Tobacco Documents Online

I I I I m n L studied this methrKl e.tensivcly to refine it and develop masimunt control ot variahks Preliminary nxasurcmenls with tobacco smuke cnnrknsates have shown no lethal action fur normal smoke. A Several studics in which roicc ul various s,rains were suhjccled Io in- halaliras of cigarette smoke al frequent intervals during their wholc life span have failcJ to produce carcinoma of the lung Srmu inflammatory chanRes were fuund, rather erratically, armong the treated mice, nd these were accompanied by various degrees of tissue change. Such changcs wcrc, however, reversible if esfxnure was discontinued at any point, and never proceeded to invasivc carcinoma even if caposure was continued 7 V1ru/ InfKlNxn of the lungs of such mice were found tn produce much rnrrre cxtcnsrve histr.patlx.ksgical eflects than simple smrrke rnhalalion. Virus infection followed by k~sR term cigarette smokc inhalalirxr pro- duicd such cflccts more frrqurNly and at hrRhcr kvrls. but wrlhuul prorhrcurrn of canccr R ('onJenutes rr/ tohaccn imrrkc introduced into the IunRs of several animal species in the form of s.Autirms or suspensinns so that dosagcs wcrc hrRhcr rhan by inhal.ur+n of nornial smoke have also failed to prixluce carcinoma of the lung 9 II has long been known th.rt IcrJmR urcthane to slrain A mice by moulh will prrKluic pulnurnety lunuas AJ Irtnrn of nrcrHine, smoke conrknsatcr rr Iohatcn snnrkr inh.latirin wa found in aCrsuncil study not to enhancc Ilus cflcct A further study diuvrvcrcJ that the vitamin niacin has a dcfrnsive action aR.iinst the urethane tumor production eflccl and that more tumurs arr ptrkluccJ in niacin deficient animals. I luwevcr, even in niacin Jeficrrnt nunals the inhalation (if tobacco smoke JiJ not increase 1hc prrKlucliun of pulrurrnary tumors following urethane fceding. Ill SpraRuc hawky male rals, fcd dicls containing 2•acelylaminr+fluorcne and also exposed to ciRarctte srnnke inhalaliun or injccted with a to- bacco smuke cnnrknsate in T.canut uil, exf+ericnced a delay in tle devel- cpnxnl of liver clunRes thal re considered to he indicative of a pre- canceroua statc (Rrrrss liver darn.rrc and hrwcrinR rrf rihuflavin c.rntrnl) Another conrknsate, preparrrl hy Ihe stanJarrlizrJ metMwl refrrred to clscwhcrc, did nM aflcct cithcr thr rate rd carrcrr inductiun rsr the final tumur incirknce in rals fed eNhr r 1 ucrlyl.rrnnusfluurenc or V methyl 4 dimrthyl amino I I It has hcrn shuwn Ih.rt vnall J~~~cs of r hrmical carcinrryrm, which at,mr wrruld nnt /+rrwluce canccrs, will Ju sn when mjrctcd intu mnlc Swia nu'c .IonR with .111311 rhr%c% rrf ccrlain crunnum viruscs, whirh IR r i also du not produce cancer alone. The invcstigalor showed that a com- binatwm occurs between the virus and the chcnrical substancc and pos- tulatcJ that the virus was able to carry the chenrical into the interior of the cell Immunizalirm rd the animals against the viruses prevented the cancer production IilTrals to show a similar binding between Ihcse viruses and cigarette smoke condensate were unsuccessful. 12. Study of the sebacrnus gland suppression in mouse skin by lwdynuclear hydrocarbons has shown that the usefulness of this phenomenon for bioassay purposes is limited by the occurrence of false positive and false negative reactions and by its rclalive insensitivity to small changes in conccntration or activity of the substances tested. 13, Cigarette smoke corsdcnsates in solution were applied to the cervia and upper vaginal area nf rnore than 200 DBA-1 mice. Thirty one percent of mice painted twice weekly developed tumors. The solvent applied alone at a similar dosage was followed by tumors in (+0% of the mice and treatment with a dry uslton applicator by tumors in 42 R96 , 14 Animal and human lung cells have been successfully maintained in tissue cultures by several Council grantces as a basis for devctopment of other possible methcx)s of bioassay. In tissue culture form, human cellular material can be used for testing. Satisfactory and interpretable methods for using such human cell material as a bioassay system for carcinogenicity have still to be developed. 15. A number of other ptsssibk bioassay systems have been tried or arc under study with various deErees of success cx promise. The overall impression gained from these many birrassay studies Is that tobacco smoke is inactive or of extremely minute activity in these several artificial syrlems, ncsne of which of course actually measures hunran response under realistic conditions. lhc results lend little to support the hypothcsis that cigarette smoke can act as a direct contact carcinogen in the human lung Study is continuing with respect to other hyptNhrlically prrssihlc motles of aclirsn. (:ilirrry At•tirity vnd A/ur-ru F'Iotu A('rHmcil study undcrl.wk to evaluate thc relative irnfwrtance of the aclivNy a/ rlhr crG. in tlre trrlal machinery uf lung ck•urance in intacl anirnah since it haJ bern reyxrrlcd that cigarette srnokc, like many ulhcr gases anJ aerrnuls, dimmishcd the aclivily uf these hair like aplsenJ.rKes which cuat rhe upper rr•spirraay Iract and whKh normally propel upward the hlankcl of mucus whrch carrics inhaled dusl anJ Jchris nul of the IunR anJ it haJ been sugXesleJ Ih.u Jcbyed clmrin:rtiun rd inh.rlcd dusl and dcl.ris, cuntain- 19

ing carcinogenic matcrial from any source, nught conccivahly increase the barard of lung carcinoma Twrs other mcchamsms of clearance operatc in addition to the rnk played by mucus flow. ( I) engulfmcnt of debris by roving phagexytes, ( 2) ahstMption of substances into the blrHKl stream which carries them to the liver where dNo.ifscatitrn nsechanisnrs are ctive. A nxthed of measuring rates of overall ekarance of radir,activity ul{ged dutta from the lungt of intact rabbits showed that inhalatitxs of cigarette smoke bad no measurable cffccl on total clearance rate Hence if one clearance mechanism wat slowed by smoke ttposurt, another must have been speeded eomnxnsurately, even though the internal bal.nce among the mechanisms may have been altered 1 his study was recently completed and has not been publuhed. While several investigators have apparently cnnfirnxd the activity of cigarette smoke in dcpressinR cilrary motility in isr.lated Ussrx from several animal tpecies, nd have Iraced this activity to specific coml+rrnents of the snw.ke, it ppears quite uncertain at present whether the depressirsn of ciliary activity can play any sigrificant role, even indirectly, in the cnmplert pattern of lung pathogenesis Lung l'rtfhultrRy .Sf t.rlir•s In IOS1, Thc ('ouncil sptmtr,rcd a tkscriptivc study of human lung pathology in which twelve pathnh,gish in drflerent locatinns, both urban and rural, participated About 3(Mtt) lungs of patients coming routinely to