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CTR HN 01 139*r

_or ro- 1960 REPORT o J t ji c SCIENTIFIC DIRECTOR /a.A1tF:N(:F: (YH/K t,l'i'ii.F., Rc.tl. •runna:O iN1/11ti'1'ItY RFaF:AIN31 c(IMMrrrFF I

SC.iF:N-rnFI(: nlrV1M1RY rs0Altli to the Tobacco Inttusary Rese>,rch ('ommitlee KRNNf?III MI?RR1(.1. I.YN(TI, M h., Sc.h, I-1.1)., ('hairman ('hnnrrllnr Medical ('olleRe of Smnth ('arolina ('harleston, Sr)uth ('arnlina R1('IIARI) 1. RING, M.n. rrn/rrtor onJ Chainnnn. Department of Medicine Wayne State I)nivenity College of Medicine I)ctroil, Michigan McKEF.N CAT'fF1.L, f'tt.f)., M h. !'rn/rtn» F,mrrllus rr/ PhormnrnlnRy Cornell (iniver.ity Medical Co11eRe New York, N Y. L.fON O. JA('OIISON, M f). f'rrn/rtsnr n/ AlrJirinr, University of (?tica/,n !)irr(rnr, Argonne Cancer Research Ilospital ('hicaRo, Illinnis PAUL KOTIN, M 1). 1'nrrl I'rircr 1'rn/rc.nr (P/ f'mhrd.lev I/niveraily of Southern Califoanii, Sch(xd r+l Medicine l,os AnReles, ('aliG+rnia CLARENCE COOK 1.11'I 1,17. Sr I) . I1. 1) , I rT T 1) Sr irnrifir l)irrrtnr, 'Trrhat cu In Iticlry Researih ('ornmittee /)irrrfnrFnrrrirur, Ruact•e Fl lackarn Meniorial I.ahoratury liar Itarhor, Maine STANLEY P. RFIMANN, M 1), Sr 1). f)irrrrnr linreritut, The Inttilute for Cancer Research Philadelphia, Pennsylvania WILt.IAM F. RIFN1IOFF, 1R , M.f). .I snu-iorr 1'rn/rtrnr of Suurry lohns Hopkirn University School (,f Medicine Baltimore. Maryland EbWIN fT. WILSI)N, Prr 1) , 1.1, n. 1'rrrJetcnr F.mrrirut ol Vitnl Srnriuirt Ilarvard Oniversily ('amhridRe, Mnssachusetts ROIlt tt 1(' II(K'Klil-f, I'll 1) 1 M(11(RISUN IIRAt)Y, M I). .1 ,in, i,ur tr rnn/n Ihrn rnr Anoa rrur .\s irnNfilr I)irr, Inr t Preface The year 1960 was one of great interest and activity for the Scientific Advisory Board to the Tobacco Industry Research Committee. As general lines frrr development of promisin6 research have become evident from ccumulated eaperience, a program consistenl with Ihem is being rapidly evolved. During the year, the T.I.R.C. responded to a request from 1he Board fatr additional funds for research grants by increasinR annual appropriatirnn to SR(Nl,(KIO. T hece additional funds will be for Support of further study in the fields of viruses, psychn-physiok>Rical Iraits (conslilulional diRer- ences), previous chest and lung infections, bio-assay, and tissue culture. (:nr.aotlon TArory of Cmoklng (Inprorrd The cnr,tinued failure of evidence which is qualitatively dilTerent or of increased aiRnificance to appear leaves the causatinn theory of smoking in lung cancer, heart disease, and other ailments without clinical or e.peri- mental proof. Meanwhile, evidence of the crrmpkx factors involved in the origin and nature of these diseases continues to increase in quantily, depth, and scientific significance. The result is that the tobacco theory is rapidly losing much of the unique importance claimed by jtts adherenls at ils oriRinal announcement. It has not received definitive support in the clinic and laboratory. One 11nr.i' Fnrf: Mnr14 Mer. Mnrf 6e Found Out With all Ihnt we have learned in the laboratories and the clinics, work- inR with aoimals and chemicals and people, e><plorinR a variety of avenues nnd approaches, the one hard fact that we must face up to is that there is so much more to find out. We will not find out from over-simplified and pcrhaps super(icial conclusirms as to causation. Such an allitud- would only stille or delay needed retearch 1o find the baqk origins of lung cnncer and cardinvascular tliseaacs, which are most powerful, diversified and deadly enemies to nur wcll-txinR Nor will they he s.dved by puhlic prrmonncemenla or by reu.lu- tirtns or by rcview committees that concern Ihemselves srdcly with suRges- tive nr inctrmQlclc dala. The answers will come only frnm the ;tccumuLatirrn :rnd ciwndinalinn of creative knowlrJp,c acqnircd in many fielda rif endr.tvr,r atrrr palient, careful study 5

SrnflUirnl Ilnfn R.qulr• Clmrlii. In hfhrr Arrn. l'he mrmhcrs rrf the Scientific Adviany Ffrrard h:rve rclx•att'dlv nraJe clear they feel that the slatistical Jata thue; far advanccJ to shnw a sr.nrirrirnf nrawinrinn between smoking and various discascs are sullicicntly suFReslive and important to juslify and, indeeJ, tu require a Rreat Jcal of further reacarch in other major areas. 1 his is necessary in order tr+ evaluatc thc e.i+linR data accurately and to make (rnsible a more scicnti/ic definition anJ analysis of the problems involved. In spite of thesc often-rel+ealed statemcnls, there aprarcntly slill exict mi.understandinRs and misstatements of cwr attitude in this malter. 1t may be of value. Iherefore, to suRFest certain s/eps in research which can be taken Its prnvitlc evidence that will have a higher degree of scientiGc value and that should help in the necess:rry definition and :rnalycis to which reference has been made. R..rnrrR Sfrp. SuRRr.red hirst, further eflrnls should he made to see whether cancer can he in. duced in animal tiseue by the direct kislication of whole smtrke instcad of by artificially rerersareJ cnndensates td smoke. Secnntl, epirkmir+InRical tlita shrtulJ he nhtaineJ hy direct clinical r+hservation rather than by qnevinnnaireet and hc:ntay opinion In such Iun,,ituJinal clinic:J studics, factr+rs anJ hahits other than smrtkinR shrrulJ also be included It is as important In knnw, for eRamhle, why the nver- whelrninR nrajnrity of heavy ciRarelte smrders dr+ rrrrt Jevchrp IunR c:rncer :s it is Irr know why the enmp:uatively amall percentage of srnrrkers Jtt. lhird, pathtdr+Rists need tn make concerted effrvts to imprrrve and aRree upr>n criteria G+r classificalion ttf human lung trnnrrrs into types such rl adenom and squarnnus cell cancer srr that stuJics n/ relative rates of incidence and of prtseihle cnvirnnmental anJ other in0uences nn such rates could be made more mrnningfrrl. Such recearch is entirely prtssihle It is aJrnilleJly Iime cnnsuminR anJ difficult hul it is a necessary tteppinReh,ne toward a level rtf knnwledpe which mud Ix attnincd on the rr+aJ trr arhrtion of the prtrhlcros that may he involved in tnhacco uce in relation 1r, health. Rrp.+rr fry rlr• .Crrrr.trlSr .Llrrl.nry IT.rnrrf 71tis year, for the firsl time since ite form:rtirtn rn mid l'/S4, the Scientific Advisnry llrrard m.rde a ft+rmal report tn thc I nhaccn IndrnaLry Retrarch ('rtnmrittee. llriet rclwnl, whith l.rr.ins trn (•:rre A. ctmsidcr. the rhanrrc Itiat h.vr rK i uurrl in Ihr l.rtt rvrrn yrart in thr alatrra rrf knrrwlrrtt'c ../ Il.r ~rl,ir~.nr.lnt. .•( .n...l-y 1,. hrelll, ir.irw• Ih. ll...nil• %ta'nlltit Ilrn Pram, and diicuscec the nceds and Jirectinns for furthcr rc-carch. l lu ISnarJ states in its report that so far as a linal srJutitm rrl cancer and heart Jiseate is concerneJ, scien(ific honesty reymres acknrrwacdgmcnt that, in the ahsence of greater knowledge of the fundanrental processes invnlved, a simple answer Iir what are not simpk Qucstitrns is unlikely in thc near futme. The Hn:vd has been fortunate in maintaining the scuuc personnel who jrrincJ it seven years ago. Recenlly, however, I)r. Julius 1t. ('nmrrx, /r., a member of the original Bmrd, found that after moving front Pennsylvania Irr (:difornia, the cnmhinalion of increesed professional reslxmsihilitics and genRra~hic distance was making it impossihk for him to attenJ ISoard meetinRs in the east with the regularity he desired. Ile has, thcrefnre, re- siRneJ frnm active memhership while retaining the same active interesl in Ihe Scientific Advisory fluard's program and the willinRness to help it in an advisory capacity 1)r. Comroe's Inss will be a very real rnx, for his kntrwlcJRc anJ originality are Rtea/. Appreciatittn alu> is e>tpressed for the eonstruclive ctrntrihutinns of -I .LR C. Rrantees and scientifie ennsullants, and of p:rrticipanls in the enn- fcrences splmenred by the Scientific Advisory FtnarJ. "I he rrmemlxrs of the 'f I R('. alar are to be commended for Iheir eontinued, Fcncruus auplxul of Ihc rescarch proRram, and fcx enabling Ihose of us reslwrn%ihtc for the frr+gram Itr work with Ihe most complete frecdom. l heir Iru.t in the mcm- hcrs of the Scientific Advisory Ilnard is stimulating and warming. C. C. Lnit r Cr irnliflr I )irr. tnr 7 ti

Report Iry Ilre S(;1EAN7'lFl(; AI)V1S()Itl' It()Alil) to tlre T/11IA(:(:(/ INI/(ItiT11Y It!•;tiFAR(:1/ f'Of111111'ITF:F. At the end t,f itc firtt tix ycart t,f r,reratit,n, the Sricntific Advicnry flr,artl dccmc it ndvic:,hlr In takc tlt,ck t,f Ihe chanpcc which havc r,t currt•d tluring tllit f,t•ri„tt in Ihe ttatut nt nur knnwlellyc t,f Il,c rclatir,n.hil, t,f tmnking to hc:,llh. In review i1t scicrltifrc prt,gram, and tn cnncitlcr thw needs and tlirt•clitm for furlher wnrk. At the rrnlr IIIr Itt,:,rd wac ectahtichcd, cpidcmildt,fica( ctuttict rcfxat- inR in acct,ciatit,n hc-Iwccn ciR:rrctte tmnking and cant'cr t+f Ihc IunKc were LcinR e><tcncivcly pul,licired 'Ihc hyptHhccic that thit rclatit,rr.hip mip.ht rcfreccnt a cantal t,ne wat hated in part u(,tm cupcrinlcnlal ttwticc ill whith it wat rc(,t,rtctl Ihil thc pruh,nFcd appflcaYl,n t,f ccrtain cirnrt'ttc crnt,kc ctmdcncatcc In the tkin of the mr+uce wac c:,l+:rhlc nf prnttucing malign:lnl chanRct. 11 it frt,m thit f.cttpcclivc Ihat arlv:rncct in nnr undcrcl,n hng nf Ihc prtr},Icnr dnrinp, fhc I+ati cix ycarc mutl Lc evalunIrJ. Maj.ir elTort h:rc hccn dcvtdrd In the inrlcpcmlcnt itrvectiP:rli,m td the two Rrcat fichk I+f cancer and t,l cardit,vaccular Jitcace. Ilterc have hecn dc/inilc atlvintrt in knt,wtcdpc and imprnvcmcntt in Icchniqnc. So f:,r at cnrtccrnt n final ct,lntinn t,/ Ihe prt,t.lcmc, ccicntitic h„nrtty rcqnirt•t ac- knt,wlydgmcnt that, in the ahccnce t,f Freatct knnwlcdfe uf thc fumlanlrntat prnt•ccccc cnnccrned, a timplc ancwcr tlt what are not timplc yncctit,nc it untikcly in the ncar fufure. F,rtrnrrdrd Rr'.a•nr.-h (Iffrr. Rr.tt llrrlrr ('nntinuctl clltatt in ttimuIafc Ihc hrnadeninc antl tfcereninr, I,f re- cc:,rch in aII arcat whcre knowltdy.c ic dt•ficicnt tdlcr Ihc hcct ht,f+e fnr L',c futnrc Much tut t,ur rea•arch lanl,r:un hat f.ecn funtlmmn•ntal nr ha~ic in char:rctcr -:,n arc:r where pt,+rtete it Irtc (t-rl.lin hul IIlr fw,c.ihlc rcwardt rre:,tcr. '11hit h:,c hrcn :,chievcd wilhnut ncl.lt'clinp t linit :tl pruhlcnrt ar'J trthcrt having (uattical aly,licatinn. N;uurnlly, it takct tintc fnr n vcnturc nf Ihit ct,rt Ir, P~t•t unltrr way, h,rt il ic n,+tc.vt,rlhy Ih:,t gr:mtt Ir:tvr I,ccn matlc It, mtnr Ilh.,n ItN/ cticnti.ft rln :,h„ul 11) mrtlit'al tthtm,lt and tdhrr rrtt•arttr in.tiuwi mn. Ihttarl4l„nl ILr ,„nnltv. rrl„rNrnlin/• an nvtf:,ll (Irnantult .nf,la,tt uI nt':,rly t•1,/NN1-f/l/ll Already appr.,aimatefy 137 cnnfrihutinns presenting Ihe rctults of work dnnc undcr Ihit tuphtat have been puhlisired in Ihe ct•icntifiC literalore. livcn Iht,up.h it mutl he admitted that the effr,rl thm f:v hac barely scr:ttchcd the turface, e.cellenl scientific studies have hccn reported, and it can contidt•ntty he assumed that the facls revealed will ullirnatcly cnn- Irihute to Ihc totutian of the broad yuestions which concern uc. Hul per- haps the mnct tignificant development has been 1hc general recognition that we do not yet have the answers, that an association between the extent of tobacco use and the incidence of lung cancer does not prove a cautal rela- tir,nchip, ttctt cwpcrimenlal veriRcatinn it ctsential and that lhcre are a numher nf other factt,rt which need to he concidered. We are not satitfied tn Ict the problem recl with statistical reports suRRetling that heavy srnnking increacet the rick t,f cancer of the (unR; we are intcresled akv in knt,win6 why the overwhelming majnrily nf heavy smokers do nt+t contract the dicease dctpitc their smoking. We are also vitally interested in the meaninS uf the rearltt, derived from Illc +tame dala, that only a tmall fractit,n of the repurlcd cxcecc dcatht in the heavy smoking group is iItributablc to cancer of the hmg. I,nnR l'atlrrrlrrRy Strr.ly oJ 3,000 Casrs In revicwinR the resu(ts of the scientific (+rt,rram, a few c(,cciffc con- trihulit,ns will he selected which are ilhnlrattvc of the v:vinut linet of research undcr way and which have contributed to a changc in viewpt,inl. A ccx,pcralive sludy of tung pathology on aulopry ntalcrial in -l,(NN) catcs frtrm 12 hospitals in notable in several respects. It reveated wide dilfcrenccs in interpretation uf the same slides by ditferent rnernhcrs of Ihc grntrp. II demunstraled a high incidence of epilhelial changes in the hrtrnt;hit,les, evcn in the rounger aRe groups and, while the incidence of hyrcrptacia and mctaplasra waa urmewhat Rreater in Ihnse with a hitlnry u/ heavy cmt,kinR, "carcinnma-in-silu" was seltlom secn. An experimental sludy in which mice were e><pnsed fa cigarette smnke daily retulled in chrnnic hranchitic in a variable proportion of mice in each group witlr cpi/heliai prnliticratiun which in tnntc instances rescmhtctl "cart:int,rna- in-silu," hut never proRrested to carcinorna and reverted to normal when expt,cure to snu,kc wnt dict•anlinucd '1hcse studies were significant ( I) in tlemnnstrating Ihe need for 1nt1(rer sludy of tittue pathology wilh reference lu Ihc rtttc uf infection and the unifnrntity of inlerprrlaliun, and (2) in hrinFing irHn yncclitm the validity of 7desi6nating hypcrplastic chanFes in lung epithclium as precanccrous. ' A large noml,er of differcnl biological systenis, including rnnuce-tkin painting, have fx•cn tried in Ihe attempt It+ ettahlith ttnnc relative fwltcncy rating Inr eifarrtte tnwke cundentate nn a rational senle r,f carcim,r.enic activity 'f he srnnke cr,ndentale hast proved to he inactive in mtrsl nt thete tetlt, and in tcvcral cates dre mclhndt have been found untalitfaclt,ry for Ihe intcnded purf>„tr. Nn dcfrnile eviderree eaitts Ihal Ihe retpnncet uf painted mtrute tkint ate inlerl,rclahte indicators t+f earcinnRenic harardi h,r the human lunr: ('nntrtyucnlly, we hnve selcctctl a few trf tht• rnntt `tttl rnitinr. hir,atcay Irchnitluct fr,t ftulher sludy nnd devetnl,menl in the Itu(,e uf I+crfet:ting a mnle ral+id nnd tcliahle atcay. 'Ihuugh it t_cuvlut be r A 9 J ©

I said that a relative potency titinR fnr cigarette smnke eondeneale has yet been achieved in any quantitative scnse, the exten+ive aSSay crprrience has created the general insfiression nf auch kehfe activity as tn shift the hxus nf attentinn to olfier plausible mechanisms whereby tobacco smoke might contrihute by indirect means to the palhtrgenesis of cancer. Studies nf the influcnct of smnkin6 on Rastmintestinal function have ahnwn that there is no signiacant effect, either in normal pcrsnns or in ulcer patients, on the eompenition, amounts or rrt.prrtict of Ractric secte- linns as indicated by eight measured paramelere l hcse findings suggest that the reported statistical eorrelation of cigarette smoking and peptic ulcer may reflect association between the ulcer-prone temperament and a tendency to smoke rather than a causal contribution of snntking to u/cer Renesis. The cardiovascular research program has shown that the response in man of the peripheral vascular system to nicotine is usually, but not always, a diminished blood flow in the skin of the extremitie., while dila- tion occurs in the deeper tinues. Changes in the coronary artery circula-' lion, when nicotine ahsorptit.n is sufficient, are in the ditectitm nf incrrased hhxxf flow sutTrcirnt to meet increased (uxyRen demand altendinr increased ntuscular wnrk. 7here is sorne indication that these tesfxtnses may he modified in the presence of a croscknnis Measnrements nf cerchral blood flnw in healthy persons stowed nn significant ehanges induced by smoking. l1i f)t'rrrtr•r•a Rr/rortrr>t Rrrur.rn Smokrra nr1r1 Nrsn-Smnkrra Evidenee has been collected in show that smokers, esl.ecialty heavy smnkers, differ in Icmf+eramenl and personality fhnm IiRht or nnn smokers. More recently, an assnciatiun hclween -.mt+kinR patterns and txxly build has atso heen demnnstrated. lbcse nhurvalions conform with earlier studies on twins, and lend snpporl to the concept that at Icast sttme part of the assrxiatirins nf smnkin6 with particular rlisrases ritay reflect a ctanrnttn enn- stilutinnal predisfxnition rathcr than direct contribution or srnukinR to causation. Studies of pulmonary physiology as affected by .mnkinR have shnwn no consistent significant changes in hhwK1 gas eachanle at rest or after one-minute step up exercise, hnt some fall in oxyRcn urlake dnrinR tread- mill e.ercise after smokinR. Pulrnanary compliance has f.een varitrusly re- ~+c.r1ed as decreased after sntokinR and Also a1 unaRected in normal fxratns. In emphyscma and chronic hrnnchilis the changes induced hy smt,kinR are pcater. l.onR•lime smokers are rernrted to show snrnewh:tl incrca;ed residual IunR vnlume, and hrwly plethysmnRrarh mcasurenrrnt indreatrs snmewhat increased airway resiatance fedlnwiny, srnttkinF, an rtlcct not dnc in nicutine A etrnsideralrlr mmrher of ha.ic uuAics have trccn efrme whit h rel•rr- +ent imiMtrtanl cnMnhulittns tct r,ut rcscarch prt,pta+n. F.ul which wi/l not be dca'ritxd here in rlrtait Some nl these are in the Pencrnl arra nt chrniic:tl synthesis and hrcakdtown of the ct-nstiturntc ttf tnlraccrr inclurling mrrhyla- linn trattittns, mNa,,,li~rn r.f fiyrirlinr cnml-inrMs, rntyrnntic fii,tu„rn r+f ((),, .nd rhr IMJyl,hcnt'l ct,nlcnl trt Iravrs ()thcr slutlies have c„nicrned If/ t fnndamental aq+ects of eareinn6enesis, and include observations on the early changes in the lunils of tumar-bearinR rats, the cyarluRy and nuclear dcowyrihtnnrctcic changes of skin and lung epithclium exposed tn catcino- gens, and the action of carcinogens on cultures of huntan IunR lis.ne. With T-.I R C. suppcxt various aetivities, designed to pntniote the ob- ctives (+f the Scientific Advisory hoard other than through research 6rants, have heen initiated. These include the preparation of a"slandard" cigarette smoke crnndensate produced under eonditktns of natural smukinR, thus makinR available to grantees a uniform product. To overcome the shorlate of inhred slraim. of mice needed in the research prolqram, a gant was made tu expand breeding facilities. In jorrtrel (:on/rrencea to Fxc)renRe Ideas, Knowledge rot the purpnse of promotinR the exchange of ideas and to evaluate the atatus of existing knowkdge, a number of informal conferences of workers in specific topics have been held. A conference of pathnlnRish, meeting to cttnsider the signifxance of changes in the lung epithclium, has Icd in a crMrperative sludy, mentioned elsewhere in this rep,srt, which has bcen the suhjcct of scveral additional conferences. Three conferences con- cerned with the cardiovascutar effects of nicotine and smnk in6 culminated in the orRaniration of a three-day public symposium on the subject held under the auspices of the New York Academy of Sciences in March 1960. In the field ~f tissue culture, the topic of two informal cnnterences, there was recognition of the shortage of trained pursonncl and provision has been made to enahle several 1aMxatories to train additional workers in the spe- cialired Iechniques required. Other canferences, all of which have contributed lo the scientific pro- Fram of the Uoard, include two on hioassay of carcinogenic compounds, one on the role of infections in the senesis of lung cancer, and two on the hcarin6 of constitutitmal or psychological diffetences on smoking habits. lhe T.I.R.C. has also rrovided funds to make possible a symprxium on At- musplreric faclors in disease heW lanuatp 1960 at the University of C'ali- furnia under the litle, "7he Air We flreathe." With the object of encouraging able students to embark on a career in science, an annual grant has heen made available Iro ench ntedical schrKtl in the lMitcd States tu provide a felluwahip for wrrrk durinR Ihe snrunur nrnnths or other holiday perirxl, unrestricled as Itn subjecl. lknrnher si/;niticanl conttiMrtitm has been a Rtnnt 1u make I+t+ssihie the prcparatirm r,f A hntrk nn the hiolugic effects of tobacco and nicrrtine which will I,c puhlkhcd in the neAr tuture. This larRe valumc, hnsed tin a very conqdete review of the wnrld's literature, shrnrld scrvc as nn invaluahle scauce htNtk fnt infurmalion on Ihe suhject. Alrrrry Itrsr•nrr•ir Arrna /irinR Stttrtfrrl 'I hc Scicntific Advisory ftoard has Itivcm mtich crmsitlcratirrn tn the dirrclittn nnd enel,ltasis of ils rescarch prrrl rattl As it can rnrra latr/it:ihly he developed in thr ycars immediatcly Ahcad In nrtttt inalant'cs stutthrs ntrw unrlcr w:ty rnncl I,r ctrnrrinncd bul the Ilnard it cit(rlrrrinR nnrl, in st,mr cnscs. Itlatts nte wcll ctlt+nR tttt c tltandinR, certain lines nf wurk and atddinK t,thcrs II

t hrxc tcccivinR rnncidetalinn arc: I I hc fx+cail.le role tit t,rcvinus infcclir,nc tit injnrics in the nril!in tit 2. IunR cancer. Vttcnsit+n nt hinacsay r.ncth,Kls (nr carcinnRcnic activitY. A crunrarative stndy of Ihc activity tit Pipc, cigar and ciparclte hrh:rccn cnrnke condcncatcs prnduccJ undcr idcntic:+I cnndititmt. 4. Imprnvcn,cnt in t1i:rRnncis of early IunR Iccianc. 5. 1 he tx+ccihle rt,lt of viruset in earcint,Rcntcic. 6. l he qucetinn of threshold dose and latenl time in chemical car- tinnKcnccis. ' 7. 7hc hiolnfical activity af smnke in termc of the rclalinnchil+ he- twctn its varitnrs cnmf,c,nenls with a view tn throwing Figt t on p+aeihle anticarcinnRenic influcnces of analnRues. R. litttncinn nf the /icsuc culture techniquc for ctudyinF nnrntal and ahnnrmat Rrowths, includinR utilizinR the newly l+crfcclccl .yn- Ihctic m47116. 9 I'urlhcr ctuJics nf the influcncc tit anu,kc and nthct atmr,cldretic Ixdlulants On the IininP tit 1hc Mt+nchi, includinR tlhc atrrvity of Ihc cilia . I(1 l t+i,lerni„Inp,ical ctudies in relatir,n to Nhnic, sncial, cct,h,Rie and cuhural rhflcrcnces. 11. A pithnlnRic study nf urhin and rnral po{,ulatinnc. 12. ('nmrncitinn nf cmnke with reF:uJ tn particle cize and cnncentta- tinn nncl irritant aclinn t.f cr+t++y",ncnts, singly and cnrnhincd. 11. Mtch:tnians of parliclc nhcurlHiun and tr:rnclxat hy rcci+itatnry ctllc, nf nnrmal and altcrnt mucr,ns cectelinn, tit nnrmal anJ al- Itrcd ciliary activily, antl of nrrrntat and altcrcd ccllnlar rcrcn- ctalinn, 14. The tnle nf thc r,utoni+mic ncrvnus tystcm in modifying thc tntal hnet respc+n<e and that of Ihe resririlt+ry cl,ilhcliunt 15. Studies nf hum:,n twins (nr the purpnsc nf analyzinR heredilary and envirnnmenral factors in diceaa.. 16. Pnssihle changes in moulh and throat micrrN,rR:rnisms in srnnken. 17. C'artlinvaccular respnncea tn smnkinR in snhjecls with :,Ihcrn- scltrosis and othcr disardcrs, including a dircct stu,ly nf rctinat vcs+els. 19. InOnence of smokinR and nict,tine nn the cr+mflncitit,n and prnp- erties of blood. 19. Cnntprricon tit the (+cythnrn~iraI And I,hycinlrrRicaI cffccr. nf smukinR with Ihn~e t.l Iranyu,tircrs 20. lhe qucstit+n of tx,scihle a1lerRic rtactian. ti. Ir,hacc„ tnuAe 21. A ct,mparican af thc I+hycical, carnlinnal unrl I-ythoh,pical char actcricticc tit cmnkcts with nun-smr,kcrc 2] 11u r/1r,1~ „l Stnl,l.inr, cm„kinp I r T.I.R.C.'. Support .lppreciated In concluding this repnrt, the Scicntific Advisory Board wishes to record its appreciation to the Tobacco Industry Research Committee for prnvidinR large sums for research and for approving all its recommcndatinns withnut question. fl is appropriate to make brief reference to the Board's experience since its establishment. "The Ilnard has held meetings at kast quarterly since its organization, and has awarded considerable money to investiaators, but this prl;sent com- n,trnication is the first report it has made to its sponsoring organization and this withrntl request. To u1 forth an evaluation of accomplishment made by this approach 'o the suhject, whilc the credit does not accrue to the Board or its memisen, certainly one of the most siRnificant occurrences is that a major business indus(ry has organized itself to determine so far as possible what, if any, effect its prtxfucts have on the health and well-being of ils customers. We must continue to search for scientific taknt dedicated to thc seeking af knowledge and support it fully so that it ma~ be freed of insccnrity which may hant.lrinR il. We must continue to kt it be known that we are in that search, and applicants for projeeled research ahnutd t.e supported if their idcas nre prnrnrsrng and their opportunitka good. We musl cnntinue effnrrs In stimulate broadening and deepening of rexarch in all of the nress where knowledge is scant. We must not be disturbed by inconclusive andlor faulty «porls, nor resct against them defensively. We must continue to promote true basie research in the inlrncellulsr processcs tit life and in the multice11u1ar living organization even thtwgh, in some inslanccs, this will have no obvious or immediate connection with the practical quection of tobacco and health. At the tobacco industry continues ils support of the search for truth and knowlcdge, it must recognize. as is Iways the case in true scientific research. Ihere can be no promise of a quick answer. The imptirtant thing is to keep on addinR to knowledge until the accumulative Iacls provide ttx basis for a sound conclusion. Kenneth Merrill Lyrxh, M.D., ScD., LL.D., Chai.nton Richard 1. Bing, M.D. McKecn Cattett, Ph.D., M.D. lxon O. Jacobson, M.D. Paul Kotin, M.1). (larence ('a,k i.itllc, Sc.D., LL.[)., Litt.D. Stanley P. Rcimann, M.[)., Sc.D. . William F. Ricnhnfl, lr., M.D. E?dwin 11. Wilson, Ph i)., 1.1,.1). 12 13

