Tobacco Documents Online

48 CTP HN 0 11 B'72

I i . EXTRA COPY REPORT O, THE COUNCIL FOR TOBACCO RESEARCH-U.S.A., Inc. 1973 ~~ ;t• ~ ~ {.~ ,, Mv~•I•. a I . 11 o I .C1 .) ~;~ ~~~• ~. ,~• f

••4 Organization and Policy 'Tlw C.ouncY /or Tob.oco Rcnearcb-US.A., loc. ..s fortuoate this ycu I. h..1.g ..rorld•nsowoed asoer r.e.Uplor. Ck. WiUl.re U. G.rdeer. /oi. th+ u.A as 3ciesti6o Director. T'iti4 p.t W!.r ..cam .ioea the deah of ~' Dr. CUrcno. Cook 1Jtt1. i. DKC+..rMr 1971. Dr. Oardner receatty reNred .. • E. X. HunM rrof.uw of A.Noery at Y.Y U.Iwalf7 School of MedkMe what ` b bad beer hdmor ad Chal.>..a ot t!o Dqortr.e.t of Ae.ro.n7 /rom 1967 191) . - ~, Or. Robert C. Hocteft, w•io J~.m brw rk! Tbs Cowc* d.oe 1931• S.t b..e ypoLM.f Rewre! DMstor. 11o W iw artil.t r AetZ n6 Sckotibo ~' Weasar for tfr /a.t two 7s.m T1.o dhtl.wiJd aM." /olr/ the Sd..df{c Ad.br7 ro.rd drrleg 197). iddYi6 (M1Asr areyt6 ..041 oaprli- b 1y >>bard. Tlwy .rt Dr. Averill ~~ ~/.. p. U.6o.. hofwor md C7dr.rm ot 1i. D'.rt.w of ht`oio6y N tL. U.fw.N7 d C.Yfor.i. Scfooi .t if.delr i. Sr Dieoo4 ..d Dr. Heory T. Lys* 1'roforor ud C1.in.r of the Dep.eu.eM of t•r..wl.. M.dki.* ud , • lv6Ye H..kl .t Cni6foo. Ud..n1t7 lebol of M.dki.. I.Os.ha. Neats.i.. ..- /' tli be l ft ttr rao d McKeca . tA 3r n . r . . 1.+r. e u >L ~; . C.Ildl ..d KeareU Metrlp L7ah b.d bees ~.ben .{.oe the tao.rd was •0 saaM.wo M 1 ~x., r/.uM an. a.Myw a~ ..o F+.a 6+os 7vo ...c..  u. , ~.rir oora+.l yd ...t axperir.oe of 16w .e.{ot ..cs of .ckocs sd roedkios did awc.b b.d...a. Th. CourdPk rescuc% proW.... . 'iL. CancY Y t!M spoa.ari.g q..cy of a progr.n of «acar<L Iao que.t.b.s ot tob.coo ur ..A YeaNi It I. t!0 oytsro.th of .n orp.lsalo. ~ r forwr/ s.rfy M 19!• by nlrve.tvd.w of lob.oco na.u(icturva, lpo.a+ ~ t J, w•aelw..anes. Rc.eatdl wrpport Irm oen a.i.ly tbron& a pro6rae of ~. .~ ~ 6rr,.t.lo•aM wpple.e.ted by coancts fot tatarcA .ilb LMYixloo. .ed {.bor.wriez Ths Ca.eil doe..ot iudf opae+N u7 rese.rch f.dUty. j. .• T!. Sekati6e AQri.a7 Re.rd 1o Tlr C•otr.cY seas eesulady to o du.t. ..pq+lat(ons for „aw•it.ld ..d for oo.a.M )+rdyy aoa .okty os th. '•!..ls of .d.ai6c merit rd rdera.co. TDo Couotil .watd. nsbrt! Sno1. /o iod.t..deM akftists who .n ., ..wad ooe.pkte ai.otjfk re..da. 1n oo.dr.t!!.6 tladr Nudie.. Uraaees atoeis ;~ .n fsyorrihN for r.portrj or publlsbi.6 t,di fi.dier r t!r .cccpte0 .deMuk e,.ser - IDro"e .wdic.d ..d .deatuc jour..l. ,.d .ockue.. Throu6A Dooeatber 1973. nsearcb prooct. \.re beeo .ppro.ed f u 299 ~L.estlo.tory I. 2111 roodkal .eAooi., f,o.'itaM ..A eaarrJ lo.tkatben. Thw .-.r& totaled ww+ th.. f26.000.000. 71ThV repor~ iedrda a l.id .r.rnt.ry of T1. Car.dl'e praeet pro6r.+. .. .eM .. 8Ms of the cwr..t ..A pe..brr nr.anh proec1u wppowled by T1w CarcR. Also Mclud.d .r+ abstracts of I 16 nre.rdr p.pam .ck.o«lodtloti ,,Carefr .uffart that ww* publi.Md {..eMNfie jorr*d& drriy 1973. A total "d 1,170 .reb ppers l+.s e..e publli.d by proiKt nelv+ru. ~ m ~ H. H. Ra+.r (ldte..,n yd Pre.1d.ot 1973 REPORT 0/ TIIE COUNCIL FOR TOBACCO RE5EARCI$-U.S.A., Doe. Tl1E (Y1lINC11. F'11N T(1RMf.C(1 RI:SF:AR(71-II.S.A., Inc. 110 Fa.t •Syrh titrert, New Y.rV, N.Y. 10022

SCIENTIFIC ADVISORY BOARD to The Council tot Tobacco Research-U.S.A., Inc. as of December 31. 1973 SHELl7nN C. SOMMERS. M.D.. Chai.nsan [)irrctor of L.uM,rarorirs, Lcnoa Hill Hospital (7inical PrnJrssor of Pathology ('olunsbia Univcrsity Colk`e of Physkians and Surgeons New York, New York HOWARD B. ANDERVON r. Sc.D. Scirnri/ic Edit,>. (retired). The lournd of the National Cancrr Institute Bcthesda, Maryland RICt1ARD M BING, M D. Director o/ Cardiology and Intranrurd Medicine Ffuntington Memorial Nospital, Pasadena, California Pru/nsor of Medicine l)nivcrsity of Southern California School of Medicine Los An6eles, California WILLIAM ll. GARDNER, PH D. ScirntilSc Dirrcrur, The Council for Tobacco Research-U.S.A., Inc. E. K. Llunt Pro/rssor of Anatrwny (retired) Yale University Schrx>t of Medicine New Ilavcn, Connecticut RC)BF:R I 1. HUFBNER, M D. ('hia/, Viral Carcinosencsis Program National Cancer Institute Bethesda, Maryland I.EON O. JACOBSON. M.D. L)ran of the Division of Biological Sciences RrRrnstrin Pro/cssor of Biological Sciences lJnivcrsity of Chicago Chicago. Illinois AVFRII.L A. LIEBOW, M D. 1'ro/rssor and Chairman. Ikpartment of Pathology University of California School of Medicine San Dic6o, California III:NRY T. LYNChI, M D. 1'rn f r s trrr and Chairman Ikpartment of Preventive Medicine and Public llealth ('rerRhtun (Inivcrsity Sch«.) of Medicine Onraha, Nchra%ka I NANS MEIER. D.V.M., Dr. Mcd. Vet., M.R.S.II. Srnior Sraff Scientist 1 he Jackson Laboratory Bar Harbor, Maine IONN P. WYATT, M.D. Pro/cssor and Htad. Department of Pathology University of Manitoba Faculty of Medicine Winnipeg. Canada sclewrift S1a/f of 11.. Couaell WILLIAM U. GARDNER, PN.D. Scientific Dirccto. ROBERT C. IIOCKE7T, Pu.D. Research DGrrctor JOHN li. KREISIIER. PH.D. FREDERIC W. NORDSIEK, PH.D. Associate Rescarch Director Associate Research Director VINCENT F. LISANTI, D.M.D. Research Associate

Introduction Introduction CONTENTS Cunent Status of the Rescarch hopas ....... 5 7 Canctr St ud ies . . . . . . . . . . . . . . . . . 7 Chroek Respiratory Diseases . . . . . . . . . . . . . 9 Cardiovascular Diseases . . . . . . . . . . . . . . . 13 Pharmrnlnev and Psvchooharntscoiotv . . . . . . . . . 13 Epidemiolotty . . . . . . . . . . . . . . 14 Abstuacts o/ Reports . . . . . . . . . . . . . . . . 15 Studies Related to Cancer . . . . . . . . . . . . 15 Heart and Circulation . . . . . . . . . . . . . 28 The Respiratory System . . . . . . . . . . . . 34 Phumscdc+Ry utd PsychopharmacoloIlly . . . . . . . 51 lmmurxAM . . . . . . . . . . . . . . . . 61 E pide m iob6y . . . . . . . . . . . . . . . . 65 The Normative Aaing Study . . . . . . . . . . . 67 M iacell uKou. . . . . . . . . . . . . . . . 75 Active Projects . . . . . . . . . . . . . . . . . s0 Compkted Projects . . . . . . . . . . . . . . . . 66 Index of Senior Awhon . . Index of Principal Authors . . . 94 The interaction of the genetic or conslilulional factors and the envkn.- mental conditions to which an individual is exposed over the course of m.r.y years probably contribute to the expression and nature of the ying-associued diseases. Those diseases thot have been statistically associated with smoking and health are predominately age-associated diseases. In some instances, an Indl- vidual may have an /nherited tendency /or a disease, for example empAysema, and the associated .nd presumably conlribMrory inheriled dpha-l-anti/rypue defkiency. During the p.st few years much has been learned of viral eapression and cancer in laboratory animah and of chemicals which, when modifkd by entym.s that may be prexnt, can transform normal body cells into cancer cells, po.sibly through initiating viral espres.ion. Chemicals thau may thentselves be quite i.- active In Inducing cancer In laboratory animals may make srnall and ineffectlve amounts of known cancer-causing chemicals capable of transforming uorwr.l cells inlo cancer cells. It is now possible to monNor the environment of iebrad laboratory mice so that the viral, chemical, immuoological, and genetic qualiiea can be knowingly controlled and varied. The env'wonmenl of laboratory animals can be controlled more apeclYcary than can man's environment. Even when genetically eontrolkd and predisposed laboratory animals are used, exposure to known or presumed usar-Invdi.~ ehemicats mual eRtend over prolonged periods. Only morwrsygodic (ideMicall twins afford a genetic unlfonwNy is w comparable to that of inbred laboratory animals. Il they are disoordant 1. dr` terminabte environmenul esposurn, these twins could provide data that may lead to the determination of the relative Importance of genetic and eaviror• menld lacrors. Such studies art being undertakew in countries in whicj dr mortality from lung cancer reportedly differs more than fourfold. The transformation of cells in tissue eulture lus been studied i. Iwpes of obtaining a rapid and reliable method of dqeeting small amounls of ea.cer- causing chemicals in materials to be tested. The occasional "sponta.eaua' va,..- formation of cultured cells, the'resence of 1a1eM viral antigens and odser qraY- ties have not permitted etclusive use of cultured cells for ddection or qwdMa• tioe of cancer-causi.g .ubuawces. Up to this tinse, the resd/s dlirwr, ir Rencr.l, those of experiments with intact animals. The in rlrro techniques pwvide the methods of investigating mechanisms of cell transformation at a aubcetlular or molecular kvel and of search for inhibitors of translormation. Revcrslon of transformed to normal cells and selective inhibition of growth of uaa+lormed eells can also be deteqcd /n vitro. The discovery that the kvels of inhibilors of protcolylic enzymes ie rhe blood of persons highly susceptibblo emphysema are low, has reveald Y kaM one objective hereditary predictor quality for this pulmonary disease. Pursher- more, informarion on the sources of prote.ses, the mechanisms of rher aklion on body tissues and rhe characuri.rics of their Inhibitors continue to be .ow.er. The affe-associared atherosclerotic vascular diseasn, panicutarly those in- volving the crwonary artteies, continue to be /nvesuigaled from nceir sescrk and environmental rntcrrelatwnshrps An enzyme that makes cl.oksarod nsur• soluble, lecithin cholesterol acyl-transkrase, may provide informalion /oc slgnifi- eant advances in alherosckrosis. 5

Nicotine and its metabolites, under sonx eircumsunces, have Jircct or in- Jireci cllecr, upun nerve cell.. lhe development of raJwirnmunuas.ay methuJs for the Jeteclion of nico/ine and rneuholites is lacililahng work on rncratwhc studies and nuy rcveal speafie nerve eells upon which they may act or may have binding sires Significant advances in the psyehopharmacolngic.l mpecb of smokrng may he eapectcJ as mNhoJs develop to permit eapbratiwr of a dwect nicotine lnnJrng t cellular or subcellular kvel. Some of the renearches supported by The Council are at the cellul rr and suhccllular levels It is mtportant that advances continue to be made at such methodological anJ conceptual kvels /o assure continued progress in other aspecls. The support uf hasic research in Immunology or virology, for easmpk, may contribute signdicantly to an undenlsnding of smoking and hcalus The more than 100 papers reporting investigations supported by The ('ouncd that were puhlr.heJ during this pasl year reveal the breadth of the overall reuarch interest *u t usr l1. (3aat»rr-a. PN 1). Scienlilk 1)ircclor Current Status of the Research Program The research program of The Council for Tohaeoo Research-US.A., Ioe. espanded funher in several directions during 1973. with studies eelatiot so cancer still receiving the greatest emphasis. Studies of chronic pulmonary diseases and epidemiological investigalioen have also bee. eapanded. Among the latter, the study of identical twin populations as a nseans of separ.ti.j gewetic from envvonmenul factors in Ihe genesis of diseases has been ettendcd. Researches on cardiovascular d'nease" and on phurn.eolopr and psycho- pharmacology were continued at approaimately previous kvels. As herelofore, Ihc emphasis was mainly upon the etiology or pathogenesis of tl,tse aRing associated eonstitutional diseases with a special iotereu in the discovery of factors predictive of suseeptibHity or resistanee lo them. Since the published results of Council-sponsored studies are .bstr.cted elsewhere in this Report, our intention here is to give perspectives on tbe nature and eatent of the program as a whole. the distribution of emphasis arnon& its parts and on the purposes and plans of approach in such a way u to aid in fittrng individual research reporH into a conmest. It will be recognized that many studiea acknowkfting Council aid represent small methodological steps toward ultimate pals and Ihal some arc by-products of the main cflort. Canccr Studies During the year just ended. The Council concentrated major attentioa upoa an eatensive, systematic, multilactorial and step-wise study of carei.oge.csis in a number of contrasting mouse strains. The object of the ongoing study is to define and measure several genetically mediated biochemical characteristin that are thought to determine and predict the responses of these animals to eaternal "carcinogenic influence.," especially to chemical substances introduud into the lung with or without promoden or special conditioning. This under- taking is to discover and define conditions under which truly malignant, aggressively invasive and lald squamous carcinoma of the lung, with mctastaae., analogous to the human disease, can be obtained repetitivcly and predictably in such animals. l he importance ol this goal is gnphasired by eaperience showing the ua- certarnries in diagnosis of nsicroscopic, incipient lesions by purely rnorpholopcat criteria and in the use of such ksions as end points in eaperimental reu.rch. 1/ this aim is naineJ, in the contcat descrrbed, it should provide in/or- mation in b/ochcmKal, tenclK, viral or immunologic terms how the snimal. that develop this dIKaY diflcr Irom those that prove to be reswsunt or immuoc lhrs n the kind of rnlormarion Irom animal eapenmcnts JccrncJ rewst likely to provide promising clues /ot spplrcatuon to human studies 7

/nadrquocy ol MouscS4in Peintin6 llx ('ouncil's often repeatcd disutisfaction with the conventional mouse- skin painting with amoke condensales as .n indieator of "tobaeeo carcinoteni- eity" uems in good part from the well-known and very great differenus among •nimal Mrains and species in their responses to treatments of this kind with known end paenl chemical .gents. Without information about the biololical bases for such diRerences, any arumption that the resuNs of such mouse eaperin.ents can be estrapolated direcdy to other rpecies, especially man, is highly presuraptuous. A('ouneil-sponsored study completed during the year employed wrousaskin esposure so whoM fresh smoke in Its aerosol fonn in comparison with skin painting with .rnoke condensate from the same refaence cigarettes. Tl+e results appewed to show that Me condensates produced hothly utifactu.l re.ulu. If onwfirmed, this study noems likely further to reduoe eo.fldenoe in dse skin painting teehnlvw. Similar uncertainlics pert.in to the signiRcuce of nearly .U smokc in- halation studies heretofore curtied ou1 with animrda because of {nadce uata deinitiow of the animals and poorly controlled or unquantitated etpAUre condilio.s. For the current nMrhifacyor1 al prolect, the tnouse h.s been the spxks setected because it oAers the n.asimum potential i. (arms of definabk renelic .nd bioefremicAI susoeptibility or resMa.ce factors and thus may hop fuUr provide the shortnt disces.rbk route toward huma• relevance. 11 should be under.wod that the highly Inbred mou+e stralns used in the study rue euen ~ially laboratory ereations end never esisted as such in the undisturbed ata e of nalure. They must therefore be regarded as "bundlcs of traits;' not as rlirect models of man, ao that caperimental results will be rclevanl to man (or Hhcr armah) only inwfu as the same traits arc present and simrlar in import. "Fteder" Studies Carried Out The present project became poasibk only sfter a large number of pre- lirni.ary or preparatory bioio=ical projects had been carried out as "-fecdcn" to provide basic information essential to Its design. Previous Annual Rrports have describcd or listed many wrch investigations. The program b uitl passing through syslenulie, step-wise developmental phases including subcutaneous injectio.s and lung Implantations of know. "eareirwgens." When suf:icient informatloo about susceptibility and resistarwe to such carcinogens hat been aocum.tasoL {ong-term, chronic espowrm of contrasting "de6ned" animals to inhalation of whok, fresh tobacco smoke or its gas-vapor phase are con- te.rwpiated. llrcu will require the production of smoke under conlrotled con- ditions, from tobacco products of known composition and chuactcristics, delivered quantitatively and monitored by tissue dosage measurements A battery of tcsts and observations is being developed and refined for application to the treatcd animaM. Several snvrec contracls for carrying ou1 the necessary ehemical, physico- chcmical, analylK, mcchanKal, •nd calibration work conlrnue in operation at a high Icvrl to support the dcvoon of the eaperimcnts In such carrfrJly cwwrdkd tong term amokc inhalation eaperimenls, using hithly su.crprihlc mNc of lahu.atory dcs«gn and other strains with contrasting combinatiorn of putative susceptibility characteristics, either the appearance or non-appearance of squ.mous lung carcinoma (or odher canccr), should provide, nor immediate conclusions, but scienlifie information on a new plane of interpretability and potential relevance to man- Biochemical and 6enetic F.ctors in Cancer Among the biochemical or genetk factors rekvant to cancer wsupibilky or resislance in mice, three may be mentioned here• (1) the Renaically- medialed presence of aryl hydrocarbon hydrosylase (AHH) i.ducibility, wbich determines the ability of the anim.) to convert various inactive but polestLl cucinogenic substances into an active form capable of attacking the cellular nuclear rnaterial, (2) the genctically, determined esptenions of Indigenous "C-type viral genome," and (l) competence of the Immune system and iu ausceplibrbty to dcpression by "carcinojeatic" influences or agents. During the pau year, ('ouncu'-sponsored stud'w reported evidence of a genNie relationship between susceptibility of mice from several strains 1o )-methykholanthrene (MC:A)-induced arbcul.neous Iunwcs sd the ioducibJiy in these mice of aryl hydrocarbm hydrosylase. Inducibility was controlled by a single .utoe:ornal dominant gzoe and reflected in eve-to-ten timea greater MCA susceptibility in "indueibk" animal.. These repons stimulated other investigators to study AHH levels a.d inducibility in m.n, with tesuks su{Resting that {n man also, inducibdity in controlled by a single (incornpkuly) dominant gest. This,resuha in a diuribu- tion of inducibility in a random population into three groupinp - low, Wer- mediate, and high - essentially in accord with theoretical prediction. A preliminary study of AHH levels in human lung cancer p.tieeb cated tnu nearly all the victims of this disease in the aampk had either iMer- mediate or high kvcls of AHH inducibility. The Council has uodertakes to support eflorts at simplifying and etpediting the tea prcceduren for use 1n clinical studies to evaluate their potential In aresung cancer susoeptibiluy or resistance in human populations. Other cancer investignioas, collateral t;o the projeq describe,d, included: in vitro studies of malipust tr.nstormalion of iung epithelial cells and of possible induction of squamous metaplasia in ecUs already maligaaat; efforta to identify the agent or agents thAt produce .heep-luog .denomatosia and to transfer these to miee; Immunological studies of tumor•auoei.ued stipens in human cancers of ovary and hrnot; tesearch into pfasm.-membrane associated UNA; genetic studies of oncogenesis and vertical virus transmissiorr 1s the rabbit; mechanisms of suppression of cellular immunity by carcinogenic hydto- carbons; work on the role of cydie AMP in carciaoscncan; esplocation of melhods for enhancing the immune responses to neoplastic lissues; and evalu.- tion of chromosome changes as indicdbra of m.lignant transformation. Chronic Respiratory Discasts 'Ihe lung u a unique organ. It is a double structure with two very similar halves in practically constant motion, eap.nding and contracting in a uniaon so perfectly balanced that it would appear to defy the laws of physica. We 9 0

know that rhe balance Is possible only because of an internal coaunt by a matenai, the "sur/actant," that equalizes dd(crences in tension that would orherwise result hom dif/erent degrees of distension of the air sacs. In addition, the lung has an enormous internal surface of thin mcmbrane, equivalent in an adult man to abow hal/ the area of a tennis coun. The entire blood supply of the body must be transported a1 frequent intervals to one side of this membrane srr/acc, spread over Ns es;unt and then earried away, whde air is moved in and out from the opposite side for absorption of otyten and removal of carbon diuude and other substusces. Thus the lung is tremendously involved in transport of materialt tts renieal position in man, contrasting with the horizontal position in most other rw.as.b, alters the eflects of psvity and creates certain problems. Besides thene mechanical operations, the king and bronchial wrlaco are eaposed lo a great variety of backria, virsues, duas, Sases, smokes and Hhcr ealraneous muerrals that musw be kifked, reteowd, detosifkd, inactivned or otherwise disposed of. The lung has renurt.ble tapacitiea for thex functions. ( hromc diseases of the lung sueh r"bronchitif" and "emphysem" are disocden that tenerally develop BraduaMy .ad progress over a long pcriod, wtgcstint that they have their basis in a gradual lou of efficiency of otre or rssore of the mechanisms mentioned. Their association with the aiting process and a tendency to "run in (amilin" aho suqesu that some congenital de- ficrency in one or more of the functions described may prtdispose to rela:ively early development of these disorders. The pathogenesis of Ihese diseases, that is. the successive steps in breakdown of normal mechanhms which f nally bring them to recognition at the clinical kvd, has been very obscure until recently and still presents a great chdknte to science. They are not by any means new diseaurs but they have become more prevaknl as causes of illncss, incapacitation and dearh, s the acute fatal infectious diseases of Ihe past have been elrminated, allowing potential victims to reach a more advanced age. Neither bronchitis nor emphysema occurs naturally in animals in a form that could hinceno be regarded with assurance a duplicating the human disrKden and thus serve as a reliable medel foe e.petimentation.' Although "chronic bronchitn' and "emphysema" are separate condrtions, each occurring in several distinguishable types. they are often associated ~n the same individual, which complicates the probkms of etiotogy and pathogenesis. ( hronic bronchitis is necessardy deflned in clinical rather than in path- ological terms, chiefly because uncomplicated bronchitis is seldom .ccn by pathologists in the normal course of events. Tl+e disease, or syndronse, is characterized by recurrent acute infections of the lower respiratory lract, especially in winter, by mised fSora of v'raI and bacterial agenb, and is tcncrally accompanied by chronic cough and abundant production of mucus. Ir is thus unlike the acute infectious disea~[s caused by specific organisms acting in a speuRc manner nd running the familiar type of corrse to death or recovery. Biopsks have %hown over-growth and activity of mucus ucrcting cclls in bronchitis Neverthekss, the nature of the basic defect has not really been estaldi.hcd, whether eaceu mucus, a defect in the germicidal syucm, an auroimmune manifroutinn, or u.me other factor. Whcre thc diuau has become edahlished. inhakJ environmental irritants may well at1ravaie rhe symptoms While theie is an rmpresuon of long standing that familial pre- ditpusiuons may tu%t. the various clinical entities grouped under the term "bronchiris" have not so far been clearly enough distinguished to permit clear separation of genetic from environmental influenoea. Tobacco Smoke Inhalation Studie. As one approach to the bronchitis presMem, The Council h.s maintaieed long-term studies of the effects of many factan, including tobacco amok• inhalation, on the disposal of living bacteria Implanted into the lungs of mioe. When bacteria are inhated, a mobilization of white scavenger eeUs (mauo- phates) into the lung b stimulated. TBess white cells engulf awd datroy ma.y types of organisms and foreign particlo. Ttse Msdies with mice have show. that inhalation of tobacco .moAe produces a similar mobilization of macro- phages. Though some of these defense cells .re isactivated by eootact with the smote, the available numlas are so Bready increased that the overall capacity for bacterial destruetioa is nol diminished. Similar studies of macrop,'latcs recovered fran the lungs of human subjects after ,moking have sisows that they m.laais a high bacterkidat capacity despite some changes in appearance and in oraygea requirements. These observations do not support the hypothesis that smoking oonuibutes to development of bronchitis by depreasioe of the tn.aoplute defense apiw infection. Emphysema is more definobk th.m bronchitia in physido&al or path- ological terms. Basicaily, it is a:a isaeaae in the site of the air sacs (alveoli) beyond the terminal brondsiotes (a'r ducts) due lo los of elauicity or actud derruction of the alveolar waqfl. Obstruction of the terminal broochiotes may contribute to these processes. E.nphysema can either be difluse throughout tbe lung or located in "islands" distributed through woneal tissue. (t tends to be propessive, with increasing hyperinBation, airway obtructioo, and residual lung vdume, defective muinU of psn, and eventual bteathkssness and oaytet starvation. The tissue destruction, once it has occurred, cannot be repaired. Emphysema can be diagnosed .rutomically, with measurement of the type and eatent of deatruction, by postmortem e:amin.tion of lungs suitably inflated and fised. ('linical diagnosis has been more difRcult so that death certilkales in the past have made poor distioction between bronchitis and emphysema and also have provided rather generally unreliable classifkatioos of either disorder as to type. Greatly improved methods of measuring the mechanical functions of the lung and more sophisticated radiological techniques are now being employed increasingly. Ensyme. T/rot Destroy L,ung Tissue Because damage or destruction o( the elaslic structural substances of Ihe lung is a basic feature of emphyserna, it has long been surmised thal entymea capable of breaking down these aubsunces, p.rticularly elastin and eollaeen, might be involved T his concept hst been supported by esperirnenu in whkh the Injection of vuKws "loreign" proteolytic ensymn into animals w.. (ol• lowed by lung dcstruirion mrxe or ku resembling human emphysema At present a great deal of study is being concentrated upon the search fur enzymes capable of destroying lung tissue that might be present in the lung under real life condnions. Rre lung itself produces protcases, particularly II 10

during its embryonic uages, and the sature nd functions of these are being investigated urMkr a new Council grant. Moreover, the macrophages and small lymphocytn, which play a major role in defensc of the lung against infeaious organisms, produce and utilize proteolytic enzymes in the process. Proleascs, released by disintegration of these defensive white cells or leakage of enzymes from them, can themselves damage the lung. Normatly this is prr-ented by enzyme inhibitors such at the atpha-J-aetitrypsin that circulates in e.se blood. 1 he emerging picture is one of a delicate balance between protealylie and anti-proreolytic activitiea in the luep searay for its defense against infection but capable of damaging its slruettre IL t!!e balance is disturbed either by over-productioo of proreases or trder-}rodut:tioe of inhibitors. A number of the studies curteotty being spoasored lpy T)a Couacil, as wilt be eviJent from the listing of current projects, art twnarned with IueR prote.ses and their inhibitors as possibly contributory to empbrser>v. There has been considerable publicity orer the discovery that one tuch enzyme iehibitor, alpha-l-aNitryp.ia. Ir eoyesiuMy defieieet ie .an: persoas and that such persom m:y be eapeeL/y saaceptible to empbysema. iDough the situation has beee oomplieaud by the discovery of several diHerxnt forms of aotitrypaie with diAeressces r activiry, k ervertbelese appears to be ermly esubiished that a hereditary predispoahio, does eaist. Oee Couocil-aponswed project is studying the possible relations of the several genorypes, as determined by blood assay, to responses to ee.lro.nkatd stresses In a large human population. This study has also produced evidence of familial predisposuioos other than thoae suribueabk to antiuypsie defkkecy. Another hypothesis, not .eoeaarJy (e conflict with the proacase-aoti- proaease coocep, views lung tissue destructioe as due to changes in its aoti- teoicity that invite attack by the body's own "foreiRn Iissue° rcjectioe mechannm. Such changes conceivably could be produced by relatively slight chemical aturatrons of the lung structural substances by inhaled pollutants. ('ouncil-sponsornf srudies based on this hypothesis continue to produce ws- gestive results. As implied by our comnenu on the function of lung surfactant, a de- /kiency or maldntribMNion of this agent would be cspected to produce significant matfundions of the lung. A Council-supported invesliptoc sucoeeded in adapting certain physiological lung functioa measuremesu (oe application to saull rurimals, including living mice. This promisn to be useful in eombirutioe with postmortem lung ex- amin.tiorss for studying age-related changes (e mice of different suains, in the search for a belter emphysema nwdel. Sucb function meawrements may also become a useful tool in determining whether eflecb of various inhaled agents, including tobacco smoke, are temporary aed reversible or persist nnd prosresa to the stage of posrmortem observation. 6esides the numerous funclioes meNioeed above, the lung also has metabolic activnies such as nmovHeg frore the blood atreans a number of hormones that ue active In the mediation of inflammatioo, io the regulation of blood pressure and in mobJis.tion of white blood cells. -two Council- sponsnred studies arc espkxing these subjecu. Seventeen projects In the field of chronic pulmonary disease s.ere active in 1971, Two of these terminated during the year and /our new unes were aplnoved for acuvaion early In 1971. Cardiovascular Diseases Notable progress was made during the year, under Council spoesotship and independently by other ievestipton. I, the deve{opmeet of 4tususo- prweise chemical assays for nicotine and its major tnetabotites. These show of providing a rapid, precise and highly specific method for way of ekods and relsted compounds in body Auids, especially blood plasma. Such ruethods, when perfected, should make possible the studies of nicotine pharmacodyeraio that have long been needed for solution of rtuny importaet prcbkms. Amons these are the kinetics of nicotine absorption from the various tobacco products under normal conditions of human use (ciprettes, pipes, ciRars, souA, chewing tobacco), the peak kvels to which nicotine rise, in blood, rates of inetabotism and eacretion, etc. The effects on these kinetics of genetic diflerewees, of habituation, of taking oommon household eredicinn, of temperature, esercLe, and many other factors should then become teeasurable. Application of such measurements to human populations could add axw dimensions to Ihe ieterpretation of epidemiological studies of cardiovascular disease in rclaUoo to various forms of tobacco tase by showing whether or sW nicotine can be ievolYed. Conferences with scientists from a number of countries aro furlb.r u- pbring the feasibility of international twie studies to test more rapidly .ed decisively the implications of Swedish researches on ideetical twins whfa dis- cordant smoking habits. These suueat that genetic factors are predosie.at over environmental ones in the genesis of evdiovascular diseases. Assistance to the Swedish study continued meanwhile. Aside from epidem3ofogica) studies bearing apoo cardiovascular diaeus, thirteen experimental or clinical studies were supported durios the year. Taer proceeded along the lioes described in the 1972 Repon, with a yield of wasy publications that arn abstracted ebewhere. Two of these studies Isaw now terminated. A new project was approved for study of possible effects of tobacco aawta inhalation and of nicotine upon development of coUaterd oorooary blood low following acute or chronic occlusioo of a oororsary artery io dop. Pharmacology and Psylchopharmacology This phase of The Council's program continued along the liees deacribtrd in last yeu's Report. Current emphasis is being placed upon aMeruioaa ie nicotine pharmacology that result from chronic e.posures through habilu.tio., adaptation or enzyme induction. (Aher pharmacological probkms await further development of the new analytical techniques to provide procise inlorsealion on the cuncentrationr of nicotine and of Its various rnetabutotca present at particular trnses in specific tissun and at specific sites. Studics of nicotine effectt on animal behavior are presently receiving little emphasis, not because there is any dearth of academically interesting problems that could be appeoached by eanring techniQues, but ratl.er because the new analytical mcrhods rnentroned as being in reasonable prospecr shoutd inacase the sophisticNion of any future studies in this arcam to addttion, there ar• th. 12 13

imporlanl probkms of whether and to what eslent the implications of rat- learning and bchavinral studies can be transferred to man and then of cvalwding their practical significance in human life. One new animal bchavior study of unique character is, however. IrcinR inaugurated currently. The investigator has ahown that a rat behavior IerroeJ under the influence of a particular drug X can be made contingent rpon presence of the drug state. Such behavioral patterns can then be used as tests to determine whether the rals wbjectivefy perceive other drugs as X, as nca-X, or as reinforcers or antaRonists of X. The elotts of nicoline and sonse of its analogs and metahotites will be studied in this conleat. A human behavioral study, reuelly begrt, will eaplore the eflccts of smoking deprivation on group problem aolvi.j processes in terms of r.peed and accuracy. Epidemioloff Including conferences on potenliah for Internalional twin uudies, aia eprdemrolugrcal investigations were active durins 1973. Tl+ese on-going projeets, described rn previous Reports, rve producing a large number of signiflcant and rekvant findings on the constitutional and behavioral diflerenon at many drflercnt levels among persons who have plaeed themselves by sclf-sekclion into the sevcral categorres of smoking behavior. As the numerous reports from these studies tcach publication they ue abstracted in the Annual Reports. Sevcral, at well as many by prcxluct papen, are included in this issue. Ruer, at Ilrr .e , t• 1'u 1) kcscarch Ihrrctm A l,stracts of Reports FnlNrwins are abstracts, approved by the authrxs, of reports on new rc- se.u:h aclnowlcJ6rng support /rom lhe ('uuncd that have appeared in scien- tific juurnils since publication of the 1972 Report. The name of the recpient is in itahcs. '1 he ah.tracts are grouped under these headings: 1. Studies Related to ('ancer, (1 Hear1 and Circulation, 111. The Respiratory Syslem, IV. Phartna- colo6Y and PsychopharmacoloRy, V. ImmunoloRy, VI. EpidemioloRy, VII. The Norrrmative Aging SiuJy, and VI11. Miscellaneous. 1. Studle. Related to (:nncer Mf'TAH()11(' ('()NVf?RSION OF BFN7()f.IPYRFNf: BY SYRIAN IIAMSIFR I IVfR MI('ROSOMFS AND BINDING OF MEIAHOIIIFS TO D!?OXYRIBONl1('I.EIC ACII) Binding studies reported here show that epoxides, phenols, and other metah.Ailes uf benrolslpyrene IHP/ formed in hamster liver microuxne systems may not just be end products, but may be further metaMibreJ to bind to 1)NA. Speciflcally, nalysis of inelaholites of generally Iritiated hent<s/s/pyrcne /'ll-HPI produced by a Syrian hamsler liver mierosonsal systens has revealed the presence of a number of dihydrodrhydro.y derivatives of BP including 4,Sdihydrosy-l,3-dihydrobento/a)pyrene. (klection of this melaholile is taken as evidence that the K-reRion I,S-double bond is acted upon by a micrrnonul hydroaytase to form the •,S-epotide of HP which is subsequently converted via eposide hydrase to the dihyJrodiol. Incubation of several 'll-BP merabolAes with 1)NA alone gave littk evidence for spontaneous covalent binding Ilow- erer, when hamster liver microsomes were present, a nsetaholite recently identified as 7,S-Jihydroay-7,SrhhydrobenroLlPyrene was found to covakntly bind to 1)NA to a tenfold greater eslenl than BP itself, suggesting that this cumpuunJ may be an irttermediale in the pathway leading to binding of BP to DNA in rivo. Borgen, A., Darvey, H., Caslatnoli, N., (-ror4er, T. T., Rasmussen, R E. and Wang, I. Y. Journal o/ McQklnaf Chrrn/irry 16(S):502-506, 1973. OOther .eplw.rf: U. S Public Hcalth Service, and the Cancer Research F'ursds of the llnivcrsiny of ('alifornia. Frorn Ihe Cancer Rescarch Institute and Ikparunent of Ptunruccurrcal (bem- islry, Ilnivcruly of l'aldornia, San Prancrsco. INI)II( 71ON 01: ARYL HYI)R(X'ARBON FIYI)R(/XYI ASF IN III/MAN SKIN 1 he +ryt hy.hrx artKrn hy,hn.yl.1.c whrch hydrosylares thcnrAwl 2lpyrcuc ( HP ) has been shown to be ntarkeJly rnJuccJ in aninuls e4pu.cd to IN)lycychc 14 15 .

