrrlntc+l cl+ ar.+n++ t+, t111y r t t'nl..+ntl r!+c t'c/w+•t d rnict rrl.unr+l d S linu • Il,c nundrr t+l I+,i,Itrt.r :+a 11" r tnntrnl. I I1+~I .+linhnl n+l++n+ur. rt'+lutrtl tlr.vauti In t 62 per cent, wirh a retention ratio of 3 A. ('rutiarnc injectirnrt chr,wrd RI) I+cr ecnt clr:,r:rnce with a rctcnlit,n ratio of 2 4 I lyp r+ii:, rr.uhctl in 70 IK-r ccnl clc:+r:,ncc :,nJ a rctcnlirrn raUn of 2 5. Ofhrr Rrnnfor: U S Ptrhlic Ilcalth Service. "IMP(1RTAN1- 11F.1FRMINAN7S IN Pl)I.M(1NARY RIiSIS'IAN('I 1O IIAC'1 f:RIAI_ INfI (TION " F1y (i. A l.aurenti, ). 1(:uarnt•ri and R It I--.ndripa, 1)ivicinn of Recpiratnry Fyiceatrc, New lcrecy ('r,IlcRe of Mcdicine and Ilcntittry, Jeruy (•ity. Mrdirinn ThrnotrrL, 22/I.4R 59, 1965 ((7rantcr: I aurcnyi) I hie ref,r,rt Ikacrihcs the remarkahle caPacity of the normal Inwer recl,i ralnry trat-1 to clear bacteria and remain cterile. 'Ihe rahid elcarance nf acrntoli7etl c(al+hylrKncci (rnm Ihe IunRs af mice yuanlitalcs Ihie prnleclivc ft,ree and r+fierc a Lrcdiclahlc tyalent for Ihc irwcslil;atian td I,utmnnary rccic/ance Io anl,nrrx contapinn lhccc atudics show that smtrke inhalatir+n and alcohol eaua marked impairment of Ihic funclion. In addilinn, it wae fnund that the pretence of rnJinary pam neRalive pathoFcnc in thr intecliaal flora of Ihc mnuse predicPt,ces to cmukc inlcrlcrencc with the I+ulmt+niry diclx.ca) of inhalcd bacteria. ()th.r. Rrnntnr: 11 S. Public llcallh Service. "1'I.1'CTRON MICROSCOPY OF nRSTRI1CTIVf? Pill MONARY f'MI'11YS1'MA " Ily R('. Reynnldt, MI), Accittant I'rtdcctnr, I Inivcccily nf ( r~at G,utt,we ttcrn Aletlic:d Schrx,l, I)allas. Alydirueo 7 hnrur ntr, 22 2 11 161-170, 1965 lhc rccidual IunR in mi,ted Panlnhular and cenlrilnhnlar ernl+hycema cnncittc nf a nclwnrk r,f lihrnut tr:,lrculac cnnlaininR lhtt,nchi, hlrw,d vrccclc, and Iyml+halicc Alveolar mrmhranec arc virlually ah.rnl, Flr•ctrt+n micm ccrq+y t,l the tra)x•culae rcvcal% that they arc covered by lylK• I anJ tyl,c (I alvcnl:,r cl.ilhrlial cc11s Thc elatlic fihers are thick anJ cnll:,p.en ic abundant It is tuppcated Ihat emphycema ia hatically an atrophic rrrK•ccc invttlvinp the alvrtdmeapillary mcmhranec. lhe ditaPla•arance nf thc meml.r:,nec ic atcn ci-1tcd with cnll:y,tc of thc alvcnlar cannct-tivc Iitcue lilk•rc :nuund rfhc hrnnchn vaccul,,r framcwnrk of thc (unp. V11. (:rfiemielr•y nr(tl Rinrhemiory "1)I?II'RMINAII(1N OF NI('OIINI: IN SM(/A1 RS' 111(IN1: ISY (iAS ( I IR( )MA IOGRAI'FIY " Ily Nc:,l I McNrvcn, A:maya I I I(.u•uy•ham S:,r,h,rJ 1':Ha./,nrk :rnd Rall+h I IA+afn,:,n, Wrnccclcr I r+nn+l.ni+m I,+r I cln•r, rnrr,t:,l Itinlrrpy. Slrrcwchury, fvlncc Nururr 2111t )1(1( 7M'r, Nr+,r nth+ r 211. 11/6% ((iranlrr. 111urfrnan/ Sincr Ihc rt•Lrtiun nf nicnlinc nhcrrrf-itinn hy tm++lcrt Ir+,++rru+.uy rha cmw it rn+l lullv unrlcrtttHKl, a tlntly wac ,u,Arrl:rkrn r+/ Iht rluenr+l.tlu+n nt nicutinc antl ilt mcl:rl,+littc in Ihc hr+Jy tlurJt t+f crnukcrc I+y rut.tcurinl- nrt u ~ aH 49 m

i finc cccrctinn rd arr,r+krrt and nnn tmukcrt I hc mc:r.utt'd nurrtnrr crtrctirrn in n,R rlay rc t3hulatctl as Adlr+wt Chrrrr Ir,hfaccn Nn or .m,.unl Nunrmr rtcrr/u.n I ( /P.lfrttrc 4 • O IO 2 " 10 1) 27 3 " 25 () 74 4 " 27 1 17 3 " 30 10 S(/ 3 " 31 346 5 " 31 4 O(. 6 " 4 3 S R I 7 ('iR.rs 20 R ~ O 1O R " St R R tl/ o Pipe 20 R 0 I I T he variatit,n in nicntinc excrctit,n hctwccn individualc, tnhatcn lnrmt, and amt+unl n( It,haccn consumcd, it prnhahly a reflet'lir,n of the cmt,kinR hahitt of the individual "SItHItNIf f`Ai T17RNS OI.- RAPI1)I Y F'RUI IFFRAIING (()NN1:('- 11VF I ICCItI C" fly Rr,hcrt Auvin Mrlch, (icruKc UCry and Mitharl A NauRhtr,n, Ikp:rrlrncnlt n! Surptry antl 1lirrl.hy.icc. St'hrw,l of Mcthtinc, Jrrhnc Iln(,kim 11nivrrtity, Il,rlrurn,rr, Mrl ft-lrrnura rr Rnrrhvvrn .Irtn I(M) ' 2 (+11 (,1r,, May 4. Iyr,S ((ir.+ntcc (icy) in the (+att cfuJres nf cmnnronvr• tiauct havc IK•en limited mainly to the analysis d/ nnly I t.r 2 per tcnl yd the total m:rct nf any given cunnective titcuc, and vitlually nrrthinR accmc tu have tiern kntrwn alawf thc remaining "incoluhle" materialt Recently this lalwrratt,ry found that all conneclive tietuce with the exccplinn of hair keralin can t,e ttdnhilirrd in ItN) l~ dichlur- natetic acid antl that subunits ean be rcprrnlacihly isnlaletl from the tnlutitmt hiVinct diRcrences have been noted in the suhunit patternt and in the chemical comlxicitinn of rnonotlicperse and exPerimentally aldt•hyde crtns- linkctl fclatinc, and in the skins and atxtac (d clunnnloRically ynunR antl uld animals, including man 1'yually strikinR difTcrcnccs havc been noted in ctmnective tittue ncr,platmc I he tulrunit patacrnt nf certain of thete con- stiture the tuhttanct' nf the rrcecnt fnrlimin:uy tc(wut Ihcy arc rcrurdrd primirily tn inJicatc the uselulnctc and lx,ctihlr imlw,rtance of thr an.,lytical mcthrtil in Jcvclut+irrR new areas r,f invectillatirm I)thrr Rrnnrnra: National Inatilulc nf At,hrilit anrl MctatMdic 1)i.cotcc and Amcrican ('anccr StK'irty "Sl'Nt111 Cl` (II Ill NI()IItC111'1 NIAI'IlI NI S I5 ANI) ttl I I S OXII)nIlON 1'Itt)I)1/('IS" 11y I Iiuhu 1lrrycr :uu1 I'rtrr 11rrn(rIJ, Ilu, Rt v:vr h Imutntr, (:unhrnlt, " r•, M.rtc l nnrr,rl I -f f nhrllr,l ( r rr) vnr.lt I? Itr) Ild nl-rrl lirnr I'rr,C (( r.rnlrc I 11„rrn(.urVctl „(' lal.ellctl l.cnro(rct) rcnta/,hcnc, known at 1.4.q.10 Jihenil,yrene, „(' IaLcllctl Lcrvr,( rt( ) rcntaPhene-S,R ditd, diacclate; anJ „( ' labelled l.rn- ?n(r.O(K•ntancrnc S,R-dianr have been synthecirett fnr the study nf the dictrihuhrrn. Ihr mctatMrlic fate and the nxnle of aclitrn r,f the carcinogenic hythta•arlhrn Jrl.cn/f,yrcne, which al,rcars to diffrr from tNhcr known car cinnRenc with rcR:ud to thecc factors lhe eiFhl ttcl,c in the cyn/hccit Procednrc are described in thit PaPt•r lhe readtc of the biological experiments obtained are reported eluwhcre Other Rrnnr.rr: National Cancer Institute. "IHI: L(X'A117A'IION OF Sll('CINIC. 1)f-IlYl)R(N:1'NAS1= ('Y1O- (111tUMl? UX I1)ASr ANI) Ah1iNOSINf: 1 RIPIIOSI•IIAI Atil? IN ('lI I A11-1) RI-SPIRATORY FPIrII1:1.IttM." 11y Ilertha R('rrcc, AlcRantlcr SlrKk antt (7uncan ( IICatIlctlnRtnn, Ikrartmentt of Analonty and Pedi- atricc, f)uke tlniversity Medical ('cnler, Durham, N(' lnu.nul rf llttrrr rhrnnirnynnd('vnahrnrirrry 13/R.(J7-6R3, IY(.S, ((;rantrc SPt,ck) f itcuc culhncc of rabbit tracheal epithelium with ht•ating cilia were incubated in a mctlium f+crluccd with cigarette snxrkc at a ctrncentratinn equal tn ttrc cmnkc (rf nnc cigaretle per ml of mctlium, whicIt rctuhcJ in the ct•cca lion t+f ciliary activity in 15 to 20 minutes. 1 he fx•rfuccJ mcJium wat tlten removed, the ticcuc chamber was rinced twice with the cuhutc rncdium, anJ frcth mcdium wac adtkJ to the Iiccuc: all thc smoke culvrct•d cilia wcrt• nhtcrvetl to rrmain molionlcct llcinR a I 6 dilution of smoke perfutcJ medium, ciliary rnntility wat nhcerved to slop in 30 minutee. Removal of the smoke Ierfuet•tl meJium antl replacement with freeh medium rewltetl in a return to normal ciliary rnrr(ihly within IO In 15 minulcs. FPithclium with beating cilia wae positive for adenncine Iril.hntPhatax (AlPaee) while the epilhclium with non-hcatinR cilia wac ncpalive fnr A I Pace, or weakly positive in a few scatlereJ areat. 1 he pretence of Al Pace in LcatinR cilia and its atnencc in non hra(inR cilia suRRecrs Ihat o.iJative enrymet aetrKi:ucd with mittwhnntlrii at thc haec nf the cilicHCd cclle anti atknntine ftil,htxl,hale (A'I P) furnith the energy for ciliary mtHility (hh.r Rrnnrnr.: National Inttitutcc nf Ilcalth and Amcriran 'Thnratic SoIciety. "( ITI OR(K;I NI(' ANI) NF(Xllt OR(GI NI(' A('ll)C IN ( I(inRl I I V SMOKI- " 11y W:rrrcn Stctk, nnw at 1'ratric Rryrrnnal I.rlarr.utrty, NR(', Satkatrwm, S:r.kanhcwan, CanaaLt; noJ S 11 WrnJcr, ( hcnn.rrv Irrh.ul mcnt, I/nivrrtify rr/ Oklahnma• Nnrm.ut lrrAnrrr, 1rir.r,. '! tl 55, rl.urh 26, 1')65 (Gr:rntcc Wt•ndcr) t Iting t hrr.tn:rlrr/ ral hic Prnccrlntct di vchqw•tl h,t thit tturtv. t hlrrtr, fcnic ant) nrrr hltun),t•nit' atirlc wi rc id, nlihctl in t'tu.u t, tl t nnr t ntr.rr, . rrl lar ticnl:rtc m:utcr Irr,m thc m,rirt.ftc.rm .nurkt• rd ?tttqt nrrn Idt,-r t rf~.nr rtr. I,utchctartI on the rqrcn tn.trkcl a, 51 Sn m

