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CTR HN 011536

i. • ! ('ORICItJAI, WO NOT I2EMOVE UNLESS Tp~; rAKE A PlIOTOCOP y .~ ~ . : ~. _ SCIENTIF.IC DIRECTOR.< aaRovcE ooor ,•,rrnt, ac.n. -4 m TIIE (:OIINCII. FOR T()OACCO RE_SEAR(:11-lI.S.A. ~. m ~ : m am 0 m ~•

4 t f . `.P ~. ~, lZatiO[1 '` . , ~'olicY~ - ' r. , ~. - •.. _ ~. . . . ir~~~,T1~ Caa;acr7 bor lbbipo~ l.p.rclhll•t.A• L T ~ 4 ^o+ e pr'oitr.. °S t+e..att! 1NO !pa'ti°om artobaco w0 a.d be.fti. It Me. -~i~I i~. r.{~~d V Mfl~ 1YS4.y Ir~.~tlM f!< IObaCOO erae4tKlY[tlt. •: ,;' ~~- ; ~po+ior~ !sd w~r.~r.qo, prb .rc~ r..eudt tbrpr~b . proa.m d ;, 1t t?t/p , , r ~ ~A 4 Zide.tl6S /1QTboR Do.rd /b Tb Carocil .d®ieisten tbis pIffints- :' b•+W prope,. Tb Boerd wrready oo..iMs d w. .cieeelsL ..d eo«ton .bo .+abe.L tbdr rapec!}ve L.titvtiaisel dlW.timr. A Wt of the Board oe.nber..pqcars an par ~. i TU Scie.tiAc AAri.or7 So.r'Q bas fw0 tc.pos.3bWty for reaeercb potky ••.ad prop.a+mkc Ai . Board II doea .ot directl2 e.tage le reseerch tor ': 7U0 Oo.uail. .oM dau T1e C',oeMr kacu opa.t4 .ar r"altlch facility. Unots•i.-aJd for re.ep.rcb are made by the Board to lodcpeadcot aci- ~'. ,_' , s~lael pbo ue raursd coeflpkte aicnri6c trttdom In conducting tlxir t~~ti rM..fcb. T1ey.ipee.re re.poeribk for rrportin4 or publithing their findings til/ woepted ltieatJlt e+aeeet-tMough medical and acientific Journalt ' f7,727,000. ' • - ,, . t ~ .r ~ ti,~. A Wt, pf rY.e.r~ prvjocU wpQoreoe !2 itre Council 4 included In Rspoet• ALo iocluWed .re abstr.cta o( 62 re.earch paper., .cknowrkdg- ~' C,oteed ivpport, th.t have .ppe.red in .cieaWlc Foueaala since the ~ 1p63-" Rcporl Md tlrorgh December 1964. A totel d 401 lvch papers !!SA S' ~. ,yry beew ribil#od bt Vrsat rccipienis. TMOT.T V. BafTMRT W. T. IIOiT ((Jl 1..: :. • . (]..Ir~..n '~ !•aeeMli..INr.e~er T11C (:()(RV(]L POR T)dA(:(:() REaF:AR(lt-I1.9.A. 633 T1IrJ A.e..., New Yerk, N. Y. 10017 ~pt}K !00 borQitab, aal.ettklatM yd fc.carcb in.titullon.. These Irant award. •~~(hesta by Ibs WKd t5rourb 1964 ha.e been made to 212 Kicotiat. In , a= ` ANN(IA1. HEI'ORT uJ the ti(;1!':N'1'1!''1(:. 1)ilt!•:(:7'()It (7.ARF,N(:B (aN1K 1.1f'TLF:, S4:.1). I I

SCIF:NTIF'1(: A1)Vlti/)RY 1){/Alt[) to 'lhe ('ouncrl l(or I uhacco Rescarch -U S A. KI NNF1II MI RRII I. 1 YN('lI, M I), St 1), l.l. h, ('hnrrnrun ('honrrllrn and l'rtr/rstnr o/ I'arhofogy Medical ('(rllesc of South ('arohna, Charleston, South Carolina IIUWARI) H ANI)IiRVONT, Sc D. Scirnnhc f-Jrarr, The Journal of the National Cancer Institute Bethesda, Maryland RI('l1ARD 1. HINO, M D. 1'ru/rrsor anJ Chairman, Department of Medicine Wayne State lJniversily ('ulkge of Medicinc, [ktroit, Michigan Mt K FI:.N ('A7'1Pit 1) , M 1) 1'rofrrtrw I ntrrNUt tn/ 1'l+urmat nLrfy ('runcll trnrvcrsity McdKal ( o11cRe, New York, N. Y. I EiON 0 lA('OHS)N, M 1) 1'rnfrttur and ('hunrnun. Ih•partmenl of Medicine llniversity of ( h+cagts llnrctrw. ArR(mnc ('anccr Research Ilospital, ('hica6t+, Illinnis PA111. KO11N, M 1) A nrrI rnrr 1)rrrr ror lrn f rrJd SruJrrt National ('nucr InslUtutc, Itcthc.d.r, Maryland ('I ARFN( ri ('(1OK 1 I111 F, S( 1), I 1 1), I ttt I). .Sr irmr6r 11rrr+ nrr, Ihe Cr+unul (ra I tthacco Rcscarch - l I S A. 4 F llrrrr rnr F rnrrtrut, Ruscoc 11 )rikson Mcnwrial I ahuratrny Hat llartKjr, Maine STANI NY P RI IMANN, M I), St n ~ (hrrfrrN Ernrrirur, The Insutulc for Canccr Research Philadclphia, Pennsylvania .w7. WIt L1AM F RII:N11OI-F, 1ot , M 1) .~:~.. !'rn/rjtnr I-.mr.irur rr/ .Surxrry ~ lohns Ilupkins llnivcnity Srhomd of Mcdiirnc. Italtimurc, Maryland m Ptt 1) 1 MtsRRICON f11tAt1Y, M 1) ~. R 1(' II(x'KI?1-1' RO1t1: tn , . A r na urrr .1r irnrr/Sr I Lrrr hw A t r,H rarr 1, rrnlrn~ l rnrr r,rr 0 7 Lv'S CJ G u r (7, P ~ (<1 N n I t Edwin B. Wilson. Ph.D.. LLD. 1879-1964 Ur. Edwin Bidwell Wilson, whose career spanned the fiekls of authematics, physics, aeronaulics, sulitlics, epidemiology and sociology died on Decearbcr 28. 1964. hr. Wilson had servcd as a member of the Scientific Advisory Buard to The ('ouncil lor I tobacco Research-U.S.A. since 1954. lie was a professor enserilus of vital statis- tics of the Ilarvard University Schad o! Public ttcalth. Dr. Wilson had been a vice president of the National Academy of Sci- ersccs and edited its Proctedints from 1915 until his death. lie taught mathematics at lwth Yale and llarvard and was chairman of the Department of Physics at the Massa- chusctts Institute of Technology. Dr. Wilson served as a consultant lo the O/6ce of Naval Research for many years and was a recipient of the Navy's Distinguished Civilian Service Award. Ile was a past president ol the Amcrican Statistical Associaticsn, the Sucial Science Rcsearch Council and the American Academy of Arts and Sciences.

TA/t1.F: OF (:()N"TF:N'Tti lhe PrrIrcss of Research 5 Abstracts rrr Rcrmxts . . 26 Psychn PhysH'hr8ical Studies . 26 I ( arJNrvax'ul.r Ihscasr 1(/ ('arcinoRcncsis 9tudies 41 ()thcr (-anccr Studies 47 Pulnu.nsry Physirrlrrgy Studies ('hcmwry & llitthcmittry Studies 48 SI f'harmsc(Ji>Ry & PsyiMr Pharrnai"d"Ky Studies 55 Other Studies 56 R ccipicnts ul Grants 58 i 1'he Progress of Research The Council for Tobacco Research is committed to a oontinuing and etpaodin` progrsm of experimental and clinical studies of human diuases. The Council's pro6ram, therefore, is primarily one of medical research, which spreads over into the various related branches of science that can be brought to bear upon problems of disease. Withid the broad field of tnedi- cine, emphasis is placed upon etiology, that is, upon the facton, influences and agenls, both internal and esternal, thal may have something to do with the causation of disesse, rather than upon methods of treatment or cure. 7 his emphasis upon disesse genesis is due to conviction that prcvenrlvc mes- wres will probably do most eventually to reduce the toll of those diseases that are now our greatest kiUen. The selection of diseases for study is based on the relative present inci- dence of the disease as well as its importalsce as a cause of mortalily, and the degree to which it has been reputed to be auoeiated ststislically with lobacco use. The various diseases which have been selected for study ats belong to the broad category of constitutional diseases. These include, amons others. the cardiovascular diseases, lung cancer, ukers and the various chronic respiratory ailments. In such diseases external agents are difficult to identify, often compks or multipk and of minor importance or even impMent unkss and until lis- sues of the host organism respond by reactions characteristic of their basic and predetermined biological and biochemical makeup. llris situation is in marked contrast with that found in the infectious diseases where one or more specific external agents are involved Thcse in- fcctiuus disease agents invade the cells and tissues as enemy aliens snJ they rrmain su, mrpauinR, killint, destroying the cells and tissues wluch they inv.rk "I hc invrsnRator can devckhs techniques to isrrlrle thrm and tn rnutivate ur rkstruy thcnr In turn without harm lu the hv.ty cells In the trwrstituuunal discaus. Ihe situaurrn is ddlrrenl ('rnrcr crlls arc a part of the NKty nJ arc naf slicn to it 'lhry •rc mrKhlicd hut arc very much st hrnne Sinularly, the aging cclls of the circulatory system are still hjK1y cclls, impaired and wcakrncJ in function Irul still not strangers P 5 s v r 9 m

4 3 ~ 70 ...~. .i:.. 0 1 ~ In cooslitulional diseases the prncess is inrrRrarrd with the rflccted cells In infcctious disease it is a competitive and dual process and the agent is nor inrrtrartd with the cell, but is an antagonist The research program of Thc Council received impetus from the pub- lication of several epidcmioloRical studies that reported morulity from a score of diverse diseases to be hither among cigarette smokera than among rson-srrxrken; repcsrls which havt been and still re the subject of much debate among statisticians on tcchnical grounds. Ifowever, such epidemiok>(ic studies are helpful since they contribute hints and kads for clinical and esperimental investiRators. The Council seeks to utilitt such hints and kads to a masimum degree in ordcr to pursue the shortcat and most realistic roules toward the "l of practical preventicsn or control This coursc, howcver, requires some cautkxs. The mathematical association of one variable with anothcr typically raius a numbcr of alternative esplanatnrr hypcsthcscs T1sis is particularly truc when the clala used have been Rathcrcd from nature by observation, without the intcrvcnlitm of esperirrsenlal planning nd controls to minimite the cRects of disturbing variabks The cstablishmcnt of any one prnsibie csplanatcxy hyf,tsrhrsu requires e.clusic,n of all other reasonable altcrna- tivcs This is c>ftcn a difficult task When an auc><-iatKxs bttwccn the incidence of some discase and cita- rrtte smokina is rcpttrttd, thrrc qucsttnns ursc 1. Is ciRarcttc srntAtnR a c au%c 4,( the tIIKa%c, / t J.rs it omtnhutc in some way tn rts cuwIt,Ry, whcthcr wc.ktV, trr~~nKly, lrrct tly ter indtrcctly7 2 Is cr6arcttc smwkcnR an tnth.attrr m twn.ntmr.nt trf c,rngcrutal char- actcristics that prcdrsf.Crse It, rhr tlncast crr rhat cnRcnJcr a pattern of living habrts, mnc or more of whMh may cause, ur prcdrtlxxe to the disease? 3 Is the asscxiation fortuitous of an artifact due to technical operations? We wJl kave Ihis third question tu Ihe statisticians. If either of the first two questions could be answered definitely, the answer would probably su"est measures for prevention or control of the disease A positive answer to the first might lead us eventually to some change in tobacco or tobacco ameke that would have protective value On the othcr hand, a positive answer to the second question wuuld suggtsl atscntitrn to the smoker rathcr Ihan to the smoke f?ach qucstrttn suKgests certain lines uf rrsearch, quitc drllcrtrN ttncs rn each case 1/ we knew (ur certain whtch hy{MoIhcsts wa srnrctt, we cuuld pl.rs antl guuk rruarth mucli mtuc cRrurnlly antl ctttnnmrcally Sutcr we do nut kntrw, rrs ncc catc t,f ny tlr+casc, we havc little chuic'e buI to putsue studtcs 1uyFc.trJ by each possibility 'this has been lhe (-nuncil's fNtlicy. P u P I I I In annual reports over the past I I ycan, 71se Council has provided es- tensive reviews of its work in the fiefds of lung cancer and cardiovascular disease. New developments regarding these topics will also be discusscd bat. Tl+o ('ouncil's ulcer studies are of special interest because they i0us- trate the natural history of a research effort in the field of coautitutional disease etiolM. Beginning with repoAs of an ssocialion bttweto smoking and uker, The Council over a period of yeart has suppostcd reseiuch de- si6rsed to esplore and evaluate various esplanatory hypotheses. These Council-supported ulcer studies illustrate both the difT'iculties of research into constitutional disease and the many by-products of such rc- search which often have an independent scientific value of their own. I'eplic Ulcer and Smokirg Tlsc term pcptic ulcer really includes two diseases: ulcer of the stomach and ulcer of the duodenum. These are generally believed by physicians to dif(cr in their etiokw<y, but they do have some common features. No one seems to have studied the relative iruidence of these diseases in ci6aretle smokers and non-smokcn, either separately or lumped together simply as "uker." One survey rtported, however, that dearhr from uker. though not very numerous, were about four tirsxa as frequent among cigarette smokers as amona non-,mokers. Another similar study found a ratio of 2.e). Mortalily figures are really not very satisfactory in this case because scores of people who get ukers are able to keep these under control or have them cured so that eventually they die from something else allo- sethcr. We need to know what proportions of people contract ukers among the groups with different smoking behavior. Neverthekss, these studies were interpreted as showing a strong asusci- lion between ciEarette smoking and uker mortality. As mentioned before, we can ask three basic questions about this association: I. fkses cigarette smoking cause uker, or contribute somchow to its causa- licsn, whether dircclly, indirectly, strongly or weakly? 2 f).rcs heavy cigarette smoking show the eaistcnce uf conslilutitrnal quali- Iica that ntake a person susceptibk tn uker n. that make hirn adrspt a palltns of life /sabits that tend ta hriut on the disease? 3 Is Ilse asstK'iation accidental ur dtte to a technical artifact (etua ins prupcr sarrsphnR ur s.rect other cause? It can hardly he said that when lhe ('ouncil's ulcer studies were begun, 7

hyptithcsis hat receivcd no support from this work anJ these investigations have not yrclded any practical suRgestiuns lur ulcer prevention Ilurrugh mrxfificalions ol lobacco use tx alteratUrm tit tobacco products Whrk, from the stantlpcYinl of pure logic, the first working hyfwithesis has not been disproved, it has been weakened by lack of suplxxt from ex- temive perlinent atudy. llence, it hecanx reasonable to consider the second hyprNhesis~ 1hKr heavy cigarrttr tmrrkint show tht atistrrxt o/ cunrtuurinnul quolrnrr that maAr a prrrrrn tuttrptyMr to ukrr trr that ma4e him udupt a pattern nf h/r haf+us that trnd to bring un the dirrasr? It is widely bclicvcd that peplic ulcer is to some cnnsitkrabk degree a "psychostrmalic" disease in which a genetically dctermincd predisprnitirrn makes certain kinds t>( pcrstsns respond to certain degrees or kinds of stresses by rkvek,pinR ultcr r'r Presumably slrtss would nM induce ulrer with•rut snnre degree rr/ prtdisfwisilwxt and 1ht pctdlsposllNrn al,rne would not pro duce the disease w,tMrul some degree of stresa ahovc the threshold of the indrviAual's tultrarsce Onc would espcct a reciprocal rtlatiunship: the higher the prcdispcailkrn, the less the atrtts reyuircd for precipitation or ovcrt discasc T?icse mnccpls, which have been drvclry.cd to yuile a snphivicated Itvclr'r atc in harmony with the «trrnJ wrnkmR hylwrlhcsis and pruviJ; a ptnsihk hasis lur it It has alsn hren suggcsled many timts Ihr1 sonrc cll;arcltc snurkcrs may pursue this practice as a resf+rontc Irr strrss nIJ fru.ttatnrn, tit in the scarch hor relief from such In this cvtnt, their genetic tit crrnurlulinn:rl ahilhlics to handle stress tsr frvsuawm might hc cspccted to dctcrmine ur inllucncc their need or desire to sm(Ae Combining these two conccpts, it appears entirely reasonable to porttu- late that pcrst)on who are so constituted as to he likely candidates ftx ulcer mi6?II also be of a type especially inclined to seek stress-relkf through ciR- arellc smr.kinR Such a silualiun would be cspcclcd to prcxluce a statistical association between smoking and ulcer murtality. Yet, in Ihis case an asso- clall(M would MN imply that smoking nude any conlrihutirm to causation of the discasc On the crrnlrary, it would suggetl that if smoking is truly elfrctivc in reducing slress, it might tn that rrtrnr ai lually hrlp thrne predisrWascd tn ulcer to defend thrmulves against slrctt influcrscct nd r)wt tscrcitr srnnrr prcvtnlivc rllrclt Ilrit it a crwnllary uf Ihe tetrrnd hylwrthrs/t hu1 n nra nrcctsary Ir, tit vcrilrcaurwl 'thc stcond hyl+4rthesn Jryrnds only ulw.n tlrr Irr^Irr.nJt., !/1.a,.n, l •nd ttrtY. 11 /1 IAr /n/1nrn.r .•l I'n.A..l.rrr. lu.r.rrr (Ip.n l.u .nrrrrrn,J Ihrrr.bemrr A Strnt..rru.n tht P.Ychrrin.lY/ra 1)u.rirrlY, r ~ul, ,01~ potlulale that ulcer susceplihks sa,A slress relief IhrouRh smokin6, whether tx not they achieve if If they achieved complete relkf, presumably the asso- ciation between ulccr and smoking would disappear altogether. The yuestiun whether smoking affords some degree of relief may be susceptible to investi- Ralion through a suilably designed study of uker-prone persons divided a1 random into smoking nd non-smoking groups for comparison. Several Council studies hcar upon the question of perstxulily in relation to smok- ing, and uprm its possible "Iranyuilizin6' efletas, at the kvel of psycho- pharmacolo6y. Test of the second hypMhcsis. that ulcer susceptibles as a group may restxl to relatively heavy cigarette smoking as an escape from slress, has hc6un, but presents some difficullks. Stress is not easy to define or measure and, msloritwsly, "one man's stress may be another's pleasure." It appears necessary lo arrive at a method of describing or identifying the ulcer prone person in tcrms of some group of physiukstkal, hitKhenlical and/M psycho- logical characteristics that can be measured. An idcal profile should make possible Ihe reliable itknlihcatitm of the individual who is ralher highly susceplibk to uker under rclatively "normal" environmental condiliuns. 1 Presumahly any person, evch a highly resistant one, could develop ulcer under eslremc conditions l Short of the idcal, which may not be attained for a long time, is the development of a profile capable at least of separating a Rrrtup of the rela- lively susceptible from agrrwp of the relatively unsusceptibk with a mini- mum degree of overlap If the susceptible Srtwp then contained more or heavier cigarette smokcrs, whether or not they had ever had uker, the hypt>thcsis would receive support (though hardly proof). [kvelopment of this type of profile appears to lie within the realm of attainability in a not- Icxt-dislanl future. There are many other diseases, notably cardiovascular conditions, for which similar crileria ftx idenlifscalicxs of the highly susceptible would be very tksirable, and many efforts to establish such profiles are underway under various auspices Studies of this kind are slill in their infancy. None has yet been highly successful hut slow, steady progress is being made. Tlris type of research nlust certainly become a major efltsrl in the fulure since it appcars to offer the best hrq.c rd reducing Ihe loll of Ihose slowly-developinR cunJi- Iirrns that are preunlly Ihe IeadinR causes ol sickness antl tkalh A vast utd al,nnst uneapbhed nplrnlunily Iks here within Ifsc realrn u/ hluthemlttry 1 he rtlatrvc levels and actrvrlks tsf the varirws cuzymrs and enryme systcros as revealed fry eaaminatirrn of urine, hlt>,rd, saliva and freshly csci.cd tissues secm likely to bccomc the basis for descrifYlivc profilcs that will revcal Icndi ncics and prcdisprnilirms to imhat.nce even hrng hefurc I

rn ~ 9 actual disease tkvch+ps Such birrchcmic3l prnfilcs prr,mise to become an eventual vrong diagnostic resource anrl a rnajrrr guide to cnnslitulional disease prevention In the case of ukcr, one new arluoach toward the tkvclapmcnt of means for identifying the prcdrspined has been x+ught Ihrnugh studies of the taste sense It has been shown that genetic factors predominale in determining taste sensitivity to 6 n prr.pylthrtwracil (PROP) and evidence adduced that this measurabk characteristic sorsxhow refkcts the basic hiochemical makeup of the human hrrdy It had been postulated also that these differences in sensilivity to bittcr taste might conelatc with the incidence of certain gc- nctic dise•ses, nd some confirmatory evicknce had been collected A('ouncil study investigated 1•ste sensitivity to PROP in duodenal and gastric uker patient• in comparison with naxm•1s Significant drfferences were fuund hctwccn the ducxfen•I uker and the gastric ulcer subjects ??se former were more sensitive t•sters Subjects having htah ulcers rescmbkd the duodenal grrwp (iastric ulcer patients tended to Ise significanlty less sensitive to PROP whik duwKlenal uker patients and thrne with Iwrlh ulcers showed a greater t•ste unsruvny Ira I'R( )P than normal suhjccb 1 he data therchac supfwnt thc concept that durr.knal and gastric uker arc drftcrcnt dise•ses, nd suggest • crtnsutuurrnal haus at least fnr the lat)cr 1 hr y also tuggest that mr•surcments nf taste scnsnrvily to I'ROP might con.rihule to a prurik for scgrrgatnrn nl thrrsc prrdr+ptned tu gastric ulcer (rrrm the "normal" prrpulatiun hut Ihal thrs rs prrrh.hly nrH the case for dwKlcnal ulcer candidates Subjccts without ulcer bul who smrrke at least nnc pack of crRrrNtes per day were alut tested for PROP scnsithvity, lhrse relatively heavy smokers showed a significantly higher prrtpr+rtirm ul insensrtive tasvers in comparyson 1u non smokers. 1hus, this Iimilcd approach to a complcx probkm does pruvitk snntc eviikncc of one cunstrlulirmal Jdfcrcncr cunt- mcm to gastric ulcer patients and lo relatively hcavy cigarcttc smrdus to that cslcnt, it tends to supporl the hyl.rrlhcsis under considcration An obvious question is whelher Irrng term smrrking ilaclf mrtihfics taste scnsitivity A study rif yrnrng pcrstrns, snntc n1 whrtrn are jusl IxRinninK to smrtke, has been unrkrrskcn in sn eHorl to dcterurrnc whethcr Rrnctically hased taste acuity rhxs indced att as a dclermur.urt rrf Acvcl,yrrnr, snurkmg practices 11 has f.rrn shown alrrarly 111,01 « nvlivny Irr I'R/11' is stnul:rr in hrHh sescs up tn Ihe age ro( (h 1t/ yr•rs, hut rhrr-rlh•r t/rtrrssrs m mnlrs at the ratr rd III1t1 Ihtcshuld (Kr yrar anJ to Irnrrlrs it Ihr rar u/ Illllh lhresh4rld prr year In sumrnary, it r an iv %Inlcd that /ac~rnt cvirlcnt c frrun Crrunr rl sludics 12 r fails to suppnt the Iryp,slhc.is that cigarette snu+king cuntrihutes to the genesis of pcptic ulcer, and is better in accord wilh Ihe concept that genetic characteristres which predispuse to uker also tend to encourage smoking It cannot be said that Ihe matter is finally or conclusively seltlcd Many gaps in knowledge have been indicated in the discussion above. Among the needed additional studies are the following: I. lipidcrniolagical studies to esplore any possible statistical correla- lion between cigarette smoking and incidcnce of peptic ulcer, with separate consideration of duodenal ulcer and gastric ulcer s sep- arale clinical and etiological entities. 2. Carefully controlled clinical studies of uker healing under defined regimens, with random division into smoking and non-smoking suhgrrrups for crtmparisoo. 3 Ilcuer utethtrls of defininR and classifying stresses and of ineasur- ing the reactions of suAjects to them. 4. f=.aploration of other psychological, bic.chemical or physiological characlcrislics of Juudcnal and gastric ulcer patients with a view to irnpruving the reliability of differentiation between high-suscepti- hks and low-susceplibks. 5. Within a group of highly susceplibk persons, preferably without overt uker, observaticsn of the relative incidence of overt disease anrnng randomly selected subgroups who smuke or refrain from • smoking. 6. Psychnlrrgical and psycho-pharmacok+sical studies to assess nico- tirx or smoking as a"Ir•nyuiliter'• or reducer of stress effects. 7 he study of peptic ulcer deserves considerahk attention in its own right, nut so much as a majtx cause of mtxlalily but as the source of much disctrnrlurt and sullering in our modern stressful society. Ifuwevcr, ulcer has been discussed at snme kngth in the present in- stance more particularly tn illustrate the nature ol Ihe problems that are faccd in the study of cnnstilutitmal diseases and Ilse kinds rd •rpproaches that 'Ihe Council is makmg to their invesligalion, In fact, these same prtrhlctns and apprusches have duminaled 'Tlx Council's more eatensive invcstiga- tiuns o/ twth lung canter and Ihe cardiovascular diseases llefutc Ihe sulblrcl is IcII, it rhoulJ Ire Iwtmlcd rwl also that lung canccr patbcnts shuw a mut hgrrater hislnry rrr Isrptrc ulcer than the gcnrral fwqrula lurn Iltis facl suy,grsts thr thought tha whatever faclun preJnlrusc to ulccr may prove to ht• releterl lu thusr rhat also predislwse to carcinurru of this site. 13

..v~ ~ ~ S~~.'~$ ~4"a (t• ~ Uri ~ Q. ( irrrsIi/rilioifvl I,vcfors ift ( urrliorascular l)iscnse 1 he general ccxrsitkrations that h.vc hccn applied in approaching The study nf pcptic ukcr re equally valyd in rclatitm lu scveral of thc leading cardiovascular discases such as atherosckrosis, hypertcnsion and stroke. Numcnws studks have been carried out rcgarding the effects of nico- tine or of snrnking upon the physiological or buncemical factors that are considercd to h.ve some possibte relation to the etirtlugy of the cardiovas- cular discases Many of these were enumerated in the Council's 1963-64 Annual Report So far no ckar picture has emerged of their etiulogy, and the fxnsible relations of tobacco use to the suspected factors in etiology are still kss ckar A vast body of informaticsn on the acute pharmacobgy of nicotine has been built up, both by Council sludies and othcrs, but concepts as to how such effects could contribute chronically to genesis of cardiovas- cular discascs remain highly conjectural A number of working hyputhcses have, rd cnursc, been set up and are under test. f erhaps thc studies most relevant to The question are those in which human or aninul subjects have been c.posed chronically to nicotine or smoking for kin6 pcricxls Rabbits or hens kept on rather rtificial types of athcrugcnic drers dtd nrH ahtrw any convrnctng differences in Ihc condition of their arteries if given nrculmc rrgul.rrly with the dict. A human autopsy study, nnl sprrnst+rcd by lhe ( oumd, %huwcd Ih:rt any association csisting hclwccn smoking Pracuccs and the devrlt.rmcnt of arlcriosclcrosis or Icsions resulting thcrcfr,nn is tcnuous anJ mctmtlumvc A sinnlar autopsy study has b<ch sMmstucd uvcr a Ittng f.crurJ by "1 he Cuuncil but results are nul yet available l hc well known prospective stuJy of the )'ublic Flealth Service in Franringham. Massachusctts rcp+rlcd, arnong numcruus other findrngs, that cigarette smttkcrs have no greater incidence of angina pecloris than non- smokers Sincr this syndrome is regarded as most often being a chronic mani- fcstation of coronary artery sclcrusis. this finding suggests that smuling drres not cause or accelerate such sclcrosis Still furthrr, as evidence of The non-involvement of smoling in the chronic development of sckrutic cliseaus crf thc vascular system are thc statistical indications that cigar and pipe anwkcrs have very nearly the same incidence rrf thrse diuascs as non smttlers. cven thuugh they prtthahly absnrb as much nicntirx as cigarrltc srnnlcn At thc prrscnt linrr rhrrclorr, tlic wcrRhr rit rvulrntr is aKa-t thr cnnccpt that ctthrr rnctNtnr ra smtrlmg in/lurntrs thc rthrrm. krtrut prtKrss 1 hc prrsvhtlity rrmains, howcvcr, thal smoking may ctrnlrthutc in s-trnc way lu prrcipit.tuwm t,f an acute cflistKlc in pcrsons whtr have r prctli.lutsing 14 P • t basic sclerotic condition. Since the factors bringing al>,rut acule cardiac ischemia or 1hn+htbosis are sbll quite obscure, several Crruncil-sponxxed studies have been inaugurated with emphasis upon clotting mcchanisms and the possible acute influences of smoking or nicotine upon Ihcse. On the whotc, therefore, it may be said that whik there is little evi- dence at present to support the first hypdhesis, which attempts to rclate cigarette smoking to causation of major cardiovascular diseascs, yet this hypothesis cannot yet be considerLd as finally rukd out. Mcanwhik investigations wggested by the second hypothesis have been underway. The Council has contributed for many years to a study of the precursors of hypertension and coronary disease, which aims t identi- lying characteristics that may form the basis for profiks capable of scparat- ing highly susceplibk persons from those of telalively low susceptibility. Such factors may include 6enetic; physiologiul, metabolic, psychoksgical and environmental ones. When human subjects are classifsed by a single taclrx, the overlap between groups is so large that relative risks of dcvehK+- ing disease cannot be estimated with any cerlainty for the individual. When, however, the differcnliation is based upon the presence or absence rr/ several faclots. the degree of differentiation is improved and overlap diminished. 71se people presently under study do rstA as yet shuw any evidence of cardiovascular disease themselves but have been divided into groups of presumably high, medium or tow susceptibility on the basis of a nuntber of factors with special emphasis on family history, since these diseases have been found to show familial trends which are considered 1u have a genetic basis. f)iscriminant function analysis has been useful in the investigation since it masinsirts differences between populations. In one such study, nine vari- ables were used. The somatic variables used were heiRht, weight, systolic pressure, diastolic pressure, pulse rate and serum cholesterol level. I sycho• logical variabks were scores for dcpression, anaiety and arsgcr. Subjecls grouped according to the history of hypertension among their parenls (ho/h, father, nsnther, ncilhcr) showed significant nsean ddfcrcnccs in syslulic presurc, diastulic pressure and serum chulestcrol, but no signifi• cant ditlcrcnccs in psychukssic:al factors. A similarly condtKlcd study of pcrsons in relation to parental coronary Ji.case (fancer, rntNher, neither) shuwcd mcan significanl chtlrrcnccs in ansrrty and tkprrwrns, hul nrwsc (r-r any 44 the tiR sumatir varirblcs WfKn Itrur gnrups of wh)ccls were crrnstruclyd ras Ihe hasis rrf prr+cncr in their parrnn (nruhrr, father, mulhrr. Iwr1h) u/ either hyltcrtrnutrn ur coronary di.case or Mrth, aignificanl mcan dilltrcnccs hclwecn thc.c grtHrps were luund wirh rcclxct lu an ttrty, systtrlic pressure and dia.tulrc prcuurc . 15