hydrocarbons such as 1-rnethykholanthrene or D!•. Is the present study, tissue culture was used to determine whether the carcinogen-metabolizing enzymc. BP hydronylare, is present in neonatal hurnas foreskis, and whether it is indtcibk in this tissue. The resulHanl d.1a slww that hurnss skin has detectable kvc)s of BP hydroaylase, and that this enzyme is inducibk; nareover, substantial ( iflex- ences in basal and inducible levels of the enzyme were demonstrated This dirterence may be genNically determined. No eotselation was found between the inducibility of hydrosytase activily is the ucowsl.l foreskin and the race or aae of the sather, or the medication jirea so the swother prior to delivery. Th. eszyme system Ihat hydro.ylates /P ne4talnn takotisamide adenine dinuchotide phosphate and s+decvlar oayRew. Eapawte of the akls homoBenates to nit -o0es or CO resulled is little or rw en=ymak atxh•(tia.- It was also shows that irduci- bility of hydroaylase activity was Seater Is bwwss din than in neonatal r vdent skin. The presence of hydroaylase is Mrwas iis and its ability to be inluced may be knportun protective mahaslraas apiwst carcinogenetis in man, since human skin h often esposed to polyeyclk hrdroeatbons in 1he environvnent. However. the eaaa rok of BP hydroay(w is esetisogenesn b slin uncktr. Alvares, A. P.. Leibh, S, Kqrp.r, A., l.evis, W. a.d Coasey. A. H. Drvl 6lr..AoYiw.../ D4pubkw 1(1):1l6-)90, 1973. OtA.r a.Pr+rl r U. 3. Public Health Smioc. Prom Rockefeller l)siveniwy, New Yort, aad the Department of Biochetnistry and Drug Metabolnm, HoAmann-la Roche Ise., Nutley. N. 1. INDUCIBII.fiY OF BENZO(a)PYReNe 11YDROXYIASE IN HUMAN SKIN BY POLYCYCI.IC HYDROCARDONS Beaz.ofabyrenc (BP) hydrotylase activity ia inducibk by polycyclic hydro- orbons is cultures of neonatal bumaa foreskin. This study shows that the eszytne system which hydrosyhdea 11P requires nkoainamide adeniee dinucko- tide phosphate (NADPH ) ssd rsokcular o.ygea, and that its opt:rwwn pH is 7.4. Etposure to carbon nwwaide eoarpktely iaAibita .ydroaytase activity. When skins were ineubaled is a growth rnediurn containing benzia/snthr.cene (BA) two- to taK-fold Iscreaues in the amanl of tsP Mytro.yfase wen observed. Maairrwm enzyme levels wert fousd whes the skis was incsrbated is the presenee of BA for 16 to 24 houn. IsducibYily of hydroaylase activity was Rrealer in huw+as skin thas is neonMal rodent skin. Considerable vuiability ia the basal kvels ssd in the indueibiliry of BP hydro><ylase was observed is foreskirn obtained from 1) subfects. These studies isdicure that human skin can metabolize polycyclic hydrocarbons .sd that the levels of the hydrosylase, as well as the inducibilily of the enryme is skin, may provide a useful mcans foe evaluating individual diAeresces is IM eapaciliey of hurruss to metabdina environmeslJ earcinotens. Alvares, A. P., Kappas. A.. l.evin, W. and Conrxy, A. H. (-Nnl..l rhan...roln~y .n/ TAr.aw..tkr 14( 1):)0-40, 1971. O1h.. .uPport: l/ S Puhlrc lleslrh Service Fram R..trfrtkr tr-rr.o. Nr- Vo.k end the 1)aparrnxnt of Biochemistry •nJ I).vt A1r~.h./....• ILA.n.nn I• Ru1a In. Nurky, N I POLY('HLORINATQD BIPNfNYIS:A NEW TYPE OF INDUCER OF CYTOCHROME P-44t IN THE LIVER TAis study shows that Aroclor 1234, one of the polychlorinated biphenyls mlalures manufactured in the United States, is a potent inducer of the asicro- somal hemoprotcin, cytochrome P-44d, and of beszo(alpyrene hydrotytase and ethylmorphine N-demethylne. 71re COdiflcreece spectrum of miczosoeees frorm rats treated with Arocloe 1254 has an absorption ma.imum aa 44• nrn. With ethylirocyanide as the ligand fu reduced micro.ornes. Arodor 1254 treatasent causes a shift in the 4S3-sm peak to 453 am and increases 1he ratio of aMorb- .nce of 455 nm to that at 430 am from 0.3), obtained with ustrealed rals, to 1.24. These findings are similar to those seen in rats treated with the polycyclic hydrocarbon, 1'methykholathrene, but diAer /roen those that characterize cytochrwne P-450 in control o: phenobarbil.l-lnaled rats. Aroclor 1254 ueat- meM results in a tripling of cytochrosse P-448 content and a I0 fold leacrease in ber.zo(alpyrene hydrosylatio.s. However, it causes a signifkast enhancement of ethylmorphine N-demethylas:. These data wqeN that Aroelor 12S4-Isdueod eytochrome P-448 may be atatyticaNy diRereM from the l-methykholaslhrese- induced P-44tt or that the he+rroproleis(s) induced by Aroclor 1254 may be a mis(ure of cytochrorncs P-41B and P-410 enhibitinR catalytic propenies of both cytochromcs. . / Alvares, A. P.. Bicken, D. R. and Kapyar, A. ProrreAln`s of rAe Narbnal Academy of Sclencer of rhr (InlrrA Sraus of Arnerira 70(S):1121-1)2S, 1973. Ot/iar ar'Porre HoQnun-lA Roche Ine., U. S. Publie Health Servioe, Na- lional Institutes of 1(ealth, and Scaile Family Charitable Trusts. From The Rockefeller Univenily, and the Department of Medicine, Cor.etl University Medical Colkte, New York. EVIDENCE OF A GENETIC RELATIONSIIIP BETWEEN Sl1S('EP'TIBIL• ITY TO 1-METHYL('HOl-ANTHRENE-INDUCED SUBCI/TANEOUS TUMORS AND INDUCIBII.ITY OF ARYL HYDROCARBON HYDROXYLASE • The presence (or inducibility) of aryl hydrocarbon hydroaylae (AIIH) is known to be associated with the cytotoaie action of polycyclic aromatic hydrocarbons. In this uudy, the authors report a close correlation belweeo susceptibility to )-methykholamhrene (1MC)-induced subcutanewu tumors and the genetically meduted presence of AIIH inductwrn. In a 4enclic syslem where AHII induubdlly sepegated at a single autosomal dominant gcne, mice carrying the Aha (or inducibk) sllck were 3-10 times mwe sensitive to M('A turnorigenesis than were their rwninducible (AhJ/AhM) liuermates. In backcro.s animals /(C37B1./6XDBA/2)XDBA/2), 10 of 12 (111l%) mice with tunrrs were AFIFI imlucibk. lAis was sulislicully significant (P <0O2S) (the c.pccad rcnpnnu was 31/% ) and clcarly indicated a rclauix»hrp belwecn this enryn.e system and M('A carcinotenesis. Kouri. R 1: , Ratrie, It. and Whitnure, C E. (RfkroMb-loru-af Au.xlorer) 1 r, 17

/ournal o/ the Norlonal (-anccr Inrrllure 31(1 ):197•200, 1973. From the Ikpanmcnt of ViralAChemicat Oncology. Microbiological Auociatcs. Bethesda. Md. RFl.AT1ONS11IPS BETWEEN ARYL HYDROCARBON HYDROXY:ASE INDUCIBtI ITY AND SENSITIVITY TO CHEMICAI LY INDUCEI7 SUB(-UTANEOUS SARCOMAS IN VARIOUS STRAINS OF MICE This paper reports an observed tauoclation between aryl hydrocarbon hydroaylasc (AHH) ie>,fucibility a.d auroeptibilMy to 7-mNhykholan:hrene (3MC)-induced tumors AmonIf 14 atrains of twice, a dired correlauon was observed between scneitivity to JMCJ.duced Mdcutaneous tumors aid the hepatic inducibility of one of the hydrocarbow-1s.etabolizinR enzyme s)stems, AHH Every sarain showing a c.rciaoRcwic Indea (a measure of sewsitl•rity to chemical carcinogens) >60 was inducibk for AHH and every str>.in Mith an Indcx <)1 was noninducibk. (.'loaer e.aa>inalioe i.volving eight strains iadi- catcd th.u uniw sensitivity was coesislest over a wide range of 3MC cflncea- trations, but was not consistent whcn beao(ak+yrene or 7,12dimdhylb:ntla)- anthracene were used as carcino6ens. Moa suain, that were noninduue k and insensitive to )MC-induced tumon also eahibiwed a high incidence of :ype C RNA virotcne espressioe, as demonstrated by the 6roup-specifk antiteis chu- acleristic of these viruus. On the other hand, suains showin6 a low in..idenct of virogene e.pression were usually inducible for AIIH and sensitive to 3MC- induced tumors lhe resulrs support the idea that certain chemical carc nosens are mtlahoiiully activalcd to a carcinornic inlermcdiate and indicate that the AHH system plays a role in thu activation. Kouri, R. E.. Sakrno, R. A. and Nrhitmire, C. P_ (AfkroDloloticaf Asrociates) lo.rrnd of the Narionol Cancer Irurlrrra S0(2):767-76e, 1973. Other arrprlr Nationd Institutes of Health. From the Department of Virdk'hernkal Oncology. Microbiological Associates, Bethesda, Md. IN VITRO TRANSFORMATION ASSAY OF MAJOR FRACTIONS OF CIGARFTTE SMOKE CONDENSATE (CSC) IN MAMMAIJAN CELI. LINES This study dealing with the transforming activity of 12 rnaior (ractions o( (-SC on ral and mouse cells infecud with C-type RNA tumor v'ruses, and on ummnlectcd hamtter cells corroborates some of the results previously obtained s. TAe same three CSC fractions (1 41'.. in vrvo hy .nMhcr group of inveitrptw weak acids Iphendl. clher'soluble: neuttab, eyclohesancsotubie; newrals, nitro nKihane soluble) slwwed translornwng activily. Whereas two other Iracuom ,.h.KS, cd flcreet411r.ctro.ulrba.rselxtorc, insulubk)~ uxd nl~lrro changes in infeded mouse and nt cells• but none of the fradions altered untnfected mo«.e and rat cells. According to the aahon, these Andinp are coosistent with pre- vious reports that rnouse and rat cells are readily transformed by chemical carcinogens and smoke esuacts when they are preinfected with C-type RNA virusn, whereas cells treated with chemical or virus alone are not uansfora.ed. They suggest, thercforc, that since /n riro assay systems are time coosuming, hn vitro transformation .ystems of the nature they describe have certaio diatind advantages particularly for rapid quantitative assays of putative urcioo6ens in tobacco smoke as well as In orher suspect environnxotal eulcrials. Additional studies are underway to determine the opimum doses of CSC fractions for in- ducing tran.sfornution especially in the infected rnotna cell ayMem. Furthermore, the investiptors oote, subfractionatiow of two especially carcioo6enic fracliona (l.e., phend, ether-sdubk; oeutrals, nituomethane-sdubk) should be done ie order to determine the particularly aaive factor. Rh4n, 1. S. and Huebeer. R. 1. (MkrobloloRkaf Auocieres) lroctel/nRr of the Society /o. ErRerlwtewral Biology a./ Mirdklwe 142 (1) :1001- 1007, 1973. Oth.r arrr.rtr National last;luta of Health. Prom the Departmeot of Viru. Research, Microbiological Associatea, and Viral 'Carcino6enesis Bnsch, Natloaw Cancer leutitule, National Institwes of Ilealtl, Bethada, Md. TRANSFORMATION OP RAT EMBRYO CELLS IN VITRO BY CHEMICAL CARCINOGENS This b a report on nsuks of experiments showing that rat embryo celY can be tranaformed /w rqro by polycyclic aranatic Aydrocubons and that they then product lunots whe. Injected into newbortn rsts. These cells also had tbo following properties: (1) they were earpholo=kaMy .Itered, growing as ro- dornly oriented muhdayers; (2) they showed losr of contact inhibitioe and in- aased growth rates; (7) the cells transformed by )-mcthykholanthrene werv orore resistant to the toxic effects of this carcieoge.; (4) they produoed pro- Qessive(y growing. .erWly transplantable hreottt when Inoculated into newborn rus. Although the exad eroch.nism of this In rlrro transformation procus is still unknown, these data wyest that chemiW oeoogenesL can be studied in cell cultures derived (rorn rat embryos. Studies to further quantuate the chemical /n vlrro tnosformatios of tbe rat embryo cell ayueat described here, are In proprca.. • Rb4n, 1. S. aod Hucbnea. R. 1. (Mkroelololka/ Associrr.) C.wcer R..rrcA )l(4):693-700, 197). OtA.W arr'.rtr National Ca.cer Iwitua. Pros Mkrobioiogkal Assoeiates, and Viral ('ucinoticrwis rsranch, National Ca.oa InMitute, National Institutes of 1(ealth, Bethcsda, Md. 19 IS

26 had viable epilhelium. in which 29 histologic ftalet were identified. Five were paihobt2ic, with squamous melaplasia in two instances and with localized dysplasia .ufTiciendy marked to be considered as possibk carcinoma in rit" in three instances. Of I I) cultured eaplanu, 106 bore viable epithchum in which 110 histotogic states were ideetif(ed. When Initially present, columnar epithclium was retained In about 70% of eaptaets; this retention occurred rnore often if esplants were from whole broechi rather than from biopsies. Nine cultured eaplants showing dysplastic or aquaewua metuplastic epithelium w_re from patients yielding such lesions Ie (reaR nmpiei. Dysplasiat were as highly cellular and replkative after mainteeasc. Is erMwa as they were before incubatioo, suggesting continuity of replicatios ttrrwa8 pleomorphk celb, consistent with potentially preneoplasrie lesions. Squr+sou..xiaplasias were poorly sustained. SweNiek and sioukhing of eoTnul cells s.ete consistent with (dlure of t3e system to sustain this abnormal state or with early phaw in the reversal of jqua.notn meUptnla In mps cvMun. O'Doeoell, T. V., Croc4e., T. T. ewd Nusws L L Cancrr Rein.rcA 7l (1) :78-17, 197). Oth.r .rrr.rtr The American Medlcal Aasoeiation-F.duc.tioe and Research Four.datloe, .ad the U. S. Public Health 3erviot:. From the Card'avascular Research 1.atMute, Cancer Research Ins;itute .ed Departnsca of Medicim. U.iversity of Callforeia School of Med;cine, Sa. Francisco. INTRATRACHeAL INSTILIATION METHOD FOR MOUSE LUNGS The rnouse is an ideal e.perieweatd .e4na) for earcioolIenesis studies .ed ietratradxal instillation is a reliable way to ktroduce carcinogens iero animals. Howerer, becauue of the tenall .ise of the tsotre, ietratncheal instiNatioa treatment of mice is difficult and Is rarely used, thus eacludint .is eacdket caperimental nwdcl. Now, a reliable ia.Lr.cheal iauiqatioe technique haa been developed which permits the repeated sidminiatntioes of prccise volumes of particulale suspension into rna+se luop. 1s this study, benzo(.lpyrene (BP) adsorbed to ferric o:ide was used to tettt the feasibility of the method. The maprity of the animals survived (our weekly trealnsenu. Histological and fresh tissue sections showed extensive peeetntion of both chemicals into the lunk patenchyma; howevcr, while BP was eliminated from the organ rapidly, the ferric oaide wu retained for over 100 days. These dust particles were observed inside mxrophaBn cdlMed arwr.d terminal bronchioles and lymphoid tissues of the lungs. Ho. W. and Furst. A. (Unfrerslry o/ San Fra.rtrco) Owolojey 2 7 : )t11-191, 197). Prom the lostitute of Chcmic.l BiobM, Ueiversity of San Fraacisoo. Sae Frsnciuv LUNG CARCINOOENI?SIS BY BENZPYReNe INSTILLATION Becauu of iu prevaleace in the air, be.no(•)prrene (eP), a carciookeek polrcyciic hydrocarbon produced by the lecanpktI combustion of all orp.k tn.tter, 's .uspected to be oee ef th. uwn o( hurea. lung easocr; but ao far. the use of BP ie eaperinKStal a.irwal reodels has (ailed to provide .wacreu evideece of malignant respiratory tumor forrnatios lealogwu to the neoplarea found in nue. The present report t+urneurizea an attempt to use NIHSwir mice as a modcl in which to study the earcir>oBeaic effects of BP oa' lu.ax. following Ita admieWratio. 6y inlratrached ioui4aioa. Re.uks wllseal that the kthal effects of t/P on this maw atraie are largely related to the frequency of treatment rather dw to the dosage .drninistered. Accardi.8 to the wthors, both the lyntphoid t.rperptasi. ..d foamy tn.uophaBes observed In the BP- treated lunp are Mtributabk to t,he i.vasioa of foreiips Irrit..u. While tAa Irscidence of eeop4sis was 20 tbnes higher thare that sors.ally aoee ia this .utis of miec, tbe resu(tie8 papiltary adesaes were eowsidered beoiBa. It may be, t)seretore, that the chetnic." merelr eeh..cea rhe preaispoaitioe ot thia wnhb lo form the tumor. 1o the authoes' opinion, thw tailrar. ot tsP to i.dtw. waUI- eaocy is thae aeint.y sugoe.ts uver.l poribi" iaerpreutioe.: (1) the etperl- rnenW coaditioru were twt conducive to malignant tureor induction; (2) the aryl hydrocarboa Aydtoaylose enzystaak system of this mouse strain wsitipan against tumor formation; (D) the pulrtwn.ry a.aWmy of die mouu may .or be twitab{e for carci.ogesic rpudies; (4) t/P talo.a may eot be resporaalblo for ma6pur tumor tortaMiok and othet eo(.cton rasay be iavolved. Ho. W. and Funt, A. (U.Irerslry oJ S.ra Fr.nc4ro) hoceel/np oJ the Waraw PA.rws.co(oYr Society 16:146-149, 1973. From the Institute of Chemical Sio{oBy, U.ivvslt7 of Saa Fr.eciseo, Sa. Fraecisco. KARYOTYPIC. VIROLOOIC, AND IMMUNOLOGIC ANALYSES OF TWO CONTINUOUS LYMPHOCYTE LINES ESTABLISHED FROM NEW ZEALAND BLACK MICE: POSSIBLE RELATIONSHIP OP CHROMOSOMAL MOSAICISM TO AUTOIMMUNITY Two separate continuous cultures of lymphold cells were Isolated from tM aplexn and Ilbrosareorea of a(emale New Zealaod black (NZD) nwuse. The cells from thex cultum do nol produtx antinuclear or antierythrocyt" aaI- bodin but syothesize a great deal of virus with the morpho{oBic and bkrclten.ical properties of RNA tumor viruses. Interestio8 karyotypie aboorrnalitka .ud a unique "C-type" virus were noted in both cell lines. The inua v'rus p.rtkks had a buoyant density in aucrose of 1.16 g X crn 8, 70B RNA, and RNA- directed DNA polymcrasc activity. The virus was Infectious for NRK, NZB, (NZB X NZW)P, and (NZW X NZW)P, .rnbryo., aed for ttAtll/c )T) cells, but not for NIH Swiss cells. All celb from established lymphoc7he cul- turu, as well as wme emh.yo cells from NZB mke, showed b.r7otypk abeormahtics. 7he pomibihty of duon.oso.nd mosaiciun is augrwed Ltrnrr, R. .f. er .!. 22 23

hoctrd/np of the N./ond Aa.dnny o/ Sckncn of rht Unlrad Srorrs of Awrtrira 69(10):2965-2969, 1972. Otwr •r' prfr Naioeal Sciext Foundation, U. S. Public Hcatth Service. National fnrtNUtes of Health, Atomic Paergy Commisrion, and National Foundation - M.rch of Dimes. From the Departnxst of Pspcrir.eaul Pathology. Saippt Clini: and Rexarch Foutdation, La lolla, ". CANCEROGPNFS/ NEI PftAMMENTI RP.SPIRATORI tSO-TRAPIANTI DA TOPI 1lAl,/c/Cb/Sa IDRAIJNA-TIPLATTATI Variouw parts of t!e rnpir.rory trset of VALB/c/Cb/Se (aAt.B/c) mice have sfawr ddfereat suscepibilkin b the curcinopesk .ctiou of hydr.zine sulph.te. Thc LreM of tW L.estigNio. wa lo further etamine the modiAca- tiom (ourd in the respiralory lissue of SALD/c mice brieAy treated with hydra- zise suiph.te, whes it wa. Irtroduced into synjeneic hosts. Respiratory tract tsswe fro.r such iaact but previouwly tre.ted virgin mice of both seaes was, dretelore, tra.oplurted into sy.geneie bsls which were in various hormonal uatea. Neither the trachea .or bronchi of the controls or of the hydr.zine- treatod dooors sho.wed aoy important changes. Only two ( 1.2% ) individual dveolar rdrnomu were obser.ed is the pulmonary tiswe uken frorn the con- troh. That t.lee from mice treated with hydrazine sulphate, however, showed alveolar .dtoomaf (211i ), bronehiolu adenomas (119b ), and eareinomu ( 1 S9i ). It in intcresting to note that it takes an average of ee wceks for hydra- tirae-indurxd bronchootar a.knomas to develop, whereas the average time for similarly induoat al.eolu adeoomar is only 40 weeks llruc, the prolonged suevival h.rc of the :rafrs, atuinal af  result of the techniques used in these espetime.rts, allowed tumixt to develop in the bronchidar cpithclium, which (s arp.rrcrly kas suweptibk to hydrazine wlphate than its alveolar counterpart. TAe e.do*eerous .srian ainulation of test mice did not seem to inuease the .aliRaa.ey el tumors i.duced In the grafted tissue. fl,ia.rifioti_ C. ( Stv.rl, L ) L.rari An.row.l. t.roJoorka Pern& 33( I):17-26, 1973. Frosm the Dirisioo of Cancet Reseatch, Usivenity of Pcrullia, Perugia, Italy. IPERTLASIE TIROIDEE L' TUMORI POI.MONARI DA METILTIOURACIIB PJO 190NIAZ1DI3 IN TOPI Ct+A/Cb/Se TAio.r.dl has becs rf+ow• to induee thyroid hyperplasia and tumors in various atzai,e of snke; but among the other derivstlves, none has been shows to pasc.r in oww inhibiting effect on the growth of turnors, either spontaneous or i.duced. in other otgans. 11 has aho bee• showw that varior chemical c.r- uoojens do not accentuate the effect of thiouracil on the thyroid gland. The cvnent nveitiption wsr undertsken in an attempt to eatend Ilre research eon- cuning de influence of the hormonal fsctor on isoniazide (INI-irufuced pulmonary carcisotc"s In mice by etnnining the sctivity of nxthyhblouncil (MT), a thiourea decivative associated with INI. In the intact, untreated, oon. trd, virgin CBA/Cb/Se (CSA) mice, the incidenu of pulmoaary tumo~n was 14% in females, 0% in maki; none of these animals had thyroid \yperplasia. In the MT-trealed group, 2% of the eukes .ad 4% of the females had hag tumors; for thyroid hyperplasia the respective iscidenoe was 0% ..d 4%. TTr INI inczeued the freauency of lung twnorss to 36% in m.ks and 74% In femak+. The combined adminiuratioa of INI and MT Induced ht.g wors (24% in maks, 54% is fennaks) ud thyroid hyperplasias (677F ..d 71x ). 7T.ese results suggest :hat the MT reduord the carcieoge.k actioa of INI wbich in turn favored the lrenislesu of thyroid hyperptsia begun by M'1' 6('EA mice. The author cameot easily e.ptain the reaso. for the interterence betwecn the two substaacen. Biaeiei(ori, C. (Sere.l, L.) L.vo.l Anarorn4. r.raloglc. 1e.vgi. 3)(1) : 27•39, 1973. Prom the Division of Cancu Researzh, Univer.ky of PeruRia, PerugiaItafy. INFLUENZA D1 FATTORI INTRINSECI NeLLA CANCeROOP..NI'Jl POLMONARB DA IDRAZINA NEL TOPO 77This revkw wnmarizea the results of sever.l ieveatig.tlom deall.s with the influence of endogenous ovarian stimulation on hydr>siee sulfate (H3)- ieduced pulmonary carcisogenesis is various uraim of mice. In Ltatl virgin CBA miee, dw incldence of spontaneous pulmonary turnon (p.t.) Is low, but administration of HS in propessively reduced do.n iscreasn It in females more th.o In rn.ka In iotact virgin BAI.e/c mice, 25% of the maks and 4% of the females develop p.t. In some of the esMimental groups reduosd doee. of HS affect the females to a greater degree than the maks, u sryped by the higher iscidence of tumors noted among them. The majority of apo.ta.ear and HS-Inducea p.t. seen were adenomas. In both BAl.B/e sd C,Ht+ r.ia lo various hormonal uates (l.e., breedinit, gon.deetomizsd, (oreed breedi.g, a.d pseudopregnant), sporuancous p.l. were rare; but HS focreased the frequency in all groupr, and Nimulation by endogenous ovarian horrnonts raised ths degree of malignancy as well. The malignaet tumors were carcisornu, o(te* lavadw and met.stasiud through IAe blood streun. According to the .uthor, these results confirm the influence of ovarian hormones on hydrazioe-ieduad pult monary cucinoseeeais In mite as well as Ihe carcinogenic actios of reduoed HS doaes. Biaociflorl, C. (S.r.rl, L.) Rtl.rlone al XX ('onregno Interrealonak Tosco-l'miliano di Pocumotl,kilosl. ( Ravenn 27-2/ Mayio 1972). Rsr.gne di rarolot{a delf Appar.re Rrpp4+ wcb 2):21-)S, 197). Prom the Inslilute of Anatomy srrd Morbid Histology, tlnivenily of Piu, Pi.., and Ihe I)ivirioe of ('ancer Refesrch, Univernty of Pcrugia, Italy. 25 24

ASPFTTI l/t TRASTRUTTURALI DEL CARCINOMA ALVEOLARE DEt POt.MONE A lung neoplasia, which displayed the histological charactcristics of an .Iveolar ull cucuwma, was studied in the ekctron microscope. The general ultraS tructure appeuance of most of the neoplastic cells was simit rr to that of the type-B dveotu cell, aod some contained the typical o.rniophilr- and lamel- lated bodies which arc the distinctive feature of type•B cells. These observations suggest that the neoplasia derives froew the alveolar epithelium, evrn if the dif- fkulty of esplaining the presence of an occasional mucus-secreting cell re+nains. The principal morphologic aspect., the diagnostic problems, and the histogenetis of the alveolar cell urcioonu are discured. Bucciarelli, E. (Severl, L.) l.vorl Ar..r.w.r1. r.foloelc. renyie l2(2):IS-6), 1972. From the Institute of Anatomy ..d Parhologk Histolotgy, Univenity of Perugia, Petugia, Italy. FATTORI EXTRACROMOSOMICI NELLA TUMORIOENESI POI.MONARE SPONTANEA DEL TOPO BALB/c/Cb/Se 1?strachromoaornal facton, such u whole body (rndiatioo, may be involvcA in the spontaneous lung tumorigeoew of BALB/c/Cb/Se (BALB/c) mice. In an attempt to study these lacton, lung tissue from newborn BALh/c mice wau grafted subcuuneously, botb into a poup of adult syogeneic recipients previ- ously eepoud to whole body irradlatroo, and into a similar untreated Qoup. Some of these control mice had been thymeetomise.d at birth. Alveolar aderw- mas were observed only in the lung grafts recovered from the irraduted recipi- enu This suggests that whole body irradiation activates a lung tumor gent io BAt B/c mice. When lung tissue from oewborn BALB/e mice was implanted subcutancoualy into 16- to 2Omo.th-oid ayn2eneic recipienu, only rare {nfts took, none of which showed evidence of alveolar adeooaus. Llowever, when whole blood from 16- to 24mooth-o{d BALB/e mice was injected intraperi- toncally into newborn recipieots of the ame suain, 56.2% of the recipients developed lymphatic kukemia after a tnean latency period of l9'9 days. One of the leukemic animals showed muhipk pulmonary adenomas at awopsy. SQuartial. F. and Bdh, (). B. (Sercrf, L.) Lavo.f Anaomia rarolotlr. rcruei. ))(1):S-1S, 1973. From the L)ivlsloo of Cancer Research, Unlvenity of Perugia. Perugia, Italy. INTRAFISS(IRAL MID-ZONAL ANTHRACOTIC LYMPH NODE PRFSFNTINCi AS A COIN LESION When an asymptornatic pulmonary coin lesion presenu itself in a patknl, the f1rt1 urk of the .rtendlng physician is to determine whether the lesion is henien oa rn.litn.m In rhr ceu reiN.rrrd here•  minimally cakifled midronal p„Ino.nluv n le,n.n rfV-r-r IIrM.twO/ny toH .hatnUU1, proved to he an n,.t( Ihe p.nrin ,if ul.fiuu,in rn Ihu niKlule was not typical of that seen in some of the noncancerous lesioos, and the smJ amount of peripheral cakifkation seen here would cause one to ooasider the possibility of malignant neoplastic disease. Upon' inspection, howevu, the solituy ksion proved to be a well•/ormed anthracotic node without any @ror or histologic characteristics of malignant change. This caae appean to be unique in that a somewhat peripheral (midtarul) benign lymph node, present. inR as a coin leaion, was found to be situated inuanuuratlr radsa tlua intraparenchymally. Rogen, P. M., Ayres, S. M. and Ribaudo, C. A. CAen 61(S): S01-S02 ,11172. Other awrrortr U. S. PubGc Health Servict. From St. Viewaw'. Hoapitd and Medical Ce.ter, New York. ULTILAST1tUCTURAL ASPECTS OF PAPILLARY AND SCLER()SINU CARCINOMAS OF TNE THYROID This electroorokro cwpy study of sia thyroid papillary carcinornrr, fow of which were of the scierodag .ariety, was undertaken in a. attempt to clarify the precise nature of ;he Interstitial material found is the acieroeio{ carci.o mas. The authors report that the neoplastie cells had a highly variable cytoplum even in different areu of a single tumor. Numerous lightly-packed mitochoa- dru and abuadaM eytoplasmie fil.ments were frequent features. There were paralkl, tubular profiles which could represent "paracrystal:' or variants of unooth endoplasmic reliculum. Three of the turnon contained cells with aecretory-type aanules moryhobgiully iod•ntinguishabk from thoee of pam• follicuiar ulls. The characteristic nuclear .acuoles .eeo under the light mkro- acope were found to consist of cytoplasmie evaginations which retained Iheu continuity with the main cytoplasmie mass. In all tunwrs, the interstitiurw con- taincd irregulruly arranted, delicate fl6rils, while collagen Bben wer+ aca.ty. The mkroAbrBs were particularly abundaet In the sderosing urcinornaa where they seemed associated with teduplinted basal laminae around cpithelial and vascular structures. Cellular debris observed io the spaces between basal IanJnae suggests periodic renewal of cell populations in neoplastic papillae as well u in capillaries; basement lamina production .eerna to be a ckuly d'Jlereollaud character of these malignant cells. The authors point out, nwreover, that while reduplicated basal laminae :re a feature common to a variety of repantrve processes, they have also been observed in several other luw-grade malignancies GoafJ, V. E., Oould, N. S. and Benditt, E. P. (Sabbatical stipend recipient) Cancer 29:161)-1625, 1972. Other auprorfe 11 S- Public Lleatth Service. l:rom the 1)cpanments of Pathology. ltnivenity of Washington Sch.wt of Mc01 ciru and ( hJdren's 1luspital. Scaltle. 2fh 27

