Jump to:

Council for Tobacco Research

Annual Report of the Scientific Director [St]

Date: 31 Mar 1994 (est.)
Length: 35 pages
CTRMN011501-CTRMN011535
Jump To Images
snapshot_ctr CTRMN011501_1535

Fields

Depository Date
25 Sep 1995
Master ID
Ctrmn00010849-2859

Related Documents:
Author
Little, C.C.
Request
118
Type
ANNUAL REPORT
Box
005
UCSF Legacy ID
avr30a00

Document Images

Text Control

Highlight Text:

OCR Text Alignment:

Image Control

Image Rotation:

Image Size:

Page 1: avr30a00
CTR HN 0 1150 1
Page 2: avr30a00
.' .. • S.IL.T[l.l•//. 1 ~ •,- ' . s ~ . 171ti.1i/~ ,: ,1' ' ~~ ' tf a ~ t r ~ ~~'ay: •rt vl ro(? w ~ 1"•~ Y: . .'1 '. I®® 0 -+1!F•tT .' ~!\/ ' t 0 ® ® J m ® ® ® ® ® ® 0 ® 0 m 0 . .4 ® ® , `. . ,!4'. .,~.;. . .~ ... ,. •.~. l,ah! . . 0 ~.1~1''t 0 ® ® ® O O O ~ U u i ANNIIAI. Itl:l'(llt'1' tp/ the ti(;LI:N'1'l l 1(: IIi lt t:(:'1'(/ lt /7.A1{F:N1 F: / (N)K L1T1'1.{•:, ti.••11,
Page 3: avr30a00
TABLE OF (:()NTFNTS I P.gc ()bservations . . . . . . . . . . . . . . . . . . 5 Rese.rch Findin6s . . . . . . . . . . . . . . . . 16 Abstracts of Reporta Carcin<isenesis Studie. . . . . . . . . . . . 29 C.rdiuvascuLr Studies . . . . . . . . . . . . . 32 Studies at the Cellular Level . . . . . . . . . . . . 43 Pulmonary Physiology and Anatcxny Studies . .... 45 Psycho-Physis>Jo6ical Studiep . . . . . . . . . . . 48 Tobacco ('hemiatry .od Biochemistry Studies . . . . . . 49 Pharmacology Sludies . . . . . . . . . . . . . 51 Other Studies . . . . . . . . . . . . . . . . 52 Recipients of (hants . . . . . . . . . . . . . . . . 55
Page 4: avr30a00
ti('If:N'1'IFI1: AI1VIti11Ftl' I1/1AItI1 tr, Tl,e ('uuncrl for 1 ut,acct, Rctcar( h 11 S A K1iNN1:"T Il M1=RR11.I. 1.YN('I1, M T) , St I) , 1 I I) , l'hu,rm,,n ('h,mr rllrrr and 1'rnfrrlr- of 1'arhnbrty P1cd,cal ('u1kRc nf South ('arolina, ('hiricstun, Sr,uth ('irr,lu,a FIUWARh 11 nNl*RVONT, St' F). Sr irnn(rr F.Jr(r., lhe lournal of the National Cancer Inttrlutc lTcthrula, Maryland RI('I-I^RI) I IfIN(7, M T). 1'rufrrs(x ond Cha/rmon. Tkparlmcnt nf Medicine Waync Statc Univcrsity ('ullcRc t>t Mcditrnc, Iktruil, MrchiRan McKTTN ('AT"T1'1 I., Pt/ I), M 1) 1'rnfrtnrw F mrriluf of 1'harn+exv,lnxy (-rrrncil tlnivers,ty Mcdreal ('r,Ilcgc, New Yurk, N Y . lTON 0 lA(`OBSnN, M I) !'rnfrrJtrr and ('hairmon, fkriartmrnt of Medicine Tlnivcrsity of (Ticago lhrr,rrrr, Argunnc ('anccr Rrtrarth Ilutl,ital, (l,icagn, 111,nuis PA1,1. K(y1lN, M 1) ArrtMlOlr 1>,trrlrn 1- frr1J 'Irr.,lrrr NjI,r,nal ('rn(cr In.wutr, II„h( ..l~. Meryt,rnJ ('I.ARF?N('F? ('(X)K I IT11 1', Sr h, 1 1 I) , I t r 1 L) Sr irnri(rr' llrrrr fr>., 1 hc („unt,l for I r,hat cn Rrscart h I I S A 1)irrrl(or Fmrrirur, Rcnctx Il lit kson Mcmurial l.alx,ratury Flar I-farhtx, Maine STANL.F?Y P RF?IMANN, M T)., Sc T). Dirrr(nr F.mrrilut, l1x Irtttitute for Cancer Research Philadclphia, Pennsylvania W11.LIAM F. RIF?NFIOFT, lit , M 1) 1'rvfrsx,r E.mrrirur of ,Surgrry Johns I-lopkins T)niversity Sch,wd r+f Mc,licrnt, Italtirn,ac. M:,rylanJ L?F)WIN Ll. WIISON, PRt 1) , 1.1. 1) 1`rnfrtrtw F.'mrrifus of Viro1.Sl,uitrirr Ilarvatd / Inivcrsity, ('amhrul}•.c, Mea.r, I,utrttt ttOItFf( 1'f Illu KI I 1, I'„ Ir 1 M(tR1tIC()N Itltn(1Y, M 1) I„r+ nrlr Cr rr,ur/rr I Lrrr rr+ , i Obscrvations A dccade has passed since the Tobacco Industry Research ('ommittcc, now called 'IAe ('ouncil fur Tobaccu Rcscarch-ll S A., anJ Ihe ScicnUlic Advisory Iluard began their wurk. During these ten years a majur rescarth program on the rclatiunships uf smoking to health has been initijled, arnplified, and has gradually assumed clear-cut shape and directinn. Research on these and related problems has sirnilarly eapantkd undcr nrany other auspiccs- Federal health agencies, voluntary hcallh and sci- cntific orKaniratiuns, universities and nretlical schtwds, anJ Icaching and research hospitals. Significant advances have txeurrcd in scientific knrrwktlgc and untler- standing It now seems appropriate to review thc prugress anJ thc laublcros of this first tkcatk, and to a,nsitler thcir implicatit,as fnr the future. Perhaps the mosl significant aspect of such a review is Ihe rcalintiun that Ihc passage of  substantial period of time-and the accomplishmcnt of a substantial body of work--havc not changed (he fundamenlal prub- Icros. As is uften the case in hasic scientific caploration, intensive rescarth has raised more new questions than it has answered. Ihe task before us is, if anything, larger and more conrpkx than it appeared a decade ago, and the majta research problems underlying the rclatirrnships uf smoking In health, though sornewhat better dcfined, remain Formidable. At Ihe time the Board was establishcd. Frrr c.am)tte, when epi dcmiulugical studies reprxtin6 an ssrxialion Fxtwecn eigarctte smoking and cancer uf the lung were being advanced as a majttr suplwrrt for the hypothesis that this relationship was causat. the nced for inlentivc resc'rnh in nuny areas -bitsassay, 6erxlics, palh<,h,gy, hirxhemitlry and t,thcrs ur er<plnrc this nd alternative hyptNhests, anti Iu clucidatc hrsic undcr lying biological mechanisms, was evident In the intctvcning th'cdtk cRl,crl rucntal wrak in the vatit,us arcas has raised nrany new iatues 'I hc nerd for (nlther InuwlcdRe (withtnrl whi.h any hylwHhcsis will latk crmfinna tiun) is still clcarly evitknt After ten ycars. Ihe fact rcmains Ihm Inr,wh•dKe it intullicirnt rithcr lu (nuvidc atkyuatc prrNd of any Iry/,trnccnis lit lu dclntc rhr th.ttit rnrth.tn i.m. /1r IlcJlttl anrl ditcatc wrth which we ar: crrnccrnr,l It r. Irnc nuw t it w,,t in 1'!t•j tfhal tnntinucd retc:,rth in all arc.,t whrrc 1m,wlt'dl;c it Jcfit ra nt „Ilcrs thc ht•sl h,ya• for thc futurc S
Page 5: avr30a00
I Whilc the suhstantive arcas t+f rctcatch, and shecilic rr:rarch resulls have v:rncd widcly dunng flns dccaJc, cctlarn hrt+aJ firintrtdt•s h:lve crncrgcJ which scrve as a uscful RuiJe It) furthcr planning Arn++ng thcse nlay be litted Ihe fullt+wing: ( 1) Thr f/nrhnnRlnr Narurr u/ 111.ro.r ('unccptN+ns tit disease vary enocmously with changes in methods nf detecting antl tkfining Ihcm. Every new techniyue-anJ there have been many- /nr the tklcctic+n, tkscriptinn, analysit, treatment rrr hrcvcntion uf a drs.casc enthy tends to alter. to tnmc c.tent, perr rprinn of thal cntity. l hus it is easy to forget (but im(+nrtant to rcnrcmhcr ) that thc buvr nururr of that entity- whatever it is - rcm.int unthangcJ 'ihe naturc c+f Ihe intr.ccllutu haxhcrnital I+rtxcss Ihat inuutcs Ihc dcvck+f+n+cnl t+f a tqoamnus cell circinnnra tit the ItmK, /++r ct:uul+le, was the s.rrnc in 1664. 1764. I Nh1, .nJ 19fh1, dctpite all the t I+jnKcs in k nnwl- edgc .ntl view t+f it that h.rve t+fturrcJ durrng that timc sl+an I hrs undcr- lytng crrnvacncy rd the basic prrtcss rnust hc :rpprcciatcJ tlurrnR thc search ft+r fartrrrs whn h rnay inrtrate, xcrtcr:rtc ++r dcl:ay its cx'currrncc II is cyually irn(wtrtant tit Le awarc that any r+/ tlkvc nurlrfy+ng fatnrts trnrhl t+ngina/c, int'rcite, d+n+v+rsh or tlrsal+f.c.it wrth the passaRc rd tirne and with thange in tnr+ ttanl t't-nJ+ln+nt, antl th.rt tht.c rvrutt ttwhl rn turn Ir,ttl tu th.nKcs in the rrl.rtrvc /rcyucnty rd Jrflt•rrnt dncates lhc clucid.rtu+n r+f suth f,utrus iv in+lw+rtant in Iltrctt hrr.lwrrlitm to Ihe cxtcnt that they thrnw light t+n Ihe has+c and as yt•t tmlx•rfcctly UnllerstlwNl rnrc'hanisms whith thcy aflect • (2) Thr I1i.rlnrtiun ffctvrcn l)irrrf ('nu.r, I'untrifLufinR Cau.r, ARRrnmrinn an.l Nun 4prririr A..orintion 1hc intfwatancc nf these dittinctrttns in the scarch fur hasic knt+wlcJhc has alsrr I+ccr+rne evitlcnt during thc h.rst dicaJe Ihry mutt ir+llucntc r+ne's tlnnkrng rtnt <+nly with regard Il+ hacic n+rthinit+ns t+f drsratr hul Ast+ with regard In cnntrul, prcvcnfir,n ancl Irc.iln+cnt. 'lhe (xt+hkms raitetl by tt+mhutn+s which have hrrn idcntified as luim:rry causes" tuf a (trseatc entuty (tt+r etemVIc thc tuhertlr I+atillus in tulK'rcuh+tis ) are scirnlifx ally tlmtc dilfrrrnt f+t+nl thu.c r:+r.rd hy ctm tlninns wluth h.rvr Leen iJrntdirtl a acnnr~ tit trrt:+rn n+•Lrntrs, tit hy ct+mF+tit+nt i+kru+liid at nrrn yx•trtfit.+lly •+tttrrelcJ with e Jrtr.rtr cntrty 1 rir+h~ r +h~- frrr•1•Irrn. •1 1•y nt. wh+t Ih .nt• rnr m tht'r/ .r, ., il, JJI. r. nr Ir..- rL...r ulm h,ut• r/•1 •„... r,.n nr I.•...I t.••r...... n I r r 1 he I:rtler are maners trf universal ctsncern, whilr Ihe h+rmcr hKUs ancn lion on the need to tlefine the mrchanisms of selectivity and thr n.turc tit Ihe susccptiblc purtitm of Ihc IrNal population. Yet another type tit pu+hlcrn is raisctl by facttrra which through association may appear tit tre seleclive hut which are not c/fcctive agcnts in the discase at all, for caantple, the t'ating of cnrn and pcllagra. Again, the distinctitsn between agents which act "causally" and Ihrne which aggravate or exacerbale the prugtess or devclapnrenl of a disease once it is established is of obvious imptrr/ance bWh to an untlcrstanding uf mechanisms and to the design of effective intervention 1}scse diatinctions underlie every ctmsitkratinn uf morbidity, mnrlality and prevention of disease. 'I hc+e disrinctirsns have ntN heen adequately investigalcd in connec- tirxt with Inng canccr, cardiovascular or txMr discaus, hy the types af study which can yickl Lcttincnl data, and the design anti cunduct tit such study ren+ains a ntajttt prohlcrn for the future. (3) The fmportance o/ Ilorr Forfor. In IN..n.r R..puna Although the esscntial role of host factors in disease resprmsc is rccug nired, very little organized research to tk6nc and analyze these factt+rs fras been or is being cunducteJ in the area of amuking and hc:rlth 1 he fact that such research~is dilf.cull, costly nd Iimc-consurrsing has unduuhtedly been a deterrent; one may recognize the practical infltKnce of this situation on the individual research worker who naturally prelers to sckct prtstslcros towards the xrluticsn of which nKmths rather than ycars, and years rrthcr than a life-time, will conlribule. I lrlsl facttxs promise particular pertinence in cRploration tit the prohlcnl of Iung cancrr, which trccurs in pcrams who have never lxrn c.fxtsed to dlc alleged c:+usative agents, antl which also occurs in only a very small pro pt+ttit>tt ur those who have been so eraposcd, so that a nlajnr st'irntdic tyucstinn ccntcrs ttn the "why" anJ "huw" uf the dctet'titun and sclcctit+n t+f irtdiviJuals who will tkvelt><s lung cancer '1 he available evidcttt•c dernands attention to gcnctic, constitulirxul and other h++st facturs Snch knuwleJge is lacking In the devchtpment of Ihrs knnwlrJge t+ne 11111,1 toe realistic and palient lhe nurulx•r tit Jrllctcnl Rrnctic rrr tunstitu nrmal patterns amrmg hunlan inJivitluals it vust, and the drtrrnr urm Irctwrrn nmN nf Ihem by any siruldt• r+t trmvenrent mcthr+./ rs nr+t as yet I+f.rttit:a 1 hcy are unhkcly h+ t.c tit thc gcnt'tic'ally simlJr tylrr whn h r'ln t.t• +1r1ct IrJ hy thr rnrlhrrJ. tit nrlh+alut Mcntlclrnn :ur.rly.r., Ilr+ y wrll, m ull prr.h,+hrhty, tt+rtlrrhnlr tn tht• dranvcry tit hurht•nutal tyl+r. th.+/ crn Isr ~.aK r.rlrtl w+lh tclet+vcly mt rc•+.tvl tit ttrt rca.cJ rrtk% tit .+ hr.t n mJcvrJu.+l 7
Page 6: avr30a00
(4) 7Ih7 lYerd Jor Accurer•y o/ I/nro 7he nceJ hx accurac'y of data r% such a hasic scrcntrfic prcccpt that it scrmt Rrrtuitrrus trr stite it-and yet it has sr+ rdtcn been uvcrhwrkcd in studies in Ihe smr k inR and health field that it must cuntinually be emphasizcd Often, in epidrmir,ltsgical studies rm large human populations of in birr clinical studres with individual human subjccts, it is tinrply nrrl feasible to nf,lain clala of tht desired accuracy. Thcre are ohvirrus ethical and practical Innits tn the estent to which human bchaviur can he crrntrolkd or human bcinss suhjccted to esperimental prrrccdures. This intrinsic limi- lation in research design does not, however, alter the resprrnsihility to apply rigrvous standards anJ to set careful limits on the intcrprc.atinn of the resulting dala Problems of this scsrt of particular pertinence are the limitations of pent Mrc classificatiixr (e If , as in death certificatrs) as cnmpared lo direct obxrvatrnn (e g , antopsy ); Ihe culkclicxs of data by trained persrsnncl whose accuracy and reliability pf obscrva1/tN1 have bcen estahhshcd by the usual uicntific prncedures; the lailure in statistical analysis Io takc account of many uncontrolled variables A parlicular problem in the currcnt slscc'trum of research on smoking and health is the lack of intert.ive, direct longitudinal study of various types of smaller f+rrpulatirrns asscrnhlcd and cr+ntnslled, mcasured, tested and oAsetved frx the origin anJ development rtf chanRet in physiological processes of pcnsihle significance as precursors to, or steps in, the origin .nd development of chronic disease Such studics require hmR tcrnr eflurt by highly trained personnel ancl they are ctxtly; yet the urder of accuracy of data frnm such effrxts is likely to make them much more important than further repetition of less esact types of studira Fufure Research There are several ways in which the main lines of future research may he listed and discussed Nut nrr malter in whal way this is (fomc it shrruW he remembcred that many uverlapping and inter-relatcd Io,mct and problems will cross the h.wndanes within any attempted clas.ilicvtirm At the present The ('snrncil frw Tuhacca Rescarch is esl.eciAly con- ccrrsed with the initiation and supfwrrt of rescar.h under the hrlhrwing broad headings A More direct observational clinical pathrrlrrgic studics rrf special cr+ntrolkd pr.f+ulations It Iscflrulr.,n •nd evaluati,m r.f rnr'lluwls of t,ruassiy ha whwdr unoke and rt% pr-.ducts, mslu linK chcnnial analyti% of snurkc I t (' I:pidemiologic and statistical :nalysis of nrorbiddy and mortality data. I) Study of psychophysiological differences as host facturs of pn- tential importance. A. l'Unicaf-P.rhologlcd StrdJe. Hack of any eBorts to devise and develop better and mrrre meaningful research in this field lie certain factual observations of detcrrninative value I.ung cancer is a rare discasc. Of those who have never smoked, a very snrall fraction develops lung cancer; smoking is nnl a necessary precursor to the discase Of even the hcaviest sntokcrs bWh in amount and in duration rrl the habit only a very small fractirm develop lung cancer. ()ne prrrhlcm therefore is to discover what characlerislics (chcmical, physiulugkal or psycho emotional ) the people have who develop lung cancer, both srnrrkers and non srnokers, which other individuals do not 'Ilsis utvulvts a type of dtrecl, observational clinical study utilizing tests and analysis of indtvid uals over ksnt periods of time. There are many ways in which new and more promising studics may !x set up. For esampk, if certain conttcslkd prspulatiuns in large medical centers could be under frequent direct observation and tests, clues tu significant factors in the origin of constitutional or chronic disease such as cancer, cardiovascular disease or chronic rrspira/ory disease might well emcrge. A pikN study along these lines is already in progress. It may he necessary to focus the attention of any such particular espanded clinical study on one or two objectives chosen from the following: lung cancer, cardiuvascular diseases, chronic respiratory diseases, psycho- emolinnal types Wherever possible, however, data on all of the major problems should be gathered. It should also be noted that the use of twins involving a comparison of identical and nexs-ieknlieal pairs is a valuable technique which has not been used nearly to the nptimum rkgree. Various factors as to which data are already availahlr in epidemio- lugical studics should also be borne in mind and shrruld he inclurkd wherevrr the prospect of obtaining pertinent and valid daln +rcros RrKKI AnurnR Ilsete m•ry be listed history of previous lung infcclions, inhalalirm vs mMr inhalation, family history of rnruhidity and mortalily, ru-cupatiuoal hazards, etc. It. I)rfinJtir-n ond F:r-nfuntlon o/ MNhodt of llloe..ny :nnrr yrars .rt- the (li.tingurthed bira'hernitt I)r A 1 IlrraKrn Smn stated lu the ti.icrHrtic Advrsrny Ifreard to the 'luhaccu IndusJry Kcscurh 9 ©
Page 7: avr30a00
(lonumttce thal istd,rtir+n uf nlrnttti:rhlc chcmtc.rls frtim tuhactr( snurke and itt Jcriv.rtives wtwlJ not hc J Ifitult Ilc lurthcr rcmerlcd th.tl Ihc Imrlenti:J nurnhcr nI suth thcmrcals wuu1J be great anJ that the real luttrht-auan trf chcmnal /ratuunttum uf smtrkc is the vahJily :utJ aphhcahrlrry ru nun td the rnctMrl of rtxthtxlt tJ hruassay utcJ in measunng the phyutdtrgn.rl cflects of Ihe.c vatious suhslanccs as they appear in u,haccrr srntrlc. KnnwlcJgc td thenriaal compositinn and physical prtyr•rnes iuf srnuke it in fact vcry rnuch more advanced than the techniques lur hirtingical ssay of /t+r evaluation of the eRects of Ihc suhstanccs un living aninrals. As assay techniques gradually are improved or Jcvised, including assays for measuring ptysible "carcinogenicily" by even scmi-quantitative nrelhtKls, our gcneral plan has been /iru to measure over all cflccts n/ whole snntke and then. whcn a Istnsihly significant hitdr1n.d cffccl hrs Ixen Jcte.teJ, tu trace it Itr thc specific suhstanccs ur prtKxrtict that may hr reslwmsrhac for it 'T hc sINN hrhl of emhhasit has thcrclurc Irccn cunsistcntly tar Inuingy ralhcr than tin chrmittry In actr+rJ with this gencralplan, frw etample, 'The ('unncil has cnn- ccnlratrJ much mnre altcnlitrn upon the tcst and trial of systems ftrr cvaluaring thc Nnsrhlc cartmoKcnrcily nl whole smoke nr uf smukc con- dcnsatcs prcp.rrcJ undcr vcry c,refully Jrfinctl and rcprtrtlticrhlc cnndi- litrns, than ul+nn the nnt.ruon anJ rJcntih, auom nf suth hrssvhlc inFrcdicnts as ppdynutlc.r hytlrrKarlunrs Whrlc scvcral hyJrtxarhrmt elf this clats have been rJcnufecJ in crlrcurcly tm.i11 tr.urs ut tigarelle tnurkc hy in- vestigattxs unJcr trlher s(won.ur.hrl+. Ihrst rJcnuhtrturmt heve nul an.wered the htime qucstnrn whelhcr suth tratcs atr ahnve thc IhreshtrlJ of hiuhrgrcal srFndrtance undcr thc attuol tunddwun ul hum.tn life Ilcnce etrncenlratiun ulxon htuassay still cotnmarrJs attentarn tit a rnuch gteatcr degree Ihan does chemical analysis -Ihe Councd fur -Itthaccu Rcsearch plans tu ftrevs majtrr attention on critiquc and frank evaluation of Ihc prescntly uscJ mclhtrtls ul hnraasay. I here would seem In be certain ratnmal conclusiuns that can be drawn in the primary selection rtf nrcthrrls anJ assay 'Ihrcc td Ihcsc are as folluws: I Whcrcver possihlc, the nrpan trr fiauc which tihnwt p:tthngcnie changes in man should hc tlu targct tnK:rn ur listuc rn litc annrral uud 11 Whcrcvcr ptnsihlc, thc aKcnl of ayrntt .ucl.ctlcJ of ctud"gic•al ( athi ~cntc calracily in m:rn %huulJ IH ulqncrJ In .inim.tl% m 11hc s.rmc thnnical furut .s Ihjt rn whfth it is apLIicJ I,- m.ut, cg. whulc tnnolc t ( Ill Whcrcver possihle, the suspected agent or agents shuuW be applied to animals by the sarne route that it is applied ar man l his dtrcs not mean that other methods or assay may ntN tte t-x/ul trr valuablc 11 entphasites, however, that if comparistsns between animal cRperitncnth and man re to be made under the most valid and scientific cundilirtns which are attainabk, variables should be reduceJ to p minimum and similarities be increased to a maaimum. Though dilleretsces amung animal species tested will always prevent their simpk and direcl eatrapolalitro ttr humans. data gained through such tests certainly can aid understanding uf basic bitschcmical processcs and suggest clinical observations that should he made directly on humans. Whenever and wherever artificially isolated or prepared fractiuns or crrmptsnenls ur the naturally tsccurring form of a complea suspecletl agcnt are used to prove the physiological activity uf that agent certain princtples scent tu apldy: First; it must be shown that a similar isolatitm or chcmical process lu that which artificially protluces the Jerivalive, takes plate naturally in human snroktng. Results obtained with  rxsn-equivalcni Jcrivalive .rc clcarly ntq comparable to the actual problem in vivu. Second; it must he shown that any efiect of a prcp:rred derivative or component can be and is obtained by a less amount and by dtrsagc equivaknt lu of kss than that which actually challenges the hunun tissue Iligher cnn- centrations or larger doses rd the challenging nulerial create an entirely Jd(crcnt sel of circumstances biochemically spcaking, and Iherc/ure are nut cuntparahlc with or quantitatively transferable to the proltknr in humans. 7 hirJ; Ihe melhtxl of application or contact with the challenged tissue must Ite of Ihe same nature as the natural method of contact or applica- titrn in humans 71se eRecls of possible mechanical ur bitkhemical trauma in •a Jillctent e.perimental procedure must be recognized as variables not naturally tsccurring in man. If an eapcrimental target organ or tissue Jieerent from that of man is selected, the rcastxn for the choice must be stated and eultlaineJ Such factors as greater convenience, economy and other material advantages must Lc lrankly laced, evaluated and balanced againsl the scientific varia- hles and dilTerences involved Faeltxs of this sort have a slrnng frruttirul ahlsCal I'tcmalute or erroneuus cunclusitsns drawn humm isnsuunJ prcmi.es t:rn, huwcvcr, cunstitute a great ubstacle to Ihe search (ur Ihe truth Nu maller, IhcrcftNe, huw long nJ arduuus may I.e the rtrad ttt a lunfn•r cvahratirrn of mcthrxls of hinassay antPlu Ihe rlcvcl'qrmcnt of a trrunJ fHrsla•tlivc in thcir inlcr tclatiumhifrt, Ihat trraJ tntust l-c IravcltJ lhc ('tnmtil intcnds to du its Ix•sl tu see that this is /he case' II I (1