Mean diflcrcnccs in serum chtdcstcrul and pul%c rate only aflprnachcd signific ance. ('umulativc frequency distrihutittm nf the lunctit+n scores of the four grnups rcvcal in detail the clcar separation nf three uf the four groups 1?u wldcst scparation Iies between (iroup 1, with Iwn negative parents and (:roup 1 V, with two positive parenls, with no crossing over; (irrlulr 11, the father yx,sitrve, mother negative group, takes an intermediate Mlstlirln while Group I11, Ihc father ncgalive, mcs(hcr positive grnup shuwcd little dillcr- cnce frrlm Gr<lup I The subjectf were all males and this finding suggests a scx dtllcrence in the ,nnsmissksn of characterislics A relalinn between smoking practices of subjecls and the cardiovascular disease historics uf their parents was shown previously by the same irivcsti- gators 1 his suggesled not only that constitutional characteristics play a role in determining smoking behavior but that these charactcristics may also be linked lo those that predispose to discases of this kind 'I hc invcstrgat us have now analyred the smt+king practices rlf the same people in rclaUnn Itl the same nine snrnalic and psychological variables lhe men wcrc first dtvukd inlrl three groups ftlr comparisrrn: ( 1) non stnokcrs and (tccas/11naI smwkers, (1 ) heavy ctRuettc smokers and ( J l intermediate smtlkcrs (Itght and mrakratc ctR.rctlc smttkcrs plus combined snurkers of cigarctres anti n,hcr furms of Inhatcnl A highly signdicant dd/crence was found hclwcrn Rr luln ( I 1 and ( 71, a.iu.rllcr vl•nilir.int mne bt'Iween ( I 1 and ( 1 ), hut ntr vRntht an1 tliflcrt n, t h, t..t rrl (? 1mnil f 1) I.ilrrI a divivtto was nlJde Illlll rlrfll g/oall,• 1 I 1 li/t h m/, 1/••11 •n.i. t~ r% . (i 1 thn%t' whtr smtlked less than oncc a dry, ( I ) .-•4, r. ~•I I r.- I11 trl.trtttct de11V, (<1 smukcrs of I I Itt 1V cigarcttcs ds Iy. 1% /"I ~mt I+et k mr mwc drdy, (6) pqsc snulkcrs- (7) smttkcrs trt aIl ,hrcc /t~trus n1 t.-hacco, and /M) cr snrokers 7hcre were loo few snlnkers ttl ugars unly tu of pqses plus cigars to form a group Analysts of these eight gnlups shtrwcd significanl di/fcrcnces It appeued that n<ln smokers, occasional smokers and pipe smokers formed a conslcllaticxt of similar perscros, whilc former smokers and nrixcd smokers appeared lo be quite a bit alike, falling about half-way Ixtwcen non smukers and heavy smokers. In both Ihree-group and eiRhl-grnup ennlparistms, the rnean discrim- inant function score of ntln-smokcrs was al one ewlreme and that of heavy cigarette snurkrrs a the other In the Ihree Errnrp crml/larisnn, pulsr rate and an>ttely ctNruthuted mint Its the dtllerentulu.n In Ihr rtyhl gtr.rtl+ anolysis. Lulsc tatr tuntrtl+ulyd the nlusl, wrth t h,d.llctul, drJlrt0it Iltrsvurr anti anRrr tttntrlt.utulg trs a/essrr rrlenl Whtk it mirhl Ilc argued Ihal suth stnnatic (:uttrrs as pulse ratc, diastolic pressure, w th.dc,trrol level nnght Ihcm.elves tre allcrcd hy recent trr ctm I i tinued smtrking, it seems ralher unlikely that anxicty or anger scores would be altected by smokrng, and such psychological characlcristics sccm more likely to he a part t>< the congcnilal makeup which may influence the kinds crf smoking behavior adapled. On the whole, it appears that rather substantial support has been atkiuced for the hypothesis that common or related constitutional factors may influence both susceptibility to cardiovascular diseases and also smok- ing behavior. Despite these sludies, there is still no assurance that the best somatic or psychological factors for differentiation have as yet been found. Thuse employed were selected somewhat arbitrarily on the basis of suggestive studies by others, ease and reproducibility of ineasurcments, etc. There is every reason to suppose that other illuminating ones can Ix fuund by con- tinuing investigations of this type, and the relative success heretofore at- lained should encourage inlensificaticxs of the search. Reference has already been made lo the opptxlunilies that may fit in the use rd biochemical measuremcnls Glydiocxlscular Disease arrJ Stress One Council-sponsored investigator has looked into rclations between stressful occupation and incicknce of cardiovascular diseases Since stress cannot easily be measured by objeclive rrxlhods, an indirect melhcKl has been used. Among lawycrs, physicians, and other professional groups. there are specialties that by common agreement are particularly stressful while others are relativcly low in stress Assuming that a large group within a high-sUess specially must contain more persons subjecled to stress than a corresponding group in a low slress specialty within the sadse professicsn, comparisons were ntade of the iclative incidence of heart and arsery diseases. A significant difference was found. There was also a correlation with the amount of cit- arelte smoking Ilowever, persons who slopped smoking showed signifi- camly lesr cardiovascular disease incidence than Ihrtse who had never snwkcd at all This finding is not in accord with Ihe conception that ahcre could be a cumulalive chronic effect of smoking or of nicotine upon the cardiovascular system II has been interpreted s indicating that voluntary '•shtphers•' are  selected group containing an eac•ess of persrrns whu can handle and resrdve stress relatively easily Such sludies are continuing (It/rrr ( ardi0fYlu•ulur .S'Irulrrs A long series of ('uuncil assistcd studies has culminated in dcvelup- nlenl of an trnl)ruved rnclhrxl using rubidium a14 clearance for measuring Ih : I7 0

coroniry hln,rtl flow in the huntan hr.rrt, withuut rny traunratic prrtcedures T1iis rncthud mjy now t.c jprhcjhlc to imprttvcd assessment of coronary attcry cundttit.ns in /stTulatitN+s suhlcttcll to pn+spcclrvc stutly in rcl.tnm to environmental (actors Eilsewhere, the tole of blt>,xl sugar in regulating non cstcrified fatly acids in the serum has been clucidaled, and glucose kuding shown tu inhibit btnh the increase in Irce lalty scids and the increase in cardiac stroke vulunse that may be induced by nicotine or smoking under fastinR conditions. In ancxhcr IalxKatory the biochemistry of artcrioscleroric changes is under investigatiun with emphasis on the rok of arterial acid rnucr+(w)lysac- chsritks. An effect ts( nicotine in inhibiting the Irpid-clearing activity of hcpsrin has been rrbservcd ('crehral bkxxf flow has been measured by a phr+t<,graphic tcchniyue h>tlowing retrograde injeclitxs nf a cr+ntrast medium intu the brachiul arrcry (lgarctte smr+ktnR was found tu incicase flow in the tcrcbral aeterics 'Thrs effect is anrrhutrd t,+ thc carM+n rhuurk tnntcnl tu/ the smtrkc since it was duplicated by inhaktl (Y/, hw nrA prrrlutcd by nicrrline injcctit+ns lhrs study call, altl'n1Nrn t/+ tTx• {a+.uhle pharmacnlagical and physio- logical srRrr+ficancc t+t carM+n drt+srtlc in sonic effects produced by smoking Nuntcrt+us tNhcr UIt1/1.Yra~(UIJI +nvcsttgasi++n< havc been puhhshrd by vanr+us ( truncil Rrant rrt r(acnt. ilurinR the year jusl cntkd In the present cuntc.t they will not hr revttwcd in dtt.ul, but a11 arc li.ted and abstracted clscwhcre tn this tletwxt C ion.ctrtutioirul /•(rctnra vrt(l Smr7Ai,'t~,r Earlicr rc(xxts have referred to the rrlatiuns drscr+vcred between body build and smnkinR practices 7ltcse must havc S gcnctic basis f'rnjcctcd studies will attempt tu tk,crminc whether there arc parallcl relations between btxdy build and susceptibility to certain diseases 'T he studies showinR rcla- Iivcly close resrmhlance in snsoking rracliccs of itkntical twins as compared to fraternal twins ( nul (•ouncil-vptrnsnrcd ) have often been cited Thcse also reflect a genetic basis A current Council research prajcct has shown yuite siRnificant tliflcr- enccs in types of occupation selected by smrtkcrs as cumpared tn non- sn+okcrs, as well as f.etwcen thtr.c sclrctrd by cig.+rcttc, ciKar and py+c snu+kers Mnreuvcr, crrnsislcnl gratlyd solurnccs r+l arranRcrnrnls nl r+ccu paln+nal frcyurncirs arc ctnrrl.ttctl with rlrrrres r./ tttb,ttc+. ct+ntuml+w+n It is rcaturuhlr Itr tuncludc 111.11 snnrkrnR twhavit+r r. .rss+q r.rlrtt with t+crv-n atity, anrt Rrnrnt rnrl.hratir+rns may he I+tr.enl Srvrr.tl ncw .Ir~~trtt h.tvr a.t++t+I+uyly I-t't'n %t.ut+•d tn I-A (turthrr utlu .,n,l I+lnni~.il~lt .~. /Ur.~turct) .rt thc psychoingical level hy several diBcrcnt methods These may lay Ihc lounda- liuns (or later studies of personality as related to disease su.ceplrMltty Carcirnogenesis Studies Approaches to the investigation o( cancer have also been oriented on the basis of the three hy(x)fhcscs that have served in this report for classi6• cat.on of varitsus invcsliRatiuns into the etiulogy of uker and cardiovascular disease. The ('ouncil's ty61-64 Annual Report contains a dctaikd review of sptxtsored cancer sludics, particularly Ihtne crxrccrned with the bioassay of cigarette smukc. This previous report concludcs: "Tlte overall impression gained from these many bioassay studies is that (Uhacco smuke is inaclive or of etlrl•mely minute activity in Ihesc several artificial systcros, none trt which o( course actually measures human respunse untkt rcatislic conditions ibt results tend little to support the hyfxNhcsis that ciKarclle smuke can act as a direct conlact carcinogen in the human lung " 7ltese bioassay studies have been undertaken in order lu test the first hypothesis regarding reported association between lung cancer and tobacco use. It is recognircd, however that numerous factors, intrinsic as wcll as estrinsic, play a role in Ihc pathagcnrsis of canccrs of Ihc several sites. fieuer understanding tsf the relative tole of such factors, whether from the realm of cellular biology or (rom empirical ubservalion, may well bring atxwt more cllective prcvcntive measures in the foreseeable future. Such measures are likcly to ht multipk, and operable upon several diffcrent kvcls I (;anrrr oJ the ()rol (:as+ity Clinical cspcricncc and epidemirsltsgical observations have amply dcm- txnlratcd the asstxiation of liver damage with cancer of the otal cavity. ('truncil sponsored studies have investigated the effect of induced liver damage in mice upon their response to benzpyrcnc applied to the buccat n+uct+sa ( ivcr damage was produced by administratiun af catlwn tcha• chlnride with or wilht,ut alcohol Squamous cell carcinumas frnm bcn>•pyrrne painung rkvrhqxd eatlrest in mice with liver damage int4ucrd hy h++th carht+n Irlr,rchlurnk •nd alcuhnl, and afw+ul Iwo mr.ntlts later m Ihrrsr trt•atcrI wnh rnhcr rd thcse aprnts rltmr, and two nutnths .trll later and at a rnuth (nwer Icvcl I/, Ih1.1r trcall'd wilh nenhcr u/ Ihr Iwu liver lu.m. 1'arallcl gnrut+% in whith cil;:rreltc smr+ke er+ndensalea were altlrhetl tu Ihc huccal cavrly drvch+l+t-tl n++ tunu+rs 19

lhctc c.pcriments are currenlly hcing repeated with anirnels in which liver d.rnugc is induced by dietary ckficiency alnne, without tnsic aRenls, a srtualinn that may concslxsnd more chtscly 1o curnmc*n human csrcrience. PnssrhIc mcasures for prntecunn of the liver are also untkr investigation I: .rt'rnnrcnts with smnkc ctmdcnsalcs are being repeated with higher dosages. lhe ruk nf liver d:unaRe in the reslxmu of Mhcr nrRans to chrmical carcinrr- gcns is alsu to be investigated according to plans under development .Cturfira with f:rrm-Frrr Alicr The ('uuncil has sptmsnred a scrics of carcinogenesis studres with rrxlcnts whith arc not rsnly free frnm bacteria hut alsu front all tornmsm known viruses Subcutancc+us inoculation rd strrric 1 nscthylchrrlanthrcnc in nil was frrlHswcd by drvchopnscnl uf hKalifcd ncuplatms m Iwrr strains rr( Rcrndree rats and in fuur strarns of Rcrmhcc mrcc lhe trlx•s. locations aml lalcnl perKxls were snnJer tu those snduced by the sante agent in conventional control aninials It thus aprcarrd Iha/ bacteria played no role in this instance of clxnucal cartunnRenesrs anrl no funttUt+n of the cttmmun known viruses was observed A rrrle by s.rnse rx cult virus cannot be comptetely ruled out if dclrcurrn of suth thrruld trr IKyrmrl the scnsrtrvrty uf present detection tyslrnss In trthrr ctl•rrrrnrnt. Iynrlth.urt Irukcrnu w.r% rltcitcd hy whrrlchrxly X irr,rth.rlrnn rn Krrmtrtc nn.i rd \wr.. Wrhtt,r, ( 11I enrl ( t]I11 srrarns whcress it did nrrl rrcur in nrrn ur.rdr.rrcJ trrnur,lh Sinte cylrydasntic viral incluvrrrts cuuld hr dctcttcd hy clcr Irrm nritrrruut+y in crlls frrrrn the cn- brgcd Ihymus Klanrls, it was crmslwltJ that an rxcult IcukcmrrRrnic agent crrulJ hc Ir.rntnrrltcd ro sutccssrvc gt-nrr:rhuns by vcrUCal Irjts:ry,c thrrHrgh the ovum nr pl.ccnla 'Ihe rclcvancc of these studics tu tmtkrstrnding of the rclatirtnships between viral agents, radrannn antJ thcruical :rKcnts in earcintrgcnesrs is manifest ('irrrs tihrrlir•a InvcstiRnlirtns cnnlinuc tn rrhtcrvc thc hi.lr J:rlhrdugic~l c(Irtts rd cig- v,rnnrn rcttc srtnrkc mh,rlaurrn rin the Irml;% rd ntitr. Iw-rh alrrnc and with )trrtrcalrrrcnts rrf thr IunR, at wrrh vrr.rl ,r/-yrrlt ut thr• farM/uUu.n ril url.uc Inrns SJrctral rllurts arr Ja'rnR rn,rrlc i., .rlljtn Iw'r,rr yu.rnlnaUrrn rrl .rrrnsrrl rnhatAuun f.y rtrvrl,rtrmcnl of hrrKhrrna.) •nd I hyurrluKaal nrcth.rrls td tr vr c.nnr.rrmR rtlt,uvr twnaRe 0 Ir rN etlx'trcJ Ih,rr ncc Irrrrgurm rtf rnhal.rliun 0 ~ tturlrct wrll lie r.p.rnrkJ /urthcr as nir-rt' srqphr.Irt,rlcJ mclhrrds /rrr ctrn- 0 c a ~, 20 o r r trolling esposure are perfected, so that the effects of numerous possible vari- ables can he assessed in a systematic fashion. As a by-product of the work involving virus damage of the lun6s, es- planled kidney cells have been trealed with certain viruses in virro .nd Ihe morphological alterations observed. C. ultures containing altered cells are being transplanted back into host animals to observe their behavior. Observalions of the nuckolus as affected by carcinogens and other ageols have continued. Other reports related to carcinogenesis are abstracted elsewhere. Other Concer Studira The chromosomes of kukocytes cultured from cancer palienls, prin- cipally with lung carcinoma, have been studied for abnormalities t.cfore, during and after treatment by radiotherapy. Palterns of mcususis have been studied in  series of 5,RR5 cancer cases in Massachusctls. Melastasis to the lung occurred in 26% of all cases, most frequently from Icslis, breast or burse, but often also from other sites. 1 he persistent danger of confusing secondary tumors of Ihe lung with pri- mary lumors was illustrated by a substantial proportion of cases which showed misdiagnosis ors the original hospital repcsrL ('lassifscatinns of lung tumors into histological types was reported to be uf linrited value because of the prevalence of mised types and the fact that only the terminal phase of growth becomes available for analysis, with point of origin ubscure. 1'ulmonarr I'firsiology Two Council studies have begun investigation of the lung suriactant now recognired to he essential for regulation of surface tension in the alveoli. Effects of the absence or impairmenl•of surfaclant in various clinical disorders are being observed. 'Ibe site of origin of surfaclant and hitxhem- ical influences affecting production are under investisation. 1 he cnrrelatitm of ante rrsorlem lung function appraisals with patho- lugical findings in whole lung, posl-mortem. is being undcrt.rkcn rn a pro slwctive study Mure precise definition and diagnusst of chrnnic puhurm.rry diseases is the Rual uf scvcral clinical and palhuhrtiic'al studrrs /1rm'hemrr'al ,S'Irulrrs lThc isulrurrn and nlrnlnctatnnr rrf /xrlylrhtnals anJ rcl,rtrd suhtr.urrrs frrxn luhaccu and luh:rccu srnrrkc h.ss Ix•cn asrnimvd, wnh Iruhlrcauun nf reports during the ycrr 21

Thc lunR term systematic study of the mclah„hsm of nicotine in the maninialian bcxly, including man, has prtrcecdctl at a high level with pubti- catinn (I/ eight rcports 1 he general picturc rs unc of rapid tkgradatit.n of mcnrine into ntxr tutic mclafx)lilcs I nuum labeled intermediates have been used to tracc dispcnal rtwtes 1'hormnrfrlogy and 1'sychoharnrncrol(>t;r}• Systcmatic study of the mode of action of nicotine at various synapses has been continued Meanwhile increasing emphasis has been pl.ced upon the psychopharmacology of nicodine as mentioned clsewhcre in Ihu report. Dogs, monkeys, cats and man have been included in such studies in several ccnters. Specific actitrns on thc central ncrvous system have been described and (he eflects of Ihcse upon behavior are being srwght On September 11. 1964. a d.y-kx+g round tabk conference was held in lAe ('ount,l oRices for drscussion of 7Ar Dchavrtrrut t-flcrrs of Nicotine and Snsolint In addition to members of the staff and of the Scicntific Ad- visory Buard, (he ftslhrwing project directors and guests altcntkd. Barbara B Brown, Ph 1) ,('ahforniu C'olkge of Medicine E F f)omino, M 1) , The University of Michigan Medical Schotrl Paul S T.arutn, Ph 1) , Metlrcal Co11cRe of Virginia Edward W Pchkan, M 1) , Hoston llniversity School (if Mcdicinc Carl C Pfciflcr, M 1) , New lerscy Ncuro Psychiatric Institute Duane G Wcrvtl, Ph 1) , 1 hc Vnivcrsrty of Kansvs SchrNrl of Pharmacy Kcn ichi Yamamntn, 1 he llnivcruty nl Michigan Medical School Mr G F Ttx1d, 1 obacco Rcsearch ('ouncil, Iontk+n, England Clucs to the effects which seem pleasurable of beneficial to tobacco users appear most likely to he discovered within this ficld. In combination with studies of Ihe psychological kvcl, illumination of the needs which persons, particularly of cerlain typcs, seek to meet by snsoking may he at- tained in due coursc, with possiblc clucid.uun of the degree to which such needs are nsct by the practice. ,Smokirtbr arlrl I'ilanfin C Thc scicntific literarurc contarns scvcral rcfxals.urKctitinp, thal Irrhxto usr may thmim.lr thc effective supply of at. r'rbu at rt/ rn thr INNIy nr .n, rr:rsc thr rlcnunil fur Ilns vrUnun 1 hc mqpIrt.UrN~ ~d sur h rrlNrrls h thAl .rnnl~n~ nrtrht trrnlribulr I r t 'n.1rU rns mtturntrd hy •.r rnhr, rr r. l dcflt rrno y U 0 n Itrc ("nuntrl .INrrr acJ an rnyuuy rntrr aarNhrt atr.l rucuUnc rrldlurn 0 0 © ships on thrcc lcvcl. r ~ v. 22 o Animals capable of synthesizing their own ascorbic acid and others dependent on an eaosenous supply were both treated chronically with nico- tine, but no change in excretion or lissue content of the vitamin occurred in either. In vitro, a destructive effect of nicotine on ascorbic acid was observed, but this was found to be dependent on changes in p!t rather than upon prop- ertics inherent in the alkaloid. The effect was not considered likely to be of biologic consequence within the buffered systems of the body. Although chlorobutanol, which stimulates biosynthesis of ascorbic acid, protected mice significantly against toxic doses of nicotine, ascorbic acid administration did nW. Ftence the chlorobutanol eflect is not thought to be mediated through ascorbic acid. These studies did not sustain any claims that nicotine influences ascorhic acid availability or requirements of mammals. Summary As research gocs on, evidence accumulates bearing on different theories of possible action of tobacco in regard to various constitutional discaxs. Over the yean, however, evidence to support the thesis that cigarettes exercise a direct carcinogenic effect on man has not been furthcoming. 'l his has been a source of frustration to tlxne who hoped and hyputhesized that such action could he demonstrated and that one or more components of smoke might be identified as being particularly suspect, thereby creating an opp.xtunity to remove or to counteract such substances. Failure to confirm d'uect carcinogenic activity of smoke, despite estcn- sive research, has resulted in the extension and diversification of effort to in- clut'e other mcthtxfs of research and to evaluale other theories of ptnsibk activity. Whik support fnc direct carcinogenic activity has been lacking, evi- dence in support of the sts<alled constitutiunal theories of host teactiun to environmental challenges has been steadily growing by presentation of new data and by new experimental results. 1'he theory of constitutional diversity as the basis fur individual diffcr- cnccs in susceplibility and resistance to cnvirorsmcntal challenging agents involves grcal cttmplcmity and recognizes many obstacles tu srmplc unJ rapid analysis. Ihe hruhrRit.l .nJ thi4xhrmital 1rNrndsliun (ut suth inJrvrdoal drllrr ences is cstahlr.hrd at IcrtlluatUnn of the ovuro, by thc cnndrioasNm n/ thal cell wilh the slxrm 7 huusantts of individual hereditary chcnucat unrts called genes are cr+ntributcd by each of these cclls. This gencral prrwcsc is 23 N

commom to all kxms of animal and plant life in which sexual rTprcxluction e><ists, ('cxnpksity of the interaction of genes during subsryuent development of the individual and diffsculty in identifying them does not invalidate their importance even though it handicaps their analysis and manipulation This must he kept in mind because there are many who still mistakenly believe that unless the genetic basis of a situation is simpk, it cannot be considered of great importatsce. It is also well to remember that the esistence of a genetic influence has been established beyond any doubt by the isolation and perpetuation of many strains of laboratory mammals in which Ihe type. amounl, estenl, and lime of cancer incirkrwe is definite and predictabk and rrpealab(e In these animals genetic diflerences influence the manner and rate at which drflrrrnt organs and tissues age nd become abrrormal in function The brr.ad genetic factor has hccome ckarly evi,knt because one can manipulale the sekctivc process of inbrccdin6 In laboratory animals This, of course, is impractical in man. While we cannM manipulate human malerial, we can and should rec- o6nize that there is strong evidence that the vast number of different genetic backgrounds and types in man present a situation similar to that in other mammals in which individual resprmx to envirtxtmental challenges is, to a lar`e dcRree, and possibty to a most basic and imporlant eslcnt, determined by the genetic makeup of the individual It is also of interrst to note that the broad principle involved scrm. to apply not only'to resl+c.nse to chalknges tnward cancer hanutirrn hut al.n In those toward uker formation nd toward cardiovasculrr dysfunctirrn and disease. T7scre have been several separate studies in which comparisons between identical and non identical twins under similar and under difierent cnvirrrn- ments have been made and smoking habits, olher behavior Iraits, m<xbidity and mortality recorded All such studies have shown that The similarity in crxtstitutksnal reactioxt of identical Iwins is far greater than that between nun- isScnlical twins It shtwkl bc emphasized that in man the nature or degree rrf the process of transmitting by herality these various constitutional tyl.cs from one generation to another is not of prrnrary imlortancc 'Ihis ii im- pcxtant in animals where matinRs are planned and crrntrrdkd Ffut nrr rurc can, frrr a mtrment, believe that man will iunwrNrsly Idan Irr avrrrd mekruR The types of matinRs in which even the mrat serious rr( surh trmyrk. Rcnr•ta' factrxs may he involved And even if he drd srr (dan, hit rlunccs rrf crrntridGnR or eliminating individuals who present greater health rnks (by sr) drrinR) would still be nr•gliRihlc a a practiul mattcr U 0 0 0 nn the other hand, the recognilion of the unavoidable and universal esislence of diffcrent individual human genetic types and the search for criteria by which we can recognize among the population those individuals mosl likely to he a serious risk in the case of cancer, ulcer or cardiovascular disease is probably entirely practical. The recognition of the exis/ence of susceptibility and risk inside of our individual bodies is the mrnt eflcctivc and the nHnt hopeful way of being forewarned and forearmed in the application of preveotive medicine . i 25 24

Abstracts of Reports Fach rccipicnt of a grant in aiJ frnm The Crhrncil Fur Tobaccr, Re- scarch --II S A, is resl.onsrbk for the initial prescnlaur,n or publication of the results of his research at scientific meetings or in rl,Prnpriatc scicntrfic journab. Following are abstracts, Moved by the authors, of reSCarch rcpnrts acknowlcdtin6 support from lhe Council that have appeared in screntrfic journals since pubhcatirxs of the 1963-64 Rcport of the Scientific I)rrccttx. TAese abstracts have been grouped under the lulluwins headings: I Psycho-PhrsitAt~gical Studies, 11. Cardiovascular I)iscase, ItI. ('arcmo- Ecnesis Studres, IV. Other Cancer Studics, V Pulmonary Physiolog1 Studics, V1. ('hemistr Ir Biochemistry Studrcs, V11 Pharmaculr,gy Psycho Pharmacoingy 'Ludres, V111 Other Studies 1. I'ayclto-Phy,ioluRical Studies "TASTE THRFSNOl.F)S FOR BITTF?RNFSS ANF) CIGARETTE SMUKIN(: " Fly Arnokl R Kaplan and Edward V. Glanville, l.atxxatrny of Medical (ienetics, ClevclanJ F'sychiatrrc Institute; and Roland Frschcr, Research Division, 1)cpartmcnt of Psythratry and Ikpartment of I'hysio- H>gical Chcmrslry, Ohiu Slatc Ilnivrrsrty Mcdreal kh,r.d, ('ulunrhus, Ohru. Nature 202.1360. June 27. 1964 /(irrmtc Krhl.rnl T-his cummunicali„n rct,ads thc ..•-ruur,n I-Iwccn the srnr,krng hahits of 31 to S/) ycar old nulcs auJ I, nr.rli s. .,n,1 rh, rr taslc thresh,dAS (or two bitter-tastinR comlxrunds, yurmnc .rnJ 6 n la„I,yIrhnrur.rcrl (I'R(P). a phenyllhiourea com(xrunJ, taste scnsnuvrty lu whrth r% hum4l.rlly ,Ir,,rnb- utcd, consistent with the hypothesis of a snnplc Kcncuc Jrchotumy '1 he es(~crirncnls ctxrfirm a rclatiunship between smukmg :rnJ biltcr taste Ihres- holds. From a tolal of 266 subjects tcsted, only the 34 "heavy smokers" who used 20 or morc cigarettes daily and 40 mm-srnokers in Ihe samc age range were sckcted for comparative esamination The most significant Jillcrence in tsstc threshold for quinine was observed between the male smokers, with a mean threshold of 7.8, and the mak non smokers, with a mean Ihreshold of 4 6, a highly significant statistical Jrffcrcnce (P l/ IXII ). -1 he fcmale smokers were also kss sensitive to quinrne, but the drflcrence was lcss fiRnihcanl (P 0012). 'Taste unsitrvrty /nr I'ROP, like th:H /or yuinine, as luwcr in smnkcrs than in non snmkcrs in )Mdh nralcs (/' l/ l/lt ) and ~males ( P 0 (11)4 ) <i, OtA.r grenrer, Nati„nal Institutrs of Ilr.ltfh ( 2) u 0 m "A(i(i, SI:X, ANI) fnSll: SI:NSI I IVI I Y " 1)y Idw:rrJ V(il.,nvrllc, 0 0 B m m Ph),.nd Armdd R K.I'ten, 1'hl), 1)rl+rr,mcnt of Mcrhtal (icncthrs, I hve- c ?~ - a ,. s land Psychiatric Institute, Ohio, and Roland Fischer, PhD, Ohio State (lniversily Medical School, Columbus. lournaf of Grrconrufuty 19/4:474- 476,(ktober 1964 (Grantee: Kaplan) TTu c/fccts trf aging on taste sensitivity were determined in males and Femates between the a6es of 3 and 55. There was a gradual increase in sensitivity in both sexes up to the age of 16-20 years, followed by an exponential decline. Sensitivity to 6-n-propylthicwracil (PROP) and qui- ninc were similar in both seaes up to the age of 16-20 yars, but thcrealter male tasting sensitivitr decreased at the rale of 0 052 threshold per year For PROP and 0 066 lor quinirx, compared to declines of 0 026 and 0(N3 re clively among Femaks Females were more sensitive tasters of hydro- ic acid at all ages. OrJ<er grentors National Institutes of Flealth. "nIFFF ' RF:NT1Al, TASTi? St':NSITIVITIFS IN DUODfN/1l. AND (iASFRIC U1.('UR PAT'IE:NTS." By Arnold R. Kaplan, PhD. Edward V. Colanville, PhF), and Wilma Powell, Cleveland Psychiatric Institute, Ckve- land, Ohio; Roland Fischer, PhD, Research Division, Department of Psychi- atry and Department of Physiolcssical Cbemistry, Ohio Sta1e Univenity, Columbus; Mario Kamionk.owsti, MD, and Bertram Fkshler, MD. lkpart- ment of Medicine, Western Reserve University School of Medicine at Cicvc- land Metnqxslitan Cicnera111ospilal, Ohio. (:astrurnrtrolury 47/6: 604-609, December 1964. (Grantee: Kaplan) Genetic Factrxs predominate in determining taste sensitivity to 6-n- prnpyllhiouracil (PROP). They are less important for quinine, another bitlcr esmrpound, and appear to play a minimal role in tasle sensitivity to hydrochhaic acid, The distribution of taste thresholds For PROP is bi- modal compared with the morxxnodal or "Gaussian" curves obtained lot quinine and HC1. The possible rote of constitutional facton in ulcer was investigated by delcrminingg tasac sensitivity Fur PROP, quinine, and 11('1 in 121 subjects with duoJcnal and/or gastric ukcrs. SiRnificant diflcrerxes in tasle sensitivity for PROP were found between the 68 ducxlenal ulcer subjects and the 34 gastric ukcr subjects. Duodenal ulcer subjects were more sen- sitive tasters both by chi-square evaluatitm based on the assumption of a bimodal Jistribulicxt (P<.01) and by nnn-p~rametric tests which involve no assumptiuns as to distribulion (P<.001 ). Subjects having IrHh ukers resembled the duncknal uker group adhough the number of subjects ( 19) was Nro small to permit significant statistical conclusions. A volunteer group shuwcd I'RI )1' sensitivity similar to the Rastric ulcer suhicc,s Nu significant dillcrcnces were found Fsctween any of Ihc Rrrrups Fur either quinine nr IN') taac srnsitivily 'llusr dala +ulrlw,rt tlsr concept that gaslric and durwlcnal ulrrrs havr diRcyr~g consUwti~rnal baclrruunds and Ihat thcst Jdlcrenccs may rnvrdvc ilic genetic facturs. nthrr Rrnnrur: Natiunal Inslitutcs of Flcalth. 27