autopsy were investigated, yielding 8,590 sections from males and 3,1+61 from femaks. llx study illustrated many drfticuhies in defining histnpatho- logical changes and in interpreting their ptxsrble signhcance in relation to malignant discasc. "('arcinoma-in-situ" was diagnosed in only seven cases and these were 11 patients with lung cancer. Snnre degree of hypcrplasia occurred rather more frequently in smokers than in nnn smukers hut this type nf ksion was commrm M,Ih amung cancer cases and among non-cancer control cases and was even more cittcnsivc in the trachea where cancer rarely txcurs "1 he type of lesion ( alypical metaplasia ) nlhcr than the /umtsr itself nxrst frer)ucntly found in the lungs r,f Iung cancer palrrnts was not mtxc frequenl in snx+kers Ihan amnnf, nrm srnrAcrs I'nrdiuvosr-ulnr Rrswnr-lr l ihc /'r,un, il f,at alli.t.,r,•d a subsl.nlr.J 111.1111% fun,l G,r Nudym/ I1,c c:u,l,,,vas<utar syNcm rrm hulih .rn l,h.ca.c Jnil f,n invcstigalune :rny shurl of InnR Icrm clfr, rs nf sn,,,kmg anil ,d ru„H,nc nl„m Ihis systcru i I. A long series of pharmaco{otic studies has described the mechanisms of nicotine's action on the nervous systesn, espteiaUy at ttre synapses. 2. A comprehensive series of studies o1.ico(ine metabolism has identified nd described nrany of the pidducts into whieh the alkaloid -u rapidly converted by the mammalian body irstluding esan. The rapid conversion of nicotine into (-)colinine, a relatively inactive subslanee whkb tetsds to relax the vascular muscles, helps esplain the relatively transient and non-cumutative character of many nicotine eReds. 3. Nicotine was formerly regarded by many as a pretsor substance, that is, as an agent that constricts the blood vessels and raises blood pressure. More detailed studies sponsored by The ('ouocil have shown that coo- ttriclion of vessels is usually confined to Ihose in the sAin of the ea- /remities, thtwRh so.ne individuals show an opposile reaction. Eilood flow in the skeletal muscles is generally Increased by nkrwine !•luw in the cerebral circulation is unaffected by normal doses. Most impot- tantly perhaps. the fbw of blood in the coronary arteries is increased by nicotine in normal persons, while the work of the heart muscle is gently stimulated as by mild eaercise. In the presence of sclerotic disease of the arteries, this normal eapansion may not be able to occur. 4. Studies with a new instrument called a vibroeardio6raph have shown that the overall effect of nicotine is closely analogous to that of mild eserTise. 5. It has been shown that persons engaged in stressful occupations have a greater incidence of cardiovascular disease than persons engaged in similar but less stressful ones Assson6 these, the persons who discon- linued smoking had much less heart disease Ihan those who had never smoked These results are beuer in accord with the hyptrthesis that per- sons under stress find relief through smoking than with the hypothesis that smoking causes, aggravates nr precipitates disease. llte particularly low incitknt:e among stopped smnkert seems to reflect  seiection, in this grnup, of persons who are able to adapl relatively well to stress and Is inconsistent with the idea Ihal nicotine could esert any cumulative pharmacologic effect. 6. lesls of anirnals with diels conducive to arterial srlcrrrsis have failed trr show with added nicotine any significant or consistent effect of the nicotine in acceleraling tx ggravaling the disease process 7 Studies of hurnan suhjecls by a tarRe haltery of physiological and psy t hrrL,Rit•al tcsrt have shown that tsealthy younR men give patcrn rrf res(.rrnac. Ihal cr,rrclatc with rhe rK-currencc of certain cardi„vascular diseases arnang their ancestors 1Tese patterns of reslwrnac arc con- sidercd tn he indicative of predisposition tn such discases, since these 21 ?(1

tend to "run in families " Young men with these patterns of response are aIur more likely to be cigarette smokers 7 hese studies therefore suggest that hereditary predisposition to certain cardiovascular diseases i. Iso associatcd, non-tausally, with cigarette smoking as a matter of constitutioa. d In additicxr, a large number of studies have contributed to basic knowl- edge of hc.rt function, physiolo`y, metabrrlisnr, biochcmistry and re- sponse to drugs, without direct and immediate relevance tu tobacco or nKot n1e. 0(kse trcrop of scientists has shown that healthy persons wt,o show an alkrgic .kin sensitivity to tobacco esUacta are likely also to show stronger effects of smoking upon skin surface temperatures or blood flow in the skin or muscle of the estremitics 7Txse acicntists have there- kxe suWsted that certain tobacco eficch. especially uprtn the eardio- vascular aystem, are due to specific allergic susceptibility of particular individua)s rather than being Reneral pharmacological responses. 10 Smoking (twociavettes) Ilas been found to produce an elevation in the free fatty acids in the blood strum 'This rise was higher in persons with history of hcart discase th.n in normals lhis kind of response is eon- aidered to he a normal reaction to any stress that releases eateehola- mines, which nicotine in ukyuate dtnes is known to do The esaRger- ated response by heart paucnts may rcflctl their constitutional difler- ence frmm normal persons 11. In normal populations (ercludinR hypcrtensivcs), no differences in reatinR blood pressure were found hctwccn smokcrs and non smokers In broader studies nf workinR prTulatirxu, smoking was assruiated with lower systolic and diastolic pressures. No evitknce for large or important differences in circulatory reac- tivity hetween aroups of hahitual smokers and non-smokers was found I.ittk evidence of deterioration of cardiovascular "fitness" was seen in smokers pcrforrninR work Icsts 12 Hy means of moving picture s ray photographs following injection of a radioopayue substance into an artery nf the arm, it has been pr»sible to make visihk the flnw rrf hlrxrl in the arterics nf the hrain ('igaretle smokinR imrnediatriy prior 11) The phfrl,.Praphy nnrnrally increases blrxxt flrrw in the cerchral t ivculatinn lhis rllrcl is au-rrt.rd Irntativcly to carMut di<rsidc in the smnlc hut Iwr~srhlc nutrtinc cflctts are undcr tluily 11 Ilr au.r rlrvalyd kvrls of M-1 ih-drtrrr~~l have hrrn rrl-rtrd to I-r aurxraLtd wuh card„rv.,uul.re rh•raus. irveral ('rmnrrl sturhes have rni tu.k_l r.n Ihrs IiLa.I i nnrl-nrM It has t.trn thrrwn that I , age and ses influence the blood kvels, which also vary with the lahora- tory techniques used. The serum choksterol has a rather wide range of normal values which vary with season while chronically high values tend to run in families. Influenza infections were followed by sharp, transitory fall in this blood component but the cessaticxs of smoking by a small group of students was not followed by any such drop. Admin- istration of vitamin B,s did seem to {ower cholesterol. Most significant perhaps was The finding that cholesterol rose during times of emotional stress, as during ecamination periods for students. This finding has also been corroborated elsewhere under other auspices. In another study there was an indication that the distribution of cholesterol between alpha and beta lipoprdein fractions might differ between smokers and non-smoken. '[lsis difference seemed to pualkl differences in customary fal consumption between the two 6roups. This study, ursconfirsssed elsewhere, found an increased preference for fatty foods among smoken. A great deal of the work sponsored in this field by The Council was reported in a public symposium held at the New York Academy of Sciences on March 24, 25. 