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n I I c I SI;IE N"1'IE'I(: ADVISORY 1t(IARU to Thc Council for Tobacco Research - U.S.A., Inc as of Dccember 31, 1974 SHELDON C. SOMMERS, M.D.. Chairnwn Director of LaAorarorks, l.enots NiU No.pital Clinical Pnr/ruur of ParAolo[7 Collc~e of Physicians & Suraeona o( Columbia University New York, New York RICNARD M BING. M D. Director r,f Careiororr a.d rnrromural Medicine NuntinRton Memorial Ho.pital, Pasadena. California ProJrssor of MrAicint University of Southern California School of Medicine Lo. Angeles, California 1OSEPF1 D FF:LDMAN, M D. lhad, IhQartmcnt of Immunopalholo6y Scripps (linic and Research Foundation 1~ Jolla, Cdifnrnia WI[1tAM U GARDNER, PH 1) Scirnri/Gc 1)irrc(or, The Council for Tobacco Reacarch -1) S A, Inc. E. K. f/unr ProJrstor nl Anatomy (rmrriluw) Yale llnivcrsity School of Medicine New Havcn. Connecticut ROBERT 1. IIUEBNER, M.D. C.hir/, Viral Carcino6encsis Program National Cancer Institute Bethesda. Maryland LEON O. IACOBSON, M.D. Dran of the !)ivision of Bicrlotical Scicncrs RrCrmrrin Professor of Biological Scirncrs Univcrsily of Chicago Chicago. Illinois AVERII.L A t.tf:BOW, M.D. Pro/rssrrr and Chairn.an. Ikparimenl of Patholo" University of California SchcxA of Mcdicinc San 1)iego, Cali/ornia /Ii:NRY "1 I.YN('H, M t) f'rofrttnr rind (hoirmun 1k 1+.,jin rni ~,1 PirvrMivc titcdicine anJ Public /fcallh (icir) t„n lfmvrrvtv S h1.1l Od Mcdi(Inc ( h).hr. Nchr.i.l. IIANS MEtER, [) V.M., Dr. Mcd. Vd., M R S If. Srnior SraO ScirnriV The Jackson IaMoralory Bar Ilarbor, Maine 1OIiN P. WYATT, M.D. Director Tobacco and Flealth Research Institutc University of Kentucky LcRinaton, Kentucky gc1rat16e StaR.f The (;ounrll WILLIAM U. GARDNER, Pa.D. Scientific Director ROBERT C. FIOCKETT, PH.D. Research Director JOHN FI. KREISNER, PN D. FREDERIC W. NORDSIEK, PH.1 .t ssociare Research Director DAVID STONE, PH D. Associare Research Director A ssociare Resrarch Dirtcror VINCENT F. LISANTI, D M I) Research Assuciatr

Introduction CONTENTS Introduction Canccr-Rclatcd Studies . . . . 7 Abstracts of Reports . . . . . . . . . . . . . . . . 13 Cancer•Rclatcd Sludies . . . . . . . . . • • • • 13 The Respiratory System . . . . . . . . . . . . 20 Ficurt and Circulation . . . . . . . . 33 Neuropharmacology nd Psychophysiology . Pharmacology . . . . . . . . • Immunology and Adaptive Mcchanisms . Epidemiology . . 43 . 47 52 . 58 Miscellaneous . . . . . . . . . . . . . . . 69 Active Projccts . . . . . . . . . . . . . . . . . 72 Completed Projccts . . . . . . . . . . . . . . . . 79 Index of Senior Authors . . . . . . . . . . . . . . . 88 Inde: of Principal Authors . . 89 ( t The investigarioro supported by The Council for Tobacco Research - U.S A.. Inc. that were published during 1974 are summarized in Ihia Ar.r•.ual Report under their specific titles. These investi8ations relate largely to sludio of cigarette smoking and smoke derivatives and probkms of health. They have been grouped into categories that are oriented toward either specific diseases or o.g.ns, or that are d'ncipline-.ssocialed, i.c., epidemiological, immunological, or psycho- or neuropharm.cologic.l. The heallh-rclated disturbances associated with cigarette smoking are also .ge•associaled manifestations that often require prolonged periods of observalion in intact animals; therefore. In vitro cellular sludics and even sludies with microbial morkls have been undertaken. Man is the only animal that smokes for hn own satisfaction. Hcnu, stud- ks are continuing on why man smokes and those diseases to which he is .ub• ject and which may be associated with amoking behavior. Such ob.ervatio." supply inferences or associations but fail so demonstrale e.use% or mecha.i.rns. Animal models must be used for such experimentation. Animal models for the study of the problems relating to tobacco srnokiag and health are not easy to devise. Smoke e.posure is stressful for animals and presumably prolonged pcriods of smoke eaposure will be required. Extensive studies have been undertaken during 1974 to determine the most satisfactory animal model for smoke inhalation studies. Mice have been chosen beesuss .hey have been inbred and selected for differences in response to strer, rss- ceplibilities so diRerent disease:s, and differences in histocompa.bility and anligcnic characterislics. Mice of different inbred strains differ in the capacities of their liver microsomes so Incre.se the levels of enrymes that melabolir.e a carcinogenic hydrocarbon. )•methykholanthrene, following the injeclios of inducing aRents. These enzymes, aryl hydrocarbon hydroaylases (AIIHs), ar+c inducible in mice of aonre strains so that cancer may be e.pre+sed while .01 expressed in mice of other strains. These enzymes arc under genetic coulrol. The vailabiliry of mice of inbred strains provides much genelic control (or the animal model. The interaction of environmental variables on esantlaqy identical genotypes also can be studied. The human eounterparts to mice of inbred strains are provided by idcnti- ea) twins. The Swedish Twin Registry, which has provided data on the smoking histories and the incidence of pulmonary and vascular disease symp/onr in monozygotic and like-sesed twins born in Sweden between 1886 and 1925, has been eapanded to include similar rfaa on twins born between 1925 and 1959. This will provide additional data on a population that has a bng life eapect- .ncy and a very kw lung cancer incidence Arwrther twin regisuy has bee• started in Finland where the reported incidence of lung cancer is about Avc times greater than that in Sweden. lhis should ar.ssrnent greatly the numbcrs of i.kntical and non-identical hke scscd twins that are discord.nt for smoking esperience .nd other environmental e.posurn Furthcrmore, the twiru among those receiving multiphasre health checkups in the Northern ('aldornu K.ucr Perns.nente Mcnccal ('.re Program •re being survcycd as a potential wwucr of identical .nJ like scacd non idcnrrcal twins that havc rather c.rcnrnvc mcdr eat and health hnlories and .re fuxn diAerent racial rruu/» SraniA..n1 diAer- ences have already been reported in the pulmonary function tests of repre• S

I ! tentativcs of the different racial IrMrps. Not nnly is intormation hcmg uht:rineJ on snr.rling capencncc Mrt on a wide range of envuomncnt.l csp.tsures and ocaopational acuvrtres in rcl.ruon to morbidity and mortality Ihe twin rckis- nies should prnviJe a valujble source for many other shwlics that will inclnJe the effects of multiple environmental variables on individuals of identical scno- typcs and during the prncess of aging. Studies on lamdral predisposition to disease are also being done The tendency for canccrs to occur in swnt families is Ire+ler than in olhcrs 'This tendency may be restrrcled to cancers of certain sdcs or to two or nwre sucs. The prcdisposrtiun of persons with knowa genctrc conslitulions to acquire emphysema a/w has been demonstrated and nsay be caused by deficiency of a subsunce or substances that inhibit proleolytic en:ymes. Individuals with this genclic deflcrency, fortunately only a small percent of the populatan, are par- trcularly vulnerable in -'smog- environmeMs. Emphysema also occurs in indi- vidua(s without thn spccrflc gcnetic deficiency; a special risk im/rcr.ror rs pro- vrded by the family history, an indication that other umdcntUfkd ge.xnc deter- minants of prednpositiors may esisl. The epidemiological projccts o( interest to I he Council involve mostly prospective studies of selected populations that pro- vide special contrasts for genetic or enviromnental similarities or Jdferences. Basic research n also being funded on the chemical identification of pcoltascs and their inhibitors .nd how they intcract. The levels of proteases in different organs and in normal, embryonic and cancerous tissue-i are being studied Furthermore, estcnsive cfluru are being made to improve the A1111 assay, using human tissucs, to promote its application to human cpKlcmioloti- cal studies. Wrthrwt basic investigatron, the improvement and perfection of ndytkd techniques and the devclopment of new or modified concepts of disease prevention or control wJl be ItmitcJ. WILLIAM U. (;ARrsr+ee, PN D. Scientific t)ucctur I Caticcr-Rc9atccl Stuclics Among the diseases that have been associ.tcd .tatisucally winc cigarette smoking in population srrklics, c.rcuwma of tht lung has app.rently received the greatest auention. Neverthek,s, thn Jrsea.c occurs only rn a small minor- ity even of heavy smokers. lhis emphasr:es that research on its pathogencus nrust include consideration of possihle suAstamiul ddfererkes among tndrvKluals hrNh in their genetic characteristics and in the numerous conditsontng inllu. ences tn which they have been whjecteJ. Many anomalous and contradictory aspects of ,he epidcmiologrcal flndings have been JcscNhcJ, and the great dillicully of conducling human sludies with controls adcqualo (or resolution of Ihese anomalies has been recogni:ed. lhc reasons for this are both ethical and praclical. Nence, tht crucial questions °whelhcr, how, to what talent, under what condrtions, and in whom" rrrwking could contribute to pathogcnesis of the disease remain unanswcred An alternative approacb to the problem of descrnbrng the interactions of intrinsic and ealrinsic influences in Ihe process of carcinogenesis lies in rhe design of suitable nsodcl ayslems involving animals, animal lissues or cells or. in some inslancn, human Iissues or cells. Superficial eaperiments with inade• quately defined species or atrains, whether whole animals or their ti.wres or cells, will ral solve these problems. lhere is strong basis fow doubbing that mouse skin painting with stored coedensales of the particulate phase of smoke. altered in physical state and in chemical compositKSn and lacking moN com ponenls of the gas-vapor phase of "whok, fresh normal snwke;' can eslablish, define or quantitale the "carcinotenit hazard" of smoke inhalation by msn under life conditions. The design of such model systems is a most er<actin~ entcrprise, since the question of the applicability of the results from Ihese nsorkls to man in hn actual environments must be asked at every stage and eventually answcrcd The Council has, neverthekss, undertaken to develop a series of rrsodel sys /ems for the purposes mentioned and to caplore slrategies for relating the results to man. CarrinoReneais a. a M.al(i-Sta6e Process r I 6 Tlwugh the term "earcinogen" is often applied to Individual chemics compounds or mistures as rf "carcinoRcnicity" were a specific or unitary prop erty of matler, like a molecular wtight- an absorption spectrum or a dipob mramnl, it is well known that this is not the case Irxluced carcinolenesn - rathcr a ororeu presunscd to requue a series uf scyuentud changes in the bu, logical systenn of the host 7 htse, in turn. are presumeJ to Jeperw) both upu, the rnitial, genetically influenceJ characterntas of these systems rw1 also utw, a series <.f separate actions by the eaternal inciting agent or agents that requu quite spccifk physical or chemical propcncws arnJ condrtmons. Sur h agcntu ha• hahdually been grouped together as "caacinoCens- or "pincntial carcinogens Ncverthckss, it is wcll kn.rwn that "carcrnoten" fnr one apecies, strain 41 tissue under parlrcular circunsuanccs. may n.rt he a"carcinogen" (or anorhr species. strain or IisuK. nr rrnder othcr circumslanccs. Metabolic modificatnon may be necessary to crrnverl the eatern.l `poler 7

tial carcinnRcn" into a form that can directly attack sonse particular struclure in the cell ('ells rnay be more, or even esclusively. vulnerable to such attack durtng srrnse particular stage of drvisKrn Hcnce, influcncea that sunmulatc cell division or arrest the process at a particular stage may play a sigmfscant role in the process Factors that alter the normal DNA repair mcchanilms may be implicated in allowing abnormal combinations to survive. [krepresation of a viral tenome or n oncoscne may be implrcaled. When a normal cell has been transformed into a malignant one. the activities of the immune system in its many manifestations may determine whether the transfrxrtsed cell can survive, clone and prolderate. Undoubtedly these are only a few illustrative eaamples of the krnds of factors involved and wsa.y othen undoubledly awai/ discovery and description A strategic goal in the research program is to identify those animal atrains in which such individual lactors are combined in a way to produce ma.imal cancer susceprMhty, Another goal b to create such comhinations of traits by genetic manipulation. As a eorollary, the discovery or producturn of strarns with other combinations of such traita should help assess the relative roles of such pulative contributing factors to the overaM process of carcinojenesis. Sysfens. /or Chronic Smoke Expo.ure by the /nhafation Route For  long trnse the lung has been the organ of primary interest in The Councd's cancer research program Therefore, its program has been premised upon the concept that approprutt whole animal test systems shr„dd he based upon the chronic inhalauon of Iresh, whole cigarette smoke generated under defined conditions that simulate as nearly at posstbk those ecperienced by human snsokcrs, from ciSarcttcs o/ dcflned arsd constant compoutan, and administered in quantiutcd dosages to carefully selected and dcfined animal species and strains. [kvclopnsent of mechanical devices for accomplishing uch esposures of animab has been an eaacting, trmetomumint task even Iter the estabinhment of criteria for acceptable corwlilioru. Despite the seventeen-year his'tory of lhe ('ouncil's smoke inhalation esperience, recognition and definition of these cri- teria have developed only with time. TAese have been detailed clscwhere. Two devices that meet many or most of the crileria reasonably well for mice and other small animals have now been developed and a numher of uniu have been in use on a trial basis in Council proiccts. lhn eapcrience has led to modifications and improvements on both. With Mrth types of device, current emphasis is being placeJ upon the efuanhutron of dar+age to the respuatory Iract by use of separate traccr mgredi- ents for smokc paruculatcs and lor gas vapor phase. I hrwgh hununs smoke voluntarily, often probably for the rrlrtl of strns, the cnnddron+ of saxrke inhalatw.n by esperimcntal animals arc nrvedunury and stressful so that the contributions of tensions to the oveeall espcrimcntal results must t.e conuJcrrd caucfully Animal containers lor nse in smrrke urhalalion Jcvicrs havr had tu he JrsrRucd to minrmrre these eflecN Met1...1s Int uulrRat- urg Ihcrn, nce r Jc of hahrtuatron in reducing them and the usc of unccp-ed "mat hinc cr+ntrol ' an m..ls I rr estrmaUnt their m0uence have all had to be a rJrrd r.tenavrty i.r avurJ complrcatmg ol»ervauwms on snioke ellects per rt. Thoush smoke inhalation studies with animals have been spcrosorcd almost continuously by The Council since its organization, the progrevrve improve- ments in controlled and monitored systems are e.pected to jusufy beginning a new and more extensive series of esperinsents a1 a higher level of sophistication within the coming year. FssentuUy the same inhalation systems can obviously he used in atudies beatint on cancer, on cardiovascular diseases, on chronic pulmonary dneases, on pharmacology and on other questions. Selection of Animal Su6 ject. for Cancer Studie. Princpks underlying the aeketion of animal species and strains foc carci. noIenesis studies have been described and these re being used as a guide to aekction of animah for the forthcoming new snxrke inhalatnsrs eaperimenu. There appear to be more cogent reasons a this time lor use of the tnare than any other speeics, and this is our thoice for present major purposes. Aside from the obvious advantages of low cost, ease of handling, modest apace re- quirements, short life sp.n, eatensive e.isling information on their viral and bacterial fbra and methods of controlling Ihese, there arc others of even greater importance. Many inbred mouse straim eaist which show greatly contrasting degrets of wscepibitity or resistance to carcinogenesis as observed empirically over the years. lltese differences are now being related progressively to genetic factors and Interpreted to a significant degree in terms of biochemical mechan- isms. In such mouse slrains, moreover, the implicalions of competitive coo- cepts of the viral etio[o`y of cancer have been eap[ored much more eaten.ively than in any other species. 7heir immunological responses to eareinolgen{e events have also beeo investigated quite inlensively, though they are aill ia• completely understood. Despite the disadvantages of small lung size, meager volume of blood for tests, drfierences from humans in lung structure, and the fact that mic. sre tase breathers. the use of mice from strains that have sharply eonlr.a(ing susceptibilities to the process of carcirqgenesis presents a unique taperinxntal model. 11 a particular regimen produces carcinoma of the lung in one such strain but not in another, and of these strains have been deacriba( with respect to genetically influenced biochemical difierences, the results may provide valu- abk inferences regarding the roles of such biochemical factors in the procesa of carcinogenesis Such inferences should furnish leads toward the search (or analogous biochemical bases for cancer susceptibility or resistance in man. In a long series of preparatory studres, a number of biological and bio- chemical characteristics deemed likely to he related to cancer susceptrl.iluy have been studied in many inbred strains of mice. A number of papers have been published describing these studies and when are in preparation Among these prcliminary studies was an em{,irical survey to compare and quantitate the relative (and contrasting) overall susceptibilities of a numbcr of mouse strains, both inbred nd rarwlom-bred, to margrnal, suhautannws dosn of aeveral polycyclic hydrocarbuns known from eaensive e.perrrnce to be "carcnwrrcnic" to nsKe in 1he cornvtntional sense lbese hydru.vrlruu In eludcd 1-methylcholanthrene (M('A) and henro/..)pyrcne 7he sutauuneous route was used because doses crMdd he aJmmwereJ wnh precision, nd the 9 0 I

I i m tr B © m W Co (-n treatment zone kept undcr close scrutiny On the basis of a carefully dcviscd scoring system, very strrking differences in Iumor responses were /uunJ among these slrains. Strarns sekcrcd from the spectrum of varying subcutancous susceptihdities were then subjected to direct instdlatron of the aame polynoclear hydrocarhons intu the lungs, in varKxn media and by several technpues. Squamous cell lung carcusomas have arisen at different rNes among these animals, shovrns that some strains at kast are suxeptibk to Ihis disease. Continuing espcnrnenls are eapccted 1u reveal more fully the magnitude of these strain drflcrcncrs With- out the assurance that Ihe animals to be used in smoke inhalation eaticriments can develop the disease under inve+sip/ion. the interprelalion of ncgative re- whs from such esperiments would be impourbk. The Metabolic Actinotion ol Polycyclic Aromatic Hydrocarbona (PAH.) Some PA11., at knt, must be mNabolirrd to active lorms before they can tramform celh, induce turssors or produce mutations. This activation is accomplished by enzyrnes of the lamily sernKd "mised functan oadases" found in the mkrosomes of the cells of many tiasuca. The enzymes that pro- duce the change are designated uryl hydrocarbon hydroxylases (Alllls). These entymes occur in cells of many lissues of both mn and animals N' moderate kvels and are probably in some way .ecessary to life. In swne ani- mals, however, esposure to certain polycyclic aromatic hydrocarbons stimulates production of an increased kvel of the enzymes, while in others it does not. Those that respond to such esposure by production of more (and perhaps drAcrcat types of ) Atilt are said to be "A1111 inducible." In the eaperimenls cited. Atilt inducibility ranged widely in mice of ddlerent strains and was correlated with the susceptibility of the s/rain to M('A- induced subcutaneous carcrnogcnesis. Twis may well be one clue to the bio- chemical difference hetween more susceptible and less susceptible animals with respect to induced cancer as contrasted with spontaneous cancer. Many other subslances can stimulate Atilt production in "irsducible" animak. TAeae include internd agents such as eortkosterod hormones and bibrubin; esteraal ones including barbiturates; chlorinated hydrocarlxx» such as UDT and certain defoliatin= agents; and compounds that occur in several vegetabks. Exposure to such compounds in the environment may, therefore, increase sorne aspects of eaKer susceptibility in bolh animals and men who are Atilt inducible. InducihJrty of the Alll) system by M('A has been rcported to he geneli• cally based in mice. Susceptibility to induct«sn by methykholanthrene was rcpnrted to aegrciatc as a single auto.Ofnal dominant gene in crMxs between inducible and non inducrble strains. Puhhshed repurts of these mouse studies from The ('r„rncrl proeram stim- ulatcd uther invcsti`atoms (not ('ouncil ponsored) to study Atilt Icvels arsd irwlucibJrry In man, w Iest the concept that this function nught Le under gcnctK cun,rul iii man as well as in mice. fur several rrasuns such determrnations in man have been much more ddlicuh than in mKe Ihe ('ouncJ unJeruwk to ssist the research of the to invcstiCators alluded to. Also, looking to the practrralrtscs of extcndrng such stud,es to large human SrrNrps fur elucidation of the mrMk of mherrlance, lhe ('ouncd inau6ur.ted dduronal efforts to improve the Atilt assay systems woh respect to sen.itrvity, accuracy, replrcaMlity and specJ Populations of lung cancer patients as well as human lamrty ag`resrations (kindreds) character- ired respectively by unusually high and very low familial levels of cancer incr- dcnce, already under stutly (or other purposcs, are available lor survey as methcxloluCical developments permil. Other sludres relating to Atilt induction include more detarkd investitr lion nf the melahohc routes for henro(a)pytene, of the mtcrmedrates fornxd, the aclivnres of these in cell systems, the enzymes that produce and desuoy them, and of agents that may bloct their formation. Immrrnocom1.efence o/ Mouae Strain. Mice of all the contrasting strains that are candidates for use in chronk cigarette smoke inhalation studies are being given an ealcnsive battery of pre- liminary tests /o deteet any large differences in the basic competence of their immune systems. The tesls are then repeated during experimental regimcnt to delect any consistent changes in the hope of determining whether immunoloti- eal impairment may be a factor contributing to the end results of lung term experiments. MufaRrn..ia and Rryxrir Mec/rani.ma Metabolic activation of potential carcinogens and alteralioru in immuno- eompeterxe re two of the seyuential changes that may he involved in the multi-stase process of carcinotenesis in many cases It appears that both im clude 6enetic bases for susceptibility as well as foc the interventron of esternal gents in an interplay. There is a widespread belkf that the conversion of  normal cell into a potentially malignant one is closely related to the process of muutlon. Sensi• tive nsodel systems for appraisal of "nwtajenrc potential" of environmenul agenls suspected of a role in carcinogenesis have been developed by several investigators In The ('ouncit program. some of these are being assessed for their applicability to tobacco snwrke and its nujor Iractions as an adjunct to the inhalation c.pcrirsscnls When cellular componeN., esl.ecially those in the nucleus that are he. lieved to regulate the acuvnres of the cell, uncludrng drvisrun, have been changcd, perhaln by muraRcnesis. into a potentially maligrunt stale, it u widcly Lelieved that normal rcpjir mcchamsm may reverse these chantcs by cluninar ing the nsorhficd cell curuponcnts A deflciency or dcprrssron of uxh reparr pracntial nuy consnwte rn.Nhrr step in he overall prrKrn of carcrnogrne.i• MuJel syslems prulrrxJ fur j.x•ssiut the e/liY rcnc y of rrparr mri hanisms •re under study in the proRram is anudrer slcp in the rnvcsugatwrn of conuaabno suscepUhildhes in mouse atr.ms 1I

Srncrke hrlrnMtion in Relation to the ('arr•i rr trRrn gioai. 1'rores. The principlcs, concepts and developmental sludies that ha+c been de- xrihcd briefly are being incorporated into the design of the new serit. of lonc- tcrm chronic cigarette snxske inhalation esperrmcros. In these t.pcrrmtnn, mice will be used that have the combination of factors nsost conducive to cancer suscepliMliiy, on the basis of present knowledge For the rcasons out- lined. mice of other s,rairn with contrasting susceprrhihtrcs, nn the hacis of available bxx:hcmical rnformation, .rill be employed for compai i..rn If un- equivocal sqnarncsus cell carcinomas of the lung should develop rt a suhstmtial kvcl in some striins and rsnl In othen, useful kads into the study of human susceptibility nughl be suRycstcd. By "unequivocal" lung carcinoma Is meant a cancer anatr•Fous to the human disease not only in morphology but in hehavior, being aRRres.ively in- vasive, mclasutic and rapidly fatal. IKagnoses are to be made irxfcpen.kntly by several capericnccd palholotists. At the present stage. "pre carxerou." ksrons- rhouth they are to be described and recorded. •re not regarded as acceptable end points In one Council sponsored pro}ecl of several ycan' duration, a Sendai virus infection invaded a colony of mice that were under chronic smoke inhalation caposure I ung lesions were found that could easily have been mis- diagnosed morphokssrcally as early lung carcinoma, but which were ultimately shown to be atuihut.rhle to the virus. to regress rn many eases and to occur in controls not e.pnsed to smroke. This esperrenct recommendc R''eat vigilance with respect to prevention and deiection of infeclions in smoke inhalation slud- ics, as well as cauUnn ur J$aRn mn Obvioutly, resuln /runm su.h mou.c e.ptrimtnts coukl not he carapnlattd drrrrrly to hunrans, srnct the hsRhly susrtprihle mxc repit%tnt comhinau4ins of eharaetertthcs rhal may iacur never ur tarely in rnan I)cvclupmtru ul Ihc drs- ease in al/ suarns woulJ proviJe lesc Studance ut ihe kinJ mtntinneJ Its oc- currence in nonr of the strains would suggest that the trcaunew r. rncapable of bringing about the ncctssary sequtnual changes of the carcmoRtnk pnrccs% In any case, however, the model syslem should have other important uxs. Ilumans do not live under the rigidly controlled "hot house" envrrunrsscnts pro- vided for caperimenut mice. lhcy are generally eapoud to cunsidershk amounts of "potential carcinogenic agenti' in the contemporary environnsent. Tlse model can he used to espbre conditioning tRecta of small chronic doses of lhese agents The human situation can be simulated to some degree in mice by administering "primrng" doses of such "carcinoeens," trw small to produce cancer aMrse, and then suhjectm8 theu mice to chronic smoke inhalation ,o determine whether the latter shows some type of "prurrsoter" acuvrty SimJarly, the possuhk synerlInlrc toln of controlled haclenrl •nJ vrr.l in(eclxrns, e.- po.urc to agents that prorhrct inflammatron, mtchamcal danuRc. hcat Irauma, presence of lung inlarcrs, hormone and vit.min ckRcrencre+ or e.cescea. Jep.ni- Iwns of ashtstnt, immunosuppression or shmulalron. liver dy+fn(xnun, and many other factors common to human eaperience can be studied empuKally or on a ralxrnal basis s t j RunraT C lirx ar sr. Prt 1) Reseuch 1lircctur Abstracts of Rcports Following are abslracts, approved by the suthurs, of repsrts on new rc search acknowledging support from The Council that have appeared in sckn litk journals since publication of the 197) Report. The name of the recipicn n in italKS. TTse abstracas are grouped under these headin8l: 1. Canccr-Related Swdrer 11. The Respiratory Syslem, II1 Hear1 and Circulation, IV. Ncunpharmacobt• and Psychnphysioloty, V. PharmacoloRy, VI. Immunology and Adaptive Mccl. anisms, V11. Fpidemio{oty, V1I1. Miscellaneous. 1. Canrer-Refetecl St..rlie. TRACFIF.OBRONCHIAL EPITIIELIAL MUL.TINUCI EATION IN MAI IGNANT DISEASE During a continuing study (2,9fi) cases Ihua far) of tracheobroncbirl to folialed cytobBy in surgical patienls subjected to endouacheal annthnia, th authors nNed that individuals with krsown malignancies scemed to have ur usually numerous mullimrckated ciliated eells Further e.amrnation of smc., taken from 112 patients known to be suRerinB frons a wide variety cf malit nant tumon confirmed this observalion. Multinuckation was 2 08 limes nwi frequent in this population than in a supposedly malisnancy (rce control Sroo matched by sea, aBe in decades, and smoking habit It is hoped that recot nirion of this phenomenon may lead to the devclopnsent of a new kst (n the diagnosis of occult cancer, and may open new pathways /or inves/itauo of canccr-hosl relationships. The authors •re currently tackling the Rrsu ul jeclive by looking for occult cancer in eontrols who have high pcruntatn 4 tracheobronchial epithefial multinucleation. Chalon, l. er at. Science Iti):S2S-S26, 1974. Other arrpports National Cancer Inslilute From the Department of Anesthesiology, Albeit Liinslein Colkge of Medicine Yeshiva L)niversity, Brona, N. Y. 1FIF. ('I'1 t I11 AR IiV1iN1S ASC(X'LA11=r) WIllt RI'(:RFtiCIUN ANI) PR(XiRISSIUN OF MURINE IM(1L.UNI:Y) SAR( ()MAS Prcvicxn hislopathobgic claaifktions of Muloncy urcomas have diAar widcly, ran6inP from a benign, reparative -i nflammatory reaction to mt.r, chynul .arnxna Furthernxm, a compkre sequcntral analysis of the ctllul infiammatury evcnts accon+panymg Aoth tunwsr prugresuon and relrcisrrn still lackine Ihe awhors, there/ore, cMae tu inJuce Muluoey tiuco.n in r.r- nalal and adult mrce in orJer tu charactenre Ixith its hosarltosrc nature aI 12 I) I '

the course ul events that develops following the injcclion of its tr:rnsplantahlc cells. In nconales, intramuscular injcctions of either I(/r or 1(P' cclts Irom a cultured murine (MrAoney) sarcono line induced neoplasnn that prrrRrescJ In adults, only the larger dose prrduced Ihn eflecl; adult mice receiving tU' cells usually developed tumors that regressed. lhe Rrowlhs aere esarnrncJ by light mrcroscopy at 2-1 day inlervals throughout the course of therr Jev.lop- menl and suhsequent reArnsNSn or progression Initially, all tumors were in- filtrated with polymrrrphnnuclear leukocytes - mainly neutrophds - and edema was extensive. By the ersd of the second weck after inoculalion, this acute in- flammalory inRltrate had been repiaoed in adult mice by one consisting ot mononuckar cells; neonatal mice never drcveloped significant numbers of these inflammatory cells in their tumors. Of particular sigmfkance, since mrNxsnuckar inflammalory cells were associated intimately with tumors durrng the process of regression, was the disappearance of these cells 12-14 days after rnocula- /an from tumors destined to progress in adult mice. Ilyperplastic chan6es were lound in the cortrces and meduRae of regional lymph nodes drarnrng Ixs/h progressinR and regressing sarcomas The dcvelcspment of secondary neoplasms was common, and the distribution of these kuoru was relatcJ to the ages of mice at the tUnse of irwculalioc. Russcll, S W, and CorAranr, C. G. Inrrrnorlond Journal oJ Carsrrr 1)( 1):34 61, 1974. Other auppor/: l/. S Public Hedth Scr.ice. From the 1)cpartrnent of Esperimental Pathology. Scripps Clinic and Rcsearch Foundation. La 1o11a, (-.1 IIFRI'.L)ITARY I.l'MPIIOSARCOMA IN WII RABHITS ANL) HI'R1 1)11 ARY IIt M(1t Y I I(' AN1=.MIA ASS(K'IA 1 Fl) WI I 11 TFIYMOMA IN SIRAIN X RABHIIS Among their "partially inbred" rabbit Nraina, the authors searched lor those genes which produce susceptibility and resislance to certain types of tumors. lhcy (ound such a situation in the wirehair (WII) strain: lyml.hosar- coma occurs al a nscan age of eight monlhs; susceptibility is conferred by a aiogle aulosomal recessive gene designated b. There is tenlative evidence wMch points to the presence of a C-type RNA genorne coding lor the interspccles dc- /erminanl of the group specific antigen. Ilighly positive reactions were obtained with potent antiura produced in rats to the p-A(is of murine C type virus. Complete (infectious) C-type particks have nol been found by dcctron micro- scopy; thus, cell free transmission has been negative to far, and ssays for ••helper- activity have been inconclusive. Howevcr, cellular IransmrssK,n rs successful upon imxulatiors of lymphosarcoma lissue into felusts 1'resumably, the 1s gene confers susceptibility to virus induced tumoritenesis I be mvcsli- Ralors have also observed thymomas auoualed with hereditary hcmulyuc anemia in strain X rabbits In these rabbils, which are genetically related to ssrain W11, ancmia ~K'rurs at ahout (Sve monlhs; susceptibility is cunlcrrcd by ..rnKlc .u~.r~ r nal rrlrsirvr Rrr.e, aymtwdrrcJ ho I he J.ta fur ,hcu Iwo Jn -.h L..rh imxepl+ ul cCncl.c wxcplrh0hly .nJ Ihe ..Jv...... r .,f . .,r.l /rnunrc I Afrirr, ll. and Foa, R. R. Bibliorhrro llurrnorolooriru (No. 39: Unifyipg ('(incepts of I eukcmra):72.92, 1971. Otbrr auppr.rt: National Inslilutes of Ileahh and the National Cancer In- tlilule. From Tfie Jackson Laboratory. Bar flarbor, Me. INFLl1F.NCE OF PRFINFFCTION OF CS7R1 /6 MI('E WtIN (;RAFFI I I:.l/Kl?MIA VIRUS ON 1.MElHYLCIIOI.ANTHRENF-INDl/CFD Sl1H('UTANEOUS SARCOMA (b oncosenie agents which induce diflerent types of rscoplasms have an eflcct upon each other? lhis study on the combrned eflects of the (iratR leukemia virus and )-methykholanthrene (MCA) attempts to answer this queslion. It investigates the mutual infh,ences of virus-inJuced kukemia and chemKally-Indlsced sarccsrna in CS7B1./6 mice and eRamines turthcr the launcy period as a determining factor in Ihe comoccurrence of induced neopla.ms ddlering in cell type. Results from these experiments showed that when C37H1./6 mice were given both Graffi kukemia virus and M('A the deveMp- nsent of either leukemia and/or sarcoma was dependent on the dose ot each carcinogen given A high dose of virns reduced sarcoma rnJucruon because. due to the high incidence of leukcmia. /he survival Imre of the mice was kss than the average latency period required for tumor development A hiRh dose of MCA (3(1QrR) increased the incidence of knkensia rnJuclion by a low dose of vinis without fleclin` the incidence of sarcoma lhis occurred since the latency period for sarcoma and kukemia coincided and 'S% of the mice developed both leukemia and sarcoma The combination of a low dose of virus and a low dose of MCA dK1 not aiter the incidence of leukemia or sarcoma; however, with this combination of virus and chemical carcinoRcrn. the average latency period for the development of kukemia was delayed and the average latency period for sarcoma induction was accelerated Grafli virus faikd to increase the incidence of M('A-induced sarcoma under the conditions studied Whitmire, C. F.. and Salerno, R. A. (Aficrobiolotlrul Arsorlorr,) ProrrrJintr o/ the Soclrry /or Ea prrimrnrol Biolory and AfrJirinr 141( 2):674- 67t1, 1973. Other .upport: National Institulcs of Neaith. From the 1lepartment of Viral Chemical Oncoloty, Micrrd.ioloAical Associates. Hethesda, Md IIYL)R(>t'ARH()N MI'IAH(11171NG A("IIVIIIY (11' VARIUIIS MAMMAI IAN (-E1I_S IN ('tll.l(1RE Recent in viro studies strongly sugRes( a rrlatUomhrp between kvclr of hydrocarfr)n mrtaholirrnR enrymc activity and srn.rhvny to ju)lycyclic .ro- m.rtic hy.IrrKarl.r.n inJurrd chcmkal carcrnoRcnr+~s In the limilcd nun.lur of ln vu.a syster.n avaJahlc. the kvrl+ of Ihese enrymcs nuy wrrnRly udluence the sensitivity of cells lo tran.lurnutran uK1u.rJ by cerlarn /vdycycl,c aro- IS