"OC('IIPAIION AND SMOKIN(: IN ('U1.1 Fi(iI? GRAI)1)AI1 S" 1)y ('arl (' Seltzcr, Rcscanh Fclluw in Amhroput,.Ky, 1'c.rtxaly Mutcurn, IlarvarJ lMrvcrsrty, arrd I),cpartmcnl of NutriU,rn. Ilrrv:uJ kh,Md uf )'uhlhc IIcalth, Ilustrrn, Mass, lou+ntrl o/ Applied l'tyrlro6rKy 4H/1.1 6, Febtuary 1964. "(X'('l1PAl1ON ANI) SM(1KIN(i IN ('O1 1 EGI: (iRAf1l1A I I•S" fly ('arl (' Scltzcr l'+vrholuRaul Rrvicw 71/I:I-I8. 1.uruary Vchruarv 1964 lhe results of a study of 895 nxmbers of the Ilarvard ( lass rol 1946. thirteen years aflcr gradualicxs, with respect to Ihc associatiun of ttccupa- lic)n and smoking bthavior, indicate tlatislically signnccant ddlcrenuatuons bctwccn smukcrs and non snwrkers; belwecn t'iKorelle, crgar, and pilx snwokcrs; and in accurdance with ckgtte or rate uf crgarcllc snrukrag Ihe significance of these findings a(Spcars lo relale 1u the influence uf Lcrson- ality and conslitulirrn un smokmK hchavirx. Smukcrs ate sigruficantly murc heavily rcprcuntctl in Ilusmcst ('unt.rcl (pnxnotcrs, salcsmcn• rNail and wM,ksak dcalcrs, buycrs, etc I and in thc held o/ ( Irg,rnrr.rntrn as a whrdc• as wcll as in tts subdrvtsuro rrl husrncts exccutrvrs rd all types Nun-smt,lcrs, un the tNhrr hrnd, arr sil;ruficantly mtrtc hcavdy rcprescnlcd in the licnrral ('ullural gruup c"nvtung rrl auurneys, collcRc prufcssurs• ckrgyrncn. tcachcrs ut high and rkmentary, schrNdt, anJ ctl.cctally in the "r,rhrt" Krncrrl culrur.il suhJivtsutn (p,ur- nalrsts. Irhraruns, rnuscum curatra., cth ) No srl;ndreant drllcrrnccs are apparcnt I-rtwcrn .nu,kcrs and n„n in„Irrs in thc I rchn„h,Ky• Ou1J,ru. Scicnce, anJ Ails an,l Vntcrlanuncnt Kr,•ulunKt, wnh the IM+ttihlc r>ccpuun of surgcuns 114.11 trm,krrt havc nnuc than Iwrtc thr Ianl,tnw,n of .urKcons Ihan srur,krts, wilh ncc d,llcrcntc tl,...ly alwl.ru.rthtng Ihc S^S. Icvrl ul siRnihcance lhe OrRrnirawm clmtd,tat„on, c.rn,l,Idred by the majr,r and minor eueculive sulKhvttuunt• dishlays an cutctt of crg.rr :rnd ciKarcltc sm<,kcrs over those e>;pcc'ICd• and a drfrtrency u( pipe smukcrs Ihc (irncr:rl ( ul- lural group eshd,rls a particularly large csccts uf prl.e smukcrs .nd a Icwcr Ihan espcctcd ptu(wrlNm of cigarcttc .mukcrs A(rorl fmm the Icntkncy for research scientists to kan luward Ilx pipe and crKar, and thc iuhjrcls in the field of Arts and lintcrtainmcnl lu snn,ke cigarcllcs only, thc rrmain- ing occupalicxtal classificalitmt arc not cs/xcijlly distinguishcd as to Ihe frxm in which they use their tahacco I)ata on the rate of ciRarcltc snu,krng strikingly indicate a numhcr of consistent, graded sequences of arrangr•rncnts trf the rrccupatitmrl frcyucn cies ccr,rding to the rkgree uf h,haccrr ctmsun,fdirm 'l hus• with rcyard lu the Organiralirxr Rruup, there is a prurrrssivc rncrcrsc of (Krtr,ns in this classification as thr amrwnl u/ c,rnrct/c smokinr incrrascs. Ir,nn 114^. amrmg 1Mru snurkinR kts thr.n It/ tir..vcttct J.rrly /.rrtYressivcly t„ 4'111"S• in srnukrrs r,r 1 nr m,we (iicks 1 djy ( unvcrsclv. rrt Ct it ntr An.l (;rnrr.rl ('ullute thrrr Arf t unvslrnl rr.ulr,) ,k, ,rjtrt m rr, ul,dla,n.,l Ir. Inrn, rrt wrrh mcrrauJ am„unt of tnwkmy 1'ratliu,mt'rt of Arts and I ntcrl.imu,irH trn,l 1„ Itc r,rhrr ., ry fu-.rvy .m,.lt•rt f 1,1r ,no,ri 11.1( l. J:nly 1,y .n,uAcrt nI "i r. . 1 11 1. 1 ., I,v U 0 0 0 . i It is of consirkrabk import that the results (sf the analysis of our data indicate Qre ertistcnce uf sulislically significant differences in tobacco hahits. If indeed the particular fors of occupatiunal ddlercnliatirm do in fact rcfkct sr+me gcnerat rclalionshipmto Iac(ort of ~serxn+ality, then it be- comes reasonable In ccmclude that smoking behavior itself is associated with the individual's personality. To what eatenl our occupational group- ings have genetic implications is difficult to ascerlain, but the constitutional elemeM is not to be ignored. These findings reinforce the evidence of other studies which indicale that snruking hrhavitr is significantly influenced by hosl factors within the individual and hence represents manifestations of distinctive crmslilulirxral make-ups. '1 he implicalirwu of this slalement relative to the pruhlrnr of smoking with health arsd discasc are not irkonseyuential. "STI /11IES ON FI('rI/RE I)RAWINGS: STRl1CTl /R AI. ANI) GRAPI II(' C'l1ARA( "1VRIS7I('S " By I crrna Wise )rmes, Phl), and ('arolinc Iledcll lhomas, MI), Johns I lu{rkins I lniversily Schoul of Mcdiciru, Ifallrnwre• Md 1'tri'hiurrir Ouurrrrly $upplcmcnt, Volume 39. Part I. 76 11(1, 1964. ((:ranlee: '1 hurssas ) A total of 725 while male medical students u( the classrs ut 1952 through 1963 participated in lakin8lhe Ilurnan FI((ule-1)raw/ng Icsl, a rec- ugnized testing procedure for personality assessmenl for nrnre Ihan Ien years llre evickncc rrrldcd by this study supports the hypothesis th•al slnrclural and graphic characterislics of figure drawings can be reliably coded for psychrdrrgieal determinations. 71se findings show (a) that drawings of individuals are mcoturahly different on a variety of characteristics and (h) Iha(, drawings have a mul- tiplicily uf crrmhinations of individual characteristics which can Ix uAjcrrivclY idcnlified. l his study therefore can he regarded as a prnilive step toward establishing objective means for Ihe use of the Test as a screening device in pcrxsnality appraisal, that can be applied also to other types uf subjects. Further Jesrarch as a part of the School's long-term Study of Precursors of Hypertcntirm and ('rxonary f)isease.houW delernsine (a) lu what estenl rinKlc variabks or r onrtcllatirms of variables can differentiate between prsp- ulat' s of inlellrKent, healthy young adults and (b) whether mcaninglul n cnrrcluriuns with other aspects of Ihe long-term study will Ix revcaled. Or6f.r Rrontor: National Ilcart Instilule. "PR/('l1RSORS OF IIYPFRTENSI(1N ANI) CORONARY I)ISFASF. AMONG III:AI'171Y MF i 1)I('A1. S11/h1:N•IS: 1)IS('RIMINANT . VI/N(-11(IN ANAI YSIS I l)SIN(i SMOKIN(: IIAI/IIS AS '1111; ('RIII:RI(/N" fly ('.rrrline Iledell 'lhrrmas, lArnnld ('Lrtc Rrns, aml ('rrulyn 1) IlrRudrrrh" -m, Ik',artrnrnl of Medk•ine, )rrhns Itoyr4urt Ilnrvrr frly kh,Md r,t Mrthtrnr, IlaluuuNC, Md NulF.rrn u/ the l.,hus IL•r'4r.rr ll,.rprruf 1I5/1 114 194. August 1964 ((itan/cc. ahruuatl '1 hc famrly hish,ry and psychuhrfit-aI arakcup o/ 111t.11 whrtc malc mcdreil tludrnh in the clancs uf IY4H to 1961 h:rvc hrrn t.uclullv rnvcs ~r ,, 29 a~ ? .~ ~ U e

IigaltJ and di><umented. The smrding hihits trf 4R1) were dctcrmincd Srnuatuc varrablcs mcasurcd were hrrRhr, brrJv NnKhr, blrNrl prr+turr, heart rate, and rholrorrrd lrvrl. Ihc psythodtrgrcal varuldts drfrrrtvnn, unrirry, and anger were measured by a chciklrst of 25 lypcs of bchavnn tn hahrls of ncrvous tensron Ihscrimrnant function analysis of the data f.ermitlcd s/udy ttf gnwp- ings n( the sublects with respect to a number uf varrahIcs and dctcrmmation of whether tht rtrops were ddferent, how they were related Itr each othcr, and which varra~dcs are of nsost value in distmgurshmg bttwccn the groups. 1 hc men were hrst combined into Ihree gruups: 3R6 nttn smokers and t.ccasionxl smtrkerr, 141 heavy cigarette smokers; and 165 inlerme- dute smokers: Ir6hl and modera/e cigarette smokers plus combined smokers of cigarettes and other forms of tobacco. 'There was a highly significant diflcrence in the varrables sludied between non smokers and heavy cigar- ctte smukers, a smalkr significant rhflerencc between nun svnrrkers and Intcrmediate smukers, and no significant drRcrcnce between htaty and in- Icnnedrate smokers f rrr further dixriminrrnl analysis, the men were divickd inlrt eight gn'utn ( 1/ ?9h Idclung nun smrders; (2) 116 whn snrtrktd less than once a day. O) 70 who smoked I tu 1(/ cigarcttcs daily; (4) S2 smokers of I I to 19 cigarcttes daily. ( S) I Sp smokers of a pack or more daily; (6) 4) prf.t unolcrs; (7) h(1 smukcrs of all three forms ril Itth.cctt; and (R) 56 es smtrkcrs, ) cigar and 4 prpc and cigar smukcrs wcre JnrardcJ as trwt few to nuaturc Analytrs td thesc eight groups showed vgnificanl overall drflcrtnccs it apf.cutd that non smrrkers, tKcasirrnal smrrkcrs, and pipe smttkcrs lorm a ctmsttllalrun td rather srnnlar rrstrns, whrlc loiriter smokers arrd mircd smokcrs prtar In f.t quilc a hu atrkc and lie atwrut half way between rwm srnolcrs anti hcavy vnuktrs In MNh three g.uup and eight Rroup c'nrnf.ansrms, the nrran discrirni- n.nt functrun scrrrc of non smokers was at tme estrcmc anJ Iha1 of heavy cigarette smtrkcrs at the other In the three group ctnuparisnn, heart rurr and aniirry contributed most to the differtnnatfDn, in the eight group case, hrart rare contributed the most, with rhrrlrsrrrnl. Jru+nrbc prrrrurr aml anger conlribuling to a ksser cxtcnt. llx f.cf that Ihe groups are found to be arranged in a meaningful or r by the discriminant functitxt suppcxts thc crmclusiun thrt real dif- ( cnccs between Ihese groups exist Orhrr grantor: National flean Institute li. f.ardiot'nstrrrlnr I)IvMIsP "NISI(K IIFMI('^1. 1)I MUNSIRnIION (Jf III'InK1' tlI I Xlltil: Nf)tIS NtIRI•I'INI•/'I1/(INI: IIY AIt/t1 Nl tt(ilt' I 1111 ItS IN I'llltrr" Ily 1. l Anr.clrlnt Isclrartment nl I'hy.adnyy. Il-./nn 1lnrvrr uy Si hrwl nf K1rd,<rnc, Ilu.tnn, 1.(ats .Srr.n, e 14 1 51/1 Sltd, luly 1I, I'l6 1 Adrencryrc hhcrs in isr,lattJ rat ins prcfi.rr.ruons wcrc Jconrm0r.itol htst,Khrnritally by ntc.rns rr/ the furm.ilJrhyJr t- -nJtn%,iturn Icthnilni ln the presence of aJencnine triphosphale (ATP) there was a ncl uplake n( nrnepmtphrrne added in vitro by thc adrenergic filrcrs, prrKlucing a markcd increase in tissue content and a striking increase in 1he fluuresccnce trl the adrenerRic fibers In the absence of Al Ponly a slight increase in flutwcsccncc was observed when the tissue was caposed to high curtcenlraUUns of nurepinephrine. lhesc findings indicate that the norcpinephrine taken by the tissue hom the medium is confined to the adrencrgic fibcrs. 7 he need for ATT lcnds sup- lo Ihc view that this consl,cwnd is necessary for the binding of catc- rlamiocs within the adrenertte strxage sites. Or6rr gr.nrorr 11.S. Public Healah Service. "ME('NANISM OF NICOTINE INDUCED VASCULAR Rf?SISTAN('F. IN l lil? Sl)f'ERIOR MESFNTERIC- ARTERY 01: 'fI1E ('A'f " Ify 1 P I.on nd C. 1. Hrghgenbolen, (kparlmenl of Pharmacolu`y, ('ullege o/ Met~icine, State llnivcrsity of Iowa, Iowa ('ity. Ar.hrvrt lnrrrnornrnulrs dr Phurrnorrrdynumir 149/)-4:Jd5-)92, June 1, 1964 (Grantec: l.rxtg) NiccNinc has been demonstrated in a number of preparations Irt mimic the eRects of sympathetic nerve stimulation. lltis study was designed lu test !he possible mechanism of action of nkotine in an organ with dual autonomic nerve inncrvatirm-namely, the intestines. The vasnconstriclnr and vasodilator resprsnscs to inlra-arterially administered nictrtine were sludied in 55 cats. Guancthidine, bretyllium and reserpine inhibited the vascsconslrictnr response of nicotine and sympathetic nerve tlimulatiun. IiexarnellNrniunt bromide did not antagonize the respon se to sympathetic nerve stinrulatirm or to norcpincphrine but readily blocked the vasrsconstrictor response to nicotine. Ilemicholinium had no effect on the response to sympathetic nerve stimulation or to nicotine if the vagal nerves were not stimulated, but with vagal nerve stinrulation, it readily inhibited the vasuconstrictur action of nicolitse. (t is postulated that the vasoconstrictor resprxrse to nicotine is indirecl, and that the site of action for nicotine is (he vagal nerves; and that this represents an example of parasympathetic activity modifying sympathetic transmission. i "GLl1('nSE R1.(X'KA(;F OF NnN-FSTi* i RIFlFh FAT1 Y ACIDS IN- l'Rf:ASI: PRO1)l)('Ff) BY SMOKING IN IIVAI'IIIY ANf) IN ('OR- C)NARY Sl1HJF(-1'S" Ily Inuis A Snlufl nd 1lcinr SchwartN, Division of ('ardiulogy. Tcrnple llniversily Medical C'enter. Philadelphia. 1'a Amrr- iranhrurnal rrl the Afrdrral Srirnrrr 24?/S:SRO SM4, May 1964 ((:rantee St r1oR ) 'fhc Idasnta wnA rtJ hhw+.t rrtl free fatly acid rttlarnsrs tr gluttvst Irrading wtrc rltlcnnmtd in I 1 healthy and 4 dia1N•lie sul.jet ts od 1wHh uaes, .It hathrtual sm mkcrs There was no change in red hlrwal ctl( fatty acid cnncen'r,rtitm 1 lie percentage dn.p in plasnra frcc latty acid was appruximattly the same in thc healthy and in the diahctic subjects Frwrnr 71

/rrarr symptoms of shock occurrcJ in the normal when his hlrxxl sugar fell to or bcluw the fasling level but was still within Ihe normal range. A subsequent significant rise in plasma free fatly acid occurred only in the normal and followed the ma rirnum drnp in hlrxxf sngar. Smrsking failed to change the free (alty acid Irallerns after glucose Ioadie If mcotine's presumed eRec1 in promoting atherosclerosis is solely lhrou8T; a rise in plasma free fatty acrds, the present studies suggest that rcvcral picces of candy txfore smoking would prevent the alleged atherot- ckrolic effect of smukin~. Ihis does not, of cuursc, exclude the possibility of changes in spcciRc (a11y acids or nicolinc as predisposing causes d alherosckrosis In the li6ht of these observaliona, the suggested significance of the re cd rise u+ plasma FFA in relation to athcrusclUosis should be rc- ' cslitated. ther rrowtor.: Fleart Associalion of Southeastern Pennsylvania and the Ar(erse Oickkr Research Fund. "G(.(/(Y)Sf: III (K'KA(;F: OF i11F INCRFiASf: IN STROKF? VO( l1MF? PRUI)lK'f?1) BY SMOKIN(i." By havid ('. Mcrses, Donald Powers and I.cwir A SokrR, 1)cpartmcnl cs( ('arJkd.rBy, Temple University Medical ('enter, Phrladclphra, Pa ('ircufanon 29/6 82(1 924. lune 1964 (Granlce: &)IoR ) 7lsc percentage changes in thc cardiac output, stroke volume, and heart rate were cktcrmrnrd in seven healthy h.bitual snrokcrs after smoking two cigarettes, after intcavcnrius gsucox, and aflcr smrrking precedcd by glu- cuse administration No significant chanRcs (sccurrcd afler glucose There was a signifit ant rncrcasc in cuduc uurl)ul, stroke vulume, and heart rale after smukrnR Pretreatment with Rlucusc did not change the heart rate response to snrr.king Ncverthelcss, thc carJrac out(.ut resprrnse was dimin- ished This rkcrcasc was due to a block in the incrcase in stroke volume induced by smoking The results indicate that the cardiac-output response to smoking canmN he clraracterired by studies limited to the posl ahsorptive state. After all, the amount of glucose used in these expcrinsenls was less than one fcwrth of that present in Ihe averaRe American meal The inhibiting effccl o( `lucrne on the responscs to tobacco su~csl that thcsc may he nutrilional resprmscs rathcr than harnrful ones Our unpublished ohserva- tiops indicate that mild escrcise after srnuking prrxluccs an additional rise i"carduc rwtput and stroke vcslume OrArr grantor.; Heart Association of Southeastern Pennsylvania anJ the Arlene 1)ickkr Rescarch Fund. "I:RYIIIR(K'Y/1(' PllOSP/lOI IPllt I INOI 1 1(' A('ll) IN Iti(-111 M1(' IWAR/ 1)ISFl1Sl: . AN(1 IN 111•^1 111 "(/y 1.-urs A S~drrtl, MI), I'rr+ (rssru r4 ( hnrr.l Mrdkrnr, •nd (Irrnr S.hwarV, Mt), )'hl), Itru.r.lh ( trrrrnrst, Icnlldc I/nrversily Mcrlrcal ( cnrcr, 1'hrl.rlc1Phia, 1'a I unrrr 2 116R 1269. I)rrrnncirr 12, 1964 (Grantce: GrloH) 0 ~ 0 r The erythnxytic phcxpholipid fatty-acid contcnt and pattern were uuJ as markers in a group of patients with acute myrrcardwl InfJrclNrn and in a group of persons clinically and radiographically free rrf athcun- clcrosis to Jctcrminc whether the diets in the two groups had over a long peruod contained different propoxtions of saturated to unsaturated fally acids. Erythrocylic phosphotipid linokic acid, which tends to vary linearly with the Iinulcrc aciJ content of a diel consumed for six weeks or mure, was the acid which displayed the greatest individual variation. But there was no statistical difference between the two grwps in the level of this acid The investigation therefore did nol support the view that the cause of myocardial infarclion is a diet high in saturated fa11y acids and low in luraled (alty acids. i.r grentorsr (1 S Public Nealth Service and the Hcart Association uf thesslern Pennsylvania. 16 "STROKE VOI.(IMfi ANtI CARDIAC OUTPUT AFfF.R SMOKING IN '1111: P()S11'W1N1)(AI. AND IN TIIF: FAST'IN(i S I'A 11: .." Ify I.ouis A. Scdofl, MI), and Ik+naW V. Powers, MI), Tempk Ilniversity Medical ('enler, Philadelphia, Pa. Anerrican lot.rnuf ul the Mrduul Srirncrs 248/ 6.69) 696, Ikcenrber 1964. (Grantee: Soloff) Cardiac output and slroke volume were measured in eight healthy male vuluntcers aged 19 to 26 years, who were habitual smokers, in lasling state before and at IS, 30 and 60 minutes after smoking two cigarettes within 1(1 to IS minutes. The tests were made 30 minutes or immediately aftcr ingestiun of glucose; after drinking a volume uf water equal lu the volunte of glucuse solU(Nm; and without glucose or water adrninistralion. The results reconBrmed the obserYalnM that smoking incrcases the heart rate, cardiac output and stroke volume of farlin¢ habitual snsokers. (iluasx by moulh, whether 1•rken immediately or 30 minutes before srnnk- in,;, blocked the increase in stroke volume and cardiac output provoked by smoking, as previously demonstraled after intravenous administration of ~(ucase. 1 he water alune had no hemodynamic eRccls and did not in- hilrrt the effects provoked by smoking in the fasting slate. These studies suKgrsl that the physiological act of eating sugar pre vcnts the cardiac effects of smoking which may occur in the fasung state ilic cardiac reslwrnse to smoking cannot be fully charsclcrired by stuJres lin eJ to the puslahscsrplive slalc. r~(Irf,.r Rrnnrr.r: 'Ihc Arline 1)ickkr Glass Chapler of the Ifcarl Assrrcia tiun uf Sr)unccatrrn Pennsylvania . "I IISIVIN'S Mn( I()RMnfI(/N 1)IS(Y)R11ANI INI/tA('AVlIAR1' 1•11('If((u'nf(1)I(K;/(nl'lll(' ANII I'RI•SSI/HI: RI•1 A11()NtiIIII'" Ity Slanlry S Mrrlrs, MI), Willisrn I lacrrhy Ir , MI), rnd Ilrnry 1) MrIntursh, MI), t 'rrdirrv.r.cular (.atKUaruy, (luke (fniversrly Mcdreal ('rn tcr, lyurham, N(' .(nt.rrr rrn l.Ournof uf ('urdiuf.rty 14/S.721/ 712, Nu vcrnber 1964 (Grantcc'. Mclnlosh) 33 31

Althr.uEh Jcxtifsed in 1966. tthe diaRnosis r>t Fhstcin's malfrxnulion wat nuck erc1usivcly at the autr>(+sy tablc unul 1950 Srncc thtn a clinical Qrcture hat cvulvcrl su that tht ihasuosrs may be strongly suspcclcJ rrn the basis of roulinc evaluatir.n It may tsc cr+ntitmcd by cardiac cathctcriratinn lhis case Jrmr.nsttatcs that mKmrl atrul inlrrcardiac clcctrical com- ple>;cs and ptessures can he ot.uincd in a paticnt wrth Fhstcin's n+alfurma- tn+n d thc Irp of the clectnKk catheter is withdrawn through that porlion of the vilve attached trr the true annulus of the tricusprJ ring False negative as wcll as previnusly reporlcd false pr,sitive trscinKs may hc obtained ('areful anaa,mic kscalizalion of the IncusriJ valve is rnrf.crative in patients tuspcclcJ o( having Ebstein's malfurm.ruun. llse JraRnu.rs can also hc cssnfirmcd by the production of vcntriculat cxuasysir.ks nr monu- "alrial- Phasic ventricular compktes when the ekctmde is pressed against y(d" ventticular enckkardium. L//OrAnr gr.rrtor: Nalirxsal Ileart Institute (2). "Nl1( 11:1(' A('Ih ('ONII:NT OF 1ltRKEY 11FART W1l-Ti A NOTE (1N III-MO1)YNAMI(' FINUINGS" Ily Rrrf.crt (: Sumncr, Mf),'lhumas C Iluyk, Ill. Itcnry 1) Mclnto-,h, MI1, and Rubcrt Fi. Whalcn, MI), ('ar- drovaxutar l aMxatrrt f)uke llniversrly Medical ( enler, I)urham, N C. Imrriran !r urnu! u~ rbysrulncy 2p7/S. 11U2-11f16, November 1964. (Gtanlce: Mclnfosh) In order to stuJy the marked Jisparity in the thickness of the kft and tiRhl vcnlriculat walls rr4 the turkcy hc.ut, ckso.yrrhunuclcic acid (1)NA) and tif>tmuclcir acid (RNA) and rrnlcrn contcnt of the kft .nd righl venfricular rnyr.cardrum were JclrrmmcJ in fuwl, .rRe 4, 6, and I I weeks and at maturity Tlse 11NA conccntratxrn in the riKht veniticular lissue was found to be significantly greater than in the klt vcntrKulrr tissue in each brtd of caoh age lhe 11NA cuncentr,liun of fxrlh ventncles, hrrwever, dt:creased with increasing xe Prrdein esstseentraurrn in fxrth venlricks increased as did prufcin/1)NA rali(n Although RNA crxxenlralirrn shrswed less cunsistent chanRcs with aRe, the RNA/E)NA r.tirr incrcascd II was corsctuded !s a result n( 11sexe studies that the prcdr+minanl ccllular changes that occurred with age were Ilx resutt of hypertnrphy. In addition tn the biochemical dettrminalions, ekclrncardirry.rarsss and hernodynamic data were ubuincd on birds in rrch Rroup. Although pol- monary artery pressure is con,pauhk Io that of othcr laboratory animals, a markcdty ekvated systemic hhwxf rressure dcvelr.rs in Ifse turkeys he- Iwtcn the ages of 6 and 1 I wccks -1 he role ul hypcrlcnsirrn as a Jelcnninant 6/ ccllul.rr size in the left vcntricle was not elucnletcd by this study (ltflrr Rrsntor.: National Iltsrt lnstdulc anJ Anrrrrr'an Iltart Assr,tr.rli-m ~., rn ~ ~ "AR IfRIAI A( It) M11('(11"t)l YCnt ('1lAR1U1: ('11AN( :1:.C 1fY I'Rs) I AMINI• " fly Irr 6"rc, k11), Hu0un 1 rniversny tia h~«rl of Mr•drr mr .rnJ Masuchuactts Mrrn"rral llr++f'rlnls; Yrrknr Ianak,r, MI), M~ssarhuscfts Mtm(qul flosf+il+ls, and IlrtulJ A Whitc, 1s11), llarvard IvlcJical Sihrr)l 1.1 P ? t and Veterans Administration Hospital, West Rosbury, Mass. Archivrr of Pathufoxy 7Rl3.lbl-IR5, Septcmbcr 1964. (Grantee: (:ore) After the repealed administration of prolamirsc by vc+n over a 1wo• weck pcrird, the putmonary arteries of rabbits display a 50% augmenla- tinn of their acid mucopolysaccharide (AMPS) content. AlthrYuKh each of (hc specific AMPS moictics par/icipates in the increase, there is suggestive evidence of a shift in their relative proporlions; hcparitin sulfate incrcatcs and chonJroitin sul/ale H diminishes. A smaller increment of about 20% was observed in the aorta hrrt was not associated with rectsgnizabk mnrpholasie alterations. E)espite the idcntity of the estraction proccdure. the f+nal yickl from the esperimcntal aninsats was not as purc as that obtained from controls. Substantial in- creases of reducing sugar and of protein were found suRResting a SI)co- protein constituent of the acute pulmonary arterilis which occurs in these rmsls. Olli.r R "U(.CERA flON OF ANf) EMHOLIZA-r10N BY AT11F.R(IMATA " fiy Ira Gore, Massachuse/ts Metrsorial Huspitals and Hoslon (Iniversity Mcd- ical C'entcr. ('hapter in "E'volutit„s of the Adxrosrirnrric Fluqur," R. J. funcs, EJtttx; published by the University of Usicago 196a:315-33:. Ukerated alhernmauws plaques re a eomplicatwsn of advanced imimal disease. 1'hey occur mure commonly in Ihe arteries of prrpula- tions affliclcd with a high incidencc of alhettrsckrMre Jisease, and they Icxnt a greater proportion of the intimal process in "coronary" than in "ntmrrxunary" deaths. Factors in the development of uleeratirms are mechanical stress, ischemic neerosis, and hemorrhage The conseyuences are an enhanced tendency to lhrombosis; weakening and atlcnuation of the media, the essential mechanism of neurysm formaliun; and the rckasc nf alhcrumalous debris into the circulation. Such debris may occlude small arteries in various orRans l he Irc- yuency of alhcromalous emboli varics with the extent of the ulccraled ksiuns; they were uhserved in about half the patients whu had aneurysms of the abdominal arrrla 1 csiuns are mo.t eommtmly observed in the kiJney, spken, and pancreas. Itypcrtension and aznlemia arc frequent findings with renal invulvcment As shnwn eaperimenttny, they persi%t frr many munths MyrrarJial infarcts and/or cerebral infarets are cutnrnnnly presrnt in tlxst palicnl, hrA rN+ly e.ct's( iw.nslly can Ihey be shown tu he rhrrt tly rrlrtrd tn athrrlMrnlMrlk• Invrrlvcment of the erarmar) anJ,hrr crtcbr.J urlrtir% ('rrrl.rul arlrrul a/htrrrtrulwrh are astrt•iA/rd wilh r hiKh fa~rtr rr tnrn M anrurysm% ur thc Ivrrairu,rl aurta ('nusrderinR the usrrat u•vtrny of athcrrr.rlcrusn us Ihc aUArrminal anrta, invulvernent of tFht Inwcr rit Iremiurs secrns rclarivcty uncummun. In parl, at leasl. this re/kcts the in- he uency with whah the Icfs are eRamined at aulupsy thrr Kran/nr: Natinnal tnstilutcs nf llcalth. • 35 ranror: National Institutes of Ilcalth.