Page 8: avr30a00
('. f p/rLntlurnRy and Sfnrl.ti.n! Annly.l. 11 is generally ctrnccdcJ scientrfically that cpidcmitdngtcal data cin mrutalrry are nrrt the h»is for dctcrrninmg the origin rd the drtica• es in which lrrhacco has hccn asscrtcd Io play a mle Such data will hc suhjcct trs continu- ing stuJy antf evalualirrn by "ilsc ('uuncil for I t.hacco Rcxarch and by othcr gcncies active in supprating laborato.y or clinical restarch Fnr esample, statistical findings have suggestcd future rescarch needs alung a numhcr of lines. I Methrals fur definite quantitative measurement rd rhe extcnl and dcgrcc of inhalation need to he devised in order tu facilitate the determination of the rnk. if .ny, which that pmcrss may play in any estimated or observed physirdrrgrcal activity uf smukc The presrnt "4ucstnrnnairc" rx "I+Crsonal opinusn" mcihrrl yd csti nruing the amuunt nf inhalatiun is mN as accrnate as would he uthcrs that can hc rkviuJ In such n impcxlanl issuc as the quantitatinn of the claimed effects of snsoking, the nrrst precise and imptrsrmal rrxahi.ls rd mcasurcmcnt which are avarleble are csscnlial to snund scrcnttfic cvaluatirm 2 It wrruld he imfw+rtanl to Jctcrrntnc any cumulattvc cllccts of ex- ppxurc Irt smrrkc and whcthcr accuntnlatitrn if any prrx'ccds at a study nJ nuthcrnaur.rlly f.rc.lntahlc ralc Studres ate tKing, and shrruld conlrnuc Irn ce, m.r 1c In hnJ whcthcr any "thrc.hrrld" rcla- litmship ctists 3 A mak csccss in inciikncc uf and in rnurtality frtrm must if not all respirattxy discases is particularly nlarkcd On what is this de- pendent? To what degree are cndrxrine factors involvcJ in Ihe genesis or ckvelcKsment of these diseases? 4 There is ample evidence that confusirm exists (in a witksprrad nnd quantitatively significant scale in mrxlality records because of failure to distinguish primary cancer of the lung frurn sccondary rw mctastalic canccr in the Iung Addrtirrnal crmfusinn csisls in that lung cancer is not ckarly distingui.hcd frum ulhcr h.lhological ksions which can Ise cnnfused with it These siluaur,ns must tx cnrrecled before an accur,rle piclure rrf causahve or crrntribulory factors in primary lung c:mccr can lK• uhlaincd S /1lthrwgh the actual numhcr rit dcaths frrtm lung cancer is irs- trcasmR hcrausc rrf Irrlrulrurm yr.rwth anJ hcrau~c rrf larger numlrrs rd Lrr,nn, rn thr hrphr-r •t•,r 1•rrwl,s, Ihr r.r. uf incrcasc in tl.f .Kt tnrrrrltd rk.lh r.ili- h.r, lac'n stnwtnK rl'.wrs %tntc 1V111 0 0 v t r*~ n , IZ U ,,, o , 1 his declining rate of incrcast, viewed in the light rd actual and per capita consumption of cigarettes during this pcrirKl, raises a serious question concerning the validity of the simple causation theory and dcmunstrates the need for continued study and observatiun. Undoubtedly new `roupinas of data, new types or techniques of analysis and indeed new typea of cootrolkd popslaliuns will suggest and develop other probkms of interest and importance for further investigaticsn lf the limitatic„ss of epidemiological research as well as its suggestive and stimulating value are kept in mind, increased activity in such studies will be an impurtant contributor to increase in knowkd6e. Il. P.yc/io-PAy.leloff" SrreHa. T here havt been eonsiderabk numbcn of studies in this field, all of which suppcxt the belief that snwrkers of diAerent types and rkarecs may dtflcr frexn each other and front non-ameskers in psycho physiuWrsksl characteristics reflected in habits of living. ('ertain ckments, inherenl in the nature of probkms of Ihis usrt, make their solutirns comples and difTseult, however. 71sis fact, while a rkterrent to undertaking research in the area, does not constitute a valid reason /ur neglecting to recognize the importance of tho topic or to take the steps necessary to its further analysis. A promising hypothesis is that types and degrees of smoking, as well as the practice of smoking versus nun-smukin6, are retkcliuns of characterislic reactions uf the individual in his adjustmenl to his life cnlrcricnce Scientific study based on this hypulhesis might find different categories rr! biucirernical, ncuroluKital, psychological, endocrine and emo(iwsal drives or needs which the individual experiences and which he Iries to satisfy or to control by one or more uus of, or abstinence from, a number of things such as lubacco, alcohrrl, a,ffce, trarsquilizers, esercise, narcotics and frKxl. Such study mitht also find that the heavy cigarette snsuker, the moderate smoker and the non- smuker will prove to he different in their psycho-physirrksgical characteristics, as the parallel groups under the other eatetories of re"msive hchavira lu life e.pericnce may also he. Personality analysis by queslirrnnaires rrr by lay interviews have been mark and these have pruvided kads which are suggestive and which nray be developed by more refined nsethcxls of research Uut it is unlikely that it will be sufficient to try to cnmpkte the analyris of probkms rrf psychrr physiu Ingical nature by Ihis usrt uf npinirm-baxJ evidcnce. In Ihe prrKCss of rktectins, recurding and sekclinR significant drfler- ences in ways that can be undersUKKI and analyzed, there are certain guides I3
Page 9: avr30a00
which may probably hc accehteJ frnnr the uutcet Atrcntinn shnulJ bt ftrcuscJ tus thc earlier statcs Itf individuel Jcvclopmtnt durmR whith the innatc charactcristics are easier 14) identify and ttr separate from those prtafuccJ by or largely tkl•entknt upon the strcin-ectrnurnic envirtmrsmcnl In this way rnc might t.c able to mcasurc and record various JcRrccs tt/ stahihty and in.tahdhy, aJjustmcnt and matadjustmcnt and control and lack of con- trol which might well devek>p into factors of great imptulancc for adults or atlnkst-cnts. II is interesting that rssnst physical anlhrtsruhtRical studies which attempt Itr ctnrclate morphology and psycho cmolianal traits have been ntatk on adults In the adult stage the tkteclirrn and measurement of the psycho emtNional category o/ traits is complicated by the invtdvtd, cumula- tive resfarnsc to all the cr.m(.kritics and changing elements uf the stx-in- ecnnnmic cnvirr.nmcnt that the indlvidual encuuntercd uvcr the years Such rescarch is usrful and interesting It would Lc much mnre so. hnwevcr, if a htumlatit+n of critical studics of thrldten and adoksccnts was built under It by future rescarch a An attempt sht,ulJ he made Iro, tn fiml and to study charactcristics whrth invnlvc clt+sc cnrrclatirrn rrf mcnl.tl tu ermtHirm.l hchaviur with variatrun in srrmc dcfinathlr: rnd nrr.ri,nr.rlrlc huKhcmic.fl rrr Ithysittlogical prrxcstt•s ( "rrlr /u.irrry llresc arc a few tr/ the nr.rnv vtrrnlrh, larrhkmt trr fht- trrntrtrntcd as the research conurnres rtn Ir~h.utrr u.r nnrl 1110111.101 hr.rhh Ihc Inhaccn Industry Rescarch Ctrmntillcc hes been an uhsirvcr anJ tnitintnr nf re- search in this field over the penrKl nf an entire decade lhe c.rcriencc gained during this period shtwld aid lhe Ctruncil ftst Tnhaccu Rcsearch-- U S A. as it carries on this irnfnrrtant work ('crtainly the research prob- kms to be faced arc diflicult -Thcy are the pruhknrs ptnt•d It+ medicine by the very nature of constitutional and chrnnic diseases llse etiology of these distases must he sought cwl .nJ idcnuficd amtmg 311 the lacturs Ihat ficct human health from the hr,l Irr the final decade trl thc human life span Iltrwevcr, thc nulhvrk fr+r a snlutinn Itr these mcdical ptr-tdcrns is mtae erscuuraRin6 ttaliy than it w.rs when thr lt+haccu InJu.uy Rcsearch (•umnrince was founded ten years ago New agencies havr jrrincd in the scicntrfsc cflrnt In unJcrslarsd /arrblcros rrl tnh;ttttr usc rnd hutuan health Ritcnlly rhe Amrrican MrJtc.l n%.rr i.tttrrn amtrrrrncrrl a rnulrr rnrlhrm Jnll.rr /r.r.nr h t/L-,r Ihr I rrlrr.r1 (irrvnnnrrnl r. rttr.rnrhny rr+ -rwrt .ulr1.nn1 rd tr-r rri Ir rrr rtu% rrr.r I1hr rr is rvrrV rr.rtrrn In F.chcve Ihel I hc Ctrurnttl fnt 1,•1 Ir, I II\ \„rll N. •rlrl. Irr -rlvr.rlc .nrrl t•Ilrttrvcly c'rr tn t urdinatc its proRram of research with thosc of other intcrc.tctl aRcncics Thc result can only be an increase in medical knowkdgc which nuy resolve questions regarding lubacco use as well as increase 1hc Ihcrrlreuuc and ptc ventative resources of human medicine itself.
Page 10: avr30a00
i i Researc•h Finclings The Tobacco Induslry Research Committee was formally organiud 10 years ago to create a pragram of rescatch into fundamental health prohkms. The program was espected specifically to develop facts regarding the effects r.r tobacco use A panel or ycientnts and physicians agreed to serve as a Scientific Advisory Board to the Committee, est.hlrshing pl+licy, lkfining problems, seeking investigators well qualiAed to attack such prohkms, receiving appli- calilms lot `rants and selecting those which the &rard approved for the award of research funds. The Committee has not attempted to devek><+ any laboratory facilities of its own It was dctermirsed al the outset thal the research of the ('ommittee would he accomplished through  program of pants in •id to inikpendent researchers working in their own institutions. 'Ihe ('osssmittce's Ixrlicks .nd activitics have continued under its recent rcdrsignalilra as The I'lwncil for -1'ahacco Research U S A, a After s decade of support of research it secros appropriate to review some of the scientific findrngs that have been rn.de TTirough the end of 1963 Ithe Scientific Advisory Hoard recommended almost S(K) grants for rescarch sturlres and 7hc Clrurx'rl has in turn made awards totaling s6.o]g,0U0 The actual output resulting from The ('ouncil's program has taken the form df scientific papers and repixts published by individual investigaton in medical and scientific jewrnals. To date such publications have reached a total of more than 350 reports It ia to these rcplrrts Tlse Counci. must turn in attempting to evaluate the accomplishments o( its prognm. ()( ecwrse, it is impossibk to list sll of the achievements or'Tlu Council's research Flowever, this review will attempt to cite some significant illuslra- Iive esamples. Rinoaaoy /or TumoriRrnic Action A major difficulty with attempting to deduce a causal uHSnectioo from the stulistical asslKiati/M betwcen cigarette smoking and the incidence of various tylres of caneer, especially cucrnlrma u/ the lung, is that there are a number of other rsonrausal reasrms for ,bc esistence lsf such an associa• liun which can he postulater) nd rnutt he eullurkd bcfure ny final judg- mcrrt can be rcached Suur rhr trmlrkal rtlrlarialr.ry hyl..,rhrait rviyinally adv.ncrd was Itre I,.~.~~lul~lv rh., r i~J-.n,.' tn- lr nupLl he.r - t.vilv a% a rtnrrl tnnlaet ear,-..'r- • t.r y. n.n..l., r..f h.n~ 1., , " %L-ni"n1 .1 rn the eflrrrt Ilr develop reliah(e and yuantitative mcth/k1s for assessing such possible activity in clsmparislxl with that of uthcl substances and nsistures that are common in the environment and whose lumorijenic action is known. I. A survey of mechanical smoking devices was made and conditiuos de- fined under which a relatively uniform cigarette smoke condensate could be made reproducibly. The conditions were so specified as to fall within the range under which normal smoke is produced by human cigarette smokers insofar as poasibk. Inattention by previous workers to the importance of combustion conditions to the chemical composition and biological activity of smoke condensates may have vitiated Ihe results o/ many other earlier investigators. 2. Painting of smoke condensates from commercial cigarettes and frnm cigar tobaccos and pipe tobaccos smoked in cigarette form on the skins of mice has shown that their relative activities are inconsistent with the statistical association between cancer incidence and the smoking of cigarettes, pipes and cigars. Moreover, the high dosages of smoke con- densales required in these esperirtsents, nd the nearly life-long treat- mcnl periods required fot minimal tumor production, attest to the weakness of the activity of all such preparations and raise doubts as to whether normal human smoking could ever produce a dosage such as to elicit this type of action. 3. The painting or feeding of potent earcinornic rubstarsces has been shown to increase the tolerance of mice to transplanted tumon or normal skin from other mouse sarsins, which transplants would be rejected in the at.scnee of this pretreatment. This response could be related quantitatively to the dosage of carcinogenic substance and (hw used as a hioassay tool. Standard cigarette smoke condensates tested by this method were inactive. 4. It had previously been shown that several carcinogenic substances in- jected intravenously into certain mice would produce lung adenomu in numbers that were a simple function of the dose of carcinogen given. These results were confirmed In a study sponsored by The Council -ihcn standard cigarette smoke eondensales, freed rrom alkallrids so /hat they could he given intravenously in large doses, were administered in the same manner to Ihe same straln of ndce. No increase in the numbcr of lung adenomas was observed. S A one cell animal, poromrciunt touJoru.n, has been shown to he rapidly killed by esplrsure tu ultravilrkt light after overn(Kht contact with many carcinogenic suhsunces of Ihe prdynuclear. hydrocarbon family in estremely small cl+ncenlratinn. ('ltuncil projects have re- 17
Page 11: avr30a00
I I I I m n L studied this methrKl e.tensivcly to refine it and develop masimunt control ot variahks Preliminary nxasurcmenls with tobacco smuke cnnrknsates have shown no lethal action fur normal smoke. A Several studics in which roicc ul various s,rains were suhjccled Io in- halaliras of cigarette smoke al frequent intervals during their wholc life span have failcJ to produce carcinoma of the lung Srmu inflammatory chanRes were fuund, rather erratically, armong the treated mice, nd these were accompanied by various degrees of tissue change. Such changcs wcrc, however, reversible if esfxnure was discontinued at any point, and never proceeded to invasivc carcinoma even if caposure was continued 7 V1ru/ InfKlNxn of the lungs of such mice were found tn produce much rnrrre cxtcnsrve histr.patlx.ksgical eflects than simple smrrke rnhalalion. Virus infection followed by k~sR term cigarette smokc inhalalirxr pro- duicd such cflccts more frrqurNly and at hrRhcr kvrls. but wrlhuul prorhrcurrn of canccr R ('onJenutes rr/ tohaccn imrrkc introduced into the IunRs of several animal species in the form of s.Autirms or suspensinns so that dosagcs wcrc hrRhcr rhan by inhal.ur+n of nornial smoke have also failed to prixluce carcinoma of the lung 9 II has long been known th.rt IcrJmR urcthane to slrain A mice by moulh will prrKluic pulnurnety lunuas AJ Irtnrn of nrcrHine, smoke conrknsatcr rr Iohatcn snnrkr inh.latirin wa found in aCrsuncil study not to enhancc Ilus cflcct A further study diuvrvcrcJ that the vitamin niacin has a dcfrnsive action aR.iinst the urethane tumor production eflccl and that more tumurs arr ptrkluccJ in niacin deficient animals. I luwevcr, even in niacin Jeficrrnt nunals the inhalation (if tobacco smoke JiJ not increase 1hc prrKlucliun of pulrurrnary tumors following urethane fceding. Ill SpraRuc hawky male rals, fcd dicls containing 2•acelylaminr+fluorcne and also exposed to ciRarctte srnnke inhalaliun or injccted with a to- bacco smuke cnnrknsate in T.canut uil, exf+ericnced a delay in tle devel- cpnxnl of liver clunRes thal re considered to he indicative of a pre- canceroua statc (Rrrrss liver darn.rrc and hrwcrinR rrf rihuflavin c.rntrnl) Another conrknsate, preparrrl hy Ihe stanJarrlizrJ metMwl refrrred to clscwhcrc, did nM aflcct cithcr thr rate rd carrcrr inductiun rsr the final tumur incirknce in rals fed eNhr r 1 ucrlyl.rrnnusfluurenc or V methyl 4 dimrthyl amino I I It has hcrn shuwn Ih.rt vnall J~~~cs of r hrmical carcinrryrm, which at,mr wrruld nnt /+rrwluce canccrs, will Ju sn when mjrctcd intu mnlc Swia nu'c .IonR with .111311 rhr%c% rrf ccrlain crunnum viruscs, whirh IR r i also du not produce cancer alone. The invcstigalor showed that a com- binatwm occurs between the virus and the chcnrical substancc and pos- tulatcJ that the virus was able to carry the chenrical into the interior of the cell Immunizalirm rd the animals against the viruses prevented the cancer production IilTrals to show a similar binding between Ihcse viruses and cigarette smoke condensate were unsuccessful. 12. Study of the sebacrnus gland suppression in mouse skin by lwdynuclear hydrocarbons has shown that the usefulness of this phenomenon for bioassay purposes is limited by the occurrence of false positive and false negative reactions and by its rclalive insensitivity to small changes in conccntration or activity of the substances tested. 13, Cigarette smoke corsdcnsates in solution were applied to the cervia and upper vaginal area nf rnore than 200 DBA-1 mice. Thirty one percent of mice painted twice weekly developed tumors. The solvent applied alone at a similar dosage was followed by tumors in (+0% of the mice and treatment with a dry uslton applicator by tumors in 42 R96 , 14 Animal and human lung cells have been successfully maintained in tissue cultures by several Council grantces as a basis for devctopment of other possible methcx)s of bioassay. In tissue culture form, human cellular material can be used for testing. Satisfactory and interpretable methods for using such human cell material as a bioassay system for carcinogenicity have still to be developed. 15. A number of other ptsssibk bioassay systems have been tried or arc under study with various deErees of success cx promise. The overall impression gained from these many birrassay studies Is that tobacco smoke is inactive or of extremely minute activity in these several artificial syrlems, ncsne of which of course actually measures hunran response under realistic conditions. lhc results lend little to support the hypothcsis that cigarette smoke can act as a direct contact carcinogen in the human lung Study is continuing with respect to other hyptNhrlically prrssihlc motles of aclirsn. (:ilirrry At•tirity vnd A/ur-ru F'Iotu A('rHmcil study undcrl.wk to evaluate thc relative irnfwrtance of the aclivNy a/ rlhr crG. in tlre trrlal machinery uf lung ck•urance in intacl anirnah since it haJ bern reyxrrlcd that cigarette srnokc, like many ulhcr gases anJ aerrnuls, dimmishcd the aclivily uf these hair like aplsenJ.rKes which cuat rhe upper rr•spirraay Iract and whKh normally propel upward the hlankcl of mucus whrch carrics inhaled dusl anJ Jchris nul of the IunR anJ it haJ been sugXesleJ Ih.u Jcbyed clmrin:rtiun rd inh.rlcd dusl and dcl.ris, cuntain- 19
Page 12: avr30a00