"11)I NTIt I('AIION OF7 SAI I('Yl.t(' ANI) ISOVANII 1.I(' A('II)S IN ('!( iARI: I I I? SM(1KF.." Ily W Stcck, (-hau ltwa Yang and S II WcnJcr, ( hcmittry I)cF+artrtxnt, Univercity of Uklaht,ma. Nurman ( hrnutrry anJ InJu+rry 0I).5(r0.561, March 27, 1965. ((:rontce: Wendcr ) F'arliculate matter from the smnke of 2(NX) non-fihcr ciRircttcs pur- cha.cd (,n the orcn market was utractcd R hours with Irnlanc and then R ht,urs with nxthannl, conccntrated to dryness in va un, re-cxlr:rctcd with mNhan<d nd clutcd with water. Successivc frat'tiuns of 1(M) ml each were cntlected, cnnccntrated in va-wr to a smoll volume, and studictl qvalitatively by rapcr chromatnRraphy "Two phenolic acids not previt,ntly rciK)rled in ciRarctte snxikc were identified as salicylie and iuwanillic acitls "11)UNTIFICATION OF 4O('AhFFOYLO111NI(' A('l11 ANI) RF.- LA f FI) UITS11)IiS IN lUflA('('O FROM ( I(inRF .l-T FS " fly A 7ane. W Stcck and S I I WerKkr, ('hemistry I)cp.rtnxnr, Univcrsity nf Oktahoma, Ntuman Tr,hnrrn Srirnrr 9:R5 R7, )une 11. 1965 ((irantce Wender) luhaccn from 76(1 non filter cigarettes communly uud in the United Slatcs was fw,itcd with aqtxous nxthant+l, filtcred, and re eulracted IhinR chrnmatt•Rrarhic proccdures, chh,rrRcnic, nctahlnrrRcnic, 4 0 caflrr.yl- quinic ("hand 51O"), ferult,ylquinic, antl p-ct•nmarnylquinie acidc and IO- caftenyl. and I l) feruh,ylghrcnu were itkntilicd No previt,us rcference to the it)entificatit.n td "hand t Il)" in e ttracrs frt,nt currd tohaeco nr from green Inhaccn filanls has been Gnmtl "A S1'NIIIFSIS 017 1 0 4 ll ,,,n,l t!r I I 10 11 r)1'I l)I IINI(' Al'II)S" fly A. 7ine and S II WrnJcr ! Ir,r,urnv ,ui,l /rr,/rnnr •2d 11114 II/1S, )unc 12. 14ht ((;rantcc Wrn,Lrl I o obtain rc/rrcnc c.I:,nJ.u,l. I,,r rJ, nn1r, .,rwn .Irulrt . uf "lhrr (ctulnyl quinic acid icr,mrrs, a numlv r r,f whrt h h.,,c ta r n Imuml rn trd,.u t,,, I,rrtat,a s, tomatoes and ct+lirr, thr I!/ 4 r 1 .rnrl t! r IrruL,ylyurnic :u rJ% h:rvn cwcn synthesized anrl Rf valucs t,ht.,tncd hy I~.,IK r t hrnmit„fir:,(,hy wilh variuuc stdvent .y%trms Authentie 1/) rcruh,ylymnic itid suhhlrcd hy f)r 1' G,nd- heimer was alct, tested artd recordcd in the tahulatit,na, tt,gcther with chluro- Rcnic acid "F'AF'f?R ('IIROMATt7(;RAf HY IN IlFN7FNf?-A('FTl(' A('If)- WAIF.R AS AN All) IN ESTIMn11NG URI T. IIYUROXY1.CROIIPS IN 1'Il1.N(1L1(' (YyMI'OIINI)S" fly W Stcck and S II Wcndcr, Chcmis- try I>rpartnxnt, University of l)kl:,htrma, Ntuman Innrnnf r,( ('hrr,manror- rarhv 19/1 564 571, Seplcml.cr 1965, ((3rintce: Wentkr) I he Rf vaiucs nf Rh I,hcnnlt, phcnrdic at iJs, cuumarins. Irlrrmrlic alde- hytks, and at'etufihenr,nes have trrn dctcrmincd rrlrrimcnlally in the Ixn. zcnc acNic acirl water ( I?t 72 1, hy vt,lunrc) Nulvcnt syvlcm. ,ntl the rr~ullinR v:,lucs Itavc been atutlicd nN a rncor,a ol c%lim:,tin/, (rrc hydrmyl rrnuln in Ihcar tnrnlM,unrtv Ilhc rc%r,lrs inrhr.ur• Ihnt Ilu% ~rdvcru %y~tcrn is alrpht ahlc ftu thc cttimalu,n n( Ihc runnlTr nf Ircc Incenrrlic hyrlrrnyl ~rnulx t,rc.cnt rn manv Jitlcrcnt tyh•v rd Inc-nt,lic crrmlWruntlc Ihc cr,hrr rcactir,na :,ntl Ilm rt t r nt t nf marry rr/ thrtir tmny-urrntl. 1,e.c .,Lr, IK•cn rccrnd, tl "T-LAVON171h ANT)CFRTAIN RfTATf?t7 F'IIFN(11 I('('()Mf'OIINI)S IN I'AR 1 S llF 1 Ilfi TOIIAC('O FI.nW1iR." Ily R Watanal+c antl S 11 Wender, Chemistry Ikparlmcnt, University of Oklahuma, Norman A.r hnvr of RLti hrmitrry anA Riophy.titt 112/1:111-114, (ktof.cr 1965 /(irarnlrc' Wender ) Identification and distribution studies have been made of flavonuid anti related phenolic ctxnpounds present in four kinds of floral apT.cndaRes nf tobacco. Starnens contained rutin, scopalin, esculctin, chloroRcnic acid. glucose elerivativcs of p-eoumarie and ferulic acids, and an unknown Rlrrcn sitk of kaem(,fcrnl. lhe last three were found only in stamens ('nrr,llas (fictals) contained seopnlin, eseuletin, ehMr~Cenie acid, rutin, nictrrQurin. iaxluercilrin, aslraRalin, rutin-7-Rluctnitle, antf nielo0trrin-7-Rlucuside Ihe last five cnmlrtunds named were found only in the pclals. '1 hc laat three have not been rcfxxted previously to he present in tob:tcco lissue '1 he calyttes or tepals contained eacuklin, ehlort>Renic aeid, seorolin, rutin, a yucrcelin. l tliplucnsitk, qucrcclin-),.l'-dimcthyl ether, and qucreetin l rncthyl ether 1 he laat three were present only in the calyaes 1 he pistilk cnntaincd c.cnletin and chlnrnFenic acid, hut none of Ihe abnve flavunol Ftycu.itlcc of ruclhyt ether derivatives virt. Phrtrmr<l'oloRy and /'syl•ftrr-I'h/trmrtr-oloRy "SING1 ti PX 1 RACTInN MFTFI(yh FOR 1111: SIMI II VANUOI IS I'1.11OROM1 I R I(' hfil FRMINA-1'ION (1F SI:R( ) I()NIN, 1)()PAMINI:, ANI) NORFI'INFiP1IRINfi IN IIRAIN" fly Robert M I•Icming antl Wil- liam (7. ('lark, f%ychopharmaeoluRy Res. I.ahs., V. A. Ilml. , Scl,ulvcda, ('alif., and I)ept. Ilinl. ('hcm , Univ. Calif. ('enlcr fttt (lcahh Sci , 1 uc AnR;- Ics; I?ric I). Frnttcr (now at Ilniv Chicago, III ), and )nck (' I uwnc, V A Ilncp (Resc:rrch), and Narthwcstern Univ. Mcd. SchtMrl, ('Incagt, (nt+w at V. A. Ilntp., Tucson, Ariz. ). Analyrical ('hrmitrrv 17; 1,.h92 h9(,, May 1965 ((irantce: ('lark). A mcthtxl has been developed for a single ctrlvcnl cxtractir,n and the simullancuus dctcrminalion of scrotonin (SI11 ), dul,iminc ( I yA ), :tnd nrnc- pincphrine ( NF ), in kss than I pam uf brain ti..uc in thc hrc.cncc and in thc ahscncc n/ rcl:rtivcly IarFc anwunts t,f Ihcir I,rct'uraa :nuinu :rt iJ. :rnd snme rel:ttcd amh,gs Fsscnlially the mcthtxl invr,lvcc ucctr,nc cootr:,rlitrn t,f the arnint's frr,m hrain hnmt,Kenates; rcnxwal of the ncch,nc hy cvalauutit,n in vtNrnr: c.U:tclit,n uf the retidue with hulamd s:aur:ncd wilh 111)IN II('1, adrlitinn of Ircl,tanc tto rcturn thc amincs to an aqucnuc ph:rac; I,a.a:rcc td Ihc ayucnu. I,Ir:rnr Ilut,urh an it,n cuclr:m(;c ctdttrnn whiclt tct:nna tlrr amrnc% hul nut tlrc nmintr acids; and clntit,n :tnd flttttrttmctric :rn:dy.i, n( Ihr :unira•a Ihc r.riratirrn antl Ouruesccnce yrctra r,f Ihe :yry,arcnl tl'I I. I)n rml N1: c.tratlt-d trr,m mt,mc hr:un wcrc tuund tn h:tv;• thc %,unr I'rnrr.J 411,00 atlcriarirm aa Urc :rutl.crttic :tminea I lie c.tr;rt'tir,n rt-cnvcry rr/ t:u It .unrnr w:tc unittnmly (.t"r whcn curtt(l:rrcd tr, cdcrn:d .I,,nJ.udc :,n,l 'r 1 Itl/''i whcn cnmlrnt J t,, intcrnet .t.rntl:ud. I hc lur,t'crlurc t':rn IK• ,nrtl Inr u..ut. nthcr t)r,rn Irr:nn I nng. hc:rrt :,nJ inlcuinc havt• Ir-cn analyictt .:,uM.,t rrrrrty 51

i Oth.r Rranror.r National Inctitutrs of Ifealth ( 1), Natinnal Acv.ci.tinn of Mental Ifca!rh, American Ileart Ascra-iatiun, and American I cRnrn I'utit No 11143. Van Nuys, ('alif. "NI( ()11NF: FFFF.('f ON TIIF SLFFP CY('I.E OF Tllfi ('AT." Ily I dward F 1?frmino and Kcn lchi Yamarnnlo, 1)crartmenl (,f I'harmacnhrgy• llnivcrsity of Michigan. Ann Arbor. Scicn<c IS(1 6)7-(,1R, (ktrrt.cr 29. IVhS (Grantee: f)omino) Small doses of nicotinK (0.003 to 0 01 mg/kg of txxl~ weil:ht ) given intravenously to alccping cata with indwelling hrain ckctrndcc farxluce ( I) initial ckctrnencephakrgraphic activalion which was accnml.anicd hy hehav• ionl arnusal; ( 2 ) a few minutes Ia1cr, slriw wave slcep; and ( 1) within 15 In 1(/ minutes, fad-wave akeP Although prril+heral afferent sttnnAariun, rc!ease nf rpinrlrflrine, anr/ arginirK vascr}+ressin canarihute to Ihr initial arnucal cffccts, the primary actinn (if nicotine alrrcars to he nn the central ncrvnus system Uthrr Rranbr t 11 S Public Health Service "NICOTINF LNf)1!(-Ff) ('FG ANf) f11IlAVIORAI. ARO(!SAI." Ily Ken Ichi YamamrNn, now at Shinrx+pi Research I atxxatnry, (kaka, )afran, and Fdward F 1lrrmino, 1)crartmcnt f+f Pharmacnlopy, (tnivcrwy of Michi- Ran, Ann Ancl+r ln/rrnorrrrn~l /rvnnr~l r/ Nrrurq harmrrr nlrrRy 4 h 1tV-)7), Nnvrmher IVf,S ((;rantcc I)omtrxr) Ik.scs (+f /) tM!5 I) 01 mp IR ( ) nrcnthnc given inLravcnrnrc!y nver I minute hrfxlucrd Irancrent hrhavrr fal arrrusal and I I (0 actrvatirrn in cats with chrfmic inrlwelIurR hrarn rlcttrrKks 1 hc cfTctts uf nrcrtlrne were cvidcnt when the animals were in natural clrrw wave Idcep) c!cep ac frhticrvcd tx'havr iarally and by the 1:1:(3 with rccnrdinpc frfrm varirruscnrtrcal and culxfntical sitcs After nicntine adrninicrratinn, the animals were arr+uccd fnr a few minutes and later bccome sleepy behaviorally and shnwcd FU(i slcrw wives. lhis was frequently followed by "aclivaled" or fasl wave skep 'Ihis Irhe- nomcnon was nM evident following infusion of equal vulumrs of warmed saline solution In equal doscs (}) nicMine, nicotine-N mide and cutininc did not affect FIiC and behavior in slow wave sleeping cals Ilrrwcver, eyuilrreccnr dnces of ( I) nicatine (I) OS mR, kg) and nicfrlinc N n><idc ( I S mg'kp) rroJuccd sliEht behavioral and 1:1:(i arrrucal in t'alc with cluw wave skclr Massive rkrses of cntinirx (25 mglkp) given inlravennucly were Iccs eRcc- Iivc than ( - ) nicotinc in doscs of //(11 mp kg Fqnifireccnr dnsrs of clli ncphrine (F) (0(N)2 mg'kg). rhcnylalanyl lycinc vacnrrcacin (S(1 milli- unitcikg) and I)MPP (0(105 rnRAp) rrrxluccd weaker Vl'G activation and Ix'hnvifrral arnucal than ( ) nicrHine f'rrtrcatmrnt with ttinxthidiniunr (2 nrp kP.) Irrvcntcrl thr cardin vaa'ular cf/cctc of nicotine hut drd nrtt altrr (•rc:rlly itc Ix-h:rvinral arnusal nr I I(' Jl liv:rtwrl efTl'lle f rn Itir -rhi r!r.rnd nrrr .nni!.nnrr~r rlt r• nrp ~)• I r~~fn~rlrrClV !rlrqkrt! i Ihe cardinvascular actinns of nicotine as well as its eficctc on FFG and hehav- ior. l.arger does uf mccamylamine interfered with the natural sleep cyclc of the cat, fly use nf such pharmacoNigic techniques it is concluded that the behavioral aroucal and fF.(; dcsynchroniring eRects of nicotine are duc Ini marily to an action on the central nervous system rather than peripheral aflerenl stimulatinn or rekase of various neurohorrmrnes N<rwever, thece later effects contribute to the total phenomenon produced by nicotine in intact animals. "MI?('IIANISM OF T11F SYMPATHOMIMf TIC RFSPONSF. OF Illfi r'AI'S IRIS IU NI('OIINN." fly Richard A. Atkinsun, 1)arrcll Witt, and 1. P. I Amg, I k'partmrnts of Anesthesia and Pharmactrkrgy, ('<dlege of Mcdr cine, Slate l!niversily of Iowa, Irrwa ('i(y. Jnurnaf rr/ l'hrrrrrmcalrrxy unJ f t/rcnmrnruf /hrrapeu/i(f 147/2: 172•Ig0,Februaty 1965 ((kantcc 1 rrnRl Nicnline hitarlrate was injected into the common carotid artery of adult cats ipsilalcral to the eye under observation at doses of 75 pg/kg in 0Y:'e saline srdutiun Injections were made at intervals of 11) minutcs, a schedulc and dosage which yielded consistent resronses confinec! tn one eye. I he Irancient ipcilateral dilatation of the pupil was inhibited by phcnrulaminc, bretylium, tnlaroline, phenoayhenramine, reserpine and guanethidine. Removal nf the ciliary and superior cervical ganglia did nol affect the mydri atic rccponse to nicotine allhough, in this situation, il was inhibited by hesa methonium, tcaramc,hylammonium and hemicholinium 'iherc was no pharmacological evidence of the prescnce of chrdinerpic fibers in the roctganglionic sympathetic pathway to the iris 1 he sympathn- mimelic respfmse to nicotine was dependent on the relcasc uf calcchfdamincs from pnctpanplionic sympathetic fdicrs supplying the iris It is suRgc%ted that there may he ramifying sympalhelic ganglia dictal tu the cu/x•rirn ccrvi cal ganglion 1 hc e.cision of Ihe latler structure may not have IufalucrJ complete sympatheclnmy, and nicotine may have cauccd mydri:rcis hy climu lation of thesc "ganglia". "A PIIARMA('OL(X:IC'A1. STRAT7:GY FOR Illli S1111)Y OF ('I°N- 1RA1. MO1)I)IAIOR I.INKA(*.t:S." Ily 11. (' S:dx•Ili, MI), LM.titute fnr Medical Rcsearch, ('hicago Medical School. Illinnis ('hapter I 5( p:rFcs 14 S 1142) in "Rcccnr .IJvancrr in Rinlrrricaf 1'rychiatrv." Vrrlumc VI, cditcd hy Joseph Wartis, MI), puhliched 1964 by Plemrm Prca, Ncw 1'fnk ('ity ((iranlcc: Pmfcsair James F.. P. '1-oman, ('hairnran nf 1'harm:rcuhrpy, ('hi cago Medical Schcxd ) -This paper discussrs a set of pharmacolugical critcri;r dccil-ncJ In tccr for fxnsihle central rnrxlulatnr mcchanisms and tn caaminc thcir rrde in ht•havinral amt nrurnluRical funclirrns and Ihcir mrxlihcaliun hy nrcrrtrnt' •rnd drugs of current clini(al usc. 1)rup aurtagfrnicm ctuflit•s were u%cJ Irr cunhrru the rclatitnochfh t.ctwccn a givcn druR effect and its 5u.lx'c,cd rnrrdul:rrrrr action f'rperirncntal tinflinrc with I,IIC1-IIILIII/lrc, /rllllrr rrlllrlll (, :111tI I tiI) 2 S 55

