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S(:I7:f+17•IFIc AnVISaPRY IN/ACt0/ In I he ('ouncil for Tobacco Research - U S A KIiNNI:I II MI•.RRII.1. I,YNC'lI, M U., Sc.l)., 1.1..1)., ('huummn ( bunr rflur und l'ru/rssnr 6mrritus of Pathology Mcdical ('rrllcge of South Carolina, Charleslon, Siwth ('arulina •IIOWARI) It. ANUI:RVONT, Sc.U. Scirnri/ic Ldra.r, 7he Journal of the Natiunal Canccr Institule Bclhcsda, Maryland RICI IARI) M[)tN(:, M I). I)rrn t.r u/ ('ardirrlugy and I ntrunrural Alydir inr IluntinKton Mcmurial Itospital, Pasadena, California I'.n/rssrw n/ Mrdreint lJniversily of Southern C.lifornia School of Medicine l.os Angcles, California McKI:E:N ('AT11?l.l., Pu.[)., M.l). I'rrr/rssrM Lmrrilus u/ l'Iw.ma ulrrRy C'ornetl linivcrsily Mcdical College. Ncw York, New Yurk RO©E:R 1' J. I IUl=BN1:R, M.1). ('hir/, Vital ('arcinogencsis Branch National Cancer Institute Bethesda, Maryland LEON O. )AC'ODSON, M.D. I)ron of the l)ivision o/ Biuingical Sciences Rrgrnslrin Pro/rssur of Uinlogiinl Sciences University of Chicago. Illinois CLAY"1ON G. I.(>USIJ,. Pn.[)., M.1). llasrings I'ru/rssur of Mrdicinr and Pathuingv l)niversily of Southern California SclKxsl of Medicine Lrn Angclcs, California C'LARFN(•E: C'(K)K LI'ITLI:, Sc.U., LL.I)., Lttt.l). Scirnti/ir I)irrclrn, The Council for Tobacco Rcscarch - 11.S A. lhrrctur l:rnrritus. Roscoe 8. Jacksun Memorial I.aiNUatury Bar IlarMrr, Maine WILLIAM F. RIL:NtIOFF, 1R., M.D. !'ro/rssor Emeritus of Surtrry Johns I lopkins Univeraily School of Medicine, [taltimure, Maryland SIIfLIX)N C. SOMMERS. M.1). Rrsrarrh I)irrctur,'I he ('ouncil for'Tubacco Rescarch - ll S A l)irrclrrr u/ 1 nAorararirs, Lenua I till I luspilnl IYrr/r~~~rr of PurlprLoRy ('ulumhia I lnrve(sily ('trllcgc uf 1'hysirians :rnd Sury,euns Ncw Ynrk, Nrw YrNk RUFII'.R7' (' II(K'K1: .'I"f, I'n 1) AffIM IOIY Sr irnnJu lhrn /-,r 1. MORRISON 1IRA11Y, M I). JOIIN 11, KRI ISIII lt• I'ir 1) AssrK ialr Jr irnlrfir I hrrr lur Assrr iulr.1( irnrrfa l)nr•r ror VIN('IiNt' F I tSANt1• I)M I). .1r irnhfir Ass,H wtr •Relired

(:ONTt:NT4 Introduction . . . . . . . . . . . . . . . . . . . 5 Status of Current Rescuch . . , , . , , . . . . . 6 Multivariate Analysis , , , , , , , , , , , , , 6 ('ancer . . 8 Cardiuvascular F)iscascs . . . . . , . . . . . . 12 NiccNine: Psychn PharmacoloRical and Fkhavioral ERects . . 14 Chronic Respiratory Diseases . . 15 Abstracts of Repxxts . . . . . . . . . . . . . . . . 18 Psycho-Physiotr+Rical Studies CarcinoRcncsis Sludics . ('ardiovascular System . Rcspiratory Systcm . Neurophysiology . 18 22 32 45 55 Studics at the ('cllular Level . . . . . . . . , . . 58 ('cll and Tissue Culture . . . . . . . . . . . . . 62 Fpirkmiok>Ry . . . . . . . . . . . . . . . . 67 F'harmacolo8y and PsychmPharmacolo6y . . . . . . . 69 Metabolic Studies . . . . . . . . . . . . . . 77 Chcnristry and Iliochemistry . . . . . . . . , . . 81 ( )Ihcr Studies . . . . . . . . . . . . . . . 84 Reviews . . . . . . . . . . . . . . . . . 86 Rccipicnts of n(livc 1'rujccts . . . . . . . . . . . . 94 Rccihicnts uf ('umpIrtcJ Projccts . . . . . . . . . 106 I Ilt COd11Ca011 The Council for Tobacco Research-U.S.A. was established in 1954 for the purpose of providing financial support for research by independent scientists Into all phases of tobacco use and health. From the bc6innin8, full authority and responsibility for policy, dc- velopment and direction nF the research efFort were given to a Scicnlific Advisory Board to lbe Council. This FFoard currently consists of 10 physicfans nd scicntists who retain their afTilialiuns with their respcctive Institutions. With their combined experience and knowkd8e, and with the advice or other experts from the scientific community, the members of the Advisory Board have worked toward one goal-to develop a research program to provide significant data about lung cancer, heart disease, chronic respiratory ailments, and other diseases. Through thc years The Council has provided the funding to enable the Scientific Advisory Board to develop and expand the research program. From 1954 through June 1969, the Board awarded over 4(M/ uriRinal Brants, and many more renew.ls, to 239 scientists in 186 hospitals, medical schools and research institutions. In the same period, these research workers published 728 scientific papers on their sludies, supported in whole or in part by The Council, in the profeuional literature. Studies from the Advisory Board's prcgram and from other prosrams have produced much valuable data In the past 15 years. They show, however, that we are not dealing with simple discascs and that we cannot expect simple answers. But the members of the Ifuard and of other scientific or6anizations re optimistic that answers will tic found. Investigators are constantly reporting results that will some day he pieced to8ethcr to help solve the puruk of these complex diseases. It is apparent from the great amount of research reportcJ so /ar that a variety of genetic and environmental factors may be inwrlvc.l I hc ('rwncJ for 1uhacco Research will c'ontinuc to wp/M.rt xknlffic invc.rUKa tirm and to work loward a beller undcrslanilin8 44 Ihe uuny unanswcrcJ questions that remain. 'Ihe response from physicians nd scientisla in IeadinR instirutions tu The Council's oRer d research support is most gratifying and cncrruraRcs The Council to adhere to the demands of a realistic and scientific aphruarh 5

Stattis of Current Research (-ertain epidkmicAugical studies have associated cigarette snruking with total mortality and morbidity rales and with mortality frcxn lung cancer, c.rdiovascular diseases, chronic pulmonary ailmenls, and various cNher diseases. 'Ihcsc ass.xiations have been widely interprclcd as siRnifting a causal role for smoking Ilowevcr, it is an accepted fact that a sta•istical associalirxr is not necessarily one of causation. The information obtained from cpidcmiolugical studies may be helpful to investigators in framing necessary c><pcrimental studies. tlndctlying most present intcrprctaticros of these epidemioiugical studies is n assumplir.n that cigarette smokers and rnmsmukeis are sufficiently similar in other respects so that it is Icgilimale to compare their murhiJity and rnrxtality espcriencc and to attribule obscrvcd differ- ences tu  sole faclur, smuking. lhe restricted momdactrxial intcrl+retatirrn of smoking as a causal factrx in total nxsrlalily or in relation lu tcrlain discascs ignrucs thc validily uf  vast anxwnt of research tclaling lu Ihe pussihlc inllucncc of many uthcr factors cx crmtbination of lacturs. Multivuriate. Analysis lhrce questions about epidcmiuluFical studies reported un tobacco are: ( I) Is cigarette smoking really a cause of increased mortality, either in general or from certain diseases? (2) 1 low and to what c><ICnt do smokers and nvnsmokers differ in gcnctic traits or Rcnctically inlluenccd hahits and patterns of living? (3) Are Ihcse gcnctic traits ra Rcnctically- inllucnced habits and patterns of living Ihcrosclvcs, singly rrr in gruups, influcntial with regard to dcalh rates'? tit ~tislicians gcncrally agree that it is imlwntant Irr wcight all known nr prnsihlc facturs, individually and in grrrups, as rn:rlhcmatical Incihchors of any cvcnl (suih as mortality) prcliminary tir sclccling Ihose wrlrlhy n( rclativc Irriinity Ihis is a very lal.onious Ia%k Ixcau.c numcnrus faclras atc I , I invr>Ived, and most of the large data collections that might hear rrn dte prcdicturs for longer or shorter life have nol been so ana(yzcd. Any mcaningful ana(ysis, of ccsurse, requires that adequate and accurate data on such factors have been gathered initially. Of equal im- purtarxe is the need for developing ncw, reliable and (aster computcr methods capable of handling these complc dala. Aware of this problem, The Council for Tobacco Research is engaged in the study of the development of such methods. Pilrrt Studr u/ /.on6evity A pilot study of longevity has been done in a gfuup of S(M) recently d•ccased velcrans in the [3rsston nea. A large budy af informaliun has (KCn collected on Urese subjects as part of a Council-supportcd pruject. 'I lie new mclhtxls of multivariate analysis were applied to see which factors would have served s the best predictors of lunger or shorter life, if they had been so employed at the outset. Many lactors, it was fuund, tcndcd to "cluster" with cigarette smoking statistically so that grwal predictions of longevity (in these data) could be made by use of a"prufile" of such other factors with smoking ilscl/ omitted as a predictor. 11x result was substantially the same as when snroking alone was used. In other wurds, the finding showed that smoking (and also alcohol use) appeared to "tummarize" and to be associated with other groups of characteristics. There was a significant by-product of this new approach. 11 was found that certain statistical associations between cigarette smoking and length o( life can he eap(aincd by the sccularity effecl-that is, the general change in prevalence and kvel of cigarette snwking with time. Secularily is dc- scribed in the words of the investigators: a consequence of rapid s,><ial change and the prolonged human life span. Thus, the yuunger deccdcn,s were part of a"selccted" population having, pcrhaps incidcntally, a dilfcrcnt cigarette smuking pattern than did the pupulatiun rcpresrntcd by Ibc oldcr dccerknts. It is e.pcctcd that these preliminary arplicalirrns uf multivaroatc analysis will Ise carried out on data collected in several rrdicr llrunril s(Krnarrcd prujccts on subjects not ncccssartly rclalcd to Ir1nl;vvuy but tu melhrKls of diuFnusis, etc. 1)i/Jrrenr•e. If#-trorrn Smokrra arul Nnrumr.k~r. Othcr (•ounk il suplwntcd prrryccts h:we stn-wn st:rthslii.rlly sit-mhi.int dJfcrcnccs Ix•Iwccn sim,kcrs and mmsnrokcrs I hcsc arr indii,Nuins /ur lw% sible use in ahc multivariatc rc analysis uf existinK data trdicolr,nc It 11.1% 7 6

been shown, for esampie, that there is a prevailing diflerencc in the dis- tribution of body build types. tnvcstiRatcxs have found personality diflcr- ences. One researcher has reported observations on a number of factors that differ in smokers and nonsmokcrs and may he predictrxs of early heart and artery disease Still another researcher has found a siRni,icant difference in basic brain wave patterns o/ smokcrs and oonsmokers. Cancer Lung Cancer Snsoke /n/ra/atJon E:ptrlmerrt. Previous Annual Reports have specified the etacting criteria for con- ducting realistic eaperimenls involvinR smoke inhalalion. It is impe.rtant to restate these criteria which have been derived from the resulls of er<ten- sive research and from consultaticxn with esperts in many disciplines. First and foremost, meaningful data can be obtained only i' the whole smoke delivered to the varitws parts of the respiratory tract of the animal Is in the same physical nd chemical state as that which re rches similar anatomical areas of the human durinR nrarnal cigarette smukinR To aeaxnplish this, it is ncress.ry tar heve a mcthanital devite--a smoking machine-that simulales hrnnan smwkrnR as thouly ss prnvble. This device should be able to dcl,ver putscd arni+unFs rd smtikc in a quan- titative and reproducible manner 1 he nu.hine shuuid hc so dcsiRncd and constructed that it will be ppnsible to measure accuratcly the lime between two successive puRs, the time of the pull, the volume of the puff, the estent of dilution with .ir, and the number of puRs per cigarette. C'are must be taken so that the temperature ts( the burning tip does not exceed that reached when a human smokes a cigarette, nor should the cigarette be "smoked" beyond a minimum butt length. The machine should have a port to permit sampling of the smoke stream for chemical or gas ehromatoRraphic antlysis, if desired. For frac- tionating the whole smoke and to permit the biu.uay of the Rascous phase, the smoking machine should be designed so that a('ambridRe fittcr can t.e attached. For comparison hetween labtxalorks, It Is desirable that  rcler- ence type cigarette be used. (lhe llniversily of KenhK4y is now p(Yrducing a rclerence cigarette ) lhe animal receiving the smoke should be placed sco that only its breathing apparatus is in the nrainslreanr of the smuke and no farthcr than the distance of the human nose to the main branching rd dre airways in human IunRs. '1 he animal used should be fully descrilxd as la aRc. Rciutic background, weiRht, nutritional state, physical conditiun, virus cumprmcnts, cxtcnl of surgical trauma, and the degree of stress to which it is subjccted Appropriate numbers of bo:h sham-smoked and cage-held animals should servc as conlrrtls. '1 hc end points sought should include more than mcxphological oItera- tions .nd the presence or absence of tumors. For proper interpretatiun they also should include appropriate biochemical measurements and their analy- sis. Multivariate analysis should then be applied to the data obtained (rom the systematic observations of the controlled paramctcrs relative tu the smoking machine. Ihc animal mcxfel, and the biological sud bicrchcmical measurements. Hy these mcans, it nuy be possible to develup bioassay techniques related to cigarette smoke. Past e><periments, where the sole objective was the attempt to induce tunan, must be carefully and cautiously intcrpretcd in light of tuday's knowledge. Sra(a61e Animal Mo.i./a NeMLd '/bere is a Rreat need for suitable animal models (or inhalation studies related both lu lung cancer and chronic respiratory ailments. Pending dev-h+pment td such models, tests have been designed under ('uuncil supprxt to provide a careful, quantilative, descriptive picture uf any and all observable morphological changes in the lungs of mice exposed to whole cigarette smoke rx the gas-vapor phase. 7hese eapcrimenls will be analo6- ous in design to those now being completed with oxides of nirrugen, ozone, and carbon mrmoside. As regards lung cancer, it would be very help/ul lu havc a positive animal model of the human disease. If squamous cell lung canccr thc type reported to tx most common in humans - could he produced by sume sinrpk and acceptable procedure and at a reprtKlucible level, it could be possible to plan systematic eaperinxnts to determinc what addkd facturs might induce it earlier or delay its appearance. Any such /aclurs found to contribute to susccptibilily or resistance in the animal mIMIcI cuu1J then be checked in humans I tre 6ua) is to trldain clues lu Ihe Ixrssrhle, tunlyd+urury Influence of nuny inacrnal and eattrnil fat:krrs in Ilu aninul m«Icl and then see if lhcsc arc related to the huruan es(xricnce in any way In addition tir snrakinR, a Rrca1 many ulher laclurs necd to hc cvalu ted in Ihis way One is the effect rrl vitamin defic'rencics, cs/+c.ially vdanun A. Another is liver danuge, which has already hcen shown by ('uuntil 8 9

sulqarrtcd studics to predisprne Ilr cantcr uf lite ur.d cavity. An-llhcr is dislurbancc of Ihe hoamt.nc balancc. Another is air pldlulil/n. I here arc nuny more. Ih-u.lopment oJ 11rINrratut nnd Tet•hniques lhe ('twncil has long supported research to develop apparatus and control methods for smoke inhalation esperiments and also to find salis- faclory lechniques of measuring lung surface tknagcs, especially of lite particulate phase of the smoke. Ctxniderablc progress has been made in dcvelupnlcnl of ilnprovcd mechanical cyuipmcnt for such studies, and several new dcvices are nuw undergoing esacling tests. Feasibility studies have been c/mducled and it is espccled that there shtxtly will be initiation of ncw, long Icrm inhalation wt.rk combining the use of improved eQuipment and also of hcller stand- ardircd aninral substrates. Certain animals, /or eRanrple, have long been considered inappropriate for mcaningful inhalation cxpcrimcnls. With the use of presently available and partially improved smoke esposure devices, scientists working untler a grant front 7he ('ouncil have exposed guinca pigs to short-Icrm, chronic inhalation of whole smoke in order to obscrve whether changes w/luld develop in the osidalivc cnryn/c activity of isdaled lung mtlxM,ndna Ihe stress effecls of handling and machine eRprnure without smlrlc inhalalH/n have Ix-cn asscsscd in cunlrl4 animals 1 hesc sludies arc nrlw hring eRlcnJcd tt/ Ionyt•r Icrw cRlHisures and to inhalation of gas vaplor phase wlthuut partUtulatc nlallcr or nit(-llnc lllou.eSkin PainfinR anti LrrnR (:anr-er l he induction of skin cancer on micc painted wilh cigarctlc unnke condensate ("lat") has bccn, and still is in some circles, accepted as evidence that smoking can contribute to human lung cancer. Ill/wcver, smuke condensate is rwst whole smuke. lite skin is not like the lung, and studics supplutcd by 7he Council have shown that various tissues ir, the same animal respond very differently lu a sing)c chclnical carcinogen. 'I Ix oral cavity lissucs of mice, fur exanlple, are nluth more resistart to IKntll(a)pyrene than their skins. It nlust he emphasired that there is no rcliahlc evitlcntc thsl thc cundensale fraction t'an pnKluce tu/nurs in the lungs uf eRIH'r1114'l1IJI aninlals Many eRpcriments wp/wrrlcd hy 'Ihc ('ountd and hy uthrrs have failcd tnnlldclcly Irr prtKluce lung tununs whcn sulutiuns ur c/nulv,,ns Id tigarrllc tmrlkc clrndcnsale were ilntillcd dirctlly intl/ Ihc lunls of Jutks. h.lnl./cra an l nnic Inlrttilm /t( snlulc t/lndcnc.lle rnwl.ilms inln lite I hhwKlctrcam of rni.c and ol lung-damaged rals ladcd tll prrKlutc lung lumurs, though IK•nro( a)pyrene emulsiuns did so undcr Ihc samc tcth- niyucs. Ihcrefure. there is no reliable evidcncc that the "lar" Ilat1i1N1 uf cigarette smukc atls as a lung carcinogen even in eslxriutcrd:tl animals VIrUSCS ll/fd G(f11fCr A growing field of research is concerned with the role of viral fattlrrs in human cancer. It has been known fur a long limc that viruses are dirc.tly involved in a numlrcr of animal cancers. 1 bc Council has sprmstxcd a nundxr of studies which lout hcd in tluc way or anolhcr uptMr 111e possible rtAc of various virus infections in lite gcncsis td cancer. Recent tkvclrqxnenls in the study ut virus cancer intcr- rclatinnships, spunsured by olher agcncics, have produccd nwch evidcnce to support a unifying hypothesis which combincs genetic concepls with con- tcmpurary knowkdge of the nature and action of viruses. '1 hcsc developments corxerning viruses lentl lu place new and in- creaud emphasis on the condition of the host in carcinogencsis cRl><rimtvrls and intnxfucc new dimensions and controls into animal test mtKlcls. -lhe ('ouncil has untkrlaken lo supptxt research ctNmcclcd wilh the testing and development of stxne phases trf this virus-canccr dlcory. At Ilk same limc, it is helping to develop new and beltcr-conutrllcd ccll cullure and whole animal nNUkls flx measuring lite inlcractiun uf wsccplihilily faclurs wilh eRlrrnal slimuli in lumur protluction. Su.h nrtKlcls, it is ho/.cd, will be uscful as assay systcros for Icsting lite effctls uf whulc, fresh, nurm:d cigarcllc slnukc or its fractions (particularly the g:IS.v:yK,r pllasc) or cnmptmcnls murc realistically than is possibk with crudcr rnclhods. IllcuGlcr Cunccr I)ata relating to bladtkr canccr in hunrans arc sparsc Ilthcr Ih:ln Ihllsc concerned wilh IKCupaliunal factors, where there is a nluth clrarer piclure. '111n,rgh several epiderniulugical studies have reputtcd a staualicul ass/Kia liun IK•Iwccn ciparelte snKlking and eancer rrf Ihe bladdrr in huluan nlalrs, lite qucsliun Id whclhcr thcre is a causal rclaliunanp rcmains IIIK•n I hc finJmf;c Iur fcm:dcs wrrc tvlnlruhclory, and thcrc wcrc intl.nantrnt rrsults Id aninlal cRpcrinlcnts wilh tigarclle snu/le clrndcnti:ltc V/lel ttetl~u.s fivl lite p.lst 1 t yr:us du n/rt sh.lw a fll,'llltlt arll ritc in rrliv-rrctl t.l. ..d btedLh 1 cantcr. Ilcntc. lite rcpwrrtcd Statlstll'JI :ISSIKIallull h.l. Lltkt l I.Itn n.J I R planallun I11 11

In 1965, a h,vlxtthcsis was advanccJ to Ihe cflcct that nicotrnc miRht so Jisturb the mctahidism of Irypluhhan as to result in ahm+rmal accumula- tir.n of certain rn.rmal intcrmediatcs rclalcJ chtmicilly it, suhslaucs whirh, when implanted as pellets in the hladdcrs of mice, were fuund its prr,Juce cancers in that spccies. A basic postulate of this theory was that h1aJJcr cancer palicnts Rcncrally show a Jisturbance of tryptuphan rnetalxthsm akin to that claimeJ to occur in smokers. '1 his hypnthcsis has been investi6ated in three JiRcrcnl cenlcrs as part of ^ broad b1aJJcr cancer study that included clinical, pathuh.Kical, bio- chemical ^nd espcrinsental aspects. Contrary to the hyF%Nhcsis, four out of five bladdcr cancer patients were found to escrete tryptuphan -nelab- oliles in a nornral pattern even ^fler tryptuphan loading tests In mict, the lihcral feeding of vitamin C prevcntcd pr«luction of bladder c^nccrs by implanted pellets of J-hydrosyanthranilic aciJ, a normal Iryplnlshan metahulite. 1 he coroparative excrelion patterns of nine tryptrrphan ntclatx+litcs by snrukinR ^nd rxxtsnKrkin6 subjects have also been under investigation and reprxts are scheduled for early publication. As part of its spunsorship of sludies in this field, 'I he ('uuncil ctrn- tribuled to the supfxrrl of a symf..nium nn "Iht I:pidcrniuluRy and I'IiuloRy of Iluman BladJcr ('anccr " jrdnlly afMmsorcJ by the ('anccr Itescarch Institute of the New UnRland Ikac.ntcss Ihralrital, and Ihc Ikpartmcnl of Pathoh+Ry, &.stun (lniversity Srhr>,d of Mcdismc the symp+sium was held June 6 and 7, 19611, in Huslnn, and mmt of the papers prescnteJ were published in Ihe /nurnol ol l lrr Nor.nrmf ( unrrr /nirrrurr, 41, 217 (1969). Cardiovascular 1)itieascs C'ardiovascular diseases accuunt for more dcalhs among I1 S males than any other disease category. 1 he cardiovascular system itsclf is subjcct to a variety of disorders. The most cummon of these is arleri.nclennis, the result of unknown pa11xr1oRical pnKCsses that lead to pruRressive Inas of resiliency of the arterial vessel wall accumpanicJ by incrrasrJ ripdily and narrowing of the luntrn A conurnm uyucl is ahrupt rx'iluv..n by Ihruml>,rsis, and the effectf includc a faulty supply of hhwKl to a lirwc or rwRan, inadequate to meet its nccds I rryuent c.uncyucnccs are to mna,n furnrs rrf hc:nt attaaks, brain sttoke. Rangrcne of a Irg, rulrture of thc aurla, and certain kinds of high bkKKl pressure. Ihcrc are a nurnt.rr of su"cucJ factras in arlcri.rscecrulic diccascs I includrng lipid nrclalxdism, vascular connective liswc d.rm:r);c, cnJrKnne dvsfunctinn, and fihrin deposits on the vessel wcJls. I)ict, hypcrlcnsrnn, rrhxsily, lack of crcrcist, psychological factors (stresc anJ Icn+wn), and smukinR have been rnentioneJ as possible csrntributnrs Some aulnpty studies have reported no association cclwccn suurkiug and arteriosclerusis Others have reported Ihat hcavy ciRarcllc sm44rrs have more cxlcnsive lesions of the coronary arteries than do IiKhl or nuncmukers 1 hese data are limited in quantity. 'I ht lesions repr.rtcJ also require further study to determine if they Jifler in quality or palhuKcncsis between smokers and nonsmokers, since smoking has not been dcmun- strated to have an etiologic significance. 1lietary chulcsterol has been cited by many as perhaps the majrrr factor in heart drxase. Ilypcrlension appears lu run sccund in inqx,rtanic, according to somc investigators. There have been reports claiminR a rcla tionship between smokin6 and hypcrtcnsion but, paradoxically, it has been found that men who are heavy cigarette sruokcrs generally have lower blood pressures than nonsmokers. It is obvious that the siluation, in 6cneral, is cunsylcR and ubccurc Trcin Slurlipa in Ilrarf INall-oae Twin studies cr>twlucted both in this country and ahrr.aJ undcr uthcr auspices have casl Joubt on smoking as a cause of heart disease. "1 hete studies help to cmphasize (by their control of factors which would ulhcr- wise vary between smokers and nonsmokers) the impurlance of not only continued work with twins bul of mullivariate analysis. If srnrrkrnR twins have no higher mortality than mmsmokinR twins (as indicatcd by pre- liminary rep+trls), such a finding emphasizes the need for caution in evaluating uncontrolled statistical studies. With support from 'fhe Council for Tubaccu Rcscarch, two scicntists undcrlrw+k a study of the el-ecU of environmental fpclurs un the develop ntcnl of athcnnrlerusis as revealed by aulrMny of acri.knt victinrs 1 hrir work, with sul+p.ut from other snurces, was later eslenJeJ to lie iniluJcJ in the Intcrnati.mal Atherosclerosis Project. lhcse invrsliRalurs found fatty streaks in alm.nl all rhe anrtas of IM.ys anJ Rirls aKcd 14) 14 and sinrJar strcaka in the cononmy :utrnc.. of most hrrsuns aged 21) 29 lhe slreaks are clinically IWrnllrft :1nJ Iwdrll lially reversif.le, they noted Ilowcver. they said alhcrus.lrr..uc Ic+wns may ^)pcar in Ihc curunary arlcrres 1hcfure the age of 2t- :rrul rh..t rlrc eunversiun of fatty strcaks to lilrruus playrics rKCurs at an a-arlrcr :.t-c m pupulaliuns with high curunary hcarl drsc:rsc murhidity and nuurahry I) 12

Nicot hic: I'sycho-I'ha rrnacologica I and Bchavioral I;f fccts Some oC the bases for human use of tobacco are certainly to tx founJ in social or psycholoRical needs. However, on the ssumption that others might also be fnunJ in the realm of psycho-pharnmacrdogy. Ihat is, in the eRects of smoking and/or nicoline on the central netvous system. 'The Council has suppcxtcJ a number of studies in this ficld, several tit which have been summarizcd in previous Reports. lhe volume of this work reached a level decnrcd to justify a public symposium on "'Ihc f=Recb of Nknline and Smrrking on the ('enlral Ner- vcws System" which was sponsoded Krinlly by 7 he C'ouncil and lhe New York Academy tit Scicnces on April 7-9, 1966, and published by the Academy in March 1967. Grantees of The Council participated in the session as did a considerable number of other independent investigators from the l)nited States and abroad Work reptxled at the symposium established that nicotine docs dcfi- nitely pass Ihe blood brain barrier and aRccb brain activity as shown by electroenccphalographic tracinga two1h in animals anJ in man. Ilccausc of the rapidity (if these brain wave chanRcs, it was postulalcd that smokc may also s/imulate nerve endings in Ihc IunRs tit send signals In the brain. 7he cflects ts/ nicotine on the brain are not always the same. I)cpend- ing on the slate of the nervous syatcm and on the Jrrsagc, an "aruusal" or "wake-up" effect may occur which is reflected both in brain waves and in behavior. 71tis effect is accomplished by a dilation of the pupils and a slight rise in blood pressure. Confirmatitm that this was due to nicotine came from esperiments involving direct instillalion of the alkaloid inlo the brains of animals. In larger doses or in a diflerenl stale of Ihe nervous syslem, a peculiar steady state of hroger duration is pnKluced which may be described as Intermediate between krlness and slccp. 7 his has been JcscrihcJ as a "tranquilizer effect." 'Ihese finding.s confirm Ihe suhjctlivc rcprxts of ciAarcltc smokers (islcnskrn of the clectroenccphahl.raphic stadics Irr hum:rn suhjctls has pnxluceJ umre ntnervalions that appear rclcvant tu the yucsuun wlry urnx persrrns nced rx want lo mnke while tNhcrs do ruN 11 was fuunJ that the prevailing encephahrgraphic palterns of nunsmokers JJler mark- edly from those u/ smOkers or fxrsons who haJ never tx•cn snuokcrs, even lung aftcr Jiccrrnlinuance of the habil A markeJ ddfcrcnte in thc ability tu produce Ihe "alpha" pattern by conscious effort also csistcd between these groups. Sincc long discontinuance of smoking by (ormer heavy smukcrs did not alter these relatinnships, it was postulated that the difference in prevailing brain wave patterns has a congenital basis and may csplain Ihe function of smoking to nnxlify or "nurmalize" central nervous system activity. It this finding is camfirmed, it will indicate that smokers and non- smokers may have imptxlznl basic constitutional d4ferences which also may produce differences in their prcdisprnititm to the development of cer- tain Jiseases, especially those of a"psychosomalic- nature. Since prcdis- pcnitivn to cardiovascular disca%e has been attributed to Jillcrcnces in psycht>fogical or personality lype, il becomes impcxtant lo investigate pcnsible correlations between types as defined by a psychtdugical Icsl and as distinguished by encephahsgraphy. Besides these eflccts, it was repuMed at the symposium that small doses of nicotine have a favorable eQect on the learning pruccss in txrth rals and uxne other animals when they are made to perform certain aclirrns to receive a reward cx to avoid a disatmforling eaperience such as electric shock. Several ramifications of this basic finding have been pursued further and certain pharmaculogical mechanisms were elucidated in sunic cases. Chronic I1cshiratory I)iscuscs llte Scienlilic Advisory Bwrd has long been aware of lhe need fur research into chronic respiratory diseases and has awarJcJ many grants in this field. 'I here is a teporlcd increase in such Jiscates as causes ol illness and death but whether there has been any curnparahle Irue increase remains questionable. 'I here is reason to believe, in any event, on Ihc hasis rrf rescarch findings. that one important factor in any reported incrcasc is Ihc res.ue, particularly with Ihc use tit antibiotics, of many pcrsons hum dcalh duc lu severe lung infctlirMn lhey then live rm wilh d:unagcJ lungs trr Jcvchqr chnmic respiratrny ailmenls later in life. ') he IKnsihlc inflwrnce td ciRucttc suruking rm Ihc caus:rti4,n or cx accrhatiun uf thrunic respiralury Jiscascs is Jrllicrdt tit a.scss (/uc rrl thc di/hcuilies is Ihe inabi6ty lu JrstinKuish adcquatcly Irlwcen (hrunic hrnn chitis anJ cmphyscma. Ifulh conJiliuns are uflcn fuunJ lu ccu cent in inany patients. 'Ihe accurate classi/icatiom and recugnitiun uf ernphysciua by the 14 15

medical prnfession have really not dvanccd very far For example, de- compensaticxr in chronic pulmonary discasc nd cardiac abnormalities are not yet accuralely distinguishable. Standarrlised Techniquta Ntedrd Further, standardized techniques are nceded lo compare the prevaience of emphysema in different societies or different ccwntries, an apptoach that is IonR overdue. Suilable morpholo`ic criteria frx properly classii yins, quantitating nd evaluating emphysema have barely begun to ernerae in the past five years. The necessary techniques are now used only in n few Institutions. Even fisalion of lunp in the expanded statt, the essentia' first step in establishing the presence, type and degree of emphysema, is rarely practiced. l?eath reported from emphysema cannot presently he defined with any accuracy as to what actual pathologic conditions may be presen.. No uniformly applied, scienlific.lly sound clinical methods are now in general use whereby emphysema can be identified and quantitated. The basic kn<+wkdRe and even the definition of chronic bronchitis are still IackinR dcspite some recent notable cunlribulions fkynnd the need to standardize, and even mrxe to find better clinical and patholoRic diaRr.enlie criteria for chronic brnnihilia. there are also problems of its possible rela- tion to repeated viral and bacterial infectiuns over a lifelime, particulate and nonparticulate irritants, ginR, changes in the bronchial mucusa, and hypersensitivity diseases. 'The Council has supported pioneering studies to describe anatomic emphysema more quantitatively and to ddferentiate amons the several dis- lin6uishsble types. It has also sponsored a number of clinical studies of pulmonary funcliim, for description of short-term effects of inhaled agents, including tobacco smoke, in subjecls of various ages nd in various condi- tions. lhcse have been dcscribed from time to time in earlier Annual Reports. More recently. The Council provided support for a sludy of The siblinss e>t chronic respiratory patients 1 he siblings and the patients were the test group and their spouses served as a control Rruup 'Ihis invesliRa. lion revealed the esistence of a familial tendency to funcliomal impsirmcnl of the lungs. (hher investigations have contributed to the present impressive evi- dence that certain genetic enzyme deficiencies (alpha, antilrypsin) slronRiy predislwne to enrphysema in homnryRutes carrying this gene and Ihat even hcterozyRotes may shuw an enhanced degree of prcdisl>•rsitiun. InJlept6 Cfiniea/ Studit. Undtr R'.y The Council has recently provided support for major lung lerm, in- depth clinical studies nf chronic respiratory disease enlilies in two Eeo- Rraphically separated urban centers. A third clinic that spccializes in iunR function measurements of young children has morc recently been added to the project. The hope is that Icm6-term repetitive examinations of patients can provide ccxnprehensive information on pcrsonaf characteristics, family his- tory, manner ot life, environmental espasures (including tobacco smokinR), conlributory infeclions, response to treatment and course of the disease. The extensive clinical and '.abrxalory dala compiled by the investigators may prrxluce better de6nilions of the various clinical emities and more reliable methods of differential diagrKxis. It seems obvious that such definitions and diagnosis arc absolute prerequisites to any real progress in the study of the etiology of chronic pulmonary diseases in terms of the interplay of intrinsic and estrinsic facton. 17 1fi

Abstracts uE llcpxorts Fach recipient of a grant-in-aid from The Council for 'Iuhaccn Re- scarch - U.S A. is responsible for the initial presenlatiort or publication of the results of his research at scicntific meetings or in appropriate scientific jcwrnals. Ftdlnwing are al.stracts, approved by the authors, of reports on new eRperimental research acknowkd6ing support from The Council that have appeared in scicnlific Kwrnals since publrcation o( the 1966-67 Report of the Scientific (hrcctcx. '1 he name of Ihe grantee is in italics. These abstracts have bcen grouped under thesc headings: I. Psycho- Physiological Studies, 11. Carcinogenesis Studics, I11 ('ardiuvascular Sys- tem. IV. Respirattxr System, V. Neurophysitdngy, VI. Studies at the Cellular I.cvel, VII ('cll and Insuc Culture, ViII. fpidemioloRy, IX Pharma-:ology and P.rycho Pharmacohrgy, X. Metabolic Studies, X1. Chemistry an-F Bio- chemistry. XII. Other Sludies, and X1I1. Reviews. 1. I'rycho-PhyaiofrrRicrn[ StudiPa ALTCRATIONS IN TIIE 8I:IIAVIURAL ANO 111(X'IIF: .MI('A(. EFFECTS UF Ii1.EC1R()CONV(11.SIVN SII(K-K WITI1 NIC(YIINE Flectroconvulsive shnck (F.('S) adnunmtcrrd tu esperimental animals riRftt after condrtioned-response training priKlu.cs a rNrr,grade arnncsic effect. In eapcrimcnts wherc mnc wrrc IacUCrtcrl with nrtraunc sellatc, this amnesic response to shrxk was srfnrhrantty hhalcd by thc JruR Ihc attenuation of the relrogfade amncsn w.r% pirtrtutarly apl.arYnt whcn drug treatment was given 45 to 60 minutes fauir Irr trarnarg Ihc high incRlcnce of conditioned response retention in drug trcatcd nirce was paralleled by  reversal of the predicted cRcct of L'CS upon brain senNonin levcls. While the rclationship between ECS-induced clevatitm in whole brain scrotonin kvel and F.('S induced retrograde amnesia is n<>t necessarily causal, the niccNinc-induccd reversal in hcwh areas of the customary F('S enects sug- gests a postibk corollary of the drug-irxluced facilitation of memory con- solidation. E.-simon, W. F.. Steinberg, M. L. and Golod, M. 1. Ptychonomir Srirnrt 12 ( 3): 107-1 OR, 196R. nth.r Rrnntnr: National Institulcs cr( I Icalth. Front the Ihpartmenl of PIychr>tr~gy, Oucens ('ollcge of the ('ity (Inivcrsity of New Ytxk, I lushing, N. Y. 1AS1l; IIIR[SIIO1.1)S IN 'IWINS ANI) SIItLINGS l aste threshrdds for hydrrtifiluric acid, quinine, aud 6-n propyldrioura- cil (1'Rt)1') wcrc dctcrmincd in pairs rrf munu7yg.rtrt' tM7.) twins, Jvygr+tic (1)7.) Iwins, and siblings (SIB). The numbers of pairs involved wcre 75 MZ, 71/ I)/., and 7R Slli, for the latter two compounds; 26, 45, and 45, respcctively, for dre acid. Significant differences in intrapair valiance werc found ( I) between the MZ and the same-sex I)Z pairs in thresholds for bittcr-tasting PRUP, and (2) between the male MZ pairs and the male UZ or male SIB pairs for hydrochloric acid. The difference in intrapair thres- hrrld variance was not significant for bitter-lasting quinine. Intrapair differ- ences observed in the ML twins indicate that nongenetic (actors also influ- ence taste thresholds. lhugs, smoking, and the menstrual cycle are among the environmental factors t:ut may aRecl taste thresholds. Other obscrva- titxu showed that, with all three contpounds, repc a.ted taste Icsts on the sanre subjects yielded high numbers of results similar within a single thresh- old range. Also, in 31)R subjects, ccxrclatiorts between thresholds (or the different substances were positive and significant. Kapfort, A. R., Fisher, R., Karras, A., (3rifftn, F., Powcll, W., Marstcrs, R. W. and (ilanville, (:. V. Acra (:enrrirae Afrdiruc rr CcmeffolrrRiae 16(3):229-244, 1967. Ot'h.r grantor: National Institutes of Ilcalth. From the 1)epartntent of Genetics, Clevcland Psychiatric lnstitutc, l'Icvr land. • I 1'FIYSIOIACiICAL ANU PATIIOL(Xi1CAL CORRlil-A I IiS 01: E)II'FERENCES IN TASTE ACUITY l he effects of various parameters (genetics, dietary prcfercnces. age, sea, smoking, biological acutty, personality, mcnslruation, dutxlcnal ulcers, and gastric ulcers) upon taste acuity are surveyed in this relwrt. When nxinu7ygutic (M/.) twins, OizygtNic twins (1)Z), and mxMwin sibling (SIR) pairs were tcstcd (or intrapair differences of taste thresholds, it was seen that Ihe intrapair differences in the MZ pairs were significantly Icss than in either the UZ or SiFI pairs. In other studies, sensitive tasters of quinine and 6-n-pnrpylthinuracil (PROP) reF+orted relatively large numlrcrs rd fo«Kl dislikcs and a pre(crence for mdd-tasting foaxls, comparcd tu inscnsitivc tastcrs. -Ihe xnsilive tasten included a relatively hiEJr pruprxtinn ul nrm- smukerc, compared to the insensitive taslcrs, who includcd a relatively high proportion of heavy smokers. Taste threshold was ncN found to hc relatrd to age or sex when smoking habits were cspcrimcnlally cuntrrrlled, but heavy smokers were observed to manifest decrcased taste scnsitivily with increascd age. 1'hascs of the menstrual cycle were srmtctimcs a.srK•ialcd with significant changes in taste thresholds. Apparently, hiRh taste sensitivity for Ixrth quinine nd /'ROI' may be assrKialcd with hiRh gcncrol systcmic rr- at'tivity, and vicc vcrsa 'I hcre also a'~pcars to tic a INnsd.lc aa.rriati~rn with pcrsun;rlily di/lercnces. Imlividual JJkrences in tasle acuily pattcrua, rr latcd tu Frrth genetic and nrxrgenetic variables, have also 1K•en assrK iatcd with significant dillcrcnccs in peptic ulcer pathrdr-Ry. UurKlcnal ydtcr 11.1 ticnts, as a grr.up, were signiftcarntly more acnsilive lu thc taatr ul 1'I(/ lt', but not rd yuininc rx hydnx•hloric acid, thrn either gastric ulccr paticnts of nonpaticnt c-ntrols. IR 19

Kal+lnn, A. R. Prngrrrt in llumnn Rrhaviur (;cncrirl, F)ahimure: luhns llupkins Press. 1969. pp 11- 66. (hh.r Rrnnror.: State of Ohin, 1)epartment o( Mental Ilygicnc and Cra- rcclion; and the Nalir,nal Inslitulcs of Ilcallh. Frnm the I.atxxatury of Mcdical Genctics, Cleveland Psychiatric Instilute, C]eveland '1111? !)IS(-nNTINIIATION OF CIGARETTE SMOKING: A MUI-7IPI.E !)ISC'RIMINANT ANAI.YSIS Multiple discriminant analysis, a technique which permits analysis r>( categorical dependent variablcs, is described in this paper. 'Ihe slaled technique was applied to an analysis of the relationship between a smt,king discontinuatit,n lypt,logy (smnkers, smokcn who have been unable ta quil, and quillers) and 11 psychological ard socinlogical facttxs theoretically rclaled In srnnking behavior. 7he II indcpendcnl variahlcs studied were: (I) average daily cigarette consumption; (2) mention of specific present health ailment; (1) smr,king behavior of wife; (4) aRe; (5) educatNM; (6) age when started smoking regularly; (7) chance orienlaliun score; (R) e+ttraver- ti(.n scfqe; (9) neurr,licism scrtte; (Itl) consumption of hcer, wine, or whiskey; and (11) Ilr,rn's attitutk tr,w,rd smoking scale. Using Ihcsc vari- ahlcs, a ma>timurn (IkeIIINMN) (llnllN,n (nt eich sml,king group was cr,m- puted in nrdcr to stuJy gpr,up crMllifurihnns in the prcdiclr,r space lhe results of this statistical sludy are inturf.,,ratcd in Ille hdlnwing related abstract. Straits, H ('. (Karr, F7du,l Srudirt nnd lJrurr in Smr,Arnx lrrhnrr.,r, '1 ucsrm I he l)nivcrsity of Ari- zona Press, 1967. pp 79-R1. RIiS(1ME UI-' '11I1i ('lII('AGO S7lIUY 01: SMOKIN(: Ill?11AVIOR In order to examine the pnx•ess of giving up cigarette smnking, per- sonal inlcrviews were conducted with G,ur groups of males: nnnsmr kcrs, es-srm,kers, current smakers who tried hul were unable lu quit SmckinR, and current smokers whu had never made a serious attempt tu stup sm„k- inR. In additirm, brief interviews were cnntlucled Willi the current asstf-iates (clnscst relalive-- usually Ihe wifc, clnscsl friend at wurk, chnest friend away frum wtNk, and family doctor) r,f the resprmtlcnts in nrdcr to eaanline interfxrsrmal cnvinmments An alleny,t to r;tl,p s,nr,king was aarwiatcd Willi the prescrxe uf physical ailnlcnls (cspcti:dly Ihtnc ca-ily cr,nnc(tcd Willi snloking), heavier tobacco cnnsumlHir,n, less sul,lnulive intcrpersr,nal environments (I,arlicularly if the wife was a nnn.rm,ker ur an e><-srn,-kcl), a relatively unfavr,rahle altitude /l,ward srn„kinR, and a nr,n fatalistic r,ut- 1rw,k r,n life Sur ressful quitlers trndcd h, f.c r,l,lrr anrl lu hnvc the alw,ve- mrnti,mrrt char:,,trrialics (wilh Il,e er,el,ti,al n( I:,lalisrn) Irr a Frcalcr , tti n/ Ih.,n IL••~i im.,l•Ir 1„ %1,-1, Slrails, 11 C (Knlt. I:Idru). .Studn•t mul lsrucr in SrrurkinR Rclravirrr, Tucson: l he llnivcrsity of Ali- rrma 1'ress, 190, I,p 7)-7g. Fn,m Ihe lkparllncnt of Suciology, University of ('hicagr,, ('hicaRu. TASIIi, OIX)R, ANf) TAC"T'1l-G UISCRIMINA'1:ON llliFORI? AN!) AVf I:R SMOKING !)iRetential sensitivity was measured before and after sntuking a ciPa- retlc by seven snlokcrs, using sia mmsnNrkers as controls. Stimuli cunsi.tcd of the tactcs of slcruse, sodium chloride, citric acid, ca0einc, and quinine hydnKhloride; Ihe txftm of vanillin and 2-hulanonc; and Ihe viscrnily Pro- duccd by a carragcenan gum. No significant "just noticeable dillerenccl' were ohscrved between smukers and mm-sn>okers, nor before versus after smoking. 'I-herefore. the data supcxled neither Inng-term nor sharl-term in- fluences of cigarette smoking. Practice eRects were noted among the control gruup, as mrxe correct resprrnses were obtained on the second than on the first set of sulutions in most of the test stimuli. I'nnxhr.rn, R. M., TraMre, 1. M. and flarylkcrPikiclna. N. 1'crcrydiun and P.rychrrplrytic.r 2(11):529-512, 1967. Frcxn Ihe University of C'alifnrnia, 1)avis. 1'fll?('t O1' ('I(iARf:7-fl: SMOKING ON PAR(YI'IU SI'.('RIi71ON l he eRccts uprm unilateral parotid secretion 44 indcpcndcnt visual, taclilc, nlechanical, nlfacttxy, arKl irrilational slimuli asslKialcd Willi srn„k- ing were mcasurcd in a small graup tA smukcn nnd ntrosrn„kcrs I llc I,acc effect r,f srnr,kiog per se was eslahli.hed se'taralcly using a);n,up of SII su/ukcrs. In all gruups, smoking Irrr rr slgnihcantly increased pan,(id secretion (1 5 to 2.1115 tinrcs greater than resting Icvcls) Silnple 1•rclhlc, dfactury, and vi.ual (watching another smoke) stimulalit,n I,r,oluced nn significant difJcrcnces. The act of drawin~ through an unlit ciparcllc and of inechanical hlrKking of the rn,se, causing muulh hrcathing, resultcd in siRnilicant incrcascs in secretion Snloking a ciRarcllc while wcaring I;npl•Irs which cumpklcly climinalcd visiun pnwluccd considcnl ancl hil•hly sl)~ruli- canl dccrcascs in sc.rcliun crnnparcd t„ smr,king withr,ul visu:rl „hslrur- lir,n Since rcalin/ kvcls alsr+ wcre Inwcr wht•n visirwn w:rs I1LK kcrl, it Is snfp-slyd 111.11 Intrr(t•rcnle Willi Incnt.ll l,.ncCnlydUwn m lllt(nUmn rc~ullr,l in inlnhdinn 44 «, rcliun which is undrr aultwrumic t uuur,I Ilarylkt,t l'ikiclna, N, I'nnrtborn, R. A( and Shannr,n, I 1.. ArtlnVfJ o/ I!nvin rrrn~nlnl llrvdllr a7(S) 71) 71R, 1968 Frnnt Ihc I)c1+:rrlmcn/ nl Vrw,d Scirncc and 'Icthnolnry, 11„i,cr"ly ~d ('aliltxnia, I)avis. 21