11. Ileart and Circulation MEASUREMENT OF THE INITIAL RATE OF SERUM CHOLESTEROL ESTERIFICATION This paper presents a method for the measurement of initial rate of serum cholesterol esuriflcetion. The technique b a modifkd version of the assay described originally by Stokke and Norum, a• assay system that allows the combined measurement of keithi. clsoleNerol acyl transfernse (LCAT) and substrate efficiency in plasma or serww sarnpks. Improvements derribed here include the depression of backbtot.rd vahrcs as wdl as an incfcase in the overall efficiency of the procedure. Study of healthy mak humsn subjects revealed that thc Initial rate o( cholesterol esteriflcation increases linearly with the individual's serwn•free choksterd eoMest. [arko. A(: , Rutrnberg, H. L. aaid Soloe, L. A. Suu hrn.ita7 MrAIcinc 7(1) : 17 /-1 8), 197). O1i1er aw'rorr: U. S Pubiic HeaNh Ser.ke. From the Division of Cudiology. Department of Medicine, ettd the Fels Research lestitu(e, Temple Univeesity Health Sciences Center. t'hiladelphia. SERUM ClIOI ESTEROL ESTERIFICATION IN PAT1eNTS WITH CORONARY I(EART DISEASE: IMPORTANCE OF INITIAI. RATE OF ESTERIFICATION EXPRESSED AS A FUNCTION OF FREE C'IIOLFSTEROL Lecithin choiesterol acyl tnsfvrurc (LCAT), the prirnary earyme re- sponsible for estaiilcatioe of free cholesterol in pfasma, may also serve to retard the efiect of forces that favor intra-anerial accumulation of choksterd and the developmcnt of atbaoedcnosis As a preliminary test of this hypothesis. In vitro initial rate of eslerilkatios of cholesterol was eneasurod in the .eta of 12 healthy men and 17 wtee with heakd myocardial infarction. The rates were linear in both group. for ebout 40 twMwtes, with a tendency for duratiow of linearity to be longer the higher the eoncenuation of free choksterd. No obviow relationship awW be demonstrated between the rate of esteri(kation of cholesterol and the level of trittlyceride. When the initial rate of cholesterol esterifkation for each subject was plotted against his respective serum-free cholesterol kvel, the data could be fltted to two straight lines, one for the healthy group and the othet for the coronary group. These two lines demonstrate a significant difference between the two groups Comparison of the data for the percent cholesterol errerUkd per ntinute also shows a tower efiSckncy of cholesterol esterifkNion in the coronary group as compared to that of healthy Individuals. Soloe, L A, Rutrnberg, H L. and Lacko, A. 0. Ar....K+. f(...r lor.w.f a( 2): 15). 161. 197 ). from the I).vu-ow of (lydrofogy. Department of Medicine. Temple University ItraltA Sc.rnces ( eraer. Phdade/phu INFLUENCE OF NICOTINE ON EXPERIMENTAL ATHEROSCLEROSIS AND ITS DL*T[?RMINANTS The aulhon report on their use of coronary an&graphy and appropriate histologic, histochemical and ultrastructural techniques in order to invcdigate the pathologic effects of nicotine on several tabbit orgaas and cardiovascular tluue. For these studies as well as for delenninations of eervm lipids, their test .nimals were subjected to wch determinants of arteriosckrotic heart di.ease (AsHD) as either hypercholeslerokmia or hypertensios, or both; untreated rabbits were uxd as controls. A realistic daily pharmacolofic dose of nicaioe failed to quaMituively or qualitatively affect atherosckrosis of the awta, e.tra- mural and intramural coronary uteries, visceral ksions, or serum lipids. I. either normotensive or bypertensive rabbits whether or not they received suppk- mentary dietary cholesterol. There was so appreciable diAeteoae In the appear- anoe of coronary aaRioRrams obtained frorn nicaine-treated rabbits with and without atherosckrvei.. Anglography did ahow, however, that the hyperte.dve rabbits had kss tortuous eoronary artaies, bistoloRicaUy reflected by Rreater luminal aren tha. are rrxe in noMwlessive animals. Hypertensiott Iwcrcasod the atheroeckrotk prooen in the .arta and ooron.ry arteries of choksacro[-fed rabbits, while sioolise failed to Influence Lduction or maintenance of rtad hypertension. Although the dinical significance of these obscrvationa b u.oer- uin, the euthors point out, they do suuest the .eed for further isetuiry oo.- oer.ing the role of sicotiee in the developme.t of AsHD is man. FtsAe., E. R. er .1. Arrll/ves o/ t'.r/io/oRy 96(1):29t-)01, 1973. From the Department of Pathology and Radioiop, Shadyside Hoepltal, and the Univrtsity of Pi(tsburgh, Pittsburgb. LIPID METAbOLISM IN PERFUSED HUMAN CORONARY ARTERIES 1• thia M vbro esperiroe.t. the awhors deal with lipid syaheals a.d choksterd uptake in atheroscktotk but.a.a eordeary arteries periwad with pulsatik pressure. Roth r`C-acaate and •Hehoksterol were added to the pcr- fusior. fluid. Results show that under these e.perimental eonditiorn, 1M arterial wall fails to synthesir.e chokstetol from aoetate. Whik only very lirnlted .y.- thesis of cholesterol esters from acetate was observed, there was arteriel uptake of free droksterol from the pertusioo plasma. Tl+e addition of nicotine to the perfusion flud did aot influence arterial cholesterol uptake, but did affect the synthesis of lipid from acetate by changing the distribution of 'K:-.cetat. ia phospholipids eod ulglyceridet . Morita, T. and eing, R. /. rrocecdinp o/ rAr Soc4ry for E, ptr(wrenrr e(ofotr an/ Mc/k /we 14(1( 2) : 617-622, 1972. OtA.r awrprlo Kenneth T. and Eiken 1.. Norris Found.tkxr. From the Huntington Memorial Hospilal, Pasaukna, ('elifornia, and Ibc Uol- versity of Southern California, [ os Angeles. 1 22 29

m n m CORONARY Sf OOD FLOW IN RELATION TO ANGINA PE('TORIS An evaluation of methods used in man for the determination of coronary Row is oeoessuy for the critical intapreration of data relating coronary flow to angina perctoris. In genenl, methods for measuring coronary blood flow in man can be divided into (1) methods using diffusible Rases, (2) methods using dif/usibie subsuncn, or subsuncea which actively enter the cell. (3) measure- ment of coronary unus Row by oootinuoua thertnaldution, and (4) methods to measure phauc coronary flow by twea.a of the ultrasonic Doppler flowmeter. Careful analysis shows that prvettdttres which determine nutrient coronary flow are influenced by the preseoee of ttaderperfuaed cardiae muscle. M(a promising ate those noninvasive methods which tdiJitt indicalorn which, during their passa4e through the heart, an acUvely taken up in the myocardiurn. There is w general aRreement concerning coronary blood Ilow ehaafies in angina pectotia and ischernk heart disease. Howe.et, evidenw suggests a dimtnutiou rather than an Increase. In pNients with coronary artery disease, coronary flow faib to mpood ade+>uately to vasodilator drugi A. esp+anation auy lie in the ao-edkd "coronry steal": a decrease In resistaoott of oonoocluded veueh at the pre- npillary k:vel could resuh Is a decreaat la blood flow to muscle supplied by that utery. The Importance of coronary collateral circulation Is &:saibed, nd the development of collaterals from preformed thin-walkd blood vessels is discvssed. Basic principles underlying coronary mkroeirculation, w they affect the osyges supply of the heart musck, an stressed. Sing. R. 1. and Ilellberg, K. Cfrrularbn 46:1146-1154, 1972. OtA.r arrport r Amerkao Medical Asuociatloo - Educatioo and Research Foundatioo and Margaret W. and Herbert Hoover, Jr. Foundation. Prom the Huntingtoo Memorial Ho.pitd, Pasadena, California, and the Ud- versity of Southern Cdifornia, Los Angeles. ME?ASUREMFNT OF CORONARY PLOW IN ISCHEMIC HEART DISEASE In this short review, the authon outline the various methcds developed over the years which have made it possible to study coronary fkrw in normal Iedividtals, in those with coronary artery disease, and in closed cheu esperi- mental animalt; •rtd they describe a number of esperiments as well as their Rfulti A more recent test uses I.oprderehol and correlates the depee of coronary artery disease with the change in nutrient myocardial flow response which follows its Infusion. There appears to be a positive correlation between the severity of coronary artery disease and the response to myocardial blood flow lhe authors also point out the relationship between the coronary mkro- circulation and the metabolic rerJuirements of the heart. Of special signif{cance is the fact that when blood pressure Is lowered by hemorrha4c, only a lew capillaries uc perfuud as the perfusion preuure latls below bO mm H4. Since these capillarar reprrxnt functional shunts, the authon speeulue, a similar dehc ency un rr~+t in heart repons nuurieheJ by atherosclerotic coronary arteries, especially as blood pressure dropa. Clinicdly, this clearly implies that maintenance of blood pressure so as to guarantee adequate mkrocirculatloa. Is most important in order to prevent cardiac necrosis and diminiahed cardiac contractility. eint. R. and Heliberg. K. In: Likoff. W. rt al. (eds.): ArAeroarferosb and C'oronary Hr.n Disease. New York: Orune R Seratton, loe., 1972. pp 146-149. Other arrrortr American Medical Association P_ducatioo and Researc! Fouodatioe, t oe Ayeks County Heart Assoeiatioo, aad the Mavppret W. and Hubert Hoover )r. Fouedation. Prom the HuotioRtoo Memorial Hospital, and the California lostituta of Tech- nolop, Pasadeoa, Cdiforaia, and the Usiversity of Southern C'alifornia School of Medicioe, Los Angeles. CHARACTeRIST1CS OF THE DICROTIC NOTCH OF THE ARTERIAL PULSE WAVE IN CORONARY HEART DISEASE From the oacillometrk studies of othen it appears that the normd patten of the peripheral pulse wave as measured is young healthy childre. abowa •/ ckareut dicrotie notch. With ioaeasioR age a smaller perceouge of perso.s demonstrate this dictotk iacisura. Using floser vaaculopaphy. the merAod de- scribed by Iss, H., Feioberg, A. W. and Cohen, B. W. in 1956, the authors obtained tracings of IfnRer pulse waves on consecutive wbjects in the Ftasly- ham Study during 1963 and 1966. Readable tracior were gotte>l o. 1.778 subjects. FledinRs sbow, that io t.aks the .unsber of "oormals" (Claa 1: deflnite dicrotic notch) haa dropped to lens than 50% by age 45-54 and to less that. 10% by aRe 65-74. DistribtMkrn of tAa prevalence cases of coronary heart disease (CHD) shows aigsifkaatly hiRher perceetaRes of CND ih twb- jects with vasculoRrams with no d'ntinet inciwra (Class IV); the kaa pro• oouoced the incesura th. greater the amount of CHD. V.scubgram daaa ta related to age and blood pressure level. However, In nonhyperteosives the pre- va)eutx of CIID b still found to be related to vasculoRram classes. Cipr.w smoking also shows a weak relationship to vasculogram class, but api. CHD in nonsmokers is found to relate to vascWogram class, indicating that the rcia- tionship is independent of eiprette smoking. Relative weight is inveraely related to vasculogram class for reasons which are not clear. According to the authors, no physiologic reason is known which would lead them to attribute diuppur- ance of the dicrotk notch to the development of ('HD. It is thercfore oooduded that the changes in the appearance of the peripheral pulse wave reflect changes (n the arterial walls, inchding the coronary aAUiea, and may bc a o.euura of the degree of atherosclerosis. D.wArr, T. R.. Tfhornas, H. F_., Jr. and McNarnua, P. M. Anttotory 24(4):244 255. 1973. From the Boston University Medical ('eoter --- Framingham Heart Study. Boston. 71 30 I

EVALUATION AND TREATMENT OF CARDIOGENIC SHOCK This review etsentially reiterates an earlier discussion of the subject pub- lished elsewhere (Mrdic.( Tin.rs 9tf(7):1)7-132, 1970). Here, the awhon describe the diflerent Iypes ol sl+ock, the various clinical maniCeslalions, and how to assess the shock state. They ureas the importance o( eva'uatin6 firway adequacy and gas eschange, acid-base balance, and renal function, as well as the need for continuous mwdtoring of arterial blood pressure; anJ they describe the various techniques invdred. Trealnsesl (and outcome) of ahock depends on whether its origin is suiUly eardioRntie, or whether it resu(u from a d'rseased eoronary bed, or folbws Aeut sur6ery. The aulhas discuss Ihe rationale for the use of vwrprnsartt, alpha- and beu-adre.xrgic agents, )-hydrosytyramine (dopamLr), and tnelhamphetamine, a :alecho(amine- nkasin6 agent, as well r 6/wason, s/aroida, and antibiotics. Muelkr, H. S., Ayrer, S. 61., Mattzara, 1. T., GianneCi, S., )r. and Grace. W. l. Resilrwr and Sr.O Myski.m. FebnsarT 1972. Other srrportr U. S. Public Health Sen(ce. From St. Vincea's Hospital and New York Usivenity School of Medicine. New York. EFFECT OF PtASMA KALLIKREIN ON COAGULATION IN VITRO In this study of one of the at" aloeg the latriosic pathway to blood aoagulatioe, rabbit and humas plasma were usod to determine whether kallikrei. has any cRcct on the promotioo of coagulation in rlrro. Human ot rabbit plasma katlrkrein is highly purified form aecekrated the partial thrombop(astin test of nbbjt, but sot human, plasma Ir a do.edependent fashion. 7Tn clot promoting e/lect of kalldrein was inhibited by preincubation with plasma or by treatment of the enzyme wrth plasma e,-macroglobMdia or soybean inhibiton. Prekallikreis did not substitute for the coagulatio. abnormalties of human plasma defkient is Ilalleman factor, plasma Wroenbop4uie anteoedent, Christmas faetor ar awihemophilic globulin. Wuepper, K. 1). asd Coch..wr, C. Q. Procrrdlnp o/ the Society for Eirer4rsewwf S1oloty r.d Mrdk/ne 141(1): 271-276, 1972. Otheir .rtr.rtt U. S, Public Hea1tA Service. From the Department of EapirirnesW ratho(op, Saipps Clinie and Rcaeatch Foundatio., 1a loqa, Ca1. THE RORSCHACH TEST: AN IMAGE ANALYSIS The Rorxhach scores of 586 healthy young medical studd:nts, who were p.rticipants in a bn=itudinal study of hypertension and coronary disease pre- curson, were studied by mearo of an image analysis. Four perwnallty ratlo[s were identified which aecounted for almost fl)% of the total conarKxr variation: irNclkctual prixlucthvity, form, human rnovemenl, and holism. This provides the clinician or reuarcher with the means to describe individual personality 32 characleristics in terms of four uncorre(ated personality facton rather thas ac- cording to some larger number of interrelated Rorschach variabks. Schori, T. R. aod TAomar. C. a. lou.n.( of Cllnk.( PiycAofory 28(2):195-199, 1972. OtA.r au'prtt Claytoa Fu.d, Nalioad Institute of MesW Hca1tY, and Natiosal Heat1 Institute. From Philip Morrb, U3.A., Rkhrtrond, Va., rd The loboa Hopk4u Udv.nity School of Medic3ne, Baltimore. CARBOXYIIEMOGLOBIN AND THE ACCESS TO OXYGEN: AN EXAMPLE OF HUMAN COUNTEREVOLUTION Access to oxygen is one teeawn* of evoluriowarp station. At tbe top of the evolutionary suk, maronulian oaypee delivery systems eaist for dr rsa/or purpose of providin6 an internal esvirooese.l suflkiently rich is oxygen to permit tissue respiration and the productiote of energy. The respiratory char- acteristic, of herraRlobin, the oxygen carrier of the btood, may be defi,ed by (1) the oay6es upacily, and (2) the shape of the di.sociation curve. Carbosyhemogbbis (COHb) dters tbe oayhemoRlobis dissociatiow arve (s such a manner that oiygew is released to the tissues with great difficuhy aad at a lower oxygen tension. The know. effcets on hean and braia of brearAing low concentrations of carbon rnora.ide are primarily related to this kftward shift and perhaps also to combination with myo6lobin and eerui. Yon- eowuininR enzymes. (lernoRlobinosy6ew eouilibria in the presence of COHb rexmbks the equilibria of rrore pr(mitive forros of hemoglobis asd riw r(se to the wuestios that Ibis decrease is the aceess to oxygen is a forw of eoustertvdutioe. Ayrrs, S. At., Giaenclli, S., )r...d Mudkr, H. ArclUves of Enrkwansenrd He.hA 26(1) :8-1 S, 197). Other arrr.rte U. S. Public Health Servke. From the Department of Medkine and the Cardiopulmonary IAboe.tory. St. Vincent's HoapiW and Medical Center, New York. INFI.UENCE OF CARBON MONOXIDE AND OF HEMODILUTION ON CEREBRAL BLOOD FLOW AND BLOOD GASES IN MAN In thrs Nudy, the influences of moderate carbon rnoooaide eapo.ur. ud hemodilution were compared in an attempl to gain information about the e0ecu of three variabks: the otygen binding capacity of the blood, the ahift of the osyhurwglobin dissociation cuive, and the blood viscosity. ('erebral blood flow (('BF), arlerid and jugular venuu+ pll, P('O„ PO„ O, aatunuos pcroest, s.d lactate concentration wete measured in Ave patients before and after rrwHfe+sre carbon monoside espoaure (mean carboayhemoStobin cuncentratwrn 201(. ) and In another five patients bc(ore and a/ter hemodilution using a sulutton of buaia. 33

albumin The tenon"' intra-artetial injection method was used (or the flow measurcments. The arterial oxygen tension remained constant during :he studies. ( BF increased both a(ter carbon monotide exposure and after hernoJilution. Tlse increase was more pronounced alter carbon monotide exposure. This could be esplained by the shi(t toward the left of the otyhemoglobin dissocLilion curve during carbon monoxide e.pastre. Jugular venous oxygen tension decreased sliRhtty during cubon monoxide exposure but remained constant duing hemo- dilution ('hanges in blood viscosity might contribute to this finding It is eon- cluded that a highly efficient .seeb,araiam maintains the brain's osy len supply during both condrtions. Paulson, 0 B, ParvinL H-H., Ofesa., 1. a.d S4InAo/. E. Journal of Applied Physiology )J(1):111-116, 197). From the Department of Neurology and Clinical Physiology, Bispc9jeril Hos- pitd, and the (kp.rtmeot of Clinical Chesnhlry, Rigshospiukt, (',spenhaRes, l)cemask. 111. The Respiratory System NEUROEPITHEI.IAL BODIES IN THE RESPIRATORY MUCOSA OF VARIOUS MAMMALS: A LIGHT OPTICAL, HISTOCHEMICAL AND UI.TRASTRUCTURAL INVESTIGATION Various electron miaoscopie lechnipues plus several routine, as well as speciflc stains such as silver and Fakk's fluorescent amine, were used to study fetal, neonatal, and adult lunp in rabbits and other mature mammals As in the human infant, each of thesc techniques revealed the presesce of rotramucosal eoepuscles, so-calkd neuroepuhclul bodres, througlxout the imrapulrrsonary airways. These bodies are composed of more or less paratklly orrented, non- edialed, cylindrical ulls which extend from the basement membrane to the airway's luminal surface, displaying prominent cyloplasmic argyrophilia, less pronounced artentaffinity, an intense yellow fluorescence. Electron microscopy shows that these granulated cells eoeuis truiwly two kinds of dcnsecored vesicles, of which the first type are acro(oniw positive, as demonstrated by the • laim-Etcheverry technique. The eeuroepithelial bodies also contain intracorpsn- cular nerve endrngs which create synaptic eed forwutions upon the granulated cells. Although the fwtctions of these woanin-produeing oorpuscks remain ue- scttkd, thex bodies may be related to the reeently reported AFG (arlyrophilic, fiuorescent, and granulated) cells, and are perhaps involved in various mucoW, bronchial, and hronchiolar neurosecretory processes. According to the aWhors, however, they mosl probably rue chemoreceppors, swretch reccpron, and/or tactik receptors modulated by the ee*wral nervous syslem. l..arwrrynr, 1. M., Cokelaere, M. and Tlsnrynck, P. Irnnrhri/r /r.r Zrll/warAunt xnA )WIlrorloPiuAr Anoto.nlc 1)3:369 392, 1972. Orlher .urporf: Nalbnaal Fonds voot Wetenschappelilk (hrderzock (Bclgium ). From the I aborauxy of Pathology and Hislology, Katholickt Univcniteil te I cu.rn Sclxx)7 of McJarnc, 1 ruvcn, Bcltium. I SEROTONIN PRODUCING NEUROEPOTHELIAL BODIF-S IN RABBIT RESPIRATORY MUCOSA The inlrapulmonary lining epithelium of rabbits contains newly ideMUied corpuscks composed of a:gyrophil, arkentaff{., yellosw fluorescent, ultrwrwc- turatly granulated and innervated epilhelial eellular organs. These art proved, by electron microscopic cytochemistry and mkrospectography, to be a source for inlrapulmonary production of serotonin. Probably they art intrapulmoaary neuroreceptor organs modulated by the central nervous system which exhibit local secretory activities. l.rwrrynr, l. M., Cokelaert, M. and Tbeuoytsck, P. Science 1 10:110-11), 1973. Otb.r arPprtr Natioe.al Fonds voor Wetenscluppclijk Oodcr:oek (Belgium). From the tabrwatory of Tathology, and Hislolop, Katholkke Univcnitck te I.cuven School of Medicine, Leuvee, Belgium. THE ULTRASTRUCTURE OF LYMPHATIC VALVES IN THE ADULT RABBIT LUNG Four adult rabbils were used in this study of the ultrnwuctural features of lymphatic vducs. Electron microscopic investigation revealed that the pulmonary lymphatic valves are not simple duplicates of the lymphatic vessel waB; they have an identifiable structure of their own. The valves consist of an unimer- rupted central connective lissue core, covered ora both sides with a single layer of flattened endolhelial celb. Near the valve i insertion in the lymphatic verel wall, the connective lissue core reveals a distinct thickening being composed mainly of collagen bundles. Elsewhere it contains mainly elastic fibers and Ane fllamenu, enclosing also sdne rather peculiar connective tissue cells. Nervous nd muscular elements were not observed. The endothelium is conlinuoui and eahibits no open junclions. The valvular basemen( membrane is better developed than in lymphatic capillaries. The enddhelial cells contain numerous cytoplasmic filansents which might be endowed with contractile ptoperties. The ultrastruc- tural features sugtesl that the function of the lymphatic valves is mainly passlve. They are firmty inserted in the lymphatic vessel wall by collagen llben and their moving parts are slender and elutic. Their endothelium appears relativdy impermeable and is firmly attached to the sublacent connective tissue. Lnuwtrynt, 1. M. and Boussauw, L. Zriuclhrl/r /ib Zr/1/ocxAunp.nd Mkror4oplarAr Anaromle 11):149-16J1, 197). Fronr the Ikpartnsent of Flistoltrgy and Palholoty, Katholieke Univcrsitet t/s leuven School of Medicme, Ituven, Belgium. STRIATED FILAMENTOUS BUNDLES ASS(K'IATED WITH CENTRIOI ES IN PULMONARY LYMPHATIC ENbOiflel.lAL ('eLlS In the r.bbit, the cndothcli.l cttts of pulmonary lymphatic vcsscls and valves generally contain two centsioks situated between the nucleus and the (]olti appararus, which are almost invariably assocuud with ouc to s(vctd 14 35

slriated hundtes Qf two to sis Alaments. These Alamentous bundles reveal a cross banding of alternating Ane (d0-100 A) electron dense bands and much broader clear ones with a variabk pcriodicily (600 900 A). The lu+gitudinally oriented filaments seen within the clear bands .re about 40 A in di.meler. The bundles re attached to the ccntriole at either or both ends, nd sxnelimes in the middle. Although their actual function Is unknown, the authcrs speculate that these uriated bundles might be vestigial roorlNS (rom ndimen:ary cilia of lymphatic endothelial cells. Their actual significance, howevcr, remairn to be i.vestigaled. L.uwrryrnr, /. AI and l3oussauw. L lorrnd of f/lrnssrrucrure Rc.e.rcA 42:2S-2fa, 1973. From the l.aboratory of Pathology .ed Hhtoiop, K.tholicke UuivcrsiteN te Leuven School of Medicine, I.euverti Befsisre. FILAMENTS IN FIflROBLAST IN PULMONARY ALVQOI-AJI WALL The /unp were inAated with 2% 6fvut.Wehyde, pori-A:ed with I% osmium tetroside and processed for electron microscopy. The eell body and processes of the alveolar Abrobfast an loca(ed In the interalveolar septum. These cells oonl.ia lipid dropiets which are eapccially twnserous In newborn and young mice. Small bundles of drtue filaments arm formed in the cytopl.srn adjacent to the nucleus oc in the process away frorm the cell body. In the protr-isded wall of the alveolar duct, a AlameNcorstai,ing process may be located t,tRether with supporting connective tissue flben. The ILaments usually run a strorghl parallel course in the cyloplasmrc procrss In the alveolar wall, a Abroblast process very often ends around a capillary outside the basal lamina of the endothclial eclls. The Alaments in such a procen run in a curved fashion following the contour of the capillary walls. The anatomical ananRement of the Alamcnts in the abeoblasts in the alveolar uea wucsts supportive and contractile functions ie the Alarneots. Hung, K.-S., Hertweek, M. 3., Hardy, l. D. .nd Lowll, C. G. /.: Arceeeaus, C. l, f ed ): lOrA Anwwal rrocrrdinrt of rAe Elecrron Mkros- eopy Sockry of Amerk., f.or Ante/v, 1972. Otti.r .r'porti Environmental Protection Agency. Hughes Employees Give Once Club, and Hastings Fund of the Univenity of Southern California. From the Dep.rtments of Anatomy and Pathoiogy. University of Southern California School of Medicine, L.os Angeks. INNFRVATION OF PULMONARY ALVEOI I OF THE MOIISE Il1NO: AN FI E(TRON MICROSCOPIC STUDY Whrn rhry rrurhed the nerve supply to the alveolar duct+ and alveoli of m..uu• lunli rrn,lrr the r/rru.rn mrcruscupc, thc .uthrws norcd that in the •I.r../u J...ir iLrrr -rrr u.u.lly rxr.r burxllrf rrrntrfling of at many as nine 1r, unmyelinated asons surrounded by connective tiwue Aben In the latcntitium surrounding Ihe openinRs of the alveoli. In the alveolar walls, taeeve rwrdlee consisting of as many as Hve unmyclioaled aaom were located in the intersUtiurm between pneumocytes and the npillaries. TAe unmyetin.ted aaoer cootai.ed neurotubules and some mitochordri., and were partially or compktdy wr- rounded by Schw.n. cells. Two distinct types of enlarged nerve endi.p were identiAable. The Arst contained nuny small milochondria and was either uso ciated with the type I pneswnocyte a fowrd alose ie the interstitiurn. The second was packed with numerous IarRe, densecore vesides and was in close cootacs with the type 11 Pneunwcyte. It b suRRes(ed that the fIM type of codlag Is ses.sory while the second is motor in 4rrdio.. Huog, K.-S, Hertweck, M. 3., Hardy, l. D. and LowN, C. G. TAc A ns.rk.n lown.d of A n.rorwy 133 ( 4): 477-4%, 1972. (HAor awrr.rtt PaviroemeMa) Prolection A6escy .nd Hastinp Fou.datio. Fund of the Udversity of Soulheen CalifonJa. From the Departteests of Aauomy. Pathology .ed Medicioe, U.)versity of Southern C.liforw School of Medicine, Los Angeles. ELECTRON MICROSCOPIC Of3SERVATIONS OF NERVE ENDINGS IN THE ALVEOLAR WALLS OF MOUSE LUNGS The nerves .nd their eodinp ie the alveolar walls of moux lu.p wers studied with the eleetroe microscope. Methods used lor this eaamination wen those used routinely for the study of awm+J lung structure and the effacu ot inhdation of air pollut.ots, influenta vituocs, or both, os the respirauxy trad of mice. Of the 40 rniu whose lungs were eaamined, 12 were oonveWio.d and two were germ(tet controls, while Ihe other 26 had bcen used is vatious inhalation e.perimenu. Groups of unmyelina(ed aaons surrounded by Schwane cells were located in the inlentilium in the walls o( the alveolar ducts .ed alveoli. The sons coot.ined many neurotubuies and some mitocho.dria. Two types of enlarged nerve endings were IdentiAed. The Arst type had many sstaM mitochondria and was either closely associated with the type I peeumocyte or located a)poe in the interstitium. The second type was Aikd with lar{e, deo.e- cored vesicles and was txat the type 11 pneum(c:yte. It is suggested that the Arst type of coding is sensory and the second type is maor in function. Hung, K.-S, Hcrtwcck, M. S.,,Hardy, l. 1). aod Loaull. C. O. Anrcnran Review of Rrrolratory !)urmt 101(2):32tr-3)), 197). Othor .uP'ortt Environnxntal Protection ARency, HuRhes Empioyeea (llv. Once (-lub, and Hastinp Foundation Fund of the l)nrversity of SoWher• C.lifornia. From Ihe t)cpartmcnes of Anatomy. Pathology and Mcdrerne, l/nivaslty of Southern California Schoof of Medreine, l os Angeles 37 I

L1LfRASTRl1(-TIIRE OF NFRVES AND ASSOCIATED CFI IS IN NRON('HI(N Aft FPITHEI IUM OF TFLE MOUSE I.UNG The nerves and their associated celli in the bronchiolar epilhetium of the mouse lung are studied with the ekctron microscope. Single unmyclinatcd asons, some of which are enlarged and contain many small mitochondria, ue ctoxly asiociated with groups of specialized cpilhclial cells. These cells are iJemrfied by having numerous dense-cored vesicks in the basal cytoplasm. The apical surfaces of rheu cells are eaposed to the bronchiolar lumen The peri- nuckar cytoplasm contains bundks of bcanching mrcrofllaments Many of Ihese cells hear a single cilium is their laterd srrtaces adjacent to the bronchiotar lumen These nervc-epi(hclial ccR cdwpkacs probably function as sensory receptor orpns in the bconchloles. Hung. K.S., llertwcck, M. S., Hardy, 1. D. and Locull, C. G. lourn.t o/ Ufrrau.ucnrrr RcuartA /):126-4)7, 197). Ofh.r .rpport: Environmental Protection Ageruy, Hughes Fmploye<s Give Once ('lub, and Hastinp Foundation Fund of the University of Southern Calrfornia. From the l)eparlmearts of Anatomy. Pathology, and Medicine. Univenily of Southern California School of Medicine, Los Angeles. CRYSTALS IN PULMONARY ALVEOLAR MACROPHAGES IN A(iED MICE hor this study, the lungs of mice sacrificed inlraperitoneally with diabulol injection were inflaleJ with 2% glutaraldchyde, pos(-flaed in 1% osmic acid and processed for electron microscopy. The cytoplasm of the macrophages had chuacteristrc cell organclles and inclusions. In addrlion, varying numben of elongated crysuls were dispersed throughout the cytoplasm Thr•y occurred singly or in Sroup% and were surrounded by nsembranes, imlxdJed in  matrit showing differcnt electron densities. When In groups, the crysl.ts were roughly pualkl to each other. Cross strialions having a periodicity of JOA were present on sorne of the crystals. The crystals described were not seen in the lung macrophates of animals living in the synthetic smos or ffllered air environments and sacrifked up to 12 months of age. Nor were they seen in alveolar macro- phases of young mice by others. Crystals In the alveolar macrophages appear to he very similar to those observed in the reticular cells and mauophates in the bone marrow. Older mice showed more bone marrow crystals. Thus, crystals in the cytoplasm of pulmonary macrophates ppear to be related to the age of the mrce. llertweck, M S . l.ootfi, C. G. and Hung, K.-S In. Arccneaua, C. l. (ed ): !hr .Tnnud rrorccdiner of the Elrrnon Mlcror- copr Soriny of Amerka, New Orleans. 197), Or1it•r arpporr: Environmental Protection Agency, Hughn Fmployecs Give Oncc Club, arxl llaurngs Furwd of 11x llnivcrsury of Stwthern ( atr/ornia l rrwn the (kparimenrs of Anatomy and PatWogy, llnivcrshy of Sowhcrn ('alifr+rnra Sch..a of Medicine. I os Angcks FREEZP-FRACil1ReD I.AMELI.AR BODY MEMBRANFS OF iHP RAT LUNG (;REAT AI.VEOLAR ('EI.L There is increasingly slrons evidence that the peat alveolar cell (Type 11 alveolar cell) of the mammalian lung is implicated in the physiologically crucial surface tension properties of the cell-air interface of the alveoli and bronchioln Moreover, it appears that the lamellar body contains the important aurface active system. In this study, lamellar body inclusions of the rat lung great alveolar cell were studied by conventional thin sectioning and freezc-etchinR. The former conArmed prcvious reports that lamellar bodies re released into the atvcolar space and rekase, among other things, tubular myelin, which ia associated with lung surfactant. Replicas of Aaed or unflaed freese<lclsed material revcal highly structured intracellular lamellar bodies In which the lamcllac may be concentric or disposed in parallel planar series. Fractured lamellse bear particles of about 100 A, and linear sculpturing similar in spacing to eaua- cellular tubular myelin. Trans.erse fractures show that Iamellae are about 60 A in width. The appearance of frccze-fractured and etched lipoprorcin and pho+lholipid membranes is discussed, and it is proposed that the surfaces revealed wilhin the lamdlar body are associated with the elaboration of surfactant components. Smith, D. S., SmbA, U. and Ryan, 1. W. T4iue & Cell 1()):137-46t, 1972. OtAer aupprrr National Science Foundatioe, U. S. Public Health Service ..d loAn A. Hartford Foundation. From the Department of Medicine, Papankdaou Cancer Research InstMute, and tne Howard Hughes Medical Institute, University of Miami School of Medicine, Miami, Fla. TUBULAR MYP.LIN ASSEMBLY IN TYPE It ALVEOLAR CELLS: FREEZE-FRACTURE STUDIES The Arst structural evidence of membrane compk.ity withia ths l.meMar body of Type 11 alveolar ulls is presented herc. In this study, the authors tried to coordinate esamination of thin sections with that of freezettched material. The results suggest three thinp: (!) Lamellar bodies have a much more regular structure than hitherto believed. (2) The kafkts of sonic larwellar bodies reveal a unique substructure of ribs and inuamembranow partkks displayed in form and spacing (400-500 A) like those of tubular mydla n seen in the airspace. ()) As in other membranes of high melabolk activMy, the fracture face is covered with partkks So-Io0 A in diameter. These frceza- etch findinp of the previously undetected organization and suborganisation of Iamellar bodin suggcst an eatircly new .N of morphological criuria for evaluating the maturation of lamellar bodies and their role in the inuaccllular assembly of the reiicular components of the airspace lining. Sm/rA, l/., Smith, (). S. and Ryan. /. W. Anarwnical Record 176(1):125 127, 197). lti .39