were cnn.ittrnt with Ihe hyfxrthcvs that thcsc apcnts Prntlucc "irnf ltancrfus dnrupuf.n tit sevcral crntral mrxlul:ftnr me(hanisnn tit cunu.isl, ;fpcnts with selcctuvc syna(+tic attilrns, irxluchnR nitnune, {trrxluccd hchavirrfal eficcts lfnly at ncurf.hrRical or (.Cri)ficral trrS rc duscs 1 hc schcrnc prescntcd, although cansidcrahly more com)+licarcd than the usual dothrrlflmies tit chr+hncrRic adrencrpic, ctcitalnry inluhitrny, etc mcchanisms, is ncverthclcss recc>Rnired as being a gross over sinrlrlifrcaliun of thc neuru Pharrnac'otoRy of the txain. (fr/rer Rrantor t 11 S Public Ilcalth Service. "l1SO1)E (-OMPt I I AI)(1RFS EN 1:1. ANAI.IStS 1)I=1- I=I.1'('1 ROFN('E- FA1.(K7RAMA "(l/se nf comruters in the analysis of F1 G) fly Iifctnr F. Salvlli, I atxrralori0 tk Psic0farmacatlfRia, Ilucnos Aires, Argcnlina ('irnf ra r!nr rrrrpoa rlln 21 64 74, 1'chruary 1965 ((:raruce Prof 1. E P I ornan ) I his papcr rcviews the uu of digital and analog comPuters in the analy- sis of the cleclrocnccphah+Rram It Rives particular emphasis to averaging of cortical evoked f.otentials srxl the use of this technic for Ihc uurly tit central drug eflccts Several eaampks are drawn from the author's work with nico- tine and other druRs which act ufxon central synalnes ( Vanqucr et al , Fed. Proc , 1.t,24R,19(.4 ) 1 he use and limitations c,f currenl nx•Ihrxls uf autnmatic analy-~is tit the srtmtanenus I T(i and Ihe Ixn%ihlc u~rfulncts rff I+hasc hl:fnc analy'•is (suR- Rcs(cd by loman rl al) arc disrusacd Other Rrnnror.: (-onsejo Nacitfnal Jc Investipaci.rncs ( icntilicas y I rcnicas (ArRentina) and Aux'iac'irfn ArRentina Irara la Ayuda al I nfcrm-) Mcrftal "nRll(i Flf f( 1S ON f:I.F('TRI('Al 1.Y-INI)JI(TI) RAG1: . 11f:IIAV- 1OR IN ('A 1 S" fly Alan Katu, sfxmsored by A. J Varqucr, MI), Rcsearch Instructor, 1)ivision of Rctfavioral Sciences, ('hicaRo Mcdical Schtx,l, Illi- nois. ChicaRnMrAiralSrhnf>rQrmrrrrfv25 2:4S,Summer 1965 ((iranlee: 1)r 1. 1-.. P'foman, Prnfessor and Chairman of Pharmacology. Chicago Medical School ) Previous invcstiRatnrs have shown that muscarinic aEcnts induce in previously normal cats a temporary rage state consistinR of hissinR, biting. attack, salivation, and Pilocrcctirsn In the present exrcrimcnts rage was clicited by electrical stimulatinn thrffuRh clcctrtxks chrr+nically inyllanted in amypdaloid and hypothalamic repirrns I lectrical stimulation aL+nc failed Inelicil the (ull fledged riRe behavior charactcristit-rff drug induced hostility'y only IiissinR, escaf+e, and bitinR reactinns were ohtainccl 1 thr rflcc ts of varirrus tlrup,s rfn this elcctrir ally induced rapr lrhavinr tit tnts .hmw rh:rl hiainR alq,r:frs tit Ix• fafiliral,d by IMrth muu:urrnil nnJ nicrrtinic tl,vp%, rualx• a(qx•ars tit t.c t'firnarily niu.c:uinic, and hitinp «cros In Ix• unalTcttctl rither by hfrf nr anti tliulincrpil cumlxfund,; I1thrr Rrnnr.•r I S Puhlfi 1irallh Vfvllr I IX. Other Sf ff dIPf "11117 ' RFI ATI(INSHIPt7FSMOKIN(7TO111F?OlffC(1MF 01: PRF.C- NAN('Y " I!y Paul l tnderwood. MD, l.awrence 1.. Ikstcr, MI), I ucker 1-affitte Jr., M[), and Karl V. (;regR, MD. 1)cpartment of Obstetrics and Gynecology, Medical College of South Carolina. Charleston Amrriran lnurnaf of Uhttrrrics and Gynecology 91/2:270-276, January 15, 1965 (Granlee- Hesler ) A statistically significant decrease in birth weights of infants horn to mMhers who smoke in comparison to children of non-srmtkinR nxothers was found in a sludr of 4,440 1ntpartum women representing Ih,I5R PreRnan- cies, who were mterviewed regarding smoking habits and previous PrcRnan- cies 1 hc decrease was inversely related to the number of cigareues smoked daily and to higher sociocconomic status. A two-fold increase in prematurity occurred in smokers in direct proportion to the cigarettes sn>iokcd daity. A mother was classified as a smoker if she smoked during the latter half of her pregnancy. A slight increase in ahortion rate was found among smokers, hut Ren- crally not significantly. There were no significant increases in stillbirths, major fetal anomalies, or maternal complicalions txtween srnctkinR and non. smoking motfxrs, but there was a su"estion of an increase in the incidence r,f premature rupture of rrxmbranes in smokers. Smoking ditl not interfere significantly with breast feeding. In the lahulations, (iroup I rclates to I,4R7 questionnaires representing 4,126 pregnancies at a private hospital with patients of above average eco- nomic status; Group II to 509 questinnnaires on 1,216 pregnancies, mainly arrt,tnq unwed mothers and irKfiRent white patients; and Group III to 2,44S questionnaires on I0,R15 pregnancies among indigent Negroes T.ble t Numher and percentaae of women divided imo their retpective AnffM Smoken (packr of cis.rertet per d.r) Group Non .mnken < bS M in I ? 1 Smoking hisrory No % No % No 'R. No 'R 1 965 5112 134 9 0 2(17 11 9 2R I I R 9 II 257 506 62 12 2 (,R 114 121 2 3 R 111 1.790 73 2 395 161 171 6() Rv 1 R Tahk It Rirth -riahri o/ inf.nh In ar.mf (:rnup Nnn .moler. Smnkrr. Ipuhl rrr rf.urnn prr .t.r / Sm<rkins hirrr,ry t N l1luI 1 3,522 3,349 3.236 1,169 11 11.304 3,171 • .1,146 31)92 III 1.126 2 V1R 2.965 11111 S r, 57

1 he IarRe majority of Ncpo mnthers ( Rv J^ ) smnke ks% than Il/ ciRarcttes daily or not at all 1 hc average private hncl+ilal wllilc infant weighed )Vh Rrams more than the Negro infant in the non snurkinR groups. Whether the influence of s(.cilxcorx+mic factl+rs is due to nntritir.nal, envi- r/.nmcntal, emolinnal, or medical rcasons can only be one's supf.nsition. A siRnificanl qucslion that remains unanswereJ is whether the dccrcased birth weight of infants hrxn to tnyokers is detrimcntal. Sy Re-ciPicnl.4 of Grauits Following is a list of all recipients of grants al+llrovcd by Ihe ti.icnlilic Advisory ltuard since initial grants wcre made in lalc 1954 Somc of Ihc projects have been completed (:RANTFF. ANI) tN4lrr(1TNHV ( t ARFN( I M Al:R1 SS, M 1), ('hrrf, ( n.Jr.mna ulnr ! uh•rranrry, Veleram Admrnntralrun ( rnler, 1 tw Anaek.: Au.rrnfr ( /rnr•./ P.n/rnnr q Alydl rrnr, I/m.rrvly of (ahlrnni., Im AnRelr. AN111()NV A AI HANI S/ , Pr/ I), !li rnr.•., Nr•rrrn,rn nd Af.LM•Jn Rrvnrrh 1)ruwrn, Ihe Wrnrfhed Mncertnn Rur1e Rehrf Fnundalion, 7Ttie Hurle 1 ormdaliun RehaMlitalion ( enIrr, Whrle Plaien, N Y. ANI11nNV P AMAR(KF, PN I) , f R M S A.urronl Prufru.n, f)r(+arrmrnt r•/ flh.urnru r and G rnrr rrh+fl, The AIhany Medic.l (-nikge of llnion llni .enily, Alhany, N V, 1: 1 AN(1FI AKOS. M n, Pw n. Prn- /rrrm r./ Ph.unl.q(., &nlnn Univenily S(h..rd of Mrdrrine. Rmlon. 1) Ml1RRAV ANGFVINF, MI), I'.n- frurn .•/ /bthnlncr, Ilnivenily of Wi+ronain Mrdiul Schr.nl. M.divrn. IK)MIN(N) M AVIAIN), MI), rrofn- Irn n/ Pbmnr.u,A..rr. Univclsily ut Pennsylvania Sch.m+l of Medicine, Phil- adetphia S111't11 N M AVRfS M U, !)nrrlnr. ( mJrr•rulnr.•nn.r l.rh.vnrr.ry, S/ Vincenl'a 1h+.prl.rl, Nrrr Yor1 (ity I RI I11 RIK H RAN(:. M 1), P.n/rrr•'r unJ ( h•n- r••n. (r.pr.rrnrrnr nl PurL., hr••R•Rr- lfw Inhm /ln(•Im. Ilnwn.rly. \.h.rd uf Il/prnr arwl I'uhhc 11rihh. Hal/rmurr PRIIJE('f l fi1.G Me..ruernrnl of Ihe funclinnal aarn. d the human hearl hy (rrqurnr v'(rr Irom •n.lysn of it. .•I+uh.+na rnrrtf the effrct of nicnlrnr on pr•.Irrn .nA •mino acrd metahM.h.m In huu+.ot ('hronr.xnme pallrrni in t,.rlrrnlq with car crmuna of I're Iunt, Lefurr, dunnR, .nd after tre.tmenl Rele.a of crlechol.mine, hnru l.ted heart the iwr Pathotollic-analnmir study nf cellular ch.ngei in human hrr+nchi I-f1ecN of nicotine and ciRarelte tin neuroteme mrchan..m+ rn amnl m/t Ibe lun/ Me.auement of al.enlar arlerial nilroten ddference by Raq chrnnvlutraphy The di//u.inR capacity o/ the .Iveolar membrane in MJmon.ry ernphyam• Relation of .ir M+Ilut•nn Iu de.eh+pmrnl nf chronic pulrnonary Jraea.r nf 7he eflects uf rnr.wred .mall amrnrnli e.rMty hemrrRl•rhrn r+n urdrmr.pn Inry function in m.n 1nlrrarUOn uf vuu.e. wdh mu•..... a.( /hr te.Pnttory /r..l, .nd Ihe rf/r, 1 ul .rra Irnn in Inn./n•n nf the mrrr •n rlr.rr y%/+ /rrn 1he mk of hvptrrlau in h,.ur rr+rymer I K1111 K1( A W IIARNI S_ /. . M I), Prn 1), Arunr•dr I'..•lrron ••/ A/n6•rnr 1o chronr. d.maRr 59 to

1 CRANTFF. A"11) INSTfTIfTt(/N end PArunln~irni ChrTnrry. lohn. IloPkina llmversily Schnrd of Medr crnr, Raltimore Md fnnw Pro/rsvv of MeJrcat $crenct, flrown (Iniverdly. Pro.rdence, R I ) R/ RF[)FRI( K RFCKFR, Ptn f), AJro- rlnrr P.r.frrrm nf Anafnmy and Dlrrr. ror, I aMral.xy of Prrinasl Scirnce, fluke llnirer.ity Medical ('ewter, [)or ham, N C. RAI PFI S RF('KFR, Pit h, Prnfrunr rrl ('hr.nnrrr, llm.tnily of Ilocrstnn Ilrroslon. f eus SAMI/1 1 RI I t/ T M T) Dirrrfnr, 1)i rrnn~ n/ ('nrdrnlrer, Philadtlphia Gen rr.l Ilrapital IIYt AN A Rt('KFRMAN. M 1), Arr.• riarr (;Irnrre/ Pr.•/rlrnr nl Alydurnr. .nd Al VAN I RARA('ll, M I) ,('nn rolranl in Afrdulnr Crdlere of Phyli eians and Surlleons, Columbia llniver Cnhrmhia llnivrnilt Rrsearch Strrict, (inldwarcr Mrmonal Hrnpital New York RI('IIARh I RINO. M I), Prn/rrrnr nf Afrduinr end ('hnirm.n, nrpnrrmrnr of Alydninr, Wayne S/alt llmrtruty ('oltr/te of Mrdicine, t)etrnit PRf)1F(T 11,11 F, Pouihk eflecH of rn.trrnal intake of nicotine ulr,n the drvrhrpmR felt,, and neonate A study wrth the rat and NrMa 1411 An Invesligation of rpeclr.l pu.meters of aromatic hydrncarbnnl A rpettr.l investiplir.n of arnm.tic hy drncuM.m and thrn rnmplt.es wdh proteine The effect of nicotint on cardiac irritation in the prestnce of rtserpine, .nd the ef fecl of nicotine on cnrnnary blood flow of d.p wilh cornnary imufHcieney Fflects of nicotine on the morphnloRt(~ of coronary arteries and anrta; Rhrrrwrlyfic effecb of nicotine on human and animal pla.ma-; eflech of cessation of smoking on strum chokcternl le.els of chronic amokers; the effecls of ri)tarelle smoke on frrt /atty acid Ievtls of sub {rctq with myncardial Infarclions Non irrit.nt ciRarelle fmnking with nhrrr..tinrn on the carbon monn.ide cnrKrntuation of arterial hkr.d and alvtolar Ras afler smnlinR with Inhalalion nd after non inhalation smnkinR The effect of a non inh.ling technique of ci/taretle smoking on the carbon monoaide bl.xd kvels and •enlilalnry func lion of healthy subjecN .nd palients with chronic respiratory dise.se TTu effect of smnklnR on the enronary hlrrxf flow and certain phasts of myrr e.rAial melahnlism in palirnls w,lh arterfosclrrotie or hypertem,ve cardi nvascrdar disease Slodirs in cellal.r phy+ioiory of ht.r1 musc Ie Messurtment of cnrnnary hhrwt Rnw hy mtan, of raduracl,valrA •Ihrnnin The rrtrrl .f .mnkinr ..n r.•r.rn+ry hhw.A fl,rw In rr,lirnh ..nh .rlrnr•irlrrolrc he.rf d,.ra.r .nA the r/lrtt nl mcntine nn .roraRr nf aminr, in hr.rl mus.lt A(r..nrrrnrnl nf cnr..n.vr h1rrvl f6.w wilh a ivrlrm u4inR cnrntiJrncr crnrnlinR. t (:RANTFF. ANI) tNTTTt\RT//N / RFf) O R(X'K, M S, Pw 1), Senlnr ('enrrr Retra,rA Srbnrlre Rtwwell Park Memorial Imtitute, Rinlo(;ical StHion, Sprinwille, N Y (see Moore) IIFRMAN V R(1FNIO, Pnf), Nrad, ('Armrury and pu.rArm(rtry Drpar(. n.rnr, Spindletr.p Research ('enter, I e. inel(on, Kemu(ky IAMFS F RONNIiR, PN 1), Prnfrrrnr of Rrol.rr(., ('aldornia lnstitute of Tech nnkryty, Pasadena. WAI TPR M R(x)KFR, Prr [).. Prnfrrrnr, and ifrnd Drparlmrnl of PAarmarnloR1. Iloward l lnivtrsity, Wtnhinttton. D C. TOM G RpWPRY, PH D, Pesticide Rn. fdur laAorernrv, Chrndatry Drpar( mrnr, Nnrlh Carolina State ('n11eRe. R.leigh. (nnw E.tramural (>peralions sn.1 Prncedures O(Rc<r, I)epartmeM of Ileaith. Education and Welf.re. Re thesJa, Maryland) RARR/1RA R RROWN, PH f)., Research I'rrrflfJnl of Erpr.imrntnl PtyrAla(ry. ( aliforni. ('olkge of Medicine, l.os AnReks )nSFF RROZFK, Pn h, Professor and Chnirmnn. Drpnrnnrn( of PrycAoloRy. 1 ehigh Ilni.enity, ReNhkhem, Pa. SUF Rll('KINGIIAM, M f), Atriunnr Prn/rtsor nf Prdiarrirr. Columhia llni. rersity, ('nllege of Physicians and Surgeons, New Y.nk Cily RFN/AMIN RI/RR(1WS. M 1), Asurl. nrr Prn/r.rnr ,rf Alydicinr, Ilnivenily nf Chic.Ro, ('hitaro I' M RIITT, M I1, l'hief Porhr G.RIv, I ns Angeles (nunty IkapAal, 1 ot AnRrltf. t •Irfr.rnra PR(11F.CT TTT1.1A the effect of nicotine and change in heart r.le on cardiac meuhnlism snd related subiects Studies on cardiac metabntism with ape cid reference to myocardial .m,tia Inresligalion of the biological eRects of cigarette smote An Initial study of the effect of model free r.dicab in c.rcinollenesis Fn,ymaie study of inethylation reactinns in p1eM tissue Sludies on the pt»sihle sensitiralinn of Ihe vaseular mechanism Iro ca/er6M.laminec fullowing nicotine administration TDF. and endtin re.idues in cigaralte smotle Nieolint and smokinR eflects on electro eneephaMRrvm corrtlales of hehavirw, ensotional fesponsireness and viau.l pereeption in call RioloRic.l ch.raeteristin of men .nd their smoking habils Studies on Ihe develnpment and binloelY of lung surfaclanl T)xrracie cnmpliance in chronic nMtrvc (ive lung divase , P.IholnRie analnmic stndy of cellular than[ts rn human hrunrhr Clndv of frut mel:rl dnr.Rt rd p-lrn.m ary •nd livrr 1i..ue by .prrlrnR,.phu .nd chennul melh,als RI( IIARI1 (1 R)I RRUM 1'n1), rrr. Ihn.ynthtti+of the P1ri,Lne rmR nf m,n rrrr,.r nf ( I,r.r,rrnv, h(rtMRan Srale line llnivrr.ily, I a.l I anama ' 61