E1SITEII.NI:SS OF I'(iFR RAl1NGS (>1: t'NRSONAI.IIY IN FI)UC'A'1 tONAL RIiS1:AR('ll 1 he rclatitxnhip between personality nd academic success, thnugh recr+gnired as im~+cxtant, is not well urxkrttaxl. 1)a1a repuled here (ctm- IriMrlcd hy 1,42R students from colleEe, high scMr)l, and nursing schtMd) indicate that rccr ratings of personality can be hclpful in clarifying this clusive relationship. E/sing this metlwJ, rafers e>tamined each of 42 hipdar r rsrrnalily Irails nd selected the five members of their pxr gn,up nun/ c the left hand {xde (positive nominatitxu) and the five most like its of+posite on the righl (negative). The theoretical rationale umkrlying this rating method and tlre mctlxulalogical probkms encountered in its use are disrusscd in delail Results are presented conccrning the reliability and factor analytic structure of peer data nMained in all three fxq,ulalions studied, and cnnrcrninR the prediclive vatidity of pecr and mm '~cer data obtained in one sample of 349 college students It was concluJeJ that Ihis rating system is a valid and useful one, and, particularly, that the peer variables hehrnRing Iu the factor called here "slrenRth of character" are impxxtant rxminlrllective eorrelates of academic tuceess. Smirh, G. Af. f:durorivna/ and I'tvr hrr6oRiro/ Mraturrmrnr 27(4).967-9R4, 1967. Othrr Rrnnrorr: Il S Public Ileallh Scrvice and Spaulding Polter ('har- itable 1 rusls. From the Ikpartnrent c,f Anesthesia, Ilarvard Mcdical Schoul, and Ihston Elniversity, Ekntun 11. (:arrinrrgcrer'si. titrulira Animo/ Experiment. 111JPA11C: CAR('IN(xIENFSIS IN ('11A/('h/Sc MI('E? ANl) ('b/Se RAIS hY ISONI('UIINIC ACII) Ill'URAIIUI: ANt) I IYURA7.ING Sl11.P11A1 l? I rrr appro>tirnalclr ten ycars, rcccarch in this latwralury (in iscnict,- linie atid itydraride ('NII) has IKxn Jircctrd luward elardying whcther INII and its dcrivatives (1) act carcin„rrnicany in lung t'antrr reso+lanl mice and in rats, and (2) induce tunu,rs in muuu and tat Iissucs rrthcr than those of 11re lung. lhe rresent palxr sununarires this actunwlalcd wtnk and puts tpecial enq.hasis ufx,n tlata perlaininR to Ihe numlx•r, inci- dence, nd induction time t,f turnqrrs i4 thc liver in c.pcrimental rnitr anJ rats On Ihe basis nf the accumulaled resulls, it ii cmncluJed that a njaliK- nanl /umur nray result from the use tA INII lhe validity r,f Ihis t'unclu- sio,n is attcstcJ to by the fact that hydraiinc, which has bcen shuwn to tK tartinr,Kcmc, is the prrrxipal mclatw.lttc ol INII Sevcri, 1.. and Niom rfi.,ri, ('. I.-urmJrr/ drr lYnnunal ('onter Institute 41:331-349, 1'76R. Ilthrr Rrnnt.rr: Anna Fuller Fund. From the 1)ivision of ('ancer Research, University of Perugia, Italy. E/t:IRASIR(Il'IURA 1)1?1 'IUMORI POI.MONARI INIK)7-1I ('UN IURAY.INA SU(.FAIO IN 'IU1'1 IIALtI/c/C'b/Se 1 he ultrastructure of pulnN,nary tumors induced in 16 (iAt.ll/c/('h/Sc mice with an ayucous solution of hydrarine tulphale was studicd hy light and clectrun nricrrscnhy. tlrxkr the light micnscupe Gre pulmtrnary turutus werc c1•rssificd ns srrlKl arwl papillary atknomas slwwing st+nrc dcgrce of anald:nia. t)ndrr the ckctrun microscrpe, a chnc similarity was (uund Ix Iwccn Ihe atknumalous tells and normal alveolar ccl(s suggcslrng au alveolar tttiFjn of such Lulmorury tumors. The eresense u( Ihrcc lylKS u/ viral particlcs, namcly: rn,racisternal 4A> parlrcles, elongalcd or tuhular parliclcs siluated in the cislcrnae of endoplasrnic rcticulum, and inunalurc C particlcs, is rcfxulcd here. Bucciarclli, E., Rrnncifiuri, C. and Rosi, F. l,ov../nnr. Pat. l'rru)tia 2R(I):41-55, 1968. I)tlh.r grantor: Anna Fuller Fund. From the 1)ivision of C'anccr Research, l)niversity of Pcrugia. Ilaly. 1?SISl1 NLA E)1 lIN I~ATTOR1: ORMONI('O NIa I.A ('AN('I:R(X:I:NFSI I'()I.MUNARF . DA II)RA"1.INA llx sp.ntancous incidence of lung tumors is low in intact virgin and pmadretomircd ('11A/C'b/Se mice of both sexes. IliKh daily duscs u/ hydrarine sulphate (h s ) increased the incidence as (ulhrws'~ intact virl;ins: malcs 7I.%., fcnialcs 91/%.; gttnadeclomired: malcs 72%, fcmalcs RII^,- Il.s. given in smallcr dtncs is nwre active in fcnule than in uudc virgin r»ice. In grrnadectr,mired mice, the lung lum(x inciJencc is lower than in the treated intacl virgins (a11Kit hiRJrcr than in unlrecdcJ cunlrt.ls), and Ihc dillcrcncc Ix•twccn tlrc sexes practically disappcars. I)aily du.cs rd t) 56 mF of It s. gave R7'"• lung tunaxs in inlact (cmale virRins and N/;t. in inlact virgin malcs; (12R mg daily gave 56'iS •rrnd Ih"'o reslrcclivcly, and 1/ 14 mt; duily 41/%„ and 7 %. 'fhc lung lumur incidcnce in grmtadcclr,nmcd mitc was 2R^ln in fcm:dcs nd 21% in malcs with 56 mK daily, 24''1~ and 1 I'"• reslK•tlivcly witlr 112R rnK Jaily and R^,4, and I1"L- with II I•1 rng d.uly Ithcsc results sul-yc~t that a Ih4unu,nal fatl4u may Ir inv4,lvc.l in I ulnum.uy carcinr,grncsis fry h s in ('DA/('b/Sc mite liionr,151(ori, ('. Lav. Anat. Pat 1'cruRia 29(I) 29-41, 1969. (hhir grantor: Anna 1-ullcr Fund From the l)ivisirro of ('ancer Rcsearch, llniversily of PeruFia, Italy. 23 22

A('('Ii1.fiRAIION OF GROWlll OF ('IIF?MI('A1.1-Y 1NUtIC'I?1) TUMORS BY USE OF '1 RANSPI.AN fA l IUN 'I I;C-I iNI(' Previous studies of subcutaneous tumor formation following irijection of SIK/ r-g of )-1,9,10-dihenypyrenc (henrcr(rs1) pcnlaphene) have shovn that, in general, 50% lurrxrr inciderKe is reached in 11 ttr I S weeks, and I(X)% tumor incidence is seen after 25 weeks In the present study, subcutaneous injection sites /rnnt 40 donors were pr><.led and transplanted into 10 recipi- ents. When carcirnogen had been kft in nfu in the primary host I'or five weeks or longer, tumors arox from transferred injectwm siles in ttie sec- ondary hosts with great speed which was significantly incresud over the rate of tumor development observed after primary carcinogen inirction. The 50% level occurred as early as nine weeks and the 1(K)% Irrel was reached from eight to 12 weeks after the original carcinogen InCctMrn, or about threc to seven weeks after transplantation at the injectwon site. Thus, this technique shortened the time required /cw carcinogen Iesting. Results of this esperiment suggest that five weeks of contact with caninogen suffice to cause malignant transformation of mouse fibroblasts in vrvrp. 1lnmAur)irr, F. and Treger, A. C'ancrr Rrrearch 27:1203-121), 1967. Orhrr Rr.wf.r.r U. S. Public Ilealth Scrvice, Virginia and 1). K. Ludwig Foundation From the BioRcscarch Institute. (-ambridge, Mass. EXPIiRIMFiNTAL S1l1DIFiS ON lI1F. INFIIBIl1UN OF CARCIN(XiENFSIS BY ('1(iARETl1' SMl)K13 ('UNDfiNSA'fES AND C'ARC1N(X;F?N-RELAT EI) SUBS I ANCI:S A series of esPerirnents was undertaken to study inhibition of tumor growth in mice by crgarelle-snwkc condensate. llrese experiments included: (I) quantitative determination o( spontaneous lung adencxnas in female A/He mice receiving intravenoaa cigarelte-smoke condensate injections; (2) aystematic st.dy o( the lung idenoma incidence in untreated A/Ifel mice; (3) determination of lung adenoma formation in mice receiving i.v. injcctions of TcAon particks in Rin6er's solulion, Ringcr's solution lone, or denkotini:cd ksbacco tar in the same vehicle; (4) olnerva(ion of the eRecl of i.v. (njections d condensate on induced subcutaneous sarcomas, and (S) on transplanted sarea.nas. In addilirm,  series n/ espcriments was run with the derivatives o( benro(rslllpcnlaphene to determine the carci- nngenicity of these poteaNial inhibitors. Resulls indicated that the i v injec- tion (if tobacco-smoke condensate arrested thes~+~mtancrnua lung uknornas of A/Ilel mice at an early stage and inhibited thcir suhscVucnt pr+wth. Tlre growth rate of induced and Iransf.lanted urcr+mas was dnwed sigaifi- eantly by the condensate. The tested inhihiaNs reduced the number of lung tumors and reduced overall earci nic putency. 1 hw, evidence is ~e- sented here that ciRarelle-smoke corx nsale contains subdances that reduce lumrK growth under certain circunntances llnmhurgrr, F.,'1'rcger. A. and Roger. P. T'aM•nrd A I rrs llorm/ul ('iRorr(fr, National Cancer Institute Monugraph No. 28. pp 259-270, 196R. OIb.r Rrnnror.: National Cancer Institute. 1)ivision of Research Facilitics and Resources; Virginia nd 1). K. Ludwig Foundation. From the Iliu-Rcscarch Institute. Cambridge. Mass. MUDIFIfRS OF CARCINOGENESIS Sludies are presented here on two experimental systems for the testing of carcinogens in mice; namcly, subcutaneous injection and site inspection, and intravenous injection and study of lung tissue. In the first esperimental system, the eflccl of sia Jiflerent vehicles upon Ihe carcinugcnicity of S(10 r of bcnzo(rsl)penlaphene (DBP) in (*S7B1/61 mice was esamincd. I)i0er- encea in the rate of Iumtx dcvelop rnent were slriking, with average lalency pcrirx)s ranging from 16 weeks svhen peanut oil was used as the vehicle lo 62 weeks when 11,0 was the carrier. Concomitant studies showed that nxidative derivatives of UBP administered to the test mice at critical times reduced the rate of growth of DBP-induced tumors. In the i.v. sludies, lung adenonu incidence was measured in DBP-Irealed and control mice of ten variant strains. Both strain nd age differences were appreciable in these tests. llere, also, derivatives of UBP tuch as diacetuay 1)111' and 1)11P-quincxte acted to inhibit the growth of spontaneous and induced lumorc Since complex mixtures such as tobacco snkrkc, air prrllutants, and fossil fuels contain tumor initialofl, promoters, and inhihiturs, it is imprutant for this to be kept in mind when such mistures are being tested for carcino- Renic potency. llurnhurgrr. F. and Tregcr. A. 1'rrrKrr+t irt F.'rrnimentul Turnor Rrsrarch, Bascl/Ncw York: Kargcr, 1969, vol. 11, pp R6-99. O(her Rrnntor.: U. S. Public lleal(h Scrvite. Virginia and I). K. I.udwig fuundatiun. From the Bio-Rescarch Institute. ('ambridgc, Mass. A('C'FiLERAl7:U CARCIN(X&N 11?STIN(i In expcrimcnts with male ('5781/6) micc aud m:rlc Syri:rn Iraurdcrs, transplantation of combined carcinoKcn injcclion sitcs frrmt (unr 'aimary hrnts into une secrmdary host siKnfic:urlly acceler;rted lumnr Krrrwtlr in thc secondary recipient. 'shis aeceleration of malignanl Rruwth rr-curred re F:udlcss ut Ihc tirc rd the initial drnc td catcinoRcn. 1fi.trdnr~i.nl, ryUo Irrrical and cytlKhemical studies of Ihe carcinuFt•n injecur,n srlr•s tn ruue shrrwcd nn inrtial.lassical frncifn-l>taly rcacliwrn Irdl4rwinl; vilhhIc inlc4 lnm While this rcaclion rcKresscd in cunurrls, in thc 1)HI' inlcrtrd ;ronnals atypical RNA Io:rJcd fiF,rrrhl:uls incrcascd in numl+crs a.ounJ tFhc inlrr umo sitc and aaswucJ tlic Iraltcrn typical id /ihnrsarcrmoa In thc inilial inllammalory rc-'ptmsc was Icss rnarked. Ilonvcvcr- thc alyllis,J Iihiu 24 25

hlasts seen here occurred in small clumps Ihrrrughnul the suhcutanclrus fat as well as through Ihc periphery of Ihe injection silcs, 7he results rr( trtcsc euperimcnts suRgcst that the RNA loaded fihrnhlasl represents a prcnt rlig- nant cell form, which, kf1 in thc original host, tkvclrrps into fihrrrsarc irna slnwly, and when transferred into a fresh htnt, more rapidly expresses its malignant behavior. flomburRrr. F. and Baker, 1. R. PrrrRrrtr in Ezprnmrrrral Tumor Research, Baacl/Ncw York: Karger, 1)69, vol. 11. pp 354-394. Other grentorrr (1. S. Public Health Servlce, Virginia and I). K. I.wlwig Foundation. From the Bio-Research lnstitute, Cambridee, Mass. TIIF. Nfl:t) OF EXPFRIMENTAL INIULATION STl)UIIiS IN ANIMAIS FOR 1111: PROBLEM UF 'lllli INI L(IIiN('1: 01: CIGARIiI-1E: SMOKE ON THE IND(1CTION OF LUNG CAN('I:R This report stresses the great need for experimental model sys,cros which permit JupAication of the human hahit of cigarette snNrking as clrrselr as ptnsihle in lalxsratory animals. Tht autfwws review their own work witfi inhalation techniques and express a desire to stimulate concentrated ellurts of and ct>flabtxatiun between scicnlisls from varitxws disciplines nf chcmistry, biology, pathdngy and expcrimental cancer research in developing and pursuing large scale inhalatitx+ wtxk with fresh cigarette snsoke. Su;h a rNnt and concentrated pmgram would pcrmit direct analyses o( the hiu- hogical cRetls trf many sushcctcd faclnrs, intlutling air pirllulants, rcy+ira- ttxy diseascs, rathalinn antl rrlhcrs as wcll as tig.uctle smokr It wuulJ oku permit asses}rnenl and exclusion t>t thute faclurs ulxcurinR an c.act cvalua- liun between particular factors airrne or in comhinatinn and Ihe qKcur- tcncc of pathtsingical Itcntitrns, and thus it would he nf great valuc frrr clarification of causes and pathogenesis of lung cancer in man. l.euchtenhrrRrr, C. and l.euchtenbcrger, R. Zrirte-h(i/l fur Priivrntiv-Mrdizin 13:122-129, 196R. Other grantnr: ('iba-Basle, Switzerland. From the Swiss Institute for Experimental C'anccr Rcsearch, l-ausanne. RI:PROl)t1C't'IV1: FFFF.('fIVFNFSS IN CROSSI;S BETWI;FiN FIVE INBREI) S7 RAINS OF MI('E In Ihc course of ongoing genetic studics of carcinngencsis in nrice, detailed records were ke~ on ccrtain uf Ihc rcp rt~luclive uclivitics t-l micc protluced by 14 crrnxs fxlween Ilx /ive inbretl strains ('311/llrl, ('57111./ 1+1, MA/Myl, ('31IcB/Fel, and A/I lc) I lie data presented here rcprc- srnlinp tNdy Ihe first F, litlers prtnluccd hy Ihe (ruracs 14 the five parcnral sUains incluJc, for each of tlrc 14 tn,sscs, di.lrnbuti4rn of liltcrs hy silc uf liltcr; age tr( rnrdhcr at hirlh (r( firsl litter; tnlal in/ant nwrlality; R, of "lusl" Intcrs; raliu of inlatl tu tkplctrJ litlrrs; sizc (d inlad and Jchlctcd litlcrs; ^,i. (if t)c/dctrd litters in each size categttty, and sc>t ratios of intacl and depleted hllrrs. 7 his material is presented for Ihc frnelit of trthcr in- vcsligators inlerestcd in analyzing the genetics and physitduRy rd mice with di/terenl viral and constitutional faclors in various conrbinatiuns. l.ittle, C. C. and Murray, W. S. Journal of thr NatNpfal Cancer InJfltntr 42(2):219-225, 1969. Other Rrnntnr: National Cancer Institute. From Ihc lackson Laboralory, Bar Narbor, Me. C'AN('FiR(Kif:N1:.Sl FPAT7CA NF.1 TOPI CDA/(b/Se F N1:1 RAl-11 Cb/Se 1)A Il)RAZINA SUl-FATO 7 he spontancous incidence of tumors of the liver in ('BA micc is 11% in malcs and 4% in femaks. Administration ot ist.niazid (INII) tlid mlt ahcr the numhcr of liver tumors, but hydrazinc sul'thate (IIS) raiccd their incidence It. 6296 in males and 71 % in females. 'l lte avcragc induc- litxs tinrc was 6R and 61 weeks, respeclively, after start trf Irealmcnl. Ilisloingicalty these tumors were hepatocarcintxnas. In ('b rats, liver lunwrs were olrscrved in fuur out uf 13 IIS-Ircalcd rals and in une uf 49 INII- trealed animals. Spontanetws liver tumtxs are never seen in ('It rats It is emphasized that a malignani tumor could originate (rum tlrc use uf INI1 I Scvrri, l.. and Diancifiori, C. F'pmnrfnRia 13(2):199-20R, 1967. Other Rrnnfor: Anna Fuller Fund. hrom the 1)ivisiun of C'anccr Rtsearch, University of 1'crugia, Italy. TIIMORIGUNESI POI.MONARF, ('ON O SI:NZA INFA/(II 1)A I-I.11OR(X'ARUON, l)A ISONIA7.IhG (1 IURA'LINA SU1.1-A1U IN RA I 1( ()SIIORNE-MI:NIN:L/Sc (hhornc-Mcntkl/Se rats of both sexcs, with and without Ilwtrticarhlrn- induccd nrulliplc pulmonary inlarcls, were irxrculalcd intralxrit0nc:tlly with high doscs of isuniazid (INII) and hydrazine sulphalc (IIS). I.unF Iumrus dcveltMxd in Iwo male rats treated with INII ant) in fuur 11% injcclcd tals Pretreatment wilh Ouuracarlxm did nu/ enhance the action rtf INII and 11% as could hc clearly seen by the fact 1ha1, u( the sitt tuntors, three tlcvcLqTd in Ilutatkarhtwr Ircoled rals and the other three drvclulx•d in rnls withmut OuunK•athtm induccd pultntutary inf:ut/s. IlistoluKically, Iwtr rsf Ihc lumms were early atknonurs. Iwu paprnary cntcinrunas, unc ana1rla~tir rart rn"mu artd tme undi/lerrntiated cpitkrmoiJ cnrcirHrina Ncithcr /N11 nrrr IIS was t'alrahlc uf inAucing squarnuus mclahlasia even in hrunthi oud hrrrnrhnrth enclorud wilhin pr.nunlarct uirndie areas In adArliun, Ihrt•r r:r/s rnrK ul:rled with IN11 dcvch.twA tlrar ccll t'rrtimmrns rd thr knlmy Ilrts kr'lnry t'arcinuma is a lunrsrr which ducs not t><tur slwntancuu.ly in t6c ulncro,cd strain of rats. 26 27

Ribacthi, R. and Giraldo. G. (Scvcri, l.ut in) (.av. Anar. /'or. PcruRia 28(I) 5-19, 1969. From the 1)ivision of Cancer Research, University uf Perugia, Italy. ('AN('E ' RS INUtI('1a) IN UIfFERFNI' SPIi('11:5 llY ('UN f INIIO(IS , RAUTATION Although s/xcics and strains o/ animals differ in their tcnt:cncy to develop tumtws srt,nlaneously, radialion cacinuRcnesis Icnds to ovcrride cspccted diHercnces in susceptib8ity. A y source t>( continutros radialiun (cobalt (H/ wires) implanted in young adult rodents and capablc of inducing canccrs of the types expected in this sptcies, will also prtnluce cancers which rarely tkvelt,p spontaneously 1 Etese are epitkrmtad carcinonta td tfte esopha8us and lung and, also, tntct>Renk sarcoma F.Lcrirnests with micc, rals, harrntcrs, Ruinea I+iBs, anti dwarf rabl.its show Uut the ral appears susceptible to lung cancer; Ihe mouse and hamster slightly r.uscepli- ble to tnteu8cnic sarcoma There appear to be Oplimal drne and dtne-rale ranges frx carcinogcnesis, but thcsc may be obscured by biological varia- lions. f4'arren. S anti (iatcs, O. Archiver n/ Envirnnmrnrot llralrh 17(S) 697-7(14, 1969. nOther Rrnnrtrr.r U. S Public Ilcalth Srrvice and Atomic Fnerfy ('um- mission From the I alMnalowy of 1'ithM--Fy, IL~~.irJ ( an,rr ('iunmic~i ~n, anrt thc (•anccr Rcscarch Instttutc, Ncw I rtl•LjnJ Ikdtunta Ilrslntul, (:linir•ol Inrr•sfiRafirrna RIiSII)IIAL CIIROMOSOMAL A13fiRRAlIONS IN FI:MALE CAN('ER PAltENTS AI--fF.R IRRAh1AIlON 11Il:RAPY After thcrapcutic irradiation c><{~ostrre, residual chromtnomal defccls were repeatedly seen in the culturct) I)mplttxylcs of 14 patients studied. Radiation ellccls were assessed by analysis (r( cells frur» serial, s~ntcd pcrinceral Mmnl cultures obtained durinK arKl allcr Ihcrary. 'Ihe rnilial and nttnt imnxdiale eRecls were quantilalivc, anti affcclcd the rrcyurncy of eclls with chrtNntntrrne conrplements devialinR frunt Ihe nrxnral cunytle- mcnl of 46. llris increase in the numbcr o( ancuPhrid ccllt rose tu a Plitcau thrrinR therapy Althtw8h by rnte year after the crrtttlusisrn id Ihrrapy Ihe numl.cr of cclls with Ilte normal trrnqrlcmcnl u1 46 chrnmu.rrmcs LcKart a shrw rise to Prctrcalnxnl Icvcls, Pt•rsisling slructural alxrrathi-ns ul the thrinnrnrnncs wcre sccn long after the tcrminalirm uf raclialion Ihcrapy. Arnmrr.rr, A. I'.- Plotz, 1? J. and Slcin, A. A. Ft tlrcrinrnrtnf and Molec,dar I'adroLrRy 7(1):58-91, 1967. 11rh.r Rrnnror: Antcrican Cancer Society. From the fkpartmenl of (Nntetrics and Gynecology and the Institutc uf Espcrinrcntal Pathology nd 'inxicolo8y, The Albany Medical ('ullcge (>t Union Univcrsily, Albany. N. Y. t.A RI('I:R('A Ula.l.'ASI)ESlO NE:1 T(IMURI MA1.1(;NI PRIMI7IVI 1)1?L POLMONE Forlr-cirJrt lung cancers, collected over the Ihree-year pcriotl 19067. were analyred itx asbcsha bodies. Oihcr p+ssible causal facturs suth as smokinR and the prult.n(Ccd adrninistralinn uf drugs used in hrlrcrculusis therapy were vlso crmsitkrcd. Of the 4111 cases sludicd, 23 were srra at nccrtqny anti the other 25 at surgery. Ilis/olo8ically these lumors wete as fulluws: anaplaslk (69%), squamtws (22%), adentkarcinutna (4^G0 and nrirtcd (4%) in thc necrepsy malerial; anaplastic (2R7o), squamous (5670), adt•nncarcinoma (4%) and mixed (12%) in the surgical ntalcrial Under Ihe given experimental conditions, no asbcslos bodies were found in Ihcst IunRs. As rcl;:uds Ihe tNher facltxs studicd, o( the 23 necrtq.sy ca.cs, 15 had been srntrkcrt, scven had been treated over a prMracled PcritKf with drugs uscd in Iuberculrrsis dterapy, arwl four were ExMh smukcrs and had had anli- luhcrcuhnis Irealment. Analysis of this material showcd that clinical diag- nosis anti diaRntnis at necropsy are still dillicult. 'Ihesc ubst•rvalirrns serve tn limit tbe value of statistics on Ihe incidence of lung carcinrNna. 1'eactK•k, 1'. R, Riam-ifirrri, C. and Bucciarclti, li. l.uv. Anar. I'ar. l'rruRia 28( I):29-)9, 1968. Frum Ihe llnivcrsily of Peru6ia. Italy. 1?XAMINA'f1ON OP Ll/NO SMIiARS I-OR ASI1F.SlOS BO1)IIiS IN 109 ('UNSIi('(IIIVr: Nti('ROPSIfS IN PI:Rl1GIA Smears prepared frtxn the necropskd lungs of 109 Lerstms dying of various causcs were examined mkrosttq.kally fur asbcsltn twulics. 1•ivc ol the pcrst„u nccrupsicd were Ieenagcrs, and the aKcs nf the ulher aubjrcls rangcd /rnm 23 lu 9(1 years. Ashcsttrs Mxlics were found in rmly unc caae, an R1-ycar-old man in whom two ashesttn btKlies were dclrt'tcd All hul 11 rrf Ilrc Pt•rsons ncerulnicd had bcen residcnls rd Pcrugia. a nmn irnduslri:J city, ra rif nciyIiIwirinR small tnwns and villaRrt in tlnttai:r 'Ihr I4iw in tir(rttcc ( I%) nrdrd in this rural area stands in auiktnF cr.mr;rtl In thr 211'X% tur nnnc incirknt'c rcpKlctl hom nuny other Parts td Ihc wrald widr ulhrrwisc cunyratatrlc hospilal IN'pnlati,Nrs and lalwualtery I.rtihtrc. . 1't•acrKk, P R, Rr'nnrfirra, ('. an4I ISu.ciatclli, I: liur,yrrnn Inu.nrd rr/ ('unr er 5' 15 5 15 R, (969. 1--rum the Ilnivcrsily of I'erugia. Ita1y. 29 29

RI:fROSPI:CIIVIi SIiAR('II FOR ASRIiSIOS 11OUII:S IN Nli(•RUI'SII;S ANI) /f1Ul'S1f;S ON ('ASL'S OF PRIMARY MALIGNAN f I)ISEASI? O1~ 1 I IE 1.(JNG A total of 53 primary malignant Iumors of the lunR, diagnosed be- tween 1965 and 1067, were hislolo6ically confirmed. All the lumors, with Ihe exception u( five observed in scalene node biopsy, were re examined for possible assru'iation with asbestos bodies. No ashestos bodies were found in any case Smoking and antituberculosis drugs were also invcs- IiRated as Pxnsihle causative factors, but it was not possihle to establish a definile asstxiatitxt with the (umors. (H the 53 lumtns, 39 werc in srnokcrs nd 14 in MM- or es-snwrkers. Anlituhercutosis drugs haJ been used in seven cases in which there was also active pulmonary tuhcrcuhnis assuci- a/ed with the malignant disease. Peacock, P. R., Rinncifirrrl, C. and Elucciarclli, E. F.nrupeon lrnunal n/ ('untrr 5:147-133, 1069. From the Universily of Peru6ia. Italy. l1N T RFATFb Ilt.AhUFR CAN('FR: 31 AUfnPSY CASES Tumrrr histology and patterns of spread were studied in these 31 un- treated blatkkr cancer cases. Nu metaslascs were found in I I cast•s, cipht patients had mclattases in regional nrnlcs nnly, eiPJrt patients had mctas- lascs in regional mKlcs and elsewhere. aud four patients had nrctattascs at sites other than regional r>,Klcs lhc frryucncy uf mctaslacis in this serics, as in scrics of hcaleJ cascs, is relatrJ Iu depth r+( lumur penetrati++n in Ihr bladder wall anJ to bl+w+J vcsscl mv,rsnrn by lumr+r IlnttduKically. Iransi- tional cell carcinonia was sccn in IR ta.cs, cffrJcrnund carcin+rma in II) cases, and fxw+rly drfferenli:rtcJ adcn+K art inr+ma in Ihrec. ') he histologic grade nr type of lumrrr was nu/ appircntly related tu either the dcKrec of estensitm or Ihc distribution of nrctaslascs. Frirdrfl, G. ll and M('auley, R L. The Journal of IlrrrlrrRy IIN):293-296, 19hR. nth.r Rrnnror.: U. S. Public Ilealth Scrvice and Atomic Energy ('um- mitsion. From Ihe 1 alwualory of Palholr+Ry, PrmJville Ilr+spilal, Wallxrlc, Mast., and Ihe Cancer Research Institute, New England lkaconess Ilospilal, buslun. lII1? VAS('III.AR SUPPLY lO MFIASI-A'll(' '1(1MURS O1 IIIIi 1.UN(7 I'ulmonary arlerial anJ venous patlcrns in 44 mclntlalic pulnu+n:uy nc+qd:tamt wcre invetthRated hy meana r+f vinyl ncclalc cr+rrrni+m sfwt nnrn%, r+n ntf•tvnq ral+hit' r.nminatirrnt, an+l mi+rmrnfjvltr:y+hii late stnrhrs I hc vinyl att•Iare s/xtirncns rcvcalcJ ccntral nvaaul:+r arras with Ix.+lu.c fa•riphrr:J l+ntm"rn:rrv :rrtrrial anJ vcnr+n. :nlti+rrnrtiun Micrr+stry+ic stuJrca Ir+4 .I. I J. h.. ll. ++iJ,n„ +d la,lh Lnlrm,n.nv .rrtrri.rl :mJ vt'nuuc vrl+l+ly in all spccimcns. •Ilte histologic tlemonstralion of pulmonary arleri+dc- vcnulc shunlinp within Ihe ntulules supporls this previously /w+dulatcd mctfianism for hyl+rt.cmia in hematoRcntNrs spread mrlasl:dic pulmunary nctrplasms. Signrficanlly, the denwmstratitns o( arterial presence in all mctaslatic pulnronary neuplasms studied lends supput to Ihe cuncepl of pulmrmary arterial infusion themothcrapy fur metasutic prdrnonary Jisca.c. hronchial artery infusion is, however. the rtwte of preference (ur brun- chuRcnic carcinonta. Millrr. R. lL and Rosenbaum, A. S. .Slrrlrrry, (:ynrrnlr+Xy ti Obsrrrrirs 12S(5):II)09-1012, 1967. ntlrrr Rrnnt.rr: (I. S. Public Ileallh Service. Frr„n tlte I)anicl H•auRh Institute of Anatnmy, 1cRerson Medical ('ollvKc, Philadelphia. STtll)II~S IN "1111? lillO1.(x;Y ANI) PREiV[iNflON OF Itt.Al)1)I R CARCINOMA I:xcrction of 3-IIOA and 3-110K before and after thc aJrninislration ttf a 2 gns Iryptophan loading dose was evaluated in notmal individuals, Paticnls with a history rr/ bladder lumor, arnf smokers. "1 his samt• cvalua- tion was rc ateJ after nral administration tr( cnuuph ascorhit: atiJ Iu secure siFnif~ant ascorbalc kvels in Ihc urine. Smokcrs were included in this s1uJ~ because of previously publishcd ubservalirrns sup);t•ain); a rcla- lirrnship bctwecn cigarette smoking and bladder carcint„n:r. Ntr dillcrenccs were seen in the urinary excretion of 3-11OA and 3-I1OK arurnrK the Ihrec gruul.s. I kterminatic.n of cinnaharinic acid (cumprwnJ I V) was fuunJ to he significantly higher in the urine spccimens fronr p:rticnts with a history of bladder luonrr, dun in the urine from norrual nr+n-smnkcn Ascurhic at'iJ adutinislra(iors uniforndy prevented consfxrund 1 V fuunatbun When urinary chemiluminescence (('1.) was measured. Ille mcan rnunl appcarcd cun.iJcrahly higher in urine specimcns from palicnla with a history of bladder tumors and smukers than in urinc sl+ccimcns (rr m mrrnmal non-smrrkcrs. Oral administration of ascorbic acid suf+f+resscs (l in all instances. Sr lrlrXrl, l. 11., 1'if+kin, (7. F., Mishimura, R. and I)nkc• (: A. 7lunurrrinnt u( rbr Amrrirun AtJrKioliun .+/ (:r.rnu-I/rrrrnrv .Irn/rr+nr 60.14-21, 19hR. Othrr Rrnntur: Nalional ('ancer Inslilule. I-'rom Ihe Ik•I+arlmcnl r+f SurRcry. Scttion of (1rulrrFy, 1ul:rnr tloivrrsily Stlurd of McJrtrnr, New Orkans. I h11'1ASIAIIZ/.n/IONI{ 1'O1.MONARI? Ii A1.1.(1IRAI'IANIAIIII 1IA (SAR('OMI MIIKINI I)A MI: III.(YIt.ANIRI•NI-) In a study uf nrclattalic Rrowdu JcvclrqrinK in thr lun/;. Ihrr c mrrhyl chr+lanlhrcnc-inJu+cd munnr sarcr'mas wcrc Ir:msld:rulcJ rn .r•nrs aml thc IKhaviur +rf the Ir:ur.l+lants was oh.crvrJ I:xannnalinn fur lunl nr+t.r.l:r.ct 31

in Ihc rrcipiemt of the ttrain specific lumnr iarfraftt gave t'nntlanlly ne0alive results, even in the cates whcre the Rralt h:rd hccn rcnuwcJ to prolong the life of the mr.use Asf,ecific suhlincs uf thcsc lum,qs Rave risc In lung mclastates only in the rccipicnts from which Ihe graft had been surKically rcmrtvcd 'Ihe highest irx:idcnce of lung mclastaat (3A 5"7,1) was in the recipients rif atrecific lumnr isngrafls from which the Iunux had hccn surKically renroved during the third or fourth weck. f ussitde faclrrrs allowing the IunNrr cclls spread by the primry growth In survwe and mulliply, in spite rr( the immuniralinn of the recipient induced by the antigemcily of the tumor, are discussed. MaltVeff, N., (Srvrri, l..) l av- ,/nal. f'ar. 1'rrnRia 2R: t 29-144, 19hR. Fnrm Ihe 1)ivision of ('ancer Rcsearch, University of 1 crugia, Italy 111. (:nrrtiornscttlnr Svafem llrerf A ('OMPARAIIVI: S/IIUY OF NIIR(X7LY('FRIN ANI) PRO1'RAN( )LOI. A newly dcviud strain gauge cathctcr was utcd to measure the action of suhlinguwl nitroglyccrin and mlravr•rnrut prrqa.rnulul on slwnlening of right venlrit'ular fihcrs in paticntt wrlh and withrrul coronary arlcry dis- ease. Ilcmrxlynamic pararnclcrs and changcs in Ihe nsidatirtn rcductirrn prNenlial of hearl muscle were also drtcrmincrl Nitroglycerin dccrcascd ahortening and vchxily of .htrrlcning nf vcnlricular lihcts in n-mm:d anti artcriusclcrolic suhjects Alw tfcctcated in LtNh Rruu~s wcre Icft vcntricular cnd-diaslolic and syslemic pressure, Iensinn-limc indca, stroke inJcs, peri- rheral resistance nd left venlricular minute work, whereas heart rate was mcreaccd Intravenrws pntpratNdol Icd lu a fall in vehtcily of sh<xlcning uf myrxardial fibers, heart ralc, stroke imkx and left ventricular minute work. Ilowever, there was an increase in lensiun-timc index antl peripheral re- sislarxe with no change in syslcmic pressure. Lcfl vcnlricular cnd-diastrrlic pressure rose significantly in artcrfusclcnNic paticnls.'Ihe tnycxarJial nxida- tirm-reduclion potential increased after nitroglycerin whereas it fcll after prtrprandrd in nnrmal and artcrirnclcnrlic patients. Rrrhin, I' , Cnwan, ('„ Puri, P., (ianguly, S, Ik Flrryric, 1: , Martincr, M, Stock, T and 1lrnR, R. 1. ('irr nlanrrn )6(2):175-1 R6, 1967. (Itfar Rrnntnr.r 11 S 1 uhlic Ilcalth ticrvice, Mithir.an Ilcarl Aartiatinn, Aorcric:rn Mcdical AsstKiatirrn I Jur•rriim auJ Hcu•arch Vuund:rti-rn, anJ Ik•Irriil (icncr.d (lntpilal Rcscarnh ('rrrptrratinn Frurn Ilic Ik•pirlmrnt of Mcditinc, Waync Statc Ilnivcrtity SchrK l nf Mcdi- t ine. I ktrr,il 1? IIIT(T 01: NI(Y)IIN1: ON CONIRA("III.f1Y (1U "1111? INIA(-I III ARf A slrain RauFc calheter assembly was uscd tu study thc cffccts of nicrNinc rHr IhC inttantanfrNlt frxce-veh,city rclalirms of Ihe intacl Icl1 vcnlriclc in chrtcd chctt dugs Nicoline was adrninitlcrcJ with anJ withuul prior "a adrencrgic blockade with propranutul in an allcnr'rl 146 dclcrminc whether Ihc myrxardial eRccts of nictNinc arc mediated IlurruEh Ihe rc Icase of nurepinchhrinc. Results show that nicotine augments mycx'ardial amtraclile statc as indicated br an incrcase in Mdh the furce and vckxdy of shnrlcninR I~indings ncNed when hela-adrenergjc Mr><kade hrcccJcd nitvNine adminittraliun suggest that pntpramdrd impairs the norcpinclrhrmr likc clfccls of nicotinc (xr the myucardium while it cnhances Ihc pcriphcr:J vasr+presurr action (ol nicotine. f uri, 1'. S, Alarny, 1) and RinR. R. 1. Innrrruf .r/ (7init al 1'lmrmaoluRy ond the Journal u/ New 1)rugt R(5) 245- )(11, 196R. Othrr Rrnnt.rrr: ll. S. f ublic lkallh Service, Michigan Ilcarl Atsrciatirrn, American Medical Association Education and Research Frrundaliun, and 1)ctmit (icncral Ilospilal Research ('orporaliun. Frtmr the 1)cparlmcnt of Medicine. Wayne State University SchrKd of McJi- cine, Iklroit. F.VALl/Al ION OF MYOCARDIAL FORCl:-VFI-()('I l-Y RI?I.A'11ON IN ('LOSl:b-('1 ILSf IXX;S 'fhe furce-vehxily charactcrislics of the left vcnlriclc in 35 chncd- chcsl ancsthclitcd dugs were sludicd by means of a slrain-gauKc catheter asxmhly. Instant:rneout velocity of shortening wat dclcrmincJ at an isri- Ienglh (.rtin/ un the curve of fiber shortenin6, by drawing a tangent tu the curve relating height of dc/kclion to time. Ventricular pressure relaled in lime lu thc isrrlcnRlh pptinl was uad as a measurc of force. Inslanlancuus fracc-vehKily relations at a constant nrusck length could thus he stuJicd. Alterations in afacrload induced by inflating and deflating an intra-aorlic balloon and by mclho taminc kd ta rcciprt+cal chanFcs in frace and vehKily. Ptsitive inrNrr>(»c dru(Cs, i c., epincphrine, mxcpinephrinc, and isripnNCremd, on the other hand, shifted llte force-vchxily curvc upwatds, ur upwards and to the righl, indicating either an incrcatc in vchKily :drme or an incrcate in fnrce plus vehmily, resl.eclivcly. '1 hctc results Innnted tu an augmentalirm uf the contraclile state of the heart. Itcta adrenergic hhxkade with pnq+ranuhJ Icd to a dcclinc of twrth forcc aud vchk:ity. Puri, 1'. S and RinR. R. 1. Arnrriean luurnal u/ l'hy.sLrl.rRy 214(h)1271.127'), 141iR Othrr Rrnnt..rr: 11 S('uhlic Ilcnllh Srrvicc, Michyg:ur I lcarl AstrK i.uiton, Amctican Mcdi.:d Assrrcialirrn Udutatirrn nnd Rcscarth I uunJ:rtiun, enJ Ikhrrit (:cncral Ihrslrital Rcscarch ('orprtratiun. Frnm thc I)cparlmcnt of Mctlicine, Wayne State llniversity Sclirwrl uf MrJi cine, lktruil. 33