Othrr .upport: U S. Public Health Servict, National Science Foundation and John A. Nartford Foundation. From PapanKOlanu Cancer Rcsearch Institute and the Department of Medicine. University of Miami School of Medicine, Miami, Fla. FREF7E-ETCH STUDIES OP THE PLASMA MEMBRANE OF PULMONARY ENDOTTIELIAL CELLS Endothelial cells, esaecially tboa. of the hang, art capable of metaboliring a variety of circulating hormond wMueoes. Currcnl evidence ineicates that the relevant enrymes are burcd on the p4sma rnembr.rw or within the attached caveolae intracetlulares. 1• the pesessl study, freeze-etch techniques were used to improve underpandisg of the Gr.e Mructure of endahelFal cells and to extend investiplions of poaarEi" aitea of enzymes capable of metabolizing circulating vasoactive agents. As I. other eelks sludied by frecze elching, intramembranous particles are found ow both inner aspects of the plasma membrane. In undifferentiated areas of plasma membrane, the parlicks appear to have a random dntrrburiow. These arcas fracture so Ihat approaircately equal proportwm of the particks adhere to the eytoplasmk aspect of the outer kanet aod the csuracellutar aspect of the inoer leaflet. However, tae particles organize into roscttes and plaques at the base of caveolae, and, after fracture, the rosetln .nd plaques adhcre predominantly to the eytoplasmk aspect of the outer leaflet. T he peculur organization of particles in asaoeiation wilh caveolat supports the concrpt that cavcolae have a s1omal skektal slructure and raises the posubility that the organuatwn may be (n some way related to pinocytosis. Smith. (/., Ryan, I W, and Smith, D. S. The /ourw.l of (-rtl Siolory 56:492-/99, 197). Other .rr'prtr U. S. Public Hcahh Serrioe, National Science Fouodation and John A. Hartford Foundation. From the School of Medicine. University of Miami, and the P.panicolaou Cancer Research Inslitute, Mumi, Fla. ELECTRON MICROSCOPY OP ENDOTHELIAL AND EPfTHt:1.lA1. COMPONENTS OF THE LUNGS: CORRELATIONS OF STRII(-TURE ANO FUNCIION Evidence indicates that the hydrolases Ievdved ie the metabolism of circu- lating adenine nuckotides, ansiolensin 1, and oorrre of the kinins, are located on or near the luminal surface of puimonary endothelial eellt. Here, the authors attempt to determine the specilk cellular site of Ihis enzyme activity by iden- nfytng the special uluatructural features which might account for il, lhis partrcular luminal surface is endowed with endorhelial projections and caveolae, many uf the latter opening directly into the capillary lumen tfuough a delicate duphr.lm Ihc +irfacc arca n. Ihcrtfore, vastly increased and thus particularly well-suited 10 process sorne circulating vasoaclive substances. The invesrlptors present new evidence indicating that the enzymes responsible for their metab- olism are actually located on the luminal plasma membrane and the caveolae. Freezettch sludies reveal globular particles ( 75-100 A) within the framewort of the endotheliat plasma membrane which appear to organize with respect so the caveolae. In their opinion, these particles and the subs,ructural spociallza- lions of the caveolar membrane rees ia thin sections may rcpresent enzyme complexes or binding sites, or Ihey may be relaled to the reochanism of pino- cytosis. This technique also brinp out the striking organization of thk lamellar bodies within the giant alveolar cclls. Fractured lamellas beat globtdar partkles arranged in an array that matches the reticular organization and periodicity of the tubular myclin component of surfactant. The authoes discuss she poasibli relationship between lamellar bodies and mitochondria. They also suggest that tubular myelin may be elabo.ated in association with the lamellate bodies and rekased into the air space by e.ocytosis. Smirh. U. and Ryan, 1. W. FrArrerlon Procrrdiwrt )2(9):1937-19ri6, 197). Other .u'Port: U.S. Public Health Service and John A. Hnford Foundation. From the Department of Medicine. University of Miami School of Medkise, and the Papanicolaou Cancer Research Instilule, Miami, Fla. THE RESPIRATORY GI-ANDULAR SYSTEM IN THE RAT'S LATERAL NASAL WALL IN NORMAL AND POLLUTED ENVIRONMENT3 In the adult rat, the laleral nasal wall rwntains two e.oalr» .ystems. the lateral nasal and the maxillary. The former gland, a mucus-secreti.g unil, drains through several ducts into the nasal vesubuk, while the larler Is a aerous gland which drains into the rrratillary sinus also via numerous excretory ducts. In order to examine the inlearity and intrinsic protective mechanism of the maaillary sinus and gland in a polluted environment, these investipton exposed a group of adult rats to whole cigarette smoke. Almost imrnedulely, bah matillary epithelium and submucusal blood vessrls reacted protectively as shown by epithelial hypertrophy and a wbmucosal inflammatory reaction rotiowtd by hypersecretion of the ma.illary gland. According to the authors, all these changes might be considered mdphologie modifications necessary for protection of tissues against the fwther efled of ciRarette smoke. Although she reaclion to the snwoke ceunponenls was very severe, spontaneous healing of rhe Insues studied proliressed rapidly after cessation of the experiment. Vidit, 8., laybr, 1. 1., Rana, M. W. and elsarar, d. f). Anaromirrhrw Anrr/gcrr 110 (suppl ):d)-l1, 1972. Ilthrr auppo.tr National Institute of Mental Hcalth From the [kpattments of Anatomy an;1 Physio(oty, St. I ouis I Inivenuy School of Medicine. St I ouis. 40 41

i OZONE INTERACTION WITH RODENT LUNG: EFFECT ON SULFIIYDRYLS AND SULFHYDRYL-CONTAINING ENZYME ACTIVITIES Evidence from various sources indicates that the biologic tosicity of ozone (O,) may be attributable to its otidant effect on cellular osidation redudion balance and metabolic activities. The present study attempts to clarify the nature of this effect on pulmonary metabolic palhwaps, particnaady those involving wl(hydryl (Sit) /unctio.s is membrane protein and nonpJotein com- ponents. The authors repott that forowinR short in vivo esposwes to O,, SH levels in rat lungs decreased 1/% /or the protein fraction 9PSH) and 41% for the nonprotein fraction (NPSH). Similarly, short in vino esposure of rat hag homogenate produced a 20% loaa for PSH awd a 95% loss /or NPSII. Tbex results suggest that tou of hmR SH is an important consequence 0/ acuk O, streu. The short tn vivo saposures aho resulted in a 13-)0% depression in the activity of several enzymes containing S11 groups at the functional sites such as Rlucose-6Phoaph.te dehydrogenax 1(i6P01. gluthathione reductax IGR), and cytochrome c redunnes. However. follow- ing prolonged in vivo 0, eapo.ure, hrtg SH was maintained at normal kveb and there was a)2% rise is G6PD activity as well as a 20% increase in cytochrome c reductax activities, suggesting that lungs of chronically e.poxd animals make metabolic cellular adapulions that may be related to the develop- ment of lung osidanl tolerance. DeLucia. A. l., Hoque, P. M. Musta/a, M. G. and Croas, C. E. Ttit Jorrnai of J.So..rory and ( linkd Medicine tf0(1):339-366, 1972. Other support: U. S Public fleahh Service and American Medical Association Committee on Tobacco and Health. From the Deparsments of Biological Chemistry. Internal Medicine, and Human Physiology, UniversNy of California School of Mcdicine, Davis. OZONE INTERACTION WITH RODENT LUNO. 11. EFFECTS ON OXYGEN CONSUMPTION OF MITOCHONDRIA Ozone (O,), a eonstant alnsospherie component and a major constituent of pholochemical smog, is considered an envirommerqd pollutant becaux of its capacity to oaiwhre wllhydryl groups (SH), unsaturated fatty acids or enzymes. Since many of their enryme activities are SH.kpenden/ and their membranes contain abundant uroalurated phosplsolipids, mitochondria may thus he im- pwtant targets for 0, activity in the lung. The authors describe their studies of uxy{en (O,1 uwdization in ral lung mitochomfria following 0, caposure, on the premix that such respiratory activities may oller xnsitive p:~rameters lor the detection and evaluation of 0, effects on o.wlalive metabulism. Male rats (60 90 days old ) e.posed in viro lo O, (2 ppm for I hours, or 0 9 ppm for 10•20 days) end suspensions of rat lung mhochoalria ecpoxd in vitro 110-15 ppm 0, (ur 2/1 minuwes) were studied for oaygen eonsumptiun /i t. succinate usKlauonl. horh the homosenate and mitochundtial prcpararwru ahxxhrd a total of lll 40 nnsoles O,/mh protein (2 1•S 0 ppm/min, depawhng on the amiHont n1 ua.uc uwd 1 A/tcr short term high kvel eapinures in viro, the 0, c„mu,npr„mn raie in the humogenate or mouK'honJnal Iracbon decreased 42 I about 25% (p<0.02) compared to the oaNroh, while /n virro, respintion waa depressed 23% (p<0.001) and 45% (p<0.001) respectively. Ie coelrar, long-term low level O, eaposures increased aMular Os utilization as much r 45% (p<0.02) ia horeogenates, SpeciAe activity (l.e., succioate oaldau activity/mil protein) in the isolated witoehoadria/ fraction was only 13% (p<0.03) higher in the lunp of e.posed rats eorepared to those of controls, thus failing to account /or the overall stimulation of mNochoodrial respirMion observed ie eaposed rat lungs. As shown by transmission electron microscopy. however. Ihe large alveolar (Type 11) oeNs were three IiWnes mors nwoerow (p<0.01) in eaposed rat lungs than in those of controls. Since Type 11 xlh contain many mhochondria, their prdiferuion is likely to increase the 1et.l mitochordrial population iN the lung, thus signifkastly contributing 1o tha respiratory augmeatatios observed i. O,e:posed rat hrnp. The authors suggest that hrng mitochondrial activity wy se*ve as a biochemical indea /or possible changes of celWl.r eonstitucscy iN the kings following chronic e.posure to oxidant. Muatda, M. G., DsLucia, A. j., York, G. K., Arth, C. aed Crou, C. E. /arn.d of Lbo.+ro.y.nd Clinkal Alelk/wr /2(l):)57-765, 197). aAer snpperlr U. S. Publie Health Ser.ioe. From the Departments of Siologicd Chemislry, Internal Medicine a.d Husn.. Physiology, School of Medicine, and California Primate Research Center, Ud- venity of Cdi/ornia, Davis. PULMONARY MACROPHAGE RESPIRATION AS AFFECTED BY CIGARETTE SMOKE AND TOBACCO EXTRACT Thb report deds with a biochemical model designed to as.esa the harmful eflects an pWrnonary macrophaRes of various tobacco and tobacco anwke fractions li e., tobacco earact, smoke condensate and its gaseous a.d partictilate phaxs, as well as other selected components of tobacco and tobacco smoke). The present study demonstrates the effects of cigarette tobacco and lobaoco smoke on macrophaRe respiration. Aqueous satracls of cither cigarette smoke or tobacco affected the M rNre otygen uptake of pulmonary nsacrophages. Tobacoo estract produced a biphnic effect on macrophage respiration, perhaps panty attributable to nicotine: stinwlation at low concentrations and lehibition at higher ones. Snwke eatract, however, caused progressive inhibition of respiratioa as a fuarctbn of conoestruion, perhaps because of i1s cilia-/osk components. Both typn of eatracts affected eell viability as determined by sosiw uptake. The authors also detail the methods used to prepare the e.traces. York, G. K., Arth, C., Sturnbo,`l. A., Cross, C. E. sod Musta/a, M. O. ArcAirtr of EnrMonmenr.llltdiA 27(21:W9t+, 197). OtAer eMpprrr U. S. Public Health Service and Research and Medical edu- catioe Fund of Tuberculosis and Rnpiratory Disease Association of California. fProm the Ikpartmcnts of Internal MeJicine, Human Ph)sir>togy, and Siotogical Chemistry. UniversNy of ('aldurnia at 1)avis Sihool of Mcdicine, and Ihe C'alilornia Primue Research Center, 1lavis. 43

m m 0 ALVEOLAR INJURY IN ACUTE CARBON TETIUCIILOf:IDE INTOXICATION This paper deuih strvctval dteralioes observed In rat 'unp following CC1, ingestion, a4erations whizh may represent a model syurm pertinent to other inhalants. In animah aacriAed 1, 4. 1, 12, and 24 hours after rcceiving aa oral dose of CCI, (0.25 tuj/100 po), light microscopy discloaed focal perivascular edema, atekcuais, aad herrarrhages. The earliest ultrastructural changes occurred in Rranular p.euerocyks' Inclusioerv with lamr)lar attenualioa and decreased osmiophNia. Diaruptlon o( ribosomal agprptcs, endoplasmk retkuluns, mirochondria, a.d decrent In tnuhlvesicular bodies cu+rsed at four houn. Senall vesicks ia puular Meta.oc7le., inaeared eodytha)ia! pioocytosir. and septal edema appeared Ialet. 3ub.clrestly. there was Rraaular as well as mernbrataa.s pnearwcyu ..cto.k aadothdial alouAMaL denut atioa of eedo- thclial basal 4rnia4 i.trncyibar7 /LIe1.1 attnptio., torm+.tioa of wwral thrombi and iarra•alveolar AMi.. Earty c(la.Aa resuk from the pp lrnonary crcae- tioa of CCt, which acts as a lipid sotv.r s4os alveolar wall ekmeets. Possible formatios of a proairnata /osis tlrouRY a zesobiotk eazyme system remains speculative. Goat/, V. E. aod Smuckkr, E- A. (Sabbatical Stipend Reeipient) ArrAf.cs o/ lrucn.d MnNc4v 12t:109-117, 1971. OtA.r .rrr.rtr U. S. Public Health Service. From the Drpanteeot of Puholoq. U.ivcrsity of Washington School of Mcdieine, Sestik. OXYGEN PNEUMONITIS fN MAN. ULTRAST1tl)CTURAt. OBSERVATIONS ON Tt1E f)EVELOPMENf OF ALVEOLAR LESIONS High concentrations of otygen adminLtercd for 1002 periods ol tirna "e potentially harmful to the lunp. Ekctron microscopy of lung samples obtained post morrcm from I S patknts who were trea of pre<tiMing pufmooary disease, but developed o,ygcn peeurrronitis (respiraror.luall syndrome) aftet inhaling the µs for persoda of 14 hours to 30 days (40-100% O, eoneenualion: ma.imurw lotal pressure. 760 tnm), revealed several changes. The earliest Involved the memyrassouts pMumocytea .ed eadolhdial ce1h, resultinA eventually in their widespread sloughisg. Graeular peerw.ocytar were also damaged and the alveolar septa showed siRniAunt i.terstitial edema. In Ave uscs, endothelial doughi.g was followed by Abrie throrwbi formation. After about four to sever, days of capowre, the denuded b+sal l.minae were covered on their epithelial aspects by hyalint membranes. Alur one week of etpo.ure, there was con- spicuoua alveolar reepithelialiration by panuiar pneumoeytes. Sepu) edema persisted tMoughout the period of e.pawre, but beyond approieimately 10 days. /here was considerable aeptal eell prdiferatioa with deposition of irwcrstiual collape., ela.un aad mkro6brUa. Goafl, V E.r .f. (Sebbaical stipend recipient) ( nfw...ro.> f-nripNun 26(5) ,o9.71M, 1972 u i OtA.r .arPortr U.S. Publk Health Servke and Fooda Natlonal Suirae d. Ia Recherche ScieetiAque. From the Departmenta of PathoioRy. Univenity of Washington Sdsool of M.d1. cine and Childrea'. Crthopedic Hospiul, Seattk, aod University of (3earra Medical Schod, Geeeva, Switurta.d. CENTRILOBULAR EMPHYSEMA EXPERIMENTALLY INDUCED Y CADMIUM CHLORIDE AEROSOL Rats ez.posod to a polydiapcne aeroao( of cad.itrw chloride .olwian toe one hour on 3, 10, or 13 occasio.s developcd actate vascular ooaeeation and alveolar henrorrh.p fotlowed by polyw11orplqrwckat ceM itanltnstio.. A Sra.ula- tio. liseue response which tended to be localized atarad rppiratory hro.cLioya eubseouently occurre/. Ry the le.th day frer eapowsre, the py.ulatio. tlnw had .afertonc r.pid tr.ndorr.atio. to be scar tisue wilh diWatiora, dironiom. and destructio. of ad/aoc.l alreoU. Tha appe.ro.q of the lesiow" rnerwbad human centrilobulat ernphysewa. The severity o1 the ernphysenu ae n.eawr.d by the mun lisear I.tercept method was rdated to the number of eapo.urea to cadmium aerosol. Measurement of tiawe c.dmiure eonMmed accurrMdatbn of cadmium in the lunp of eaposed anirnds: the coaceelratioa of cadrniua was proportional to the uwnber of ezpo.ures. These data, wheu considered ir eo.- fundioo with Mudia by others showi.R that there is ae iecreased cadnrhra eontesu in the kidneys and livers of patkob with chronic obstructive hrt disease and that the body butdaa of eadeniuar i6 positively associaad with tha number of pack-ycars of eigatetle unoked, suggest to the authors that ther. Y a possible link betwee. cadraium lehalalioe trom dgarette smoking and the development of eentritobdar emp\yaerna. Seider, 0. L., H.yts. l.A., Konhy, A. L urd t.ewi., G. P. Anrcrk.w Rtvltw o/ Rcspln.rory DLeam 104:40-11, 1973. OtA.r.rr~r rtr Veter.m Admi.iwratio. Reaearch Serviee, U. S. DeparY..ear of Ileahh. Educatio., and Welfare, National Hean and Lung IrwkuM, a.d Massachuutta Tuberculosis and Rapiratory Disease League. From the Departments of Medicine and Patholop, Boston Uolversj*ty Sc\ool of Medkine, Veteram Adminbtratiora Hoapital, and The Mallory I.ritwe of Patholop, Boston. PULMONARY RESPONSE OF MICE EXPOSED TO SYNTHETIC SMOO The authors report on their audy of the pulmonary response i. apecW pathoAcn froe mice following A to 12 nwnth.s of coetinuoua e.posure to ey.• thetic smog (SS) composed of low kvels of ('O, NO;, O„ arrf SO,. 71.a /ltersd air (FA) and SS eapoeure chambers were identical In .ite, a'r coodirio.ed, and supplied with absolute particle and activated charcoal Altered air. Tba S3 chamber received NO, and SO, from compressed gas cytinden and O, from an electric teneraor. CarAon mono.ide was ambient is both FA and S3 room.. (7as concenuatwom were measured wNlo rtandard monitoring equipment After one month, mice in SS consistently weighed ku than those in FA, but the luap of SS mice weighed signiflcamly m(we in relation to body weight. Theue wera no changes in the lungs of FA mice over the period of oburvation, but Ihor 45

of SS mice developed marked hyperplasia of the bronchial lining membranes, thrckenrng of the alveolar wall tiuucs, and increased free macrophagcs in the regions of the terminal bronchioles When the animals were rcrrsored from the SS chamber after four months, the hyperplasia regressed toward normal The labeling inde was significantly higher in SS esposed mice Ihere were no sig- nificant drflerences in collagen and tlastin, surfactanl nd kcithin contcnt, or histochtmrcal staining, between the lunp of FA and SS espoud mice. Loolli, ('. G. rr of. Annds of Orcuporionul Nytlrnr 13:231-260, 1972. Other support: National Inst'Ntwe of Allergy and Infectious fliscaus, En- vironmenul Protection Akency, Hughes Finp{oyees pive Once ('lub, and Hast- ings Foundalion Fund of the University of Southern California. From the Deparlments of PatholoRy. Medicine, and Bioehemistrh, University of Southern California School of Mediei.e, Los Angeles. MUCOSAL CELLS OF THE SMALL faRONCH1OL/3S OF PREMATURF.LY BORN HUMAN INFANTS (600-1700 a) ' The end bronchioks of eigh1 preeWure live-born babies, w,!ighing 60U- 1700 S, display a rich mucosal diversity which is influeneed by Ra.tational age. Noncd'uted cells, though clearly distinct from rodeM Clara celts, s,.em partially adapted for secretion and may posaess a significant endoplasmic reticulum, vacuoles, various lipid inclusions, actire Golgi z.one, frequent literal (inler- cellular) osApouchings, and a surfaee ooal. Ciliated cells may show a changing cilia to villi ratro, localized drflerentiatqo of aurface coat, and various inclusions. "Neurosecraory" cclls apparcndy differ sonsewhat /rom those of adults in their shape, relative abundance, organelks, interullular associations, and perhaps staining of granules. In addition to the secretory characteristics of certain of its «lls. the end broochiole occupies the stnleRie apea of the idealized, lunnel- shaped, "unit {obuk." Tlsus, the intimate triad of bronchiolu mucosa, smooth muscle and vessel appears early is fetal hiatory and penisu, possibly in asso- ciation with secretory regulalios, perhaps In concert with some aspects of neurosecretion. Tlse mucosa may wbserve growth and lobubgenesis, as suggested by the occasional intrapolalion of pluripountW celFs or mature air-blood barriers; indeed, these diReresslW features apparently harmonize previously discocdant theories of centripetal and centrifugal lung development. The authors consider the fetal lung an assemblage of dynamically interactive lobuks for which the diflcrcntialing bronchiolar components may provide important func- tions of regulation and ,ecretion. They suggest that in eertain circumstances the premature ventilation of these delicately attuned bronchioks may flnd them still adapted fa intrauterinc existence. How their secrctay and rekulattxy functions would then fare, and how this might modulate lobular lursction, are significant questions that further morphologic studies may clarify Rosan, R. C. and l.r.wrrynr, l. I+I. flrlndKt wt 1'orh,.lofrr 147 t17-171, 1972 I rwrr iht 1.Lvar,.r~ 4-1 PaMd.yy .nd Ilnrolngy, Kalhuhtlc llnrvetiitcu te I tu.tn 1.K...1 ..t A1t.h-K I ru.tn 11tlawm . INTRAUTERINE PNEUMONIA. AN 1?XPERIMENTAI. STUDY In an attempt to inrestigale the palhogenesis and pathology of coasgeoitd pneumonia of the newborn, several agents supposedly responsible for ioduciy the disease were injected directly inlo she runaiotic cavity of 9) term or near- term rahbit fetuses. During autopsy performed 12 ro 72 hours later, both lunp were studied intensely aod the aspiration of the injected wbstaeces determi.ed by their presence within the af.cdar parenthyma. Under these eapeuimesul cooditions, human meconium, nbbit amniotic cellulac debris. Rastrk juia, aad acidified amniotk fluid did not produce any granulocytk bflammalory reactiot either in the pulmonary parenchyrna or within the fetal wrcmbranes. T1Ths injec- lion of bacteria, namely Sr.ryrararcur Jrndb, EuAtrkAls coll, SropAyfococrru .urrrs, and KkArlrfls prrrn.ow/.e invariably caused a rssorpholokic pkture of acute chorioamnionitis (:S fetuaes). Iw mosl of them (19 fetuses), eaaminuion of the lunp disclosed Ishtopalhobgk evide.a of experimentally provoked prseur+onia. Tltis "ietraWteriot pnnrrsowla" bears a close rexmblance to the hwnan infant's "conflea,ital paeuesonia; e#aracterized by a predomi.aady polymorphonudear in/ra-alveolar exudate inlerminRkd with amniotk fluid alls together with the ab.eeoe of septkemia and of fWrin within the lung exudate. Neither the umbilical eord nor any other fetal rrsucous membranes l.r. con)uoc• tival, tonRue, hypopharynkeal, ikal intestine, aoorectal, and eaternal Reniul) in contact with the bacceria of the amniolk fluid, revealed any inffammatory ksions. Tlsese observalions argue strongly in favor of the exclusively bacterial origin of Intrauteri.e pnaurnonia. [.auwrryru, l. AlX rt .l. obloRy of the Nrowrr 22:)01-71ti, 1973. From the Iaboratory of Pathology and Histology, K.tholieke Uaivenltek t. Leuven School of Medkine. Leuven, Belgium. INFLUENZA AND THE INTERACTTON OF VIRUSES AND BACTERIA IN RESPIRATORY INFECTIONS In this revicw, the author points out that much is knowe about tbe epidemiology of viral and bacterial infeclions of the respiralory traey of asan. Since influenza virw infections occur mosl (requently as epidemic outbruks, the close association between influenza virva and secondary baclerial infections is generally recognized. This review is iruended to demonstrate the primary role that influenza viruses play in rendering the respiratory tract suscrptible to secondary bacterial invasion. Tl+e author shows that all the features of rynn- Rntic infectiuns of the respiratory tract (n man caused by viruses (parsicululy influenra) and bacteria can bec duplicated in cuperimenlal animals. Alao, he points out the importance of immunrtatron against influenza virus infectioru which prevents desrruclion of the pulmonary lining membranes, the primary defense system of the lunks. Wider use of influenza vaccines, specifk antiviral agents, and antibodies in prevention nd treument of influenza virus Infections and associalcd bacterial complications n emphauzed. l.ooll/, C. G. AlrJinnt 52(5) 169 151, 197). 46 47

Ot)rer support: F1ughey Employees Give Once Club and 1lastings Foundation FunJ of the l)rtivcrsity of Southern California. From Ihe [kpartrnents of Medicine and Pathology. University of Southern California School of Mcdicine, Les Angeks. EFFFCT OF AIR POLI UTANTS ON RESISTANCE OF MICE TO AIRBORNE INFLUENZA A VIRUS INFECTION Pathogen free mice esposed to NO,, SO„ or 0, and subsequently chal- knged, along with unesposed mice, with heavy kthat clouds of influenza A virus showed no differcnce in the resuttaet lung vuus liten. In every case, lung virus tners increased rapidly dutinif the /rst 12 hours. By 24 hou,s .nd there- after, high titen were present regrdk» of the kind and duration of pollutant eaposute. Mice espoaed to NO„ along with control miee, liven subkthal airborne inAuew virus in/ectiow showed the saene degree of virus growth in the lu.6s and evidenced the same henualutination inhtbwion (li1) and neu- tralirinj antibody responses. Likewise, mict in a ffltered air roor.t (FA) and in a synthetic smot (SS) atnwsphers o( 6-10 ppm CO. 0.6-01I ppm NO„ 0.)-0 45 ppm 0„ and 2.2-2.4 ppm SO, and the. subjeded to sublethal influenra virus infections showed the same lunj virus growth and aetUbocty responses. Msk mice were mote susceptible to inrbeaza virus in(eetions than female mice. Both FA and SS mice of diRerent ye groups, vaccinated witto inactivated virus, showed comparsbk .n(obody responses over a four-month period. Looi1/, C. G rr at. In: Hen, ) F. Ph. (ed ): A1rAorne Trwrn06rloe and AlrAorne In/rction, Utrechl, The Netherlands: Ooethoek Publishing Company. 1973. pp, 225-231. Other aupport: Environnxnlal Protection Agency. Hughes Empbyen Give Onu Club, Fli l.illy ('ompany, snd liaslinp Fund of the Universitl of Southern California. From the Department of Patholoty. University of Southern California School of Medicine, Los Angeles. EFFFCT OF VITAMIN A INTAKE ON TNE PATHOLOGY OF AIRBORNE INFLUENZA A VIRUS INFECTSON The studies reported here show that there were no significant diRerences in the growth of virus in the Funp or antibody response in the three groups of mice on the no A(NA), regular diet (RA), and high A(HA) dkts. Fpithe- lialiratioe of the alveoli was present in all pouinffuenz.l ksioos rcgardkss of the Joet. /lowever, mice on a NA diet with no liver vitamin A shuwed siI- nifkantly more squamous melaplasL and kcratinizAtion of the regener.led bronchial epithelial eells in the residual InAuenr.l lesions than were seen in the lungs of groups fcd NA, RA, .nd IIA diets but showing vit.min A in the livers. f/n.ub. ('. (: •r s! In Flers. 1 F Ph led ): A/.brne T.umrr"iubn ond AbDorne lnJrcrlon, tlur(M, lhe Nrthertaads Oonlwck Publishing ('ompany, 191), pp. 248-25) I 11 ( I OtAer support: Environmenlal Protection A6ency, Hughes Fmptoyns Oive Once Club, 1=1i Lilly Company, and 11as1inp Fund of the University of Souther. California. From the Department o( Patholo(jy. University of Southern California ScAool of Medicine, Los Angeles. EXPERIMENTAL AIRBORNE INFLUENZA PRS-A INFECTIONS IN GERMFREE MICE Pulmonary changes in fiermfree, monocootamiaaled and conventional mbe provoked by inhalation of influenu PRt/-A vitus are similar. Whe• 6ermfrec mice were eeposed simultaneously with conventional mice to airborue vrue, the growth of virus In Che lungs and the hemagglutination inhibition (HI) aed neutralizing antibody responses in the two groups were the same. (:ermfrce .m) monoeonlaminased mice showed similar lung virus growth. Gcrmfree mice infecled only with the airborne virus showed more penistenl lung virua litns and kss pronounced II'1 antibody response. Neutralizing antibody .lao was present in sera of 6ermfree mice sacrified at seven days and later after otuet of infection. L.oosll, C. G. er .1. In: Heneilhan, 1. 11. (ed.): Gerer/ne Rrsr.rcA Aiologkd F.ffecr oJ Grwtolk+k En.ironnsrnrr, New Yort: Academic Press, 1973. pp. 395-404. OtAer supportt National Institutes of Health. Environmental Protection Agency, Hughes Fssployees Give Once Club, Eli Lilly Company, and Hastinp Fund o( the University o( Southern Californi.. From the Ikparlmenls of Palholoty. Medieine, and Biochemistry. University of Southern California School of Medicine, Lo. Angeles. PULMONARY SURFACTANT What is the role of pulmonary surfactant in the pathogenesis of pulnson.ry diseases? Based ow laboratory nperiment.tion and literature survey. M appears that there is little doubt as to the importance of pulr wnary surtaNaat In maintaining the normal pressure-volume characteristics of the lu.g. However, eacept for fetal irematurity, there is no kwoww disease stale In which thera Ie a primary deficiency of pulmonary surf.ctanL Hyaline membr.ne disease of the newlsorn, long considered the prototype for a primary deficiency of surfacunt, don not now appear to resull from an absence of pulmonary sutfactant. TAe lime has come to inlerpret more critically the Indirect, qualitative measurenbesu of surfactant clivily in disease According to the author, a secordary decteau in surlact.nt production and/ar inhibitbn of activity may play an lmportam role in the pathogenesis of v.riiws putmonary Jrseases, atthwr8h which ones and to what eatent is not known at this time. Only with the developmeM of more direct. Quamiaative measurements of sur:acunt, and a more critical assessment of the paihologie, functional, and biochemical deransemeMS of the lung will we understand the proper rok of pulmonary surlacunt in di.eaa. N/drn. A. ll lournalo/Uccuoariond /6lydkinr 1Sf)/:lsl-IeS, 197). Other supportf 1/ S Public 1leshh Service. 49 48

From the Pulmonary hisesse Section. L)eparlmcnl of Medicine. Temple University Ilealth Sciences ('enter. Philadelphia FJ(TFNSIVIi Ml/I.TISFGMENTAL BRONCHIF.(TASIS PRFSFNTING AS A TRANSIF.NT PARAFIILAR COIN LESION Tbis case history illustrates .n unusual presentation of bronchiectalk disease and emphasizes the need to conaidet the bronchiectatk sae fllled with dehns in the differential dia6nosis of pulmonary coin lesion. The flnding of a 2 cm parah,lar coin lesion in a patient with hemoptysis suggests a variety of etiologies including nesplastie dist.se. Of considerable interest in tLis particular case, however, was the diuppeannee of the win lesion seen in the upright chest roentgenogram taken shortly after adnsission Tomography cJemonstrated cystic changes in the npest of the left bwer lobe in place of the former nodular ksion Further investi6.lion by mea.e of bronchor.phy revea:ed the true nature of the underlying diseae, umely, saecvlar bronchieetasis Rogers, P. M, Ayrrr, S. AI. and Ribaudo, C. A. CArsr 62:499-501, 1972. Other arrport: U. S. Public Health Service. From St. Vincent's Hospital arsd Medical Center, and New York University School of Medicine, New Yo.k. INFI.l/ENCE OF CIGARETTE SMOKINO ON THE SPIROMETRIC EVALUATION OF EMPLOYEFS OF A LARGE INSURANCE COMPANY The increasing incidence of chronic obstructive lung disease accompanied by the greater use of spironutry prompted this study which ttempts to: ( I) provwle rtliabk ventilatory slanduds in the form of prediction equations based on a healthy population, and (2) assess the role of smoking as it aflects spiro- metric test results Forced eapiratory spirograms were formcd on 1.059 healthy employees of a large insurance company in conjunction with their routine, periodic health evaluation. Reliable predictioa equations for forced vital capacity .nd forced espiratory volume in one t+eooed, based on multiple regression analysis, were derived for this population considered representative of while- collar workers from a large metropdita arta. Among men, cigarette smoking was assoeiated with lower forced vital capacity (FVC) and forced espiratory volume in one second (FEV,), and the level of cigarette smoking was dose related to the impairment of spirometrk function. TAe dats sustest reversibility of this impairment on cessation of cigarette smoking. Among women there was little difference in FVC and FEV, belwetn current ciprette smokrn and those who had never smoked ciprtttes, but these values were greater in the younger es-smoken than in the younger nonsrnokers. These differcnces, Lowever, dis- appear rapidly with advancing age. Grimcs, C. A. and N.nrs, d. AmrrJcan Rrvlrw o/ Rrrplr.rory nbrasr 10S(2)'27) 202, 1971. From the Fmpu>yre Hcalth Strvice, Medical Ikparhnenm, Pr«kntal Irrsurance ('ompany of Amrrica. Westtrn Flomt (Mice, lai. Angeles, and the Ikpartment of Flralrh Scrrncr, ( ahlornma State ltnivcndy at Northrrdte. I AUGMENTATION OF CHEMOSENSLTIVITY DURIN(; MIL.D EXERCISE IN NORMAL MAN ' In order to answer the question of whether chemosensilivity ooetributa signilkantly to the hyperpnea of e.ercese, hyposic and hypercapnk ve.til.tory drives were measured in eight normal men during mik/-to-moderatc eacrcise. Hyposic ventilatory drive was measured as the shape parameter. A, of Laocapsic V.-P,os curves at rest and at three kvels of exercise with oaygen upp.ka averaginil 18 8. , 25.5 and )4.2% of manimal. Hyposic ventilatory drive b- creased by 204%, 219% and 800% above restin6 values for these three tscr- else levels respectively. Neither resting hyposic drive eor rhe augesent.lios with exercise was altered by !-.drenergie blockade. Hypercapoic drive was incrcued by eserclae from its reuing kvel. However, in corNrast to hypo.ic drive. N appeared to reacls a mnsimum kvel at the second exercise kvel and .howcd liltk tendency to i.ucase further at higher work Loads. These chaeges Yr hyposic and hypercapae venlilatory drives may be t,ributabk to increased peripheral chemoroceptor sensiti.ity. Wril, l. V. rr .t. lorrnal of Appllyd rAytioloty ))(6):f/1)-l19, 1972. OtAor ar'p.rfr National Inslitutes of Health, Department of Health. Educa- tio., and Welfare, and American Thor.cie Society. From the Cardiovascular Pulmonary Reseueh L.aboratory and Wcbb-Warisi Institute, Universi(y of Colorado Mediul Cester, Denver. IV. Pharmacology and Payckopharmacology THE PHARMACOLOGY OF (4,4'-BIPHENYI.ENE-BIS- ( 2-OXOETHYLENE) I-BIS-/( DI-2ETLIOXYETII YL. ) METHYLAMMONIUM BROMIDE) "DEO" The authors report on their use of various animal prep.rations to sludy the effects of DEO, an anabRtse of the corresponding dimethylamwanhrw bromide (DMAE), on adrenergic and nuromuscular transmission, and ot tbeM responsa to muscuinic, nkaink, and sympathomimetic aRenu. ResPores to nicotinic stimulants were antagonized or abolished in alt preparations after elther in vivo or /n vitro administration of DEO. This subslance, they found, eompdi- tively blocks the responses of guinea pig ileum to acetylcholine and autyl /- methylchdine (Mch), while during superfusion in eoncentratione which block responses to nicotinic aRents, it reduees the responses of vw deferentia to norepinephrine but not to KCI. Neuromuscular transmission in the rabbit aciatic nerve-nsusck and chick biveM.r ctrvicis nerve-muscle preparations was blucked by DI:O concenuatiocn which did not inilially facilitate coatraaioas or coetract the muscle rtself. The compound did not enhance the responses of th. cat nictitating membrane to pre- and poslganglionie stimulation, epinephrine, or no.- tpinephrine. These results suggest that I)FO is a potent aetimcorink and antimuscatink agent devoid of ganglionic blocking and sympathornimetk action., and that it n a nondeprrlaririn4 neurornuscular blockin4 agent Its ute of aclw., unlike that of UMAF, appears to be limited to the prt- and postsyn.ptk oiw tinic receptors and to pos,synaptk muscarinic receptors in the guinea pig ikum. SI 50