ing carcinogenic matcrial from any source, nught conccivahly increase the barard of lung carcinoma Twrs other mcchamsms of clearance operatc in addition to the rnk played by mucus flow. ( I) engulfmcnt of debris by roving phagexytes, ( 2) ahstMption of substances into the blrHKl stream which carries them to the liver where dNo.ifscatitrn nsechanisnrs are ctive. A nxthed of measuring rates of overall ekarance of radir,activity ul{ged dutta from the lungt of intact rabbits showed that inhalatitxs of cigarette smoke bad no measurable cffccl on total clearance rate Hence if one clearance mechanism wat slowed by smoke ttposurt, another must have been speeded eomnxnsurately, even though the internal bal.nce among the mechanisms may have been altered 1 his study was recently completed and has not been publuhed. While several investigators have apparently cnnfirnxd the activity of cigarette smoke in dcpressinR cilrary motility in isr.lated Ussrx from several animal tpecies, nd have Iraced this activity to specific coml+rrnents of the snw.ke, it ppears quite uncertain at present whether the depressirsn of ciliary activity can play any sigrificant role, even indirectly, in the cnmplert pattern of lung pathogenesis Lung l'rtfhultrRy .Sf t.rlir•s In IOS1, Thc ('ouncil sptmtr,rcd a tkscriptivc study of human lung pathology in which twelve pathnh,gish in drflerent locatinns, both urban and rural, participated About 3(Mtt) lungs of patients coming routinely to autopsy were investigated, yielding 8,590 sections from males and 3,1+61 from femaks. llx study illustrated many drfticuhies in defining histnpatho- logical changes and in interpreting their ptxsrble signhcance in relation to malignant discasc. "('arcinoma-in-situ" was diagnosed in only seven cases and these were 11 patients with lung cancer. Snnre degree of hypcrplasia occurred rather more frequently in smokers than in nnn smukers hut this type nf ksion was commrm M,Ih amung cancer cases and among non-cancer control cases and was even more cittcnsivc in the trachea where cancer rarely txcurs "1 he type of lesion ( alypical metaplasia ) nlhcr than the /umtsr itself nxrst frer)ucntly found in the lungs r,f Iung cancer palrrnts was not mtxc frequenl in snx+kers Ihan amnnf, nrm srnrAcrs I'nrdiuvosr-ulnr Rrswnr-lr l ihc /'r,un, il f,at alli.t.,r,•d a subsl.nlr.J 111.1111% fun,l G,r Nudym/ I1,c c:u,l,,,vas<utar syNcm rrm hulih .rn l,h.ca.c Jnil f,n invcstigalune :rny shurl of InnR Icrm clfr, rs nf sn,,,kmg anil ,d ru„H,nc nl„m Ihis systcru i I. A long series of pharmaco{otic studies has described the mechanisms of nicotine's action on the nervous systesn, espteiaUy at ttre synapses. 2. A comprehensive series of studies o1.ico(ine metabolism has identified nd described nrany of the pidducts into whieh the alkaloid -u rapidly converted by the mammalian body irstluding esan. The rapid conversion of nicotine into (-)colinine, a relatively inactive subslanee whkb tetsds to relax the vascular muscles, helps esplain the relatively transient and non-cumutative character of many nicotine eReds. 3. Nicotine was formerly regarded by many as a pretsor substance, that is, as an agent that constricts the blood vessels and raises blood pressure. More detailed studies sponsored by The ('ouocil have shown that coo- ttriclion of vessels is usually confined to Ihose in the sAin of the ea- /remities, thtwRh so.ne individuals show an opposile reaction. Eilood flow in the skeletal muscles is generally Increased by nkrwine !•luw in the cerebral circulation is unaffected by normal doses. Most impot- tantly perhaps. the fbw of blood in the coronary arteries is increased by nicotine in normal persons, while the work of the heart muscle is gently stimulated as by mild eaercise. In the presence of sclerotic disease of the arteries, this normal eapansion may not be able to occur. 4. Studies with a new instrument called a vibroeardio6raph have shown that the overall effect of nicotine is closely analogous to that of mild eserTise. 5. It has been shown that persons engaged in stressful occupations have a greater incidence of cardiovascular disease than persons engaged in similar but less stressful ones Assson6 these, the persons who discon- linued smoking had much less heart disease Ihan those who had never smoked These results are beuer in accord with the hyptrthesis that per- sons under stress find relief through smoking than with the hypothesis that smoking causes, aggravates nr precipitates disease. llte particularly low incitknt:e among stopped smnkert seems to reflect  seiection, in this grnup, of persons who are able to adapl relatively well to stress and Is inconsistent with the idea Ihal nicotine could esert any cumulative pharmacologic effect. 6. lesls of anirnals with diels conducive to arterial srlcrrrsis have failed trr show with added nicotine any significant or consistent effect of the nicotine in acceleraling tx ggravaling the disease process 7 Studies of hurnan suhjecls by a tarRe haltery of physiological and psy t hrrL,Rit•al tcsrt have shown that tsealthy younR men give patcrn rrf res(.rrnac. Ihal cr,rrclatc with rhe rK-currencc of certain cardi„vascular diseases arnang their ancestors 1Tese patterns of reslwrnac arc con- sidercd tn he indicative of predisposition tn such discases, since these 21 ?(1
Page 13: avr30a00
tend to "run in families " Young men with these patterns of response are aIur more likely to be cigarette smokers 7 hese studies therefore suggest that hereditary predisposition to certain cardiovascular diseases i. Iso associatcd, non-tausally, with cigarette smoking as a matter of constitutioa. d In additicxr, a large number of studies have contributed to basic knowl- edge of hc.rt function, physiolo`y, metabrrlisnr, biochcmistry and re- sponse to drugs, without direct and immediate relevance tu tobacco or nKot n1e. 0(kse trcrop of scientists has shown that healthy persons wt,o show an alkrgic .kin sensitivity to tobacco esUacta are likely also to show stronger effects of smoking upon skin surface temperatures or blood flow in the skin or muscle of the estremitics 7Txse acicntists have there- kxe suWsted that certain tobacco eficch. especially uprtn the eardio- vascular aystem, are due to specific allergic susceptibility of particular individua)s rather than being Reneral pharmacological responses. 10 Smoking (twociavettes) Ilas been found to produce an elevation in the free fatty acids in the blood strum 'This rise was higher in persons with history of hcart discase th.n in normals lhis kind of response is eon- aidered to he a normal reaction to any stress that releases eateehola- mines, which nicotine in ukyuate dtnes is known to do The esaRger- ated response by heart paucnts may rcflctl their constitutional difler- ence frmm normal persons 11. In normal populations (ercludinR hypcrtensivcs), no differences in reatinR blood pressure were found hctwccn smokcrs and non smokers In broader studies nf workinR prTulatirxu, smoking was assruiated with lower systolic and diastolic pressures. No evitknce for large or important differences in circulatory reac- tivity hetween aroups of hahitual smokers and non-smokers was found I.ittk evidence of deterioration of cardiovascular "fitness" was seen in smokers pcrforrninR work Icsts 12 Hy means of moving picture s ray photographs following injection of a radioopayue substance into an artery nf the arm, it has been pr»sible to make visihk the flnw rrf hlrxrl in the arterics nf the hrain ('igaretle smokinR imrnediatriy prior 11) The phfrl,.Praphy nnrnrally increases blrxxt flrrw in the cerchral t ivculatinn lhis rllrcl is au-rrt.rd Irntativcly to carMut di<rsidc in the smnlc hut Iwr~srhlc nutrtinc cflctts are undcr tluily 11 Ilr au.r rlrvalyd kvrls of M-1 ih-drtrrr~~l have hrrn rrl-rtrd to I-r aurxraLtd wuh card„rv.,uul.re rh•raus. irveral ('rmnrrl sturhes have rni tu.k_l r.n Ihrs IiLa.I i nnrl-nrM It has t.trn thrrwn that I , age and ses influence the blood kvels, which also vary with the lahora- tory techniques used. The serum choksterol has a rather wide range of normal values which vary with season while chronically high values tend to run in families. Influenza infections were followed by sharp, transitory fall in this blood component but the cessaticxs of smoking by a small group of students was not followed by any such drop. Admin- istration of vitamin B,s did seem to {ower cholesterol. Most significant perhaps was The finding that cholesterol rose during times of emotional stress, as during ecamination periods for students. This finding has also been corroborated elsewhere under other auspices. In another study there was an indication that the distribution of cholesterol between alpha and beta lipoprdein fractions might differ between smokers and non-smoken. '[lsis difference seemed to pualkl differences in customary fal consumption between the two 6roups. This study, ursconfirsssed elsewhere, found an increased preference for fatty foods among smoken. A great deal of the work sponsored in this field by The Council was reported in a public symposium held at the New York Academy of Sciences on March 24, 25. 26. 1960 and published in a monograph entitled, ('urdlo- varcufar F.#ects of Nicotine nnd SrnoAint. (Annals of the New York Aca- demy of Sciences, 90. Art. 1, pages 1-341. September 27. 196() ) Thou6h many transient effects have been more fully measured and de- scribed in our pre>Rram, no evidence of any significant contribution by smoking or nicotine to causaliexr, aggavaliexs or precipitalion of any cardio- vascular disease that contributes importantly to mortality has emerged. f.ll ronTc Respiratory l)lseoses In the study of such chronic diseases as the various forms of bronchitis, asthma nd emphysema, primary problems remain in defining the various clinical entities, in developing reliable methtxfs for differential diagnosis and in studying the natural history of development of each individual disease Solution rd these prohlems would contribute materially to development of mrxe rncaninR/ul epidcmir>to`ical studies for relative evaluation uf environ- menlal and iMrinsic factors in their etinhrRy. 'I he ('trune tl has, nevertheless, sponsored a numl.cr of studies that crm tribute tuward untkrstandinR of these diseascs. 1. A scan hinR patMdngicsl study of crnphyscmatous lungs has improved the diflerentialinn among several forms of cmphysenu, has contributed to their careful description and has recnrdcd several types rrf collateral 23 22
Page 14: avr30a00
r 1 changea that occur in consequence of or in parallel witb the emphyse- .oatoua condition. 2 A series of studies has been spnnsnred to dcsuit.c better the breathing mechanica of both norrnsl peruxn and those with various chronic lung disease and to improve metbods for mcasurint the several .spccb of lung functioa. 3. Using these metboda of teeaauri.g lung functioo, the effects of smoking both in normal wbjccts and palients have been tneatured in several different cceters. C'igarelte smoke inhalation has been shown to produce a mild coeatriction o/ the brsxschi, in most perscxu, which lasts from 10 to 80 minutes. This is not due to nicotine or any other volatile sub- stance and can be prevental by several drugs. In uwne studies, habitual smokers showed reduced "vital capacity" and increased "rcsidual lung volume" but the dificreocc was not slatis- tically significant ie all Patients with severe emphysema generally rhrrwed decreases in arseri.l blood nsygcn saturation after sr.urking but this drd not occur in norrAals rx those with mild emphysema. Mechan- ical resistance in breathing and increased work o/ breathinK were ob- served in paticnts with cmphyscma and bronchitic diseases a/ter smnk ing 4. A Irxrg terni clinical stutly ul rhrginrc rr.piratnry drtust patients is bcing suplxrNcJ by 1}ht ( r-unid in iidl,rl-rehon with uthrr granling agencies lhis has resultcd in scvcral Irntitrvc tlchnnUr+ns rrf Ihc lung diseases and in clmK i) mrtMwls rrf drtlcrenlial diagnusis which are under trial It u too early tu judge whcthrr these dcfimtions and diag- ocsaic nxthoAs will be fully validated by eapericncc, will undergo furtber rswdificatitxs, ex will gain general acceptance. S. Another long-term clinical pilot study has begun in which patients will be folkrwed for a number of ycars with repetitive Iests and funclion exasurements succtakd ultimately by detailed pathological examina- tion of the lungs, pmt mortem Our hope is that the comparisrm of fuocliom tests during life with the condition of the lungs found ftcr decease will help to illuminate Ihe rclatirrn between syrnptnms and pathnlogical changes of variuus types (IIr•rr tittnlirs Whik a stalislic.l asuK iath.,n hclwrrn r,r..rctte smrrkinR anrl mr+rtality (rurn lwl+trc ut.rr hat l.crn rrlMntrd, tt rt not rlcrr Irorn tl-c slatustical rc- laiwn aLnrr whrthrr srnnlrnR t"ntnhutct Irr the cUnluRy or agRravatirNl ,d I.r l,r,, .I, ,, ..r +h, rhr r. n, r 1. I.r,uh , r rt a dnca.c .fllictrnR ccrtain ,y u 0 0 0 N 7 tcmpermental types of persons, the kinds of people most likely to devchrp peptic ulcer are also inclined to seek relief from anaictics and frustrations by smoking. 'Ihe ('nuncil has sponsored a series of studies to determine whether smoking would affect any of the physiological reactions that arc believed by many clinicians to play a part in uker production, particularly the hyper-secretion of acid by the stomach. The effccb of cigarette smoking on patients with and without a history of duodenal uker were studied with respect to volume of gastric secretinn, hydrogen-irsn concenlration, "free-acid;" pepsin concentraliras and cwlput, uropcpsin, plasma pcpsinogen, dissolved gastric mucina, viscosity of gastric juice, intragasrric balloon pressure and inlrogastric temperature. No signifi- cant diRerenccs were frwnd in any of these responses between normal persons nd uker patients. Smoking just before cx during measurements produced no significant change either in normals or uker patients except in the case of plasma pepsinogen which was decreased to a small degree. 'il+e absence of significanl physiological responses to smoking in these areas tends to knd suppurl to the concepl that ulcer prune persons seem nrNe likely than others to srnrrke cigarettes. Efforss to describe the uker- prone individual in terms of biochemical and psychological characteristics are continuing. StnokinR and Rody Weight In a('ouncil study comparisons of cigarette smokers and non-smoken in a middk-aged group of business men have shown that the nrm-snsoken tend to be heavier than the smokers Individuals who wAuntarily slopped smoking without having any illncss which prompted them to do so or without adopting ny other special regimen of living, showed a substantial gain in weight within the ensuing two-year period. The roean gain was g 2 pounds. Overweight is itself associated statistically with increased risk of certain diseases. The increased weight of non-smokers and stopped smnkers would seem to mcrit further evaluation as a potential health risk. Ifirth WrJRhI of Infants A('ouncil rprrnsnred study of 16,226 cases in three diRerent typea of hospitals caphNCd reports nf a lower average birth weight rra in/ants a( rnrdhers whn srnnked during preRnarx•y as crrmpared to thrnc (if nudhcrs whu refrained Inrm srnnking during t)se prenatal petind In a private hrnpilal and a hrrme /or unwcd mothcrs, the hirth weights of the infants of smrrking mnlhers were lower than those of nnn smuking rrxrthers (thuuKh varying considcrably from year to year in sonic grrwps), but there was rur signi6-
Page 15: avr30a00
I i cant diflcrence in the rates trf strlihirth. Axrrliun ur birth cumplicatiuns. Among the patients of a charrty huspnal serving low income patients, the birth weight difference was vcry snrall and still no significant difierence occurred in slrllhirlh, stxtrlNrrs rrr cnrnphcations between the groups Only in the home fnr unwed mothcrs was the prematurity rate significantly higher amextg infants of smoking mrahen Race was mnre strongly related to birth weight than snrnking I)ahies uf negro mrrthcrs were lighter in weight than babks of white mtrthers and this statistical rcl:rtiumhip was stronger than that between sn,oking and birth weight 1'sychrr-PftysirrlrrRir•rrl SttrrliPa A key probkm that pervades the whole effort In sludy smoking and health is the question whether the types ol persons who choose to smoke cigarettes are hasically different in cnnstitutron, persnnahty nr life patterns from tyl.es who cMxne not ta smrrke thenr Such hasic differences might themselves infiuence life etpecuncy and suscepUbihty to drsease. A series of studies have bcen sponsored by The Council ar  beginning toward solving the compkt problem of inherent differences between non- smokers and smokers of various types 1 Pxtensive data on 252 selected college men collected over a twenty- year period showed sip+ificant differences in physique, physinlogy, career selection, and personality between nrsn-smokers and heavy eig- 'arrtte smoken The smokers slso tcntkd to marry and change jobs more often, to indulge more in the use of coffee and alashol, to lose weight over the yean and to show more testkss energy, more extrover- sion, and greater social gregariousness. 2. Two anthropometric studies of this and another group showed differ- ences in prevailing body types among heavy cigarette smokers and non- smokers as well as difTerences between these and pipe or cigar smokers. SntokinR and l'rutein INeta6ulient Reptxts that nicotine has an effect trn protein mrtabnlivn in tlre rat h:rvc prrrmptrd lhe ('nunt il Nr slMrnsur hum:rn.tuJies un hrrAcrrn rnrt:dMdism I-rndinf.s indreate that smrrkmit, can anmcwtut rcducr the iv.rlehrFhty of inr,c.IrJ prnrrin as indicatrd by Ihe FhIrMMI ICVCIs 401 scvrr.rl amrnrr .arJ. At Ilrr prrsrnl, nir clmical srRnfitance is alt.rthrJ nr tlns rllr t..Irrn thrre is n„rnr.rl I'r"rrrn and ral,rri rnt.rlr r Meiuuretrnent of /nRalatian Since there are many evidenees that smokers cannot judge reliably the extent to which they inhale cigarette smoke or report this accurately on questionnaires, several studies have been undenakeo to dcvek+p methods of measuring "physiological smoke exposure" by determining indicator sub- stances in blood and urine. Since there are smoke ingredients that are ab sortxd through the alveolar membranes but not through the oral and buccal area tissues. Ihese studies show encouraging progress. Belaavioral Effects o/ Smoking It has been shown at least in mice that nicotine tends to concentnte rapidly in the brain tissue shortly after absorption. A direct eRect on the central nervous system, described as an "arousal eRect" has been detected which is believed to be due to nicotine per x rather than mediated through catecholamines The consequences of this eReet on the kaming behavior and refkxes of animals are being studied with a view to throwing light on some of the responses that may underlie the human use of tobacco. to other studies in the arra of psycho-pharmacoktgy the effects of nicotine are being compared with those of various tranquiliurs and other "psycho-active" agents. Other Activities In addition to its program of gnnts-io-aid The Council has also sought during the past 10 years to encourage new research ideas and endeavors. To this end, The Council has convened a number of of1-the record con- ferences of scientists with common interests to review research progress and explore future needs. During the past 10 years, conferences have been held on problems such as: lung pathology, bio.ssay, and earcinogenesis, virology, cardiovascular diseases, atherosekrosis, effects of nictNine, cell and tissue culture, chronic lung diseases, psycho-physioksgical aspects of smoking. In additwtn, The Council has cooperated with other agencies in the planning and support of public symposia on topics pertinent to its interest. lltese public symposia have been published and widely disseminated for information of the scientific community and the general public ilre ('rwncil has recognbed tlse need, not only for .pecific researches rm dcfincd prtrbkms relevant to tobacco use and human health, but also for IIK traininR crf young scientists and physicians in research In urdcr In assist in nrccling this necd, lhe Council has annually nrade rvailahlc to every medical schrKd in the United States, a fcllowdtip for assisting at Icast one 27
Page 16: avr30a00
i degree candidate in each school to spend a summer term or other "b(1-term" in research under the direclion of a seniur aufl member No restrictioa of any kind hss been placed on the suhjects of study that can be elected by such pre doctoral fcllows A total of 640 such fclkowships have been awarded through 1%] In order tn make the vast scienlific lilersture on tobacco and its eliFoets more accessihk to invtstitaton, The Council sponsored a project for eolke- tirxr, evaluation and cnmpilaliou of weA material into a mcxu>lpaph A book titkd: "lobacco: E.perimeetal and Clinical Studies. A cnmprehernive Ac- count of Thc Wf1rW I.irerature,' by t.atson. Haas and Silvettc was publisheA by Williams and Wilkins ie 1961. It 6 900 p.ger in length and is based upon study of more than 6.000 articks published in about 1.200 journals Ihrouth- out the world As a collateral activily, these scientists hsve also produced a series of cnmp.chensivt, critical reviews oe a variety of specific sub}eeH. This activity is continuing in preparation of tuppkmeotary volumes for latcr publication I ' Abstracts of Reports Eiach recipient of a Rranl-in-aid from The Council for Tobacco Re- scrrth - 11 S A, is responsible for the initial presentation or publicalion rd the results rr/ his rescareh at scientific meetings or in appropriate scientific journals. E=ullowin6 sre abstracts, approved by the aulhas, of reseatch repor(s acknowlcdgin6 suppoA from lbe Coutxil, formerly the Tobacco Industry Research Committee, that have sppeared in scientific journals since pubh- calion of the 1962 Report of Ihe Scrcntific Director. These ahstracts have been grouped under the following headin6s: I. Carcinogenesis Studies. 11. Cardiovascular Studies. Ill. Studies at tlK ('ellular l,evel, IV. Pulmonary Physiology and Anatomy Studies. V Psychu- PhysioluRical Studies. VI Tobacco Chemisrry & Biochemistry Studies. VII PlurrnaculuRy Sludics, and V111. Other Sludies. 1. (:orr•inoRenesis Studies "IIOS"1- I'A("IORS INfLUENCING Tlil: BEIIAVI(1R (F SUIi('11- TANIiOl)S SARCUMAS INE)ll('Ia) BY ),4;9,1t1 1)INI:NTI'YRIiNl'. IN C 57 111./6 MI('E." By F. llomburscr, A. 7•re6cr, and 1. R Ifakcr, Itio- Research Inslitute, Cambrid6e, Mass. ('unrn Reieurch, Volume 23, Num- Ixr 9, pages 1539-1544. October 1963. ((Council grantee: Ilomburser) The rate of formation and behavior of subcutaneous fibrosucomas induced in C 57 BL/6 mice by sin6k hypodermic injeclions of SO(/ micro- Rr.ms of l,4 9,10-dibcnzpyrcnc in peanut oil are reproducible and predict- able. No mctaboliles n( the carcinogen were detected in escteta e><cepl im- mediutely following injection, when r;onx leakage may occur from the injection site. The rate of Gsrmatinn of tumors was lower in females than in maks, but it was independent of body weishl al the time of injection, subsequent growth, and (in males only) of age at time of injection. All tumors formed were transplantable fibrosarcomas, eon/ainina traces of carcinogen as far as 11se third transplant gerscr:rlion. (:ruwlh rates of the established tumors were cunstanl fra al.out two weeks, brd varied considerahly Ihereafler. Caloric reslricliun severe enoush to prevent significant weight gains during the induclirrn pcrirKl prolonged lutcnl umcs siynificantly throughout Ihe period u( lunwr dcvclrlpment. Sevcre caLonc rc.lnriouu mainlained fur 7,9 and 2) days, which re.ulred in nurkeJ wcrylq lussc., was wi/hnal msrked ellecl un Ihe Kruwlh rale rd urduceJ tumurs mca%unnR I im br di.rur,er Iluwever, thc survrvel /nnr of animals thrtstrcrlcd wr% sigmlicanlly pndunrcd. ln /T)r/1r• Rrnnr....: NatUOn:rl (:rnccr Inshtule, nnd Ihe Vny,inia an~l 1) K ` ~/ , uJw•r. I uurulnufnl 0 ' 0 "M(/tISI~ SKIN 1'AINIING W1I11 SM/lKl: ( UNt1UNSA1I:S I ROM ~fl (1) x U r (-I(iAltJ:l I I.S MAUI OI• PII'I., ('I(iAR, AN11 ( 1(;AI(1. 1 11: 'a()IIA('- 2V d
