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CTR HN 011431

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TARI,F OF ~(Y)NTF,NTS ~ aN Ln ~ ~. m m J"'k Ln m Preface by f)r. C. C. Little . PaRc Progress of Research Cancer Research . . . . , . . . , , . . , R Ifuman l.un6 Studies . . . . . . . . . . . . . Ib ('ardiovascular Studies . . . . . . . , . , . . 17 Psycho.physioloRical Studks . . . . . . . . . . . 22 Tohacco Chemistry and fliochemistry . . . . . . . . 22 Other Studics . . . . . . . . . . . . . . . 21 Ahslracts of Puhlishcd Reports Cancer R esearch . . . . . . . . . . . . . . 24 Ifuman Lung Studics . . . . . . . . . . . . . 12 Cardinvascular Studies . . . . . . . . . . . . . 14 Psychu-physiolnRical Studies . . . . . . . . . . 49 Tohacco Chcmistry and Riochemistry . . . . . . . . S(1 Other Studies . . . . . . . . . . . . . . . SS RcciPicnts of Orants . . 60

SCIF:N-TrI-Ir AnvIS(lRY Il0Afen tco the Tobacco Industry Rtstarch Commillce KF:NNRTII Mf'RRIF.F. LYNCII, M.T)., Sc f)., 1.1. 1) ,('hnirnrun ('hnnrrllnr and I'ro/rtvrr of rnthnlngy Mrdical ('oIItRe of Snnth Carolina Charleston. South Carolina RICIIARF) 1. RIN(7, M.D. rrn/rttor and ('hai.mnn, Fkpartment of Medicine Waynt State 1 tniversily College of Medicine 15etroit, Michigan McKFFN CAl'i F * F.1., Pn.D., M F). I'rn(rttnr )"rnrri(r+t of rhnrmornlngy Cornell llniversity Medical ('ollefve New Ynrk, N Y. LF(1N 0 lAC'nBSON, M.D. I'rrrfrttnr onJ ('hoirmnn. F}tpartmcnt of Medicine. l/niversity nf ChiceRo a 1)irrrmr, Argonne Cancer Reaarch Fknpilr,l CTricaRn, Illinois PAUL KOTIN, M f). rnnf rrirre I'rn/rttnr n/ rofhnlnxy llnivtrtity of Srnilhtrn ('alifurnia. School of Mcdicine F.os AnReles, ('alifnrnia C'F.ARF.N('f C(X)K 1.ITTl.F., S(- f)., I.L..h., l.trr f). $rirnfi/ir 1lirrrfnr,'Itrhaccn Industry Rcstarch Comntillct Pirrrrnr l-mrriru., Roscnc 11. lackaon Menrnrial I.ahr,ratnry Flar FFarhor, Maine STANLEY P. RrIMANN, M.n., Sr D. l)irrrtnr Fmrrifu.t, The Inditute for Cancer Research Philadelphia. Pennsylvania WII.LIAM F. RIENI/nFF. la.. M n. rrn/rttnr F-mrritut of .SrrrRrry lnhns Ifni.kins University School of Medicine Italtimnre. Maryland FI)WIN R. WF[ SON, Fh1. F)., 1.1 F) rrn/rarrr Fmrrifut of IVifnf .Ctnrivirt Ilarvard I./niveraly ('anlhridRe. Ma%aschusctts Rtllll'R"T (' Ilf)( KT:TT'. Pff I) 1 Mt)RRISON IIRnI)Y, A1 f) rr f ' I )i i .4 rr, ~w inrr St irnrrln 1)rrrr Inr r rrr r ,~(.cnr infr .~rirnfif I Preface A monograph on cancer morhidity', issued by the ltnilcd States Puhlic Ilcallh Service, commented on statistical and epidcminhrFical data as follows: "In the ctudy of cancet, a disease that apparently can be induced by  multiplicily of etiological agents, one cannot teal- istically expect to do more than identify factors that appear to he frequently associatcd with cancer. The prooF of an etioloRical relationship must then he sought through more intensive clinical or experimental studies." 7 his is suhstanlially the position adopted in 1954 by the Scientific Advisory Nnard to the Tobacco Industry Research Committee. It was rcaffirnled in 1960 and remains unchanged al the present lime. It is a prtsitinn Ihat Also ia held by many othen, includins slatisticians and rescarchers. i Evid.nre oJ 1'nrlou. Poufble Ferfor. During this period siRnificant evidence of various possible contributory causal factors in lung cancer has been accumulating from both statistical and experimental research. Previous lung infections, air pollutants, genetic factors, stress, hot- monal influences, viruses, diet, and other possihle influences are being invesliRated further and, as they are, a more accurate perspective of the whole picture of lung cancer causation is emerging. These factors arc not cited either to answer ot to evade the question as to what role. if any, tobacco may have in the origin of lung cancer. They do not and will not deter the Tobacco Industry Research Committee fronl continuing to support independent reseatch which is trying to answer this question. l.nnR ('nnr.r Origin l. Compfet nnd Ob.crre The present situation emphasites the truth of what we and othcrs have said rtpcateilly. 7he origin of lung cancer is complex and slill obscure. There probably are many contributing factors. Ifewever, development of research into various aspects of the lung cancer propram has had to t+c carried on in an unusual and somNimes dif• ficult psychological clunnte. This came ahnut becau.e /herc arc Ihosc who would insist on accepting ns a proved fact the hyprNhesis that ciRarrlle smnkinR rePrtsenls a primary causative factor in IunR eancer Ihis p-niP "'MnrMJHy hnm tnncrr in Ihr Uniftd [t.fr.." Puhtie Itedrh 6lnnnriaph Nr. th It C 1)rp.rlmenf of Ilerlth, 1 ducalion and Wrlf.rr, ION, W.dhipRrun, 1) (' PiRr 4 5

makca t,nc rd Ihc rm,.t dcfinitc and hlunl dctiRnitir,na nf a tfx•t;ilic c:trrac that h.tt hccn adv.rnrcd /r,r any nt:rjnr ry(a rd canccr, and Ihcy dn an .tt t tirnc whcn acrt'ntc ia till trying In dctcrmine file h:raic miFint of thia diac:rac l hn%e whr, rnnat '+clivcly prnntrrlc Ihit hypr,thcaia have cr,naiatcntly ipntactl nr, al hcat, have minimi?cd the fact that numcn,ua directly rclcv:rnl ctrt'rirnrnla eithrr havc f:tiled to auril+rut the hyPr,thcaia nr h-.tvc rn,vitlcd only wcik nr nnccrt.iin data. -1 hit aitnatirrn hia tcndcd to nbscure the reil nahrrc rtf the prr,hlcm antl a1au file aipnificnncc of resc>trch findings Ihal are not ctfntidcnt with prc- cnnceived attiluJct toward tnhacco . Since itt incc(+tion in IVSA, the T I R C. haa advt,catcd devcln(,ment nf en accruate and ohjrctive (+ertpcctive. T hit pnlic-y it reflected in Ihe tluality t,f file acicntials who Inve hcen Riven rctcarch Franla by file Sci- cmific AJvianry Flrr.trd• in the kind nf work they arc duing. :urd in Ihe acr,rct of rcacarch rrlu+rlt they have publiahcd in Ihe lileralturc. llrc ctmtplcc nalure t,f cancer nriRin it itaclf a tlclnyinc f:iclr,r :tnd no imrnrnt of cnlhuaiatm for any t,n4 Ihcnry can either h:talcn tn lacvcnl Ihe evcnhral dclcctirm and analvaia of the variuua comfa,ncnta antl t•Icmcnlt thit are involved Trmrnrn nnd f'nnrrr /1nolhcr f:utr r trf imf+ort;tncc in the Fcncral paychtrlr,Fic:tl climate thil aurrrruntla thc Iung cancer fon,hlcm it thc tovcr cntph:raia t,f thc nde allriF+ulcd tn irritatinn in Ihc c:+rcim+gcnic prt-t•caa. 1 tic mnllcr ia trf great intcreai ttr the clinician. 1 he t,hvirnra Irauma ciuacd by x-tay hurna or Ihit tcaultinl• frnm the ariplic,tir,n td ccrt:iin chcmicala tt+ the akin trf LrF.rx:rtray anintak ia a atriking phcm,mcnr,n and quite naturally attr:rcta file altcntir,n nf Ihc rc- aearc'h wnrker nr clinician. It ia well trr rcntcntbcr• huwcvcr• Ih:rt any kind n/ nhvit,ua irritation rrr ir ia not nccea•:uily or even utually a prccurtnr to the caatntial inha- ccllular chanfc r+r chinpet thit cnnatitutc whnl it c:rlled m-lifn:tncy If it wcrc, it ia pn,h,hlc Ihat hum:tn bcinFa wt+uld hmg irtr have l.ccn wi(,c'd t+nt hy canccr In anv Ir:ruma r,r area nf irritalir+n there :tre cr,nccntric rinFa nr h:tnda r,f tiaaut' crrmrr.actl t+f the following lyfvca t,f ccllt: (a 1At file central Ix.int of the Itium:r. cclla :rrc killrtl and Im,ken down 'ihcy e.innnl form cancer /1, /(lhuairlc n/ theae are d:rnr.rped ce11a wilh im/,airc,I funt tirrn and rrilncrA fv.wcr nf crll Jiviainn f hcac :trr nnt I,r, t ur-ra r,f r:tnrcr (c) Surrnuntling Ihc whnlc :r/leclcd area arc nnrm:rl cclla cntircly un:dlcctcd (tl I 11 t rrrnr rr rK urrt, ir it /rnrrrr.f in dteorrrr w•hir h lirt Artyrrrn (h) nnd (r ). lMrr inrrn r anrl vitiAfy unlmrrned rrflt nrnv hr rrlra,rJ /rn.rr t rrrrrulizrrl runtrrd anJ oi•tuulh• mrry dirrrlr• nrnrr rnprrl/v rlurn rln the nnrma/ onrt. In the pnrccaa uf uncontrolled and, up to nnw, uncontrollable j;rnwth tnat charactcrirca cancer formalion. there may be obacrvcd t hangca in the mrmhcr and rnnr(+holt+Ry of the chrnmcnomct. From time In linrc auch changes have been contidered to fx of etiological cignificance. Such changct arc probably of little or no actual significance in cancer cauaalinn. 1?tere nre many recorded obscrvalinnt of hiehly malil•nant tumnrt with file nttrmal number of chrtmnnomcs. -Iherc utc nlar nrrny tyf+ea of mm lumnrrnrt cells with striking abnormalitiet in numhcr unJ/t,r ctmft.rm:rlirm n/ Ihe chrnmtKomet. Science nruat lunk inuJe the ccll't mosl minute nnd dclicale atrucrurca nnd mual analy?e %nd e.plain itt fincat and mocl inlricatc /unclitma fx(urc the dillcrcncet between the nurmal and nraliRnant cell are undcrtltw+d. l•:1ri.fem7nfnRirn( Crpdi.. Naf f:nnnR/. It it tmyll wnntlcr, therefore. that th: data derived tt,lcly frnnr cpi- dcminltiRic:rl studict leave much lo bc dcsircd as a fnundalitm tin which lu I+:rac swccping and dttgmalic hyptHhcacs nf cancer c:ruaaliun, Scicnliata. phyaici:tna, ond the public arc rccnRnitinR that fact in ever incrcaainy num- IK•rs, and are admilling the need of far more knowlcdcc th:ut we mtw ~traacat bcft+re thia crwnplc>t probkm is fully untlctattMnl and thc :rnawcra ttr ila ntany ch:dlcnRes can be expccted. While the'anawcn we « ck are slill not within tnrr Frnap, we now have a far better umkral:rndinK of the yuettirmt. ('karly. prt,Frcat it fn'inr m:ulc 'I he findinFa t+f thr patt ycar, aa rcfmrled by acicnliala lhrtnrEhnul the ctiuntry. intlic:ile real htq+t• fnr eventual tulutinns tn thc ch:tllcnf•ct t,l c:tnct•r• heart diac:rae :rnd rrlhcr conalitution:d nilmcntt. I wiah tt, t•xprcas tincerc Ihanka to my aatnciatct nn file Scientific Atlviaury Iln:trd. :tntl In thc asauciatc acit'nlifrc dircclura uf Ihc I I R ( ' . ()r. Rnlx'rl C. Ilrx kctl and hr. 1. Mnrriann Iltatly. Dr. I lr,ckt'tl• whr+ h:ra been tlnacly aaat ciatcd with the Ilnard't reaenrch pnrFram fta eiPlit vcara. Ict. m:rdc ru:rny valu:rl,lc cnntrihulitma Itr the review trf rcac:rrch rtn Ihc payca fnllnwing While Ihia rcvicw illualr:ttca the acrIfx• antl ct•nnrlcaitira td Lrrrh Irma heinp invt•atit-.ttcd, it it eaat•ntially t,plimialic and At'acril.trvc rd Kr•nuine IunFreaa. C. ('. I itllc .Crirnrr~~ l)irrrlrrr 7 F,

"1'lrc Progress of Rcsearcii Prngrest nf Ihr 1-nhaccn Indudry Rescarch (-nmmittce prnRrim, as dcvchrrcd and carricd out by Ihc Scientific At)vianry Ilnanl, is rcllcctrd only in p:rrl hy the incrcasinR numf.cr of paf.rrs puhlishctl hy rccipicnts (if Rrantc Since the 1964) Re(xrrt, 60 new puhtishcrf parcrs h:rvc :r(qvc-arctl. hrinFinR the total In 222 Abslracts of the new puhli.hcd wnrks are in- cludcd in annlhrr tectinn of this Report. Mere numhrrs of papers, however, do not mcisurr thc siRnificance (if rescarch prnRrett A review of complcted and cnnlinuinR research Rives rcasun to believe that some of the )car's develnpmcnts open more direct patht loward discnvcrics that may he expected to contribute practical m; a- sures for coping with certain formt of cancer and cardirrvascular cfiuascs lhis review estays to estimate the state of prnRrest in sevcral fictda, to asscss the intpacl of certain findinRs, and to define the nature of tontc un- tnlved prohlcros The discustinn is divided into 1hcse scctinns: I Cancer Rescarch. 11 Ffuman I.unR Studics. III Cardinvascular Studies IV. Taycho-Phytio- IoRical V Tobacco Chemistry and 11ir+chrmiatry VI. Other Studics. 1. (:anrPr RPSrorr•h In planning cancer research it it helpful to tlislinRuish two differrnl levels of attack A full and final tnlution of the canccr prnhlcnr may he exrcctrd to ennte only when we une)crstand the hasic hinlnRical mech- anisms of cell differentiatinn and or the regulation of metabolic and cell divisinn prncesses 1 he most fundamental investiRations of the day are at this level, and more effeelive participation in such InnR-range nd hasic research is definitcly nne goal nf the 1 I R.C.'s program. At the same lime, research at a less hasic Ievel can be e><pected to produce uscful infnrmaliern and snmetimes to yield immediatcly applicable mcasutet for partial control or delay of cancer in Ihe human prrpulatinn Many snch measures have indeed hecn dcvelopcd in the pasl. Wrll dcsiyncd cxperiments at this level may he succetsful in nfprait- inf the relative rfTrcts of many controllable e+ttrinsic, as well at inuin.ic. I:rctnrs ulx+n the level of incidence of particular fnrms nf cancer in animals f'crhaps the he.l hope td developing control measuret fnr snnu fnrmt uf moiiRnancy in Ihc rrlativrly near future lict in sludirs nf this tyre. Scientific hiatury Inmiilca many risct whcre tuch reaeatch nnt nnly tnlvcrl inrmrdi:rle Lr~~hlrma hut al"r Irr-Jntrd .cicn/ilir by trrr~luc/t rrt rvcn rrr:ltrr ultimatc i value. Pasteur's discnvcry of induced immunity may hc Iraced to his origi- nal attack upon the practical problems of Ihe beer and wine industries. 1 he Scientific Advisory Board, along with other scientists, has cnn- sistently held that pathogenesis of bronchotenic carcinoma must be a compkx phenomenon and that real profr,ress toward solution must be c.- pecled through discovery and relative evaluation of a whole serics of con- trihutory factors. Thit position has sometimes been misconstrued as im- plying that no progress in the control of lung cancer could he eapected until the whole cancer prohlem could be finally and fully solved at the hasic level of biological discovery. This is far from the true meaning nf this position. Tl/F, F,X/'F.RIAfF.NTAI. AI'PROACII The several reports of statislical associatlons between cigarette smoking and lung cancer incidence made it logical to develop research to sce if smoking could play a direct, primary role in the etiology of the disease. To be s.ire, statitticians worthy of respectful attention did point out many anomalics and inconsistencies in the statistical picture. Some even yueslirrned scriously whether hiascs of several kinds might not invalidate the reprtned relationships. lhese legitimate questions about the statistics could, however, he left fer eventual resolution by qualified experts In Ihe field of epidemi- oloRy and statistics. 'Tlie testing of the question concerning tobacco as a pntsihle causative factor called for e.tensive eeperimental research in the laboratory and clinic. Stntf.rfrnt A..ocfnllon f:ennot rroo.l;euaedlon The point requirinR re-emphasis is this: Even if a statittical aaocia- tion is assumed to he completely valid, It does not and cannot dcmnnarate that smoking is actually a factor In the etiology of human hrnnchnRcnic carcinoma. 11 has been shown, for example, that there is an excellent corrclatinn between socio ecnnomic class kvelt nd the incidence of "chronic hrnn- chitii' in flritain. No clinician or stalittieian would suRRett for a moment that the amount of money a man receives per annum could of itself cause any disease, unlets he were actually infected by microhes frnm cnint rrr paper money. We automatically proceed to consideration of such mat- Icrs as dietary aJcynacy, housinR conditions, kind of clnthinR wnrn, nalure (if enrplnyment, level of medical care, amount of rest or citcrciar, nature of recreatinn, exf.oture to the elemenls and othrr factrus whith rnay he nnrrtrd by incrunt' Hnt1 which in lurn ma) in/lut-nce incidrnrr ri/ Ihr diseate. m U1 q 9 c> ~n

llre c> istcnce nf a slatiatical acsociation drxs nnt ditcl</sc the numhc•r nf intcrrnrdiatc variahles that may lie hclween the end resull (tliceatc) and the cnvirtrnmental factor orRinally taken into accnnnt 'ihe useful function of finding such a cnrrclation thut lies in the clues and hints turncd ull which may hc further and srparately validatcd. "Fnllnr-y of Ml.plnrrd ('nncrrt.n..:" In the particular illustration just Rivcn, the impnsaihilily o( a dircct cautal rclationship is sutficiently obvious to prevent investiRilnrs from mak- ing premature or feke inferences. In the case of the refxorted asancialion between tmnkinR and lung cancer• the statistical evidence is actually no dif- ferent from that nf the income-hrnnchitis situation and does nnt, nf itaelf, permit any more reliahle conclusian with resf.cct to direct causation 1)r. Itrrkann his callcd this fi?ure u(+nn the nrfrnrrntly nhvinus aa an esample of the "fallacy of miaplaced concreteneas " A allrmiae thm smokinR could hf a prime cmuaativc factor in IunR canccr cnuld hc uard only aa a wnrRinR hvrrrrhrsir hut not m. a proved fact. Neverthclcsa, thc habit of ucinp, Ihit hypntheaia frnm day In day as a Rcncr- atnr of e:herimentil tlcaiPna aecma tn have induccd tnrnc « icntiats In forget itt wholly tcntntivc d.:etut Fvcn pa an hvputhcaic, it acrn.lllv c,,ntainrrl l vrrv arri luc limit:rtinn- Only a very tmitl lirnrlrrtirrn nf r.en tlrr llr:lvlro ~rnwkcr. cvrr rlcvclrrps Ihis dlSfaac and it akn nccnrs amwmF m,namlrkrra 1 hia ia actlnllv drnng evidence that the etinloRy of the Ihtf:rtf ic cl+rnplcx ind that a mmtf.cr nf influcnces muat act in concert in iti Rcncais lhc irilplicition ia atronF that there must he factcrrs determining the drgrce of atcccfrtihility or rfaiatincc in individuais. It would arrcar to be a rromiaing enterrriae to determine what thcac factnrs are• with the view nf utilirinR Ihcnt in control nf cancer. Yct this f+rrttihility has hcen largely ignored in rraclice. lhe rclativcly low inci- dencc of IunR cancer in heavy srnnkers at well aa in the pcncrnl r-Pul.thon hac been attrihutcd rather f+re-emptnriiy to "natural diffcrrnccs in cut- cflrtihility," as if thcat were unirnf.ctttinl nr inaccccaihrc to aturly Gilliam's recent nhacrvatinn of the diminiahinR r:rtc of incrc:ne in hmF cancer in- cirknce auOPrata thf ftradn:rl diaaprcarnnce nf i partic'ularly au.cfftihlr pnrulitinn Animnl tnhnlntinn Tr.r. Con.i.t.nrfy 1YrRerlrY One way uccJ to dudy the hypolhesis that cigarette smoke might I.c a prime causalivc factor in the gcnesis of lung cancer was animal e><rcrimcnta- lirm '1 hc mo.l directly pcrtincnt of these experiments were the nurncmus studics in whit h anim:lls of several spccict were made to inhalc fresh, whnle ciRarcltc sn.okc at frequent inlcrvals over ksnR'perinds of lime, often JurinR the whole n:rtural cpan of life after weaning. These cxrerimenls cnnaistently failed to prr.ducc cyuamous cell carcinrnnas of the type that arc most prev- alent in humans. lhcce failuret• in view of the numher, extent and duration of the testt hv many able nnd experienced invettiRators, militated nRaintt Ihe aur- mise Ihar Uohacco smnke could be a primary factor in the inductirm of auch canccrs Ilnwcvcr• the prohlcm of species diRercnces in susccptihility cnuld hc raiccd• and Fencral iRnorance of thc effects even of strnnR c:ncinnrenic aFcnts nn the lunr tiaaues left the reasnnt for negative rcanllc uncertain. Fnrther work has helped clear up the uncertainties. It was Inpicat to extend these studict to investiFatinns in which ani- mals were madc to inhale aerosnls or fumes of potent, known carcimrr.cns, includinr mcthylchnlanthrene and l,d-hcnzyprene. Such c.pcrimcnls rm rats by Kuschnct were alto negative. ARain, the rcsults cnold I.c intcrpretcd in sevcrat wayc. The efficient lung ckansing mechanisms (inclurlinF mucus /1r,w, phipocytic activity, and absnrption, metaholian and cxcrftinn) nf thc healthy animal might not permit a contact limc, nt effective dntaRe, adcyuate for carcinogenic action. The prnhlcm of sfacies diflcrences In susceptihility cnuld f.crh:/p. atill he raiacd• though Andctvont had IonF hcfnte shown that syuamrluc IunR carcinomaa could he induced in C-S7 black mice by IranafiriinR thrrads im- preFnatcd with 1,2•S,(.-dihenranlhracene through the IunR 71rit had dcm- onctratcd that mrrusc IunR cella are biologically vipahle of tranaformatinn into maliFnant tisaue of this histoloRical type. Riftton and Shuhik have shown that larye tlncfc of carcinorcnic hy- rlrr+carlHmt introduct•tf inln the Iracheat nf duckt and ham.rcr% rc.fa'ctively in nil cnlutinns will prrxluce cancett of varirrua tyfns Simil:rr fffM'rlnlf/lla u.inR tobacco tmrrke condentatet have failed tn pnKluce cancer 'I hfae citf.crimcnts have, hrrwcvcr, further cnnfirmed the L•rcl that lune% of .cv cr:/l :Inim:ll apfcirs are hirdnPic>,lly t114cffHthlc tlr m:rlipnant ch.lncc whcn rlrlaa~ca Irf kmown tartimrrena are auflit'irrtl and rnnlact tlnlr ik l/inl• cmrnph I Itt I I

Trnumn nnrl ReR.n.rntfon Po..iMy (nrotr.d Anrlcrvnnl's studics and their extensinn by Kuschncr using thread trancfixion inarnduced the additional factor of trauma along with increased contact time and interference with normal cleansing mcchanitms 1 he relatively high incidence of squamous cell carcimnnas in these eRf+erimcnts drew attention to the possihie role of trauma and Ixrhars of attcmptcd regeneration in susceptibility of the lung to carcinoRcncsis. Suhsequently, a series of studies showed that a number of radioactive and potent chemical substances can induce epidermoid IunR cancers in rals and mice. Thcse studies are not directly illuminating with respect to the ctiuloRy nf epidermoid lung cancer in man, because they were carried out on animals and they employed very powerful agents not widely en- countercd by human beinRs in ordinary life. The studies do, however, dispel any doubts about lack of species susceptibility. Meanwhile, clinical and epidemioloRical studics of human suhjccts by a numbcr of investiRators pointed toward the possibility that damage to the IunR, followed by reReneradnn, might be  predisfxning factor in human lung cancer, whether the damage was due to tuberculosis Iesions, infarctinn, or mechanical injury. Winternitz long ago pninted out the frequcnt occurrence of severe mctarlatias in the lungs of persons who died following influenra in the 191R-19 e(+idrmic and had called attention to their "precancerous appear- ance." Several investigators had attempted to produce lung cancers in animals by repeated influenza infections hut, th<wph metaplivic ch:rnRcs were produced, no truly invasive lumnrs developed. (:nnr.r F:xprrlmint..rith 17ru.e. fly ctrmbining repeated influenza infections with inhalation of syn- thrtic smog. Wisclcy, Kotin, Fnwler and Trividi have obtained invasive and metnatatic squamous cell carcinomas in the IunRs of ('-S7 black mice at a suhstantial level of incidence. Almost at the same time. Martin and his crdlafx.rators showed n synergistic action between scveral viruscs and a sfx- cific chrmical carcinogen by obtaining tumors when combined small dtnes nf virus and chemicals were given. Given separately, at the tame levels, thcsr aPents failyd to induce cancer. Stanton also htas repcssted the induction of syuamnut cell hmR car- cinnmas by chemical carcinogens administered intravenously into rals in which nrrat of IunR infarction had been produced. lhrar rr,rnl rvrntt err citr l to illustratr the ral.id Irvrli-l+inrnt nf n„ lh-1. f,.i "-1, „r .,lu.r.u•ui crll a ari 'n„n..I m I n.ni. it InnFt These methods provide a basis for evaluating the relative rRccts of many other extrinsic and intrinsic factors on the rate and level of incidence of bronchogenic carcinunra in animals. fly suitable desisn, it should become possihle to evaluate the effects of aae, se><, nutritional atatus, excess or defi- ciency of hormones, stimulation or depression of the reticuhocndolhelial system, cancer prornotinR aRents, various types of trauma, irritants, mucus cnmfxnition and ahundance, activity of cilia, efficiency of detoraification mechanisms and many other factort. Te.t. (:ontfnue on ToAorro SmolrP Tests of tobacco smoke In this experimental biological system have not yet been completed. So far, the indications from these and many other tests of the activity nf tobacco smoke, are that the smoke is much too feeble to play a role in the etiology of lung cancer as a direct contact carcinogen. 1 his does not necessarily exclude tobacco from having any role at all, nor is any such role established. More investigations are necessary on the suR- :Restions of possible indirect, contributory roles for tobacco. As the experimental systems described gradually permit the relative evaluation of all the f+ossibte external and internal in/luences listed atxrve, it ahould become fxnsihle to determine whether and to what extent tobaccn smoke can cnntribute, whether as irritant, promoter, modifier of ciliary activity, in/lucncer of nutrition or by any other means. It is a task of con- siderahle maRnitude, but the rneans now seem to be at hand. The fortunate spect is that, as the contributions of the various suspect factors are evaluated, melhods of nullifying or blocking snme of them may become apparent. qr course, the f+rohlems of species diflerences and rele- vance to man will remain to be resn(ved. Nopefully, effective methrKls of reducing Ihe tnll of human lung cancer may become evident from this type of work. C1/RRt;NT CONTRIItf/TInNS FROM T.1.R.C. 1'RnCR.4Rl The program of cancer research supported by T I R.C. Rr.rnts pro- duced several significant developments during the year. The suggestion that some transmissiMe agent is pr«luced by ccrtain tumnrs has come from further study of the increased concentrations nf deorayrihonucleie acid (f)NA) in tumor-hearinR rats In tissues distant fnom Ihe actual tumor. F.tracts of IunR, kidney, liver and splecn rrf rats f.enrinR Ihe Walker 256 carrinnma and the Jensen sarcoma have been hrund trr ini cnrl+runte Ihymidine It` more rapidly than thnte frmm nnrmal rats, inAiiat. inR a fxrstihtc influrnce frnm the tumnrs. I. 11