LUII-ISUEN'LYMIiS IN INFARCTIiU IIEARI' Ml1S('l.li Myocardial infarction was pnKluccd in 20 drrRs fnr Ihe purprrsc of studying Ihe e0cct (4 coronary artery occlusion and myocardial in!arction on the 1.1)tl isocnzyme pattern of the ischemic heart muscle N.IlrrwinR infarction there was a siRnificant change in the number of Ll)II i-.nzymes in the ischcmic liuue. In normal dog hearl muscle l.l)II displays unly three isozymes, whcrcas in the in(arcted heart muscle all five isrrzymcs can he observed. The qualitative changes in LDII t>t infarctcd heart musrle were accompanied by Quantitative changes (n LDIa activity in the ischen ic area. Activity of LUII declined following coronary occlusion and dirninshcd to 219G of normal kvels ten days afler in(arclion llsis diminution is in put due to  rekase (if l.1)1I into Ihe coronary sinus blood and in par: due to inactivalion of the enzyme tx altcred enzyme kinelics accumpan/inR the changes in isoryme pattern. Gudhjarnsson. S. and Ptivcr, I). M. (Rinir, R. 1.) l.i/r SG ienr rs 7:621 627, 1968. OOther Rrnnturrz 11. S. Public Ikallh Scrvice, Michigan Ilcart Assrxiation, Amcrican Medical Assnciatinn Education and Research Foundalion, and Iktroit (kncral Ilrnpital Research ('r-rprrraWm From the Ikparlrncnt of Medicine, Wayne State University School d Mcdi- cine, tktroit. CNS IiVOKfU C(1RONARY ('IIANGUS AN11 ('ARI)IA(' ARRIIY?IIMIAS AN11-ARRIIYIItMI(' 1'f(()1'FRIIFS l)f MC.IIUrAMAII: Cerehral mapping of ncuroanalomical hxi having jurisdittion over coronary blood flow and other cardi«lynamic altcralirms has la-cn accom- plishcd in unancsthetizcd fiuser drrRs. (N.scrvatiuns bascd on 1'/ success(ul eRpcriments in adult doRs of both uRCs show Ihat, of Ihe 1,977 discrctc (xoints stimulated in the tcknccphalon, dicnccphahrn, rnescnccphalun and metencephalon, 7R1 cvoked changes in axrmary blood nnw, aortic- hkxxl flow, aortic blood pressure, hcart tate and myocardial tension. 'I hc highest crmcentzation of positive cerebral points which elicited cardiuvascular changes was found in the mescnccphalon. These expe rimental resulls appear to implicate discrete cerebral hxi with the productirro uf specific disnrdcrs of cardiac rate, rhythm anti cunduclinn. Other c. `xrimcnts with mebulamale shuwcJ this drug hr tie an c0ective anti-arrltythmk aFcnt aRainst Ihosc autonomic end c/lccrs evoked by clcclrical cscitaliitr of the reJ nucleus and/ur its neural cunncclMrns ('orrult, A/. N, 1r., I.yun, A 1: ,(irrlirnko, R. I , hunst, M, RcnF, I1. V, Jr , arN1 Vrud, 1). II Arz hircr Inrernurrunufr dr 1'hornwt oJyrwrnir er Jr I hrruprr 17 1(2 ) 462 474, 1968 Orl.rr Rrnnr.rr.: Wallacc 1.slMUalorics and lhe Merck Inslitutc (ur *lhera- pcutic Rcscar(Il Frorn the fkpartmcnt of Medicine, The Drookdalc Ilrrspilal ('entcr; and 14e Ik•parlmcnt of Analomy. State University of New York. I)uwnslate Medical ('cntcr, flrooklyn. Itll'I.ANE ('INI:.AN(:I(KiRAP111C UIiTI?RMINA-11ONS (/1' Llil'I' VIiN'1 Rt('III.AR FUNCf IUN: 1'RESSURE-VOI.UMI; RI:I.A'rI()NSIIIPS (nslanl lr.instant changes of left ventricular volume in ntan were mcasured using a biplane cincan6iocardiosraphic technique. '1 he results of prnl-nMrrlem studies in 13 human hearts and of studies in six patients with various forms of heart disease are presented. Nincty-sevcn vulunu ubscrva- liuns uver a volume range of 30 to 150 cc were recorded in the 13 pust- monlcm hearts. (N the six Patients studied, one had no valvular disease, one had patent ductus arlereosus and a vcntriculat septal dc(ect, while the remaininR four patients had valvutar insufficiency and/ur stenusis. 1'ressure and vulumc were related for the construction of pressure volume hNrps and the tkterminatioo of the klt ventricular pressure-vrAumc work for e~'cction. ('nmparistm tr( pressure-volume work determined fronr Ihc IrMrps and sUuke work calculatcd from conventional laboratory techniques shuwcd that Ihe dctcrminatiun of the pressure-volume work was more infutmalive Ihan the conventional calculation (if stroke work. Racktcy, C. E., lkhar, V. S., Whalen, R. E:. and Mtlnruih, fl. 1). Amrricmr Ilrnrl hrurnaf 71(6):766-779, 1967. Other Rrnnt.rr.: National Institutes of Ileallh, American Ilcart Assrxia- lion and l.i(e Insurance Medical Research Fund. hr+xn the ('ardiovascular I.aMrralnry, Ikparinunt of Mcdicinc, 1)uke l)ni- vcrsily Medical ('cnter, Durhsm, N. C. IN('RIiASI'1) StIRVIVAI, WITII f'ROI'IIYI.A('lIC (11I1N11)INIi AIAUR IiXI'VRIMI:N I A1. MY(X'ARI)IAI. INUAR('I I( )N lixperimcntal myrrcardial infarction was pnaluccJ in (,1) farm piys by Rradual cnrunary rxclusirm with an Ameruid conslriclor placed arounJ the Ic(t antcrior dcsceiMlin6 coronary artery. "1-wenty animats were treated wnh 10 mg/kR/h hr of yuinidine (an anli arrhythmic agcnt). Icn with S rng/k/./h hr, and ten with 2 S mR/ kR/6 hr fur a lulal Ix•rirKl r>< 72 huurs I wcnty animals scrvcd as crrntrrrls Scrum (IuiniJinc kvrls were mcawrcJ al h hour intcrvuls SiKnihcanlly irxrcascd survival, wlrcn .onrparcd tn r4rnlr4d%, was oha•rved in Ihrr.c aninuh Ircalcd with S and 11) mR/kl;/fh hr rrf qtnmJinc, but nul in Ihrnc rcccivinR 2 S mp/kR/h /rr. (tuJcr Ihr rlc.rrilK:d c.lw•ti mcntal cundilinns, dc"iprcd to causc a rcpr4Kluirt.le, t irn.nr"nt int,u,lu"u, yuinidinc Ircatrrn•nt in niMrlo.ic and well tidcratrJ Auacs signiliranlly uw t'tcascd survival Vurllxrnuuc, thcrc is n du.e Icvcl hclow w/nrlr thn cllc.t is lost Whcthcr Ilic results uf this s1uJy arc •rpphrahlc lu ru,rn in I,rcvcnr ing suddcn Jc:rth is unknuwn 35 14

1 r Ilurst, V. W., 111, Morris, 1. 1, )r , Zefl, I1. 1, Ilackcl, 1) II and M(lntush, 11. 1). Circulation 36(2):294-303, 1967. Oth.r Rrnnfor.r Natilmal 1leart Instilutc, John A. Ilarlfnrd Foundalion and North Carolina Ilesrt Associatiun. From the ('ardiova+cular Laboratory, Department of Medicine, and the Ikpartment of Path/dosy, E)uke University Medical ('enler, I)urhanr, N. C. PRF_SSIIRE ANI) VOLUME CIIANC;ES OF TI lE: LEI'f VEN7 RICLE IN A('l1TE PIiRICARf)IAL TAMPONAUE In experiments with eight do6s, acute pcricardial lamporna 1e pro- duced the eepecled hemodynamic alterations, namely, depression in cardiac oulput and elevation r>t left vcntrkulsr end diaslolic, right alriat, and perK•ardial pressures. I/eart rale was not significantly altered. t-ell venlric- ular end-diastolic volume also behaved in the expected manner and was found to be siRnificantly reduced. The phasie pattern of left ventricular diastolic filling was not altered although the rate of early diasl/>f,c filling was reduced. l eft ventriculsr end sysil>fic vdume was not significantly changed. Although left venlricular funclion was shown In be tb'presscJ by significant falls in ejeclion fraclion and nxan systolic ejection i ate, the relati/mship of Ihese parameters to myocardial cunlractility was eanmined and found, under lhese esperimenlal condilions, tn he inconclusivr. Craig. R 1, Whdcn, R. F.., llchar, V. S and Ml Inrlrsh, !l. 1). Amrril'an Journal n/ (-ardadnRy 22( I) h5-74, I VbA. ()th.r Rrnntur.r Natitrnal Ileart Institute and North Carolina Ilcart Asso- ciation. ' From Ihe Cardiovascular I,ahlxalory, Ekpartment of Medicine, Uuke Uni- versily Medical Center, t)urharn, N. C. PIION(X'ARUI(X,'RAPI-IIC 1)ISCREPANC'IES IN TIIE ASSE:SSMENT OF MITRAL SI ENOSIS PhonocardioRraphie, cardiac calheleriratilxs and surgical data are an- alyzed and compared for six patients exhibiting milral slenosis whose phonocardioRraphic findinRs failed to predict the milral valve area as esti- nraleJ by the other two methlxfs. 7 he corrected Wells' indices (01 minus 2 OS times) ranged from - 5 to I I and were discrepant to actual valve site in all sis patients Analysis of UI and 2 OS intervals usually permits a reas/rnable estimate of the degree u( stemnis of the mitral valve. Iluw- evcr. the intervals are altered primarily by pressurc changes. Altcralil,ns /,f other factors such as flow, valve slillrsess, snd regurgitation may resull in discrc'nncics c>f these mcasuren,ents As dcrnlntS lralcJ in Ihcsc paticnts, the Wclls' index is not an aln/Aute crilcrilNt ld Ihe scverity 44 rniiral {IennSi7. Racklcy, ('. E,('raiR, R. 1, 1<1l lnroJr, ff 1) and OrRain, 1: . S Ar/ lucrt of Intrrnul Afrdn inr 121 SI1 S1, 1968 16 Ofhe . 6rnntor.: National Inslitutes of Iledlh, Amcrican Ileari Associa- tion and I-ife Insurance Medical Reseirch Fund. Frurn the Ikpartment of Medicine, Dukc University Medical ('enter, Uurham, N. ('. NORf:PINIiI'IIRINI:- AND IIEPARIN-1NUUCIiI) C'IIANGIiS IN PLASMA fRFE FAlTY A(.'ll)S: A COMI'ARISUN Ii1iTW1&.N PAIII:NI'S Wllll ISC'fIf:MI(: III:ART I)ISI:ASE ANI) N()RMA1. YOUNG AI)UI:IS SiR nrxmal subjects and six patients with  history of nryocardial in- farclion were given rwxerinephrinc (1) 2 rg per kilogram per minute) and hcparin (1(X) mR inoravcnausly) in an cRort to determine wlrclhcr Ihe druRs' r spective lil.ulytir eOecle would reveal changes in plasms free /atty acids in tlre diflerenl subject Rrtwpq. All studies were done after an overnight fast and an overnihht smoking prohibition. Free fatty acid increases in plasnra after mrrepinephcine occurred more slowly and to a significantly Icsscr degree in Ihe coronarr group. This diminution was particularly apparent in rcRard to pa:milokic sciJ. The heparin scnsilivc lill/d fMMd in the clxunary Srlrop eemlzined significantly nNxe palmiloleic acid than the rnnmal; and (>tl minutes after injection, significantly more slcaric aciJ re- rnaincd in Ihe plasma of Che crxrxrary subjects. I leparin was alut Kivcn five minulcs after norepinephrine infusilxr was stopped '1'en mimrlcs later tlrcre was a significantly 6realec increase in the two saturated acids, myridic and Palmitic, in the coronary group. Thest findings seem to support previuus rnvesliRaliuns which have flwnd increases in the more salur:rlcd fatty acids in the plasrna uf patients with coronary artery disease anJ indicate Ihat this is a rcOccli/xr of IipoRcnesis from carbohydrate. Rulenherg, 11. 1.., Schwartz, 11. and SrrfuLY, l.. A. American Ilrart Journal 76(2):11f3-192, 1969. OOther Rrnnfor: 1/. S. Public Ilealth Scrvice. From the Ik partment of Medicine. Temple University Ilcallh Sciences ('enter, Philalklphia. ('ORONARY AR71?RY DISEASE ANb 'I III: CUN('1:1' fOF CARI)IAC FAILURE In this discussion papcr, a plea is matk to abandon tile ahslracl, n/rn- upcratiunal term heart failure and to descrihe the ways in whuh the hr:ut functions abnormally. Such an opcratiunal apprl,ach clcarly shuws that any lyl•c of failure clinical, hinphysical, f„lMitcmital, m/,lccular ucty Lc presenl in Ihe alnence of eonPestive heart failure, a lyl.e that reyuirrs Ihe pnrtiril,ali/wt ld ealratny/M:ardial (act,us. I-orrlhcrrunre, Ihc ul,crariia,.ll apl,raianc tlrarly indica/cs that one cnrnn/,t dt.tinpuish Ihc lau.c lil,m cOccl without knuwlcdKe u/ Ihe IcmfM,ral rclaliuns of Ihc Iwl, Ilctauar /d viciuus, invululcJ caust cflccl-cau.e circlcs, dcath is usually nnt causcJ by eichauslilro uf Ihe hcarl hut hy eslracardiac faclurs that arc ini,nnl,.inhlc with life. 'tlre intcrrclaliun%hiln of Irllra anll c111ran1ylK:IrJ1aI IaltUrS I,ar- 37

/icipatinR in the dcterminalicm of heart function and the cuntinuance of life following myocardial infarction, venlricular ancurysm and ischcnric heart disease are discussed in dclail. Snl.,g, r.. A. Amr'rican Journal rif Cardiology 22(I) 43-48, 1969. OOther Rrnnror: ll. S. Public Ileallh Service. From the I)ivision of Cardiolo6y, Temple Univcrsity Iicalth Sciences Center. Philadelphia. {'auu/ar Syatrnt Efl'fCT OF NI('O7INE ANI) VASnPRF_SSIN ON ('AP11.1.ARY Ill OO!) FLOW ANl) ('APAC'ITY 01: lllli IERMINAL VASCULAR lIVl) Tlre effect of nicotine and vasopressin on the capacity of the terminal vascular bed in heart nd skeletal muscle r>< dc s was investigated In normal heart muscle highest values were oblainel in the apea Nicotine had no significant effect unless the blr>,x1 pressure inereased to very high values Altcr vasrqxcssin no significant chanRcs were found in hc rrt ntusc/e, bul vasncunstrictiun was prcarnl in skeletal muscle. ('apillary bhxd flow delernrincd in heart. IunRs, anti krdneya rd rats increased in all org: ns after nicotine In conarul rats, a ahl;htly Lul significanlly higher cairill;iry bhMrtl flow was frrund in Ihc rrght vrnunlc Ihis drllcrcnre disal+lrcarcd in nicotine tteated nirnals an.l IK-rarnc rm-tc prt.m,un.cd altcr inp.nmn u( vasrrpressin. Rakutan, K, Uu Mctnil De RrKhcur..nt. W . ILrnl m, (. Itr.r:rtuh, W, TsclKrpp, 11 and fling. R J. Midicma rt 1'lutrmur'rdnRia fitprnnvnradr. 17(2) 1110 I2R, 1967 OOther Rrnntnr.t 11. S. /'uhlie Ilealth Service, American Medical Aacncia- tion (iJucation and Rcscarch Fuundatiun, and Iktruit Gcncral Ilosp tal Research ('orporatiras. From the Department of Medicine. Wayne State University School of Medicine, l)etruil. PIIYSt(ri.(X',IC Sfl/l)IES ON Rl:.vAS('III.ARI7.A1ION OF '1'l1E IXXi IIF:ART IiRper{mental studies dcsigned tu evaluate  revascularisaliun upera- lion (Vitscbcrg procedure) under curKlilirrna simulating occlusive coronary rtery diacase in man were carried out in adult nx.ngrel dogs. A sigrulicanl reduction of capillary bhxx) flow am1 a shght decrease ul vascular capacity in 1he teft ventricle were found following triple erwnnary nccluttlM After revasculariratirrn, capillary MrwK1 ftuw and va%cutar capacity incrrascd siRnificanlly in the implantatirm area In animals treatcd with Ihe Vinchcrg prrxcdurc. rnytK'ardl.rl en?ymes rcprescnling the Fmlxlcn Mcycrhuf path- way, Ihc r ilrii atnl cY~ Ic, and thc IK'ntuac phucf,hatc shunt dill ncrl show significant alteralirrns Active cellular oxidation was demonstrated in con- trols and animals treated with the Vinebcr6 prncedure, hut not in nnn- Ircatcd animats with triple coronary occlusion. These resulls indicate that the new source o1 e ttracnronary blood supply, bn„rghl about by implanta- linn of a systemic artery into the venlricular wall, increases the rate and distribution of capillary blood flow and improves o.idative metatwlism in the myocardium. Tschopp, 11 M„ Rakusan, K., (ludbjarnason, S. and RinR, R. J. Journal o/ Tbrnacir and Cardiovauular Surgery 55(4):466-47R, 1968. OOther Rrnntor.: 11. S Public Health Service, Michigan Ileart Association. American Medical Atuuialion Education and Research Foundation, and Iklrnit General Ilospilal Research Corporation. Frons the Ikparlnecnt of Medicine, Wayne State University School uf Medicine. Detroit. EPFF(T OF NICOTINE AND VASOPRE-SSIN ON TIIE 'fERMINAI. VASCULAR BEU OF 7IIE IIEART In eupcrimenls with dogs and rats, studies were made of the effect of hicnline and vasrrpressin on capillary blood now and capacily of Ihc 1er- mina( vascular bed in different parts of Ihe heart and in skclclal musclc In normal dog hearl muscle, highest values were obtained in the ape.. Nicutinc had no significant effect unless the blexxl pressure incrcatcd lu vcry high values. After vasopressin no significant changes were found in hcarl muscle, but vasoronstriction was presenl in skeletal muscle. (•ap8lary bh>,KI flow dclermincd 'cn hcarl, lungs, and kidneys of rats increased in all urgans after nicotine. In contnd rats, a sliRhllr but significantly higher capillary 1drK>,) flow was found in thc right venrncle. 7his difference disappcarcd in nico- line lreated animals and became more prnrsowrced after injeclion of vasu- pressin. Rakusan, K., I)u Mesnil De Rcxhemonl. W., llanlon, 1., llraasch, W., Tschupp, 11. and fling, R. !. ('linic•al rlrarmrx,luKV and Therapeutics 9(1):24-30, 196R. Other Rrnntara: ll. S. Public Ileallh Service, Anrcrican Medical Atsrxia- tiors Fclircatiun and Research huundatiun, and Detroit ( icncral I luspital Research ('nrporation. hrcxn the Department of Medicine. Wayne State llnivcrsily SchrHrl rr( Mcdicine, Iktroil. '1111i A'1'11iNIlAllON RY RI:SI:.RPINf: OR (IIANV.11111)IN1 ()1 'Illli ('lll'ANI:U(1S VAS(K'UNSIRI('IIUN ('AI/SlA) IfY 'I(11tA('l'l) SMOKING B1rKxl flow in thc hHN of nurmal suhjccts smuking twrr ciParcttcs w» mcasurcd before and aftcr the expcrimcrnlal administratiun ul at:rtc eholarnine-dcplcling agent (either reserpinc or Ruancthidinc) I'rc drul; cigarette smoking pnKluced a significant decrcase in bl(Xnl /luw and an i I i IR 39

increase in vascular resistance in the ftHd Adrniniaration uf Ilrc calc- chrdaminc dcptclinR agents markedly attenuated of bhkked thcce cllc.ls. After large daily ciinical doses ,.f rcacrl.inc for three wccks, cif:rrcnc smuk- ing produced no tiRniticanl changes in hlrMKl flow or vascular resist:urie in the IrKS(. After the adminislration of gu:rnethidirsc, the percent mcrcasc in vascular resislancc during smoking was significantly smaller than it had been in the pre-drug sludics. l hcse results indicate that ciKarclte smuking cscrls its eflcccts on the circulation in the skin via the sympathetic nervca, and that the rclcasc of catcchrrlamines from the adrenal medulla is nrN imprutant. '1 hc resulls also suggest that patients with peripheral vascular discase who refuse to stop smoking may benefit frum Ihe use of calc- chutamine depkling agents. C-rr(/man, 1. 11. Amrrit an llrarf Inurnal 74(2):229-234, 1967. Urlrrr Rrent..r: National Institutes of flealth. hnan the 1)cpartmcnt of Medicine. University 1ltnpilal, Boston University Medical ('enler, A<nlcxr. Ffff;('f OF PROPRANOI.OI. ON 81.(1n1) PRFSSl/RE ANl) SKIN lll.(X11) f tOW 1)(1RING ('1(iARI 1"l li SMOKING l he eficct (if Ihe hcls recep Ir.r arfrenergic blocking aRen1• pmprane.lyd, on Ihe increase in arterial hlrwxl pressure srsd cutaneuua vascular resi.tance causcd hy cigarette anurkrnR anJ nxrdure was investiRated in 13 normal male smukets. Arterial hlrrK) pressure was mcaaured direclly Irum the hrachial artery snd hw)l blr~Kl flow was dclctmrncd by venous cx-crusion water plethysmt+grahhy In studics hcfarc and altcr iropranolyd administra- tion, smoking two ciRarclles (ten sludics) or receiving 4 mg nf ni.:uline inlravenously (eight sludies) produced a significant increase in average mean h1aKd pressure arK1 foat vascular resistance. Percentage chanptes in mean lslorKl pressure and fo«N vascular resistance from reslinR Icvcls (lurinR smoking rx nicotine infusion after propramdoi were nn/ significantly dif- ferent from percentage changes obtained before prupranohd. Prupr.rnolol allenuatcd or prevented the rise in pulse rate seen during cigarette smoking and intravenous nicotine. It is ctxxlurkd that patients trcated willr pro- pranrdrd will not show an esccsaive increase in their hltxid presswe or cutanenus vsccular resistance during cigarette smoking; the rise in pulse rale will be attenuated or prevented. ('n(ymon, 1. 1). 7hr hrurnal rr/ Clinn"al I'harma-alrrRr and rhr luurnul tr/ New 1)ruRr 9(l) 19"44, 1969 (Irhrr Rrenl..r: Nnti rnal Institutes of Ileallh s rorn Ihe I)cl+artmenl (rf Medicine, Ilr+sdrn Ilniversity Schrwd of Merlicine; anrl Rrrlrrt 11,rw.r n i vana Mcmrrriat. Ikpartrncnt of ('hnical l(cscarth, I l,r,.rr,it~ It. .l ~r.r1 Il ~st~~n A MI('ROMF , 111Of) FOR Tllfi l)EIERMINA"11ON OF A('I11 Mll('UPULYSA('('IIARII)lS IN VASCl/1.AR TISSt1f: llris rcprtrt dcscribes a highly reproducible micro prcxcdure for the dclerminatirm o( acid mucopolysacclurides (AMPS) in aurtic Iissuc, which seems to overcome some of the ljmitalions inherent in previr,usly reported methods. 7 he procedure involves prnlcnlysis of approaimatcly 1// mg of dry, defatled Iissuc followed by scparalion and purificalion ul AMPS by chromatography on an Fcteola cellulose column. Following clcctruphrKCCis and subscquenl akian Mue staining of AMPS fracliuns, quantilatnm rd Ihe fractinns is accomplished by densitomclry. In practice, this micrumclhtKl was uacd to determine AMPS in the aortic tissue (intima and nrcdia) of a group o( 15 healthy New Zealand alhino rahlsits '1 he dala obtained in this espcrinsent crwld be considered as the standard quantilics of AMPS in Ihc aortic lissue u/ this particular animal spccies. Slefarsnvich. V. aMl (i.rrr, l. lnurnal aJ ('hromatrrRroplhy 31(2):47J-478, 1967. Qth.r Rrenror: National Institutes of Elealth. From the Ikpartment o( Pathology, Boston University Medical ('cnlcr, Boston. ('APILI.ARY IIEMORRIIAGI? IN AS('t)R81('-AC 11)-UF.FI('If:N"1' (iU1NEA PIGS: 111: IRASI"RUCTURAL BASIS 1?lectron micr<ncopic study of the capillaries in scurbulic guinea pilrs diaclnscd two types of sharply (ocal ksitms associated wilh cafallary hern- nrrhage. l he Icsions, induced by (ceding ascorbic-acid deficient dicts (ur pcrirKls uf one to five wceks, consisted tt/ endolhclial junclianal .cparalions and of cytoplasmic disruption. 7"he former was the more cr+ntnrun, hul both lesions were accompanied by attenuation aral loss of Ihe hasemcnt mcruhrane and by dcpktion of pericapillary collagen. (;rrrr, l., Wads. M. and (ir>,K)man. M. l.. Arr-hivrt o/ ParhuluRy 85:493-502, 1968. (/th.r grantor: National Institules of llcallh. From the Department of Pathology. Dostors llniversily Medical ('enrcr, Boston. l?V„LIIAI"ION 01: VASCULAR RESPONSI:S 'fO ('1(IARI? I-I li SMOKING Venous txtiusiun plrthysmugraphr, capillarrrserrpy and ~rrlhilal I.Ic lhysmoRra''hy wcrc carrK•d rwt un 28 liahrlual .mrrkt•rs in an ;rnr,mld trr evaluatc Ilre rule played f,y envinNtmcnlal Icmlrcralwc rin Ihc v,ntrA,rr resprrnsc tn srrwking 21 of the Ircrsrrns sturlicd wcre sullcriny Ir"nn rdditcralive erlcri:d di.rasr Rcaults s wwcd Ihat ncrrr is a cunsr:rut rrlalnur ship tK-twcen skin arnd ruustic IrcrfusirHr in vasxul:rr re.loimsc lu .nuAm1; in the lower estremity An incrcaae in one is accrrmpanieJ f.y a rlr t rc.rsr in the uther nntl vice vcrsa Mtnl imlkrrlamly, chaogcs in rcl.uirnuhrp 41 ri~

between skin/muscle pr•rfusinn depend quantitativcly and qualilalivcly tm environmental tcntpcrature. At nculral temperatures (22 5-21.5" (') vas- cular responses tn cigarette smrrkinR are qunntitativcly at their hrwco '1 his neulral Icmperalure ran8e, alur, represrnls the turning point in viscular resptmses. Skin perfusion which is dccrcased at 2(1(/"(' following cigarclle snKtkina shows an increaac in respnnse to cigarette smoking at 25:)"CVice vcrca, muscle pcrfusir,n is incrcascd at 21) O"(' and decreased at 25 (1"(' in response to cigarette smokinR. A concomitant scrics rrf skin tc%ta with Inhacco eslracts showed that skin sensitivity reaction may hc delrcndcnt lu a very large e><tenl on the prcparatiotl and comprnilinn of thc extract. RrAitch, W., Mcssina, E. 1, Terry, F.. N, Rouen, I. R. nd Slcele, !. M AnRiuGrRy 19(4) 232-23R, 1968. From the New York E/niversity Medical ('cnlcr, New York ('ily. llrrno.lynnnrir. SYSIFMI(' ANI) MY(X'ARDIAL IIFMOUYNAMIC RGSF'ONSFS 10 RFI.A I IVIa.Y SMA1.1. C'()N('F:N I RA I IONS ()1: CARRUXYIIE:M(K;LUBIN (C'U1113) Measurcnxnls of acute cardicxcspiratorr changes following the in- halation of cartxrn mrrnoxkle were undertaken in 26 cardir>S,ulnwnary paticnts 'lhesc mcasuremcnts, made helr,re and after acute elevation u( ('OIID to an average r>/ 11196% ti:rturalnon, showed that venuus nxygen Icnsirxt dccrcascd flrrm 39 to 31 mm IIR, and %iRnificant incrcascs in minulc vcnUlaUtm, cardiac nutpul, rc•riphcral oxygen cRlractinn, oxygen cunsumpliun and the alvcrdar arlcriil oxyyen thlfcrrncc were trhaervcd. Also, coronary bhMx1 flrrw and myrKardral cnlraclioHr ratios for oxygen, laclalc, and pyruvale were delcrmincd in a series nf dt+Rs and human subjects. ('oronary hhxxl Mtw increaxd and e4 lraclinn ration dccrcascd following acule elevation of ('01111 t he decrease in myraardi•rl oxygen etlractirm ob%erved wilh increasing ('U118 contrastb with the increase in systemic oxygen e><traclicxt and constitutes an adaptive challenge to the cornnary circulation. In addition Io the experimental studies, chroanalo- Rraehic rncasuremenls of hlrttd ('Ollll concentration were made rxt conlrtrl suhfccls grouped by smoking history and on an "exposcd" group of sub- jects working as tunnel guards in  New York citr tunnel. The mean saturation levels in lite bhxxl rose cuncistcMly for Ihe different smuking Rrnupa (mrn snxrkers: - 1 0; 1 pack: < 2 0; 2 packs: > 3 0) ; siRnilicanlly higher saluralirrns were observed in the "•cjtlxscd" lunnel guards. Avrrt, N Af , Murllcr, 11. S, (;repny, ) 1., (iiannclli, S, lr , and Pcnny, ). 1.. .Irr'lrivrt o/ 1•:n.dn,nmrntal llralth IR(4) (i99-7(W, 1969. (hhrr Rrnnl..ra: 11 S Public (lealth Service and New York Ilcait Atiau ('i.lt/ M Urom lite Ik•pirlrncnts rrf Mcdicinc and Surgery. St Vinccnl's IhispitA and Mcdi. al ('cntt r. Nr w 1'ra k('rty lllli F I I 1(-f OF /t Al)RFNI:R(iI(' HL(X'KAI)1? (I'ItOI'RANOI (I.) ON I I Iti ('1)A( it l1.AH11.1 IY Uf I I lEi BLIK)I) A('R( )SS '1 / I1: I IIIMAN I11{AR 1 Simullancr,us analyses of hhKx) samplcs from lite left vcntriclc, the cntanary sinus, and a peripheral vein were carried out in 14 palrcrds in a sludy of the e0cc(s of pmpran„k4 (a /f bhkker) on lite clullinR and lihri nrdytic syslcm hr all of the samples a Ircnd tnwards a pruhrn(;alion o( lite plaana cua8ulalirrn limcs and a Ircnd towards a dccrcasc in several yd the Idasm:r cnagul:tlinn carnsliluents was found. 1 he dccrcase in plasma Ac- 8tuhulin activity was stalislicatly significant. 7 fre decrease in anrhlrcnurphilic faclrn activity was Grund lu hc significant in the rlasnra sanrples uhlaincd Irom dre left vcnlritic. In dditirxr, differences in Ihc degree of change affcctinR lite prnthnrmhin tinres and plavna tecalcificaliun times were mncd Exlwccn lite peripheral venous hlotxl and the central cardiac hhxxl SiRnili cant changcs tncurrinR across Ihe heart related to the anlihcarc+philic /a.tnr Thcse findings are discussed in context of their relevance 10 lite usc td propranuh>t in cardiac disurdcrs. Also, the prwsihle presence of a crintmd nsechauism of coagulation by tympathclic discharRc mediated Ihruugh 1f-receplnrs is discussed. Puri, P. S. and Mammen, E. F., (RinR, R. l.) Mrdicina er Pharmor ufnRia F.tfrrrimrntofr. 17:239-247, 1967. OrR.r Rront..r.: U. S. Public Ilcallh Service and Michigan Ileart Assu- cialion. Frum lite Ik'parlmcnl of Medicinc. Ikparlment of /'hysiohtRy, 1'harr»acul- ogy and of 1'alhology, Wayne State University SchrxA of Mcdicinc, Iktntil lI1F FFFfi('U OI: C'IGARIiTfFi SMOKING ON VARIOI/S ('1.() I'1 IN(; 'I IME: 'I I:SI S Frwr clotting lime tests-- the Iwo-luhc Lce-Whitc clotting timc in glass and in silicone tufxs, the flowing clotting time in lite rulaling plaslic kNop (Ibrombus fornralaxr tinrc) and a stationary clotting time with hlrwwl in lite plaslic hMrp- wcre performed on aliqunls r>< native hhoxE ttMaincd fmm 3R normal drrnort. Ill.xxl sam'des were drawn from the 30 male and eight femalc suhjecls hcfrrre smukinR, immediately after snnrking unc ciKarclle, and IS lu 20 minulcs after cessalirxt of smokinR. Accelerated cr+nKul:Hiun, dcfined as at Icasl a 10% dccrcase in the control clotting time, w:n shown after snrnkins in 31 nf the 38 subjecls by the flowing clultinK limc test; whcrcas it was only found in 17. IR and 21 suhjrcls• reslx•clively, by lite rdhcr three static thNtinR time prnceJorc•s. Furthermorc, thr crvcr:,hc h•r. ('crnlaf•e drercasc• in lite chollinR lime wa. Rrcalcr with Ihc /howinr, tlisttrnl., UnK /rsl than it w:rs wdh the three Whrr nx•asurcrnrnla Uvidrnrc ia di% cusacd hcre which suyFcas thal nxrtirnt uf Ihc hhNNI i. iml10nt.rn/ in JemrwntratinF accelerated chAlinR in the 'neeenr~e rd :~ny f.rm t~n whu Ii wr~uld cllccl pl:rtclc•IS, ur clutlin~ /N•r sr, or IHHh l:rrxrfhrrK• If. and I'nRcllxrR, l.. 1'. Va.uufur I)ioravs 5(4) 226 2)tl, 1969. 42 43

I From lhe ('edars Sinai Medical Rescarch Institute and thc Dil isirm of Mcdicine, ('cdars-Sinai Medical C'cnler, Los Angeles. TIIE IIEMOf)YNAMIC EFFFCTS OF: PROPRANOLOl, I-IYI)R(R'l Il.OR11)E AFfIiR SMOKING The effects of prnpranolnl hydrochloride, a prwent beta block ng druR, on the hemrxlynamic responses to smoking were studied in fir- ynunR, nrxmal, chronic snxokers. In all sub~'ecls studied, proprannlul f~rL'nwcd by smoking siRnificantty dccreased nrd'uc output and significantly rncreascd blood pressure and calculated systemic peripheral resistance con pared to smokin6 alone. Furthermore, the combination pn•tuced nausea •n(I a vague sensalirxr of uneasiness in each suhject. Clinically, the observalion that P randcd plus smoking increases calculated total peripheral resistance U lowers cardiac output may be important since this combination of effccb could hc harmful to a cardiac patient. Frankl, W. S. and Solofl, L. A. Amnican lournol of MrAicol Sci'rnrrs 254(5) 623-628, 1967. Ot14.r Rrsnrsr.i 11. S. Public Flcalth Service and Heart Association of Southeastern Pennsylvania. From the f)ivision of Cardi<doRy. Department of Medicine. Temple l)ni- versity Nealth Sciences Center, Philadetphia. ADSFNCIi OF PI.AlI:LEI F:1I1.('f ON I'OSTIIFPARIN LIPO1-Y I I(' AC1 IVI I Y lhe effect of platelets nn the li/xdysis induced by the intravcnous infusion of heparin (I(111 U/kR) was studied using two tcchniyuear>f mcas- urement. len-minule poslheparin samples of the platclet-rich ano ptatcict- (xrcx plasma of 13 subjccts showed no significant diflerenccs in pr~theparin liprdytic activity as determined by an in vitro assay. Nor were there any significant diflcrcnces found in the posthcparin samplcs of platclel-pcxx plasma, platelet-rich plasma, or whole blood of these same suhjecls when concentration of free (atly acids was measured before and afler incubation at 37°C and at room temperature for 30 minutes. Studies in additional subjects suggested that mechanically trapped plasma, in the course of ccntrifusatirm to obtain platclcts, may account for sonu of the increased activity previously thought to be due to platelets Other studies revealed the importance of minimal delay prurr tu incubation of whole blood and plasma samples in order to avoid dditiunal lifxdysis and tu achieve re- pnxluciblc results. RutenberR, 11. 1.., Stern, A(i. and SoLo//, /.. A. Amrriron luurnal u/ PhysrnlnRy 215(S1 I(X)5-IO(M), 19(rR. (1th.r Rrnnr..rf l/ S 1'uhlic Ilralth ticrvicc I'nrm thc I)cparlment (d Medicinc, Temple Univcrsity Ilcalth Scicnccs ('cnlcr, I'Int:rdr. lt+hial 44 IV. RPspirntory Systprn /rhyaiotrrRy PlI1.MONARY IiFFECfS OF TOPA(-X'O AND RF?I.AIFI) Sl1DSI'AN('I:S: 1. Pli1.M:)NARY CX)MPLIANCE AND RISISI'ANCE IN Tlll: ANESTIIETIZf:D t)O(; Inhalation of cigarette smoke and' intravenous injection of nicotine caused a hiphasic rise nd fall in pulmonary .esislance in the anesthelited dog 1 he sensitivity of the dogs was remarkable since one puff of cigarette snurke was sufficient tco induce an immediate increase in pulmonary re sistance in all siR dogs so tesled. llris initial rise was followed by a fall in all the dogs. Subscyuent puffs of smoke consistently caused an inhi:d bronchcxonstricti~.n. In most inslances. Ihis was a response limited to t1K airways since pulnwnary compliance and systemic bkwd pressure were not influenced. lolerance was rwN demonstrated in these eaperinxnts since repeated administrations of cigarette smoke were not characterized by any alteration in the intensity of the pulmonary response. l he mechanisrns for the biphasic effect on resistance were partly idenlified. Adrninistratir.n of alropine eliminated the bronchoconstrictor response, while sympalhectomy abolished the bronchrKlilalor eflect. Aviodo, t). M. and Palecck, F. Archivrt of Environmental Iltolrh 15:187-193, 1967. From the fkpartment of Pharmacolosy. University of Pennsylvania Sclxxd of Medicine. Philadelphia. P111.MONARY EfFE(TS OF TODACCO AND RELA'f1:1) SIIDS'fANC'fS: 11. COMPARA'fIVE FFFEChS OF CI(;ARf:I'Ili SMOKE ', NI('UTINE, AND IIISI'AMINE ON '1lIE ANES"CIIETIZEI) CAT Inhalation uf cigarette amokc by anesthetized cats caused a mono- phasic increase in pulmonary resistance in most of the e><perimcntal trials whcre a change occurred. A general pattern of compliance falt arisinR frum rn increase in resistance was noted in lhe cal's resp rnsc to ciRarctte smnke. When nicotine was injected inlraveneously. the cllcct scen mrnt frcyucntly was a hiphasic action on blood pressure, an initial fall followed by a ri.c. Ilictaminc, administered either i.v. or by inhalation, evuked a rcductuM in compliance, an increase in resislance, and a fall in hh>tx1 pressurc A cum. pariarn of thc reslwnces uf the dog with thosc of Ihe cal shuwcd Ih:rt the rurrsl crrnspicuthrs Jrllcrence was the character of Ihe ch:rnRc in putmrrnary resi.tancc in rc%lwinx tu cigarette smtrke 'Ihe cat rrslNrndcd uaunlly by ur incrcasc in resistancc, whereas the duR res/Mmded hy an incrra.r I014-wcJ hy a Jccrcax '1 his ddtrrrnce mcans Ihat a hmnchrKhlawr mci hanr.m n prescnt in 1lK d~rR hut nrH in Ihc cat A brunchrkurnrrictur rncr h.rnr.m, mi thc olhcr hand, is prescnl in tarth s/xcics. Since utlr.•rirui•nta in m.rn, publishcd by uthcrs, rcpiul hronclKrconstrictiun without any hrun4,hrwhla- •5

lion, it would appear that the uniphasic response seen in the cat is some- what analoR(ws to the human response. Palecck. F. and Avind.+, 1). M. Art'hrvcs o/ Ernvi.nnmenral lltolrh 15:194-203, 1967. From the Ihpartment of Pharmacology. University of Pennsylvania School nf Medicine, I'hiladclphia. P111.MONARY EFFIiCTS OF TOBACCO AND RELATFI) SI/HSIAN('FS: 111. INIIIRITION OF SYN1If1'.SIS OF IIISfAMINE IN VARIOUS SPECIES In the aeries of esperirncnts reported here and in the two pre(edinK papen, dop, cals and rabbits were used to stutly the pulmonary e/fects of tobacco and to investisate the basic mcchanisms involved in prtxlucinR the ohscrved effects In contrast to the rewlts rcptxtcd with dogs and cats, the most outstanding feature o( the espcriments with the rabbit was that cisa- tclte smoke, nicotine and histamine did not Influence pulmonary resis ance. Indccd. the Inhalation of ci~t arelle snxrke did not cause any significant change in Mtxsd pres.sure anJ puhrxxrary mechanics, nor, for that n itter, did the inhalatirxt of histamine. When taken toRclher. these experinents demmstrate, in n Indirect manner, the preitive role of histamine in mediating the cllects of lobaccn. Ilistamine was shuwn to mediate the bronchrK•rrnstrictiun from onc pu If of cilearctlc smoke in the dog and from five puRs in the cat lhe rahirit, whith did not rcafxrnd to histamioc by bronch<,conslrictinn, also did nrd res(~ rnd trr cigarette smuke so Ih:u Ihc role of histamine has heen shown in alt Ilrrcc sfrctics Palccek, F., (hkoui, M and Avral,r, It Af. Art'hives o/'E.nvirnnmrnrn! lleoldr I 5.21)4 213, 1967. From the Ikpartnxnl o( PharmaculrrRy, llniversity (if Pcnnsylvania Schrxrl of Mcdicine, Philadelphia. f)11:I:I:Rf:NC'ES IN TIIE F:FFIi('IS OF INIIALATION OF Sl1LFl1R I)IOX11)F; ANI) ('1(iARF:77li SMOKE Inhalation of SO, has been shown, heretoforc, to cause bronchocon- slriclion In laboratory animals. Hy the use (d appropriate surgical or chemically-induced tkncrvalinn prnccdures, the influence of three neuro- genic mechanisms upon this bronchrrconslriclion was investigated These nrcchanisnn (all previously shown to he responsithlc fur brrrrnhrKnnstric- tiun following cigarette snKrke inhdatiom) arc: (I) inlr:Arrbar rcllcn nrcdiatcd via the vagus nctve; (2) intcrh+har rc/lcx nrcdiatcd via the vaRut ncrvc, and (3) direct stimulation of parnsympathclic RanrJia In espcrirncnts with eiRhl ancsllKtircd dhgs, ntr rKrwws mcr hanisms crruld tre shrrwn In Ihe SO, c.lroscd rhrrs, bronthrnnnstuittirm wu% IimitcJ tu /hc c.lx..ctl tuhc and was un:Jtcttcd by dcncrvati.in. lhe cnprraurc nf a pcrfuud Irncc to SO, did nod causc an clcvilirm (rf Ihe pcr(usir,n prccsutc. Aku, Ilrc htrmthi.rl ar,criec wcre diLNcd hy c><larsure tn SO„ wlrcreas thcy are arnslrittcd by cigarettc smoke and nicotine. The ftwr reasons just enumerated support the cunclusiom Ihat S(/, drxs not influence the lung in the samc nranncr as cigarette smoke where the role of nervous mechanisms is casily pruvcn. ('ho, Y. W., Samanck, M. and Aviado, I). M. Arr hivr.r rrJ @nvironnu•ntol Ilcoltlr 16(5):651-655, 196R. From the Ikparlmcnt of Pharmacology. University of Pennsylvania SchtHrl of Medicine, Philadelphia. ('AR()lIl) RE('EPIORS AND HRONCIInM(YTOR RESI'ONSIiS: I?1:1•IiC'IS OF ('1(:AR1:7'11? SMOKE. 1-OHFiLINI:, ANI) ('YANIhI? Using anesthctired dogs, cigarette smoke was applicd to the left lower hrbe of the lung e>cclusively and the efiluent Mtaxl was collccled, Lcrfuscd into the car.ttid bifurcation area and ultimately allowed to reach the sys- tcrnic circulation. "I hrce of the ftwt doRs so treated shuwcd slrrrns hrun- choconstrictirm of the esprnet) lobe but the bronchtrconslriclor tcslwnscs of the olhcr lobes were Icss intense. Results wilh these and olhcr espcri- mcnts kd to Ihe conclusion that bltxx) csprned to cigarette smukc had nr, important action on carotid sinus receptors. Additiunally, sitt tlrrRs were 'tmploycd lo test the responses of the carolitl receptors to chemical stimula lion. 7 his was acconrplished by the repeated injection of luhclinc into one pcrfused carotid artery. Srxlium cyanitk was likewise uscd to invcstiRate the mcchanisms behind hronchomotrrr response. 'The harorcccptrrrs in the carotid sinuses were stimulated by Ic.heline and cyanidc, resultinR in hton- chocunslrictiun. When sckctive dcnervalion of the sinus hanucccpturs was carried trot, the rcmainin6 body chcmoreceplors resptrntlcd by brunchutlila- tion. Klitk, A. M. and Avinhr, 1). M. Arrbirvcs of F:nvirnnmrnral Iltalrh 17(1):65-70, 1969. Frnm the 1)cparlmcnts of 1'Itarmsct>1nFy and Ancsthcsin, llnivcrsity of I cnnsylvania $thtx+l of Medicine, 1 hilatltlphia. MI?('IIANISMS FOR '111Fi HRON('IIUI)ILATOR UFFF.('1S OF COR71('OS'II:ROIUS IN Tllf: SENSI-I1Z1:1) RAIiHII' Esperimcnts tkvolcd to the nalysis of the nxchanisnt for (hc anti- asthmatic propcrlics of two ctMnmonly used steroids are sumurari7ctl in this rc{~+rl. A total of 74 rabbits was used in eight gruulx o( cr<Ikrimcnts in alutlri•s slartinR with maqcnsitbcd rabbits r1t1 pnK-ccding tu scnatircd omcs Icsls includcd mcasurcmcnls of mcclranical prrqK•rlics ul Ilrc IunR as wcll ns of hislaminc rclcase In rahbits following Ihc aculc rrt t hnrnic administr:rlirrn of crthcr synthetic tkaanrcthasunc or nalurally rhr urrmt; Irydrocrrrtisunc I tic hnnKfirnpasm sccrNUpanyiuR anNphylaxia irr Ihc ral.l.it was reduccd IrY fKrlh desnmcttusrnk anJ hydnreurlisune. 1 hcre wr-rc 1w,r imlMrrtanl mcclianisrns unrk•rlyinR Ihis ellcct. '1 hc first w:n a dcplt•1iorn rd bislaminc content in thc lung Gdhrwin6 unc week uf d:riiy aJruiniar.rUmn ~,1 cither curlitrntcruid. Ihc .ctrmd was a rclasatiun rr( Ihc hrr,nthi:rl sm~lh 46 47

r ~...~ ~ .~.. I muscle detected by a(all in pulmonary resistance immediately following an acute intravcnuus injection. 1 hcsc resulls can be used as a basis for developing new steroids with ukclivc pulmonary acbions. ('arrillo, 1., R. and Aviadn, 1). M. 7ht Itrurnol of !'harmacofnty and Eipcrimcnml 7hcrapturica 164(2):302- 311, 1968. From the f)cpartmcnt of Pharmacology. University of Pennsylvania School of Medicinc, Philadelphia. ADENOSINE DIPHOSPIIATE AND VASOA(TIVE SUBSTAWCfS flistaminc, adcnosinc diphosphate, adetsosine triphosphate, serotonin, and catecholamines are all vasoaclive substances suspected of bcing re- leased during trauma. Study of IS cases of pulmonary lesions including fat embolizalitxt, pulmonary cdema, and coneeslive atckctasis, showed that the release of these vasoactive substances it, indced, the central point in the formation of the lesions in the lung. Investigations into the chsngc s of lun6 function brought about by nonthrxacic trauma have been ccvxluctcd in tltigs by the present author and br olhcrs. These studies indicate ~hat the substance or substances resp,nsibk fnr the pathogenesis of pulmtxrary lesions must be characterized as capabk of increasing pulmonary (airway) resistance, increasing pulnxmary vascular resistance, nd decreasing pul- monary compliancc. Sonic of these functional changes can be reverseJ by drugs such as the sympalhtxnimctics, sanlhincs, and corticotteroit s; digi- talis; and imipraminc. (N the five sub.t:rnccs released during Iraunu, only txx (histamine) originates fnrm Ihe Ir.rum:rtrred Irssucs; three (teroarnm, adcntninc tliphrnphatc, and adknntrnr tnlrhutl hatr) rrriRrnatc frran Ute MtMxl platelcts; and one Icalrrhul.unrn(-.) trmut ftrnn nce tlrctr:dvrd gruups of cells related tn the symp:uhr rrt ncr.ous cyttrm I:ach ol thrte subslances, when il is carried tu thr lonyt, rccrtc a Iratlcrn n( acutm drl- fcrcnt from the others 'lhe furegoinR r-htcrvalirrnc su)~gest thc irnlxsrtance of channeling future research eflrrrls int(w an invesrigatiun of the physiolugi- cal effects of these vasoaclive substances. AvioAo, 1). M. Thr lnurnal of Trauma 8(5):880 890, 1968. From the Ikpartment of Pharmacology. University of Pennsylvania School o( Medicine, Philadelphia. MON(X'ROTALINE-INDUCF.I) P111.MONARY I IYPERTE:NSION ANI) p C11L.ORUPIIFNYLAI.ANINE (PCPA) 'Ilte manner of palhogK nesis of nxxstxrotaline-induccd pulm~~nary hypertension was studied with the aid of 1'('PA, a substance used 1o dcplctc the content r>t 5 hydrosytrypumine (S1t1) in the rat lung In thc first part of dreie rs /.rrimcnts, pulmonary and tyNCmic t'ircufaliuns were stuJicJ in rrnc crrnuu) and Ihrce eslxrimcnlal Rrtrups of rats Rals fcd with nrrrno cnrtalinc for unc mrrnth showed an clrvaliom in ptdnumary rtcrial pres- sure, but nurmal systemic blrxid presaure and clct:tnxardiugram 1he 48 concurrent adminittralion of PCPA reduced the eslcnt of puhm.nary hypertension but did not prevent Ihe hypertensitm cornedctcly Rats receiv- ing PCPA only devcluped a mrsderate degree of pulmirnary hypertension. In the sectxtd part of the study. the reaction of the airwars was invesligatcd by measurements uf pulmonary resistance. 71te inhalalion uf cigarctte smoke and intravenous injcctitm of nicotine cautcd an increase in pulmu- nary resistance, partly by a vagal mechanism and partly by the release of humoral agents, parlicularl~ histamine. The control rats and rats treated with P('PA respomkd in the same manner to cigarette smoke. Ilowcvcr, the responsc to nicotine was converted from a brorrchoconstriclor Itn a htonchodilator response. In these rats, the kvel of S11T in the lung was rcduced, indicating that PCPA caused a depletion of this important humoral agent. l hese resulcs support the theoiy that 311T is responsible ftx the palhogenesis of mcx:ocrotaline-induccd pulmonary hypertension in the rat. Carrilko, 1.. and•AvioAn, !). M. l.ahurarnry Investigation 20(3):243-248, 1969. From the Ikpartment of Pharmacology. University of Pcnnsylvania School of Mcdicine, Philadelphia. FFFIXT OF Pl1l.MONARY BL(X)D FLOW UPON I.l1NG Mf:C1IANICS The contribution of the pulmonary vascular Ixd to pulnuxury mechanics was ssessed by studying an isolatcd, perfused, and ventilated canine heart-lung preparation. Airway pressure was continuously rccurdcd in this prcparatitxr during abrupt, slepwise 100-2(X) ntl inflatiuns, and suh- seyucnt dcflations. Comparison was made between thc nunfxrfuscd and the pcrfuscd states. Pressure tracings were similar during dellation in the {+erfused and the nonpertused lung. 1)uring inflatitm, in the nriddle range td lung inflation vulumcs, the peak inflation and eyuilibriunr airway pressures were greater in Ilu nonpcrfuscd slale. Lung distensibilily was Ihe same with packed red cells or plasma perfusatcs and was not changed by varying the pcrfusiun rate up to 220 mI/kg per minule. Iwring cyclic ventilatiun, dynamic contpliance was greater in the perfused than in the nunlxrlased state in Ihe middle range of inflation volumes. Static dittrnlirrn of the vascular bed produced similar resulls. The data suKgest that both Ihc actively perfuscd and the statically distended vascular bcd pruvidc int- portant structural supptxt which facilitates the nirtvcmcnl of ras rnlo Ihe terminal respiratory units at lower airway pressure. (iiannelli, S,)r ,.( vr.s. S M. and Buchler, M. 1?. The luurnaf (o/ (Yinuaf lnvistiRarbrn 46(I11):1625-1642, 1967, OOther Rrenrnr.: Ilcallh Research Ctwnt'il of the ('ily td New York nd Nalional Institutcs of Hcallh. lrom the Ikparlrncnb trf SurRcrr and Mcditinc, St. Vintrnl'. I/rralrir.rl nd Medical ('entrr td New Ytrrk, and New York llnivcrsrly tichrwrl of Medicine, New York ('ity. 49

