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CTR HN 011616

I EXTRA COPY REPORT / TI-IE COUNCEL FOR TOBACCO RESEARCH - U.S.A., Inc. 1972

1972 REPORT , 01 ~ lll~ m 41D m TIIE COUNCIL FOR TOBACCO Ri"r.SEARCIC-U.S.A., iue. TIIF: COUNCIL FOR T()1{A(:(:I/ RF:YF:AR/'ll-ILS.A., Ine. 110 E..! 59tV Sired, Ne.+ Yoh, N. Y. 10022

ti1:1FNTlF'll: AI1V1S(N1Y IL//AR1/ to 'Ihc Council for Tobacco Rescarch-l1 S A. Inc as of Ikccmber 31. 1972 SIIFl.l7nN C SOMMERS. M l),C'hairman Rrsrarch l)irrnor, The Corr.cil foc Tobacco Rcsearch-l. S.A., Inc. Uirrctr>w of I.aAuratorws, Lcaot Nill Floapital ('linira! Pro/rssor rr/ Potholoty Columbia Universily Co1kAe of Physicians and SurAcons New York, New York IIOWARD B ANL)I:RVONT, Sc.D. Scirnri/ic l:drror (rnbrd). T1se Journal of thc National Cancer lnstitute Bethesda, Maryland RICIIARD M BIN(;, M D. l)irrcror of Cordiology and Inaan+wal Alydicinr f luntinstnn Merrxxial Itcxpital, Pasadena, C'alifornia Pro/rssnr n/ Mrdrrinr l Iniversity of Southern California School of Medicine Los Antclcs, California McKFE_N CAT-1 Fl.l., Pit D, M D. Pro/rssor Fmrritut u/ Pharmoroloty Corncll llniversity Medical ('ollc6e, New York, New York WILLIAM I). (;AR!)NER, Prt D. F K. Ilunr Pro/rssor of Anatomy Yak University School o/ Medicine. New Havcn, Connecticut ROBERT J. IIUEBNFR, M D. Chief. Viral Carcino6encsis Brarxh National Cancer Institute Bethesda. Maryland LFON O. JACOBSON, M l). I)ron of the I)it•islon of Biolotiraf Scirncrs Regenstein Pro/rrtw of Biokrtiraf S4 irnr rs llniversity o( ('hica6is, Illinois CLAYTON (i 1.(X)SI.1, Pit 1). M I). llastrnRS Pro/rssw uf Mg,di(inr and PurhophoXy I Iniversity rrf Sr+uthcrn Calilurnia School of Mcdicinc l.r.s AnRclrs, ( aldnrnra KIiNNETIi MFRRILL LYNCH, M D., Sc.D., l.L.l). Chnnrr/Lrr and Pru/rssur F.mrrirus u/ Potlwluty Mcdical C'ulle`e of South C'anslina, Charkston, Stsulh (•arohna IIANS MEIEiR, D V.M., Dn. MED. VeT., M.R.S.lI. Srniew Soog Srirntist The Jackson l.aboralory, Bar 11arbow, Maine J()i1N P. WYATI', M.l) Pru/rssur and ifrad, 11,p artnxnt of Pathology l)nivcrsity of Manituba Faculty of Medicine Winnipc6, Canada WIl•LIAM F. RILiNFIOFF, Jrt., M.1). Board Mrrnhrr Emeritus ProrfrsfOr f nKrlptl of SYrgrry Johns Ilrtpkins University School of Mcdicinc, BallinNUe, Maryland ~Srirntifir tilafi o( Tlser (:ounril ROBI:RI' C. 11OCKI:Tf, I'tr l). AcringSr irrnrifir I)irrctw J. MORRISON HRAI)Y, M l). JOIIN 1I KRIiISIIER, Pit D. A ssrN iurr Sr irnN/ir I)irrrfur A+srh iurr SrrrnNhr I)irrr arr I-R1'l)I RI(' W. N(1RIISII K. 1'n 1). V1N('I N I F. I 1SAN7I, 1) M 1). A stur rurr' Sr rrnu/ir I)irrrrur , Xr rrnri/ir Asrrr. rru.•

i CONTENTS 1 etroductic>,+ . . . . . . . . . . . . . . . . . . 5 Curreot Slatus of the Research Propam . . . . . . . . . . 6 Cancer Studies . 7 Cardiovascular Diseasa . . . . . . . . . . . . . . . 8 ('bronic Respiratory [)iseases . . . . . . . . . . . . . 10 Other Studies . . 11 Abstracts of Reporu . . . . . . . . . . . . . . . . 13 Behaviorai EAecb o( Nieoline . Studies Related to Carcinotenes» Cardiovascular System . . . . 15 . . . . . . . . . 33 Rctpiratory System . . . . . . . 52 Pharmacr>Josy and Psychopharmacr4o8Y . . . . . . . 66 tNctaWic StudieS . . . . . . . . . . . . . 70 Chemistry and Biochemistry . . . . . . . . . . 71 Epidcmiolocy . . . . . . . . . . . . . . • . 78 Immunob6y . . . . . . . . . . . . . . . . 81 (knetics . . . . . . . . . . . . . . . . . 86 Active Projects . . . • . • • • • • • . . • . . . 89 Complctcd Projects Author Indca . . . . . . . . . . 13 . . . 96 Iniroduction Tfie Council for Tobacco Reaeamb-Q1.S.l.., Inc. is the spotuorleg a~o.cy of a program of research into queationa of tobacco uae and health. It is the outgrowth of an organization formed early is 1954 by representatives of tobacco manufacturen, growen and warehousernen. Research wpport has beew mainly through a program of tr.nts-in-aid suppkmeated by contracts for rexarch with institutions and (abwaloriea. The Council does awt iuelf operate a.y research racllitr. The Scientifle Adviwry Board meet- regularly 1o evaluate applications /ot aranuin-aid and contracts for research, using scientiAc merit and relevance n the sole criteria. Research grants art made by 7he Council to independent scientists who are aeured complete scientilk freedom iw conducting their studies. ()ranrar a/one arc responsible for reporting or publishing their /lndinp iw the accepted scienti/ie manner - throuA medical and acientilk journals and societies. TArough December 7972, research projecta have been approved foe 22) investigators In 199 hoapilab, universities and research instuutioru, 7Ue.e award" totaled more tha• $23,000,000. Thr reporl includea a brief summary of the present research propum of 7Ae Council as well as lists of the curreot and previous researcApr~ u sup- ported by The Council. Also included are abstracts of 127 reararch Papen, acknowledging Council support, that have appeared in scientific jouroals durt.y the period covered by this Report. A total of 1,012 .uch papers hu been pub- hshed by project recipienu. 11, N. RAMM Chairman and Presiiknt S

I Current Status of the Research Program The rexarch progrsm of The Council for Tobacco Research-U S A., Inc. hu progressed further during the lasl 11 momhs with a conhrued mapr emphuis upon cancer, chronic puh.o.ary disorden, eardiovaaculnr drseasea, and the "ptychopharmacology" of uwoki.g, is approaimately that order. The actual aumber of formally separasa proiecta is at present aomewht,t ku than Ihe historicJ murimum, refleetiwd a Iedrea of aggrekation into cerrain untera for the advantapes of Interaction among e.riwr different skills and mNhods. Seventeen of The Cou.ed's cvrnM projcets involve the espoaure of animals to the inhalation of Iobacoo nnote. Several others have been under• takea with the obtect of 'w.ch.diy srwoke exposure as soon as the necessary preliminary b.dot,cal work Aas beew suflkknly, developed. Iw all these inhalatio. .rudiee the aiwr Is to so control cord;tions as to insurt exposure to "fresh, whok, normal" tobacco smoke or ils pau-vapor phase in nu+rwlo.ed dose., In defined an:nah of several atrains and apecies, usually pathogen (rce and virus proHled, foc lirwe perioda determined by the aims of the eaperiment In several casea this is a lo.a-krm or normal lifeume c.posure. Cigarettes or oaher tobacco products of defined character.tics are employed. Concentration upon amole inhalatiot, eaperrments reflects the conviction that rcalntic studres murt be based upo. and evaluated by eapo.ures aimulating as nearly au possible those e.perrenced by human amokt:n. Sn.oAre Esposure Devire. fkvelopment of mechanical devices for accomplishing such eRposures with anirrula hu been an eaacunk, timc<onsuming task, even after ccubl6shment of criteria (or satisfactory conditions. Tlwugh The ('ouncd has been sponsoring smoke inhalation research (oe 17 years, the recognition of Ihese criteria has developed only with eaperiesct. The preaent proliferation of smoke inhalation atudies i• many Quarun ernphrizea 1!w neod for recognized standards to which all such studies muu conform, it a great con(usion of contradictory flnd- inp iN the scientiflc literature is to be avaided. Two devices that appear to meet many or most of the necessary criteria reasonably well an now a1 hand. Ur ie a relatively ineaperrivc and simple machine which should, hopefuly, be adequate foe use with intelligent care where relatively modest numbers of amalt animah are to be empbyed by in- veslfgaton who are rliNod aa biobgina but not necessarily as mechanics. TAe other device is more costly but should eoreserve manpower when larr numben of small anim.h are to be e.poced or when the use of large animals requires a greater amoke generating capaeity. A number of the srnaM rwachinss have now been diuributed to Council- rporrored iave.taptors .nd are in u.e. Conserauendy, a coosdcrahk increase in the flow of research results from direct sn.oke inhalation studres is to be e.poctcd llcrp,te these devctopmcnu, there are still many t>trks to be carried out 6 I to describe mexe fully and to measure mon aceurale!y the performance charac. Ieristics of these devices, especially as applied to animals of diflcrerM size aad different respiratory mechanicY and behavior. Especially important is devek+p- ment of better methods (or measuring the actual amounts of arnoke paniculatea deposited in the lunp of Ihese several species and strains of animala under actual operating conditans. Such measurements are necessary for reliable deter- minalion of dose-responar: relationships. Means for carrying out these studiea are being sought as a support foe the eaisting and growing program of inhalatios studies sponsored by TAe Council and, inereasingly, by other agencies. Fssentfally the same smoke exposure devicea eaw be used in studies targeted toward cancer probfems, pulmonary duease probiems, cardiovascular probkms, metabolic probkms, pharmacological probkms, and o/hen. In maay cases, paralkl eaperimenla are being conducted of planned 1o c.o.npare uy effecta of whole smoke inhda/ioa with those of the flas-vapot phaae (roe from parliculares. 1n all amoke inhalation taperirnenta invofving animals, the factor of atreaa ia being conaidered because, unlike man, mou anunats inhale snwke Involu.- larily while uationed in Gevices that impoae restrainl, noi.e, handlrng, and other disturbing influences. Tlria requires the use of `machine toMrols" eapo.ed to all conditions tacept the actual presenluion of amoke, for cornpariaon with unhandkd cage contro4 as well as with eapoted animals. Nabiwalion prcwrw- ably reducea stress and is a consideraliow in esperirnental design. fiiochemical monitors of streso, are also being eaplored. Thia problem has generated two mapr projccts in its oww right. Pethosene.i. Sttrdie. The Council p.oRr.ie inchrdn a sekction of promising k.ds inso an understanding of (acton that nuy be significant in the pathogenesia of dr several proup. of akin111-auocialed conNitutio.ul dirasea which are cw.esdy major causes of human motbidily awd wwrtdity, and also those reputed 1o ba linked statistically with tobacco use. Topia selected foe study are those deaned nwst likely to reveal important ueps in the pathogenesis of these diseases that may be tested is human ep4 dcmiological studies or developed into new and more meaningful bioassay lests, either in smoke inhalalion studies with whole animals or in organ or tissue culture systems of several kinda. By pathoseneais we meaa the progrca- sive succession of changes from no.mal, whether hntoiogical, biochemical, imnNnwlogical, uructural, or oaher, that lead to or are cor.comitant with d.eaae corditions. Caticer Studies Tlrus, in the cancer fkld, there are presently su Council aupposed nudlaa aimed at a betrer undcrstanding of how genetic faclors control wneeptrbiliry or resistance, and how the w called ('-type vrral genon.e may operare in eo.- tribwink to or.cueenedr Such knowledge is not only neoessary foc .ekctiy appropriate animal strains (or srnoke inhalatiou work but al.o (or defining isdrealors of susceptibility that can be applied to man. 7

lwo other cancer studies that do not presently involve smoke !spc.sure are in the fieW of immunulogy nJ are simcJ at learning how the hoddy mechanisms that bring ahcsut the rejectron of grafted tissues and o:gans as "foreign" material also operate in relectrng newly formed cancer cr IIs The work includes the ohjcctrve ol karning why thn rejcction system rlocs not always succeed in dettuoymg cancer celh and whether it can he stimulated without undesirable side effects It has been shown that Ihis part of the immune system is depressed by several of the "carcinornic" hydrocarhons and, if suitable new and scnsnive indicators of this depressive effect can be dr vebped, studies are contemplated for deserw.iwir.g whether chronrc tobacco su nu\e inn halatrors produces any such depressbw. (An e.tensrve completed tudy of immunosuppressinn by another rnedsor) iievdving stin transplsnlstion failed to show any effect by tobacco smoke eowdensates.) One relatively frequent type of human lung cancer is squamwis cell car- cinoma. which is seldom (ound (w nwinuls. Seeause squamdn eclls are not nwmally presenr in the lung, /hert nws( at ro.we time be • mNaplastrc con• verswn of other cclt types into squan.orr celb. It is not known whether this conversion occurs before or after the trawsfotmation of normaA cells into cancer cells. A new project has bee. desiped to determine whnher e.posure of living human cancer celis of other ryp;s b tobacco smoke w dl evoke squaman rnetaplaaia. Anin.d Modelt for Squan.osa Cell Lrn` (:.nter In medical ricnce, discovery of rncthods for producing a good duplicate of a human disease in an espcrvnen/al a.unul has often provided a basis fot rapid protreu in dcscribrnt the patho.*enesis of the disease and in finding methods of prcvention, delay or cure It has been more drfficull to develop such models /or the constitutional diseases than for the rnfectrous and deficiency diseases because of the strong tenetic aspects of susceptibility in the first. Several rnethods, however, arrived at by luck or necrdenl, have been reported for producing squamous cell carcinonu of the lung in animals. lwo Council propcta include mexhfic.tion of such animal models in the hope of producing the disease predictably and reliably and at a kvel adequate to permit syslematic studies of the influences of age, aea, urain, horrnone kvels, nutri- tasnd state, efficiency of the rnmune system, infectrorr, and other factors on the incideece of the disease. Such ierormalion dsould provide guidelines for the design of better oriented human studies. Cardiovascular Diseases As with cancer, curdiovascular diseaw are of compks eliology that in- cludn many contnMitory factors. among which hereditary prcdnpositurns may play an important rok. lhe predominant influence of genetic factors ha been further emphasized in recent years by sludks of identrcal twins with drscord.nt snw.\int hsbitu 1h -uth Ihe ('rwncil drd not participate in the spon.urnhip ol Ihc sho.hts .arrrtA iwi *on a C+rtJoh twin registry ur Ilvt original carcnsKrn of thrse sao-lits rar a i-in i4J,t0wm an tl.e IlnoteJ titslts• it u.upporlmt tsplnls. lions into the prnuhclitin of enlarging the sampks through international co. opcration. Ihe go.l is to obt.m more estensivt and cuncluuve data without waiting for the slow accumulation of morbidity and mortality figures from the original sampks. Meanwhik, the multivariale n.lysis of large e.isting human data collec- tinns is producing new perspectives concerning the rcpotleJ statnlical associa- tiom between smoking and the incidence of thest diseasn. The position uken by thc ('ommdlee that reported to the Surgeon General of the U S. Public lle .1th tiervice in 1964 was: "Male cigarette smokers have a higher death rate from artery disease Ihan nonsmoking maks, but It is not clear that the suoci- alion has causal signifkanct.- lAn statement is supported by increasing evidence that self-sckction of populations into those who "Irlie, need or wish (o arttOke` and those who do not, produces a non-random division into groups that ate not comparable with respect to nxxbiduy or life e.peetancy. Nenee, attribution of eaperiential diflcrcnces to the samc factor (smolling) that served as the basis for separation is ncocsaarily inconclusive. AlrrKSt hdi the current ('ouncil program in the cardiovascular (kld, aparl from the epidemiolntlical work already mentioned, is concentrated upon the study of atherosckr(><is or srtetiosckrosis. Qoes smoking have any effect upon the initiation or progrenion of these conditions that lead to incapacitation or death± One current project includes smoke inhalalion. Most of the uudies involve or include research on the eBects of nicotine. In several investigations, the initial nicotine research is to be followed by whole smoke inhalation. Induced hypertension is also being studied as ae additional factor in the totd design. 1 hree of Ihe asheroac~!rosia studies involve whok animal subjecu, two are irn vitro eaperiments using both animal •nd human lisaues for species wm- parisons, and one is a biochemical study of reactions in human blood. One of the animal studies, using chiefly p.imates, is eoncenlrated especially upon the (ong lerm cfiecu of chronic slresa in producing persistent hypertcnsion with consequential cardiovascular chanjes, when other influences are well conlroikd. Invesligation of potential nicotine effects In this contest is includrd. Carbon Monoxide Strdie. Another feature of the program is the incluslon of carbon rrrseosidg studies. Chronic inhalation of this gas by prirnates is being underlakeu to kyt a hypothesis that such espowre cas, hasten alherosckrosis. One sludy, at the cellular level in virro, is attempting to show whether the processing of falty materials (akin to those that eoat the arteriat walls in atherosclerosis) is dTtcttd by nicotine or carbon rnonoade eNher separately or in combination. All the malur human epidemiological sludiei have shown that cigu and pipe smolecrs drflcr very little in their cardiovascular disease e.perieoce from nonsmokers despite the fact that the smokes of these tobaccos have a relatrvely high nicotine content in a relatively alkaline environment conducive to rapid absorption in the oral cavity even without inhalatiwr Ilencc, the ('ouncd has been strening 101 many yesrs Ihe neeJ for precise quantitative and kinetic mcasurcmcnts of the relative naoUne absrNptiurs during the mumal smoking of cipreNtes, citan .rd pipes Analylical meth.n)s adcquue for du purpusc have been lacking A('ouncrl prolect is erdeavoring to develup n rmrnurxxhenucsl 9

assay method for this purpose 11 is gratifying that the government agencies have now recotnrted this need arnd have sobcitcd proposals for the develop- ment ol such mcihixls 11 the nicotine recerved frum these thrce forms of smokmg (and Irom chewing tobacco) should be closely simdar, thc cprdcmro- kKaal differences in disease rncrdencc among the users of these severaf producls could nrw be attrrhuted to nicotine (.l, rl»lic Respirotory 1)iseoses Ilistorically, several of The Council's Nudies of short- or lons ter n tobacco smoke inhalation by animals and rwan have included an eAort to dc.cnbe any obaer.ahk changes in pulmonary mechania or alterahons in the cells or tissues. lhs inlerpreutron of such observatior is relation to pulmonary dru.sea has hcrclofore been handicapped by the orneral lack of knowledge concrining the uap in pathogcnrus of these d.serun It wa., thcrefore, been conaidered neces- sary not only to sponsoe studin aimed at a better clinical dutrnclas between the several human chronic pulmonary diwrden but also to seek rnd follow clues to the prednpoulrorss and alseruio.m that determine the count of their paihoefcncss. Apart from lung canur, "chronic bronchite" aed "emphysem t" are the pulmonary diseases of special interest to Tlte Council Neither is really a single drsease and, therclcre, subdivisions into distinguishable clinical ent tics occur at research progresses ifu Council has contributed to the deveLspmenl of clinically diurngunhabtc suAgroups through subsidy of human paticnf studres in depth Both these diseases or group. of diseases are very incornpletely under• stood with respect to etrolo9y, which may well difler in the different subgroup.. FprdemsotoRrcat suudres in the past have been confused by poor chmcal da- cnmrnairon among acveral entrtres. lleredif.ry Prndupo.i/iow ro Ee.phy.ew.. Neither bronclutis not emphysema oecura commonly in animals in a form knowa to be clearly analogous to that encountered in man, so there is still uncertainty with respect to ths suitability of any propoaod animal model for studies directly rekvant to the human problem. However, uveral promising approaches have developed. One is the discovery that certain human individuals have a hereditary predrspoeilioe 1o emphysema due to a congenital defkiency of a cuculalrng antitrypsin which funclions as a protector of the lung pinst proteolytic attack by esollenosa oc endogenwn agents. The implicatwns of this fSnding are being pursued by aludy, oof a large human population. Estensive health and empbyment hislories are available for rnembers of this population who are also accessrbk for blood uaays of anti prdeasn. In the light of very recently developed information ow rnelics of the deflckncy, this study will attemp4 to relate the several genotypes 1o diAerences in respo.se to enviroer- mcntal rnflucwccs Animal wo.%, including sn.oke iohalalion study, is capilaliting on this discovery by obecr.auor to deuimi.e wt.ether changes tn anti prutease kveb may correlate with development of esperimental cmphysema or may be affected by cigarette smoke inhalation 1 here rs also recent evidence that emphysema rray be an au/oimmuno disease, caused or aggravated by chemical changes in the lung that cause lung lissue to be recognized by the immune system as foreign material and, lhcrefore, subjected to destructive attack. lhis concept also provides possible approachn to detection of those individuals who are especially susceptible to cmphy.ema and to ways of testing whe7her esposure to tutwke makes any conlributiuo to chances in the anutenicily of lung tissues. While the etiology of "chronic bronchitrs' in humans is still quite obacure, it is.considered very probable that an impaired capacity to clear bacteria from the lower regions of the lung is an irnpo.fant aspect of the disease. lhe Council long ago undertook support of studies to measure the rates of disappearance of viable bacteria lrom the lunde of mice after quantilated implantation, as affectod by I number of factor@ inclArnR whole smoke and ps-vapor phase inhalatio.. lhcse studies were folbwed by others concerned more particutarly with she pulmonary macrophates ao the probable major eflectors of the ckarance proceau. Both in vlro and in vitro smoke e.posures have been made, ard are conlinuing, to assess the toasA functional rnodrficaion of this protective system while avoiding the artifaclual ailuatio.n easily created by esclusively !w vlrro e ape r iments. Research findings about the protective function of the pulmonary macro- phages have led to other Council-aupporsed research on the operation of tAe.e and related defensive systems. At the end of November 1972, an infonnal roundtabk conference was arranged by Nafl at the requcu of the Scieaifk Advisory Board to lhe Council- Memben of the Board and stafl, investigators conducting studres on pulmonary defense meehanisrns, and several psesl .cicw- trsls mel to evaluate progrcu, eachange information and generate new ideas. 01her Studies P,yehopharwe.colo`y The Council is currently supporting Ilve studies in the beld of psycho- pharmacology that are directed toward further elucidating the paradoaical arousal and tranquifizing effects of nicotine and its facilitation of the learning process in animah. Chronic eRects of nicotine esposure have now been recognized in the sense that a shift has been reported to occur with time in the relative .ensitrvity of particular areas of the brain to nicotine as well as to other substances II was predicted that this thift in the brain area of major nimularion should have behavioral cornequcn4s in the promotion of "purposeful," u op- posed to random, activity in habituated rate receiving nicotine, 1 his prediction appeared to be upheld in tcsl e.perimcnis. Because human amoicrs ordinarily receive nicwine ch.onicslly, it can be reasoned that pharmacological e.pKrimen/s wuh naive anrmals may produce rewlts that aue not wholly relevant to the usual human situatrun flence, a new emphasis has developed concerning habituation effects on the psychopharma- eobgical responscs Io mcoline. 10 II

i Epiderrsioto6ica/ Studie• Four ep«kmiol•ugical studies are in progress which involve the analysis of large bodies o/ dau already collected by other agencies One es a continurng inveuigation inlo which it ia possible to introduce new tests upon the same subjects about whom a great deal r already known Fmphasin is upon the basic diflerencn, al many kveh, between those persons who have chosen to smoke cigarettes and continue srtsoking, thoae who chose to smoke but later ducon- tinued, and those who never adopted the praetice. Comparisons are also being m.de of the constitutional characteri.tio of cig.r, pipe and cigarN;e smoker.. One study provKks cornp.ri.or between men and women, whrles, black., (kicnuls, and Spanish Arneric.wa. trk differences that distrn6uish these several groups in rel.tion to a.wofti.s practices are relevant to 1(re question whether sell sekctron invalidates or rNulilka the causal interpretatioe.s that have been placed on statistical corretatioru belween smoking and disease. If smokers and noounokers are drqereM klwda of people, there may be basic cenatitutional dJferences in drease naaceptibility wnla/ed Io smoking prscticer. fhe data collected also contain rnaterial (or wsawy other multifactorial srudres Metabolie shu/ie. Two studies on mctabo4uw rue lookinR wNo relation. betwavn smoking and protein metabolism and Into the poraibke i.fluence of nicotine a.d smoking on the metabolism of various druK Y weM Y the possible effects o' drugs and medreinals on nicotine rneubdiam In the body. lAe current program represents a eoncescd effort by the Scientil(c Ad- virory Board and the scienti/k w.fl of The Council to achieve a new and higher degree of integration arnong Its eksne.u and a sharper focus upai key prob- kms in the area o/ tobacco and health rexarch. Robert C. Iloekett, Pit D. Acting SckntifSc Directur m (n O O m co cn 12 Abstracts of Reports I:ollowing are abstracls, approved by Ihe authors, of report. on new re- sc.rch acknowkditing support from lIK ('ouncd that have appeared in.ckMi6c jcwrnals since publication of the Report lor the year endrng June 30. 1971. lhc name of the recipient a in ItaIK.. lhe abstracts are grouped under these headings: 1. Behavioral Effects of Nicotine. I1. Studies Related to Carcinotienesn, 111. Cardiovascular Systerrs, IV. Respiratory Systcm, V- Pharmacology and Psychopharmacology, VI Metabolic Studies, VII. Chemistry and BioAsemistry, V111. Epidemioloty, IX. Immus- olo[y, and X. Genetics. 1. BehaoioraJ Egecta of Nicotine SIl1D1IS ON 111E MECHANISM OF AVOIDANCE FACIL_ITATION BY NICOTINE Does nieotine facilitate avoidanoe acquisition by enhancing memory eow- solidatqn or rnerely by atinwlating performance? To answer the queatio., a series of etperimenb waa run on 229 femak SpraRue-Dawky rats. AninuY were divided Into groups cnd trained (o. 15 one-hour seasiona in a diariwi- nated kverpreas avoidance situation with buzzer as a conditioned stimulw. More rats receiving wkotine, 0.1 n.g/kg, I p. irwnsedia(ely before each onoAotw daily session (presession) (eachcd a preaN karwing criterion than did aali.e conuoh, and rats receiving 0.1 mg/kg of nicotine performed better tham cow- trol. but not as well as those receiving the higher wicarne dose. Rau Rives similar doaes of qu.rlernary nicotine bismethiodide In an identical pre.ea.io, esperiment did not learn more profkientty thata controls. Other groups of rats were given four doses of aicoline in photocell activity cars and the dow of niaNine which facilitated avoidance acquiailion depressed sponlanean snotor activity. LAler uudies in which rats were given 0.1 and 0.4 mg/kit aicotine or saline i.p. immediately afrer each session (postsesaion) showed that the drug also facilitates avoidance acquisition by this method. hinally, rats were again trained with prerssion nicotine, but .aline was substituted for nicotine begin- ning on session 16. No drug dissociation effect was seen. lhus the resulu of these studies suggest strongly that small doses of nicotine permanently facilitate the consolidating neural mernoay trace and do not enhance avoidance merely by stimulating performance. t,ir4,on-C. K. r,yrhovhurmacorotiu (errr ) 22:)S7-)6e, 1971. From the (kpartmenl of Pharmacolory and lo.iculo=y, University of Kansas School of Ph.rmacy. I awrence. ('1/O1 INFRGI(- ME3('IIANISMS AND AVOIDAN('U BE'FIAVIUR A(Y)(IISIIIUN. I:1/ Y('1S OF NI('OIINN. IN MI(-li 1wo groupr of IS male ('F I strain mice were given rnu.perrtonc.l ro- jeclions of nicotine sulfate (I 0 rng/kg) or an equivalent vulunme of 0976 salro. I)

This treatment wat followed, 45 minutes later, by giving each animal a single training trial in an apparatus designcd to provide for the acquisition of a passive avoidance respnnu, consisting of loot shock given when a mixne stepped through a hok connecting a small vestibule to a large darkened chamber. Response latency linterval between placement and entry) was always undcr 15 aecondt A/esung trial was Riven 60 minutes after training lhcreaflcr, active voidanct training was initiated. Mice trealed with nicotine sulfate showed, as compared with the sahne-Irealed conlrols, a decreased incidence of active avoidance conditioning without effects upon either passive avoidance acquisition or escape behavior. The dlecy of nicotine was to reduce titnificantly the ratio of bound free acetyklwliwrt in the cerebral corles. This change was accounted lor by a decreased coMCM of slored mine, particularly in the synaptic vesicks, without any ehanW itn the turnover of the "free" storate pool A difference in the ratio of braia aeetykholine storage pools accounting foe different modes of avoida.ce is wnesled. E unwn, W. 1, and F-sisman. S. 0. prycholorkd Rrporh 29()).9ta7-11), 1971. (Irl:er a.ppsrt: Nalronal Instituses of Health. From the Department of PsycAolo", Queem College of the City University of New York, FknhinL N Y. (-HANOFS IN ('HOLINFRGIC A(-TIVITY AND AVOII)ANCE Bf?FIAVIOR BY NI('OIINE IN DIFFERENTIAILY ItOUSF.D MICE lhe brhavuxal and cholincrgie effects of the drug, nico/ine, appear to be dependent upon endogenow changes conferred by differential housing In Ihis eaperinstntal study, mice housed either in isolation or in groups of five for 165 days were treated acutely with erther nicotine sulfate (I 0 m`/kg) or saline prior 19 being trained to acquire a passive avoidance recponu Isolated mice showed markedly reduced passtve avoidance karning, but with nno/nse veat- ment their avoidance acquesuru.n was comparable with that of troup housed animals. In the case of the laner, nicotine did not affect woKlance acquisition rate. Active avoidance training, given following passive avoidance testing, indicated significantly impaired learning of the avoidance among nolated mke, without any effect upon escape from footshock. Nicotine-trcated, isolated animals showed  significamly greater incidence of active avoidance behavior, but group houscd, nicotine-treated mice showed appreciably reduced active avoidance responding Parallel studies of acetykhohne porrls in +he cerebral eortes of differcntully housed, drug lrealed mice indicated that ~xdatKon kd to a significant decrease in the ratio of 'hound':'Iree' acetykholine; nicoline treatment led to n ekvation of this ratio among isolated mice, but truup- hrwud animals given nicotine showed a significantly decreased rimn Ihe in- teraclion of differcntial housing with drug Ireatmcnt may serve a+ a model from which cholinerkic mechanisms related /o avoidance behavior may Iu viewed. Eun+an, W D fnrrrn.rlana! Irrurnal of Nrrrourrncr 2:199.206, 1971. (1tArr .upporr: Nalninal Instdutes of Heallh From the 1)cp.itmcnt of Psycl.oiogy, (hseens College of (he City Univcrsity of New York, I lu+hing, N Y. NI('OlINE ('HANUFS IN EEG AND BENAVIOR AFII?R INIRAVF.NOUS INFUSION IN AWAKE UNRFSIRAINI:1) CAIS This investigation was undertaken in order to determine whether IMra- verwws (t v) infusion of small doses of nicotine would induce in the awake, unrestrained cat, a similar phase of inactivity and FI:() hypenynchrony as has been reported for sleeping cals. lhc awhors showed tkat, sn the awake anirnals, i v, infusion of 10 pg/kg o$ nicotine usually led to an initial behavioral arousal and EIYi desynchronizalion in the ccutea and subcorlea. 1 hc hippocanpug eshibited theta rhylhm, and the amygdala an increase in rhythmic burst activity Protracted immobility wilh hypersynchrony in corte and lhalamus, and high voltage slow wave activity in hippocampus and amykdaia fd{owcd. Fpiwdca of slow wave and REM skcp were often noted. A 10-SO rg/kg dose of nicotine produced similar behavioral changes with increased ckctrocorrrcollram (F;('o()) dcsynchroniration or Ilaltening. A 100 pg/kg dose elicited marked changcs is behavior and so.nctimes temporary FCn(3 silence lhus, they conclude, nrcoture infuyon kd to an initial pJsasc of bchavwsral'and FF(i arousal, followed by a phase of prolracted immobrlny and FF(1 hypcriynchronitation indicating seda- tion. According to these investitators, the period of hippocampal theta rhylhm and increased amygClala bunt activity appears to be characteristic (ot the i.itial action of nicotine. Sl.dnicki, S. W. and StAarlPl, U. H. ArcAives fnfr.narionalrr dr 1'horwwcodrw.mir rr dr TArraoir 197(I):72-lS, 1972. From the Mason Research Inatilule, Woreesler, Mass. 11. Studiei Related to CorcinoRrnprti. HISTOL(K;Y AND UI-TRASTRUCIURE OF CU1.lURF1) IIUMAN TUMOR CEI IS EXPOSED 10 ANTISERA lU TFIE NI[RVE OROW7H FACTOR Various cell chankes described in this paper appear to represent a speeiRc type of antigen antibody injury. In the work reported here, several dilutions o( anti-nerve growth factor serum from rabbits or horses rmmunrred with punfkd nerve growth factor were added to rapidly growing, 48 hr monolayer cultures of  human gIk.hlastonu (C)S6) and of an H. Fp 2 cell line ('ytotosic effects. beginning two hours later and usually progressing to complete cell death at :7 hewrs, were sludred In vitro in stained covershp prtparalrons and by electron rnicroscopy Anuscrum made in lhe horse had N.ut one fifth the cytotosK acuvily shown try nliscrum made in the rabbit It I-p 2 celh were aMwt flve tmws as reuslant as (')S6 eells In fKNh cell Irnts, nrany n( the cells survrvrng the anliscrurh showed nuckr with generally intact memhranes, containing '0 lo 50 or niore reMrakd chronMnoNnc like Mrdres, uiitcsting pruphase mu.N6c activity ('onUol nw.nirlayers receiving normal rahhd or hor.e serum were eomparahle to the untreatcd contrrds Ihe cyloto.ic and cyrocidsi etlects are probably of thc antigen antibody type IS 14

Pin\ertrxr, 11 . Bhaeae. D. Rana, M. W. and FFoltwict, S ('an.rr Rrrrarrh )1 14tl)-14e7, 1971. (ItArr awppurt: National Instrwte of Mental Health. From the 1)epartmcnt of PhysiobRy. S( l.ouis University School of MeJrcrne. Sr. I oun. ANTITUMOR A(-IIVITY OF ANTISERUM NERVE GROWFII FA('IOR (AN1I NGF) In an ttcmpt to determine svActher anlinerve growth factor tanti-NGF) aftecls the growth of chemically inductd twnors, newborn ('F-1 mice were in- jcclcd unccuunecws)y with "Wtlkonm" anti-NGF for the flrst Ave days of life in increurnR dr.ses ('ontrol mioe teteived .w equivalent volume of hrxse serum. On day 27, all ammals were injecKd subcWaneously with 3 mg of brnio(a)- pyrene Three days Lter, hs1F of the rnioe which had rectived hrxse serum were given three rnfcctrons of wkotine daAy. Results irxficatcd that pretrca/mcel of nimals with anti NGF delayed the appearance of lumws induced by hervo(o/pyrene While in the control mice, tumors began to appeat frorn day 27 of the fir,t infcctron of bcn:o/a)pyrene, their appearance occurred only at day 90 in immunosympathcclomartd mrce. LiLewise, nicotine prelreatmcnt also dclaycd the appearance of tumor until day 100. Both these tretlmenu, i e., anli- N(iF and nicrainc, not only delayed the appearance of lumon but also caused lower incidence of wmcxs Whrk nicotine treatment delayed the first appear- ance of tunror and reJuccd the percentage of incidence of hurrxs, it caused significant increase in the averatc wetghl of a tumor. Bhocor, d, and Rana, M W Proceedings of thc S(crcly for I rprnmcntal Biology .rr) Medicine 11NI1198)- 9144, 1971 Othrr .rpport: Natu+nal Institute of Menial llrAlrh From the Ikpartmcnl of PhysKduzy. Sr I ouis (Intvcrsily khool uf McJrcine, St. I .ouis. CHFMICAF. ('ARC'IN(X;ENFSIS IN SYRIAN F(AMSTERS This is an eatensrve review of the papers on chemical carcinoscncsis in Syrian hamsucrs (!<lrrorricrrur •urarvt aY/0/Yr) which have been puhhshed since 1966, when the tasl comprehensive nne on thc subjccl appeared For the purptne of his JiuussKxt, the author divnks Ihe various papers Inlu sevcral groups classif-icd according to the systerna involved in addition to two other categorres, check pouch lumon anJ immunology of chemically inJuccJ neo- plasms In the seclNNl entdkd "Genctics as a Mr>,)rlymg Factor in ( hemical C'arcrmrllcnesis in Syrian 1lamstcrs," the author Iw describes some hitherto unpublished material of his own demonshadnt that genctK Iacwrs determine the rc.ponse ol hamslcn to subcutanccws inrcclwins of 9, 111 Jnuclhyl I, 2 henranrhraccnc (1)MIIA) (Canccr Rcs )2 1M) IM., 1972) Ile cuncludrs that nncc, in hn opinmrn, ncw significant rok of gcIKIK f,..tur• in ccrt.m types (if chcnoocal carcinnKrrxvs in Syrian hanrsten has been clearly Jcmun•lratcJ, it is inywntant tt uw int.rc.l linrs ur their hyhrids in such wor\. I Homburger, F. (Rio-Rrrrmrh Consrfmnrs, Inc ) In /(omburRer F. (ed ): Putholoyy r./ the Syrian Nar.urrr. Pruerru in Espr6 mrnruf l rnror Rnrarch, Vol. 16, Basel: S. Karger, 1972, pp 152-173. Other sppport: U S Public Health Service, Virginia and 1). K I.ud.iiq Fcwndatiun, Fannie F. Rtppcl Found.tion, and American Medical Association -Fducatron and Research FounJaticxr. From the Bio-Rese.rch Instilute, CsmbrKlge, Mass. IIIE UFAF DF.X 1 RAN.POLYRIBOINOSINATE-POI.YRIB(x'YTIDYLATE ('OMPLEX: PFIYSICAL PROPER711S AND INIERFERON INDUCTION To be abk to delineate the mechanism of interferon enhancement, uudles were made of the pbysKochemKa) and biological properties of the rI•rC-DPAE deslran complex. E.periments were carried out on human neonatal cells and mqu+e I. celk which were grown as monc>tayers in MFM containing 15% (v/v) (clal calf serum and incubated at 77° in a S'X ('O. uncnphere. Bovrnc vesicular stomalan virus 1 VSV) was harvested from VSV-in(eclcd mouse embryo cells. To assay for interferon induction, cells were eaposed to rl•r('.DI:AE destr.n complexes in solution A for one hour at 2' or )7'; then the cells were washed and incubated in fresh medium fo. If/ hours. A series of tests waa then run. In summary, the results of these eaperin.enu suggest that DEAE desuaa potentiates interferon production by delivering more of the rI•r(' compks to Ihe triggering site. It does so by increasing the uptake of rl•r('. through the aggreRalion eflecl, and by renderinR it ksa susceptible to endonuckascs. Pitha, P. M. and C.rrrr, r'. A. Virolory 45(l).777-7t1, 1971, O/At'r aupportr American Cancer Socie/y, Maryland Division. From the Deparlmenls of Medicine and Microbiology, lhe Johns Ilopkins University School of Mcdreme, Bdtimwe. SIRFPTOVARICINS INHIBIT FOCUS FORMATION BY MSV (MI.V) COMPt.EX In an attempt to sludy DNA polymerase inMhition, the eAects of urcpw- varicins were tcsteJ on the efliciency of Iransformatarn by Mokrney munne sarcoma leukaemia complex (MSV) in virro. Also checked were the abihtia of the streplovaricm compks. aa well as Ihc purdl,eJ sueplovartcins (A and Dl. su abort trarnformatinn of B+Ib/ 3111 cells by MSV. I or these studies, cells were grown in thc presence of incrcasinR conccntratans o( antibiotic until cell growth ratcs were rrb+trvcJ to slow lhose s(reptovaricins (complcs and I)), which are acuve inhibitors rr( the MI V 1)NA polymcrase in ccll free mr.lures, hLKkcJ the formation of MSV-rnJuccJ loci 1 concentrations which Jwt nd impau thc Jrvri,ion rate of rwrmal cells In thc caae of cornplcs and O, focus (urmaNK.n was bl.akcJ at conccn/ratrxn of anthhwrlic aM.ul fuur told kta than that which J.•crcax ccll growth In cuntrast, the stnnunally related rnacrohdc A, whtch IjcLs inhrbnory adMM on the vual enrymc(s). was ina.tive in Unuc culturc Ihcsr results suggest that Il.c cllccts on hhr k.Jc of tran./urmatwrn art Jue to a selective inhibition of RNA .Icpcndenl 1)NA Irdymcra.c hcuusc inhttN 16 17

lion of fucus formation parallels the inhibition observed in the enzyme assay. To lest whether ternporal relatwnshrps eust between virus between virus specific protein synlhesis and viral ONA polymeraae functrors, the native dmreric form of the virus induced interferon protem was added to Balb/ ) f) cells rt different bme intervah. before and during infection. Results here inJrcale tt at the re- Quuemcnt for vuns specdic protein synthesis occun within the first 24 hours, as does the function of the "reverx trarncripuse.` Also, it was seen that the antiviral effects of streplovaricin U and interferon were adddive, wurstinR that enhanced rnhrMtron of focus formaliow taw be achieved by simuttaneous block- ade of transcription and translatio.. C'erter, W. A., Brockman, W. W- sud brde., E. C. Nerrrr New eiolory 2)2:2t2-211, 1971. O(Atr .upprt: American Cancer Sociery, Maryland Division. From the Fkpar,menls of Medreina awd Microbiok>lly. The lohnu /lopkina Univenity School of Medrerne, Baltlwtort. SLA E(`TtVE INIIIBITION BY STREF?OVARICIN OF SPLENOMF(3ALY INUUCFF) BY RAl1SC11ER LEUKAEMIA VIRUS• This paper reports the effect of urepsovaricin cornpks on Rauscher Icukaemra nrua (RLV) infection of mice. ln Ihese anrmals, RI.V induces iniually .n erythrnAlastic proLferatpn which results in splenic enlargement. A change in the cfhciency of virus induced cellular proliferation is reflectcd in a dccreau in spleen werghl, whrch thus strvn as a quantitative parameter of chemotherapeulrc eRccl flmnfected animals grven streplovarrcm complc for IS days had no change in spleen weight RI V rnlectr.n resulted in a three to four fold rncrenunt in spkcn weight by day I S In contrasl, streptovaricin treated mice, fed drug Irom 24 hours before infection until sunfsce, had smalkr apleens throughout the period of observation Chcnxuherapy resulted in about a two-fold reductas in spleen weight. Borden, E. C., Brockman, W. W. arsd Crtrr, W. A. Nature New Siofory 2)2:211-216, 1971. O(Aer .rrporl: American Cancer Society, Maryland Divisicsn. From the Ikparsmesu of Medicine and illicrobio{ogy. The Johns Flopkins University School of Medicine, Baltimore. •P.MWJ r: sd..u.. trrww N fbyw..kr. 1 3ri_.~q.lr t.aer..d ~....ae. t.v.v.J. .r vr.. ANTIVIRAI. A(-IIVITY PRO[)l1CED BY TFIE POLY('Ylll)Yll(' ACIU IiEXA1NOSINATE SYSTEM Mrnt studree indicate that only the double stranded homnpnlymcr pair of p.>tynosinrc and polycytidylic acid Ipoly IC) can ir.Jucc interferon. h,rl in a few cell Irncs, ungle stranded polynuckotxlcs, poly I or poly (', can serve as rn- duccrs when they are applied at high concentration or in the presence of la•lytr..r. .rtnq.rurwls Rc.cnlly. it has Leen nhscrvcJ that succcssuvc adrnrnrstra- 1•.•n .d rfw r••rr.~l••.wlrnI h.wrrrlydynrrr. r.n cyu.l r./ snrhal thc anlrvuat .. ".rr. ••1 rhr 1.•1, 1( ...nt.4. I l.cse p. l,.ul.r .,uJres n 1gcsl. ainant ulhcr prnsubdrlics, that th: compkmentary polynuckotKles may form a compks /n vivo, nr that the two strands might functwn independently within the cell In an effort to further clarify the role of secondary structure in order to ursder- stand the mechanism of rnductinn by both polynuckotides and natural viral RNA, the authors tested a compka formed between high molecular weight poly C, and low molecular weight oliro I. While this cornpka has the ume chemical comprnition s poly 1(', the slabrhty of rts douAk heh drRera, so U,at tlv: secondary structure can easily be manipultted. leaving the primary slructure rntacl. Results indicate that both components are necessary for in- terferon induction and that the secondary structure of the polymer is no( critical. Pitha, P. M. and Cerrrr, W. A. Nature New ewlory 2)4:105-106, 1971. Ollver aupport: American ('ancer Society and U. S Public Ilealth Service Frorp the 1)cparlmenta of Medicine and Mrcrobiology. The lohns llopki,a Unrverrity Schrxrl of Medrcine, Bdtiniore. SF.I.F.Ci1VF INHIBITION OF VIRAI. Fl1NC'TIONS: THE ANTIVIRAt- A(7TION OF INIERFERON ANl) STREPTOVARI('IN This is essentially a review artick describing and discussing several of the advances that have taken place, as well as some of the still unanswered rauea trons, which concern Ihose working in antiviral chemolherapy. Recu.gninng that both cytolytic and on(olIenic viruses may have common mechanisms of protein and nuckic acid synthesis although they cause antithetic effects on cells, the authors suggest a possibly similar therapeutic approach to thcsc two types of viral infection. In parlicular, they are concerned with two compouods, interferon IIF) and streptovar{cin (SV), whkh seem to possess both of the ekments essential for broad clinical applicability, namely, specJkity in action and a wide anliviral spectrum. Interferon selectively blocks viral protein synthesis and is considered a major bulwark of host defense in primary virus infection. Streptovaricin inhibits the RNAakpendent DNA polymerase, present in all of the RNA tumor viruses strxlied Ihru far and apparently euentiai For lumorigenesis. Not only does SV decrease the efficiency of RNA tumor virus oncogenesrs without a measurable eflecl on normal cell growth, but it also bkscks replication of vaccinia, a cytolytic DNA virus. TTrus. SV appears to act specifically on vuus-irsduced even/s, reflecting a specificity mN inherent to nsoN antitumor drugs Aho discussed at knrth, are the prnsihle mechamsms of IF induction nd the evidence /or its suhuml structure in the human, as well as the action of SV as a reverse Iranscrrptase inhibitor Certrr, W A, Prtha, P. M, Brocknun, W. W., Borden, li C. and Marshall, 1 . W. AlrJurnr SIOI:Id) les, 1972 Ot6rr .upp..rl: I1 S Public 1lcalth Srrvice, Jane ('o(hn ( hrWs Fund, and American ( anccr Srxaty, Maryland Ihvrsion Fnxn the 1)cparlmcnts ol Medicine anJ Mrcrohiulo[y. Ihc l..hns Ilopkinm llnivcrsdy Schcx)l of McdKrne. Raltrmurc. 19 IM