Page 17: avr30a00
(Y)S" Ily I: II,,n.hurRcr, A 1rcRcr, and ) R flakcr, Hrn Rcsearch Insti- tulc, (-amhri,IRc, Mass Inurnal nf rhr Nurrrrnul ('rnn er fnrrrtrdr. Vulumc 31, Number 6. pages 111S.11S9, (lccemha•r 196 1 (('uuncil grantec: Hom- burgcr) (;rnups (1f ('AF, mite nf both seses were suhjcctcd to skin painting Ihrrwghtlut their Irfctrmc with ctmtknsatcs of thc srnuke of cigarettes made uf pipe, cigar, and cigarette Itsbjccos, and with accirlne and benzo( a )pyrene. AII Ihc condensates caused skin papilksmas and up to 23 per cent epider- moid cancers 1 hcrc were slightly more cancers in femaks than in nuks. The formation of these ksions was shrwcr with cigarette smoke contknsate than with the nther two cnntknsatcs The acetone cuntrols showed no patho- logic changes Cotnbustitsn temperatures were practically the same 1nr all types of tobaccos The I 1)S11 (r/ these crlntknsatrs was lower for males than for fem.rks, ankil krwcr fur prlse smnke cun,krnate than ftu the tahcr two facept hm the shRhtly Rrcater trrrit;ry uf the prllc smnke contknsarc mamfcsted hy Rrcatt•r wcrghr Itns and mratrhty, ncvrc were nu drflcrcnces trl the systcrnic clfectt rd Ihc rr.nrknsates In Ihe rrsfrlnst td rnKC rn j1rlvtcrl sm.-4c cr.ntlensates, thcrc arc mnre CrMlrat]Kt1Unt 14, human rcattrr-nt Ihan rfx•rc arc sundantics Whcrras rnur- taltty data show a grratcr rnt Kk•ntc td lung cantcr rn men than in wtlmcn, the (cmak rnitc in this study rkvcl I~J slri!htly rnclre skin canccrs than the males tlx mKr skin systcm f.cars littlc resrmhlant'e tu the human lung as a IarRct tnRan hrr tuhattr/ sm.-1c t"nJ,nsatr Whdc il rcnranls a valuabk Irwl trw thc study rd tartrm-Kt n(s s, rl.,u Jcnvcrl frum it arr nnt drreclly applkahlc In the cvaluaturn of the v1;n htantr rr( rrsults tdtt.uncd by clinical statistics "CYTOI O<iI('AI. ANI) ('Y I(K III MI('A1. I:FI-H -1S (1F A(;I:NTS IMPI I('A11 t) IN VARIUIIS PAIIIt)I (/<il(:AI. (Y1N1)1I1(1NS: 1IIE EFFFt"T OF VIR(/SLS ANI) (1F (-I(iARlil 11: SMOKE ON 111F. ('11.1. ANl) ITS N(I('LEI(' AC II)S " fly ('ectfie L.cuchtcnhcrgcr and Rudolf ltuchtenhergcr, Swiss Federal Institute of lcchnulogy (1:T Ii ). Zurich. Switzerland Inrrrnarinnaf Rrvirw u/ ('ytrrlnRy. Volume 11, pages 281-326, publishcd 1963 by Acadcrnic Press (Council grantce: ('ecilie I.euchtcn- bergcr) lhis review s)xlws th.rt thrrc •rre rcl.rlivcly fcw studies in which special allcntitln has been ftKuscd rm the fxh.rvitn rd Ihc rntraccllular nurlerc acids and ils correlaticxs with nxrrphtrlufrc.l cell thangcs a/tcr vuus rnfcclirms and hcr ctrrtnure to cigarette srnnkc It is rvirknt Ir,+m these stuthcs thar crll tkath, prrt'rrkJ t.y sulry,rrsdun of mntrsis, tlrtrcac al nutkii atnh entl llrrnrni., rrr tcll prrrhlrt.rtrnn, Irrc t'rJcd by strnn laurrn n/ nuttrvs asvrti r.itiJ wrtFl inn,Irr.Nt' utu rratc of nuilcit' atuds, are very lrryuent reslwalses 1.1 .rftnt. t-l Anr-n ur unkru,wn uaturt'. whrt h t ausr p.uh,rlrrKtt it t rrntliurlns I hc rtt c/1u.rnal c'cllufer and rnu I, it it ul Il.,rtcrn altcr vnus inlcctinns, wlhcrc tcll tlr.rth n I+rrtt'rlcl hy nu,I,K ;Knl lsnrhrtn, r..itlu.illy nul very .nrl'itsnK f~.m , "rt.uk r. 111, Int I th.,t vtrn% rn/t't Uims atc Ihr urnly Il.rthn- U 0 0 ~ r i logical ctxldititsn knnwn where an agent which itsclf is cunrptned uf nuckic acid replicates its specific nucktsprotcins within and at the eapense of the cell. Although this sequence may nut he dctec(abk in every virus in(ectiun, w nevcr cells display such a succession of events the possibk presence of irus inleclion shuuW be further etplored. Ozlier Rronror.; National Institutes of Health; and the Brush, the Fran- chester Fertility, and the Elsa U. Pardee Foundations (Cleveland, Ohio). "CYTOI.(K;ICAL AND CYTO('HEMICAL ALTERATIONS IN TIlE RESPIRATORY TRACT OF MICE AFI'ER EXPOSURE TO ('1(iA- Rla-fE SMOKE. INFLUENZA VIRUS, AND NOTIt." By Cecilie leuch- tenberger, Rudolf l.euchtenberger, Fritz Ruch, Kayo Tanaka, and Tatsuya Tanaka, Children's Cancer Research Foundation, Bosttsn, and lkparlmenl of ('ytoingy. Institute of General Bo(any, Swiss Federal Institute of Tech- nology (1?. f 11 ), Zurich, Switzerland. Contrr Rtseurch, Volume 23, Num- ber 1--Part 1, pages SSS-565. May 1963. Correlated hisloksgical, cytukrgical, and cyttschemical studies were made of sequential changes in the respiratory tract of 309 femrk and 211(1 mak ('F, mice after esposure to the inhalation of cigarette smoke at the rate of Vz to 3 cigarettes daily ftx peritKls (raxn 30 to 121) days, eacepl ftx rest pcritxJs of I to 30 days; following inlranasal intKulatitKS with PRg influenza virus at varying intervals; and folkswing a ctsmbination of both treatments at the same Jtxe rates as in the first two erapcrimcnls. In order to carry out significant analysis of the results, only those mice were utilized which could be matched in regard to doscs, e.pcrinsenlal pcriuds, and life spans. Atypical proliferative lesions occurred in the respiratory tract in all three tesls, accompanied by nwtkrate intracellular DNA. RNA, and protein increase. '1 he frequency of lesions was lowest after inhalation of cigarette smoke, higher after influenza virus, and a cumulative eflect was noted after the combination of virus and cigarette smoke. Mild atypical proliferatiuns and ,quamtws-ccll mctaplasia occurred in a few of the control mice Nccro- tizing bronchitis was observed only in mice eaptssed to virus, with or without smukc inhalatiun. In the tests with cigarette smoke inhalation alune, nsales seemed to e.hibit a sumcwhat lower (rcquency tuf alteralions than fcmaks 1 he changes occurred prcdrrminantly in the small bronchi and bront-hiules. -Ille Irequcncy and the dclorce of allcralions were strikingly lower and uflcn mildcr than in nnce cslwrscd Itt virus, and particularly Ihan in mice e.pt+scd It, the cont- hinstam In sturlyinR tlrr sequence o/ events /rdltrwing influenza infectiun, Iwu cutstlrlctely dr/lrrrnl and rtplx+srrc ellects, ful/uwing eath rrthrr, wrre recng nized. I Ilctt I wrs thrrjclerrtcd by absctntr tul nulosis. Increase rn site rd nutko6, nutlcr, and cylttplasm acttrutponietl ftequently by (rurnatnro r,/ slllrerical rntlusnrns, arld n/ arglrrmerala/ns of bast/plnlhc maaes anruud rtuc'koh and within cytuplasrn; Ilus Iltucess Icads In swellrng uf cells, ccll desttuchrln, and net'rrHitmg hrtmchius [Ikcl II is t haractrrvetl hy the tlccurrente uf many mitrru's, a t.ylid mullr/rK•al hylu•rlrla.i.l, antl frrqnenrly c r 31 I n
Page 18: avr30a00
I i atypical pndrfcr.tion of tpi/hchal ctlls rd hrnnthr anti hr„nthiolcs -Ilscse cclls htcornc rntrcasingly Jytpljatrc rrr are trantlrumt•J rntrr :rryprtal cprJcr- muiJ cells lhe hrqucncres ul nearly all markcJ alter.lirms afttr influenza infection were consukrahly higher in fcmaks than in malts Ilowever, the malc mice displayed Ilre higher frequency of pruhfcralion after cnm6rnrd eaposure to crgarctte smukc and influenza virus, partkularly in squamrrus- cell mcraplasia and Iransgressitxts of cpilhclial cells into lung parenchyma. 1 hc observed frequencies of all Ihc proliferative anJ/rw atypical changes no(eJ rltcr the combined uposures were generally higher than would be obtained by adding the frcquencies found after cigarette smoke alone to those ftwnd after virus.Mne. The prescnt studies stress nM only the significance of subacutc influenza virus infcctitrns, but also o( the te: difference itself in the frequency of res- piratory changes A propecl has been planned to caplorc Ihe influence of set hormones (m Ihe devtlopmcnt of such ksions, alone or in crxnbinalitxs with influtnza virus .nd cigarette smoke. "P(II.MONARY LFSIUNS IN lxlciS FROM MFIIIYI.('lIOI.AN- 1I11(FN1: " Ity R If RigJon, M 1) , anJ (:untcr ('orssen, M 1) , lhrivcrsity of leias Medical Branch. Calvfstun Arrhivri o/ ParholuRr. Volume 75, Numher 3, luges 32)-311. March 196) (Council grantee: RigtAm) Ifrnnchial cpilhclial hyrerltlasra anJ, in a few inslanccs, uluamrrus mela/dasia occurred in a m.purly uf 19 Jrrgt rnltcleJ intrahrunchully with methylcholanthrcnc Srntc similar h tirm. rN:cur sprrnlantr,utly in the tlug, it becomes dr/hcult to evaluate tlrc Irvwnt that rnay fulluw mtrahrrmchial injeclron of this c.rcmr,Rcn A/ctnrn .uV(;csuvc of a syuanurut tell carcin- oma was found in a lut.l area (rf lung m rrnc rd ncc JrrR., 12 Jays afler aJ- nrinistralirrn of nrtthylchrrlAnrhrcnc. hu1 no nrct.ro:r%cs were (,,unJ I he cr<- pcriments indicate that the dog is m,t vatnf.ctrxy lu usc in ncr cilxrinrenlal Study of puhnonary carcrnuKcns svncc atutc aRd chrumc mllrmrnatrun is found to occur sprntancuusly in many nf Ilrcte annn.ls Othrr grantur: National ('anccr InsUlutc. 11. Cordiot+aacular Sttrdiea "POSITIVE IN(YfRI)PI(' RF.SPt)NSIiS ANI) ('AfF(-1Il)IAMINE (Y)NfI:NT OF ISl)1.AlI:I) RAIIfIII AIRIA I'.XI'OSF•.1) 110 IYRA- MINIi" By P.. T'. Angclaktn and M 1. 'Yorchrana, Ikprrunrnts of Phyti- olugy, Bostun I/niversity Sthord (if Mcditinc. Ifr,ttun, anJ Karrdimk In- slilutcl, Sttckhttlm, Sweden Ar lu I'h yurdr.tu u 1t undrnnvrr u. V nlumt S'), Numbcrs I-2, pages 161-IAtl, ScptcnJrer (ktular 1963 lhc nuratlrtnalinc (NA) cuntent rrl itrd.IrJ rahhrl .ur+ was ts.rn lially unchangcJ A+llowing ptrfusrrrn wrlh tyraumc (IINI rr.'ml ) fru 1t/ minutts Ovcr thc svrnt pcrrorllhr IN,trtrvc m,rrrr,lrit clkrt rd Iyrarmnc was strll )S Icr trrN nl rlrc (+r~1 rtt(Nm.t Ahrr I~r,d„ny,r J CrIN111/rf (2 1 huurt) the NA tr,ntcnr ,ktrt.uJ ah.rut 211 Ittr rr'nt :rr,d thc rnr,rr„prr cllcct a1Nwl Stl htr t tm r In grneral, lhcre was a correlation between the reduction in the re- sponse lu tyramirse and the NA content. Ilowever, the NA content war mdl 40 SI) pcr cent of the control value when Ihe tissue responded no longer to lyrarnine At Ihat lime the tissue was fully responsivc to adminislereJ NA, I hc reduction in the NA content of the tissue could nts( supply more than a total of I) 1 to 11.2 rg NA over 2-3 hours. This suggests a considerable synthesis of NA in vino if the effect of lyramine is indeed mcdialed through NA release I)ircct measurement showcJ that 30 minutcs after the end of a prt. (ungeJ lyraminc infusion the NA tissue content was resltxcd by an amount crtrrcsptrnJmg to rhout 2/1 per cent of the control value. lhis, howcver, did rlnt restorc the response to tyraminc. • ~Irlrer Rranrorr: U.S. Public I(eahh Service and 11 S. Air Force Office of Scientific Research. "('NEMI('AI. ANI) IIIST(X-IIfMI('A1. EVALUATION nF Tllt; f1IS- 'IRIBIIIION OF ('ATIi('II(ILAMINIiS IN 11111 RA111111' ANI) (il/1NIiA /'IG III:AR'I-S" By E T. Angelakos, K. huse, and M I.. l'or- chiana, Ikp.rlmenls of Physiolugy and I-listobgy, Karulinska Instilulel, Slockholnr, Swctkn, and I)cpartment of PhysioMgy. Boston l)nivtrsily Medical ('cnter, Mass. Acra Physirrlrxica Scondrnavira, Volume 59. Num- bers 1-2, pages 1g1-192. Seplembcr-Octobcr 1967. (Council grantee: Angelakus ) ('Ircmical determinations of noradrenaline (NA ), adrenaline (A), ant! Jnpaminc (I)A) were made in the right and kft atria and ventricles (RA, I.A, R V, LV ) of rabbit and guinea pig hearts. T he concentration uf these airlines was also sludied in Ihe sino-auricular (SA ) ntxk uf the rabbil. Sonic of these lissucs were also eaantincd for the distributiun of calecholamincs using a hishkhemical fluorescence technique. NA was the predominant catechulansine present in atria and venlriclcs. It was more concentrated in the RA than I.A and in the RV than in the LV of Ihc rabbit and guinea pig. In the latter NA was distinctly higher in the atria of the ventricles. By contrast A was more concentrated in ventricles than in atria of both species and accounted for abtrol 5-10 per cent of the total catcclwtlamine content. DA was found predominantly in the atria, more in RA than in I.A. Iligh ctxuentratiorss (if 1)A were found in the SA ntrde region Ilislochcrnical studies on rabbit tissues showed that the cattcholamints were founJ within nerve struclures A high density of flutxescenl fibers anti fiher brmdlcs was found in thc SA mxk region. An crtcelknl correlation bctween Ihc histo- chcmical anti chrrrsical findings was obtained whcn (KAFt NA and 1)A were cuosiJertJ. k;-''llrArr granrrrrr lI S 1'srblic (lealth Service. "II1f'. R/)I li(11- l'AI1:('IIO1AMINI?S IN Ill/i I-R1T FA1'fY A('ll) RI:SI't)NSI; . 1O( '1(:AR1;I'11? SM(/KIN(i " fly Alfhtd KtrslA,aum, M I) , Rnst.m Khr.rsanrhan, M 1) , RrymrmJ I: Caplan, M 1) , Samutl ltcllcl, M I), •rnJ I cunard I Fcin(.crg, M I) ('irru)uri,.n, Volume 2N, Numlrcr I, pages 52-57. luly IY6J. (('rwncil grantee: Bclicf) 33
Page 19: avr30a00
lhe n,ks Of the adrenal gl.rmts and the syntpathetic nervous system in the rist of free fally acid (1 1'A ) after anr,rkmg was mvcsligatcJ in I I normal subjects and in R subjects who had prcvinusly undergone brlatcrnl adrenalcc- tur»y for the trcatmcnt uf hypertension In tests on I I subjects who smoked thrcc cigarettes per h,rur for a ) hour f.crirxl, urinary free catechulamine eitcrethun increased 21 {~ r cent (2 5 rnru„gram/htrur ) and total catechulamine escretion incrcaud 16 per cent (J I micn,grant!hour) Al the start of the smpkmg pctrr+d, two crga- reltes were smoked in a 10 minule period A rrsc in fFA uccurrcd in all subjects during the smoking period. To tktcrminc the eftect of sympathetic ganglionic blockade on the FFA res)xtnse In smoking, control tests were matk on 3 normal subjects in which 2 cigarettes were sntoked in the manner previously indicated, following which sympathetic ganglitrnic bA~ckatk was induced with trimcthaphan carop hrnsulfunarc and the snnrking tests were rcpcatcd. No risc in I FA after smrtling (rcturred following hlockatk In 6 of the R patients who had previously untkrgnne bilateral adren- alccl„my. Iherc was no signrficant F-I•A resfw+nse to sm„-irtg two cigarettes in the manncr dcscrrbed; in the r+thcr 2 thcre was a minimal cflcct All were hahrtual sm„kcrs erccpt one. wfiu hed given up smuking 6 years previuusly. 7hese findings indicate that for cigarette snsuking to catrse an increase in srrum I I:A h.+th the adren.J gl.,nds and the sympalhclrc ncrvous system nrust be funUu,rt,ng, f,r„h.rhly to I,rnKlutc an cflccrrvc Icvct Of circulaling catet hulannncs ~Ofltitr Rrnnrurr: ItS I'ul•hi IIr.,I,l, k,r.,,c .,nJ N,,lurn.,t Ilrjrt InslUtule "I'IIYSIUIOlil( NASIS It)R PRIr1111111111N A(iAINSI SMt)KIN(7" fly Samuel Ncllct, M I), and AIIrcJ Krrshlv„m, M I), Ihv„n,n of ('artli- nlugy, Phdatklrhta (icnerrl Il,sl„tjl, •n41 (ir,r,h,atr II,'.prt.,l, tlniversity of Pennsylvania. Phrladclphia (haptcr in "Curunary Iltart 1lrscase," 2he Stvrnrh Ilohncmonn Sympusrum, 1462, edited by W. I dt,f1 & J. la. Moyer. (Published 1963 by (irunc & Stratlun) This review of esperimenls in this lal,,,Wn(y and by others may be summarized as fnlluws: ( I) Smuking involvcs a stress mcchanrsrn in nurmal suhjccts: this is greater in patients with coronary artery disease (2) Smoking results in an increase in cardiac w,nk which is adcyualcly mct by the nurmal hcart, but whrch may be inadcyualcly met in the presencc of corunary in- su0icierscy ( J) 1 be king range etlccH remain It, he evalualcd livitkncc is available whith snggtsls that thrunic srn,rkrrs arc mrrre likely to tkvchp disturbances uf IqnJ mclalwrlnm, drvtl„p a grcatrr inti tknce (sf cnrunary artery tliscast at in cancer aMc, and rnarufcsl a higher IMCidcnt'e of t,lronary rxclusiun 1f ~ Orh" R~nnr,rr : 11% I'ul.lr. I lr.rlrh Sr rva c V 0 c~ 0 "N(RMnl M1tt( ARI)IAI MI IAfIOI ISN1"ItyR,thardl Il,ng ('hrls- 0 1,r in -( 11Cr,1 I)r.r.,,rIhr llahnrvn„nn Itrn(rrmurn, 1962, edited by W. 1-ikuR & I. F1. Moyer. ( Publishcd 196) by (;rune & Stratlon ) "('UNIRA('TIl F PR(117i1NS OF NORMA1. AND FAII IN(: IIIIMAN IfF.AR-1' " Hy Mary I. Ncbel, Ph I) , and Richard 1 Uing, M h f~-chivcs oJ Inrernol McJa inr, Volume 111. Number 2, pages I9()-195, February 1963. These two reviews esplore the progress in scientific knowledge of the diffcrenl conditions encountered in nurntal and failing human hearts. INC first review presents clinical and experintental findings which illustrate the limited valuc of cakulatitsns of the state of cellular tsxilatiun in heart muscle from a comparistm of the ratius of the oaltlatlrlrl-reductnrn pxNCntial in arterial and in ctsrunary vein bltsod. 7 his is but a step in the aearch for methods which permit cuncluirons on the intermediary metabo- lism of the heart from arte-iuventsus balance sludics. Furlher tflorts will be made to accomplish this goal by more specific and refined hitKhemical mtarn. It is bccoming increasingly ckar that an untkrstanding of congestive heart failure hinges on the study of cntlocrincs and on the knowledge of physical chemical prnpcrtics of the ctxslractilc proteins F'aradoaically, in apite of much medical progress. the role of the heart must:le in eliciting The in of evcnts kading to congestive heart failurc rentains very much in dispute, the other study shows. Much of the disagrcemcnt is the result of divergence in techniques and of preparations used. In the studicspe rftxmed in this laboratory on mytnin eulractcd from normal and failing human heart muscle obtained at autopsy, the ATPase activity, relative visctxity. Iigh1-scatlering characterislics, and sedinsentatim c(xflicient were measured. It was found that the Al Pase activity of myosin prepared from failing hearts was slightly greater than that obtained frorn nurmal hearts. Data occumulalcd on the reduced viscosity of the normal ^nd failing heart rcveakd a much greater scatter in both preparations at low cuncenlra- tions of myosin, which may reflect difliculties in determining the myosin concenlralits, among other things The resulls of the relative viscosity mcas- uremcnts therefore farkd to reveal any striking differences between failing and nurmal human hearts. f)iflercnccs appeared in the dissymmclry value Ixlwecn nnrutal and fatling hearts obtained by light scattering. Assuruing a rotl-shapcd particle for the tnyrtsvn mokculc, the length of the mytnin mukculc catrat Icd frunr the larbng hurnan hrarl appeared its be less than that obtained frunr norntal hearts One 4-f the ctNrstanl findrngs in the studies was tlsat Ihc sethmenlutrun dragrams of rnyoun prepared front failing hunran hrarts shrrwcd nune MKmdarics of pcaks than Ihrrst of nryusin prcpared f,rrnr u,umal heArts, sug,tstin/ th.tl thc rny,tsin frurn farhng hearts was not hrnm,grncrn,s ur was less slahle than nurmal carthac myusin. lhese rtsults, allhuugh still prcliminary, suggest that nsyr,sin frrrm failing hearts undrrgrtcs chrngrs in nrukcular shape and ur wcrght, tun- )S rf 1.1 O
Page 20: avr30a00