IIUMAN NASAI. MUCUS FLOW RAl ES In ten cnnsecutive tests in each of 12 human vnlunteers, nasal mucus flow rates were found to vary about ninefold within the Rrc„rp, yet each individual's flow rate proved sufficiently constant Irr permit him to he used as his own control in studies of the ellccts rd esperimental alteration of the eslernal and internal environment of the nose. The wide variation in conveyance rates among individuab ma~ have been due to anatomic features and mucus viscosity. In tesb of thc eRecu t>t esternal in0uences, sis mild environmental changes (includin` esposure to nasally exhaled cigarette smoke) proved to have little rx no effect. I lowevcr, nasal Oushin6 and drinking very hot tea increaxd flow rates by more than Ihrecfnld and just over two(old respectively. Fkm rates recorded in 24 kFurs who had differing degrees of nasal pathology indicated that even with distortinn, scarrins, rx crosicm of intranasal struclura, any remaining intact mucosa which was protccted from the direct impact (if unmodified air functirrnrd at normal rates. Ilcrvy crusting d mucous membranes was found to inhibit or prevent mucus flow. Bans, B(1 , Mukherjec, A. L. and RanR, F. R. lrrhnr llnnAiro Mrdicof Jnurnof 12)(1) 38-48, 1967. Otl4.r Rrnn/nrr ll. S Public Ileahh Sctvice From lhc Johns Ilr.pkirn University ('enlcr for Medical Research and Training. ('akutta, and the Institute o! Prratgraduatc Mcdical 1'.ducation and Rescarch. Ihc l)niversity of ('slcuna. India 1111: lIL'IRASIRII('1lIRF 01. 1111: I.AMINA I'RUPRIA UI: Tltf? IIUMAN BRON('I1lIS A detailed descripticxr of the ultrastructure of bronchial lamina pnipria is presented here. 'Ihis loose connective tissue consists of a framework of colla6en, elastic, and relicular fihers through which runs an exteosive plexus n( nerves and blood vessels. Besides many flbroblasts, lymphocytes and macrnpha6cs, there are large numbers of mast cells and plasma cells. 7hc mucus glands develop from cells with an elaborate erx)oplasmic relicu- lum systcm, and the intercellular spaces between the developing mucus glands are distendcd, presumahly as a result of active water absorrtion. Thc lamina propria is separated fram the mucosa by the basement larsina, which consists of a thin amorphous shect of tissue. Since the lamina pmpria provides Ihe essential nutritional and structural support hn the epitfxlial eclls, and since it undoubtedly serves an imlrrrtanl physirdriRical (unction as wcll, it is hoped that this rkniunstralnm of its ultraslructurc will stimulate Interest in this Ion6-iRncxed tissue. ~ G f flrnriks and Aryant V RrinAman N ~ m Ln . .., , . . . Amrritan Review rr/ Rrrpiratury 1)rrroar 99 219-22R, 1969. l„D 0 r m m 1'r4mi thc 11cfvirhnrnt rrf Mrdicint. Wiync State ltnivcrsity Schrwd of MrJi.~nr Iktr~,~t m J Ln N I 1 1 1 1('f OF ALCUIIOL ON T1lE MOBILIZATION OF ALV1iOI.AR MA('ROI'11AGFS The effect rrf alcohol on the numbers and viability of alveular macro- phaRes in the lunKs of mice was measured by combining techniques for quantitating the pulmonary clearance of bacteria and alvecdar macrophagc harvest. Immediate)y following the inhalation of staphyloccxci (0 lime), the number nf alveolar macrophages harvested increased 2.5 times basal yield. Fiflccn minutes after bacterial exposure, macnrphage counts of control mice dropped 35'X% and those of akohol-treated mice decreased 42%. In the control mice. the elevated (0 time) kvels were restored at 30 minutes and maintained fur four hours. In contrast, macrophaRe yields of alcohrd- treated mice remained at Ihe lower level observed 15 minutes afler aerrnrd esprnurc. Alcohol thus exhibited a deleterious effect on the mrAriliratiun of alveolar macnq.haRcs, namely. 1he maintenance of a macrophaRe resptmse in relalicxr to a bacterial challenge. Akohol had no effect on Ilu morpho- logic characleristics, viability, and numbers of macro+hases ursder basal conditions and the mrnphofosy and viabilily of moM'lized alveolar cells. These results are correlated with clinical evidcrsce of the adverse effects rr/ alcohol on pulmonary infection. (iuarneri, ). 1. and l.ourrnti, G. A. Thr lournal u/ t.aAormn.y and Clinical Mtdicine 72(1):4U-S 1, 1968. Oth.r Rrnntnr: U. S. Public Ilealth Scrvice. From the New Jersey College of Medicine and 1)entistry, Jersey ('ily. AI)VI:RSE f31~F1:C1' OF OXYGEN ON TRACIIGAI. MUCUS f1.UW When tracheal mucus flow was mcasurcd in young cats by a particle- Iransporl tcchnic, it was seen that any deviation- high or low -frum ambient o><yscn Icnsiun in 1he inspired air had an adverse effect on mucus flnw. The inhalation of 10% oxygen prolonged the transport time 43%, and 40% oxygen caused a 23% prolongation; 1(N)96 o.yFcn prrKtuced nrarkcd impairment. Basal mucus flow was improved, and tbc advcrsc effccts were prcventcd and reversed by epinephrine compounds and aJcmr- sine triplunphate. AII the cpirscphrine comp<+uods accelerated particle Irans- port siRoificanlly eaccpl Ilre lowest dose ((/.15 mg/kg) of sulx-utancrwis epinephrine, and Ihc onset of improvement was rapid in cacti casc. Arknosine triphrsphate by acrosol and intravenously also shurtcncd tsans- pnrt time in the samc range (2R%), and its eRecl, as with thc cate- chrdamines, was brisk. 't'hese resulls, which are inlerpreted in tcnns of inhibition of carbrrhydrate metatxslisns by oxygen and the ptnirivc c/lkt 1 of catcchtdamines on rhis functiun, suritest a sublk, I+ut IwNenlr.rlly 41.111 Rcrous, furm of otyRcn tuacity. f..rurrnli, (J. A.. Yin, S. and (:uarneri, I 1. The New h:nXland /nurnrrl ol MrJir rnr 279(7).331 319, 1968 Oth.r Rrnntr.r: l1 S. 1'uhlic Ilcallh Service. Frum the 1)ivisirrn of Rcshiratory 1)iseases, Ikp.vlrncnl of McJi.inc. Ncw Jersey C'ullc);c of Medicine and Ik•nristry. )crsey ('ily. S1

0 ratholoRr PI1LMONARY FMPIIYSEMA ANl) ('I(;ARlil'IE SMUKIi: IiXPI:RIMFNTAI. INI)(1(:11ON ANI) USE OF I1RONCIIWI)Il AIURS IN RA"IS Faperimcnts reported here represent the first attcmpls to measure lung mechanics in four groups of ra1s: (1) normal; (2) normal cRprrscd to cigarette smuke; (l) c.pcrimenlally induced emphysema, and (4) rspcri- menlallr induced emphysema eapoaed to cigarette smnke. Nrrrnul rals cx ned to cigarette smoke daily for 1(1 weeks did nrN dcvclup sisns of purflnonary emphyccma. lhe rats wbjected to e.perimcnlal ligation rr/ the trachea and intralrachcal injcclinn of papain dcvclupcd signs of pulmr.nary entphyuma, bu1 capnsure to ci6.rclte smoke did not unirnrmly influence the various signs l-unctional residual capacity was rKN markedly c9cvated although histrrluRical esamina/ion showed a higher percentage 44 air spaces in emphysematous rats eapreed to cigarette smoke. Cigarette smoke caused an increase in pulmonary resistance only in the rals with experimenlal cmphystma Rals exposcd to cigarette smoke responded to isrprulcrcni>f (a bronchrxlilat(x) more intensely than did the unenposed rals. 'i he above rcaulls are nf particular inleresl because they question the validity of thc wiJely acceplcd belief that cigarette smoke can promote the development of pulmonary eml.hysema. Ilo, FI nd Aviadsr, 1). M Arrhivrt of Fnvi.rmmrnral l1r.rlrh 1h(6) R65 R7/), 196R. f"rom the !)cparlrnenl 44 I'harma(ohopy, l)niversity of Pennsylvania SchrNrl of Mcdicine, I`luladclhhia LI:SIONS OF 111F lX)RSA1. VAGA1. N(1('LEUS IN 1111: RESPIRA fORY l)IS1 RI:SS SYNI)ROMF In an attempt to assess the irnfxrrtance of the central nervous systenr in the respiratory distress syndrexne, clinical and nccrnpsy data on 44 nct)natal dcaths were obtained and the rkrrsal medulla nhhrnRalas were examincd. lh,tsal vagal nuclci in 26 of the 44 neonatal dcalhs showed chrumalolylic damaRe of 2(195'h+ of the nerve cells. lhe adjacent hypn- 6lossal nucleus was usually not aflecled [ktrsal vagal nuclear Icsions were significantly correlated with maternal primiparity, premature birth, the presence of pulmonary hyaline mcmbrancs, and pulmunary alvenlar hemorrhaRe. 'Ihese observaliuns emphasite the inrptxlance of the central nerwrus system in the respiratrxy drstress syndnwne, IlhuupJr Ilrr chanRcs described may be either of printary or secondary lype, and may trc either the cause nr Ihe resull of the a,xnialed puhmmary abnrumalilics Rur AinRhnm, S, Srrmmcrs, S(' and Shcrwin. R 1' 7hr Amniran Iourna! u/ ('linir al 1'arh.dnRy 4R(3):2(+9-276, 1967. OtArr Rrnnlnr: National Insti/utcs rrf Ileallh. Vrum Ihc Ikputmentb rd Pcdralri.s and 1'athulugy, ('ulumhia llniversity S2 I Cbllege rrf Physicians and SurReon., New Yotk ('ily, and the 1)elrarlmcnl of F'atholugy. Ilniversity of Southern ('alilurnia SchtHd of Mcdicine, l.r+s Angeles. IiXPI?RIMENTAL RIESPIRA'IY)RY UISfR1iSS SYNt)ROMI?- 1. ('F.NIRAL A(f1ONOMIC ANI) IIUMORAL 1'AT11O(il?Nlilt(' FA('IURS IN 1'(11.MONARY IN1(IRY 01: RA'IS INU(1('UU W1111 IIYI'1?RFIARI(' OXYGI?N ANU 'Illl? PROII?('17Vf: EI 11.('IS OF llAR1f11l1RAl F.S AND '1 RASYI-Ul. Adult rals ci<prncd to high oayRen pressure (1101') were studicd lor changes ol hrainslcm, adrenal and heart cpincphrine (li) and norepinc- (rhrinc (Nli), and /rx changes nf Ixainslcm and lung scrolornn (S1I f) A significant loss rd Iwainslcm NE was noted I5, minulcs aflcr 11(/1' c.lhrsurc. A/lcr 30 minulcs, hnwcver, mN only was Ihe dcplctiun of brainslem calc- cbnlamines more complcte, but significant anxrunls of catechrrlamincs had been dischar6cd from the myocardiurn and adrenat glands. Pretreatment with barbiturates completely prevented these catccholamine losses Hnin- stcm 511 I' was unchanged in I IUP, but lung 5111' was decreaccd 50% a(tcr 30 minutes. Barbiturate prelrealmenl was only partially '~rrrleclive hcre, whereas '1'rasyh4 was completely effective. In other lests. Ilre palhuRencsis of pulnxinary lcsirxn in dru6-Ireated and unmcdicated animals exp~ncd to 11OP was studied by light and ekctron microscopic, hislrKhemiral, and surface tension methods. Inflammatory mechanisms in the ral lung were called to mind because early damage to endolhelium r>< the small venules was inevitably accompanied by local deRranulation of the mast cells While ullcrinR their protection in different ways. both barbiturates and Trasyh>I markedly inhibited the pulmonary damage. RurAinRham, S., Srxnmera, S. C. and McNary. W. F. RirrluRia Nrrrnarurum 12(5-6):261-251, 1965. Other Rronror: 11. S. Public Ikalth Service. From Ihe l)cparlmenls of Pediatrics and PatholuRy, ('uhnnhia llnivcnily College ol 1'hysicians and Surgeons and Francis I)claficld Iluspitnl, New York; Ikpartmcnl uf Anatomy, Boston (lniversily Schrwrl ul Medicine, Ikntun. RIi1.A'11ONSIIII' UI-' SYMI'iOMS (1F ('tIRONI(' IIRON('11171S ANI) l?MI'lIYS1:.MA '1O WFA'1111?R ANI) AIR 1'U1.L1111ON 'I he sevcrily rd aymrtoms in  froup of ('hicaMo art•a paticnls whh chronic airways r>fntrucbon slNrws a marked scasnnal /lui tualirrn 'I hr colder Ihe wcather, the rnnre severe Ihe symplrrms UailY syrulrtum .cvrray is rhnelr di cr~rrelaled wilh Irrw d.rity lenqa•ralure anJ wulr Iny,h tul(ur osiJe Itvcl SrRnificnnt eorrelaliuns are alstr nulcd with nilrrrus rr.rJrs, srNrwfall, and srvcral odrer mctcornhrRical aru) air Iwrllutiun mrasurrrnrnr+ Iluwevcr, many u( these relatUlxMShqls are e.plained hy sinular scaimnal pallcrnt of sym)Hrrms and envirr„nncntal condhtirrns, anJ whcn I>,rth scacnn and daily tcnq+cralure are held conslant, only hydnKarlwrn level shnws 53

n inderendcnt correlation with symptr+ms It is concluded that cunditions which Icad to extrcnx cold weather are often assrrciated with an eraccrha- tion of syrnptonu, but the specific causal factors cannot be idcntificd llnder the conditions uf these studics, at least, air contaminanu do nrH appear to play a nrajor rtrle in producing these symptomatic e tacerhatirrns. Rurrn»•s, R. Kellogg. A. I. and Auekcy, 1. Archrvct of Fnvirrmmrntaf lfralth 16(3) 406-413, 196R. Calculations were carried out with the assislance of the [liuh+gical l'ciences ('twnpulalion ('entcr, University o( ChieaAo, supported by a Rran1 frum the U. S Public 1(Calth Service. frtxn the Ik partmcnl of Mcdicine, l/niversity of ('hicaRo, and the Ik•part- ment of Air Pollution Control. Chicago. P(II.MONARY EFFF("fS O1= SUl FIIR UIOX11)[: PXPOS(IRE IN T((F? SYRIAN /IAMSIIiR: I. ('OMfiINEU WII11 VIRAL R(:SPIRA'IURY UIS[:ASE Syrian hamsters were subjected to long-term chronic eaptnurcs of SO, at high concentralit.ns (650 pf+m) (:roups of animals were co-challcnRed with a viral respiratory infection either at the beginning of their exptnure to SO, or aftcr 7S dailr SO, esprrsures After scrial sacrifice of suhjects and contruls, histopatholt.bical sludrrs o( file lungs and Irachea were made. (.txrR-term e.pw.sure to SO, prrMluccd no siRnificant hislopathrdr+Kical changes in the trathea and lungs of ,hc hamsters. Pathological chanRes in the lungs were minimal and crrnsistrd nf loss of cilia in focal areas of tracheal r{'ithclium and rrf a varicty tr( minnr irritilive phcnomrna. 'Ihcre was nrt tlditive histupalhohoRy in animals doubly challenged with a virus infection and SO,. '1 he results indicate that Syrian hamsters can tolerate daily eaposure to high concentratiuns of SO, with no marked e/Tects On Ihe basis of these observations it w„uld seenr that, if SO, dors produce harmful changes durinR smog epixxlcs, it must do su in conrhinalion with other comptwnds of polluted air. Ctrldrin6, 1. P., Ctxrfrcr, P., Ratner, I M. and GreenhurR, L. Archivrt tr/ Environmental Ilralrh I5(2):167-176, 1967. Other Rrnntor: ll. S. Public Ilcalth Scrvicc. From the [kpartment of Surgery. Albert Finstein College of Medicine, New York City. 1)F.SV(IAMAT-I VI? INTF?RSTTT'IAI. PNFUMONIA A case history is presented of a palienl wilh dcxluanutive interstitial pneumtmia, a disease which was first tkscrihed as a diuinc/ entity only two rcars aRo The tliaAnrnis in this case wns eslahlishcd by IunR hw,lny lrrtlow- rng the onscl td dys/rnc which was thr paUCnl's rrnly symplnrn /'hy.ical findinRs were limilcrl to crackhrrR ralcs heard over Mdh hascs Ihc chctit rrrcntr,cnrrRram shrrwed a fine infiltratinn radialinR frnm htrlh hili Irr file hascs Iktcrirnatirrn rrvcr  Lcritnl uf limc wac dcmrrnsttatrd by scqucnlial function studies. The clinical and pathological features nf this disease are hr-e0y reviewed and the first electron microscopic ubservations in desyuam- ative inlerslilial pneumonia are described. (:n11, A M, MrNary, W. F., Jr., and Gaernler, F. A. Mrdreina 7hnrat alis 24(5).317-329, 1967. Orh.r Rrnntnr: National 71car1 Institute. From the T horacic Services. Bostnn University School of Medicine, Ruston. ('ON IROI.L1i1) VF.N'I Ii.ATTON WI l ll IN'fPRMITTI:NT' POSIIIVI: I'RFiSS11Rli HRI?A-f11IN(: IN 'lllt: MANA(il'.MF.N1 OF A('lffE VF.NIILAIORY hAII.URI: ASS(K'IATI:I) Willi ('IIRONIC ONSI Rll('l IVE PULMONARY 1)ISEASE In 19 Qaticnts with 21 epiuxks of acute ventilatory failurc, only ftwr trials cuuld be nranaRcd by assisted intermittent ptnitive-p ressurc hrcalltinR. T he remaining 17 episodes were managed by conlrulled venlilatiun in file following seyuence, employing either entlotracheal inluhaliun or Iracheus- Inmy: autnmatic machine cycle, oayRen depressiun, and drug suppressinn. Simple machine cycle was ellective in 41 % of cases, particularly in file cr.maluse patient. With agitated. uncooperative palienls, u><yRrn drpression and drug suppression were cReclive in CslablishinA contrtil A hylxrvenlda- tion period (1wo to six hnurs), direcled tu eliminate hypuscmia and acidosis, and a maintenance period (12 to 3(1 hours), whrre cunlrrd ventila- lion was continued, pcrmitted full medical therapy to correct file acute precipitating faclnrs. -Ihereafler, conventional assisted inlrrmiucnt ptnitive- pressure breathing and non-assisted breathing were ptrssihlc Wciss, F. 11. antt 1)nlfano. M. 1., (S.gaf, M. S). Annaf.s n/ Inrrrnaf Mcdicinr 67(3):556-567, 1967. Other Arantor: Pittsfield Anti-Tubercultnis Association. hrom file I)epartmcnt of Medicine. '1'ufls l)nivcrsity St'htwd of Medicine, and the l.ung Station (Tufts) and I and 3 Medical Services (fufts), Ifrrsarn City (lospital. Boston. V. Nt•urrrpRy>rioloRy SOME ('11ARA('fF-RISTI(- f-.IiG I)1(=1--(:REN('I--S NI--TW1:./?N IIF.AVY SMOKER ANI) NON-SMOKER SUlllli('IS An analysis of [?F.G patterns in 42 suhjet'Is with varianl snarkurg histurics (I) IKavy smrrkcrs, A average srmrkcrs. 15 ntrn srurikcrs. anJ 6 frurncr snNrkers) was undcrt:den in an attenrpl In delCrnune whrthcr 1•I (i atlivily is thlfcrcnt in smukcrs and nun smrrkrrs Ih.winR :r baac I h„ n F.1'.(: rec'nrdinR scasirtn, eath sutbicct's IxrcrlNual activdy wai tr+tcd by capcrimcntal cvrKatirrn rrf tcnlral resfwrnscs lu ctdur- tr+inR tMrth 11rc 1,lrutrc Oickcr antl vicually cvrrkcd resrtrnse Icchnics 'Ihc I'V.(: hattrrns uf h:rt.nu:d hcavy smtrkeu rtrntaincd significanlly Ic.s allrha and nwre hiKh trcqucncy 55 S4

I (13-2R c/s) rlr-yrhmii- activilr than did those trf non smokcts Rcsri+nscs to MNh phtNic flicker .nJ flash chcitinR Ihe visually evoked respotuse were significantly di0erent between Ihesc two groups 1=.1?(; activity an•1 visual resptmses for average smukcrs anJ furnur snN+kers wcrc gcncralfy inter- mediale between thosc of the mxt-smokers and hahitual hcavy smukcrs. l he ubservcd ddlerences in tKrth suslained E.F.(: patterns and res->,rnsive- ness inclicate ntarked diflcrenccs in central ncumnal activity xlwcen habitual heavy smokers anJ ntm-smokers, and suggest that Ihc dif:erences may hc conslrtutional in origin. RrnN•n, R. R. Nrurop-rychrrlnRiu 6:38IJR8, 1968. From the Ikpartrnent of Psychiatry and Iluman Bchavior, Califurnia ('ul- IcRe of Medicine. I tn AnRelcs, and the 1)eprlnsen/ of Iaperimtntal Psy- chiatry, Velerans Administration Ifmpilal, Sepulveds, ('al. TOBAC'('O ('1(;ARIiT'1E SMOKING AND PA'1ELLAR RIi1:L1?X U(iPRF:SSIUN Tests to Jetermine the eRecls of smoking cigarettes of diRerinR nicotine content on the patellar rcflcs were corxlucted in 115 healthy young men. In each Irial, the subject smoked two identical cigarettes with an interval nf 25 minutcs bctween. The patellar rcllen was elicited automatical y every two scarnds by a mechanical hammer 'fhe refiea was recordeJ srilh the use af a strain gauge transducer anJ Ihe cleclrrrmyoRram d the ipeilateral quadriceps femouis muscle. A negligible depression was prtxluceJ by smoking a nicvrtine free klluce ciKnrcuc. A low-nicrNine tobacco cigarette showed appro>lin,ately 45% rkpressiun within five minutes compared with a 67% dcpression afler smtlkurr, a htRh nicoline cigarctle. 'Ihe depression caused bi the secnnd cigarette was crrmparable in degree and duration to the effect d the first ei~arelte Nu atcumulative rx tachyphylactic effect was observed. It is concluJed Ihat Inbacco smokinR prusluces a renrarkable, short-ICrm depression of the human skeletal-motor systens. 'I he depression of the patcllar rc0es seems to be related to the nicotine content of the cigarette smoked. I)nnrinn, E. F. and von Baumgarlen, A. M. c-liniccf rhnrmurnLtgy and Thrrnlorutiri I(1(1):72-79, 1969. from the Ikpartnxnt of PharnuctrloRy, l)niversity of Michigan. Ann Arbor. I)R(t(i INlUV1ION IN7O 1111: ('A1'S 4111 VFNlRt('I.li: EFUli("fS l1PUN IiF(i ANl) AUIUNOMIC SYSIFM To obtain information on the eflecls uf drug injection into the 4th ventricle, lidraaine (lexal anestlxtic), thinpental (general snesthrlk). and strychnine (stirnulant and convulsant) were iujected into Rallantine para- ly>'eJ cats. Norepinephrine was also includeJ in this study since this eom- ptrunJ has hccn shown ttr rrct'ur in ccrchnrspinal Ouid 'Ilte Icvtl of viFil- I ance td test cals was monitored by recording 1=F(;, tcnsir,n of the nic- tilating memhranc, and blwld pressure. In intermediate or high doses all Ihe drugs investigated pnxtuccd EFG desynchroni>•atiun and sympathetic aclivalirm, i c, symrtums which indicate an increase in Ihe animal's level of vigilance. Minimal effective doses were: lidocaine 10 pg, thiopcntal 30 pg. strychninc It/ t,R, and norepinephrine 3t.s. Since the cerebrtxlrin:d fluid of normal humans contains approaimately 00017 pR,'mI of narepincphrine and since it was ohserved that a total Josc uf It) pR tr( m,repincphrine had to he injected to pnxluce el--.c desynchroniratiun and sympathetic acliva- /irrn, it appears Ifral m.rcpincphrine at this sile is not involved wilh the control of Ihe cat's kvcl of viRi(ance. S&horppl, 1l- Arrhivet inrr.nariunofn dr rhornrontdynantie tr de Thr.ofrir 169(1) 44-54, 1 )h7. OrA.r Rrnnrar: National Institutes of7lealth. Frtwn the Worcester Foundation for Esperimental Bitslogy, Shrewshury, Mass. NI('OTINf; TREATMF.NT OF SrLf:(Tfil) AREAS OF 'fltl: ('AU BRAIN: I?FFIi('1S UI'ON Eli(3 AND A(1TONOMI(' SYSfTM Cats were paralyzed with gallamine and nicotine was injected into the vertcbral artery (VA), into the carotid artery (CA), into Ihe fuurlh vtnlricle (4VF '), or inlo the third ventricle (3V13). Nicoline, at the stated Joscs, pru- Juced the following changes on ekctrocorlicoaram (li('tC1. Icnsiun rtl the nictitating membrane (NN)), and bkrod pressure (BI'). r).,.e r,r Nicalinc - 01.R F('r~O NM RP P('o(i I" tOaR NM RP F('o(1 NM IIP 1tla: IIw/rR NM BP VA tl/ n li) 1 11) IIvI I11~1 I I/I11 Ilt It Iltlil cA 0 0 0 tI1 0 0 I1~1 /I) (I) III I I I I/I 4V1: 0 0 0 1 (1) 1ItiI 111i1 1 1/111 )vr. n o 0 0 0 0 1/(11 (1) (I) Sym(x)ls ( I ). 1, I I nd I I I indicate variuus degrees of Oattcning of the retractiun of the NM and rise in BP, O - no e/lect, ( I ), 1, I I I I I: various degrees nt F('o(i synchrun'valiun and decrease in BP. I/ I indicates increase followed cx interrupteJ by detrease. 'lhese and similar nbservalitms with encc'rhale isrrle cats inJicate (I) nictotinc acts directly upon frunlal and tawlal arcas rrf the tat l.rain hy prrKlucing an irK-rcase followed by a dcc'rease in viKilancr, (1) it is parlicularly e/fct live ulxrn the lower brain stcrn, and ( t) it pro.lu, cs Juc, 1 e/lects ulrtnl carJiovascular centers whith ate inJclrndrnt (runt tlic cllrr Is upon Ihe level nt vigilante tof Ilhe aninlals Schnrppi, fl. lntrrnutiunal Inurnul of Nrurtrr/rornwt n)ngv 7(1) 11/7-22t/, 19r,H m ~ S6 57 t-n Ln

From the Worcester Foundation for Fsperimental flioloyy, Shrcwsbury, Mass. NfIIROPIiARMACOL(XlY OF EARTIIWORM GIANT FIBFRS 1he eflects of a variety of neurotropic drugs on excitability and acti.,n potential Gwm td the giant nerve fibers of the tarthworm ventral cord were studied with external electrodes. The reactions of these fihcrs were then compared to Ihe reaclions of frog sciatic myclinated fibers. Farthwurm giant fibers were like frog aciatic myelinaled fibers in the ly{+es of chanRcs induced by most drugs lested, the worm Rben being gencrally mure scnsi- live. E=arthworm fibcrs differed from frog sciatic in several respecti: they were not madc hypereacilabk by cakium depletion; they showed relxlilivc firing with high ('(MccMrali/M of cakium; they showed van+ienl Inwcring of Ihreslxdd by chotinesterase inhibikirs, and calclcclrotr+nic rel+elitive firing could be blocked by d-tubocurarine. Some of these findings nuggest that N cholinergic receptors may funclion in earthworm but nol in Irog myclinalcd fibers In the earthworm fibers. Ihcroselves, there were certain rclaticxnhipa involving spike wdtage, spike amplilude, and threshold which held true over a wide range o/ varialions of nerve properties by drugs and physiological maneuvers. Toman, l. F.. I', and Sabelli, 11 C. lnrrrnari.rnal lur.rnal n/ Nrunirharm.r..4ngy 7(6):54)-556, 196R. Orhrr Rrnnrnr: 11 S Public Ilcalth tirrvicc Fmm the (-hicago Medical Sth~~ l. Ilruvrraly .,f Ilralth Stirn.ct, (-liciKo V1, Sf(irlirs at thr (:r'llrrlrrr Lr'vf'l TIIFOkY 01: RIiSPONSE TO PAR7IAL I)EPL-F.IION OF ('F:1-I.111.AR PRU7 EIN The phenoma of repair and hyperplasia of cells and their constituents appear to be cflorls toward sclf-prescrvatinn in response to depletion. Starting with the principle Ihat, "If a synlhesir able, intrinsic ctrnstitucnt rrf a cell is matk to t>t+rrate t a runcli..nally insunicicnt level by any cause, the cell will resitl Ihal displaccnxnl Ihrrnrgh an allempt to reslone func- liarnal suQicicrx•y b7, irx•reasing the amount of that constituent as quxkly s fxnsihlc " the frowing resp.rnxs are deduced or prcdictcd: (a) resruca- titrn rd rells, (h) hylxrplattic reslxrntet r.f cells and listucs, (c) antilwKly furrnalion frum withns all ccllt hy IarRct prtJifcralion full.rwing depletive effects of any kir>,1, (d) a mechanitm for nalural resislance of all cells, (e) c'ircul:rlion of nurmal ce11 pr.ltrins in body OuiJs lu varying deRree, antl (f) hyf+crscnaitivity and autuscnaitivity (aul.r-immunc) cffccts in many living systems In this w'itc. antibody activity and hypersensitivily arc evcr present aspecls of the synthcsis and structure of normal cell prulcins in all tissucs. Rarnrs, F. W-, Ir. Mrern.uinnal .1r.hives of Allergy and Applied rmmun.rf.,Ry 16:(h)J52 360, 1960. Orli.r Rrenn.ra: National Institutes of Ilealth, American ('ancer S.xiety, American Ileart ALstwiation, American ('arkcr StKicty- Maryland I)ivi- sirxr, Nutrition fuundatiors, Ihnxrn Runyon Memorial Fund, MAlun M. Frank Foundation and Noazema Corfwrati.xs. From the Lkparlments of Medicine nd Physiodogical ('hcmiary, '1 hc ).,hns Ilopkins University School of Medicine, and 'I lsc Iluspilal fur lite Women of Marytand, Naltimore. ISOTOPIC AND FLLIORESCEN'1' STUDIE:S OF PROI F:INS OF SKIN GRAFTS AND IIUS7' Evidence for an exchange of protein between graft and host was sought in a series of esperimenls with rats and guinea pigs In a first experiment tesling grafl-lo-host protein Iransfer, iso- and allugrafls of skin from mice previuusly given S"-L-nxthionine gave cvidcnce of direct transfer of labeled macrumukcuks to host skin as carly as lite first 44 hours after transplanlation. Opptnitely, transfer of husl prtNrin tu grafts waa indicafcd by labeling hosl proteins in various ways, including injcctiun td isnluRous serum protein. Also, fluorescent rabhit anliscrum, made by injrcli.rn of whtdc guirxa pig scrum, was found to rcmain altachcd tu Iwo- and five-day-uld allogratts of skin in guinea pigs. Ault,- anJ isogenic grafls did mH show this. 11 seems possible that certain Rl.rl.ulins noxm:dly present in the host's scrum infiltrate Ihe htxnugraft nd pcrls:rl.s are I>,.und lo s.Nne rd its conctiluenls, at Icast as early as Iwo days aflcr skin Irans- plantali.rn. '1he uhscrvcd results were prcdKlcd frrMn the Ilhc.rry of resitt- arke and antifrxly prrxluclion promulgated by Harnes in lite 1960 pal.rr abstracted afxwe 'Ihe results adw document lite predicted transfer t./ protein between Rraff and corresponding lissue of hust. 'Fhc caf.crintcnlal work thus Iends suplxxl to the mechanism of graft rcK•rliun which ic suggested herein and helps Indirectly to support Ihe ncw caplanaliun trf immunity. Kemp, 11. G, Picrce, G. E, Seip, W. 1"., Ifurch, ('. (' , lr , M.,rrcl, S(' , I:dgcrltns, M T , Ir , arxl RarnN. F 11'., /r. luurnnl ol CrlAd.rr and ('umlrararivc l7ryri.daRy 61(2):121-I 14, I'0hJ (hli.r Rrnnr..r.: Nalional Instilules .J I lcallh, l l. S 1'uhlic I lcalth Set vn r, American ('arxer Ga ic1y, American Ileart Atstxiali..n, Amcn. an ('aourr Srxicty Maryland Ihvitirwr and Mdh.n M VranA I uundauun From the Ih•Parlmcnls of Medicine. Surgcry, and r'hysi..l../:ic..l ('hrnliwy, l he luhns I l.h4ins I lnivcrsity Schrxd of Medicine antl 'l hc I Iu%lutaI fur lite Women of MMyland, flallimore. I SR S9

i PROI.IFI:RATInN AN1) RESISfAN('E (1F I?PII)FRMIS IN RUSPONSE: 10 IIARMFUI. SI IM11I I I:vitlence reported here shuws that the skin of mice and guinea pigs rctprmds to application of a large numbcr of harrnful suhslantes (nitric acid, dinitrofluurrrbcnrene, and tnbacco smuke cnncenlralc, in particular) by hyperplasia and prtrlifcralitxt. 1 his pro(iferalive response was measured by noting chanRcs in epidcrmal thickness. The dcRrce of pruliferatiun is some function td the amount of agent applied, htHh cr'nccntratirm of agent and Iotal amrrunl over  period of lirne being variahles 'Ihe cRct:t may he a strictly cellular one since it is not a(lected by the presence of esccssive, proliferated ti:sue. "Ehe resp~nse appean to lake precedence over the normal ccxstrol of lissue nd cel)ular growth. In searching for an assccia- lion between hyperplastic eRects and the development o/ resistance, (Caure pads impregnated with smoke corwlcnsate (SC) were aI'(~licd to the dorsal skin of guinea pigs 71x SC prnduccd hypcrPlasia tc~ularly or, in Ltn><,er concentratitms and amounls, damaged the eprdcrnris. When SC pads wcre pplicd to a S('-pretreated arca and a correspondin~ untreated area, hy{+erplasia occurred nn the pretrealed site whereas Ihe untreated area eRhibited necrosis and cellular damage Pretreatment was Iherefure ihown to prutluce greatly increased local resistance to the agent used. 8ornro, F. W., lr.. Srip, W. F. and Aurch, C. C. Prrxcrrfings of the Srtiirty /nr E.rl.rrimrnral Binhrgy and Mtditinr 129(2): 5E4-593,1965. Other Rrnnfnr.: National Cancer Incwute, American Itrarl Asscxiatinn, American Cancer Socicly- Maryland I)rvrsion, Uarnon Runyon Mcnroria) Fund, and Millun M Frank I-uundalrun From Ihe Division nf Biological and Medical Scicnccs, Brown llnivcrsity, Provitknce. R. 1, and the Ikparlmcnts of Medicine and I'hycirrlrrRica( Chemistry, The )ohns 1(opkins University School o( Medicine, Ffallinrutc. Al.l FRATIONS IN CF.LI. PROLIFIiRATION IN MOUSE LUNG UOLLUWIN(i IIRf•.1'IIANE F.XPOSl1RF: 1. TIIE NONVACUUl.A7 FD ALVEOLAR ('1?LL ' An autoraditrRraphic study of ahcralions in cell proliferation in mouse lung was carried rwl for 21 dayt after a single intraperiloneal injerion of urethane. Initially, over 70% td labeled cells in control and cspcri nenlal animals were nonvacuolalcd mom,nutlcar cclls lying tm or within Ihc alvetrlar wall. Injury to Ihesc cclls waa indicated by a decreased IohclinR indcit and decrcascd pain cnunls over Incclcd cells ') he pcrirwt of inhihi- lirrn of cell divixiun ftorn six hours tn Ihree days after urelhanc injcclir+n was frrlhrwed by a pcrial of incrcaxd cel( proliferation in tlre alveolar wall whit h lasted 7-14 days 1 hc lallrr was accr+mpanicd by a tra.rcil~rr] hyf.rrpl:nia r~f hcrivaacular frrci of rnr,ntrnuclrar trlls, sranc of whicl1 (,nmcd auhplrural nrrlulcs It was cnn(IuJcd that Ihc majrrr inhihiu,rn of tcll rhviait.n an,l Iht• lalcr pnrlifrrativc reslnrnac rrllcclcd alleralirma in Ihc I„ ImLil ..n ..I n.-n..,, u. -Ielc l al., ~d.rr t. ll% I Irit Ianli/craUve rrall,urtC lu r.i a urethane appeart Lett explained as a repopulation of Ihe dan,ay,cd alveolar ccllt, eilhcr by allcralions in cell cycle, or by an inllus of prccurs,rr tclls frvrn Ihc circulation. Kari//man. S. 1.. Thr Amrrkun /nurnal of I'alhnlnay 54(1).E)-9J, 1969. From the lkpartnxnt of Pathology, State llnivcrsily tif New York, Brooklyn. EVII)EN('li FOR IN7 RACEl.Ll1LAR TRANSPORT OF RAUIUAC I IVI: 1'RUTl?IN IN ALVEOLAR ('ELIS l he kinetics oE the subccllular distribulitm of radioactivity in cells which have been pulse labeled with Rfucosaminc-l-"C sunest attachmcnl of Rluct.samine to protein at the microstxnal level followed by transfer of the labeled PrMcin tu particles which sediment at I5,0(K/ R. I he uhat•rved curvcs in Ihrs esperimcnl ckarly fll a precutstx-producl rclali,rnship Such data strongly favor intracellular protein transport. These fintlinRs, which may be entirely unrelated to the bio.ynlhesis, of surfaclant, assume Iwrtcn- tial significance when it is recalled that Ihe 15,(MN) R fraction prubahly conlains many laminar bodies and has the greatest ability lu luwcr surlace tension. Massaro, 1). Nature 21S:1SU5-1506, 1967. From the Department of Medicine. Duke University School of Mcdicine, 1)urham, N. C. AI.VE:OLAR ('I:LLS: IN('ORPORA77ON OF ('ARIiU11Y1)RA 1/: IN'IY) PR()II:1N ANI) I;VIUEN('1? FOR IN1RA('E:I.I.l/1.AR PRU'l FIN '1 RANSP()R 1' Alveolar cells incubated with radioactive Rlucusaminc. Ralacttnc, and nunnasc incur(xrrate radioaclivily into prtNein; that is, into malcrial in- soluble in ctd~ and hul trichluroacctic acid and not exlracled by lipid stdvents_ '1 his incurparalitm is inarmrdclcly inhibited by Irorrrmycin hydru- chloritk. lhc kinetics of the suhccllular dislrihulinn of radiuaclivily arc cunsistcnt with a precursor-pnnlucl rclalionship hctween mirrusrrmal lu,r tci!• and Ihe prulcin of particles sedirncntinR at IS•IIIN) K. II is Ihut suF Rcstctl that alvcr,Iar cells incnrptxatc Ihesc suhslanccs inl,cl iulu prulcin at the micnrsrrm:rl level with sul.sc(lucnl Iranslcr o( Ihic ncwly IorrucJ nlaterial (tr particles sedirnentin6 at IS,tXN) R. Afnrrnr,r, 1). /,rnrrurf ,r/ (Yinrr uf InrrruRurrun 47(2) 166 )74, I9hR (hh.r Rrnnrur: American 7horacic SrxiNy. I;nnn Ihr 1)rpar/rnrnt of Mcditinc, 1)ukc I/nivcnity Sthr„d of MrJ„mr, and Ihc I'ulm,Miary 1)iscasc Scrvicc, Vclcr.rns AJnnnistraunn I I~ .In1.J. 1)urham, N (' hI