(:AP 111N('!Il)NS IN NORMAL ANL) TRANSFORMP.1) FIBRC)BI ASIS IN ('1111tIRE Intcrcellular contacts are essential for various functkxul phem.nxna Fkc- trophysNdog.cal studies of cacnable and non<tcrtabk systems ha~e demon- slralcd Ihat rntcrccllutar contacls can result in the cslablishment of luw.resist- .nce parhways which ionrcally couple the cells Studies of the povrhle slruc- tura) basn for the bw resistance palhways, have reveakd, in ccrt.rn orCannms, scptate and gap junctions between inver/ebrale cells, and gap /unctirvss hetwecn vertebrate cells ('umbirscd morphological and ekctruphyswlugrcal atudres of escitable cclls imply that the tap jrrnction is the low resuunce uruaurc. 'lhe aulhors report the unambiguous ideMiAtNiow of gap fursctions betwten cells in rrsoewlayer culturn of txsth rsornul .nd Row sarcoma virus transformed fihro- blas/s, known capable of ionic couplinlL Ihrough the use of conventional thin ssclions, lanthanum usspregnation, and frt+eze fracture. No aon occludens couk/ be identified. Pinto t)a Silva. P and (3ilula, N. B. (Fnlrwbrt, fl. N 1 f,rrrlmrwul Cell Rrrr.rrA 71:)9)-101, 1972. OtArr .rrrwrfr National Inailuta of Health, Gray Institute for Molecular Biology. lane ('olfin ('hJds Memorial Fund, Atomic Energy Commrasion, and U. S Public 11ca)th Service. From the Department of Medicine, l/niversay of California Schoo' of Medi- cine. San Francisco, and the tlepartnscnts of Botany and Physiology-Anatomy, University of Cahfornu. Bcrkeky. 1HE CLFARANCL? OF BFNIC>(A)PYRENE ANL) FERRIC OXIDE fROM MOl)SE II/N(;S Llersre(a)pyrene (BP1. found in tobacco condensate and smoke of diversified organic matcruh, r one of several airborne substances which are potential or povcn carcinogens and contnbute to the increased incidence of pulmonary diseases which have become a major. world-wide problem. The metabolism of BP hu been eslenuvely studied in laboratory animals and one researcher has shown that a saline suspension of the compound adsorbed onto ferric oaide cao snduce cell carcinoma in hamster lungs. Several mechanisms for removal of particvlalcs from the alveolar region have been proposed. lhe general opinron, however, is that macroplsates pha6ocytixt the p.rticks and either migrate to the lymphatic nodes or are Iransporled by the intcrsiitral fluid to the terminal bronchioks, cilrar motiong then voiding the material thrcwrgh the trachea. Although this usually happena very slowly, only tracey of BP were found in hamster lungs I S days after a single trcatnsent. Since the degree of carcinogenicity of any wbslance apparently depends upon the mo.k of contact and the species of animal involved, the way in which drRerent species eliminate a substance from the lunp may have an important bcaring upon its ability to induce tumors lhis report presents the inilial results of studies on the clear- ance of BP and ferric owide from mouse lunp lhc data reveal that BP is eliminated from nMWSe lungs faster than Irorn hamster lunp, arnd that Ihere sre two distinct skarancc ratcs Iw BP and ferric o.ide, the (ormcr hrrns slmrnt cumpktcty rlhmnaicd by the loruth day whrk 70% of the l.ttcr was still presrnr s/ter sw.c week Ihc rare ddlcrences for the two com)xMrnrls suggest 20 thal two inrkpendent renw)vnl processes are in opcrauon Apparcntly. BP r wtubilrted in thc lungs and met.Mditcd either by rnlcr.tdral thssue or hver. The presence of an rrrducible BP hydroaylating enzyme in various tnsues has been rcpurted, and it may be that the speed at which it can be rrsduced and its specific activdy plays an important role in determining the BP cucinngenicuy in the mouse lungs. Further esperimenution to determine the relatronshrp between drnage and clearance rate is necded, as well as the study of BP meub- ohsm in mouse lungs which is now in prugress. lio, W., Benlon, M. and Fusr, A. Procrrdmer of the Wrrrrrn Phnrnrardoty Soclrry IS'SE 60, 1972. From the Institu(e of Chemical Brobpr, University of San Francnco, Sa. Francisco. l)1SSIiMINA1F.t) RIIABL)nMYOSARCOMAS FORMFI) IN KIIi-IENS BY ('1/1.111R1it) III/MAN RIIABIK)MYSARCOMA CELIS This paper describes, for the first time. the successful lransplanlation of cultured human rhabdomyosarcorna cells in kittens by prenatal inoculation. T( e cultured human cells (RD cell, line AI2) were inoculated into the fetuses of three pregnant cats at approximately 40 days' Rntalinn. lhree o/ five surviv- ing kittens from two /iuers developed disseminatcd rhabdornyosarcomas 16, 36, and 60 days alter birth, respectively. One full-grown stillborn knten of the third cat had rhabdornyosarcomas in the liver and thymus. 7he tunwn in all ki//ens loasked like the original rhabdomyosarcoma from which the RD cell line was derived. Cell lines derived by tumor cell isolation from three cal lurnws consrslal o/ Iwo cytobgic typcs rraemblingthose of Ihe original lumor-polygonal cells and strap celh. One cell line was inoculated into (ctal cals. and rhd+domy- osarcomas composed of human cells formed in two ol three surviving kittens .t 1) and 47 days after birlh, respectively. Although the parcnt R!) cell kna containcd no detecubk C-type virus particks. two cat tunwrs and one cell Irne derived from one of these tumors contained C-lype virus particks of unknow• origin. McAllisler, R. M., Nelson Rees, W. A., lohnson, E. Y, Ronry, R. W. and Gardnrr, M. S. /ournol o/ the Narbnd Cancrr INIIIYrr, 17(I):60)-b11, 1971 , Other support: U. S Public Heafth Service and National Cancer Institute. From thc (kpartment of Pathology and Pediatrics, University of Sourherw California School of Medicine, Childrens Hosprtal ol l.us Ankclcs, tos Aageln, and Naval Bromcdical Research l.aboralory, University of (-ddornia. School of Public Ilealth, Oakland, Cal. IN VIVO IItiMAN HAMSIER SUMATIC ('Ell. FUSION INIII('ATEL) BY (;Ll/('OSF.6PIIUSPHAIE UL:IIYI)R(X:ENASE AN!) IA('TAtE UEFIYI)R(X:ENASE PRUF11 FS A human hunslcr hybrid, predominantly hamster hke in character and behaviur, has L.ecn produced !n riro In work «portcd hrrc, Uansplantarwrn of a human lymphorna to the check pouches of uneondnwned, adult golden hamsten 21

resultcJ in permancnlly Iransplantahk lumors which Sruw prugrc.avcly and kill their ho.ts Ihrs lunwr syslcm, (iW-17fl, has a harnsler spccdic lactate Jchydrorcnasc r.a•nryme mobility patrern and both human .rsJ ham.lcr Clu- crne 6 phusphatc JrhyJrogcnase enzyme pruliks when proprg.rtcJ in the hamster or in rnco, thus suggesting thal GW-47N u a human hamster hybrid. GalArnMrt. O. tl1, 8han, R. D and Pavia, R. A. Cancrr Rr.rorch )I(lil:l l~e-IIS2, 1971. Other aupp..rf: National Cancer Insldule and American Cancer Socicty. I rom the Ikpartments o/ PNholoRy, Temple University School of MeJrcine. PhiLJelphia, anJ University of Pittsburgh School of Medreine, Pittsburgh. ALlh.RAT1UN IN Ct:t.l. PROI.IFERATION IN MOUSE 1.UNG FOt.1.OWINO I1RF1t1ANE EXPOSURE. 11. FFFtiCtS OF ('IIRUNIC t!XPt)SURE ON 1FRMINAI. •RONCNIOLAR FPt111F1 t(1M In this sludy, an attempt was nsrk b oulline the cycle time of dividing cells in hronchrolar epdheliurw of sormal wsice and compare this w th the cycle time in hyperplasuc eprthelium of wuce chronically eaposed to urcthane. For this purpose, animals treate.l for 10 weeks wnh drinking water containing 0.1% urethane and thew controls were injected with sIl-(hymidine; wtor.diographs were made of lung hssue and mean Rrun counts of labeled nuckr in terminal hnwrchrolar cpithchum compared in the control and urethane-treated groups. In conuoh, the dechne in mean grain counts of lahekd daughter cellt between 24 houn and 4 days after '11 thymidine injection was compalrble with a manmum cell cycle hrnc of about 60 bours. In conlrast. the hypcrplasrrc hrorschrolar eprthchum of the urethane treated animals showed an ekvated labeling irs.ka and dclKKnt pruductr..n of labeled cells over the 6 day pcrKxl a judged by decline in mean grain cnunu lAese findrnRs were interpreted ss showing that the hypcrplasia and high labeling indes dNd mN rlpreunt (aster turnover or shurteneJ cycle hut reflected an increase in cell cycle Irrne or of population nenewsl time. Kauflmon. s L.. The American lournaJ of Patholory 64()):3)1-S)S, 1971. From the F)epartmcnl of Pathology, State University of New York, Downstate Medical ('enkr, Brooklyn, N Y. A1.1F:.RAi1ONS IN CEt.I. PROIIFERATION IN MOUSE LUNG FO11.OWIN(; IIREIIIANE EXPOSURE. Ill. EFFE.('IS OI' CIIRONIC I-XPOSURE ON IYPE 2 ALVEOLAR FPIIIIFLIAL ('F.t 1. In thn paper which is part of a continuing series, the auth.rr eaamines the eRect of chronic urethane esposure on proliferation of Type 2 alvcolar cpithchum in mke by rneam of autoradr)paphy. e'ontrol animals and thrise eiposeJ /or 10 weeks to urcthane in drinking water were injeclcJ with 'tl IhymrLne anJ sacrnfiaeJ at rnrrrvals ranging from 10 minutes to 7 days Mean grain aounH of lype 2 slverAar cell us the two grewps showed that the cell cyck tume ul tesl mice waa pro6mlcJ whcn compared with n esumareJ 22 hcnir cyck (or ccx+- Irols; Ihis was accompanied by  fivc(oW increasc in Lncclrn6 ux1ct in leu anim.ls. ll'ouArnrrn, S. L. 7hr Arnrricon lownuf o/ PuthulnXy htl(2):)17-)26, 1972 From the Ikpartmcnl of PNhulotY, State University of New York, Ikrwnsute Medreal ('enter, Brooklyn, N.Y. ('FI.1. ('YCLF 1)t=.PENDFNT IMMUNE I.YSIS OF MOI ONI:Y VIRl1S- 1RANSF(/RMFD I.YMPII(K'YItiS: PRFSt.N('E OF VIRAI. AN71(;I:N, ACCt:SSIBILIIY 10 ANIIBOUY, ANU COMPt'EMEN7 A('IIVAl1ON "The espression of Moloney kukcmia virus on the surface of a viral- induced lymphoma «ll, availability of the virus to anMi-vual antihody, and the nature and eslenl of activation of the compkmenl syslem durinR the cell cycle were studied iw vitro. Viral antigen was present on Ihe cell suwtace, accessible to aqtrlwwly, anJ was able to aclivale compkment in the presence of antibody throughorq all cellular growth phases, whik cytolo.icny was conflned to the (ir phase of cell growth. In addNwn, when cells were arrested in nsetaphase, virJ antigen could be demonslrated on the cell surface by immurwfluorescence, and buddmg virus was seen by electron microscppy. All nine components of com- plement were activated on the addition of antibody throughout the cell cycle. Additional esperimenls indicated that in the presen.e of ansrbvdy. C) and/or ('1 were immunospecifk.lly brwrnd to viral-induced IYmphoma ce11s throughout the cell cycle as a result of complement .clivalion. These results indicate that the inability to Iyse the cells in the presence of speci6c anti viral antibody ud complement during the loprithmic phase of cell growth is not due to the lack of ecpressron of Moloney tirus anligen(s) on Ihe cell surface, inaccessibility of this surface antigen(s) to amibody, or (ailure to activate the complement eflccror system. lernrr, R. A.. Oklstone, M. B. A. and Cooper, N. R. rroce.eins, of rhe Nationaf Acdrrny o/ Scirr.cei, U.S A. 6tl(10) 2581-25(f6, 1971. Other aupporl: U. S. Public Flealth Service, National Multiple Sckrosis Sucicty, and U. S. Atomic I:nerp C'ommission. From the Ikpartment of E.perimental Pathology. Scripps Chnic asd Research F--uundalron, I.a lolla, C'.I. 1?Ci1MA7lON QF ('EI.1- NUC'LEI ('UT AT lHF SIIRPACf: OF 71SSUE SEC. t IONS rH thymiJrne is often used to estimate the rcplKitrvc potenwl of a cell population, measurcd as percentiac IahckJ nuclei in sururadwrgraphs Several diltKOllres, howevcr, prevcnl the absolute quanutatiun u( incorporated pre- cursors fruns sutoraJrographs of thick scclMns (1) triuum crours weak (t psrlr.ks with IimilcJ path kngth and is thus nKVsl susceprd~le to sel/-al.urrprwn; (2) any ddlcrences in the Jry mau per unq area will affect the nature of ncc Jar• when grain c.n.n1 compaursuns are to be made among Jdtercul crll typc., since the sel( absorption coeflkient increases with rncreascJ Jry mass, dccreas 22 21

ing the autorsdiographic efficiency; ()) when ouckar diameters vary among the ccll populalrnns of diflerent tisaue sections under comparison; in a thick aectiexr, the probabdity that the large diameter nuckr will fall within the tril.um- uWoradrographic range is greater than that fcw small diameter nuclcl, possibly d.stor,mA results A simple method is dexrrbed lor estimatinA the numhcr of euckr rn a tisuut scction which sre cut and eaposed at one of the section surfaccs. TAese can be easily eakulated when section thickness and nuclear diameter are known The method 'n most useful when percentage nuclei labeled by trituted prccurson are to be compared among various cell populs- ticwr with diflerint nuclear diameters. Modak, S. P.. I ever, W. E. and UppuAur(, V. R. R. (1-eucArenbrrter, C.) Erpcrlmrws.f Crff Rru.rcA 70(2):IAS-Kfl, 1972. Other arpperfr Swisa National Fouodatiow .nd U. S. Atomic Energy Corn- minins. From the Department of Cy1oclewristry, Swis Institute for Esperimenul Cascer Research, IAwa..e, Swilaerlaad. MYELOID I-EUKEMIA IN 7?IE RAeB1T (ORYCTOLAGUS CUNICULUS) TTThis is the Arsl de+eriplion of a case of myebid leukemia in thc rabbit, a henulopoiNie neoplasm never hereto(ore rrported ia this animal. This particular case occurred ia a I).S-monthold slrsi. lll,p msk and iu fealures were dis- 1inAuuhabk from hereditary lymplrourcama by cell lype, organ im•olvement, and distribution of tumors. The investiAslors are proceedinA with genetic studin rn a. attempt to identify the Acnc(s) conferring susceptibility to mycloid kukemia, and to determine whether an oncogenic (RNA viral) genome is Involved. Mekr, ll., Fo., R. R. and Crary. D. D. Cawrrr Rru.rcA )2(6).17d3-17[7, 1972. Olhrr.rppert: National 1nalNutesof Healt)t. From the lacksoe l.aboratory, Bu Harbor, Me. RNA TUMOR-VIRUS ANTIGEN EXPRESSION IN CHEMICAI_LY INDUCED TUMORS. VIRUS~'iENOME-SPE.CIFIED COMMON ANTIGENS DETECTEI) BY COMPLEMENT FIXATION IN AIOUSE TUMORS INDUCED BY )-METHYLCHOIUN"THRENE Tl+is report describes the lumor-inducing talects of a single 150 rg dox of )-methykholanthrene (MCA) given subculaneously to weanling rnice of 12 inbred and four noninbred atrsins. All mice of the 16 slrains were uealed at four weeks of aAe. Mice wert essmined weekly for eight months for tumors at the injection site and for other neoplurns. The MCA-induced tumors, which were nearly all subcutaneous sarcomas of mesenchymal origin, contained com- pkmcm Asing antigens reactive with rat anteer. sekcted lor high titcrcd re- acticxts to the gruup apccifk (gs) antigens of the (' type RNA twnor virus. Since mxmal nxsciKhymal tissues (musck and subcutaneoua) did not reveal p I antigcn, the concurrent aclivalion, or derepresaion of phenotyprc eeprevion of viral or viral-rcl.ted antigens in many of the tumors, suggests that oncogencs of ('-type RNA virus genomes have served ss specrfic determinants of the in. duced cancers Bccause other studies ahowed that the virogenea and oncogenes ol the C-type RNA viral genome are vertically transmitted as repressed genomes, probably as a parl ol natural Aene rnheriunce, it is hypcwhesired that the carcinogenic scti(us of MCA is achieved by directly or indirectly derrpressins the endugenous RNA tumor virus oncogenes that must be in all mouse cclls. Whitmire. C. E.- Sakrno, R. A., Rabetein, L. S., Huebner, R 1. and Turner, H. C. (Mirrobiologkd Arrociarn. Inc.) Journal o/ rAr National Cencer Instlrrrrr d7(6):1211-1265, 1971. OtAer supportr U. S. Public Health Service. From the Department of Viral Chemical Oncobty, MicrobiobAical Asaociates, Inc., and the Vird CascirroAencsis Branch, National Cancer Inuitute, Natio.d Inslilutes of Ilcallh, Bethesda, Md. ACTIVATION AND ISOLATION OF HAMSTFR-SPECIFIC C-TYPE RNA VIRUSES FROM TUMORS INDUCED BY CELL ('1/1.TURFS TRANSFORMED BY C19EMICAL CARCINOGENS This paper presents evidence that Ahe 1alent or rep.esaed hamster-epeclAc kukemia virus (IIa1.V) reswme may be widely disseminated in hamster colonieu, but can be activated and isolated only under certain conditions. Cell eultures of Syrian hamster embryo were treated (or seven days with 0.1 pA/mI of 1he chemical carcinogen )-melhykholawlhrene, or wi/h 0.1 or 1.0 pS/m/ of cert.in fractions of cigare(te-smoke condensate dissolved in acetorse and diluted i. Fslk's Minimal Fssential Medium with 10% fNal-calf serum. After the initial 7day treatment, the chemicala were renaved permanently and the culturts were subdivided as needed. Cell cultures transformed by methykholsn(hrene or by ciAsrelte-amoke (raclions 6•nd 9 produced malrAnaM tumon at the siN of inoculation after 1)-110 days. New cell lirses were established /rom repre- sentative tumors. Although the cell lines were negative (or infectious virus before inoculalion into animals, hamsler-spccifk C-type RNA virus was isolated from lumors or from cep lines derived from Ihe tumors. Since inlectioua C-type viruses are usually no( demonstrable in hamster tissuea of normal or tumor o.rgin, it was concluded that the chemical Ireatmenl and activatiow of the viruses are related events. Frceman, A. E., Ke11oR, (:. 1., (3ilden, R. V., I.sne, W. l'., Swain, A. P. aed Huebner. R. 1. (1Nkrobloloeird AssoriorrrA fnc ) r.ocrreintr oJ rAe Norlonul Aralemy o/ Sclrncr., (/ S A. 6E(10).?)e6 2)90, 1-I71. • OtArr supp..rl: National ln.litutes of Hedth. !'vurn Microbiological Associates. Inc , and nce NatKmal ('.nccr Inuiruu- Bclhesda, Md . flOw I ahoralnrKs, Inc , Rockvllk- MJ , and I a+rcrn Marlcdnll and Nutrhional Research Urvrsion, Agrrcultural Research Scrvrce, 11 S 1) A, Philadclphia. 24 25

RNA 111MOR VIRUS Rr ANTIGF.N AND TUMOR INf)UC1ION BY VARIOIIS /K)St S(1F ) MI:.111Y1 ('1I(N.ANl1IRF.N1' IN VARIOUS SIRAINS 01: MI('E 1RFA1F:1) AS WIiAN1.INGS It has been wRRcstcJ that chemical carcinogens induce tunwrs by direct or indirect Jereprcuron of endogenous oncogenic informaticsn pruvrlcJ by in- hcnlyd, largely covert. (' lype RNA tumor viral Senrxnes postulated to be prexnt in all vertebrate cells. In thest sludies the dlect of various d4nes of 1 methykholanthrcnc on suhcutanccxn tumor induction and the occurrence of the murrnc ('-type RNA group specifk (fr) viral antigcn in tumor tissuet were eumincJ in weanling mice of ti genolypically diRercat suains. Tumor incidence anJ latency, and the occurrence of Br antiBert in the resulting lumors were compared to show the relationship o( these rnponses to varying doses of the urcinogen nJ the natural espreuiow of the C-type RNA tumur virus Lenome of the dillerent niouse strains. Tumor iecidence was related to the ckne of ) mcthytchcslanthrcne, hut tr antigen was indepcnJcnt of the dosage •nd refkctcJ ns natural e.presuon in this mouse strain. Itntopathuk>eical csamina- tMrn showed no rrtatrrn of luwsd type to c.rcrnogrn dosage or atrain The marrrity of the tumors studrcd were urcornas. TAcse results confirm carher oncs which sugcsreJ that the gr antiges e.pression induced in tumors is de- pcndcnt on hrxt regulatory controls and that such controls of virotene (tr) antigen and oncogene Itumor Induction) espressions of C-type RNA viral gcnome are irdepcndcmly affected by  c.reinogen. Whrtmire, C. E and Sakrno, R A(MkroAiolorical Aiioclarrs, lnr.) ('ar.rrr RruucA 12(6) t t 29-11)2, 1972. Other support: National Cancer Institute and ll. S Public Health Service. 1'rom the Ikpartnunt of Viral<-hemical Oncology. Mrcrol.iological Associates. Inc . BethcsJa, Md INIIIBITION OF CIIFMICAL ('AR('IN(X;FNI:tiIS BY VIRA1. VA(( INIS The demonstratcd high prevaknce of ttoup specific antigen espression of the type C RNA munne leukemia viral genome in chemically induced tumors in mice supports the concept that endogenous RNA virus depression or activa- tion provides a significant detertninaM of ehemicalty induced cancer. The feasibility of inhiAaing chemical carcinorneaia by vaccines prepared from these viruses was studied in two genotypicslly different mouse strains. Mice were vaccinated at 4 weets of age with a single inpction of formalin inactivated virus combined with Freund's complete adjuvant nd challenged suhcut.ne- ocnly with 150 rs ) methykholanlhrene at 0 weeks of age. The mi;e were observed for whculaneous tumors at the sile of inoculation for a period of S nvonths. Rauscher leukemia virus vaccine reduced the incidence of ) mcthyl- choianthrene-induced subcutaneous sarcomas from 78% to SOrA% in the BAIB/ c('r mouse IP < OS). lwo inactivated vaccines prepared /rom raJratton kukemia vrrus and a wild murine leukemia virus derivcd from a) mcthyl- cholamhrene tumor reduced the incidence of sarcomas from 96% to )) and 17'f,, respcctivrly, in the ('5781 /6 mrwse (P <(X)I and P. 01. re- spectively) Iheu rcductions in tumor incidence by virus vaccines hclp supluul the conccpl that typc C RNA viruses servo as delcrminants of chemicaliy inJrccJ cancer. AJJitiunal slrKares ul wch viral vaccincs in thc arc.tnscnl and prcvcnuun of canccr arc uccess.ry. Whitrnire, (' F: and 1luchnrr- R. 1. IMic.o6iuluKicul Arrorrurrs, Inc.) .Icirru r 177.60 61. luly 7, 1972 Orlrrr sup/srrrt: ll. S Public Health Scrvice (National ('ancer Intutute). From the Department of Vual (-hemical Oncology. Microbiologrcal Associates, Inc, and the Vual ('arcinoLenc+n Branch, National Cancer Insutute, National ImUtutet of Fiealth, Bcthcsda, Md. INIIIBITION OF ('NEMI('A1. CAR('IN(X;ENN1tS BY VIRA1. VACCINES l:.otenous interferon inTrbitcd the )-melhykholantnrene ()-MC) induction of suhcutancous fihrosarcurnas and of lung adenomas in ('F-I mice. None of the 26 anrmah treated wnit interferon developed multiple lung adcnomas. whereas M out of 1I1 ue.tcJ with pMnphate huAered sahne (PBS) developed the (bmors. 1 hc inci.knce or tnre of rr antigen dctccted in aplccns by the complement ff.;rtion test 1 final lissue Jdutwns of 1:20 to 1.140 JMl not differ in the treated and untreated groups. Although the mode of action through which interferon prevents chemical eareinorenesis is unknown, the authors feel that the following mechanisms of anliviral and/or cellular eflects of interlerow nwra be conswlercd: (1) inhibition of the growth and multiplication of both tumor anJ normal cells; 1_s) nonspecifie enhanfement of macrophaffie activity and lymphoeyte cytdo.icNy and/or (3) viral snhibition of a postulaleJ vital inlermeJiale, such as the endogenous oncogenic type C RNA virus, that may be responsibk /or chemical tumor induction. Sakrno, R. A., Whitmire,`C. E., Garcia, 1. M. and Iluehner. R. 1. IMicro- hiuluKit ul Auoriorrs, lnc.) Naturr New Brology 2)9(tlR):)1-)2, 1972. Otber support: ll. S. Public llealth Servict (National Cancer Institute). From the Ikpartment of Viral Chemical OneoloRy, Microbiological Associales, Ine., and the Vrral ('arcinotenesis Branch, National ('ancer Intbtule, Natio.al Inslawtes of Heallh, Bethesda, Md. SUS('FP1111l1.11-Y OF ('IIROMOSOMIS FROM PAIIENrS Willi I)l)WNS SYNDROME 10 7,12-DIMtiIHYl.BtvNZ(a)ANIIIRAClN13- INI)U('ka) ABI:RRAIIONS IN Y/IRO TTe chromosomes of patients with Down's syndrome are signiM1camly nuuc suscepubk in vitro to damage by UMBA; this increased susccptrbddy n not Jue to a deficrency in ability to repair DNA damage. In this uudy, the elfcals ol 1)MIIA on the chroaxnomes of seven patients with Iko.vn's syndrome and ten healthy volunteers were sludreJ. ('hromatwl gaps or hrca\s compnad the vast maNsrny of ahcrrations proJuceJ in the chromrnrxnes of both group. Snull rwmhcrs uf IlnChr(Mlalld eschantes and Jaemrrc chrunrrsa.mes were alsu ohs.rveJ. Ihc lymphocytes of patients with 1)uwn's syndronse were no/ Jcficicnt in thcu bihry to rcpair DNA damage Induced by uluavic>act light or 4 mUUyuuKrline N oxK)e anJ, at the Joscs used to produce chromuw.nul shcr- rations, 1)MIfA JiJ not significantly inhibit either repbcauve I)NA synthesis 26 27

or the repair of JamaRe induced by ultraviokl (ight or 4 nitroquinc(ine N naide in n.amal lymphucytes or in Ihose from patients with 1)own's syndrome. OMHA did aN srrmulate unscheduled DNA synthesis in the lymorocytcs from patients with t)trwn's tyndrorne or from normal controls. O'Bricn. R l. , Poon, P, Kline. E. and PrAec, 1. W Invrna-hond lou.na/ o! ('ancer (42) 202-210, 1971 Other support: lohn A Ilarllord Foundation. Professional Staf' Association of the I os AnRAcs ('rarnty-llnivenity of Southern California Mrdical Cenler, and (1 S Public Health Service. Front the 1)epartment of Patholoq. Uwivenity of Southern Cslilorni^ School of Mcdicrne, I.os Angcks. DNA RFPAIR 1:O1 1 OWINO EXPOSURE OF li(1MAN LYN PIi(X'Y1IS lO 4 NIIRO(jUINO( INE-I OXIDP. lhe ca-clnolen, 4 -nlroQuinoline loside (4NQO) is tnown to induce unscheduled DNA synthesis when admia'rstered to a variety of mammalian cells, including human lymphocytes. The demonatntion of unscheduled DNA synthesis in a cellular system, however, does not prove that suclt a system is under`orng DNA repair. It is raecewry, to show that, at the time of the un- schedukd tynthetis, -eplrcative DNA synthesis is not oecurring, or that incor- porstion is taking place in DNA which is not undergoing rephca'ive synthesis. Such evidence can he obtained by demonstrating (1) unschedukd DNA syn- the%n in the presencc of a-nown rnhrMtor of rep(rcative synthesis such ^a hyJroayures 111111 or (2) urcorporatson into DNA known to have been previ- ou%ly rcplresred and whKh as not in S phase lAu paper repocts the results of such eaperunicros, usrng freshly obtaHxd human lymphocytes from venoua blood DNA danutc is produced with IN(x) and ultraviolet radiation (l1V). and DNA repair is dcnNMn/sted That study confirm the conclusion reached by others that 4N(jO inducn unschedukd DNA synthesis in human cells, and it shows that this is a function of both the concentration used and of time. In addition, the authors provide strong evidence to support the hypnthesn that it is indeed repair DNA synthesis which follows the administration of 4NQO to mammalian cells. lacol.s, A. /.O'Brxn, R L. Prlc-, 1. W. and Paolilli, P. InrernrorJomal lournal of Crscn 10:1 1 t1-127, 1972. Other srpport: John A. Hartford Foundation, Mary R. Wright Estate and U S Public Flcdlh Servioe. From the lkpulmenl of Patholop. University of Southern California School of Medicine. I.os Antek1. INFI UFNU DFGI I ORMONI OVARICI NFLI.A CAN('FRO(:FNF-SI P(11 MONARf? l)A II)RA7INA SOLFATO IN TOPI C)I+h/('b/Sc The (')llh/('b/tie mice used here have a bw inciJence of prJmonary tunurrs (p r) 111a11y admrnnlratron of hydra:ine aulphale (h a) at a dose rste Of 11 m( r• r.-r.l .1 I)It mg- rncres-cJ the utirJersce of pt's, and their --1-cr IK-,,..r as L.IS...r inra. r vugrn maks :h'1L and 1, (cnules 48% 21 and ); gonadcctomiteJ maks 4% and 1, females 19% and ?; breeders )91i and ); forced breeders 1S% and ); pseudopregnsnts 44% and 4 Flrstobgrcally, the p t's inJuced by Is a. in intact vi-gin and gonsdeclomiied mice were 93% adcnomss and 7% carcinomas; in breeders, forced breeders and pscurbpre[- nanls the percentages were 68% and 32%. 7he higher incidcnce of Is a-induced p t.'s and the increased number of p 1.'s per female mouse in comparison to that of males, and the greater morphological malignancy of these tumors is breedtrs, forced breeden and pseudopregnants in comparison to intact viriie and gonadcctomired mice, conf(rms the implication of ovarian hormones in Is s.-induced pulmonary Oumwigenesis in p t.-resnunl CG11b/('b/Se mice. Biancifiori, C. (Srvcrl, L.) "v. Anor. Pat. Perrgia ] 1(1):5-17, 1971. Other support: Anna Fuller Fund. From the Divuion of Cancer Research, Univertity of PeruRia, Italy. TRAPIAKII ISOOENICI IN OSPITI ADULTI E NEONAT7 DI TUMORI POLMONARI tNDOTiI CON IDRAZINA SOLFATO IN TOPI BALB/c/Cb/Se: STUDIO ULTRASIRUTTURAI.E The flnl 22 transplant generations of • lung tumor induced by hydrasiae sulphale in a BAI.B/c/Cb/Se mouse and Iransplanted in newborn and adult syngeneic hosls, have been studied in the ekctron microscope. As peviously reported for the primary tumon, the transplanted neoplaslic cells conacrvod all the features of the normal alveolar type B cells from which the tumor originaled. Of the three types of viral particks obaerved in the primary lumors. that is tubular, intracislernal A. and C. the tubular particka dis^ppcared and the intrscisternal A particles were considerably neduced in number whik thcre was an increase of C particks, particularly in the transplants carried out in newborn hosu. C particles have also been observed in a lung meNSslaan of a mouse with a transplanted tumor. No virus was seen in the normal lung liwr. lhese data confirm the derivation of rrwuse lung lumora from type IN alveolar cells and suggest that the neoplastie transformation of these cella and their transplanlation in newborn hosts may provide favocatrle conditiosu for C particle replication. It has not. however, been possible to establish ^ny eliololti- cal relationahip between the C particles and the lung tunwn. Bueeiarelli, E. (Severl, L.) Lar. Anar. Pat. Prrsitla 31(1):19-31, 1971. From the Division of Cancer Research, l)nivenity of Puugia, Italy. SENSIBILITA Al. METI(`OLAIJTRFNE DEG(.1 EPITEI I UIiU.'AI.BERO RESPIRATORIO IN T'OP1 BALB/uCb/Se The acnsirivity to merhykholsnthrene (MC) of bruncMolo alvevrlar and Irachco brunchul cpitheb• has been investigated in MAI B/c/('h/Se mK• Fragmenls of lung tissuc, large bronchi and trachea were unprcgnarcd with M(' ^lone or miacd to talc sterdc powder in the conccnuations u( 1/10 and 1/1(Ml. The impregnaleJ fragments were then uansldantcd into the subcuuue- 29 I

uJcnuaras, uus lat pads of synKcncic h.nh MC causeJ the Jc.clupnscnl of arypical adcnomas, nr malr6nant "aderK+mas" Irorn hrurKhwln alvculJr cprehcha and pr„liferat+om, atyprcal prnh(ctaUOns with squamrHrs nh•IJpla.rJ. ur syuam- out mclaplasiu. m sl(uJnMN/s ccll carcinomas front Ira.hcu hronwh+al cpuhcl+a 1 he frcyueniy rd vansplants slww+ne hronchwdo alvcrdar aJcrn+nus or tuchco- hronch+al tunKUs aftcr treatment with decreasing conccntratruns ut M(' was as lallows M(• al.+nc; aJcnomas 40%, lumors 9(1'T, ; MC in tak pnwJcr 1/ 10; aoknr+mat S1'X,, tunK.rs 7A'x; MC in tak puwJcr 1/I(K); adcnumas 64'X,, wnr+rs 14% It is concludcJ that the sensitivity W MC of hron.hurk+ alvcolar epdheha is mrxh h+Rhcr than that of trachco-brorKhiJl epithelia lluwcvrr, the laUer are not rclractury tu the carcinorn as can he sccn by the alnus.t consunl tumor growth after rmprcgnation wilh MC ufune. tiquartmi. F and B.drs, O B. (Srvrrl, L ) l av. Ana( Pat Prrurro )tll):)3-36, 1911. 1 rom the Ihvruon of ('anccr Research, Ilwivenity of Pcrugia. Italy 1l1MORI POI MONARI E MAMMARI DA IDRAZINA SOI FA 10 IN IUPI HAI.B/c/('b/Sc GFSTANTI FORZAIE E PSEU! iRAVIDE 1)sc incidcnce of pulmonary tunwrs (p t) in BAl.B/c mice was 20% in Forced hretden and d% in pseuakrpregnanls; the number of lumors per mouse was I and I. Flntologically att lumots were aJcnomas FlyJrarnre sulphate (h s) raised the p t incrdencc to 96% in forced brecden and to 95 ;. in pscudopregnams, rhe number of tumors per mouse was 10 and 1'_ 1lntulugi- cally, in the fnrccd hrecdcrt, 57% were adcrnxnas and 1)% carcuw,+as, whdsl in [ht pseudoprcgnnts the percentates were 60% and 40% Ihcsc results confirm the influence of endotcnorn ovarian slimulation in h s mJrKCJ lung carcinogenesrs in n+re Mammary lumon were rot ohs(rvcd in the cunuols nor in the h s treated p+euJoprcgnants but h s irxhKCd these in )8% ol the forced btecdcrs. lhe Mstolollrcal piclurc was of urctular tubular, puly6onal solid and papillary cystic carcinomas. lhe induction of mammary tunwrs in the h s.-Ireatcd forced breeden may be related to the horrsxsnal /actur anJ to kngth of time the carcinogen remains in the ducts. Biancifiori, C. (Srvnl, L.) lav. Arw. P.t. Prrurl. )I()):79-90, 1971. From the l)ivision of Cancer Research. l)nivenily of PeruRia, Ilaly. PRI:SFNZA 1)1 AN11(iENI GRUPPO-SPF('IFI('1 I)F111i PAR11('111E C NFI LA FASI'. LIO(IIUA L)1 Tl1MOkI AS('(Ili Dla. 1O1'O ImmunoJ+Rrnion slrxlics for the prtsencc of typc (' partick grrarp specific antrRcn% were cauried out on the IwuiJ component of ascdts tunwrs on the Srh, 1(Nh arsJ 1 Sth day allcr grafting 1 wo lines of a..uca 141111.,11 wcre u.cJ, A11'(' I anJ I hrlKh, anJ }wrth originated in a spunrancuu% mo++.e m.+mmary a~rcrm rna In ncC h#4u+J pha.c ol twNh lumurs the `ruulr v(w'adK' rnt+Ra'ns aplwar early, arc evident un the Sth day altcr IrJnsplJnlJtw+n a+ul havc a IcnJrn. y In ur rrat Jur+ng the I.d-+n1 JJy% Numctuui curnldc,c tylh• (' +hwh .rt fa.rhwtJ by nce na-pla.r+. acll., arc .uNa+nrJ +n Ihc a.citcs hyruJ Anli ccllular anl+h.-dics wcrc alsu .IcmunslrrtcJ in the sscnes I+ymJ, hut rus amr gnwrp sp.a/ic anl+gcn anhhuJres wcrc uh.erveJ Ihn fact sugcesls that the moux rs cumplcttly u>ferant to Ihc +c.urKl antigen krhxchi, R (.Srvrni, L.) I rrv. Anut. Put. Prrugla )1O1.91-102, 1971. I-rom the 1)ivrsion of ('ancer Reuarch, University ol Perugia, Iuly. ('AYPE PAk I1CLFS IN PRIMARY ANI) TRANSPl.AN7 F.l) 1 l1N(i 11IM1)RS INI)U('ED CN BALB/c MICE BY 11YDRAIINE Slll FAIt:: L.I.F('IRON MICROS('OPIC ANI) IMMUNODIFFUSION SIUbIFS 1)espde cstensivic ekctrurs microscopic uuJies, oncogenic vuuscs have rarely bccn obscrveJ in sponlancous or chemically induced mouse lung tumws. Is a previous ckctton microscopic invesugatias. the authors noted vwus par. 4cks nf thc type asuwuteJ with rmMnc kuRcmi: in a number o( tumors trwloccJ by hydraiine sullate in BA) B/c mice. lhut, in view of the possible activation of an RNA onculIenic vuus by chcmrcal carcinugcns in a system othcr than the lympFwrcucular Irssucs, in which such a phesxxnenon has alreaJy been well Jocumented, this observation prompted them to /urthcr invcsugare the drs(rrbution anJ origin of Iheu p.r,rcles in primary lung tumors inJuced in BALB/c micc by hydrazrne sulfate, transplants of ,hese tumors in newborn and adult syntcneic Mnls taken between dsc first and Iwcnty-/oursh transplanl gcneratiuns. and samples of normal tissue from lumur bearing mrct '1 hcse were studied in the ekcvon microscope lor the presence of virus particks; immunodrRusion studies for the' presence of type C group specJk viral antrtcns were done on both transplanted tumors and on normal Insucs of the sarne mrct. 1 he rseuplastic cells of Ihe primary and Iransplanlcd luwwrs retaineJ the typical suuctore of Ihe ccli of o.ipn, the lypc-B alveolar cell Cylindrrcal, lype-(', and rntracisternal A virus earucks were observcd. ('ylrndrr- cal particks were scen only in the primary tumors and. characlersaically, originated from Jark, rramJar, cyst like areas of the neoplastic cells C par- Iicks budded from thc neuplaslic cclls or were secn in 1he in(erccllular spaces in )Srb of primary lumurs, 62 5% of transplanlcd (utnors in newborn micc, and 31% of those Iran+planted into adults lnlracas(ernal A parlrcks wtrt secn in the neoplastic cells of M11'X of the primary lumors, ?Scx% of the /urrsas transplanted into newborns, and in 12.5% of thost grafted into adul(s. In 63 6% of the normal lung tissuc aampks, only intracistcrnal A particks wuc observed. lype.C, trnup-spccific viral antillens were demonstrated by im munoJdltnrors in the tramplanteJ lumon hul not in the normal o.eans uf tunx+r bcarrng mrce. Ihcst Jata sugtesl a poss+blc acuvatK+n uf type(' virus pu6cks in typc-B alvcular cclls by  chemrcal carc+nogtn Oucccuclli, 1: . and R+hacchr. R, (.Crvrri, L L luuw,d rr/ the Narronrd ('uncrr hnrnrutc 19()) 671 678, 1972 I rcxn Ihc Ihv+suun of ('aoacr Rcscarch, l/mversity ol Perugu. lraly NI (Ik(ril ( RP.IOkY APPI AkIN(i ('11 I S(/F /1(IMAN SI (.MI NI AI HR(IN('III llndcr the clcctrun rui.rasuq.', human nu+cosJl cclls Irum the segmental )I 1q