In three diRcrent laharalr.rics, c> f+nsure (if culturrJ cclk h+ murke and mm Srnnke yatct wat studicJ witlt dcccriflirm rlf rnnrLhrrlrrFicil changrs, alteratinnt in Rrnwth ralct, and mr+Jificatinn rrf mrKl.rl v:tluct of chrrmi.anmc numt.ert. Fflecls nf irratliatinR human arnninn ccllt havc been sirnilarily de- scrihcd Since rnnrphnlnRical changcs and plniJy rd chnnnrntxnc cvnctitu- tinn are nrd simply or Jirectly diagnostic of maliRnant mrxlilic:rtirrn, it it e.pcctcd th,l future studies at the cell anJ tissue cuhurc Ic"lt unJcr T.I R('. tuffxrrt will place increasing emphatis (+n changes in thc dynamict of the living cell I urthcr quantitative cytnchcmical studics on the rcl:rtirrn of f)NA to varinut patlhnlnRical ctrnditirrnt also point trrward thc crrnclutirrn that Jcviatirrnt frnrn ntirmal in amtrunt and tlittrilmtirrn tof 1)NA irc nnt tf,ccifically draPnrrdic nf maliFnant Irandnrm~tirrn, hut r:tthcr rof /•rnwth rir rcPcneratirrn rrPardlets of cautc, nr (if f)NA virut in(cttirin Nn lernR Cnnr.r. In A/ire f:ip.Ard to Cmnke A new summary revietved the hittolnRical, cytrrlnRic:J anel cytrrchemi- cal slndy (if the Irnchcnhrnnchial trcc and IunRt td mice exfx),,cJ Irr ciRa- rette smrrke It confirmed the Irrcvir,udy rcl+r+rted variability (if respnnte, ranging frnm ahccnce of siRndicint hitlnlrrRical chanFc. IhrouRh mild bronchitis with swnllen epithelitim and mild hyf.erplatia. Ir+ severe hrnn- chitit with a typical basal cell hyrerplasia, tquamont cell mctn flatia anti occasional dysplatia or "carcintvmn-in-titu " Invasivc carcintinra was n.rr found "ihe extrcme variability of respnnte, regarJlctt uf thnc anrl Jur:rtir+n (+f exposure, pointed to ennuihutinR factnrs, such as latent virut infectirmt. characteristic of the individual animal. LnnR-contiuucd studies with the white Pekin duck have culminated in rrtxluction of nnn-metastatic ncoplatmt of varied type in the IunRt (if hirdt given methylcholanthrene in fxilysorhate Rl) by inlratrachcat infutinn. lrt- haccu smoke condensates timilarly infused have not produced lumurt. RIl).4SSAY AfETIIOI)S r , Ihc Ihntt. "Rclvivc potency." therefore, implies cnmparisnn rrf activity within tnnrc ficcJ or stanJardi,ed hiohrRical system. rach such tystcm will prtxlnce itt own scalc, since there are wide varialit.ns in rrnctirm Mrlh arrnrnr and within species. If several tcalcs hatcJ on diRcrcnt,biohtgical phcnnmcna, other than actual tumnr prrwluctinn, are scl up. Ihcre, is no guarantee th:tl any p:rrallclitm will exitt between Ihem in the relalive fxxititrnt astumed by Ihe varinus agcntt tested. If a degree of parallelism should cK-ctn amrrnR several tuch scalct, it might encourage cnnfidence in their tignilicancc, ctrecially if nne a1 least is baseJ on actual lumor prutluction. Ohvimrtly a mcthnd more rapid and conlrnllahlc than rnuntc tkin painlinF, and rrquirinR only very small quantitiet nf tesl tuh.tancc, wnulJ l+c ,rf great praclical vcJUe in sf+tedinr rescarch. In thc'1 I It ('. Rranl proFram nver Ihc past half drvcn ye:ut, a acrae (if mNhrwrt have f+ccn tried utd in the attempt to tctt fur thc rcl:rtivc "carcinnFcnic rntency" of tobacco smoke and other subtlancct Such in- fnrmatinn would, it was IhouRhl, hclp atsett the hyptsllxtit that tuch amrrkc cr+nlrihntct In human cancer as a contact careimrFcn nnJ help Jcternrinc where emphasis in retenrch should he direcled. None nf thctc earlier :tltcmprt proved tn he tatisfactnry for relative quantitative ev:tlualiun. Mr4at, hu1 nut all, gavc complclely negative results. llul even thnuFh not whrrlly satisfaclory, these many sludics produced an nverall impression thal tnhaccn smnke (if nnrmal character, In its Icnunut state, it Itxr weak a carcintr'cn. if it is nnc at all fnr humans, to act in thit capacity as a Rcncrntur (if human lung cancer. i F.nrortrnRlnR Rf'-ar.It. In Tflr.e Aren. Now the hcncfits of this work arc coming to fruitirm. lhc retcarch fnr more tntisfactnry hit.assay methnds has entered a new ph:rte which apfn•nr% encouraging alnnp three lines: I. A mclheKl based on the activity of "earcinugenic ayenls" in cnhancing growth of Iran.pl:mtcd tumor anJ nnrmal skin yraltt - hat hccn shrrwn capable of quantitatinn, and an "activity scale" fnr a IirPe tcrict (if highly purified fwdyeyelic hydrncarhnnt is in Numernus studies have been supf+ortcd by Rrants in the eRrxt tn canttructinn. nhtain a more cxact quantitative mcthtrtl nf testing frx relative nver-:+II 2. Frnthcr ttandardi?atinn is in prncrtss Irrr a pnitrrm:rn "carcintrRenic portcnciet" (if varinut suhttances and mi tturet, includinR natny /ra carcinrrFenie hydrnearhnns, hased nn Ihe resprinae rd m tn trrhacco smnke and enndentatet I'unnrrrrrurn r.nrnJrmmr In ullravirrlct anJ rclaleJ radinlinrn frrllnw- On a ttrictly thenrctical hntit, "eareinnFcnic prrtency" is nnt an in- inf c.hrrturc Irr thc hyrtnrcarhtrnt in hiFFt dilutinn A actr nrl r. hrrrnt prr,pCrty rvf a chrmical arrhoancc It:rthrr it it thc rcl ult nf an LrrtcncV sc:rlr is :rl.r- trr 1r enntlruclyd hy Ihit mcthrtil, with ute intrrattirm rrl ~r,mc kind Lrtwccn on agent anrl a tlynamic IivinR entity -- ,rf thc tarnc s:rnrlrlct trf hiyhly purilictl hydrrK'nrhrms m tn © I4 IS m

3. A third prnjected scak is to be hascd upnn animal skin tumnr prnducti<,n by an accclcratcd mclhtKl, if plant malcrialire. The relative evaluation of various "unknown" suhstanccs on these scalcs is cnntemplated in due course, when background infnrma- tion becomes adequate. Cnn/errnrr on Rlna..oy and Carr(noR.nr.l. Many of the matters outlined above were discussed in a round table conference D++ May 25. 1961, in the offices of the Committee. (letides memhers of the Scientific Advisory ilnard and staff, the following guest scienlists parlieipated: nR. T. 1) f)AY, tJniversity of I eedt Schnol of Medicine. 1 red., FnRland DR Wi1t 1 f R F HI'-CT(1N, Natinnal ('.ncrr Inailule, hrrttrada. Md t)R hRfl)t)Y FIOMRl1R(iFR, Rio Re.e.rch )nstitute, Inc ,('.rn- hridRe. M a+. F)R ROIIFRT W_ I-Illl l.. NmAwcstrrn llniversity, F.vanston, 111. F)R l-IIAR1 TS 1. KENSI.FR, Arthur I). I.iltle. Inc ,('amhridRe, M .at hR. WII I IAM E. P(1ft_, l)niver,i/y of PittthurRh, Pitt.hurRh, Pa. DR MURRAY I SIIFAR. Nalir,n.t Cancer Inttinrle, Rethetda. Md UR ('ONSTANTINfi S SIFP/IANO, Slrhhann Hrorhers, Inc Philadrtr,hia, P.. I)R I-IARO1.1) STEWART. Nalional Inatitutet nf Flealth, Relhr+da. Md MR O. F, lO1)I), Tobacco Manu/acturers' Standing ('ommillee. I ondon, FnRland. 11. Iltlmnn Lr.nR Studic+ Among studies on pulmonary function and physiology was a ciRnift- cant contribution in the measurement of "airway retittance" by the mcthexl of body pkthysmnRraphy. Inhalation of cigarette snroke both by normal pcrsnns and patients with various lung diseases, whether habitual tmnkers or nnnvnnkerc, produced a mild hrnnchnennstriction lasting from 1(1 to Rtl minutrs in mt,tl individual,. The effcct did not appear Itn mcdiate through nicntine nr other volatile suhslances aml crnrld F,e preverrted by ist,prrrtcrcnttl I)ata were Inadcquate tn warrant rclatinP of thit cllcct cautally In initfitir+n ca aRRravatinn of chronic pulmnnary diaeaa A rrvirw I,as .t,p-rarril tlrtcribin(- emf,crirnrr in Ilre crn,tsrr.,rivr alndy ,i1 (•ahuoe>fit al :vt:,tnmy r,f Ihe I,umin hrt,nchi:rl trce and lunpt whit h Ihe Scientific Advi.r,ry (tt,art) initiated in 1954. Alxtul .l,OINl catet were in- vettiPalcd, yicldinP R,Sv() alidcs from males and 3,661 fnnn femalca. Particip:,tinR wt•rc 12 fathok,Riatt in different Mcatiuns around Ihc cnuntry. 1lrc rcview rcf.r,rt, chictly nn prnMems of diaRnncis and clacsificaliun 'I he study it now hcinK extcndcd under auspices of the llnilcd Slates F uhlic f Ieahh Scrvice. A more tlct:rikd refxirt by one (d the participants in the cooperative ttudy has indicated that only 4R percent of the cases could he a+ncidercd normal and fewer nf Ihese occurred among smokers than among nnn- smnkerc Rcarltt of such sludies indicale the many prohlems in defining pathological chanRec and interpreting their significance. Ill. Cnr.liornscttlnr S/f1rltlPa Several nf thc carditrvatcular diaeates have hcen rcpnrted by invttti- Ratnrt in cpidcmi,drtPy In he asancialed with the use of tnf.accn, ctpccially cigarel/et As in the cate of the other asseuiatinn, these repnrts have given impctut to additinnal sludies on the cpideminlnRieal level as well as to many nf a clinical nr c.f+crimental nature. The object has been to determine whether the actnci:rtinns are truly meaninRful and whether they reflect any cnnlrihulinn by tmnkinR to the etiology of theae ditcaces, or whether the tink with snmkinR it only fnrtuilnus or indireet. IhrnuFh intcrmcdialc ct.m• mnn factnrs. i Mnny nrhrr Fncn.r. Al.o /f.InR Crur/lrr/ Among other L•tctnrt trnder investigation in studies of cartliovatcular discate dcvclnpmcnl are heredity, emotional constitution, slress and the individual manner of reaclinR to stress, physical activity in rclation to caloric inlakc, rclativc h<xly weipht, mclahnlie charactcrittict. Ihyrnid activity and dietary h;thitt, eepecially with respect to the amnunt antl kindc nf fat cnnsurncd Scx and ethnic origin are also involved. Recent prnprctt in several centcrs suRpests that a distinctinn may need In hc drawn Ixxtwccn IhtKe influences that hlfect the rale of presRrct- aiun nf chronic vawul:rr deFenerative prncetses such as alherntclernait, am1 Ihnte that may hclr prccipitale acute epiaxks auch as myncardial infarc. titm, thr mcchani.mt n( which still clmk full chrcitlatir+n. Vvidence rmrrtsinR frnm the Tnh;reca Inth/ttry Rcaearch ('nnlnlrllce prnhram and ekewhere supt-eett that the prevalent tyl,cs of chrr,nic v:,tt ular tkqlcncr:rtinn are nnl ai/•nific.rntly influcnccd in ralr or rlcPrcc by tAr I,criralrc n,lr.nni.tr:,rn,n .d nr, r,Ime in .m:rl) anu,unlt .,vcr :r L,nr• la r-d nr hy Ihc mtKlt'nrlt• I,r.rtUtc rd tntt,kinP f y avcr.rP,e Iti•r.,m. Slrll yd,arrrt• ur 16 17

Ihe mccli.rni.mc that l,tccirititc an acutc epittxlc in pertnns with advancc•d undcrivinF voccul.r tlitcase, who arc aontcquentty mnrc vulncrahlc It, all kindt nf ttrctt. F/huts Itt sr,lve these prohlcmt tit the cpiderninlr,Fical level arc fraufht with many dilficnltict Prearmahly the dcRree of v;rcc'ulir tlcRcnerntinn in human hc inFs can he accurately determined only at aulnpty by anatnmic nxthndt I hnuph aecidcntal deaths ennttantly prnvide tamplet which cut acrntt all linet of age, tex and race, the problem nf acquirinR the needed data on life hahits of thete victimt, by retrnsl+ective mcthtxlt, is formidable. Prntr%cctive audics. while permitting hetler accets to informatinn aMwt Lersnnality, dicl• smnking. Ma1y build and the like, do nnt cnneluce to actluisitinn tit anaU,mic information in a univcrsal nr nnn-tclcctive, randrnn ntanncr anrl thut dclx•nd u/wrn vaRucr clinical indicafir,nt nf cardit,vatcul:v L:rthut„Ry 1 hcy mu.t, mnrcnver. (h,r I,raetical rcatnm, u.c IM,I,nlatit,nt cnnfined to the nldcr age Ernurot. Ifmme,n Ar(rrlra Arr F.fnrnin.d 6 t)cspile difficulliet, a pathnk,Ric-an:)Inmie ttutly of human artrrict, rccnvcrcd frnm accirlcnt victims. it bring suropnrtcd Pertistcnt and in- peninus tflortt are mnde to acqnire and validate at mitch dala at IH,ttihle. retrntf,eclivcly, ahr,ul the pertinent charicteristict and lifc hahits of the suhjccts. ln enmpare irl+rnaches. techniqurs and findlnFt in this ficld• a cnn- frrencc wat held during the year to which scicnti.tc involved in studics involving timilar tcchniqucs end pruhlcmt were hroughl Inpcthcr. ('onfrrrnrr on Arhrroarlrrn.l. Crurfiro lhis cnnlerence wat held in the nrfices of the Tnhacen Industry Re- acarch (•ommittcc (in May 26. 1961. In addition tit s1aR and mcmhc•rt of the Scienlific Advitnry linard• the following invcttiRitnrs p,rticipatcd I1R W11 I IAM (7 PfAI)1-NKOrr', New York St.,tr hrp:,rtmrnt of Ilcatth, Alhsny, N. Y. I1R 1/1OA1AS R h.m, M.,.t IlAWf11 R• ll S Puhlie Ilc-1l)h Scrvice, I riminR- IrR IHA (iORli. vclcrans Adminktr:rlian Ilnapir.J- Wc%l Rn.hury, M.,a . anJ Ilarvard MeJical School 11R (i1 ()RIn (7A110 and IIR. MI('ItAI I I.YONS. New York - ity (Inivcrvtv ( nlttl:c of Mcdicinc• New Ytnk ( ON 1)R 111 NRN' (' tR , and MRS MYRA I RI('ItAR1)S. Mi(al l cn , 1 r„u.,..n., Ct.,/r Ilnr~rr.ity tth,~,l n/ Mril~i inc Nrw fhlr.,nt 1:, CJ © ItR (il ()Rt:1 V MANN, V.~n~1nlnh Ilnivrrvey C,hrwdof h1r,h,inr. m N,,.h~rllr, I rnn IR I)R 11'YKIf)IIR 11 RINZ1.IiR, New York llospital-('ornell Mcdical ( entcr. New Ynrk, N. Y. 11R WII HUR A. 111(IMAS, Albany Medical CoI1tRe, Alhany, N. Y. 11R. (il VR(il-. I WAKfRI.IN, American Fleart AtvKiatian, New York ( fty 1'roFrraa rn tirn.lirt n/ Tnhnrro E/j(.rh An cpidcmirdugical study on a large population of living male sub- jccls, including m.rny measurements and functional tcsls, provided no cvidence tit larl;c tit irnportanl dilferences in eirculalnry activity between gmup% of h:lhrtual .rutrkcrs and mrovaokers. 7 here wat little evidence uf Jctcrirmratiun of t:ardiuvascular '•filness•' in smokers performing work tests. Ilcuvy smrrkcrs had cnnsistently k+wer relative body weight, and higher L:rt:rl rr.y'cn crmvumptinn. Oilfetences in resling blood pressures were cithcr nnnaKnitic:mt tit tcndcd to he lower among smnkets. Itecau.c tit rcl,t,rtcd ditfererxes in the relative incidence of itchemic hc:vl tlist•:rse runnnl; the thfee major elhnic gnwps of Sewlh Africa, a stuJy t wat n+:tde :)mtmg (d1O healthy rcpresenlalives of these gruups, (•unsidcra- tirm w:t% rivcn lu trnukinK habilt, ineume, uccupalion, diel, anlhrupnmc(ric mcasurcrut•nlt, arterial pretsures, and total bkxxl cholesterol levelt, as wcll as di.trihulinn tit this lipid between alpha-and hrta-lilxrprotein. No .iRnitir.ult rclalionchip was faund hetwecn smoking and aRe, income, n:rlurc tit tacupation, hciRht, weight or degree of ohctity. A highly con- ti.lcnl dilfcrcncc was luund in the dittributinn of eho/esterol hclween Ihe :rll.ha-:md Ix•I:r-lil,trprnlcin (ractions, however, and these diflerences were pur:rllcled by dilicrcnces in the customary dielary fat intake. It was there- Inrc pnyartcQ thel snnding may e>tercite an Indirect in/lucnce by mtxlify- inl• the .clcctinn ol I(aKtt through elfccls nn the latte sente. Suhsidiary .IUJic% hrnvidiJ tnmc prclinrinary e.idence that smukers may prefer salty, sViced and hiFh-L•rt ItwKts and ntay esperience a diminithed sentitivily to hittcr t:r.tc. In a long tcrm prn.rc•ctive study detiRned to elucidate llre precursnrt rd hyrcrlcn.iun :tnrl ct-nmary disca.c, it has been reportcd that whitc nctle mctlic:tl atudcnt. whn arc the oR.prinR nf two parentt uffectt•tl with Ihese dr.c:t.c•t, :tre tignific:mtly diffcrenl from the ollsprinR tit Iwo unaliecled I+:rn•nt.. On the :rvrraRc• the tnnt nf the a0e.ted parentt are 1(1 httunds Fhcnvirr, m„tc frcqucnlly have hyl+crchrdetteremia, sh,rw higher tcttinR .ystulic hhMxl /ncarnc Icvels and we more likely to he smnkcrt. Whilc thcac dillcrcnce. :rrc nr,l yrcat, they ure eompalihle with thc hyla,thr.it r,/ multif:rctt,rial inhr-rit:,n,t• Ihc•ac r.htervalirrnt recall lite /N,tsil,ihly th:rt .nr„kinlt h.rlnt% m.tv rrtlrtt pre ctittinR cnnstitutinn:rl fat-Nnt. r:uhcr th.tn nccct.arily cnntrrhutrnr cauetlly In prrHlucinji, the diflerencet Io

I a, c r`. ,Stud-v o f Srrum Frr. Fntty Ar1d• The ohservation, from animal studies, that nicotine may rtlease cpinephrine and norepinephrine from depots and Ihus indirectly trigger the mtrhilitatian of free fatly acids (Ff:A) into Ihe citculation from tissue fat deposits, prompted a similar study in  limited number of human sub- jccts. "1 he smokinf of two cigarettes was found to produce an elevation in scrum free fatty acids. The response was not related to aRe, sex, Reneral smnkinR habits, type of cigarette or pre-smokinR level (if FFA. Total cholesterol was not affected. Non-smoking controls subjected to otherwiae identical procedures also experieneed a moderate but smaller increase in FFA. Such mohiliration of FFA was to have been exfxcted as a normal part of the resf+onse to any stress on the tympathctic nervous system. As such, it rctluires quantitative evaluatinn In relatinn In thc effects of all trther feums (if stress to determine whether such effects are of any real sipnificance in the atheroYclcrotic processes. Meanwhile, a different Rrnup of investigators has shown that in the pontahsnrptive state, the human as well as the dog heart extracts a cnn- sistently higher percentage of free olcic acid than of any other free fatty acid present in rterial hkxvd. It had been dcmonttrated prcviewely that energy prnduclirm of the heart tlei.rnde laryrly nn fatty ecid mNnholism. Animal studies of vascular I+athr.loyy, th(rur.h much mnre easily enn- Irolled, are impeded by problems of %f.rcies dillerrncrs and rtiflicultiea nf interprcintinn and aprlicatinn to human heinRt Ilrrwevcr, furthrr •tudics have been eonrplNed with rahhits fed cholcstertrl and cnlar,nsecd oil, nicotine, or a combination of all three, in comparison with cnntrnlc. A previous study had reported an apparently synergistic eflect of nicotine in spcedins and intensifying the production of peripheral circula- tory changes and cardiac damaRe, with necrosis, by the atheroRenit diel. In the present exf+eriment, however, the peripheral circulatory changes were minimal and cardiac necrosis absent. Since ergonovine had been used previously for lcsts to assess cardiac functional status, it was added to the reRimen, and the necrotie conditions were aRain obtained. These necrotic elfects are now attributed by the investigators to the addilional action (if erRomovine in the combination [Rccts formerly cnnsidered attrihutahle to the cholesterol diet, with or without nicotine, have diminished acctudinRly. Rr.pnn.r tn C7Rnrrrrr SmnRfnR by Cnronn" I'nNrnfa lhr rnv,K lrrrli,rl rrslwtntr Irv riParrttr tmnkint, in Iialirntt with ctrrr+nary fi,r:r" h;r~ I"n mrlsnrrrt hy tathrtcriratinn trchnhlucs 1'trvinut dudics h,d shnwn that smoking enhances myocardial blood flow in normal sub- jccrs. 1lcart rate was accelerated in both groups by smoking and :rrterial pressure generally rose, hul these changes tended to be more pronounced in the coronary group. A uniform increment of left ventricular work was also more pronounced in the lalter. Myocardial oxygen usaRe was virtually unchanged T he coronary subjects did not experience increased myeKardial blood flow during smokin6, perhaps on account of the "fixed coronary resistance" alleged to exist in such palients. There was no evidence of myocardial ischemia during smokin6, however, even in the coronary group. A study of DuerRcr's disease among young men in the Orient pro- duced evidence that this disease is distinct from the atherosclerosis or emholism ot the peripheral vasculature that occurs more commonly In the Unitcd Slates, and where actual existenee of a distinct fluerRer's syndrome has been qucsliuned. While all lhe 62 patients observed were smokcts. Ihe study suPRested that the etinlnRy and palhrgenesis (if the condition are probably complicated. Whether the essential ksion is truly an anRiitis re- mains to be proved. Pipe and ciR.ir smoking have been shown to prrxfuce circulatory effects (a drop in skin temperalure, increase in pulse rate and hlrxxl prcssure) similar to but less marked than those found following cigarette smoking or tobacco chewing. IlallislrxardioRraphie changes were less than those follnwinR chcwinR, hut greater than those following cigarettes. In an effort to throw light on the physiolo6y of relative hyperrcactivity to smoking by certain healthy young adults, in terms of blood pressure, heart rate, or cardiac outpul, the effects of preliminary small intravenous drxts of hexamethnnium, mephentermine or of a talt-solution'placcho wcre studied. lndividual differences in homeostasis were revealed but the changes were not readily grouped and the resulls were too varied for sirnple classification of suhjects. I Fundnm.nln/ Stndtrs of Cnrdlmvr.rufnr Cyarm Numenws contributions to study of the cardiovascular system alonR hmdamental lincs were made during the year by recipients (if 'lohaccn Industry Research Committee support without immediale bearing uF+r.n the eflects of nicotine or smoking. OIhers eonarihuled new or inq.rttvrd techniques for study (if this system. A notable series of such paf+ers centered auormd the mNaholic nc- livitics (if the hrart mutcle unrler varinus ennditirrns antl inflnrntcs anJ of Ihc rclatinm t,ctwrrn hir~chemicat events and druy, actir,ns, anrl tlrr resulting mechanitil and trthcr functit.nt. Othere dcalt with thr rntirrnatr 21

td rrrrtincntc -,a kractl urrrn hirxhcnrical ct+nciJcratinna, anrl wirh mrth+xlc t+l nrc. mint tmrnr:ny I.hxxl Ilr+w antl td :rcacaainl ttar+n.rry :rrlcry imnflrt rcnt y A t+t't•inninl- Ir.rc :datr I+ccn madt• :rt Ihc crdlrnc td nt+rnr.d ral hih' :rnrlic anJ rnrK'arrfi,rl ttll, in rirnr. Variunc nuLricnt rncrlia lravc Ix'cn lcatcd :rntl Ihc rcl•rtivc frr,wIh Ix+lcnti:rk t+f acvcr:rl ccll lyl+cc tlclcrnrincJ l)hjrclivcc arr tr+ nl.acrvc mcl.tht+lic activitict -It they nray I+c affct:tctt by a:rnt+ua c+t- U.rnct,uc auhaf:rncca, including nict+linc. 'I hccc cnntrihulitrnc atc imrtttlant ccicntific:tlly In thc furlhcr clutly r+f c:rrtlitrv:racnl.rr dicc:tcct and ahtlr:rclc of all auch p:Ilx•rt are inchulctl in Ihit rclxal IV. Ira~fllfr-I'Ir3.rrrlnRirfrf Sfrrrlir. 1 hr 1•cncr:rl t+hjrctivcc t+f rcccaft II in Ihic ficlJ have ht•cn dret uaarJ in Ixcvinrr\ rclx+ttc, :rntl 3 ctyntinninC rrr+rr:rm ic in thc f.rtat•cc nf e.l•:mainn ('utrcnt rcfx+rlt includc a atutty nf rcl:rtit+nahiM hctwccn ctmctilutitrn antl t+thcr ch:+rrclcriaticc nnd ainAinl: in a Frt+np of cuhjcctc all td Italian famity tail-inc frt+nr thc :rrc:r ncar Nal+lct. I can men were ftnrnd tty crnnkc nuuc 1h:rn att+ul nncc, hrrt thc tlictt wcrc nt+t cipnificanlly tliffctcnt Slit•Itlly hir~hcr ccrmn cht+lcatcrtd w:rc ft+untl amnnp amrrkcrc, hut cipnrficanl dif- fcrcnccc wcrc nr+t t+hccrvcd Ix•twccn trntrkcrc :rnJ nnnanrtrkcrc in anlhrtr• p+mctric ntciclrrcnrcnl, in phycic:d :rclivity or in :dcuhtrl t:r+ncnmf.lirtn. An anal,ycic uf thc amt+kinp frncliccc nf n rrrnrp td Il:rrv:vd nrt•n in crnn(,ariann wilh tht+cc t+f the pcncr:rl f+tq.nl:rlirm h:rt alctr nfqvcarrtl, ac a hy- f+rtxlucl nf a nn+rt• intt'ncivc ttutly t+f arunkine wc tcl:ltt•d ttr Mxly huiltl V. T.rlrnr•r•n CIeenti.rrv rtrtrl Mfrrlrentiarv A tcricc td alndict tin rncchinicrnc of hitrcynthctic of Nio-nritrrrn alka- IniJc hac rcichcd f+nhlicntit+n at culminatinn t+f a Inng-ct+nlinucd prt+Fram trt aludy Mcthanicmc t+f m:rnun:rli:tn and h:tclctinl nrctahrditrn n( nit'ntinc and relntcd :rlk aIt+irlt have 1.ccn Iraccd thrnuFh arldititrnal st:rgcc wilh full irlcnlificntit+n t+f inlcrmcdiatct hy exaclinR mcthrxlc. Scvcral new ctm- cliturnla of tnh:uctt have hecn itlcntificd. Scvcr:rl ycntc :rpn the qucctiun w-vt riicctl whclhcr the fr+rmrr uac r+f :rracnic:rl inacclit'idt•t mirhl have cnnt:rminalcd Ihc cr+ilc ul ItJ.accn prtrwinF arr,ta with cr+ncrqncnt hmF aualainctl int'rcacc in arct•nic ahcv,rf+tit+n hy I-+h:tccrt plantc A tllrrc-yc:rr atudy t+f thia auhirct, rcfx+rlctl prc'linualy, ah++wct1 Ih.rt cuth a+il ct+nt:rmin:ttinn Irm. nt+l txcurrt•d Irr any cirnilit:rnt Orrrcc A n. w it t-rt i+n rnrth-lr+lr-py nf acmi nrlt rn nn:rlytic l+n arat rnic ...r,~,~, . n.... I,u1~l~•1„ J will Lr~ rhl.~lr +ny Iu1~nr V1. (Ifher Strriflirs (11hcr cludiet include reports frnm the conlipuinR invetlipalitm t+f nicrdinc ~h:rrmaculn~y which cmphasi7cs cspecially cffcclc upt,n Ihc ccntr:d nerw+oc syalcnt with an ultimale view to elucidalinR snme of the bacct ftur the uae nf ttrh:rcco by humant in the cnntext uf tire silualinnc Tt+h:rcco uae hat been found Itr have no inffuencc on the tucurrcnce (rf criicrxlcs in tn-callcd "periodic" diseate. A notable event in 1461 was publication of the comprchentivc mr+ntr- Rraph. Tnhmrrr, r,rrerimcnrul and (7inir'af SwAiir, by I)rs. 1,rsnn, IIaaR and Silvette of the Mcdical Collcge of Virginia. This R(K)-paRc Mx+k, whnce cnmplclinn wac atsitted by the Commillee; shnuhl greatly increice the accectihilily nf tcientifrc literature in the field and lhus slimulatc and f:rcililate new reccarrh, while conlrihulinR significantly tt+ Ihe dcvchqrrncnl trf hetter perapt•ttivet 'I'he Ix><rk Is a camprehensive accormt trf the wurlJ li/rrature, I+astd on uudy of mtxe than 6,((N) arlicles publiahctl in ahtrul 1,2(N) jtnrrn:rlc. It hat been widcly and favorahly reviewed. Other comprehcntive reviews of Ihe literature on the eRectc of tobacco on sl+ccific rxfans or syttems appeared durinR the year. Thc litcrature an IunR cancer from 1930 to 1960, wat reviewed by Rirdnn and Kirchtrfl, who prcvioucly had puhliched a review of the freritxf 19(NI 1930. llrc laler arlicle, containing 455 refcrences, noted that varinut facttrrc have fxen chrdied in the etiology of IunR cancer, including tuherculosit, influcnra and other chett diccatec, nccurational e.pocures, atmncpfrcric pnllulanlt, anJ tobacco. It concluded that the cause of humnn hmR cancer it unknown. Afrdlrnf Ctrnf.nr Frfrorenhrpse Since IUSS the Tobacco Induetry Reteatch Committee hat, upnn rccnmmcndatit+n of the Scientific Advitt+ry Rnard, been cupptalinR a prtr- Fr:rfn dctigncd to ttimulate inlcrctt in hacie research among mcdic:rl tchtwd sludentt. Thic prt+gram wat again in eReet durinR the year among Ilu n7litm'c acercdited mcdical and ottenpalhie «htx.lc '1he imfxrrlancc t+f such a prnFram was recnpnired in the April 1961 rt•pttrl nf the 1'rcaitlcnt's (•rrnference on Ifearl hiceace and (•ancrr. lhit rcf+trrl caid that h:rcic rcccnrch muct be tuppnrtcJ at the chicf ctnncc nf ncw knnwlcrlpe and rn/'cd Ihal mnre ynung pettrlc nf nutet:rndinh ahihty t+c rccruilcd into the ht•allh fieW. ltndt•r the (cllt+wchip prtrgrmm ol the T I R(•., alnttrnlt. in ct+nculla• liun witlr thcir :rJvi.ura, trlcct the suhjcclc Ihey wiah t,t attrdy Uc:ma nf Ihr «'htxda t'hrx+ac Ihr fclh+wa, antl Ihc wrnk ic th+nc tlurinr cunrn+cr r+r r+lhrr r+ll Itrrm limt c umlr r Ihr aul+crvicit+n nf cclx•ricnccd rrat•archrrt In Ithr I:+•t tcvcn vr•rra ttrmc tlr:rn S(NI yt+nnrI+crat'n. h:rvc rrccivcrl Irllnw.hiln + Ilcrt'+I Ly 1hc 1,,,ticntific Advr.my Il++artl. 21