Results of Research The constantty gowing number of puhlished papers on sludics sup- ported by the Tobacco Industry Rescarch Conrntittee is a mcasure of the prnRress of the research proRram. These papers, which lotaled approxi- mately 137 by the end of (ktnher 1960. are ahatracted individually or listcd elsewhere in this Report. An additional 22 papers, given at a cardio- vatcular conference held during the year, were subseqaently published and re listcd on page 22. In this section are summaries of the findinRs and major points in several important fields of study. At times the summaries may cov-r re- search not yct puhlished in full. Not all the studies in progress or com- pleted are tliscu.sed here. Thr%r aumrnarirs are• I(-ancer firse>trch; 11 Ifurnan I unR S/udics; III Ilcirt and ('iTculatn+n; IV. Ptychn phyiinlopieal, and V Tohaceo (-hemidry 1. (:onr Pr Resrnrr•h Sevcral studict on Ihe effects of tobacco srnoke and of smoke con- dcnaales nn anim-A liccues h.ve been rcptrrtcd JorinR the pasl year, at well as a number t+f cnllatrr:rl atudies in the cinccr firld whith diJ not involve the use of tobacco Tobacco smnkr c~ ndrm~trt in Ii.lurJ f ctrnl;rlunr wcrc intrniluccd into Ihe trachea of young adull duckt tl.rrlv rwer hurR rrrinds ul trme ann en- cnmpacsing up to 110 injcctiona No changes WFr.cctinR ncoplasia dc- vclnped, thnugh .nme acute and chronic reactions occurrett Mnh amnng treated docks and in same untreated birds as well at in some receiving only petrolatum. M one of a series of control sludies, ducks were also given rncthylcholanlhrcne in aeveral forms by the nra/ route. GaslrointestinTf system tumors were not pr«fuced by Ihcse means. An ex/ensive study was ctrmpleted to deterrnine and compare the eRccls o( various inhaled gases and aerosnls on the activity of the cilia of hrnnchial epitheliurn and the rate of flow of the mucuus slrcam. Various inh:rled aRenls, including tnhaccn ~muke, were (ound to he capable of /emptaarily inhihiting ciliary activity nnd delaying movement nt the mncous htanket. Tbe eorrclatinn o( Iheae effects with meupholagic chanRes of the reapiralnry erithrlium was nhrr heRun 'lhrse ohscrvatinn+ have cm/+haaircd the need (nt further wttrk tn evaluate the hmctierns r+f ntucaa ae a prr+tective mnterial, the drf.cnrlcncr of iti functinnt ufxm c'hcrniral anJ I+hy.icnl cnm f++ni/ir+tt., aftil ,I+c (:+t lmt whith t'~n nmatify cr+m(ti~tilinn T he tnrch.rni.rns I , that influence ciliary activity seem also to call for further elucidation, af dtxs the overafl tofe uf ahe ciliary-mucus system in proleclion against exlraneous inhalcd careinr>Renic aRenls. New studies have been authcxired along such lines and an investigation of the effects of air ions upern cilrary behavior has bccn undertaken. Smnlr. ffnr no E:erct on Mnn.e /,unR Ad.noma. Two scientists, reporting further on their tobacco smoke inhalalion sludies, (ound that the incidence of Rrossfy visible lung adennmas in female CFr mice is unaffected by prolonged snwke exposure. ('ollateral studies have included extensive observations of the chrom- osome numbers and pbidr of human and animal cells cultivated in virro, and obscrvatirrns on the responses of mousc and human cells cultured in virro tn acetaftkhyde eapenure. Another researcher has nhserved the sensitivity ot Ihc rnnuse fore• stumach to carcinoRenie hydrucarht+ns painted nn the skin nr arlrninisleretl orally, and has suRgested the utilization of thia scnsitivily as a hnais for  bioacsay technique. An eRperimenl has shown the enhanced ability of lissue slices from several organs of rals bearinR (he Walker or Jensen tumar to inccapotate labelled Ihymidine into deoayrilxHSUckic acid (1)NA ). Annthcr investigatnr ha% reported detailed pathohrRic studies of the interrelations helwecn inflammation, keratini>'atirxr and RIyu+Rcn deposilion in alvcnlar mucosa and gingiva. l:nn/.r.ncr nn (:.ll nnd Ti.aue Calturr TTre T.1 R.('. has been supporting research in the ficld ol tissue culture (or some time. I he wotk las included attempts to eatahlish strains of dif- ferent human lissues, especially lung lissues, so that reaponsea of such lissues to carcinoRenic and other agents could be ohsetved. It is hoped that this area of endeavor will provide new and helpful in(ormata)n a(xwt the mechanisms of carcinogenesis. (irantee+ and other scientists working in cell and lisare culture or related ficlds of reacarch met for a diacussion nn May 24. 1960 AmonR thuse present, in ,ddilion to members of the Scienlific Advirtrry 1lnard, were Ihe folltrwinR: OR. PIIt1.IP ('(x)PI: .R, hR. IVY (IO11)RIN(i, MR. MORRIS KI I:tN, Mt.erl F.indein ('olltRt td Mtdicint, Ntw Ywk, N Y. 1)R. (iFUROI O (',f Y, 1)R. MARY Rt t7O, M1SS Itt:.t)A I INI)1'N, I innry ltu.•rll ('.ncrr Rr.cuth I slw.nurmy. Ir.hn. /IopAin. lt4..pil.l, 1lallimnrc. Maryl.nd DR. ('1 ( 11 W i 111('II It N141•R(;I R, ('hildrtti% ('nncct Rt.c.'r.h 1'uunAation, 1luslon, hta.iachusNl. 14 IS

f)R. AI.VIN S I IiV1NV, Indiana (In/ver\Ity MrJ/l':d (-rntrr, Indlan- qrdis, Indian. DR 1111 1. P. MAI)UROS, Ihc Itrktncn Inaitute Inr kIrdic.t Re- je.rch, ChicaRo, Illinnk DR IX/NAI 1) M. PA('fi, Inainne for ('rlhdar Rricarch, ltnivrrmity of Nchreak., I.inculn, Nrhra.ka DR O I fOI I AK• DR. lAIStrO K(1K1t1111, MRS PAICY S Mf1RROW• IMvcr Medical Re.esrch ('rntcr. Inc , Unver, 1)clawue I)R (-. M POMfiRAT•, 1)R. A. AWA. DR. Y. OIINUKI, lhc llni- 1)R vcr.ily of I c.a. Medical Rranch, (:alve.t,.n, I curs AI.AN S RARSUN, Pa11x.k+Ric•Anatnmy I)cPartmcnr, Na/innal In.titurei of (le.llh, Rethe.Ja, Maryland DR. SARA/1 E. STF.WARI, L.horatnry of RiolnFy, Natinnat (':rnccr Inititurr, Rrthnda, Maryland 1)R. ('HARIIY WAYMOUfll• Rmcrx R. )ackurn Mrnu.rinl I aMor- tory, Rar llarl.nr, Maine I'IrnlnRy ( an/.renre On May 21, 1960. an informal conference covering llie suhicct nf virtnes nnJ thcir plrssilhle relaliunship to human cancer was hclJ I)iscus- sinn centerrd un the present slatq nf knowledge concerning the role of viruses in c:rrcimrFenesis, and prnmisinR areas for future rescarch. Meml.crs (•f The Scientific Advisnry 11narJ attendctt the sessitrn, as did Ihe following recipients of l I R(-. Rrants nnd nthers doing research in Ihe ficlJ: I1R, 1/1(/MnS P ANI)I RSON. Ihr InditWe for ('ancer Research, ('hil.Jclrhia, Pcnrnylvania 11R. 1'I111 II' 1)R IVY (i()1 1)RIN(:, AIF.rrt (?invcin ('nl- IrRr nt M"hcinr• New Ynrk, N. V. 1)R. (il'(/R(71? (71:Y, DR A1ARY Rf1.1/, I innry Ilnwcll ('ancrr Re- nearch I alx.ratnry, lohn. Itnpkint Ilntrit:J. H:rllimnrr, tvlaryl;rntl 1)R. ('f('I1 I(; I 1:(1('1111'Nf11 R(i! R, ( hildren'. ('anccr Rc%carch 1'ounJatKrn, Rnitnn, Ma..achusrtti DR. AI.VIN S I 1?VINE, InJirna thtiversity Mrdical ('enter, InJian .I+olis, Indionn DR. R111. P. MAf)URf1S, The Ifeklr.cn Inaitulr for Medical Rr fr.rch, ('hiuRo, Illinois DR. ('IIRISTUPIII:R M MnRIIN, I)ivision of Infrctinus 1)i.r.ers• Scton IIaIt ( nllcRe tlf Mcnccrne, Icrsey ( ily, New )rrsry 1)R C. M POMFRAI•, The Ilniver+ity of lr.a MeJical I)rnn(h, (:alvcdon, Ir.a. DR. AI.AN S RA/ICON, PalhnlnRic-Anatrmty 1)cpartmcnt, Nati.m:J Inslitrnrs of Ilralth, I1ct/,csJa, Mnryl.nd 1)R. SARA11 Sl1 WAR 1, 1 ah.xarnry nf Ili.d.r~y, NatinnA ('nncrr In.litutr, RrrhrsJ., Marylnnd 1)R. IIt)WARI) M 11'MIN, 1)ivisiun of fln.lnr.y, of Irihnnh.Ry, PaV/JCr1J, ( NIIlnrnia (':Jilnrnin Inatilulr I/R ( IInRIIY WAYM()(/III, Rrn...r 11 ),"'n Mcrnnnll I [:ven prior to this cnnference, increascd emphasis had heen placed upon rescarch to evaluate the possible rnk of viruscs in carcinoRenesu. I he study of virus infections of the respiralory system of rnice in producing tlysplasias either with or without smoke inhalation had heen undertaken as an t•><fension of the smuke inhalation sludies. Investigatinns of the inler- aclinn of pdynuclear hydrocarlXins and of trace melals with viruses have alsn been sf+trnsnreJ. Synrpmium on "TR,, Alr Rt'. Rr.ethe" On January I(i-18, 1960. a conference was held at San Francicco on '•Man and Ilis I?nvironmenl: lhe Air We Breathe" under the combined auspices of the llniversily of Califnrnia Schrwl of Medicine and University F:atensiun-I)epartment of Continuing F:ducation in Medicine and IItalIh Sciences. Partial financial assistance frx the meeting was contributed under a grant aprrnved by the Scientific Advisory Hnard. 'Ihe Ihrec-day scssiun crmsirkreJ the environment as a whole and frtwu Ihe widcs/ birrla8ie point nf view. Seienlisls came hrnn the Uniled Statcs, FnRI:mJ, Wales, ('eru, and New 7.ealand, and many disciplines were represented. Among those present were physicians, palhnlnRisls, physiodo- gists, ecnlogists, town planners, and engineers. 'fhe problem of air pollution appeared lo he uppermnst in the minds nf virtually all the participanls, and the subjccl nf smnR was stressed in many of the papers. ll)e statistical analysis of lohacco in relation to lung cancer was the theme of a discussion by two scientists with cnnlraslinR views. Une siynificanl report was made by a New Zealand scientist who Jis- cussed his finJinRs on lung cancer among EnRlishmcn who miRratcJ 14, New 7.ealand as compared with nalives of that country. Itolh Rroups had the same c~mstilutinnal or hereditary makeup, the snmc way of life, at>,1 sintilar eating anJ smukinR hahils. Itul Ihe former camc frum smnR-fillcd industrial alrnnsphere into an unpolluted atmosphere. 1'he incidence nf lung cancer was J/) percent higher amnnR Ihe iatmi- Rranls generally Ihan arunng the native-born white residcnts 11ut imrniRrants who came tn New Zealand telatively late in life, n/ler spcndinP llt or more years in 1•:nRlaml, had a lung cancer incidence alxiut 75 prrcrnt ahrrve Ihat for New 7ealanJrrs (tf the same age. The Nrr.cceJinPs of The sympraium are esreclcd Irr l.c huF.lishcd shnrtly. 11. llrtmnn LunR Slrrrli('. lhe nrrrl fnr mnre ndequa/e and comprehensive mcthr"ls for nrrn%ur- inr. nnJ rv;JunUnP hnm:m lun/ lunclinn has FK'cn rrt'rrpnvrJ us rnrc nirans rd irnlarwinP thc study r.f clnrmic anJ prupressivc IunF Aict.r.cs A I 1 RC O. A r r, 17 J 4~

I i Rtanlce haa I+uhh.hcd Iurllier wttrk rcf+outinR :t hattcry tit tuch teats with irnrrnvcrncnta and rmKlilicatitrns. I hc cflccta nf amtrkinR nn cuth hulrntmary functitm h:v:unctcri have Previt,ucly I.ecn rcht,rJCd in a nunJrcr cd puh- Iiahcd .tudic+ New studici havc hccn undcrt:rkcn ttt crnplny lihc IxK1y plcthycmoRraph for mtnc prcckc dctcrminalion tit airway rctistanc'r and reaiduml IunR vtdume, 1'articipaliun in a prtrclx•ctivc study nf chrttnic hing discIce h:r% alco been cllcctcd in the cxf.ectatitrn of attaininR morc prcciac t/clinitittn tit these clinical cf+ndilit+ns, IK•tter relalive ev:rluation of etitdugic factrrrs Ihat cun- trihutc tu their oriFin or aRFravatitm, and fullcr undcralantlinR td their intcrrclalinnshirs, natural hictnry, and Ircalment. 1 I1. llr•arf and (:irr•rrGrfirrn A cr+naitlerahlc numher u/ investiratitrnc in this field reacltcd puhlica- tifm durinR thc year, nf whic'h mmc than half wete nf a fundnrncnl:rl n:rturc LcarinR no drrect, immct)i:rte rtlation Itt tobicco clfectc hnt hn+:tdcninR the hasc uf underclandinR of cardittviyular mclaMtlism and funclnms lhel c arc dcacril.cd amnnr the eh.trac/c hrllnwinR Ihis seclinn. One Rrvrup trf ~t:icnticlq his ahnwn a cftrrclatinn between allergic re- actiont to Itrhacco c%tractc in henlthy tuhjccta :rnd their circulitrrry rc- SLtlnse4 tn amnkinR at mcisurrd by plNhyamtKrafhy, h:tllislnc:rrdit,l:rafhy, and tlcctrtt arditrRral hy 1 hctc rccults aukl-ctl a title of tnh:ucn ccncilivity in dctcrmininR the individual ditfcrcntcs in cardittviacular reaf.f.nacc that have hmp lxcn rcflcctcd in 7filircnt diccrcrancict amnnF thc IimlinRs tit dilfcrcnt invcstiKittrrs . The cnnalitnliftnal and heretlitary comptrncnta ftf rrctlitlxnilitm ttt cardittvatcular Jiae:tte h.tve rcccived furthcr clucidalittn thrmuFh the ctathes tit another invctitir.attu. Fvaluatit+n nf facttaa influencing scr.rrn chnlcsterul Icvclc frt+m (1ay Itt d.ry has perntittcd further cttntirmaliun nf the corrcla- titm between high mcan and rel:rtivcly /luclvalinR chtdcsterol Icvcls and thc inciJcncc t+f ct+rtm:ny tx'clu.it+n Familial tcntlcnt-ics in rcC:trt) trt hftth ttctIuvitm and hiyh aerum ch-clcstcrol were ohscrvcd Il.•rrrlirnry Unrtnra nn.f Snr..kinR /trhnri.rr ('nnstilutinnal tlifTcrcnccc between vnrrkcrt and mm anurkers have Itcrn rli%cnvcrcd whit h suyFett Ih.tl hcrcdit:try lat tr r. Ll.ty a vi/;ni/ic.tnl nrle as dctcrmin:trtta td %nntking f.clravitu within thc cnvirrrnmcnlal Ir.rrnrwruk uf Antcric:rn Ide Ile,tvy ciF:vetlc vntrkcra alwrw a.Irikinfly hiphrr in- cidcncc rit thc ~,cnctically dctctmined al,ility 141 I:t0r Inccnyttltinurca -Ihc .vm-kt-r.:t1.n, av .1 rr~nil., rntnc.ftt n P.ivr a ln%t.rry rd hvla-rtrn"wn tit I,trcntt Iht-y lr.rvr hrl•,ht•r ruc.ut v;ilncs hm hrarl ratc artd Iwl.c lactttnc, hil.hcr thulcstcrnl v4luea, annpri.c a IarRer profwxtitm tit heavy individuals, and mtrre rtltcn report e.pcricncinR anRer and an urRe tu eat when under slress. 7 hc crRt+metrinc stress Ictl for tcvealinR cruunary insuniciency in Lcrcnns with early coronary disease has been furlhcr stutlicd by trbscrva- titrns rtf thc cllccls tit Ihc drug on isolated ht:rrt% of chttlcslerul-1cd rabbits. Crtntparisnns with Ihc actitm uf vasopressin and nicotine have been carried nul. One researcher has reported the occurrence of lipid infiltration into thc iris of rahbils fed cholcslerul as a dietary additive. Additiun of nicotine to such diNs did not obviously rnodify the cfTect< of cholesterol. f:nrdifrr.vrrrufnr Sympoaium A cnnference on the "Catdiovascular Cffccls af Nicotine and Smoking" was held under the auspices of the New York Academy rif Scicnces in New York ('i1y, March 24-26. 1960. with a grant awarded by the Scientific Advistxy Hoard. In the expressed opinion of the participants, the Rreatest achievement of the mcetinR was to assess impartially the effect of cmt+kinR nn the heart and circulatittn. Thirly-four pafxra were presenled by scicmiatt engaged in cartliovatcular research, and two panel discussions were hcld an importanl phaces of this work. The crnnference, Iherefore, includcd an excellent repre- scn/alic.n of the investigators who have been studying Ihe effects of nicotine and smokinR on the heart and circulalion, and provided a funrm for dir cussinn of Ihcir eapcrimental findings. lhe evidence pre%cnled gave no indicatinn that smoking has an adverse effect un the normal heart or inlerfcrea with the ctxonary circulatittn. 7 hree papers presented tlala suMslinR that the tRccls of nicotine are allered by the prescnce nf coronary artery disease - an iml+rntant topic for further investigation. II was generally agreed that smoking shnukl be diccouraFed in patients with peripheral vascular diseast because, in many such pcraonc, smoking may result in vasoconuriction in the skin. Some evidence was presented to implicate an allergic basis for symptoms frnm smokinR when Ihey occur. Also or ttut.tandin6 interest was Ihe finding that differenc•ea in response to smnkinR apiKar to be in part genetically delerntined. Another sludy ahnwed that ndrninittratifm nr large dntes of nicotine to animala hrr f.rnlnn'ed hcritwla did nnt rcauh in palhnluFic changes rtr inlerlcrcncca with Prowlh. 'Ihe 14 (talrcrs presented al Ilre Ihree-day cnnfcrence, a% well as the cnnnncnts m.rde in twit panel diccusaiftns, were puhliahrd in full in the Serteml.cr 21. 1960. isave nf Annnh rrf rhr Nrrv Yr,.A .If f,drmv r~f .~llrnfrJ. 'Ihis ptihhcalifm's table tit cttnlents. IistinR the pafxri by lille and authttr, is given on page 22. t' 19 19 tn

I V. 1'tyr lrrr-~rlr y.irrl uKerrrl InvediRatlnns aimed at descrihinR differences between smrrkcrs and nnrrsmnkcrt and atso relatcd to the nranncr of smnkinR, have cnntimred with increasing attention. ('ommittecs of the Scientific Advis.ay 1loard, wnrkinR with cullaMnNtinR consullants, have underlakcn ill review the e.istinR literature that may he pertinent to the situation and to hold periodic mectinRn for consideration of work in progress. A preliminary anthropomctrk study of smnkern and nnn-smokers, conducted to determine whether there is any significant constitutional dif- ference as reflected in body build, has been published. A correlalion be- tween  particular pattern of anatomical trails and heavy smokinR was diccovered, and it was deemed to he of suQ'icknt magnitude to jusffy an enlargement of the study to include a larger populatinn of sludentt at f hrvard and Johns f Ic.pkins Univcrsitics. Other traits that reflect hio- IoRical make up are also to he included in these studies, and nther kinds of pnpulatinns, including a Rroup of relatively nldcr pcrsons. Are undcr invettiRatit,n. V. Talrrrr•rvr (:/rPrnr.lry Reports in this field include hirxhcmic:d invcstigations of nicotine formation in plants, the course of nicotine nuidatinn by haclcria, the kinetics of nicntine nxidatinn by air. the idenlificatinn of previuudy un- idcntified camfnmcntt of tohaccn cnuokc, and the fate of certain insccticide resitfucs. Uf particularly direct pertinence are the newly reporlcd ohscrvatinns on the course of nictrline melahcrlicrn by mammals, which have m,w been extendcd In man. ihe formation and etcrelinn of O cntininc as a major melahnlite have been confirmed and the study ill pharmacoktRic effects of this metaholite has been undertaken as a contribution ill the undcrdinding of nicotine cffects. Prrxfucts from the further mclilw+lism of (-)-cotinine have also been isolated and identified by rignrnus methods. N.rn linok I:ooer• R'orfd Lirrrnrurr on Tn6nrro nrs. f.arsnn, IIaaR, and SilvcHe tif the Medical ('tdlcre nf VirFinia, culrninatinR  project assisled hrt a number rd years by the ticicntific Advisory nrrartl, have cnmplrtcd a IwMlk titlcd "Inh:rccrr I:xl+crimcnt:r) and ('linical Studics " the Mwrk. RIX) frar.cs in Icnyth, is a crrmprchcn-tive account of the wt.rld liletnltue and it F,:r.ed rrn sturly r+f mrrre th:ur h,(NN) nrtitlcs pvf.li.hrd in alw+ut 1,71N/ it+unutls lhis majra nrhlitimn In the tcirntific nnrl rnrdical literattnc on h-h:rc'crr, wlhirh i% ill hr IruhtiOhrd in rarly 1961. /nrrnri.r. Irr Lr rrl vrry I-tryl nt.i~t.~nrr Irr rnvrUry:rtrrrn in the /irlrl As a crdlateral activily, thcce scienlisas havc al.rr laurluccd a« rics uf compr(hcnsivc, critical rcviews on a variety of specific sul.jccls hearing uprm tobacco use and huntan health. Four such reviews which have ap- l.cnred durinR the year are summarized in the ahslracts. F'4f.rr.•ari1r f rnRrnm '1 he ?'.I R.C. mcdical student felluwship program was aRiin in effcct durinR the year. I his program has been renewed each year since 19.55 when il was originated upon recommendation by the Scientific Adviany Iloard to ctimulate interest in basic research among mcdkal studcntc. Suhjects for study are selected by the students in cunsullatiun with their advisnrs. Recipients of the fellnwships are chosen by the deans of the medical schnnls and the research is done during summcr or rrther off- Icrm pericxls under the supervision of eapericnccrl scicntials- Several hundrerl young men and women have participated in the fxtrKram in thc h:nt siR years. I Q 21 1' 71/ ~ r1

Tnltle• of ornirnir Annnl+ ttf the New York Arnrlr•mv +tf tit i~rtrr•N Sclrirnrlu•r 27, 1900 1'ar1 1. 71tt• Alr•nrl.linn .nd Fair of Nirntinr lnrr.rrlurtrrry RrmnrAt. fly ('arl 1. WigRcrt. Nicntinr and Il. Rrrtnnira! Sourrri.• Hy R. F. t7awtrrn, Maric I Srtll, and h R. Chritlman. .fbtnrprion of Nirurinr /rnm t'arirnu Siirs.• fly )anet 'fravcll .Ih.r.orrlinn of Nirnrrnr t/ndrr i'oriorrt C'ondilrnnt nl Tnhnrrn i/sr.• fly P. S Larton. 7hr F:+rrrrir.n and MrroArdism of Nicntinr.• fly Ilcncctt McKcnnit Jr. 1'.rt 11. 1'}..rna.roloRlr.l Arllnna of Nirnlinr rnr) Toherro 5mnAe Cnmpnnrnrt nf /'lhnrntnrntrrAic lnfrrrtt in Tnhnrrrr S.rrrrAr fly (' 1 Kcntlcr, 7lrr l4rnrnrnrnhrgirnt .Ictinnt of Nirnlinr.• fly fttliut 11. Crtn+rt.c, Ir. 7 hr A4n lrnnitrrt rrf (:onXtinnir Rt.H rImlr I'rndln rrf hv Nn nrrnr • !ly I:tlward W Pclikan. i(rtinn r+l NirnNnr nn the ltrnrl fly 1 I larnld lturn. 7hr l*/Int .r/ Nirr.nnr und SmnAiyR rrn lirr .Cri rrtirrn n/ I l.frnrhlrrinr. fly I)inicl T. Watls. I'.rl 111. The InQuenrr n( Nirnlinr enrl CnrukinR nn the Prril.hr•r.I (.irrnlStion Thr Artirrn nf Nirrrlinr nrt rhr I'rri(rbrrnt Cirreulrrrlrrrr. fly ) IL:trrdJ Iturn 7ltr Arnrr (i/frr t nf ( ignrrffr CrnrrAnlg rm rhr ItrKitrrl ( m ulrnrrrn rrr llrutth anJ t)rtrorr.• fly Jack I:rctmrl and (l:tirc Ward Infhrrm r nJ Nir nlrnr nn tlrr /tfrrr J) IrrN rr) KrtlmR .CArfrlnl Muv Ir• unJ llrr f)iXitt in NrrrnrulSnhjrrrt.• 11y Ilnn+ Rrtttcnslcin, (ict,ryc f'rircc, 1i11icr Rl1tt, I1Tvltl f fltlCr, antl Ilnl;h I`/rtnlprmcry. Ft f/rrt nf SrnrrAmg nn thr 1'rriphrrnl ('irr rdation in It.rrnurn w /' nrirnrunrnrn/ 7rrnrrrnlnrr.• fly 1. Fdwin Wrxu1 7 hr ./r t.rr F./Trc t a/ ('hrrt•inR 7 nhar r n nnd SrrrnA inR in llrrlrNrurt il.rrrJ, • Hy David (.. Simnn and Arnuld IRlaocr. Rrrynrntrt n/ rhr I'rrilrhrnA Vrirrt in Af~nr Irr tlrr tnlrnt'rnnut A,lrninitrnrtinn n/ Nirrrtinr • fly )rthn W Vcktlcin and A. W. Ih,rtlcy. 7'rrhacr u!1 vfrrrtrntirivity.• fly Vinccnl l. Fontnna. 7rrharr.. fttrrrtrnnrivilv 1'rrq+l+rrui ( irrntnrnrv Irnt+firath-tt • fly W RcJitch, K. Mcckclcr• 1V ttruwn, and ). M. Stcclc 1'wrl IV. Aclinn of Nirotinr .trrl SrnokinR on ('nrnn.ry f1rrnleliun I'llvtirdrqt• of thr ('rrrrrnarv t irr rr)ntinrr 11y 17r.na1r1 I:. (itcl'P ('ur lrnr !/)rr I t../ Irrlrar rrrnrrrrr v~rMnrrl lrrrrr trrmr rr/ Nrr un.rr ' !ly S.unutc) Ilcllct, rarnt•t W Wt••1, ;tntl S:rnliayn VGurnr.rn 1 r tirrnt n/ Nu rrlnrr nnr( .irnrr.A/nR rn (.1r.ntrrry ( err trhrrr..n urtrl Al-r rn,li.rt !)rl-rr.r Iluh:nrrnn t1y (irr.rlrl A Ktcn nnd Ilrcr•rtr.tc i( 51.t'n,..l •,~....rr.l I.r . r...r,r 1„ .ht tr.,.n rh. t.,rm... Irrdu,hr r o..u..itv. Crrrnnnrv Rlnnd Flnw and Cardioc Oxygen MMoholi.rm nnrinR icntinr- lnrlnrrrl lnrrrn.rrt in Left Vrntriculor. Work.• fly Ivan r. 11v urte, A. Jane Williams, Louis Potsicter, l. E.Schmitthenner, J. It. Ilafkenschiel, and Cecilia Riegel. FjJrrl nJ ('ianrrttr Smoking on Coronary Circulatinn and C'ordioc Work in /'alirnrr with Arteriotclrrotic Coronary Distasr.• Ily Timothy 1. Rcgan, flarper K. Hellems, and Richard 1. fling. Tobncrrr SmnkinR, the F_lrctrocordiograrn, ond Angina Prctori.r. fly ltertil von Ahn. Par1 V. P.nel nlsru..lon Significance of Flrcrrocordiogrophic and Botlirtorordingrophir C'hanRrr Indncrrf by Smoking. Isaac Starr, moderator. Participants: Frank W. Oavis, Jr., flflrje Ejrup, and John 1. Kelly. )r. P.rt V1. (llher A.Lre1a of thr Ph.rrn.eolop of Nirotinr.nr) Sn.oUlnR Thr F(frct nn Rats of Chronic Exposure to Claartttr SmrrAe.• [ly I1. B. IIaaR, P. S. t.arson, and J. It. Weatherby. Chronic Nirntinr I'nitoninir• By Clinton I1. Thitnes. Nicotinr nnd SmaAinR on rhr poa Bolli.ttocordiogram, By Aldo N. Corbascio and James W. West. Effect of Cigarette SmoAlnx on the /nfroocufar Blood Volume, By Victor G. rcllows and Jerome W. Bettman. Circulatory Rrsponrrt to Smoking Lt Healthy Young Mrn.• fly Caroline Iledell 771omas and Edmund A. Murphy. Compnrisrn of C'ordiovascufor and Related Chornctrri.tir•f in /tnbitual Smokrrs and Nontmoktrs.* By Ilenry Blaekburn,losef Ilrozek, llenry 1.. Taylor, and Ancel Keys. P.r/ VII. F.fRrrra of Nicolinr.nd SnroklnR In C,.rrliov..rul.r his..rders Cardiac F,Brrtr of Nicotine in the Rabbit with Exprrimrntal Coronary Athrrnsrlrrotit.• By Janet Travell. Seymour 11. Rirvler, and 1)~inthy Karp. The Chrnnic F.Brcrs of Orally Administered Nicotine in Cho/r.ttrrol-Frd Rahhira.• ESy Duane 0. Wenzel. Jasbir SinRh Kamal, and James A. Turner. Thr CardirwntrutOr F(jrctt of SmokinR with Special Reference to Nyper- trncirrn. fly Cirace M. Roth and Richard M. Shick. Fflrrt nf Nirnrinr on the C.»r>nory Blor.d Flow in the l'rr.rrncr of Corcrnory Innrf/irirncy' .fn F.~tprrinerntal .Sltldy in /)n>tt.• Ily Samuel flellet, Jamct W. West, 1JRo C. Manmli, Ot(o F. Mutler, antl f'arrlo Rosti. 7'reharr-n rItlrrFy in Coronary Ar(rry !)iseasr. Ity lttserh I4arkavy and lily 1'rrfm.,n. ('rrl V /11. /'anrl Ili.ru..lt.n h:(/rrYt rrf SrnnAinR in /!lfrntrt a/ thr /'rriphrral 1'atrntnr Svvrrrt 1i A Iiinrt, 1r , nnMlrralnr Pnrticiltanlt: Fttwin Wt>,rr1, Ilup}h t,trrntprrotrry, (iracc M. Rolh, and Rrrttrrt It. Gr.rtr •Af.iard t+y . Rr.nt in •iA trom the lnh.crn tndu.ny Rr.r.rch ('ommitlit. r' 2 ) ,1