matic hy.lrocarhnns lhus. hefnre slarlinR any large scate in virrn Irsmforma- non prrrFram. p~ucntial human ccll lines should he screened su a, tu idcnti(y Ihone with high entynx Icvclt Thn approach has been parliaulerly u.eful in eluci&linR the rclatinn.hips between hydrocarbon metaholumR entymc activity and sensdivity hr hydrocarhon induced cytoloxicNy Ilere. the authurs cumpare two prraedures lor measuring the enzymes lhe one desiRned tot mcasure henzol a1anthracene ornhrced aryl hydrocarbon hydroxyla.e activity could Jetecl and quants(y enzymc aclivitrcs in low passaRe rodent cells. hut could not rcproducihly detc.t Icvelt in intermediate or high paaaRe nkrute, rat. or human cclls. The method dcsiRned to measure the ahilily of a cell to convcrt henrolal- pyrene Irom an orRamc-u>tuhk to an aqueous acetune-soluhle (ornr. proved more reproducihle When nwdiM1ed, this particular technique proved to he an e(fective screening tru for the detection of those lines with higher levels of hydrocarbon metal.M.hzing enzymn. Kouri, R F, Kiefer, R and Zimmerman, F. M(MirroAlototirol .+lrrnriorrr) In VJrro IO(1 i 21 :1t1-2S, 1974 OtArr .nPport: National Imtilules of Heallh. From the nepartmenl of Virall'hemieal Oncology, Microbiological /lssociates, Bethesda, Md GFNf•.TIC CONTROI. OF Sl1SCFPTIBILITY TO )-MFTFIYI.- CIIOLANTIIRI:Nh INf)11CF1) Sl1BCl1TANEOl1S SARCOMAS The aulhors report on their use of a mouse genetic system to estend their observations on the rclationship between aryl hydrocarl.nn hydrosylau ( AHFI ) inducil+shty and sensitivity to 1 methylcholan+htene ( M('A ) induced tumorrtenesis Ohurvatrnm reveal thal AFllt inducible mice are pproximately 12 times more sensitive to MCA induced (umorrRencsis than their n.roinJucihk Idtermatcs live type of parenlal cross (maternal influence) plays n.r role in this sensitivity IMtt regulated espression of the Rroup-specific (R+) anuten of type-(' RNA virusc%, although also sepcgating in this genetic systcm, d(oes not seem to play a major role in this enhanced susceptibility to M('A careino- Rennis Results are discussed with the view that the enhanced sen.nivily of the AIIIt inducrhk arumals probably results from rapid and e/licirst metab- olism of the chemical to its ultimate carcinogenic form. Recent information suRResls that these ohservatiom may he analoRous to what occuirs in human Ix.pulalions wherein the degree of AF111 indueilrihl) is genetically cnntrolled (probably by a single Intns), and inheritance seems to he crxlominiint Thus, there may he a correlation hetween the presence of (or susceptibility to) lung careinomas and the alkks regulating eapression of high or inlermrdule in- ducihdrly II so. the genetic system presented here may provide a vrluabk model for studying this probkm in human populaliona Krwri. R 1: , Ra/rre. If , 111, and Whitmire, C. FWurnMolurirrnl Ai.n.iotrr) Inrr.nononar lournar of Cancer I)( S ): 714 720, 1974 OIher .upport : Natu+nal Inslautes of Ilcalth 1'rom the tkparv.Knt of Vual ( hemKal Oncology. Micruhrusu`K al A.%Ki,.tes, Iklhcs+l.. Md F.N('AI'SlI1 A1ION OF I.YMI'll(X'YlE 1)NA IIY VI:SI('l11 AR SIOMAIIIIS VIRUS Several aninul viru.cs are known In incnrporatc hmt DNA during their replication and maluralioo, hut this procest was Rcner.lly thought to be char- aclcrutic o( uncuRemc DNA viruses with a nuclear phase of rcpltcalNrn. Ilere, howcvcr, the awhors denonstrate that an RNA vinus which is not considered oncogcnic, has no known nuckar phase in its replKation, has its own RNA dependent RNA polynserase, and .huts ufl host DNA synthesis can contain tip tu 10% of its genetic mass as I)NA. In addition to vrral RNA, vesKubr sUxnatitis virus ( VSV ), grown on the WILz-)A line of cunlinuously growing human lymphocytes, contains DNA which is found in twth the B and 1 virus particks and is resntanl lo deosyribunuck.se Ihrt I)NA is intimately asso- culed with the virus and appears to he incorporated into the viral rihonucko- protcin slruclure produced by treating VSV with Nonidet P40 followed by ('s('1 isopycnic banding. In con(rast, virus grown on B11K 21 ('1 ) flbroblas(s has no detcclabk DNA. The virus-associaled 1)NA has n isopycnic denrty of I 699 if X cm a in Cs('I, identical to that of human hNA Its average molecular weight is 90 s 1(P, as delermined by velocity sedimentation in sucrose density Rradienls, and studies of its conlour knglh in the ekclron microscope. The DNA'DNA reastoeialion kinHres of this particular nucleic acid demonstrate that it is of host origm and rule out the possihi6ty that u originates from contaminating microorganisms or minrchondria T he analytical cnmpksuy of Ihe virus assoeialed DNA shows that S(1Rr of its sequences are homologous to the repeated DNA sequences o( human DNA and that the remaining 50% are homologous to human unique scquenccs On Ihe avcrage, there is one mokcuk of DNA for each (our virion puticles Whether or not viruses such as VSV are capable of oncoteme inlornulK)n "transducuon" ro unknown, but it is a possibility which can he tested. Kin6sbury, I). T and Lernrr, R. A. Procrrdingr of the Nnriann( .IraJcnry of Scienrrr of the (In/Urd Srarrs of Amrrica, 71 (S):175)-I7S7, 1974. Otlrir support: National Cancer Inslitute, National Fuundation .- March of I7imes, and U. S Public Ilealth Service. From the I)cpartment of Medical Microbioloty, llnivctnty of C.lifurnu ('01 kgc of Mcdicine. Irvine, and the (kpartment of Fsperimental Pathobgy, Scripps ('Iinic and Research ('oundauun, 1 a)olla. ('.1 I)11lFFRFNIIAI RI S1'()NS1' (1F SN111'S .1N1) ('17 Ifl A('K MI(':= T(1 ('lIRONI(' INIIAI AII(1N (IF ('IGAR1 1"11 SMOKI' PIll MONARY ('AR('IN(KiFNUSIS ANI) VAS('l/l AR AI II RA11(/NS IN I l1N(i ANt) tI1 AR I 114% gcrirtiC Jd(crcn(ct helwecn nuume shjrf,. infli1(ncc Iheu rrstx.n.e /u chronic inh.lrtion of cigarette snwke? Ihe qur+tuwn ts e.pl.ured in IMs study 17 16

comparing the effccts of chronic smoke inhalation in Iwo slrains of mice. Snell's and ('57 Black, sekctcd for their respcctivc tendencies wuh aging to develop sponuneous IunR cancen and vascular alreralwms in lung and heart plus lymphoid cell infilrratrons arnund bronchioks and bronchi Only rarcly do Sncll's mice spuntaneomly develop nrch v.scular ksitxrs. whilt (-S7 Hlack mice do not develr,p spnntaneous lung cancers The latter strain rs alsro espc- cially well known for its escelknt immune response. lhe two nsouse types indeed had a notably different response to chronic smoke inhalition After inhaling whole cigarette smoke •nd especially its gas vapor phase. Snell's mice developed lun6 sdemxarcinomu mote frequently and earlier than the cnntrol animaH, while the ('S7 Btacks did not. llwae mice, however. had a higher incidence of vascular change in lung and heart after w-holr cigarette smoke inhalation - and nnt after that of the ps vapor phase - while no vrch effect was noted in the Snell's strain. Resuhs suqes( lhat cigarette smnke enhances esisting genetic susceptrhililies in these Iwo strains, Mr( immunological pro- cesses may play a role in these differential responses as well Chronic c.(+rnure to the las vapor phase decreased the total number of immune competent cells per spleen in Snell's mice and slill more prolonged esposure to higher snsoking kvcls Ir,wertd their antibody hinding capacity to polyvinyl pyrn.lidnne. -Ihese observations wtkcu that the presence of lymphoid cell inflllratrons in C57 Black mice may alter their lunr: response to cigarette smoke. 1 he relation- ship between lymphocytes and the frequency of sponlaneous tumun in ddler- ent strarns of animals and their responsn 1o cigarette smoke merits further invesligalion. - I.ru(hrrnhrrrrr, (' and I ttxhtcnherger, R. Onrnloty 29: 122 119. 1974 I7rom the Swiss Institutc for I'spcrimental Cancer Rcseuch, (.ausanne, Swittcr- land. TNE FXPFRIMFNTAI. FXPI ORAl1ON OF EIEALTIi DAMAGING F'A('TORS IN ('IGARE:TIE SMOKE AlthougA several skklies have wtgested that cigarette smoking is a health hazard, being particularly important in the etiology ol human lunfi canccr, it is pteuntly stdl ddlicult to determine which spcufic snN,ke components re nrnrous The main reasons for this uncertainty are the largc numf.er o( cmnke components with yet unkm)wn hit,IrKical eRects and the drflrculty ol duphcal- ing the human snwrkrng hahil in lafxxatory animds Accor,hnR Irr rh: :urrhors. htrwever, the available e.pcnmental data juslify the h,lh,wrnp cn.r.luswros (1) Ilealth damaging factors, such as Ihose contrnhulrnR Ir, carun„Rcnesrs. are found in both particulate and gas vapor phascs of cigarette snw,ke (2) Painting erperrmcnts in animals and esposure o/ cultures tn the p:urrculate phase, namely ciR.urrlt "tar," have shown that Ihis (rxlr.n hn .a.trm,/,~tnic pra1rrtrrs in skrn trachra and laryn (1) Inhal.hon CRprlnnrnll ur anun.ls and r.l.,snrc nl nnn.l anJ hnman IunR cultures rn frc.h crRarcnr •r -kc have dcrnnmlr.lcd tnh. c n. nl ul t art,nr,Rcnest. nul unly aller c%lw,.urr 1„ whrde ciRarelte smnke but also afler esposure 10 the gas vapor phase alone (4) 11 is urgent to characterize the reaponarhk components in particulate and gas vapor phase and their mechanism of action. (S) The public should he informed Ihal, based on present knowkdRe, ci6are11es with either reduced "lar" or reduced gas vapor comtiluents cannot be consideved sa(e, that is, smoking Iheae don nol eliminate damage to health such as the risk of lung cancer. Leucbtrnbrrtrr. C. and Leuchtenber`er, R. Sotlal- und lydlvrnrlvmrditln 19:41-43, 1971. Ottier support: A. S. F. C., Switzerland. From the Department of Eaperimenld ('ylochemislry, Swiss Inalatute for F~t- perimenlal Cancer Research. Lausanne, Switrerland. MODIFIERS OF CARCIN('iENFSIS The environmenl undoubtedly delermines to some e.tent the oulcome o( Interaction between chemical carcinogens and cell conslilutnls. Any envfron- menlal factor affecting Ihis reaction, /herefore, is a modifier of the carcinogenic process, as are sonre of the inherent properties of both carcinogens and cell constituents. While modifiers operate as of the mornenl of contact between cell and carcinoken, Ihey may in facl have been active in conditioning one or the other prior to contact and c.rcinotenesis. Equally important is the possi- bilily that modifiers do not affect the carcinogenic process rtself, hut the devel- opment and growth of the resulting neopl.sm. Consequently, numerous (acton such as cocarcino{ens, promoters and inhibilora of carcinoeenesis, immuno- logical inhibitors of lumor growlh, vehicks and roules of administration, and host Lclors can be considered nwddiers. The aulhor's objective in this knglhy review dealing with chemical modifiers is to make those working toward the development of an effective system of cancer prevention thoroughly aware of the available data. I1is comprehensive discussion presents the various aspccu of the subject under five main headrngs: ( I I Importarke of ( hemical ('arcino- gens for Man; (2) Biological Modifkrs; (3) Physical Modifsers of ('arcinu genesis; (4) Chemical Modrfkn; and (5) niscussuon of Inhrhuors of ('hemrcal ('arcinotencsis Graphs and tahles are used whcrcver necessary arxl a very long bibliography is appended 1fomAurtrr. F In: IlornhurRer, F. (ed ): The rlrplrrpatAnloty r,/ ('uncn Bruluay an.! S/o- cArmiirry, Basel: S. Karger, 1971, vol 1, pp I10-1Stt Other .upp+.rtf II S Pub6c Health Servite, Amencan ('arxrr Sacrtty, s'annie FF kippcl 1'uurulatrnn. Viusrma and 1) K I rklw,g 1 uunJatrtws, and Bio-Rcscuch ('ornullants, Inc. From the Bio Rcscarch Institutc. ('ambndte. Mass 18 19

i r a, m m 11. The Rr.piratory System INTRAPl11.MONARY NFl1RO.EPITHELIAI. BODIFS: 1IYPOXIA-SF.NSITIVE NEURO(CHQMO-)RECEPTORS It has long been postulated that in addilion to central and peripheral chemorecepton. the lung contains inlrapukrwnary air chemoreceptors which have a regulatory function governed by acrodonin; but in spite of sup~ortinR physiologic evidence, their presence hai wol boew histologically demon-.trated. Investigating this problem. these aulhors have previously identrfkd and de- scribed the socalled neuroepilhelid bodies (Nee's) in the mammalian lung, including that of man, and have shown that they contain serotonin as well as other substances. E(ere they report on their rrludy, by light and ekclron micro- scopy, of NEB's in rahhits subjected so esper(menlal hypoaia tJrder these con- dilions. NEB's were found to secrete the dense-cored, serolonin containing vesicks at their basal vascular pok. The aulhors propose that among their various possible neurorecep/or functiom, lhese NE<!'s form an intrapulmonary chemoreorplor system which is sensitive to hyposi and supplementary to such well known central and peripheral chanoreceplon as the carotid body. They secrete not only aerolonin 1" probably also associated amines or peptides which could inAuence the pulmonary vasoconstriclor response, and are regu- latcd by the central nervous syslem. Lsrwrryru, 1 M. and Cokelaere, M. Eaptrienti. 29(11) • 1)d4-I )s6, 1973. Othar aurport: Nationard Foods voor WNenschappcCiik Onderzock (Bel- gium). From the I,aboratory of Ilistopathoiogy. Katholicke l)niveraiteit te I euven School of Medicine. l.euven, Belgium. NYPOXIA-SENSfTIVE NEURO F.PITHEI.IAI. BOE)IFS: IrITRAPUI.MONARY SIi('RF:TORY NEURORECEPIORS MODULATED BY 71iE CNS Several routine and silver slaining methods. Fakk's fluorescent amine and other histochemical tcchniques, as well as electron microscopy. wrrc used in an allempl to further elucidate the slruclure and function of the reccntly idcn• lifled mlrapulmonary neuruepithelial bodies (NEB's). lhe lungs obtaincJ from 94 nconatal rabbits and sia neonatal mice showed that: ( I) during hypwra the corpuscular cells of the NIiB's secrete their derne r ioo ni reatment vesicks 111('V's) at their basal vascular poie; (2) E r rescrP Prc the NFB's of odherwise rwvmd animals suRer from a distinct amine dcplctiun. the corpuuular celh displaymg dccreascd yellow fluorescence and emptied or otherwise abnnrmal IX'V's; (I) as observed by ekctron mrcro.copy of acrn.t aections, the NI H's are innervatcd by numerous unrnyelhnaled fiher+ with IKdh allcrcnt hke and cflcrenl hkc endingi which are in synaptic contact auh each 20 orher as wdl as wilh the curpu.cuLr celh; (4) cytochemrcally, corpuscular cells arc posuive for acelykholineslerase; they olso have a positive reaction to Ihe u ~IYcerophosphale dchydrollenase technique and to Sokrr's lead hema- losylm slain for polypeptide- and amine-prrrlucing endocrine cells. lhe au- thon propose, Iherefore. that the NEB's provide an inuapulmonary, hypoua- sensitive ncuro(chemo-)receptor system in addition to the well<stablished un- tral and peripheral (r;., carotid body) chemorccepton. TFey conuin and secrete serotonin, and probably related amines or peplides, which could ir.tlu- ence the pulmonary vasoconslriclor response. Also, according to classic nwr- phobgic crileria, the NEB'a possess both aRerenl and eflerenl innervation. Their various other possible functions in normal and diseased lungs are mes- lioocd briefly. LAuwrryru, !. M. arnd Cokclaere, M. Zclrschrl/t /ur Zcfl/orulirnt rnJ m/RrorAoPucAe Anaromie 14S(4):121-540, 197). Other support: Nalionaal Fonda voor Wetenschappeliik Onder7oek (BeL lium). From the IAboralory of Hislopalhology, Katholicke Universiteil it l.cuvc. School of Medicine, Leuven, Belgium. BRONCNIOLAR NEIJRO-EPITIIP.LIAL BODIES IN THE NEONATAL MOUSE LUNGS The neuroepithelial bodies in mammalian airways are inlramucoul oor- puscks composed of nonciliated cylindrical epilhelial cells. lhese contain ckre- ly-packed oval nucki with compicuous peripheral chromatin condensalions and rather dark granular cyloplasm; they estend from the basement membrane to the airway lumen. 1111rasaruclurally, these speciaheed cells are associated with inlraepilhdiat aaons which k+se their Schwann cell shealhs. This makes them difficull to identify and has led some investigators to consider them cell processes ralher Ihan nerves. The present paper aims to clarify the ultrastruc- lural characlerislics of these uons in newborn mice by presenting results of both light and ekctron microscopy studies which demonstrate the orillin of intraepithelial aaom. Electron microscopy of lung lissue from a total of 120 speciPic-palhogen (ree Swir mice, ('D-1 slrain, one to nine days old, showed that the nonmyclinated ason under the neurocpinhelial hMdy penctrates the baul lamina an) emcrs the epitheha( (ayrr After pcnetratK.n, the intracpuhclral ason conlaining numerous mNochondria k»es its Schwann cell shealh. Lcuxnes enlarged nd rami(ies anang the eprthelul cells. 1 he esrahlishnscnl of mito chondria-rich structures as a.ons is particularly significant because similar slruclures associated with the granular lKulrachruky) cells have rccemly been idenliHed as cell processes and nw ncrvcs E'urthermnre, the aulhnrs ruqrsl, their rnrxphnQiRi..l nrganitalwrn supprvts Ihe prnbahilrly rhat inuacpidvchal nerves together with their asxxialed cells function as scnsury rrccptors in the bronchioks. 21

Flung, K Snd Loosli, C G The Amirican lournol of Anaronry 140(2):191-200, 1974. nrfs.r support: Fnvironmcntal Protection Agency. Howard Huahes Fmploy- ccs Give Once ('lub, and the Hastings Foundation Fund of the University of Southern California. From the l')epartnscnts of Analomy. Pathology, and Mcdicine. University of Southern Cahlorma School of Medicine, Lod Angeks. T1tF. ROl-E: OF TIIF PUl MONARY LYMPIIATICS IN THIi [)hFFNSIiS OF THE 1)ISTA1. l.l1N(7t MORPIInIlXilCAI. ANI) FXPFRIMENTAL SIUDIFS OP TNE TRANSPORT ME?CHANISMS OF INTRATRACHEALLY INSTILLATFI) PARTICLIS This paper, which also contains a lxief review of the atahori earlier studies on the microscopic anatomy and ullraslructure of the pulmrsnary lym- phatics, presents an espenmenul study of the uptake and renwval of inlra- Irachcally instilled carbon and ferritin parlicks from the alveoli of newborn rabbits Results show that: (1) in the alveolar lumen, (errilin particles mis much rrxxe easdy with the surfactanl material than carbon parlicles, although both are pha6ocytrred by alveolar macrophages and neutrophds: (2) since the alveolar cells are tightly inierconnected, formrng an impermcahle harrier. the tracer parsicks can reach the imrr.utral tissue cnmparlment only by a Irans- cellular route lypc I alveolar cells seem to have a vcsicular type of transport for fcrrrtdn and carhon, with fairly large nurnhers of Icrrrun mulcculc% hcrng phagocytized and apparently digc.icd in sccundary lysosomes, type It alveolar ccllb also phaprcylrzc both Iraccrs, npecully lcrntrn, strongly suKgctuns a double function for this cell, namely sccrelwtn (rI , surfactantl and phaRr><y- tosis (c t., ferntm, carlxtn and lamellar material); (1) inlcrstrtul connective tissue cells of debatable origin also contain phagocytized carbon or lerrnin particks; (4) the tracers very rapidly appear in the lymphatic lumina mainly through the open inlercellular lymphatic junctions which act as inkl valves activated by the anchoring fllaments. Lymphatic endolhelial cells also phagocy- tize ferrilin particks in large vacuoks and secondary lysosomes: ferritin par- ticlcs .re seen in micropinocytolic vesicles and coated vcsicks; (S) blood capillaries in the inter-alveolar sepra are morphologically much less adapted for the uptake and removal of particks than the lymphatics and seem lo play a minor rtdt in ckarancc• displaying only a limited reaction to frrrrtin hul no1 to cubnn; (6) many parlrcks art retained within the larger nrways to 1re rc• moved by ciliary aclivily; (7) the bronchiolar nonciliatcd cylmdrrcal, or so• called ('lare cclls, are also capabk of pharocytizing (crrrtm molecules. m tn m Laawcryru. 1. hI and Bacrt. 1. H. Ann.b n/ rhr Nrs. Yortt Aradcn+y o/ Stkncrr 221 :2J4 275, 1974 m m D Frnm the I aMratnry of Itrstopathology, KatholieTc Univcnded tc l.euvcn S.h<xrl r-f MrJu inc, I cuvcn, Bclgium. p r- 22 MI:CHANISM OF AC11ON OF a-t-AN111RYPSIN Biochcmiin~ aincal evidcnce su«esla ttiat a-l-antilryp~sin has two inhibitor sites, one cont o posituvely charged residue and the other an aromatic or kucine resirLrc, with both sites having a binding site lur the aarve moiely of serirse proteases. Fsperimenls designed to lesl this hypothesis show that: (t) Irypsin and chymotrypain compete for inhibitory sites on purified a I-an1i- trypsin, suggesting that the inhibitor has the same or overlapping inhibitory sites for Ihese Iwo enzymes; (2) Irypain inactivated by duu.propylphcssplwro- fluoridate fails lo occupy inhibilingsites on a-1 •antitzypsin; (1) a 1-antilrypsin inhibits suhtihsin, a proteolytic enzyme that contams scrine. histidrne, and as- parlic acid residues at its active site in common with mamnulian serrnc pro- teases; (4) a-l-antitrypsin fails to inactivate acetykholincsteuse, a nonpro- Ieolylic enzyme wlwne active site conlains a reactive scrine reudue• sulitestin` that this residue alone is not suflicicnl for rnhibilisn hy s l-antrrrypsin; 1S) treatment uf a-I-anlitrypsin with phcnylRlyosal hydrate blocks its action on trypsin 1.ut not on clsynastrypsin, a change in activity which is presumptive evidence that arsinine residues were modified by the t.catmcnt: antilrypric activity can be regenerated with removal of the blocking Rroups lhex resuhr are consistenl with the hypdhesis that Irypsin and chymutrypsm arc inhibited at two different aites on o-1•anlitrypsin and suggest that the uypsun inhibitory site contains a posiliv6y charged amino acid. Cohcn. A. d. The lournd o/ 8iolock.f Chcmivey 24S(20) :7055-70t9, 1977 Other aupporf r U. S. Public Neallh Service. From the Medical Service. San Francisco General Ilo.prul. and the Specialized ('enter of Research and Department of Medicine. Umvcrsrty of California, San Francisco. Pl1RIFICATInN OF PIIFNOTYPICALLY UNAI.TFRFI) a-I-ANTl l-RYPSIN This procedural paper describes several nsodifkatiom of the method of Shamash nd Rimon that enable ptnification of phenolypically unchanged a l- anlitrypsm from subjccls with phemttypt Pi,,,, lu this improved mahod. thrct Icchniyucs rc employed seetuenlrally protein prccipitariun at conlrulkd p/1 and akrrtw,l arncentratsns, nNlo e.changc adumn chromatography, ar.d prc• parativc polyacrylamide ctl ekcuophoresis All Ihe mrwlrfkations descnAcd hcrern nccur in the third technique T hn merhrKl results in recovery of an average of 12 1% of the Iryptrn inhibiting capacity of the scrunm Ihc a I- anlitrypsin prepared in Ihrs manner mainuins the hercroRcncity in acid starch gel immurnwro-.rcd tel ckclrophorrsrs that characlerues a I anruuypsin in whole scrurn lhn ohstrvarion pn,ves that the pherwuyprc chuaclcnures arc not dependent upon scrum Lrcturs ARo, this purified inhibitor resemhlcs a I- antitrypsin in scrum more closcly than a-l-antrtrypsin prepared by previoualy '1

dcacrnlxd methods In addition- the material h.rs RS-I(X)76 MoloRic activity, misraaes as a single hand in polyacrylamde gc1 clcctrophnresn with sodium dodecylsulhtc. srn1 m/Rrates as  hand with a cathrrl/c shouldcr at ptt 7 S in pnlyacrylamrdc gcl clcclrophoresls ('o/ien. A. e arul Fslt.t, R. Biochimir. cr diephyrira Arra )J6:J99-402, 1971. OIAer sr.pport: Il S Pulslic HeaNh Servioe From the Medical Service. San Fnaeinco General Ilospital; the Department of Medicine. Umveruty of Califorwia School of Medicine. San I:rancisco; and the Chest Division. Pacifk Medical Center. San Francisco. PURIFI('ATION OF TWO POPULATIONS OF IIUMAN ALVFOI.AR MA('ROPIIAGFS FROM SURGICAI. SPECIMENS T?lis paper presents two new methods that have been developed to purify human alveolar macrophatcs relrieved by sransbronchial lavasc lrcxo ulr6ical lung speclmens the MI method yicWs a large number of normal rnacrophaRes that are suruhlc for metabolic and functional studies soon after retricval The cells can he u.ed in suspension cullures or while adherent to tlass T he ucond method partialty purlfics another population of macrophates This method, which involves centnfu6lng the lavatcd fluid through a dense mcdlum, resulU in a 10 fold IxrnhcatK.n of foamy macrophaffes As measured on a surface balance. estracts from these foamy macrophages lower surface Icmlon in a manner similar to that of lung wrfacrsnt Although the origin of this particular maerophalle is rol certaln, a physiolopc role in the metabolism of lung sur- laelanl is sugrsted. CoJ1en. A. e. and Gecry. D. Ansnkan Rtvirw of Rrtpirarory Diitue I0R:972-975, 1973. Other support: l) S Public Heahh Service. From the Medical Service. San Francisco General lloepital, arxl the F)tpart- ment of Medicine. Univenity of California School of Medicine. San Francisco. INTf?RRFI.ATI(1NSHIPS BF.TWFEN TTIE ItUMAN At VPOI AR MA(-ROPIIA(;F ANI) ALPIfn-1-ANTITRYPSIN 1luman alvrolar macrophales have been implicated as the source of an enzyme c.pahlr rrf causing emphyurna in o 1 anntrypsin drH.rrnl pat/cnls- but prt•n"us .Ilrnrt./r lu Lti ac srnh a sahslarKC have farlcd /lhr c.prrrmtnt.l wnr~ rrl..rtr.l twrr h~.+rvrr rkm..uslra4rs thAl nrrt rr/rly d.r thcsr cclss nor- ~n.t~t .nnu~r~ .1 k••r 1.y . I anl.llylnur, hul rl,rr con- tain Ihe inhibitor itself. As determined in this series of e.pcriments, alveolar macrophagcs lavaged from human lungs possess nlawrmat proteolylic activity sl p11 3 0; but pF1 profile curves also show what may he a secondary peak of activity at a shghlly higher ranRe, suRRestinR the presence of a second protcaw Proleolytic achvity, measured at ptt 4. 1. is inhibited by purified a-I-anturypsin Fluorescenl antibody studies show that the inhibitor is also present in normal alveolar macrophages. When such cells were taken from a patient with a honazyftosts deficiency of a-1-anlitrypsin, they displayed kss fluorescence a/ter incubation in autobtous serum than afler treatment in normal serum. Macra phars from normal wbjecls showed masimal fluoreseersce when removed from the IunR, and additional incubatioe with normal human serum did not increase fluorescersce. Cohew. A. a Thelourndo/(7lnirallwrsrirarlow 52(11):279)-2799, 1973. OtAer au pporf t U. S. Public Health Service. From the Medical Service, San Francisco General Ilospital. and the Specialized Center of Research and Department of Medicine. University of ('ahfornia, San Francisco. TFIE MOL.F('UI.AR STOICIIIOMETRY OF TRYPSIN INHIBIf1ON BY IIUMAN AI-PFIA-I-PROTEINASE INIIIBITOR Human a-l-proleinase inhibitor (a-1-PI), or o-I anlivypsin, is rnpomibk for more than 70% of plasma's inhibitory aelivity. It has always been aswmed that this protein interacts with proteinases at a 1:1 molar ratio Recendy, how- ever, /wo preparations of this inhibitor isolated by suhstantially drfferent pro- cedures, have been found to bind a Rreater proportion of trypsin. suggesting that one molecule of a-1-PI may h.ve multiple inhibitory sites. This report summarires the rnults obtained by utins two drRcrent preparations of highly purifind human a-I-PI to investigate the sloichiometry of inhibitor interactron with porcine Irypsin. In conlrasl to other reporu, one mok of a-I Pl wu found to inhibit two moks of trypsin F)ise gel ckclrophoresis indicates that this 2:1 compk is formed preferenlially even in the presence of free o-I Pl The mechanism responsible for Ihe inhibitory action of a I-PI is srill unknown and there are as yet no reporls to suggest whether any ut its Lxrrsds are ckaved during the rcactwsn Ihe investigators are currently sludyinR rhis asl.ect- as well as aUenspting to determine rf lartcr proteinases such as pla.min are Inhrhrled In the same stoichiomctric ratio as rep.uted here for trypsm, lohnaon, b A. Panncll, R. N. and 7'.ovir, /. elochrmlcaf anJ elophyrlrrJ Rnr.rrA ('onu.wnlrerr..nr 11( 1) iR4 1119, 1'!/J OtAer supporf: National hrNdutts of Iltallh From Ihe l)tpartmcnl of Himlxmntry. University ol (korgia. Athens 2S :t