Abst racts of Rcports Fach recipient of a Tobacco Industry Rescarch Committee Frant-in- aid is rc~hnncihlc for the initial f+rcccntatirm or publication of the results of his rr%carch in ccientific mectings or in appropriate scientific jnurnals. FotlnwinR are ahstracts, approved by the authnrs, of rescarch rcpnrts, with acknowlcdRcment of support from the T LR C., that have appeared in scientific journals since the last Report of the Scientific 1)irrctor and thrrnrRh 1)cceml.er 1961. The name of the scientist tn whom the T.1,R C. grant was made is given in parenthcscs where required. ('rtpirs of ah- stracts in previous Rcpcsrts are avaiFahle upon rrqucst. -1 hese ahttracts have been grouped under six headings: I Cancer Rescarch; II. Ilurnan LunRStudics:lll ('ardiovaccutar Stutlicc; IV 1'%ychr.- phycir 11rFiC.l1 Slutllr4; V. Tobacco Chcmidry and Itita-hcmiatry; artd VI. ( )thcr Studics I. Cancer Re.rr:rch "Tl1MOR-!IOST RfF-ATIONSIIIPS STl1D1Fh 1N VITRO FXPFiRI- MHN 1 S WI I1I ( F-I.L-FRfiE SYS I IiMS." R~' Leopold R. C'erecedo, Sister Marian loce Smith, and lesus Vicente. Fkrearrment of (liochemiatry. Fordham l)niversity, New York City, and 1)cpartntent of Ilicxhemistry and Nutrition, School of Mcdicine. University of Puerto Rico, San luan. Archrvcs of Rinthrrnirrry and Rirrrhvsics. Vol. 92, pages 4R4-4R6, March 1961. (T.I RC. grantee: Cereccdo) Purlro., of .ru,fy: Previous shrdics by the authnrt have shown that in tumor-heannR rats there is an increase in the denxyrilNonuclcic acid (1)NA ) concentration of certain tissues at a distance fron, the tumor. l hese enects of the tumor could also he shnwn in virrn whcn the incorporation of thymidine Fl' and adcnine Cr' into the DNA in slices from lumnr-hearins animals was compared with that in the tissues nf control animilc. It was decided to investigate whether the stimulatury effect of the tunwr could also be shown in cell-free systems. Pror.dnrr: The incorporation of thymidine-llt into DNA was stuilied in high-speed supernatants of extracts of IunR, kidney, livcr, and spleen of normal rats and of rats bearinR the Walker 256 carcinoma and the Jensen sarcnma. FYndinR.: An increased incorporation was nhcerved in the w(+ernatants of the liver and Ihc spleen nf the tumrn hcarinR hntle as cnrnpatrd with that in the mrrmal cnntrota. The eflect of the lensen lurnnr trn the incorpnratitrn was more rirnnuuneed than that of the Walker carcinrnna -11iia inuca%ed activity was slin Irrund when the incorPtrratitrn of the IhymiJinc 11' was studicd in thc ~nrcrnatant fractirrna rrl thc turnru, Ihcm.ctvcv It ia travtrn- ahle Ill a«urnr 0111 t lnme factnr rrtwlnced by thr tumra an l tran~mirted tn 1hr.r ti.~uct hy way of thc thliw.l it involved in thit l+henr+mrnrm (Ithrr Rrn..rc.rar t/ S F'uhlic Itcalth Scrvice and the I)imrm Rtrnyon ~ Atrni "n:rl I irnd "TIIE F:FFECT oF SMOKE AND NON-SMOKE GASES ON CELIS IN ( Ii1.L ANI) ORGAN CULI URES." By Philip Crnper, M.1)., FACS, and Irene P. C7uldrinR, Ph.D., Department of SurRery. Albcri f:instcin Col- IeRe of Medicine, and Drnn>c Vetenns Administration Ilcnpital, New York. SurRirof Fnrum, Vol. 11, pages 72-73, 1960. (T.I.R.C. Rrantee: Cooper) Purpose o/ .rurly: Studies have already been accomplished on the pcn- sihlc effect of cigarette smoke on luns, in vivo, or on tissue slices, in vitro. The present study was initiated to investigate the effect of various 6aseous agents on cells at a cellular level. 1'roc.Aur..: Smoke from cigarettes, cigarette paper, or onionskin paper was injected into mammalian cell cultures. Controls included similar cul- lures exposed to atmospheric Eases, carbon monoxide, illuminating Ras, and other nnn-smnke gases. The gases were Injected sfter a growth period of 24 hours into Ilasks containing an original inoculum of 1(K1,0()p cells in 2 cc. of NCTC-109 synthetic media to which 10 percent horse serum had been added. Three cell volumes (0.3, 1, or 1.5 cc) of smoke were injected; total cell count of each culture was made after an additional 411 hours. Daily microscopic observations were made. ('ells in a Rose perfusion chamber were observed directly after the injection of cigarette or cigarette paper smoke. Cigarette smoke was alco injected into embryonic rabbit lung organ cultures. Lung organ cultures of I R day old rabbit embryos. grown for 24 hours in synlhetic media, were exposed to 5 cc. of cigarette smoke, and sections were prepared (rotn the tissue after an additional 411 hours. F7ndinR.: All smoke aases tested altered the growth curve of the cultures significantly, and a reduced cell population resulted. The chnnRes induced by cigarette paper or onionskin paper smoke were more pronounced than that produced by cigarette smoke. Non-smoke Sases tested showed no sig- nificant effect. Cells 6rown in a perfusion chamber became enlarFed, showed surface "hlchhinR', and increased eytoplasmk granularity and vacuolation. The embryonic lung organ cultures showed arrest nf growth and deRenera- tive changes in the tissue after exposure to cigarette smoke. l he effect nf the smoke gases, over prolon ged peri<x1s, may conceivably prrKluce chronic inflammatory changes in the lung. "A PRnTOT.nAN ASSAY FOR CARCINOGENIC FIYI)R(X'ARIIONS." Fly Robert W. Ilull, Ph D., Department of RiohMieal Science, Ntathwestern ttnivercity, Evamton. Ill. 1'rrrrrrAinRt, lnrrrnolirrnnl ('nnfirrnrc n/ I'ru- rntnalnRy. PraRue, 0eehnslovakia, Aug. 24. 1961. 1'urfro.r of .rudy: Although the hasie mechanisms nt phnlrKtynamic ac- tinn are still unknrrwn, e.ploitation o( the phennmennn of realamee ri/ PnHrrytra tu ultraviolet and related radiation for use in the dctcctirrn rrf hydrruarhuns in high dilution can have considerable utility in Ihe arca nl cancer research. 1'rerr.lur.: Srttutitms ttf hydrrKerMtns in water are prepared by either rrf two nlethlNh, I fle crllatet in an amount of Rlass-disliikd water cqual ur the v.dume of hydnK arhnn srrlutir.n are addcd to PyreR al.rrt Iest lst.rtrs or slanrlard alitks comtaininR the smrenaiuna. The eitiates are cunccntr:rtcJ so as to provide helwcen 20 and 30 ciliates per dcpressirrn Ihe.cilcrtr% 25 74

tnutinrly uaed are 1'aramrcitrm caurlarum Rrown in axenic mctlia or in mcdia cnntaininR Arrnhnrrrr arr.rRinit- Cr+ntrnlc in the IeN arc ciliafcs hamlled in eRactlv the same manner except thal the hydn+c:uhnn it vmittcd. The crliitcs in the hydrncarFxm susf,enait.ns arc held in total d.,rkncss for one hour or more and then expcned to liRht of known qualily and intcnsity. The time intcrval. between onset of expnure and imrnr+hihty nf W) percent of the ciliatcs is recorded. The effects (if varinus known light wave lengths between the maximum hacteriocidal wavc-IenRth and vicible light were examined. F'rndinR.: T he work done to date dcals with .landardisalion of the assay techni(ue as regards ils I) reproducihilily and range of sensitivity, 2) the efTecl of the quality of the irradiating IiRht, 3) the eflect of various intervals of exfanure of the ciliates to the test comf+ounds prior to irradiatir+n, and 4) variations in scnsitivily to a series of diRerent hydrocarbons, some of which are estahli%hcd carcinnRens. In Reneral, hydrocarbons Ihat are knc+wn front mammal tests to he carcinnfenic show a shorter kill tirne in the a.1 ay system than do hydrncarla+nt whose carcinoRcnicity has m+l been cstahfi.hrJ 7 his aaay prrdrels that certain of lhese ct+n,rounds Ic.tcd will be (r+unJ to be Nfective carcinogens. It can he concluded from Iheflala now al hand that this assay systcm is sensitive and reliable In the dc(cctinn of polycyclic hydrocarbons in high dilution It can he anticipated that (urthcr characlerisatirm of the tesl may provide accurate prediction of carcinnRenk potency of the hydrncarbnns. -lhere is alsn the very real(x ossibility that this assay system may provide a means for direct atlack on the hasic ntechanisms of chemical carcinnRencsis. "pOANTIT'nTIVf? ('Y7(X'HE?MICAL ST Ul)IHS ON T1IF RF1.nT1ON OF I)liOXYR111ONUCI.FI(' ACID Uf' Cf•LI.S TO VARIU(IS 1'A'111O- L(X71('Al. (Y)NI)I f1ONS.° fly Cecilic Lcnchtenhcrger, Ph I)., and Rudoll l.cuchtenherger, M.1)., The Children'. Cancer Rcscarch fr+und:rtir.n, Rnstnn, Mass Rir+chrmlral Phormor.>1nRy, Vol. 4: paRes I2R-IG1. Augud 1060. (T.I R.C. grantee: Cccilie LcuchtenhcrRer) F'nrpo.e of arrulv: The possibility of  direct correlation between the functional staRe of a cell, be it normal or ahnormal, its micnxc++pic appear- ance and its chemical composilion assumes particular significance in view of the fact that a change in function and mnrpholo F•y of a cell is nu+re or less the e.pressiim of underlying and often preceJinR chemical alteration. Simultaneous morphological and chemical investigation at the tinFle-ccll level miRht not only throw light on etiology and pathnRcnesis Mrt akn might help greally In the detection and understanding af discase. In particular, special attention In the study of dcoxyriFxrnucleic acid ( I)NA ) in ahnnrmal cells and in cells under pathologic conditinns suemal nreritcd in view uf the important role of DNA fnr cell life nd cell continuity, ita quinlilativc stahility under nr+rmal conditions, and il+ chne rtlatinn%hip tn thc Rcncs Pr..ridur..r I)urinR the Ia.t 10 years the quantitative hehavior nf DNA in cells has been rxtenslvely tnvestiyated by micrnal.eclnq+h++u+mNry >•nd inlerferrnce rnirrr,.++q+y in relali+m to fnur ralhul++piral I+rrKr.,ca, ( I 1 a+ngi+ nt .ttcss, ( 2) tumnr., (1) vir+rl ir+fcclu+n1, nd (4) infrrt hly In ttndym~ ( 1), &'ps were sul+icclcd /n pa.trcct++my and th++ltcy~lctturny, and cells nf Ilvcr and adrenals were analysed for DNA canlcnl In flte case r+f (2), hun,an precancerous and tumor tissues were studicd and c+Hrtrastcd with nnrntal hum:m tissue. Under (3) different typesof hurnan and other cells infected with diRcrent UNA-containinR viruses wcrc examined in iirrr in the host and in lissue cuhures, and in (4) more than .12,(NN) sperm cclls from over 2(NI men and from over 100 bulls were analyred for DNA cnnlenl. F'inr!inR..: ( I ) Analysis of more than 7,0()0 inrlividual cells from livers and adrenals front 17 dogs showed that DNA content remained unchangcd ofter surRical stress, although a considerable elevation of lyrosine was nntcd in liver cells and in cells of the adrenal medulla after surgery. (2) It was found that all normal tissues, no matter what their origin r.r nretahulic functinn, contained cells with a similar basic mean DNA crmtenl, whereas the DNA content of precancerous lesions and utali6nant tumors was found to be increased and revealed a much larger scatter from cell to cell. T tre deviating DNA data cannot he considered a speci(ic criterion for malignant Iran.fnrmatinn of cells, hu1 may be explained mainly on the basis of growth and miltNic ltrncrsscs present in most tumora. On the other hand, cnn-lancy of DNA in nnrmal tissues indkales that an Increase and large scattcr uf DNA in such tissuc must be looked upon with suspkiom of mnlignancy, un- Icss regeneration is trt be expected. BeniRn cells disclosed essentially a normal constant DNA quantity. (3) Study of different types of cells infected with different 1)NA-cnnlaining viruses in sirH in the host and in tissue cultures revealed a peculiar combination of intranuckar Warre conRlnrneration of DNA masses associated with striking increase and variabilily n( DNA 1 his almnst specific response of cells to an Infection with a UNA-containinR virus was noted irres(~cctive of Ihe type of such virus (vcnnca vulRaris, adcnovirus, efc.), of Ihe species and types of cells Infected (hrrman, insccl, nrxmal, or cancer cell), or whether the cells were still in .rirn nr explanted in tissue culture. (4) In contrast to the remarkably constant rind unifnnn haploid DNA content in s(xrm from fertile haman males and hulls, the DNA content in the slxrm from infertik males was frequently variable aml significantly lower than that from fertile ones. In addition to the various types of human tumors studied, the relation of DNA to sprmlaneous and transplanted animal tumors was alsn investi- ~,ted. Principally there were no essential diRerences between the DNA hchavior in huntan and in animal lumors studied. This similarity of DNA res(xarse deserves special cnnsideralion, because some of the animal tumnrs s rdied were tumnrs with a known vital etioloRy, namely Rnus sarcnma of c chicken and F'ulyoma tumors of mice. OIRr r Rrnntor.: (I. S Public Health Servke, Elnnh Foundation, I:ha F 1'ardee Foundatinn, and Franchester fertilily Fund of Clcveland, 0 "A ('ORRI:I.A 11:f) IIIS"IO1 (X31CAL, CYTOI.(Kil('A1. ANI) ('Y 10 ('Il1iMI('A1. ST(tl)Y OF '111E 1RA('f1EUHRON('IIIA1. I RI1E ANI) 1.(/N(iS OF MI('1: F.XPOS(il) TO ('1(iARfil-1E SMOKI?" Ily Cecihc I cuchtenl+erRcr, Ph UY and Rudolf l,euchtcnherger, M 1) , In.litul (iir nllFcmcinc Rntnnik, 1? I/1, 7l)rich, SwiVerlantl, .Irru M.diq a.f+,rndinnvu a. V+dumc 17/1• Sul.l+lcmrnt 1(i9, pages I(/2-11R, 1961. On the ha~ia ++f thc dala prcwnlcd sn far, it appenrs that cxl+nsurc t+ cirarclle sm++ke will evt+ke altcratir+ns in Ihe branchi r+l sume mitc xutu- R, 2~+ 27 rn ,r.

marired as follrrws: I. No significant histoloRical chanFcs. 2. Mild bronchitis; swollen epithelium frequently associated with mild hyixrplasia. 3. Severe bronchitis and (.erihrnnchitis; atypical hasal cell hyperplasia, squarnr+us cell meraplasia and occasionally histopathnlogical chanRes consistent with the terms "dysptatia" or "carcinoma in .tiru," One or more of the above changes may be observed in Ihe same animal. Although, on the evidence of these findings, one may he tcmpted to conclude that there is a dircct cause-effect relationship between cigarette smoke and thc epithelial ksions, there are mainly two findings in our study which impose caulion against drawing such a conclusion: 1. A striking difference of response is encountered front mouse to mouse which occurs regardless of whether mice were exfxxcd tn relatively low doses of cigarette smoke for a brief period or a relatively high dose of cigarette smoke for a long period. In each of the groups, over S(/ percent of the mice did not shnw any bronchial ksions, while 25 percent showed mild and 20 percent dycplastic lesiona. 2 1 here it absence of  rrlatinnship between dose nd length of ex- T,surr to cigarette imoke and frequency nd severity of lesinns produced. is evident that, in spite of the cnnsiderahle increase in length ol exl+nsure and numher of ciRarettes, the rehtirmthip between mice showing no siR- nificant chanRes nncf mice showing mild and severe chanPes in the hrnnchial tree did not alter rpreciahly. 11 it indeed astonishing that, among the last Rroup, no inva.ivae hronchoRenic ca+cinnma has been observed although these mice had been esposed to enormous quantities of cip,arclte smnke. and, whcnever t+.lstihte, fnr nearly their whole life span. The widc spectrum of findinRt and the independence nf rlusr and dura- tion of etpe,cure to cigarette smrrke would « rrn to detract fnmi the im- prrrtance of ciRarclte smr ke as an injurious agent invari,hly aflectinR the major hrnnchi and would, ra1her, point to contributing factnrs characteristic for the individual animal. Amon the many Irrx.ihle host factrrrs, vinrses descrve special cnnsideralion - t~e mnre so since they occur with a certain frequency in mice, sometimes in a latent Grrm, and are capable of producing respiratory Ietinns and proliferation of bronchial epithelinm. There are two main lines which we are investigating at present. The first is concerned with the detection of latent viruses in mice prior to e.- rosure to cigarette smoke. The second is eoncerned with the effrct of ex- t+ttsure in virut in addition to the exposure to ciFarettc smoke. "('OMMON IIIIMAN VIRUSES AS CARCINOGF ' N Vf ("1ORS." fly ('hridnpher M. Marlin, M./).; Sigmundur MaRnuttnn, Feiluw of the Squibb Inslitute for Medical Research Foundatinn; Philip ). (io%cicntki and (ier:rlJ 1: Il:rnsen, National Inslitutcs nl Ilealth rrsc:rrch fcll-s; Sclun Ilall (-nllcge of Medicine, Jersey City. N. 1. Srirnrr, 1)cc 15. 1961. paRrt IvRS-Ir)R6 (T I R C. granlce: Martin) 1'rr.p.r.r o/ .rrrrlyr It hat been a continuing paradna that carcimogcns ttrrrngly imf+licatrJ in hurnan Iumorir.enetis, rhr+ugh Irrrsrnl in thr hrnnin rnvirmnmrnr in nrdy trace amr-unts, nrdinnrily wFfl indurr nrr-lrlaaia In ;rnrm.rli r,nly whcn 1Htn11n1Urrc1l in relativcly largi• 111714111111% r1r wrlh vHrnrat t+hyak:rl rir t hr•rnicil "crr carcinrrRrnt " Spcculatinn rrn pocaihk natural nI cn-carcinngens led to consideration of the possible role of conrrnon, non- tumor vinnes. Studies were performed in vivo on 290 male Swiv white mice front a colony proved free of polyoma virus and which were reported to have a low incidence of de nnvo tumtxs. Pairs of known chemical car- cinogens and common viruxs in different combinations were administered by injection. The viruses used (vaccinia. ECIIO 9, Coltsackie Ilr and Poliovinrs 2) were harvested fiuids of fully infected tissue cultures of mnnkty kidney; by the routes siven, they evoked negligible mortality or ntorbidity. The carcinogens injccted and their respective drtscs, judged to he lon small to induce lumors, were (00 micrograms each of V,10- dimethylbcn?anthracenc-1,2 (l)MDA) or of 2-aminofluorene (A.F), anJ 75 nsicrograms of 1,2;S,6-dibenzanthracene (DRA). To determine the role of immunization, half of a group of IOR ad- dititinal mice were immunired against vaccinia virus nd half against fRozen-Ihawed monkey kidney cells prinr to administration of cither vac- cinia virus or frnzrn-thawed monkey kidney cells plus either 1)MItA or propylene glycol. F'inair,R.: Malignant tumors occurred in 5 aroups of mice that received crrcinrrRen-virus Pain, and in no other Rroup s. T'here were S maliPnant lumort each among 16 mice injected with bMIIA and vaccinia virus, y of which were living at 3 nronths, and among 12 mice injected with I)M11A and Poliuvinn 2. 7 of which survived to 3 months. There were 2/umars each among 12 mice injected with AF and F-CHO 9 virus, with 7 living at 3 mrrnths, and amonR 12 mice injected with AF and Cor<sackic R, virus, of which 6 survived to 3 months. Four Ihymomas - turnnrs known to arise de ne+vn in this mouse strain - occurred in the 161 mice alive after .l monlhs. After R montht, the only tumors ohserved in the immunizalion era- juriment mice were 4 lymphomas in a group of R mice that were not rmmune to vaccinia virus and were given vaccinia and hM11A intra- l•critoneally. in vinu studies! ('areinngen-hinding by Polinvirus 2- arrrr'xim-tcly ltl (NN) mrrlecules per virnr tissue cultorc. 50% of infcctiuus dr,cc - wat dcnwnslrated in rirrn, with (he use of I)MRA-9-('r41. The re-tuhs aflirnr in vivn interactions of viruses and carcinogens previously Jctcrit.ed by other investigaton, and are consistent with tlrc rc(+rut I+y 1) V. Wi.clcy ct :rl. (Proc. A A('.R. J:27R, I')(rt ) uf cnhancvr1 chemical carcinnPencsis in mice repeatedly exposed lo respirnNny viru.rs. If such interaclinnt occur in nnture, it may prove prssihle lu rrrlucr ne•rr- plasia currcntly ascril.c(l to chcmicnl carcinogens by inununizatirm nhain.t a Vlrut. "VIIANGfS IN Mt)f)A1. VAt I/F.S OF ('IIROMOSOMFS AFII R I/t RAt)IATION OF IlI/MAN AMNION (7it 1.5." ny Mat,hirrr t\lirut:rni, 11 A, and Y 1I N.rkanidri, Ph.1), now ot IhrkkaiArr I/nivrrsity, lutran; Y:+svJu l)frnuk i. M S, nrrw •t Pasadena, ('aI , I oundatirrn fnr Mr•rhr :rl Rcsearc'h, and (' M 1'rancrat, Ph 1), Trstue ('ulture (.ahrrratnry, I)c!":rrr- ment c+f Anitrrmy. University ui Tuas Medical Itranch. (ialvectrrn .4 (' 1 m tn ~R 29 n

( r-n(r-rrrrr r irr Rrtrnrrh nn thr Rnoh-rhrrnl+y if (•unrrr, r:rl•cc S!, (,q, April 196 1 l I I It (' frantee: rtrnrcrat I I'rrrlrn.r ../ .rnrfr: ('ytt,hoFici1 t•.itninalinn (if irrarliatctl cclf. uf whrdc nrl-:rnmns tI/ nr:rny wnrkcrs invite ~tutlies in this hiltl, with Ihc u%c t,f ccll cuttrrres• n( tnccraive Rimma riili.uir.n on the mqxl.rl clirtnm ~trrual numt,cr (if a human :nnnir.n strain. I'rnrrrFrrrr: A hnmin amninn cell strain with a mndal value (if 7S chrmmo- s,nncs wis cultivitcd for tw(, days prior to irradi:rtiun with IINMI r (if r:tmma rays ftnm a r.rdir+active cobalt snurce. lhe (nc%crvatitrn of chrtrmtntrmct was m,Je with the use of phase contrast micrnscr,py. F'indin)rr: 1 he population of human amnion crlls showed scvcrc injury frt,rn the ratliatinn On cultivation, healthy Ionkinp cells were resttrred; ht,wcver, they now had 73 chrnmcxt+met. Repetition of the trcauncnl t,n the new suhlinc rctlut:rd the modal value of chrmmoanmcs It, 71. I urthcr re- duclit,n nl thit valuc did not occur :ttter irradiatinn ft.r tht• Ihirnl ,ntl even ftsr the /t+urlh tirne Othcr human antninn cells wcrt irradritcQ ft+ur ,irntt tlurinF S(1 d:ryi withnut nrakinR tuhcultures l he mt,tl frequcnt chrt.mntnme rnunhcr at the clevcnth suh-culttue (if the ettahlichcJ arhline drt,l.hcd fmm 75 In 71. lhe atnpFinR of the mrnlil value at 71 invitct furthcr ttudret cun- cerninR this type uf radioretistance. "C(1Mf. ( UMrARATIVFi Ff Ff:("ISOf SMOKFf) rArF?R.1(/11A( (Y) ANI) ('I(iARf I If:S UN ('IIROh1OS(1MFS IN l'lIlf(1'• Hy Akin Awa, Yatuahi OItmiki, :(ntl (' M rrrmcr:rt, r:t,,drna (('al ) I r,nnrl:ttitm fnr Mrdicil Rcsc:crch, Irrnt Itryarrrt nrt Ifr,rlnAv.nrJ Alydncrrr, Vrd 19, I,:rFc's tIR-52R, I all 1961 . ( 1 I R(' I t'llirwc Awi :rml Ohnnki) Mitnlic and chrnnrrnnmaa an.rly,,ra wcrc t.rrncrl rrut in tht III (• slrain cclls cxhrctd drrcctly tn Iht' tnwkr collcctcrl Irntn ( A ) whrrlc ciF- :trt',tcs, (I11 t0h:tccn alnnc. anrl (t ) I,.rf,cr .rl„nr Mrnl,hnh-pi:rt trha•rv:r lirms rt'vcalcd that rafxr tmrrkc inthttrd vcvcrc vaturtlv:rtnrn of the cytn- I,lasm tnpNhcr with pycntrtic nuclei in mt,at ct'll. In ctmlr:ttt• little cvi- dcnce (if ccllulit tl:tmafe wis thuwn hy exrtnure of smnke frtnn whtrle cigarette antl trtnn tobacco nlnnc. 'Ihcre wis a decteate in the rate of the mitt,tic index anrl a ctrntid- cr;rhle increiec in the nunrher of ahnttrmnl divisirrnt at a result (,f the trcnl- ment with cach suhdance, rirticularly with pilxr smnke. ('ontraclit,n rtF clntrnu.ann+es was nrtticed in snme metarhaect etpa-,uJ to trntrke frurn whoIc ciFarctlcs and frnm tuhacct, In enntrasl, p:(rcr smnke hrrttlucctl a )•h incidence rd chrmmosnme stickinett. 1 hcse mitotic ohnnrmalitict -and the thifl in the mtwlal chrnnrtr.nmc nrntt,cr rrf thc III C strain are briefly discutacd (lfhrr Frnnlnr: 11 S Public 1lcahh Scrvice. '•1'itI MONARY NFOr1 ASMS rR(111(I('I'F) flY Mf?lI1YI ('t1U1.AN- l IIItINf IN 1111! ' Wltlli? 1'1'KIN I1(1('K " Ilv R 11 Riyd,,n• I)cf.trt. urcnt rrf I',thnhrry, l)nivertity nf l etat Medical Ilrant h, C:rlvcslrrn. ( nnr rr ltr,r,rrrlr, Vrrl 11, I,arcs S71 574, Miy IVr.I /'u.p.r•, r./ lhr rrsl,irnrrny tr,.%ct in the rluck it timil:n in nrany w. ~. t.. iho o tn mnn In prrvn,ua c.I,rtinrcrHS cartinrnn:rs an l aarcrtnt:rt ui I n III, n11ir:,tnrv tr:ut ~,I white I'rkin rlntk. pivcn :tn in1r:t frtchr:rl injection (if mctlrylchnlanthrene sutpended In pnlytorhate RU Mnre detailed invcsliFatinn wat considered desirable. I'rnredurr: Sixly-sit dncks were given 3-melhylchnlanthrenc sutrt'nded in a I (~c' rccnl aqucnut solution of polysnrhate RO, and 2S,were given (mly the pulysnrhntc. A small catheter was placed in the trachea thrnuRh the external I:trynx, and t,ne 25 ntl. injection of the solution was given within an interval of 2 fn 1 minutet: 250 mg. of inethykholanthrtne was given Irr 22 duckt, 125 niR. to 2R, and 62.5 m6, to 16. The birds were sacrificed or died at varying inlervalt, and the respiratory tract removed in tntn for exantinatinn• FYndinpr.: No tumors occurred in birds receiving polysorbate alone, but striated amyloicl in the livcr, and local areas of necrosis in striated muscle, appeared in some of thesc ducks. Many neoplasms occurred in the retpira- tnry tract of birds receiving melhylcholanthrene, the first appearing 56 days afrer injection. Sonu of Ihe tumors were neurnfibromas, and olhers were RnnRlioncurnrnas, hemnnginrnas, squamous cell-Iike carcinnmas, adcnucar- cinrtrnas, antl unclassified types of tumors. Frequently a single tumor showed n variety of histolnRical paltcrrn. No metattases occurred. Methylchnlan- thrcne cryttalt peranted in the tract for long perinds. Since amylt,id and ninscular necrnsit appeared in treated duckt and the ennlrolt, these eRectt do not appear specifically related to melhylehnlanlhrene. l he prohlcnv of amyltridosis in the duck is nnw under study. I)th.r Rrnnlnr: ll. S Publie Ilealth Service. "I.FSIONS IN I)l1C'KS (71V[N MLiTF1YLC110LANT/1RFNE." fly R. FI. RiRdnn, M 1)., and S. M. McAnelly, ff.A., University uf Tcxns Medical Ilranch, Galveston. Archives o(1'athofngy, Vol. 72, pages 4SS-4h4, October 1961. (T.I.R.C. grantee: Rigdon) Prrrlraar of atnrlv: In a previous experiment neoplasms developed in the resprratnry tract of white Pekin ducks following  single inlratrncheal in- jectinn of inethylchnlanthrene. The present study was matk to observe the pathologic changes occurring in the respiralory Iraet preceding the develup• ment of Renplatms. Prnrrvlnrr: Twenty milliliters of a solution of 50 mR. (if mcthylchol- anthrene in polysnrhate was injected by tube into the trachea of 21/ ducks 36 days old: 2 af Ihese birds were killed S'/i hours later, 2 after 7 days, 2 after 11 dayt, antl 3 died on the 26th and 27th day. One was killed nn the 35111 day and Itl were killed on the R4th day following the injcclion. len other hirds 4(1 days old were given 6 to 9 daily injeclitxts and 111 nlhcre were Riven 10 mR. ftir 7 to I(6 timet; all duekt given multiple injeclittns either died or were killed al intervals of 9 to 72 days following the firal injection of Ihe carcinogen. lltt• respiratory tract including only the lower Ihitd of the trachea wat removed ond several seelinns taken ftN hittolt+Fic tUrrly Fin.NnR.: An acule and chrrntic in/lammalory reaetinn (n-curt in thc lunp. of whitc rekin ttuckt ftdlt,winR the inlratracheal In+eclirm n/ tnrrhvlth-d nnthrt•nt In rnlytt,rfr:rtc RI) Atatxinlcd with fhit inflanntntnry rcat Inrn i. rcrcncratinn, hyFK•rldati:t. nnd rnetaldatia nf fhc hrtxtchial chitht•hutn Mcto rlisia nc'curt at early at 7 tlayt after treatment Ilcmanfitmrat. adcm.r:tr cint+mas, and filbrtr.atcr+mas arc rrescnt in the IunRs 72 dayc h,lhrwinp. the • m ~„ ll tn m r