/ Ahstracts of Rc-ports Fach tcci(.icnt nf a Tnhacco Industry Rcscarch ('r+rnmiltce gront-in• aid is resrtmcihle (ar the initial preo;rntation at puhlicalirm of the results o( his research in scientifie meetinf!s or in aptin,priate scientifrc joutnals F-nlhrwing arc rhstricls, approved by the aulhurs, uf rescarch reptrrts, with ackmrwlcttgrnenl of surptal frnm the T.1 R.(•., Ihal have a(,(+carcd in scicnlific jt,urnals since the last Report and lhrnuph (h:to(xr 1960. Titles td earlicr pal,crs by granlees abstracted in prt:viuuS Re(•t+rts rd Ihe Scicntifsc hireclor are listed at Ihe end of Ihis section. 1 he n,rne of the scienlisl to whrrm thc T I R C. grant was made is Riven in (+ircnlhescs whcrc required. These ahstracts have heen K+nuped under six hendinRs: 1. Cancer Research; I1. Iluman I.unF Studies; 1(I 1(tart and ('irculatinn; IV. 1'sycho- physitrh.Rica1; V. I obacco (•hcmistry; and Vl. Ulhtr Studics. I. ('ar+rer Kr.Pnrrlt "A S7UO1' OF 1II1? SfiNSl1IVIJY Of l1(1? MO(ISF, FORPSlOMA(-II TOWAIi,I) ( I?ItfAIN 1`OLY('Y( LI( IIYf)RO('ARIIONS" fly Fred r. ht.ck ftnd I1r,up,l ss W, King, (tuswtll Park Mrrut,rial Institutt Itinlt.gical $I:rtit,n, Sl•rinpvrltt•, Ncw Yrirk. Irrrrrnnf nf rlrr Nnlrnnnf ( nrrrrr frrrtrhNr. Volume 21. py,rs 911.1419. Oclo)rcr 1')59 (1 1 R('. Franlct: Ot+ck) / urpn.. n/ .trrrh rOurinR pi1r,t st++rlhct nf thc rflccls of ci).irrtle smnke crrndcnsatc nn Ilhc rnr,u.c Ir irr, r vl•nrlr rnt nrnnla r n( I,:rlnllnrn:ra wcrc rrlr- served in the fprcalnrn,u h of ('S1111 nnr r,ahr, h h,rrl hct•n •'p.nn,cd•• rmce with ahuul l S mr. trl 7,1? dnr,ctlrN lt.,nit,rt.rnrhr:rtcnc (I)MIIA), suR Retting that the (rncttnm.ach ntr}•I,r crvr :ts a IcM attc It,t scrrrninF weakly cafcinrrrenic hyr(rrK:,r)n,ns, 1 n mvrNq•,rlc Ilttc 1,rncrl,ilily, Ihc ct(cclt r.t orally administtrtd I)M11A anrl 1.mtlhylthrrl~nthrcnc (M('), and alsn hcnz(a)anthr:rccnc (IIA), were srurlicd ProrrAnrr.: (•51111. mice wcrt dcrtivcd of (rant (nr 24 hr+uts and then intuhated IhrmrFh the earphygus, each aninial receiving 1).1 ml. (.f heavy mineral oil ct.n,nininr 1) S nrp rrf tcs/ crrrrnf+twnd Rtpcatcd drrsts were given ltt some at inlcrvnl-t n( 3 trt 7 tl:ryt, arN( tllc 1mn1:1ls were nlatntlmed without (urthtr trcalmcnt until F~Hric palailitrmas were found ct.nsistcnlly amtanR the nnimala that died 1)A111A :rrul M(' prrnrps reqnircd a I+erhat t,t R In IO mr.nlhs, and the IIA series were kilicd a(ICr 16 nrnnths, althnuRh lumnrs had not been found in the (wnt rnrrrtcm nratcrial avail:rhle. Finr(inRr: A sinRlc intrig:r.tric alq.licatinn of (1 5 mg tr( titht•r 1)MI(A ar M('Ravc riar tn a trrres(tun:rch Innrr» intillcncc ro( RS^,:~ and %1"S,, rr-,hcc- tivcly Multifrlc a f(+licalinns IrH:rlinf! A rrr R rnr! I,rrHluctd (•:qrillran:ra in all 44 treated animilt an l carcinrnnas in G Amrrnr 7 7 mice reccivinl-. 4 rrt R mr. o( RA hr ttrrm,rth h,ht, 2 dcvchqacd 11a),ilhrmls uf thc Grrtalrun:rth aftrr ((, n11,ntIt1, h,N m, Ntmtns -V(•rr:1tcrl +nu,nf. Zrr nricc 1trilcA t,ncc will. (1 ~ mr. r+t ItA Ihc rl,rt. inrlicn/r•rt Ih:tt Iht nnrnac frnral,.rnnth is mrnr arn.rthvc trr tin/;/r :,t•I•hr.rlr rna nf tartit-rrns Ih:,n Ihc akin "1-ttMOR-I1OSl• RF?I•AIIONSIIIPS STUb1FiF) IN 1'l7RU, RXPFiR1- JNI S W1111 1'ISSl1E SI,I('fS " fly l.enpnld R. ('ercccdn, Sister Marian use Smith, and Jesus Vicenle. F)eparlmcnt of Itiuchcmistry, ftrrdham (lniversity, New York City; Department of Biochemistry and Nutrititrn. Schtarl of Mcdicine, Univcrsity t.( P1teHo Rico, San )uan; and ('olleRe nf Saint Iai?a(xth, ('anvent Slalitrn, New Jersey. RirrrArmicnl nnd Rirrrhy.riret Rrrrnrch ('ummunirnrinn,r, Vol. 3, pages 32R-332, Seplcrnher 1960, (T.I.R.C Rranrce: Cerecedo) Prtrpnr• of .nrdy: Previtws studies have shown that the presence of a tumor causes cer,am chemical chanRes in the host tissues at a distance from the tumar, which are reverscd when the tumor reRresses. This work undertook Ihc stucty of the ineorptxation of thymidine-11' into deaxyriho- nucleic acid (1)NA), and of adenitx-R-Cr4 into DNA and ribnnuclcie acid (RNA), in slices of tissues of normal and tumor hearinR rals. Prnr.rlnrr: Lungs, liver, spleen, and kidneys were eatirpatcd from rats hearin the Walker 256 carcinnsnrcoma and Ihe Jensen sarcoma, and from muntaTrats, ant( tissue slices madc, llx Incorporation of adeninc R-t't4 and Ilrymidinc 11' inlrr /tfie 1)NA of lissues nf Ihe normal rals and carcinoma bearing rats, was detcrmined by radioactivity cnunler. FlndinR.: Slices of liver, spken, and (ang of rals hcaring Ihe Walker tumnr incrnrtrratcd Ihymidinc into DNA Io a nrarkcdty Frcatcr e>ttcnt than did the sliccs of correspondinR normal tissues, whereas Ihe kidney did nnl ,htrw any change. Similar resu(IS were obtained in rats bearing the Jensen snrct+ma c><ccpl that chan(;cs in the spleen were more pronounced In the ex(+erimenls with adenine in rals hearing the Walker tuntt,r, Ihe DNA in the liver, splecn, and lung shnwed greater activity while the kidney did not show any change. In rals with the Jensen sarcnma, the tumnr caused an increase in the activity of the 1)NA of the liver, splten, antl lung. As Iu the RNA, both tumors caused a sliRht rise in Ihe activity of the liver. In other lissucs, a drop in lhe activity was usually ohxtved. 'l he pattern (if thymittine and ndcnine incnr)axation in vitro by Ihe orRans of norma/ and lumnr- hearinR ra1s, especially by Ihe liver and spleen, are in harmony with Ihe results whiclr ("crrceda el al 11959) trhserved in vivrr, l1t/rrr Krnnror.: U.S. Public FFeallh Servke and the Damon Runyon Memarial Fund. '•I:FFF(T OF AIR I'OLI•IITANTS ON CII.IATfiI) MU('(/S S(f('Rl?"f- (N(i 1?PI ( I 11: I,Il1M.•' (1y Ikrla M. Tremet, ('h F. , Ilans 1. 1•:rlk, Ph 1)., and Pcntl Ktrtin, M.1)., 1k'partment td Pathnlngy. Univtrsily nf Stnnhcrn C:dilrrrnia, Srhrwrl of Medicine and Los AnReks ('trunly ( icncr:rl I lrrs(rilal. lnrrrn.rl n/ Ihr Nntinnal Cnntrr Intrirulr, Vol. 2,1, pages 979-99A, Nrrvcm hcr 1959. •'ITIT(T Or ('1(rAR1:7-fE SMOKE ANI) ITS ('ONSf I7t11:NTS ON (-1(.IA1(1) Mtl(lIti Sl'('RI?1IN(i f:1'11111:a,ItIM " fly Il:rns /. Fall, ItrHa M 1 rrmrr, rand Paul Kt+lin. Inurnnf trf (Irc Nntirrnaf ('anrrr frr4rirurr, Vtr1 21, paRrs'IVV 1012, Ntwemhtr 1959 (T1 R('. Rututcc Falk ) I'r.rp...p n( rnrdl.r: 1lndtr ntumal ctrmljlinns. Ihc rlrrw vd thr nrucnus tlream In tht• rr.(ritahrry lracl (+revent. Ihe atcumul~tirrn u( (,arlictulatt matter trn the rr.lnratt,ry epitficliunt. T he maverttcnl of Ihis strcam it relatrd 25

I t m N N t• .i D to two factnra: thc whip-like action nf the cilia, which provitlec the propellinR fnrce, and the amnunt and cnnaittcncy of thc rnucuc. 1 hcae studicc wcre inttituted with the ultimate aim nf yuantitatinR the inhibitory efTects of in- hated tuhctancet on ciliary activity and flow nf Ihe mucous stream. The first paper ia cunctrncd with the develnpntent and atandarJiFatinn of methods for rlclcrmination of the eflectt om mocous now of exprxure to irritantc in the pnllutcd a/mntphere and with correlation of the physiologic findings with mrxphnlnpic chanRet of the retpiratory cpithclium 1 he sccnnd paper com- pares the cffects of cigarette smoke with the retpnnse to irritanh in polluted air. Pro.r..Er.r..: The measurement of mucous flow wat first undertaken with the uce of eateriorircd and in sinr tracheohronchial scgmenlt in anesthetiYcd rats or rahbits; paraltel studiec were performed nn icntated trachcohronchial segmenta from the same animals. II was stxm found that Ihe data were com parahle trnlh qualitatively and yuantitatively. Further work was done on Ihe ecr+lthagcal tract o( the frnR, which waa technically Icta cnmplicated, becauae envirnnmental agcntt crnrld he inUrxluced at rtxrm tempcrature Ilere alco, it was fnrmd that the qnaitative findings were similar and et<tra- polatat.ility nf data wat not aRtctcd In the firtt p.iE.cr, the animal tpcciment were expnccd to the test acrmnh undcr cnnatant conditient by twn mcth<x1s-one a"hy-pact" mcthrK) whirh attempted to dnf+licatc in vivrr cnnditicros of ex(aicure th:N cUtl in thc majnr part of the tr.chenhrnnchiil Iree. the other f,y impinrinR the aernorlt dncclly nn atlectcd arraa in tndcr Irt duplicate in vivrr cnnditinna occurrinR al hifurc.-itinna nnd anRnl:rtinna of the recpiratory tract. -1 hc rate of flow am1 nthrr phyainlnRic and hictrtlrrp,ic chinFct were tlctcrmincd, and conditioni prior trr exprranres were utcd ac cnntrnlt In the accnnd study, file ctpcrimcntt were reErcatcd with c iRarctte smoke. 'Ihc smr.kc wat dilutcd in a mixinR chamher, and a por1 r,n was pasted over the tistrrc by eilher file inr .ingerncnt or t,y-~'ast method. Furthcr Icsts were marle hy applying micro rlrnp qu,ntitjca of water sr+luhle com- pnncnlt of ciRarette srnoke to the dnwnarream end of the ciliated epithclium .pecinrens. FlndlnR.: The initial recpnncc of the cpecimcns nf epithelium to natural antt artificial cmrrg, mmnircd hexcne-2 (in lieu (if gasnlinc), and nlher individual and allied cnmfxoundt uaually waa a Iransient increate in mucnuc flnw, ratc, which wat rapidly sut.crccdcd by a tlnwdnwn in the flow rale of rnucut, followed hy slow recovery tn the hace line rate. 1 he efT!ct was fundamentally nnntprcifre since ettcntially unrelitcd cheniicnl conrrnunds cnuld prndnce the enet-tt Atan, the rrefalnce wis nnt cpeciet qucr.rc. lhe initi:rl increaae in (low rate varird in intentity with the ral+rrnlre a(-ent, whereat the dowing and recnvrry perirxla were relatively crrnttant, mr+re f+eraiatrnt, and larrely indcpendrnt n/ the Iect aPent I)irecl impingement nf file lett a/cnts pnNluceJ a more r+van/ilivtly intenat, thnnFh yrrnlitativeiy similir, rcelttrnte aa trrnyrnrrd In t'rr hy Qaat mrthrwl ('hnnprt in cnnaittrncy nf Ihr nnrcut nltn r.ccuntrl, anrl will Lt r•vahlnird in Lrtrr wnrk. Mrrrphrdrrric chrrhra rrvrnlcll a mnrkrd inrrrnae in file rrnnrt.rr rnrl :x tiortv r-t thr I•rdMrl rrllt '1 hr intcntily rd hittrt- I,.,rh.l,prr r Ir rr~y.. p.rr.dlrlrrt rhr rnrrntrtv ol thr .rhnrrrrn-il I~hyairrln0ic r.rl. n.. In the tet•s with cigarette tmoke, brief stimulation of epithelial flow dso was fnlluwed by inhibition and recovery pericx)t. The impingement melhnd eliciled Ihe strongts( original stimvlalinn, hut the inhibition effecl was most intente after the aqueous solution test, and recovery never returned to the basc line flow rate when this method was used. I)asically, cigarette smoke in all ils various fractions, as well as in its entirety, primarily decreased the rate of mucous flow after a short pre- liminary acceleration. The deceleratinn persisted for • considetahte period and was relatively conttant for both whole smoke and its various com- r nets. Filtration resulted in a smoke which had little or no altering effect yond a brief initial acceleration. The elicitation of a response to both air pollution and cigarette smoke establithes that from a phytiokrRic point of view a hayard existt during eaposure tn virtually all measurable concentrations of these agents. T1,ese repetitive ctudies are believed to parallel the human situation. Orlr.r Rrnnror.: U.S. Public Ileal•h Service and American Cancer Society. "A (Y)RRF.I.n1Th IIISTUI.(X71CAL, CYTO1.(7GICn1., ANI) ('Yl'(1- ('11EMI('ALSIUI)Y OF lllEi TRA('1EIiUI1RUNC'FllAl. 1R1?13 ANI) LUNGS OF MI('1; I;XPOSI?1) TO CI(iARE?TTIi SM(1K1;. Ill. (iN- A1,1'E:RFI) IN('11)I:N('F- ()F (iRt7SS1.Y VISI111.1? AI)I:N()MAT()(IS LUNG TIIMORS IN FEMALF. ('P MI('F AF1FR PROI.ON(:FI) I:X- POSURC '1O ('1(:AR[:TTEi SMOKE." fly Rudolf I.euchlcnherRer, M 1), and Cccitie Leuchtenberger, Ph.n., The Children's C'ancer Rctearch Foundation and Department of Pathology, The ('hitdren's tlospital, Itoalon. Matc.; and William Zebrun, M.1)., and Patricia Shaffcr, Ikpart- mcnt of Pathology, Wectcrn Reterve University. Cleveland, Uhin. Cancer. Volume 13, pages 956 95e, Scpt.-Ckt. 1960. (T.I.R.C. grantee: ('ecilie 1-euchlenberger ) Purpo.- o/ .tudy: In the course of the aulhors * majrx crxrelated study of the sequence of events in the respiratory tract of mice after exposure to cigarette smnke, attention wat also given to the adennmatnut lung tumors so freyuenlly nbserved in ceranin strains of mice. This repnrl dealc with the incidence of grotsly visible adenomatnus tumors in the IunRs of ex- perimental mice and in non-eaposed controls. Pror.de.r.: A total of 397 female CFr mice were examined I death, between three and 28 months of aRe, of which 166 were non e><pnted controls and 211 hnd been exposed daily to the smoke of r,ne-hnlf to eight cigarettes, at hnurly intervals, for perirKls ranging from t7 to 600 dnys. 'Ilre mice were not smoked un week-ends anrl hnlidays At certain pcrirrlr after eRf+rtturq the e><pcrimental mice and thcir conarnlt were killed nnd Ihe Froatiy vieihle ademrmatrmrt tumurs were rrcnrckd. FPnrUnRr: Nn ttntistical difference w•t fnrmd in the frrqucncy of the lung tumnrs I-elwren the cnnrrnlt and the etpraed nrice. Ahout nne third nf thc mice in IHrth grmrps had tunuut rnnKinR /xtwern I and (A mrn in tire I tie hicluluRical tcaturca nlan were very airnilar in tMNh Rruuht file tumrat nunl frcqurntly arcn were lanlyn adenrrmas. Whrrr tnnttrdc and cRpnacrl mfie were urnngrd nccrnding Irr file nft at wlrich turnnrc were nhacrved, a rtlatinnahip httween a/~c :rnd Immor incident'e w;rc alqiarent Wilh the ewceptinn Ih:rt Ihe ewlalSrJ n11Cr rr.iched 27

an incidence of 40°,''~ at aRcs of R in 10 months, compared to that at 11 to 14 rnonths in the controls, the plotted curves for cnntroh and e><poscd mice are vcrr similar for all aRes. When mice were grouped according to length of time of etf.nsure In cigarette smnke, it can he seen that at I I to 211 months nf age there was cssentially the same frcy ucncy of adennmatnus lung tumnrs when e><posed to smoke for 17 to 99 days and for IIK) to 199 days, while Ihe tumor fre- qucncy in mice c><(+~~scd from 200 to 6(K) days incrca.ed to 66^~. Ilnwevcr, it thould he nnteJ that non-txposed controls of the same age also had a higher tumnr inciclcnce - namely, 56% - than that found in mice expnscd for 17 to 199 (lays. Whether e>< ~sure to cigarette smoke may snmctimes accelcrate the development of I},e tumcws cannot he answered at this time. In view of the small samplcs, more experiments with larger numbers of mice should he carried out in order to determine whether such a difference is significant. "STUn1ES ON TIfF. EFFECTS OF ACETAI.DF:FIYF)F? ON TISSUE CELI S('lll-TIVAT C:f) IN V1TRO." Fiy l)onald M. Pace and Alice Elliott. Institute for Cellular Research, l)niversity of Nebraska, l.inculn. Concrr Rrrramrh, Vnl. 2/l, pages R6R-R7S, luly 1960. (T 1 R.('. Rrantcc: Pace) Purpo.e o/ arudy: lhere is considerable interest in the possihle toxicity, carcmo~e nicily nr cocarcinngenkity.o/ the constiluents of tobacco smoke, in which acetaldehyde occurs in concentrations of 0 9R to 1.31 mg. per ciaarelle, depending upon the kind of lohacco. This invesli6ation was untler- talen to accerlain Ihe short- and lonR-lerm efTects of this substance upon several types of tissue cells cultivated in vitro. Procedur.: Four cell lines were used: Farle's strain 1. cells, mouse liver epilhclial cells, human skin cells, and llcLa cells. Routine suh-cultures were made once a week for the firat two 1lrains and snmetimes each 3 or 4 days in the latter two Ohservations on the toxicity and poscihle influence of acetaldehyde ulxm rate of proliferation were made pericxlically, usually 4R hours after replication. (kcasioncJly during the shurt-tcrm espcrirnents, and in all except the firsl series of long-term eaperiments, the percentage of viable cells in a culture inoculum was ascertained. Purpoae of .nrdi..r In the course of in vitro development of moo mam- skin cells exposed to 2.0 mg. acetaldehyde per ml. seemed to resemhle those of the control, except for a definite granulation and vacuolizatinn, but care- ful exunination showed that the cells were dead. The cells began to rcund up and detach within a half hour when e><posed to R 0 mg. acetaldehyde. lhus, these two concenlrations pmved toxic to the cells in a matter of hours in the lesscr and oi minutes in tFx stronger concenrratinrtm. A scc<md series, expnsinR skin. IkLa and liver cells in 1.0 and 001 mg. acctaldehyde, also shnwed toxic effects In a matter of hnurs in the larger cnncentratir,n, as did  third series usinR concentratinns af 0 5 and 0.OS mR respectively. On the bnsis of the short-ternt findinRs, 001 nrR and /) O5 nrR con- centUations of acelaldehyde were ch~nen for the honR lerm stodie., f.cinI~ the least to.k in effect At these enneentrntions cell prnliferaNnn nl'l.e.ned In he rnxmnl nr was arhrally stimulated (rRee d lcrr the liver crlls in 11()S rnR /ml ), IcajinR tc, thr.e quettinns- I)ors srit stinwlatlnn cc+ntinur at IimR e /he crll+ arr relwned7 1)u Ihe celle return to their neurnal rate erf gmwth and then cnnlinue to prnliferate as though nn acetaldrhyde were Kresent7 Is there 3 gradual accumulative effect of the suhstancc that may inder later gruwth? Frrrm the results it is evident Iha10 05 ms. acetaWchytk per ml is toxic to the liver crlh. 'I he 1. and (IcLa cells prnliferated well, at least for the firlt f,~w weeks, hul cells e><pnsed to this concentratinn never incrcascd as much as the cnntrols. After a period of several mnnahs, however, the acetaldehyde hecr.mes inhihitnry, and the cul/ures may (lie out Lr;cluse nf its presencc. It aIcn appe,rs as though those cells which shnwcd the e/fecls u rcetaldchyde accumulatinn recover if placed in normal nutrient medium, nless the limc of e.rosure to this substance had been excessive. nt6.r Rrernrnr: 11. S. Public Health Service. "ON Tllr CIIRf)MOSOMF: NUMFIERS OF FII/MAN AMNION ('rLIS IN PRIMARY ANI) STRAIN ('ll1.Tl1RFS." fly Y. 11. Nakanishi, M V. Fernandes, M. Mizutani and C. M. Pomerat, Trssue Culture I ehoratnry, heparlmcnt of Anatnmy. Univenity of Texas Medical Rranch, ralveston. Tuos R.yarrra c.n Rinl.,)ryand Mrdirinc, Vol. 17, pages 345-353, hall 1959. :SMOKfi (Y)NI)IiNSATFS ON I.l1NQ CF?LI S IN TISSUE ('lI1.TU Rf.TURf WIT11 SPF('IA1. RF.FF.RfiN('F: '1O CIIROMOSOMAL ('IfAN(:F:S.'Ily Yrdr 11. Nnkani.hi, Mawhiro Mizutani and C. M. 1'umcr:rl. l'riur Rr- rnrrt rrn ItinlcrXy ond Mrrlirinr. Vol. 17, pagcs 542-59I1, Winter 1959. "1TIE DEVEI.OPMENT OF A KITTEN Ll1NG CT?l.l. SfRA1N AND 1TS C11ROMOSUMI:S." By Yuh H. Nakanishi. 7.rittrhri/r /iir 7.rl/f.x- .lchrrnA, Vol. 51, pages 13R-ISt, 1960. "TI1E nfiVELOPMENT OF A NEAR-1)IPLO1D IN VITRO STRAIN F:ROM A SMOKE-(Y)NbF3NSATE INI)I1('EI) MOUSE Tl1MOR." fly Masahiro Mizutani, Yasushi Uhnuki, Y. 11. Nakanishi and C. M. Pnmcrat Tr tnt Ren.rrrs nn Riofogy and Mrdirint, Vol. I R, pages 455-469. Fnll 1960. ((T.I.R.C. grantee: Pomerat) 1•nrpc... oJ .rndlsr In the cource of in vitro development uf mnst mam- malian cell strains of both normal and malignant ori6in, chromosome mmncers havt been found to undergo changes from diploidy Io a helero- ploid state. Such Iransfnrmatinns are associated with slruclural chanRes in addilinn to the nunrerkai increase of chromosomes. Fstahlishcd cell strains invite quantit:rtive studies on the eRect of chemicals suspected of influencing the chrrnnusnm:J complex. AccordinRly. Ihe work included ntlcmpls to develop erithelial lung slrains with and without the presence nf suhstances in tnhacco smnke cnndensates. Such nuhstances and hcnzryrene were em- phrycd to dctennine whether the chromosnmal ccpfiguratn.n of an csta- hlished IunR strain could be altered. rrorr.rur..: 1n the fir.t st-udyrlacental tissue fnrm a healthy woman was ohlained. 'I he trst nhjects used eonsiated of Ihree ty('rs cr/ mm~iun cell dcrivatives, lxciuse mmninn cell strains are consideted In Ix partic'ul:uly usrful for virnhor~ical sludica and rnar he aRected t.y irrndialii~n ns well 'Ilre ccll culhuci were trypsinized nml ehrnmosnrnet were ccrunted f.dluw- inR a Inotracted qeries of auh-cultures In /he srccornd dudr (un/ tissues frnm a 215 tnwmth nratc humnn frtus and frortm ncwtb,,rn to Gcur-weck-ctld kittens were ulcd as tesl matcriats; I m 28 29 X, N 0