CRANtFF AWI) Ir~YllilfllON SK/I R M I M11 1' (A/1/1 I Pn lf . ( hounrnr. c hr,,•rrrrv IrrParrnrrnr, ReRrs ( ollrtr. Wrdnn, Ma.s WIIIIAM H ( ARNI SMI),Pro/rfsn. nf Parhrd••cy. ttmvrruty of t)tah (bl- leffe uf Medrerne, Sail I a1e (-rty MAR( (IS N ('ARRO1I, la, PMf), (hrr/. /)r•ru.w of I'h.rmarrdofy, The /1rr.oldde //oapnd ( enler, Rroollyn, N Y 11 (1P(11 I1 ( FRI ( f I1O, Prr t)Prr•fer rnr n/ RrrrA.mrrrry an/ Nrrnrr••n tlnrvtrvly of Pntrln Rico. Schord of MeJrcrr.e. San luan Iformerly Profes swv nf Rinchemnrry, / nrdham tlmver uly, New Yor1/ Wit I IAM (: ( 1 ARK, PN t) .('Ir,rrn! Atr.rrrarr Pr•.In..v n( Ph.rn•h•rn,d <ahlnrnra ( hrmnrry, Ilmrn.rty of Mrd•ca1 ( tmrr. 1 nr Angelra G, Pr••Irrr.•r •.l I(ANS i( 1 ARKI I) Runhrn.rtr.r,l nlr~rnh~a Ilnr.rr.~~l r •.I IrRt n( Phyaci.n. an.l \-a-n. Nr. Yor1 IrtlueJ xr 1h.lll tnY 1) ((11 1 MAN h( t, . rti, ('horRr. Prrr/~heral Vaacular I .1.•r. Inry. Maasa.huarln Mrmmul lal., Rn+lnn 1)ANII I((1IIfN, 11 V M, M P 11 . A1 ruronf Prnfrn.v nf I'Hrrinore F(•rAr- j anA Puhhr Ilra/rh, ScMnl of Velrrinary Medreine, Ilnivrnrty nf Ptnnralrania, PhrlaArlphra It11I1tS It f()k1R()1, ta, h( 1), fh•rr• r~•r !.r•~h~ .nu rrL•r Rrvnrr h Ir.urnrrr, Irn~.rr~~ry r.f 1+hf••rn• A1r•hral ( rn PRI)PF(7 1fI1 F. ( ornparrann nf nalyUcal mrlh.rla by de/errnrnrnR the (.ercenl rrrn.rry of arsenic ddrd al Innwn Irvrla In to hacco sanrPlra and a hrn.d aurvey of the amnunl of arse+tic prrvnl in tohaccn aamrlrs from a wrJe va•rNy of sources Puho{oR.c analomic studres of cellular changes in human hronchi ('enlral netvuus sydem evnleJ Ihmiaa and cronnary lJrwtil Rr.w arrhy A study of raelv tlumrul rh.nRes in Ihe lungs of wmor hrar/ng nts nd mlce I f7rc1 of nicnline anJ relalrJ suhatance+ nn amrne Irvtls in Ihe ntnnrn aNlem P-l-lar•r arl-l.n nf tht ••hrlt hhKrJ rrllk nf r r .nJ Ihe rflrrl nn whde LL.•,1 •rll.,r,v/~ra •~f rarrrn~.frna, n.•n•r,..n .~n.l r.rhrr •nRutn.ra I Lr rRr. r~.( H nr ~dR. .n,l / ia •r. .rlhulmr t.alr.h•.larr••nr~Jrl•IrlrnR r• h1~..1mR .Rrnr.l ~•n tht ayurrylhrrrc .aarynn .rnrlu.n _lu.rJ 1.1 luh.u.n amnlinR anJ by rn.rrr•nmrnlal M•.ly crrJrnI Ihe role of calerMdamrne rtlra.e hr.rn IIK adrenal rnedulla in cau.rnR the cir tulalnry tllrcts seen Jruiof tobacco smnlint lo survty radioRraphrcally Ilu IunRS of all dr.R+ paaainR IhrnuRh the velerinary clinia+ and Mnphal af the tlnivrraly nf Pennaylvania Vetennary %cINM.I in nrder lo Jrltrrmne Ihe prrv.lrnce of (nrlresnnary abnormaldira Jrle.lablr Ly Itrn mclhr.s a cnr.lparahve I•ulmnn sty drva.r uuJy tn drhne Ihe P.tltrn, of rear•inlury dnesae in ammal+ in limalrly aharing m.n't rnvnnnmrnl and prn.rdr rn/nrma.on rn Ihr rflrtls uf •.r L•11••lu.n the r(Ittl nf arnnlinR urrrn .-ay reanl a n. r ,lnnlsvv nf r a.r hnlnrrt• nn rmph.arm. Il? (:RANIFF ANt) INmllrll()N ttt'AN M ((1NN(/RS- M1y Au.+riare flurr rnr, llrpurrnrenr n/ l nMnur.ry hlrAnrnr. SI Muy's Ilmpilal, Madr snn, Wiacon.in P1117 IP (-(x)PrR, M 1) ,( h!e/, Surtlral Vclerana Adm/ni+IrNinn Ilof. Pnal, Rrnna, N Y;(7rnirol Prn/nrne nf .torr(ery, Alf.nl Finslein Medical ('nikge, Rrr.na (formerly Pro/rsa.» n/ ('Irnrral Sr.rRery, Rmlon Ilnivenilr 4-h.ol of Medicine .nd l'hlr/ n/ .trrlr. ral Srrvicr.nrl lhrrrr..r of Srrtirl/ Rc. verrA Inhn.nr..r1, Ve/erans Adm7nis Iral•un Il.uaprlal, Prnvr.tence, R. I I RORI'RT I (-RAIN, PNI), Arairron( Prn/rnrn n/ Tnrudr.Ry, (Inivernily of ( hnato faer F Ka1i) ( F( 11 F( ROSS, Research Ikparlmenl, SI )mePh rIr»prlal, Rurhanl, (-alifrx. ma (sre Salishury) A1111-RI 1)AM(1N MI), Pn1), Ariir. Innr Prafrnnr rr( AlrJrra! MrhtnPrrl. nRe, I)rpnrrmrnr if lnAorrrra! //vRrtnr, IluvuJ Sch.nt of Puhlic Heallh. Rrnlnn R/ 1)AWS(1N, Pit 11 formerly Prr./rr- sur r•J Rnrnry. l olumhia l/niversily, New Yor1. ANI)RI W S 1)IRN/ R. Phl O, Eveu. rnv, Piyr An Rnnrrr h, 'Thc Age ('tMer u( New FnRland, Inc , Hnslnn, Mass lace Whi.\in/ /1)WARI) I1)OMIN(t, M 1), Prn/r~coe u/ fhnrnrarnrr.~(r. Umversily of Mich iRan, Ann Arlwx RAI PFt I Iy(/R1 MAN Pu I), !)irerrnr .n/ lWurcesltr I Mrnrlabon fnr I (rrirnenlal Rrdofy, %hrewahMUy, Mass /n..w at Cynle. ( or(oulion, Palr. Alln, (ahf see MrNrvenl IAMI S I 11YAR, Pu 1), Aruuant Prn /rrov •f Rrnl..sfr, Rtll.rmrne (blleFe, I nruavJlr, Ky 1/1/tN W 1( KS11 tN M I1, A..mnnr l'rr./rrr•rr n/ lnur..nl Alrr6.rnr, ( o11rRt uf hlrJrcrne, Clate Iln.verarly of lowa, Inwa ( Ily PROIF(T TfIT.E A sludy of Ihe al/eratir.ns in the human Mnnchi.l wall occurring with aging. with parlicular tmph.+ia rm clnlic In sue chanRcs and a+sncia/ed chanRes in the bronchial lumen sia A sludy of the eflecls of ci farcrle smolinl on levels of Ilaslric .crd, Pep+in, and uyopepsin A study of Ihe eRecl of eaeracls of lohac co on cultures of lumor .nJ mnmal celh. Animrl transPlanls of tumor h. we from liscue cullures Study of cnrnhlned eRect of in/'~cled .iral aRcMs and cnvironmenlal Lclnn, in cludinR cucinn~em arw/ tobacco smnle, on the (r.chevrhrnnchiat tree and pul mnnary payenchyma of ea(.erimrntal animals and on lissues in rxgan cullure Studies on the combined eflects r.f inRuen ta viruses .nd sulphur dinaide on lung pathogtnesls in Syrian hamaers Social and p.yeMdoRical cnrrelale+ nf adrqMinn anct dncominuanon nf tigar clle smnking I'Reels of smnlinR anJ nf nrcotlne on Ihe heart and euclAaliun An mlrRrahve study Raty form, smolin/, and alcohol con sum(Nion amonR Italian Amencan men An invtaliRalron of the mrlaM.lism nf ryrrJ/ne (rrmppnrmts in the luhatal Plan( PsycMrbRrcat nJ heh.vinral th.ractera tres of rnhalrr+ among vnnlen Hlects nf sol•acta amnle and nicnlrne nn the central ntrvmn syslem Fvalnalion of lohacco cnn.urnplrun nn the haai+ ot nicrNine ur mtnlrne mela hdde+ in Iwr1y flurda anJ carl.•n mon uade cnnlenl of hlrrrJ Nnrmcoline cnn.ersinn anJ re+u/tlnR P'R menl chanRes in terlarn vanrlirc n/ lnharcn Rrapr.nae, of Ihr (.rrrpheral . na rn n•.o /u Ihe m/ta.rnnua adrnrnralrabnn u/ nrtohne ( rrN Idruwl fh.w r.~y.•nara b. anudrnR rn /he p/eaence nf hlprrlrprrnra an•1 hy (.rrlenarun ' (1 3