first ttf 16 intralrachea) injcctit.ns ttf the carcinnFen. In view nf the presence of aquamttus mctaplasia ant) tihe ahaence nf typical syuamrtus-cc1l c:trcinnmas in the IunRs of Ihcse ducks the yueatinn is raiaed refcrahlc tt+ thc fiithrtRencsis of thccc neoplasrns. Melhylcholanthrene crystals mechanically rthalrucl thc Iumcn of Ihc srnall bronchi resulting in atelectasis and suhscyucntly Pul- rncmary fihrtnis with an assnciated pulmonary eniphysenia. (3thrr Rrrinrr.r: U. S. Public 1(ealth Service. 11. llumnn Lung Studies "ACUTE EFFECTS OF INNALATION OF CIGARf:71 F SMOKr ON AIRWAY ( ONI)U(-TAN('E." fly )ar A. Nadel and lulius II ('nmrt.e 1r , Cardinvascular Research Inslitute, University of ('alifnrnia Mcdical ('entrr, San Franciacn lnurnal eJ.(pplird !'hy.riafrrry, Vol. 16, f+aRcs 713 716, luly 1961. (7.1 R C. grantee: Comrne) Purporr n/ .rn.r( r: Previous studies of the acute e0ects of inhalation (if cigarette smoke on "airway resistance" are of doubtful siRnificance, a) because sonic of the methods uset) require an initial deep insPiralion, which we nnw know may itself decrease airways resistance, and h) hecause none of Ihe tests mcasured airway resistance alone hut rather a combination of faclnrs, includinR tissue resistance and voluntary muscular efltut Accnrd- ingly, we used the body pICthysmnRraph techniyue to obtain a sensilive measuremcnt of airway resistance ahone. Prnrrdurr: Farh suhjecl sat in the elnsed 900 liter btwly Plcthyamngraph fnr a few minules, then panted thrnuRh a flownuter for several eecnndc, during which time his airway resiatance was measured at flow ralcs nf 0 t liter per second. We then closed a shutter hetweFn the mnulhpicce and the flnwmeter and measured the subjecl's thoracic Ras vnlumc (7(iV) pIcthyc- mnRraphically. F.ach test consisted of four ennaccutive meaawemcnls uf airway resislance and 1GV. We calculated all data as airway cnnductance ( I/resistance )/1(iV to correct for variatinns in lunq vnlume durinR testinR. We tested 4R suhjects whose IunRs were mtrmal, including male am1 female smnkcrs and m.n-smokers, and 22 Patients with a diiRnosis of rulmonary emphysema, aalhma, pulmonary fihrosis, sarcoidtxis, or mitral stcnosis, all eiRarette smokers. Fin.FInR.: In the healthy suhjects there was nto siFnificant tlitlcrence he- twcen male and female smokers and male non smukers, hut airway enn tluctance/f (iV was siRnificanlly hiFher in fernale ntrn-amukrrs in tltr cunlrul statc We sttnlird the acute eflecl of cigirettr smrrkc inhal:ttitm in 16 hcallhy suhjctta 121 anwkers and IS mm-smukcral and 22 snutkcri wilh carJirr- 1+uhnun;trv tlrar7se; the airway ettmhrctance/I(iV ratin Actrc.ractl aftcr thr rnh.tl.tlirm trf ciRarette smrrke in hrrth /rtw/rs I he rllrt ta wrrc ahnrt.t im nrr•r1r.tlr; Ihc nrrart thnatirrn of cllt•tt wna lt rninnlca Irnlhnlalirtn trf 11 S t.rn~nt r...lr.~rrrrnrrl :rrr.,.rd rrvrrtrr) rrr tirrvrnlrrl IFhr rltrtt rd tit•:rrr/It' I thc ,1., rr- r,.nJur I.uu r 1 t i V t.rn.rJ I,y rnh.rl:tlrnn . i rrrrl rrrh.tL,Jr,-n ,•1 na nlrnf Or f Our stwly indicites that mild brnnchoconstrictinn, insuflicirnl trr cauae symptorns, rrcurs immediately in most individuals after inlctliliun trf ciR• arette smnke, lasts 111-R(/ minules, anti reoccurs with a second cigarette We suRpesl that thert are insufficient and inadc9uate data at present ttt warrant relating the "hronchttconstricticwi' of smoking causally to the initiation trr afRravaticm of chronic pulmonary disease. ()rhrr Rrnnror: 11. S. Public 1leallh Service. "Ttlr PA711OL(X:I(' ANATOMY OF THE BRONCIIIAI- TRI_-.f; AND LUNGS." Ry Stanley P. Reimann, M.f)., 1)irectnr Emeritus, Inatilute for Cancer Research, Philadelphia, Pa., and Member. Scientific Advisory Iloard to the Tobacco Industry Research Committee, Archivrs of 1'nrhnfnRy. Vol. 70, paRes 757-762, December 1960. (T.I.R.C. grantee: Pathologic - Anatomic Study Group) Twelve e><perienced patholoRists from various parts of the l/nitcd States underlnak a study of the pathnloFic anatomy of the bronchial tree and IunRs in spccinrens ohtaincd frurn routine autopsy serviees and surRical e~tcisions. 7 he object was to cataloRue chan6es, sites and ineidence in theee orRans in relation to aRe, se><, uccupation, place of residence and work, use of tohacco, and canse of death 'I he classrficatitxn used were: normal, hyperPlasia, syuamous metaplasia, atypical metaplasia, carcinoma in s/rte, careimoma. About 3,(NK) cases were investigated yielding R,590 slides from rnales and 3,661 slides from females adjudged suitable. The border line cascs prn- vnked disagrcemenls, many of which could not he reconcikd. In addltinn to cnnferences, selccted slides were eirculated and many pathtdtrFisrs re- examined their own slides a year or so after their original diaRmrsis Sonic of the limitatiuns e.f the practice of palholoRie anatomy were discuaaed. 1'rom raw compilations the results were equivocal. Rigid statistical appraisals were made and were published in seParate parera (F It. Wilsttn & M. II. Ourke, 1957-60). It was shown that a eot>(+cralrve s(ndy is ncctlcd in problems in which large amounts of data must be collected anJ in which basic prncedtucs in a particular discipline can be collectively asccaacd. "A SfIInY O1' TIIE TRM'IIf:O1lRON('HI/41. fiPl7lll?I IUM ANt) CIIANGf:S RFI.A I1 1) TU SMOKIN(3." Ily K. R. ('nns, M I) , IAmald V. Wals, M 1) , G Keith Palmer, MO., and E. D. Warner, M11 1), 1)t-part- ment of Pathuhtyy, Velrrans Adminislratinn Ilospilal, Itrwa ('ity, I:r lrnnnnl of rhr l.nrn.Crnrr M1frdi,nf S'ucirty, Vol. 51, pages 117-14(1, Match I'rht (T.I R.C. grantee- Warner) rnrpo.p of arndv: Of the first 915 autupsies at Ihe IlnsPit:J durinR a sitt-year LeritKl hrnncht,Renie carcinoma was diagnosed in I lV caacs ( I S fx•rrenl ). '1 Fhe purlNrse of this paper is tro discover the dcfrce and tvhc trl met:rltl.atic chanPrs rtcc•urrinR in the bronchial epithclium :utd It, delrrnnnc whcl'ter or nrrt thesc changes are related (1) to previnus smtrAinR, :rntl (2) In the dcvehq+menl rrf faonchnRenic eareinnma 1'r... rrhrrr r I rflren rcl+resrntalive scctinns nf the trachcn and lhr larpr anrl .mall hrnnthi wcrr arlrctrd in each of 1411 nutrrpsy caars rrrrvrd .urLrblc ha atudy, intluthnr. 26 paticnts with carcinnrna of Ilrc luny lhc ar t lnrna wcrc clasai/ictl aa m,rrnil, hyln•rplaaa, afuirnrruc rnct:t/d:r.ra- al~lrrcal tnct:thlasia, carcinnmi rn trhr, and c:vcnttrm:r I hrre wcre 11 nnn amrrAt•r., i 11

I'/ IiFhl, 11 nnxlrrate, SG hcavy, and 21 very hcavy crn„kcrc am„nR thc 140 ca~cs. Findinrr: Thc hr,+nchial tissucs of only 49 percent nf the cavca cnnhl he c„ncidcred nr,rn,al, cnmpricinR 44 percent of the ct•ctinnt frnm cm„Acrc and 61 hcrccnl yd Ihc secti„ns frum nt+n smr,kcrc ( arcinuma wac f„und r+nly am„nF cmr•kerc, ac was carcinoma in vlu, and the tatter wac fnun,l ,,nly in r-lticnts wilh IunR canccr: the 7 indanccs fnund were fcwcr th:m ,mc wr+uld ct(+cct if carcim,n+n irn rirre had preccded the devctuprncnt ,d carcim,ma of thc IunF Attht.uph the sludy fails to support thc prcmicc that carcin,mta ariccs frr•rn prc ewicting atypical mclaplaslic chanpcs in hrnnchinl cf,hhclium, r snrnkinR level of FfA. There was essentially no change in the cCrum tt,tal chnlcctcrnl or IriRlyceriJes during the experimental peritnl. I hcrc was a sliRht increase in I FA over a 20-to-40 minute period in the nnnsmr+king contrnls sliRhtly afa+vc that anticipated from fastinR alone. l he five suhjects who "chain-smokctl" all developcd FFA elevatinns which penisted duriuR the 60 minutes of ohservation. An eventual, delayed increase in serum kvcls of cholesterol and other lipoprotein lipids, as occurs in animals after epinephrine, is a conceivable result in humant after smnkins. This, at kast, suRRests an e><plartalinn 1(or the higher chnlesterol levels often found in smokers. If, as many invecti- il ic evident that thcrc is a ciRnifrcant acsnciatinn between certain cpilhcli:rl )Catnrs believe, a disturbance of lipid metabolism is a factor in the dcvelr,p- ch:,nFcc in the tncheohronchial tree and the prcccncc of m;rlil•nancy. It ment nf athcrosclerosis, the effect of cigarette smoking on lipid mctaM+lism wnuld accm that a histnry of cigarette smukine is ciFnificanlly rel:r,c,l to the sM>,dd be given attention in considering the palhosencsis of this dicnfder incidcncc r f carcinnma, and Ihc rcfnre difficult to iy-nnre A linal ,Iclcrmina- \ Other Rrentor; (1. $. Public ffeahh Service. ti„n r,( thc rcl:+linnchip between trnokinR and Ihccc relh„h,pic:,l clcmpcc will "T'IIf: REI•AT IONSI(IP HETWEEN BIOCIIf;MICAI- A(TIVfI Y ANI) rc,lnire rnu(h mrar shrdy. MEC11AN1('A1. FtINCIION OF T7ff; I•IEAR'r." fly R. J. IIinR, M,1). 1I1. (:rzrrlitrrn.rrrlrrr Cflldir't "IiI 1 fY'r OF ('ICARETTF. SM(tiKIN(i ANf) NI( nl INF ON SI?RI1M I It1 1: . I A 1 1 Y A('II)S." fly Alfred Kerchhaum, h1 a) , S:,nmcl Itellcl, k1 I) , I-r/w:vd R 1)ickslein, M h., and I ennard 1. VcinhcrR. 1'Fh I) , 1)ivisinn nf ('artlird„Fy, f'hiti,Iclphin (icm•ral Flr+cpital ('irrulnrirrn Hrtrllrr lr, Vol o, p:,lcc h11-b1R, May 1961. (T.1 R('. grantee: Iscllctl Prrrpnrr rrf .lnrfr_ : It cecmctf important to invcaliFatc how the cRecls of nicnlinc inlloencc thc metahc+licm td Iiritlc, rarticularly since rcccnl ctudicc h:,ve chnwn that free falty aei,ls (1 FA ) are rapidly relcace•,I into thr circn- lali,m frnm tiscuc fat dcprxitc f,JlnwinR the athniniwitir+n ,rf cf,incrihrinc and m+rcf+incl,hrinc and following s,ress cRccts on !hc cympalhclic ncrvnuc systcm 1'.nr~dnr~.: f'aticn,s and pcrsnnnel at Philadelphia General Ilnspital were sclected at random, includinR 7 nnrmals, 7 coronary heart dieeace caeet, and 17 palientc with varivut other tliaRnnses, aped 16 Io 72• including m+n-smrrkers as well at smnkert All lests were m:rJc at Y a m. in f:rslinF condition In 17 tnhjrcls, 2 eiFarettes were smukcd within a I1/ minute rc•rirH1 fllraal saml+lcs were taken hcfnre smnkinR, immetfiatcly therea(ter, and at 111, 20 and 41/ minutes after ecssatinn nf snu+kinF- Another prnup nf V suhiccts cerved as cnnlruls to dNermine what elTect the rf+erirnent:rl pnKe,lurc itcclf wmrld have f fastinle, prcraratinn, venif,uneturc. rtc 1 Scv- er.I r,f the crrnrrr+ls inhaled deeply to cimulale smnkinr rlurin(• thc initial tll minrric fK•rir,d liach n/ S suhjccts annked 6 cif•arc'tlcs in 411 minutcs tn stnJy thc rllrct nf "ch:rin tmnkinP" am11 VA enncentrilinnc wcrr rlrlrr,ninrd at 10 minutc inlrrvils for a Intal fxri„d ,if hll minutrs :+flct cm,,krnR nrJr•d Fin./inje.: In :,I) 17 tuhicctt whn srn„At•d 2 cit•arctlrt Ihc I I A Irvcl% rr,.c at Ihr cn,l „1 Ihc .n,,,kinr LcrinJ, mnsinr,rm elrv:,ti„n ,KCUr10 numrtr. ler,r I wcnty ymt •1t1 rnirmlrt nllrr trn„Ainr Ihr I I A Irvr1% werr .,,11 :,h„vr th, I„r.rnnAinl• I, v, I in mr,.l in.l:,ncrc I lie I 1A rry,nn.c ,h,l rn,l :y~l~c.rr h, I.r rc/.rrrJ 1„ c,/•,•, tct. tnr„kinl• h:,l,ilt, tvl,c r,f (il•:,rc,tr u.crl, or I,re- t ( 1'rrM'r~dln~r, Mh Inrernarlonaf Conerett o/ Internal Medir inr, llasel, Switzerland, 1960. • RRecent studies have further defined the myocardial utilization of fatty acids, and reveal that, in the fasting human, the mean myncardial extraction of free fatty acids accounts for 42 percent of the total fatty acid ealraclitm, while the esterified fraction makes u the other SRpt rcent. Since r+leic acid appears to be the fatly acid primariPy used by the heart, it appears Ihal, in cnntrast to previous conclusions, the myoeardium uses preferentially un- saturated fatly acids. In the most commnn types of heart failure, ahsence of alterationc in ulilization of oxygen and suhstrate by 1he heart probably denotes absence of invnlvement of metabolic factors within the heart. llris by uclusir+n points In the organs of energy utilization. the contractile proteins, as the site of the derangement in the myocardium in this group. Sludks undertaken nn actnmynain hands, although not yet conclusive, support Ihis cnMentinn. Thus, it has been sflown that the contractility of these bands from hearls nf human suhjects dying from congestive failure is impaired. While there is nu doubt that the blood concentration of catechnlamines influences myocardial funclinn, the pharmacologic role of catechr+(amines stored in the heart muscle remains unsolved. The release of stored catechnl• amines is nf inleresl fxcause it is rekvant to the main topic of (his dicfus- sion, the relation af funcliona( activity of the heart to the integrated enzyrne activity. The pharmacoloRic impnrtance of the stored calechol:rruines is as yet uncertain. 1 his review auR`ests that work on cardiac metabnlism has nrnved frt+m the scarch (r,r utilizntinn of suhslrales by the heart Io the invcstiFatinn n/ the re(:uir+nshir hetwrrn biochemical and mechanical funetinn "MY(X'AItUlA1. ItI Sl'(1NS1? TU ('I(TARI1-Ifi SM(1KIN(7 IN Nlt/(. MA(. Slllt)ff('1S nNl) I'A111:.N'IS W1111 CURONnRY 1)t\I AS1 " Hq T'. 1 Reran, M 1> M. I f rank. M 1) , 1 /~. Mc(~in1y, M 1) , 1 7rJrl, K~1 1) . II K Ilrllcros, fN 1) nn,l R 1. 11inR• M I/., 1)trirtmcn/ r,f Mr,hunr, Wayne State (Inivetcily ('<dlrFc nf Medicine, f)etrnit, Mich. ( mrrLur.•n, Vulume 21, paRet 1G5.1h9, M:rrch 1961 (1 I R('. Frantre 11inR1 m tn 1S „ 14 R~

J I'rrrfr...r n/ a(rrdy: In a previrnrs study Ihe early restir,nte to ciparelte smr,kinR wis istociated with cnhanced rnyra'irJi:J hlornt flow in nnrmal suhiccta Whcther a similar situation occtns af(er Ihe knr+..n peril.hcral hcnn,dynamic resl+nntts have been es/ablished and maintained recluircd et- aminaliun. To assets the potential role nf tobacco as a canse rd myrrcardial iachemia. Ihe rcar(.nte to srnt+king in patients with coronary artcry discase has been contraated with that occurring in cnntn+l subjccrs. 1'rnrrdrrr.a: 7 he study group comprised R suhjcctt with cr+rnnary artery ditease who had incurred an acute myocardial infarctitm al leact one year previously and 6 control subjects who had recovered from acute benign illnesses. AII the patients were habitual smnkers. After an overniRht fast, the patient was catheterired through the coronary sinus and right atrium and a needle was placed in the brachial artery. Resting coronary hlrKal flow was determined in the recumbent pcnition and the patient began cigarette in- halation at 43 second intervals. Two standard nnn-fillcr ciRarencs were cnnsumed in about 23 minutet, so that the initial increase nf pulse ritc and presaure was larpely maintained during the suhsequent 12 minutes of nitrtws n><ide inhalalir+n. Upon cessation of rnhalalinn, cigarette .rnr+king was re- sumed at the same rate and was maintained throughout the cnronary blood flow sarnptinR. Ileart rate, arterial pressure, and a left ventricnlar lead were mnnitored throughout the smnk rR and were relatively constant during this prncedure. Finrlinor. ~ nurinR cigarette smoking both the coronary and control grr.nps had siRnificant acceleration of heart rate. A unifnrm rise nf artcri.1t pressnre wat seen in the litter and, with one e><ceptinn, in thc coronary Rrnup. Further, there was a tendency for these hemcxlynamic chanr.ct in he mr+re pronounced in the cornnary Frnup. AII control snhjccts had an incrcasc in cardiac inde>< as did all hut Iwn in the coronary Rrr,nft A unifnrm increment t,f left ventricular work dnrinR smoking was alto more prr+mamced in the coronary grrntp. The altendant changes in coronary hlond tlnw were not significant in either Rrnup This phenomenon, combined with an unaltered myocardial n>,ygen e ttractinn, resuhed in a virtually identical myocardial nxyRen usaRe as in Ihe cnntrnl state. ll+ere was no evidence of myocardial ischemia in the coronary suhjects during smoking. Failure to find increases of myocartlial hhxxl flow and oxygen usaRe in the coronary suhjects durinq ciparette smnking may plausihly Le rrlnted in the "ft ted cnronary retistnnce" allcRrd t caist in such ratrcnts. Th:+t Ihe ahnnrmal coronary vasculaturr is ntrt s(+nnsihle becomes apparent from the similar reqrnnse in the suhjccts ithrnrt evidence of cnronary diuase. nrGrr Rrnnlnrrr I1. S Puhlic Fleal(h Service. American Ilrart Assr.cia- linn, Michifin Ilcart Asst.ciation, l.ife Insurance hledical Re~rarch Fund• nhhr+tt I nlN,raunics. anrl the IlurrnuPhs-Wrllcrnne Funtl "SIY)RA(ilI OW ('AlF.f.'f1(11.AMINf?S IN *t11I: /1f'nRT- I I I f(T OF AMINIi OXtl)ASF. INIIIRIIf)RS" fly Kw,hrt K.+kn, h11), nrlh:+naaint ('hry.rrMru, M It . nnd Rich++rd I fling. fv1 I) Anrnrrn.n /rnnnnl rrf ( n.dr nLot,v. Vrrlnnir h• rnRea I 11N) I I I I• 1)rct•nd'cr 1')(dt "I At I(rltC At I I('11N(3 MY(K'Altl)1Al. S1()ItA(il ANI) ItI I 1:ASI:. (r1 (A 11 ( l f( )l nM1NFS " Ily Kyuhri Kakr,. M 1) , Athanacir,a ( hrya- t/, I t,hnu, M f)., and Richard 1. fiing, M.D. Circulation Rrvorrh, Volume 9, paRes 295-299, March 1961. 1 he factnrs afkcting myocardial storage and release of carecholaminct were invct(ipatetl in these two studies 7he addition of dihydrosyphcnylala- nine (f)(1pa) to the f,erfusion fiuid of a heart-IunR preparation matkedly increascd Ihe cathechnlamine concentration of the isolated heart. In rivo, the combination of ipmniarid and Dopa had the same effect. while ipron• iayid alone failed to influence myocardial amine concentration. In animals pretreated with Dopa and iproniarid, nicoline caused a significant (kcreaae in m7ocardial catecholamnxs. It is likely that stimula- titm of the adrenal meJulla and sympathetic nerve endings by nicotine elevated catecholamine levels in blood, with subsequent storage in the heart and olher orRans. "Mf:TAf1Ot.1(' A('TIVITY OF THE INTACT HFART." hy Richard 1. fling. M 1). .Inrr+hnn /nurnal of Mrdicine. Volume 30, pages 679-691, May 1961. 1he difference in composition of blood colkcled from an artery and from the coronary sinus is determined by the procesAes of intermediary metahtdism in Ihe heart muscle cell; bu1 because of storaRe of suhatra(es and their interchange in heart musck, the coronary nrteriovennut diRerence reflecls only a balance and permils no cnnclusiona as 1o the palhways of intermediary metahulism in the heart muscle cell. The limitatinns of such biochemical nbservations are exemplified by studies (in the nitrogen equilibrium of the body. This furni.hcs infnrmalinn on the halancc between dielary protein and ils telalion in protein breakdown or prulcin synthesis; hut such studies Icll nothing of the r.rte ;tntl dclaee nf deaminatinn. Iransaminatiun, ttccarhnRVlalion, or other inlermctli:rry pru- cessts nf prolein metahulism. It is therefore casential h+ cnn+hinc mctn- holism balance atudies with investigations of cellular metahuli.m '1 his re- (~+rt is primarily concerned with in rit•o studies of mctaM+lism uf d+e mrrmal heart, the anoxic heart, and the diabetic heart. ()f' A7RIA1. ANI) VfN1RICl1LAR FIf1Rl1.1 Al ION nNl) Vf:NI RI('f II.AR T'A('IIYCARh1A ON ('ARfiOIIYI)Al /? MI:t n- flOLISM (N: TIIr IIhART." Uy Michael Klarwein, Ph I) . Kyt+hei Kakt+, M 1) , Athanasint Chrysnhnu- M.f)., and Richard l. hing, M 1). ('irr rrlnrrrm Rr+r.rn h, Vtdun+e 9. p:+Res R 19-R2S, July 1961. Chanpes in Ihe ratio phosphorylase-a/total phosphurylase in heart muscle, aa well as the rnyncartlial concentrations nf glycngen, Flucuac-6- phospha(e ((:-(• 1'), I:tctate, pyravatc, fructose-1, 6-dq+hutpha/e (11)P). rhhytlrt+nyacetnnc 1+ht+al+hatc (1)11A1 ), were followed cf+vinF artiticially in duced vcntricular t:rchyc:trdia, ventricular lihrill:dion, aml :Hrial /ihrill.ttn+o 1 hesr c((+crin+cnla wrre carried out with ant) wilhoul supfNnl r+l rhe cnr.a+ary circul.rtir,n Whcn c+'rr+n:+rv clrcnlnUnn wna nrrt mnlnlalned, ncrivc I+Ihr,ald+nryl.+ac incrt.+acd, thrn diinini.ht•d in henrl muttlc durFnr. nlt Ihrrr crrnrlrU+rn., annl.,r Ir+tlh.+nrr. rrtrrrrtr•d in akclt'tnl nnrale Whr•n crvr.n.+rv crrtnl.Hrrm was nnu+fatnrJ, n" th:+nr.cs in tarhnhvdr:+lr intcrmrdi:+lra rrr m/'hna. hht,rl~:ra' a uctivrtv wcrc rcctatlcd. Iht••c rcaults drnnmatratc Ihat Ihc 17

mctahrrlic ch,nFet encountertd in heart mutclt tluring thcte arrhythmiat arc the retuh rrf innltia. "Rf-('f NT' 1'R(1CRFSS ANI) PRF$1:NT PROIiI 17MS IN 71117 111-11) OI S11(1CK." 1'ancl I)itcuttion hy Richard ). fling trd~.,ur,rn r'r,rtcrrlrnKr, Vol 2t1. p..)-rt 72 71, July 1961. 1 he changtt in my<Kardial metahnlitm during hcmr+rrlragic thnck are not itnlatcd trc'currcnccs hut follow the general pattcrn of mytKanlial ant+xia rrtultinR frtrm dirninithcd coronary blood flnw. ()or the hatit of c.fKrimcntt pcrformcd on the ann>tic heart during venlricul,r tachycar,lia and fihrilla- (ion, it it pottihle that chan es In phntphnrylate a actlvrty alttr (Kcur in the heart mutclt durinR thock. hethcr the ervyme Photf,ht,fructnkin:rtc it the ratc-limiting enzymc in heart mutclc during hcnurrrhagic thtKk rcmains to hc ettahlithcd. "CONTRA('TILf PROTFINS OF III:ART MUS('1 F IN MAN " fly Richard 1. hinR, M 1). and K. Kakn, M 1). ('irtt,fnrr,m, V.dumc 24, p.lptt 4R) 49(1, AuRust 1961. Part II. The cnntraclility or actomyotin hantlt prcparrd front heart mutcle of patientt who hid died in cnnRcslivc failure wat diminislhcd at cnnrparcd In thtxe prcpartd from normal hcarts. lhit may have heen file rcsull nf dcfrc- five protcin tynthcsis. The incrcatc in heart fate was cnrrefatcd with the actrvrty of photphnrytase-a in heart mutclc and with changct in carMrhy- drale intcrmediatcs (lactate, (i-6-P nnd Rlycop•cn ). licart rates over 300 per minute were asulci:rlcd with a Iransicnl in- creasc, followed by a decrcate, in phutphnryl,tc-a activity: glycogen di- minithcrl, whilc lactatc and 6, 6-P incrcatt'd. I he rrxidatinn rcductron ptrlen- linl in heart rnusclc became mnrc ncgative. In the ahtence of myrKardial anoxia, the incrcatcd ratc of ttimulati,rn of file hearl pr(aluccd no allcra- lions in either thc concentrntion of carbohydrate intcrmcdi1tct tir thc phosphorytase-a activity. Alteratinnt in funclion or the heart that cnrwe into play uptm rarirl changes of cardiac activity are the rctult nf thc intcRr:tti,rn of tcvcral divtrsc hinchcmical ccllular rcaclinns. The contractile (~nNCint are hut following the lead of the cellular elcments cunccrncd with file lurrductinn of energy. "IiXTRA(TI(7N AND RF.I I:ASfi OF INI)IV111OAL FRFF. FA I 1 Y A('ll)S IlY 'f l lri 1IIiART ANI) /'A I UF.PO I S" Ify Marlin I: Rrrtl,lin anJ Richard 1. IIinR, Ih•pirlmcnt nf Mcdicine, Wayne Sl:rle Ilnivcrtity ('nllcge nf Mcdicine /nrnnnl tr/ ( lirrmral InvrrriRuli„n. Vrrl 4/1, f.:rr.cs I 1RO- I1R6, AuRutt 1961. Purptr.r nf .rurfvr 11 has prcvimrsly been dcmrmttritctl that in the prld- ahtnrptive ttale cncr y rrrKfucrnn of file hcirt dcPcmis larycly t,n Lrny acid metaHrlitm AltlrnuRh file Rcm•ral tnrnttvcr r:uc td in,hvi,tu;,l I 1 A hat hcrn ttudied, nn invcsti/atinnt hnvc ht•cn un,/c,l:rkcn t,r A,.c lvcr their latr in the fhrarl nn,uk. 'Ihe prrtent v1uJy dcnls with Ihc my,K.,r,t,.rl c!. Ir.cti„n of inJividu:rl IFTA, includinr. irt rclco.r by n,hl.o.e ti..nc f'rnr.rlnrr.t 11um,m I+rttlrnlt flcr r+f nlttalNlll(' IIf1,1f1lert, /l,inf ur whnrn w:,% in cimlrarivn crarl failurc, nn,1 anctthrliztd tl ~t, were vluJ,c,l in a (:ralinR ttmc (m-nary vcnrnra hhwal rrf man an,l thrR wus ohtiincrl hy catheterizatinn of the coronary sinua; timultaneously, arterial blood was cnllccted Irorn the brachial artery (man) or from the femoral artery (dnR). BhwKt from the saphenous vein (doK), which drains largely suhculanemrt tissue, was also coltcctcd. Frce fatly acids were determined in the various blood specimens. FintlinR.! In the pcxtabsorptive state, the human as well as Ihe dog heart extracted a consistently higher percentage of free okic acid than of any other FFA present in arterial blood. This acid was also released at a higher rate of fat dcpots of the dog. These flndings suggest a high turnover rate of free olcic acid• It appears likely Ihat an exchange belwet;n plasma trigly- c ides and free fatty acids in heart muscle, resulting from lipoprotein lipau tivity, may be respnnsible. tlrrr Frnnlnrrt U. S. Public Health Service, Ametican lieart Attocia- tion, Michigan Ilcart .lssociation, Life Insurance Medical Retearch I~unrl, Abhott l.aboratories, and the Burtou6hs-Wellcome Fund. "R<:IIAIIII.ITATION IN F/EART DISEASE." Br Richard 1. BinR, M I)., Uetroit, Mich. ./rchives o/ Environmtnrof lleafth, Vol. 3, pages 62•65. September 1961. Re6abililation in congestive failure and coronary heart disease is dit- cussed. Proper diet and moderate exercise are impdrtant and return to work is helpful to the patient. "CONGFSTIVE NEART FAILl1RE. ITS PIIYSIOPATFIOLO(;Y ANI) TREATMENT, WIT11 SPECIAL REFERENCP TO IN'IRAC1A111.1? lIF.ART FAII.URF,." Ily William 11. Morse and Richard 1. Iling, Wayne State University College of Medicine. Po.rrRraduafe MeQrcinr, Vul. 10, paget 293-3(x), October 1961. The relationship between the phrsiopalholo ic faclors involved in heart failure and Ihe manifestalions o( the disease 11s not clearly undcrskaKl. Clinical signs and symptoms are caused by disturbances in eleclrolyte and water balance. A . in heart Speculative theories have been advanced concerning Ihe role failure played by cardiac metabolic disturbances, changes in the mnlecular structure of aclomyosin, cxcretion of aldoslerone, relcate of anlidiurclic hormnne, and perversion of the normal mechanisms of txHh fluid vnlumc and srxlium regulation. Treatment of cnnr.estive failure is slill chic0y emf'rrc• cnsrstu'g nf careful r.Fulatitrn of s~rdrum and water intake and admimtuntiun"uf drRh:rlit and diuretict. "f)O1'A (1PI'AKF. ANT) CAlTiC1IO1.AMINf C-ONTFNT IN I/I?ART ANI) SI'ITU.N." 11~~ ~A. Wcgmann, K. Kako, and A. ('hrytohnu, I)cpart- mcnt of Mcdicinc, ~'~'ayne State l)niveraity ('olleRe uf Medicine, 1)clrt-il, Mich. .4rnrrl, trn /trr.rnnf tr/ /'hyrinfnRy. Vol. 21/1, pages 671 676, l)clul.cr 1961. ('I I R('. pnnrre. IIinR) 1')L Ililrydrnyphrnylnlanint (Ikrpa) was infusrd in mrmgrtl dnRt undcr variuut cr~n,l,li--ns in tudcr to sludy ilt uptake and inllucmc rrn file strnage nf nurcpincphrine and cpinephrine in Ihe heart and aldcen No in- crease in content u( Ihese calecholamines in the heart and tplecn c<ruld tre I I 19 1R