r I i I I e.flants were stt up In eultnrc hnllles with the uce tit avian pIa•:ma clots, to which EaRle't mcdium with 111"F hnrse sctum was addcd. 'I wo kinds of smale c-t,ndcnsales were u%ed to tcsl the cclls, as was hcnzpyrene alone and htnrLyrenc in contbinatinn with a smt,ke condensate. '1 he third study presents a more detailed account tit Ihe kitten Iung experinrents. The fourth study was concerned with similar exreriments with a cell strain from a(''H male mouse carrying a suhcutaneuus tumor induced following injectit,n of ciRaretle smoke eondensates. FinfirInR.: In the first study, the chromosome counts of human amnion eelh obtained in freshly isolated elements before culture were 42. 48 and 55. The ntost frequent numbers in 25-day primary tissue culture prepara- tiorn were 46 (25'7F ) and 4R (21%). C'ounts made from cells nf trypsin- ized cultures fined on the 351h day of incubation (2nd suh-culture) had a range from 60 rn 77 with a peak at 67. Cclls in the 401h sub culture (191 days from tht initial trypsinizalion) shnwed a range fn,m SR to 90 with a peak at 66 In Ihe latest ohscrvatiuns in the R4th suh culture (664 days) n( a trypsinizcd culture nf amninn tiesue without crubryt,nic e>tlracl the most freyurnl chrnmusr,rne nurnlrr was )5 (h2%) in a narrower range of 69 to 7R• In the sccnnd study. Iwo epithclia( ccli strains were cstahlished from the lung of the male fetus, one 'rum cells in the presence of a cigarette smoke condensate (fIL.-S) and alSr,lher front an untreated control (IIL.C). At the outcct, the most freqnent chrrrmosnme numhers showed a shift to lower valucs in treated cuftures, then a widened ehromosnme sreclnrm developed to a staFe tit "great spread" in hnth treated and et,ntrol cullures. Finally, a narrow f.eak of hercrnplr,ids bccamc estahlished et 77 (FII_--C) and 76 (111-S) The NI: C strain was chatlenEed with two fractinns nf smoke conden- sale together with acetrxu and untreatcd conlrols, as well as wilh benzpyrene alone and with hcnzpyrene plus one t,f the smoke fractions. In the two controls in each changed environment the modal value was constantly at 77 for each observation from the 61st to the 81'st subcultures (during 95 dars). In conlrast, the new modal value of 76 chromusnmes was estnh- lished after the appearance of dicentrie chromosomes in snme pa.ssages. It will be necessary to recheck whether pretreatment with the smoke con- dcnnte is significantly important in the estahlishmcnl of a cell strain and whether the chromosomal chanRes are associated with malignant conversions. In the third sludy, the most frequent chromosome number in the primary culture of kitten IunB lissuc svas 3R (in 6R^,'n of Ihe cclls). With either Ihe increasing numbers of suh cullures or thc l+trirK/ of cultivation, chromtnome ntnnhers shnwed a decrease of diplr,ids and an incrcase of Iririlr,ids t,r tetra(,Irrids 1 he Ialest uhacrvatir,n on the chrtunrrsr,rne numhc•rs trf the srriin tm Ihe 41 Ith tlay after the I,rinm:uy cullure druwtd Ihat Ihe mnst frcyuent chtnmtnnrne mmihtrs wrrt '11) ( 22'Y. ) and '7] (2(i % ) Ohservatiun r+f milr,tic activity r,t trlls in Ihc .trnin tultnrrs hy I,ha.c nJcrr~~tr.l,y %hr,wcd a riiinr. Inolifcr:rli„n in,tcR durino thc t,rat acvcn d:,ys nftcr inrK ulatinn Ir, rhr (ra,rrh itarly thc ruir,in:rl n,ornr Irrn,nr wa-, irlrntifr-r1 as A Icirnnyrr~arcran:,, a lunrr,r of 11rc vura,th mucclc titKrs conlaining im(.cr- i fectiy differentiated embryonic cells. The induced lumors showed no in- vasir.n and spreading AuI grew under the skin, st,metimes to a size larger than the hnst itself, withotd invasion. Tlu most frequent chrumosomal cnunl frr,m prim:rry eaplanls of this tumor was found to be 41 (42`9i. ) and hyp.,tetrapluid numbers ranged from 74 to 77 (2490 ). In IJrYo two number distributinns were found, one in the diploid range (40-43) and the other in the tetrapluid range (74-R2), suggesting that the e.planls contained mixed cell lines Following the 161h sub-culture the modal value for Ihe chromtnnmes seemed to persist t 39, with a narrow range of distributicxt fmm 3R It, 42. This mrxlal value has remained withrwt shift to date (63rd sub-culture). No evidence krr the heleroploid transformation of chromo- somes was nbserved. In order to ascertain whether or mrt this fnouse tumor strain waa malignanl, cells from several of the sub-cultures were inoculated into male ("Fl mice. In four separate tests with varying procedures the results were negative three months or more after inoculation, "[:FFIi(-I OF'[OIIA( C'OC'ONf)ENSATEON RESPIRAlYIRYIRACf (1F WI11T F, f'fiKIN 1)O('KS." Dy R. 11. Ripdnn, M.1) , Professor ol 1'athnluRy. Vniversity of 'feaas Medical Ilranch, (Dalveslon. ./rr-hiva of PorhnfrrRy. Vol. 69, pages SS-6J. January 1960. Prrrpo.r of .rudy: In previous work lhe author investigated the mech• anism of removal of fluid and particulate matter front the respiratory tract of while Pekin ducks, and found that liquid petrotatum and India ink entered the lungs and air sacs and remained there for varying periods of time. A study of the effects of tobaccn'eondensate on the respiratory tract was undertaktn in view of e><perimenlal studies by others of the effects of application of tobacco condensates and inhalation of cigarette smoke on various species of birds and mammals. Three ml. of cigaretle smoke condensate were added to 19 ml. of liquid pelrolatum, and one-half milliliter of this mixture was put Into the trachea nf young adult ducks once each day, except for holidnys, for a maxinrum of 1301imes. Histological studies of the Iracheas frunt 99 normal ducks, 26 Siven petrolatum alone, and 26 given the tobacco condensate mi><lure, were made at varying intervals following trcatrnenl, FlnrfJnR.r An acute and chronic reaction occurred in the trachea of a few of the birds instilled with the tobacco condensate mixture. A similar re- action, however, was present in normal birds and In some of those receivin6 only the petrolatum. Either Ihe tobacco mixture was phaRocylosed, tit it passed hetween the epilhelial eells lining the respiratory tract tn reach the adjacent srrama, and subseyuently it enlercd Ihe lymphatic and blood vessels, nnrmal channe(s of etiminotiun of inholed suhstnnces. 'lhere was nothing in this slurly tn suggest neoplasia. An unetpcc'ted findinR was the tKt'urrrnre of arnqIuiJ like malcrial in the liver tit three tit nine ducks given th tnhaccr, cmultneate for the lanFest (,trirats - 1 111 injectiuns in all nylrlidusis has not Leen assrKiated wilh ey,nettc smukinR in any rd Ihe 1 nnan stnti.tical studies Irh.. R.n..r..r r 1I S 1'uhlic Ilt:1slh Scrvice. "111f: 1 11 I('I (W 1•11: IIIY1 ('llOI ANIIIRI:NIE ON 1111? GASIR(/- IN I FS1 I N A I. I RA('1 0 1: T11F 1)(1('K." Ily 12 11 1(ipdrht, M 1) , 1'ro- K 3I t> 7(1 ro

feseor of Pathology, University nf T'exae Medical flranch, (7alvcctnn. Trtos Rrrnrtt nrr ItinfnRv nnd lllydirinr, Vol. IR, pagrs 275-2R1. Sumrner 196t1. Purporr of .rudyr Past erperimenls have shown that variations in the occurrence of inerhylcholanthrene-incluced tomrrrs do occur in rlifferent tit- sues in a sinRle hcnt, that sonie recearchers have produced tumors in an animal while others have nnt, and that there is need for an e><perimental approach tn the prnhkm of enrcinogenesis in rach hosl and in each tissue. lhis study was underlaken lo determine the hnmrn response of ducks to the oral administratinn of mcthylcholanthrene. Pror.drrr.r Twenty-one •fecks ged 19 days were given 7.5 mg. of methlylcholanthrcne sua(+endcd in I nrilliliter of liquid petrolatum daily for 30 days, at the rate of frve each week. A second group of I 1 ducks were given 311 mg. of mclhykhotanthrene crystals miRCd with 270 mg. of fluur in a gclatine capaule, at over-all rates which supplicd 600 mg., 1200 mg. and I RIN) mR. of inethylcholanthrene respectively to three prrwps c.f birds. I)irds died or were sacrificed from the 2R7th day on and the intestinal tracts were examincd. Ffndi'nR.: No tumors appeared in the gasln, inteatinel Iracls of any of the ducks -ihe melhylchrdanlhrene crystals were shown to t+e rapidly e><crcl d, and the ahsence (tf nrnplaeia may he e>tplained hy this failure rif ahsty~itian of the carcinogen. 1 he ttudy emrhasizes Ihal narplacros accepted o he hasrt nf "a.anciation" with a carcimogcnic agent always she~ultl he itically evaluated. Othrr Rrnntnr: II S Puhlic Ileallh Service. "(X'Cl1RRrN('E: ANI) ROI.F. OF GI.YCO(iUN IN TIIf: Fr ITIIf:I.tUM OF IIIf: AI.VI?<)I.AR Mlf('USA AND OF '1111i Al IA('III?1) (iIN(;IVA " Ily lo,eph P. Weinm:rnn, Julia Meycr, Uururhy Mardfin and M. Wcist, 1)ivisitrn of Oral ('athrdrrry, (Inivcrsity of Illinois. ('rdlcge of 1)cntistry, ( hicaRo, Illinnis. Arnrrir nn Inrnrrul rr( ,1 nnrumy, Vol. 104, pages 3RI-4112. May 1959- "f)F(iRf:F OF KFRATIN17.A11ON ANI) G1.Y(Y)(;fiN ('ONIfiNT IN l llf; I/NINfI.AMI:I) AND INI 1.nMlil) (i1N(;IVA ANI) AI.VfiOI.AR Mtl(Y)SA." fly M f). Weics, 1 P. Wcinmann, and 1. Mcyer. lorrrnnf rrf Pr.inJrmrnlrrRy, Vol. 30, pagcc 2(IR-21 R, July 1959. (T.I.R.C grantee: Dr. Isaac Sch!.ur) Prrrlrn.r of .tudlr.: Recent ttudicc of thc free gingiva have investigated file e(lcctt rd in0ammation on keratininrtion and glycogen dcpositiun, and have slresud file Lrcl that variable rtefreee uf keratinitatirtn may occur in the sanx specimen in different pvts ul the free gingiva. Theu sludies crtm- parc the diRerent regions of the free gingiva, the attached ginRiva, and the alver+lar mucuta of uninflamed sf,ecimens with retpecl tn de ry,rce uf keralin- izatiun and contenl trf RlycoRcn, and tfinvrdipale Ihe interrelatitrns hrtwren infl:unrnatirrn, kcratiniratinn, and Rlycr.rrn in thr.c rrgirms, Prr.rrdnrra ~ Ilil.rtct'tal hiepsic+ uf Ringiva anrl alrvrrlnr ,nn(nvr were rrth- laincrl ltrrm 52 mrn 27 71) years of nre Mrnl yd file nrcrt wrrc riF.rrrtlc srnrtkrrs, anmr utcd other furnn trf t.4,acco, nm1 n frw wcrc mm .nu+lrtt (;lyct~Frn wa. r.tim:rlctl u.)nr. file prrimlic end ntid Sthifl mrrh-I cr-n Irollcrl b~ rh:rttatr diOcttirrn; rlryrccs rit kcr:rtinir:rtir-n were dclrrrnincJ rn N M1J using 1lenslcy's specificalions of Mallory's connective tissue stain; inflam- matirrn was evalualed from the density of inflanrnratory cell infiltration in the connective liscue underlyin/t a given epithelial region; and cell size was estim:rted frum the cell density estahlished by cell counts. FJndinR.: In the absence of inllammation. the tendency for keraliniza- tion shows a regional gradient, being least marked in the crest region and most ntarkcd in the attached gingiva. Likewise, a regional gradient in incidence and concenlralitxr of glycogen was noted, the deposilion being nrost marked at the crem and least marked in the attached gingiva. Study of inflamed rrRinns showed that in0ammalion reduces the tendency for kera- linization and increases the tendency for deposltk>n ol slycogen. t he alveolar mucosa Iras a nnn-keratinizing epithelium and contains glycogen in all specimene. Keratinization and glycogen content are inversely related in un- in/lamed Pingivat regions, more markedly in inflamed Rin~ival regions and mrnt arke~lly in Ilre alveolar mucosa. The glycogen depostls in the alvenlar m sa may have a structural function in maintaining the intcgrily of the Is Ot/r.r Rranr.rrr U.S. f ublic Hcalth Service. I 11. llumon /,ftnR Studica "p11YSIOL(K)ICAI. RfiSfARCII IN ('lIRt7N1(' PULMONARY bIS- EASE: AN I:VALUAI'IUN OF ALVEOLAR AERATION, OXYGEN ANI) CARIION nI()XIt)f3 l'RANSFI:R ANI) '1111; PULMONARY ('IRCUI.A 1 ION." Ily llurley L. Motley. M.1)., I.'(^('1 ,('ardio-Respiratury Latx.ratruy, University of Stwthern California Schtxrl of Medicine, Los Angeles. /)irrovs n/ the Chcst. Vof. 311. pages 250-26(/. September 1960. Purpo.e of .tudy: There is great need at Ilrc present time for further studies on file pulmonary circulation In chronic pulmonary disease. An adeyuate clinical evaluation of pulmonar~ function alsn requires measure- menls on 1he venlilalory stalus, and on the transfer of onyFcn and cartxrn dioRide in Ihe lungs. Single tests of lung function on a single acpecl of the question are un-mliefactory. Important aspects of recent physiological re- search in chest medicine will be reviewed. Prorrdrare end jrn.finR.: Measurements relating to alveolar aeratinn in- clude spimgrann of tolal, titned, mid-ettriratory and nta>cimal breathing capacity; rc.idual air; intrapulmonary mvng; evaluation of brrrnchnspraam; and special devices for air flow which measure the rapidity with which air can he exhated from the lungt, amt.nR other variables. Significant infornra- lion on air Irapping is pruvided from the shape of the recorded spirogram Itacing. '1he maraimal ttrealhing capacity pnwi>les significant infurmatirrn un file fxlhrwt acliun of Ihe ehesl and lun ~t in addition tn file IimeJ vital c:rp:rcily mr.nurerncnta. Ilrnnchocpasm it lxst evalualed Itcfnrc and after aAminialratirrn rtf a hrunchrKtilalur druR. Residuul nir mrncurement and Ies1s of tnrrnpulmunnry mi.inR are vrr~' hnl+rut.rnt in the evaluatiun of IanF furrctitrn. In fuur ye:va' etlxrirnce wit11 an improvcJ hclimu t'hncd cFrt uq nrethrwt mrae nc(urnte rrculrs ruc uhl:rinrd in .evrrc rml+hysenra r:r.ca Ihnn with file oxyrcn chr.cJ circuil, unless a nilrugcn mctcr is uscd Irr m+milur Ihe nitmRen wathrnit Re6duil 33 • 12

.z ~ .~.. ~ Sh, ' air has been a mnH scnsilive tcd to detcct ch:rn}!cs in pulmnn,ry slalus, hul it may hc correlated poorly with the chest menlRenogtarn. lhr nitr(+pcn washout on oxygen breathing is n most sensitive test for the cvaluati(rn of intrapulmnnnry mixing in the IunRt, and reve:rls most graphicalty the prescncc of e ltcnsive nhstructi(.n in many of the smallesl respiratory airways in asthma and emphycema. "1 hc curvc of nitrtrgcn cx- halation with the sinple deep breath of oxygen and the nitrogen meter has not been found satisfactory in quantitative evatuation of inirehulmonary miRing. The nitrogen single deep breath test has been ohservcd to irnprnve after breathing an irritant such as cigarette smnke and to worsen after ad- nrinistration of a hronchodilator, just the reverse ot the vital capacity measurements taken at the same time. Valuahle information has been derived from sludies of the pressure volume rclationship of the lung (compliance studies), which are fxst cnr- relaled clinically with total vital capacity. For satisfactory clinical evalua- Iion, however, the compliancc lesl does not appear to provide any more siFnificanl infrrtmati~rn Ihan is obtained from lhr spirnRram. Adequacy of oxygen and carbon dinxidc transfer is evalualed pri- marily front arterial blood oxygen saturation and carMm dir+xidc cnnlcnt at rest and with excrcisc. These and many other aspccts of recent pulmnnary research will serve to fill the nce(Ffar accurate pulmonary function tcsting, for better diign(nis and Ircatmcnl, and should he uscd along with If`e his- tnry, the physical and Ihe rnenlRcnological cxaminalion. '1 he rulmomary physiningisl must cmplny an adcquatc battery nf tests wcll clandarJi?ed and suitahlc flrr muline utc umlcr a11 hcalth conJilinns, an(I Ihc infruma- liry( sn ohtaincd in turn must he imrilaclcd corrc(tly as well at theine pendahle Orh.r Rrnnh.r: 11 S f uhllc Ilralth Scrvlcc 111. Ihnrf anr! (:irrltlrffirrn "T 11F. MY(X'ARI)IAL Mf 1 Al1OLISM OF FR11("fOSli " fly Willi,m 11. L)anfurlh, M 1) ,( harlcs f:. I logancamp, M I) , Fred 11 Nallard, M I) , and Richard 1. IIinR, M.l)., Washingt(m University School of Medicine. St. I.ouis, Mo. American lournol n/ rhe Aledirol .Srirnrrt, Vol. 219. Lagcs 477-4R4, October 1959. (T.I R('. grantee: HinR•) f urpn.r of atudy: In view of research which shows that the muscular suhstancc of the hcart has the ability to ulilize a wide variety nf f(wrdstulfs, depending to a larre extent on their availahility, a study was unllcrtakcn to dclermine whether the myocardium extracts siRnificant quantitics of fructnse and whether this carhohydrate aflecls the myrxardial ulilvatiun of tither subslrates. Pror.dur..: ('athrters were placed in Ihe c(ur+nary sinuscs of eleven human palients (Iwu diaf>etics, threr with milral Uctnntis, onr wrlh aurlic insnfl}cicncy, nne with re('enl fxricnrditi., two wilh unc.lrlaint•d c"nr.cslive hrar( fnilurr nnd lo withuul (Ieleetrd heart Ihtr.rse) In a f:rstinv, statc (hc(nrr iniulln adlniniuraliun lo the (IINI-('tlct). n11rf1al hI1M/(I was r.htaintil '1)r thnr i. n- 1''ntr%.nr nf Mt-liiinr rn,l ( -harm.n, t)tp.rlnkM of Mrdicine, W.tnt %,.,r I'n..r.uty (0/rRt ol Mn6iinr, Ut~rn~l, Miih 14 t r I an1l cnronary blood tlaw was determined. Artcrial anJ ctrnmary sinus samples for fruclose, glucrne, pyruvate. Iaclyle, and kctoncs were obtained simullancrrudy, and the average of two cr.nscculive blood samples nrca- sured. A priming dose of fructose, varying between I S and 41) g., was adminislered, and intravenous infusion of 10% fructose in saline was maintained cunstantly. Sampling was carried out twice during the course of the infusion and the substrates were again measured. Six aneslhetizcd doga were calheteriud via the coronary sinus nd the femoral artery, and also received 10% fructose in saline at a rate calculated to deliver 0.5 g. per kg. body weight in 30 minutes. FlndlnR.: With initial arterial and coronary sinus levels of fruclose at zero, arterial fruclose kvels rose slightly between the two samplings in four palienls and fell in five of them, while arterial glucose rose in all palients, varying cnnsiderably from one to another. [flood pyruvate levels rose in the majority of palients, but not in the diabetics, and there was variation in other measurements. Most of the dur showed a slight positive myocardial fructcne balance during lire frucUru rnfusion, and one showed a slight negative balance at the tirne of M+th samplinRs. In two doRs the coronary simrs concentration of fructose was greater than that in the artery five minules after strrpping infusion. Negative myocardial balances of fnrctnse were detecled in other animals I S and 30 minules afler the onset of infusion. It is possihle that the variable results were due to movement of fruchne in and nut of the heart muscle as the resull of changes in plasnm concenua- lion of Ihis carhohydrate, but other factors such as variatinns in cardiac activity cannot he excluded. The tesulls showed that myocardial utiliralinn of Rlucose, pyruvafe, lactate and kelone bodies were not noticeably affected by ruclrne in normals or diabetics. rRrr Rrnnrnr.r U.S. Puhlic fkallh Service, l-ife Insurance Medical escarch Fund, American Ileart Association, and Hurronghs. Wellcome and ('o., Inc. "Mf:TAfl()I.IC ('fIANGES IN IIF-ART MUS('LF f)IIRIN('r ANOXIA." fly (:erhard Mich:d, Siegfried Naegle, William 11. 1)anforth, Fred U. Rallard, and Richard 1. Ring, Department of Medicine, WashinRtr.n t)niversil~ School of Medicine. St. l.ouis, Mo. Anrrrican lnurnof of l'hy.rinlngy, Vol. 197. pages 1147-1151. I)ecenther 1959. (T.IR.C. Rranlce: Ring) Purpo.e of .rrrd,r: Studies of metabolism in the heart muscle following a perial nt anoxia have demonstrated impaired oxygen uptake if caronary pcrfusion is interrupled for more than two bours, and such hearts nlso pro- dnce significanl amnunts of lactic acid despite normal nvailahility of oxygen. Ifence rt w.rs decided to study changes in nryncardial metahnlism in greater rktnil durinR ann.ia, particularly in respcct of altcratinns in concentradons uf t•.lycor.cn, high ener(ty phcnphales and pyridine nucleutides following rkath (if Ihc tcsl aninral. rrnrrdrrr.: Following anesthes6 the chetls of 12 rnnn/rcl dtrRs were ulrcned, tlrr Ixricardium incitcd, fhe anrta xevered, and nlNwl h:rll ul Ihc left vrntuiclc rrmuvcd After a ptritxl of one half, one, nr two hnurs, another specimen ut 1he Icfl ventricle was removed for analysis. 35

!`•IndinR.: Anttcia pntiluccd concittcnt ch:tnfrt in :dl suhctanccs studied. 1)iphnclrhr,ryridine nuclet+titlc (1)1'N) IICI'rC:KCtI in a11 cxrcrimenlt; re- duccJ diphttci.htrryritline nuclctttirlc (I)f N1I) intr%~atcd shghlly, stt that a thtrr in ctmthinct) v,tnre -ccnrrerl, r,rticrnarly in the acontl la+ur (ilycttRcn strtret in antttic heart nmacle tlitaprearcd raridly and chnwed a prrtFreative deidctitm aftcr t)carh. 1 hete stwliet illuttrale tlr:rt ttxYgcn lack Ie:rJt to rapid dephutrhrtryt:,tinn of high enerR phrnphate cr~mftrndt and to Ihc suh- sequ nt frnnrath+n ttf intuRanie p~mphorus. O.r Rrnn-nr.; II S. Puhlic Ilealth Service. I ifc Inturance McJical Re- earch 1 und, An,etican Ffearl Ass(xiatinn, and IlurrttuFhe. Wcllcttnre and ('o., Inc. "MY(>CARI)IA1. FXTRACTION OF Rh" IN TIIF. RARf1IT." ny Robert F. Mack, hivid U. NoIting, ("harics f?. Ihtgancamp, and Richard 1. fling. 1)epartment of Medicine. Wathingtnn llniversity Schtwtl of Medi- eine, St I.rroit, Mu. .finerican Irmrnnl of P/r)•dtrhrXy, Vol. I97, pages 1173-1177, 1)ecemher 1959. (T.I R.C. (i'tantce: fling) Purpn.e o/ .tu.lr: lhe isolnpe of Ruhidium (RM") it widely uad in hinlnFic:d aludict I.cc:tnte of its armilarity to pttlaatium. lihe ul+take ttf thit calittn by heirt muarle tnggcsted to tdher ex)a•rirncntert a metlatd of yuan- litatively tlelcrrnininR blrxXt flrrw, but the prescnt authnrt trhtervcd no np- parenl rclilirmthift between theaylwn cvente in dnR studict. lherefttre, furlhcr evalualittn of this facUtr was undc-taken in r:thhitc. f-nrr.fnre: 1'erfnaittn was begun immediately after exlractinn on isttlated rabbit hcirla with warmcd uRyRcnated rahhit hhwtd containing Ira(ec of Rh"". ('ardiac cnnlractir.ns rctumal promptly. and the rnrtflnw hhrtal front the heart was cnllectrd, nmeasuretl and the plaarn:r cnncentratitTn of Rh•4 determined 1'erfucit.n was ct,nlinucd for 21) rnin,det, fx•rnrittinR cr+mp: riam of values for myocnrdial extractitm al a wide variety of now tates, both early and lite in the experiment. FrnrlinR. : '1 he mcan value for myocardial extractirm of Rh", during the firct len minutct of infusitrn it all r:tles of now w:rt 41.1% r 9 13. a value similar to that tthscrved by the authnn in dng eRhcrimentt (46'7 ), which seemingly Ixae no rclalinnchir to either ctmcenlr:Hitrn or now rate. Ilow- ever, the present inveatiRatinn dcmttnctratet a relatirtnchir not only between the myneardial exaractirm and the rate nf flttw, but also between Ihe myn- cardial ettractittn and the Icngth of time of (htw, since extraction perc'entaRe was tiFnificantly lower durinR the l:dcr fxntitm of pcrfutirm at a wide variety rrf now tatet It it ctrnceiv:rhle that varinhility in myttcardi.d or lat a elecutdyte content in the etl+crimenlal animals may lie rcal+ttmif.le litr e wide range of cxtraclitm vahres determined, eh~r Rrnnf.rrrt 11 S. Pahtic Ileallh Service. I ife Invnancr Medital Re- sr.trch Furttl, Amt-rican I lcart Attrtciititrn, and I h-llm:rnn I.al(trt hc, Inc "MY(N'ARI)IA1. MIJAHOI.ISM 01 VAI"1Y A('ll)S." Ily I rrd II Itall:rrd, Willtam 11 I-;tnfnrlh, SierfrlcJ Nary;lc :vttl 16th:nd I Itinr, 1)c (t:rrlmt•ntt If Mcdit inr, Wathingtnn I lnivct~ity nnrl W,tyrnc Sl.rlc I lnrvcr+uy Itturrrtrl if ( 111n.nl LnvttJrnlr.r.r, Vul 1't, It.rl'ct 1I1-121, May 196d0 1 I I It (' pr:rnrcc Ilinr) I'rn l~. .. ..l •rr..l• N- nr rcu i"h ILy ,.Ihrr .uillmt~ h:ra 01-n Ihat ( I the princip:,l, lipid fraction of platma Mncerned with the transpnrt and metahrdism of fatty acids is the ncxusterified or frec fatty acid (1•I•A) frac- tinn, and that the heart uses a amcitkrahle amt+unt of FFA. 'Ihe pretent study was undertaken to determine further The role of (atly acidt in rnyo- cardial metahnlism. Prored..r..e Coronary sinus and arterial blood samples were obtained simultaneously by catheter front human subjecls and determination made of bkxxl flnw, 6lucnse, tutal fatly acids (TFA ), and FFA. The patients had hypertensive, rlxumatic or arteriosckrotie heart disease but were not in congcslive heart failure. Fasting individuals were tested and then given orally two ounces of a fat emulsion containing 199f, saturated and BI% unsaturated fatly acids, and metabolic studies were carried out three or four hours later when little or no lipemia remained. After blood sampling from the initial studics, 1(1 mg. of aqueous heparin were given intravenously and repeat metabolic studies were conducted 20 minutes later. Two sels of ex~xriments were performed in dogs:myocardial utilization Of fany acids was determined in fasting dogs before and 20 minutes after hepnrin injectiun, while a second Froup was given l.ipnmul three hours txfnre it timilar cycle of determinalmns; in this group coronary hltKrd flow was measured during laclescence and after clearing of the plasma with heparin. FlnrlinR.: The data on myocardial metabolism of fatty acids by fasting man and dog reveal that FFA average 6% of the mean arterial level of '1 FA in the human and about 3% in the dog. In the fasting human the mean myncardial extraction of FFA accounts for 42% of the TTA elttrac- tion and the esteriGed fraclion makes up the balance; in the dog the FFA fraction accounts for only 23% of the total fatty acidt extracted. The oxygen extraction rotios were 264% and 65')4. retpectivcly, confirming other experiments which s)H>w, that in the fasting slate most of the energy in the heart is derived from fat metabolism. Ingestiun of a fat meal increased both platma concentration and myocardial extraction of FFA. Fleparin induced a fall in plasma concenlra- lion of TFA and an increase in enncenlntion of FFA. TICe studies demon- strate that esterified fatly acids account for more than half of the total fats extracted by the myncardium. Myocardial extraction (if fFA usually de- pen It upon (he arterial concentration or Ihis fraction. •r RrnnL.r.: U.S. Public Heallh Serviee, I.ife Inturance Medical Re- . arch Fund, and American Ifeart Association. "F.FFfi("1' OIT ISC'IIFM1A AND R[:OXYGiiNA11ON ON 61.Y('O1.- Yl1C RF ' A(-flON AND AOENOSINEI Rll'11OSPIIA'1 F. IN IIFAR I' MILS('l.E." fly William If. f)anforth, M I)., Siegfried Naegle, M 1). and R. 1. llinP, M.1) , 1)eparlmcntt of Mcdicine, Wr}thinghm I lniver.ilr antl Wayne Stale Onivertily• (-irrufatlrrn Rr.rrarrh, Vtrlume R, ItaRes 965971, Scl'tenrher It)6(1 ( 1I R('. grnnlee: IIinR) Purpnre of •tu.ly: I'rcvlput wrtrk by the nuthttrs tlenutnatralcd that mytrcarrlirrl 1•Iyrr+r.cn fallt, while hiflt ener(y Irhrrtithatet :utd tdhrr crnn pttunrla vary in eirtut directinn, durin~ the f1tat two hnura nt inJuccd rnytt- cardial iachemia in dn(;t. lhix wtuk it cttncernctl with detailet( c'hanFet in 1,, 37