1`Srr ..:+. .~. 0 ~ t.~r m ~ ,_. ~ B © ~ Further evidence is presented demonstrating that nicolinks act predominantly at presynaptrc receptors, at gangha, and at the neuroefkctor junction. Chiou, C. V.. Long. l. P., Greenberg. S. and Shrivcr, D. A. ArcAivrr inrrrnaNonalci Je PA.rns.rodynanle tr de TAlropir 199( 1):29-42, 1972. From the Department of Plursnaooiogy. College of Medkine. University of lowa, Iowa C'hy. EFFFCT OF 4,4'-BIPHENYI.)?NEDLZ{(2-0XOET?IYI.ENE)-B!S- (2,2-DIETHOXYETHYL)1 DIMETHYLAMMONIUM DIBROMIDE (DMAE) ON ACCUMULATION AND NICOTINE-INDUCED RELEASE OF NOREPINEPHR1Ne IN THE HEART Rat atria and pufused gui.ea-Pil hsart were used to determine whether or .ot DMAE produoes its aai.kotWc eQects by inhibiting nicotine-induced release of norepinephnne. Resuhs showed that DMAE produces a dose-rclated iehibitio, of norepisepMine accumulatio. is both isolated rat atria and perfused tuinea-pit heart, matirnum inhibition being observed with 0.75 to 7.1 a 10 • M DMAE in the stria and 4.5 a 10' M in the heart. Similarly, this compound aMago.izes the release of 1-•H-.orepiaephri.o produced by lynmine and po- tentiates the chronotropk eflecl of I-norcpiaephrioe. Tlse+e data re consisteol with the view that DMAE produces poteatiatioe of the effects of norepinephrine by inhibiting neuronal uptake in a cocaine-like fashion. The compound also blocks the positive chronotropic eAoct of two nicotinic agoeisls, namely, nico line arxf 1.1 dsmethyt 4 phenylpperarinrum iodide, and prevents the nicotine- induted release of 'H-norcpinephrine bons adrenergic nerve Ietminals. The akolinic receptor apqenn more sensitive to DMAE than the receptor rrspoo- sibk for transporting norepinephrioe across The neuronal membrane. IYtir/.tl, T. C. usd Srasted, M. The /orrnal o/ PlurnwroJory and E:rperMa+ud TAer+p+ark+ I f 1( I):191-204, 197). Prom the Department of Pharrnaeology. University of Virginia School of Medicise, Charlottesvilk. TTIE EFFECT OF SMOKING ON SERUM SOMATOTROPIN IMMUNOREACTIVE INSULIN AND BL(X)D GLUCOSE I EVEIS OF YOl1NG ADULT MAI-ES Serum somatotropia levels are affected by cigaretle smoklng. In this study of 10 healthy, young adult maks, the effect of smoking on serum growth hornwne, immunoreactive Insulin, .nd b/ood glucose levels was determined after an overnighl fas1. An additional 10 nonsmoking young maks served as a contuol group Thirty minuWes after the onset of smoking, somNotropin k.els had risen from a zero time kvel of <1 to 11.t niiml The levels then started to drop but rematncd well above control levels for the following hour. Blood glucosc kvcis rrnc /rorn a mean zero time value of 73./ mil/ I()0 nd to a mean 52 value of 88.8 mE/ 100 ml 30 minutes after the onset of srnoking, but the eRed was transient. Immunoreactive Insulin kvels did not differ from zero lime valucs until 60 minutes from the onset of smoking. Even at this trme. the rise was only sbilhtly above zero time values. The nonsnwking controls displayed no such changes in serum growth honnase, immunoreactive insulin, o+ blood glu- cose concentration. The somatolropin elevations dexribed above were believed to result from central stimulation of powth hormone secretion by nicotine. Sandberg. H. rt .!. (eellrr, S.) The lor.rnd of Pharns.rolop anI E+perlnsentaf TAerrrertka 1 ti4( )):787-791, 1971. OtA.r ar'pertr Commonwealth of Pennsylvania. From the Division of Cardiolop, Philadelphia (',eneral Hoapilal, Philadelphla. EFFECT OF CHRONIC i+DMINtSTRATION OF NICOTINE ON ACETYI.CHOLINESTERASE ACTIVITY IN THE HYPOTHALAMUS AND MEDULLA OBIONGATA OF THE RAT BRAIN. AN ULTRASTRUCTURAL STUDY It hu beea suggested th.t wrne of the central nervous eystem effects of nicotine are mediated through the release of neurotransrnitler in the bnia, but a/ter its administration most invesliptort failed to observe any deMhe changes in nonpinephrine conlent. Similarly, nicotine repeatedly admi.btaed for sin weeks /aikd to affect coocentrations of endogenous n«epinephrine in rat brain, but chronk treatment increased that compound's turnover r.u. Because of an increase in brain acelykholine output after nicotine, and o/her evidence, others have suggested that cholinerific mechanisms are most impona.t in the central nervous system effect of nicotine. This study wu an attempt to determine it nicotine pretreatment could alter the activity of acetykholin- estcrase (ACAE), as enzyme responsib{e /or destructlon of acetykhoGae. The investigators found the enzyme mainly (ocdized in the perinuckar space and eistern.e of the rough surfaced endoplassnie relkulum in the neurorss of the posterior hypothalamic nucleus and the hypoglossal nucleus of the rat brain T7,ey also noted enzyme activity in the neuroglial cells. Chronic adatiaistration of nicotine ( 1 mg/kg aubculaneously, flve times daily for /-16 weeks) de- creased AChE activity in the perinuckar space and in the rough surfaced endoplasmk reticulum of the hypo6lossal nucleus neurons. Since eaperimeMs were perfamed 12 hours after the lut injection of nicoline, whea very little of the compound, or none, was kft in the brarn, the awhors eonchrk that in the rat brain, adminisuatio(r ol this substance eserts a sustained neuronsl decrease of A('hE in the hypotknsal nucleus o/ the medulla oblonp/a, (-han4, P.-L. , Sh.pe. S, and Taylor, 1. 1. Sr.in Rrrerch 14:7S-t4, 1973. OtAer suPrortr l) S Public Ile.lth Service. From the I)epartments of Anatomy and Phyuology. St. I ouis &J.ool of Medicine. St I ouls. 53

MA 11 tRATION OF T1fE ADRFNAL MEDU1 1 A: 1. tIPTAKF AND SIORAGE OF AMINES IN ISOIJITED STORA(iE VESIC'1.1•S OF T31E RAT In this study of developing rat adrenal storage vesiclcs, albino Wistar rats wcre sacrifked at 10-day intervals from birth to 50 days of age. AJr,rnal storage vesicles were analyted for catechoiamioes (CA) and for uptake of "C-epincph- rine (F) and 'If nsetaramind (MA). The properties of these vesicles which accompany devek.pment can be suommarited as follows: (1 ) at bir th, veskks have higher than normal densities; (2) af 10-20 days, lower than rormal den- sities, elevated uptake of MA coaspred to E uptake in the IiRhter prrticks, and Incteased ratc of cR1us (10 days); (3) at 30-40 days, densitics pproach adult (S"ay) levels, and relative uptakes of MA vs E approach adult. (TanRes in the density of labeled vesicks were evduNed by centrifugalion on continuous sucrose demity Rradients. At birth, both E• ud MA-labeled veskks were more dense than veucks from SOday-o/d rats. By 10 days, howevet. E- and MA• labekd veskks were lighter than iroraul. E-labekd vesicks returrscC to ratrrsal by 20 days, but MA-labekd ves{cks did taot approach normal densities ue1rT J0-40 days- These dara suggest that rhe rate of vesicle synthesis is luw at birth but increases rapidly thereafter. The heavy veskles at birth may represent "over- loaded" vesicks, whik the lighter ones at later times may be "underbaded" due to the rapid synthesis of new vesicla. Slorain, T. A. SiocArmkal rAarmardoty 22:202)-2012, 1971. Othar aupport: 1)uke University Research Council. U S Public liealth Ser- vice, North C uolina Hean Asxxiatron, and Walker P Inman Fund. From the Department of Physiology and Pharmacology, Duke University Mcdi- ul Ccnter, Durham, N. ('. MATURATION OF THE ADRENAI. MEDULLA: 11. CONTFNT AND PROPERTIES OF CATECHOUMINE STORAGE VESICLES Tlu content and properties of eatecholamine (CA) storage vesicks were studied here in order to elucidate the nature of the development process in the adrenal, to help identify how changes in uptake and storage can occur, and to determine the rok of neural input in the maturation of the gland. For this, albino Wistar rats were sacrificed at lOday intervals from binh to 50 days of age. The adrenals were analyzed for CA and dopamine-p-hydroxylase (DBO), and purrfkd storage veskks were analyzcd for CA and ATP. At binh, all three paramcters were 1 3% of 50 day kvels, about 10% at 10 days, 20 )0% at 20 days. 40 33% at )0 days, and 70-73% at 40 days Although ap three increased approsimately in paralkl. CA/DBO was below normal from birth to 20 days and CA/ATP was above normal at 10 days. At birth, the vesicles were more fragrk, but discontinuous density gradient studies indicated fewer "lighl" vcsicks comp.reJ to aduhs At 10 and 20 J.ys, however, more "light" vesicles were present and vcuck fragility was the same as In aduhs Neonates diJ not secrete adrensl ( A in rrsponse to insulin-induced hypoglycemia, but secretion war ob- sur•cd st all nthci agcs IusLieJ neonatal adrenals s well as adull adrenals eshibited Ca r'-0ependent CA secretion when esposed to high K' concentra- tions. These data suggest that there are age-dependent changes in (he coetent t nd properties of adrenal 1'A Ilorage vesicks which aflect the uptake and uor- age of amines in the vesicies. The maturation of vesk/es is probably deperdeM on the relative rate of synthesis of vesicle comporsents, which in turn are af- fecled by the degree of neuralinput to the gland. Slorkin, T. A. QlocArmkd rharmaroloty 22:20))-2044, 1977. OtA.r .upportr Duke University Research Council, U. S. Public Health Ser- vke, and Walker P. Inman Fund. From the Deparsmea of PhysioloRy and PharmacobRy, Duke University Medi- cal Centa, Durham. N. C. HYPOTl1ETICAI. MODPL OF CATECHOIUMINe UPTAKE INTO ADRENAL MEDJLLARY STORAGe VESICLES Recent studies from several laboratories suggest that the uptake of catechoi- amine+ into adrenal medullary vesicks is mediated by a mobrk canier in the vesicular membrane. The author proposes a schematic model of the uptake system in which catecholamines attach to the earrier on the outside of tha membrane and are detached on the inside surface by the action of ATP. Also idenlified are the probable sites of uptake inhibition by such agents as reserpine and Nrthylmakimide (NEM). Slot4ln, T. A. LJ/r Sclancri 17:673-6t1, 1973. Otf7er support: North Carolina Fleart Auociation, Pharmaceutical Manufac- lurers Association Foundatiun, and U. S. Public Health Service. From the Department of Physiology and PharmacoloRy, 1)uke University Medical Center. Durham, N. C. BINDING OF AMINES TO PURIFIED BOVINE AI)RENA1. MEDULLARY STORA(;E VESICI.E MEMBRANES Purifled storage vesicle membranes derived from the medullae of bovine adrenal Slarsds were used for the binding studies rcported here. Results obtained show that epinephrine and other ansines which are taken up by isolated storage vesicln of the adrenal medulla are fxxrnd to the vesicle membranes; they Iso sug`cst tlut thrs binding is to a cvrrter involved in the uprake process In this s1uJy, the cflerts of adenine nuckotides on binding 44 amincs to punbcd veskk membranes did not correlate with the effects on uptake and storage in rntact vesicle preparations or in re-formed "emply" veskln. First of all. ATP de- ereaseJ the binding of epinephrine to puriBed membranes. Also, its eRect was magnesium- aoJ temperaturc indeperxknt and was not blocked by N ethyl- maleimkk T hcse studies inJicbte thal the binding is not Jue to uptake by re- formeJ vesicks and that the ATP nsagnesiuns stunulated uptake of amines by storage vcuclcs is not Jue to an A I P m.rgnesrum nscJuicJ mcreasc in the 54 55

I 1 .I}lnity for a transport molecule. The Scatchard plot indicated that the effect of Al P on the binding of epinephrine was of the non-compelitive type for the high aflSnity binding sitc (chanje in the number of binding sites wrthout Iterations in K.,..). lhe studies .Iso demonstrate a high afTinny binding site in the mem- branes whox amine spccrfkily and sensitivity to rrserpine and N-el.iylmaleimide behave in the manner predicted for an amine carrier responsible for uptake into the veslcks. Storl7n, T. A. and Kirshner. N. aloeAew.frd Phar+n.eorogy 22:2492-2497, 1973. OtA.r ssrpportt U. S. Publie Health 3erviee. From the Deparunent of Physiolo*y at.d Pharmacology and Drpartment of Siochemisuy, Duke University Modical Crater, Durham. N. C. THE EFFECT OF COL[) STORAOE ON TFIE ADRPNERGI(' MECHANISMS OF 1NTF3TINAL SMOOTN MUSCLE Present histochcmkd and plunnaooioilie data suuest that prolonged cold storage causes sekclive and complete degeneration of the adrerses6k mechanisms of the guinea pis taenia caecwn. After tMee days of cold storage, the specidc fluorescence of the adrenergk Abers diuppearnd from ap tissue ayers of the taenia caecum sod smooth muscle (tben. In contrut, cholincs:erase active substances were still demonstrable in all tissue layers. Cold sto.aRe (l-7 days) decreased the tissue noradrenaline content and did not modify the cholinesterase enzyme activity (4 days). In cotd uorod urip.. the inhibitory response to oicotioe, 1,1-dimethyl 4phenylpiperaziniurn iodide (DMPP), or electrical transrnural stimulation was aboluhed and enhancement of the contractik re- sponse occurred. Crold storage also inhibited the inhibitory action of tyramine. Similar results were observed after reserpine treatment. In fresh taenia, the relaaalion produced by nieotine. DMPP, and electrical transmural stimulation was inhibited by adrenoceptor blocking agents and brNyliurn. These results suggest that the adrenerilic meehanisms of the taenia caecum ue more labile in cold storage than the cholinergic reochanisms. llattori, K.. Kurahashi, K., Mori, 1. and SMll.ra. S. Srlrlrll lorrw.f o/ rA.rns.coloqy a6:12)-I)7, 1972. Othrr srpp.rt r U. S. Public Health Service and American Medical Asso- ciation Education ard Research Foundatioa. From the Department of Pharnueology. University ol Hawaii School of Medicine. Honolulu. CENTRAL NF.RVOUS SYSTEM METASOI.ISM, [)RU(i ACTION, AND IIIGHER FUNCTIONS The clinical use of ekclroeonvuldve shock (PCS) is well documented and there ii ca.nu,lerahk +peculatioe as to the mcch.nism or mcchamsms throulh wh„h a Ixrwlu.cs its therapeutic rerults A s{Kcrnc rnrerretau<xnhip between Idh.unr .alis ....yprammt .nd I( % hau hccn prrq.ntd. uid crrtain brain sub- ,rr~~r~ ~h.h r,,.% tyrallrl .u.h • rrlN~.ri~h~h hr,c f.ecn cunurlcrrd lhc pur Sh poae ol this discussion is to propose a model system within which chaaRp IN the nervous system resulting from drug action may be related to a least o.e behavioral function affected by such treatmenl, with the hope of pos.ibly W- ins a source of eaplanation in these changes. As a result of his eaperime.u on mice, the author suggests: (1) that lithium carbonate and Irnipramine actu.lly have certain effects is comeeoo: .nd (2) that sorne of the differences .oted between these two oomqounds may be diminaled by adjustinR such facton as dosage, bnin upake, dtoratioe of aetion, the nature of the ekctrolyte, and other metabolic chanRes which occw, thus making their therapeutic indications more similar. In his opieioe, wch an approrch, moreover, nuy uttimately serve as a basis for preventive chemotherapy whae oertain comrrwts fatures of brala function are invd.ad. Essns.n. W. a. I.: Steith, W. L(ed.): Drrp.wJCerrlnd Frncrbn, SprinsAeld, Ill.: Clarles C. Tt.omaa, 1970, 13. PP. 131-173. OtA.r .npp.rtr Natbeal Iwuitutes o1 HealtL. From Queem College of the City University of New York, Flushins. METASOLIC AND BEHAVIORAL CONSE.QUENCES OF NICOTINE This discuasioe sumnsarizn a numba of related biochemical atad behavioral Mdiop which suqest thw nicotine may be a potentially imporsan( p.ycho.ctiw agent. What seems to Merje frons thex investiptions, is a series of contQks Interactioru irsdicating that multiple chemicsl systems may be Involved at differ- ent kvels in the mediatioa of intracellular and synaptic events related to ths process of memory oonsoiidation. Furthermore, an earlier suggestion that ta<oo- tine, as well as some of its metabolites aed asalogues, behaves very much Ilka other compounds with psychoactive propenies is reinforced. Nieotioe appears to have biochemical and behaviord effects strikingly similar to those of wm- pounds which serve as antidepressants but ue not MAO inhibitora, and may, therefore, be capable of such a role. According to the author, this possibility merits further investigation. Euman, W. S. In: Smith, W. 1.. (ed.): Drwrr, Derefopnwnr and CtrrArol Funcrlow, Sprleg- field, IN.: Charles C. Tlronsas, 1972, Chapt. 16, pp. 271-217. OtA.r aupportr National Institutes of Health. From Queens Co1kRa of the City University of New York, Flushing. t)RU(i EFFE(TS AND LEARNING AN[) MEMORY PROC'NSSFS This eatensive review attempts to oulline, ie this era of ever-increasing numbers of psychoactive drugs and their concomitantly increased therapeutic use, the effects of such agents on karning and memory proccssn Following a general introduction and a passa11e dealing with the effects o( drugs on maau- mokcular substrates, the author devotes the nes/ IS sections to 1 I ) the re.pec- tive role of cholrnergie mechanismr and of ekctrolytes in these proceswcs. (2) the effects of eight specific suMtances / e, rrbonuckic acid, strychnine, pentylene- S7

lelrati,le, picrotoxin, nicotine, cafleine, uric acid, and magnesium pemoline) and sie groups of compounds (i.e., amphetamines, melanonitrdc dcrivatives, calechoiamines, barbiturates, sedativn, and mood stabilizers); and (3) the mo- lecular interactions of various agents with brain S-hydrosytryptamine (S-lIT). The last four palles summarite the emerging evidence and siamlcanl trends which may ultimately Itad to new nreas of invesliplion. (337 relerences) Ertrnon. W. B. Adroncer in Phamnrology .nd CAen.wArn/y 9:211-))0, 1971. Other .rrportr National Institutes of Health. From Queens College of the City Univerrity of New York, Flushing. NEUROCIIEMICAI. CHANGE! ASSOCIATED WITH Et.E('TR(CONVUISIVE SIIOCK The author's purpose is to review utveral areas within which neurochemi- cal changes are associated with elnctricalty induced oonvulsions -io that such changes may be considered further under experimental cond'Nions as well as within conceplual frameworks where they tomy have behavioral re4:vance. With this in mind, he discusses the effect of e{ecttoconvulsive shock (ECS) on cere- b.ovascular permeability, energy metabdism, cholincrgie respons:s, and bb- ~enie amines, as well as the macrornokcular changes associated with electrically- induced seizures. He concludes that with the rapid advances being made in the application of techniques from molecular biology, immunology, nd ekesro- chemistry to the study of brain metabolism and function, a number of relation- ships intentionally omined from this review should become apparent in the oear fulure. Etzm.n, W. Seminars (n Pryrhiotry ,:67•79, 1972. Other ar.pportt National Institutes of Health. From Quecrn College of the City University of New York, Flushing. IMPROVEMENT OF PERFORMANCE ON AN ATTENTION TASK WITl1 CHRONIC NICOTINE TREATMENT IN RATS Working on the hypothesis that chronic eicotine treatment would result in an improvement of performance via the relative shift from "driveoriented uousal" to "ineeolive-orrcnled arousal;' the authon studied behavioral changes in nicotine treatcd rats. M.le Holrrman nts were uaincd extensively on an attention task which required them to respond with a single kver-press to a very short, variabiy presented stimulus for food reinforeement, but which also required them to inhibit inappropriate responses. After performance had stabi- btcd, two groups were treated with either nicotine base or saline for lour wecks. The groups were crossedover so that the first received saline and the second mciHine for an aSdrtional four weeks. A)-week saline recovery period followcd. Ras were tested ow the attention task daily throughout all periods Analysis of Ihc data rnd+ca+ed that reprdlev of the treatment order, rats performed more t efAciently under nicotine treatment than under control conditions. The improve- mcnt in performance was most notable in the reduction of inappropriate responses during chronic nicotine treatment. Tfie significance of the behavioral changes are discussed in relation to proposed nicotine-induced neurophysiotogic changes and the two-arousal hypothesis. Nelsen, 1. M. and Goldtre/n, L. PtrchopAannordorl. 20( 4) : )47-)60, 1972. From the Neuropharmacology Section, New Jersey Bureau of Research I. Neurology and Psychiauy, Princeton. CHRONIC NICOTINE TREATMENT IN RATS: I. ACQUISITION AND PERFORMAN('E OF AN ATTENTION TASK Results of this study on the eAects of chrooic saline aaf nicotine tteatment in rats during acquisition and two perlormance phases of a visual attention task, indicate that nicotine impaired acquisition of this task. During the two post-acquisition performance phases, however, the animals performed rmre eflkkntly under nicotine treatment than under saline, reprdless of the oondi- lions under which they had learned the lask, and regardless of whether they received nicotine during t(se /lrst or second performance phase. 7he authors dis- euss their observations in relation to proposed nieotior-induced neurophysiololic changes and the two-arousal system hypothesis. Nelsen, /. M. and GotdtteJn, L. Rerrarch Comnrrnk.tiont in Chemical Parliolosy.nd Phormocoloty S()):611- 691, 1973. From the Neuropharmacoiopp Section, New Jersey Neuropsychiatric Institute. Princeton. CIIRONIC NICOTINE TREATMENT IN RATS: 2. ELECTROEN('EPHALOGRAPIIIC AMPI.ITUDE ANI) VARIABILITY CHANGFS OCCURRING WITl1IN AND BETWEEN SiRUCTURES In Put I of this Iwo-part sludy, nicotise was show0 to have diRereotid eRecls on the acqui.ition and performance of a behavioral task. This repon represents the uthors' preliminary attempts to characterize the conicai and subcortical electrical changes induced in rats by a regime of chronic nicotine treatment. To do this, the eBects of nicotine treatment on the amplitude and variability of eortical, hippocampal, and reticular formuiun electroencephalo- grams were studied by means of,an amplitude Integration technique. Uuring chronic nicotine administration, the amplitude and variability of cortical and hippocampal brain waves decreased compared to saline kvcls, whik no .ignin cant change occurred at the reticular formation. Several trends appeared wirh nicotine treatment which were not clearly e.hibited during uline. Firss, there was a positive correlation between variability levels of the corsca and the hippocampus during nkWine treatment Second, there was a negative uxrctatiun between cortet and reticular lo.mation, and flnally, variabilities of the hippu- eampus and reticular formation were negatively related. 59 se

Nelsen. 1. M., Pclley, K. and Gofdirrln, L. Rrrrorch (-ommunications in Chrmiraf PrAolory and PharrrracolnRy SI!): 694-7(N, 197). From the Neuropharmacology Sectioa, New Jersey Neuropsychiatric Institule, Princeton. SOME VIEWS ON TT(E NEUROPHYSIOLOGICAL ANI) NFUROPIIIARMA('OIOGICAL MECHANISMS OF STORAGE AND RETRIEVAL OF INFORMATION In an attempt to clarify the qual'uative nature, underlying mechanisms and functional consequences of drufl-{nduced arousal, the wrhors performed ekctro- physiologic and bchavqral studies in the rabbil, rat and man. lheir data sup- port the eaistencc of two prob.bly rwutuaUy Inhibitory subcortical s)stcros, borh of which produce cortical acsivation but functionatly differem forms of arousal; one of these appears related to the retkvlar forsnation, the other to the limbic system (particularly the hippocarnpus). Direct ekctroencephalograFhic (EEG) measurements in the rabbit show that amphetamine can concurreotly affect the reticular famationarortea, and hippocampustortes interrelalionsl+ips. Other EE(; data, however. irsdicare that in man, the rclative effect of acute doses on • the two systcros is rnntrollcd, at least partially, by the'r preesistinA sutes. The highly variable pcrformance o/ rats tested on a continuous attention task after acute doses of amphctamine, indirectly supporis the premise that the base line stale of the tysucm dictates their response to pharmacobgic manipulation. Additional evidence indicates that. In rabbiu, nicotine atso aflects the reticular formaliors-oares and hippocampuscortct interrelauonships, but to different degrees depending on whether its administration is acute or chronic. Acute do+es act primarily on the reticular<rortcs relatuinships, while chronic treatment causes a gradual shift from•thc predominantly reticular formation control of arousal to hippocampal control. Bchavioral testing of rals operating on the cors- Iinuous ttention task reveals that nicotine initially causes impairment of per- (ormnce, but that with chronic treatment rats perform more cB.iently than they do under control corsditiorss. Acquisition studies with rats on this sanw task indicate that unlike its effect on performance per zr, nicotine dierupts karn- injf. The arousal system related to the reticvlar formation does appeer to control the general reactivity of the organism and provide orpnization frx response, while the second system (related to the limbic structures, particutarly the hippo- campus) provides control of responses through incenlive-related stimuli. The functional consequences of manipulating the two arousal system are discuved in relation to information storage (learning) and retrieval (pcrfornunce). Goldnrin, L. and Nelxe, J. M. In: Tippel, If. P(ed.): Mrmory and Trrnrfrr o/ !n/ormarlon, New York: Plenum Publishing Corporation. 197). 155-191. (hAer support: (Mice of Naval Research and 11. S Public Ifeairh Service. frnm the Bureau of Resrarch in Neurology and Psychiatry. Ncurnpsyehiatrie Imrrrure. Prrnceran, N I V. Immunology MECHANISMS OF RELEASE OF GRANULE ENLYMFS FROM HUMAN NFUTROPHILS PHAGOCYTOSING AGGREGATED 1MMUNOGLOBUI.IN. AN ELECTRON MICROSCOPIC STUDY The reaction of human neutrophils with immunologic compkses or aava ptes is dependent upon specific surface recepan. If the aggregates ara of a suitable size, phasocytosis ensues: particles .re engulfed and grenules are released into the phatocylic vacuole. A proportion of potentially iolurioar granule constiluents, however, kaves the rseulrophil through mochanisms which do not involve cell lysis but appear to be a consequence of the normal depa- dation phenomenon. lbus, if for any reason the vacuole is, or later becornes, open to the outside, there may be catracellular release of the Branules, eruymes. By means of electron microscopy, the author demonsuates four possible rnech- anisrns which might nsarpholoRically accounN foc the escape of vacuolu conlenls from human ncutroplsils ohagocyloaing aggregated Y-globu6n. According to thir dau. there was rro rekase of lactic dehydroRen.se and the cells were not lyud Estrusion of granules seemed to occur primarily into vacuoks. Such vacuoks, however, may occasionally have direct access to the esterior, as for esampl.: (1) when they apparently open to allow additional material to be ingeMcd; (2) when they remain connected to the eaterior by a narrow s6r, (3) when Iwo celh are involved in phagocylosis of a single particle (aggregate); (4) when esuusion of granules precedes the complete closinj of pscudopods around the aureptes. Henson, P. M. (CocA..nr, C. G.) ArrArlriz and Rhrsins.Nim 16(2):20J)-216, 1973. OtA.r aupporl: U. S. Public Ilealth Service. From the Department of Experirneetal Patholofly, Scripps Clinic aod Reaurch Foundation, l& IoUa, Cd. IMMUNE COMPLEX DISEASE IN EXPERIMENTAI. ANIMAIS ANI) MAN This publication reprelents a thorough and compreheosive review of the mechanisnn of immunologic diseases produced by immune compkses. Studies In expcrimental animals of pulrrsonary, glomerular, vascular and synovial InAam- malion are presented. The implication of Ihese basic studies in our current knowledge of a vuiely of human diseases is supported by immunologic and pathologic flndinp. CorAranr, C. G. and Koffkr, 1). ` Advances in Immunoloty 16:ISS-264, 197). Other a.rpportr lt. S. Public Healrh Service and American ltcut Association From the [kpartment of h.perimental Pathology, Scripps ( yrnrc and Reuarch Foundation, I a lolta, Cabfornu, and the Ikpartmenl of Pathology, Mount Sinai School of Medrerne, and the Rockefeller University, New York. 60 61

IMMl1NUl (X:I('AL Ih1?FI( IEN('Y ASSOCIAThD WITH ('I(iARF I"1E SMOKF. INFIAI ATION BY MICE Thn study was designed (I) to determine the immunosuppressive effects of both ciprettc whole snwke (('WS) and cigarette vrpor phase (('VP) on the primary and secondary immune rcsponse of mice, as reflected by heteroantibody production to a srngtc nonprolderating antigcnic slimulus, nanely, sheep erythrocytes; and also 121 to demonstrate the eRects of total dose and time of esposure, in relation to antigen injection, on the immune response capability. Inhalation of (-WS or ('VP, from which any panicks greater than 0.Jr in size have been removed, signifkanllr Impairsd immune response capability in mice. Significant rmmunosupprenive eRects on the humoral ntibody response to a single anurmc strmulw wen evident in animals esposed to smoke for seven days before or two days after adminfsln(ion of antigen. Impairment of the Immunological response capabilNy appeared to be temporary with recovery occurring about 14 days aftcr e.poture. Differeni lengths of exposure prior to antrtenre stimulation neither produced ao add'wive impairment of the immurso- logical response, rsor rendered Ihe experimental animals nwre lokrant to CWS or CVP TAe immunological deficiency was specific to CWS and CVP inhalation rather than to nonspecific debilitating strcu factors. The inductive phase was the period of the primary and secondary immune response most sensitive to impairment by esposure to CWS or CVP. Erfxr, H. 1. n .f. Archivet o/ Envi.onmcntJ Health 27(2):99-I0I, 1973. From the fkpartment of Immueobioiogy, Mason Research Institute, Wor- aester, Mass. STEItO1D EFFECT ON ERYTHROPHAGOCYTOSIS AND HEME OXYGENASE INDUCTION IN MACROPHAGES fN VfTRO The authors report on the'r attempt to devise a convenient system for the assay of macrophage function in individuals with diminished host resistance to infection. Their model, which is based on the in virro phatocylosis and de- gradalion of antibody-coated erythroeytes by periloneal macrophages when iecubated together under aerobic eondilions. nd the subsequent conversion of heme to biliverdin by heme oaygenast, measures the activation of this substrate- Inducible microsomal enzyme. Results demonstrate that /n vitro phalloeytosis of antibody-coated red cells by macrophars stimulates microsomal heme o.y genase, apparently by suburate-mediated dose-related enzyme ind-actioe. larger numbers of erythrocytes, however, require the addition of tluco.e and insulin for maximal oaygenase stimulation. Pharmaoologic doses ol hydn.ccxtisone also suppress Ihe substrate-mediated stimulation of heme osygenasc wvhout affecting erythrophallocytosis, apparently because the steroiJ irsMerferes with glucose transport or utilization; addition of insulin and glucose reverses this inhibitory eAect. It is conceivabk, thnelore, that other macrophalle enzyme systems which may be stimulated by degradation of phallocytosed particles are nlso dependent on an intact glucote transprxt mechanism and thus may have a nAe in such conJiuons as Juhetei in which the tendency toward increased infection could hc d,rc to in+p.irmcnt of mocrophale function The uthors hope that this convenient test system, or a modification thercof, can be applied to the acarch for macrophate defects in impaired host reslstance to infection in man. Gemsa, D., FuAcnDert, N. H. and Schmid, R. In: Braun, W. and l)ngar, 1. (eds.): Non-Specl/Gc Focro.s /n/luerufnR Hoar Resbtonce, Basel: Karger, 1971, pp. 129-1)6. Ot/ler arpport: U. S. Public Health Servict, the Americtn Cancer Society, and the Walter C. Pew Fund for Gastrointestinal Researth. From the Department of Medicine. University of California School of Medicine, San Francisco. ISOLATION AND CHARACTERIZATION OF PLASMA MEMBRANE ASSOCIATED IMMUNOGt.OBULIN FROM CULTURED 11UMAN DIPLOID LYMPHOCYiES New techniques for radioactive labeling of the cell surface and Iso/atiow of the membrane permit the actual chemical holation of Mem-tg, that Immuno- globulin associaled with the plasma membrane of lymphocytes. In order to rudy Mcm-1g and its possible role as a model of the andRen receptor, the lacto- pero.idase iodination method was adapted to label turface proteins of cultured diploid human lymphocytes. Membrane associated immunoglobufin of the r,K type was isolated from WIL,-A3 cells as well as from their puriAed membrane preparations by deterflent solubilization ol labeled membrane proteins and sub- sequenl precipitation with specific antisera. These data indicate that using our condi(ions all of the labeled immunoglobulin was membrane bound. The molec- utar weight of the bound nalecvle was estimated to be 263,0()0=13,t00 by sodium dbdecyl sulfate gel ekclrophor(sis and on reduction was separated i.to proteins with mokcvlar sizes identical to r and IiRh1-chain markers. The com- binalion of two r and two light chains /o give an "1gM (immunoglobulin M) moeorner° configuration should give a mokeular weight of 180.000 to 200,000 Possible reasons /or this discrepancy are discussed. Kennel. S. 1. and Ltrn.er, R. A. lournal o/ Molecadar Qiofogr 76:4fa2-S02, 1973. OtAer aatpport: National Science Foundation, and National Foundatbn- Mareh of Dimes. From the Department of Experimental Palholoty, Scripps ('linic and Research Fouodation, 1-a lolla, CaI. PI1YS1('A1. PROPERTIES OF CY1OPl.ASMIC MEMBRANE- ASS(X'IAIEI) DNA ~ Sane of the physkal properties of a cytoplasmic nsembrane assocl.ted DNA (cmDNA) isolated from a dipbiJ human lymphocyte cell line have been examined. This cmDNA extracted from lymphocytes labeled with either ('ll) or ("C( had a specific activity lower than nuclear DNA eatracted from the ume cells Analysis of cmDNA in Ihe clcctron microscope shows that the m.rlecules are linear and have a mean lengrh of I 71mm Nuilear 1)NA anJ cmt)NA Aand st identical pinitrons in both neutral and alkaline ('s( 1 gradients wrnh buoyant m 6) m 62 N

