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ANDREWS OFr1CE PRODUCTS CAPITOL HEIGHTS, MD (K) I

1975 REPORT oJ TIIE COUNCIQ. FOR TOBACCO RESEARCII-U.S.A., Inc. TIIE (:OIIN(:Il. FOR TOItA(YY/ Rtat:AR/'11-11.ti.A., loe. 110 t:..l 59t6 11.er1, New Yo.k, N.Y. 1 1N122

SCIENTIFIC ADVISORY BOARD to The Council for Tobacco Re.earch-U.S.A., Inc. aa ot Decembe: 31, 1975 SHELDON C. SOMMERS, M.D., Chalrnmn Director of l.a6oratories, (.eeo: Hill Ho.pitd Clinlcal Professor of PatAolory Co1k~e of Physiciuu ! SurBoo.s of Columbia University New York, New York RICHARD M. BINO, M.D. Diredor of Ca.Jiology aid Intr+rnv,d Medicine Iluetington Memorial Hwpltal, Paa.deaa, California Pro/essor of Med(dne Ueivenity of Southern California ScSool of Medicine Los Ans ela. California JOSEPH D. FELDMAN. M.D. Hed,Depa rtment of lano.nop.tho{op Scripps dioic and Research Fotrdatio. La Jolla. California VVii1.lAM U. GARDNER. Pu.D. Scientific Director, The Council tot Tobacco Reatarch-U.S.A., Inc. E. K. Hunt Professor of Anatow"y (emer(h.s) Yak Univcr.it7 School of Medicine New Havea, C,onoecticvt ROBERT 1. IiUEBNeR, M.D. Chief. Laboratory of RNA Tumor Viru.ea National Canoer Institute Betbesda, Maryland LEON O. JACOBSON. M.D. Dbecto., The Fnnklia McLta. Meawrial Research Institute Regeiuteln Professoe of A/oloslca/ Sclencw Univenitr of Chiup Cbicaso, luisoir AVERIIL A. LIEBOW. M D. Pro/essw a.d CAad.mmn. Departmeat of Pathology University of California School of Medkme San Diego. California HENRY T. LYNCH. M.D. Profes.or and C.hebw.on Ocp.rt..c.t of Phevc.tive Medicine and Public Health (lrcighk,. Urvctrt7 School of Medicine O.aha, Ntbf..ka HANS MEIER, D.V.M., Dr. Med. Vet., M.R.S 11. Senior Staf/ Scientist The Jackson I.abotalory Bar Harbor, Maine LEE W. WATTENBERG, M.D. Professor of Pathology DePartment of Laboratory Medicine and Pathology lJniversity of Minnesota Medical School Minncapolis, Minnesota JOHN P. WYATT, M.D. Director Tobacco and Health Research Institute llniveraity of Kentucky Leaie6toa, Kentucky Seleetiie S1aR.t The C.o..ndl WILLIAM U. GARDNER, PH.D. Scientific Director ROBERT C. HOCKETT, P>t.D. Research Director JO11N 11. KREISIIER, PH.D. DAVID STONE, Pw.D. Associate Research Director . Associate Researcb Director VINCENT F. i.1SANT1, D.M.D. Research Assoclate I

i CONTENTS Introduction . . . . . . . . . . . . . . . . ' . 5 Studies Related to Respiratory Function and Chronic Pulmonary Diseases . . - . 7 Abstsscts of Reporb . . . . . . . . . . . . . . . . 14 Cancer-Related Studies . . . . . . . . . . 14 7 he Respiratory System . . . . . . . . . . 24 1lcart and Qrculatlon . . . . . . - . - . . . 33 NeuropharmaooiM and PsydwQbysioloty . . . . . 47 pbarm.co{op . . . . . 53 Itnatutw{op and Adaptive Mochadsms . . . . . . . 55 Epidemlobpr . . . . . . . . . . . . . . . 62 Active Projects . - . . . 66 Compkted Projccta - - - - - - - - - - - - - - 73 Indc: of Principal Invcstipton . - - - . . . . 83 lndei of Senior Authors . . . . . . . . . . ' . . 84 Introduction The Annual Report of 1973 had one of ib seven aoctiona dcvolod 1o the presentation of some research on hmg functioo and chro.ic respiratory dirr eues. During the past two years. studies on respiratory functioru of nun and I laboratory aniat.ds bave advanced greatly. Sophisticated biochemical rnethods i have been used 1o study Ihe defense mechanisms of the lunp, their response to Ihe internal environment as determined by the genetie background of the i I like-seaed twim, but also the Iwins as Individuals making up a crore section o4 the populations. Puheonary function of populations at different ages and different arere of residence and diAerent oecuPalions hae been detetmincd and the eAects of familial or hereditary In/luencaa have been described and discussed. New observalions have also been made on lung slructurc; neuroepMhellal bodies have been found is the human lungs and described in detail. ihcir function Is not known with certainty. They probably contribute to the normal function of 1he lung. Even at this tine, new Mtucturee and potential regulatory mechanisms of lunp, which provide that narrow interfact between envitoa ment and blood, can atdl he discovcrcd. i The following review of the studies related to reapitalory function and chronic pulmonary diseases reveals the interests of The ('ouncJ in tbeae anaa sub/ect and theur response b eaternd rrnwh. The aburacu of the tnvesliptioem that have bten supported during 1973 in this and in other research areas .re included in the third section of this report. lhe previou. Annual Report emphasized the researches that were related to cancer and to the considerable effort that has been made so develop mnhods for the delivery lo, aed rekntion of smoke or .moke components in, different Parts of the respiratory tracle of mioe, the animab that had beea aelected fot the snwke eaposure eaperiments. Thir year i Annual Report emphasitea Inve.tiptiosr that have been u.dsr- taken on the respiratory systern and on the epidemiology of respiratory di.- easee. In some ways the classilkatiow ie eomewhat arbitrary. For eaunpk, em- pbysenu might be eoraidered under the respiratory ayslern, but becatw masy studies on this d'aease involve hereditary and environmental componeds, otrtals studies might be clnsiAed wader epiderniolop. The rapid developnKN 1s theae arer during the but few years led The Council 1o convene a twoday idornal conference during 1975 at which a number of investigators coneerned with the luafe proaeia-destrqring en:ynw .nd their inhibitors had an opportu.Yy to communicate and compare their moel reeeat investigations. Tlr aubjocto di.- cus.ed in detail are presented in the following aection of Ihim reporl. Identical twin., like laboratory animals of highly Inbred Nrdr. Provide the best meaae of dclamining the imPact of the environment on the genotype. When enviroemental factors are direordawl the eapression of the oenotypc nray be modilled. TM New Swedish Twin Registry - twins born in Swedcn from 1926 1o 1959 - hae been completed with some 32,000 eMrica of like-eeaed twina. A FisriaA Twin Registry has beew eospibd and anuch ksforsnatlon i being obtained through responses to aueetionnaites. The contrasting Mcidcaoes of pulmonary cancer and coronary heart disease in Sweden a.d 1. Finland should add ddniAeanoe so the dala that may be derived rrom Mudia of thne registries. The Nudia wiN involve not only the identical and the .o.-idedical. t J 3

static clastic recoil pressure, total pulmonary resistance and flow rates, forced deflatKrn, and nsorphunsctry for mean linear rntercepts and intcrnal surface area, as well as general pathological and histological evaluations. In summary, no sitnilicant ahnurmalnies were observed in the animals exposed to dust with or without nitrogen droaides lhis study dNd not produce an animal model (or emphysems. In another study by a different investitator, hamsten were exposed to long-term chronic cigarette smoke inhalation but gross emphysematous changes were not seen. Studies o/ Osone Orone, a powerful oxidant and a very prevalent and active constituent of atmospheric smot, can severely damage the lung as can exposure to abnormally high levels of oxygen. A scientist sponsored by I he Council undei took to study the cflects of these agents in rats and rworskcys in order to discover what changes occur in the lung meubdrc and enzynse syslersu and how they might be pre- vented or reversed. When the study is compkted, dse informalion obtained shouW be useful as background for analogous studies of tobacco unoke inhala- tion and provide a basis for observationa on possible interactions between to- bacco smoke and smog. 1 wo drstinct aspects of ozone effects were found. Short•te: m, high-level c.psnures 12 to 4 p p m I for two to tight hours destroyed large Ixoportans of the suilhydryl compounds present in different portans of the lung cells, with profound lowering in Ihe levels of enzyme activities involved iu cell division and repair. In contrast, exposures at the level of 0 2 and 0.8 p p m. (or two to seven days produced no deuructwn of sullhydryl compounds or depression of these enzyme syslcros, urstead. the activity u/ the systems was increased. thcse etlects of low Icveh of ozonc may ecplam in part the tolcrance or adap- Iation to such eapusures that thrs scientist and oncers have noted in animals and in man Morphr,tosiscal studies have parallelcd these hsaxhemrcal uhscrvations. laposures to relatively high concentrations of oxygen are being made for comparison, and studies of tobacco snsokc inhalation by rats with or without previousozorse espvsures are now under way. Preliminary eapcriments with mke, employing realistic dosages of cigarette smoke daily fur three wceks, showed no histological evidence of maior patho- logical change. lhe lunp, however, had higher levels of specific activities of the antiosidant enzymes, glucme-6-phosphate dehydrogenase. Slutathione re- ductase and gluuthione peroaidase, which may refket adaptive response to oai- dants present in the smoke. Other lung biochemical asoys have been added to the protocols; for esampk, the effects of o.idants on collagen synthesis. Pulma nary fibrosis is olten a sequel lo long-term chronic respiratory damage by such agents. De/en.e Mec/h.ni.n.s o/ tbe Lung A previous Annual Report (1977) mentioned studies on the defense me- chanisms of the respiratory aract against rnhakd partrculales, both inanimate 'du.ts*' and mKroortannms, especially by mobilization and functron of pulmo- n.ry roacri-phatcs Rates of clearanCe for aspirated SwOhyfoCocCW aureYJ hare 0 a been measured as well as the mobilization following such aspiralions, of creased numbers of recoverable macrophages. 1 he effects of tobacco smoke halation upon rates of disappearance of viable orpniams from Ihe lung /a , have been reported, and Ihe total engulfinent and killing activity of macrophr populations recovered from amokes.posed animals are now being dctcrmrr in vitro. In jluensa In jeetlona Influenza idections, atili prevaknt, resuM in significant persfsknl Ir damage in man. A veteran investiptor of this problem has published a detu description of the sequential effects of influenza PRII-A infections In mi Wi1h the advantt#es provided by the opportunity to sacrifice anirnds seri. at all stages of thz process, these observations generally have conflrmed and tended those avaiJabk frons human por-nso.krn e.aminatiorsa. A scparuc view applied Iheat findinp 1o interpretatioe of potentially serious ovesequen of human hsthrcrsa and suggested preventive meaaures that should be appl to prevent such iafectioos. A tnethod for producing rrsore consistently a persistent vitami. A defkie, in mice made it possible to study the consequences of such deficiency upon aequelae of infection. Squamous metaplasia and keratinization of the broncl membranes were significantly greater in the animals with little or so heps vitamin A and the pou-infection lesions showed more e.teesive epthr noduk formation. These and observations from othcr quarten have renev interest in relationships betweea this vitamin and cancer susceptibility ot sistaoce. Clinical Surtreys oJ Lung Frnetion "Y'aptive" populations in the ftoaoa area and on she West Coaat are 1 viding the opportunity to describe relations of age, sea, raos. Ii$M unok, heavy sewking, industrial exposures, aad other factors to pulnso.ary functr changes over an extended period of time, through repetitive resaami.aioaa Respiretory Distress Syndrome o/ Newborn In/enta Ilyalrne membrane disease in newborn infants, associated witb prcrwatu, maternal diabetes and complications of pregnancy and deiivery, produces I mortality. It is due to IaMure of the infanl lung to expand propesly dta livery and ia usually accompanied by formation of a"hyaliee rnembrane" I structure, observed in the alveolar spaeea, ducts and bronchioles, coasisu of generated lung surface cells and blood ekmenls, and contains large .mount fibrin, an elastic, thread lrke, insoluble protein material. The ate{ectasia (r expansion) has been ataributed to a deficiency in wr/actant and the flbtin cumulation to a detective balance between the systems normally rapoor for its formation and its removal. 9 I

Abstracts of Reports Following are aburacts, approved by the authors, of reports on new re- search acknowledging support from The Council that have appeared in scientifk 'ournals since publication of the 1974 Report. The name of the recipient is tn italics. The ab.tracts are grouped under Ihese headinp: 1. Cancer-Related Studies. 11. The Respiratory System. Ill. Heart and Circulalion, IV. Neurophwrmacolopr and Psychophyuob6y, V. Pturta.co/oRy, VI. Immunology and AcJaptive Me- chaniams, VI1. Epidemiology. 1. (',.wc.r.R.l.t.d Stadiea CORRELATION BETWEEN BALANCE OF SPECIFIC CHROMOSOMES AND EXPRESSION OF MALIGNANCY IN HAMSTER CELLS In cell cullure, abnormal chromosome patterns occur rapidly in hamster fetal (HF) cells after Irea/mesd by various polycyclic hydrocarbons. The close association between thia aneuploidy and malignant transformation has been dis- cussed, and it has been suynled recently that malignant cell Iranslormation and tts revenion are determined by the balance between specdic chromosomes containing information for either the "espression" or "suppression° of malig- nancy. In this uudy. HF cells transformed by 1-/l-D-arabinoluranosykptosine (ara<;) and dimelhylmrro.amine (DMN) were used to aee if a specifk chromo- some imbalance could be correlated with the expression of malignancy in trans- fonned cells. Four ara1;- and one DMN-transformed Syrian hamster cell lines were established. AN produced tumors when inoculated into newborn hamsters. SpeciDc chromosome changes were observed in these lines which were cort- sntent with changes described by other investigaton. ('lones that had either high or low malignant potential were derived from two Bbrosarcomas produced by one of the ara-C-transformed cell lines. The expression of malignancy in these clones was associated with an excess S, chromosomes over 7. chromo- sornes. It ia important lo determine il the same relationship between the balance of speciAc chromosomes and the expression of malignancy can be extended to other mammalian species, particularly the murine aod human systems. Some of this work ia now in progress. Ornrdkr, W. F. rr d. lournal o/ the N.Non.l C.nrrr lnrtlrrrt 34( I):157-162, 1975. OtAoe srrrortr National Cancer Irlilute. From the Division of Hematology Oncolopy. Deparlment of Pcdialrics, Chil- dien's Ilo.ptal of Ins Anjcks; the Pediatric Oncology Pro4ram, University of S4wthern ('a6fornia School of Medicine. l.os Angeks; and the [kpartment of Vual Chenucal Uncoloty, Mucrobwbgical Associales, Inc.. Belhesda, Md. I I I STRAIN DIFFERENCES IN THE RESPONSE OF INBReD SYRIAN HAMSTERS TO CIGARETTF. SMOKE INHALATION Striking diAerences occur among different lines of hamslen with respect to the susceptibility to acute lo.k effects of smoke and to the hyperplauk response of the laryna to smoke. In this qudy, male hamsten, 102 frore each of two inbred lines, were exposed to cigarette smoke twice a day, fiva darsl week for up lo 100 weeks, in a modified Walton revcrse-unokinR machine. Sixty sham-unoked and 60 cage-held controls were used /or each urai.. Smoke exposure for up so IC11 weeks had no effect on mortality in either draiw, but reduced body weight. Carboxyhemoglobin levels increased markedly innrodi- ately after each smoka expowre but returned 1o baseline levels in ler than 24 houn. Serum Iriplyceride levels and virus profiles of smoke-eaposed a.imak+ were unchanged. Chronic smoke exposure increaaed relative wc*M of the lunp and heart in both uraies, but /o different degrees. Over 9" of the smoke-esposed animds of both strains slwwed hyperplaatic or .eoplartic chanRes in Ihe larytu. However, microinvasive eancer was nearly Ave ti.w more fretJuenl In one strain than in the other. In the inbred li.e tnae su&- cepttbk to laryngeal hrperplasis, two animals developed naaopluryngesl tutwot., one of which wr mdisnant. Smoke exposure induced rare beni6n squawwtr papilbmas in tha air paaagen of both uraios. The alraia less suaceptible lo laryngeal hrperpluia cshibiled more pulmonary .denomatosis, but Na Lcide.w was not si6nilkastly affected by suake exposure. Bernfeld, P., Hornburyer, F. and Ruulkld, A. B. (elo-Rei..rcA Cowrrbaar., /nc.) lournn/ oJ rhe Narlon+t C.ncrr lnuirrre 33(4):1141-1137, 1974. From Bio-Research Corodtanu, Inc., Cambrid6e, Mau. MODES OF OROWi'H AND SPREAD OF A TRANSPLANTASLA VIRUS-PRODUCING MURINE (MOLONEY) SARCOMA: KARYOTYPIC ANALYSES According 1o karyotypie ..alYses, cell elones from a visua-producia& tra..- plantabk nsurins (Moloney) sarcoma Nr (MSC) eontaised a aet of d.kla, structurally rearranged "nurker° chronwaorees.'TAese identifying m.rken were not present in cells newly transroneed by reurine sarcoma virus ( MSV ). Tlur, after MSC injection, il was possible to delermine it there was any causal tw lationship between MSV produced in viro and the sub.eyuent development of primary and aecondary neoplasms. Each adult and neonatal mouse {ivea IM MSC devck.ped a proprenin{ primary sarcoma. Many had aoco.dary put- monary ncopla.ms as well, and soate neonates developed secau.dary, ap{eee snd periosteal tumors. AH the •79 metaphase spreads prepared from primary s..- comas a.d secondary puhnonary neoplasms contained MSC masker chronw- sornes. In con/rast, cells explanted (rom a perbsteal neonatal mouw (unsor uni- formly lacked such markers, even thoirXh the primary sarcoma of the s.... mouse consisted of MSC cells exclusively. Sirnilarly, none of the 140 metaphaw spreads from sarcoma virus-induced primary lumora contaised MSC murkcr chromosomes. Primary sucomas and secoodary pulmonary ooopiaads, the IS 14

i INHIBITION OF DNA REPLICATIVE SYNTIIESIS AND DNA REPAIR SYNTHESIS IN HUMAN AND MOUSE CELtS IN CULTURE BY CI(;ARETTE SMOKE CONDENSATE FRACTIONS As part of an investiptioo Into the mode of actioa of lumor promoten, a study was made of the eRens of cigarette smoke eondeosata (CSC) frac- tions on replicative DNA synthesis and DNA eacision repair syolhesis. A total of 12 CSC fractions were tested for their abilily to inhibil these functiooa is cultures of human Abroblasts and Srrir twoare embryo cells. None of the /rac- tions showed say specificity toe Iha WMtion of DNA repair aed, in Aeneral, repair synthesis was less acaeitlvs to iohMioe tlan was rsplicative synthesis. Tbere was aowu: correlation between Ib WibMory, actioa of tbs variow /rae- tioas and their activity in bioassays perforrned in other laboratories, including in vitro cetl traroformation and baclerial arutapeoicity. 1s most instanues. DNA synthesis was more sensitive to i.hibitioo Iw tha huwun ce8s than is the mour cells. lTr specific compounds re.po..ibM for ,he activity of the condensate Iractiom hsv..o1 been ideetitled. Ranuusen. R. E. L!/e Sciences 17(S):767-77), 1973. From Ibe Cancer Research IosUtwa, University of California. San Francisco. MFASUREMeNT OF NITROOEN OXIDES 1N TOBACCO SM1)KE BY MEANS OF THP. CHI?MILUMINE9CENC13 M13THOD Chemical analysis of fresh lobaeco raoke to determine the ronteot of nilrosamines that may be prescN under the conditions of actual hunun smok- inA has been ddficutl with traditional methods because of the tirtre reQuired to carry them out. Formation of precursors neceswry for oitro.amine produc- tion in the presence of aminea occurs only by tinte depeoden( resctioos, so that artelactual formation duriaj the oourtr of smoke analysis by older methods has appeared very probable. lo order to obtain reli.ble bask data, it was ooe- sidered necessary Arst to rehvestillNe 1ho kinetics of the precurso. reactions under the conditions actually present is smoke. T3e actual nitrosating a" for twnioa Ia believed to be dinitrogeo trl- oaide (N,O,). an unstable compound which Y oot present in tresl.ly formed tobacco ssaoke but formed only when .quiraolecular proportioa of aNric oaide (NO) aod of nitroAco dioaide (NO,) are present aimult.aawdy. The authas underbok, r a Ars1 atep, b rtatwn the concentratiorn of tba /wo latter osides of nitrogen in sreoke at a brief bul carefully deAned Interval fol- lowing its formaticM+. Earlier work by diffkuk methods had Indicated that NO is by /ar the predominating oaide of oitrogeo In fresh smoke (Norman and Keith) and is only slowly osidizod to NO, under actual smoking conditions. TAe present authors undertook to repeat such determinations by use of the recently developed chemilumineseence method which can determine NO auao- trtativrly- and almo+l in+lantaneoudy, in the presence of NO, It should. tfirrrl..re. he m.w h k.+ LlorMws, rnwe accurate and allow better control of the tmv 1aMVN 1hu nrw trthntq..e depeod+ upon the selective oxrdauon of Nt1 h. ..r..nr U. I...m rk•tt..o..allt •.uord NO,..hrch rcacuon is tmmediate- ly followed by the unique and measurabk emission ol light in the 0 6-3 pru wavelength region. Thirty-uven diRerent tobacco products were thus tested to determine the NO content of their freshly produced smoke. Thn ranred from a minimum value of 190 ag/mt of fresh smoke for Aue-cured tobacco cigarettes to a mawl- mum of 1,300 nA/ml of smoke from Spanish black tobacco cigarettes. In Aen- eral, high values were obtained from cigaretten made from air-cured (burky, black, and cigar) tobaccos and low values front 1ho,e containing mainly Aue- cured or oriental types. Following this type of specific NO determinatiow in the total smoke mis- ture, which may also contain smaR amounls of NOf at the defined time of the assay. the mi.ture can be passed through a catalyst 1o reconvert all the naro- lien oaides back to NO. By immediate reappliestion of ehe chemiluminescence procedure the total o.ides of nitrogen can then be estimated; the differeoce be- tween the two assays serving as an assay for the original small content of NO, present at the time of the initial assay. Systematic eatension of the present studies to this and other aspects of the total problem is contemplated. Nerra6. G. e. and DOoger, M. In: Bo6ovski, P. and Wa:ker, E. A. feds.): N-Ninoio Compounds !n the Es- vironmenr. rroceediwp of the Wor4inp Con/erence Held ar the Inrern.tbnd Apency for Research on Cancer. Lyon. France 17-IO Ocrol.rr, 1973. Lyoo: International Agency for Research on Cancer, 1973, pp. 177-179. From the Microanalytical Laboratory, Hamburg, Federal Republic of Germaey. Q-NAPIITHOFI.AVONE ACTIVATION OF 6-HYDROXYMETHYI. BENZO(o)PYRENE SYNIHETASE In their series of studies on the properties of aryl hydrocarbon hydroay- methyl symhesase (IfMS). Sloane er .t. have demonstrated that model ao- maic compounds could be metabolized to the aryl hydrosymethyl derivative by either the direct hydroaymethylatioo of the benzene ring or by osidalioo of the aryl side<haio methyl compound. These studies showed that the methyl &roup hydrosylatioa was mediated via eytoehrome P-4SO, whereas the 11MS reaction was independent of this pathway. Of interest here is the fact that 6- hydrosymelhylben:o( s)pyrene, a metabol'Ne of hen:o( a )pyrene, has been shown to be carcinogenic by several sels of investigators Now the preseat ,uthor re- ports that a-napthoAavone activates the aryl IIMS ol both the microrowral membrane-bound and soluble enzymes of ra/ liver and rat lung. The enzyme catalyzes the hydrosymethytation of benru(s)pyrene to the 6 hydroaymcthyl derivative. , Sloane, N. H. Cancer RereorcA )S:)7)1-)7)1. 1975. Other srpportr American Cancer Society. From the Department of Biochcmisuy. Univcusuty ol ienr.esuc Cenkr (or Heahh Sciences, Memphis. .21 20 I

Only very recently it was discovered that normal human embryonic lung fibrohlast celis (and those of many other mammah) regularly produce high levels of plasminogen aclivator. This is a protein that converts plasminogen, an inactive substance present in the serum, Into plasmin, an enzyme that destroys fibrin. The aerum from infants with hydine membrane disease is deficient in plasminogen though it is not cksr whether this is due to the continued produc- lion of the activator or to eacessive inhibition of the plasmin produced from it. In a Council-supported project, piasminogen activator is being prepared in quantity from cell cuitures; it will be concsntrated, purificd, characterized and used so produce labeled antibodies for studying its presence and conccntration at specific sites, and its roie in normal eells as well as in disease states. Relevance of this work estends beyond the problem of the respiratory dis- tress syndrome. It ha. reteswly bee. discovered that normal cetls, other than the esceptional ones of embryonic ha.jL though they quite generally produce very little plasrnirwlles aclivator, will aearly always increase this production at least 3Pfold when transformed into the malignaM staN. Indeed, this property may be a useful indicator of malignant cell lransforwution. Such transformed cells show a number of chanees in behavior. Tlrey will grow oa soft apr (unlike mosl normal alh), they show incre.sed mipation. they are agglutinated more readdy, they display an altered morphoiopr, sd they produce tumors if trans- planted into mice with low or irnpaired 'weamtee nspomiveness. While normal embryonic bng cells show a similar ability to grow on soft a=ar, they do eot show the altered morphology or produa tumors when so implanted. Ingenious systenr have been designed and applied for studying the bio- chemical c.orditiom within the cell that govern the production of plasminogen activator and iu accumulation or drsposal is normal lung cells as compared to cancer eelb. Protesea end Protea.e /nhi6itors in Reletion to En.phy.em• TAere are subuantial iodications that human pulmonary emphysema may result (rom "di{estion' of the lunlfs elastic structural material by enzymes /fxrxe..n) that attack the proteim of which it ia composed. One indication is that papaisi, a plant protease miature that does not occur naturally in animda, wip nevertheless produce destructive lesions similar to emphysema when in- stilled directly into the luop of animals of several species. Another, reported only a few years allo, is that persons having an ab- normally low blood level of a protease inhibilor, originally designated as alpha,- antitrypsie•, ue particularly likely to develop emphysema at an early age. This observation reinforced the idea that the disease might be caused by p.oleases from some sourse, either internal or eaternal, if or when their action is not properly controlled or "wrned otT" by an antiprotease. A third, still more recent indicatioa is that certain human or dog blood kukocy/es, particularly polymorphonuckar kukocytes and macrophaloes from the peritoneum or lungs, when isolated, eoncentrated, broken down, susperded in a medium, and imtilkd inlo d" lunp, produce emphysema. The eatent of the lesions produced is dependenl upon the prolease activity of du preparalions, •SGnic i tug onh.h.oow is n..4 .trcAk fow to ypwln but bon,ls n numhcr of p.otta.r., alpba.- •MOIN.+t.s n a Mw. wu.-t I I I I and those from polymorphonuckar kukocytes are more active than those from macrophages. Both types of cells concentrate in the lung in defense against in- hakd particulate matter, including infectious organisms. 1 hey contain powerful proteolytic enzymes packaged in small vesicks inside the cell walls and had not been considered likely to harm the lung structure under normal conditions. Thc new e.perimenls, therefore, raised the questions whether enzyme leakage from the kukocyte cells or disintegration of these cells within the lung might bring the prodeases into direct contact with the lung tissues and thus contribute to pathogenesis of emphysema under real life conditions, if not properly countered by protease inhibiton available in adequate concentrations in the critical areas. An overproduction of leukocyte proteases or an abnormal access to critical zones might contribute so the process. A Delie.te Bel.nee A delic.ne balance between proteofytic and antiproteolylic activitia i. Ihe lung is necessary (or defense against infections, but damage to the lungs t6em- aelves might occur if the balance is disturbed either by overproduction or eaa+- sive release of prole..es, or by underproduction or inadequate access of in- hibilon. Ealensive studies by many investidators, including several sponsored by The Council, have shown that alpha; antitrypsin deficiency follows deNnite hereditary patterns in human families. T1rcse studies support the concept of an inherited susceptibility lo emphysema and provide one erplanation of the em- pirical observation that the disease tends to "run in families." The picture is complicated, however, by the e.istence of several variant forms of this a.ti- protease, which differ is their efficiencies of antiprotease activity. At least twenty different phenotypes have been described that represent the various possible combinations of the genes controlang Me alpha; antiproteaae types and produc- tion. Moreover, there appear to be familial aggregations showing high em- physema predisposition that is unrelated to this antiprotease, suggesting that other factors awt yet described may be invdved. lhere is no reason to suppose, for eaample, that aruiproteases other than the serum alpha -antiprotease aad its variants may not eaist in other organs and play a role in t6 total picture. Ad- ditionally, the role of lung surfactant .nd its effect, it any, upon proleaas and antiproteases is snot fully understood. ' Several grants by The Council have fostered studies of protessea aurd anti• proteases in relation to emphysema. Much effort has been devoted to puriAca- tion of serum alpha, -anliprolease and its variants so that their Nructurd aaid molecular weighls could be delennined, the sequential arrangement of the com- atiwent amino acids worked out and the biochemical nw.des of action ir the inhibition of protease activity described. R.diolabeled antibodies have bees used to show where these inhibitors bind to tissues. In these swdies, wmp.ri- sons with other protcase inhibuors from different sources are helping to define and describe their likenesses and differences and especially their specific actiw.s The isolation and description of proleases elaborated from lung macto- phages and granulocytes have also been undertaken to find out which onee ara musl active in attacking lung structural proteins and how they react with is• hibrtors Ihis has entailed eaplwation of mdhoda fur collectrng, scp.rating and culturing Ihese several lypesof cells. II