"OI1SF.RVAT1(1NS ON TIIP_ FAlf: OF ('ll(11.1?S1FRO1. F-MHOl.l." By I(iurc, FI 1.. Mc(bmbs and R. 1.. Lindyuist, Pathology Ikpartments of the Ntaton l/nivcrsity Medical ('cntcr, Massachusetts Memorial flos- Fitals, and the Peter Efcnt Brigham /luspilal, Bnston, and Veterans Admin- rtUattnn l lospital, Wett Rusbury, Mass lournvl u/ Arhrrurcfrrnsrr Nurarr h 4/6:327-5)S. Novcmber l)e+cember 1964. (Grantee: (itxe) Following intravenous adminislratit.n of a su%pension of fine crystal- line chalestcrol in hrinxdosous serum to rats and rabhits, mullipk cm(xrli are found in the branches of the pulmonary artery. Farly they are associated with thrombosis and a diffuse as well as focal inflantmatory reaction of the vessel wall. Thc intrinsic acid mucopolysacchariJcs particjpatc in this pnx- ess. A prompt kucocytic response to the crystals early hecomcs mononuckar and foreign body giant cells appc ar s soon as 24 hours. licfore the end of the first wcck crxh)thclium has grown over the crystals. Smaller ksicsns become estrutkd into the alveolar spaces and these become fewer with time (Nhert become encased in fibrous litsuc and may slowly prnelr.te the arlerial wall to /tc in the adveMitta Fvcn after 4 months in rabbhs and 9 nyrnths in rals, chtdcslerol crr stals td embolic origin can ttill be dcmrxs- tt acd in the pulmonary arterial channtls. rArr gr.nror.: (/ S Puhlic llealth Scrvice and Massachusetts I(eart . ASttK1alK1n "111F. AN fA(;()NISM H!:1 WFFN NI( Uf INN AND M(1(Y)POI.Y- SA('('IIARII)li A(-I IVI IY " fly 11 1 Whrtc, MI), Harvard Medical Schaol, I(iorc, t•11), ll.,stom Ilmvrr"rv 1,h'.d .4 Mcdurnc, antl Il 1 I.arkcy, AH Vttrrans Admirn%tr.rnvi Il...Wr,t R,i.htuy, Mass Nrurhimrar Nroltoria crrrrmrnr.irr 1 J )lu! I1h, IWr1 ((irantcc Gire) In tuaminrng htwitytK ttrvrtt it has hrcn ,h,-wn that nxrlunc in• hibils Ihe ht{~arin ( nr other AMPS ) NmiuljtrJ.Ic.nng at uvuy ( as mcas- urcd uptically) tit the rtlcast of nrm c.tetncvd Litly rtid rn tura Meas- ured in vivo, howevcr, clearing factur activity hut not non cstenhed fatly acid producing activity is inhibited It would seenr that nicotine in small quan- titics aNcctt this rekasc of the lipolytic enrynte In larger quantiucs, though, nictNine Iso inhibits the prc-furmed enzyme. Clotting studies show that nicotine nlagonizra heparin both in plasma nd in fihrinogcn thrombin mistures. 1 he authors have no chemi- cal evidence of an interaction to esplain these (unctional antagonisms. "INFl.(/f:N('F? OF CORONARY AR1FiRIAI. PRI:,SS(/RF? ON (Y)R- ONARY VASOMUl(1R 1UN(1S" fly ('ccd V (-ross, Ikpartmrnt of Medical Research, St Joseph 11011F.1131. Burbank, ('aldtania ('rr.rd,nu~n Rrrran•h 15/2 Supplcmcnl 1:87 9August 1'161 ((iranlee: P F S.lis- bury- deceas.ed) 1ht tx•havna of the ctxonary vcssrls in Irrnt% n( cornnary vamnu4trr t rnus has been ctamrncd in dugs lo assisl in Ihc study of autirregulation t><curupary hhxxl flnw 'ihn auttxegulattun hccirmcs evitknl by a relatively constint fluw alicr chanRes in coromrry artenrl la.ssure; in this study it i was observed only under conditions that separated central coronary arterial pressure from atxtic pressure. ('kat evidencc of coronary autore~ulatioo was not observed when aortic and coronary pressures varied to~ethcr and the nervous connections of the heart wcre preserved. When the performance of the heart, systemic arterial pressure and central coronary pressure varied within physiological limits, changes of coronary flow appeared to be determined by variationa of coronary pres- sure. Ilowcvcr. it was not possible to decide whclher this constancy of coronary vasomolor tonus was due to an intrinsic property of coronary musck, such as reactive contraction in response to stretch or to rvout or otbcr rrsechanisms. Ot/ler gra,.torr National lleart Institute. I "N(K'LEAR RIi30SOMFS, AN EARLY FACTOR IN TISSUE RI?PA- RATION." By S(iwfbprnas.xr and C. IJc Schryvcr, Wayne Slak Uni- vcrsily ('olkge rr/ Mcdtcine, and I/arpet Ilospilal, Iklnrit, Mich. Bio- cArmiral and Biuphysica! Research Comnsunicmiont 11/1:12-16, 1964. (Grantee: R. 1. [fing) Myocardial infarction was produced in dogs br ligation of branches of the anterior dcscending coronary artery and glycmt-2-C" was injected intravenously. 1?re animals were sacrificed at various intervals afler in- farction, from 4 hourt u~ to 6 dayt, and cell fractionation and nuclear eslraction were performcd. llse data scem to indicate that immediately following infarclion and destruction of myocardial tissue therc is a rapid response and renewal of cell material replacing Ihe nccrotic musck. The early renewal of cell material was further indicated by the incorporation of labeled Rlycinc into nuckic acids of the infarcted tissue. The first step in the reparative process seems to he synthesis of nuclear material, followed by reconstruction of mitochondria and microsomes. ~tAar rraetorat U. S. Public Health Service, American Neart Association, Michigan lleart Asscscialicsrs, I.ife Insurance Medical Research Fund, Bunou6hs-Welkome Fund, and the John A. /lartford Foundation. "MY(K'ARf)IA1. PROTEIN SYNTIIESIS IN CARDIAC IIYPf=R- TR()PIIY." fly Sigmundur (iut)bjarnasat, Michael Telerman, ('hiyo ('hiha, Paul 1.. Wolf and Richard 1. Bint, Wayne State University College of Medicine, and Harper llutpital, Delr,oit. Mich. lrrurnaf u/ InArrruaay and (7inirof Mrdi, nv 61/2'.215-23), February 1964. "PR(Yfl?IN MI:IAIt()I ISM IN ('ARIIIA(' IIYPI:R'I"Rt)PIIY ANt) /11?ARl F111 I//(1? " ny Sirmnndnr (it/dh)afnasMM, Michael '1'clcrman and Richard I Hing Arnrnron ltwrnal of PAyfi.duty 206/2:294 298. Fcbruary 1964 ((:rantee. [ling) The rale of rnytx-ardial protein synthesis was studied in the hearts of nornul rabbib and of aninrals with esperimenlally produced cardiac 37 16 P O P

bypertrophy and acute and chronic myocardial failure. Cardiac hyper- trophy was accompanied by an increase in protein synthcsis, however. there was no incrcased myocardul protein lurnuver fate. In acute heart failure the nte of myocardial protcrn synlhesis was diminished as com- Pared to prdein synthesis in cardiac hypcrtrophy In chronic heart failure uscacpnralicors of glycinc into kf1 venlticular protein was mumal; how- ever, because o( incrcastd~ otein synthesis in skcklal muscle the relative incorpnration of tlycine-2-l'' was diminisbod. The lurnover tate of myo- ca ral protein during cuduc hypertrophy was not altercd rAe. gr.wror.r U S Public Ilealth Service, Arnerican 1lcart Asseciation, Michi~an tfea.t Assckiation, Life Insurance Medical Research Fund, Burruughs Wclknnrc Fund, and the John A. Ilartford Fouodation. "711E? E?FFf(TS OF NOREPINEPIIRINE ON 7FIE FIEMnhYNAM- I('S ANf) MY(X'ARDIAL METABULISM OF NORMAE. II(1MAN SI/B1E('TS" By lose Ribcilima, Vcrnrm E Wcndt, licrminin Ramo., Sigmundur Gudbjarnaum lhewuas A Bruce nd Richard 1. Bing, Warne Stale t)niversity ('rdkge of Medicine, and Har(+cr llospital, Iktrral, Mich. Amrrican llra.r lrrurno! 67/3:672-67R, May 1964 ((.ranlee: Bins) Sludies on the circulation and on cardiac metabolism were carried out during intraveruws infusion ol norepincphrine in 15 human subjects. lhere was a marked increase in the myocardul infarctirxs of free (atly acids No significant chan6c in corrrnary hlrMxl flow or myocardial oaygen etxuumplurn was observed ('orunary v.scular resistance and myocardiul efficierny increased A rise in the drflerence in the redui potential (lactale/ Fyruvate) between coronary venrru% and artcn.l hlrwKl was found (luring infusion of nrxcpinc(p hMrne 7Ttrs dcmrrrrstralcs u><reascd vaygcnation of 7,16 btarl muKle untKr these clMllltnrn/ rr gr.wfor. r U S Public Ncalth Scrvice, American llcart Assnciation, ichig an I(eart Assoeiation, I ik Insurance Medical Research Fund, Bunou~hs-Wclkcxrse Fuod, and the John A. IlarUurd Foundation. 'TliEi DETERMINATION OF CORONARY FLOW F.UIIIVALENT WITN COINCIDENCE C'O(1NTIN(; TtCEIN1C'." Br Richard J. Bin6, Arvin Bennish, (ierhard Bluemchen, Alrxrto Cbhen, lames P(ialla6lher and Edward 1. Zakski, Ikpartmcnt of Mcdicinc, Wayne Slalc (tnivcrsrly ('olkge of Medicine, and Narrer Ilrnpital, Delroit, Mich. C-ircufouon 29/6:S))-e46, June 1964. ((irantce: 11inR) 'il+e coincidence counting technic was used to measure the clearance equivalent of rubidium•S4 a. a/unctUOn nf curratary flow by the hunun heart in vivo. In crperimenls on isulalyd dog heart i1 was found that changes In rale of perfusion of Ihe crnrnury atttries failed to influrrKe Ihe myocardial e.ltactrnn ralio of RM'. Alteratiuns in heart ralc wcrc alsrr without cflnct NitrriRlycrrin in,rc.ud the clcarancc aluivalrnl of ruhidium R4 in patients wrthmut rmonary hrart dnrasc In Irrncnt% with r'rrtun;uy heart rhsc.%c Ihr rlnrK I, .l t,, fill in i Ir.r.ni c ryurvilcnt I thc mcthrKl has 1KCr1 I I helpful in distinguishing between normal iodividuala and those with coronary artery disease. rA.r `re,.ror.: ll. S. Public Nealth Servioe, American FEean Associa- tioe, Michigan Ileart Auociation, Li/e Insurance Medical Researcb Fund, Burrcwghs-Welkome Fund, and the John A. Hartford Foundatioo. "MYCX'ARf)IAL INFARCFION IN PROGRESSIVE MUSCULAR UYST;tOPIIY." By Howard S. Shapiro, MD, lose Ribeilima. MI), and Vernon E. Wendt, MI), Wayne State University Colk`e of Medicine, and Ilarper Ilospital, Ektroit, Mich. Americon lownol of CardiuloQy 14/ 2:2)2-2)6, August 1964. (Grantee: R. J. Bing) The case of a 26 year old man with progressive muscular dystrophy and an acute myocardial infarction is presented Involvement of the myo- cardium by muscular dysVophic process is briefly reviewed, nd the rut nccurrence (1/ myocardial infaretion in progressive muscular dystrophy is emphasized. "PROTEIN AND Nl)(1-EIC ACID SYNT7IESIS DURING T11E? RE- PARATIVE PR(CFSSES FOLLOWING MY(X'ARI)IAL INFARC- TION." By S. Gudbjarnason, PhD, C. Ik Schryver, MI), C. Chiba. MI), 1. Yamanaka, MS, and R. 1. Bin`, MI), Wayne State University College of Medicine and Ilarper Hospital, Iktroit, Michigan. Circulation Research 15/4:320-326, October 1964. (Grantee: Bing) Myocardial infarction was produced in dogs by ligation of branches of the anterior or posterior descending eoronary artery. T he rale of in- corporalion of tlycine-2-Cr• into heart muscle protein was studied over a period of ais weeks. The infarcted tissue showed a rapid diminution in protein synthesis after infarction; on the third day the incorporation into the infarcled tissue rose above normal and reached a maximum on the fourth. The borderline tissue also demonstrated an early increase in protein synlhesia with a maximum ineo.poralion 48 hours after infarction. The changes in the concentration of RNA paralkled those of the iocorporatiun of 4lycine-CfO. Tlte concentration of DNA increased on the second day after m/uclion and reached a maximum on the tenth day. The studies demonstrate the rapid reaction of the heart muscle to injur~ and the increase in protein and nucleic acid synthesis of infarcted and bordcrline tissue. The firsl step in these reactions is the synthesis of nuclear material followed by the reconslruction o( milochundri and mic nnea. .r ~11 S Public /(callh Service, American Ifcart Assrrciatinn, rchi~an Ilcart Associalam, (.ile Insurance Mtdical Re.earch Fund, the Burnw~hs-Wclkome Fund, and John A. Flartfrxd Frfundatirm. r "MTi('FI^NISM OF Ilfi^RT FAIl.11RE " Hy Richard 1 IlinR, Mf), ('lyrk Wu, MI), and SrKmundur Gudhjarnsrns, Phl), 1)epartrnenl of Mrrlictne, Wayne State Ilntversrty Schs„rl uf Mcdwine, and Ilarlx-r IIrrsI+ttul,. Ilclrrul,

Michigan ('irtulunnn Rttrarch 15/5 Supplemcnt 11 64-69, November 1964. ((iranlcc HinR) ( onRestive heart failure can otcur as a rccult of hypcrtcnsuon, coronary arteriosclcrosis, valvular diXase, thyroid drscase, or ancmia, amr+ns other things lindncrine drstutbanccs accompanyrng conRestrve heart failurc ap- pcar to be secnndary trs primary disturbance in the myr.cardium Despite a large volume of studres, the fundamental caux c>< heart failure, so commonly encountered in clinical practice, still remains obscurc. lhe main facts about myocardial failure can be summarized by rtatin that Ihc eitraclion of substrates by the failing human heart is not a~ttred, that there is diminished contractility of the hcart, and Ihal the enzyme pattern of failing heart musck is altercd. Thesc conclusions appear contradictory. They point ou1, howcver, that only a variety of pproachcs may furnish an answer. It is quite ponsihk that further studies of the cause of these altcratiuns in enzyme spectrum may prove rewarding rA.r grantorrr ll S Public Iicalth Service, American Flearl AsaK'iatNon, Michi6an Ileart Asuxialion, E.ife Insurance Medical Reuuch Fund, the Nurruughs Welknnx Fund, and the John A. Ilartford Foundatiors. E c9 "AFISENT 1.F.FT PI11.MONARY ARTFRY, RI(;IIT-SIDFD AORTIC AR( If ANI) PAIPNI- 1)l/(-11/S AREI:RIOSIJS WITH RI(;Iir TO E.E:FT SIEl1NT" By (lyde Wu, MI), Raphael Bakoo, MH, Raymond S. Kurtzman, MI), and Vernon F Wcndt, MI), FAC(', Wayne State Ilni- vcnily ('olkSc of Mcdreine, I)ctrurt, Mrch Amcruun Journal of ( ardi- oloty 14/S 71)2 7l)8, November 1964 ((irantcc. R J Ring) A patient is rc(Mnted with an ahxnt Icft pulmonary artcry, ri`ht- rided aottic arch, patent ductus arterrusus and right tu left shunt A brief review of the cmbrynloRy of the arntic arihcs is prcunted, and  possible cmbryobaic basis frx this ccWrdruun is p~roulated An c><ter»rve review o( the lil ature rcvcals only I similar case with this unusual combination of cu rvascular anc~malres, and in that patient a predominant left to right .h ( was present trller granrorar lt S Public Ncallh Service. American Ileart Association, Michigan Ifeart Assrsciation, Life Insurance Medical Research Fund, and the Burrou6ha-Wcllconu Fund. "(7{AN(;ES IN MYOCARDIAI- EiN7YME PA7TF.RNS IN Hl1MAN EIFARI' E)ISFASE." Hy SrQrnundur (iudhjarnasun, Christian Dc Schryver, (;ilhert Ilunn, and RicharA 1 BinR, Wayne State Iln+vrrsitr ('rrllc~c of Medicine and Harper Ihnq ital, 1)ctruit. Mich. lrwrnaJ nf 1nAr~urnry and ('linical Mcdicine 64/5.796 8(/1, Novcmher 1964 ((;ranlcc Hrng) The activities o( inlrac•cllular cardiac enrymes were determined in necrops~' material from patients with normal heart musck nd frr~m p.- licnt. whu had died from crrnRestive heart fulure (('l Il ) rrr uttrirn( Irrrrlrc hearl dncax (^SIII)1 Ihe results shuw a siXmhcant reduclirm in the activity ed ise.cnrate dehydrn6cn.u in cardiac muscIe of patients with ('IIV and ASII11 thc acuvrtres rd lactatc rkhydrogcna.c arrd aldulase were 0 0 ~ • las decreased, whereas the activity of glyceraldehyde phosphate dehydro- 6cnase was increased two to four limes. -ITxsc changes in enrynie activities of cardiac muscle could indicate impairment of oaidative rnelaMrlism and enertypr raluction in the myocardium and a conrpensatory increase in anaerobic ph(ssphrxylation. The data indicate that human congestive heart failure could be as- sociated with altered metabolism. The primary cause cannol be identificd since the observed changes in enzyme activities can be the result of allcred mitochondrial function. The reduced mitochtxulrial eecrgy production could be accompanied by adaptive changes in the cytoplasmic enzynu ~+at- tern in order to compensate /or the decreased aerobic energy productKSn. Similar changes are observed in artcriosckrolic heart disease. OtAer Rrar.torr: 11.S. Public Health Service, American Hear1 Association, Michigan Ikarl ^ss.+ciation, Life Insurance Medical Research Fund, the NurrouRhs-Welkornc Fund, American Medical Assrxiation liducaliun and Research Foundtam, and the John A. Ilar(ford Foundation. "MEASl1RE'MFNT OF ISOMETRIC CnNTRACTION ANI) F1EC- 7•I(h4 TIMF HY lTfl: VIBR(K'ARI)I(X'rRAM." By Clarence M. Aaress, i Slanky We6ner, 1)aniel 1. Blcifer, Flarky M. Estrin, Kenneth Sc•hruyer and (;erald 1-abins, Institute for Medical Research, Cedars of Lebanon Ehnpital, and University of California. Department of Medicine, I.os Anseks. Amrrican Journal of Cardioloty 13/3:340-341Z, March 1964. ((;rantee: Agress) llrese studies dcmonstrated an accuracy of 0.002 second in the meas- uremcnt o( heart function intervals in cbsed<hesl subjects by the vibro- cardinFrans. The accuracy was far greater than that altained in testr of other indirect mcthrK)s of estimating isometrk contraction and ejeclicsn, all of which contained theoretic and practical sources of erresr. Study of the vihrocardnr6ram ftx the me.suremenl of these inlervals has indicated the practical advantages and greater accuracy of lhis technique. ~rArr grantora: I.os Angeles County EEe.rt As.soeiaion, National Acro- /nautics and Space Administralinn, and private donations from Samuel W. V Banowit, Eidwud Rothschild and Geor6e M. Thonspson. 111. (:arcinoRenelia Studira "•rllEi I+I•F('f OI. I.IVER IMBAI-AN('E ON lHl; 1)FVfI O1'MFNT OF (1RA1. 1lIM(/RS IN MI('1: FO1.1.OWIN(D '1111: AI'1'1.1('AITUN OF IIFNLPYRUNI? OR '1'()BA('('(1 'IAR."'By Marlin Prrnrel, 1/t)ti, ('Iricf of Oral PathMrh.6Y, and Anthony (' (liutlina, MI), Srnior Rcsidcnt, Ocpartmenl of I'athrrlngy, Newark ('rly /luspdal, N 1. /4rurnal n/ the NeM•u.k ('rry ILrrprral I/1. 12 24, July 1964. ((iranlet: Prulrcl) l.iver danugc was induced in 6roups of inbred Swiss Webster nrice by periodic injeclnrns of a 10% ('( 1.4-uhve oi1 srdution and/ur the use rr( 41 40 ~~ . t.

15% aqueous ethyl akohol for drinktng 'The anirnals were drvi,lyd into two espcrimcntal divisions, bo(h wrth tqrul numhcrs r+f males and it maks. llu mrce in the first dtvrsiun were swabbed 4 tinxs a week on (he right bucc3l labral muc(sa with (1.1% hcnrpyrcne acetrme solution (HP), each ).plrcation ctmtarntnR 0016 mg of bcnrpyrenc lhe mice in the other drvisirxt were swabbed similarly with a 20% compsntle cigarette smoke condensate in acetonc solution, each application containing 0.(178 mg of whuk tobacco tar. In (he first division, squamous-ccll carcinoma bccame evident in group A mice (akoho1 E('('1-4) at the 7th month of IIP applrcation, ar.d two months later in group B mice (akohol) and group C mice (('('IA). ('ancer did not dtvebp in group 1) mice (on normal regimen) until the 111h month Based <n the numbcr of animals surviving 1 the firut mrmth of thc study, cancers developed in 46% r+f the A, 50% of the H, 40% of the (', and 15% of rhe 1) mice. The rerults indreale that the lalent pcrNK1 of cancer devehy.r.mcnt in the anmuls with indured liver damaRe is crxiurktahly shortcr than in the animals rxr normal regrmen Mrce in the ucr+nd cspcrlment.I dlvrsNM which were painted with comp~ rte crRarcttt smnlc ct~ndcnsate drsclosed no evidence of tumor development (-ontnrl animalr painted with actlone also disclosed no evi- dtnce of tumor dcvclol.nKn1, o(casllMal hyperplast/c changes were noted in the caal tprthtlmm un micrrrscopr( cuamirsauon "lllE; F:F FE:(-T OI I IVfR IMHA1 AN( F ON TI-IFi I)EV1A OPMF.NT UF ORA1. T(IM(/RS IN MI( 1: f(11 I UWING Iflt: APPI.I(-A1ION OF: BE'.NIPYRFN1 OR It)111('( () I^E( " Hy Martin Prrrtrtl, 1)1)S, Anthony (' (iiardma MI1, and Edwin I1 Albanu, MI), Newark (ity Ilosp rtal, New Jersey Oruf .Curxrry, tLal Afedurnr and Oral /'uthoLofy Il(/5:622 615, November IVM (Grawcc Ptuttcl) Our findings have demonstrated Ihat induccd liver damage in mice painted on the buccal mucusa with bcntpyrene markedly enhan:u( tumor yield and substantially reduced the lalcnl pwrkxl yd tumor devclopmcnt. An csplanabon of the roac of induced liver dama6e on oral tumor dcvelup- ment has been relegated to its interference with benzpyrene melatxrlisnt. Animals given alcohul to drink showed the hi hcst ptrccnlage o( canccr dcvclopment. A pilot study is bcin6 conducte~ to dctcrminc the role o( akohol as a pronwlcr associated with oral tumori6enesis. Mice in the second cxpcrimcntal division, which were painted with a 20% comfxrsrtc cigarette smokc rondcnsatc in acNirnc sipluu rn, show no evidence of Iunxor devchopmenr aftcr 14 monlhs of simrtar trtatrntnt, with or withuut induccd liver damage 'lhc Brst paprllorna produccd with bcnzpytcne appeared in the 6th munth rif Itsts; Ihe first canc(rs appeared in the 7th m<tnth "INI)11(-IION OI- NI•()I'I nSMS IN (A RMI RI F I((11)I N1S lil' )- MItI11YI('ll()1 nNII1RI NI=" 11y Mrrrrs E'ullard, 1' MatsuraNa srul 1 C. Salomon, l obund Laboratory. University of Notre 1)amc, Indiana. Inurnal of the Notional ('uncer lnarirute 33/1 :93-99, July 1964 (Grantee: Pullard ) Localized neoplasms were induced in two atrains of 6ermfrce rats and in four strains of 6ermfrce mice by subcutaneous inoculation of stcrile 3-mclhykhoanthrcne in oil. Tlte types, locations, and latcnt periods of t.re lumors induced in gcrmfree animals were similar to those induced by the samc agent in conventional control animals. Bacteria have no role in chemical carcinoRencsis and the function of viruses is not apparent. The Rermfrce mice had no antibodies to polyoma virus. K virus, mouse denovirus, and mouse hepatitis virus, and showed no immunity or tol- crance to vaccini or Iymphocytic choriornenin6jtis viruses. Howcvct, failure to detccl a viral Anra may reflect limitatirms in sensitivity of de- leclion systems T'issue cultures prepared from fetuses and frum kidney tisaucs from jcrndrec mice and raH were observed for long periods; they slNrwed no cytcKrathK eRecas. ./Other irrawtorr U.S. Public Ekallh Service. I "OE:RMFREE ANIMALS AND BIOLOGICAL RESE?AR('FI." By Morris Pollard, Direclor, Lobund Laboratory. , lJniversily of Notre I)ame, Indiana Science 145/3629:247-251, July 19. 1964. TTu use of gcrmlree animals may be of help in solving many biological preshlents, a review o( some of the current research programs conducled at Notre 1)ame and at other laboratrxics here and abroad indicates. Before an animal can be successfully used as an instrument of rescarch, its para- mcters of physiological "rstxmaky" should be known. (iermfree tudents have a distinct anatomic anomaly which is related to the absence of bac- terial species: the cecum is thin-walkd, enlar6ed, and filled with fluid. Tlre relicukscn(lothclial system is paKly developed though functional. Indi- vidual lymph ncxks arc underdeveloped. The low kvcls of inttnursc glob- ulins in serum reflect the absence of viable microorganisms. Thus far no virus has been isolated from Scrmfree nimals by con- ventional procedures, but the possibility that sonic viruses arc trans- mitted congenitally cannot be disregarded. If the ullimatc results indicate thalgc rmfrce rodents are virus-free, then such rcxknls provide an uncompli- cated medium in which to examine the effects of nun-viral carcinogenic initiators. (:ermfrec mice are suscc)+tihk to a number of rival Rcnls, including (:ross leukemi virus 'Ihc initial allcralion induced hy Gross virus is in the thymus sland; and thcr:afler the gernrinal toncs of the lyrnphalic lissues undergo irreversible hypcrplasia. (iermfrec mke and ralt dcvtlup neoplasms rd the lung, brcast, and subcutanaws tissues following adrmnnlraUuns of chemical carcinor.cnic agents OtArr Rrawtor.: Office of Naval Restarch, National Institutes of Ilcalth. Ikp:rtment o( the Army. Nutrition hrrundation, Naional Science I=rtanda- tirrn, AUrmic FnerRy l'ummrssiun, and Ihc University of Ntrtrc I)atne 43 a 42 J N