4 l ~ t" •i' .r: ~. .~a~... 0 (1, n LI ! *e'd m ~ : ) O. (:RANIFF. ANf) IN1FfTtr11ON R/1( I111 RS, 1)1)S, norrrnr Inrrr furr, ol trnn+ob•A•tn.l Rnrerrh, Scr IerKe Revnrrcet I ,N,ndalN,n, ( ..n Mrd1le. Mau IIANS I F At K, Pit 1) , frnin• Rrrre•rA An.r.err, nrpnrrrnrnr of PerhnlnRr, t/ni.ersily ol Soulhern Csliforni• ScMrJ of Med,cine. I m Anti.les (no. F1tad, ( hrmrslry Stclw.n, ( arcnsniftnt. ris Studirs Rranch, National ('sncer lnanute, RelAtsda. Md ) 1)ANA I I ARNSWOR111, M 1). Ilrn.r K(/brr. Prn/rrm. .. f lt.rrrnr end I)r rr,r,rr n/ //nnnnrr llrnlrh (•nr.rr Ilat•ard t)m.tn~lr. ( amMrd(tr, Mn. I+te Ilrath anA M. Arlhur 1 IRnNK (' /fR(7tISON, 1/1. M)). PAern.e.nf ( (rnr.nron, llrporlmre/ of oie.. Alhany (N Y ) Medical ('oltrre W11 I 1AM I FISIIRFIN, M I) /umkr Ihr direcl,r,n of SAMItFI. L ANI)1 t MAN. h/ 1) , M P I I, ('nmmis.,oner of Ileallhl. l hrrl FprdrminlnRnr, ( hi caRn 11..ard nf Ilrallh RI!SS1 1 I. S F ISIIFR, M 1). (~hit/ Alyd u.r/ F.ronunr•, Slalt nf Maryland. P.n )rnr•r n/ I rgnf Afrdn.nr, tlnive/trty n/ Marylanal Medical School, Rallimtne R I IRFl1)IANI)fR. M1), nlrr.t.•r nf lnw.rr Rrvn..A, Mounl liion /1rn pilal and MeJad / enter. San I r.n cr.cn (dece.std. see I rer.ch) / RI It! RI( K A 1 RI N(It, A R, 111.rr r,,. „1 f nnr n I Arnr,•rAr•apr Rrven h, Mr•unl Ihnro.l and Mr•htal t.nrrr, \an I r.nr n,n Iae 1 rrrd I-.1.rt PRt))F(T Tfll t Mrlahnlrc imrnrlaliomhrps txlwen lo h.cco smnot ard the humsn mouth Fuminalion of ci(tvetle psper and cipr. cnc smolie cnnderoatts for .rornatic polycyctic hrdrtx.rhons A compilation of Ruorescence .pect •a of plycyctic •romalic hydrncarhom and clotely related compou mis whrch .rt ol Inleresl in Ihe rhrdy of sir pnllulanlte ar.d cigarette trmde in rtl.l.,n so lung c.nter elw.lney 1hr eRectr of InhKcn fmnke CnnJtMalt on Iht defense mtchanrsms nf Ihe ral in dtlolrRc.lnln Of p011CyCIK arnm.IK hydroc.rhont and the competitive inhJ.Jion between Ihe pnlycrcIK hydrocarhone in condensale w.th ntard to t'arcinn(trrasis The phycic.l •nd chemical prnperties of mucus under normal condiriurn .nd /nllnw,n(t eapo+ure to .rrox,l 6rilanls Prr,r,n.l•Ir and tmnkin(t in cnlltRe Rrad u.rrs. a hlrrrn ycar follow up ttudy I tle,ls nf tnhaccn smnlr upnn Ihe hrnchnn ul the tudrov.uul.r system rn animsls and man Prthn phrs,nloooy nf IunR in tterialric pa henH PrtMrlnttic .nrlomic study of crllular chanRei in human krnnchi I.prrimrn(I nn Ihe pnt.,ldr earcrm,Rtnic .nd cncflcrnr.ggrmc atllun n( Inhacco prrk)ucls ( .rtrnnforniulr. cr.c•r(rnnMm.rtr and nu.artmrrlrnnrly uf J•rlary (arl.n. rn rrlalrnn tn prJmnnuy tun,nn P.•. v/.k inlrrrrlnlronthrp o/ Inhattn ha.r' an~l ibrt.,r r f., Inn / hrmr• .1 .IUJir. nra.in CRANTFF. AND fNSTTIlR70N lA/'K I RFtINI/, M 1), Mrurenr Prnfrj. tr.- n/ Phn.nrn.r•L.Rr MedKal (blkte of Vrrginra, RKhmond AR111I/R FURST, Pnn, nr•rtrnr, In. rhrurr n/ (Atmrf ol RrnLret, llnivertlly of S.n I r.ncitcn (7FORCF O. (7FY, M I), nlrrrrnr, Frnnry.lfnw-ell ('nnrrr Rtnerrh /eA• nret..ry; Ars.rinrr Prnfrrmr of Sur• Rr.y. /ohm Flnplins Universily School nl Medicine. Rallrmtwe, Md. r TTIOMAS M G(X KF, M I), Asrnrfefr I'•n/rnnr of Prrvrnnvr Afrdirinr and (.rrnnu.nrr. IlrnlrA, New Jersey Stale ('n11eRt of Medicine and rknli.try, ler• szr ('ily. N I (m,w sl Sl.le l/nlversity of N Y, I lpstate Medical ('enler / IRA Gf)RF, M f). Prn/rrcnr .n/ Pa/h.d, nR•, Roatnn llniver.ily School of Med icint; ('hir/ of 1.rMwernty Srrrirr, Veltrarn Adminislralion Hospil.l, West Ro.Mny, Mass (;FRFR1/1)F Y Gl)F'1S(IIA11, Prrl), Afvrrnnr Prn/rccnr of Rl..rArnuvrr, f)rprrrrnrnr of ParhnlnRr and Afrrrn- l..rrlntr, 'The Rmleftller Institute fnr Mrdic.l Research, New York (cre ('farle / A() ARK GR111 IN, Pn 1). l/red of Riwhrnuvr /Ir~n•/nrrnr, M 1) An Jrr..,n Ilnapilal •nJ lumur Imbade. (lmver.dy of It.as Medical ('enter I (rwrttnn AR I'111/R I l:R(YfS M S. (rnir.r R,.R rhenu,r, S.arthwr.r Rra.nh Inahult, San An(omo let., M(aRION 1(:RtISSMAN, Pn I) , M 1). Arr.vrnfr ( Imr.nl P.••f., n. ,./ Alr.hrrnr Ilm.er.rly u/ t alilnrnr• Mrdre.l (Ynlrr, I.n AnRrlei hS PR(IlF(T TTi1.F. ('nrrelalion of mullilechnical procedrnrs pcrftKrned on the perirheral circulatmn of normal individuals in lecumhtnt and ctect pmilions.nd after estrcise hefore and .fler sham and actual smoling A sludy of the ef/ects of ciR.relle smolinR on the Pcriphcr.l circulation of indr riduals with .nniasckrosn obliteram •nd rNher periphtral •.scular diseaxs. ul/ilisin(t mulli(echnic.l pvoccdures A cnnlrolkd study In e.•.luate the eRecl of adminituafon of Ir.ce mel.ls (wdh nr wilhnW eaposure tn ci(t.relte vewtle ) On Ihe Incidence of pulmon.ry .deno m1t In Strain A 111Ke Niclel In rtla(ion to the smoking and lung cancer proMem Fellowships for studying the culture nf hrm.n /ung lis,ae and the effects of known and pc.ssihk carcinnRenic aRents opnn urch tissue ('haracterislics of norm.l cell pow/h In cullure in relation to inrasi.e c.rcin oma, especially in the lunoo, A study of Ihe nasal and pharyntled hrc lerial 11nr• of smoYtr., mm smnkers arwl ta ansnlers The influerae of envirnnmental /aclors on vlaial inlimsl constiluents and func 1 N.ns Inleraclirms of arterial acid mucopolyraccharides Prnlenlylic •cliviliet of the while blood ctlh of man antl the efTet/ nn while hhvvl cell acrrviCas of cartrm,Rem, n,r trrtinn .nd o/her in0uence. Ihe eflecl of e.tr,.ure In ciRarelte smnle nn the rnducunn of c.nctr hy thrrmcal ( amry,unJ. Ihe rr.rlrlainn nf •celnni/nlr in h•dy Rur.1. lu Inhactn ucwfor Ihe rflr,l nl crnnlinR tin crrnun Itw.tn, (urk Iron,

(7) .+4 70 irvrl CRANIfF AN[) INS1fllI11(/N ('ARI (' GRIIIVIt. Prr 11, M l), .Irrn cintr rn PAru•dnfy nnd Phermo.nl.•fr l/m.er+rty nf Penn.ylv.nia (:(.duatr Schnol of Mrdrernr. PMLJtlphra fnrnr 1« lurrr in Ph)sioln fy, I Imversitr nf Ilon1 Knng) 1 RANK F(aJT11RIF. Prr h. P•nJrr.o.. and FRNIST 11OI)(iSON, Pw1), Aa- rrrranr Rrrro,A P.nfrl,or, I)r/v.•rmrnr o/ l:nr.,m.Jn,tt, Norlh ('.rolm• Slae (blkte. R./elgh Ft R IIAA(:, M h. Prnfrrmr of PAer mer.d,.Rt, M.dreal (nIkre of Virglni., Richmnml Ide(e.vd, aee I uwrn) i I IIAI)IIY, M 1) . Pn 1) , hn/raa..r .nJ rAn.~,an hrf•errmrnr nf PArn.d- .nfr. lrnr.erany of UIIaM.m• Medreal ( enlrr. (Hlahum. ( rty InooA .1 Mrch rR.n State Itmrtnrll, F.N I.rMinss Mrch I 1(KI P11 11 NAI KI'NC( /11/ 1, M 1) , Im,+ a Mrdreat IkP.rtment, Sar.dnr Pha,m.reu/u.l., C.n I r.naraeo, ( .Id 1 RI( IInRI) I IIAVI I, M 1) A,n•r,rnt •I A(rA•nr. I/nrvervl, ,•1 ( alJorni• Mr.hc.t Cchdd. C.n 1 r.n c isco HYRRI RT R IIAWI/IORNF, M tl . (~Anrrmnn, /)rrynlmrnl of Swfr•r llm versity of Penn,yIrani• (:r.Au.te Schrwd of MeJicrne. Phd.delPhi. CI ARK W IIFAT)1, M h, P•rrl•~rn• nf Alydrrrnr end l)rrr,lnr n/ llreltA .Irrvl.rr. Tuftt llnivtnily, Medlo•d. Mas. Isee I.rmworth and MMrthar) NORMAN W 11/'IMSTRA, Pn 1), Ar urlnnl r•c./rn.n r./ P,rcAnl.rfr, ewd Ih rrcfnr. 1lrivrr Reh.vi..f I.M,ralnry, 1)rparlment of PsychnloRt. l/nirenrl y of S.,ulh h.knu, Vermillinn PA1/1INF IIF17FR, PI/f), Rr,rrr•rA Arvrinrr rn ('yr.rhVr .nd (tn•.hrm /urr, San /c.nci.cn In./ilule of Mtdi ul 4irnct.. C.n Iunaistn (we Rich PRO/F('T Ttlt F (:RANTFF ANT) rN1TTTTlTT()N PR()1F(T T111.F. Pharn,acol••pc s1ndy nf nrtnrme and rt 1 AWRI N('F t /It STFR, Ih, M n. Tht relalir,n.hip nf the u.e nf ,ol.ana la/rd all.lnrdc rn•/r.r,rr nnd ('Arri•nron, Orl.nrrmrnl (NrtlucN In the mrl(r,me of PreRnanr, n/ OMrrln, r ond (; vnrcnl.•fr, Mcdreal College of Ga,th ('arolina, ('h.rk.lon F RRF ('!IR TIS 1101 F, Pn 1) , M f) Rirahtmical .ludiet of nico(ine and ils rrn/r....r nn.l ( Anmm~n, /)ir idon n/ inlermeArate melahnhles nd thrir rf Riologic.l ncrdahnn of urhamae rn.rclr Prvrhrer•rc RrvmrA. Medical Co11eRe fecw ury,n cerebr.-1 .utonomic mrch.n cides of VirRinia, Rrchmnnd isms ('erebr.l .olnnomk chanres Prnahrcrd by tnhaccn snw.le, nicMine m col,mne, a meuholile of nkotirse Pre~ antinn fnr Inrhllcalinn nf a L,nl on IIK bw,l.•fK Nperlc of tuh.c;n and sn.nlinr 1 n[.1 tRech of the inh.l.uon of Inh.ccn smokt urrm Ihe (wrlnw.narr. Perirhera) ancl coron.r) vascul.n ceds Meauremem of coronary hl«,d flnw, urd,.c worl and carduc ntyRtn anJ carM,hydrale mrlaM,bam in m-vmo,rn arvt arrhrrcla hrfnre •nd •f7er in/r• rtnrar. mrnlrne and after amnlinR UanAarA rrRarrlle4 A alu•Iy r,f the eflrctN of tmnlrnR and mrr,hne aJm,nralralrnn nn ayr.,palhn .Jrrnat funaturn and fally ac,d mr/ L,h.m Arlrn,Pls lo mdncr pulmnnarr nrnPlaama rn r.perimcnNl •mu,ila by rrlv,aure o/ the IuchrnMnnahul ty.lrm to In haccu smule Perannalily and smnfinR in cnlltRr Rrad uates. a fifteen year fulluw uP eluJ) 1 flrctH of amr,linR nn +rndainrd Perform ance in a .imulaled d,ivrnR taak hiauloRir.( A tOmpar.hvr arrrdy nf e.rly .nd I/NA ,hanRes in Ihe rpidermrs nf Iwu •Iraim nf rnice /f/7 11htM nd Cwia. Wrl'Jer.1 •hrr d.ilv ar.pl,u Ir. n. J wh••le rifarrlte vnnlr tnn Aen..tt (.h,ne nd cnmhinrd w,lh crnlnn nrll .ml the carcin.,Rent 2(/ melhyl,hiJ.nlhrrne nd 1.4 henrr1y RA rrnt i R(/Sp I 1. 1 11(11 M A N, M I) , Prn/r, r.•• nnd llreJ, /)rparrmrnr nf Pr.rAnl r'et. I ouisian. Ct.le l/niverals $chard of Mrdrunt, New (lrk.m Idece.sed, set Mc(idl am1 C/n.nssl I R/lN)Y /t(1MRl/R(:FR, M fl, Prrrl drnt onJ 1)rrr,rr.r, Rio Research Imlitute, Inc , ('amLridlPe, M.st. RORfRT W 111/11 , PI/ I), P•nfrtrnr of Rr.d.rfrrnl S.rrnrrr, (~lurid Slate ltni~ versity, 1 al.hssre (if(1RIi1' /A/Y/RSl)N, M1), r•,r/ravrr rurJ (lraJ u/ RmbnlnRr, 1lnirersisy nl Southern (aliforn•• Schurd of Medieine, t os AnReks IhRRY IInRT )A(Y)RSON, M h, hi rrrlnr of Flr.l..rpArri.rlnfr, New Yort F)e and Far Infirnury. New Yor1. 1111111C 11 IA('ORCON 11. M 1), A„n r r.rrr rrr./rrtnr n/ .SruRn y nnJ /brrr t.•r / lurficnl RrrrnrrA ( nllrile of Merh eint, Ilniversi/t' of Verrrw,nt. lhuling ton (Now I)irect.n of Tumor and Val eular Restauch, Mt Sina Ilo.pit.l. New Vort, N Y / MIIRRAY 1 IARVIK, PIrI). Ac...rrnrr al rLn.m,,, rJ,•f.. All.erl Einsltin (n11eRe of Medrunt, Rruna, N V. P./hnlaRic-.nalnmit sludy of celhd.r chan/les In human bronchi Tbe InRuence of loh.cco smoling on .cnle mtitvc.rdial Inlarction S/te(ies on urcinnRtnr.is •nd Ihe bio •asay of e.reinnRCnie assen(s ('r.mparalive studies of ef(ectl of v.rrnut tobacco smole eondenaales on sliint of mice Systemic eRects of three Inbacco smole eondens./es Riologk.l effects of ciss.retle smoke Phn((.dynamic NI/va1N.n of carcinogenic hydrocarhonv (a) a.ndardna/ion of asaay IechnirJues olitving prnturua, /bl in.es/1Ralion nf Ihe mechanisms of .clivaliUn and response In aomalrc c.rcinogens by Prolopo• The influenct of certain tnvirnnmenlal frclras in Ihe Renevs uf nroPlaasic disease in tul.ercuhni+ patients am1 in chddren A cr,mpari.r•n nf eltclroretinnRraphy .t a mt.m ol evaluatmg t),e r/lecl uf vaw-cnnalrictor druRs urym ctrthr.l .ml rttinal tireul.t•rrn wilh uther lech niyues for IhiA dtterrninannn I unR lu,mntranaplanlaion 67 Pdol aludy nf hal•rluaUnn to nicnlrnr /., n.rnns „f rhe.rr4 munlit)s