V II. Ce'll anti Tie+rrr (arlfrrr(' ('YlOI'Alltl(' 1?111'('TS OF PARAINI-I.U1: ' N7.A VIRUS IYI'li 3 IN UR(iAN ('lI1.IlIRUS 01: IIUMAN RfSPIRAIURY 'fRA('I IISSIIIi Organ cultures af hMh fetal and adult respiratnry tract ticsue sup- ptirted grnwlh uf parainfluenta virus lype 3 for cRtcnded (+eriin)s In this scrics of prclirninary sludics, viahle uninfected cultuwcs of human reshira- lury tract mucnsa were maintained for as long as 50 da~'s. When inJivrdual cullures were inoculated with virus, cullures uf IracTica prepared frr+m dult cadavcrs yictded virus for as long as 46 days; virus was rctuvercd from the medium bathing the fetal trachea for as long as 31 days aftcr inoculatitm ('ytc.palhic changes alttif.ulahle lu parain/lucnrs virus I ype 3 first hecanx apf.arent in hulh fetal and adult tissucs apprnsimalely 175 INrurs after ImttulatNM. These alteralinns were increasingly nhvious with time and persisted tither until the epithelium was dcstroyed tx the lissue underwent frank necrenis due /o nunspecifie causes A variety of cytologic alterations atlrihutahle to the virus ppcared durin6 the crwrse uf file infettw.n lhese eyk>ralhic changes are descrihed and correlated with file virohrgie observations ('roighroA, 1. F. ntf Brcnnan, B 1 The .Imrncon I~r~rnof n/ l'odu~! ~Rv 51(2) 2R7-3lXl, 196R O/hrr Rrnnrnr: National Ileart Institute rmm the Ikpatrmenls nf I'athnh-Ry, f ctcr Ilenl Briyham Iluspilal and Ilarvard Mcchcal Stfioa>t, Buslon CIIEMICALLY ('IIARAC'T h.RI7.Fl) ('ON(-IiNTRAI 1=.1) (Y)RO1)II;S FOR CON77NllUl1S ('EI.L C'ULl URE (1 I I1: 7("s ('ULTl1Rli M1:1)IA) A new series of chemically defined media (the 7("s media) has been developed for conlinuous culture of mammalian cells. 7 hese media contain amino acids at kvels about five to 30 tinxs the amino acid concentrations contained in mcnt chemically defined media now in use. 'Ihe prnFxtrlional- ity patterns of the amino acids in the 7("s media are, in general, similar to those found in animal tissues nd food proteins of high biological values and, therefore, avoid gross imbalance. In addition to amino acids, these media contain fat soluble vitamins, the pcityunsalurated fatly acids, and Irace elements known to he nutritional essenlials for the mammalian urganism 17 (ilyceruphosphoric acid diuxlium is used as the huRer in these media in place of the usual bicsrtwrnate buffer. '1 hc capacity n( the 7("s media to sustain satisfactory growth has been dcmunstratcd by Iwn cell lines. WR('-216 and M8111 IymphnMast cells, which have been rnainliincd in these scrum free media for five and two years, rr.spcclively. I ing. ('. T., (:rv, (: U, and Richters. V. l:'rlrrrinrrnlof('rfl Rrtrarth 52 469 4R9, 146R (hhrr Rrnnhor: Arncriran('ancer S4Kiely From the Finneyclluwcll ('ancer Research I.aboraltay, (kh:rrlmcnls of Surgery and 1'hysiological Chcmistry, The Johns llupkms Mcdical Inslitu- liuns, Ballimore. illF? 1?S7AB1 ISIIMf?NT OF A CEI.1. I.INE OF IIUMAN IIORMON1:- SYNIIIISILING TROPIIOBLASTIC C'ELLS IN VITRO A Iruphnhlaslic cell system which synthesbes chcxionic gonadntrnpin htrrmrNre has been eslahlishcd in vitro and may prove lo he the firsl lura- lional human emhrytmic cell line in continuous culture. In file atlcmpts to cstahlish  cell line, a tnlal of seven choriucarcinnma s(+ccimcns wcrc cs- I+lanted in cullure Microscopically identifiable IunNrr ccll grnwlh tKCUrrcd in file primary esplanrs of three spccimcns. 1he lissue frum which file cell line way eslahlishcd was a specimen which had previuusly been serially IransplanteJ in Ihe banister check prwch in the latwnalury trf IhK•lur R lkrV. ('htairrnic Runadcqropin hcwmone produced by these t-ulhues serves as a marker hrr idenlificalion of the trnphnblastic cell No intcrruptinn nf this property nor change in cytologic display has occurred (luring I S ycars in conlinurws culture. '1 he continued proliferalinn nf the unditlcrentialcd cylntrophol>tasl is being slabilized in serial cultivation. t Paltilln, R. A. and t:ry. (:. 0. ('onrrr Rrsrorch 2R:12)1-1236, 196R. O/h.r Rrnntors: U. S. Public Ileallh Service, Uamun Runyon Memorial (-und and American Cancer Society. From the Finney-Ifowell Cancer Research l.abnratnry, I)cpartrnent td Surgery, 1he lohns Ilopkins Medical Institutions, Baltiroure, and the Ik- parlrncnt of Gynecology and ObslNrics, Marquette Stfiutd uf Mcdicinc, Milwaukee, Wis. IN VITRO IUFN'FIF1C'ATION OF TI1Fi TROPIIOBI.ASII(' SIIiM ('lil.l. OF llll? IIUMAN VILLOUS Pl-ACENTA In an in virro scart:h for the epithelial stem cell of the placcnla, cclls frum erminal bcds of cell column eytotrttphnblast uf the first and c:uly secuns trimester placenla were cultured. 'These beds have been shnwn hy Wislocki and Padykula to represent the generative suurce ni new and espanding placental villi in vivn. 'The morphnlogic characleriaics nf Ihrse cell cnlunms cnnfirm their cytutrnphuhlasl cnmprnilion in Ircmatnsylin ;nrd cosin sectiuns. (lntkr the dissecting micmxope comparahle arcac wcre sclcctcd antl explanted in tissuc cultures. Prinury growlh uf cytoarrpphohl,u with characterislic mic'ruvilli miRralecl lrnm Ihe%e ccll cululnns :uul h.rvc been fullowed by daily microscupic ohscrvalinn Iluman choninnrt run:rdit trnpin was tklrclyd in file rnedrunr in which Ilrese rclls wcrc /trown 14.1 a limilcd perirK) t.f linre, rouRhly c'umparahle In file pcriod Jurin/.. whi, Ir milnsis tKcurrrd in cyt4 rlruldruhtasr (I is cnnc'ludrd Ihnl Ihrsc tclls rc Inc sent the functiuning e'ylotrrhthublasl uf the rKxmal placcnta Pattillu, R. A., Crv. (:. O . Iklfs, FF and Mattingly, R F. Amrrieanlrrurrwlo/OAsrrrntsand(:ynrrnlnxy I(MI(4) SR2-SRR, 14hR. h1 63

Other Rrowforss U. S. Public Ilealth Service, Damoe Runyon Plemorial Fund and American Cancer Society. From the Finney-}lowell Cancer Research I-aboratory, Ekpartment of Surgery, The Johns Nopkins Medical Institutiona, Bdtimore, and the Ik- partment of Gynecology and (Mstetrics, Marquette School of hledicine, Milwaukee, Wia. CARBOHYURATE METABOLISM OF CHORIOCARCINONiA IN CONTINUOUS TISSUE CULTURE Ee this attempt to deUneate deviant metabolic pathways in turnorous tirue, a tissue-cultured cell line of choriocucinorns (line BeWo) was used to study glycogen metabolism by comparing the tumorous and normal trophoblast. Rs id cellular pow occurred with elevated glucote In the anediuro, and coRee staining by the periodic acid-SchifE technique was dense. Lowered ~ucoae resulted in reduced trowth, cell injury, and reduc- tion In glycogen posils. A comparison of rapidly growing choriocurcinoma in tissue culture with the growth of normal cell-column cytotrophoblast suggests a correlation betweee them related to the factor (Rlycosen syn- thetase) contributing to glycogen aynthesis. The lAck of glycogen in the tumor cells of the patient from whom the strain was initiated, and its presence in the tissuetultured cells, suggestt a reversion to an early function of the cTtotrophoblast in this response to the kvel of glucose in the medium in which the cell line is propaRated. The presence of such n inducible p.thway offers evidence that certain cellular tunctions may be repressed in the tumorous state, while retainins the capacity for induction by the appropriate substrate. Pattillo, R. A., Gey, G. O., Mattingly, R F. and Woodruft, 1. 1). O6ftrtrics and Gynecology 33(2):I53-I59, 1969. Other Rrentor.r l). S. Public Nealth Serrice, Damon Runyon Memorial Fund, nd American Cancer Sockty. From the Department of Gynecology and Obstetrics, Marquette School of Medicine, Milwaukee, Wis.; and the Fintxy-flo.rcll Research hboratory, and bepartments of Surgery nd of Gynecologic Pathology, 'I he Johns Hopkins Medical Institutions, Baltimore. PRIMARY INf)l1C'TION OF PLAQUE FORMING ANTIBODY PROI)UCIN(; CELI.S IN SPLEEN ORGAN CULTl1RE When sheep erythroeytes were used as the antiRen, primary stimula- tion of mouse spleen frasments in vilro eikiled plaque forminR sntibixly producing cells Based upon a relatively IarRe number of rdnervaliuns, an assessment wat made of the reproducibility of /his response when mea.ured nn the fifth day after anti~cnk stimulation. All splcens testcd gave fraR- mentt flut responded to tix erythrrrcytes 'lhe 'xrcenta'e of re+IwndinR fragments fnmr individual tplcens varied from 17 to R7%. On the fifth da~ .fter stimulsti4xt, the numbers of plaque fnrnrinR cells in stirnuiatcd cultures avcraRcd I 12 per IlY cells with a range frum < I to I(IBO per I(M 64 t rells. Values significantly above the controls were reached in 72% of the cultures In addition to 19S antibody producen, evidence of induction of cells making other t pes of immune Rlobulins was obtained. Free antibody was delecled as autinins in the tiaue celture medium. Although the re- producibility of response probably can be improved, this system for assesa- rn6 the primary immune response br Wtro can undoubtedly be applicd to many problems in immunoloRy. Noftermonn, O. A. and Nordin, A. A. Proceedings of the Society for ExperLnentol Biology and Medicine 127:675- 67e, 1969. OOther grentert U. S. Public Ileallh Service. From the l.obund l.aboratory. University of Notte I)ame, Notre Uame, Ind. Fl1RTHER CYTOLOC;IC.AL AND CYTOCIIEMICAL Sf11U11S ON TIIE BIOLO(71CA1. SI(;NIFICANCE OF TIIE GAS PHASE O1~ FRESH CIGARETEE SMOKE , Cultures of kidneys from Snell's mice >tnd cultures of slime mold were esposcd to puRs of whole fresh smoke, the gas phase from fresh unfiltered cigarette smoke, puffs of the same gas phase after passing IhrouRh an activated charcoal filter, and acrokin. Such cultures, esposed once to puffs of the gas phase from fresh unfiltered cigarette smoke, displayed a sequence of inhibitirm of RNA .ynthesis, loss of RNA, pycnexis and cell destruction from 1-24 houn after es ure. The same gas phase sftcr passin6 through an activated charcoal her did not produce any alterations in either type of culture. Acrolein, a gas phase constitucnt of fresh cigarette smoke, had essentially the same cell damaging effects un mouse kidney. and slime mold as had the gas phase from unfiltered cigarettes. I.ruchrrn6rrRc,, C., Schumacher, M. and Flaldimann, T. Zrirtchri(t /u, Prdvrnriv-Meditfn 13:130-141, 1968. Other grantor: Association Suiue des Fabricants dc ('iRarettcs. From the Swiss Institute for Esperimental Cancer Research, E.ausanne. ('YTOL(Xi1C ANO CYTOCIIEMICAL EFFFi("fS ON PRIMARY MOUSE KII)NEY TIS.Sl1E ANl) LUNG ORGAN ('t)I.7lIR/:S AFIF?R IiXPI)SIIRE "1O WI1O1.1'., fRFiSll SMl)KE ANU IIS (7AS 1'ItASE hl(()M 11Nf11.aFRfb. ('IIAR('OA1.1-11:I1•.R1A), ANI) ('1( iAR '1()11A( Y-U ('1(iAR1:Tl 1'S Mouse kidncy tisiue nd organ cultures of cmhryunii imHrer IunR were espencd Nr tfhe smoke from a ciRerctte without a littcr, tFhr sarur lylrc of ciRarette with an activated charcoal filter, and a cigarette rnade ~if cil•nr tuharco l'he smukinR machine used for these esprnures is fully drscril.rd Iapused cullures were examined at various inlcrvals undcr thc pluw 65 1

micnncupe for an assessment of the sequential alterations evoked hy the smr,ke. ('ytttloRical and cytcschemical studies showed no significant diRcr- ences between cell danuRrnR activity (r/ pulls from whole fresh smoke and from tlune of the Ras plrasc. Ilowever, while pufls from unfiltered riRa- rencs evoked rapid destruction of mouse kidney tissue and lung urRan cultures, such damage was absent after the smoke passed Ihrouth a charcoal filter. On the other hand, cultures esposed to smnke from char- coal fdtered cigarettes disclosed a temporary increase in the mitotic intlcx over that of control cullures. Puffs from cigarettes made up (rum t igar tobacco produced less and nomewhat different damage frorn that t,bservcd after eaptnure of cultures to smoke from unfiltered cigarettes. l.cr.chrcnAcrRer, C. and Leuchtenber6er, R. ('anccc Research 29(1):R63-E72, 1969. Frnm the hepartmen/ u( ('ytochemistry, Swisa Institute ftx Ei.Pcrinxnlal ('ancer Research, I.ausanne. I:FFf('1S OF NfTR(K;EN DIOXIDE INIIALATION ON (;IiRMFR1iE MOl1SF LtIN(7 1 hc exposure uf Rermfree mice to NO, has made possible Ihe pro- ductic~n and characteri7atir~n of a chcmically induced lesion nol altcrcd by Ihe prescnce of respiratory disease causing organisms. Structural and metaMdic alterations wcre very rehrrxlucible and appeared to involve F rimarily the hmnchi(>rar epithclium and alveolar thssue near Icrminal runchiulcs. At no tirnc were innamrnatruy reactions nlrsrrvcJ. ('tmncctive tissue, culla6`n, and clastin were not increased as a result tr( NO, es{rxure. An observed increase in O-„ 1.1)11, and ncid Pht,sphal:nc nclivity sulegcsls that a slimulalirrn in cell activity resulls frr,m NO, inhalaliun rather than dantaRe and dcstruklitm, at least at the levels of exposure dcscrihcd in this study. Furthcrrnure, the ppeararxe of the lesion in specific places suMsts that only cells in direct contact with NO, undergo structural and mctalx>fic change. (lcarance mechanisms did not appcar to be impaired by NO, exposure, since the lung ckarance rates of Rcrmfree capirscd and sermlree control mice frx aerosol clouds of SlanhyLrorrwruc oureu.r were nearly akntical The work presented here clearly indicates that the availa- bility of Rcrmfree animals and the technique ftx exposing thenr provide a uni~ue and valuable e:f.erirnental mtxlel for the investigation of the rrde of chemical and bioktRical agents in the c1ioIt+Ry (f acute and chronic lung disease. Ruckky. R. 1). nd I rM,rli, ('. C. Arrlrivcs of F.nvin,nmrnral Neahh IR(4) SRR.591, 191,9. (1th.r Rranr..r.r ll S Public Ilcalth Service nd the Ilastin/,s Fuundaliun 1unJ Frum the IkPartmcnt nf Rirxhernistry, University of Southern ('alifornia S.htxd uf Mt'Aitmc, L(rs AnRrles i CONfINIIOl1S VIRAL REPI.ICATION AND Cf1.1.I1t.AR NEOPLASIIC TRANShORMATIQN IN Cl1LTl1R1-S OF NORMAl. RAT 111YMI1S INfE:(TE:1) WI'ITI GROSS LEiUKI?MIA VIRUS To develop a system for the study of Cross kukemia virus Wi.V) replication in vurn, cultures of embryonal rat thymus were infected. Rruwn for long intervals, and periodically examined for infectious virus. Sulxr- natants assayed in susceplible animals induced leukemia in 9396, and electron nticra6raphs of cultures confirmed the presence of abundant virus particles. C'cxnparahk cultures of spken and kidney did not support viral replication. Morphologic diderences were noted between the appearance of virus-infccted and contrd cultures. Isotransplantation of the former in conditirx+cd rats resulted in formation of tumors at the site of injectiun. Tlrese tumors had Ihe histologic pattern of reliculum-ccll sarcomas, were serially transplantable in non-conditioned hosts, nd continued to carry the initial (i1,V. The thrmus, which is  tarRet organ for (i1.V in v.vu, appears to be similarl~ (avtxaMe (nr Its replication in vi[rn. In addition, nenplastic transformation has occurred in these cultures, presumably in- duced by CLV. loachim, 11. I-L and Elcrwick, L. (Sommert. S. C.) ; Inttrnarirmnl lournal of Cancer 3:61-73, 1966. ()#h.r Rranrorr National Cancer Institute. Frorn the 1)cpartnrenls of Pathology of the College 44 1'hysicians and Sor- Rcons and the Francis Iklafield IlrKpital 1)ivision of ('tdumhia I Inivcrsity, New York ('ity, and the University of Pennsylvania S.fitwil of Mcdu ine, Philadelphia. V111. F.l)idr•mio[oRy PIIYSIUIIE: AND SERUM PEPSINOCI:N llre relationship of serum pepsinogen and body build was studicd among 1,9R7 Army inductees and 141 Italian-Anxrican faclury workers. AnxxtR the Army inductees (age range 17 to 29 years, mctrt age 21A r s), serum pepsinoRen was slightly but significantly assrki:dcd wilh y build. Lean and rnaxuline-k.ukinR men had Ihe hil;hcr levels. ('rulli- cicnls of currelainn between serum pepsimrRen nd the three srnnatutype components (cndu, mcsu, and ecttmtorphy), and for smaller numtxrs Rynarxlromurphy and the pundcral index ranged in absolute value Ik•twcen I/J() arn1 //.1, (1' •- 111)2 to <1)IMK)1) Coc/lit:ienls r,f rcFressirrn were aki, highly siRnificant likewise, amnnR the Ilalian-Amcrit'an /nclury w„rlcrs (age ranfc 22 tt, ht years, nrcan aRe 126 years), currclatitrn tr,ctliticnts hctwccn scrum pcl++inoRcn and the live furcgrrinR physical trairs, ninc tMwly dimcnsiuns, and seven pairetl cnrnhinatiuns td diencnsi,rns I,uiutid with siruilar map,itude in the sanrc direcliun, bul nune hcrc rcat hr c1 statistical siRnificance 'I lie aFxwe findings, if cunfirmed, slrcnltthr•n the t:nc fnr a canstitutional factur in peptic ulter. 67 hh

l)anxrn. A. and Pnlcdnak, A P. l/umon Rirrlrrdy 39(4) 355-367, 1967. Othrr Rrnnrorr: American Ileart Association and Massachusetts (lcart Association. Frcxn the Department of Anlhropolo((y, F(arvard Univcrsity, Cambrid6e, Mass. ETIINIC GROUP AND SERUM PEPSINOGFN The pcxsihilitr that serum pconWn is a"cnnstitutional" trait --thal is, an innate, relatively constant bbinpcal characteristic of the individual, presumaMy genetic fn oriain-was investi6ated in three groups of rriddle- aRcd men 1(vin6 around Boston, Mauachusetts. Subjects consisted 4 201 healthy veterans of World War 11 and the Korean conflict. 141 Italian- American workers In a single factorr, and SI men serving as I)rnlan cun- tru(s in a cardiovascular study nt Irnh-born brothers. Results show4-d that serum pepsinogen kvels did not difler, either In mean value or in vari rhility, anwrn6 thc 133 men of Irish drscent, 196 men of Italian dcscent, nnd 64 Jewish men. A previous report by ('roo6 (1957) of elevated levels amon6 young men of (rish origin was not confirmed. f)OmIM, A. and BcII, B. lnurnal o/Chronic Uiararts 20(10) Rt)3_R08, 1967. Other grnnn.rrr American Fleart Associatiun and Massachusetls Ileart Association. From the (kpartmcnt of Anthrryadnr.y, Irarvard Ilnrvcrsity, ('arn'rridRc, Mass., and Outpaticnt Clinic, Vetcram AJhnnustratrr-n, rtushrn PRIiD1(1'IN(i ('ORONARY IIVARI I)ICI ASI I ROM ItOI)Y MI:AS(JREMIiN(S 0F FRAMIN(iIIAM MAI I:S A total of 1,625 Framin6ham malcs, aged 35-69 when measured, were described by two major anthmlsrmctric Icchniques (txxly build ratings and separate rneasurements), and these descriptions were applied to the various manifestations of coronary heart disease (('I1D) within the study group. Body build ratings (snrnatrNypes) distin6uishcd those men who developed ('(11) from those who did not (NCI1D), )I of the effect being at the younger ages (35-49 yr) and for manifestations of ('111) other than myocardial inhrction (MI)--namcly, angina pectoris, coronary in- sufficiency, and sudden death. Both the somatotype ratings and Ihe pattern of separate rtxasurementt showed that mcsomnrf+hy (muscularity and bony rnhusticity) as well as adiprnily clharaclcrircd the young FraminRham male with ('III) other than MI (('all) NMI). In further study, a thrrc way disc riminant analysis re6res+ed hrxly measurements directly rxr disease slatus. ARain, those with ('Ifl) NMI differed significantly frum the N('l11) and ('111) MI Rruufn 'Ihe magnitude rrl eRect, as distirKl frnm i1s stNiatical siRnificarxe, was suFAcsled by the nwch greater hkcllhlxa) (fKlwctn 4 I and 7 1) that ('(II)-NMI would occur above rather than below the high tcures of the discriminant function scalc. 1=saminatiun of the scparate body measurements contributing to this strong assrx:iatirm showed that weight, chest dcpth, upper arm circumference, and subscapular ckinfrrld, hut not heiRht, triceps skinfotd, or hand grip strength distinguished among Ihe three ('l1D uutcrxne groups at highly significant levels. '1 he work prescnted here, in addition to confirming differences between C'(1() in early and late adult life and between CfID-MI and CHD-NMI, shuwa that physique contributes to the risk of ('HD measurably and independently of blood pressure and serum cholesterol. 1)onrnn, A., Damon, S. T., Harpendin6, 11. C. and Kanncll. W. 11. lrrurnal of Chronic l)1srasei 21:7s (-802, 1969. Other gr.ntor.r American Ileart Association and National Science Fuun- dation. FnNn the Department of AnthropoloRy. Ilarvard lrnivcrsity, ('amhridRe. Mass.; and Ilcart 1)isease Lpidcmido6y Study, National licarl Inslitule, Framin6ham, Mass. AN rPIDEMIOLOGICAL STUDY OF LUNG CANCER AMONG FEMALFS Lung cancer among women Is discussed on the basis of the changing mortality rates of lung cancer over a 42-year period; the cigarette smokinR hisrcxics, as reported by their relatives pr (riends, of 540 femalcs who died of the disease; the inciCence of certain environmental and heredilary factrws repnrted by a segment of the living /cmale lung cancer population, conlrasted with a series of ccxnparahle controls; nd Ihc lung cancer aumissirms fcx females in 12 hospitals river a 10-year perirxl. 'I he results of dris study led to the following conclusions: There is a prnitive relNlirxr- ship between cigarette smoking and undi/ferentiated-epidcrmoid lung can- cer among fernales, although there appears to be no relationship between cigarette smoking and adenocarcimNna-others (n women. ('iRarctte snurkinR does not appear to be related to lung cancer amrxr6 females in a large pnhxutiun of all malignancies of the lung. While there is sonre cvidcncc to suggcst that certain host factors and previous chronic respiratory dis- eases ntay he responsible for srxne of these cases. the eliuhrRy of  large number of lung cancer cases among females still remains uhscure. fwrmAurrf, ll. !.L and lluyck, F. P. Growth 32(1):41-56, 1969. FFrom the New England Deaconess 1(ospita(, Boston. IX. 1'lurrmar'nloRy anrl 1'syc/tu-I'lurrntar•rrluRv RI'.(i1ONA1. 1)Iti1R1B(1'11ON 01: 'IRIIIA11-*1) A('Ii7Y1('11()l INV IN RA I' BRAIN Acelyl '/1 chuline when injected into the riRht (atcral vcntrr.le of SpraRue-Uawlcy rats accumulated in tlrc brain tissue with rclatrvc raprdrty In specimens oblained 30 minutes after injcction, analysis of hN.l radro- 69 hR

activit in vnrinus regions of Ilse Main indicatcJ that acetyl-'If choline was not lazen up equally. 1 he diflcrent:es in uptake amung same regions were higJrly significanl, with the Rreatest accunrulatittns of acclyl '11 choline eKcurring in the hippocampus and diencephaltm '1 he nttled dilferences in regional distributit+n suggest that local accumutalion is not hutuiluus, but may rellecl the degree of invtclvemenl of at:etyl.huline in Ilse activity of these regions. Kramer, S. T.,, Sciftcr, ). and Rhotat, B. Narwr 217:1g4-1g5, 1968. (Ith.r Rrnnror: U. S. Public Fleallh Service. (:rnm the Department of Pharmacolugy, New York Medical ('ullcge, New York City. 111F: r;ffF('IS UF NI('OflNt? ANI) OT1IIiR DRUGS ON 1llti RIiI fiASE UF IN1F.(-IIil1 '11-NURI:PINEPIIRINIi AND ON t:NI1KKitiNUl1S NURt:PINfiPHRINI: (-EVEIS IN TI1f: RAT BRAIN In this pharmacological study, '11-ntxepinephrine (5r.c) was injecled into the righl latcral ventricle of male Spraguc-Uawley rats. Altcr one htwr, acelylcholine, mccamylamine, d lubtaurarine, nicotine, seruttxrin, hista- mirx, gaha and 1) acclykarniline were administcrcd; in most cascs by the same inlravcnlricular route. 1he animals were killed Ien minutes later and their brains assa}ed (or endr~gent~us and labc•kd ntuepinelthrine. Acetyl. chtdinc, mccantylaminc, histamirx arid nN:utinc prtxlut:cd a siRnificant re- lease of 'Il ntrrt•pincphrine bul dNl mrl affccl Ilse Icvcla of cnt'uFcntrus ealechtrlamme in the txain d IuFxcuranne signrlrcanlly reJuct•J MNh the labeled and endugcnnus Ievcla rd mNCl+incphrine, whilc scrnlnnin, Paha and d acelylcarnttine failed Irt a0ect either one ('trntrary ta canc4-r tx•licf, the present study showed tlcarly that even very Sm:Jl d,rccs nl nic'nline caused a siRnificanl release (r( rnuePinephrine RhaRor, R, Kramer. S. Z. and Seifler, 1. F:urorcan luurnaf n/ PlrarmatarrXy 2(3) 234-235, 1967. Frnm. the Ikparlmcnt of Pharnuct>tugy, New York Medical ('rdlcgc, New York City. PIIARMA('OI.(XNC I: ' V11)1?N('1: . VOR ('l1C)1.INfiRGI(' Mli(•1IANISMS IN Nl:(KY)RII('At. AN!) LIM11I(' A('IIVAfING SYS11'MS 'Ihis palxr summarires stvcral pharnmatvrltrgical invcsliF:rlirrns td ccn Iral chtdincrRic fdtcnomcna. I ulluwinl; rxrc avcnuc tr/ aqlprrraclt, Ihc cllccls td fnur rn (ItluKarinK) nd 2 n(nitMinit•) chulincrgrc al;nnists on Ilse awakrdccp cyclc uf eats were studird hcfure and aftcr Ilse adminialr:rliun td nr and n anlagrrnials. 'Ibc /indinga rd this study srrcngthcn Ihc crrntc(d of an in/inratc rcli/iunslti`t hclwrcn 1*1:.(i crfccls and trchavirrr in Ihts wakc- slccP cytlc I Irc Krrrs hchavnrral cnn.cyncntc of I[I•(: aclivatinn is tlc:uly a"akr. rqr or st•rtc Inypont.nrtlv, hy Ihc uac nf Iht• v:rririus nr %nJ n chtdincrgic antagonists with diRerenlial abilities to In•nctr:rte the hhNNI- hrain harrier, it was pussible lu determine if the actions of thc variuus chttlincrgic agtrnists given intravenously were primarily ccntral ur pcriplN•ral in origin. Onc dramalic finding was that nicotine had a dccalcJ central nervous syalcm arousal ellect. A second avenue of approach lu sludy of cenrral cholinergic mechanisms was attempted with hemichtthniurn (II(' 3), a drug which decreases acetylcholine synthesis by interfering with choline lransptxl. Results with IIC-3 demonstrated a dissx>tiation Ixtwcen the netKnrlical and limbic activating systems. In summary, the culkctive evitknce for implicating chdinergic mechanisms in neocorlical and limbic syslenr 1+(i activation is quite imrresaive. 'lhc efkcls ol small doses nf nicnline (as (rccur in tobacco smnkmR) are dramatic, but shtxt acting and re hhKkcd by hcmichuliniunt. 1 his suggests that brain acctylchrrline must be present for nicutine to eaert its central nervous syslem acliuns 1).rmin.r, t. P., I)rcn, A. T. and Yanramoto, K.-1. I'ruKre'st in R.ain Retea.rh 27:337-364, 1967. Orlr.r grantor: U. S. Public ileallh Service. From the [)epartment of Pharmacolo6Y. University of Michigan. Ann Arbor. COMPARISON UF MUSCARINIC ANt) NI('Ol INIC C'11UI.INUKGIC AGONISIS ON SELh-STIMULA"IIUN BNIIAVIOR Rals with chronically implanted electrodes in the lateral ptstertrr hypMhalanws were trained in Skinner hutes Io press a lever which dc- livercd a brief electric shock to Ihe hypothalamus. Aflcr an inilial training peritxt. those rals whuse rate of response sugKcsled that the shtck was pttsitively reinforcing were used to study lhe eRects of chtrlincrl;ic agunists and antagonists tm sclf-stimulalitm rates. (:radcd doses of the chulincrgic agnnisls phystrsligmine salicylale, nicotine tartrate and arcculinc hytlru- chloritk were administered subcutaneously either alone ur 311 ruinutcs a/ler the adminislraliun of one of four antagonists. 1'bystsligrnine c:urud dc pression of self-slimulalitm. 'Ihe magnitude, latency and Juraliun trl this effect were duse-rclated. Arecdine had similar actions, but Ilse depressinn was Icss dramalic and of shurter duration. Nicoline caused hrphasrc cllrtts. Ihc initial depression was somclimes fulltrwcd by facilrlaluNr, anJ Ihc actions were much less cunsident. I'relrcaUncrtt wilh Ilse anlagrrnicls t rccamyl:uninc and scuptdantinc hltxkcd Ihc transit•nt drl.ressanl clfctts of nictdirK.; mclhcc(qwlantinc and Irimclhidinium had ntt cllct l I hc dc pressant c/lt•c,s uf 1~(rystnliRminc and arcculinc wt•rc hlrnkcJ Ly stulM-l.t ntinc and t•ottanccd by mccarnylaminc. Mcthscnlxolantinc nnd IutuclluJrn ium were rrmut h Icss cllcclivc. I hcsc rc.ulls suhrest th.rt ruu.canrnN CINrInI('r~`tl aFrmiUs whith (n•nclrnlc Ilse IdtNNI Irratn Ir.trrtct dr/rtca +clt slimulahr.n trn a ccnlral basis, wlxrtas nictNinic thtrhnrrtri' al rm.t. h.r~r ctunhlc~ tlcpress:tnl atN) stirmAanl cnc•t ls ur tNHh tt•nual nnJ Ircnlnc~r:rt rn iprn Ulds, M IS and I)nmina, h.-. I•-. The fuurnnl rrf l'hrurnnrulURY ar1/A F.t)IfrnOtt'nfUl 7IqYU)4YIhr t 1/hh/?t 1R'/ 204. ly(ry 7,r 71

I il I I Orher Rrnntor: U S Public Ilcalth Service. I:ronl the Ikparlmcnt of Pharmacology, University of Michigan, Ann Arhor. 1)IFFFRF.NTIAL A('lInNS OF M AND N('11OIJNF:RGI(' AGONISIS ON T11E BRAINSf EM ACTIVA'IING SYSI IiM Rostral and caudal midbrain transected cats were used to study the diRercntiat effccts c>t arecoline and nicotine on nccxorlical and limbic (iF.G aclivalion. In the caudal midbrain transccled prcparation, nicotine induced marked !:E(3 activation in both the neocorteit and hippocampus After bilat- cral lesions of the midbrain reticular formalion in the same preparation, hl:(i activation was not ohscrved with nicotine in doses up to 11111 r,g/kg. The 1-1:(; eflccts or nicotine were blocked by atropinc and mecamylamine, hul not /rimelhidinium. In the rostral midbrain Iranseclcd preparatirm, no EF:(i activation was noted with nicoline. Arecoline induced dissch ialitm o( the F.F(i in the hippocampus and neocortes in the rostral midbrain tran- sccted cat Markcd hippocampal slow "arousal" waves with no dcsynchrrm- iratiun of the ncocortical 1:I:(3 were seen. Thcse cRects of arecoline were blocked by alropine. In the caudal midbrain prcparation, even after bilateral lesions rd the midbrain reticular formation which blocked nicotine aclivalion, arecr>tine still induced hippocampal skrw "arousal" waves with- out neocorticat dcsynchronization. I hcsc results indicate that the silc of nicotine action on the rostral forebrain activating system is located primarily in Ihe midbrain reticular fnrnration, whereas arecoline acts on the midbrain reticular frxm.lion as wetl as above the level of the mesen- cephalon Kawamura. I1. and I)nminn, F.. F Intrrnotinnal Journol of NruropharmorodnRy 8(2) 1l)S-I 15, 1969. Orh.r 8ronror: l1. S Public Ilcalth Service. From the (kpartmenl of Pharmacology, l/nivcrsity of Michigan, Ann Arbor. ('III:MI('AL AI-T[:RATION OF RI?LEASE ()1' S-IIYDROXYTRYPTAMINE FROM ISOLATEI) GUINEA PIO SMAL1. INTESIINE Bioassay of the bathin solution in which sections of guinea prg small intestine were contained indicated that this isolated lissue is capable of releasing histamine and S-hydrosytryptaminc (5-11T) into the fluid medium. The content of 5-IIT in the control bath increased rapidly for the first ten minutes and then dcmonstrated a gradual increase fcx an additional Iwo hours Ilesamethrxtium (10 pR/ml), alrup ne (I r~g/ml) and nicotine (0 5, 1 ex 5 rg/ml) were added to the hath uslulinn to study lite eQecb of these chemical agents on the intestinal retease af 5 111. Iksa- mNM+nium increased the concentration of released 5-11 r. Atropine and nicutine demnnatra/ed no markcd altcratiexr Itre significarxe r-f Ihis ' hility r+( iadated segments u( guinca pig small intcsline to rclc:r+c 5 111 is unknown at Ihis time, allhouRh it is suRFc+tc4 Ihat lite retcascd 5 I I f may crrntnlhutc !n lite incrcatcd mrdilily uf isal.rtcd scRmcnts. 72 I Burks, T. V and lwrng, 1. P. Arr hirrs Inrrrnorrunolrs de Pharmocod ynomir rr dr 7 hfroldr 172(l) 161- 171,1968. Oth.r grantor: 11. S. Public lleallh Service. I:rorn thc Ikpartmenl of Pharmacology. University of Iowa College u( Medicine, Iowa ('ity. ANTAGONISM OF GAN(;LIONIC STIMl11.ANTS BY o,o-BIS (DIMI:1 I IYI.AMMONIIIMA(.'1:-fAI 1)I:I IYDE 1)IIi111Y1-A('L:1 A1.)-v,p•UTA('EI'YI.BII'III:NYL BROMII)1? (UMAIiI Studies comparing cocaine and UMAIi interactions whlr varinus nicolinic agents have shown that DMAE eshibits an "anliniculinic" activity that is grcalll dillcrcnt from that found for cocaine, In calxruncnts whh dugs. UMA1: antagonized the ganglionic stimulating actions rrf nicuturc (NIC), letramcthylamnoniunr bromide (fMA), dimethytphcnylpipcr:vm ium iodide (DMPP) and acelylchdine (A(h). Pressor res).rmses to splan.h- nic nerve stimulation and central vagal nerve stimulation indicated that transmission tluoug)r ganglia remained unimpaired at levels of UMAIi sufficienl to block the ganglicxric stimulants. NIC was nNnt readily bhKkcd, while KC 1 and nerve stimulation were unchecked by UMA1:. '1 he scyuencc of sensitivity to blockade was: NIC >'fMA > DMI'P > ACh > Kl'I and nerve stimula/ions. The respiralocy stimulating action of NIC was completely abolished by DMAE. The abnve sequence of sensitivity lu bhxkade by hMAE was confirmed in a series of tests using lite cat nicti tating membranc-ccrvical sympathetic ganglion preparatiun. I)MAI: is the only known derivative of the hemicholinium (FIC-3) structure that euhrhils either catecholamine potentiating aclions, or the selective anlinicutinic action. Wong. S. and l.ong, 1. P. Thr lnurnol of Plwrma-ornay and E.lrerimrntal Thcroprurirs 16a(1):176 184, 1968. Otlr.r grantor: American Medical Associatirnr l:ducation and Rcscarch Foundalion. hnxn the Ikpartment of Pharmacology. University of Iowa ('ultcgc tr( Medicine, Iowa City. I ANTA(;ONISM O1- T111i AIIRI('l1LAR SfIMlI1.A'IING A('fI(IN (W NI('OI INF. IIY a.i/ 1115 (1)IMIAIIYI AMMI /Nl( IMA( I:I AI UI: IIYUI? UI1.111Y1.A1'lilAl.) p./i UTA('Iil YLllII•IIIiNYI. Ittt(rMllW, 1)MAI: I)MAF., lite diclhylacclal dcrivalivc rd lite alJchyJc rd hcnut hrduuurn. was uscd tu Icst Ilre anlagunism rd nkotinc induccd symp.dhclrc and I~er.r sympalhctic aclivatiun and trr cvahralc lurasympathclic Ranyhmnik inlntn tirrn In this cx/xrimcnt, :drial ratcs and cuntractilt Lxcc rctl.,rn.cs wcrc measurcd in Ruinca pig hcaras superfux'd by VciKan's suluuun (.ontrull, 73

nicnline (20 pR/ml); 1)MAF; anJ 1)MAIi I nicnline. Nicutint, alunc, clitilcd a hiphasic resptma in Ihe isrd:dcd Ruinca piK atria r)MAF., in cunccntraliunt rd OOS (I 5 pK/rnl, w,rs an cflctthvc antayunisl Of Iwrth the chromNrupic and inotropic aclitxrs n( nicotine Iltrwcver, I)M AI? altxie, in concenlreliuns 20 liunet Ihe effective anti-nicutine concenlralirrn, prrKluceJ no alteralim in the normal atrial rale t.r force Also. this cnncentralion uf UMAF: prrxluceJ no alteration in responses to electrical stimulatir*n r,( the right vaBal nerve 'Ihete sludies demonstrate thc pdcnl niculinc hlrKkinR aclirxr of UMAF in guinea pig atria without apparcnl :dtcratit,n in para- synrpalhclic ganglionic transmission. WonR, S, L.mR, !. P. and (iross. F. n. Arr•hir•rt lnrnnarrtrnolrt de Pharmandynamir tr dr Thfropir 176(2) 425- 433, 1968. From the hcparlment o/ Pharmacology. llnivcrsily of Iowa ('ollcRc Of Medicine. Iowa ('ily. MIirAHOLISM OF (- )-('OT ININF-2-"C IN TIIE RAT A route to the synthesis of a number of nicotine rnelaholiles bearing a"(' label adjacenl to the pyriJrne rinR is described This synthetis, which s/arls with the cnntknsatinn of ethyl niculinate-7-"(' and Jiclhyl succinate, prnvidcs '/1 pyridyl) r-o><uhutyric acid. y lI pyritlyl)hydruxyhutyric aciJ, y-() pyritJyl) r methylaminnhutyrit- acid. curinine, anJ demclhylcrdinine, as well as Ihc two alkaloids nicotine anJ nurnicnline. After administration of (')-colinint 2-"( • to the rat. the rnme Mas e.amineJ chrmualnKra/.hically (or radioactive arrJ Ki-eniR (wnrlive ((.ynJrne) sulstances I he Reneral pat- tern 44 escretion Of the raJrtr:rtttve K,K•niK p,rsrtive sahalances, resemhlyd Ihtne previously encuuntcrctl in aauc rrthcr q.ecict and p:uallclcd thal found earlier with nr%nisrrlrr['ic malcrial Ihc radionclivily u( adminittcred (')-ctrlinine was elirninaled with a hiFh Jepee tr( elliciency ('/1) 97% Of the administered dose), predominantly by way of the urine Virtually no radioactivity was enctwnlered in eRpired air, suEgestins little or no ctrnver- inrn trr nicutinic acid. Sinrilar exl+erimentt where carrier nicotine wat empluyed failed to provide evidcncc for the rcversibility Of Ihe metabolic reaction nicotine -. cWininc. Mnrsclli. P. l-., Ong. I-1. I1., flowman, F. R. and Mt-Kcnnit, N., !r. lnurnal tr/ Mcditirral ('hrmirrry 10:1013-1(136, 1967. Orh.r Rrnnfnrar American Medical Asttx•ialiun /'ducatinn and Research Foundation and American 7ohaccu ('rnnpany. Fnan Ihe lkpartment of PharnuudnRy, Mcdttal ('olicl;c Of Virginia. RichrnunJ. I:1I1(•1S OF SI)MI? NI(Y)IIN1: . MF.1A11OI IIVS nNh REI.AI1:.1) ('OMI'O(tNItS ON ISOI.AII•.1) SM(K)1I1 M(IS('L1: 'I hc acUomt ~d a tcrics Of coml>,runds slru.turally rclatcJ Io nicotine wcrc r'hscrvcd un inrdalcJ rat JuuJcnal st•Omcnts arrd on rahhil JurKlcnal I anJ ileal segmcnls Rcsults generally support a conclusir+n that pyriJinc, pyrru:idmc and N-methylpyrrulidinc tacrl a nictnUne like cllrcl (in Ihc prcparathuns 'Ihis tentative hypothesis gains support Irum Ihc dt•munslra tiun that Ihe action of nicotine and these compounds was siuularly alfcclcd by hcsamclhunium. Iclraelhylammonium, alropine, cocaine, diclJurrrisu- prolcrcnol, phcnttdamine and btclylium. Three mamm:dian rnclatiodilcs Of ( )-nicrNine, ( -)-colinine, (--)-demelhylcolinine and -3-pyridylacetic acid were exarnined for eflecls on itulaled intestinal segments ( )-( •otininc cauteJ a rclaxatitrn response a1 a concentration in Tyrode's sululiun ap- proathinR 2 R a 1(I' M. (-)-lknxlhyleolinine produced similar cflccts. 3 Pyridylacetit: acid produced small stimulalory and inhibilury chanRes at cuncenlratinnt in the rxdet of 10 s M. T be results wilh the entire series of conrptwnds appear to he consislenl with previous tdnervalitms that dcyr.rda- Iwn M alteration of the carbon skclelon of the pyrrulidine ring ol nrculine decreases nicoline like activity. Kim. K. S, llurrelleea, 1. F., 8owman, E. R. anJ Aft Knrnir, ll., /r. The Inurnal o/ Phurmat-vluRy and Exfoorrimental Thrraprurict 161(1) 59- 69, 1968. Orb.r Rrnntnrr: American Medical Association (?ducaliun and Research Foundation and American Tobacco Company. Frnm the lkpar/ment of Pharmacttto6Y, MeJical (-ullcye u( Virgrnia, Richmond. ST111)1U5 ON 1111: EX('R[:TION 01: S-O-1'YRIhYI )- 1I:IRAIIYURO1•(/RANUNE-2 ANI) ITS INIVRMI-.1)InKY ROl F IN '1111? MI:IAHUI-ISM OF NI(-UIINIi Aflcr Ihe adrninistralion of S-(3-pyriJyl)IelralryJrufur.rnunc 2 to the ral, the urine contains five or more KucniR pusilivc cumlwrundc '1 wo Of Ihcse, mclahrditcs of Ihe administered eurnptrund, were isulatcJ hy mcatnc of gas chrumatoRraphy and idenlificd (in derivative ltum) as r(3 pyridyl)- y-hydruxybulyric acid and 3-pyridylacc(ic acid. 'Ihc pallcrn rd cMcrt•liun of the KtrcniR-ptnitive compounds resemhles in part that uhuincd frum administration tr( nicotine or eulinine and provides addilirmal cvidcnce lur the intermediary role of y-(3-pyridyl)-r-hydroxylwtyric aciJ, rr the cur- respundinR Iaclone, 5-(3-pyritlyl)Iclrahydrtduran,rne-2, in thc hu,natirm u( 3-pyritlylacctic aciJ from nicotine. In the ral S-( 1-pyrrdyl) Ictrahydrrr- furannnc-2 was virtually devoid of Ihc Jepressant prtqn•rUCS Of r huly rrdacclune In curmmon wilh culinine and ulher mc/alwditc% Of nitnnnc. thc acute 1u.icity rd 5.(3 pyri(lyl)tclrahydru(uranunc 2 was tr~nvJcr.rhly Icss Ihan that Of tlrc parent nit'uline. lhrwvnun, 1. K(Ah Anrnir, Il., lr ) VirRrnrn l.ne.rnnl o/ .Sr icnr r 19(2),l 11 121, 191hR Ihh.r Rrnnr..rr: Amcrican lrrharcrr ('orupany anJ Anuruan MrJital Assrxiatian Fdu.ariun and Rt•scarth 1•trundaliOn Frrrm Ihe I)cpartmcnt Of 1'harmaculuRy, Mcdical ('rrllc);r ro( VnKinr1. R icl uuond. 75 74