"RAI)IAl1ON-INhII('I:1) LEl1K1{MIA IN GI'RMI:R1?L• MI(-G." By Murns Pollard and I Matsuzawa, (.otsund L.abtlrattuy, llmversity af Nulre Ihnlc, Induna 1'rtKrrJrnst p/ rhr S.Krtfy /t.r f.tlsrrlnrrnrul Bruhrry onQ AfrJrtrnr l16/1: V67-Y71, August Seplemtxr 1964 ((iranlcc: Pullasd) l.ymphalic leukemia was elicrtcd by whtlk-INx)y X-irradutiotl in germfree mrce of Swns-Wchster, ('J11, and ( 57 8I strarns. 7hc disease was not observed in untreated Rermfree conlrul animals lhe kukenlic ksit+ns resemhlcd Ihtse induced by X-irradutnrn in conventional counter- part animals. (-yluptasnlic vrral incluswns were nutcd by clcctrun mitro- sctpy in cells fhum Ihc enlarged thymus glands. In analyzing the technical details whereby the animals were entered into and maintained under germfree condNitxls, one can ctulclutk that the nccult Icukemtrgcnic agent was perpetuated in sutcessivc gcneratams of "I'lle by "vcrtical" passagc, thrtwgh Ihc uvum or thrtrogh the platcnu J(IrArr g.ant..r.r O/litc of Naval Retc+r(h and l/ S Public 1lcalth Service "A1N11(i1 N SIIM(II AIC'.I) hl-SOXYRIIIONlK'1.F1(' A('ll) SYN- 1111•SIS IN 111K<) IIY SVNSllllt1) MOl1Sl: MA('RUPIIA(i6:1" Hy l)crritk Rtrwky, MI), /`h17, lJnivcrsily of Atklaide. Auslralia, and ('ecdie I cuthtcnbrr gcr, MA. Phl), Imlalul Suisse de Rccherchcs lis- pfrrmentaks sur Ic ('ancer, Univcrsrty td l.ausanne, Switzerland I ontrr 2:7)1 715, (klr,hcr 3. 1464 ((iranlcc Icuthlcnhergcr) Inicclitm u( varinus antigens in r-rt,r into immunizcd nlice has been shown to bc accronrp.mcJ by raprd rnn.rIk ailrvily in pcrituncal macro- phages, hul Ihcre has becn duuht as ttr Ihc tnigrn of the new p)pulathnn of cells undcrgrnng mttuvs ActtnJrnKly, cvrJcrxc Irrr dnrt't slrmulal.nn of nucnphagcs was sriughl by in vtnrr adJdHm rd rntrgrn to rnuusc (icnlancal macruphagts maint.rned in trssuc tulturc '1 wo pertinent facts cmcrgc (rtrm Ihc csllcnmcnls. Firstly, in tissue cultures of nucrrqrhrgcs Irum c-rntrul nute, ilthough no rminut figures were ubservcd. DNA synthesis was nevcrttltless gr/ing on in a few cells. Scctxldly, this DNA synthesis was greatly stinlulatctl in macruphaRes taken from imtrlunized mice after the antigen was athkd It thus seems likely that the rn vivrr hmlings of active miUrsis rc(+tntcd by ulhcrs is duc to the prtstluctkm of tlaughler cells by the prc esisling mactophages. "TIIF. SIGNIFI('AN( F. O1= 1111: IN1Rn('IA 1 IILAR NlI('LFiI(' ACID MF.fAl3OLISM ANl) llIl= IIOSI ('Iil l.-VIRIIS RI:I.AIIUNSIIIP 1=OR VIRl1S INF+('llONS" Ily ('etdre Icuthtrnhcrger, Imunrt fur Allgerncinc Flir/anik, Fidgcniissnchc 'Icchmsche Ilr.huhulc, 7urith, Switzerland Brhfr.rrhrrv AlirrnArnl"Xiru 4 IR 42. 1964 In view of tlle fact that the cculnKy trl t'clls is crrntndlyd hy lts trwn genetic tnaterial 1)NA, the invasttn rd frrreiKn grnctic malrrral (virus I )NA (tr virut kNA) wIrulJ t.c ctlK'cltd IIr a/lt'tr thr Iich.viur td nce h4rsl tell nutlcit atrds and Ihus hrrrvnkc a thJnl,r rn rhr nIrrnJl ccll rtuliogy Sirnultanr, .us ty1. -h'Kical snrl cyt.hherlutJI analv.r. rIf scyucnlial nutlcrc atul anrt mmph"dnKual allrtitwns aIlcr rn rrr,, anJ rn vrtnr infcttirms, whh a varirly trf viru,cs, lseroril the detection of a rcnurkahlc phcnrlnlenun conlrmm to all of them. I:ach of the viruses euamined so far, whether it is an "infectious virus" or a"tumor virus," a human virus or an animal virus, a 1)NA virus ur an RNA virus, elicits within Ihe same host two s(rikin6ly di(Icrcnt effects trf opposite nature, which succeed each other: Effcct 1, defined as representing a hosl cell-virus rclalionship favor- ing vrral rcplicauon, is characlcrizcJ by synthesis of abntxmally high 4uanuties of tyl.e s(sccihc nuclcic acids (i e, I)NA after infection wrth I)NA viruscs, and RNA after infection with RNA viruses), whcrehy, in each instance, the corresponding nuckk acid remains either unchanged rrr is even decreased In cnntrasl, FIlccl II, defined as representing a host cell-virus rcla- tarnshi/l favtning rrll re(rhtaiun, dtxs nu( reveal such a type slxcific ab• mnmal rncrcase uf Ihc nuticic at•ids, hut is characterized hy only mrn/cralc UNA and RNA rncrcascs similar lo thrnc in dividing cells td surrnul lissucs and rrf tumors u/ non viral raigin lhis contrasting behavirrr of fhe nut:leic acids in FIlccl I and Effccl II is also reflected in the morphological and mc.abbrhw altrrawlns of the cells. In Ff1ec1 1, visible viral activily, in the sequence uf inlraccllular in• clusitwls, abnornral chromatin paltcrns, cell damaKc, necrosis and cell dt-alh orcurs. 7his sequence is assr><ialed with complete suppressitsn of nurnul nsclalxrlic cellular aclivilies, such as cell division and cell growth. In ctmlrasl, I:lict-1 It, after infeclitsn with the some virus, reveals none of these mruphtdt+gical, nsetaholic and harmful alleratitsrls to cells, but is charactcri.cd by stimulating cellular activities, such as cell divisian, cell gnswlh, mumal and ahnorrnal tissue proliferation, and, in stmse cases, ftlrnlatitln uf lx•nign and malignant lumors. Although 1?Ilccl I and Effcct II are never observed within the inmr cell. they can be found in different cells of Ihe sarne cell type or lissuc of the sarne htat, such as epitheliuns, indicating that the kind uf chanRe evaked in a cell by a virus does not necessarily seens to be dependent ulstm the cell origin. Another pertinent feature of these virus studies, which tkscrves con- sidccation, is the ubxrvalian that "lumrx viruses" anZa "infectitlus viruses" evt+ke es%cnlially thc same sequence of fundamental ccll- and nuclcic acid alteraliwwls in host tissues, although their final manifeslalians muy drfler '1 he hyppHhc.is is advanccd that prtslifcratiasn and malignant transfrx- mJlitm in fOcct II is nrrt caused by the dircct action of the vinn on thcsc cells, but Iheu trllular abnormalilks are the cnnwqucnce of uptake and Ir1tYNIN/raI1,N1 trf at.ntlrnlal viral ccll breakduwn prtKlutts inltr the gcnelic al+lsaralus uf such ntnl infected cells. 1/0hArr Rranr..r.: Natirlnal Institute of lli'alth and ('iha, Ilascl, SwrUcrland "N(I('I.FOI AR '('APS' 1'RO1)(I('II) NY A("IINOMYCIN I)" Fly R C. Reynolds. NO'I1 MrmlKirmcry, and Itcn IlugFhcs, I)rh.lrtmcnl td /'alh I 45 44

oingy, l/niversity of Texas Southwcstern Mcdical Schc>,rl and Wncxllawn Ilrnpilal, Dallas, Tesas. (on(rr Heuunh 24/7 1269-1277, August 1964 ((irantee: Montgomery) Actinomycin D produccd specific morpholugic alterations in the nu- ckoli and nuclei of (TanF liver cclls in tissue culture. 1 hesc changes ccxt- usted ol: (a) a proiresstve decrease in the size of the nuclcnli, (b) re- drstnbutK,n of the components of the nuckolur lo produce two types of auckolu "caps," and (c) production of intranuckar inclusirms These nu- clear changes were identical to thoae produced by the carcinogen 4-nitro- quinoline Noade. Nuck.r and nuckolar changes of this type were not produced by nitrogen mustard of by 2,4dinitrophenol. these findings sug- gest that 4-nitroquinoline Noside, like actinomycio I), may have a spe- cifsc effect on the.ynthcsis of DNA-dependent RNA. TAe majnr bicschcmical effect of aclinomycin D is an inhibition of RNA synthesis brought about by a direct crMlbrnNNM cr/ ,he dru` with DNA. Apparcntlyactinomycin D blocks the Iemplater respcrosihk ior as- umblinf DNA dcpendcnt RNA lhc oburved changes in the nuckoli and nucki o( ('han& liver cells may, in fact, represent rcprrxlucihk morpho- Io`ic m.rkcrs fnw spetif9c biochemical reactirms-i e, the inhibition of syn- thesis of DNA-depcndcnt RNA and the transfer of available nucleolar RNA ((om the nuclurlus to the cytoplasm. VorR.r gr.wrorr Damon Runyon Memorial Fvnd. "-illMOR 11OSf R1l A1ION%IIII'ti SI(IItII 1) IN 1'l1Rl) F'XF'F:RI- MENIS W1111 1ISS(I1: SI It I ti" 11y I rrqwdJ k( rrr.rJr+, Sr-tcr Marian )ose Smith, and Iesus Vucutc I/cli.rlrncnl uf lln0hrnusrry, I•r,rJhant University, New Yrwk ('ny..uJ I)cIr.rrrrncnl r,f Ilnhhcnrrttry rnr: Nutlrliun. School of Mcdicine, (Inivct.rlr rr/ Nucrtrr Hr.n, San Juan .lrrhtvrs nf Bioclumistry and Aiophytn, 111Nj 1 7 I 1, l)itubcf 1'Jh4. ((iranlce: Cerecedo ) The incorprx.tion of lhymidine I-Ir into 1)NA, and of aJcnine-B-C" into DNA .nd RNA, was studied io slices of liver, spleen, kiclncy, and lung of normal rats, of rats bearing the Walker 256 carcinoma, and of rals bcar- inF the Jensen sarcoma. Similar experiments were carried uut with the ttdsated thymidinc in rats beating the Murphy-Sturm lymphusarcom.. An Increased incorporation of the precursor was observed in the liver, spken, and usually also in the lung of the tumor-hearing )xntr, the spkcn showing the grealest activity Littk or no change occurted in kidney tissues. Thcse in vitro experiments confirmed previous in vivo studies which showed that the presence of a Iumor causes certain chemicaS changes in the host lissues at a distancc flum the tumor Thex changes are revcrxd when the tumnr rcgresses. OtAer grar.tor.: Nariunat ('anccr Institutc and 1)arnrm kunyrrn Mrmurial Fund r I V. O/her Cancer Studies 'Y'IIRnMOSOMAL PATTERNS IN CANCER PA'l11iNTS DIIRING TREATMFNT." By Anthony P. Amarosc, 1'hD, hRMS, 1>tipaumcnt ol Obstetrics and Gynecok.gy, the Albany Medical College of Union Itniver- sity, New York. New YoaE Srate Journal of Medicinr 64/19:2407-2413. Cktober 1, 1964. A study was made of chromo"mcs in cultured kukocytcs from white blood cells of patients with cancer, principally carcinoma of the lung. When- ever possibk, the blood sampks were obtained prior to as well as after radiotherapy. Abnormalities were recognized befure, during and aher treat- ment. The dama~e after radiotherapy appeared to he largely random in the chromosomes aAected in the different cancers, and the spccific aherralions differed from cell to cell. Ilowevcr, there did seem to be some crurclalium between the appearance of persistent ahtrrant chromosumes and their fre- qucncy. While the peak irscidcncc or "plateau" may remain unchangcd, the Irequency may change. sAer `ronsorsr U.S. Public Flcalth Service, Atomic Energy ('ommissinn, and American Cancer Society. "Ll1NG CAN('ER AND METASTASIS." By Shields Warrcn, MD, and Olive (7a/es, Ml), Laboratory of Pathuh,gy, Ilarvard ('ancer ('ommissam, and C'ancer Research Institute, New England Ik-rcrxsess Fluspital, Bustun, Mass. Arrlrivrr u/ Pathufuty 78/5:467-473, November 1964. ((hantee: Warren) We have studied a series of 5883 cancer cases (including sarcoma and leukemia ) on which autopsies were perfurmed at several Massachusetts Institutions from 1914 to 1960; in 4(112 of these cases, 1(IS2, or 26 per cenl, were found to have metastasized to the lung. lhe most frequent to do so were cancers of the testis (72% ), followed by brcast (57% ) and Ixme (51 %). hrons a numerical standpoint, there were 247 metastaxs to the lung in 432 breast cancer cases, 86 in 437 rectum canccrs, 65 in 34K stomach cancers. 59 in 193 prostate cancers, and 411 in 163 lung cancers, with ksscr numbers from 35 other primary cancer sites. There is always the possibility of confusing secnndary Iumors of the lung with primary tumors, in spile of radiologic or other nuans uf clinical examination cr1 the patient and even auh>(ssy findings ('anccr of the lung has been divided by various authors into several histologic grnups, with crrn- sickrable variation in the nomenclature. lhesc classificati•ons arc uf limited value. Most lung cancers are of mi.eJ cell tyl.es, not IcndinK Ihcroselves ta conformity of inlerprclalion. Furthcrmore, a sinrtk phase uf Rrnwlh, nd that must often terminal, is frequently the only nnc avrrt.rhIc /ur ark- quale analysis l he vatit nujruity rrf the 1614 primary pulnurnary c:rnccrs in Ihis %crrc% originatcJ frrun brunchial epilhchunr Unly a srn.rll nunficr uf c.nin rma. could he dcrnomtratcJ to arise frnm alveular ccll. 'lumurs uf tlrc /ioct 46 47

bronchi may hc cnnhrscJ with a)vetslar ccll cancers In aJvantt•J Icsinns the snatt,nuc point of oriRin can nnly l.e guessed al fhum hnlul,,l;ik tyl.c anJ from tnsuc rclalurnships V. /'ulmorsary Irhysir,luRy "PUI.MONARY SIIRFACTANT ANI) All?l L'(`IASIS" By Alt<tn I Sutnick, M 1). and l.4tuis A. Sulufi, M.l), Division of ('anliuh,Ry, l cmple l)nivcrsrry Medical ('cnter, Philsdc)phia, Pa. (nrsrhuruL,ty 25/5.676- 6f)1,Scptemlxr-(ktober 1964. (Graatcc: SoloR) Surface activily of atclectalic eatracts was studied with a surface film balance. All 16 atekclatic apecimcns demonstrated decreased surface ac- tivity regardkss of ctk>ksgy..(H thtrse 12 no/ asuKnred with pncunwnia, contiguous lung tissuc was normally surfacc aclivc Only uclcctauc lx,rturns, no matler how tmy, wcre inactive. To clarify factors involved with the 4•IClcctauc specimens •ssuxiatcd with pocum++nu, 23 specimens of prxumoma were studied All )xtK)uccd 1n•ctrvc cstracls likvcn of 19 ctrntr6uttus stctions studred were alsU ab- rnrrnul Into this gnwp fcll the 4 atekctatrc rcas I he oppusilc lungs, un- involved wuh pneunstsnia, were ruNma) lhcsc findings suggest that •.)ccrcasc in Pulmt,nary surfactant nuy occur secundary lu atckclasrs duc tu nuninfccu,rus lactors A surfactant antagonist may be prtxluccd durrn6 l,uhur.nary rnfccu,rn, and dillusc uul into ncighlxNing lung ttssuc, causing the a/rlrctasts ,xtarun.rlly scen with Q~cumonu lhrs ctNxept rml,lhcs th.lt onccr suh.t.rntcs rntrrKlutcJ int,r thc >tlvcoli may also result in atckctasn JOthrr jr.ntor: llrc Hcatt Asst<uuttn of St,uthcastcrn Pcnnsylvania "Pl)LMONARY St/RFA('TANT IN IIFAl.l11 AND UIS)iASF " Ily l-ouis A. Solon and Alton I. Sutmck dlt.chenutef (7lnirs, 1964. Nts, 4, "Tbe I.ung," pages 49 61. (Grantee: So)ufl) Uife would be impossible without stmse substance which counteracts the tendency for the force of surface tension Io drrve air out of, and Ito collapse, alveoli This substance is an slvcular lining composed of a lipu- protein and called pulmonary surfactant. Evidence is presented that absence or impairmcnl of pulmonary sur- faelant is implicated in a number of clinical Jrsurdcrs Sonic of thcre arc thc uneven distcnliort of alveoli rn erematurity. the furtnNrun of hya)inc mem- brnncs both in the respir•tory drstress syntlrunse of tn(anis and in thtwe who have been on a pump osyRcnator, anJ atclcctasis whr/hcr due trr pulrm.nury emhuhsm, bronchial t,tsstrucutrn, pulmtrnary eon.pressittn, shallrrw hrc.4lh i" or apnea and that asstsciated with pncutnnnia lt is auticipatcd th,1 ncw 1/t)eative Iherapy wsll he tkvch,l•cJ as knt,wkolt•r ,d rhis asl,ctt of f,ul 0, ~/tn„nary tnc, hanK+ ,nt rcasrs 4n ,. (Ill,rr R.nn/.,r Il1r 11, tt 1'cnn.ylvAnId ~ t. "t'OMI'ONI:NTS OF At.VI:OLAR ARl1:R1A1. O. I)II I•I RI;NI Ii IN NORMAI. MAN." lty Stcphcn M Ayres, AnttsrncUC ('rr+cntcll., and livJt)kia (ira4xwsky, tkparUncnls of McJicinc, Sarnl Vinc'cnl's llnspstrl, New York ('rty, and Saint Michael's Iluspilal, Newark, N 1. /nu.nuf u/ AppLrJ /'hyutrh,gy 19/1;43-47, January 1964. (Grantee: Aytes) 'fhese studies cnnlirns those of Rilcy and ('uutnand ( I Appl 1'hysiol 4:77,1Y51 ) that a Jdlusiun gradient d.rcs not exist bctwecn alveolus and end capillary hltkKl in the normal subject breathing roum sir at sra level Tlte alvct+ta(-artcrial oxygen difference (A-al)) is classically believed to be due tu Irue venuus shuntinR, unequal distribution of alveolar ventilalian ( V a) /u pulmonary capillary flow (Q), and diRusiue limitations. Btcathing nxrm air Ihe ddfusiurs cumpunenl of the A-al) was negligible . lktermin•atiuns of the components of the A-at) were osatk in nurmal suhjects at Ihrcc Icvels of inspired 0, concentration: 14. 21 anJ 11111%.; the A al) avcraRcd 7 1, IS 2 and 37 I mm!!1K respeclivcly.'1lrrce iml>,ulanl sssutnptit,ns ate matk in the cakulatitsn uf tht vemxts shuntL I)'1 he mag- nilutk ui the true shunt is not allered by hrcathm6 different O, cuncenlra- litwss. 2) Tbe nuslurc of all sources of the veno-ar(crial shunting ha. the same n, content as the mixed pulmonary arterial bhxxl Wlufe this is true for alveolar shunting anJ true pulmnnary arlcry-pulmunary vein cummunr- cautms, it is patendy unttuc in the casc of 7 hel.esiau vcin% dr.uninK imu the kf1 heart, whcre 0, content is muc0 lower than pu)nuwtary artctlal hilxxl. 3) hurina the breathing u/ II)O% osyKen complete eyudtbrium between alvcular air and end-capillary hkxsJ is ptesenl, perautting the use of alveular oxygen lcnsiun for end-capillary oaY6cn tension. i "f)/FFIISING ('APA( 17Y OF TlIE Ll1NG IN PlI1.MONARY IiMPIIY- SIiMA." lly Stephen M. Ayres. Meta E. ISuchkt, anJ Rulh (:. Armstrong. lkparlment of Medicine and Cardinputmueary l.atwsratnry, St Vincent's Ihnpital, New York ('i1y, and (kparlnrcnl of Medicine. Scksn 11311 ('tdkge of Medicine and Ikntiatry, Jersey ('ily. N. J. /rwrnuf of Applied 1'hysu,tt,ty l9/6:9R1-9R9,Septenrber 1964. (Grantee: Ayres) Steady state ('O and 0, methsx)s for measuring pulmonary diflusiny capacity ( I)l. ) may he aRccted by abnormal distribution of inspired gas relative to perfusion, and frequently fait to separate abnormalities in di(fu- sinn Irom abnormalities in distribution in patients with obstructive cmphy- scma. lhe present study descrihes a melhod for nrcasurinR O1. by rchrcath ing carlx)n nsnno.ide at normat restinK vent-ila/txy ratea and .tsnspares Ihe results in nurrnal patients nd in patients with chrunie ubstruclive emphysema. l he 1)I ,,, by thi% mcthnJ in 41 normal suhjects averaRcd 70 R- R 6 ml I,mm is-m IIK and was clutcly correlated with fxxly .irr :rnd IunK wrlumr Only 1 of 25 t,+lit'rHs with t,hNruclive enqslfiysema had a 1)I ,„ lcss Iltan lyfic 95°4, errnfidenre Irvel .tlthuuyh Ihe mc.nn v.tlue fur alI of thr (,atn•nts ( 16 K nml/ntin nrm f IF ) was .ivuthc:vuly lttwcr than rhal n( t1n• ntamal Ivtnq, (t is ennelw)ed that hrss of dillusinK.urf•rce rs nt,t a,cumrnun eause t,f t,.yhrrn'r Kluhrn tlcsaturaUun m uh.lruttrvc cml,hy.ema 49 ~ ~ (n

r l hc sludres rndicale that (rvcr :rll I)I ,„ rt•nr.,ins mrrnul in cnrlrhytcm.r until lalc in Iht crturse of /lrc tlr.c.r.c whrn I•ur.t• (+.w,rly vcnlil.,l, l v,rlumcs cntroach upon thr wcll vt•nlrl.rtcd regr,-n. At Ilu. lanl•rc..c., v,l.ir t.rl..rtdy, alvcnlar vcntrl.rlir.n, and uhrmu4ly tlrlln.mg Crf1Jt /Iy 4Ictrt•rst• lht tl.rla do nnt inilitrlc, hrrwcvcr whcthrr thc rlrtrt•etc rn 1)I ,,, is dut to hyprrvt•nulathom, unJcrfx•rfusiun, hrss of rh/lusrnl; snrl.rtc, r.r atlual slrucrural chengc within tlre alveolar caprlljry rncn,hrane Orl4rr Rronror.: Ameriean Tlsoraeie Sociely, New Ierscy McJrtrl Rc- scarch and Ica(hing I untl, and 1/.S. Public Flcatth Scrvit•c "'('IIRONI(' OfISIRI)CfIVE I.IING hISFASIi' SYNI)RI)M1: . OP ('I.INI('Al. IiX1'1'1)IFN('Y." fly John P. Wyau, MI), Prufcssur of Palh- oluFy, arsd Vernrrn W I•rseher, IfS, Oeparlment ut I'a/hrrh.Ky, SI Iawis llnrvenity Schrxd of Mt•dicnx, St I,rwrs, Mo )'rntgrnJuurr /NrJir rnr )h/S: 441 44R, Novtmlxr 1964 ((1ranlte: Wyatt) With careful anlemcxlem .ppraisal and pathological invesligalions on a whok lung basis, significanl advances have been made in Ilse understand- ing nd correct dugnusis of chrtxtic pulmtmary disease. With such an ap- proach, omnrbus Icrms such as "ubstructive lung syrxlrume." "asthma and emphysema." and "chronK irrcversrhlc lung disease" can he ehnnnated and correct etholugic and pathogenic tactras rn Ihese dr,oparate frams of disease elucWated. Ikrangcnscnts in the (untti„n:rl p.iremelers nf Ithe lung encountered in the em/.hyscma trunhltx arc al.o nh.rrvcJ rn ulht•r I;cnrr.rliicd lung drs- ordcrs: cystic hhrrrvs of thc luny„ tht "hrmcyt mih lung," :rnd gtnuinc aslhrua Ftwr cascs rlcscrrLcJ hc•rr rll nuere s,,nir "l the m~rrl~hr luKrc fca- lures that separate Ihe dillcrenl lypcs uf thtontt uhouuiuvc IunK dr.case. "P111.MONARY AI VFOI AR ( 11 I. IN('I.l1SIONS TIr1:IR I)f;VFI.- OPMIiN I IN 111F. RA I" 9y Sue Ilutkrngham, I)ryprrtrncnl rrl I'cJi.,lnts. ('olumbia Universily, New York ('ity; Wdham 1: MtNory )r., Ihp.rrlmcnt (if Anatomy, llnslrrn l)niver.ily, Mrst ; and Shcldrrn (' Srrnnncrs. I)cl,.rtt rsscnt of Palhoingy, ('ulunrhia Untvcr.ey, Ncw Yurk ('ily .1'rrrn,r 145 I192-119), Scptembtr 11, 1964 (lir:rntcc: Itu(kingham) ('ytuplasmic inclusk)ns in Ilrc .f•ctral pulnurnary alvcular cells d:rdult, newbtrrn, and felal rals were invt•.1r1;a1cJ by t•Iccurm mrcrovrqry and hr.lu chcmistry, and lung ctuatls were analytt•d /nr surf:rte tcnsinn atli.vly I hc inclusiems were ptnnive in the rc•nr~)rc acrJ Sthdl test allcr drgcau,n wrdr diaslase and were not stained with trrluuhnt bluc; Ihry /,rnrcd rnyclin ligurct and p.rsstssttl alkalinc phrr.phalast aclrvny Iloth Ihc lyhn;rl .url.rcc Icn.wm activily and the rnclusirrns rkvclul.cd Iwu djys In•Irnt• hvlh I hcst• la4qK•rtU" tliflert•nliated llre in( Iutinns frrrm rmtrkhrmt)ria ~~ tr, Othrr Rrnnrnr. : I hc I IcArl I unl; I rKrnd.itiirn anJ Ihc M.rss:rthu.clls I lt:nt O r) tn L r_. Assntralinn r a SIt Cr, P ~ m O rJ V1. (:hemistry and Biochernistry "IhIiNIIFI('AlION OF AROMATIC ALI)EIIYULS IN ('/(iARlillli SMUKI: ANI ) IN I UIfA('('U." [!y (.lrau-Iiwa Yang and Sirnon 11. Wcndrr, ('hcmrslry Ikpartmenl, llnrversily of Uk1alNrma. Nutruan. 1'hytrtihrnuutry 3/1 :1 )-22, January 1964. (Grantee: Wender) The following free phcnulK altkhydes have been identified in the particulate phase of snroke front five brands of non-filter crgarcltess p hydtuaybcnzaldehyde, m-hydruaybenzaldehyde, vanillrn, and syrrngaltk- hyde Ihese aldchydcs, together with pruloealcr:hualtkhyde and S-hydru.y- melhylfur/ural, have also been identified in the smoke ol cigaretlcs prepared without the usual flavorings or other atWilivcs, and in the elhet and elhyl acetate e.tracts uf tobacco (rum cigarettes. "SI'1~.('IRA1. Il)I~N1-I1~I('Al'/ON STUDI[:S UF Plfl?NOl.l(' A('II)S l)SINO AI.l1MINUM ('IIIARIt)E." dy Y. Nakagawa, M. R Slrctlar and S 1/. Wendcr, Chcmislry Ikparlment, l/niversily of Oklahunra, and Bio- chemistry Ikparuncnl, University ol Oklahtsna Schoul of Mcdicine, Okla- homa ('ity. Anulynrul Hruchenniitry 7/2:374-378, March 1964. (Grantee: Wender ) l he ultraviolet abuxption spectra of phen)lie acids in methyl alcohol and their speclral shihs on addition of aluminum chksride in mcthyl alcuho: were studied Ilydror<yhe:ntoic and hydruaycinnautic acids e.hibitcd sig- nificant bathtxhrumic shifts on addition of the aluminum chlnride, whcreas hydronyphcnylacelic and hydrvayphenylprtKsitsnic acids did ntH '1 his mcthod using aluminum chluride has proved to be a valuable aid in ptrsilive idenlificali<xs of individual phenolic acids present in micru ansounts in a natural product mixture such as in tobacco kaves. JOtAer Rrantur r National Inslitules of Ileallh. "FORMAT'ION OF NORNIC'OTIN[i AND OTIIFR Mli'1'AIIUI.111[S FROM NI(Y)1INE IN Vl'lRO ANI) IN V1Vl)." fly Nick M I'apadn• ptrukrs, Medical ('ollcgc of Virginia. Richniond l'unudiun /rrurnul tr/ IJiu- thrnrirrry 42/4:4)5 442, April 1964. ((irantee: E. ('. 11u11) Norniculine antl formaltkhytle were formed front nicoline by an cn- zymalK preparalion (nun rabbit liver. NornictNinc was idtntl/icd by paper chromatography and was isrrlated and characterized by physical and chcmical mcthtrtls. Incuhariun uf manicotine with the same Icsl sy.lcm give rr,e Io dcmclhylcr+linmc; which was also found in chrnmaUr);rams rr/ liver c.lratls following the intravcnrrus aJnsinislratHm of mnnictNine to Ihc r•rhbil ('hrnmaArPranms from livtr, kidney, and urine earacls sMrwed /he fnrmalwm of nurnicraine, cutinine, drrnelhykutinine, and nicrrunc (' usiJc, Irrlhrwing the inlravtnuus adminislraliun of nicrrline /rr Ihc rnl;rcl rahlut 1 hest mclatwrlK' shrdres mdrt'rled that niculine is dcmclhylrlcd Itu nrrruiirr tine which is lurlhcr r+xidrred lu deruclhylcolinine 51