Jcnsnics (if 1 699 g/ml and I 752 ti/ml, respectively. Native cml)NA is douhle- suandcJ and ha, a mute fraction of guanine plus cyto.inc of 40 ' 1% . SheueJ, denatured cmI1NA reassocrates as two distinct Raclions whose rates of rcasso- ciauon drRer by about four Jccadcs. T he results of Ihne studies supprxl the auWhors' previous conclusion that cmDNA repreunts a unique sfecies and does not resull from mrclcar lysis Juring e.lraction prexedtwes 1)N/. 1)NA reasso- eiation kinetics of cml)NA indicate Ihal it is less comples than nuclear DNA and therefae, cmUNA miglw be used to amplify sesrne as yet t.rsdefined func- tions in the cell. Meinke, W., Ilall, M. R.. CwldMCi., D. A.. Kohne, 1). E., nJ ltrnrr, R. A: loun.al of JNrdrerfor R(olory 71(1):4)-36, 197). OtA.r erpportr National Institwes of Health, National Founduion March of I)imes, National Science Foundalion, and American ('.ncn Society. Calrfornia Division From the Departments of MkrobiokKy and Fsperiment.( PatFwloRy, Scripps ( Irnie nd Rexarch Foundalion, I a lolla, Cal. PFRIO1)AiF INf)l)( Ff) (YMPHOCYTE TRANSFORMATION. 11 ('HARA(-IFR OF RCSPONSE ANO ( OMPARISON WIIFI PIIYTO- IIFMA(iGt 111ININ ANU POKEWEFD MII(X;EN STIMl11_ATION SoJwm pcriodatc (N.I(/,) is mitogenic for human peripheral lymphocytes The purpu.c of Ihrs partrcular rnvt%u`auon was In charactrrirc the response of human lyni(+htxytes tn prn(rlate wn 11O 1 an,l cnniryre u.wrtlh thal evuked by Iwo convnonlr u.cJ ph)l,rni r. tru., I.hyt~ hrm.R~luluun I I'.IA I and pokc- wetd mrto6en 1 PW M 1 Rr.uln rnJ.e rlr thal It 1%rmrulatct the Irnns(urmatiun of a small profwuon of hunun ptnpheral hltral lymph.+cylcs rnlu bla.t eelh: Ihe resprxrse kmclrc% are srmilar to rhuw ohtarncJ wah f'lIn and PWM (he morphology of intermediate forms and hlasl cells as wclt as the magnitude of response suggest that the IO, responsive lymphocytes may he more similar to PWM affected cclls than to PIIA-teactive ones. lhe degree of response varies with tymphocytes from diflerent donors, hul al oplinrorn 1O- concen- trations only brief esposures are necessary. Prolonged treatment or higher concentrations are nonslimulatory and toaie. However, the surviving lymphocytes retain their ability to respond to both PIIA and PWM. According to the authors. this model seems to have the signiflcant potential to help clarify the initialing evcntt in lymphocyte Iransformation Although il is imrnunologically ne.nspeciflc, it shoulJ reveal much about the nature of surface reactive silea anJ, perhaps ultimalcly, about the manner in which spcrncc alteratinns in Ihese sites lead to nuclear dereprcssiun. rorltr, 1. W. tt .l. E.Prrlrnrnral Cell Rrsrurrh 71l:279 286. 1971. (1/hrr ewpport: Robert and Mary Wright Fstalc, lohn A NartforJ Ftwnda uon .nJ Rr(lrarJ Kmg Mellon ( haril.bk lrmts 1 r.'m thc k1o.sm.rn I aM+ratorics of Fspcnmcnt.rl Patholosy, Ikparlnxnt of 1'ah..6.rv. IIn.v r, i, n( Sounccrn l alilurnu Sth tol of Mcdre ne, ( os An`tle% V1. Epidemiology SMOKING HABITS AND THe I.L'UKOCYTQ COUNT lo this study of the characteristic, of smoken and ooosmoken, alrltlnk differences were noted when the total kukocyte count was correlated with smoking habil. In 86.498 multiphasic esaminatans, meao kukocyte count, were highest in eigarette smoken, intermediate in eacilaretle and cipr oc pipe smoken, and lowest in nonsmoken. The highest, t.est highest, and lower kukocyte counts were found among memben of the whil., yellow, and black races respectively. The kukoeyte count was related to quantity esokuf, ioh.lalion, and /rrsoking duration. Most groups who changed smoking habtts showed corresponding changes in kukocyte counts. Higher kukocyte eountr in smoken appeared IarRely to be a direct effect of smokioR, although a smatl pan of the irsuease seensed attributable to chronic bronchitis. A contribution of gersetic or coaslilutioaal differences belwan arrwken nd nonm)ken was not ruled out. "Normal" kukocyte count values should take into account qt, sea, race, aed smoking stalus. Ftkdmwn, G. D. rt at. AnAlrtr of Enrfronn,rnt.l Ht.llA 26:1)7-147, 1973. Other .rrrrorf r National Center for Health Services Reacarch ..d Dev.1oP ssxnt, and Kaiser Foundation Research Inatitule. From the Department of Medical Methods Reseanch, Persnaesnl. hledicd Group, Oakland. Cal. CIGARETTE SMOKING AND EXPOSURE TO OCCUPATIONAL HAZARDS In in attempt to determine whether there Is any relationship between ea- posure to work-related eavironmental harards and ciRucs(e vnokind, (h. awhon conspare the frequencies of reported eaposures in a sample popJatiot of 70.289 mee aod worne• reaivinll Ka:er-Permaneote Multipbaaic Health Chcckupr. TBe subjects were white, black, or aiental, 13-79 yean of ye, aad included cigarette srnoken as well as noasnsoken. In almoat all r.ee-aa roupr, snsokers were more .pl than noramoken to report occupatiooal espowrn to a variety of chemkals, furoes, sprays, aed dusls, as well as to eatreme heat and loud noise. No eoesistent differenm were noted betweeo amoken arad trom smoken In espoaures to insecl and plant sprays, X rays, radiradivily, or dua violet radiation. Men were more likely to be eapo.ed to several of these hraards than womee, and black meWmore likely than white. llse authors wqcu that in studies dealing with the role of smoking in certain diseases, dd/erences in occupational e.porures be taken into accounl, just as the eflcct of srrsokini should be conskkred when evaluating Ihe coosequences of ceruia such espoaures. Frirdmms. G. D., SieRelaub, A. B. and Seltzer, (-. (-. Amtriron l(turnal of EPiJrmiulogy 9!( 7):175 1s), 1971. 64 65 1

Other support: National Center for Health Services Research and DcveloQ- ment uwt Kaiser Foundation Research Institute. From the Department of Medical Methods Rcsearch, Permanaite Medical Oroup, Oakland. Cal. COFFEE DRINKING PRIOR TO ACUTE MYOCARDIAL INFARCTION. RESULTS FROM 771E KAISER-PERMANENTE EPIDEMIOLOGIC STUDY OF MYO('ARDIAL INFARCTION These authors found no asaociatioo between coffee drinking and a sub- sequent Ant myocardial infarctiow. Answess to a questionnaire item sbout heavy coffee drinking by 464 persons (trt7i white) who subsequently ~kveloped  fint myocardial infarctiors were compared to thoae of two control Qoups, one of which was carefully matched ro the uses for uandard coronary risk fac- to.s. A revkw of other studies of coffee and coronary hearl drse rse suuests that discrepancies may bc related eitha to the sekction of control subjects or to cigarette smoking which is prongly eorrelsted with coffee drinkmf, lhey con- clude that coffee drinking Is tsot an esublished risk factor for myocardial infarctioo. KLtsky, A. L., Friclnsrs, G. D. asd Skgeiaub, A. B. losrrnal o/ rAe Arnerk.n Aledkvl A»oeirion 226(3):34454)- 1973. OOther srp rt: National Institutes of Health, U. S. Public Health Service, and Kaiser •undation Research Institute. From the Deputmcnt of Medreine, Kaiser•Permarsente Medical (-emcr, and the Deputmenm of Medical Methods Research, Kaiser-Permanente Medical Care Program. Oaland, C.I. MAIL SURVEY RESPONSE BY HEALTH STATUS OF SMOKERS. NONSMOKERS, AND EXSMOKERS This report deab with the resuits of a mail survey of ciprette r+noken, nonsmokeh and et-smokers designed to probe for diQerenccs in survey response based on smoking and health status. The basis for this analysis was a queuion- naire concerning  number of health related matters including smoking which was mailed in 1971 to ),2ti7 tnemben of the Kaiser-Permanente Medical ('are Program in the Oakland-Berkeky, California, area. The population was grouped according to health uatus as measured by reported activity (unlimited or limited) and sense of well-being (well or tsoi-well). Replies indicate that diRer- ences in responsiveness between these groups may introduce bias into the results of such surveys dealing with smoking and health. Smokers wcre sluwesl to respond while es-smoken were the quickest. lhe only statistically significant diRerenee in response by health status or disability was observed among men who did not feel well: thcy responded mwe qurckly than men who reported feelings of well being. Among women who reported limited activity, smuken respcsrwkd festrr than nonsmokcn ( Oakts. T W t••J-an (; h and Cclircr, C I.....,..o. 1..,•,.~i . I ( r.J.......r,.r, vA( I t 1n St 1971 Otlrer •upporfr National Centu for Heal,h Services Reseuch and Develop- rnent, U. S. Public Health Service, and Kaiser Foundation Research Institute. From the [kp.rtment of Medical Methods Research, Kaiser Pouodatio. R.- search Institule, Oakland, California, and the Department of Nutritio.. School of Public Health, Harvard Uoivenity, CambridRe, Masa. V11. The Normative Aging Study RETINAL FIEI.D SHRINKAGE, AGE, PULMONARY FUNCTION, AND tiIOCHEMISTRY Ch.npea ie retinai fklds, dark adaptalioo, and critical flicker fusio. ha.s been shown to omr with age and oay6en deprivation. The mechsoiam Y presumably metabolic. The present paper nises the question as to whether normal variation in pulmonary function affects shrinkage of retieal fklds, a.d further investiptes the relative tAects of age and pulmonarY fu.ctloe, r weM as  further set of independent variables consisting of biochemical s.d hematological parameters. Retinal field shrinkage was studied with Goidmana perimetry in 144 healthy subjects of the Normative Aging Study. SigniAcant relationships with fkld shrinkage were given by total vital capacity aad forced eapiratory volume is one second (FEVr) with age held constant. 1t additioe the effects of a number of biochemistry v.riabks were eapbred. Higher serum pepstnoten had a significant effect with pulmonary and age eflects eo.lroUed. TAis may be related to physique since tall, kan men have bee. show to kave higher serum pepsinogen. The failure of serum cholesterol to figure siRnifk.aUy suuests that retinal field shriakqe is awt due to :therosckrosls. aeu, a. Aging and Hrmew Devefoprwewt 7(1) :10)-110. 1972. From the Veternoa Administrslion Outpatient Clink, Boston. SIGNIFICANCE OF FUNCTIONAL AGE FOR INTERDISC:IPLINARY AND LONGITUDINAL RESEARCH IN AGING This paper introduces a series of papen on various areas of functional age: biochemical, auditory, anthropometrk, psychological and social. These nrcasures were developed in the Veterans Administration Normative Aging Study to assist in the interdisciplinary andysis of aging and change in aging patterns over time. llw concept of (undiunal aite refers to a measure of .tc other than that of chronolufZ(caI age. lhis is an important dissinction, siece aging rates do not perfectly coincide with cMooolo6ical age. A functional qe is taken as the estimated age calculated from a rellression equation wh:rc the x values are predictors of chronological age. lo sum, functional age ha theoretical significance in bringing about better un.kntanding of aging procasn, the intenelatronships of aspects of agin6, and varying rates of aging Nrth lungiludinally within domairn, and relative ratcs of grng a.ros dwn.lns Functional age also can he brought to bear on studying aging varubdhy in individuals and suhkroups, and relatinR such varuhdny lu their ddlerentl.l chatactcrntics N^ 67

r . Bell, B Aeinr and Humon l)tvelopmcnt )(2):143-117, 1972. From the Veterans Administration Outpatient Clinic, Boston. . AUDITORY FUNCTIONAL AGE In the ,udiologic research of the Boston VA Normative Aging Study, an .udito.y functional age measwe hn been developed to reprexnt the eslent to whtch an individual is older or younWr than his age peers in ternu of his hearing ability. Sisteen auditory nseasures were placed in a stepwisc regression procedure: air and bone conduction hearing at various frequcncies, speech reception threshoids, speech discrimination scores, and two and three frequency averages. With chronological age as critaiow, the resulting equrion yielded o auditory age cakulated (rorn two variables: air conduction .r 8.000 cps nd speech reception threshold. Because of redundancy .monR the lai ter number of rnea+ures, these two eneclirely indes the larger number. The two nclude high and {ow frequency measures so are scnsiti.e to high frequency loss .t older age. Bell, B. Atint .ndHumun f)erelopment )(2):IS)-a17, 1972. From the Veterans Administration Outpatient Clink, Boston. TFIE NORMATIVE AGINO STUDY: AN INTERDISCIPLINARY AND LONGITUDINAI. STUDY OP HEALTN AND AGING T1se Normative Aging Study la a comprehensi.e, interdisciplinary, looti- tudioal study located in the VA Outpatient Clinic in Bostoo, M.u The study was inaugurated in 196) by the VA because of its statutory responsibility for the mcdical care of 25 million war veterans of whom two million are now 65 years of ate and over. Approsim.tely 2.000 mak .Neruu are enrolled for their lifetime as research subjects and undergo recurreet esaminalions admie- istaed on an outpatient basis. The focus of the study is on non-pathological aging, so that the subjects were carefully rcreened to satisfy rigid health criteria regardlca of age. The study is dislincti.e because of Its large N and the socioeconomic diversity of its population. Parametas include dinkal reedkine, biochemistry, special senses, oral medkioe, uwhropometry and behavior. The study is designed to investigate the relationship between normal aging and the natural history of chronic diseases. Snsoking has been idcntifled in some quarters as the most powerful negative predictor of longevity Studies have been completed on the relationship between srnoking and laboratory values, and on the social eorrel.tes of smoking with partkular reference to smoking cessation. The investiption of enrironmental correlates of age change through- out the longitudinal design will also suggest the intrinsic or estrinsic nature of the aging process. B.rl. B, Rose. C t. aad Damon. A. Atllnr and Hrn..n [)eveiopnvn/ )(I). S 17, 1972 I rrm tfu Vcttt.na Administration (utpatkot (link, Boston 68 DEPTH PERCEPT7ON AS A FUNCTION OP AGE Substantial physical changes of the dioplrk media (kns turbidily, glar. sensAivity) begin6 at 10-IS yean, whereu retinal (melabotic) chanpes bcgin after age 60. The irnportant peroeptad skill of binocular depth peruption was accordingly investigated to determine its place in Ihis rtsodel of ocular aging . In this pro}ed, binocular depth perception was checked in 164 healthy subjecu of the Normative Aging Study. A modi8ed American Optiul Compaoy Verhoell Stereoper was used as a testing device. The Verhoe0 qeteopter u.es the number of correct responses to a se1 of three ban at diRerent distaocea to measure the furthest distance at which the relative position of the tMce rods is seeo correctly. The resulh showed a marked diminution to make staoopic judgments occurred in the Rfth decade. Comparisons between T-test resulu obtained tor meaw age 20 and those for mcan age 30 are insignifkanl; oompared with mean aje 40 they appear slightly siRnificam, but compared with mean ages 50. 60, asd 70 they become very signifkanl, This Indicales that between mean age 40 osd 50 a critical change ie ueraspsis occun. Bell, B., Wolr, E. aad Sern)wir, C. D. Afinl and Hunsas Derelopment 7(1) :77-t2, 1972. Frons the Veteraar Administntioe Ouwpatlesl Clink, dostoo. LADORATORY FUNCTIONAL AGE The reaulla of several laboratory and pulmonary function tests frvs a group of healthy mals veterans were entered into a regressioo equation with chronological age as the dependent variable. Forced cspiratory vdunw, erythrocyte sedimentation nle, and hemoglobin had Beta weights which, whe combined with a co.utant, gave  laboratory functional age. This functioad age was compared with the subjects' chronological age. It was found Ihat some subjects were functionally older than their chronological age and sevaJ otda orses were considerably younger functionally than the majority whose vahres fell within r 2SD of the mean of the group FunctWnally older or youngei individuals from the psycAoloty. socioloty, and nthropurnetry disciplines of the same study were compared with the laboratory functional aRe. Nearly all were older or younger in all disciplines, suggesting that perhaps aging occvrs as a whole in dl phases rather than at very ddlcrent rates in the variour body systems. 9uroey. S. W. ( Befl, B and Rose. C-. t.. ) Aging and Humon prvefopment 7121:1l19-191, 1972. From the Veter.ns Adminnlration Outpatient Clinic, Boston 69

CROSS SECTIONAI. ASSESSMENT OF LABORATORY VARIABI P-S IN A HEA(.THY MALE POPULATION: /1. CIOARETTE SMOKING AND LABORATORY VALUES This paper analyza dais from a larpe, healthy, male population to see If signifkant dif)erenccs esist between laboratory variables in healthy males who smoke only cigarettes and those who have never smoked any form of tobacco. 7hese proups were chosen because they are homogeneous. Usio7 the 95% confidence interval, a total of 145 sep.rate significance tests were performed (29 laboratory variables X 5 ap Rrwrpa). The sutisticd analysis oJ these tests shows statistical dilierences between ciprdle snaken and nonsmokers in serum alpha-2 and gamma Rlobulis is fr.diom over multiple age (,roups, and hemoglobin, hematocrit, phosphorua, urine reaction. total bilirubin, and WBC in random age groups. Cholesterol kvel, although having a slightly lower mean and failing oA at a ltler age in nommokess, is sot statistically diiierent from the smoken. It would appear that cigarette snaking has little eRect on most laboratory lesls is a larpe {roup of healthy rnaka. Buroey, 3. W. and donus, L. ( erf1, /. aaid Rou. C. L. ) Atiwg awd Nrrnan Derclopnsrnr 3( I):19-94, 1972. From the Veterans Administration Outpatieet Clinic. Boston, and Genexe Computer Center, Rocheyter, N. Y. INVE.STIGAlION OF CHANGES IN CLINICAI- LABORATORY TESTS RELATEf) TO AGING ANf) SMOKING A multivariate discriminant aoa)ysis of laboratory tests was run on 502 subjects of the Normative Aging Study who had at kau two scqucotial complete physical and laboratory eaaminatiorn. Those subjects under 50 yean of aae were esamincd at a Bve-year intervd and the majority, over 50 years at time of admission, were esamined at a three-year interval. The muh~variate dis- crirnisarx analysis of laboratory variables showed that Bve variahks (fasting blood Rtucose, blood glucose two hoan following injestioo of 100 Rrn. of glucose, total serum protein, hereo=(obie, and cholesterol esten) wrre changing significantly in the 222 subjects who were over 50 yean of age on entry into this study. It Iook the cornbined ef)ect of fifteen variables to predict any age change is the subgroup of 280 subjects who were 25-49 at time of entry. A further subgrouping of current cigarette smoken and those who had never smoked showed no significant diflereoct in the laboratory dala in either age cohort These data are unique because they were gathered frrwn a heaNhy populalion who had passed ngid health criteria for aJmrtlancc to the study. In other longitudinal health studies, such as the Framin{harn, Mus. and Tecumseh. Mrch. qudies, escelknt health was not a criterion for ioitral admisaion to the study group Burney, S. W. and Fnskin, K. (Srfl, i!. and Rour, C. L.) Atlng anAllrrman !)rrriupmrnr )( 1) :91-101, 1972 From thc Vrtrr.ns Adrnmrs,ratioa (hrtpaticnt Clinic, Boston. and Geoexe ('omputer ('entrr, Rcxhester. N. Y. PREDICTING AGE FROM BODY MEASUREMENTS AND OBSERVATIONS The subjects for this study were 600 male veterans of the Normative Aging Study. Boston VA Outpatient Clinic. From 31 body measurements ud two qualitative obxrrations on these men ranging in age from the third to tb. eighth decade of life (mean aRe, 43 years). suteen measurements plus grayness of hair and baldness were entered into a multipk-regression equation to predict chronologic age. A total of 10 variables gave an R of 0.77, prcdretinp ape with a standard error of estimate 5.811 years. Thc predictors` in order of their contribution, were prayness of hair (r = 0.64), hand pip, ear breadth and kngth, sitting heijM, nose breadth bideltoid breadth, abdominal depth, trlceps skinfold, and baklnna. Eight variabks did not contribute significantly: heigM, wcight, chcst depth and espansion, bi-iliae bceadth, upper rm and calf circumferenon, and nose length. Functional traits predicted age more dosely than did gross body dirnensions. Damoe, A. (drtl, d. and Roue, C. L.) APintard Nrman Devrlopnrnr )(2):I69-17), 1972. From the Deparlment of Anthropology, Harvard University, Cambridge, Maw ANTTIROPOMETI[Y IN THE NORMATIVE AGING STUDY OP VETERANS: PHYSIQUE AND AGE, SERUM CHOLE.SiYROL, URIC ACID. AND PERSONALITY TAe notion that human body form and (unction are related Is strong 1. folklore and literature, and in medicine dates back at kasr to Hippoaues. The Normative A&g Study is in a position to test this bclief among large numbers of healthy subjects followed over their adulr lifetimes. From this study, eross-sectional age norms have been established for healthy men. Physique rus been related to number of offsprinR (men of average height have morel; to eleetrocardiographic variabks (asis "deviation" depends on heart position and chest wall twnformation); to serum uric acid and cholestero( kvels (higher in stocky than in kan men). Relative weight has proved to be an unteliable aiterion of otresity, Anthrolwnwtric data from the Normative Aging Study are serving In various other basic and applied research invntigatiuns, includint factor arulysis of physique, variability of physique, computation of u.matWype from body measuiemenls, and relauon of physique to persooa)uy, p.ychomutra abilities, and smoking habiu. Damon. A. and Seltzer, C. C. (Bell. D, and Ruar. (- L.) Aging and Human I)rvr7opmrnr )( 11 :7t-76, 1972. From Harvard Onivenity and HarvarJ School of Public 1(e.lth, Boston 71 70

('LINI('Al. h:VALUATION IN THE NORMATIVE AGING STUI)Y l ife ecpccuncy is determined by disease development and the process of aging, which has been defined as the to(al eflect of all changes which occur in sn organism as it ages and which rtndcr it more vulnerable or less viable. Much is known ahout the significance of control of dnease to the length of life, and changes in life espectancy have largely been the result of this disease control Funher altcration in the length of life will be greatly dependent on control of the aging process. Lklk is koowa about the biochcmistry, physroiop, genetic, cnvironrnenul and other faetors involved in aging as they relate to the human subject in a clinical setliag. The Norm.live Aging Study is attempting to improve our definition of the ciieical aging process. Through the prospective evaluation of a population previously de(etmincd to be normal the various factors resulting in aging may be described. Once reco6aized, it is hoped thal alrtralion of these fadors migfM allow sarr ooraud of the aging proceas. t)awber, T. R and Tl+omas, H. C., Jr. (Lf, f. a.d Rou, C. L.) ARlng and Hurnan DcrclopmcM )( 1):6)-69, 1972. From Boston Univenity School of Medki.e, Boston. PREI)ICTIN(', AGE IN TT1E ADULT YEARS FROM PSYCHOLOGICAL ASSESSMENTS OF ABI(-ITIES ANI) PERSONALITY Predictions of chronological age at the time of eaamination were made from scores on the 12 suMesls of the General Aptitude Test Battery and the ('ancll Suttece Personality Factor Ouestionnaire for 970 men ranging in age from 28 to 81 years Performance on the three ability tests, l)isasumbk, Tool Matching, and Turn, accounted for about 25% of the variability in chronokurcal age 1 hree scales /rom the Catttll Questionnaire. Factor F (wrgency-desurllency), Factor Q, (kigb vs. lo.w scl/-seotiment), and Factor I (scnsilive inscosihvc), accounted for 8% of the variance in age. lhe combined contribution of both sets of measures to the prediction of a6e was about )0'1G ; the amounl of common variance was about 5% when these nseuures were used together to predict age. Scores on the ability tests and the measure of surgency declined with age, while scores on the mea.ures of self-sentiment and sensitivity iocreaxd with ate. Forwd, 1. L. ( aerl, e. sod RoK, C. L. ) AgintsJHunsa>. Dtrrlopnsrwt 7(2):173-182, 1972. From the Vetcrans Adrninislratioo Outpatient Clinic. Bostoo, and Harvard Medical School, Boston. AGE [)IFFEREN('E-S AND PSYCHOLOG1C:Al. ESTIMATES OF ABILITIES AND SKILLS In attempting to assess ge differences in abilities and skills, it Ir imporsanl to know more than Krs1 an individual'a age. Socioeconomic Iactois and educational backprwnd, coupled with the kinds of work esperrenec a penon has had. may hc equally important determiners of his ability or prMCnual to perform certain u%ks In adJirKSn, the physical and mental demands of any partu.ular job or ratik are usually overestimated by the worken and their immediate supervisors. As a result, older workers are often considered unsuitabk for jobs they could actually perform. It is important to understand the streelths sod weaknesses of different mcthods of assessing ability. Some mNhods may be unfair to certain age or social groups, while others may lead to asaessnsents irrekvant to the work situation. One investigator has indicated that uainabilNy tests (usually a miniature work sampk) are more useful foe predicting occupational success /or older workefl th.n standard ability tesls. Many a6e-rclated chanpes is abilities may be interpreted as stemming from a general slowing down with aoe of lhe central nervous syslem's capacity for prooessiee information. TAis slowieR Is p.rtkuluty apparent when a person muu deal with information from several sources at once ira sovel or highly eornpka lasks. With eaperknce, or apeciali:ed Irainiq, • number of the potential deficits In the abi(itin of older people may be miaimized. Porard, 1. l.. a.d Carr, 0. D. (BirN, fa. wd Rosr, C. L.) lnlrsrrld Gccw.rofory (1) ) :71-96, Spring 1972. Othar arpportr National Instiawe of ChMM Health and Hureae Developmc.l. From the Normative Aging Sludy, Veterans Admiwisuation Outpa/kat C(ink, Boston, sod the Dep.rtlmeol of Psychiatry. Harvard Medical Schod, Bouo.. AGe-RELATED DIFFERENCES IN MENTAL PERFORMANCE This project reviewed the eflecta of age and ecooomk .(atus on two sds of ineasures of cognitive perfornuece. One set consisted of the 12 Mrbtnu of the General Aptitude Tesl Butery: the other was a group of laboratory4ued e.perimeots. The relationships among the various measurea of performance within and betweee the two sets were eaami.ed. The four principal Oedi.p were as follows: (1) Age•re(aled dediaes 1t performance were found 1n all subtests of the General Aptitude Battery. Perlormance declined kast I. thoee subtests where the effects of aocioeeonomk statua were strongest a.d aor is those subests where qcioeoo.oraic status eRects were weakest. (2) It is rae dif(kult for older Iadividuah to (a) retrieve special iaforsnation from short•tcYs memory, (b) rsonilor two verbal sequences eoncurreetly, and (c) i.iUate a response in a twothoke discrimination. Variations in pertormaooe on those tasks were eot systematically related to socioeconomic status or education (3) In both sets of trxasures, tbe major ete-r+dated diflerences In the k.cl of performance were observed between wbjeets ie their sisties or scveotin aed the younger ones. The largest aRe•related decrements occurred in tasks which were probably nrlalivcly unfamiliar lo cookel or in form to the wbject. (4) Thrre was little overlap among assessments of abNuks represented by the Iwo sns of ineasures. For future study, a new set of eaperimco/s was dcsiRned lo tesl Sa from the No.malive 'Aging Study so as to yield longitudinal as well as crors-fecl/[XIaI evaluations of age diRneoces is cognitive perlormance. Fozard, 1. 1.., Nulull, R. L. sod Wau6h, N. C. (dcll, fl. and Ras., C. L) Aging end )funai Development J( 1):19-4),1972. Ot)her.rpportr National Institutes of Hcatth. From the VA Outpatient Clinic and Ilarvard Medical School, Bosto., and the Institute of Human Scicnces, Boston College. ('hcstout Hill, Mau. 72 73

I I ~ t +J' , :z .l.~. 0 (-" I-Alk a, ~ ,., m m ('^.x o. m m T11E VFTERANS ADMINISTRATION LONOITUDINAI. STUDY OF ORAt. HEAl.7H AND DISEASE: METHODOLOGY AND PRELIMINARY FINDINGS The purpose of the present study b to evaluate the distribution, detet- minants, changet and interrelatiooships observed in oral heaNh, ctal disease and oral function frorss flndings of periodic euminatioos performed at regular inrcrvals in a population of mak veterans in tood health at the orwsd. Most oral flndinp of nondental tiswtes were neR.alire; ho.revet, kukoplakia was relatively common, being presenl I. 11.9% of the subjecu. lrukoplakia will be studied on a continuing b.sb In a speeial project and evaluated in relation to the use of tobacco and the \asil of ebeek chewing. About 6'5% of the subjects reported they did not use tofs.eeo. Sorne t% of the cigarette smokera use more thaa one pack per day. Cigar a.d pipe sreokers constituted only 16% of the total sample. In the .eat uerin of croa-tabulatio.s prcpared, the oral health of users and tsoswcrs will be oocnp.rcd. Kapur. K. K. rr at. (Irff, 1. uJ Row, C. L) Arnr ..d Hunson Dtrrlopnwwr 7( I):125-1)7, 1972. From the Veterans Administntio. Outpatient Clink, Boston. SOCIAL CORRELATES OF SMOKING IN A HEAI.THY MAI.E POPULATION This is a prcliminary eaploration of smoking behavior relative to social characteristics in the Normative Aging population There were definite findings with respect to the nonsmokers and the caunokcrs, but none with regard to the amount of cigarette smoking lns smokmg in terms of nonunoker nd easmoker was telated to English- speakinj ethnicay. Jewish religroo, nonwhite race, not marties' or not wNh w,fe, higher level oor:upatron, higher education, upward career mobility and upward n/ageneralional mobility. A dominant age effect in the flodinp issued from the facs that kss smoking was related to older age. Many of the ilems which related to kss smoking alw related to older ate. Pouihk esplawtiosss are that as people grow older their changing life styles rtauire ksa support from smoking ot, rnote simply, their appetites decrease. These findings are limited by the sre of bivariate asalysis. A multivariate approach is ptanned with the nse of discrinainant function aaalysis. Rox, C. L. AgMg an/ Human Dtrrfop+.wwt )( I):111-12l, 1973. From the Veterans Adminiurauion Outpatiea Clink, Boston. Tl1E MEASUREMENT OF SOCIAL AOE Social age Is defined conceptually rn a chaoging composite of social life styles. attribsates and attitudcs at variow pohMS of the life cycle. A simple- variabk meesurt of social aife was developed by regressing chronological ale on a number of social correlale. of age. The correlNes Upped life uyk,% rclating to famrly, work end retirement. The estinsated age, is units of ycan, -.s uktn as iht wxul agt lhis composne nuuure was calculated for subjects 74 of the VNerans AdminisUalion Normative Aging Study froan a tcn-vatiable equation. "Old" social age was indicated by a greater degree of settling in to one: job, more staving oR of retirtrnenl, less likelihood of movinff and ooot.cn with relatives and greater likelihood of wife's employment than is true of one i age peern. The measure is useful for Itstetdisciplinary analysis with other "ages" similarly derired, such as psychological age, biochemical ya and auditory age, as well as for social gerontologie analysis of subpopulations defined on the basis of are-invariam criteria such as social daa and urea eaperieoce. Rosr, C. L. Ag/nt.nlHun..n Drrrlopnstnt 3(2):153-16A, 1972. From the Veterans Admieislntioe Outpatknt Clinic, Soatoo. AOING AND PREFeRENCB FOR LATER RETIRI°MPNT The hypotbesis was Isves/ipted that older worlen who are losper I. tM work role are more anaioro to remain working and prefer to retire at a Irer age. In the esperirnental dpiRe, socid ctatr and health wert affe4.variad benuse of the aele,ctive .ature of the VA Normative Aging population. T)rcu two ma}or onaluniaunta of the relationship bdweea age and later retitanea preferenoe were therefore eoetrolkd. A Mepwiae repea.ioa a.alyais rosrd t<at later reliresnent preference was related to age and social class factors, the Iwo acting independently, ud with age more thaw twice as imporunt as social dar. This finding is problematic because of (1) a lrersd to earlier maaiddory rellr.- rtsest related to increased industrial produetlvily; (2) capacity for longer work life, related to impeovemem in health and longlevity; and (l) a tread to tooernanual occupatio., which is lns vuloerabla to age deaerned. Is su..ary, desire to stave oQ teliremeM increasea with tKe at a time of wcieW pre.trun for curtailment of work role. The aolutio. to this dikmma lies either Is eapu- sbn of work roks or massive change in values frvoring earlier retirement. Rost, C. L. and Mogey, J. M. A gMS and Human DtrtJope.rnt J(!):15-62, 1972. V111. Mi.celbneou. HUMIDITY OUTPUT OF TNf3 CIRCLE AtaSORtiER SYSTEM In the circle absorber system, IarRe Oteiatlons io the humidity of inspired pses cam be cspected with variations in fre.sh-ps inflow, ve.titatory t.i.uta voluroe, or C'O, eah.lation. 19 order to attempt the predictio" of humidity vari.tioeu in this system during its clinical rse, the present Inveatiptors oo.- eenlrated on this factor (n a circle system and erected a series of curves aw1 noenoRrams which allow anesthesiologists to estimate the humidity of leepired pses in telation to the three varlables mealioned abov.. To do thi., tbd humidities of gases inhaled from the circle absorber system werc mcasur.d in a model "paticnt." The periods of subrUtatiort of the system fullowing vutuioar in fresh-ps and COr inflows, e.hakd water vapoe, and previar use of the apparatus were assessed. lhe eflects of variations in fresh-gas and lY)r in8ows, 75

respiratory rate, anJ tidal volume were measured in stabiliztd sysle:ns After subdrzanon, humulares were found to range from 27% at room te.nperature (with low minute volumes and (-Or inflow, and high fresh-olas inflow) to 90% (with high minute volumcs and CO, inAow, and low fresh-gas inflow). Data colkcted were used to construct nomograms upable of predicting the Sumidities of pses inhaled by patients. Ch.lon, I. rr.f. AnrrrArriology )>!(S):41s46S, 197). From the Albert Einstein College of Medicine of Yeshiva University, New York. A MEC[IANISTIC STUDY ON THe PORMAT7ON OF THE NON- VOIATILE DEGRADATION PRODUCTS OP p,p'-DDT ANl) p,p'-TDE IN p,p'.DDT- AND p,p'•TDE-TREATED TOBACCO SMOKE In this last of a series of esperinsenta oa the breakdown o( p,p' DDT In tobacco sm(skes, the authors preseM several conclusions. Tobacco saripks con- uining 20 ppm p,p'-DDT, 200 ppm p, j-DDT, 20 ppm p,p'-TDE an(! 200 ppm p.p'.TDE were snsoked, and ther smoke condensates analyzed for drgradation products such as p,p'-DDT, p,p'-TDE, p,p'-DDE, p,p'-DDM, transdichloro- stslbene, bis-(p-chbrophenyl)methane, and p,0-0ichbrobenzophenone. The de- gradation patlcrns and the amosants in which these degradation prorlucts were prcxnt in smoke condensates showed that: (1) during the smoking process, the more volatile compound has a better chance of not being destroycd; (2) the higher the amount of pesticide prexnt io tobacco, the greater is the percentage bu of peuicidc upon smokrng. (3) a+wkrnp being a pyrolytic reaction of very shott durnion, "pnmary," 'sccorsdary" and `teruary" reactions take place in the order grven; (4) reKt.ons which have lesser energy requirements occur more readily than those which have a higher requirement; (S) in the instance of p,p'- TDE-Ireated tobacco smoke, some p,p'-DDE is also formed by dchydrosenation of the parent compound. ("hoirr., N. M. and Tlrekkekandam, 1. T. drUrilltr zrr T.bs4/orarArnt 7(2):ts-92, 1973. From the Department of (-hemistry, North Carolina Agricultural and Technical State University, (irecnsboro. GUSTATORY RESPONSES DURING PERIODS OF CONTROI.I.ED AND AD C/ff CIGARETTE SMOKING Is taste influenced by wrwkingt In an attempt to answer this question, three psychophysical enethods, drfleren(ial sensitivhy, perceived intensity, and degree of liking, were used to measure gustatory responses among n(xnmokers and among smokcrs who were placed on two-weck schedules of increased and decreased cigarette comumption Varying the srsokc Ievels had little influence r.n the unoIrrs' umirrvay to the ustcs of sucrose and sodium cldrxak Ihroulth-sr the r.l.rrin.rnr(, rw mn.ukrrs v,rrr sholhtly more urtmdrve than .....,ttrn t„+rr --n.,i. .rrr 4..rrhtJ Io fr'nc Conrp.runds by smukrrs I than by nonsmokers. Derree of IikinZ of the test solutions was unrelated to smoking. A subsequent eaperrnent showed that 45 nonsmokers were dyhtly, but not significantly, more sensitive than were 45 smoten to the tastcs of sucrose, sodium chloride, citric acid, and quinine hydrochloride, with no differences in the'r sensitivity to the odor of 2-butanone and to the viscosity impartcd by carrajeen gum. There was a slight inverse relationship between sensitivity and the number of cigarettes smoked per day. Smoken liked oo/fce signiflcantly better. Few chaages in body weight were observed, despite the smokeri subjective assessment that their appetites nd food intake were inversely related to the number of cigarettes smoked. r.ntDorn, R. M. aad Trabue, 1. M. rrrcrprion & rrycAopbrslrz 1:1)9-144, 1973. From the Department of Food Science and Techoolop, llniversity of Calr- forni., Davis. MEMBRANE INTERCA[UTED PARTICLES IN HUMAN ERYTHR(CYTE GHDSTS: SITES OF PREFERRED PASSAGE OF WATER MOLECULES AT LOW TEMPERATURE Although it has been suggested that hydrophilic pores may acr.ouN for characteristics of the movement of water molecules across erythrocytic oras- branes, no dired evidence associates such porrs with actual structural diAer- entiations within the membrane. Fteeze-fracture and freeze<tch studies of lw lated erythrocyte membranes show that they consist of fluid bilayer doaulm traverxd by proteiaeontaininp interulatioes ("tncmbrane-intercalaled partl- cks`)• The present eaperiments suppon the hypothesis that the topology of polar and apolar spaces of the membrane-intercalated particles is not oo.ce.tric, but that the hydrophobic spa= are equatorially distributed; axial orpnlzatba of the hydrophilic regioas could then result in hydrophilic cootlnuity across the membrane and might provide  structural basis for the passage of \ydro- philic molecules. Sublim.tion, al -100', of erythrocyte membrane suspensio.s (incubated at p[I 5.5 to cause aggregation of membrane particks) uu.es pro- gressive and se{ ective sinking of the membrane retions comprised of aggreptcs of intercalated pvticl": that is, sublimation of water molecules occurs pref- erentially across these membrane regions. Results indicate that under thcse esperimental conditions, the membrane-in(ercalated particles provide a prcfcr- ential structural pathway for passage of water molecules acror erytbrocyte Shost membranes. •Pinto da Srlva, P. (Fudrnbtrr, N. if.) frorrrd/nts o/ the Nerbn.l Arailrrny oJ Srfrnrrr o/ the (lnlrrd Sr.rrs of Ansrrka 70(3):U)9-1J4), 197). OtA.r ar.pportr l). S. Public Health Servkc and F.(fna McConnell (Lrk Foundation. From the University of Cahfornl School of Mcdreinc, S.r, Francn(o •PrwM .Yr... C..a.r (-awcY t.(o..~r. t~. S.It, t..rN..~., t.. 1Nrp, ( J 76 77