dctccrcd aflcr I)r+pa infutinn. Apparently the rate of convcrtit+n fit hora intto murrinrrshrinc t)ncs not depend t+n the supply nf the cuhclratc. "MYU( ARI)IAI. Mf;fAltOI.ISM IN PRU(iRFSSIVIi MttS('UI.AR I)YS1 RUI•IIY " fly ). f'. Sundermeyer, S. (iutlhjarnasnn, V. fi. Wcndt, 1'. Il 1)cn Il:~kkcr, and R. 1. Iling• Wayne State llniversity ( nakge of Mcdicinc and ifarf.cr Ilocpil:d, Detrt+it, Mich. ('ircutnri.r.r, Vt+l 24, pages 114R-11t5, 1)cc. 1961. Thc cardiac nutputc were elevated in all of eleven paticnts with prn- p•reccive nmuacular dystrtphy studied by the authors. 1)il!erenccs in oxida- Iton rcductinn (+trtential between arterial and coronary vcnons hlta'c1 were pocitive, cuRRccling glycolysis in the heart muccle. Stimulation of glycnlysis t+y inorRanic phocl.hale was cuggesled by Ihe rclationchip bctwecn inorganic rhochhate cuncemration in hhxrd and the myncardial glucote eatrnction. lhic suRgcclc the possibility of uncoupling of osidative phns(+hnrylation in the myt+cardiurn. 'Y•OMMON (-(R( III.ATORY Mf?nS(1RrMFN1'S IN SMOKF.RS ANI) NON SM(1KI:RS " fT Ilcnry Rlackhurn, M 1) , locef flrouck• I'h O , and I Irnry I.. l ayh+r, f`h ~).. I.aM+ratnry of PhytinloRical I IyRrcne, I InivcrtFly td Minncanta, antl Medieal f)cparlmcnt, Mutual Scrvice fnturance ( or)- panicc, St fiul, Minn. C-irculorinn, Vol. 22• pagcs (112-I124. I)ccrmher 1960 ( T I R('. yrantce: fTrorck) I'nrhn.e of .rurlv: Nn convincing theoretical or e>< rimental hacie hac been ettahlitht•d ~hus far to e.plain the hip•her car invaccular rmtatalily ratcc in trnnkcrc than in nnn snrnkcrt thnwn in ceveral e(+idcrnitJt+Rical studict The (+retrnl P.rer it ct+nctrnrtl with rettmp- pulcc rale intl Lltw+d prcccurc antl circurilnry rciclnmc to trvrra I+rrttr,r tttmulr in ntilc trmtkrrc and non-vnnkcrc Prorrdrrrr: I our srudy Prnnl+s cnrnfnting I J/V 1 nirn apc+l 1 7 It+ f,7 wrre examined: Rroup A. 2R6 nntltllr aRctl huvnrtt antl ~rt+(rctn+nil rncn. p•rnnp Il, (S9 ntale univcrtity atut!rntt; group (', 414 ratlrt+ad cml+lt+ycrt. and grou~ 1). 214 city firemen Rcplrct tn vandarJirct~ questtonnairct rcfardinR rmt+king were Rrouhrd under never cmnkcd, occatinnal tnmkcrt, liKht smokers (under tO cigarettes daify), mrxtcrate smokcr. ( 1 I In 20). heavy smokers (21 or more cigarrltes daily), and stopped cmoking fnr at leatt one year. FYndinRr: Relative bcxly weight was concistently lower in the heavy cig- arette smokcrs compared to thoee who never tmoked. flatal nxyRen con- sumptir+n wac slighlly higher in smoken than in non-.mokcrs. 1'nlce rate during work and recovery wae tiRnificantly higher in one group t.f midt!Ic- aycd mcn if ria1M+logic e>ttcc in the Isroup are concidcrcd. In "nnrmal" pt'pulatinna, comt•what precclcctctl for ahcence nf hyf+erlenaion, m+ tlif- frrcncec in recling hlrxxl pretcures were fnnnd hrrwern cmt'kerc and non- antAert In the hrnader slutlics, invttlving camlrlrc of the wrnkinp. pt+fula- tinn, vnnking wr,c .cttxinted with Itrwct cyNt+lic anA di:+ttt+lic I+rrcturrc Yt+un/ ttudrnt jfrt+up., with tht+rl durrtlinn fit .runkinp" h.tbrl, .ht+wrd mr tipn+fu ant tlillrrrr+crt hrawrrn arnnkcrt .ntl nr+n vnt+krrs 110, a..+r rnllr+nl h+rmtl dt+ m+t !ntrviJr rvidrnt r ft+r ImP,r t+r i...1+r+Hnnt tlr/Trrrnt rt +n t utttlnltrrv trat lirvrly t.ctwrcn prt+ul+c fit hal+itnal arnt+krrt and nwn trnt.lrrc !)hrrr rt Ir'flr r+rrlrntt• ft+r rlclt•ritttatinn t+f c:+ttlht+va.cular V "filnec." in smnkerc pcrforming work Iesls. The small magnilutle of the ditlcrcnces found in circulalory mcacuremenls, plus cerlain strorcec o( hiac, rreclude ccritwc concidcralion of thecc factors ac underlying cauccc of the mcrcau'd mortality rate among smokers. Other unanswered queslionc ere the importance of individual recponses and hyfxrsencitivity to smokinF, and the significance of acute pressor and other effects of smuking on rersonc with latent or manifc.t cardiovascular disease. "EffECTS OF I1YPERTF.NSIN ON ARTERIAL PRESSURE. IIfnRT WORK ANI) CARI)IA(: OXYGEN UTILIZATION." By Ivan f:. Forte. M.D., Lmris PotRieler, Ch R., and Jerry D. Schmilthenner, M.l)., with the ascistance of 1. 11. flafkenschiel, M D., and olhcrs, 1)ivision of Research, t-ankenau f Irnpital, Philadelphia. Circulotion Rr.rrorch• Vol. R, pages 12)5-1241. November 1960. (T.I.R.C. grantee: llafkencchiet) Ptrrlrn.e nJ arurfy: The effects of acute increases in left ventricular prec- sure work on coronary blood fhtw, myocardial oRygen, and carhtdty<Iratc utilisation required invectigation- In Parlicular, there was need for tcclinR an e.(verimental plan in which many ohservaticros could he ntade on a few ammals, each scrving as ils own control. f'rncrrhrrr. The drug Hypertensin was used, since it appears tn correcpond completely with the naturally occurring angiotensin, and ic an agent which might increase left ventricular pressure indef+endenlly of any incrcaae in left ventricular stroke wtxk or hearl rate. Young healthy dogs were used as suhjects in paired pcriods of ohservation, comparing the chanRes from the firet to the cecond conlrol period and erxnparing the diRerences found with changec obcerved from the control to the drug-infusion et<(.criment. '1 he variouc cardiodynamic and metabolic functinns were calculated and Iesred for statidical significance. FinrfinR.: The siRnificant hemodynamic ehanges induced by the droR were increased mean arteria) preesure and increaced left v,enlricular wnrk. A greater cardiic lactate utili-lion (luring the Ilypertencin infusion wac the only cl.ange in cardiac metaholism. The nttygen tension in left ventricular venous hlotxl was not reduced during the action of the drug. 1 hc fintlin fe appear tn suPporl the thesis that coronary reciclance ic rcleulalcd Itt inturc adequate coronary blood osygen and lactate transport for the retluircmentc of cardiac o>tygen and lactate melahnlicm. Z C rRrr Rrnnrnr.: 1 I. S Public Ileallh Service, C-ontmiltee on Prr.hlcnte t+f l~krrhol uf the Natn+nal Academy of Sciences-Nalional Rese,rrch ('uuncil, iha Pharnlaceutical 1'rtxtucls, Ine., and f(eart Astacialion of St+nthea.tcrn Pennsylvania. "PRAC-TI('AI. I.IMITnTIONS OF Tllf3 KETY MI?TIIO1) 1'OR f)F 1VRMININ(7 (Y)RUNARY 11.1.(X)h PL(1W BY INI•RARI?I) ANnI.Y- SIS OI.- ItL(K)t) NIIROUS t)XII)fi." 11y lven E. Iorle• MS, ltnric Pt+lFictcr, ('h It , lrrry F.. Schmillhenner, M 1) , INrnler Neal, M f) • and I I1. Ilnikrnachirl, M 1) , 1)ividon of Recearch, l.ankenau IIotl+itUtl, 1'hil.r tlrll+hia Amrri.nn lfrnrr /rnnnnf. Vnl 61, pages RI-I(7• 1nnu.try I'1nl n1 arvufr: '1he Rrretecl need in Ihe area fit tliar.nt+.tic -tItulirc in riatienle with cnrt+nary arlery tliteau ie tlre development t+l a 1+rcct.r It•.1 to mcnaurc cottmary rrtcrial hhxxl flow in humanc, a lark of wluch trcn+t 41

to have been an impnrtant limitinR factor in the Sclectinn of paticnls fnr, and, hence, the survival rate of Ihrtse undergoing cndartcrcct,mry I'r...r.fprr; Preliminary to altcmplinR development of a sinthler mcthnd of rneacurinpctactnary hhx.d nt>w applicable Irt hoth intact animals antl man, it was (rrst nccccsary to learn the limitalions of the Kety-Van Slyke nitrous oRiJe manometric at well as the direct infrared analysis tcchniques. 71te objective was to cstablish the rcp roductihilily nf an e.perintenlal dcsiRn in which the same animals were used repeatedly, using the contbincd aneclhcsia, morphine F)ial urethane pentobarbital. FinrlinF.: ( I) 1 he blood analytical technique usinR the principle of infra- red ahsorption is practical, time savinR, and comparahle in precision to the mannmclric method. (2) DurinR steady statcs Ihe Kcty nitrous uxide Ictt is quantitative and reproducible, and, at the present time, is the bcst methcxl of rcasurinR coronary blood now in intact animals, O.. Rronrnr.: U. S. Public Neallh Service, ('ommittce on Prohlems o( cohal of the National Academy of Scicnces-National Rcsear(h ('ouncil, iha Pharrnaccutical Products, Inc., and Ffcart Association of Southeastern 4'ennsylvania. "MFAS(JRF'MCNT OF CORONARY BLOOf) FLOW USING RAnIO- A(7'IVF IOF)INE ('OMPARI:U 1VITI( NITROUS OXIUI:." fly Ivan F. f'orte, A 11., M S., Jerry F. Schmitlhenner, M f)., and Fluntcr S. Neal, M n., with the assistance of Joseph 11. Ffafkensehiel, M 1) , and others. C'irruta- thrn Rrrrarch, Vnl. 9, paRcs S47-SS1. May 1961. Purpo.p of .rrufy: The theory on which this study is based is that after injection into either the pulmonary artery or left venlricle, the first activated bhxxl to reach the right ventricle on recirculation rclurns by way of the coronary vesscls. 'I he nswers sought are, (a ) is il possibk, f+y injecting a radinacfive hotus, to record an isotnftt-dilulion curve in the blood of the coronary sinus draining the left ventticle, and, if so, is this dilulinn reflected in the proximal pulmonary arterial circulation curve or in a prectxdial curve, and (b) if such curves are meaningful, how dr+es myocardial hhxxl flow and its ratio to cardiac output compare with blood flow valucs recorded tmost simultaneously by the nitrous-0tide desaturalion methrxl7 lhe present rcport dcalt with questinn (a) alone. Prn.•rdure: Coronary bkxxl now was determined by scinlillation counter in anestheli7ed dnRs before and after injections of radioactive iodine. "I he first two cra(+eriments attempted tn obtain isotope-dilulittn curves while con- tinutwsiy injecting a radioactive sodium iodide solutittn, which proved un- salisfactory, and the nertt fnur experiments involved raftid inject nn nf hotuses Ihrnur'h a c>,Iheler in the distal puhnonary artery. In Ihe nrxt rlcven exf+errrncnt., the resullinR eurves were armparerl with Ihuse ohlaincd hy the use nf a catheter in the anrtic rrrnt or Icft ventricle as rhe ate nf injrclitrn Fln.l7nRr: An istrlnpe-dilufirtn pattern was nhFninnhle in trnly Ilurc rrf eir.ht d"Ps teslyd Ihrse resulls are Inlrrfine/rd at indrt:NinR Ih:+l Ihr rarlitr- iantty.c thluLit•n mr!hrwl for the drtrrnunafirrn rrt t rnrrrtary htrw,rl fhrw It Inrlv.n Ir. ;rl•Ir rn thr rsnlr wilh frrrtrnl In•.lnrrnrnl.rfr„n 1•rr :nr~r r,t ltrr in l fhr rr, frnir al ,lillir rrllrr t rnt.•l~t'rl rrt 111c nulhrwlt a1.1..I )Ihrr frenMra a U. S Public Ncalth Service, Commillee nn Prnhlcnn of Alcnhrd nf Ihc National Academy of Scicnces-Nalinnal Retearch ('rruncil, ( iha 1'harruaccnti~al 1'rtKlucts, Inc., and Ilcart Assot:ialirm rrf Srtulhcatlcrn 1'ennsylvinia. "lllfi R(11.1i OF EXERCISE TESTS IN TIIE DIAGNOSIS OF ('UR- ONARY AR I FRY INSt/fhICIF.NCY." By 1. Fcxtc, M S., 1. 11 Ilalkcn- schicf, M 1)., ). E. Schmilthenner, M.D.. 11. Ncal, M 1)., and Fi. A. 1)auRhcrly, M 1)., Cirdiac C'linic and Research Divisinn, Lankcnau IIrK- pital, Philadelphia. .Imrrican l/rart lournaf. Vol. 61, pages 756-762. June 1961. Pnrfro.e of .rurfy: flecause of the lack of informatign on cardinpulmnn- ary paramelers in the carly recovery period after myocardial infarclion. Ihe treadmill test was applicd to a few patients in order to ascertain whether such IeslinR is feasible as a general procedure to determine the rate of re- covery and what ambulation therapy ahould be prescribed. Prnrrdrrr.: Fii hl healthy volunteer male subjects aged 33 to 60 were first tested at a work~oad of 370 kilo(1 ram-melen per minute for 10 minules on a Ireadmili ( Ifl percent ~rade at 1.73 miks per hour for 10 minutes). A(tcr a 211-minule rest period, the subjects underwent another 111-minutc tesl precisely like the first. Various cardiopulmonary parameters were recordcd. Similar tests were then carried cxr t varying %vork loads with 3 prslmytt- eardial patients and 3 patients with primary hypertension taking depressor drugs and were compared with the results with healthy subjects. FinrfinR.: Preliminary studies on !1 healthy subjects show that the rc- sponse of ventilation, oxygen uplake, and heart rate to treadmill exercise varying between 300 and 600 K6.M./min. is linear and reproducihle. Patients recovering from an acute myocardial infarction were observed to he able to tolerate an exercise wotk load of 370 KR.M./min. up to I() minutes, if able to he ambulatory. Testing at Ihese work kvcls in sclccted patients shows that the treadmill walk can be performed wilhout undue a rchension, e.ccssive increases in hcarl rale, or marked S T-seRmenl dis- acement in the periad 6 weeks to 6 months afler myocardial infarclittn. Oth.r Rrnnror.: (1• S. Puhlk Ileallh Service, Commiltee on Prttblems nf Akoho) of Ihe Nalional Academy of ScietxerNational Rexarch ('ouncil, hs Pharmaccuficat Pr«fucls. Ine., and Neart Assncialinn a( Suutheaslcrn Pennsylvania. "CIGARFiT1Fi SMOKING AND ISCIIFMIC 11FART hISFnSf " fly 11 Ilrnnte-Slewart, M I) . MRCP, Department of Mcdicine. Univcrsily of ('apetnwn, and (irexHe Schuur Ilospital,Capt/own, S.wlh Ahica, fnrmerly at I lnivcrsity of Minnesota. Rritith Mrdicat lurnrnaf, paRcs 17'J. 1R4, 1 cF+ 11, 1961. ('1 1 R('.'ranlce: [)r. Ancel Keys of the University nf Minn e.rNr 1. ( I n lx rrnd with cnmpanion pieces in tante 1ournal "l AS 117 1'fR('1:.1'11()N IN SR11)KI:RS ANI) NON SMl1KfiRS." Hy 1. 11 Krnl. M fl', ( ft It , Mrrnlcn 1/'crrin, It Sc., 1)Ip INcI , anJ 11 /ln•nuc .l'rrwart, M 11, MR( 1', Irarrs 1114-1R7, and "SMt)KIN(i ANI) 1(N)I) 1'!(11 I 1t I N( 1'S " Ily 1'rrrin, Y,ntl anrl 1lronlr Slewarl, paPct lR ) INH 1 Purpn.r of andvr Scvcral epidemirrh+Rical studies have rcl.rrrtrtl a st:r Iiatical rcl:tlirm•hil. Iretwccn Ihe prevalence nf iechcntic he:ut dt.cate arnd ~ vr f , 41 r~

ciRarette smokinR. On csamininR Ihe associatir.n one ia imn,ediircly con- fronted with two major 1xratihdihet. Firstly, has the smrrkinR of a ciRarcttc a dircct effect by interfering with either coronary blood flow rrn heart actinn'r Sccondly, is the effect indirect in that bath cigarette smnking and ischemic heart di-icase mortality are related to a third and common factrrr? Pr.rr.rlrrr.: Ilita were obtained from 6(K) apparently healthy South African malcs aped 25 to 55 who were actively engaged in their occupatir,ns, concerning their incnme, occupation, smoking habrtt, and cuslrrmary dict, with particular emphasis on items or rood that contain fat, such ac mcat, dairy prrxlucts, cRRs, marRarines, oils, etc. Amhroprsmctric measurements were recorded and cholesterol chemically deterrnined in the hftKxl scrum. Fach racial group was dividcd inlo three incomc classes, bul the economic scale it such that the high-income Ilantu would overlap the economic level of the low- anrl medium-income Cape Colored, and the high-income C':rre Colored would tx on an economic par with the low-income fiurr.pcan_ ('iR- arNtc %mrrkcrt were anslytcd cparatcly frnm pipe snrokert and hc,th were classifird into hcavy, medium and liRht smr,kinR Rroup.. FlndinRr: No relationship could be found between snrnkinR and aRe. In- crinu, nccupatinn, heiRht, weiRht, or degree of nhesily 'Ihe arterial prct- sures of heavy smokcrs fendcd Io be slightly lower than those nf non- smnkcrt, hut the differences were not sr(mficant. A highly cnntistent difference shown was the didrihutirxt of chc~lesterol between the alpha- and beta liporrotein fractions. l hit held true at each age nnRc, for cactr race, and for each income sub-Rroup. Such differencet were parallclyd by dif- fcrences in the customary dietary fat intake, hut these diflcrences were not ttatislically tiRnificant. 1 hete findinp,a do not etclude the potsibilrty that increased ausccptihility to ischemic heart ditease in heavy cigarette smokers could arice from the blood-pressure changes during smoking. On the tither hand. the mechanism for the increased susceptibility trf the smokers could operate via the changet In serum lipid found. The fint comrenirxt study showed that the tsste thresholds for "hitter" were significantly higher in smokers than in non-smrskers, while no differ- ences appeared for sweet, sour, or sslt. The aRe of the smnkcr, and thus presumably the duration snd amount of smoking, both adverscly affected the tentitivity tn bilter tastes. The second companion tludy showed that non-smokers prefer hland frsod and a fairly high propnrticrn of smokert prcfer salty and apiccJ food Smnkert cnnsume more fat than nnn-tmnkers, but the diffcrencct are small Ilcavy smnkers cnntume siFnificantly more meat and eRgs than do nrm- smrrkers, and the latter contur.ne mnre fat in the frrrm uf cakc.. twcclt and chocolate 1 hesc diet preferencet may act'rrunt fon the difTerrnr e. in .crum chrdcsrrrrJ Irvcl% that have been reported in surveys on .mokcrs and nrrn- smokers. "ItI1F/tGI R SYNI)ROMF. IN 111f. ORII?NI " fly Victnr A MtKmi( k, M I) , r.nd Willard S Ilarria, M 1) , 1ohns Ilopkins I lnivcr.irv %t h-d of McJrcinr, Italrinionr, Md Ihr fomrr, paFrs IIII IIIN M:ry Iu, I lhl ( I I K(' fir..nrrr McKusick ) 1'urpn.r .J .rndv: '/he (•rctiimrtion that in the Oricnt the clinical and pathological picture it less obscured hy a hiRJs frequency of alhernsckrcxis and thrnrnhrxmholic ditesse than in Western countries pronrpted a study of the llucrgcr syndrome in Japan and Korea. Prnr.rrr.r..: Since early 1957 the Presbyterian Medical Center at ('hnnju. Knrea, hat admitted 62 patients with the diagnosis of IluerRer's discate, all malcs; 2R of thcse who responded to letters were studied at was a control group of 2R Korean malcs. All but S of the 2R patients were farmers or farm workers whose dict consisted mainly of rice, pickled cabbage and other vcKetables, soya-bean cakc, and soya sauce. A11 were smokers, and mott snnrked heavily. Serum choksterol and fasting blood sugar levels did nut differ significantly from those of the controls. Visits to 6 medical centers in Japan revealed that most university medical services admit 10 to IS patients annually with the IluerRer syndrome. The a6e, sex, and social and economic status of the patients are essentially the same as in the Korean patients. FlnrlinR.: There appears to he In young males in the Orient a form of obliterative vascular disease which clinically and epideminloRically, and pcrhaps histnluRically, does not have the charactcrisUct of atherosclennit or multiple ernholism. 'The etiolo~y and pathogenesis may be crrmplicatrd. lhat the essential lesion is an anRulis remains to he proved. AnC111 tis or nnt, the+athoRenesit is not undentood but appears to differ from tf t.ther vrr(cular diteases particularly atherosclerosis. I th.r Krnnror: U. S. Public Health Service. "NORMAL RAR[IITS' AORTIC AND MYOCARDIAI. ('F.I.f.S GROWN IN VARIOUS CULTURE MFDIA:' fly T. Kukuhu and (). 1. Pollak, Dover Medical Research Center, Dover, ihl. F..rp.rimrntnt ('rft Reaarch, Vol. 24, pages 413-42). September 1961. (T.I.R C. grantee: Potlak ) Prrrp.r.e o/ .rrrdy: In preparation for studies of the eRecls of tobacco derivatives on arterial and myocardial tissue eullures, it was necessary to establish optimaL conditions for in vitro growth of vascular cellt. Prnlrerlrrr.: Segments of ascendinR, thoracic and abdominal aorta and of heart papillary mutcle were removed from adult rahbitx os soon st ptnsihle after death, rinad in sterile isotonic saline solution, and cut into piecet about one millimrlcr syuare. In vitro cultures were started within two hnurt. The fluid medium was changed twice a week. Microscnpic uh-,crvntinns were made every othcr day for about three weeks. Five separate nutrient media were tested. FfndinRr: LlndiRercntiated fibroblasts from heart grew hest; cella frrvn ascendinR nnrts F.rew better than cells from thoracic or nhrluminal arrrta Rahhit « rum prnrnnteJ cell /~rowth f.est; horse serum and human serrun enhancrd Rrowtfh nrroe than elucken serum. ('e0t Rrnwn in chicken serum tlifTereJ nuul hnlrrFically from cel/t cultured in met(ia with tirhrr srrum adr/itivts (irrrwth in mrdiunt wilhout any serrmr rrternhlcd t'hracly Ihe re tul/a rrhlnincJ with chickcn scrum. For practical rraanna, hoaat acrurn is tuitcd he.t nt nrlrlirive tt, mttrient mrdiurn fnr fn virr.r cultures r~f ral'hn.' c ardirrvnscular cellt ~!)thrr Rrnnlor: National I Icsr1 Inttitute 45 •14