bronchi of aJul,s appcu to he neurouvesory 1 hey have a low cytoptasmic density and cunrirn snull, dense• rncmbranc txwndcd granules l:rAdct cells containing identical cytoplasmic granules are also sccn in the hronchul mucota. 7 he ryrrsrhk ruk of nrurosecrctory type cells in she gersesrs of bronchial carcirsc»J tumors and oat cell carcinomas is recornireJ, as well as their lunclion as chcmoreceptors and in the secretion of peprrdcs and amuses. lhe « lls described in this rcport may serve as a primary or accessory sourcc of goblet cells under ordinary or unusual condiliona, such ^s various disease stutes. If the ncurote•crerory type cells are iwdeed invotved in the genesis of carcinoid tumors and oat cell carcinomu. Aowever, rssosl of the bronchial ,rce can then be considcred a potential site of oriRin. IFrve additional newly-observed bronchial alteratMMs were preaeMCd by M. Marprct (.ont at the Intcrnatiunal Flistochemntry, meeting at Kydo. These are: darhk-layered sur(acc nsucus and two layered mucus droplets in cpithclium, abundance of intrxpuhelul mast ulls. Irpochrome deposits and cytoplasmrc PAS stained oagarsciks of urwktcr- mined type in cduted cells ) Terzakis, l. A, Sornn,rrr, S. C. and Audensotb B. liborNory lwrnrlrallon 26(1):127-1)2, 1972. From the (kpartmcot of Patho{ogy, t<noa Hill llospital, New York. THE EMFRGIN(i (]FiNETICS OF RNA TUMOR VIRl1SFS Recent work in the vird fktd has uncovered much informaliao necessary to sct the state for agenctic andysrs of RNA tumor viruses. Conditional kthd mutrants of avian sarcoma viruaca have been isolated and characterized physK>Io2icr,IFy, rarul several types of nonconditional mutants have been de- t+crrbed, the ease with which RNA tumor virus mutants can oe obtaincd suggests that there will noon be eoough of them to allow eshau_tive genetic studies. This edrtorid considcn the likely ramifkralions of RNA tumor virus genetres and formulates speci8c Aypahr~es which are testabk and thus may be proved or refuted. The characteristic features of inheritance among RNA tumor viruses most be diclated by the structural peculiarities of the viral ferwrne, its possible interaction with the cell, and its replication and assembly into progeny vituscs. The •vat genome is probably the 70% RNA estractable (rom purified virrons, though genelic contributions from the 7S component have not been -uicd out. The 70S molecule does not seem to have a contrnuous sugar phosphate backbone but ^ppean to consist of )SS subunits hnkcd to- gcthcr by hyJrotcn bonds. One 70S mokcuk may contain 1-1 tuch subunits this segmemation of the viral gcrso+ne must have important genetic conse- quences and serves as a-ey assumption in the three hypwhcscs presented in this paper. VnIr. r. K. lournat of the Nnnund ( oncrr hurUurr 411(1),3 9, 1972 0l/srr ruplrurt: Nalurnal (lnccr Instilute froro the I~cpArrnrcnr ul MKrohnrlugy• lJaavcrsuy of Suuncern California $ hrM l of A1cJ-ni• 1 irs Angclcs GFNFIlCA1.I.Y STABI E REASSURTaSENT OF MARKERS DUR1NO MIXFU INFf:C{ilON WITN AVIAN TUMOR VIRUSES In this ^vran viral uudy, helper-independent Rout sarcoma virus (RSV) and avian leukosis virus, both characterized by a different hosl range, were allowed to interact durinC mised infection of chick embryo fibroblasls. Several cultures of type CIU chicken embryo fibroblasts were infected at a multiplicity of about I with PR RSV of subgroup A and one of the following kukoais viruses RAV-2 (subgroup B), NT-877 (subgroup C). RAV-7 (subgroup C)• or ('arr 71fber associated virus (CZAV. subgroup D). Alter eight days and thrne lranders at 2-day interv-is the cells were compkrely translormcd, and culture fluids containing high titcrs of virus were harvested. Focus rruays were carried out according to uandard procedures Results of these esperirnents demw- atralcd she presence of pcoseny sarcoma virus with an espanJcd host range as compared to the parenu6 PR RSV-A. Espcriments were designed ^ho to test r progcny of mrsal infections for the preaence of genetically atable viruw w~ich combined the cclt-transforming ability of PR RSV-A with the charac- Ieristic host range of the kukosis virus that had participated in the swiaed infection. The eaperirnents described here indicate that miaed infectiorr with certain pairs of RSV ranC avian kukosis viruses give rise to stable combiwlion forms which carry the host range marker of the lcukosis virus and the Iranra- Iormalion marker if RSV. Formally Ihew agents may be regarded as either avian kukosis viruses which have acquired the ability to transform or as RSV which has eRchanged its bosl range marker for that of a kukoaia virsu. llsr evidence for genetic recombioatiow is promising but still quite preliminary. Yogr, P. K. Viroloty 460) 917-932, )971. . From the Department of Microbiology. Univenity of Washington School of Medreine. Seattle. 111. Cardiovascular System THE RENA1. CIRCULATION This review of renal physiology is mainly conccrned with she Intrarenal distribution of blood fluw, the physiological conseqocnces of changes ira din- tnbution of flow, and the vascsdar anatomy of the -idney. 11+e authors atrer that measurement of total organ blood flow is insuflicient to aascas overall functional stale of the diseased kwlney; distribution of blood flow within the -rdney must ^Iso be dctermined the authors discuss she varqus melhods currently available for the meawremcm of renal blood flow drsrnbution in man, and suRaest that much remains to he esplored in basic renal physiology; and they Jcscrihe the results of renal vascular anaromy studies in Jogs. then apply the general pattern to man in whom it appcars to he srmdar they cwxluJe that the rich adrencrgic and clwlrncrpc innervarrrn Of the renal vessels, and thcrr responsrvcncss to ncurollcnK stimulation. suggest that the aurwwmuc ncrvorn system has an mrlrrrtant role in the rckulauan of flow drstnburasn; humoral factors. however, such as anrKrtcnsin• antuLureuc hormurse, aJrcnal ttcroidt, ^rx! orhers, m.ry Aw be mrpurlaut in rcgularint rmrarenal hkiod itow )) 32

in Ixallh and Arxvx .nJ rncrcatrng knowledge of Ihesc mjy k.J to rmprovcJ therapy uf rrnrl JiutrJcrs Burgrr. A(- arK1 /IcrJ, I A. New 1;nKfunJ bwrn,d u/ MrJrrrnr 284: 4Il?-490, 1971 OtArr .upp..rr: U S Puhlrc Iftallh Service. From the Ikpartmenl of Physiobgy, Har.ard Medkal School, Boston h!'.CRFAtiI l) SYS1OI IC 81 (XN) PRESSURE 111ROt/G11 l)PI.RANf (-ONI)I1IONIN(i 1F('IINI(jUES IN PATIENIS W1111 I-SSfN1IAl- FIYPF R TENSION lhis report describn the use of operant conditioninp feedback techniques to bwtr systolrc blood pres.ure in stve• patients with modcrale or severe hypcrlension, All were .mbula(ory, ssad had an average age of 47 9 yeara. Mtanrngful dccressts in systolic blood pressute, rangtng from 16 14 mm of rnercury, were obtained in five of the palienls- According to the authixs, Mtw. ever, the thcrapculrc valuc of such kchniques still remairo to be established. Benson, 11 , Sy+aprro, I) , Tursly, B. a.d Schw.rtz, O. E. (BnrRcr, A. (-.) Scirrw. 17) ()')9d) 740-742, 1971. Other .rpport: National Institutes of llealth, IloRmann-1A Roche Inc ,nd (Mice of Naval Rtx.rch I rom the Hsrvard Medical 11ni1, Boeton CNy Ilospital, Dcpartmcnl of Mcdi- crne, and Mauachusetts Mental Fleallh ('enter, /larvard Mcdreal School. Boston. CARUTAC OUTPUT At REST IN iFIE SQUIRRF:L MONKEY: R01 E OF P AI)R: NER(i1C ACIIVIIY Receol stuJres have shown that in the squirrel monkey, persistent elevation of mean systemic arterial blood pressure can be induced by schedule-conlrolled behavior and while the cardiovascular mechanisms underlying such hypertension are slill unckar. these inveslijaton fell thal because adrencrgic infl-rences have been implrcated in o(her welltharacteriztd slaln of ekvaled arterial pressure, additional in/ormatwn on the dependence of the normal cardiovascular function of this animal on adrenergic activity would be useful in the characlcritation of behavioral hypcrlension, Consequently. they measured resting carJuc outpul, hlood pressure and heart rate, nd their dependence on fl-adrenergic tone, io the untralneJ, unaneslhelited squirrel nsonkey. lhe resting cardiac output was 319 t 61 (SI)) ml/min, and the resting heart rate was 2A) ± 4) (Sh) twats/ min; treatment with propranolol hydrochloride (201-) 0 mg/kg, im) decrenstd cardiac output and heatl rale, hut not mean systemic arterial pressure. lAe nuarm.l effect of proprarwbl observed aller doscs of 1 0 or ) (1 nrg/kg was a 2S'X. .kcrease in catduc output and heart rate; mcan syslcmtc artctial preysure anJ n.can rrght .uul pressure were rxM changed srgmficantly; cakulatcJ stroke vulumc remnncd conslant, whereas calculated total perqdrer.l re~nlan.e was marleJly incrc..cJ Ihcy cnnclude that 1ladrenerrrc rctivrty pl.rys  malur rolc rn the Jclcrnnnahirn of res/ing urJrac cwtput .rnJ heart rut: in the un. .nr+rhrlurJ tyrrrrcl ni"nkcy 1)rarcn, 1 M, unJ I IcrJ, 1. A. (B,oKrr, A. (- ) Ararrirun luurn,J n/ Phytirdupy 2??1419N8-99), 1972 Oth.r.upp.rrt: (1 S. Puhlk llealth Scrvrcc. hr.Nn the I'.y.hnhiulogy l.ahoraloty and the Ikpar,mcnl of Phystoloty. Flsr• varJ MeJrcal Schuul, Boston. 1Y11? 1'FFI'(°r OF INIIAI AlION OF ('IGARIiI"IE SMOKF. ON VI NIR1('(11 AR 1-11iR11.1 A'1I(IN ll-IRES11l)LI) IN NORMAL IXX;S ANl) IXXiS WI111 ACllll? MY(JCARDIAI. INFAR('l1ON Ihe eRcct of inhalation of cigarette smoke on the ekctzical ventrkular Bhnllation thresholJ (VF1) was studicJ in dwmal JuRs and .krgs with acute myocrtJtal inlarction Two groups of esperiments were pcrformcJ. In the flrM grotr/+, the VV1 was JclcrmmcJ in iwtacl dogs by Jcllvrrrnr ekctrkal wnpulsn through the chest wall. In the seconJ group the imptdus were delivered directly to the hearl through previrsusly implanted eprc+rdial ekclrodes. In Group A the VFf was Jeterntincd in 12 normal dogs at 1S-minute inurvals before, and for a period of 9(1 minutes fter, the nimals h:.J inhakd cigarette smoke O cigarelln, each containing appro.unately 2 mg nico(Ine, in 10 minutes) Similar stuJics were also perforrned in dogs with e.pertmenlal myo- cardul infarction in the acute uaje. Iklermina/ions of VFI' in Gruup B animals were pctformed before and after inhalation of cigarette smoke at IS-minule intervals lor Iwo hours. len corMrol and ten smokmg caperimenls were perlormeJ on nwmal dogs. Results showed a dccrease in VF f that avelagcd 30 to 40% of I/ie conlrol value in normal dors as wcll as in those with acute myocardial infarclion. lhis ellect of inhalatiun of cigarette smuke was evident )0 minules after smoking, became masinmm at about 45 minules, and lasted for about 90 to 120 milutcs. In the dogs with myocardial inlarcuow, the VIT was lower than in nlxmal dogs and was decrcascJ further after inhalation of cigarette smoke. lhese findings are of interest in view of the increaaed incidence of sudden death observed among curunary patients who are heavy cigarette smokers. erflrr, S.,• DcGuzman, N. T., Kostis, 1. B.. Roman. I.. and 1 kischmann, 1). Arnrricon Ilrorr /owrnul 111)(11:67-76, 1972. Other support: Naticxul Inslilutet of Ilcalrh arsJ Amcrican Medical Asw- C/a1Mtn. From the 1)ivaKrn of CarJKrlogy, Philadelphia (:cncral Iluspdal, Philadelphia. I I I I F('f 01' ( I(:ARF:1-II: . SMOKI'. ON 1111: ( ARI)IOVAS( III AI( SYSII M IN D(1(iS A tutal uf Ii Ixvllhy m..li nwn8n'1 JhrCs wa% uu-J rn Ihrs s1uJy u/ the elfect ol inhil.rluon of crgarcllc surwle un Ihe I.crn,4lynjuu, s ol the dux V.rrotn krKrwn ph.rmicolu6rc.rl agcn,s, rK, lyr.6nrn1c. prulrr,rrA,r1. wcrc used 14 35

to modify the evoked response of tobacco smoke in an attempt to sain insighl into the mechanrsm involved in that effect. Cigarette smoke was admmistered in a metered dose tone puR of 100-cc volume and 2 5 seconds durarion) to five dop for a per14xf of 90 minutes. Smoke caused a siRnihcant drop in systolrc bboJ preuuwe (p < 0S), and lower diastolic pressure, heart ratc, and slightly increased renal blood flo..; however, thex later eflects were rrrr statistically significant. Smoking did not aher significantly the effect of lyramrne on heart rate or renal artery flow. Nowever, in three dogs systolic and diastolic blood pressure response after smoking was significantly increased whik in two other dogs it remained unchanged. Chloeiaordamine (2 mg/kg) caused  significant long term depresaron in the rryMolic and diastolic blood pressures and in the heart rate. PropranoJol either coaplefely abolished, or reversed, the preadminis- lration reVonse to •nwlle of syslolic preswre, diastolic pressure, and heart rate. It is concluded, lherefore. Ihal the reduction in aorlrc blrnd• pressure during snwkmR in •neslhesiud animab may be attributed in part o rhe central eflecta of nicoMine and in pars to the vuodAatwn causcd by the action of re- lea.ed caKcholamrnes on Ih• peripher•I a-reuptors. IAar.r. 1/ . Rueh), A., Rao, P., Raaa, M. W. and Ilughes. M. 1. r.orrrdlwgr o/ the Socfty /or Eirrrlnvwra/ AioloPy and Mrdiclne 137(3) 969- 972, 1971. From the Ikpartment of PhysioloRy, St. Louis University School of Medicine. Sr Loun. TIIE EFFFCT OF NICOIINP. ON RE(iIONA1. 81.001) FIOW IN 721E CANINH FIEART The eflcct of nrcMrnc admrm+tunon on regional myrxardul blood flow was esa+nincd in normal hcartb ar>,1 after partial wrrursry artery occlusion. Under nornul circumsunces as wcll as after infusion of nicotine in normal hearts the subcnJocardul por,ron of the myocardrum had • higher capillary flow than the subepicardial fraction. Partial coronary artery consuoctson alone did no( alter this relationship; however, when it was followed by infusion of nicotine, a significant reduction In capillary flow in the inner portion of Ihe myocardium compared so the outer p.rt was observed. It appeared Ihus that the admirxstration of nicotine in the presence of partial coronary artery stenosis resulted in a decrease in rclalive •ubendoeardial perfusion, despite an increase is the 1o1a1 coronary flow. These effects may be related to the rckase of cate- chotamines. and similar observations have been made alter the adminrstr•tion of norepinephrine under the same cirewnslances. M•thea, P., Rival, 1. and Dinr, R. I. rrorerdingr ol rAr Society /or EirrrJmrnraf Qiology and Medicine I 7/( I):J61- )61, 1971. Otlrrr •urport: Michigan Heart Aswcialion, American Mcdicnl Associatwn- Educ•tion•I and Research Foundarion, and Detroit Oenerd /losprtal Research ('orporation From the Ihpartment of Medicine, Wayne Sute Universiq SchoiJ of Medicine, 1)etioit. THIi ('ORONARY MI('R(X'iRCULATION IN 1HE POIASSIUM ('HLUR11)E AkRES11:U HEARi In ordcr to obtain clear viwalrration of the finer structural arranRemc.ts of the capolary bed, studies were made of the capillary crrculatiow is the perfuscd cat heart arrested with potassium chloride. lhe eaperimeets were concerned with the coronary capillary circulation of the kft alrwm, raiall transillumination ('apolary red cell velocity was measured using cinernqolira• phy and color films (16 mm 24 frames/•) and frame to (rame analys'r of red cell progression Optical maRnifkalion on the film was (rorn 20 to 30 Iirrw. ('•polarics were visualized as lying on either side of the muscle fiber. Numerous imercapillary •nastornoscs which communicate through interconnecting loops of varying kntths were visualized. Capillary diameter vatie• from 4 to fi rm. ('onstancy oI capillary red cell velocity was presenl a/ from 75 to 210 mm flg. With increasing perfusion pressure, the number of capillaries with d'escer.ible red cell movement increased aa perfusion pressure rote (recruitment). In •ome c•pill•rics, abrupl arsd eslreme changes in red cell velocity were observed at the same pcrfusion pressure. About 10 to 30% of alt capillaries showed oouacr- current flow in adjacent capillaries. Hellberg, K.. Rickart, A., Wayland, H. and Shg. R. l. IOYrnd o/ AldreY/Y and Crlfufar Cardiology 2:221-270, 1971. Other arprorfr American Medical As•ociation-Education•I and Ratarch Foundation, 1 os Angeles County Ileart Association, and 11. S. Public Iteam Service. From the Huntinpon Memorial Hospiul and the California Institute of T.cL- noloRy, Pasadena, C'at.,' and the University of Southern California School of Medicine, Los Angeles. REPARATIVE PROCESSES IN HEART MUSCI E FOLI.OWINU MYOCARDIAL INFARCTION In this discusaion, the authot compares the reparative processes which follow myocardial in(atction to wound healing nd attempts a correlatioe br.- tween the morphologic aed biochemical ehanRes involved. Wound healing eo.- sists of three staRes, each characterized by activities of a particular cell popula- tiorr and by definite biochemical processn: (1) organization of the clot, ea- pressed in the myocardium as heawrrhallie foci and cell necrosis; (2) wsitiratioe of white blood celh followed by lysis and ph.gocyloais of cellular dcbris aad other foreign material; (3) migration of AMoblut•, ard synthesis of oollage• fibers and other proteins which form •car Ii.sue. As they occur in the myo- cardium, these events are all reflected biochemically by: (1) change in acid phosphalase activity, an initial drop followed by a marked increase is particle- bound enzyme activity indicating that after in/arction, hydrolytic enzyme• are first released from lysowrnes in hearl muscle and local connective tissue ec1Y, then from the rrsooocyses and flbrobtasu involved in the reparariv p.ocea.; (2) an initially reduced, thew augmented, incorporation of filycioe-2-rK; into heart musck, which is a mrware of myocardial protein •ynthe.r, the early reparative procea• apparently .rarting In.the cell nuckus; and a dmdar curw (or cellular RNA content which irdicatey an early inactrvarwn of the cellular protein synthcsizinR mechanisms, and espreues the protein synthnuinR ability 36 37

n ~4 .rs+ ~ AJG r..j. .y:. i of the recovering tissue through increased numbers of microsonxs; (7) a rise in DNA on the sccnnd day after mfarction to a masimum 90% above xxmal 8 days lalcr, indicating renewal of cell material in thc injured rrea; (4 changes in eniymcs and metabolic pathways implicit in the shift frrwn v:rohic to anaerobic myocardial metaholum, meruurable by the ATP and Iactate contents of u+farcted heart muscle, oscillatory in nature and attributed to the collective effecl of the various ccll types involved in the reparative proccss; increased hpN1 synlhrsn also demonstrated by incorporation of acelate-I-"C nay con- tribute to the maintenance of anaerobic pathways Although myoflhr Is do not rcgenerate, the author, using clinical observations on wound healrng, has suc- cets/ully stimulated the reparative processes in dop, after eaperimrtul myo- cardral mfarctron. Treatment with ascorbic acid increased incorpcralion of glycinc-2.r`C into infarcted liwse prolein by about 100% in spite ol (he fact that these anurnals did nol show any evideeoe of vitamin CC defkren.y; meth- androt,tenolone. an anabobc androgese, iocreaaed incorporation by 211-249'A.; bovine growth hormone taiscd it by 161%; small .kvses of insulin 10 units) seemed to srgnifkantly increase il; asd a combination of powth horrnone and insulin raiscd it 251%. lhe author atreiacs, ho.rever. that it is difficult at the present time to apply the results o( these aeimal eaperimenu to tlte human patient with myocardial in/arction. Diwt, R. J. Cerdlofoty 56(1 6) llt-]2t, t971/72. Other rrpport: American Medical Association and Hoover Foundation. From the HuminBton Memorul No.pital, Pasadeaa, Cal , and the University of Southern ('ahlorou School of Medreue, Los Anpeln. RECOGNITION OF CORONARY ARTT?RY DISE?ASe Tbn discussion deala with the re"nilion of coronary artery disease and the latest techniques used in the procer. The report describes several diagnostic aspects: (1) history and physical eaamioatioa; (2) recognition of coronary artery duease by meana of the aotalkd eoro.ary risk lacton, with special reference to the lipid pro8k; ()) reeognitioe of coronary artery disease by rneans of the rest and cxerci.e electrocardioram (L'KO); (4) recognition of eoroaary artery disease by means of coronary arseriotraphy; and (5) recognition of coronary artery disease by meana of noninvasive techniques The authors feel that while history and physical eaamioalion remain the diagnostic leystone, serum choksterol kvels and triiltyeeridca most usefully represent the lipd profile with 11e stress FK(3, especially Ihe one following the standardized 8raded escrciu tesl, an important adjunct. In their opinion, moreover, aekctrve cor- onary arlerioRraphy oAcn the besl way to recognize coronary utery disease and to determine its severiry. Provided that well defined criterra are applied to its use and certain precautane uken, the mortality rate is low and there are few complrcalu>ns Ihus, changes In coronary micrncrrculalK.n may be rmpli- catod in the cause of atypicd angrna. lbey add that noninvasrve Iechmyues n.ay bc imp.wlant in thc presumptive diagnosis o/ coronary artcry disease. (1) the fracnnn (if I VFI /klt vcntricular efecurwr ermc) to 11(-1 (esternally de- trrm .rJ r.rs-drrnrt rr,nrr.rtr.n luncl allcr c.crcrsc shuws a(pMK1 coirclalKtn IrnctrwuJnrRr.m, : i ncc a1Kt t.rJ-elruu and especially after esercise, offer additional help; (3) the nrhKlrum 84 coincidence counttng technique is a simpk method for the (1etcrnnn.,ron of coronary blood flow and reserve in man; with the use of isoprolerenol, recognition of acvcre atherosckroUc heart disease may be possible. Aint. R. l. Hellherg. K. and Pachinger, O.• N•r York Srerr lorrn.l ol Medkine 72(14):1818-1822, 1972. Other support: American Medical Associalion-Educalion and Research Foua- dabun, Los Angeles (-oun;y Heart Associalion, and the Norra Foundation. From the Huntington Merr,ocial flo.pital, Pasadena. C.I., and the University of Southern California School of Medicine, Los Angeles. •Fr.e....rr FYWI u r.rf.ly...0. TECIINIQI/FS lO MEASIIRF CORONARY BI ())[) F1.OW IN MAN lbis is  review of the lechniques currently usrd to measure coronary blood flow in man and presently applicabk to patients. lhe melhods described are all based on four ddferent principles: 1) the use of dif/usibk 8ases such as nitrous oaide, rgon, isotopic krypton and aerwn, or other subuances suc\ a. antipyrine and radioactive iodine; 2) the use of lipid-insolubk diffusible aub- stances that actively enter the cell, such as isotopic rubidium, pol.asium, or .odium, to measure nutritional blood f{ow; 3) the use of dycdilulioe or lhermoddulion to meawre coronary sinus Bow• 4) the use of an ultrasonic Doppler 1lowmeter to meawre phasie coronary blood velocity. lbe advanla8es and disadvantages of the various reahods menlioned are discuesed. This lype of approach may reveal changes in the functional response of coronary circula- Iwn but more ai8nificanlly, it yields Rreater inu8hl into the behavior of coronary circulation and is urtai• to in/lueaee both the basic and cli.kd coocepts of ixhemic beart drseast. elnt. R. l., Riclart. A. and Hellber& K. Amcrk.n lournd o/ Crdloloty 29:75-t0, 1972. Other .r'prt r Norris Foundalio" ud Los Angeles County Ileart Ano- cialion. From the HuMington Memorial Hospital, Pasadena- C.1 , and the University o( Southero California School of Medicine, l.oa Angeles. STUDIFS ON 711H CORONARY MICROCIRCl1LATION BY 1)IRI:CT VISUALIZAl1ON With use of high speed cinematography of the coronary mkrocircularioe, counlercurrents and asymmetric tapolary arranRenunl were found. Ibis bar far teaching importance lor the osygenalron of the heart musck and makes drHrhtful previous cakulations for the o.YBCn transporl Iro.n the capolary to the auroundmg trssue Recrurtmcnt, denoting an increasc in the number of eapillaries, was observed with a rru in ptrfuaMrn preuure in the arrested hcarl and alter the adromi.lution of nirro8lycerrn in the healrn8 hcart. It can occur in the presence ol autorcgulation Ikfimle patterns of reJ cell vcwKrry in the capolaries of the k/t atrium crncrBcJ Ni..Nrne and mtto8lycenn had hl,k eflect )9

on red cell velocity Ilowever, after hemorrhage atone, and following the administrauors of nitroglycerin alter hemorrhage, marked changes in red cell velocity were aeen 1lcnwtrhsge akxse caused  marked diminution in red cell vchrcrty; hemorrhage followed by nitroglycerin reversed red cell velocity to normal value+ desprte a pcrustenl diminution in blood pressure. Two maror peaks in red cell vtkxuy were oh+erved, the 8ra1 large peak immediately preceding or at the onset of ventrrcular synok, the second small peak immedia ely after ventricular sysrok Sorne atreralrons in Ihis pattern were .cen after hernorrhalle and after the .dminntralion of ilroglyceris. Ilellberg, K., Wayland, H, Rickus, A. L..ad dint, R/. Amerk.w Jo.rrw.f of Ca.diolo=y 21(S):593-397, 1972. OtAer .uPPorlr American Medical Arociatiors, Hoover Fnur.dation, toa Angeles County 1lcart Associatio.. Norris Fowdation, and U. S Publc Health Scrv/ce. From the Flunringson Mcmorial Ilo.pital and the ('ahfornia lmlitute of Tech- nokrgy, Pasadena. ('aI , and The Univeruty of Southcrn California !chrxrl of Mcdreine, (os Angeles F(11(X-ARI)1(K7RAPI11(' FINDINGS IN EXPERIMENTAI. MY(X'ARUTAI. INFAR('i ION OF TNP. POSTERIOR LEFT VI:NTRICULAR WAII. The effects of esperimrntally produced infarction of the post:rior left ventricular wall on the echocardioliraphie configuration and motion of the posterioc k(1 ventrrcular endocardwm were evaluated in 20 closed cl<st dop. Fleclrocardiolirams, phonocardrotirams, apescardro1rams, .ortic and k/t ven- trrcular pressure curves, and the latteri first derivauve, dP/dt, were recorded simultaneously and supcrimpoacd on the «hocardwitraphic tracing C mclation of the echocardrolirams with the other measurementa permitted the calculation of kit venlricular voldmes, eomraculity, and systolic and diastolic time inter- vals. SpeciAc nchocardKliraphic changes in the confl1Juration of the pcnterwr left ventricular ersdocardrum occurred synchronously with left ventricular mechanical performance regardless of S-T segment changes in the ekclro- cardiotram. Reduction of etcursion of the posterior left ventricular endocardwm and its mean and mas.mal velocity were indicalive of the eaperimenul posterior wall infarction. ('hanites in the echoeardiographie configuration of the posterior k/t venlricular endocardium could be correlated with upright and inverted T wavei. Experimental infarction of the poaletior kft ventricular wall was always reflected in changcs in the poaterior kfl ventricular endocardias echo, whether the infarction was Irammural or nonlr.namural. In conlrasl, the ekcttocatdio- gram failed to show changes i• nonlranswwral infarclion. According to the authors, this study may form the b..'s for •n interpretation of echocardro- graphic flndinp in posterior w.ll ief.rxtioa in anan. Stefan, 0 and Qinr. R. l. AmerKM Jor.nd of C.rd/ofory )0(6).629-6)9, 1972. (Ithcr support: M.rlarcl W, and /lerberl Iloovcr, Ir , F<wndatKm From the Huntinltun Mcnsocial Ilo.pital, Pasadena. ('al , and the l Imversity of Southcrn (-aldo...a Sclaool of Medrei.e, lua Aetieka. tllOSYNl/11iSIS OF I IPIUS IN PERFUSFI) C)(Xi AOR I A ANI) ('ORUNARY AR II[RY. 1. IN('ORPORATION UF 12 rr('I ACi:TAIP. IN IO 1 HE I IPII)S OF Tl1RL'li AOR I I(' 1_AYI Rti ANI) OF T 11P. ('URUNARY ARIF:RY IN NORMAI. ANI) IIYPFRI.IPFMIC IXXiS Although Irpid metabolism has been the suhject of many invcstillationa the espcrrnantal conditions varied to such an ealenl that it has been difficult 10 compare these results. The present study, lhcrefore, was designed to use capenmental conditions .omtwhat approsimaling the animal's sirualksn in vivo. Hence, aorlas and coronary arteries of the same dog were perfused with the animal's own natrve serum (or I houn using pulsatile pressurn. l_.pK1 synthesis from 12-rr('I acesate was compared with the corresponding lipid cnnlenls m three aortic laycrs and in coronary arteries. The influence of an atherogenrc diel on the arterial Ipids was then studied in this system. In control anrmah, r'('-incorporatwn into Ihe total lipids was highest and nearly identical in the coronary arterres and in the a1NIK Inlima including sevcral layets of media Imtim'); incorporation into the lipids of the NNtrc adventrtu nd medu was approsrmatcly one Mth, as coropared to the intima 1 he percenlage dlslr.IN11MM of r'(' label f.ctwccn the dd.cren/ Irpids was idenlical in the inthma and mcdu. Th- inhma contained the highest amounl of uneslcnfka) fatty acids; the per- centage "('-incorpo.ation was low and approsimatcly the samc in the wrtic layers and in the coronary arteries (< 6%). The aortrc media had the highest concentration of free slerols which comprised approsimuely 90% of the lolal sterols rn this tisure Percentage radioactivity was low (< 5%) and within Ihe same range in the aortic tisues and coronary arteries. Sterokslers were mostly present in the coronary arterin, paralleled by the highest percentage r'C- incorporation ()96); low concentration in .ortic layen were aausciued with low percentage radioac/ivilks (< 1%). ()iglyceride contents were low in both wrta and coronaries, but there were relatively higher ansounls and radioactivi- ties (6%) in the adventilia lhan in The mcdu (7%); "C-aclivny was higher in the coronary arteries (10%). The tritlyceride contents and the perceMap "C-activity were highest in the .ortic adventiti (S 196 ) and in the coronary arteries (2S%): the concentrations were ealremely low in the media and inlima, but radioactivity was relatively high (11 and 14%). The amalleN phosphatide amount was measured in the coronary arteries; rr('-incorporarion was high in the intima and media (76%) and low in The advcntitia (39%) arwl coronary arteries (53%). Animals fed the allseroRenic drel conluoina mainly butter fal, sucroae, choksterol, and thiouracil, developed severe hyper- lipemia, but glucose levels were unchanged. Tlrere were no morphologic changes in the vcssels and no alteration of r'C-incorporation into their W/al lipids. There wcre, however, signiAcanl changes in 6pid concentrations and percentage "Cdisurb.dion: (1) reduced concentration of unesrerifkd latty acidl in the aortic intima with only mudcrately diminished r'(' incorpocatnws; thc opposite was true in the media; (2) decreased radioactivrties and slightly In- creased (alty acid contents in the`coronary arteries; (3) moderately elevated free sterols in the rnlima, and increase in the corresponding percentage radio- activity: (4) sterol concentrations of the coronary arterrca were urr~hanred. Ixn radioactivity diminished; IS) increased sterolcs/er contents in thc inpma arrl media with ekvarion of percentage radioactivity in advenutia and mcdu, (6) augmenled diglyccrrle uxtcentratrxrs in the medu and euronary uterres wuh diminished percenralte "(' acnvrly in advenuua and media. Thcre were no rekvaM altcrations in the uitilyceridcs and phosphatrlcs of any vcssels lo 41 40

cunuul animals, ("('1 acclate was mainly incorporated into Ihe fatly acids of Rlyccrides 19K S-o) and phosphatiJes (946%), this difference hcmg highly srgndii.nt. Ihe Jrcl tr.ated aninuls incorporated I(X)'%r radso.cuvrry into the fely.errk fauy acnls, and 99% inlo the phusphatrJe /alty acids, this differ- cnce wis also srjomficant. Kupke. I R (R,Mz. R I) lournul o/ A(nlrr ufor ond Crllu/or Cardrofoty 4 11.26. 1972. Other support: Nurru Fourrlation. From the /luntington Memorial Hoapitd, Pasadcna, ('al, the University of Southern C'alrlornra Schoot of Medrine. I oa Angeks, and the Institute of Hinchcmistry, MeJonmsche Ilochschule Hannover, Hannover-Kke(clJ, Federal Republic of cervnany. JL. BIOSYNTIII-StS UF IIPIT)S IN PFRFUSFI) INKI AOR1A ANl) ( ORONARY AR 11 RY. It. IN('ORPURATION OF 12."(') A(' -:1 AI F. INTO I.IPIIX% 01: TWO AORTIC LAYERS ANI) OF THE CORONARY ARIERY 11N1)ER 111E INFLUENCE OF NICOTINE llris ia a continuation of the .uQwr'a investigation into the biorynthesis of Irpids in the dog Since the previors t.perimenls indicaled that the control animals' vessels cchrbncd different bprd p.l/erna and a diflerenl respcxne to the atheroresrc dee/, the purpose here was /o uudy, !n vitro witl the same pcr(uswsn systcm, the duect cftecl of nicotine on Irpwd mcrabnlnn. in normal dog aortas and crxonary arterres. lhe results showed that .llhoc`h nicotine alters the hprd pattern of two .onic Iayen (rntima including several layers of adjacent media (mtrms), and medu), and of the coronary arterres, u does not markedly affect "(' rncnrpruatwsn into the total lipKls of these sessels Per- cenlatc radroachvily, at relerrcd to the absolute total lipid radioaclivuy, was sigmRcandy diminished in Ihe free ucrols of biuh aortic laycrs, and in the coronary arterres, whrk the absolute "('.activity of the free slenas was also decreased in the aortic laycn. but was unaffected in Ihe coronary arteriea. lhe uncuerrFicd fany acids of the aoaic mcdia, and the stehdesten of the aortic inlima showed a significantly elevated absolu/e "(' incorpocalion Moreover, unequivocal alterations of the absolute radioaclivilies of the coronary arterial lipids were observcd: (1) the "C-nclivily of the ateroksters and of the triglyccr- iJes was sitnificantly increased; (2) N was only moderately augmented in the uneucrdkd fatty cids, diglycerides, and pho+pAatides. There were no clear-cut alteralions in the lipid concentrations thus far detcrmined. According to the autlwx, the present study denw.nstrates that nicotine modifies the artcnal lipid patlern, but the response of dog coronary arteries is different from that of h 0 e aort.. t Kupke, I R (8rnz. R. !J ~ /or.nal ol Moircsol..r and Crll..lar C.rdiolory 4:27•1q, 1972. ~ m nrArr support: Norris Foundation rn ' Leas r al, the (Iniveruly of From the Iluminglon Memorial Ilospital, Puadena, ( ~ m Suuncern ('ahfnrnm. School of MedKine, Iw Angeks, arxf the Insrrrute of Le~F m Bon.henustry, Mrditrniuhe Floahschuk Ilanrxrver, Ilannover KleelclJ, Federal ~ Repuhlw of liefrnany (U lU 42 I HIOSYNIIIESIS OF 1IP11)S IN PVRFUSF.D 1)O(i AORIA ANI) CORONARY ARIFRY. Ilt IN(()RPORAIION (W Is_-"('1 A('FIAIE INIO S11,ROIS ANI) 11P1AKF OF 1'111('11O11:51[RUI. IN lI1RFE AORIIC 1AYFRS ANI) IN CORONARY ARII-RY U1= NORMAL ANU HYPIiRI.IPFMIC IXX;S ANI) UNUF.R 1111i INFI.UFN('E OF NI('OI IN1: In this third report on a continuing series of e.perimenls. the author describes n elTort Io compare the sterol conlenl. the ansuunt of newly ayalhe- sircd steruls, and e.operNws chukslerrrl in different layers of the perfused .orls and the coronary artery under the same eaperimenlal conditwns. In d)R aortas and coronary arteries perfused with the animal's own serum which conla.'..ed 1"('Iacetale nd Isllkhoteslerol, the conlrots showed an amount of esogenoua ('llkhokstcrd which was nearly the aame in the three .orlic layen, but it was significantly higher in the coronary ar/eries. lhe inlinmal slerols incorporated the highest amount of "(', whereas the highest sterol conlent wu found is the media the ralrs pcr cenl 1'11/cMdcslerol: percent /"('Islcrols, as related to the total sterol conlent, was approarmalely the .ame, 1(1, in the wrtic laycrs; it wu 60 in the coror.ary arterrea. Nrcwine rcduced "('-rncorprwalion into slcrols is the aorlic layern. The dif/erence in the 1'H/chokslerol uptake by Ihe inlinms and media was more pronounced while the coronaiy arteries remained unaf- fecled. Animals eapose~ to an alheroRenic diet showcd no morpholopcal changes despite a severe fsyperlipernia. The sterol content was slightly incrcaaed in the aoclic inlima •rd the corresponding r'C-incorporalion was signdkawtly elevated. '1he 1'Hkholnlerol conlenl was only Increased in the adventitia. In the coronary arlcries, the "C-incorporalion into sterols was diminished and the (s11)chokslerol uptake was increased. Severe morpfKSbffrcal changes were ohscrved in one animal. (\s compared to the other animals caposcd to the same diel, the "C-incocporation was increased in the total Irpids of the aortic inlima and of the coronary artery. The content of slerolesters and thcir radioactivity were elevated in both vessels; the sterol content was also aug- nenled but the corresponding rK'-activrqr was markedly dimrnished, mainly i. the aorl.. lhe anwunt of (sHkhokslero/ was in the same range as 1he other hyperlipemic animals. Tlse author concludes tha1: (1) in comparison to the aorla, coronary arteries of rsormal dogs more easily e.chanRe their chokNCrd with the serum lipopraein-ehokslerol; 42) the high sterol content of the aorlic media is obviously rsot related 1o the amount of cholesterol derivcd from the serum ard to the sterols synthesized Jn riru; (I) the ratio percentage ('11/chokslerol: percentage I'r('Islerols, however, appears to be corrclalaf in the anrlic layers It is suggested that nicotine allers the uan.port rnechaoiarr for cholesterol in the aortie wall As the aoru becomes more diseascd, eaogenow choksterol, as compared to Ihe newly synlhesircd surnls, become. predo.ninant. 'lhrs phenomenon has already been observed in corunary arlerres murphobgicatly not diseased. Kupke, 1. R. (eier, R. J) , lournd o/ Molrculor and ('rflufor ('o.drolory 4.215 268. 1972 Other .upporl: Norris Foundatwn From the Iluntinglon Memorial (linpqal, Pasadcna, ('al, the (fnwerury of Southern ('alr/urnia Sch.nd of MeJrcroe. I os Angclcs, .rwl the Imthture of Biochemislry, McJirnnische Ito.fischule Ilannuver, Ilannover Kkclcld, Fcdcral Republic of (icrmany. 4)

l/IF FSIIMAIION OF BI.(X)r) P1 ATEI ET Sl1RVIVAI.. ilI 7111: R(1Bl1SINFSS OF 111F. BASIC MOI)FIS A set of mathematical rnodels has been derived to estimate platclct survival and is hased on the K1ea that this foilows a multiple hit (or gamma) Jrstrrhu- twn. lhos p.pcr is part of a acrrcs dealing with estimation from real data anJ, particularly with testing the truth (or at least the rolwstrscss) of the model Attention is directed here toward the dnlortion inurwhrceJ by using the muluple hit (l.mma) nKxkl for the construction of popularion curves where some of the underlying assumptions .re violated. The three violatrsns, over which, because of physiological evidewce, thert is greatest occasion for corscern, are consnltred in sonse detail. Tlsese diMortiona are: (t) a latenl interval which esists between hru so that true survival would follow a Ramma dntrrhuuon shifted to the righ1; (2) the probabilily of responding to an environnrcMal insull may change with the age of the platelet so that survival would follow an I:rlantian dittrrlwlMM; and (J) platekt destruction may be governed by com- peting p.oceues of drflainR rclNivt Iseporlanats. I/ndcr fairly Rencral conJi- trons, the discrepancies bctwee. these r.odcM (i/ true) and tlse `hest /II" (mrni- mas) gamme functrors of integral order rw small (less than 3%) cspecially when compared with the kind of eapesiwse.tal errors usually encountered Until such time u.ery precisely measured data are availabie, it seems that the multiple hit model may be t.sed wwh co.dldewce at least as a d:vice for estimating the mtan. The author points ou(, however. that the estimation of the number of hNs to deslructioq, or the rssean waiting time betwcxn them tcpar.tely, is likely to be imprecise. Ntverthekss, the estimation of 'he mean (which is the ratio of the number of hiu to the reciprocal of the waiting time) may still be much more ulssl.ctory than eNimates not taplicny rkfcndcd by ratioeal nsodcls 7 he latter consideration ir statistical and plans are to deal with it later in the series AIrrphy, E. A. ThrornSoAstr DiarherG fl.rrnorrhagic.26(3):U1-44>!, 1971. Other.upprt: l). S Public Heahh Service. From the Departnsents of Medicine and Biowtatistics, T7se Johns Hopkins Uni- versity School of Mcdicine, Baltimore. MODFIS OF TFfE DFSTRUCTION OF 81.001) PI-ATELETS Tbis discussion deals with the development of mathematical mod:Is which describe the survrval of blood piatekte. These efiorts illustrate a pattern common to the development of all such models and largely consisted of three steps: (1) construction of prrmitrve comrnon sense Indices which appear to describe the data in special casn; (2) attempt at defining a set of asuxn., often unreat- istically simpk, whKh provide a unifled theory for the descripli.rn of these Irrlrccs and foc the comparison of result. otherwise incommensurable. (1) al- tempt to relau rhe asiorru in such a way that they make the nxr)cl mure realistic and more fteuhle wnhout making it morplKrus. Ihe author roncludes thu one of the nx.dch devned. the multiple hit m4x)cl, can be used to estimate the mean surviva-1 of plarclets with some degree of conlWenc.e. Murphy, E A. In 1'aulus, 1. M(ed ): Plualrr Kinetiri, Amsterdam Nor1h Ho11anJ Publishing Cumpany, 1971, pp 80-91. Other support: U. S Puhlrc Health Service. From the Ikpartments of A(edicine arsd Bioalatislic., 1 he Johns Hopkioa Usi- versily School of Medicine, Baltimore. P111 MONARY AR7ERIA1. CIIANGFS WITIf A(lE AND SMOKINU A yuantitahve, histologic analysia of individual components irs the pu1- mnn.ry artery walls was unrkrlaken in 126 smoking and 67 nonsmoking mala al various ages Arterial wall structure was correlated with cardiac right ve.- trscular wall Ihrckncss n an attempt to relate vascular suucture Io vascular reuuance. Ihe percent of small pulmonary artery walls comprised of .orma) cuoular ansaqh muscle dccrcascd with are more rapiJly in smokers than iw munmokers. Ihc younger nonsmokers had less arserral longitudinal muscle tlsas did similar aged smokera. Between ages )0 and 70, collaRen content of arterial walls increased from 8% to 25% in nonsnwken and frorn 15% to 39% I. smoken. The vascular abrarmalities may have little functional imrportarap because there was no significant increase in cor pulmonak as the abnormal comtnutenrs increased in the arterial walk. Smokers had thicker tight cardiac ventricks than did nnntmarkers, presumably due to incre.aed vascular resistance at sonse ute other than the small pulmonary arteries. Natyt. R. l.L and Dellinger, W. S. Archivts o/ Parholoty 92:2d4-2te, 1971. Other arpport: l1. S. Public Nealth Service. From the Department of PalhoioRy, Pennsylvania SIa1e University College of MeJrcine, Ilers)scy. MFTABOI ISM OF ADF.NOSINf: " S'-MONOPIIOSPHAIE: DURINO C-IRCUI.AI ION TI(ROl1G1I 7lffi I.UNGS It has been reported that shock assoeialeJ with crush injury nd related lis.ue injury may he partly due to the release into the circulation of vasoactive subslanccs, anxrnj them, the adenine makotrdcs Borh .Jenosine 3'-Iripho.- pAate (AIP) arrJ monophosphale (AMP) are known to disappear during circulalKrn thnNigh the tungs, lwt the mechanism by which this is accomplished has nnt Lccn prcvrcxnly rklincJ. Bascd on the results, in rats, of their kinetic stuJres, others using isolated pinocytaic vesicks, and tytuchemical localiiation., d,: authors cornluJe that .Jcnine nuckotrks entering the cuculation are rapidly metafxrtucJ by pulmon+ry, enJothclial, pinocytotie vesreles Cylochemical evi- Jcrsce mJicatc% that this occurs mainly in thnst ves+clet open to the vascular lumen, a.kyuwtety pruv«Img for the return of ineNholrles to the circulation I he resulu. Iurthl'rnNxe, 1Mlw that puxrcyhMre vesrcks carry out functions aher than fluod Iran.port 11 is .uICr.1CJ Ih:y pArlicipate in the met.f..Jnm of dhose raprJly de grjJiJ agenl. wP.Kh arr nur rct-brneJ by the lunp I lx kuuns aswl angiutcnun 1 apparently /ir thn category as well as the r.knirse nuclcuudes, as suplxrned by the l,rct th.t the nul,rtcJ vesKk nd platma nKnlhralK pcllcb convert 4S 44