L1TE('i OF HFrA A1)RfNVRGl(' Hl.(X'KIN(; A(YNIS ON llll: NORAURI: " NAt.INF- CONIFNf OF RA1 I11?AR1 1)I1URI? ANI) AFI ER NURAI)RI:NALINI? INI-USIUN Four of the newer bcta adrenerlrjc bhtcking agents (M1199R, M11999, Ko592 and INI'I:A) wcrc chccked for their elfcct un endugcnuus roradren- alinc levels in the rat hcarl. 'Ihcsc drugs were afso studied for their ability to influence the annrunt of noradrenaline rccuvcred in rat heart ar (I spleen following an infusirm of Ihis neurotransmitter. M11'/99. Kir592 a td 1.( 1) and I)( ) INrf:A did not produce any significant changes in Ihc nuradren- atine content of Ihe rat heart following single injections (drna ;e range 0.2-1O mg/k 6) or following chronic administration (IO mR/day/7 days). M1199R pn>eluced a significant decrease in the nrxadrenaline cu.tcnl six hours frrllowing a single injection of 10 mg/kg anJ, also, after chronic administration. M1199R (10 mg/kg) •Iso produced a 50% dccrcare in the arrKwnt of noradrenaline measured in the heart following an infusion of this amine, whereas neither M11999 nrN Ki1592 had any c/fcc1. 'Ihese data are IrK)kcd ufvrn as evidence frw the fact that M1199R a!ters Ihe uptake of noradrenalinc into certain adrenergically innervated tissues. Wrir(all, T. ('. F.urorran Ie,urnal rr/ I'harrnornloRy 2(3):163-t6R, 1967. Orh.r Rrsnrurr American Medical Association Fducalion nd Research Foundalron From the tkpartnrcnl rr{ rharmacrdoRy. Univrrsity of Virginia School of Mcdicine, ('harloltcsvillc IN1 1 I1f N( •fi UF NI('U I INIi ON ('A I ti('11OI.AMIN1: N11i I AHO1 ISM IN 1111' RAT 'Iht effect of three diRcrcnl drncs nl niculinc on Ihe 24_huur urinary etcretion of cpincphrinc, nore~iinehhrinc, mclancphrine, nnrnxlanephrine and 3-rnethoxy-4 hydruaymarx)clic acid has been investigated in rals. All three duses (I/.I, 1/5, and 1.11 mR/kF) pnMluccd a statistically significanl increase in 1hc excretirxr of epinephrirK and its major 4r•mcthylalcd urelalxr- litc, mctancphrine 'Ihere were no significant changes in the cacrcliun od nnrepinephnrx, nrKnrclanrphrinc, nr 3-rnelhoxy-4-hydruxymamlclic acid. lhis Ied, thcrefure, to the conclusion that the release of cpincpluine, frorn the adrenal medulla by nicnlinc, is much morc impnrtant in prrMlucing the various pharmacological responses• than is the corrcspondirng release of norcpincphrine. IVrsrlufl, 7' C anJ Andcrson, G P. Arrhrvrt Intrrnon, umlrr Jr l'lrornmrralynurnir rr r)r Ilrr+uprr IMl(2):411- 42R, 1961. (h)hrr Rrnntor: American Medical Auociatiun Vducatiun and Research Foundalirm Frnrn the Ikparlmcnt of f'harrnacuhrfy, (Inivcrsity of Virginia SihrMd of Mcdninc, ( harlrrttcsvillc A('lION OF A III:fA AhRENERGIC RF('t;/'1OR IlI (X'KIN(; AGI:Nf (/N II11? I'USIIIVI: CIIRUNO1RUI'It; RESI'ONSI. ANI) lll'IAK1; U1= NORI:rINI?r11RINt: IN 'fl•IL PI:RI•uSI'.L) (;UINI?A-rl(; III:ART The positive chronotropic response of guinea-pig hearts after a 20- minute perfusion of norepinephrine (NE) was significantly reduced by three different concentrations of Ml 1998 (10 •, 3 a 10 ••nd 10'M). l his effcct was clearly dose-related. All three concentrations of Ml 199R significanlly reduced the increase in Ixart rate resulting frorrr the Ni: perfusion when the blocking agent was continuously perfused 30 minutes prior to and during the NE treatment. MI 1999 blocked the increase in tissue NfE and incrcascd the content measured in the pertusale eRluent. Therefore, il is concluded 1/ at Ml 199R can antagonize NtE uptake. The highest concentration rr/ M1 199R did rxd influence the pcnitive chrornNn,,+ic •clion d('a('I„ which suggests that blockade of NE uptake is not a result of myrrcardirl depression but is prnbah!y a specific eflect. The blockade of N1: uplake correlates re•sonaMy well with the receplor-btocking properties o( this drug. Fxperiments utilizing reserp~ne and Ihe monoamine oxrdase inhibitrrr, nialamide, seem to indicale Ih•t Ml 1998 is antagonizing Ihe urtake d Nli into the attonal membrane r•Iher than the transport and/ur binJing in intraneuronal storage vesicks. Wrt!/afl, T. C. 7lrr lrmnrral of I'IrarrnacrdrrRy and I:.tprrimrnraf Thrrapruur.r 1(r2(2):239- 245, 1969. OOther grantor: American Medical Association liducation and Research ' Foundation. From Ihe Ikparlment of Pharmacology. eJniversity of Virgirnrr tichrxd n1 Mcdicine, ('harlollesvilk. X. MPtaLIIltf srurGr'a f•.II•li('f OF ('IGARIiI-IE, ('IGAR, ANI) rIl'li SMUKIN(; (1N NI('UfINI: LXCRIiIION: T111: INFU/f:N('1: 01: INIIALIN(; Ilsing a gas chromatographic method to determine thc nic-r+tinc crrn- tcnl of the urinc, tcsls showed that 29 nnrmal nraJc snnrkcrs surr+kinR ciga- rcllcs in the cualonury manner rA inhaling cacrctcd Ihrcc tinres Ihc yu:rnUty uf uirrHine Ihat they cstcrclcd aftcr srnrrkinR pilxs ru ci}~ars in Ihc .uslunr.uy manncr td nrd inhahng 'lhcre was nu vRnrfi::rnt Jdterrnrc in nr.nlrnc txrrrlion Ix•twccn ciK.rr anJ pipc srurdring furlhcr Ic.ts in tcn sulyc'ls shnwcd no sipntficanl drflcrt•rx'e in mran nicotinr cR/rC11iN/ d riR:rrcrtr•s, eirars aud pipes were all srnr-ktd with inhalinK, rrr d all thrce were anurl4•d wilhr.ut inhaling In tcsts with ancslhclitcd drrgs, cyurv:dcnt anrnuurc ul cigarcllc, cigar, and rilx lohaccu smoke were adnunislrrcd intralr.rchcally with inhalaliun kert aonstant Nicrrtine eacrctirm was simdar wrth cm h tobacco furrn. '1 hese findings indicate that the Frcater nicrnure e.crelron 76 77

with cigaretle snxrkin6 is a result of the tendency tit inhale cigarcttcs and not to inhale cigars and pipes 1 he diflcrcnces in nicolinr cxcrctitrn are mnst probably a consequcnt'e of similar diflcrenccs in nictrline absorption. Kcrshhaum, A, Rrllrr, S, I lirabayashi, M, Fcinf.erg, 1.. 1. and Ftlhcrg, R. Ar(Ittr•rt rr/ Inrrrnol Afrdirinr 120(3):311-314, 1967. Other Rrnntor.: American Medical Association Iiducalitm and Research Fuundatiun and National Instilulta of Ileallh. Frtxn the E)ivision tr( Cardiology, Philadelphia General Ilvspilal, Phila- dclphia. ('1(iARU :1'1 F, ('1(iAR, ANE) PIPE SMOKING: SOME E)IFFEREN('ES IN B1OC'IIE:MICAL EFFECfS 7ht influence of cigarette, ciRar, and pipe Imokin~ on hltxKl lipid cnm{+mitiun and calecholamine etcretitxt was invesligaled, and the role of inhalal'ntn in the ohserved eRecta was aacertained. llsing cu,ttrmary smuking habits, subjects showed greater plasma free falty acid (FI'A) mobilization with cigarettes than eigars; this eflecl was reversed when ciRars were inhaled and cigarettes were not. In dogs, with the int,alation factor conslanl, there was no diRercnce in FFA or triglyceride r rslxxtse to eigarelte, ciFar, or pipe smoke, end tht eflecls of nicoline were srnrilar ta ttrhacco tmtrke. (•atethulanrine excretion in smokers was Rreater with cigareltes Ihan cigars; urinary nict-line e>teretiun was greater with citarcttes than with either cigars or pifn•s 1hi. was rcvcrscd when ciFarctt-s were not inhaled and cil-art antl Irr/k t wt rc In tlt•g%, c.lwsturt• Itr thc thrrc Icsl suhslances clit itcd ntt dcmumlr.tldc hllt rcnt ct rn ctlhcr t alct h d.nnute output or nit'tttine crcrc/run Ihr hnJtnr•~ tlrnt„mtr.HC Ihat Ilic ~rcatrr lipid and calccht,larnine rt•sl.tsritt• 1,s up.,trcrtt• anilkinl! r% duc In the tentkncy to inhale cigarcttts, wrth rr%ulr.utt Itrt,ttcr nittourte ah%nrptrtrn Kcrshhaum. A and Rrllrr, S. C:rriolrict 23(3) 126-114, 19611. Otb.r Rrnntor.: American Medical A.sociation F:ducatitxr and Research Ftwndation and National Institutes td Ileallh. From the EXvision of Cardiology, Philadelphia Gcneral Ilospilal, Phila- dclphia. EiFf E("1' 01: SMOKING ANl) NICY)1INF. ON AI)RE:N(XY)R'I ICAL SF(-RFl ION 'Ihe eflect o( niiutint tm Ihe sectrltuy ctivily of Ihe ndren:rl etrrlrx was studied in man, in the du(S and in the rat. In eight human subjrtls, heavy cigarette tmoking elicilet) a 27-7795 rise in plasma I I hydrnsyctx- licuttcroid ctmccnlralitms, compared Itr a nnrmal diurnal (ntl durinR turttrtrl trtncrvaliunt with nu srnuking Intravcnuut adminislration tit nit-r- line lu ancslhclrred dogs rewlled in a h47.% rise in Plasma ctrrhttnlrrt~iJs; anA, in r:tlt. Idasma errrlict.tlcrnid ctrnrenlralitms irKteascd SR'X• allcr intra1.critttncal atlmnustralitrn of nictrlinc It is surrrslt•d that Ihis stimula- litm ol adrenucortical activity is due to enhanced curttctrlrupin relcate resullinl; /rom a nicotine induced increase in sympathclic and calt•thtda- mint atlivily. Brcause td Ihc physiological and palhuhrgital imlarr/ancc td adremscurlical htrrmoncs, their broad use as therapeutic al;cnls, arnd their rclationship to lipt-protcin synthesis, the eRtcl uf cigarcllc smuktng un adren,rcurtical secrctitm must be seriously regarded. Kershhaum, A., Pappajtrhn, 1). 1., Brl(r(, S., Ilirabayashi, M. and Shalhha, I1. lnennul tr/ Nrr .I rnrrit an Mrdiral Asstxiatiun 203(4). 113-1 16, 1969. OOther Rrentt.r.: National Institutes of itealth and American Mcdtcal Acsucialit.n F:ducation and Research Foundalion. From the 1)ivision of CarditAogy, Philadelphia General Ilospilal, I'hila- tklphia. A('OMPARATIVF~ S1'U1)Y OF ('IGARF.TiE, ('I(iAR ANI) I'IPI: SMOKING t-:FFF('TS ON BI.OOI) LII'IDS, CATF('IIOI.AMINI? E:XC'RIi11ON ANI) NICOTINE CON1ENf OF '1I1E: URINI? This paper summarizes a series of human and animal experiments tk- , signed lu compare the eflccll of diflerenl naxks of smoking on bhwnl lipids, calecholamine etcrelion, nicotine absorpliun and nico/ine est•relion. In dogt, with 1he inhalation factor conslant, there was no dificrence in any of the parameters studied regardless of whether thc tcsl substance emplnycd was cigaretle, cigar or pi(~e smuke, or nicotine. (IsinF cuslautary sm.,king habits, human suhjec/s showed greater FhA mt+biliralion with cigarrttcs than cigars, a fintling which was reversed whcn cigars were inltaled and cigarrlles were ntN. Calechdamine escretittn was Rrcaler with ciRarcltrs than cigars. Urinary nicotine eaerelitm was Rrcalt•r wilh ciRa- rellcs Ihan cigars or pipes. "lhis was reversed when cigarcltet were not inhaled and cigars and pipes were. 'Ibe findings tkmnnstralc that Ihe greater lipid artd calecht4amine res(xmse to cigaretle snntking is due to Ihe Iendency to inhale ciRareltes, with resullanl greater nicolinc abaxption 'Ihis is suhslanlialed by the higher level of nicotine excretiun with cigarctle snKrking which is equalkd by cigars and pipes when they arc inhalcd Kershbaum. A. (Rrllrr, S.) F..ttrait drs Acta CardiolnRica 23(4).317-329, 196R. lhher Rrnntt.r.: American Medical Assuciatiun and Natiunal Instrlutcs of 11ca11h. Fn+m the I)ivititro nf ('ardinloRy, Philadelphia (icnt•ral lltninlal, I'hil:r dt•Iphia. 1:1114'f OF SM()KIN(i ANI) NI('OIINI: ON 1I1V ('RYSI AI.I.I7A I ION OF ('11O1.F.SI VRO1. Rrccnt sludics have shuwn that scrum lipid c.lratts frtan thllrrcM individuals rrtnluir diflcrcnt ralct of crystallvation tit chodcctcr-,t frum a standardt7cd sttlutiun of chulcslcrol in IriE,lyceridc. lu Icsl whclhcr tuhaCtu 7R 79

srnl/kinR anJ nict.linc aJrninistration have any cflcct on 1Jtc ch/.Icstcrul crystillr7alilrn ratc (( CR). studics were cr.nJuctcd rrn humanm arnJ anrrn:rls. In Ihc hurnan IcsU, a siRnificant inttcasc in ('('R values rx'currcJ with scrum catracls af hhxxl laken ftnm eight norntal sml.kcrs 11/ minutcs after ciRarctte smrtkinR A sirnilar risc did not dcvchrr after cifar nr pipe smukinR 1 herc was no change in C'('R after culfcc, hul an inctcasc tx'currcd when cuflcc was (ulluwcJ by smuking. 'Ihis t.hscrvcJ drflcreoce suggc•sls that lice fatty aciJ (fFA) mobilizalion is nut rarl of Ihe rnc•chan- ism rtf IIK cigarctte sntokins cflecl on C(•R since both cn/fce and smr,kins increase scrum I fA ctxxentralions. In si>r ancslhetircd dugs. Ihcre was a significant increase in (•('R after intravennus nictNinc. '1 hus, results sh/,weJ that scrum lipid cxlracts of bhtod taken after cigarette snnskinR in humans, and after nicotine aJnrinistratitm in JcV. , consislcnlly increascJ Ihc (•('R. 1 hese observalinns suggest a Ixnsihk contribulinf n.cchanisnr in Ihe hiRhcr incidence of severe crxonary athcroxlerr»is in crRaretlc smttkc,s. Kcrshhaum. A., rarrajohn, 1). 1., ()sada, 11. and Rcllet. S. f•:clroit.fct Acro ('ardr.drrRico 23(6) 54R-557, 196R. ()rh.r grnnr.rr.: National Institutes of Ilealth and American Medical Assrxialivn FJucalion and Rcscarch I uundalion Frnm the Oivision of Cardiology, Philadelphia General Ilnspilal, Phila- dclphia. OIISIR(t(-IIVI: I lIN(i I)ICI'/1SF ANI) .., AN111RY1'SIN UFI I('1VN('Y (iI NU III: II Rt)/YlL(1CIIY PrrKCCJing on thc hyfx-thcsis 111.1 IunR Insuc is Jcstrnycll in inJ/v Juils wh/ne scnrms are dcfic'icnt in ..,-anlrtrypam hc•cauac uf thcir tn:thillty lu inactivate rrntadytic cnrymes rclcascd JurinR iullamncuray prlx-cs.cs in Ihe IunR, tcsts were run flrr an asuxialiun hctwccn hctcrr./ygrosity anJ trfntruclive lung Jiscase 'ibe phcnl.tylKs t.f scrum ..,-antitrylnin were Je- IcrmincJ by antiKcn anlifxxly cnnscd clcctrrrrhuresis. l here wcrc fivc hnmrrzyRrttcs anJ 25 helcruzyp•lcs frrr the Jcficicncy Rcnc fuund in a Rruup d( 103 patients with ubslrlxlivc IunR discase. Ihe frcyucn•:y nf hclcrozy6ules was 14^i% and 9°•'F% in Iwo c/.ntrol groups with diRcrenl mcan alcs of 3(+ and RI) '1 hcrc was only r.nc hctcnrzyl;lttc amtarR 39 hc althy malcs over 70 years uf aRe. IlcternlyKtnity may bc a rreJisfxrs-inR fa.lur in chrrtnic ohslructivc IunR diwasc, csl.ccially in Ihc nralc Ixrhulatiltn. Sh..u1J sluJics rd IcuFcr fx.rulalilms clntlinn dtis high incidcnce of .t, anti- Iryrsin tlcficicrxy and inJicalc thal .u.h a Jcfnicncy rcndcrs an inlliviJual nrure susatl/tihlc In Ihc cffcc'ts /.f ciK.ncUC srnukc anlt Irrc/h\1MnC3 hmn lil rlh.truttrvc lunr. Jracasc, a Iarr.c sc;Jc rlctctdrm rr.rl•ranr wrrtdJ Ix• ucclul in rrcvcnlinR Ihe unscl ta this IarRcly irrcvcrsihlc and increasinRly asrum.ln lhafase Kncl•ix-rs, 1: , I allat, It and l.lrrt.nr, R R S/ Irrrl t• I!• S R09 9(11. 1')h/) IIrL. r t.....r.'. •,1 ..,.. •1 In.~,tul •. .•I 1 t, dth I rant Iltc I resm. '(('al )(kncral I luspilal, and ('althl.v;tst'ular Rcscatl h Inshtutc, llnivcrsily of ('atifrrrnia San Frarx'iscu McJrcal ('cntcr, Srn f rancistrr. f•ITf(-r 01: CIrARF•illi SMOKING ON URINARY ANI) SAI.IVARY "1I111)('YANA7F-.S lhir.cyanalcs were mcasurcd in Ihe urine of ten smokers and seven nr.nsnarkcrs and in thc saliva of eight smukcrs anJ two nr.nsnu~kcrs in an allcmrt Irr carrcl:rtc the ccwnlxwnJ with snwtking schcdulcs of incrca.cJ, rx+rtnal, anJ rcJuced cigarette consumplion. Ohscrvcd Ihirxyarn:uc Icvcls were unly rrrul:hly rrthxalianal lo snarking patlcrn, wilh Ltrpc inJiviJu,d varialirwr. S:divary Icvt•Is, w!tk'h JiQcred Krcally helwccn stnr.kcrs anJ nlro smukcrs• crwrclaled hcttcr with cigarette conwnrrlarn lhan did urin.tty levels. Altht.uKh Ihi/+cyanate Icvcls cannrN serve as a Prccisc indcs rd indr- viJual smukinR calxtsurc, Ilrc reliability af salivaty mcasurcmcnts cntdd Lc cmpluycd lu scparalc large populations of srnukcrs and mtnsrnukcrs. Barylkn-Pikiclna. N. and I'unxhurn, R. Af. .4n'hivrt rr/ l.rn unnrncnlnl Ncolth 1715):739-745, 1961 Frunt Ihe 1)eparlmcnl of Food Scicrke and fcchnuloKy, ltnivcr.ily /d ('alifnrnia, ()avis. XI. (aa'pme>tlry rtnd IliorhPnti.fry MUIT('UI.AR SIRII('IIIRf.S ANI) ('AT/11.YII(' n('IIVIIY. 1. ('A IAI.Y7I(' PUI.AR(x;RAP1IY OF 'I IIIAMINI', UXY I IIIAMINI: ANI) 'I IIIAMINF I'II()SrIIA I I:5 '1hc bilxficnucal mcch.tnisrn rr( Ihc clkrvyrnc 1hi,uninc I.yrl.l.hu.l.lc.uc (cocarlxrayl:rsc) is cspturcd in this earcrimcnlal invcsliralirm /d Ihc cal.dy tic Ixrlarngrarhic actrvrlics of Ihiaminc and its urFanic dcrivalrvcs Whcn such aclivilics wcre studicJ Juting /hc intramrdecular rcanaut cntrnl /d lhc Icsl suhslanccs ill a basic st>tulirm. Ihc half-lifc rd tlrc Iwllarnyr;qllhtc ma ima was sit minutcs frrr Ihi:rminc, 19 mimNCS (ur c.xarlxl.yl.r.c, 1S rninulcs fur Ihrannnc numophrnhhatc and IRR minulcs fur llxylht.unrnc 'I hc Ihi:mtinc hhl.clthalcs :ytpcar In tK m/nc stahlc in Ihc Int yl Irr d/hyllrn Ihiachrranmc furtn• whcrcas Ihiaruinc is ctrnvcrlcJ runrc ralnJly Il. /hc ycll..w thi.d fnrm Alth/.u/1h it thas Ix•cn naannc/) 111.11 Ilhi:uurnc• ,uiJ c.x :ulw.tylase h.rvc thc s:rruc reat u.ln rnct haur.m. rc.uUv hl rc rn/h. .ltr 111.11 1hr:uuirne anJ l.xarlx..ylasc tlrllcr 14.111 in re;atUnn nic.ll.llu.rn. n/l.l tc:xthl.n ralca ut /l.halll.u~ ann111N11.11.1I sr.lulilln An a1lrny.l iv ln Ihis re/wu/ tl. cr.rrcl.rle the talalylic IHd:uu/!r,y.hi/ .nltvdlr. .d Ilu,.nln r and clx'arh..eyla.c wilh vuntc lif thc slnlclurc•s u/ rhix vuhvl.ln... in Ihl cuhall/ws amm.1niaral aduul~n. (iuJhjarnasnn. S /RrnK, K I I 91

Oth.r Rrnnhrrs: U S 1 ublic Ilcalth Scrvit:c, Miihigan (lcarl Asaxiatirm, Anrcrican Mcdical Asstsciation I?ducanun and Rcscarth FuunJ.turrn, anJ Iklruit (icncral Ilospilal Rcscarth ('tnlarraliun. From Ihe Ikparlmcnt of Mcdicinc, Wayne State llniversity Sthool (if Mcdiaine, lklroit. SIA1311.Il.AIIUN 01' URINARY 3•IIYDROXYAN'IIIRANII I(' ACID RY URAI. AI)MINISIRATION OF L-AS('ORIiI(' A( II) lhis paper presents a fimpk method for the slahili7alion uf urinary 3 hydrotyanthranilic acid (3-IIUA). Consecutive serics of fnur uvcrnil;ht specimens of urine were ct>fkcted from each of five lunwrr patients Allcr cotlcction of the second spccimen, ea.h patient was given I"ascrrrbarc orally lu cause spillaRe rd ascurbalc inlo Ihe urine. Knuwn amrwnts uf 3 I/l)A were then adtkd Iu Ihe urine samples arKl allowed to int ubalc at 37" frw siR hrrurs. Results showcd that in spccimens I and 2, collcttrd txfore ascorbale administration, mean percentage recovery (r( added 3 I I( )A was about 5t/7f. ; whereas, in specimens 3 and 4 Ihc 3-I IUA recovery was atxwt 1/N)76 and urinary ascorhale Ievels were elevated as citpcctcd Since urine ordinarilr renmains in the bladder for at kast si>t hours. the ilalxll7atlrNl o/ urinary 3-11OA by txal adminislralion td 1.-ascorhic acid before aolleclion td urinc specimens might Rivc more reliable data cnnccrning the urinary e><crclion of 3-IIUA by patients with IunN+rs o/ the bladdcr Pipkin,(i R, Nishimura, R• Flrnowsky.I anJ Srblrgrl.1t fl. I'rrK rrrlrnRt if the Sea irty /nr E. ttirrrnrcnual RuhrRv nnA A1.•drr inr 126( 3): 7112-7114, 1967 Illhrr Rrnnrnr: Natiunal ('anccr Inshlutc From the 1)cparlmcnl of Surgcry. Scctic+n rtl Urulrtgy, lulanc Ihtivcrsity Schtxtl uf Mcdicine• New Orlcans. Ul)ANIIIAIIVI: . 1)F1[RMINAIION OF ('111 ORO(iliNl(' A('ll) IN PI,ANI• IISSIIE UY ('OMBINIih F'ULYVINYLPYRRUI.IIX)Nli CO1_l1MN ANI) (;AS CIIROMAI(XiRAP1IY A ncw, spccific, and sensitive chromatographic melhtxl for thc quan- titative dcrcrminalit.n of chlorogcnic acid in plant tissuc has been dcvcl- tsl+cd Polyvinylpyrrnlidune crtlumn chromaltuRrap Ity is utili7cd (trr prc- litninary quantilalivc isolatinn of chlurtrgcnic acitl from wholc cxtr,.cts of plant tissue. lhe partially puri/icd chlrrrugcnic acid. after convcrsiun ttr thc lrimclhylsilyl tk•rrvativc, is then (urther purificd and quantilrlivcly dclcr nuncd hy Fas thrrrmatugraphy Il.c prctisirrn and accuracy td Ilria niclhrwl resull frtnn Ihc very encclive prclirninary quanlitalive separalirtn prrK•rdure, includiny hoth e.trartion arKl aolumn chrom:H.r)•ral.hy sleps• arnJ 1ronr Ihe sl~ct irlt ily rrblairnrJ thrrnrlrh the ctwrrdmalcd crdhnnn and raa chrr,matrr- Rral,hy slclrs I hi dcscritxJ pnK cdurc wJs dcvchq.cd sl><•a'i(it ally Ilr r~•nu1vc :t11 /rcc thlr r~frnic atid (rnm ti-h•ucrr Irssuc F,IuJlly Fr94w1 rrwll. h:rvc :rhu Iacn 4.bl.uncd in caIrJ.th, rn ril h.m.ttu and Ir.ur Irl:url tissuc Ilhc rncthrwl uaually rcquires only a few grams of frcah plant lisue (t.r analysis, and ils cacnti:d fcalures appear readily applicable lu thc analysis uf utlrt•r plant phcnolic compounds. Wilson, l. I_• Uuntap, W. l and N'rnArr, S. !/. Inurnal nf ( hrrrnrnarXraplhy 35(3) 329-335, 1968. (Jrhrr Rrnnt.rr: National Science Foundalion. hrtnn thc (•hemistry Ikparlnrent, l)nivenily of Oklahurua, Norman. A 'IIIIN I.AYI:R ('11ROMAlO(iRAI'11Y-1-lLUOROMFiTRY MI:I lIt)I) fOR Ul/ANIIIAIIVE ANAI.YSIS OF SC•UI'OLIN ANI) S('UP( )I.IiI IN IN 1 UIIA('(Y) An imrrovcd, rclalivt•ly rapid arxl precise quantitative mcthud capahlc of dclcrrnrnurg Iractional micrugrarn amnurlls nf h(Itll sf111N/I111 JIIII Slt11Ndf tin in Itrlhacco c.lracls is described. '1 his new pnxedure has two nralrrr advantages ovcr ol4lcr medrods. First, baNh sto{>,rlin and scuprdclin can l.c determined fnNn the same chromalogram, whereas many of the utlhcr publishcd methrxJs detcrntine only one of Ihese, usually scrrprtletin Sccrmd, since scopolclin has a Ilutnesccnce intensity which is apl+rrrAintatcly ninc I timcs greater than that (>t scofxrlin, much smalkr amuunts uf scnlnrlctin can t.c readily dctcrmined under the condilions employed. This rrprescntt a dislincl advantage since the amount of sc(>p.dclin faesenl in prrrpcrly handled lubat:cn lissucs is usually much amallcr than Ihc arnount of scrqwrlin present. Winklcr, A('., Ihrnlap• W. l., Rnhrbaugh, L. M. and IYrndrr, S llL luurrral n/ ('hromnnrgrnplry 35(4):570-571, 1968. Other Rrnnror: National Science Foundation. 1'rnm Ihc I)cparlrncnts tr! Chcmistry and ifutany-Microhiulrrl:y, l/nivcrsity of Oklahoma• Ntxman. Ul)ANTft•Al7Vli ANALYSIS OI: S(Y)1'OI.IN ANI) S('O1'O1 RI IN IN lUliA(Y'O PLAN7S 7'RIiATEI) WIIII MAI.EI(' IIYURAZII)li 'ftrhaccn plants treated with a prcparalicxt containing m:tleic hydrJ7ide were harvestcd al varirrus pcritKls <d limc and separalctl inltr Icavcs, stcros, :rud rtKHS. I he anurunt t>< scttprrlin and sculwlclin prescnl in each p:ut was then quanlilalivcly dctcrmined hy a rrccnlly tkvclu1x•d Ilun IJycr t hrrr matographic rlu~rrirnctric pnKedure and conrparrd to Ilu :tmrrunl le1 «ul"w lin anrl scnladctin Int•arnt in ctaNrol Irlanls harvcstrd al Ihc ..unc utnc ticrqwdin cstK•cially, and. Itr a muth Iracr dcrrrc, uu'tidctur wcrc InunJ lu int rcaat• tn atcnrs Nnd Icavcs ul Ilhe malric hy.lr irirlr Ur .t1~ J Id.tnl. aa cr,mparrd wtlh Ilhc crrne.IMrnJinR cunurJs I he hq•.hcat IcvcIs ol sr u/141lin and srrqHdctin werr nutcJ rn slrm liaaue. wilh 1114. larl-cr rn.rc:ra...r.niu F• when mure Ih:m I S days had elap.eJ allcr Ircalmt'nl Winkler, Fl (' , Ilunlap, W. l., Mi7cllc, l. W• Rrrhrl.au1•Ir• I M:tml IVrnJrr, .S. ll. q? 1 91

ToAarru Srirncr XI11:19-21, 1969. Other Rrnntor: National Science Foundalion. From the Ikpartments of C'hemistry and Botany-MicnrhinhrRy, ll iivcrsity of ()klahrrma, Norman. X11. lllhr'r Sludi.'a llrol l'arity MIC'ROSCO/fl(' ANt) MI('RORESPIROMFII'.R (OO,) Sllt/)Y OF 111[: [:FFf('f Of: CIGARE 1TE SMOKtN(', ON III/MAN ORAI. SOFT 7ISSl1ES In this investigNion (d the oral lissue-- smrrking problem in a nrro- skewcd population, talivary plt was tested and file clinitally ntirnul- appearing oral tissue of human smokers and nonsmokers was esamined by rouline micrnrscnpy, by differential slaining, and by examination nf tissue oxygen crwrsumplNrn ((X),). Results showed that the pit of saliva in smokers was significantly below that in nonsmukers. Ilowevcr, there were no significant drrtcrcnces in the 00, tif both gingiva and buccal mucosa in this group of snmokers and rnmsmokers. Moreover, no hyperkcratusis or hyperparakeralosis was discovered in the 16 buccal and gingival biopsy specinrens from the smokers, whereas four slightly hyperkeratotic areas were seen in the 19 cGnically nrrrrual appearing gingival sections of the m+nsnn+kcrs Ihe existence of Pirakcrattnis and any amount of apparcnt epithelial hypcrpla.ia were equally distributed between file srnokcrs and nomsmokers (hypcrplasia, seven Ir+ eiKht; parakcrattnis, ninc lu cil;Jrt). Manhuld, 1. 11., !r , Rustogi, K. N., Ik+ylc, 1. L. and Manhold, 13 S. Oral Surgrry, Ural Mrditinr, and Ural 1'.rtluduKy 26(4):567•572, 1968. OOther Rrnnr.rr: ('ulgale-Palmtrlive ('ompany. F=roni the New Jersey College of Medicine and 1)cntistry, Jersey C'ty. 1)1FF1:RI:N('ES IN TIIR FINF. S1Rl1CIl1R[:OF TifE? MU('OSA OI: MOUSE C'f IIiEK ANI) PALA7 E Ilistofogical studies were cunductcd on oral cavity muctna lakcn from ten young adult male albino mice. (/ltrastructural diRerences betwecn moux palalal and huccal mucosa were dcmt„ntrahlc in each of the six muctsal laycrs and grew more nrarked with outward pru ressiun uf thc cclls SGwne rrf the ultraslruclural diflcrcnces, c g, in the T:unrtcr rd the eollagcn fibrils, in density of eytuplasrn, in sirc and freyuency of dcs- mostmtes, and in the morphtrlogy nf thc keratin layer, apfaarr•d dircttly related to the adaptive diflerentiation td file two regiuns. A sccunJ Rrnup trl u1lr.rslrutlur.l differences between thcck anrl p:d:rte, rclaling tu file nrganiralian nf tonofilaments >,nd tu the staining of dcnsc honlics and plasma rnemhranes, etanprised ditlerentt•s of prrrhahlc hut nut u( tlcar cut :rtl:yl,rvc sil'niht ant c I here was a third group ul finJrngs, i t• ,[hc drllt•r- ences between the KIIG of chcek and palate and sonic findings rcliting to di appearance of thc dcase bodics. Ihal was uf unkmown functional significancc. (hmanski, C. P. and Meyrr,l. Tlrr Journal uJ lnvrltiKarivr 1)rrmatoloRy 4g(4):3(19-317, 1967. Other Rrawtnr: 11. S. Public Ilcalth Service. hront the Oepartmcnl of Oral Pathology, University of Illinois C'ollege of Iknlistry, Chicago. S•IItUI1iS IN ORA1. I.Iil1KOP1.AKIAS: XI. IIIS7Y)PA-111OI O(iY 01: 1.Ea/KU1't.AKIAS IN INDIANS C711:WIN(i "I'AN" WII11 lOBACCO Bir>tnics of the cheek obtained from 16 male palicnt. with Icuko- plakias and frtrnr sis healthy young males were sluJicd fru yuarNilalrvc differences. All of Ilu patients chewed tobacco in a"pan," whitc nunc tr( the controls had ever chewed or smuked tobacco. Ouantilative dctcrnrina- lions were made of Ihickness uf epilhelium and uf the kcratin layer; spacing and height of ctmneclive tissue papillae; relative length af basal L•rycr; and number of mitoses per I(Nf nricrnns of cjrilhelium. 'Ihc quantitative mcas• uremcnts were remarkably similar within the eunlrrA gruup, hut varied greatly amtNrg the leukoplakias. Because of the c><trcnrc variability in epidrelial thickncss, the Icukoplakias were divided into a"Ihiu" r.ruuh and a"Ihick" gmup; and, within these grorrps, sume suggestive rtxrclahuns between variahlcs wcre rMNCd, e g., between tire relative Icngth rd Ihc has:J layer and file mitrrtic ratc. All of file (cukoplakias shuwrd Irank kcr:runvaliun or xmikcratinizaliun. While keraliniring traits declined witlr markcd inlra- epithclial reaction lu inflammation. they persisted aRainst all dct;recs of in0ammation in file lamina propria. Inflammation was far morrc severe in file alrrrphic ("Ihin") grtwp, but the iknsity uf rniKraling inll:unm:rtury tells was Ihc same in fxNh groups of leukr.plakias. •1 he Icukoyrlakias td hrrth Rruups carue frunt patients tr( similar age antl fairly similar duraur'n of the chewing habil; htwvevcr, tbe daily es/wnure limc Iir toh,ra.u in 11.111 was, on Ihe average, twice as krng in the palicnl willr sUrnphic chilhc6unr Mrvrr, I.. uaftary, t). K. and Pindb.xg, 1. 1. Arra OdunrulrrRira Scondinavira 25:397-435, 1967. From the tkparlmcnt of Oral PalhtrloRy, ('tdlcRc rrf 1)cnlialry. Ilnivrrsity rd Illintris, Chicago; Nair Ikntal ('ullegc, Itrnnhay, India, and tihc I1rlr:ul nrcnl td Oral I'alhulugy, Royal Ikntal ('ullcgc, ColKnhal;cn. Ik•mnrrk I I'r.Rnanrr I X1'1'RIMI:NIA1. SI1I1)IF.S ON NI('OI INIi A111ORI'II(/N IN RA I S 1)IIRIN(~ 1'R1~.(7NAN('Y 111. 1:I I fl-1 OF SIIII(lIl'ANI (1liS IN11-('llON OF SMA1.1. (71RONI(' I)OSIiS lll'ON MOI111•It, I-HI I/S, ANI) NFONA'I F. Relro.pcclive and pmslicitivc clinical studics on Ulc cllrt 1 rd hc.rvy xs

smoking by pregnant women indicate an increasc in the incidence of aborliun and in premature and undcrwcight infanlc. Pnpul:rlion and Ireat- mcnt varial+lcs are not easy to control in human studies When crrn rullcd populations of pregnant rals were injected twice daily with (1 5 or I(/ nrg nicotine per kilogram throughout pregnancy (daily doses within the range uf 11wne atnanccd by heavy smukers), birth weightt, survival, and Jcvel- opmental status differcd rw whit from these same parameters amung saline- injected ccxrlrol rats. When dosa8es of 3.0 or 5.0 mg nicolinepcr kil.rgram were given twice daily, pregnant r.ts consumed /ar less frKKl and I;ained Icss weight than control mothers. Uclivery dates were prolonRcd Feyond term by Iwo to four days or more. Youn~1 were underweight and f,aal in appearance. There were no abortions and no premature young. Wlrclhcr Ihese effecls are directly due to nkoline action ahme or In other secondary cRects, e.8 , starvation or dchydralion, awaNs the outconx of further studies now undcrway. Rer Aer, R. F., 1-ittle, C. R. D. and KinB, I E. Amrrkan lournal of OAttrtrkt and Gynrcolory 100(7):957-968, 1965 ()t/4.r Rrnwtnrrr Arnerican Medical Association F.ducation and Research Foundation nd IloffmannLaRnche Company. From the Department of Anattxny. Labixatory of Perinstal Sludies, Duke Medical C'entcr, Lhrrham, N. C. x1t1. RPt'ie'uv CURRfiNI* SfATUS OF CARDIAC SURGFRY: PART I Modern cardiac surgery, which began in 1951 and grew explnsivcly thereafter, is critically examined in this review article. While new concepts for correction of defects are continually evrdving, present nrajrrr efforts are direcled toward modifying established techniques of per(usion and surgery and, of equal im(xrrtance, establishing the proper application of these techniyues to cardiac disease. ('Iose attention is paid to the reaction of various phrsical parameters to the biological demands imposed by cardiac surgery. MaNor sections of this review paper arc devoted to (I) Preorcra- tive evaluation and managemenl; (2) Management uf open heart surgcry, and (3) P<ntopcrative management (iiannclli, S., Jr ,('onklin, F. F., Ayrrt, S. M., Koyam, R, Itondiuk, 1. snd ( iregory. I 1. NrM• Yrtk Srnrr 1onnnaf of Mrdir inr GR( 2(1) 266(1.2(r71, 1969, (hf.rr Rrnnt.rrr: 11 S Public Itcellh Scrvicc anrl New York Ilcart At.t) ll,ltllrn. I rran St Vinccnt's I1<,spital and Mcdic:rl ('cntcr, Ncw Yurk ('ity. C'URRI,Nt STATUS OF CARDIAC SURGF.RY: PAR1' II F'arl I) of Ihis four-part review of modern cardiac surgcry is dcv1acd to the treatment of congenital heart disease. Types of cardiac di.cace (1is- cussed here include atrial seplal defecl and anomalous pulmrmary venous drainage; vcnlricular seplal defect; tetralogy of ha1NN; obstruction of Icll venlricutar outflow tract; transportation of great vessels, and corunaty artery anomaGes. Since the clinical and hemodynamic course of certain surgically correctable heart diseases is incompletely understrxrd, a crwrpera- tive, prospective study is underway to facililate reconstruction '/rf Ihc natural history of three of these cardiac pathologies. The lcsiuns (xxing stuJicd are aortic stemsis, pulmonic stenosis, and venlricular seplal defecl 'I hc natural histurics, insofar as they are known, are presenlcd here. (iiannelli, 3 , Jr ,('unklin, E. F., Ayref, S. M., Kozam, R., &rrdiuk, 1. and Grcgury, 1. 1. New )'tw4 Sratr luurnal o(1Nrdirint 68(21):2779-2789, 196R. Othrr Rrantnr.: U. S. Public Ileallh Service and New York Ilcart Asso- c1a11/N1. From St. Vincent's Ilospilal and Medical Center, New York City. CURRENT STATUS OF CARDIAC SURGERY: PART III In this consideration of surgical treatment of acquired heart discase, sectinns are devoted to hypertrophic cardiornyopalhy, aorlic valve discase, milral valve discase, and tricuspid valve discase. Conditinns undcr which patients are candidates for surgical therapy are discussed for cach d the diseases. Since the development of valvular prostheses has allowed the application of open-heart surgical techniques to Ihe treatment of valvular heart disease, valvular prolheses are discussed both generally nnd in con- necliim with specific valvular Icsions. In general, the status of valvular prostheses is discussed by considering the problems inhercnl in Ihcse valves and the attempts that are being nrade lo overcome thcm. Of tlre live calegtxies of pruMems with valvular prostheses (hemrKlynatnic, durahilrly, IhromMrsis, infecliun, and dcslruclion of formed hlowrd clcmcnl.), il has been sh<wvn that anticuagulation therapy redrK'es the risks frum tlurtmhus formation and crxrlinuing research is going tm in all five arcas. Allhrruph the lutally satisfaclrrry valvular prudresis has not yc1 been dcsi(;ned. Ihcrc is rcaurn to bclicvc that continued improvements will correct Ihc cr<isliuR prohlcros. (:innnclli, S, Ir ,('onklin, 1: F., .11•rrj, .S. A/ , Kuyam, R, Iloudruk, I and ( ircF4rry, 1 1 Nrw 1'nr4 .Clnrr /"urrral of Mrdrn inr hR(12).21)13 2411, IVhN I1tA.r Rrnnt..ra: (1 S 1'uthlic Itcalllr ticrvkc ,uu1 New Y,nk Ilt.rrl A.. , l'/a1nM1. From St Vincent's Iltnpilal and Medical ('enler, New Yonk ('ity. 97 Kr.