ANIONIC SITES ON THE MEMBRANE INTERCALATED PARTICLES OF Hl)MAN ERYTIIROCYTE GHOST MEMBRANES. FREEIE ETCH LOCAI.IZATION Freere-fracture and free:e etching techniques reveal eaclusive asscxiation of a ferrilin derivative (with high isoekclric point used as a marker foe anionic sites) with the regwns at the outer and inner suriace of the human erythrocyte =hosts membrane which correspond to the membranc-intercalaled parlicks. Al 1he outer surface, the sites include sia{oglycoprotein. Eaclusive association of nionic sius and membrane partick>, alo.= with comparison of the nursber of sialic .cid residues and intercalated p.rlides, implin clustering of acidic groups over distincd sites at the surface. Association of the label with the outer and inncr surface regions which correspoed to the membrane inlercalated particks, provides further support for the concept of proteintontaining structures which ate intercalated and traverse the hydrophobic matrix of membrane regions with bilayer orgasii.tion. Pinto d. Silva, P., Mon, P. S. aid Fr./.wle+*, H. H. E.yerirnrnrd Crl! Rru.rcA a1:127-12tf, 1973. Oth.r arpprtr U. S. Public Health Servia tusd American Medka! Associa- lioa, Committee for Research on Tobaooo and Health. From the Department of Medicine. Ueireraity of California School of Medi- cioe, San Francisco. EXOCYTOSIS IN THE ADRENAL MEDULLA DEMONSTRATED BY FREEZE-ETCHING Present evidence strongly indicates thu esoctine, endocrioe, aru1 neural secretion depeod upon a pheeornenon called esocytoais whereby the secretory vesick (uso with the plasma membrane thus creating a stoma which alb..s passage of vesicular contents into the ettraeeMular space. Although both biocheminl and electron micrneaopy studies support this eoncept, available methods have made it difllcult to provide tesoephologie evidence of such a mechaairm. The application of heesedraetute teehniques, howevet, these authors report, overcomes certain problems by making it possible to eapose large areas of plauna rnembrane. Replicas of fractured cMornaffln cells from both stimulated and unstimulated golden hamster adrenal glands indicate a range of activities thoughl to be chuaeerislie of esocytosis, including attach- ment of secterory vesicks to the plasma rnembrane, fuslon, estrusion of eontents, aud membrane retrieval. In addilioQ. this approach provi.ks a visual represenlatiora of the e[ttet of /eoetory activity. Stimulated cells conlained abundant freeu-fracture proales of erocytosis siles, while these were iofrequent under condilions known to inhibit catecholaroioe aecrelion, namely absence of calcium in the systcm. Sr*lrh. U rr a! Stirntr 179 79 82, 197) Other arrpportr U. S. Public Health Service, National Science Foundation and John A. Hartlord Foundation. From the Department o: Medicine. University of Miami School of Medicine- and Papaoicotaou Cancer Research Insrituwe, Miami, Fla. ELEL'TRON MICROSCOPY OF ENDOTHEIIAt. CELLS COLLECT ED ON CELLULOSE AC ETATE PAPER As a flrst step in focused studies of specific cell fundions, the aulhora have developed a method which allows eaarninalion of iaoiated endorhelial cells at the level of ekctroa microscopy. The method is described in derap i. this paper. lhese flne structural studies show that the mcthod of obtaining endothelial Hr{ulchen preparalions on cellulose acelale paper yields a continuous pure monoiayer. The endothelial cells thus obtained retain much of thcir structural inteRrity, and the cells make a viable Inoculum for tissue culture. The method of tissue preparation described here should be adaptabk (or the electron microscopic esamination of Hiutchen preparations of a varkty of other tissum. Smirli. U. and Rya., J. W. Tluw< & Cell S( 2):) l l-) 76, 1973. Oth.r.rpportt U.S. Public Health Service aod John A. Hartford Fouedat{o.. From Papanicolaou Cancer Research Institute and the Department of Medki... Univ.rsity of Miami School of Medicine, Miami, Fla. 79 79

I 1 t I Active Projects Following is a list of the priocipal investisaton or inslilutions of projecls under way or activated in the period since the previous Report, together with the respective project titles. Completed projects are listed in a lattcr sectioe. PRINCIIAL tNVGTIIGATOR OR INSTTIl1710141 ANTTIONY A. ALBANESE, hrD., DI- rrcror of Woraroaer. Tbe Brrte R.- Aabililaliow Cealer, While Plains. N.Y. L7tOJ[Cr TTTI.c EfflCI O/ CijaltlN Y1lotling on Kr1Mr1 ribo.rcka.e, red blood cctl uealine a.d cyclic AMP k.ek i..un DOMINOO M. AVIADO. M.D., r.ofr} sor oJ rA.riw.rolosf. U.i.enNy d Perwrl•ani. School of Medreiwe, rfil- adelpAia A. CLIFFORD BARt3ER, M D., Rolert Henry rlr/srr Profruor of f AYdoiorr, N.rvard Medreal School. Bwow. BPNLAMIN BELI, M D, Drrrcro., and CHARLES L. ROSF, hl t), Aarirunr Director. Norr..eri.r Agrng Srrlr- Vct- era6. Adminlflra11o11 O111pa1KM C IrnK, Boeloa. tARUI BENACERRAF, M D, FJ>.'s Prolrrror .nd C'A.vn+.n, tkp+r~mcnl o( ~attwlosy, Ilarrard Mcdrul Sctwol, Bouow BL1DtIDEV BFIAGAT, hID, Iro/ruor o/ rAyriofory. SI. I.auie U.i.cr.ity School of Medkine, St. Louis. RICIIARD 1. BINO, M D., Pro/rcaor of Alrlkinr, UNrenlly O( Soullsefa Cau- fornia School of Medicine. L.oe Ast- r In; YrrlNwe Aauociatr /n Siow.elk~.f ntinrrriwg, C.Ilforwia lnstiluk of TccAnotoly; Dwrclo. o/ Car/iofoty and fwrraw.w.f Afrlkinr, HuMin111ton Men.oeid 11o.pu1, Pasadena. Cal. R1O-RPSPARCH (-ONSULTANTS, INC., Cambridge. Mar. 810 RPSFAR('11 INS11Tt/1E, INC.. C'ambrMtle. Mau Rro.clor.aacaAar elecb of ciprelte ea.oti. Id.eaos of ciprel(a a1wL. ow polmo ..ry ..vilp.erl.o ud bto.cbwp...r •r\avloral hyperterio, and ar(crloeck- roai.: e*Kb of aiCOUnt and carbon WOOOt/dt A eleoAind reaearch propun ie tbe Nw- rwati.+ Aging Study Control of rpccifk cellular and humoral iw+rnunc rclPonKr to nooll.Yic aed ao..eoplaslrc Ue.ucs ERcct o( clroak adminiaratian of nko- ti.t a.d .owling on braie biollcaic aminess The e[ect o/ nicoline on .tb~tro.ckroeie (iw rirro Modics) Carbow e.onotide and coronery alhero- tckro.ie Delenni.allo, of the ueerulr.eea of the plde. Syriaw hunucr ar a model ani- real for ernoke inhalation .1.dice Aa etp.e.ded study of mouu skin ee- pwure to whok frcJ smoke condtn- ule compared to ekia pau+ting with - coedcn..lce 80 i PRINCIPAL INVEJTICATOR OR IN3TITUTION JACK CHAt ON. M D., Auiu.nr Pro- /rrro. of AnrnrArirofoty, Albert Ein- stein College of Medicine of Ye.hrva Univcreily, Bront, N. V. CHILDRFNS HOSPITAL OP LOS ANGELES. Loe Angickf. CIIARLES (l. COCHRANE, M D, Scrnpir Clink .nI ReurcA Forwl.- Non, LJ lolla, Ca1. At LEN B('Ol1EN, M D., M D., M- .Irr.wt Pro/rawr of Mrlk/wr. Unioer- eily of California Serrke, Saw Fraw- ci.co General Ilo.pilal, San Fra.ci.co. IOHN E. CRAIGHEAD, M D., rro/ra- ar of ratAofotl. Uaivcrsily of Ver- monl Medical School. Burliapoa. T. TIMOTHY CROCKeR, M D., t ro/rr aor of Mrlkinr. U.lvenity of Cali- fonia Colkp of Medicinc, Irvine. CARROLL E. CROSS. M.D., Amoci.rr lroJrrur of MelkMe and Hrwwn tArriology; Dirrcro.. Sr[iiow of rrf- n.on.ry Mrlklwr; University of Cali- f«aia School of Medicine. Davie. TIIOMAS R. DAWIlER, M.D.. Aa.ocbrr Iro/ruor of Mrlkiwr, Bo.to. U.ircr- aity School of Medicine, Roato.. CARLTON K. ERICKSON. hr D., As- .ori.rr t•rofra.or of rArw..c.V and 7olkofoll. The UniKrsMy o1 Kara• School of rbaraacT, L.wrt.ce. WALTER B. ESSMAN. M.D.. hrD., •ro/rrwr of hrcAolortl.nd 1tlorArnr- lnry, Queene College of the City of New Yortt, Flushing. JOHN R. ESTERLY. M D, A+sociarr Professor of IarAolofl, llelveraily of (-hk.ao School of Medicine. Chicago. IIANS 1 PYSFNC'K, I•n t)., D Sc., rro- /ruow of IryrAolofl. lnrilute o/ hy. cbiatuy, tlai.cr.ify of Londu.. t or.don, England. EDWIN R. FISHFR, M D., Director of l.bo+.rorlrr. Shadyride Nrrpilal; ho- fru.w of P.rAolnry. Um.creiry of hlt.bursh School of Medrerne. Prlta• burgtt PROJCCT TTTL.L Relationship of t.rwLinp, Meroid. /y ereneuual cycle to puln+oerry c~to ~Dboloiy asd mrcopoly.acckarWr ChWcs i. /r.cAeobro.clW cyfotow Relalionship belweew acll Iraeator.rlo., chrornoaoenal ctunBes, aad turci.o f/enesis The wlediatiow of ie4wwtorY L*IrT af tifwe Hu.ua alveolar maerophatles .ad ew• pNy.er.. EpilAelW eel/ (ranalonnalkr. .d ur• cinana Mductios by "C' " RNA viru.cs See Le.r. l. A. L°leae of tobacco .woke o. Wlr warir alveolar Inacrvpba l.arl~ pbapcylk aaivMin, and biocbsYtry Sreolia~ elaafe., risk factoen .~d cardb vaecylar discue ERec(a of wkolint os frwe wui.tcloW; iw the hrppocaw.pua drrr.y kar.ly Studin of .kotine act{o. uipote r.wT I:on.olidaliow Melabolic R.powr b urw-lobaooo treo\e iateractioaa Rwolwioe o( pulmo.ary I.wry Tle lnAerltance o( c!e roilall t•aNl FRect of tob.cco vnoke •.d koelr o. Nr..c1WO and fuection of coroaary vterrce and plasma lrpid. I. r.bWl. 11

t'RINCITAL INV ElT1CATOR OR INStITI1TION LARS FRISF.RO, M D., Professor of EnrYonwuwr.t Hyrirae, TUt Ka,o1i.- .kt Instituwe, Sloclholrn, S.ede.. GARY D. FRIEDMAN. M D., Srnlor E/lfrwuoloti,r, Kaiser Foundatio. Ree- se.rch Insritute, Oe\Ian1, C.1. H. HUGH FUDFNDERO, M D., rre/csr sor of MrLcinr. University d Ca1L foraa Medical Center. San pl•..cieos; /rofrn.or of flartrrroloft and /nunr- nororr. University of C.ti/or.i., Serkeky. LFONIDF GOIDSTEM/ DSc., An. ri.rr Pro/enwr of trycki.rry, lslitule for Mental Health Scicntes, Rwten Mediul School. Pncala.ay, NJ. JOSEPH 1. OUARNERI, Pu D., Arren!- rwe Mirroirologur; Drrrcror, Mkro" oroty )Abor.rori.,: Long Island )e.- ish-Hillside Medical Ceuer, Queer HosPiul Center ARlluliow, lanafca, N.Y. PAUL HAMOSH, M D., Aulsfaet lro- /ruor of rAyrwloer and elo/Ay,k,, Georyctow. University Scsools o( McdKtne and DerwWry, W.ahinstoa, D C. HERSFRT R. HFRSCOWITI; PsO, Asdrr.nr lro)enor of Mkrolrlolo[ t Gcorletoar. l)ni.crwy School occ Mcdreine and Dentwry. Washinpoa, 1) C. 1fT RESEARCH INSTTTLTfE, CWnp. ATTAI.LAH KAPPAS. M D., Iro/rs,or .wI Se.br rAyrki.n, Rockefeller U.1- versity, Ne+ York. SItIRLEY L. KAUFFMAN. M.D., tro- )rr,or of /adoloty. S1ale University of Nc. York 1.)ownaale Medical Ce.- tcr, Drooklyn. IFROMF_ Kl FINERMAN, M D, Hn1, Drrbrow of LrAoloq Rrserd and s~ cl, Clinical P.rAolorf, SI. Lu1c's 11o Ck.cland; /ro/rswr of rarao(oiy. C..e Western Reser.e University ScAool of Medicine. Cleveland. PAIJI. S t.ARSl/N, PnD, H..t /ro/r, joe ../ Medread ( crlkge of V.r11m.. Richm..nd rROJ[CT TTTLE EpidernioloRinl studies o. the S.edisJ Twirl Regiwy CVncleriatico of smokers and no.- trmolcre Coiaor. antibodies {n rttalion to Ihe .tblogy, oof c..pleysema ReA.vioral and ckctro9hysiolotkal ef- f.cte of the 'c6rowic .ico/ine aate' Iw rse. T1s f./ucwoe of este.ded eaposure to cy.relk snwle on pulmonary re.isl- n.ce to In)ectios as related to alveolar ..aora.a ane .wuocuiary (unctio. Tie, tf1oN of smoking on the `amsll air- ways- The rok of t`e macropAaec in the Im- rnuwt response: eflect of tobacco prod- .cu oR n.acropaage function Eflecta of tobacco smoke on pulmonary alv.d.r wacroaaRc. Tobacco ereolie: efects on detoalecatiom wccfa.ier MorpAornetric study of rnousc lung et- psed to earcinotien. Eeperirncn/.l emphysema: the eRects of proloesed dust and nitroren dioside t.powre on the physiologic .nd rnW- phornetrie Peramettrs of the hamsler /ung Abstracting and claulfying 0c litertlure on tAe bKdolicd eflectf ,rf tob.cco, and prcparaiion of maniscripl for Suppkmenl III to "TobaccJ' (1961) 8 2 rRINCI PA 1. IN VF-gTIGATOR OR INSTITl/T1ON IOSEPH M. LAUWERYNS• M D.• hr D., rro/es.or and Cb.knsaw of Pathology. University of Lewe., Leu- ve., Selgitun. RICHARD A. LERNER, M.D.• Auo- c1.rr, Scrippc Ch.ic and Researdl Foundation, La Jolla. Cal. CECIIE LEl1CHTENSERGER, h1.D., Hr.I. Dro.rhar.r of CyrocAembrry, Swiu Institute lor Eeperimenlal C.n- ccr Reseauch, I au.annc, S.itrerland. JAY A. 1 EVY. M D., Aul,r.wr Cllnkd lrnfrt.or of ffr/k/wr, University of Cahfor.ia, Sa. Francisoo. CLAYTON O. LOOSLI, Pw D., M.D., Ha.ring, lroJ.,,or of Me/icb.e and l.rholory. University of SoWhern C.li- fotnu School of Medicine, Los As- socks. HERBERT McKENNIS. 1.., rs/.D, rro- Jnsar of lAuw..cology, Medical Col- lege of Virfiini., Richmond. HANS MEIER, D.V.M.. Ste/ Scknlbl, The )acison Laborswry. Bar Harbor, Me. MICROS1Ol.OGICAL ASSOCIATES, INC.. Bethesda. Md. CIURI ES MITTMAN, M D., Direrro., Drp.rh..rnr of Rrqir.rory Dirrarrr, City of Hope National Medical Ccn- kr, D+urtc, C.I. GEORG s. NFURATH, M1 D, Mkro.. .w.lrnta ).borarory. Hamby(/. We.l eierrnany. At BERT H NIDEN, M D, /ro)rru.: of Mr/irini: CMrf- r.ln.on.rr porarr Serrion, Departse.s of Medicrne, Trmpie Ilnr.cruty Scho..l of Medi- cinc. Phil.dclphi. (Now /ro)nror of Rfr/wrnr, Ure. Posl'r.duale Medre.l School and University of Southaa Cdifornia, ('Arr), Pulmonary Dnr.ur Srrtron, Martin I Whcr King Hosprul. Los Angeles ) PROJECT Tfilt TThe lymphclics of the lung; Ibe4 role I. Rad Iransport and ckaranoe of .ir. borne particulalc /n.uer is uorwal .nd eeperuncntal corditions and i. .uiwe lung diseases Sludil:s on pcrsistcot vird infaulo. Comparall.e cytoclnnk.l, cytological and histological studies of ccrty ..of chronk efleds of ciprclte s.mke oe thc respiratory tr.ct of S.cR'e and CS1 Black Inice Prevenliow a revenal of ab.ortnal ratea of re.pir.tory epilhe8um produced by ciprctte srew\e cordcasate and be.co. I.I pyrcnt The tRects of i.h.lalios of liolt cr.Ae, syalutic .moll. uebicM air .lo.e ..d in cowbiauiow on Ihe respirYOry Inct of tt.ia EQecb of fresh cigarette nwoke Wl.- tiow on the respiratory tr.u o/ mla Biological activity of tobacco nwo" oor.- poncnts and a/IKd sub+la.oes O.eolicnesis In Ihe r.bNl: ve.Mle .u& oeplibility, vertical v..wwlrlon of virvs and environrne.tal i/illue.ct. In rlrro Ir.nsfo.matlw rrdlcs .Mb de- Rncd cbemicals •.d tobacco co.at.- Y/H Developrnenl of a ratiowal raodel ryrsar for rispnlo.y careinofie.esb Hereditary susuplibility to bro.clkb- emphysema Kinetics of nitrotamia fornwlo. In 1o- bacco s.noke Flletts of cillereue u..o1e, noeious fumes • and drup on thc terminal .u..rs m

rRINCIrAL tNVGTriCATOR OR fNSTfT1JT10N OAK RIDOE NATIONAL LASORA- TORY, Oak Ridge, Tenn. )OIIN W. PARKFR. M D., Aaociw f'ro/r.wr of rarhofogy. Uwlvcra4y wf Sowherw Cwlifornie ScAool of M.d4 cine, Los Angekt. EROCESS A INSTRUMeNT CORPO- RATI(1N, Rrookly., N. Y. T1MOTl1Y l. RPOAN, M D., ho/ruar of M.JirLw; Dbrcro.. D/.iabw ./ Crlro.a.crlr Dl.e.ars, Coik/. of Medicine awd Dcntistry of New lcr:y, Ne..r1. HtOlCCT TTIlz The cfemkal, phrkal, and oqeretional char.ckriraiow of Iwo lype- of devices (or the gewer.tiow e.d wMeQueM tt- pwre of aniatals to freei cillrHta ernore M.cYnw{.mr of wpprerfo. of cellular Iru.ity by crcrnogcwrc hydrocerbo.. CaMr.ctlow of w. taperM.cnlal devip for mo.itored eyo~wt of rnall ea- Reri.ewW et.l..l. b k.b.cco rate jnyt.Uo. MoMftnt{ow of We)(os nmoli.g wucWe 1n oow.eciion wilh a .er prototyPe Vrlabks alectiry the ordiov.ecvlar ts- yor.rs lo clro.it emoElnR ROtiERT C. ROSAN. M D. AnocWr Rlboeomal prameten of lobular diRu- , ., uo- clatc MrnrM The Wietar Iwallwa of Irolruor of /arAolory .nd IrLaukr, 51 . Louif Uni.cruty School of Mcdi. enlialOw , Anatomy .nd Riolop, Miladelpaia. eine; Auofra/r farholotur, Cardin.l A. STANLEY WELTMAN, IM.D., Auo- Oknnon Memorial Flowul fo. ( hJ ciare lrofeuor /n lhrwracofoer and dren. SI. Louis Rrrrrch, Sroollr• College of EAu- macy, erootly., N. Y. Auociar. RONAID P RUSIN hrD The actioe of .kocine on the adrenal , , . State lJni t ro/cuor of rAarn+auolory vend DUANE O. WENZEL, M.D., rro/et.or - verrty of New York Do.nstale Medi- and CAairnvw. DeoartmcM of rAwreu- Srooily. cal Cenur cology and Toaicoiogy, The Ualvenity , . of Kanau School of rharmacy. l1NA S. RYAN. M.D., Srnlor Sckntbr, The roie of eedothtlial and cpitAclW ta.rence. Iyewkolaoa Cancer Rnearch ln.tl- ee1lY is t.on-veNilatory functions of the tule, MirLtcl; Aulrwwl Pro(ra.or of hrap Mrlkine. University of Miami Sclool of Medreine, Coral Oebke, Pla. WAYNE L. RYAN, M D.. Pro/rsior of slacAt,nlu.~ University of Nebe..ka Colkgc of Medrcin., Omalse. SCRIPrS CIINIC AND RESEARCH FOUNDATION, l, loUa, Cal. Ll1C1O SEVP.R1, M D., Dirrcror r+l Dran, 1nrrUrrr of Anatomy and larhol- ogr. Divr.ion of /'.ncer Re.earch, Uni- vtruty of f erulia, Ierudia, Italy. ('ARI (' SF'IT7NR, PND, Pcalady Museum. tl.r.ad l/mvcruiy, (am M dlc, Mau Tle )',S' cyclk nroewpbosRAae system is e.relnowneeie ItwmuwoloRlcal competence and chemical earCjworweW A1lempu to identify tbe vi'el .scnt(.) reapon.iDle for sheep luog .dcnomatotls r.d to transfer tlh aeoplr.uK disease lo rodeas Constitutional etudke relative to smoking and coronary heart diree.e 84 PRINCIPAI. IN V ESTI(:ATOR OR INSTfTUT1ON T1tEODORE A. SIATKIN, fhM D., Ar- slarenr rro/naor of f Aarnr.coloty. Duke University Medical Center; Dur- Iswm, N C. LOUIS A. SOI.OFF, M D., f'.o/t.sw of Me/'nnc, Temple University HedtR Science. Center, f'hiladelpAi.. SHELDON C. SOMMERS, M.D., Dkec- ror of La6o.aroritr, l.enot Hill Hos- piul; Clink.! 14oJrr.or of tarAolory. Cdkge of 1'ryskians and SwReo.e, Columbia Uwivcr.ity, New Yo.\. JAMES TRAVIS rwD, Auociate ho- fcr.r of Iloclirwr4rry. University of Oco.gie, A(fter. UNIVERSITY OF SAN FRANCISCO, S.. Fruciacoa ELLIOT S. VFSI'LL, M D.. rro/tuo, end Chdrw.ew. DeFwrtaent of M.rme- co1My. hnn•ylv.nia Stue University College of Medicine, Hershey. YASUSIII WATANASE ht D A rROJECT TiTll Maturetron of the adreYl sedulle. catecholaminc uorce i. .otr.l ..d Itypertee.ive rau Purifiution and phyeioloRk JpJ/lunu of lecithin cbokrerol acyl uwndere.e / LCAT ) Studice of huntaw lung .nd ov.rian car crwomr Rlochemitlry o1 clro.k ob.urdlve Ly ducaae Irduniow of puarwoue oeu cacd.a.. I. t•c mou.e R.rioimmuno.auy for .icai.e Studiee ow oncopenic vlnucs Acute and chronic efoete of .lootl.e .wd CthoioRicwt aspects of yon(aw.oudl yperlenaive and woteoterlvr, ..1N r.ta The effect of nko(iwe and tarbo. .ow oaide ow vascular livid dYt)o.Mb. 1S

Completed Projects Following is a list of the principal investigators or institutiotu of projocts that have heen compkted prior to the periaW covered in this Report. Several of the individuals tsarned arc decettsed. Ihe litlcs and affiliations listed are those in eHoct at the time the work was completed. CLARENCE M. AGRFSS, M D., Ano- ci.rr Cl/nk.l rrofrrror of Mrdki.r, t)nivnsity of Calrfornia Mcdical Ca- ter, Los A.gcks. ANTHONY P. AMAROSE. PwD., It .rrncro., DrP.rrnrenr of OI!rtrenk..wd GynrcoloPt, The Alb.wy Mediul Col- kae of l)naw l/nivcrvty, AIM.y, N.Y. E T. AN(IELAKOS• M D., M D. Pr.- Iruor of rhyrloloty. Boeton Universi(y School of Medicine. Boston. D MURRAY ANGEVINE. MD. U.1- verury of Wisconsin SeAool of Mcdi- cine. Madison. STFPIIEN M. AYRFS, MD, Dlrrcror, f.rdwPulnron..y (iAoruroy. Saint Vincent's Flospiul, Ne• Yrxk. OSCAR / BAl CHIIM, hr D• No.un9r rrolrrwr of Mrdicmr, l)mver.wy of SouWhern C.h(nrnia School of Medr cine, I oe Angcles FREDERIK B BAN(3, M D, tro/ruor and Ch.km.n, Dria.rtmrnt o/ l.tAo- trloloorr. The )ohns Hop \im llniversily Scbool of Hylrtne and Public Health, Baltimore. BRODA A. BARNES. M D.. PM D., Pro- lrssor (A/flrotr) of PAYuolot /. ('o1o- rado State l)nivcrury, Fort Collirr. FREDERICK W. BARNES. 1s., M.D., Auociorr rrofrru.r o/ Mrdk/wr, T)re lohnm Hopki.. l)niversity School of Mcdicine, Balrimore. T C. BARNES. D Sc . Rrrruch Sctrntbr, Philadelphia Slate No+prul, Phdadel• phi.. R FRFDFRK"K BFCKPR, M D. Ano- r..rr Irofrnor of An.tomf.nd Dlrrc• ror, leborarory of rrrln.ul Sr/rncr, Duke llniversuty Medical Center. Dur- ham, N (' RAI Pit \ N/ ~ Kt R Pn tt . P-l.n.x SAMUEL BeLLET, M D., D4rcfor, Di- vlslow of C.rdlobl7. Philadelphia Oe.eeel Hoyital, Plwladelpbia. JOHN A. seVAN, M.D., ho/rs.ar of PA.rws.cology. Universitr of Celiforwi. School of Medki.e, Los Anseks. CESAR! BIANCIFIORI, M D, Division o/ Cancer Re.crcA, l/nit<nMy of PCrvp. PcrvRi., Ita1F. IIYLAN A. BICKERMAN, M.D.. Aul.r- .wt Iro/nior of Mrdiclnr,uvf ALVAN L. I+ARAClI, M.D,Conirlf.nt rn Mrd• kbw, Columbia Univenity Colkte of Pfysici.ns ud SurReons: Oold.atcr Mcreorial Ilospiral, New York. FRED O. BOCK. PN.D., Auocl.re ('oncrr Rrtr.rcA Scirnror. Au.lolicat Stotkr.., Ros.ell Part Memorial Instl• 1utt, Sqrint.dk, N. Y. IIERMAN V. BOF.NIO, PND. Hrad, CArnrhtry •nd f)lochrmnuy Drpart- mrnr, Spindktop Research Center. Lea- mglo., Ky. JAMES F. BONNER. PND. Professor of eloloty. C.Irfornia Institute of Technology. Pasaderu. WALTER M. BOOKER. hMD, rro/rs- .or and Hrd. Dt rtrnrnr of lA.rr.r.• colo~y, Ilo.erd Cnivereily, Washing• tow, D. C. TOM O. BOWERY. PN D., Irukldr Rrildur LSrrraor7. Chemistry Drperr- rnrnr, North Carolina Stale Colkte, Rakigh. GEOFFREY 1.. BRINKMAN, M D, Ar• .oe{.rr Pro/ruor of M.Jxinr. Wayne Slase llnivcreNy School of Medicine. [k V oil BARBARA B BROWN, PNI), Chief. EePrrln.rnra/ PrycArarry, Veterans Ad- m/nHUalNxf Ilorpital, Srpulvcda, (-as. R hYM(tNU R BRUWN, Phr t) .Prr'h" hna ol !)nr nl,qr. I Ini-rr+vls, of Wiu..m,n Mrdu.l ti.h~rd. M.Jiwn nr. I i JOSEF BRO7EK, PMD, rrn/enor and Choinnon. Drparrmrnr of ltychololy, Lehigh University, Bethlehem. Pa. SUE BI/CKINGIIAM, MD, Auirtant rrolrnror of Pedr.tacr, Columbia Uni- versity C(4kpe of Physicians and Sur• geons, Ne. York. BENJAMIN BUR ROWS, M D,Aueci.rr rrolrsror of Medicine. University of Chicago. Chicago. E M. BU7T, M D.. Chief t•orAolotbr, I os Angeles County General Hospital. I.o. Angeles. RICIIARD 11. BYERRUM. PnD, rro- Irssor of Chrw.bny, Michigan Stale llnivenMy, Fast Lansiwg. SISTER M EMILY CAHILL. Pn D., Charmon, Chemistry Dep.rbnrnt, Re- ais Colkte, Weston, Mase. BRUCE F CAMERON. M D., P„ D.. Howard Hughtr lnuitrre, Universily of Miami School of Medicine. Miami. Fla. WILLIAM II. CARNES. M D., Univet• sily of llub College of Medicine. Salt I a1e City. MARCUS N. CARROI L, 1.., Pn D, Chir/- Divbion of rharrn.coloq, TAe Brookdale Ilospital Center. Brooklyn. N. Y. WILLIAM ALVIN CARTER. M.D.. Astutant frolruor of Mrdiclnr .wd MrcroEiology, The )o6s 11opkins Unl- versity School of Medicise, B.Mimore. I EOPOI.D R. CERECEDO. Pw.D., Pro- Irrror of Biochnnirrry and Nutrition. llniverrity of Puerto Rico School of Mcdreine. San Juan. SANFORD CIIODOSII, M D., Aubr.nt rro/ruor of Mrdk/nr. Tufu llnivcrsity School of Medicine, Boslon. (Iwilialcd under Maurice Segal. M D.) NAITFR M. CHOPRA, PHD. rrolrr- ror ol C-Arndrrry, North Carolina Aari- cultural and Technical Slak llniver• u1y, Gretsbwo. WII 11AM (3 ( I ARK, PND, D1lrttor- hrrAoyh.rnur..lot7 RenrarrA LAur.- tory, Veter.ns Admimsualioe Horpital, Stpulveda, (-al. /IANS f t I ARKF, 1)Sr, ho/nw. ol DuxArmuur. Colu.nbu I)nwenny ( olk,e of Physicians and Su-~eont, New Yurk lAY D C'OFFMAN, M D, Srctlon Had. rrn(rhrr.l Vucrlor Drp.rrn.rnr, URI versrry Ilospil.l, Boa1o.. DANIEL COIIeN, D V.M., M P.H., A. mranr rrolnror of Veterinary Erid.ns loloty and rrNk Hr.lrA. U.Iver.My of Pennsylvania School of Vtletiwuy Medicine. Phlladclpai.. JULIUS 11. COMRO@, 1ll., U D., Dtrre lo., Crdiov.scrbr Rrre.rcA lwAru, Ueiversity of C.liforwia Medkal Cee ter, San Francisco. DEAN M. CONNORS. M D. Anoclur Director. Drp.rtmrwt of rory Mrdicinr, Sr. Mry'. Hoa/lul, Madi eow, Wie. P1111 IP COOPER. M D., CHnkrl lro/rr we of SrrrgerR and Dkrcror Sr~1/.1 L.t•.or.rory of CrOrl.r r~yrbloey. Albert Eiwein College of Medicine. Chief. Surgical Srrvke, Veterattr Ad miniuratiow Hospital. Brpu, N. Y. ROBERT L. CRAIN. Pht D., A.ubtanr Pro/enor of Socio/ory• University of Chicago. Chicago. CECIL E CROSS. Rr.r.rcA Deprtnrr.t. St. Joseph Hospital, Buthant, Cal. ALBERT DAMON, PM D., M.D, C.e fwrr on AntArooology; Rrse+reA Auo rlore in Mrdic.f Anthropology. body Museum. Harvard Universlty. Cambridge. Mau. R. F DAWSON, PN D., rro/rrsor lor .nr, Columbia U.iversMy, New ork JOHN P. DELANL'Y, M D., Pw D, As wri.rr rrolrrtor of Surgery. U.Iverdty of MinnesMa, Minneapli.. ANl)REW S. DIBNER, hlD, Ec.r rrivr, t iycho-Rrrr.rcA, TAe Age Cen ttr of Ncw England. Inc.. Boston. EDWARD F. DOMINO. M D., rrofrr .or of Pharn..cology. U.iversMy ol Mrchitan, Anw Arbor. RAIPtI t. lX)RFMAN, PwD, Dlrectoi of I.6or.r...ur. Worotrer Foundalan (or E.Penrnemal SioloAy, Srre.'.b'xr. Mass. JAMES / I)YAR, hrl), Aubunr f.o . /rr.or o/ Sloloer, Bcllarwl.e folkp. ouisnl/e, Ky I RI( 11A111) 11 FAR11!, M t), ( Arrl • Pulnron.rr Fnnrl/..n /."aawt. ./r untont rr.,frnta. of Mrdk/wr, tlnlvcl .iry ol ('brca.o. C'brc.1o e7