firming the o(,ilurm that cnnRtstivc hcart fadurt is at Icasl initially a disease of tlptontraltllc pnilcins rd hcart nwslk rrn Iht rnolccular Itvcl ()Arr Rrewror.: 11 S Public Ilcalth Strvice, American Ileart Assnciation, ivllchigan Iltart Assr+c/ation, I r/c Insurancc Medical Research I und, llu Nurrrrughs Welkomt I und, and the John A flartford Fuundatiun "111F PRIiS1:N(-f: OI! IIIIMURAL- FA('1()RS IN IIOMtK;RAFT RE- 1E-'('1ION OF TIfN TRANSPLANTFF) IIEAR 1" By 11 R Ranlos, C ( ltiba, P Schrillmtycr, P L Wolf, H. Pcars„n, and R 1. flrng, Ikpartrncnts of Medicine nJ Palhobgy, Wayne State University ('nikRc of Medicine. nd Ilarpcr Ilcnpilal, Lklroit, Mich. Tronrpranrorrr,n, Volume 1, Number 3, pages 2E14-2V2, July 1963. ((Council grantet: Iling) The mechanism of rcjtctir.n uf the transplantcd drsg hrart was sludicd in cxpcrinlcnls rn rivo and in vinn Vascular Lcrmeahillly was measured by dctermming the dcgrce of tissue radioaclrvrty after inlravascular mjcctirln of radirul.dinattd albumin Unc hrrur ftcr translrlantatic.n, vascular pcrmca- blhly was rncrrascd Ihrs was nlrac prnrnlunccd when Ilrt rcjrctirrn was accrkralccl In c.pcrimcnts in vrrrn ptrfusiows rd the isnlatcd heart with hrunuk.grws plasma ckmnnstratcd slightly rncrcascd c,y1rllary ptrrntahdlty rMx hrlur afltr Ihc rmscl nl pcr(usurn. I+crfusrA w/th stnsvthrcd plasma causcJ a significanl rise in vau'ular permeability ( rllular reaction was absent in the homr.- grafted heart nrx Mrur allcr Iranyll.rnlatir/n In nnly 1 rr( 25 Lcrfusions rn vra„ was cellular rcauilwi prescnt charactcnsrrc o( humngraft rejecliun. This nccurrcd in hcarls pcrfuscJ with scnsrtucJ plasma Tht rtsvlls rllustralc that hrlrnnKrift rcjccunn can crlmmcnce with signs rlf incruscJ vau ular pcrmtahrlrly nnc hour aftcr trart.plantaunn l hcy hrr- Ihcr shilw Ihal humtaal faclrws may lrlay a prcllumrnant rulc in numrsgraft rc -lion rhrr gronror.: l) S Public Ilealth Service. Amtrican Ilcart Aaslrciation, Mrchigan Iltart Association. I ile Insurance Mcdre'aI Rcscarch I und. lhc Hurroughs Wclkumc Fund, and the John A Ilartflrrd 1'uundatiun "STI/l)IFS ON 1711i 1RANSPI.AN71ih HFART. ROl F OF (iAMMA- (3LOBUL.IN IN TRANSPI.AN1 Al ION IMMl1N1'I Y." fly ('hiyo ('hiha, liro Yamanaka. E:dward 1 Zaleski. Paul 1. Wolf and Richan: 1. (ling, Waync State llnivtrsily ('ollegc of Mcdicinc and Ihrpcr fluspilal, Detroit. Mich PrrxrrJrnRt u/ thr.Srrrrry /rrr F..pernnrnrol BinlnRy unJ A(rJunrr, Volume 114. Number 3, pages 617 6411, L)ccembcr 1961 (('ouncil grantee: fling) Scnsitiralirxt of the recipient mirnal with s/ kcn M>nlrrKrnalc resultcd in a significant increase in Ihe strum g:rrnma rlnhulln Ir:rcurm and suhsc- yucnt ar cckratcrl rejtctinn ul the graft In carirturnal casrs In whn h scrum grmnu ghlFlulln Icvtl dld nrd Incrcast. !hc al l r Irlatrcl rrlcr turn was ah•crnl 1 rtalmcnl wnh h MI' rcduccd thr Valu+na y,lrrbulul level :Imt the gralls in tlhcst sninlals shrrwtd prulrrnirtJ survival RrJortlr.n rd r..rmnl.l ylrrlhuhn hy r.rh.rn/•r Ir.m~lu~lnn (arlrrl Ir. (~r,~hnrY vrrtilv.rl Innc uI Ilrr yr.rll Iltcst /r ~ull. •r, vr .r~ ~,-t -Ih r/„ ,~~ w/1r r1 hunn.r.rl /J.Irq• I'rl'%l I11 1/1 IIIC M,in.,. rl I/. ,.r.., I.I,, r..l, irr li,~rn,~l.r.ill rrtrrllnn h.r Rrenrura: I1 S Puhlic Ilcalth Service, Anrcricarl IIcart AssrKiahon rc/ugan Ilcart Assuriatrun, l.ife Insurance Mcdreal Rc,tarch Fund, lht lfurruughs-Welknme Fund, and the John A. Ilartford E=uundatuon "DI.(N)h FLOW IN T IIE: 1111MAN C'AL.F hIfRINI: lOIfA('('() SMUK- IN(i " Ny Jay 1) ('oflnran, M 1)., and Stanley L. lavclt, M l) . 11 ('h . 1: ' vans Mcn.arial Ikpartmcnt rd (linical Research, Massachusclts Memorial l/os- pilals, Iluslr)n ('irculution, Vulumc 28, Number S, pages 932-Y)7, Nuvcar• ber 1963. ((Council grantee: ('ullman) E1hxA flow in the human calf during the smoking of 2 regular mrn- fillcrcd cigarettes was measured in 17 mKmal subjects (avcr'rgc age 2111 years ), in 4 patients with sympalhcclumized limbs, and in 6 palicnts with arlcrioxknniu oblhcrans. The dis:(ppearance rate of a r.diuisulrryK injrclcd into a muscle was used Io indicate nrusck cap illary hhwxl Ihrw, and pkthys mngraphy was used to measure total hkxxE Auw of the calf, includmg I>+Hh ikin and nruscle r I 1 Thcrt was a significant incrcasc in ntuscle capillary hhoo1 Ihlw in 14 c>r Ihe normal whjccls while pIcthysrncrgraphic blood fluw changes were variable and mN srgnificanl. 'lhrec of the 4 symralhcclrunircd patients showed an irscrcascd drsappearance rate of the radruisrllupe during smrlk- ing; the arleriusckrosis ufslilctans patients showed no change in musck capillary bhKrd fluw during smoking. Repeat studies on subjects wlxs had  more rapid disappearance ratc during smoking reveakd the corislancy (rf the increase in hhKSd flow. "Sham" snuoking tests indicated that inhalation was not a factor Intravenous injec- tiuns of nicoline, in doses comparable to Ihe amrwnl conlained in cigareucs, was also dcnxsnslrated to increase both muscle capillary and wul calf bhwd flow significanlly. E:vidence that the sympa(hetic nervous syslcm probahly was not involved was derived from the increased isrNopc disappearance rate in the three patients with lumbar sympatheclcxnies. While skektal muscle bhMKl Iksw may increase during cigarette smnk- ing, skin flow definitely dccreases, a factor es/ most imprul•ance to the patient with I eriphcral vascular disease. Thcrefore il is slill of impurtance lo rccnm- mcnd that paucnts with ixhemic pcripheral vascular discasc stop smoking "IIYPI?R('llOIrSTIiREMIA ANL) PE1LMONARY ARTVRIA1. Ili- SIUNS PRUI)lt('1'.1) IfY 711R(1MHOPI.ASf1N." Ily Irj Gore, M 1), Kcnrr/ T'anaka, M 1) • and Ilcmard J L.arkcy, A If , 1)cparlmcnt uf 1'ath• uingy, Mass•achusclts Memrxial Ilospilals, Duslun; Vclerans Adrnini.traurln Illr.pit:rl, Wrsl RuRhury; 1)cpartrncnri rd Palhulogy, Ilrrstun Llnrvcrsuy and ILnvard Mcdreal S.Iuw/ls; an1l Ih•harl/rlerll of Nulritiun, Ilarvard Schlmrl rll Puthh.' Ilcahh, Ilustnn /hr Anuvrrun /rrUrnuf rrl /'urlwlnKl. Vrrhnnc 41, ,>. Nunrf.cr I, Iragcs 145 15h, Murch 1'Ih 1 '•PI11 MONAIII' ARfVR1At. I I SI(/NS /'Rttl)It(l l) IIY PltrrIA c) M1NF " Ilv IGruc, K Irnake, M I rnlrr(r, 11 1 Whnr, and Il I I.ulcy n U /,rurrUd nJ I'nrhrrlrrKV rrnJ lfnrrrrrr.Lrr;v. Vrdumc BM1, Nurnlhcr I. Il.lgcs 2t1'/ . 11 .f, luly 11161 (/ uuni /I hr.rnrcc ( irac ) U 17 0
Page 21: avr30a00
A chnlcstcrnl enriched Jict acccnlualcJ the inflarnmatl+ry lesinns of pulmtmary artcries of rahluts whtth resuhcJ from mlravcnnu. injcctirms of thrnmlK+l+laslin, but had nl+ cllccl on Ihc rxcurrencc of intravascular thronrhM+sis ('l+nt•urrcntly. Ihc aflcclrJ hulnu,nary channrls displayed an incrcascJ ctmtcnt of acid rnuct+pulysacchar,Jc With repcatcJ e.pt.sures to thromhnplaslin Ihc tnflanu+utnr~ rrsptrnsc drminishrJ, but incrrascd yuan- tities of acid mucufadysaccharitJc persisted in the pulmonary ancncs. ('on+Farcd with chuksterol-Icd ctxrtnds, esperilncntal animals eR- hihited cnharsceJ pulmonary thcrosckrosis, but Ihis early eflect subsided as the inflanrmatory rcaclitm wancd. llsc loss of such enhancing activity despite continued escess of vascular acid rnuct+plrlysacchandc was in ctsn- Iralhcli/sn to the hyprNhesis that ftsral etces+cs of Ihese sulrslanccs were the prin+ary event in athcrtrgcncsis Rcrcatcd inlravcnc+us adrninistratw+n of prulaminc rrlHllk-rJ inflam- matnry intrmal ksw+ns rkntrcal in krnJ, thMMrgh not rn JcKrer, with thnse that hdluweJ IhrnmM+f+lasun inlrclnms PrrNamrnc is a ha.ic Irtntcrn hcar ing a high positive charge, anJ is knnwn In cumhrnc with and In Lrccrpitatc atid muct+pp+lysactharkks, whrch bear an trl+ptxrte charge It rs, Ifterefnre, .n Kkal aRcnt to tcsl Ihc prufxxrUun that an mteraclion which precipitates in situ Ihc intrinsic acrd mucr+pm+lysactharitks is the cause of arterial inflam- nuttxy Icsw+ns in e>tpcrm+cnlal emhlrlK pulmonary vascular Jruase With prldongan/m of the prl+/aminc esperimcnlal f+criln). the asscsci- a1cJ pruhfccatrve rratlilrn rn Ihc pulnumary artcrics p/ngrrlscll to intimal fihrnas, anJ the afl:ttrd vrs.cls Jr.(+IaycJ a (l+nsiJCrahlc IrlcrcJse in acid n111CUINlIytJlthArllks Ihc IulhrwrnK Lutnrs are suKgcslcJ tu c.Ptarn the "immurrrly" l+f the syslcunc arlcrr,il systcrn In I+rlHanunc rn/ct'til+n ( 1) a greater drlutrnn of the pr/+tanunr with hllwnl, tl+ the Iw+mt whcrc alt of it nuy be ht+unJ In scrum cun.thwcnh, (2/ the greater vrllkity nf systrmic arurial hhwnl, which reduces the ex(+lnure of a given vascular seRmenl; anJ ( 3) the greater yuantity o/ acid nrucuplJysaccharidcs inherent in the struc- IurC t>< systemic artcrics. tAer Rronrnr.: National licarl Institute, Massachuatls Heart Assncia- littn, the John A 1lartfurd Mcmnrial Fund, anJ the FunJ for Rcsr arch and Tcaching. Ikpartmcnt of Nutrition, liarvard School of Puhlic llcahh "('IiRFBRAL ('IR('ULA11ON ANI) '('f?RIi11RA1. IS(-IIFMIA'." Ily Rl+hcrt A. Kuhn, M 1) ,Oivisitm uf Ncunrsurgcry, All Sl+uls Il/+.pital, Mnr- ristuwn, N 1, anJ St ('luc's IluslTilal, Ik•nvrllc, N 1 11'...1.! NrrmrLrKy, Vulume 3, N+nnl+rr 9, pagcs 7111 7t2, N/wrmhrr IkccnJrcr 1961 Uscd ah+nc in thc Jragn/+Nrs rd tcrrhruvasculrr Ji.c.l+r. Ihc classic mcthrxl of mfcrrntrAl rcasuning has scvrrrl scrn+us IlAws It rl'nntcs rnrn Illrtcly ll+c c.trcmc rnJrvrJual nu.rlrh4d4lf,r. v,tnalnhly rn thr vAaulAr sys Irrn, it as%umrs, /.ftrn tntlnrrttly, Ihdt rn+t•,nlul shrltlcs wcrc trur r/rrAS+ncs nf the cflcc/ lrl unly a sinKk t-truA/rrc rKcnl, it rclrc% ufHln in.rnJl.t uulwrn Jcrahlcs ar+J untcrlemlrrs uI hr+lllry IAkrnK, anJ it h.unsvilcrc.l /l+ I+r IAc- tual IirnAlrty msh'ad I d a nuth, 41 It iclllmg I+r"l,ehrhtrrs unly r nrK to concomitant changes of blood pF1 or oty6en tension When ccxnpcn- satory carutiJ barorcccpttx refleses were controlkd by separate pcrfusion, it was found that hypothcrmic dilatation of arteries anJ veins was atlrihu- labk 1n a direct influence of cott) bltxxl on systemic vcsscls, and to a ncurn- genic nrcchanisnr, elicited by pcrlusion of the carotid vessels with cocsl blood Syslcntic bltxld cooling slowed the heart rale, augmented mytxardial contractile slrcngth, and retarded the rate of chan e of left vcntricular vol- ume us that cookd hearts cjectcd blood more t~wly nd rrlaRed more slowly. Other effects were noted. 11 had not been appreciated heftxe, but is evident from these dala, that hyptNhcrmia increases the heart's vulneu- bility to vnlume ovcrloads, in spite of its pMCnliatcd ctsntractile slrength. llsc cxperimcnts suggest that hypothermia, when combined with adequate monitoring techniyues, n0ers promise in the managcment of non-surgical heart disease. Physildl.gical nbservatitms were made tsn cervical cerrhra) flow in hunr:ms Juring rapid angiugraphy subsequent lu right brachial injcctitm. It w.rs found: (a ) Burr size influenced markedly the velocity in nurrnal cervi- cal arteries (brutiJ flow rates in the neck and brain wcrc much higher than in the vertebral basilar systens. (b) In the absence of arlery discasc, car- t.alatcral carotid compressitm results in an increased rate of f1ow, probably ttrihutahk to a drop in cerebral vascular resistance. (c) Rotation ul the head alters cerebral hcmolynamics, probably by decreasing the cffct:tive pressure head in cervical arteries. These findings indicate that Ihe surgical correction of carotid. bilurcatitsrt stenosit will be placed on a scientifically sound basis when it becomes feasibk to conduct accurate flow studies before and after restoration of the lumen. "INTEGRA'l IVE STUbY OF TIIE C1RCUI.ATION IN MO/)ERATf: FIYPOIIII-RMIA." Ify Peter F. Salisbury, M U., Ph1), Cecil ti ('nns, and 1'. AnJrt Richen, Il S., Inlcnsive'i'reatment Center and Ikpasamenl of Medical Rcsearch, St. Joseph Huspital, 1lurbank, Cal A.ncrirun /uu.nul of ('arJadnRy, Vulume 12, Number 2, pages 1f1A-19). August 1963 (('uuncil grantee: Salisbury) l he influence of blood cooling on the circulation was e tamincJ in Jtits with mcthotls ranging in compkxity from isovoluntic bealing hcarts 1u ani mals with clused chest, fitcd cardiac twlput, and spontaneous respiratitsn. Tlsc effects of hyptuhermia were referabk to the lower temperature itself and Oth.r grentar: National Cancer Institute. "('IR( 111 A 1ORY 1:1-1:firtS OF ARTt?RIAI IIYI'( )XIA "/ly Peter F. S.dr.httry, M 1) ,('ecil F('tnils, und ('harlcs I llarrrm, M 1) Orpartmrnt Uf Ml'IIIt'JI RrSC.IrCh, 1t h+scph Iluspital, anJ the I tukthrrtl Aircraft ('rrr. I+laAlit+n, Iluthanl, ('aI Arrutplpr AlnArinr, Volumc 14. Nunrl.cr I(1, hagcs')15 411, ( kl/+fK-r 1961. U 0 (15 It is Prnrrally kmrwn that arlcrial nrygcn tensiuns as low as SII rnrn Ilg ocy);en saturatiunl arr tl+lerated by men nnd aniruals hul that ~ v r scrirnrs mallunitil+ns ld thc urcul.rnun t'an causc Jcath whcn Ihc artcrial pOr (alls t)cluw 411 mnr IIK 39 v 19 0 „
Page 22: avr30a00
I he carditwascular ellccts nf hypotria were stwlied with methods that kept artrrral hltwKl r!I cttnstont and recordcd hI/NM1 tttyRcrr Icnsittn, which was vaned Scveral different crpernnental prcparatutns were uscd, ranging in cttrnltle.itr frum istdated hearts to vrrtually intact. lightly anesthetized d~tRs 'i he "acure circulatory crisis," which sul.ervenes when men or animals are suJJrnly esl.rtsctl to arteriat tr.ygcn Icnsutns below 45 rnm IIR, was ntN rcprtnlucrhlc unless MtMta1 having a pO, below 4S rnm Itg rcached the com- rmwr cartrud arteries ^rlUfieial perfusiexs of the carotid arteries, but no1 of <Nher vascular tcrritttrres, with mnekrately hyfatiic bttxxl causes reflex brady- tardu, with simultancrws eonstrictiun of systemic arteries and veins, and cute severe hearl failure. 1 he previnusly unproven concept 11131 hypessia causes cule eircula- tory crises through refleacs is proven hy these esperimcntat data, which demtmslrate a neuntgenic origin (if the "hy/xt.ic crrsrs " localize the re- ceplrws, and flurd insight into its mechanism {N11rr Rrnntor: NalMnal CantYf Inslltule I A(-IliFi IS(IIF:MIA OF INNIiR I AY!?RS OF VIiNiR1('1/1.AR WAI 1. " Ity Ptter F. Satishury', M 1), Ph 1). ('ecil F (-rou, .nd P. AndrE Rrchcn, N S, St louph llosprlal, Ifurhank, Cal .Inuriron tlrurr lourrwl. Volume hh, Numl.er 5, pages hSt) 656. November 1961 RcRurnal blood flt1w in heart mus.lc was studied by adding a dye to coronary hI w~d I he pcrKardnnu was tl.,ud (-orunary and aorlic pressures varied rndel+cntkntly and wcre ctmtu-~llcJ 1 When the k(t vcntrniular di.N~~hc hrc.aure tocc:rme elevated above 25 mm 11g, and when the cor.mary rrtcrrrl luestnrc w,is reduccd hclnw 7(1 mm flg at the sante time, cstcnsrvc shccrs rtf hcart rnuscle rcnrained unstained by the marlcr dye, thus furnishing tlirccl cvidcntc that thc inner layers of the kft venlricular w.ll had been dcprivcd of their bltKKl supply whik the heart was beating. Ischernia of the inner layers must he explained by an excess of local intramyrxardial pressure. that pcrsisls even in diastole. 1 hrs ischcnsia may esplain the "descending limb" rtf the systolic pressure-vulume diagrans, which is regularly trhscrvctl in trcating vcntritks hut not in hcart muscle strips Ischenna o( the inner laycrs td venlritular wall can initiate vic'ious cycks that cause sudrkn death in persttns with curunrry stemr.is; it is a cause of irreversihk cardiac d;nnaRe that t an Icrrnin:rtc lile +uJtlenly without kavipg obvious traces rktcttahlc at auttqpsy \/ (1t14.r Rronl.rr: Natitm•rl ('anccr In.ututc 'I?1 !-1 (-1S()1 AR 11:RIAL. IIY1'()XIn ()N 1III: III nR I AN1~ I A1I()N AN IN1I~(iRAI1V1' S11111Y " fly ('ccit 1' ( rtttt 1' Antlr(' Rrrhen, ( It,ulrs I Narrtrn, and Pttt~r I~ S.tli.hury, I1rlt.irUucnr ul McArt.d /tt.rartFh, Cr r.trhth IIt yu1.J, and I trklrecJ nvtrdll ( tnlw'r.iutm, Ilur hank, ('aliftnnia ,~rrvrr, trn l.-rnnul of I'hvu~tb"rv. \'t,ltnnt' 2/~5, Numhcr S, haKcs 4l.1 7'li, Nt.vcniltcr 1961 1( ttun.il Kr.rntcc S.rli.hury) I An integrative series of investigations of the cflecls rd arterial hypoaia were curKluctcd in anesthetized mrmgrel dogs, progressing front simplified systems, where cause-and-effect relations were relatively ekar, to the vir- tually int.rct animal with separately perfused carulid arteries. Arterial pOs bclow 40 mm Iig (about 7S .°o oxygen saturation ) caused edema rtt the heart nrusck; however. the contractile strength and perform- ance of isolated hearts were compromised severely only when the arterial pUs had fallen below IS mm. Ilg (about 25% saturation). The "acute circulatory crisis" which is known to occur when the arterial oxygen saturation falls below t10% was not caused by weakness r.f the heart musck but by reflexes from the carotid artery territory: even when the oxygen saturation of systemic arterial blood had fallen as low as 50% this did not cause heart failNre as ksng as the carotids were perfuscd with blood of normal pns, Severe heart failure occurred when the blood in the carnlid arteries was moderately ~Sypoaic (p()a bebw 50. taturation below 8(176 ) while Ihe rest of the circulation was fully o.ygenaled 'I he dala presented here are hcW to prove thal hypoxia causes poten- tially kthal circulatory crises by means of refk.es which induce bradycardia while simultaneously constricting the systemic arteries and veins. Since hemodynamic patterns of severe, acute heart failure occurred solely from reflex bradycardia and concomitant overload per heat. the inference must be drawn that nuxkrale lachycardia may be a useful func- liunal adaplatiun, not only in hypuaia, but also in other circulatory states Z wlxff the heart is overloaded. ther grentorr National tlcarl Institute. "TIIC•. ACl1TF. EFFECT OF ('HEWIN(; TO[IA('('O AND SMOKIN(7 IN fIAl1ITl1Al. USERS." By David t.. Simon and A. Iglauer, C'ardiac 1-aburatory, Cincinnati (ieneral llospital, and University of Cincinnati, Uhio, College of Medicine. KrrisfauJ-Bucherei, Volume 21, pages 256-261, 1963. (Council grantee: Simon) Cigarette smoking. In the normal young men no significant change in cardiac output was found after smoking ordinary cigarettes. While showing no change in cardiac outpul. these same rsormal young men showed con- current stati.tically-significant increases in pulse rates and tkereases in skin tcmperatures of fingers In our subjects there were no changes in the funn of the hal6suxarAkrgram following cigarette smtrking. l'uhacco chewing lbe chewing of tobacco in a gruup of older men who cheweJ ntbaccn habitually produced an mcrease in pulu rate arrd hhwwl preaure, a det'rrase in skin Iemfxrature uf the fingers, and chAnRcs of the FhallitrtwardruRrarn in almmost all suhjccts ( igar and pipe smtrking '11re uaual ellecls of Urhacctr srnnl inR on the cuculalittn were 1tHmJ (that is, an incrcase in polse and ItLwwl /ae.sure, drrrp in alrn temlrrahue of fingers), hul were nrrl as marlcd as tlhe c/fct Is usurIly fuunt/ hdlltwrnK c'iRarelte smtrking trr thewing lulracttr 1 fhe irrcidcnce of changcs in Ihc hallnh>tardirrRrarn in this study was less than that /uund following chewing tnhaccu in a simrlar age grrrup, but grcatcr than that 41 4(1
Page 23: avr30a00
Found following cigarette smoking in a younger age grnup T he cireulalesry eflecls of cigar and pipe smoking wrre Jpprrr.rmatcly the sarne ('irculaurry changes were slightly kss following low nicotme cigars and pipes compared with standard cigars and pipes Sham smoking or sham chewing did not produce eirculatory changes. "PI.^SMA ANl) RFiO B1.0O1) CEil.l. hREiE FATTY ACID RF- SM)NSIiSTO(;1 U('OSE LUAUING WIT1I A NOTE (1N THE l?FFE('I' OF TOBACCO " Hy E.ouis A. Sc.k)R, M.1) , Protessnr of Clinical Medicine. ('hief, l)ivision of ('ardiology; Heint Schwartz. M l) , Ph 1) , Research ('hemist, and F=aye BaWwin, B S.. Temple llnivcrsny Medical (-enier, Phila- delphia lmrrrcnis /twrrw! rr/ the AlrJuof Strrnrrr, Volume 246. Number 2, pages 2(1(1 21/5, Augusl 196) "BlOMICROS('OPIC OHSfRVATIONS ON VAS(X"ONSTRI(TIVEi ANI) TIIROM11(XiINI(' 1+11(-1S PRUI)ll(.FE) HY 1ON(;('IIAIN S^1 IIRA El l) FA 1-1 Y A('II)S WI I IIIN I III? VAS( ll1 A II/Rl: OF llll WIN(;UF AN l1NANI;S1111'11/I:l) HAI"' Hy l.nuis A. StrMsfl and Mary P Wretknun Nurure, August ), 1961, pages 495 196. (Council grantce Srrlrrfl ) lhe plasma and red hWnA cell free fany acid (/-TA) resfwxsses to Rluctne hudtnR were tklrrnnncd in I I hcalthy and 4 diabetic suh)ects, in the first tunly There was nn thanRe irn I I A cuncenlraUun in red blood cclls I he prrccnlaRc drnp in )d..nrJ I-I-A was approsimatclv the same in the healthy and in thc drahclK suhlccl frrrrnr (ruste sympurnrs of shock 1Kl-urrcd in thc nnrmal whcn his Ed.mwl suy,ar fell in on celuw the fasting level hul was strll wnhm the nnrm.l rnrgc A suhscqucnl significant rise in plasma I-I-A trcturred rmly in the nurmal suh)ec,s ind IrrllrrweJ the maxi- munr drrrp in hlrnrtl suRar SnrukinR farled to change the F FA paterns after glucose loading Tbe chcntrcal ch.nses and symptoms are crrnsrstcnl with a release nf catechola- mines evoked by the lalling bhwxl sugar In the light of these observations. the suggeslcd significance of the rise in plasma FFA in rclaUUnship to alherosckrosis rcptxled by some authors should be teinvestigaled Saturated fally acids injected inlraarterially produced an intense vaso- conslrlCt/lM and thsombr in the hal, in the second sludy. Intravcnous injec- titms do not produce the vasnconstsrclive eflects, but the platelet lhrombl produced are both more abundant and larger. The fact that saturated fatty acids are thromMtgcnic to thc living dog and hat su"csts that this property ii eommtsn lo the manuruhan species anJ tenJs lo unite f)uguiJ's ( 1946) hylwrthrsis Ihrl rlhrrrrxlrrrrsis is a Iranshnmauun nf Ihrr.rnlxrsis with the mure crmnnunly atc'eplt-s1 hypulhcsis thal alherrrxlcrrrsrs is a faull of fat rnrUhrdnm 1lnwcvrr, ttus work inJisrles tlul saturatrd fatty cids .tsn prtxlueo va%rK,rn.lrHnrrn rrf artrncs Ilus ttlrtl may Lc rrlually t.r nunc my.urtanl than us lhrrrnrlr.-Rrnr. ef1e.1 in Ihe euuLrRy nl athcru.elerusrs, whrch is an a(If/1JI Jr.rnrk r Orlr.. R.onro. 1~ • fvf'lk Ilcalrh 4r,,uc : 42 U r r 111. Studiea at the Cellular l,evel "Nl1CLE:OI.AR 'CAPS'-A MORPIIOE.OGIC [?NT'1"1'Y PRODU('Eil) BY TTfE('AR('IN(X;EN 1-NITROOl1INOLINE? N-OXlht;." By Rolland C. Reynulds, Philip O'B. Mcmlgomery, and David H. Karney, Department of Pathology. University of Te.as Southwestern Medical Schtwrl, Dallas. ('oncrr Reseorrh, Volume 23. Number 1- Part 1, pages S3S-53g. May 1963. (Council grantee: Muntgomery) Distinctive morphobgie changes produced by 4-nitroquinolinc N-oside in (.Tsang liver cells were demonstrated by means of histologic strains, electron microscopy, and time-lapse motion picture sludics of the phase- conlrasl microscopic images of living cells. The compuund is a sinspk chemical tlerivative of quinoline which produces skin cancer in mice and is unique in IKing a carcinogenic agent which produces characteristic nuclear alterations. TAe principle changes demonstrated in this study were (a) nucleolar eshaustion manifestcd by a progressive decrease in Ilse size td the nucleoli, (b) fusion uf the nuckoli, and (c) ttparaliaxt of the pars amurpha arid the nuckolonerne lo prtduce two Iypes of nuckolar "caps " % Other Rr.ntorr t)amon Runyon Memorial Fund. "CXPERIMENTAL APPROACNIS TO N11C1.EOl.AR FIIN('11ON." By P. U'B. Mnnlgtmxry, Jr., and R. C. Reynolds, University of 'fesas Southwestern Medical School, Dallas. E.cperimentnf C'el! Resrure h, Supple- rnenl 9, pages 17Q-175, 1963. This review describes  five-year study of three diRerent types of ap- proach to the problem of nuckolar function in the normal and in the ab- normal cell. In the first approach it was shown that nuekoli nray be transplanted from the nucksls of a dtaxx cell into the cytoplasm of the recipient cell b~ means of micrnmanipulalitNS with subsequent phagtkylosis. Such nuclculi gradually disinls-Rralc over a period of many hours. In the second approach, the es{+eritnenls demonstrated that ultraviolet rnicrrrheam irradiatiun of the nuckoli of living cells may be carried on cun- linutsnsly for pcritrds of up to 12 hours, with a resulung loss of nuclcnlar ahstrrption whith ap/xars within 4 l0 6 hours lltis Itns of ahsnrplinn arnuunts to apprusimatcly, 990 per cent rl the end of B huurs and is mrt accumpanicJ hy uluavu,kl aburrptiun changes in Ihc remJinJcr of Ihe nuclcus or in 1he cylulrI.rsm. 'I he third .plnrrach lu nuckolrr funclirrn h.t becn a study ut stsucrur.l alleraUuns in /he nuck•rrli of ('hang liver cells treated wilh a varrcly of carclnogenrc ay-rnls anJ me/ulwrlic inhrhilors With fuur of Ihex crrnqwrunJs llte uuthtrrt hrvr fuunA a dnunclwe and c'rrnsislenl allecatiun in Ihe nut /t•rrLr size arsd struclure. IIk•se four cnmlarunds are the carcinogenic agent, d Nilruquinulnx N osiJe, and Ihe inhibitors of nucleic acid synlhesis, Acli- nornycin I), Pruflavin and Acridrne OranRe Tlse changes prtKluced by these 43