IIIIMAN PAN(•RFA11(' FNZYMFS: CFIARA("i1 RI7.Al1ON trF ANIONIC Hl1MAN TRYPSIN Recently improved prraedures for purifying human pancreatic proteaset have made it possrhlc to dctcct an anionic form of human Irypsin, at well as to purify this protein and investigate its propertres The enzyme was isolated from acetone powdcrs of human pancreas by salt fractionation fotlowcd by ion eschanRe chromatoRraphy on SE-Sephades C-25 and on DEAF-Sephade^ A-S0. The preparation was homogeneous as determined by disc ekctrophoresn and sedimentatic.n equilibrium centrifuplion studies, the latter ako indicating an ettimated molecular weight of 25,1100 for this entyme. ('nmpariton of anionic trypsin with the cationic entyme shows a high degree of similarity not only in molecular werght• but also in the amino acid composition ut each pro• tein as well as pF1 optrmum ^nd ability to diftest casein. The ^monic Inrm, however. has only a weak cross-reaction with antilx+dies directed toward the caNromc entyme. and is much ksa stabk than that proacase It is also rapidly inhrbited by soybean trypsin inhibitor and, to a kuer, esteM. by porcrne Karal pancreatic inhibitor and ovomucoid; all three are poor inhibitors of carionic tryptin Mallory. P. A. and Travis. I eiochtmisrry 12(15) 2847 2851, 1973. OtAer auPport: National Institutes of Heafth From the Departmcnt of Bxschcmntry. Univenity of Georgia. Athens FUNC'11ONA1 AND BI(X'HFMICAI. FFFEC'TS ON THC I lIN(; FOI.LOWINO INIIAI.Af1ON OF Ct(iARET1E SMOKE AND CONSi1TUENIS I. NIGN• AND LOW-NICOi1NE CIGARETTFS IN MI('E •Tl+is study has esamined the eRects of chronic inhalation of cigarette smoke in two strains of mice, using lechniques prcviously developcd by these investigaton for rncasnrin8 pulmonary function in this specics The influence of aging was invesu8ated prror to delcrmining the cflccts of snxokc inhalatron •1At nicoline content of the cigarette and The duration of caposurc were varied in Ihesc e.pcrinvenrs No combination of these vari.hles showed a caucc atwl eflccl relatN.nsMp between cigarette smoking and chronrc abstrr.nuve pul. monary disease Daily inhalation of cigarette smoke for (ive ot rcn weeks did, however, cause the following: (1) increascd pulmonary resv%tance; (2) decreased functional residual capacity; (3) decrcascd pulmonary camplunce; (4) decreased tK1al volume; and (S) increased wcl weight of the Irmg relative to rcduced Ixwly wcrrhr Ihere was no change in pho+phohpid cruucnr of the lung the increase it .iImonary resnlance and dccrcau in lurxtrnn.l resrdual nKC>~nercunlcnl of htvcsc ~arclrtaar>,Ipllvcpdur•- cap•c',t~xr flesh Ihty were tion of esprxure, indicating that both are caused' hy a combination of the nicotine in parriculates and constituents of the vapor phax The decreased pulmonary compliance was elicited by inhalalron of fresh whok /nwke but not by the ps•vapur phase. This would indicate that the causahve factor is in the particulate matler, probably nicotine, because the appearance of decreased compliance depended on the nicotine kvel. The decreased tidal volume as well as increased pulmonary resislance, or bronchospasm, occurred more readily in ICR strain mice than in the Swiu slrain. Roth strains developed tolerance to bronchospasm after ten weeks of eapcnure. llure was no increase in fundronal residual capacity and, hence, no functional sign of pulmonary emphysema in mice that had been espoxd to cigarette smu-e for five or ten wecks. Avlado, U. AI. and Watanabe, T. Toskolory and Applied Pha.marototy 30(2): 18 S 200, 1974. From the Department of Pharmacolo8y. Univcrsity of Pennsylvania Schrpl of Medicine, PhJadelphia. FUNCTIONAL AND BIOCHEMICAI. EFFECIS ON T11E Ll1NG FOI.L.OWIN(7 INHALATION OF CI(iARETTE SMOKE AND CONSiITUEN IS. 11. SKATOL-E, ACROLEIN, AND ACE1 ALDEIIYDL° Daily esposurc of mice to the 8as-vapor phase of cigarette smoke for Ave or ten weeks has eliciled bronchoapssm and decreases in functional residual capacity. To help pinpoint the causative facton of these eflects. Ihreo con- stituenh of the gas-vapor phase, skatok, acelaldehyde and acrolein, were tested in male Swiss mice Oral ingestion of akatcde caused pcrtmonary con• reslinn that was manifested by an increase in pulmonary hemo8lohin content and a decrease in pulmonary phospholipids. There was no increase on functional residual capachy and, hence, no pulmonary emphysema in mice that had tither ingested skatole or been administered an inlrafracheal injection of papain The latter procedure caused decreases in pulmonary compliance and in the antl• Irypsin aclivity of the blood, both of which are coincidentally seen in human forms of pulmonary emphysema. Acelaldehyde, the second consutuenr of cigarette snsoke strwhed, when inhaled by mice for flve weeks c-used a tcduc• hon in (uncliunal residual capacity similar to that cncounrerc.l in mice e.- prnrd to the gAs vapor pluse of cigarette snwr-e Acrolcrn, she rhird cunqxxnKt whose eRcc'rs ^re hcrern reportca, causcd a reduclwrn its pnlmanary rumpbanre, but this effect is not seen in mice ealxned to the gas varyrr phase of cigarette smoke. Watunahe. T. and Avlodo, 1) At. Tuakolary and Applied PharmocoluRy 70(2):201 21W, 1974 From The Ikpartment of Pharmacolu6Y. Universvly of Pcnnsylvani^ School of Mcdicirx, Philadelphia 27 26

, t 1 r .+:.. ' Ll1NG CI-11. MI1(K'lIONI)RIA: RAPID OXlf)ATION OF (iLYCF.ROI.-I PIIOSPIIAIF BUT SI.OW OXIUAIlON OF 3-1-tYl)ROXYBl11-YRAI E Although Blycerol-l-phosphale (G-1-P) and 1 hydrosyhutyrate (1-HO8) are not uwal rricarhnsylrc acid cycle inlermediNCs, they can he osrJrred through the milochondrul electron traruport chain to drhydrosyacetonc-phos- phate (nIIAP) and 1 osyhutyrate (3 08) respectively. The oxidation reduc- tion process can scrve to transfer reducing equivalents from cyloplasm to mitochondria, simulrantously furnishing cytoplasmic nicotinamidc adenine dinuckoliJe (NAI)) lor continuation of glycolysis In additinn, the 1 HOB/1- OB ratio has bccn uscd to determine the -iytramitochondrial free NAI)11/NAI) ratio in liver cells and pulmonary alveolar macropha8es (PAM). Mdoclusndriat oxidation of G I P and 3-11OB, therc(orc, may be physirdo8ically significant not only in the conservation of energy by ottidatrve phosphorylatron. Mst also in the reprlation of rnttaholac utdualion reslricted by inlrace11u1ar cornpars- rnenution This cnmmunrcation reports the relative rates of G-1-P and 1 11108 oxidation in lung mrtochondria. Aa judged from oaygen consumption, lung mHochondri oaidrred G-1-P at a ratt (30-35 nmoks 0:/min/mg prolein) comparable to that of 2aso81utarate. or SO to 60% that of succinate. The 3 1109 oxidation rate was slow (6 8 nmoks 0-/min/mg protein)- correspond- init to 20% that of 2 oaoglutarate or 10% that of succinate. In addition to pro- viding NAn. G 1 P oxidation in lung mitochondria may also incrcase the livadahilrty of phospholrprds for oxidation and coupled energy production. The -slow oxidation of 111(lB might be related either to lack of an operative en- zynse system or to rtt inhibition by fally acid oxidation Althtxr8h PAM mito- chondna manifested charactcristres srmilar to those of total lung mdochnrxhia, it is not certain whether asl lung cell types have the same potential lor oaidiz- in& G-1-P and 3 11011 Muslafa. M. 0 and Crorr, C. E. Amcrkan Review of Rtrpiretory nirtait 109:301-10). 1974 Oflrer .u pporl: ll. S. Public Health Service. From the [)epartn.cnts of Biological Chemistry. Internal Mcdicinc. and Iluman Physiolo8y, University of California School of Medicine and California Primate Research Center. I)avrs. TIiE (iRANUT AR 1-YPF 11 PNF.UMON(K'YlF AND I UN(i AN11OXII)AN1 [)liFENSE It has long been known that type 11 ctlls, which covcr areas of the alvtolar surface no/ lined by type I cclls, contain larncllar inclrnions rcptcstnunt syn- thcsis sitcs (ot pulmonary surfacunt, the phospholrpid rich suhstarxt primatdy rtsponuble for alveolar stability More recently, howcvcr- three other rclatcd cnnccpls concerning the type II pncumonocyle have also been suRRc•.Icd: ( I) it parlrcrpalts rn lhc ,rnlury anJ rtparr prrrrsses nl p,Jnu,nary partn.hyrnal Insut; ( 2) it may I~r the pro[rnitnr of the m„re numtr„us type I alvri,lcr rprlhchal rtll%, anJ 1 1) Ihc rr1,0•livc .Japlrve rc+(xrnst Jelcrnunes, to some tslcn/. the susccl•11l„I iy „I I1,,,g p.rrnihy,ua to ucrJ.nl slrc%s Ihis editorial sunuuantes 28 I these three mutually complementary concepas as lulhrw. ( 1) As a reparative ccll, various csperrments have shown that prolJerauon of type 11 cclls occurs early in the coune of repair of Irm` injrny causcJ by a nwlrrplrcdy of irri- lants; and recent uttrastrsatural and cytokinelic stuJics indreate that type 11 cell hyperplasu occurs in o.idant rnduced lung damage. Ihrs response sums to be well developed within 18 bours of o.idant tsposurc. (2) Sequential cyto- kinetic and mutpholo8ical observatKins of lung repair altcr oaK).nt damage havc shown type 11 cells - hul not type I cells - in mitosis; morcover, alrcr alvcolar injury, labeled thymidine is initially founJ in type (1 cclh, only later in Uansi- tional cells, nJ flnally in type I cells (3) Reparative type 11 ccll proliferation coincides with the temporal appearance of lung tolerance to o.iJants A possihk mechanism of such tokrance was sugScstcd to one investigator by the favorable influence of Hluuthione ((]SII) on the susccptrbrlcty of the lung to o.idants. Also, consrderabk increases in glucose-6-phosphate dthydrotenase ((i6P1)) occur in lung lissue a/ler low dose- tolerance prcK)ucmg e.hnures of animals to o.idants lhe au8mented (i6P1) aclivuy prrrl+ably reflects increased activity of the hesose-nutrwrphosphate shunt. Recent findings show that low- dcxe oaidant e.posure. (kvels that caused noticeable type 11 cell proliferation) result in increased levels of GSH. Blutathiorse reducuse- other drsutflde re- ductases, and Blut.thione perosidase in the lung 24 to 48 hours a/ter the initi.- twn of taposures. The close, temporal relalion of the occurrence of biochemical and morphological changes and the o.idant tolerance development is striking In summary, reparative type 11 cells may well he considercd a part of the alveolar antioxidant defense system. Crou, C. E. A nndf o/ Internal Mtdl. inr 80(1) :109-4I 1, 1974. Other .u pport r National Inslitules of Iltalth. From the lJnivenity of California School of Medicine, Davis EFFECf' OF OZONE EXPOSURE ON LUNG M11(>CIIUNURIAI. OXIDATIVE MI:TABOI.ISM Although morphologic chances resulting from ozone (U.) have bcen rc- ported in lung muoclsondtia, the functional eQects have not been adequately investigated Ilcre the authors attcmpt to determinc rl Oj inhibrts lung cellular function by interacting with mitnchonJria which contain a high de8ree of un saluralcd lipids in their Ihpoprotcm memhtancs anJ are rhus susccpubk lu struclural YINI /urM1N)naI alltratMms by osrJirint a8enls RruJrs inJrcatc tha Os c.pcnure rndtrJ affects stvtrcd basic mdochondrr.l hu.chuns. ( 1) the rate of sufn/ralt: uswlation; (2) Ihc'rhddy to per/urm o.HLlrve Phusphurylatwrn; arKl (1) cerlarn pcutxabilrty characterrstics lung m.uo.hr,nJna /IUm young heallhy rats e.poud to 4 plxn O, for (rrur houn, a hrgher level than cepecrcJ in ambient almospheres, were prcparcJ with the usc o( an rs„lomc huffercJ aucrusr mannunl mtdwm (-omparrJ to cuntrrd prtP.ralruns Ihc c.pmrJ mdrKhnnJrra nurult.NtJ a Urwer uityRtn cunaumpunn rare (.11 agnarnts uf the tcslru.tary charn htm8 .uutpnhlc Io l)r c.ir,.ure) anJ Jrnunrshcd cfh cicncy of coul,IcJ phusl,hr,ryl.hun Mcmhr,rne pcrnrcahrlrly rncrtacJ cunuJ 29

erahly. 7hrol ( Sit) Icvelt dn+pped ?OR, indicating oxidation of mtroihondrial protein -S/f 6roups, an mrprrrlant mechamsm of orid.nt damaRe I ipvl pero.r- datron was evMknt in rnr.r lbere seemed to he smular, d smaller. cl,+nRes at lower Os kvels (helow I ppm) Mn these were not cons.<fered sign.fic.rnt in the lesser numher of animats studied. Yet, indirect effects such as 1) rnduced release of lysosomal hyJrolases in the lung may also potentially contrrMue to lung mitocho.xlrial damaRe in riru. lhe authors are currently inve.tikatrnR the possibility of favorably modifying (lrinduced damage with various anliosi- danls protective against thiol oxidation awd lipid pero.idation in vitro (such agents have proven helpful 1o certain plaets against photochemical c.alants). Nevertheless, they do not fcel Iha1 at thia point in time the evidcncc that (>ti directly aRecls lung mitochondria /w vlvo is indubitable. Mustafa, M O., De Lucia, A. 1., Crou. C. E.. York, O. K. and 1)unRworth. D. t-. Clrerr 46(1) :16S I ttS, 1974. Other .urport: U S Public Heallh Scrvice-National Inqilutes of Health. From the Departments of BioloRical Chemistry. Internal Medicine and 1luman Physiology. School of Medicine- tkpartment of rathology. School of Veterinary Medicine, and California Primate Reaearch Center. University of California. Dw'n. FFFFCI S OF SIIOR T.l FRM OZONE EXPOSURE ON I.t/N(l MTT(X:FIONURIAL OXII)ATIVE ANE) ENERGY METABOI ISM This'sludy demonslrales that mitochondria in lung cells may be impor- tant targets for orone (O0 interaclions, and that interference of O, with lung mitochondrial o.idative and energy metabolism may significantly contribute to the overall lung damage that results from acute esposure of aninuls to this osidant Shorl4erm, high kvel Os eaposures (2 ppm (h for ta hours, or 4 ppm for 4 houn) deprest lung mitochondrial Os consumption, coupled pM)aphoryla- tion, and respiratory control in rats and monkeys. 1 ung mitochondria from control animals were relatively impermeable to added reduced nicotrnamide adenine dinuckotide (NADH), bu1 those from esposed animals shu..ed in- creased permeability as judged from NADII oxidation which was a threefokd increase over the conlrols. The depressed pulmonary milochominal functions observed in esposed animals may be related to atteratron o( membrane permea- hility due tn lipo) oxidation arKd to inhibition of respiratory entymcs (Aehydro- genases) due to oxidation of functional thiol group.. Mwtala. M. O and Cron. C. t:. Archivr, oJ Dlorheml,r.y and Riophyilct, 162: SlSS 594, 1974 Other .upport: O S Puhlic Health Service From Ihe Ikpartrnentr uf Ifittlusical ('Lemntry, (roern.l MeJw rra. .nJ Ilu.oan I'hynnltrRy. S.h-Md nf Mcd,cine. and ('aldornu Prinutc Rexauh l'cntcr, (Jni- vcnoty trf (-ah/urnu. I).vis )O I THE ROLE OF PULMONARY SURFACTANI IN EIEAt: fN AND DISkASI°_ In this carefully considered overview of the role and importance o(pul. monary surfactant. the author crrtically surveys Ihe historical h.ck~rousd, established measurement lechniques, data defkiencies, and pressing research needs of this intriguing lung subslance. It has long been kr.own that the ter- minal bronchioles and alveoli of the lung are lined with a substance, pul- monary surfaclant, that markedly reduces surface-active forces, stahdir.ea the dyeoli and prevents ate"ectasis. This lining compka consists predominantly of saturated pho.pholipds with dipalmitoy( lecithin (DPL) as the major active component. An adequate amounl of'active surfactant is essential for normal IunR funclion. EEowever. the role of surlacuM in pulmonary disease is diRicult to asaess because this substance cannot he quantitatively measured by direct means. Currently available techniques for measuring surfactant are lung oorw- pliance, surface activity of lung estracts and biochemical measurcmenu of lung photpholipids. (n the presence of patholosic changes, however, thex qualitative indirect measurements do not allow us to distinguish a primary de- fkiency in surfactanl from a secondary one, from inhibition of activity or from inadequate sampling. The lung is rich in DPI-, Mrl the /raction of total lung DPI. which is surfaclant is not known Although the large alveolar cell is probably the source of the lining compka, there are two other cells is the terminal airways which actively synthesize DPI., the Clara cell and the mono cyte-macrophate. Changes in metabolic activity and numbers of these cells in pathologic sutes also need to be known in order to evaluate properly allera• tions in lipid metabolism in disease. Therelore, the author concludes that the eaact rok of pulmonary wrlactanl in disease is, a1 present, essentially un- knowo and speculative. Escep Eor fetal immalurity, there is no known clinical condition in which a primary deficiency in surfactant has been cstablishcd lEowever, the author believes that a secondary deficiency in activity of the lining complea does play an important role in the pathoRenesis of many dr• ease slates, but in which ones and to what eatent is not known Similarly, a primary deficiency in surfaclaM activity will probably be uncovered in lime. In conclusion, a few eaampies are presented to denxtnslrale and emphasize the currenl pitfalls in interpretation of available data. There is an urgent need to develop direct quantitative measuremenls for pulmonary surlactant and mwe critically ctxrclate the palhobgic, functional and biochemical derangementa in the diseased lung. Only then will we know the proper role of pulmonary .ur- faclant in disease. Nidrn, AlDorrt N. In: lohnalon, R F(cJ ): Pufmonary ('are, New Yurk : (3rune and S/ratton. Inc., 1971, pp a)-101. • Ofher support: U. S Public Ileallh Service. From the t?epartment of Medicine, 1)rew Postgraduate Medreal Sch.al, t.o. Angeles 11 I

RFVFRSIBI E hAMAGE OF= RAT UPPFR RFSPIRATORY 1RACT ('Al1SFD BY C'I(;ARETTE SMOKE Because of the need to determine the specifk reaction of tlse masiltary gland and sinus to an etptrimenlally-induced environment, this pr,-liminary in- vesli8ation was designed to clarify: (I) the eRect of whole ci8aretle smoke on the masillary epithelium and gland; (2) Ihe progress of morphaL.BK changes in Ihe epithelium and Rland as a function of smoke dosa6e; and 11) the mor- phologic chantes in the epithelium sd gland during the perind of recovery. Adult SpraBue-Dawky rats were eapoeed to whole cigarette smot e for diRer- tnt periods of time and then saeriAeed at various slages of recover,,. As studied under light microscopy. histologic prep.rations of masillary sinuset and glands showed aeveral changes: (t) the masillary epithelium lost colursnar ciliated celh and hypertrophred: (2) Iht submucosa displayed evidence of an acute in- flammatory reaction: ()) in addition to other morphologic mod fkations oc- curring in the masdlary 81and, individud goblet cells containing ar id mucosub- stanccs diRerentiatcd within new maadlary epilhelium; (4) :arravauutar IympAocytes, polymwphors,rckar kutocytes, and macrophaRes migrated in great numbers from the subrmttosa to the sinus lumen by way of the epi- thelium; (S) some migrating cells invaded the lumina of eacrelory ducts; (6) the masillary sinus contained a massive amount of pus; and (7) rsicroahceyaes were scattered throughout the epithelium of animals esposed to smoke for • longer time. In spite of the morphologic changes induced by the caperiment, normal structure around the matillary sinus was retstabinhcd quickly after cessation of srnolin8 and throuBhouW roco.ery. Vidic, B, Rana, M W and eAarat. e f). ArrAlvtr o/ Orolwrntol,rty 99( 2) 110 I I l, 1974 OtArr support: National lnshtute of Menta) Itcalth and 1/. S Public Ilcalth Ser.Ke. From the Depariment of Anatomy, (leor8etown l/niversity School (if Medicine. Washington. 1). C, and the 1)epartmcnls of Anatomy and Physiology. Saint Louis University School of Medicine. St. Louis. CNANC)PS IN TRACNEOBRON(1f1AL CYTOLOOY NOTED DURINO ANFS111/3SIA (e this tracheobronchial cytologic study, snxan from 4,571 patients un- der8oin8 general endo/racheal anesthesia were screened for the early diagnosis of bronchopulmonary tumors In addrlion, one or more of the following meas- urements - to1.l nuclear score, percentage of goblet cclh, total cellular scrwe, percentage of muhinuckated eells - was made, accordin8 to the particular study in protress Results fcll either under the heading of changes in cytology caused by anesthesia or chanRes in cytology coincident to anesthcsia, and the following plserwmena were ducovered: (1 ) sieniflcant cytomorphologic chan8es occur in the epithchal cells of patients who inhak dry nesthclic gases for longer than one hewr; (2) the tracheerbronchial epithelium undtrjnes vanations rn morpholngy which resemble changes found in the endometrium during the memuual cykIr, (1) mcresttd numhen of muttusuclesteJ cJuteJ epitheGal cclls and a generally higher degree of multinrklc.twrn are found in patwnu with etlrathorac.c mali8nancres; (4) cytomorpholosrc damage in smolen prc- cedes reductions in lung function; and (5) tracheuhronchial washmp may be used to diagnose inhalauonal injuries sustained in fires and, of course, to dr- cover unsuspected mal 8nant condilions of the lung and bronchus. Clialon, l. New Yorl State lournal o/ Mrdlcine 74(12):2185-2189, 1974. Other supportt National Cancer Institute and Arnerican Cancer Society. From the Departmenl of AncslhesioloLy, Albert Einstein ('ollcite of Medicine of Veshiva llnivenity, 'The Brone, N. Y. TRACHI:oBRONCFIIAI. CYlOL(X:IC CHANGF:S FO1.1 OWIN(7 LOWER AIRWAY TIIERMAI. INJURY: A PRLLIMINARY REPORT Esfoliative cytology is a technique which might provide a relatively aon- invasive, atraumatic means of making a definitive duRnosis of the thermal damage to the lower airway caused by smoke inhalation. In this paper, t!e r.- wstigaton describe Iracheobronchiai cytology from nine patsenls with over- whelminR clinical evidence of inhalation injury sustained in flres Cytology was grossly abnormal in two palienb; there was moderate evidcnce of damage i. Icwr nwre cases: nd smean from the lau three patients were normal. Thcre was a positive cqrrelalion between cytologic damage noted in smears and scverity of clinical flndings during the first hospital day. Sequential scrial cy• tnlogy in two patients reflected the course of the ksion during therapy. These results appear very promising both from the diagnostic and prognostic points of view. lhe method is simple, praclical, and inespensivc; perhaps it should be evaluated at other huspitats. Ambiavatar, M., Chalon, /. and Zargham- 1. The lourna/ o/ Trauma 14(4):280-289, 1974. From the Ikpartment of Anesthesiolop, Albert Einstein (-olk8e of Maficiae of Yeshiva University. The Bront, N. V. 111. Ilrart and (art•nlafinn CORONARY BI l)nI) FI OW AS.SFSSMt:NT WIfH XF.NUN ANI) R1/811)IUM -Ihis paper presrrNs a clinical tcvicw of the mclh(wls uung rssXt and "Rb for the dclcrminjhun of cor4aury hkxr.l flow Alhh aiKh cnronuy Nood 8ow has heen mcasurcd in man for over 25 yean, an iJcat cl1mcally applicable 32 33

method has not been eslahlr.hcd yet The hes( meavue availahle mrw, bascd on the authors' tsperrentc. seems tn he the "Rts coincidence connrrng tech- ruque snsce it nuastures nutrrtUonal flow throuch the whok heart rcR.rrdlcss of changes in myocardul fluw JnrriMuion. ard since rt is a nonmv-rvrve technique. 1 he main linntauon rsf Ihis system lies in its inaccuracy (or al.,ulute quantufi- calwrn at high flow rates AlthouRh the determinatiun of nurrrtional hlrrwl 11ow by thc rubidium clear.rncc technique underestimates very high flow rates. it reflects an accrualt estrnrate of directional changes in myocardial blood nuw. In the atnon mcthod, the major problem arises when flow is not uniform throuRhoart the heart. as is certainly the case in coronary artery disene 'Ihen the calculatron of flrrw from mullieaponewlial decay curves is pruhicnutrc. Another Jiffscuhy is the dependence of the numerical flow value on the tissue- bhttxl partition cncfTicient and ils ponibk changes in a diseased state An addi- IN1naI dnadvant.Re is the requirement of catheterizatusn of the coronary artcr- ies; howevcr, thrs permits separation of Row through ritht and left coronary circulation and direct correlation of flow values with anatomrc varialions seen by coronary arteriography. Pachinger. 0 M.. Tillmanns, ll T. and Blng, R. !. Srnunars irs Nuclrar Mrdicinr 3(2):I31-131, 1973. Other support: Hoover Foundation and the Wright Foundation. From the HuntrnRton Memorial Ilospital, Pasadena, Cal , and the University of Southern California. I os Angeles Sflll)I!_S ON 111F (OR(1NARY MI('R(X'!R('l11 ATION BY 1)IRHCT VISl1A1 llAfION Since little had been published on phasic Row in the coronary microcircu- lation, these sturlres focused on (1) the anatomical pattern of the coronary mKroclrcula11tN1 and rts relationship to the direction of flow from one capillary to the other, and (2) phasic flow in the coronary rmcrocirculation To caplore these Ihinp, the coronary microcirculation of the cat was nburvcd by trans- illumination of the left auium. In most insaances, high speed cinematography was used; red cell velocity was determined by frame to frame analysis during both phases of the cardiac cycle Countercurrents and asymmetric capillary arrangemenl were found Ihrs has far reachinR importance for the oaygenarinn of the heart muscle and makes doubtful previous cakulations for the utyRcn transport from the capillary to the surrounding tissut Rccrurtment, dcnonnF an increase in the number of capillaries, was observed with a rise in pafusion pressure and following the admimstralw.n of nitroglycerin It can occur in the presence of sutore6ulalion l)cM1nite patterns lor red cell velocity in the capd- taries ol the left atrium emerttd Nicotine and nitroglycerin had lrllle eRecl nn rrd ttll vchxity Ilowtvtr, ftA{owinR hemorrhage alonc, anJ altrr Iht ad- nrrmrlr.rum rd rurrr,Rlyitrrn frdlr-rnR henurnh.Rt. m.rkeJ thanFr•. in the rrd rrI! ..I,.rty ..rrr vrn llrrrrnrrh.lt -meJ • m.rlcrl dmunulrrvr. whrn frJL L..r.l 1.~ n~r...rr„r,„ ,r rr.,rlr,A rrr . nurlrJ rn,rt~a rn rrJ crll vcl.xtly .tr,l.,r. . Lr.,.r...~ .~..,..,. ....... .r, I Binl, R. /. ez al. In: Maseri, A (ed ): Myocordia/ Blnod F'lor• in Man Afrrhu.lr and SitniF- contr rn Coronary 1)israrr. Turin: Minerva Medica, 1972- pp. 21 )3. Other aupport: American Medical Assrscialion, 17(vnvcr Founduion, Los Angeles County Heart Associalion, and the Norris Found.hon. From IlunlinRton Memorial /lospital and California Institute of lechnolo(ly. Puadcna, Cal , and the University of Southern Cah(ornia, I.o. AnRetcs. LIPID METAB(11.ISM IN HUMAN CORONARY ARTIiR11:S Mechanisms of the formation and.upsake of fipids into Ihe perfused hee- man cornnary artery are discussed in this paper. For the caperimentu per- formed, human plasma was used as a per(usate; '11 labcled cholesterol and s'C-acetale were added. Cholesterol was dispersed in the mcdium by sonica- lion. The results revealed lssl both alherosckrotic and normal coronary arteries of humans faikd to synthesize cholesterol and cholesterol esten. but thal they did incorporate "C-acetale into other lipds. Similar readts were obtained in human saphenous veim perfused at arterial pressures In conlrast, uptake of cholesterol from the perfusion fluid was demonslrated in atherosckrouc and normal human coronary arleries, as well as in human .aphenous veins In this study of lipid melabolnm, results illustrate that under the conditions of Ihese esperirnents, normal and atherosclerotic human coronary ancries, as well as human saphenous veins, synthesize free fally acids. IriRlycerides, and phcx- phtdipids Cholesterol and cholesterol esters are not synthesized, but enter the arterial wall by insudation or imbibilion only. Bint, R. J. N al. In: fMalla, N. S(ed ): Rerenr Advancer in Srrdie: on ('ordrac St.ucrurr and Mnebofizrn; Vol !- Myocardial Mrra6olir.n, Ballinwre: University Park Pres., 1973, pp. 33-Si. Other support: Noover Foundation and the Norris FourKlatwsn, From the Iluntinglon Institute of Applied Medical Researth, Hunlintton Me- morial Ilospiul, Pasadena, Cal., and the University of Southern ('alifornia, I us Angeles. 1,1141) MHfAB(111SM IN PI'RI:lISl1) ItItMAN NONA111FRO S('l 1iROI l(' C(1RONARY AR Il?RII S ANU SAPIII-NUUS VFINS 'Ihia study of Irpid synthesis .m/ cholesterol uptake in human nonathcro sclerotic corunary arteries and per/uscJ saphenous veins confirms previously eapressed opinions that there is no chuleslerol synthesis in human arteries Wtlh this series of espenmenls, the anrhurs dcnxinslrae that nenher normal nor atherosclerolie human coronary arteries can synlhtsize any cholesltrol from acetate, anJ that h.qh .rc capjbtc uf pnducmt only small answmts of ehoksteral esren (-MAcsterol uplalc, moreovtr. is identical in nornul and theruxkrutic arterncs, leading Lr the trrr)clusron thit the large amounu of 35 14

lipids observed in the walls of athcrosckrotic veacls derive (rcnu hlooal In (cneral, saphenous vems synthesvred the same amorml of phosphrrl.pids, free fatty aciJs, diglyccrrdcs, and triRlycerides as the coronary arterics Only dis• eased coronary artcrres incorporated nare phospholrprds than the saphcnous veins perfused si relatively low prenure. Free cholcstcrot wa% not synthesaed in Ihese veins, but cholesterol uptake was bwer in those pcrfused at 4S/ 1Smm 11g than in either coronary arterrcs or veins per(used at artcrial pressure ( 1 J0/ 1(x)mm lit). Ilashimoto, FI , l dlmanns, 11 . Sarma, 1. S. M , Mao. 1. 1lolden, F and Bint, R. !. Arhtrmclrroilt 19:15 45. 1974. Other support: Norris Foundation. Oould [?ock Fund, and the Wright Foun• dalion From the ItuNm`tors Memorial Ilospital, Pasadena. ('al , and the llnivenity of Southern California. I os Anjeks FIl1nF. EXPFRIMENTAI F. 1)P. I:AQMINISTRATION PR(ILONGFE 1)'Al('OOL Sl1R IFS I.IPIt7FS ARTFRIEIS, L'ULIRASTRUCIURE Er LA PERFORMANCE CARDIAQUFS In the couru of the last few dec.des, the notion of ethanol rclated myocardlopathy has gradually become established. This report deals with an attempt to produce an e.perimental model of alcoholic myocardi(,pathy in the dog by prolontrd admrnrstnuon of cthand (400 ml 25% ethamsl/24 hrs for 7 to 6 nxmths; average blood Icvels 100 mg/ 100 ml, peaking at 240 mt/ 1(10 ml 3 hours after ingestion) After three months, all arterial lipid lractions were clevated Fkctron microscopy of the myocarJrum reveakd some focal nxsdi6cations: mitochondnal dctencralion, dilation of intercclhAar junctrom. anJ widemng of intercellular spaces Angiodensin adminrstratusn rndicaled diminished myocardial conlracthlity, but bud state vcntricular per/ormance did aN appear altcred. The same results were noted afler sis n~onths of alcohol ingestion when both the milochor+dria and the sarcoplasmic reticulum also showed diminished affinity for Ca ( 4. Yet, in spile of this and otherwise functionally impaired mitochondria, basal ventricular contractility was not aRected. This would indicate that biochemical modifications at the cellular level are rnol suffiaent to cause the reduced basal ventricular function which charactertres alcoholic myocardiopathy in man. The esperirnent.l pnKluction of this clinrcal picture scems to require that the contracthk elrments thcrn• sclves hc directly affected and, thus, ncceuilates a longer caposurc W ethanol Fauvel, I M, 7 dlmanrn. It. T., Pachingcr, O, Mao. I S arK1 DinR. R I Archivtt dti maladirt dso ra•ur t/ dtt roisfroua 67(7) :S)7-M46, 1974. (lthrr support: 11 S Public Health Service. American Medical Asuxiauon and Itorwer I oundatron I rom the llunrmeeron Mcn.cxul Hcspilat, Pasadena. ('d , and the l)mvcrstly of S.nithtrn ( ahfrwrna. I r>• Anttkt ('IGARIATF. SMOKIN(: ANI) CFIOLrS1FROL UF RAHp11S A 1111 ROS( Lt ROSIS Fsposure to smoke from one cigarette per day in a simulatcd smoking machine for 11 tu 13 months faileJ to quanlativcly or qualitatively affect atherosclerosis of aorta and tatramural as well as intramural coronary arscrin, visceral lesions, or serum Irprds of chokstcrol fed rabbrts SrmJ.rly, no drflcr~ ences in these parameters were observed in norrnoclwte.terolerarc rabArts sub- jected to "snrnkrng" as compared to appropriate contruls Smokrnt aleo fadcd to influence the appearance of coronary an6ioRrams in rabbus ol the various groups studred. l.unp (rom only one rabbit subleclcd to cigarette snwking ethrhrted rarc fr.ci of mdd atypra o/ mucosal epithelium of malor bronchi Although these firsdings, which fail to reveal any adversc cAcct of crgue/tc srnokrng on the structural integrity of the cardiovascular systcm in thc rahbit with and without induced atherosckrosis, are rK)1 ncccssanly applicable to those that miRhl occur in man. they do prnvoke the need /or furthcr mqurry rcRarJrng the causal role of cigarette snakinR in the developmcnt uf athcro- sckrouc heart discase in man. FitlYrr, E. R.. Wholey, M. ard Shoemaker, R. Archirrt of Parhaloty 9d:411t•421, 1974. From the [kpartments of Pathology and Radiology, Shadysidc Ilospital, and the Univenity of Pitlsburgh, Pittsburith. Srl1[)IES ON ENZ.YMATIC ANl) MnI.ECl11.AR PR<7PFRi1FS OF LI:CIIFIIN:('IIn1.FSiEROL A('Y1.lRANSFFRASI? In Ihis paper the authors eaamine human serum cholesterol estenfkalion and present the findings of their work with kcithin:chokstcrol acyltrans/crase (I.CAT) purificatwin and characteriyatron In the first instance, cholesterol esteriRcalion in human ,erum was measured in healthy male and (emak suh- jccts using a modified version of the Stokke and Norum assay /echnique. Strong positive correlation was observed belween the rate of cholcslerot cslcri• lkation and scrum free cholesterol estcnfication, sugRcstins that the /.urru.nat r.ic of cslcrdkatron is a more useful piranselcr for cownparalivc studors than the rate of cslerification In their 14A1 stu.bes. highly punfled cruynre prepa rafinns werc o1Nained by using the comhined ttchmyues o/ Jensrty tradrent ccntrrfutalutn. I)F.AE cclluk.u chromalugraphy. and aflinuy chromatngraphy A slable 4(1()0 fold purified preparation was obtained as the result o( this pro- cedure, yielding /wo different hands on acrylami.k `et clectrophoresis dcpend• ing on whether or nM MMIn1ns Jrwkcyl sulfatc (ShC) is presrru Molecular wcight detcrmmarNrns on cahhrateJ gel cnlunms Crvc a valuc of 9S (1(N) in the abacnce of ShS and atxwl S0,(X)O in its prescnce, indicating a munonscr Joner relationship 36 17