17) 70 ..i. ~ the glycnlytic palhway uf heart muscle during 15 minutes (if anaernhiosis and when the ischrmie heart it again perfused with osyFenated hlood. /'rnredrrrtt Samples of myucardium frum mongrel dnRs were taken before removal of the heart and placed in an oxyRelt frce saline bath. Saline was nuthed through the left coronary bed through a sulured eannula to prevent formation nf micrnthrombi, and a second sanrl.le of myocardium was taken after 15 minutes of anoxia. The coronary system was then perfused with well oxyRcnatcd hlra+d and further samples obtained from a previously undamafred section of the left ventricle. The method of sampling miRht tend to hiat the results, since parts of the myocardium distant from the large coronary vesselt mutt he taken Rrst, but this should not aRect glycogen delerminalions. Several other related tetts were nrade, including some with perfusion of blood directly from a donor dog. Find7nR.: During the IS minute period of anoxia the fall in glycngen was as expected, and there was an increau in hexosemnnophosphale (IIMf ) and in lactic acid. 'f here was no accumulatirm (if fructose 1, h diphncfihatr, dihydnr.yacetone phtxphate, or ryruvate. Adennsinctriphrnrihate (A'f r) declinrd at etf.rctrd When the annxic hearts were rrrfuted. there was an initial adynarnic rAa~e ( I to 2 minutes ) followed by fihrillatinn nr irreRular, ineRective ventricul:n cantractiont ('hanRes in rnyrxardial Rlycngen eon- eenlratitrns were incnnttant ('oneentratinn of IIMP declined rapidly lo nrar normal levcls at the end of Ave minutet. ('nncentratinn of A f P rose (lorinR the firtt twn minutct; when K('1 wat adrtcd to the pcrfuainn nuid, A T P concentration reached the initial level in 4 to 10 minutes; in exf+eri- ments in which the heart was alhrwerl tn heat (rr to fihrillatc, no consittent directinnil trcnrl in A I 1 could t.c rlitccrncrl after thc first 2 minutrt Snme tMl of the f.crfusinn itsclf mutt be invoked to explain the decline in IIMP with enntinued Rlycngcnolytis lthh.r Rrnntnr.: II S Puhlic Ilralth Strvice, I.ife Insurance Medical Re- seareh Fund, American llearl Ast(.ciation, flurnruRhs, Wellcrrme nnd (-n , Ine., and AhMrtt I ahc+ratnriet "f OSSIIILIi MF(-IIANISM OF TIIF, f)f?('I.INF. IN Mfi('IIANI('Al. fiPEICIFNCY OF 7IIF. ISOI.AT I?1) IIEART." fly K Knko, 1. 1). ('hnudhury, and R 1. (ling, Department of Medicine, Wayne State lIni- vertity Co11eFe nf Medicine. fktrnit, Mich. Journal nl I'harmarnh+Ry and Erprrimrnhd i hrraprurirJ, Vol. 1111, pages 46 54, Septemhcr 1900. (T I.R.C. grantee: fling) rurlrn.r n/ rrndyr 11 is the purl.rnc of thit paper to describe eRpcri- ments dealing with mrchanisms nf the decline in nrechanical efficiency of the isnlatrd heart and with the r.rtsihle innuencc of liver and spleen in altering its mechanical efficiency f'rnrr.fur.: ('trrnnary nnw, glnrnte. Iactite and kctnne ht>,1ict were de- termined in clnsed chest dngt by cathetrrs into the crnonary sinut and the riRht ventricle aml in isolated hearrt by hearl-lun/ tirrlraratinn In etprri- tnentt in whi.h livrr nrtd tl.tcen were intluded in thc pcrflnirrn cirtuit, thete rrrRans werr qrritkty renurvcd hrrrn a rhrnrrt nnirnnl nml irntnrJlatrly (on nrcted to thr circnil rrt the hcart IunR Incriratirrn, whn h had hern ohci atinR frrr 41, minutrt ( lthcr etl.erimrnts crnntr;nrd contr:rt Idity rd nr trmrymin 1,311411 hrnn %laontanrrrutly faiGnR artd nnrmal hrartt JR i FlndlnR.: In the closed chest eaperiments oxygen and glucose ueage fell significantly and lactate and ketone bodies also decreased. There was no significant change in the oaygen eatractinn ratio of glucose, lactate and ketone h<wlies of the isolated heart as compared to the heart in JfrY. The eRecS of the inchrsion of the liver and spleen was a significant decline in myocardial oxygen consumption, hut myocardial usages of glueose, lactate and ketone txxlks were not aRected; the oxygen extraction ratio of ketone bodies did rite, however. Contractility of actomyosin bands prepared from hearts failing in the heart-lung preparation was nrN impaired. Cardiac autput, left ventricular work, and myocardial effickncy de- clined significantly in all tests. Inclusion of liver and spleen in the perfusion circuit raised myocardial efficiency by lowering the o><yren usage of the heart. The heart rate deelined. Addition of small quantaies of nnre~tine- phrine and dnpamine to the perfusion fluid increaced myocardial efficiency wilhnut significantly altering heart rate. Following the onsel of operation of the heart-IunE prcparation. the concentration of catechnlamines in the pcrfutale gradually diminkhed. This trend could be partly reversed by rnclusion of liver and spleen into the perfnsion circuit. I)t . Rrnnrnr.r l/ S. Public llealth Service, l.ife Inturance Medical Re- rch Fund. American llearl Assoeiation, Burtrrrghs, Wellcnme and ('o., Inc , and Abbott f.ahrxatorks. "IMPORTAN('E OF CHGMICAL TRANSMISSION IN CARf)IOL(XiY ANl) NE(JROPIIARMACOL(XiY." Ify Richard 1. flinR, M f)., Wayne State Univertity College of Medicine, Detroit, Mich. Archivet nf Internal Mrdfrrnr. Vnl. 1(14, paRes,658-671, October 1939. "TIIf: IIfART IN CONGESTIVE FAIL(1RE." By Richard 1. Bing, M.l)., Wayne State University C'ollege of Medicine, Detroit, Mich. Trtas Starc lournal (i/ A/rAirinr, Vol. 55. pages 9J1-9)6. December 1959. "Mf:TAII()I.ISM OF TIIF 11l'sART IN FAII.URE." fly William I1. Dan- furth, M.1)., F. H. Ilallard, M.1)., K. Kako, M.D., I. b. Choudhury. M.l)., and R. 1. fling. M.D., Department of Medicine, Washinglon University SchrNrl nf Medicine, St. Louis, Mo. Circulation. Vol. 21, pages 112-123. January 1960. "PIIYSIOl-(XiY Ot' TIIP_ MYOCARDIUM." By Richard 1. IlinR, M.1)., Wayne Slate University ('olle e of Medicine, Octroit, Mich,; and William II. I)anforUr, M I). and Fre~ H. Hallard, M 1)., Washington (lniversity Schrx+l of Medicine, St. Louis, Mo. Journal of the American A4rdirnl At7n- rinrirrn, Vol. 172. January JU, 1960. ppages 41R-444. (T'.I R C. grantee: IIinR) T hesr frrur studies are revkws of recent research hy the authors and nlhert contribuling to knowledge of the hcart in health and disease. The (ir.r paper ttresset Ihe equal importanee uf ehemical Iransrnillers such Af acelytchrrhne nrrd nr.repinephrine in both circulatory and ncurophysinlnRical evenlt Ilrr tmmnu,n denominatur is the innrrvatinn of Ihe hrarl and .crilrthcral 611,40 vetsrls hy the autonnmie nervnus tyslem 'I1rr phytirrlnRicnl Ihasit nf rxcitatirrn ntul mhihitinn trf the centtal nervnut system it Ihrn rccrrpniird m a matter of uniyue interest to the earAinhrRist. lhe most attractive aslxcl of the mutual antagonitm nr synrrRism of 39

! chemically related inhihitors is the mystery of this problem. For exarnple, little is known of the relationship of norepinepInine to heart failure and to the intrinsic regulation of the coronary circulalion The tools availible to investiPate circulatory anJ neurophysiological relationships are still too crude to solve the firohkm. In the rrr.nrd paf+er, il is noted that the rnle of the heart muscle in cnnFestive failure probably has manr facels, just as the clinical and dynamic feitures of heart faihrre vary with Ihe ty/+e of disorder and the mtxfe of ils exrerimental prrMluctinn in animals. In general. however, myocardial failure occurs either acutely - which usually is observed experimcntally in the heart-lun~ preparation - or chronically - as seen in clinical conges- tive heart fai ure. There is snrne evidence that acute myocardial failure, whatever its origin, is accompanied by disturhanees in the metabolism of the heart muscle. This Jisturhance in energy prnduction conceivably may kaJ to diminished cxpulsive power of Ihe heart and to progressive circulatory failure. Chronic myrxardial failure is difficult to reprrxluce experimentauy, on the alher h:rnd, and the results of dog studies may not be entitciy appli- cable to man. It is now possible to study heart metabolism by coronary sinrn catheterirarlon and thus to demopstrate that the myocardial usage of oxygen, glucose, pyruvate, lactate, fally aciJs, aminn acids, and kNones is not different in patients with congestive heart failure, in individuals with comf+ensated heart disease, and in those without evidencc of heart disease; valucs fex the respiratrxy quotient are n)sn identical in these grtwps. Since the mechanical work of the heart is usually decre:rsed cxcept in high output faiiure, tlx failing heart appears to be ckficicnt in its ability to utiiire energy for effective muscular contraction. Further support for this conclusion has cnme from studies of con- tractile proteins (aclnmy(sin) prepared from human hearts. lhe exacl nature of disturhances in the contractile elements o( the heart muscle is as T et uncertain, however, and the pathologist is unable to find specific changes n heart muscle of paticnls who died in congestive failure. Since there are manr factors which can lead to myoeardial faiiure, it remains to be seen huw disturbances in the heart muscle can he manifested in the general signs of heart failure, c+f which cdema accompanied by sodiunt retention is the most importantL One Iherefnre must search for a connection relating the disturhances in the heart muscle with both the posterior pituitary and the renal tuhnles. I lere, trKo, many factnrs have been shown to e>tist, and definitive knowledge is quite scanty crmcerning the direct stimulus to srxlium rententiom. The third p:rfxr is particularly eoncernctl with studies of Ihe three phases of cardiac metabolism - enerFy rroJUclirm, energy amcervatir~n, and energy ulil'vntion -- which show m:ukcd diflerences in the unJcrlying rnechanisrns of heart failure lhns, in failure with pn+honRcJ nvcrhvaJ r.l Ihe heart mustle. Its r+ccurs with hyf.ertension, valvul:rr henrt di.c..c and tteriosclersmlic heart disease, an nl.mrrmalily of cncrRy utilinrtinn secros n+nsl likely In rrthcr silualhrns wi!h heart failure, r"n Ihc other han (, there "hrnrs Irr he a rtcfrct in energy irnatuclirm ra concurvatimr: in anernia, myrxardial failure rceul!s in insuflirient Iransrrrrl of nxygen h,r substrale 40 nretaMtlisnr, white in hyperthyroidism uncoupling of oxidative (+ho.phoryla- tinn may lead to failure of energy conservation. In hemorrhagic shock and myocardial infarction, general or localir.ed anoxia leads to defective energy production. Spontaneous failure occurting in the heart-lung preparation is in all likelihood the re%ult of diminished eateeholamine and cholinergic sub- stances of the perfusion fluid. It is apparent from this review that no com- mon denominator exists as a eause of heart failure. The /nurrh paper reviews advances in knowledge accomplished by studies of the heart at the molecular level. Anatomisls are now studying its submicroscopic morphology, while physiok+gists and clinicians are ex- phxinR the electric activity nf heart muscle cells and heart melaMolism; hiophysicis,s and pharmacologists also are making valuable contributions to the new approach to hearl disease and its treatment. The r.dvent of calheterization of the coronary sinus has made it pos- sihle to stuJr the use of varinus substrates by the human heart in +inr and to ohserve the myocardial extraction of substrates and oxygen. Metabolic studies by this Iechnique have demonstrated the importance of fatty acidf in the nutrition of the myocardium. fly the introduction of microc/ectrnJes into the interior of finRle cells frtxn the myocardium, the aIriuvcntricular node, and the ventrkular conducting systen,, it is now possible to follow electric changes and Ionic fluxes in small units. lltis method has thrown new liFht on the significance of potassium and oxygen and the mechanism of fibrillation and pulsus alternans. Comparable advances have been made in the chemistry of mycxardial proteins, the basic pharmacology of the heart, the pathological physiok.Ry of isehemia and anoaia, and the mela- holism of the myocardium in congestive failure or after infarctinn. Or r Rrentor,: U.S. Public llcalth Service, Life Insurance Medical Re- ~rch FunJ, American Heart Association, Durroughs, Wellcome and Co., Inc., and Ahbott Laboratories. "VASCULAR RESPONSFS TO SMOKINO TOBACCO COMPAR[:D WITI I RESPONSES TO SKIN TESITNO nF TORA(X'O EXl RACTS." fly Kurt De('rinis, M.D., Walter ReJisch, M.D., hA('P, Vincent ronlana, M.D., Arthur Lewis, M.D.. Marion li, SultherRer, M.D., FAC'P, and 1. Murray Sleele, M.1)., New York University Medical Research f)ivisinn, ( ioldwater Mcmorial Hospital, and E)eparttnents of Medicine and Ihrma- tuh'gy. New York University College of Medicine, New York ('ity. Annal.t u/ Imrrnal Mrdirint, Vol. 52, pages 19)5-104(. May 11060. (T.I.R.C. grantee: Sul.,herger) Pr.rpn.r nJ .rudy: It has been reported over the years 1hat, in a certain percentage of suhjecrs, smoking of tobacco causes vosoconslriction of rt.eriphernl vessels, as indicated by decrease In srnface temperature and ako I+y plclhysmrr raphicnlly measureJ hhrod Ilow. lhe mechanism involved in this reslxmse ias Lcert the subject of some cnntroversy l.ikewise, diarepant views errncerning thc vascular heds Involved in~conatriclor rrsponses to tohacco smrrkinF have Ixen eaprrad To gain further irrfornatiun in this area, i{ was drerJrd la cotrelale vascular responsef to tobacco wilh srnsi- livity respe.nscs in the skin. Procrdur..: A Rrv,up of R0 healthy smokers, including 27 femnles and I 41

tn ,. . rJ 53 males, aFcd IR 10 50 (average age 36), was Ictted hcftue and after smoking a ci(tarcrte in six minutes under stable rtHtm Icmreralure and humidity conditiairts, and after refrainin~ from smnking or eating al Ieast one hour before the test. Pleahysmographre base line tracings, clecxn.cardio- grams, and hallittncardiograms were taken. l he RO suhjccts were alao tested with intradermal in~etions of various lobacco exlracts, and reactions were read after 10 minutes. FlndrnR.: Of the total RO healthy suhjecls, 38 (47.5°h ) revealed changes in at least one of the six circulatory measurements after tobacco srmokinR, while 42 (52.5% ) showed no response. Only 10 suhjecls showed changes in the ballutocardinRram, and three in the electrocardiogram T wenly- eight subjects (35% ) showed a significant decrease in bltxrl flnw: 52 (FSS''o ) showed no change; none showed an increase. Surface temperature showed a decreace in only 11 subjech. Uf the RI) suhjects, 32 ( 407F ) showed a positive skin reaction to the tobacco extracls- and 4R (h0%) renrained negative. Of the 4R subjects with negalive skin test, 41 revealed no siRniticant chanFe in mratured peripheral hkKxl fltrw after smoking; the remaining five sul+jccts Ihrrwed a significant decrrasr in bltwKl flow. On the other hand, of the 32 suhjech with Potitive skin test to tobacco. 21 (h5 6% ) showed a dccrcase in blood flow after smnking, while I 1 showe ntr change. lhcte results saRRest that a~~iitive immediate wheat reaction to skin trets with krhacco eRtracts may irulic:rte a suhjecl's tendency to ahm,nnal vaacular rea('' rntet, ec),e~cially voacul:rr enntlrictittn and t(ccrc:rtr nl peri- pheral hhx~d flrrw, after ciRiretle smuking. lhe tiRnificance of the lack of correlation in the rrapcintes in anface Icnq+crature and in blood flow has to he acccrtaine l Ihrouph further wrrrk The clur might well he that hkKx1 flow to the IcR indicates prethxninanlly mutcle flow, while turface ternpera- ture is a function of Ikin fltrw r.nly. "('llOI.FS1fRO1. CFfARA('T[RISII('S." fly Caroline Itedcll Thomas, M I) ,)tdrnt Ilrrrkins Univertity Sch<wd trf Meqicine, fl:rllirnore, Md. Alnryltrnd .trnrr Afrdrrof lournol. Vtd R, paRes 2-F, January 1959 PPoints thal are /mfhMtanl In know in ttrder lo understand and interpret bkod cholesterol levels in patients are as folhtws. Firs1, the Itttal serum cholesterol of hcafthy adults has a wide range of normal values Second, the exact numerical vnlue of cht+lestend varies conticJerably with the par- licular la(xiratory Icchniyue entphryed, and Ihttuld he Judged within that framework. lhird. there it little rn nu difference in the cholesterol level after eating as cnmhared with Ihat in Ihe fastinR stale. '1he fourth and fiflh irnlMxlanl facuat are aFe ami seR, which have quile a Lenrinr, on fhe (htdetlerrtl Icvel, A siRth prrint it th..t dctf'ite mcaturahle flucluatirrns. Ihere is relative conttincy of chrrletlerrd levelt over a(+erirnl td weeks or mttnths in a nnrmal intlivitlual. A Icvcnth point Iut tu drt with Ilrc chtslcclrnd rd ralicntt with crorrrnary ditt•aac. It hat IKCn .huwn Ihat thctc f+:rticntt havc hi('hcr mran chrdrtlrrrd Irvels nnr) tlral Ihrir leveli fluttuMe runre wirlcly tlian Ihrnc rrr hralthy hcrvrna ttf aimit,v 'I ht• t(ricttitm rd wht-thrr Ihctc nltnhrilr- fnr, r.li Ilhr +hlwnt:rn r r4 t linical rtrir:t.c Lrcornrt of irnrnrrliatc iinl-rtnncr Ily/•crtli"lc.trr"Iriui:r rrrur. in pcr.oml in alqparcnt RrNNI IKalth It :tlq1rars 42 I that high cholctterol levels and coronary occlusion are chtsl!ly associated and tend lo run in families. Additional shrdies are being made to dctermine, if Lossihle, whether an asancialirm of higher cholesterol levels and.moking found in our students represents an inherited or constitutional difference rather than an effect of the smoking habit. "COMPARISON OF SMOKERS AND NON-SMOKERS. 1. A PRE- LIMINARY REPORT ON THE ARILITY TO TASTE PIIENYL- TFIIOURF-A (P.T.C.)." By Caroline Bedell Thomas and flernice Nirsch- hcxn Cnhen, Ihpartment of Medicine, lohns Hopkins Univenity School of Medicine, ftaltimore, Md. Be.lftrin of the Johns trorkins Ilntpirnl. Vol. 106, pages 205-214. April 1960. I'r.rp...e of arndy: There is already !usme evidence pointing toward Psychologic, physiulogic and metabolic differences between certain groups of smokers and nt.n-smokers. f)emcxntration of well eslablithed genetic differences would be even more conclusive, because such inMrrn traits are presumahly stable and could not he the result of smokinR. In order to explore Ihe rreyuency of several genetic Irails amonR Rruuls of healthy smr+kers and non-smokers, it was decided to sludy the characleristics of blood dnnors at the Johns Ilof+kins Ilcnpital, and to report preliminary findings on the ability to lasle Phenylthiourea ( P.T.C. ), a compound that is an experimentally valuable aid in testing taste levels. I'rnr.vfnrr.: Taste lests, usinR filter paper impregnatect with P.T.C., were carried uut on 597 white and 232 Negro male domrrs at the )uhns Ifnpkins Ilcxpital Illnod Rank. Each dcxtc» was inlervicwetl as lo his smoking hahils. The subject was asked whether or not he lasled anylhinR, and if so, what the taste was like. /le was then grouped according to ability Itn taste P.T.C. FJndinR.: Among both while and Negro donors, significant dilferences in ability to tatte P.T.C. were found between smokers and non-smokers. Among white male donon, heavy cigarette smtrkers showed a strikintoly higher pn>t+nrlittn of laslers than did non-smokers (65 9^7e versus 42 7'7„ ). Former smtrkert, occasional smokers and light smokers closely resemhled the non-smttkers as to profxxticxt of tasters. The significant findings were unrelated to age. "CIIARA('fFRISTI('S OF SMOKERS COMPARrI) WITII N(1N- SMOKIiRS IN A 1'OPUl-ATION OF 11fAI.TIIY YU(IN(i AI)III.TS, INCI,I11)IN(: ()ISCf:RVATI()NS ON FAMII-Y II1S1()RY, 111.0(lf) f'RF.SSIIRf?, IIIiART RATE, IlO1)Y WIi1t:11T, ('IH)1 I:.C•ITR(11. ANf) ('FRTA1N PSY('IIO1-(Xi'IC TRAITS." Ily ('aruline Itt•dctl l'hnnus, Ik• parunent nf Mrdicine, lolms llnf+kins Ilnivertily Sc'hrwd of Medicine. Ilaltimtne, Md Anrrnlir tr/ lntrrrrnf Medirinr. VaL 5.3, Pares 6'17•71R, (k-ttrhrr 1960. rf .Iu,fyr Ref+rrrlt that mtukers, especially heavy smrrkrrs, have a higher rntxtality ratc from coronary hcart rliacatc than r1n nrtn- trnrrkert m:rle it imlrtut:rnl trr tlclcrrnine whrllrrr Ihrrae whr) smrrke are fundnmerdalfy tlrllcrcnt frrnn Ihrnc who dn ntrl, or whethcr Ihey arr rtacn- tially alike. If alike, they may t.e contidcred ae a sinFle Pnlrutatitm with a 43

unif(rrm life e><pcctancy, hul if smt+kers have cnnstitutinnal drlTerences fmm n(in %nuAcrs, the two I;rtntl+s might have dilferent mttrlality rates, an(I rmt p,rrmr ctruld not serve as a ctmarrtl fur Ihe othtr in slalistical studies. It was deci(Icd to sludy Ihe smnking hahits and tHher characteri.lics nf Itl succettivc cl:nses of nredical shulents in dctail. Prnr.dnr..: 1)etaifed information was obtained from 597 men and 60 wttmen ctrncerning srnnkinR hahils, family hist(try, mensurtrnenls tif hl(KKI pressure, heart rate, Ixight, wciFht, and chntes,cr(d level, as well as results nf a cnid presa+r test, a double Mas(er cxercice Iest, a hallistncardinp,raphic smoking test, and a Rnrschach test. All suhjects were in gtwwf hcalrlh and free front clinical evidence of hypertension and coronary heart disease. Fln.linR.: SiRnificant difTerences recorded showed: (1) The smokers, as a Rrnup, more often gave a history of parental hypcrlension; had higher mean values for heart rate and pulse Pressure; higher cholesterol levels; comhrised a IarRer proportion of heavy individualc; and more often reported anger and an urge to eat when under stress. (2) Nnn-smokers, as a Rrnup, had hiFher mean values for diastolic rressure; mnre often rcfhirted de- creaecd activity under saress; and mrxe nfltn gave a high numltrr of .vhile space response in the Rorschach Iest. (3) A parallelism existed Letween Ihe prtsence nr ahscnce of faclnrs thought to indicate high suscePtihility tn hyptrtensinn and/nr coronary4disease, on Ihe nne hand, and the presence ar absence of the habit c.l smoking. t.n the other. (4 ) Ihna(I areas of sirnilarily were found in the recfrmses tn the cold pressor. Mastcr and hallisl(.canlinRraphic smnking testt; in academic excellence; and in most of the Rorechach variables. (5) 'I he dilTerences observed in the parental hislories indicale that smttkcrs ami nrm crnokt•ra have a sttmtwhat (IifTerenl htritaRe, and .uRResl Ihat at Ieml arme t,f tlle v:ur.tu.mc fttun(1 in imliviJual t aits may hr• genetic in origin ~hhrrRrnnror: U.S. Puhlic 11c.rhh Strvite "f:FFFiC"fS OF P.R(i(1MIiIRINF (I lt(;()NOVINf:) ()N 'IIIF. ISO- t.AT[:1) A111U.RUS('LI:ROI1(' III-AKI OI 1111: ('I1(111~SI1:R(/l.- I~I~.h RAR141 f." Ily Ih+rnthy Karp, Seynutur 11 Rinylcr, an(I )anet 1 ravcll, h"artrnent of Plrarmacolnry, ('urnell University Medical ('ullel. ' e, New Yrnk, Ncw Ynrk. llrirish 1(mrnaf rr/ I'/rornracrd.rRy, Vul. I S, P:tFct 1} {.144, lune 1960. (T.1 R.C. grantee: 'Iravell) Purpo.e of .nrdy: Intravenous injectitms nf trRnmetrint (11.5 P. ergrn nnvine) (+ttxluce a transient S-T segment tleprestinn in the electrocardio- tn ~ CJ N m ~ co co grarn that is characteristic of coronary imufficiency in patients with cornnary artery distme. Like ehanges are induced in rahhits with exTxxrimental curonary, aatherosclerosis. l hese chanRcs d(+ not occur in man or test ani- m:tl with a mnmal cnrtrnary eirculali(m In the ahsence nf tiata, it seemed imfftrrlant to study the tlTccts of Ihis drug directly on Ihc ctirtrnary . circulation. Prnr.dure: 'Two Rrtrur+ of male hulch ral.hits were slartrd at the wme lirnc tithcr on a t1rKk diet or on a similnr dict with aJJrlinn (l/ 1^%• chulestt'red Scrial erRnmtfrine ttsat were (hmc aftcr h ttt R wrrkl t.n the (lirts nnll thrrcalttr uaunlly at wtc)ly in,crvah untrl thr tr.t IKcamc lu.nitivt' ('~mlird rIr(trlK.l/duol!ramt wcrc tuktn Lchac, and 5 and It/ 4 .1 i minules after I+enttrharhiltrne injecli(m. Fr Rr.metrinc malcale 0 05 mR./kg. w:ts injected intravenrnnly and ekctrocardinFrams nn Iwo Icads repeated after 1, 3, 5, 7 and 11) min. or kmger, depending nn the doratinn nf eRect. One nr two days after the erRnmelrine test hecame (xxilive. Ihc athero- sclertrtic heart wat isolated and the ctxonary circulatitro Ixrfuscd; control rihhils were treated similafty. After Lerfusion the heart was fixed in f(umalin and sectinns taken for pathological sludy. FindlnR.: A Itttal of 29 atherosclerotic Irearts of chnlcsterol-fcd, crRo- metrine-pc.cilive rabbits and 32 normal hearts of ergometrine-negalive aurtrnl rahhits were perfused with various drug.s. Most of the ergomctrine- P(xitive hearts (96% ) showed advanced intimal alherosclerosis of the small inlramural arteries; one heart showed a less advanced change. The IarRer arteries seldom showed such changes. No changes were seen in the conlrol hearls. Initially coronary f1ow, heart rate and amplitude of conlrac- linn differed in mxtnal and atherosclerotic hearts. With respect to ergo- metrine, coronary flow was the only parameter to show a significant di/ler- ence in the resl+ronse of the ntxmal and athernsclerotie heart to medium Atxes nf Ihis druR, hut Ihe changet observed with smalkr and larger d(nes were not statistically significanl. The diRerence in the flow reqNmse of the normal and atherosclcrMic heart tn er"etrine was striking during the wearing off of a vasnpressin-induced reduction in cornnary flow. In cc.ntrast to Ihe reprotlucibk effects of a given dtne t,f ergometrine, va-opressin induced tachyphylaais in the isolated heart. Furthermore. the cffecls of vatnpressin were essentially similar for normal and atherorn sclerotic isolated rabbit hearts. These observations suggesl fundamental differences in the mechanism of action of these two drugs on the heart. One may speculate that the effects of erRometrirre on coronary flow are metliatetl at least in part through mnhilitalion of cafechnfamines, whcreas vaapresdn acts more directly on receptors. When catcchulamines are depleted durinR atherugenesis, a direct aetion of ergnrnetrine on reccPttxs may tmmaskcd. Ornntnra: U.S. Public Health Service and )txiah Macy, Jr. tundation. ' "I-IPIf) INFILTRATION IN TIIE RARRIT IRIS." by Duane (7. Wemel, James A. Turner and Donald Kissil, Sehtx>f of Pharmaey. University of Kansas, and the Veterans Administration Hospital, Kansas ('ily, Missouri. Amrricnn lrrurnal of Ophrhufmotogy. Volume 4It, pages 535-537, October 1959. (T.I.R.C. grantee: Wenzel) Pr.rpo.r o/ arrndy: Although lipid infiltralion of the aclera and crxne of the rabbit and human has been relxxled, similar effects have been unnnticed in the iris. This is the first tn report otnervatinn or lipid infiltra- tiun in the iris frnm choksterol and cottonseed oil adminislralion in the dict of eRpcrimrnlal animals. Prnr.dnr..r Nicotine was given for 24 hours In Ihe thinking water uf Itrnte groups nl animals in yuanlilies Itr enrresfmnd to Ihe use ttf varinus amounts of Inbacco hr homans, wilh trprtqniatc controls. '1 lie cycs were suhjccttd fn ~rrns •nd rnicrrncnpic slw1y. , FlndlnR.r Ihrrt were no ohvinus di/Tcrences httwet:n the eys rlf nnimnls receiving chukstcrtrl alone as a dietary addilive and those also rcceivinR 45

nicotine. Microscorically, the iris was virtually comf+letely infiltrated with fat-filled macrophaRes. Similar defositiuns includinR large vannrlcs of falty material were found in the ciliary h<KIy. Sectirms through the PrMerior sckra revealcd the fatly material to t.e depcxited in all layers nf the wall. 1 V. I'aychrr-ph ytlionlr)Rica[ "MASCl1l.INITY AND SMOKINn." Ay Carl C. Sclt?er, Peabncfy Mus- eum, Ilarvard lJniversily, CambridRe, Mass. Srirncr, Vol. 130, pages 17116- I707, December IR, 1959. Prrrpn.r nl .nrdyr In order to obtain a fuller understandinR of the ap- parent relationship of heavy smoking to lung cancer and coronary disease. It was rcrtinent to inquire into the nature of Ihe individuals who practice the smoking hat.it - their f+erax+ality, phpsiolo6y, and hinRenetic character- istics. 7his report dcals with one aspect of the somatic bingcnetic ntaterial - nantely, the hcxly build of these men as relatcd to their sm<rkinR habits. Prn.•P.lur.: lhe basic data on which the analysis was hased were derived from a follow-up study of 252 ITarvard snfrh<xnnres first seen hetwecn 1938 and 1942, who were selected for their lack of visible ahmormality. In the course of the Physical anlhrnfudARical examinatinn of the suhjccls while still sophom<aes• each individnal was rated with respect to a txxfy-build complex dcscrihed as Ihe "masculine component." which refers to the elemcnt of mascalinily in the individual as indicated by his external morfohnlogicat features. lhe more the pattern nf anatomical Iraits tends toward the extreme ntasculine hxrn, the stronger is the masculine corn- ponent; the greater the departure fnnn the extrerne mascntine type towards the more feminine build, Ihe weaker Is the masculine component in the imlividual. FinrfinR.: Weakncss nf the rnasculine component was siRnificartly more frcquent in smokers than in nomsnurkers, and z'rpnificantly more fre(luent in heavier smrrkcrs lhan in non-sm<rkers and mrxlcrale smokers combined. 'Ihe increasetl frcqucnc) nf the degree of weakness of the macculine cnrn- poncnt was cnn.i%tent and prnFressive, and the heavier srnukcrs showed the Rreatest prnrortiun of indivi<luals with "weak" r<r "vcry wcak" mascu- line comp<mcnts fhcae <lata suRReat that for a chccified type of individual, stn«kinR may be a reflection or certain personality and hehavirnal trails which are characteristic <rf his hioI<rFical make-up. V. T.r/ior•.vr C/rr•ntiory l I I F . l.IrlT('T Of INf))I.ri 3-A('IiTI(' A(-II) ON rORMAt.hl'.IlYI)t: Ml:f /11IOI.ISM " Fly ('lillnrd S Saln, Kerckh<df I.at.<rrnlnrics of Itiuhrpy, ('atihania lnwitutr <rf '1c.hnrrhrry, 1'asadcna l"urnnl rrf llJ,d,r):rrnf (-hrm- itrry, Vi rl 2115, parcs 2/)A7.10 I, luly 1960 ( I I R.( . grarHCr: I )r Tamcs Ifnnnerl 1'nrl,.," ,•1 •r.••rs • f'I rnl tr..ut. rrarlilv inc. tl rnitr ILr• mrlliyl /rrrnrp of 1 „n ~I....,,.n. ,,,i., rh, iu, 11.0 ~ a, r,A 1., rr, .ul"l.on,r•a, nilliu'oicd Ly Ihe I hnrmonal action of indole-3-acetic acid, but f<xmaldehyde aprcars to be a stilt nrrtre elfcctive melhyl rrecursor in plants. The present invesliRation was undertaken to determine: (a) the effect nf ft»maldehyde upon the Rrowth rate nf the oat coleoptile, (b) the rate of formaldehyde incnrfxxa- tiun into cell wall components as well as into other cellular fraclions, and (c) Ihe influence o/ indoleacetate upon such incorporation. Prnr.rfure: Colcoplile seclions were cut below the lip of oat seedlinp grown for 96 hours in vermiculile, previously soaked in distilled water, and were floaled nn unbuffered aqueous solution of formaldehyde-C". A series of duplicated experiments were conducted itx incubalicxr Txriods ranging up to 240 mimltes, each representing a different day and a fresh batch of seedlinRs. Radioactivity was determined. F'indinR.: formaldehyde was incorf+orated most rapidly inlo substances soluble in Rl)~o ethanol. Snfntantial activity also appears in the cell wall fraction. It is of interest that formaldehyde incorporation into pectin in- creascs with time. Indnk-3-acelic acid promotes the incorpnration of the lahekd compound into pectin and, at a la6 of one hrwr, into residual Peclin, and also depresses the mctxjstxation of formaWehyde-C" into nitrogenous comPt>.mds. • "INSFCf 1Ctn1? RI:SIhEIES ON TOR/1(-'CO." fly T. (:. [Tnwery, W. R. E;vans, 1'. T:. (iuthrie and R. L. RabEr, Departments of ('hemistry anti f:ntnmulnRy, North Carolina State ColkRe, Raleigh. ARrictrlruraf and Fnnd Chrrniirry, Vol. 7, pa6es 693-702, (klober 1959. (T'.I.R.C. 6rantce: Rnwery ) F`urpoae of .tudyt Information has been lacking on the magnitude and fate of insecticide residues on tohacco, although a few partial sludics have been reported since the advent nf organic insecticitks in tobacco culture. The major pesticides used trn fhre-cured tobacco are Tf)E: and endrin, which are usually applied more frequently and claser in time to harvesting than other pesticides, therefore constituting a greater potcnlial ha?ard. rroc.dur..: Fifty or mnre leaves of green and /lue-cured tohacco, S0- leaf sarnplcs'nf fluc-cured tobacco from commercial auction markets, and frve-pack s:utlples of commercial cigarettes were taken fnr anatyrinR. Total nrFanic chhuine content as well as Il)Ei and cndrin contents were measured by sensilive lafx+ratory methods. Fin<finRr: Ralhcr high kvels of ThE and endrin residues may tKctlr on green tuf.accn a1 prnninR. There is approximately a 40% hrss of these resi<lucs during fluc-curing, hut the residues tend to go slirhlly suhcurface and little <rr nn arlJilinnal loss occtus during commcrcial Lr(Kessinr I)ilu- tiom of Ihe pc.ticirle rcaidues hy blending widr nthcr 1<rhacctn and nddilivcs dnrinF cnnuoerciat ciR:vcttc rnnnufacture rrducca thc Icvcl of tlrcae incecli- ci4lca in cil-.:ucltca A/q+reciahlc tlia.ipatnm trct•urs during smuking• but small nnd dclcct:rldc nrrnrunls of 'IY)li Mre still frnmd in the n.aimlrcam smoke rrf coaunrrcim cil-arctlcs. Sludit•( tin Ihe fate <rt endrin rc%itluea in cir:uelte amntc luut <ut Ihc .ile, Ievel nnd fate of the inaccticiJc dcriv<•d inh.llali<rn plrfrtucts in mannu:tlk tire in rr<rFress. ~/'j-~rh.. Sr~ulhcrn /(eftinnal Resear<h Pmjccl S 22 anrt Shell ('hemical ('urp<nilion. 47 1 r.