(:RA'rIFF ANI) 1'a1-111f11111c)N nNI)R/ W A KANI1lIIS( 11 Prr1), A,,r•r,..rr ll~rr.r.~r ,•/ Nrvorrh. Rr•.(•x It /...Iann ~lemorul 1 atr,rarory. Ru Ila~hn. Mr nRNlfl I) R Kn/'I AN. Pnl/, lhrrrrnr, 1•.h.-nr.... ,•f NfrJnal f•rnrb. f, ( kve lan,l /'atth,arrn Inurlulr an.1 Ilrnpd.I IIRnI( 11 K/15pAR/AN, M 1), Arrrrf. •nr fl,rnr,n, ( ~.drnvnrcr/or I~Anr• rn.. ln vrr.r•v rn AfY.hrrnr Il.h.w m.nn Mrdu al f ollete and Ilraprlal, Phdadtlrhra I I 111() K A 17, Prr h, An.vlelr Prn/rrr,.. n/ tlnrvertrty of (hicarn (vr(run) S/IIRIIY I KAIrtIM^N, MI), fr a.,rnnr Pr••lrr..v n/ Parh..L.ev. ll.re 1lnrvtruty of Nt•r Ynr1. 14,wnalart Mr.h<al (rmtr, Rrrwllyn_ N V AN( f 1 Kf) s, rn I) , Pr„/r,r.•r „f Ph.r rnL•cunl Nvirunr anA Inh nrarn.r nJ Phtu••h•trra/ IIrR•.nr Irni vrrvly nf Mrnnranla Schrx,l nf ruhl.( Ilrolth, Mmnrarntrt 1US1 rFl R KIRSNI R. M 1) r,/ Alydr.rnr lJnr.ertrry of ( hrca/tn ScMxrl of Medicine PF11 R II KNAPP, M I), Rrva•rh rrn /rn••r .•/ Prrchrnn.. Roalnn l)nivtrtily S(lxxd of Medicine, Roston. KhNNFtlI P KNI/I)1SON, M I), Ar riU.nf ( hir/, (aA.•,alr.ry Srrvnr, Vel trant /ldminitlrali.m 1lrwpilal, Srallle Wash ; Prn/rrrr. n/ Parh.rl.rR.. I/ni vertNy of Wathin/lon Medre.l Sclxxd, Srall)e AIVIN I KOSAK, Pnt), Aunrrnrr Prnlnr•rr .,/ ( hrrnrrrrr, Waahmglnn SQuare (~ollelr, New York llnr.traily. New Yr.rl. RtfIV Rl A Ktr11N, M 1), All 4nr1. Iln.prlal Mnrrran.n. N / and Ar•-- nnrr Pr••Irrr, , /lrrru,•n n/ Nru.•• trnerr llrrn .•unr .,/ Srnrrrr, Nr. 1rr.rvvCrarr II~r~11rRr uf Mr0hc-rr, lrr m 1 r,v N 1 PR(tJF( 1 Tfll F. Iu Jrtrrrninr In what rrlrnl tnhactn 'larmunrct the at Iron r.f c arr m.•Rrnrc hrdrn cul..m ,n the tlrn anJ olher tntuct (~.am,nalinn of the eitrnt ol, and cnn~ tlnnrrnnal ha.is (nr tnrrrlahnnt he IwtPh the fullnw•ng ( I 1 laslr Ih,eah o1Js fnr Vnrnrnr and A n prnrylthinur .cil, (2) cnntlrhrhnnal prr,haprnrtrnn In palhuh•~•c vanal•lea, 11) inJ,viJn.l d-Rrremrt in vnutmR prxrrcet, and 1e1 1r..J Jralrlet lhe rflrtl nl lohacrv. sn,.,lrng nn the cali Ivr nf tflr o.nonary arlrnrt Srxial and ptychnlngical cnnsnainlt on the lramlatron of mrMivtt into achon lhe cate of cigartnc tmnlinR Tn rnvnnRate the palhnRtneais of urt thane rn,luced hmg aden.,m,r• in mice, speuhcally the idenUfxaunn of the cellt wh,th Rive rise In the Jen.mat, and the Rne tu,rclnral chanaes rn Iheat cellt durinR nrnplatia ( haratlernlict nf inen, rnctuArnR rmnl rnR in M,pnl~lrnna drRrrrnR in the in crdencr uf tnrnnary heart Jra..e lhe effrcl of Inhactn tn,nlrnl rnpnn hatal Rattric ttcr0lxtns in man InvetliAalinn of persnnahty furlnrrt at socialed with eclremes of smokrnR hehavior ralholoRic - .natnmic tln.ly r-f cellular changet in human bromhi lhe itnlstinn and idrntificarinn rd certain Inwer Mn6rng cumpr,nrnlt u/ crIlarellr amr •1 e /b..J,lr rflr,ta nf .•1in~ an~l nitnlmr ul.rn ce.rb,al tntularn,n (, R 1 I:RANIFF'. AND INSTm/TlOfV MAR VIN Kt1S( IINI R, M D, rrnfr»nr r./ I'.uhr.lnRr. New Yor! l)niversily ( ollrRe of Med•cine; f)brrrnr n/ Pa Rrllcvue 1loaprtal, Ne+• Yorl ( IIARIIS W IA Rf11F, Pn1), Ar. uvnwr Prn/trr,•r nf Fnrrrr.n.nrnenl IlrRrrnr, It.pnrlnrrnf of Prerrnfnv AIrJn .nr. /eRerson Medical ('olkge, PhJadelphra IdeceaxJl IIIIIMAS U I AIPPI Y. M 1), Pro/rrwe ,./ Pru6..l.•cr, Northwctttrn llmvertily Medical S.Mwd. ( Anoman llrpulmrnr n/ Pod...b,cr, Wetley Memurial 1lrnpdal, ( hruR.. PAttl. S I ARSON, PIIf), hr./rrsrv of Ph.rrnr,n..l•.rtv, Medical (ollette of Vir• flrnu, RichmnnJ (see Ilaa/t and Mc~ Kenmt) R(1(7f R K I ARS(1N, M 1), l'hirf of AIrJn.wr, and 11rif P11 R Mc( I IN l l('. Ihr 1) , A rr•n inrr P.n/rrtnr ..l lli. olnRy. I resno ('(xrnty 1loapit.l. I resnu, ('alr/ornia (7(ISIAVI A I AtIR1 N71, M 1), Ar nrrntu Pr../rn•n ../ Alr.hrrnr mr.l llr rrr hn I)rrrrr,•n ,•/ N• rPu.n.nr 1)rv.r.rr New /tt.r•y \I.Ir ( n11rRe of MtJnrne, lcrtey ( ity, N I f 1( n Ir 1 1 11( 1111 NRI R( il R. Pu fl , nr n/ (.r.n 6I r.,r+. 1wr.. In•rrU•rr nl f,,mrr Rett,url• .n•1 ~It.hul ..r,.r a...ra...rrJ wuh the %aM.•I, linr.ervey of I aut..nne. %wA nrLnr,l rl ••,mrrl) t,.n.•r f h..rrr.r Cr... ktamnrr.l 1:rh.r.rlun.... Rr.w.It Ilu.lnt.rl. Ilr,r,ll,ne, Me.. 1 P1t11Ji(T 1f11.F: P.thnluRic - analomrc ./udy nf (ellular changes in human hrnnahi FRect ot ciltarellr smo\e on pulmnnary cltaranae PatholoRic - anatnmic tludy of tellolar changtt in human brunahi ClassiRcalinn, prnRm..it .nd etndnRic fac lors of prim.ry lumurs of the IunR FvaluNion of nxxrIxdr.Ric thanRes rn Irnchtohronchial lrer in patients frrmr sektled study group (Ste I ithhein) comparisr.n of chanRes in ua.hrohron chial epilhtlinm in smolers and m•n .mokets, with special referrnce to hm# carcirtomas in mrnsntnlerf Preparation for publicatinn of a Ixxr1 on the hinlogic atpecH of Inhacco anJ srnoking Fnrymalic Ir.ndntmationt nf nhulint and related comprxrnJs 'f he postihlc tffec/ of tobacco smoke aml nicoline on .scorhic acid mrlalvliarn Mechanitms of retidancr tn nAmonary pallxry(ens in mict etry•acd lu ary.retle srrwrle Sludies in bronchitis • correlNed inve.li Ralion of (a) the ellrtl nf ann,RrnR nn Ihe hacleriulupy of Il,e re.pu.nrrrY Iratt of humant, anJ Ihl the rlleal of Cr(ta rcl/e smule anJ anl/ur Jrnar.le (arr p.J lulanl) nn the tlr.rinR u( hatlrrra Irnar the rrtpuatory Iratt of tm•rll amm.lt (mice, ra1s) F(Itc/ of crRarrlle tmntte nn p,rlrnnn.ry retitl.nce to infet thon A currrl.led hitlnlnRrt.al atl.d..pnal and h..hrn Cyawhemnal .Indy ..1 the Mnrxhr..l trre nf nu.e erl••.rJ lu ty. rclle sm••Ic . the rnterrelat.nn between in0urnra vnua infeclinnts t./...aure Ir. trR:nrltr .rn..1e n.l nlher lar run in the Jn,l••Pr.rnd n/ pulmunar y anal br..na /u.J Ir.rnna in mi.t 69

CRANTFF ANI) IN41111111(/N AVI R111 A I lt Pl1W, M I), (horr.non Irrpnrr.nrnl .•/ rnrlr.rl.•Ry, Yak Unrver uty S(hn.rl of Rlydreine. New 11.ven, ('onn FCTf N t) 1 INI)SFTH, MO, Pu D, As 1,110.1 l Pr.•/nrr. n/ Sr.rrrry, (/nivervlz of Mrnne+..la Mtdreat Schncfl, and S/.Q Ihvn.raw, Sorn.el irrrrrr, Veler.rr Admnnrratron 1lmpild, Minnt.~o1 u (n)- at SI )rneph's 1lr..p./.l, SI Paul. Mrnn ) ROR/~R T 11 I INNFI 1, PN 1) , Arrrriarr, rr.,lrn.•r n/ ( hrr.nfrrr. l/mvrr+rly nf Vrrmonl Rurhn(Inn (nnr .1 Nerrnn.l tc rn+r I rnrndarnn, Wathrn(ron, I/ (1 /If RRI Rt l I(1MRARII.M 1).M P/1 . Rrvarrh Inurn,rr, Nr. lnaland Oe. c.rnr.. Ihr+pnal Rm1on / r tON( ,,, Prr I) , 1'rn/rrrnr .,/ PAn..... ...1,.(r Cr.rr (Inr.rnny nf h... ( nllr(r nf MrA~cirv In.. 1 rly Kt NN/ 111 A// RRII 1 1\ N( II A1 11 ti( I) 11 It r I•, r/r,• on,l I'•,~(. ••• n/ /'„rl,,.l,•r. an,s,I 11R111 A A/r IVI R M 1) .cr.r.r.rnr I'..,/.n... r,/ Mednal ( nllr(r of Grulh I arnhn. ( h.rlrfl(,n hAVII) P MANN I. , Prt I) , Aruvr,.rr /'rr./rrurr r•/ Phn.w.m.•L.Ry. Itmplr Vmvtnily ScMxd of Pharmac). Phils delphr. 1O11N P MANOS. M 1), Inu.urrnr in Vnnln(r and Rerlrnr•InRr, Medre.l ( ollrRe of Soulh ('arolrn., ( hale+tun t I1RtC1OPfIFR M MARTIN. M 11 / nrmnly Arrrrmnr Prn/rn.rr .•/ Alydr rrnr nnd itnnrn. /lrrrur•n nl Inlrr ....... Itrrravr, N I Cla/e t allrRe nl Mrdr.ine, lertev ( iry, N I INnw a GrnrRrlnwn Ilmv Sthnnl of Med. W a+h , 1) (' 1 rRO)c('r TtII.E Tu inve+IrRale Ihe fnrmaion ut pulmon ary aurfaclanl in fetal •mrnal+ •nd il+ presence rn the newtxun Meaturement of the diflrrrnlial hlrxxl Rnr in the mammah.n IrrnR dnrmR the .cule period nf +na•1e rnhalatr.rn, uting the oprn cht+t an.nul •rnl the mclMxl ud pnncrp k of Ramma rmrllhnR radio. .clive (raded micrn+phrrrt Tl.e nudainn of mrnh..r by Ita+rnut oryten rnr(h.m+rn, pr,wlu.rt an.1 Ir nrrr.• The .Wn.rdatinn of nKMrne 1'pidemrrln(ical flctnr+ in lung cancer ( .rdro..aular prnprrlir+ nf nirntrne I nrrhrr +n,die+ roncrrmn( the avmpahn mnnel,( •ttrum nf nrcohne I mrrnnn,rnlal fat/,.r+ and prrhnnnary dr+ ca.r I A.Iralrn du+l I llrrl nf r,•Larcn vnnle .nd Inhscro re+ rJut+ nn mrlh)tttwrlrnrhrrnr rndu+td skin t.nrnoRtnra+ in mrat The separation of the varrnu+ +ulxellul.x neopla+tic parlicles hy u/trw fillralirrn mtlMxl+ and their ch.r.clrrirahnn rn latx+ralnty •nimalf and in tr++ue cul Ime+ of v.riuus etll line, Pn+uhlr intrr.rlimm if vrro+r+ nd +uh Uan,r+ rn Inharcn +mr,lr [nnJrnaale t/()NA11) 1 ).InC5ARt/, M 11 r Inrl. ( nny..rnrnr r.urel f•rr.drn.r ,d .hrruu, tn Ir,lrrrV„"r.r lrr,r., kr .h l.rh„rrr hr~,n,h~r,. F ~ r.•.. A 11.•.(nr,.l .nJ rln.rn•, r,-r rn ~ IIIrJi, . /i .,,Rrln,.n (Inr.r/ar11 „f i CRANIFE AND INSTTr(T11ON ('11AR1 I S (' McART11t1R, PN 1) , Plrrhn(.•ryrq rn the fJni••rrirly Nrdlh .trrrirrr llarv.rd Ilnivertily, ('am. hridle, Mn+. (aec Ilealh •nd Farm ror l h ) ('IIARI FS R M(t'ANTS, Pn 1). A+so crerr Pro/.etrrr of .toilf. Schnol of Agricnllure. North t'.rolrn. Stale folktte, R tleich IIfNRY (' M(GII1, 1., Mf), ArrinR Ilred, /Irpnrlnvwl n/ rnhnL.Rr, I twri +iana Stair Ilnrversity Sclxrnl of Meditine, New (hltsrfs (.ee /lolnf.n and Slrnng 1 IIF: NRY t) MrINTI)SH, M I), Prn/runr n/ A(rdrr.Rr nnJ /Irrrrl..r, ('erdrnvnt.a- Inr loh.rranve, 1)u1e (lnivenity Mcdi cd ('enter, I)urham, N ('. FhWARI) MrK/ F, M 1) . Prn(runr enJ ArnnR ( hmnnen, and WII t IAM M I)AVIS, M 1), Rrfrnrrh Af.ivenr, f)r porrmrnr nf lbrh,•l.q., Medic.l ('n11eRe of Srxrth (.rolina, ('hark+lnn Isee Pr.ll Thnmat) KFI I Y T MrKFF, M 1), Atrnrlelr Prn. /r.rrn of Alydulnr, Medical College of Srxrlh l arnlina, ('h.ricslon IIFRRhRT h( KFNNIf, 1., Pft1), Prn. /runr n/ PhnrwrnrnlnRy, Medicd ( ol. kRe of Virginia, Richmond (see I a- w.n ) VI('fOR A MtK(1S1('K, M 1), f rn/n j .rr n/ AfrJrrrnr, with RI('IIARI) M G(1()DMAN, M1), Frrfnw• in AfrdL rrnr, )ohm Iso(+1im (lnivertily ScMtnl u( Medicine. Ra111more. Md. ROSS I Mr I t'AN. M 1) , Afnrinlr Prrr. /rrurr rrl AlrJurnr, I~mnry Umvrrtity Cclxxrl nf Mtdrerne, Atlanta NI AI I Mr NIVt N, Pu 1).lhe Wnrcet Irr 1 rxrndannn f••r ( .prrnntnlal (ho1 n.y. C/nr../.ury. Ma+a Itre tAu/manl IIII IA MI YI R, Pu I1, ArurintV rr.r/rr. fr•r r•/ (1,..1 Prrrb,./rre. Itmvcralry r•f Ilhnnr. ( nllrRr nf IMnuatry, ( bnaRrr IItRNARI) 1 R111tIR,/1S,M11, 41 urronl 1'.••l. •..•. the 1lemrl IlauRlr In fhlulr nf nn.rlhrmt nf Ihr 1r11rr.nn Mtdnal I n11rRr, 1'hiladrlpln• PR()lF.(T Trfl.F. SnciN .rfd perumal delermin.nlf of tmr.to ing hchaviur T)fe social mediation of snwr\ing hehavir.r Anenic conlenl of snits and Ihsrxplion by Ihe tobacco plant l~fe effecN of environment.I f.cton on development of a/her..ulero+i. .+ re veakd by .ulupty trf accident rrclimt A study of Ihe eflectt of hyperl.aric nsy itenalion on coronary •rlrry draeaae rn /he e.perimen/al .nrm.l and man ('.reinnRenesit in the laharatory animal a eompari.on of +prrir+ re+rxm+e /u sundardued f11e. nl .ppl,calron Study of hmg funclion in .mulrrt .nd non smnlert Fnrymalic Iran+formaturn+ of nicoline and related cnmprwnd+ A eomhined Renetie, phy+inlnlir, clinfcal and epidemiolngic sludy of Ruerfter't disease A study of RuerRer't di.ea+r amona the Jewish ethnic ttroup+ in Ifraal Tob.ccn and cnaaulalion. A s1udY of genelic faclnr+ in va+crdar diae.+e To male recordinR+ of norm.l and palho A.Rie hreah +uundt Nicoline and i/+ rorlaxdrre+ rn L.Jv Rrrid+ .d tmalrr+ An nr.l tH•dnpc aruJV rd mmvru•krr. and tro.rlrra An in.r.lrR.rln•n nf 111r bh+•J .upplv Of mrla.l.•Irt enA I•uur.u) meh.n.rnr lumnn ul the LmR U ~ ff 7I J 'P