26. 1960 and published in a monograph entitled, ('urdlo- varcufar F.#ects of Nicotine nnd SrnoAint. (Annals of the New York Aca- demy of Sciences, 90. Art. 1, pages 1-341. September 27. 196() ) Thou6h many transient effects have been more fully measured and de- scribed in our pre>Rram, no evidence of any significant contribution by smoking or nicotine to causaliexr, aggavaliexs or precipitalion of any cardio- vascular disease that contributes importantly to mortality has emerged. f.ll ronTc Respiratory l)lseoses In the study of such chronic diseases as the various forms of bronchitis, asthma nd emphysema, primary problems remain in defining the various clinical entities, in developing reliable methtxfs for differential diagnosis and in studying the natural history of development of each individual disease Solution rd these prohlems would contribute materially to development of mrxe rncaninR/ul epidcmir>to`ical studies for relative evaluation uf environ- menlal and iMrinsic factors in their etinhrRy. 'I he ('trune tl has, nevertheless, sponsored a numl.cr of studies that crm tribute tuward untkrstandinR of these diseascs. 1. A scan hinR patMdngicsl study of crnphyscmatous lungs has improved the diflerentialinn among several forms of cmphysenu, has contributed to their careful description and has recnrdcd several types rrf collateral 23 22

r 1 changea that occur in consequence of or in parallel witb the emphyse- .oatoua condition. 2 A series of studies has been spnnsnred to dcsuit.c better the breathing mechanica of both norrnsl peruxn and those with various chronic lung disease and to improve metbods for mcasurint the several .spccb of lung functioa. 3. Using these metboda of teeaauri.g lung functioo, the effects of smoking both in normal wbjccts and palients have been tneatured in several different cceters. C'igarelte smoke inhalation has been shown to produce a mild coeatriction o/ the brsxschi, in most perscxu, which lasts from 10 to 80 minutes. This is not due to nicotine or any other volatile sub- stance and can be prevental by several drugs. In uwne studies, habitual smokers showed reduced "vital capacity" and increased "rcsidual lung volume" but the dificreocc was not slatis- tically significant ie all Patients with severe emphysema generally rhrrwed decreases in arseri.l blood nsygcn saturation after sr.urking but this drd not occur in norrAals rx those with mild emphysema. Mechan- ical resistance in breathing and increased work o/ breathinK were ob- served in paticnts with cmphyscma and bronchitic diseases a/ter smnk ing 4. A Irxrg terni clinical stutly ul rhrginrc rr.piratnry drtust patients is bcing suplxrNcJ by 1}ht ( r-unid in iidl,rl-rehon with uthrr granling agencies lhis has resultcd in scvcral Irntitrvc tlchnnUr+ns rrf Ihc lung diseases and in clmK i) mrtMwls rrf drtlcrenlial diagnusis which are under trial It u too early tu judge whcthrr these dcfimtions and diag- ocsaic nxthoAs will be fully validated by eapericncc, will undergo furtber rswdificatitxs, ex will gain general acceptance. S. Another long-term clinical pilot study has begun in which patients will be folkrwed for a number of ycars with repetitive Iests and funclion exasurements succtakd ultimately by detailed pathological examina- tion of the lungs, pmt mortem Our hope is that the comparisrm of fuocliom tests during life with the condition of the lungs found ftcr decease will help to illuminate Ihe rclatirrn between syrnptnms and pathnlogical changes of variuus types (IIr•rr tittnlirs Whik a stalislic.l asuK iath.,n hclwrrn r,r..rctte smrrkinR anrl mr+rtality (rurn lwl+trc ut.rr hat l.crn rrlMntrd, tt rt not rlcrr Irorn tl-c slatustical rc- laiwn aLnrr whrthrr srnnlrnR t"ntnhutct Irr the cUnluRy or agRravatirNl ,d I.r l,r,, .I, ,, ..r +h, rhr r. n, r 1. I.r,uh , r rt a dnca.c .fllictrnR ccrtain ,y u 0 0 0 N 7 tcmpermental types of persons, the kinds of people most likely to devchrp peptic ulcer are also inclined to seek relief from anaictics and frustrations by smoking. 'Ihe ('nuncil has sponsored a series of studies to determine whether smoking would affect any of the physiological reactions that arc believed by many clinicians to play a part in uker production, particularly the hyper-secretion of acid by the stomach. The effccb of cigarette smoking on patients with and without a history of duodenal uker were studied with respect to volume of gastric secretinn, hydrogen-irsn concenlration, "free-acid;" pepsin concentraliras and cwlput, uropcpsin, plasma pcpsinogen, dissolved gastric mucina, viscosity of gastric juice, intragasrric balloon pressure and inlrogastric temperature. No signifi- cant diRerenccs were frwnd in any of these responses between normal persons nd uker patients. Smoking just before cx during measurements produced no significant change either in normals or uker patients except in the case of plasma pepsinogen which was decreased to a small degree. 'il+e absence of significanl physiological responses to smoking in these areas tends to knd suppurl to the concepl that ulcer prune persons seem nrNe likely than others to srnrrke cigarettes. Efforss to describe the uker- prone individual in terms of biochemical and psychological characteristics are continuing. StnokinR and Rody Weight In a('ouncil study comparisons of cigarette smokers and non-smoken in a middk-aged group of business men have shown that the nrm-snsoken tend to be heavier than the smokers Individuals who wAuntarily slopped smoking without having any illncss which prompted them to do so or without adopting ny other special regimen of living, showed a substantial gain in weight within the ensuing two-year period. The roean gain was g 2 pounds. Overweight is itself associated statistically with increased risk of certain diseases. The increased weight of non-smokers and stopped smnkers would seem to mcrit further evaluation as a potential health risk. Ifirth WrJRhI of Infants A('ouncil rprrnsnred study of 16,226 cases in three diRerent typea of hospitals caphNCd reports nf a lower average birth weight rra in/ants a( rnrdhers whn srnnked during preRnarx•y as crrmpared to thrnc (if nudhcrs whu refrained Inrm srnnking during t)se prenatal petind In a private hrnpilal and a hrrme /or unwcd mothcrs, the hirth weights of the infants of smrrking mnlhers were lower than those of nnn smuking rrxrthers (thuuKh varying considcrably from year to year in sonic grrwps), but there was rur signi6-