I acko, A. (7 , Varma, K(i . Rutenberg, N. L. and SnlnA, f.. A. Scandinavian lournai o/ Clinrcaf InvrrriRarion J1(suppl 1)7) 29 14. 1974 Other auppart: U S Public Health Service and the /tearl Assocutiun of Soulheaslern Pennsylvania From the I ipid Research I ahoratory, Department of Medicinc, and Feh Research Institwe, Temple University Ilealth Sciencts ('enter, Philadelphia INIIIRITION OF I FCITFIIN:C/lOl FSTFROI. ACYI.IRANSFFRASF FOILOWIN(3 INTRAVENOUS ADMINISIRAIION OF IIEPARIN IN MAN The authors report on their use of heparin, which is known to activate lipoprotein Irpa.e. to determine whether the ensuing hydrolysis of plasma glycerrdn and ckvation of free fatty acids affect the rate of cholcsterol csleri- Bcalron A marked dccrease in the initial activity rate of kchhin choksttrd acyltcansferase (l CAT1. the enzyme responsrhk (or eslcribcatinn of free cholcsterol in human plasma- was obecrvcd in the sera of .uhj.cts who re- ceived 5.000 unds of heparin intravenously four hours after a 1.200 calorie meal Tl+is inhibition coincided with a marked elevation of serum free fatly acd concentration &.th cflects could he observcd as rapidly as one minute after heparin administration When heparin was administered to fasung sub- jects, enzynx activity was inhrbrtcd only in Ihme whose serum trrglyccride levels were suffictcmly high tn produce free fatly acid concentraunns in e.ceu of 1,(lU0 pequrv/1 In vitro addition of free fatly acids (palmuic acK11 and lyso- lecithin to the reaction mu, separately and lo`ether, Iso resulted in reduccd enzyme activity which could in turn he reversed by increasing amounts of serum albumin The data support the concept Iha1 this protein has more than one binding site for free falty acids and lysokcithin: one site binds up to Iwo moles of free fatty acids per nsok of albumin; the e.cess free fat4y acids com- pete with lysokcithin for a second sNe, the binding capacity of the latter being •pproaimalely one mole of lysokcithin per rrsok of serum albumin 1 hus. 1 CAT inhibition may he caused by • combination of elevated free lany acids and unbound lysolcctthin. the latter being • product of the I ('AT rractinn which apparently cannot be removed from the enzyme surface when (rre fatly acids already occupy lysnkcithin binding .ilcs on strurn albumin Rutenberg, I1 L, l-.cko, A. O. and SoloQ. [.. A. Dlochirnkaer tfiophyrka.Icra 726:419-427, 197). Other .rpport: ll. S Public Hcalth Service and the Heart rtsnociation of Southeastern Pennsylvania Frnnr the Ikp.rtmcnt of Mcdreine. Temple llrnrvcrsity llealth Scrences (-enter, i'hrLdtli.hra I SFRUM CHOL.ISTEROI. FSfFRIFICATION IN SPF('ll'S RI:,SISTANT AND SUSCEPTIBLE TO ATHEROSCLEROSIS Species differ in their ability to accumulate lipids in their arteries and in their propensity to develop sponlaneous and e•perrmcntal alhtrosckrosis. In • •e•rch for •.pecin with biochemical char•clerislics similar Io Ihose o( man, the authors measured Ihe physiologically importanl initial rale of chokaerol esterifkation in the •era of rat, rabbit, pig, dog, guinea pig, and man lh• assay used for this study was a modi(kd versiors of the technique introduced by Stokke and Norvm which measures kcithin:chokslerol acyltransfer•.e (t.CAT) activity. Results show that the rate of esterifkation Iends to increase with scrum free cholesterol levels in all specie• and that it is higher for ra/ than for any other specks The fractional rate of esteriticalion, however, app pe•rs to be a more useful tool for comparative sludies '1 his f.acliunat rale (% cholesleaol esteriAcd/minute) Is highest for rats, followed hy guinea pigs, rabbits, dots. pi[s, and men in decreasing order. Based on Ihis and other e.- • perimental Hndrnp, i1 seems possibk that Ll'AT activity is involved in plasma tipopcotein and cholesterol metabolism and consequently could be used to aid in the evaluation of model .pecin in e:perimenMal •therosclerosis. Ixko, A. O., Rutenber& II. l-. •nd Solofl, L. A. ArArrosc/rrod. 19( 2 ) :297-305, 1974. Othtr.rppsrtr Neart Asaociation of Southeastern Pennsylvania and Ihe U. S Public Health Service. From the Department of Medicine and the Fels Research Institute, Templ. University Ilcdlh Sciences Center, Philadelphia. INFLUENCE OF SMOKINO AND NICOTINE ON ('ERFBRAI. BLOOD FI.OW AND METABOLIC FAIE OF OXYGEN IN MAN The effect of smoking rd of comparative doses of inlravtnously-appleed nicotine upon cerebral herrsodynamica and otidative metabolism was studied in two series of patient• totaling 35 subjects. Regional cerebral blood flow wu determined by the raaXe inlracarMid injection method ('akularion of the cerebral •rterial-venous (a-v) oaygen difference was based on the hemoglobin concentration and on the apcclrophotnmelric determination of the o.yrcn saturation in arterial and venous blood from the jusular bulh Smoking as well aa nicotine increased cerebral hlood flow but decreased a v difference leaving Ihe eerebral metabolic rate of o.yRen unchanRed 1he conclusion is that unok in@ as well as me-otine has an eRect upon cerelNal vasculau reusursce euher bteause of a direct action upon vaindar smooth muscks or via she veteutrve nervous syslcm Nicotine in the doscs ohuincd by .mokinR .loes not change the ralc of o.idalive cerebral metabolism. S4lnhl/, E., (Nesen, 1. and Paulson. 0 B Icvrnal o/ Applic4 Physlulrrpy )S(A) IINI N2?. 1971 Pr.xn the Ikparlmenl of Ncurn/.rty. Hispehlcrt lluspilal, ('r.prnhaten. Ikn mark. 18 )9

INFI IIFNCP OF PF.RFIISION TIMF. ON NORFPINI?PIIRINF tIl'fAKli, IIEARf RAIE ANI) INTRA('ELLUT AR ('ATIONS IN (it1INFA PI(i IIEARTS The purpose of these studies was to measure the Na 4 and K 4 Ievels as a function of per/usinn time and Io correlate these ions with the •rptake o/ norepincphrine. An additional puryose was to ace if there were anv chantes in the sensitivity of the receptor. To do Ihis, hearts removed from m:,le guinea pigs were connected immediately to an Anderwn Craver coronary perfusion apparatus via lhe aorta Four groups of hearH were perfuscd for the following srudies: (1) uptake of rsorepinephrirse. (2) inulin spsce, (3) ekctrolytcs, and (4) dose response curves The dat. showed there were in fact marked alters- lions in intracellular Na t concenlydions, the uptake of norepinephrine. and the responsiveness to rsoproterenol as a(ursclion of altering the per/u%ion time. An incrcase in intracellular sodium paraflekd a decrease in uptake. Mrt Ihere was a return toward the normal cnviroemcnl upon continued perhui.'n Thcse studies have ob11`NNls implrcaliocss in investiplio.n carried out on the effect of drugs and other perturbatrons on the uptake of norcpincphrine. Wrrrfoll. T. C and Peach. M 1. Irorrrdinrs of the Sor Wy /or Ezlrrlmrnral e(olotr and Mrdicine 142 ( 1):76- el, 197) Other surport: U S Public Hea1e1. Service. Frnm the f?cpartment of Phsrmacok.lly. l)nivenity of Virginia School of Medieine, Charlottesvrlk. BFATINO htIRAT1ON OF Cl1LTURFD RAT NP.ART CF11 S AS AFFECTED BY DRUOS AND OT1tt'R FACTORS Cultured rat heart musck (M) cells provide a useful model for testing the direct effects of drugs and poisons; ho+rover. if other cells are present in the heart cell cultures, it is difiicull to analyze Ihe metabolic properties and pharmacologic reslxrnes of M cells. This is particularly trne since relatively pure crdtures of M cesls t95% ) are rapidly overgrown and will usually heat for only two to four weeks Hence, In an attempt to estend Ihe durstion of M cell hedinR. the inve+ti6alon decided to test aeveral overgrowth inhibilors and to make modifkations in Ihe mcdium. In these esperiments. the bealing duralion was prolonged by inhihiting the growth of nonmrnck cell+ ('okhi• cine, actirxxnycm I). hydrocortnone, rginase, and cellophane all slowed the rapid overrowlh of M cell cuUures and eslendcd /he duralion o( bcatin`: however, most of these agents produced some signs of losrcrly in Ihe M cells. htod,fkaticxn in the medium and melh(xls of addition were shown al.o to affect heatinR duration the suMtitulion of gamma tbMdimlree aenim in the mc- dium for fetal r al/ urum was found to he the most promising o/ the treatments Acosta. 1) . Wrnrrl. 1) (' and Wheatkv. I W. 1'11JInIM /1I11t11 J/ kltrJr(/1 ( UMnlunllJnonl 60) 261 271, 1974. O'lr.r aupport: NalionrJ Institutes of Ncalth and Ihe Kaw Valky Ileart Associaliun. From the Department of Pharmacology and Tosicolory. School of Pharmacy. University of Kansas, I.awrence. AN ASSFSSM[:NT OF 1{UMAN CARDIAC TRANSPLANTATION In this editorial, the authors review the hiuory, development and cur- renl slatus of cardiac transplantatqn Proceeding from mythology through early esperiments to successful Iransplants, they outline early results; also included is a chronologic table of statislics accounting for world wide cuse distribution and wrvival rates as of 1972• Attention is focused on the trans• planted heart's physiology during rest and eRercise, its hcrmtdynamics and neurohormonal activity. Cr.midcrabk space is devoted also lo the rejection Phersonscnon, acute and chronic. and its possiblc causes, deteclion, prevcntion, and treatment. The authon discuss current immunologic techniques and re- search likely to minimize the problem in the future, and they attempt to relsle sorne postoperative results to the antirejection measures used, diet and prc- esistence of pulmonary vascular disease Still other major oMtacles, in their opinioa, are the logistics of organ procurement, sloraRe and preservation with maintenance of viability, as well as the moral and ethical issucs involved in patient selection. Regarding this Ia,.l poinl, one particular surgical leam whose etcclknce t diagnosis and prognosis apparently results in a signifl- canlly higher survival rale among transplant recipients than among patients awailrnR operation is sintkd out. The writers reeomnsend that preservation of a chronologic detailed hislory, findings and treatment should he mandatory for all potential transplant recipients. They conclude with the aJmonition that this type of sruRcry, shoukd he continued by specialized teams, even in spite of its still low success rate and high costs, so as not to jeopardi-te Ihe poui- bility that it may one day become a routine procedure. Fadali, A. M. A. and Soto#, G. A. Amrrlcan Ilrarr lourwal66(6):7?1-7)2. 1977. From the f)cpanments of Surgery and Medicine. Temple University Health Sciences Cenler, PhiladelpAia. MFASt1Rl?MFN I' (1F I YSOSOMAI I RA(ill 11 V PROt)t1('FI) BY I/YPOXIA, NI('OtINE, CARBON MONOXII)F.• ANI) IIYPhROXIA IN ('ULIl/Rl?h I?Nln)IIlta lOlh ('Ft I S Tlse role of the lyuaorne in normal cellular physioloRy or discase. ar well •s in drug action and toaicity, remains to he Armly estahlnhed It is known, however, that  nunrher of aRents can slier the perrneshdrty characrrrrsrus of its membrane and Ihus m<Nlulate the av.rdahrhty of rts enrymrs to rhr cell The effecls of thc+c hydrolytic enzymea can range Irom rever%ohle cellular damage to complete aulolysn, and it has been proposed that methrNls fur mca- 41 40

surinR lysosomal permeability could be used to detect early slaRcs of cell dam- a6e As part of  contmrdng study of the drrect to.icity of varnous agents on Fronr the Ikpartment of Surgery and Medreinc, TemPle (Inivcr.hy 1(ealth specific cardiovascislar crlls and of their possible role in the eluilot,ry ol cardio- vascular diseau, the arrthon describe a metMxl for measurinR lyu.urmal fra- gihty The results are reprrducihk .nd can he tested for statistical significance Cultured neonatal rat heart endolheliod cells were used to evaluate hypoaia, nicotine, carbon monoitiJe, and hyperoxia for their potential lahilirin` eRects on lysosomes Althouth all trealments were toxic in that they reduced cell number, only nicoline arsd hyperoxia dp+ificantly labilized lyuxomes in the concentrations tcsted. 7?m incrcased lysosornal permeability proJu:eJ by nico- tine was followed by extensive eellular v.cuo(ation. and the reaction was both lime- and concentration-dependeM. Whik hyperoxia affected a sirnilar change in lysosornal pcrmeaAility. the increase was rapidly followed h) cell death. These rnults, however, do nol preclude the pnsihilily that nicoline, hypoxia, or carbon nxsnoxide might interact to produce effects rat seen with any of these agents akxrc Wirncrl, D. G. and Reed, B. L. ReteorcACowvnunlcerioru in CAernkd P.uAolory and Ptiarmaroloey 7(4):745- 714, 1974. OtRrr supp++rt: U S Public Nealth Service and Univenity of Kansas Gen- eral Rescarch Awards From the Ekpartment of Pharmacology and ToxicoloRy. School of Pharmacy. University of Kansas, I awrence T1IE PHYS1n1(X,Y OF SIRON(i IM(ITII)N ('ANNON'S S(-II'N11ft(' I I CiA(Y RI? PXAMINFf) In this paper, presented on the occasion of the 16th Annual Bowditch I ecture and the l(X)th anniversary of ('annnn's birth, the author recounts some of the scicntifx events shaped by Bowditch and Cannon which have led to cunent concepls about bchavioral control of physiological phemanena. As a young researcher who had started x ray observaion of peristaltic waves at the suggestion of Bowditch. Cannon observed somNhing during the coune of his gastric modility studies which caused him to deduce that excilement might pro- voke a flow of drenal medullary nccrelion, and that changes originally in- duced in the digestive organs by nervous impulses might be continued by cir- culating adrenahn lluee techniques that Cannon later inlrr+hK-rJ to snrdy this emot«.nal production of adrenalin were based nn: ( 1) an adrrnalin hir.assay, (2) the supernormal sensitivity of the denerraled heart to circrdatrng aJrena- Ln, and (3) removal of the cerebral cortex which caused "a sort of sham rage `'fAroughr>at his adrenal emWion studies. ('annon described the physio- kr`ical mechanisms wherein behavioral phenomena might promote organic drxase, described what is now calkd the "defense-alarm rcaclron," and prxtu- L1rJ the delrtrrKws orRamc rffccts of physiolnlical reactions in m-lcrn man unahle to cuuntci envuunments0 threats by physical activity. I his hypothcsis was still not thoroughly tested as we entered the 7O's, hut there are now experimenu under way at Flarvard Medical Sclotd which suttgest that bcha vroral phenomena may induce organic disease. Ihc+e expenments are fully described in this paper. Using squirrel monkeys as suhfccls prrmardy, the au- thor and other investigators started sludying the long term effects of behavioral phenomena Because the cardiovascular system responds quickly to envrron- menlal sUmuli they us,d continuous measuremenls of systemic ancrial blood pressure and heart rale to quantitate reactions to various behavioral procedures The objeclive of these experimenls was to induce consistent cardiovascular responses to environmental stimuli over periods of many months Now, those behavioral procedures which proved mosl effective in producing hypertensive responsts are being testcd for their possible rok in the pathogcnesis of hyper- tensive and arteriosclerotic cardrovascular disease in subhuman pimatcs In rctrospect, Cannon's hypothesis that strong emolions mighl induce organic disease aoem entirely reasonabk but il has taken 60 years to Jevekrp be- haviord techniques for exerting sustained control uvcr physiolojkal phen.o mena. The aka stated in Cannon's diary that pathological effects of emouon are due to failure to have normal exN in muscular movement can now be tested prospectively in subhuman pritnales. Herd, ). A. (Dartrr, A. C.) The Phyriolotift 15:3-16, 1972. OtAer surport: U. S. Public Elealth Service. From the Ekparlment of Physiology. Harvard Medical ticlx.ul, B&xton. 1 V, Neuro plrarmacology and Psychoph ysiology TOLERAN('F- TO 171E EFFE(TS OF DAILY NI('OTINI: ON RAT BAR PRESSING BENAVIOR FOR WAIER REINFORCEMENT In the ru, chronic nicoline adminialration (025 mg/kg nicotine lartrate, i p., twice a day for I S days) caused initial disruption of bar pressing behavior for water rernforcement, followed by rapid devclopmcnl of tolerance Because nicotine also causes the release of anlrJiurelic hornrnne ( Ahll ) which might reduce the animal's drive for water rcinforcemcnl, the aulhors tested the effect of AI)11 adminnlralwrn ( S 10 umis/kR, s c.) as well Since, in contrast to nKo. tine. Ihc hnrou.nc .uppresseJ,water drinkinR behavtirr only after an ininal perirxl ol latcrKy, thr auuhors concirKfe that nkaute has a direct effecl nn bar pressing behavior which n unrelated to the rclease of AI)11, and that darly exposure kads to tolerance. Dom/no, E. F. and I uls, M. P. PAa.nrutnlnty Rin.Armirrry and BrAavl.rr 1(4) I4S-44M, 197) From the (kparlmenl of Pharmacolo6Y, (lniversuy o( Michrgan, Ann Artwr. 42 4)

1 ~ .~+.~ . +~e 3`V .1 ...1. ~ Z 1 ~ 0 ` EFFECI OF NICOTINE ON THE SWIMMING ENDURANCE 01' RATS Swimming to eshaustion (forced swimming or swimming endurance), as determined by their inability to surface afler repeated attempts. is a convenient method o/ eaposing laboratory animals to eaercise 11 has been used etlensive- ly to evaluate the action and effectiveness of drugs on physical performance. This study attempted to determine the effect of nicotine at various oose levels on 1he swimming endurance of rats iw a water lub. In an attempt to gain in- sight into the mechanism by which nicotine affects endurance of swimming rats, the influence of various drup (eedalises, antidepreuan(s, central stimu- Isnts) on (he changes in swimming tirus induced by nicotine was eaamined also. Results showed that nicoline, in sJl doaes injeckd, produced jigni/kanl decreases in the swimming lime of ra1s. Tlrs may he a tranquilizing effect since, like nicotine, chbrdiazepoaide and diazepam caused deterioratirm of per- formance, whereas methylphenidale, ( f)-amphelamine, and (-)-amyhelamine led to performance improvements. Wbcn drugs were used in cornlunslion, the performance-slimulatrne effect of inethylphenidak svas compktely biocked by nicotine, whereas that of (})-amphetamine and (-)-amphetamine was only parsially antagonized. Nrcoline adminislratiow increased the impairmenl of swimming endurance caused by eh/ordiazepottide. QAatar. S and Wheekr. N. N.r.opA.rmacoloty 12:1 t61-1165, 1973. Other anppsrl r U S Public Health Service. From the Department of Physiolop, Saint Louia University School of Medi- eiee, St. Louis. NICOTINE RELATED NFl1RO('HFMICAL CHANGES: SOME IMPLICAII(1NS FFOR MOTIVATIONAL ME('NANISMS AND DIFFEREN('FS This artick focuses on the fact that, either directly or indirecily, nicotine induces biochemical changes in the brain - other than those related to its effect upon the cenlral nervous system - which could have motivational sig- nificance. The sulhor discusses oonre central biochemical changes caused by nicotine and shows how certain eordiliom known to alter specific drive states can also modify nicotine i uptake, melabolism and neurochemical effects. Spe- cific sections deal with: (1) brain indoleansine changes; (2) cellular specificity of nicoline-related central eflects; ()) nicotine-induced central cholinerbic effects; (4) differential housing as it affects neurochemical status and nicotine uptake; (i) eholinergic effects of differential housing and nicotine; and (h) cerebral protein synthesis as interactively affected by nicoline and diflerential housing. Tables and graphs suppkmenl the drseussion. II is suggested that Ihese data will perhaps slimulate further eaperimenlal efforl to relate the motiva- tion for smoking tobacco to the pharmacologic effects of nicotine. E»man. W. S. In: Dunn. W/.. )r (ed ): Srnoling Aehavior: Motives and fncenhvrs. Wash- ingron, 1) (' V 11 W msoon & Snns. 1971, ('hape +, pp S 1 .61 I mm f).u.ns (t4irtr „t the tay 11.n,vcrssly ut New Yurk, I lushrns 44 I RETROC:RADE AMNESIA AND CEREBRAI. PR(1IFIN SYNINESIS: INITIATION AND INIIIBITION BY S-NYDROXY-fRYPTAMINE The studies reviewed here capbre the significance of S hydro.ylryplamina (S-HT) for memory processes and .nsnesic events, and consider the relation- ship of such effects to cerebral protein synthesis. In an initial in vitro eaperl- ment, the author scrulinaed the effects of S-HT upon synaptosomal prolein synthesis in the cerebral cortex and limbic system, and found 24% and 32% inhibition respectively. These S-HT-relakd effects were statistically significant. Results from another esperimenl invesligaling the effect of intracranial 5-111- adminislration upon forebrain S-11T content as a function of aCe indicated that brain S-I1T increases, IS minutes following injection, are aee-related. The ea- pected 100% increase almost atlaincd in 20- and lO day-old mice, was some- what reduced in 1S-day-oW animals and was markedly attenuated in 17day- old mice. Since the praein-synthetic-reRulating properties of S 111" and its tissue uptake or dispositias as a function of age may be especially significant in metnory consolidation. this issue was explored further. A telationship bc- Iween Ihe two effects of S-IfT was clarified in developmental studies wherein mice of 17 days of age showed marked resistance to the mnesic effect of S-IIT and significant allenuation of its inhibitory effect upon cerebral protein synthesis; the laller observation was probably related to both age-depeadeal rates of cerebral protein synthesis. The behavioral and biochemical effects of S-11T in these eaperiments appeared related to the retention of S-HT is brain tissue after intracranial injection. Where such retention was reduced at critical ages, both amnesia and protein synthesis inhibition were decreased. Etzman. W. Q. Tohu Hoano 1(2):61-67, 1972. Other supporti National InslNuln of Health. From the Department of Advanced Psychology. Queens College of the City Univenity of New York. Flushing. NEUR(1MOI.FCULAR MODUI.Al7nN OF EXPERIMENfAL1.Y-INDUCED REIROGRAI)1: AMNESIA Summarizing a sequence of eaperiments, the author shows that the eaperi- menlal induction of retrograde amnesia in mice by ekctroconvulsive shock (1?('S) may he mimicked through the inuahippocanspal rniectKSn of S hydro.y- tryplamine (5 Ili). A single poss-uainmg F('S treatment has heen shown to cause (1) re/rosrade amneua for avoidance behavirr in the mouse: (2) change in brain 5-111 level arsd melaMdism; and (3) inhibition of retronal protcrn synlhesn Injection of physK*rbrcal quantrlies of 5-/11" into the hipprrcampal region of mice also induced retropade amnesia and tnhibited cerebral protem synthesis This appears to be a specific S(IT eAect, since rNher andop ot amines fadcd to proJuce a comparable behavioral reaction Ikiause Ihcre seems to he an age related eRect of resistance to anmesic treatments correlated with increased brain 5 111 in the 17. to le day ow mouse, i1 may well he 45

that these animals undergo a critical stage of brain development with respect to 5-111' metabolism at that point. lhis phenomerxsn which seems to he unique for this parucular age interval and specific amme is not observed with other substances that could be involved in the memory fi.alion process Ihus, it is speculated. the relationship between amnesic treatments and altcrations in brain S-!IT kvels or metaholrsm may be esplained in terms of their related effects upon cerebral protein synthesis Sevecal molecular interactions having possible significance for synaptic rnodulation of changes associated with espcrimentally- induced retrograde amnesia are discusscd. Essmen. W. 8. ('onJini. Nnrrolotica )5:1-22. 1977. Other as.pporr: National InstilWe of Menlal Health. From the Ikpartmenls of Psyehology and Bioehemislry, t?ueens College of the City Uoiversity of New York, Flushing. EFFECT OF ELECTROCONVUISIVe SHOCK ON (-EREBRAI. PROTEIN SYNTHESIS Thin discussion considers sorne of the parameters by which the eAects of ekctroconvulsive shock (ECS) on prdein synthesis may be functionally pertinenl. One such functional proccss is the Osalion of the memory trace and its disruption through ECS and several other possibk agents. For eaampk. changes in indoleamine melabolism may be the way in which ECS affects pro- tein synshesis. Spacifkally, it inhibits S-hydrosyuypumine (S-NT). probably as  result of 1-RNA binding When menured by 1•C kucine incorporation inlo several subcellular (raclions obtained from diAerent mouse brain regions fol- lowing ECS. the cerebral co.tes synaptoaortre fraction (isolated presynaptrc nerve endings) showed martimal inhibition. Although still preliminary. these eaperi- trsents suggest that ECS mediates inhibition of a1 least two classes of proleins, probably having both functional and siructural significance synaptically, and also specific polypeptides or proteirn distinguishable by their nsolecular weiRht. that reside in each such protein class. Whether the ECS-semilive site and mofe- euks also respond to other agents, however, remains to be shown Neverthekss. these results do indicate several areas where the effects of ECS on cerebral protein synthesis may be approaimaled by S-NT, which also has an amnesic effect It is probabk that synthetic events related to structural changes in the synaptic membrane are important both for the functional iotcgrrty of the synaptic area, and the maior functional phenomena operahve in nKmury and amnesic procceues. E» man. W. e. In: Fink, M., Kety. S. S. Mc(iaugh. l. and Williams. T. (eds.): The Prycho- liology of Convrhrve Therapy. Washin6lon. 1). C c V. !I. Winston i Sons. 1971, Chapt 1ll, pp 2)7 249 l:rum (rruns ('olkile of tbe (-rty Univcrsuy of New York, Flushing. 46 V. I'harmatolr.Ry L'FFF(T OF NICOTINE ANF) U7111-:R DRI1(:S ON IHE RFLEASE OF sI1-NOREPfNEPHRINE ANI) aN-I)UPAMINI: FROM RAF BRAIN SI.ICES Nicotine is known to stimulate the release of norepinephrine (NE) from peripheral adrener6ic ncuronm and /o have marked neurological and behavioral effects on the central nervous system. lhis study was designed to determine rf nicotine also releases NI: from other areas ol ,Ihe brain which contain rwv- adrenergrc nerve lerminah, and whether it relea.es dup.mine 11)A )/rom the slriatum, an area rich in drq+aminergic nerve terminals In addmon, the author attempts to study the releasing mechannm by e.ansinrng the effect of varioa-s pharmacologic agents known in influence the aclirrn of nicotine on peripheral ~ adrener6rc neuruns Results indicate that in the rat. nicotine: I 1 I signiAcandy I I increases the release of sIl-NE from incubated slices of hypothalamus, corsc and cerebellum, with tSe greatest re.ponse noted in the hyp.thalarnrc tnsuc; (2) rekases sH-NE from superfused slices of hypothalamus, an effect depend- ent on ealracellular Ca4 t and diminished by prior addition of hesamethoniuns or acetykholine to the superfusion medirun; (1) produces a similar «kase o/ sil-DA from striatal slicea, an effect reduced by acetykholine, snetbach:Jine. hetamethonium and lidocaine. Morphine and cocaine had no eflect, but phenosybenzamine signi/kanlly increased the rekase of 'il-DA induced by nicoline. The author corschuks that nicotine can release monoamines from central nerve lissue, an effect which is dependent on earacellular ('a + 4 and is produced by reaction of the classical nicotine receptors In addition, this study provides support for the "snuscarinie inhrbitory" hypothesis which sug- gests that acetykholine may modulate the release of DA and NFE frorn central neurons in a manner simrlar to the way in whkh it affects the release of NE from peripheral adrenergic neurons. Wrst/all, T. C. NesrroDharmocology 1)(e) :69)-700, I971. Other aupport: U. S. Public Health Service. From the i)eparlmenl of Phatmacology. University of Virginia School of Medi- cine, Charlottesvilk. OI MIIS('ARINI(' A(i(1NIS1S ON I111 RI I I AtiF /IF IsI11N(1RA1)RtiNAllNti UROM 1a1C GIIINI?A PI(: PI Rf l/ti[l) /IFART Previous perhnion e.perrments u.inR various tissues have shown that acNykMslrne or other muscarinic apunisla decrease 1he rekase of noradrena- Irne following sympalhetic nerve stmurtatinn 7 hese ohservatNrns have given rrse in the hypothesis that acetykholsne relcaacJ er..m a dwAonerek nerve inhihiV she rele.ne of nowadrenahne frnm an aJlxent adrencr`rc nerve by means of an inhibitory actwn .ro muscannic receptors Here the autlwsrs report 47 1

Ihat both acttylcholine and methacho/inc prevent the release of I'llInraadrena- line ('II-NAI by nicotine in the guinea pig perfu%cd heart and show that acely/choline fadk to release 211 NA from Ihe periused heart escept when used in very high concentrations 110 sM / However, il alrnpine (10 'M I n added to Ihe per(usron solutron. 10'M acelykholine wd) readily release 'll-NA These results arc consistent with the given hypolhcnis and demonstrate that muscatinic agoni.ts also decrease the release of noradrenaline induced by nico- Irne Further, evrdence is presented suggesting that the muscarink inhibitory receptors are much mote sensitive to acetykholine than are the nicrNmrc recep- lon. This teporl, therelore, supports the concept thal the muacarmic mhrbitory mechanism acts as a means of regulNing the release of noradrenalinc. Wesr/al), T. C. and 1(unler, P. E. lournal of Pharmacy and PAarrnarobgy 26(6) :458-460, 1974. OtAer .upport: I) S Public 1(ea(th Service. From the Ikpartment of Pharmacology. University of Virginia School of Medi- cine. Charlottesville SPFCIFI('ITY OF 81 (X'KADE OF T{IE NICOTINE-INDUCED RE1 EASE OF all•NORI:PINF.PIIRINE FROM ADRENERGIC NEURONS OF 111E GUINEA-P1(i FIF.ART BY VARIOUS PNARMACOLO(iICAI AGENIS There is now convincing evidence Ihal, in addition to many other effects on the nervous aystem, nicotine and related drugs can induce a direct release of rsorepinephrine from adrenergic nerve terminals A large number of pharma- cobgic agenu, howcver, have the ability lo block this nicotine induced rekase of norepincphrine Among these blockers are hesamethonium, morphine, co- caine, bretyhum, lidocaine, phenoaybenzamine, and desmethylimipramine. This study used per/used guinca pig hearts to compare the ability of several of tht:se agents to aher the release of nicoline-induced notepinephtine, in order to ob- tain information on the mechanism of this blocking action and to assess its specificity. Tyramine. KC1, aminophylline, and prostaglandin Fs were also studied, as were prostaglandin Er and cokhicine, which have recently been shown to decrease the release of norepinephrine altet nerve stimulation. The following agents inhibited the nicotine-induced release of sN-tsoreprnephrirse by tnore than 90%: hesansethonium, morphine, cocaine, brelylium, ao/ lidncainc. Cocaine and bretylium decreased the release stimulated by tyramine, hsrt only INkrcaine lowered that inductd by KCI; narc of lhese agents hbcled the stim- ulating effect of aminophylline. Cokhicine signiM1canlly rkcrcasrd the mco• line-induced rtlease, but not that induced by tytamine or K('1. Prrntaglandins Fr and Es. however, decreased the release of sN norepinephrme induced by nicoline. KCI, and aminophylline, but not that produced by tytamine 7he con- clusions are that: (1) lidocaine blocks Ihe nicotine induced release of nor- epinephrine by a local anesthetic action on the adrenergic asoerl memhrane of the gunnca p,g heart, whereas heaamelhonium bktcks the nwounrc receptor; (2) cocarne, hreryhum and morphrne block the nicotinic reccptor, ur act at .omc later step i.ctwecn receptot activation and noreprnephrine release; (3) 48 i cokhicine appears to have a specific anticholinergic effect in decreasing release of norepinephrine; and (4) pro>,taglandins Er and Uh.ah decrease the rekase of norepinephrine at a step in secreliun coupling common su nerve stimulation and the administration of nicotine. KCI and aminophyllme. Werr/afl, T. C. and Brasled, M. The /orrrnal of Plharmacology and Experimental Thrropeuria s 189(1):639-664, 1974. Otber aupport: U. S. Public Nealth Service. From the Dcpartment of Pharmacology. University of Virginia School of Mcdi- cine, Charlotlesvilk. EFFECT OF AMINOGLUTETHIMIDE ON NOREPINEPIIRINE TURNOVER IN TIIE RAT IIEART Aminoglutelhimide, which interferes with cholesterol side chain ckavagc in the conversion of cholesterol to pregnenobne, has been shown to inhibit synthesis of all adrenal steroids of biological activity. With this action, amino- glutelhimide could be a valuable tool in enabling one to sekcttvely inhibit adrenal cortical sleroidogencsii without significantly disturbing the functioning of the adrenal medulla. In this study, the authors attempted to inhibit selectively the adrenal cortex with amitoglutethimide and thus to determine the eatenl of involvemenl, if any, of the adrenal cortett per ae in the control of synthesis of norepinephrine (NE) in the rat heart. To do 1his. NE lurnover was measured by two different methods in male Sprague-Dawky rats Results showed that inhibition of adrenal sleroidogenesis with aminoglutethimide does noa change endogenous NE kvels in the ral hean, does not influence cardiac al/-NE up- lake in the rat, does nol dter the urinary eacrelion of epinephrine or NE. but does result in an increase in turnover of cardiac NE when injected /or six or ten days at 200 mg/kg/day. Similar observations have been made follow- ing adrenalectomy and hypophysectomy. Adrenal cortical insufficiency ia a common denominator of all three of these experimen/s. Results het•e also ardi- cale that the increased cardiac NE turnover is not seen before six days This stsdy, therefore, succeeded in demonstrating an increased wrnover of NE in the ral heart on inhibition of adrenal steroidogenesis with amrnoglutethimide. Tltis adds to the evrknce that there is an interaction between the adrenal cortca and NI: turmwer. Wcst/alf, T. C. and I ewis, T'. C. , ProcerAinRr of the Society for Eapcrinrentrrl Biology an.t AfeJ,rrnr 142141 1295- 1100, 1971. Ot/ier .u pport r U S Public Heaith Scrvice. From the /kpartmcnt of Phatmacolo`y- Unrvcrsuy of Virsmu tichtnil of Medi. eine, ('harkttlesvdk. 49 I