11 I t I "('IR( III.AIORY F-.FFF(-1S OF 1'IP[: ANf) CIGAR SM()KIN(7." Ily 1)avrd I Simctn, M f)., and Arnrtld IFliuer, M 1)., (lnivertity rtf ( incinn:rli ('tdfcRt• rd Mctlicinc, ('incinnati, (/. .lrrrrrirnn Irnnnnf rrf Mrdrrrrf Srrrnrr•.t• Vtrl. 241. riFet 22-10, January 1961. (T.1 R.('. Rranlce: Simnnl f'rrrfrnr .,/ .nrrfy: Much attention has been dcvotcd trl the cfTcct rr( tmnkinp cifarcttct,t on tht circulation hut relatively little infrorm:rtir+n h:rt been avaiLrlde rm the circulatory action nf pipe and cig:tr tnurking. Iltcrc- (t+re, it wat rtccidcd to gather data on the circulatt.ry ch:rnFrt cau.cd hy tmerking reFular commercial and low nicotinc ciFirt and pipe Irthicrn and to compare thc resullt with other studies on cigarctte stnuking autl chewing tobacco. Pr..rrdnrr.: A Rrctup of 25 hahitual male tmokcrs ranfing from 21 to 69 yeart in aRe, r.f whnm 15 smnked cigars and 10 tmuked fipct, were ttudicd dnrinR rcfular and sham smoking periods under identical ctmdrlit,nt. HalhttrK irrlirtframt, hhxxl pretture, pulte rates and skin tt•rnpcraturct were sludicd during and after the tmoking reriods FindinR.: Ilre usual tllcctt nr ttthacco tmokinR nn the cirtnl:ttirtn were (t+und (drrtp in tkin Iempcrnhtre, increase in pulte and hhHM1 prctanc), bnt were not at ntarketl at thntc utually found following ciF:trclte trnr+king or hohacco chcwinR 7he incidence r~f changet in the hallittritcardioframt wat Ictt than rhat h,und following chcwinR k+hiccn, hut Rreatcr th:,n that frunnd frdlnwinR ciparcrte tmhking. ('ircuhtnry chinFct were tliRhtly Ictt GdlnwinF low nicvtine ciFars and pipct when cr,m(.ated ht ttanrlard ciFart and fil.ct Sham tmrrkinp- did not Fnxluce circulatory chanpet. "IIIE ( IR(-ItLA1ORY RFSf'ONSI:'fOSMl)KIN(7: 1111? I7I t 117 OF SMAI 1. 1)OSI SOF lIt:XA(•11.1(IC)N1UM ANI) (fl MI I'111.N11:Fi- MINIiON llft PA'I TIiRNOF R!'.SI'ONSI: _"Ily(arrdinc I1cdcIl Ihrtmat. M 1)., and f:dmand A Murphy, M 1) , hcpirtrncnt if Mc(licinc• )trlrnt f Ir+pkins I lnivcrtity Schtol of Medicine, Italtimrtrr, Md lrnrrnrrf n/ l hr.mk- Ihrrotrr, V<rl. 12, pages S14-S41, Nnvemher 1960. (1 I R('. grantec: l hinmas ) Purpn.r of .rurfy: f)urinR a standard hallitlc.cardingraphic smoking tett amnng healthy yttunR adults, tnnic tuhjectt shnwcd hyperreactivity rtf hhwal prettnre, hcart rate, or cardiac r+ulput in variout crtmhinatirrnt, while rrthcrt with timilar tmnkinR hahilt thowcd littlc change or even a negative rctf".n.c In nrder to invcttiRatc further these individual difTerencet, it secmed worth while In allemht tn change the rrtrontc to smoking by mtwlifyinK the Fhy.irr tr pic ame of the subjects with difTercnt pharmacningic orhtt:rncct I'rnrr.(rrrr.: Ohtcrvntiont were made on the circulatnry rctpnnte tu smrrkinp a tinOle ciRarette frdlnwinR amall &ut Ilf hrRantr/hllnlllnl, r/t mcirlrrntermint, nt nf place)Nf (itrrtnnic trxlium chhuiJc trrlutittn), arl miniNCrcd f+y intravennut injcctirtn. '1 hetc tuhtt:rncct wrre Ovcn in ranrhnn tudcr in a tcrirt of te(taralt rhtuhlc hlind rttrt Sr•vcn hroltlry whrlc mnle tnhjrttt Icnl A tettt apiece r+n dillercnt tlavt, 1 with rarh r,f the nclivt• Llr.rrnrarrl"pitnl t'rrl'arnlinnt "nrl 2 wilfh thc ItLtrrhrt 1hc nmr w:rt Irr Irrtr rlurr nunr+rnel nrr~turahlc ctlrctt. Sinct tt•n%ilivily v;trrrt frrnn .ul.lctl Irr .ul jrtt, tTrr at~l ny,ri~lr Arr.c h:ul trt hc fr,nnJ hy cc(xrifncnt Fin lir.R.7 Aftrr injcctiun nt Ihc pI:tct•Lrr, tlrc :rvcraFe circnl:ttrav rco~(amtc 4(, to smoking one cigarelte was similar to that in a larger series previttutly reported in which no injection was given. From the duplicate placebo tettt an ettimate nf nce averaRe variability of these tests could he madc. llexamethnnium did not influence the mean resp~nte to tnrnkinP to far as could he judged by a paired comParison with thc placcho tests. 1 he heart rate was furthcr (though nrN srgmficantly) increated, and this might have been expected since both heRamethonium and smoking independently tend to increate the heart rate. When the nxphentermine sulfate and placch) tetts were cnmpared, however, both the change in systolic pressure and in cardiac twrput after smokin6 were significantly altered by mcphentermine. lhe other variables were not thus affected. llu constancy within the in- dividual of the meaturements obtained after a cigarette Is smoked, previously reported as the "ceiling phencxnenon,'• is im(+aired but not entirely ab- olished by small dotcs of these druRs. In this respect the "ceiling phe- nomenon" retemhles a cardiovascular homeostatic mechanitm. In conclusinn it appears that this experimental approach revtals in- div(dual diRcrences in ht~meostasis, but that these changes are not readily g wped. At present the results seem too various and tcx, complex to permit simple clastificalinn of subjects whkh could be used for screening purfxnes. nrl4rr Rrnntor: Veterans Administratitxr. "PATtI()IiFNETI(' INTFRRF:LATIONS IN IIYPFRTENSInN AND ('URONARY AR7 FRY f)ISEASf:." fly carnlinc pedcll '1 humas, M I) , Johns flopkins University School of fWcdicine, Raltimore. Md. l)irrotrt of the Nrrvuut Svrrrnr, Vol. 22, pages 39-4S. April 1961. Purl.o.e of .turfy: In a long-term prospective investiRatinn of the pre- curtors of hypertension and coronary ditease, studies are being made ttl the occurrence, nanrre and interrelationship of certain genNic, phytiulrtFital, metabolic and psychological characleristks in healthy lttluns Ifrqpkint medical studentt. 'f hey are being followed over the years to delermine which factors or constcllations of facants are most frequently atsuciatcd with rhe early nntct nf dittatc. It is the author's hypothesis that multiple faclnrs play a determining rt+le in the etiology of these disorders. lhe exact furm of disease and age of onttt in a given individual is thought to depend on the nature and mnnber of factors in his own genetic inheritance in cnmhinalirrn with the particular environmental stresses encountered as he goes through life. Pro~.dn..r: lhe characteristks of 2 e.trcme Rroups ttf ttudenrt were examined - Ihnte with 2 definitely aflected parents and Ihttte w'IMrtt parentt are both free frnm hypettension, coronary diteatc, ohc•tily and diahetet. AmonM 741 white male medical studenta observed in the lir.t 12 clittet ttndicd. 13 gave a hittory of hypettentian in both parentt, I I had a fnthcr with cnronary Jiteate and a mother with hy/xrtentittn, nnrl 1 re/antrd that hMh patemt had cnrnnarr ditcate. Aflrr rieltrrnininR thal Ihr Uai1t undcr tt'tutiny were amilarly drttrihuted in thttt 1 tmall pttuln• fhe .turly wat et.tcnrtrd tn Ihr nunternut facUin diflcrenti.ling 1ht-m Irtnn rhr "nrrrrnal" rrrrult FrndinR.: Ihe t4lthring rtf 2 partntt nRected with hyfx•rtcntirrn anrlrtrr currrn:try diteatc arc tiFnficantly dilferent in a numlx•r trl wavt trrrnr the 47

nRapring of 2 unaRected parents On the average, they are I(1 p<,nndt heavier, mnre frequently h:rve hyf.crchnlettcrcmia, have hil-hcr reslinR aythrlic hlrtiKl pressure levclt, and arc more likely to hc anurk<•ra '1 lie nll- sfrinP nf 2 nhecc parents arc dislinRnished for thcir own cxccc.ivc wcifhl and also have hir.her chnlesterol levctc. 'Ihe hmad implications of theac studies are that the ofTtfrinF of dif- fcrent kinds of human matinRs have significantly ditfcrcnl phyaioloPical, rnetit>„lic anrl rsychnloFical characteristics, that the differencec uarally are not Frcat, hut ti,at they are compatible with the hypothesis of multifaclnrial inheritance. Alto, the ability to predict high susccplihility tt+ hypcrlcnsion and/or cnronary artery disease in a given individual may well dcrcnJ upon the idcntification and appraisal of a constellatinn of factors rather than upon an sinRle characteristic. When the prehypcrlentive or prccnronary indi- v ual can he idenlified wilh prccision, the proapccts for the prevcntion tit ese ditorders will he bright. rh.. Rrnnrnr,: ll. S. Public Ffealth Service and Veterans Admin- istratinns "('ARf)IOVAS('l1l.AR INTERA("TION Of: NI(Y)11Nf?, I:R(;ONO- VINF, ANl) IIYPF.RCFfOL.f;S1t~.ROL.f:MIA IN 1111: RAllllll." Ily 1)uane G Wenrel, Ph.f)., James A. lurner, M I), Scoll W. lordin, M I), antl lashir Singh. M S, l)niversit nf Kansas, l awrence and Kantat ('ity, Kan ('irrerlnrinn Rrsro.rh, Vol. ;, pagcs 694-C,99, May 1961. ( 1 I R('. grantee: Wcnrel) I'urpn.r• n/ .turly: It is important to delermine possible cautes for the ohacrved interaction of nicolmc and a hvrcrchr,lcverolcmic <licl in fu,th the ntyrxardial and the rcripheril vascular clJccts encounlcrcd in rabbit cxperiments. rrnrr.frrrr: An inilial expcrimcnt employed 4 prc,ups of 12 fcmale alhino New 7ealand rahhits: an untrcatcd control Rrr,up; rahhils receiving 1.14 mR/Kg./day of nicotine in drinking water; rahbitt rcccivinF I percent cholestcrol and 5 percent cutt<,nsccd oil in the dict; aml a Irwrth grnup receivin6 nicnline and the choletternl-cottanseed addifivcs Various circula- tory antl vascular readinRs were taken at intervals and compared to pre- treatment levels. After 24 weeks the animals were s.icrificcd and the hcarts and femoral artcries were examined Ilecause of the lack of nt:ukcd micro- pathological changcs in the cholesterol and nicrninacholcstcrrd hearts, addi- lionaf grnupt of rahbits werc tested with errnnovine injected hecausc of itt vahrc in demnnttrating alterations in the electro cartliogram indicative of cnronary disease. FinrfinR.: '1 hroughout the rnttrsc nf the initial cxl.erimcnt, the f+cripheral circulatinn was tlcpressed, the sqstnlic prctanrc clev:rtcd, and the coaRula- lir,n ratc srrede<I f'eriphcral pathol<,fic changcs were minimal, and arcat of cardiac nrt'rocis ohservctl in a similar prcvious ttudy were aharnl In order Irr drlcrmine the c>,ute tit Ihis appnrent discrepancy, n tcnnd Rrnnp ut rab,6la was airnrlarly Ireatcd except Ihat err<,novine wat aMlr<I I<r lhc t1ie1. lhc 74 wrrk hialydr,~ical ettanrinat{un Ihit titne rcvr,lcrl carrtinr nccrmlN in I ~nimalt rr, rivir,R the cr+mt,inrd ni<ntine t hrrltatrrrdrrr.r,nuvim• Irr.ImrrH lua r/lrr t Ihn"l n.rl f.rrn al.Ininrrl wilh rl,hrr rnicr,tlnr <n r M~fr.rrrnl r,r will~ r~ ni< rmr anl thwlraterul trrRcthrr. c11' rOrh f I' f ~ h K ~ ~ r Rrnn rrn nrvcrarty o :,nt:,s (icncril Rcscarch hund . IV. ('avcho-I'hyrioloRicel Sttldietr "('ONSTITI/TION ANf) SMOKINC." ffy Albert namon, M f)., Ph I)., Ikparlment of Fipidemiology, Ilarvard School of Public Ncalth, Boston. Srirnrr, pages 339-341. Aug. 4, 1961. rurfrna. n/ .rndy: lhe detection of dcterminants of tobacco smoking would help in undcrstanding and possibly preventing diseases said to be associated with smoking. Since the use of tobacco may vary from one cnlttrral grmrp tn anothcr, it was considered desirable lo study suhjects with a common culture and a similar biological background, and who thus con- stitute a relatively homogeneous group. rrnralur.: Snch a group has been under investigation since 1956. In I95R it comprised 167 male factory workers whose parents were born within 75 miles of Naples, Italy. Of the workers, 151 were taan and raised near Ilostnn. Mass., and the other 16 near Naples. 7 corning to the I1 S. heforr the age of 11) and 9 when they were 10 or older. Smoking hihils were ; gratkd in 5 categories: never smoked, rare or occasional smokers, mtxlcrate smokers, heavy smokcrs, and ver~ heavy smokers: more than 30 cigarettes or 11) cigars or pipes daily. Standard techniques were followed for anthro- pometry, for somatotyping, and for serum cholesterol and hhxal pressure dctermrnalions. Uictary dita were obtained through a 45-minute interview, e1c., and activity was graded in 5 categories based on estimatcd c><crlinn both on and on the job. FinrfinRa: The results show a consistent and statistically significant tendency for Iean men to smoke more than slnut or fal (but not nrotcular) men. This ass(xiation was not the result of diRercnt dicts, since smukinr, and caloric intake as well ns intake of component foats were indcpendent tit each other. 1 he presenl findin(Cs confirm reports by othcrs tit slightly hiRhcr serum choleslernl among smt.kers. Contrary to previnus finrfinrs, sm<,kers in this series were no less masculine in physique, were no more active, and cnnsumed no more alcohol than non'smukers. "SOME HARVARI) MEN AND Tftf SMOKING IIAIIIT." Ity ('arl ('. Selber, Ph.l) , Peabody Museum. Ilarvard llniveraity, ('an,hridgc, Mats Flomnrrl.lbinrni Rrnllrtin, Feb. 4, 1961. As part of a mnre intensive study of related biolt,gical faclors in tobacco smukinr. by Harvard men, a survey was madc of the smnkinR habits uf the class of 1946 through questionnnire, to which V27, or R1.4 I,crccnl n/ Ihe members, responded. Twcnly-five percent were classitied as ntrn- trnokcrs, compared to I R prrcent in the ll. S. ptrptulatiun; 59 Ixrcent were current reRulnr sm<~kers; and 16 percent were (ormer reRulnr vnrrkcrs wM, diacrrntinucd lfre hahil for various rcaaons, atw,ut thc snmc as thc n:Hirm,tl avrrnge. Whrle IR Irrrrrnl tit lhr rt'/ular atmrkrra In Ihr I1. S alartcJ smrrkinr. Irchne thefr slelrrnth hitthdny, <.nly 3 Irertent td thc Il:vvnr<I rncn .1.ntrrl ao early. lhc avcraFe amakinR histary tit cturcnl smnkcrs was I S 6 yr:,rs, while lhe average duration of smokinR for the e><-sm<,kers w;n I I 4 yc:rrs, 49

suFgeatinF that the period 1954-55 was 1he lime in whith m:cny amnkcrs "hrc+kc file I+ahit." Aniong currcnt smokcrs, 60 2 percent .mtAc cigarrttcs c,nly. 12 rer- cent cigircttes and Pif,e, 5 9 percent tir:rrclles and cigars, and 2 R percent all three tnhaccn fnrmc; 9.4 percent cmoke pipe only, S v percent cigirs nnly, and 1,9 percent cigars anrl pipe f'or the U. S, cigarcttc only arnnkers ct+mprise 76.3 percent of all smokcrs and contbined cigarcttcs and other fnrms of smoking total 94 percent. "f7he f larvard mcn are also heavicr smokers than the national average: 9 percent of Ihe cigarette smokcrs consume over 2 pscka tlaily, against .l percent for the U. S.: 46 percent cnnaume between I and 2 packs daily, sgainsl 27 percent for the U. S. The Harvnrd smokers tend to be found more frequently in the field of husiness conlacls and administratinn, editnrs, educators, and museum curatnrs, etc., whcreas there are proportionally more nnmsmr.kers among cnpinecrs, angcnns, clerRymen, teachers, and lihrarians 'Ihe pil,c smc,kcrs are mnrc frcqucnlly found amnng research Scientials, culunal aclminislra- tors, lawyers, cnllege professors, and achtx•l tc.chers. V. Tnhnrr`irl ('hPnhary and lliochemiary "(l1OSYNTIIf'SIS OF ANARASINF AND OF NI('(1TINF 1)Y FiX- ( ISF1) R(X)1 ('t11.TlIRfS OF NI('OT IANA Gt-Att('A " Ity Marie 1.. Solt, R. F. Uawson, and I) R('hristman, I)cpartmcnl nf llc,tany, ('c+lum- hia llnivcrsity, Ncw Yr+rk, N Y ancl Ilr(w+kh.+vcn Natn,n.rl I ihrn;+tc+ry, Ilptnn, N. Y I'Innr !'hvtinL.Rv, Vc+l 15, f.,rRra NR1 R').f, Nnvrn+l.rr 1966 (I .I.R.C. granleer haws(,n I "TIIE IlT(1SYNT111?SIS OF NI('OIINfi I R(lM NI(Y111NI(' A( II) CIIfiM1('Al- ANI) RAI)I(X'IIFMI('nl. YI1 I US" Ity R. I I)iwacm, 1). R. Christntan, M. 1-. So11, and A. P. Wolf, hertartnient o( Ilc+tany, ('rJomhia l)niversity, New Ynrk, N. Y., and Flrt.nkhaven National l-ahotatnry, tlptnn, N. Y. Archives of Rinchrmisrry and lliophysirs. Vol. 91, paRcs 144-I5(1. November 1960. "IIIOSYNTIIESIS OF TTIF- NICOTIANA AI.KALOIf)S." Ily R. F. Dawson, tkparlment of ltntany, ('nlumhia 1lniversity, New Ynrk, N, Y. .Irnrriran Scirnricr, Vol. 4R, pages J21-.14(1. Sc~ teml.cr I`/h(/. Isntt+pic Iraccrs applied to the study of tnf,accn alkatoicl hic+synthesis have rcvealed that nicotinic acid is a common prccursor of nicotine antl anahasine Nicr,tinic acid contributee the f+yriJine ring tc+ eath alkale+icl, while ornithine and lysine contribute the f+yrrnlidine ancl pil,crictine rinFs, respectively Nicn/inic acid is prnhahly tedured 1-f+ prinr to ct+nchininp with the prccursnrs r+f file pyrrnlidine and pipcridine mrr•itics l hia crmt Iu.u+n Is suf,/N+rtrd hy file fact that hydrngen isnlnlx lalK-1 t+n file I,yriJcnr rlnF r+f nicr+linir nricl ia Lramfttred /n tilh U+ the Pyrichnr +inr. nt nit nUnc frr,m nll I, aiu na r+n file Iivridine ting ewerid numt,rr !, file rrcecnrrncr rd file l"nnct.+tecl 1.6 clrhvclrn intennrclinte hclps tn exl,lain the c+therwiae chcm- uiIly I-flc, nLt clral,l.cc rmenl r,t the canc,,syl rrrml+ ccf nit'crtine ncict I here is nr, indicntirm in these cxf,erimenls of the nature of the circumslances which cr+mf.cl the plant tci synthccire apparently terminal prcKlucls frc+m .uch mc1alK+Iically uccful inlerrncdiatcs. One nf Ihc impressivc aslxcts of alkaloid biosynthesis by the cnciaed root cultures nf N. ruhnrrr.n and N. Rlauro is Ihe e>ttraordinary rate atahiGly of the Proccss. In our cxrericnce, alkaloid production rate is a clnna) (i e. inherited) character and is not subject to ready mtxlification by the usual comlumcnts of ro+t culture cnvironmcnt. Of particular interest in this cr+n- neclinn is the f:rihrre of added precursors such as nicotine acid, either alone or with lysine or with ornithinc, to increase significantly the yields of anaha- sine or of nicotine. The hiosynthetic apparalus for nicotine and for anahasine are con- sidercd to he scparated into two distinct compartments in the c.ciscd rr>,+t, namely the growing root li~ and the matured root axis. Ifowever, the prr+h- Icm of explaininR ratc ctnhility within compartments still remains. At prescnt, i srems well to adnfd as a working hypothesis the prosF+cct of a common alc-limiling atcp for both growth and nicotine production. !)rb.r R.~nf..r.: I lniversity of Missouri, Princeton University, Cr+lumhia llnivcrsity, Rockefeller Foundation, U. S. Atomic Energy Commissitm, and rl he American Tnbacco Company. "llTTi GIIIf1FRT?I.1-TC ACID INNIf11TION OF NICOTINE IiIOSYN- TTff:SIS." Ily M. L. Srrlt, R. F. Dawson, and D. Ft. Christman, fkp:trlmcnl of Tiotany, ('olumhin l)niversily, New Ynrk, N. Y., and Iirtx.khaven Na- lional lahoralory, Ilpton, N. Y. Toborcn, Scirncr, Vol. 5, Pages 95-9R, Sept. R, 1961. rurp.+.r ol .rurly: F. V. Parups (1959-1960j has shown Ihal the re- dnced nicotine content of tobacco plants treated with Eihherellic acid is duc to a reduced rate nf aynthcsis and not to an accelerated destruclir+n r+f nicotine in the plant ht+tly. Tbe authors have shown that the bitnynlhcais of nicntimt pnssesscs not only suhstantial rate stability hu! alsrs a rate de- f+endency on growth II would he e>sperimentally advanlageous if Fihherellic acid were ellective in altering these rate relationships. rrr.rirdrrrr.: C:><ciaed root cullures af Nirnlinne taAocam l.. var. Turkish were treated wilh Fihherellic ncid, and labeled nicotine precnrsnrs, nicrainic acid nnd ornithine, were added to the eullures. After harvesting, M+th Ihc dried root lissue :rnd the cr+neenrrn/ed sfxnt culture solution were celraclrrl, and the nicotine sn obtained was assayed for radivcativity by slanclarrl prt.ccdures. FinrfJnK.: Atlclitir+n nf Rihhcrcllic ocid tn the culture mcdiurn 2'1 days f+cft+rc harved forcalnced a marked reduction of nicotine outrut. tl+e rnasi- mum effcct r+f ahcnrl SI/ t+crcent txinR obtained at a concentration r+f I Iq+m Fihl+ercllic nciA tiinnl:+r ellet'ts were nhtained by addinP file equiv,rlcnt nl 'i I'Inn at ryth uf .cvcral five day Intervnla durinR the cutture paa•:t{'c I trc Inc.ence n/ grhhrrrltic ncld was nol aasc-claled whh nn nrerletnterl rntc t+/ clratrut tinn c+f nclJr,l Ial+rlyd rucrdinc Whcn Inheled nict+tinic nc rJ c+r Lrhrlrcl rnnitltine waa .ulrlrhrct Icr the c crllures with and wilhr+ol `ihherclhc nrid, the rcaults were qu:rlchvrly Ihr aame: nit'ntine yicld waa nRain rc+tuceJ nl+ 1" Stt fx-tccnl hy Fil,bctcllic acid, hut Ihe rcduclinn in yield rwcurred I:urcly at thc 5I S/1

n ..4 N s'0, .z z tt, tn 0 0 m .~ ~ c><pcn.e of endt,gcnnus precursors. T hese results show lhat thr inhihihrry litm trf gibberellic acid on nicotine hiosynthesis very fikcly tucur~ :u three rlTcrcnt points in the nretaholic sequence. nrlrrr Rrnnrr.r: U. S. Atomic Energy Commission. "1)EffiRMINATION nF' ARSENIC IN FLf)fi-CURfI) -TOf1AC(•O ANI) IN SOII.S " Fly H. G. Small Jr. and C. B. Mc('ants, I)cpartntcnt or Soils, North ('andina Agricultural Experiment Station, Ralcip.h. .Srnf 1t irnr r .Sr>rirry of Arnrrito I'rocrrdingt. Vol. 25, pages 34f.-34N, Septen+l.cr- Octnf.er 1961 ( f.l R.C. grantee: McCants) Proc-cdures are described for the semimicro anafysia for arsenic in flue-curcd tobacco and in soils. The plant material is JiRectcJ with a mi><ture of nitric, sulfuric and perchforic acids and thc soil with sulfuric and per- chluric acids. Ar,%enic is distilled directly from the diReatinn flask, absorbed in an irxtine st,lutinn and determined colorimetrically by the mnylhJCnum- hlue nrctht>'t1 Thc dita show that Fmd recovery of arsenic and repntitucihility nf rciulti were rrhtiincd, f hc scid JiRettion method fnr plant malcrial oave rcculti tlnarly cttmrsirahlc to those ohlaincd by n>tidition in an (t4yRcn Mtmt, Thc eviJcnce from anils indicates that the digestion and tlntillatinn rin,cedure employed removed suhEtantially all of the arcenic. Ihc cvidrncr presented sugpccta 9uite strt.nRly that with wet JiFcclinn prnccdnrr•s, reculta can he obtained Ihat arc e(uilly at rcliahlc as thtne frnm the fwmh combustion method 'TTAMMAI.IAN UF?GRAf)Al lON OF (-) NI( OTINfi "TO 3 PYRII)Y1.- A('E=.TI(' A('IE) ANI) OIIIf:R (-f)MPOE1Nf)S, by flencert McKcnnis !r , FdwarJ R. flnwman, and I.enno[ Il lurnhull, Tkrinrrmrnl t+f f`hirm:rc- oh+gy, Mcdical (•ollcgc of Virginia. Richmond I'nNrrrlMRr, SfMtrtl• for li+- prrir»rnlOl Rtnh,gv and Mrdrrinr, Vnl 107, paRcs 145 14R, May 1961. ( f.1.R C. grantce: McKennis) Purpo.r of .rurlv: Research by the authors end olhcrt hac led to the identification of a wider complexity in the metaholitrn of nicntinc than was estimated only three years before. It wat decided tti invrstigatr furthcr the metabolism of randomly labeled (-)-nicotine Ct' in nrdcr to aucrtain thc sequence of inelaholic reactions. Prcx.durr: Randomly-lahekd (-)-nicotine-('r' was administered intra- vcnrwsly to Iwo mongrel doRs over an R-hour period at a dntaRe of 4.25 mg /kR. Urine was collected from the bladder by an indwcllinR cathclhcr durinR infusion and a suhseyurnt 19-hnur )+eriotl Radioactive dclcrmina- titms were made and ehmmahyramt preparrJ In a ctmtpanirrn study (-) cotininc was administered t+rally tn a,hird doR. FlnrNnR.: I Thc pattern of winary e><ereticm of ('r' in thr dog following intravcnttut adminisltatirrn of (-) nictHine (-" was c>tnmincd chrruualtr- Era)dtically hy imhrtwed (mxedtues 2 lhe frsclitmatcd urinr .hrr.vcd ('t' nctrvity cnrrc.{%,ntlinR chrnmatttRraphically In /Fhc knrrwn mctahrdttrt cr'tininr, r:vnma ( I hyridyf )-Fnmms mcthylaminrrhntyrit at irl, rlr•.rnNhyl t ntnrrnr hvJn..vt ~~rrnrnr, >,ml r.mrma ( I ryririvl/ hct:t .ar N nrrtlrylhulyr .rn.~J, 1 n,,,,.,,y ,,,.un urv. l.nt~lir~1 re~lr~..rt/r.r r.,rnlu.nrnt. thc vrurr crrn. „.t , n ~ rI•.I . .. I..,•.1,"r, 111 r0~1.rt rlrt :It irI . 4. Following nral administration of (-)tolinine, 3-pyridylacetic acid was istdatcJ from urine and ch:aacterized by analysis, melting puint, miued rnclt- tng Munt and a,. its picric acid salt. 5. A precursor of 3-pyridylacetic acid is rn formal grttunds gamr»a-( 3-pyriJyl -(xlu-osyhutyric aciJ, dcrivahlc /r the known nulahulite gamma-(3-pyridyl)-hcla-ottt-N mcthyl rtyramide. Irh.r Rrnnrnr: The American Tobacco Company. "1)EMET-IIYI.ATION IN TI-IE METADOLISM OF (-)-NICOlINE IN VIVO." fly Ilerf.crt McKennis, Jr.. Einosuke Wada, Edward R. Itowman and 1"ennnR 13. l urnbull. Ihpartment of Pharmacology, Medical C'oltege uf Virginia, Richmond Narerr, pages 910-911. June 3. 1961. Prnrpn.e of atrr.fr: niccrepancies esisled among previous sludies of the PhysitdnRical disposition of nicotine randomly labeled with carfon-14 Scv- cral workcrs found no radioactive carbon dioxide in eRpireJ air of mice artJ dogs aftcr intravenous administration of the labeled nicotine, contrary rn rrcvir+na work by the Virginia scientists which indicated that mctahtdicm nl nicruine involves Jrgradation to single-carExyn metaholites. "Co rccadvc the apparent conlradichun, labelled nicotine containing a high level of activity in the methyl group was employed. ' I'rr.r.dur.: Male albino rats received intraperitoneally a synlhesinJ nicotinc-methyl-('" and expired carbon dioside wa% collected in srrJium hydroaidc traps and Ihen precipitated as barium carMynate. FlnrfinRr: f)urinF the first 6-hour period after administration or the nicu- Iine, the respiratory carExrn dioxide from 3 rats contained an at•cragc trt 5 7 percent of the administered radiuactivity, with individu:d value,% 7.5, 41/ and 5.6 percent. Further elimination in a suhseyuent IR-haur period gave cumulative valucs of 12.R, 6.2 and R.4 percent of the administered dnae. In addilit+n, a small hut significant amount of carhon-14 activity was present as urea in the individual 24-hour urines, as determined front carbon ditr.ide evolved by urca--e. Since Ihe radioactivity of ranJtxnly labeled nicolinc-(-" is c><crctcd tn the catcnt of 94 percent in the urine of rats, the addition of carhon-14 dcternrincJ by carhon dioaidc in these studies Rives a total clim- inalic+n appmachinR 10t1 percent. This provides convincing evidence that, after sinelc Jtncs, .toraEt of nicotine or its metaholitcs (ccurs tt) only an c< mcly limited ct<Icnt. The resuhs point to the importance rtf sinFle- rhon comfxrands in Ihe metahnliam of nicotine in the rat. I)rh.r Rrnnror: 1 hc American Tobacco Company. "NOR('OTININIi (hl?SMfiTNY1,COTINtNfi) AS A URINARY M1:fA11OI.IIE? OF N(1RNICOTINF.." Ry fiinosuke Wady, I:dwarJ R Ilrtwman, I.ennuot It 'lurnhull, and Ilerhert McKennia, /r , I)er:utmcnt tr/ I'harmacrdt+Ry. Mcdit'cd l'n11cRe ttl VirRinia, Richmond Inurnul rrl Af.drr rnnl rrnd 1'rnrrrnnrr.ntrrl l hrrrrivey. Vol. 4, paKef 21-3t), luly ('lr.I I rJhrwurR intr.tvrnuua ndmin{stralitrn or (-) mornicutinr, Ifte drrR c- trNc% in rhe urinc n voricty rrf KncniR Lrr+ilive cumlHrundt A thlrnrdrrrm r.trutt of Ihr :rlkaliniicd urinc crrntuinrd nrucotinmr, nrnnrtutrnr, :tntl trthcr crvttfrrrncnta Ihc ayuctrua ph:r.e rem:tininK frnnr ncc chl rrrdurm rR Iract t'uN:uncJ R,mma-( If pyrithl)-Rarmna aminuhutyric :rcirt, whrt It wat Iaclami~cJ ttr (-) nnrttrtininc (2-0 ryrithl) PYrnrhthrnc 5) IZctlutUrro trl Sl