I i cant diflcrence in the rates trf strlihirth. Axrrliun ur birth cumplicatiuns. Among the patients of a charrty huspnal serving low income patients, the birth weight difference was vcry snrall and still no significant difierence occurred in slrllhirlh, stxtrlNrrs rrr cnrnphcations between the groups Only in the home fnr unwed mothcrs was the prematurity rate significantly higher amextg infants of smoking mrahen Race was mnre strongly related to birth weight than snrnking I)ahies uf negro mrrthcrs were lighter in weight than babks of white mtrthers and this statistical rcl:rtiumhip was stronger than that between sn,oking and birth weight 1'sychrr-PftysirrlrrRir•rrl SttrrliPa A key probkm that pervades the whole effort In sludy smoking and health is the question whether the types ol persons who choose to smoke cigarettes are hasically different in cnnstitutron, persnnahty nr life patterns from tyl.es who cMxne not ta smrrke thenr Such hasic differences might themselves infiuence life etpecuncy and suscepUbihty to drsease. A series of studies have bcen sponsored by The Council ar  beginning toward solving the compkt problem of inherent differences between non- smokers and smokers of various types 1 Pxtensive data on 252 selected college men collected over a twenty- year period showed sip+ificant differences in physique, physinlogy, career selection, and personality between nrsn-smokers and heavy eig- 'arrtte smoken The smokers slso tcntkd to marry and change jobs more often, to indulge more in the use of coffee and alashol, to lose weight over the yean and to show more testkss energy, more extrover- sion, and greater social gregariousness. 2. Two anthropometric studies of this and another group showed differ- ences in prevailing body types among heavy cigarette smokers and non- smokers as well as difTerences between these and pipe or cigar smokers. SntokinR and l'rutein INeta6ulient Reptxts that nicotine has an effect trn protein mrtabnlivn in tlre rat h:rvc prrrmptrd lhe ('nunt il Nr slMrnsur hum:rn.tuJies un hrrAcrrn rnrt:dMdism I-rndinf.s indreate that smrrkmit, can anmcwtut rcducr the iv.rlehrFhty of inr,c.IrJ prnrrin as indicatrd by Ihe FhIrMMI ICVCIs 401 scvrr.rl amrnrr .arJ. At Ilrr prrsrnl, nir clmical srRnfitance is alt.rthrJ nr tlns rllr t..Irrn thrre is n„rnr.rl I'r"rrrn and ral,rri rnt.rlr r Meiuuretrnent of /nRalatian Since there are many evidenees that smokers cannot judge reliably the extent to which they inhale cigarette smoke or report this accurately on questionnaires, several studies have been undenakeo to dcvek+p methods of measuring "physiological smoke exposure" by determining indicator sub- stances in blood and urine. Since there are smoke ingredients that are ab sortxd through the alveolar membranes but not through the oral and buccal area tissues. Ihese studies show encouraging progress. Belaavioral Effects o/ Smoking It has been shown at least in mice that nicotine tends to concentnte rapidly in the brain tissue shortly after absorption. A direct eRect on the central nervous system, described as an "arousal eRect" has been detected which is believed to be due to nicotine per x rather than mediated through catecholamines The consequences of this eReet on the kaming behavior and refkxes of animals are being studied with a view to throwing light on some of the responses that may underlie the human use of tobacco. to other studies in the arra of psycho-pharmacoktgy the effects of nicotine are being compared with those of various tranquiliurs and other "psycho-active" agents. Other Activities In addition to its program of gnnts-io-aid The Council has also sought during the past 10 years to encourage new research ideas and endeavors. To this end, The Council has convened a number of of1-the record con- ferences of scientists with common interests to review research progress and explore future needs. During the past 10 years, conferences have been held on problems such as: lung pathology, bio.ssay, and earcinogenesis, virology, cardiovascular diseases, atherosekrosis, effects of nictNine, cell and tissue culture, chronic lung diseases, psycho-physioksgical aspects of smoking. In additwtn, The Council has cooperated with other agencies in the planning and support of public symposia on topics pertinent to its interest. lltese public symposia have been published and widely disseminated for information of the scientific community and the general public ilre ('rwncil has recognbed tlse need, not only for .pecific researches rm dcfincd prtrbkms relevant to tobacco use and human health, but also for IIK traininR crf young scientists and physicians in research In urdcr In assist in nrccling this necd, lhe Council has annually nrade rvailahlc to every medical schrKd in the United States, a fcllowdtip for assisting at Icast one 27

i degree candidate in each school to spend a summer term or other "b(1-term" in research under the direclion of a seniur aufl member No restrictioa of any kind hss been placed on the suhjects of study that can be elected by such pre doctoral fcllows A total of 640 such fclkowships have been awarded through 1%] In order tn make the vast scienlific lilersture on tobacco and its eliFoets more accessihk to invtstitaton, The Council sponsored a project for eolke- tirxr, evaluation and cnmpilaliou of weA material into a mcxu>lpaph A book titkd: "lobacco: E.perimeetal and Clinical Studies. A cnmprehernive Ac- count of Thc Wf1rW I.irerature,' by t.atson. Haas and Silvettc was publisheA by Williams and Wilkins ie 1961. It 6 900 p.ger in length and is based upon study of more than 6.000 articks published in about 1.200 journals Ihrouth- out the world As a collateral activily, these scientists hsve also produced a series of cnmp.chensivt, critical reviews oe a variety of specific sub}eeH. This activity is continuing in preparation of tuppkmeotary volumes for latcr publication I ' Abstracts of Reports Eiach recipient of a Rranl-in-aid from The Council for Tobacco Re- scrrth - 11 S A, is responsible for the initial presentation or publicalion rd the results rr/ his rescareh at scientific meetings or in appropriate scientific journals. E=ullowin6 sre abstracts, approved by the aulhas, of reseatch repor(s acknowlcdgin6 suppoA from lbe Coutxil, formerly the Tobacco Industry Research Committee, that have sppeared in scientific journals since pubh- calion of the 1962 Report of Ihe Scrcntific Director. These ahstracts have been grouped under the following headin6s: I. Carcinogenesis Studies. 