I .1 .~. 0 }„'14 ,.~ ,.. ~ ~ ~ m W "NI('OTIN1i-I' OXIf)E: A MF-1A11O1 ITF.Of NI('OTIN(i IN ANIMAI. 1 IS1l IF " lly N M P.(.ad„pr,ulus, 1)rvisrun of Nturr,lrrgy. I.atvnatr,ry of Ncurr,chcn,istty, The McJKaI ('ullcgc of Virgmra, Richrnond .Irrhivrt of Bu,rhrrnivey and Fir.phyurJ I(Ih/1-1.1(32-185, July 20. 1964 ((irantee: f'.. ('. Ilc+fl ) Incuhation nf nicotine with an enzymatic rabbit liver preparation showed the fornuti,+n of a new nicot,ne mctatw,lite, nicotine I' oside 'fhis mctaMdlte was nulatcd by chromatographic pr,x:edures and chd raclerizeJ by physical, chcn,ical, and radioisdopic methods A simple chemical pro- cedure for the prcparation of nicolinc-1'-osiJc in crystalline form is also describal. Nicotine-1'<,siJe has not been repo.tcd heretofore as a urinary metabolite of nicotirx. In our in vivo espcrin,cnls it was observed that the conccntraUun of this rnclabc,lrte in rabbil liver was smalkr than the othcr metat>„hlcs iikntrficJ 'lhcse observations indicate that nicntinc- 1' osuk is not a tcrminal ).rrxluct of nicotinc nmctafKrlism but mslead an intermcdiulc in u.mc ha.chcmrcal scQ uencc o( nKotrne metabolisnr lhc role of Ihu com- pound in the mttrn,cJury mcubr,(rsm of nicotine and the biological actions which it pnKluces rcmain to be elucidated. "1)ISI'OS/ I ION ANI) FATi? OF (- -)1'OTININE 11' IN TFfE: MOIISE." Ny lidward R Nuwman, F-skd Ffansum, I ennos B. Turnhull, Ilerbcrt McKennis Ir, and ('arl (i Schmitcrlnw, Ikp artments of I'harnucnlogy. Medical ( ollcRc r,f VrrRinia. R,chnumJ, snJ Royal Vctcrinary ('ollcgc, Stockholm. Swcden. /r,urnul n/ l'h,rr.nwrduRy and F.sprrrmenral 7hrra- pcutics 141/1 101 1(/8, March 1964 (Granlcc M(Kcnnis) 11,c JislrihulKm and fate of Iruium I,4hclcd cntininc were studied in the mouse /tcr intravenous infcctuw, lhcre was a rather even distribution among various lissucs csccpl for a hiKh cunccntretir,n in cscrctury organs, such as the kK)neys and urinary hladdcr, and a conccntrat,on to sc,n,c cslenl in Ihe ccret.cllum Urinanalysrs revealed the )ncscnce of the nuubolites dcmethykotininc, hydrosycotinine, and 3 pyrndylacetic acid lTse mclab- olism of colinine thus follows in the mouse a pattern previously established in other specics. OtCrer grantor.: Swcdish Tobacco ('ompany, Thc American Tobacco Company and the National Insululcs of Ilcalth. "AI)nITIONAI. ROl)T EiS IN lllf MF.TAIIOLISM OF 1-A(-lil YLPYR- IUINE." Ny Ilencorrt McKennis lr , I cnnns Il Turnhull and I:JwarJ R. Bowman, Department of Pharmacnl„gy, Merlhcal ('allcgc rd VirRinia. Richmond lnu.nal r,/ RrulnRirul ('hrmuny 214/4.1215 12211, A/.rrl 1464. ((lrantcr. McKcnn,s) The mNalw,li.m of 1-aeetylpyriJine was invcoiPalyd in the numfrel dnR aftcr rnat and rnrravrnuus .,Jmrrvs,ratir,n uf thc c-om/it,unJ A pa/.cr chrr,m.at„Prald,ic cotam,nati„n r,f prrrrs%cd urrnc sul'gcslcd the I,rescnrc of  v.rrcly r,/ incl.,hulii,•s, in,lud nK I ( 1 I)yr,(lyl)Nh:,nol S? -The quaternary ammonium fraction from the urine was chromato- graphed (in paper to provide separation of N'-methylnicutinanuJe, a pte- virru.ly rccordeJ mclaMdile of 3-acelylpyridine, and N-mcthylatcJ 1-O- pyridyl)cthanul -The lauer was characterized as a S-nilrobarbituric acid salt in crrmprrison with a synthetic d/ derivative. T?,c basic fraction of urine afler administration of 3-acetylpyridine to the Jr,g yrcldcd ( 3-pyridyl)-1,2-ethancdiol, which was characterized as an optically active S-nilrobarbiluric acid salt, an O,O'-0iacclyl derivative as the picric acid salt, and by osidation to nicotinic acid. ~Arr Rrontor.: National Institutes of Tfcalth and The American Tobacco Company. "MAMMAI.IAN 1)E(:RAI)ATION OF (-)-bEMf:Tf1Yl.('OTININP.." Ily Sorcll 1. Schwartz and Ilerbcrt McKennis )r., Tkpartmcnl of Pharms- cohrRy, Medical ('olkgc of Virginia, Richmond. Nature 202/4912:Sy4•SVS, May9, 1964 ((ir.ntce: McKennis) fk~radation of the pyrrolidinc ring of (-)-nicotine in a number of mammal'ran spccies involvcs the formation of the inlermediate, cotinine, which in turn is densethylated by the dog and the ral, but possibly not by man, to give the urinary metabolite (-)-dcmethylcolinine; this is also formed in the metabolism of (-)-nornicotine, a companion alkaloid to nicotine in many situatiwms. Natural (-)-Jemethykotinine was adminislered orally to rats. A chromatographic esaminatron of the utinq following estcrificalion pro- ccdures, suRgcsted the presence of y-(3-pyridyl)-y-osobutyric acid, r-( 3-pyridyl )-y-hyJrosybutyric acid, and 3-pyridytacctic aciJ. The oso acid and the hydrosy acid were chemically identifieJ after conversion to derivalives. T hese data point to Q°~ sibk metabolic sequence which begins with the intermediate y-(3-pyr~y+l-y-0tobutyramide; this is andogous to the inlcrnxdiate y-(3-pyridyl)-y-o>ta-N-methylbutyramide, which has been shown to arise from colinine in the rat and to undergo subsequent mctabol- ism to the ketn acid A more delaikd esaminaliars of the pyridyl compounds /tvolved in the metabolism of demelhyko(ininc is required. ,f OtAer Rrenror: The Arnerkan Tobacco Company. I "MI:TAROI.IC REi1.EASE OF MI:TIIYL GROUPS FROM A SERIUS OF N-MI:f11Y1.PYRIDINIUM (:'UMPUUNI)S;' Hy llcrbert McKcnnis )r , FdwarJ R flowman, Antonio Tlorvalh and )ohn P. Iledkrk. )r., Ik- partment of Pharmacology. Medical Cr>IkRe of Virginia. Richmond Nature 2(12/4v11.M1y9 7(K), May 16, 1964. (rrantee: MtKennis) Since the quantity of N-rnethylpyridinium compound present in man,- mahan urinc in many studies mry be relateJ, in past at kast, to the relative stahihty ur IaMhty of the methyl group on the quaternary nitrogen alorn, a crrmparison was m:,dc rd the ease with which such gruups IafxleJ with cathr,n 14 c,rulJ cntcr into usidative pathways, using labeled respirauny (-O, of the rat as :rn indicator. From the series of crnnlw,unds sludicJ it 53 ~

hcconres apparent that there is a nrarktd variation in the suscehlrhihty rrf quaternary N mcthyl groups to mctaMvhc nxidalnon the yualcrnary N- mcthyl group nf cotininc mcthrmium irwLJe afforded hnle cartwrn Juoxrdc in comparison tu the N mcthyl group r~( 3 acctylpyrrdmc mcthrrmum iuJtJe which cuntnbutcd -1 to 8`.cr ccnt td irs radioactivity In the respiratory cartKrn dtuxrde. Ihc value rohurned following adminislratirm uf N'-methylnicrNin- amiJc was suflicicnt to account for a small but siRnificanl (001 0 11 per ccnl ) portion ul the mcthyl grrwp in the form of respiratory carbcm dioxidc. ~ )tAer Rr.ernr.: The American Tobacco Company and the National In- shtutes o( I Eeahh. "TNF; ME:TAHUE I(' UORMATInN OF y-(1-PYRII)Y1.)- IIYI)ROXY- Hl1TYRIC A('II) ANt) 17S POSSIHt-E. (N-Tl?:RMFhIA~Y ROt 1: IN TI(E MAMMALIAN MErAHOI.ISM OF NI(-UTINF-." Hy llcrhert McKennis lr. , Sorcll l. Schwartrc, l tnnrrx H Turnbull, Finnsuke f arnakr, and F:dward R Hnwman, Ikpartrr.ent of Pharmacsrh+fy, Medical (-rdlcgc of Virginia, Rahmrsnd Irru.nal of Brulotr<'ol (-hrmrrrry 2)9:198I-J989, Nuvemhcr 1964 ((iranlct: McKtnnis) YO-pyridyl t oxuhut~ric acid, an inttrmedialc in the bacterial and mammahan mclatx+lrsm n( (-) nicolrnt, kives rist to r-( )-pyridyl )-y- hyJroxyhutyrrc arrd aftcr administration to the rat, the dog, and Ihe rabbit. Tbc hydrnxy ackl, which was preparcd (tscmrcally by reduction of the kNu acid with srKhum Manhydrrdc, was cronverlrJ to the lacume, 5-(J pyridyl) tclrahydndurantxsc 2, by mtlhannl sulfunc uiJ and then resrrlved in the form of ( ) and ( I ) tartrate salls 1 hc resulting cnanlittmorphs were charactcriteJ as the craresfoonJrnR prcralcs The synthctic Icv<aMatnry picratc cnncspc.n<ted to the product that was isolated from rN and rh+8 urine In cnnlrasl, the urine uf rabbits yicldeJ a raccmic picrale of S( 1 pyrrJyl)tclrahyJrrduranune 2 that was iJcntificd in comparison with the synthetic crrmprrund -Ehc evidence suggests Ihat the ratio of optically active y-( 1 pyridyl)-y.hydruxybulyric acid to raccmic acid in the urine rr/ the rat and the dog excceds that in the urine of the rabbit der Ihe condhions of the study. ,/ Other grantor: The American Tobacco Company. "A1.1T?RNATE? ROl1TFS IN TIlF. Mv fAf)OE IC 1W(;RATIATION (1F T llli PYRROl.ll)INE RIN(i OF NI(-OI IN(:," Hy Ilertrcrt McKcnnrs lr , Surcll 1. Schwartr, and l-Jward R Howmrn, I)epartrncnt u( PharmacrrlnRy, Mcdical (-r>flcgc td VirRinia. Ric'hmund lorurnof of Hird(qrirnr ('lrrmirtry 2J9/I1:199(1_)996, Nnvemhcr 1964 (Grantee: McKennis) An cxlcnsirm of previous stuJits un the melahrdisrn of Iwo inlcr- mcdialcs in the rnclalKrlism of nicotine. (- )-cntinine and (-) Jcmcthyh n- tininc, hat tstrnullyd thc crwrUructirm of a stnnmary snccmc for mammahin mrlrts diun rd ni, oHinc In Ndh the rar anJ rlcmcrhykrrlininc un IcrFr+cs dcRrarl.rtinn t, t t I t,yrtJylt r ur„hulync acrd anJ r( 1 ryriJyl) r hyilrr-xyhutyric aciJ Tlre kclu acid was identified after conversion to the mtlhyl estcr while the hydrrrxy acid was identified after crxrversion to the picratc n( the laclnne form. The pattern (if cxcrction of urinary pyridyl aciJs aflcr adminislraticsn of (-)-rkmcthylioluunc is similar to that observed •.fter aJminislration of (-)<u/inine. The administration rsf (-)-ccslinine to man kd to the urinary cacrc- lion of )-pyridytacctic acid, which was chemically idenlifted for the first time as a nrctaholilc of (-)<orinine in this specics. Rrantor: The American Tobacco Company. V 11. 1'harnrar•oloRy and P.yc/ro-Pharmaco[oRy "RUI.ATI(1NSIIIP Elf'1WE:FN fiVOKED RESPONSE CIEAN(:E , S ANT) IIIAIAVIOR 1-OI.I.OWIN(7 SMAI.L IX)Sl3 OI: NI('OTINE IN IIIE ('AT" Ily lamcs I:. Shryne Jr. and Oarbara H. Hrown, CaGfornia Colkge of MtJicinc, Lus Angeles, and Veterans Adnsinis(ratirus 11ospF1•rl, SepulvcJa, ('atilrwnia Prr><.cdrnss of the Wtstern Pharnxoco(ory .Suriery 7:58-60, 1964 ((iranlce~ Ilrown) Thc preparatiuns emplnycd in these sludies were chronically implantcd, freely muving cats, with ekclrudcs implanted in fornix, scplurn, and the hip- prrcampal furmation After cxtcrKkd control evalustinns, nicalinc was aJ- rninistcrcd intramuscularly in doses rsf 30, )7.5, 50 and 70 pg/kg, mounls cumparable to the amount of nicotine absorbeJ in hurnan smukinb (f 2 to 3 cigarettes. huring the first 30 to 60 minutes after nicoline, cats were either rcla- livcly akrt or indicated uneasiness. Ekclroencephalograms ( I~.EG ) recorded during the first hour generally displayed n akr/-awake pallcrn and were Jislinctivc in that this pattern was suslained, contrary to usual control rtcords This was followed in the second hcwr by generally IclharRic, druwsy, rrr light slccp (n:havior. (-hanRes in specific EEG characteristics were con- sistcnl: thcta activity was increased in abundance; amplitude and amount of IiE:G phutic following to all colurs increased in all animals; bu1 no con- sistent changes in F.1:G or bchavicxal arousal thresholds to tone occurred Wlx'n drug effects for all evoked responses were plotted together in a scattergr.m, expressin8 changes according to the direclinn of behavioral changc, a wide varicly of resprrnses were obtained T he sc•ruer was climin- ateJ when responses of a spccific responding slruclure to a specific stimulat- in;; slructure were sumrned frx different Joscs, and the direction uf change was fuund Irr Ix crmsislenl (rw each dosc of niculine. With the two smallrr duscs the majonrly of resprrnscs changed in the direction of wakcfulness, whcrcas at S(1 r.R/k); most respl+nses chan(reJ in the Jircctinn nf skep rnr nayt evnkcJ reslNrnses sIlH1Kd, txc11ah1hty-resplrnslvtntss cmvcs returneJ lu crrnrrrd values wilhin 90 nrinutes a(Ier administraliun of nicotine "I I+f(T (/F Nl( (11INP. ON ('A fE4'IH)LAMINI: ANI) SI?R(1TY)NIN I IiVl:l S IN I'll'r) " Hy 1: /lanann, I) -T- Masutrka and W(r• ('Lnk, Vc•Icr.rns AJmrni.tr.rtirrn Ituspital, Sepulveda. (-alif ; Mcdical ('cnter, llni- 55 Sa

vcrshy of ('a)ifornia, Lt» AnRetes; and t.oma I inda Flniversity. Schtxtl of Medreine, 1A» AnRcks. Archrrrt Inttrnanuwlrs Jr l'hvrmrxudywmrt rrdr 7hfrvpit 149/1-2:15)-16(1, May I, 1964 (Grantte: (-lark) lnjcctK+n of nicotinc in mice, rats and guinea pigs resulted in s)ower csttcholaminc ctxnent in the adrenals of rals and guinea pigs. A ktwtr str- o/omn concentration in the intestincs of rats and guinea pigs was ot,servcd, but statistical signifscance was not establishcd 1 he catecholaminc and serrNonin kvels in thc brain, the heart and the spleen of all the spccies studied remained una0cclcd or possibly slightly elevated in the hcart. AccordinRly, no evidence hat been obtained which suggests that nico- line causes an incrcased release of catcchc>tamines and/or serotonin from tissues other than those rich in chronuthn or entcrrKhromatfm cells, such as the adrenal mcdula and /he intestine, a least in tlx specks sludred. Orh.r grsr.tor.r American C'anctr Srtciety, Natiunal Institule. ,r( Flrahh and Nataanat Asxxraticm (rK Ment.t IFcallh. V111. Other Studies "EF FT("TS OF ('ARF1nN hlOXIF)F. INI{ALATInN UPnN ('F:.RE- HRAt. HF tX)I) FF UW." Hy Robert A Kuhn. t)eparlmcnl c>t Ncuro- surgcry, Set,rn FFall (-ullege of Mcdi.rne, )ersey (-ity Medical Centcr, N 1. (7rnirvl 1'hn.mo.nL-Ify vnJ Thrruprurn t 5/3 277 211(t, May-lunt 1964. lTsc methrn) uf inducct hrathi.it art,ry rnlccuwm wrs cnuplcd with high- speed hhn changing Iu rnvr%ugrtr Ihc t/I„ t% rd u,I,.rl:,l (()ut.un ccrchral bhxxl fluw in 7 n,nrnal sutycth I )nc nnmo, rnholruwn nf a nutrurc uf '0% 0, and S`X. 0Or tctiullyd in tu,rc.+v+l .r,tt'trol 16+w an+l m.tca%ctl nuntf.cts of visible vesse)s lhc cerebri1 srtc ++I rttnmn ul +nhrlcJ (Y), apl.cirs tu be the arteriuk caprllary nclw(ork "IN VIVO ANI) rN VITRn STl)F)IFS ON TIIE OIILSTION OF A HIO- F(X;IC RELA7IUNSIIII' l)l:l WITN NI('(/TtNE ANF) AS(-ORHIC A(-It)." Hy R(. Tahct (now with NcuuTharmacoloRy Research, Schering (-orporation, Hkxrmfietd, N 1) and P. S F.asson, lkpattment of Pharma- cology, Medical ('6lkRe of Virginia. RKhmrMd. .Irrhivrl lnttrnariunults Jr I'hvrmoaorlynvmir rlJr lhfrupie 151/1-2:243 259, Scptemtxr 1, 1964. ((irantcr: Larson) In vivo snd in vitro studies on a Fwnsibk (bi)loRic) rclalir.nship be- tween nicotine and ascorbic acid has resultcd in the following findinRs 2 A destructive efiect of nicotine on ascorbic acid in aqueous solution and in whole hhwKl rn vitru, which was dependent on plF change rather than the nicrdtne prr st, was obscrvcd. 7his effect is unlikely to be of biologic tignificancc. 3. ('hlorobutanol pre-treatment, which slimulatcs biosynthesis of ascnr!sic acid, pruduced a significant degree of rrolection in mice against the toaic effects of repeated sub-Iclhal doses of ma+tme. SKF 525A, on the other hand, significantly decreased the tolerance of mice For nicotine, but had no cftect on ascurbic acid ucretion. Since ascorbic acid administration by itself could aflord rw significant degree of protccticsn against niculine toaicity, it is doubtful that the protective activity of chlurubutanul can hc attributed to its ability to alter the availability of the vitamin. a 1. Animals (rsts) capable d synthcsizing their own ascuthic acid re- quntmtnts, and anin,a)s (guinea pigs) dependent i+n catRenous vit.+nun C, were treated darly with nicotine in suhstantial dnscs h+r 31) nd 12 days resF.cctivcty, with no discernible changt in ascr+rhrc acid eactttirut A,IJi- V O ~ ~" thc nrct+anc ucated rats showed nu chsngc in either whulc tx+dy or ti,.nally ~ (S) m , sdrenal asiurhrc n td tmntrnt as c~nn)+arrd tr+ thc cnnttuls r P 7• m (?l C.~ Sh 0 P s

Recipiews of Crants I:RANTF.E ANI/ INtiTITlrT10N PRO)ECr TITI.E PRQnPRICK rY. 1lARNES, ). , M D., The rok of hyperplasia in lissue responst i'nllowin6 is a list o/ all recipients of grants app roved by the Scitntific Phr D Auoriarr rro/rrwr of AIr/wGr to chronic damage (('- P) Advisory Dt,a(d since initial grants wcre made in late 1951. It should be .nd }AyeJoloRkaf CArnslrnP. )ohws ooleJ Iha/ sume of thc projectt have heen complcted. Hophlas Unl.ersity School of Medi• cine, Saltlrnore, Md. (t.ow Pro(cssoe of I i CI1APfTF.E ANf) INSTfTIrTIIMI CIAReNCP M. A(7RFSS, M I), CA/./, CYdIO.a.cYler ( efo..IO.y, VeNerana AdmrNiftr.IK1. Crnter, l oe A.gks; As.rociur ClYna.l Prolruor of A(rdl. e+ar, Va.ernly of ('al/fornia, 1 oe Aapcke ANTII()NY A At RANFSP, Ph (), fs/ nNor. NYbulow end MruA,Jrr Rr•r.rfA (A./rron The Win/frtd Masltr. a+. Rur1e Relief Poundal{o.. the Swle Foundation ReAabilr/alio. ('en Ier, Whire Plaraa, N Y. ANTIIONY P AMAR(>SF. Pr/ O, F R MS. frrtuan/ rro/rn.+, /tr(~.r.rr.anr of (1Arrrrr.a r rnd Ihe At bany McJKal ('ulltlt of Unrun llnr rcrsuly, Atbany, N Y !! T AN(;I I AKl)S, M I), Pu h. P.,. frrtw r,/ rAnrol..tr 11odr.n I/marsrty Sc hotr! of MtJrc rne, Rutlon D MURRAY AN(IFV/NP, M 1), F.r. /rraor of r.tholol y. Uni.rrsay of W n co.d. Medical School, Madlco.. IX)MIN(:O M AVIAIX), M 1), Auorl. .er rrolrnor of rArntsrnlr.ry, llni.er srty of Ptnnsylv.nia School of Mcdr- cine, Philadelphia. STEPIIP.N M AYRf•4 IA D, Dircrrn., Crdb/.lmo.ur~ L.~or.rnry, St VinccaP. /lospilal, Ne. Ynrl (71y; Annr •nr Profrnor of AfrdYinr. Scion 11.11 ('ollefe of Med.cine, terxy ('ily. N 1 rRFDFRIK 11 RAN(;. M f), Pr../rrr- .wr ('Aoum.rn. (n.pu,rmrnr of r.uAn A.rJ,rrr. 1 ht 1du.. 11r,r,1 rn. l/nrvrrsd y. 4hrYrl r~f //tprnr u.~l /'ul~h~ Ilr.lrh, P.Irun„r r PR())F.(T Tf71F. ('Y" a.Mrr.r p.N.r r....o.rcl. •'r 1.dr..r. A rrw.r1 a- a.w. rrw..d .. r. r.wLrr MusuresrYral of the function.l slalus of the humsn hca.l hy hetiutncy spec trum analysu of ils vrhratu.n,l enc.ay IC-P) The efrrct of nko/inc on /~ rwrm .nd ndaq ac.d mtl.holrlm m /rirnr.m a n d aq ( hromMnmt pallerns rn panrnls wilh carcrnurna uf the lunt, htfurt. Jurrna, and afler Irtalmcnl 1 P t Rrles.e nf caurh..laminrr frnm the iso Ia1tJ hearllPl Patholotic an.rnmic sruJy nf (rllul.r changr/ m human brunchl IC Pt lRreH of nlco/ine .nd cipretlt smnkinR on neurojtmc mech.nisrnf rn the lung IP) Mrasurtmenl of alreolar arttrial nitroaen ddlerence by aas chromaroaraphy (P) the JrRu.rna capacily o/ the aLrr.l.r mr/nhr-ane in pulmun.ry ernphy'rma IP) Rtlalion of aa p.dluhun In de.clopmenl of chronic pIJm/MAry d/scase Inlrrac/rnn nf rrnral .r,h mrNrrt. ol the rr.pu.rn. y rr.. r, .uJ the r11rr r of v..na tn.n rn fuu,nr.n.,f Iht urutr+dr..ry r/l~ Irnr I P / Medical Scienu, Srow. U.i.crsitE, Provide.cc, R. 1.) R FRFt)FRI('K SFCKFR, Plt D, Arso- rrarr Prufrrra., An.ron.y.nJ Dirrrro., I abocalury t.( Perinalal Science. t)ulc l/nlrcrtay Medical l'enlcr, Durham, N C. RAI P/I S RF('KFR, PIID,ProfrrwroJ ('Atnurr.y, (enrvcnrly of 1louwtos. Iluudon, ire SAMUEL SFIIFT, MI), Di.rcror, DI• rli.on o/ Cudroloay, PhilaJelphia (icra• ad Hospital. IIYI.AN A. SICKERMAN, M D„ Aa.o• riarr ('l/nkd rrolraaor o/ Afrdlr inr, and AI VAN L. SARACN, MD,('c.n rYtrenr m A(rln.nr, ('alkge of Physi cians and Surgew s Collwnbia Uwiver• sily; ('olumbia 11.i.enitr Research Ser.ice, (;uld.ater Memorul Ilospital, New Ywl. RICIIARI) I NINO, M 1)., Pro/nwr of A(rd.crnr .nd ('Aannvn. F)rft! rrmrnr o/ A(rdremr, Wayne Slalc l7nrversiq ('oltege of McJrcine, f)tlroit. Sy Posaihk effec/s of maternal mlale nf nicdinc uqon the developing lelus and nconale. A sludy wNh the ral and $uine pre An inve+ligaliow o( sprclral paran.rlcn of arornarrc hydrocrharns IP) A.ptclral invesl/aalion of awma/k by droeartaons and then comple.es with prolelns Tlx eRec/ of witoline on cardiac irriration in the presence of rescrprne, and the e/ fect of nico(/ne on corunary blood /low of dop with eorunary /nsufRcrencT IG-P) ERecu of nicolinc on the rnrrpholoay of coronary aelerKs anJ anrU, hbriMrlyllc eRects of wkdine on human and am wat plaarea; e/lects of cessaNo" of snwhi.s ot lerum cholcstcrol tc•cls of chronic smokers ( P ) No.Irrilanl cigarette unolina wirh ob ursaliows on the carbon rm/nucide eon(enlratiow of arterial bh..J .aJ al.eolar gas after smol.na wilh inhala tiow anJ afler mM rnhdalrtM snK.klng (P) lhe eRecl of a non inhaling technique of eiqrelte smot.ina on the carbun nwxro.• ide bkn.d k.els anJ .cnlilalorr func• liuw of heallhy sul.iccls and pal.enls wilh chronic respiralory disease The effect of smoling on the coronary blood Ruw and ctalain phases of myo cardial mclaholism in palccnls wuh arlaNfsekrdie or hyperlensi.e cardr orascdar discase IP) Slw/ies is cellular physiology of hearl anusck (P) Meuuremenl of coronary blood Row by meant of ndioac4vatcJ alhumrn The eRee/ nf emolina un crnonary Mrrnd flow ial palKn/s wl/h •rlerrnstltrrN/C heart disease anJ Ihe e0tc1 of nrcnunc oN sluraae of .mmes in htarl rnuxte (P)

CRAPIT?:F- ANf) INSTITYITI()N PRPD 0 B(X'K, M S, PM D, Senier Cawcrr RrararcA Srirnrilr, Rorwell Parl Mtn.orisl Insuilurc, Brologkal Sca- tio., Spri.l.dk, N. Y(sct Moort) PNl1JF.(T T1Tl.E Measurcmtnl of coroaary DIuaJ flow with a trstens wing coieaidenct cuunl in@; the esecl of mcohne anJ chae/e rn bea.t rNe ty cudiac mcr.hol.crn teJ rt)atcd sub/ect, (P) Sludret on csrJr.c mNthob.m wi/h cpe. cul rctcren.e lu myncarJul tnous (P) Lcesllptioo o/ the biolotical eRecu of tlgarcl/e smoke (C P) )AMP,S PDONNFR, PN 1), Pro/r.anw of ' / l PntymNk study o( mtthYlahon rtactinns ' , , IinrAnnrrny, ('olumbia l/aFvtrsil/ ory. ( b ahfnrwia lashluwe of 1«h wolosy. Pss«k.a. in pla.t tru+.e I( P) ('dkgc of Phytki.nt rnd Sor~tont, Ntw Yorl (rtbreJ, srt (iWllchal/) TOM (7 Bl)WFR Y PH I) rrrrklJr Rtr if)P a.d e.Jnn rtudntr rn ci{.rtlle , , 1/rr l.loraro.t. (Arntfitry l)rr.•l s..olt (C P) IAY 1) (()FFMAN, M/), fAylk/an i.. 'A h P l V /w.N, NptA ( srotuu Statt ( dlcRe ( arer, cnp rra tscubr I ahort , R.kiRlr. lory, Mrss.chuselct Memurid Ilospi- rals. Boston BARBARA R BR(1WN, PM [l, RrrtrcA Nndine and smoking tRrcls on eketro rrnfrrlot of f.r0rn.wrnrlol r/]tArt4r. ' encephr"ram corrtlarts of Ltha.rw, i ( tlrfotnit ( ollrae o( Mcdrer.r, 1 nt Annekt enwwronal rtrponcrvent+r tnJ rtu.l ptrreprw+n rn cals )l)SFP eR(17FK, PM Il . Prolr..n. a.d R+nkyied ch.racttridics of n.en and thtir ' Ch.vma., Drj-r/..rnt of lnrAolnlt. .rrr+Ires hah+t. Il P) DANIFI COItFN, D V M, M.P 11., Al- l<hish Uarveruty, Btthlehem, P• turant Pru/ruor of Yrtrruary, Epidemi. olnty and Pu6)rc lfrafd, School of S11F Bll( KIN(:IIAM, M 1), Arrlrra-r nn rht Jtvtl~+pmtnt n,l MrJ,+ly Vetermaly Medicint, Univasily of 1'rr.(Nrrv n( frJior.u t. (+•lun+/.u 11nr •trulY. (b11eRt of Phy.nr.nt anJ tiur Itrr+m. Ntw Yor1 ( sly ol lune .n. 1, i.n1 1 P I Pennsylvania, Phdadelphia. RFNIAMIN B11RRl1WS. M Arrnt( lhnraarc ciwnfd.4n.c in rhrr+nic uhUruc at, I•u/runr ../ AIrJw rwr, /nrrtnd) of ( ha.So, ( h.c.6o l+.e lun0 Jnt.u P_ M 1lfTT, M D, Pro/rnor of PrrAol Patholotie .natomic study of ceNular on, Uwiversily of Southern Ctldrwnw chan$es in human bronchi (("I ' School of Medicine, (-Alrf ParAofnlnr, SIuJy of Ir.cc nxtal stwsst of pulnwn OMROF, 1.., M D., Dlrrr• /1/l1US IL ( t os A.ee/e. (:ouay l/osp.ul, ( a An ftlta sry and (iver tissue by spectogl.pluc and chemical axthods (C: ) rar, Crdiora.rrlar Rn.rrA Inrntrn, University of Califoraia Medicd Ce.- 1cr, Sr. Frs.cisco RI('IIARD U. •YERRIIM, PnD, Pto Bio.ynthnis of the pyridiee rin{ of nico frrror oJ CArnturry, Michisa Sule trne (C P ) f1PAN M. C(1NNURS, M D, Arsociatr Uaivenily, East l.asi.A l)irtctor, DrParrmrnt o( l aAurrrory Mrdclne, St Mtry't l/trpi/.l, M.Ji• S1SrFR M. P.MILY ( Afllll, Pnf). ('Aalrnca., CArnr/rrrr DrP.rtmrnr, Cornparison of analytical metl+.rfs by Jeltrmrnin# Ihe ptrcenl rteuvtry of soa, W ie. Rrsn ('olkge, Wectnn, Mau a.senie aJJeJ tl known It.elr ro lo bacco sampler .nJ a brwJ survey of P1111 11, (Y1nPPR, M D , ('Art/. .trrCkal IIK amount of .rfrnK prtKnl ru 10 btcco samplts frum  wiJe vtrrrry o/ Sn.kr, Velctras Adminir/rHarn I/otPilt1, Brt.•t, N. Y.(Yrwunt rrofrurw +n ...ur+tc /( / d V 0 of Srrgrry. Albert hrnsttie Medical Broas 'o11e ( e WIIIIAM It t-ARNI_S, M 11, Prnfrlrnr sr P.Ihoto/ic anatnm+c 11uJ+t• o( ctlk 0 . . c , m B o/ P'sAnt,,lr. Itnr.rnuy of lhah t r>a Itse of MeJKine, ylr I atr ( Ay chanser in human hron+ln 1(1') J ! s u+ 60 P 61 0 r 0 CRAN'f EF. AND IN.STITVTION LEOPOLD ('FRF.CEIN), PwD, P.o/rr• >'or oj SiatArmuery and Notrition. Uaivcrsi(y of Puerto Rico, School of Medrei.e, Sa. )uau (fo.rnerly Pro(ei aor of Biochcmistry, Fordham U.iver- aitr, Ne. York ) WII LIAM O. CLARK, PN D., Clinkef AtrorLtr ProJrtror of rAyirologwal CAr.ninry. Ueiversily of Califpaia Medical (:coler, Los Aegele... IIANS T. CI ARKI? D St-. P.oJrsror of PR01F'.Cr TITI.F A Mudy of early chemical changct ie the luep of lurnur beating rNs and mwt (C P) EJtecl of nicotine and rebteJ suh+l.ncts ow aminc kvels i. the ncrvous tyclem (C--P) Pro/eolylk aclivNks of the while blood alls of men awJ /bt tecN on whlle blood tcll wu.itres, of crnuw~tm, aWrilion arsd other inftuentcs /(') Ihe rlfecl of Reueolfla anJ (:u.nethiJine (calccholamme depklins rn hhtling atents) on Ihe symp./hrlic vaqrcon. clricliun induccJ by tohacco tmoking •ad by envuunn.rnt.l brtilr cuadmR lhe role of ulecholarnme rtleau from the aJrcnal medull. rn cau.ing the cu- culaory efle.ts seen during lubacco smoking To survey tadiogra~hrcally the lunts of .11 do- s pauin~ Ihrough the vtlerrnat) clinics and hospital of the Universi/y of Ptnnsrlvania Velerrnary School in order /o dclermine the prevaknce of pulrnonary abnurmaiiucs .klectablc by this teetlwd - a cumpaativt puimun• aty lisease $40417 to dcfSne the pattcrns Of t!spt attMy disease in Mlmalf i11- tinulelp .hariwg rnan's eevieonnrcnt n.d Vrovide infoeutariuu oa the e/fec/s of .ir pullulio.. The eAed of .nalieR upon airway resist ance (C- PI A.a1Psis of eue hlstorks on emphysense ((') A Nudy of the altcralions in the human bronchial wal/ occurrng with aging, with parlicul.r emphasrs on elastic tls aue chatqet and assocrareJ changes ia the broachial lumen eitt A sludy of the eff~ctb of cigaret/e rmolin f on kvels d{'a.uk , ac iJ, pepsin, and uropep.i. (l' P) A study of the effect of etlracls of lobac. co oa cuhures of tunmor and normd eells A.imal Iranplanls of lumor la~ sue from lissue cullmea ((' P)