Page 24: avr30a00
eurnlv,unJs cunsist ut ( 1) Frhausliun uf thc nucleuli chareclcrizcJ by a tkcreaseJ nuclcul.rr mass tlx nu.lcnh lusc their irreRular (rrnllwr and assume a unifurm spherical sh.pe. 12) the prrxlucUun of inrranuclear inclu• si.rn Ixxbcs whkh appear to t.e rich in RNA; and (3) the rcorRanization (of the electrexr dense granules of the nuckolr to prrlduce three dnlinct struc- tural crxnponents• two of which have been designated the "hgt•1" anJ "dark" "nuckolar caps". These structural alteratiuns appear to he retated in some wa7 to the arrest of RNA synthesis Aclinomycin 1) is known tu specifically inhibit the synthesis of chromosomal RNA by attachment to the 1)NA templates responsrhk for its synthesis Pruflavin and AcnJine Oran6e inhibit DNA s well as RNA synthesis. "OI1SFRVAT1ONS ON TFIE EFhE(?S OF MI;T)IANOI. ANI) F/)R- MAI.I)P.IIYI)E ON ESTABIJSII[I) (•El.l. I.INIiS ('lI1.TIVAl7?1) IN VIl'Rl)" By Alice Elliott and Ik+naW M Pace, Department of 7.xrln6y and Ptrysiulu6Y. Itniversity of Nehnsla, I.inculn ('onodlun I,a,.nul uf Rup chcrnrsrr y ond f`hyswLr[y. Volume 41, Number 2, pages 2910 1l)1, I•r hruary 1961 ((-lxmcJ grantee Pace) Shurt term erpcrimcnts were used to investigate the effects ld variuus conccntraliuns o/ methanol and•flwmakkhyde ulxxr cclls grown in virru. Mouse liver epithelial. 11c1.a, human IunR, and skin cells were esplrsed to several ctlncenlrations rrf methanol l be same ccll Irnes, eacept Hcl.s, were suhtectcd to Jiflerent concentr.urxts of furmakkhyJe Relatively hi);h crlncentuaurrm rrf inethanrd wcre rcyuired to produce rapid tusic e/fects Not all lal Irnc% rr.1-n,Jcl1 .rlrle to nnlhrnrrl (lutcen- tratiuns uf 1 5 rnR; nJ were Jcl rJr,llr rnhJ•rna y rn , j.c of hum.rn tilrn, lung. nJ IIcLa cells. lhn clrn/cnlrrlu,n. Jl,la'Jll'J lu cnhentc Rruwtlr in liver eells AI higher tunccnU.u4m. Iht urclhenrd wa Irr4rc lu Irvcr cells as well as to the others Concentrations of furmahkhytk greater thah 0 035 mg/nil were tosk to mouse liver, human lung anJ skin cells. A concentration of (/01 m6/ml uf furmakkhyde inhibited proliferation of these same cells -Ilrese three cell lines did not sppear to differ significantly in respect 10 thcir sensitivity to formaldehyde Of the substances invcsti6alcJ to date. formaWchydc appears to bt the most tosic. V41Arr ffrewforf II,S Public )leahh Service. "1IIE I 1 EfFE(T OF ('ICrARFi7TE SMOKE (•ONUF?NSATE UN R/1B- KuiAc anJ O 1 R AR ('lit I S IN Vf J RU " H ' CARI)IOVASCI)1 ,, y . • S B Pollak, [hwer Medical Research ('enler• Inc , IArvcr, I)cl. F:.p..rnvnnJ unJ Mulcrulm farhnlnty, Volume 2, Numhtr ), pages 2y/1 251/, )unc 1901 (('ouncil Rrantee: Pollak ) ('isarctle srm,ke cundcnsates (( S(') I.reparcJ frunr rey,ul.rr unry+pcd, tknicutinircJ unu(yaJ, filter 1rpllcJ, unJ Jcna rrlunrrJ tfillcr ul,lw d l rgar Nlcs wcrc Icslcr1 mn arrrLil anJ nryrKrrJral lcll. Irurn rahhrl~ rn rrrr,, 0 t. 0 hl J c. ~ rlr •. c All Ihc l./.crrnrrnl. rrr lulcJ nrnrlthrqrrt n al .rllcralums wha h rctrnr v " rn .rtr, r.,,I,Lu,•n .I mr rmr 1 N I ur c.nlrcr wrrrl ( ill% Irunr )hyla•t r u~ d4 ~ l, J choksteremic animals did not recover as readily as those front m+rmocho- ksteremic rabhits after single eaposures to CSC. Morphological alterations of cells esposed to CSC from filter tipped citarelks, whether denico/inized or no1, were much milder than those treated with C'S(' fr<xn regular untipped cigarettes. Diflererr.•e in growth curves anJ recovery after esposure were ne`li6ibk it one eompared CSC from regular and from denicotinized cigarettes. Ilowever, powth waa far more altcre4 b~ CSC from untipped regular or denicotinized cigarettes than by ('SC from 61ter tipped citarettes, whether or not deoicotiniztd. If one bases comparison of the effect of CSC and N aMrse on the nico- tine content of the coodensale, one finds that the CSC is about 30 times more potent than nicotine. The opinion that nicotine played but a minor role in the effect of CS(' on the cardiovascular eells received wpprxt from comparisons between the effects of unlipped and of lipped regular anJ de- nicotinized cigarenes. Presumably, the fiher o/ the lipped cigarettes eflecls reduclirm of the particulate phase of smoke. Estrapolalion of observations made on in vitro cells hun) rabbits' ,orta and myocardium to in viro situations in man is hardly feasilde. llx repeatedly made observations of greater vulnerability of cudiuvascular cells from hyperchoksteremic rabbits may be utilised for studies of tissues from me with varying blood cholesterol levels. r Osl~ e r Prwwtorr National Heart Institute. IV. Pu./rnonary Physiology and Anatomy Studies "THE RPSPIRATORY EPITHELIUM OF PATIENTS WITII I.UN(3 CANCER." By W. I1. Carnes, M.D., Department of Patholo6y, ('olkge of Mcdicinc. Uniyenity of Utab, Sah Lake City. Symposium on The Morpho- foticd P.rcurto.a of Cauer, edited by L. Severi, University of Perugia. Italy, 1962. An pproach to the probkm of establishing definitions and standards of classification for lesions encountered in the respiratory epithelium of man was found in a collaborative study of some 2300 cases among patholo- 6ists in 12 cities of the United Sutes. lhe types and entent of abnormalities in the respiratory epithelium found in 119 cases of lung cancer were com- pared to twice that number of eontrols matched by age, ses, race, and date of rkath. Singk cnns sections o/ the trachea, each mainstem brunchus, each kshar bronchus, and the linsular branch were caamined by a uniform rssethod. An epithelium was classified as hyperplastic when it had a thirlncs. of four cells rM more consisting of basal or columnar cells rescnrbhn6 the n..rmal llcncc, it is  very common ksinn, but it war even nlure utensive in the trachca than in the bronchi There was no substantial drflerence between the lung cancer cases and the controls in this respect ('imsiderint 45
Page 25: avr30a00
nr 0 @ the rarity of carcinnma in the trachea. these data scem Irr indicatc that hypcr- plasia in general cannrrt be rcRauded as a prccancentus Icsion Mclaplasia of all lypes was Icss than half as frequent nd much less estensive in the bronchi than was hyperplasia lts incidence in controls wilhoul cancer was only slightly lower than in the cases with lung canccr, and controls with other cancer were intcrmcdute The same slight trend was shown in Ihe tracheas whcrc metaplasia appeared tco he about as eirrrsrivr as it was in the brcxrchi When the four types of ineuplasia were dtstinguished, there appeared to be  substantially greater incicknce of atypical nxtaplasia in the bronchi ol the lung cancer cascs Iban in the contr<>Js No definite diRerenccs were found in the incidence of the three other types Whik the other types of nxtaplasia were quite as frequent in the trachea s in the bronchi, atypkal mctaplasia was seen in the Irachcs only once, and that was in a case of lung cancer. A classification of carcinoma in ritu was made when the atypicality of a segment of epithelium cstendcd to all the cells t>r the entire thi.kncss of the epithelium 1 his lesion was encountered in only 7 cascs, all of which had invasive carcinuma The coincidence ot atypical mctaplasta with carci- m+nu in ritu is high enough to supfMHt the contention that it may be a prccrnccr<ws lesion . V,6rzh.r granror: l/ S Public Nealth Service "THE? RE?SPONSF? OF MU(lrS SU('RFTING E?PITFIFL1l/M AND MUCIIS 10 IRRI7ANIS" By If.ns 1. F alk, Paul Kolin, and Winifred Rowklte, lkpartmcnl rrl Palhrdogy. Schrxrl of Medicine, llniversily of Southern Cahftrtnia, L<+s AnRelts .Innall rrf the New YtNA AraJrmy of Sciencei. Volume 1(16, Article 2, pages SR3-M)g, March 30, 1963 (Council grantec: Falk ) A multifaceted approach was used in investigating the effects of Irrilanu on the physiology and lnstnanatomy trf the respirahiry cpithclium of animals. Specific areas studied were: I. Abnormal retenlion cd 11001 could not he demonstrated in the res- piratury tract of rals and rabbits not espened to the effects of ir-TitantU. 1Tse eficcl of inhalatiors of artificial smog (ozunizcd gasoline, 2 plrm osi- dant ) no the retention of carcinogenic stwrls in the respiralory Iracl of nbbitb was then studied. After exposure to contmcrcial soot after differing periods of esposure to synthNk smog, the aninuls were placed in a smog free cn- vironment for varying perirKls of rccuvery, and the mentnl of strot was determined gravimetrkally Ahnurrn.rl ctmcenlratiuns of srwN iii test animals diminished with estension of recovery time frurn 4 to R and to 24 hrrurs 2 Measurcmtnl of Ihc cflcct of irritants un mucrws nrrw in Ihc Iracherr hrnnchial tract of rats and rahhtts rncrnnNercA Irchnical ddittultics in Ihc rnaintcnance of trrnstant tcnpttaturc and hunudtty in the lae.rnte r-f arlr ficially Intrrwlur rJ rnvinnnmrnl agrnts Actrudtnr,ly, rnut u. .r'r rtunR t ilialyd clrilhthurn (rr~m Ilrr tsrqrlhw/,r.l /r.r.t rd Ihc Ir,q. wr% uwrl ut tr.r% uf fusttvc (lrrw rl nrir.rnr~ r~rr Ihr rl.rlhrlirrrn /1~~ I~.r.~) r•r IrY rlntrl unlunYrnKnl r~,n~t.lr'nl rluJnU 11, I-.t nrl~nt.r rr„ nt A t lalivc respxmse occurred when the agents were applied dircclly lu the tissue by the mtcrrKtrop tcchnique, Transient imnxrbilily frequently resulted at the impingement site. Similar qualitative eRects in reducing mucous flow were observed alter the exposure of epithelium to artificial smog, natural smog, nd ozone Fsposurc to cigarette smoke duplicated the typical response following exposure of the epithelium to polluted air. 3. Various pharmacological agents with parasympalhctkonsimetic properties reduced in prevented the inhibitiwr of ciliary beat and mucous flow by cigarette smoke, used exclusively in thcse experiments. 4. Structurally it was possible to demonstrate a considerable degree of parallelism between alterations in physiological functions and histopatho- logical abnormalities. An increase in the number of and activity of goblet cells was the first histological change noted. 1'his progressed until there was almost complete replacement of the normal epithelium by hyperplasia and hyper.eaclivity of mucus• producing cells. The relation of interference with mucous flow and epithelial desquamatitas to the tNentitsn of stMN is believed lo represcnt a step in the palMrgenetic sequence in which compounds that are nM in themselves carcinogenic theoretically facilitate Ilsc biological ac- tivity of compounds possessing carcinogenic properties. E)esquamation of the epithelium following exposure to irritants is supcr- ficial, and the basal layer of cells remains intact. The sequence of dcsquama- tion and regeneration following exposure to irritants may ultimately result in the replacement of the normal epithelium by one showing nxlaplasia. Exposure of CS7 Black mice infected with influenza virus to aerosols of ozonized gasoline prafucld the characteristic metaplastic changes noted, but in addition the ksions progressed to brorschiolizalion of the alveoli, alveolar thickening, keratiniration, and ultimate developnsent ofsy uansous cancer. Cuntrol mice infected with influenza virus alone in esposed to syrr- thelic smog alone showed none of the changes starting with keralinization. 5. The possible relation or inftuenzal infection and air pollution Io the rok of mucus altcration in the pathogenesis of lung cancer was investigated also from the viewpoint of virus binding capacity. Several non-specific in- hifsitors of viral agglutination exist in the blrnsd of many mammalian sptcies, and most consist of mucoprMeins with diRerent ekcltophrsrclic mohilitic• Most viruses of the influenza type are able to liberate themselves after bind- ing to the mucoprolein through the acliors of an enzyme which destroys the receptur, however the normal flow of mucus tends to remuve Ihe virus from the Irachnrhront'hisl trees A significant reductinn in the inhihition liler of rnucuus sccretirm u/ the snail following ozone exposure was dcruunslrrted. ' It is apparcnt that inRucnza virus can act as an adjuvant tu Ihc carcino gcnic potency (d srnrrg and that smug can act as an adjuvant tt) Ihe Invasive. ness ur intlurnja vuus in IwNh imt.rnces the prulet'rive cllti 1 rd nwi u. may tic markt'rlly rrrluicd ur dt'strnycd ~/(/tRrr Rr.rnnjr: N.rUrm.J ( :uttcr Inattule 47
Page 26: avr30a00
..,k. .~~. 0 ~ 0, trl V. /'.ycho-/'hyair)LrRical Studies "TASif 1tIRF.SIIOt f)S, ('IGARIiI 11: SMOKING, ANf) F:(X)f) D1S- LIKE:S " By Roland Fischcr, F. (infTm, and A R. Kap lan, Research Divi- sirxt Ikpartment nf Psychutry, Ohio State llniversity Medieal Schrwl, Co- lumbus, and LalKiralray nt Medical Geneties, Cleveldnd Psychiatric Institute, Ohio Afrdu inu F sprrimcnralu, Volume 9, pages I S I-167, 1963. (Council 8rantee: Kaplan) To1e thresholds for quinine sulfate, U S P, and 6-n propylthiouracil, 11.S P (PROP) of 127 subjects, mostly eo11e8e students, were determined twice without modificatinn of the Elarris-Katmus procedure including the final sratin8 out tcchnique. The data were analyzed in relation to the smok- ing habits of the sanse individuals In addfilisn 12 of the above vnluntecrs were subjected to taste t?rresh- old tkterminatirrnr for sodrum chlrnKk, hydrnchbrie acid and tucrene. -1 hesc lattcr data were analyied in relation to faK1 aversions using  listing of I IR hxxls cscludrn8lhose unfamdur or never lasted lhe proprxturn of smokers is lower arrwin8 sensitive tatiters of quinine than amon6 inscnsitive lastcrs 1hs cr,nvcrse relationship is si.nrlarly true. Krut et at ( 1961 ) also hwnd a i'mil.r corrclatirrn between smoking and taste insensitrvny to bitter comp.)unds 1 hese cnrrelationt are anakrRrrus to those which we rrhserved between high 1«xl dislikes and low (sensitive) taste IhreshoWs f rr quinine No significant cowrclatinn was ohssrvcd between amount of fo«xls dis- liked and laste threshulds /rn hydrrKhlmie actd. SrKlium chloride and suc- rose 1?ris is analogous to a relxwt hy Krut e1 at which indicates lack of correlation hetwccn smokin6 anJ laste Ihreshr+lds for swcet, sour and salty. Apparently, f4xx1 and cigarette aversions are analogrrusly rclated to taste threshuWs for the fnur "clauical" taste qualities Vtfrhwr Rr.nfor: l) S. Public Ncalth Service "ADDI(TIVE ASPE:CTS IN HEAVY ('IGARETTE SMnKIN(i." By Peter I1. Kea pp, M.D., (7urks Michael Bliss, B A., and l larnet Wells. B.A., lNvision of Psychiatry, Boston University &hrwl of Medicine, Boston. .fmrricon Journal of Psychiarry, Volume 119. Nurnber 10, pages 966-972, April 1963. (Council grantee: Knapp) Fifteen heavy smokers were ohx•rvcd in a state (if sudden abstinence from cigarettes and were contrasted with  comparable Rmup of ckven subjccts alkrwed to smoke aJ hAitu.n llsc subjcsts were paiJ volunteers horn the State Unempluymcnt rolls, obscrved rn Rrrrups uf five in sucreuive weeks Fach Rrrnrp wn under nhscrv.tiun (rrr I1/ Mrurs a dar durin8 a cnn tinuous S day pencxl Pulse rates were taken 6 tirncs tlady and hl4xxl pressure rcadinRs 1 tinrct daily Fach suhj<•ct was Rrvcn a d.rsy hattcry of p,ychn- mqr,nr trUs, a sclf rating mcwwl yuc+titinnnrc, acnrr Irrnn.l inrcrvrcws at tirne nf tcstinR, and rnlrxmal conversahons thruuKhrrut the test week ('ardiac stowinR, presumahly vaRotrmic, and a IowcrinR rif diaslolic IdINMI prrtsurc qKt urrcd in thc withdr.wel grouli Othcr less cacar cut cont- 18 I plaints of distress, such as "emptiness" and slow passage of tinse, seemed related to the state of abstinence. The cardiovascular findiugs were replicated in a group switched under eontrulkd, single-blind conditions fronr high- nicotine to low-nicotine cigarettes. Ikavy smokers thus appear to eshibit sonx addictive features, showing not only social habituation but mild physiologic withdrawal effects It would appear that the opposite of va6utonie action, namely chronic sympathetic stimulalion, is one result of heavy smoking. With appropriate motivation very heavy smoking can be given up, though just as readily resumed. 1. general the esperimental8roup showed marked drnial of concern about an) discomfort during the Ieslin8, as well as about any dangc rs connected witA trsbacco. l.atenl ansiety, however, was readily mobilized by questioning. (Yinically, smoking appears to represent a eornpka learned ps)choso- matic patlern. Primary pkasure from the habit occurs but appears to E+easrne suMrrdinate to secondary use of it to war,d ofE pain, especially an.kty or a sense uf k+ss 'The hypothesis is advanced that the molor acr of smolin8 contrihutes to the relaain8 aspects of the habil, whereas, in compromise. Z sym hetic nervous unwraf is mediated pharmacologically by nicotine. rlirr grantor: American Cancer Society. V1. Tobacco Chemistry & Biochemistry Studies "TIIE SYNTIEESIS OF IIYDROXYCOTININE ANf) S1U1)IES ON ITS STRE)C7"URE." By Iferbert McKennis, lr., L-enno. B. Turnbull, Ed- ward R. Bowman, and Eincnuke Tamaki, Departnsent of Pharmacolo6Y, Medical College of V'v8inia, Richmond. Journal r.J Organic ('hrndirry, Volume 28, Number 2, pates 383•387. February 1963. "N-METIIYLATION OF NICOTINE AND COTININP. IN E'IVO." By I lerbert McKennis, )r., Leneott B. Turnbull, and Edward R. Bowman. Jour- nal of Biological Chemistry. Volume 238, Number 2, pages 719-723. Feb- ruary 1963. "SfUDIES ON THE DEGRADATION OF THE PYRROLIDINE RING OF (-)-NIC'Ol'INE !N VIVO." By So.ell L. Schwartz and Ilerbert Mc- Kennis, lr., Journal of Biofotkd ('Armittry, Volume 238, Number S, pates 1807-1812. May 1963. (Council trantee: McKennis) "FORMATION OF METABOLITES FROM NICOTINE BY A RAB- Ilff" l.IV1:R PREPARATION." By N. M. Papadupcsuk.s and 1. A. Kint- rirn, Journal of PhornuacoGrry and t'aprrinwntof Thrraprutici, Vulumc I,t), Number 3, pa8es 269-277, June 1961. (('cwncil grantee: E3. C. Ilofl) In the merat„rlism of (--) mcrNine in the dog, man and other specict, o-tidatirm of the pyrrrrlydine ring kads to the formaliun nf (-- )-counine, whicfi in turn gives rise ru a nunrtrer of additional rnetabrrlilcs In tine first srudy. Iwo 1)1 p.ns Id hydrosysotinine were obtained by lutal synthests. Resolution of one of these pairs provided an (.ptically active form which corresponded to hydrusycutrmne that had been isolated frum'the urine of snwkcrs and the urine uf dogs after administration of (- ) cntimne 19'.
Page 27: avr30a00