I Detecting the Em phy.ema-Prone Individual Avowed aims of these investigators are to develop hetter methods for de- tecting high emphysema prcdisposuron in individuals, materials for early du`no- sis of the disease and, it is hoped, agents that might bolster defensive mechan- isms in the body and arrest progression of the disease. A related but compatible aim is to determine whether, how, to what es- tent, under what circumstances, and in whom tobacco smoke eapusure could contribute to the etiology or patholie.esi% with a view to countering any such effect that may be determined. Tlris aim obviously reQuires studies to ehscidate tlse uages.nd mcchanams of pathoK.esis. In this contest a study was supported by The Council to measure levels of hurg kukocyle proleases in groups of persons characterized respectively by normal, intermediate and low levels of alph.,-antilrypain. The purpose was to delerwrine whether there were differences irt protease kvels between persons with and without certain pulmonary functional abnormalities (considered in- dicative of emphysema) within each of the groups or betweew those within these groups who uooked and those who did ssw. The proteases asuyed were granulocylt elastase, granutocyte calhepsim and arooocyte eathepsin, all of which are capable of damaging lung structure and aN of which ate known to be in- hibited by alpha,-anlprotease. No signiAca.t differences in the kukocyte pro- tease levels were found between perwns wilh or without the lung functional ab- aorrsulities or between those who senoied or did not smoke. Thus, no esplana- tion of the reported associations between nssoking and such functional ab- normalitrn emertled from this study. Modieed eaperirnental desipu may be de- veloped for espbring this question further. Another research team, supported by TLe Council, has been concentrating aqention especially upon the proteaaes Ih.t can be eatracted fronm the poly- rnwphonuckar kukocytes and pulmonary macrophages. Theae esuacts produce emphysema-like lesions when instilled into as isolated dog lung maintained /n vbro. Results obtained by Ihis method were shown to be comparable to those fowsd iw living dogs wben similarly treated. Tho introduction of proteases through the air pasuges (s the living dog was tnors effective in producing ao- physema than isjection via the bbod vessels. A new sntrproteiwass has been racovered In washinp from dog lunp. It differs from the alpha,-antiproleinase iN the blood and from other known pro- teasn inhibitors. and may function as a regulator of lung proteolysis. In the model system, this antiproteinase prevented thr: production of emphysematous kaioas by ela.taar: (aa effective digestant of Ihe structural lung substanu, elastirt). it rnised with an tlatase before instillation of the latter into the lung. Similar aMiproteasea have been recovered is washusp from monkey and human lungs a.d are being studied similarly. antiproteases and by synthetic ones, and their abilities to break down trachoo- bronchial cartilage. Two others are more clinically oriented. In widely separated roliraphical areas, large, unselected populations of newborn intants of various ethnic origins will be phenotyped with respect to the alpha,-antiprotease mentioned above.l he plan is to conduct mulufactorial studies of these children nd their relatives prospectively over a period of years in the hope of elucidating the interaction of genetic and environmental factors. I (:onclu.ion Fresh clues and concepts have stimulated a strong wave of new interest and activity in this bng obscure and bdlling field of chronic lung drseases and pro- ductrve research appears to be reaching an unprecedented level. As The Council participates in dws propess, we will be approaching the objective set forth is our 1973 Annual Report: to contribute toward meeting the chalknge posed by the need to establish the etiology and pathogerrcsis of the chrooic obdructive and other pulmonary diseases. I I New Studies o/ Protewa.a .nd Proteaw /nhibitor. ibree ncw swd'ws in this area have been Inaugurated. One of ttse,e, at the biochemical kvel, r.volves study of two Vrote..es iwlated from human kuko- cytes. an elwaas aad a cAysorrypre hke protease, to characterum their spe- cdfc .crrvqres, tAcw rwhdaaa+ or lnaetivalan by the various nalursfly oceurrisg Ro.e.r C. lloc[aTr, hs.U. Research Diroesor 12 ' 13

lesions most frequently encountered in this system, developed by replication and metastasis of MSC cells, respectively. Virus recruitment of new tumor cells appears to have only a minor role in the spread of sarcomas in neonatal mice. Russell, S. W., Francke, U., [luenner, L. and Cochranc, C. G. lorrwd o/ the Nurionaf Cr.ccr lnnlhwtt 3)()):f101-d06, 1974. Other arrrorf: National Institute of ANerp and Infectious Disea!es, Natior- ai Institute of Child Iledth and Hw..n Development. National Foundation - March of Dimes, and American Heart Asaociation. From the Dep.rtment of Eaperimen/al Path~. Scripps Clink ard Research Foundation, aed the Department of Pediatrica. University of Cslifcrnia at Saa L)rego School of Medicine. La ldla. 711E ONCORNAVIRl1S GLYCOPROTEIN gp69/71: A CONSTITUENT OF 7HE SURFACE OF NORMAL AND MAUGNANT TIIYA(OCYTES The gp69/71 Slycoprotein, which has group, type and inkrrpeeies anli- kenic determinanta, is one of the importaM asMigeas involved in tir: sicutralira- tion of virus by antibody. In this report, the authon extended th:ir previous audies of oacornavirus-reialed proteins ard showed that gp69/71 ii present on the surface of virus-induced IympMma eeds, as well as on virus puticks, and the surface of normal thymus cells of noene mice. In gp69/71- rnice, conver- siors 1o the gp69/71' phenotype accompanied kukemogenesis. An interesting difference in apparent molecular size of vinu-related antigens of the 70,000 dalton site class was detected in lymphoma cells present in involved apkens as compared to those found in involved thymuses. Also, it was shown that mice infected as neonates with Scripps leukemia virus make antibody to Sp69/71 and some make antibodies to mokcules aasociated with the surface of their own tumors. Results of this study show that antibody to gp69/71 can react with the surface of three independent structurea with replicative potential (virus, eoreral thymocytee and tumor ce1M). Such uMibody may have diAercnt coa- seque.cee for oocornesw, depending on aho locdialioo of the antillen. Del Villaeo, /. C., Nave. 11., Crokee, 1111. P.. Lsrner, R. A. and Diaon. F. 1. TAe lorrssd o/ Erperbwenu./ k/elkine 141(1) :172-1 87, 1975. Other.r'rortr National Foundatioe - March of Dimea. U. S. Public Healtb Service a.d Ilse National Cancer IrtitulY. Prom the DepartmeM of /mmuoopatholopr. Scripps Clinic aad Research Fou.- dalio., La )dla. Cal. ('P-I.L-MEDIA7F.D IMMUNITY AFTER INTRATRACNEAL. EXPOSURE TO I-MEil1YLCHOLANTNRENE, AND CTS RELAl1ONS11IP TO TUMOR TRANSPI.ANf GROWTH IN C)11// MAI MIC@ ImmunoM(ic deficiencies are often noted In association with eanur, but the esact nature of this relationship has not beea fully cbaracterired. lbe eela- 16 i live immunocompetence of an individual, however, definitcly plays a mapr role in the ultimate susceptibility or resiuance lo cancer. Numerous studies support the concept that it is the cell-mediated immunity (CMI) which is largely re- sponsible for Ihe body's defense against cancer. Ilere, ('l11/1 Mai miu wen inslilkd inlralracheally with MCA (four 500 rg doses of l-me/hyklsolanlhrene in corn oJ, at weekly intervals) u part of aa investigation aiming to deteraune the levels of chemicals at which tumorigenesis occurs in various saraies and whether the animals' immunocornpeleace is affected. Effects on CMI wen r- sessed three days after each treatment by measuring DNA synthesis raks with sH-thymidine in allogerseie and splecn lymphocyte euNures. Spleen. Ihymus aod hmit were weighed arw) peripheral hlood kukocytea counted. Syngeneic and allogeneic tumor cells were inoculated into control and test mice to determine whether CMI data are biologically relevant so tumor gtowth. Tlre CMI and tissue responses were aeain evaluated 7, 14 and 2!i days later. Preliminary data based on spleen lymphocyte responses to phytohemagglutinin, pokeweed mito gen and albgeneie anli,len indicate that MCA suppresses CMI. -Lhis effect was naw pronounced in response to pokeweed miloden, however, indicating that the e-lymplsocyla were most affected. Although only syndeneic transplants were successful, lymphocyle cultures from all lumor-inoculated mice demon- Mrated enhancement oC T-cell activity and thus CMI, regardkss of MCA es- po.ure. It will be of iscerest to follow the kinelics of this effect in the bost ud compare N to the rale of tumor transplanl growth. Tlsis study suggests ahal pul- tswaary exposure to pdycyclic hydrocarbons in mice provides a useful wtodd for characterizing the undalyinR mechanism of respiratory carcinogeeetis and hoel immunocompeleace. Demoise, C. F., Kouri, R. E. and Whitmire, C. E. (Microbloloil,k.f Aaaoclwa) In: Karbe. E. and Park, 1. F. (eds. ): E+rrri+nrntal lynt C.ncer. CercMo- ptnesL awd sioars.yr, New York: SprinlIer-Veri•g, 1974, pp. 72-d0. From the Departmen/ of Experimental Oncology. Viral-Chcmicd Carcieo- getsesis Section, Microbiological Associales, lac., Belhesda, Md. ARYI. IiYDROCARBON HYDROXYLASE INDUCTION IN HUMAN L.YMPIIOCYTE CULTURES BY 2,1,7,t-TETRACHLOROD19ENl(lr DIOXIN Recent studies have shown that 2,),7,11-lelrachlorodibenro-rdbai. (TCDD), a toxic contaminant formed during commercial aynlhesis of tAe herbicide 2,4,5-trklslotophenosyacelie acid, is aboul 10,000 1imes sran po1eN than 7-methykholanthrene (MC) as an inducer of aryl hydrocarbon hydrosyl- ase (Alll/) activity in the ra1 liver. Furlhermon, In contrast so MC or a naphlho/lavone, it fully inducqs the hydrosylase aclivity in the livsr, kidney, bowel, luns and skin of so-called "nonresponsive" mice. l he biological hal/ life of TCDD in the ral is about 17 days, with Ihe induced hydrosylase aclivily aod associated cylochrome P,4S0 remaining elevated for more Ihan )S days. lbus. TCDD may become a serious environmental conlamsnant for m.e. Evidence for the appearance of this losk agent in the food chain has already been n- porled. lhis report indreales that individuals having genetically Mwer ba.al and MC-inducible hydroaylase actwitres also have lower ICDIDrnducibk hydiosyl 17 0

( SIMON H. WENDER. PH D.. Re>rrch lru/n.or of Atochemiitry. UniversiNy of Oqlsbaawa, Norrear< DUANE O. WENIEL, PH D.. rro/ruor .wd Ch.um.w of rhrmescolop M/ Ta.icofotl, Tbe University of Kasis.. School of Pfermacy, L.rrence. FREDERICK F. WHISKIN, M D_ Di- rrdo,. Dtririow of Health .wI hrso.- .Gty Eqrdterirm. The Age Ce.w af Nc. England. /wc, 11oe1o.. ROOER 1. WILLIAMS. M D. rroless.r of Chtmur.yDtrfctOr. Clqtoww ow- /aiow /tochemir.l luu&wr. T1e UWsi- vcrsitf of Tessk Austin. i DANIEL H. WISEMAN. M D., AuiN- .wt l.o/eiwr of reli.nk.. Uwivetsity o( Souwiserw C.li(orsia; ChNbew i D!- ririow. Los Angeles Counly Oenerd HosplaL Los Angeles. 1. EDWIN WOOD. M D., lnnructo. Iw Mrlic4.r. lostoa Uaiversir~,5cbol of Medicine. Soaon. SUMNER WOOD. la. M D_ Aulu.nt ho/es.or of ruAofoir. TM IoMs Hootwu Urversiry School of Medi- ei.e, BaMir.ore. JOHN P. WYATT, M.D_ rro%aor of I«holoSr. Louis Uwivcrwr Sclool ot Medai:r. St. Lor.ie. INDEX OF PRINCIPAL INVESTIGATORS ~ Avisdo. D. 1N., 33 eeQ, s. and Roac, C. L. 62.63 Benedict. W. P., 14 Bial, R. 1., 35, 36. 37. 3/ Homburger. F., 15 Lauweryn., ). M., 27. 21, 29 Lerner. R. A.. 16.61 Looeli, C. O., 30, 32 Camero0. S. P.. 4?. 46 Caslro, A.. $3, 56 Chabn,1., 24 Cocbraoe,C. U.,11, 40.41.42.57.38o39 Lynch. H. T.. 63 Meier, H., 19, 22 NeuraW, Q. B.. 20 Rasmureo. R. E.. 20 Co6c., A. B., 24, 23 Rose. C. L. 63 Cross, C. e., 30 Dowsey, H. F., 39 Friedrnaq O. D., 64, 63 FudesberL ll. H., 39.60 Pun1, A.. 23, 24 Rubie, R. P., 48,49 Ryan. U. S.. 50 Sloane. N. i1., 21 Siatl., T. A.. 50. S/, 32 Travis.l., 33. 34 Ooldstci., L. 41 Ouaraerl,l. 1., 31 HarooaA, P., 26, 42, 43 Veseq, F. S., 57 Vidif, S., 61 Wentel, D. O., 43, 44. 53. 54 Helawra, N. W., 47 WAitraire, C. 1-, 22 82 /3

i n.turally occurring proicinase inhibiton, and specifkity for synthetic substrates. 7 he nm.epr difference between the two proteaxs, other Ihan the lack of elaslo- lytic acuvrly by human protease E. seems to be in their ionic characters. Por- cone clastase is a cationic enzyme while human proteaae E appears to be anionic in nature. The drsvmdarities concerning elaslolytic activity and ionic character appear to be directly telated. These studies also show that althouth human protease E lacks the ability to digest the structural protein clastis, its biological sitnifkance as a digestive enzyme is scarcely allcred. Mallory. P. A. and Travlr~, l. SiorAemirtry 11(1):722-770, 1975. Other arrporfr National Inultuleaof Health. From the Department of Biochewristrp. U•iversity of Georgia. Athens. INHIBITION SPECTRA OF THC HUMAN PANCREATIC ENDOPEPTIDASES The purpose of this study was to establish accurate and concise data con- cerning the effect of seve• naturally occurri•g protcinase inhibitors on the human pancreatic cedopcp,dases, catiosic trypain, anionic trypsin, chyrndryp- sin 1, chymotryp.in 11, and protease E(an elast•se-like protease). lhe inhibi- Ion listcd in order of their decreasing effectiveness were a-l-proteinase inhibi- tor (•-1-antitryp.in). Iwna bean tryp.i• inhrbitor, soybean trypain inhibitor. Bowman-Birk (soybean) inhibitor, Kunits pancreatic trypain inhibitor, porcio• Kazal inhibitor, and chicken ovomucoid. The relative orders of resistance to these inhibitors indicate that human protease E dernonstrues the least swcepli- bility while anionic trypsin is most susceptible. The complete order fot the human pancreatic proteases with respect 1o reaistaoce to .aturally occur- rin6 wthiWors is human proteasc E> chyrnwrypais 11 >chynatrypsin 1 >cationic trypsin >atwonic trypsin. TD• contribution of each of these pro- lcolytic enzymes to the total proteolYtic activity of crude pancreatic eatracts was also investigated using specific active-site direcled rea6ents. The general arend borne out in these data shows that the human pancreatic proteases lend to be kss sensitive to naturally occurring i•hibiton than their homologous enzyme couMtrparts of the lower specin Thua, according to the atthors, any human nuttNional significance previously atlached to these inhibdors must be reevaluated with respect to their specific Inhibition of human pancreatic pro- teasea. Maliory, P. A. and Tr.vis, l. The Am.ric.n /ournel o/ CNnka/ Nrrririon 28a2l-s )0, 1975. Other support: National InNitutes of Health. From the laeparuncnl of Biochemistry. University of Ueorgi., Atb!os I INTRATRACHEAL INSTILLATION OF ASBESTOS IN MICE Here the authors report on a simpk technique developed for iaMilli•g aa, beatos frhers directly into mouse lunp. Using inlratracheal inqillatioo, the ie- vestiprura placed measured amounts of asbeslos dust into the lunp of 2- momh old NIHSwisa and C37e1/6 mice. The asbestos 6bers could be detected by negative phase contrast microscopy raaminalion of the Nained alidea. This study showed that although the iatratr•cheal method is not identicai to iah.la- tion, it is an effective method for placing • quaatitaliv amount of aabestos dust directly into mouse hmp. 1/ does appear that the asbestos fibers remain in the lunp aod act as a pulmonary irrilanl. The health of the tested animals deteriorated as a result of the treatment with asbesto.. Eaperimenta are •ow underway in the investigators' laboratories to determine the clearance rate of the asbestos and th• long-term eQecta of the asbeatoa treatments. Wilooa, K., Marar.a., W. aod Funt, A. (Uwirerriry o/ Sae Fr.nclrco). Proceedings of rAe Western rAarw..cdoPy Soc4ry 17:217-2J0, 1971. From the Inatitute of Chemical Siolopr, University of San Fraociaco, Sa. Francisco. I I I. Ne.rl .wd CJreaT.tion CARDIOOENIC SIIOCIC - ITS MECHANISM AND TRL'AT1rtENT CardioBc.k shock ia a 1•ttn used to de.is.ate the ocarr»ao, of th• si•ck syodromo by reuon of pimary cardiac dyafu•ctio.. Here, r in b.wot.b6ic abock, tbere ia a dimi•uliot in ooroaary /bw •sd a reductioe 1n myocardW o:y6ee usa6e, as well as myocardial ischemia and aaoaia, which renrt 1n tha central and peripheral changes which are defined aa `dwck.' T1a Litid bio- chemical changes ia Ma heart muscle is eardiogenie shock are a projecl{os of thosa encouetered I• myocardial infaretioa Various studies show that bio~ ehereical changes in eardlogenic .hock and myocardial idaretioa aQec1 certain enzyme srstema as well as mitocbondri•1 functioa and eadtatioa~oar.ctba coupling of the myocardium. Thia was dernonNrated by a diminution In mito- chondrial respiratory function aaid by a decreaso in cakium uptake aod binding in freshly infarHed areas. lhe hemodyo.mic chan=ea in cardioscoic d.ock lie primarily In diminished compliance and reduced e/'eclion fraction. Cardiac out- put and coronary ilow are reduced. TredmeN of cardioloenic slw.ck has ber• disappointing when purely medical mcana ue empbyed. None of the alpha- or beta-adreoeryic drugs has beea able to appreciably decrease the hrgla mor- 35 ~ 34

THE ROLE OF THE HOST IN THE DEVELOPMENT OF IN YIVO MODL'IS FOR CARCINOGENESIS SIUDII:S This paper reviews the factors which the invesliptors feel play a role in the selection of the best possible animal model systems for respratory carcino- genesis. Their discussion of the inbred mouse system used in their studies, in spite of various anatomic disadvantages, presents several aspects of isost control over susceptibility. The topics dealt with are: (1) susclptibility to chemical carcinogens; (2) chemical carcinogen reetabolism; (3) viral etiology of cancer; (4) tumor immunology; (S) other 9esetk controls of neoplastic developmenl; aod (6) cells at risk to earcinogerw and DNA repair. The development of cancer depcnds upon the integrated response of the host to the carcinogen and to the initial transformation event. Genetic factors determine the host's po- tential to respond to chemical and vitd earcinogens, whde endogenous and esogenous environmental factors influence the realization of the genetic poten- tial. In chemical carcinogenesis, for etampk, it has been shown that aryl hydrocarboo hydrosylase (AlIH) i.dueibilny is under genetic control, but tumors will occur, a1beM to a kesser degree and after a longer delay, when large do.es of polycyclic aromatic hydrocarbons (pA11) are admmistered to nonisducibie mice. Induction of AHH by noncarcitotenic materials may also influenee the effects of PAH carciroitens. In viral earcirwtienesis, evidence porsu to genetic transmiasaw o/ the RNA oneo6enie vintscs with eapression of the viral itenorne under host control. Once the initial cells have been trans- formed by chemical or vird inductioo, the devefopment of cancer is dependent on the host response. This is under nusnerow influences with immunosurveil- lance probably the flnt line of defeare against these transrormed cells. Genetic control of immunocompetence is evidenced by the variety of responses to va- rious antigeoic stimuli in genotyprcally different strains of mice. Immunosup• preasive effects of carcrno4en., drup, infections, and other factors appear to make possible the initial act of establishing clones of transformed cells by overriding the immunocompetence of the hosl. Other variables related to die1, aging, suesa, and more, affect the host control over the carcinogenic event and may be related to the increasing susceptibility to carcinogens and/or the in- crease in "spo.unewus tunars" incidence. The authon hope their studies will establish the integrated bost raipooea to the events occurring in respiratory carcieo6enaia. Whiunire, C. E., Densoise, C. F. and Kouri, R. E. (MkroMoloskd Aisociater) In: Karbe. E. and Park. 1. F. (eds.): Eiperirnrraral Lrnr Cancer. C.rcino- rewesL and Iio+r..ys, New York: Sprieprt-Verfa6, 1974, pp. 2047. Otiirer .urprt: National Cancer Institute. From the Deparuneot of Eaperineotal Oncolory, ViralChemie:al Carcino- geaaia Section. Mrcrobiolo6ieal Asaociates, l.e., Bethesda, Md. TRANSPI.ACPNTAL INDUCTION OF PRIMARY RENAL IUMORS IN RABBIIS IREATED WITH 1-ETHYL-NITRUSOUREA Newbo.n and young (C311aA)F, mice treated with 1-eth)l nitrosourea (1:Nt1) dcvelop pnmary tumon of the kidney as wcll as othcr organs Re• portcd here a the laeyue.l aad almost exclusive induction of rend tubular cystadcnomaa a cysudc.ucarcrorau ts two slraw of rabbits by ttansplaccotd I administration of ENU; this agent also cau.es tumors similar to the Wi4e.• type. Pregnanl rabbits of the two partially inbred strains 111 and WII were given a single inlraperitoneal dose of ENU (60 mg/kg) in trioctanoin on day le of gestation. Controls received solvent alone on the same day. Of the (S strain 111 progeny that survived more than eight weeks, 14 developed primary renal tumon at a mean age of 3.3 months. Five other strain III propeey diod trom other cnna at an early age. In eontra.t, only three of the seven uraia WII offspring wrvivinp more tlun eight weeks developed renal tumors after about the same latency period (3.9 rnooths). In each strain, either read tubu- lar cystadcnomas or mixed nephroblastornas appeared to develop within small renal cortical cysts, which in strain 111 may be explained by the high Irequeocy of a recessive gene (rc) for renal cysts. Is strain WH, however, they were induud by ENU. This differential strain incidence suggests that the pre.eeu of the rc/rc genotype for cyst formatioa increases susceptibility to reaal tumor ioductioas by ENU. Foa, R. R., Diwas, B. A. and Meirr. H. lowwd o/ the N.rbw.f C.ncer lnrdtute 34(6) • 1439-14/!I, 1975. OtA.r asr'rortr Natioad Canxr Institute and Hycel Inc. From The )ackao. Laboratory. Bar Hatbor, Me. PULMONARY CARCINOGENESIS BY TWO ARYL NYDROCARBOW ON THREE MOUSE STRAINS 'Mat the susceptibility to polycydie hydrocarbon carcirsoileoa.ia is rddd to ioducibke aryl hydroearbon hydroayksse (AHH) is the current oo.eept luted here on three different mouse strains. Beaw(a)pytcne (B.P) and )•wtetiyt- cholaruhrene (3-MC) suspended ie a 6e1Nia aolutioa were inatilked katr.uacrr ally into the luop of these a.irnaM. The CS7B1/61, the raadorn-kwd NIH- Swi.s/Mai, and the DBA/21 strains were selected for their respecdvety Nik, vuiabk, and low AH1t ioducibility. Tbe 3-MC was more carcisopic and loaic thaa B.P to 1he NIH-Sww/Mai a.d C3711A/61, but had keaa toak d.et on the DBA/21 mioe. The NIH-S.rir/Mai bad the highest total kaa6 tw.a i.cideoce and 1he C37M/61 1he lowest. 7La eAeclive cumulative card.o6eak do.e of 3-MC appeared lo be 2 ny. Regardless of their hepatic AHH acti.ities. ar mioa were equally tesisust to pulnw.ary aquarrsotu cell carcieoaa i.dirc- tion by both chemicals. In the (hree atrai..` the 3-MC induced only a undl perotrtta6e of Mia snali6aancy in the young addts. It did, however, produw a higher iecidenoe in 1he mature CS7B1/61 animals. The rates o/ cardaoseaa+is and lung clearance o/ carcinogens observed ie'this study suggest ebN in tb moaue, target tissue AIIII may be a more relubk indicator of .usoeptibilily to polycyc8e hydrocarbon eareiarolieneais tham hepatic AIIII, and tha rola of At/lt in tumor /ormation may be secondary to genetic, physiologic or vMsl f actas. Ho, W., Wikoa, K. and Funl, A. ([/nl.vralry o/ San Fr.wrlrco) le: Karbe. E. and Park, 1. P. (eds.): Flrrrtwrenref lant C.ncrr. C.rr/wo- g.nrs/t.nd Alo.rsqs. New York: Speiniter-Vertag, 1974, pp. 62-71. From the In.titute of ('bemical Biology, Univcnity of San Pranckhoo, Su Fraecisco. 23 22

graphic characleristics of the bronchial and pulmonary vessels are recollected briefly. The discussion devoted to the lymphaties focuses on their most distal inlrapulmooary endinp, aaenely, the jusu•alveolar lymphalics. According to electron microscopy studies. Ihe ullrestruclure of the pulmonary lymphatic capillaries is compatible with great permeability and active transport. Most iolrapulmooary lymphatic valves appear to be mooocuspid rather than bicuspid as wmrnooly suggested. (,wwer7wt.1. u. Acre C"oloske Suppl. 19:137-167, 1971. Otlbr aup/.ertr Natiowaal Poeds.oor Welewchsppelijk Ondcrzwk (Belgium). From the Laboratory of Pathoioq at.d Histolop. Katholieke aloiven8eit a Leuven School of Medicise. Lewves. Wgiuat. NEUROEPITNELLAL BODIES IN THB HUMAN CHILD AND ADULT LUNO This study attempes to establish whether the neuroepithelial bodies (NEB'a) previously demoestrated ia the htnp of varioua mammals including adult rabbits and human infanty, penid Into adulthood in man. Lung tissue was ob- uined from five children and 12 adults during thoracotomy and immediately Aaed in Bouin's Aud. Alternate aerul aectans were stained wi,h hematosylie sod eosi4 with Van Campeohout's modified Bodian silver proaeinate method, or Orimeliui silver nitrate technique. Mocro.copy reveakd typical NFB's in the broachid, bronchiolar, and even the alveolar epithelium of these human lunp. As in the other specie.. 1he.e corpwcular bodies consisted of ovoid to triangu- lar groups of celb, 20 1o 40 fwide st,d 15 p hi6h, intercalaud within the respiratory mucoss. The cells thettuelves were nonciliated, and rather large (6 p X IS p) with a ckar, slightly eosinopbilic and distinctly argyrophylic cylo- plwe, a.d eatended from the basemeM membr.ee to the airway lutnee. They were usually close Io at kast one cspillary in the underlying lamios propris• Although the function of theae corpuscles remains unsettled the suthon eut- 6est that the NEB's may constitute u iNrapulrrwnary. hyposia-scnaitive ocuro- (chemo)reuptor system modulated by the central nervous system that might influence the pulmonary vasocon.trktor response under both oormal and psthob6ic cucunuta.cee. L.rweryiv, l. A!. aad doddeeris, P. Anw.kew Review o/ Rerplretory Disease 11(4):169476, 1975. Other erprortr Natioeaal Fonda voor Oes+oakuodi6 Weleaachappclijk Ondcr- xock, Belpum. Prom the I shoratory of Hiatopatbobgy. Katbolicke Uoivenileit te L.euvea, Iruvee. Belgium I NEUROEPITHELIAL BODIES IN MAMMALIAN RESPIRATORY MU('OSA: LIGHT OPTICAL, HISLOCHEMI('AL AND ULTRASTRUCTURAL STUDIES Having previously reported on the occurrence of ocuroepithelial bodka (NEB's) in human infants, the authors now describe analogous structures throughout the respiratory mucosa of various mammals (rabbit, cµ lion, monkey, rock-badjer, pig, hedse-hog)• Studies combininS light opics, micro- spectrography, cytochemislry. and eketroe microacopy show thr,l these newly identified corpuscles in the intrapulnanary lining of epithelium of letal, soo- natd and adult mammals are eompoacd of ararrophik, arsentallin, yellow Auo- resceet, ultras/nrclwrUy granulated, and innervated epithelial cellular orgar 11 is aujillerted that these NEB's probably have an ietrapulnwnary, recepor lunc- Iion which is modulated by the central nervous system and wbich apparsstly liberates various.ub.toaKes withiw the IunR, one being aerotoeio. L.rweryx., l. U. eN d. Chest 63(Apcil Suppl.):22S29S, 1974. OtA.r supports Naaoaaal Foeds voor Weteaycbappelijk Oedersoek (BsL Ou°t)- Frora the Laboratory of Pathology and Histobp. Katbolicke UdvenrMek u Len.ven School of Medicise, Leuveq Belgiur.. AOOREOATIONS OF DENSE ORANULPS IN MITOCIIONDRIA OF ACTIVE PULMONARY LYMPHATIC ENDOTHELIAL CELLS Since it i. weU kuows that eww active aitochoadria display aa olwed ene atructure, these i.veslisaors decided 1o ex anine pulmonary lymphatic eo- dothelial cells i. light of the possible associalioa of their ckara.oe sdidtia with changes in their wtitochondrial morphology. F.aperirnea.lly, a/o/a/ of 16 neonatal rabbits received itlr.trscheal iaMiMations of /errilin or earbon p.r- ticks: three corresponding animals were kept ae cootrda. At low mapiBcNios and after Trumps' /lsatioe and staitdng. lung tiswe aeclions showed electroe deruie. round so oval dots (diuneter N141100 A) in the mitochondtid teatris of the pulmonary endolAelial cells which had absorbed /erriti.. Though It waa diflkult to aacertain the eaact number of grsnulsr aggregations per maocbo.- drioa, it appeared largest is the lymphatic eedothelial cells which contai.ed the most ferritin. Similar aggreptions of detne Rraaulea were not found in wito- choodria of lymphatic endolhelial cells Irom control animals, nor wern they seen in the group of animals that had beee innillated with earboe prrtkke. Alihough Ihe precise .ature of the demonstrated granuks remains ueeaplainad, it is suggested that these aprejations are related to an increase of the endo- thelial cell metabolism which was stimulated by the er.docytoeia and d'yatiw of the ferritie particln. L.wwrrywr. /. 6I. aod Bsert, l. Erperlrnd. 71(7):6)9-612, 197J. From the Katholieke Universiteit te I euvee School of Medicioe, Leuvea, Bellium. 28 29

of research. Becau.e of concern with human wefl-being, studies are being done with human subjects when possible. P.pidemiological studies especially must relate to human populations. In other sludia, animal models musr be used to reveal information to augment our knowkdge of the etiology and pathotenesis of those aging-associated diseases of the pulmonary and cardiovaacr l.t systems. WLLLIAM U. CjAUtNEl, PH.D. Scientific D rector Studies Related to Respiratory Function and Chronic Pulmonary Diseases The Council's 1973 Report presented general concepts and plans wldcrfr a~k the research program in respir.tory function and disease. Along these lina, a dozen projeNs in a number of research inslitutes were maintained duri.t tb year just ended, with collateral support by ccatact studies for equipment dc rdopment .nd mcthodolopr. ...5~ ~ I I Anb..el Stadie. On.olving /w6.l.tbw Bspo.ure. In four uudip anirnah wete exposed chrvnically, by iahalation, b arnb widely present in hu.o.a environments. One inveeiplor, who had developed methods for a+easur(q prlrno.a.t functions in rnioe, .uboclcd anirn.ls of two aulies so cigarette snloke inWatioo daily for five lo ke weeks. Nigh- .nd bw-aiootine reference ciprell.s were used to eomp.re the eQects of di0etw nicotine levels in ueokes otherwis varry similar. Effects of whok, fresh snwke inhalation were similarly eanpued wMf, those of the p.•vapor ph.sn alone. Th. latter, being substantially fns hoao particulates, contains only trnces of nicotine. Measurernents of functional residual capacity of the hxys shvoed thr emphysema wan nut produoed. 7Ue Nrws diAered in sa.eeptibilNy b Mcrearw in pulmonary resistance lbroeebp.t.wl, whieh was elieited by wbfr snwte and 1o sane extent aho by the pll-v.por phase, but both str.bn d.reb4ed almost contpiete toN:rancrt within uw weeks. A deerew in puMnon.ry oontpli aaoe was reported to be aasoci./ed with Ave- to ka-week inhalation af staok- from the hi6h-nieotins reference eipretle, by1 this was not eliciled by tb ps vapor phase alone. FJlects of acetaldehrde, nerokin and staatole, whic, an low kvel, but in other eaMeats knoww lo be chemically activs, ooatpone.b of tb pwvapor phase, were measured in separate bu1 parallel eapetintents. Me.nwhik, becawe of suqestions is the literature that cumulative tracr of inhakd cadmium might be a factor in the etiology of entphysema, a stud) similar to that jusl described was begu. with cigarettes "prirnod' with Ih.e levels of added cadmium compounds. Because fly ash and nitrogen diotide are found in the atmospheres of wan; cities where chronic pulnaw.r~ .itments are prevaknt, .norher investigator eo posed ham.lera for ptolon~od periods to atmospheres containing thw oom pounds. 11e too had w impressive series of physiological and mwphob6ical ta methods applicable to the hamaer, an animal regarded from other studies a being relatively susceptible to h.n6 damage. The animals were exposed chrow cslly for about 14 mondu either to dust aloee, to dw1 wNh niuo4ea diaaid. o to amMent air. Srwne of the animals wen teeapoeed to ambient air .br fo twoweeks following the othereaposures. After aacrifke, measurements were made of atalic compliance of tha lunt 7 I