/ I CRANTFF. ANt) INtiTIT(171(/N ROPt RT I f RAIN, Prt D, Anrn.nr Prolrr.or of .5....Jnly. (lnrvcrLly of (hn.p Iste F. K.It) AISFRT DAMON. M11, hrD, Aula r.n/ r.u/rtr... of AftJwrf .UvA.o(.ol oRy. Lrt/. •In.rwl of lnJrrfrfrl Hye.rwt. Ilar.ad ScM.ol of Public /Itahh, Boaos R P. DAWS(1N, Fhr b, r.o/rnor o/ Iwawy, ('olumbi. Unlvefsrty, Ntw Yor1. ANf)RPW S DIRNFR, hcD, F.trr tl.t, MfyrAo RrrtorA, Tl.e Age ( rmtr o( New England. Inc, Puaun, M.ss (w Whiati.) FoWARI) P fX/MINO, M 1) Itn/rfrm o/ I A.rnsrololr, (leivtruly of Mhh Ip•, A.. ArMr. RAt PH 1_ fX)RFMAN, PN f) , flrat rnr of lnbot.ror4s, Worchtsler FounJe lio. foe F?aperlmenul erology shftrrs bury. M.ss (no.. •1 Synrea (otptwa- lion, Palo Allo. (-a1 I /AMFS 1. DYAR, PwD, ArrlLr.wr rto /taaa o/ Sw,lnry. Sell.rmrne CCo1kAe. louiavilk, Ky. 1C/HN 1M. ECKSTEIN, MD, Asrnr.wr ho/rnoe of Inrrrn.l AfrJn rnr, (olltge of Mcdkl.e, Sutc (lmsersrly of towa, lowa City. IIANS L PAI K. Pw 1). Stwro. Rt.ra..A Au..rr.rt, f1./`~ rn.rwr of Irdlnl,.ry. Uwircrtit~ of Soulher• ('atrfurnie Sahoul of Afedi.rne, I in Angeles /m,. /ltad. (hem/afy Setlr.n, ( arCln.ytnt ns SIUJ.tr Punth, N.nun.l ( an.rr (n+l.lurt. P.Ihrr,/.. MJ I h; N11/oJ1:/T 71T/ F. Study of comhined tf(rcl of rn/r, led vir.t agtnls anJ tnvuun.ntnl.l f..aws- in tluJlng cuunuetns aml ra.haunsmult, on Iht uarhrnhfonthul Irrt and pul moevY p.rtnchyma of ecpr.lmtnl.l a.irnals .nJ on buues in u.ean culture I( I SIuJ.es on the cumhrneJ effra Is of mflutn ra vuuvts mJ sulphur J.nu,k (rn Iung palht><tntsrs rn Syr.an Il.,n.ltrs Socia/ and psychological corrr/alts of .Ju{wia.n and dniun/lnuahun of ugare1/e smulmIt 1( I Nedy (o.m tmolinse, and alroh..l consunsp(H...rocwrle Italian nnarr.an mtn (C P1 Aw invtsliplion of the mrlaholism of prriJrnc compounJs in Ihe lub.cco plaet IC P1 Psychologkal and behavioral c-loaracler islicr of inh.Itrs among tn.nlers (C P) I-ffecH of lohacco +mole and nicolint on the cealral nervous sy,lem (P/ F.vdudion of tobacco cnnsumplron on the b.sls of mll.tlne W nN.,1.fK nlfl• bolnts in buJy fluids anJ c.rhun mon osl.k cunlcnl u/ hlu..l 1 P/ Notnicoline CorlYer7Nln and re.ulhnt pig mtnl changts in ctrl.m vaf.ts/es ol lubacco 1(1 Responses of the periphtr.l vr,ns in man 10 Iht int/avenuus aJrnln/,lldn,n uf nlsw/ne I( YI Ftq1 blood flow respt)naes to +mulurg in the preuoce of hyperl.pemu .nJ hy perlentuun 1(Y) F..min.lion of ciprtlle p.prr anJ trol.r tlle smnle con,knsars 1..— no.nsua pcrlycycllc hyJrocatbr.ns Il / A CIImpII./1tM uf flu..rearnte tp•alra uf prdycytIK •rurnana hyJn~ uhnnc •n,l clus[ly rrLleJ .um'wrunJ. ./u, th art uf inrertsl in Il.t s1uJy nf .n 1.,•/lnlan/l, •nJ yarene srnolt in rtl.Uun lu Iun~ un.rr thuln~y I( 1') I CRANTF.E AND INST171fi1(kl( DANA t.. PARNSWORTH, M D, Hrnty X, Olirtr Iro/esaor o/ lfyrltw. .w! DI- rttb. of f/wrrteauy Ht.bA Str.rtea, Il.r..rd UwJ.trs/1y, C.rnbridele, Mar. (.e. I lea th ud Mc Artlw ) PRANK C. FPRqUSnN, 1.., M D., CA.irws.w, Iltpr/nstwt of lAwwvao!- ot). Alb..y (N. Y.) Medical College. Wit 1 IAM I FIS/IRP.tN, M D. (under the direclinw of SAMUF,L L. ANDEL• M A N, U D, M P.11, Commi.dower of Iledlh) CAir/ EjoiLnrioloran, Chi- caRo bo.rd of 1(c.lth RUSSEIL S. FISHER, M D., CA/t/ Afrd- k.f Eaa.wiwtr, Sule of Maryla.d; ho- e»or of [t Alydrriwr, U.i.enily of G.r,l..d e.:nl Sc.ool. .dli.,uee. 11. L. FREEDI.ANDER, M D., Db.cror of Cawree Rrar.rtA, Morwl Zb. Ho.- prtal rud Medic.l Ct.1er, San Fr..- ciaco. (dccea.ef/. .n Preach) FREDeRICK A. FRENCH. AIF, Dlrec- br of CMCer CAtwraAtryy Rtae.rcA, Mouo1 Ziow Hocpital and Medical Ccnlet, San Fra.cisco.(See Freed- tendtr / JACK FREl/N11, M D, Anurewr rto/n- ao, of rh..mn.olocy. Medical College of Virpnia. Rrchmond 63 rRj(1JECC T171.E Th. efec(s of lob.cco enwlc condcw.Ne or• Ihe defesme nyechanisme of Ue ra Is delolilk.lios of polycyclic arornalic \ydroc.rbons a.d the cornpetiNve u Arbrlios betwecn /he polycyclrc hydro carba.. I. cowdc.s.le witl+ reprd lo c.runoRewcsis (C-P) TTle phYsic.l ..d cAefnkal properties of n11KYe rMdef f•orm.l condilioln •r/d fdboi.R eap.uce lo .erosol Iniuaa fC-PI Pc.nowalily, ersd unoling in college p.d wle.; a Rflee.-year follow up .tudy (C) ERecu of /ob.cco .mo1e upon Ihe func lio. of Ihe cardio.ascular syslcm in ..insda ased .... (C ) Patlso-phyuoloRy of lung In tericttic pe (Krlle PalA~-.eaotnic eludy of celluler c,.ufn In human bronchi ((') Pipetis.eas o. the posslble c.rcinoetc.ic alad COCnlc acllOtt of lobacco latodYela (('i- f ) GrcIroRe.kNt, coc.rdwo fcnkilT ..d .oN-carciooffenkHy of dretary f.ctore Ir1 relalrow 10 v111mcw/M~ (Yn1p.. POf- Iib1e iwlcrrcbbonship of lob.cco base. •.d dKt.rp f.clors Chemical studies on pTridine bases locluding niecu ...lop (C / Conel.lion of rnultilcchnkal proccdures perlortned on /he periphcrd circulatson of .ormal iedividuaFs rn rewmben/ and etoel poulro.s and .fler e.ercise before and d/er sham and .ctual smoking (('--P) A rudy of Ihe eflects of cielaretle smoking os the perlplard circula/ion of /ndi tiduale with .rlerlo.clcrosb ohtiltr.na a.d olhct pcriphcrad vacul.r Jrstascs, utUhnng n.ulntec hna.l ).f oatdures 1( -P)

GRAKTT.F AND INSTFRrTtON ARTFII/R PURST, PMD, DHKIor- Iw 1rUrrr of CArw.k.l f)rololy, (Jni.trr,r) of Sa. Fre.cisco. OPOROP O. OPY, M 1), Dirrcro., frwwry Ho.rlf C.nrn Rrrr..VA (il. or.rar7Arwci.rr Irofruw of 1rr. rt7, /oAr /loplins llnivtrsity School of Medki.e, Raltimore. Md. Tl1OMAS M l7(ICKP, M D, Ar.orlae lro(nror of lrtetnri.t Ntlk/wr •n/ Co.nw«ntrr Hr.lrA, Scto. /IsA ('ol- k/t of Medtti.e and Fkaiatry, lerxy C~y, N I I R A OOR P., M D, t•ro(rr.o. o( P.rAol aYy, M+lo. l/wrvervl School o( Mrdk..c, ('AirJ of IaIor.ro.y Srr•kr, Veltraro A m.ni,Val.os Ilospira/, Wesl Rorbur), Maas QFRTRI/Ot? Y OO1TSCItA41, Pu O, Arnu.wr f•.olruot of l1,aA.w,ur.y. Orr.rrmtnl of r.rA,.tncy awd A(n.o Holo/y. TAt RocLrfel4r lasuilu+t lot Medical Rtse.,th, Ner Vort (.ce ( larte) A. Cf ARK ORIFFIN, PM f) , Hro/ of •brArw./t(ry (tr).a.rw.rwe, M I) As du.o. Hotiqil.l s.d T umor Insrrtute. UsivcnNy of ltus McJical (-catr, Nouwoa ARFH(1R L. GRUS.'S- MS, Stwlot sla- eMwan, Soulhreu Reuarch Irta,twe, Sam Anto.io, Tct. MORTON 1. OROSSMAN, PM D, M 1), ArrociMr Cltwk.! rro/rwv of Alydl• cinr, U.IversflF of ('./iforsia Medical Cesler, L.oe As@rka CARL C. ORU/17IT, Prl [), M D, Arro ci.rr G rAYslolon and rA..m.rolnry, Ualeersit of Pe.osytvaaia Or.duac School ot~ Medklsc, PhiladclPAi. (no- 1 erturer in Pfiy.loloRy, l/sr.enrtF of flo.tt Ko.g) FRANK P (]1/111R1P rnI) rrultnar, anJ FkN1S1 11UIH 5)N, 1'n1). A, nrmwr R.vm,A l.u/.nr.., !).~+r.r~,.wr of Fwrnw.rdo(y, Nutih ( aruhna Srate ('er7ler, RJei1h PROJECT TITIE A co.trolled suudf lo e•sluete the cRect of .Jminislration of (racc mcult (..,rh oe "IthoW etposure to cigarctte smolc) o. /M incidcece of psltnonarF .dtno. nu I. Susin A pKt Fello.shlpt for qudying the culrurc of \.rnan lunf litsue and Ihe effecls of Itnown and posubk carrinosenic agents npw such uasuc (C--P/ C11.r.clcriqics of .otwlat ctll gro.rlh ia ew/(.r. {e releeion /o invavve c.rci.- nrea, espec/.lly in Ibe 1ung A sludy of Ihe ..sal and pharyngtal b.t kriJ lot• of smn\er., son .mo\ers and t. .molt,r (C ) The in/lurnce of rnrironmtntal taclnrt on •rle,ul inumal conrtnucn(. anJ func r.cMs lnteract.ons of arterial acid mucoi+oly.ac. rharnksiP) Prdedylk activ/tin of 1he .hitt blood ctl/s of man and the eRctt on ..hne bluod eelt acUrilies iof esrclnn/rnt, nu un,oo and aher isAucoces I(-) Ti.e eReet of etposurt lo cfgarelte tmote o0 thc inJuctu.n Of (anctr by cf tmKal compovoJs W P) The eorrrluion of autuniurle rn hady (lurds to lobacco uuge The eReci of smoling on certain yillric funclionr (C ) Pharm.edo~ ie etudy of nkorine .nd re lated dl.iuiJs (( / Rudo/ical onJa1.nn o/ ca,hsmetr .mtcri . ~det r CRAKTfI: AN[) 1flST/TVTlON 1(. 1!. IIAAQ, M D., Pro(rssor of rA.r- ne.co/oity, Medical Colkgc of V'wsinia, Richao.d. (decuscd, .cc Urso.) F. I IIAf)1)Y, M D, Pw D, r'ro/rs.or and /lr.A. Urpnrlwcrwl of rAysiaJasfp. Unmversity of lHl.horne Medical Ce.- /er, Oll.hom. CNy IOSEPH II. IIAFKPNSCNIEL, M tD., nirec(or, C.rlro,ubnon.ry Un(r, (...- Ic..r Noapilal, Philadelphia. RICFIARD 1. F1AVPt., M 1) Asdsrrsr Pro/ruor of f(rIKMr. UnSversNr of Cslitor.la Mtdk.l School. S.. Fr..- cisco. IIERSERT R. NAWTHORNE, M D., Ch.irm.n, Dr,.rrw.rwt of Surgery. Uwiversilr oC rc.attilvania Gr,duale School o( Medki.e, PhiladelpAla. CI.ARK W. HPJITH, M D.. rrolessor of I(r/irlnr .wd Drrecror of Hr.ltA Srrv• krs, TufU U.leersily. Medford, M.s. (we aod McAr(Aor) NORMAN W. IIFIMSTRA, PMD., As- nrrent Proftfurr of rsytholoty.w! Di- rrctor, t)river dchavior lAbor.lorf. Ikp.rlrncnl of Psychdodf. U.ivenily d Suu/h D.kora. Vcrndlho. PAULINE He17eR, Pw D., Rr.wcA Associatr M Cytolory .nl CFrrrcArwc- Lrrry, Sam Francisco lestitute of Medi- cal Scit.cq, 5a Fraocieco. (aee Rich- .rds) t.AWReNCP 1. NESTP.R, )a, M.D.. ProfrrrAor .nd CA.Irw..w, Dep.rtw.ewt of Obrtrrrks and Gynecology, Medical College of South Carolioa, Ctur/eNon. FOfiC CURTIS 11OFP, MD., MD., rro'ruw .nJ ('h.lrww, Drp+rrmrnr o/ NrrrdoRk.l Scirwrr, Medkd Col- kse of Virgi.ia, Richmo.d R(1SSP-t L L. 1101 MAN, M D, Pro(s- .or and Ht.l, Dtpn.rwcrn( of r.rAol ryy, I ouifia.a Slate Univcrslty School o( Medicine, New lhkant (deceared, see Mc(ldl a.d Slroog) PRO)ECT TIT1E Preprs/loe for yublicauon of a book o. (he bioioSk aspects of lobacco anJ sswl(i.{ (C-P) I ocal eBecU of the inhalaliun of /obaccu smole upon Iht pulrrlunary, peripAcr.l a.d co.onary vascular bcds. Mcasurerned of mrorury blood /o., csrdiac .ork ..d cardiac osygcn and qrbohydt.le aal.bolism in nor.note.. dve sob/ecb Wore and after i.ne• vc.oru okoti.c aod afltr nau1MR .Ia.dud clpretle. (C-- P) A s/ud~ of /he eRecu of amolin~ .ed .koli.e adrninh/raliu. on symparho adre..l fwclk" aod lally ac.d mela boll.. /C) Allewyts to i.d.ct pulmonary neoqlasms Is earakweMal animals by t.pu+ure of llr Uaeheobroochlsl system to to baGcO aoWtlt/ (C) Peno.ali/7 and sw.oling in colleRe Rr.d. wte.: a/fleca year follow up study (G-P) ERtete of smoking on susuinedpt rform_ .nce in a srmulaled drrving Isn~ IC-P) Aoowplatt Uve elody of early Aislob}ka1 trd DNA ebartp is the epidcemn of lora Nes6r of ..ke (CS1 el«t<s a.d Sair Weblers) a(ter daily apqlica- 11or. .f .bok clpreue .n.oAe to.• dewls (slot.e ..d combined Mi(h tro/tr oll) tod the urcioofern :0- ne(hpkholulhrea and ),1 bcnepy eeM (C) The rel.llooship of the ux of /obacco produeU lo the oulcome of pregnancy Oloelxmksl studies of nicoline sad its intermtd.ate melaboli(es and their tl fet(s upun certbrd .YIlM,M1K mechaw isms (P/ PMAolotk- arotomk study of craulsr changcs I. hum.n broncM Il-) llle bflucect of lohacco srrwrling on acule mfocardial infarchon ((') a r 65 tu

CRAfeTF.E AfrI) tNSTTTlR1OM PRPI)DY 11OMeURGPR, M D, t.rrl drnr .wd h.rrrr..., Sro Reeea.ch tnsri Iurr, Irc, ('.nrbridK, M.u ROlt-RT W 11t111-PhD,r.ofruorof lk.loe.rd Sclewfrr, Plorlda State U.i. .rr.iry, T.I.haasec OPORQP IACOR,x)N, M D, )'.n/rr.or awl Hra/ ol R.Jlole~ y, l/alversir' o/ So.MAfI• ( alr/or.Y JeAoof of Nedl ei.e, l oe A.gek. 1PRRY HART /AmRSON, MD, DI .rcrnr of ElrcrropAynolor y, Ne. Yor1 Pye ••d F.r LArmarT, Ne. Yor1 1tJL1tIS H lACOSSQN 11, M[), Arro r{ur rrofrnwr of Sr.rrry ul llr.e.rn. ef Srrg k.d Rr.rrrA, (oflegt of MrJr eW, Udae.ily of Vermont. SurLnif ton ( Nor hrrct fne o( 1 un.... .nJ *~ .. eWar Reaevch, M1 Srn.i 11irM'.1_ Ne. Yo.1, N Y ) MURRAY C IARVIK, Pw h, Au.ulore lro/rs.or of rAr.w.rnfo~r, Alt.art PLete/. Co1kp of Medicine. Srone, N, Y. ANDRL'W A. KANDtfTSCH, Pw I) , Su/ ScieMlrr, Roscoe S loclso. Mc tt.oci.! Labaaorl. Se.r Ilubor. Me. ARNOI D R. KAPI ANt PN D., Dlcecror- l.Iewurnry of Alrlka! (:rnrrkr. (1e.e L.d Psrchiatrk InMitule and Ilrrpit./ HRAT('II KASPARI/1N, M f), A.rlrn anr Illrr.rn+, ( .r/b.au r!w ! rbo.a n.ry /nrnwnr iw A(rlu/nr, fhhne m.nn Medreal ('o/kle A liu.pit.l, Phd.delphu PRO)F.(T TIT1.F Studies on carcinogenrsn and Ihe bio ru.ay of c.rcinoften.c .frnt. IPI Comp.r.bve sludies of eRecn of various lobacco .nwke coeden..trs on .Gm of mice (C P) Syslee+k effecle of three tobacco smoie corko+ares (C) Rwlolrcat eRects of crgarette smo\e PAolodye.mk activatiow of carcinottenk hydrocarbons: (a) sl.ndardirelion of usaT tuh.pi.es utilizing pcdosoa; (b) InvestJpliow of the ma.hannms of acllvaio. .nd responfe to aromalk tyres.opcu by protoso. (P) TA. LRue.ce of ce.t.ln enrirosment.l f.c/oes I. Ihe rewed. of .eoplastic di.rse ro tuberaulo.u par.e.t. and iw cbUdre. A eomprrlsow o( ekclydctiwotr.pbr a. •..eao of evaluatieR the effect of vesncorstrictor drup upow cerebral ud retrul circulaio. .uh aher technlQun for thn dclermie.twa ((') I ung homotruaplanlatior (C P) PJo1 •ruJy of h.biluauwr tn nuoune by mrenr of rhe.uf munlry. 1( ) To delermine to a.hN euent tob.cco 'tar' .rimics the c(ioo of carcrn..genk hrdroc.rbo.s i. Ihe alin and other liasun (C) Psaminaio" of the eaent of and constilutkrnd b.sis for, aMrelari/Ms be Iver• the foilowing. (I) taste thresh. o1Js frw quinine and A n pr..(.ylthiour .eil, (2) eoeMitullonal predrrppritur b thdo* variables, 11/ individual di erc.ces {n s.w\lnll pr.aices, and (4) foud dnh\es (P) Ihe efhrr of tobacco smol,ne nn Ihe uli Mr uf Ihe [o.nnary .rlrnr. I CRA[KiEE AND INS'iTiVflON P1.111U KATZ, PN D, AssarWr rrofeuor of Surud..n, UsivenitP of ChktRO. (see Cram) ANCPL K P YS, Pre D., Iro/ruor of rAys- lolntiral Hyrknr an/ Dirrrtor, l.b- orarory oJ rAPr(oloRka! H)•`wwr. Urd- versit' of Ml.nesola School of Public Healt\, Mia.capolls. IOSPPH tt. KIRSHER. M D., rro/raw of Alrlkiwr. U.Leni/P of C1kap School of Medki.e. PFTER /1. KNAPP. M D., Rrw.rrA rro- fruor, of rsyrA/rrry, RoNo. Ua.er.i1P ScAod of Medkiwe. Ro.1o.. KPNNL•111 P. KNIlDT3ON, M D., As• souanr CA/rf, /aloearory Srrtke, Ve/• en.s Admlaslr.lion Noqft.l, Scat(k, WaA.: Pro/r.aor o/ IarAo1effy. U.1- .ersNY of Waabi.Rto. Medical Schod, SeaU.. ALVIN 1. KOSAK, PM,D., Assoclad Professor of CArmun7, W..hinpose Squ.re Co(kge, Ne. York Uuravershy, Ne. Yorf- ROf)!?RT A. KUHN, M.D., An Sode Hoepild, Morrislo.., N. 1. ud Asfo. rf.rr lrofrssor. D1r/alaw of Nrwo- srr~.rY. Deprcwwwr of Sw~..~, Seto. H.It Cdkee of Medicitse, dr.cy Chy, N /. MARVIN KUSCHNER, M D., fro/ruer of P.rAoloh. Ne. Yori Uwi.er.iy Cotkp d Medki.e; D/rerror o~ 1a- rAoIo17, BcJk.rr Ho.pi1W, Ne. ort. CHARIPS W. lA RPl.I.l, hl D., As• Ew.reww.rM.f slsrrsf Pro/esaer of Hy,iow, Dr~rt nvM of Prrrenrl.r 1Llk/ne, leAee.o. Medictd ('olkge, Philadelphi.. (deeeaaed) THOMAS C. LAIPPLY, M D, Professor L Padlolofy, North.eslcrn U.irersiy Akal School: CAalrmaw. Drp.rr• w.rwr of ParAolol), Wesley Memorial Na.pit.1, (bkaDo. rROIEfT T1T1-E Social .wd prchdoRk.l co.strainls o. tAe Lwlatk~. of rnotives into acti,i.: , The casc of cigareUe smo\ing (C) CUracteciuks of ee., including swo1. it.~, I. popul.doa diRering in the i. cide.c, of coroe.ry hearl duew (G--P) T1se efect of 1ob.cco anolinR upon buaf petrk .eccetbea in erae (C) t..eulp(iow of pcr.oeulltY featwn u nociHed .ilh earernca of swtollnll behavior (P) ~.IUolo~k-.«loenk slud>• of ceurlar choatqca I. hum.n bronchi N' P/ Ttn bolNlo. and Identifkalion of cer. 1a1n lo.cr-boilinR componcats of ciE ue(le sarole (C - P) roesibk eRects of smoking and •kaine upow cerebral circulabon (P) rNholoRk-.«lomk s(udy of cellular cfwRn I. bus..s bronchi (C) E'leeY of clprelt• smole on pulmonary clearance IC / P.(hologk--.«tomk study of ocllul.r ehN/es in human blonChi (( ) Cluei/kalw., propwsis asd ctloloRic f.ctors of pria..ry tunwrs of the lues Esalualion of morphologk changes in IracheoMonchial tree in parrn/s (rom srlected study group (See Fr.hhein) ('u.np.ri.os of eh.ncesIn /rachrobroncAia1 eprthelium on srmrlers and .oa- smolers, wrlh epeual rrference to Iu.R carcinomas in non ,nKAers 67 66