I p~ "STt/nIF.S nF llfE Ill(Xif:N/?SIS nr 'r11F. RING sYS-rrMS OF NICOTINfi." fly 'lhnmat Coriflilh, Kenneth P. Ilc•Ilman and Richard L. nyertum, Ked»e (ltentical I.ahtxak+ty, MichiFan State (Inivcrcity, 1'ad l.ansinr. Jmrrnaf of RinhrRir'aI (Yrrnnttry, Vol. 215, pages R(N/ R04, March 1960. ( r.1.R C. grantee: Ilyerrum ) rnr/rn.r n/ ./er.fy: Other reaarchers have shown that the pyridine ring of nicotinic ncid is utilitIccf to form the pyridine ring of nicr+linc in sterilc cultures nf tobacco rrwtl, hul data are inadeqnare r+n t+lher possif+le inter- mediales in Ihe hit+synthetis of the ring syslemt of nicn/ine. 'rhercfore an investiRalion wns made of the incorfxwatinn of several C" lahclcd ct+nt- r-unds, which miRht he intcrcrxwerlihle with acctale in mctalKdiam, into nicrNine in intact tobacco plants. rrorerfurr: Tobacco pIanls were grown for Iwo'to three months in a Rrcenlmute, anJ n/ler removal n( the rtwNs were placed in an inorganic nutrient s<dulinn to allow new rncHs to develop. Radimmctive nicotine was synthcaiycd from plants fcd hydroponically with iatKlcd acclales, Prnpirm- atcs and Rlycertd, and was degraded to obtain carbon 2 t+f the I+yrndidine ring at harium carM+natc. When prnf+itmalc-2-('" wat fcA, carbon 2 of lite pvrrnlidinc ring contained 12 ' uf lite labeled carlMln and 42% wns aso- cralcd with carfw+nt 3. 4 nnd S Whcn Rlyccrol-1.1 ('r4 wat aJminialercd, 6% of the Cr' wat ssociatcd vtah cancon 2 and 27% with catlwms 3. 4 and 5. FlndlnR.: If the nstumption is made that a symmelrical inlermediate is fnrnrcd durinR the incnrf.oratinn t+f the lal.cicd precurt<+rt into the pyr- rnlidine rinR, an ryurl yuantity rd Cr' wnuld be asanciilctl with carfw+ns 2 and S, and Ihit I+ittern wt+uld he ct+nsi.lent with the f+oslulatc that fxrlh prnhianate and Rlycerrd cntcrcd Ihc tricarhr+>cvlic acid cycle and were cnn- vctted to Flulamatc durinR the synthesis td the pyrrtdiJine ring of nictdine. llre pyridine ring of nicrHine from the rorr>(.iunate-fed planls cr+nlained 39% of the C' and S7^'r of the IahclcJ carhr,n when Rlycertil was the prccurtnr. If all the glycerol was metah+liycd Io,ncclate durinR its incorp- oration intn nicntine, only 40% nf the original ('" wt+uhl be exl.cclcJ In reside in Ihe f+yridine ring. Therefnre. glycerol mutt have Lecn utilired for pyridine ring synthetis by a metabolic pathway that eRcludes acetate. "Mt:TAfIOI.ISM 017 NICOTINF IN TIIE l1(1MAN ANI) FA('RIiTION OF PYRII)INF (•OMPOUNI)S IlY SMOKf:RS." fly lidwanl R. Ilr,wtnan, I.ennnr 11. Turnhull, end IIcrlKrt McKennis, Jr., I)eparlmcnt t+f I'harma- cr+loFy, MeJical (a+IleRe r+f VirFinia, Richmnnd Jmrrnal rn/ I'hnrnrnrnf.rgv and F.tprrimrntaf Thrrnprtrrir.t, Vol 127, paRes 92-95, (ktt+hcr 1959 ( I'.I.R C. Rrantee: 1)r. P. S. l.arsnn) rrrrpn.e n/ .fudyr II hat heen r+lnerved frcqtrcnlly that nnly a small fraclinn td Ihe nict+line nhaahal in the tmt+kinP uf tr+hacct+ is excrrtetl hy Ihe Inrmin, an l animal c+tf+crirncnlatit+n tht+wt Ihis Its he• Ihr Ivr+hahle resull of clive mrtatw4ism anti not storage t+r elimirtalitro by nthcr p>tth- ways. Ihia wt+rk was untlcrtakcn Indc.crihe tlurlirs rm the isrdati,,n nf tt+nre of lite mrlalwdltct r+f nlcntrne (+rflfnt /n the Urlnc rd the hmmnn nt+n •mukcr and of I+yriJinc cninl>,+unJs tnrs.nl in lite urinc of humrn amwkrrt l•rnrr.lrnr.: A ninn+al nJutl niac n.,rt srnr+krr trtrivt•t1 an rnal .'rr.r of 10 n+R t+f I nir"tinr tl:tily fr+r Ihrcc tl.+ys in cr+n.rrutive h++urly tluscs td -1 4R mR. each in Ixlaline ca(+tules, and ntetaM.litcs were exhausiivcly c>alracled and ith•ntifictl by standard pmcedures. llrine of snu+kert ((+11 I. I was nb- laincd fn+m lalw+ralr+ry wrxkers and extracled by the same mcthtuts. F'inrlin~.: IAving the 3-day rerintl 1he non-snu.kcr eatrctcd ahnul 10% rd the ntlminittcred nicotine in rhe form of cutinine. Since the smokcri urine was crdlcclcd nnly during rhe daylime and wilht+ul dala tin respcclive trnt+king habi/s, the f+rrccnt:rRe of rnetahM+lism cuuld not he calculatcd. ('hrr+maa+pral+hic evitlcncc pt+inled In lite Rrescnce nf cr.linine, dt•smcthyl- crNininc am1 hydm>tycrNinine in all Ihe samplcs uamined It is inferred, at indicalcd in th+R sludics, that lite pathwny uf nicotine nrctalKAism in lite huncut may t+c niculinc -• cntininc • hydrt+xycotinine rlus dcancthly- ctrtit{ine. ( rrr Rrnn/nra: (1.S. Public f feallh Service and The American 'robaccn ompany. "/)f:MI:111Y1.AT1()N OF C()TININf; IN VIV()." fly Ilerherl McKennit, 1r., I t•nm+R 11 'I nrnhull, Fdward R. Itnwrnan, and liinusuke Watta l.nrnrrrf (o/ tlrr Arrrrrirrrn (7rrnurul.C.airry, Vt+l. 81. I+ages )t)t1-1954, AuRusl 5, 1459. "Tllli ISOl.AllON ANf)S'rRU(T(IR1:OF A Klif(1nM11)1? 1(yRMI'1) IN llll: MWrAllOt.ISM UF NI('O1'IN1:." fly Ilethcr/ McKennis, Jr., lidward R. IA+wman, and LcnnrrR (1. Turnbull Jr+urnrd .+J lhr Arnniran (Yrrnriral .C.v irfv, Vol. R2, raRes .1974-.1976. Anl:usl 15, 1960. ( 1'.1 R('. grantee: f)r f'. S. l.arson ) I'nr/ro.r.rf anr/ir.: 1hc mctalw)lism of (-)-nict+tine in mamrnalt Icadc h+ lite e>ct'relinn of (-)-cotininc and a variety nf cornl+nncnlt not frnmd in thc cnntmlc I hcse Rarcrs represcnl furlhcr rctcarch intt+ Ihc idcnlily and mctalxdic rolcs of thcsc suhstant•es. rrnr.drrr..: In Ihe earlier study, attention was G+cusctl solely on the isnl:diun r+f chtuttdtxm-a+luhlc mcl:rfaditet rd nictdinc and ct+linine in dufs. In Ihe .ccr.nd slndy, scparnlit+n in crystalline form td a chh+nd+.rrn wlubte anmphotcric mclahulile was undcrlakcn. Finrlinga: I lie isnlatinn of (-)-cksmcthylcolininc nnd hyclrt+xycolinine at a result nf lite rnclaM+lism nf aHininc in thc first thrdy allirrncd the inm- Iwulancc r+f the role nltrihuled In cutinine ns an inlcrmctlialc in nicr+line mel:rhrdicrn. II was :dsn af+parenl that manr new rnelalwdic- ralhways ft+r lite deRrad:rlir+n nf culinine musl be cansiJctc•d. At n result td Ihis nnJ I+rcvitnn aluJict by thcse null.nas, .even melahr+lie curnln+nt'nls have been cl+araltvl which rcptesenl ntwrul 1(N% of Ihe tnl:d mclat,tdilcs r+f nicr+linc. Ilcncc. Ihc mcl:d-t,lism uf niirNine in humans and I:dw+r.rNnv animals l+tc- •cnls :t tlivcrtity and t•r+ml.letity (ar in etcess t+f r+rigin:r) ratim:rles. In lite sccr+ntl tlutly Ilrt• ia+latitm t+f ramma-/ 3 I+vriJyt l-Irla ttS t+ N- mtlhylhutyrvniJc ac a rc.ull yd admini.lralirm td 1.) cr+tininc Ir+ Jur.t further enl:ui•rtt Ihc knt+wn rnle t+f cr+linine ar an intcrmt•tli:+lc itn nitnline mcl: lism. ~I rr. R.nnm..: f I S Pathlic IIc:dlh Scrvi(e nnrl '1 hc Amrrican 'fr+hacco •r,n,hany. "tllli OXI/),111ON O1 N1(YITINIi I KINI•.il('S OI Illli 11(JtI1/) 1'IIASIi I(I A('I ION NliAR RO(/M 1U.Mf I t(i.lltl(1: " Ity. Rt+hrrt 11. t 49

Linncll• fkrartmcnt of Chemialry. University nf Vermnnl, fturlington. 7nFnrrrr •C,rrnrr, Vtd. 4, raFcs R')-VI. April 2')• 1960. 1'rrrp...r n/ atrrdy: Atlht,ugh Ihe chcmical tkgrndalinn ant/ nxid:Hinn of nicotine have been inveatigatted er<tensively, the kinetics nf the reatlit,n nf oxygen with nicnline has not previuusly been reported. Prnr..hrrr: Nicotine was vacuum didillcd, and redcd fresh nr afler stnrage for varinus f,erinds under N,. Tn obtain kinetic data an apl,atalus was con- slroclcd with a reac/iun flask mounted on a ah:tkcr which had variable amplitude and spccd. Rates of O, uptake are strtmgly decreased on ex- posure of Ihe nicntine to ait or o>tygen. Findir.R.: The kinetic data from 15°-40° C. gave an over-all activation energy nf (r.R kcal An increasing infrared hand at 5.9 microns indicates colinine is one or file prcxlucts. Tlxse e rrerimenls provided strnng evidence of file free-ratlical nature of the o:tidatitm of nicntine, which fnllows the general rnechanism nf nlefin nxidatitm, and a nicnline hydroperniide may hc exf+ccrcd as an inlermctliate. Further work is undcr way to isnlale the prnf,t,sed hydrnf,rrnxide and to provide mnre dctails nn the mechanisnl of file reactinn "ARSIiNI(' ('ONIt: .Nf 01' ("OMMIiR('IA1. 'f"(111A('("O, 1917-195R." fly F. li (iullvic. ('. R. Mc('rtnls and 11 (I. Small )r., l)cpartmenls of VntnmrtanRy and Sr,ils• North (':f4nlina State ('nllcge• Raleigh. 7r,h.,rrn Stirntr, Vt,l 1, p.lpcs 20 22, May R, 1959. (-1 I R('. Rrantee: Mc('anls) Purpnrr of .nrrly: Scattcred aml crnrflictinR data on the ar-4cnic content of I4,hiccn hivc al,l•cartd frnrn rnne 1„ fimc aincc it was first rrrttttrJ in 1927. Since ('!S2 arecnic cnntfw,nn,ls have been rcmoved frnm tl'c list nf rccnrnmcndrd intectititles, and slrcnunns t•11„rls h:,vc hcen madc tn rcduce the use td these ns,tcriak nn b,haccn In view of the interesl in this suhject, ciRarelles antl 1„hac-, sirnrlts lu,alncetl thtrinR Ihc rcri„tl 1V17-I')SR were oMained fnr analysic• In Jeterminc their arsenic cnnlentl rrocedrner: Inhacct, samplcs wcrc nhtaincd from file fnllnwing srn,rces: 1917, 1911, 1915, 1`)51 - cnmmt•rciil hran,ls nf•cignrcltcs; I'151 through 1V57-etrmrt,sile samplcs of Inhacco fn,nl variuus U.S. areis; 1957-- Ihree popular brinds (+urchased in February; 195R -- sia rt,pul:+r brands purchased in April antl an addilinnal eleven purchased in Ikcernher, inclad- ing regular, King sire, filler, and menlhnl cigarNles. lhe As/O1 content of the tobacco was determined by standard procedures. FfnrllnR.r lhe dali shnw an incrcisc in arscnic in cigarctlcs fr„m 1917 (I2.R to 17.5 p~m) to 1951 (51 (/ tn 56.5 R~nt). wilh a sharp decrease thereafter: (R .S 1o 12.3 ppm in 1457, 5.1 h/ 14 4 in April 1959. antl 2.7 tu 6 5 in l)eceml,er 1 V5R ). '1 he cip:rrette tl:tla ct,rrrtfx,nd closely to arsenic values found in unmanufaclurcd fluc curcd tnhaccus (nr 1951 17. 1 hc evi- dcnce here is Ihat the nrsenic eonlcnt nf present-day American ciR,rencs is within the range of 1 tn 12 ppm• with an averngt of ahtrul 6 rpm. "IIIE RAC"11iR1Al- OXll)ATION UI: Nf(Y)l INIi. II1. '1111: IS(11.A- "Ill)N ANI) 1f)FNiII:ICA"11ON OF t5IIY1)ROXYI'S1:111K/1)XYN1('O- 'I INIi." fly I awrencc I llnch%tein and Sydney (• RittcnherA• 1)el,.Irtmcnt td Ilacleriningy. Ilniversity td St,utFhcrn (•nlifrnnia, I r,s Anfclrs. /,nnnrtl r'f fh,ih,irir rd / v,..ni,n r. Vt,l 211. t,agrs 741-7V9. Mnrt h I Vat/ ( 1 1 R c Pr antcc It illcnl,rr f) 50 rurpnf• n/ .trufy: Previous studies by Ille authors have eslahli.hed that an en?ynre fractitrn obtained from a nit'otine-nxitlising h:tclcritnn calaly?cs file o.idatit,n of nicoline ahd 6-hydroxyniculinc. "I his work was undertaken In identify the product of such o><id;Hiun. Prnr.dr.r.: ('ell-free e.lracts were prepared of a giam-negative bacterium isnlaled frt,nl soil and grown in a medium containing nicotine and other ctmrpuuntls. ItllravinlN spectn>rhott>.nelry, paper chrunratugraphy, oplical rtNalinn and nther dctermin:dions were performed as dcscrihed in prcvinus palx•rs" (i-IlydrorrynicMine (6-OIIN) was isolated from growth 'rnedium, and that Ix,rlinn of the crude bacterial er<(ract which precipitaled at 41) to M1% saturatir+n wilh respect to ammonium sulfate (Ihc 40-60 fractitxl) was shown tn oxidire 6-O11N In the absence of inethylene blue, althouFh sut•h extract will cala(yse Ihe aerobic osidatHrn of nicnline only in the presence nf file dyc. Other tesls indicated that the cnrnlx.unds furnled by file crude exuact, at the eapense uf nicoline, and by the 40-60 fraction• at the expense nf 6-OIIN, were identical. Idenlificaliorl of the oxidation rnwluct was underlaken. FlndinRr: I lie prtttluct isolated Iras Irccn Identified as 6-hydroeyp.cudtw,r<y• nicotine nn Ihe basis t,f etemenlal analrsis, (IV ahsnrrlit,n spcclra, and similarily Ito such :t cunlptrund uhlained by other melhtwls. '1 he comlaamtl has been nhtaint•d frtmt nraidatitxl by reslinR eellc, crude ewtracts, and an amrnnrlinm sulf:tte fraclinnaled extract nf (he nict,tine-ntitli7ing hacteriurn. l he metala+lic evidence shows this cttmpr,und tu he Ihe second nxidalive prtxluct in the bacterial metal.nlian t,/ niculine. •'ll)I:N11I;1('A"fl()N ()F FS(-l)1.f'.TIN IN'1()IlA('('() ANI) IN ('IC'rAR- U:1T1; SMOKE.•• fly 1.. 1. 1)ieternlan, C. 11. Ysmg, Y. NakaFawa, and S. 11. Wentlcr, I)epartment nf (-herniary, (Iniversity nf (lklaht,nta, Nnrman. Lhrnml u/ UrRnnir ('hrrni.ftry, Vtd. 24, rages 1134 -) ( J6, AuguN 1959. "11)ENfIF-ICA'llON OF CAFFI:IC AC'll) IN ('1(iARliIl li SMOKF..•• fly ('hau-Ilwa Yang, Y. Nakagawa, and S. 11. Wcndcr. /.nrrnrd rr/ Org.trrir ('lrrmivrr, Vol. 25, pages 6SR-6/><I. April 1960. 11 .1 R C. Rrantce• Wentler ) Irerp.n.r of .rndi..: In the puriGealion of scrt(+rtlctin rrt,m cie:/rctlc cmnkc antl (rorn varitws It,hacctr e><ttacls, Iwa nt nuuc intcrtering hlue IlunrescinR ctunpulmJs I+c•r.i.letl with Ihe sctqa,lclin Ihruu);h several /,:rl,er chrtnnatn- Fral,hic dcvclt,l,ments. 'f he purpcm of these stutlics wa. ttl iJcntify these inlcrferinR t'nrulnnmds. /'rnrrdnn•.: Itl llte fira audy, «tiwatitm, purificutinn :tnd identifiralinn w:ts t:uricd t,ut in Ic:rvc< aml flowers frt/nl rrccnht,n.c tt,haccn I,lants, in Ic:rvc. frnm tturlcy, f urkish and Iluc-cured It,hatcu• :md in Iltc tn:tinUrc:rnl .n,nkc Irnnr ct/•Itl hr.mtl. r,f t'irart•t,cs. In Ihe .ccnnJ .ludv llte smt,ke fr„m crl:ld hr:tnd< td cip:urltcs aa wcll :n file 1t,haccr, fr,.m 1211 cif:ucltcs of vne hr:tnd werr utilirctl. Fi.ulirtF.: 1:s,ulrlirt ((.•7-tlilty(lrntyc,turnurin) was itlcrttifictt fnr Ihc liro linu• in tl,c lir.t .tody in Illt• 11„wcrr :lntt Icavc% td Ihc 1 rccnln,u.c 14.1111s and in lluc curctl :u0 :,ir curctl t„h:ttcr, lcaf samldt•s (hr nctin.uram atm,kr „f thr t i1•ertnt•. c,n,lainr•d only a tr:tce :mtmunt t,f c.cnh•tin tn Ihr sctund ttutlvo, t.,lli,r nti l wa% itlcntiht•d irl ci):art•ttc %nt„kc fur file lirsl 51

time reported by any invcctlRalnr, ahhnugh previnucly rel+nrted hy others in variouc cnrcd trrhaccoc Fach r+f the cight ciR,rette hrandc tested was (t+u lo cnntain frce calkic acid in thc mninatre:rm snu+ke. .r R.nnrnr. : U.S. Puhlic ! Ieallh Service anJ Atonric f:nerRy r+mmicsicM. V1. l)the'r Strtdir. "FITECTOf' NI(Y)TINF: ANf)TOBACCOON Mt/SCLI? 1=lIN('TION." Ily frnst Ficcher, M.I)., Ilerhert Silvelte, Ph.l)., P. S. I.aram, 1'h I)., and 11. It. IIaaR, M 1), Medical College of Virp,inia, Richmond .fineriron lnrnrml of 1'hyriral Medreine, Vol. 39, paRes 63-77. April 1960. (1'.I.R.C. grantee: llanR) The effect of nicotine and tobacco on skeletal muscle has received far less attention in the literahne than either the practical imrort:rnce of Ihe neuromuccular system or the scientific intercct Ihat nicotine actinn on mucclc Jeservcs. A review of tnc-tervalitms on the suhject shows that the direct effect t+f nicraine on motor functions is due lo its aclir+n nn Ihe ncrvtdrs systcm, ula+n the mux'Ies Ihcroselves, or to simult:mct+uc effect upon both. Subject he:ulings reviewed hNe are nicotine action upon the cerel.rum and the thalamus, nn the spinal enrd, on somatic peripheral nerves and on sensory nerve endinRs, direct action on skeletal muscle, the effect of denerv- atinn on nict+tine'c action on muccle. Ihe exact site of its skeleta) mnccle action, and the irnln+rtcmce nf thc p:tralytic phacc of rmncnl:v actit+n in acute nicotine (+tua,ninR, all of whicfr relate to animal exrerimentalit+n; in the realm of hum:rn studies. the review Jiscnsses the effccl of emokinr on hurnan muscular efficiency and clinical cr+ndiln+ns affecting rnusele funclion. InvestiRatinn has shown that human muscular efficiency is very much mrne influenced by psychntaRicrl than by Phycitrh+Ficat factrrrs The once widely l+cld belief that inlermittent claudication c-in t+e directly caused by the micuee t+f tobacco is now declininR, anJ it ic bet'<+minR increasingly recngni?cJ that Ihis condition is hut a symPlt+m trf chronic cuclusive arterial diceasc, althnuph there is strnnF clinical eq+initm that tohacct+, in certain instances, may influence the nalura) crnnse of peripheral arterial disease. Ilt+wever, the acute vaa+constrictr+r effect of smnkinR is mainly evident in the ckin circul.Uit+n, anJ any nicr+line effect from snurking nPon the muecular circulatiun muel Le rerarJeJ as Jr+ut.lful Muscle cranrln are a syrnl+lnm of ninny dilfercnt Palh.doqgical ctmdiliinrs, hut vaccular dicnrdcrs are nu h+nFer reg:vrled as ttf eli+dol-ical imfxatance It has been reported that tremtu ic t+ne of the neurt+muecur:rr dictmh:mcec which may tKcur in chronic tt+haccr+ )+t+istrninR, hut it wtndd alq+c:rr Ih:d, c+r far ac thc rirdinary smoker is ctmt'erncrl. Ihcre is little of nn tmtt+warrl e(lcct irf Il+e hahit nn skeletal muccle (+inctit+n. "MfiASItRUMFN1 OF lY)IlA('('O SMOKIN(7" Ity P S I ar.r+n, 1'Ir 1), 11. Il I l:r:ip, MO , and I) Silvette, 1'h t) , Motic:1l ( ldlct'c of V+rrini:+, Richm+md Mr~br~rl lirnrt, Vt+l RR, l+:rp.cs 417 •1!') Al+ril I'/rdl ( 1 I!( ('. Rr.ntce Ila,rg) A compreJrensive review of medical literature dealinR with the subject shows that, almtnl invariahly, the smoking hahits td patienls in clinical and epidemitrlo6ical studies are (lescrihed in terms of daily consumption of ciparettes or tobacco in other forms. The results hear a very indeterminate nJ perhaps undeterminable relationship to the effective dotaite to which the patient is subjected. If a f+atient is asked how many ci6arettes he smokes daily, his answer - even if he can actually remember - is meanin¢less unless we know Precisely how much of these cigarettes is "burned rnlo the moulh," and then how mitch of that ptxtinn of the smoke is actually depnsiled on sus- .ePtihle lissues and/or absorhed into the blood slream. The manner of smokinR (ft+r e><ample, with or without inhalation), the duration of smokinR, the rate of smokins, the portion of a cigarette consumed, and other variables e>list. In additiom to these nncerlrinties, there are virtually no consistent and comParahle mNholls of ralinf smoking habits in the literature. 17re mean- inR t,f adjeclives such as "light." "mrrkrale;' "heavy" and "escessive° vnries ct+nciderahly with each wriler; many studies convert pipe smoking and cigar usaRe into cigarette "equivalenls, and even the criteria of "non- smokinR" vary frnm author to aulhtx. All of the factors entering into "effective drKaRe" can he reasonahly well eslimated, given the time and ttoubk, bu1 there is another factor of f+erhaps even greater inr(+txlance: the patient's conslilulit+nal or Renctic make-up, which is so far largely undeterminable exccrt hy its ullimale influence or effect. Morenver, a mullitrkk of writers over very many years have insisted upon recognition of the fact that men vary in their sensitivity or susceplihilily to tobacco. A yaantitative yardstick applied tn trne smoker is not necessarily valid for another. "T<71IAC('O AND RrNAI. FUNCTION AND DISrASFS 01: lllfi URINARY lRA('T. A REVIEW OF TTIF's EFFli('IS OF SMOKIN(i ANI) N1('(YIINFi AI)MINISIRATION IN MAN AND ANIMAI.S" Ily P. S. Larst+n, Ph.l)., 11. B. IIaaR, M.D., and 11. Silverle, Plr 1) , Medical College of VirRinia. Richmond. 1'irRinin Mrrfirol MnnrAfy, Vtd. 97. pages 332-341, June 1960. (T.I.R.C. grantee: Ifaaa) A survey of the world literature on tobacco has failed to discover any previous cnnrprchcnsive review of the effects of smokinR on renal function or the refationchip t+f tobacco to diseases of the urinary tract. It has pointed np alco the rel,live p:,ucily of observations uf the efleets of nicntine tin tenal nnd urinnry-tracl functirm in expcrimental animals. Ihis review may serve the double PurM+ce of indicating what is known, and what it wt+u1J he dc.irahle to kru+w 11 comprises the followin6 eleven suhjcct headinRt: t:rtect or h+hacco on tlre mcchanisms of renal secretit.n in animals; effect of nicoline tnr Ihc et+rnlwnitiun of urine; hiat•pathtduRy nf the kidney in at:ule and (hrunic Ptristming; eflecl uf luhacctr (in water hal:+nce; ellecl af nicotine nn the ureter and urinary bladtkr; eRecls t+f ant+kinR and nicotine nn ren.il function in man; eflecl of smnkinR and nit.+line t+n the er+m)a+silir+n n4 hmnan urint: nict+line tests for neuru hyl+t,l.hyceal func titm; smokinR mnd diseaces t+f Ihe urinary tracl; Iherapculic nces trf tnhact'n 53