CRANTFF. AND INTTfTI(T1UN /AMFS (1 MII 1 FR, M n. PN 1) , hn fr-sr- of rrrchrnrry •nd rrrrhnLrR., end l)rrtrror, Alrwrel llrelth Rrverrh lnmrrtr, l)mveruly of Michrg.n, Ann Arhor FI1/G11 M(jN1(`iOMFRY, M D, Aa.orL •Ir F.n/nrnr nl Mrd(rrnr. Unl.ershy of PemnYl.ani Medical School, Philadelphia r(rP MONiGOMFRY, lrt . M 1) , Irn )rtrw of r.rAol.•R1, and RO1 1,ANn (' Rt YNOI 1)S, M 1), Arrnr.ns rrn/rr l..r of Palhol..ff, l/ni.ersity of Te.ias, Southwentern Medical Setsool, t)allas (:PORCF F MOORF, Pul), h11), /)1 rrrrn., Rrwwtll Park Mensorial tnai tule. PuR.lo, N Y(.ee Pock ) KFNNF.T11 M Mt)Cf R, M 1), Arrrrlnnr rrofrrr,v n( Alrrhrrnt. (irnrctlrr+n llnrvtrsity Mrd~c.l kMr+l, Hi+hinR ton. 1) C FIIIR t I Y I 1 t MI ) T I I Y M r) . r-f.r t.rr n/ Afrdrrrnr and l)rrtrr.n ! ar,h- Rtrt•r•ar.n) (aA.r.nlorr, llmar+dy of Sr.ulhrrn (sldnrnu S(hool (If MrJr eine, 1 rn Angtles WIl I IAM S MItRRAY, Sc I). Srnlnr SlaLT Srirnlul 1 nrrrilur, RmcrK R lacks.+n Mrmrni.t 1.lx.rstruy, Har Il.rlax, Me I)ONAI 1) A( Pn('P, Phl l) , r.,•frrmr n/ rh)Ir.rln(r •nd 1)irrrlnr, lnUnuN /or ( rflul.. Rnt..rA, (tnivtrsrty of Nthra+ta, I incntn PROIF(T TTILF. The behavioral eRtcls of rmolrnR under slrtss InRuence of tobacco smoking on the bkxsd flow of skrn nd of muxlts of cilrtrmtrtf in fymPalhrclomrred and un.ympashectornired suhiecls InRuence of nicollnr 1I. I.nd tobacco snsoking nn blood flow in human skin and skeklat musclt (nnsrllarkm of Iht role of the nucleolus in the r.ormd am1 the rn.hRnan/ cell Nuclear chantes prnduced by chemrt.l eareinogem An Inveslipliors of the physiolnRical ef. /ects of direct inhalalron of tobacco smoke by lahoralory anrmals and Ihe study of Ihe biolngical respnnse of IaMrNory animals In contrnurwn in gtslinn of diellohaccn prorlnct rnitlurts hllrcli of acolt and chrnnic ciRartlle .rmrlrnR ufwrn Rhrrnolylic athvily and hL..d r~~.Rut,dnrn m man A tlu4. r,l rtw rfltr It n/ vnnlrnA on pul luncnnn Tlre prnduction nf Renctically cnnnnikd animats .nd tumnrs Int ust in espcrimental research on loha.co in relation to health Studies of the mammary lumnr prnmol inR Quddies of  virus like principte, ursdtr varying hornson.l and apng conditiom Ctntlic studits of carcrnnRtntsn Fellowship for training in /is.ue cuhwe lechnrynt. Study of the effects of wh.ccn .mnke cnmlrnMnls (in variodn srraiM of lnsue cclls cultir.IrJ /n ru.n In•t.liRainns on rtlpiralinn and glyco lysis, •s vtlt as prn•rMe chrnrnov..nal v.ri.lrnns in eHabl4.hed ccll bntt whith ha•e hern tsprned lo ciRare-tle smnke anJ smRlt comlilutnts of sm-Ae 72 r (:RANTFF. ANT) fN4TTRTTION AI-PFRT P PAl MFR, Ps. D, and NnR• MAN W FIEIMSTRA, PN n„ Arnn- .n/ rrofrnotr of hycAolojr. Drp.rl- n.rnr of 1 ryrAolot/, Uni.enitr of South nato/a, Vermillion (1)r. Palmer no. at thc llnlversity of Tokdo, Ohio) ROSP. MARIP PAN(:RORN, P S, M S, Asrlp.nr lo,.d TnAnnlocul.nd l.rr• Irrrr. I)rp.rln.rnr of F..nd ,ftlrnrr and TrrAnolo,y, University of ('alifornia, Davis, Cali(ornia FDWARn W. PFI.IKAN, M.Q, CAdr. nren and rro/ruor o/ rAerm.colnRy and Esprrimrnr.l TArr.lwrtirs, Poston University School of Medkine, Soston. OTAKAR 1. Pnl.1.AK, M.D, Mn, Errrotivr l)irrcror, Dover Medical Re• search ('enter, Inc., Oo.er, [kl. MORRIS PO11 ARD, rw n., Dbrctnr, LuAund LnAor.nvy, Univer.ily of Notre 1).me, Ind C M. POMFRAT, Pss D, nirrrlor of Rr.rlnRrrol ReormrA, Pasadena Fctanda- uon for Medical Restareh, Pasadena, ( lh( I dece.std 1 H, R PRAI'1111OMAS, M n., l)ren .nd Pro/rrsnr n/ PoJhnlney, Medical ('ollege of Snulh ('arolina, Charkslon (aee F McKee) MARTIN S PROT7F1, PS, 1)nS, I)rpnrtmrnl of Orel ralhnl~rtY, Newark (7ty tlnspiul, Newark. N 1, 73 PR()JF:(T Tf1t.C In.estigations on cRccts of carcinngens and study of the cflcct of ethanol and carcinoffena on physioMgkal, mctabolk, and morphological changes in diploid cells under aerobk and anaerobic con- ditiorr Penmulity correlatci of smoking and nonomoking In adolescents Inleraclbm of gustatnry, ol(aclory, Lc- fik, and thermal sUmuli among smokers and sson smolers Studies of structure activity retationship. .monR drup which afletl nicotine sensitive phy.iological nsechanisms Possible effect of tobacco derivalives on arlerid and snyrscardrat tissue cullrues Chemieal and viral carcim+aenevs in the uenk ("Krm(ree") animal Fellowships for studyint the culture of human lung lis.ue and the tRtcts of \nosrn and po+sibte carcirmgeme agents upon such tissue Pa/holellie - anatomic studY of cellular ehrnges /n human bronchi Application of a new bioassay /echnique in e.amination of cigarette smoke con den.atts for p..»ihle carcinoplens Carelnolienesis in the IaMwaory, animal a enmparison of species response to slandardired sites of applicalinn A comparative srudy of Ihe tflecls of 1 methylcholanrhrene and cittarelle smnke cundtmale apptred to the ord tnsuts of S+isq mice I lt R 1 condi liuned wilh a1coM+t andlar carbon tetrachloride A comparative study of the efltcls of induced liver damage on Ihe dcvtlopment of tumors of the oral mucosa .nrl slrn following the applitahon of tnhacco Lr in inbred Swiu Webster mice

I r CRANIFF. AND INSTfTl1T1ON WA1 iFR RTI)ISl'll, M 1), A+uxrarr f rnlrn.rf of ( bmrral AIrJu rnr, New Ynrk lJnivrrvty School of Mtdicine, and NY(1 Rexarch Srrvice (inldwarer Memorial Ilmprlat, New Yorl (fK Sulrherger ) FtORART A RFIMANN, M f), lro/rr. r,.r oJ MrJrcinr, Il.hnemanw Medical ( otlrFr and Il(nprul, PhiladelpNa VI(YOR RI( I/AR/)S, M f), ('Ai./ nf S.•rrrr. Preshytrtlan Medical Center. San I rancrun, cdrf (xe Ilrirer) R Ft RIGIX)N, M D, Prnlrrsnf of la IA(,lnRy anJ (NrrrlM, lI1r.Nalnl• of F rprrrn.fnul rarhrdnl., llnivrsily nf Te.af Medical Branch. (7alvestnn SYIINFY C RITTFNRFRO. Pn 1), r•.• /runr of Rorrr.inln(r. Vmrrnrty of So.rlhtrn ( ahfnrnrr, I o. Anfftler RPNS(/N fl R(lP. M f). An..lnrr r••. ffUOr nf to.Rr•v. 1)rp.r.f.nrnr .l (~ frry, llni•rrsity of Cahfornia ScMr.l of Mediclne. San I rancisco ('IIARI rs 1 R(1SP, A M, Sfnlnr hlrrr tnr, Veleram Administration. (hrlra lienl C'linic. Roslon, Mass RFNIAMIN A RURIN, Pu O , An/rr anr Fro/rranf of P.rMlr NrahA anJ rrrrrnNrf MrAirlnr. R.ylnr lJnivtrsily ('nllelle of Mrdicine, Florntnn. Teus (no+ Manster, RinlnRical Prrdncl. I)e vcln('!^~nt, Wyeth I shnr.lnrits. Phrta delrhu ) !1/'NRY I RUSSFK, Mf), F A C P. ('nemltnnl /n ('arJlnralrwlnr flivnv if S Public /leallh Servkt llrspital. .nA I`rfuJrnl, lhf Ru.st1 f nandaiw.n Inc . Sl.trn IJand, N Y WI11 IAM cl RIlSSI:t I M 11, rorh.d.. r1rr1 r hrr/ M 1) An.lrrann IL..r.r.l PR(11F( T Tfll f. Vascular re.lx.mts tn 1..h.ccn smoking in patrems with vaxul.r Ir.rau Vascular rr.pnmet nf thr Irn rnicrncrrcu latnrn and cerebral crrcularrnn to to bacco smolrng in m.n The possrhle rflect of loh..cn nr nicotine inprriodrednorders,anrwly recognited syndronre A co.np.rative study of the rRfcts of .Lok and fr.cl:nnal ruracts of cita rrrte smoke and IMse of known carcinogrnr nn (1) the c)rn1..Fy and nu clear f)NA cr.n/enl of eMArrmis In various .Irains of mice and/or 12/ the eyto"y and nurlear 1)NA conltnl of Iunt and epilhelium of the bronchial Irn of min and hamsters TReetr of tobacco smolte comlensa/e on the rrrpir.+ory traet and other li+wes of the ducl The hacterial drilr.dalinn of nicotine and rrlarrd crxnpound. lhe nhjeclive of the rrnK(1 is the flnrrdal.nn of Ihe intrrmrdr.ry rnrtahnMrn of nicoline ornlalw.n Srudy of Ihr •crinn of nrRrtirrly charged Krm un nachrnlnnn.hr.l crliary actinn in the human patient G.cial prrd.c/nrl of IonRr.iry An evaluadon of the phennmrnnn of tumnr pnwlh enhancemrnt a an .saay for carcinogens among the rydycyclre hvdrocarhnns and related comprwrnds Inlerrelaliomhip hetwrrn emnrinnal dreas (nccurnnnal ), tnhaccn cnmumplinn •nd coronary heart div.ae Slrra rrartinns in smnlers nd nnn fmnlrn a dHerminrA by urinay (.lr r/w.l.rnrnr r.crrt.nn rilholuRrc ananmre audy nf cellul.ar c hanRra u. /nrman hr nnchi 14 i (:RAMFF ANf) fNTTTTI/Tl(NN p1 TFR F SAI KRURY, M f), Pw 1) , llrnJ lnbnrr.v Trrahrrrnt ('tntrr, $ainl lnsrph Ilnapital, Rurhanl, Calif. (deceased -afe ('ross) PAl/l f) SAI TMAN, Pn 1) , Arddanr 1'rnfn.nr n/ Rinrhfmirlrr, Universitv nf Soulhern California School of Med kine, I os AnReles lll RI('11 S('l1AFPPI, M 1) , Srnl1 Srlfn. lift, Worcester Fmrnda/ion fd Fsperlmen(.1 RioloRy, SMewsbury, Mass. AIVIN R S('IIMIf)T, PnO, INrrr/f.r of ('nrrnvlrnR, tufls l/niversity. Med ford, Msss ISAAC SC'IInvR, D 1) s., ht D., D St . PrnJrsrnr of ll/unJnAy and F.nrJrrynlr.R• and f)fan. IJniversily of Illinois Col. kAe of [kntistry, Chkafto Idectased) MAl1RICF. S. SP(:Al., Mf), C7in1ral Prn/rsrnr of Afrdirlnf. Tufls l)nivn- sitr School of Medkine, Senlon, Mss ; Oirrrrnr, !)rparrmrnr of lnhalarlnn Thnapy, Rmton City Flospital CAR1. C SI'117FR, PwD, Rfr.err6 Ffllaw in J'hrrira/ AnrArnpnlnRr, Ilar- sard Ilniversdy, (amhridge, Mass , and heparlment of Nutrition. Ilarvard Schonl of Pablic /ltdlh, Soston C11AR1 TS F SIII RW(1(1/), M 1), Ar rirrnnr Prn/fvnr n/ RnJinfnRq llnireraity of Rrwhe.trr ScM.ol n( Mednine and Iknlrslry, Roche.ter. N Y IyAVIh I SIMON, M 1), Invnnr.n In 11IrJrr rnr anJ 1 rlL.rin ('nrJr...nu rr Lnr Rrvnrr h t Inrvrraity of 1~inc innali (fullrRe of Mrdr.rne nnd (arAim I ah nratnry, ( lna rnn.a. ( 7rnrral 11uarilel PROIF(T TTTI r InRuence of nicotine and calecholaminn YIool cMnnary va.mmotnr Innuy In nor rrm.l and Nherosckrrwk dop The ensymalic mechanism foe Ihe darl Rtalion of Cn, by tobacco Some aspects of amino acid melaholism In tobacco kave. Investlgalinn of the direct stimulation of paratympathelic nerve lerminals by nkotine Study of dli/udes toward, as well s to ,lent, type and history of. tobacco nrw+t (ng in a young college pnpulalinn Study of oorne of the relationships of smnllin, •nd rM.n snw.kinot to farnily histrwPw type o/ second.ry schonling, academic inler esls, .cademk achievtmeM, .nd, aocial relalionships characteri.tkt Flisloklgk changes In the nral. pharyngeal and nasd tissues of esprrimentd ani mah and humans auhjecled to tobacco srnole FflecH of cigarette lmolinR on lung func lion in normal subKctb and patients with certain respiratory dixase condi lirnn Relationship nf ciRarelle smoking so chronic (obrslructivt) pulmonary em physema An Integrated study of ancillary and ne.ly devek.ped parametrrs to dclineate the diflerenl types of the chronic bronchitis eyndromt and their evaluation Morphnk.Fv.nd smolinR in college Rradu .In: a flfteen ye.r fullow, up s1uAy Ilarv.rA/ohns IlnpYirn sludy of body fr.rm as relaled lo smolinR, amt Ihr prtenrsors of hyperlensinn and coro nary artery disease InveUiRalion inlo the nalural history of earcnw.ma of the hrnR with patlicular rrference lrr the radiuparhic arrru •nce of urch prnce.cea. the rarhesl manifeUatinn of cancer nn (heat X r.y photnRraphs anrl the lahulahnn nl Iht relNionmhir of •rnnkinR /uhrM •n.l rxeupati..n with Ihe rncrdencr of IunR cancer Thr tOrclr nf chrwinR tnha.u. nn the cudiora..nlwr .yalrm ../ m.n The rflrtla nf rifr •mnlrnlr and rrlt.r •malin/t on Ihf urdr..r..auler .l.lrrn nf nran 75