11. Cardiovascular Studies. Ill. Studies at tlK ('ellular l,evel, IV. Pulmonary Physiology and Anatomy Studies. V Psychu- PhysioluRical Studies. VI Tobacco Chemisrry & Biochemistry Studies. VII PlurrnaculuRy Sludics, and V111. Other Sludies. 1. (:orr•inoRenesis Studies "IIOS"1- I'A("IORS INfLUENCING Tlil: BEIIAVI(1R (F SUIi('11- TANIiOl)S SARCUMAS INE)ll('Ia) BY ),4;9,1t1 1)INI:NTI'YRIiNl'. IN C 57 111./6 MI('E." By F. llomburscr, A. 7•re6cr, and 1. R Ifakcr, Itio- Research Inslitute, Cambrid6e, Mass. ('unrn Reieurch, Volume 23, Num- Ixr 9, pages 1539-1544. October 1963. ((Council grantee: Ilomburser) The rate of formation and behavior of subcutaneous fibrosucomas induced in C 57 BL/6 mice by sin6k hypodermic injeclions of SO(/ micro- Rr.ms of l,4 9,10-dibcnzpyrcnc in peanut oil are reproducible and predict- able. No mctaboliles n( the carcinogen were detected in escteta e><cepl im- mediutely following injection, when r;onx leakage may occur from the injection site. The rate of Gsrmatinn of tumors was lower in females than in maks, but it was independent of body weishl al the time of injection, subsequent growth, and (in males only) of age at time of injection. All tumors formed were transplantable fibrosarcomas, eon/ainina traces of carcinogen as far as 11se third transplant gerscr:rlion. (:ruwlh rates of the established tumors were cunstanl fra al.out two weeks, brd varied considerahly Ihereafler. Caloric reslricliun severe enoush to prevent significant weight gains during the induclirrn pcrirKl prolonged lutcnl umcs siynificantly throughout Ihe period u( lunwr dcvclrlpment. Sevcre caLonc rc.lnriouu mainlained fur 7,9 and 2) days, which re.ulred in nurkeJ wcrylq lussc., was wi/hnal msrked ellecl un Ihe Kruwlh rale rd urduceJ tumurs mca%unnR I im br di.rur,er Iluwever, thc survrvel /nnr of animals thrtstrcrlcd wr% sigmlicanlly pndunrcd. ln /T)r/1r• Rrnnr....: NatUOn:rl (:rnccr Inshtule, nnd Ihe Vny,inia an~l 1) K ` ~/ , uJw•r. I uurulnufnl 0 ' 0 "M(/tISI~ SKIN 1'AINIING W1I11 SM/lKl: ( UNt1UNSA1I:S I ROM ~fl (1) x U r (-I(iAltJ:l I I.S MAUI OI• PII'I., ('I(iAR, AN11 ( 1(;AI(1. 1 11: 'a()IIA('- 2V d

(Y)S" Ily I: II,,n.hurRcr, A 1rcRcr, and ) R flakcr, Hrn Rcsearch Insti- tulc, (-amhri,IRc, Mass Inurnal nf rhr Nurrrrnul ('rnn er fnrrrtrdr. Vulumc 31, Number 6. pages 111S.11S9, (lccemha•r 196 1 (('uuncil grantec: Hom- burgcr) (;rnups (1f ('AF, mite nf both seses were suhjcctcd to skin painting Ihrrwghtlut their Irfctrmc with ctmtknsatcs of thc srnuke of cigarettes made uf pipe, cigar, and cigarette Itsbjccos, and with accirlne and benzo( a )pyrene. AII Ihc condensates caused skin papilksmas and up to 23 per cent epider- moid cancers 1 hcrc were slightly more cancers in femaks than in nuks. The formation of these ksions was shrwcr with cigarette smoke contknsate than with the nther two cnntknsatcs The acetone cuntrols showed no patho- logic changes Cotnbustitsn temperatures were practically the same 1nr all types of tobaccos The I 1)S11 (r/ these crlntknsatrs was lower for males than for fem.rks, ankil krwcr fur prlse smnke cun,krnate than ftu the tahcr two facept hm the shRhtly Rrcater trrrit;ry uf the prllc smnke contknsarc mamfcsted hy Rrcatt•r wcrghr Itns and mratrhty, ncvrc were nu drflcrcnces trl the systcrnic clfectt rd Ihc rr.nrknsates In Ihe rrsfrlnst td rnKC rn j1rlvtcrl sm.-4c cr.ntlensates, thcrc arc mnre CrMlrat]Kt1Unt 14, human rcattrr-nt Ihan rfx•rc arc sundantics Whcrras rnur- taltty data show a grratcr rnt Kk•ntc td lung cantcr rn men than in wtlmcn, the (cmak rnitc in this study rkvcl I~J slri!htly rnclre skin canccrs than the males tlx mKr skin systcm f.cars littlc resrmhlant'e tu the human lung as a IarRct tnRan hrr tuhattr/ sm.-1c t"nJ,nsatr Whdc il rcnranls a valuabk Irwl trw thc study rd tartrm-Kt n(s s, rl.,u Jcnvcrl frum it arr nnt drreclly applkahlc In the cvaluaturn of the v1;n htantr rr( rrsults tdtt.uncd by clinical statistics "CYTOI O<iI('AI. ANI) ('Y I(K III MI('A1. I:FI-H -1S (1F A(;I:NTS IMPI I('A11 t) IN VARIUIIS PAIIIt)I (/<il(:AI. (Y1N1)1I1(1NS: 1IIE EFFFt"T OF VIR(/SLS ANI) (1F (-I(iARlil 11: SMOKE ON 111F. ('11.1. ANl) ITS N(I('LEI(' AC II)S " fly ('ectfie L.cuchtcnhcrgcr and Rudolf ltuchtenhergcr, Swiss Federal Institute of lcchnulogy (1:T Ii ). Zurich. Switzerland Inrrrnarinnaf Rrvirw u/ ('ytrrlnRy. Volume 11, pages 281-326, publishcd 1963 by Acadcrnic Press (Council grantce: ('ecilie I.euchtcn- bergcr) lhis review s)xlws th.rt thrrc •rre rcl.rlivcly fcw studies in which special allcntitln has been ftKuscd rm the fxh.rvitn rd Ihc rntraccllular nurlerc acids and ils correlaticxs with nxrrphtrlufrc.l cell thangcs a/tcr vuus rnfcclirms and hcr ctrrtnure to cigarette srnnkc It is rvirknt Ir,+m these stuthcs thar crll tkath, prrt'rrkJ t.y sulry,rrsdun of mntrsis, tlrtrcac al nutkii atnh entl llrrnrni., rrr tcll prrrhlrt.rtrnn, Irrc t'rJcd by strnn laurrn n/ nuttrvs asvrti r.itiJ wrtFl inn,Irr.Nt' utu rratc of nuilcit' atuds, are very lrryuent reslwalses 1.1 .rftnt. t-l Anr-n ur unkru,wn uaturt'. whrt h t ausr p.uh,rlrrKtt it t rrntliurlns I hc rtt c/1u.rnal c'cllufer and rnu I, it it ul Il.,rtcrn altcr vnus inlcctinns, wlhcrc tcll tlr.rth n I+rrtt'rlcl hy nu,I,K ;Knl lsnrhrtn, r..itlu.illy nul very .nrl'itsnK f~.m , "rt.uk r. 111, Int I th.,t vtrn% rn/t't Uims atc Ihr urnly Il.rthn- U 0 0 ~ r i logical ctxldititsn knnwn where an agent which itsclf is cunrptned uf nuckic acid replicates its specific nucktsprotcins within and at the eapense of the cell. Although this sequence may nut he dctec(abk in every virus in(ectiun, w nevcr cells display such a succession of events the possibk presence of irus inleclion shuuW be further etplored. Ozlier Rronror.; National Institutes of Health; and the Brush, the Fran- chester Fertility, and the Elsa U. Pardee Foundations (Cleveland, Ohio). "CYTOI.