1"('IPhe• angiodcnsin I to an`iotensin 11 Thex nxtaholic mecharnms, not descrrhed prcvwrusty, may conslpute a major control for the pnxessmg of circulating vasoacnvc substances by the lung. Ryan, 1. W. end Smirh, 1/. 7ranrarnonr of rhr Auoriarion oJ Anrrrkan rhyslcian. R4:297-)06, 1971. Other suppurt: ll. S Public Flealth Service and Florida Hcart Association. 1'rom the Departnxnt of Mcdicine, the University of Miami School of Medi- cine and the 1(osvard Hughea Medical Iwltule, Mumi, Fla. MEl ABO1 1SM OF (e 1 1"CIPHENYLALANINE) ANGIOTC-NSIN I IN 1111: PULMONARY CIRCULATIUN Antiotensin I ia mctabolired during a single circulation through the lung.. When (1O 1. 1"('Ikucrne) anerwtnsiw I ia used as the suhurate, the pulmonary- verwus cfflucnt ccxNaun radw.ctrve 11w I,est, owc or mrxe large (;i 'J res.Jues) (' Icrmrnal honsok.llues, and a nonradsowctive pcpiide having the chromato- graphrc, ckc,rophoretic, and biological propertrs of angiodensin 11. In thu srudy,(fi l. 1'•Ciplxnylalaause)-angiotensiw 1, was selccted as the substrate for pcrfusron through rat lungs because the radroi.oropic labcl is in the angiotensiot It moicty, and Aecause its ckttrophorelic properties allows unequivocal separa- Iron of awgiosensrn 1) lrom all the lower phewyl.laninecontaining hunwbgucs of anWemrn I ard 11 lhe rnulls confirmed that .ngiotenaun 11 is indeed a metaholrc product of lungs pcr/uscd with angiotcnain 1, and also agree with a ptcvKws study on the point that pulmonary conversion of angrotcnsrn I into an&rolcnwn 11 n rx1/ rJuanrruh.e, the yield of angiolensin I1 being about I 5-207. According to she aurhors, the r.prd mcufrdhsm of angwitcnam 1, the failure of lung to retain uTmfxant Quanwres of u nr of rU metatrllio pruducts, and the near quantitative recovery ol radwachvrry in the vcnnui cfftucnt, suqest that ansirotcnun I, I kc Ihe a.kmr.e nuclcurw)es and hfaoy\rnin, ta metalsdir.ed by entymes on, or close ro. the lumrnal surface o/ pulnwrnary endothclwm Ryan, 1. W., Nicnuyer, R. S, Goodwin. 1). W. and Smirh. U. slochrmk.llourna7 125:921-92), 1971. Other rttpprt: Florida Fleart Asaoeiation and Nalioa.l Iratitules of Health. From the [kparsmcnt of Medicioe. University of Miami School of Medicine, and the Howard Flughcs Medical Inuitule, Miami, FIa., and the Ikpartment of Biochemistry, l)nivenity of ('oLorado Medical Ctnter, t)enver. FNI)OTFIFI IAI. PRO/F.CTIONS AS REVEAI F[) BY SCANNRJG I:LECI RON MI('ROSCY1f Y Recenl evidence indicates that enzymes on, or near, the surf.ce of en- JMhclul cells are rnvolvcd in the nseubolwn of rapidly degraded circulaling suMtances, such as the aJenine nuckwrJes and pulypeptiJe hrNmur.ca, which are nrn relaineJ by thc cctl itself Scanning ekatron nucruliraphs of /Mlhnnnary artery endwhclrum reveal the hitherto overksokeJ Iac1 that its cnt re surlace is cavcrcJ by a mcsh*utk of minulc, nrtgular, fintcrlrkc projccti.ms Jrsun- luith.hlc hurn ihr rcKular p.tna.ks of micruvrlli characrcrntic of many vertcbrate nJ invertebrate epilheha, arsd from flaps or marginal (oWt. While their function is un\nown, these projeclions obviously pcatty incrcase the enJolhehal surface area arsd affect fluid dynamics. lhcir size, dcnsity, end naturc of the meshwort they form, could conceivably produce an eddying flow of cell free plasma a{ong the cell wrface. T1ria may he particularly signifkanl in large high rbw vesuls, such as Ihe pulmonary artcry, where nutrienl capil- larics do not penelrate to ;he endoahelium, and in which slower flow of pluma along the cell surface would favor the tachange of inetabolrtea and the mcla- bolism of circulating hormones. Srnith, U., Ryan, 1. W., Michie, D. D. and Smith, D. S. Scirnct 17):925-927, 1971. Oth.r support: Fksrida Heart Asaocialion, U. S Public Hcalth Servio., a.d National Science Foundation. From the Tkpartment of Medicine and the IlMvision of lhoracic and ('ardio- vascul.r Surrry, l/nrvcrsuy of Miami ScM.ol of Mcdrernc, t)se Iloward Ilughe. MeJrcal Instrtute, and the Papanicolaou Ccwter Research Institute, Mraml, F1a. SUBSTRUCTl1RAL FEATURFS OF PULMONARY EN[X)THELIAL CAVEOLAE 11 has been suggested that caveol.e iMr.ctllularts, or micropinocytotk veticks, always aecn in erdolhelial edh, are iwvolved in bulk tranapott, cnguM- mcnt of fluid taking place by invaRinatwn of part of the endothelial plasma membrane with subsequcel vesiculasion and 'aNracellular transport. ReuM evidence also indicates that rat lung endothe6al caveolae are capable of metabolizing certain vatoaChve subalances, end that Ihey possess substructwal specialiraliom which d'nlinguish them florn undiflerenliated plasma membrane. 1 he authors report on their ekctronmicroseopy atudies of ral pulrwonary erdothelial caveolae which reveal dense knobs at the point of fusion of cavedar rnembrane, diaphragm, and plasma membrane, wggeatinR a circular atractun whose function, possrMy, is to maintain the patency of the stoma and the it tegrity of its diaphrasm. The inner concave wrface of the cwcolar membrarr also contaim regularly spaced globular struclures which may be cntyme ch.dera or binding srtes 1Tis hypothesis is supported by the distribution of lead pho.- phate dcposits, formed on reaction of caveola 3'-nuckotidaae with AMP in the presence of PMNO,h, which corresponds with the spacing of globular aruc- tures. 77scse sutntructural features are conswkred with reference so the rok of caveolae in the metabolism of circulating vasoaclrve auMtances It is fclt that such substructural specialization as is described here appears lo provide the morphukrgical evidence (rx the newly recognittd specific metabolic activities of caveolae. ~ Smirh, f/. and Ryan. I W. Trrrur d('tlf 411/ 49 54, 1972. Other support: 1I S Public Flcalrh Scrvrce. From /he Ikparlment of Mcdreine. Ilniversity of Miami SchiKrt of Medkrnc, and the IlowarJ Hughet McJrcal Instuute, Miami, hla 47 46

ANGI(11[NSIN 1.. MIaABOI ISM BY PLASMA MFMBRANF. OF 1 UNO According to the anthnri postulate, circulating anRiotensin 1 and brady- kmin, like thc adenine nucklNidcs, re metaholrted hy enzymes lucatcd nn thc lummal surface of pnlrssonary erslksncelist cells lhosc controlling thc srctuhul ism of adcnnune S' monophosphate (S'-AMP) have heen located w lhin en- do(heli.l cavrolse inuaccllulares open to the vascular lumen Ihc :vidcnce suggests that anjrotcmm 1, hradykinin, and S'•AMP are metaholized h r snmdar mechannms, and rn the present invntigation• the authors have esterwk I studies of the kinetics of dnuppcaunce of (1f-1.-)'cCbhenyla/anine) angiolensin I durmg circulatlon through the IunRs, and eaamined plasma membrane and attached lung caveut•e lor their abdity to rnetabdize •ngic>temin 1. -1 he (aic 1 d angilr ten.in I and the suhccllular kscatiorr of ils wrcubolic enzymes in the p1 Imunary cuculatwn may be of physiolotic signiBcanee since one of the meta~.uhtes i• angincensin (1, the most pntent hypertensive substance known Results o( thcse e.periments indicate that: (1) (e-l.-)rrC/phe•ylal•nrne) angirs(cmin 1 is meuhol- iz.ed wn one passage through hbod-fret lunp, •pprosimalely 20 prrce,sl of Ihe radKSactivily emcrtlrng as •ngrolen.in 11, the rerwainder as luwer honw4op, (2) radioactivity is nM retained by the lunp but h•s the sanse vdume of dn•rrbu- tioe and mean transit tane as blue deatraw, a oompound unlikely to eave the intrwascular space; (1) pl•srna wsensbrane fractions o( lung •re capable of convertrng anaiotensin I to angiotenaiw 11. Tlx combined data indicate that the circulating •ngrotensin I is metabolirtd by enzymcs of the luminat surlace of pulmonary endoncorlial eelh. Ryan, l. W, Smith. (/. •nd Niemeyer, R. S. Srkncr 176:64 66, 1972. OtAer arpporf: (1 S Public Ilealth Service. From the Department of Med.crne, (Jnrverrly of Miami School of Medicine, and the Iloward Ilughes Medical Ins,nute, Miami, FIa. PF.RICARDIAI. ('Fl I ULAR RFSPONSE DURING 7NE POST- MY(X'ARh1Al- tNFARC TION SYNI)ROME This is a case rrport involving • patient with poslmyocardisl infarction syndrome (1)rcukr's syndrome). Cytologic ea•mination of pericardial fluid aspiratcd during the second bout of this syndrome, five months after the onset of acute myocardial infarction, reveakd neutrophilic polymorphomrckar ku- kocytes almost e.clusively (9S%) with • few rrsesothelial cells interspcrxd among them Yet there was no evidence of in(ection. It is suRgcucd that this response might be characteristic of this syndrome, •nd that previlxu replnts uf a serosanguinrws fluid being associated with this complrcatiun nriRht t,e at- Irrhuted tn contamination with blood from epicardul e.tensKrn uf the acute myocardisl infarction lhis patient was stdl heins maintained on prcdnisone IIS morHhs after the initial onset of illness so as to prevent clinical csaierhatKrn of the prslmyncardial infarctrnn syndrorne SrrL"(1. 1. A Arnrnrun Nro.r lou~not M'_(h) sl?.816, 1911. (Ithrr .app.rrr: l l S I'uhlK Ilcslth Service 1 rurn thc Ikpa~n c ~ rA Mcdicurc, Ienrplc (Inovcnily Ilcalih tiatrncrs ('cmcr, ('I.INI('A1. SI(iNIf1C'AN('E OF 7HE AN(il(X;RAP•11(' b1iMONSTRAIION OF CORONARY AIIIEROS('LI-ROSIS lhis editorul u•clually a review of the diagrKntic pit(alls inherent In the use of coronary artcrrorraphy as a dusnostrc tocsl. Identification of the coronary vesscls, usually easy in the normal hcart, can he dit6cu11 or impourble in the abn)rmal organ. Uifficultres arise because of faulty techniques, the presence of many variations and anomalies, and the prescnce of disease and ca'lateral vessch Correct iaterpretation of the films often requires knowledge of the natural distribution of coronary alherosckrosis, as well as that of the major coronary arterres and the number of their branches, which vary from heart to heart lhe eaent of stenosis and ils actual ef(ecl upon coronary blood Row cannrN be accurately desermined, •nd because the coronary anlioEram u too insensitive to visualize the entire collateral circulation includrng capillary flow, this technique abne cannot he rned to assess she •dequacy of the corotaary circulation. While the •u1h,x feels that coronary angiography is a rematkable achrevement, essential fur evalruting coronary anawmy in the living and u a pruluck so the surlorc•1 relief of coronary artery obslructic.n, he emphasizn the urgent need fIw p.actical clinical merhesds of measuring bkrud flow and lht drop in pressure acrou a stenoan, as well as Ihe number of eapillaria pcr unit volunse of myocardiucn, in order to be able to •ssen the sigmfkance of coronary artery •tenosis. Sdo#, L. A. American /Iewr lournd fl)(6):727-7)1, 1972. Ot6rr arpportf U. S. Public Health Service. From the 1)eparlmenl of Medicine, Tempk University Ilealth Scienccs CAtaec, Philadelphia. CARDIAC t)ETFRIORAl1ON REPI.ACING CAR1)IAC PAIN AF7ER SUR(:F.RY TO REVASCULARIZTi 111E IIEART Three patienls with cardiac pain of long duration were selected to illu.- Irate, with detaikd reports of their c•ses. the f•c1 that cardiac deterioratioo can follow surgical revascularization of the heart though there is co.npkN relief of pain. 7he author discusses some of the mechanisms p.vsaibly nrsporw- bk for this parado.ical sutuNion which seems to occur particularly •lter saphenous vein bypass. l wo e.planalions seems most plausible: (1) a decrease in bah the concentration and duration of substance P 1• presumed catabolic compound which activates the surrounding pain-Iransmilling nerve (then upon reaching a sufficiently high concentration over a surticiently prolonged perind of time) as a result of imprnved coronary (low; and /2) either destruction or change in reactivity of the perrcnronary nerve pksus, or both. lhus, surgical damage to the myucardium with dcstruction of the pcricuronary nerve pk.us could kad to cardiac deteriorotinn even if cardiac pain is clrminated by the procedure. lhc author strrsscs tha( medical or surgical relief of cauduc pain, therefnre, is rwrl tantar.xwnl to improvement of cardiac (unctron and d/as rwH preclude its dcrcrwrratron Sol.rtlf, L. A. Arnrruon ltr.ur /nurnul R4(4) 446 450, 197? frunt the Ikparrmcnl af Mtduinc, Tcmplc Umvcrstly Ilcdrh ticicn.cs ('cntcr. Phdadclphia 4Y IN

i ASYMPTOMAII(' RAPII) F.("TOPIC TACIIYCARDIA INI)ll('FI) BY ANI) PF.RSISI ING 1)l1RIN(i PROI_ON(iEr) FXFR I ION An attack of prolonged parosysmal venlricular tachycardu hrou:Rht on by physical activity frequently causes incapacitating symptoms. '(hrs rcpurt, how. cver. deals with a case of prolonfled and unusual Iachyurdu in • healthy )9 ycar oW man. lhn arrhythmia, prohably vcnlticular or atr.<wcnturcular lunctional with aberratron, occurs with a rNe of 211/min Jurint suenurws tscrtron in the upritht pcnition whenever this e.ercise is vigorous ensugh to evoke a sinus uchycatdos of 110/miw, persisling until esertron is dcueased and the sinus rate falls below 1110/wrs. The patient is free of cardiac -.ymploms bath at rest and while runninR several osiks duly, yet during this time the artythmu is alrsKnt constantly present. Flls EKO does nW show any wilnifkanl changes in the S-i "rrxnt either during or after esercise. It is le.t ,hat, in spite of the cctopic tachycardia, this patient docs no1 have undrrl)rng heart disease, particularly of the coronary artery typ.. Rutenbcrg, 11. 1 arrf Soloo, l.. A. Arn.rkon Io.rrnd of ('.rdlolory 29.401411. 1972. Other .rPrort: 11 S Public Hedth Service. From the [?epartment of Medreine, Temple University Health Sciences ('enter, Phdadelphia IN VfIRO SF.Rl1M CHOLFSTFROL ESTERIFICATION IN CORONARY ARfFRY DISEASP. The artenal wsll conlains variabk amounts of choksterol, cholesterol esten, and pfw-Apholspkll, the totsl amouol rep.escnting a balance between that which has been synncesrr.cd or haa entered the wall and that which it has dis- carded Comparatively few Mudica have been designed to determine either the mechanisms involved or the capacity of the arterial wall to dispose of thrs accumulation of cholesterol and cholesterol eompounds, attribulcs which play a part in preventing caccuive lipid .ccumulation in the arterial wall. The pres- ence of aa equilibrium between free serum cholesterol and that of the red blood cells bas been demorwrated, however, and it has been shown that the flux of free cholesterol frorw the cells 1o the serum increases as the serum cholesterol becomes esterifled during irscubalion. If a similar type of equilibrium eaets between free plasma cholesterol and that of the arterial tisaue, then a decrease in cholesterol esteri8catiol in plasma might be important in the rate of development of atherosclerosis. As part of a continuing investigation on lecithin choksterol acyl transferase (LCAT) activity, one measure of which is in vFrro chokstcrol esterifkation. the authors report on their attempt to deter- mine whether thn capacity is decreased in the plasma of patients with clinically manifest atherosckrwis of the corouary arleries as compated to a control group of 12 healthy 16- to 6S-year-oW men with a mean age nf 55 and to a younger group composed of 15 men and S women, 27 to 12, with a mean tc of 27. the sthK/y includcd two groups of paucnts, for a tdal of 60 subiccrs: 11 nscn and I woman, ranling in age Irn.n N to 7) years, with a mean age of 37, suflering /rurn acure myrxard.al mfaretron, and I $ men and I woman, 17 to 70, with a rnesn of SA, who haJ cMonrc coronary arttry drsease, but who were lice uf acWe my«a,JrJ snlarntKr. When the nxan serum in vitro cholesterol t0 e+terif-ication, as JctermrncJ by the decrease in free chrrlcsterol concentratiod aftrr rncuhauon of serum for ), 6, 24. and 48 hours, was compared in the four gruups, the oritinal Jala revealed a significantly dccreascJ cstcrdkalion in sublccb with chronic artery disease in contrast to the group of alie-matcheJ conlrols (p < 00S), nJ a signi/kantly increased free cholesterol in subpcta with acute myocardial infarctrun as opposed to the ase matchod healthy aub- jccls (p < 0 05). l hese four groups were then compared a/tcr elimination of those subiecls with total cholesterol >)00 mg. per I(X) ml. and < 195 mg. per 1(X/ ml. because o/ the opinion that a meaningful analysis could be madc only if the mcan total cholesterol concentration was constant (or cach group and in order to avoid the prnsrbJity that, since cholesterol eslcrdication tends to be higher in subjects with hyperchoksterokmu, those groups with coronary raery disease might shov mean eacrifkalions that were overly weighted by including more subjects with total choksterol >)(X) mg per 100 ml l/pon statistical analysis, the mesn bs rUro cholesterol esterdicatK.n bu found to be arlindkantly dccrcascJ at 6 hours (p < 0.02), 24 h..urs, anJ 1(1 houts (p < 001) in subjects with chronk co.onary artery drseau when comparad to age- matcheJ conlrols, and was significantly decreased at 6 hrwn (p < 005) and .tl hoers (p < 0.01) in subjects with acute myocardial infarction when corn- pared to age-malched eonuols. The average alope descnbing chokaterol esteri4 cation over time was siRru&anrly decreased in acute myocardial infarctioa and chronic coronary artery disease (p < 0.01). On the aher hand, there were no significanl diflerences between the young healthy group and the older aae- matched healthy subjects. Although these (lndin£s suggest the po.ubility that subjocts with coronary artery disease Aave an ICAT dcfkiency, the authors slresa the limitatiorr of Ihis study, /or i1 is unlikely that a Arm coactu sion will be available until an accurate method of determining the initial rat. of plasma cholesterol estbriflcatiow is wailabk, and until the enzyme is puriflod. Ruknherg. Ff. 1.., Steria, A. Q., Soloo, L. A. and Sraverman. S. deB. Awserkan Hcrr lo.rrnaf s1()):)11-)11, 1972. 01Aor.arrror/: U. S. Public Health Service. From the Divisioe of Cardiology. I)eparlrneaN of Medicine, and the ()cpartreeat of Bioarelrics, Temple University Ilealth Sciences Center. PhilaJetphia. ON TIIE RATE OF CNOLESTEROL FSTERIFICA I ION IN ('ORD BL(X)1) SERUM Because of the lack of stabk homogenous enzyme preparations, the activity of lecithin cholesterol acyl Irans/erase (l('AT), the enzyme reported to esteri/y cholesterol in human serum, has been studied mainly in partially puri&d prcp- arations or in whole serum. Although there have been reports that LCA T activity in cord serum is signdkantly lower than in adult serum, until recently, the available techniques precluded Ihe shK1y of initial rates and the eflect of nstive enJugenrws suMtuatcs on the reaction With Ihe development of a new tcch- mque which permits the nseasurensent of initial rares o/ I l'A 1 activity and the use of enJugerwNn Iq-proums Juring rhe auay, howtvcr, the UMnparuwM latwten corJ serum nJ adult serum hecame p.v,sit.le Opun measurins the initial rate of 1('A I actrvqy, the authors found that corJ scrum had about one dnrd as much frce and esteriheJ cholesterol nJ abuut wse half as much S1

I.('AT as adult serum When adult 1 CAT activities are plotted against the individual' serum free choksterol kveh, • straight line telatiomhip resulu (0 101 - IK)S% chok.terol estcrdkJ per minute) CorJ serum L('A1 activities (.113! 0407% ch)lcstcnd eslenfied per minute) f.ll mainly above the adult line. According to the authon, these results show that cord serum can evterdy cholesterol of a r•tc equal to, or higher than, adult serum when 1('A I acuvity n related so the amount of serum ftre cholesterol present. L•cto, A O, Rutcnberit, 11 L. •nd SoJoo, L. A. lJpidr 746) 126-129, 1972. OtAtr swrrorl: U S Public Ile•1th Senke. From the t)ivision of Cardiolop. Dep.rtnsent of Medicine and the Fcls Re- .carch Inurtule, Tcmpie Univetrty Health Sciences ('enter, PhiLJrlp[sia. IV. Resp+rotory Systen/ TRACIiFOBRON(-F1LAL CYTOLOGIC CNANOFS DURINU T11Y MENSTRUAL CY('t E In an ongoing study being coMucted for early detection of c.rcinonu of the broochus, e.smination of the tr•cbeobroochial secretions /rr,rn •nes- thetiud patients madc i1 apparcnt that femaks displayed cylorno'pholopc changcs not sren in males. Whether these chanrs were connected with the menstrual cycle or nd was not known. To ascertain whether the rnenstrual cycle was involvcd, smc.n were made from bronchial washinp of patients undergoing genera) entkNracheal •neuhnia. Cyclic cytomorpholotirc changes were observed in the ciliated columnar epithelia of younger lemales but not in epilheh• of males and ofder women. 1)uring the proliferative phare of the menstrual cyck, the nuclei of the eJuted cells were found mainly in the basal position. Following ovulation they ascended to mid poailion, •nd as the sccretory phase progressed thef migrated toward the apea. After pproximately the 25th day cells with basal nuclei predominated once nsore. (lobkt cells proli(erated concurrenlly, probably indicating rnetapl•sia from ciliated cells with hish muco- polysaocharide content. These cyclic fluctuations may possibly protect /emaks from inhaled irritants and earcirsogerr. "In the present series, our maks were fotrnd to smoke two to three times as many cigarettes a day as did our women at compar•bk ages This does not wRiciently e.plain a 7.1 irsciJence of carcinoma of the bronchus between maks and femaks in the general poprda- lion llse unaccounted factor could well be related to the changes we have dernonsuNed in this study." ('hdon, /, loew, 1) A. Y. and Ortln, 1.. R. lou,nel of nce Arncrir'.n Medical A„orJariow 2111(1 )) 1928 1911, 1971 Other surporf r Amcraan ('arscer Society. Frexn the f)epartmrnt of Anestheucdo[y, Ibe Albert Fmstein College of Mcdi- croe of Yeshiva t)mvcruty, I he Bt(xss, N Y. I I ( VOI l1MF ('ON1 kOI LF1) RELATIVE f1UMIl)I I Y USING A CUNSIANI-1FMPFRAIIIRE WATER VAPORILfR Althoudh evsdence suttests that precise humidification of anesthetic gases is desir.bk in order to protect airways and maintain body temperature, cspc. cially when nonhreatlung and high-flow systems are useJ for prolonged perads, none of the commercially available water vaporizers accurately maintained selected relative humdittes in such syslems. lhis report deal• with the design of a new apparalus which meets the authori criteri• by delivering a relative humidity of 60% of room temperature (22-26' C). T6is amount of moisture apparently prevents the type of damage to the ciliated 1r•cheobronchial eprthcl- ium which is observed when dry lases are used clinically for mora than as hour, since there are no evident cytologic changes after three hours of anesthesia In the authrxi opinion, provision for precise humidilkNion at desired levels will eventually become mandatory in anesthetic systems. I new. 1). A Y, Klein. S R. and ('h.fors, l. ,AM.,ncir,ioLorr )M2/.1t1-Ie1, 1972. From the Ikpartmrnt of Anesthniolop, lhc Albcrt Einstein ('olkge of Medl- crne of Yeshiva Univer•ity, lhe Brons, N.Y. EFFECTS OF DRY ANETTItETIC GASES ON IRACHEOBRONCNIAL CII.IAI:ED EPITIIELIUM In the course of their research on the early detection of bronchial carch.o mu, these aulhocs eaaminod Iracheobconchial secretion. /rom •neuhcUmd patients in the study :nd noted that the secretions of those receiving dry !•.n through a tsonbrealhing system manifested eytomorphofogic changes not seen in those of patients placed on • eirck-absorber system. They decided, therclore, to determine, by varying the humidity of inspred gases, the presence or •bsence of significant cellular changes caused by dryr.ea, and the time of eaposura necessary to produce such changes. Investigated were sis patients receiving general anesthesia via endoaracheal tube for three hours or more. Sia patieou eaposed to 60% relative humiduy at room temperature (22-26' C) and ut esposed to saturaled humidity at )7' C served as controls Ciliated epithclial cells were obaincd by bronchial lavage with 5 ml. physiologic saline solution immedi•tely after tracheal intubation and at hourly intervals Iherca/ter; smears made from the auctioned material were Aaed at once, stained by the Papaaico- 1•ou methoJ, and eaamined nsicroscopicatly Cellular damage was asacsud numerically by a point uorinR system. Smears obtained from patients who had breathcd dry gases for mwe than an hour showed significant changes. Afhes three hours of inhalation of dry anesthetic gases. 19'%. ol the cells had damage to the cilia and endplate, )9')f% had developcd cytoplasmrc changes, •rd IS% nuclear changes. lhere were'no significant changes in the anscars taken /rom the controls. ('hufon, /, 1 oew, 1). A. Y. and Makbranche, ) Anruhnlulory 17(l) 118 141, 19)! 1-tom tl.c 1)cpartmcrd rif Ancs/hcsiulogy, Ihc Albeit I rnstcrn ('rdlrgc of Mcdr eine of Yeshiva l/nrvcrsrty, I hc Brunr, N Y. Sl 52

i '111ri NRON('111AI. IiP11111'1 lt)M IN CNRONIC BRONCIIIIIS: I I:XIY11IA11Vt: ('Y1(1t(X;Y t)URING STAB11:., A(-Uft: NA('ll RIAI. INI 1(-11()N ANf) Rt`X-()VFRY PIIASFS l-shdr.tivt cytokMsic esamination of spulum, which has been useJ primarily a% a duRnoslrc technrque in canctr of the lung, can he usc/ul als.r lor the investigation of changes in the bronchopulmonary system in chronic bronchitis anJ other nonmalignant drsorden. In this sndy, 26 patients with tsuhlishcd chromc bronchitis provided sputum specimens durrng the course of 4 ) clinically evident esacerbatr.ns of acute bronchial infection. Qualitative and quantitative dcterminarions of the types of bronchial epithelial cells esfoluied in their sputum were carried out during Prciwtection stahie slate, acute esacerbation, nd recovery. Rcsults showed that bo(A the daily sputum volume and the cclhrlar concentratrwr (sputum cel4 pes ml) larcreased significantly during acute bactcrial exacerbation and then decreased tJjndicanUy during the pos;inrection recovery phase. Quantitative chanRes froen the acutt exacerbation to the re- covcry phase inclu.led some decrease of degenerated basal cells and ar• increase of degeneraled ciliated cells over both uahit and .cuN phascs. ('akulatwns frrxn these data wgjtu that the average paieM wNA siabk chromc hrorKhrt» dcnudn 3 26 cml of surface mucoaa daily; IAio value increases to 10 10 cros per day with the acuu esacerbalion. Specific dynamic changes of the lronchial epithelium in chronic bronchial disorden can be esarnined during life in a serial and repetitive manner, using the apu(um produced as a«Bectinn of the pathologrc alser.trons in the bronchi "11re repeated sequence of dct•neration .nd regeneration implied from the dala in the preaent study lus been ahown in animals to provde an optimal envuonmen( for malrgnant transformation in the presence of carcrrK.irnre suhuances; however, subtects esfotiating mrtaplastic cells followed in thn laboratory for up 1o ten years have not derrkrnsiraleJ an incrcased incidence of brcxschollenic carcir.oma.' CAr.dorA, S and Medrei, T C. .(mrricanJtrrlrr of Rrrprarory lNuarr 10d(6)a<ea 999. 1971. From the l.ung Station (Tufts), Boston City Ho.pital, Boston. TIIE RETICULOINI)OTIIELIAL SYSTEM IN CNRONIC BRONCHITIS. 1. QUANTITAIIVE SPUIUM CELL POPULATIONS DURIN(3 STABLE, ACUTE BAClER1AL INFECTION. AND RECOVERY PHASFS Qualitative nd quantitative measurements of reticuloendothelial system cells in the sputum of 26 chronic bronchitis palienb were performeJ durint 4) acute bacterial esuerbations aa well as in the preinfection stable ua1e, and during recovery. Nculrophih were predominant at all lime, their greatest number being observed during the acute phase. lhe number o/ huHocylcs was greatest during recovery; monacyles, lymphocy/es, and plasma cells were found in aigndicandy grcsicr numbers during acute infection than in the stable state; the nunrhers of plasma cells subsequently decreased by the linse of rccovery lhe rn vrvu phag.cyrrc indcs of hrsuocyles for bacteria was increauJ in both acute infcctirxq .nd recovery phases, whereas that of neutrophds was un- chantcJ IAnt phaen'ytrnn by histiocytcs was dtpressed during acutc in/cctiun, but ccll phaSocylus,r /olluwrd the patlern of bactcrul ingcslusn I arge muno nuilear hntKrcylcs prcJomrnalcJ in all phases tht presence of all thcu cclls 54 I in the sputum of chronic bronchitis patients appears to be a dynamic reflectioo of the inflammatory process in the bronchial system. Result@ suggcat that the inflammatory response observed during these clinical phases is mwe coeristcat with acute rather than with chronic inflammation. II may be that '-chronc-' bronchitis is the result of a series of superimposed, sequtntial. acute inflamma- tory insulu, and that it is these events which, by their repetitive tuture, givc the impression of chronicily rather than the indolence of the inAammatio. Wcll It may he alao, that an underlying defect of host defense mochani.ms may represent the true, chronic aspect of the disease. According to the authors, these data suggest that most of the sputum hialiocyles originate from monocytcs milrating through nreas of inflammation in the bronchi •nd that alveotu macrophates contribute very little to the response of the reticuloeedwhehal system in chronic bronchitis. Medici, T C. and Cbodosli, S. Amrrkan Rrv/rw ol Rrrplr.rory Dbror 10S(S):792-11M, 1972. From the I ung Station (fu(h), Soaloe City llo.pital, Bo.to.. fN Y1TRO STUDILS OF T11E FOAMY MACROPHAGE OF POSTOBSTRUCTIVI3 ENDOOENOUS LIPOID PNEUMONIA IN MAN TAe lunp of (satienl. with °poMObaructive lipoid pneumoaia' ooMal., distal to obNructcd (xoochi. IuRe, loamy-appearinR, alveolar macropiaRcs witb many large cytoptasmic vacuoks. This report presents information aboaN thr clinical syndrome, aa well as about the pharocytic characteristics of tbese abnormal celis and the lipid composition of their vacuolar contento so wluch they owe their appearance. Cells from resected lungs of patients with non ob.aructive cndobronchial lumors were used as controls. The foamy wucro phars were larger than normal ones, but contained similar includorr. Thdr phajocytic rau was normal /or their .iu and, like the one for normal alveolar m.crophaRes, was depressed by low OI (ewsia+ but not by hiRh CO. kn.ioa A white precipitate formed in the culture medium of foamy macropha=ea taken from 5 patients and grown in vitro for 4 houn, was removed by ccarifutialwe from the cuhures from 2 of these patients and analyzed. It was ahow. to b. a lipid containing a high percenlaZe of dipdmitoyl kcithrn, the major wrrlacx active component of the IunR-lining (yrer. This is compatible with tAe nulfln lion that lung macropisages have a role in wrfactant melabolum is p.tienta with obstructed bronchi. No similar malerid could be separated from the culture medium of normal macrophaRes. Case heslories, the course of patienu' Wnna, arnd the histologic appearance of the surgical .pecimens, suggest that Infectiun is not easeMial to the accumulation of foamy macrophagcs. Cohen. A. A.nd Cline. M. 1. Amrrlcan Rrvikw o1 Rrtplrilrory Disrasrs 106(1):69.78, 1972. Other aupport: lJ S. Public Ifealth Service, A. 1.. Ilobson Memorial Fund Ruse Tornhtrg Fund, Avery Cancer Research FunJ, and CarKCr Rcacarcl Funds of the lJmversuty of Caliform.. Frnm the CardMrvascular Reuarch Institute •nd the ('.rKer Resc.rih Inslitutr I)cpartrncnt of Medicine. llnrvcrsaty of California SaMrd of McJKnac, S., Francuco. 55

(31, I t'n • r_ I11) 1 A(' I A 1 F hI 1IY1)RO(:FNASE IN SPUTUM FROM PA fl':N I S WI111 ('HkONIC (111STRU('IIVE LUNC7 DISFASIiS 1( 1) lactatc dchydrogens.e activities have hcen studied in a widt variety of mammahin ussue., ctlls, rn1 body fluids, and some of rts propcrires have been deternuncd (lprrmal conduKrns have also been established In sslrva, the source of the entyme was stuihuted to oral kukocytes Ipolymurphonuckar neulrophol.) Other uudres have shown that spulum taken from individaals with chronic ofnvuctive lung disesse contains both cellular and nonccllular indrea- lors which can help to asscss the etlent of the problem Dependent upon the type of drsease, human sputum oonlairu sukruntial, of varying, nu!nhers of bronchial eprthchal and inflammatory oella, especially neutrophds, eo onophils, and hrstrocyles Imacrophates). Similarly. in twch patients, sputum Iactale de- hydroFenase activities varied with the inflaweulory sute. lhis is  report on the aucmpt to quantitate and partially characteriu 1/ { 1_lacute dchy(rogenase in human sputum hoawgena/es, in thc hope o/ adding to the urnfenunding of chronic obstructive lung drseasc by conlribWi.ll so Ihe systematic uudy of a broad spectrum of essential melaholie eospowewts and odher coneutuenu auo- cuted with the Inflammatory slate aod host de(ense mechaniu.u of such paients Study of the stereochtmical spaeiAei/y of lactate dehydrolenase at pF1 9.1 demonslra/es that whde b(-)laclate activily is either absenl, or present in very low concemratrons, there is a substantial amoun( of 1(; )-lactate-depen- denl activity in the sputum of these palieW. The lalter form of the enzyme appean to be primarily of the heart (1t) lype, which requires optimal low conctnltatqns of pyruvale for masimal activity. lbis form, moreuver, has charactenstics similar to those previously found In human uliva. 'The poly- morphorwckar kukocyte is also a major cellular type found in the human sputum specimens 1 he actuvrtres of whok spvtum humosenates were found to he virtually the same at thAne of tpAnum homogenate supernatant cstracts Freezing and thawing of whuk homogcnatcs resulted in a vsriahlc luv of enzyme activity tirlkl, S. Shahnk, 11 A,(-Aodorh, S, Mcd.cr, T(', and Burgi, 11 7Ac loucnaf o/ Cobucarc»y and ('hnrra/ Alydirrnr 7941) Ihl-4A9, 1972 From the Science Resourccs Foundahnn, Watertown, M.ss , the Tufts I ung Station. Iknlon (lty Ilospstsl, Boslon, and the Asthma Klmik, Bcrnische Flcihtadte Flcdrtenschwendi- Switzerland. AI.VFOI AR MACROPFIAGFS: STRU("TURA1. ANI) FUNCTIONAI- I)IFFEREN('FS BLIWFFN NONSMOKERS AND SMOKERS OF MARIJUANA AN[) TOBACCO 11re investigation compares cells nd acellular material recovered by bronchnpulmonary IavaFe from the lunp of nonsmokers with similar material from the lunp of m.njuana and tobacco cigarette amokers. lhe volume of ccllular and cellular material recovtred, the sire and ultrastructure of macro- phsgts, and the capacity of rhose macrophages adhering to BIsss to irKOrporstc ('anJrJa dArronr wete obxrvcd in marijuana smokers .nd nunsmokers Since the utn..uucrare of macrnphalfeo reeovered frum tobaceo snwrkers ias been stuJrcd, Bsass .Jhcswtn nd phaPaytrc capacrlies wcrc the only characteristics uf toh.ccu sunnkcrs' n.acrophaRcs essminal. ('ompariu.ns of mat.juans snKrkers' S6 and nonsmokers' macrophaFcs revealcd ullrasuuclural ddlc,cncer confined to the cytoplasmic inclusions Ncedk-shaped structures and pale. uftcn circular areas wrthin inclusions were common in macrophagcs rccuvcrcd /rorn the lungs of manluana smokcrs but were rarely observed in the cells of rwrnsmokers I argc pale rcas within inclusicxn and highly ckclrcrn dense areas withrn inclu- nons were virtually confined to the cytoplasm of m.c:rnphages frorn marquana smoken. Functronal comparisons of macrophaFc (rum nonsmoking voluntcers and from smokers of erther marijuana or tobacco sh..wed that these cells have similar capacities to ingest heal-kdkd CanJrda ulhrruns Howevcr, a higher percentage of macroPhaFes from smokers of marijuana and tobacco adhered to glass than did those from nonsmoken-perhaps indicating a diAtrcnce in net negative surface charRe. lhe functional diflerersces found between the macto phages of tobacco and marijuana unokcrs and nommokcrs do not indicate  diminution in the defensive capacity of these cells Maon. P. F. (i ,('oAen, A. S, Fin/ry, T. N. and l.adman, A. 1. 1 aborarory In.r.tlgarbn ?5(21:111-120, 1971. 4ffic• a.rprft National Ins(rtu(cs of Ilcalrh. A I Ilrrt+x+n Mcrnonal Fund, Rrne Tornbcrl Fund, Avery ('ancer Research Fund, and Unrvenny of ('ah lornia ('ancer Research Funds. From the Pulmonary 1-abortlory, Mount Zion tlospilal, and the ('ancer Re search Institute and Cardiovascular Research InslNutc, l/nivenrty of ('difornta Medical ('enler, San Francisco, and the Department of Anauxny. School of Mcdicirse, -I he University of New Mesico, Albuyueriluc. RFI.AIIVIi IMPORTANCE OF GENETIC ANI) FNVIRONMENTAI- FACIORS IN EMPIIYSEMA lhis is a short summary of the results of a systematic study of flrMdegree relativcs (aiblinp and offspring) of all severe chronic obstructive pulmonary disease (COPD) patients referred to the Valley Medical Center In Fresno. ('ahfornia, which was undertaken in order to evaluate poasibk senetic eonurbu tions to COPD. lbe data consisted of the following: routine history question naires, chest a-rays, spiromelry including forced vital capacity (FVC), (orcal espiralory volume (FEV) in I second and in 3 secorx)s, and masimum mid espiratory flow rate (MMF), residual volume (RV) determination, calculation of total lung capacity (ll('), RV/TI (', and measwemen/ of serum Irypnn inhibitory capacity. Marilal partners served as con/sols, and along with the relatrves, were classifsed as nornial, mild to mo.kralely abnormsl, ur severch brxrrmal, according to their pulmonary lunction studres When the two groupr were crNnpared with respect tu prevaknce of hnormahtics, resulrs inlrcat0 that: (1) the drfference in prevalence of abnormalities loetween the relsuvcs am' conlrnls was significant al the 1% kvcl, suggesting. hul nw pruving, a gcKlr contrihutiun to the devcwrpnsent of (Y)P/); (2) a definite and highly ugruBcsn, relatwsmhip was Iso suKKc+red between anwrking rwI dcvelu(wncnt of ((1PI) (1) when family relatrrnsMp and smoking were nalyied logrncer, rK.nsmukc, eunlruls had the krwest prevslcnce of t.mlrnlOhtaY 1211';6). rwl smukar rels lives hAJ 1he highest 1'_71'R.), the rw.nsnwrler rcl.uvcs .ud snwker conuu/. h.d atKrut cyual prevaknce ul ahnurm.hutf (14 1';:, arnd 1111'(,, rc.pccuvclyl 17