('ORTICAI. CUPS FOR COLLECTING FREE ACETYICIIOI INE IN AWAKE RATS The cortical cup procedure, which is becoming an incteasingly popular - lechnique for col/ecling the acelykholine aponlaneou.ly released (rom the sur- face ol the cerebral cortea, generally requires that throughout the eaperimenl the animals be either aneslhetited or imrnobi/ized with a neuromuicv.lar blocking agent. This paper, however, describes a method for the colkclion of acelyl- choline umpks /rom the cerebral corlex of freely-movinR rats with chronically implanted bilateral cortical cupa. Tht transparent nylon cups remain usable for at least two months after implaMation and will hold enough l.ocl:e's solulion for the acetylcholine released in a 1S-minule period so be anal-r:ed by the kech muscle bioassay. The fact IhN the release of acelykholine increased after nicotine administration (04 mg/kj i.p.) illustrales Ihaf in rats 1he method is suilaAk for determining drug -induced alleralions in neurolransmiller release during on-going behavior. In addilion, when i1 is combined wah appropriate chemical or broassay rnelhods, the technique is potentially u.eful lor collecting other putative neurottansmil/en released frorw the cortea of the rat. Erirkrow, C. K.. Graham, D. T. and U'prkhard, T. PA.rmaroloty, RiocAembtry and eeAav/or 1:743-746. 1973. Oth.r .u pport : National Imlitule of Menlal Ilealth. From she lyeparlmenl of Pharmacology and Toaic.olop. University of Kansas School of Pharmacy, Lawrence. STRt1CTURF. n('TIVITY RF1 AIIONSHIPS FOR TIIE RISI?RPINfi I IKF A(-IIONS OF DF.RIVAIIVI-S OF J3-CARBOI.INI? IN VITRO Although the eaperimenla reported here were undertaken to determine whether phyaico<hemieal /aetors play a aignifkant role in the activity of P- carboline derivalives, the resullanl dala suggest instead that it is Ihe slructural specifkily of the site of action that de/erminea she derivative i activity. In this sludy, the abilities of 10 derivativea of ISsarboline to competitively inhibit the ATP-Mg/ +-slimulaled uptake of epinephrine were eaamined in isolated rat adrenal medullary slotage vesicks. Uptake was inhibited 72% by harmine, 64% by harmaline. 59% by 2-melhylharmine, 43% by harmnl and 25% by harman. Norharman, 6-melhoayharman, 6-methoayindok, b-melhoayleua- hydroharman and yobimbine did not inhibit epinephrine uplake, nor did any of the 10 derivatives aflect metaraminol uptake. lhe potencies of epinephrine up lake inhibiton were unrelated so the lipid solubdily or pK o/ she dtu6s, sn6- gestins that differences in activity reflected differences in affinity for the cale- cholamine tran.pnrl site. Ilarmol, 2-methylharmine and harmahne were them- selves incorpnrated into the vesicks, but their incorporation was less dependent on Iemperalurc than that of epinephrrne or melaramimd 'Ibese dala suggest that (1 carlwHne derrvalrves inleracl with a calcahulamote carrier on she out- nde surface al the vesicle membrane and that the attachment involves at kast I three portions of the mokcuk. The different atruature-actuvity relationshipr fot inhibition of epinephrine uptake versus uptake of the P carboline deriva- tives themselves indicate that two separate prncesus, inward Iranspurt and subsequent inlravesicular binding, contribute lo the measured uptake. SfotR/n, T. A. LlJeSciencei 1S(l):4)9-454, 1974- OtAer aup portr American Neart Association and Faculty Ikvelopmenl Award in Pharmacolop from the Pharmaceutical Manufacturers Association Foundation. From the Department of Physiology and Pharmacobgy, Duke University Medi- cal Center, Durham, N. C. DRUG-RP-SISTANT Ei=FECT OF ADENINE NUCI.F.O7IDES AND MAGNESIUM ON CATECHOLAMINE EFFI UX FROM ISOLATED ADRENAL MEDUt.LARY S7ORAGE VESICLES Adenine nuckotidea and divako/ calions have vital roks in she uplake, storage and release of catecholamines fro,m adrenal medullary vesicks. Tha incorporation of amines into isolated vesickts is stimulated by ATP and s.y- nesium (Mjt +), which have also beew implicaled in the mechanism of cau- cholamine secretion. Reserpine inhibits incorporalion of amines. '11The lalra- vpicular atorage cornpka probably consists of four molecules of catechola- minef combined with one molecuk of ATP. A question which she aulhors are attempting to answer in their series of taperirnents on isolated rat adrenal storage vesicks is whether ATP and Mgt 4 directly aRec1 the rate at which amines kak outward across she vesick membrane. lheir data support previous observations that adenine nuekolides, divaknl ealions, and teserpine decrease the binding of ealecholaminn 1o purilled adrenal storage vesicle membranes. Results also suggest that: (1) efliu: of ealeeholamines from /he vesicks is not a simple diffusion prooeu but may requirt the interaction of she amine wilh a specifk component of the vesick membrane: and (2) the reduction in amine eQlua produced by the addition of ATP and Mgt t may result from i.lerfer- ence wilh this interaction. According to the authors. these studies denamtrate that ATP and MgF• reduce amine etliu, by a mechanism independent of ils uptake inlo the vesicles and not blocked by drugs which inhibit upake. • lhir effect may play a rok in the stability of calecholamine storage. SlorAfn. T. A. and Green, 11. O. ' Biochemical Plwmorolory 2):2190 2192, 1974. Other auppo rt: U. S. Public Ilealth Service. American Ifears Anocialioa and North Carolina Ilearl Association. From the /kpartment of Physiutngy and Pharmacrdogy, 1)uke University Medical Cenler, l)urham, N. C. 50 51

RF.SERPINE-I.IKF FFFFCTS OF HARMINE ON ISOI.ATED AI)RIiNAL MEDUI.LARY VFSICI FS Because of i1s structural similarities to reserpine, the actions c.f harmine on adrenal medullary vesicks were esamined in order to clarify the rrechanisms involved in dr.rg cflects on amine uptake and storage. llarmine m:,rkedly in- hibiteJ the ATP-Mtr #-dependenl incorporalion of epinephrine in:o isolated rat adrenal medullary vesicks. Tlse inhibition (SS% of epinephrine incrap.ira- tion) was both competitive and reversible. In contrast to this- meuraminol in- corporation, which is predominantly AT*-Mgf + -independent and reserpine- insensilive, was decreased only 23%. Hannine had no effect on elllur of epine- phrine from adrenal medullary vesicles, Indicating that the effect on incorpora- liorr was due solely to inhibition of mplakt. No lemperature-depenJcnl rrp/ake of harmine Into the veslcks was dtlected, implying that the eRecls cvr the up- take system are purely inhibitory. Tlris report also describes the effects of harmine on the binding of amiwtes so vesicle memManes and its rffects on several ot the enzymn involved Isr epinephrine- biosynlhesis and degradation. The data suuesl that the P eaeboline group of the harmine and reserfoine struc- lure is responsible for the afllnity, witis the amine uptake mechanisri and for inhibition of uptake, while the rensainder of the reserpine mokcuue confers irrevenibility- A mobile carrier its ths adrenal vesicle membrane may be the aite o( action. Oree., H. O. and Sfor4fn. T. A. Molecutar Pharmacology 9(6) :71t-733, 197). Other aupport: Norsh Carolina Heart Association. From the Department of Physiology and Pharmacoloty, Duke Univenity Medi- cal Center. Durham. N. C. V1. Immunology and Adapfiue Meclrani.ms STIMULATION OF IIEME OXYGENASE IN MACROPHAGf-.S AND LIVeR BY ENDOTOXIN According to the evidence presented here, endotosin stimulates heme osygenase (IIO) in macrophages in vlrro and in liver in vlro. The activity of this microsornal enzyme system- which converts heme to hilirubin IX- is nor- mally stimulated by heme awd hcmoproteins, presumably reflecting substrate- mediated enzyme induction Tlre stimulation of 110 by endotosin. however, ap- pears to involve a rnechanism which may differ from this type of inductnrn. In rat periloneal macrophages engaged In erythrophatocytosis In vitro. em/oto.in atimulated 110 activily-which was additive to the substrate-mediateJ enzyme induction produced by the iniested erylhroeyte hemoglobin. Fndotosrn did sot appear to injure the erythrocytes; nor did it enhance the rate of erythro- phaLocytosis. In intact rNS, endolnsin treatment increased HO activity in both parenchymal and sinusoidal cells of the liver. 11 is likely that endotosin stinw- Fates 110 activity duectly, which may account for the reported rise in bilrrubin s formation in endoloain 1rcalcJ animals. lhl% eflcct nn 110 may repretient part of the general activation of phagocytic cells by endotusin Gemsa, D, Woo, C. H., Frden6erR. H. N. and SchmiJ- R. Thrlorrrndo/ClinitaJIwesrixarion S)(2):617-651, 1974. Other support: National Institutes of Health and the Walter C. Pew Fund for Gastrointestinal Research. From the fkpartmeol of Medicine. Univer-tity of California School of Medi- cine, San Francisco. BIOCHEMISfRY AND BIOUX:Y OF COMPONENTS OF THE PLASMA KIiVIN-FORMINO SYSffM The author de6nes the inleractions among various components of the plasma kinin-forminR syalem, with particular emphasis on the molecular char- acteristics of kallikrein ond Factor XI of the blood clotting system He de- scribes a human prekal(ikreir deficiency previously known as the "Fktcher factor" coagulation abnormality. In the absence of prekallikrein, neither the intrinsic clotting nnr the bbrinolytic syslern is adequately activated when plasma is esposed to glass. This observation. crxspkd with other lahoratory dala show- ing that tallikrein activates Ilageman factor, prompts the aulhor to propose that this enzyme maintains optimal rates of coagulation and flbrinolysis thtoujh its reciprocal activation of Hateman factor. Wuepper. K. 1). (Cocilrane, C. G.) In: I epow. I I1. and Ward. P. A. (eds.): /n/faaunation: AfecAanlr.nr and Connol, New York: Academic Press. 1972, pp. 9l-(17. Other aupport: National Multiple Sclerosis Society and U. S. Public Ilealth Service. From the Department of Fsperanental Pathology. Scripps Clinic and Research Foundation. La lolla, Cal. T11E STRUCTURAI. CHARACTF.RISTICS AND ACTIVATION OF IIA(:EMAN FACTOR The structural characteristics of /lateman (actor, the parent component of the inltirnre clotting- kinin forming, and flhrrnolytic systems, have been characteriteJ. the whstance hat a muleetdar weight of t10.U0(I and M is acli- valed in bolh solid and fluid phasn. In the soliJ phase the nokcular conQau- ration changes- e.posing enzymatic silcs. In the fluid phase, on the other hand, enzymatic activation induces molecular cleavage yielding enzymatically active fragments. Plasma enrymes capable of activating Hateman factor in the fluiJ phase include kallskrein. ('ac1o. X1, and plasmin Fach of theae is part of a system activated by the parent mo/ecuk. Ihus. Iherc is a reciprocal activation of Hateman faclor by ita suhstrales. On a molar basis kallikrem p++scssea the greatest activity in this regard. Solid alale activators include vascular basement 52 Sl

membrane, collagen, and bacterial lipopolysaccharide. Immune aggregates are inactive. CocAranr. C. G. irr at. In: Iepow, /. H. and Ward. P. A. (eds.): In/lammarion: Mrclraniirns and Control. New York: Academic Press, 1972, pp. 119-1)R. OtAer support: National Multiple Sclerosis Society and U. S. Public Heallh Service. From the Department of Eaperimenlal Pathology, Scripps Clinic and Research Foundalion, /.a lolla, Cal. ACTIVATION OF HAaEMAN FACTOR IN SOI.ID AND FL111D PIIASES llareman factor can be activated in both the solid and the fluid phases. In the solid phase, the activation results (rorn eaposure of Nageman faclor to various insoluble particks having negative charges on their sur`aces, such as Alass, kaolin, and eatracel/ular membranes. The binding of 1'"IIIIaAeman factor to the negatively charged surface was markedly inhibiied by either plasma or purified plasma proteins. In she fluid phase, HaAemi.n (aclor was activated by kallikrein, ptasmin, and Factor XI (plasma thromhoplaslin ante- cedent). The capacity of kallikrcin to activate Hageman factor was more than 10 times that of plasmin and Factor X1. The data oRer a plausih'e caplanation (or the observation tha highly purifkd kalbkrein pronales clotting of normal plasma In additron, the combined rrsults of this and previously reported dNa from this labxualory indicale that the reciprocal activation of Hageman factor by kallikrein in fluid phase is essential for the normal rate of activation of the inlrinsie-clotling, kmm forming, and (ibrinolylic systems. This paper also re- ports changes in the structure of Hageman factor incurred during its acliva- tion in fluid phase by plasma enzymes and in solid phase by insoluble, neta- Iively charged particles in the absence of detectable enzymes. The data form a base (or understanding the mechanisms of Ha`eman factor activation in pathologic conditions. CocArane, C. G.. Revak, S. D. and Wuepper, K. D. The lournal o/ Ez perlmental Medicine 1 l1(6) :1561-1 Slll, 1977. Othrr support: U. S. Public Health Service and the American Ileart Asso- ciation. From the Department of E.perimental Pathology, Scripps Clinic and Research Foundalion, t.a lolla, Cal. A SIMPLF. MF.Tf1OD FOR IIQUID SCINTII.LATION COUNIIN(7 01: 'r'IOf)INF. AND a'CIIROM111M USED IN AN1IGFN BINt)IN(I AND ('Y IOfOX1('l1 Y Sl llr)I1?S In iMs trl.•of thr .ntht-rt ton-paic .unvrwwn.l gantma %(r•.UOmelry .1..1 1..p...1 ., o.~.n.~..•u .......~.nt mroh.rlr u%8nt g.mu1. r'nu1Un` cun t4 i ployed in studies of antigen-antibody interactions and cell-nsedialed immunily. Resul(s indicate that "-$Iodine and a'Chromwm can be counled wNh equal, it nM Rreater, efliciency by a lirauid scintillation detector than with a convrntion- d gamma speclromeler. The melhod described here is rapid. ineapensrve, and sensitive. Moreover, it has wide application in research and clinical laboratoric.. Herzcowltt. H. e. and McKdlip, T. W. lorrnal of Immunobsical MetAodi,:237-262, 1974. Other asrpport: Research Corporation and Washington Hear1 Association. From the Department of Microbiology. Cxortelown University. Schools of Medicine and [knlislry, WashinRton, D. C., and Becknun Instruments, Inc. Sdver Spring. Md. PROPERTIES OF AN ONCORNAVIRUS OLYCOPROTEIN: EVIDENCE FOR ITS PRESENCE ON THE SURFACE OF VIRIONS AND INFECTED CELLS - Surface neoantivens which appear in the cell as a result of infectiow with oncogenic virus are important (or several reasons: (1) their location makn lhem potential targets for the bosl's immune defenses; (2) they may serve m marken for an oncol,enic viral genonse whether or not i( is compktely es- pressed; and (3) they may be responsible for changes in membrane properties which lead to the aNered behavior of Iransfo.med cells. In order to fully u.• denlmrd (he role of neoantigens in oncoAenesis, however, these nwsl be iso- laled and their mokcular aa/ure determined. This report describes the isolatias and siome of the physical properties of an antigen present on the surface of a continuously growing eulture of lymphocyles (SCRF 60,) from a New Zea- land Black (NZB) mouse. As previously shown, these cells are persistently iu- fected with an oncogenic C type virus, the Scripps leukemia virw (SLV). 1hc isolated antigen is a glyeoprotein with an apparent mokcular weight of about 70.0m dallons, which accounts for ahou( 0.1% of the total cellular amxso acids and about 10% of the cellular glucosamine. Studies on the SLV produced by SCRF 60, showed that a glyeoprotein of identical radioactive labeling prop- erties and ekeclrophorelic mobility is present on the virisn surface. cons/ilut- in` about 10% of the amino acids and about 50% of the glucosamine. This protein reacts with sera which neutralize Motaney, Kirslen, Rauscher, AKR, and, of course. Scripps viruses. 7hese data suggest that this is the antigen de- lected when murine leukemia cells are studied by Inlmunolluafescenu and that it may be involved in virus neutralization. Kerurcl. S. 1., Del Villano, B. C.. le.ry, R. L. and [.erner. R A. Virology SS(2):461-175, 1973. Otber aupport: National Science Foundation. National FuundatwM Much of IKnses, and National Institutes of Ilealth From the I)eparlmcnt of Faperimental Pathology. Scnpps Clinic and Research Foundation. I.a lolla, ('al SS I

7 i t APPROACHES TO THE QUANTITATION ANt) ISM.ATION OF IMMUN(XiLOBULINS ASS(K'IATED WITH PI.ASMA MtiMItRANFS Gene espression can be altered by events at cell surfaces throush a yet unknown mechanism. In the immune system, however, a sintk molecular spe- cies, the immunoten, clearly induces cellular proliferation in a limited mrmber of reactive celH Recent studies, furtherseore, suggest that it is the union of immunaten with memhrant-associated immumotluhulins which iniliales cellu- lar proliferation and drAerentialion. Investigation of the nature and amount of memhrane-associated immunottlobulins, therefore, seems 1o be a step toward undcrslanding the immune process and specifically the phenomenon of ahered gene espression. In this paper, two genera/ approaches to she quantitation and iso/ation of immuno6lahuluss naoeialed with plasma snemhranes are described in detad: (1) a modifkatiow of the antigen-binding capacity test for quanli- la/ing memlaane-associaled insmu"lobulin and total imrnunogloMrlin in va- rious drploid human lymphocytes - a technique reported sensitive enough to detect as little as ng of immunoglobulin protein on the surface of 10' lympho- cyles; (2) the use of immunologic reagents and radioactive labeling, preferably along with immuno-adsorhent columea, as the most efficient method availabk for the isolation of inembrane-associated immunoglobulins. Theoretically, the (a11er lechnique can provide an immu"lobulin sufficiently pure for charac- leriring its molecular weight, physical shape and structure, and even for ae- quence analysis Actual sequencing of inembrane-associated iminunuslobulin, however, awaits more sensilive detection techniques or  vigorous cell culture program. Kennel. S. 1., Del Villano, B C. and Lrrner, R. A. Marhodf ln Moferular Diofogy 6:1-ltr, 1973. Other support: National Scieoce Foundation, and National Foundation- March of Dimes. From the Deparlmenl of Esperimenld Patholop, Scripps Clinic and Research Foundatioe, La lolla, Cal. PERIOnATf?-INDUCED LYMPHOCYTE TRANSFORMATICN. 111. EFFECtS OF TEMPERATURE AND pH This paper presents data derived from esperimenls e.ploring the eAects of varying pit and temperature on sodium periodate (NalO.) -indnced lympho- cyte transformation. Results show that the optimum conditions for NalO.-in- duced lymphocyte transformation occur at low concenlralions of Nal()., low lemperaturt, pit between 6 and 7.5, and with short periods of e.prnure to NalO.. Etposuwes for prolonged tnnn at elevated temperatures or to NalOr at pit above 7 S result in diminished responses lhe finding of maairnum lympho- cyle re.punst un.kr these conditions is compat.fdt with Ihe prrqwxal shal the (rruenng evcnt in Na1(1. sransforn.atwn of lymphncyles is the o.wlation and tk.vagc of rhe Lu terminal carbon atoms uf ualre acid l:.prnure of 56 I lymphocytes to NaIO4 under conditions of higher lempcralutc, higher pit or lon6er esposure times does not si6nificantly reduce their ahilily to respond to phytohemasglutinin or pokeweed mitosen. 7 hn finding suggests thal tirese milo6ens have different target sites from that of Nal().. or that they are acting on different populuioos of lymphocytes. Pa.4er, 1. W. et al. EiDerinenrd Ceff Research E):220-221, 1974. Other support: Wright FsIa1e, Mellon Charitable Trusts and the Harsfnrd Foundation. From the Department of Palholop. University of Southern California School of Medicine. Loa Angeles. PERIODATE-INDUCED LYMPHOCYTE TRANSFORMATION: IV. MITOOENIC EFFECTS OF NaIO. TREATFI) LYMPHOCYTES UPON AUTOLOOOUS LYMPHOCYTES Lymphocyles Inactivated with mNomycin C. CoM, or ultraviolet irradialion and treated wish sodium periodate (NalO.) are capable of transforming aulo btou+ lymlhmytes /w virro. In conlrasl, autologous NaIO.-trtatcd erylMo cytes do not have the capacity lo induce lransformation of autobgous lympho- cytes. In a one-way autobttous mised lymphocyte culture (A-MLC), utilisiag previously inactivated NalOrlreated lymphocyles as stimulator cells (Ls) surd untrtated autologous lymphocytes as responder cells (Lr). masimum trfliaed lhymidine uptake (sH-TdR) - an assay of the lransformation responaa - occun three days after the inilialion of the miaed culture. Maximum aH-TdR incorporation is usually achieved in cultures in which the i.s/Lr ratio is 1:2 or 1:4. As with the direct NalO. transformation of lymphocytes, the A-MLC response can be blocked by sodium borohydride (Na811.), suggesting the pns- ence of a surface aldchyde. Overosidation of 1he cells by NaIOs also di.in- ishcs their abilily to induce an A-MLC response. The authors conclude that in the absence of any detecuble mitogenic factor found in the medium, this transformation response may well be due to recognition of surface alteralions produced by 104 osidalion. They suggest 1ha1 although the mechannms under- lying Ihis reaction arc obscure. Ihis model may be important for elucidating the early evenls in Ihe Irittering of lymphocyles. O'Brien. R. 1.., P..Rr..1. W., Pr~nldli. P and Steiner, a. The loa.nd o/ Immunology 1/2( s ): IuR,-1190. 1974 Otber support: Ilartford Foundation. Wright Estate. Mellon Charitable Tnnls, and the Profcssional Staff Assoeialion of Ihe I os Angeles ('ounly-Um- versily of Southern ('difornia Medical ('enler. From the Ikparlment of Palholop. University of Southern ('aBfornia School of Medicine. los Angeles. • 57

V11. F.pidenaiotoRy CIGARETTE SMOKING AND SERUM CIIEMISTRY TES7S Based on dat from the Kaiser-Pennanenle Mulliphasic Fsaminalions, a series of studies has been compiled on the characteristics of smokers and non- smokers. lhis latest paper focuses altenlion on data concerning the serum con- centratwns ol eight suhstances - albtrnin, gbbulin, glucose, uric acid, cho- kcterol, creatinine, calcium and glutamic oi.loacetic Iransaminase (SGOT) - in over 65,00(1 men and womew. The purpose of this study was to determine whnher or not these various serum levels differed in cigarette smokers and nonsmokers. Where differences were indeed found, the authors analyzed the (1) persistence of the drflerences a/ter stratifkalion of the suhjects by variables considered to be potentially mediating (actor., and (2) relation of the diRer- ences to amount smoked On the average, creatininc and albumin levels were lower in the smokers of both aeaes, while the opposite was true for 1-hour post challenge serum glucose. Globulin levels were consistently lower in the women smoken only. Uric acid concentrations were lower in the men who smoked Cholesterol levels were higher ia the white men who smoked but not in the black mak smokers Calcium and SGOT levels of smokers were quite similar to Ihose of nonsmoken. Alcohol consumption played a role in smoker- nonsmoker ddlerences in serum Rlucose concentration. Nowever, for the other tests no additional factors were identified that could ecplain Ihe relatKrnships to cigarette smoking Thus. Ihey may he either directly affected by smoking or related to undefined unJerlyrnR differences between smokers and nonsmokers. Dak., 1.. O, Friedman. G D„ Siegelaub, A. B, and Sellzer, C. C. lorrnol o/CA.onic Ditrarrs 27(6):293J07, 1974. Other support: National Center for Health Services Research and [)evelop- meet and the Kaiser Foundation Research Institute. From the Departmenl of Medical Methods Research, Permaneole Medical Group. Oakland, Cal. RACIAL DIFFERFNCFS IN SERUM AND URINE GLUCOSE AFTER GLUCOSE C/IALLENGE In the course of a study of the characterislics of smokers and nonsmoken, rather striking racial differences were noted in serum and urine glucose values after glucose challenge. Data tabulated for RR,0(11) white, 12.(410 Mack and 4,)00 oriental members of the Northern California Kaiser Ilealth 1'tan showed several trends. Finl, serum glucose levels measured one hour after ingestion of 75 gm of glucose were markedly lower in the black group than in the white and oriental groups. Also, glycosuria at one hour was less common in the blacks than in the whites, but it was distinctly more common amon6 the (hi- enlah Racial dillerences in ate, height, weight, triceps akin/o1J 1hKkness, com- p/cfencss ot tlu.nse rnReslwn, time elapsed srnce last eahnll, umw. .-1 Jy whcn the tesl was prr/ornxJ, thrarirk usate, educational kvcl, and crRrrclre smoking hisiory did not capl.in thc.c findings I Dales, 1.. G., Sietelaub, A. B.. Feldman, R., Friedman. G. D., Seltzer, C. C. nJ Colkn, M. F. Diabetes 23(4):327-332, 1974. Other support: National Center !ot Health Services Research and Devcbp- ment and the Kaiser Foundation Research Institute. From the Department of Medical Methods Rescarch, Permanente Medical Group, Oakland, C.1. SMOKING AND DRUG CONSUMPTION IN WIIITE, BLACK, AND OR11?NTAL MEN AND WOMEN As shown in a survey of 70.2R9 white. black and oriental men and women undergoing a Kaiser-Permanente Multiphasic Health Checkup (MIIC), dg- arette smokers use more medicinal drugs than their nonsmoking counlerparts Thus, among hlacks, whiles and, to a lesser eatent. Orienlals, more cipreue smokers than nommo2en report taking cough medicine, analgesics ranging from aspirin to prescription drup, sedatives, hypnotics, and lranquiliaers. They also take more cardiovascular, anlicoa`ulam and diuretic drugs, hornwnes, oral contraceptives, metabolic and hematinic drugs, amphetamines, reducing pills, antibiolics, sulfas, and gastrointestinal drugs. The only preparations taken by a larger percentage of nonsmokers were those for alkrgic conditions, anlihisla- mines and aslhma medication. Aho, there appear to he numerous racid and seaual diflerences in the frequency of drug use. Possible reasons for the difler- ences between nonsmokers and smokers with respect Io the use of such a large variety of drugs are eaamined. Sellzer, C. C., Frlrbnan, G. D. and Siegelaub, A. B. Awterkan loarrnd o/ Public NrdrA 64(3) :466-47), 1974. Other arp rt: National Center for Health Services Research and Develop nmenl, Ihe Kaiser Foundation Research Inslitute, and the Fund for Research and Teaching. Dep.rtment of Nutrition, Harvard School of Public Health. From the Department of Medical Methods Rescarch, Permanente Medical Group. Oakland, Cal., and the Department of Nutrition, Narvard School of Public Neallh, Boston. DIFFFRFNCES IN PULMONARY FUNC(ION RFI.ATFD TO SMOKING HABITS AND RACE This study represents an attempt to evalusie differential effects o( smok ing habits on pulmonary function sa measured by spirometry in white. black. akd oriental suhjecis. For this purpose. three nxastues of prdmonary /unctM'n namely, forced vital capacity (FVC-). forced eapiratory volome in nne scconat (FEVr), and peak eapiralory Msw (PFF), were sualied in a racially mucd populalion of 61.0116 snwrkers and nonsmoken, aged 20 Io 79, who had had .r SR ' 59

kasl one Kaiser Permanenie Multiphasic Heallh Checkup bclwcen 1964 and 19611 the e.pccted relatronshrps with age and sea were noted for rach of the racial groups When the same age- ses, and smoking categories were compared, whites showed markedly higher mean pulmonary function vahres than blacks and Orienuls The FVC, hFVr, and PEF al) reflected important racial distinc- Iions between smoken and nonsmokers. Among whiles of both sesei, the mean pulnw.nary function values were higher in nonsmokers Ihan in cigarette smokers in virtually every age group. No such differences between smokern nd non- smokers were noted among blacks nd Orienuls. This could not he esplained by the analysis of data relative lo dro amourd of smoking or its dun lion, or 1o inhalation o/ ci2areue smoke. Morcover, there was no readily afparent es- planation for a lack of signiflcanl diRerrnces in mean pulmonary function valuea between smokers who inhale and those who do not. Seltrer, C. C.. Siegelaub, A. ta., Frltdrn.., G. D. and ('olten, M. F. Amrrksn Rtrltw of Resoirato.y Dbt.re 110( S):391i 6(1R, 1974. Other st,' port: National Center for Ilealth Services Research and Ikvelop- tnent, and Kaiser Foundation Research Institute. From the Department of Medical Methods Research, Permanente Medical Oroup, Oatlaod, C.I. CIGARETTES, AI ('OHOI., COFFEE ANt) P@P'TIC lIl-CF.R to this epidemioloRic study. Kai,er Permanenle Mulliphasic Fsaminalion data werd used to scrutinize the relationship of cigarette smokine, alcohol and coffee consumpion, and education to a history of peptic ulcer. lAe study pop- ulation included 76,656 white male and female subjects. 30 to 39 vears of age. In men the prevalence of peplic-uker history among cigarette smokers was 2.1 limes that in nonsmokers; for women the prevalence was 1.6 limes grealer in cigarette smokers. Duration of srnoking, quantity smoked, and in- halation were all relaled to a history of peptic ulcer. In both seses, duration of smoting was the most strongly related measuremenl. Although akuhol and coRee consumption were correlated with cigarette smoking and the two bev- erages reportedly stimulate gastric acid secretion. Ihey were not positively re- lated to prevalence of peptic uker; these correlations did not esplain the rela- tion of cigarette amoking to peptic uker, nor did educational atlainmenl or body build. Frirdrnan. G. n, Siegelaub. A B. and Seltur, C. C. The New Enttand lournof of MedlcJnt 290(9):469-473, 1974. Other support: National Center for Heakh Servicn Research and 1)evekp- menl and the Kaiser Foundation Research Institute. From the Ikpartment of Medical Methods Research, Kaiser Prrmancme Medical ('are Pn.grarn, O.kland, Cal , and the Department of Nutntnrn, ilu- vard SchMKd uf Puhlrc lle.llh, Hoslun I A/.('OliOl- ('ONSUMPIION BEFORE MIIO('ARI)IA1. IN1=AR('7ION: RhSUL1S FROM THE KAIShR-PI'.RMANENIE EI'll)GMIOI.IX]1('AL SfUt)Y OF MYOCARDIAL INFARCTION In a search for new prediclon or risk taclors for myocardial infarctioa. the authors studied 464 patients who had undergone a mrdtiphasic health checkup from 1964 10 1970 and who subsequently sustained a first myocardial infarction. The many variables recorded during these checkups included akohol consumption and the standard coronary risk factors: cigarette smoking, ekc- Irocardiotraphic abnormality, systolic bkrod pressure, diastolic blood pressure, cholesterol level, glucose kvel, and triceps skinfold. For comparison purposes, each patient was matched with an ordinary (age-sea-race-malchedi control and with a control also matched for risk factors. Results showed a statistically significant negative association between akohol consumption and a subse- queM firu myocardial infarclinn. There was a larger proportion of tectoukn among those who had a myocardia) in/arclion (P<0.t101). as well as a smaller propuxtion of moderate (two or kss drinks per day) and heavy (three or mwc drinka per day ), consumers of alcoholic beverages. Alcohol consumption and cigarette srnoking were strongly correlated habNS. The lower consumption of alcohol by the patients studied apparently was not the result of reduced intake because of known heart disease or risk-(aclor-relaled diwases such as hyper- tension and diabetes mellitus. Possible esplanations include indirect associa- lion of drinkint habita with ethnic orisar, psychological Irails and o/her un- known risk factors for myocardial infarction, or a protective effect of akobol. Klatsky, A. I-., Frledaraw, C. D. and Siegelaub, A. B. Annali o/ Inrrrnd Mrdkinr ! 1( 3); 294-301, 1974. Other support: National Inslilutes of Hcalth, the National Center for Nealth Services Research and Ikvelopment, and the Kaiser Foundation Research In- stitute. From the Department of Medicine. Kaiser-Permanenle Medical Center. and the I)eparlmenl of Medical Methods Research, Kaiser-Permanente Medical Care Program, Oakland, Cal. SMOKING HABITS AND PAIN TOLERANCE An analysis of data obtained from 66,410 subjects in the Kaiser-Perma- nenle Multiphasic Screening program indicates Ihat, in comparison with aon- srnoken, deep pain tolerance as evidenced by the Achilles tendon preasure less is significantly diminished in white male and female cigarette smuken Thia is not observcd either In black nlaks or in oriental suhjecu, but there is a strong suggestion of somewhN diminished pain response among Mack lemak smokers when compared to the same group of nonsrrwskers. T)rere are no clear eaplanations for any of these results at this time In the authurs' opinion. al- thouth the effect of smoking on pain perception needs attention. serious con- sideration must be given to the ponsihk role of carnsluulw+nal ddlerenccs be- tween smokers and nonsnwrkers. the authors add that a/ternalive hypotheses Involving Ihe role of prychosoc:ial and cultural in/lueocet as well as response lwas of differential smoking groups mmt also be esannncd 60 61