(K;ICAL AND CYTO('HEMICAL ALTERATIONS IN TIlE RESPIRATORY TRACT OF MICE AFI'ER EXPOSURE TO ('1(iA- Rla-fE SMOKE. INFLUENZA VIRUS, AND NOTIt." By Cecilie leuch- tenberger, Rudolf l.euchtenberger, Fritz Ruch, Kayo Tanaka, and Tatsuya Tanaka, Children's Cancer Research Foundation, Bosttsn, and lkparlmenl of ('ytoingy. Institute of General Bo(any, Swiss Federal Institute of Tech- nology (1?. f 11 ), Zurich, Switzerland. Contrr Rtseurch, Volume 23, Num- ber 1--Part 1, pages SSS-565. May 1963. Correlated hisloksgical, cytukrgical, and cyttschemical studies were made of sequential changes in the respiratory tract of 309 femrk and 211(1 mak ('F, mice after esposure to the inhalation of cigarette smoke at the rate of Vz to 3 cigarettes daily ftx peritKls (raxn 30 to 121) days, eacepl ftx rest pcritxJs of I to 30 days; following inlranasal intKulatitKS with PRg influenza virus at varying intervals; and folkswing a ctsmbination of both treatments at the same Jtxe rates as in the first two erapcrimcnls. In order to carry out significant analysis of the results, only those mice were utilized which could be matched in regard to doscs, e.pcrinsenlal pcriuds, and life spans. Atypical proliferative lesions occurred in the respiratory tract in all three tesls, accompanied by nwtkrate intracellular DNA. RNA, and protein increase. '1 he frequency of lesions was lowest after inhalation of cigarette smoke, higher after influenza virus, and a cumulative eflect was noted after the combination of virus and cigarette smoke. Mild atypical proliferatiuns and ,quamtws-ccll mctaplasia occurred in a few of the control mice Nccro- tizing bronchitis was observed only in mice eaptssed to virus, with or without smukc inhalatiun. In the tests with cigarette smoke inhalation alune, nsales seemed to e.hibit a sumcwhat lower (rcquency tuf alteralions than fcmaks 1 he changes occurred prcdrrminantly in the small bronchi and bront-hiules. -Ille Irequcncy and the dclorce of allcralions were strikingly lower and uflcn mildcr than in nnce cslwrscd Itt virus, and particularly Ihan in mice e.pt+scd It, the cont- hinstam In sturlyinR tlrr sequence o/ events /rdltrwing influenza infectiun, Iwu cutstlrlctely dr/lrrrnl and rtplx+srrc ellects, ful/uwing eath rrthrr, wrre recng nized. I Ilctt I wrs thrrjclerrtcd by absctntr tul nulosis. Increase rn site rd nutko6, nutlcr, and cylttplasm acttrutponietl ftequently by (rurnatnro r,/ slllrerical rntlusnrns, arld n/ arglrrmerala/ns of bast/plnlhc maaes anruud rtuc'koh and within cytuplasrn; Ilus Iltucess Icads In swellrng uf cells, ccll desttuchrln, and net'rrHitmg hrtmchius [Ikcl II is t haractrrvetl hy the tlccurrente uf many mitrru's, a t.ylid mullr/rK•al hylu•rlrla.i.l, antl frrqnenrly c r 31 I n

I i atypical pndrfcr.tion of tpi/hchal ctlls rd hrnnthr anti hr„nthiolcs -Ilscse cclls htcornc rntrcasingly Jytpljatrc rrr are trantlrumt•J rntrr :rryprtal cprJcr- muiJ cells lhe hrqucncres ul nearly all markcJ alter.lirms afttr influenza infection were consukrahly higher in fcmaks than in malts Ilowever, the malc mice displayed Ilre higher frequency of pruhfcralion after cnm6rnrd eaposure to crgarctte smukc and influenza virus, partkularly in squamrrus- cell mcraplasia and Iransgressitxts of cpilhclial cells into lung parenchyma. 1 hc observed frequencies of all Ihc proliferative anJ/rw atypical changes no(eJ rltcr the combined uposures were generally higher than would be obtained by adding the frcquencies found after cigarette smoke alone to those ftwnd after virus.Mne. The prescnt studies stress nM only the significance of subacutc influenza virus infcctitrns, but also o( the te: difference itself in the frequency of res- piratory changes A propecl has been planned to caplorc Ihe influence of set hormones (m Ihe devtlopmcnt of such ksions, alone or in crxnbinalitxs with influtnza virus .nd cigarette smoke. "P(II.MONARY LFSIUNS IN lxlciS FROM MFIIIYI.('lIOI.AN- 1I11(FN1: " Ity R If RigJon, M 1) , anJ (:untcr ('orssen, M 1) , lhrivcrsity of leias Medical Branch. Calvfstun Arrhivri o/ ParholuRr. Volume 75, Numher 3, luges 32)-311. March 196) (Council grantee: RigtAm) Ifrnnchial cpilhclial hyrerltlasra anJ, in a few inslanccs, uluamrrus mela/dasia occurred in a m.purly uf 19 Jrrgt rnltcleJ intrahrunchully with methylcholanthrcnc Srntc similar h tirm. rN:cur sprrnlantr,utly in the tlug, it becomes dr/hcult to evaluate tlrc Irvwnt that rnay fulluw mtrahrrmchial injeclron of this c.rcmr,Rcn A/ctnrn .uV(;csuvc of a syuanurut tell carcin- oma was found in a lut.l area (rf lung m rrnc rd ncc JrrR., 12 Jays afler aJ- nrinistralirrn of nrtthylchrrlAnrhrcnc. hu1 no nrct.ro:r%cs were (,,unJ I he cr<- pcriments indicate that the dog is m,t vatnf.ctrxy lu usc in ncr cilxrinrenlal Study of puhnonary carcrnuKcns svncc atutc aRd chrumc mllrmrnatrun is found to occur sprntancuusly in many nf Ilrcte annn.ls Othrr grantur: National ('anccr InsUlutc. 11. Cordiot+aacular Sttrdiea "POSITIVE IN(YfRI)PI(' RF.SPt)NSIiS ANI) ('AfF(-1Il)IAMINE (Y)NfI:NT OF ISl)1.AlI:I) RAIIfIII AIRIA I'.XI'OSF•.1) 110 IYRA- MINIi" By P.. T'. Angclaktn and M 1. 'Yorchrana, Ikprrunrnts of Phyti- olugy, Bostun I/niversity Sthord (if Mcditinc. Ifr,ttun, anJ Karrdimk In- slilutcl, Sttckhttlm, Sweden Ar lu I'h yurdr.tu u 1t undrnnvrr u. V nlumt S'), Numbcrs I-2, pages 161-IAtl, ScptcnJrer (ktular 1963 lhc nuratlrtnalinc (NA) cuntent rrl itrd.IrJ rahhrl .ur+ was ts.rn lially unchangcJ A+llowing ptrfusrrrn wrlh tyraumc (IINI rr.'ml ) fru 1t/ minutts Ovcr thc svrnt pcrrorllhr IN,trtrvc m,rrrr,lrit clkrt rd Iyrarmnc was strll )S Icr trrN nl rlrc (+r~1 rtt(Nm.t Ahrr I~r,d„ny,r J CrIN111/rf (2 1 huurt) the NA tr,ntcnr ,ktrt.uJ ah.rut 211 Ittr rr'nt :rr,d thc rnr,rr„prr cllcct a1Nwl Stl htr t tm r In grneral, lhcre was a correlation between the reduction in the re- sponse lu tyramirse and the NA content. Ilowever, the NA content war mdl 40 SI) pcr cent of the control value when Ihe tissue responded no longer to lyrarnine At Ihat lime the tissue was fully responsivc to adminislereJ NA, I hc reduction in the NA content of the tissue could nts( supply more than a total of I) 1 to 11.2 rg NA over 2-3 hours. This suggests a considerable synthesis of NA in vino if the effect of lyramine is indeed mcdialed through NA release I)ircct measurement showcJ that 30 minutcs after the end of a prt. (ungeJ lyraminc infusion the NA tissue content was resltxcd by an amount crtrrcsptrnJmg to rhout 2/1 per cent of the control value. lhis, howcver, did rlnt restorc the response to tyraminc. • ~Irlrer Rranrorr: U.S. Public I(eahh Service and 11 S. Air Force Office of Scientific Research. "('NEMI('AI. ANI) IIIST(X-IIfMI('A1. EVALUATION nF Tllt; f1IS- 'IRIBIIIION OF ('ATIi('II(ILAMINIiS IN 11111 RA111111' ANI) (il/1NIiA /'IG III:AR'I-S" By E T. Angelakos, K. huse, and M I.. l'or- chiana, Ikp.rlmenls of Physiolugy and I-listobgy, Karulinska Instilulel, Slockholnr, Swctkn, and I)cpartment of PhysioMgy. Boston l)nivtrsily Medical ('cnter, Mass. Acra Physirrlrxica Scondrnavira, Volume 59. Num- bers 1-2, pages 1g1-192. Seplembcr-Octobcr 1967. (Council grantee: Angelakus ) ('Ircmical determinations of noradrenaline (NA ), adrenaline (A), ant! Jnpaminc (I)A) were made in the right and kft atria and ventricles (RA, I.A, R V, LV ) of rabbit and guinea pig hearts. T he concentration uf these airlines was also sludied in Ihe sino-auricular (SA ) ntxk uf the rabbil. Sonic of these lissucs were also eaantincd for the distributiun of calecholamincs using a hishkhemical fluorescence technique. NA was the predominant catechulansine present in atria and venlriclcs. It was more concentrated in the RA than I.A and in the RV than in the LV of Ihc rabbit and guinea pig. In the latter NA was distinctly higher in the atria of the ventricles. By contrast A was more concentrated in ventricles than in atria of both species and accounted for abtrol 5-10 per cent of the total catcclwtlamine content. DA was found predominantly in the atria, more in RA than in I.A. Iligh ctxuentratiorss (if 1)A were found in the SA ntrde region Ilislochcrnical studies on rabbit tissues showed that the cattcholamints were founJ within nerve struclures A high density of flutxescenl fibers anti fiher brmdlcs was found in thc SA mxk region. An crtcelknl correlation bctween Ihc histo- chcmical anti chrrrsical findings was obtained whcn (KAFt NA and 1)A were cuosiJertJ. k;-''llrArr granrrrrr lI S 1'srblic (lealth Service. "II1f'. R/)I li(11- l'AI1:('IIO1AMINI?S IN Ill/i I-R1T FA1'fY A('ll) RI:SI't)NSI; . 