In the second study evidence was uhlained on the melhylation of the pyridrne rin6 of (-)-nictNine and (-- )-cotinirsc in viv,r pr,urrwinR a,lminis- traticsn of (-)-c(Ninine both man and the dog cscrcted (--)-cotininc methonium icxm in the urine. FnrmalirM of T-O pyrKlyl)-r-osobutync acid from the mculx)lism of cotininc in rats and cAips was demonstrated in the third study. The addition of randomly lahekd (-)-nicotinc-('" to hrrlifxd enzyme preparaticxrs of rabbit liver, in the fourth study, led to the prrxluctirrn csf R or nrore toctalxslites of nicrNine. Chemical nd physical d.ta indicated the prcye(cc of cotinine, nornicotine and tkmethykotrnine. ttAcr gra,.tor: The American Tobacco Company "(Y)MPRFHIiNSIVE SPE?C`TROS('OPI(' INVESIIGATION OF Pt)l.Y- Nl1(-L.E'sAR AROMATI(' IIYhRO('ARIIONS I. ABSORPTION SPI'.("IRA AN11 SIAtE? ASSI(3NMIiN1S FOR 111H fF1RA('Y(I.IC IIYI)R(x'ARIiONS ANt) T11I?IR AI.KY1. SlI1tSllll111:.1) UERIVA- 11VI S" Hy Ral`h S Nccler, India Scn Srn6h, snd !?litafxth A Jackum, Ikpartmenl of ( hcmistry, t In+versrty (d Ilrwstun, Teias 1 hr lnurnof of ('hrrnuot Phyrrcr. Volume )R, Nymhcr 9, pages 2144 2171, May 1, 1963 "F.11: ("1R(1N AFF-INIIIFS ANI) 1(1N17A11UN P01FN1lAIS OF AROMA11(' IIYI)R(J('ARHItNS " Ily Ralph S Hccler and W F? Wenl- worth /rwrnof .,/ the ,4nv.n u,, ( hrr.u, ul.Srk rrrr. Vohrmt RS, Number 15. pa6cs 22111 2114, AuRust 5, I'rn) (( rrun.d Rr.ntcc Itctlcr) In thc first srudy. the ah.rwplwn st.ru. wcrc invcstiRatccl and slate assiRnnrents nurk hK tKnz(Utlnlhr.r,rnc. IKn/tttl )phcnanthrcnc, chry- scnc, triphcnylrnc. nal+hrhucnc, .nJ pyrcnc, .nJ wrre crrnrp arcd with ezistin6 theractrcal and csl.rrmrrnr.l sturlics I he rdrntnccatr<~n rr( ckcltonic transitions were mark frN all m-murncthyl denvatrvcs uf nce above hydro carMms escepl Irrr naphthacene. the Irkatnrn nf its tnplct statc is still qucst ionahlc E><istins theories were found to Le Rcncrally satisfaclnry for the pre- dictirm of Ihe rsrdcrs of the low lying statrs- but had varying errrrr regarding the encrRics In several cases. the tlxories did mo1 predict the proper number rif even the lower-tyina states ('ertain rnnleculcs showed spectral feature characteristics espceted fram steric interactirms, 1 he spectrum of henz(u)anlhracene in particular was shrrwn to consist of a large number of Iransitirrns 1 he nther arrniprrunds crrnsiJcrcJ cunlaincd fewer but, nuncthckss, a consiJcrahlr numlxr of transitirms It was lxsssihk to sssiRn the nature trt the Iransrtwns anrl, in rnust cascs. Iu prcdrtt Ihc Iwrlariratirrns c:pcclcd In the second study, mrrkcular clcc•IronrRauvrlirs were estah6shrJ for these and some other hydrucarlwrns. Ihe mrnt svKnificant crrnrlusinn was that these ap)xareJ to be cunsunl With thrs a.wnrpurrn, irrnrnuon polcn- tuls were prcrlictrtl Irrr some casrs whou erlxrmrrnl.rl valucs Irave nrd hecn deternrrned Fsumeted valucs Irrrnr clh..uKc Irans/rr s(xtlra aRrce well wdh the predretrd vJlurs UslrnuUnn rrt elctUnn atlinny values frlr A large num- txr of rrtlirr arrun.rtic hydrr.carlwms w,rs mrdc by crtraprdatinR a phM uf r caperimenlal ckctron affinity and absorption frequency rewlls from the first study. lhcse data shrwkl prove very useful in studies involving charge transfer compkscs, particularly those of biological importance '11x elcclron affinity data represent the first of such informatkrrs on nsolccules larger than diatomic ones. todrr grantor: 11.S. Department of Ilealth. Education and Welfare "PYROLYSIS PROhI/C'IS OF RUTIN, Ql)ER('ETIN, ANI) ('IILORO- GENIC AC I I) " fly Aksis 7,ne and S. 11 Wender, Chemistry Ikpartment, l)niversity of Ollahoms, Norman. Tobacco Scicnce, Volume 7, pages 34-36. Feb. R, 1963. (Council grantee: Wender) Rutin (yucrcetin-3-rutinoside) and chloro6enic acid ()-caRcoylquinic acid) src among Ihe principal polyphcnols present in cigarette tobacco, but neither has been frwnd in the smoke from cigarettes. It was therefore of interest to investigate the products of pyrolysis of these two compounds, as wcll as those of qucrcetin, the aglyctsnc tr( rutin. (N the compounds (rf+tained in the rapid, dry distillation of these Ihrce asmpuunds, calechol and 4-mNhykalechol, derived frum all three, have been prcviuuslY identified in cigarette srnuke, as was resrncinul, dcrivcd from rutin and yucrcclin; furfural and S-hrdror<ymethylfurfural, derived frons rutin only, and bcnzoic acid and 4uint</e, derived from chluru6cnic acid only. Paper chrrrmaingraphic analysrs rd the pymlysis products of all three cumprxrnds indicated llre presence of wher cumpuncMs, as yet un- identificd. l hc olhcr identified pyrolysis prodtKls have not been reprntcd in cigarette snurkc thus far: they were S-melhylfuran-2-aldchydc, (from rulin); phloro6lucinul (frtxn quercclin); and 4-ethykatechol (Irum chl(wrugcnic acid). : V11. Pharmacology Studies "S(1M1: PIIARMA("OI.(X:I('A1. A(TIONS OF NICOTINE ANI) A Mli('11ANISM FOR TI1E POSIfIVIi ('IIRONOIROI'1(' RFS/K)NSH 1() NI('(YI INI:." Iiy 1-hryd Edwin I.eaders Jr I)issertalirrn submitted in partial fulhllrnent of the rcyuirernents fur the degree of Ph 1) in the Ikpart- mcnt of ('harmacolrrgy, Graduate ('ollege, State University rrf luwa Ihr- srrrariun Ah.rtrur rr 2l/5:64-49R0. November 1962. (('rruncil gran(ce: J. P. luns) 1 he etia ls uf niculine, mrrepinephrine, acetylchr,line, and syrnprthetic and prrasymlrathctic nrrve slimul.lmrn on pcr/usirrn pressure rn the lelt rlexcndrnR a'rrrrrnary arlcry were sludred in open chrs/ nurnKrcl doKs 'Ihe rl/cchan/sm uf thc ).rnruvc chrunrNrutrir res/wrnse lu nicrNrnc was al.u studied using isrdated cal atria prrparatirrns wnh'raraaymparhruc (vaRi) and sympathchc (Mnt-Kanglirrnic Ihlxra rd thr slcl a1e R:rnl;li,r ) ncrves in. /:rct llx e/lrtls of Kant;hcctumy anJ reserpintzaliun (rn nce respurnc Iu nrt'uline were ahu studred Nicotine adrninistcrrJ intra aUerially Inrxlucerl an incrcisc in crrrrrnary vascular resistanic, as rndrerteJ hy an rntrcasr in lxrfuvrm Irreuurc, as a St SI)
Page 28: avr30a00
resuh of symparhetic nervous system •rctivuy t,t rclease of tatetholamines frunt chrontaflrn tissues 7he ctNrtrattcle larce of thc rnytKarJturn was in- creasctl with mtra curonary adrnimsU.Urm of nicotinc ur norcprnephrine and sympathct.c nerve stimulatitm Vagal nerve stimulation or intra- coronary adminnuatu+n of accryltholine usually tkcrcasctl the force of ctrotractiun lhe involvement of the parasympathetic nervous system in both the negative and positive phases tsf Ihe atrial response to nicotine obviatcs the necessity of pcsstulatint sympathetic pntlia in the heart to esplam these actitxss of mcotine It can be poslulated lhat nicotine elicits its hiphasic response by initial stimulatitxt of parasympathetic ganglia in the atria which results in a negative chrtxxMrt><sic eflcct The ability of the parasympathetic nervous system to influence sympathetic nervous system activity has been dentopl+strsted. 1'_~0tA.r gr.wror r 11 S Public Hcalth Service "A('flON OF NI('O7INE ON 111F. AS('UNl)IN(; Rf-A1(-ll1 AR AC'll- VA'1 IN(i SYS I FM " By I) ti Knapp and 1: 1: Iksmino, 1)cpartmenl of PharmacoMgy, l)nivcrsity of MtchrRan, Ann Arhtx Intrrnotronal lournol oJ Nruropharmor-rduty, Vnluml I, pagcs 333 )SI, Ikcenrbcr 1962. ((-ouncil grantee: Domino) Intravcntws injcctiuns of IO to 211 r.R/kg of nicolinc in rahbits, cats, dogs, and monkeys produced clcttr.wntrphrh,gram (UF(i) activation re- sponscs in all four spccres f hc nrcr Irenrsrn and srte of action of thc FFG activation cffrct was c.pltned in thc d11g It was shuwn that hcnphcral nerve reccptr+rs were not csscntrally rnvolvid rn this cllc., I urthcrmurc, the F.F.(; activation cflctt of rnc'utrnc dul mit a(qKJr rcLttJ Irr fluttu.tuons in hhnnl ressure nor to increases in cirtulatiug Icvcl. td clancphrmc, nortpmchhrinc, ~-hydrosylryplarnme, or vasoprcvsur Studies in reserpinc-prctreated drrgs sugKcui'd that nicrrune does nul owe its F?E(i activatiors eflect to the release of central stores of catcchula- mlacs or 3-hydrosytryptununc On the other hand, there was no evidence that negates a cholinergic mechanism for thc effects of nicnlinc. It was tenta- tivcly concluded that a likely rnechanism for the PF(; activatiun by nicotinc is by mimicking, cx possibly rclcasing, acctykholhnt in the central ncrvuus system. Hccause nicotine did not prtKluce FFG activation in prelvtrntinc or post mammillary cAr~s, but altered elcttrtta) acrrvrty u( thc tkrg rcucular slah, a ponto-mesencepha ic site of action fur the EI-(: activalion cflc(t ti( nrtutrnc is proposed In all four spccies, Ihc U1 (T attrv.r,ron tkrsc of nurrunc curre- sponded lu bltxxl levels of ntcutrnc wfnth arc tomaurnly achrcveJ in Ihe habitual use of tobacco by rnan VII1. fl(lsr•r ti(ralira "111( R11 A IIONSIIIP (t/ SM()KING l(1 1111; Otllt OME OF PRI (iNAN( Y' f1y Paul lUn.ktwlr.I M I) , I awrcntc I. 1(csicr, M 1) , 1,2 u, 7 a 0 0 I I I lbcker I aflitte, Jr , M I) , and Karl V. (:rega, MO , Medical ('ullcge of South ( aruNn., ('harkstun Papcr presented before Annual Mceling, 1)is- trict I V, .I mrrican ('ollrtc n/ Obstetric iont ond (; yntt-ulcrgtstt. Washingtun, I) ('., Nuvenrher 9, 196). (Council grantee: liester) Iletwecn February I, 1960 and December )1, 1961, 4,440 postpartem women representing 16,138 pregnancies were irNerviewed regarding smok- ing habits antl previous pregnancies by obstetrical residents at the Medical ('ollege and Roper Ihnpitals in Charkslun. llse results found by each resident were strrkingly similar. The patients were divided into groups by relative economic sutus: (1) 1.487 questionnaires representing 4.126 pregnancies among the well- to-do; (11) 509 representing 1.216 pregnancies among women of mostly average ccontsmic status or lower; and (111) 2.445 representing 10.815 pregnancics amonE Negrnes, 99% of whom were indigcnt p.tients. 7he resulu are drawn (rtsm a11 prcgnarkies escept for birth weights, which for accuracy represent nnly the present prcgnan:y. Infants of non-smokin` molhcrs were larger than Iht»c born tu snrukers l his diflctence increased with the number of cigarettes smuked daily. A progressive decrease in differences of birlh weight between irsfants of smuk- crs and ntsn-smokers occurred with decreasing economic status. Nun-smok- eri infants weighed ))) g mtxe than smokcrs' infants in Group 1, 213 g more in Gruup 11, and 115 g tnorc in (Droup III Although birth weights of newborn infants decreased in mothers who stnokcd, tNher facturs, possibly nutrititsnal, may also play an irnptxlanl role. A statistically significant increase in prematurity (under 2,500 E) was found among smoking molhcrs, again directly proportional to the number of cigarettes smoked. 'fhe lower the socitscconumrc group, the higher the incidence of prematurity, the (xre escepliors occurring among srnokcrs of (:resup Iil who smoked over one pack of cigarettes daily; this was pnrluhly due to the small number of cases, since only 3.8% of the Negro mWhcrs fell into this group. The occurrence of major fetal annmalities was consistently lower among smokers. 'the number was very small, howcvcr, rnd chance could have played  part. Maternal conrplications of pregnancy were in inverse ratio to sucirrctnsumic status. ihc abortion rate and the total fetal wastage were slightly highcr among srrakets, bul the stillborn curnptrnent of wastage was not affected by snxrking. Weighl gain for smokers and non-smokers during pregnancy was ap- prusimatcly the ~amc, but the dala were nu1 known in many ca,cs, especially in the NeRru Tts cotplure tNhcr passibilitics, ctdlec and alcohol drinking were tabulated A higher percentage of the smakers drank cullce and alc'tdtul, IMnsibly a rcnettN.n td the lat:t that thc smoker was a lense, an.itrus wuman usrng nturc than ursc outlet fun her net vtws cnergy Ihesc data do nrN indicate that crgardlc smtsking is thc only factor gnvrrnmR fxlth wright anrl incidcnte of premarurity. Nurrrtrunal rnvtrrm rucnlrl, cmotarnaf ra meJrcal rc.sons nsay tre I>,rssrhle factrrrs in Ihc sociu ccuntrmic ddlcrcnccs Irwnd If thc matcnul drel was inrdctluatc, /ur in stancc, tlre infant wuuld havc k.s lat mxurally luesertl, ,herchy shnwing less S'1 P
Page 29: avr30a00
eflcct tu cig.rcllc smoke A siRnifxanl yucdu+n Ihal remains unanawered is whether the Jccrcascd birth weight of Inlanls txwrn tu sml+kcrs is Jctrunenl.l. It appears that in wr+nscn trf normal fertility. smuklnR prr+bahly does not cause any true dtfhcully '1 he obstetrician (xssuhly shlwlcl recommend ab- Atcn(irrn to patients with an Infcrthhly problcm or a ptxlr ubslclric.I hlstory. "MA/My SIRAIN 01: '1IlE MARSFI A1.IIINI) MOIIS[i " Dy Wllliarn S. Murray. Senlnr Slafi Scientist, Roscoe 8 lacksan Mcmlwial I.ahrwatt+ry, B:rr t1arMK, Me /cwrnul rr/ Ihr NaNc>rwl ('cnrrr Intrrlulr, Votume )O, Nurnbcr ), pages M)5-610. March 1963. l)ala on 424 treated and 920 untreated females of the MA/My Jcriva- tive of the Marsh albino mouse indicate Ihal this strain is highly susceptihle to the virus like mammary turrxlr incilcr tx nnik aRcnt, yet appatcnlly car- ries ntxx of It, a characteristic acquired without etpcrrmenul manipula- IKM lhe sulAkn appeararsce of a rn+n mammary lurnor slrain ( 12th gcn- entit.n ) in a strain previtwsly recorded at being highly lumcsrous (st/ain ! 3 uf Marsh alhm(i stuck ) raius the questNM. was Ihis a 6ene1K mutalian uusrng a physu+tr+Kic change in the parcnt slnck, or was it a chanKc in an (nlrinsrc or car+nsre sllmulalor rtacllnR u{~x( an unchanRed physiulu6Y7 lhc I,rllcr curxl~rrrrn appcatt more prrrh.hk Ihc MA/My stram has rc- maineA free 1+1 mammary cuclnlsh+a Ir+r )0 Rcneratifsnr over a period of ywi ~ Othrr Rranfur: llmcn(an ('anctr $rK/cly r Recipients of Grants folh+winR is a list of all recipients of grants approved by the Scienti6c Advisory Nrurd since initial grants were made in fAle 1954. 11 shuulJ bc noted that sr+nlc of the projects have been compkteJ. (:NANTEF: ANI) INSTITlT1ON1 CI.ARE.'N('P_ M. AORFSS, M 1), (-Air/, CarJlorastafw Loborurwy, Velcr.nt AdmmhlralNM1 ('cnler, I w Anatkt; Avorl.rr (Yiniwvl rrofrrr.w of AIrJi• cinr, ll.ivcnqy of ('atdcrrnia, 1 os A.ack. ANtll(1NY A At SANt-SI'., Phl), LN rrrtnr, Nruulon wJ MrroAoLK RrrrortA f)rvorNrn the WimfreJ Mastcr. w+n Rurke Relref FounJalion 'the burle F.wnJ.uun Rehabilitation ('enler, Whrlc Plarns, N. Y. ANTtIt/NY P. AMAROSE. Ph /), Ln trrNr ro.. LlrpurrMrnr of Ubsrrhi6 r rnJ (:ynrnJuty, lhe Albany Medical (-ol- kge of l/niaM l)nr.ersily, Atbany, N Y. rll(1JBCr TTttJE a.arrrr r•.l.rr r...~l.r.1: "I' aJ4.u. . r.rwf Aon .rr- r.A11.A.1 •r 16. r-) McasuremcN of the functional status of the human heart by freyuency sptc Irum analysis of irs vibralrunal cner[y (C P) lAe effecl of nko/ine on ~.r.wein •nd ami.o acid nxlafxrhsm in hiun.ns ('onsislenl chtomowme changes of cul (sueJ leulucyles anJ hont m.rrow a/1er raJla/iun rherapy lrw cuncer of Iht lung H, T AN('.PI AK(1S, M1), Phl), Ano Rekase of calecholamines from the iso tl.rr rro/nsor of L AyrralrrAy, f01rNOn Usrversuty School of MeJicine. Soslrwr. 1) MURRAY AN(;IiVINE, M 1)., /ro /a1cJ beart ( P t Patholoitic - anatomic sludy of cellular /ruor ol PorAolury, l/niversNy of Wh- contia MtJrcal S.hool, Madrsun. chanats in human hrotk-hi ((' P) Stl-PIII N M. AYRES, M 1), Dirr.t.r, Measurement of alveolar arlerial nitrogen ( YIJN•/rNLnNMYry LnbrNWr4r. SI Vin differtmc by aat chrumalopaphy IPt ccnl's Nrnprlal, New Yo.\ ('tly; As.irt- onr hofrtvv n/ MrJN inr, Sedrt Flull ('ollcge of MeJrcine, /ersey ('ily, N I FRFI)I Rt('K W RARNFS, 1. , M 1) , Psi 1) , Annk wrt Prnfnrrn o/ M.JN rnr onJ rhrsrnlnrNal (-brnurrry, )r.hns ILMkirn ltnivenily Schcx+l of MrJi- lhe rotc of hyperpl,tiia in li+.ue re.ppMu to chrunic damage 1( P I tine, R.Itrmrwe, MJ (now Ploltarx uf MtJrc.l S.rtn(r, Nrown Univtrsily, PrusrJenct, R I ) KA11'11 S n/(A/R. Pnl), M1•./rrr,• An rnve+Upli..n uf Ibe %pr,tr.l anJ y I/mvtr.rry of tlouslnn, rhrumaroarrphir char.rrtrrr~/rts uf I (uu.uM. I t. rum+ti+ hyJrrwulr.n. tl'/ P SAM1/11 /11 I I/ 1, M/), I),.•,r.•. Irr rirN~nn/ ! , •Ju~l..tr 1'hdaJrlphr.l.rn tr.l Iru'prlal lhe rRtrl of ni.nnnr un.arJ~.n inu.h.M /n tht prr.rnte ul rr.riprur, ...n. 1 11.r rf fe, t ul nNOlure un rurrm.uy bhwrl flnw nl Joas wlth turunar y rrr.u/hr rrn. y (( P) IrflrcH of ni.nline nn +he murphulusy of 55
Page 30: avr30a00
CRANTI f: ANI) tNSTITt1YTl1)N IIYI AN A BI( KI RMAN, M n, Arro rt.rr ('f/nrul Prn/nr..r r.l MrJn.nr, .nJ AI VAN I 11AMA( 11, M 1),(..n INI,Yn/ ,n ALJr. rnr, (-t>1kK of Phy.i clans and Sur~erw.c, (~olumbra llmvtr uty, ('olumtw. llnr.tr+rtr Reaarch Serace, GoWwarer Memorral /lrnpr/al, Ne. Yor1. RI( IIARh 1 DINtI M 1). P...Irrrrw ul A(rJrrnr •nJ ( fll/~ r,nvnr ul A(rJu rnr. W.ynr Stae l/nr.rnny ( ollrrr of MrArt tnr, Ikrrrwl e PRFf) 0 B(X'K, M S, Pn D, Srn.nr Cunrrr Rrrr.rrA Sr/rnrlrl, Rus.ell Pert Memorial tnwtule, Bnrloensl Su Iiot., SpinRalle, N. V. (see Moore 1 1AMP.S P BONNPR, Pn 1) , P.,rfrn.w of Rlolory, California lnslitule of leth noluly. Pasatkna. TOM 0 BOWP.RY, Pw 1). PrrrorrJr Rr. Idvr labacao.y, !'hrnul/ry f1r(.ur/ mrnl, Ndlh ('arolrna Sult ( o11rK, Releigh R/1RRARA R RROWN, Pn 1), Rrvn.rh Pr,rfrunr nl I..prr,.nrn/ar PrnA.,.rrr. ( elrhorm. 1 rJlrer of Mr.h, ~, 1 ir. Antrlrr t. ~r6 t~n..r.. . w.~ . .. 1 1'R(t)E(T TITl1: coron.ry arlrrkt and atwU. RMmdylk tflettt of nicorine on hurnen and ammsl pl.sma; eRects of trssslnm of smolr.g o. serurn choleslerol levtls of cMonic smoters (P) No. krilanl cqarelte smoltng .ilh ob servalinns on the cartwn monuuJe concenuartnn of arlrrral hltrd and alveolar gat after smotme .rlh rnhala lion and after non inhalslroa smotme lhe eRrcl of tn.ntm{ rwr the crvnnary M.r+d Mvr anJ ccrlarn phasts uf mya eardral meldxrlism in pahtnte with srterN..clerohc or hyperlrnsrve carJr OraKUlar dlseaY (P) SluJas in cellular physidoty o( heart musck (P) Messuremenl of eoronsry blood Row by mtant of radio.clwaled albumin lhe eRecl of smoking on coronary blood flor' in palrenls with arltrioxletdk heart dittau nJ Ihe tRett of nkWrne ne ttoraK of amines in heart muscle IP/ Meaturement of crwonary blooJ Ror with a system uting coinclaknce countinif, the etfect of nrcodine anJ change in heart rate on cardiac metabolism and related subrec(s (P) In.eslig.lioe of the biotoeical eRects of cigarette smote (C P) Fnfymalk slrwly of rnethylarioo reatlions in planl lisu.e W P) inPM end endrin rrndoes tn citarelte smole 1(' P/ NwnUnr anJ .rnntme rRrtli nn rlr,trn rnteph.t.rsr.rn tnnclars uf Ivh.rwr, tm.•rum.J v.r~••nu.rnn~ •nJ rraul r.~rtr~rw.n ~n t.rs N~„t~y~. J, 1..,., trn.r~~ ...f rn,n errd thr+r i /;RANTEF. AND INyTITV1T(N7 SUE Bl/('AIN(111AM, M D., Arsist.ns RrnrwrA Pn./rr.rur of Prdwrrks, Co- (umbra Uni.enity ('dkRe of Phytici.s end SurKons, New York. E M Blf1T, M 1) , Prolrsor of P.rhol. ogy. Univetuty of Soulher. C'aliforni. School of Medicine. C'hirf P.rAnlorrl, I.os Angeles ('ounty Hospi(al, Lo. A.- Kks RICHARD ll. DYFRRUM, PMD., P% /esso. of CAcmrsrr'y, MkhlRa• Stale U.iversily, P.N I .nsi.g StSTFR M FMtl Y('A11111, PND, ( AY/rn/On, ( hrm/stry I/rP.rcmrne, Rep. ('o1kK, Weslun. Msss W I I 1 1 A M 11 ('A R N FS, M D, Pro/rsrer of Pathology. lJr.i.ersity of Utah Col. kK of Mcdkine. S.111 ate City. I EOPOt D CF.RF.('EDO, Pit D., Pro(rr- ror of fliocArn.irtry .nJ Nrrrrhw.w, Univetsity of Puerlo Rico, School of Medki.e. Sa. luaw (formerly Pro/n• sor of Bioehemislrr, Pordhar. Ueiver- sily, New York) Wll LIAM O. C'IARK, P(t.D., C1/wk.l Asroclsr Pro/rawor of PAyslololic.f CArmisrry, U.iversily of C.lifor.i. Medical Ceaq, Ler AaSeks. H/ NS T. CI ARKP DSe, Pro/e»or of ewcArnsbay, Columbia Uwiverslly Col1eK of Physkians sd 3w~eon., New Yorl (re(rred, soe Ooelsch.M) /AY 1) ('OFFMAN, M n, Insererrlor 6e Mrdirinr, Mars.chusells Memorial Hospi/als, Boeton. 1)ANIt:I (Y111UN, 1) V M, M P 111 Ar .n,un/ Pr.F rr.or of {'rrrrin.ry I!PlJrmluLr11 anJ rvAl.. N..6h. Scho.J of Vetennary Mttlaine l)ni.ersily of Pennsylr.ma, Phdadtiphia PROJECT TIT7E Studies on Ihe de.etopmcnt and biololy of lung surfac(anl PNlwlo*-...lowk study of «ndar ch.aRee in hrw.s broochi (C ) Study of trace mel.l Mor.ge of pulwo.- .ry ..d Li•e. Ihsue by spectoqaphic ..d a-Aemic.l eiethod. ( C ) Bio.rahe.is of the Pyridl.c r1se of OKo- Iw (C-- P) ComWl.oe of ..aly(k.l rnrthrrds by Ie/errwieiw~ the P~ rcewl rtco.erf tr/ .rse.k .tldcd at \no.• le.cle to to b.cce s.mpks and a broaJ survey of Ihe .mouM of •rsenk present is to. b.cco s.mples from ...idc variety of .wrco Palholotk-..alomk .nrJkf of cellular ch.nge in human brunchi 1(' P/ A study of early chemical changes in the lunp of tumoc bearme ralf and mice (C- P) EAed o( .koli.e and related subslancee aw .mine le.eh in the nervous system (C-P) Pro(tolytk .eNvirks of the .hile blood ulls of wse. •nd the elect on while blood cell .clivUics of carcinoKae. .u4ilio. ..d other influences IC) The cRecl of ,ob.cco smokine on nulri Bve dekld musck b1otW Ao r as Je lermi.ed by Ihe r.Jruisulopc J1s.ppcar .nct technique (C- P1 To survey r.Jk+paphkally 1he lunos of all dogs p.ssmR I~rnueb the vtlerrnary elrnke •r.d henpi/al of Ihe l)nr.ertily of Pennsylvania Velermary Schcrd in order to delermrne the prevalent.e ol pulmwrary abnurmalil.es detestable by this mtlhoJ - a crrnparauvt pulmon .ry JIKaK study In Jtbne tltc palltrnt of re.p rra/rwy Jruax in tpwm.ls in Imuttly sharing mani en.uunmrnl anJ provrde informarir.o on the eRrt11 of ew pollulion 57