C'l1RRl?NT STAll1S OF CARI)IA(' SUR(iFRY: PARl' IV 1he fourth and final paper in this scrics of articlcs on catdrwc surgery clMlmues the discussion of IrcalnKnl of acquired hcarl distasc, witlr sf.ccial attention being Rivcn to paccmakers, rcvasculiriratiun finrccdures, and sundry ntcthcx)s of circulatoty support. Permanent paccrrc+kcrs are used frequently now in individuals with asymplomalic chronic complete heart bh+ck While many espcrimcn(s have been perfurnrcd to evaluate mcchani- cal support of the p++nrly contracting hearl. total mechanical replaccmcnl of the heart Iras bccn accomplished so far for rNdy brief f+tritKls in e><pcri- mcnla( animals In the absence of a workable nuchanical suhslilutc for Ihe heart, the dream of many investigators has been heart rcplaccmcnl with a bitdr+Ric substilutc. Although 1hh has now been accomplished in humans as well as in animals, at Ihepr cscnl time human heart Iransplant:dinn is an cspcrinxnlal prtxedurc and sht+uld he restricted to Ihtne few Rruups equipped tn ntakc mtaninRful ohtervations on such paticnls .1lthuugh lechnically (+onsible, the long-term contribution r+( transplantatit+n to Ihc Ireatmcnt of i9inical htarl disease has yet to be tstablished. (iiannclli. S,)r ,('tmklin, F.. F., Ayrrr, S. M., Kozam, R., Bordiuk, J. and (ircRtwy, 1. 1- Nrw )'t+rk Srorc Inurnof r/ Mrdit inr 6R(2)).J(Yf6-)058, 19fiR. OFlrrr Rrent..r.: 11 S Public Itcalth Service and New York Ilcart Asco- cratNN1 From St Vincent's I IrKpilal and Mcdit aI ('enter, New York ('ity. TOBA('l'O SMUKING ANI) A I 111 !tt fti( ( I 14( ) I 1(' %'Ati( 1 11 AR hIS1:AS1? 'lhis Ihr+uFhlful rcvicw pi!r•r ..dl++ta r.t+nl clad+nn l+lit.+l, IoFical and cRlx•rirntntil slu+l+ct whn h Fh.+vr dc.+lt w+th Ih+• v)-n li+;+ncc +d srnr+kinR in tl+e Rcnt•si-. and rlcvclul+mcnl ++/ c+tht•r++alcn+ais I hr t•I+irscn+i++- (r+Rical and path+dof+cal studics prc%cntcd sh++w II+a1 a ctr+m) :+wr'iati++n esists between srn++kinR and athcr++alcn+sis On the othcr hand, cRlx•ri- mcntal sludies, undcrlakcn to determine whelher this asaxiatie+n rt•presents a cadae and eRccl rclati+mship, have hccn few in number and cr+nlraditt+xy in Iheir findinRs Rcccnl(y, rnuch has been learned concerning Ihc effect of smukin8 and nicotine on various metatwlie, h++rm++na(, hemahduRic and circulatory processes invulved in alhcr++pt•nesis. lisperimenls concerning scrunt fret fally acid levcls, scrurn triklyceride.., plalelet survival, calechula- mine rclcasc, and than8es in circutatr+ry functit+n arc dealt with in great tktail Kcrahhaum, A (ReItrl, S 1 A(olultrr ('nrdr.rvarr ulare 8(1): I-19, 1967, Orhrr Rrnnlorar National Inslitutcs rd Ilcalth and Amcritan Medical Asu4raln+n Udutati++n and Rtscarth l++undalit+n. 1:rrnn thc I)iviai++n uf ('ardi+d++fy, f`hilndcll+hia (:cncral ll++arilal, 1'hila- tlcl(1hia 1111: (Y)MPARISON OF fXPFRIMf-.NfAL ANI) ('I INI('A1. F.VAI IIAFION OF AN7l-AN(',INA1. AGI:NIS PharntacoloRical and physiological studies are cr+rrclalcd with clinical observali+ms in Ihc Ihrte seclNSts of Ihis cuntparalivc review pal.cr -llre stctiuns noted are as fr>Jlows: (I) mt•Ihutla used in Ihc investigation of anti-anginal agcnts; (2) tlre action of nilroRlyccrin (Rlyccryl lrinilralc). and (])!teta adrenerKit blockers and other anti-anRinal a(tcnts. Ilascd un cum- parative laboratory and literature studics, the conclusion was reached that anti-anRinal eficcts cannot be equated with coronary vastwlilalit+n 1 ht mrnl important physiuluRic prercquisile for anti-anRinal action appears lu Le diminished mrt.cardial tcnsion, resulting from a diminution in the vul- ume of tht vtntr.cular cavities and, to a lesser dtRree, a fall in left ventric- ular pressure. PrcfcraMy, this should be brought afxrut, nnl by a dircct effect yd the druR on the myocardiurn, but through its pcriphcral attit+n Nitroglycerin fulfills these crmdilicrns. Rina, R. I.. Puri, P. S., Robin. E:., Martintz, M. and t7Rawa, K. ('fini.nl PhonnocnluRy New York:PcrRamon Press, 1968, vol. ), pp 29 4). O/A.r Rreetur.: ll. S. Public Ileallh Service, Michigan Ileart Association and I)elroil (ieneral llospilal Research Corporation. Urnm the Ikparlment of Medicine. Wayne State l/niversily Sch+K+l of Medi- cine, Detroit. CONSTIllf11ON, GIiNF.TI('S, ANI) BOl)Y FORM IN Pt:Pll:' lllA'FR: A REVIEW ('onslilulit+nal facltxs of several kinds have been dcmonelratcd in peptic ulcer. Gcnelic studies show increased frequency rd ulcer anw+n6 Ihe relatives r>< ulcer palienls, as well as concordance of sile. ltlt•crs, parlit-u. larly durMlcnal, are more frequent in rwtn-sccrelnrs and in lursuns r+/ bhrul group 0. lhe b1,Mxl group association has been reported amuns Japaneae and Nigerians as well as an>,n+F I~urofteans and Americans l:aslric liyptr- secrelnNl, a major (actor in duodenal ulcer; probably has a cunslilulional basis-analtxnic, (Cenetie, or physirdo)tical. On the averaRc, linearily +>t build charactcrires not only persons who develop pcfNic ulcer. hul als.. Ihu+e who do ptKxly with il- Persons with gastric and duot/cnal ulcers difler epidtmitdoRically, behavio.ally, and Renelically. 1 htre is. Ihercfcre, a real constitutional basis for peptic ulctr, though its lutal effect for the pt+fwla- lion is small in ctxnparrsun with the environmental tklcrntinanls rtAccad in Ilte allercd site, set ratio, and frequency u( ptplit ulcer durinR dre present century Ftvr the individual, htvwever, 1he inAucra•t• u( ht•rcddy r+r cAnst/1utMM may be crucial. I)onm..n. A and Poftdnak, A P. /rwrnnl uf ('Irr++nic t)irra.cs 2((10) 7R7-R()2. 1967 Othir Rrawror: American Ileart Assc><iatiun. 1'men the Ikpar(ment of Anthrt>ro(uRy. Ilarvard llniveruty, ('ambnJRc. Mau. ttx 99

Il1.AUUIA ('AN('FiR: AN IN('REASING PROI11.IiM Matcrials pcrtaining to the inciJence, etiology and prevention of hliddcr cant'cr are reviewed in this summary paper. A rise in file ovcrall incidcnce uf hladdcr cancer his been rcprxtcd in the United Statcs. Ung- Iand and certain other countrics. Lpidcmiolugical sludics in human beings r,nd experinrcntal studies in lalxxatory aninrals have shuwn Ihat thc inci- dcncc rr( bladder cancer is incrcased with exposure Irr ccrlain aronratic amincs or their dcrivativcs Man is enpoaed to these aRcnls chiefly Ihnrugh industrial contacts; and, in England, workers exposed Irr f1-naphthylaminc and certain other compounds are eligible (cx health conrpensalion if they dcvch.p bladdcr lumrxs Other environmental facltxs which have been cited to eotplain 1he increased incidence of bladder cancer include cigarette smoking and the incrcasing degree of air pollution in urban arcas. Fn- dngc nous carcinngens-- their idenlification and the elucidation of their role in bladder cancer--are also considered. Abnormal patterns of tryptophan rnetabt>tites in the urine are of particular interest in this regard 1 wo pre- vcntive measures needed at Ihis time nd urged in this paper are 1he idcnlificalion of high risk populations and the cytologic screening of same. Frirdc((, C:. !l. and Burrxy, S. W. Cancrr Auffrrin 2U(3)'42-45, 1968. O/hrr Rrantor: l1. S. Public Health Service From the Department n( Pathofngy, &ntun Ilnivcrsity School of Medicine; Cancer Research lnstilutc, Bcnton. PESF1C11)F: RfSll)Ul=.S ON TOIIA('C'U This is a comprehensive revicw uf residuc prublcrns nn tobacco from culture through commercial processing In recent years• residues rr( in- organic insecticides have decreased sharply and the levels of arscnic are nf little significance at the presenl linx. Organic insecticidcs can he delercd at relatively high IeveFs during the early phases in the culture of tobac_o, but thcst levels are reduced significantly in the flueruring proccss. 1)ur.ng the smoking o( cigarettcs 90 to 90% of I l)E, 70-811% of endrin, and 95% of carbaryl and (7uthicxr are dissipatcd. Thc intake of the mnst common insccticide appcnring in tobacco snNoke by the one-pack-per-day inhaling smoker is approximately equal to the intake nf insecticide in Iris daily faxl. Special purpose pesticides such as malcic hydraridc and (unRicides do mrt at this time appear In prescnt a residur problem Rcsiduc prnbkms on tobacco deserving Ilcnlitm includc munitruinR r>< cnmmcn ial tohaccu, Is0latir+n and idcntif/catinn d sidk slream cumponcnls of snnoAc, nlcnhfKatNM (s( lkcUn11Ny1tNtn prlxluct7 of mainsarcam snnrke, nnd the rc- tenlirrn of inscctitiJe residues frrlltrwin/, usc• of cirar, pipc, snu/f, rnJ chcw.nR luhact'tN. Gulhrie, /'. F. anJ Ilnwcry, T. (i. In "Rcsi4lur Rcvicws." Slrrinper VcitiR Nrw Yrrrk Inc , vol 1a1, 1967; Iqr 11 Sh Q)rfrrr grantor: (1. S. Public Ilealth Service. From file Department of F:ntomology, North Carolina State (Inivcrsity, Ralcigh. TI IE NA I URfi ANI) SIGNII:1('AN('F. w7f- PIiS f l('IUI: RFSII)l II.S ON IOFiA('CO ANl) IN TOUA('('O SMOKE All aspccts nf Ihe pruMem rd pesticide residucs rxr tobacco and in tobacco smukc arc closely scrutinir.cd in this thuruugh review pal.cr. Start- ing with a discussirrn of Ihe initial application rd peslicirks Iu /rrharcrr (dants, file disrrilrutirxt, hnscs, and degradations of the various fxslUCrdcs are followed thnxigh to an ultimate con.idcratirro of residuc Irdcrantc re- quircmcnts. On the basis of thc dala prescntcd, it is ccxrcludcd that resrducs rd inorganic insectit'idcs used tm tobacco have dccrcascd to Ihe ulcnt that they ate primarily of acatkmic interest only. Organicpe slicitks, whdc they can often fie detccled at high levels during Ihe early phases of cuhurc, lux front 40-99% of the residues during the flue-curing proccss; ircurinR is much less eRective in destroying the residues. Uuring Ihe smoking of ciga- relles, much of file ptnl-curing residues of the various peslicidcs is dccnm- d or transferred to the sideslrcam snK+ke. The levels of pesticides ound in mainstream snxske of commercial cigaretles, or eRl.rclctl frrNt/ rcommendcd trealment, are below the tolerance ascribed on frxxl by several countries, llowever, additional research, continuous survcillancc of manu- factured tohacco, and augmentation with non-pesticidal or dccreased pesti- cidal methods are strongly recommended. Guthrie, F. E. BcilrilRc iur TabaA/r,rtc huna 4(6):229-246, 1968. Othrr Rrant..r: (1. S. I'ublic Flealth Service. From the IXpartmcnt of Entomolugy, Nor'Ih Carolina Statc Onivcrsity, Raleigh. I DNA IN Tl1MORS ANI) VIRUS INfF:CFlONS In this sclective review paper, an attempt is made to asscss tlre inter- relation between viruscs, htrs/ cell 1)NA, and malignanl tr,.nslnrmatimn. Individual scctioms of the paper are devoted to: I. 1)NA in cells uf norrnal tissucs aud of lissucs from pathological processes other than tunnrrs and virus infections 2. 1)NA in cells or tumors with unknown etirrhogy, rrr ul hrnuns rd knrrwn hul rvun-viral etiulogr. 3. 1)NA in cells u/ virus udcttnurs and rrf tumurs with viral ctirdugy. the emphasis in this pulx•r ia pI;rcrd priraarilv rrn scqurntial and crrnelatcd morlrhuluRrc:d nnd nudrr. auJ altcraliurn o/ cclls Fl.Aung thcir slatrmcnts upour ettcnsivc (htcr;uurr rc scarth and pcrsnnal lafinattwy ntncrvalions. file authurs crmrlu,Ic 111.11. on file h;rsis o./ preunt day analyses• efre 1)NA Nnd /tNA p.iurrns nr tunnas, includrnK thrrsc t'auscd by viruscs, t'annlrt Lc ton.rdr rcd ttr hr spccific. On the other hand. Ihe formatirrn nf IarRe yu:mtitics nf 1v/K• spccific nuclcic acids within cells early a/lrr virus rnfrcthuns, rr..ulunf-. m cell dcgcnt•ratirrn nnJ tell dcalh, is not nhscrvcd in :uty ulhcr I~.~thnl t~ :rl vl

condiliun cr<amincd, and tllercfnre can t,c rcgardcd as being arc•citic fur virus infcctiuns. t.rurlrlrnhrrRrr, C. and I,tuchtenhcrgcr, R. HandMrch dr lliverehrmic 111(3) 1-5), 1966. Other Rrnntur.: National Institutes of Ilcalth, Drush Foundation. Fran- chester Fertilily Fund, Elsa U. Pardce f:uurxlatiun and Ciba Fuundalion, flasle. Switzerland. From the Swiss Institute fot Etperimental Cancer Rcsearch, Lausannc. CY iYX'IIEMII: 1)E=R KREBSVERANbtiRUN(3 ('ytcschemical studies on t)NA nd RNA indicate thal: 1. All maliR- nant tumnrs, irrespective of the ctinluRic factcx invulvcd, are characterircd by ekvatirrn of 1)NA and RNA content and fluctuation in nutlcic acid conlent from cell lu tell. Ilmvever. these varialitms also are seen in vital infcctioms, benign /umurs, and rapidly Rrnwin6 normal tissue. 2. hNA and RNA in cancers display divergent chcmical and biological properties frum nornral cell 1)NA nd RNA. 'Ihese chanses, howcver, arc variable and cannol be regarded as a specific criterion of malignancy. 3. 7 hc cylo- chemical data available al present n0er rro reliable evidence that a funda- mcntal diRercncc ci<ists between nucleic acids in cancer and those in nor- malty growing tissucs Ilnwever, spccific UNA and RNA changcs may be present in file cancer ccll, and file cr,minuatir,n of rcaearch in this area may unveil anrtrnahcs in Ihc genetic crKlc „f the canccr ccll I rurhtrnhrrRrr, C and I cuchlrntK•rl;cr. R Schw•rizrrHr hr n,rdrrrnur hr 1{'nr hrre,, h, rfr 96(14) 445 456. 1966 Oth.r Rrnntor.: National Institutcs r,f Ilealth and ('iba fuundatinn, I)asle, Switrcrland From the Swiss Instilute for Eiapcrimental Cancer Rcsearch, I.ausannc. ACl1lE P111.MUNnRY EMDOI.ISM: 1. RI:VIEW Acute pulmonary cmtxrlism. which is probahly the comnancst Icthal pulmonary disease in the l)nitcd States today, is chnely exarnincd in Ihis enmprehensive review paper. In addition, since pulmex+ary enrtx,lism can- nnt Fx adequalcly reviewed in isolation because it is Ihe nuddlc and musl ><criuus component rd a Iriad, the rrllur nxnmhcrs nf Ihc triad vcnuus thromtwnis and puhnnnary infarctir,n are tuuchcd ul"rn AllhuuFh studies have he•cn madc. file Irue incirknce nf I,uhn„nary r•mlM,liam is anin„wn Ih,wcvcr. file 1nQuwinR clinital at:rtra arc clcarly aarniarrd with an in crcaard incidcnce r,l acute puhu„nary cmlr,lisrn (1) age. (2) cardhac drs urrkrs. (1) the puati.perative pcrioMl. (4) maNu Ir:ruma. IS) nrrx,.lasms, Ih) hl,Hwl Jyata.i:n. 17) prcynancy anJ the catly pntrartum I,crriNl, (R) infcctlnn anrl n,.,l„ulrrtir,n, /41 ,~fK tily. (111) sLrrnunu+ (./1„rl. ( I 1) luort.a aval shunl aurRcry. and 112/ irnnu,luhty Iluumlasrs. whrch is alnurt always ttu' taucr rd pulnN,nary cmfw,lram. is chncly c,rnsrdcrrd in a acttii,n JcalinK wrth h.Uh„Frnrar• I hc rrst rd dua PilK•r is Jcvrdcd trr a comiJcr~-n„n rif nroncrl pulmun:ny structural and functional rc•Iiti,mships and rd file Ix,thn- physiulul;ic manifcstations ul pulmunary culM,ham .Q,lrr//, l.. A. and RrKlman• T. Anrrrirurt Ilrurt luurnnl 74(5):71(1-724, 1967. ()ther Rrnntr.r: l). S. 1'uhlic Ilcallh Scrvice. I'rnrn file Ikpartmcnt of Mcdicinc, Temple University Ilc:ddt Sciences ('cntcr, and Ihe ('ardiopulmunary I.abtaatory, Veteran's II,r.)ital, Phil,r- dclphia. n('O11: PlI1.MONARY I:MBOI ISM: 11. ('I INI('AI. Part 11 of this overall review of acute pulmnnary cmh„Iisru dc:ds with file c linical manifcataliuus, 1rcalulcn/ and prcvcntirrn ul this Iclhal Itutnw nary discasc Aa comnHrn as this discasc is, its clinical rccr.grntiun rcrualns dillicult anJ often nnpussihle. 1 his is so hccausc thc Iung has nrr pain fibers, and has a large vascular rescrve, mkl becausc clinical manifcstathuna, when present, ate variab(c, ctmrplc>t, and not infrcqucntly cunydclcly ubscvrcd by thc untkrlyinR disurdcr. It is unlikely Ihal additi„rr:d clinical observations will significantly increase accuracy rrl dia/:nu.is I his inrre:r.cd accuracy will dcpcnd uprm the tlcvchrpmcnt uf new scrceninlt tcsls anJ thr (ullesl use of thu.c presently available. 'IlKSe laltcr arc nce tri,J rrf *r, crascd scrwn lactic tkhydrrrpcna.e and hiliruhin wirh a n„nu.,l scrurn Rlu/amic u><alacrtic Iransaminase, frcqucruly rclK:rtcd clcrtrr~:udrntr.uus and r,rrnlRcnngrams of Ihc chesl. lunr scanninp, auJ (h,yh•fully) ulu:r suund It wuulJ dcfinitcly appear at Ihis limc Ilral Ihe Ix'+I hol,c• 1ru rcJuc- inF file murhidily and mortality from pulnrun:uy crntadr lics nul irn rrcat- mcnt hut in prcventirrn. .CrrlrrQ, l.. A. and Rndman, T. .1 rnrrir un Ilrrnt luurnol 74(6):R29 947. 1967. Other Rrnntur: U. S. Public Ilcaldl Cc•rvicc. Frnm file Ik-partnrent of Medicine. '1'eruple ltniversity Ilcallh Sciences ('enter, and file ('ardiopulmonary I a!>,xatrrry, Veteran's I lrrsl,ital, 1'hila delphia. 41 V~

Rccipicnts of Active Grants Fullawin~t is.list of all recipients o( currently active grants (as of July 1, 1969) Ithat havc hccn approveJ by Ihc Scicnllfic Advisory H(IarJ Prujccl lillcs arc also irxluclcJ A number of projects have been cltnlplclcd since initial grants were InaJe in late 1954 and Ihe recipients of these are Iis1cJ in a later section. CRAMTEF. AND IN3T111rT1OP1 ANTIIONY A AI RANI Sf , Prl n, nl. rr,rnr, Nraruinn .n/ A(rr.h,Jl, Re. 1ranA Iy/.//,,M, The RUrIt Rehahdlla 1«In ('enter, White Plalns, N. Y. I70MIN(:U M AV1/11x). M n, Prn• frilnr of PAnrnrn...l.rRy, l/ni.truly nf Pennsylvan/a Schoo( u( Mrdfcine. Phd. adrtphia STFPIIFN M AYRFS, MI), nrr(r,., (a.J,.•pnlw,nnary f.A.rar..y, St Vmcenl's Ilu.pflal, New Yufl ( i/y 1'R(/)nT TITLF. Tht eRect of nicntlne on p1nlr/n anJ amino acid mtlah,llism in Aumanc 1-Rec1c d nk(wine and cigaret)e smnklng on neur(yenk mtchamsms rn Ihe IunR Tldtr.nce of lungs to Inhaccu amole with apeclal yefertnct to pdmr.nary emphy. stma and vascular occlusive leslons Meauutmtnl of alveular arlerial nilrogen dfRrlence by ga, chromN(yraphy lhe JIRu•ing capacily of the elvenlar memMane in pdmnnary emphycrma Rr/Nlon uf aiy paJIu1NM to akvehrpmtnl n( chronic p/lmau+a(y dlsta.e 1 hr efltcts of (ntaan(eJ small am.n,nlN of callw,cyhtmuRtuhm on cuJnur.pua Infy funtttirn in rnan 1 Rrct u/ /ubactu amulmg un human mya csudul mtlaM.th.m US('AR 1. RAI ('lI1JA1, Pn 1) , l/avlnRl Pmfru(Ir n/ AfrJn,nt, Ilniversily uf Suulhern Cahfornu SaMosll of Medi- cine. I os Angeles I-RFUI RIK f!. RANO. M t)., Prn/r!!rw an/ CA.oman, flrp.rrnlrnr n/ Parhn• lin1nty. The /ohns I-t/TR ins Universlty School of Ilylicne ana) Public lltallh, Rsl/lmnrt. SAMIII I. R1 1 I P f, M I), lrnr.r.rr, t)nr. u.rn .r/ ( mJr.d..RY, PhtlJrlphu (ian rral Ilu.pllal. PhdsJrlphls Iktrrminanl+ of Ihe awuse of rfnphyvtmabr unc h il fs Inleraclilwl of viruves with nuama uf the recpralory Iracl, and an analysis u( the eReels of environmtnlal varlali..nf un Iht function of the rnucucllufy syalem The eRecl of nic(Nint on earJiac i(ritaliun rn the prewnte 1.1 rtsrrpne, and the tlltcl ul niaollne un clwunary hl,rrl R,Iw on darts wnh c.wl.naty In.nfh.wn(y I-Rtalc n/ ni.,nlnc nn tht mwph.Jua y[ ul (IMIIna1y a/1e1Kf anJ aanla. I1h11n,Nyl/c tllttls /d nic..llnr .rn h(unrn and amnul plaana; eRrcls nl ctsuhnn ul ao..llng un .rlu,n aharle.ltrfd krtl. ,d af./•.n,i sm..lefa; Ihe ellells .4 a/y.urllr ./n,.It nn f)ee fally alid kKls ul whte(IS wdh my.a al dul 1nI a1t I1. M• Ihe r/lral u/ ma.dfnt m vali..os pa/amNtr..d urJn.v.vul.lr lun.llun /:R \P(fVF. AIYI/ INtiT1711T1(/N 11)IIN A III-VAN. 0611). rrufrla..r ,.f P/rmw.r,.d,rA•y, I lnlvrrsny of ('aldtwnu Schaw.l of MeJlalnt. I uc AnRelts. H111)111)I V RIIA(iAl, PIII), Alal(rnrr rrnlrlt,rr ,.l rhru.rL.Re, SI I oui( Uni. verany ScMM.l of MeJlclnt. SI 1(wus. ('FSAR/[ HIAN(1111/KI, M1), /hftu„n of (nna n Rr,rw, h, UniverulY of PrfuRla. IYnl6u, haly KI( IIi1K1) 1 HIN(i M 1), P.,r/ra,v of MrJu Inr, I/nrvers.Fy u( S,anhtrn ('alrfurma ticM.ul ur Medrc.ne, 1 us Angelrs; Rrvarl h A,ua la(r, ('ahf.wnfa InUll,ule of lechmdu[y; I)ur,nw n/ ('arJn4.rRy an.l In(rn.nu.,,l AtrJu,nr, Ilunglinlllon Mcmurial 11(nplat, Pauakna, ('al WAI 11'K M R(M)KI R, Po 1) , Pr.r/rta,r on,r I)rt'nrln,rn( of rl,r(nl,,,,rl. nRy, IluwafJ Ilmvcrsny, Washingrun, 1)('. (31-O11 RL•Y I HRINKMAN, M 1), A. r...,ntr /'n.lrn..r .f AIrJ,.,nr. Wryfw Slfde I/n/vrraly loaMrd of Mr.h,ufr, Ik11.n1. RARHARA H HKItWN. Pu1), ('In.-l, I (prrlrnrnrnf Ymh.nlry, Velt(ans A.1 m/n/111a1MM Ilu.pnal. SepdvrJa. ( at PR//JF.(T TITI.E Facilnalinn of va.,wunNrilt(nn hy nKOllnt and rtlaleJ agenl. Ihe mtchani.m of madine inJucrJ rc leact of caleclwJaminrs F:Recl uf cigarette smoking arwl nicothne Ira the Ji.pxilinn of cale(hadarnines in eaperilnenlal coronary arlery msuRickrky I uns lonwwissene.is hy i.onuriJ (IN11I. ils mrlaMflnc hydrvlne snlphale (h s 1 and trqhtr (krrvarhves uf hyd(ume in mice a(Id in (NIKr spellts Ihe t/1cc1 u( snwl\ing f.n Ihe c,runacy bluod Row and cetlam phavrs of rnyo e.rd/al mtlah..lnm in pallents wl/h ultritnclerulk 4.1 hyperlenvve card/ovavcular d/.eavt Studies in cellular physiuluRy u( hearl muvck Measnremenl nt c(wana.y bhrK1 Ruw by means of raahoatuvalcJ dhutnin The tRecl (d snsnAlurt t.n u.unary M,wa! Ih.w in palknls with at/enu.altrldic hearl Jicrase and the ellral u/ nKnhne on slnralse (d anunes in htarl (nusale Meaanemenl of tu/onary bhw.l Rnw wilh a cyslem ucinR tufnlydrnat clrunlfnil. Ihe ellecl (d madme anA ahanRe in hearl fate nrl cardiac melalad(.m anJ relalcJ subiecls SluJks nn calJiac mrlab..barn with spc cial rt/trtnte lo myuaarJul anuua the inMlenct o/ mtolme un ILpIJ unnlrr.iliun 4.1 vaccular wall of Il.e awunary vt..elc; ils tRecl nn Jlslril.uUun ,./ aan onary ft,lw S/u.lies t.n IIK p..%.iblt ~emiluall,.n (rl Ihr va.adar ulr(hant.m In calraholammr. (aAluwlng mcutinc aJnunl.llall,w 1 he eRetl ol airaltllt un Ihr ,dua mnrua,.pn .Untln,.r uf lhr bnr.ahul m1ll.na N,a.dme an.l .m..11oR rllrlc. nn rkal,,. tn(tphal,q/am ,an/(lalr. ,.1 brha.,..l. em.M,un.l rtap.msivtnt.. an,l vlwa) pr, cep/nln in c.ls Faphwalinn o/ the d,0efrnats ur 1/ (i pa11CIn .- illh/e(IIYC a1,1, l.nlCtllfS In s/ll/flrr and 1(IManll.lfl •I,LtCal• 95

CRANTF.E AND INSTITlrT111N RAYMOND R RROWN, P/I[), rtnlrr- pw of (Antrnl Oncol.rry, University of Wncons.n MeJ.c.l Scl.ool. Madi.on. SIIF Rll('KIN(i1IAM, M D, Aunranr rru/rruw of rrlwuur. ('olumMa Urw. versflt Cnikgt of Physklans and Sur• reuns, New Yorl (11y. (decea.ed) BRI/CF. F. CAMFRON, M 1) , Plt D, Nn..r/ NrIArr ln.mrn, l/nivertily ef M.anmi Schocrl of Mtd.cinc, Munci. MAR('l/S N. CARR(H l, 1. , Pw l) , cAw/, 0r..n.rn of rArn.anh.(y. lht Broohd.k Nospilal Center, Broo11y/(, N. Y. Wtl l IAM Al VIN ('ARTf'R, M D, Ar- ruuwr rro/tuw of Mrlwrnr and Mr- froAw.l..fy, lhc Inrant 11op1ins llrnver- wY School of Medic.ne. R.hirnort. SANFORD C1I(NX)511. MD. Aruuant rro/ru.r o/ Mrlniwr. Tdu llnrveruly School o(( (editiwt, Le+.on (Incl.aled r.nder Maurice Sttal. M D 1 NAITFR M ('NOPRA, PtrD, Ar..+ra.r nn/raaor of ( Arnau,y. The n,.uultwJ .wd lechnical (o1kTe of Norlh C.roliwa. (ketnshoro JAY D. (Of"FMAN, M 1), Sr.n.u. llr.d, rrnrArr.1 /'.uulr (lrrarmrnr. Umtermy 11wViu1, Waow /(111N F ('RAIOIIFAI). M 1), Au.nurr rto(rrr.w u/ r.rA.d..ty. University u( VtrmutM MtJasl Schaul, Rwbnsl..n T 11M(11/1Y ('R(X'KI R, M I).. rt.•lrr Mw o/ Alrlu.wr, ILpwcmrar../ Rn.rrn.l Alrl...nr, University u1 Cahfotnia MeJ icsl ('enler, S,n I r.nci.co 1•RIIJF:IT TIl1.F. I:RANI'F.F. AN1/ IN!iTITIfT1/)N 1'RIIJL/T TITI.F. F11ec1 nf smr.ling un Ityp/uPhan mctah..- AIRIRI' 1)AMUN. PhD_ MD, !rt- B.K1y l.wm, am..linR and a6 uh.d u.n.urnp Irvn in man rurrt on Antbtnry.Lyfy. Rr.rarh As.o- lion amons (/ahanAmer.can men ..oN.n Mr/u.l Anrhr..pduty, PeahoJy M.wptwdolKal crrnNl/nllcwl In Iht Jevel.. Sludies on the devclopmcnl and hiol..gy of Muxum. / lar vard l/niverwly, ('am- hridge, Mass. p menl n/ alhcrosclerr.l.c dt.ea.es and lung wrf.clanl hypcrlen.ion Spectropholometrtc s.say of csrhon munoaide and nn1rc utnk hemo{lotun FDWARU F. b()MINO, M 1), rrn/ru.w .r/ lAanuw.d..rr. Universily of Michi- Ran, Ann /Uhcw. Fflecle ..f lu(.acco smote and nNUl/nt on Ihe central nervous syslem ('en/ral ner.rnn .yslem -- evolcd nhy- 14nias ud corowary Nood 1{o. ()nc~ y and the .nliviral action of in. lerleron ( htonic bronc•ilit tMNKs Tht Jepadalwwl of DIYT. ThFF and I)iel d.m in ciRarelle n+ainslream and udc- •Ueam Yn4atf )'he tlltc/ of Rau.olba and (:uanelMdua (caltcholamine depklins rw Moc\rnS atlentr) .wc Ihe .r(m~pathtl.c vavarw.- t1rltlnlin IndY(t// r~y /.doa[co 1nM.Itn6 and by tnvwonn.eMa/ hady ard.ns )he ruk ul calechnlarnine rtkase (r.wn the aJrenal mtJul/a in cauune the c/r- culalory eAecls seen durint a.haca. .wx.1 inR lrrhacco smoling in /wman whjeclt dur- ing Irta reuploi Mu.l.de Ihc eRec/ o/lnhaccoundinT and sympaIhelk werv.wws sydt/n on Lnw cap.llary and .rrcrioawous .hw1 Mu.d Row Ri..l.Ky anJ cy/upalhic eRects rn/ re.rira1.wy and w.aKrnrt vwuw.n.wRan cul /utts o( humsn rcywr.l.wy uacl In.ut R.ohKh ac hvily o( Inhucu un..1t .MJen fatev on rtv(wal.wy mw...a ~J r..drnev, can.nts anJ ptwnale+ in ur$an c+J10re:  h.c1.a.Krt and aul.waJ...eraphK +IUAy Prevenluwr .w rt•etcal cA af.n.wmd clale. rd rr.p.tsl.wy el•idalrum p..wluaed by cr11sntlte wr4e uw.Jen.ale and ubnt.. lalplrtnt 9h RI('/1ARD 11 hARI F. M 1), Cha/, rrl. nu.n.uy fun.rr..n f.A.worrry. Au.rr.nt rr..frn.w u/ Alrla.nr. University of ( hicsso, (l.icago. RFRIRAM 11( 11F1, BS, DUS, /7i- rrrt.w. Intntrer ../ Sr...na.d..Ru.l Rr- aror.A, Sctence Resources F'nunda/ion. Water/oven, Mass. HYMAN 1'N(il l BFR(i. M 1), Anrnl inR rhnuron, ('edan of I cMlcon llos- piUl, I.us Angeke. CARI 1-()N K. FRI('KS(/N, hl D, A,- autont rrn/rsr.w u/ rAorn.o.ul.K y and Tnuruludy. T he University nt K.nsac Schnatl of Pharmacy, I awrence. IIFNRY 1 FSBFR, Prl D, Resror.A !n.- n.uw.doRnt, Mawn Rt.eatch Inslilule, Wotcefler, Mass. WAI 1FR R. FSSMAN, P//I), rn./r.s.. .r/ r.yrA..l..Rr. (J,reens ('dkge u/ Iht ('ily ul New Yor1, Ilushing . TIIFOIK/R1 N PINI FY. M 1). Ar..wi- otr rruJr...w nf Mrlu.nr, lht l)nirer- sily of New Mec.co Schoul of Medrc.ne. A llwquer Que. OII RFR I 11. FRIFUFII , M 1), .trma RrrrnrtA AlLh/Ib, CIn.rt Rrsrw.A Inrrowrr, New Fn11land 1)tacontss /lus pital, Roslon. AR 1111/R I I IRS I, Pit 1) , f)urr r.a, I ruV .r/ (-Armw.l Ib..Iaky, I/nivtrlwv of Ssn I rsnt..cu. San 1.anancr. MIIRRAY R(GnR11N/R. M I). A.....r ulr rr.•/rr..• n/ Pnrh..l.~et, (lniver.dy ul S.wlhern ( aldroma tiah.rrl u/ MrJt tine, I ot Angtle. Eapanded analysis o/ pulmnnary funatiun Jala us.ng computer lechmolut/ Melah.dic inlcrrtlation.hipa htlaen 10 hacco rnwte and Ihe human mawlh Stm.ling and the IMomlants nl human M.K.d: rnccharn.m nJ prevenllon Mech.nism o/ karning faulru/iun by nic r-line Sludies on immunoatpp.e.c..e tllech u1 r'Mde SnN.(t and Ra, varyw ph,K In- halalrun Studiet uf maWin( r.l..m up.n nmtmrwy conudula/Nwr See 1 adnman, A / 7 he palhu1ttncsi. ul hurnan h1aJJtr . anatr A Cuw./r.JIrJ lludy lu evaluate Iht tltt.l uf aJm.u..lrala.n .d La.e .ntlal. (.rlh rw rt1M.u1 talw.vua /u.iputttt .m.,\r) .w. the wNIJrrMr .4 rJ.n.w...r ,Jtm. roa..n Sua.n A r.awe Nnlr) in relalwn lu /ht .nr..1.ng anJ lung can.tr pruhkm An epaknu.,hyMa1 rt.rarrh pr.,Ri..n. un /he eliuh.Ay uf hunun ..u..t. 47

(:RANTF:F. ANI) INSTITI/Tl()N UEUR(iE U (;I•Y, M 1). t)orrror, Flnn nrylln.rlf ('antrr Rrarerth IJA/VYbwy; Ar..rlnlr rro/rll.w n/ SrrRr.y. 1he tnhm Ill.y.k/ns Unr.cnNy ScM.r/ uf Mcdnclne. Salllmtxe OAVID M G1)1 OFNSI'R<3, Sc D, M O.. Rtvan h A.u4.atr rrn/rsaw of rarh.rlJty, l/nivertNy, u( PittsAurgA School of Medicine. Pnlslnarlth. PAIII. (:OI 1)IIARI R, I) O S, Arl.niarr PRI))F.IT TIIt.F, lhe cutlure u/ hunlan IunR t/sur anJ the eRetlt of \nuwn and rym/hle talcnw, gentc agenls up/'n slnf/ lisaue l haracletislrcs nl n.umd cell lruwlh in culture in retalwM lu invasive calcin Iwna, especially rn the IunR Htltreltanaptanlalitxl sll/dies wilh hunun bng canaer The produclion of an1lh,Jira to lohacco rra/rawr n/ rrnnL.nn.l.ry(y. /larvard YIN.lie Q,Mknsalt ur um,te In animals . y o tw taico Sclwnll of Medicine All I School of l)enlal Med/cine. Sostun nd humans . nrqucrquc. ( n- ibated under I heodarre N. Ftnky, M I) ) 11?(yNll)E (1U11)S11IN, OSc, Rr- A study of hioekclric Jlfitrrncet helween II wrr h Sl ltnrnt, Rtrrrar of Rrsrarr h In NrrrdnRy anJ rr)th.arrR, New /traty Nturuqsychiatric Inst/tult, Psinceton. nklMrne haMuultJ and nun hahrlualtd nr{anisrns hy use of Mgh ene/t) pM». phatc clanpawnds PA I S I ARSON, Ptt 1), Haag rrn/rr s.n r/ IA..nu..doRy, Medical ('trlkRe of Vitginia. Richmond 1(f$I P/t 1(il1ARNFRI. Pn O. I)trrctt+, f'rlrnonry ArrnllNrl,rRy CaAwarnry. 1)ry..rrn..nr ,I Mrdn.nr, Sa1M Vlncen( the effecl of ciprelte smole t.n the immunnhlAical anJ melal.ullc lunatn.n of Letrlar macrl.pha1tes 1(txpttal. WorteNe+. Mast (lnt//altd under (luuave A I aurenri, M 1) ) NURMAN W III tMSI RA. Phl l), An.. Fftrtls Id vnoling on sudained prlform~ (latr rrorru.lr nf rv, hJMIrr. Itur.l.+ l)rltrr Rrhalr.n I 1A..ot,ay. I lm.rlu/y of Stwlh Ua1Wa, Vtrm,11«w, ance in a slmulalcJ Jrlvm& It\t 1((K:1 4 K. I ARSON, M O, ('hrr/ of An In.r.1lR.lll.,n .A the Ielallnminp Lt~ A(rJnlnr, Irrtnn ('twnly Iltnpilal, Iwrrn .m..lm/ drp.lvan..n an.) sl.ras Fltsnu, Cd. 1 rl.,l. .4 \.n..11n/ Ln perlphrral r,.u.l a,udy Krl.l,,.n\hlp Lrlv.ren \ry.nlantuu. sm..~ mit anJ /nJu.rJ m.w„1 ahan/e O1.f A 11011FRM/1NN, MI). Rr A An Inve\Illahun tul the in .r/lr.. Irans (iI/SfAVIi A I Al/RUN71, M.1)., Atlur- ant rr.r/nur ../ A(rd.rlnr DnrU + uarlh Sritnrist, (n~~nd l.haal.wy, hwmaln.n uf ge/mfrre mammalun cells ; . , lln•I.t..n ../ Rrlpmmor , lllseava New UniversNy of Na1rt Uame. Notre hy chemical careanoRem y . ler.ey ('utkte t,/ Medicine anJ ben- Uame. tnd 8 An investigatilm of Ihe rtlatiunship of kulemugenetn lu antJ`enic slunulall.,n titlly, Iertey (-ny. fR1 Df)Y llOMMURGI- R, M I), rrrri- Stln/ies tln cattim,lltnesis and the Mu. ('1:('111? I fl1('llll'.NNI RUFR, Ptt l), IIraA, f)rpJrunrnl nf (rnuhr.nnrry, drnr and flue.r.r, Sio Research Insh- lule, Inc . ('amhridre. Mats. astay, tof earcirrrgenie alen/t Swfn.lrnwule ftw hapr rimenlal ('ancer ('.rnparatlve s1uJKs of efftCls of valu,us Researah• I ausanne, $wltrertand. hlAaccu srnu\e tan.kn+alcs tm s11nt t,/ mice Syslemic eflrttt of Ihree Inhat(o snrlte O1WA1 1) R. I(1N1 5. M 1), SI. I ukr's 17,r.p1al. Nrw Yort ( Ily. cun.knules 11/oluAical eRrtts of ciplelle tnsule I[.alualwrn Id plAmnnary /unUi„n, Inau IIK raftlrll a(t t./ In IN.r/nal c/u1J.cn an.l IMnt wllf, a\rhala, M.,n.hur., Ir thruna pnru.nnnu. ulh trqutnl In mleali.+.s nl iII I,nds, p.uUalAally Ihu.c t.u/stJ hy knuwn vltal .(trnlt vH (:RANI'F.F: ANty 1N!iT1T'l/l1(loN St11R1 EY I KAt/1 1 MAN, M U.• Arr.,- rlnrr rr..frrlnr ../ 1'arhJl..Ry. h..wnslate MeJlcal ('enyrr, Slale Un/vtrsily of New Y,a1• N..w.\lyn. AARON 1. 1 AI)MAN, Pyr,l), rrn/rstw and ('hmrarnn, 1)r0arulrnt of Anat- Ihe lln/verut omy f N M PR(/)!:(T TITLF. To invetligale the palhuReneas ../ ure Ihane indllced Iu1nR adrn..na. in nuar; speciflcally U.e IJrntdiaarl.ru ..1 the cells whiah gIvt rtte 1.. the aJtn,.nu+, and the hne sttlwtuu/ thanges rn Iht\t cells during nenplasia ( arcinlrten induced alteraGons in the trll cycle ul the lype 2 alveular e(wlhrlul cttl FRtcl nl cigatelle smolinR un Lpl,ls and mtrphtrh.Ry .d alvtaJar IinlnR uulrtl.I .nd matluphages Prtpatation Lw plnditati,.n ul a f4w4 nn Ihe hprllKic aspecls of lohauu nJ sntll\ int Enaymatie ttansformahuns u1 mc(Alne and rtlated et.mpnunJ\ ISee MaKennis, 11) 'tlte pwsil.k eRrat uf lnhatcu smule and nkulint on a.cnrt,ie aud melal.uhsm Sttbsidy (ut puhtiaalitm ol a supplenlent to the motwlCraph,'•Ilrhxtu• Mechanisms u/ resiaanct to pldmunary patMlRens in nlite etpusrd lu clplelle smul e 7r.1 of the hyp.qhetis thal the suaeptibihly to deal.rp ..r nd lo Jrve/arp tm- physcm in smu\ers is gcoelltally dt. It/mined See (iuarneri, 1. 1 A erwrelalrJ hisluluRaal, cy11,h~Raa1 anJ eyhnhemiaal slu.ly uf tilr na.hr., Mtlnchia lrre ut /tuat ttry.stJ 1u u{.ttne smn\e lht inlenelal/un Ltlween m0urn.a vi/u+ m1et1/1M., r.(tih1/1e Itu tlRaNlt •/n.,lt and ulher fr.l.w\ in the Jr.rhq•lnrnl ,d INIIImYIAIy a.MI h/.n,.I1/.I n/M t A hanparallvt ttpe.anlrnl.l \nnly /.1 Iht r.Jrs ../ .nh.J.uron .,I ...... la . I4. rttlts tunlauanR y/ar nf unule h.wu uR.urur. hrr .,/ lu.t nIt1.J.. wh.lanlr rr.pn.l.Jy uJ..lu,n. wnh nlnurn7a vnu., ruA Ihru /n/rr.rl.l li..n hw Ihr .kvtl,q.nltul yd I~r.m.hl.J arpl plhn..nacy k.urn, n, m/.t YY

i (:RAfwTEF. ANI) INtii1TSIT11ytV 1. P 1 UN(i, Plr 1), Pn./rurrr n/ Pharnro. rnlr fy, Slate llmstruly of low• ( ol kst u( Medreine, lowa tlly. C'LAYTON U 1O(1SI 1, Pw I), M D, If.urntr Pr../rrs.r n1 Mrh.mc and P.rAnluty, I /ni.erulr of Scwqhern ('ali- lotnra School of Medicine. 1 u. AnReks. IX)NAt 1) S 1()l/R1A, M D, AtMMN/r Ptu/nun of Mrlnrnt, ('otnefl Ilnivtr- uly Medrrd ('olkge, New Yotl ('iMy. KFNNF111 Mt-RRIt I I YN(-11, L/ I), Sc D, 1 1 D,('Aenr rflor and Pru/n u.r of PaA.d..ry, MrJud College of SoulA ('urdrna, ( harkuon. I ln associann.n wnh F«de A Mcl.er, M 1) ) I ORDF A Mt I V I R, M D., Aru. urr Prulru.r of r.rh.J..ty. MtJrcd ( al kfft of S.wlb (arohna, ( h.rlrslun HFRSFRr MrKFNNIC, 1., Pnl), Pr,r ~ttor .r/ PA..wr,nnLrRy. MeJrcal ( .4 at of Vn, rnu, Rahnu.nJ IlmrraltJ under Pwl S 1 arwn, Ph 1.) 1 WIII.IAM F MrNARY, l., P//D, .4 r Rnuun 10,101, hn/ru.r n/ Inarnmy. l)nivetsNy Sclw.ul of Medurne, Rrnlun INFS MANIN , Pu I) . Aurrr.nr Prnfct arrc of /InrrArmuu7, ('ollege of Physi. ci.m .nd Surtnrn~ ( dumhil lJmar• si/y,'Ncw Yu11 ( ny, 10114 H. MANII01 D. 1. . 1) M I), Prn- /niur .n/ Dorlrnr of P.rArd.rly and Oral I)wnaus. New lersey C'dkse of Medreine and Denlrstry, Itrsry ( sty IN)NA11) 1 MASSAR/), M D, A.nnlnrc Prn/rnar n) Alydniwr, (Iturt e Wa.h inRton (Ini.enrly ti.Mrol u1 MedKrnt, WashinitIl.n, 1)( 1'R(/JF:(T Ttl'LF. (lx+.parHl.e c ytnc hemicai, cytutuRical and hrslolulrcal sluJrts ul errly tlleals nl creartlle smule (whrAr, /as phaw, arwl- slnutnls) in mrct and in b-ue and urRan cullures Innn mice and human. ( ardiuvascular eflctts uf niculme Fur/hcr sluJies cuncrrnmg sympalM.mi tntllc K111Mf nf nNIM/1K l.ung liuuc rt.ctions lo .IIMNnt chemi- cal and hidugn:al agenla $/uJiet on myCMoaine Fnvironenrnlal fac/urs and pulmlwlary Jra (aK: (. Ashrslln dust (1 Ashesltn and co carcinuRens, viral and chemical Ste I ynch, K M I nrymah. Irans/ormalrnn ol m(rrme anJ rrlsrtJ cump..runJs Iht hrdoh.ty, M.I.ahtnu,uy anJ utlraalrualurr ul nutmal and JrscaxJ lung the role of heredilary cla.laat inhibillw Jefkiency in the tliulugy ut pulmunsry rmphystma FlsvaJylie hrealeJown in Ihe rlirdogy of pulnurnary emphystma StuJy of Ilse purported relalron'.hip Ix- Iween rnullnR anJ chanRes in hu.nan Lral t/sMre in Yr\'Ir hy rlnlnlK m/(ruacl'Py, Jrnertntial sNrning, and mkrurr.pnunsrltr nKlhl.h, and /urlhrr sla L.Iwal trummalurn uf 1wo urrr, u/ J..1a prtunlly in Ihe prrnarpal s-ruq.l,w s pnstssinn t.rapuall.t racial prtvaltnat u/ aht.rnrc M ra.c hrlis Advrular cell+ prulrin and I,yt,.prrNtin hiusyn/heus 1'rnlrin tymht.-a anJ r,rrlrun hy lratheal n.u...u CRA(v'f t•:E ANII IrvSl IT11T111fV KI NNt 111 M MOSI:R, M D, Arunanr Pr.•/rruw .r/ AfrJurnt, (:etwselown Ilmversrly MeJraal School, Washrngttsn, u c. I t)Ml1Nt) AN IUNY MlIRP11Y, M I), Sr 1), An.rromr Pr.r/rruw a/ Rr.runrrs- rr. l enJ AIrJu mr, (lniverslly of aJo Medical ( enter, 1)envcr. RI('11AR1) 1. NAI Y/:, M 1), P.u/rrvw and (Ywornnw, I)rfrurrnrrnr o/ Purh..1- uRr. Pennsylvama S/ale Ilnivtruly ( ullege of Medrerne, Htrshey. ALNI R I It N11)1 N, M 1), Prn/n...r n/ Mrlurnr, l)urrrrw, Pufnrunaty Dutnrr Snh.rn, llry.arr.rvnr ul MrJrunt, lem- ple t)nrversrty Schlxp ol MeJicine. Phd. adclphu. IN)NAI l) M. PA('F:, Pn 1) , Pru/ru.n u/ PAywdnRy nnJ !)urt/rr., fnlrhlMU /ur ('rtlufsr Rrstar.h, l)nivenny of Ne. bras\a, I inculn ROSt MAR11. PAN(iBORN, 11 $, M I), Aarurunr Fu.rJ l r. hn.du~ur .n/ l.rr - lurrr, I)rpon..vnr o/ Fwrl Tcirnce .nJ 7rrhnolulry, University of ('dilornla, Davrs. MARY S11 kNC PARS111/=Y, Pl/ O .- Ar.lvanr Pru/runr u/ Ana/u.ny rn (/A. rulnrr .nJ (lrnr.ol.rty. ('olltge of Physicians anJ Slntruns, ( cdumhu llmveruly, New Yu.1 ('ily. S N Pk AI/IIAN, M 1/ , Pu 1) . I'.../ru,•r ..1 Ph.rnr.n..l..[I. IlowarJ (lnlvrr.dy l ldltet uf $Ir.In.ne, Washmslun, I/ ( MARIIN ti PR()1/11, /(S, (11/ti, (hr.f, frrpn.r.rvnr u/ (h.f Iurhnh.Rr. Ntwarl ( sty Ilu.pnal, Newar\, N I 1'N/))F:/T '11TLF: URtch of aarde anJ ahruuu ciRarcltr unrArng up.wr hl.rmulyba aalraly and hltwxl cuagulal.um in M.n Wr.lsmg rnd in Jrlad an al.prupriatt mc:rm n/ dcltrmiomR the Jurau..n u/ survrval of Ihr Imman p1a1c1e1 Snur\inR and the pulm.mary hhw..l vecarl., a yuanlrlalive, m.wpMdugr. .hrly F.f1ec1. nl crgareltc amuie, clruFs and m.c 1rNH fumtl.M the It/r91nal auways wuh ape alal rekrrna lu Iht Itnuuul lnnn ch-wrlrs Fr11..wship /tK training in Iia.ue cullurt ItchniylKs StuJy uf the tRecls .f lubaCto sn.u\e cunddlKnH on vnrpnn Irarns of Usaut crlls cullwaleJ in .rr... InvesllgalUOns url teapuahun and glyaaly• ai+, as wrll as p+..alhle lhamW4nnal varialnns in cslahli.hrd cell lines whnh have been capnsed 14, ciRarttle snude and /mRle cunatrluenls ul vrar\t Invealiliabanls un e0esls u/ cutimKens and study u/ the tllrcl u/ elh.md and c.rcmoRe.:a un physild..paal, mrlahrJa, nd mrwphulullaal ahanRrs in .hldn.J celh unJer ,elld.ic anJ anacrubic Cundrli..ns (nleraclilns uf Rusla/ury, .dlatlury, lacldr, and Ihermal aunulr enwn~ srouker% anJ twrnsmulter. t~Rccl nl run.nlutnt. nl 1.,1.3 ...... uir .•n nurrnal an.1 urwhgn,uu huuran rc.pn li.ry epnhrluw, rn urr,. hlltcl ../ luh.uar..m.,tr r,n u..rmal urnuw lune Ir..ur I l/r./ u/ nr.uunr ..n 1..h,..n,. A aump.r ..urt .tn.,ly .,l Ihr rrtr,~. ,.1 ) ultd.shlp,Luu/urur .nA ..R.uri.r .m.dr .nnJrn...lt ..pph..l r,r /ht ur.J Ir..ur. u/ \wr.. nu.r /11 k/ u,rn,ln.,.nr.1 wrlh ahubul anJ/..r ..uLun Irh.nhl„n,lt