1O( '1(:AR1;I'11? SM(/KIN(i " fly Alfhtd KtrslA,aum, M I) , Rnst.m Khr.rsanrhan, M 1) , RrymrmJ I: Caplan, M 1) , Samutl ltcllcl, M I), •rnJ I cunard I Fcin(.crg, M I) ('irru)uri,.n, Volume 2N, Numlrcr I, pages 52-57. luly IY6J. (('rwncil grantee: Bclicf) 33

lhe n,ks Of the adrenal gl.rmts and the syntpathetic nervous system in the rist of free fally acid (1 1'A ) after anr,rkmg was mvcsligatcJ in I I normal subjects and in R subjects who had prcvinusly undergone brlatcrnl adrenalcc- tur»y for the trcatmcnt uf hypertension In tests on I I subjects who smoked thrcc cigarettes per h,rur for a ) hour f.crirxl, urinary free catechulamine eitcrethun increased 21 {~ r cent (2 5 rnru„gram/htrur ) and total catechulamine escretion incrcaud 16 per cent (J I micn,grant!hour) Al the start of the smpkmg pctrr+d, two crga- reltes were smoked in a 10 minule period A rrsc in fFA uccurrcd in all subjects during the smoking period. To tktcrminc the eftect of sympathetic ganglionic blockade on the FFA res)xtnse In smoking, control tests were matk on 3 normal subjects in which 2 cigarettes were sntoked in the manner previously indicated, following which sympathetic ganglitrnic bA~ckatk was induced with trimcthaphan carop hrnsulfunarc and the snnrking tests were rcpcatcd. No risc in I FA after smrtling (rcturred following hlockatk In 6 of the R patients who had previously untkrgnne bilateral adren- alccl„my. Iherc was no signrficant F-I•A resfw+nse to sm„-irtg two cigarettes in the manncr dcscrrbed; in the r+thcr 2 thcre was a minimal cflcct All were hahrtual sm„kcrs erccpt one. wfiu hed given up smuking 6 years previuusly. 7hese findings indicate that for cigarette snsuking to catrse an increase in srrum I I:A h.+th the adren.J gl.,nds and the sympalhclrc ncrvous system nrust be funUu,rt,ng, f,r„h.rhly to I,rnKlutc an cflccrrvc Icvct Of circulaling catet hulannncs ~Ofltitr Rrnnrurr: ItS I'ul•hi IIr.,I,l, k,r.,,c .,nJ N,,lurn.,t Ilrjrt InslUtule "I'IIYSIUIOlil( NASIS It)R PRIr1111111111N A(iAINSI SMt)KIN(7" fly Samuel Ncllct, M I), and AIIrcJ Krrshlv„m, M I), Ihv„n,n of ('artli- nlugy, Phdatklrhta (icnerrl Il,sl„tjl, •n41 (ir,r,h,atr II,'.prt.,l, tlniversity of Pennsylvania. Phrladclphia (haptcr in "Curunary Iltart 1lrscase," 2he Stvrnrh Ilohncmonn Sympusrum, 1462, edited by W. I dt,f1 & J. la. Moyer. (Published 1963 by (irunc & Stratlun) This review of esperimenls in this lal,,,Wn(y and by others may be summarized as fnlluws: ( I) Smuking involvcs a stress mcchanrsrn in nurmal suhjccts: this is greater in patients with coronary artery disease (2) Smoking results in an increase in cardiac w,nk which is adcyualcly mct by the nurmal hcart, but whrch may be inadcyualcly met in the presencc of corunary in- su0icierscy ( J) 1 be king range etlccH remain It, he evalualcd livitkncc is available whith snggtsls that thrunic srn,rkrrs arc mrrre likely to tkvchp disturbances uf IqnJ mclalwrlnm, drvtl„p a grcatrr inti tknce (sf cnrunary artery tliscast at in cancer aMc, and rnarufcsl a higher IMCidcnt'e of t,lronary rxclusiun 1f ~ Orh" R~nnr,rr : 11% I'ul.lr. I lr.rlrh Sr rva c V 0 c~ 0 "N(RMnl M1tt( ARI)IAI MI IAfIOI ISN1"ItyR,thardl Il,ng ('hrls- 0 1,r in -( 11Cr,1 I)r.r.,,rIhr llahnrvn„nn Itrn(rrmurn, 1962, edited by W. 1-ikuR & I. F1. Moyer. ( Publishcd 196) by (;rune & Stratlon ) "('UNIRA('TIl F PR(117i1NS OF NORMA1. AND FAII IN(: IIIIMAN IfF.AR-1' " Hy Mary I. Ncbel, Ph I) , and Richard 1 Uing, M h f~-chivcs oJ Inrernol McJa inr, Volume 111. Number 2, pages I9()-195, February 1963. These two reviews esplore the progress in scientific knowledge of the diffcrenl conditions encountered in nurntal and failing human hearts. INC first review presents clinical and experintental findings which illustrate the limited valuc of cakulatitsns of the state of cellular tsxilatiun in heart muscle from a comparistm of the ratius of the oaltlatlrlrl-reductnrn pxNCntial in arterial and in ctsrunary vein bltsod. 7 his is but a step in the aearch for methods which permit cuncluirons on the intermediary metabo- lism of the heart from arte-iuventsus balance sludics. Furlher tflorts will be made to accomplish this goal by more specific and refined hitKhemical mtarn. It is bccoming increasingly ckar that an untkrstanding of congestive heart failure hinges on the study of cntlocrincs and on the knowledge of physical chemical prnpcrtics of the ctxslractilc proteins F'aradoaically, in apite of much medical progress. the role of the heart must:le in eliciting The in of evcnts kading to congestive heart failurc rentains very much in dispute, the other study shows. Much of the disagrcemcnt is the result of divergence in techniques and of preparations used. In the studicspe rftxmed in this laboratory on mytnin eulractcd from normal and failing human heart muscle obtained at autopsy, the ATPase activity, relative visctxity. Iigh1-scatlering characterislics, and sedinsentatim c(xflicient were measured. It was found that the Al Pase activity of myosin prepared from failing hearts was slightly greater than that obtained frorn nurmal hearts. Data occumulalcd on the reduced viscosity of the normal ^nd failing heart rcveakd a much greater scatter in both preparations at low cuncenlra- tions of myosin, which may reflect difliculties in determining the myosin concenlralits, among other things The resulls of the relative viscosity mcas- uremcnts therefore farkd to reveal any striking differences between failing and nurmal human hearts. f)iflercnccs appeared in the dissymmclry value Ixlwecn nnrutal and fatling hearts obtained by light scattering. Assuruing a rotl-shapcd particle for the tnyrtsvn mokculc, the length of the mytnin mukculc catrat Icd frunr the larbng hurnan hrarl appeared its be less than that obtained frunr norntal hearts One 4-f the ctNrstanl findrngs in the studies was tlsat Ihc sethmenlutrun dragrams of rnyoun prepared front failing hunran hrarts shrrwcd nune MKmdarics of pcaks than Ihrrst of nryusin prcpared f,rrnr u,umal heArts, sug,tstin/ th.tl thc rny,tsin frurn farhng hearts was not hrnm,grncrn,s ur was less slahle than nurmal carthac myusin. lhese rtsults, allhuugh still prcliminary, suggest that nsyr,sin frrrm failing hearts undrrgrtcs chrngrs in nrukcular shape and ur wcrght, tun- )S rf 1.1 O