(:RANTF.P. ANT) fNTTTT1fT1ON ()FNP M SMfTII, Mf).. Arnrr.nr Prn. fruar nf rryrho)ocy, Hanard Medreat School, MaasachusHta General Nospi tal, Rtwto. t OUIS A S(1l OFP, M O, Profrutw of ("hnlr.l A(rdu lnr w/ Ch/rf, D/v/ak+_ of Carl olory, Temple Uwlverdly Med- k.l Center. Phitsdelpitis PR(UC(T TfTI-C The rrlatwins belr.rrn rmo\ing and per annahty The eflcct (if lohaccn smnking on sur factam, speciflc fatty ar ~ds, cardiac per. formance •nd mctahotlsm of adipose ti..ue PRNFST SDNI)IIFIMPR, Pytl), Pno- (run. oJ Planr Slnchtmirrry, SINe l)ni.trdty Co1klr of Forntry .1 Syn eu.e lJni.e»hy, Syr.cu.e, N Y. T. M SONNFIIORN, 11rt1, D4Nn. frhhrl Sr•rkr PrnJrraer of lonlMy. ndisna (Inisenity, Sloorninjtomi. SAM S()ROF, Pnl), HraJ, Dror of Macrn-ofrrrlar Chrn.lrrrl, The Imtihrle fo. Cancer Re.earch, Philadelphia, P. AI /: XANUFR SP(x'K, S S, M T) , A, alrrenr Profrrrar of Prdr.rnlrr, fhulr l/nianhy Medical Centrr, ITuham. North Carolina FRFhPRI('K I STARP, Mf), Prt1), Pr.•lrrror of Nrrrldnn. Ilsrvard Scfx.d of Public Health, Bostna C. /IAROI U STPFFPP, M I) , D(rrrn•r of 1 ahnraror/rr, Methodist Nospilal, Memphis, Tenn IACK P. STRONO, M D, Arxr/aur Prrrfrrsnr of Perholary. l ouldana State Unlvenity School of Medicine. New (Alcan. (,re Flolman nd McGill) MARION 9 SUI7SPR()PR, M 1), Prn- Jrs+nr and Cha/rnsan. Drparrmrnt of I)rrmalofn(y and Syphifnfnry. New York (Ini.cnity lfelkvue Medical ('en- Ier, New York (retir.d, see Redisch) The purilkalion and structure drlermin.. lion of cnrnpounds clnxty related lo chkwnjrnic acid C/rc11nil and rslcndinit the Slepham. P.raTr11YT Itst for carcinnfOtmcily ChtmKal and physical stud,rs of the lissue proteins involved Hr chermcal c.rcinogenesis Tl.e influcnce nr ciprrlte smnkr on tiliary activity and histology of the (racheo- hronchi.l Iree of the rabbil I .prrimrnlal sludies of cancer ulilirinit a nrw /rchniVorc In see If various 'Ianrruacled (rom Inbacco may incite the formation of lung tumors The influrnce of ciRurlte smole Inhalar tion on histn"ic thanRc+ produced by Intra.rnous hcuchkxofluorobutane In rata TTx eRotts of tnvlronmrntal factnn on develnprnent of alhennclernas as re- vealed by ,utopsy of sccidrnt vietims Investiption of the eRrcts of tobacco on the human vaxular system, hased on the fact that certain tobacco eRecH •re due to allrrlic susce(Mihility nf sprcific individuali rather than to obli- gatroily tosk prndr«ts in lohaccn sm.Ae, and that patumc with ncthrsive v.aut.r disrasrs rr+ry.nd d.flrrrntly than hr.l/hy ,n.nlrr• RI~NATO TAGItIRI, Psct). Arrrwlorr ('ritic.l rr.iew of lileratu•t on pcychcl P.,~/nw•r ~f PnrAnLy.. r:rad-rr oly of smoking of Srnnrrr Ahdnbrrnr- Il.r.ard flr~twry. RnMn. i (:RANTF.P. ANT) fNTTTTUT}pN ('AR(11 1NF Pf hF11. TNOMAS, M D, Art.rintr PrnJrfrnr of Mrdrrinr, lobm Huplnn (lnivenity School of Medi- cine, Rallfmnre, Md TISSII/' ('11t II/RP ASS(X'IATION JAMFS P P. T(1MAN, Pa1T), hnJrttnr anl (-hairman of PAarn..rnfnRy, Chi. caRo Medical Schoc>t, Imlitule for Medical Rexarch. /ANIT TRAVFI 1., M D., Assnr4rr Pro. frwrr of ('hn(rsl Pharnwnlncy, ('or- nell Univenity Medical Colkge, New York. P IT. WARNFR, M O., Prolrasor of r.- rhnlr.Ry. State llnivenity of lor.s ('ol kge of Medicine, low. C'ity. S11IF1 I)S WARRFN, M D, Dirrrrer of f.oh.rrntnrirc, ('anrrr Rrtrarch /nfri. lurr, New Fngland 1)eacnness 1lnspilal fknlon. RARRARA K WATSON, Pit ll_ Arr/u- an/ RarrrinlnRur, MasvchusetH (:encul 1lospilal; Rrrren h Acuwlalr, (kparlment of Sacteriobp and Immu- nMrity, /lar.ard Medical School 1OIIN S WA(I(:/I. Prt 17 , PrcrJroior of (hrmurry, KfRRY W. BOWFRS, Pn 1)., Arsirrunr Prn)rrw.r of Chrmtr- r.r, Massachusrtu Institule of Tech nnM.~y, ('amMidcr RI(IIARI) I. W/:(IISI FR, M 1), (-llni rel Phru.d..Rrrt, Montefkwe /IrHpiral ImGtute of Rruarch, Pittsburilh. P PR()1F.CT TTTT.E Tlre signiBc.nce of diRerenl individual patterns of circulatory rnponse to cis •re/tt smoking Sludies of gcnc(k differences (rclween srnolers and non smoken Studies of psychok.gkal differences be /ween smokcr. and non-smoken as shown by comp.rison of fipue draw Inp Psychobgkal char.cteriNici of healthy Toun4 aduMs and Iheir hioMfical im plkaron; a enMinuing sludy In depth with special reference lo the precursori of hytKrtemion .nd coronary heart dit east and to smoking habits To .ai./ In establishing of summrr train Mg eourst in livue eullore lechnitpres at l)niversily of Colorado Medical School, (knver, Colorado. .nd (lniver- .i(y of Wiscorrin Mech.nisms of the p+ycholropk ef/ect+ of nkmine The study of actiom of nicotine upon ten Ud synap.es and its correlation with the mechanism of action of bchavitrr. 1a11y active drup FRecn of nkotine In the rabbit with es perimental coronary atherr.sclerosis Palholnitk-anatnmk study of cAlutar eh.nees in hum.n bronchi ('orrelation of bronchial epithelial chanRr, with comparable changes in other or 2ans-e palhoh.otic-.nalnmic srudy TTx pattern of inelas(asis of carcinoma of the lung in man Nislopalhnlogy of hum.n /an@ cancer Immunologic and virntopie atudirs on the role of influenr virus in malignant trll IransfnrmNion Fkctrnn %pin resnnance fprchrncupY r,f paramaRr.elic species drri.a(de fn.m tnhacco and related systrms I flrcl of cigarette •n..•IinR nn rrrrh.al bMxd flow, cerebral mr1aF..h.m, hlarrl RasH, bhx+d pll, arlrrial (wrlse ptessure turves, elertrr.cardwitrams, and eleclroencephalop ams 77 7(,

r4- CRANTFF AND IN.411TTTVTIOP( RUSSFI 1. W. WFI IFR, M O., P.rAoln• fin, Memorial //rnpdal of ('hnter ('rntnty, Wea (heaer, Pa ; Au.nrere Prnftum of rerh..InTr, tlahnemann Mrdreal Cnikle, Philadrlphi. SIM(/N 11 WFNhf R, Pn/), Rror.r.h Pr.rfrnor nl ( htrmrrry,, Univtrvtr o/ Otlal.nma. Norman f)(IANP O WFN7FI, P.rD, rrolnx.f of ScAcx>f o( Ph,rm.cy. Univrr.ity of Kanc.s, l..rentt TIIOMAC C. Wf:SI I AI 1., P.r 1) , Arnu .nr Proleuor nl rAo.m.r..lnee, (/mvrr ally of Vlrlrnia, I h.rwHteevitk. Vu itini• FRFI)FRI('K F WIIISKIN, M 1), C M, nrrect.M, niriJnn of Health •nd rr.rnn.hrr F.prll.hrru ., The Ag ( enter of Ne. Fngland. Inc., tsoston (aee Dihner) R(KiFR 1. WILI IAMS, PN D, rrolrrsnr of Chrm/rny and Dfr~foe, C/.rfoe Fnrndnnnn Ai.+rhrnJcel Inrrllart, The Unl.crsily of Teaas. Auslln, I FIIWIN W(N)f), M I), Mrtrwa.e in hfedrrlnt. Souon llnivtnily School of Medicira, Bo.ron (no- Professor of Mtdreint, Medical Colkgt of (:eorgia, Augu.u ) SUMNFR WCK)f) 1., MD, Anirrcnf Pro/eune of r.rUustf. Drp.rnnrnr nl rerhnlarf, )ohns Ilnplirr Univrnity, Battimore, Md 1(111N P WYATT, MO, Prolrtvr nl r.rAnSI I rnin llni.tr.iiy SMMd of Medreine. St I ouis, Mo frwr. Pro. Ie.cnr and fMr<tnr, (k~'artment r.l Pathuln~y, lln.rrnily ol Maminha. Wmmpe~, ( anida 1 al! PR())F(T TTTI.F, PathoMlic- anatomic study of cellular chantea in human hronchi A selected, talendtd •nd dela kd study of human bronchi.I mucm A au.litative and Quantifative .ludy of the indivldual polyphenol content of cigarette tobacco and the smole and Yrrn' resulling froen ciguelte smolting and also studr of Ihe Ihte of these conpounds in tht animal re.piratory syMtm TAt idemifkalion of indi.idual p.dyphe aolk cnmpound. prewnt rn the sr.w.lt from ci[.reltes aed the preparalion, .htet Irarrbk, of /hew cnmprwmss for sludirs on their mttaMh.m .nd poadbk effect on human health Tht determinatiow of the chronic eflrctH of orall~ .dministtrtd nicoline on serum cF+okstcrol nd phosplrolrpids Iht ekctrocardiopraphic response to trgora.vine, and the .axular pathrdoty of thokatrol fed rabbiH r A study of antrhyptrtensi.e acte.ily of nicotiry Action of rncMint on snhcrllutar diuri butunn of caiechotamine" and scrolomn in bnm and heart Pr/rw study of smo\ing hahd+ of Age ('cnter membtrs An invntiRation of biochemical facton associatcd with suscep/ibJity n lung cancer The effect of prolonged Inhdatirm of to baeeo +mole and of peolunted aMlin- encr frr.m Iht ua of tobacco on the Feripheral raxular re+p)mt h. .cute rnhalation of tobacco smote in man Fvahution of ctw+MRic factne., such as oeeupatinnal h.rards and haMes, and pathnMgrc prcuharitin in tfn- long Itrm survival of patienrs folk+wing rtwetion lur bronchogenie e.rcino.+.a An invrshsi.r.on into the n.ture of the pilmenlary Innrn. rn crntrdnbul.r tm phywma 79 i