(:IIAN'1 FF: ANI) /P1!iTITtITtI)N WAITIR RIhIS(/1, M1), Arlnt/arr rrafrlarr nf ( Irnn.l Mrdninr, Ne. Ylwl llni.ersny Sclxx,l o/ Med/cint, and NYV Re.earch Service, (ioldwaler Mtmorul Husrilal, New Yor\ ('Ny. Wit 11AM R1 (:/ 1 SON, M O, Ptnfraa.w and (Aaonran, I)rrarrn.rnl oJ Mrdual Om..ln1r, Mtd/caI ('utkSe of Vnltinu, Richnl.N.d W1111% R Rtl_SFN, Pn 1), StnuN• Rro- rhrnuu, f r/r lrrrnrrs /hrfbwn. 111 Rt. aeuch tnttnute, ( h.caRn. (In/t.ated undtr A Weirnlocl, Ph 1) / I(/SI P/I 11 R(K:hRS, M 1), flnly Namt of )t+us IIn+INlal, (iad.den, Ala R/)H1 R1 (' R(riAN, M I). A.uv,.n/ Pr../tnw n/ rarh.dn/r, SLn/o.J Ilm vtruly, Sun/orJ. ( d ('ItARI l$ I ROSI, A M, trn/.N I)ntl rrw, Vtlftans AJminlstlalNln, Outra lienl ( IhnN;, Rotl.wl 1(NIN R ROWI ANI)S, Pn 1). Smt! t. r8 rnrnrr, Gwnhwt\I Rt+each Insnlulc, San Anlunin, lea 111 RI( II 11 M IIn1 PP1, M 1), I)nr.nN u/ Nrurupharnnn..l..(ty. Maaro ke. search Insthlule, W.NCr•sttr, Macs t/lk<iIN (I tc 1111(:11, MI). /'nl), I'r.,ln.nr unJ ( Inn.m~n. {rr unn .•1 11'r .~lusr. lltr.ur.ntnr „/ ~urRtrt. lutant 1lmvr/aly kM~4 ul M[J.unr. Nr+ I hlr.n\ PR/))F.(T TIl'LE A c.NUrarNive slnJy of Ihe efleala ol In- duted llvtr J.rmaRt on the t/evtlufwntnl nl lunxws .d Iht aNat mlNn.a anJ .Iln /olluwing the rpllcalNm u/ lubaccu sunokt anmknsaltt in inMrJ S.vns Welxltr mwe Vascular ye+Punvs to lohaacu \mnling in plitnls wnh va.culal dl.ea.e Vaaculat rrqxlnvta /d the tt.n mlcl.vrcu I.lion .nJ terthr]I urcul.ri.wl 1u 1d.acto srnolting in man lhe tflecl ul Iuhacco snw.ling un rhycur logic and Phalmacul..gic vat.Nndlw sllmuli RES funtlitrn, lum.w induction uld loruwlh fflecN ol luhacco smoke on cellula/ re+ INr atNNl A s1uJ/ n( Ihe incidtnee nl fatal htxl suaal+, sUulta aoJ INAmunaly rml.ul Lm in INJmnnaly tmrhyama paUtnlv Hllwla6-pldnu.naly Jy.rlaaia C,.. 1..1 preJa l.N \ ul lon/ttvdy A dtladeJ invr.hphnn ul the n.llnn of Ihe reacuun Ltlwan hwduF..al nule- rlal+ and alnln\(.Ixln' llNll]IIIIn.11\I\, usinR ekcl/un paranlaRnellc rt..wlamei nnJ IqMn.d arr.lluquric lechnlyuts InvtcliRati.N1 u( Ihc Jirtcl slimulauun ..I rala.ynlpalhelic ncrvc Icrminals by ma. d Int Nlcrdlnc adrnini\ualinn Iu rn.tra) alta\ uf Iht cat hrnn- cllt(tH Nry.n 111i and utno..mn .y.lem 1 hanRtt In 11/1 an.l trh...l..r InJu.tJ w/lh IIK INrNIJIItJ 1n11irfn.nn aJn.rn L/rall..n n! vmal/ duw+ .d ru..alnt In Ilmf\ILIntJ J..6+ I/.e n.lt ul uy /Nuphan mrl..l..ld.s in Ihf thnintty al 1.I..JJr1 IunuN L,rnuhun 1 I:RAPITEE Ary1) IIVST11'1ITIOPI MA1/R1( I S SI GAI , M 1), (7rni(al rr../r.r.N nJ AfrJNrnt, lulls (Iniversny ScMnd of MrJ.crnr Uorlr.w, !)rrafr- nvrrt of Inh.rlonnn 7hrrapy. Rutlun ('ny I luapnat, Hustun. I11( Il) S1 V/ R1, M 1), 1)unnr, lnui- lurr r.l ARNhrd ,I n.n..nr y nnJ /Au..L.tr, l)r.uunn ..f ( un rr Rfu-un It, Omvetslly rd PeruIra, Pelulfl., Italy S/1111t SIIIHn/ A. M I), Pu 1), A.u.ru.r Prn/nl.n ../ Pl..n..nd..d..lty, Omvtrsny 411 Ilawan Sc huul of Medicinr, Ilurx.- lulu. (iUNli M SMI/1(, Pn 1), At.nr.rnf P...- frT.w ..( P,y.h.doey, Ilarvnd MeJaal Schlx4. Mas.achuxlls l:enaal Ilusp/- la/. Ruslun. 1 u('111: . SM1111. rn f) . rrn/r,,.r u/ Ru._ fhrnr/ury, 1)allmoulh Medical SchtNll, llanuvtr, N II IOIIIS A SO1 O/ f, M 1). Prnfr.u.r n/ (-hnn n! A(rJu nrr und ('!ur/, lln r.r.'n of fNr.6..1..Kr. Itmrlt Univtt\by McJ. iul (?nler. 1'hda.klrhia. SIIIlIH)N (' SOMMI'Rti, M1), rt..- (rru.r ../ rurh.d..Ky. (ldleRe uf Phyai• eum and Sullteum, ('olunmhu Ilniver- sNy, New Yorl (ny. DAVII) M SI'nIN. M 1), 1)nrrrur, I)rp.nfnn'nr ../ I'urh..l..Ay, lht HrIN.lJale Il.npilal ( tnler, HnN.Uyn, N V. ( Akl)I INI R1 1)111 111OMAS, M 1), A\uNnnr Pr..fr. ../ Alr.h.mr, 1he luhns 11up11us IJmverary \ch.wl u( MeJnlne. Hn11nu.Ne PR/))F.(T 1'171.F: Sec ( IxN).nh, S An apfwuach tu the s1uJy ..( inlunal lactlws in lung cattmu~tntsa. inRuence ul hlw/n.wrts Hhxul h.wne carcinogcn+ in m.nlst lung lumur itr ne sH Sludy ul anaUvlty t.l va.cul]/ h.aN: Iu nw:ulint Iht rtlalnrns htlween sluuliln/t and INr+nnalily lhe inh/bnion u( cyl.xhnwnt c ouJase t,y tnhaccu smule Ihe eflecl u( I.J.atcn ./uulinA on s.ulIK1an1, \pfuh, lally a.rd., \srJuc rtr. f.wm.lo\c anJ mt1al.Jl.m ul uJ1lNrst ti.wc Srtti6c rllrclv uf smulmA nn myrxa/dul mtah.lna\, my.Nwdrat .nHalNJlsm and un rntymtv anJ LNnItJ tlrlutnlt ol Iht h1.NIJ 11u.1 f..cl..rv in alunun ratulnnaly mflam n.ulnln, enlphy.ema auJ Iun` \anael Pulnrunary rarrnahynl.J atlc..Juw\s in an au/aq.acJ "mN/n]I" Mqad..h.,n av re. 1]IrJ Iu aRt, xa anJ tnvunnmtolal lacl.ws the •irndl.anaf ul dJltlrnl nl.h.nln.l p.Jlt/no n( auaul.dury K•p.n•t luayt• relle vuu\mR SluJrev af R[otha ddl[/rnat. Irl..crn a/kl nnn.n/.A.r. Y/u.ht. .d L.y.h,.lnp.al ,Idlrrtnus Ir L.rro w1r1. w.J m.u.n.u\r.\ \ .b..wn l.y \un.p.na..n ..1 bp .nr Jraw /nA. r\yah..l..e/\..I Ih./r..\tfl/~t/\• .,I hr..lllly y..unR ..Jull. .ul,l Ih. u bn,l..ru at rmph a.lla.n, a u,nl.uu/rnR .1uJy In J.Iah. v.nh ./rual Itl.rrn.r 1.. Iht prt.lu.w. u/ hyl., rlrn.aul anJ ..:I..nnry Lt.ul .h. t.lat anJ L..m.du./; ILJ.J.

rz : (:RANTF'.E ANt/ IN4TITUTI(1N IAMFS E. P. TUMAN, Pu 1), rrofnr.r •n/ (/bonr.n of Ih.rn.aolntl, C'IM- c.to Med.cal School, Inudule fa Med- ical ResearcA. ( hicyu. LIE SNA TSAI. PstD, Re.rrcll Auor6 .rr, Ary.rr.nrnr of Lrbol.Ky, Y.k UnirenM7 School of Medicine, New Fl.rerl ('onw. ROMEO A. VIOUNF, M D, Aaoelur [ rofruor of rarAolor y, Y.k U.iverwF School of Medicine. New ll.reR Conw. SARtiARA K. WATSON, Pst D, Auirr- .nr larrrrolotut, MusacMrsetts (3eIl- tul Iloyilal; Rrrr.rrA Arwc.u.. Dr- p.rlnwnr of [!.l rr.rolot f .nl Imw.rnol- ot1. Nar.ad Medic.l School. soron. 1()ttN S WAII(iII, PNI), rIU/rs1.w n/ (-ArmunY, MatsxAuxstt Insliwtt ul TecAsoloty, ('.mhridte )ONN V. WF11 . M 1) , A,rut.nr rru/er ror o/ Mr/urnr, l/ni.eruty of Cola.Jo Medical ('tMer, Lkrtrtr. A WFINSrO('K, Psll).. Rrrr.aA Rro- tArrnbr, Life Sntncrr thrldon, fl t Re- Karch InNNYIt, ( Akallo. SIMON It. WFNDF.R, PND, R.rrucA rroJrnor of SiurA.r..Hrr~, (/ni.ersiy of (M1.haw., Nam.n DUANE O WFN71:.1, Pst D, P.nfrn.. o/ tA..rna.ol..rr. SchMwa of PAarmacy. UnJrersily of Kansas, I arrence PR(/)E(T TITLF, A sludt of the preamas of hyperlcn.run and cr.onary drxast ( igarelle snN4mt palterns over Irnxprufiks of famer smolers a.mp.reJ .rlh conlrnuint smc.ters .nd nonsmi.lers Mechanisms of the psycholrupic effects of nicotine TAt sLdy of aclirwn of nicoline uprwr ccn 4d synap.es and irs uwrelaln.n with the nsechani+m of action of hehaviur- l./lr active druts ' Slydy ow /ht aclirilytd hislWine Jetarho.- 71ase during the deveM.pnsenl phase of collateral arcuLNion in the lung of Ihe r.c wr1A litated pulmonary artery Ilislot:Aernislrf o( tpillselral mucim in carcinoma of the lung Immunologic .nd rMologK studies IM the rrde of snlluenta virus in malitnanl cell Iransfamatwn Flec/run spin res.n.nee srecltoxupy, of M am.tnelie +pecus dernvaMe frrxn to cu smuke and trlaled syslems Frtells of cigarette smulint and 44 chr..nic ar.way /rhfIrUCINtl1 in hyprsrc venhl.. I.wy drive in man See Riesen, W. R A qualitative and Quantilalrve itudy rd Ihe Individual pulyphenol content of eita- reue tobacco a.d the smrie and "lars" resullin` frum cigarette smut<rnt, study of the latt of these curnpuunds in the animal res(stalnrp ryslem ERect of citareOe sawlke and ils trrnpu- ncnls on free pro/ine in anrm.l liss.rc cullures Ihe delerminalion of the chsanc eflecrs of urallJ dm/nrNered nwra~ne uw strYrn /huleslerul and pMnpA,drprJs. ItK ek/IrntatdNyrapMc rt.ry.nse tu ertnnuvine. and the vascular palhuloty of cMdrsterd (ed rahf.ils A.InJr of anlihyper/ensisr a n.ily of nK Ul lne Fhccts of inlermoItenl nicoMine aJmrmdra tw.n on h1t..J presaue and my..c.nlwm i I i l'RANTEE AND IN9TITtfTTON PRO)E(T TITLE TIIOMAS C. WFST1 Al l-, PN D., Auin- Action of nicotine on suhcellular dislnlw .nr Irofruoe o/ IA..r.r.c.doty, Unitnws of ca/echdamines and setolunin in versilp of Virginia School of Medicinr, br.in and heart (Tarlalesville. - InRuersce of nicotine and related drop on the u1Ma\e s1Mage releaK and turnover of caleclw{arnines in central and pesiph te.llnsue DANIFL II WISFMAN, M D., Asuiu.nr Penlslewl Pulmowary dysfunctiai fullow- rr../ruo. of lydunrcr. Uni.ersitr of inR sprcrfic, lower respiraap drscaxs Southern ('alifania; C-Ad6rn'. Divr- during chiWhood .wn. I or Angeles (-ounty (icner.l Nos- pital, 1 os Anteks.

Recipients of Cornpleted Projects Following is a list o( ¢rantccs whose projects have been compleled prior to the period covered in this Report. Several of the 6ranlcls are de- ceased. The lillcs and affiliations listed are those in effect at the time the work was complclcd. CL.ARFNCF. M. ACRFSS, M D., Aus cAerr Clrnlral Pru/ra.w of Mrdklwr. University of Caliio.wl. Medical Ca.- ler, I o. Aqeles. ANTHONY P. AMAROSP, Ps(.D. /n• irrrrrar, Drparrn.rnr ./ ()D.rrakr r.d CpnrrorePyT)K AIe.wT Medical Col- kae of Uwio. Uwi.ereMf, Als.ay, N.Y. F.. T. ANOF.I.AK()S, M D., P11.D, Prs /rrwr o/ PA'dolo*n tlbMow U.Leeary School of Medicine, /o.row. D MURRAY ANOEVINF_ MD, Ud- .eraNy of Wl.cow.i. Sclool o( Medi- cirse, l.lade.ow. RRODA A RARNFS, M D, P>t D, Pro- /ruor (alUurr) of PAyuoloR.. Cok.. udo SrNe Oni.errly, Fo.l ('olbns. FRFDFRI('K W. RARNFS, 1. , M I), Ats,nrnrr Pn./rr.•r of Mrh,rnr, 1he /ohnf, 11.•q1in. (tni.ersqy Schoul nf Medrelne, haltimo.e. T (' RARNFS, DSr', Rrreo<ASrrrn/nt, Philadelphia Slale Nuapilal, Phdadel phr• R. FRFUFRICK RFCKF.R, PN1), Aiun ru.Ir Pru/ruor n/ Anatomy and f)nrc- rIM, laAMII,My of Prrrna/wl Irrrnrr, Dake University Medical ('enler, t1.o- h.rn, N. C. RAI.PH S RFCKFR, Ptr D, Pr../rsr,n ol CAenrlpry. University of Ihwslon. I luuslow. IIYt AN A RI('KFRMAN, M L), Aru.r anr Pro/ruw .r/ Mrdnrnr, and AI VAN I RARA( 11, M V, Cnnrubanr u Mrd /. rnr, ('o/umbi. t)nl.er.ily (ollege ol Phys.cians and Sur~t om; O,JJwaer Mem,wial ll,npl.l, Ne+ Ynr\ ('ilr I R1 1) (1 R(K K, Prl l), An.n,.rr ('an,n Rr.ro.A S„rnnrr, Rnrl.r~u.f .[ranon, R,.swell P.rk Memorial Initilrle, til+r,n~r,l/e, N Y. HERMAN V. ROENIO, PuD, Hrad, CArmurry and• eiwArnwa y Drpr(- n.riu, Spindk(oq Re+eares ('enter, I.ea- Mtrow, Ky. IAMFS F. nONNFR, Prt D, Profruar of fiolpgy, ('alifwnia lrwilute of Tecb- woloIy, P...dena. TOM 0 ROWERY, PM D., PrJrlclde Rn- ldrr fibr.rnry, CArm/iuy Drp.rl- mrnr, Nor(b Carolina Slue Colkge, Raleigh. 1OSFF RRO7FK, PND, Pro/rswr and CAaiman, Drp.rrmrne .,1 Pr"Aology, l.ehla\ (lnireraly, Rethlchem, Pa. RF.NIAMIN RURROWS, M D, Aisorinrr Prolru<w of MrLc.nr, t)ni.ersily of (hKa(jn. ('hKaao. F M R(ITI, MO. ('A,r/ F.rA..fnttin, I os Angeles ('ounly (kner.l llnapilal, I m Angeks R1( IIARI) ll RYERRIIM, Pn D, Prn- (rruw nf ('Armurry, Mnh,gan Slate Unr.ersrly, Fast I ansing SISTFR M FMIt Y('A/lll I, Pr( 1)., CAanman, CAr,niury Ilrparrnvnr, Regis ('ulklte, We+h.n, M.u, WIt 11AM II ('ARNFS, M 1)., (Jnirer- .i1y of llla\ College of Medicine, Sdt I .Ie ('ity. I F.OP(N 1) R CFRFCFIX), Pn l), Prr.- /rrvw u/ Rio.Armurr, and Nunuu,n, University of Puerlo RKo SaMKd of MedK/ne. Sn luan W1IIIAM (i ('1 ARK. 1•1,1). ll.rr,r.•r, Pry. A.qA.rnra.,.l.•tly Rr,r.., A I aM•ra r.nr, Velrrens Administuiw,n ItusPN.l, Sepul.eda, ('al. IIANS 7. ('1 ARK1-, t) S< , h.•lrsu•r ../ Rux Arnn.n r, (olumh,. ( Imrrr ta y(',d kle of Physieians .nJ Surgeuns, New York. DANIFI ((111FN, L) V M, M P ll , A.- i,.oenr Prn/ruor of Vrtninery P.ppdrm- iuln(r .nJ PrAhc IlydrA, University of Pennsyl.ania Schud of Veterrnary Medicine, Phil.delPhia. IIILIUS H COMROF, 1. , M D., Dirrr- rnr, Crd,nrucu/ar Rrir.rrh Ininrurr, Univenu~ of C.li/orni. Medical ('en- ler, San 1-raaisco. DEAN M. CONNORS, M D., Aunewrr I)rrrrrw, I)rporrrornr o/ 1.Aorarory Mrdi<inr, SI M.ry'. 11orPilal, Mlwlison, W is. P11111P C(X)PFR, M.1), Clinira/ Pru/rr. i.w of .Srrerry and DrrrUrw, Sw~i.d I.aAor.rwy of (-r/rrlar PAyri..l.rRy, Albert Finuein Colkge of Medicine; CArr/, Swe.<al Srrrkr, Veler.n. Ad- mirsiaratiun Ho+pilal, drona, N.Y. RORFRT l.. ('RAIN, PND., Aa.irmwt Pro/rswr of Soriofoty. Univer.ily of ('hicato, C.'hicaoo. CF.C'll. F. CROSS, ResrarcA Drp.rrmrnl, SI. loseph Nospit.l, Surb.nk, Cd. R. F. DAWS()N, PH D.. Pro/ru.r of Rnr- any, C'olumbi. Uni.eesily, New York Cit y. ANI)RFW S. 1)IRNFR, PH D., f:'.r.rnrr, PryrhuRnrarcA, The Age (?nler of New Fngland, Inc., I(oston. RAt Pit l. IN)RfMAN. Pu 1), Dor,hw of IoA,Mannlr). W.MCCSIer 1'nunJalron (ur 1 .Perimen/.l Rioluay. Shrewshury, M ss. JAMFS 1. 1)YAR, P// I), Aun/anr Prn- /ru•n of Rmh•Rl, Rellarmine ('ollege, I.ouis.illc, Ky. 10111,11 W. F( KSIFIN, M I), Anhranr Pr.•frovw u/ Inrrrnnl Mrduiwr, Stae University of luwa ((slleae of Medicine, Iowa ('ily. IIANS l. FAI K, Phll), Ad/unrl Asuni- alr Pru/rs..•r, I)rp~vlnlrnr o/ Parh.d,•fy. (Inirerniry of luuthern C.I/lurnia S<Mw,l o( Mrdu,nr, I m Anarkr 1)ANA t IARN%WI/Kt/1, M 1), llrnr, KObrrr Pr../ru.w .,f IIrR,rnr nnd lll rr,lw u/ l/n,rrrurF NrafrA Srrr,.r,, llarrard (lmrersdl, ('amhrwlae, M.as. IRANK (' IFR(IlK1)N, l., MI), (Aaun.on, Urparrn.rnr of PAnrmn.,d- oRy. 7he Albany Medical ('ulirse of Union (Jnivers,ly, Albany, N V W1111AM I 11\11H1 IN, M 1), ('A,rf of f.p,drnwA..R~,( hKa9o Roardol lle.llh, ( hKa[n RUSSFt I. S I-ISIIFR, M D, llni.e.•ily of Maryland Schu<d of Medicine. Ralll rnore. S. l. FRI{FI)LANI)FR, M I), Doruw of Can.rr Rrsrnrch, M,nmt 7w.n ttusp1.1 .nd Medical ('enter, San Fran CrKo. FREDERIC A. FRF:N('H, A R, Dirrnnr r./ ('anrn CArna.IArupy Rrerar.A, Mount Iion Ho+pi(al and Medic.l ('en- kr, San Franciscu. IA('K FRF(1ND, M 1). Auuranr Plu/rr. >ror of PA«mwvrlo1y, Medical College of Virffinla, RkMnond. THOMAS M. (X)('KF, M I)., Ainurarr Pro/rii..r u/ Prrrrnnrr MrJrclnr and Crnnnrrniry NralrA, New lersey Slate ('ulkae of Medicine and Demistry, ler.ey ('ily. IRA GORF, M.U, Pr../rr.ur of PatAol. orf. Roslnn Universify Scho.ld of Medi- cine: ('Air/ .•/ l nA.warury Srrrnr, Velerans Adeninislral,un llospiul, Wcst Ru.hury, M.s. OFRIRIIUF. V. (i(/1'tti('11A11. PrrD, Asrnr..nr Profrrr... of RuNArmr.rry. ('.dumhu (Iniveruly ('ul/eae of Phyveians and SurRruns, New Vo/k l'ny. A. ('1ARK GR111IN, Pu1). /lrad o/ AunArnuvrr 1)rp,nnnrnr, M 1) An- <krsun Ilospplal anJ 1 u,mn InslM,ne, 1lniversiry ol leaas Medical /'enler, 11W1rtM. AR711(1R t. (JKl)SS, M S, 3rnu.r Rur chrnus/, Suuthwest Rese.rch Inst,tule, San Antun.u, Ie. M11R1(/N t(iKIKSMAN, Prll), M 1), Au.nrorr ('l,nr,nl I'rn/r„nr .•/ )k(rfi- rrne, Ilni.elsd) nf ( al,lurm Medual ('enler, 1 u. Angeles ('AK1 (I:RIt11/11. l'n 1). A/ l), .en,. .iau m PAnu•f•.Rr ..nJ l'6.. .,h.Rr. Ilmveruly uf 1'aru,.ylrama lin,h.ar / SaMw,l uf Med,unr. 1'b,t.,klphu 1 RANK V 171111111t1 ./'n 1) I'.../r,...r. and IRNI YI 11(/IN.~/tN, 19.Ir. A, ruranr Rr.ru., l, I'n./r, ,, f Irp.nrn,rwr n/ l.nn•n.nl.•rr, No,lh11 .,ahn. ]lale ('olleae, R.1e,fih, 107

It. . HAAO. M D. rro/rssor of rA.r- ...colof7, Medical Coltege of Vkgini.. R ic frnond F. 1. IIADDY, M D, hM D, rro/ruar .wd CA.knww, Drperrw+rwr of rA/t/d- 0tt7. University of ()•IaAoma Medical Cemer, Ollahoma Cily. )O6FPH H. HAFKFNSCHIEL~.~ Mrdrrd Dererrwvnr, Sandot oturKalti San F/.ncisco. RICIIARD 1. IIAVFI, M.D., Auis..r Professor of Mrhrewe. Univer.N of Calrforwia Medical Sebol, Sew Ftr.w- cisco. HERBF.RT R. HAWTHORNP M D_ CA./rw..w, Dr~.rrwaM of Srerr/. U.iversM' o( hnneylv.wia O..duaie School of Medkine, /fY.dellii.. CLARK W HEATH, M D, r.o/rssor o/ Mrd.rine awd i)rrcra.o/ HrdtA Srrr- krr. T.fu Uni.er.iy, MeMo.d. M.r. PAULINE IIEI7FR, h( D. Rrsr.rcA Ar- loti.rr /w ('/r.do" .wd C/torArw.lur/. San Fr.ncisco InuirMe of Medical Sci- ences, San Fraacisco. LAWRFNCE L. /IFSTF.R, 1. , M D., rro- /euor end CA«rw.aw. Dr/wrw.rwt of OAsrrirks .nd (i/wreolof7, Medical Coflese of Sourh Cudrna, ('sarkwon F.eBP-CURTIS H(}F, n( D, M D, P.o (rtxn .wd CAebn..w, D/rtsiow of rq- rAierrk Rrse.rrA, Medical ('ofkRe of Virgini.4 Ric4r.ond. RUSSELI. L. H(M.MAN, M D., t ouisuna SINe University School of Med.cine, Ner Ork.m. ROeP.RT W. HlJll., rs( D., rro/ruor of Ib1oR(rvl Srkwcrs. Flwid. StNe Uni- eeesi(r. Tdt.h.nre. DEOROE /AC()BSON, M D., rroJrsor .wd He.d, orPrin.ewt of R.hufo*). University of So.l\er• Califorwie Scl.ool of Medicine, Lw Arye/e1. 1FRRY IIART IA(Y)BSON, M 1), 111rrr ter, DiYir/aMr o/ lINIIOPA7rJolOR/, New Yoei Fre .wd':u Iw~r..uy, Ne. Yak Cit7. /llt 1111 11 1A('(>eSON It. M t), Asw. rrerr rrn/ru.r of Sr/n~ and ifirr.r.r o/ SrrRr.el Rrrr.rA, llwi.er.il7 of Ver- n.onl ( o1kRc of Medkiwe, Burl.nFron. MURRAY F. IARVIK, PRr [), Assoriarr rro/r»or of rArmroloqy, Alberl Fin- Mein Cdkge of Medicine, Broea, N. Y. ANDREW A. KANDUTS('H, rND, Sis Srlrwri», Roscoe S. Jackson Mem- oeW Lahoratory, Ber Harhor, Me. ARNOLD R. KAPLAN, hr D, Dirrrro., L.boreror' of Mrda.l Grnrnn, ('kve- l.wd Ps)c6i.rric Ins1i(u1e and /lospii.l, Cse.dand. HRATCH KASPARIAN, M D, Arslstans DYrctor, Crdbr.xrfr L+A..reto.7; lwsrrreror in MrdKiwr, Hshnemann Medical Cd/ege and /loVir.l, rMta- delPhia. ELIHU KATY- Pw D, Arcoriasr Professor of Soclolog7. Uni.eaiN7 of ('lkapo, Clityo. ANCEL KEYS. MO, Dlrrrro., L.Aore- tor7 of rA7sioloriref H7Rirwr. Univer- M1/ of Miwncsol. School of hMic He.hh. Minne.poli.. /OSP.PH B. K I RSNER, A/ D, r•o(ruor o/ Mrdkinr. University of Chicuto School of Medicine, C'hicago. PFTFR 11 KNAPP. M I), RrorerrA rro- /rr...r o/ rr).Arerr7, Roslun University S.h.ril of Medicine. Bos11M KI-NNIF111 P KNl/t)IS()N, M 1), lJni- verul) of Wa.hrngron Medwel School. Seauk. ALVIN 1. K(KAK, Pw.D, Arawierr rro- /ruor of CArnctblr7, New Yow\ Univer- eity, New Yori City. ROBFRT A. KUHN. M D, Auoci.rr rro- /ruor, Dlrblow of Nrrrosrlrr7. New lersey Sl.re Colkge of Medicine, lersey Cilr. MARVIN KUSCIINFR. M D, New Yorl Uwivereiy Medical ('entn, New York Cil /. ('l1ARtFS W. I.BPIIF!, Pn1), Arurr .w1 rrolru.r o/ hnrb..ww.rwral I!) ~ R/rnr, Ikptarln.enl of rreventive Medl eine, le/ler+ow Medical ('otkK, PKd.- delPhie T1IUMAS (', I AIPPt Y. M 1), rro/ruor of rerA..l,.Rt, Norlho,ewrrn University Medical Sahool, Cbre.2u. I l1R I i AVFRn 1. A. t 4EBOW, M.D., CAdrn.en, DrCernnrnr of rerAolor7, Y.k Uni- versily School of Me.dicine, Ne. Haven, C onn. FSTEN 0 t INDSFTH, M D. P)r D., SI. loseph's teospilal ResearA LaboraMory, Sr. F.ul, Minn. ROBERT H. LINNF.Lh hr.D., Auocierr rro/ruor of CAr.wistr7. University of Vennonl, Burlinpo.. IIFRBFRT 1.1 OMBARD, M.D., M.P.11. AOfl.err, ('.ncer ReseucV Inslilule, , Ne• FnRland Ikaconer Ho+9itd, Bo.- )nn. CHARt FS C. MMRTIIUR, A/ D., rs7- rAoloRisr to the Uwirrrdr7 Ilr.ltA Srr.- krs, lluvard Vnl.ersM/, CaniMidge, Mse. CHARLFS B. McfANTS, rw.D., A»o- rlar rro/rsror of Sorb, Nortla Cuolina Stae CdkRe School of ARtharKure, Rakig\. HF.NRY C. McO1l.L, la., M D., Anin~ Head. D.p.rtwwwt of r.tAolog7. L.ow• sian. Slate University ScAod d Medi- eine, Ne. Ork.n.. HENRY D. MCINT(>SH, M.D., rro/raaor of Mrdkrwr .wd Directoi, CMd.o.as- rrlr l.Aoretor7, />tik. University Medical Center, Durhasw, N.C. FDWARD McKEE, M.D., rro/ruor.nd ArrinR CAeirm.w, Drp.rrwwM of r.- sAulop, Medical Cdkse of South ('as- din., ('harkslon. KF.LLY T. M(-KFP M.D., Anocietr rro- /rssor of Mrdk/wr, Medical Cdkge of South C'udina, Clusrlewo.. VICTOR A. McKUSICK, M.D. rro/rs- wr o/ Mrdrrinr. TUe lohns Hepf im University School of Medicine, b.hi- rnae. ROSS 1. M. 1 FAN. M D., Asxrierr rro- /ru.r ol Mrduiwr. EmdT University Se/Mwd of Medicine, Atlant.. . NHAI. I. MrNIVFN, MI), TAe Wor- ces/er Found.rion lot F.perMnenr.l B/ olop, SMew.l+ur7, M..e. /)AVII) F MANN, rn 1), Aswrietr )'ro /rI4M .rf rArw.euoiof/, Temp~e llni- versiry Sch.wl of Pherm.cr, Phit.del- phia IOHN P- MANOS. M 1), lnurrrr.v in YiroloR7 and DrrrrioLrtl. Medical Cdkge of South Caroline, Cturkro.. CHRISTOPIIF.R M. MARTIN, M D, As- i/sbiwr Professor of Mrdic iwe and Dirrr- to.. DRr/slon of In/rcUors Drxaur, New lersey State Cullege of Mcdicine, /erse7 City. lUt IA MEYER, IH D., Asu.rietr Pro/rs- sar of Oral r.tAoloR/, Uni.ersii/ of Illinois Colkge of Den(isrr/, (:hic.go BERNARD 1. Mtt_t FR, M 1), Annrewt rr../rst.r, The I/anirl RauRA twrnrmr of Anoron.r, /eRerson Medical Culkge, rliladelPhra. IAMES 0. Mtl I FR. M 1), Pu 1), rro- /nwr of rs/rAwtrr ewI Dfrrrr..r, Mrnral Health Rruer.A Iw- akutr, University of Mrchqan, Ann Arbor. HUGH MONTGOMERY, M 1), Auo.i- .rr Professor o/ A(rd.rrnr, lJnirenii7 of Pennsylvania ScMx.l of Medicine, rAiladelphia. r.O'S. MONT(iOMFRY, 1.,, M 1). rro- /rrRor .r/ r.rAula[l, University of te.as Soulhweuern Medical Scbol, Dallas. GEORGE t'-. M(K)RF. Pu 1), 1611). D/- rector, Ro.rell Pnk Memoriel Insti- suWe, BuR.b, N. Y. HURLEY 1 FE MO1 t F.Y, M U, rrn/rs- ur of Mrdkine and Dnrd rw, ('erb.r Rrspr.ror7 foA.wat.n/, llmrenqr of Southern Cd.frwni. tichw,l of Medi eiwe, IovAngeks. W11.LIAM S. Ml1RRAY, S( 1), Srn.,r Stes ScIrntur, Ruxae B Jackson Me- wwrial I.horalory, B.r llerh.w, Me. ALBFRT B. PAl M/- R, 1'nl). Mrb/anr rro/rsu», Drp.vtn.rnl ../ 1•.r.A..L.RI. University of Trdedu, Toaedo, O. FI)WARI) W. PU/ IKAN, M 1), ('Aa.r wvw, l/rpartmrwt ul rA..rn.o..d,.Ri, awJ F.prrrnrrwr.l 7Ar.../.run. r, N...1.M I/m vrr.ir/ Salww.l u1 AlydKine, H.,u..n OTAKAR 1. PO11 AK. M 1). ru L). Esr.r/rrr Illrr.rw, Uuver Med..e) Rr .e.rch ('enter, Inc, I)uver, 1)r1 MORRIS P(NIARI), Pw1), lhuir..., LuArnd I oA.nar.w7, Itnivn..i) ut Nune 1).me, NrNre O.me. t.rt 1W

14 C. M. PUMFRAT, PuD, Orrrrr,r of Srdopr.f RrrtotrA, Pasadena Fonnda. )ion for Medical Reseath, Pasaden., ('.1. It R PRATT THOM/1S, M D., [)r.w.n/ Prn/rrsor n/ Perhulnry. MeJic.l Col- ktle ol South ('.rollna, Chaukuon. I/OBART A R1 IMANN, M D. Pro/r.- u.. of MrJn.nr, //ahnernanw Meiital C'olkge anJ /lospil.l, P*iludelpW. ROI I.ANI) C. RFYN(M.tn• M D, As- rlrrewr Pto/rrwt u/ P+rA.dory. Un7.et- .i(~ of Te.n Srvth.euerw Medical School, [1tillac VICTOR RI( IIARI)S, M D, CAir/ of Srrtrt. Presby/eri.w Medical ( eMCr, San Frantisco R H RIODON• M 1)- Pto/rru+ of P.- tA.J..pt. llni.ersMy of Ie.a. Medical Br.nch, Oalveuon SYDNFY (' RITIFNRFR(7, Ihr D, Pto- /rswr o/ R.rrrtwd. t, Uei.eruly of SoWhrr. ('ed.fornl.,~ o. Angeks RFNSON R R(W, M D, Arr....r. Pr.. /rrw• of SrRrry. ( Arr/. ('.r/..( twgrry, Unr.asdy of ( .bfurnu tirMol of MtJltlne. San 1 renr/stu ('l1ARt FS I R(KF, A M• Irwo+ hur. Lrr, Vtttr.ns AJmm.Yratr..., (%dpa licnl (limt, Busrow BFNIAMIN A R(1BIN, Pu 1), Mewarrt, 1lolojite/ Prodr, it f)rrrfupnrrwr. WyetA l.hda.wies, PAJ.Jetphla IIFNRY I Rt1Sti1'K. M D, F A C P. Prrnbwi. IAe Rus.e1 FuursdNiun, Ine.. Stalen Is1anJ. N V. W. C. RUSSFI 1, M D, University of Teta. Medical Center, I/ous(on PF.TFR F. SAI.ISBIIRY, M.D, PMl), 1fr.J, Iwrrnrirr I rrunwnr (?wrrr, Saint /o.epA 11o.pN.l, Burbank. Cal PAl)l. SAl TMAN, PaD, Au/v.nr Prn- /rrtrr, Orp.rrmtnt n/ fli.rtAtw.lu.y awJ Nrctn/ow. l/niverilly of Cannhern ( dr fotnia School u1 Medieine, t oe Angeke. At VIN R S( /IMlhl', Phrl), fl.rru.+ o/ ('nww.rhwR, luft. Unirersity. MeJf.nd, M.n ISAAC S('llOltR, I)1)S, PrnD, 1)St, l/rnn. (.•flrr•r .,l I/rn/r.rr/. Iln.vrra/y ('AR1. ('. S11.171:R• Pnt). Rnrorth f rl6.. iw Phyruaf AnrAnq...l.Ry, llar- ..rd llmvcrsNy, ('.mhrnrge, Mas. ; I)r. parmrnr of Nrnurnn, Fl.rtard School of Puhlic Iledlh, B.ntun. CHARI FS F. SHF.RWOOD, M D., .U- /suwt Prn/rst.n of R.dwfnty. llniver- .ily of Rochester Stlrx.l uf Medicine and Dentislry. Ruchesler, N Y. DAVID I.. SIMON. M 1), Fwvrurr..r, f)r. prrmrnr r./ Iwrrrwu) Mrdr.rnt, ( lntm.11 (ieneral HtssPiul, (-incinnau GFORUF W SMFIIFRS, M 1), An.r-r- .tr /w P.rh,rf,.py, Norlhwtsrern llmver- .ily Medical School. ( hrcago FRNFSf S(/NUIII-IMFR, Prrl), A.... trrr Prn/rr>.r o/ RnrArmuny, (1dkRe of Foreslry, Srale Uni.asNy of New Yortt, Syr.cuee. T M. SONNF.BORN, PND, Mlhurw .Arl Srrrwe Pr,./rtuw of 7nn1,.Ry, un• llmverfNy, Bloomrndton SAM SORO1 , Phr 1) , Hr.I, Arp.rrn.rnr of Ma.run.ofrrrler ('Arwu.rry lhc tn. Mrlute (or C.ncer Rese.rth. PhdaJcl- phl• Al I XAN/)I R SP(K'K, M 1). Aruvnnl Pr.•fruw..l Pr/..n.r., Uu1e llnrversny MeJu.t (enrer, D.uham, N. (' I RFI)RI('K I STARF, M 1). Prr./ru•w n/ Nurnuon. Ilar..rd llnlveluly Sclkrul o/ Puhht Heehh, Rust.xl. C F1AR(H 1) 5114 1 FF, M D. 1lorrnw of 1.sMwerorirs, Meth.w)ISl /lusplul, MempAis. IACK P STRON(i, M 1), Av..nerr Prrn /rskr of Parholuly. I witun Slate (lnivenily School o/ Medicine. New (kk.ns. MARION R. SI/I 7RF.ROFR, M D, Pr..• /rsl.+ and C'A.nnlew, flrp,urwrrnl o/ f)rrm.r..fujfy •n/ SyphJ,J"Ry, New Yrwl llnlrer.ity belkrue MtJ/td ( en ler, New Yt»t ('ity. RP.NATO TM)I1/R1, Pnl), Ar..nlar Prufr.n.r of riyrh.J..ly. (IraJ.ulr School of Business AJminivratiun, IlatvarJ llnivetsdy, Bostnn II Rl1Ml. U 71IUMAS, P111). rrnfr..,n I nK.nrrnnR, (Inirer.ny u( 1 ah/..~nu lltrkrlrt i I TISSUF ( l)I.TURF ASSOCIATION. IANt:T TRAVFLI., M D., Auot(ar Pro- /ruor .rl (7rwir.f PA.rmatology, Cot- nell Unrverslty Medical Cdkge, New YrKk ('ity. F. D WARNFR, M D., Pru/e»or of Pe- th.A..17. Slate llni.erut1e of Iowa ('ol• kFe of Medicine, Iowa City. S1111'1 DS WARRFN, M D, Obrtrue of f.A...r.wirn. ('.w. rr Rrrtrr A lnulrr/r, New FnglanJ [)kacor.es Ilosqital, B.n• lot1. RI('l1ARD 1.. WF('IISI FR, M D, Cfrw!- uf Phyu.JuRut, MuMellrlee N.npi/.l Inaitute of Rexa<h, Pnlshwo. RIISCFLI. W WFI I FR, M D P.rh.do- Rr.r, Mernmwial Ilosptal o~ ( hr.ler ( ounmy, Wea ('hesur, P.. FRFDFRICK F. W/IISKIN, M D, (' M, I)rrrttor, Urrur..n of I/re1rA enI Prr. low.fit~ FqrdrArium, lhe Age CtnMer of New Fngt.nd, Inc., Boaon. RO(iF.R 1. WIl.1.lAMS, PND, Pro/rsr..r of Chrmuu) DrrrU.w, ('tayhrw ForwLriow RintAemir.l Inrrrrurr, 111c llni •eraty of Tearu, Au.tin. . l. FDWIN WOOD, M 1), fwur~nw /n Mrdiriwe, SoNon l)nrvcraty School of Medicine. Boston. SI/MNFR W(KN)• /. , M 1). Aubrenr rt.•/e„rv ../ P.tAul.s y, lbe luhm Ilop. lim llnivet.ny School of Medulne. Bdbnwre. 1011N P. WYA1l'. M 1), Pr.•fru.. of P.rA.Jn~y. S1. 1 oun (/nlvetaty Saluoul o/ MedKlne, St I Wrn 11I

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