Seltzer, C. C., Fried.nan. G. D.. Sietelaub, A. B and Colkn, M. F. Archive: o/ Envlronmrnad Health 29(3):170-172, 1974. Other support: National Center for Hedth Services Research and Develop_ ment, and the Kaiser Foundation Research Institute. From the Department of Medical Methods Research, Permanente Medical (inwp, Oakland, Cal , and the Depanmeol of Nutrition, Ilarvard School of Public Health, Boston. IIF.ARING I.OS.S IN ADULTS: RELATION TO AGE, SEX. EXPOSURE TO LOUD NOISE. AND CIGARETTE SMOKING In a study of the characteristics of smoken and nonsmokers, ,lse authors examined the n><litory sensitivity of 33.146 while men and women 30 to 59 years of age. lben, to the variables of age, /cx and cigarette smokrng, noise eaposure was adJed in an attempt to a»ess the possrbre contributKw of each of these factors to hearing loss. Results showed that significant hearing loss (40 decrbeh or more at 4,000 hertz) was more frequent in men than in women, increased wiih age, was greater in those reporting exposurc to loud noase, and slightly greater rn male cigarette smokers than in male ronsmokers. On the hasis of these data, the authors feel that cipre,te smoking rnay hear some relatan to hearing loss in men, but that this rclationship is small when the other pertinent facton of age, sex and ooise exposure arc taken into ac- count Sie`elaub. A 8, Friedman. (T (). Adour, K and Selrrer, (' (' Archivrs of Fnvoonrnenral Neohh 2942) 107 109, 1974 nther urporl: National ('enter lur Itralth Servrces Research and (kvelop- ment and t Karur Foundation Research Institute From the Department of Medical Methods Research, Kaiser-Permancnte Medi- cal Care Program and the Department of (Holarynsototy, Kaiser Foundation Ilospital, Oakland, Cal., and the Department of Nutrilion, Narvard School of Public Nealtb, Boston. CIGARETTE SMOKING AND LONGEVITY IN TF1E FLDNR(.Y Although several medical authorities affirm that cessation of smoking im- proves life expectancy and that reducing a suspected risk factor aBects sub- sequent mortahty. the authrx'a previous eaamination of data for populations unrkr 61 led him to question whether these alleged effects are consistenl. Moreover, regardless of the evidence supporting these asserlions in younger pofWlatMln, data on British doctors aged 65-84 contradict these views. For this guwp, the available evidence showa no beneficial cllecl on longevity during the 12 year period studred lbe trends in death rates among the older British doctors did nmN para/kI the falling trend In cigarette smoking over the same Imre periods A partncularly inlnpring inconsistency was the declrne in death r.res lor luull un.cr in the period 19%3-57 to 1957 61 followed by an increase I from 1957-61 to 1961-65. The author concludes that cessatwn of cigarette smoking among elderly British doctors did not affect suhsequenl mortality. In this group, regardless of the tok that cigarette smoking may play in affecting longevity at younger ates. the reduction of cigarette smoking did not appear lo prolong longevity after age 65 had been attained. sertzer, C. C. Medfraf Coun/erpoinr 6( 2):29-33, 1974. Other support: Fund for Research and Teaching of the Department of Nu- trition. Harvard School of Public Nealth, Boston. From th- Department of Nutrition. Harvard School of Public Ilealth, Boston. SMOKIN(i, WIi1(i/1T ('l1ANGE, AND AGE: A IANGITUDINAI. ANALYSIS I( I stop smoking, will I gain weiRht, or does my age determine my weight level? To answer these queslions, 870 healthy, adult male veterans, aged 20 to 69 yean, who arc enrolled in ahe Boston area Normative Aging Study were examined during a five-year period. This slalistical study showed that In Ren- eral, regardkss of age cohort. a greater number of ex-ciRarette smokers gained weighl, more weight than did other men. Most particularly, ex-cipreue snwk- ers between the ages of 40 and 54 showed a subslanlial weight gain when, ac- cording to National Ncallh Survey stalislics, men in that qe span normally gain little weight. Ilowever, while both chronological age and cessation of cigarette smokine were si6nificantly related to weight chan6e, together they accounted for only 7,5% of the variance in weight chan`e, sug6eslinR the importance of other factors in explaining Ihe weight change over a five-year period. Garvey. A. 1., BwsE, R. and Seltzer, C. C. (Bed, B. and Rore, C. L.) Arclilves of Env(ronrnental Hedth 2s(6) :327-)29, 1974. From the Vetcrans Administration Outpatient Clinic. Boston. AGE AND INTERPERSONAL FACTORS IN SMOKING CESSATION Two independent variabks, age and an interpersonal faclor, are examined for their relative importance tcs smoking «ssatwsn- the dependent varrabk. The interpersonal factor, defined hecF as mMivation provaled by interaction with emotionally significant others (lamily, friends, acquaintances), was invoduced as an index of aReclivily. An earlier review of Ihe lueralure suggested that affective interpersonal factors play an important role in starting the smoking habit among young people. The authors. therefore, developed the hypothesis that afleclivily as measured by the interpersonal (actor and age would also have an in.kpendenl and a combined effect on smoking cessation due to age- related changes in affective orienlation. Analysis of a national probability sample tends to support this hypothesis. 62 63

BossE, R. and RoJe. C. L. lournal o/ Heolth ,ir Social Behuvior 11(1) : Ni1-1e7, 1973. Othcr support: National Clearinghouse for Smoking aod Health, ll. S. Pub- frc lleahh Service. From Iletlenic College. Brookline, Maa., and the Veterans Adminiwalion Oul- palient Clinic, Boston. FFFF.CTS OF AGE UPON RETRIEVAL FROM PRIMARY ANI) SECONI)ARY MEMORY There is a demonstraled karning-memory deficit that is associated with advanced aAe, and It has been proposed that retrieval processes accounl, at least in patl, for this age-telaled deBcil. To leu /his e.perirncnlally, the retrieval processes of young (R = 21 years) and old ;R = 36 years) subjects were compared in both primary and secondary memories. Suht:cts of both age groups conducted serial and eshauslive retrieval searches in primary memory. The speed of the young subjects' searches was about twice as fast as thoae of old aub%ecls. Similarly, all of the subjects eonducted serial and eshaustive searches in secondary memory. A8 searches of secondary memory were slower. Young subjecls, however, maintained their speed ad•.an1a`e over old subjects. These results demonsuating the old persons* slower retrieval searches in secondary memory, in combination with those in primary memory, es/end the scope of the original proposal that retrieval processes account, at least in part, for Ihe learning memory deficit of individuals of advanced ate. Anders, T. R. and Fozard,l 1. (eell, 8 and Rorr, C. L.) Developrncntd Psychology 9( )) :111-113, 1973. Othrr a.rpport: U. S. Department of Health. Education and Welfare and ('anadian [kpartment of National Healttt and Welfare. From the Department of Psychololy, Dalhousie University. Halifas, ('anada, and the Veterans Administration Outpatient Clinic, Boston. FFFF(TS OF A(31: ANI) SIlMl/1.US REPElIT1ON ON 7 WO ('/1O1CE REA('T ION l IME In this study, mak volunteers, ranging in age from the 2/1's rhrouAh the 70's, performed a twochoice reacUon-time task. lhe subjects rclcased one key with the right hand upon presentation of a red light and anuthcr with the left hand when a green light was presenled. Each sltnsulus occurred an equal number of limes in a sequence of 40 lrials, bul the prohabilily that it wrarld do sn twice on aucces.rnn was only 25 Mean respnn.e lalency ur.rcascd wrth are ,Uh,.uFh •,~ubd.~s 10 n..r 1lonuduv alreiaimiss v.cre Rcncr.Jly rc.tM.uJed I,. +ro. .l „nulur rrl.lilu.n% 11111 `ncg./rve rcicn.y.' c11eC1 0 is consistent with an especlancy theory of choice-reaclion 1ime, since stimuli and resprytses were repeated only. rarely. Older indivrduals responded as rapidly. or even more rapiJly. to aUerations than did younger ones; they were evidently guided to a similar eslent, therelore, by the scqueMial dependencres inherent in the series of signals. Although the older men were individually more variable than younger ones throughout the course of the esperiment. they were more homogenous as a group. An analysis of the frequency dn- Irihvlions of response latencies suggested that the older individual`b longer choice reaction-time reflects impaired psychomotor rather than dccision-making efficiency. Waugh, N. C. et of. ( Bep, B. and Rote, C. L. ) lournd o/ Gerontolory 20(1) :Ibb-170, 1973. OtA.r s.rpporfr Veterans Administration and National Institutes of Hcallh From the [kpartment of Psyehialry Researeh, Massachusetts (ieneral I/ospwd, Boatoo. FACTS AND FICTION ABOUT BEHAVIOR CIIAN(JFS WITII A(1F: IMPLICATIONS FOR T11E CONCEPTS OF OBSOI.ESCENCE AND VffALITY AS APPLIED TO T11F. ENGINEER Section Il of Maintaiwing, Ttrhnicnl Competence in the O1Jcr Engineer deals with behavioral changes associated with aging. The major purpose of this anicle, and of two others in this section, is to provide background infor- mation about behavioral atipe. All three articles stress that chronological age itself is not a sufficient basis for understanding individual diRerences in the behwion labeled technical obsolescence or vitality. lhey also point out that conupts such as obsolescence and vitality have little utility either as descriplive Iabeh or as Auides 1o action when their meanings are restricted to the work role of an individual. In order to understand the meaninA of obsolescence. the totality of the ialeresls, molives and personality of an individual devebpin{ through his middle years mus/ be taken into account. The present artick, moreover, in addition to presentinR a framework for interpreting social and psychological asinA. Ar+es on to make some general recommendations, rclaled to obsokscence and vitality, to Ihe individual engineer and to the organization which employs him. Fozard, l. 1-. ( Bed, S. and Rote. C. l.. ) In: Ihrblin, S S and Shelton. (1. S. (eds ): Alnintainine Technicul Competence in the l)lder EnRineer. Washington. t)C.: American Society for Fnaincennt Education. 1971, pp. 55-71. Other sup porl: Normative Aging Study of the Boston Veterans Administrs lion and Nalional Institutes of 1lcalth. From Harvard Medical School. Ik.stun, and the Veterans Adnunistuuion (lut- patienl ('Imrc, B&»lon. a.4 65

FFFIY'T OF SMt7KIN(: ON BIOOD PRES.SURE Nlrtird pressure changes as related to smoking habits were measured in  Io1al of 849 hcalrhy whne male veterans, aged 25 l0 64, sclectcd Irons the Normative Aging Stody Only those whose systolK- and diastolic pres.ures did not exceed 140 mm 116 and 90 mm Hg respeclively were chosen Irons this on- going prospective study of aging at the Veterans Administration Outpatient ('linic in Boston Body wei`hu, blood pressures and smoking habits were dclermined upon entry inlo the study and again about five years later. Of these men, whose mean age was 45. 794 had cigarette smoking habits which fell into one of the following categories: (1) nonsnwkers, (?) current smok- ers, (1) former smoken, and (4) smokers who quit during the study As noted in most previous studies, current smokers had lower mean bGKxd pressures and body weight upon admission to the study than did nonsmokers and former srnokers The blood pressure trends of quitlen, however, diAered from those of continuing srnnken. Recent quilters displayed significant increases in systolic blood pressures in all calcgories of weight changes, whereas in smokers pres- sure changes were directly related to weight changes Whenever weight in- creased during the surveillance period, quitters also showed greater systolic blood pressure gains than continuing smoken and higher diastolic pressures over the flve-year interval when associated with weight gain; but those who lost substantial amounts of weight showed virtually no change in biood pressure. In continuing smokern, on the other hand, weight bss led to a drop in diastolic pressure, while weight gain did not affect Ihrs measurement significantly. The author suggests that cigarette smoking lends to inhibit elevation of blood pres- sure even in instances of suMtanbal weight 6airn, so that with removal of this effect. as in auntcn, sharp risn in pressure become evidcnt. Ile mNes, fur- thermore, that the risk of attaining hypertensive blood pressure k.e{% over a 6ve-ycar span is far higher fnr the recent quitters than for the contimring smokers. To what degree blood pressure changes relate to how recently one has quit tnerits investrptan. Sel:zer, C. C. (Arll, 8. and Rose. C. L 1 AmtricanNcartlournd d7(S):SSS-564, 1974. Other support: lhe Fund for Research and Teaching of the Ilarvard School of Public Hcalth From the Normative Aging Study. Boslon Outpatient Clinic, Veterans Admin- ntration. and the Department of Nulrition, Narvard School of Pub•ic Health, Boston. PREVALF:N('F 01: ABNORMAI. PR(1TEASE INI/Iq1TOR PIII-NOtYPFS IN PAlIEN1S Wlfll ('HRl)NIC OBSIRIJCtIVF l.l1N(i 1)1ti While it is clear that severe anlrtrypsin deficiency prrdisposrs to the de- vclopmcnt of chronic obstructive pulmonary disease (('UPt)), the role of in- termedute deficiency states remains questionable Thn report rkals with an attempt /o clarnly this ryunl The study was intentionally conJu.teJ at an m.thrur«m that was nM engaged in thrs area of research in nrdcr Ir, ebnon.te any •I.,nfrng of Jara rhr4"rgh pre/crtnual casc rclrrr.l Ihe ur.J.nae aut ab nurm,l prwcau mhJhrt.w phcndypes was higher among (Y)PI) patients than 66 in normal subjects. Intermediate as well as severe anutrypsin deficiency ap- pears to predispose to the development of this syndromc. 7 his was most appat- enl in patients who were young, smoked littk, did not live or work under conditions associated with bronchitis, and who were otherwise unlikely to develop these diseases. Afittman, C., Lieberman, 1. and Rumsfeld, 1. Amerkan Reritw o/ Respiratory Piaau 109(2) :295-296, 1974. Other stupport: National Heart and Lung Institute. Frosn the Department of Respiratory Diseaae, City of Hope National Medical Ceoter, Duarle, and LaVioa /lospital, Altadena, ('al. SCREENIN(3 FOR ar-ANTfTRYPSIN DEFICIENCY This paper reviews what is currently understood about the relationship of chronic obstructive lung disease and liver disease 1o ar-anlitrypsin dcfkiency (AATD), and considers whether screening programs for this protein defect are justified. The authors conclude that while current knowledge does seem to jus- tify AATD screening arrwng patients with lung disease. general population sur- veys cannot be considered practical or unequivocally worthwhile. MNhods aow under study may permit the economical and reliable detection of deficient phenotypes with few (ahe negative or positive results, but the most important reason for general sereening, namely improving the future health of those with positive results, has not yet been established to the satisfaction of all Ittvesti- gators. Currently in progress : te large-scale studies of AATD incidence ananp patients with lung and liver d'neases, as wel) as prospective longitudinal studin of the health status of asymptomatie earrien. 19 the data support the hypothesis that this protein abnormality makes these individuals susceptible to the harmful effects of environmental irritants. then screening should be established, at least in certain ethnic populations atrwns whom AATD seems to be mote prevaknt. MUtman. C. and Lieberman, 1. frrael lournal o/ Aledkd Sekncer 9(9-10) : I)11-1)1 f!, 197). Ot/ler support: National Institutes of Health. From the Department of Respiratory nisease. City of Hope National Medical Ceoler, Duarte. Cd. PREDICTION AND POTENTIAI. PREVFNlION OF INI)t1S1 R1A1. BRON('Ii111S: AN EPIIIEMInL(Xil(' SIUI)Y OF A(iROI/P ()1' ('()KE OVEN WORKERS What are Ihe rqks that Iob type. cigarctse smoking and genetic (ac/ors play in the development of industrial bronchitis? ('an an understanding of familial /endencies towards bronchitis and emphysema be tned for disease p.e- venlion7 In an attempt to answer these queslwrns, a survty was conducted among 246 coke oven workers for which each man complcled a standardutd questionnaire, arN1 blood samplcs were obtained Irons each /or alphar ants Irypsin phenrNype (Pi typel analysis. A total o/'dI men O)1i of all workers) 67 I

reported having respiratory symptoms; in 42 (17% ), Ihese complaints were consistent with a diagnosis of chronic hronchhis. In the over-all group the severity of symplonrs was related to cigarette consumption, hul smoking did not account for all cases of chronic bronchilis Fourteen men had deficienl anti- trypsin phenotypes (seven PiMZ, seven PrMS); seven of these (S0%) reported having respiratory symptoms. Eleven workers with the normal antitrypsin type /PiMM) reported a family history of chronic obstructive lung disease; seven (6196 ) had chronic bronchitis. In the subgroup of inen with respiratory com- plainls. the severily of symptoms was related to the type and duration of their work on the ovens as well as to their unoking and family history. Work, smok- ing and family history accounted fot 40% of the variability in the severily of symptoms among men with chronk bronchitis. These findings suggest that the worker group Is composed of men with a range of susceptibilities to the devel- opment of bronchitis At least part of this variability is kenelically determined. If suseeptibk sub)ects can be identified during pre employment screening and are effectively eacluded from hazardous oecup.lions, some cases of chronic bronchitis may he prevenled, Mirrn.an. C. er af. The Arnerkaw lorrnal o/ Aledklne 37:192-199, 1974. OtAar auPprt: Nalional Heart and Lung Institute. From the Respirytorp Disease [)epartmenl, City of Hope National Medical Ceoter, Duarle, and the Medical DepartmeM, Kaiser Steel Corporation. Fon- tana, Cal. INFLUENZA VIRUS EPIDEMICS: A CONTINUINO PROBI EM loHuenta virus infections play a primary role in making the respiratory tract susceplibk to bacterial invasion. In this comprchensive review which in- cludes a detailed section on the disease's epidemioloty. the author esplores the synergislic rclalionship between influerm, other viruses, and secondary bacterial prseumonias. This relationship, which is evident in man, can be duplicated in esperimenlal animals, as demonstrated in mice infected through esposrue to acrosoh of nebuliced mouse-adapted influenza virsa. The severily of these in- feclions depends on the amount of virus inhaled. The importance of immuni- ralioo against influenza virus infections in order to prevent destruction of the pulmonary defense system, and thus secondary bacterial infections, is discussed eslensively. According to the suthor. there are a number of eRec/ive influenza vaccines and specific antiviral agenls, such as unanladine hydrochlorile. avail- able for human use and physicians are urged to take advantage of them as well as of antibiotics for the benefit of their palienls. Epidemic infkren:a, h.nvever, remaiw a continuing problem governed by many uncontrollable (acto+s. L.oosfl, C. G. Geriarrics 29(10) :101-120, 1974. OtAer ar.pport: Howard Hughes Employees Oive Once Club, and the Ilast- inp Founda/ion Fund of the University of Southern California From the Ikparuncnts of Medicine and PNhology. University of Sowbern California Sch<x>I uf MedKrne, 10. Angeks I V111. Miscellaneous INHERITED DISEASES AND VARIATIONS This chapter from The QioloRy oJ tkt Laboratory Rabbit deals with the role of genetics in disease states of t7ryctdaRus rabbits, a field which has been seriously neglected in the pnt. Whik the rabbit has become widely aocepled as tRe animal to use in immunology and reproductive physiology aaperimenta, only a handful of investigators have boked into rabbit Senelics. At this time, approximately 70 genetic loci in the rabbit are known. About one-third of these deal with hair coal and another third control blood groups and antibody production. lAis chapter focuses attention on most of the remaining loci and genetic Irails which have been recognited, namely, a large number of disease conditions and physiologic or anatomie variations. lhey are divNled into two broad groups: (1) Ihose controlled by approaimately )It mutant genes and (2) some 10 addilional condNions recognized as most likely familial or polykemc, but presently lacking fully documented modes of inheritance. The conditiows controlled by single (mutant) genes fall naturally into the following eight groups: ( I) behavioral mutants; (2) aeuromuscular mutants; ()) ocular mu- tanls; (4) oral cavity mulanls; (5) skeletal mutants; 16) hematoh+gical mu- /arws; (7) fienilnurinary mutants; and (d) other mutants. Tluoughoul this sec/ia+, the name(s) and description of individud traits are given as sub- headings, followed by the possible genotype(s) of affected animals. Enlilks described in the familial or pdygenic eondNions section include abnormal ear carriage, acrometialy, aorlie arleriosekrosis, familial neoplasias. hereditary premature senescence, resislanee/wscepUhiluy to infeclion, scoliosn, walteing, and hyperlension, among others. This discussion slresses the importance of pre- serving such mutant slocks, and presents The places where these special stocks can be traced and obt.ined. Liodsey, 1. R. and Foa, R. R. (Mtitr, H) In: Weisbro/h, S. (ed.): The t!lolocy of the LaAotprory Rabbit, New Yort: Academic Press, lnc., 1971, pp. 377-101. Other sr~ ports National Institutes of Health, National Inslilute of Child Heallh and Human Development. Veterans Administration, and Endowment Funds of lAe Jackson l.aboratory. From The Jackson Labordory, Bar Harbor. Me. TIIE MAMMAI.IAN INTERVERTEBRAL DISC. llll: t'OLI.AGEN OF WHALE FETAI. Nll('LEl1S PUI.P(1SUS Tlre amount of hydrosyproline and total amino acids found in whale telal nucleus pulposus collagen is normal for mammalian collagen and about the same as that reported for human interverrehral disc collasen '/he whale (eld mrekus is a fihrous gel which prollressively changes to an almust Alxous struclure in old age Since this change may he associated in part with an altera/ion in the mr>.mt of carhohydtate linked to collagen molecuks. the 68 69

carbohydrate and mino acid composition of the nucleus was iwdied, as well as the properties of its purified soluble arsd insoluble collagen. Pronase, which affects the strong interactions between collagen Bbrils and pro(coslycans, was used to facilitate Ihe estraction of salt- and acd-anlubk fractions from fetal nucleus pnlposus collagen. Soluble cotlagen preparations were also r-btarned without the aid of pronase. Insoluble collagen was purified as gelatin. 'Ihe amino acid and carbohydrate composition of these preparations was es-.entiatly the same. The salt-solub(e fraction contained 2% neutral carbohydrate, present as galactose and glucose in 1.5:1 ralio, trace amounts of hesosamine. Mrt no uronic acid. The galactose to glucoae rNio, however, was higher in gelatin preparations. Carbosymethykcllulose chrortalography of neutral salt-estracted collaaen (afler pronase) sfwwed two ehrornatographic components correspond- iag to al and 611 chains of rat lrndon soluble collagen. The two Iractions showed the same amino acid composition bul diRered from rat tendon collacen a1 chains in Iheir high hydroaylyslae a.d carbohydrate contenl. The amino acid eornposilion of the fetal whde nuck,r oollagen at chains separated by chromatography was about the same as that of the al-Type 11 chains flrq reported for eollagen isolated from aeraal cartilage of lathyrilic chicks. Ludowieg, 1. 1., Adams, 1., Wang, A.-C.. Parker,l. and FrdenDerR. Il. ll. Connect(ve T(urt Research 2:21-29, 1973. OOther supports U S. Public Health Service. National Institute of Arthritis od Metabolic Diseases, and the National Science Foundation. From the 1)epartment of Orthopedic Surgery and Section of Hematology and Immunology. Department of Medicine. University of California School of Medicme, San Francisco. STRl1CTURE OF DIBROMOTICONINI3, A BROMINATION PROnUCT OF NICOiINI? The authors have re-esamined the (ale of the nicotine pyrrolidine ring on its osidative bromination to dibromotieonine. From chemiea( and spectral (includin`'sC nuclear magnetic resonance) properties. dibromoticomne is now established as ),4-dibromo-S-hydrosy-I-tnelhyl-S-()-pytidyl)•As-pyrrolin-2-one. The bromine atoms can he selectively replaced by hydrogen under proper chemical reductive conditions to give the isomeric monotaomo(iconines ('ata- lytie hydrogenation of dibromoliconine provides 5 hydrosycotinine, an im• portant intermediate in the biological (IeSradation of nicoline. McKirnnir, H., Jr. er al. Journal o/ the Chenucaf Society Perkin 1(19) :2046-2049, 197). Other auppo rt: American Tobacco Company and the American Medical Association fAucation and Research Foundation. From the r)epartment of Pharmacology. Virginia Cornmonwealth lJniversily, Richmond, and lituss ('hemical Laboratory, 1)uke Unrversily, Durham, N. C. I 1:('FF('T OF SIRAIN, SFX. AND CIRCAI)IAN RIIYIIfM ON RABBIf SERUM BILIRUBIN AND IRON 1 FVfI-S The need to establish normal baseline values (or serum iron (SI). total iron binding capacity (TIB('), and hdirubin kvels which might be used as preclinical diagnostic criteria prompted Ihe study of variations in these para- meters in relation to circadian rhythm, strain, sea, and age in the rabbit. In- vestigation of 411 adult hybrid rabbils revealed that the time of day aRecls the SI levels and the ratio of SI to TIBC. 1he lalter often being med to diagnose iron deficiency anemia. Moreover, there is a difference in the TIBC and in the St to TIBC ra/io, depending on whether maks or females are used Analy- sis of the data on 240 anima(s- involving 12 inbred or partially inbred slrains, showed that the parameters tested are all influenced by strain and SI ia (ha only one unatlected by sea. Normal rabbit bilirubin values are so luw that .es or strain had no apparent effect. These data do provide baseline values (or the rabbit and are consistent with those for man insofar as Ihese parameters are affected. Foa, R. R., l.aitd, C. W. and Kirshenbaum, 1. (Mrler, H.) ProcerdinRs o/ the Soeiety Jor EiKrl.nentaf eiology and Medlclnr 14S:42t- 427, 1974. Other aupport: National Imlilutes of Ileal(h (Division of Research Re- sources), National Institute of Child Health and Human Ikvelopment, and Ilycel, Inc. From The lackson I aboralory, Bar Harhor, Me. SF1.1?CTIVE REMOVAL OF ALBUMIN FROM PLASMA BY AFFINITY ('1(ROMAIO(IRAP1fY Many human plasma proteins have been diflicult to isolate or purify be- cause of albumin contamination which can also inter(ere in the detection and assay of minor protein components. This report describes a new technique for the quantitative removal of albumin from plasma, based on the fact that shn protein has the unique capacity to form very ti`hl molecular Msnds with dyes. The removal of albumin Irnrn human plasnsa or serum is. there(ore. easily accomplished by the passage of either one (hrouFh a cotunm of sepharnx blue destran conju6ate: this oeeurs without sisnificani ksa o( any other proteins. Blue destran was chosen as a ligand because of its singular ability to bind alMrmin regardless of the Mdler medrum's wrnic strength (-Finically, the re- nwwal of albunun increaus the sen.itrvuy of ass.ry sysrems now used, and shiNdd make even minute armnuntso( uhraHmal plrsma ptotems descclabk nd alenufiahle. Travir. J. and Pannell, R. ('linical C6inrlca Arra 49:49.S 2. 1971 Other auppurt: National Institutes of Flealth From the Department of BiochemisUy. llnivcrsdy of (Seorgia. Arhens_ 70 71

Active Projects Following is a list of Ihc principal inves1i6a1ors, or instilulions, of projects under way or activated in the period since the previou t Repurl, together with the respective project litks. Completed projects arc listed in a later section. PRINCIPAL INVFSTIGATOR oR 1N3T1Tl/TION PROJ[CT TiT1.E lOSFPH C. ARCOS. D Sc,!•ro/rssor of Alydarwr, Tulane University School of MeJiclne, New Qrleans [X)MIN(3(1 M AVIADA. M D, t•ro/ts- s.+ u/ Pll.rww..loey. University of Pennsylvama School of Med/cine, Pfil- sdelphu. A CI IFFORD BAR(iFR, M D, RoAerr Hrw.' f/r.orr Lo/rssor o/ f Alsid- olr. ihrvard Medical School. /ouoo. BFNIAMIN Bf:11. M D. Durrror. and CHAR11cS 1. R(KF, P/I I). Aniuawr Dorrror, Norn.anrr Ag.ng Srudr. Vel. erans Admmrslral.un (lulpahenl C11n.e, B.nlon BARt/l BENA(-FRRAI . 1,1 Il , f aAraw Pra/ruar and Cha...nan ..f ParA..loff. Hanrard Medical Schwrl, Buslon RI('HARD 1. BIN(3, M D. rru/e,lur of Alyderinr. University of Southern Call- furnia School of Mcdlcine, 1 os An- Jeles; Visiting Atroci.ut .n Aiuwlydird npntrr.nA, Cali/ornia lnslauu of TecAnolugy; Dirrrrur of Cardiology awd /nsranswd Mrdicint, Huntington Menswi.l Hospilal, Pasadena, C.1. Synergistic effects of polycycli.: hydrocar- bows and nilrosamines in pulmonary earciwoAcnesis Polemial repessua of wletabol.c aclivaliow of nnrosamincs Br.ncAo.ascular eRecls of cigarelle sn.olt Inbsence of cigarette smoke on pulmo- .ary emptsysersla and brorlc/sospasm Behavioral hyperlension and ar/eriosck- rous: effects of nicai.e anJ carbon .wowosidc A snso\ing research propam in Ihe Nor- malrvc Ailina Study l nnuul u/ spruflc eellular an./ humural Immune les(4.mts to neuplaslK and na.n ncuplaa.c Insues The eRec/ of nicotine on aherosclerosis (in vitro suud/es) Cubon rlsonoside and coronuy alhero- sckrosis Mechanisms of the action of carbon .nonoaide on atherosclerosis I PRINI'IPA/. I N V F3TIGATOR l1R INST/171T7ON JACK CIIALON, M D., As,oren/ rro- /r.urr o/ AnrsrhrswG,Ry, Albert Fln- s/e/n l'ollcge of Medicine of Yeshlva llniversi/y, TDe Brona. N. Y. (Now AaNK10/r rrufr,uw of Anruhraiul..ty, New Yurk llniversify Medical Center. New Yurk.) ' ('1111 t)RhN'S tll>SPITAL OF t.OS AN- GFIES, Los Angeles. (-IIARI FS O. COCIIRANE. M D. S. notis Cl.nic and RtsrarcA Fornda- rw.w, 1 a lolla. Cal. At1FN B('OIIFN, MD, PwD, As- shraws rru/rsNN of A(rdainr. l/nivcr- sily of ('alifurni. Servke, San Fran- clsco General Hoyilal, San Francisco. T. TIMOTHY ('ROCKI'R, M.D. rro/n- NM of Medicine. UMrerWr of (,.11- f.wnia ('o1kRc of Mediciwe, Irviae. CARROII. F. CROSS. ht.D., Associur rru/rsNM ul MrdKrnt and Nunr.n rl4ysiolosy; Durrro,. Section of rd- nwwrry Afrdicine; Ueiversily of Cdi- furnia School of Medlciwe. Davis. THOMAS R. DAWBER, M D., Associau rr../tsu.r of Mrdiriwe, 1loslon Univer- sity School of Mediciee, Bostow. H. FRED DOWNEY. Psr D.. Assistant rru/rnar of rAysioloty. U.ivenily of Teaas Ilcallh Science Center N Dalla; Drrrcr.n, C.rdiorauuf.r Research. Cu- dK.pulmonary Inslilule, Methodist Hos- pilal of Dallas. Dallas. WAI TFR B. FSSMAN, M D. Pf/ D., rr../ns.w of r,yd hoGrty .nd si.w Ihrwr- i.rry, (Aeens College of the Cay of New Ycrrk, Flushing. % tn - GUENTHER BODF.N, M D., .N,oriart Pru/r,sor o/ Mrdarnt: Assist.nr DI- rrrlur, (:rnrral Cliniral RrrrarrA Crn• rrr, Tempk University HeaUb Scienees Cenler. phdadelpbia. Rl)BF.RT F. BROOKS. Pitt). Ar...rlarr Pro/tss.n of rarbalogy. University ot (7regorl Medical School. Portland. AI-BFRT CASTRO. Psr D, Senior Stltn- r.u, Papanicolauu Cancer Resea.ch In- Effect of nicotine and ciAarcl/e uno\e on seerelin aecreliuw orplwloa.cd studies tM induteJ pulmu nary cmphyscma in r.bMls Nicotine in blood de/eclion by radlo- Mnmunuassay IIANS I EYSFN('K, Ps/D, D.Sc., f•ro- /r.uw ../ Psy.Aol.rfl, InslNule of Pay- chulry. Univerury of 1 ondon, 1 ow. dun. f nalanJ 11)WIN R I/SIIFR, M 1). Durth.r of I..h...m.w.rl. ShadysiJe Ilo+pilal: rr..- /ru.r ../ ParA..J..ry. Clmversi/y of Pi/asMnth Schuol of Medicine. Pi11s- Mn aA . B m J m QN sulule, M/ami, 11a (Nuw lhrr.r.n ../ rhr 11,.•m..wr f ah...rr..r y, Dcpa.ImpU ut MrJwnc. I/nm.rrsuy of Miami %.h.y.l .d K1cJ.a.nr, k(u.n., I Is I 2 Wit 1 1AM 11 1 1]fIMAN, P/s D, r.o fri..w n/ P..tludusy. Ilor.r.w, rr/Is ('aw.rr Rrsrar.lr frnrrr, Tulls llni vcasiry Sch.wl of MeJa/nc. Buslun PRIIIE(T TIIT.E Changes in Irachcotxunchial cytology Relilionships belween cell uansforma- lion, et/raww.ornd changes and car anoacnesis The medialion of inRammalo.y Iw+ury of /issuc Human alveolar macropLaacs and aw- tshysema T1c wc/ic defect lo a1pAa-1- anlMrypha de~ienl patients Scs Levy. l. A. Cigarette 1moAe effects on cerlaia asPecu of ru luna sssc/atwiism Snlosin` classes, risk faclors .nd ardia vascular disease Fflecls of lobacco smoke and nicolirr ota coronary collateral blood Row Sludies of nicotine action upow mer.orY consolldalion Metabolic response lo suress 1ob.eoo MnOlie InleraclNN11 The inherisance of daernsinanls of Ib snso\.na bdw1 Fflecl of t.d.accn sn.oke .nd nicolina o- ssruc/urc anJ h.nc/wn of coronary anlcrics anJ plasma Lp/Js in rabbMa Cancer phen.wspe p...hle wrrch may /n- sye b/.m.b..Remc canaer 7l