firming the o(,ilurm that cnnRtstivc hcart fadurt is at Icasl initially a disease of tlptontraltllc pnilcins rd hcart nwslk rrn Iht rnolccular Itvcl ()Arr Rrewror.: 11 S Public Ilcalth Strvice, American Ileart Assnciation, ivllchigan Iltart Assr+c/ation, I r/c Insurancc Medical Research I und, llu Nurrrrughs Welkomt I und, and the John A flartford Fuundatiun "111F PRIiS1:N(-f: OI! IIIIMURAL- FA('1()RS IN IIOMtK;RAFT RE- 1E-'('1ION OF TIfN TRANSPLANTFF) IIEAR 1" By 11 R Ranlos, C ( ltiba, P Schrillmtycr, P L Wolf, H. Pcars„n, and R 1. flrng, Ikpartrncnts of Medicine nJ Palhobgy, Wayne State University ('nikRc of Medicine. nd Ilarpcr Ilcnpilal, Lklroit, Mich. Tronrpranrorrr,n, Volume 1, Number 3, pages 2E14-2V2, July 1963. ((Council grantet: Iling) The mechanism of rcjtctir.n uf the transplantcd drsg hrart was sludicd in cxpcrinlcnls rn rivo and in vinn Vascular Lcrmeahillly was measured by dctermming the dcgrce of tissue radioaclrvrty after inlravascular mjcctirln of radirul.dinattd albumin Unc hrrur ftcr translrlantatic.n, vascular pcrmca- blhly was rncrrascd Ihrs was nlrac prnrnlunccd when Ilrt rcjrctirrn was accrkralccl In c.pcrimcnts in vrrrn ptrfusiows rd the isnlatcd heart with hrunuk.grws plasma ckmnnstratcd slightly rncrcascd c,y1rllary ptrrntahdlty rMx hrlur afltr Ihc rmscl nl pcr(usurn. I+crfusrA w/th stnsvthrcd plasma causcJ a significanl rise in vau'ular permeability ( rllular reaction was absent in the homr.- grafted heart nrx Mrur allcr Iranyll.rnlatir/n In nnly 1 rr( 25 Lcrfusions rn vra„ was cellular rcauilwi prescnt charactcnsrrc o( humngraft rejecliun. This nccurrcd in hcarls pcrfuscJ with scnsrtucJ plasma Tht rtsvlls rllustralc that hrlrnnKrift rcjccunn can crlmmcnce with signs rlf incruscJ vau ular pcrmtahrlrly nnc hour aftcr trart.plantaunn l hcy hrr- Ihcr shilw Ihal humtaal faclrws may lrlay a prcllumrnant rulc in numrsgraft rc -lion rhrr gronror.: l) S Public Ilealth Service. Amtrican Ilcart Aaslrciation, Mrchigan Iltart Association. I ile Insurance Mcdre'aI Rcscarch I und. lhc Hurroughs Wclkumc Fund, and the John A Ilartflrrd 1'uundatiun "STI/l)IFS ON 1711i 1RANSPI.AN71ih HFART. ROl F OF (iAMMA- (3LOBUL.IN IN TRANSPI.AN1 Al ION IMMl1N1'I Y." fly ('hiyo ('hiha, liro Yamanaka. E:dward 1 Zaleski. Paul 1. Wolf and Richan: 1. (ling, Waync State llnivtrsily ('ollegc of Mcdicinc and Ihrpcr fluspilal, Detroit. Mich PrrxrrJrnRt u/ thr.Srrrrry /rrr F..pernnrnrol BinlnRy unJ A(rJunrr, Volume 114. Number 3, pages 617 6411, L)ccembcr 1961 (('ouncil grantee: fling) Scnsitiralirxt of the recipient mirnal with s/ kcn M>nlrrKrnalc resultcd in a significant increase in Ihe strum g:rrnma rlnhulln Ir:rcurm and suhsc- yucnt ar cckratcrl rejtctinn ul the graft In carirturnal casrs In whn h scrum grmnu ghlFlulln Icvtl dld nrd Incrcast. !hc al l r Irlatrcl rrlcr turn was ah•crnl 1 rtalmcnl wnh h MI' rcduccd thr Valu+na y,lrrbulul level :Imt the gralls in tlhcst sninlals shrrwtd prulrrnirtJ survival RrJortlr.n rd r..rmnl.l ylrrlhuhn hy r.rh.rn/•r Ir.m~lu~lnn (arlrrl Ir. (~r,~hnrY vrrtilv.rl Innc uI Ilrr yr.rll Iltcst /r ~ull. •r, vr .r~ ~,-t -Ih r/„ ,~~ w/1r r1 hunn.r.rl /J.Irq• I'rl'%l I11 1/1 IIIC M,in.,. rl I/. ,.r.., I.I,, r..l, irr li,~rn,~l.r.ill rrtrrllnn h.r Rrenrura: I1 S Puhlic Ilcalth Service, Anrcricarl IIcart AssrKiahon rc/ugan Ilcart Assuriatrun, l.ife Insurance Mcdreal Rc,tarch Fund, lht lfurruughs-Welknme Fund, and the John A. Ilartford E=uundatuon "DI.(N)h FLOW IN T IIE: 1111MAN C'AL.F hIfRINI: lOIfA('('() SMUK- IN(i " Ny Jay 1) ('oflnran, M 1)., and Stanley L. lavclt, M l) . 11 ('h . 1: ' vans Mcn.arial Ikpartmcnt rd (linical Research, Massachusclts Memorial l/os- pilals, Iluslr)n ('irculution, Vulumc 28, Number S, pages 932-Y)7, Nuvcar• ber 1963. ((Council grantee: ('ullman) E1hxA flow in the human calf during the smoking of 2 regular mrn- fillcrcd cigarettes was measured in 17 mKmal subjects (avcr'rgc age 2111 years ), in 4 patients with sympalhcclumized limbs, and in 6 palicnts with arlcrioxknniu oblhcrans. The dis:(ppearance rate of a r.diuisulrryK injrclcd into a muscle was used Io indicate nrusck cap illary hhwxl Ihrw, and pkthys mngraphy was used to measure total hkxxE Auw of the calf, includmg I>+Hh ikin and nruscle r I 1 Thcrt was a significant incrcasc in ntuscle capillary hhoo1 Ihlw in 14 c>r Ihe normal whjccls while pIcthysrncrgraphic blood fluw changes were variable and mN srgnificanl. 'lhrec of the 4 symralhcclrunircd patients showed an irscrcascd drsappearance rate of the radruisrllupe during smrlk- ing; the arleriusckrosis ufslilctans patients showed no change in musck capillary bhKrd fluw during smoking. Repeat studies on subjects wlxs had  more rapid disappearance ratc during smoking reveakd the corislancy (rf the increase in hhKSd flow. "Sham" snuoking tests indicated that inhalation was not a factor Intravenous injec- tiuns of nicoline, in doses comparable to Ihe amrwnl conlained in cigareucs, was also dcnxsnslrated to increase both muscle capillary and wul calf bhwd flow significanlly. E:vidence that the sympa(hetic nervous syslcm probahly was not involved was derived from the increased isrNopc disappearance rate in the three patients with lumbar sympatheclcxnies. While skektal muscle bhMKl Iksw may increase during cigarette smnk- ing, skin flow definitely dccreases, a factor es/ most imprul•ance to the patient with I eriphcral vascular disease. Thcrefore il is slill of impurtance lo rccnm- mcnd that paucnts with ixhemic pcripheral vascular discasc stop smoking "IIYPI?R('llOIrSTIiREMIA ANL) PE1LMONARY ARTVRIA1. Ili- SIUNS PRUI)lt('1'.1) IfY 711R(1MHOPI.ASf1N." Ily Irj Gore, M 1), Kcnrr/ T'anaka, M 1) • and Ilcmard J L.arkcy, A If , 1)cparlmcnt uf 1'ath• uingy, Mass•achusclts Memrxial Ilospilals, Duslun; Vclerans Adrnini.traurln Illr.pit:rl, Wrsl RuRhury; 1)cpartrncnri rd Palhulogy, Ilrrstun Llnrvcrsuy and ILnvard Mcdreal S.Iuw/ls; an1l Ih•harl/rlerll of Nulritiun, Ilarvard Schlmrl rll Puthh.' Ilcahh, Ilustnn /hr Anuvrrun /rrUrnuf rrl /'urlwlnKl. Vrrhnnc 41, ,>. Nunrf.cr I, Iragcs 145 15h, Murch 1'Ih 1 '•PI11 MONAIII' ARfVR1At. I I SI(/NS /'Rttl)It(l l) IIY PltrrIA c) M1NF " Ilv IGruc, K Irnake, M I rnlrr(r, 11 1 Whnr, and Il I I.ulcy n U /,rurrUd nJ I'nrhrrlrrKV rrnJ lfnrrrrrr.Lrr;v. Vrdumc BM1, Nurnlhcr I. Il.lgcs 2t1'/ . 11 .f, luly 11161 (/ uuni /I hr.rnrcc ( irac ) U 17 0