I ('ONSTANT-RATF INP(JSION APFARATI/S" Bt O"rN11N 5 M, KrNNU, Fow..e /~ BuwM.N, •nJ 11I..t\/ M.KeNNrs, 1. 7,•ut..lnrr e•'J AP!•h.J I'ho.n•uuf.•er, Vul 1, ratc 61 64. ).nu..y 1959. 1 T I R C Ar.nlet-: 1)c. P. S 1..xrn) 111E BAIIFKIAI.OX11)A1fpN OF Nt(YIItNE. I NItY)1tNP OXIIIATIIIN NY ('111; 1 RFP PRI'PARAII(1NS. 11. TIIN ISOLAIIUN OF lI1F FIN`oT I1X11)A11V1' YH(/1)U(' f ANII IIS I IH NII11( AIIUN AS (1) 611YI)RI/XYN1( (/IINF'• t.) I I Ib.u.celN .nd SeuNr• C RrtrrN.r.o, Depatlmcm o/ NaUC.inluWy, ttn/-cruly ..f S..ulhrrn ('.10ofnla, lo. An`rlce loornoI ol pL'lor/rvf Vo1 214. pascr 11111) .nd 156 Il, J.nuary 1959 1 t 1 R('. tr.nlre: Rnlenfry) "1111 1)AHK I IXA I I(IN (11 (Y). BY SIICC'lll FNT I FAVI S. K11 I All,ll lf ( IIAN(:/A SIlRS1.QttPNT T(> INITIAI. FIXATION ` Br P.u( Sal tM.N, VMl.N1. 11 I rNr u, Gru..:r M KvNrt.cr, ('1 rot Snt7 end Ilra.ra Stor en., Tkpulnmrnl n( HNr chtmi.rry anJ N.nti- liun, Sthtw.l of MedNine. Uni.errwy d Sow/.crn C.h(ntnia, 1 m Anaelet flanr PArtL•l..fr. V.d 72• No 1, p. r. 1972ftt1, Mq 19/7 "hARK FIXATI(SN OF CO, BY S(NY'TtIeNT IFAVFS: C'ONSERVATION OF TIIF I)ARK /-IXF.D ('O, I/NI)FR DIIIRNAI. ( ONDITIONS" B) Gr,+ar KuN,rar .nJ P.ul Sa, rY.N Il.n. 16ru.durr. Vol )), pyer 401) 40). No.embrr 19111 "(/ARK FIXA710N UF CO, BY TUBA(-('O I PAVFS" by (:r..wr KuN/u.e• llroe Snlt, and P.ul 5u twaN. P/ewr Phrrbb.rr, Vol )4, p.srs 121 127. M.rch t919. IT.1 R CC sr.nlee Ssllrn.n) "II>FNIIFICAiION OP SCOPOLETIN tN CIOARPTTF. 1OBACCO AND SMOKP..` HI (11•'• Ilw. Yawq Yal,sNl 11 WrN,r., Ikr•.u.mrnl uf ( berniJry, Ilni.crsrty o/ hllrhrwn.. Notm.n lorrn.l o/ Urrewlt ( Ar,nhrrr, Vol 2/, No 2, paJen 204 201. 1-rbtuary 1918 "/(IRMATI(IN (1P SCOPOI.PTtN FR(1M PSCl1/IN ANU PS('1rt F11N IN I/IP. RAT•" Br ( N...11w. Y.N(., 11 1) Rsa.urr, P I Prr..ar1, M Ran•) S 11 Wrrwe.. ArtA,rrr n/ P/utArw.Mrr.wJ BbpArr4., Vul 71, No 2. p.p. 111 )19, lunc 191/ "S((/POIITIN IN ('(1MMERl'IAI. 1(1BA(-CO PRO1)11('IS" R) (n.nllwa Y.NO, Y.+ouu Naau.w.. and A.rnN 11 WrNnr• TvA.cte Sc4wte, Vol 2, p.ee. 111 114 Augusl 29, 191/ "ql/ANTITATIVP STIIDIPS OF SC(1PO1 FTIN IN ('1(7ARFTTP SMnKP ANI) TOBA('(O" Ht ( N.r.11wa Y.NO. Ya+uvu Na.ccwa, nd SL.uN W.NUrs. Anelrucd ( Ae•n/u.r, Vol )I, pqtr 2041 7044. tkecmher 1911 (T I R('. @nnlee Wtndr.) V11. (lth.r .4jfudi,os "IMM11N(11 (X71("Al. AtPP/'TS (1P 1r/RA( ( n ANL) %MtIKIN(: " Br 11 Sn.rr lr, l'N 1), P. S 1Pul), and (1 B Il..n, h111 t4r'n,mn•. ••f 1'humu.d,q), MrJr.l ('.•Ilqr of Vireim., RNhn,nnd A+.r.uaw /1(rJ.•of V,•1 71e. Nu t, p.1n 161 119, Nuamhcr 1917 "MPhI(-AI IJSPS OF TOBA(Y O PMI ANU PMI `ot NI " R. It Cu.e.rr Pn h. P S 1..v.N, Pu 1), .n.f 11 B/l..u. K1/1 1,,,,,,,. al.J•.••I V.•1 V p.•~rs ~1! alle• Scp/cmhcr 191s / T I R C s,.nuc Ila.r l ^(AN( FR /1F 1111' I l1N(7 - TIIP SIX RA11f1 A III VII W(/1- 11/1' YNt)R1 FM" Ry IL.rN .nJ K It IhPuvnrm ul Yuh.A„Itr. Ih.nrr.,rr •,I Irea. MrJi.al Br.n,h, Gsl.ruon Tr..t Rrpn.h on D,.•L,rr •n/ A(rJ.n••r V.4 11, p.sr. !9 48. Sp..ns 1919 IT I R ( r..nlrc RrsJun) c Rcci picll ts of C71 a r1 ls Follnwing is a list of all recipienls of grants approvcJ by the Scienlific Advisory BuarJ since inilial grants werc made in lalc 1954. It should he nuteJ that sulnc uf the pruryxls have hccn complclcJ. CItANTEF. ANII INSTITUTION CI ARI N( 1: M A(iR1iSS, M 1)., ('Aie/, ('arJr,rr,w fdur I uA.wurury, Velerans AJ.nmi.uanrn ('enter, 1 os Angeks 23, ('rldurrni. T) MURRAY AN/i1 VINIl, M h., Pro- /ru.rr nJ 1'otAul,.Ry, l)ni.ersily of Wie• eumm MeJ.ul SahINA, MrJison, Wis- tumin 1'HI/Jt•:(T TIT1.E r'(- w4.Irs r,q.ee "r' 4lltr.r e e.P.+. rw .w. 6.r .rrw Pral,6.ol) 1 hc Mtasuremenl of the Funclitwul Stu• Itw of the lluman Ilearl by hretlucncy Irum Anulysis of ils Vibnbon.l I Msy P.(hrdogic- Analnmk SIuJy of ('ellular l hange. In Iluman Hrunchi I(') I RI 1)I RI( 'K W. RARNFS, 111, M 1), I'n 1). AnrN rulr PtuJna,w n/ AIrJt. ine unJ PAyu.Jnti.ul ('Armis(ry, luhns Ilrplins Universily School of McJ.- cine, Nsl(Imore S, MarylanJ RAt P11 S. II1:('KhR, Pn 1)., Alrntiarr I'.u/rrru. n/ ('htmn(ry, l/niverfily of ILNnlon, Iluuilvn, Teus SAMIJI l R111 I!i, M.1), hbecro., DI. vrv..n of (LtJiuhrRy, Philadelphia (:cn- tral Ilu.pil.l, Phda.klph/., Pennsyl- Y;1ni. RI( IIARII I HING, M f)., Pru/rter.r of Alr•A,urt •uraI "Aulrtnun, 1)e/~utrrnrnr u/ Afr,h. ulr, Wayne Slale Ilni.ersily ( r,11cKC of MeJiarne. I)elroil 7, Mich• ig:m (fwmcrly Prufessw of Medi.ine. Wi\hlngl.n l/niveraly School of MeJi• cine, St I nuis, Mitvwri, .nJ Profts+ot r.( I aperitnen).1 MeJicine nJ (linical PhyauloRy. Ihe MeJical ('olkge of Al..hurv... Rirmin/ham) I Rl t) (: 11f K'K, M S, Pn 1) , Jen)nr f'.r.nrr Rrv•r..h 1,rrntla, Iteahh Re .cauh tnc . R.nrwrll Pa.1 1)n•i.run, Huflrlu, Nrw Yorl (sce Moore) IAMIS 1: H(/NN1 R, Pn 1). Prn/rrtur n/ (.I,hum. Imlilulc of Ic.h. nnluey. ( .hturnu The Rote of lly(arpl.aa in Titule Respunx to (-luumt O.nnage ((' P) An (nvesliRaliun of Ihe Speclr.l and ( hrtwn:,lngr4phie ('haraclerillia of Artwnaic IlyJru.arbun) lhe I flecl of Niadine on ('.rJirc Irlita. hilily in Ihc 1're.cnce uf Rt•selpine, and Iht Uflct'1 of Nicvbne on (.qon.ty 111uuJ 1-1ow of 1)ugs wilh ('uronary In.ufficicrky ((' PI lhe Ii0tc1 of Smo\ing on Ihe ('oron.ry Ntww) hlow anJ l'erl.m Phu.c. of MyoncuJ/ul MelaFNdi.m in I'nlienls wnh Ar(trin.clerolic tw Flypetlen.i.e C.rJiovra.dar 1)iseast (1•/ SlttJles in (ellul:.r Physiology of I/e.rl Mu.ile (P) Mcawtemcnl of ('uconary BhroJ Flow by Me.n, v( R•rdi.mclivaleJ Albumm Tht L•flccl of Smnling on (-or.Nlay RI(wJ Flow in 1':.henls wilh Arleri o1cltrolic Ilearl 1)iseace anJ Ihe Hf fecl of Nitn(rne t,n Slurage of Aminer in Ilea.l Mu+cle Inve./igaiun o/ (he Niologicrl FRccle of ( Itt.rclle Smuie /(' P) I~vym.lic ShrJy v/ Po/clhyl•d/on Re.c Irun" in t'In,f I L.ue I l 11) 61

(.It (Nl ) F: ANtI IN.\'1 IT1tT1(IN IUM U IltlWl-kY,Pll l),PrslniJr Rrr rdur I uh,rrulut., ('hrnrirny Ilrpurrrnrnr. North ('urolina State (-ulltffe, R3Icfith, Nmlh ( rolina 1tKl 1 RkO7FK, Prt t) , r.o/rrr.w wJ ('hwr.uun, llrr.uhnrnr r/ PsYrhnlnRl. I chrgh tlnivr'rsity, Hethtehem, Pennsyl- v3nra ((armerly Protessoe, I.aboralory of Phy,iotn{ical I Iyffiene, Ilniversily uf Minnetora School of Public lleallh, Mtnneap.dis) 1 M H V IT. M 1) . Prulrrror o/ Pa/AnP 'Ty. Univrrsily of S.nrlhern Cahfnrni School of Medicine. (hir/ Pmholr.RN. I os Angelcs County Rlospitat, I ot Angrlcs 11, ('alifnrnia RI( llnkl) 11 RYI'RRItM, Prlt), P- Inn.r n/ 1Arrnirrry, Michigan State Ilniaraly, 1..1 I anvng, Michigan 51SIFR M !'MtIY CAIIItI, 1!nO, ('lrnirnrnn, ('hrm(rlry l)rpartnvnl, Regis (-olltge, Wetlnn, MasNathrnclts WIl I InM 11 ('AKNI S, M 1) , P.ufr+'^' of /'urhnlnpy, tlniversny of U/.h ( nlIcge of Meditinr. Sall 1 a1e C'ily, I)Lrh I I()PUI 1) ( FRr('I IX), Ptt 1)., Ptu/rt lar nf Rrra hrrnirl+y nn,f Nurnn.~n, Uni.er%ily of Pucrlo Rico, Sthn.d of McJrcine, San Iuan, Puerto Rko, (ft-- merly Prolestur of Rinchemiaty, FurJham (/niversily, New York, N. Y/ lIANS l('1 ARKI', 1)St , PrnJrrun nl Hrnr hrmirrry, ('olunrhia lln..crvly ('ullrlr of 1'hyricians nJ SmRenn., New Yor1, N. V (+ee (intr.c/ulll lltl IIIS II ((tMRnh. la, M1), /h.,r rnr. L.n..rrr rJrr. Rnra.. h Lnrrnrr,, Uni.rr.uy ur (alrfnrni Me.hi.l ('rnlrr. S,n l~runcisco, ('lihnnia 1)1 AN M t rlNr~tIRS, M 1), Anorrurr Iuh,•.,rr..r. R/.,rY'. Pyt(Y)F('r 't / rt F: I1)1: •n.l I-n,lrin Re.iJuts in ('I9arclle Smu\e ((' 1') IhnhrKi..r1 ( haractcrnlics of Men nJ lhen Gnuling Ilnbrls I( P) Paholugic Anatrnnic Study of ('ellular ( h:rnget in Ilumin Bronchi ((') runr Pnr/rs un of MeJw al Anrherrp.d- nry,')rporr.nrnr of In.lustrial Nyeirnr, . , t tursumption Among Italian American Men St•nly of Ir:,te Metal Slor,rge of Pulmtm• ary nJ livcr lis.ue by Speclographic lh Js ((-) l M J ( h IlarvarJ School of Public 1lealth, Bomlon, Masvchuseus n tmrtr an e R. F. 1)AWSON, P/t l) , lro(rnor of ' An Investigation uf the Metalarh.m of Hiosynlhrsis nf Ihe Pyri,hne King of Nic. RuranY, ( olumhu IlniversUy, New Yw1, N Y. PyriJinc ('ompuunJs in the Tohacco Planl ( P ) (-lrnc 11') I ANI)RIiW S. t)IBNhR, Pw D, EeKY• Psychologkal anJ Hehavio.al ( haracter. ('rwnpuiarxr of Analytical MclhtxA by rr.r, Prtrhn R.varrh, lhe Age ('enler of New IinfillanJ, Inc, Btnlon, Massa- chusells (see Whislin) nlics of Inhslers An.nng Smnlers Ih-ttrrninmg the Percent Rrcnrery of nrsenic AdJeJ at Knnwn t evcts to 1 1)WARI) F. tN)MINO, MI). Asi6tanl 1?Rects of Iobacco Smute anJ Ni ti Irrh.rtcn S-unplc- and .r Hr,raJ Survey of Ihe rlnwunl nf Ar%enic 1're.enl in luh:rcto Sarnple. Irum a WiJc Varic/y ot Sr,urtcs , Pr.rfrirru u/ Phurmucnfoly. University of Michigan, Ann Arboc, Michigan IO11N W. F( KSTFIN, M[), AasLranr co ne rm the ('en/ral Nervous Syslem Rcspnn.es of the Peripher.rl Veins in Man Prulrr..rr o/ Inlr.nul McJir inr, ('ollette to /he In/ravenous AJmini.uatiun of of MeJicine. Stale University of lowa, I'.dhrdoKVt nn.dnnric SIUJY nf Cellul:n Iowa ('ily Iowa Nrcoline /1' 1 ( hanKc% in Iluman Ihnntlu (() , Fuul BIouJ F1nw Responses In Smoking in the Presence of Ilypalipemia and A SIuJy 'uf I arly ( ht+rui.rl ( h:rnRts in ItANS 1. /-AI K, Pu l) , Srnior RrsrurrlY I (ypeltension Eaarninalicsn of ('iRaretle P.ptr anJ ('if Ilrc 1 unK. u/ Iwurn 1lrnurK Keh :rnJ Mrcc 1( 1'/ Auu.ruV. l'r(runnrnr u/ PurA.rl.rl(Y. 1lnivcrsilr of Suulhcrn ('alilornia arellc Sm..1e ('onJensales f.u Arumauc 1'trlycytlK Ilydn.carhons (('1 Sthrnrl of McJnine, t t» Angeles, ( .lifnrni A('nmpilalitro of Ihrurrsttnce Spectra ut 1'rrdcul)tir AtUrrlrt, of Ihc Whilc Ilhrw) (ell% of Mcn :rnd the I Ilert rm White 11h.w1 ( tll Atnrilrr• nt t:ntinnRt'm, Nulnhuu .rn~l (IILcr h~nurntr. Il 1 (ha• I Ilcrl n( Gnrrlrna 11(un Airway An.Jy.+, u( t.r.c Ilr.rr,rrr.,.n 1 nrphy.rm.r A tilu.IY rd Ilrt Alltr.runn. rn Ilhe Itum:rn Ih,n , ln,l W.JI //., u r nK .•nlr nt:rnK. r ~~. r. ~,~ rL, Ilr~n,J~,.~l I unrru wc (:HANTF:F. ANI/ INSTITl1T1()N P11111P ('(X)PI R, M 1), ('Air/, Surticaf Srr". r, Vetrrans AJminislralion Ilor pfnal, Hrons, New Yort: Clinrr.l Pro- /rrrr.r of Surgrrl, Albert Einstein Medical ('ollese, Brona (formcrty Pro- fesstrr of ('linical Surgery, Btnton Uni• versily Sthuol uf MeJiune; ( hief, Sur• ifical Scrvite, and /)irector, Suegical Research I ahoralo.y, Vcleran. AJmin- istralion Ilospital, Providence. Rhode Island) At H19RT hAMON, M D, PuD, Anit I1nNA I FAkNSWORT11, M I), llrnry K, tl6rrr P.n/ruor of ll y(rrnr unJ l)r rrrl..r ,./ rrr.rrr ,uY llr,rrnc vrro,urr. 11.r..rJ Ilnrvr~.lly, ( Itl, Maaahusrrtr (rte Ilra/h anJ htr,lr/hur I PH(1)F:(T TITI.F: A SIuJy of Ihe 1'ITects of ('itareUe Smo1- ing on 1 evels of (iaslric Acid. Pepsin and (lropepsin I(' - P/ A Study of Ihe Fliect of Ftracts of To(.acco on ('ullures of 1 umor and Normal ('ells Animal Iransplnts of 7 unsor 1 issuc hom 7 ilsoe ('ultutes buJy Form Smuking and Al uhol ( Polycytlic AunnatK IlyJrtwarltinn and ( lusely RtluleJ ('ompounJs Whnh Are of tnleresl in Ihe Study of Air 1'ollutanls, and ('igartrle Smule in Re lalion In I ung ('anter r•tiulugy /(' P) lhe Hllecls of 7nbaccn Smu1e ('nnrlrrn aate un thr Ue/cnsr Mcthamsms of Ihe krl in I)t1U.r11tY/11M u( Polycyslic Arumatic Ily.lrutarlnrns anJ the ('um. ptli/ive Inhibilion Hclwern Ihe Paly• cytlre /IyduKarMsns in ( onJtnsale wr/b ke{.rd In l art muarnea. t'ersonallty and Smnling in ('olltae (:raJ uales: A/-i/teen Year F.rlhrw up SIUJy (( / 61

I 1:11 ANTEE AN1/ INSTITIrf•I/1N I kANK C. FI.Rli11S(yN, 10, M 1).. ( Anrrrnan. llrporlrnenl v/ Phormur (,l toey, ^Ihany Mrnccal ('ollege, Alh.ny ti, New York 1111SS1.1 1 S 1 1SI1FR. M 1) , Ch/t/ AfrJ i,ul Ermrrrnr•, Slate o( Maryland; Ph.l/rnnr n/ I rcal Afrdnmr, Onivenily of MarylanJ McJrcal Schoul, Hattimore, MarylanJ H 1. I Rl f I)I ANI)I R, M I) , f)irrclor r•f ('un. rr Nr ar.nr /r, Moant /ron I Io.pr la/ and Mraha~l ( rnrer, S:rn 1 r.nar.a.r IS, ( .lrfrsrma Isrc Iremh) Ikl I)/ k1( K A I RI-N( 11, A H, Rrrr,rr, 7r 4, .. r•n, A/a.unt /n.n Ilu.lnlal naruu, and Mrdraul / rnlrr, S.n I rj ( ,rLLunr.. Isar I rar.Il.rnJcrl /A/ A I HI IIN1), M 1), A.drhrnf Pr.-lrr f I'h,r..n.r.,.l.rrr, MrJra.rl ( rJ1r[c nfrVnRrnra, Rrahrm•nJ 19, Vrrgrnr.r (-/ (lR(F 0 S GI Y, M I)., !)irrrfrrr, r I rnner II..+•rff l',#mrr HnrurrIh 1.rAnralury, Irrporhnrnl n/.~nrRrry, fuhm Ilopkrn+ Ilnapila, H:dlirnrwe, MarytanJ (:I R I R(/1)1 Y GI11 IS( IIA1 1., I'u 1) , A,nafdn/ Prrr/n-r n/ Nr.rhrnnrr.r. l>rpnrlnrrnl r,/ P~nh„L.Kr anJ n/rr..r I,rn1 he krr, krfAlrr Inailnlr hrr AlrncLa1 krsc.rah, New 1'tNk 21, N Y 1at• ( I.vle) n( I ARK (:ktl 1 IN, Pu 1), llrn.l o/ lli.r.lrrr.nnfry Irrlrurnrrnf. M 1) An Ja•rsun /lrr.pu.d an•1 1urnur InJdulr, Umvrrsily r./ Ir+a. INtJi(at ( rnter, Ilunslrrn 2t, Ir..,s Muk IrtN 1(ik<r\~AIAN, Pu 1) M 11 . .4 „.„ ,rr. r h/ t'.,r(rr,,,r „( Al„1. ' . (/nrvrrsny r•/ ( aldrnnr.r h/adra .rl (rnlrr, 1'•a Anlr,lrs 2a, ( ahhnnt. 1'tt(y)I•CI' 7I11.F 1'ffrctH trf Inhacco Smnke I/pon the Funttiun nf Ihe ('ardinvauutar Sysltm in Anvoala anJ Man (C) Path.Jn/rc Analon+ie SIUJy of (•eltular I h.nlcs in Iluman Hrunclri (('I F.tpcrirncnls on the I'usslhlr ( arclnuRrnK and ('ucarcinngcmt' Acthun o/ luhncco Prtnlucls 11') (~arcinncanicily, I r.c-cinnerniaily und /lnth a+rUnnKrrutny u/ Ilrcl.ry I 4a tult in krl.rnrrn tn 1'ulrua.nury 1 umurs 1'ut- sd•I. InlanrLrunn.hrp a.l 1 uh.ra, •r 11.rscs ,rnd 1).rl,.ry Ival.ar. / I,nnu.J St.rdret un 1'ynJme H..et InaluJrng Nr.rtin A-InR. ( rurel-.liun u/ Mulli Irthna.J /'nrrJurtv 1'rr/urmrJ un Ihc I'crrpha~r:J l uaul.r~ hun u/ Nnrmal InJivr.lu.rls in ka•cntn. I.rnt an.l I:ICC/ 1'u.dinnv an.l Aller Iacrai+e Ilcfnre unJ nllrr Sh.un and Ac1u.J Srnuking W1 A SluJy uf fhe IIkats td (~ig.rrrllc 1rnu1• inc un Ihe /'crrplrrr.J ( uaul.rhun ul htJividn.ds wnb Arltriusaleru.rs 11h1i~ rrr:ruv .rnJ (Ilhcr 1'ara{•har.rl V:rsaula, 1>i.cau., ltuliiing Mulli Ictlmiaal Pro- aeJurti 1'clluwvhipv hrr SluJyinR Ihc ( rdlnre of Iluru,rn I rm[ In.uc an,l the I llralt ut Knuwn anal I'.rv.rhl: ( .rumrRrnic nRa-nl. I lpam Suah 1'tulculyGa Atlivilrrt u( Ihe Whitc Illnoal ( all, ul Man 'rn.l Ihc I rfrcl rnt While 111rr.~1 l clt Atlivnies uf <.ranrr'I;rns• Nntnu.rn ,rnd ()tl.cr InO,ran,a's 1( 1 1ht 1/f,r1 uf 1-+pn•r'rr In / ir.•rallr .l'nrnla .rn thc InJu.lnnr o( (.r rarr hy ( hrnuanl l'urnp,nrn,lv I( I'1 r 1 hr I 11r, r,-/ \nrrrt ir. K „rr ( rri. ,rr /:.r.lrra I rrr~, u„rr. (,d i (:IIANTEE ANU INITITIITI(/N 1'HI/JIE(T TITLE ('AR1 ('. (:k111171f, PHf), M1), PharmacoluticSludyu( NkotineanJRe• Aurarulr in PAy,u.L.Ry nnJ PAarrnu. Ia1cJ AllaloiJs W/ rnlnRy, liniversily uf Pcnnsylvania (:raJoale Sch..o1 of McJitine• Phil.- Jctplua 4, Pennsylv:rma Imrw I ectuter in 1'bysiuluty. Ilnrvetvily of llong . Kon61 11 H IIAA(i, M 1) , Pro/naoe of Phar- nr..r..Mrdreal (o11eRe of Virginia, krahmonJ 19, Virginia )OSIiPII 11 IIAI KhNS('NIF1., M 1), llurvh.r ('.rr,h..PrJnt.rnury I/nrt, I an. len:nr Iln.pual, 1'Iu6rJclphiA 31. Penn- sylv.mra kl/'IIARh I IInV11, M1), ,(rtirlunr I'rrr/rr..y u/ Al..lr. nr, I/nivrr.ily u( (aldornia Me•hc.l 5ahoad, Sin Franciscu, ( .Jdurnw /1111111kf k IIAWIIIOkNl, M1), ('hnirnrnn, llrp,ulrn.nr rrl fnrjrrry. I1,livcrsily o/ 1'a•nn.ylvunia Graduae ScMMd of hlydnine, 1'hiLJelphia 4. 1'cnnsylvania ( I ARK W. 1WA117, M 1), Pr.r/r),tw r./ Alr.ln int unJ I)urr frrr r.f llrrJlh Strr. H,•r, luflt (hnvrrsiry, Meditwd, Mastr chuxlt. Iformrrly .1 Ilarvard Unive,- sily, ('amMrJre, Ma.uchutel/t) (see Fermwurlh anJ McArlhur) 1'n1 II 1N1: . 111 1/1' k, Pn l) , Rrrrnrr h Aauairnr in ('ar.'1nKy unJ ('yr.nbrnrr.frr, San 1r.rn.r.au Instilulc nf McJit:rl Saicnacs.'S.m Pruncivco IS, ('ali- farrni:r / vec kicharJ. / I A W k l Nl l' 1 I II Sl l'R, )tt , M f) , fI.......... n. Ilrryolnrrnl r•l l16.frfnr r.rrrJ I: tnr.,•lncy, Medical I ulla•(;. nf S.nrllr (anrhnu, Chatlettun, \nuth ( .nuhn• I 11111( I lk I/ti Ifl /ll~, (•n 1) , M l) , a, .m,l 1 b,n•rrr,r.r I1r/vulrnrryl „/ Nr .rl,rcr..d \, r. n, r. Mrah.al ('nllrgc uf/Vn~uw, kithr.nond 19. VnSiniu kl/\\I 1I I 11/r/ MAN, M I),Prnfrranr „I ll„r,l h, p, r r.r . nr nf I',nlr..l„r•r, ILrnnr.rn.. Sr.rrr rl/ruv,r.nr \.hrr./ .,f MrArune, Nrw rhlram t.'. I uuisian.a (.I, a sra M. / idl 1 0 PfeparalNM f/M hrhlicatir.n uf a Hook un the Niuh.gic A+pech of I..h.tco n.l ils Sn.u1e (C- P) Meaalllernent of ( Mnnaly HIIMhI 1•Inw, Cardi..c Warr1 and ( urdi.e O.ygen and ('arhulrydrale MeIaMAN/l1 in Nornmo- /emire Suhjects Nefure and A/lcr lutra. vrnuns NiaNine nd After Smulmt SlanaLaJ ('iffuretlea ((' 1') A Slrwly of the Pflttls of Sm.rlrng aoJ NNulint AJmrnivlr,uron un Symp.l6o adrenal Uonclinn ana/ I a/ly Aaial Mtlahrdrsrn Altempl. lo Induce 1'ulmunary Nenplatms in P.ptrmaen/al Animats by 11.pr..are of Ihe lrr(heo hronchi.l Syf lem to fuhaccu Smoke If') Per.nnalily and Smuling in College (:raJ ualc.: A hifleen Year I uHow up Slndy ((• P) A Comparalive SIUJy of Farly Ilislolugi cal and I)NA ('hanRes in 1he 1 pi.krmis uf Iwo Slrairn of Miae ((SY Hl:rcls and Swiss Wthtters) After 1)yily Ap plicalions of Whule (1Karelle Smule ('ondensate (Ahrne and ('urr.hineJ wilh (1Mun (lil) and Ilrc ('autiungtnf 20 Melbyl.holanlhrene and 1,IIItn,py• rene lht• Relaliunship of Ihe Ilsr nf 7ohaacu 1'Induals lu Ilrc //ntaumt• uf I'raCn.q.ty Ccreb.,d Au/nnumi(• / ~h.rnCrs 1'rrr.hratd Iry luhr.au SGm.ka•. Nrauliaa• ur / u Imine, u /Na'Lrhrdnc rrl Nnr•rnte 1'.rlhuluKri Ao,dnrmr \/uJy uf I eHnl.rr / Lenrrs in Ilnm.m 14nn, hi 1( 1 Ihc InRrwnce nl /uh.r \rnnlrnk nn Aanlc Myrrc.rrJr.d Inl.riarnrei 65