a• tn .• rJ f> rn cn Ir nptically nctive nnrcntininc with Iithiurn aluminum hydride rctnllc(t in Ille fnrmali„n (d a miRlure fit nplicilly aclive and rq.tic:rlly in;lc/ivc n,nnicr,tine "lIll: nI1SORf•T-ION O1: NI('O11N1: 1•ROM Itlt: ItRINARY Itt.nl)- h1 R(/ 11I1? I)O(i." fly )Incptt F. li(Irzcllcca, t)cp:lrlnlenl c,f Ph;lrma- cnt/,Fy, Mcdical ('(,Ilepe of Virpinia. Richmnnd, .Irrfrirct Inrrrnarrnnrrlrt Ar !'lrn.rrrorndt•nn.nir• Vol. I1), papes 444-451, Oct I(16I. (1 I R C'. pranlcc: Ikrhert McKcnnis Jr, Mcdical C(Illcp,c nf Virpinia) rarf.n.r of Nr..ly: There is an apparent incnncistcncy in Ihe findinpt of tcvcral authnrt as to the rclalive excreli(rrt and ahsorptirm (,f nicntine, reportcd in Iahnralnry sludies with dogs and catc, which rcquiret resnlu- tirln. Since bladder reabsorption of nicotine might have a I,carinp nn the Ioxicolnpical cflccls of nicotine and other suhstances it was decided to re- investipatc the ahsnrption of nicotine from the bladder of the dnp. Prn.•rrfurr.: Adult mongrel dogs of both uxes were ancslhctizcd and carotid hlrro(1 pressure, retpirolian, cleclrcrcardinprams, anJ urine (wtflow were recorded. 1 he bladder was drained and clcansed t+y a cithetcr, through which stdulinns were instillcd nr oulfbw during /xrfusinn cxcurted. After apprnrriate intravennus test dosct to dctermine the reqxmtivencss (if the animals, a 20 mp/mi solnlion (if nicotine in an apprupriatc bufler was pcrfuscd thruuph the bladder mt a rate of 1.1 ml/minule. lhe p!1 of the pcrfusinp fluid from the bladder did not change more than O 2 pll unit during the exrerimenlal period. F7n.linRa: lhc aha.rption of nicoline from the hlidders of Ihe ck,ps was dcmonstrated "1 here was no significant difTerencc between the cexes lhe hysinlnpical chinRes taken as an indication of nicotine ahsorrlion were hanpes in hhwxl pretwre, respirarl.n, and urinary rwtll(/w Within the It ranpe invcstipated the rate of ahsnrpli(in appeared to he dcpcndenl upon Ihe pFt fit the nicotine snlutinn. (lth.r Rrnntorr: I1 S. Public flcalth Service and The American Tobacco Company. "TIIE DACTIiRIAL OXIDATION OF NI('OTINE. IV. T1IF. ISn1.A- TION ANf) If)FNTIFI(-ATION OF 2,6-1)IIIY1)ROXY-N MFiI11Y1-- MYOSMINF:." and "V. IhFiNTIFICATION OF 2,6-1)IF11'1)ROXY- F'Sl:UU())XYNI('OTINE AS T11E TIIIRU OXIhA'1IVE PROt)l1CT." Ily S Ft Richardaon and Sydney C. RitlenhcrR, Deparlment nf hactcrinlnpy, llniversity of Southern Calif(.rnia, L(rs Anpelcs. Jnurnnf.r( ffinlllprnl ( hrrn- irrrv• Vnl. 21b• papes 959-964 and 9(,4•9(,7. March 1961. ( 1 I R('. p.anrcc' Rittcnberp). Pnrporr of .rur(r: Prevican studics in this strict have ettahlishcd 6- hydrnxynicntine :+nd 6-hydror<yptcud(w)xynicotine at the firo and sccl,nd nxid,tivc prr,ductt of nicotine metaFwditm by a tllil h:lclerium '1 hrsc snrdict were undert:lkcn tn clarify the .uhscquent rnclaMllic tran.furmatirms (,f nic(Hine and 1(, idcntify the third oxidative pnxluct 1'r..rrrfnrr.: '1 he t,xidation nf nic(rtine, (S-hydrnxynic(,tinc and h hy4rl/ty- p.curl,r,synicnlinr by apprnpriate enzyme flaclil,nc w;rt aturlicd man/. mrlri/ ally 1.10 ~Lr, Irr,(+hrdnm~tricnny. The (noolntt h,rmrrl by Ihr Ihrrr tw,l, 1,r /,r1r •Irl, 1,.1111t1/,n, rc~l,cftlvcly, nf thctr \I,h\trTtt•t W:IS •yr1111,'~I/(•11 rnwnlathc:,tlv :Inrl iv,litcd in cryttalint• fnnn 511 I Find7nRa: lhe isni,ted compound was identified as ?.h•dihydrnxy N• methylmy(,sminc nn the hasis of its chemical properliet and its clcmental analysic 11rc cnmpnund was not further metabolized and appcars In t.c a side prnducl nn the main pathway of nicotine degradation by the hactcrium enlployed. 1 he true third oxidative product was identified at 2,b-dthydr(.xy- pscudnoxynicotine which, in the presence of the proper enzyme fraclinn, is further metaMtliled; otherwise it is cnnverted non-oxidalively and nnn- ertzymalically to the metabolically inactive 2,6-dihydrnxy-N-nxlhylmyot- mine, the compound previously isolated. "PAPIiR C'IIROMAT(X;RAPIIIC DETERMINATION OF RItlIN IN lY)FtA('CO." fly C. 11. Yang. W. Chnrney, W. Dunlap, E. l.. Murphy. Y. Nakapawa, N. Scully, R. Walanahe and S. Wender, Chemistry Ikpartrncnt, University of ()klahoma. Norman, and Medical Research, Argonnc Natir.nal Lahoratory, Argonne, 111. ToAocco Scirncr, Vol. 4, paRes 23R-242, Dec. 21, 1960. (l'.I R('. Rrantce: Wender) Prncedures which use the aluminum chloride or boric acid cilric acid reaFents, hul dn not srparate the rutin from other ftavonul RIycnsi(Irs nr from chlarnRenic acid nnd related depsides or other ponihle interfering suhttanccs, may not bc accurate for quantitative analysis of rulin in many tobacco samples. Three chrnmatnRraphic methods develnpcd for dctennina- linn of the rulin in tobacco ate described in delail. Experintentt involving addilinn of known quantities of rutin to a tobacco extract before chrttmaln- raphy utually pave 95 percent or beller recovery of the added ruttn allcr itc atsape through the analytical procedure. nth.r Rrnnror: ll. S. Atomic Energy Commission. V1. nthPr SIfIdlell "SOME EVIDENCE FOR A MECHANICAI. RECI:PTOR IN ULTAC- TORY FUN('TION." fly Showa Ueki, Faculty of Medicinc, ltnivertity (.f Kyuthu, )apan, :ind Edward F. Domino. 1)cparlment of Ph:nmandnEy, llnivertity of Michigan. Ann Arbor. Juurnol n/ Nrrrrnphyvrd.rRv, Vol 24, pnpes 12-25, )anuary 1961. (T.I.R.('. grantee: Domino) Pnrp nsA of atudy: In certain fish the olfactory orpans are scncitivc uo mcc'1anical as wrll as chemical slimuli, whereas in mammals there ic an ah.cncc ot c(+nclucivic evidence for a mcchinical receptor in I/lfactnry flmc- lilm lhit sludy was Imdert:rkcn in an allcmpl to provide armc cvidcncc fnr such a hypothesis. 1'.n..rhe..: f lccurKlet wcre implanled surgically in anc%thctizcd dr,r. :Ind mnnkcyt in varil,uc nc(rcortical and rhincnccphalic clrncturrt intludinp the rdlactl,ry hnn,, amy}.dala, and hip(.(.canlpus. One nn,nth I.Itcr v;uusw, i•atct :Ind /"hnifer/,u. .ut..tances were applicd Ihrllu)th :r f•LnS cannula in .crtcd inl(+ tlle n/nc, and rlc•ctrical "hursl." in Ihe varillu% r/1L,cll,ry .uuc turct were rccr,rdrd F7nrlinpr: Wnvrs nf 711 fit 41/ C./acc. were tecnrdrd syrtchrlmnua wilh imltiraU„n in thr rnr,nkry and with insl,irntirln nnd c.l•ir:lunn rn Ant•a Ih,• pIrcnlnncna wcrc I,rclh,minantly ihtilalctal FIt•ttric'al aclrvity r/f annl.rr trc- qucncics c(luld Ix• chcitcd hy hlnwinp rlh+m :tir, varil,ua p,:rtcs ami s(,lullun. St

into thr nnatril It appeared that a mechanical cnrnl.rincnt wis invnlverl in thcke I+hrnnrncni Ihcrefnre studies in acutc drrRa Riven h.cal anc~lhcaia and Pl:rccd nn artificial re-tpirnlinn were undertaken lividence wic nhtaincd that in ahout ~11 f,ert•enl nf the dnRs electrical dkch1rRes were rccorrlcd in the rdfacHny hulh to rx)nr-frce owyRen, nitr<tgcn, anJ cirhnn durti<Ic, anJ were derendcnl ul.on the velocity of gas Oow. 'l he areas in the tdfactury hulh whcrc mcchanical reapnnccs wcre obtained werc re/ativcly few crrnt- Pnred Irr thrne arcas respondinR to odors. In all the animals studred thc elcctricil recrimaet to all odors including tobacco smrrke were enhanced with increasinR flows of o>tysen when the Ihrw (if the material wac kept cnn%tant. '1 hus the concentration of odor per unit volume (d paa was ac- tnally decreased at a timc when the olfactory bulh resfx)n%es were n+arkedly enhanced. It is concluded that preliminary evidence has been nhtained for the ccictence of a mechanical receptor in olfaclory functiun It ic hyfxahevrcd that one of the reasnns tobacco smoke ic so effectivr in zlimul,ting rrlf:rctrrry hulh diicharRe is Ihat its smnke parliclcs are vna/l ennurh Irr mrch:rnically as well as chcmicilly FK,mhard the nlfaclnry reccplnrs. "f_I fT'('1S (H' MF('AMYI AMINf; ON TIIF. (iOI.G.1 Rf?( IIRRFNT" (()I I.Al1:RA1--Rf?NSI(AW ('FI.1. SYNAF'SF. IN Tlfli Sf'INA1. (Y1R1) " Ily S tteki. U f~(yushu, JaPan, K. Kr+kctcu• I)cParnncnr of P~ychiatry, and Fi. Nh.minr Ihpirtmcnt (if T'harmacr+InRy, I Inivercity of Michir,n. Ann ArMir F.~}.r.Snrrnrnl NrurrrlnRv• Vr,l. 1, P,Fcs 141 14R, February 1961 rurroar of .rudv: The facl that mecamylamine is a secnndary amine with "nicrrtinic" blocking Prrrf.erlies cuRfected that it would act at the (inlRi recurrent cnllatcral Ren%haw_cell aynaPae in the ~tPinal cnrd 1 he exreriment was deiiRned to test Ihis hyPnthesis, rrnr.dr..r: Twenty-nne adult cats rrf both u>tcs were ancohctired, and the spina) cord was expnced surgically and prep,rcd for elrctric:rl --timula- tinn. A ~lass micrnpipette waa inlrrxluced inlo the Rcmhaw cell intcrncurnn ponl, and electrical activity of the cells was recorded All druFc were aJ- rninidered intrivennusly. Flnd/nR.: Antidromic stimulatinn nf the vcntral rrwits PnKluced eetra- cellular diccharRes of the Renchaw-eells for variable f+erirKk (if time. Minimal /n no -.pontaneous activity was recorded The Principal eRccl r+f mecamylamine was tn decrease the terminal diuh:trRes of the Rcndhaw cell to antidrnmic %timulatinn. Nrr elaborate stalittical analysis of the efTect% was undertaken. Not only enuld mecamylamine alrrnc reduce the :+rliv;ly (if Rt•mhaw cell% 11ra1 were fired anlidrrnnically. hul it would alar block the :+cthon r+f nicotine and phya.nli0mine Nicotine w:ra very eflective in aimul:rl inP Ren.haw cclll directly -The e(fectivenets rd tnecamyl:rrnine tn drfiress the (iolri crrll:rteral Renshaw eell synapse is adJrtinnal I+harm:rcrdr+ric:rl ~vidence that this is a"nicr+/inic"-type chr+linerp.ic --ynaf.e in the ccntr:rl ncrvrWt ayttern Ilrhrr R.nnnn t I S Puhlic l Irallh Srrvicc "< Ilnl+(ilNr ( ttN('FI'IS (11 lfll? ROI 1: (/f 1OISA( (<) IN 1111 KtANn( il MI N 1 r)1 UISFACI'. " Ily 1'.ru1 S I ar.rm, I'h I) . I f.rrvcy It I IaaR, M I) , and Ilerbert SilvNte, Ph.h., Medical College trf Virginia. Richrnrrnd. .1 nvricnn lnrrrnal of the Afedicof Scirncei, Vnl. 24(1, piRes 61 J- (,1t, November 1960. (T.I.R.C. grantee: HaaR) For almnm as hinR a-. people have been using tohaccn, writers have been apeculilinR nn its role in the genesis of disease. Fi>tcept fnr a few genuinely tnhaccrrFcnic diceases (of which the most uneyuivocal is tnhacco allerr(y), the etirdnRical role of tobacco is just as ohscure today as, say, a century ago; hut a curvey of a considerable tample of the clinical tobacco literature of the past 50 years has revealed a significant change in opinion regarding the place or tobacco in the management of certain dmeaces. 1 his latter is indepcAdent of speculation or opinion regarding tobacco etioloRy. T has, there is no perceptible agreement among clinicians concerning the role of tobacco in the etiology of thromboanRiitis oblilerans, bul there is unanimity that tobacco erscrts a harmful influence once the disease is eatah- liahed, and should therefore be strictly forbidden pNienls with Ihis condition l he preant paper is concerned only with lohacco-use in Ihe manaRe- mcnt nf certain discauc tobacco alkrRy, anRina, and amhlyn'.ia; c:rrdim vascular dicea%es; chronic btnnchilis, pulmonary emphysema, am) pulmonary luberculrrvis; and peptic ulcer. (l is empbasised Ihat, with the perhaps srdc exceplinns of tuhaccn :dlcrRies and nicotine hypenenciliveness, the ul.verved influence (if tobacco or tuhacco-smokinR on the course of any diseace af- fnrds no valid infurnialinn concerning its etinln~y. One may venlure N+ Rcneralire Ihal, where once snu.kin~ was calcRnncally furbidJcn in many in mcxkralinn by compe/ent nulhruilict diaeases, it is now permitted lbe main crrnclucions to be drawn from this survey are clcar enough In the caie of specific tnhaccc*enic diseases properly diaFno%ed, the canrr of the dise:rse, by dcfinition, tobacco, may be forbiddcn without dnuh(s and shnuld be prohibited withouteq uivncation. If one defines a nun-tuhuccrrRcnic diseasc as one which occurs indistinRuishahly in both tobacco uccrs anrl non- uaers, regardless of its respective incidence-rates, then it may F.e cuncludcd that there it nnlhinK better than abstention from tobacco, though sumetimes there nray hr somelhinR worse: emotional disturhances of rinc arnl ar another, or the auhstitution of an even less desirable habit (for e><anrple, nver ealinR ) fnr that (if nuderate tohacco-smnkinR. -1 he fairly recent realva tiun nf ph7tician~ that the °psychic" Rcnx1 effects rd tnhaccrr-amrrkinR rnipht rrulweiRh rti "snrn:rtic" harm, represents the "changing cuncefH" uf the titlc "SUMIi (: ' Ff F.(-FS OF NI(•OTINfi ANI) SMOKING ON MF I'AItOI.I(' Fl IN('"T IONS." fly P S I.arcon, Ph T) , II. 11- 11aaK, M.1) , arrd if tiilvcnc. Ph 1)., I)cPartment of PharmaenlnRy, Medical C'rdlrRe nf Virfini:r. Rich tnund ('hrriruf I'hnrnrnrrrlrrgv and 7hrrnprulic,t. Vrtl. 2. Ir:rFec RII.IIM!• January Fchruary 1961. A.urvey nf mrdical and scienlifie literature on the rnctahrdic etlccts (if arhaccn has rlrnwn nltentinn to the relative deficicncy in thia arc:r (if invc.tig:rlinn, and tlrc need to study the cRects of nicnline u.inR cr~nccntra tirms Ihat inclur/r Iho.e encountered in man. Studies ahrrw Ih:rt nirruunc :rf'fK•nrs t'nh:rhle ,f increatinR beat orrwluc/iun. oxyRen erm.um(~Iinn, mrra hrdre r:rh•, anrl h6na1 aurar 1 fre elfecl r+n .erurn eMole.lerrrl anrl li/. ln~ l m Icvcl% i. nrrt yet r h:n (:rncr:rlly, thc Icvela aPl.ear 1u he Iriphr•r irt .ruokrr, th.ut in non .mokcr.. fiut tihc rc:ram hrr tlhc dillcrcncc ik trh.cnrc Ir i, rntcr Sl 57

csting Ir+ note thal there are few clinical rcp.+rts which inrldic:rtc nicr+tine .+r I++hi+t•o ~rnr+kc ctioh+yically or tNhcrwite in deficiency nr mrt:rhr+h+ dnnrdcrs S.+ p.rrcnt a.Irug ns nicotine can be madc h+ hivr :rn inllucncc tin mctah.+fxm, whelher in the intact organisnm, indivirtu:d r++y:ms, tis%urs, ccll., or rcllulir cr+mponrnls - when uted in sufficient yuantily It n+:+y f+c Cm- F+ha%ircd that if is the concentration of nicotine r+htaininf; in the cclls (+r intraccNular fluid of normal smnkers which alone carrics any validity in assccainR the elfects of tobacco smoking "V.pcrimental" concentrations of nicotine must be malched to those "nnrmally" nccurrins in lissues and body fluids of smokcrs Only such cc.n- centratiuns can elucidale the pharmacoloRic aspects of tobacco smr+kinR: concentration many limes these eapress only the toxicoloRic characteriatics of nicotine. If tnxic doses or concentrations of nicotine have no dcmnn- strahte effect on metaholic or other aclivilies, this negative evidence is very probably valid with respect to tobacco smokinR; whercas the c.mverse is, equally prnhahly, far from true. It is never a work of supererr+gati.+n Io rcpcal that tobacco smokin6, as it is performed by the smoking millir+ns, is pharmacnh+Ric, and only very rarely indced a to.icnlogic phcn.+mcnr+n. "A(."TION UF NICOTINE ANI) 7ORA('C-O-SMOKIN(i ON 'TIIF- AI)RUNAI. Mlil)l/(.(./1." Hy II. Silvelre, Ph I)., P. S. 1 itson, Ph 1)., and II. 11. FIaaR, M 1)., l)epartment of'PharmacohRy, Medical ('oIIeRe of Virginia. Richmond .Irthivrt of Internal Medicine, Vol. 107, paFcs 915- 931, lune 1961. A review r,f the er<Iensive literature on the systcmic elfects of nicotine and smoking shnws that both may stirnulatc epinephrine relcacc frr+m the adrenals. either directly or rellestly. Tind+,Rcnous cpincphrinc and levartcrcnol er<ert a wide variety of eflects in the Fxxly, hu1 epincphrinc rclcaic frrlm the adrenals remains on the whole an emcrpency "frRht ur ffirhl" rncch:+nicm. 1hc studics ahr+w that Ihis efTect of nicotine or snmkinR :rtfccts r+r etiec/s n+any M,dy functir+ns, relatively trivial (e g bl(xxf suRar ri~c) or relatively impr.rtant (c.R. v.:stoconstriction). Sto fir as.mukinR by man is concerned, Ihcse findinRs raiac two qncs- tions. f-irst. is the dtne of nicotine dcrivcd from smokinR sufliricnt to nctivate the epinephrine-relcase mcchanism, directly or indircclly'' 1 he answer apf+ears to f.r a rather cesitant afTitmarive. Sccr+nd: If so, is a rr(+ctitive slimulation of the epincpfninc relrase mrch:+ni~m, and suhscyucntly of epincphrine "shock orRans" (particul:rrly the cardiovascular system), t+f any long lerrn conscyucucc to the h:rhitu:rl smr+kcr't 1 he ancwer to this questir+n ic still unknown. On the whr+le, very few elinicians have elected to advance this rarticular mechanian to etplain the eRects of smoking nn either the Fenesis ++r crnusc r wt•re ohscrvcd in three othcrs. It is suggested that similar invt+lvcmenl may occur in tither vrclims of periodic petilonitit_ Ilepatic inv+dvrrncn/ in (x•ri- rtilic rerilnnitis raisc. two mattets for speculation: Ilas it a he:rrnng tin lipid rnctahrdi.m, (rr ;iccount for the etfect of a dict low in fat Ih:rt rcdaccs the severity and frequency of symptomt in some victims? AnJ, does the ac- curnulatirm of plasmacytes and other cells in the liver, scrusa, anrl el.cwhcrc play a role in hypcrFlnbulincmia that usually is present in periodic prri- tonitis, and the result:tnl development of amyloidosis? "CANCER ()1: -1IIF. LUNG 1930 TO 1960: A REVIEW." fly R. 11. Rigdon and Flcacn KirchrdT, Department of Pathology. Univer.ity r+f Icaas Mcdical Ttranch. Galveston. Tr.to.r Rrporr: on RioLrgy anti Afrdir;ar, Vol. 19, pa),~s 4bS-313. 1:311 1961. (T.I.R.C. grantee: Rigdon) Introducing this review of 455 scientific papers on cancer of the lung. the authors say more has been written about this disease in scientific litera- lure and the lay press than any other neoplastic disease. The question - Is cancer of Ihe (unR clually on the increase, and if so to what eatent? -- remains unanswered. 11 Is not d{fticult to understand the confusion when we rememher that the hasic data nn rntxtalily incitknce comes front death rcr- tificales. II was 1913 before we had nation-wide death reportinR in the UnrNed States and 1939 !x(ore hronchoRenit carcinoma was listcd as .uch on our vital stalistics Regardless of whether the increase is only apparent or real, in 1960 cancer of the lung ranked Brst as the causc of death /rom cancer among men. The role of srnokinR in lung cancer, although suRFested before 1900, cnntinued to be the burning question between 1930 oand 1960 1 he hypo• Ihesis that smnkinR causes lung cancer Is largely bascd on sludics crnnparinR the smoking hahils of patients wilh Mher disSases or of healthy pcrrplc and on slutlies in which the causes of death are compared in Rrnups of people whnse smr+king habits have previously been estahlishcd. Uhvioudy froun thit review it is evidcnt that the etiology and the pathuRenesis of pulmnn:vy cancer in man is not known. nf car(linvascvlar discase - t+r, in fact, of other diseasec aa wcll in srnnkcrs "IIrrA'TfTIS -- A fTATURE OF Pf'RIOI)I(' PIiRI"TY)NIIIS" Ity m tn ~ Ih+hart A Reintann, M.T), I lahnemrnn Mcdical ('.+l1eRe and Ih+s/+ital• 1'hil:trlcll+hia L+rn.rul of the .I merican Afrdir.d 1t~.h innnn, Vol 1 1R, I+aKra 114-11t, Oif 71, I'!(+I. r,+ m v+ Itc(+:+tiris +x (rnrrrl in two ratknts durinf, tl+iirktrs -+f I+rri+wlir I+rri- runiti.• :rnrt r+vrrr and inat+parcnt jaunrlice, hcl+alr+mcRaly and shlcnrmrt•Raly 59 W 5R ©

Rccipicnts of Grants FtlktwinR it A list of atl recipients of Rrants approved by thr Scienlific Advisnry Ilr,ard since initial Rrants were made in late 1454. It ahrruld he notcd that some (tf the projects have been completed /:RANTFF- AND 1NSTfTlrTlt7r( PRnJF.('T TITI.F. 1./rr.r.r ("C- ..r...r a.. Arr. r.AILArI Ar rAr a•.wr.rl ('1 /ARFN('1. M. A(7RFSS, M D., ('Mrf, (-err/rnvnrrulnr I.rhnrnlnry, Velerant AdminislrNion ('tnter, I 0+ AnRelel, ('.1 1) h(1IRRAY AN(iFVINP., M D, rrn. /rrrnr nf r.rhnfnRy. Itniver.ily of Wit con.in MrAlc.l Srhnn/, Madiarn, Wit S1FPI1/ N M AYRFS, M D., plrrrrnr of Rrrro.rh, (lrporrmrnr of I'rr/mnnor. Phrrnr.lner Sninl Michnelt 11o.ri1.1, 4 Newark, N 1. FRFI)FRI('K w RARNFS. f., MD. P/r h,.t rvvlnlr rrnfrornr of AIrA.r-rnr and /'hrrinlneirnl C-hrm/frry- Jnhn. Ifopkirn (/nivrr.ily Sehnnl of Medr cint, Ilaitlmore, MJ RAt Pit S RF(-KFR. PH [), Arrn.lnrr irrn/rfrnr of (hrmtu•y, Ilnivrruly nf I lou.lon, / lnu.tnn, ) t. SAMUFI. RFI I IT. M 1), I)Irrrrnr, r)lO vinnn n/ ( erAlnlnRr, PhiF.delphi. (antrnt Ilrnpil.l, PhiLJrlphu, Pa RI( tIARI) I RIN(;. M I) . Prnfrrrnr of Mr.lu rnr nnrl ('hnlr•nnn, nr(wvrrnrnr n/ ,(Infrrrnr, W.iynr $Inlt Univrrsity (-nttrrr n( Mr,tirinr, Ih/roil, Alich Mtacuremenl of the functional ctaur of Ihe human hearl by fre0rrency +pec- trum analy.it of its vrhrarionnl tnrrRy Palhotolic-- na/omk ctudy of rtlluI.r change.In human l..omhi I( I Mea.uremenl of .tveolar arttria/ nitrngen drRtrence hy gni chromatoRraphy lhe rolt of hyptrplaaia in liaue rtapnnse lo chrnnic damaRe (('- P) An invr.r,R~rvn of the .prrtrrt and rhrum.rnRraphrc rh.raurrrarc. uf .rnmarrr h/drrxarh..n. The eflert of nrcncine un c.rduc irrilalinn in the prr.rnra of re.erpmr, anA Iht rf ftcl of nicoline on curnnnry hlrx.l f1n.• of doRs with coronary insunuiency (r--P1 Fffectl of nicotine on the morpholoRy of coronary artcriea and aorta. fihrinnlylic eRrclt of nicotine on human and nni mal pl..ma, eRect, of crSsaln.n nf smokinR nn %trum choktlnnl levtl. nf chronic smnker+ The eRecl of imnking on the coronary hlrxxl fhnr nnd ctrtain phasr, nf mvorxardial mtl.holiam in p:•ritnrt wrlh nrtrrin.clrrolie nr hylrrlen.r.r u•rJi uvusardar dr.r.r~r 11'/ SluAitq in ctllular phy.iolnoly rrf htnrr mu.( It I P I Mra.raement of cnrnn.ry hlMxt flnw by me:rn. nf radrnactivnlrA nlhnmin 1/•r eRrrl nf .mnlinR nn cnrnnarv hlrnrl fl.•w ~.rvnrt .nb •rr...r•.rlrrnrir hr,nl dr.r.nr .•n•1 rhr r/1rr1 ••/ nrrnrrnr rvr an•r..rr nf aminr. rn hr.nt mu.clt h() I r (:11AfVT{'F. ANI) INCTITIITI()N FRFD O. RO('K, M S., P/r D., Srnlo. ('unrrr Rrrrnrrh ,~rirnrrrl, Rotwell Park Merno.ial Inslilule, Riotogkat SL- lion, SprinRville, N V. f.ce Monre) IAMFS F. RONNFR, PN D., rrn/rrarrr o/ Rr..lnity, c.tirornia Institute of Tech- noloty. P.mAena, C.1. TOM f. ROWI'RY, PN D, )-raNrlli Rrr- iAro Inhnrerorr. ('hrmbhy prpert- mrnr, Nmlh Carolina Slate Cnlltat, R.IeiRh. f(/SFF RR(17FK, Pt( D, /Yo/rraor and ('bnirmen, f)rryrrlmrnr of IaychnlnR., 1 thiRh Univer.ity, Relhkhem, Pa. F. M. R(/TT, M D, Prn(runr o/ 10erhnl- nrtr. Univercity of Srwlhern ('.liforni. Schr.ol of Medicine; Chief rarhnlnRrrr. 1 rx Anltelec (ounmy Ilrr.pilal, l.oi An- Rtles RI(-IIARD 11. RYFRRUM, PI(D, Pro- /rnnr nf ('hrmirrry, Michigan SINe Univeraily, Fa.l I_an.ing SISTFR M. FM11 V CAHI11., PrrD, ('hnirmen, ('hrmlrrry prpar(mrnl, ReRie ('olleRe, Weslon, M.s.. W11.t IAM FI CARNF.S. M D, Pro/rarnr n/ Pnrh..fnRr. Univervty of 1/1.h Col- IrRt of Mtdicine. Cdl I nke City. 1 F(1P(N D/TRF('FfX), Pn f)., Prn/ra- vn nf Rirr.hrmiury an/ NrrrriNan. Itniveraily of Puerto Rko, School of Mrdnint, San /uan Ihxmerly Proftr- .nr of Rinehtmi.try, ForAh.m Unlver.ily New Vnr1, N V / IUNS T('t ARKI', 1)G'. rrnfrrrnr n/ Rrnchrmlrrry, (binml.la (fniverdly I ollrRe of Phyduans and Surarnn.. Nrw Vnrk, N V Irtllred, crt (:nlt.r hn1t1 IAV 11 ( 1)/ IMAN. M 1) Inrr.urmr rn AIrJh rnr. M...nr h.r.rlll Memnnal Ilnaprt.J.. Rn.rnn PR(1JF,(T TIT1.F, Meauremenl of coronary blood flow with a syslem usinR coincidence count. in.: Ihe ertecl of nicotine and chanRe in heart rate on cardiac melat.oti•.m and relaled suhiecls InvestiRalinn of tht hioloRical eRech of cippretle fmoke (('--P/ Fnrymnik study of inelhytation reaclinm in planl tiaue (('-. P l TDF and endrin re•idues in cigarette .moke 1('- P / RidoRkd rharacttridk% of men and their .mokin(t hahils 1('--PI PNhnloRk-.nnlnmk .tudy of ctllular ehanRes in human hrrmchi (1 ) Study of Irace melal .tornRe of pulmnnary nd liver lis.ue by .pectopaphic and chemical melhnJs 1(') Rio.ynlhe.ii of the pyridine rinR of nkn. line (P) Comparison of .nalytic.l melhr.ds by determining Ihe percent rccovery of ar.enie added •1 known levetc to lo- baceo tamples •m1 • hro.d survey of Ihe amount of arsenic pre.enl in tn hneeo samples from a wide vnriely of uwrcef Palhologk-.nalomie s1uAr of cellutar ehantel in human hronchI (l-) A study of early chemical chnnRe• In Ihe 1unRc of lumnrl•enrinR rat% nnd rnrcr (C. PI PrMtolylk •clivhiel of the while Mrx.t etlla of inen and Ihe eflrrl nn whilr blrwxl cell acNvilit% of cnrrinnRrns n1r17illon and nthrr inR.rrncr• Ic 1 Ihe effrrl of Inherrn smnlinR nn nurrl livt .ktlrlnl muult /•Ir•,.1 fl.n. .. r1r crrminrd by the rnArn..nlupr drs.rPl.rar •nce Iechmwut 61