I PKINI'IPAI. INVEST7(:AT(/R (/R INS(1Tl/T1(/N 1 ARS FRIBFRG. M t), Pru/nsnr o/ f.n.u..wrnrnral NvArenr, lhe Karolin- s\s Inunule, Stoclhulm, Sweden. (iARY D. FRIFf)MAN. M D, Senior EP.Jn.ri.durirr, Karxr Foundation Re- seuch Inshtule, Oalland, Cal H t(l/(:H FI)DFNBFR(i, M D, Pro/ia- r.w ..l Mrd...nr, UnrvtrsMy of CaM- furnia bkd.cal ('erucr, San Frannaco• Pru/rrur u/ Oxrrrr..lnev awd farwrr- geolorr. University of Californi., Rerte- ky. I FONH)E GOI DSTEIN, D Sc. Aaw rllfr Pr.IfrINN n/ Pr7rAlarry. IAM/tute fur Menral Hcalt\ Sciences, Rwters Medical School. Piscataway, NJ. H)SFPH 1. GUARNFRI• Pst.D, Anrnd- rng MaroArol.rtur, D.rrrror, MirroAi- ol"tr LM.rrr.wrrs• lung Island /ew- rsA Hdlude Medical ('emer, (r.eens Hospral ('enrcr AfiliNion, /unaica• N.Y. PAl/l. HAMOSII. M D. Arrurans Pro- lrr..w of PAyu..l..rr unJ R..yAyucs. anJ Alyd.r.nr. (ieu.tlctuwn l)mversily SeM.ds of Med.crnr and [km.slry. W asb.nglon. 1) (' NORMAN W IIf:IMS1RA, PHD, Pro- /rsa.r oJ Prych.dn~y, D.rerrw. Nrnran Farrnrs la6o.aro.y. UUniversity of South Ddo1a. Vermdlion. HFReF.RT B. IIFRSCOWITZ. Pu D.• Asuvanr Profrssnr of Microftiioloty. (ieorgetown Universiry Schools of Medicine and Dentistry. Waabinpow, D ('. .- HARRY L. IOACHIM. M D, Anrnlin PerAulotisr, Lenos Hr11 Hospital; AI /unrr Pro/rran of Pathology. Colk4e of Pbysicians a SrrAeons of Columb,a l)mversi/y, New York. /1 ROME KI FINFRMAN, M D, Nrad, D.vnu.n of ParAokrry RrsrarrA and Can.ral Pathology. St. t ule's Hc~sp1d, ('Icveland; ProJrrrur nl Parliolo*r. C.x Weuern Reserve Universily Schoul of Medreine. Cleveland kII( tI^I I I I AaIM a( 1) P...Ir1.... ..l I'..~. 1. s. ro.. ~...s 14...r.ary At..1.. .~ . ...... 1... 1 ...1 PROIECT T1TLE Epidcmiological studres on the Swedish 7win keg.ury Characleristics of unolcrs and noa- smokers Survey of Iwins in the Northern Caiifor- nia lleallh Plan Collagen antibodies in relalion lo the etiology of emphysema Rehaviord and ckc(ropiysiulogical ef- fMS of the "cMonic nKwine sute" in arts The irrAuence of ealendeJ eapowre to cigarette rrw\e on pulmonary resisl- ance to infection as relaud to alveolar macroqbage and mucocilury function The e/lecl of smoking an Ihc "small air- ways" Effects of smoking deprivudon on group problem solvrng processes Effects of smoking depri.ation on risk- takieg behavior The role of Ihe macropAnge in the im- mune response: effect oi tobacco prod- rcls on macropbaAe funclion Studics of human lung carcinomas liaperimcmal emphysemr the e/1ec1s of p.dunacd dust and nurusen drussde taprsure on the physadlutic and mur- (thrxnelric parametera ul she hamster ~und Immune /lirlhamsnit ..f mUI/NIl mem- b..ucr 14 I PKIN('IPA/. 1NVESTIGATOR OR INS1IfU110N PAUI. S. I.ARSON, PH D.. Haar Pru/rs- s.w u/ Plrogrnia..dogr. Medical College of Virginia, Richmond. 1(nFP11 M. LAUWHRYNS, M D., Prr D., Pro/nsor and Chairman of Parfudury, l)niversity of Leuven. Lerr- vcn• Belgium. EDWARD LFETE• PH D. D Sc.• Pro- frs.nr of (-hrwrlsrry. UniversNr of Minnesaa, Minneapolis. RICHARD A. LQRNER, M D. Asso- srerr, Scripps Clinic and Research Foundalion, La /olla. Cal. JAY A. LF.VY, M.D., Aas/s/anr C/inical Pro/rssor o/ Mrd.cinr; Research Asso- riarr• Cancer Research Institute. Uni- venity of California, San Francisco. CI.AYTON (). I.OOSl.1• PH D., M.D.. Nuuinrs Pro/r»or o/ Mrdirine and ParAoloty. Universily of SaNtiern California School of Medicine. Los Anacks. HIiNRY T. LYNCH. M D. Pro/essar and Citau'man u( Prrrrnrirr M.dicine and Public HrahA, Crer~bton Univer- sny Schod of Medicine, Omaha. Neb. R. O. MASON. M D., !1(.D., Pro/essor u/ Pathology. llniversity of North Carolina School of Medicine. Chapel 1/81. IIFRRERT McKF.NNIS. la.. Prs D.. Pro- /ru.w ol Plrarn.a.olugy. MMedical Co1- kge of Virginia. Richrnoed. HANS MI-1FR, D V M„ Srnior Sra# Sci- rnnrr. 'Ihe lactwn I aMwator~. Sar IIarM.r, Mr 1)(IV MI('l1AFl I Pn D.• Aniuenr Pr.r- frrpN ../ N..hhrmuuy and .1nrerry, 1lnrvccsdy ..f ('alr/urnia Scho.d of Mcduinc. San Franc.sau PROJECT T/TI.E Abstracting and classifying the literalurc on the hir.lurrcd cfleclc of Ioircco, and preparation of manuscript lur Supplement 111 to "Tobacco" /19f,1) Followin, manuscript for Supplcrnent III throuAb prinlind and prep.ratron of wbjea indea Tbe lymphatics or tbe lun@: their rok ar t id lcansport and clearance of air- Mwn ewne partrculale maltcr in normal and esperimental conditions and io various lung diseases Synthesis and biological activity of nko tine analogs Studies on persistent viral infcaion Prevemion or reversal of abnormal Ma1es of respiratory epirhebum produced by cigarette unole condcnaNe and beaao- (it1-Py7e^e The effects of fresh ciAaenle .nwlt ir halation on the respirato.y lrad of mice Heredi4rY factors, cigarette snwUy rmd cancer arcidence in ),261 families Aryl byaocarbon bydrolylaugs (AHHI: cancer tenetKs Effects of nicotine on imeractiona of piateku and enduthelial cells Bido@ical activity of tobacco .mole components and allied wbuances Oncogrnesis in Ihe ubbi/. JJene/ie ws• ceptA.day. vers.cal Ir,nsmoaion of vuus and envnw+menW rnlluencte lransplacemal effects of nitro.oeom pounds in inbred ,trains of mite aad rabhns FQects of cigarcur snw.\e on pulrnawor fiArublasts and c.dlyen and Ms rt1. Lun so emphyscrna 75

PRINI'IPA1. INV M-STIGATOR I/R IN111 fIITTI/N MI('R()n1t110(:1(-A1. ASSOCIATFS, INC. Ilclhc.Ja, MJ CNARI FS MITTMAN, M D, Darrror, /)trenn.rwr of Rr,po.ary Dntaur, (l/y of Hope National Medical Cen- ler. Duarle. Ca1. C.1'l)RG R. NF.URAT11. Ph/D, Mrcro- .m.drrarl (.aAorarory, Hamhurs, West (:ermany. AI RFRT 11 N/DI'N, M 1) , Frn/rnor of AfrJu rnr, Drew PoslpraJuale McJnal S.Mrd and Ilmvrr.ay of Southern (bli/uenu; CArr/. riJ.m.norr Di.ratt Srrrion, Martin 1 wher King 1lospnal, I os Angeks. OAK RI[X:E NATInNAI. I.ABORA- tURY, Oak Ridgc, Tcnn MA1 C(N M C PiKF. Pu D., IroJtssor o/ (-or.n.nwnrry Mrdrernt and rrsi- anrtr- l/niveruhy of Snwloern Caldor- nu Schuol of MeJicrne, I os AnAtks. PR(K'fSS A INSTRUMFNT (Y)RPO- RA11(1N, Br«.llyn, N. V. Rc1NAl I) 1 RA1M11%S1 N, Pu 1) . A. u.rrn. Irr.rrr. A IAr...a.-er.r I lmva- sny ..1 1 al.l.ra.a 1 awrer Me.car(Is In s$.iurr. %.n I raw..au PROIE('T 11111.1E Sludies of in rivo chemical carclnogene- sis Improvement and slandardifalion of Icau (ot uyl hydrocarbon bydroaylaso in- duclion in human tissues Dere{opinA mouse carcino4enesis model systems for use in inhalallun studies Study of carcinogens (MCA. UMBA, e(c.), cipreue smr>•e corwknsates anJ conJtnsale /ractions by subcwaneuus ,ad pulnKxury inlroduclion into nsice DeveloprneM of facilities /o., nJ initia- (ion of, a uudy of chronic tobacco rnoke inhalauon in nwux uralns with corurasting susceptib.hucs to car- cinolicnesis Hereditary susceptibility to bronchitis- emphysema Kinetics of nitrosamine /o.marion in to- bacco smo\e Fflects of cigaretle smole. noaiorn fumes and drugs on the terminal airways The ehemical, physical and r perational chuacttnration of two types of de- vices for the lteneration and subse- autnt eaposure of animals lo Iresh cigarette unote Study of the relationship between sus- eepihilhy to certain cancer: and uyl hydrocarbon hydrosylase ( 11/11) ac- /ivily Conslructinw of an esperimerlal device for monlloreJ esposure of small ea- Perimenlal animals to tobp'co smote inhalation Mudi/kNion of Walton smolina machine in connection wilh a rKw prulydype Fflecl of eu carrinogens anJ lumnr proo- nunuudran molcrs un I/NA rrparr in tells wscepnlJe 10 cbcmud ,r.nslur- r11a1nM1 76 PRINI'IPAI. IN V FSTIGAT(IR IlR /NS1111/T1ON TIMOIIIY 1. RF(7AN, M D.. /r../esHw u/ AItJr. rnr; fbrrc r.w, t)irnr..n ../ ('nIJb11'InruLrr pruasrr, (-nlltRe ol Medicine and Demistry uf New lersey, Newark. DANIFI. B RIFKIN, Pw-Q, Aslistnnr Pr../rs...r o/ ( At.niral Bdd.Ky, T he Rockefeller Univcrsity, New Yorl- 1(111N A. RUSF('RANS, PN D, Arwci- art In•/naw ../ rlurnna.J..el. Medi- cal Culkge of Virginia, Richrnond. RONAI D P. RIIRIN, Pe 1), Au.niart rrnlrrwr u/ rAarnracul..Rr. Slale llni- .eruty u( New Yor\ Duwn.lale McJi cal (-enter, Rrou\lyn (Now )"../rruw ../ Flrarnr.r.Juty. Medical Co1kAe of Virginia. Richalorwl.) UNA S RYAN. PND., Srni.r Scirnriu, Papanic+daou Cancer Research Inai• tsue, Miami; Assistnnt h../rsuw u/ Aftdreinr, llnirersity of Miami School of McJicine, Miami, Fla. B. V. RAMA SASTRY, D St•, Pw D, rro/r.wr o/ IA.rn.orol..Ry. Vander- bilt l)niversity Scbol of Medicine, Nashville, Tenn. SCRIPPS CLINIC AND RFSFARCII FOUNDATION. L. lol/a, Cal. CARI. C. SFI.T7FR, Pu D, N..nnrry RerrarrA Aru.riarr, Peabody Muxurn, Ilarvard UniveraNy, Cam6rifte, Mass. '-l1('10 SF.VFRI, M D., Dirrrr.r and hr...r, Insnrwr o/ Anwro.nr and lnrh.d- .rky. Divisir.n of Cancer Rexarch, University of Perugia. Perugia, Italy. CI/ARI FS R. S/IAW, M D., Cbir/, Srr- rr..n a/ AftJu.d (JrnHa s, M. 1). An• dtrw.n Iluy.ud and Tunwr Inditule; rn./ru.w uf The l)niversi/y o/'leaas at /l.wuun, Ilaw.wn. NATI/AN 11. SIOANF, Pul). rru/rr- A.w r/ BunAr.nnby, The (/niversuly of Tanncssee ('enter loc Ihe Ilcallh ticience., Memphis. 11/1'(HN)at1' A. CIOIKIN, Pnl). A.- uU..nr 1'r.•lr....r .r/ /'b..nue...l..r:r. Ikrie (/mversity MrJrcal ('emcr, Uur ham, N ('. PR(I)F.(T T1T1 F. Variahle. alfc.ring the cardiuvascular rt• .pumcs lu ahrumc smoking Pro/eases proJuccd by mammalian tissue Slatc dtpcrldent properlics of nicaine- relateJ compounds The action of nicutine on the adrenal gland The role of endorhelial and ePilhe/ial cells in nun-vem8atory /unctlos of the lungs InRuence of nicotine on the « kas. of Kelykholine in Ihe human plaanta and its implication on tbe fctal po+sh Imwlunological competence of wmuse arains in relation to eloewsical eareino. genesis Comtitu/innal studies relative to smoking awl coronary hearl discase Attempts to identify the viral agent(a) respunuMe for sheep lung adenomato- sis and Io uans/er tbis neoplaMie die ease lo rodcnls Hydrocarl.on metabolizing enzyrnes aad lune cancer IYlccl of hensu /.) prrene anJ derivr tivcs on man.malun IunA cells Maluralioa o/ Ihc aJrensl rnedulla: calr .lad.nnne s/ures in normal and hyper. 1(nllve rals 77

PRIN( IPA1. IN% lST1CAT(IR 4/R INSIIT111110N 1 l)1115 A SOI OI F. M D. R6.nrhr f. r r. r f).sr.wrunhrJ Srn u r f•ra/nior; 1'ruJa...r o( AfrJ.unr, lh.r. tur, Rr- rru.. h L.p.,l L.Awurwy. AMr.nAer, Rr- srur.h AJ.n..ry anJ Rrr.rw- CommU- rrr l..r the (Y.m.al RrrrnrrA Crmer; Temple Univasny Ilealits Seienees (-enmer, Ph.tadelphu IAI.IFS TRAVIS. Pn D. Arsoc/ate Pro- frn.n ..l R.orhrmirny. University of l:ewpa. Arhens l/NIV1 RSITY OF SAN FRANCISCO. San F rancisco l1NIV1 R%ITY OF SOUTIIERN CAl l- 1 ()RNtA, t os Angeles. STFPHI N F. VATNFR. M D., Ar>Is- tum rro/erior of MrLc.nr, Harvard MCOKal Scbcwl: AssorNrr in Mr/Kinr, Perer Bcnl Briabam Ilospird, Boston. ELI IOT S. VESFI L, M D., ho/rssor ond Chnrrnwn of rhermacolory, Pena- sylrania S(are l/nirersily College of Med.cine, Hersbey BRANISI AV VIDIC, S D, Professor ../ Anato.ny, (iew~etown Uaiversily Sctwul of Medicine, Wasdingwn, D.C. GFORGF. WEINBAIIM, PN D., lbsri• rntut, Pulmonary Di)rou Srcrios, AI• bcr( Einstein Medical Cenler, P1ila- detpbu. A. STANI FY WFLTMAN, PN D, A»o- cwrr Professor rn rharmarnlaty and Rrvarch, Brooklyn College of Plur- rnacy, Brooklyn, N. Y. DUANE 0. WENZFI., PnD, Professor and l'huoman of lAormocoG'ly anl Tour.do(y. The llm.ersny of Kansas Sclnrol of Pbarmacy, I awrence. 711OMAS C. WESTFAI.I., Phr D, Ar.o- r.orr Professor ..f rAurmucololy. Uni- rers.ty of Virginia Sctwwl of Medicine. ('harldlesrdle. PRWECT TIfLE PUrIfICaINIn anJ physiologic sipnificance of lecithin clKdesrer..l acyl Irans/crase ILCAT ) Role of kcnhin: chokstrrul acyl tuans- krase Il('ATI in cholcsurul maabo liam in hcaltb, disease and during smoting Bioehemiury of chronic obstructive lung disease The eaperimcnral induction o/ sQuamous eeR carc.norna ia mouse lunls A study of aryl \yd.ocarhon hydrnaylase inducihi/Ny in cancer paucros in si Los Angeles County Isospnals Nko(ine-induced refka coronary vasodi- lation Radiownmunoassay for nicotine PAumacolinclics of nicotine in smokers and nunsmukers Pbarmacolincrics of nicotine in naive and habituated eipreue, cigar and pipe smokers TAe effect of cigarette smoke on lung metabolism luna proreinase: anNproleinase balance and the effecl of cigarette smoke on rsis in(cracrioe Acute and chronic effects of nicoune and rhological aspects of spumaneoudy Cperlensive and notmorrnsive mak ra(s The effect ol nicotine and carbon rnon- oaide on vascular lopid disposition t Completed Pro jects Following is a list of the principal invesligak)rs, or inslitutions, of ojeels that have been completed prior to the period covered in this cporl. Several of the individuals named are deceascd. The titlcs and a/51ia- tions lisled are those in eflect at the time the work was compkted. ('LARENC'F M. AGRESS, M D., Auo- . wrr Clw. al Professor of Mrficinr, University of California Medical Cen- Icr, 1-os Angeles. ANTIIONY A. At BANESE. P)r D., Di- re.rw of [aborotwks, The Bwks Re- t.abilaauion Cerer, Whi(e Plaiws, N.Y. ANTHONY P. AMAROSE. hr.D., /w- urwrw, l)rpart.nrwr of OAMrrhic..nl (:ynrcoloey, The Albany Medical Cd- kae of Union U.iversily, Albaay, N.Y. E. T. ANOFI.AKOS, M D., Pw O., rro- /aaor of rhy,ioloty, Boston Unireraity School of Medicine, Boston. D. MURRAY ANGEVINP M.D., Uni- versiq of Wisconsin Sctwd of Medi- cine, Madrson. STEPHEN M. AYRES, M D., Director. (-arJ.oprlmonory L.twratory, Saint Vincent's Hosprd, New York. OSCAR 1. BALCHUM, Pr( D., Haar/ng) lro/ennw of Mrlicinr. Univtrsiry o/ Southern California School of Medi- cine. I; os Angeles. FRFDFRIK B. BANG, M D., rrn/ruol and C'hair.non. Drparrnrrnr of ratho- bud..ty. The lobes Huptins l/niversiry School of Hyaiewe .ad Public Heal(h, Bdrimore. BRODA A. BARNES. M D., Pn D.. lro- /rs>.w (,14ilrur) of rhysadory. Colo- rado State UnirersNy, Fort Collins. FRFDI'RICK W. BARNFS, la., M D, Asur.nte Professor ../ A(rJuinr, The Johns Ilap\ms University S4lwut ot Mcdicine, ballimore. RALPH S. BECKER. PN D., Professor of ChrmiurP. University of /louuoa, Houston. - SAMUEL BELLET, M D, Dwecror, DI• •ision of Carlidot y, PhiladelpWa General IlosPdal, Philadelphia. NH/N A. BkVAN, M.D, Professor of Iharnracoloty, l/ni.erwy of Califor• wia School of Medrcine, Loa Aqeks. BUDHDEV BHAGAT, P1r.D., Professor of thysf.duty. S(. l ouis U.i.asiwy School of Medieine, SI. Louis. CESARE BIANCIFIORI, M D., DLWw of C'anrrr Rrtrrrh, Uni.enily of Peruaia, Peruaia, Italy. HYI.AN A. BICKF.RMAN, M.D., Aadsr- an( Professor of Mcliclnr, and AL- VAN L. BARAC//, M D., Coatrlra.u In Alrlrcinr, Colkele of Physicians A Suracons o( Columbia U.ivcrsirr Gold• waser Memorial /lospi(a1, New Ypk. B1O-RESEARCH CONSULTANTS. INC., Cauebridae. Mass. B1O•RESEARCH INSTTTIfTl, tNC, Cambridae, Masa. FRED G. BOCK. PwD, Associate Caw• crr Rnrarch Scrrmiu. Biological Sto- ri..n, R.awclt Parl Memorial InwMWe. Sprinavd/e, N. Y. IIF.RMAN V. BOFNIO, Pn.D., Nral, Chraristrr and aiocArmisny Dr~ n nrrnt, S4~mdle(op Research Center. lss• Ina1lN1, )~y. IAMFS M BONNFR, Prr D., Professor a.f Radoty, ('aldwnu LMHu1s o1 Tcchnaloay, Pasadena Influence of nicotine and rrlaird drugs T. C. BARNFS, D Sc., Rrtrrrh Snrn- WALTFR M B(K)KFR, P)r 1)., rrofer on the uptak• swra/e, release and rut, Philadelphia State Hospul, Plila- aur anJ HrrJ. Drlw.unrnr of rhorma- turnover of c.Iechrdamines in central delphra. roloty- Iloward Uni.eraily, Washing• and peripheral tissue R, FRFDFRICK BECKFR, PnD, Aeso- lon, D C. rwrr Yr..fn.a. ..J Anar...ny unJ l)ur.- TOM () B()WFRY, Pwl), IraM/Ii r..r• (YA...an.rr .l frr.nawf S..rmr. RruJur l uharrL.. y, ('l.rmnlry lIrw r- I)uke limversqy Medical ('emer, Dur- mrnr, Nwr6 Carolina SIa/o Colkje, ham, N. C. Raleigh. 79 79

1 L GFO1 FRFY 1. BRINKMAN, M D..l.- nw..nr Pr.r/rn.w ../ AfrJninr. Wayne 11ate llmvcrsny School of Medicine. Iklrod BARBARA B BR(1WN. PwD., CMr/. lL sPtrnnt.nnt Psys hwrry. Veletans AA- minislraliun Iltnpiul, Sepulveda, Cal. RAYMOND R. BROWN, PhtO, Pro/n- s.w of Chntral Oncol.rRy. Univctsily o( Wisconsin Medical School. Madiaoa 10SEF BRO2EK, PH D.. Pro/rswr rf ('Aairnraa. Dtprtmrnt of P,ychobry. I ehotih Univetsny. Bethkhcm, Pa. SUE Bl1CKINGIIAM, M D.. Asslu.ru hn/r,,.w c./ PtJ.nrtkr. College of Physiclans A Surgeons of Cotwnl>V t/nwersdy. New Yorh. BFNIAMIN BURROWS. M D, Assocl- arr Pr../tr,w of Medicine. UniverlNy of ('ha,go, Chicago F M BI1TT, M D, Chief PotAd.,P/q, I os Angeles County General Hospdal. I us Angeks RI('IIARD ll. BYFRRl/M. PND, Pro- /n,w .r/ CAr.annr, MKhogaa State Umversdy. Fasl I anung SISTI R M 1/6111 Y CAI111 I. PsMD, ('h.nn.un, C6r..uu.r LJrpa.untnr, Rc- A.s Collefc, Wcston. Mass BRU('E F. CAMERON. MD. PND. d.•,.atJ /lugArt fmhturc, Universtlr u/ Miami Schoo) of Medicine. Miami. I la. Wit I IAM 11. CARNFS. M D., l)niver- s,ty ol thah Colklie of Mcdicinc. Sal( I ate (-ey MAR('US N. CARROI.L. /... PtsD., Chu/, Drri,ion of Pharmacololly. The Bruotdale Hospital Center. Brootly0. N Y. WIIIIAM ALVIN CARTER. MD. Arsruanr Pru/rruw of Aftbr.nt and Ah.tnAnJ..gr, lhe lohns H.+piins Uni- versny School of Medicine, tlah,more. I.fOPO11) k CfRF('FIIO. Pstl), Pro- /rrsur ../ ftanhnnnrr~ anJ Nutruron, llmver.,sy of Puerto RKo Sehool of Mcdic,ne, San lu.n SANI t/R1/ ( IlttlttKll. M 1), Anurant a/ Ah.L..nt, Tu/1s Ilmvettns ti,tnnd .J McJ,.mc. 11uJ.,n (Im L.dtd ,.nJrr M.u..,c 1e~.1. M 1) 1 NAITER M. CHOPRA, Prt 0. Pr.,/n- ' ANDREW S. DIBNF.R, Pu D. F.-.ec- WILI IAM I FISIIBFIN M D CAit/ s.n of Cbtnnsny, Nurlh ( arobna Ap , urnrt, Psychu-Rr,rrcA, lhe Age Cen- , . , of f p.Jimi.J..Ay o Board Chica f ricul(ural and Technical Stae llnivcr- ter of New England Inc. bualun , g o o Heallh Chica si(y. Grccnsburo. . , . . , tR W11 11AM G Psn D Dirtctnr CLARK FI)WARD F DOMINO. M D, Pro/rs- . RUS.SFL1 S. FISHFR, M D, University . . , .. , ,..r u/ Pharnw. olutr. UniversNy of of Maryland School of Medicine Bal- PsytAnplrarnrr.d..~y ResranA L.Anra- Michigan. Ann Arbor. . linsore (ary, Vclcrans Adminis/ration IlospN.l, . Sepulveda. C.1. RAI PH L. DORFMAN, Po D, Directo. B L. FRFFDI.ANDFR. M D.. Director o/ I.oMMat,M/r,, Worcester Foundation of ('ant rr Rt.rr.n h Mount 7ion Hos- HANS T. CLARKE. DSc.. Pn./rsro. o/ for Esperimcrttd Biololly. Shrewslwry, , pital .nd Medical Center Sa. Fra.- RiocAtmiury. College of PhysKian ls Mass. . c,sco 3 w~ew. of Columbia University. New . Yorlt. IAMFS l. DYAR. PH D.. Assistant Prc.- FRFDERIC A FRENCH A B Dirrt- /rssuM ../ fJN.G.tr. licllarmine Colkae, . . rrw of Carwn fhrmorAtrapt ResrrtA JAY D. COFFMAN. M I). Stction I uuisvdk, Ky. , Mount Zion Ilospiul and Medical Nrad, Prriphtral Vn,culr Dtparemrnt, Uni.ersi(y HosPitd, Bouon. RI('l1ARl) II. EARLE, M.D, Chief. • Center. San Francisco. DANIEI. COHEN. D.V.M , M P If. As- puant Pro/tssor o/ Yttnrnory tpi- drw,bfcryly and Pu! ic Health. Univer- sily of Pewwsyl.ania School of Ve1er- inary Medicine. Philadelphia. JULIUS H COMROE, 1... M D, Dirrr- tot, Crd.orascutat RrurrA fnuitrre, Uni.ersily of Cdifornia Med.cal Cen- ler, San Francisco. DEAN M. CONNORS. M D, Au..riare D.rtrtnt. Deprtment o/ 1 aA1n0/ory MrdKine, St. Muy: Ilospnal, Madi- wn, Wrs. P11/11P COOPER. M D. Clinical Pro- /rrs.w o/ Surgery end Durcr.•r. Surer- far tLalNNNt1N1 rl/ (-tlruLV Phr,nnf.rry, Altxr/ Einsrein College of Medicine of Ycsluva University; ('h.r/. Snrsrn.d Sttrrtt, Veurans Admin.slratiun Hus- pNa1, The Brona, N. Y. ROBERT L. CRAIN. PwD, Assistant Pro/ruor o/ Sorwloty. Universily of ('hicago. Chicago. JOHN E. CRAIGHFAD. M 1), Pro/es- aw of Pathology. Urqversity u( Ver- nrorsl Medical Sehod, Burlington. CECII. E. CROSS. Rrsrrrh 1ltpartmtnt, St. Joseph Ilospaal, Burbank. ('al. ALBERT DAMON. hs.l), M I)., Ltc- rurrr on AnrAtnp..loly; Rrstr.A Anu- tiatr in Mtd.tal Antl.rapdoty. Pea- b.dy Museurn, Ilarvard University. ('amMidge, Mass. R F DAWSON, Pn D. Pr../rr.nr rn/ Snr- . any, (-.Oumh,a l)niveruly. New Yurk p/11N P. 1)1-1ANFY, M1), Pu1), A.- ,.nr..rt P.../n,.w n/ SrrRrry. Umversity of Minncsuu. Mmne.paAn. BO i I PYIn1U/MY) L'Ynll/un L.MAMMNOI/; As- sntant P,ofr,s.M of Mrditint, lJnivcr- sily of Chicago. Ct•icago. IOIIN W. ECKSTEIN, M D., Asisranr Pt../er>,a of Internal Mtdicinr. Slale llniversity of Iowa College of Medi- cine, Iowa City. BFRTRAM FtCHF.L, BS. DD.S., Di- rr.tor, Inmrgott u/ Stonwtorurira/ Rt- sercA, Science Resourees Foundation. Walerlown, Mass. HYMAN ENGFt.BERG. M.D., Atrrnd- rnR Physetian, Cedars of Leh.wn lloa- pilal, I us Angeles. CARLTON K. ERICKSON. ht D., As- s.olwtr Pro/t„or of PA.rn,...d..~y and TnsitoloRr. lhe llnivesswy of Kansas Schoul of Pharmacy. I awrence. IIFNRY 1. FSBER, Pw.D., Rrurrh Im- nu.n.durist, Masow Research Institute. Worcester. Mass. 1011N R. FSTLRLY, M.D., Auorlue Prufrsaor of L'arrt.daw. Universily of ('hKago Pri(tter School of MedKine. Chlcato. HANS 1.. FAI K. PH D, Adjumr Auoci- att Pra/esurr, Drpremrnr of Pnthcd- aK~ l)niversNy of Srxahern Calilornia Schrol of Medreine. I os AntReks. DANA l.. FARNSWORTH. M D. flenrY A(16rrr Prn/t,un ..1 ffs~[rtne and ll.rrcr.a 9, nrvrniry llrablr Srrurrs, Ilarrard i Nversiry. ('amMidle. Mass. FRANK C. FFRGl1SON- 1... M D.. ('Iw,rmmm, l)rparr.nrnt of PMat.nw'.d- ..Kr, The Alhany Medical ('ollege of Ilnn,n I/nivcrsily, Albany. N Y. TIII;OIN1k1- N. FINI FY, M 1). Diret- tur../ Pulcn„n.uy Resrorh h f nM.rorwl. Mount lion lluspiul, San Frrncisco. JACK FRFI/ND. M D. A„irtant Pro- /tstw, oof PArnra..dc.gY. Medical Col kge of Virginia. Richrnond. GILBF.RT H. FRIFDFt 1.. M D, Chief r./ ParlYololy, St. Vincent Hospi/al, Worcester. Mass. ARTHUR FURST. PN D, Dirrcro., fa- sntrtr, aof Chtn.icol eroloty. University of Sa. Francisco. San Francisco. MURRAY B(iARDNFR, M D.. As.o- ciert Ptcr/rn..r of ParAology, Univer- say of Southern ('ali/ornia Schoo/ of Medicine. t us Angeles. GEORGE O(iF.Y, M D, 1)irtrtnr, F/a- nr/-Hnw•ell ('.mar RrsrrcA l.lra- hwy: Asu.tmrr Pro/rss..r ../ Surgery. 7he /ohns Iluploins l/niversi(y School o/ Medicine. Ballsmwe TI/OMAS M(:O('KE, M D, AswrWt Pru/rs,or of Prtrtnti,v Addicinr and ('onununrev Nralrh, New Jersey Sla/e ('ollege of Medicine and Dcnsi.try, lersey Ci1y. DAVID M. GOIOFNBERO. Sc.O. M D.. Aru.riurr Prc./rn.w of ParAol- oRy. Temple University Hcalth Scl- ences ('emer, Philadelphia. PAl// 001 DIIAIIFR- D O S. Asa.riarr rr.,/tss..r ../ rr.a.J..Mnr.,tv. I/.rvard Schuul of Ikmal Medicine. Botton. IRA (:ORF, M 1), Prc./tr..n of Pa/Dd- ..Ry. Boslon University School of Medi- eine; C'lur/ o/ LaA.noru. to Snvi. e. Veterans Adminiuratiun Ilospiul, Wes/ Ro.bury, Mass (:I RTRIII)1' V G(ll-IS(-IIA11- MD. .Nus.onr Pr../tu.n ..l fl..whrmnr.~ ('o1kAe ul Physicians f SurAeona o~ ('.dumAia Umvcrsuy, New York. Ll