(4) a further attempt to rclate the increased familial prrvalcnce in this study to o,-anbtrypsin deficiency failed to esublish such a rclatronship; but this can only he clarifkd by further study utilizing more dcfSnitive tcchniqucs lhe authors add that it n qurte likely that aher genetic dcficiencres may be rsso- ciated with ('OPf) in additron to Ihat of o,•anlitrypun and that Ihe analogy with nonspherocytic congenital herrsolytic anemus due to a variety of red cell enzynse deficiencies seems appropriate. 1/ thcse genetie factors can be dcflned, fwtherrno.e, it might be posuble to dclineate that segment of the poputrtion which would be adversely aflected by srnoki.g or othe. environmental :d1u- eoces. Frdtnberj. ll H. and I arson, R. K. In Mittman, C. (ed ): rrfnrowury EnspAyun.n and rrorro/yzL, New York: Academic Preu, 1972, pp 65-67 Othwr support: AmcrKan Mcdical As.ocistiow-Fducational srd Research Foundation From the lkpartment of Medreiwe, lJnivenity of Cahlc.rn.a School of Mcdi- cirse, San Francisco l OW YIEI.D OF PUl MONARY SURFACTANT IN CIOARETTE SMOKERS 7hcre are drtrnct drflerences i the bronchopulmonary lavage yields of smokers and non.mokcn In the present e.periment, crKSobronchial lavalie was perlorrncd on crglsr normal srrroZcn and etght normal nonamoken, and aerial lavalies were performed on Ihrce o/ the former who stopped smoking after the initial lavatic All but one of rhe srrokcrs used filter tippcd ciolarales, but they all smokcd one or moce packages a day frKloMonchial lavalic sediment in unoken reveakd a marked deficit in the volume of the whrte aeellular layer (sw/aclam) s comparcd to that of worumokers. The volume of wrfactaaw rapidly returned so nonsmoker levels when the subjects stopped ,moking. l.ipd analysis of wrfactant (rom smokers and nonsrnoken revealed no qualitative diAerence, bul the total lipid content and in particular lecithin was seven Iinses leaa in smokers. This defkit of wrfaclanl and its rapid return after ceuation of smoking are compatible with the hypothesis that cigarette uraking reduces the production of surfactant or increases its removal. Finky, T. N. and Ladman. A. l. TAr Nrw Entlanllournd o/ Mrdklnr 286(S):22)-227, 1972. Other rrppN: National Instrtutes of Hcalth. From the Pulmonary l aboralory, Mount 7ion llospital and Medical Centcr, San Francisco. SIFRI?OMI('RO.ti('OPI(' Fl1NNFl-IIKE: AR(-1111F('1lIRE Oh 1'ltt MONARY LYMPIIA7IC VAI.VFS A•terrnmrcro+rop1c Ierhnrqlrc which .Iluwrd direct observalinn uf pul- mun.ry lyml,h./,c v.l.rs w.s u.cd I r stu,ly these rlrurlurrs /hrnoRl.rwt Ihe lun~~ .d tv.rlvc hsl- +h,, ,I,rJ v,ih,o fl.c J.ys of Mrlh RcsulFs tudr.alc Ih.l these valvcs are not hicuspid, as wss previously ,huughl, hut consist of one srmpk funncl- or cone ltke structure lused around the lymphatic vessel wall at the Largcr proaimal opening, and aaully suspended within its lumen lhis "monucuspwl" type of valve which seems to be hocd by a double layer of endothehal cells supportcd by a central framework of connective Ihaue would, moreover, be well adapted to the eatablishmenl of one way flow and drainage of lymph since such a structure u probahly occluded by reverse flow. This type of valve seenss to be present s well in other body organs where it providcs for channeled flow and drainage of lymph. l hrs study emphulzes the im- portance of direct visualization wilh a minimum of artifacts whenever correct anatomical relalronahips sire to be established. larwerynr, l. M. Lymphofogy q4):125-112, 1971. From Ihe lkparlmcM of Pathology. Katholicke lJnrversilcit--l.euvcn Neder- lands Schod of Medrerne, leuvcn, lklliium. SECRETORY CELIS IN 1NE PREMATURE Hl1MAN LUNO lAlfUl-E This repoa describes cells with the ultraslructural characteripin of rscuro secrelory cells in the lung lobuks of premature inraMs. l.unEs obtained /rorw two infants weighing 600 and 1.600 g were dissecled urder the microscope, fiaed in phosphate buffered glutaratdchyde, embedded in 'Epon; sectioned, wd stained by RcyrwW's method The characteristic cells occur intercalated awwsig mucosal cells of amall bronchioks and aho amonR respiralury epithelia. lhc typical cell is small, 'ure{ularly cuboidal, and ealends below the usual level of other cells lining the lung nearby but its prohk does not usually touch the lumen. Typiclly, it does not insinuale long narrow protoplasmic processes between or around cells. The numerous inclufions have a centrally located core of tightly packed material, surrounded by a clear rim. "Ihe cytoplasm 'rs typically quite dense so 600 R, and less so at 1,6110 S. lhese flndinp suggest a rclatios ahip between the fluorescent granulated kinin-like, amine-Irke, or neurosarewry cells previously observed They also resemble APl1D «IH, materials (rom aomc of which may he broadly characlerized as vasoaclive and muscub-active; soms are mediators of ncuronal activity. lhus, the locatrsn of these cells in the bronchiolar or apical portion of Ihe• rarmal fetal lobuk is consistent with the idea that this locus is probably a resula/ory center of lolwlar activity. Roaan, R. C. and Lnrwrrynr, 1. lal. Narurr 2)2 60 61, 1971. From the 1)cpartmcnt of Pathology. School of McdKrne, llnivcrsity of I,cuven, l.euvcn, Belgium '1111: FINE SIRl)CIl/RE OF IIIF. Il1N(i IN NF(1NAIA1 "l1YAl.INI MhMNRANI'. UISFASE " lhis paper rcvrrwr ll.c pulnu.nary palhuhrgy u/ nruusrsl "Ilyslrnc Mrin hranc 1)ucjsc-' 111M1)/ u.rn( Irsh/ and clcctrun nlr.ruxupy with vssiular in tcctiun c.pcrinscnls Prcltmrnary Irr .+n un.krstanJms ul thc pathuluoly uf IIMI) 59 ss

17) +.4 76 ...:fv z i I m ~ ~ O ~ m ~ ~ ~ is some knowkdge of the hasic unit of the lung The prenulure lunt n built up o/ basic umis, the rr.puatory krbulcs, whose stuucnrtc is drOcrcnt frum the adult lung lohuks The appcarance of the lungs in IIMI) dillers depcnJmg rsn the postnnutem inlcrval In addrtron, reparative arxd reactive changes rKcur if the children live any suRndkant kntrh of lime Pathulugical studrcs show that the hyalrne membranes .re stdl the most reliable criterion leading to the dug mrsrs of IIMI) ihcy result from severe lunj damage (eprthclul necrusnl, rn- crcased plasma ttansudatKSn, and Inhaled amniolic flurd. lhere are mtllrple, apparently related mechanrsms involved in The pathotenesn rK1 outcnlne of IIMI), and it is not as yet certain which is primary Important factors seem to he high pulmonary vaxular resnlance, impaired or deficient sur/acunt acUvity, increased alveolar wall ptrmcabrfity, and Iransudation, inhaled amnioMic f1uK1, and inadeyuate fibrrnnlysrn system. Larwrrync, l M. In lrorrrdrner o/ tAr XIII Inlrrn.rlowal Cowtrrar o/ lydranirt, Vienna. August 24 Stplembcr 4, 1971, Vsenna: Wiencr Mcdulniachtn Akadcmrc, 1971, pp )47-7S1. OtAer arrppurfr Belgium National Fonds Vooc Wclcnschappclijk Onderzoek. From the Ikpartrssent of Pathology and Ilistob~y, Katholicke Univernleil- l.euvcn Ncderlands School of Mcdicinc, Leuven, Belgium. TIIE UNIT I.OBl1L.E: A REVISED CONCEPT OF 1 HE NI ONAI A1. I UNG The unit bbuk is the basic structural and functmnal module of the lung , In the premature rnfant lung the mar.w components of the unit lobule re the air-bkxsd barrier, the imenaccular seplum, and the saccular wall as compared to the air-blood harrier. Ihe rmeralvcolar uplum, and the alveolar wall in Ihe adult lung. In both premature and adult lunjs the unit apca contains a muscular terminal bronchiok, muscular pulmonary artery, bronchial anastomoses, lymph- alin nd nerves. The terminal bronchiok actively regulates flow and volume of gas, the air-hlood barrier pazsively permits gas diRusiocs, and a rich cellular diRerentialan alhowa that function ia a result of many simullaneous and com- pks interrclationships including that of wrfaclanl. In the rapidly growing neonatal lolwte. there is adaptation from a fluid-filled secrelnry, slate perfused al hiRh pressures arwl low flows; in the adult lobuk, vcntilawry functrun is e.ercrtcd in steady state at low pressures .nd high fbws. The cellular compcssi- lion of the neonatal lung is carefully considered here. F.perimenlal and chmcal data suggest the role of the unit lobule in o.ygen tosicity, neonatal emphysema, and hyalrne membrane disease. Larrwrryru, I M. and Rosan, R. C. In Iluntrnglord, P I, Beard, k. W., Ilyucn, F. F. and Scopcs, I W Icds 1. rrrlnaral Mrdiclnr r.,wrrdrntr oJ the Srrond Erropr.n Contresr of Yrrinaral Mrdirrnr. I ondun, April 1970. Bscl S Karger, 1971, pp 259-26). From the I rpenmcnral I ah.xatory for ('ardiopulmonary and Genilal Pathol- o1Y. S4hiwl o/ MedKrnc, llnmveuay of Ituven, Ituven, Bcllrum. 60 111F PUI MONARY I YMPII VI:StiI:IS ANI) 1'11I IR R(/l 1: IN PULMONARY ('LEARANCE 1 he authnrs present an c.aenslve review of the suhlect with 13 refcrcnoca Iu the luerature, including 12 published between 1969 and 1971. It is divdcd into the f.rllowing 6 sections: 1. Inlroductiun 2 1 hc localization and the claadicauon uf the pulmonary lymph vessels 3 I hc alveolar ckatanu and the jusla alveolar lymph vcssds. 4. The histological struclure of the pulmonary lymph vessels 5. The ultraslruclurc of the lymph vesscls and the absorption of lymph. 6. 7 he composition and structure of the lymph valves. Buuuauw, 1.., Baerl, 1. and L.auwrryn., I. M. Tijd. voor Grnrr,Arndr 2f1(I)fll-91, 1972. O/Aer aupporlr National Heart Institute and National Institutcs of Heahh. From the F.perimental I aboratory for Cardiopulmonary ard (Senitd Pathd- oRy. Kathohcke (lnivcrutcil---Leuven Nederlanda School of Medtcine, Lcuvc., I/iellewm. CENTRIOLFS AND ASSOCIATED STRIATF.1) FII.AMENTOl1S BUNDLtS IN RABBIT PUI-MONARY 1-YMPHATIC EN[1OllIEL1AL CELIS Although they are known to be present in perhaps every living ccll, w`nr they may have any of several diverse and important functions, and in spile of their challenging highly organized slruclure, there has been a noticeable lack of precise reports on the ullrastruclure of the eenlrioks in lymphatic endothelial cells. This, coupled with the occasional ekctron microscopy obaervation of peculiar bundks of slrialed filaments associated with cenlrioka in the erndothclial cells of pulmonary lymphatic valves and collecting channds (i e. pulmon.ry lymphatics provided with a layer of smooth muscle cells rsd/or valves) i. the rabbit lung, has prompted the authors to proceed to a more ayslemalic lnve.ll- gation of thcse particular cellular organelles. The'u ekctroe rtskroscopy study ol the pulmonary lymphatk collecting channels and their valve• in the rabbrt reveals that the ersdolheli.l cells generally contain Iwo centrio{ea which are almost invariably associated with one to aeveral atriatcd bundks of Mame.u This structure corrrsponds well with that of the orelanclk in other ull typea, although the filaments were seen only in endolhclial cells and not in she peri- Iymphalic connective tissue cella. The bundks consist o/ 2 to 6 fllameMa of about 40 A diamelcr, and show a cross banding with a periodicity of 6(10 to 900 A; they are attached either at both ends or in the middle of the crntriok. The authors conclude that although their actual function is still unknown, they might be vesligial rootkta of rudimentary cilia of lymphatic ersdwhch.l ull., or be assocuted with the role of cenlriolcs in cell drvision, cellular ameboid movemcnt, or organiution of cell cytoplasm. All .re possibilities which remain to be invnNgated. Larrwrryrv. /. M. and Boussauw, 1.. Zrltuhrl/r pr Zrll/wuArng «rd MiRrorloPfsrAr Anoromlr 121.417 427, 1972 From the I aboratory of Pathology and Histuloty. KathMdicke 1/nivcrsiteM-- Leuven Nedcrlanda School of Medicine. Leuven, Bclgium. 61

NF.IIROFPTT111;1 tAl. HOI)IFS (NEiURORF('FPTOR OR SFCRF.IC)CY ORGANS') IN HI/MAN INFANI BRONCFILAI- ANI) BRON(-11tO:.AR E:PI 1 F11:I IUM Biopsies taken from the lungs of IS newborn babies at autopsy and studied by means of hrstochemical techniques demonstrated the presence of bronchial and brunchK,lar cellular corpuscles which the authors call rxuro- epuhelul bodies. While the (unction of these corpuscular, argyrophd,c, in- ncrvateJ, and fluorescent structures remains unknown, specialited receptor organs have been noted in the resprratory mucoaa of adult rabbit and dog hrorschiotcs; clustcrs of argyrophdic cclls on which werve f>ben end have been Jcscrrbed in the cat; and iskt rcceptcrrs compored of cubical cells have been nkntrfkd in adult rats at the "mecting poiN of several alveoli" and in the hrcnchial mucosa. tl may be that Ihese neuroepilhelial bodiea are rclatcd to the recently repuned bronchial artlyrophilic, fhsoresceMr and granulated (AF(i) cells which arc perhaps also pepride and aminc-producing, and possibly to the Irptrfe- secreting (APl1D) cclls of other th.ues and oapna. lhey might be involved in mucosal bronchial and Monchiolar neuroaocrelory processes. The .whurs poslulate, however, that they are mos( probably chemo-, stretch , baro-, and/ot tactile neurorceeptnr o.garu, and apeculate that they may be slimula!ed by inhated pollutants or parucks pcesent in irrpired air which have bypated the cough rcfka. In thrs respect, it is inlcresting to note ora report that the nerve termrnals of the acrcalled "iskt receptors' in the alveolar wall and the bron- chwlar mucoda of the rat lung diuntepated altet inhalation of coal doal. L.urwrryru. LAI and Pcuskens, 1 C The Anaromkal Rrco.e 172(l):471-4s1, 1972. From the Tkpartmcnt of Hntopathobgy, Katholicke Univeraiaeit -Ctuven Nederlaods Schor>t of Medicine, Ituven, Belgium. TiIE BENAVIOR OF MACROPHAGFS IN LUN(3 ('ULTURIS AFIE:R EXPOSURE TO Ct(;ARt{TTE SMOKE. EVIDENCE FOR SF.LE('llVli IN1118ITION BY PAR11('ULATP- MA7TER ANT) S1tMULAIIUN BY TIIE GAS PIIASE OF CELL METABOLISM OF ALVEOLAR MACROPFIAGFS The present report deals with biological effects of charcoal flltered whole cigarette smoke or its gas phase on alveolar macrophates and epithclioid cella in cultures of lungs esplants from Snell's mice and (loWen hamsters In each esperiment a minimum of sis groups was used, each group consisting of four matched cultures: two controls, one eapoaed to whole charcoal fittereJ (WCF) cigarette smoke and one esposcd to the gas phase ((i('1 ) of charcoal filtered cigarette smoke. Results showed that after ecposure to WCF snsoke the number of outgrowing etlis was markedty reduced, whik after eaposure to G('F smoke the number was essentially the same as in the control cultures. 1 his reductrrn of total numher of cells following WCF smoke did rnH involve the cppthclr)iJ cclls, but was a selective damage to alveolar macrophages by the cigarette .mukc In conua+t to rhis, it was found that the (N'F vnuke had a stimulating cflecl on l)NA synrhrns of alveolar macropAages but nw cpincclwviJ cclls Ihrs interesting finding not only points again to the greater sensitivity of alveolar macrophates to facrors from charcoal filtered cigarette smoke, but also shuws that parUCUlate matter has a hio/otical activity quite ddlcrcnl from that ul the gas phase. L.rrchtrnbrrgn. C. and t.euchlenberger, R. In IAl.urio, N R. (ed ): The Rrricrlo.wdorAeNd Systcns anJ Immrwr Phrno- nrcna, New York: Plenum Presa, 1971, pp 347-360 OtAer support: Association Suisse des Fabticants dc Cigarettes. From the 1)epartment of Cytochemistry. Swiss irntisutc for Faperimeotal ('ancer Research, l.ausanne, Switrerlarsd. MORPIIOI (X3I('AL ANi) CYT(X'HI:MICA1. EFFE('iS OF MARIJUANA ('IGAREI-IE SMOKE ON EPIIHELIOID C'Et.IS 01: Ll1N(3 EXPLANIS FROM MICE A model system dcvcloped for ecposing IunR eaplants to puf/s of Iresh cigarette srtw.ke in standardiied condaion* was used /or theae eaperiments Lung e.plants from Sncll's and ('3781. mice wcre prepared on covcrdips and e.posed in a arswking machine to pr/la of (rnh cigarette smoke. ('iprNtn were prepared with tobacco alone arsd with the same tobacco miscd with marijuana 10 S-1 g) in a powder form. Two types of marijuana were uaed. one containing 04% telrahydrocannaAino) 1T11C) and one containing 4% 111C. (-ytulogical characters and chronwsornal behavior during mitosis were studied in live cultures under phase eontrast, and in the original unsquashcd paineJ cultures 6-240 hours after esprssrrre. Results showed differences betweew con- trul cultures and those esposed to eigarelte smoke with and without marijuana C igarette smoke alorse was cytotosic a(ter four puffs, whik cigarette .moke with marijuana had little cytotoakily. Nowever, altcr 24-48 hours of eaposure to marijuana cigarette snsoke, the shape of epithelroid cella and nuclei was affected Indications of abnormal proliferaliors were accompanied by an increase of mitotic indea and by stimulation of DNA synthesis. 11 thus seeor that the addition of marijuana lo cigarettes produces a srswke which evokes morpho/olli cal and cyUUhemical dtetalions in epilhelioid cells of lung eaplanls, such as atypism, mitosis and DNA synlhesis, to a significantly higher degree thaw doa amoke from cigarettes without marijuana. L.rrchtrn6rrerr, C. and I,euchtenberiter, R. Nature 274:227-229, 1971. Othrr .upport: WurW Htalth.Organitation and Association Suisae dcs Fahricants Jc Cigarettes. Frrxn the Ikpartmenl of ('ytochemislry, Swiss Instuute for FapcrlnxMal Cancer Re+earch, l.ausanne, SwrtterlanJ 1'I FF('IS OF O7ONI? ON ('FI I. RENEWAI. IN P(11 MONARY AI VFt)1 IO1: AGING MI('F. ShKlres have shown that oione 1O.) can sigmhcamly ahcr the bachemiHry. morphu{oty, anJ physK.logy of cells and tissues In rhe (unlo. rhest cluntlrs have parlKUlar rm(wortarscc, lur they inslude a hreakJuwn ul .ell n.rmMane. •-r1 eJema (ormatrurs, whKh nuy eventually lead lo pulnwrnary faJurc. lhu Nu,Jy 6l 62

was Jesi6r.cJ to Jrtrrminc the effects of Os on cell renewal in the hulmonary alverdr n( aging nrrcc, as mcasurcJ by changes rn the I.hehng irxka (number of IihclcJ cclls/alve-rlir ccll.l (bnseyuently, groups of a6rng male n,ice were c.p.neJ hsr 6 hours to different conctntralinns of O, then sacnficcJ 1 h)ur alrer rmrapcrrto.w•al inkchnn of 10O rc of Iri/uleJ thymHhnt, at rntcrvals of 1, 24, 49. and 72 hMiu Ihe Iabtling indcs was significantly lower than in the cunuols for the first 411 hours following esposure. then approached ur Inwnl t+rrpasstd the contuol values after 72 houn Inhrbuion of cell labeling was about the same at each O, concentration /ested. llsese results sugAesl Ihat, in Ihese ammals, one of the rnural responses of alveolar tisaue to (?y is a reduction in F)NA symhesis Fvans- M F., Mayr. W- Bdt, R F and (eosM, ('. G. Arrhivrs n/ Fwvirnwnrrwral /lydth 22:4S04S), 1971. Orhrr .upporr: ll S Puhlic Ileallh Service and /lutrngs Fsundaln,n Fund, l/niveruty o/ Scwthern ('aliforrua School of fvlcdicwvc From the I ile Scrence Ihvision, Stanford Research Insutule, Menlo Pat\, ('al ; Ilancock I ounJatron anJ IkparlrsseM of Biological ScKnccs, University of Southern ('alrfornu, Ur»versrty Park, I os Angcks, arxd the Ilastings Fcwnda- t,on. Ikp.rtmcnl of McJKmc, lJniversity o/ Southern California Sclsool of Medreinc. I os Angeles l lll{ PA I FI(XTFNI'SIS OF' PO.CI INFI IIENZAL ('OLLAPSE OF IIIE Ll1NGS OF MI('f 11 has been oMcrved that micc infccttd either intrannally or by atrotol with suhkthal drxes uf nx.usc adaprcd PR/1 A vinn develop pneunwmris which is fullowcJ by scarring and pcrmanent collapse of sonx of the involved lobes; but mice actively imnwmtcJ with homoG.Acws virus, develop bronch tis and focal prseunksnite wnhrwt collapse (ir scarring when e.puxJ lu virus aerosols. 7hcu invesligators report on their uud,es concerninA the mcchanrsms involved in /his pcnlmflucNal cr>alapse, in mice whjeclcd to s+rhklhal ck»es of airborne PRf3-A influenza virus Conventional histologic staining procedures were used to currclate the development of the lung ksions with changes visual-xeJ by ckctron mKroscopy and hntochemical enzyme auins, and with changes in sur- faclani levels. Fkclron microscopy reveals that influenza virus propagates both in the noncrliateJd 1( tara) nd ciliated cclls of the bronchi, as well as in the types I anJ 11 cells lining the dvtoli. thus destroying them. Lactate dehydro- tcnax (I 1)11) and Clucose 6 phosphate dehydrogenase ((:I-6 P1)li) activity uxd as cell markcn showcd that destruction of the bronchial and rlveolar lining cclls was estensive 7 days lter oenct, at which time Ihcre wa ckar evrdcnce of lung collapse. At about Ihis time Ihe Monchial lining ccllr began to rcgtncrate, but nn/ the alveolar lypes I and 11 cclh; the hronchial lining cells showed marked hyperplasu 9 to 12 dayr afler onsct By 14 days there was tvidcrKC ol pcrrphcral growth into the alvcolar ducss, which resulted in rrbsuuc- tiun anl permanent collapse of the involveJ krAes. 1 he dcslruction of the type 1) cells, fullowed by collapse, correlales with the decrease in wrfacunt kvels in Ihe in/crlcJ lohcs arnd n considered an important reason /or collapsr of Il.e invulvtd lung ('u(ulalrng anlUbody prevents the destruction of lype 11 cells by the vuirs and, thcrefore, prevents the poslinflucnral eollaptt seen in un- vaCcmalcJ mKe l.ooJi. ('. G, Buckley. R. D., I1arJy, J. D., llcrtwcck, M S, Kow, S FI, Screbrin. R, Ryan, 1) P. and Sunson, S. F. 7.aroorrionf of the Asroriurion of Amtric.n Physir u.ns 84. I t12-189, 1971. Other aa.pporl: Fnvironmtnlal Protection Agcncy--Air Pollution Control ORice. Ffughcs Employees (iivt Once Club, Fit l dly ('ompany, and Ilaurnp Foundation Fursd, University of Scwthern C.lilurnia. From the Ikpartmenu of Pathology and McJrcine. Universuty of Soulhcrn California School of Medreine, l.os AnAeks. SOLlIH11IZFD ELASTIN AS A SIJBSTRAlE FOR ELASTASE ANF) EI.ASI ASI: INHIBIlOR F)ETEKMINAl1ONS Ihis nsclhocksbRy paper describes a ksl for clastase using a compktely uduhk suMtratc prepared hurn elastas and consprning a mapcsr portion of the cdastnn nsukcule. lht kinetics of the reaction of Ihis su1..Irale with pancreatic clastase in IksrrwsAetuws solution show rapid and complcte drkeation. good re pr,xlucibPuby and apecrdkity with sensitivity a1 kast I(1 tunes Arcatcr than dipa. uon of orcemtl.stin. ~,n adJition, there n no rsornpecifsc inlerfetcrsce by added proteins such as albatnSn l his test can be used in the presence of odhcr prolnns, including serum, and is especially suned for the sludy of serum claslruc inhibi- ton in hcallh and disease. Kclkr. S. and Mardl. I. eiochrmkal A!e/icine 3(4):)42-)47, 1971. From the Oepartmenl of Biochemistry. ('olumbu lJnrvcnity ('olkpe of Physi- cians and Surteons, New York. PROII:IN SYNiIiFSIS BY LUNG FOLLOWING PULMONARY ARIERY LIGATION The present study rJso.rs that one week after pulmonary arttry liplion, under in vitro corrlitiosn, the protein speciflc activity alraur higher kvela in nonhcnwrrhaRic tissue from thc Irkatcd side of dog lunp than tissue frorw lhe nonlikated side. Pulse-labcling eaperimenls and increasing the kucirse pool in the suspending medium indicate these diflerences are tsot due to ddlerenon in degradation of radioactive protein or to differences in Iho.e precursor poot+ that refkcl readily changes in eatraccllular amrno acid coscenuatiow. Recorn- bincd mKroscxnca and pll 5 fraclron malerial from nunhcrmxrhapc ucr of the hpted side art more active in kucirse-"(' mcorporation Ihan sunilar lrac• Iw.ns from the nonliAaleJ side. ('rossvvcr eaperinsems show that this incrca.cd activity resKlcs in the microxxnal fraclwn Nonhcnxrrsha4ic arcu on the lipled side have a slightly'lowcr dry wcrght to-wel weight ratio and slightly morc 1)NA, nsodtralely more mKrosomal prrNCm, and tnarkedly more RNA per mlhgram of dry weight than Insue /rcxn the rsonlrgalcd side Srmdar changes were nolcd in these rneasurements when e.pressed per mdlr{ra+n trl 1)NA. Ala,saro. f>., Weta. 11 and Whrtc, (i. luurnal o/ Aopdrd Phyuololy )1111 S 14, 1971 65 64

Ottier support: American lhoracic Society. From the Pulaurnary 1)ivisron, [kpartmenti of Medicine and Surgery, Velcrans Adminrstrarion, (:corle Washington University Medical C'enler, Waihingron, D C. V. Pharmacology and Psychopharmacology FI FLC1 OF ('I(RONIC ADMINISTRAT7ON OF NICOTINE (NN TIIE ('ON('fNIRA7IUNS OF ADRENAL ENZYMES INVOLVEI) IN THF SYN111fSIS AN/) MF.TABOLISM OF ADRENAI.INL' Tlsis study was undertaken to de/ermi.a whether chronic administration of nicotine can lead to induction of adrewa) lyrosine hydrnaylasr and also to the u+duclion of adrenal enaywsa Plsewyl t/lund-.miwe N-mclhyl tranaferase (PNM n which catalyses the co.venbn of soradre.aline to adrenalrne. Male rats (lloltzman ur.in) were used in aR eaperimenu. Nicotine (I ml/k4) was inlected subcutaneously •ve lime each day foe sia days a week over a period of 12 weeks. Control animah were iwjecred wiUr saline only. The rtsults of several biochemical uudas showed that chronic adminislr.Nion of nicotine increased tyro.inc hydroaylaet concentrNion, but did not aRoct PNMT, cauchol 0 methyl tranaferau, or morso.mine oaid..e. lhe csltcholamine coo- eentratqn of the glands was increased. tAalae, e. and Rsna, M W. 1rlrtrAlorrnato/ rAarmarolory 4 )(1) 2S()251, 1971. Uther arrr.rl: U S Publrc Ik.lrh Service. From /he Departmcm of PhysK>lo(y. St I outs University Schoul of MedKine, St. Louis CIIOt.INFRGIC MUI)UI.ATION OF SINGI.e LATN.RAL GENI('ULATfl NEURONS IN 711N CAT Tsse lalera) leniculate nucleus is known to contain catecholamines. 5 hy- droaytryptamine, acetykholine, cholir.eaterase, aod choline acetyltramferase. Elcctrophysiolotic and ioatophoretic studies iedicale that rnorwaminea usually deprer lateral genkulare neurons. There art reports that acetykholine, however, escilcs about 50% of these ulb and depresacs 4%. The authors report o0 their investigation of the eflects of physoNigmine, nicoline, and scopolamine on the activr(y of single lateral geniculate neurons in the cat. Mostly P-cells were selected. Their responses to ipalaleral optic tract and midbrain reticul.r formauon stimulalion increased. Inlravenous doses of 25 rt/kg of nicoline and phyxnligmine rrgmfic.ndy incrcased the spontaneous firing rate of single Irenicu- lale neurons. A aimrlarly, aadministered 0 5 mg/kg dose of scopolamine de- pressed their Ming rales to control kvcls. Physosrigmrne enhanced the discharge rale which followed oplic nerve stimularion, this effect being depressed by sa.pilamine Phyn.srilmine further enhanced the eRecu of midbrun reticular formation stimulari.-n, whik siopoiamine reduced thcse in aboul 96% of the ncurom stu.hcd In reneral, traina of pulses to the reticular formation (250 r 112/sec, 50 msec train duralion, 00Sa.1 macc pulses) were more eflective than single slimulr lhe conclusion is that there eanls a malor chohnergic fsciluatory system which influenccs lateral geniculale neurons. 1 he writers postulate that this involves the reticular formation and suggest that the evider.ct presented indicates a predominant muscarinic type of cholinerojrc mechanism. Neverthe- kss, nicoline in small doses similar to those which re inhaled during tobacco smoking lso hss a facilitating action indicating that a nicotine mechaeiun r Iso present. Both direct ar+d indirect influences seem to be operative. Matsuoka, I and Domino, E. F. NrrropAa.nraroloty 11(2):241-231, 1972. From the Michigan Neuropsychopharenaeology Research Program, Department of Pharmacology. University o( MichiRan, Ann Arbor. 711E RFI ATIONSIIIP BETWEEN EXTERNAI. ('AI ('IUM (a)N(-IiNIRA7ION ANI) 711E Rli('OVERY RA71: OF AORIIC SIRIPS 1•RUM NK'OIINE TACIIYPFIYLAXIS Nicotine is known b elicit a sympathomimctic effect In adrencrgica)fy innervated tissues believed to be mediated by release of the adrenergic t.ar- mrtler, rsflrepinephrine, since the effect is abolished afler tissue depkdon of the catecholamine by reserpine or cold storage treatment. Ikplction of et dokersoan catecholam:we s/wes by agents which act through eatecho4mine- «kase mechanisms is considered responsible for the devclopmea of tachy- phylaaia, but the nature o( the nicotine-irsduced reacuors Is not clear. Those authors report on experiments designed to delermine whether or eot the de- ve{opmenr of nicotine t'chyphylaais is related to depletion of r.orepinephrine stores. Repeated eapo.ure lo the same concentration of nicotine produced ucAy- phylaais in rabbit .oclic slrips, with cornpkte recovery occurring SO-60 minutes following washout of the (1ru nicotine application. Incubation in medrws eo.- taining epincphrine (10e M) or dopamine (10s M) does not modify reoovcry time, but a high concentration of cakium bns (Ca t r) in the medium cuts Uu" time in half, whereas a{ow Ca t 4 eorscenlrali4.n inhibits both the nicotine- induced contraction arid recovery. 7)tus, it appears that nicotine tschyphylaaik is not due to catecholamine depklion, but 1o depolarization of the odre.ergic of the adrenergic nerve ellector site which prevents the rekasc of norcpioe- phrine. SAlbaro. S., Hattori, K. and Sanden, B. ErroPran lournal ol rtiarmacolory 16:109-112, 1971. From the Ikpartrnent of Pharmacoloty. University of Flaw.ii Sch.wa of Modl- cine. Ilonolulu. 7RANQUILIZIN(l AND EL1CTROPIIYSIOI.OG1('AL EI-1=EC1S 01: NI('OTINE lhis Is a reporl on an attempt to Ieal eeperrmentally the hypwhesu that the cenlral nervous system ((-NSI eRecu o( nicotine ate e.erted through ce.uat mechanism. analogous to Ihose involved In rl• aulorwrmrc peripheral action., that is: (1) by mimicking and later blocking acclykholrnc at -'nicotrnrc" receprur siles; and (2) by rekasing endogcmms neuroamrncs. ('onscqucntiy, various drup 67 66

with .utonumic effects were compared and combined with nicotine in e(eclro- physrological eaperrments Some behavioral uwlies were Iso conductcd t.r pro- viJc a corrclate /rx the elccuophysiological actions tcamined. As dcrnomlratcd by the spontancoui ekctrncncephakrgram (EEG) of nunancsthetrrcd riibhits, intravcnous mcotrnc drflcrenually affected the rpsilatcral and contralateral direct reaponsn cvokeJ by direct stimulation of the anterior and prnterior nWor cortca: and it induced drphasic eRects on both the direct and the vnual re- sponses evoked by flash uimulation of the optic cortea, prohably because of its diphasic effect on cholinerlic receptors. The inhrbitors of catecholamine rxtab- oarsm- a methy(-pars tyrnsine, a-methyl-DOPA, 1etr.ethylthiuram drsulfld:, .nd parryline, markedly rnodrficd the effects of nicotine on the visual t+okcd potentials, thus demonstrating their deptode.et uporl erwlogeraus catechol rmine kvcls, and reduced mcotine-indueed depre.roo of moua eapknatory bchavinr. Nicotrne prolonged barhuurak sleep i. rwip .ad reinduced 1Jeep after recovery from anesthesia. Auopinie drugs did .o1 block .icotirse-irduccd barbr;urate potenlialion and EF.(i arousal. The wlhors oowclude that the CNS elfe:ts of nicotine appear to result Irocw the activaliow of spt,cifk nkotutk cM>fr,rergic recepors and to be partully dtpe.d..t on e.dop:oous catechol.mink mechan- irns. Sabclli, N. and Giardina, W. 1. (Toas.r., /. E. r.) sioloPicd r,ycMarry 1(2) 103-130, 1972. OfArr sarrprf r U. S Public 1(eahh Service. From the f3rp.rtmcnt of PharmacokKy, C\icap Mediu( School, Chicago. STUDIES ON THE A(-UiP AND CHRONIC DE'.PRfSSOR ACTIONS OF NICOTINE IN TFIF RAT Tlse mechanisms by which nicotine can influence the blood pressure h.ve been ealeenively sludred These include cAects upon the central nervous system, sympathetic ganttia, carocd body, adrenal meduNa, .nd adrenersic nerve end- inp. In this study it was found that chronic aeotieitation of rats increased the prtnor respoene 1o rsoreprnephri.e and decreased the resqonse to tyramine. Chronic trcalmest of rau with 4.56 mg/kg/day of wicotine in the drinking wale( produced a depreswr respnnse, u wRmenled pressor action of rwreprne- pltrine, and a reduced preuor action of tyrarnine. In eontrasl, rau made acutely tolerant to the pressor effect of .icotiew were nrbaesitive to both norepine- phrine asd tyramioc. Trealment with guawNhidine, for ten days, also sensitized rats to the pressor effect of twrepincpbrine and reduced the response to tyramine. It did not modify the response to any of the other pres.or substances which had been tnted in nicotine-Ireated rau. As with chronic nkotine treat- mcnt, guanethidine did not influenct the dcvebpment of renal hypertension in the rat, but lowered the preswre so normal kvels when it was aJministered during the secondary phase of renal hyperlensiors. Wcntrl. [). (:.. Armeh, N. and (Yark, 1 1. Archlrrr lnrr+natlonakr /t rAarnsrodyn.rn4 rr dr Thlroolc 193(1) 2)-26, 1971. I'n.m shc Ikpartmtnt nf Phumact>kr/y nd TosicoluSy, l)niversitry of Karuas til IMM.1 rf Pharm.. y I...rrrwc STUDIES ON TFIE MFCI-0ANISM OF TOLERAN(-E 70 NICOT7NE'- INDUCED EI.EVATIGNS OF URINARY CAIk('11O1.AMINIS In rats treated daily with nicoline there is an ekv.tion in the urinary eacretion of catecho(amines which reaches a peak following three days of treatment. liowever, cfler seven days of continuous administration thcre Is a marked fa(IoA in the urinary levels and by 11 days the unn.ry calecholamusc escrelion is essentially normal. This study investigated the mechanism of the return to normal of the ekvNed urinary catecholamines Three possibk mc chanismt leading to this phenomena were eapbred: (1) that continual nicotine exposure kads to an induction of earytne activity resulting in an incrcased metabolnm of the alka:oid, (2) that nicotine eaposur. results in some altcra- twns in the storqe or eekase of e.techolamines, and (3) that some .Itcrauoe in the inactivalion of the aminea occurred. The data indicate that alur chr.mic nicotine there was (1) no increase in the metabolism of mcotrne itself determincd from mcasurcments of nicotine oaidase activity. (2) no •Iteratiun in the ew- dolenous tissue kvels c4 calechdamines determined by fluorometric analysis, (T) no allcratw,w in Ihe tissue uptake of ('ll)sorcpinephtine, and (4) no aJternion in the turnover of noccpinephrine delermined by measuring the declrne of ('11) norepinephrine In the heart following i.v. adminislralion. On the other hand, there was a significant increase in she monoamine osidase activity of the heart and liver and an increase in the talochol-o-methyl Iransferase activity a1 the liver. It is concluded, therefore, that tolerance to nicotine-inJuced ekvationa of urinary catecholamirses is due to increased metabolic enzyme activity resulting in faster metabolism of the tatecholamines released from the adrenal medulla and .drenergrc nerve terminab. Wcrr/dl, T. C. and firase, D. A. Qi«hemicd Pharmocology 20:1627-1636, 1971. From the Dcpartrnent of Pharmacobgy. University of Virginia School of Medi- eine, Char{ottesvilk. THE MECHANISM OF ACTION OF NICOfINE ON ADRENER(IIC NEURONS IN THE PERFUSED GUINEA-PIG NEART It has recently been observed that certain drugs (cocaine, phenosybensa- mine and desipramine) which block the uptake of norepinephrine by .drenerigrc neurons also reduce the nicotine-induced rekast of '11-rwrepinephrine from tM sympathetic terminals of the isolated pulmonary artery. This suggests that the sympathomimctic action of nicotine, in the pulmonary artery at kau, might depend upon a functional norepinephrine uptake mechanism nd that perhaps nicotine must first be taken up into the neuron as a prerequisite to the reka+c of norepinephnne. Tlris particular study was designed to eaplore whether there t.ists an intcrrelaticxrship between neurona( uptake of norcpincphrine and its nicoline-induced rekase. In orQer to reach a conclusion. the authon (1) directly compared the effect of nine diverse pharmaeologic agents (cocaine, phenosy- benramine. metancphrine, bretyhum, he.amcthonium, morphine. Iidocainc, piperocaine arwd tclroJulosin) on the uptake of norepinephrrne, with the eRccl of these agents on the nicotrne induced rekase of catecholamrne in the perfu.ed guinea pis hcart; 1'_) studied the accumulation of r'(- nicotine in the guinea pig heart: and (t) cumpared the release of norepir.r/.hrrnc by lyramine with Ihc rekase by mcotinc Ihc results ahow a dnwcialrun bctwccn drugs whKh bkxk is 9 69

fwrth the nplake and nicotine induceJ rckase of sIl nr.repirkphrtne anJ tho.e that lust I.L.ck the nnuthne tn.hweJ relcast u/ catcchul.rmurt. Ahh..uKh the rxd-stcJ `unaa pre hs•arl accumulstcJ "(' n.colrnc, prelrtalmcnt of Anim:ds wrth h hydrosyJ..p.,nunt, in dvstt sullicicnt 10 cause JegcncrJtww. u/ adtcaKVR.c rserva• Itrnnnals, diJ rwt altcr this uplikc of lahtkd nKUtUnt, nor JiJ mculust (I l(w) r,r/m1/ ahcr the nl.t,,kc of ssl norcptnephrtne by the per/u.c,l htarl Renw.val nl ('s' 1 Ir..nm thc pcrfusKSn medium. ur addition ol hdu.ainc IS a 11/• M). asmplttely prevented the release of 311 nurcpincphnne by n.iuUnc, hul JiJ nol inllucncc the rclcasc of amine induced by lyramtnc 1he authons con. c1uJc that nicotine cauxs a rckasc of r.otcpitsephrinc by acting on a•'rcceplor" Io.itcJ af the level of the aJrenergic nerve terminal and not by Jiaplaccmcnt of nnrcpinephrine after uptake rnlo the neuron. In their opinion. Ihu shKly also su(ycst., Ihcrefore, (1) that the sympathomirrsctic rctiom of nicotusc, in the pcrfu.cd hearl at ka.t, are independent of an intact norepincphrnse uplake mechamsm, and 1_s) that nrcMme need nnl he initially taken up into Ihc adrenerg.c neuron before d can release Ihe wnine. Wrufall, T C. and llrastcJ, M The lnu.wul o/ lhaunrarrJury and Eaprrimrnrd Thrraprulict 1f12(1) 409 419. 197? From the Ilcpartmcnt of Pharmacoloty. University of Virginia School ol McJi- cint, ('harlratcsvtlk V 1. Mtta/xylic Studies I:FFI('T OF ('I(;Akl I"IE SM(1KIN(: ON PROIFIN ANI) AMINO A('1[) MVIAflO1 I1M I IRYPIOPIIAN Metabolic stud.cs of 17 1nr.Icrs an1 nomrnnkcrs aged 22 to 69, who were recovering Irom varr>,rs Jrsahl.ng eprsr.des, and of 11 hcallhy, nornul snw-lers an.l nonsmolers rang.ng in arc from 16 to 17, were unJertakcn in order to try to determinc the cflcct of a`arene smoking un protein and uyptophan meul.olrsm. Results irxlnate that cigarette smoking may reduce eHecuve protein ulJrration, an effect pcxsvhly related to the reduced mehholrc availability of amtno acid nitrogen ReJuced Iryplophan utilization appears to he associated with the relative impairment of protein utilization which may he overcome, in part, by increaseJ protcin cakxie intake. According to the authors, these sludics tnJiute, /urltKro.ore, that contrary to aorne rcports, aberrations in tryptophan mclaholnrn are not likely to induce MadJcr tumors. AlAonrsu. A A., Orto, 1.. A, Wem, E. 1t anJ ZLvattaro, I) N. Nurnnnn RrpOru rnrrrnnrional S(1) ?IS-3SR, 1972. Frum Ihc Nutritton and Melafr.lic Rcsearch Division, llse Burke Rchahthutwn ('cntcr, Whitc Platns, N Y. MI IAHO11(' (Y)NIRIRl1I1ONS 10 (iASTRIC UI('ERlXi1:NF.SIS IN Mt( I I o.wl skprivatwsn and m.nrohiliralion were .tuJrcJ here as fxwus con Irihulnry In g..ara p.dlwrlnry .n micc, alxs cuntrlcrcJ was thc rclan~~n.hip Lttwrcn thr cni-t.osy ~d .u.h ga.nnk changcs anJ the rulc playcJ by sau.c S hy~hu.ylrylw. n~~K Is 1111 M./ah.dK factors asti,titaleJ wuh Ihrs rulc ul t II I w, ic slr. Jr.lly w.th  v¢w toward ttstUng Ihc hylwthcsrs that allcra,<rns in gastric S 111 metabolism relate tu thc clnAugy of gntrrc tdctrusencsis In this e.pcrinrcnl, mice were suhkctcJ /u tmnx.Mbtainn anJ/or prior v.rryurg tnlcrvals of food deprivation Srumachs were e.ciseJ and ca. annrted lor palhology. degree of aciddy, and diflcrences in raslric amrne conrenl anJ metahodnm tmnxrl.ducd mrce showeJ a grcalcr rncr)cncc of Cas/rrc kstons Ihan non mtna.hilhr,cJ anmmals, and imnw.lsdrtalw.n alsu cuntrthulcJ lo changes in castric S 111 concentratron. l)kcrated animak, us gerscral, had higher g.urK S 111 kvels and ekvated gastric tissue p11. Inhibition of a malor metabolic degradativc pathway Inr S-FI f in pstric tissuc resullcJ in a parado.ical effect rwM found in either brain or heart; changes rn the rate of Baslric S 111 con cenlrahun chance after enzyme inhibition were related to imnsob.htaluon, durs lion of laslrng, and uker incrlcnce. A biochemtcal mechanism u suyaeslcJ whereby the cuoksp of stress-inJuced ksions may Le e.plarncd. F.tunan, W S., Ftsman, S 0 nJ (7olnd, M 1. Yhyuolory and BrAarior 7:309-516, 1971. OOther sa,pp..rt: 11. S Public Health Service. From the 1)epartment of Psycholojy, Queens Collcke of Ihe (lly University of New Yurk, Flushing, N.Y. V11. Chemistry and Biochemistry llil: FFFF("I OF ALTFRAIION OF INTRA('Fl1 l1I AR 2,1 UPG ('ON('IiN I RA I IUN UPON OXY(iC•N BINOIN(i OF IN T'A(T FRYIIIR(X'YIES CON1'AINING NORMAL ANI) MUTANT III:M()<il ()BINS lhis paper reports the differential effect of variable intracellular concen- Iralions of 2,) Jiphosphoslyeerale 12,)•DP<i) upon the ()e b.nJ.ng aRinily of intacl erylhrocyles from palients homotygous and heteroiyRous lor skkk eell hemotlohin, as eompareJ to those containing 11bAA, Hb (f(', Nb AC, Ith Ki+ln and corJ hlo«>tl. Ihese sNwl'as were done by a contrnuous recording polar ographic techmyue. Resulls showed that the oaygen a0inuy of cells conutning Ilh A(' and ('(' is normal. Ilh SS is considerably kswer while that of Hb AS and ti(' is inlerrssediate. CorJ blood and cells with Ilb Kiiln have an increased a/linity for o.ygen. Plo1s of P,. (the partial pressrne of osygcn required to half saturate hemoglobin) against ',11)P(i concentrarons presduce asymptotic curves in all cells studied. the effect of chan6es ul ?.1 I)P(i upon oaygen htndint in the types of celts slrKbed eapressed as 1'..,/ ?,1 1)I'G decreases in the lullowtng nrder. SS>IAS anJ S('1>/AA. A(' anJ ('('/>/1: anJ Koln) lhe mulecular basis for the incrcaseJ respnnse to '.1 1)P(i by cellt conlaintng Ilb % as comparcJ to Ihc normal respr.nx of hemoglobin S in sululw.n is hr.cfly Jtscussed . I i.n, C-Y . Roth. S, Harkness. I) R and Carnrron. H F Hrdw hrn.ir u! oind HonpAyur.rl Rrv.o. h('ornmunu rmnnr 4SI I 1 I S I 1111. 1971 Other auppr.rt: l/ S Vclcrans Adm.nisrralion anJ lJ. S. Puhhc Ilcalrh Scrvkr Irr.m tht (lcp~runtntI ul Mcdicine anJ HrKlhcrn„uy, tln.vrrsety of Mumr S.hMriI u( MtJ.iu.e and thc Vtlcuns Adn+tm.lralu.n IIu.pHal, Mumi, FIa. 71 70

RF.GULAl1ON OF OXYGFN DISSOCIATION BY 2.) DIPHOSPIIO- GLYCF:RAIF. IN TIIE HUMAN ERYTHR(KYTE Although the osyhcmollnbin (osy Hb) dissociation curve has been estab- lishcd and an attempt has been made to analyte Ihe mechanism responsibk (or its sigmoid shape, a separate problem has been that of relating this curve to the one for whole blood or cell wspensiorr. While these have the same gencral shape, ttve one for blood is to the right of the one for Hb or hemotysate, irrf.:at- ins lower oaytcn aflrnny. lhis shift is panly eaplained by the combined cGecl of COt and the diflercnce between inlraerytArocytic and plasma pll, and partly by the change in ?,).lophosphoglycersc acid (DPQ) concentration. This corn- pound acls at  colsctor /or o.ygenation, the nortnal human erythrocyte kvel being around 4-S mM, and accounting for nearly two-Ihirds of the total orgrmc phosphate of the red cell. Ir has been shown, furthermore, that 2,1 l)P(: is increased in hypo.ia srrf decreased in hyperoala, the pathway (or Ns synthesis and degradation being through Ihe pfvo.photilyceric acid ahunt, with synthcsis related to glycolysrs. While the influence of 2,)-DPO on o.ygenation In various hemotfoMnopathres has been uudied. N has tsot been well documented In sickk cell ancmra, fot csample, blood osygen affinity b lower than normal and is accompanied by increased 2,)-DP() kvels, ahhough insufficient lo acccunl for the decreased o.ygen affinity. llvis is a report on the aulhors' sludieu of o.ygenuion in bloods conlaining Hb C and His S with several factors taken under considcratioe (plt. COT, 2,) DPO tnodifkatiorn), aa well as on their dclaikd e.smnalicsn of data on both horrwtygous and hnerotygoua sickle cell condrtans, which were carried out in an attempt to reconcile the discrq+ant magnitudes between thc right shift of the blood osygen disaociation curve and the increa%e in crythrocyle 2,1-DP(i. Tlvey conclude that a reistionshif. of 2,)-DP(i binding to tickling is reasonable and may operate through one of Iwo mechanisms 11) sickling may lacilrlalt 2,)-1)P(1 binding (or conversely) resull- ing in a tight shi/t of the osylien dnsocislion curve greater than eapecled at a given 2,) 11P(I kvcl; or (2) there may be increased binding of 2,)-DP(7 to llb S without re/erencc lo the akklrng process. According to Ihe autl.ors, lurthcr sludics on the relationship of 2,)-DPO to sickling and osyRenatan in sickle cell disease, and detailed hinding studies of 2,l-DPO to purifkd herno- globins A and S, are required b answer Ihis question. An associated s.udy determined a greater toxicity of CO (carbon monoside) on erythrocyle oxygen disaocialion In cells from wbjects with sickle uR anemia. TAus, the influence of esposure to Ihis gas (either in amoking or auto exhaust residue) must also be considered in a complete analysis of blood oxygen uaraport. C'uncrow, e F., I.isn, C.-Y., Carvajalino, O. 1., Ro1h, S. and Harkncu, D. R. In Uacde. K, Florecker, B. LL and Whelan. W. l. (eds ): Molccular Bmit of eiologic.J AcNviry. rAAeS Syrnpoiirm. Vol. 1, New York: Academic Press. Inc. 1972, pp 169-196. OtA.r supportt 11 S Public Headth Service. U. S. Veterans Administratinn, Rsyne Tlaher Ksrp I aMrratones (or tlematoiogy Research, and 1lesrt Assocu- t«m of Grcatcr Mosmi I rom the Prpamcntauu (-ancer Rescarch lnstitule, the [kpartnscnts of Mcdi- cine and It.Kherimuy. Ilmvrrtuy of Miami Sclxwl ol Medrernt, snJ the Vetcrans AJminittr..own Il.npiul, Miami. F-Is SYSIEMATIC STIIDIFS ON Tllli BREAKDOWN OF o.j-DUT IN TOBACCO SMOKES This is still another paper in a continuing series of studies dealing with the breakdown of jv.p-DDl in tobacco smokes. Flert, she authon describe the nKrhods used (11 lur amoking p.I-DDT-tresacd tob:cco, (2) for collecting tse smoke condcn.ae and chromtosraphing it on activated Fbriul and deactivated alumma columns, srd 11) lur identifying the nonvolatile p.`DDT pyrolysrs prrnlucts in thc smoke c.w.kmate. 1 he +even following pyrolysis pruducts were iJcnuticJ o./ U1)1. p.j DDH, p.j-1DF, p./ DUM. Irara.p.jdkhlorosltlhcnc, hrstoihloruphcnyl methane, and jo.j drehlorohcntophcrane. ('Anp..r. N. M and [ksmanski, /. l. HrrulRc tu. tuA.r1(orsrAunR(4)/:119-141, 1972. From the Ikpartrnenl yd ( hemislry, North ('arolrns ApKultausl aod Tcchnical Slale l/nivu.ity, (ireenshoro. ' SYSTFMAIIC STUDIFS ON TIIE BREAKDOWN OF p.j-DDT IN TOBACC-O SMOKES: INVESII(:AlIONS INTO IT/F PRI'.SFNCE OF METHYL CIII.ORIDE, DICIILOROMtl11ANE, ANI) CIILOROFORM IN TOBACC'O SMOKES This is part of a continuing study on the breakdown of p.j-DDT in tobacco amokes. The present paper is a report on inveslrgalions into Ihe prescnoe of tnelhyl chloride, dich:oromelhane and chobroform in tobacco smokes, aad the signrfkance of the amounts in which they are present. According 1o dala ohtained, therc is no ch)oroform in the smoke of tobacco samples containing no p.I-DDT, there is a tinear relationship between she amount of p.jf-DDT present in tobacco and Ihe amorml of chbro/orm found in the tobacco snake; and ahout 4 6% of the lrichloromethyl rnoiNy of fe.j 1)I)T in tobacco is cow- verted iMo chbro/orm. lhis would indicate that R.j Dl)T is the only sauce of chtorof.xm in p.ji-DDT-tresled tobacco snwkcs. In pesticide-/ree tobacc.o. there is no compound which is known to have this grouping 1 he absence of dichloronvethane in tobacco smoke condensates suggests that either dichloco earbene is na formed in tobacco snwkn from tobacco treated with p,`-IH)T, or 1ha1, as is mote likely, dichkuocarhene i/ IormeJ reacts with other cow- stiluents of tobacco amoke, such as water, in preference to hydrogen. The amount of methyl chkxi.k proJuced in tobacco smokes suggesls that methyl chloride chlorine conses mainly /ronr tobacco inorganic chlorrnc. Furuhernwre, the facl that the amount of inethyl chloride is app.rcntty independent of the quantity dp.j DDl- in tobxco, indicates that the pesuci.k dors not con- trihute substantial amorrots of nvethyl chloride to luh.cco annAcs lhe resulrs also sug~est that methylaion~is a resclinn of map.r rmlwrlsnce in tobacco srrKrkes. In the wthori opinion, this is lurther supp..rted by the (acu that. (1) nc.t to ('(/ and ('0:. methane, which can he /nrmcJ hy the .clwar of hydro1en on rncrhyl free rad.cals, ia the nNnt abundant orgamc cornp.s.nl in Inhacco Rmukes; (2) elhane, whKh can Lc formcd by the duucrujr.un uf mcrhyl raJ. c+et, rs onc )f the m.lor curupnn.ols of the b4.acco snw.kc+, anJ (t) rn•Mt u/ the mcthylation resclirms arc already nvcr by tl.c umc snwrke cun.knsatcs arc colkctcJ, 71 72

('hol.nr. N AI and lherrnin, I R An.dyei.,d ( hrr.rirrrr 14161 14116 ItI1R, 1972 Frnrn nce lkparlmrnt n/ ('hemostry, Norlh ('arolina ARrKUhurA and Icchmcal Stale I lniveraly, l ir. c nsltirr.. BRFAKt)OWN 01 ( III ORINAlI t) HYOR(X'ARNIIN PI SI I( I[)fS IN IuBA( ( 0 SMU/:I \ A SII(1RT REVIEW the p.nsihd.ty th,t pestrcaks in tohacco smokes may prove to he a health hatarJ lo a lartc ,egmcnt of poprda/ion haa been ovcrlo..kcJ until reccmly In this rev.cw, the uthor p.wnts oul that prior so 1967, must of she work .kxrc on the breakdown rd pcaocKks in tohacco amoles dcdt with nDt and 11)N. So far. the JcAraJatron pr.Khrcts of she former havc been WentiflcJ .: 1)1/1, 1)I11', 11)F.. t)I)M, rir• and rr.wr-p,Adichbroailbencs. r,6Jichkwr>f.rnto- phcnone, chhNt>+.en7crK, chkaoform, and methyl chlnrrk which was ouantru. tively shown to consc mainly from inorpnic chbrine 1 he writer then Jcscrihcs his own study on the hrcakJown of p.`-Uf)T to cigarette srnokes, begun wah his coworkers in 1%7 in ordcr to determine the /ate of the !l0-t!S% of the pesticide in cigarett,r tobacco which 's {oal during smoking. Ile reports that although only two out o( the proposed three phasts of the uudy have been completed so far, these have hclpcJ to understand the mcchanisms of pesticrJe breakdown in tobacco srr.Aes and have e+tablished useful gurdelines for future studies on the urhjecl C'hopra, N A(. In Tahrxi, A S(cJ ) Forr o/ Prrri.ldrs lA Ewvironmrnrr Procrrdincr of the Srcond fnrrrnaHond II/PA(- Contrrrr o/ Priticidr Chrmisrry, Vol. VI, New York: Gordon and Brcach Science Puhhbshen, 1972, pp 245-261. From the tkp,.rtment of (`hcmnlry, North Carolina Agricultural and Technical State University. ( 7rcensho•o lHt: FIRSt (-OMPONFNI OF "1F1E KININ-FORMING SYSIFM IIJ HI/MAN ANf) RABBIT PLASMA: ITS RELAl1ONS111P TO ('LOI-11N(; FACTOR X11 (IIAGEMAN FACTOR) Studies are presented on the isdatiow, characteriiuion, .nd activation of the prccursrx form of the first component of the kinin-formin` system in rabbit and human plasma. Functionally, this moiccuk is the precursnr ol the activator of prckallbkrc'en (Pre PK A) which, as the evidence has sh.wvn, is iJcntrcal to the initial componenl of the intrinsic ckNting syuem. Ha`cman fachir (/utur XII) The protein was found to be a nw.kcuk of 111/(UX) I'(/,(11M1 mrd wt as Mrr- mineJ by gel fillrahon, to acJimcnl at 4 3-4 6S, anJ to prnsess ckclrophurctic charge characteristics of P globulin with an isoekctric point of 6 1. ('o.hr,.nr, ( C, anJ WlKppcr. K t). 7he /uurnol o/ F.rprrmrrntdl Mrd.rlnr 114(4) 986 1Ot)4, 1971. Other rupporl: ll S 1'uhlic Itralih Scrvice, NatM•nal M.dUplc ti.tcruus ti.nrcty, rMl Amcr.carn Iteart Aswciauon I rom the Ikparuncni oI I'lhcrtnKnlal Palhology, Scripps ( hnic arxl Rcs•ar.h I uunJatiun, I a lull.. ( a) I llll? KININ FORMIN(; SYS11iM: 1)FI.INEAItON ANI) /4C-11VATION 'Ihc kinm furmmg syslem is prominent among the varroua systcros that might play a role in vascular injury. AlrcaJy evidence c.ists that rmplicales the kinin furmin` system in immurxrlogrc rcacUon. llowcver, there has been little utiilactory information reported so Lr regarding the mechannms ol the kinin formrn6 syslcm. lhn paper is devwed to definrnt the components of the system, Jescrihing their activation as far as possihle, and Jiscussrng some pre- limrnary Jal on the activation of the first component; caperimenls /or ths study were dcsne on rabbit and human plasmas and breakdown product.. Reaults of this study differ from other studies in that they demonstrate the presence of  single prokirumrgcnase and kininoCen in the plasma of rabbit and man. Perhaps the nwnt important technical feature that differentiates these studies from whcrs is the separation of compcsnenls in their precursor form When the plasma was protecteJ from activatrun, kininogen was only frwnJ m the k.w molecular wcight fnrm. 'Ihe work done here has demomhatcd three steps in the lornution of kuun in rabl.il and human plasma. the stcps consist of con- verswn of a prccur,nr or procniyme to an active form hr rR A r.nrW F..W X1/ I -+ PRA Nyr~.. F.crer I rrMla.qrt..r--- -• Krd.we+..r / r....rr I [W. Activation of the kinin forming system was tested with eRtracellular baserncnt membranes of rabbit kidneys. The results indicate that only a small amounl of activation resulted from the mislure of immune precipitate and /lalieman factor. Iwq the crude preparation of 1he renal basernent membrane was found to be hithty active in converting Hageman factor /o its active form. ('ochronr, C. C. and Wuepper, K. [). in Micscher, P. A(ed.): lnrmrnopothology: Ylth Intnneriond SyrnPOairnr, New York: (7rune i Stratton, 1971, pp 220-235. Other arpporf: U. S. Public 11ealth Service and the American F/ears A..o- clalllln. From the Ikpartrnent of Eaperirnental Pathulogy, Scripps ('linic and Research FuunJ\tNM, La )olla, Cal. IRANSI A1IONAI. M(1BIt IlY OF 1HF. MEMBRANE INIFRI'ALATFU P.1R11('l l_S UF H(1MAN FRY111R(K'YIE (;11US1S. pFt l)FPENDF'.Nf, RI.VI.R11tll F: A(;(iRF(;Al ION . Although the chcnsical nahuk ol nwsl of the plasma memhranes' partnks is unkn.rwn, recent wurk suctcs,s that those of eryrhurcyte Rh.nts anJ sarco- plrsrnic rctUCUltun may rcprescnl prolem containrnA sucs l crtain c.pcrrmrnis hjvc shown rhil piuaics are ahscnl on the Irccic /rxh.u faccs of Ibpal Lmellar ph.acs, or on th..+c ul purc hpiJ car.cts, frum crydhr.wy/r gh.r+t mcmhrAnc., hul thal th.y rre presrnt on the Ira.rurc (+.rs ul hp.J vrsirlcs to lamcllar Irpwl 1.1r,acs cunl.rrnurg rrylhrocytc Ahost ur s,acuplasmk: rciwulurn mrmbtanc prWaos OIhcr% hrve shuwn Ih..l the p.nlwks iuntauo A or B 71 74

antigens, influenra virus, and wheat germ agglutinin receplors lhus. it is evident thal the membrane particks mual include the slycoprolein and/or glycolopd responsrbk for these surface characterisrics. Whether or not the parlrcks of a given membrane type are chemically uniform, and whether each particle comots of a single macromolecuk or of severat, still remains uncertain. As a result of his own e.periments repor(ed in this paper, however, the author concluJes thar: (1) the membrane p.rticks of human erylhrocyte glosts can be aggregated; Ihis reaction is p11- and iwsic strength dependcnt, occurs within kss than 2-4 minutn, is rtvenibk .1 pH 5 3, and can be prevented by glutaraldehyde fiaatuxr; 12) Irarlalqn.l movement of the enembrane parlicka abng the plan of human erylhroeyth ghoats is responsible for their aggregation and redispenion; (J) the erythnoc7le ghoM memMane can be envisaged as a planar fluid domain formed by a bilayer twembrane continuum which is inter- rupted by lucalired yet mobik, probably prokic, intercalationm. Pinto da Silva, P. (Frdrw6rre, H. H) lorrnal ol ('ra elolory S)N)1:777•7t7, 1972. O(Arr .rpport: U. S. Public Ilealth Service, Atomic I:nerly Commi.sion, and rhe Jane ('o(fin Childa Memorlal Fund. From the Section of Hematotogy and Immurwlogy. Departmenl of Medicine. University of ('alifornia School of Modicine, San Francisco. ADI)ITIONAI. R()(1TFC IN 711F METABOI ISM OF NICOi1NF 10 3 PYRII)YI A('EIA11[ Investhsarhon of dihydrrxncisnrcoune meulr,rum in rau and dogs lollnwing the adminutratKrn of dohydromct.nrcurrne ddumaratc revealed that /I/ in the ral, the R, values and retention rhmes of methyl esten prepared from acidic Koenig positive melaholites in the urrne u such thal they suggest rhe presence of 3 pyndylacctate and 4{) pyridyl)dutyratr; (2) the escretion pattern of acidic melalwdites is similar in dop; (3) chemical conversion of the acidic metabolites to their mNhyl esters for aeparalioe by preparative gat chromatography yields methyl ) pyridytace(ate identifi.bk by meNing point, elemental an.lysis, and the infrared apectrum of its picrie acid .alt, u well as me(hyl 4 ()-pyridyl)- butyrate which was idenlifled by mw opecUo.copy, melting point, elemental analysis, and the infrared spectrum of i(s methyl ester picrate. I:vKknce from previous studies indicates that 7-pyridylacel.te may be forrned from (-)nicotine via either (-)cotinine or (-)demethykolinine. In view of a previously published report that dihydrometanico(ine is a metabolite of nicoline in the ra1 the present resultu .unesl a third roule (via dihydromel.nieoline) to )-pyridylacetate. Meacham, R. FI ,)r., Bowman, E. R, and RfcKrnnir, H., Jr. I Ar lournal of Blologk.l CAcmbrry 217(7):902 90s, 1972. OtArr .rpporrr Amcricn Medkal Association -Fducatron and Research Frnrndation and AnrcrKan Tobacco ('ompany. From the (kpartment of Pharmacobgy, Medical College of Vrrginu. Rich- mond 76 RFA("11ON Of: N1I R(X:EN DIOXIDE WI11/ BI (X)D ANI) I.UNG (Y)MPONENIS 1 his paper prcunls evidcnce that a chemical intcraction of muoolen dioudc and the double bonds of lipids is a gcneral nMNk of atack upun brologrcal mokcuks; a reaction pathway is soggested. In atkLtK,n, another type of laoloolr cal reaction of nitrogen o.idcs- the interaction wnh hcmor{of.rn-i. described In thesc e.perwnenlal under,rkings, ekcuun sprn resonance studies of thc cffecls of NOj and cigarette smukc were pcrlurmcd. In vn•o e.posure of small animds tu NOt and to cigarette smuke ha hccn mrerprcted in terms of pd lutanl reaction wirh the herne moiety uf hcnwRlobrn. Resulu imply that thc pollutanu have migrated through the crythrocyle membrane. So as to under sund the eflects of these pollutants upna the membrancs Ihemsclvn, varK,us model systems have bcen sludred, particularly the interaction of NOr wuh unsaturalcd lbpids. lhree stable (.ee radicals have been characterized as prod ucu u/ these rCKIMNN, and a sMal-liv(d initial (ree radicd was obscrved, thc suuclure ol wMch provwks evidence as to the initial reaction site and mechan run Results o/ smoke esposure suwbcs with in rivo blcKd sanrpks and in vbro henwglohMn solwrons mAicate that conskkuhle prrnein denaruurion occurs in the e.posure reaction, along with the formalion of the N()-hemoglubm comples RowlnwJs. l. R. and (;ause, E M. ArrAivrs o/ Inrr.nof AlcAicine 12R(1).91-100, 1971. From the [kparlmen/ of Physical and Biological Sciences. Southwest Research Insulute, San Antonio, le.. A RAPII), SIMPI.E METIIOD FOR ISOLAIING PINOCYfOT1C VFSICLFS ANf) PI.ASMA MEMBRANE OF LUNG A rapid and simple technique for harvcstinR highly purified lung plauna membrane and pinocytotrc vesicks is described lhe method ia b.aod ow she fact that in lung. S'-nuckoaidase is restricted to pinocytolic vrsicks and areas of incrpien( vesick formation along the plasma membrane, and that P, released from AMP can be precipitated as lead phosphate at or near the aubcellulsr site of S'-nuckwidase. 7hese lead phosphate deposits greatly inercase nce density of pinoeytoaic vesick+ and attached plasma membrane, dwr allowint their collection as a pellet after lorw-speed centrifugation (230 t 11) tMough sucrose (d-1.Iti). The pelkl, which haa biochemical propertin such u are described for ull membranes of other tissues, contains long strands of plasma membrane, and the vesicles retain their characteristic morphology inchrdint the delicate diaphragm covering their .uomat.. This technique is c/ftcic.l. un be performed in ku than 90 minutes with equipment and materials availabk in virtually any laboratory, and is applicable to larlle quantities of all liswes in which S'-nuckolidase is rerricled to plasma membrane or prnocytotic vesicla Ryan, I W. and .trnlrA. U. Siorh/mki rr BiooAy.ic. Acr. 219.177-110, 1971. OtA.r support: National InsrirWes of Ilealrh and Flo.ida Ilcarl Associatioa From the (kpartmenl of Medicine, l)niversuy of Miami School of Modkin<, and the Howud 11ughes Medical Insritute, Miami, Fla. 77

Rr( (yVfRY 01: 1 A11t'l l'1) (Y1U1 fSrFRO1. ANI) ('11u1 r.S1 f RO1. I SII R% I ROM IIIIN I AYFR ('lIROMAI(x:RAMS Ihrs rcpurl Ja•.crnccs a rM•w technique for the recnvcry nf rarhoachvc alKrlisrcnd (rurn thin laycr cMtMn.dulrams I IC1 ) which is usually uclucvcJ by scrapmK the aJstnha•nl u1T the 11 (' platct and suspcnJrnt the scrapruRs in an approyurale mc.lnnn Inr scintillation coarnling. lhe anlhurs, howcver, suRdcsl the asc of a minual punch in order to ehminate any ddliculNcs anJ potential h.uards of the older nxtht.d. According to Iherr saalres and as IcsteJ for the 11 C ol 11111 ch.+ksterol, the recovery of radioactive sampks can be sub- sunually accckrateJ wilhoul ion of accuracy when plastic-hased plater are uxd in cond.matiun with a manual pwscA. Although they feel that this tcchnit7ue rcpresen,s a suMtanlul improvemeat over previous ones and shu,dd have reneral applicability in a wide variety o/ syalems. they recrxnmcrwl careful prior testrnR in order to delermir the proper esperimenlal conJrlMns for each crnnpaMrnd. I acko. A G, Rwenhers, tI 1. , and Sob/, l.. A. (7rni.a ('Al.nk.r Arru )9 S(X+-S10, 1172 Other support: I/ S Public lkalth Service. F rom the [kparlmtnl of Medicine and the Fe6 Research Insluute, lemple tJnwcrsrty Hcalrh Sciences Cen/er, PhJadelphia. VI11. F.pidemioloRy hIFFt?RFN('1 S 11F 1 WI FN CIGAR AND PIPE SMOKERS IN IIFAI.IIIY WIIIIE VPIFRANS flcuuse cigar anJ prpc smoking arc quite dnnnct and drffercnl forms of tt>l+acco usage, thrs partrculau study was urk)erlaken in order to determine whelhcr it is valid to classify such smokers into a singk category (or slatnlrcal purprnes, or whether they JrRer from each other with respect to certain nwrpholo`ie and u+cioeconomic characteriatics. Conxquently, a serrcs ol healthy white veterans were ttamined for anlhropornelric, somatotype, occupatiiasal and eJucaliaxral description fealures. The subjects, selected frum a scrres of 1.6911 aJult, whitc, male veterans from tht Normative Aging SIuJy ol Ihe Veter- ans AJminislratwrn (hrtpatienl (linic in Boslon, were 2S-M at the tnne of their ctaminalion, their mean aRe being 41.4 years. Only ptne cigar snu.kcrs (always smokcJ ergan only) and pure prpe smokers (always smoked pipes only) were included in the analysis Results indicate that the pure cigar amokers have larger mcan bodily drmcnsions, greater lateralhty of htKly suucture, and are mure t,ftcn cntkrmorphrc mesonmrplss than eclont<Nphic mesonKUphs; they have less furmal education anJ have lewer representatives in rnanaterral occupalruns. Ihus, it appears that pure cigar smukers anJ pure pipe utwrkers arc qune Jdlerent krnds uf peuple, and that the practiee af curuMnurg thern utlo A single circgury lor snrJy ul asu.cialKSn with other chAractcrislks may wcll hc un- Iust/1KJ tia•IUrr, (- 1 /H,ll N onJ I(,nc. (' 1 t„ /u_r,./ /~• Il-irA : 51 11 104 7 141, 1972 I rom the Nurmalive Aging StuJy, It..nlon (hrtputrcnt ( Irroa• Veterans Adminis tu.ttum, and the lkparlnknt uf Nulrnrun, 1larvaud tiahu.d ul Puhhc Ilealth, It...trrn. SM/)KIN(i AMON(7 WIII IF, If1.A( K, ANI) YI 1 IOW MFN AN[) WIrM1 N: KAIC1 R 1'}:RMANI`Nlli Mlll.lll'FIAtiI(' IIFA1.7/1 LXAMINA I ION bA fA, 1964-19AN '1 hi. first rcptal of an onKoing study conccrning the a:haracleriuics of smokcrs and nonsmokers, descrihcs the strdy population and utlinR, the mcthtNs uxJ ftx determining and classifying snsoking habits, and the dutritw trun of thcse habits according to skin cdor, ses, and age. Among the 89.066 while, hlaak, and yellow men and women included in this sludy, there west inJ.•cJ .ubslanual Jdlercnces in smoking habits in tclatinrs to these variahles, as rchtrted during a Kaiser-Pcrmanente mulliphasic health chcckup given in San Fr.rniscu and O.AIrnJ. Ca11f1Nnra, in the years 1964 19A11 lF.e dala show that in this prrticular population sample: (1) cigarctlc snxrking was mwt prevaknl amnng men than women; 121 the '_Q-29 and 30 )9 year groups con larned the lartcsl prnportion of smoken; (3) on the average, she yellow &roup had the lowesr perccntaRe of cigarette srnokers, and in mosl aRe-us Rroups of smukcrs, they were also least apt to inhak; a smaller proportron of cigarette smokers was ak,o noted among ('hinese than among lapancse, particularly in women and younger men; (4) current cigarette srrwking was more prevaknl in hlaak men than in white men: nd (S) amonR cigarette smokcrs, whites were nsost apt to inhale and to ursoke at k.at one pack per day. Frbdnran, G. D., Seltter, C. C.. Sregelaub, A. B. Fclalman, jt. and Colkn, M. F. A.nerican Iournd of Ejaidernioloty 9N11:2)-)S, 1972. Other a..pport: National Center (or Heaith Services Research and [kvebp nscnt, U S Public Health Service, and the Kaiser Foundatioa Research In slrlule. Frorn the Ikparlmenl of Medical Methods Research, Permarsenle Medical (irrbirp, Uakland, ('al. l lll: AN I IIRA('OI I(' PNFUMO('ONIOSIIS 7hrs is  cornprehensive review dealing with all those pncunwconioses lu which carlxm is n importanl contributor. Structural alteratiarns in the lung causeJ by pure carlwsrs du not usually produce a(unclwnal dtsturbance. Mutr ofren, however. the elcmcnl is a.lrni.eJ with other subsunces whrch often cauu mote sctitws pulmonary drsordtrs lhe author traces the orrRin and develop mcnl nf anlhrxosn as a Jncase entity Ile esplains the deposition and resenrwrrn tr( anrhrncolrc particks anJ rkscrihes several types ot anthracosis and Iheu rcl.alrun.hrp In v.rKHrs flctors such as graphNe, tarhon hlaak, carlw.n clcatrt.lcs Itbh.rto urd ulher auntnaonly cnctMrnrereJ arr (rdlutanls A sepau/e and dr tailed .can~~n it dcvulcJ tu aual wrukers' pneurn rconr.nes ((WP) Spc.rlk.lly this Jrsaussurn Jc.Js with the rulc o/ mine dust artJ au padlrNants, struclur.l Ih 79

Italures anJ pathorcncsn of CWP, car pulnsonak in ( WP, funcl.onat struclural crwrcFatwm, and the irsrNfcnce of neoplasia in ('WP. the uthrn cunclu.ks that CWP is uau.Jly a Jncave of miscd elrulo`y, pn,sihly in /.cl. Ilrc rc.ull of a nunrf.cr of Jn..rJ.•rs Prcvcnlron appcan possible with a reJuctwn in coal Jusl cuncensratrun An cacnuve biMw+ltrsphy is inchrJcd N,ryr. R I ('rr.rnr Irrpur uo P,nhrdnry S5.)7-65, 1971. Frcxn the Ikpartment of Pathobp, Pennsylvania State Universiry ('olk6e of Mcdicrne. Iiershcy TIIE 1'PII)EM1O1 (X:Y OF PFRINATAL MORTALITY- IIIF POWER OF TNE AUTOPSY It has recendy been shown (hd epkkmiologgic sludies of perinarid rnortality based on dcath cerrifkates are unrdiabk, mainly because the drarh& are often une.ptaineaf In many hospitals, only a smaM proportion of c.us come to wtop%y anJ thcse are usually not analyzed in sufficient detail to identify all the disease procnses that may be prexnt. Furthermore, much polentully useful rnformaliun is discarded without analysa. lha study illustrates that good autups.es contribute to the undenlandinR of common perinalal d surden, as demonstrated by recent analyses of 1044 consecutive perinatal post sN.rlcros at a New York ('ity hospital The data included 361 sbllborns whose gestational age rantcd from 20 to 44 wccks, and 61) newborn infants, of whorn none lived Irasger than 72 horus lAis group was mullrracial (+tl0 white, )71 black, and 191 Pucrro Rican) and representative of several socioeconomic kvels and ethnic hackFnrunds Results indicate that: (1) reprdkss of race, undernulrilion can a/fcct Ixxly and orisn wcithl, so that in the United States ccooomie slatus appears to be a Jclermmant lactor in infant rnwulity, 12) anlenalal bacterial infections might tx an important cause of prematurily and consequent perinatal deaths in the pnw urban populalion of the United Sutes, with blacks caperiencmg twice the rate of infectrorsa (congenital pneumonia or chruio- amnioniln) encountered in whites and Puerto Ricans; (3) in the Unrtcd Sutes, males have an eccessive risk of neonatal death in compariuxr to (emaks; (4) liveborn, premature, scxnewhat undernourished infants, urbject to sustained neonatal hyposia (hyslrne membr.ne disease) are most vulnerable to cerebral intraven/ricular hemnrrhage; (5) hyaline membrane Jrsease (IIMI)). a common cause of death in premature infants which is associated with surfactant de- ficiency, may be rclated to deficienr eorticosleroid activity so that circulating Iwrmone levels are inadequate to irsdrrce enough surfactant, as supported by the /acts 1hat: (a) the aJrenats from 11MD enfarNs contained kas cortical cells than those of non-afflicted rsconates; (h) a correlaliun was /rwnd between evidences of anrenatal bacterial infections (which atimul.le corlicusleroid production), signrfkantly larger adrenal adult zorse cells, and the absence of IIMD; (e) anenccphalie neonates with very subnormal adrenals haJ sfxwt one- half the mass of oumophdre giramrks in pulmonary rype Il Ivcular cells as Jd "nwmal" conlrols, these inclusioru reportedly being Ihe anatomK repre- senla/Km of surlaclanl, the author sho discusacs the incidence anJ possible origin of hydramnws and oligiohydramnium, nJ implies that carcful autopues should be conducted on every infant dying jus1 belore or alter birth W Naryr. R. L. Tlre Pediatric Clinics o/ NortA Anrrrica 19(2)'93-)I 1, 1972. Other aupporti U. S. Public Ileatlh Service. From the Department of Pathology. Pennsylvania State University College o. Medreine, Ilershey. ('OA1. WORKERS' PNEUMOCONIOSIS: (`ORRELAIION OF ROENTGEN(X;RAPHIC AND POSTMORTtM FINDINGS It is probable that coal workers' pneumoconiosis a no( a sin6lrr di.ca, process but a composite of multiple disordcrs, ea:h of which may vary i incidence and severity (rom one patient to another. 71ha autopay study of r bituminous miners oWer than 20 years of age showed a corrclaliow betwer the rocntReno6raphk featurea of pneumoconasis and postmortem qua.(ilauvv anatomic me..wemenls o/ some o/ the disease processes comli(u1in6 IAe d. order. Ihe volume of dust rnacuks and noduks, and their silica (silrcow dwarJ, and collakew conlenl appear to be aitwi&aM contributory factors to tM X ro abnormdities. On the other hand, these lalter structural sbnurmalnid were n• related to dyspnen and lhus ate probably not well eorrebted wMh ovec, putmonary, (unclioa. iyspnea, however, was related 1o she severity of emph, sema and chronic eor pulmonak whieA, un/ortunately, ue not always reco, ni:able on s-rays. A number of minen, rnoreover, who drd not show a, roenlgenographic evidences of pneumoconiosis in spite of dusl macules co. t.ininR silica asd collagea, did have etephysema, cor pulnsonak a.d dyspnc Naryr, R. L. aod Dellinger. W. S. /orrnd o/ the Anwrkm Atfrdkaf Assocl.(ior. 220(2):'-2)-227, 1972. Other sarpprtr U. S. Public Health Service. From the Ikpartrnenl of Pathology. Pennsylvania State Univcrslty Colkgic Medicine. Hershey. IX. Immunology MECFIANISMS INVOLVED IN THE DEPOSITION OF IMMUNE COMPLEXES IN TISSUES An aclive process for the deposition of circulating Immuoe compk, appears lo he responsrhle for this phenomenon in both a laboratory rnoJcl guines pip and in acute immune compks disease (serum sickne.s) is rsbb- A summary of the mechanisms by which deposition of immune compleaes n• occur in acute immune complex disease (serum sickness) of r.bbits is prc.cn, in this paper. Immune compksn and protein mokculn circulate in a hw veuel. In the presence o/ basophil kukocytcs with adherent hornocyto(mt (IgF.) anlibody, the antigen induces release of a solubk inlernsedure I intermaliale activates platekts to clump enJ to release vasoactive amrn 'There smines then cause an increased permeability of blood vnuls, espar• in ueas where the platekts clump and impinge upors MoxH1 vcuels With increaud permeahrMy, macromokcular ( y 19S) immune cumpleaci hec.', m

cmralyw-J :dnnK litrcring mcmbrance in the vesscl wall 'Ihe dcp.wtcd com plcRCs /lhrn inducc rnfl.rmmalory inlury. ('.rrA.rnrrr, ('. G llrr lnurn.J n/ F.prrrnrrnrrd A(rJnrnr 1 J1111):75-119, 1971 . (1tA.r .upp.rrt: l/ S Public Hcalth Service. National Mtdripk 4lcrosi tilKKly, •/xl American /lcart Assocul.on. 1'rrr.n the 1)cpartment ol Faperrmental Pathubcy, Scripps ( hruc and Research I rwnJatHxr, I a 10113. ('al 1/11: 1 1 1 1(' 1O1 (()MPt.FMFNr DFPI F.TION ON NI l) I Rl)I'11I1 MI(iRA / lON IN A( ll l l IMMl1NO1(KiI(- AR I IIR111S Rated on the fact that cnmpkmcnl chemMaclic faclurs have rccendy been found in human prnl fluid nMarned frww p.tients wnh rheumatnnl .ruhrrln, a rok h.s hcen ascrrhed to Ihese lac(on iw the devcla.prncnl of tmmur.utorrc injury. In order to s1uJy the influence of compkmenl components uprrn the nwrvcmen( of neulrophrls to immune conpkaes in vezscl walls arnd Ihe Jcvcl- opment of immunobgrc mrrry, these investigators used the immunc crHS.ptca injury of rabbrt .ynovtal tissue as a model to compare neutrophil migral on in riro and the rnlury of a reverxd passive Anhus IRPA) reaction in anim.ls with an unlnturl.ed conspkrncnl sysum, as well as in Ihose lacking certain complement cornpotmrnl. To this end. suspensions of purified neutrophils were nfuscd in the joint space of rabbits with induced agranulocytopenia which were prepared lor an RPA reaction in the synnvul tnsuen. The neutrophtls migrated through the tissucs to the site of antigen antrhody<ompkmenl deposition in Ile walls of blood vcuch; inlury followed Ihe aceumulation of Iheu cells in the vesscl walts and was assessed by kaliaRe of radrolahekd proteins from the crreu.anon into the joint space, dcprnnron of carM.n black from the c/rculalNM into the area of Ihe injured vesul, and Jtaprdcus of red hl.xxd cclls. Ammas genetically deficient in ('li nr Jepktcd of ('1 with cohra verxrm factor shuwcd a reurrkd nte of nculruphil migration through the synovial tnsues to the sitc rd anhgcn- antilxxly eomple., sml inlury was both delayed and diminnhed in those de- ficrent in comptenxnl. Resulls indicate the presence of complement dependent chensolasis rn rn-n, arsd Jcnsorulra(e the reconstitution of immunotugrc injury in neu(ruphd dcptclcd animals by replacernenl with purified neutruphds. IkSharo, C. V, McGra.)c, M T, Ilenson, P. M. and CocArunr, C. (:. 7Ae lou.nd o/ lrnnrurnoloory 1o11(S).14111-1119, 1972 Ihbrr srpport: 11 S PuMic Health Service and National Multiple Sclerosis kKKly From the tkpartmcnl of lisperrmcnlal Palhuloly, Scrrpps ('linic and Research I awndatron, I a lulls, ('al t111 1NIFRA('llc)N OF II/1(iFMAN FA('IOR ANU IMMUNE ('(1MPI I XI % Ih s tt a r.h•rr ~rn thc auilwrs' studtcs of the pansthlc inlcracw n of I1.6c- m.rn I..tor (rum human ur rahhrl plama with a varrrly of unmunularrrc rc- acl.url. /lalhl:rtly. Ihey luund rwr cvKlcncc n( uch an t111cr:JClNrn anal nchhcr IsrnJrng rrt r.~Judalwlcd II+Acnsan L.rclor to rmmunc iggrcgatcs nnr its depklrro Irrnn tlk svipcrn.lc w.r• oh.ervcJ ( IcavaCc of /hc Irl.clcal mukcuk mlu u, 10.101011 nwdccul.u wct4hlachvc IraKmenls was n.rl J.tcal.hte after rncuhauon with in+mrnnc armplcacs Ihe w.l.rlcd f:rclnr wav lar m..rc xn+nive to acpvo uun /han in pla.ma or .crum, hut rmmuno/nArc r.vc(.rnt% did nu1 consistcndy acthvatc it, as JctcrmrncJ either by convcraion .rl prcAalfrkrcrn to ils enlyma lurm or by ahnrtcninR ol Ihe clutUng time ol I.ctor XII deficient plasma A varrcty of tmmuna.luKre stimuli were /c.lcd 11) anusen-antilr.dy cornpkses tn Lrluhlc nr prectpturcd lurm; 12) particulate anugcn-antulwxly crxnpkscs. r c symu.an ann tynrsvn in which a.urlace was presented lor activation. 111 hum.rn 1KM 16<i und 16(i-tL.di (nceumaloid factor) complc.cs; f11 tmntunu acRrcRatrs cun.rstmif nf hcat or Ins di:uolucd hcniiduse arCrcCalcJ nryclrrm.• prrrt.ms of all human imnnrnorkrMdrn classcs and .uhc6sscs. 1s(i. IgA. IffI) 1`M, anJ IGI: . ^hs.npuarn wqh rmmunc aR6reAalcs drd naN rcducc Ihe quanntl ul /IaKemin Ircl.x in .ululion. nor was it Auund lu thc prccipuatcs; the pa•. cncc ol plasm.a or scrum wuh Immune aRgrejValc. dwl n.n Sencrale its acuvnl cuhcr 1hc only prrplralnRlsof /mn111notihrlMlhm capable rrt activating /laticm.o fxtur were latiurd to be cnntammated with bacleria. which had the ume cAca, whcn ivd.dcd P.ru.:unrunuw ulrulrKrnes werc rdennhed in two instances arnd f rolr in a Ihird. ('rK Arunr. C. (:.. Wueppcr, K. /).. Arkcn, 8 S, Rcvrl, S 1). and SpieTelbcrg It I.. 7Ar /uurnd of ('linirullncruistiuion SI(IUI'_7)t+ 2745. 1972 Othrr nrppr.rt: U. S. Puhlic Heallh Service. National Multipk Sckrou S.kicly, and Amcrrcan Ilcaut Associalion. 1'rom the Ikpartment of Fsperimental PalhourFy, Scripps ('linic and Rneurl frHnsdanrrn. I a Jolla. (-al l)t)AN111A1IVF ASI'1'(TS OF PI.ASMA MI'MIINRANI -ASS(X'IAIFD IMMl1N(Kil UH()l IN IN ('IONI?1 01: 1)IPI 011) IIl1MAN I YMPII(X'Y 11'ti The ansatnl uf t and A chains and Fc fragment associated wilh the pla.m mcnsbrane and in the entire cell has been mcasurcd lor eight linn of hum• lymplxrcytes and 21 clones derived from two diplotd Inses. Ihere was conenlr- uhk varrilinn in the nature and amotml of nurnhrarse- assucialed immunooll.A+- lin and Irw.l immunoilbhuhn anwnR Jiflercnt cell lines and elonn ('ells wu ddlercnl phcnolypcs for mcmbrane-associated rmmurxsfs{r>Arrlhn were ulduc tu show that il is not simply absorhed /rum the culture medium onto ti• plAsm memhranr The methods are useful /or selecting variants which b• or have altered mcmhrane-asuscialed rmnrunoAluhuhn I rrnrr, R. A . Mc('onahcy, P 1. and Dr.on. F. I .1, rrm r 171 Ml 6'_. 1971 . (1rArr sup/...rt: l/ S Public Ileahh Strvuc. tl S/Niwnk 1-ncrgy l'r11- n11Y\N111, •rNI Nruwn Ilarcn Pund, Rcscar.h ( urpuuuon I rum thc Ik•parutw•nl of IKpcrimenlal Pathuingy, Scrtppt ( hnic and Rescar. 1 nutnlauun. 1 . lullA. ('rl e) e2

SYNIFIFCIS Oh C-YIOPLASMIC MFMBRANE-ASS(X'IAIF.D DNA IN I YMPFI()CY T F. NU(-l El1S lhe type of DNA associatcd with Ihe cyt(plasmic membrane cd human lymphucyres in culture is synthcsitcd in the nucleus during the growlh phase and rramporred to the plasma membrane In order to investigate Ihe tume and pl.ce of mcmhrane-associated DNA aynthesis, e, density labcl previously de- tcrmined suit.bk. S dcosyurrdine IBudR), was used At indicated by various uptal<e rates. this partr.ular l)NA is a stable nwletuk and not a contaminant derived /rr.m the ckgr.dation producu of dead cells. I1.11, M R, Mcinte, w. Goklskin, D. A. aad Lorrwcr, R. A. Narurr Nr. lfrc.lnty 211(f)ee. 22): 227-229. 1971. OtArr surport: U S Public Neakh Serviee, National Institutes of Heaith, and Amerrcan Cancer Society, From the Deparsmcnrs of Microbiolop and Eaperimental PatholoAy, Scripps ('tmic and Rcsearch Foundatiow, L" lolla, ('al. AN IMMl1NO1-(X)I('AI. STUDY OF THE FATES OF NUCI-EAOt AND Nll('LFOLAR MACROMOLECULES DURINO THE CELL CYCI.E These investigators report the use of irwwwanofwswescence employing spe- eifk antibodies to detect nuekar .nd rwckolar wucromoleeules during the cell cycle in synchronized diploid humas lymphocyle.. They found that the rnajority of "available" DNA dcterminanH were adj.eeM b the nuclear membrane in phase (:r, the period in cukaryaic cell cycks between rnelaphase (M) and the onset of DNA synthesis llntone-.asociated DNA was present throughout the nucleus in phases Go and S (period of DNA synthesis between (:r and Gr. which is the phase belween S.nd M) and asaociated with chromosomes in metapAase Singlc stranded DNA was .oe detected in phase Gr cells, but was ahundantly 'p.esen( midway through phase S. Nuclear morphology changed markedly as cells proceeded from Go Io M, during which nuckolar fragmenta- tron and the appearance of nuckolar con(ents in Ihe cytoplasm were otncrved. ('ytoplasmic DNA, not seen in Go or S-period cells, appeared adjrccnt to plasrrut membranes in metaphase eetls. Accordi.g so the authors, these studies dcmonstrate that specific .ntibodies apinN twekar and nuckdar macromok- cuks could be important reagents for the determination of the fates of certain macronwkcuks in cultaryotic cdh. Tan, E. M and Lrrnrr, R. A. lournd o/ MoJccr/er Diolory 6a:107-111, 1972. OfAer .rpprtr National Instilutes of NeakA. From the Department of EaperimenW Pathobgy, Scripp. Clrnic and I esearch Foundation. La Jolla. Cal. SYNTHFSIS OF PI ASMA MFMBRANE-ASS(X'IATED AN[) SF( RlilORY IMM()N(X;LOBUI IN IN DIPI.OIt) LYMPH(X'YTI S Alterations in gene eapresaion result in the synthesis of cell specifSc poiy- peptrdes during the prraeu of cellular diAerentiatioo. Since the immune system I I offen a specialized c.ample of this phenomenon in Ihat cells synthesiue im munogkrixdins (1S) whose /ate presumably changes during diflercntiatioo, a clone of continuously growing human dipb.,d lynsphocytcs was selected as a model for study of the mech.nisms involved. In testing ((i,) lymphocytes must of the synthesized 1S is inserted into the plasma membrane (M-1g) wherc it presumably serves as a receplor molecule for antigen recognition. Following e.posure to antigen, those cells destined to become antibody (ormen undergo numerous divisions and diRerentiate into plasma'cells whose 1S is secreted into the estracellular fluid (S-lg). lhis drlfetentiatiun, "driven` by anligen, ends when enough antibody to remove antigen is secreted. In growing lymphocytes. however, differentiation seems to be arrested between the G. type of cell awd the plasma cell, and the 1S they secrete is inserled into their plasma membrane as a presumed recepror. A method which quantilates the amount of IS in the plasma membrane and cytoplasm (C-1S) was uscd to study she amount and/or hall disappearance time of M 1S, ('-1g and S 1S in logarithmically growing ard syncMonized cells treated with ptWein inhibitors, in an attempt to approach control of the ddletenliatiow process. The hatf disappearance time for dnett able plasma membrane aswcialed arrd eytoplasmic immunoRksbulin was meas ured. lhe amount of plasma membrane-taasociated and cy/oplasmic irnmuao globulins of synchronized cells in the station.ry (Gr) phase of the cell cycle wa studied, rs well as RNA synthesis. The rewlts suggest that perhaps both secreted ard plasma membrane-associated 'wnmunoglobulin may be separately controlled by the cells. Lrrnrr, R. A., McConahey, P. 1., )ansen, I. and Diton, F. ). The lo.rrwd ol Eaperlwvnt.f Afcdklne 175:176-49, 1972. Other aup'orts U. S. Public Health Service, U. S. Atomic Energy Commia sion, and Brown-/lazen Fuwd, Research Coeporatwn. From the Department of Eaperimeotal Patholop, Scripps Clinic aad Research Foundation, La loAa, Cal. PRODUC-IION OF MACROPIIAGE MIGRATION INIIiBIT1ON FACTOR BY CONTINUOUS CELL LINFS The migration inhibition factor (MIF) responsibk for macrophage mlitra tion inhibition, a tesl widely used as an in vitro correlate of delayed hypcrscroi tivity and cellular immunily, ia released by sensitized lymphocytes of several species when sensitized cells are incubated in vitro with antigen. II has bcen repeatedly emphasized that MIF production is the result of a specific immuno logic reactan, and that its deteclion in virro reflects a state of cellular Immunity in vivo. Recently, however, MIF has been detccted in the medium of con tiuuously growing cell lines, presumably without antigenic sumulation. lhu paper presents evidence tha(: (I) MIF is released by both lymphurd and Abro blast cell lines in continuous growth; (2) its release is asuxiated wirh rhe actrva Iron of reslinp cells into mitotic ones, and particularly with S phase cells; (11 it is associated winh delayed hyperaensitivrly and cellular rmmunuy Lec.usr specifk antigen u.duces a small number of sensiured cells to drvr)c, and run because it is a specific mediator of these mechanisms l ubergen. 1) (i , Fcldman, 1 1) , Pulloc\, F. M and I.rrnr., R.~ The /ournal of 1:.prrrrnrnru! MrJiunr I13(_') 211 _'AA, 1972 94 85

i Other .uppurf: Natronal Institules of Hcalth Fnwn the Ikpartment of I'aperimental PatholoTy, Scripps ('linic and Rcseatch Fourw/atron, La lulla, ('al TRANSf'ORMAIION OF HUMAN LYMPH(x'YIFS BY SODIUM PL=.RI(lt)A 1 C• lTis is a preliminary rcport, in a ktter lo the cditor, of the authors' invesli- gation into the hlastogemc eflect of sodium periodale (NalQr) on human peripheral lymphocytes, aimed at readsiw8 a better understandina of the nscchanisms of blastogenesis. Only a brief tapoaure to NalOr is neccsaary to produce sugmficant transformatiow, but a 30-minute esposure produces a masimum response, as measured by sN-thymidine incorporation at 72 Mwrs, an indcs of DNA synthesis. t.ymplsocytes from ti patrenlt with chronrc lymphocytic leukemia 1('l l.) did .o1 respord to NolOr in the range of con- cen,rations stimulatrrry for normal lymphocytes. TTse lymphocytes fronr anorher CI.1. patient also failed to show increaae i. DNA synthesis seven days after NatOr treatment I hrrs it appcars that the abnormality is not a delay in response as n seen with phytuhemaggluunin (PHA), but may be due to absent or blocked pcrrodatc recepUx ur~-s According to the authorti and as indrcated by their preliminary work, it n tempting to speculate that NaIOa chemically modifies the cr11 membrane by o.rdrzing membrane substarsces. They suggcst, furthermore. that the perrodatc mechanism of action is different from that of other hlaslo- genic agcnn. PFtA and anuillobulin antisera. TDeir opinion is that thrs work ahuuld dd to the un.kntandrnA of early evcnls is lymphocyle lranslormation. rarRrr, I W,O'Bricn, R 1. , I uLct, R I and Steiner. 1. L.uncrr 1: 101 104, 197,1 Otlser ,uppurt: Lrrhn A Ilaulrxd foundauon Lkpar/nstnt of ParlKrlogy. Un.venuy of Southcrn ('alJornma Schrkrl uf Mcdi. crne, 1 os Angckr X. Cenetici )iFMOLYTIC ANEMIA ASSOCIATED WITH lFIYMOMA IN IIIE RABBIT: GENETIC SlUD1ES ANI) PATNOI.(XiICAI. FINDINGS TAa communication reports the hereditary basis for hemolytic anemia in strain X rabbits and discussef the palhological flndinp. lhis hereditary trail represents a new nsodel (or sludy of anemia and is caused by a single aulo- aomal, recessive gene. Hercddary hemo(ytic anemia is rapidly (ata: to both aeaca with a mean survival time of 4.75 months. In rare prMractcd cases it is associated with thymic hyperplatia and thymorna Because aurosornal recessive inhcritance is indicated the symbol he has been assigned to the gene responsiMe for .kvclr.lxnent of the hcmolytic anemia The possibility ctisls that It rs wtcNi- cal with the gene (b) ctxdcrrrng waceptrbilily to tymphosarcurna in strain WF1 rahhits, since all aflccted animals in bodh strains have the sanse common .nkrsuy in urain X the hemolytrc ncmia in rtrain X tabhits appears umdar eb I t to that of NZB mice and represents, as in man and the doA, an immunopathy Although more information is needed to decsde whether the same gene, ha, .vhrch is responsibk (or susceptibility to immune hcmolylrc anemia also prt- drsposes to thynsoma. the possrbdily exists that il may rnleracl with a vertically transmitted vrrus analogous to the murine C-type RNA genome. Foa, R. R., Afrirr, ll., Crary, D. D., NorberL R. F. and Myen, D. D. Oncology 23:172J112, 1971. (Ither support: National Inslitules of Hcalth and Robert Sterlierd Clart Foundation. From lhe Jackson I.aboratory, Bar Harbor, Me. GENI? T IC PRFDISPOSITION TO TUMORS IN 1 FIF RABBIT lhe dcvekspnscnl and frequency of rabbit lurssws ue Rrcarty, influcncod by ate, breed arsd other constitutional (actcxs Ideally, for orscosenrc atudits, tumors occurring with high frequency in animals kaa than one ycar old ..e required. At The Jackson Laboratory, several strains of rabbits etiat that mrel Ihese oncogenesis requirements. A high incidence of lymphosarcorwa .rd Ihymorna associated with immune hemolylic anemia occurs in strains WN and X. two genetically related strains; susceptibilities are conferred by two aulowraal recessive genes, Is nd hs, respectively. Orher tumors noted in Jackson l_abora- tory rahbits are mainly nephrobtaslomas and eputhelut tumon of erdocrwre organs including the ulerus in mature rabbits of strain WI1. X, 111 and thcir hybrKls. In conunl, lumota were not observed in strains OS, ACEP, A, C, and Ills. Fot, R. R., Afrirr, ll. and Crary. D. D. l)ir Narurwisirnscha/rrw S6(9):437-ISS, 1971. Other aupporls National Institules of Health. From The Jackson L.aboralory, Bar Ilarbor, Me. RABBf(' MODELS OF HUMAN DISEASE AND TlIE7R BI(X'IIFMICAI. C1IARACIL'cRI2AlION In this rcview the author surveys the history of the European rabbil'a development as  laboratory animal and a rssodel for the study of human dr- eases. As supported by the results of his own esperinsenls dealing with Ihe effects of sct, slrain, diurnal rhythm, and a6e, on certain physiological parame- len (including the effect of age on body wcighl)- he atressea that physiologrcal rsd biochemical variables are definitely aflected by all these factors. A sum- mary of the information avaqabk to date on various disease rnodcls thut far identified in this animal (Oryrrolacrt fYnlfuLYf) foltows, and is so outlined as to deal with: (1) what genes arc involved; (2) what patholojies they reacmWe in man; arrl () what known clinical paransNCrs characteruc them Specifically discusstd are: 11) acM.nJrop(asia lac/acl; (2) atatia (a./at,) (1) audw+lrna scrrures, cpdcp+y (ep/ep): 141 huphthdrnia (sw/Iwl; (S1 ahundrodyurophy (cd/cd); (6) dachs (Da/1)a); (7) puuitary dwarfism (1)w/1)w); (el hemolyuc arscmu (ha/ha; (9) hyprrAonadu (hg/hg); (10) lymphosarcrrrna (Is/b); (11) mandrbular prugnarhrsm (mp/mp); (12) o.teopouosrs (os/os); (I)) renal cysts . 87

(rc/rc); 1141 sprna hifiJi I.h/sh) AS s+ImmariyeJ hy (he author, it has [1us been dcnrrnsual.•J that a suhs(an(ial number of mulaliuns have occurrcJ in the rabbll, rc.rJnng in p.thuNrteres similar to human ccxlsululKmal Jlxrta, arr) Ihal, while cerlarn var111MNH in the normal values ol du many known chnical paramelcrs are known so be associated with dlse.se conditions in nun anJ with genc mutulron in Ihc ralshil, further investigation of these mulanls in the rabbit coulJ he a tremendtws aid In underslandmg the comp/e.rlies ol humau abno(- matules anJ drsca.e IFslensive Mbtiotraphy on mutant gene appended 1 Foc, R. R lMrrrr, Il ) Proc IlyrrlVrr Sympor 1.9-2), 1972. OtAir .rpOurl: NatlKrnal Insli(ules d IleahA and Flycel, Inc.. Houslon, Tea. From The Jackson I alxxalory, Bar H.rbot, Me. I Active Projects Fullowin6 is a list of the principal investigators or inslitutwwu rr1 projects under way or activated in the period since the previtws Repr>.t, tuWher with the respective project lilks. Completed projects are listed in a later section. PRIN(:1/'AI. INV UtiTII:ATUR //R IW1TITl1T1ON AN711()NY A. AI.BANFSF, Pt(D, Di- rr, r.a, Nunuwn rnJ Mrrabd.r Re- sr..t.b lh.ruon, TAe Bu/le RtAabilua- Ik.n ('enlcr, M/hilt Plains, N. Y. IN)MING/) M. AVIADO, MD, Pro- frr...t of PArw...nl..~y, Unlve/sny of Pennsyl.am. ScMrol of MedKrne, PAII- adclPi/• A. ('LIFFORD BARGi=R, M D. RuArrr !lrwry P/nsrr Pro/rswr uf PAynofo- gy, Flarvard Medical ScAool, BoNon. BFNIAMIN BEI 1., M D., Orrerrne, 'and ('/1A111 FS I.. ROSE, hr U., Arw/.nr 1)rrrrrrw, Nrrn.rn•t AgIng Srrdy, Vcl- trans AJminiur.tion OulPalicM Clinic. Buslun. SAMUFI HFI I F.T, M O. Dirnr.w, DI- vnir.n uf frliul..Ry. Philadelphia (:eneral F1osp(J, Pbiladtlpbia. (Ik- ccascJ 1 BARUI BFNACFRRAF, M O. FaAyaw Pr.r/rrNM Yr1I ( IW/rn/tln, Dcpc nmen/ of Palhuloty, Har.ard Medied ScAuol. tkwon. B11D11DFV BHAGAT, Pu D., Prn/ruw of PAyual.rty. St. 1 uuls Uni.crtNy Sclsool of McJKint. Sr. louis. RI('l1ARl) 1. BIN(3- M 1), Pr.rfrrs.rr n/ AMJirrnt. (lnrvtrsity d S.rdheM Cdl- Lwnia Sch.wl of Medicine. I us Angelcs: Rr.ru.r Ir A.u.. r..re, ('alilarniu Insrnulc u/ Tethn.Auty: lhrrrr.w .rl CwJr.d,.Ry unJ Inmm~ural MrJr.rnr, Ihrnlmglun Mcm.M ul Ilosprlal, Pasadena. ('.1. HIl) RFSf AR('FI (-ONSI/I TAN7S, IN(' . Camhndtic, Mass. ' HI() Rl til'Ak('11 INSIIIl/1F, IN('., ( 'unbrntae, Mass HAk11ARn H NkUWN, Vnl). (hr./, 1 .prrrnrr.u.J P.y.br,nn. Vtltuns AJ- nunrtu.u.rn I1usprlil. SeMdveJa. C.1. PRO)FaT TITI-E Effect of cillarellt snsolins on serww ribo/wxkase, ccd blcroJ cell utulne .nd cyclic AMP levels in ma. Tolerance of lungs to tobacco snwrke whtt special refercnce ro pulnsuw.ry cnyAysema and vascular occlYYve k+rr.. Browclrwse~l.r eflecls of citiut((. nwolia Behavioral hypertension and u(erioeck. tosls: tfftcls of nKtM/r1e Social prediclots of Iongtviwy 'A smol<inp rese.rck uuJy rw 1He Nonna- (Le Aging Study Tlte effect of nko(ine on var{ous pra.• t(ers uf cu/Jwvastular lunction fonlrul of specific cellular and tsuwaal immune resPunus to ncoptaslic and nonweuplasrK u.aues FRecr of cigareue smoking •nd wicwrnc un the J..pnrrw)n of caucbu/an+iwt/ In etpcrlmenlal cwonary arttly 4nuA1 cicncy The e/1et1 of nicolrne on allscrosckrusus (le.auosluJ.cs1 Fvalutllon of Ihe {o1Jen Syrian lamsler as a m.nk/ animal fur tubacco .rnule inhalalurn sruJres ('ompsrlwn of Jrrtcl m.wnt tdrn t.pn wre r.s wlkdt, fresb uprtue ,mulc enJ m.nrst skin p.rnung wub um.It .umkntat. 1-.pl...ar.un uf nce J,/ltrrmts in 1 f(! p.ntrn - suhrtcnsr u.rt c.wltlH(s rn sur,dtr anJ nuo,rnuler wbreaU 89 A 01

/ t t PRIN(:I PA1. IN V FSTI(;ATOR (//t INSTITIITt(/N lA('K Cl1Al-ON. M 1), Auul.wr Pro/rr- r.w of Awellhruululy. Albert Fmucin ('olkae of MrJ.crne, New Yorl Crry. SANFORD CFIO(X1S11, M D, Auiu.nr Pro/ru,r of A(rJ.c.nr. Tulls llwlversity School of Medicrne. I)oslon (lwrluled Under Maurrcc Se/al, M 1) / NAITER M C110PRA, P.r D, tro/rr wr of CArwrurrl, Notlh (-arolina Apri- cul/urat and Tec4»cd Ststt Univeruly. (Letwsboro. CFIARI FS O. COCFIRANe, M.D.. Snyr t('hwtr anI Rrt..rcA fe.wt.- lrow, I a lolla. C.I. AIIFN S COIIFN, MD. PwD, Ar t01.n/ Profrnrr of AlrJ.cur. U.iar- sMy of ('alrforwu, Saw Fra.ciace. 1O11N F. CRAIOIIFAD, M D, Auarl- •!r t tn/ruor of r.lAal..ly, lJwivusny of Vern.owt Medtcal School. R.uliy- low T. TIMOTIIY ('R(X-kFR, M D, lro- /ruor uJ Ahhunr, llnr.rrtily of Cali. (orm Sc" of Medicine. San Fraw- cruo CARROII. F (-R(KS- MD, Arrur.w/ Prufruur of Jwrrrn.l Mr/r.nr, Unrverrily of C'ddotn.a School of Mednrne, l)avis. TFIOMAS R. DAWHI R, M D, Arrorlur Yrufrrur of A(r/urwr, 8otlon llmtcr- sny School of Mcdrernc, Bouon. IOIIN P 1)FI.ANF.Y, M D, hr D, Ar w.larr rroJrnwr of .fwlrry. Uwlvenity of Mtnnesota. Mlnncap>aia. f:IyWARD F DOMINO, M D. ProJrr- rnr u/ fAmnwulnly, llniveewy of MKlIllan, Ann Arb[M. SFRTRAM FICNFI . S S, D D S, Dl- rerlnr, htrlrrrlr n/ .Srum.r.dallr.f Rr- 1rNcA, ScKnct Rcsourcts Foundalion, Water/own, Mau CARI TON K FR1(-KSON, M D, Ar uurn! Yru/rn.r uf rl..rnr..ul..r y.wJ Tuuud..cr. lhe l)m.eruty of Kansas Schw! ul Pharmacy. I awrcnct. WAII'IR R ISIMAN, MI), hrl), P.ufrnr.r of rn. h..fuer .wl I/.u. hrn.. nu r. I).atwr ( ulker o) 14 (-ry ol New lu.lt.w~ Yn.1, I PRO)E(T TITI.E RctalionthiS of tnwling, aueroiJs and nxnslrua cyck to pllmonary cyawnnr- p(wtotfy and mucop>fysaccbartdcs Chronic bronchrtlt entrlies The dritrada/ion of DDT. TDE and Drtl- kirt iw ciRarette wuiwrrun and rrde- rrtar. Irsolea Tb ILCdiNio. o/ i./lawunaory injury of liwt Rob of lisc hurwan a/vtolar m.croyAqe iM Ihe poductiow of cwlpAysew,a EPitRetlal cell Iransformalwn t nd carci- oowu i.dtucliow of C•lyp: RNA vlruset See Levy. 1. A. Eaects of lobacco smole on thc prtmo- •ary alve.Aar macroPhale -- eyluliwetict, pAalocylie abrlrlres and btochem ittry Srr"Lin, clauet, ritl Laclurt and cardio- vascular drtcase The Influences of unoling and nicaine on circulalion in Ibe bwer limb ERecls of IobKCo unole and nicotine on 1`t eewtral nervous tyYem Metabulie relationships of human cprlum in claronic obuructrvc lung Ji+raxs F/lectt of nicwine on free acetylcAoline in thc hrppocampt durm/ karntng SruJus uf nKO/ine action ul.un ruenuwy c..nwlrJatwn Meubol.c rerprnx to uretu --- tubacco UnO1,e HI/er.Clwnr 90 I PkIN1:IPA1. INV k_STICAT'l/R I)k IN,TtrUTION 1ONN k I.JfFkl Y, M D, Arrn.rarr Yru/trr..r ../ Irrl.ufuly, llmvcraity of ( hna11u Schc.ui of McJKrnc. ( Arcago FI)WIN R I ISIIhR, M 1), L1r.r.r.N of L rh.wulwrrr, ShadyuJc Huspplal, Prtls- bursh (7ARY O FRIFDMAN, M D, Senior LorJrnuufolur, Kaiur FounJalion Re- teucA In.bwle, Oalland, (-at. H IIl1C.11 Fl1DFN!lERO, M D, Dir.n lur, Srrhun u/ lltnwluLrly wnJ lmnrr- wuluty, llniverwy of ('aldurma MeJi- c.l (-enler, Sam Francnco: frufrrnur u/ Awlnwdul w/ L.anlYMduly, Univte- tuy of ('alrTwwu, terlrky. 1 FONthli (i(N DSf F1N, D Sc., Rr- v.r. A S.Irwn.l. Rrrrur of Rr.r.r. h/w Nruroluly .wJ Ly.hwlry, New Icrsey Neuroptychiatric Insliwle. Pnnceton. (Now al thc tntrirwc for Menlal /Ica1/A Scicnctt, Rurters Medical School. P..- cataway, N. 1.) IOSFPIt 1. Gl1ARNFRI. Pw D, Dirrr- l.w, hJnu.n.ry ArruMul..ly LsAur.- h.ry, Drparrnrrnr of MeJKrnr, SaiM Vlncem Ilu+pplal, Worceuer, Mass. 1 Nuw at I ung laland IcwitifNtIlsiJc Medical ( eMCr, Ouctn. Nuspiul Cew- ter Affllhatwn, Iatnaiea, N. Y,) PAlll. IIAMOSII, M D, Aui.r.nr t'ro/rn- ..n u/ rhyrid..ly and A.oOhy.n r, Georgelown llniveraNy Medical Sclwd, Wa.hmalun, D. C. BFRNARD HANFS, ht D. DepartnceM u/ 1lydlh Science, Caldurwia Stale Uni- vertily, Nurt6ridge. 1011N A HAYFS, M D, Acwrl.rr P.ulwlociv, Mallory Invilulc of PatAul- uFy. Mo+lun CHy Ilo+plal, eoston. IIlR81 k r B 11I RSC-OWIIt. Ptr D. .I.... r..e! rruJrr.w u/ AhrrnAr.duRt, Gcut/clown lJnlveruly S.hcwlt of McJ icrne anJ IkMnuy. Washm/lon, 1) ('. tll KFSFAK('ll INSfIIl1TF;C'6ic.su A1 t At 1 n 11 K APPAS. kI 1) . Llru.l. 1.1o. .rrl.wy u/ A/rrrhuL.m uwJ fh..ruuu.d- uc). k.Kleleller llmvrr..ry. New Y.al PRO)E(T TITt E kesoluUUn of pulmonary injury FRect of rubacco .mule and wicWlne on uructure and function of coto.ary u Icrret and plavna bpds in rabbus C6aracterluat of snwlcrs a.d wonrwolt crs Collagen •nuboJres in telauow lo IM etl oluOy of cmPhycrm Aw anatytit of bchavwtal and kkil changes ptoduced by cAronic wkou.. adminUlrallon rn rale The influence of eatended etposure lo cill artllc tntu\t on prlrtlorlary rtalNlMe lo rnfeclwn at related to alveolar rw.c rophagc and mucocdtary funcliort Effccl of .mulinji on she "renall aMsrayi Spiromelric evaluation of 1200 .orw+al adults A JeladeJ morplt.>lopcal.rudy of thr tpulum and MuncAral /ree iw ruitnrr wuh cMunrc IMOnc111/1a followrq dt Ia.teJ clinical tludy Juriq life 1he rok o/ Ihe macrupAape iw rhe imwrunt re.ponser cllect o/ tobacco Productr un macruphagc (unclwn 8wener/elic and enJ.rcnne eflecu of we.r and Iheu mrerrelatwwrhrps wllh 16e c/ fec/t of tuhaccu stnole rnhalalu.n 1 fleclt of ru0accu smule rnhalarrr ou alveol.r n.acr.phajet and lung wrlac la.u in aw.mal muJtls Pulycychc hydr.r arb..nc t/ltctt on Jr luuh.arwn mcabanruns 9t

PRIN(:IPA1. INV F_tiTII:ATOR oR INST'ITIrTI(/N SIIIRII-Y 1. KAl1F1 MAN. M D, Arur- .wrr trr.r/rrYM rf YrrAulaqy, Do.w- sute Medical Ccnler, Sralt l)wrvuuwy of Ne. Yort, Broollyn )FROMF KtFINFRMAN, M D, Hra/, l/rrbr.ua of LirA.rJ..ef Rnrrrh .n/ ( Hmu! r.rAd..cr. Se I rd,e's Hoyi(at. (Icrcland, rrr./r.wr of rmAarl.rfy. (ut Weslern Reserve Um.cruty School of MedK/ne- ( kveland rAUL S LARSON, hrt), Haejr Prc./rs- r..r of rAarn.r.ulogr, Medical Colkp of Vrrglnia. R.cMn.rnd 1(XFPIt M LAUWFRYNS, M D, Pn D. Prufruur ()r/.werrur rw ALrto.ro/ic An.r.i.nl: ( h..r.w.w, t s/rriw.rw/eL Litbr.rwy of CrLordw...wr~ and (:rwrrJ LrAolo*y, UwrverWy of Leu- vrn, I raeq Bcllwrw. RIC'/1ARD A. l ERNFR, M D, Aa.or(rr, Scripps C1i.ic •od Research Founda- tiow, 1 a Jolls, Cel. CF('ILE 1 El)CIITFNBFRGFR, Pw D, Head. Drrarrn.rnr of CyrofArn.uny. S+iss Inur(wc fw Feperi.nrnral (-e. ccr RcsearclL I .ucannc, S.NUrland !AY A. I EVY. M D. Arruraw) C/rniral P.o/ruw of J1Irlrrinr. Uwivenilr of Cdifornia, Sew Francisco. (Iwilrered under Tand\y Crocler, M D.) CLAYTON O. L(X)S1 1, M D. M D., Ha.rints Pro/rawr of Mr/rcinr and LrAo1..[y, l)niver+ily of Southern C.li- forw Sc" o/ Medicine. 1 w Angeks. INIS MANDI, hrl), Ard.renr holrr- sor of Lothrner.nr, (-olkle of P6yei- ciarn and Surgeons, ('olumbu llnivcr- uly, Nerr York (-ny. MASON RFSFARCII INSTITUTE. Worcesler, Mass ('1/AR1 I ti Mr AR 1111IR, PN 1). I/ntrcr- stty IlcalrA Sc.~acr. 1larvard l)mver- sity, ('ambrrJ{e, Maa rRO)E(T TITI.E Carcinugcn induced estcretiuns in the cell cyck of the Type 2 alveolar epnbrhal «II Fsperrwcn(al empt,yscma the ef/ecl of prolonged duel and mlrogcn dwerJc ca- 'osure on the pAyunluTrc and mrwplw- rnelrie paremcteuof the bem.tcr lung S.beily for publication of Supplement No. 11(o IKe scww{r epR ` f obac a u" AM(r.Nis` and cleudyiq the hlenlure os (he ts.oleykal eRects of I..Aaccu- end peprMiow of wanu.cript f« SupR(c- wt.1 Ne III so It rwum>ire~, 'los la.oco' Tv lyta}Ratks of (Ir lung; tbcir role In Ruid transpor( and clearance of air- boc.e prticulak wauer Studin on RersiMCM vrel infection Coenpruive cylocbemical. cytoloTkal and Msrolqrc.l uudies of early and eMowie effecls of elgaretle Ynule on the restoirarory Iract of Sncll s and C7) Blectt ..ice Tle role of chemicals nwd viruses in nco- Platlie transformation of mc.VSe and rnrer rcy.ralwy epilbebal cc11s The eflecls of inhalation of wbo/e smoke, synthetic srrwll. ambient air .1une and in eombinaliull on the resp.rao/y tract of mice Flsslolylie breakdown in the etiulu/y of pulmunary emphysema Mechanical and biological evaluatron of mechanical devices lur the munitored esp.»ure of eapenmenlal smmais to tobacco u.wkc inhalation Sharpening of the d.Rerrncrs lxtwren p..p.J.rrum Mnut.nj and rwrnsmnling by recenl QunlUng ot m.ny .nsnlrrs and the implra.bnn (.a dynarurc ccplansh..a of vnu\rng labavurr 92 I I PRINI:IrAL tNVE9T1(:ATOA OR INSTITUTI/IN IIFRBERT MCKFNNIS, Ltt, ht.D., /ro. (rrr.r of rAarmoc..fory. Medical Col- kile of Vuginia, Richrno.d. IIANS MFIFR, D.V M., Sr./ StkneW, The )eclww l eboralory, B.r Narbor, Me. MI('ROBt()L(X31CAL ASSOCIATE!S, INC., BetAcsda, Md. CNARLFS MITTMAN, M D., Dlrrrror, Ihprrrmrnr of Rrrpsr.rorR Dlbr.srs, ('wy a! 11ope Nali.wl Medie.l Ce.(er, 1)uarte, RI('l1ARD 1. NAEYP. M D., Profrasar .nI ('A.rm.w. De/+rrwwwr o/ rorAol- ojy, Pcnwsylvaw Sr.(c UnivereMy Col- kle of Mcdreiwe, Ncrs4cy, AI BERT H. NIDEN. M D, Le/ruor o/ Nrd.nwr: Dlrecrw. PnJwwwr Disrase Srcrron. De'eruneM of MeAicr.e. Ta.• pk Umve.siey School of Mediciwe, P~d.dcl.iu. IOHN W. PARKER. M.D. AuorWe rro/ruor of rarAofogy. Useiversi(r of Soutbern C.liforr,fa Sefool ed INadi- cine, I os Arycks. PROCESS ANI) INSTRUMENTS COR- PURATION, Rrootlyq N. Y. ROBERT C. ROSAN. M D. Aa)ocMu rrolrssor of rirAulo1)r awI lrli.rrics, St. I ouia U.Ivcrwy Medical School. SI. Louis. RONALD P. RUBIN, Pw 0.. Anociale Pro/rrwr of PA.rmocolo`y, lbrn,(a1/ Medical Cenrcr, S(ate ll.ivcrWy of New Yor1, Broollyn. WAYNE L. RYAN. rN D, Professor of entiArmnr.r. Unrveruly of Ncbasle ('olkge of Medicine. Omaha MAIIRI('E S SF(iAl., MD, Cbn.ral rrufrrr.w of Sfrdrrrnr, Tufu Unmvrru/y Sclw.ul of Medicine. Dirrrrw. L)rparr- mrnr of IwA.lau..n Therapy. Bo.low ('wy I lusplal. lliuuon. l l)( 10 S(iVI'R1, M 1)_ Uwr( rur, lnrrl rurr of AfwArJ Aner.uny awI LlusoloIry. I)h.trr..n of ('an.rr RrrrarrA, l/nirer- tdy of Pcrulrs, Pcru/ia, Ilaly. PR(I)E(T TIT1l Biologrcd activity of tobacco a.o\e cos pncrws aed ell/ed wbrawoe. Onco~cnesis is the rabbit: Re.ak sr.uR Itbdwy, verlicat Ir.nrntsebs of vrus and ewvirowrnenral inRuenoes In vitro and in r/ro s(udies d(be Idu ence of taOeewpY maler/ala on .r1/.e tionolla(enl C(ype RNA viruen 1laedit.ry wscepibilwy to bro.c)ilu employaenu Srwo4ing awd the pulnwwary biood vee scls: .,u.rire(ns, r.orpholorfc rudy Elects of ciffuHte sesoLe,Arup ed .o low fwwts ow the Ierrwind .irva~e rr\ ~p~eci.l rekre.oe to the cb'aice MecRa.l.m" of wpynrlow of allelar lw n.uwi(y by carci.orcrrc RyArocarlews Cowrruclion of an earcrYwedal lsebe for rsowiloteel earoeure of aoeY ea 'eriwen(.1 sww.ala to sobaep s.o&e asW.liow 11(ro.cRopdnwnuy dysRLaa1. Ribosorwal puame(ers of lobrar Mes eNialiow Tle action of nkdini w(M rdrenat gland The 1', 3' cyclk monuplooepiasa sysre.. In earcrno.eneus See ( 6odcu\, S AUcn.Rls to idcnufy the v/ral yr.r(a) rrsprrnubk for .hceP lung .4awmaro us and to transfer 1\u .e.>!(uue dra cesc to rodcnts 9)

PRIN(:IPAI. INVt=iTICATOR OR IN1'1'IfItr111N SHOII S11111A)A, MI), PrtU, Pto/rr- r.r uf Phw.nrw.dotr• University of 11a- .arr Scbawrl of Mtdrerne• llunolulu. FRIK SKINN0I• M 1) • Chrr/, DrP.rr. •.nrnr of Nrr.dott. Bnoebrrrg Ilotp- ,1a1• Copenhagen• Iknmaul. THF(/IX)RF A. SIOiKIN, PMD. A.- unr.ar rro/rrwr o/ Phrn.adorf. Uule Umvcr.iry MtdKal ('e.rer, Qr- \am, N. C, I/NA SM1i11, PNU, Srn/ut StknNU, Pap.aicolaou ('anctr Reseuc\ l.w/• Iwe; fnu.rcrw Of MfdN1M• l/M.et.ry of Murwr School of Medreiwt Coeal (iabies, FIa. t O111S A. SM OFF, M D• rroJruot of Mrdwrnr. Temple University He.lt\ Scrences Center, Mdadclpfw,. SHEI DON C. SOMMFRS, M D_ Cbn/- c.l Pro/rewr o/ t•uAolo~f• Colkge of Pftysiciaru wd Swtco.k CdutnDl. llmversNy, New Yo.k Cwy. PROjE(T TITLE Srudy of aensirivqy of v.Kuler tnwe Io nKdlnt The ntule effccl of vnoking upun rcgional « rebral bloud Bow In .mulers and nonwnottcrs; tAc effec/ of some phyrio kr{iul uinwli upon cerehr.l blood fbw is swoters and nonsmckers MtlwNion of the adrenal medulla: cate• chdasitae Yoas in wurmal and hyPer- kw.iv~ rMs The rok of eadorbetial a.d errsclr.t cclle M woas .earilauty functions of rAc lunte PwiAca/iow and physiologic sissnirlcance of kcilhiw choksrerd acyl t.ansfera.e (LCAT) Hoe( (ac(ora 1n cMonic pulmonary intlam- ma/ioq errNysetwa and /ung cancer S(udics of Iwwwa. Ir.ill and ovarian car- ci.oteu DAVID M. SPAIN. M D, Dr.rrro., Dt- Prlnronary parenchymal alteratioas iw .w Cerrnrnr of r.rllola.gy76e brooddale luyw.l Ce.rer, Rrooitya, N. Y. rwro~+ted aotmal" poqrAatic.a as re- Iuc~ lo age, .ea and e.virotunental faclor7 '; ~ .,.., )AMES TRAVIS, P„ D., Auu..nr Pro- letwr of /rotAtnrurry, U.rvtrWy of orti., orti., AtRca. (h UNIVERSITY OF SAN FRANCISCO. Rioc4rniury of cltoac obsrructive lunt di.cast Inductioa of aQuawwue cell carcinxna of San Francrsco. the lung is mice ...3 El I IOT S. VFSEI 1, b/ D. 1roJruor Rad/oirwwwwoasa.y for nicorinc .r~... .nd CA.orn.w, DrP.rrnernl o/ Phrn..-~ edotl. Pennsyl.ania Sutt UniverWy College of Med/ciwe, Hcrs,ey. 0 PF-TFR K. VO(3T, Pn[), rroJruof of A.iaa Iun.ot viruses ia mammalian hosu I Murol.olntr. University of W.ahiwe- }~'d CN lon Sc" of McdKlnc, StNtk. YASI/Slll WATANABP• PrrD, Tle Srud.es on o.cotenic viruses ln Wnru Insrdult of Anarorny and Biol- m P\rla.klpar.. 1.M r m A SIANIFY Wft IMAN•P.rl)• Atrn- Acute and cAronie tf/tclt of nK..arne on ^li m kD tJ A rurr ProfrlMw, Rtf(alch Insrnule of Ihe Brrrrll~ n('olle/e of Pbarmacy, Bruollyn, N. Y. spontaneously eypcrtemive .r.d nurmu- tcnsive mak catr PRIN/:IPA/. INVESTI(:ATOR /IR INSTITUTION I)l1ANE (7 WENTFL, Pnl), ProJrraor .nd Ch.rrn.en• lkpa rtnaM ol PAarau- colu`y and Tosicolo~y, The University of K.nsas 5csool o( Pharsnacy, Law- rence. THOMAS C. WFSTFAI h Pw D, Ar- ior.ere Pro/nsof of PArrw.rototy. Usti• verury of Vrrginu School of Medacine. Clarldlesvilk. rRO)ECT TITLE Nicotine .nd carbon monoaidc o..aecv- 1.r Irped dnpocil/on Influence of nicdine and relalei wp on rbc up.le. Mo.ate. relear .d turno.er of ca(ecsolamincs in arral and peripheral tissue MeclfaniN of KIMDn of n10o11Y ON per.phcral and oearal .curo.a 95 94

Completed Projects FolAtwins is a lis/ of the principal invcsli6ators or inslilutiuns o( Vn,jccts tbat havc b(cn cumplete(1 prior to the pcri(x1 covered in this tptrt. Scvcral rtl Ihc individuals named are deceased. The litlcs and afllhalions listed are (h/+w in eflecl at the lirnc the w(xk was completed. CI ARFN('F M A(7RFSS. M D, Asw rwrr ('hw1..) Pr../ru.w a/ Mrllrlwr, lJn.veruly d (-.Id.wma Medical Cew- rer, 101 Annka. ANl11ONY P. AMAR(KF, h( D., Iw- urwtcw, Drp.rln/rn) of (IAMtrrr,cl .r./ (:ynr(,J..ry. The Alt,any Medical Cot. kae of Un.o. llwr.rrwy, AItAa.y, N.Y. F. 1-. ANGFI AKOS. M D, Pw D, rrr /rrwr of PAywrloty. Buuow l)nr.er.iry ticAool of Med,cine- Bouow. D MURRAY AN(3FVINF, M D, Ur- rtrsily of Wiscew+sun School of Medi- c/ne. M.J,.on Si1 P11FN M AYRFS, M 1), Dwrcror, ( urJ.npuln.....ory t.rs.wnr.wy. SI. Viaeenl-r Ilu.p.ul. New Y.wl (lry. OK'AR I BAI ('NIIM, Pte D- Hwnlnlr Pru/rtuw of A(rJn+nr- llm.efury of Snwhcrn (-aWornu Sch.xJ of McJi clnc. I M Angeles FRFDFRIK B BAN(i. M t), P,n/n,w unJ ('lwlr..now, flrpa•Invnl of hrh„Audn~y, lhe /uhm IIup lln. l)nl.erulY S.1w.ul of Ilygwnc .nJ Puhl,c IIea11A, Balbmore BRODA A BARNI'S, M 1), P(tD., rro- /nuw fAffif.otu/ of PAytudofy. Colo- udo S(.(e l)niveruly, Foat Cdlins. FRFI)ERI('K W. BARNI:C, la., M D., Auocwrr t.o(rruw uJ Mrllrlwr, lhe lohns FluCiws Uniaruly St6ool of MedKlnt, allunore. T. C BARNFS, D SC . RrLr.r(A S(irnrur, Phdadelpeia Slac Flospi(al, Phda.kl- phu. R FRFDFRK-K BF('KEiR, PND, Ano- rlulr Prr.fr,wr of Atironly .n/ Dlrrr- rw, I.A.worory u/ Prnn.r.1 Sllrwrr, It•dc l)nwerury Mrdlul ('cnltr, IAu- hwm, N ('. RAI PII S lll ('KIR. Pu 1), Pn.frr,.w a/ (-Arn.nrr., l/mrrluly uf Ilouuun, 1 L.uN..n IONN A. BFVAN, M D, Pro/rtuw of NArw.rulufy. Univeruly of ('alrl.ania School of MeJKine, Lue AnArks CE3ARE IIIANCIFIORI, M 1), Dl.inuln of C.rrr RrurrA, llm.rrtNy of PmrwBia, PeruFia, Ilaly. IIYI.AN A. N1('KFRMAN, M 1) , A.u,t- .wr rro/raw of Mrdarlwr, and AI V AN 1. BARACII, M O, Co.urlunr In MrJ klwr, Cotrwtlda lJnivtruly C.J1elc of Pliyekiaws and Surgeuns; (:o(dwa/et Meww.ial 11o+pi(al, New Yorl Cily. FRFDO. SOCK, h( D., Atuwiarr Conrrr RrarrcA Scirntiu, f)iuJarfir.l Srafiow, Roswell Park Memorial Insulule, SpinRr,lk, N. Y. EIFRMAN V. BOFNIO, PuD, HrnJ, (-Arwwrry .nJ IIIocArauury 1)rpurt- r..rnt, Spindklop Research C'emcr, I ee- mpon. Ky 1AMFS F BONNI R. PN D. Pr..lrll.u ../ M...l..It. ( .h/n.nu Inti/wle uf Ie.hn.d..ar. Pe,.Jrna WAI11R M H(tc)KIR, Put). Pru/n ..•, unJ IIraJ. Itr{`~ rf.nrnr u/ I'A..rnu- l.~l.~f/. 1luwarJ llmvtr.uly, Wathmg (on, D. C. TOM (3. BOWE?RY, h( D, Prerl.IJr Rrn- !/re LAor.rory, CAr.nlury Orport- nvwt, North Carolina Sule ('ulleae, RakiN. GEOFFREY 1.. BRINKMAN, M D, As- sorsorr Pro/rluor of Mrti.lnr, Wayne S(a(e Univerury School of MeJ,cine, Iklroi(. RAYMOND R BROWN. Pul). I'r../rr- ior of Cbw,rol On/o6+ry, Umvtr.dy of Wrseonsin Medicel School. Madlvun 10SFF BROlFK, P,r D. Prn/rn. r.nI ('A.,rw,.n, Drpnrrn,rnr n/ P,nAuR.ry. l thyh llnlver.uy, Belhlchem, P. SIIF BIl('KINl7f1AM, M It, .c.u.ronl Pro/rrwr of P.Juhkr, ('.dulnbu Un/ ver.Ny ColkAe of Physicians n 1 Sur- scuna, New Yutk l'ny. 96 I i HI:N/AMIN BIIRROWS, M 1)- A.,.n wrr Pr../ruw u/ MrJlunr, l)mvcru(y of ( hic.tu, ( h.caso. F M R1) 1T, M D., CA/r/ P.rhulnIrnr, I os Angeles Counry (ieneral /losp.ul, 1 os Angeles. RI('IIARD U BYFRRl1M, Pw O, Pr,.- /rraw of CArn,urry, Michipn S(Ne l/n,rcrtily, Fasu Lanung. SISTFR M. EMILY CAH/I1., PwD., C'Awnron, ('Arrniur y f )rprtrnrnt, ReRn College. Weaorti Mau. BREK'E F. CAMERON. M D- Pw D., tl..wwd tfurAr. fwu.turn. Uwiverwr uf Mlaml School of MedK,nc, Mrarlu. WII t IAM II, CARNIiS, M D., E/wi.cr- uly of 11(.k ('dkAe of Medkiwe. Sall I ahe ('/(y. MARCIIS N. CARRO•1., 1.., P((t), CAir/, Drr/liuw of PA.rw.orology, TLe Brootdde Ilospi(al C'ewer, Rruoklyn, N. Y. W1111AM AI.VIN CARTFR, M D. A,sluant t'rotn.ur of Mrd.rrwr .wl Ah....Aw./.Yt. lhc lohnf //„Cint Uni- versify Scka,l of Medicine, alliwwre. LFOP(N D K. CFRE('FDO, Pn D., rrr- /rtwr of elocArn.urry on/ Nrmew.w, llniversuty of Puerto Rico School ut McdKine, San luan. W/I t lAM (3 CLARK, Pu D, Dirrrrw, f iyrhupA..m.rulu~y Rr.r.rrA tuAuro- t.,ry, Vclcrans Adm,nulralwn 1luspilal, Scppdveda, C'al. HANS T. CLARKE, D Sc.. Pro/r.wr of ta.urhrnrntry, ColurnMa Universuly ('ol- kAe ot PAysiciuu and SurReons, New Yur\ Cuy. lAY D. COFFMAN, M D, Srrriow Hrri.l, PmltArrof V.scrf.r Drr.rrnwwt, lbn- vctuly Ilu.p.rd, 9os(on DANIFI ('OFII:N, D V M, M P FI, At- rurmn/ rru/rt,w o/ Vrrrrlnrry EPIJrrn- u.l..gy and PuALr flr.IrA, llniverslly uf Pennsyl.an,a ScMKd of Vela,nery McJKrne, Ph11.Jclphu I )lll Il1S 11 (-l)MROE. la, MD, Darr. nw, C.eJ,trY14Yl.r Rrvar. h tnuuulr, l/mvtrady u( ('.liru.ma Medical ('en tcr, San I rancitcu. 1)FAN M(YINNOKS, M 1), Ar/•u.eu 111rnrw, f)r/~.rrrnrwr u/ f eA...ul.wr AlrJlnnt, Sr. Muy's Ilusptal, M.J/wn, Wu. 111111 1 P(( t/ )1'1 R, M 1). ('Lwn af Pr../r.. uw ../ %nrrrry uwJ D.rnrw, ~wlluf t.uA.wunwr r/ Crrfufw PAyu..l..et. Alher.l 1,n.reln College of Mtd.clne, ('Alrt, ~nrruaf 1rr.rur, Vtteun. Ad m,murau.w+ 1luspp/a1, Browe, N.Y. ROBERT 1.. CRAIN. PNE)., Auln.wr t•r../rr,w of S.rrrolofl. Univtru(y o/ ( hKago. Clwca90. CEC11 F.. CR(XS, Rru.r(A Dryoru.rwr. S(. Joseph Nospilal, Bcubani, Cal At BFRT DAMON. Pf 1)., M.D., [a- rrrrr ..n AnrAr..p.duly; Rr,rrrA Aun- riar tw MrJ,rnt Anrkropology, Peabdy M.seww, Ilarvard l)ni.erswy, Crw beidge, Mas. R. F. DAWSON, Ps( 1), Pro/r...w of /w «l, Coluwbi. UniversMy, New Yorl cwy. ANDREW S. DIBNFR, PN D, C.rrMJrr, rayrAu-Rrsr.rrA, 1 he Apc CetMet of New FnAland, Inc, Bos(o.. RAl Pfl 1. DORFMAN, Pw D, D,rrrro. u/ t.ufrwurw.rr, Wurceutr Fbund.liun fur E:aperunenul B,oloAy, SArtwrbwy, Mass. 1QMFS I DYAR, PuD, Ani,uwr Pr.. /rlur ../ Rwlofy, Bellarrnine Colkae, I ouuvdk, Ky. RICHARI) 11. FARI F, M 1). CA/r/, Prl wurw.ry fun. now I wf,.raory: Aulu.wr rro/ru.w ../ Afrb.lnr, llniversNy of Ct•Kato, ('hKa/o. tO11N W. F('KSl1 IN, M 1), Asdu.wl rru/ru.w u/ Inlnnsf Afrdulwr, S1tlr Uruversily of Iowa ('olkge of MedKiar. lura ( rtv. IIYMAN 1 N(iF1 BFR(i, M D, A/rrwJ rnr PAyn.,on, (-eJars of I eMwow 11w pilal, I us Angeles IIFNRY I FCBFR, Pu l), Rrlr...A hn nu.n..f..rru, Maw,n Researc\ Inrnule, W.uauer, hlast. IIANS I FAI K. Pe( D, AIlunrt A,NMI are Pr.•Iru.w. Orp+wanrwr u/ P.rA.rl.qr. llnweruAy of Suuthe,n /'ali/urn+. School uf A1eJ,c,ne. 10s Angeke. 1)ANA 1/ ARN1W()R 1//, M 1). 1(rwlr x (Ilr.rr Pru/n...r .rt t/tllrwr.wJ lh rr.ror u/ I/nnrrwy ttrollA Sn.wn, IlarvaeJ llnwcruly, ('an.bidac. Ma.a 97

F'RANK C. FFRGUSON, la, M D, Cheow..n, Drp.rr-rnr of rharw...o1- o`y, Thc Albany Medical (-ullegc of llmon l/nrvere./y, Albany. N. Y. TF1FO1)ORF N FINI FY, M D, D.rrc• tor of rr/monry Rr.r.r.A I.ll'o.ero.y, Mount lron Ilo+prel, San Francieco. (Formerly al Tht l)mvcus.ry of Ne. Mearco School of Mcd.cine, Albur,uee• Vue) WI/ I IAM I FISIIBFIN, M D, CAI./ o/ Fy.Irnewlotf• CH.caAo Board of Ilcalrb. ( Srcago RUSSFI L S FISIIFR, M D, Univcc.ilr of Maryland Scbol of Medreine. Ralrr• nwre. ~. L FREFI)4.ANDFR, M D, Dlrrcrr of C.wcrv Rrw.rrA, Mouee 7800 Ho.- Pira1 and Medical Ccrwer, San Fraa t /sco. FREDERIC A FRENCH, A B, Drrera of (-owrrr CArw.dArrqy RrurrA, Mounr 7.0. Hospiw.l and Medreal Cen- kr, Sa. Fra.cieco. JACK FREUND, IJ t). Auw.wr rrolrr- .or of rArn.rdoty. Med.cal College of Virginia. Rrchmond. (IL.BERT H FRIEI)FI t_ M D, CA.rI o/ rorAoJo(~, Sr Vincent 11osynal, Worcesler, Mau ARTHUR Fl1RST PH I), Director. lerrl- rrrr o/ CAriwrol I.olofl, llaivqaily of Saa Francuco, San Franci.co. MURRAY B GARDNFR, M D., Auo- crrr tro/nwr of r.rAoJo1y. Uaver.ul of Sowbera C.Irfornia Scfad of Med.r- eine, l oe Angeks. GEORGE O. GEY, M D_ D/rrnor, l•rnnry-Howr/l C.ncrr RrurcA Ll• ororo.y; Auociore rro/ruor of Srr- 1cry. Tbe lolles Iloplinf llniversely hoot of Medicine. Banirwore (de- uascd /. THOMAS M GOCKF., M D, AuorWr troJruor of rrtrrwHrr A(tJ.nwr owI (:on.e.rAuy HrolrA, Ne. lersey Srale Colkye of Medicrne and Iknriary, Jersey CNy. t)AVII) M (;OI DFNIFRU, St 1). M 1), Ar.u..err rrolrr.or ol r.rAol. ofr, Ttmpk Itmvr.ul~ Ilrelifa Sao en. r. l rnlrr, P1,IoJrlpa.e PAlll. GOI DIIABER. D U S. A n.a lmr rro/ruor of trnodonroloty, flarvuJ School of Denlal Medreinc, Bo+run IRA GORE, M 1), rro/nror of rorhol- otl. 9ouon Univenn~ School of Medi- crne; CA/rl of /.aAw.rory .trrrur, Veleran. Administration 1lurpirLl, Wcu Roaswy, Mau. GERTRUDE Y. GOTTSCIIALL. PND, Aui,r.M rrolnwr of DiorArwei,rry , Calw.lia Unrvcrsi(y Colk~e o( Pfysi• ~ ~ SWQcoV New Yorl Cily. A. CLARK ORIFFIN, Prr D, Head of lbr4r.w/ury Drr.rrw.rnr. M. 1). An- dnto. Hoyiral awd Turrwr Inqnurt, lleiwt.Yy of Teaaa Medical Cerue., Horrow. ARTHUR L. OROS3, M S.. Senior Iio- eAe.d.r. Southwest Reseauch Inwrlwt, S.. Aaoaq Tea. MORTON 1. OROSSMAN, Pit D, M D, Aa.orYrr Chnicol rrofeur of Mrdi- ci.r. Uaiverairy of Califorwia Medical Ce.wr, Loe ArrRcka. CARL C. ORUH7IT, hr.D, M D., Arso- rWr iw rAy,iology .w/ rlwn..colory. Ur.erwr of Pe.naylvania Graduate School o/ Nedrcu+e, Philadelphia. FRANK P. OUTHRII_' Pw D, rrolrswr, a.d ERNEST HO[XiSON, Ptr 1), Ar- wr.nr RrurrA rroleru+r. DrP.rrnnrnr of E.uonsolon, North Carulma Sure Co1kK Rakigs. II. .. HAAG. M D.. rroleswr of rAr. ...rology, Medical Colkge of Virginia, R ichrwowd. F. 1. HADDY. M D., hr.D, lroJruw and CA.Mw..w. Drtorroscwr of rhy,lol- otly. Ud.ersiry of Oftlaloma Medical Cearer, Ol1a`oma City. JOSEPH H. HAFKENSCHIEL, M D, Alydir.l Drr.rrrnrnr, Sandoz Pharma- ocwicalt San Francisco. RICHARD 1. HAVEL, M D, A,ruranr rro/ruor of Mrlirrwr, Universily uf (.'ddornia Medical School, S.n F,.n. coco. IIFRRFRT R IIAWIIIORNN, MI). CA.urnuw, Dr~# r/n.rnr of S.rrf rrf, llnivenu' o( PcnmYlvania (iraduale Scfswl o( MrdKrne. PA.IaJrlpbu 91 ('1 ARK W IIFATII, M D. rrolrsroe ul Mrd.. rnr nwJ /)orr f.r ul IIrnItA Arrv- ..rr, lulls Unrvcrnuy, MtJIwJ, Mns. NORMAN W IIFIMSTRA. PrrD, Ar- ,.. raer rr../rr.w of r.rrA.don; Drrr- rw, Drd.rr RrhtlPllr (..Aw.r.rr, Uni• vcrsily of South Da\aa, Vcrmctlrow. PAUI INE IIFIZFR, PN D. RrurcA A,- wrurr in ('ywloRy .n/ CyrnrArwrinry, San Francisco Inyrnule of Medscal Sci- cacc; San Francrsco. LAWRFNCF L. HESTER, la., M D. rro- Iruw .nl CArirn,on, Drr.rrmrnr of O6.rrrrrr, and Gywrcolofy, MeJrcal Colkgc of So.w\ Carolina. Charkrrow. EBBF. (Y)RT IS INWF, Pw D, M D, rro- Irrs••r •nd Cls.rws.n, Dwls/on of r,y- rAr.rrw RrrrrrA, Medrcal Colkee of VM//n1a, RKIMnond. RUSSFLI. 1.. HOLMAN. M D, l ouisian. Slare Universiey School of Medici.e, New Orkans. OLE A. H(x.TERMANN, M.D., Rr- rracA SrlewNU, (,otrrad L.br.ro.y. Univcrsiq of Nare Dawe, Nare Dame, tad. FREDDY HOMRURGER, M D.. rrrsl- drnr ond Dirrcro., Rio Reseuc\ Insri- ruwe, Inc.. Cambridge. Mau. ROBFRT W Hl)LL, Psr D., rrolr..r of liologicd Scirnrr,, Florida Srale Uni- vcrsily, Ta1laAauee. GFORGE IACOBSON, M D., Professor .nd /lrod, UrP.rrmrwr ol R.dwlofy. Unrversiry of Southern California Scfaawl of Medicine, Los Angeke. IFRRY HART IACOBSON, M D., Dirrc- rw, Drvinon of EfecuopAy,iolor), New Ywk Eye and Ear IaAreuey, New York Cily. • IUI.IUS 11 JACOBSON 11, M.D., A„o- tvore rrofrrxr of Sw`rrr owd Drrcrar of Surlu.l Rr,rrcA, llarversNy of Ver- morw ('olkge of Medici,e, Burlington. Ml1RRAY E JARVIK. PMD,~As,oci.rr rrolrraor of rArmrolotf. Alberl Eia• uern College of Medicine, arone, N. Y. (15WALD R. IONFS, M D_ Sr. Luhe'e Ilosp.lal, New Yo.t ('iwy. ANl)REW A. KANDUTSCII, PteD, Sros Sr/rnrur, Tle lackeo. Laboralory, Rar Harbw, Me. ARNOI D R KAPI AN. PN D, Darrcror. I.o6wnrory ol Medical Grwrrir,, Ckvee land Psychuuic Insriluce and HoWel, CkvelanJ IIRATCII KASPARIAN, M D, Aulare.r Drertor. Crdror.,c.Jr Inururror rn A(r/arnr IlaH.esu.e Medical Co1kRc and Iia.Pwal. P}ylr delplora. F.LIHU KATZ. Pit D., Auocl.rr rro(ruor of Sociology. Uavcrei(y of CVcap, Cloicalo. ANCFL KEYS. hr D., Dlrrrrr, [..bro• rory of IAy,iofol.c.l Hytb.r. Ur.er- eiry of Minnesota School of Piablic Ikalrh, Mrn.caPulie. /OSFPII P. KIRSNFR, M D. rrolr.ra.f J11rlrr.w.. Univerury of Clsicage School of Medicine. ('l)icyo. PETER H. KNAPP. M D_ RrrrrrA ho- Irr.or of 1`syrhwry. Soro. llrvutiy School of Medicine. Rouow. KENNETII P. KNl1DTSON, MD., ll.l- .eruly of WasAinpoa Mediul Scfeol, Seaulk. ALVIN 1. KOSAK. Prr D, Ar.orirr rr.r /ra,or of CArwrirrry, Nc. York Uai.er• aMy, Nc. Yor\ Chy. ROSERT A KI111N, M D., Aa.ocWrtro- /ruor, Ihvuion of Nrrro,rfrry. New Jersey S(ale College of Mediu.e, lauy City. MARVIN Kl1SCI1NER, M D_ Ne. Yafr Univeraily Medical Ceaur, Ne. Yort City. CHARIFS W. I.BEIIE, Pr,D. Awu- oar Professor of Ewrrownerwr.l H,• Rirn.. Deparurmenr of Pre.eai.e Mcb cine, leffer.un Medical Colkp, Pful.- delpiia. AARON /. LADMAN, Pw D., reo/rrwr on/ CA.rm.n. I)rrarrn..nr o/ Awo• nry, Tlu lleivereiry of New Meaiao Scbea of Medain., Albspuerr.u. THOMAS C. LAIPPLY, M D. tro/rrw of r.rAo1oly. School. Uaverrf Medical Scatool, Chicago ROOFR K. t ARSON. M l), ('A/rl ol M.d.ru.r, Freeno ('ouary No7r.l Fre.wo, Cal. OUSTAVF. A( A11REN11, M D. CAir1 of Mrdk/nr, Saint ViwcM I al,lo.PM Woroeuer. M.u. 99

AVFRILL. A. I.IFltOW, M D, CAoirn..n, Drparnmrnr of r.rAutotl. Yak Uni- •cr.uly School of Medicine. N(w Ilaven, Conn. FSTF.N O 1 1NDSF.T H, M D, PM D_ Sr' lux{~'s Ilu.pus Rexarcb 1 abotuoey, Sr. Paul- Mi... ROSFRT II. I INNFI l. hr D. Ar>al.rr Professor o/ CArwrwry. Universicy of Verrnonl, eorlinro.. HEReFRT l.. I OMRARD- M D., M.P.H_ A/ifurr- ('anocr Research IasrNu(c, New Eqland Dcaconeaa Iloaoat, 1a, ruw. 1. P. I ONQ Pw L) , Professor of P4r- w..roloRr, Srue I/ni.eraNy of Iowa ('olkge uf Mediclwe, low. Cwy. MNAI D R l n1/R1A, M D, Areoti.rr Professor of A(rLrrwt, ('orneR t).i.v- e.ry Medical Colkp, New York Ciry. KENNETH MERRII L t YNCH, M D_ Sc 1), l l. D_ C4wrrffor swf rro/re- s.r I w.rrrrr, oof PrAo%Yy. Medical Col- kle o( Sowb (-ardr.a. (lwkron (Is •swciatio..rh Forde A Mclve., M D/ DAVID E MANN, P.M D. Auorlerr rro- /rrwt of lArw..r.rlr.ei,, Terr.pk t1ni.erurf Sclriol of Pfarrnacr, hd.del ria /OIINH.MANt1O1D./s.DMD,Pro- /rswr onI Drrerror o/ PsAulo{y ow/ ()ral Daelnosi., New Jersey ('olkp of Mediciwe and Denlistry, Jersey Chy. JO/IN P. MANOS. M D, Inurrcror l. Vroloty and Aorrrrwlory, Medical Cdlcge of SowR ('ardina, Charks(o.. CHRISTOPHER U. MARTTN, M D. Ae- sruawe Professor of A(r/.riwr .n/ Drtc- ror, D/r/sioo of !n/rrr/ors Disrasrs, New Jersey Suk Colkp o! Medkine, lerser City. L)ONAI D 1. MASSARO. M D., Auociowr rrofrr.or of Alrlinwr, (ko.~e Wa.K- inaron Univnsily School 01 Mediciwe, WeaAisylow. D. C. CHARI.FS R MCCANT4, hr D., Asso- rusrr Professor of Sode- North Carolina Srane ('o/kp School of Agriculture. Redey /IENRY (-. M(()1L1- la, MD- ArNwF Nre/, DrP.rrwv.I of IarAoJo*f. lorrr- eiana Srart O.r.uwf SaIsrwl of Mcdr cine, New l)rkar HENRY D. McINTOSH, M D, rro/ruor of Mrdirinr and Drrrrot- ('arJroru- crl.r I..bor.ro.f, Du1c ()niversily Medical Ccrrer, Durhas, N C. FDWARD McKEF M D, Professor .nI Acriwg CA.irnrow, Dribarrmtnr of re- da1ory, Medical College of Sourks Car. duv, Charleuon. KELLY T. McKEE, M D. A»ori.,r rro- /raaor of A(rdarnr, Medical ('o11ege of So.(R Cudina, Cfuskslow. VICTOR A. McKUSICK, MD, !Yo/rn- sor o/ A(rduiwr. Tle loane Hopl rnZ t)nivereily School of Medeone, balti rwor.. R(I63 L bk1 PAN, M D_ Asso+L.rt Pro. ruer o{ Nrd.rlwr, L~wory I/n.rerw) bool .I Me6cire, AUwa. WILLAM P. wcNARY, la., Pw 1). As- .erderr Pro eaaor of A.arowry, RoNON U.iverWy School of Medki.., touon. NFAL L McNIVEN, PuD., The Wor- ctsaor For.darion for Eapcr.ncnl.l Bi- ology. Shre..bory, M.r. lUL IA MEYER, t1r D_ Aswrl.rr I.olr,- aor of Or.l ParAoloty, Unrvcrauy of Illinots Cdkge of Dcrisrrf, CnicaRo. RFRNARD 1. Mll I ER. M D. Aa.ur.wr rrofruot, The Daniel IarjA lwrnrurr of An.rowry, /clferso. Medical College. Pleladclpliu. JAMES O. MIL L.ER, M D, PN t)., rro- Jruor of hyrALrr] and Ir)rAolotf: Dlrrcror Alrnrol Health RritrcA Iw- at(rrrr, tlavereiwy of Michigaw, Ann A rbw. HUGH tr1ONT'OOMERY, M D., Assoc/- .rr Professor of Ih/irlnr, l)niversiwy of Ptrruylva.ia School of Medicine, Philadelphia. P. O'1. MONTOOMERY, la., M D, lro- (rwfr of r.rAolo(1. Ilni.ersily of tcau Sou(\weda Medicel ScKool, D.RaL OEOROP E MOORE, PNI), MD, DI- rrtrer, Roewcll Parl Memorul Imri- lwe, R.Jlab, N. Y. KENNETH M M(KF.R. M 1), Aeri,unr ho/rr.or of Mr/rrrwr, (:ruracro.n U.rvcrwr Med.cal ScSo.A, Washing. w.k D C. 100 i HURLEY I.EE MOTLEY, M D, t ro/n- sor of Mr/rrrsr .nd Drn rrw, Crdw- Rrrprroro.y (.bot.ro.r, Universiry of Sourbern California School of Medr- cine, Loe Angcks. EDMOND ANT IIONY Mt1RPHY, M D, SC U, Asioti.re Prulr..w of S.osrorn- nrs on/ Mrdurnr, The JoAm Ilootins tJnnersily School of Mcdicine, balri- rnwe (Formerly at Unrverwy of Coto- rado Medical Cerwer, Lknver.) Wll LIAM S MIIRRAY, Sc.D., Srnlor Sroe Srlrntbe, The /actso. Labwao.y, Su Harbor, Me. DONAI D U FA('P, Psr L), Professor of lAyrrolory 0wI DYresr, Iwurrwr for ('tllulr RrYrrA, 11.1.et.ily of Ne- lrska, I Lcoln. ALIIERT R. MLMER, Pw.D., Awv.wr ProJrssor, Drp, rwsrwl of PsycAologr. University of Tokdo. Toiedq O. ROSE MARIE PANORORN, RS., M S., Ass.ss.n1 Food Tecf..olo(iu and Lre- rrn, Drr..rnvN of Food SlirKe and TerAnoloRT. U.iver.wr of Cdi/orwia, Davis. MARY STEARNS PARSHt.EY, h.D_ Auluonr Professor of Anatomy Me OR- LrfrK! and GJnrco%gy, College ef Mryeiciawe and Swgcons, Cohrbia Universiwy, New York City. EDWARD W. PELIKAN, M.D., CA.ir- we.w, Drp.rrn+enr of lArn..rolotly and Etprrirnrnr.l TArro/rrrrs, 6oMo. Uai- teniey School of Medicine, Roslow. OTAKAR 1. POI.LAK, M.D. Pw D. Eurrrire Dirrcro., [)over Medical Re. search Cerwer, Inc., Dover, Del. MORRIS P(M I.ARD, M D, Dirrrrot, I oArnd 1.Iorrory. Uni.crsiry of Nare Dasae, Nare Dansc, Ind. C. M. POMFRAT. PMD, DLerror of 1l.01ofrrd RrarrrA, Pasadena Fewwda- lion for Medreal Rcecuck Pasadrna, Cal. 11 R. PRATT-7110MAS, M U, Dr.n anI Professor of hdlologr, Mcdaal Cul kge of South Caro1„u, ('Larkswo.. MARTIN S. PROTTEI., S S, U U S, Chief. Drprn.anr of Oral Pathology. Newart City Hoepul, Nc.ark, N. I. WALTER REDISCII. M D., Auociw Professor of Clinrrol Mrdw/nr, Ne. York Universiey School of Medicine, .wd NYU Research Scrvice, Ootdw.ur Meaaorial /luspwal, New York City. WIt 1.1AM RFOFI SON, M D, Professor and CA.irnuw, Drporrrrrnr of Mrdrral Uncology. Medkal Colkoe of Virginu, Richwood. HORART A. REIMANN, M D„ tro/rs- sor of AfrLrrnr, Il.Anerwanw Medical Co1kRe and IiotPiul, Pliladelpil.. ROLI.AND C. REYNOI L73, M 1). A. .Isranr Professor of P.rAolotl. L/averr w~ o( Teaas Sour\weucrn Medical SclooL D.11.s. VI(.'1OR RH:IIARUS, M l), l'Alr/ e/ Srdrtl, rreebpllnaw Medical (:enret, Saw Pra.cucu. WILLIS /1 ~ RIESEN, Pn O, Sr.Ior lis. rArnJu, Life Sruncrs DirWw, /IT Researcl Insliwae, Chic.go. (/wiaud wder A. Wcin.(ock, K D. ) R. H. RIODON, M D. Professor o/ Ps- rAodoRr. Uwiversi(y of Tesae wedkd Dr.wcK, Oalveaon. SYDNEY C. RITTENRERO NeD., rro- /esxr of Lcurlolofl, tjwirerwE of SowUcro Calrfo.rw, Los AnRdee. ENSON R. ROE, M.D., Aasoc/w /ro- /rawr of Sriftrr; CMrI, Crdi.c Sr- I l. University of Califo.nia School of dicine, San Frawcisco. K)SEMI H. ROGERS. M D., lidf Nre of /e.rs Itoyilal, O.dsdeR AL. JOHN R. ROWLANDS, hr D., Sref Srlrar/.r, Sowhwesl Research Insslluu, Satt Anlon.o, Tea. BENJAMIN A. RllflIN, Pd t), AWrr.wr lro/nror of Public NrahA, Lla)ta Uwiver.My Cdkipe of Medicine, Hou.- lon. HENRY 1. Rt1SSF.K, M D, F.A (' P, rrrsidrnr, The Ruastl Foundalwq Inc, Srarcn (sland, N. Y. W. C. RI1SSEl1, M 1), t/.ivcr.ry of Teau Medical ('crwer, 1louro.. PF:TER F SAI ISBIIRY, M D, hr D. Mr./, Jnren.rrt Trt.r.nrwr ('rwrtr, Saint /ueeyh Hoepicul, llurban\, Cd. 101

PAllt. SAI.TMAN, hrT), Anlrunr rro- /rtror, Drrerrmrnr of Awchrmiur~ .w/ Nrrrirwn, University of Soulkra Cdi- fornia School of Med.crwe, Loe Awgeks. Ul RICH 11 SCIIAFPPI, M D, Dwrcror of Masow Rc- ecatc\ Inuuuwe, Worceucr, Meu. IORGEN U. SCHI FGFt , M D, ht D_ rrolrs,or onJ Char....n, 3rtrww of Uro!o~ ~, Dvp.rr".r"r ol Swtrry. To- lanc l)wi.crsiwf Scho..l of Nedkiwe, Ncw Orka.s. ALVIN R. SCHMIDT, rwD, Dlrecser of Co..nr.drq, lu/u llwi.ersJtf, <t4ei focd. Mass. ISAAC SCIIOUR, DDS, IwD. DSc., Oron, C..IIr~e o/ Drwuur~. University of Illinois, (1ka1o. CARI. C SELTZFR, he D. Rrwch I rilor rn IhI,icol Anthroplup, H.r- v.rd llniversiry, CuwMidtfe, Mees-; D.- Rorrwvnr of Nwruaw. H.rvard School of HhWic Ikdt14 BoMOw. CILARI.FS Q. SHERWOOD. M D_ As- suronr Lofrsaor of R.Iaolog'. Uwiver- sity of RocAerer Sc" d Medici.c •wd Dcntiury, Rocheuer, N. Y. DAVID L. SIMON. M D. rn,rrrcro+. Dt- ja.rrwwm oJ Inurn.l 11rJ.crnr. Ciwcr- wali Oencral Hospral, C'scinwl. OEORGE W. SMFTTFRS, M.D.. As,ocl- orr b rorholop. Nort\wcstera U.iver- utr Medic.l School. ('Licago. OFNE M. SMfTTI, hc D. Au/uw lro- /ruor of rrycholotf. Ilarvard Medical Schod. M.ss.cluxlts Oe.er.l Hoyi- td. Roslon. LUCIL.E SMITH. Prt D. t ro/cuor of slo- chrwdurf, Dr,rtwouth Medical Sclool, Hanove.. N. H. ERNEST SONDHFIMER, rw D. Asse- ciar Iro/rasor of Ilochrmiatr'. Colkee of ForestrZ, Suu University o[ New York. Srr.cwe. T. M. S(/NNEBORN. M D. Dbtln- fwrAr/ Service Professor of Zoolotl, ndlana U.iK/M11. Rlaanin{(o.• SAM SOR(1F, MD. Flrrl, DrPorrnwnr of A(o~r.w..olrtrl.r Chrmurr', Tle 1.- wNU1. lot Cencer Re,earcS. rlil.dcl- pbia S(/1/TIIWFST RI %FAR('ll INSTI- 1111 f-, Can Anronw, I t e AI.EXANDER SPOCK. M D., Auurunr Professor of rrJ..unc,, t)ute University Medical Ctnler, DYrlfaln, N. C. FREDRICK 1. STARE. M D, t ro/r,sor of Nruuww- Harvard University Scbool of hAlic Ik.lt4 Bo+lon. C. HAROI D STFFFEQ M D., Director of LAIorororir,. Mtltqd.sl Hospit.l, MesyLis. IACi P. STRONG M D. Asu+" ierr Iro- /raw o/ IotAoiorf. Louisiana Slue ~rai.nnMT School of Medicine. New O.le.... MARIOH R. Sl1l.ZRERGP.R, M D. rro- /rawr .wI Ch.lrm.w- Drparmrnc of Dr.nWOfot, onI S'rh.lologr. New Y«k Lld.ereMy Illellww Medical Ccs Mr, New Yo.& CMy. RENATO TAOIURI. ru D., Associate rro/rssor of rrychdoRf. Grsduate School of Rwi.etr AdrniniYrNiow, Hrv.rd U.ivcr.(y, Boao.. CAROLINE BEDELL THOMAS. M D, rro/rssor Ew.rr/uu of Mr/iclnr. The lotw Hooiwe Urversity Sclrwl of Medici.e. M.Mlwwre. JEROME F. THOMAS. hr D. Erofrs,or of S.wiur) Entiwrrrlnt, University of California. Bcrtcky. JAMES e. P. TOMAN- M D.. lrofeswr on/ CA.irn..w of IA.rman>lotY. C hi- cap Mcdical School. InuiNu.e for Medkal Researcl4 Claicatio. JANET TRAVEL1, M.D., Auoriatr rro- /rssor of Cli.k.l rhrn..colojr,. Coc- .eR University Mediul Colkdr, New Yort CMy. LIE SHA TSAI. M.D., Rruorch A,wci- re. Drprrmrnr of Porhologr, Yak U.iverililr School o( Medicinr, New Haem Coww. ROMEO A. VIDONE. M D. Au..rr.rr rrofr„or of Pathology. Yale Uru.er- .itZ School of Medicine. New Havcn, Cow.. P.. 0. WARNFR, M D. Frnfru.w of r.- rholot) tirae University of lu~r. ('ot kgt ol Mcd.une, Iowa ( uy. S111P11)4 WARRI:N, MI). Dr.err.r ..l lAAa.r.roe.rt. l.ntrr Rr.r- h In.nrvrr. New En/1.nJ lk.conc., Flo+p.ul. Hu+ ton. 102 BARBARA K. WATSON. ht D. Asriur- owr ponrrwrlogi,r, M.ssacAusctU (:es- er.l Hospul; Rruuch A.ururr, Or- rorrmrm of fiocrrriology .n/ Dnmrnol- ogl. Huv.rd Medical School. Bos(ow. JOHN S. WALIGH, hM D.. Iro/ruor of Chrmtsrry, MassecIsu.ctH Inrilute of Tec6nology, Ca.rbrdgc. RICHARD l.. WEC.HSI.ER, M.D. Cbni- c.l thy,wlorrst, MotMeflore Hosptal I.Mitwe of Rcscuck PittsEurah. JOHN V. WEIt_ M D, Aubuwr rro/rs- soe of Mr/ulnr. University of Cob rado Medical Ccrer, lhover. Rt/SSH1.1. W. WEl l ER- M D, rrholo- #dst, Menwwlsl Ilo.pitJ of Claeuer Coualr, West CKesur, Pa. SIMON H. WENDER, M D., Rrsrorch rro/ra.or of flochrndsrr'. University of Oklabnu, Norwaw. FRFDFR{CK 1:. WIIISKIN, M D. C M, Drrcror, /)..ruon of Nrolrh .nI !rr- ,wr.luy t:ysnbFrrrm, lAe Adc Ccrcr of New England, Inc.. Buctow. ROGER 1. Wll.l IAMS. rN D., rro/r,sor of Chrnuw'; Dirrctor. Clq/ora Fa.rn- dotbw Iruchimicol lwsrqrrr, T1. U.i. verswy of lelas, Auai.. DANIEt. /1. WISEMAN. M.D., Auldo.r Irofr,vw of lrJi.trics. Uwisyailr of Souwlsern Catiforrw; Chllirrw i Dl.l- siow. l.os ANck. Cou.1y Oc.cr.1 /loapral, Lo. Awgeks. 1. EDWIN WOOD. M.D. In,rrrrro. b MrLciwr, Sowow Uwiversity School of Medici.e, Bouon. SUMNER WOOD. 1N., M Q, Au/sr.wr rro/r,u.r of rothologr. lle Irr•w. Ilor tiws University School of Med,crre, .ahin.ore. lOHN P. WYATT. M D. Iro/rssw of /.tholotT. SI. Louis t/wivcniNy School of Mcdicrn~e, Sr. I ouis. l0l

INDEX (by .e.br atdb.r ) Albanese, A. A., 70 Barger, A. C.. 34 Belkt, S.. 35 Beoson, H., 34 Bhagat, S., 16. )6, 66 Biancibo.i, C., 29. 30 Bins, R. 1., la, 39 Bordew, E. C.. I. Boussauw. L. 61 Bucciaretli, E., 29. l t Camcron, B. F., 72 Carter, W. A.. 11. 19 Cha1001, 1., 32, 37 CAodosh, S., 54 C1aprk N. M.. 7l, 74 Cocbr.ne, C. ()., 74.75. 112, 13 CoAe.,A.B.,33 De.9taro. C. V.. 12 Dr.zra, l. M., 3 5 F.k>,d. B.. 36 Erick.on. C. K., 1 l F.,wmn, W. /., 14, 71 Eran, M. 1.. 64 Firaky. T. N., S• Foa,R.R.,t7,t! Freeman. A. E., 25 Friedman. G. D , 79 Fudenhefl. H. II .51 Goldeoherg, D. M., 22 11aM, M. R., 84 Hel9berg, K., 3 7. 40 Ilo, W., 21 Homburger, F.. 17 laoobe. A. 1.. 28 KauRmaa, S. L, 22.23 Keller. S., 65 Kupke. 1. R., 42. 4 3 Lac><o, A. G., 12, 7! IAuweryns, l. M., 39, 60, 61, 62 l.erner, R. A.. 2l, dl, 13 t..eucstceberger, C., 6) I1ae, C.-Y., 71 Loew, D. A. Y.. S) Looali, C. G., 65 Mane, P. t?. 0.. 57 Maaaro. D., 65 Mathcs, P., 36 Mauuot., 1., 67 McAlliater, R. M.. 21 Meacham, R. H.. Ir., 76 Medici, T. C.. 55 Meier, II., 24 ModaR, S. P.. 24 Murphy, P_ A., 44, 4 S Na.rc,R.L,43,t0,81 O'11rie., R. I., 28 P.rter,l. W., 86 Pi.lertoa. H., 16 Pinb da Sil.a. P., 20, 76 Pitha, P. M., 17. 19 RiE.cshI, R., lt Roa.., R. C.. 59 Ro.land.,1. R., 77 Ruk.Eerg, H. L. 50. 51 Ryan, 1. W., 46, 411, 77 Sabelli. H., 61 Salerno. R. A., 27 Seltzer. C. C.. 78 SltiMu, S.. 67 SmitA, U., 47 SoioR, L. A., 48.49 Squartini, F., 30 Stadnicki, S. W.. 15 Stetae, 0.. 40 Ta., E. M.,114 Terukia, l. A., 32 Tubergen, D. 0.. tS Vott, P. K., 72, )l Weezet, D. G., 68 Wea/lall, T. C., 69. 70 W6itmire, C. E., 23, 26,21 I I Y 104