JOHN W. PCKSTPIN M D., Avlrtawt rroJtaror of fwrrrwoj A(r/k/wr, State Uni.treily of /ow. CoIkRe of Medl- cine, lo.e City. ReRTKAM PICHPL, 33. D D.3 D6 rrcror, hurlrurr of Stowrwolotkoi Rr- searcA, Scicace Resouro=s Pousdat{os. Weterto.., Mass. HYMAN eNOP.LePRO, M.D.. AntwL Iwg rA»kiow, Cedars of lib..o. Ho. MW. Los A.Rek: HeNRY 1. P3RP.R, Ptt D, RtwrtA /e.- wwwobgirr. M.eo. Researc! IrUbM, Wotoewor. M.ee- HANS 1.. PALK. PM D., Al/rwct AuscE ur rroJn.or. Drjowtw.rwt o/ rorAol- e~7 U.LtnN7 of Sowhcr. C.Lfo..l. Scbd o/ Medki.e, 1. A.Rtiee. DANA L. PARNSMWORTH, M D., Htr~ K. Oll.r+ Professor e/ Hysirwt.wJ DL rtctor of Ua/rnrky HrolrA Servket, Har.ur U.i.er.Af. CawreridM Maa PRANK C. PEROIISON, 1. , M D. CA./rw..w. Drr.rrwvwr of rArw..ro(- e~1 Tle AMb+.f Medical CoMep .l U.iota U.awr.iry, Albe.y, N. Y. TNPODOR! N P1Nl.P.Y, M D, Dk.r ter of rulw.ow.r? Rr.rrcA IA(ro.orory, Moo" Zio. IloqiW, Sur Pre.cl.co. WILUAM 1. PIS11ePIN, MD, CA4f of Er/Jewdolon. Cfkago Board Ue.dtl, Cftkyo RUSSELL S. P1SHP.R, M D, U.l.enlt~ R.hl of M.ry/ad Sclod of Medki.e. abore. 9. L. PRCPDLANDPR. M.D. Dlrtctor of C.wcer Rrre.rcA, Mor.t kSo. Hos Plul ad Modkal Ce.1n, Saa Pr..- cf.co. FRED[RIC A. FRPNCH, A.M.. Ditctor oJ C.wetr CAtw.orAenyy Rtx+eA, MouN 710s, Ho.pital rrd Medical Ces1er, S+. PrscLoo. JACK FRPl/ND. M D., Au(rr.nt rro tr- ro. of rAarw.ocolon. M.diul M of Virillda, Rkfso.d. O1l.ePRT H. PR1P-Del.l., M D.. CAkJ oyMal ol r.rAolorf. SI. Vloocu 11 rVoeenrer, lla.e. ARTIIIIR Fl1RST, Pr D, Dbecto.. I+rL rrtr of CAr.wk.! Ilolner. lld..nit/ of San Fi..croo. Sau Pr..u.co. MURRAY S. OARDN[R, M D., Aao- cl.ur Professor of raAabjry. Unlrereity of Souther. Celif«da School o( Medi- ciec, L.oe Angeke. OeOROe O. OBY, M.D.. Dirrcrw, f4wy-Hovtll C.wctr Rru.rcA [Atr- owory; Associate rro/ruor of Sw- ~er7, T)c lo\ne Hopkins l)nivenity Sclod o[ Medki.e, salt{aoce. THOMAS M. OOCKe, M D., Auori.tt rro(tr,.or of rrerlntlrt Alydklwr owJ Cowuw.wdry~ HeohA, New )tr.er Stete C,o11rM of Medkist sd Dcnllstry, )erry CYy. DAVID M. OOLDENSCRO Sc D., M D. Au,xi.tr Professor 0/ r.rAol- ot1. T.wPI. U.ivtr.hT /lealth Scl- e.ae Ceder, Pfil.delpAl.. PAUL OOLDHASeR, D.D.3., Aa.ocfut rrofeasor o/ rtrfotowtototy. 1(erverd School of De.W Mcdki.a. i/wo.. IRA OORe. M.D., rro/euor o/ rorAot- ery, aowons U.iverdty School eI Medl- cYr; CAit/ 0/ Laboratory Srr.kr, Ve+er.r Adwl.Mntlo. HotOital. Wtr RotAwY, Mar. OERTRIIDe Y. OOTTSCHAI.I, hr D.. Atr/rt.wt rroJtrror of SL.cArw.l•try, ColurnA(. Un,vcreity Colkre of Pfy- .kiur e.d Suripeoa, Ne. York. A. CLARK ORIPFIN, M D, Hr.I of f{ocAtw.btry Drportwvwr, h1 D. A.- der.o. Ho.PiW .wd Turnor l..titute, Udv.r.My of Tee.e Medical Ce.ter, Houetoa ARTHUR L OROS3, M s., Senior 0b- alawtw. Soutl.eel Research I..tltuM, S.. Asb.io, Te=. MORTON 1. OROSSMAN, Pn D.. M D., Asroci.te Cl/wkol rrolrr.ar of ALII- tr.. Urvtr.Nr of Caluor,d:, h/edkal Ctat.er, Loe Ayda. CARL C. ORl1HIIT, Pw D., M D, Asro- cl.rt M rA'rblo8, and rh.rw.oco(or). Udvtc.hr of Fe..eflv.nia nr.duett 3ekool of Medkiw, Klladellik. PRANK e. O1I171R1P, M I), rrofr.- .vr, tv.d eRNPST HOiKIS<)N, PM D, A.sW.nt RrrrorcA Professor. Dq.rr- wrw/ of Ewto.wolo y, North Cerolin. St.u Cdkge, RekSRA. H9 HAAO, M D, rro/erior of rA.r- worolot" Medkal Cdkge of Vi16inu, Rk Vwo.d. m I F. 1. IIADDY, M D., Pw.D, Professor .nI CA.irrn.w, Dr~../wrrnt of rAyrlo!- orr . Univercily o( O\lasorn. Medicel Center, Oll.homa Ciy. 10SPPH H HAFKENSCH1eL, M D., Dktctor, Corllopu/w.owory Uwlt, The Lanke.au Ilo.pilal; A..ociate M Mrll- clwe, University of r•enmylvaul. School of Mcdkiwe, Ploi1.delPhi.. BERNARD HANPS, P>t D., Detatn.enl of Health Science, C.lifanu S41e Univer.lly, Nortt+ridp. RICHARD 1. HAVeL, M D Assistant Professor of MrlkMt. Uw3vereM' of C.liforwi. Medical Cc.kt, Sam Pr..- citco. IOIIN A. HAYP.3, M D., Associate rarAoloR4t, M.Ibry InMilure of P.- tholoq, 6o.to. City Hoqi/aL Boston. HERBERT R. HAWTHORNe, M D., CArlrwrow, D.~r.rwanl of Sr~rry. U.ivereYr ot Pe.rfl..wl. Or.duate School o/ MedkMs, Pfll.delvua. CLARK W. NeATH, M.D., hofruor o/ Medicine and Dkrcrar./ HrdrA Srrv- krr, TYfte U.iver.itl, kledford, Me.a. PAULINE HP.IIER, Pr.D. Rt.ercA A.- ro~(.re M C`tolo~ .wI f=~tocAriw/4try, S.. Pn.cieco LetNuY of Medk.l Sckwce., S.. Pr..droo. IUWReNCe L. HESTER. 1... M.D., rro/tuor awd Chairman. Dtrorwvnt etrkr and C,Medied 91ol Sout! C.roli.., ~ Iwow. esse CURT13 HOFP, Pr.D., M.D.. rro/t.aor awd CArkww. D/r4iow of rrycA4trk Rtu+.rcA, Medkd C-dkge of Vir&i.hk. Rklr-d. RUSSI?LL L HOLMAN, M.D., Larfel- w Sule University School of Mtdi- cine. New Or(cua. OLE A. HOLTPRMANN, M.D., Re- rrarcA Stlrwrl.t, Lobrwf L.Iorotom l)nivcnitf of Notre Da.w, Noln D.rne,l.d. FRPUDY HOMRl1ROPR, M D., hrd- /rwt ond D/rrctor, Rio-Rtse.rc# In.d- 1ute, l.e.. e'uwbe/dp, Mea ROBERT W. Hl/l l., Prr D., rrefrr..w V I/olorkd Sckwrrr, Fkxida Stat. .Iver.Ny, T.M.h.uce. GEORGE JACOBSON. M D., rrofr.ror awd Hn.I. Drrorrwrrwt of R./lo(o1~ Uaver.M~ of Southern ('.lifania School of Modkinc. l.oe Anocka. JERRY HART IACOSSON, M D., Dl rector, Division of EfecrrorAydolop, New York Eye ud e.r LAr...ry, New York. JULIUS H. JACOBSON 11, M D.. Aaro- cbte rro/ea.or of Surrtry owJ Dktrtor of SurRkol RtwarcA, ll.lvenk7 of Verwonr Cniktle of Medkl.., Rtr- liylo.. MURRAY E. /ARV1K, Pt1 D., Atsxl.re rrofra.or of rAi.rw.ecoloR7, Albal Pl.- aci. Colkie of Medki.e, bro.a, N. Y. OSWALD R. JONES. M D., 3r Luk.: Ho.pW, New York. ANDREW A. KANDUT]CH Pra D., Sra/ Sc{rwt(rr, The l.ckaom l.6otaorr, t.r ILrEor, Me. ARNOLD R. KAPIAN, PaD. Dker Ior. L~orvory of Melkrl ~ewrtlu, Ckveland Psychiatric lerlau .J Ho.Pirtl, Clevela.d. HRATCH KASPARIAN M.D., Arr(.wr Dlrecror, Cordlor.ur~.r [.L+ror7; Instrrctor Iw Afrlkbt, Flah.ewu.. Medical Colkge .nd Ho.lisNal, Pfila- dellhl.. eLIHU KATZ, Pw.D A..ociw MIc.- aar ol SocloloR7. i/rJvec.M1 C1/d np, CAkap. ANCEL KEY3, Pw D., Dk.cr.+, i.Ar+- ror7 of rA7rlolo.*k.l H7R/ev. U.Iver- wr of Mianc.ou School of P.Wk Health. ML.e.p1Y. JOSEPH R. KIRSNlR, M.D. rlv/a.+r o1 Afedkiat. U.Iwttity .f C1ka~. School o( Medkir CR{ry.,, PETER H. KNAPP. MD., RnrnA rro/rasor of ri7CA{.nyRaolota U.4 v.rary School of Medkirr, Raeuw KPNNET71 P. KNIIDTSON kID. U.l- vtr.Hf of W.ehA.pow Mjkal School. Seattle. ALVIN 1. KOdAK, Pr D, A..x1r. Professor of CAtw.brry, N+.r York UwiverJty, New Yo.k. ROBERT A. Kll11N, MD. A..oriar rrofrr.or, DlrLlow of Nrr++wrrl. New Jersey Srue Collep of Medicia. Jersey City. MARVIN Kl/S('IINPR, M D, Nt. Yo.k U.ivenh7 Medkal ('enter, N.• Yor k. /9

CHARLFS W. l..sELI.E, Pw D, Auln- .n! rro/rUor of F.nvMonmfnr.l H . tir~r, DrO.rrwrrnr of rrrvrnrivr MrI - cb.r, )eRersoa Medicel Colkgc, Mlla- delpAia. AARON 1. LADMAN. rw D, f ro/ruor and CA.irwr.w. Drp..r-rwr of Aw.ro- a+y. Tle University of New Meuioo School of MedKine, Albuquerque. THOMAS C. LAIPPLY. M D, rrofrtsor of IrAoloty, Nortb.estern Uni.erSlty Medicd School, Chicago. ROOER K. LARSON, M.D., CA/eJ o/ Mrdklne, Frcsno Couay Ho.Ritaf, Frc.no, Cal. OUSTAVe A. I.AUREN7], M D. CI1l.J of Mrdkinr, Sr Vincent H u/oqi Worcesur, Maw a AVERIIl A. LIESOW M D, CAdr- a.ew, Drip.nw.rnr of i.rAology. Yale U.iversky School of Medicine. New Haven. Conn. FSTEN O. LINDSPTTI, M D., hM D. St. Io.epA'. IlosRiul Rescatc\ L.boratory, St. Paul, Mine. ROEERT IL. L.1NNel L, ht D, Asocl- ou rro/ruer oJ CArnrl,trT, l)nivcnity of Vert.oal, Rwli.g+o.. HERSERT L. LOMRARD.M D. M P.H, A/fli.re, Ce.eer Re.eerch lnstitrte, Ner endl.d Deaconeae Hoqital. Roao.. 1. P. LONO. M.D. lro/r,.or of •A..• ...colon, SuN Univenity of lo.s College of Medki.e, lo.e City. DONALD R. I Ol1R1A, M D, Auoci.te Professor of Mrdk/wr. Cornctl Univct- dty Medkal College. New York. KENNF-TLI MERRILL LYNCH. M D, Sc D., LL D, CAr.crllor r.d lro(r,- .or E-rrirr, of Pathology. Medical College of Sout\ Carolina, Cloarkslo.. (In aeroclat/on .Itf Fords A. Mclver, M.D.) INES MANDI-, M D., Aulhw..r Irofr,- .w of D/ocArrwLrry, Colwnbia U.I- vrnwy College of Myakl.ns and Sw- Icone. New Yor1 DAVID t3 MANN, PN D, Auocl.tr lru/rr.o, of lA.r.n.,ntogr. TeTPk tlni•ersity School o/ rbarmacy, trorl.- dclphi. JOHN H. MANHOLD, 1. , D.M 0. Professor and Dfrerror of Pathology and Oral oierwod,, New Jersey Col- kpe of Medkrne and Dcntiury. lersey City. IOHN P. MANOS. M.D.. lnttrucror Iw Virology and e.cterlology, Medical Cnikae of South Carolina. Charkslon. CHRISTOPHER M. MARTIN, M D.. AslsM.wt rro/rsor !<Irdklne r~d Dbrnor, DLWow /w/ecr/or. DI- w~aaro, Ne. Jersey Ia Costae of Modlcf.., /enep City. MASON RESEARCH INSTTTIITE, Worcerar. Maa.. DONALD 1. MASSARO, M D.. Aasori.rr Professor of Rfrdkbr, Oea~e Was~- L~ta. U.IvcnNy Sefool of Irledicine, W..klyw., D. C. CHARLES •. MoCANTS. Fsr D.. Auo- rfue rroJr,.or o/ Soll,. North Carolina StaN College School of ApkuUrre. RakisY. CHARLES MeARTHUR rw D., Univer- .ky HealtR Servloee, F+iar.werd U.iver- sltr. Car.bridipe. Ma.. IIENRY C. McGILL. 1., M D., Acrhe Head. Drrarrnsrwc of Pathology. Lou1- eiaaa Stue University School of Medi- cine. New Orkana. HENRY D. McINTOSH, M D., lrofrr .ar oJ Mrdkb.e .wd Dkrctor. Crdlo- rraecrl.r i.J`r.mr7. Dute Uai.enity Medical Center. D.rh.w. N. C. FORDK A. MclV F_R, M.D.. .t a.ocl.tr lro/ruor of PaAoloty. Mcdicai Col- kp of South Carolina, CAarkron. (Sce Lynch. K. M.) EDWARD McKEe, M D., rro/ra,o..nd Acting Chairman. Dry.rtn.rw1 of 1'.- ,Aololy, Medical College of SoutA Cardina, C1rukUO.. KELLY T. McKee, M D. Asu.rtar Professor of Aledklwe, Medkaf Cul- kge of SowA Carolina. Clurketon. VICTOR A. McKUSICK, M D. Irofc,- ,p of Alydirlwr. The loMne 11"p Yim Ilniver.Ny Sc~ool of Medclned e.ltl- nsore. ROSS LL Mcl.PAN, M D, Auorlorr Iro• /ruor of Mrdkinr. Fmory tlnivcrsily School of Mcdicine. Atlani.. 90 I WILLIAM F. McNARY, Is.. hM D., Ar• ,oci.rr Iro/ruor of An.ronry. Boston Univereity ScAool of Medicine, Boston. NEAL L. McNIVeN, hr D, The Wo.- cester. Foundation for E.Ocrinre.tal eiolo.y. Shre.sbury, Ma». JULIA MEYER, hM D.. Auocl.ur t ro/r,. ,or of Oral r.rAology, Univenhy of Illinois Colk/fe of Dentiatry, Chicago. SPRNARD 1. MILLER, b1.D, Aulu.nr rro/rnor, The D.nkO A.rgA /nulrWr o/ A wuonr~, )eRereo. Medical ColkRe, rhiladclrbra. JAMES O. M11 l F_R, M.D.. IM D, Pro- (ruw of Psychiatry .nd P,yrAolory: Dirrcror, flrwral Nr.drA Research /w- n/rrrr, Univeraily of MieRlpn, Ann Arbor. HUGH MONTGOMERY. 11141).. A„o- clre Professor of !<frdkiwr. U.i.ershy of renroy~Ivaaia School of Medicine. FfYadclp`la. P. O's. MONTC)OMERY 1.., M.D.. Professor of r.rAoJor', ~Iniversity u/ Te.a. Sout6.cMerw Medical Sclool, Dallas. GEORGE E. MOORE ht.D., M D.. Di- rrcror, Ro...ell hrL Mea.oriat lawi- Irle, tlulldo, N. Y. KENNETH M. MOSER. M.D., Aul,r.nr ho/euor of Alydkinr. C3torRetow. Unirenity Medical School. Wasking- ton, D. C. HURLeY LeH MOTLEY. M.D.. trofr,- .or of ffrdklrcr .nd Dlrecro., Crdlo- Rrsplr.rory L.lor.rory. Universitr of Southern California School of Madi- cine, I-o. Angeles, EDMONDANTHONY MURPHY,M.D., Sc.D., Auorlerr Professor of SlorraNr- rk, and Mrdk/ne. The lo6m Ilopkine University Scbol of Medkine, dalti- n+ore. WILLIAM S. MURRAY, Sc D., Sr.for SN/ Scknrlu. TTr /acfeon Laboeatory, t!u Harbor. Me. RICHARD L. NAEYE, UID, rro/r,.or and CA.Irw..w, Dr/.rrw.rnr of /.rAol- ory. rennsyl.aala Srae lJnlverelty Col. kp of Medici.e, (l.rslaey. DONAI D M. FACE, hr D., Professor bf rA),lolory and Dirrctor, IwrNrrrr for Crllr/r Rr,rocA, l/niversity of Ne- br aaka. I lncoin. ALSERT S PALMER. M D.. A.du.nr rro/rnor. Drrarrr.wnr o/ hycbolop. Univenity of Toledo. Toledo. O. ROSE MARIE PANONORN, 8 S, Ml.. Aulu.nr Food Technologist and ler- rrrrr. Department of Food Sc/ence rrd TrcAnololy. U.ivtnity of Califotaiit. Davi.. MARY STF.ARNS PARSHI.eY, /r D., A„lu.nr trofruor of Awuowq M Ol.- ,rrrrk, .wd Gy.ecoloRr. Coturlla Univerrhy Cdk~c of Fhytkiane aad Surecowa, New York. EDWARD W. FeLIKAN, U D. CAd, w.on, Department of lArr..avl.ry M/ E.rr.l.wenul Tlvr./.rrfo 1oAen, University School of Medkl.e, •ode.. OTAKAR 1. POl1AK, MD., rr.D, Executive DMector, Dower M.ollkal Re- .eard Cenur, Inc.. Dovp, Dd. MORRIS FOII.ARD, PwD., D~enr Lobrnd [Llror.tory. Ualvenif af# Notre Dame, Notre Dawse, Ind. C. M. fOMERAT, h D.. Dhecro. q Ilolo`kd Rr,rarcA, Faeadewa Forn/a- lio. for Medical Reatan3, faee4..e, C.L H. R. !•RATT-THOMAS, ILD. D.en and rroJea,or of Pathology. 1/dkd College of South Caroli.e, CAarLeNO.. MARTIN S. tROTMh R.S DDS. CA4J, De rwrewl of Orrl i .rA.k~~ Ne.uk Cw Ilo.oitaL Ne.rl, !1. ). WALTER ReDISCH, M D Aeroc/re rro/ruar of Cllr.k.1 flrllciwe, Ne. York U.iveniry ScAord of MericMe, and NYU Research Service Oold.a4r Memorial Hoyiul, New vort. WILLIAM REGEISON, M D., Iro/r..ar and CA.kn.aw. Dr~.rrn.rwro/ Mrdlcd Onc~lofy, Medkal Colkp of Vkoutia, RkAwn>na. HORART A. RF.IMANN, U D, f'.v/r. .er of M.dkJnr, IIJ.em.nn M .l./k College .nd Iloeolul, t'fY.delrie. ROLLAND C. REYNOL DS. M D, A,- .lrawr f'ro/r,u.r of ruAoloey. lldver .il~ of Te.a. SouwA.eM.rn M.dk.l Scbol. Dallas. \(1(TY)R RI('HARDS, M D, CAIrJ of SurTrry, rresbyteria. Mediul Cwer. San Franci.co. 91

i WILLIS H. RIESEN, M D., Senior 11io- chrmfse, G/r Sriencer Dfrlrion, IIT Re.c.rch Iwslltuu, Chkago. (In$l.ted ..der A. Weinelocl, Ihl D. ) R. H. RIODON. M D., rro/ei.or of ro- rAoloty. Uni.enity of Te.a. Mcdiul Br.nch, Otl.eaton. SYDNEY C. RITTENRERO hh.D, rro/euo+ o/ leA../otoqyljnivet.lty of Soutlerw CalYor.:., Los Ayeln. DENSON R. ROE. M.D. AarocW. rr. leur o/ S CAiaf, Crllec Sr• rr.~~ U.iwof Callfor.i. Sdwoi of I~Icdid.., Sr Frrckoo. 1O?E.?H H. ROOlR3, M.D, Holy N.raa ot Iw. Ho.'ital, (Iad.dertr Al.. IOHN R. ROWLANDS, Fr.D., J+ea, ScknrW, Sout•weal Reasard IrUMtr„ Sa. Aweonio, Tea. RP-NIAMIN A. RURIN, PM.D., Aul.rnr rro/ese. oI rrblk NeebA, Rarloe Ur- vertily Colkr o/ Medicine, llouato.. HENRY 1. RUSSEK, M D P A C.t., rreollewr. T1e Ru+.ek ~oredalba, Inc, Slau.. Id..d, N. Y. W. C. RUSSELL. M D, Usiver.ky of Teau Medical Ct.ter, HouHo.. PETER P. SA1JSSURY, M D, hr D., (le.d, Iwrenrire Trrunwnr Ce.ter, Saiet lo.clA+ Hoepital, Rurla.t, Cal. PAUL SALTMAN, ne D., Auhrenr rr+o` leuor. Dr~.rrn..nr of RiocAenrbrrp end NraNbw, U.iverdy of Soutberc/ C.Worda School of Medkl.e, Lw Ae.ekt+. ULRICH H. SCHAEI PI, M.D., Dkrc- 1e. o~ NeworAern.ecoloty, Maaow Re- wrd Iwhub, Worcesta, Mar. JOROEN U. SCHLEOEL, M D., Pu.D., rro/..sw ond CAabn..w. Secriow of Urobty. Dtprrw.ewt of Srrtery, Tuter U.i.enMy School d Medki.e, New Ork.r. ALVIN R. SCHMIDT. h1.D, Dkecar of CooiuelMt, TufU Univ.rsltr, hleb- ford, Mnae. ISAAC SCHOUR, D D3., rH D.. D3c., D..w, Coll.;e of Dewrlu.y. U.dvenity of IlHwds, Clikap. MAURICE S SPqAI, MD., Cllnk.l rro/.uor of M.Ilclwc, Tufu U.i.ereily School of Mcdieine; Dlrertor, Dcp.rt- Wrnt of lnA.feulon Therapy. doelon Cfty Ilo.pi/.l, Doetoo (Scc CAodvA, S ) CHARLES E. SHERWOOD. M.D., Ar- d+r.wr rro/eure of Ral/dot~ Unl~rer .ifT of Rockeaer School o/ Mcdiciec ud DMekery. Roc>eslei. N. Y. SIIOII SHIRATA, M.D., h1.D., rro/e} .r e rharw..cototy. UdverJty o1 Ha School of Medicbe, Hoeolalu. DAVID L SIMON. M.D., Ihutrrcro., D7rt..ewr of lwterwol Mtdk/we, CL- elne.U Owerd HoYkal, Ci.ciu..U. E1R fKfNH01, M.D., CAk/, Detarr- ~.f, ~C..te.,erviot Y'e!/ert Ha.F1 Oe~OROE W. 3METTB••R], M.D., Aw dMO ie rerAd N..1lweMern U.4 .~,ati w..kre~.e~ c.Ir.p. OCN! M. 3MITH rr.D., Aubrwr rro- /saw N rrycAo~etS. Har.ard Medk.) Sc#eot. M.r.cl.rM. Oa•etta! Ho.Fi- W, Rawa LUCILE SMITH, FzD., rro/erwr of •/ecAen.l+wy, D.rl.owR Modical School. H..ov.r, N. H. ERNPST SONDHEIMER, Ih1 D., Aao- cWe rrvfeesar o/ IloeAemWrS. Coi- kts of PoreetrT, Seaw UalvtrsMT of New York, Sfr.ctr.. T. M. 3ONNESORN, Tw.D., D/n/w- I We1 Serrke rro easor of Zoology. Zi.r U.ivertiq, loo.inttos. SAM $OROP, nr.D., Nad. D.perr.w.nr of Manon.olecrlr CAen.l4e.y, The Let1eAs for C..at Reaearch, 1'fila- 414ble. 3OUTHWQ3T RESEARCH INSTI- TUTl, 3.. AMO.io, Tea. DAVID M. SPAIN. M.D.. Dkerrar, De- r.rtew.wr of rarAelolf. TM Rro.oldal. Hoepital Cswr. Reootlyn, N. Y. ALEXANDER SPOCK. M.D., Aulw.nr rro/eawr, oof retalerrk,. Duke U.l.e*- eMy M.dlcd Ce.1er, DrrR.., N. C. PRCDRICK 1. STARE~M.D., rro/a.or of Nrertr/ow. Harv.rd .iver.ity School of LWk He.l1Y, Ro.rw. C. HAROLD STEPFQP, MD., Dkrcror of Latenuork., Methodist Hoyllal, Me.1' ia. IACK P. STRONO, M.D., .+.+ocl.re r.o/tuor of htholot), Loui.law. Slate Usivereity School of Medici.e, New Orklne. 92 I I ! i MARION s. SULZREROe.R. M.D., rro- lnror and Chrkn.an. Deparrnrenf of Dernwroloty and SypIY/fology, New Yorlt UnivenilySelkvue Medical Ce.- ler, New Yoet. RENATO TAOIURI, M D., AssocMre rro/.ssr of rrycholoty, Oraduate School of Su+ieeee Adrn{.ietratio.,, Har.nrd Univer.itr, Boao.. CAROLINE ReDELL TlSOMAS, M D.. rro/ruor EnarYrs of Mr/k/we. T1e lob.e Ho9tiwe U.Ivst.iy Sclod of Medkl.e, eelt8.or.. JEROME F. T1IOMAS, Pw D.. rro/euor of Sanitary Ewt/neerint, U.iver.MT of C.W«nle, Rerleley. JAMES E. P. TOMAN, 11r D., rro/..- so. and CA.irn..n of r/wrw..color), Chicago Medical Scbaol, InYiNwe (or Medical Research. Cbicap. JANET TRAVELL. MD.. Auoci.te rro- leasor ol Cllwk.l rhwneeroloty, Cor- aell Univershy Modkd College. New York. LIE SHA TSAI, ht D., Reuerch A.w ci.r., Department of %rAototy, Yak Univerwly School of Medkiwe. New H.ve., Cen.. UNIVERSITY OF SOUTHERN CAL4 FORNIA SCHOOL OF MEDICINE. Los Anileks. ROMEO A. VIDONE. M D., Auoc,tiere rro/easor of rnAolofyY.k Uwiver- Jty School of Modkr.. New Haven, Co.n. PETER K. VOOT. f w D., rro(ea.r of Mkrobfolotf, U.i.enity of Wdlly- a. School of Medkir, Seattle. E. D. WARNER MD.. rroJea.or of re- rAoloty. Sl.le ilniver.ily of tows Col- lege of Medk/.e. low. Chy. S+IIEI DS WARREN. M D., Dt.~cfoe of IAlor.No.lre. Cancn Reuwc~ lnul- rure. New Entla.d De.co.s Howi- ul, Soelo.. ARRARA K. WATSON, Pw D-, Anlu- anr Recrtr/olotier, Man.chu.ette Oe.- eral Ho.pital; Rererc4 Aa.ocire, De• prhwenr of Secrer ew1 /..mrnof- on. Hervard Mcd ScRool, Rodo.. JOHN S. WAUGH, Fr.D., rro/eur e{ ChenrArrS, M.a.cR..etb IrUewa af Tech.oloty. C.wEeidr. RICHARD L. r1TCHSLPR, M.D,CIb- kd rh)slolotlr. Mo.reforr HoWi1d IwrMwe of Reaearek Ff1rEtrt/1- IOHN V. WtJL MD., Aselrr rro- /e..ow o/ Me/k1v. UNwsflr of Col. rndo M.dical Caatrr, De..er. A. WEINSTOCK. rw.D., Re.wrA 11r cAewriu. Li/e Scbwce. D/rfsfo.. 17T Reseucf 1..1Y.u, CRkaRo, (3e. Rlr .e.. Willis H.) RUSSELL W. WELLER M.D., r.tA.1- otiu, Me.wrW Hw~IJ d CfrW Couny, WeM Clsesler, Pa. SIMON H. W>'NDER, FrD. Rerred rro/e..o, of /lochewrbrry. Udwnhl of Ol1..n.n, Nor.a.. FREDERICK E. WHISKIN,MD.,C.M. Dkecror, Div/alow of N/a4A ewI rt/- .ow.llry Eqril/1el.uw, TAe Ap CsWr of New Entland. l.e., Rodan. ROOER 1. WILLIAMS. M.D. rn/uer o/ Ckwr4try: Dbcclor, Cley.o. reew- /rlow .IocAen.icel Iwetkru, TM Ual- venily of Teau, AwU.. DANIEL H. WISEMAN. MD.. Aad.w.r rrojea.ar of redlerrk,. UdvertMl d Soweer. Caliroe.la; C.Yb,r: D•L, .tow, Lo. Aa~eka Co.ay Orad Hoyital, Loe A.sde.. 1. EDWIN WOOD. 161.13, I.rr.csor b N.Iklne, So.tow U.iw.itT School of Medicir, Roelo.. SUMNER WOOD, la. M D., A.b.r rroleuor ol raAo~stT, The lA.e HoPllwa U.iv.nhr School of M.& ckr, 11dWwp.. 1O11N P. WYATT. M D., rreJe.r ./ ruAo/ot,, S.. 1 our Uedv+reil Sdodr of Medkiee. Sr. l.oule. 93

INDEX Alvarn, A. P.. 13, 16, 17 Ayres, S. M., 3) Bell. B.. 67. 69 Bianciflori, C.. 24, 25 Bing, R , 30 Borgen, A., 15 Bucciarelli, E.. 26 Burney, S W.. 69, 70 Chabn, 1., 75 Chang, P.-L., 33 Chiou, C. Y., 51 ('hupra, N. M.. 76 ('ochrane, C. G., 61 Damon. A., 71 DawAer, T. R., )1, 72 Del.ucia, A. 1., 42 Eslxr, H. 1., 62 Easman, W. B., 56. 57. 59 Fisher, E. R., 29 Fotard, 1. L. 72, 73 Friedrnan, G. D.. 65 Gemsa, D., 62 Goldslein, L., 60 Gould. V. e., 27, 44 Grimes, ('. A.. 50 Harnori, K., 56 Henson, P. M.. 61 Llerlweck, M. S., 38 Llo, W., 22. 23 Hung, K.-S., 36, 37. 38 Kapur. K. K.. 74 Kennel, S. 1., 63 Klatsky, A. L.., 66 Kouri, R. E.. 17, Is Ixko, A. G., 28 OF SF.NIOR AU'i71ORS I auweryns, l. M., 34. 35. 47 L.erner, R. A., 23 I.oosli, C. G., 45. 47, 48. 49 Meinke, W., 63 Morita, T.. 29 MueMer, H. S.. 32 Musta/., M. G., 42 Nebm 1. M., 58. 59 Nide., A. H., 49 O.ke., T. W., 66 O'De+wneN, T. V.. 21 Pawgborw, R. M., 76 Puter, 1. W.. 64 r.rlaoe. o. B.. )) Pinto dr Silva. P., 77, 78 RAIns. 1. S., 1 t, 19, 20 Rogen, P. M., 26, 50 Roaaa, R. C., 46 Rose, C. L., 74. 75 S.lerno, R. A.. 20 Sandbcrg, H.. 52 . Schoti, T. R., 32 Sawkin, T. A.. 54. 55 Smith, D S , 39 Smilh, U, 39, 40. 78. 79 Snider. (i 1 .45 Subfl, L. A. 28 Syuartini, F., 26 Vidit, B , 41 Weil, 1. V.. 51 Wes(fall, T. C.. 52 Whirmirr, C. E.. 21 Wuepper. K. L)., 32 York, G. K., 43 94 ?T ' I I INDEX OF PRINCIPAL INVESTI(:ATOR9 Ayrei. S. M., 26, 32. 33, 50 Bell. B., 67. 68.69.70.71. 72. 73, 74.75 Belkt, S.. 52 Bhagal, B.. 41. 53 Bing, R., 29. 30 Chalon. 1., 75 Chopra. N. M., 76 ('ochnne, C. G., 32. 61 Crocker, T. T., 15. 21 Cross, C. E., 42, 43 Dawber, T. R., 31 Fiber. N. 1.. 62 Essman, W. B., 56. 57. St Fisher, E. R., 29 Friedman, G. D., 63, 66 Fudenberg, H. H., 62. 77, 73 Furst, A.. 22, 23 Goldslein, L., St, 59. 60 (:ould, V. E.. 27. u Hanes, B., 50 Llayes, 1. A., 45 Kappas, A., 15. 16, 17 I.auweryns, l. M.. 34. 35, 46, 47 1 erner, R. A.. 23, 63 Lang, 1. P.. 51 Loosli, C. G., 36. 37, 38. 41, 47. 48.49 Niden, A. H., 49 Pangborn, R. M., 76 Parker, 1. W.. 64 Rose, C. L., 67, 6', 69, 70. 71, 72, 73, 74. 75 Severi, L.., 24, 25, 26 Shibala, S., 56 Skinh#j, E., 33 Slolkin, T. A.. 54. 55 Smith, U.. 39. 40. 71, 79 Solo(f. L A.. 2s Thomas, C. B., 32 Weil, 1. V., 51 West(all, T. C ., 52 Whiunire, C. E., 17, It, 19, 20, 21 95,