i other noninvasive method (systolic time intervals) were measured. Separation of the two groups was accomplished better by eN.CO Q•Doppkr peak than by systolic time intervals. It would aeem, there(ore, that ef:CO Q-Doppter peak is a useful inde: to evaluate the myocardial contractile state since thu iodea is readily obtained nooinv.aivcly. Lahikawa. K.. su fRs. H.. Sarma, R., 7illoaer. H.. Fauvel, l: M., Oetzeo. l. H.. loa.w., J. L sod OJng. R. !. l.pwe+e H.art lorrwd 16(1) •22-35, 1973. Oth.r..rr.rtr Wri6bt Fouodatiau an/ tb Hoover Foundation. From the Hu.ti.Itoo Menrorid Hoapitd, t•a..berra, Cal.. th. Urvcnitr of Snuthcrs Califoniia. Loa Ao6elea, aod Kltl! Uoiv.rsiry School of bledicioe. Os.tt, l.p... and tri•Ilycerides, snd plwpholipids was measured, no influence of CO os lipid synthesis in the arterial wall could be demonstrated. In contrut, arterieft corich were exposed to CO showed a higher uptake of cholesterol than their respondint controla. The concentration of CO in the per(usate did not alter the degree of cholesterol uptake. These results are in general agreement with those of others who found that CO .i6nidcantly increases the permeabifiry of endotbelial membranes. S.rma, l. S. M., Tillmanna, H., Ikeda, S. and eGrt, R. /. AtA<roackrouls 22:193-19i, 1975. Ot6.r srrp.rtr Norria Foundatioo. Frova Huntington Memwial Hospital and the California Institute of Teo1- ook+Ry, !`...dena, Cd., aod the Uoivenily of Soulbero Califoroia, los Aaplas. COINCIDENCE AND NONCOINCIDENCE COUNTINO (a'Rb asd'aK): A COMPARATIVE STUDY The vae of r+dioerrclidea for beart 1.u1i+6 4a bees iecreadnl over the last few yean. We moM frequently used iwtopes beinR sK and more recently a'Rb. 'i1Thr neport compares the accuracy of ims6iq asd resolution obtained with tDeae isotopes by coincidence and wacoi.cidcrx counting of phantom preparstioas and i.olated, infarct,ed dog bearta Special emphasis was placed o0 the deRrea of resolution. Ttse results clearly demonstrate the auperiority of coincidesoe counting with a resolution of 0 S cm. Noncoincidence counting failed to reveal even nzable defects in the radioactive source. Furthernwre, since "K decays only by nelatron ema.ion and thus cannot be used for co- incidence counueg. it appears that •'Rb - which also ha. a,horter hal( life. Is more easily produced, and 'a Ic.a eape.rive - is the more deaerabk isotope to uae for ibis procedure. Deds, S., Dukeo. ll., Tillmaoon, H. sod lf/wg, R. /. /orrwd oJ Nrck.r Afcdklnt 16(7):65/-661, 1975. OtA.r.r"+rtr Hovver Fouodatlon a.d tb Norria Fautdatio.. From tba Hwtiepo. Memorial Hoapitd, Pardeaa. Cal., and the Uoiveniry of Soutbeo Califoroia, Lo. AeRelea. T'HE EFFECT OP CARBON MONOXIDE ON IJPID METABOLISM OF HUMAN CORONARY ARTERIES Carboo naoooalda (CO) eapowut kw beao Yoplicated before io the In- crwe of lipid aocumulation in the arterirs of hum.os and Ai~m~aL_ oa this study deaiisl with cholesterol uptake aod lipid ayotheai. y arteria were perfused In vitro willt blood containing high or low coocentra- tioas of Ct). Upid .yntheas io tbe srteriat walb was investigated by iocorpora- 1K+n of ('•CIK'etaic. and cholesterol uptake was studied by using 1'11/cho- katerol as a uacer When the synthesis of eboleaterol. eboleaterol ester, d!- l/NIFORMITY OP TRANSMURAL PERFUSION IN ANESTHti*T1ZeD DOGS WITti MAXIMALLY DILATED CORONARY CIRCULATION In this traaamural pertusion study, wsonary, blood flow (COF) wr .eaa- ured ekctromqteetic.lly, ..d regional myocardial blood Aow ( MBP) wr cors- quted from ti..ue upakp of 7-10 /a radioactive .ricroaphcre.. Metabolic di4- tioi ol the oorooary elreulatroe wY induced by occluding thc coronary artery for 10 or 90 aecords, and pharm.colollic dilatioo was induced by kafu.M1 pspaverine into the arsery. In aeveo dop. diAerealy labeled mkroapheres were administered before coronary artery occhrcion, at the peak reactive hyperank response to a 10•aecond coronary arlery occhrion, and early io thm riai.R phase of the hyperemic reapore followinR a 90-aeoood coronary artery occlruipo. MBF was distributed uniformly across the left ventricular free wall before oa clusion and at a peak hyperemia alter Ihe 10-seoond ooclusioa, but early 1n the hyperemic responae b the 90-seeond occluaioo CBP preferentially perfused aubepicsrdial tiasue. In a.other group of seven dop, microspberea were ad- ministered be(oi•e coro.ary artery occhnion, al the peak hyperemic Oow after a 90-second occluslon, sod at the peak flow during local iotracoronary iofu.ioo of pap.verine. Tbe left veotricutar free wall was uniformly perfused under each condition. However, in 12 vetrted, RbriMating hearts with coronary dreulalioea dilated maximally by perfusion with venous blood containing either pep.vetloe or adenoaine, left veotriadar blood flow was preferentially directed to the wrb- endocardium. The wthon conclude thN the eoronary circulstioa of t,8 oor- mally functioning canine heart can dilate maximally without causing relative wbendocardisl iachemis because of a gradient of vaacularitr that favors tha wbendocudium ard coropenaatea (or systolic fbw limitatio. io that rrAba Downry, H. F. .t d. . CLerJ.tlon RriercA 37:111-117, 1973. O'A.r suF'ertr Cardiology Fuod and The Amerkao Heart Association Tam Aftuiate, Inc. From the Cardiopulmooary Institute at Methodi.t Ho.pital and the [kpot• rneas of Phy.wb6y and Internal Medicine, Univenity of Tea.s Healtt, Sde.w. Ceeter, Dailaa. 38 39

THE DFSTRUCTION OF TYPE 2 PNEUMOCYTES 8Y AIRBORNE INFLUENZA PR!-A VIRUS; ITS EFFECT ON SURFACTANT AND LECITHIN CONTENT OF TNE PNEUMONIC LESIONS OF MICE Siooe the broochid membranes as weq n the alveolar type 2 poeumo- cytn of mice are destroyed by dtborne inlluenra PRd-A virus, it seemed worlhwisik to study the effect of this destruction on the surlactaot and pho.- pbolipid (lecithin) content of noda[.e1ed and infected lobes in relation to the onset of in/eclion. Electron ank"aco" of tbe kings of miee which received sublethal doses of sirborsa PRt-A rirw revealed that the virus ptopapted io ciliated and nonciliated bronc6ia) oelr r well aa is types I an3 2 alveolar pncun.ocytes and destroyed them. T1s repserati.t broachid n.embrana were meuplastic and pew peripheraMr kab the wnoundiy alveolar ducts a.d alveoli to focw epitrelial nodules eawYy obaruclioa aad ool/ape of the ia- volved Iobes. The devr{oprncm of Iu.R lesions correlated neptively with pho.. pbolipo leveb sinoe dipalmiloyl kcitbia kvds decreased dgoificantty with in- crcased oo.solidatio.. The diAerencn behreen tba kscitbia content of sos- coruolidated and co.adidated tlous was greatest eight to 10 days or anom after the o..et of iafectioa Tbs 8ntrsrclioa of qp. 2 paesrmoc7tes by the is- Ifuen:a virus and their failure to repe.crate is 1lourbt to account for 1he low phorpbolipid kveY in the involved bbes, and is thua co.sidered sa important uuw of poMialh.cwl eollapse is nria. These obsenatioas support the view ahat type 2 poeunwcytea atr a nuor aouroa of wwAactast le maarmatias hwp. l.oadl, C. O. er al. CAest 67S (Feb. Suppl.):7S-14S. 1973. OtA.r..pp+rtr Esviroeme.Na! Protection Agency. Howard Hughes Empby- ee. Give Oac. Club and Ha.tiop Foundubo. Fund of the University of South- era Cdiforda. From th. Departments of Patbobp aed Medicine. University of Southern California School of MedirJn.. Lfla AnReles. BIOCHEMICAL AND MORPHOLOGICAL ALTERATIONS IN THE LUNG FOLIk)WINU OZONE EXPOSURE CoaccMratio.s of oely 0.4 pprr of oroaa (Oc) rnwY cause changes is hu+{ nirway reaiuanoa is buauaa, and only a few paAs per rnillioo may eaum aevere pulmonary edesna aed pathologic cbaep is rau, mioe. rdrbits. and ~uiera pigs. lhe precise mdecular rnechanisres of lung iojury are slill ua- knowa, ho.revcr. Y is the possible roM of preventive and/or therapeutic inter- venti4MU Naperimental esposure of rata and monkeys showa that Oc can alleet iwo duunct acpecie of pulmwnary tissue melsbolum: (1) shorl-lerm. high- k.el ecl+utc+ ..u.e .cuw JocruNStive changes such ae sulfhydryl (SiH) osi- J.u„a soJ .,1 rwt•na s.u.u~ca. and (21 whacute. low level ci- posures cause adaptive enhancement of reducing compounds and incrcase of enzyme activities. Acute eaposures (2-1 ppm for 2-d hrs) lower nonprolero wl(hydryl (NPSH) levels by as much s 30% a11er sie houn, an effect whKh leads to diminished levels of cellular reducing compounds or enzyme inAibilioa, but which may be transient and reversibk under appropriate conditrons. Lung mitochondrial and microsomal fractions showed significant concomitant SN loss and depression of marker en:ynw activity. Low-level eaposune of tbe animals (0.2-0 i ppm for 2-7 days) did not produce net Sit o.idation or di- sulfide formation, but imlead increased h.ng NPSH and (iSH kvcls by up to 50%. These compounds, involved in cell divisiom and repair, may also suppk- ment lung antiosidant defense mechaniun.. The activity of esurymca eooocsaed with NADPH production and disuldde reductiom also increaaed. u did abst of mitochondrial and microsomal marker enzymes. Correlated morphololie studies showed byperplasia of epitheliW and interstitial eelh, aa well r u 1.- creased number of macropbRes and kukocyw in the eewual retioas of tke pulnwoary acl.L Do Lucia. A. 1., Mustats. M. U., Croar, C. E., Pkapper, C. O., Dunlwortkv O. LL and Tykr, W. Ankrk.n Iwrtltaue of CMwrkd EnliteerY Syrnprlcun Strlu 71(117):91100, 1973. (Air: rart I, toll.tlow Control.nd Cltan Enrrll•) OtA.r .r'prir U. S. Public H.aw Ser,rb a.d tbe Califor.ia Air Re.oup. Deprutwteat. From the Udrenity o( Califorwia, Davi.. CLEARANCE OF INHALED BACTERIA FROM THE MURINE RESPIRATORY TRACT The muoociliary app.ratus and alteolar wucropbape eyNenm oonqrir tb major resident defense mechaeisme of the respiratory tracl alaiesc inhaled Is- asanate and 'wfectioua agenu. This study eaaadaes the response o( 1lan d. feoae mecbani.nn 1o inhaled Sty4ylococrcu arre.u wN6 the aid of IeJaiqrw permitting paired Nudies of tracheal a.d Iuas clearance of bacteria a.d .ath- ods for invealiluins ceMular defense in Ire rwpiraory Iracl. S. .rrnu wr rapidly cleared from the trachea of reion dler aeroaol irnpladation (lHl 1s 15 misutes, 3.% in 30 atinwes, 72% ie I bour, ts% (. 2 kwurs, a.d 95% in 4 hours). Lung ckaranee„ although equally e8ec/'we, was not as rapid ()11i In 13 minutea, 44% in )) rninutea, 33% i. I bow, 74% ia 2 boun, and N% in 4 bours). The wmben of alveolar rnacrvpbaRes har.eated fro.n 1h. aaurir lunp were meawred under bntl conditions and dter chalk.l, by aaperi_ rnental conditions. Eapowrs so aeroaolirtd phoaphaw-buAered awpenab.s of viable S. errrrt had a deAnile effect os macr,Aphale numbers. Inun.diately after eaposure (0 time), macrophape counts wrer. Increased 2.0 tisira basal levels. Macrophqe yields at 0 time were turther Increased 2.6, 2.4 a.d 2.3 times basal levels by the deposqion of 19,000, 131.000 aed 211.000 vi.bl. Naphylococci, reapeclively. ibia magnitude of Increase over basal yl.ids was taken as an indea of macrophaae mobiliralioo. These results denaasuata the individual participation and combined efficacy of t6s mucocdiary .nd aiwdar 30 I

PRINCIPAL INVYJi1GATOR OR INSitilII10N RRANISLAV VIDi~_ D.S.. rro/ta.ar of Awuo+wy. Oeoraeto.. U.iwrwy Scbools of Mcdou.e eed Deriarr. werw.a,oo. D.C. IRENE Y. WANG. Pw D. A..iawn Re- surcA CAewua. Cancer ke+earci IrBL Iwe awd Hooper F~rd.~w~ Uaver- ~nr of Celd«wie Sctqd o/ 14e_ idw- , Sr Fre.eiecs. (Now Aadwwr rnJer ior ol /a.wrrwology and MicroAieloq. Medic.l Ua.er.iwy of SowA Cara/f.k CMrkqo..) OEOROE WEINNAUM• Pw D_ lfwc4 rwnAr. rufw.ow..y Dw.r: Secriow. A!- bert Ei.Yer. Iiledicd CeMr, PWr~ dciphie. T1tOMAS C. WFSTPALL, rw D_ rn/i.r io. o/ rArw.rolory. Uwi.ettity d Vir- Rid. Sclool of Meiaiei.ti C1r1am. .rk. OP;OROH rVOI.F. l1St_ D. !•tac. r.oJer .or of rAp.blorird CAewdsny. Deprt• .+ewr of Nwritwn eed Food Scuece. M.necIsr-eu. IwrNwe of Tecl.oloaf. Caabnda.. Mau. PROJ[CT Tiill Tb eded of ciA.rette .awke oa luy .euboli.n deaelic AiQeranop i.1kr !w vitro srw.bo- (irw of cbneiu) careieoAeea bY Mum.s ar/ noaw Uwa L..y protel.aw: erripoaeiaa.e bel..oe .rA IAe efect of ciaarau ee.oke ow this 1.wr.aio. Adfon of doWi.e o0 peripker.l and oe.- uel .ewoer in e.i..le cAro.icallF e.- *oreA b Ytatir TM elea a[ vilri. A om elycoprolein eyrbreir i. ror.al ." Freca.ocrow re.arNory qitt.clwe• 72 I Connpleted Projects FoUowiag ia a Wt of the principal iavestisators, or inatitutiar, o( projeda that have been completed prior to the period covered io this Report. Several of the individuals named are deceased. The titks and 1AUia- tbot listed are thwe ia eAect at the time the work wr completed. CLARENCE 1`I. AORESS. M.D., A.ao- cwe Cliwicd rro/ecsor of M.Ik/we. Uavenity of Cd'dor.i. Medical Ce.- ur. Los Ayelee. ANTHONY A. ALRANPSP, Pr D. D/- recror o/ l.Da.rrAu. l•s bwke Re- AebiNlYiow Ce.w. Wt+iM Plai.m~ N.Y. ANIIIONY P. AMAROtSE. Pr.D. Iw- .nrno., D.prrmewr of ObrN.ici owI GyrwcoloR). Tie Albany Medied Cal- lep ol Uro. Un.a.ily. Mb..y, N.Y. 6. T. ANOEI.AKOS, M.D. Pr.D. ho- les.ar of rAsa/otoRF. RoMaa U.irereity Sclool of Medici.wk t1a1... . D. MURRAY ANOlViNQ MD.. Ud- ~ r o1 Wbco.ri. School .1 Mesi- STEHILMN M. AYRES. M.D. DAtirrer. Cer/ioPdw.owrr L.ilor.ro.t. S.i.l Vi.oer'e Ho.pitA Now Yerk. OSCAR I. t1ALCHUM. N/ D.. N.r/me rro/eawr of Me/kMr. Udvenit7 of Sew\er. Califorda Sc`ool e/ M.N- eLi.. Lo. A.{eka FREDI?RIK It. l1ANO. M.D. ea.or .wI CAdrw.e.. Dery.1nwuer ./ .rAa Scsoal of Hriier ..a Pt~We HaMR tldti.or+. A. CUFFORD RAROER, M.D., Roilerl Nrw.r rJ#i/er rro/es.r of rAyrbt- os1. Her.erd Meiical Sct+ool. !<o.10.. •RODA A. RARNPS. M D. PM D_ ho- jeuav (A/IIIMe) of rAlrblatl. CdO- redo Suu U.IvenMF. PeA CeYiwa PREDt'RICK W. BARNES. h. MD.. A+.oclere rroleau. of AIeIkMe. Tw lob.e Ilo.kiw. U.Lu.Mr Sclool of Mediciwe, mehie.or.. T. C. tlARNP R.sercA Sc4w- tler. Pbii.del~p ~i. p~ ~i. 1)3c. Siate Hoyit.l, PWIe- "phis' R. FREDERICK BECKER. h.D_ Auo- ci.re rroJe..or o/ A+.erowry and Direr ro.. L.1a..lary of rer4.erd Sciewce. D.ke Uwivereitl Medicd C4a1er. Drr- M.tiN.C. RALPH S. !1L'CKBR, PtD.. rr.}er d CAew.irry. Ua.er.4F al Howoq IioU••o• S R8U.1*T, M D. ~~~ AMP1. rlUa.v.l HoqM.L _ e~ RARU/ RlNACERRAP, M.D. l.irw. r.o%rar. and CANrww o/ rrA.Mw. Har.ard Melical Sdo.l, Dew. JOHN A. BEVAN. M.D_ rr./ia..r o/ • rArw..~s1o~ U.i.ereY, d GY/ar- .ia Scbol o( IN.dici... Lee Arplr. l1UDHD8V RIIAOAT. Pr.D_ rn.l..w of rAl+iolopq. Sc. Le+i. Uai...MF ScAoot ol Medciwr. S1. l.erll CESARE tiIANCIPIORI, MD, D/d.Y. of Cancer Rerr..cA, Ud..nMF e! Pamyi., t'e.>.ow IWy. HYLAN A. RICKeRMAN, MD. AaMM .M h%aw. of M.IkMr. crd AL. VAN L. BARACH. M D. G.u.i../ in MeJkM.. Collegs af PAFitl+w A S.rytor of Colir.bi. U.Iw.Mr.' Oo1L wwer M.mwid Hoyitd. New Y.A. 81O-RESlARCH CONSULTANTl. INC. C.wticiye. M.r. l110•RPSP-ARCH INST1TiJin QIC., Ce.nbciCp. M.r. PRlD O. ROf:K. Pw D. Aawdr. C.+ cn Ri.ercA sc/ewdd, ll/ot.sk+d fe& riow. Ro.weM Pe.k Me..ocW L.tM.* SteiepiNe, N. Y. HERMAN V. tkOEN10. PrD. BwA CAew/ur) and I/ocAewd.ny De~.rw wwru. Sliadelq Ree.arc! CeMr. Ls iyto.. Kr- IAMP.S P. R(NiNER• Pfr t). M/eawor o •Aoloe,. C.ufar.ie IerMrw et ech.oto.r. P...ea.e. 73

FENESTRATED ENDOTNEI.IUM OF THE ADRENAL GLAND: FREEZE-FRACIURE STUI)IFS Although there appear to be but two morphologic b.rrien, the basement membrane and the endothelium, little is known about the mechanisms by which adrenal medullary and cortical honuoees pau from the interstitial to the vascu- lar space. Using the Ireer.e-/racturiog techoique, the authors have begun to elamiee the adrenal eodothelium r a barrier to horrnooe passalie, and several structural characteristics have earrped. Two major leaturea of both cortical and medullary endothelnwn seem b be /eaeqratiooa and caveolac. While the latler may play a pan in bormo.a tra..port, there is so evidence on this poiet, aod tbe /eeestrae would appear b ton. lar {ess of a barrier so diAmion. Ths more numerous wsedullary uveolas, bwever, may have a function in the pro- cesing of horrwones and related n+b.ta.ees. For «ampk. ATP, speciik pro- Itins and epinephriee are rekaaed /roat tba cbroma/Bn edM durinQ eaocytow. Epinepbriee enten the vascular sQaea but ATP does .at. It may be that tb. ATPase eszymes, wbich are a cowr..o. /eature of other e.dothclial caveolae, occur r. the adrenal eedotbelMue as wer. Tha Rlobular particks and piu seen on the te.estrae aed o. the (radure taoaa of the plwna membraoe, moreover, wuest. It the concept of side.doas in membranes also applies to teoestrae, tha possibility that subataoces leaving the vascular apaee may be processed diQer- eotly from those wbelasas eaeri.R it_ Ry.n, U. S. er r. TUrwi Cell7(1):Ii1-190, 1973. O1A.r esspp.rtr lobs A. HarUord Fou.datioa and the Natiooal Institutes of Health. Frorn the Papaoicolaou Cancer Reaearcb Institute and the Departmrnt of Medi- eine. University of Miami School of Mediciee, Mumi, Fla. ADRENAL MEDULLARY STORAOE VESICLES OF THE SPONTANEOUSLY HYPERTENSIVE RAT The adrenal medullary veakks of .orsoteoaive Wi.ur rau (NWR) and spootaoeously byperxmive rats (SHR) wen eaamined is order lo determine whether increa/od sympatho-adnea/ activity plays a role in the ekvation of blood presaun !n the SIIR. Whib a11•metaruniooi uptake was the same, iaoo- latod SIIR vakks displayed a greater d6sily /or epiecphrine than their NWR couolerpart., u evidenced by a higher uptake of r'C<pinephrine/100 pg of eodoAenous catecholamines. Tlris dilleresce in uptake was due to a lower Km in SIIR epinephrine. Storage of amina wr the same in SIIR and NWR, as demonstrated by measurements of eateeholamine:A/P ratios in purified vesicks, and c111uscs of cndogerw+us and eewlyincorporated amines from the vesicles. 1 he higher talu. u1 taorcMd.minr. ro dopamtoe /i hydruylase (1)1111, a matker tur a.tr.p veorksl f.runJ u. 1i1R r due to. (1) (ewer ve.kks per gland; I (2) kss DBH per vesick, as indicated by an increased precursor:product ratio; and (3) a higher calecholamine content per vesick, as shown by an increase in the ratio of hesvy:liiht vesicks on discontinuous sucroee density gradients. Insulin administration caused greater catecbolarnine depklion in SHR than in NWR adrenals but induced lyroeine hydrosylase and dopamine A-hydroayl..c activity in both strdns. These resulls are not eomistenl with the view that sympatho-adrenal hyperactivity occurs in the SIIR, but the data suggest that bypoactivity occurs perhaps secondarily to the hypertension. StorA/w, T. A. and Oras, H. O. siocAemk.i rArrnarotory 21:17I-1!(l, 1975. OtA.r arpprtr American Heart Association. Walker P. Inman Fund and the Duke University Research Council. From the Department of Physiology and Pharmacology, Ilrrke University Medi- ul Ceater, Durbarn, N. C. SECRETION AND RECOVERY OF CATECHOLAMINES BY THE ADRENAL MEDULLA 11 is generally aeoepted that ueeretioe troru the adrenal medulla occurs by the process of e:ocytosis. While a few of the eaperiments which helped eluci• dale this complicaled, two-slep phenomenow are presented here, the maior body of this paper deals with the quaalal aspects of secretion and the evenls wbicb occur during recovery of the eatecholamine stores. Investigations conducted by the authors and various other investipton, ootably Viveros er at. and Krone- berg and Schumann, are discussed here. From these studiee and otben not described here the authors can reconstrucl the events which nast probably rccur during physiological secretion from the adrenal modulla. Stimula/ion of the splanchnic nerve causes rekase of acetykholine which, in the preseew of Ca+ f, resuhs in the quanlal, eaocytotic release of the contents of the oecre- tory vesicks. Immediately after secretion the vesick membra.es are detached from the plasma membrane and retained by the cell. ()uring recovery, new vesicks are formed which contain the normal complements o/ soluble proteias but are deficient in ATP and catecholamines. Subsequendy, these vesick, re• gain their normal content of ATP and ealechnlamines. As a(urther eonnse• fauence of neural Mimulation, tyrosine hydno.yl.ae activity increasess. which mosl likely accekrates the rate of recovery of the utecholamine store.. Kinhner. N. and SlorA/n, T. A. , In: Usdin, E. and Snyder. S. (eds.): Fronrlers iw Catecho/atnlnr ResearcA, Oalord, EoAland:Pergamoa Prea, 1973. pp. 447-452. OtAer support: U. S. Public Health Service. From the (kpattrncnt of Biochemulry and Ikparlmenl of Physiology a.d Pharmacology. Duke llniver.uy Medical Ceoter, Durham. N. C. J tn 70 51 f.

( COMPARATIVE STUDIES OF THE PRODUCTION OF ANIIB()UIL'S TO ANGIOTENSIN I While ankiotensin I antibodies have been wsotesafully produced by im- muntrin6 animals, little is ktsows about either the formation of antihodies in d'Jferent species or their persistence over substantial imervds of time after immunization. Such informalioo, bowever, in siSnificasA In the productioe of antibodies for radaimmunoswrs of sa6iolessie I sod reds activitl•. In this report, the author describa Ihe us. of rabbits aed Vosts in iromu.iz.lion pro- pam. Iastins up to one year. A.Ilbodka ts ae6iotemis I-BSA were produced in the two diRerent .pecies so compare Adr apecilkity. binding cap.cities. tiwer., aed cods. The antibody respo..e was apt/id ever wbNaMial ieMervsl/ of time following cornparabb imnm.izatios in diRutM anbas6- TUs pau iproduoed large quantities of antircrww bul dtis bd to be furtha purided In order to oblaia adequate titer aed sRieity. The rabbieti on tbe other baed, produced soti- bodies of high tiler, high sAimitp s" adequata .pscifcity, but ths vohane-yietd of aslirera was coasiderably, kless Uaa W/ o( p9b, it eetkdy sde<pate for most purposea. The e.pensa of raid.y aalarra In rists and rabbits were corn- p.rable. Although the initial ooU of pab ww Y6her thsn that of ralaits, this was o/ae1 by the far smaller qu.aities of a.6io/ensi. I required. Thz rabbits received about 50 tirna as nmcb aatipes r did the psta. Carrro. A. RrzercA Cowuwrwkarbws b CAewdcd ParAofory and pMrwcobp 11(3): 199-302. 1975. Otker.rpp.rlr Florda Juvenile Disbete. Research Fouodatbo. Frorn the Ikpartments of Medicier and Patholo6y. University of Miami School of Medicioe, Miami. Fla. NICOTINE ANTIBODY PRODUC(ION: COMPARISON OF TWO NICOTINE CONJUGATES IN DIFFERENT ANIMAL SPECIES Tnin report deaY with the peep.rstion of two .icotine protein eonjuple., the specific characterization of ttae of tbese conjugates and the production of antibodies is psta ssd rabbits. The low aNiMe.kity, lack of s functional group and the need for pre.ervation of the sntyeuie pyrrolidise riog rnoiety in eko- Uas require the introduction of a functioaa) {roap a.d a(airly long rigid linkage so the macromolecular carrier. Tb. preparation and charscterization of N-succinyl-6 amioo-tx.-.kotiue-BSA ssd 6-(.-smwrocapramido) •tw--nicoline- BSA ane described. The nw/ecular ratio of .iootiee to BSA is each conjugate was 10:1 sad 11:1. respectively. (losu inoculated with the 6-(.-aminocapta- mido/-or-amino nicotine conjugate produud aatibodies with a higher titer and better sAieity and •peci/icity. Also di.cuued are comparative studies of setibody productiue. purJkatao, .old phase a.wys in contrdkd pore klw, titratioo, and specificity. I Carrro, A. and Prieto,l. QiocAemka/ ond alopAyrkd Reterch Cotnnrrnk.riotu 67(2):St)-SS9, 1973. OtAer aupporls Florida Juvenile Diabetes Research Foundatios. From the Departmeots of Pathology aod Medicioe. University of Miami School of Medicioe, Miwli, Fia. RADIOIMMUNOASSAY OP PLASMA NICOTINE IN FUBINTUATED AND NAIVE SMOKERS A new rsdioimmueoeusr for .icoliee is deacribed which roquiraw o.ly crude /nethykne chloride aatractiom of plaama sampks lo reduoe bi6b bis.t valua. It is .uAkieetly .easilive and tipcciec to permit estimation of aicotioe is human plasma in the presence of its principjl metabolile, eotieine. Plasma sroo- tine concentratiom determined after iohalatios or 10 puQs of cigarette saroke were hilther at each of seven poiNs in time for habituated thas for saive smokers, individuab who had .ot .moked for the previou. 10 years. Mes..ico- tine conc.entratioas in sia habituNed and sia naive snaker., one miwute after oasatioa of snwki.l, were 20.63t1.1 aed 7.6t2.9 na/ml, respecUvrl7. Studies on buccal abwrption of .ieolire ie volunteers who smoked 10 puRe. holding each in the mouth for 10 seconds without inhalation of unoke, revealed similar plasma nicotine concentratiora, one minute after emoking, of 1.1s0.1 and 1.2 f 0.2 a6/ ml for habituated and wive smoken, respectively. 1s e.ch wbjecl, blank valua for aicotite were obtained prior 1o smoking and rub- trscted trom subsequenl plasma nicotine eoacealratioaa. Mcss of blank values for .iootiae I. fasted wsive and habituated smokers who refrained from smoking at least eight bours prior to the eaperimew weru I.St 1.) and 7.ti0.7 ng/sul, respectively. Nairw, C. F., Ir., Mahais., D., MiljkoviG D., Milikovie; M., sed Yezeil, E. S. C/4dc.f pArtnoroJop ort TAeraprwkz 16(6):1067-10a9, 1974. FFrom the Departments of Plunnacolo6r. Obstetrics and Gynecology. ..d Bio- ebemiury, Tbe Pennsylvania State University College of Medicine. Hershey. ACi'IVATION OF RAT MAST CEI.LS BY LOW MOLECULAR WEIGHT STIMUIJ Tttis paper reports oo part of a seriea of atudies esamiaind the iorerscdon of low rnokcular weight, eonimmundullie activators with efloctor cells. /. /hir i.vestiptioa, two radiulabekd mast cell acttvaton, compound •ti/k0 a.d a eatioac protein from neulrophib, were shown to bind almost eacluuvely 10 37 56

i ai6oiflcance since they seem lo have the capacity to ioitiate a.heroulerosia through (ocal or generalized vascular iojury. The classical techniques (or Ihe measurement of cellular injury both (n rivo and in ritro are notoriously in- aeositive, so highly sensitive methods were developed which involve !n rlrn measuremeot of the increased permeability of lysoaornes aod riitochondria. Using these methods, fourday primary eover6lns eulture. o( rat heart muale (M) sad endothelioid (E) cells were lreatcd (or 30 minutes with S x 10' M to 3 x 10 • M stearic, oleic or linokie acids in a FFA/albumin ratio of 6:1. labilaation of lysosomes and mi/ocho.drfa wae measured by acid phosphat.aa and succinic dehydro6enar ataitsi.d activity respectively. Stearate or liookate, but not okate, labdired M eell lyaoeowa at 3 X 10 ' M. Ly.osomea o1 E cells were oot si6niAcantly aRected by any of the FFA at 3 x 10-4 M. The activity of these FFA for M cdls lysoaorsea waa Y+.oieNa - rkarale> okale. 6oab E and M cell mitochoodria were ai6nillcandy labilisad by oka/e or liookate. S x 10' M, and by atcarate, 5 x 10 • M. The order of activity waa linoleate>okatc>nearale. Treatme.t of cultures for 24 buse with 30 tr(Iaal of bydrooortisooe before the FFA at 3 x 10 • M provided ai6.Jcad Prolectios ody apinu atearate-induced lysoao.d labtaaatioa Aeerta. D. aed Wew[ui, D. O. ArAnasc4ro.lr 20:417426, 1974. Other erpp.rf r U. S. Public Heah1 Servba. From the Department of PYarnseoo{op and Tosicobty, The University oI Kaeua School of Plarto.cy, L.wrc.oa. LASILIZATION OF LYSOSOMES AND MITOCHONDRIA IN SITU •Y HYPOXIA AND HYPOXIA-RP1.AT['D FACTORS Many diseases or environmental eooditioaa subject the eardiovascular ays- tem to hypoala or iachemia. While the depcea.ios of intracellular p11 by tactic acidosis is believed responsible (or the toaicity of iachemia, neither bypoaia nor carbon moraaide is appreciably loaic for cultured bean oelh, aod It is bypotti- eaized that their eQects an mediated by tn rlvo (ac/ors. This iovestiptioo .ou6ht to determine whether hypoala or other iehibNon of ATP tormatioo may interact in ritro with /w rlro byproducla of byposia web so free fatty acid and acidoeis to produce cell injury. Primary eullura of rat hean muscle and erdo- thelioid ulb were uaed 1o study the labilizatioa of lyaosomes ,od tnitochoodria by bypoaia, "bypoaia .ubelitwea", and the in riro-related factors of free (atty acid sod acidosis. SubWwi.aMy-acliv. Mveh of vuious a6ents were tested: bypoaia (1% O,, 4 dayr)' 3 x 10' M eod'wm atearate and albumin (6:1. 30 minutes); KCN (1 x 10' M, I hour); 2-deoay6lucose (3 x IO s, 12 hours): acidosis Ip11 6.9, 30 minutes); and eombi.atiooa. The cyanide plua deoay- 6lucoac labilized the orpnella is bolb cell types. Milochroodria were nwra sensitive to injury than lywsomea, and eswcM ullo more sensitive than endo- theboid cells 1t a concluded that ae.do.ir is an impottant factor in the injury produced in cultured ulls by atearic acid, and could be critical in the develop- I I tnenl of In rlro injury from hypoaia, ischemia, er disease states kadin6 to io- creasod pluma levels d(ree fatty acids. Wentef, D. C. and Acoata, D. Research Cornmun4.donr !n CAemk.l laMoloPy and rAarnserotop 12(1) : 173-176, 1975. OtAor supports U. S. Public Health Service and The University of Kaasr General Research Awards. Frorn the Depanment of Pharmaoolop and Toaicob6y. School of Pharmary. University of Kaaa.a, Lawrence. COMPUTER ANALYSIS OF AUTOMATICALLY RECORDED OXYGEN DISSOCIATION CURVES T6a chemntry of oay6en tranaport in dre erythrocyle is represented by a noe-lisear functional relationship between otygen reesioa and oaygen ralura- tion of the hemotlobia oontained in the eeM. Thia eurw is usually characserir.d by two puunetere, P•• (oay6en tensiom at hd/.aluralion) and t>te Hill 0o.- atant, •(a tneasure of ai0noidieity). secauae ol Ma eon-larcar fuwcdo., Y would be preferable for Ihe complete charecteria,tbn of oay6ea dirociaioe to measure and analyze tlte eaire curve rather than PM alone or a discrete rnrir ber of points aroutd S0% tupuuios, such as is required 1o cakulate a. 'iLis report describes a computer program for analysis of continuously recorded o.yRen dissociation eurves. Routine eakulaioe of P„ and o is carried ow aulomatieally, and the complete curve eapressed as percentage sa/uration versus pO, may be examined. The analysis was devised for curves obtained by varioua iuvesligators and Ihe same program may be used 1o analyze disaociatba curves produced by the recently eoremercidly available Radiometer DCA-1 Dissocia- tion Curve Analyzer. Details and advantages of thia program are out4eed by the author. Canrerow, D. F. Is: Sruky, D. F. aaid Richn. H. 1. (eds.): Oryprn Trow.prt to T/urr. IA.r' morobpy, 6l.rAenwird Stssdkr and Neonatology. New York: Pkauaa Pub lishing Corporation. 1973. pp. 92)-92t. Other aupportr Natioaal 1euilutesof Health. From the Papanieotrau Cancer Research Institute and the Division of Netna- tology. Department of Medicioe. University of Miami School of Medicios, Miami, Fla. OXYOF.N BINDING TO HUMAN ERYTNROCY (E CELL POPULATIONS Old rexarch lines which seemed to allow an evaluation of tha "life hi.- tory" of an erythroey/e wqh respect so its o/ygen transport (uncliow have becn challenged recently by Increasingly compk observations Both classical vkws and new understandings are presented w Ibis paper as it speaks of movemrnt J 45 m 44 n

scopically•obser.abk formazan jranuka. The e:teot of intramilachondrial forma:.n deposition depends upon the N8T incubation period and the degree of mirocbondrul membrane injury. Pseudo dark-Aeld microscopy and a atan- dardized rating scale were used at flaed intervals to areaa the e.tent of granule formation. Both vitamin A and cblorpro.nazine increased the rate of mito- chondrial staining. Brief prcflaatioe of cells with cold acetone also labiliud the mitochoodria, as did a delay ie changing the culture medium. Dilferences betweee control and treated cells .vere analyzed statistically by % semi-quaoti- tative method. TDe authors ares. eha the technique presented here depends largely upoe the use of ietact aWs - ntrer than noctiooa - for its eflectiveoeaa. Acoata. D. and W.ntel. D. d. NtrrocA.wrkd /oun.d 7:13-56, 1973. Oth.r aarpr.rtt U. S. Public H..Mb Srrvio.. From th. Departmnt of Man..co{o6y .ed Toakoio6y, School of Pharmacy. Usiverrty of Kaoa.., L.wreaoe. TH[i LYSOSOMAL PeRMP.ASILJiY TEST MODIFIED FOR TOXICITY TESTINO W/TH CULTURP.D HEART 1?NDOTHFIJOID CP1L4 A roodifled ly.o.omal fragility ted suitable for use with cultured ceY. is described here. The perrneabilrt7, and thus fryility, of the cells' lyaosonal mem- branea to tbe 6-fQycerophoephate aubstrate is measured by assessing the degree of particulate ly.oaornal staining folbwia6 eaposure to the (lomori acid phos- pbause ataie under carefully controlled cooditioea. Monolayer cuhures of neo- nalal rat heart codotheliod cells were uaed Ie all esperimcots. The timeeourse of lywsornal staining for cells eapo.ed to various treatmeots (normal aalioe, iwtonic sucrose, 0.23 M wcrose, distilled water, aeetate buAer pH 3.0, cold acetone, neutral /ormalie, wctic<tb.nol, Tribe X-100, hydrocorusone, cbloro- auioe, .nd vitamin A) was compared with that of control cells stained under identicd eoeditioaa. Statistical diReresas 1. Maieie6 betweee the teat and eoe- vol eclM were determined by the Wikazo. Signed Rank Test and also by w 6rasioe ualysia folbwieg a(raarfornutioa desiRmed /o allow for the tatura- tion character of the reaction. The auroc.eas of tbn modibed technique depends upon meUculous methodology. It M eapabls of demonstrating both lywsornal mernbraee labilitatioe and suabilisatioe, aeoo.d- .ed tbird-atage Iywsomal ac- tiv.tion, aad appareet (ywaornd enzyme lorr or dattuction 4s iltw. The tecb- dqtre also aibwa the degree of rsversibM or hMataSe lyso.osal activatioe to be subdivided oe as almwt continuous briq aad in suitable for iaveMi6ads6 tle eeecu of drup and other ageaN. oa 11141 ldqrity of the Iyaosome in Nw. Reed, R. LL aed W.rsul, D. O. HlrtocArnsk.l loavw.l 7( 2):113-126, 1975. O1A.r w'prtr U. S. Public Health Servioe and IA. Univenity of Kansas (3eeerd Research Awards. From the t)el+arlment of Pharmacology end Toaicolopr. Usiversity of Kaoaaa School ol Pharmacy. I.wrtoc.e. i I I Vl. Immunology and Ad.ptioe Mechani.na. CLINICAL APPLICATIONS OF RADIOIMMUNOASSAYS OF DRUGS IN HUMANS Until recently, aimpk auays to estimate the levels of drugs and their metabditea in physiological fluids have not e:ialed. The cosveetjosal waya (6u-liquid chromatography and this layer ehrwnNOgnphy) ere timeeoemrr.- ie6 and inseesitive, and not applicable so the analysis of large numbers of samples. However, rad'aimmuaoaway, a techeiqw bued o. the competitioe between labeled and u.tabeled arAiSee for binding 1o a limiled .rreber of aitr on a apcci[Ic antibody, i..ow being used. DurieR /he last two to throe yeara, methods for the productiow of a.Nbodiea lo several drugs. aed ae.aitive, apeciDc radroimmunoasaaya for the 1es1in6 of pioo6rnw amoueta in body auW have beee developed. Ztioae radioirnrTMUwtrsays require only a misireum quantity of blood or urine and are rapid. simple proeedures. These .ew techniques ue be used not only to..creeein6 but to obtain a better understanding of the physio- lo6icd mechanisms aod disappearance rates of thne drup and their anclabo- 6tes. le thia paper, the developercnt of sensitive and apeciAc radioirnnweoar.y systems for the quantitative determination of barbiturates, morphroe. LSD, and amphetamines ia reported. C.rtro, A. Afed1low Intern.rfowd 3(l):11-1), 1971. From the Departmeet of Medicire. Uaivenity, oof Miami Scbool of Medicir. Miami. Fla RENIN ACTIVITY SOLID PHASE RADIOIMMUNOASSAY A reliable mea.wement of renio activity is quite importaet bec.uae of Ma usefulness in the diagnosis of hyperteaaiw aute.. Until 1967, Ibe meawus+.+1 of plasma reein .clivity was carried out mainly by bioassay, with r.diolreaawo- asaaya of generated n6ioteesi. I beiy dereloped later. Now, a.olid-pbw r.dioimmurw.sa.y for wteawtemeat of rseie activity (an6iotesaia I 6eeeratb.) io plasma is reponed. Angioleosin I aotiaera were attached to diarotized atyl- amies and N-hydrozy succieinide eoNroUcd Pore gla.a, and react.d with labeled and unlabeled .epotesairr I for aaturNion andyais botb before aed after incubation for oae hour. Chelatio6 agents were used lo inhibit the eow- venioe of an6iotearie I so ae6iotesrie 11 /n vine. iLia araay Is aiapb, r.pi4 accurate, and aubjoct to automation. Corro, A. , Rtsa.rcA Conrrnunkm/oru lw CArnJc.l r.rAoJoey .w1 rA.rn.rdogr 11(3): 193-191, 1973. Other supports Florida Juvenile Diabetes Reaearcb Foundation. From the Ocpartments of Medicine and Pathology. Uaivenity ot Miarei Scbod of Medicine. Miami, Fla. '33 54

toward the construction of a truly adequate picture of red cell and blood osy- gen transport in health and disease. At Ant, the problem of evaluating oxygen transprxt of hcmoglobinopsihic bk+oda seemed to be relatively slraightforward, related to posssibk variation in Inlrinsic oxygen binding and to 2,3-diphospho- 6lycerate (DPG) kvels in the uU, which could modify oxygen af1'inity. Now, the picture is much more complex since it is clear that the pr<cess of oxy6en transport Is dependent on many p.runeten, inchrdin6 some con:erned with the physiolo6y of the erythrocyts itsel/ and the variation of thea parameters in the mixed population of cireula/Mg erythrocytes. The authors are beginning to seperate out certain of these p.rameten with cell fractionatiat of cell types, as,d eo.trol or evaluation of other chetnicd /acton than DPr3, wch as CO or oxidi:in6 agents. Ths abiily so npWly measure many oxy6enation dissocia- lioa curvss permits an wesameM of t0ese features. A contintously recorded dirociation curve also highliAYh the bnportsece of whole cc I lacton, such as ths sickling: pheeomeno.. Si.ce tlte various speciAe parametety do not act in iwlatkon or i.dependeatly, tJw authws are akso studying their iraerrelationships. Camcr,ar, I. F, Zucker, R. a.d Hark..ss, D. R. A ww.b oJ the New Yor! Acalriwy oJ Sckncd 244:60-71, 1973. ah.r.urr.rtr National LsWutr of HeaN16 American He.rt Associatio., aad t!e Veterans Adnristrtdio.. From the Papanicolaou Canoer ReaearcA Institute u.d the Department of Medi- cioe. U.iversiry of Miawi School of Medicin., Miami, Fla. WATER SORPTION ON DEOXYOENATPD HEMOOLOBINS CC, SC, SS, AS, AND AA Five dooxypenased human berw6fobins (Hb), CC. SC, SS. AS, and AA, genetically related to each other through one set of alkks, were studied within a Mcliain ornvimetric aorptioe system st 2!' C. Water at relative vapor pres- surns ranging from 0.11 to 0.39 was used r the adsorbate. 7he deoxygensted forte (Hllb) of those genotypes containing the relatively lasdubk sickle Hb (SS. 9C, snd AS) were compared to the ferric form (Hlib'), eQuivaknt to the oay form (IIbOr). For aM Aw Hbs, the HHb did not show a si6nificant decrcase in sites accessible to water vapor with relation to the normal Hb AA or the solubk Hb CC. bth the HHb and the HHb', however, showed a slight increase in the number of pof.r sites eccessibk to water vapor in those genotypes in which the wbstituest in tLe sixth posilion from the N terminus of the two beta chains had a positively charged side chain, such as in Hb C. Nevertleieas, when baherwul equilibtia were established /or the Ave libs and piouod is terms of the BET eqwtion (or mondayer coverage, the resulting curves showed that the transition lrorn 11111s, to HbO, is accompanied by a siptiAcant decrease in mo.+olayer coverage but only in those samples containing Ilb S(kss ao/uble as HNb). These data complement what is presently under- Mood about the soI-gel transformation that occurs with Hb0 deosygenation by showin6 that: (1) the drastic reduction in solubility of sickte-cell Hb's can- not he cxplained by a signJAcaat reduction of 1he polar sites available lor Ay- dration and must be due to a polymeriWwn of the tetrameric mokcuks; and 1 (2) the increased monolayer coverage of the sicklecell HHb's compared to tha HbO; s is in the direction expected from the observed increase in di.plaoescnt of the beta chains with deoxygenation. Funhermore, when added so the resulta of crystalbgraphk analysis, the obser.ruion that HHb binds protons more readily than HbO, sugjesls the possibitity_ that the central cavity say be is- vdved, and that movement of the chains aneoven previously buried poba binding basic groups. The increased percentage of pular sitn bydrated is tlHb' as opposed to HbO, /or each genotype observed would atpport that hypothesis. Kiliots, P. l. and C.n.rron, 1. F. ebplyw.cs 11:1633-1639, 1974. Other.rrprtr Camille and Henry Drey/w Fouodatio., National Lsdpdas of Health and nkr America. Heart Asaociatio.. From 'ibe New P.neand Institute, Rid@edeld, Coor., and the Pap..iootsou Cancer Itesearch Institute. Mismi, Fla. IV. Netrroph.rwt.cotosy ond Psyehophyeiolosy 7tIH EFFECTS OP SMOKING ON MOOD CHANGE This paper reports ave studies in which tbn eRects of smoking os mood change were measured. Esperimewla 1-IV focused on the eAc+ca o1 arnokisd on variow aapects of psychomotor perlornta.es, and meruranent of mood was usually incidentd. Piperimesw V, however, was designed 1o evahute tis eA.cts of smoking on waod change whe. twbjecu were exposed to a highly urwful Wn. Subjects for these experis.ewts were assigned 1o nonuooker, s.mk.r-d, prived and rnoker poup, and Ihey behaved accordingly duris6 tY prfors- anee task or during the Aha. In each of these ahsdim mood wteasurea wen ob- taieed immediately before and after a subject participated in tM task dM was required in the experiment. 7La Mood Adjective Check Lis1, which bas bro.d oovera6e of mood stales, was used to teeasure the subjects' tnood is all cra The data obtained here atroaaly w6pts that smoking will modify sood Naw or, rnwm speciAcdly, will teod to reduce Auctuatiow or chanp 1s arood. 7yp4 cdly, subjects who smoked durin6 the various eaperiraeal.l coaditior in.oh- in6 psychomotar or perceptual taska showed si6niAcant mood changes i., at moss, two mood (acton (1pti6ua and eonce.tratio.). while subject. is 1b smoker-deprived and eonsatoker Rroups showed chanp io Ave or su at the mood (adors. Hdnur.a. N. W. In: Duna, W. L., Jr. (ed.): Sowllwt ScA.vlo.: Motlrc. awd fwcewNvw. Waab- legton, t). C.: V. H. Winston i Soos, 197). pp. 197-207. From the Department of Psychdop. University of South Dakota, Vermillion. _J m 46 47 ~ it)

present an unusually wide spectrum of foreign nuckic acids to the host, appear 10 be the most likely immunogenic source to triuer an ANA response. This seems especially true since (NZB x NZW )F, mice spontaneously make anti- body to every recognizable macromokcuk synthesized during their repiicNion. The authors clearly demonslrate that an SLP-like syndrome and lymphoma can indeed be induced in immunologically normal (BAI.B/c x NZB)F, mice by in- lection of neonates with a murme ksukemia vinr (MuLV). 71ut Mu1.V propa- ptes in the oewboras was indicated by 6rratly elevated serum Mu p-1 kveb, proportional to the vinu dose givea. The ANA respoase, which was maairmue at eight so 16 weeks, was also related b tha tinu dose as was the incidence of kiornerubnephritis which approached 50% is tbe animals receiving the highest doae. Femaks had biaber ANA trws and gloamrukonephritis incidence than maks, although serum Mu p-l le+ela were equal. While SLV 60 A did not sigoificaatly aAeN direct Coaeba' 'witivily, the incidenoa and onset o6 thymocytic lympbown were linearly related to tk+o amouat of virus inoculated. High aenaw Mu W1 kveb predicted IywtpAoma developrnent and reflected iocreasea in the anawrt of ideetiow virw is the apleea Neitber the admini.- tration of SLV 60 A to 6-week-old (RALS/e x NZB!P mice, not that of ~ activated 60 A or active AKR virw to newborns was lolbwod by tumor i.- ductioe, autoimnm.ity or high .enr. Mu p-1 kveb. Crocker, •. P., )r., Del ViBaao, B. C., lerea, F. C., Lerwer, R. A. and Diaoa. P. 1. TAe lor<rwaf of Eriierbnenrd kledkinr !40(4):1028-104i, 1974. OtAer ao p.rf r National Cancer /nrtitut., U. S. Public Health Service and Nationa! iuadatioe - March of Dimea From the Scripps Clinic and Reiearch Pouaid.tion, La Jolla, Cal. Vll. Erid.wdolon' MAIL SURVEY RESPONSE BY SMOKING STATUS A detailod anokin6 hiatory questiosairs waa mailed to a serin of 1,917 white male veterans partkipatin6 in the Nonmtive Aging Study, an ongoing prospective interduciplinary study of aging. Response time from ma1ing data to return dale was determined and then compared by various smoking categories. Although a total response ratc of %% was achieved after siu moaNhs, results showed that cigarette smokers' response ratn were considerably lower than those of other smoking eategories both within 30 days and within 60 days of the original mading date. Cigarette smokers wouW, there(ore, be under-repre- aeoted it data collection had ended within this time span, or to some eatent even alter su rr.onMs frorm the trrne of the original maiiiog. 7be response rate also seemod rel.l.d 1o the nuiwber of eikaretta arnoked, with Seavicr amoken being sloweat to reply. The implications of theae results with rnpect to cohort studies of smoking and health are discused. Seltzer, C. C., Boub, R. and Qarvey. A. I. (QeR, e. and Ro.e, C. L.) Amerkanlournd o/Epldrmlofosy 100(6):433-437, 1974. OtAer su'portr Department of Nutrition, Harvard School of rublk Health, and the Normative Aging Study of the Veterans Administration. From the Department of NutriKon, Harvard School of Public Health; the Normative Aging Study, Veterans Administration Outpatient Clinic, Boston; and Iklknic Colkke, Brooktioe, Mar. A(3B, SMOKING INIIALATtON, AND PULMONARY FUN(TION The relative c8ects of age and smoking on pulmonary (unctioe was ea- amined in 1,316 male parlkipaw of the Norsnative Aging Study, as oapi.l project at the Veterans Administration Outpatient Clinic in Boston. Tba arno.w of smoking was measured by six variables taken singly and r a ooapoaNs: (1) number of years subject smoked; (2) number of cipretles per day; (I) fraction of cigarette smoked; (4) dep(h of inhalation; (3) oumber of puAs inhaled; and (6) twmber of years since quitting. These sia eompoaeaus of i.- halation were thes aoored and their arithmetic mean defined aa a subpct's over- dl inha1alioe acore, u iedea of the cumulative amount of ci6arette smoke brought into his lusp. Two .leparise seultipla regressions with vital capacity (VC) and forced eapiratory vdume at one second (FEVr a) ar the eriteria were rws againsl this iadet. AV aod the aia arnoking components aocoartad for 24.4% of the variance in VC aed 28.3% in FEVr.. Two-way a.alysa of variance showed the ap decline i. VC eo be substantially BreNer !or biob inhakra than for low iehakn or nonsmokers. Age and the inhalNiois i.dea were also noticeably and indepeadently related to the decline in FEVr a. In addition, results showed that the overaQ smoking iobdatios iedea peoduoaI a greater eftect on FEV r_. thas on VC, an effea that rssults from the (ad t!M FEVr_, is a better aoeaaure of airway obatruction than VC. BosaE, R. at d. (Rare, C. L.) Arclllver of Ewr4omnrente/ HedtA 30(10) :493-491, 1975. From the Normative Aging Study, Veterans Administration Outpatient Clink, Boston; the University of Manachusetta. Boston; and Hetknk C'oiiep, Yrook- lioe, Mau. CLUES TO CANCER RISK: BIOLOGIC MARKERS T7ThC analysis of genclk, biologic and epidcmiob4ic information lor th. usignment of risk (actora to a patient holds many implications tor casoer de- lection, control and prevention. In this paper, the investigators report on aaveral biologic marken identified in their study of two larV kiodred. (Family 0 and 62 63

i PRINCIPAL INVf,iiGATOR OR iNS17TlfflON 1. ANDREW MIITCHPI.L, hM D.. A..lr- ewr rroleawr oJ Aworoay. We,we Stue U.ivernt, Sclool of Medici.e, Dcuoil. OEORO B. NeURATH, hr D., Mkvo. o: d l.b..ra.r. HeuerrL We. f• OAK R1DOH NATIONAL LAIORA. TORY, O.l Ridooe, Teaa MALCOLM C. rIKE, Pu D, Ire(.ue. o/ Co..w..ww, .hiic4we ond P./ler. ~.. Uwi.e..Mr oI SewWs C.Wae.ie Scfoal ef Mdki.K L.e A.Re/.. iLARI RANTASALQ M.D, M/eeer owf CAebw.rey rdik He.dA Scirwee, U.i.enw, d Ildef.ll Ikki.tL Pi- Ie.J. RONALD E. RASMU3SeN. P..D_ A• ,i,...r ReterrcA rApiofolIst, U.i.ee- .it, of C.lilor.i. Ca.csc Rasarch 1. ritaK Seo Fr..cieoe. (Noo Aa.ocbre Re.e+rcA H,dolor/al. Deli.Ara<M e( Cor..Y, ..d 8.viro..re.u1 MdL ei.e, U.i.er.it, of C.Iilor.ia CoRqe of Medid.., Irvir.) TIMOTHY 1. ReOAN, M.D., he%.ror ./ A!e/kiwr; Dl.ec/er, Dl.ls/w o/ Crd/ov.adr Di,e.ent Ce1 .tkp Mediciwe .wd DeMn" o/ Ner Lrry, Ne. )eree, Medical Sclool. N.n.rL DANIEL R. RIPKIN, Pw.D. Art,twr rro%s,or o/ CA.wdnl Ilolod, TY Rocfe/e6r U.i.enM,, Ne. Yort. CHARLES L. ROBQ PM.D. C1/wk DYee• w.; D4.crar of No.wr.Nve A~/wt Srul,. Vefeew Aiiwiwieva{o. OM- ptier Clf.ic. Raeo.. JOHN A. ROSECRANS. PM D. A,s- cwe rro/cuor o/ rArw.ecolor,. Medl- ca1 CoUqe of VieRi.i., RkOweN. RONALD P. RUBIN. Pw D., rro%as. o/ rAorw.oco/ot,. MeNcd Cdiqe af Virsf.i.. RlcMoed. UNA 3. RYAN. rw D, S.wfor Sdewrla, Peoenicol.or Cencer Re.eere! ,wl• lu1e. (iAo.m/. Asurr.w/ r.o/euo. o/ IN.h.lwe 1/A.....r1) ../ Muwm Scfod of MeJr..e/ f.lu..l I1. PROf[(.'T TTi1i A eerd, of t6e eRecte of .kdlne on loee1.- 1ro. fn t\c rat wit\ prticu/er rc/eresoe to inplenWio. ud the tiare of oaeet of p.rwrilio. Ki.aia of .ivoe..l.e (ornetlo. Ir to b.coo eaot. De.icee tor Ib e.powe of e.pe.iew.l.l Yir..Y lo v`oM 1ob.oco reokr ~b.,.ic.l ..d ayeraioa.l lt.d, e[ Ib relar/oWr en.roee wr op1Ni1N~ 1o eKruim e..oere .wd eryl \,i.crAo. A,dr..,1... (AHII) w YvY, Tb Pirir'ibi. Rqletry knew need .rots~M t~. Dc~rNA~npir~lA ~sells woqeibM /e cleriral tr.../or- V.rf.lk. e/octly tke c.rdb+..ctil.r w qo.w b clrooie eewliy Troieaea prodro.d by eeeue.ll.m k.g lirr. A ewokre.nrd preRrs Is tb Nor- .Yie. Asiog Study St.l4 depe.de~~ rtke of .kalw- eL1eLreL1eL oos Tb .etbn of .iootlwe on the .dn.e1 It•" E.doerS.e fu.clior of the Iunp 70 I I i PRINCIPAL INVISTIGATOR OR INST1il)TION R. V. RAMA SASTRY. DSc. Pu.D, /ro/eur of r/ww.ocoloe,. V..der- OiM Uwiver.M, ScRool of Medki.e, Neehille. Te... SCRIPPS CLINIC AND RPSPARCH FOUNDATION, La IaRK Cd. CARL C. SELTZER. P..D.. Noworr, R.srrcA A,aorfu.. PeMlody M- serwS, Herverd U.ivereM,. Cr.beW", M.r. CHARLES R. SHAW, M.D, CAk/, Secn How of lNrdkd Gew.nkR M. D. Aw- dcreow Ilo.oitel ..d Trwor IwMwe; P,o/e..or o/ Abfo". Tte U.Iveniy .t Teue r Hwa.k fleiroa NATHAN H. SI.OANR, h.D Ro/.r .a. o/ 1bcAewdw,, Tb ljwl.r.k~ of Te..a.ae Cs.w iar 1he HsaNf 3cie.oeK Mewwiia. LOUIS A. 3OLOFP M.D. RlrcAe P. j Senke ho%a,or; rro/eaor MeMci.r Diertee Re. rr.cA L.l~or.ary, Taqli U.1- it, 3ds.o.e dree, lfil.- MARC D. THAMPS, MA. Sewfer R.- rrcA Pdb., M.~r. CfWe .d Por.- drioR RocleNer. Mir. JAMES TRA Pw.D. Aaedr. M- /euw of . U.iwaN, .t Oeor66. NAe.s. EMIL R. UNANUr, MD. Mdq.eRnslr holeteor of lwwrrwo~.rAdo~,. H.r- Roe/e.. ..rd Medicd Scle4 UNION CARBIDE CORPORATION. Nude.r Divieloat. O.k Rldp, Te... UNIVERSITY OP SAN PRANCISCO, S.. Fr..cUco. STEt'HeN P. VATNeR. M D_ Auociue Iro/.,,or of M.dklwr, H.r..rd Medl- ui ScAod ..d Peur ReM MIyAr. Iloepul. eodo.. BLLIOT 3. V 8SQ1.1_ M.D.. rro%„or .wd CANrwvn of rArw..co/oc,. Peww.,l- vewie Sua U./vereNy Colkr of Medi- cine, Miho. S. Hcr.hey Med.cel Ceaer. Hcrdoey. PROJiCT T1TlZ /./.e.a d.icaiee on tb eeleaee of troelykboline lo Ihe Mnn.. Plece.ta e.d w iwriiutiw on W teW ao.tA Lrwo.oloOkJ oosPele.M ..W cbeOkd prciwoRe.es1. Cowetkwlo.d etrdiee reiaM so e.oti" rd ooro..r, Rs.rt dhere H,drnc.rtio. .wabollclq .-,... .d {w" ca.o.e PJ.q af beweoi.k,euo ..d deAv.dwe M f.Y.IIM {r.{ Oellr Rdb et MdtAl.: dmleaueoi .ry1 tlr.er /eew (LCA7) {s edoksked ..t.M. ~~ .e•~l a.... .r .ries C.rdf.o mrcl..oe.ee}1oe..d r..ia w kae. ~ o( cfro.k e6etrrcNv.luq ,daPa~ ~, o( .eerd ..w .eoNNd Ci.r.aerira/{os of ede.d aqe.rs ef. kwe Do.VHry rrdke LdueUow of puewow aR M.go earele*- .ni.tbwwue. NiooUs•Mdroed nie ooro..ry ve.odl- INio. R.dbirwwwowy for .bwlr PRerw.oollwNke of .kdlr I. gaoAen ud .o.enwiue rf.rwr.ootlwdk. of wbollae 1..e1.. ud h.bituaed ci{uetu., clµr ..i p1p ouloteu 71

tional esperirnents showed that P-diosane, 20% (v/v), blocked 100j6 of the elaslase inhibition and 16% of the trypsin inhibilion, but did o01 affect chymo- trypsin inhibition. The effect was reversed by diluting the diosane to I*i (v/v). The variable susceptibility of the eoxyma to blockage of the inhibitian by low concentralions of p-dioaane also suggests that hydrophobic bonds mrjy be im- portant in the interaction of elastw sad trypsin with o-l-antilrypsin. Nowever, a-l-aotitrypsio could be specifically displaoed from Sepharo.e-bournl elaslue with an irreversible inhibitor of that tusyrm. Competitive inhibition ii inferred by the displ.cement of .-1-utitrypsio frow elast.se by so irreversibie inhibitor of the emyme which binds oovsleNly M eb r:aiyree-active site. Furtlr:r charae- tcritation of the product of sAMity chnoa~sphr of the .-1-antitry fsin on an enzyme dBaitr column may provide a mear d ideetifykog the enzyme nhibitory .i1es. Cohen. A. 1. elorAinka er BlopArrke AN. )91:197-20Q 1975. OtA.r su'r.rtr National Heut ud Lus 1slitsAe. From the Medical Service, Sa. Prs.eisoo General Hospital; the Pulmonary Specialized Ceaer of Research. Depaetmeot of Medkina, a.d the Cudiovascu- lar Research Iswitute, University of Catifor.ia, Sau Franeisco. AIR BOLUS METHOD COMPARED TO SINGLE BREATH METHOD FOR DETERMINATION OP CLOSINU VOLUME Clusisl; volume (CV ) is deut.nined either by the single breath nitrogen (SBN) washout metbod or by methods employing a single bolus of test gas. 'i1The SBN taetbod has bees used widely and is now standardized. 'ibe bohr a+etbod h.a ths advantage of being rnon sensitive. but usually requires rrare eotnplea apparatus. Here, the wthors prese.t and dcseribe a method whicb .dds fie seesitivity of ths boiw method to the SBN method without tnaior modifkatios. In eine out of the 12 norm.l male subjects tested, this method produced tracings that were superior so tboss obtained by the S8N technique becauae of a steeper rise of d+c nitrogcs stope io Phase IV. CV was not affected by the breathing of 100% otygea. This particular method Is suggested as ae inespensive modibcation of the SBN oethod for use in subjects with poorly discernible Pba.e IV. H.nro.h. r. ..d Taseirs da Silva, A. M. Aewerk.n Rrr/ew o/ Respir.rory Diu.as 110:)tt-320. 1971. Oth.r.upr.rtr Veteraos Adaninislratiw. From the Department of Physiology and Biophrsics, Georgetown Uoiversiry Medical School. Wuhiobwn, D. C. BASIC STRUCTURE OF TIIE UNIT LUNG I.OBUI.E OF NORMAL AND DISEASED (RDS) PREMATURELY BORN HUMAN INFANTS "Cl+e respiratory tobuk of the premature or even the mature sewbor. infant is not merely a miniaturized adult lung lobule. This fact, emphasized at the very beginning of this discussion, is as signi8cant to understanding the Patbolotr and physiopatholoty of aeonatal hyaline membrane disease (HMD) as is some knowledge of the lueil: bnie unit. 7 he fint section of this rcview, therefore, describes the besic atnrcture of the premature respiratory lobuk. Tbm major morphologic differences betweee the immature aod adult lung lie is t xne of the parenchyand strocturea, the blood vessds. IrtnpAatiu, and ssuro epitheliat bodies. TTrese afCed neonatal ventilatory o+ecA.nin..urfactaa syaha- sis. pulmonary perfusion, iMercellular permeabililr, and active traesport. as well as the fetal pulmonary vasoconatriction, rapid vasoddatios upon aeration and pulmonary hypoperfusion of the respiratory d'alress syndrome (RDS) as- aociated with hypoaia. The second section eonsiders the pulmonary pathology of HMD as revealed by light sud electrow microscopy, and vascubr in' esperiments in babies who died after presenting idiopathic RDS. Ili monary vascular resistanu, Impaired or deficient surfactaot activNy, iacreaaed alveolar wall permeabdiq and transudalion, inh.led amoiotie Ruid. a.d so inadequate fibriuolysia system all seem to be importsd facton in the p.tho- jennis and oulcoma of KMD. Other elwackristics such as epithelial .ecrwis and hyaline membr..e formNion, lymphantiectasis and lymphatic congestb., interstitial sad reparative phenwnena, s well as pulmonary edema and hernor- rbaRe seem to be saondary pbenome.a. Siace It appears that HMD may actually be isduc,ed before birth, rrare date should be obtained about aM p- tation, lnlrauteriee development aed birth of isdaou sufferios from /bis ay.- droma. L.rrerynr. I. M. 1.: Otuek, L. (ed.): Modern reriw.raf Medk/ne. Chicago: Year Book Mad4 eal Publishen, Inc.. 1971, CAapt. 26, pp. 759-)79. Olilwr ar'r.rlt Natioosal Fo.ds voor OeaieeskwadiR Wekoscttappoljk Ooder- roek (Belgium). Protn the Department of Pathology and Hislobp, TAe Vessliui Iastituu, Katholieke Ueiversikil te Leuven School of Medicine, ard the L.boratory of PNholop. Academiacb 7iekenhuia St. RspbaM, Leuvea, BelRium. MORP1fO1_O()ICAL STUDIES OP TNE slAOl) AND LYMPHATIC MICROCIRCULATION OF THE LUNG Some knowledge of the lueb i rnicroar=hitecture Is essential ro u.derNa.d- isyj i1s microcirculariow. T1This review wmmarires the .iknUksal characuriNks of the blood and lymphatk mkrocrreulation in the respwaury bbula of Ihs adult lung. lher...e thrce distinct morphoblic entities at this kvel: the air- blood barrier, the intcralveolar septuni and the alveolar wall. lhe major lopo- 26 1 27

H. HUGH Fl/DEN9F.R(i, MD. Pro/ra- t.w u/ Mrdirinr, llniversNy of Cad- fornia Medical Cenler. San Francisco; rro/tnror o/ /ocurwloty and tmwro- noloZl. University of Ca1ifornia. fierle- ky. ARTHUR Fl/RST. hr D., Dlrrc(ot. fn- uitarr of Chemical thology, University of San Francisco. Sa. Francisco. MURRAY R. GARDNER. M.D Aar ciate Hro/earor of t•.rholop b.i.ay- sily of Sou/hern California icloai of Medicine. Loa Angcles. GEORGE O. OEY. M D. Dhtrt.r. Fii.- wry-No..rR Cawrrr Reae.n4 LiAwt tory; Anociate Pro/rn.or ~/ Sr~ery, The )ohns l/o~iws Uni.ersi( Sclaoly of MedKine, Railrn.ore. THOMAS M. OOCKE, M D. Associaee rro/ruor of Preventive Mrliciwe and Commrnisy Health. New Jersey Slala College of Mcdiciwe and DerMistry. /er«y City. DAVID M. 001 DFNOFRO. Sc.D., M D, Arsociae Pro/rsi.w of Pathol- ogy, Temple Univcrwy Nedlh Sei- enea Cenler. Philadelphia PA1/1. 001 DHARPR. 1) 1) S. Arwci.re Professor of lrnad.rwtul..lr, Harvard School of Iknlel Medicine. Sos(on. IRA GORE, M D, rro/ruor of lathol- oRy. Boston Universiry School of Medi- cine; Chwl of t.aboratiwy Srrvke, Veterans Adminiuralion Hospital. Wetl Rualwry. Mass. GFRTRl1DE Y (:OTTSCHALL, Pn D., Auutawl !'ra/rswr of thorhrwdsny. College of Physicians i Surgeons of Columbia University. New York. A. CI.ARK GRIFFIN. PN D., Head of Siochemittry Dtprtmtnt. M. D. An- derson IlosPilal and Tumor Inui(u(e, l/nivcr.ity of Tcaa. Medical Center. Huuslon. ARTIII/R L. GROSS. M S., Senior !io- cher.rtv, Southwcu Research InNi(utt, San Anlonio, Te.. MOR'fON 1. GROSSMAN, hr D.. M D. Associate Clrniral hu~rnor ul Mtdi- renr, University of Cr dornia Medical (?n/er. I os Anaeles. (-ARI (' (1R1/1171T. Pn1), M1). Ar- t.nrart in /'hru../r.er and Pharmacof- 0L1, l/nwcrsuiy o( 1'tnnsylvama (irad u.~t 1.h..o1 ui MtJuone. Pbdadtlplva. JOSEPH J. GUARNERI. Pn D., Artend- int AbrroAw/osur Dnrctur. MitroAi- olory l.Aoraro.irr, Lons laland lew- isA-Hillside Medical Center. Queens al Center AfMiation, Jamaica. N. . FRANK E. GUTHRIE, Prr D.. rro/rr- wr, ud ERNEST IIODGSON. Pn.D., Aar4tawt RrsearcA Professor. DeO.rt- taeewt of Ewtoneology, North Carolina 3(a1e College. RakiRll. H. B. HAAG. M.D. t'ro/tssor of PAr- wr.cab>tf. Medical College of VirRWa, Ridwond. P. 1. HADDY, M.D. PM D, 1'ro/eawr .wd CA.irwsew o/ Physiology. llni.cr- aYy of Oklahoma Medical C'eaer, (1•- f.how. Ci(y. IOSEPH H. HAFKeNSCHIEI., M.D.. Di.enor. CrdioPrdwcon.ry Unit. The Lanlenau Horqi(al; Assotlue in Afrdi- clr.e. U.ivenily of Pennsylvania School of Medicine. PliladelPhia. BERNARD HANES. PN D., Dtporrmtnt J o HealtA Science. California S(ale niver.ity, Northridge. RICHARD l. HAVEL, M D, Assistant rro(etrur of Alydtrine. l/niversity of California Medical Center. San Fran- crsco. HERBERT R. HAMTIIORNP., M D.. ('hatrwr.n, Dr~+.rwunt o/ Sur~rry. University of Pennsylvania (iraduale School of Medicine. Philadelphia. IOHN A. HAYES. M.D. Auociate raAolorlrr. M.l/ory Institute of Pa- (loology. Boston city Hospital. Boston. CLARK W. HEATH. M D. Pro/essor of Mediriwr awd Dsrrcror of Health Strv- kes. Tufls University. Medford, Masa. PAULINE IIEIZER. PM D.. Research Arwciatr in Cytolo y and Cyt~>, htmin try. San Francisco ~nslilute of Medical Seiences. San Francisco. I.AWRENCH L. HI:STF.R, la., M D., Professor and Clwir.non u/ f IAsrrua r .wd (i'neauf..8f. Medical ('ullesse of South Carolina, Charleston. FIlOF. CUROS IIOFF. M/), M1). Iru/tuor and Chairman. !).•urow of IsytAtatrtc Rerrarrh, Medical College of VII(jlnla. RKd111Vnd. 76 I i RUSSELL L. HOLMAN, M D.. I.rwisi- ana S(a1e Universily School of Mcdi- cine. New Orkans. OLE A. IIOI.TERMANN, M.D.. Re- uarrh StitnNst. Lobrnd I atwruoty. University of Nare Darne. No1re Dame. Ind. FREDDY HOMBURGFR. M.D.. rresl- Trnt and DNtrror. RioResearch Inati- Iwe. (r.c, Cambridge. Mass. ROBERT W. HULL, P>t D. Professor of Asototsr.t Stirnces. 1•brida SIa1e University. Tallaraaset. IIT RFSEARCH INSTRUTQ ChicaRo. GEORGE IACOSSON, M D., rro/esson and Neod. Dr/+rtmrnt of R.dralogr. University of Southern California School of Medicine. Los Angeles. JERRY HART JACOBSON. M D. Dl- rrtror. Division of ElertropAls/ototy. New Yorl Eye and Far Infrmuy. New York. lU1IUS 11. JACOBSON 11, M.D.. Aseo- riatr rro/rraor u/ Surgery and Dirrrtor , of Surgical ReuartA, University of Vermont College of Medicine. Rur- linglon. MURRAY 1?. JARVIK. PND., Associate rrolea..n of rhrm.coioty. Alberl Ein- sleiw College of Medicine of Yeshiva University. The Rrons, N. Y. OSWALD R. /ONP.S. M.D. S(. Lules llo.pilal. New York. ANDREW A. KANDIfiSCH. Pa.D.. Sus Scientist, The laAson Laboea- (ory. Mat Harbor. Me. ARNOLD R. KAPLAN. PND., Dirrc- to.. Lrlorato.y of Alrbrat (:rnetirs. Cleveland Psychiatrie Institute .rrd Hospital. Cleveland. ATTALI All KAPPAS. M 1). Pro/tunr .nd Senior rAyskian, Tbc Rocke(clier Universiq. New Yorl, HRATCH KASPARIAN. M 1). Msist- .nt Director. Crdwva,rY/Or l.Aora- toryt Iwitrurtor in Mrbrine. llahne- mann Medical Cdktfe and Iloswlal. Philadelphia. tl 11111 KAT7_ rN D. Anoraur t'r../rs- aur of Soaiolargy, llnivcrsuy of ('lsi- cago. Chica.o. SHIRLEY 1.. KAUFFMAN. M.D., rrr~ /rs.or of rrtAuloty. S1a1e llniversNy of New York Oownsule Mcdical Cc.- (er. Srooklyn. ANCEL KF.YS, Pu D., Director. La1at tory of Physiolosical Nyskwr. Univer- sily of Minneso(a Sc" of Public Health. Minneapolis. IOSF.PH R. KIRSNER, M D., rro/tnor of Mrdsrisre. University of Chicago School of Medicine. Chicyo. JEROME KLEINERMAN, M D., Nt+d, Dtvision of Iatholosy RrsrarcA .w/ C.wsc.t Patholo9. St. Luke: Hw~i1al, Cleveland; trol rsor of rasAdo4y. Casa Western Reserve ll.iversMy School of -Alcdiciwe, Cle.el.rd. PETER H. KNAPP. M D.. RewtrA ho%ssor of Psychiatry. Ros(oo Uai- versi(y School of Medicine. Roa(ow, KENNETH P. KNUDTSON, M.D.. U.1- versily of Washington Mcdical Scbd. Seattle. ALVIN 1. KOSAK. PH D.. Auoclue Pto/euor of CAtmutry, New Yorl Utriveesily, New York. ROBERT A. KUHN. M D. Associate Professor. Dsvisiorn of Nt..rourstry. New Jersey Slate College of Medicine. Jersey City. MARVIN Kl1SC1/NER. M D.. New York University Medical Center. Naw Yort. CHARLES W. LaRE1.1.E, PN D., Au/at- ant rro/tswr of Envirowmeat.l Ny- #irne. Department of rrtrrntire Mtil- cinr. te/fersow Medical College. Phila- delpltia. AARON /. LADMAN, Pu D, h./euor .nd Chaaman ../ Anatomy. ile I)ni- ver.Ny of New Mesioo Schod of Medicine. Albuquerque. THOMAS C. LAIPPLY, M D. Iro/ts- wr of Pathology. No./h.eaern Unl- ver.ay Medical School. Chicago. ROGER K. I.ARSON, M D, Ch4/ ol A(rdrrinr, Fresno Counly 11oqUal, Fresno, ('ar. (i1/S1AVF. A I Al1RENZ1, M 1), Chief a/ A(tdarwr, St. Vincent Hoaplat Wotccstcr. Maes. 77

Family N) manifcsting the "cancer family .yndrome." A particulnrly valuable marker was found in the major histocompetibility aypem. HL-A, when their studies identiAed an asaocuatioa, indicated by higher overall relative risk, be- tween an HL-A haptotype (2-12) and cancer in Family N. The presence of carcit.oembryonic antilen (CEA) and SV40 viral trandormation of skin tibro- binu may also serve as important nurters. Findings of CEA in Family N showed a clear pattern, with the pcalest elevation of CEA in patients who had caocer, the neat highest ekvationa in their Arstdelree retativea, and significantly lower vahw (in the .ormd rasle) ia their aecond-delree relatives. The Mdinp . of SV-40 viral translorm.tioa in PasMy 0 were parallel to the CEA results. Retationships of the ADO blood oorp. /o cancer are aow under Intensive audy, as la tbe bepatiti.arocLtad aaipe.. LywcA. H. T. tl .1. An.rrk.n F.iwlfy IAyiklew 11(3)133-131, 1973. Other e.rr.rtr NNiod Cawoar Institute. FroaF the Departrns.t of Pn.eaiw Medki.a ud Public Healti>. Ctcilhto. U.ivenity Sc1oo1 ot Mediciar, O.aSR Neit. HPaLTH SERVICE UT1L.lUT1ON BY SMOKERS AND NONSMOK ERS This esptoratory study reports ow differeeaa in the use of heaHh servica, available through a prepaid health plan, by amoten, notamotera, and e:- amoken. A aampte of while men aed woreeR 20 years of age or oldcr, was studied lor tbeir uae o/ preventive and treatmeax facilities. Health eaaminatioorr especidly Automated MuUipb.ak Hea/th Testing (AMHT), were used least by .atottrs and moat frequently by es-enwten. By social ctaas, approaimateiy twice u ma.y upper aed middk claw anale smokers as nonsmokers or es- aawten look so health eaamiaatioe. A similar but wt so obvious trend was .u!leated io womea. Lower dar auak and femaM smokers had the lreateat percentages of persons taking .o heatth eaaoiutiooa. Frequency of visits to a doctor'a omoa was highest for rnab a.roten and femak ei-aaaken. Male amoken aged 60 years or older m.de far the highest demand of a11 a!e-ata lroups for hospital aerrioa, the most etpemive type of health aer.ice. Survey- iod their resutt., the wthon fed that eiprette .mokiod habits ought to be taken tato account in estimating Inodical care utilization aod coau that wlq be t:perisooed by a particular population. Oatea, T. W., Frkdww. O. D.. Stltner, C. C., Sieqelaub, A. S., aod Colke, M. P. tlcdk.i Cr. t 2(1 /):93l-966, 1971. Other a.rr.rtr U. S. Public Health Service and Kaiser Foundation Researcb Iartitnb. From the Department of Medical b/etbod. Rc.carch, Kaiser Foundation Re- aearcb tosutute. l)akland. Cal. I CIGARETTE SMOKING AND CHEST PAIN A total of 70.208 amoten and .ommoters underloing multipMaic AeaMh checkups answered nine self-admioiuered questionnaire itema about cha/ paia. Analysis of these questionnaire responses showed a greater proportioa of cya- rette smokers than .oaamoter. (l.r., averaloa of 1.6 timea more in wbita aea and 1.3 timea moro is white women) admittieg to nine types of cbe.t paia. Tbia etcea in smokers was greater in younger individuals, and applied abopA equally to aolinalite qed tsonanliaatike pain. The atnokieR/chest pain arocia- tion was aot explained by greater akoboi or co/ee eo.ar.ptioe, diwia:hed pain tolerance or leas reliability among amoken; aor did it appear to be anedi- ated chiefly by e.oe.s coulh, ahort.e» of breuh, coronary d'aeaae, or mtuculo- atcktd complaints in .moker.. Alttwuglt aanotera averaged mwm compl.iats thae .otumokera, che.t paiu resembled ckariy asatin!-related ayr.pmre~ such as couth. when Me number of each subject'a cpmpl.inta was co.eidered. The arnoker-to-oon.moker ratio" were remarkably airnilar within each race-aea group fot this divcrae eotketiow of chest pain cawptaiwa. 7bus, thia questio...irr b.aed evidence suggests that there is as aroeinioe of cigarette awmti.g wltb cbeu pdo. Sut boc.tre 0ia asaodatios was aot resVicted /o a Particulm tyN of pain and because none of thae asaorftd complaiuta were found etciwivety is tanoken, tbeae data aupat Uat the "7obaoco aaffioa" concept be di.cm*d or reserved for ran patienta with coronary heart diaeaa in wba. a.otisj eteaJly provokes at4iaa peclori.. Frlrlnw, G. D.. Sieqdaub, A. R. trd D.laa, L O. Awwetz oJ Iw/erw.l NeAk/we !3(1) :1-7, 1975. Other aMrr.rtt Kaiser Foundation Research Institute. From tha Departae.t of Medicat Me16od. Reaearclb Kaiaer-Perma.ew Madi• eal Care ProRas, O.tla.d, Cal. t 65 64

WAITER M. BOOKER. h1.D, lro/rs- ior end Nred. Drpn amrnf of rhrere- rolnly. Howard Universily, Wasli.s- lon, D C. TOM O. BOWERY, rsl D, trukldo Rnidre Lalooretry. CArwrlury Dr[+~s- n.eet, Nor1! Carolina S/ala Cdle~ Raleigh. . OEOFFREY L. SRINKMAN, M D., A.r Socuu rro/rsror of MrdJNwr, Way" S/ale U.ivessily School .1 M.dre Dctroir. ROBERT E. BROOKS. rw D, Aa.ocfw ho/rs.or / rAolo/yUnlversily .f Oregow Me ' Scboot ror(land. BARBARA R. RROWN, Prl D., CAk/, Esprrbwenrol rtychi.rry, Velerw a-A miniUr.Niow Hoyi/4 SquWedK CaL RAYMOND R. RROWN, hM D_ M/er er of Clinkof Onrololy, U.ivenily o( Wi.oo.siw Medical School. Madieoa JOSEF /ROZEK, Irl D, ho/rssw ond CMirwsen. Dr/rrmrnt o( f iycAolo{y, Lehigh Unisessity. BelNebr, !'a. SUE BUCKINOHAM. M.D_ Asdrtone rro/essor e( rrdattics. Colkp of roysicLns ! Swgcone of Colu.+bl. UdversNt, New York. BENJAMIN BURROWS, M D. Asso- cene Professor of Medicine. Uniretsily of Chicago. Clsicuto. E. M. IlUTT, M D_ Chief letAo/og4e~, Loa An/eks Cowlly Oerural Ho.pN.L Los Asycks. RICHARD U. BYERRUM. /ra D., h.- Cs.w o/ CAen.lstry. MiViW SUM aivenitr, Eart Lansing. SISTER M. EMILY CAHILL. hr D. Cheirwse. o/ Chen.Esr.y. Reti. CaUep, Wewo.k Man. BRUCE P. CAMF.RON, M D, 11M D. Howard H.r~ hre lnrtUrt., University ol Miand Scbol of Medici.e, Mia.il. Fla, WILLIAM II. CARNPS, M D, Unlves- aily of Uuh College of Medicine. S.I/ Late Cily. MARC-l/S N. CARR(N 1., /a.. rw D, Chief. Drrltlow of Ihern.eruloly. Tlb Brouldale Huepul Ceaer, Brootlylk N. Y. WILLIAM ALVIN CARTER. M.D. Auiuewr rroJruor of Medicinr end Micro6bloly. The Johns Ilopkins Uni- venily School of Medicine, ldlimore. LEOPOLD R. CERECEDO, hM D. rro- euor of IwcAnnisrry and Nrrritlow •ivecwy of Ioerto Rico School .4 Medidne, Sa. l.a.. CHILDREN'3 HOSPITAL OF LOS AN- OELES, Los A.Reks. SANFORD CHODOSH, M D.. AcJuent l.o/f.rer of MedKinr, Tolls Univef- .ily ScKool of Medicine, Boelon. (1.i- IIMed wrder Mwict Sepl, M D.) NAITlR M. CHOrRA, hl D, lro%e- tmr oJ CAews4n', No.IR Cardina AR- sktiR.nl ..d TecR+kal Slata U.iver- aNy. Or.erbore. SYILUAM O. C1.ARK, hr.D, DLecroe, !`s7cAopA.rm.cololt Reirrch Lbr.- rory, Veterans Admui.trat{o. Hoe'iW, Serld.edR Cal. HANS T. CLARK DSc, rro/euar o/ s/ocAemlurp Col Re of nysicians i of Cdumbi. U.iversily, New Sw~eo.K Yort. lAY D. COFFMAN. M D. Srctlon Head. Peripheral Yoscrlr Deprtment. University I/o.pild, Bostoe. DANIEL COHEN, D.V.M., M.r.H_ A.- druww rro/rur of Yrterlw.ry Epl- drn.1o1ogy and Public Heelrh. Univer- sYy of felwylv.nia School of Veur- inarY Medici.e, tUitsrd+clpdia. JULIUS H. COMROE, /., M D., Dbee- Ior, Crd/or.resdor Research lnuitrte, U.ivenN' of Califor.ia Medical Ce.- /n, S.. Prawcaco. DEAN M. CONNORS. M.D., Auocl.ue DLecsvr of t.boruory Medicin., St. Marr's lioeplal, Madisoa, Wie. PHILIP COOPER. 1011.13, Clfnlc.l rro- /easor of Surgery and Director. Swll- cd Laboratory of Cellular rhr+iolon Alber( Einslein College of Me•licine o~ YeJi.a University; Chief. Sw~icd Srrrier, Veterawe Adrni.isiralio. Flo. Piral, Tbe Rro.s, N. Y. IOHN F CRAIOHEAD. M D. r•ro%s- sor of PetAololy. University of Ver- mool Medical Scsool, Bwlio/4i.. 74 I I 9 ROBERT L. CRAIN, MD., .(rsiuent Professor of Sociololy. Univenily of Cbeca/o, Chicago. T. TIMOTHY CROCKER. M.D., f•ro/rr- sr of Afrdtnne. Universilr of Cali- (ornia Colkge of Me.diciwe, lrvine. CECIL E. CROSS, Research DrP.rtmenr, S/. Joseph Ilospild, Burbank. Cd. ALBERT DAMON. M.D., M.D., Lec- urrrr on Asrhroploly; RrurrA Asso- cieu iw Mrdud Awthroyololr. rea- body Moseom, Hward Unrversily, Cambid/e, Maa. THOMAS R DAWBER. M D, Associate I'ro/euor o/ Mrdicine- Rouon Univer- shy School of Medicine, roslon. R. F. DAWSON, hM D.. Professor of sot- ony, Cdwnbia Universily, New Ywt. IOHN P. DELANEY, M.D. M D., A+- .ociere Professor of Swlrry. University of Minnesola, Mirneapolie. ANDREW S. DIBNER, IH D., Esrc- wire, t.ycAo-Rrsrrrh, TU Age Ce.- /er of New En/1and, Inc. RoMon. EDWARD F. DOMINO. M D., rro%s- sor of rA.rwr.cololr. Univerwy of Michi/an, Ann Arbor. RAI.rH L. DORFMAN, ltM.D., Director of l.bor.torirs, Wo.cesler ForndNiow for Eyerimenlal Bidody, SMew.bry, Mass. JAMES 1. DYAR, hr D.. AssW.wt rro- ,etsor oJ Jliololr, Bellannine CoRqe, Looisvilk. Ky. RICHARD H. EARLE, M D, Chief. rrlero,s.ry Function LeAOrrory; As- .iueM rro/nsr oJ Medkine. Univer- .i1y of Chicago. Chicago. JOHN W. PCKSIEIN MD, Assistant Professor of fntrreej Medtnwe. S1.te Unircrsi/y of lows College of Medi- cine, lowa Ct1y. BERTRAM EICIIEI. B.S., D D.S Dl- rectr. lnurtrtr of Srumetololrcel Rr- uerch, Science Resorrees Foondalion, Walerlown. Mass HYMAN F.NOHI BERO. M D. Atrrnd- lnl lhysicren, ('cdars of Lebanon llw- pilal, Los Angeles. CARI.TON K. FRICKSON, ra D., A} so.oete rru/rnvn of rhoneocololy and T.rsicoluty. The University of Kam.e School o( Karmacy. L.wrenu. HENRY /. ESBI:R, M D.. ReurcA /wr- nrrnofo/iu. Mason Research IsWiIW, Worceuer, Mats. JOHN R. ESTERLY, M.D-. )(ssoriue Professor of r.thololy. University of Chicago rrlleAer School of Medicine, CAicayo. //ANS L. FAI.K, rn D., Adjunct Auocl- ote rro/rrsor of r.thololy. University of Soulbern C.1t(ocnia School of Medicine, l.o. Angeles. DANA L. FARNSWORTH. M 1)., Hrwry K. Oliver Professor of Nyrrrnr owd Director o University Health Serrker, Harvud Jniversily, CarnbidAe, M.... FRANK C. FEROUSON, 1.., M D. Cheirwren of rherrnecololy. The AI- ba.y Medical College of Union Un{- versily, Albany, N. Y. TIIF(>DORE N. FINLEY, M D.. Dbee- ror of Pulmonary Rrsrrch l.bor.try, MorxM Zion Hospilal, San Fra.ci«o. WILLIAM 1. FISHBEIN, M.D., Chief o/ Ep.drrntololy, Chicago Rond ot IkaM16 Chicago. EDWIN R. FISIIER, M.D. DMecror of Libr.twies. SAadyside Ho.pilal• rrr swr of t.rholol~, UniversN~ of PNlsbwA! School o1 Mcdici.c, M4r bwlill. RUSSELL S. FISHPR, M D.. UniressY~ of Maryland Scbool at Medki.a, ial- limore. B. L. FRFEDLANDFR. M.D., Dlrecrr of Cencrr Reuerch. Moom Zion Ho.- pla) and Medical Ceeler, San Pra.- tisco. FREDERIC A. FREN('H, A B, Dirrc- tor of C.etrr Chrnrothrrepy Revnch, Moonl 7ion Ilospiral and Medical Cenler, S.n Francisco. JACK FRFUND, M D., Autstenr lro- /esnr of rhrmerol..l1. I(edical C.o1 k/e of Vrr/inia, Rrcbmond (ill BERT 11 FRIFDPII., M 1). ChI:J u/ rethol.qr, St. Vincent Ilosp i~ Worceuer. Mau. 7S

It. Tlre Respiretory System CYTOLOOY OF RESPIRATORY EPITHELIUM AS A PRFDICTOR OF RfSPIRATORY COMPUCATIONS AFTER OPERATION The morphologic integrity of tha etliated tracheobronchial el1ithelial celh sote in smears obtained withia 10 aaYfuta of the onset of anesthesia and quaa- titated by a scoring systern, dslsrioratas pr+ogresaively with increauing smoking habit and oonstitutea tha moat aeaalliva iadea for the prediction af dimarished rssiqanca to the strea of anesthesia and .uryery, as well as of incllrient chronic obstructive lun6 disew la semken. CMeaic cigarette srrwkin6 har beee shown to alfen the vac4oeroochial ciliated epitlelium, causing a strala on the muco- ciliary traesp9rt system wk3ch evennsaUy results in broachid.r obwructioa. la- (ectioe is invariably auperirnpoasd ol bbckage, and if progresaive, leads to the devebprnest of ct.roaic obuructive pulrao.ary dise.sa. flecause kuag function tests are not suffkieetly sensitive to deted early airway dama6e, direct viwalita- tion of nsorphologic changes ia cilialed oeds seemod to o/Ier a pot:Mia/1y mors sensitive iadex of the eakM of rnuowal f.rol.emeN. T6w, the .utAots wc- tioeed cytologic material directly froe. the ewooaal surfaces of pntients under- going general endourscheal anesthesia prior to surgery. Thia particular popula- lioo was selected because of tha diflkuldes iavolved in obtaining uncontami- nated sputum cells from awaka wrbjetu. Noae of the 111 people iocluded in this study bad aay symporro of pulaaaary, disease. Correlation of cytomorpho- bgic mea.urcments with the postoperative pulmonary complication rate amon6 the various groups of amokers was very close. Only a few oonsmokers had post- operative pulmonary coreplicalioa. (7.9% ). but this rate climbed steadily as tla amount of smokie6 Increased. reaching 43% io very heavy smokers. CeUu- lar morphologic integrity deleriorated with Increases in daily cigarette conwmp- tioa. Preoperative peak eapiratory f)ow rata aad tMrod vital capacity were u.- dfected eacept ia very beavy IrT,oken. The authon wnest that those in whom Ur peranta6e of normal cytologic factors decreases below 60% should be advised 1o slop srnokie6 oe M kaN to reduce their eiaarette aoowmptioa S CAdon, I.. Tayyab, M. A., aad Rat.wthas. CAeis 67(1):72-)S, 1973. Pros the Deparuneat of /lnesthe.iolopr. Albert Einstein College of Medicine of Yeshiva Uaiveraty. faroaa, N.Y. DETERMINANTS OF CHRONIC OR.SI'RUCTIVt? PU(.MONARY DISEASES IN PATIENTS WITH INTERMEDIATE LtrVE1S OF ALP11A,-ANTITRYPSIN Among individuals with abaorm.l conc.entrations of e,-antitrypain, Ihe MZ heterorygotes are the mou common of several phenolypcs associated with ia- termedute conuntrations of the prote..e inhibilor, and their propensily to develop chromc obstructive pulmonary disease (COPD) remaine eoouovenid. 24 I This study attempts to determine if smoking or kukocyte cotwenlrslions of protease and elaaase are significant delernsinants of COPD in persona over 40 who have the MZ phenotype. Subjects with normal (MM) or MZ pheootypc., 40 years of age or older, were grouped according 1o 1he presence or absence of COPD and to their smoking history. Comparison of the two genetic groups red veded a very high incidence of COPD (70% ) amons the heteraay fious smoken aa opposed to a significantly lower one ()S% ) among the homosygous smokers. No diflerence in the Incidence of COPD was noted between the two phenotypes NsonR the subjects who did not smoke. When the activitin of leukocytic cnhepains and elastase were measured in order to determine It these enzymes were related so 1he development of COPD amonS older hetero Zy{otes. she re.ults did nol indicate a population of patients wqh this type of enzyme deficiency. T:xse data suggest that the MZ heterozygotes who smoks are much more likely to develop clinically significant pulmooary disease Ih.a either MZ nonsmokers or MM ,moken. The pathogennis of pulmonary die ease in these persons, however, cannot be eaplaiaed oa the basis of the pro- tease activities studied. Klaylat, R., Fdlat, R. and CoAsn, A. P. Anstrkan Rerirw o/ RrsPlnrory Disease 112(1) :71-75, 1975. Other srrrsrts Nalional Heart and Lu.s Institute. From the Medical Service. San Francisco General Hospital; ahe Pulaso.ary Specialized Center of Reseatcth. Department of Medicine, and the Cardbvaacu- lar Research Institute, University of California; and the Department of Medi- cine. Presbyterian Medical Cenler, Saa Fraaicisco. THE INTERACTION OF a-1-ANTTTRYPSIN WITH CHYIrOTRYPltN, TRYPSIN AND ELASTASE Although a-l-aatilrypsin Is known to Inhibit many proleolylk eozy.w aed its jenetic defkkncy has beea associated with the devebpment of amphysenu. Its eaact mechanism of actioss remains unknown. One hypoahesis suggests tt.N the molecule has two overlapping inhibitor si/es, one containing aa artioyl reaidua which binds to proteases that cleave peptidea at such a poiot, and ths other ooa- taining an aromatic amino acid or kucyl residue which binds to proteaaes Ihal act a1 one of these two (oci. In addition, it ia propoud. Ihere is an inhibilory site which inactivates son.e aspecs of the active site of serine proteases. Other reporu indicate that the enzyme actrvity can be blocked by makylation and, therefore, suggest that there is a lysine al the lrypaia iohibitory site. -Ihe preaeal study ea- amrnes some of the characteristics of the interactions of a-l-sntitrypein w/th three of the enzymes with which it reacts rapidly: chymotrypsin, trypda and elaslase. 7 he di»ociation constant of all three ensyme-inhibitor oonsple.n was too low to measure kinetically, but wae esumated lo be <S X IO sM These results indicate that a-1-anlitrypsin is tightly hound to the three enzymes studied, but do not allow discrimination as to the oature of the iahibitba. Addt 25 16

1 Active Projects Following ia a list of the principal inrestigators, or instituttons, of projects under way or activated in the period since the jrevioua Report, together with the respective project titles. Coaopkted projects arc listed in a later section. ORtNCR~~~ A1~OR LF.O O. A1OOD, Pf D.. rro/eaor o/ RiocM/wlwy .wI froi. R,.rrrA, Ce.- 1er /o. Mw Rescarcl, Tle Uer.enN7 of Rodra.ee Medical Ce.ur, Rocfsr w, N. Y. JOSEPH C. ARCOS, DSc, f1o(ea..r of MflKi.e, T.lewe Us.reniy Scttool of Mediuar<, New OrkW. DOMINGO M. AVIADO. M.D. rro/e,- ,o. of rArew.rolof~ Uttivenk~ of l+ceruyl..r. Sclod o~ Medici.a sbclr4.. RENIANIN BEU- M.D. Diecto., Nen iworfre Al/ae Srrh. Veter.a. Adrniok. tr.liw OW}slica Cliac., 1104400. (Now E.vriuu ) WILLIAM E. RENeD1CT, M.D., AuW- .wt rro/.uar of rrdi.tc.c,. Uwi.enMr of SowAen C.iifo.wia School of MeA.- ei.e. DivWo. 01 Henulologf s.d Med kd Oe.ark>L Ch46cr Hospital ef Las Aqek. La AWks. RICHARD 1. 11NO. M n. Iroleoor of MeNclwr. U.i.asit~ of So.lher. Ca4- forwis Sc~ool of Idedici.e, Los Ar.- Y4WwR ADori.u M /bw.r/ic.f rZLe.lw~. Cdifor.i. Lrkrle of TeclsooloSr; DLector of Crl/o1oty .w/ Iwtrowrra/ M.Ilclwt, Hwtiyloa Memorial Ho.oit.t, he.dc.k GI. OUENTIIER ttaODEN, M D. A..oci.te rro/r,ao~ o/ M.Irciwr; Aa,Lawt DrK- ta , Grwa.l Chwko/ Rrurc6 Ceirar. Te.+p1e Uwi.er.itr Heak! Scie.oa Cs.- le., Mil.delpkia. A1.RERT CAST/IO, IhM D. Dlrntor, Hon w.owr l.br.twyAuocWe rro/euor of Mrtkiar, ll.i.eruly of Mia•1 Sclool of Medicine. Mi..rl. Fla. JACK CI/ALON, M 0. Aa.ocWr rro/ts• ,or of AwruAr,loloq. New York Ud- .er.ity Med&cd ( 'eater, New York. lltOfR(.T TR1 R lMl..itKd elecu of .kwis ..d rperi- 40.. SY.rrSlwk eR.c1s of polTcrdk y*ttiOr sm elilfoYmMem nro..rSM ,I a.i.. 1•meri.l «preuors d metabolic aai.aioo of .iuwwi.es Iwire.a. of eipretle s.oke ow rylr.o- ..rY s..p6ywna s.A Eeorc>tosp.rw S.. RoeR Clsrks L. Malip.at Ir.r,.for.wloq awuaenesis aYd tibrLos~w ~rod~Miw o( ciprello roks ooedewte fr.etio.. Nsel..ins of /hs .etioo of wton .m.oaidt a. Mlsrorckrosie FJ.er of .icotir a.d ciµrene s.wts o. sK7etls acreliom Niaoli." i. blood: deN«tioo by r.dio- lw.wo.nal Lyys. 1n u.ctstobro.cl6w cttololr EOldcs~ of trsct.cobrooctfl.l eu111- .uck.ulow 66 I f t I t•RINCRAL INVRdi1CATOR OR INSTtTUT10N CHARLES O. COCHRANI; i/.D.. Mnw- Ier. Scr~yp. Cli.k a.d Reesara Faw- daliosL La lolt., C.1. ALLEN a. COHEN. M.D, 1'rt.D, Aadu- .wt rro/ruar of Mrlicb.r fw Re.Newce. Uni.er.ily of Califorw School of MeA- 'ci.c. S.n Frs.ci.co. (No. Auarlre rro/ea.or of Mrliclwe, 'fewqle U.i.ee- twr Hc.Nlt Scicaoa Ce.1er, Tlilde~ CAlR ROI.L B. CROSS, M.D. Aaoclete rrofc„or of Mt/iriwr onJ Haw.w rAroolftl: DYrc.o., Secrlow of rrt- w.o...y M.Ifx lwr, Uwlverell~ of Cdl- forai. 3ciool of Melicis„ D..Y. H. FRED DOWNEY hr D. As.i.r.wr rro%„or of rAt>~~, Usi.ertilr of Tear Hc.Nft Sc,ewo. CsMer N D.R.a; Diredor, Crlbrosc.dr Rr,ercA, Car- dio}W.row.ry LnitwK Matrodirl Hos- rital of D.IIeK Ddl... WALTER t1. ESSMAN. M-D Rs.D. rrof.DOr of r,,cAo/oay o~/ ilocAewr Wr7. Quee.s Collqs of Uw City U.i- •a.itS of Ne. Yorlt, FMrN.R. HANS 1. EYSENCK. M.D., D.Sc Pro- /euor of Psychology. l.ril.le J hf- eWl Ud.enUy .f t.os>/seti 1.0g- a.~ `~rd..e. WILLIA61 H. FISHMAN. lN.D. rro- /t.,or o/ raAofot': DMector, Tr/ty Co.cn Research Ciwar, Tdu U.i- .er.iy Sc~aol af Me~kls, tileao. LAR3 FRItiERO, M.D, rrofe,wr .wf CAstrwuw of EwrMowwwwa/ Hr~kwr, Tl.e K.rofittda 1.MMrts, Sloc\ao1., Swede.. OARY D. FRIEDMAN, M.D., Sealo. E~ wriofa~lu. Dep.runeM of.Medical Melhod. Research. K.ieer FowrAMiow Reeeuclt 1..1ewe. Odiswil, Cd. OERAI.D 1. 01.F.tCH, M.D.. Caurb.wl Iw MfI1cIM, Research LeborNory /ar Aller~ic D'ue..eR Mayo Clwc, Rocles- 1er, t~li.a LFONIDE OOLDSTEIN. D.Sc.. A,.o- c/ae rro/ruor o/ r.rtA/strJr, Iwstilwe for 6lewld Hcah\ Sckwcee, Cd{rp of Mediciwe A lkntiury of NeW lereef, Rwjcrs b/edscd School. PiKaer.y. 1`20/t1t.T TTIls Tle wediNiom of infl.rn.alorL MkrT of rh.r. Tir Rertetk defea in dp6.li.tkrypi. acficieM }.tieMe Cloarepo sww\e stl.w os oerW...pc1e of re11r.R.Naedis. Flecl..t IOb.cco siDile .rrd miOd1Y eto ouro.ny collateral bloott rb. 3rrdlw ef dooli.e scttom tpoe reoery coraWsiio. MM.raik reepor /o eM...ae6.eso s.ot. Wasstlo.. Tl. LMrMa.oe ef 1Y ti.otiy tut,lt Ca.oer /6ewa W+ Cro1Ns .61ch e..! ~ 401111. M..io0 arc caonr PTidewb{o/kd radJes ott Ilte o.v l..L w swim re.islrr Ct•.r.de.iaks of s.wltsn .d .o.- ..mtters 7Ws respINry fe.dbilay M.Ay H,Per.eslUvMy 1o awlRer from /ol.oae .s a f.cws i. /b p.ut.opsoeY af cl+roeilc 6ro.clili. TM "ct•roale sJrnIMs e«.N." ewa a,aWt+: a leh..ior.l ./A ekaroe.oetsbdo- p.Ntic ..aly.ie of LOucod ../ etow Leepr t•yper.af..tioo lo rW 61-

macrophase systerns in respiratory defenme. In addition, this study oRera meth- oda to asse» the susceptibility of each defense aystem to etperimental coedi- tioos of suggested clinical and 'mdu.lrid aip,ifkaoce. Guorneri. l. !. In: Underkofkr, L. A. (ed.): Devebjir»ents Iw lndatrtrid Alkroslolory: rro- ceedinti oJ the TA1rry-Fbrt General Meetlng oJ the Society Jor Industrial MkrobloloPy, Washin6ton, D. C.: Aasuicaa Institute of Biological Sciencea, 1975. vol. 16, pp. 2)2-24t. O/A.r asr'prlr Natioaal IeMltsrl.o( ABaQr.nd Infectious Disease. Prom the Dep.rtment of Pathoio6y, Queer Hospital Ceoter, Loe6 Island lewis6•Hillside Medical Center Affitiatioss, lasaka, N. Y. POSTINFLUeNUI. PULMONARY LESIONS IN VITAMIN A DEFICIENT MICB People aed aeimab with vitarni. A de6cie.cy develop squamas. aed kera- tinizin6 mnaplasia of the msscosr ancmbrara 1s the r+apirMory tract and other organs. Sinsilarly, siroe the 19at-19 p..deswie. hyperplaala n.d squcunow meta- pluia of the tracheoboncbial epithelial lieisg and alveolar epitheliditation have becn repeatedly observed in individuals with influenra A virua iefectiooa, whether or not there were cornplicatiorr. Mioe given sublethal influensal infea tion. also show pulawnary lesions reaanblin6 those found in fatal human easa. It has recently beeo shown that the talent of aquamoua metaplalia and kera- tini:aion of the bronchial lining membrases varies with the vitamin A nutri- tional Malus of the infected animal, being aignifkantly greater in anirnda lo which the hepatic vitamin A content was low or absent. In this Mudy, a more reliable method for producing vitamin A delkkncy In mice was used. There wae no aigeificant di/feretscea in lung vinr growth and antibody response be- tween the.ormal (RA), deficient (NA) or Ityper (HA) vitamin A diet groups of mice. Eplhelializatioe of the .Iveol.r ducts and alveoli due to peripheral growth of regenerating bronchial epithelial oe1Y occurred i& all postinAuenzal ksions reg.rdleaa of diet. However, the posti.Buea:al ksiooa ia NA mice with .o liver vitamin A showed e:teesive epitbelial .oduk formation with si6d- Bcaetly more .quanwus mt/aplaaia and ker.tieitatioa tham was aees in the Iunp of mice on RA and HA dieu. The importanoe of the animali vitamin A status in determining the estent of puanous metaplaaia and keratinizatioo is poaioDuerud ksioer of mice was emphasized. Looru. C. 0.. Hardy. l. D. aoA Stieso.. S. P. 1.: K.rbe, E_ and Park, ). F. (edt.): Esperlwrentd [-np C.ncer. Cardwo- tene.ls and Sloauayi. New York: Spriotiet-VerlaL 1974, pp. 265-273. OtAer support: Howard Hu6hea Employea Give Once Club aed the Hastinp Foundation Fund of the University of Southern California. I:rcxn the lkpartn.enta of Mediclne and Pathology. lloiversity of Soulhern ('alJo.nu Schod of M.dra.e, Loa Angeles. I I REGULATION OF BRONCIIOMOTAR TONE DURING ANES-IIIP-SIA This artick reviews a nesw classifkation of bronchomotor machanisms formulated (or 1he bronchodilalon .nd antiasthmauc drup. The manner in which bronchospasm may develop in the anesthetized patient and the cRecta of anesthetic agents are discussed within thu classtfkatp0. Htre, broochomotor mechanisma are divided into eight groups with relation to anatomic location and pharmacologic response. This particular system is also based on results obtained from investigation of the bronchopulmonary effects of nicotine and cigarette amoke. Some of the mechanism., however, have been denanslrated only in animal eaperienerqa and their occurrence in the human lung remains hypothetical. The various groups are discussed under Ihe following headinp: (1) Refletes Involving the Medullary Centers; (2) Bronchomotor Asoa Re- lktes; (3) Bronchomolor Mechanisms Involving the Autonomic Gan{lia and the Adrenal Medulla; (4) Chotiner6ic Reupors in the Airways; (5) Ad renertlrc Receptors in the Airways; (6) Rekase of Ilislamine and Other Bronchoactive Substances; (7) Musculo/ropic Receptors in the Bro.chial Muscle; and (t) Mechanisms that Influence Airway Resistance. le the last part of Iha review, the author discusses several groups of pharmacologic asema used in anesthesia - inhalalional aneahetia. intravenous anesthetic aed ad- luvants, other central nerwus system depresaanls, local anesthetic., aad auro- muscular blocking drugs - with relation 1o their effect on several of the pr.- viously discussed bronchopulmonary featurea, parsicularly cholinerbie reaptor., adrenergic reoepon, rekase of bronchoactive substances, and muaculotropic receptors. Avlodo. D. M. AnrrtAesioloty 42(1):61-b0, 1975. From the Department of Pharmacoloq. University of Pennsylvania School of Medicure, Philadelphia. HUMAN PANCREATIC ENZYMES: PURIFICATION AND CHARACTERIIATION OF A NONELASTOLY7IC ENZYME, PROTEASE E, RESEMBLING ELASTASE Usin6 activated eatracta of human pancreatk tissue, these ievsali6uon have isolaled an enzyme component which has many striking properliea In com- mon wah porcine pancreatic etastase, although it has no appreciable elauofyric activity. 7 his paper reports on the purification and characterizuion of this e.• tyme, designated protease E. 7ht purification procedure included ult fracriona- tion followed by iontschan6c chromatobraphy on SE-Sephadea C-2S and on DEAE Sephadet A-S0. lhe homogeneity of this eniyme was demonatratal by disc ekctrophoresis and by sedimentation equilibrium centrifugation studies A compari+on of human prowcasc 1: wqh porcine tlauase reveals a high degros of similauty bclween rhe Iwo prolerses with respect to inhibition by acuve- site directed peptKk chluromerhyl ketones, stabdny, decreased susuptibility to 32 33

mast cells in wspcnsions of fat peritoneal cdb. A correlation was obtained be- tween the binding of activator and release of 'H-serotooin at low concentra- lioos of activator. It was shown that activator binding was substantially en- hsnced by Ihe release process itself, thus denwnsuating that release of amines esposes new sites for binding of activatot. Saturation binding studies using compound 48/ t0 indicated that approaimalely 6 x 10'• mokcules of actival.x could be bound per mast cell under conditions In which release of vasoactive amines occun. A third mas/ cell activator, polymyaia B, was shown to compete with compound 4E/A0 for binding to t.ast cells. In addition, a technique has been described for determining aenrraldy the release of amines from mast cells. 'll-serodosia was incotporaled in mr1 cells /w vitro and specifically re- kasod by a6eata which stimulab tb eara. Morrisoa, D. C.. Ro.er, J. F., He.ro.. P. M., and CocAraw, C. G. TAr /orrn.l o/ Immwwobty, 112(2):S73-S62, 1974. 01A.r.rr'.rtr U. S. Public Heah1 Satrioa and Arneriea. Heart Associatlos. From the Departmea of Eaperineatal Patldogy, Scripps Cli.k and Research Foundation. La Jolla. Cal. THE INITIATION OF MAST CELL DEORANULATION: ACTIVI7 Y AT 7IIE CELL MEMBRANE The recognition process which elicits a generalized Inflammatory cell re- sponse to lissue injury may be reurrcted to the cell membrane, with the sub- sequent iedirect Uaosler of in/ormdan to the interar of the cell. Or, in the abaence of a membraae, permeability barrier interaction of the activator mok- euk may be mitiated by tht: direct uawler of information as a result of the intracellular incorporation of the activator molecule. Vatious stimuh, including hnnwse compkaes, an.pbylatoairr and polymyxin B, have beee shown to cause de6ranulatioa in seutrophila, basophils awd mast all.. If the mechasism by which cells are stimulated is to be fully understood, it is imperative to de- termioe whether or .ot slirnulatioa ol the cellular cytoplasmk membrane by low aokcular wei6ht stimuli is suIDcieN b i.itiate a cellular response. By covalemly bindin6 the low moiecul.r weight nust cep activator, polymyais B, to a. insoluble matria of Sephaross 40. the authors demonstrate bere that mast cells in preparationa of rat peritoeeal ce1M bind to Sepharote 4B•poly- myaio B beads, but not to control beads. This isteractioe at the cell membrane stimulates degranulatiom ie the bound ceBs, rtyultiag in the rekase of bioleoic amien. Morriaoo, D. C. Roser, l. P., Cocb.wr. C. G. and Heoaoa, P. M. The Journal of Immunolop 114()):f66970, 1975. Other.urprtr 11. S. Public Health Service. From the Ikpsrtment of lmmunopatholM, Scripps Clinic and Research Foun- dation. La Wla, ( al I I THE ARTHUS REACTION: A MODEL OF NEUTROPHIL AND COMPLEMENT-MEDIATED INJURY The Arthus phenomenon is a tissue readion produced by antibody a.d aotigen, which activales cornpkmesN tompoacnts and causes neutrophilk Muto- cytes to accumulate. This reaction has served aa a model of acute immunological Injury of tissues from which a great deal of information o11he infiamm.lory pro- cess has derived. In this boot chapter,lhe authors consider the ArtMr reaction from these standpoints: (1) production of the Arthus reaction; (2) antibodw i.- efficient in provokin6 Arthus reactions; (3) eridence favoring the role of formed elements of the blood in the Arthus reaction; (4) socumulatios of neutrophih at aites of imnwnolo6ical reactions; (5) iejurious eoostkueala with- in neutrophils and structures iw tissues damaged; (6) the effect of certain agents that influence inflammation; (7) comparison of the Arlhus v..culitis wit\ other inflammatory vascular reauiows, and (fi) healias of Ihe Arthus reaction. la summarizing these obsrmations. It appears that in the Arlhus aod related re- actions the neutrophil has emerBed as a cell of critical irnporlanos. Removal of newrophBs haa resulted in eompk/e or .early complete abroptioa of Mnw tural injury. The mechanisms by which aeutrophi4 eater the site wl.ere a.1ip" and antibody have reacted are sow at kasl partly understood. 1s ma/ nao- tions of the Arthus lype, depletion of complement or sao of antibodies 1hN do iwt bind complement elRciewty results i. diminiswcd aecumul.tiom of .eutrs phih. Two means are understood whereby complement can effect migratio. of neutrophils: chernotaais and imnwne adherence. Both may play a role i. Ur Arthus-type reactioas. Neutrophib on uiawlalion by immu..olo6icd auteplr release injurious cellular Btanular constituents to the outside by a proonr of elocytosis. A variety of ptoteolytie entyma have been measured that ad os slruc(utal substrates in vessel walls: the basement membraaes, elastic (aasiaa, and collagen. Other reactants such as eationie proteins dfect vascular perer- ability. It may be. U/erdore, that thae eoaalAueou produce much of tha lesbm that defines the Arthus-type reactiooa. CocArane, C. G. and lanoQ, A. In: Zweifach. B. W., Oranl, LL and McClusky, R. T. (eds. ): TM /w/Iw- rnatory rroceu, ed. 2, New York: Academic Press, 1974, vol. l, pp. t3-162. OtAer.r'prtr U. S. Public Health Service aaid the Americas Heart Aasoci- atioo. From the Department of Eaperimental Patbolop, Scripps Cliok and Reaeani Foundalion, La Jolla. Cal. ANTIBODIES TO COLLAGEN IN PATIENTS W1T11 EMPHYSEMA (N 422 patients with emphysema, approaimately 70% had aetibodiea against denatured colla6en, whereu only 9% of normal controls matched tor ate, sea and ethnic origin had these antibodies. Patient titers ranpd up to 1:16 sa s9 I

Iality. Future hopes ue centered on circulatory assist devicd, primarily those employing counler-pulsation- fin#, R. !., Tillmano., H. and Fauvel, l.-M. In: Malioin, T. 1. et. d. (eds.): Acrre F/uld Replocernent iw the Therapy o/ SAocR, New Yort: Str.iton Intereostisenul Medical Book Corporatior., 1974, pp. 23 3-239. Oth.r a.rr.rtr Hoover Foundatioa, Wri& Foundation and the Gou:d Dock Fund. From the Huetingtoa Memwial Iloapital, Pwdeaa, Cal.. aed the Utriversity of Southern California. (.os A•pka. METADOIJC EFFECTS OF ALCOHOL ON THE HEART The authors follow the elioio{y of alcoholic cardior.yopathy from i•Nlal descriptions to the active area of research that it is today befoa susunarkisR their ows inveatiptioas isto the cardi.e effects o/ proloa6ed ethaool admi•is- tratioa ie the dog. As parl of a brief discurion coeeersing Um era:haei.ms of myocardial contractility which dalit be disturbed, they dao comider tbe possible effecu of ethanol on the sareoplamaic retkulum, emitocbon9ria and oootnanik proteins. 7Leir owe studies indeed indicate that this alcohol is most Gtely directly 1o.ic 1o mitocho•dr* aa suggested by sucb significant functional changes as dimioutioa in: (1) milochoedrial NADdependew iaociuate de- bydroycoa* (NAD-ICDH); (2) t.itoct.ondrial oayges consumption and res- piratory, eoatrd indica; asd (3) myocardial ATP eontest. That myocardial eoetr•dility is still aornul after three moatV of aloobol istiestioe. however, is spite of serious biochemical aller•tio.w i..rilochoedria, suggests that it is i.- depende•t of the i•tegrity of atitoebo.drid fwelion. Prolonged ak:ohol inaea- lios d.o seemed to affect cakwm (Ca+f) ei.di.g a.d uptake. Disturbances in Ca++ tr.rpon simitar b thae /orr.d (u tuimaM wrllr myocardial lailure were discovered afler alcohol eapowre. witr both the a•reoplasmic reticrrlwu and the mitochoedria sbowiel diori.iied Ca++ binding and uptake. Because changes in s'yourdial coetractility do oot develop until long .f1er ethanol e=- posure. it is suggested that these actually depend on direct ievolvement of the contractile elements of the beart such aa is found i• both acub myocardial i.cbemia and hereditary cardiauyopathy of the hamster. The effects of an even more prolonged period of eMand satpowr+ (about two years) are eow being studied is order so test this premise. Sing. R. 1., Tillreaens. H. and lkeda. S. Awwds o/ tAe New York Academy of Sciewces 252:243-249. 1975. Other nrrprtt NatioaalleMquW of Health. From the Iluntintton Memorial Hospital. Pasadeoa. Cal.. and the University of SoutAcro Cddurnu, I,o. Angeles. I I EFFECT OF PROLONGED ALCOIIOL ADMINIS7RATION ON CALCIUM TRANSPORT IN HEART MUSCLE OF THE 17(Xl Previous ob.er.ations suggest that one primary myocardial aberruios which occurs after proloajed ingestion of alcohol is a biochemical malfu.ction 01 mitocboedria accompanied by ehanges is calcium metabolism. This study is maioly eoocerned with the effects of prolon6ed akohd ingealion oa t:akium binding and uptake by sarcopla.mic reticulum a.d mitochondria, and with bow this may relate to alterationa in mitochondrial respiration and cardiac co.- tracli6ly. In dop, calcium bindins and uptake by sateoplasmie reliculwn and nitochondria declined alter sia moMhs of alcohol indeation, suggesting a di- minished aBrnity of the reticular and mitoclrondrial membranea for calcium ions. The endogenous calcium content of mitochondria and aarcopla.mic re- ticulum alw decreased. Yet, prolosted akoAol admiaiMralion /aikd to a11er cardiac contractility, although contraction and relaxation kndcd to diminish following an6iotcnsis administration. These resuMs illustrate that in the rtku- lalory, mmechanism of cardiac coNraction or relaxation involving myoAbrdlar eakiurw Iranaport, oee uep la weakened is dogs maiwaiood on ako6ol tor probeled perioda of time. D/ns, R. !. er J. C/nW.Nwr Researcb 3S(1):33-78, 1971. OtAor ar'r.rtr America. Medical Association ErAucatioa and Reaearch Fou. datios, The Hoover Fou.dation, 1he Noeri. Fouodatio., arad the National 1m stituta of Health. From the Huoti•ktoa Memorial Hospital, rradena, Cal., aed the U.iverslty, oof Southern Caiifor.ia, Los Aytoka BLOOD FLOW VELOCITY IN TH8 CAROTID ARTERY AS A MEASURE OF MYOCARDIAL CONTlRACT1LIlY le Ave nwaatl dogs and in 43 hoapital patienla, Doppkr Row v.{ocity eurva were obtained lMravascularly from the aaoeediag aorta using a Doppler eathNer and/or /raascutaneously from a carotid artery using a Dopplar probe. The erst derivative of kit ventricular preasure (dp/dt) and eledrocardiograo (ECG) were recorded sinwNascarly. The following three iodicea were rneas- ured from the Doppler Oow velocity curves: (1) maximum aeeekraliow of blood flow (dv/dt); (2) time from onset of ejeetion to peak Ibw• and (3) lime iMerval between the beginning of Q wave of ECt7 to the peak of Doppler /ow velocity curve (E(:O Q-Doppkr,peak). Arrro.R these three isdioea, only ECO Q-Doppkr peak demonstrated • significant correlation betwee• the values measured intravascularly and trarnculaneoanly. Also, only ECO Q-Doppler peak showed signifkant correlation with maximum of dp/dt (maa dp/dt). Sinoa ECO Q-Doppkr peak showed correlation with heart ra/e, the diNereece between ob- served and predicted ECO Q-Ibppkr peak (eECO Q Ibppler peak) was cal- culated to exclude the effect of heart rate. Thera was a aianiAcanl oorrelatioe between eP.CO Q[bppkr peak and maa dp/d1. 1• 13 patients with coronary artery di.east and in 16 healthy subjeets, eEfO Q I1loppler peak aod the 36 1 37

ne activity in their Iymphocyln. As shown in these studies, 40 to 60 times less TCDI) is needed in the growth medium to induce AHH activity in cultured human lymphocytes than the MC concentration required for maximal hydrosyl- ase induction In cultured lymphocytes from 19 healthy human volunteen, the estent of AIIH Induction by TCDD or MC ranged between 1.7- and 2.9-fold. Those individuals having - presumably under genetic control - lower basal and MC-inducible hydroaylase activities in their lymphocytes also have lower TCDD-inducibk activity. Because of their observations, the authors suggest that the variance of e:prnaioe of hydroayk..e ioduclion eoled in t9eir eaperi- tnents more closely fits a unimodal, polypsk (1.e., two or more genes) pattern lhan the uimodal, or single gese, fortr of ieheritanoe recently propo.ed by other investigators. Kouri, R. E. el. d. (MkroAblogkd Asaociaer) LI/e Sclrwces 15:138S-1S9T, 1974. From the Departme.l of Virai-Chemital Oncology. Microbiological Asoociates, Inc., and Section on Devebpn.esW llurtnaoolop, National InstibNe of Child Health sod Human Developmeot, National IsMilu/es of Health, Betlesda, Md. THE SIGNIFICANCE OF ARYL HYDROCARBON HYDROXYLASE ENZYME SYSIEMS IN TIIE SELECTION OF MODEL SYSfEMS FOR RESPIRATORY CARCINO(:ENPSIS The authors describe the types of aryl hydrocarbon hydrosyl.ae (AHH) response observed m mrx.se pulmonary lnaues following treatmenl of various strains with either polycyclic aromatic hydrocart.ons or tobacco related ehemi- eals. Istratrachesl instillation of )-mnhykholamhrene () MC) showed that pulmonary AHH: (1) can be prelerentrally induced at doses <200pg, in eon- trast to the hithet doses which induced hep.urr en:ymes as well; (2) levels increase 6- to t-/old within 24 hours to a broad plateau lasting up to 96 hours; ssd (3) induction is host-regulaled, segregating as a single autosomal domi- nael gene in croaus between CS7B1/6 (inducible) and DBA/2 (noninducible) avaim of mice. Although DBA/2 pulmosary tissue is slightly inducibk, in costrst to the noninducibility of hepatic tissue, evidence indicates that this re.posr results tran proliferation of coanilutive A11 11 and is not true "ia- ductios." Eapowre to whole smoke from ona IAI cigarette will preferentiaUy iodtros pulmonary AHH, a response which may be under the same genetic con- trol as that induced by 3-MC. Eapo.ure to the gas phase alone does not have this eAect. A1 least four fractions frors eiRuette smoke condensate derived from IAI tobacco are capable o/ isducinq at least a 2-fold incre.a in pul- n.o.ary ANH allet 3-MC intratracheal (wdlalion. According to the authors. it aants r if the enzymatic potential of the lusg tiswe itself may be a rnapr deterrnioaatt In the uNinute (ate of tbis orpa is aoy carcinogenic process. Kouri. R. E., Demdse. C. F. aed Whitmire, C. E. (MkroaJofoek.l AuocWei) In: Karbe, P.. and Park, 1. F. (eds.)' Eaperlnrrnt.f l.rne C.ncrr. Carcb.o- Rrnrslr and A/oau.rr. New Yort: Sprleger-Verl,p, 1974, pp. 49-61. 1'rom the Ikpar(ment of P-sperimental Oncology. Vira) Chemical Careieo- tcnew Sectiun, Microbiological Associates. Inc., Bethesda. Md. STRAIN DIFFERENCES IN ARYL HYDROCARBON HYDROXYLASE INDUCTION BY 3-METIIYLCHOLANTHRENE IN RABBITS The basal levels of aryl hydrocarbon hydro:ylase (AIIIt) activity .aA the entynfe'a isducibilily by 3-methykholasNhrene ( MCA ) were detensi.ed in several rabbit strains in order b ideawify any Mrain differences in AHH ac- tivity and to correlate theae with the carcinogenic efiecta of hydrocarbon. 1s this experiment, the liven of aia partially inbred strains used in chenaic.l ur- cinohenesis uudip were homogenited and anayed. Straie III showed the highest enzyme activity upon induction by MCA, or four so Ove linw that of the noninducible straiat WH, which bad the lowest ensysn activity. Slrai.s X, OS, ACEP, and AC nlso showed "1ow" indtrcibilily. The Pr hybride of slnir 111 asd WH reveded a differential response to the isduuios of li.er AHH activity by MCA: the ksrels of isduoed hydroaylase activity were eossYtcrly hither in (111 x WII) F, rabbila lhas in the reeiproul (WH x 111) P, hybridr. All possible crones betwees these two "eatren.e" Mrair ars sow beisg a.alyred 1o atimtle the surnber o/ Besa isvoWed is 16dr rraposs diAa¢ed to MCA. Diwas, B., Foa, R. R. and Afekr. H. rroceedinla o/ tAe Sarlety for Eaper4wewtd Slofory .nd Medk4v 149:52& 529, 1975. Oth.r eurportt Naciorul Cancer Isstitute and Natiosd lowitutes of HeaYL From The Jackson Laboratory. Bar Hatbor, Me. MALIGNANT TRANSFORMATION OF MOUSE CP11S BY CIGARETiE SMOKE CONDENSATE A kow-oicoliee cigarette amoke oosdew.aN, i1a 12 fractlo.a, as0 a r.ee. uilu/ed sample were tealed for their sbililr b induce lram/oraWios is GH/ IOT 1/2 CLS mou.. ceBs. This /iut ir soted fe+r iu remarkably low sposu- seoua rale of trassfonsatios. Boalt the ende oosdewte and tba teoo.adtutsd aampk. Y well a. two specifie fradiow., wets found b isduo. 1rs.fa.aios in thu lise. Tltese transformed oclls produced fibrauroreaa whes twbaMworr Ir isjected into 6- to t-week-old aynBeseio tsloa previously Itea/ed with a.1i- thymocyte serws. AcoordieB to Ib asthors, it dwn appsars Ihd LLn Pardorlar cell line can be tned for Iha deleclios etd nneeaing of po/eaid o.roper. Furtherrsae, preliminary teaulu indicate teM iejeaios of trasdormed oelk into 3-day-old rdce rather than into Ihe 6- to S-weekold admab prodtrosd e higher incidence of tumors more rapidly. Thin wgdeau that H taay be aore efi'icacioua to use younger aswnab is /alisR this traesfoemed erJl lirr tor tumorigeoicity. Additional studies are seaded a e.oeArs tais obaer.uioa. Benedict, W. P., Rueker, N.. Pawt, /., aad Kouri, R. E. (Mkrob/dool/rd Ae• .orbte.) C.ncer Reae..eA 3S( 3) :8S7-t60,~ 1973. From the Division of Nematolop-Onoobpr. Department of M.dkiss. (1U- dren's Ilospital of Los Angeks, University of Southcr• Calilorsia Schod o/ Medicine, l.os Angeks. and Departmeat of Biochemical Ooeolopr, Microbio- logical Associata, Inee., Betheda, Md. ' I~ I 19

SOI.l1t11.E MEI)IATORS OF INJURY OF THP. MICROVASCUI.ATURE: HA(;t?MAN FACTOR AND TNE KININ FORMINO, INIRINSIC Ct.OT11NO ANL) THE FIBRINOLYTIC SYSfEMS lajury to the microcirculatioa resulta Irom • compkz interaction of hu- moral and cellular mediatora. Tlrt function of leukocytea and the complement system in Ihis process has been well docuesented, but while the Halleman factor systems - kinin forming, intrinsic clottin& and 1lbrinolytic - are also anpecled of participation, definitive infornution regarding their rok is still lackiog. This report, which summarizes rooeet obaerwliotr c,ompikd in this Iaboralory, docu- menu mrne of the inforrn•tion aoortwiatod by several other investigalor• during the last few years. Frarn Ihia, •twral eharaneriMica of HaRemaa factor have emerged: (1) This prdeit, wLwr tt•oiecular wei#M is about 90.000. is activated b both solid and buid pAaw: (2) 1n solid phass, the molecule inter- acta with negatively charged particles withaN uoderpinR cleavage; also enzy- matic activity is •cquired. Preurt.aWy reurlti.g from a co.Alouralional change in iu urvcture which e.po•ts at enzymatic aMa; and (I) is fluid phaae. Ih• eazyrnes kallikrei., plauwis. a.d pbrn• tltrvrnboplaatis anlecedeat (elotti.it Factor XI) activate Hageman (ae1a, which ie hurnan plasma Is readily cleaved during Ihi• aciivatio.. Evidence b presested indicating that kallikseia is lhe most importaM euid phue activator a.d that the adivation with kdlikrtis in essential for the normal function of the iMtinaic dottio& 6briswlytic aed killis- forstusll systems. Inforsnation oa the to4 of these aystase in ianmunopathobgy, aawaits careful aaulyaea of the funclilun of individual eompooesua and tech- aiques for their accurate detectiow and qwntitatloa. CocArawr, C. G. at d. Alkrovascrlr ReseercA 5:112-121, 1971. Other a..'rorlr U. S. Public Heaith Service and American Hear( Aa.ociatioa. From the Department of Eaperimeatal Pathology. Scripps Clinic ao.f Reaearch Fou.datioo. La )oila, Cal. STRUCTURAI. CHANGES ACCOMPANYING ENZYMATIC ACTIVATION OP HUMAN HAGEMAN FACTOR While it hu been kno*rs that activation of IlaReman factor by the action of protwiytic tnzymcs ia aocompanied by cleavage of the native esolecuk, as of now th• actual ailes have not been def/ned nor aH the resulting /raPnenta idenlifled. 1• this attempt b deted aad characterize the•e cleavage •i1e., the structure of Ilaileman (actor, isolated from human plasma, was •nalyzod be/ore aed after enzymatic activation. Rewlh showed that the purised molocuk i• a uoSle polrpeptide chain of $0.000 e.oitcular weiRht (mol wt) .edimentinR d •.SS. The tancenlratioe of Harm•n factor in normal human plasma was fmand to Ae 29 rl/ml with vari.tion betwetn individuale ranging from 13 to 17 pg/ml An .ntsM, .cwt an.lya...( the nrikcuk was pcr/ormcd. 'Lre•lmcnt ol the muldui. ..rA k.llstt.ke, plumio, cx trypun resulted in cleavage at I two primary sitea, yielding fragments of 52.000. 40,000, aod 28.000 aal wt. No further changes occurred in the fragments with tubsequcnt reduction. Pre- kallikrein-•clivaung ability was associated eaclu•ively witb the 25,000 moiety. Rsvak, S. D., CocMarrr, C. G., )ohnston, A. R. and HuRli, T. @. T11e lownd o/ Cllnk.l fnvrztittatfow 31(I) :ti19-627, 1974. OtAer arrpNr U. S. Public Health Service and American Ilcart Arociation. From the Departmeat of Eapcrimcatal Pitholopp, Scripps Clinic aod Retwrcb Fouadatioo, La 1oUa, Cal. TLIB STRU(TURAL AND ENZYMATIC PROPERTIES OF THti COMPONENTS OP THE IIAO[-'A/AN FACTOR-A(.'i1VATND PATHWAYS Central to ah• i.itiatio, ot 1h• eazyesNie er•rRe• along the pathway. ol kioio foneatiost. coagulation •ed Rbrioolyaia ir the activatioa of Hqawul lactor (HF). Rece.l wu6ie• is the i.vestipton' laboratory and elsewhers i.di- cate that this activation anay prooeed by at kast two diaioct wrochaaiue.r both of which produos as active enzywre capabk of initiating aU of the HP-activated pathways. 1s addisioe, it haa bees demoonrNCd that both kallikreim aad adive lactor X1 are capable of activating precursor HF by a reciprocal activatioo at- chani.m. 1s this wmmary paper. Andi.p are Pternted which de.eribe Iha enzymatic and physical properties of the preewsor and activated nwlncvka of HF, prek.pikrein aad Factor XI iwlated Irom htwaan plasma. Precw.or I/P, which has a molecular weight of approaiYnately 90,000, is ahowa b be a aiyla Polypeptide chain. It can be activated by contact with negatively charged wb- atances and by eazywWic action. TL• seat teaior aectioa of thi. Pap•r de..lr with the enzymatic properties of activated HP. lhe work iach.ded bera shows that HF activated with both enzymatic a.d .onenzymatic activators io a. adiv enzyme which a. •ctivale the iaitiN eo.npot.enb of the HP-aclival•d pathwaya, hydrolyse N-.-acstyl Rlycine lysiee esler, and iahibit various pro leaso inhibiton, anwty which are diifopropylAuorophosphato and lisu beam tryprit inhibitor. Th• remainder of this paper aunwnariz.e, the pre.e.t keowl- edge of the aructure. activation and enzymatic properties of (he initial ensyoa of the HF-activated pathways of coagulation aed kiois formatioo. Ukvitch. R. l., CocArawt, C. G., Revak, S. D., kiorsiao., D. C., a.d toh.- Non. A. R. , /n: Reich, P.., Rltklq D. e. and Shaw, C(eds.): Pror.s~rr awl Ibborhal Control. Cold Splnt Nrlor Cow/errnett or. Cell rroU/errbw, Cdd Spring Hatbor, N. Y.: Cold Spring 11•rbor laboratory, 1973, rol. 2, pp. 85-93. OtAer arrprtr U. S. Public Health Servie• and Aercricaa Heart Association. From the Ikpartmcnt of F..pcriMneola) Immu.qp•tlwtop, Scrlpps (link •sd Research I:ounJatwo, l& loll•, (:at. ~ 41 ~ W J.

TFIE PARTICIPATION 01: CELIS IN THE INFLAMMATORY INJURY OF TISSUE This presentalion, while reviewing some of the newer developments in in- flammarory process research, underscores the important concept that the in- Oammalory process involves a series of sequential interactions between plasma components and cells that lead eventually to the disruplion of tissue. As of sow, numerous eodogenous and etogenouw agents have been idenli6cd that stimulate mflammatory cells to nwtrate, phagocytize particka, and discharge their 6ranuks and injurious corwtiluew to Ihe outside. When the stimuli are associaled with a surface. Ihe release of isjutioua constituents from the inflam- matory cells ia greatly heightened. Abto, atudies of the cells have shown that the processes of esocytosis of cytoplaarnic panuks, phatocylosia ano chemo- lasis require seriee esternse cs:ynre., ATP generating systems and divaknt nrioes, and in general appear to be facilitated by an inl.ct micro/ubular sys- tem, low levels of intraccliular cAMP ud elevated levels of e(iMP. At Ihe preseat lime, rdearcb activity is iaBararrratios is focused os the analysis of the mecbanitm of activation of cells by humoral atimuli Evidence is accumu- lating to indicate that distinct reocptor silcs 1bu bind .peciec hursord acti- vators esi+l on the surface of inflammatory eells. S1imu1alios of the cell results from activation at iu surlaoe. For eaampk, il is apparent from evidence that has been presented 4bat speci6e r.cot;nitios aites eaist ot the membranes of seutropbila, platekta, aad mast cells. Coclbawr. C. O. The /oarna/ o/ Inrtui ptlrt Dcnnatology 6I( 3):)01-)06, 1973. Othar .upportr National Heart and Lung Institute. From the Department of Immueopatbolosy. Seripp. Clinic aod Research Fousdatios, la Iol1a, Ca1. UPOPROT@IN LIPASE IN RAT LUNG. THE EFFECT OF FASTING 1ipoproteis lipaae ir as ea=yrrre wbich hydrdysea blood triglycerides in or near 1he capillary wdl, thus catalyzing asd re6ulatiss their tissue uptake. In the lung. triglyceride /atty acids and blood free falty acids are the mais souroa of palmitic acid for aurfactaM sydbesis. This artiek describes a study of hr.= lipoprwcin lipaae and the effects of futiaR on enzyme activ,ly. l.ipo- proleis lipase activity was measured is dried detailed preparations of rat lung, with doubly labeled cbylomlcros triglyceride used as the substrate. Enzyme activity waa Wrear for Ibe MI bour of iecub.tioo at 37° C. It was c.>mpktely iahibited by 0.5 M N.CI. lhe optimum pll was 1111.1. Lungs Irom soslauu+g tals hydrolyzed chylomicron ui6fyceride at a rate of 1).00 rrrwks/il/hr; the activity ra/e was unchanged by an t- 1o 72-hour fast. Ileparis infusion Into isolated luep caused immediue release of lipopro/can lipase into t/~e venous eflluest In amounu equivalent to about 10% of total htn6 lipoprol:in lipase activity in bo/h L.tin{ and noa/.Miag rats. Sinte 1he ability Io terrMwe blood triglyceride is directly related to the level of lipoprotein lipase acti.ily, these rrsulta indicate that tAe hry r one of the few orilsno abk to rtrrwwe blood utllyccrrls eBtcrc.rly dwrn6 /aury. 0 0 1 I Hamosb, M. and Han.oili, P. B1ocAimica er BiopJtrrlca Acta 3s0:1)2-110, 1973. Other aupprtr Washington Heart Associ.tios. From the Department of Anatomy and the Departmenl of Physiology and Bwphysics, Georgetown University School of Medicine, Wnbis6toa, D. C. THE EFFECT OF ESTROGEN ON THE UPOPROTEIN UPAS@ ACTIVITY OF RAT ADIPOSE TISSUE Working on the arurnpdon that female ae: hornwnea might aAea the activity of adipose tissue lipoproleia lipue is rals, the investi6atorr admiai.. Iered either 17psslradiol or pro6esteroae b females after ovariectomy a.d to rrraks. l.ipoproteis lipw was measured is aeelonetther<.tracled preparations of adipose tissue wilh doubly labeled (r4C-fattr acid, sH-tlyceryl) chybmicnun tri6lycaride as substrate. Results showed thal there was a marked decrease is Iipoprolein lipase activity in epididymal adipoae tissue of maka treated with 17p<stradiol for a period of ei6ht weeks. Pto6esterooe had so eAect. Is ovariecloenized fet.ak., the kvd of lipoproleia lipase activity in adipose tianw rose from a control level of 10.10s 1.6 U/B so 22.72:t:..I U/B tbree weeks after the operation. Plasma triglyceride coacealratioe was in the normal range in both control and ovariectorsited rats. Admirwtralion of 17/iestradiol Io orarieclomised tata caused a marked fall is lipoproteie lipse activity: 17d. eslradiol (2.5 rg/day) lowered the enzyme activity to 9.00*1.2 U/& whereas 25 rl/day further decreased lipoproieis Upase activity b3.2t0.6 U/s. Blood triglyceride levels increased from O.Bt0.03 tusol/rnl is ovariectowizod rats to 1.It0.09 rmol/m1 in 25 jag/day, 17A<slrad'rol-lrealed rats. Proplerosn administration had no eAect. Lipoproleis Iipaa activity is the beaty asd hrrt6..as unaQecled by horrraas treatmeM. The Iwthors suggest that the rise Is bbod td- 6lyceride coocentratios., whkb aoeompasiea biBb plasma tltroBes kvele. eaJd be due to the marked ishibitios of adipose tisaue lipoproteis lipsae aclivity. Hasm.b. M. aed Hawso.A, P. The lownd o/ Cfinka/ Inre.rlgatJon 33:1132-11)3, 1975. OtLer aarpportr Waabis6tos Heart Aaaocia/ios. From the Department of Aoatomy and 68 Departmest of Pbysiobp aad Biophysics, Georgetown Usivenily School of Medicise, Waabisgtoa, D. C. INJURY PRODII('ED BY FREE FATTY ACIDS 70 LYSOSOMPS AND MIIOCIIONDRIA IN CULTURED HEIIRT MUSCLE A11D ENDOTHELIAL CELLS Free falty acids (FFA), wbes added to Iha die/ of various speckm bava been shown to product byperchoksterokstia a.d inereard atherosclerosis. lbese dietary I-FA have received much Nleslio. Y alherogen.. but PPA wbJized from eodocccoous {ri6lycstides may be of eves greater p•tboBs.tk 42 43

and hither, compared to liters of 1:2 and 1:4 in the normal sera. 71se anlibody activity was found esclusively in the 1S(7 fraction and the aolijenic specifkily, determined by hemagglutination inhibilion, was directed primarily to a2CB3 with some antibody activity to a2CB3. No correlation between titcrs of anti- bodies to collagen and kvels of al-aoti/rypsit could be demonslrated, nor were any of the scropositive palients deficient in al-anlitryp.in. It is concluded that antibodies lo collagen in patients with emphysema probably re/kct destruction of pulmonary connective /issue, and the demonstration of their presence may serve as a basis for the development of as aasay for early detection of this disease. Micbaeli. O. asd Fulanberg, H. H. Clinitd lrnwrrwobey an/ Irwnruwp.fAolop ):1fa7-192, 1974. O/A.r aur~or 1r National Lstitula of HaMb. U. 3. Public Health Service and American Medreal Asaocratioa - pAucalio.d Research Fouadation. From the Departmenu of BiocbemiMry, Surgery and Medicise. University of Calt(orsia School of Medreine, San Francisco. FREF2E;-E'.lCH STUDY OF COLLAOEN: 1. NATIVE COLLAGEN FROM TENDON AND LUNG OF RATS Although joint collapee chanpr art probably hnportant ia rheumatoid arthri/is. little is yet known about the ukrrtruclure of colla4eo. In light of these facls, it seems that nrw methods are soeded to study the a+rmal fiea structure of collagen fibrrls and to help identify alterations in their structure during aging sod pathogenesis. In thi. Mudy, the freets-fractun secheique, which doea t.ot rely on chemical fiaatives aod this sections of tiawe, was used w eeamine the Ane structure of nqiw collages fwet rat tesdon and lung. lbe collagea Naments were organized into a spiraled lamellar aubstructure within each Abri. SnuN particks, tepreae.tiag the broken eads of the coNape. Ala- nseots, were found in nearly straight rows when the lamellae were broken lrans- verselr. Framentous connectiaa were shown which span the inter6brillar matria and unite all of the fibrils into a retindar network. The ebrila wera coated wph material that was greatly hydrated in r/ro. Sublimation occurred more rapidly Irorn some portions of the ooatiall substance than /rcm othen, resulting in a banding pattern with a 610 A repeal distance. Beltoa, 1. C., Michael4 D. and Frlen6rrl , H. H. Artbritis an! RArurnairnr 11(3) :443430, 1975. OtA.r arpr.r1r U. S. Public Health Service and the California State Univer- sity Foundatioo. Ilayward. I.om O.c I)rp.rrn.enu nf Malrrm. Brothemrtiy and Surgery, llorvenity of (.ldormso. Saa I ran.W u i MODIFICATIONS, SOME CYTOCHEMICAL PROPERTIES AND TRANSPORT OF INTRALYSOSOMAL MEMBRANES The lyaosomal uptake of membranes and their subsequent autodi,estion contrasls with the iavolvemenl of Ihe sanse structures in varioua cellular fuec- uons. This investlgalion on rat lateral and wusillary glands was inteeded 1o determine membrane morphologly and cylochemical properties during ialra- lysoaomal digestion. 11 also attempted lo clarily the destination of inlralyaoaomd tnembranes wilh respect lo the cellular and ealracellular environment. Cyto- chemical methods (acid phosphataae, ruthenium red, phosphotunrti~ acid, and silver telraphenylporphine aul/onate) followed by ebctros microscopy revealed two types of modi/katios related to the inlralyao.omal tnembranes: the forma- tion of mydin-like figures and the alignment of mesnbrana in pain. The fira occurred moM often ir the Iysosome and occasionally In some other orpnrlks (e.g.. secretory granule, awHiveskular body. Uolgi apparatus). Some Agurea were seen in as e.ocyloeis-like procta of eatrsrion from the lysa.ome iato tha cellular interior. There wera indicatiom, ewreover. Ihat 1he ceN rekased thw membranes either inlo tha lumen or toward the basal lamina. Acid phoapha/w was demonstrable in association with the myeti.ated snesnbraoe in the lysoao.d medium, in various celhAar locations and i. the cxRular enviroarnea. ile pos.ibk importaaee of aomo inlenWid ceYs io the Iramport of Ihae .ero- br.nes from the acisar base outward Mas noted. Tbe aligned atembra.ea wn seen only as iodividual couples wilhin the ly.oaornal interior, amd foreution of multilamellar compkzes by /urther cross-bindirg of inembranous pain waa aot evident: ahey displayed a local oecwretrce of presumably lipid globules a.d a continuity with the already eaistin6 lipid droplets. Both types of aUued stcs- branes stained with phosphotungslie acid at pH 1.3, dthough they did .ot react to silver tetrapbenylporphine wlforute. Moat of the data suggest that Na two membrane varieties represent diQeresu paltarr in autodipestioa r+lsu, a. Tht AnKrkaw /orrnai o/ Anatomy 141(7) :)61-)74, 1974. OtA.r au/rprlr T1a Washiqloa Heart Ataoeialio.. I rore the Departmeat of Anatomy, Oeor6e/ow. Uaivenity Schools of Ydi- ciea and Deoliary, Washiogto., O. C. lMMUNOPATHOOENICITY AND ONCO013NICITY OF MURINE LEUKEMIA VIRUSf?.S. 1. INDUCTION OF IMMUNOLO(]IC DISPJISB ANI) I.YMPIIOMA IN BAI.B/c x N2:B)Fr MICE BY SCRIPPS LEUKEMIA VIRUS ~ This study attempts to defiee a pouibk viral role io tba edolopy of a lupus-like disease of NZ nice which mimics Ihe systemic lupus erythawabwr (SLE) of man. Murine lupus is characterized by antinuclear antibodies (ANA) and immune-comfle-type Rbmerulonephrilis, aed is thc NIB rrJoa by CooKSM' type antibodies wilh associated tsenatylie larcmia. ll.a ANA aeees paramount since they appear early and are significant ia the production of gIomerubneplhrNis. Moreover. the uncornavirusea whKh ro/ac1 asw/ roroa aad 61 691

INIIIBfT1ON OF EPINEPHRINB AND METARAMINOI. UPTAKE INTO ADRENAI. MFDULI.ARY VESICLES BY ARALKYLAMINES AND ALKYLAMINES Two amine uptake mecbasbros appear to operate In isolated adrenal medullary storage vesicles; one site b.s a high affinity for epinephrine and b.v capacity, while the other hr a low afilaity and a higher capacity. The low affinity site u nonspeciflc aod doea .ot display competitive inhibition by agents which aAecl the high afinity. ATP-Mg++ stimulated transpon system. Epine- pbrine is incorporated primarily by the ntLaulated mechanism but melaruninol appears 1o utilize primuiy t4e .o.Miwutaaed system. Is the inhibition studies reported here, the high a/lLity ayMn, was inhibited in a purely competitive fashion by a variety of indokaninaa ..d phenahylamines, but the two classes of compounds displayed different arudww-activity relationships. Suba1i1u1on on the etarbon decreased the .WWia of kadokamirw to inhibit stimulated epinephrine uptake but enJu.eed activity of phcaethylamines. Rint hydrotyl- ation reduud, and methosyl.tio. dbnirubd, the inhibitory activity of trypta- mioe but the aame subttNuenes wurtedly enhanced the actvity of phenethyl- amises. Studies of cornpounda with neNricled sidechair conformation indicated that a eondensed wrucdue favored activity in indokamines, while an extended chain enhanced inhibitioo by pbenetbykarwine+. Linear alkylamines of 5- or 6- carbon length were also able 1o inhibit active epinephrine uptake. None of 1M agents inhibited the nomtimulaled uptake oonsponent of inetaramiaol, which uses primarily the low Nlinity syMeiw. These data suggest that while iedole- amioes and phenethylamines do compete with epinephrine for attachment to the high aAloity transport site im tha vesicle raembrane, the point of interaction is probably solely at the locus which binds the amine nitrogen; the remainder of the two types of molecule probably bind to at least two diderent sitea ad- jacent to the N-bisdiell area. Slot4lw. T. A. er of. e/ochnnkd rAa.rnerolop 24:1413-1419. 1973. OtA.r esrrp+rtr U. S. Public Health Service end the American Heart Aasoei- ation. From the Depanmest of Pbysiolo:y and Pharm.eulop, Duke University Medi- cal Ceater, Durbats, N. C. EFFECTS OP RESERPINE ON THH ADRENAL MEDULLA OP T11e SPONTANEOUSLY HYP@RTENSIVH RAT The sympatho-adreaal axis eatecbolsmins disposition of Wistar-derived spontaneously hypertensive rals (SIIR) a markedly different /sore that of normote.sive Wiatar rats (NWR). The present study esamincs the effects of reserpine which evokes a refks symp.Iho•adrenal diacharge, but also causes catecholamine depk/ion by iahibiti.g the adenosine 3'-Iriphosphate (ATP)- Mg'•-dcpendent transport system in the adrenal storage vesicle membrane. Since both neuval input so the adrenal and calechotamine upti,ke ind. the veac/es apqear to be alrered r the SHR, it is conceivable that antehypercensive drup wd/ also act ddsre.Uy r the SHR. Admioistratioa of rescrpioe to groups I of NWR and SHR demonstrated that: (1) rcaerpine causes a luger initial de- cline in adrenal calecholamines in SHR tban in NWR, a diAerenu eliminated by pretreatment with chbrisondamine, a 6an61ionic blocking agea1; (2) n- serpine produces a larger increase in SHR catecholamioes and dopamioa a hydro.ylase several days later which is slowed but not prevented by chbrisonda- mine prelrealmenl; (3) ve.ickes from SNR or NWR incubated with reasrpiaa in vitro exhibit equivalent inhibition of adenosine S'-tripho.phata (ATP)-Mgs'- stimulated adrenaline up.te; (4) recovery of uptake is more rapid r SHR than in NWR after reserpb.e inhibition, and this is associated with a bura of new vesicle synthesis in the SHR wilh chlorisondamine prdreatmeal reduci.t the number of oew, immature vesicles in reaerpine-1realod SIIR- and (3) both SHR aad NWR scctete equal proportions of the'a adrewal catecholamina eo.- lenu alter nicotine administration. ?hese data suggest that the SIIR sywpatho, adrenal system has a. enhanced refklt response to teserpine but that tbY drut is equally effective in SHR and NWR is producing blockade of veaicular cate- cholamine transport. Theae altetalioas ca. inukedly aAect tbo actioas of .ulo- nomic drup in the SHR. Slor4lw, T. A. IrlttsA /ourna/ o/ rAriwecotop S):)d9-7S6, 1975. OtA.r.."e+rtt American Heart Asaociatiorl. From the Departme.t of Pbysioiop asd Pharmacology. Duke University Yed/- cal Ceater, Durbam, N. C. V. Pharws.eoloty A PERMEABILITY TEST FOR TH6 STUDY OP Mf PO(_'HONDRlAL INJURY IN lN VIVO CULTURED HEART MUSCLE AND ENDOi1iFl1O1D CBLL4 Aphou6h morphologic changes in orpedksa often rtfloct 16e earcst ot cellular damage caused by poisons or diaease, in miwchos+dtla such wodiha- tions do not readily localize either the primary injury aite or Its .mcla.ism There is a generally more sensitive indea, tha increased penacabilNy of a prea cellular membrane, which appears particularly applicable to mitoctw.dria since: (1) the intact inner milochoodrial membrane is relatively impetwreabia to many substances including amall molecules .od ioaa; aa+d (2) the i.duetioo of latent miteuhoedrid dchydrutena.e activity is related to ehaepes i. .ne=- brane permeability. Thua, a.easuremcnt of either the amount of permeability or the degree of inuami/ochondrial enzyme acOvation could be a vduable guida t r euly cell damaae. The cylochemical detection of Iw rlrr rnitochoadrlal damage detailed bere depends on the increased rate of demosatrable succinata i3ehydrotenase activity brought about by injury so cultured rat heart cells. Whereas an intact mitochordri.d membrane limits she rale at whkb Niuo Blue telrazolium (NBl ) and phewzi.e methoeul/ate reach /he eezyme, i.jured mitocboodria allow these reactaou to reach it more rapidly and form mlcro- 32 53