. ~ A('1 ARK cRlfl IN. Ptr [).. llrnJ r/ flr,rlrruu.lrr ll,l.,~rlnn'ru, M 1) An- aicrv.n ILr.pitjI .nJ lunan In>tnole, Itrnvenny .d Icaas McJrcal Cenur, Il.wr,l.m. AR 11111K 1. GROS1, 111 S,.Srni..r Aio cArnrnl, Suuthweu Kc.carch Ins(itute, San Anlonn., les. MOR TON I(3ROSSMAN, PH D-, M D., A,u"r•ue Chnnof Prr•/rsun of Afrdi- .Inr. Ilnweruly of Ca6fornia MeJicd ('enter, 1 os Angeles. CARI- C. GR(/1171T, PH D., M.D., A.- )Inlafr in PAyu.dnyy and PAarne.rol- nRy, 1lnivcrsitr o( Pennsylvateia Grad- uare School o/ Med.cine. PAdadclpW. fRANK F. (71/IHRIF. PH[), Pro/rt- srw, anJ FRNFSI HOIX3SON, PseD., Arrnrun/ Rr,rar. A Pr../ruor, Dr/ar(- mrnl n/ Enru.m.fngr, Norsb Carolin. State College. Rakiab. 11. B HAAO, M D., Prn/rssnr of PAar- n,acolu[y, Medical College of Virlinia, R Khmond. F. I IIADDY. M D, Pu D, Pro/nwr an/ CAarrnran. Drparlnrrnl of PAytro!- oRy. Ilnirersity of Olla6cxna Medical Center. Oklahurna ('ay IOSFPH H HA/ KFNK'IIIFI , M D, /)Irrtl/rr, CarJn•pulnr.•nary (lnn, The Lanltnau Hospnal: AI,IN rarr rn AIrA.• rlnr, Ilniversity af Pcnnsylvanla ScMrul u( Medictnc, Philadelphia 81 RNARD IIANI S, PH 1) , Arpnrlnrrnt n/ HrabA Sr Irn. e, ('a/dornu Stale l)nlversity, Northr,dgt. RI('l1ARD I IIAVF.L, M D, Auirlanr PrrrJrnar of MrJlrinr. Ilniversily of ('alifornia Medical Center. San Fran- cisco. t()HN A. IIAYES, M D., Arsociatr ParA.Jngisl, Mallory In./itule of Pa• thology. Boston City Ilospitat, Bouon. I/FRNFRT R IIAWTIIORNP, M D, ('Aaparan, Drparfn,enr n/ Swtrrry, tlmversar uf Pennsylvania (:raduNt Sthuw.l of MeJtcine, PbiLJelphia. ('I ARK W. I/FATH, M D, Prn/nror of A/rdnrne and Arrerl.w of llraf/ASnr- nrt, Tufls Unwcrsily, McJlord, Mass. PA1/1 1N1: 111'I/I R, PH 1) • RnrocA A....r r.nr rn ( rr.dncr und ('tl,r hrnnr- ar %..o I /on.r .,r (nshrnle uf MtJrcal LAWRI:N('t: 1.. 11FS11 R, la., M D, Pr.r/r...a ..n.1 (Yrnn.nnn. I )rrynr.nenl c•l (oh.lrrrn , aa.f (: ynrr nl.rKC. Mcdw al (',dkge of SrNNh ('ua,llna. ( hjllc.lun FRNF ('URT1S 11(FF. Ptr 1) . M D., Prn/r,s.n 101.1 CArurrnun, /1r.•rsrnn n/ Psyr Aunrrr Rnr,.rr A. MrJical College of Virgin/a, Richmund RUSSFII. 1. I/OLMAN. M D., I onisi- ana State University ScMn.l of Medi- cine, New (kkans. Ot.E A t1O1.TFRMANN• M D., Re- urrA SI iewltbr, L..hnnJ 1 ahwal.wy, University of Notre 1)ame, Noire Danse, Ind. FRFDDY IIOMBIIRGI R, M 1). Prril- denr and Doe, l.n, Br. i:escarch Insti- twe, lnc., CaobrdAe, Mass. ROBERT W. HULL, Pw D, Prn/nsar of IruJoltiral Stirnrrs, Florida Slate Univeraity, Tallabassee. IIT RESEARCH INSTITUTE, Cbicallo. GEORGE JACOBSON. M D., Prc./r•sor and Head. Drywrnnenl of Rwhnb.ey. tJniversi(x of S(whern l'aldurnia' Sahool of Medicine, I us AnAelcs. 1FRRY IIAR 1 IACOR%ON, M I) ./)i- rrr Iw, l)..-runn uf f Ir.lnrpbr.r.•LrKy. New Yurt. 1'ye and I ar Infinnary, New Yoch Jill II/S 1) /ACOHSON 11, M 1). Asso- crnlr Pr,.Jrurrr r•/.SurMrry rrnJ I)or.l.w n/ Srrgira/ Rruarrh, I/niversily of Vermon( College of Medicine. Bur- lintton. MURRAY E. JARVIK. PssD, An..riare Pro/rssor of PAarnr«nlnRy, Alhcrl Fin- ssein College of Medicine of Ycshiva University. The Brona• N. Y. OSWALD R. JONES. M D., SI. 1 ute'a Ilospital, New York. ANDREW A. KANDIIIS('ll, Pul), S/as Scirnriu, lhe lactwn l.alwra- to.y, Bar /IarMsr, Me ARNOI D R. KAPLAN, Pu D., fhrec- ew, faAuro/wy r./ MrJnaf Grnrrnr, Cleveland Psychulric Institute and Ilosprul, ('kvelanJ. ATfAI I All KAPPAS, 0611). Pr..lr.vw anJ .Srnr.•r Phr,nr.an, The Rucliefeller (lnwcrsrty. New York 82 i IIRA7('ll KA\PARIAN, M D, A.ci,r- aal I)rrrr r.w, ( ruJw. u.. uL.r I.r.b.NO- Lny; Ihr.ura rw rN A/rJn /nr, llahne- mann Medical ('olkge and lluspual. PhJ..klphia. 1:1 111U KA17, Pit D., As,.aiate Prc./es- u.r .•/ S.Mlyduty, Univcrsily of Ctti- casu, Chicago. SIIIRI F.Y 1.. KAUFFMAN. M D., Prcc- /r.un l./ Pr/hulc.Ry, Slale University of New York Downstate Medical Cen- 1er, Bruollya A?U'FL KI'YS, Pn D., Dorrrw, L.Mwa- 6ny u/ PAruof..Riral I/yKirnr, Ilmver- s/1y ..( Minnesota ScWul of Public Ilcalth, Minneapulis. I(riFl•11 B KIRSNI:R, M 1)• Pra/r»or c•/ AleJrrlnr. Ilnirersuy of Chicago ScMKd of McJicine, Chicago. PFTI:R 11. KNAPP. M D., RrunrrA Pr../rsaw of PsytAiaur, Boslon Uni- versNy S.hool of MeJicine, Boslon. KENNF.TII P KNUDTSON, M D, Uni- versity of S:NashinAlon Medical SchCSd, Seattle. ALVIN 1. KOSAK, PH Q.. Asaria/r Prn/rss.w of CAelnisrry, New Yo.k l/nivcrsity, New York. RONI RT A. KUHN, M D., Aswxiarr Pru/rruv. Drrition c./ NeurulnrRny. Ncw Jersey State College of Mcdicine, /ersty l'ity. MARVIN KIISCIINFR, M D. New Ywl IJniversity Medical Ceeler, New Ycwk. Ct/ARLFS W. I aeF1.LF., PH D., Assi.r- anr Prnfeu..r c./ }:nronnnun/a/ Hy- grrne, I)rponnrrnr of Prr.vnlnv MrJn I ine, /tMerson Medical Colkge, Phda- Jclphia. AARON I 1ADMAN, Pre1). Pra/euar anJ CAaarnnw, I)rpwenrrnr ../ An.nn- n/r. TLe Univetsity o( New Meaico School of Medicine. Allwyueryue. T1H)MAS (' I AIPPI Y, M(), Prr.les- nn a/ PruA..b•Ky. N.uthwe./crn I/ni- versny Medical School. ('Mcago R(1(iFR K. 1ARS(1N. M1), ('Are/ n/ Al.•Jn inr. Fresnu C.M.n/y 11.npual. Fresnu, ('al (i11ti1AV1 A I AIIRI•N71. h11). ../ Alydn rnr. 1i Vinccnl 1luspnal, Wurcesler, Mass (Y`( II 1 11111 1111 NN1.M(iFK, Pul) //ru.l. ltrl.nrunrnr .•/ ( yLrArnuwr Swi.. In.ruulc lur 1`epcrimcn/al ( an cer Ne.crlch. I au.anne, SwMterlanJ AVI'K111. A. 11111OW, MD, CAor nran. I)rpubcrrnr ../ Purhrdrqy, Yalc Ilnivcr.ny Schuo) uf Mcdicine, Ntw Ilavcn, ( unn. FS11 N O. I 1NOSI: .T/t. M D.. PN D, St l..xph'. 11u.pul Research lahoratorr %l P+ul. Minn. RONI RT 1/. I 1NNF1 1., PH D, Ararl arr o/ Chrnuury. Uwivershy of Vernnml. Burbnslon. 1(hRBFR I' I.. 1()MBARD, M D /N P.11 , Af/.b.ur, ('anccr Rtscacch In sthlule, New I nAlanJ Ikaconen Ilos pplal. Nuuun I. P. 1 ONG, Pes D.. Pr,./r/NM of Plw nun'.d.re,•, Stale Onivcrsi/y of Iowa College of Medicine, lowa Cily. DONAI 1) B. 11/1JR1A. M D. Arwrcia/r Pr../.•,vn ../ 1HrJaine• Ccwnell Ueivp sily 111eJrcal ( ullege, New Yorl. KFNNFTH MFRR111 t.YNCH, MD. Sc.D. 1 1 D., ('AnnrrNor anI Proln scw 1:'mernlws r./ ParA.dofr. Medical ('ulkge csl South ('arolina, CAarkaon (In a.x.cialiun wi(A Forde A. Mclvcr• MI)/ INFS KIANDI . Pn D, Auiuanl Prn/rr aur of RL.rAr.nlurr, College of Physi cians i SurRcons of Columbia Univtr sisy. New Yr.rl. DAVID 1' MANN, Ptr D, Arurriur Pr../rur.r of PAnrmara6.ey, Te/nplc I/niversity Schtwl of Psarmaey. Plotls delpbia )O11N 11 MAN11O1 D, t.. D M 1) Prnfrran and /Iirr.rnr n/ ParAnlultr nnd e)r.J /baACw.ur. New /eray ('u1 kfe of MeJ,c,ne and tkm,qry, lerrtr l ny. 1(1//N P MAN(ri• M 1). Inurnrr•r r^ {'nvl.q•r r.od Hw Inl.d.rKr. Mtdnal ('.dlcge u/ S.wth ('aroltna. Charlrsuun ('11RI%InPI1/ R M MARI/N. 0611) Asu,Innr Pr..fe.urr .r/ Alydrune anJ f)Ir.v r..r, lln r.r..n ../ /n/er r«.ne Pn r.n... New ftray Suu College of MeJ.c.ne. /eruy ('ity AIA%l1N RI SFARI'll INSIII I1TP, Wurstsltr, Mass 8)

. S IK)NA11) 1 MASSARO. MD., Atuni- urr Pr..Jr...w of Afrdnrnr, (icorge WashmRton University Schu.r) of Mcd.c.ne. Washington, 1) C. ('IIARI I S B McCANTS. Pn D., .Nro- .wtr I'ra/rlMw ../ S.wlr, Nurlh Caro- Irna Stale College School of Apicui. lurc• Raleigh. C/IARt FS McART11lIR, PN D., llni.er- sity Health Services, Narvard Univer- sny, CambriJge, Mass. HI NRY C. Mc(ill l,/. , M D, Anlwg I1raJ, Dr/.rrn.rnt of PurAal..ty, I oni- ciana S(ate llnrversay Scbol of Mcdi- cine, New (kkans. IIFNRY D MtINTY)S/I. MD, Prn/rs- .w 4 AfrJtu rnr an./ Dur.Iw, Crdio- .Xaurf .nurf.n Lhoeanwr, Dule University d.cal (-emer, Iktrham, N. C. FOROF A McIVFR. MD, Arvu{ur Pro/rrpr of rath..loRy. Medical Cd- lege of S.wnh (arolina, ('harkuowl /Scelynch,K M) FDWARD McKT F, M D• Pr../ersor . anJ A.frnR CAnuman I)rparlnvnt ../ Pa/h.dusy. McJ.ce/ College of South (-arolina, (-harlesrun KFILY T. McK/ F, M D, Arsocwr Pro/rre.w of AfrJurnr• Medical (-ol- kge of South Carol.na, ('harkston VICTOR A. McKUSI(-K- M D. Pro/rs- s.n of Mrdarnr, lht Johns /1op kins University School of MeJrcine. Ball~ mosc. ROSS 1.. Mcl FAN. M D, Associarr Prolrruw of MrJirint, Fmwy Uwirer- sMy Sclsool of Medicine, Allanta. W11.LIAM F. McNARY, 1.., P(( D.. As- soxwrr Pr../rrww ../ Anafwny. Boslon University School ol Medicine, Bos/on. NFAI. 1.. MrNIV1:N, Pe D, Tle Woe- « s(er Foundatwm fur Fspcrinsee(al BaMMy, Shrewshury. Mass 1111 IA MFYFR, Ptt D, Ata.cratt Pro- /rta.r ul (Iral Purhu6.Cy, University of 11/inuis ('o1k2e uf Ikntistry ( IN.ca8o ItI MN4at1) 1 0,111 1 1 )t A111, e.u....~. 1'..•1.,, •• 1 h. I....... I N..... h lw....urr . / ~. ....-... L.L...m \/r.l...l / ,d IAMFS G. M11 I I:R, M D.. Pu 1), Pr..- /r...n u/ P.Y.Amhv urJ r.etl..J..Ry: D.rrrr.w, Alrnml l/ruh/r Kr.run h In- uirNrr. University of Mtchtpn, Ann Arlrrr. 1111011 MONTGOMI'RY- M 1).. Arw- riarr Pr../rss.w ../ MrJn rnr, I Iniversily of Pennsylvania School of MeJrcine, Philadelphia. P. O'B. Ml)NTGOMFRY, /. , M D., Pro/rsuw ../ ParhuLny, Univcrsily of Tctas Southwestern Medical School, Dallas. (TF.OROF F MOORF, Pu 1) , M D, Di- rrrfo., RosweR Par\ Memt>,ul Inui- (urt, Bu/lalo, N. Y. KFNNF.T11 M MOSFR• M 1), Arsiuanr Prn/resrw o/ Mrbrrnr, (:eorgelown University Medical School. Washing- low, D C. HURI FY I FF MOTI FY. W. D., Pro/rs- s.r ol A(rd.. iar anJ Dnr. rnr, ('nrdro- Rrrprarory L.A..rrory, Univeraily of Southern California Sehocl of Medi- eine• I os Angeles. FDMOND ANT11ONY Mt)RPHY, M D. Sc D. AMUwiarr P.ufrtt.o o/ Ra.uanrns s anJ Mrdi. rnr, 1 hc Johns N.pltns llntversity School of MeJi- crne, Balt.mwe. W1111AM S MURRAY. Sr 1), .trnior Stag Scrrnrru, lhe lactsun Latwra- lory, Bac Ilathor, Me. RICIIARD 1.. NAF.YF M D, Pro/rssw anJ Chaan.aw, Dryortnrrnr ../ Parhol- oty, Pennsylvania SINe llni.ersi/y College of Medicine, Hcrshey. DONAI D M. PACF, Pu D, Prn/neor of PAysioloRy and Drrrrtnr, Institate /or Cellalar Reur.h, University of NcMasla, I inadn. Al BFRT B PAI MFR, Pn 1). Atuvanr Pr../rsr.w, Drrr s.nrnt .,/ r.y.h..luRy. UnwersNy of Tuledo, TukJu, (/ ROSE MARIIi PANGB(1RN. BS, MS, Atsiurunr f.rrJ Tr.hn..6.Rar anJ I.rr- rnrtr, llry.urrnrenr nl A..rn, r unJ Tr.hnaluRy. University of (-ahftnnia. Davis 1O11N W 1'ARKI R, M 1). A...•..orr /'.../r...n ../ I'.u4..l..er. I/mvrr.ny ../ \.h.rd u/ MtJ1 ..or 1 „t MJ i MARY YtFARNS PARSIII.I:Y, PnD., A..nrunt Pr../rsw.r r./ Awuh.nry in (16- uttrns and (:ynrr.d..Ry. College of Physicians i Surgeons of Columbia 1lmversuy, New Yor\. EDWARD W. PF.LIKAN, M D., C4w- nwn, DrOa•rnrrnf of PArnsacolory and Eaotrrnrenral TArraptntics, BoNon Univcrsity School of Medicine, Boslow. OTAKAR 1. POI.I.AK, M.D., PN D., 1. cr. rtirr Dr.rrrw, Dover Medical Rt- search ('emer, Inc., Duvcr, Del. MORRIS P(N 1-ARD, Prs D., Dirrcro., I...ArnJ /.A.watwy, Uwivers" of Nuve Darec, Noire 1)ame, /nd. C. M. POMFRAT, P(r D., Dirrrfor of enrloRuaf RrrrrcA, Pasadena Founda- /iun /or Medical Research, Pasadena. Cal. H. R. PRATT-TIIOMAS, M D., Dran and Prnleuor of Par/wd.qr, Mediea/ ('cJ1ele of South Cardrna, Charkslow. MARTIN S. PRO7TF1., B.S., D.D.S., Chu/, Deyrrenrwr of (bal Parh.doRy, Newark C-ny Ilospl.', Newark, N. l. WM.TFR RFDISCN, M D., Auoc(atr Prulrseor of Clinird A1.Jirinr, New York University School of Medicine, and NY1/ Research Service. Goldwater Mem.rial Ilospilal, New York. W11 1 1AM RFGFI.SON, M.D., Pr..frtsar and ('hasrnran. DrpurMrrnf a/ MeJdral ()nr..l..Ry, Medical College of VirAiwia, Richmond. IIOBART A. RFIMANN, M D., Pru/rs- s.w n/ Mrdreinr, I/ahnernann Medical College and Ilosp(al, Philadelphia. ROI I AN[) C. RFYN(H DS. M D., As- asfant Pro/r,NN o/ PatAnG.Ry. Um.er- si(y u( "lesas Soulhweslerw Medical Sc IKrd. 1)allas. VI(-1(1R RI('l1ARDS, MD, l'hlr/ of .SurR..r• Preshylaian Medical ('enter, San /•ean.rseo WII 1.15 U RIFSFN, P(( D- Srni.n Ri... .Arnnnr, J.Ir S.ue.re Dtriu..n. 11T Reseach In>tuwe. ('hicagu (lndiated un.kr A Wc.nsl.r\n ru 1) ) R 11 RI(:IN)N. MO, P.../r..o. ../ Pe- eh.d..RV, 1lmversity u/ Iesas MeJNaI Nranth, l7alvcslun SYDNI-Y C. RITTFNBFRG, PnD. Pr../rs.nr a/ KuUnroluty. University of Suulhern Cdrfornia, Los Angcks. BENSON B. ROE, M D, Aswrlatt Pro- /nu,r u/ •SnrAery; CAir/, Crbac Sw Crry, Universi(y of California Sctwul of Medicrne, San Francisco. JOSFP/1 11. ROGERS. M D., Ildy Name of Jesus Ibspi/a/, (iadsdew, Ala. ROBERT C. ROSAN, M D., Assorlarr Proftssor of ParA..lory awd Prdiarn.. St. Louis University School of Medt cint: Associarr PasAolot.u, Cardutal (7knnon Memorial Ilospul (or Cttd dren, S(. lcwis. IOHN R. ROW1ANDS, hrD, Sraif Srirwt/sf, Suwhwes/ Research Iwrituec. San Antonio, 'Tca. BFN/AMIN A. Rl1BIN, PwD, Anisuant Profrsror e./ PuAlir HrdfA, BayIw University College of Mcdicine, Ilou slon HENRY 1. RI/SSFK. M D, F.A C P, PrniJrnr, The Russek Fouwdatwa. Inc., Suten Island, N. Y. W. C. RIISSFI 1, M D, UnivenAy of Teaas Medical ('entcr, Iloustow. WAYNF 1_ RYAN, PeD, Pro/nso, of ai.ahrrnierrr, llniversi(y of Nebrasl. College of Medicine. Omalu, PETFR F. SAIISBURY, MD. PaD. Hrad, Irntrnsrrt Treatment Crwrn, Sarn( loseph Ilosptal. Burbawt, Cal PAUI. SAI.7MAN, PM.D, AsshtantPro- /e.u», Depnrrnrrnr of eiorArmltrry and Nnrrur..n. Univcrsily of Southern ('ahfurnia School o1 Medicine, 1 os Angeles UI RI(-Il 11 SCIIAFPPI- M D, Dl.rr f.w ../ Nrruaohr.nar.daRv, Mason Re search Institute, Wawcesler, Mao. /OR(iFN U S('NlF(:fa MD, Pnl). Pralrruw an.l ('hunnun, .Sr.Unn .•I ftralaRy, l)rpeort.urnr of (urIrrry Tulane llmversuy School of McJKtnc. New ()rieans At VIN N S('11M1h1• PuD, I)Irr.r.n •#1 ('.nu..rl.nR, Iu/Is llniveruty, Med /.nJ. Mass ISAAC S('//OI /R. 1) 1) S. P.M D./) tic . I)r..n. (.Jlrer "I llrnnury, ilroveruly ul 111mun, ( h.c.8o 85

AIAI /kl( 1: S SF(:AI - h1 I). Chnirul af A/rdn,nr- I.dls Univrf• .uy Sch.u.) .d MtJ.c.ne; l)nrruv, Dr• /.•u,.n.nt ../ InhuLm•.n Thrrnpr, H.n- lun ('dy I/asMlal- nostun. (See Cbo- J.,.h- S ) CFIAKI I S F. SIIFRWOOD. M D, As- „uan/ Pr,.(rwv .,/ R•,JnduCy, llnirer- sily of R..cheuer S.hw.l of Medicine and Denl.dry, Kochruer, N Y. S11O11 SHIRATA, M D, Pn D, Pro/rs- nr al l'harn.nr,d.•Rr. University of Hawait School of MeJ.crne, Hwtohhr. DAVID 1.. SIMON. M O., Iwvrwtor, lJrpw/n.rnc of ln/rrn.d Mrdirinr. Cie• emnali (icnerd Ho,pnal. CineinnaU. ERIK SKINHNI, M D, Ch/r/, Drprt- n.rnt ../ NrwuluKr, tiispehie,R Hoyl- Ial- ('openhagen, Denmarl. GFORGF W. SMETTERS, M.D., Auo- ratr /n ParhuluIr. Norlhweslerra Uni- versily Medieal School. CtsieaAo. GFNE M. SMITH, Pn D, Au(uant Pro- /rswr a/ P,ycholusy. HarvarJ Medical School. Massacsusetls (ieneral Ifospi- lal, Soslon LUCII E SMIT)1, PN D, Pro/rnor of Ri,n Ae.mury, 1)artmuul! Medical School. Hanover, N 11. SHFI DON C. SOMMFRS. M D, Dirtt• t.n of Lahorarorrr,. I enoa 11111 Ilos- pnd• Chnical Pr.rftn.w of Puholofy. Colkge of Phys.cians A Surgeons of ('olumbia Universily, New Yort. ERNEST SONOIIFIMF.R, PH D., As,o- tratr Prolrrwr u/ BiatArntiu.~. Cd• kee of 1'oresury, Slale University of New Yorl, Sytacuse T. M. SONNFSORN, PND, Diuin- AtJ Srrrrrr Pru/rs,or o/ 7uol..8y. Muna llniversily, Bloomington. SAM SOR(1F, hl [) . Head. Department of A(wr.,molrrular Chrnnrry, The Inunule for Canccr Research. Plila• delphu. SOUTHWI:ST RF.SI?ARCH INSTI- I lnE. San Anlonio, 'ret. DAVID M SPAIN. M O. Dtre.lar. Dr- rrunrnr of Purh.duer. The Ilrookdak n.ppd ('enler, flruollyn, N Y A11 XANI)l- R %P(( K M/). A.uuawt P•••Ir.,•r ../ PrLa.w., Ilti\r 1104.41. sny MeJ..a11 emtr. Ihnbam. N(' I KFIN:RI('K 1. STAKI°- R1 n. Pr../n• NN of Nurrim,n, IlarvarJ I/nivctsily ScAoal of Puldic lleallh• Hu,lon C IIAROI1) SIFFf1-F. M1), 11or,r..r of Ca/4NYIUrIr/, Me1b1Nhs1 Ilu,pi/al, Mempais. JACK P. STRONG, M O, A.a.riutr Piulnsar of Purh.Juey, 1.w.isiana Stale University School of Medicine. New Orkaws. MARION fi SUI 7.tiERGFR, M D, Pru- /rssw anJ (-huirnran. Drrw.urv,nl u/ DerwtN.,lury anJ Syphd.d,.lcy. New Yorl Universily-tieKevue MeJical ('cn• 1er, New Yo.l. RENATO TAGIURI, Ps/ D, Aua. iu/r M1o/tssor of P,ychology- Graduate School of Business Adminnualion, Har.ard UniversNy, 6os/on. CAROI.INE SEDEI.L THOMAS, M D., Pro/rssor Ernrrirus o/ MeJiu inr, The IoAn. HopUns University School of Medicine. 6allimwe. JEROME F. THOMAS. PN D. Pr../r,sor of Sanlsary F.ntinrrrins, University of C.li(otnia, Berkeley. JAMES E. P. TOMAN. PuD- Pro/e,- ,.w anf Chaun.an of Pharnmr..fuRy, ('hicago Medical School. Institute fur Medical Rescarc6, ('Aicago. JANET TkAVF1.L, M D, .(ru.rrate Pro/rssnr ol C'/inird Pharn,arnlu[y. Cornep University Medical ('ollcge, New York. LIE SHA TSAI, Ptu D., Research As,o- tiue, DrParr.ntwt of Puth.do[y, Yak University ScYrwl of Medicine. New H.vew, Con.. ROMEO A. VIDONE. M 1), .Inntiatr Pro/tnor of Puh.doAy, Ya.e Univer- sqy School of Medicine. New I/aven, Conn. P1=.lER K. V(X:T. Pwl), Prnlrunr o/ Mi.rusi.daey. l/niversuly of WasArng• lon School of Medicine. Sealdc. E. D. WARNFR- M D, Pru/rau.r of Pa- shol.s) Slale University ol Iowa ('ul kle o! McJ.cine, luwa City S111F11tS WARKI•N, M 1), l•.r .•I Rrfrar.h /n.rr. Iru. New UnAland Ika.uness 1luspi ul, Boston 86 I I c YAS(I1111 WATANAIIIi- 1'ul), A....- . rulr Alrnd.rr• I hc W.%I.r In.tilult of An.d.wuy anJ I/NAaty. I'hdiJtlpMa. IIAKItAkA A WA1]()N, 1'nl). Asu.t• ..nt Rn.Lrwl••pr,I, Ma.,achuxlls (ien• cral lluynt.l: Rr.rur.h A,..n.arr, Ur- Iw.unrnr ../ ftu. trn.dney and lnrnrwn..!- ..yy. /IarvarJ Medical S.)w,ul, HusWn. 1OHN S. WAII(711, PuD, Pru/rss..r of (Y.r.n,.ay, Massachuscus InsINWe of IcahmJuCy, ( amlwiJge. KI( IIARI) I WI ('HS11 K- 1111)., ('bn- nul I'hyanL.cnt, Munlrfwrc Iluspilal In,iilule of kesearch• PNhMash. 1(IIIN V. WI•Il., M 1)., A..nrnnt Pro- /.•..ur ../ MrJn,nr, (/nwersily of Colu- LJ.. McJrc.l ('emcr, (knver. A. WFINS7(X-K, Pt/D., I(rN•,Yrh Bu/- . hr.n..l. fa/r S..rn. r. /).rniun. 11T Reuarch Insti(ule, Chicago. (See Rie- sen, W/llis II / kUStil'11. W. WFI.LFR, M D., Pathul- ...nt, Memorial Hospital of Chesler ('ounly, Wes`CAesle,. Pa. SIAI()N 11 WI NI)I k, PIl l). Rrnrwrh I•r..fr...a .•I Hnnhrrru.rr), UnivetsNy u/ (ill.h.wua, Nurman. FI(fb1 kl( K I WHISKIN, M D, C M., I)n,•tar, Ilnrv..e ../ Nrulth rnJ Prr- wnuliry l:yu.hl.r.urn, The Age Center of New I ngIanJ, In. , Noslon. K((i1 R 1. WILI IAA1S, M 1)- Pro/trwr o/ Chr,n..tr): I)or.tur. ('hurrun Fuun• JalNnr RnNhrnll.Yf (nsltlYlr, The Uni- vesuly of 'leaa., Auslin. DANII-1 11 WISI:MAN- M D, Auur- anl PrnJr....r ../ /•rJ.ut.r..- l)nivctu/y' of SawlAcrn ( .Idurnuc ChdJrrw', I)i- ri....n, I os Angelrs ('uunly (:eneral Ilo,pna, I .s Angeles 1. LDWIN W(K/I), M 1), In.uu.tor u. A/rJu,nr, M.nt..n ()nwcrsny Schrrol of Medicine. 1luslun. SUMNf.R WOOD. la . M 1). Aru,tuwt PrU/r1NN ../ PullnJurr, The /oAns Hopim. l/nr/crsny Sahool of MeJi- eine, 8alunuue. 1O1/N P WYAI7, M D, Pr../ru.r o/ Pudud..ey, 11. I ouis llnivetuly School of McJKtne, SI. I ouis. A7

INI)EX OF 1'ItIN(:1/'AL INVFtiT1(:A'f(IRti A.ijJ,,, O W. ?h. ?7 Baraa, A (' . 4? Bell. B anJ Rnse, C 1., 61, 64. 65. 66 Bhagal, B 1). 32.44 Bing. K I. 3l, 34. 3 5. 36 Ch.Jan, 1. 13. 32, ll ('othrane. C. C... 1), Sl. 54 ('ahcn, A B . 23, 24 ('tuss. C. F . : x. '-9. 30 Ikanuw. E. V.. 43 Flicl-Arn. C. K.. SO Fs.min, W. B., 44. 45. 46 1:rshcr, f. K . 37 FrieJman, Ci D., Sx, 59. 60, 61. 62 /'u,knhcrg. 11. II . S'. 69 1lcrxuwitl, 11. B . 54 Ilnmhursrr, F., 19 I.auwcrym. J M, 20. 22 I c(ncr. R. A.. 17. St, 56 1 curhlenfkrgcr. ('., 17, 18 Irx»li,C.(i..21,6x MtKennis, 11 . Ir , 70 Meier. N., 14. 69. 71 Millman, C.. 66, 67 Niwkn, A. If.. 31 Parker. 1. W.. 56. 37 Rvu. C. L.. 63 Sellier, C. C.. 62 Skinlyi. E.. 39 SMrllin, T. A.. 50. 51. 32 Sok>af, L. A.. )7. ltl. l9, 41 lravrs. 1.. 25. 26. 71 Wcniel, D. G.. 40. 41 Wesllall, T. C.. 40. 47. 48. 49 Whilmire, C. E.. 15 r • I I xx .4 , INI/EX OF tit:Nl()R AUTII/!Kti Aa..1a. 1) . 40 Amhravagar, M., 3) An.krs, I K..64 AvtrJa, 1). M.. 26 Bhagal. B.. 44 Bing. K. 1.. 34. 35. 36 &n.r, K.. 63 (-hal.+n. l., 13. l2 ('rKhrane, C. G., S), 54 Cuhen, A. B.. 23. 24 ('russ. C. F.. 211 f).rks. L. (i.. SM 1).wninn, l:. F.. 4 ) friclxm, C. K.. 10 Vssman. W. H.. 44. 45. 46 I-aJali, A. M. A.. 41 1 auvel, J. M.. 36 hisher, E. R.. 37 1rr..R.R..71 t'uiarJ, 1. 1.., 65 : I4irJman, (i. t)., 60 (;arvey. A. 1.. 63 (:emsa. D., 52 (;tccn, If. ()., 52 11j.himotu, II., 35 IIerJ. 1. A.. 42 Iler.cuwilt, 11. B., 54 Ilrwuburger. F., 19 Ilung, K.•S., 21 lnhnsnn. D. A.. 25 Kennel. S. 1., 55. 56. Kingshury, 1). l., 17 I Klalsly, A. I... 0 Kouri. R. 1:., 06. 16 1 acku, A. (:., 37. 39 1 auweryn., 1. M.. 20. 22 I.euchlenheracr. C.. 17. 18 I.inJxy, l. R., 69 I twrsli, C. G.. 21, 68 1 rNkswieS, 1. 1.. 69 Malhwy, P. A.. 26 McKennis. II.. )t.. 70 Meier, 11.. 14. 69. 7) MNlnran, C.. /A, 67 A1uslala, M. (:., 211. 29. 111 Nukn. A. 11.. 31 U'Bricn. R. 1... 37 Pachinger. 0. M.. 33 /'arler. 1. W., 56 Rusxll, S. W.. I l Rulenberg, 11. 1.., )8 Srluer, C. C.. 59. 61. 62, 66 SieSelaub, A. B.. 62 Slinhrj, E.. 39 SkNkin, T. A., 30, S 1 l ravis. 1.. 71 ViJit`. B.. 32 Waunahe. T.. 27 Waugh, N. C.. 64 Wen.d. D. G., 41 Wes1/aN, T. C.. 40. 47. 48. 49 Whilmire. C. E.. 15 Wuepper, K. D., S l 89