Page 31: avr30a00
(:NANTI.F. Alvf) 1nSTITIRION Iltl tt1S 11 (()MROF, la . M 1) , l)rrrr rrrr, C'ardnrroar/ar Rrtrnr.h lnmrurr, ttnrvtrury of f alrf.wnu MtJrcal ( en let, Sae Ir.ncr.co 1)FAN M('()NNORS, M 1), Au.rwrr llrrrtrn., llr/v.rnrrnr r.l loArwarory AlrJrrrnt. St Maryr llwpilal, Madi son, Wr. P1111 IP ('QOPFR. M D, ('Avl, Srrffiral Sn•rt, Velrrans AJnunnlra/qw l/o.- Pi1.1, Sroa, N Y; Cfuwol rroftuur of Sarjr.y. Albcrl f-imltin MeJical (olttge, Itrona e RONtRT 1 (RAIN, Phrh, Arnrronr rrn/rn.u o/ S.. LJ.rrt, llnrvtrury nf (hicaM (sre 1' Kalt) AtBFRf 1)AMON, M1), Prr1), Arrrr lanr rro/n~arr o! M.Jrrol Mrh.n/v.l ofy, l)r/`~ rrnrnr ul InJrurrd f/ r~rrnr Nuvaral SrMrJ of Puhlrc /1calrh, Boaoe R P 1)AWSON. PN 1), rro/rrr..r of SrNdny, ('olumhu t)mvrrul), Ner Y«! ANI)RFW S f)tlfNfR, Pnt), f.rrr rnrr, PayrAo RrjrarrA, lhe Art (tnlcr of New England. Inc , Do+lun, Mass (see Whirti.) I-f)WARh F/X)MtNO, M I), M1.•/errrn n/ Marn«nJufy, tl.iveruly of Mich itiaa, Ana Arbrr RAt P111. [X)RFMAN, Pn1), l)urrrur of I otta.ororkr, Worchtslcr / rrund. /wwr frw Psperlmenlal Ifruluat'. Shrtw+ bury, M.r IAMI!5 I IIYAR, Pu 1), Arrirranr trr. {rrtw n/ ItrJ,.rr, 1Stllarmrne / tdlrar, IrNirr.Alr, Kr 1OIIN W F('KSTPIN, M1), .lnrrrnnr Ir../rrr..r n/ lnrnn.J MrJn r ( rd/rgr of Mrdkinr. Slair l/m.r-ly of lu+t, fn.. / ny 1'tI11JF(T T1Tl F, Tht tRrcl of amokrng upaan arrway rruu ance (( P) Analysit of case hituorics in tmphystma 1( ) A study of the dltrrlums in the hum3n bronchid w.ll octurrne wrlh aaint, wMh pa rlrculu tmphaus un tlaslic c.s sut chasaes and a.scxulrJ changes in the bronchial lume• arrt A sludy of the e8tcls of cr'arene smoking on kveh o( gastric acrJ, ptpsin. and uropepsi. (C P) A study of the e/lecl of etuacls of tolAac- co on cullWes of lumor and normal ctllt. Aaimal Iransplanlr of tun.or ussoe (rom risuue cultures W P1 Study of cnmbined effccl of injecled viral eetala and e.viro.rnenlal fac/ors, in cluJrait carcino~es and robacco.wwlc, on the IracheoAronchut Irte and put wrooary p.re.chlnu of eaperrmtntal aermals ned on luauea in orapn cullure Saial and psychotogkat corrrlales of aJU(MMM and drscunrrnnalrarn of cia.r tnr smuling Rody form, smolina, and alc(1ho/ con sumfyroe among Itahan Amerrcan men I(' P) An invesligalinn of the mrlahnlism of pyridine compounJs in rht lub.cto planl ((' p 1 Psficholoaicat and hehavirwal characlrr Is/itf of inhaters among smolers (C P) FRectr nf Iobacco smoke .nd nicoline nn the ceetral nervous syslcm IP/ Fvalu.lion of rarhato comumpruwr on the basis of nicnline lu narume mela Mrlnts In h..Jy flurJs and carM.n n.on o.Mk (IMlfnl rrf hhMMl NrMrl,trMrnt u.nvtnw.n and rt.uhrna prt mtnl Junpa m anl.m v.rirlrt. u/ /rrhato Rtarmw Ir/ Iht (rriphrral rt.m in man tu the rnlr.vrnous a-lnumslr.l.un of n. u/rnc 11' / FawH hhrw) ft— rrsprnacs lu +m.~lma in Ihc p.cunac (if hyprrh(wmia .nJ hyPrrlrnunn SQ P i GRAIYI'I:E AIVI/ INSTIT(rT1l)NI IIANS 1. PAI K, Pu 1), Scniur RcrrarrA Atrrriorc, 17rporrmenr ol ParA.rlnfy. l)niversity of Southern ('alifornia SchrKd of Medicine, 1 os Angttes Ino. Iled, l'hemistry Seclinn, l'arcin.yene- s.s Studits Branch, Nalwnal ('ancer Instdure, IklhesJa, Mal ) DANA 1. PARNSWORTN, f./ D, Nrnry K l)lirer Prnlroaac ol Hl@iene and Dittrtor of f/nr.ertirl HcahA Srrrrcts, 1larvard llni.ersily, Camhidge, Mau. (act I1c.U and MCArthur) FRANK C FP.RQt1SON, Ia., M D., ('Aalrman, f)tporrmrnr of IAwmoru/. on, Albany (N. Y.) Medical Colkae. RUSSEI I. S FISIIFR, M[), CAie/ Alrl- iraf Etamrner, Slatt of Maryland. Pro- Irffnr of I real AfrJrinc. U.ivtrsily of Marylaod Medical School. Sallimo.e. 8 L FRFFDI'.ANI)FR, M1), l)irttror o/ Cancer RcaranA, Mount 2ion 11us- piul and Medical C'enler, San Fran cisco (deceased, see French) FRI'I)FRI('K A FRFN('H. A S, lArrc- tor nl Concrr, ('ArmnrAtraOy Rrarm.A, Moun1 linn /Iospital and Medical t enter. S.n Fr.ncrstu. (See Freed. lan.kr ) lA( K PRI t/Nl), M 1), Arrnrunrrr..frr aor nl Ph...nra.al..rr. McJrcd (ollrae u( Vuauua, Knhm.wtJ PR())EIT TITI.E P.aaminatiow of cigarette paper and crpr clle .mote condensalcs for aromaic Pdfcrdk hPdrorerbons (( ) A cumpilaliow of fluorescence spectra of polycyclic arornalic hydrocarba.ns anJ closely related cornpowrds which are of inltres( i. the ala P of air po11Wa.1., a.d ciprelle attwAe in reblwa /o lung cancer elioia>ty (C. P) TT1e cRec(f of tobacco sn.oke condensale on the defcwse mechanisms of the ral I. delosiRcalioe of polycyctrc aromalic Aydr«arbons aad the compelilivc in Aihilio" lelween the pr>tycycl/c h>Jro. carbor in coaknsale wah regard /o cuci.ofiesaeals (c) Tlre PhPsical and chemkal prrrperlies of wtwcw u.Jcr normal cunJdions a.d lolloving eaposure to aerosd irriueu (C) Persnnalily and smulinR in colteAe pad"sln; a Rfleea year follow up audy ((:) FRects of lobacco smole upon the func liuw of the cardiovascular system ie aniwuls and man (C) Palhologk--analomic sludy of cellular changes in human bronchr 1(') Qaptrimente on the po.sihte carcinnatnic and cocareiruhenrc aclrun of lub.cso poducls (C-PI Carci.Wnici/y, cocarcinoiftnicily anJ anti carcinornkily of Jrtlary /+clnrs in rdalion to pulmcw.arY lumws Pm sihk mlelrelalNMfhip o/ arhxtn L.as and Jitlary faestws ('hemrul snrlitt on pyridine ba+es inaluJmg nm.un anatop (('/ ('urrelallnn of rnulhttr hnK a1 prrreJure+ ptr/rwn.eJ on the perrldrer.l uuula/rnn of normal rnJiv/Juals in rtt runhrrH rnJ elect rarlinM anJ.fltr etrrrr.r t.tf.ne anJ a/ltr sham.nd aclual snurlrna // 1 A study of the tRt.ts uf c ia.or/1t rmr.&ma on the perrphtra/ Ciraul.rlu.u ul rnJr valuals with arltriusJero.is nhhltum and dher periphcral vascul.r rburser, uhlrnng mullrlrtbnnal pranedurts (c) 59 C t
Page 32: avr30a00
CRANTFF. AN1/ tNtiTITIRIIN( ART/1(1R FURSf, Pwl), Or•..,o., !n rnrrrr of ('Armkol fludnft. (/mvtrury of Sao /ranlMco OFnROP 0 l)FY, M t), f)iterrn. Frnnry Horrll ('ewcr, RrtrurA L.h- o..ro Atratierr P,nft„or c+/ Srr- tr•y,~ohnt Ilos.tin I)nran,ly Sthool of Med.cine, Sdhmure, Md TFI(1MAS M(1(K KF, M 1), Arn.rLrr 1 tn/r„ot of P•trrnnrr A(tJarwr .wd ('onrm..wlrr llrolrh, $tlcw 11.11 ( d lese of MeJ.crat and Iknlrclry, Itrvy ('lly, N I IRA (:ORP, M 1), I•o/etro, of racA.J ofr. ('kntun (fnmrtr.n) Sthool o( Mtd icrne. ( AMr/ n/ f.A.r..nvr Sr..d'r, Vtreren, Admrn.curhun 11ocp1t/, Wr.l Ro.hury, Mrs. 0HRTRIIhI! V OUTTS( /IAI I , PH 1), Arntran, P•n/ncn. u/ R.n.Arnurrrr, Drp..rmrnr n/ lurA.+luft nnJ A(,. •n `ndoff. T).c Roclt(rllrr Intbrurt to. MeJica/ Restarth, New Y(r1 (ae ('lvle) A('1 ARK ORIFFIN, Pn 1) , Hrrl of SkwAtn.brry flrpr•nnrnr. M 1) An dtrson Hospit.l nd Tumcx Instnule, Uarersky of le.as Medical ('enler, t(ousto.. MORTON I OR(TSSMAN, PN 1) . M I)., Asrorf.re Cl/nicaf Iro/ruar of AlrJl r/n', (/.iretsHy of ('ahfotnia Medital ('enler, Iae A.gelct. CAR1. C. ORUIilIT, Pw 1) , M 1) , A,ro tiar iw rAy,lolo" .wd rA.rrnacnl.rry. ll.hetsil~ of Pesns~1•ania OraJualt Schod o/ Mcdicint, Pfiil..klphi. (nn. 1 eclurer hr PhysJd.My, (fni.ersul) of }Icwrg Ko.s) I RANK 1' (iIlT/1RIP, ht 1), I,o/nur•. and IRNISI /1(IfK)SON, PnI), Ar ,urunr Rtvo„A ho/ru.u, flrfvrr...rnr of Fnrnnudn~r. No.lh ('unlrna Surt ('cdltr, Raltyh , P•nlr,rn. n/ rnu. 11 H IIAAIf. M 1) rno.nlnff, Medre.l (dlesr uf Vu/inia, Rrrhmund (de.eaaJ, .re I.ruwr) PN/l)t.1T TI11l: A crrnltolled .NuJy to rvelu.lc Ihe effctl of admoittra/wrn of /ract nalal, (.ilh or without erpcxure lo crpretnc tmolc) on Ihe incrdence of p.,tmu.ary adeno- ota, I. Suai• A mice Ftllo+ships fnw studyies the cutrure of bwn.• lung listue and Ihe eflects of Iwo.n and Posuhk cutinotltnrc atitenls opow such Irnue (l' P) C'haracleritfks o/ .rnmal cell porrlh ie culture is relation to invau.e carcis- ana, especially i. Ihe lung A studr of the .ssa1 and pharynteal bac- lar.l tlcxa of snwrltn, non tmu\tn anJ te rnwAtrs the rnNurnct of tnvulxMnstntal fa(IMs on arrtrr.l mhm.l comnluen+s and func 1MM11 Prortolyl.c ac1ar11Kf of Ihe .•hne Mood etllr of m.e and Ihe eRecl on rrhrle blo,d ctll sctUrnas of c.rr rrltm, nu naruw sJ dhtr iolluencer (( ) 1).e eflecl of tepcnurt 10 uprene emole oe the InJu(INM of cuncer hy chtmnal coanpoundl (l' P) TAe eRect of smoling on ctrlain yurk funcNoos (C) Pharmacolotic sludy of nicoarne aod rt- Ia1rJ e11IrwJs ((-) Nrnlufir.l ouJ.uun nf ur/unr..lr rmttn r alrt PrtparNU.n fur prdd.<arnrw of e htr.•\ on Ihc bnJ.rfrt a,perH uf 1„ha.t,r and vnolrns ((' P) U J CRAKTi:1: ANb INSTtT11T10N1 H)SFPlI /1 1IAFKFNSCt11E1, M t)., Dr.rcrrr, ('mdnrpufnsoneey f/wn, 1 an Irasu /lotprlal, Philadelphia PR/l)F:IT TITI.E Measurcw.c.t of coronary blorw) Ror, cardiac erork and cardiac oeygen aaJ carbuhydtale mcl.bolrsm in n.wmole• ai.t subjecls before and after inna renow .koli.e and afler smo\rng aa.dard ciprellea (G-P) 1 RI('NARD Profesror Califorsia cesco. I t1AVE1, MD., A»inawf of Mrbcrwr, l/nivernily Of Medical School, San Frar A study of lhe eflects of smoking and •kolre adminislralion on sympalho .Jre.al (usclioe nJ (atly .t,J meta bolisw (C) . IIEReF-RT R IIAWTIInRNF, U 1). Attempts to iwduce pulmonary ncoplasms , CAairnr.n, DrParrcnrwt of Srrgrry. Unirersily of Pennsylr.nia Ctraduak in esperresen/d animals by cspu.ure of the Iraeheobronchial system lo to. School of MeJicine, Philadelphia. ('t.ARK W NPATII, M 1)., Irofrrtor of bacco smoie (C) Ptrsonafity aud atnoling in college gcaJ A(rd.rlwr and I)urcnw n/ 11rd/A Sr.r- Me,, lufts I/nirer.uy, Mcdford, Mass. (ae Fares.orlh •nd McArlhw) aates: a Rfleen year (olluw, up s1uJy (C- P) t PAUIINfl IIF171'.R, Pitt). Rr,ra.rA A»orivtr iw Cyrrdofy .nd ('yf.aAr.n. urry, Sa• Fra.cisco Inslilwe of McJi tal Scieeces, Sa. F'rancicco. (see Rich* ards) A comparNfve shnly of carly hnrological and ONA changes in the eprJermn of two slraiws of mae /( )7 Ml.cls anJ Srria Webslers) after Jedy pplaa. Ikt.s of whole cigarclle smole coo dewle (alo.e and combrneJ wilh erolom oil) a.d the carci"cns :0 melhykholanthtene and ),4 bentpy- reN (C) The relalio.shiQ of the use of tohacco producla to Nhe oulcume uf pregnanty (C) 1 AWRFNCP. L. IIFSTI'R, ). , M 1)., Iru/r„oe ewd CArirmrw. Drpwfmrnf o/ (1Mrrttrt, and Gynetolory. Medical College of South Caroli.a, Ch.rkslow. FBBF. ('URT/S 110FP, Prep., M D„ Prn/rsaor awd CAdrn..w. Drprtnrtnf of Nrrroloflr.f Srirwrr, Medical ( trI• kfie of Virgrnia, RicMnond. RUSSI?I L L. 11(11 MAN. M D, lro/rr .,w OnI llraJ, 1)rperrmrwr of rreArJ- ufy, I ouisi.na State Univcr.Ny ScMrol of MeJicine, Ne- (hleans. (deeeaseJ, ste Mc(iill and Slrong) I RUt)t)Y II(1MHIIROFR, M 1), Prrrl- Jrnr unJ fh.errnt, SMr Rttearch Inmtllu/t, lnc , ( a•nbrrJllt, Mtu RI INI R I W IIt f1 I, P 1). t.n/tn.•r n/ hr,.l..fr„J 1,..n, n. / LnJ. Sr+/t I/m rrrrny, I.L/u..rr Biochemical sludies uf nictNint and ns rnlermeJrale mcut.oli/es and Iheir c/ (ecls upon cerebral aun.nurnic mechan ifrws Pathologk - anatomic study of cellular changes in human bronchr /l / The inRucnce of IrJ.aeco smnling on acute myuc.rdral inlarc/inn ((') SloJin on eareinottenecn anJ rhr bio- astry of carcinulru.c agcnts (P) ('omparalive snabes uf t(lerls uf verinus hrbaccu snwsle corsdtnsalcs on .Irns u/ rnMe (( P) Syslemk eRtela of Ihcte luhscru smolt cunJensales ((') I+holudyn.mk atUrarun nf rncrnurtnr hydroc.rh.ms: (a) s1.nJ.rJu.,run uf prrNUtu+, a.c.y Itchniqurs ur9rnnIT (tr) lnvtHiRdinn tr( rht mtaham.nn of aclivalrnn an.t tetpontt lu uumNrc carcinogens by pro/o,ua lP) 61 r
Page 33: avr30a00
/;11ANTl:F: AND INSTITIfTI(IN OF()RGP fAC(/RS(IN, M O, Pr,•frr„r. •nJ //r..J of ReJ,.Jnet. I/n/.er.ily of Soulhern ('alrforn/. School of Medicrne, 1 a. Angetes )FRRY /IART /A('nRSON, Mh, M. rrc/nr of F-Irrr.opAyn.dnry, New Yorl Fye and Par In6rmary, Nc. York . 1111 IUS II !A( OSSON 11, M I), Awr c.ulr Profraso+ of Surfrry awd lhrrrr.r, of Sarr4at Rrara.cA, (-olkge of MeJi cir.e, Uaiversity of Vermon(. Surllng lon N.... I)ueclor n/ lr.nor and Vaf cutar kr.r.r(h, MI Sinai Ilo.piul, Nrw Yrr\, N Y MURRAY P IARVIK, hl l), An,•.Jerr Prnfrunr of PA...n«.d..jry. Alherl h.Insrrie Co(Icre of McJKlne, Rlunt, N Y. ANf1RI W A KANII(r)S( 11. Phl l), SleLl S,bnrnt. Ro..oe H/atl...n Mr nKNral I sborNn.y, Har Mc ARNO1 I) R KAPI AN Pn 11, II•...r.•. I aAnrar...y n/ A(r./rof I:.vru r I Ic.r IanJ Ptych,alrrc Intlnulc anJ Ilu.Pn.1 1'1 111U K ATZ, Pn 1) , A rr.r urr Prr./rrr.w nf S,rnJ.•ly, lln,vcr.,ly of ( Itlca#u (see (-run) AN(-PI. KPYS. Prr I), Prn/rno.nf PAyI lnlnflret ll yR/rnc and 1)h.rr l.w, I oA ararory of PAyunlnwal llygrrnr, I)ni rersily o( Minnesota School of Public Heahh, Mlencapolis 1OS! P!1 R. KIRSNI:R, M 1), Pr../rn,•r ,.f AIrJ•.rnr, llni.rrsily of ( hwato Schru.7 nf MeJalnr P/ IFR /1 KNAPP, M f), Rrvor,A P... R.n11wn llnl.rr.uy S.h,rA nl Mrda,ne- HoN,w. KI NNI'111 P KN1/1)ISIIN, M I7. Ar rnr..nr r A.rl Vr/ crans AJnum.l,•t,..n I/.n~ IUI, Sr.111r, Wath . Pr...•f P,..A.J,•rr Ilni rrrvly u/ G allr 1•H(1JF/T TITI.K lhe Influence of certsin enrlronmenl.t faclora in the ftcnes/s nf nr..pl.Uie Jncase in tuberculo.is pal.cnll and in ehilJren A eomp.riu.n of ekclrewellnngraphy a, a weaas of evalualing the cflecl of .asoeomlrictnr Jrugs upnn cerehrat Ird relinal circulalron .rlh olher keheiQues for Ihis delerminalron (C) I I ung homo/rsnsp(antation /C P/ Pilot auly of hsbitua/lon lu ni.talne by mran, of nctsus nKrnlrys /() Tn drlrrmine In wful eurnl tobacco I.r' mrm.cs the act.on o/ c.r.rnnarnn h1J,lx.rhons in the s\,n nJ u/her I,aur. 1(' / I r.•mmahnn nf Ihe rclrnl nf .nJ t,.n tnlurn.nat ha,i. (n, u.rrrlan,n. he Iwren Ihc fultow,nj 1I/ LUe Ilne.h .J,1. I.r 4mn,nc an,l /6 n pr..pyllMuur .aJ. O/ cunsl/lul/uoal p,rd,.pnvUnn in.Lrnlu.l 1.1 palhutuIl,c rariahtes, ( I) Jlflerrntrr in smnlmg p...lites, and (4) f.nnl dlshtes Sncial and psychdo[ical cnn.trainls on the li.nslalion of nwNivc% rnlo .tlnrn: The case of ciprelte smulinR ('haraclerislics of men, incluJing smok ing, in ppulations J,flcrnnt in Ihr in ci.knce of c•wonary heart Jiseae ((' P) )he rRrcl nf I,.hactn trr.olina upnn ha+.l g,,/rK trtrrlu•m /n m.n (4 1 Inrr.na,.Unn ,.f pr,.no.J,ly fr.lwrt a. .,M,a1rJ w//h e./„n,rl ,./ snn,luy trharnM P./holnIn n.lnmi.UuJy nl rltular t h.nar. .nahuuun hrnn, lu 1 t ~I' 1 62 , i (;HANTF.F: AN(/ tN1T/TIrTIfIN AI VIN I K/)SAK, Pn1), Anrrinle Prnfrrr.,. u/ ('Armnrry, W»hingloe Square ( ollcge, New Yorl Univeasity, New Yorl R(/HI.kT A. K1//1N, MI), All Suuls 11a.pital, Molrl.luwn, N I and Au..• .r.nr Pr,•/rs...r, l)-a..n n/ Nrurrn. rurRrr y, llryrurrnrnl a/ Sloerry, Sclnn (LII /'olleRe uf Mediaine, lerxy l-ity, N / MARVIN KI/S('IINFR, M n, Profr•rsne of P.nlwlne., Ne+ Yorl (/niversNy ('.rlkRc of MeJicine; fhrrrrnr ..( Pa- rhnl..Ry, Belle.ue I/o.pNal, New Yurl. ( IIARI FS W. I A Rt l 1 F, Pn 1), A.- lillYn/ Pro/rlt.N of twr,runNlrnruf llrerrnr. I)rpurlrnrnl n/ M1rcrnrivr AfrJl,rnr, IeRerMM Medical ('ollege, 1'hd.Jelph/a (Jrteased) I/1()MAS ( 1 AIrPI Y, M I), PruJrau.r .rl P„rAuLrRy, NcwlhwcJcrn Unirenity MeJ/c.1 Sahool, CAni.rrw.n, llrporr. nrrnr o/ Pmh.d.r[y, Wesky Memwial Flusprlal, (hicalto PAlll S 1 ARSUN, Pr/ l), Frn/rrusr of PAurarwoh.lry, MeJical (-ulk{e of Vir- Cin,.r, k..hm,wal (see (taag and Me Aa'nnls / (iUSIAVI' A I AURfNTI, M1), Ar ...r,nr u.r uI AfrJ.u.r and f)i• rr, 6u, /trnv..n ../ Rrapin.l,rrr Ihlnur.. ticlun 11,11 (ldlele of MeJitine, ler.ey (ny,N 1. ( 1(-11 11' I I l/('F11!'NNfR(3FR, Pn I)., Srmnr Rrnl•.Rnr .mJ 1Ar.rrnr- Sias Me - m,N1.,I I IMMIInIKt, RIIMrIt Illnp//al, 11„w.lhnr, M.... (nuw .1 1'enlre Anli .,rtu. Hum~rwl. I.u.unnc. $wlNer I ~n,l l 1\IIN /) IINt)S1 I11, MI), Allmmnt Pr.•/rrr.v n/ 1u.Rr.y, (/n/rrrc,ly of M/nnrs.a. Mcdia.l SthrrJ, and .1nrft r)r.rn I.n. .[w~a nf Sr.vn r, Velcrans AJmrnwr.lwn I Iu.pu.J, Mlnnc.lfr.l.s /nuw .,I \I luvl.h~ Ih..pual. SI I'.n1, Mmn l Pn/yF.(T TIT1.F. The isolatlon and Idcnliflcat.<.n of ccr Lin (osrer boiling compuncnH of cig .rctlt amoke (C P) Poasible effeels of tobacco upon cerebral circulalio. (P) Pathologle - .nalornk sludy of cellulsr changes In hunun bronchi (C) F:Recl of cigarelte smo\c on pulrnonary ckarnnce Palholoffk--...lornk s/uJy of cellular changcs M human bronchi (1') (Yassificalion, progmnis and eliologic faelors of pimary tumws of the lung Preparalion for pubticatios of a Iwro1 on the biologic aspecls of tobacco and fnx.ling (C - P) t:niy/nalk tr.nsfnrmations of nicoline and related eompounds (P) The possible ellect of tobacco anwAe .nJ nrcoline lam ascorb/c alilf inelalwlitm 1(' P/ SluJies in lronchilis: a correlaled iwvesti- pliora of (a) the cf(ect of srnotinR on the AackrioloRy of the respiralory tr.cl of humans, anJ (b) the eRea of ciprtl/e smolke and urlfur dinsidc (air lulanl) on Ihe ckannft of bacteria rere the respiraory Iracla of srnall animals (mice, ras) (P) l:Recl of cipretle smule on pulmonary resislance lo infeclnwl A correlated hislological, cyto/ogical and cyluchemical stu.ly of Ihc trachco bronchial lice of mue e.p..eJ to ty aretle amnle (C P) 7?he inttrrelaliun Letwecn mflurnia rnus infeclilms, eaposure tu tigneue snwllc and Wher facl/us in the Jrvelupn.rel of prdmonary asnl brontfnal levunt in mNC (( PI Meawumee/ r.f the JlRnrra/.1 bhwd Rnw lu Ihe mammalF.n IunA Ju..ng the atule prrirrl of snk,le Inh.J..bun, uanc the npen thesl anim.rl anJ the Inrlh,.l and prrnciple of Ilumuu tlu,nmg ra.ho acli.e gr.JcJ mKrotphrlrs 63
Page 34: avr30a00
.40 (:11 A IYTF.e AND 1N4TT11 1moN lAM1;C e P TOMAN. rM I), lrulrn.rr ew1 ( Ar.umese r( rA~rrnerrJrrry, ( he c.p Med.csl rSchool, Insnture for Medical Rese.rch fANlrT TRAVPI 1 M D, Auorbrr rro. frtrn- or ('llnkJ rA~rwrornl,.rf. ('or. arll University Medical Colk/e, New rorl. P D WARNPR, h1 D. Iro/rm+of Is- cAoIM-, Sute University of loo• Col. leK Of Medkiee, lo.a City. SIIIFI DS WARRF.N, M I), Dlrrrroe of -i-.r.ror7rr, ('snrrr RnrarrA fwrrlrurr, Ne. Pigl.ed I>t•coeew Iloapird, S.wloe RICIIARD I. WP.('1(S1 FR. M D, Clint. c.l IAyr.ol.+rur, Montelkue Ilosp.td t•sli,eu of Research, Piurbwilh, Per Rl1SSPt I. W WPI t P. M D, rwA..lo rlrr. Mersorld lloyit.l of (-he+rer Cow1y, Wesl ( better, p..; An.wwrr lrofrrsor of retrAolory. llshnem.nn Medicul Co1kge, Mil.delpbi.. SIMON 11. WPNDPR, rN D. Rrrrarr A lrofrrsor of CArn.wry. Unr•errity of ()-labonr. Ndrnae PRO)f;(T TtTlS, Mech.nisms of the psychoMropic eRects of nkdree Pf7ects of ekotie• in the r.bbit with eaQerimeetat coronsrr atheroacletosis (c. P) -+tholofic - .natomk study of cellular chanres in hunun bronchi ((.'- P) Correl.lioe of bronchial epithelial ehaeres with comparable chenres ie other orlifNS - a p.tlwloficenatomk study (C P) Tlr puertr of finN.+ISrb of carcinorna Of the lung in man W PI Ilsru(rtAdtMy of human lung cancer PRecl of cipretle +mo-inr on cerebral blood dow, cerebrd mefabolism, blor>,! gasu, blood plt, arterial pulse pres- swe cuncs, eltclrocardiotrams, aed ekclrocecepA.lopaeu l(') /.rhniotk .nuomk swuJr of cellular ch.nres I. human broncA) ((') A selerled, euerxkd and del.iled study of hums^ bronchisl muco+a A au.lilai•e and u.ntil.tive sludy of the individual ~yphene,a content of ci{arelte lobecco and he smole and 't.ri resulling from cigarette srr.oling .ed also Nudy of the fale of Ihese cornpoueds I. the animal respiratory system (C P) The ldentiricatiow of iedividu.l polrphe- swlk compout.ds peseel I. the unoie / R(X)PR 1. Wit I IAMS, rn D.. Irofrauor of ('Arralrrry and Drrcror, Clayrow Forn/ssrww erocArrwk•1 Insrirrrrr, The University of Teau. AuMio. 1 FDWIN W(>nD, M D. lwrrrerror in Hrdlrlnr. Roslun tlnivtrsil School of Medicine, tScxlon (Now rolrsror of -IfAklnr, Medical Colkre of (ieorRia. Augusta 1 SUMNP.R WOOD 1.., MD, Auirrrawr Iro rsur, oof rer~ofor)r. Drr•rrrerer of rur~olon, lohea I1opAiu Ueirersiry, Saluoore, Md. 1O11N r. WYATT, M D, rrofrrmr of IurAolory. Sr. 1 ouis University Schoul of MeJiciw. St. l.ouu, Mo. A. Irvcstipt{oe of biochemical factors .ssocialcd with suscepubihty to lung ca•cee The c/ecl of prolonged inhalalion of lo bacco trwtrc and of prolonged ^bsue eece from (he we of tobacco on the mlplleral vaKular re3poese to .cele dation of lob•coo smohe I. erae (c-lie1 Evduatlos of elbloslc fectors, such an occupational haurds and habih, and NlholoRie peculiarilies I. the luer. krw ,wvivl of patients folbnirq re- secliuse for beoncM.tienk carcinoma ((:) A. I•Ksliplioo Into the nature of the rRareNary lesioes in ceolnlobular •mphyserna (C' P) from cip retles and the peparatioe, aherc Ic^afbk of these compounds for sludiea on their mel.boliim and possibk effecl on humae health. DUANP O. WP-NIPI , rw D, rrn01m1 lhe delermlealiw of the chronic eRecls of -A-nwrol..rf. Sc" Of Phsrmsry, lleiversNy of Kaeus, I a.rerKe. of orally .dminnured nic.Nrne on serum chdeslernl and phu.phraiprds, the eleclroc.rdlost^phk tr.ponse to frerNOVlne, a1NJ IIM v.nuter parh.dogy a~ tn of ch.drslerol (rd rsf.hns 1(' 1') A du.ty of tenlra1 .,tir.nr of nicWrnt r• r•J t~J FRPttPRtt'K 1' WIIISKIN. M 1), (' 0 , (Ir.rtrr.., Itrrrrnnw if IlrotrA .rwJ f n r.,~.lrrr fV~~fr~rro~.. The rlce ( enter of Nrr 1'nr1.nJ, Inc t+.nron (see rdM Hudy of rmnlrns h.MH of Age (rntrr mrrnben 1( 1') U O 0 I)rhnrr) •O 71 70 P N
Page 35: avr30a00
---

Text Control

Highlight Text:

OCR Text Alignment:

Image Control

Image Rotation:

Image Size: