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ANDREWS OFFICE PRODUCTS CAPITOL HEIGHTS, MD (K) s

1977 REPORT oJ THE COUNCIL FOR TOBACCO RESEARCH-U.S.A., Inc. 771E COUNCIL FOR TOBACCO RI•:SEAR(:11-11.S.A., Inc. 110 E..159tb 9ereet, New York, N.Y. 10022

SCIF.N77E1C ADVISORY BOARD to The Council for Tobacco Research-U.S.A.. Inc. as of December 31. 1977 HANS MEIER, D.V.M., Jr. Wg1. Vet., YJ.R.S.11. Senior Staff Scientist The Jackson Laboratory Ba• Harbor, Maine SHELDON C. SOMMERS, M.D.. Chairman Director of Laborato.ies, Lestos HiU Hospital CJinkaf ProJessor of Padwbnr Colk~e of Physicians & Surteooa of Columbia Univenitr New York, New York 1 LEE W. WATTENBERC+, M.D. Pro%ssor of Pothotoq y Department of Laboratory Medicine cac ?'atholoQy University of Minne.Wa Medical School Minneapolis, Minneauta RICHARD M. BINO, M.D. Dbedor of Cwllofo" anI /ntromr.rd Melkine H.mirKton Memorial lloapital, Paaadena, California ProJesaor of Medkine University of Southern California School of Medicine Loa Aateles, Califoroi. JOHN P. WYATT, M.D. Director Tobacco and Health ite.earch lnatitute University of KentuckJ Lexington, Kentucky J05EPH D. FELDMAN. M.D. Head, Department of (mmunopatholo6y Scripps Clinic and Research Foundation La LUa, California WILLiAM U. DARDNER, Pn.D. Sdenrt/ic Dinrro., The Council for Tobacco Research-U.S.A., Inc. E. IC: Hnnt PtiroJessor of Anoronry (erneritrs) Yale University School of Medicine New Haven. Connecticvt Seiewliiie St.R.d TD.e C..wea WILLIAM U. OARDNER, PN.D. Sc/enB/ic Director ROBERT C. HOCKETT, PH. D. ReserrcA Di+rcror DONALD H. FORD. PN.D. VINCENT F. LISANTI, D.M.D. ROBERT 7. HUEBNER, M.D. Associate ReseancAi Dbrrta. Associate Research Director Chief. Laboratory of RNA Tumor Viruses Natbwal Caneer Institute JOIIN 11. KREISIIER, h1.D. DAVID STONE, Pa.D. Betheada, Maryland Associate Researcli Dbector •Assodate Research Director LEON O. JACOBSON. M.D. Dirrcror, The Franklin Mcl.ean Memorial Research Institute RePenuteln Professor of Biolojical Sciences University d Chicaao Chicaao, IUinoia HENRY T. LYNCH. M.D. Pro/essor and Chalnnnr Department of Preventive Medicine and Public Health Crel~ton Univenity School of Medicine Om. a, Nebra.ka

CONTENTS lDttoductbo . . . . . . . . . . . . . . . . . 5 AbturKds d Reporb . . . . . . . . . . . . . . . 6 . Caaoer-Rdaled Studia , . . . . . . . . . . . 6 The Respirator2 Srstes . . . . . . . . . . . - 22 Htart od ChculaNo. . . . . . . . . . . . . . 34 Ncurophumacolop .aid PbyslolM , . . . . . . 44 PRarat.ooiM .nd Bioc6emistq . . . . . . . . . 49 /ereweoio67 and Adapive Mechanisms . . . . . . . 54 p.pideaaiolon . . . . . . . . . . . . . . . 59 MbctUane. . . . . . . . . . . . . . . . 63 ActM Pto)octs . . . . . . . . . . . . . . . . . 64 Ca.apicted no}. . . . . . . . . . . . . . . . . 73 Ldea d rrl.dp.l lavatiplon . . . . . . . . . . . . 83 hde: d Sedor At+lSoea . . . . . . . . . . . . . . M I . Intiraductimn As its quarter-century marh appvachn, The Council for Tobacco Re- search reviews ita history with a.enae of grNiOcatiov over progress in several directiorn, some degree ol frustratba in othns, and a considerable measure of optimism /or the future. In the past 24 yean, TMe Couucil 6r provided substantial support for what may wefl be the world'a most eahriv~e aao-go.ernmcN.l re.scarch pro- pam concerning tob.ooo we a.d healtb. TMe basic policy adopted at the outsrt has been rnaintaintd, that i., so place rNpeMbibility for the direction and guid- antx of the research dfort in ihe Ir.da o/ a Scienli/k Advisory doard, and 1o have the research ee.ducted 67 iw8rpewdeM Investigators in their own insti- tulions. llenee, whalever oD.tribWiar to aciewti/k progress may be attributable to The Council•a program .ri d.. ..ry largely 1o Ihe distinguished men whu have served on this Board. W!M major emphasis .po." cawoer, heart d'aeaes a.d chronic lung ailmenta, the Board has consistently ooe.seped stro.g attention to the multiple steps awd stages in the pathogenesis o1 14u agisell-asaoeialed "eoautitutional diacase.." Basis for Ihis emphasir wp a aou.ictiow tlat rapidly developing ne.w techniques and concepts in biochawolry ahould ptovide powerful tools for elucidatiag these mulliple Meya and ttyer, with a reasonable hope of short-circuiting oL blocking one or more of tlrs aa/ 11ne preventing the disease or delaring its onset. By the end of 1977. tlir prvpr+rtt Aad produced more than 1.500 reports and articks in accredited aKieMi- e iouruaii by scientists acknowledging Council wrpporl. Their ultimate stpiAcaeoe ia relalioe 1o 1he goals cannot be fully appraised at this time. 'Itie rnosak Y eompha and emerging pictures are still far from ckat. 1/ is frequently Ma1ed IW, ItlalorleaNy, many of the most important ad- vances in medicine have 6aw wnda by trpredictable enspiricd diaoovery. Yet. In these daya, such diacoveria ara trtaM likely to be,made by alert Individuals In the course of systanNie.luia Nided by a good rationale. The m.iMenance of scientilic eevitoee+e+w ooad~rdve b t+udr dbooveria is, there/ore. n im- p«t.rw re.po.aiesiitr ot .q tr.Mias oegotiz,tio.. The prerenl report ooal.in+ .bMracts of anauacripts published in 197, qrN acknowledged Cawd spo.roe.hip. TAe aestraets speak for thenmlvea. They illustrate Couecil polic! 1W Sr.Mers alone shall be responsible for d'a- e{oaing their research Andinp i. aootpled medical and scientific journals or before medical and scientific orpwiralion.. The Council is aontinuint Its Oro{ranr of support to iodependeN reaeuce- en in bio-medicine with its original /oal.- , ©

Abstracts of Reports Following are abstracts, appcoved by the aulhors, of reports on new nesearch acknowledging support from The Council that have appeared in tcien- tilk joureals sinoe publication of the 1976 Report. lAe name of the recipient is in italics. The ab.tracts are grouped under these beld'wp: 1. Cancer-Related Studks, 1/. The Respiratory Systen4 Ill. Heart .nd Citcolation, IV. Neuropharmacolop and Physiology, V. Phumacoiop ud Siochetnislry, V1. Immunology and Adaptive Mechanium. V11. Epidesniology, VIII. Macellanoou.. 1. Gwcer-Rel.ted Strdie. Rf'PRESS1eLE AND INDUCIBLE FORMS OP DIMETH YLNfTROSAMINE-DEMETHYLASE Mai. Spndue-Dawley rset and inbred strains of male mice were ustd 1s daM study of diwetb7l.)trwatwlwa (DMN)-0etnetbylase with respect to keetie charockrMka and responae b Ydueer prtlreatmerN; straindependcnce t{ R- ptsibiliy rs1 leducibility was abo inveslipted in the mice. Results d+ow that two eneytne fotse., with diRenea kinetic characleriNics and oppo.ite rrspanses b it dro erapase inducet pretrealment. trder/k hepatic DMN•demNhylaue ec- N.itq. In kinnk sludies, detennination of the Ilo/slee plot of DMNdemr.thyl- tre using a DMN aubatrak concentration range of 0.5 to 200 mM yklds t5ree lsferaoctinR line sepnenb fro+n which widely diReresM K_ and V_ may be calculated. IdeNkail7 panernsed Hofae, plots are obtained with rat and tow.a poeunUoehondrial wperwNaM fractiom, as well as with the ittdated taiao.awtes. The lowiubatr.le-ranps line segment (0-4 mM) and the hish- arbattMe-raa{e aegnre.t (30-200 mM) correspond. in both the rat and the aatw, b two dillerent eatrymNic fornn of DMN-demethylase (DMN-de- metlrYlaaa 1 and 11, respectivelf) which baw (he following diQerent regulatory esarselerittio: (1) PrNreMtwnM of rats and wwoe with the polrchkxinated biplsesyl. Atockor 1251, brinp about represaiow of DMNdemethytase I and it.ductitr• ot DMNderne,brlaia 11• both responses are stronger in the rat Iham in dr /nase. (2) PretreahnerN with phenobatbital trpreascs enz7me I in both pacia• bov.s.er, it induoea eayme 11 only In the rat. ( l) PMzealmerN with )- ntethrkhda.tMer auMtanUallt tepresses DMNdemeth7/ase I in the rat only; It Is i.eQeetivr iu signiAcanelP idluesrind any other enzymatic activity. Impor- tmtly, the genetically disdnct tsalwt of the two formm of hepatic DMNdemi:lhyl- w is suggested by t!w sub.ataslial d+lerenoes in the strain-dependence of the reptrsaibi/ity of enzyme I aad in0ucibility of enzyme 11 In a aeries of nine in- bred strains of mice. The rnara bet ooelaiaa only the inducibk-type of DMN- detncebrlaar kowever, the ranking of inducibilitks in different /rom that of hepatic enrrme H Artau. I C .r .l Z.1rwA.r/r /w R..bh- Arwa rwI AIu.NFAf 89 1e1 199, 1977 Other auppore , - Nation.8 Caeoer In.titule. From the Seamen + Memorial Research Laboratory, U. S. Public 64ealth Service Hospitd, New Orleans, and tbe Department of Medicine, Tulane University Medical Center. New Orkans. ONCO-DEVELOPMENTlLL ALKALINE ?F:QSPHATASE ISOENZYMES Previous studies have showw 1hN fwnor alkaline phosphala,es have their counterparta in relatively early stap of Iwnuw development. For e.ampk, the chorionic phase I boenzyrne in 6-10 week fropboblast mkrovillar tissue con- sists of two heat-acnsilive, L-howqerRinine-irJtibiled b.nds. The fnter one, b.nd A, e.hibib none of LM awa4ewk deterntinants known for vario.n alkaline phosphalase iaoenzymes and Ihe dosrer ons shnea dekrminants of the liver type. After 1en weeas, alkoliaa phoaphat.ae ot the tene placental type appear. in spncytiofrophoblad eelk` and the dwdonlc type beeomes much kss promi- nent. Further evidence prexMad hete Indicalea Ihat the chosionic (6-10 week) tissue iaoent7tne lacks the atMyeak detenrninnNa of term placental isoenzyme. Still more evidence auqeab Maf Ma eoutNerpert of chorionk band A is to be fouid in the fa/it. kadinZ the e.Nwts to questice whether this band is pro- duced by leruocueieoer of dse lestis or by cancer of the lung. In the present study of neoplaslic Ir..dutnnlion in relation b oncodevelopmenlal gene e.- pressiow, ebe tr.cheobroncMd ttett of Mrmana with cancer of the lung wn ehosen w the nrodel, ainw aN tnnMorwntional staaes from basal cell hypcr- plasia 1o earcinorna M aUr nn be eapeeled to be found in the nonlumor areas. Signi/kaM levels of dtdnotwrltYowie antigen (CEA) and human chotionic gonadotropin (HCO) were fowd 1n eatracta of bronchial epithelial cells from twtn•necplaslk as well as eoplrfk ates. It may be, lherefore, that the onoo- developmtntal genes for CEA and HCO we turned on early In transforming cells and persist in malipa.c7. FWlnr.w, W. Il. er d. In: Fishman, W. H. and Sell. S. (eds.): Owco-levrloomenrd CJcne E.prcLion, New York: Academic Presa, Im:. 1976, pp. 163-176. Other suppertr Natiosrl Cancer Institute. From the Tufts Cancer Research CaMer, Tufts Uaivenity School of Medicine. Boston. PIIENOTYPK' ALTF.RATION OF ISOENZYME PRO1'ILFS OF Al KAI.INE PIIUSPIIATASE IN HeLa TCRC-I CELLS GROWINU IN IMMUNOSUPPRESSED RATS When grown in culture, the human cell line, HeLa TCRC-/, produces the heat-stable eareinoplacesNal Repn isoenzyme of alkaline phosphatase e.clu- sively. However, as Ihis paper describes for the Ilrst time, a prafound alteration lakes pl.ce in Ihe isoenzyme prolYe of alkaline phasphalase when 11c1 a I is grown as a solid n.mw in hnmunoauppreased rats. Acrylamrde AeI eleclro- phoresis reveals a decrease In the Regan Isoenzyme with a somuhanahr, apprar- ance and increase In new fasl-moving iwenzyme buxls. After 70 days of 7 6

growth lw .iro, no Regan isoenzyme Is visible and a singk fast-moving iso- enzyme band is Ihe dominant isoenzyme. Tl+is new enzyme form is identifkd r the onrnamnionic (FL) isoenzyme lint characterized in the FL amnion cell line and later In a hepatoma p.tient. Upon transferring the tumon back to cul- lure, the oefls regain their original Regan phenotype after one to two weeks. Ne.erthcka, even though the esprrs+ion of the Regan isoensyme is restored, the NeLs TCRC-1 cells' isoenzyme eapression has been changed, since lhis cell line after being passed through an irnnwrwsuppresxd rat Is able to rerxpresa the oeeo.mniotie isoenzyme N certain cell demities in culture. Such growth of humaw eawa cells in inuswnauppressed snimal hosta may provide a model trystem for the study of carci.ogenic espns.iow. Sioaer, R. M. and Fisllw..w, W. H. le: Fir6man. W. 11. nnd SeB, S. (eds.): OwcodrrrloPm.nral Grnr E.orrsslon, New York: Academic Presk l.c., 1976, pp. 177-161. OtArr sr.trorfr National Cawctt Institute. Frvm the Tufts Caoeer Research Cenler, Tufts University School of Medicine, 11041100, CARCINOPLUCENTAL AI.KALINE PIIOSPHATASE: BASE LEVEL AND HORMONE-INDUCED ACTIVITY ASSOCIATED WITH EVENTS IN THE CFLL CYCLE The Regan isoenryme (a caminoplacentsl Senc product flrst discovered In a brvnehornie cancer and subseQuently found in a variety of other human eanecrs) is a placenld alkaline phosphatase isoenzyme which is also produced by the NeLa cell model system. IIeLa TCRC-1. a particular cell line which h wrorwphenotypic with respect to the Regan Isoenzyme, is esamined in this study of predni.olone regulation of alkaline plwsphatase as a function of events In the ceM cycle. Results show that DNA synthesis is not required for horewne {nduNion of the Regan isoewzyme since induction occurs in the presence of hydtoayurea, a specific inhibitor of DNA synthcsi. AddilionaMy, when partial- ly ttqnchroniud cells are dlowed to leave the S period prior to hortnone treat- ment, snd hydroayurca in sdded to prevent cells from entering the neal S periiod, hotnwne induclion of the Regan isoenzyme is stip observed. This indi- calea that Initiation of capression of hormone-induced csrcinoplscental alkaline phosphalase occurs prior to the DNA synthetic phase of the cell cycle. This Mding can be harmonized with previous wudies on other cell linn by hy/dhe- sizing a Iwo-skp mechanism of bormare actioA in which the Ant Induction step reauins DNA synthesis, while the second Mep, which is more closely rr.lsled to transcription and translation sequences In the Or period, does not. It Is this secord step which is functional In the TCRC-l cells. SinRr, R. M. and FLhmaw. IY. H. DI//trtnriarlow 3:127-I )2, 1976. Other .. pr.r1 r National Cawur Institute. From the Tufts Camcer Resesreh Center. Boston. t DEVELOPMErTAL PHASESPECIFIC Al.KA1.INE PIIOSPIIATASp. ISOENZYMES OF HUMAN PLACENT.4 AND TIIEIlR OCCURRENCE IN HUMAN CANCER The appearance In ttrnors of a devebpmental protein antigen such as Regan isoenzyme, a ploce®ta1-typt: alkaline plqsphatase, may indicate 1he re- eapression of a gene set eNaraNeristie of a particular event in early develop- ment. Information of this aort may help elsasify slages in neoplastie progres- sion. 'TTThis preliminary eomtnwtieallon descs:bes alkaline phospha/ase ekclro- phordic patterns char.ctcrislie of three plsses in early human trophoblrtic development. The Phase C(6 b 10 weeks) pattern consists entirely of two heat-sensilive. L.homarginise-Mhibised bands, the slower one possessing anti- genic determinants of the liver-bone type of alkaline phosphatase and the faster one lacking any of /hs knoww alkaline phosphatase antigenic delermi- nants. The Phase 2(11 M 1) weeks) pattern shows a miature of Phase I and Phase ) (11 to 16 weeks) boewttynN oowtponents, the Islter of which has two boenzyme bands with the cA..ticUalslics of /etm placental alkaline phosphatase. These lhree pattetas of d t.elopmdrty phse-speciM1c placental alkaline plwse phatse corsespond, in order a appesrsnoe, lo non-Repn isoenzyme, a miature of non-Repn and Reps btoewiywas sed Repw tsoenzyme as are found In a variety of human cancer tlraines. Etswtpks of each phase's occurrence In humas cancen are given, and Iw thig way s guide is provided for interpnNing tumor alkaline phosphatases tr reBeeliowa of the activation of phne-speciQe tropbo- blaslie genes. Fehman, L., Miyayama, H., DeisooM, 10. and Flsbmaw. IY. H. Cwcer ReuarcA 76:226fi-2272. 1976. Other w'prtt Natiot.d Cawoer /sntitule. From the Tufts Research L1etMer and the Depatmeia of PatholoRy, Tufts Uni- versity School of Medkiwe: the DeparlmnN of Pathologr, Ilarvard Medical Schod, and Boston Noapital(ar Wosner. Boston. REGULATORY CONTROLS OF ONCOTROPIIOBI.AST PROIFINS ANI) DIiVELOPMF.NiAL ALKALINE PIIOSPNATASFS IN CANCER CI?LIS Regan isoenzyme (plaurttal-fpprr I/kdirre phosphatase) and human chori- onic gonadotropin (IICO) are two onco/rophoblasl proteins which ate onco- developnrcntal gene products readily studied'in human cancer patients and in several eaperimental sTslema. Three such models are: (1) llel.a suhlines TCRC-l and TCRC-2, which produce Regan and non-Resan iaoenzymes, (2) Hep-2 and FL anwJow eeB lines acting as models for the reciprocal espressiaa o( de.elopmenlal genet, and (3) /w dw moduluion of developmental gene c.- pression M Ilel.a cells. in this la.l Indanee, for etanrple Hel a 7CR('-1 cells gro.w in Mnmunowpp.essed nls, fonning a tunwr noduk which eap.cssn a nee oncoanwJon (FI-) i.oeetlnw. whila the Repn isoenzyme disappcns. When these tumor cells an returned so eullure medium, however, the FL 9 g

species d'wppe.rs and the Regan isoen:qme reappears. This particular m)del ir expected to prove very useful in interpreting tbe varioun data obtained esith oell cultures and tumors from cancer patients. A chronology of early develop- sneet hr already been mo.t helpful in this reptd, since the counterparts of a number of lumor proteins appear as earl7 as 6amelo6enesis and as late as ten weeb of gestatbo. Flthw..ti W. H. and Singer. R. M. C.wee. Reu.rA )6:12564261, 1976. OrA., a.pr.ret National Cancer I..tihNe. . Praw th. Tu(ts Cancer Research Center. Tufts Universily School of Medicine, Bouu., ..d the Department of Anatomy. Fairkigh Dickinson University School d DeMbtry. Hacltensack, N. 1. EVIDENCE FOR ALTERED OEN13 RE(lU1.ATION IN HelA CELIS RETURNED TO CULTURE AFTER OROWINO 1N IMMUNO6UPPRtSSEi) RATS A pro(outd change of phenoypie espression oecun when Hel.a cells cloned for the exclusive production of the Regan isoen:ryme of alkaline pboa- 'hatw ara Rrown in imnwnosuppressed rab. In the course of a sequential al- lerstione i. 1he i.oenaryme eapres.ion during tumor growth, the Regan isoen- t7rm dia.ppean and ae osooannioa (FL) isoeas7me baomes the domin.t (orns. Tb Preaest report deseribes the isoen:yme reRulation after 1Aese cells rv teturned b culture (or at kaN three months. Thew celb In cuhure demon- atraM a detrity-dcpenden( aheratio. 1s boeruyme proflb. The ReRan i.o- enz7wu Y the dominant itwewsynw (ons in eew. sparsely populated cultures. ..hile dn o.oo.mnion iweat7wu predonan.ter in the later hi6h-desitp sta=e" o( po.lh. Such a eeM Nan wMch w be made to produce the Regan isoen- s7t.. by etilerritrR cells In low deniry asd whkh wiN re<spran the oaotrm- .ioa (PL) ioeezyme at hi6h-veM den.iy might be very useful in the study of Molat:r.n re6trlatioa in hwuas eaeoer cells. The eBects of pr~edniso(one on 14ne odlo ia e>r/1wu are variable, depending on the time of ib addition. A tnarted i.e.ear in artrme k.eb Is seen whes the hormone is added early in thw pawftr eTde. P,aa7rns bductioo b restricted to the Rep. ieocn:yme, whUe hormoae-tnedlaled d'ani.utio. M ars7me activity is confined to the oncoamnioa (PI-) Moebs7wn- Sieller, R. M. (F1.A.n.% W. N.) C.wrer Re.r.rA )6•1262-1265, 1176. OfA.r wsrr.rer National Canoer Institute. Prem the Department of Anatownr. Falrki6h Dickinson Uoivenit7 Scbad of Deotislry, Il.ckensact, N. 1. IDENTIFICATICN OF A DUTA4tiOL-EXTRACTABI-E HUMAN PLACENTA-SPECIFIC ANfIt3EN WITH ALKALINE PHOS/•IIATASE ACIIVI-IY This study focuses on the placental meerbrane-a+sociated antigens released by n-butanot, an organic sd.:ut, whieh wlubilizes a number of cell membrane components. Most of the tisax Bpid L extracted into the alcohol Iraction leav- ing the gtycoproleios, polysaocharidea and other watcr-solubk eomponenls in the aqueous phase. In this seia of experimrt,;-. bomoRenized whok-term pla- centae from different individrah were tteated c-ith n-butanol and the immuno- gens-conlaining aqueous (racUons were used w rwe hetero(olous hyperimmune .era in rabbits. ImnNrrwekcarophoresis of the anti-placenta antisera tevealed at kast sia aolillenic coanpoeeeb in the placental eatracts even ailer they had been completely absorbed with pooled male serum proteins. I(owever, the anti- sera so absorbed, designNed (-PMS). still reacted strongly with estracts of normal adult intestine and Lid.e7. Similar reaction patterns were also obtained with individual bulaaot eatr" of I I various other normal adult tissues and with a composite extract ooa/aiMitd equal amounts of each of the 1) individual ealrads. Of the sia antizenk oorapoaewtu in tbe placental eatracts reacting with the (-PMS) anti+era, only Ilr oae axoci.led with alkaline phosphatase activity retained its reactivilr. Homoje.eors placental alkaline pbosphatase contlrmed this i.nnwno{o1ic and enzymologie Identity. F.atracts ftom each of three pla- centae injected in1. /Moe pain of rabbils aR produced an identical antibody reaction with the unique delenni.anl(s) of plaocMal alkaline phosphatase. Ea- tracta of 14 olher placeMae re.cled with each of lhese antisera to form a single precipitht line of identit7. These rewdtr Rrnttr establish that placental alkaline phosphatase is a characteristic Plaonu-speeiAt (eW proteio. ChaoR, C-H. and AnRe1llo, D. (FLkrsara,l6'. R.) The lewwd oJ /wrnrwolop 117(1): f1-16. N76. Other atarr.rf r NNio.al Cancer IrlitWe. From the Tu(ts Research Cewler .rd the Department of Patholopr, Tufts Uoi- •enity School of Medicim SoMoa I DIRECT IMMUNOPEROXIDASE STAININO FOR REOAN ISOENZYME OF ALKAUNE PHOSPHATASB IN HUMAN TUMOR TISSUES ImmunohiMochemicd loeatitatiow of Regan hoen:yme by a direct perosi- dase-IabelinR technique wr obset.ed 1s eenain selected cancer tiswe cells by both light and electron microaoopy. Among Ove tumors selected for e.amina- lion, two cases (I & 2) that were hiNOChemkally confkmed by their e.lreme sensitivity to L-phesylatanirr (LPA) alm showed a specific immunoperoaidax reaction lor Regan isoesut/me and did not show any difference between rhe histochemk.l Iocalitaliom of Regan hoearyme and the immunoperoaidase stain- ing one at the light micro.oopy k.el. The Regan isoeniyme in Ihe.e cancer utls was seen predominantly in the eytoplasm containing diffuse and fine granu- /ar reaction producb, but it was aHo noled In the cell border area. Immuno- ertochemical studks at the eketroa microscopic level were confined to the lumor tissue from case I wlKre Repn boeneyme eouW be specifically demon- tlrated on the plasma membane. On the other hand, cancer utls /rom case 3 II • 10

containing L-hornwrginine-aensitive alkaline phoiphatase isoenryme acd from cases 4 and S, selected because of the absence of alkaline phosph.tase sclivity, wen: apparently wtrcaclive to the specific immunoperosidsx staining. Based on these Ilndinp, peroxid.ae-labekd antibody specific for human pl.cenl has been wocesfuliy used for deteeting Regan hoen:yme in cancer cells, because the identity of pfacental alkaline phosphatase with Regan iooenzyme kas been weR established. The authors feel that theae LPA-sensitive lumors represent a dr of cancen that should be lsveatipted from the point of view of esprea- aiom of embtyoeic genes. • M67ayasu. H., Doeltpst, O. 1., Mensoll. V.. Oandbhir, L. and Fb6rnan. W. H. Cwcer 3t(J):12J7-1216, 1976. OfAer arrpwtr National Cancer Institute. Prorto the Tdta Canoer Research Center and the fyepartnsent of Pa ihok.gy, TtJln Usi..r.ity School of Medicine, sabs; and the Ikpartment of Pa holoBy, Powd.ak. Hospital. Wdpoie. Mr. TRACHFASRONCIIIAL EPfiHF.1.lAL MULTINUCLEATION, VIRAL INCLUSION sODIFS AND MALIGNANT DISEAS6 This epidemiolngicd study was undertaken b determine asy possibk re- laliorrhipa between trachcobronchial epithelial multinuckNion. viral inchniw+ bodies„ and malignant disease. (It is already knows that patients with malig- sant di.ease have an increased incidence of multinuckation and thal there is a aaaonal variation in the number of virat inclusion bodies in the ciliated epNheliwn.) For this study, smears from /,130 patients - of whom 1.024 (V vuip A)'had various malignancies while the other 3.126 (groups S and C) wern sufferisB from many types of norunaliBnant conditions - were esamincd for 1he prvsenoe of viral inclusions and multimakaled ciliated epithelial cells. Low deped of multinuclealion were observed nwsl frequently in 1he wmmer is p.tkatM both with and without known malignancy. A6o, cylopiasmic indu- abs bodies were aeen least frequently M the summer .nd auturnn in all patients. Wbe. &.on, A and group C were eompued. siBnit{cawtly rsom patients with canoer rad ritsl 4nausion bodies. Th. aeawnal ineidence ot hiBh pt:roentaBes of swllisrckaled cells in patknts with viral incMeiona bst without known cancer (V oup E) followed the general pattern of being lowest In Ihe summer; but in t)wat patients with cancer (group D). peroeMales of nwltbwck.led cells were hlBher f. Ms summer moMAs than in any of dre other aerorn. Ttrese observe- tbae h.ve led Ihe authors so conclude MM IrachcobroncAlal epilhelW rwuNi- swckatios scema 1o be triucred (1) by malignant disease anywhere in rhe body osd (2) by the seronal prevalence of respiratory viruses. Most important- Fj, this wort indicata that respiratory viruses may have a apeciflc eRed on the ciliated epithelium of casoer patients. CAdow, 1. er .f. TAe /e.rw.t o/ RrP.wdrnlve M./tcfwr I f( J):111-/46, 1477. From Ui. Department of AeathesioloRy, New York Univenity Medical Center. N.w York. I ENDOOENOUS C-TYPE VeaUSEl: DOQ:OLB AGE!NTS IN NATURAL L9: H PROC.'SEt About 20 different varftbra1ft specks .re no.w known to harbor C-type kNA •:iruses. In nnn, 1hi ptaeao. of tbese particks is suggested by ekctron microacopic, biochemkal .ed seisloBic atudie, although  deflnite replicating human virus hq yet 10 ~e hou*ed. 7Lese endoBenow viruses are inheritcd through the term ceM anC Ibeir production is regulated by genetic information carried in the host cell. Tro classes of esdc~,~esaus C4yp* viru.ea, «o(ropic and :enotropic, which may hi vr Iheir eowNerp.ry In nwa, have been rrcoBnirtd In certain animab, putka/utl the srouse. Ecotropic vinres spread through the host, can be easily lnsamitled to alla of the sune species and can induce malignancy. Xenovopie .hraer e.nnot isfed cells from their host species but are Infectious for cells of beNrdoRosr apecies. The interactbn between these two types of virv.es eoW tea.N in the traw.fer among apecka of genetic in- formation relaling to worraal site pvoea.ea and malignancy. lbe auUwr eo.- chrdes that endoBenow C-t7pa vinrea may be positive regulators of embryo- genesis. differentiation usC normal cell devdopmetN, as wep as of the e.tremu of ehese prooesaea, eeR a=irs, awloierw.a diacse and cancer. L.4vy, /. A. tiornedkL.e 21(2):i4-fJ, 1976. OtRer a.rr.etr National Ctno.r IsrlipNs. Protn the Department of ALdidM and the Canar Resc.rcb Irotitu/e, Univer- aitr of California School ef Medicist+, Sas Francisco. ENDOOENOUS C-lYPB VIRUSFS IN NORMAL AND "ABNORMAL' CELL. DBVp.IOPMHNT In this aomprebensi.e e:asAsalios of ewdogenoua C-type viruses In nor- mal ud "absormal" c,er ievelo}serK, tlr vhwes' potential ro{e in the proc- esaes of normal swrrNio. (embryornesia sd diAerestiation) and aging (au- toimmunitr and eanoer) an discuwed. These Gype v'iroses, which are budding RNA viruses with lipoptsteiw ot»b, an endogenous, l.e., inherited in /he lienes of many specka, aed have been bwp/k.1eA In cancer in several species of animals. Study of the role of thex dnres in rAum has been aided greatly by the mouae nwdel aystem, since s.ioe develop dbease. similar to tlase of humans. Thnee classes of mwiee C-typa vMuses have beaw idenlifkkd by host range snd sero- bBical studies. Owa of these dres, eaemplilied by the aenatropic virw. M present is early embryoo, in cells undergoing normal differentiation and is cancer cells. The other daaasr. eoouopk; and amphotroyic, ue found primarily in animab with pathological - owditioa+. AN drest C-type virusea are eapressed apoManeotrl7 by oeN. N eertain frequenciea'and titen during the litetime of the mouse. A aonisnwnoBiobrds fac/or Iw been identifkd in normal mouse aerm which specifkaQy weutnliaw IM aenoUopie virus class o/ endeKenous C- type viruses. Virw eapres.lon, therefore, appears 1o be rcpdated by intr.ccllu- Iar r well r humoral faclon. These observations suggest that C•tyl.e vwu.ea play a rok in natural procere, particularll normal matwation aed aging It 12 13

Y also suggested that these murine viruses may have counterparts in humsns in wboee tissue eedo=enous vitvs particks have been detected. Le.y, l. A. C.wcer Rex.nrA )7( s ) :2957-2%!, 1977. Other aorprtr National Cancer Institute. Frar the Cancer Research Institute ..d the Departtnent of Medicine. Univer- sity of California Medical CeMer, San Fra.ciaoo. ANTIOEN-SPECIFIC NONIMMUNOOLOBUI-IN FACTOR THAT NEUTRALIZES XF.NOTROPIC VIRUS 13 ASS()CIAIED WITH MOUSE SERUM LIPOPROTEINS (MURINE C-TYPE VIRUS/ ULTRACENTRIFUOAL SEPARATION) Mouae sera sped/kdf7 acutnNoe tunottopit: but not ecotropk virusts, this netrtraNsabu being atlribMable b sotne solubla aerwe factor and not eflected by insmutwklobulins. Secwre both aenotropk vinn and the soluble neoltc lizinB factor (NP) are present in a11 ho~ne mioe. the suthors have suggested lluit NP plays a role iw the regulation of endogenous ><enovopie viruses. Interaction of NF with the virus N the cell surface may change the intereal mika and lhere- by affect normal life proeeses. This serum factor is furthet characteriusd In d+sa report. It is slable at pH 2-7 and mists ether ealraction, freezing or brief healing to 100' C. Ultracentrifugal separation of immunoglobulins and lipn- prolein dernonstrates Ihe association of NF wish the serum Gpoproleim. Oel perwreaiion chromatography tocalires it in the region of lipoproleins and IsM eaplaining the previous conclusion of others that it is an immun"lobulin. Vari- ae procedures also show that it is not the 70.000 molecular weight Nlycopro- Iei.(s) dreubtinN in maae serum in high titer. UltrscenlrifuNal fractionation of twaw Npoprolek+n Indicates that most of the NP activity is concentrated ie 16e density M/erval 1.019-1.175 d/cros. Additional studies alwuld determine whether NP is associated with oee of the major da»es of lipoproteins or with a spetiNe tei.ur Iipoprolelw specks within this density interval. Preliminary evidewoe sugSens that a protein srokty of NP may be important for neulraiiza- tioa l.,o.w density lipoproleiaa in human serum have beew teporled to have a regulatory effect on celt-mediated hnnNwnily, blocking thymraderived (T) ceM activatiow and rnited tymphocyle reactions. The reoo~nition, reported here, of a factor associated with mare serum lipoprdeins which specifically Inactivatea a virw represeuts a nonirtwnunoklobulis neutralizing reaction to an endokaaua virus by a hoN. Laon& 1. C., Kant,1. P.. Ohsdo, O. and [.ery, l. A. rrocerl/ngs of the N.Nond Acalawry of Sciences of tAe Unlrrd Stars of Amr.- /c. 'f1:276-2t10, 1977. Other nw'r.rfr National Cancer Institute and National Heart and Lung Institute. Pron+ the ('ancer RexaMh Inslihote, the Cardiovascular Research Irntitule and the Departmenl of Medicine. Univenity of California. San Francisco. I INDUCTION BY CfOARET'iE SMOKE OF ARYL HYDROCARBON IIYDROXYLASE ACT1V[TY IN THE RAT KIDNEY AND LUNG Previous Investigators have reported a relationship between the inducihilil7 of aryl hydrocarbon hydroxylase (AHH) activity and wsceplibility to the de- vebpment of skin lumon in mice ud possibly IunR cancer in man. Thn study of ciearette-srnoke-Indueed AHN activity represents an attempt to understand the biochemical reasons for sudt a Nnkate. A 1S-minult etpowre tq a 1/13 dilution of cigarette smoke /oduoed ANH in lungs and kidneys from Sprakue-Dawky rata. la bcth hseR and kidney there was a 2-how lag betwee. smoke Inhalation and the enayme isduMo. on.et. Thereafter, the Ali/l activity Increased very rapidly to atak about two hours laler, reachinN a muimal ac- tivity which corresponded itv thtea or fow limes that of normal rats. Up to four successive inhalalioro admt slqtted at 2-how Intervals induced both lung and kidney h7droaylase activilt s c.dditlvell. The matimal eQec1 corresponded to ah rN 10 timn the coMro( vahr. Compared to the kidne7 eezyme, the hwk A/1N activity was about Ihae er four tMres mae sensitive to small coocentra- lions of cigarette smoke. h(enrresweet of RNA and proleis synthesis require- teeMs showed that protein oyahesia was continuously required for the eslab- IishmeM of the AHH Iaductian but RNA synthesis was only necessary in the Initial period of the pheooemeost. To further characterize the lunt and kidney AHH activiry, the half-life of the eigatetle-smoke-induced AHN activity was compared to melhy{cholaMbrewe-Ipdueed AHH activity. Overall, the authors feel 1ha1 their results suppert the hypothesis that the inducing agents in cip- MIe smoke might not be paiyc7dk hydtourbons. Van Canlfott, ). and Cki'ew, l. IntcrnsHonaf lorrnd of Cwcer 19:S7R-SIS, 1977. OtArr w'portt Foed National d1a la Reclterehe Sciemiflque. From the Laboratoire de CrYeis Mbdicak, Institut de PatholoNie, 1.fte. Bel- gium. ARYL-NYDROCARSON HYDROXYLASE ACTiVITY IN LYMPHOCYTES FROM LUNO CANCER rAT1ENTS AND NORMAL CONTROLS • The aryl-hydrocarbon hydrvayla.. (AHN) system, which metabolires and Is induced by a wide variety of omepoundti has been shown to be genetically determined in oertaln strains of mioe. It hu aho been suggested that the level of enzyme irducibility In human lymphocytes Is genetkally regulated. In this qudy, a new technique involving r.diomNrie assay was used to compare kvels of A1111 activity In IymphocTles of hng canoer palknts and normal controls. Subjects Included 11 mde patients with histologically verifled lung cancer (nine squamous cell eareinoanas end two adenoeareinomas) and 1I age- and sea-mNChed controb. The luns cancer palknb e.hibiled considerably more variation in Atlll activity than the controls. In addition, the mean Alllt ac- tivity of the hmg cancer patients wr nearty four /imes that of the controls. Similar rrsu/ts were obtained from comparisons made between the eight ciga- rette smokers in the control lroop and Ibe aNe-matched lung caneer patieMs. The cancer patients exhibited much more variability and a significantly higher 14 15

mean level of Atilt activity than the control group smokers. While discussing the implications of this work (or lung cancer epidemiolo6y, the authon suggest that AHH, by virtue of its possibk genetic polymorphic status coupled with its ability to mctabolire certain chemical carcinogens, may be of estreme value as a marker for delection of cancer susceptibility. Ouirtis. H. A.. LynrA, H. T., Mate. T.. Hvris, R. E., Wells, 1., Caha, L., An- derson, l., Mdoner. K.. and Rankin, L Oncoio" 33:105-109. 1976. . Oth.r .nrP.rt t National lnatkub of Health. From the Department of Preventive Medicine. Crtighlon Uni.eniq, Omaha. ARYL )IYDROCARBON HYDROXYLASE ACTIVITY IN PUI.MON,\RY MACROPHAGES AND LYMPHOCYTES FROM LUNG CANCER AND NONCANCER PATIENTS Pre.ious reports have wrMested that aryl hydrocarbon hYdroa7la.c (.iHH) Inducibility may be associated with the propensity to develop lung catrxr. In order to shsdy lhis hypolhesirted relatiornhip. AHH activity was meawred In pulmonary alveolar macrophales ( PAM ) and peripheral blood lymphocyles /rom 47 patients with primary lung cancer and 56 patien/s bronchoscoled for a variety of other medical problems In PAM (rom nonsmoking patientn with- out cancer. the Atilt level was 16±2 milliunils/1(N ce®s, whereas noantnoken with primary lung cancer had values of 24t3 mdliunils/ 10a cells. Ci;arHle srrakers eonsistenlly had higher PAM enzyme vahres lhan nommoken, al- Ihouglt srtwken without cancer and smoken with lung cancer had simi'ar en- ryms ktvels. Induction of Atilt in cultured lymphocytes (torn nrn+unoken was signi/kantly lower for lung cancer patients than for noncancer patients. Enzyme indudioe wa similar in lymphocytes from smokers whether or not tln:y had hsng eancer. /mportantly, with cells (torn Individual petienls without lung cancer, a positive correlation between inducibility of AHH le cultured lympho- eY1es rrd AHN activity ia PAM was noted. On the other hand, with ce11, /rom patieau wilh primary lung eancer. PAM and lymphocyte .ahtes were not poei- Iively oorxlated. Further investiptions will be rKcesaary, to delineate the rnecha- nMtrr responsible for Ihe dissociation between AHN .ahtes In PAM and those in lymphocr/es from lung eancer patienb. Howeoer, for whatever reasons this phenomenon esists, k may be of diagnostic vdue In the early delection of lung cancer. McLee+ors. T. 1.., M«An, R. R.. Busbee, D. L. Richie, R. C.. Springer. R. R., Toppell. K. L, and C.Mre11. E. T. C.tsrer Reu.rcA 37(d):117s-11t11, 1977. OfRir wPP.rft Nallonal lnatitutes of Health, National Cancer Institute and the American Cancer Society. Pmm the ikpartme-ni of Medirine. Haflnr College of Medicine. Hon.Mn. and Ik1..rimeM• nf 11.,M,fa.l S[Kn.r. and h..ic 1ledlh lcknce.. Nurth iexas State l lm•rr.1i1 sn•/ o/w / r..t t nIM fe ../ (1.a+.paihM Medicine, Iknlon I IN VITRO INQUCTION OF ARY[. HY'DQOCARBON HYDROXYI.ASE IN HUMAN PULMONARY ALVEOLAR MACROPHF.GES BY BENZ.ANTHRACENE Ttn polycyclic hydrocarbon, beannlhr.cene (BA), is capable of inducing aryl hydrocarbon hydrotylaae (AHH) in human pulmonary alveolar macro- phaRes (PAMs). In the a7udy presented hne, time and dose-response curves for masimum in ritro inCudion of the AHN enzyme system in PAMs were established. In addition, a positive carrclNion was demonstrated between the kvel of AHH activity in E'AMs freshly k•:tVd from the lun6 and the degree of induction of AIIH in cultured PAMs from individual smokers and non- smoken. When PAMs fr+arn either smokers or nonsmokers were cultured for 24 hours in the presenoe of 10 rM o1 BA per vial, si6nific.nt induction of Alill occurred. indueed vahres o: Ai1H were over three times those of non- Induced .ahres for PAMs frowr tnwoken, while induced Atilt values In PAMs from nonsmokers were o.%r iusr lima 6reater than the rwninduced vahtcs for the same indi.iduah, indietlMt; tdM BA is s good inducer of the Atilt system in cultured PAMs. Measuc twesats sach r dre+e of the inducibilitr of Atilt in cultured human PAMs cae)d povide aw eaperimenlal system suitable for study- in6 the mechaniues respa abM for the idtiatiow o1 pulmonary carcinogenais. McLemore, T. L and Ma/n. R. R. C.nrtr Letters 2:327-333, 1977. Other ..rprtt NationallsmMula of Health. From the Departmenb of Medicine, and Microbiology and Immunolopr, Baybr College of Medicine, Houstoa RELATIONSHIP BETWEEN LEVELS OP ARYL HYDROCARBON HYDROXYLASE ACTIVITY AND SU9CEPTIBILfTY TO 3-METHYLCIiO1.ANTHRENE AND BENZOIQ)PYRENE-INDUCED CANCERS IN INBRED STRAINS OF MICE Susceptibility to 3-metbrktholanthrene (MCA)- and benro(elplrene (BP)- induced fibrosarcanas (and eareiwama) Is linkedd to naturally occurring diRer- ences in aryl hydrocarbon hydroaylase (AHII) kveh, that is, where Atilt in- ductibilit7 se6regales a a oodowtisrnt 6ene, or wherj noninducibilitr is domi- nant. Moreover, under condilittnI wht:re AHH h:vel: are arti/kiallv altered, ar occurs after trealmenl with the chemical defoliant 2,),7,8-letrachkwodihenro(sl diosin (TCDD), 1ha Inherent tesiManae of AIIII nonresponsive mice to MCA- inducrd tumon can be o+ereome. Moux genetic model systems show that when A/1H responsivenees to MCA treatment sepeples as a single autosomal dominant dene, either a sirt{le aMOawnal codominant gene or rw+nirducibi/Nr can be dominant depending on /he alr.in. of mice employed. In each of the Ihree genetic regulatory systenr described here. the level of Atilt inducibility is correlated (or linked) to wncrptiMli/y lo lumor induerion by M('A. Nthete AIIII Inducibility searegates as a single dominanl gene. su.cepubilay to M('A- induced lihrosarcoma h correlated with esprevfion of /hat jlrne function Susceplibilily to BP also oorrelales with high levels of Atilt induciAility. I/igh doses of TCDD given It hours pior to MCA result in tumor incidences simi- 16 17

lar lo tlwx obtained with MCA alone. Since the highest spccinc activity of AIIN occun IS hours after TCDD treatment, it is evident that elevated AHH activity by itself is not a requirement for enhanced tumor ausceMibility. F.s- peciany interesting are the tqectrum of metabolites formed and the kinetics of entrme formation during the tlnt 48 hours of T('Ot)rRected At1H induction. The available data suggest that it is during these fint IS hours of treatment that the neoplaslic event is flsed. The genetic data presented here also augr.t that even though the level of AHH plays a dom((t.M role in MCA- and HP-induced cancen, other genes art abo ef/eNint cancer wnt:eptibiliry. Immune competence could be another influencing (aclor. 1s addition, there probably are subtle dif- ferenees in the way the various strains met.bolae poycrclic aromatic hydro- catbats (PAH) even within Ihe "inducible" and 'noninducib{e" clusincalion. Studr of these diRerenees should yield valuabk information on the actual stepr invd.cd in the activation of PAII to their prosimal carcino`enic /orm. lhe hrft model srskm used hen pro.ides the t.nans to observe hydrocarbon me- tabolism and carcinotienesis In the &ame tiasue and thw should prove aduabk lor studying the tnechanism of tumor production by at least one class of chernL eal urtinofeas, the PAH. Roari. R. E. (AlkroMoloskd Asrsor(ret, /nr.) 1.: Freudewthal, R. 1. and lones, P. W. (cds.): rol)nrrl.ar Aromark Hydro- carbonr: CAewt4ny. Mt•r.boliswt, .nd C.rrinojernrsts. New Yort<: Raven Presa, 1976, rol. 1, pp. 139-151. Other n.pp.rts National Cancer Institute. Protw tM Department of Biochemical Oncoiogy, Microbiological Anociates, I.e., Sethesda, Md. ON 771E PROTEOI.YTIC INHISITURY EFFECT OF HUMAN FOETAL AND NEOPLASTIC T7SSUES 'fln Prokase Inhibitory activity of human fetal and neoplastic tistw:s was Mrdkd by tweant of the 11beM slide sandwich technique, a hislachemkal tech- npu. /or localizing BbrinolYsir inhibitors which uses flbrin r a substrate. Be- sides 12-22-..eek fetuses, their placentas and deeidua, the material esamiaed in- duded Mrea ovarian earcirwmas and metastatic tissue from the peritoneal cavity. On dides M.t covered by a layer of plasmirwgen-free Bbro6e.a and thtvmbirs. theta iecubated at 1' C and eovered again by a layer of urotina/e or human pl..min. the thrmnus, placenta and decidua consistently showed a suvng inhibilory effect on both plasmin and urokinase. while Bver, pancreas, adrenah. and spleen deenorsstrsled orny modente activity. Myocardium and re.al oortert rescted only weakly to nwderdey with urokinase and not at all with plasmin. The renal tnedulla, Mng. Momach. and aorta had no inhibitory effect. The ovarian cartinanas had a medium Inhibitory e8ed. but their peri- loned tnetastasn had nate. The hitherto unknown inhibitory activity of the th]rmr .trengthens the a.sumed connection between the /Wrinolytk and In+- muno{ogic .yssewn. lUa fael thM fetal h.ete. stomach, renal meduila, and aorta did wo1 displa7 iwAiMtory .cti.lt7 is wot considered conclusive of a lack of in- Mbibn i these tit.ucs /lowever, it is suue.Icd that the absence of proleo- lytic inhibitors in the metastscs might tefiect o morr aUresoive stage of tumot growth. Fornasari, P. M., PandolA, M. and Astedt, S. (K.Jfader, S.) Thrombosfs Resesc/i E:S29-S3fi, 1976. Other support: Swedish illedica) Research Council. From Ihe Departmcnt of Clinical Mediciae Adc.fo Ferratr, University of Pavia, Pavia. Italy; the Coagulation Laboratory, kTtp.rtmeM of Opthalmology and De- partment of lirnecolog1 and Ob•tclrics. University of Luaf, Allmanna Sjuk- huset, Mahnti, Sweden. ('LINICAL 11@MATOLOOiCAk. PROORESSION OF IIEREDITARY LYMPHGttAkCOMA IN RASBITS There Ia eotaiderabb diversity Iu dNa on the clinical progrnaion of ympho..rcana (1i.) botb betweew ad within species. He.e, hematoloBic pa- nrnelers were used to tNUdT 34 rs6bNs wilh herMitary ymphotancoma (/WAa) in order 1o determine W elLleai ~ropesaiow under controlled genetic eoadl- tiona. In these anirndn, d:at6ts in hesrro6,rawt erythropoietic cells followed a fairly well defined dinleal oarsr of nboul ons and a h.lt month's duration. Packed cell .ohnne, rott blood oepr+ (R11Cb) count and hemoglobin contew dl dropped. Osmotic frtqlitP i.ue..ed. Sased on these data, the apeculatioe is thN both twppesfow of ery6ropoeisia turd increased hetnoi7sis occur. Theo. Is no queslior4, howe.er, tltM both peripheral and bone rnanow granulocyln are deptesacd very early la Mo eewsa of ahe d'aease. probably quite sorne time befote the RSCs tue uRecMed. lt Is etMhw.led tlut the btal course of the ympho- aaroana, based on ehat>.a In tbe 6rasuloqr/a rather than on those in the Roca akvne, is perhaps r tsrudt r twiee aa bn6. 7ltese conclusions would be in accord with reports of nitsilar obsttrvatitms in tee cat and in humans. For eaampk, whik mattrow Ie.olsenteM Y/witiaM7 ras in Hodeekin's disease, a Coomba positive hraroytie awetwia b peseM in ib late Napa just as has been observed in the rabbit; and th. Mability, of the total kukocyte count observed here until very terminal Maon wetm teached aped with yet another report on Ilodgkin s disease. Fox, R. R., Norberg, R. P. aed Meler. N. The lo«inal o/ Hered/ry 67:376-I90, 1976. Other nrpports Natioral i.Milufsa of Health. Prom The lackson Laboratory,l/ar Harbor. Me. TRANSPLACP.NTAL CARCINOOENIC P.FFP,CTS OF COMB1NFrl TREATMEPfT OF ETHYLUREA AND SODIUM Nil R11 E IN RABBITS The Iranaplacental induction of primary tenal tumors by the adminisualioa of (<1hy1-1-uiUO.ourea (ENU) lo rabbits has been previously demonstrated. 19 1tl

-i1Thia paper now reports that the oral administration of ethylurea (EU) plus aodiurn nitrite (N.NO!) to rabbits pregnant 17-t9 days also induces primary renal tunwrs in the progeny with approsimately the same latency as tumura in- duoed by ENU. Neither EU nor NaNO, alone is sufficient for tumor inductinn; no tumors were induced in the one-year-old offspring of rabbits given EU (0/12) or N.NOi (0/1a) separalely. However, the combined treatment in- duoes tumors. The present esperimenlal results show that of 20 WFl/1 progeny that survived one month, sin developed primary renal tumors at a mean sge of 3.e±0.e nwnth.. In contrast 1o strain Wfl/l. AX/J progeny developed no tumor. (0/8) during the Arsl year of life frvrw EU plus N.NO=. This differ- eoce is probably due to a strain effect Alao, one of two surviving IIIVO/1 progeny developed a renat tumor at 1.25 nwoths of age. In al( Inslances, the ttrtwrs were renal tubular eysladerwrnas, cysladenocarcinomas, or nephrobtas- Ionrs, which appeared to develop within unaR renal cortical cysts. The data for stniw WH/1 were In accord with a previous report of primary renal tumors in- dutxd in progeny by the administralion of ENU to rabbits pregnant 10 days. Apparently, the combined treatment of rabbits with EU and N.NOs led to the formation In v/ro of ENU. Pot, R. R., Diwan, S. A. and Mekr. H. lownd o/ the Navbwa/ Cwrer hurUrre S9( 2):127-I29, 1977. OtAer eai' prtr National Cancer Institute. Public Health Service Division of Rese.reh Resources and Hyccl Inc. From The lackson lahoratory, Bar Ilarbor, Me. OENET7C DIFFFRENCFS IN THP. INDUCTION OF COLORP.CTAI- TVMORS BY 1,2-DIMETHYLHYDRAZINE IN INBRED MICP_ The symmetrical cornpound, 1,2dimethylhydrarine (DMH) Is one of the tnoN potenM and reliable carcinogens foe the induction in rodents of colorectal Itrnors, which aro histologically similar to the ones In man. While several aRenb have been implicated in the devekopmeM of these tumors in humans and animals, environmental factors have been suggested as the major determinants: tlr susoeptibility to spontaneous and induced eobroctal tumors is also thought to be governed by hercd". This Arst report on a systematic study of the role of kenetic factors is the indultion of these tumas in mice and- its associated biochemical and immunoloak tnechanisms, shows that se.erd of the inbred strains (or genotype.) are differentially susceptible to the devetopment of DMH- Induoed eolorectal tumors. When AKR//, SWR/1, P/1, CS7B1-/61, and OR tnkr were treated once a s.eek for 20 weeks with 15 mg DMH/kg body wei`ht, ooloretiyd ade+wmr or welldiRerentiated adenocatcinomas were found In fl)9L of the SWR/l, 90% of the P/1, and.alf, of the cs7BV61 mice that survived 22 or rnore weeks after the Arst injection. None were observed in AKR/1 mice. In whkh, however. the incidence of kukemias was comnan. While almost aM of the OR mice developed anat squamous cell earcinoma+, this type of /umor was not found in any of the CS781./6) animal.. The SWRIJ mice dereh.ped kukemias and putewmary adcrwrnas in addition to the colorectal tumor+. Mul- tipk tumon of diverse types were also common in P/1 mice. lheae resulls sug- kest thal the host ,kenotype oe• nquse strain ia crucial in determining the dif- ferential response to DMI(-induoed c.rcinoAenayia. Diwan, B. L., Meler, )f. and Blacksnatt. K-1? lorrna/ o/ the Neriond Cancer Iwrt)trte 39(2) :133-1Sts, 1977. Ot6er support: Leukemia Society of Meerrca, Inc. From Meby (aboratories, Ine., SpringAeld, Va. and The lackson Laboratory, Bar Harbor, Me. (lEN(rllC DIITERENCES Ihi NENZO{cr/PYRENE CARCIN(X)1?NIC INDEX IN VIVO AND IN MOI;SECYTOCHROME P,ISO-:dED1A7ED BENZO/a/PYRENE METABOlJ7E BINDINO TO DNA IN VITRO f ertain polycyclic aromatic hydroearbo.a indutx Ihe de wovo synthesis of cytochrome Prd30 In resporrive animals ud increase the activities of at least ten mictosomal nwnooslAewaaes InchsdieA aryl hydrocarbon hydrosylase, the enzyme system know~w to metabolite benso(e/pyrsne (BP). In the study pre.ented here. BP was adminislerrod to different subNnes of the inbred mouse strains CIH. C37BIJ6 and flBA/2, and column chromatography was used to seek a correlation between Ihe qwnAitative change in the site or shape ol any peak formed In vitro and Mnqr formation in .iro. Nine peaks, indicating BP metabolites bound Jn vitro /o DNA swckoaides, were reproducibly identified. When either the C3H or CS7BL/6 strain was eompared with the DBA/2 slrain, a positive general correlation wp fou.d between the carcinogenic index In vivo and each of three determiuatios is vttro: 1he size of light of the nine peaks. the hepatk aryl hydrocarbon hydroaylae activity and the total hepatic cylo- ehrorne P450 content. Peaks D. E. H, and I demonstraled relative differences among the three straim Ihat were In Ihe suune direction as the carcinogenic indea in vitro. Ilovrerer, when C7H Aioa were compared with C57BIJ6 mice, no quantitative eorrelatiow waa found bNween the carcinogenic inde and any of the three !n vitro n+ea+wemt.b. Hena, the total quantity of nuckoside-BP rnetabofiles in each of the alee peaka was not necessarily associated with bio- logical activity (l.e., eanoer bs Hwl, and aq statistically significant relationship was shown to esist between BPdeitiated tunwtilienesis Gn vlvo and the nucko- sWe-BP melabolNes generdcd /n sams. Nebert, D. W., Boobis, A. R., Yaji, H., lerina, D. M., apd Kouri, R. P. (Mkroblologkd Associ'Nwes. Inc.) ln: lallow. D. l., Koesis, 1. 1., Snyder, R. and Vainio, If. (eds ): Biolosl.d Reactive )nternrrdleren, New York: Plenum Press, 1977, pp. 125-145. Otbee sMppHr National Cancer Institute. From the Sections on PharmacokenNin and Molecular Teratology and O.ida-. tion Mechanisms, National Instilutes of Itealth, Bcthesda- Md, and the Ik- parlment of Biochemical ()neolop, Mkrpbiological Arsociates, Inc., Bethcsda, Md. I 20 21

7-MFTIIYL('HOLANTIIRENE-INDl1CF.D MONOOXYOENASt? (O-DEETHYLATION) ACTIVITY OF HUMAN LYMPHOCYTFS la th-s study, a dirtct fhrorescence assay for O-deethylation of ethosyre- uoru/lo was used to quanlitate mised-funclion oaidase activity in miloten-acti- vated human lymphocytes. Whik etho.yresorvlM Odeethylase .divity r:m6ed (rom low to nondetectable In noninduced, milogen-activaled celb, it was read- Yy observed In )-methykholanthrene-ind.ced, mitogen-activsted lympho:ytes. Results showed that the enryme activity was 4pendcnt on ast.y lime, number of ymphocytes and the presrnet of te1uoed 1ieiAinamide .denine dinucwotide phosplrle. It was also reproducibly delected whett duplicate samples of ~Aood from ons individual wcre cultured and assayed at the same time, hot quite 9.riabk when these procedures wen done on dilferent days. Since the assay preaeo/ed her. is direct (requirirK oo estraction Neya). sensitive and amenable to Womation, and ainee ethoatyre.o.uliw may be specifically metabolin d by only cytochron.e P-IIt1, this chemical may ser.r as an eAadve alternate sub- Nrsita to benzo(.lpyrene for dekrmininR mbted-frnclion osidase activity is humao tisus. turt., M. D., Mayer, R. T. asd Kouri, R. E. (Mkrobiolotkd Associ.les, lwc.) Gncer Rex.rrA )7:164-46), 1977. Oth.r a.rP.rf r National Cancer Instilute- Prom the Sioehemislry Dep.r(ment, University of Te:aa Health Science Center. D.Ras, dre United S1nes Department of Agriculture Research Serrice, College Statio., Tea., and the 1)epartment o( Biochemical Oncobp, Microbiob6ical As.oeiales, loc., Sethesda. Md. 11. The Re,pirewtory System BRONCHIAL CYTOLOOIC CHANOES DURINO CARDIOPULMONARY BYPASS: IRON TRANSPORT BY ItIS71OCYTES IN LOW FLOW STATES Although In previous studies more iron-l.den histiocyles ha.e been ser. 1. (1) Me tr.clroobronchW secretions of patients in hcrnorths6ic shock and (2) lh. hu+p of rab bled b hemorrhagic shock thaw in their n:spectire cor- tespordinR cowtrob, so esplawalion for these obxr.ations wr ever established. In this studythe bronchial set:retions of 12 open-heart sur=ery p.tknts under ardioprdma+ary bypa+a wen awyed in specimens obtained (1) bnmediately after onset of aaeslhesia: (2) during eatracorpoteal circulatioa: and O) alter lermin.tion of cardiopulmonary bypass. While in an earlier study the mean per- oratalle of iron laden hiatiocyte. (PIIFe) of 10 patients In hemorrhagic shock waa 12.1±1.4, here the p11Fa rvae from 13.6t60 after Intubatbn to 19.6t6.t atter ooe hour on bypas with virtually arrested pulmonary blood fiow, .and remained close lo the letter . ~hro one hour ofler pulmonary circulation was re- stored. All lhese Rndinp droa' th.l o sluggish or arrested pulmonary circulation allows large numbers of iron-tadea bistiocytes to appear in the tracheobronchial tnee. During cardiopulmonarr brp.fs. only the pulmonary circulation wflers, whik'ehe systemic blood eow is also reduced in shock. It seems, therefore, that PHFe is inversely proportiont+) to tltt pulmonary blood Ilov,, and that hypoper- fusioe, accumulation of mNa(roNA¢c aed t.Yitrg pH at the lissue level probably account for the pHFe dndiep. Friedman-Mor, L, C/i.fon, I., ZLrnoorf, H., wd (orkin, L R. The /ourwd o/ Trauma 16(10) •t1SJ18, 1976. OfRer ao'r..Ir U. S. Publk HeaaA Service. From the Ikpartment of Anertiwiplogy, New York U.sivenily Medical Center, New York, and the Departm:a/ of Anesthesiology. Albert Einstee College of Medicine, lhe Srona, N. Y. TISSUE PRINTS FOR STUDIES ON IRON, PAT, AND METHYL-METHACRYIATE (MMA) UPTAKE BY Ii1ST1OCYfES In this preliminary report b 11w edilors, the authors describe Iheir reta- lively suecessful use of tiswe prints ln.ltad of paraffin sections for various hslochemical Mudies. Based on their sroed for a method bolh cheaper and faster than the usual hislologic sections, they have obtained escelknt lissue prints from rat and dog traehe., hrp, kidney, spleen, liver, lhymus, and in- lestines. The technique essentially eo.shled of sequeoliaNy psessin6 areas of the evenly cut and b/otteA organ uwtTaa .pi.st a series of microscopic slides, and immediately Gaiat the priM drus obtained with a water-soluble spray /laalire. These were tlree stained by /h. Pap..icolwu, Prwsiarn blue or Sudan IV methods. In otder 1o bs satil.bls for I/lietaaopr, however, this type of ma- laial mus/ be composed of ealrathM, preferaby, nwnocellular, layers which faciMale cotrrting, .nd snwt faiWdly reproduce 1he configuration of the original lissue. While ,udr 1Mwte pri.b should not invariably replace hisloloRic sections, which stiN best represerM We actual tirue slruclure, they do have a place in laboratory and cYak.l silwtitw where a fast, reasonably accurate and ineapensi.e specimen is deaired Friedman-Mor, L, CA.lon. L, Orkia, L R., a.d Turndorf, H. Acr. Cyrolosk. 21( 2):1 d4-1 K, 1977. Frorn the Departmcnts of Anesthesiolop, New York University Medical Center. New York. and IM ARbert Eloaleio College of Medicine, The 8rona, N. Y. TNE INTERACI7ON OF Q-1-ANTTTRYPSIN W1T11 SrJLllel.8 AND SEPHAROSE-SOUND ELASTASE - AAInIty ehrorn.topaphy .nd pdy.crllamide gel ekctrophoresis in the ptetencie and absence of sodium dodtcyl sulfate were used to e.amine the 21 22

prvducts of a-l-antitrypsin and elastase interaction. Five substances can be identifkd by gel electrophoresis. Two of these are e-l-antitrypsinelastase ccxn- pkses with molecular wei6hts of 7),R00 and 3lt.)00 dalton units. Two others ate identital to the trajments of .-1-antitrypsin which are removable from a Sepharose-bound elastase column immediately after its application to ite col- umn. The larger of these components weighs about 50.000 dallons, reacis with .-1-aMitrypsin anliserum and is not aa eniyme inhibitor. Amino acid asalria shows that these two produets together an similar in composition to a-l-anti- trypsin. The fifth product is probably a fradrtent of .-I-antilrypsin missinil from the low molecular weight oontpkx. The elaaast can be separated trorn a-1- .utitrypsin In the complex by twild nrdoophilie attack. Small quantities of the inhibilor ean be ehrted frorw the elastass aRi.ity column by phenyl-methane sulfonrl Ihsoride. The data suRjest that elaqase may split three bonds on .-I- antilrypsir.. One such attack cleaves the krhibitor iNO two inactive frai.nenb while the other two produoa oowtpkses whose combined molecular wright is lower thu that of the sum of the react..ts. • Lo, T. N.. CaArn. A. S. and lames. H. L IiocAin.ka er AbpJiyrka Acaa 433:344-136, 1976. O/Aer aappartr National Ileart and Lun6lrtitute. From the Dep.rtment of Medicine. San Francisco Qeneral Hospital; tt-e Pul- nsonary Specialiud Cemer of Research. and the Cardiovascular Research In- atitute, Univetsity ol California. San Francaco; sod the Department of Medi- eiee, Temple University Health Sciences ('enier. Philadelphia. PREVAI.ENCE OF AI.PHA 1-ANTITRYPSIN PI TYPES AMONO NEWBORN INFANYS OF DIFFERENT E7/1NIC BACKOROUNDS Crossed lnwnunoeketrophoresis (Fagerhol-Laurell) was used to study seta fran 1.010 umbilical cotda In a systematic attempt to screen newborn inlauts for abnormal phenotypes of alpha-l-antitrypsin (a-I-AT) whose presence may be associated wilh potentidly lethal hepatic disease early in life and with ero- phTsema in early adulthood. A variant of the normal M patterw which is rare- ly found in later life was commonly detected in the neonates. Tbis "aep" p.t- tern, characterited by a shift of the relative amounts of peotein in the major peaks of the M patless. was fooad regardledr of taoe in 96% of newborns but in only 9.9% of infanb one nwnth 1o two yean of age aed in 18% of childree two to less years old. Maiot ethnic diRerences. howevet, were noted in the prevalenon.f o( abnormal phenotypes for this eayme Inhibitor. The oon-M phenotypes were sipubcantly more prevaknt in I/ispanic (11.00% ) than ie black (2.92%) or white (3.63%) intanb. The MS phenotype was found in 6.7% of the Hispank, 1.3% of the black and 3.9% of the white group. lbe MZ phenotype was found in 2.8. 0.7 and 1.0%, respectively. When M and non-M infanb were compated. tnean vdues of .-1-AT were higher in M than M nas-M in(anls in dl three poups aed significantly so in fhe white and llis- panie {roups. Ilowever, deeressed kvels of .-2-mscroRlobslin In M oompared with non M Inlanb were statistically sigmllcant lor all thnce troupa. lbese se- sults clearly demonstrate the iofiuence of ethnicity on the distribution of a-I- AT Pi phenotype4 amoo# newborso infants. Eranr, y. E. et d. The lournd o/ Pediaric190(4):621-624, 1977. Other support: Brooklyn Lung Association. From the Department of P.dialtia, lewistt Hospital and Medical Center of tooklyn, Brooklyn, N. Y. 1N1't.Ui?N('E Of' A('tfl E PXt"O6URE TO CIQAREITE SMOKI! ON THP. ALVEULAR MACdA?G.AOB SYSTEM Techniques for QuaNitatin6:.eR deposition of bacteria and alveolar macro- phake harvest were used in +,is study of (he response of the alveolar macro- pAaee system eo the inhalation of viable bacteria and cigarette smoke. 71" studies were performed wtde:• bwl eowd'Niona, dter the inhalation of cigarette nnoke, and after eapowre b baclerial aeroaots and cigarette smoke in sequence. Macrophage yields were ineeeased 1.1, 1.2 and 1.5 times hasal levels by es- posure Io cigarette smoke ak.wa for one, two and four hours, respectively. The inhalation of SrapArlororcrs ern.n (or 30 minWes induced a 2.4-fold increase in macrophage numbers. Within iS minuW a/ter bacterial deposition, macro- phase yields dropped ll%, but elevated kvdt were restored at 30 minules and then maintained for the remainder of the four-hour test period. Cigarette smoke introduced immediately after baclerid challenge and maintained lor up•to four hours did not aller tha m.esoph.6e se.ponre provoked by pulmonary deposi- tion of staphylococci. lo additioq, smoke inhalation had no eftect on the « 1- lular characleristics of hnq har.ests or on the viability of alveolar macrophages. Grerwert, 1. 1. TRe'lorrwal o/ Laboraror7.w/ Gbs4+d dlydkJwe t9(6) :1213-1224, 1977. From the Queens Hospi'tal Cenler AtlWatiaa of Lons Island /ewish-Ilillsids Medical Center. ()ueero, N. Y. i AIRWAY RESPONSE TO SHORT-TERM INHALATION OP TOBACCO SMOKE. LACK OF RACIAL DIFFERENCES Scattered studies imply lhal b/ack snwken develop neither the chanees ia pulmonary funetient usually seeu in while smoken not as much chroruc ob- strvctive pulmonary diseae, although their smoking habits are simdar. Since lhia suggests that bl.ck individuals may be "ptWeeted" from the consequences of smoking which lead to deterioration of pulmonary lunction, it is possibla 24 25

that they respond differently to cigarette smoke inhalation. It has already bees dwws that hereditary (acton art estremeiy important in the palhoRenesis of chronic obstructive pulmonary dixax associated with smoking. In spite of the lack of evidence linking the response to short-term inhalation of cigarette smoke to the long-term conscQuences of unokint, this report e.amines the air- way ndponsea to short tenn inhalation of cigarette smoke in healthy black .ub- jecta. Ttwr.ck gas .olume, airway resiNance, maximum espiratory flow rates, and elosin6 volume were measured is 12 headthy blrck volunteers befcre and after smokinA a cigarette. A siptiAcasl re&ctios in airway conductance and midexpiratory flow rate was found ./Nr .ewkieA. Since these results ue simi- lar to those previously obaer.ed in w)ri•e arbjecK the authors concluk that aJrway response to ahort-1mn inhalNios of cigarette smoke Is indeperskM of rsm. StiM uskows• however, is whether the annaieW bronchoconslriction caused by snwking eontribnes Is aq maamer b the development of chronic cbatrue- tl.e Pda.o.ar7 die.se. T..eirs d. Sllvti A. M. asd H.n.ad, P. CAsr 71(2):1)9-141, 1977. Pras OtorBNows Unl.ank7 Scboola of Medicine a.d Destistr7, Washirr6tos, D. G THB EFFECT ON P.XPIRATORY FLOW RATES OF SMOKING THREE CIOARETTES IN RAPID SUCCESSION 1s t5i. Mudy, ses healthy volunteers (ail heavy srnoken) smokei three ciprettea at the rNe of tes puffs/Ave rninutes, wilh Ave misutes for mea+ure- arta, between cigarettes. Maximal and partial espiratory flow rates were noted before srnokinA, after smoki.8 each o/ the three ciprettes, and one hoau after tnakis8 the last cigarette. Frorn the partid spiroAram, forced instanuercar /ow wr resd after 30 peoeest (PFEFSO%) and 75 percent (PFEF7'%) of the origisal forced vital eap.city (FVC), obtained during the initial screening of dw subject. Subsequently. /ve tnaoeuven to determine the forced eapiratory fiow were performed from total lung upaciy (TLC). Conventiona, spiro- metrie data sbo..ed sipiiAcant changes in mean espiratory flows; a response that was rnuimd atter the Ars1 ciAarctte. Changes In the partial e.piratory Aow rtttes, PPEF73% and PFEFS0IG, were almost three times higher tbas the ehaqea is matimal espirNory flow Narted from TLC. These results show that s.n.wcmeM of partial ntpintory Ao.r might be a far mae useful irdicalor ot Irritant e4ecb on airwats than .nd7sis of the maximal espirator7 Aow- volune carre. In tact, the authors suggest here that partial e:piratory flow atrt•ea be used aa a luo6/rrllant acreeninA 1est. H.noeA. r. sad Tavtira ds Silva. A. M. Clltrr'f2(3):61O6f1. 1977. Pro.w the tlrp.rtn.rnes of Mrsrolney and Reorhy.ice and of Medicine. (Jtorde- ywn Usr...ntt Stlm.4% of Medaane .nJ 11cotutry. Washington. 1) ('. THE EFFECT OF PROLACTIN ON THE ",.EC/T11fN CON7 ENT OF FETAL RABBIT LUNO Lung surfactant defkieac! b/6s prirsar7 causative factor in the respiratory distress syndrome of the newbors and in probably due to immaturity of the biochemical pathways rerpuosibk [or th's phospholipid's synthesis. A number of hormones, includiot oohiooNeruida, thyroxin and probably estrokens. in- Auenoe this process. The k-a-s.ewd, however, may act Indirectly through the stimulation of fetal prot.ct a secretion .ad, actudly, fetal prolactin kvels have been found to rise sharply before as iscnxx in pu:monary aurfactant kvcls. TKs study, 1Aerefore, seetn b de/ertnina tl[r effect of prolactia administrat'an on the pfwspholipid kveM is fetd rabbit lunp. After two dars, intramusculu injection of ovine prolaetio (I ta8) Into 2Lday rabbit tetuaa did indeed in- crease the total lung pho.{'LoYp',d ..d IedehM consent by • statistically highly aigni/kant (P<oAol ) amewt oo oorwp.red to the eoMrol group. Dip.lmitoyl- kcithin, the chief swf.es aMiw pwtpsest o/ hra8 watactal, constituted 67% of the IuwA lecithin fraclka h tsn trealed fetuaa an opposed to 44% of the oornparabk fractios in dK oosUrol.. No et.tistieally significant diRerenoes in body weight and ks6th. M>t weiBht,lw8 so body weight ratio, or DNA, pro- leis and water corMest were fo..d betwees the treated and control fetusn. Be- fore the e0ed of prolaetiti .drsisMrNio. on fetal hnu sur(actant levels can be fully evaluated, however, the pApsiologie /etal serwn prolactin kveb must be established. Abo to be asanered It whether prol.ctin bids as specifically to the fetal lung as N does b a r4.taba of other tiouea, and whether it dfects eke- trolyte aeeretios by the dvtolar oe1M. (A direct relationship between potassium •ad sur(actant seeretios kNe trscht.l /lrid hr been shown in fetal lambs.) Neverthelesu, the reaults obtained here suggest the possibility that prolactin is a phYsiologie trigger /ot Mu[aetast suLLuration, in support of indirect evidence .iready compiled. HanrosA. M. sd Naeroih, P. The lorrnd of CBnkd /wsmlraHew l9:1002-1005, 1977. Ot6e..orprtr National Heart, Lsr%.ad Blood Institute. From the Department of Physiology and Biophy.ics, Georgetown Univenity Schools of Medicine and Destistn, WashinAton, D. C. INCREASE IN TRACHEAL GLYCOPROTP.IN SYNTI/ISIS WITH ESTROGEN ADMINISTRATION Ovarioctomised nts, 12S-1S0 B in wei6ht, were used in this Itempt to determine whether estrogen .drwMiMrNion causes any change in glycopoWein synthesis in the rat trachea. Starting two weeks a/ter operation• the rats were given in}'~ iom of 23.0p~ of 17/1-tatr.diol for eight days and were sacrilked on the ninth day. Af1er a)-hr. Irrcubation period with /r'C) 6tucosamine. tracheal epithelial (ractions from treated animaia showed a 20% increase in uptake of radioactiviy into acid-insolubk material. 7be concentrstion of tree minvwpars was not affected by estroges administralioa. In view of previous dala ahowing 27 26

that D-illuoosamine is mostly incorporated into Rlycoprotein by trachea, and of the prexnt data sho.ring increased uptake of 114CI tlucosamine in tracheal epitheliwnn without any debctabk alteration In aminowsar pools, the authors conclude that estrogen can cause an increase in alycoprolein synthesis in air- way epithelium as has been pre:wusly shown in the female genital orgiins. Yeaser. H., lr., Shechter. Y. and H.nwrh. M. rroreed/np of the Society for Eipe.lnsrnt.l eidoty and Medkine 133:113- 117, 1977. OtAer.orrsrtr Aenerica. Lung Association. Prom tha Departmenu of Medicine and Physiolopr and Biophysics. (7eorge- Io... Uni.Krsity School of Medicine, Washington, D. C. OLYCOPROTEIN SP-t:'RETION BY TRACHEAL FXPLAPTi'S CULTURED FROM RATS EXPOSED TO OZONE While ozone is known to be an important atmospheric pollutant, li:tk re- search haa been done so far on Its biochemical eRecb on airway tiswse tnetabo- litrts. In this study o/ the effects of ozone, tracheal explants from rats etposed b 0.8 ppm (1.9 mg/m') of or.one eight hours per day for one to 90 days were kotubded in culture with ghrco.amine labeled with 1rC or'H. Compared with tracheaa /roen eontrol rats that had breathed only ffltered air under otherwise idealkal eorditiom, these explants demonstrated a decreased rate of slyco- protein secretion for exposure Intervals of as long as one week, folbwN by a tebound 1o a. Increased rate o( glycoprotein secretion for at least 12 weeks of continued eapowrre 1o ozone. DNailed study of the behavior of labekd glyco- proteins from the culture medium by chromatography on odumns of HioOd A-ISOm d~rmor1trated that the ratio of the bw to high molecular weight peaks 1.peued wkea there wr an Increased rate of SI)rooproteis secrelioo. 'tbs is IM Arsl teport of a direct biocAanicd effect iedviced by omne on airway me- t.bolist.. Tht .uthors. b.aittB their aswmptkaas on several Indirect lines •af evi- Iesc+n, toilsest that the cbaaBes in gIycoproMe necre/ory rate /n vitro mav have a tuwctknnal (enzymatic) be.M rather than aw teutomic (sttnctwal) one. I.e., be utated by tevenibk chanBes in enayme ooncentr.tiom rather than by eeBu- I.r hnerplasi.. 1/ this hypothai. Is true, it offen a promising new concept to be ea.plored in relation to possible therapy of diasascs Involvin6 bypenet retion of teucve withln large .irw.ys. Lask 1. A., /enninp, M. D., Sehwartsy L W. and Croa. C. E. Anre.kw Re.Iew of Retph+.tary Diseau 116(1) •693-70), 1977. OtAar.r/r..tr National Institutcs of Health. P.nvironmental Prohxtion A6ency, and PnerOrY Reaearch awd Developmrnt Administration. From the ('allfoeni. Priw.N. Research ('enler and the [kpartmenl of Internal Medicine. Univenwy o1 C'drorai,a, Davrs. I CHROMATE INHtBt17ON OF METADDLISM BY RAT TRACHEAL EXPLANTS Using sensitive biochemical lecbniques available in their laboratory, the present authors examined the tracheal e:pla.t model as  method for deter- mining threshhold levels of chromate-ioduced toxicity. For these tesu, rat tracheal eaplanu were Incubated in tisue culture medium containing various eoucenlrations of Na*CrOs. There was a boae-eelaled inhibition of mucus tlyco- protein secretion by the atplanb at all concentrations of Na,CrO, evaluated betwtee O.OI mM .nd 2•16mM. Rou of amount of slyooprolein secreted rer.us log of chrornate concentration suggested tMt there were two types of inhibition oecurring, one of which wat only observed at higher (>O.3 mM) conccotra- tiorn of NsCrO.. Also, et eo.ceNratiom of 0.05 mM and above, Inhibition of precursor (D-I•111-tluoo..mia.) ttWake and coocurrent morphologic damage in the epithelium of the tr.clred slices wen obeervrd. The histopathologic end- inp inchdcd damage to c9i.:ed eells, severe epilhelia) desQu.matron and severe cell nuclear pykrasis. The rett.#.a preaetNed i. Ihs paper show an excellent cor- relation between the oonam(raion of thromate required to elicit moryholoilical- 1y, observ.bk damage s(1 tlre oonomaralions at whicb tlucvaamine uptake by tracheal dioea is siprfica-Al7 iahibiled. They also suggest a hitherto unreoo6- nited mode of actiow of eiror.Mn io., l.e., iehibition of Rlycoprotein secretion at concentrations IhN do got elidt arorpAolotie damage. It seems, therefore, that deteretination of glyooptotweitn tucteiiow by tracheal explants oQen a nessi- tive, quantitative teehniqrnr tor attsd7inR the eQecu of soluble air and water pollutants on airway metr.baYsts. Lrt, /. A. N.l. (Cnus:, C. E.) L.Boraory InvesdNtlesr )7()):27i-279. 1977. Otber nrrpr•tr Fn.io.o..td Prokeetba Agency. From tha California PritaaM Research Cesler, University of Caliloroia, Davis. LACK OF CORRE.I.ATION BL*iWEEN OLUTATHIONE PEROXIDASE ACIIVITIES AND SU9CEPTIBILff'Y TO !is TOXICIIY IN RAT LUNGS The suggestion that 6MadAone (OSH) peroaidase is potentially impor- tant in the hing anlioaidant de(etta: taecAanism stems from two significant types of observations: (1) after rrsposws b various types of o.idanta, cytosoiic frac- uwss detived from lung AomolienNa oodein hiRher kveb o( OSli pero.idasc, perhaps induced by the otiJanl oe products of oxidation processes; (2) dietary selenium defickac7, which deerrtra OSH peroaidaae activity in lung tissue by as much tr 80%. appean to enhance hrad tissue susceptibility to hypero,ia and 1o paraquat, a herbicide whow toxic effects upon the lung may be cained by pro•oaidant mechanisms. le order to further /est the 3hypahesis that lung (lSH peroaidw activity reflects the eapacities of the pulmonary antioxidant dclense system. 0, loaicity was studkd in rw under eondilions whereby the dekteriow effects of exposure to 90% Os at atmospheric pressure for three to four days could be modi8ed by administration of anli-infiammatory qents. the dala .ug- rt( that in this eaperlmeMal tnode/ of U, to.icity there is sa consistent rda- tionship between OSH peroaidase activity and protection; nor is there any ap- S 2S 29

pareat co.relation betwcen such enzyme activity and the susceptibility of lung tirue to O.-induced damage. 71+ese rrsults, ho..ever, do show that prior aad/or ooncomitant admini.tratioa of anti-infi.mmatory compounds may rtodify hrel ousocptibtliq to o.idant Injury. It is concluded tha1, at least in this one arodd of oxidaet-induud lung danuge, susceptibility to oxidant injury does not appear related to the OSH perosidase activity in lung homokeoates. Cnw, C. E. and Last. I. A. Rtsr/eA Corwwrnk.rforv M Chrwdcd r.Aofop and lA.rm.cobn 17()): 417-416. 1977. t0th., ar'r.rfr U. S. Public Health Senios. Ftaw the Dep.rtmeet of Istenul Medicine, School of Medicine and ('ali[ornla Pri.uM Research CeNcr, University ol California. Davi.. PULMONARY L'NDOTHP-L1AL CELLS 7hb esltyr.ive re.ie.e surnnar(m the aoerespiralory fundions of the put- taa..ry endwhclial eelb. While they pos.rw many of the same proper,:es n the oonWwrors endothelium of other vascular bed., the eelb are unique in their strsteilic pe.itiow within the circulatory system. They are at the last point where 1be composition of arterial blood can be nadified, which is critical for both blood psa and nonvolatile solutes such as hormones. The pulmonary endo- dielial cells may aiso be unioue for what they do not do. Thu., perhaps mw. than asy other or6an. the lunp murt allow the unhindered passage of hormones rerJuired by peripheral tiaues. In fact, they do not degrade an6iotemins 11 and 111, asd they probably do not cku insulin to any si6nificant extent o` eliminate olytoci., .uopreasin. epinephrine, histamine, or substance P. Although MiY relaN.ely little is knowt about the ability of pulmonary endothelial cells to syutbesiaa brn+aws or so modify preformed oew or prolw.ntooes, the peculiar ph7sblopq of the lungs suaests that there may be unusual means of influencing ehe net raults of the metabolic activides of these cells. Pulmonary blood flow e.d /bw distribution are eotrepka functions of many (actms, such as posture, eaercise, airway patency, inhalantr. and others, and it would not be surprisin6 so tlnA dut 1br hormond composition of uwi.l blood is closely related so the o.enM perfoenueee of (he luup thennelva. The role of redwhelia/ cells in prooesaln6 chylankwro and iw clearing free fatt7 acids. prvsla6landins and re- lased nubstaeoea, sr well as in synthesizing prostagludirr, 1n oWlieed. Tlreir ef- ted on oo.pdatioa and /Ibrlnol7sis through the conversion of plasmino6ea so pjrmie aed the activity of thrornlwplastin and other (scion .re also discussed. r are Ihe selective procea+i.it of biogenic aeimes, and d+e metabolism of the .udeotides. kieina and angiourrins. Ryan, I. W. a.d Ryw, U. S. reAen.Now PrerreMngs 36(t)) :268)-2691, 1977. Otl6or s.'P.rtr U. S. Public Health Servia, the Hartford Foundation, and 1M American He.rt Aroclatios. Prwn tbe Dep.rtmenl of Medkine. University of Miami School of Medicine. Miami, Fla ALVEOLAR CIEARANCE AND'iliE ROLE OP THE PULMONARY LYMPHATICS An attempt is made le tyis re.kw paper b develop a synoptic schert» of the various alveolar ckarweob mecbr.isma, with special emphasis on the put- monary lymphatic system. Aarortg t`a 295 literature references cited here, ao elaborate and synthelitarg ekxMoa microscopy studies were found concerning the multiple cellular and moephologie (atlws tbat regulate alveolar clearance. Although a eomprefien.ivr .i'ew of ete.rtaea, wroehanisnta mi6ht be drawn up based on the compilation of :ortsutly e>tisliq studies and hppotbc.es, these In- vestiptors (using the rewdb of their dNailed etperiarental electron microscopy - studies investiptin6 the various a.peeta of alveolar clearance wbiM uain6 carboo and fertitia aa tracen, and a e.i" NuQy of the literature) ouUir.e Ihe follow- ing synoptic scheree of alwaLr tiearaaea involving: (1) the tracheobronchid trea with the mucociliary eeealMor awd with e.doeylods and difiestioe by non- ciliated broechiot.. spitheNal x#.: (2) eadoeyto.is and di6eniow by the a1- veolar macrophaM which kaw 6Se alwolr lumen via the airways; (3) enda eylosi. and digestion by the ceutKiphMie grawulocTtes, which leave the alveolar Iwnew via lhe akwaps: (4) ;+halloeylow by the large alveolar (type 11) epi- thelia( cells: (5) eedocyloda and .ilher digestioa or transcellular transport to the iMentiliwn by smdl alreolar epilbelid oeMr (6) the pulmonary Mood capillaries and micropinocylo.is and either digestion or cytopempsis by the blood capillary endotheN.t eupa: (7) the pulmonary lymphatics with the open intercellular endotheB.l ju.eoiona (rwais road) and endocytosis and digestion (or eytopempsis7) by the lyrwphatic eadoMeli.l oelb at Ihe luminal or abiumi- nal surface, and (S) etadoryLosi and digestion by the interstitial macropha6es, which leave the lungs via khe lymphatics. Fin.My, the relative Importance of Ihese various clearance ways aid clearance snechanams is undoubtedly depen- dent in each particular Insta.os oo t!a phYsioochetnical and biologic character- btio of the contaminating particles. The aolubilit7 of the inhakd particlrs M apparently of paramount irnportattoe In thia respect because the wk played by particle sdabilizatios ponAly prs.idn an aeawer to the intriguing problem of 1M variability of the de.r..a respoaM on studying diRerent Inhaled or in- stilled materials. I Lrwtryn., !. A(. and Dae+t, l. H. Anreric.n Rer4w o/ Respiratory D4ter 1 t S(1) :62S-6e1, 1977. Odher nrprorfr NationadFoub.oor Welensth.ppelijk Onderwck (9el6ium). Fnom the Laboratory of Padrolop and Hidology, Katholieke Universiteit te Leuvee School of Mediclne. Leu.ea, delsium. NEUROEPI'il1EL1AL BODIES: IMPLICATIONS FOR LUNO FUNCtION Neurocpilhelial bodies, the autlar's tentative name for certain particular cellular corpu.ck., have been well idrMUkd (n an Integrated mkroseopical. hi.toehemical, ullrutructura/, and microspeetrographic Investigation. 7hese neuroepithelial bodies (NE_0.), which occur widely in the mammalian lung, are m 30

intr.em.coaaty located. innenated and coatain denx-cored cellular co4puscks. Scrial aections rc.eal the ultrWructure of the innervalion of these corpuscks to be very compkx, since eumeroua unmyclinated nerve fibers are prdrnt and various ty}+es of moryholo6ically aRerent-like and efferetN-like nerve endings can be observed. The cytoplasm of the NEBs reacb positively to Sok:s lead benuloaplie stain for the identilication of endocrine celb secreting pol•tpeptide hormones or amines, and the uncorrected as well as the corrected valuts of the Ruorestxnce emitted by these eslls wtaich the spectral characteristics of pure auobnie. When subjedcd to sarioar dedees of hypoaia, the Golgi ,:otnpiex 1a the NESa of neonatal rabbib beoorwes temarkaby active. producieg many ptognrwkr. In a Ouick wrmm.tiow, the anthor qstes that NESs prvbaMy pos- sw .erioua aecretory functionr, eodt.ialing not only vasomotion but .dio other brwrnhial sad bronchiolar hwrctitnn, twcA as muco..l secrNion, smooth muscle /oea a.d (nte6ration of the acti.itin of the ou/monary unillobuks. L..wer7av. 1. M. Ie: Moore, R. D. (td.): Lrns Mrwalow .nl r6e herewrlow of Hyaflne MenrM.nr Dtruasr, Report of Ihe Se.aMiet6 Raaa t'.,onference on Pediatric Re- searek Cohrnbru. Ohio: Rou laboratorie., 1976. pp. 16-21. OA.r s.pp.rtr NubnadFoods.oor WtletuchappelijkOnder:rxk Ptar tbe Department of Patholop. Katholieke Uni.ersheie it i.euren„ l.euvee, •d6its.. IN712AT MONARY NEUROPPfTtIPL1AL BODIES IN NEWBORN RABBITS. OF HYPOXIA, HYPF.ROXIA, HYPERCAPNIA, NICOTINE. RESERPINI; L.DOPA AND 3-HTT Light tnkrosoop, , mitrospectrographyc morphomctry, and electron microo- acwpr rsed to etamine .eowafal neurvepithelisl bodies (NEM) under various eapetln+cnul conditions abow thst: (1) while the NEM appear Mructur.ty .orrnd, acune h7Poals deueaan amine /hrorescenx iwlemiryr and increases secre- bry e=ocytosis of den.e oore .esicks (DCVs): (2) hypereapnia has /6e aame eLeet+k but the core of DCVs (rapneeliser (3) h10eroaia does not appear to dlect eithar /luorescewae or esoeqtaais signi/kandy; (4) adndnYtratton of bio- lienio ea+inea such as 3-HlT and LDOPA produces high Intensity fhrorcscence, indicaUng their uptake by the corpuscular «Ib; (3) reserpiwe c.use" amine de- pktba, with a decrease of NES Mroresoenoe end an ritrastructural pillor of the [X.'Vs; (6) ietratrssheaMy administered niootine ia .ceotnpanied by de- eraaaed 1luore.cenoe and distinct eaocytosif of fra. meMed DCVs. The NP-M' reacdow 1o flypoaia and hypercapnia suggests that, in addition to being centrd a.d per{Oheral chenwreroeplors. they snsy a6o be inlrapulmonary oncs, inducing a rellet reaction through the release of DCVs at sensitive corpuscular nerre ewdinp and via the central ner.ous system. ln addHlon. the NESs may have a local intrapdmonary e4reet by directly modu4ting the hrpo.ie and hplxr- e.pnk pulmonary v..ooartrktioe. By ahuntirg blood from poorly ventilated arer to better aerated ond, this mechanism may be Important in the alreralioe of the lung veotilatN.rt/perfusioo ratio. Larwerynr. 1. M. 3r ./. Celf and Tirrrr ReiearrA 1a2(4):423-440, 1977. Other support: Nationaai Foods voor WekaschappeGjk Onderzoek (Belgium). From the Laboratory of Hislopatholopr, Kathotiek Uoiversilcit te I.euveo School of Medicine. Leuven, 3elgium. EXPERIMENTAI. EMPHYSE11ia NDUCED WITH PURIFIED HUMAN NEUTROPHIL ELASTASB: TISSUE LOCwLIZATION OF THE INSTILLED PRO7ZASB Human neulrophilie PoKwrorpMerdear kukoeyles (PMN) contain rela- tively large .mounts of an e',aatue whics he. recently been implicnted as a mediator of lung damap k oerlaie Reneticsllr-wrceptib/e individuals. 'tbs present report describes the rawdM of experiments in which purified humas PMN elastase wr instilled iulu dog haap. Rindinp show that this enrqme, acting alone, was capable of rnpidly Mducin6 ernphrsenulous lesions in isolated lungs ex slrr atd in intaet lua6s /n .Ire. 1n edditiow, /ror.en sections of treaKd and control lunp ..ere eaamMred for the preaewee of PMN elastase by the in- direct immunoperoaidase melbd trieR a mo.ospeei/lc rabbit antiaerum against PMN elrtase as the PrimarP stain. i.i6M wacro.oopr revealed dast.se bound to connective tiswrc le the trealed Mtnp, is ebae Protimity to aldeh7de-fuchsin- counteralaieed elsstin. A.iedMr e:ptxiateet winR dog bnp /n vi.w nQaie demoa+trated elastae in sroeiatbo vidt aoenecti.e tiaue ekments in the ksion area. Pan of the Instilled /rotsne could be dewronslrated within alveolar macro- phages. In addition, eletteota /ekeoaoopr aoshbined with inxnunoperoaidass staining revealed a dired aMacMrc.t of Me insliMed enzyme 1o elastin wilhie alveolar sepa. These reseU. show t,hM hunmae PMN elastase penetrated the dog alveolar epitheYal layer after ekwey MWiM.liow and that the enzyme attached to Interslitial elwin inducinR ItiMolo6k changes eanparabk to those seen In human emphysema. The hnpMcatien" of tMye Andinp for the pathoRenesis of pulmonary emphysema In ew, ...aits IM raulla ol/uture Mudio. lanofl. A.. S1osn, S., Welnl.rM Q., Daadsno, V., Sandhaus, R. A.. Elias, l. and Kimhel, P. Anwrkan Rerlrw o! Rt#p/n.rory Dhwar 115:461-175. 1977. OtAer.rpportr U. S. PubMe Hedth Servbe, Oeneral Research Support Funds, and intensal IuodiaR frora eM Franklin Institute Research Laborrariea. From the DcpsrtmeM of Patholo6f 3/aM Uni.enUy of New York .t Stony Nrook, Stonr srook. N. Y.; tha Pulmonary Dbea+e Section and Resiarch 1.- boratories, Albert Einmtein Medical Ceeter, Philadelphia; Iha Franklin Institute Research L.boratoriei, Philadelphia. I 32 33

111. Heart and Circul.tion TIIE EFFECT OF INDOMETHACIN, 6•IiYDROXYDOPAMINP., SARALASIN, AND HEMORRHAUE ON RENAL HEMODYNAMICS 'iAL paper describes the ellects of prolonged hemorrhagic hypotensicn and reiefu.ion of blood upon the renal circulation of anesthetized cats. Abo, three different drup, Mdomethacia, saralaain, an4 !f-bydroaydopunine (6-011 DA), wen Ri.es in order to is.estipM tbeir apetaal pharmacological action,. Foe ebL Nudy, plastic micrwpheres wera traed b atwwr D1ood Ibw pertuai;tT Ihe entk* kidney r well aa the outer oortat, isser eortea aad nteduila of tlhe kid- .ey. Cardiac o.tput was deternised with a Doppler llo.w probe, and tot A and regional flows were calculated. Resuha stwwed that following hem«.hage, aortk pwsse (AP), cardiac owpW (CO). total renal flow (TRF), and outer eorti- eal Sow declined significantly while the i.ner cortical and medultary fk w eit- yrered as a pementqe of TRP inctered significantly. Redittributios of blood Aow (rvrn outer oorlex to irer cortec asd medulla occurred during hemo Thaee asd after adminitratios of ssniarie and 6-OH-DA, while bdoenetbacie ( id eot aher istrne.al Aovw distrieMio.. Total reeal eow iocreased afler minfusion of blood and rrala,in, but decreased dter indomethacir it did no1 chanE~ after oocw ti-OH-DA. Thesa resuits show that ehanTes is toW atd intrarenal Qo.w Isdepe.dcnty asd are probabfp due to d/lereet mecbanisms. Fl.cber. R., Reda, S., Sar.na, J. S. M., and ding. R. l. The lowrwd of Cpska/ rA.r+wsc+oion 17( i):3-12, 1977. Other awrltortr Hoover Foundation. Norris Foundation and Wright Founda- tio.. From the Hurdn6toa Institute of Applied Medical Research and Huntington Memorial Hospital. P.sadena. Cal., the California Institute of Technoiory, Pw- deoa„ sod tha University of Southern Cddornia, Los Angeles. REFLEX SUPPRESSION OP RENIN RELEASE BY VENTRICULAR RECEPTORS WITH VAGAL AFFERENTS Se.eni teports iedkaN that cudiopsimonary reoeptors participate in the retkx coeud of sttul .aacvlar tai.taace sad of eenis rekase ntediated through clasRea ir teead t+ytnp.thetie nerve activity. intracoronarp in}ection of vera- trwn aRaloidt stimubtes .estrku(ar reoeptors through vagal aRerenu4, resultinR Is brsdreardia and hypoletnio.. Tt>H study eaamined the role of veratrum- se..itire ventricular reocpbrs In the control of renis secretioa in eight cMora- lose-aaesthethed dogs. Eaperimentaly-productd hemorrhage (10 ml/kg) caused a siptiAcaM Mcresa. M the rek..e of reais. but arterial presaure and R..1 blood Bow did not chaap siptiAcanty. The in}edios of cryptensmine (2 pi/kti), a veratrrm alkatoid, inb tbe main left coronary artery virtuallT abolished the augmented release of reaie, which teN Delow control kvels withim fow minuw twm the inieetiow. Blood pressure was significantly lower a/ter tha iajection, drvpping trorn 130 mmltg b 111 mnJig, but ehanges Is renal blood flow were not significant. Vagolomy abolished lhis refk suppression of rrais rekase. Thae data indicate that activation of ventricular receptors with vagal aRereots rdktty inhibits tite oecretba of oct*. The out:wr suggests that io addition to atrial and vestriwlc,r reoeplon, vagally innerroted pulmonary receptors may abo contribute to tBe t~ooic inSiiSitioo of the .aaomotor center. Tlanrs, M. D. An.er(can /osrn.i of PArtiolop -_33(2):Hitl-K:fi4, 1977. Other w'prtr National Isiti{ yaem of HeaM(a. Frore the Depanmest of Plyeb `.op sad Siopl7sks„ Mayo Clioic and Mayo Fouedation, Rochester, Mir. s1OCHEMICAL AND CONTRnC11LE PROPERTIES OF HA1RT MUSCLE AFTER PR(wON02 J ALCOHOL ADMINISTRATION Tt it+ report eorrelaees clay ;w 1n cardiac metabolism asd myocardial ooo- tractii9t7 in dop maintained o.t 'yooid for 29 moaM.. QyceriaNed beart muscle flbers were u.ed so stu&- ruryotardld contractility /n vitro with an ap- p.rHw designed b reootd botoctrie asd i.oloaie aoetraetiorn. Muimal tension developed (r.), nwinwtn r.1e of Ie..iom de.ebped (dp/dt nua). dme to ipeak temioa (r,) and tbe toroa .eloeity reldiossbip (V..) were the param- eten measured. These .alsa wc;tr t.cb.yed after prolonged alcohol admin's- tration etcepl tor the V... wbis3 waa dtaifkaMlY bwer than in the controls. Biochemical studies revealed triR4leaM depesic, of the mNochondrial respira- tion, diminished wcwplarndc relk+itrr caiciww uptake aad bindin6, lower erdoRenow calcium ooeknt, arrl decrered activity of intranitochondrid isoci- trak dehydrogeom (NAD-ICCH) is tlw heart muscle of akohol-tres/ed asi- mah. Howe.er, at the erd of the iat ptriod. e.ea during anRiotensis infusion, these dogs did not demonstrate t+ny airiAcaMy diflereet hemodynamic changes in dro than were noted in tbe oottlral sn{ttrit. These results suggest that, with- out any apparent hemodys.mk allerationa M N.o. Ihe corAr ttile appar_tus of the heart muscle eapoaed to akohoi w ae.er2 te maaimai isometric tension while being deficient ia the rw of erso.er of ts,eehanical work. Either the /n Hro measuremeots ue .ot wdkicaty sesrNiw to identity a small reduction in coptractilNy, or the intact mYocardiww it esdowed with certain compensatory mechanems that can overooms subtle eAasRem delectalrie only Jn ritro. The knesed isocitrate dehydrqesaa. activity may te0ect NADH inhibition, while the dimisi.Aed calcium upake a.d bi.di.R u wett as endoReeous content may IedicNe a defect in its transport a.d isltaoeMular ratorage. However, whether the contractile changes observed fn dtro resuR from the direct actios of alcohol on the interaction of contractile poWei.s or neAeet etbanoi-induced biochemiul chan&s remains to be deteneised. Sanna, 1. S. M., Ikeda, S., FLebar, R., Manryama. Y., Weiuhaar, R. and s,nt. R. l. JoM.n.l o/ Molerrf.r an1 Ceildi Cqrlolop t:931-972, 1976. Other sr' rtr National lestiWtes of Heallh, The Iloover Foundat'an, and the Norris oundatbn. From Huntington Menarid Hospital asd the H+ntinttos Institute of Applied Medical Research, Pas.dena, the Usiversity of Southcrn C'alifornia, Lo. As- jde.. aed the California Institute of Technology. Pa.adena, Cal. 34 35

REVERS181LITY OF MITOCHONDRIAL AND CONTRACTILE CHANGES IN T11E MYOCARDIUM AFTER CESSATION OF PROLONGED ETHANOL INTAKE Although many studies eaist tyins tont-term akoho/ consamplion to spe- cilk clinical and biochemical changes in the myocardium, relativtly little in- formation is avaitabk about the eRects of eessation upon these same parameters. The eurrenl clinical impression is that abstinence from alcohol reverses the ef- fects of prolonged coraumpiun, but hidthemieal data to support tf ese clinical findinp have been missing. For tbis study, therefore, mitochondrial respiration and /w rhro contractility of 617cerinated heart muscle /iben were chosen aa biochemical indeaes for rero.ery because several reports have demonstrated significant changes iu thae variables after chronic alcohol intakt. Measure- tnenls were made in rab coeuuming 25% ethanol daily for four, iix or eight weeks. Analysis revealed a paduN reduction in the ma.imd rate a/ isometrk teasion deveiopment (dP/dt,,,,), the ma.imal developed tension (i',) and the velocity of shortening N uro load (V_.). The time to peak tension (t.) padu- ally increased and mitotlsardrial respiration steadily decreased with lon=er pe- siods of ethanol injestion. These effects occurred earlier and to a 6nater degree with 6/utanule as aubstr.k than with suecin.le, which aNroduces electrons through ait. 11. l.ater, after eight weeks of ethanol conwanption, sotne IeN rab were given a nonalcoholic diet to assesa the etTects of abstinence o«t Ihese two variables. Four weeks after removal of ethanol from the diet, the uoMraclilily of glycerinated hcart muscle flhen was still significantly diminished. However, after eight weeks, even though dP/dt_„ was still reduced by M11. V,,,,, P, and /. had returned eisentialty to eontrol levels Miloehondrial respnation, also, had nearly returned to control values after eiRht weeks of abstinenee. TTse re- sults In this report demoantrate that the decline in both mitochondrial respira- tiow and /w .lao contractility can be arrested after cessation of etM.al inuke. Z1we results at the cellular level Iend to support the clinical findings that at certain Nages the eRects of chronic alcoholism on the heart can be arrested and reversed by abstinence. Weishur, R., Sarma, 1. S. M., Maruyama, Y., Fischer, R.. Bertu6iia, S., and d/wc, R. /. The Anrerlr.w lorrwl o/C.rJblotr 10:336-162, 1977. OtAW wpp+rtr U. S. Public Health Service, Hoover Foundation and Norcia Farnd.tion. Fe+oet the Huntington hrtitute of Applied Medical Research and Huntingtoe Memorial Hospital. Pasadena. Cal., the California Institute of Technolo6y, Pasa- dt:e., and the University of Southern Cdrfornia, Los An6eks. REGIONAL SLOOD FLOW. CONTRACTII.ITY AND METABOLISM IN EARLY MYOCARDIAL INFARCTION This report deals with the early effects of regional myocardial infarctinn on coronary Mir.d fl..w, the In ra.o c.rN..(tdt state. foarcrdysn and mNo- ttw.ndr,.l rt.p.r.i.•.. (.tvrn.wnlallr, swhemea was mdbated by ligating the ktr ma.n .uwer.w .k..erwlonif ,.N4.narV .ller?. and the nselahobc eflects Of ot- clusion were studied in both iatlnttted and waJnfarctcd areas of the dog he.rt. Measurements were made at I ood 3 hrs. alter onset of ischemia. Regional coronary bkood flow waa wasured ks iofaretcd, swninfarped and border/iae re6icxis using radioactive rniceoapAtres. Blood flow through the iahemic area was reduced by an average of 69% after I hr. of ischemia, and by 75% after 3 hn. lAe subendocardium of twlt botderliue region also revealed a si6nifkantly reduced blood flow afler 3 hrs. Miloehoedria isolated from the ischemic region of the heart eahibiled a aubaltrMial decnuse in the rate of respiration, and mirwr reductions in the eou71ir12 betweei oii3.ilive ptasphorYlatioa and electron Iransport, as well n in the :urtoied of ADP phosphor7lated per oay6en reduced. Levels of hesose nwnophcaphNea were elevated I and 3 hrs. afta ischemia was Initiated. At the saaw p3rne, the oonott.tration of frvctose-1,6diphtnphale declined markedly, rrAecthr{t (nh;oilia, of (lyeolyse at the phosphofructokinast level. ('oncentrations of ths - de.odw. yhosphate nwiclies, as well as crHlina pho+phate, were reduced, ohRk lkvels of treo faty acida were elevated i. ischemie tissue. The /w .ftro (iowtne(iiy of 6/ycetinaled ischemk muscle Bben was also depressed. SipifiurN tM.ges wers found in maaimal tension develop- ment, mauim.l rate of leas'aa de.elop.eM. time to peak tension, and shorten- in6 velocity at zero k4ad. IM ost of the elun6es brought on by regional ischemia occurred within the Rts1 hrar after i>lptiosi. and remained essentially constant thereafter. I Weishaar, R.. Sar.oa,1. 3. V., Marvy.rna, Y.. F'acher, R., and dlnt,A. J. CarJiolot7 62:2-20, 1977. Otlirr.apperfr U. 3. PuWk Health Service. Hoover Foundation and Norris Fundat+on. From the Huntington InstkWe of Applied Medical Research and Iluntinpon Memorial Hospital. Pasadena, GL, and 1he University of Southern Ca/ifornia School of Medicine, Le. Anjelea. REGIONAL MYOCARDIAL BLOOD FLOW DURING NICOTINE INFUSION: EFFECTS OF BETA ADRENEROIC BLOCKADE AND ACUTE CORONARY ARTERY OCCLUSION The influence of bere adrewerfk reoeptors apon the cardiovascular re- sponse to nicotine was etamined by delerminin6 the response to nicotine before and after Arrs adrener6ie blockade with propnnolol. For this sludy, 20 anesthe- ti:ed, open-chest dogs with norsnal coronary circulation (NCC) and 20 with acute occlusion of the left ankrior descending coronary artery (I.AIX)) were evaluated. Regional blood /low wa. estimated by administration of 7•10r diameter radioactive mierosplseres ktMO 1hs left atrium. Nicotine infusion re- stdted in elevation of the aysteswk nrterW and left atrial pre..nres in all dnRs, but left Nrial pressure increaKd to • much greater eatent In animals with I.ADO. TUe coronary arteriovenow di//erence in pOs decreased with nicMine infusion. Coronary vasodilation oacurred (n normal myoa.rdium bu1, in ischrmic mroeardium, blood flow /ncreased only proportionallr to anrtic pressure. Nico- line caused ventricular arrhfthmin In dop with I.AU) but not in dop with NCC. After treatment with propranolol, left atrial blood pressure rose, whereas 37 16

cardiac output declined. Heart rate also declined and subsequent infusion of nicotine had no effect on this parameter. Several results showed that brrs adrenergic blockade caused significant changes in the hemodynamic and myo- cardial blood flow responses to nicotine. Hemodynamicanr, aortic blood flow fell drastk•11y and kft atrial pressuro was markedly elevated in dogs with both NCC and LAIX). The hypertensive response to nicotine was not ahsred by propranolol in dogs with NCC, but was somewhat attenuated in dogs with 1J1DO. in both groups, there waa a large increase In total peripheral resistance which •ccounted for the ekvatioe of irlerial blood pressure in the f acc of reduced cardiac output. Downry, H. F. er d. The lownd o/ rArm.coiop .w/ E+perimrnrl T/icr.pcwNcs 202 (1) : S 5-67, 1977. OtAer •.rprtr Southweslern Medical Foundation and The Cardiology Fund. From the Cardiopulmonary Institute and Departments of Physiobgy and In- lernal Medicine. University of Te:as Health Science Center, Dallas. THfE SINDINa AND CLP-AVAOP. CHARACTERISTICS OF HUMAN HAOP.MAN FACTOR DURINO ('ONTACT ACTIVATION. A COMPARISON OF NORMAL PLASMA WITH PLASMAS DEFICIP.NT IN FACTOR XI. PRI=KAt.1-IKREIN, OR 1110H MOLECULAR WEIGHT KININOOEN 1• order to ehrcidate the molecular events involved In effective contact •etivatiork plasm.s genetically deficient In factor X1, pretatlikrein, X high nwletulu wei6ht kininoRen (HMWK) were comparcd for the ability of their Hyem•w t•etor to bind b• 61w surface a+d for its susceptibility to limited peoleolrtk cleavage during contact activation. In normal plasm., the Hateman f.cbr bound to the 61r aur(•ce, and within five minutes Its native 80.000 ssoi. wL ehaln was cleaved into two frypnenb of 32,000 and 25,000 rnd. wt. respecti.ely. 1s factor Xlddkient plarn., the reaction was similar. In prekd- IitreiwdAkkM plasma, the binding ru/• was the a.me as In normal plasm., but the ekt•var rate was significantly slower, yielding the maaimum mrmber of fra6menb only after 60 minutes of incvbation. In the IIMWK-defkient piaseu, this reaction was even dower, requiring more than 110 minuk+ of in- cub.tlon to teach cornpktion, but the 61ass-bindie6 rate was the same aa in normal plum.. Normal rates of cleavage were restored in the deAcknt ;Aasmaa after reconstltulion wilh purified human prekallikrein or IIMWK. Thew, obser- tatlar suggest that normal contact activation in plasma in associal.d with proteolytk activation of surfaee-bound H•rman f•ctor. Revat, S. D., Cochr.nr, C. C. and OritRn,1. H. TAe lovrwd o/ (7inkd lnwrrig.rbn 39:1167-1175, 1977. OtAer .rrprf r U 3 Public Health Service and the (Mke of Navat Research. From the [lep.rsmewt of Iw.mu•op.thology, Scripps Clinic and Research Foun- datio•- 11 /oUa, (-a1 MOLECULAR CONSIDERATION OF PLATELET ADHESION In this review of ideas ond theorir• foncernin6 platelet •dheaion, this phe- nomenon is considered as the Interaction of plilckts with physiolo6ically rele- vant macromolecules. Since the ernphasis hert is on the interdependence im- p(ied in the term "interactiws," much attention is devoted lo the molecular at- tributes of macromokcuks tiut specifically bind to platelet membranes and to the molecular events that occur In the membrane in resporee to wch binding. Carefully scrutinized are the role of thrombotenk components of the subendo- thelium, collaten, fibrinogen and /briu. thrombin, the platelet read'an to im- munolosic slimuli, and the p(atekt mtmbr•ne. An emerging hypothesis on sur- face phenomena durinR plaielet activation i. ahio discussed. Several salient points •re that: (1) collapen b a pwer(ul platelet activator - adlaRen fibers bein# the most thrombo{enk oaapowMN of the wbendotheliwn - while c1aslM in eoentialty nonthrornbo6enle: ~:.; among the differing types o( collarn, the higher the carbohydrate conFyi1 1„a b•.er the plakkt-..cliv.tlon capacity: O) the degree of eollyen Abril"o3eaRsis b probably a major determinant of ils activity with nnpect b platelets; ;C) ba•emeal membrane eollaRen is the weak- est Inducer of serolonin release. probably re(leetint • molecular adaptive re- sponse to the advent of thrornboerles: (S) the platelet membrane may hav both proteolylk and binding sIW for throtwbin, and the inter.ction of thrombin with the binding sites may potenliaN the activity of the prvteolrtic site: (6) tryptophan and sug.rs •re pst'b.bly taeoeawry for both complement Aaation and binding to platekts: (7) wrNso thae of hutsssna. rabbit platelets do not react directly with MwrwnoglobaNtn bMt raher with activated complement fl.cd by irnmmrse comple.cs or appeRLacd 1110: In contact with compkment-coaled IRO, the plales release ADP asd seroloni. (but no1 LDH) and undergo the morDho- loltic changes characteristic of UM telene reaction. TTmso /ast observations have led to a series of experimeab implying thN adhesion doey not require the activity of a membrane ariae esleraae, but that the release reaction does re- quite such activilr, which Is probably InArced by contact with the stimurotinR particle. The •uthors conclude with a seserul hypor'.esh outlining t.ie irter- action between platekt-.cti.atin6 mo/eauk, and platelet membrane. AIkA.dl, 0. and thfoR, K. a'. In: Spaet, T. H. (ed.): hosrass M Hen.ort.r6 .nd TAron.Aoti's. New Ywk: Onnrc ! S1r.tlon, Inc., 1976, vol. 3, pp. 29-59. Odrr •rrprtr National lwstituttesof He.hh. From the Department of Biochnnislry •nd Siophy.ics. and Dcpartment of Surgery. University of C.Nforui• School of Medicine, San Francisco. HUMAN BLOOD COAGULATION FACTOR XI. PURIFICA77ON, PROPP.RTIPS. AND MECHANISM OF ACTIVATION BY ACTIVATP.D FACTOR XII Ion eachanRe chromatography was used to purify Faclor X/ (20% yield from plasma). The specific elottiq activity of this purified form was 2S0 t 20 rnits/mR. implying that Its concentration In normal cltrated human plasma b 4 rg/ml. In the p.esenoe of sodium dodecyl sulfate (SUS) and In the abscnea l9 IE

of di.u/llde reducing atents. Factor XI showed a single protein band on poly- acrrlamide Reb, correspading to an apparent n.okcular weight of 160,000. Reduction by mercaptoethanol produced a single protein band represrntinR an apparent molecular weisht of 1).000. The evidence given here indicalea that the appear.ncs of clot-promotins activity is associated with limited cksvaRe of Factor XI by surtace-bound activated Factor X11, both in a mixture o? purified proteins and In human plasrna. The appearance of activated Factor XI activity correlated directly with the ex tenl of eksvqp of rs'1-Facto. XI.'The cizaved ac- t'naKd rs41-Factor XI retained its appareM molecular weight of 160.f1D0 in the abenoe of reducing sgents on SDS-polyacrylarnide {eM, whereas reduction pro- duoed fragnsenu of SO.000 and 33 000 mokevlar weight. In normsd human plasma containing 1as1-Facbr XI "}cctcd to contact activation by kaolin, similar molecular weight proAks wcre oblained an SDS scls. both in the ab- aenot aed Iw the presence of reducing affeMs. According to these resuhs, the .etivatton of human Factor XI, both by purified activated Factor X(1 and by the cot,tad activation system Mt plaama. involves limikd prokolytic cleavage of Factor XI yielding polypeptide chains with a mokenlar weight of 30,000 and )1.000. held together by di.ulAde bo.ds. Roarwa. 111. N. awd OriAlrti 1. H. (CocAr.wr, C. a.) TA.lownri oJ ltoiollcal Ciiee+isr.7 2s2(11) :6412-64)7, 1977. Other wrr.rf r National Institutes of Health and the Office of Naval Re- tsasch. From the Dep.rtment of Immunopathok.fy, Scripps Clinic and Research Foun- datfoa, La )oila, Cal. BIOCHEMICAL AND MORPHOL.oO1CAL ASPECTS OF THE ACTIONS AND META>lOL.ISM OF KININS Recent advances in polypeptide chanhtry and ekctron microscopy have ra.de it possible b exaraine the effects of polypeptide hornwnes. such as br.dykinin (eK). on di.cnw twbedlular events and to study the influence of twboepdar orpnelks on the metaboRsm and fates of the hanwnes themselves. During the l.st few 7ean, these wthoes' eAorts have been directed loward un- derstarding how SK and anfliotensi0 I ue eliminated during pnsabe. through the pulnron.ry vaacular btd, and what effects these polypeptides have on tisue Mrticttwr and Lunniow .t the suballular level. Th's eatensive review covers the tnajor aspects of this woA, narnely, the metaboiism and fates of eirculating kinins and .rKiotensia 1, and the actions of sK, especiaMy its relationship to proMqlandin sryachelase, and Its effects and those of tuftiote.nin N on the adrenal medulla With respect 1o the latter, it is well known that BKK and the ansioleesina can stimulate the release of adrenal medullary calecholamines. which occws by esocyw.ls involving the chromafBn granules. Howe.er, there 1s wide variation atnong apecia ln ter.ns of sensitivity and magnitude of re- sponse. and Rnk information on the phyriobgic importance of kinins or aneio- knsln in this process Nevertheless. thrrs is evidence that one Mokci,k of SK may release at knt 10 molecules of calecholamines. while one mulecuk of angiotensin 11 may release scvcrd thousand, thus suggesting a large ampli/ka- tioo of biologic eflects. The adrenal medullq, tisercfore, appears to be esquisik- Iy sensitive to BK and angioteaisie. tan the basis of their own esperiments, the authota suggest that both 11K and anifiotemin act to increase esocy(osis by means of receptor sites wlich may be rdated, although they are not identical. Some ideas for further rcaarch .re ptssented, based on the hypothesis that the peptides influence the inW. actiop~ of ebromaffin granules with the plasma mem- bram. Ryan, l. W. and R7a., U. S. In: Pisano, J. l. and Austen, K. P. (eds.) • CFen.i,uy .nd alology oJ rl4c Kd- Ubcrn-Kinln Sysrern In Hcdr/i .nI Dbc.r., Fogarty Internaliond Cenler, Proc. No. 27, Wasbington, D. C.: U. S. dovermrcnt Printing ORioe, 1976, Chapt. 41, pp. )13-11). O/Aee aurprz. U. s. Pubiic Health Servioe and the Ilartford Foundatkrn. From the Pap.nicolaor Ctsrotr Re.carcy Institute and the University of Mi.aJ School of Medicine, Mi.rmt, Fla CORRELATION OF PULMONARY STRUCTURE Wn/i PHARMACOKINETIC FUNCTION The hrnp appear to ptvxs and eliminate drugs by a variety of ineans. It seema likely that bradyhMia and anSiotensin I are metabolized by enzymes located on the luminal surfaot of pulmonary endothelial cells. The ability of the hmp to process thas substances may be e:plained largely by the activity and specificity of  single Iwtt entymt, ayiotensin coverting enzyme (kini- nase 11). The lungs cam also co..ert awgio/ensin 1 to angiotensin 11 in a mNa- boiic reaction that aiao Pield. His-Leu, among other products. llrw, on 11e basis of the evidence ava8ebk at prtseN, it appears that the pulmnnary vascw- lar bed contains an ent:yrne in solid pMse which a.n continuously process bradykinin and anpiotenaia I M eiradNins blood. Relatively small amounts of this enzyme could suffice for oowp.ratively, large quantities o( sul.strate, sirwe at the kvel of the capillary bei, I nd ot blood may ooeupy more than 10 miks of capillary length. Whether this ewtysee, which has also been found is plasma, aortic eaidotheliorn and hotnollewMee from a number of other tiswes, is re- Nricted to plasma and to andotheliwn M general is not yet known. However. the authors have found that smoolh rwusek ceth of the pin pulmonary artery do not degrade (rs41)Tyra-br.dyki.in to yield (rs`1)Tyr-Arg. Conaequently, at this time, it appean that thtt unique features of the pulmonary angiotensin coe- vertin= enzyme are related Io the strvetws of the lunp themselves and to their position within Ihe circulatory tqstem. Although the tdal amount of converting enzyme within the lungs may greatly eaeetd the amount needed to process the concentrations of substrates uswMy found In pulmonary artery blood, it is not at all certain that a11 of the ewqme bs free access to these circulating sub- strates. Many factora such an tbe deQee of .aacular di.lention, posture, esercise. quality of inhalants, and othds which may affect mean transil time, may in- fluence the eneyme-subrtra es aoona. For InNance, the lunp may hare a role in the secondary hype.aldosleroniwn associated with heart failure. It would also be interesting to know whether the processing of brsokinin and angiolensin I 40 41

keeps pace with the Mcreaaed pulmonary blood eow during vigorous ezereiae, which may rire sWoW. Rraa, I. W. and Ry.n. U. S. A4rnh.d AcNav 6(4):51Q515, 1976. Other..rprtr U. S. Public Health Service. Hartford Fouodstke and the Heart Association of Pdm Seach Cou.ty, Fla. Prvem tha hpuicolao. Ca.oer Rea.arsh leatitute, Miami, Fla. CORRELATIONS BETWEEN TI/E FINE STRIK'Tl/RE OF T11P. ALVEOLAR-CAPILLARY UNIT AND IT3 METABOLIC ACTIVITIF3 It haa lo.p bee. l.o.u that th. AwtRs aNminatt vaaoactive s"anon Ie a highly eskket nue.er, but variow urdies stww th.t actuaRT thcy are .bo eapalM of processing aeleetlwetr a large aweser d.wbtances that are very di/fereN ehemkdF7. Including 6ioRenic amines, ade.iee suckaidn. prowa- illa^dins. polprptidea. drugs, and lipid.. Farthernwre, the hnW meq costaie4 et the level of ths al.eolvsapillary uni1, enzymes .nd olher apent) active 1n eoa6ulation and aelieo.rylation reactiorr. The alveolar capillary ur.it is oonF poaed of at kast three cell tTpes, the type I afredr eell, type 11 alveolar eell, and tAo endwhelial ceM, awd of eatraoeMular malerial, namely the surfactaet lining layer, the Sasemeat snembrana and the sotadcd endothelial (ua, e aur- (aee oo.ti.g thought to consist of muoopolYsaccharides. 1n this book ehapler, th. (ocut fa on interanioar of the lunp with circalating .ubstanees tno.n or thought to be proces.cd actively, by endothelial cells. The authors review the .relahdirw of lipids, ahe proeeasinp of biol eeic anwnes. the metaboli+m of wr- ebotiAm and the metaboiira of polfpepoide hormones. This IaN sediow upe- ei/kally discnres br.drllais awd .n6ioterr.in I and the rnechanhrw of their trsp.cti.r metaboli.nt, whkh suqests a role of the Iwp in blood pressrra horneoAri.. It abo deseribea structural specidiutioaa of e.dolheN.l Plwn, twembrsr with respect to dr location of .epiotariueo..erlin~ cn:yme, awd anMiotaa odter pol7Peptlda brteoees, speci(ica11T iroulie which may not 6e oetaboliaed durieg cirrulNiot through the bep. The metabolism of proata R1a.diea, the degradalior of tlroaa of the E and F serits, .ed the sy.thesis of throm6osaea As and Ss through pros1a61andin synthetasa aystcros, aro also diacus.ed, art9oulnp still other re6ulalory functions for the hrnp. The metabo- liam of ueroid and thyroid hormones. a.d ooa:ulatloa and /IbriraiTsir are tha other poiMs covered. R7.r. U. S. sad Rrast, 1. W. le: SJW Y. S. aad Va., 1. R. (eds. ): M.rebolk Fuwcriorv o/ the Lw+R. New Yort: Marcel Delker, 1977. Chapt. 7, pp. 197-2)2. Oth.r.rrr.rtr Il.rtford Foundation. National InstNutes of Iledih and the Heart Association of PWiw Seach County. Fla. prom the Papanicolsou Caecer Research Institwe and the University of Miami School of Medicine. Miami, Fla- f ' f I I CHARACTERIZATION OF ANTISODY TO HUMAN PHOSPIiA71DYLC1IOLINE:CHOLESTEROL ACYLTRANSFERASE Presentday metlwdu of eseawrrieR Me activity of phaaphatidykholiee: cholesterol acyltransferase, the eatryn(e responsible (or esterif7ie6 choksterol, have been inadequate foc- dialirguirhinR uhreQecb of this enzyme from those of its substrates, activaton as Inhibitors. To counter this, radioimmunoa»a7 has been suggested aa a Cike/T way to aua.ti(y the emyme is plasma. lbis paper characterizes the calbody produced a(ter purilkd preparatioes of phos- phatidykhotine:chokskrol .c7hrsarderaee were injocted into goats. The ami- sere and r-6lobulin deriwd Iherdrom wcre e.amieed by the lechnques of im- munodiifusion. immwwe acyrop;aoresi. .wd immunoinhibilion of the enzyme. ResuUs showed that no vca updnN awlisera b human serum, alhumin, high de+ailr lipo9roleina. or low rie.sitp IipopeWdna were given by the purrlied en- trma ie either inNwu.o[i0wbe or imrwrrroelectroplaresis. A weak antibody tlter lvwardt humww aer>u. Jbrrnl. wr wo/ad ony after prolonged immu.ira- liow. but progressive a.a sever. i.hibilie. of activity wr observed when burw .emun wr i.ewbMed wita ierqsiwR swrourrb of r-R1obulia (rom Ihe immuee .errm- 7?rcse /lndinp show OrM .peci/le srtibodT b human phosphalidykho- line:chokslerol acyNrasCenr eae be produced. This antibody, which is free of antibodies to other secvw peoleirr and prtiedarly 1o lipoptotcine that may be associaled wiNh the eriryrsns i. Iwrnaw plwna, is being used now in Ihe in- vesliplon• laborabrp in a:periw~aw eMred al determining the absolute value of phosphatidykhoWrc:eQokNerot aryhrus(erae ie health and disease. Vatm,, K. O., Noww.y, A. H..rd Solo% L. A. eiocliLwka er Aior/iyt1n Act.416:17t.)LI, 1977. Other a.r'..tt U. s. hbie Health Servia. From the Lipid Rese.rdt La6onlory, Department of Medicine and Department of Microbiology end Inrwnolo", Teanpie University Health Sciences Center. Philadelphia. SERUM ELECTROLYTES IN NORMAL PYGMY GOATS Pygmy Roats are be1.R red etlarivelT iw biomedical research because of se.eral desvabk attribules, yet pbysioloQk and biochemical vahres tor serum elecUolytes are not avdlabM tor thna awinuls. Consequentlr, pypnr goat aerum rran both mdes 1nd feamks was analyzed ie order to determine not- mal base liees foe Ihesa eoasWneM.. The ie0uence of are was also investigated. According to the resalb, several o( IM serure electrolyte values lor pygmy poats are aimilar.to what haa btse teporled (or other ruminant species. The vduea obtained for serum sodiuw, ptaasiurn, chlaide. cakium and magnesium. moreover, ars wilhiw the limits found is human adults. 7hrse sadies also Ie- dicate that eaflraioe of rwaM pygmy poats doe not .fleet serum electrdyte levels. Similarly, these v.hrca do swt c,.ya with age. Gurro. A. er of. Amrr.k.nlo..wd of Ycrrdnary Retes.cA l1(5):661-664, 1977. From the Department of Pathology. University of Miami School of Medicine, Miarnl, Fla., and th. Heart Rescarch Laboratory, IkpartmcM of Medicine. University of Oregoa Health Sciences Ceater. Portland. 42 43

SERUM PROTEINS AND PROTEIN EI.ECTROPIIORETIC PATTERN IN NORMAL PYGMY GOATS Since the pygmy "t can serve as an appropriate model in certairu bio- logk.l Inrestiptions, it seemed important to establish normal base lines in 1his aaim.l for total serum protein and ekctrophorelic patterns of serum proteins. The results of testing showed the following base .ahrea: se -g{obutin, 0.6 ± 0.1 n.6/dl; a-plobulin, 1.0±0.3 mg/dl; ftlobulin, 0.5±0.1 mg/dl; rtlovufin, 1.6t0.1 mg/dl; total prwein, 7.3±0.7 arg/a; albumin. 1.2t0.6 mg/dl; A/O ntio, 0.1t0.3 mg/dl; and 61obu6n, 4.3=0.6 m6/dt. When the goab wee 8i- •ided into Brvupa on the basis of age awd aex, a few signillcant diRerencY-s be- came opparsnt. Of the eight variables studied, two, albumin and A/(i ratio, showed signifkantlp diQerent values due to sen. Castrated males showev) siL- aifieanlly Iowe..atun than those for fntact makn and femafes, and A/O rat'a •ahw for femaka and castrated nsaks wen siifnifkanMly {ower Ihan rhoro for Intset ntaks. Theae reswrlts irdkalt that the steroid acs hormones are in. ol.ed in tha atimulation of albumin sryMheait in the body. Alw, there were signi kant diRerewoe. In lotal aerum protein values due to aile; the 7wrnkest group of goah had tha amalksl total prote:w .alue ud the /otal .ahus increased with in re..- ins ane. Cas". A. N d. An.rrk+.w /ewwaf o/ Y.rrriniory RrsrercA lN ( S):665-667, 1977. Frorn the Department of Pathology. Univenity of Miami School of Medicine, Miami, Fla., and the Department of Medicine. University of Oregon Hiealth 3cieaeea Cenler, Portland. IV. Newroplternsacology and Plsysiolo6y MUSCARINIC CHOLINEROIC BINDING IN HUMAN ERYTHROCY7E MEMBRANES Cert.in ai1es on cellular tnernbranes from a.ariety of tissues eshibit ,e- Ixtbe, hi6h-afRmity binding tor a number of drup, honnones and other endo- jeoous wlsiuscts. Among such dtes art the orw on neural membranes for opiak-lik. .ubatanees, siodiaic choliner6ic agents and reuscarink choliuer6k agents. 1s each inManoe, there appears to be a eorrdation between the binding leleity and the pharmaeologic action of a series of analogous agents. It tus tecewtfy been deswnslr.ted that erythrocytic membr.nea have a speci/k high atlhity, for opiates and dw the physical and chemical characleristks of the binding mechanism an ainWr ia maey ways to those of the opiate-badin6 site 1n weural membr.nca. Tlris repwt establiahes the fact that the human erythro- eyse membrane eshibits h1glydBnity binding for rtuinwdidinyl ben:ilale (QNB), a drug which is apeci/1c for the mrrearinic receptors of the central nervous aTslaw and wrwdh muscle. TMa binditat, nwnv.er, la Inhibited by a{eats which a.aociate with muscarink receptors In other systems. The pharmaeofogie proAk of the .pecifk binding is also rmilar to that of neural membranes. How- ever, the binding L not atereo.ektli.e for thm 1 and f Isomers of QNB, as is also observed in the mtecarinic receptors of uatber peripheral cholincrkic syslem, the rat ir* but not in the central nervous system. The significance of the prexnce of muscariaie choMergic recepton in erythrocytes is uockar. Aatykholine b a biologic eQector in a tsumbcr of nonneurl or musck sys- tenn, sod probably predates :be nervous system in evolution. Based on the membrane characteristics of erKhrocptes, a molecular model for drugmembrane interactions has been de.elopoA, which propow that pbosphatid7l serine plays a key role in the differential .'istribWion of rniotr agents. Still another study has shown that this acidic lip'd, which is th, nujor one in erythrocytic mem- branes, jreatly eah.noea QND )iadiag fe neural membranes. Aronslam. R. 3., AAool, L. C. and MacNeil, M. K. lI/e 3d.nc.s 20:117l-11/0, 1977. OfA, r w'p.rfr U. 3. Publk (:al1i Service. From the Center for Brai. RcssareN aaw/ Dep.rtment of B'ochemistry. Uni.er- siry of Rochester Medical Ces er, :4ocbeMCr, N. Y. I ANTAGONISM BY CHOUt"MROIC DRUGS OF BEHAVIORAL EFFECTS IN CATS OF AN ANTICHC UNBRO1C PSYCHOTOMIMETIC DRUG AND ENHANCEMENT BY :VIOOTINE A behavioral techaiqw kivol.ittg eau Aaa reoewtly been dereloped. perrnU- tin6 the asaesment of a siund.ar of Mantillabte p.ychophYsical parameters that are ai6nifkantly dfeckd by If s 6lyoolNa eslers. Consequently, a.ariey of cho- liner6ic agents wen eaantisef4 for aheir abiliy b antappniu the beha.ionl c/- fects in eau of an anticboli.ertle pareholowtitwetie agent. N-methyl 4-piperidyl isopentrn7lphenrl 6lptolaN. A awnber of qu.ntiMbk parchophysical p:.run- eten eshibited by c.ts trained to peaa a lever for a food reward in re.ponse to as wdaory stirwhs wera detsrswit.e4 Tha wutnber of responxs elicited during an eaperimeMal se.ion, a.d the preferewoe for dse usc of right or left levers were anroo8 the paranselets whkh wen aignillcaM/y tnodiAed by the 6lycolate. When pAysosti6mine was adainiNered alowR with the 6lycolale, both paramelers ak{twM returned to noteul. Tetr , which has the same antf- eholinesternse potency r pb7snaliRrt+M~ had a similar but ksser effect. Areco- line, a tnuacarinic a6en1, wr sli6hdy anta8o.islk, while nicotine significantly enhanced the action of the oreolaM. It haa bem suggested that the anikholin- er6ie drugs may modify beharior Ih various operant conditioning e.periments by attenuating the habihation prooesa, and that the hippocampus is under cho- Nner6ic (muscarinic) control. The h7pothesis that the antkholiner6ic drugs af- fect habituation could eaplain the deetease Iw the cat'a rate of performance and change in laterdit7. Howe.er, ainoe Mt theae eaperimenu the glycolate did not induce the cats to make arry sswrt errots than usud, i1 is unlikely that .hort- lerm memory is d/eeted. Lowy, K.. Abood, M.1* , Dreslet, M. awd Aboot. L. G. Ner.epllwwr.rolory 16(6):79f-40J, 1977. Oth,w .orr.rtr U. S. Public Haalth Jer.ks. From 1he Center for Brain Researdt, University of Rochester Medical Center, Rocheskr, N. Y. 44 45

STUDIES ON THE RELATIONSHIP OF BINDING AFFINITY TO PSYCHOACTIVE AND ANTICHOLINERGIC POTENCY OF A GROUP OF PSYCIIOTOMIMETIC GI.YCOLATES QB (3-quinuclidinyl ben:ilNe), a highly potent psycholomimelk drvs with anlimwcarinic propertin, was used in this study to correlate the relative l:indin` .fRniliea of various anlichotincrllic agents with their psychopharmacolo6ical and antkholinergic effects. Binding to brain homogenales and nerve endintp was measured. Whew the two isornen of QB were cornpared, it was seen that the f iwmer had 13 times the binding aRinity of the J form and over 20Q times the psYchopMrn.acologkal potency. When the relative binding dRnil;- of a lwrnolo~ora series of gIycolale eskn was compared with their relative psycho- active potency, the corrclation was e.cepent; ho.rever, when compounds with heterocyclic amino rinp (..4., tropanol) other than quinuclidine and pip:ridine wer@ oonsidered, the correlation wn poor. T1he behavioral Potencks of ti.e gly- oolaN eMers studied here have been weM characterited already. In man, they produea a number of behavioral and neurvlo=kal symptoms, including f ailuci- tuUar` arnnesia, delirium, and confusion. In the present sludy, a remrrlaMe eorrelNion was found between the binding aflh+ilies of /hese psycholon.imetie esters for the J'HpB binding site and their behavioral polencies. Sone bio- eheelkal ob.ervalions, includinlt the role of Rpids in the /'HjQB bindirg site, m. abo presented. 1lwmgold, 1., Aboo/, L. 0. and Aronstam. R. itndn Re.r.eA 124:)ll-)40, 1977. Oth...rRprt: U. S. Public Health Service. From the Center for Brain Research and Department of Bioehemislry. Univer- .ity of Rochester Medical Scbool, Rochester, N. Y. ENHANCEMENT OF OPIATE BINDINO TO NEURAL MEMBRANES WiTH AN ETHYL GLYCOLATE ESTER OF PHOSPHATIDYL SERI:vE (,"beakal synthesis and wling of phosphatidyl serine (PS) der}ralives hare been toed in this attempt 1o identify I1rc mechanism by which acidic lipids eehaece the slenoapeciAc high-aAinily binding of opiates to aeura/ membranea. 3pecilkdly. PS ethyl lilycolate estet was synlhesised from PS and ethyl di.w- aoelak, purified by preparative TLC on sitica liel, and Iested along with other PS derivatives for eQect on stereospecifk opiate binding. When synaptic merr~ brann were espoeed to PS. the slereospecifk binding of ('ll/DIIM waa en- haaoed 35% over that obtained without added lipid; a comparable ooncen/ra lion of the PSesler enhanced the binding by 26%. Dipalrnitaoyl phosphatidk .cid produced a)0% eahanoemcnl, while pboaphalidyl ethanolamine was with- out effect. To dctermine whether a direct interaction between tipid and drug could be a factor in the observed opiate binding enhancement. the ability of kvorphanol to bind to a.uspen.ion of the PS-ester was measured. In contrast b PS, the ethyl olIrcolate ester waa unable to significantly polariae the Mror- cscer.oe of kvorphamd Cimilarlr, cakium adsorplwn was observed with surface eims of 1'S hw mw wah the PCe.u.r %..ae this racr .t-.ne neither cu.nhined .Nh the opeNr rw ...n.p4.ed i.k.unt th.w uw.ham.ms of atlwn .Hecting opiate binding had to be ruled otN. Therefone, it seemed probable that Ihe way acidic lipids enhance opiate binding is by a direct interaction between the pho.- pholipid and the opiate bioding ute is the membrane. Hoss, W., Abood. L. G. and Srniky. C. NerrocJiemlca/ Research 2:30)-)09, 1977. Other aorport: U. S. Pub;ic Health Seecvioe. , Frwn the Center for Brais ^.:eaea,rh and Dep.rtment of Biochemstry. Univer- sily of Rochester Medical Ccoler, Rochepet, N. Y. C1rO1.INF.RGIC ANI) NOiv-CHOLINP.R(i1C ASPF(1;4 OF Tll@ DISCRIMINATIVE ST1Ml:LUS PROPERTlES OF NICOI INE In this estenuive revies., aicotine is show. 1o produce very subtle but pow- erful effecls on behavior. Abo pwvided is aorne irnight as to why nicotine could be reinforcing in maa. T'he AomtostNk effect of nicotine on behavior suggests possible phann.coirle taes for N. Is the etciled person, it could lower arousal, while iw the sedatei iwdividr.al it could have a slinrulatory effect. Tlws, it would appear to be the perfect Iratquilitxr. Nicotine also produces powerful state change, in that under ib ii.I tre.ee there Is pealer retention of karning than in the aartrol stak; but whether this is relaled to a memory mechanism or so a sensory one is nol yet rndenlood. TAia effect h also tramlatahk in lenns of its Nimuhu-related properties in that a compound with such powerful slateeha,nRe capacity would be especled to evote proportionately powerful dis- erirnautive stimulus (DS) eflects. The dala from animal sludies suggest several e.planations as to why nua nan tMs rein/ordnR drud. Speeitically, there is sulr stanlid evidenee MN aiootine acts upon very specific receptors within the brain. While Ihese appear 1o be ehoMaKrgic in nature. Ibey also seem to be d'f- /eren/ from nwacarinic (M-clrolieetpe) receplors. While lhese sludirs also may imply that the hippocampoc is ewe specific receptor site, il does not appear to be the only senailive area in the brain since a dopaminerolic lin,c may be in- volved as well. The DS approach provides a unique tool with which .o study nkotiee since it is dependent trpotr an aniewl's ability to recognize drug venus nondrug slates, which is itself contingent rpon the stimulation of specific pharmacologic receptors. 'ilws. R b now feasible to attempt to flnd the site of action of nicotine by direct application to the brain of either the drug or electric stimulation designed to mimic ib effed. An attempt to parallel some of these studies with very precise ones in humans ahould also be envisioned. Roxcrant. 1. A. and Chnwe, W. T. In: I.al, H. (ed.): DiscdnJr.Nlw SMn.r/w rroperlier of DraPr. New York: Plenum Publishing Corpwatiow, 1977, pp. 173-1e1. Otii.r support: American Medical Association P.ducdioe and Researth Foundation. From the Ihpartrnent of Pharmacology. Mcdical College of Virginia. Viriginia Commonwealth University. Richmond. t 46 47

AMINE REOULATION OF PROTEIN SYNTHESIS IN RBTROORADE AMNESIA Admi:ntration of a single posttraining electroconvulsive shock (ESC) to tniw ek.ates brain 3-hydrosytryptamine (S-NT) and produces a retrograde amnaia, but uric acid (a methyl zanthine which acts as a mild eentral nervous srs/em sliewlant) can alter this amnesic effect. In the series of experiments presented here, the Interactions of sric acid and 3-HT are used to Illustrate both the behavioral and neerochetnkal psra" Inherent in the relationship be- Iwoen retrofrade amnesia and serolasieerRk taechanisrns, and the dfects of thwe W.ls on cetebral prolein syntbesi.. Carefully aonsidered sedions ot this reviaw Paper are devoted to: (1) retrograde amnesia; (2)" ECSinduoed sero- rosi.erRie change; (3) a{e-relNed diAerenoa is reeltokrade amnesia and is protein synthesis; (4) srnaplo.om.l protein syntbcsis; (S) regional srnaplo- tqrns warpAolop; (6) s)naptoaomal 3-1TT uplake; (7) separalion of neuronal per$arya and k8a; (4) cellular S-11T uptake; (9) cellular protein synthesis: 8CS and urie acid effects; (10) retrokrade amnesic eAects of but7ric acid; (11) etleclo of boytic acid upon brain S-t1T and eerebrd prolei, qnt:Sesis; (12) effects of uric acid upon butyric acid•induad rctrograde amnesia: and (1)) butyric acid-urk acid iMersetiorn: S-IfT c+onk.1 and protein s7etesis. O.erad, this work iedicate+ that attenuation of a teetroaade amnesic efte--t by urk acid is ca»iuent with the antagonistic effect of this same agent upon tsewochesnit:d changes produoed by t?CS or butTric acid. Moreover, certr in of ther studies support the pre+ni.e that the consolidation of the memory Iriroe is an eveat to which sdterNiotr. In specific metabolic pathways are linked. This /apar wr written with the intention of clarifying the mechanisms that link t!e i.duction as well as reversibility of retrograde amnesia 1o the induction u we.ll as reversibilit7 of biochemical eveets in the CNS. Essws.u„ W. t. and Es.roaa. S. O. Is: Delpd0. 1. M. R. asd DeFeudis. F..(eds.): ReA.vlo.rf Nerrorhernbrry. Ne.. York: Spedrsrm rublintion., loc., 1977, pp. 25-61. Pro.w Qneer CnMcte of the City University of New York, Flushing. SEROTONM AND MONOAMINE OXIDASE IN MOUSE SKIN: EFFP.Cl3 OP CIOARETTS SMOKE EXrOSURH Se.erJ reports MdicaN that skin saoweio concentration increases Ls re- tpw to snowo.miae osidw (MAO) inhibition. As a resdt. this study e:- arnines tAe eAects of /n vlrs cigarette smoke espoaure upon the content and di.podlion o/ akin serolonin and upon MAO isot:yme+. with the iMent of as- seri.R their baseline valuea snA dekrmiainR how these am modified tqr ea- pwws b 1he alkaloid and gas phases of cigarette smoke. Mak mice were ta- ptwed 1o eMber air or dgareqN smoke and the content and uptake of senNonie .and MAO activity were determined. Serotonin concentration increased as a (unction of Ur /1eM.cary o1 eapos.ue, while serotonin uptake by thr skia reachod lu wuaMw.. atser ts.e~ eollIN mewute esposures. Scroloniw.prcdfe. but not tyramlerapocdk. MAO actr.aty dccreasod after more than eight minutes I of ezposure to cigarette smoke. 7Li., along with observations on c{orsyline, a serotonin-specifk MAO isozyme inhibitot, suggests thnt mouse skio: (1) coo- tains at least two MAO isoxymp; (2) probably has greater serotonin-specisc than tyramine-specifk MAO 'sosyme activity; and (3) has MAO isozyme ac- tivity that may be differentially inhibited by e:poaure to cigarette tobacco smoke. Eszmen, W. Q. lournal of Mrdkinr e(2) •95-101, 1977. From Queens Colkge of the City University of New York. Flushin`, N. Y. AOE-RF.LATED DETERMINANTS OF STRMINDUCP.D Wtis(iHT CIIANUE IN MICE In this study of the relationship of ao to stress-induced weight changes, 60 25-day-old mak mice t:wd 60 50-day-old animals were randomly avikned to groups is which each mwse received Ave daily exposures to either air, cip- teue smoke or flllered cill)retle umke. The 23-0ar-oW mice showed a late peak of plasma cortiooMercwe elevation and a Sreakr incidence of weight loss among cigarette smoke<spaaed twioe thaw among animals e.posed to flltered smoke (gas phase) or air. Or the other hand, 50-day-old mice had a greater Incidence and magnitude d.' body weigM bse and a late plasma cortioostetoee peak after five days o( air aspuswe, hu/ not after eaposure to either gas phase or cigarette smoke. Die.w-phaNe sewlonin, while higher among 23dayold mke, did not diflerentiate well Setwees sttes conditions or relate to either weight loss or eortioosleroat elevation. It la suggested that the interaction be- tween stress and bioioRical:y active inpedients In cigarette smoke may be de- lined by eenual as well as periphenl phTaiofogkal and biochemical parameters. Eurn.n. W. a.. Kimmebd:l, P. awa Sporer. S. r+yeholorkd Reports 37:112-114, 1l7S. From Queens College of the City University of New York, Flusuins. V. Pbows.eolo" .wd BiochCmistrr RADIOIMMUNOASSAYS OF DRUOS OF ABUSE IN IIUMANS: A REVIEW Rdbimmunoaasay, a/eehniryue based on the competition between labeled and smlabekd antigen for binding to a limited number of sites on a speciflc antiAody. has been used successfully for a number of years to assay aod study dse metabolism of many polypeptides. hormones and aeroids. In 1970, this 48 49

/echniPse was used for the Grst time to dctect the presence and k.eb of a drug of ahuse, enorphine. Since then, radioimmunoas.aps have been develaped lor dNeclion of barbiturales, amphetamines. ISD. nicotine, rnethadone, metha- qrubne, and bentoykcitoniae (cocaine enetaholite). The specillc rad'aimmuno- ra7 methods are reviewed here with emphasis on applicability to rapid drug screcsin6. These reported lechniqtw, which aro simple and routine enou`\ to 6e applicable to the analrsis of a large swmber of sampks, are rapid, sensiti.e, speciec, reliaAk, and reQuire a minisnwe anrouM of blood or uriee. Most Irn- porlanU7. while these new techniques ean be srcd for screenin6, they can also be rred b obtain a better uwderMandi.6 of the physiological nxchani.rnP and disappearance rates of these drvp and thek n.etaboliw. C.rtr+a, A. .wd Mdtrs, 1t. Rese.rcA Coawwwwk.rioau In CArnrk.l Pathology and rAar+wrobp 16',2): 1977. Peaw the DeparlmeM of rathok+p. Uehrenit7 of Miami School of Medicine, Miral, PIg. rROrOXYt•HENE-INDUCED HYPOOLYCF.MIA This clinical ease report describes recurring episodes of hrpoglyeemla wNch oecvtred Iw a T4-rearoW man with diabetes and a sia-ye.r history of dttoek resd MwHSciency, after administration of proposyphene (Dar.on). When the awdeesic was taken by the patknl under controlled conditiooe after fsting, hypvSlycemia appeared after 15 hours. Howe.er, a normal rolunleer wrbieci studied during a 72-hour f.at before and after administration of pro- poarpAewe, dso e.prrknced h7Poglyaemia, but wot until atler 62 hmirs. Tht f.et MM 1. both indi.idai.Y studied the hypoillycemla appeared only whes the druB was administered in oonjrurctk+n with fastlt~g suqests that proloar- pAe/a rwsy {nkrfete with 6lueonewnesis. Prelininary data from studies of other Iwtnnl Indi.iduals suggest that the analgesic does not ileterfere with the inwwre rekw nKchani.m.e but the role of renal failute. if any. cannot be fut- ly at.cssed. Bee.use of the widespread tre of this drug. howe.er. Its potenlial .d.erse eflact..ppear soteworthy and the tnechanism of hlpogtycemi, warranta Iwtber study. Piorea: L R., Ront.tl, l., C.stre. A. and Mint:, D. H. The lo.vnJ of the FIo.iI. Afrlkd Asrarl.How 64:161-16d, 1977. OtAor..'r.rtr F{orida lu.enile Diabetes Foundation and National Institutei of Health. From the I)i.isbn ot Pmfoc+inolop and Mctabothm. Departmint of Mod.cine, and Ikpartment o/ Paihokgy. Uoivasily of Miami School of Medicine. Miami, na. 50 t A NEW SYSTEMATIC DFARADATION OF NICO77NE TO DETERMINE ACT7VITY AT L--2' AND C-S'. THE f ATTERN OF'i.ABEI.ING IN NICOTINE AND NORNICO7INE FORMED FROM 12-r'C) ORNITHINB IN NICOTIANA GLUTINOSA, AND IN NICOTINE OBTAINED FROM N. TAeACUM EXPOSED TO (r4C,rsC) CARBON DIOXIDE Although it is peaerally .ooepled that aicoline b a precursor of eornieo- tine. the methods used io the pnt to de/erwriae the pattern of labeling in the pynvlidioe rin6 of nicotine ras ptpdnoed conflicting resulu. This paper oow presents a new de6radati.w a6ew+e whereb2 the activity at C-2' and C-S' can be unambiguously deterntiaed. 1s wort $ased on this new sc6eme, radioactiw nicotine was Rrst degraded by ara following sequence: nicolise + cotinine - r1r-S'-phenylnkotine - oewsoit: aeid (C-S') + nicotink acid + b.riwn carbonate /C-2'/. The slrvctuor of 3'fAe.rl.iootist was oonfirnred by as unambiguous synthesis. On applying thb degradation 1o nicaina and .ornkotim Isolaterl fran N. ebNwosm pla.ts which Md heen fed (2-t•C/ otnithine. equal LheYss was found at C-2' sad C-i' of dr Anvtidine ring of both of these allaloids. Nicotine irdaled frorw N. r.Aarrw plants which 4d bees eapo.ed to (r•C. rsC) evbon diouide also had eqral labeling at C-2' and C-S'. These results, which corroborate previous wort en the ori6in o( the pyrrdidine ring of nieotine, are consistent with the forwnlion e( lhis ri.R oI both nicotine and oornicotioe from ornithine via a.ptar.etr;csl iMns.ediate. Leere, E. Jorrn.l uJ Ort.wk CAewastry 11(21) :)41IL3141, 1976. Other w'r.rtr National 1.MMr1es of Health. From the Naturd Products Lrboralot2. University of Minnesota, Minneapolis. T11E INTERRELATIONSIIIp BETWEEN THE METABOLISM OP (S)-COTININE-N-0XIDE AND (3)L`MNINE The metabolism of (3)-codew-No16de was slvidicd in the rabbit ond the dog. The patkrn of Koeniplesitire srbslanoes is the urine of these animals .uuesled the presesoe of aotWr, demedhlootinine, hydrosyootinine, and al• /ohydrotrootinine. 1n the dm 34% o1 Me ord dose of (S)<olinine-No.ide administered was roeo.ered from th..ri.e, while 21% of such r do.e was re- co.ered itom the urine of tlw nbsit. IsolNbw o( (S)-cotinine, (S)demethyl. cotinine, hydroxyootinine, .wi dloh7droarootinine, s such or as deri.athres, frwn the rabbit urine oosdtswed the pteaeaoe of these compounds. While the data establish the powr2tilkks of .o bMennedi.ry role for (S)-oolinine-No1id. ie the metabolism d.kaU.e, they do not elearly indkale whether such me- tabolitea as de+nethylootinine are formed .ia the (S)totinins-Noside -+ (S)- cotinine +(S)demethykoti.is pathway or via the alternate (S)-ootinane-N- o.ide - (S)-demethykolldne-NoanAs + (s)-denrethykotinine route. YI,1. M., Sprare, C. T.. BowssaR, E. R., and McKeni.b. H., lr. Drrt Mcr.Dol4rw.d Dlrtar/d.w 3(1):IS3-762, 1977. Other wrprt t Amerina To6.ooa (bmp.ny. From the Department of /'hvtnaoobpr, Medical College of Virgiaia. Rkh- reoed. sl

STUDIES ON THE IDENTIFICATION OF TOBACCO ALKALOIDS, THE1R MAMMALIAN METASOI.ITES AND RELATED COMPOUNDS BY OAS CHROMATOORAPHY-MASS SPECTROMETRY Althoush some knoww roules In the mammalian metabolism of nicotine are well established, other chemical changes that occur in the pyridinc and pyrtdidine rinp of nicotine still need to be cloael7 investipted. To proride a bash for such aw underiakin6, a systematic ps ehromato`raphic-mw ep:ctro- anqric (OC-MS) study of a series of estabirlhed nicotine mNabolites was us- wdertake.. The remits of this study of prdintiw.ry, OC-MS eaperimeals on Me drlet.wiwatioe of wiootina In plasma are rcported here. The observed (Xr MS dMa, especially whew f.cilitated by emhlph: iow detection, served as . good foundation fo. the de.elopwtewt of reliable quantitative estimnioe. o( •lood.a, its meubolites and rsl.led oowWounds. In an attempt to NhrlrMe the powwdalilits of OC-MS dclenwia.tiowa of tobaeeo dkaloide iw biological tiuid., blood plaoww wr obtained from two.wwters. L Ihae prelimiw.ry eaperMrcnts, derNtn/ed nieet]wa was added tr aw (Mrrnal Mandard b the heparh.-treated .eaorr bbod, and aw n-heaw ealract of the plasma waa wrb1ected to tR;-MS a.d7si.. TM ideetit7 of 15e s~ioodwa M the ptasma s.mpla wu ssrettaind b7 eb retention Wne, b7 reoordiw6 tlie entire maan spectrtsm and by refocrri.+6 on other tnar sualb M the wiootiwe spectrwn. Pilotll. A., Ewadl, C. R., McRewwir. N., Ir., Sownr.4 E. R., Du(.R E., and Hoiewedt, a. 1rYrigt tar Tdak/o.rr/lrnt f(6):)79-7N, 1976. OtAwr soPr..tr Awrcrica. Medical Association F.ducatiow and Research Fou.ddiou, Natbwal Irotitules of Health. American Tobacco Company, and 1M Swedish job.c+oo Company. From the Swedish Tobacco Company. Research Department. S/ockholm; the D.pwrLseM of Pharmacology. Medical College of Virlinia. Richmond; and the Department of Toaicolop, Swedish Medical Research Council, Karotiroka ).- MksMet, Stoclloim. NRMOd/Ki1ON OF NORNICOTINE AND NIC077NE IN GASEOUS MIXTURES AND AQUEOUS SOLUTIONS This study (oc+res on the teaction kinetics of witrosorwrnbotine (NNN) forntNiom in 6neorr mbttwea containing nornicotine and nicotine in ooocYn- trntions and ratios closely ttxmbling tho.e found in tobacco smoke. A omnber of model erssems were devebped in order to approairnata the eonditions of oitrosatiow thN occur ia tobacco smoke aeroaob. inchdirg d* proper sdt to free base ratba aad the aoceas of free basc to the gas phase. Results show that wrder optimal conditions for reaction iw the pseous phase, wornicoline r 1he fnec base reacted fairly rapidly and similarly to other seeadar7 bases. Nicotine al.o formed NNN, but after 15 minutes at 23'C less lhan 1% (4.7 ry/ had beew witrosated, whik norokotine yielded 31l0-3a6 pg NNN. This waeMs that the NNN for*ned from nicotine in cikarette urroke Is insignificant to the amount of nitrnsamine actualFy, contained Gt each puff of smoke while it is in- haled and cahaled during smoking. Gas chromatographic measurements of the NNN formed in aqueouu aolutiar determined that the optimum pll for 1M nitroution of noreicotins iw 0.3 ad IM buQer syslems is ).S. Nitrowliow wr almost nil at or above pF] 3.2, sd at pH 1.3. At or below pH l.s, decornpnii- tion of the unstable free wittvsr acid competes with the aNroaalion reaction. Considerable inhibition eC witrpsation ws observed with 1 M buRcn r oorn- pared with 0.2M systeer, By compwri.oa, similar study on the aittosatiow of nicotine in aqueous soluflowo showed dwA after only one hour at 22'C, 0.32 `/kt nicotine had bee. ariuosMed N pK 1.7, aed 0.20 6/k6 at pH 2.5. Tha highest amounts in this sxia were obtained dler eight days at pH 4.0 to S 0, when 3.3 6/k6 NNN wer= folrA. After 21 hoon, there aopeared lo be two pH maaiwu eorrespondw>t /u Lro dYleneel reactiow pathways. The reaction rata proceeded (aster at 60'42- aaora than 1% of the nieotine reKtin6 after 6va roirwtes at pH l./, awC tlw wratirwrr. aaiwrwn of NNN, •.19lL, formink after two hours. NewrrA. G. e., DYe6er. L+t...A NeiR P. O. In: Walker, E. A., Sopski, P. said ariciute, L (eds.): Ewrirowwrrnrd N- Ninosorowrpwnds Awd7d* wd forw..Now, Lyon: IARC Scientific Publications No. 11, 1976, pp. 227-236. From the Microawalytieal l.aborNOry. Hamburs, Federal Republic of Germany. INTERACTION OF NI'MOOEN OXIDB4, OXYGEN AND AMINES IN GASEOUS MIXTURES Previous sdrdie. oe.Arnl tlw siilrie eaide is almost the only oxide of nMro• 6ew found In lobaeeo sseoke thM b prodroed during tne normal smokinp of eannercial cigarettes. Nilto6es dioxide is wot normally present In fresh sreoke, supportiw6 the hypothesis dnt. In peneral. aiitrosamiwes are formed only slow- ly as a resuA of the slow eaidNb. of .ilrie oxide by residual oxygen in the smoke. While theee re few .etwl measwemewts of the oxygen contenl of to- baeco smoke, it is estinated to be about 10% under normal conditions. For this report, the kinetics of 6assai. taodel syMems containing the reactants iw relative proportions awd cowoeMntiom closely corresponding to thore found iw tobacco smoke were mewred is order to ehrcidate the actual behavior of the nitrosamierc precursors iw this type of gaseous mixture. The time slope, of the changing nitric oside concentrations In those mixtures were determined by ro- pctitive applications of the ehernihwnienoenoe method. This was found to be a sensitive awd relia6le tool if conditions are vcry carefully selected so as to eliminate Interference from otidtabie wiUV6en compounds. The data kad to Ihe conclusion that wiuoa.rnMrs eaw form in tobacco smoke under normat oos- ditions, though only In etttremely small quantities. Aging of tobacco smoke, especially In the presenoe of air, wIN wnvoidabl7 enhance the formation of nitrogen dioxide and, therefore, of N-nitrosocompounda. The marked eRecl of oxygen concentration and the negative eQects of temperature and of Increasing water content on the oxidation of nitric oaide constitute important wurces of 52 33

etror in studies on the nitrosamine content of tobacco smoke. It may be useful b remember that inhaled tobaoco smoke immediately enters the respiratory tract, where the temperature b about 37'C and the relative humidity is close 10 10096. NrawA, C. a.. DUeger. M. aed Pein. F. O. In: Walker. E. A.. 8ogoskl, P. and OrichNe, L. (eds.): Enrlronnrnial N- N/ne.aorwp.nL And7rlr.J Fornwlar, L7o.: IARC Scientifk Puhlicstiora No. 11, 1976. pp. 21 S-22S. Fronm the Mictwndytical Laboratory. Hawrbur8, Federal Republic of Gcr nany. Vi. lnansw.oloa .rad Ad.ptttro Meth.n.iam• M[P061S OP TYPE B ALVEOLAR CELLS IN TNE EARLY HYPERPLASTIC RESPONSE TO FREUND'S ADIUVANT Intr.renar injection of Fteund'a complete adjuvant (FCA) by way of tM marginal ear vein produoes numerous areas of granulornatous inflammalion In the rabbit IunB. Within a(ew days after injection. hyperplasia of trpe 8 (type 1) alveolar alla i..isibk on the surface of the septa in which an inflam- auloty reaction la developing A mitotic type 8(M 1 B) cell. ideminabk by IM peesteee of unique cltaaoenes which remain during mitoais and by typical .hort twicrodRi, was observed 12 hours a/ter FCA administration - 1he earB- eat timu ialtnd following treatment at which the animals were sacriflced. Ad- dldo..l MTB eeMs were found durinB the neat 120 houn, but were most nu- snarow bstweew 36 and 72 bwns, their (ncidence peaking at IB hours. Some of lhew oeRe alended .ctoa. alveolar septa with opposite edges facing two or tlu.a ditferewt air spaea: Me rest wtre located at the alveolar surfaoe. The et- /e.aion ot yp. S cells through alveolar aepte is not limited to mitotic ceNs, but M,aMe eb.er.ed ..Mh worrnilolk type s cells. Tlre e.idenoe supnta that type 8 adb tw.y be eap.ble of tno.enretN and thN both Ihis a.a mitoiia may be a tespo.r b 1M same apeci/k stimuli. 1s this p.rticalar eaperitnental yaMnk wrd tRMuM .n7 emanNe (raw dte inlerstitial ieBatmn.tio. Mduoed by Intn- aior pCA, Md.dlnB hKfen that Increase .ascular penneabilit7e chenwtactk factora, trtl .arbw wrbMa.oea released (ro.n kwtoclrtes. macrophati<s aed drttyeil pararcbynul cells. Still other evidence suggests that either focal Itcbemim dw Is capiRtr7 dtr..8r or twbataaroes released 6ae damaged capil- l.ris s..7 sd r MimuY for type R oeM rni.oaM and/or poa.ib/M mo.eme.t. Dard. D. L., Reta< R. D., Moore. R. D. sd erooAs, R. E. YlreAows AreMr B: Celi r.rAefop 2):209-21t1, 1977. From the Department of Pathology. School of Mediciae. University of OreBo. Ileait6 Scieoors Center, Portland. I 1MMUNOSUPPRESSNE EFFFi(.'fS OF )-METHYLCIIOLANTNRENE GIVEN INTRATRACHEALLY IN VARIOUS INBRED STRAINS OF MICE In this attempt to elucidats Ihe role of IAe systemic immune response dur- ini pulmonary chemical earcinogenesi, three inbred strains of mice were inocv- lakd intratracheaB7 (i.t.) with )-tnethykholan(hrene (MCA). Two Nnim, Cli1f/Mai and C378L/6Com, were aryl hydrocarbon hydroayla.e (Alllt) irducibk and a hifh incidewce of subeulaneous (s.c.) smd lung tumon was observed after s.e. or i.t. rdmiaiara/ion of MCA. In ahe D8A/2 strain. AHII is not inducibk, and few c.e. or Ir.@ tomom resulted after injection of MCA. hnportantly, the systemic Imnwatt repon.e to Boat erythrocytes was markedly wPPr'efred by MCA ow th 7 N in C111/ n.ke, as measured by both direct and indirect ptaqrc-tormin6 oeth, and in C378L/6 niks on all dara e.oepl 1)ay 21, aa meawred by indircct p(tM'(orwJwB eell.• Inwnwwwpptesion was not ob- ser.ed !. DBA/2 mkt. It b ekw, thereforu, fronm these results that systemic immarowppression esnnoc be discounted aa a ooMributinB lacto. In tumor Brvwth. The Imnwro.uppn..iee eAed noled here eorrelaled with the inducibili- 6n of ahe AHH ensYms ooatple: a.d e/ wMrwnaT tunats by MCA. te.y, R. L., 8.rrfngton, M. H., Lerwn, R. A.. OritM, Q. F., and Whitmire, C. E. (Mkrvi/oloRird A.w ridr; /nr.) C.nrrr Rear.rrb 77:)h2-711fd, 1f77. From the DeparlmeM d IAedkiae„ Utd.enit7 of Cincinnati College of Medi- dne, Cincinnali: DepartmetN of IntnrMropaholop, Scripps Clinic and ReseaRh Foundation, La loBa, Cd.; and Microbio{egkd Aasociates, Inc., Bethesda. Md. SITE OF ACTION OF A SOLUBLE IMMUNE RESPONSE SUPPRESSOR (SIRS) PRODUCED BY CONCANAVALIN A-ACTiVATED SPLEEN CELLS Soluble imawne ttspotrt ouppreror (SIRS), released into aupernatwt Buids by eoncana.aiin A-aeti.aMr apket+ oeBa, is a tactor(s) which supprerea plaaue-/ormin6 cell (PPC) rsapo.aes to hNarolo6ous trythrocytes by murine spleen cells /n rirro. The studies presented here eaatnined the ceBular site of action of SIRS In tiuppreesioo of PPC responw as a prelude to an MreNlp- tion of the rnech.nhm(a) of setion of SIRS. E.pawre o/ spleen cells to S/RS for two houn at l7'C or for etr hour at 1'C was atrBicienl 1o suppress /IR- da7 antibody responses fn .Mrr. Slwallar atpowra of splenic or petitoneal e.u- date m.eropM6es (M#) to SIRS .bo wtppressed antibody roalior ~+ by tw Ireated apknk 17mphold talr; atPnwtrs o1 spknk IrmPhoid eeBa so SIRS was without eQec1. AII the taperlsoMal resuha clearly irdieNt that Ihe target cell of SIRS i the M# populaNo.. This oondusion was derired tnom eaperime.ts wittg: (1) apknk adherent M# eaposed to SIRS afttr separation fro.n ly-- phoW ceMs; (2) splenk adherent Mi derived from SIRS-treated spleen celb; (3) SIRS-trea/ed periloeeal eardate rxB. (81X M#); and, (4) SIRS-treated ' 54 55

adheteal peritoneal esudar M+. The results are discussed in the contest of maaopha6e functions that could be aAected by SIRS. Tsdatums, T. and Pierre. C. W. TAe lor.wd o/ Immundop 117 ( 7):967-972, 1976. Othw .urroret U. S. Public Health Service. From the Department of Patholoq, Harvard Medical School. Boston. MODUl.AT1ON OF IMMUNI7Y BY MOLECULBS SBCRBTFD BY MACROIHAOBS 1Ln facb that msaopMRet sects/e some yeet(s) dfactlrg .arioan h mpho- e71. fuectio.s a.d that dds seetslion is acluar7 re6ulNed by the rnacro{iha6e's ...iro.u.eN strorKl7 wpeat (hat the aectetiou of the 17mphoslimulatorl, rnole- esie .u7 ha.e a ph7sioioRic role. 7Tte rewlator7 twrcBo. wwat likely d:.etopa •urf.R uptate o( a large bolue of an/i6en or following MteracdoW wW ) ad'p .a.t., d.es both circ.rnrta.a.+ lead to a,hort rekase of the nwkeub. I'urtber amJysis of tYs mecMnbrn and o1 the aalure of /heae lymphwtinwlatorl, nale- euks iouW provide further iesight Islo their possible biologic effect. Uw..r.. E. R. I.• MkaeheY, P. A. (ed.): InrmrwprAororY. YIld1 /nttrw.rional S)mporirm, Rof Seh.rAew (Qe1*mml) 1976. Sa.el: Schwab. ! Co., 1977, pp. 35-49. Ot'A.r w"..tr Natk.al la.tituw of Health. Prow 1!e Departnx.t of Pathoiogy, Harvard Medical Schod, oa+wo. RFAUU\T1ON OF IMMUNi7Y AND INFIJAMMATION BY MF.DIATORS PROM MACROPHAOI;S Mowo.uckar phapoc7b secrele into the extracellular environment a mrn- ber of bido6icalf7 .cti.e products which enable the p*a6ocTln to nadulale Ihe acti.il7 of sutroundin6 eelb .nd/or tiswrcs. Tlus article summarizes the most sigriAcanl a+pects of thia tundion and focuses on the maiw reaules of research dealing with the secretloe of Iymphonimulalory molecula. The products ae- cRted by Pwli«11u are classifkd inlo th.ee hNe*related eatefories: (1) etr s7ma aAectia6 extraodhdar ptvleim (oolla6enaae. etaslase, /ysosomal pro/ea.ea, plrwd.o/en acti.ator.); (2) substances involved in host defenx prooanea (complement prMein., Inlerferom Iysotrme• micrvbieidd products): aod ()) factors mgulaling the acti.itiw of •utrounJing oe/ls (lympho+timulatory mote- euloa. cab.t ..onuhun@ I.rton. M.W nu4nul.r weqhl cell slowth inhibilon). lb enacrqhy.. ...,..ye tymplwrr1mutatu.y m.decuin whfth 41) increa.e DNA synthesis in lymphocytes; (2) stirnulale the maturation of early thymo• cytes to mature T celh; and (3) induoe the diflerentiation of some 8 ulls to sntibody-secreting cc1h. The milooewic principle has been partially isolated as a protein of about 15.000 to 20,000 daltons iw size. The basal production of the active principle varies greadr (rors preparation to preparation, but Iwo different conditiorn increase the secretion of lymphoutinwlalory, mmolecules: (1) addition to the culture of various soauble or partttvlsle materiah that interact with the macropha6es (anlibodytoa/ed red cd1t, 1a1ea particks, endotoain, beryllium aa8s. bacleria); and (2) addition of activated T lymphocylcs. The state of macropha6e aclivation appears b be critical for the secretion of lymphostimu- latory molecu4s, since this alopp after a critical level of activation is reached. It is also suggested that the rwecha.ism o1 action of Immunologic adju.ants may operate through the manvphye aed release of the lymphoslimulatory factor as described here. Un.wre, E. R. er d. An.r.k.n lo.nnd of rrAobp 83:165-1711, 1976. OtAer.urpeetr Natio.d Isdtulesof Health. From the Dep.rtment o/ P.NLoiopr, Harvatd Medical School. Saaton. I THYMIC MATURATION IN YITRO BY A SBCRETORY PRODUCT FROM MACROtHAOFs In the esperimeMr peae.led here, thymocyles were cultured In m.cro pha6e culture fluid (MCP) and dN folbwi" three p.ramelers of diBerentia- lion were examined: (1) sur/ace espteriot. of rna}or histocompatibilal (N-2) antigens: (2) surface eaptession o/ Ihynws kukemia (TL) antigen: and (3) the capacity to respond in a mbed lyraplwerle culture (MI.C). Results indicate that irnmatun:% thymocy lea ean diQerentiNe M virro under the adluenea of MCF. This maturation, which oot:un durinR several days of culture, does not require DNA synthesis. It ia aooompMded by an augrnentation of surface N•2 which preoedes a br of su.oeptibilit7 to eytdysh with enti-TL and aompk- nxnt. There Is evidence Mrdicating then is no physkal loss of TI. witnin the thymus. Thymocytes cvNured with MCF also acquire the capacity to respond In an MLC. As for the mokr.wAar entity responsiMe (or the maturing eflrct, it has been separated from the principal mitoienic protein in MCF on the basis of molecular weight. Since various esperimentd procedures have eliminated interferon as the maturing motecuk. M appears that MCF conlains a thymoc7le- diRerentiating factor operative under im vitro eonditions. Selkr, D. LL and Unawue, E. R. T11c Journal of Immrnolop 116(S):17110-17117, 1977. OtAee a.r'ert r National Institula of Health. From the Dep.rlment of Patholo6y, Harvard Medical School, bouon. 56 57

AUTOMATED RADIOIMMUNOASSAY OP CIIORIOMAMMOTROPIN (HUMAN PLACENTAL LACTOOEN) The method described here is based on a novel, automated system (Centria) that in many respects is a radical departure from conventional ways of perform- kn6 radioimmunoassays. TAe new system permits the simultaneoan incubation and separation of many samples in a noneyuilihriurn asaa7, and measurements are obtained in kas than 30 mirwtes. Results for clinical samples by reference radio- Inxnutaassa7 methodology and with the Centria system compared uniformly well. No i.hcreM erTor was found in the system. The coeflkient of variation of the asaay for samples run in dup/icNe the sanre day was 3.2%, and 7.4% for samples run on diRerent days. With thb srslem. It was possible to assny mae Ihan 60 samples of choriomamrnotropin per hour with high sensitivity oed spe- ei/kMy. The specifkity, senaitivitp, aiimplicily, ad speed of Centris m:ike It a •aelui oew, ttool /or kinetk, .or+equilibrium immwroaray. Carrro. A. en .1. Clbwk.f CAen+4" 2 2(10 ):163 S• 163 t, 1976. Prorn the DepartmeM of P.tAofo.*7. Univenit7 of Miami School of Medicine, Miami. Fla ENZYME IMMUNOASSAY OF IIEPA'iTT1S ASSOCIATED ANTIGEN (HAA) le reoent 7ean, radioimmurwar.ay has become the method of choice for asdRew dderminations reauirin6 6reat sensitivity. However, other highly seriai- {ivt .nd peci/k techniques ne being souglrt, largely because of the radiow tivity kwzard. the ahort life of reagenls and the hi6h cost of equipment in- volved fa the proeedure. 'DAe ahernative method described here, also a Mnd- wkb tryp+ of knwnunoawy. uses an enxyme-labeksd antibody Instend of a rsidioacliva one. The borrrd alkaline phosph.tase-t.bektd antibody is defer- miaed by the addition of wrbstrale and photometric me.anrement of the prod- tse.t, When IW trrethod, Ihe Cadia HAA (hepatitis associated smtl6en) ewzyma k+a.r.oaas.y, was evalwled for Ib .xw.cy tgaiirrt a popular radid+wrnno- aaaaP (Auaria 11), 9'% of dn 1.063 disical specimenr testod nlrowed lir. tiam. nwi1., rl/hew twnre of drs di.crepant 2% wers relested, only two rmptes wero oowenn.d'oakls. Cordik but aepti.e Ausria; only one waa .eBative Cordia and'oaldv. Ausria. TUu., 1n cmmparksorr to r.dioMarrrrrro.r.y. this puticular bl b neladveiy sinrpie, .ava lime and mont:r, haa a IaK sheU life, aad la trler, yN duaa trd .auiBa sert.il'rvit7 or accuracy. T1rb should make It very atlroeli.e to moat hospit.h srd b/oot baaks, but especially so to laboratories 1. devekWioR Corrnerits whta• highly rrairred persoene) and furda for r.tpeeaive .ophWicalei erarripwrent trr parlicahrty, lacki.=. C.rn.. A. .n J. RerrmrA Cowrnrrn4arlon. In CArndcl Pathology d rfl..rn.rofop 16(1) : 199-202, 1977. Pran th. Deprvnes o1 Pathobgy. Hormone Research laborNOr7. Uaivcnit7 of Ml.nd 3clrod of MedKr.a, Munr, Fla. . MONONUCLEAR PHAOOCYTIC CELLS IN PERITONEAL EXUDATES OF RABBITS: A COMPARISON OF INDUCING AGENTS Numer+ous materials have bees used to induce a cell-containing peritoned eaudate (PE) in animah, bu/ eo comparative studia regarding the various methods of stimulating lhis reaction in rabbits have yet been published. It seemed useful for esptrirnenlal purpwe% therefore, to compare the number of cells recovered from rabbits al three or Ave days following intraperitoneal fs- jection of light mineral oil, tlwoglyeolate or glycogen, b that recovered from normal uninjected or aaline• rabbits. The etudates were ch.racterizad by total cell counts and by i.1 cell count proAla. Thio6lycolate stimu- lation induced PE eontainkill 30 times r many mononuclear phalocytic cells' (MPC) as that recovered frorrr worsnal urntimulaled or saline-injected rabhits, while mineral oil adnwleliorr irrersaaed the MPC yieid 1 S•fold compared with control animals. OIYeoWs alinMdNed only a rnodest increase in esudale MPC. Based on thc.e resnJb, and ai :ta eaae of administration compared to that of mineral oil. inrraperiloned i.;actkflw of Ihio6yeolate seems to he the method of droice for the slimulatics o. :~w eardale containing a maaimum number of MPC. Conrad. R. E., Yang. L CC a.d NerscorrlK, H. e. lorrwd of voc.tiowal AeA.rW 10:231-21a, 1977. Other .uP'.r1 r Natioed IawRsMe of Health. From the Departnrenl r( Micsobiobp, Oeor6etown University Schools of Medicine and Dentialtp, qrhkeRlot. D. C. Vq. Bpirlomlology PERSONOLOOICAL INTERPRETATiON OF FACTORS FROM THE STRONO VOCATIONAL INTEREST N.ANK SCALES Previous allempta lu te1a1e eocrpational groupings to personalit2 dinren- abrn by lact« an.fytke freoedures bave betn oeucwed by the fact that voca- tional interests and personality ere arol ariny comparable conceptual dorn.ins. 'RThis study attempts to eite,nrreN this problem by factoring the Slronp Voca- t{onal Interest Blank (SV1B) Wd( and dmw eaaminiiy the pattern of perww dity, corretaks b aid In the ItNetpretalion of the ooeupational scakn sroupinp. Thw, a principal aala fasbr audysH of the 36 occupational and nonoccupa- litmal scales of Form T u( 1ht SVID was conducted using data obtained from 1.06s maks in the No.w.athr. Aging Study (a mrhidfseiplinary lomitudinal study of norrnal aging and heaNh). represen11n6 a wide range of age and soclo- ewnomic e*oups. Fiva factors accounted /or 90% of the vari.nce: () Pe+soe venrs Task Oriealatloa; (2) 'ilreotNicd versus PraclieN Interaction St7k: (3) 52 59

Tough .enus Tender Mindedness; (4) Self-aasertiveness versus Retiring AI- truism; and (5) Business versus Healin6 Psychological inlerpretalions of these faNon were provided by correlsling them with the Cattell Sialcen Personality Factor Queslionnaire, the Ailport-Vernon-I1ndsey Scale of Value., educalion, and socioeconomic status. Both occupational groupings and personality corre- IaW agreed closely with the system devised by Holland in 1966. Ooe1a, P. T., )r., Fotard, 1. L and McCrae, R. R. (eoaf, R.) lannl o/ voc«ionJ aeh..lar 10:231-243. 1077. From the Uni.ersity of Musachusetb, the Veterans Administration Outpatient Clisdo, ard Harvard Medical Schod, !loatoa. A PO?ENTtAL PITFAIl. IN STUDYINO 7 RAIT-DISCORDANT TWINS Some reoeM provocative dats derived from the Swedish. Dani.h and U.S.A. veteran twin repstries niise questions concerning the relative detrimental effect on health of smokiss rrr sr as compared to constitutional or environ- ' rsenlal fadors in aasociation with snakin6. Particularly important In the Swed- kih and U.S.A. data is the fact that ideMical twin p.in with one arnoker and one sonwrwker (l.e., smokin6discordant ma+o:ygotic twins) so far show no sipdkasl diRerence between them with re.pect to the prevaknce of anilina Peeloria, r diagnosed by queslionnaire, or to total mortality. The same lach of difference prissikd In twin pairs with one heavy and one light smoker. How- ever, as well-suiled as twins are for evahrating the net influence of a certais trsit or In/luenee in epidcmiologic studies. the suthor proposes that traitdis- ootd..t twin pain potentially have an additional shared factor due to gennally prrr.akM aror rates In data gathering tbus, there may actually be a substan- tial amoua of oorroordance for the very trait that is supposed so be diuordant. A wtaerkal e:ampk is given to Illustrate the problem, and a simple formula Y deri.ed for estimating the proportion of apparently discordant pairs com- prised of pairs that are truly discordant. Any sub-group which represeMs a tMUaR proportbp of a study populatiow ao easily beoome dWped by misclassl- ied arnnben of thn rcmaisder o1 the study population. Howe.er. In studies of Iwins, rnMdassi/kation errvrs are especially apt to lead Io false discordance. Whh trsitdisoordant twirr, the poleelial dilution may lead to conservative -.va- drrions about the relation of a trait to a disease, but to noneaeaer.alive aon- ehnioes about Iha importanoe of heredity or other shued factors in its etiology. 71ws, ewtion should be esetdaed in reaching either negative esnclwions about a Ir.Ndisere assoeialion or positive ones about a hereditydisease associuion, espedally when the medad for measuring Ihe trait involves an errvr rate that , is a aibstastial fractbn of the discordance rate. Eatra efforts should be n.de M.erify 1ha characteristics of apparently discordant twlm, so as to make sMdia of this type of population r accurate aa possible. Frinfnrn, O. D. A nwric.n lon.wd of EWcnJolory 103 (1) : 291-295. 1977. FFrom the Ikp.rtment of Medical Methods Researeh, Kaiacr-Permaneste Medt- ea) Care Program. Oakland. C.1. I DATA PROCESSING PROCEDURES OF THE FINNISH TWIN Rf:GISTER. COMPILATION AND MAIUNO This paper deals with the data prvrx.inR aspects of the Finnish Twin Registry. The actual methodology ard the formation of the Registry are de- scribed elsewhere, but sonts pertwrcst background information is discussed in this report. Modern automatic data prooessing has made it possible to compik, maintain and use large population registries. Worth mentioning here is the fact that this is particularly feasible irt the Nordic countriey, where migration is followed both interndlr and abroad making it possible to trace neary all citizens of Ihese couMries. The Frnaish Win Registry ainw to include all living pain ol twins inchdins individuals living in various inslituliona. C'Iwosin6 twins from a national population ovoWs any bis Nemnwng from the use of selective rnNhods such as military raoads„ school records or mW media. The steps In- volved in estimatiss tha awnber of twin.. Iw the compilatiow procedures. in the mailing prooess. in the oodin6 ;Ad /..chi.K procedu.es, in correclion and com- pktion prooedures, and i..PdMiwg and follow-up prooedures are described Is detail. Tabks, charts, a cowrpMtx rnrr eow-sheet, and a biblioilraphy are in- dudr.d. Sarea, S., Kosken.vo, M., ::apMor l., asd R.nsn.lo. /. Xau.nrtrreystlatew ldldsoEa M(Publie Health Science Publications) 19: 1-22, 1976. From the DepartmeM of Public Health Scienoe, University of Hebinki, Het- sinki, Finland. METHODOLOGY AND SiRUCR)R1i OP THE FIttNISH TWIN REGISTRY Twin studies, which pevsids a natural way of assessinQ the relative ro{es of heredity and envirerMneM In any given disease process, have been carried out in a snuB, weNdellned way ever aisce 1975. Ilowever, In (966 the World Health Organization held a eonferenoe on twin studies in ep:demioloiy and called for the establishment of larp or waional unselected twin re6istrics lor the study of major diseaw. Denm.rk and Sweden already had twin rekisarin at that Iime, and In 1973 It waa decided 10 establish ,. Finnish -TwM Registry at the UnivenNy of Hetsk.kl. This resi+try, which has been in continuous oper- ation since ib establisfwnenl, aYwa at forrnMrg cohorts of twins of the same sex in three different age groups: (1) 0-7 yean; (2) 5-17 years; and (l) over 1• years. At prssent, the l.st oohat hr been /ormed and a ouestionnaire, asking for base-line information to be used (s follow-up and additional studies. has been seM to all the adult twin eandidata. The InNial follow-up period for Ihis study will be len yean, after which an assessment of Ihe results will determine ('nure devdopment. The four main sources of inlormation that will be avail- 61 60

abie for uae In future Finnish Twin Registry studies are the questionnaire data, additional questionnaire studies, data from oAicial records, and the results of clinical e.aminations of twins. The Helds to be studied will be chosen carefully b belp elucidate the p.rt environmental factors play on the manifestation of diaea.ea and ie mortality. Kosken.+w, M.. S.rn.. S.. Kaprio. 1., and R.rrvab, I. Kwnr.wrer.Yyrriereew lufRd.uf. AI (Public Health Scieoce Publications) 20:1- 16, 1976. ` Front the Department of Public Heah<t Sck.oe„ Uaiver.ity of Hebinki, Hel- eiak(, Pldaed. ZYOO6ITY DIAONOSIS IN EPIDEMIOI.OOICAL TWIN STUDIES BY BLOOD MARKERS AND BY QUESTIONNAIRE T1u diagnosis of the zygoaity of twins in epidemiotogicd atudies has cre- alod the seed for a reliable method applicable to a large r.umber of twins. In tlr preaent aludy, a Questiortdne method used for this purpose was further a.al.abd aed dereiopcd, and the validity of this diagnosis was .eriBed by blood matter Itkly. Thia la.t asethod is considered the moat reliable one for the delers.i.ation o( sysosky in twins. Uwtil now, however, there has eot beee mathematical treatment o( t1sis twbjed r a whole in wnUkd fortnalism. Conse- q.eaUy, eettain atatiMical, computational and theoretical cow.iderations were ad.piad aod derdopod for tM .eeds of ehis study. A general purpoae allorithm for dn dNerrnieation of oo.corda.ce probabilities of Mendelian marken in twins was de.ebped, tolietbet with a cost-beoeAt algorithen for presekction of sarlert In partieutar, a speciik simulation model for Mudyin8 jeaetk tnarkers on the population kvel wr elaborated. The questionnaire dia6noa4 delermined by oowtbination o( detcrmiaii.tie and stochastic methods and the bbod marker leat re.ult. were iw very good a6eeement. enabling the delermiwatio. of xygority of o.er 96% d respondest pain wMh nearly 100% accuracy. 7tnw, by apply- 1.e tha diAerest aeethods de.eioped and di.cw~ed In this Nudy, the zygosky diapoais o( twlr In the Pi..iti Twin Registry can be established. 3arr, 3. (Rwra.d.. !.) K.w.wrerveytr/etern /dRdrr/. Af (Public Health Sckaoe Publications) 27:1- /!1, 1977. Proa the Deputment of Public Health Scknu. Udverdry o( Hclainkl, ttd- ainki. Finland. VI1C. MF.cdr.rreot.. lAX INBRED AND MUTANT BPARINO RABBITS The lackson Laboratory rabbit colony was started in 1929 and has been developed through inbneeding owcrossin& and perpetuation and utilization of apecifk rabbit mutants ia(io three inbred and about 14 partially inbrrod strains. The stocks in this colony (which hn been ebsed since 1932) differ in a wide variety of parameten and carry a group of rnutations whose phenorypic ea- preuioen resemble human eaqlilut{onal d=easn. Theae Nraina and mutationa constitute a scienti6c resource that ia availabk for sre by researchers through- out the scientific community. A bibliography on atrain eharaeleristics and on al/ of the known nwtaM S enea ef the rabbit is malotained at this IaM.ratory. Aeirnab awd Inforn.aliow obotA desw am available so anyone on request, and collaborative research pto4nar .nr encouraged to e.pioit more fully this vah.- abte resouree. Such propama trMreMly incbdt research on ataxia, buphthaimia. Urnori6eaeai, dwarfing 6enet;, asleopetrotis, eorticosteroid kveb, estera.e., other isoeymk proleir, and ptoleas iahibitors. Fou, R. R. (Mekr, H.) ILAR News XX(7):2-4, 1977. OtAer ar'p. ft Division oI Research Resouroes, National Eye Institute, and the Nationai Cancer Ia.thule. From The Jackson Laboratary, Bar Harbor, Me. FRAC'TIONATION STUDIES OP SMOKE CONDENSATP. SAMPLES FROM KENIUCKY REFERENCE CIOARETiES Smoke c+a+denute aamplea lroa. University of Kentucky reference cipa- tdtes, IRI and IA1, smoked ew a tobot..moklng machine after conditioning. for Ia hours at 7S' P and 60% etlatite humidity, were separated into acidic, basic and neutral fractioar` thea further subdivided into 12 /ractions. T?rc eon- dcmate sampks were walysad for wiootine, phend and bento(a/pyrene (BP). The ethir-soiubk b..k and weakly aeidie fractions were tested by gas chrorna- tography for nicotine and pheaol /eapcetively. while the eitranethane-solubk (raction was analyzed for !P. TM }henol and BP kveb vpied signiflcantly in their respective fractions ftaw IR1 anwte oonderoate. but only slightly ia the fractions (ran the IAI ooderMa a..rplea. PNd, A. R. et d. (Afdol t.iro..es./r.. /wr.) Tob.rco Sckwce 1t:71-39, 1971. OtAer supports National Cancer Institute. Ftom Meloy Laboratoriea, lae.. Springfield. Va. 62 63

Active Projects PRINCIPAL MV/STICATOR nto,>•Cr TraI.ra OR a1V3IITRITION ELROY T. CANTRlLL, Prt.D, ClVab- AM !•ydrocubon Isydroaylase in single Following Is a list o( the principd in.esti6aton, or institutian, of m.w, Dtp.rrwltwr of rhrw..co%gy, alis and sub0oprtations of twrnan /ym- pto)eb wtder way or acti.aled in the period since the prerious Report, Tesas College of Osleo"Uie Medicine. Norttt Te1ae Sule Uwr.esslly Dewto. pMocytcs. and olller cells together with the respective project titks. Compkted projects are listed in , . a sate~ sectio.. ALeFRT CASTRO, ts1.D_ DlrtcYos, Hor- Nicotine In blood: detection by radio- w.owr [.Ior.ra.yAssod.rt he/taser imle.noassay of Mrliriwwt. Uwi.essity of Mi.wJ FR1N(.7P fr i1CAT Ot FROJiFLT i1T1s School of Medkia Mimok FL. L8O O. ADOOD. !•1 D-. 14e/ras ./ RbcMwtu.7 ew/ Rrdw Rtar.rcal, Cesf 1a fe.lkai. ReseuctR. T1a U.i.enily of Reclersa Madkd Ce.1., Rocles- M., N. Y. /O3!!tH C. ARCOR, _D.Sc. MJ.rw o/ M.JkMr, T.1w Vwi.er.iy 3cYod of Madkire, New Orkar. CARL O. BtICKER. M.D. Aasocirrr rr.Jtuer of trAolory. CorneR Unl- ..rskV Medkal Colkm New York. WILLJAM F. MENeDICT, M D., A»l,ta ear hoJttaor e/ lrN.nks, Un1.enNy of 3oMfesw California Sct.oal of Mcdi - eMe. Dieisien of /ten+Nolop and Med- kd Oeneliq Clildren'e Hoqilal of Loa Arydes. Le. Mlaeke. RICHARD 1. BINO, M.D. ho/rtsor of Mer/eMr. U.i.asN7 of 3oalerr. Gli- forM. 3cfod .f Mediciwe, Loa Asti tieler YlrMisill, AsaxieN /w f/owwlk+d Ewciwrrriew. Califorai. Institute of Tecit.oloq; D/.errar o/ C.rJlolesy . .wd /ww.wer+/ M.Ikiwt, Honlingtow Mes.whl Ho*ilat, !•s.dew., Cal. P'RAN~013 M. ROOY3~ ~D. Assorl- ert rv/t.aet of tler/lrwdwry. Ranr- !•seslylni.wll. L.le i Medkal Cen/er. (.'Mc.p. RAYMOND 00336, !'f.D. Assori.rt Dkthw Nwn.tNa As/ws Study. Ve1- arw Ajn.i.l+ArNiow OvtptkM Cli.k. RoAOa A. !(1N1A DUIST, M.D.. As.eriut hs /rs,o+ o/ Mrfkln~ .w/ rAy,blog). lJnl.er.i1' of (1.esow 1lealls Scknces (;anler. 'ortland. lels..lor>tl a.d Dix~elnica! sls4" wMth niooUr 3y.eraYlk e/ecu of Polycydk Ar tcocar- bo.s ad ilrwuwiaea I. pli cuci~o , ~e lenti.l rqreaor snetabolitictieNi tble nt i.l ow of oitroaa.liees Actieatilla welrbdMlw of diall"l awa cydie wkrcr.n.iwes awd V.dks of the resRo.ee to eraywa iwdncen. R4 /elio/. .biF to ltydreurbon-ailroe.wiLMe sm cardno8 e.esis In.esligaliow of tbe role of dkrp /o lobacco eoaslituenls Iw Ilise oa/Aoleneres of arterbsckro.n awd rnyoearc-.al i.- rsrcainw MahgnaM transformation. ewlajenesis and rlbrinol siw roductiow of ci y p { arefre I IACK CHALON, M.D, Assai.le rs- sor of AwrsrMddoly. New Yorld- reesMy Medicd Cema, New Yat. CHARL83 O. CO(:HR ANQ M D,Mrws• Irr, Sce{pp. Cllwk ed Rr..uc! Forw- dalio.ti (.• 1011141. Cd. ALLEN S. COHEN. M.D. fxD. Ar sociut rro/rssor of MtdkMr, Tewqle Unl.crsi/r Heahtt 3deroea Ceaer, Philadelphia. Laidelniolop of traeleobrondtial epilla lial ewllinudeMion TlM swedialbr of iw/r.alalo.y inilwy of ti.w. T1e fewctk dtfed in aiFYe-l-aaitrypria Ac/kkrr ptie.u The etternkd baais of tM desip of Itser., "rc .aeMa for ulliprolcolylic astic- Ar io tke IreMw.eM of anpiysen.a TYe reiaiows between snwtielg /nothe% Persow.liMy and feelings l.erttoeyle dasl..e<anolelnenl interao. tiows in /re Hioloq of emphysema PAUL T. (,`06TA. !r. Fw.D. Aauiatt rrofrsor of r.yrAo/m. U.ieee.ry of Maeacl..etls al Boston. Daelewa. IRVINO P. CRAWFORD. M.D Mtw.. 1e., Drp..rw/twr o/ M Scrim Cl'wie and Re.eaRY F tio., La lotlK CaL .mAe condensa/e rradions DAVID W. CRUMFACKF.R. Fa.D. H*. Oenetk and environmental factors af- nAibi/ion of eiokslernl I tate by a- /raer ew1 C Dt/ulswewt of EwrYewwwwrd. r ewIOft*' Mwwic /iofov, @[ GslerMU. bolAder. feclina smobielg behavior q As~afwwl FRED DOWNEY Fw D H Effects of tobacco srwoke and skollne om krits in .kro and in rlro . . . IMlwssM7 e1 rr~o/rssor of lArsior<oh, ooro.ary collateral blood Now 11ribNbe of e" okslerd.olate by 7-kelo- ~ Teaas Health Seknce Ce at D.R..; elolesletd Dirrcror, Cerlloeeacoler Rrsr+c#. dioOWwww.ry Iwsliwle, MNtwdbl Hor FJkd of cubew wo.odda ew.Klatwliaw Fi/a1 of Ddlati D.Rea. of Ilr arterid .rda D hD M SSMAN WALTYR R F Mel.irolk response to nresrtobooco , . . . ewd 11/scAtwr- lo A , r f r snate in/eractio.s fw .l.o .aA M.kro respowus of endo- ettelial eeRa and plakkts to niootine ul/ q syc o ro/rssor o lscry. (Ilreens colkae of IM CN7 Unl- edrads from daad.rdised eiprale versily of Ne. York. F1uMry. rnoRe oowdew.Nes r~ Dt - HUOII E. EVANS. M.D. Dk.cro Pre.aknx of Pi lypes among newborn in- A sn.otIng; reseuc\ proieec In 11e Nar- ~ ~ perrw~rwr of hHecrirs, /twktt sorr- fants of di/lerem ethnic backpounde wulin Aging Study 1al aed Medkd Center of Rrootly4 erootlyq N. Y. OAD FF-INSTEIN, rs1.D. Srwto. L.e- Seodks on pet1ide bond soeci11c/1Kq aa ha 1-alrflryodn denckncy TLa rok of al rrrr iw dbrArwJU.yTM Oeorp S. /i.e siN and Inhibition of 1wni.w ku- p ...enm of lsi factor tw 1he de.elr. a a WIea Cenecr of t.ife Scie.oel Tel Aviv coey/e O.oleasee which aee irnpiKa/ed p . r cbron/c aNway. Ob.rr4d1011 U.i.crdty. Td A.i., l.ad. Iw the p.lboaenc.is of twwlrnonuy ew- oayaetwea 64 65

PRiNC1P OR INST WILLIA /cnor AL INYTSflCATOR 1MlON M H. FISHMAN. rflD_ of r.rAol.vy: Dbecro., rro- Tr/rs PROJECT TR1= Cancer phenolype poNe which may pre- sege hrondiogenk cancer ~ C.ncrr Rrsr..cA Crwrer, Tufls Uni- i verisly School of Medkine• //opon. M.rker proAk ln bronchial mucom and (Now r.rsilrnr, 1.e )dle Curclr Re- seards Foredelioe, La laila, Cd-) neopiasms of smokers and nonsmokers LARS FRISERO. M D., rro/esror and CAdrw.r. Drr.rtw.r.r of Ew.froe- wreal HftMwr, The Kardisks l.n4 b1e, SI 1Ldwoc OARY D. PRIP.OMAN, M D. Senior EPiM R.ido0s, DrY.rrnwn/ of Mrd4vd f1lnAods RrrrorrA, K.iser Forwd.rioe R..eareh Irlkwe, Oaklw.{ Cal• MICHAP_L O. OP-OKAS, M.D. Ph D_ rr./rsaor and Ykv<'A.Yn..w. Drprr- wrwre/ AfrlkMe• Uni.e.sitr of C.li- torwi. School of Medicirr, Davis. /ACQUPS E. OIELEN• M D.. Asd.rsnr lrv/eare., L'aIo+oro.y of AIrdK.f CAen.lsrry. Tos.rolorip and Nrrirwr Instkhrq of Pathology. Unherswy LktK, LhAe, Rellwuw. OERALD 1. OLFICH• M.D. Cons.lrewr i. Mr/kbr, Resevcb LaAorelory for Allcrgie Diseasee, Me~o Clink enl Foeedalbn• Assoriorr rreJrsw. o/ !w- Mrwd M.fkMr and ln.wr.wologf. Maro Medical School. Rochewer, Mi... IOHN W. OORROD. D.C-C_ Lerrer.r Iw . Chehee Co1kR UwHer- sNy of La Lo.doe. HODA A. 01.11111013, Pu D_ Asreriae rrolesaer, oof rnrrairr Ald:rlwr and r.dfk HrdrA Creighlow Uni.ershF Ssioo/ of Me~ Ornekes. Neb• LINDA M• HAl-L, M D_ Adronr rro- u IastL /M. of OT/ ed.~~o~t1. C.w.ltidp. MAROIT HAMOSH• Iw.D_ Rrsr..rA A..r.rlrr. Drr.nn.rnr of rArdofotf and <3.awpAO" l)ni.cr.Mf 41rde ot M.d..rw. ..J Dear v1. W •.M.yeoa h 1 P;iiewiolosical sludiea on the Swedish t.in rqiMrin Crees of death in relalion to smokiaR IrbNs and other heh.vior.l and esr •irowrwewt.l feclo.s. A study on /4 S+e1iJ T.iw Registry Chr.cleri.lke of swoker. .nd noe- .wokers LonRM.imt eawsoker steft snJ ihe oo- •ort s.Wlelily study T.is eedlstry fea.lbilil3• study CkavlNirq pwaealk el.re.e snA erw- pbY.ems in n..e Cigarette unoke and piycyclk. h o- urboe metabolism In lung and k' 1 HqerseesilivNy to aMisern frow to0.ec+o r• factor le Ihe p1bote.esis of chrowic bronchitis Hanen hyFersewslllvRF to ss1lR:es fror. 1oMrcco Tfe e.elabdism o1-pyr idiwes" M reldbn lo tte inductioe of aeool..fjc Ii.ew AHH and related IrrwrwnoAenkal wurk- en: a w.soqtibilitf bde. /'or lury c.noer HeredNerp .lterelions Is ekolies se.d- livfly The e/led of elprene r*oke oe h.ot n+eleboliwn h.in.r.l lung drvelop.ne..t• a.elabolis.. ...f ayu.ar en..k. 66 I I PRINCIPAL INYGTI1GATpR OR Irq1TIUTION PAUL HAMOSH, M.D. Assecirr Pro. Jrsso. o/ rAYsioi'op a.I AioRAysks, ond A/Nicinr. OcorRe/owra Uei.ersily Schools of Medicine end DeMislry. WashinpoR D.C. NORMAN W. HEJMSTRA, PR.D_ he- Jasor of rsycAolosl: Dincro.. Haw.r. F.cros LAor.ror7. Uei.ersity of SoMh Dakota. Vermipion. HERBERT R. {IP-RSCOWIT7, P. D„ A»orAsre rre%ssor of AIke Oeweelo..n 1lwhersNr Scloolsj~ . kine .ed Dewlidry. W.sl,Myteq D.C. RONALD R. HUiCHINSON, PII.D. Rw .r.nA Di.rrror. Fowrd.aou fos fA..- ioral Rese.rcA, A.tlewe, Mkh. ALPHONSfl 1. INOENRI). Pr-D, Aas- c4re rro/asor of r [+a1t Ctrolin. Uni.er.My Sclool 61.41 cine. OreeeviMe, N. C. HARRY L. IOACHIM, /dl.D. AnrnNw~ rarholorisr. Leeoa Hil t4oqild CfW- c+/ rr0/tlsn. of Pathology. Ce~e~wWa Unitpf111 COIft« of 17~t ~ Sw~eonq Ne. York. WILLIAM /. /USKO, PR.D. Asasclue Professor of rAern..crwh:; Dlr.cro.. C/:nic+.i' rArns.coiAxNirs LdorMory. Mill.rd FilMnore HoqMd, M.N• EDWARD L. KLAISP.R. M.D. Sewter Scinuisr, The Worcesur Fe.wMios for E,pe.irneMal Biology. lee. SMeas. bury. Mar. /F.ROMB KLEINERMAN, M.D_ Mrd, Dryarrnsrnr of Pathology and r.rAel- oFl~~ A. S.int Lrke'e HeqileJ. ST1O KULLANDER. M.D, rn/rnor and CAd.w..n. D'rp.nmrwr of dlsret- rks and C>wrcologl. UnIversNr of Land. l.rx.4 Swedew. ~ AeP-1. LJ1171iA, Pw.D.. Di.rM.r. Ne. York Stale Rese.rch InwN.h for Nar tocheniislry .nd Drug Addieliost. Nev York. MICIIAP.1- P..1-AMM• M D., M/ewm of r.aAolorjp. New Yortt Uei.enMf Medi- eat center. Ne. Yort. 61 PROILCT liiq.E PJled of .rwkinR on evolutloo of Ihe euximwn eapiralory fkow-volume curve Sehavioral eRecU ow swnsnwoker. of ea- psrre to snakinR Elecls of dpretia anoke e.posure on developnen/d• cellular and molecular aspccts of the immuue re.pome llfens of ecv/e and chrvnk nkollne ad, wdni.trNion epon .weaa{on and blood /eesw.re retaq.ons in rels and bemar Adione of ce.bon monodde and tobacco rwoke on retinal metabolism and Iww Ilow Y1s Mnmu.e response at the tumor sAe ia l1111s care/110rna FJlect of rnokinR and Ns oesrlioe an drvll di.po.ilioe ltlydies of .{onad.l and cenlr.i nervow system s~ndro.ne that dillerenliares twolters Irorn twnamokers llecls of n$+eline inRe.tlon on berevlar ead blood pressure in ras Fwlhet evaluation of mioe lano of MIWe emphysema lines from Miao- biololticd Aasociales /nOuence of smoking ow human foe1.1 growth and po.lnal.l developnenl. and on OMinolysis in Ihe Alr.rd of preen.nl .omrn. AacumrJalion of •icoline and/ar damage to human p1a oeM.l and foelal lung /iuues The eQM of nicotine and urson n.o.- esids on /he Iran.pxt of amino aride inb M.M4 a.d on prolein melabdwi. Iwwnune mech.nhnns of noucaus .ws- benes

IRINCRAL INVF3TfCATOR OR IINSTTi\IriON JOSEPH M. LAUWFRYNS. M.D, rsrD. rro/tssar O.Iinerirf and CA.rr. m.n, Deprtnrewr of r.rhology and MkeoiCORfc An.ronr>-, F.aPeriwnenlal L.EorNory of 1'ulmonarr Hrstopalhol- oay. Kaholiefe Universilcil te Leuven. tAsnrM SclRwm. RICHARD A. LERNER. M.D.. A.+oci.rt Mnwler. Scripps Clink and Resarch Fou.dalioR La ldla. ('.1. lAY A. LEVY. M.D. As,isunr Clinical rro/tuet o/ Mt/kine; RtstrcA A.w- ei.rt. Cawea Resewch IrMilule, l)nl- •t/si1~ of CJi/ornia School of Nedi- eiws, Saw FrN.eirco. HENRY T. LYNCH. M.D- rn./rs.or and CA.Yw..R Deprtwawr e/ rrtvtw- Ntt Mrlkl.r .w/ rdlk Ht.IM, Ctei{Yow Uwieerwt7 School af Medi- cl.e. Ow..bs. Neh. FRANK ARTHUR MANNINO, M D, Aa.irawr rro/tasor of OFirrnkr and C)rennfopWomes'. Ilo.pital. L.oe Aw~eks CarMy/tlniversiy of Southerw Cab/or.i. Medk.l Center. Los Angeles. R. RUSSeLL MARTIN. M.D., rs+oe o/ /fdkirt. rd MkroNol /nr- n.awdop" laallor Cdkp ol Hostaw REOtNALD O. MASON. M.D. fw D.. r.rAelojW-IrrCAM/. Memorial Hoqi- la~, r..l.ehe(. R. I. OERALD E. McCLEARN. IM.D.. Dl- rertor. lwrHtMr /or eeAerlord ct- wnkr. Dtprrmtwr of rqcilolorl. Unl- rtesRl o/ C.olNado School of rhar- .,«r, .oulaes. HeRf/s'RT McKENNIS. lr. rt1.D., rro- ,t..ot o/ rAarnwcebsy. ~edkal Cd. IeRe ot Vkgidti Virginia C~ornmon- weahh Uwi.ersily. RkhnrolM. HAN9 MEIP.R. D V Ii1 . S.wir S*./ Srl. tnNM. 11e /aclww l.b.ruory. •N I/NbN. Mt. FROJtCT TiTIx The neuroepilheUal bodies: their role nd strvcrore as iMnpuheonary neuro- (chemokeceplors in nurm.) and vari- ous physiological. pharmacological and patbological condilions . Owcotrvkal Rene e.pression In normal and rwdignanl liawes roseiEle senrtk delerminanls of chemical eNelnO;eneY. FRINCRAL INVGTIICATDR OR INSTITUTION DOV MICHAELI. Iu.D. A.dn.nt rro• tasot of RiocAtmim" .nd~ Sr~ ~. niversily of Cdifor.i. Sclod ~ Medicine. Saw Francisco. MICROtlIOLOOICAL ASSOCIATE3, INC, fkthesda. Md. ftolttT TT11Z Ellects of cigNetle unolke on pulmonary Rbroblasls and collaten and its rela liow to emphysema DeveloprneM of a morse model syslem lor genetic susoepibiltly and il; relalron- ship Io In vl.o lung eareinoeene.is lkvdopnenf ol /n vitro and tn vl.o modtl s~MdM /or the Mudy of lun~ ehemicd wuceO/ibllily and c.rcino- genesis Srwoie In6alaliow earcinogenesis wudies iw Mip Hurw.w AHH rudles Rne..ch .eevioes M auoport of another SrwdinR Ys/ory iw families with lo.w and NokA (see Levy. /ay A.) high cancer incideaces 1. ANDREW MrTCHELL In.D.. Assiw- A stndy of the effects of wioo/ine on "a- Aryl htdrocarhow hfdro.llase (AHII): .nt rroftnor o/ Anaawrr WaTwa Slae tiow Iw the r.1 with nkulN ler a nncer genHica I University School of Megci.e, D.uoit. p en re b implantation and the /ime of omxt of /.rtwltio. Statisllol-~eM k evalr.tion of rial /w toc. ie lury cancer NIoeliee-Md.ocd aNeralow. I. blasloc7r ~evelopnenl. knOlantNion and utetl.e Fetal and maternal e/feds. of cirNette tuwdiow M Ihe ra1 nkoline injection and carl+ow .molirK , monoaide inhalalion in the pregnant OEORO 1!. NEURATH. I'tt.D.. MRs•o- Nilroaawdnes Iw tobacco and Ns smote: RAtr.u monkey model .wdlrk.f L.hoe.ro7. Hawb.rR, Wes/ occurrence, /onnaliop and Irawsfer Oennae).. Induction of .ryl hydrocarbon hrdosrl.: FRANZ OF_9C11, rwD Phs/t.aor e/ Dberiwiwatiow between the importana of In Iryephocytes and pulmonary rlacro• rAwm.colnjy: Ht.f, ~trrlrw on /lo- epoaide hydrflase and dihydrodiol de- cAtwrkd rAr Uulvasitl d hydroeeea.e in Inactivating wwiapewk Mairl; Maiau, We.l Iwelabol'Nes derived Irorw oolyefclk h1- iracarbona oecunieR in eitNetle smote EBects d.iooUne ow Inter.ctior of KENNETH PAIGEN. fw.D. Ofrrrwr. A penetk Ies1 of tlucorowidase In Mad- plaleku and ewdoHe/ir eens Dq.rtnrtwr of MoktaAr tl.farE. Ier eaneer 11eaRh Rese.rch, Iwe, Rees:ll Park Effects d.wohhlp and aicoliay on /ro.1h Divi.ioa. suAab. .nA fundlal dMu.aw endwhelird oeRs CARL W. PIERCIy M.D_ fM.D tro/ts- liiolosy of suppressor T oells Heredity and /obaoco-rclNed behat ior iw sor of r.Molody anf MkroNe~FJn.- the mouse a.rnnfo~~ rrAo/.rRbt-/nrAk . Ttit _ " /e.ish Hoyilal of St. Loulq ton Universil>• School of MedkMe, !k. Loris. oet a-id melabolism of ami.e wn- Trans ILARI RANTA.SAIO. M.D, hv/ta.o. The Flnnish Twin Registry p MNueMe of lobacco arnO~e and Chairman. Ot~.rrn.ewr of~ Public Ht.bA Stlrnn. Urriverakr .t i1eMIM1, CoooerNive Mudks aimed at the deKlo¢ Helsirlli; Finland. rnent of inwnuno.uare for nkotine MARILYN A. RASCO. nr.D., AaWw HirdrocNbon meiaDoliring en:frnes and lioloeM.nI Assistant rro/tsw- o/ 11- hsng cancer O.eogene.is Iw Ihe rabbit ./oR>•, 'T*e Ualvereity of Tear Slst«w Cancer CeaM. M.D. A ~~oeMwda.ow Trensplacenlal effects of nkro.ooo.n- W ard Tr.or Irtitut.. 1loudoa Counds 68 0

PRIlM(.~AL INVE311CATOR OR aSiTTiJi10/'1 RONALD E. RASMUSSP?J. IM.D. Ar ssrirr Rric.rc# rAYrio1e1tM. DrlMri- wwwr of Cow.wr.ra/ry .wd Ewrboww.rM- .f MrdkMr. Uni.er.iy of C.lifor.i. CeOqe of Mcdicine. Irvine. LYNNE M. RElD. M O.. IYol1.c# ha rmr y IrAoletf. H.r..rd Medkd ScIteaL •oww Ch./riw.w. Deprnnrwr of rr0-hR). Childre.i . Hoqh.l Medkal Ceree. 501106. HERBERT Y. REYNOIDS. M.D.. A. wrWr hWe.rw ./ i'wrrrn.l Medicine; Hee{ ldw.o+..y Jrerlo... Y.k Vw1.er• .M1 Srlool .f Modkine. New H..eq Cor. ARNIS RlCHTERS, rtr 0, As..cire hv/raar r.rAo/oRy. U.i.ersly of 7owWm i/.rai. Schod of Mediciwe. tae A.Reke. IOHN A. ROSP.CRANS. f w D. A..o- drre M/rs.or./ lA..w..rolop. Mcdl• enl Ce/e" of Vkliwir, RkVwead. UNA S. RYAN. nl D. Senior Scientist. ~q..iod.o. C..ecr Re.c.rch Iw+tl- 1w, Mirwi: Aa.oci.tr Pro/ra+or_ of M./kiv. U.l.er+.h~ of Mi Scbd.mi M MNki.a, Mi.r.t. Ft.. 9. V. RAMA SASTRY. DSc, fw.D. hdesear of Mww..rolo4>•. V.wdrt- NR U.i.er.iy Sdool of Medkl.e. N.rMQk. Te.a IAROf/ RCHMfDT, M.D_ I+ID. A. .4rrwt lr./rp.r of IbcAendxrf. DI- N.MM of /Wetic+.f ScNwni. S1.N U.LenR7 of New YorR M Sto.f Moek. 31a.f Meot. CARL C. SELTZER M.D.. Nawo..'? Rr...eA A..oci.re. he.bodT M.selrn. H.r..rd U.i.a..hl. C..rbrWK M... tilIARLlS R. SHAW. M.D. ChM. S.r Nw. of Mrdlnd Grwrrk.. M. Aw. •ec.o. Hoyh.l .wd T.nar Inwhule; h./rwsr o/ RbtoRy. Tb. U.i.ar.ilr ./ Tetr .M Houwort HouMow. NATHAN H. St OANP_ r.. 0 hofr• ror of RlorArmlr.r. T1e tiwl.e.a/' o/ Tewner.re Ce*ler fur tb Hc.1~Y Sd..cm Memphis r/eorccr mts FJfed of cowrcinohcm .nd turnor po- n+olen on DNA rcp.ir in m.mm.li.n cells .r.ceplible to c6emk.l tr.nafor- nutio. A penetk at.dr of DNA repair {s iabrcd .Irf/Y of .MOe Tle effeW of bri/.1to. .nd dnp on dr~.V e}i1bdi.rw - An ea0erimcm.l M.d* of .rcA.wir.. .r,wcsa.l..nl.r l....e bld Iw..hwow.r, arcMro...: aae/orl eorwrowrwl d kr.- w.woRlsbdi. A r..wrker of wro- pl.wk Growth sra.n+.g e/«+ro-ioog.PM Di.crlminNi.e MinwJr. Proper/ie. of .loo- line .nd related co.rpodnA. Fadoc.ine fundiorr of Ihe lunp insue.ce of .koline on Ihe rek.ro of .ce/fkAoli.e i. the f..n..p1.cemo sd hs i.ylic.Miowm on the fe1.l gro..lr Cewtr.l eicoti.k eaylors Co.ah.Uo..l .t.dke rel.li.. 1o ..u aly sd c+oro..ry beert di.e... Hi6roc..bow *wlsbollsla{ luiy oa.cer P1fM of bencdelll'rene o" dr*IaAl.a, on m.mrn.li.n lung oed. 70 I PRtNCRAL INVESi1CAT,DR OR INTIiTUT1pN LOUIS A. SOLOFF M.D. ef.wcAr P. Levy Dbtiwt./ir/1r3 Service rro/r..o.; rro/n.or o~( MrNdwr; Dirrcrar. Ra rr.rrA IJNd [.Aor.rory. Tewyl. U.1- .enhr Health Sciencc. Ce.ler. Mi.- de1o4.. THOMAS P. STOSSFL. M.D. CAk/. )W.Jir.f Owro/oly Uwlr. Mer.el..etu Oewer.l Ho.pi1.1„ Ro.lo.. DAVID N. TAI.MAOP M D Dbrcro., weWlY.rlwt trwe of Color.dlo Medkal ()ewr. De..e.. )AMFS TRAVIS, rw.D. hro/raer of SiocArwdury. U.i.er.hy of O..rfIR Athens. OERAI.D M. TURINO. MD, !hv/raor of AledkMw. Colrwlie Utli.enilF Cd- kee of np.ici.n. • S.qeo.q New York. D. M. TURNER. AI.D_ Aed. D.prt- pwn.r of Drug Mrr.lro/law ond Ri.. eAriw4ery. Ilsleto. L.oortloria E.- ~ L/d.. Herrople. Yorl.We. &q- EMIL R. UNANUE, M.D, GlWpf.clr+dr rro/r..er of iwuw Ad.rP. H.r- .erd Medk.l School. UNION CARSIDE CORPORATION. Nuclear Di.i.fow. Oak RiidK Ter. UNIVPRSfTY OF SAN FRANCY3(.'O. S.. Fr..ci.ce. Sft!PHEN F. VATNER. 161110, A..er/rr Professor e/ Mrfklwr. H.n.rd M.d4 al Scbd- Aawrrtar /w Medicine. Peter Se.t ~Srilh.m Ho*heL f/oMo.. IRP.NE Y. MANO. Pw.D, A.ytw.wr h+ /rae+ of 1..k .wf Cpwkvl In.wrnwof- op and Mk+oAblogy Medical Uol- •er.h1 of South C.roli.~ C1.rleso.. 12~34111CT TTi3.8 RoM of kchAin: ciole.lerol .cyftr.r kr.r (LCAT) in cholesterol metabo. ~t~ he.{tk disease and dwiy TM10e.tion of .M .eliAody pnoduliun a leehlti.: eioleaterol .erlthnafcr..e Fraiow.l .nMor.y of the puWewn.ry . opbaM Tie role of .I.crop~a~e-klduocd /«ior" in wwoec i.wwnNr Ri~ w1.U7 of ciro.le ob.trrdi.* lu.h Ro/ed/1k ewsywe...d i.hibitoi. is tal- Mra•• Cie.lfed b..lh of d.a.e datrticlio. 1n oEMrreli.e iunt di.eue Ill.oe.i .b.orpion of .kaine tn the .nealhelittd e.t M~I holo~Y of .or.n.l and .cti.Ned st.df of the dnr.cteriaallon of .nim.l i.i.IMion eapo.rrs de.ioe. .nd doi- usebf Do.Mwet.! .tudin on IAe hocer and 61- Mrrwe.l. Swrolt. Gprur. M.chiw. •S-0/IaneMd .woA. tro.horiry ausioe A ~ ..wer!.uu; a!0 c.rcinonw i. NEo"i..lnduee: te7e oech.lio.i EReM of cigarette .woh. .nd nio.^Ine mm oore..rP ..d left .enak.dr dy.rwdo Oewelk dlRe.ewee. In IAe in vitro mc/oLs lion of chemical e.rcieqe.. by rnuur li..ud 71 •

PWAPICD'AL tNVE9IlCATOR OII QtyTTiifflON LEE W. WA11YldBQRO. M.D. rro/rs- ..r eJ r.Molof).~~veralf o1 Mio- atewa Medkstl 3c Mi.weyoli.. OEOROE MFJNSAUM, hr.D. /bsA- eOrr4r, r.lw.owary Diarae Secriow. AI- twt FJrcr' liledkd CeMa. Pfil.- ie*h. IAMBS A. MILI. D.V.M_ rw.D, rro- /eew .w1 CA.i.w..rti Dep.rtwwwr of Y~r~ererMrf•~Sckwn, Uwl.ereirT of TVir OdDRORMWqf DU hrs-. h./er.er o/ /Msdd eTkrl ~Ae.+l,rryDer.rr..ou ey NrrMow.wl Food Sckwn, Mw.- ierlr 1.rIMw a1 TecMoloRy. Crw- brf~ M.r. K011 YOSNINAOA, F+r D As.orl.re hvJea.w of Awuawy. L.Ao..ro.1 of /eswrr Rep sirce/ew .wd Repalrc- rf.r 1MJ.RT, Hr.rd Medkal Scbd. 111101010112. rROIECT TtTLL Inttibitlot of cardnotenesi+ by benrtUsa. Ibiocy.w.le and releled compounds L-ft ~al ei.se:.ntiprorein.re b.lanoe ,wd tM e/fect of eiaretle r+wke on t\ir wpwio" rd h.clion.l corteis6on. atf Me ArUD ocM o/ /M IwK t?Red of arctwoacne on dpcero/el. nalbeefil EtTecv of .iooli.e ow Frep.wcT 72 I I Completed ProjeeQs Following ib a liat of the principal invealigators, or institutiom, of projects that have been completed prior to the period covered in this Report. Several of the individwls named are deceased. The titles and atGlia- tiom listed aro those ii effect at the time the work was completed. CLARENCE M. AORfS3, M.D. Ass cl.rr Cfinkd rro%nor of Afellelwr. Uwi.asil' of Celitor.i. Medial Ceis.- lee. Los A.,ek.. ANT/IONY A. ALSANP3P !'MD. DI- rerrr o/ L.borrrkr, TM Rearle Re- trbilMeriow Cedet, YYWe rlai., N.Y. ANTHONY P. AMAROM thrD. Iw- .narrr In Olrrrhks .wd G.Pwre.i.p. TAe AlbeaT Medical Ca1kRe of Uedo. Uwi.ersiwf, Mb..y, N.Y. E. T. ANOELAKOS, MD. PaD, M- /e,snr of rAy,iotop. Oeao. U.l.a.rT School of Mediei.e, Rudoa D. MURRAY ANOEVINIL M.D., Ud- .er.w' oi rVi.oeri~r Scf.d e1 Med/- eiwe, Medieo.. DOMINGO M. AVIADO. M.D. rn/er .w of rArw..rofor7 Uni.eesN r o1 Penn.,lv.«. SJoot od MediciW. nil- adelOhi.. STEPHEN M. AYRtM MD. Dberrw. Cr/iowlwrowrT laMrMrT. S.Mt Viwcewl•1 I/oqitd. Naw Ywk. OSCAR 1. sALCHUM. heD. MeerMrT. lro/rs.er of MeNclwr. Usd.enil~ of MeN- SowAerw C.litorwi. School of cine, Los ArRela. FREDERIK •. BANO, M.D. e+nr ond Cii.irm.w, Depnwwwr .l .rM- t,btot~. TAe loAwe IloVtis Udserskr Sctwd ol Hyaie.w rrM t'rblie He" Reirin.ore. A. CLIFFORD SAROER, MD.. R.Mt Hrr' r/ns.e rro/rasor o/ rATdd- oTT, 11ar.ard Mcdicd $~ 1001100411. SRODA A. BARNES. M.D. r1rD. rr~. lessor (A#Ml.rr) o/ rAlilol.p. C.da r.do SINe Uwi•er.NT. Fort (7eMYo. FREDERICK W. •ARNP.3, /e. MD. Auoriwe Professor e/ /NrMrMr, TtK /eM. I/oMine Vai.erdly 1choel e( Medki.e, laHMwore. T. C. SARNFS, DSc. RrseakcG Sckw- N.r. NileddMi. S1Me Ilosriul, hile- IeN~i~• R. FREDERICK SECKP_R, M D, Assoo- d.re rro/rasor of Anatomy and Dbec- ror, l.borrry of %rlw.r./ Scienre. Dsrlke Uni.ersi/r Medial Cen/er, Urr- two,N.C RALPH S. rE.CKER, t•w D.. rro%.sor I~rf. Uwi.er.isf 04 Houqow, RENIAMIN RFLL, M D, Director Em- edrra, Nrewri.e ARiwR S/u/y, Ve1cr- ru AdmMisueriow OwpuieM cGaic. Daerow. SAMUEL SEI.LET, MD.. Direcrr, DI- NW- N CrNolot y, rbibdelpW Oe.erd Horpul. PbaedeloAiu. rARU/ sENACERRAP, M.D. FdT.w rro/eisor.n/CA.irn.ww. Drp.ruwrwr . rrAotory, Har.ard Medicel Sc toslon. JOHN A. BEVAN M.D.. Professor of rll.nwocologr, tjsd.erailr o1 Calitor- eia School of Mediciwc. 108 AWeks. OUDHDEV RHAOAT, rN D.. r.o/rssor ./ rA)F+lofqtl. SaiM l.ouis Universirf Schod o/ Medkiwe, SI. Louis. CESARE BIANCIFIORI. M.D.. Di.ldwr o/ C.wrer Rrserr8, Uni.ersNr of Musi., Peraaia, Italy. HYLAN A. RICKERMAN. M D. As.W- .w/ rro/rsaor of MrNclwr- ewd AL- VAN L. RARACH, M D,. CowwUewr /w Mrdklne. Cduebia Uwi.ersky Cd kge o/ ftTskiaw. A Srrseo.s; lloW- raler Mewwrial llo.piul. Ne. Yo.h. R1O-RESEARCI/ CONSUt.TANTS, INC. Crwbridae, Mua. /10-RFSEARCIt INSTa7VTP INC.. Cen.bridae. Mass. FRED O. pOCK, t'b D., Associate (-.w- err Re.r.rcb S.dewdsr, Rl.doeic.l St.- rluw. Ro+well Parl Manwi.l InMi1We. SpJnavilk, N. Y. 73

OUENTHER fiODP.N. M D.. A,soci.rr Pro/rssor of Mrlk(wr; Aaift.nt DMrc- (o., Crwrrol Clinkd Research Crntrr, Tewoit UnivereNy He.hh Sciences Cen- (er, Mrl.delpbi.. HP.RMAN V. 1lOF.NIO, PN.D. Ne.I. Der.rtwrewt of CAn.drrr, .wd elotArnr- l.ay. SPindkiop Research Cenler, Lea- hg/on, Ky. IA.MP, P. Q~ONNER, P..D, hvJrssw / .o/~ PC...~der • 1..(it.w .I T.el WALTER M. BOOKER. hM D_ lrvJr.- arr r./ Hr.c( Drr.+ wrrnt ol rArns.- evolo,ifyHo.nrd Uwiverailt. W.,hl.t- uft D.C. TOM O. t/OWtRY, M.D., Research f'f.Jea.m, LMkIIe Rr,id.w Lobrr. , Nex1R Caroliw. Slae Calk=e, i{h. R OEOFFREY L BRINKMAN, M.D_ A.- nreire M/rasw o/ MrdYe/wr, W.~ Slae Uwi.er.Mf Sclool of Medkiwq Delroh. RORERT li tiROOKS, Ptir D. Ar.oci.tr lvw%a.e. o/ r.tAollory, Univerrht ot Or.p. Mdktd Schooi. Portlend. ttARRARA R. •ROWN. Pa D. CAIrl. Ea/Wr6wtwNf rqcAWr,, Veler.ne A - oMMrullow HoePitd. Sepdvede. Cal. RAYMOND R. RROWN. PsM.D. ho/r,- ar o/ Ct/wkd Owr.lory. Univerdll of WNoari. Medk.l SchooL M.dieow. 1(11f" DROZPIL Pte.D. ho/rau. .wd CAriw.rl. Der.trwr*r o/ h7cA.loPf• (eNA UtaFsessMf. fie(_ IMeltew. P.. SUE tiUCKINOHAM, M.D. Ar/n.v Pnj..e../ lrN.rrrks. Cd..bi. U.1- .a,r1~ CaRq. .f PUpakj..e a s.t- Reo.K No. ToA. OtSN/AMiN BURROWS„ M D. Aae- dre rfo/rne. o/ MtNcitr. Ud.er.Mf e[ CikK0. CYaye. 1!. M. OUTT M.D. Cf,O./ PLe. AwRdes C...t1 Oe.ad .l Le. A/yeks. RlCHARD U. tiYERRUM. Pw.D. h.- t..w o/ CAewdrs. Mkfiw SINe ni.ersMy. Ped l..,rby. SISTER M. EMILY CAtlll.l. Pw D.. CArin...w, Drrornnrwr of ('Arwdurip. Rqla Calkp. Weslon. Mw. BRUCE F. CAMERON. M.D.. Ihr.D., Ho.ud Hughcf Inslilule, Univcrsily of Miemi Sc`ool of Medicine. Mi.mi, F1e. WILLIAM H. CARNFS. M.D. Unlver- ait) of Utuh C.dkge of Medicine. Sah Lake CMy. MARCUS N. CARROLL, 1... M.[G_ CAM. Dirtsion of PArnr.coforr. Tloe Mootd.lt Hosplel Center. srooUyn. N. Y. WILLIAM ALVIN CARTER. M.D. Aasiarowr ho/r„or o/ Mrdklnr e.J Mkroalolop. The )oMs HoCiwa U,l- .ersMt School of Medicine. .hlmore. LEOPOLD R. CCReCPDO. Psw D.. Pr.- raror o/ I/oc/lrwdstr, and Nwrirb., nivenly of Ptiecb Rice School u( Medit~s S../«a CHILDREN'S HOSPiiAL OF LOS Atl- OELE3, Los Aqek.. SANFORD CHODOSH. M.D, Aada.wt rro/r,aor o/ Mrdkiwr, Tooth Univer- rity School of Medicine, tlodow. NAITER M. CIIOPRA, PwD, Iro/ea- aor of CArwrbt.,, Norsh Caolin. AI- riculwr.l .nd TecMic.l Sl.le Univer- . MI,. (ireeMboto. W/I L1AM O. CLARK. Pht D., Dlrrctor, rr,r Ao~llrwwdo~r Research L.Sorf tor,. Veltrens AdmrwMrelion Hoapit.l. Sepulved.. Cal. HANS T. CLARKE, DSc. rro euor of ilioeArwelur', Co1.+wWe niveraii, Co1kRe ot Mysid.a a SurReowti Neo Yort. JAY D. COFPMAN, M.D, SrcHow Rrod, PMpArr.f Y.scsJ.r Drp.rnrrar. U.ivershr HoyM.t DeMOtc. DANIEL COHEN. D.V.M. M.P.H, A.- iLronr /ro/rnor y Yep.fwr~ EP1- drwdologf.nd reAlk NrdrA, Unl.er- eity of hswflv.nl. School of Veue- In.rr MeliciwR Phil.delPli.. JULIUS H. COMROP t.. M.D., Ditire- ror. Cardiowscr/.r Research twMlcwr. UnhrersN of California Medical Cew- kr. Sam trr.ncleoo. DEAN M. CONNORS. M D. Asaocl.te Dlrrcro. Dtwrrwr of f.Ao..rar, Mrlwiw~. SI. Mer, i Iloqitd. M.duor~ Wia. 74 I PHILIP COOPER, M.D, CHw" rr. /r„or of SwPrry ow/ Direcror, SrRI- c.l Laboratory of Cr1laJ.r lJV)debp Albert Finsldn College of Medicin. Q Yesh7v. University; CA(e% S.+~kd Se.rke, Veternns Admi.IntNio= llof pa.l. The liron., N. Y. JOHN E. CRAIOHEAD, M.D. rro%s. .o. of %rAofoef. U.i.ersity of Ver- rnonl Colkge of Medicine„ Ikr/My1on. ROIfERT L. CRAIN. PwDQ An4r.r Hro/rasor of Soclofop. UnFaei/, ef Chicago. Chicago. T. TIMOTHY CROCKER, M.D. R.Jrr .er of Melk/nr, UniveesR~ .f Ca14~ to.w{. College of Medkln.~ le.l.e. CARROLL E. CROSS. M.D_ Aarsrl.N ho/ra.er of M.JkMr .ra/ Nmw.v rA,alolog,: Dirrctor. Strrlon o/ Lf- f« +y Scbol Medk~iwe,~l~vd~C.IM CECIL E. CROSS, Rrsr.rcR Drr.nwrnt. St. loaerh HapMd, Mrl..R, CaL ALSERT DAMON. M.D. PM.D, [.ee• IMM on AsMMoPoIoRJ: RraM.rA Aror ci.te iw Medical Awt y, Pes- lody Msawr Harvard .NeesltfU CrnMidye. Mrr. THOMAS R. DAWflER. MD. Aaseiw rro/naar o/ MrMclwr, RoMen Udv.r- silf Schod of Medieia,1/aa1o.. R. P. DAWSON. Pw.D. M(eawr o/ f.r- .n). ColMnbi. University. Nw Yal. JOHN P. DELANEY. M.D. hLD. Ar .orlotr ho%saor of Sr.Rer). U.i.etsRP o1 M innesoltti M LweyolY. ANDREW S. DHINER, PsiD. fdm- rairr, hycAo-Rrsrwd, T1. AR. C.M le. ot New Ewlden4l.e. D.M.w. EDWARD F. DOMINO. M.D. M/tr .er of rAwne.Wofoq. U.iqesMl ef Mkhipto, A.w Arbor. RAl PH L. DORFMAN. Tw.D.. Dlreror of Liherotorlrs,. W«asler FowAMlo" tor FaperinreM.l Biology. Sbre*aMrY. M.ss. JAMES 1. DYAR. Pw D. Aa,/aw/ hnr /r.ear o/ ab/or,. f/tperrnlwt Co11eK Loui.vi/k. Ky. RICHARD H. P.ARIP M.D, CAb/. r./w.uw.., Frw.Nen j.oRerNer,: Aa- uu.wr Iru/raaor of Mrlklwr. Unleer- w, of ('hic.m Chic.go. JOHN W. ECKSTF.IN, M D., AaaDr.nr lro/rtwr of Intrrn.l Medicine. SINe U.iversiy of low• Co/kse of Medi- cine, low. City. BERTRAM EICHE4 D.D S, Director. lrurhwr of Sro.n.tofosicel Research. Scienee Resorrces Found.lion. Weler- lowq Mae. HYMAN ENOP-LIlERO. MD., Artrn!- MV 1A„ki.w. Cedars of Leb.non Hop- pi1d, Lo. Antides. CARLTON K. ERICKSON. Pw.D.. A.. wweiar Irolepor of rA.rmocofop, .n. To.koloe,. The University of Kenw School of Pf.rw..el. Lawrence. HENRY 1. L°StlPR, Psr D. Research hw- nrrtofot/,r. Mtnow Research InauN.N. WorceAee, Maw. )OHN R. ES17.'RLY, M.D.. Aa.oc(.te rro/tnor of P.cAolotP. University a[ Chienp PrNSlee School of Medicine. Chicago. HANS l. BYSENCK, Pu.D.. D Sc.. f'.e- /rtwr o/ ParAology. Inuilule of Psy- ~. U,wy ersily o( Londorti Lon- HANS L. FALK. PN D., AI/rwd Auod- ae rrolr,sor of Pathology. Unherai/y of So.lrerw California School of Merleine, Lo. AnReks. DANA L. FARNSWORTH. M.D.. Nrnr7 [. Oliver H.o/riaor of H,tirne ond Direclor, UMrrr,ity Health Srr.kra. Harvard Uwi.eniy. Cambridge. Mu.. FRANK C. FEROUSON, )., M.D_ CA.irwawe, Drp.rtrwtnt of rArwwnd- .~ TM AR+.nr Medical College of Unlow Uaiversily, Albany. N.Y. THEODORE N. FINLEY. M D.. Obrr. Ior, rr/n.on.r, Rr,rorrA tilos.ro.,. MewM Ibo HoyiuA, S.w Fr.nciaco. WILLIAM 1. FISHeF.tN, M D., Chief ./ E rwe(olaS,, Chic.qo Doard of •H e.h . Chicago. EDWIN R. FIS/IER, M D. Director of t.larotorJr,, Shed,side IIo.pN.l; tro- rasor o/ rorAd..dr. Univenil, of i1hlwrd` School of Medicine. Pitle ewih. RUSSP.1 1. S. FIS/IPR. M D. I lwivcreit~ of Maryland School of Medicine. S.1 lirnae. 75