(:HANTF:F: ANI) INSTITIITI()N F 11OMHURC71 R, M D, Prr,lden(. Bio- Rest.rch Intlnule, Inc., C.mbrnJfe, Mwschuutts FI'RRY HART lA(-ORSON, M D, Dl rr.rrrr nl E(rrn,.physiuln(y, New York Fye nJ Fsr Infirmary, New York ), N Y. 1(11 1lIS II lA( OBSON 11. M f), Ano- riorr Prolrrror of Srrrery rnd Dirrcroe of SurRkal Rr,rocch, Collefe of MeJi- cine, l)niveniry of Vcrmont. Burling. ton, Vermont ANDRFW A, KANUI/TS('H, PNO, Sru// S.irnrhr, Rouoc B lackson Mcrnon.l I ahrwelory, B.r Il.rbor, Maine AN('FI_ KFYS. P/r D, Prolr„nr of Phy, iuA.fn al ll yrrrnr unJ l)irrcrar, f ub orarn.Y uJ Phy,in[nfiuoF Ilyfanr, lJni. vertily of Mmesota School of Public Ileatlh, Minnt.ryslis 4, Minnesota 1OSI PH B KIRSNFR, M D, Prolr,- su. u/ Afr,lu rnr, l)nivcrsity of ('hi.v fo SchrHJ of MeJiaine, (hieafo, Illinois KFNNtill( P KNI/OISON, M 1), A, ,1Uunt ('hirf, 1 uAnraWry Srrrrrv. Vel trarn AJminftlrslion Ilosptl.l, Seattle. Wa+hinfton; P.ufrjonr of Purhn(oey. University of Washington MeJical School. Seattle. W.shinfton AI.VIN 1. KOSAK. Plr 1), At,0clnrr Jrl,nr of ('hrmi,rry, Washington Stlune Collefe, New York l/nivtrsity, New York 16, N. Y. MARVIN Kl/S('IINFR, M D, Prn/rr)nr of Pathofufy, New York Univcrvly (-ollefe of MeJ.cinc, f)irrcror of Pu rholofy, Bclltvue Ilospilal, New York 16, N. Y. T/1l7MAS C. I AIPPI Y, M D, As,nrlorr Pru/rnor nl Parhnlufy, No.thwestcrn llnivenily McJical SChuol, ChKafo, Illrnois PAl)1 S I ARSON. Pu I), ProJrv.•r nl PAarmanR.ay, MeJkd (-olleft of Vir. flni., Ri./unnnJ IV, Vufinl. 1'll())!:(T TITI.F: SluJic, on Carcinufrnesr. and the Bio- assay uf ('arcinofcnic Agents (P) ('omp+rative StuJres of I-flea(t of Varl- out 1 nhucco Smoke ConJemates on Skini of Mice A Comparison of Flcctrnrctinopaphy as . Mc+ns of Ev.luMinf the Eflccl of VaSlKonllr/c1/M hruf. (/Frrn ('erchral anJ Rclinal (-irculation With Olhcr lechniyucs fnr Ihis Iklermin.lion (C) I ung Ilnmolr.nspl.nlalion lo Iklerrnine to What F.tent Tobacto '1au' Munns the Arunn uf ( arcmo- fenie IIyJr.K.rlams in the Skin anJ (/thcr li,sues (C) ( h.r.ctcrislict of Men. IncluJinf Smok- inf, in 1'opulatiunt Udlrrinf in the In- ciJence of ('oronary Ileart 1)ixase ((' P) The I Rrat of Toh.cco Smoking l)pun Ha,.l ('..Iric Scarctiont in Man /(') Patholufi. Analrwnic StuJy of ('ellolar ( h.,ngc% rn Ilurn.n Bronshi (C) The 1.nlalinn and Lkntihcalinn of Cer- tain I ower-Hoiling ( on.puncnt, of arelle Smoke ((' ) P.thoto`ic Anatomic StuJy of Cellular ( hanfcs in Ilunan Hrunthi ((') Palholufi. Analomic Slu,ly of ( rllul.r ( hrnf.s in Ilumun Hrumhi (() PntYmahc Franshnmal/un. uf Nicotine and MrLr1rJ ( .>.nrywnds (P ) lhe 1'n.a. hlr I lle.l u( Int..aao Srmrle •m( Nnaune anr Au.nbu AaiJ MelaMdi.m 66 i CNANTFE ANI) INS'rITI)TION GUSTAVF A. I A(1RFN21, M.D.. As.rL- Ianr P,ufrr.nr of AlrJirinr. Scion 11a11 ('ollefe of McJicine, Jersey Ci(r 4, New Jersey CF:CII IF t F(/('IITFNBFRGF.R, PH D., Srmrn bi.Jutnr onJ (-yrocArnd,I, Chil- dren's ('.ncer Research FounJNion, Boston. Massachusetts (formerly Asso- ciale Professor of Crtology, Western Reserve llnivcni/y School of Medicine. Clereland, Ohio) ROBERT N I INNEI I., Pw.D Arsocia/r Profe,sor oJ ('hrmiu.y, University of Vermont, Burlinflon, Verrnonl t)AVII) F. MANN, 1.., Fhr D, Auociau Professnr of PAomKOlnly, Temple University School of Ph.rm.cy. PhJa- delphia 40. Pennsylvania CIIRISIOPIIFR M. MARTIN. M.D., Aui,rant Profrrsnr of Mrditine &nJ Dirrrtor, Diruion of Infe(tiors Du- r.rrr, Scion 1(a11 College of Medicine, Jersey City 1, New Jersey ('l1ARI FS C. McART11UR, PN n., P,ycAolufi,t ro the f/nirrcsJt? IlrafrA Srrr/rrs, IlarvarJ l)niversily, Cam- briJfe 31. Masachuse(u (see Heath •nd Farnsworth) CIlAR1.FS B McCANTS. Pn D., Aaw- riurr Prn/rrsnr uf S..Js. School of Affirl• cullure, Nor(h Carolina S(a/e Colk{e, Rakigh, North ('arolin NF.NRY C. McG1I 1., 1.., M D., AninP llroJ, Deparrmrnr of P.rholofl. I ouisi+.na State l/niversily School of Medicine. New Orlcans 12. l.ouisiana (see tlolman) FORDIi A McIVFR, M D., Asai)tnnf Pculr„or of PmAutoty, Medical Col• lege of South C-.rolin., Charkslon, Suulh ('.rntin K191 I Y 1. McKFF., M D, AasocAslr Prn- /rnrw of Alydiunr, Medical College of Suulh ('.rolina, ( h.rlts/on, Soulh (-ar• obna VIl-fUR A. McKI/Sl(-K, M 1), An.- r rurr Prufrrsnr u/ f pi.lrminlnft r/rJ ('hrrl. Ihrru..n n/ AlrJual (:rnNUS, luhns IInpl.ns (Inivcrsity SchoaJ of Medicine, Battimorc 7, Maryland PROJE(T TIT1.F, SluJies in Bronchitis: A('o.rehtcd la• •esNg.tion of: (a) TAc ERecl of Smok- Inf on the Bacteriology of the Respira- tory Tract of Ilumans, •nJ (b), The FRccl of Cigarette Smoke and Sulfur 1)io.ide (Air Pollutant) on the Clcaring o( Bacteria from the Respiratory Tr.cts of Small Animals (Mice. R.u) A Correlated Hislotogicai, Cylolollical •nd Cytochemical Study of Ihe Tracheo Bronchial Tree from Mice Fa- poseJ to Cigarette Smoke (P) Tlre Oaidalion of Nicotine by O.xow Oaygen: Mcchanism, Produc(a and Kinelics (C -P) 7he Au/o.iJalion of Nicoline E.Rec1 of Tobacco Smoke and T'obacco Residrres on Melhylcholanlhrenc- Indueed Skin ('arcinogenesis in Mice (C ) Possihle Inleraclions of Viru.es and Sub- st.nces in fobacco Smuke ('unJensate Social and Personal Iklerminanls of Smoking Fkhavinr (C P) The Social Mediation of Smoking Be- h.vior Arsenic Conlenl of Soils and Absorption by the Tobacco Plant ((' P) The ERecls of Environmental Factoes on Deve(npn~ent of Alherusclero.is as Re , vealeJ by Autupsy of Accident Victims I:nvirunmcntal Faclnrs and Pulmonary 1)iuase. I Asbestos Dusl Study of I nnf Function in Smukrrs anJ Non Smokers 1(' PI A Combined Oenelic, Physiolofic, (linie.l .nJ hpiJenuuloflc SIuJy of Buer fer's 1)i.c.se 67

C1tANTF.1•: ANn INSTITIIT'I(IN )AMI S G Mtl I Fk, M 1), PN 1), rrr. /rn..r .•f rryrhwrry an-1 Pry.bnl..ry. unJ f)i.nrur, Afrnl.d llrrJrh Rnrufrh lnrhrurr, lJniver.,ty of MKhiolan, Ann Arh•u, Michipn IltlG./t MONTI'OMI RY, M 1), Asr..rl urr Irn/nr.rr of AfrJa rnr, l/nivtrsily of 1'cnnsytvvnia Medical $chocrl, Phila~ dttphia 1, Pfnnsylvania P O'k M/)NI('(1MIRY, 1., M1), .trsoaru/r r.../rn.rr oI Pulhrrlh.ey. lJniver.rly nl Tera., SrnnhweYlern MeJK+I S.hu.d, 1)+tla 11. let.r (:I Ok(:I 1: A//klkl', Prl1), M r), f)i nrr.... R., wtll P"rl Mfmna.l In.lr Lilf, IL.(I,J„ !, Nfw YrNI IKC IhKI I a InIRI Iv 111 MU111 Y, R1I), r..fi• r,v u/ AIrJ..mr unJ lrrn.r.v, (ur.h.• Rrrp..ur.,.y I uh,,.,.r„rr. llniver.i/y .d S.rolhtrn ( ..h!nrn,a Sth.rd uf MeJ, cine, I us Anetlc. 17, ( .hfnrn,a WI11 1AM S MIIRRAY, Sc I), Rrrfm.lr Ay.r ntrr unJ A,/.,nn.nuurn.n Ilv., rnr, ko.cue Is 1ac\a.n Memuri.d I+hu..r lury, Har Il.rha,r, Maine I()N^11) M PA( F. PItI), rn./r,,..r r.l rhy,r..lnRf wrJ I)r.rrlnr, Inuine/r /,.r (rllnh.r Rr.rurth, llnivendy of N.hra.la. I incoln, Nchrr.la 11)WnRI) W P111KAN, M1), A.+.• r r.ur r,,,/. ,+..r .•/ rhu. u.p nlnr•Y nn.I F rprri.... nnr! l hrr.rpruN. r, (1u.lun t/niverury S.h.w,1 of Mt,htmt, llo,lun, M.t+..chu.fn, Plll))I•:cr 'rrrt.l: the Ilehavio.~llRctl+.d Crnul.rnR llndtr Slrt,+ 1(/ /nfluence of lrshxcn Smoling tin the NIoMMI HOw of Slin anJ .rf Muaitc of Fsutmrthta in Symp.lhttlomireJ nJ llmymp.IheclonureJ Suhiecls (C) InRucna'e of Nico/ine li.v 1 anJ Tuhacco Snuding on Blofx) Iluw in Iluman 5lin anJ Stelelal Muxlc IPI Inve.1lR,./inn of the Role of the Nucltulum in the Nurmil anJ Il,e MiIqnan) ( fll An Invt.uR..hon uf Ihr 1'h)•nd.Vt.rl I I fctf. u/ I)uttl Inh.,Lm..n tJ It.h..t,u Sn,,.If by I.hurer.My Aniat.J. and the SIUJy of /bt Ihulal;rc~l Re.ry,na r,f I ahu.ulury Anim.l. tu / unr.nuou% ln~ se,hun n/ 11a1. lulvcco P.r+du.l Mrslurt. /l / A 11udy o/ rf,e I Recr, o/ Smnling on Pulm„n.r y Ium /wn 1/ 1' ) the 14uJutliunuf ('enrlit.Jly ( nnuullrJ Arnnr..1. rnJ lumnn Ln 11.: rn I tl+r1 imenUy kc.c.rah r,n luh.nto in ktL.. Ihan lu IIt.illf+ by (+1 Ihe I y+:,n.wn ol known InhrcJ Slu.l, an.! ~.wrtc. u/ lurnu( Snrrly; It,) the 1'ruJualiun of Sncl, Ilyhr,J, or Iltrcr.,i)Ftn.. lypc, a. Ilctt,mc Ntte-.%ary. anJ Icl Ihe ke. laln,n uf /hi, Mattrial lu %T+e.i6a Is- Prriu,enl.J Wur1 at the 1~.hurnl.wy (C) Irllnw.hip. fr,r Ir:rininp in li..uc /'ul- lu.r It.luntfuf• (( I %nrJy nf Iht I Ilitl. uf Inhat.u Sim,1t 1 un.hrutnl. on V..rruu. Slr..,n. r,l 1 i, sue l ctf, l uhivd/a,l ln t'rr..r I Y I A Sludy n( SurKlure Athvily Rrl.dian A.nunK I1ruR. WIn.lh A11..1 Nn.,ln,f I, rn.rtrvt 1'hyv.dnFnwl Mith annm. 11,1 rr1A/:Ak I 1'(1ttAK, f,11), Pnt). I.. uw... Ir..,,r~, . Ilnvi-r M.Ju.J Iff .f.r,,h ( fNr,, tnt , I)ntr, I)atev.,.rc tm Are r..d ..uJ ( u!huf. (,K I I i (:RANTt:F. AND INSTIT(RI()N ('. M. POMtiRAT, Pu J)., Dlrrcror of binl.rrnul RrrrefrA, Pasadena FounJa- lion /or MeJrcal Research, Pas.dena, ('aliforni. (formerly Professot of Cy• toluey. Universily of Te.as Medic.l • Branch, (:alveslon) It. R. PRATT-TI1nMAS, M.b., Drow ane Pro/errfrr of Parholoty, Mcdical ('ollege of South (:arolina, Charleslon, South Carolina HOBARf A. RI IMANN• M t)., Pru/rr- ror .r/ AfrJn rnr, /l.hnemanw Medical ('o//rge and Ilosprlal, /•hiladelphia 2. Pennsylvania VI('ll)R RI('IURhS, M /), rro/rrror of Srrtrry onJ 1:.rformr ll.ruJ, 1)rparr.nrnl n/ .curgery, Stanford Universiq Schcnd of MeJicine, San Francisco 15. (ali(ornia (sce Ileirer) R. 11. RI(il)(1N, M b, 1'ro/rrrot of ri- tAnluey unJ f)nrrrrw, laAorarory of Fepernnrnlul PorAnlufy. l/nlvtrsily of Teus Medical Branch, Oalve/lu., leeas SYI)Nt.'Y C. RITl1:NBFRO, Pa b., rro /rriar u/ burlrri.d..lr. l/niversily of Southern California. I os Angeles 1, ('a6fornia PFNSON R ROF, M I)., Auoclarr Iro- /rnv.r of SnrRrry, 11r~+urhnrnl of Sur- trr!. Univcrsity uf ('.li/nania Schtai of Medicine. San Francisco 22, C.lifornl. 111.NIAMIN A RIIRIN, Prlt)., Aas/rr- r.nr rr../r,rnr n/ ruhfir /IralrA 0.4 1'rrernHvr AIrJL.nr, Baytne l/nivetsily (ulleole of MeJi.ine, 1luuslon, leeas Inuw at Wyeth I ah.Halorics, Philatkl- pfda, Ptnrnylv.nia) Wit I IAM l) RIiSCI l 1, M 11, ParAnln. enr rn r hir/. M 1) AnJrr.nn I/n.prlrl anJ lurn,n lmrinnt, 1lmvtrsily of letas Medical ('enler, /luu.lonn 25, leuas PknJF:(T TITLF, Feltowships for Studying the Culture of llum.n Lun` '1 i»ue and the fRec/s of Known and Possible ('arcinotenic Agents Ulxsn Such Tissue (P) Palhologic-Analomk Sludy of Cellular Changes in (lunurn Bronchi (C-.P) Application of a New Bio-AsaFTech- nique In F.taminalion of ( i~arelle Snwke Condensatea fo. Pouible (:ar- cinogens (C- P) Carcinogcnesis In (he I aboratory Animal: A Comparison of Spccics Response to Slandardized Sites of Application The Possible FRec/ of Tobacco or Nko- /ine in Periodic Oisordcrs, a Newly Recolnlred SynJrtHne A(bmparadve SIuJy of the LRecl, of Whole and Fracliuna liaracts of (-ill- rclle Smoke anJ 'Ihose of known ('arcinngens on / 1/ 1 he Cytology and Nuclear DNA Content of Fpidermis in Varirrn Slrains of Mice anJ/or 12) lhe ('~/ulosy and Nuckar DNA ('on- lenl of I ung and Fpilhc6um of the Bronchial lree of Mice anJ Flamslers ((') FReeh of Tobacco Smole ('ondensale ow the Respiratory lracl and Other '1 issues of the 1)ut \( P ) lhe Bacterial Ikgradalifsn of Nicoline and RelaleJ CompounJs The ()4,jec• live of the Projecl is the 1?lucidalifrr of the Inler/nediny Mel.ho/i.m of Nico- tine O.idaliun (P) Study of the Action of Negatively ( harted lons on 7racheo Brunchul ('iliary Action in the Iluman Patient An F.valualion of Ibe Phenomenon of Tumor Grnwlh Fnhancemcnl as an Assay for ( lrcim>tens Arm,ng Ihe Pulyey.lic IlyJrrtrrhnns and Re1.ItJ ('ompuunds ((') Pah.AogkAnaomic SIUJy n( ('rllul.r ( h.n(fr In Ilurn.n 1lrnnt hr (( I 69

I (:NANTf'F: ANIy INhTITUTI(1N PAI/L 1) SAIIMAN, PND, Assistant P•nJnror of Ri.nArmiu.y. University of S.rolhern ('alifornia S(honl of MeJ- icinc. I ns Angeles 7. ('drfnrnia At VIN R S( IIMII)T, PH D., Dirrrror n/ ('r~unrrhnt, 7ufcs Univcnlty, Med- (orJ. Massachu.clts ISAAC S(-11011R, 1) 1) S. Prr D, DSc , P•u/rtfr,r.o/ Ilnhd.,Ry unJ EmAryolrrry and ()run, llniversily of Illinois ('ol. Iere of 1)enlislry, ( hicalo 12. Illin(wis Mn(1RI('N. S St'(7nt , M 1). rlinrrar rr../.nrrr nl Afr,lirine, lufls (/nivcr- sily ScMKA nr McJicinc, Boslun, Mas- sachu.ells' 1)irrrrur, f)rpr•hnrM rt/ lnhuLrGnn ThrruPy, B(nlon ('i1y llrn. prlal, Ru.1un, Mja.jchuselFs ('ARL. (' SI 11/1 R, Puf), Rr.rnrrlI rellrr. in rArr„nr IlarvarJ I/nrvtnily, ( ~mhnJ~t, Ma.. rhrntlta ( IIARI IS 1: SIIt kW(N)1), MI), At jirrunt P•rr/r.r.rr nl RrrJr.J,rRr, Ilmvtr sily of krncc.ler S.Luul of McJicme nd Iknh./ry, ku.hestcr, New Y.ak 1)AVID 1. SIMON. M I)., lnsrrr.rrrw /n A(rJirinr anJ Frllnw in ('urJinvafu.Lrr Rrrra,cA, Universily of ('incinnati ('ertle(te of MtJrcine anJ (:ardiac I ah. oralrxy, (-incinnall (:eneral Flospilal, ('incinnad 27, Ohio. T. M. SONNFRf)RN, Prr D, f)luln• f ,hrJ .cr•rl.r r•oJrsr.» of 7nr•/nrr. Zi.na llniveraly. Bloominrt.ur, InJiana SAM SOR(11, Prr It, Rrrr...ni1 Au.alarr, the Iml~w/r fur ( ancrr Resruth nd I ankrn.u 11.r.prl.1 Research In.htule, /'hd.Jrlt~hr. 1 I, Prnmylvanu I'llO)F:/'1' T111 !: lhe Fnryrnalic Meahanism fnr Ihe 1)ark Ft.jti,+n of l(/ hy I,.h.rccu 1('-1'/ Sonrc A.prcls of Amino AciJ Melaboli,m in luhacco I caves (C) StuJy of AllituJes TowarJ, as Wcll u FatcN, 7ype and /li.lory uf, Tuhacco Smoking in a Young ('ollege Poptda- lion Study of Sonic of the Rclation- ships of Smoking and Nonsmoking to Family Ilistory, T~pe of Secondary Sch..u6ns, Academic Inleresh, Aca- dcmic Achievemenl, and Social Rela- tion.hips ( haracteristics Ilisloloric C-hantics in the nra1, Pharyn- foca1anJ Na.:d li..ur.of l-.prrimcnlal Anima. SubjecteJ Io lobacco Smoke ((' P) Ftfecls of ('irarelle Smnkinr on 1 ung Funcrion in Nrumal Suhiccls and Pa- /Knl% With ( erlaln Rc\p1lalUry I)iscaK ( onJninn. ((' P) Ret:dionahip of ('rrareltc Smoking to ('hu.nic (()hshuaive/ Pulmtmary Iim- physema MnrphntnRy nnJ Sotokinr in ('olleRe (:ra,tualc. A Idtcrn Yc.n Follow ltp \IU.1y 11' 1 It,rv.,t,l I.d,n. Ilnp(in. S/-Iy .d Ilrwly Irrrrn .,• k.1.NCd tn \m.diuR, anJ Ilre 1'rr.ur.ur. u/ Ilyl..r/envrrn anJ ('ur- uuary Arlrry Oi.rna 1nvr.liRaurrn Inlo the N:dui.J 11i.trKy of ('aram,rma a( the I rurR W.Ih 1'arlicu- lar krlcrrme lu Ihe kaJrnruplni Ap- pcar.rn.e of NiKlr Pntca.ea, Ihe l~atli esl M:mifrstatiun of C'anctr on ( hrst X~kay Photnrraphs and the 7'abrda- lion of the Redalionship uf Smoking 1lahils and (fccopaiun Wilh Ihe Inci- dcn.c of I ung ('anccr ((' P) The FRccta of ('hewing Tt.bacco on the ('arJiov...cular Systcm nf Man ((- P) lhe I Rect, of Pipe Smoking and Cigar Smukinr rrn the ( .rJuw.-crdau Sy.tem of Man 1(' P1 lhecking and Fstrndinr the Slrphano rur.n.nr, ru.n I( ) l ra/ In. (.r. imrjrnla ily ( hrmicul .nd PIhy.1.a1 Slu,lirs nf Ihe li..ue 1'r,.lrm. Inv,Jrrd rn ( hrnrnal ( r.cfnnRrnt~r• (( P) 70 I I (:I(ANTEF: ANt/ INSTIT(ITIOP( 1-RVf)IiR/('K 1. STAR/i, PND, Pr../rs- s..r of Nuniri„n, Ilarvud School of Public /ledlh, Roston I3, Massachu- selrs MARION B. S(11 ZBI?R(lER, M.D., Pro- /rsfor and ('hairmon. Drpwrmenr of Arrmarrslory on/ SyPAiloioRy, New York Universi(y-Bellevue Medical Ccn- ter, New York 16, New York CnRO1.INF. B1:t)FI 1. TIIOMA3, M D, A»orJau Pro/nrnr of MrJirinr, lohns Ilupkim (/niversity School of Medi- cine, Bahimnre ), Maryland i TISSUE CUI T(IRE ASSOCIATION (rrniJrnr, 1)r. Marrarct R. Murray, Annriare Pru/rrsrw uJ Anaromy. Co- lumbia llniverJly ('ollege of Physi- eians and Surreons, New York, N. Y.) /ANET TRAVF.1.1 , M.D, Msociare Pro- /rUr.r rr/ ('liniral I'Au.nanrdrrRr. ('nr. nell l)niversily Medic.l College, New York 21. New York E. 1). WARNL'R, M D, ProJrrtnr o/ Pa- rA,dnry, Sule University of Iowa Col- lege of Medicine. Iowa ('ity, Iowa RI(-HARD 1. WI':C'/ISt FR, M D, Ct/nl- rul Phyrtnlr,rrtr, Munleflnre 1lospi/al Institute of Rr.earch. PiQsburgh 1), Pennsylvania Rl1SSFt I W. WI'l I FR. M 1), ParAolo- trst. Mcmorlal Ilospilal of ('hesler ('ounly, West ( hesler, Penn.rIv.nia; AirrIc/uIr Prn/rnnr n/ Parhnloty, Ilahnernann MeJn.l ('ollrre, PhiLJel- phia 2. Pennsylva.nia tM0)t:;(T TM.F; ttperimenlal S(udies of ('ancer Utiliting a New Techniyue to See if Various ?ars F.slracled From Tobacco May Incite Ihe Forrnalion of I.un, Tunson (C) I'nvestiption of (he E/fecis of Tobacco on the Human Vascular Systern, Basnd on the Fact that Certain Tobacco Ef- fecls are uue to Alkrgk Susceptibility o( Specilic Iwdividwls Ralher Ihan lo Oblip lo.ily To.ic Producltl In Tobacco Srnoke, and (hat Pa(icn(s with (kclu five Vascular Diseases Respond 1)ifter- ently than 1leahhy Smokers (P) The Signi/icante of DiRerenl Indi.idual Pa(lunf of ('irculatory Res(.onsc lo ('iffarelle Smoking 1 P 1 Studies of (3enc/K I)rfferencrs Belween Smolen and Nonsrm.kers IP). Studies of Psychological Oifferences Relween Smoken and Nonsmokers as Shown by Consparison of Firure Lhawinp To Auht in Estahli.hment of Summer Training ('ourse in Tissue Culture Technp' uts at ltniveni/y o( ('olurado MeJical School, Iknver, ('oloraJo (C 1 FRecls of NicMine in the Rabbit with @.perimental Coronary Atherosclcrosis 1(' P/ Pa(holoilk-Analornic Sludy of ('cllular (-hanges in Iluman Bronthi ((') Correlation of Bronchiat Ppilhelial Chanrea wilh ('omparable ('hanres In Other (hgans A Patholoric Anatomic Study (C) ERect of Cigarette Smoking on ('erchrat BIooJ Flnw, ('erehral Melaholism, Blood (iases, Bh.n,l p11, Arlerl1 Pulx Pressure Curves, FlectrocarJiorram., and Flecrroencephalurrams ((') PalholurieAnatomk Study of (-etlular ('hanres In Ilnman Rrnmhi A SelecleJ, Fdcnded and IktailrJ SIuJy of Iluman Rrunchral Mu.ma 71

cNANTFa: ANI) INSTITtmon SIMON 11 WFNDER, PMD, RetcoKA Peuftnor of l'hrmfrny, ltnivcrsity of Oklahom. Retearch Inrtitule, Norman, OIlahom. hUANF 0 W1 N7F1, h(D., ProJtmor o( Phe.mnrol..~~, School of Pfiarmacy. Unlversiy of K.naas, I..wrence, K.n- w FRFI)FRI('K H. W111SKIN, M.D.,C M., Uirecroe, Diriiion of Ifc.hA aw/ Per• mnelfry F.puif/6rlrwr, The Agt Ctnter of New Fngland, Inc.. dotlo. 16. Mas- s.chu.ctta (.ee Dibncr) 1. PDWIN W(x)n, M D. Pro/r„oc of A(rAkine. Medic.l ('o11ele of (itorilia, Augusta, Otorti. 4 1'11())F:(T TITIl: A Qualitativt •nd Quantitative Study of The Individual Polyphenol Content of ('igareltc Toh.cco and of the Smolt and 'lars' Resnltinb from ('ipretle Smoking, and Also Study of 11.e Fatt of ihese Co.npounds in the Animal Respir.lory System (C- P) The Oelermination of the Chronic [°Rtcts of Orally Adminiaered Nicotine ow Serum (holesttrol nd Phospholipid+: the Fkctrocardiogr.phic Responx to Frtinnovine:; and the Vaxular Pathol- ogy of ('hole.ternl-fed R.bbilc (C- P) Pilot Study of the Smoking H.bi(a of Age ( emer Memben ((') Tre Flfcct of Prolonged Inhalation of lobacco Smoke and pf Prolonged Ab- uinence from the (t.e of Tobacco on the Peripheral V.scular Rt.ponse to Acute Inhalation o('1ob.cco Smoke In Man (C--P) S(tMNF.R W(X)i), 1R., M.D, AftJrrant Fvalualioa of Fliologic Factor., such •s Projcuoi of rulAnlurP. neportnrrnt of Occupational IlararJs nd H.hils, and P,rrhnt.rtf. )nhnt l lopkin. l/nivervty, Patholoric Pauliarities in the L onb- B.Itlmote S, Maryland lcrm Survival of Paticnlf Following Re%ecdun (or Broncholienic Carcinoma )O/IN P. WYAIT, M.f), ProlrJ+or of An Inveaiplion Into the Nalure of the Purholnly. St I ouis Univcnity Schcx.l Pigmentary I ctiun in ('enlrilobular of Mecticine, St I ouie 4. Miuourl Fmphysema ++r,~ a !Sr' .r.3. M~.. ~ ~ .~ wY.1 B 0 rarr.{ ~ 7 `