1:1t (Nl FF AN11 IYeTII l+l l(IN II/IIItS 11 (()\(R/)1,~ I• Mt), /)nrrr.1r c,.r,(„ r u,r r.hrr rtrrr,rrr lr Inrr.rrrl.. 1lrnvrr.dV'o( ( ih(nrnra Mrdittl ( tn Irr, San I ranc,.co UrAN M(()NN/)RS, M f) • Arv.riolr l)r.nrnr, Irrp.nrnrrnr n/ l.aA,•nunrv Alr.6rrrrr. $1 M.,ry'a Ilo.pil.l, MaJi ann, Wia r1111 Ir ((x)rl R. M 1) ,('Mr/, .[urRiral Srrvur, Vt/rrana AJminiathnlinn Iltx. rital, Rrnnt. N. Y. ( Irnrrnf Prr,frn.w r,f ,Crrrtrrv. All.rrr Iinaltin MrJical ( nlltRr, 1lrnna nl RrRt ))AMr1N, M I), Prlt), Att(r ronr rr.r/rrrnr rr/ AfrAunl AnrGrnr•d .,Ry, )Irr•r.l.nrnl n/ ln,(urrrml (I rerrnr Ilarv.rJ Sahmi nf Puhlic 1lrallh, Rrnlon, Mats R r t)r1WSON, Pn1), Prnfrrv•r .,/ Rnrnnr (nlumhr. (Inivtrady, Ncw vnrk, N V nNt)RF.W 5 hIRN! R, P// I), Ferrn. Irrr, Prrrhn Rrrr•nr h, The ARC ( rnlcr of Ntw rnRlanJ, Inc , Roalnn, Ma.. (Ke Whialinl rT)WARI) F Tx1MINO, M f), Ann+iorr Prn/rvrw n/ P6urnr,unlnRy, llnivtraily of MichiRan, Ann ArM.r. /OIIN W F( KSTI IN M 1), Ararr..n( rr.,/rrrnr r•f Inlr.rrrrl Atnb, rnr, ( n11rGc nf MrJi, inr, Slalr Om.rr.ily nf In-a. In.va ( dy t1ANS I I AI K. t'n 1) ,.Trnl••. Rrrr.r..lr ,r, i,rr, rl,r,rrrn•rnt nl rnrh,.r,•r, Ilnivrr.lly nf Snnlhtrn (:Jrfr,rni:r S. h,v,1 n( hlr.h, inr 1•.. Anrrlr. 1'Ittl)F~.(T 1111 F: lht tRecl nf .m.•lint urr.n .nrw.V rrv.l :,nte((. r) An.Jytia of c.rvr hr.lnnra nn rm1./rVam:r A aludy of the ahrralinni in Iht hum..n hrnnrhial wall rKt'urmG wrrh rRmR, wilh rarliaular tmrlr:nia on rlaNic li, ant (hanRc. anJ aaart,.NrJ thunpra rn the bronchial lumtn tire A VuJy of the eRrcla of ciR:rrrnt amo\inR on kvth of palriC aciJ, rrr.m and urnrer.in 1( r) A.IUJ) of the eflect of tctracla of Inhactn on tullurra of lumrx anJ nnrm;rl cells. Animal /ranarlanla of L,mor tit. vre Irnnm lia.at Culturra (P) Slu,ly of cnmhinrJ e11tt1 of injrclt.l viral oRrnla anJ rnvironrnrnlal (arl.u., in cludinR t.rcinoRrrn nnA 1„h.cco .mnlt. on the Irachenhrr.nchia ntr :rnJ rut ~ mnnary Pnrenchyma of rrlKrrmtnt..l •nimala and nn li\anra in nrR.in cnllnrr nnJyr form. amnlinR, nnJ alcnhnl con aumr+tinn amnnR tlali.m Amr+rc:m rnrn Ir rl An invraliRilinn of tht mrla)v,li.m nf r)ri,Gnt cnmry.unda in Ihr In/..ntn rl.nl /(rl r.ychnlnRical .nJ heh.vinra trr r.lita of mhallra amnnR .mnlrra 11 I IRrcla of Ir.h:rcrn amolt and n.cnlinr on Ihr central nrrvnrla ayalCnl 11'1 Rt.PrKnta nf the rrrirhtral vtini in m.,n inlr.ivrnmra pJmmi.Uahnn nf lo the nicnlinr fr1 / rrrl Mr.rl flnw realwmara In .mnf<,n~ in the r,r.rntt of hy(,erlirtnu., an•I hyfrrlrn.inn I a.rmin:.lir,n nf ciR.irtllr r.i(,rr .rnJ cir:,r. rll.• n.nlt cnnJrn..irr. fur ...r.rrr.dit p.dycWlit hV,lr.r:nhnn. /( I !1 cnrnrJ.rl...n a,l nnn,c.rrn(r rr.lra nl rydyaV,ht arnmahc hyAr.,..nhnn. .rn•) tIn.AV rrl.r/t•1 tumt,,...... l. whr, tr ., r nf inl.rrJ in Iht •rn•Iv n( oir I•••Il,.rurra -.1 , •r urnr .n,.dr , .I LIt tNl F F: .tNn 1N.TtT1lTttln 1)ANA I rARNSW(1R1F1. M D, Ifrnry KOL,rr Prr,/r, v.r rrl ll yRirnr nnd I)i rtrlr.r of l/nnvror• IfrnAA Snrirta. Ilarvard llniverally, ('amMidgt. Maas. (att Ilealh anJ McArlhur) FRANK ('. rrR(7tISON, ).., M f) r Irnrr,n„n. Il.r.r.l..rrnl of rhnrn,rxr.l. nlhany Mrdical (blle/t, Alhany, N Y. RUSCI'1 I S rtS111'R. M f) ,('Mr/ MrA. a.d Frrurunrr. Sl:dt of Maryland; Pro. (rrtrw n/ I rlrnl Aft,Yrrinr, ttniveraity of Maryland MeJkal Schonl, Raltimort. R I 1'RFrt)1 ANt)I R. M.f)., f)irrrrnr of (anr rr Rrrrnrr h, Mnun1 7ion Ilo.pilal anJ Me,hcn( (enlrr, San Fr.neiaen, ('.I. (Jecea.ed, aee I rench) rRrhrRK'K A. rRl'N('/l, A.R, Re. .rnrr Ir A rtrn inrr. Mmmt 7inn Ilo.rital anJ MaJnal ( enter, San Franasen, ( at laet rrrrl.,mkr) lA('K PRF.t/Nf). M 1), Aa.i.rnnr Prnfrt. t,rr n/ Phnnn.nr.lr•cv. MeJic,J (n11tRt nf V ir Rini:,, R it hmr.nd G! (IR(:1'. (1 GI'V, M 1) , 1)i.rrlnr, r 11 c nn, r Rrrrnrr h I uA .ur.rrr. Itry••rrl.rr.nr n/ [nrRrrr. luhna Ilnr\m. Iln.lvr.~t, h..hrmn,t, MJ 1/(n (;OR1. M 1) I7drl. Inh•unl.•rv 1. , r V• Ir ., • n0 ........ lrnlinn Ilna (.rt.d' Wra Nn.l`ury. M.i.a PR())FYT TITI.F. on the defenae mtchnniams of the ral in tktotiRcainn of rolycyctic arnmaic hrJrnc.rhnnt and the tnmrtli]ivt in hMhitinn httwttn the rrdyc)clic hyJrn carMna In conJcnaafe wi/h reprJ to c~rcinoRtntlia 7ht Phfskal and chemical IKOrerllea of mut'tn umler nramal cnndiliom and followinR esrosurt to nernaol irri(nnla Ptrannalily and amolinR in rnlleRe Rrad uattaa f,flten yr:o (nlinw nr ./n•ly (c) Fflecls of Inhacco smnte u(K,n the func. liorl of the tardinvaacul:tr ayalrm in animals .nJ man ((') PalholnRk- nnalnmic auJy of cellular chanRea in human hronchi 1(,) Fnreriments on the (rnaihlt cnrcinnRrnic anJ tocmtinnRenic action of tnhatcn rrahrcta 1(' --P/ CnrtinnRenicily, eocnrcinnpenitily nnd , anlicnrcinnRtnic'ily of ditlary Lclora in relnllon In rulmnnary Iun.,Ka rnc. aihh~ inltlrtlnlitwtahir u/ lnhnecn haaes and dielary faclors ('hemical .ludira on Pyridine haaes inaluthnlt nratrn analoRa ('nryelalinn of muhilechnical rrrarJurta rerformt'J un the rerirhtral circrJ.finn ul nnrmn/ inAiviJu:JN in rrcnmhtnl :un/ erect rrsitiona nnJ afler eaerci.e Lrfurt :mJ afttr aham nnd :Klual .m•tinR 1( 1 A atudy of Ihe rRecla of ciRnre(te amnlinR . on the (Kripher:J citcut..linn if inJr viclunl• wilh nrterimtltro.i• r.hliltrana nnJ mhtr rrrlrheral vaarrJ:.. .h.r.nra uhlirinR multiltchniclJ rr,KrAurra It I ltllnw.hif.I fnr stuJYln/ /he rrdlmr nl hu,n.rn lunlt lia.ur anJ lirt rllrr 1. n/ \nnwn nn,l ryra.ihlr ,.u„nngrm. .rrtnl. ,rrym.nch li..ur Inlrr:rrlinna n/ nrlrri.,l nrrJ mur•.1••~Iv a.r,llr:n r,tr•

(:RANTFF. ANII INCTITIITIt7fV GI RTRVhF. Y GOTlS( IIAI L, Pn f), Anrtlanr rrnfrrinr rr/ Rinrhrmrrr.y, f),parrrnrnl nf PurhnfnRr end Mirru- 6ndnRr, Thc Rnclrfellrr Inaitutc for Medical Rese.rch, New York. N. V. Isce ( larle) A CI ARK onRIFFIN, Pn 1), Hr.d of RinrArmllrry /)ry.orrmrnr, M.D. A71- derx.n Itn.pilal anJ 1-umor Inuilute, llniver.ily of Teas Medicd ('enler, 1lnustnn. MORTON 1OR(1S.SMAN, PN f), M I)., A.r..rrafr (7rnnnt rrn/rnrw of Afrdr- rrnr, l/nirersity of ( .hfn.nia MeJie.l ( enltr, I 0. AnRrler ('ARI (' (iR1/117IT, Phrp, MI), Au..rlarr, m PAyrn./,.~r and PAn•me rnlr.Rr. l/nivrnily n/ Penn.yl.anl• (:raduale "chr.+l of Mtdicine. Phil• drlfhu Ino. I eclurrr in Phyaolnly. Ilm.errily of /lnnR Kont) 11 R. I(AA(i, M f) . P.nlrrrn. n/ PAer mocnlnAr, MeArul ('ollrRe of VrrRrnia, Richmond Idtcrawd/ /(KFPII 11 11A/ Kr NS( 111/'I , M 1) , ftlrrrfnr, ('nrAr.•rulnrnno.y (ln/r. I an trnau limPrl.l, ('hrl.drl~hra, Pa RI('l1ARl) I IIAVFI , M I), Ariinnnr Pro/rrrnr, nof A(.drrinr, Unirer.ity of (ahfornia Medical School, S.n fran- cixo. /IFRRF?RT R IIAWTHORNF, M O, ('Aafrman, Drv errmrnl of S~rRrry. Vniveriilr of Penncylranl. (iraduale School o/ Medicine. Phil.delphia. Cl ARK W IIF.ATH, M b., Prolrrrnr of Mrdrrrnr and nirrrrnr r./ IfrafrA .Cr.r. krr, Tu/lr llniversily, ed(o.J, Msr (ae f.rn.wrxlh and McArthur) PAI111NF 1/1'171R, Pnl), Rrrrnr.h Arrrvinrr in (vlnA+ey and (-ylrrAr.nunr, San Iremi.rn In+lit.de of MeJi c.l Scitnre.. San I cancivc(lo, (al /cn Rrchud.l PR(1)F.(T TI'fl.F. Proteolytk ctivilies of Ihe whilr hlnnd cells of man and the ef)ect on ..Mlr hlood cell activilies of csrcrnnRrn.- nn /rilion and other inFluences ((1 (:RANTF.F. AIVI) INSTtT(ri1()P( 1.\WRFNCF. L. /IFSTFR, 1.,, MD., Prn/rrrnr and (-Aarrman. Dr).errmrnr of OArrrrars end cynernlnRy. Medical ('ol/eRe of Srn,th ('arolina, ('harleann. PRO)ECI' Tm.F, The retalionship of Ihe use of tobacco producb to Ihe ourcome of prtenancy IC) The tRect of espmure to ciRarette .mnle on the inducthon of cancer hy chrmical c ompounJ. (( - P ) he effect of smnling on certain R.Uric funclic.ns ((') FRRF CURTIS /InFF, PN I), M n., Prn/rrrnr and Chuirmen, brl.nrrmrnr of NnrrnlnRiro! Srirncr, Mtdkd Col- IeRe of VirRinia, Richmond. RIISSFI L 1.. FIOI.MAN, M I), Pro,rs. snr nnd ifrnd, prprlnrrnr of Pe/Frd. oR., I ouisiana Slae Vniversity School nf Mrdicine, New (htcans. (deee.std, are McCitl .nd StrnnR/ Cerehrd aulonormic chances produced by tobacco smole, nkoline or cnlinine, a melaholile of nicotine Palho(oRk-anatomk study of cellular chanRes in human hronchl ((') The influence of tobacco smnking on acute myocardial infarctlon IC) F 11OMRIIROFR, M 1), Prnidrnt, Rio- Studies on earclnorne.is and the bin Re.rarch Inailrnt, Inc , ('.mbrilRe, PharmacnloR4 sludy n/ nicnrmr n,I rr M..s LrrJ .tl.lordr Il I assay of carcinngank aRtnl. (P) ('nmparNi.e stndks of eRec1i of v.rinus tof.acco smofte conden.ale. on skins of Rt7RFRT W. H1/11 PND, AnlNonf mke Pholodynamie activation of carcinogenk a i Prnlrrmr nl 7nn1nR.. Nnrthweslern hydrocarbons: (a) slandarJiralion of Prtp.ralion for puhlicatinn of a h.a.l on the hinlnRie aitrec(l of Inh.ceo and il, smoke l('- P1 Mtaauremenl of coronary hlnnl flnw, cndi.e wnrl .nd cardiac oayRen .nd earhahvdrale metaholi.m in nurmolencrve subjectt before and sfltr inrra venmr, nicnline and afler smnling .randard ciprettes 1('-P1 A cnrdy of the tRecti of smnlinR and nKntint •dmini.lralinn nn aymp]Iha adrenal functinn and (any acid mrtuMdi.m Attempts to Induct pulmonary nenpl.ams in eaperimenlal animalc by r.p.nurr of the trachtnhronchial .yattm to Inhacco smoke (('1 Perconalily nd cmnlinR In eollrRr Rrad u.tt.: a fif/rrn yrar /nlln.-.np .IuJy (('. P) A eomparalire dudy nf early M.IntoRir.l and I)NA chanRes in the tprdrrmro of Iwo •Irainm of rnice I('S) Ill.u\. and Swiss Wthvlrrc) aflrr dnily appli.. tinm of whnlt ciltarrlle imo1r cnn drmae ( alnnt and cnmhinrd wrlh crn/nn nil) and'/he rer.innR.n. 74, mHhylc/.nl.nllurnr and 1 4 brnrpr rrnt ((') l lnivtrsily, f..anaon, III. If"RRY IIART fACORSnN, M D, I)I. rrrrnr of FlrrrrorArrinlni(y, New Ydlt Fye and Far Infirmary, New Yor1, N Y. I1111115 11 IACnRSON II, M I), Asso- rinfr Pro/rsrnr nf.turRrry end f)lrrrfr.r of SurRlrol Rrrrnrrl•, ('ollege of Medi- cine, llniverairy of Vermont, Rurling~ ton MURRAY F IARVIK, PH f)., Assnc7arr PrnJnunr of PhormnrnlnRy. Albert Finsltin Colle(te of MeJkine, Mona, N Y. ANhRFW A. KANI)I/TSCN. PN.h., .Nn(1 SarntAt, Rmcoe R Ialson Me- mnri.t I ahcwatory, Har Ilarhor, Me. AN('1'1 KFYC, Pn h, Prn/.vor, nof PAys L.L.Rirnl //prrrnr and I)brrlnr, tnA. nrnn.rr nf PArunlnRbal fly /rnr. I/nivrrdlr o/ Minncaota S(hrx.~of Public Ile.trh, Minnearydn Il)CI'PII R KIRSNIR, M I), Prnfrrrnr ../ RlrAnrnr, Ilni•r.vly nf ( IdcaRn Cahrn.l of Medicine. ( hicaRn, III nsaaP techniques ulilising protorna; (b) inse.tiitatinn of Ihe mechanisms of activation am/ response to aromatic earcinogens by prntoloa A comp.rl.on of elKlfn.etinoRr.ph~ as • means of evaluatint the eficct of sasncomtrktor drugs upon cerebral and retinal eirculation with other techniques for this delerminalion 1('1 Lung homn/ran.plantalk+n (C) Pilot study nf hahituation to nkn(ine by means of rhesus nw.nleys To de/ermine to whal e.tenl tobacco 'lu' mimks the action of carcinnRrnic hydrocarbons in the slin and other tissues IC) ('harKlerl.lks of mtn, incllntinR lmn/l in, in pr.pulafinns diRrrinR in the in. cirltnet of eoronary hearl dr.race 1(' P) Tht effect of Inhatcn smnlinR ulw.n h...I Rn.uic vtcrelmnl in m.n 1(1 /T C/t (i S C.~

CRANTF.F. ANt/ INSTITtfTI(/rV KFNN1111 P. KN(II)TSt7N, MD, Ar iftlanr ( hrr/, faAnraf.xy Srr.nr. Vel. rrant Admmitlr.hnn /lotp ital, Seattle. Wa.h ; Prn/rrrnr of PnrhnlnRl. Uni- vervfy of Wachinglon Medical School. Seallle. At.VIN 1. KOSAK. PRt), Asrorlarr rrn/rnor of ('hrmirrry, W..hinglon Square (bllr[(e, Nrw Yurk Uni.ertity, New York. N. Y. RORFRT A. k(1/1N, M D Anorie(r Prn/.nnr of Neuro66qy enI Ner.rnrrr- frry, Ntw York Medical Collt(te, New York, N. Y. MARVIN KUS( IINFR, M D, rro/rrxr n/ Pathnfney, New Ydk Univcrdty ('ollege of MeJitine; INrrrror of Pa drnloRt. Relkvue /lmpilal, New York. N. Y T11OMAS C. I AIPPLY, M D, Asiorlarra Prn/nrnr of Pa/hnlney, Norlhwt+lern (Jniver.ity Mrdical Sehool, ('hicago, I11. PAUI. S I ARSON. Pn n., rro/r.tnr of Phermnrnl.r[y, Medical Co11eRe of Vir- ginia, Richmond (xe McKennit) (;USTAVF A. I nIIRFN%1, M 1), Asir- runr Prn/rrtnr of A(rArrinr. Sclon 11.11 (ul/eRe of Medicinr, leney ( ily, N. 1. ( F('111F I F(]('/IT1 NRFRCrFR, PN D, Srninr Rin6.Rrrr nnJ (-ylnrArmlcf, Sist Memorial I.Mxatrxie., Rrnoka /lmpi. ta/, Rrnokline, Matc (In reci,tcnce a1 IndilrH (ix A9lfemeine Rotanik, I~idgenn..iache lethnnche /loch.chule, 7urirh, Switrerland) }STI NO I INI)GI TI1, MO., SwRirnl Srrri.r. Vrter.m ndminidralinn Ilnc. prUl, ~/innr.,p.Jrt, Minn. Rl )RI R 1/1 I INN f I 1, Phr 1) , A+vx fafr F.n/r.... ..I c I/nl.enlly of Vr........ r Ho.1~oRr„n 1no...r C.un Re PRnJF.(T TfT1.F: r:ItANTF.F. ANI) IN'~TITIITI(1P1 ParhotnRic-anatomic .hrJy nf reuxlar I chanRet In human hrnnchi 1(-P1 I. P. I(/NO, Prt t) , Arurintr PrnJrltnr of Phnrmarnlney, State Univertily of Inwa. College of Medreine, Iowa City. t)AVII) F MANN, 1. , Pu I)., Aunrletr Prn/•fsnr o/ PhnnnornfoRy Temple The ianlalion and iJemifxal.on of cer i l)ni.er.ily School of Pharmacy, Phila- tklPhia, Pa. lain lower hnding eompnnenH of e t- arttle cmoke (C ) CIIRISTqPI1FR M MARTIN, M D., Asrirranr Pro/rstnr INL.Nnr, Dir•irinn of Mrdkinr .n/ of !n/rcqrna D/s- Po.+ihle eRectc of tobaccn uf~n cerebral circula/ion Palhologic-- anatomic .ruAr of cellular changes in human Monchi W) Palholngic-analomie Vudy of cellutar changei In human hrrmchi (C) Fnrymatic tranaformNinnc or nicnline nd rrl.tled comryrun,la (P) The Ian.iMe effect Of Inhaccn amnke and nicnline on aacorhic acid meubolicm Studies in Mnnchili.: • enrrelMed in•ecti- Ralion of (a) the effect of amnkmR un the bacteriology of the rcapiralnry Iracl nf hurrync, and (h) Ihe effect of cigarette imoke and .ulfur dio•ide /air pn11n1an11 on the clrarinR of bacteria frnm Ihe retpiratory tractr of .mall animals (mice, ralt) A correlated hidnlogiral, cytnlnltical and eytochemkai utnly nf the fracheo- hrnnchial Irre of mite e.f~r.eJ In (ig arette cmnke (PI Men.urcmrnl of the drRerrntial h1rx.J Rnw in Ihe mammahan tunR Jmin` the aeule Perirwl or amn)e inhalatinn, minR the npen ehe.l animat and Ihe nxthrrt •nd ppinciple of Ramma emrning radinaclive lr.ded micrmphrrr. The n.iAalinn of nicn/ine hy Rn.rnu+ n.ylrn rr/.eni.m. pr,.Autt. .nJ kinrlu. 1( r 1'1 Ihr :rurna.lalinn nf nicoline 66 rnrrr, Srton Ilal1 College of Medicine, rer.ey Cily, N. /. CIIARI Ft ('. McARTl1UR, hl b P.yrhnlo,e/ar In rhr f/nirrrsiry /Nrohh Srrrlrrs. Ilrrvard Univtrtily, Cam• hrid~e Mac. (ace Ileath and Farm- .n.lh1 (-IIARI Ft R Mc('/1NTS, P.r t), Ann- rlntr Prcr/rttr» n/ Snrb, School of Api• cullure, North Carolina State College. R aleiRh. IIhNRY C. Me(:11 1,/.., M 1)., AetinR /IrnA, Drprrrtmrn( n/ Pnrhnlnlfy, (.oni- aiana Sta1e Univercily School of Medi- eine New Urteana lae Ilnlman and SlrnnR I fORI)F A. McIVFR. M t), Acslrram rrnfrt.1nr of PnrhnlnRe, Medical ('nl- IeRe of South ('arolina, ('harkslon. KFLI Y T. McKFF. M t1, Aanciorr Prn• Jrttrx of Alydicinr, Medical College of Scxnh (irntina, Charleclon. I1tfRR1'RT McKFNNIS, IR . Ph 1), rrn- /rrrnr of Plrnnnmr.l..Re, Medicd (-ol- ItRe of VirRinia. Richmond (vt LarVxl) Vt(ZOR A. McK(ISICK, MI)., Asrn- r imr Prrr/rrtnr n/ FPi,frnrinlnRy ond ('hir/, piririnn n/ Atrdr.nl Crnrrur, luhnc /lnpkirn Onivercity School of Mrdicint, Rallimnre, MJ. )AMI'S (i. M1111 R, M 1).. PN I1, Prn- /rr...r of Prvrhinrrr olnd IrrrAnJa.Re. nn,l Ihrrrrnr. Alrnr.d llrnbA RrvnrrA ln.rinrN, Uni.cruty uf MrchlRan, Ann ArIwN 111I(:II M(1NT(N1M1 RY, M I)- Arurl orr rrn/rrr..r nl Afr,lir mr. I/niveraily nf Prnncylvnnia MeJual tiah.rd, Phil.. .Ir l ph r.t i PRO)f.CT TTTl.F. Cardiovascular eflecls of nicrxine F.Qect of lobacco smoke and tobacco rec iJue+ on methylcholamhreneinduced skin earcinogeneslh in mice ((') Pos.ihk inler.clinns of .Iruxt and sub- +unca In lohacco amoke condenvte (P) Social and pt rsond determinanls of smoking beh.vior (C- P ) The soeial medialion of smoking be. havioe (C) Arsenic conlen/ of w.ilt nnd nf..nrptinn hy Ihe tobacco planl (C-P) The eRccl% of envtrnnmentnl fnctnrc nn development of athercnclerocic nc re veated by autopcy of accident .ictim. Fnarnnmetal faclors and pnlmonary di.- e.x. 1. Atbeclof dusl Sludy of lung function in amnker• and noncmo\ers (C'-PI Fnrymatk' lrancformnlir.m of nicotine anJ related compamd. A combined genelic, phyiinto ic, clinical and epidemiolnRic audy u~ Ruerilrr'c Ji.eace lhe behavioral eReclt of +moAinR unJer drec. 1(') Influence of lohacco wmnkinp on rht Idrxrl flow of •lin and of nnr.tlr. rd r.lrrmilieq, In •ym(~athrtlnn..rrd nnd nmympalheclnmirrrl .uhirr rt 1/' / (nflurnre nf nicutine (i v ) :rn,l .mn~inR rxt hhrrl 11n.r m hu.n.m .krn .nd Aelelal muac/e I(PI h7

I (:RANTFF. Af+f/ IfvSTtTlfTl()P( SIM(tN 11 W! NI)t R, Prr 1), Rnrarch Pn~/rnnr r+/ ('h,u+rrf, l/nivrrdry nf (lll.horn• Rr+r.rch Inttilutt, Norman hUANF 0 WFN7I'1 , Prr U, Pro/rHrar of PAormar.dr•Ir.. School of Pharmacy. (/niver.nty of K.n..i, I.wrence. FRFOFRI('K P.. WItISKIN, M[)., C.M., f)i.rrn+.. I)ivlrion nf Flralrh end Prr_ ronafny Epu/frA.lum- lht Ale Centtr of Ne. Fnifl.nd, Inc , florton, M.n. ( xe 1)ibner / R(X:FR I W11 I IAMS, Ptr O , Prn,r+rnr of (.~hrmhrry ond fllrrcror, Clarlon /nundnrie+n Ri.rhrrnirof fnrNlulv, Thd (/nivrrMy of ir..., nu+tin. 1 FhWIN W(X)f), M f), Pro/rrrnr of IIIrJrrrnr, Mrdir.l (nllrtte of Urortti., Aujua. S(1MNFR W(X)11t ). , M 1) , Ar,hrnnr Prn/nror of Par++nlo,ey. Pr(mrlrnrnl of Parl+nlntr', )ohm flaplln. (Inirer,tity, R.flimore, Md 1OIIN P, WYATr, M I). Profrnnr of Perhnlort. St. I ovir Vnlvenity School of Medicine. St I nuls, Mo. PRO)F.(T TIT7.B A Qualit.tlve •nd ~u.ntit.tive tludy of the individual polyphennl content of cipreue tobacco .nd the amole and 't.ro' re-sultmji from ciprette timoling, .nd also etudy of the f.te of the.x eompoundv in the nimd re.pir.torT rry.tem (C-P) T)x determination of the chronk eRects of or.llr •dministered nicotine on aerum cholesterol and pho+photipid+; the electroc.rdiot(t.phk revponx to erffonovine: nd Ihe v.+cul.r pathol- ogy of chole+(erol fed rabbits (C--P) Pilot study of tmotintt hahits of Ate Center mtmheri (C) An inve.tiffalon of Mochemic.l f.cton r.x.ci.ted ..ith nuxeptibility to lung cancer 71u eRecy of p.olonfied Inh.latiM of to- bacco +mole .nd of p.olonged .bilin• ence from the use of tobacco on the Ptriphrr.l vascular reepon%e to cute inhalation of tobacco emole In man (C-P) F..lu.tion of etiologlc f.cton~ .uch •f occup.tion.l ha.rds and h.t,iro, and p.thologic petuli.ritief In 1j~e lon~term turviv.) of paienH fnl~ing rt uttion for hronchorenie e.r rnom Art Inve.tipption Into the n.ture of the pyment.ry letionf In centrllobul.r ernphyxma (C) 0 0