•. L PREEDIANDER. M.D. DirAe. OERTRUDH Y. OOTiSCHALL, Pw.D. C.nrrr RrsrerrA. MawM 710a Har A,slstura Pro/rssor of SlorAendury, Ad .nd Medkal Cenler, 3.. Fr.. Columbia Universitr Colkge of rhrsi- cius. clns R S.rdeowr~ New Yort. FREDlRlC A. FRENCH. A.R. DMrr A. CLARK ORfFFIN, Pw D_ Href. ser ef Cewtvr CAriworAneFy Rrsn..r Drprtwrrwr e/ /iocAews4rry. M. D. Moa.M TJw HorVital .d M AIera Haqilal .nd Trrna Imli- Oerer, 3.w Prsnci.oo. UiN, Uni.enMT of Tea.s Medical JACK FREUND. M D. Aaslrwr A+. C*sw• Ho"mow' ,e. r./ t•Aorwru»I°p' M.dkd Oi ARTHUR L GROSS. M3., Sen)or a/e- lafa e[ VkRidr.Rklrwo.l. chows/ar. ScatR.red Resenrs! Inslil.k, OIL1lRT H. PRIEDELL. MD. Cttie/ SM MMa"°. Tes• ~~~1' Vi.oenl lieyR., MORlON 1. GROSSMAN. M.D.. hr.D. ~'--sm Awc1.N CNwikr/ Pr./ rswr e/ MrN- H. HUGH FUDlNRP.RO. M.D, Mfrs- cMe. Uwi.eerly e+f Ct+111oswin Medical ..m of M.Iklnr Uni.enMf .f Cdl- Ceace. l.oe AnReNs. Iwwi. MeMd CteMer 3.. PrtrcMceI hNraw ef /orr .nd fwwwr CARL C. ORUHZiT, M.D. Ptl D. Ar- IM7. U.iva.MF.f .r.i.. R.rla- sedrr M tAf~+i•b1f wf Me.wwc.1- ~ 0"nn SU~d cRo 4 F1Yedel~i.. ARTHUR PURST, Pt.D. Dr.rre., )s~ .rM.re./ CMrwi/r/ Ibrer, , UM.erdtY lt7SlPH 1. OUARNERI, Pw.D. Anrwd- of S.u Prtwciom Seo Frrd.oe. InR N4+eb1pbR/p; Dfncror. Afk+ei/- URRAY R. OARDNlR M.D, Asw ~y ~~~K 1~ !r" /~ M y'HiM)de Medkd Center. Qnee.a eMa eM/ of hr/esooe Se.lleew ef C.lif rw~.3clodM .f ~r CeMer AfRLNion. t.rwnkR Mt~Meiw.. Loe ANrka OlORO!! O. OEY, M D. Okrrtw, ffn- FRANK P. OUT4iRIP M D., -rre/rs- Non~ t..rWsn. nry-HeweR Cewcrr Rrsr.rcR L.ber.- Stele Coileee. ~owrol .tl~. (erY; AsrerWr r.o/rsse. .f SrrRrrl, Tte lolrrs HoEklne Univer.Ny School if S. HAAO. M D. Pro/essor o/ IA.r- .f Medk)O.hhare. wrerofotf. Medical Coilege of Vi.ginie„ THOMAS M. OOCKB, M.D. A..orYre Richmond. heftssa of hrvrnrlvr Mrdkfwr wd P. l. HADDY. MD. h1.D. Pro/rssor Cawen....ky Hrd1A, Se1e. Hnd Col- .nd CAebwun, Orperrn.enl oI rAls!- M af Medkiwe nsd Dewtislrr. leraF o%j~, UniveesilT e(ORWaue. Mebed R H. l. Center. Oklahoma Ciy. DAVID M. OOLDENSERO. Sc.D. JOSEPH H. HAFKlNSCHIPI., M.D. MD. As>tecbre rro/isso+ ef hrAof- Direcror, G.dbpaG.av), UnU. Tie ep, Te.qM Unieer.itf Health Scl- Vsrkenw Hospi1d• Asrociere M Mr1l- ewces Ctnler, PMi/.de1FY.. c{nr. U.Iveniy of renwsllv.n)n Scrod PAUL OOI.DHARER. D.D.3., Assorlwo of Mtdrelwe• Philadelphia. hefru.. M r„l"M08-R~. If~rd RF.RNARD HANES. lMt)., ho/ruor of Scbd d De.1d Medkiws, Sowaw. Health Scknrr, Cdiforni. Sute Univer- Ll:ONID! OOLOSTP.IN, D3e., Asse- *1'. Nort4idte. ci.rr Pre/rnoro/ P+rrA)ur), I.slMwe for Mewlul He.R` Sck.at Colkge of RICHARD l. HAVEL, M.D.. Aufsre+rr Medklwe & DeMiurf of New )ersel, ~foeni. Nedinl Center~San F R rew- M~ers Medical Scbol. Pi.cMawny. C.l cisco. IRA OORP M D. Prv/.uor Of r.rAol- eFT, Sowon UeI.rrdrl ScAool of Medl, HFRRPRT R HMMTNORNP_ M D, crwe; fAM/ ./ ). a.r.r~ .T...Mr. (A./r~..w. dr~ In+rnr nl Sr. rr1. Vecre.r Adw.l..rr.u.,. /Lw~M.~ Nes Um.erurr ..f Teen.rl..ni. Ur.~uMe Ruetwt. Nr %,frra of Mrdnrne, PAdedclpAi. I I IOHN A. HAYFS, M.D. Anodw IRo/op,~s . wto.~C i~ IHo.lil.& Rawoa CLARK W. HEATH. M.D, M/ea..W ef Mrdrelnr end Direcror of //rrHA Strt- krs, T.fte Ua.etaill, Mt/tor4 Mesa. PAULINE HEIZE7t, tw.D~ Rsnod Associ.r. M Cyrelotl •wJ 1cecAewr4• ny. S.w Francisco lws1A.u o( Medical Sck.as, S.. Fra.cisee, LAWRENCE L. HP_STE>< /.. MD, ho/rssor and CAdrw.e% DrNrd.ewr e/ Obrr/.ks and Gjn Colkp e4 South Cro1M, lRRH CURTIS HOPP, MD. Po D rrefea.or wI CAd.wew% D).W.. o] P,FcMerric Rrsnnrk MeReal C.reRs of Virsiwik Rkfwot+d. RUSSELt. L. HOLMAN, MD. L..hl- .n. St.te Un)versily Scf..1 .f Medi- eine. New Ork.w. OLE A. HOLTlRMANN MD. Re. srerrA Srknrisr, Laa.n1 U.iver.)IF of Nar. Dtw,Dnere, Ind. Non 1 RFDInY HOMRUROP.R, M.D., ltesl- Irnr and Drrrrw, SioRs.c.ref Inwl- we. larc, Cnwrbrid", Mns ROSFRT W. NtfLL, M.D, hofrpor of Sioloekvl Seiene.,, Florid. aluq Univerdly, T.R.Aassee. HT RESEARCH INSTITUI$ Ctkya. GFORGP. JACOBSON. M.D. Mf.nor ewI Hred. Dy..rmenr of R.Nefo~~, Un).~er.Nr of SorwAn. C.Ntorwi. School d Medicine. La Ayeles. 1FRRY HART IACOBSON, M.D. Dl- rrcror, Divtsbw e/ Efrc+rqAfdofofl. New Yat F.re nnd E.r (nRrwwr, New York. /UL1US H. JACOBSON il. M.D. A,se- rrwrr Pro/nsor of Srrtrry and Dlrerror of SrrR/ce/ Resr.rrA, Uni.ertRf of Vermoat College o( Medieiwe, sw- lington. MURRAY P.. JARVIK. rwb., Assvci.u rro/rs.or of rA.rni.cnloer. Albert P.Iw. Meln College of Medicine of Ye.hi.a University. lhe Srowa. N. Y. OSWALD R. IONES. M.D, SI. L.Ie's Hoqit.l. New York. ANDREW A. KANDUISCH, PIt D, Sre/ Sdenrl.r, T1e l.clso. LaEorF 1orp. S.r Harbor. Me. ARNOLD R. KAPLAN, MD_ Dber. ror. L.lorwory of Afrlkwf Grwnks, Ck.el.nd PsycRidrie IdA ../we HosOitd, Cle.ei.d. ATTALLAH KArPA3, M D. Pro/ra.or onf Sen/or rArskMR T\e kockereuer Universitl. New Yor1. HIUTCH KASPARIAN, M D. Asstw- .wr. DMrdo,, Crl/er.,cr/er l.lenr- (ar7; /n,1r.Mor Iw A(.dMnr. IIeMe- w.~~MO~ Colkp .nd Hosoital, EUHU KATl: Pw.D., Assocl.r. Pro[r~r~ +o. of Soc'fdotl. Universill of C71- cyq CRieaRo. SHIRLEY L. KAUFFMAN. M.D. hr fessor e/ %rAologr, Slate Univeesily e( New York Dowsw.te Medical Cc.. 1er, Brooklyn. ANCEL KEYS, hM.D., DLrnor- l.Ma fery of lAysidol") Hyt/enr, t/niver- sitr of Minnesot• ScMol ol t rblk HenMh. Miwnc.poli.. JOSEPH B. KIRSNP.R. M D., Pro/rssor ef M.Iirlne. University of Chicago School of Medicine. Chicago. PEETP.R H. KNAPP. M.D. Rr,rrcA ).o/rssor of lsyrMenr, Roston Ud- versilf School of Medicine, So+ton. KENNP.TH P. KNUDTSON, Mb., Unl- versiy of N/nAiwgton ScAool of Medi• eine. Se.uk. ALVIN 1. KOSAK. n..Q, Asrxl.rr rrofruor e/ CArn.lary, New Yost University. New York. ROSFRT A. KUI/N, M D, Asurl.re lro/rssor. Di.lsu.n of Nrrrosrr8rr7. New Jersey Sl.te Cdkge of Medicine. Jersey Ci/r. MARVIN KI)S('IINPR, M f/, New Yorh Univeruty MedKe) ('eMer, New Yort. 76 77'

CHARLES W. L..ELLE, PN.D. A»itr- aia rrofener of EweMown.rnr.i Hy- Tirwr. )dersow Medical Colllege. Phila- delpNe- AARON 1. LADMAN. PN.D, trefessor and CAafrwrw, Dtprrwrewr of AwN- .we1. TM U.i.ersily of New Metico SJoel of MeNeiee, Albrrqreeqre., THOMAS C. LAIrPLY, MD. rrofer ,w oJ r.rA.iM. Nom we.er. U.1` .ae.M7 Medkal 5cled, C1kye. PAUL !. LARlON Pw.D, H..r M/ es- ..../ rA.wra.~Ot,. Mdiral CoRe.. .f VkRMIR RicMawd. ROOdR K. LAR". MD. CDMf of MeNciw.. Pnr. CewsI/aMN.(,~ Pre.weq Cal. OUSTAVE A. LAURENII. M.D.. CAfr of Meditim. S1. V Loea HowkmL Wwode.. Ma.. lDWARD LEETE. Pti..D. D.lc rrofr.. w+ of ~w..r.~Uai.ar.MS J Mi.wa aow MCM.nEoli.. COC7Ld LEl1CHTEN/eROER, Hr D, Ho.f, Der.cwerwr o! Cinrewld G.- s.Mr Ia.INu1e fo. P.ater oee Reaarcl, L..rawe. S.ilse+la.d. AVERIU. A. UEROW. M.D. CA.fr- «.sl Deraiwewr of t./AoioTy, Yak U.LenNy School of Melkire. New H..eti G... lSTLN O. LMD3EM MD PwD_ !1. raorT. !o.ew. HoraMal Raeaeer Lw- $1. Pa.L Ml.rz ROBERT H. UNNELL, Pw.D Ass.cf .w hr/es.w .f CAew.lrrT. Ljai.a+iy af VerrworL Mrfiart.+. HERBERT L. LOMBARD. M.D..' M.P.H. A/Yir.. C.av+ Resr.reA Is- aNr.reN EwR/awd Deaowew Ho.- PMr. ~~ 1. P. LONO, PuD. r../essr. .( rAr- CuUe~.~ Melldwe, /ow. Qt~•.f low. C1JIYTON O. LOOQU. PwD, M.D Hw.Nwp rP.fes.or el Me/Mwr .wj rrAele~ Uwi.eef Sowftern eJi- foaal. Scleel ./ M.dki.r, Lr AMeMt- DONALD R. LOURIA, MD_ Awr.rr t.ofes.e, ./ Mel4i.e. C.e.ed Uwl..e- eNy Medkal C.IMR New Yert. KENNETH MERRILL LYNCH. M.D.. Sc.D. LL.D, rrofessor Emerirrs of r.dlofon and CAownf/oe, Medical Colkge of Souw1 Cudiew CbrkeMow. INES MANDL, PM.D. Ass1u.N rrofrs- soe of !lorAemisrry. Columbia Uaiter- sAr CoMe~c of Pfysicians A Swgeons. New York. lO1LH H. MANHOLD, /... D.M.D, ta.os .w/ Diredoe, Drp.nwwwr of r y .wd Oral Dlorwosis, New lersey otlede of Medicioe and Dcw- 1irr1. lerser City. DAVID d MANN. Pw D_ Assorlore tn/essr .f tA.rw.ocologr. Tewqie Uwlwe.My Scsoel of Pl,awr.ey, rAd.- de/rY.. JOHN P. MANOS, M.D., )wsrr.ctor M Ykolerjp wd /.nerbfo/ty. Medkal Cdkge of Sorl\ Carali.a. C1.rlesro.. CHRISTOP}IER M. MARTIN, M.D Assisr+wr hofessos of Me/k4w .;J Dweclo., Dirlsbw of fwfecrions Dls- easrs, Setoa HaR College of Medicine. lency City. MASON RESEARCH INSTITUTE, Worcester, Mar. DONALD 1. MASSARO. M D. Aswc4 .re troftsior o Medkiwr. Oeoep Washington UaS.eesN7 Scwd o[ Mediciee, WasNqfori D. C. CHARLES McARTHUR, Pw.D_ rsr- eAol"/sr. Uwlrnslry He.ftA Ser.lres. Hsr..rd U.ieeeaNS, Caabridge. Masa. CHARL.lS R. MoCAN1s. Pw.O, Ass. eire rr.lessoe of So1/s. North Caes Rwa 31M. Codeya Scfed d,Larieri- 1am Rsritid. HENRY C. McV1U_ la, MD. AcrMd He.d. Der.aawl e1 rrAoloR. L,~-. ei.r Slau University School el MedL eiwe. New Orleans. HENRY 0. MCINTOSH. M.D. rrofee so+ of Medkiwe .wI Dlrerrar, Crlb- r.srrlr [iftoratory D.~a Uwite.+it1 Medkal Ceder. D.rL.~t N. C. PORDE A. MdVER. M.D.. Assvclne t.ofessos of rorAolop. Medical Cd- kp of So.ris Cueaiws, CU.rte+ror.. EDWARD McKEQ M D- Irofrssw MI AN4r( Cfbb-Mw. De/rlnrrM r.rAol.n. Medial Cdkee of Sonl Croliaa. Cftaekao.. 71 i I I KELLY T. McKEE. M.D. Associate rrofes.or o~ Melaiwe. Medical Col- kee of Sout CarolieK Cb.rkaow. VICTOR A. McKUSiCK, MD, hofen sor of Met/nwe. The 106" /1op"r Uai.crsiry School of MedicbaRi. axre. ROSS L. Mc1.EAN, M.D, As.aci.re rrofessor of Mrlkiwr, E.wory Uaia.. .Ar Scbd o/ Medkiwe, Ada.b. WILLIAM P. McNARY. 1., Pw.D, A. socl..e rro/ruoe of Awwowq. /aNOw Uwi.erOMf Scitool d Mediciwk Roe1o.. NP.AI. L. McN1VP.N, Pw.D. The W.r. «+Iet FovwdaUom for E.'erin.wl.l Rialt1. S4e...ew). Mw. JULIA MEYER. Pw D, Assciwe tr.- /e,.or ol Oral r.rAolo"U.henwr.t Illinois College of DeMMrT, (1icq.. BERNARD 1. MILLER. MD. Arls.wt rrofessw of Aw.rawy. 1eRersee MW- cal Colkte. Mil.ddrAia. JAMES 0. MILLER. M.D. PM.D., hr, le+w. .1 rsycAi.rry .wI Psqefl.l.gf: Direcror Mental I/edrA R.srre~A 1_W sHrwe. b.i.enlly of MhUR.R Am Arlor. CHARLES MTPTMAN. M.D. DbMew , Der.nnwwr of RestbrrwT D4nseR Ciry of Hop National Me/kal Cs /ee. Dwr", Cal. HUGH MONTOOMERY. MD. Ass. ei.re rrolessoa of Me/kW UsLenRF ~~Pewwsff.ar.ia Scbd e~i M.ifdrr P. O'R. pMWONTOOMERY h, M.D rhofesser, of r.rAolotf. ~lai!.enM~ J Teaas SowAwewes MeNcal SJo.l, A.Ras. OEOROE P.. MOORE, M.D, Pw.D DI- t.croe. RorweM P.st Memorial "l- twe, RaR.b, N. Y. KENNETH M. MOSER. M D.. Aas/rwr rroliuor .f Med/tiwe. OewReso- w Uei.ee.R~ Medictl Sclaoel. Wa.N.g- sm D. C. HURLEY LEB MOTi.EY. M.D. rWe.` sor of dfedkMe .wd Direcrsr, CrdM- Reyir.rery f.Sarr~ Uwl.eesl.l{• .1 SoMllerl~ Cali/oellia JC1001 O~ I~e~- eMe. Los Aiycks. EDMOND ANTNONY MURPIIY, M.D, St.D. Arsoci.re rrofessor of eloMUlsrks and Medlciwe. The lofym Hoales University Scbool oI Medi- ewne. Baltimore. WILLIAM S. MURRAY. Sc.D.. Streloe Sus SdewN.u. TAe /adsow I asora- 1orr. Sa Harbor, Me. RICHARD L. NAEYI~ M.D. trofnsor Owl CA.irwww, De~ rwwnr of rodhol. ot1. Pe~lhada S1Ne Uni.ersiry Col- kge o( Medici.e, Ikre4y. ALBERT H. NIDF.N, M.D.. rroft..r of Melklwr. Drew Posloradu.le Medical School and University of SouiAers Cdi/oiwia: CAIr/, rrlo.owr~ Di.eosr Section. Mwtiw l-.wfVer King Hoyir.il Los Apeks. OAK RIDGE NATiONAL. LABORA- TORY. Oak Ridge. Te.r. DONALD M. PACE. hM.D. rrofessor of rAfsidoRy .n/ Direcuo.. /wsrura /.r Cellular ResercA. lleitersAf ef NebeashR Lincoln. ALRERT S. PALMER. Pw D.. Auirw rrolessor of Pathology. University of Tekdo, Toledo, O. ROSE MARIE PANOSORN. M.S., As- s6r.wr Fool Terllwolotisr.wd Lecrwee. De/+n weewr of Food Sclkwn .wI TecA- aMof). Uwi.enMy of Cdi/oraiK Davis. )OHN W. PARKPR. M.D., Asssriri rarfrsw of rwAoloa~, University ei SoaAnw Cdi/o.eia Scbd .1 MedL eive. Los Aheles. MARY STEARNS PARSHLEY. Pw.D., Au/~ hofesaur of Awuowy /w OL- sreerks .w/ Grwecoi'op. Columbia Wi.ersity Colk~t af P6ydciur & Sw- RcewR New Yort. EDWARD W. rE1.IKAN, M D., C/ldr- .e.w. Dy.rrweewr of .wI Espriw..wroi' TAn.pruwlts. So+ian Uwl.etrlr School of Medicine. Rostow. MALCOLM C. PIKE. M 11.. rrof.uo. Co.ww.rwbr Melorlwe .wd trli.r- ' s. University of Southern C.li/oewi. Sehod ef Mediciwe, Lo. Angeles. OTAKAR 1. POLLAK. M D. rw D. E.eewir. Diretror, Do.er Medical R.- sewe\ Center. Inc, Dote., Del. MORRIS PO1 I.ARD, Pw D.. Dberror Lo1.nel L..Uae.rarTUei.er.Ny of} No1re Dan.e, No1ee parnt. Iwd. 7f

C. M. POMARAT. hr.D.. Dlrerroe of SENSON S. ROE. M D. Assorlne rro- ISAAC SCHOUR. D.D3. Pw.D., D3e SAM SOROP, Pw.D. !1'e.f. DePwtw.ewr Sloiork.l IYesercA. Pe+.den. Fowd.- frtror of SrRery; Chief. Cw•ILc Sr- De.w. Uwi.ersiy of IW.oh CdkAe J of Aforrownoletr/r CAew.brry. TV Iios tor Cel. Medical Rac.rcb. h.+dews. ~ U.l.eniy of Cdifornl. School o( Medicine. S.e Franclsco. Denlidrl. Chicago. SCRIPPS CLINIC AND RPSEARCH Imtilute for C.ocer Research. rfil.- theiibia- 1. N. rRADHAN. MD Pw.D. rrofes- so" o/ rAerw.rolosy. ilo.ud Uei.er- .M1 Cdkp of Mediciwe. WuAi.gtoR D.C. H. R. PRATT-THOMAS. M.D. rro/ei- smp of r«Anlagy owI De.n. Medical Coae.e of Sow1 Caroli.4. Ca.rkws. PROCPSS A INSTRUMENT COIIP/} RAT/ON. Re. klM N. Y. MARTIH S. PROTZPLDD;~C~i Dep.e..eM ./ Or~e/ rrA C1r1 IIwpNd. Ncwrk, N. /. WALTER REDISCH. M D A.selue r.ofeaaw of Cliwkd Me~ciwr. New York Uwi.er.ir7 Scfoe/ e[ MeNclwt, .d NYU Rese.rcR Sa..ioe, Oo1lw.rer Mseeid HoePiteL New York. )OSEPH H. ROGERS. M.D-. Holy Nnne of lesws HoqiuL Oed.deR Ala. ROlERT C. ROSAN. M.D_ Au«iue r.ofeuor of rrAology owI re/iurks. ,Se. Lorb Uoi.e7, School ol Medl- el.e- As.eciue ro.Aolotw C.rdinel Ok.wow Mewwei.l Ho.pa roe CYI- drewk 31. Lo.le. CHARLES L. ROSP, Pw.D_ Cllwk Df.ea Ior; Dtirlor. Noaw.e/.e AgMr Sruff, Verer.w. AlMiwid..uiow OwplieM C1Miie. ioetoa 1OHN R. ROrItI.ANDS, rw D. Se.t ScA:wla. SoMtt..esr Re.e.rc! IwMi1.u. S.w A.towio, Tea. BENJAMIN A. RUlIN. Fw.D Aadsaw rrofessor of rrNk Ne.FA. fr.~. Uwi.errily CoreAe of Medieiwe. Ho.- roe. RONALD P. RUSIN. PM.D.. rrufessr ./ rA.wu.ro/op. Medical Co1kp of VkAiwik RkM.owd. HENRY 1. RUSSEK, M.D. President. TAe Rasek Fo.wddion. I.c. S1e1es irl.nd. N. Y. W. C. RUSSF.LL M.D, Uei.er.lly o( Te.e. Medical Ce.ur. Horslow. WAYNE L. RYAN. PM D.. rrofessor of flocAenilury. Uoinrsily of Nebresk• Colkge of Mediclwe, Om.1.. PETF.R F. SALISBURY. M.D. PwD, Re.I. lwreiul.e Treuiwewl Cewte.. Seiet loalph IIo+Pi1a1. fs.rbeek. Cd. PAUL SALTMAN. Pw.D. Asslirwv rro- f.uo., Dq..rw.rws ef IlxAewrlM97 .wI N.rdNew. U.ieee.kr of SoMkee. California School ef Medicine. Loe Myek.. ULRICH H. SCHAEPPI. M D. Dkec- rr oLNero:A....oco/orl. 1(e.a* Re- aerc /rwAwe, WorceAer. Hu.. /OROFN U. SCHI.EOEL, M D.. Pw.D, rrofesror .n/ CAoirw..w. toero.rffeeM of Srgery. Tulane Uwi.er.iNy School of Medicine. New Orkaw.. ALVIN R. SCIIMIDT. MD. Dkeno' of Corwsdiwt. ?rfte Uwl•eleN1. Mei- 1o+4 M.r. TiMOTHY 1. REOAN, MD. rrofessoe ./ M.Ikiwe; Dhecsw, Di.Wow Cr1:ow..rrir D1sn..R CdhPe Medicine and DerieuF of New ler.ef. New /ereer Medical Scloed Newark. WILLIAM REOPLSON. M.D. rrofene. r.f CAob+wew, Der..awwr./ ltlelkol O~ Melical CoMqe d Virtiwi~ HOlART A. RPIMANN. MD_ rrofn- .rr of Ablk/wr. H.Memarr Medical Colkp .d HorPitd. Pv1.41plai.. ROLLAND C. RPYNOLM, M.D. As- s/Ne.f "eue..f r..Aolop. Uwl*er- eMt of T~ SowM.eMers Mdial ScV~~~~o~ l RICHARDS, M.D. CA/ef .f Srterr. Pre.h6eei.w Madkal CeO1er. yw Pr..cYw. W11.L1! H. RIESEN. Pw.D_ Senior Il/e- e#.wd.r. LI f e Sclewca D1 ddosa, IIT Rea.rdi Lrkaq CMe.p. DANIPL 5. RIFKIN PMD. Aabs.wl rrv/e..» ./ CA...ia.l 0.1e11. re RoelefeRe. U.i.er.irF. New Yark. R. H. RIODON. M.D. r..(e- of r.- rAele- ~. U.i.a*dt1 of Tear Medical ln" Od.e+oo. SYDNEY C. RfT7tNRPRO. twDr euor of Aw.erN/onr. U.Lertity e( Southern Califor.y Loe Ayda. •Q I 0 a FOUNDATION. L. IoRK C.1. MAURICE S. SFAAL, M.D. CN.k+./ Professor of M.ficlwr, T.fN Uwieee- wf Scaool of Medicine; • Dhrefer. Dw prrwrews of Iwb.l.r/ow TAeei y'. lfe.. wA Ci1r Ilopw.l. sowo.. Lt1C1O SP-VERI. MD, DiMcler, or/ Dea, 1wuk.Me of AwetawF.wf r.Mef- l~.~i.etD.iifl penn rs+r< PeeKf~ 11 CHARI.P3 E. SHPRWOOD, M.D. A. d.rows hofeiwr o/ R.4.l.rr Unl.w- .Mr of Ro«Aerer 3efe.i o1 ~Ieyd.e .wr [hwtMry. Rotfe.Ne, N. Y. SHOJI SHISATA, M.D, PwD. PWes- ew r H.w Sclool e/ ftv ' ~Fjhdra DAVID L. 11MON. MD lwekuetr lie lwcrrwd Alelk(wr. CLc~.~Ml Osn.l HorFirq Ci.dwwL ERIK SKINH01, M.D. CAIrJ DvPS6 swnrt of Nerdop. 11hpd/eeR Harai- Id. Cepe.Ue.ew. THFODORE A. SLOTXIN Pw.D. Ar stsr.m rrofe..w ./ Duke Uwi.ertily MeJleal CeM.r. D.a Larw. N.C. GEORGE W. SMETTEMD. Asro- cA0e M r ~.eMee~.i 7' vcreilr Mcdkd C7fcan.. GENE M. SMIi71, PwD. Ass/ruor r1- ScAool. M s~tetU Oewenl H.A/• 1.1. Sw1ow. LUCt1.H SMITH. PR.D. rw(esew .r NorAewdwr. D..t Medk.liwowlr School. Haw.ee. N. H. SHFLDON C. SOMMPRS, M.D. DMft- sor of [.Aor+ro.ks. Lewoa HM H.r ~Id• CUwkvf r.~o~...w of r.eAibn. (:oMMwbir i1w1.e..irT C ~ of Pfre1- e1.1M & S1M NewReowS PRNP3T SONDNPIMPR. Pw.D. Ar+- r/ere rrofeasee of IlatAewdsw5 Cd- kAe of Fore.uy. Slaw U.F.ee.~t1 d New York. Syrec..r. T. M. SnNNF.OORN. Pw.D.. DbrA.- t.r1.A.I S...ke r.efesr. .f Ldep. 1 duo. U.+.ereNy. sioawhre. SOUTHWEST RESEARCH IN3T1- TUTE, Se. A.rowio, Tea. DAVID M. SPAIN. M.D. D/renor. Do- (..Iwu~iw of I«Aofort. The srookLM Ibyit.l Cena. Rroo,lm Ir. Y. ALEXANDER SPOCK. M.D., ArMn.w rro/es.or e/ re/lotrki. Duke Uoher- My Medical CeMer, DwMwr. N. C. FREDERICIC 1. STAM M D rrofei- ww of NrriWow Hen.ed lJwi.e..e 7 Sctrool of FoWk he.Mis. foeroe. C. HAROLD SiPPPEI~ M.D. DDecrr M~ wks, Melbodiel Noyilel, JACK P. STRONG. M.D, Auoc4v hof.ssor of rorAolep. Lo.Wewm SIs,N Uwieeeeily School of Medicine. New Ork.ra.. MARION R. SULLERaER. M.D. Pro- feauor ow/ CAoi.w..w of Derw.eroleq .wf Sr r>IAWioey, New York Uwiee.- arr- ~etle.s Medicd Cewler. New Yoek. RENATO TAOIURI. Pfr D, Aa.eclde rrofeuor of rsTcAoloty. Or.Ar.1e ScRooi of se.ines. Adedwirrq{oo. H.r.ad Ura/.ereill. b.wow. MARC D. THAMES. M.D.. Sewloe Re- se.reA Fellow. Me~o Cliaie and Po.n- iwioR Rockeerer, iNiw.. CAROLINP BEDELL THOMAS. M.D. Aofesaor Ewre.irw of A(efklwe. The lofl.e Ho~in. U.i.erairr School of Medki~e. ahie.ore. JEROME F. THOMAS. Pw D., rrofissar of S.e/r.ev F.w`/we../w[. Uwi.eniy ef Cdi/orwie. ber`ekr. /AMPS E. P. T+OMAN. nr D.. r. e,- so..wl CA.Mo..w. De'..rwvws of Ihsif.c`d.R7. Chicago Medical School. Ir" wNMe for Medical ReeeacA. CAkap. )ANPT TRAVP.1.1. M D. Aaaee4ui Professor of Cllwln/ rAo.wnwolop. Corwell Uwieer.irr Medical ('olkp. New Yoek. LIE SHA TSAI. Pu D. Re.errA A.wr- ttwi /w r.rAoloat. Yak Uel.ee.ilir School of Medicine. New Heven. Cow.. •1

UNIVERSI7Y OF SOt7THlRN CAU- A. WEINSTOCK. n1D. RrsrsrA fler FORNIA. Los An{eks. tArwrbr• Ult Stltnrtr Di.lrion• 11T Reerarcla Makwe, CUicaso. !ltlOT3. VESELL, M D.4P Pr~/raet.w/ .rAd. CA./.w.w. Dy.rrnawr A~ww..cd- RUSSELL W. WELLER. M.O_ t ep, hwwsyl.ania 31we Uwi.enilf Co{- ella, MeeeorW Howpilal o[ CAewer few ~ d, Medicine. MiNow S. Hen~ef Counlf. Nrc+r Che+1er. h. , ^""~ cester• ""$bey' A. STANLEY WELTMAN. rw.D., Aaaa ViDtC, D.3„ MJrnat ~r ~te.or of ll~.rwwcdoxf .wl RRANL11~1V ./ Aw.aewrf. Oeoryelo.w Udwrfltf RrrnreA. Rraellfw Colkp of M.r- 9cloeb of Me'kiwe ad De.IMtrf, ~f• Rteollf~ N. Y. M.rlql.w. D.C. 31MON H. WENDER, M.O_ RravecM rue. ./ flrrAnwlsmY, Uwi.er.Mf ROMEO A. ViDONE, M D. A.wei.w .I LAowuk Notwn.a h./.w. ./ IuAobtf Yde UwF.er- wf x~wa of M. New H..e06 DUANE O. rYENZ![. hK.D.. 1re/twt l COVAL M/ CAiw/.R, brprfwrt.r./ rArm!• r.i.ff .w/ T..ke/erf Tle Uwi.er.Mf PlTER K. VOOT. ~ D_ iw N ~ Krwe sAo./ ./ k.rw..cf. 1..- Mkrv'Ml.p. Uwi.er.MT .f wsbiy- Nw !el.d .f Me4kiwe. 3ew1i.. ?11OMA! C. MlSIlALL, /w.D."t. R O. WARNER. M D_ Mft nw ./ t. ~~~~f• Uwi.er.itf of Vk- lhr~. StiaM Uwn+n/tJ ./ i..a Cd- ~ sdool a[ MeaeMe. CYr+ares ie6t .1 M.Mdw.. 1.~.. C1tf. •+Ie. PREDERICK !. WHISKIN. M.D. C.M_ 3H1lLDS WARREN. MD_ Dl.rr*.r M Dbtcrev, D/e/.kw ./ NrdrA .wI rtr- Ld++rwirr, Cr.rvr RtwtA lw.d- rowd/ay Eqd//Mlrrw, TUe Ap Cew/er ~:~New ~lwdosA D IIM4 e[ New EmRIawd. Iwe. Rawo.. ROGER 1. NriLUAMJ, M.D_h./raw YASUSHI MATANARl, h1.D_ Arsr e/ CArwMmy; D/reerat, Cl.fr.w 1''.w- cirr Mt+wM. Tie MMer IwwMrlr of Aabw /AerAriwko/ iwrtN.rr. TM Uw1- A.a/awf .M RioloFf_ f1M6elfiiw. •enMf of Teaae. A.wlw. BARBARA K. WATSON. Tw.D_ Artir- DANIEL H. WISEMAN. M.D.. Aa4a .wr Ra/rd./arlM. Mar.dwwfN Oew- W rr°ft-u-aro/ rrN.rrkr. Uai.e..il~ wal HeyMal• RrrtrcA Aa.oc1 ate M °/ ~~ Califo.wia: Cfiiew: DL- /.rMldep wd lwuwwwleFf. H.r- 'idook Lea Mqeka Co.wy Oewnd •nr Medical RJeaL Rodea HospAaL Los Awplew lOHN 3 r1lAUGH, /I~D. M/e.w ./ /. EDWIN WOOD. MD. Iwaerrcror b CAerwlrry. Ma.rAsen. MrtN.M .1 Mtlkl+t. /owow Uwi....Nf Sdeel of TecRwe/egf. C.wrbtirM. /MsJidwe. Ro.sow R/CHARD L NECH3LlR. M.D. CNw- ~j N/~~t ~ j:M~TTM.~o6w. krf rAf.bl.Ni : MowkRo.e Ho~ai Ho~Ma Uni.enNf e( MeA- IwMMft .f ReaeareR P1M.b..* ciwe. RaNYwa.. IOHN V. r1lR. M D_ Ar6hw tro- /ONN P. WYATT. M.D. <Mn_(root of nM M~e~IcA Cewir. Dewwry •f C.1. 3'efoef Mrk wa,l~ j d~~v f I INI)FX OF PRiNQPAd INVESTIGATORS AbooQ. L a.. 44.45.46 Arcoa, l. C., 6 Bing. R. l., 31, 33, 36 BonE, R., 39 Broot., R. E., 54 Ca+lro, A.. 43.44.49.50.58 Chalon,1.,12, 22.23 CocArane. C. a.. 311. 39 Cohen, A. s., 23 Cron, C. E., 28.29 Downep, H. P., 37 Bionaw, W. B.. a,.! Evua, H. 8., 24 Fhhaun, W. H., 7, 8, 9,10,11 Frkdrna.V O. D., 60 - Oiekw,l., ls (lr.rwed, l. l., 25 Haumo.b, M., 27 IlanaaA, r., 25.26 Henoowit;, H. s., 39 Koari. R. 8,17 Kupandct,S., 1• Lau.eryro, l. M., 31, 32 Leae, E., 31 l.erner, R. A., SS Levy, l. A.,13,11 LfAch, H. T..15 Marei., R. R..16,17 R1cKenwb.H ,lr., S1,S2 Meier, H.,19, 20, 63 MicAaell. D., 39 Mmwk 0. s., 52.53 PwN, A. R., 63 Pte.re, C. w., 55 RaMaaab. l., 61,62 Roaeerw, l. A.,17 Rfas. U. S., 30.40.41.42 SoloR, L A., 42 Th.rnea, M. D., 34 Usaeus, E. R., 56.51 WeMbwu.a, O., 33 6I ~ ;

I INDEX OF SENIOR AiTTHORS Areo+. 1. C.. 6 Arorolim R. S.. 44 S+wnsold. l.. 46 SeYer, D. L, 57 Sarn., a. N.. 39 1l.rte, M. D.. 22 Castro, A.. 43, 44, 49.53 Cha/os. 1., 12 CA..s, C-H., i l Camad, R. E , 39 Co.l., P. T., )r., 39 Crw.. C. E.. 29 Di..w. 11. L. 20 Do.my. H. P.. )7 Fnr#.". W. R., 40.49 E..wti H. E., 24 Ft+cAe.. R.. 34 Fhirn.n, L, 9 Fislww.w. W. H.. 7. 9 F1orM L R.. 30 Fo.ws..rl. P. M..1 s Foa, R. R..19, 6) Prkdenw, O. D., 60 Priedm.w•Mo., Z.. 22, 2) O.ud, D. L. 34 Or.rweri, l. l., 23 Oairgiq, H. A.,15 H.e.o.U, M.. 27 Hnwodk 1'., 26 Hc., w.. 46 l.naR, A.. 33 Ko.tew..e, M.. 61 Kouri, R. E.. 17 Lasi. l. A., 28.29 LAawerynm 1. M., 31, 32 l.cele. E.. S I r.eoM l. C.,14 .l.e.p.l. A.,13 ts.y, R. L. 33 Lo, T. N., 23 Lo.y, K.. 45 Md.e+wore. T. L.,16,17 Mich.eN, D.. )9 Mlyq.wu. H., 11 Neben, D. w., 21 Newr.rlk O. 11.. 52.53 P.M. A. R., 63 rilon, A.. 32 Re..t, s. D.. 38 Ro.eer..., l. A., 47 Rys, l. W.. 30. 40, 41 Ry.., U. S.. 42 S.rm.. J. S. M.. 35 Sanu, s.. 61.62 Singer, R. M., 7, 1,10 T.d.twn.. T.. 55 T.veire do Sil.., A. M.. 25 TAune., M D.. 34 l)e.nue, E. R., 56 v.e C.nUort, ).. 1 s V.ne.. K. O.. 42 Wehh..r. R.. 36 Ye.ger. H.. Jr.. 27 Yi, l. M., 31 84 I 10 't