CRANTEE APID IfYSTTTtIT/0W PROJECT TIT1E CRANTEE A'mD INSTITUTION t'ROIE(T TITLE PAUL S LARSON. Pw f)., Pro/rurr of Prep.ratios for publication of a bool on DAVID e. MANN. 1s., Pw D, Aaaori.re eflecl of tobacco smo\e and tobacco ret f Asews.colory, Medkal College of Vrr the biolnric sspects or tobacco and Profesaoe of 1 A.rrn.rdury, Tes.ple Wues on methykholanthrese induced gisia, Rachmo.d (sre t(aait ..d Mc amokisg (C - P) Usivcnily School of Pharnsscy. Phila- dis urciswsesie in mice (C ) Keuie ) delphis PAtyssatk uss.faaratiosa of sicotine . OUSTAVe A LaURENZt, M D., Aa- aocisrr lro/rraor of NrJ.rlwr and Dl- rrtro.. Di.uiow of Rraplr.rwy D(araara, Sctos Ha11 (-o/ltlit of Medkist, lersey Ciry. N. 1. ( F(-I) IF ( FU(-111FNI/FRCFR, PK D, f/raJ Drp..rnrrnr of (-)rovArw.i,r.~, Sw.u Insurwe of (.ncet Research, and Lu/ru.r, as.oeuted .irh the MrJKaI Schoul. Uniar.ny of I auc.nne, Srntcrlan.l (Fo.mtrl) SrnNM Ir.Jufnr awJ ( Arn.nr, S.ar A(rmorul I aMMHrrlrr, Eroo1. Ilo+/Ktsl, Rroullrnr, Ma.. / PSiP.N 0 11Nf)SPTH, M f), Annr.nr t•ro/run o/ Sr.rrry. Um.rrsdy of hlis.esota Medical School, and 5e.6 PAya.rir, Swfir.! Srr.rt, Vrteun. AdssisLlcNios Ilo.piul, M.anespo7is (so+ al St. /ouph•e Ifosppul, St Paul, Miss. ) R09lRT H IJNNPLL, Pa D, Asuocl.re M/ra.er of CAerKUrry. Usi.ersily of Vasowl, Rwlisrros (sow a1 National Sckacs Posdatws, wsshisgtos, D C. ) HCRNERT L. t.OMSARD, N D, C.nrre RerrarrA lautllrrr, New P,{iasd Me ooser HoepN.l, laodas. 1. P. t oNO, Pw D, Aasorrrr ProJe» or o/ rArw.rrolory, Srate Usirersiry of lova College of Medicise, Iora ('ity KENNP'Tll MPRR11 I I YNCH, M 1), S( 0. 1 1 I) , c-A.n<rltw .nl l.o/rnrv o/I.rAol,.rr..nJ/rIR1)1' A MrIVt R. M 1) , Arnnanr f.olnro. o/ Inn,J,.rr. Mr,Lr al (.II. fc ! S.nnh l errdint, s.d related cotnpoueda (P) T)r ponibte effect of tobacco unole ssd takocise os ascorbic acid metsbolistn (C-P) Slodks Is Mo.chilis: a cortelaled ieeesti- rtion of (a) the efle[I of smotlnlr on (ks bac/eriolory of the rr+piralory 1rae1 of hursar, asd (b) the elfect of eipret(e anqle a.d sul(ur d.o.ak (eir p1trrant) on the clrarrng of baclerra 6irs Ilat reapirRtory trscts o( smalt ,s...ule (mKe, latsl (( P) Pffecl of cisarAle emote on pulrnooary resiasssce to r/ectios A eonedabd bWologkal, cyrolo(kal aad eytochemicel study of the Ir,cheo Motschlsl tUee of mice eaposeJ to cir srtue snwle IP/ lAe istenclat{on between inRuenta virur infectroos, tposure to crR.rette smole ssJ orher faclors in the Je.etoprnesl of pulmosary ssd brcxKhral lesiosa is m..e IP/ Menurrmenr of the drRerrntisl blood flow to the mammalran lung Jurnng the .cu.e prr.<.d of rmulr rnhalat.on, uune the open cherl animal anJ the method snd principle of gamma emitting radw. aur.e 1raJrJ mKruspheres (( ) TAs oeidatios of skoainc by gasenua o.yren: mechasism, products and !i- netrct (C P) lhe autotidatioo of nicotine (C P) Epidemiologiul factore is lung cancer (P) (-ardro.sscular properlies of n+cntine (P) l urther snr.her (on.ernrnf the tympaho numrrq acnunt of Mlu.rnr Pn.ironmrntal factors and prrlm.mvy Jls race I Arhenus dust i JOHN P. MANOS. M D., Insrrsr(or iw Voolory awJ fl.crrriolory, Medical College of South Carolina. Charkstus. C/IRISTC)Pt1ER M. MARTIN. M.D.. Aaabrw Pro/ea.w o/ Mrdkrte awd Dirrcror. I)re/r:ow of In/rctiora Du- eax,, Selos 11al1 College of Medkise, Jersey CNy, N. 1. C11ARl PS ('. McART/1UR, PN D., PsycAolorru to N1e f/narralry Ilr.drA Srrekrr, tlar.ard I/si.ertily, Cam- briJK. Masa. (see Hcath sad Fues- .ort\ ) CHARI FS S Mc(-ANTS, ht D, Auo- elatr Iro/etsor of Soi6b. School of Arri- culture, North Carolina Stale College. RakiRA. HENRY C. Mcoll.l , 1. , M D, Arrinr IlrsJ. Dryrtn.ent of r.rArdory. I oui- eiasa Su/e llsiversNy School of MeJi- cise Ne. (kk.... lae Ilolmas and Stro.g/ HENRY D. McINTOSH, M D, trn/rurw of AfrJlrrnr anJ D(rerroe, ('rrJw.rurrs. f.r l.liorarwy. Du1e tlsiversily Medi- cal Cesler, 1)whahs, N. C. FI)WARD Mc KlP, M D., rro/r..or and Arrrwr ('Aarrn..w, and W1111AM M. DAVIS, M.1), Rraeo.rA A»!s(..nr, I)r. Psrnnrnr of r.Nlolar y, Medical College of South ('ardisa, Charkstow. (ace Prabl-lhomat) KlLLY T. McKEE. N D, Auociare Pro- /erao. o/ MrJaiwe, MeJksl Colkge of SosU Carolisa, Chsrkstos. HFRRI:RT Mr KFNNIS, Is., Pat D., rro- /nsor o/ Phorn.orolory. Medical (bl- kge of Virrrsia, RKMnonJ (see 1 ar- aos ) VI(TOR A. McKI1S1('K. M 1), Pro/ra ru. ..f M.Jr.rnr, r.nh 041( //ARI) M 1NM/1/MAN, A1 1) , I 111- rn A(rJr rrnr, /uhns llrrplms 1/n..rr.ily Sch.wrl of MtJrtrne, 11.IUmorr, MJ The sep.ralios of the vsrious arbcellular se asue parricks by strra Mt.auos Rnel ssd It+ek ch.racler(u/ion is laborarwy .siwsa/a stad Is tissue cu1 (wes of vsriow cell lises Poadble IslersNiows of virrses and ssb- .pasces is tobacco unote condessate (C--P) Soeial swd ~crsonsl determinanlr of amoling beh..ior (c P) The socisl rnediatiun of smolin/ be- baeior (C) Arsesk conrenl of soils anJ aMorption by the tobacco plant ((' Pi The effects of enrironmental factors on developn.enl of atheroulennis ss re veakJ by autopsy of accrJent .iclrms A study of the effects of hyperhark orr ~enatiun us eorunary artery disease in the eaperimental anrmd and man IP/ CarcinoKnesif in the LlKaatory animal. • eomprrium of spc cies response to NasdarJiteJ sites u/ applicsl.on Study of lusr function in rmolcrs and sossmolera (C P) Entyrnslk 1r.nfformatG.ns of sicoline and related compound+ (PI A combined genetic. physiotn,ir chnical and epukminlosic .uudy uf tinerar.'s diwase (C PI A study uf Surrrer'• Jnr..e among d.e /erish elhsic rruupr in hrarl lu(..uu •n,l A stuJy ur 1rnrh. f..lur. rn v..ard.r Jrcrase 69

I CLAMEE AND tNSTTTlfT1OM R06J L. MctEAN, M D, Aarocl.u Iro- /earor I/ A(rla/wr, ErworT U.i.enily Scisool of Medici•t. Atl..u. 11/L1A MEYER Psr D, Aua,riu. rrolrr. .ut of Or.l F.rAnfotry, U•i.er.ity d Il" Col)er of De.t6trT. CLiuso. RERNARD 1 Mlt 1 PR 91, M D A~ alrrrv rro/taso. Tlre h••id Ra•~ lo- elNutt of A•aeorwr of tb )t/errs• Medical Co(kRe, P/i1.de/PA1.- IAMPj O. MILL[R, M D. Pst D, h+ /.sse 4/ trycA{rry .wd laychoUry. ewI Dfetrrrle, 1Frwr.f Ar.frA Rtsr.rcA lwnbw, U•IvsasMy of 1/khip., A.. Arigar. HVOH IIONTOOMI.'RY, M D, Assoc!- w Profesaoe .f !<IrJklnr. U.iarsMy ef Ne...y1...i. Msdec.l Sciboof, Phil•. ddoaiL P. 07. YONTOOMPRY, ls, M D, lrolraaat o/ P.rAdo~y, .od R()1 LAND C. RNYNUI 1>S, M 1) , Awu rv Profrraot of r.r"y. U.iarr,t~ of Teu., Soahwlcr. Medic.l Stlwd, Da)Irls. OPOROtS C MOORP PHI). M D, nl rrtror, Ro..ell Ps4 Menorisl Isutl tu1., Ru/.1o, N. Y. (ae Rocl) KENNt3TH 1d. MOSER. M D. .farlrr.wr "ealPr of urdK{ne, (}eorlitlow. . U.iw.M' Medical 3chod. W.shiog so.,D.G HURI.EY LEE MOTIlY, M D, rroftr- nor r/kMe .wd Drtclar, Crlio- Resr Mr/kMe ..r.T LaocsorT, U.iverrh' o( So.wler~ Caaror.ie ldoo/ or fr/td/- cl.t Lr Aye1w. M1LIJAM S. MURRAY. Sc D., Rt- wrrA Assorirt, Rorcoe R ).c\so. MeMori•1 t.bor.brp, b•r Harbor, Me. 70 1 ROIECT T1T1E CRANTEE AND 1NS'TITUTION PROJECT TITLE To snele rocorJinp of nornvt and paho toyc bctarh suu•Js (C) DONAt D M PACE. Pw D, Pro/rsaor Fe1lo.shiP for Iraining in tissue culture of rAynolory .wA Dnrtro., InNUUrt /ech• uca (C) lo• Ctllu).r RrrrercA, Ueiversity oL Slydy the eRects of tobacco smoke A. or.l cytololc study of eam smoltn Neb.ula, I ucol coosliNreNe trn various s1rams of bs e.d sasokcr. sOe celle esdliv(ed sw rituo ( P ) A• 1•ve.tigstlon of Iht blar.d supply ef rwels.l.tie and primsry nuhprs•t tur.ors of the lueg T1st Irehavioral effects of sowUng uwder e(seaa (C) t.R.escr of tob.eeo ..wllng on th. trlood sow of sii. a.d of nsusclts of tatnwirks 1. en c~ctawsiud s.d aubicc ts ( C ) Lfroge.cm of •kai.e (i...) sad lob.cco a. bbod bo. La ~usa• skir rrd el d rarsck ( C- P/ 1•testiptb• of the role of /he .uckolua in tAe wormsl sod 1he melign.nt cell Nuckar chsn,ea produceJ by chemkel csrcr•o1eee 1.) A. 1•vestlplion of the physioln/ksl ef- feeta of diroct i•hslsl.on of lobeceo unole b) laboretory animals and Ihe study o( tLe biologksl respunse of Lborsrory a.ian.lr to coeli•uolr i.- p(ka -d dfet tab.cco product ala- tsr.. (C) ERects of •cae a.d chronk clprette arnohl•t IIpO. IlblLolytac Ktirrly and blood coeiulalro. 10 •rs•. A M.dy of tbe e9ecb o[ unoll.g oa Pul- so..r7 fv.c(io. (C-- P ) Tbt /toductiod of ge•etkslly controlkd •wirnals and t.mors for use i. eaptrl- rtne.lal re.earch o0 tobacco r rclslkr toheallh 1( - P1 Studks o( tM msnrm.ry tur...w prnmoe- ing Vwlilks of • •»w /rIc princlyk, wder varying horosoncd sod qing conJmona (( P) d 0 0 AL111'RT s PAI MFR, Prr D,•.d NOR- MAN W I/FIMSIRA Prr D, Arrisr- .nr Prn/rrw.r o) hy.~olo~y. D.P.rr- anrnr o/ lryrAnlo~y, llnivtrsity of South hsloda, Vermilliow. PDrVARD W PPI IKAN, M D, CAdr. wun .nd 1'rnlruo, of 1 Aun..rology r.l Eaprr/w.rnr.f TArr.ptrrira, Soston V•i.ersity Sclsool of Medrei.e, tlosto.. OTAKAR 1. 1KN I AK, M D, PM D., Earrrrire Dl.rrro., Oovtr Medkal Re- •eareh Ce•1er, 1•c , Dover, Dtl. MORRIS POILARD, PriD, Direcror, Lolrn/ L.Ior.rory, Uraiver.illo of Norre Da•x, Nare Danrq l.d. C. M. POMeRAT, Pw D., D/rector o/ Diofofir.l Rt.rucA, Pas.dtna Found•• Iioe fot Medicel Research, Pasade•a, (') (deceaseJ) 11. R. PRATT.T110MAS, M.D., Dr.n and Iro/uaor of P+rAoloPi. MeJked College of South Caroliwa, C'harkslo.. (sce E. McKn) MARTIN S. PR(YT7[?1., R S, D D S., CAirf, Drp.rnntnt of (lr.l rrrAolnfy. Martls•d Mcdical C'tnler, Ne.•r1, N. I. WAITYR REI)ISCI(, MD, Auorl.rr Prolruor of C'6nr.f Mrlrinr, New York Uni.er.hy School of Medkine, and NYl) Resesrth Servict, (io/J.aler Memorial l losplsl, Ner Yor1. ( sre Sultberp ) 11ORART A RF'.IMANN, M 1), Irolrs aot of Mrlk/nt, Ilshnemsnn MeJual College ..J Ilospi<sl, Phrl.delphi• I•.eatsqatrona ow respirqion •nd pyco lysis, •s well •s possibk chrornosocnsl v.riations in est.blishcJ cell /ints ohrc h have bet• e.po.ed to cit.rttlc smoke •wd sintile cowsuluenls ol smolt Personably c«rtlalcs of srnoling snd n.ur smoling in aJolcsaenlt SruJres o( ttructurt a,Usity rel.lionships •rr.owlf drup .hich aflecl nreolrne .ewailrve physio/ogicsl rneahrnisms 11') Possible effect of tobacco de.i.arivrs n. •rteriat a•d myoesrJrA tiuue cultunrs (C--P) Cheerk•1 •nd viral carclnolienesn in Ihe •atna /"Iernrlret"1 .nrm.l 1(*-P) Pelbwships for sludying tlse culture o/ hwnas luwg tissue and Ihe effects of Vott• •MI PotsiMe carcino/enic altnls .poo such truue IC P1 Palhdqk - anaornk s/udy of cellular chawges in humaw hronchi (C P) Aplk•1ino of • new biuaasy technique r• t..rnin.lknr of cl4artue smoke cow• de•••/ee for possible carcinofen. (C--P) Cucl.qe•etb Is the 1s4wrato.l a•imal: • eowrp•risot of .pecks retoonse to N•.d•rdiud sites of .pplKalki.. A eorrsp.r•tive study of the eRecls of 1. melhylchola•Ihrene anJ citsrcrte swwlte cosJtns.te applied to the orel lissuee of S+iss mice (ICR) cnndi dor.ed with skoho/ and/or esrbow tcrr.chltNi,k (PI Vascrlae response+ 1o lobacco snw.lin/ in paticntssrnh viscul.r Jisease (P) VascrdAr rt.ry.nas r.11be s1.n nu.raucu IarM.n and cerehcal cu.ul.rn.n ro,i.hactu smoking in m.n The possible effect of tobacco or nkMine in oeriodic ditorJert, a newly recognireJ syndrorne (C P ) 71 V c. r

CRANTFE AND INSrITIrTI(NI VICTOR RICHARf1S, M D, rro/ruor of Swger7 and E.rrrnrt Ilu/, Dr- raawrrne of SrrRfry, Stanford (l.iver- sJty School of Medreine, San Francrao (see I/cixr) R H RIODON, M D, Pro/ener of 1a- rAolor) .nt DYfctor, f.lrorvlo.y of £.~erlwvwr.f lrAo/oty. University of Teaaa Medical /r..c#, Oalvcslo.. SYDNlY C RITTeNOPRO Pt/ D. Pro. ffrsoe .f rwtYnlelery, Ijnlatsrry o/ Sowheta Cediforsla, Lo. Angeks RPNSON 11. ROl, M D, Arco.l.tt rro. /frsar of Srrrecy. Dfr.rrn.cnr ul Sr.. O+ry. Ual•craty of Catrfornia Sahoo/ of Modcci.c, Su Fraacrsco RPNIAMIN A Rl1RIN, PwD, Atrbtt awr Irofftao. of rr4lr llrald ow/ I'•f.fnrlrf AIf/krnf. SayMr University Colkre of Medicine, /l.wuon, le.at (.o. Ma.altr,SicJo*wal ProJucts Ik .elop...eN. Wye1b I aborator.es. Phil .delpsla ) HPNRY 1. RUSSPK, MD. Cow.oh.nt G. Carlbrucrf.r Dlntur. ll S PubIk Hca1tA Scr.ko Ilospital, and rrcd d.nr, lha R+Irct Foundation. loc., Suk. / da.d, N. Y. WIIIIAM O. RUSSPI I.. M D, P.rAolo- R/4r ie cAkf, M D. Anderu,n Ilo+piul a.d Turwor Institute. llnrver.ity of Teaas Modk.l Ce.ter, Ilouston. PETER P. SAI ISSURY, M 1), hr I), flfol,lnltnrirr Trf.rn.cnr('enrf.- Saint )oaeph Harpilal, Surbanl, ( al (dectaKd I PAl/l I) SAIIMAN, PND, Arrnranr hoftrror of B4~hemlmy. llnrarury of Sc•Whrrn ( alifocnu Sahcwrl u/ McJ h me, 1 0. Angeks PRO)F.f,T TtTLE A compantivc study of Ihe elfecls of whole and fnctional eeuacU of cigar eue amoose and those of knows cn cinoPens on (1) the cytology .nd nuckar DNA conttnl of epidermis in various strains of mice and/or (2) Ihe cytolooly aad nuclear DNA conlenl of tung and epithebuns of tht bronchial Irte of llKe sad hamsters (C) efkcts of tobacco smole condensale o. Ihe respiralory tract and other liuues of the duck (C- P) TAe bacterial degradation of wkd{ne and relaled eoenpen.ndr lhe ob/ctlive of the pro/ect is the elutldation of the Wecrsediary melabollsrn of akotine oaidnw. (C- P) St.dy of the action of negatively charged lons on Iraeheobronchul cdury action is the humaa patient (C/ An evatutiow of the pf.enomenaw of tunKw aro.Ih enhancement as an asay (ur carcinogens among the polycyclie hydrocnbong and relattJ compounJs 1( P) Intrrrelahnnth~p hct.ctn rmutional strets ((CCUpitMN1J11, tuh.cto cunsumpbun anJ corunrry heart Jntase IP) PalholoRK -analomic study of t:eoular changes in human hcunchr (C P) Infhrence of nlcnline anJ catecholamines up.ur cornna.y vrurmnrtw lonuc In aucrosl and athcruutcrwrc Jof2. (P) lhe enrymatic mechanism fr.c the dark Rc.hnn td (Y>r by r..h.acu f(' P) Snn.e atptcts of amino •.rJ metaMrlitm in tobacco le.ves /t- P) t CRANTEE AND INSTITUTtON ALVIN R. S7`HMIDT, PrcD, Dirfcror of COYnlfflnl, lufls University, Med- ford, Mass. ISAAC SCIIOUR, DDS, PnD, DSc., rro/fssor of NllroloRy and EreAryoloRl and Df.w. U.ivertuly of Illi.oiu Cd- kK of Ikwlrsuy, Chicago. (deceased) MAURICE S. SI?OAt_ M D., Cl/wk.1 rro/fs.or o/ M.dk/ne, ltdla Univee• aity School of Medreiwe, Itouo. M\Y.; Dlrfttor, Dry.rrncenr of In4a/a/ow TAfrqy, Rosla. City Ilos1i(al. CARL C. SlLTZER, hr D-, ResearcA Ffllow in /Aysk.l AnrAropolc.ty, llar• sard U.iver,ity, CamMidge, Mau, and Departmeta of Nutrilio., Harvard School of Public tlealth, bsto.. CHARt.t'S E. SHERWOOD, M D., As- sisuwr rrolfssor of Radlolory. Univp• sily of Rochesler School of Medicine and IkaiWy, Rocheuer, N. Y. DAVID L SIMON M D., Inercnrro. /n IILIicMe and Ffllow lw C.fJinr.ur- Ir Rf.earrA, University of ('inci.nati College of Medicine and Cardiac Lab oralory, Clacin.ali General Hospital. GF-NF M. SM1111, PtrD, An/rr.wr rro. fcrroc of FryrAnAYy. Ilarvard Medical School. MassachusetH General Ilwpi- tat, Soslon. I O111S A. StN OFY, M 1) . Pro/er.nr of Me/rr rnf Md 1'A/fl. D/r/rI/M o/C../bloty, Temple University Med kd Ceoler. Phdadelphia. PRO1F:(T TIl't.F: Sltdy of attitudes lornd, as well as ec teM, type and history of, tobacco anwliian is a young college poputa tio.. Study of sorne of the relatwe shlps of ,n.oking and nonsmoking to lamilr hts/ory, type of teecondary schoolinIL academic mleresls, acadrrn k nchieverncnl, and, aocial relatnrn ah/pa CIWKIeraslKa (C+ HisloloRk duwRes i. the otal, pharyn Peal awd ..sal tiawes of eeperrn.enral animals .nd humans suh/ecred to w b.cco smiAe (C--P) EOecta of c{pretle snwkinR on /uy fwt- lioq iM .orlnal aub/tcla and palKnl. .ilh eertais reapiralory drsease conJi Ilos (C-• P) RelallowsAiP of cip,rerte unolinf Io throole (obtttvclive) pulrlso.ary ew phlnema (C) An integrated study of ancillary and ne.- I~ devehrped parameters to dclineale 1he dilferent types of the chronic brun ehilis syndronx and their evalwliorl Morphology and smoling an college graduates: a fifleca.year follon up study (P) Hrvard Johns Hoplins study of body forrm as related to srnoling, and Ihe prccresors of hypertension and cor• o.ary artery disease. tnvtslijoalfow inlo the natural history of carcrnottsw of the lung +ilh particular reference to the radiographic appear- o.ce of such processn. Ihe esrlres/ manifeslalbm d eancer ow chest X ray photographs and the tabulation of Ihe relalionshrp of smoking habits aad occupation with the rnci.knce of Iunl cancer (C- P) The eRects of chetring lobacco on the cardiovascular system of n.an ((' P) The effecls of pipe smokrng and cyar smoking on the eurJrovascular system ofman(C-P1 ihe relations Letween smoking and Personatity (PI lln tRecl of tobacco smnting on sur faclanr, spccrfk f.rly aca)., carJut prr formance anJ metabutism of adrpr.st I/tIIK t P ) 73 72

S i a GRAKTEF. AND IN3TrTUT1(JM FRNFST SONDFIFIMFR, PND, Pro ~rua. o/ Pt.wr /rxArncurrt, State U.i•ersly Colkec of Fo.esury at Srra. cuw U.iverdrl. Syracwe, N Y. T. M. SONNPOORN, hrD, DbNn abArl Sr..ke Nrofruoe of Ioolof., f . sdia.a U.).e+.)tl. Rlooolqlo.. SAM SOROP, Pw D, RrsercA A,u.ctw, Tle I.uilure for CG.cer Resewcl sad la.le.a. 14oapiW Re.e.rcf Lsthrre, PWladdpAi.. AIEXANI)FR SPtX'K, RS, MD, Ar- ro(4rr /n rrJrrnrr, ILu1e Ilniversiry Medical (-eMer, Owhan, North ('.ro I/Y, PRP.DPRI('K 1. STARP_ PwD, Iro/rr aor of N.rrirlow, Nwvvd School of Publk Healrh, floaro.. C. HAROI D STPFYPE, M D, Dwrrror of tihOrrorltr. MNhodist Ilo.pirat, Mesphiti Ttw.. IACK P. STl(ONO, MD. Aru.(tore 1'rofrssor of F.rAoJofy, Louniana State U.ivu.lty School of Mtdnine, New Or/eam. (ae. Holsu and M(Gill) MARION M. SU17sPROER, M[) , Pro /rt.or and CA.Yns.n. Drp./rn.rnr of Drrw..lofofy .nJ SflAilotnfr, Neve York U.Iver.Ny flelkvue Medicd ('ea kr, Ne. YorL (rHired, we Redrrch) RPl1ATO TAGIURI. PN D, Arr(+riarr /ro/eaw of rmllolor). Cr.dr.re Sc/1oo/ of /urinru Ahdnurrenon, Hw.vd U.iversily. llauo.. CARO( INE REDtI l. T110MAS. M 1), Ar.ori.rr lrofrnor of MrI.. rnr, lohnr IIop11a U.ivercilY School of Mtdi ci.e, Dalrimore. Md 74 PHOJF(T TIT1.F. The purifkatioa and strucrur- determina. Inrn of cc+mpounds chsrlr relared to chlo.ofrnK a(N1 Checlinf and eurnding tf e Slephaso P.ren.rrlarn. Itfl fot carcinoticoiciry (C) CAernkal a.d phfskal rrudies of the tissue poleies involved in chemical wci.ofe.ctis (C - P) The inlluenct ol citweue smote on ciliary acrr.rry and hrstoiofy ..f the Iracheu bru.a h..I /ree of the rahbd Espetlmental qudks of cancer u(Rir'enf a sxw technique lo ece if various 11ur' utracled from tobacco may i.- cila the foeaaation of luaf lumors (C) lhe in/luence o( cipretlc smote inhala. /wn nn histuf(>tr( thanfes produced hy rnuarrmwe hea.(hlowuqu.HObulane i• rarf TTe effects of ewvironmenlal faclon on devrlopmenl of alherouterosh as re- vealed by autopsy of acci.knl vklims InveHiprion of the ef(ecls of tobacco ow the huma• vascular srsrem, based on Ihe fact that certain tobacco effects sre due to dkrpc suscepibihty of specific individuals rathcr rhan to obli- plorily 1o.k products in tobacco an.olie, and that patients with occlusive vascular diseasca respond differe.dy than hnlthy smokers ( P ) Critical review o1 literature on psychol- ar of srrwkin. The rifnificance of differrnl individual patterns of eirculstory rrsponse to crf frelle smoking ((' P) Studies of fenetk diflerences be/weee smoters arsd wesmuler (C P) Srudiee rd pe/ chotufiral ./rRrrrnrr he tacn .moltre 0-1 n(wu~whtn at rhow• by comparison of figure drawinp (C: P) t) 0 0 ~ (:RAfYTF.E AND IIrSTITlrT10N TISSUE CULTURE ASSOCIATION )AMES 1! P TOMAN, Pr1 D., Professor and ('A.rrn..n of f "Arn..roloff. Cfii- cafo Medical School. I.stirutc for Medical RtKarch. IANP-T TRAVPI l M D, Ar>r.risrr Pro- /errar of Cf/nk.j rArw.ardofy, Coe- .ell U.rveraily Medical College. New Yor l. E. D. WARNER, M D., fro/ruor of Pa- rAolofr, Srate UniversNy of 10.. Cd- kfe of Medicine, Iowa City. SIIIEI OS WARREN, M D, Dlrrcror of I_shor.ro.lrs, Cancrr RrurrA Inrrf- rurr, New E.fla.d Deacoseu Hospiul, 8or(o.. )O/IN S WA1/(i11. Prr D., rrofruor of ('Arrnuvy, KE.RRY W. ll'OWERS, Pit I) . Auisr.nt Pr..fruor ol CAernL- rry, Massachusetts laslNUle of Tech- noloqr. Cambridge. RICHARD 1.. WECNSI ER, M D., CNnI• c.f PAyrwlofirr, MonteRore Ho.pila) Imlilule of Research, Piltsburfh, Pa. RI/SSEI I W. WEI I FR. M D, r.rholo- fur, Mensorid Hospilal of Chesler County. West CAesrer, Pa.; Als..ri.rr rrofnsor of Pathology. Ilahncman. Medical Colle fe, Philadelphia. S1MON It. WP.NDF.R, PND, RrvarrA rrofrrmr of ('Arnsnrry- Ifnivcrsirr of (Hlahoma. Normaa. 75 PR(/)E(T T1ll.E Psychological characreristics of healrht young adults and their rcal inr p1.cMron; a continuing sludy depth with special reference to the precwaor. of h>pcrtension and curonwy heart dM eac .nd to smuttrnf bahrls (P) To ssist iw cs(abllshinf of aummer train inf cowse in tissue culture Iechnpuer .1 U.iversily of (:olorado Medical School, De.ver, Colo. (C) Mecha.isrns of the psycholropk efftctr of .kaine ERec/s of wkoti.a In the rabMt .hh esPerlnreNal coronary ul.ertrclerusn IC-P) Paholosk-- aea/ornk study of « llalar changes in human broncAi (C P) Correlation of bronchial ePithel/sl ehanfes with comparable chanfer In Wher wGan a palholofrc anatomic .tudr (C--P) T'he p.lters of rnetsstasis of csrcinoma of Ihe lung in man ((' P) Ifislopathol(.fV of human lur,f cancu 1('--P) Electron cpin rtsnnanct s~tcrrnxnp) ul paramafnetic species dtri.aMe (rorn tobacco and relared rystems Effecl of cipretle snsotinR on cerebeal blood faow, «rebral nselabolism, blood pses, blood pll, arterial pulse pres sure curves, eleclrocardwpams, and ekclrocncephaloframs ((') Palholofk . anatomk stud' o( cellular ehanfes in human broncAi (Cl A wlected, eslended and delaikd tludy of human bron(hul mrkoss 1( 1 A qualitative and quantitative tludy of Ihe individual po/Yphenrrl content ul cigarette lobrKco and the smoke and 'lari resulrinf fronn c/f.rtnc rnrdrnf •.d also atudf of the late of Ihrse tpmpounds in Ihe animal respuahny system (C P)

C;RANTF:F: ANf) INS'Tt'IIIT/(N( IIVANP 0 WPN)FI , Pr. 1) , P.o/rnnt o/ lh..w.rnlnj., SrMaJ of Ph.rnucy, Veivtrnlty of K.n..., I ..rtnce FRPf)PRICK P W IIISK IN, M f) , C M, n/rrrtor. nnrnnn of ll.elrh and Prr- rond/ry F~rlhlrlrnt, T1.e ARe frnter of New Ix . Bo.1o. (.ee h/h« r ) R(1(71: R I WII I IAMS, P., 1), rrr•/rnn+ o/ Chrw.lrt.y •wd llr.rrrn., (-lorrow Fow.deeww 1r...Armuo! /nrnrrr., lhe Clor•rrilty of Teaar, iluar. 1 FIIWIN W(N/11. M I) , lnrrn.rrn. In A(rJarnt. R.nron Ilni•rruty SrhtKJ of MtdK rnt. 1t.•.rr.n 1 N... L.•lnr... of Mrdr.inr A/rdwal ( 'dlr1r of (.rrr~~.. Augud. ) SI/MNPR W(X)C), 1. , M I1 , ~rr/re ~r rro/rra.r of Porhololy. lolhns 11i.plm. l/~r.rru~r. H.lUmorr, Md IOIIN P. WYATT, M h, lro/runr of P.rAolor. SI. loourt Ilmver.rty Sthool of Medrelnt, S( I rwrt, Mo Ino. Prolessor •nd hirrctnr, Ikpa rtment of rarholoty, (Inlvertrry of Maniloh., Wrnni[M[, Canada / PH(/)F./T TI71 F: lhe idrnlifl(ation of individual pdyphe nrrlrc comprwnds prescot in the smo\e from ciprernes and the prepar.doe, -here (tasrble, of these cornpoundt for studies oe their rnetabolnm •nd pouibk efftct on human health The determination of the chronic rRech of orally adminifltred nrcMrne on serum cholrtterrd and phcnph.diprds, (Ae ekclroc.rdiographk response to trgono.ine, and the vauular pathology of chokslerolJed rabbd. (C P) A uudf of .ntt hyperttnu.e .tbvily of maoline Pilot study of .rnolking habita of Age Ce.ter ntemArr. (C' r) An In•ralitatbn of biochemkal factor. ssoci.led .ith .uacepthbilhly tn lung unctr /( 1 lhe rRect of prolunred inhalation(./ to hatco .mole and of p~rdon~ed .'btlm tnte /rtxn the use of tuhaccn un the ).rrrpheral •ascufar reslr.nst to •cute rnhalaturo of lubacco .mole in fn.n /(' P1 1..Io.ur.n of tnnlr~F~c (ar lon. tu, h au .nJ luhn. anJ p.~hulu~u prt ulunhrf in the lon@ tenn .urvr..l uf p.utntt 1r41n.m~ re K~ n..n Itr hr nn. /...~r n~c r a a raurna (( ~/ A• invest{g.tinn into thr nature of the prtmtnlary (rnons in ceMnh.hulu rmphystm. 1( P) 76 - J 0 .~ o

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