PRINCIPAL INV(?STIGATOR OR 1NSi1TMfTKIN JOHN W. OORROD. D.C.C. L.crrrr iw IropAe.w.oc), Chcl.c. Colkge, Uwirer- .wy of Lo.Aor~ Lowdoq EiRla./. PAUL HAMOSH. M D. A.duowr Ire- Iraaor of rAy,ioioer and 1bpAyik,, and Hrliciwr, Geoqcdow• U.ivendy School. of MedK/., aad DtMYtrr. Wa.dnR/or. D C. NORMAN W. HEIMSTRA, hr D. Trv%- /ruor of hycAaloty; Di.rcrar. Hrw.m F.norr [Alorro.). Ur.er.iq d SoWR Dakam. VerawY.o.. HERRF.RT •. HERSCOMfM hD. Aui.awr r. aser of NkreblaloEy. (leor8ne.. Mver.ry ScAooM d MeL kis ..d Derirry, W.Ji.Eroq D.C. AI rl1ONSt3 1. INOeNITO, (hrD.. A..a ciri he/ruer of rAarw.c.l.f7. Tita AIA.ay MNical (`_o11eM .f Uro. U.1. Ke 1. AN..y. N. Y. HARRY L IOACHIM. M D. Aur./iw~ IorAolor/u. Lcw. HrN Ho.pi~ei: Ciiw/- cd rre/ruor of IorAo/oj7. Cdkp of hy.iciar & Sw~e~owm of Colrsbia U.rvcrwf, New Yw\. EDWARD L. Kl.Ale[!R. M(). Srwicr Sckwrur. Tie Wo.ceuer Fou.dNroe for Papcriwee.rd 11rol"f. l.c. Shre.. brry. Mar. MICHA['.L E. LAMM. M.D, r.o/rua+ of rrAoloRE, Ne. Yort Uavv.ilr Medi- ui Ceaer, New Yort. PAUL S. LARSON rr.D~~ H~~r/ h./.r aar of rArworojop. Nearcn CareM of VirEi.ik RkMod. /06EPH M. (.AUWERYNS. M D., rfr D., Hrofene. OrJiwrwu and CAof.- w.r of l.rAotoRy and Minaarork Aw.rorwl. ea~crin.eMal Laloe of hanmawy wrM H. Lewe+K L.veq~Rd• U tw-• EDWARD I kCTY_ M.D_ D3c ho/..- .ow of CA.e.wrr. Ur.enirr ol Mitar .ora. Me.ec.poll. raacCr TR1.R 71..WaUoli.rw of ` yridiwes' is relalios b Ne iffiMraiome olt+cooluric /iecw T1e effect ef ewolMy o. fhe `e.utl dr- .are- !>.cie of rrnoUwg depivaliom ow grow 'roMero eolvirrR Eroccua plew of enwtiy depivaLLon ow ri.k- Wiy Acha.ioe T1e rok of /Ke .r.crophap {w the Mwerowe ~MeR~~ e'raluae w Actio.e a( eorbo, wow.ide and lob.eco .raoL* an reli..l mdaboli...d frr.r- 110. Str`es of Mra. My earciwau Canr.l .crvoue eyres edancrgk fasw tb.us ud apuell. ernokOas U.wu.. ..ca..l.as of .rocoue mra- br..ee AMIraeUy and cl.rityly 1b INeraere os IM lioio{kel efecu of /ee.cco. ud fotlo.l.R ..rruiFt lor Suppkw.ea DI tlrorss, priaiq .d prq.raio. of erlbn:t immdcs hMicNion of suNle•n11U to lofrcce, HR1 TlU lymphdks of r4 L.R: their rok 1. Rri/ lratrePoA a.d ckaratru of dr- Rorne prtrarWo wNlcr is worwNl a.A saEer:a+crai eo.dirlo.. a.d i..ariow MwR A{s.ns srM•ede a.d aoiogk.l .ahNr of nko- r1r ..dop 68 I I PRINCIPAL INVE911CATDR OR IN1i1TUT10N RICHARD A. LlRNER. M.D. AuocWe Rlewrlrr. Scripps CIWc .a/ Re.earcR Fou.Aador, La IoWti Cal. JAY A. LEVY. M.D, Aa4rwu C11wkd rrofraw. o/ uelic4v; Rrar.reA A.eo- cfre. C.war Reaearcd IwMwe, Uni- veniry of Cdiforoi. School Of Modi• cr.e. Sa. Fra.croo. CLAYTON O. LOOaI.I, rw.D, M.D Hoariwp ho/raeaii of Mrfkiar a3 rorf,olot~. UwivenM~ of Sawber. Cdl- forwi.5c\ool o/ Medici~e. Loe Ayeka. HENRY T. LYNCH. M.D. tro/...o. .w/ CAobw... of IrerrMire MlJiciwe MIf rYf•IK Health. CreigMo. Ut+ive.- eilE School o! Me•ici.., Q.r+llk Nefr. REOINALD O. MASON. MD. rw.DD rro/ruar of %rAelotf. Ut,iveniy e~ Ncet\ Caroli.a School of Mediciwe, Charel HiR. (No. r.rAelos/ar#C'11ei. Me.ori.l Hoqkd, hr.wde4, R. t.) HANS MEIER. D.V.M. SeMor Sw/ Sd- ewrLr. Tir lacl.o. Laloraary. Rar Harbor, Me. DOV MICHAt+ll, (ir.D. A.eW.wr f'ro- Ira.or of liorAewdur, .wI sr~rr, Uwivcnily of Calitorwia sJooi a Meeiri.e; S.. pr..d.oo. MICRORIOLOUICAL ASSOCIATES. INC. RaKeada. Md. rROILCT Tii1i Slu&.e on perw.tt.t vlral I.fodfo. DeveloqmeM of . rwodcl .yercw is riwv for ewdyi.R c.rciwwue Plew of he.6 dR.re/N .wote MWnb. el lln reqirnory tr.d ol .k. 3.oE1.i Worf i. (naYl.e .Ml lo.w e./ Y41/ eYOer i.ciAetace. At~\`ir ~ oc.,~ Rydko.r~ (AHHk Fl.els ef .icolNw o. f.lualler of /iYdeb a./ c.do4belW csY. •O.ooreonl. Iw 1b rs!!Y: Re.erk w.. t qrl4ilUE..e.linl Yarrk.io../ .irr .desviraaae.W idre.or Tr..q/.oerd eR.cwe .f .Nr+rria.r Rard. 1s iw6re/ Mralr of okr trrd faMru RaeCU O/ el{YtHY .Mot. M /t/1~MY7 R6roNae/. .wd coU.Re. ad w rd.- lie. 1o ..pbr.eaa /o rlro tlstakd c.rcl.oReaaie /w r1ro awA M ria.o vkdsMmhal cndr ti~W D.vdorea of ..rowe.roAJ.q.m.a far Re.efie woepriEiliy .d iu nWla. riw Is M rrre luy wci.osetre.h 3rof<. Walalbw urci.oprek ta./b 1. .rlc. D.vslo'wet+l of rapW ..A Rrecir .raV prooedwee for Ib detcrwlwMl" of eo.rilali.e ..d i.dreiEle kveb ef .rY/ f.ylracarboat t.f4oaylaee (AII f.Fq (wr., rinre. (eyeci.Yf Meed ~)s rocree) /or .N/.cniom so Rov.i.r1o. Mrdie. Rae.rcf eervkr 1. .rAart d a.a(ta Froject (.o.1..7. LE A.) 6f

i CECII l: I EIJCHTENBERGFR. Pub.. DONAI D 1. MASSARO. M.D..lssocl- JAMES G. MILLER. M.D.. PI/.D.. lro- ROSE MARIE PANOBORN. BS. M3 Hr.d, DrP.rtrrmrnt of Crrorhrmi,srf. .t. rro/.ssor of Alydicrnr. George /rssor of hychiony .nd rsyrholory; . Assistant f.wd Trchnolotru owd (.ec- Swiu Inui/we 1or Eaperrmcnlal Can- Washington University School of D.rrcto.. Mrnul Health Rrsrrrh /n- twrr. DrOartmrnt of Food Science and ccf RcsearcR Lausaane. Swilsifland. Medicine. WasAington. D. C. stitna. University of MkliRaa, Anw Technology. University of Cali(orfy Arbor. Davis AVF.RII L A. I IFBOW. M D CAdr- CHARLES McART11UR. PN D.. Univer- . _ nran. Drprtn.rnt of raholotl. Yale .ily HeaLla Service.. Harvard Univer- CHARLES MITTMAN. M D.. Dirrctor. 1O11N W. PARKER. M D AsaoclW llnivcrsily School o/ Medicine. New sily. Cambridte. Mass. Dria.rtmeas of R.spir.tory Dis..srs. . rru/rssor of Ltholo[y. University of Haven. Conn. City of Ilope National Medical Ce.- Souw4r. Califocwis School of Medl- CHARLES B. McCANTS. Pn D.. .lsso- Icr. Duar/e. Cal. esne Los Ayeka FSTEN O. LINDSETH M D. PN 0. Sa. cfle ho/rssor of Soils. Nfvly Caro- . . . . . . IoseRlr'. Hospil.l RerearcR LaborMorT. d.. State College School of Agrkul- HUGH MONTGOMERY. M.D.. Asso- MARY STEARNS PARSNLEY. Rr D. $/. ~aul. M/M. rwa. RakiN. ripr lro%ssor of !<Iedkinr. University . . A»ise.nr rro/.ssor of Anrtow.~ 4. 01. o( Pennsylvania School of Medicia. stetrks and G afcolofy (',oReoe of ROBERT H I INNFLL PM D Aswcl- HENRY C. MtOll.h )a. M.D.. Actta~ Philadelphia. j . Physicians A SwRcow" of Cofr.N. . . . .rr rro/ruor of Chrwri,try. UaiveeaMy Hrd. Drr.rnwrar of Pathology. Loui- .i.e. S(ue University School of Medi- P. O'R. MONTGOMERY 1.. M.D University. New York. of VermoM. Bwlinpo.. eioe. New Orkaw.. rro/rssor of rrholodr ilwiteesi{y a / Teaa. Sou/'.e.(er. Melial 3cAoA EDWARD W. PELIKAN. M.D.. C4.ir- HERBERT L. LOMBARD. M.D.. HENRY D. McINTOSH. M D. rro/.} Ikall... w..l. Dep.rM.rws of PArw.c.lsjy M P.1/ . A/Ni.tr. Cancer Re.eareK It sr of Medicine .nd Dk.rtur. Crdlo- .nd Esprriw.fns.l TAer.purks. R.war MNWc. New England Deaconeu Ho.- r.ard.r Laboratory. Qole Uainr.ilr GEOROE E. MOORE. Pw.D.. M.D DI- University Sctiool of Medki... Roe1o.. plal. Bo.1ow. Mediul Center. Dw W0. N. C. rrcrw. Ros.eR P.rt Mewaid i.ell- IMe. RaOa{q N. Y. OTAKAR 1. POLLAK. M D. PaD. I. P. LONO. Pw.D. ho/essor o/ PAr- FORDE A. McIVER. M.D.. Auodrf EsecrN.f Dir.cto.. Dorer Medical R.. w..roloay S/we Universilr of k+.a rro/fasr of %fhodo~~ Medical Cd- KENf4ETH M MOSER iM D Asdsrau search Csrrer. l.c Do.er Del. . College of Medki.e Iowa Cily. . kRs of South C.rdir.~ Charleston. . . . . ~ Professor of Rf eNcl.e. OearRe/orno . . . University Medical Sciool Was•irrt. MORRIS POLLARD. Pr D. Dbwew DONALD R I As.ociaf OURIA M D EDWARD MeKEE. M D.. Pro/rssr , (otl. D. C. !elwd LbrraryU.ivw.YP .~ . . . . rro/r.sr o/ Mrdirin. Co.acN Uaiver- and Acting Chrrn..a. D.perunrnt o/ Nals. D.i.e. Noua DawK 1... . .ily Medical College New York l.tholoPy. Medical College of South HURLEY LEE MOTLEY. M.D., Pro/rs- . . Carolina. Charleston. sr of Mrdirinf .nd Directr Crdio- C. M. POMERAT. PN D. DY.ctr of . R M 1 b U i 1Jolork.l Rturrh Pasade.. Poril.- KENNETH MERRILI. 1 YNCH. M D. fl/ Mr) I 0/rory. rl Mer.i1~ of KEI LY T. McKEE. M D. Associat. Sowser• Califor.ia School of Medi- . 1k+O lor Medial Re.earcf. hnM.k Sc.D.. LI..D.. Ch.nr.llaw ond Pro/rs- rro/rssr o Mrdainf. Medical Col- eise I as Ayeks Cal. sor Emrrisrs of Patholory. Medical . . . lege of Souw~ Carolona CAarleslon College of Soul\ Carolina. Cloarkuoa. . EDMOND ANTHONY MURPHY H. R. PRATT-THOMAS. MD, Dfas . 11ERBFRT McKENNIS. la. Pn D. L•ro- M.D Se.D Auocl.re ho/rsr of .nd rro%ssor of P.rhobtly. Mefiicd INES MANDI_ PN D.. Auiss.at Pro/rs- . . /rssor of lhrnorolugy. Medical Col- Iiou.Nsrks and Medk/wr no loArr Colkw of Sowh Cardiwst C1wS.rA... sor of S(othrn.uvy. College ot PAysi- . lege of Virginia. RicAmoad. HoNiru Uwivecai(r School ./ Medi- eiasa ! Surgeons of ColwnEia Uruver- B.Niaiwre cine PROCESS i INSTRUMENT ODRPO- ai/y. New York. . . VI(TOR A. McKUSICK. M.D.. rro/rs- RATION. Rrootly., N. Y. JOHN H. MANHOI.D. 1... D.M D. lro%aso. .nd I)sr.rtor of Paholory .ad Or.l Dis~wods. New Jersey Cd- kpe of Medkrne and Dcali.lry. Jersey Cwy- DAVID E. MANN. Pw D. A»ocl.te Iro/rssr o/ rhrwr.roloq. TernrM Univenily School of PfanwacY P~a. delp\ia. IOHN P. MANOS. M.D.. lnu.ocrr /a Yrdory and eartrriolory. Medical CoNeee of Sour\ Carolina. Chark.low. CNRISTOPHFR M. MARTIN. M D A ut,t.n/ Pru/rnur o/ Mrdiclnf .nJ Unr.tor. Dlrtu.rn o/ /w/rrso., Db- ..v,. Ne+~ /er+cy Slale College of Mcdoctne. /crsey ( ny. MA%()N RFSI-AR( N INS11iU7E. Wot.ccicr. 161461 sor of Afrdiri.e. The Johns HoCim University School of Medicine. alli- r.ore. ROSS L. Me1.EAN. M.D.. Associate Pro/rs,or of Ahdklnf. Emory Uaiver- aily School of Medicine. Allanla. WILI.IAM F. McNARY. la_ Pu D.. As- socWr Pro(usr of Anatomy. Bouoo U.iversily School of Medicine. Bouow. NEAL L. McN1VEN. Pw D.. The Wor- eeuer Forrwdation for Eaperirnenlal Biology. Sbrew.bury. Mass. JULIA MEYER. Pit D.. Associate Pro- ,fuor of Or&# rothnlo[l. Univcr.i/y of ,1linoi. College of Dcarulry. ('hicaso. BERNARD 1. MILLER. M.D. Assbr.nt lro/rssor. Thr Daniel A.ath 1n.ritrtf of Aa.torny, Jefferson Medical Col- kge. Philadelphia. 71 WII.I.IAM S. MURRAY. Sc.D., Srnior St./ Scirntlu. The lact.o. La4ora- 1orr. Bar Harbor. Me. RICHARD L. NAEYE. M.D.. Pro/rsror and Ch.i.n..do of Pathology. Pe.raH- •aaia State University College of Medi- cine. Her.hef. ALBP.RT H. NIDP.N. M.D.. Lrro%uw ol Mfd.rlnr. Drew Poujradr.Ne Med alk ScAool and lJniverss/y of Southern C.li/orniaChir,. PuGwowry e/sf.sf Section. Maniw Lwrer King Hospital. Lo. Ansek.. DONAI D M. PAC@. PN D_ L•ro/rssr o/ PAysiolory .nd Dir.cfr. /assisrtr t C.ll.rlor RfNrclY. University of Mas\.- I incola. ALBERT R. PAI.MF.R. PN D.. Assistant Professor. Drprtm.nt of Psychology. University of Toledo. Toledo. O. MARTIN S. PROTZEL, R3, D.D.l. Chief. Der.rtwwnr of Oral r«holyll. Newark City Hoyi1.1. Nerr.rl. N. i. WALTER REDISCII. M D Aacecl.n Pro/.ssr of Clinkol Ablk/we. lie. York Univer.ily Sc" of M.dki.q and NYIJ Research Service. OaIM.Mee Memorial //o.p/al. New Yari. W111 1AM RFONI.SON. M D. ho/fwr .nd Chairman of Ahdir.l OnrafeW . Medical College of Vk,iwia, Rkj- snowd. HOBART A. RPIMANN. M D_ Pro r. sr of Medicine. Haanema.. M C.Ncde and IloqNaL PWadelplii.. R(M.LAND C. RFYN(H DS. M D. Am shtant ho/.ssor of Pathology. I)alver- .il~ of Te.a. So.lhweuera Medkal Sclool. Dalla.. 79

VICTOR RICHARDS. M D., Chief of Swtery, 1•resbyurian Medical Center. Sa. Francisco. WiLUS H. RIESEN. M D.. Senior l/o- cAemiu. Life Sciences Dirb{on. IIT Research /nrilMc, Chicago. R. H. RIGDON. M D_ rro%usr o( Ia tAofot)~ UniversUy of Te.a. Medial Sranc~ Oalvesrow. SYDNEY C. RTi7ENRERO PnD. rre/e..ur of socreriofos. Ijd.reRT ot SowAer. Caldornie, Loe Ayslr. BENSON R. ROP M D.. Auadre h.- lessr of Swtery; Chief. Crdor Sm- gtry~ university of Califer.+. Saed .. ef Medreiwe, Sat Fra.cisw. /OSFP/l If. ROOP.RS. M D, Holy Ne.e of k.rs I/oePitai, Odsderi Ala. ROBERT C. ROSAN, M D.. Asrciw Irofeur of r.rAolott and !~ M~ Sr. Louis Univer y .i~ School CiaY' Ae.oe7Me INho/ot/Y, Cardinal Gkvinon Me.wri.l Hoywel for Cbi- MeR St. Lo.k. JOHN R. ROWI ANDA I1r D.. Ste/ Sciemiu, Southwest Resrarcl l.rlhre. Saw Anton.o• Tea. BENJAMIN A. RURIN, M O, Auluanr Iro/rswr n/ P.O/k Hr.lrA, aa~kx Univer.ily Cotlqe of Mediciner Ilo.- Moe. IIENRY (. RUSSP.K, M D., r.ealdrw/, Tle Rtnuet Fondatlok Inc. SsMew 1s1e.dL N. Y. W. C. RUSSEL M D University of Tea.e MedCenter. ~IauMw. WAYNE I.. RYAN. hs.D., rro%s.or of Riec/lewr/snT. Uwirer.ilr of Nebrata College of Medicine. Ornaka. •ETER F. SALISBURY. M D. rts.D. Heod. i.re.t/ve Treorwwnr Ceenr, Solr loseN Heyial. Rwb..l. CaL PAUL SAI.TMAN, M D feuo+, Dryurmwnt o? Assfu.wr /rs IiocAew+4lrt owI Nrrrk/ow. UniversNy of Sowlcrf m Celifornia School of Medicine. Loe tn Angeles. ~ III RI( )1 1( St 1(A)'I'tl. 14 1). lN.rc I... ul N.r.yf..+w.r..l..er M.w. /• M.+ure. M.r e.au.b t.raw. _i . F' u, IORGEN U. SCHI.F.GEL. M D., Pw.D., tro/iuor .w/ CAorman, Section of Uroloty. Drprrmenr of Srrtrry, Tdane U.iversity School of Medicine. New Orleans. ALVIN R. SCHMIDT. MD. Dbecrr of Cowsrfint, Tufu Universily. Med- terd, Mau. ISAAC SCHOUR, 0 DS_ r)t D., D.Sc. Droa, Coffete of Drwtlury, Univenity .f IRi.ois, Chicyo. MAURICE S. SEOAL, M D, Cfiwk.l Professor of Medk/nr, Te/Is U.iver- dly School of Medicine; Director. De- parewear / /wA.fwlae Therapy. ro.- bon CYf o!{oryitd, Boston. LUCq SHVERII, M Da Dlrecrr and Du.R /nrkre of Anorower and t•orAd- .p. Ohisiow of Cancer Research. U.i..nitr of hrv~ fnr.yiK Italy. CHARLES E. SHERWOOD. M D.. As- afu.nt Pbo%swr o/ Rdiofo(y. U.inr- d1y of Rochester School of Medicine and Derirry. Roclcaw, N. Y. SHO11 SHISATA, M D. rn D.. t'ro/a- sr o/ lAarwe.rdoty. University of Haw.Y Schod of Medicine, liondulle. DAVID L. SIMON. M D_ Innracrr, Derartw.enr of Internal Medicine. Cin- ci..Nl Oeneral Hospital. Cincinnati. ERIK SKINHB/, M.D. Chief. Deprr- a.rnr of New y, Sispebjvil Nospi- (at, Cqe.kye nmrt. THEODORE A. SI.OTKIN 11eD., As- nistonr rro/rssor of r"n..calop. Duke U.iversily Medicd Cenler, per- Mw. N.C. GEORGE W. SMETTERS, M.D. Asro- efre /n lotAoloq~' Not)bwesler. U.I- .rw y Mcdied Sc C.icqo. OeN6 M. SMfTH, M.D. Astlsr.nr t•ro- (eua, o/ Psychology. Harvrd Medical Sehool, M....eVreetta (:eneral Hoyl- let Raer". LUCILH SMIM ItrD. lro/esur of fliocDew.4trr. Dartmouth Medical School, Hanovet, N. H. SHELDON C. SOMMERS. M D.. Dkec- ror of l.bo.arrier, I enoa H.11 Iloe- r (Y.mr.! Pr..frr.o, of r.rAoloff. p of Pby.sti.ns d Surtcoru of 1 olwnbu U..verrly, Ncw Yoe\. I t ERNEST SONDHEIMER. Prr.D., Asso- ci.rt rro/earor of flioclkmurry. Cd- kge of Forestry. Stue University of New York. Syracuse. T. M. SONNESORN, lM D,. DisNn- trLAeI Service ho%uor of Zooluty. Indi.u University. rloowing)oa SAM SOROF. Pw.b., Head. Deprtwewr o/ fH.cro.nokcel.r CAenriurl. The InstiltNe for Cancer Resercli, MYa- delOAi.. SOUTHWEST RESEARCH INSTI- TUTE, Saw Aronio Tea. DAVID M. SPAIN. M.D., Director, De- /rrmewr o/ Pathology. The RroobdaN 11.sPi1d Cerer. Rradlys. N. Y. ALEXANDER SrOCK. M n, Aoieronr Pro/es.or of Ieliwks, Dr\e Univer- sity Medical Cerer, Durttam, N. C. FREDERICK 1. STARE. M.D. ho%s- ao. of Nrrrfiiow. Har.rd l~.iversily School of H.Wic HeaAR Rowo.. C. HAROLD STEFFM M.D. Dkectoe of L.boeorrirs. MaiodiY 11oeRild, Meawbis. JACK P. STRONO, M.D. A.ax/aw Professor of Pathology. Louisia.. Stj/e UnivenUy Scbod o/ Medicine. New Orleans. MARION B. SUL2BEROER, MD, ho- lessor owd CAsirrwan of Danwoloty owJ SypA11oloty, New Yorl Univer- wyselk.ue Medical CesMee. New York. RENATO TAOIURI. Fw D. Auoc/ere Professor ol t'syt'hokty. Oraduele School of Rushnese Adsni.irratioq Harvard University, soslon. CAROLINE REDELL THOMAS. M D., Professor Emeritus of Medicine. The lobnm HopkI's U.iversity Scbol of Medicine, tiakii+ore. JEROME F. THOMAS. IM D., /ro%.wr ol Sanitary F.nRaeerlnt, U.ivas8y of (.difo.nia, ree'ekr. • JAMES E. P. T(1MAN, Iw.D.. Iro/e.- .r and Cllo/.man of rArmerolo`y. CbkaSo Medical School. I.MMWe Ior Medical Research. Chicago. JANET TRAVFI./.. M D. A.wcfau f'.o/e.w.r of CliwN.l rhaI01KOfOty, ('otnell llniversity McJical Co1/ege, New Yort. LIE SHA TSAI, t•N D.. ResrrcA Auo- ci.ue. Department of r.rAofoty. Yak l/nivctsNy School of Medicine. New Haven. Coan. UNIVERSITY OF SOUTHERN CAU- FORNIA, Los Anseks. ROMEO A. VIDONE. M.D. AssocWe Pro/ersor of N.rbololy. Yak Uaver- sitr School of Melrcnft. New Havert Co... PETER K. VOOT, PN D.. Professor of Mirrof.iofotl. University of lyarily- 1o. School of Medicine. Seattle. E. D. WARNER. M D., Professor of 1•e- rAo/otr Sra1e University of Iowa Col- k~e o( Medicine. Iowa Ciwy. SHIELDS WARREN. M D.. Dbectr of Laaworoeies, Cancer Research LdN rwr. New Eftland De.oos. Hoy4 lal, DOSton. YASUSHI WATANARE. nr D„ Aa.- ciue ltendre.. The WiNr InuN.Me ef Anato.rr and .iulo.y. r.radd.ai. BARBARA K. WATSON. hrD, Assb- , ont Lcreriofotiu, MauacMrsepe O.o- erel Ilo.ptal; Research Associ.v. De- r.rrmewr of bocrerlafofy and l.u.nra/- ets. Harvrd Medical Scl,oo~ Roro.. JOHN S. WAUGH, Pvt.D. ho%ew of Chemistry. Ma.e.cMpeue Iru1eM .1 Teclrwbsy. Crnbriye. RICHARD L. WECHSLER. M.D.. C14.- ko/ lAysiolotia. MortteRore Ho.'i(d Iwitule of ResercR, rMt.bart1. JOHN V. WEII., M D., Aeabwwr lro- /eaow of fue/idne. Uwivereily of Co/e- rado Medic.l Cemer, De.ver. A. WPINSTO('K, nr D, Re.errA IM- cAemrre, Life Scdenrer Dlvldo.. /fT Rescrcb InstaWe, CWcap. RUSSEI L W. WEI I.PR, M D_ t.+Aol• otisu, Memorial Hm.piul of Cbe.w County. WeY CbeMer, Pa. A. STANI FY WEl TMAN. hr D. Auo- clare ho/err.w /n rA.rm.rofo~y .n/ Reuar.A, lroo\lyn College o[ rbr• reacy. eloollyn. N. Y. 11 w

NEUROPHYSIOLOGIC AND BEHAVIORAL CONSEQUENCES OF CHRONIC NICOTINE TREATMENT The author discusses the following lioea of investigation concerned with the conscquenus of chronic nicotine admieiauation: (1) ideotiAcation of brais iotentructursl relationships aRetled by chronic nicotine treatment and the quan- tificatioe of the ekctroencephalographk events which are indicative of such chaagea, and (2) characterizniott of fumctioaal or behavioral corrcomitanta of the •icotine-ioduced oeuropbyaioiogit changes. Preliminary rat data cotres- poedio6 with results obtained tarliu with rabbits suggest that obotine treat- meot uwes a modi6catiots of oortialathomtical relatiosrhipa waica may be indicative of a shift toward OredotainW Nppocampal, as opposed to relicular. mediation of conical activation. Hippocawtpal domiraaoce, pharriacobgically produced by aicotine, should reauM is a stMW of arotrsal whkh 4:ohanccs this efl'icacy of iwoeotive- or paldirected leiavior. whereas arousal ueder reticular domioanaa would be more ileaernl is oatsn or more driworieaterl. 7 he eflecta of chroaic aicotioe Ireatnunt on kar»lms and postac.quirtiow perfarmaau are paradoaical. Nicotine ir detrin+eMal to tak acq+riaitioo but impraven its per- fornuoca once learned; t-is eEhanoswt is iadepestdest of the dtrorwlojy of treatment aad of the condition under which do task was learned. The obaerva- tioer detailed lera suggest a~1's~tk miechaeirm which may aeeouax for aJootim-seekieg behavior. For eaampke, habitual anwken Ioroved mor~ elRciest and better able to suatain perforra/aoa when they aookof than when they did aat. Such enhaecemeat of human performaea oorresposds with do oicotise-isdueed improremeot is rat be-avior. If the some neutophysiolo6ic mechasiw operates I. both apeciea, the self-administralioa of nicotine could be viewed an the seeoker's attempt at manipulating his relative arouaal to the ata4 which would enhance his ability to perform. Nekree, 1. M. (Goldruln, L.) In: Sio6A, J. M. and Lal, If. (oda ): Drug AAdkdon, Vol. 1 Neur.rbiobgr and tn)Irenrer on IleAovlw, New York: Strattoo Intercontinental Medical Book t:;orPoratioat 1974, pp. 173-126. From the Institute for Mesual Health Sciencea, Rutgers Medical Schod, Pia uuway, N. J. ANALYSIS OF THE ROLE OP CYCLIC ADENOSINE 3'3'-MONOPHOSPHATE IN CA'iECHOLAMINE RELEASE Many horwwna and seurotrseawJtlar weataeeea activate the aecrelory ma chanism of a variety of tinueti and cyclic adenosina )',Y-nwoophosPhak (cyclic AMP) has been implicaled in dw wolacular eveals aswciated with this action. More recently, howerer. aocwewlatin6 evidence indicatea that cyclic AMP may rwl actually partkipate directly in controlling ae+cretory activity. It seern rather that it is the redistribution of cell ealewtw (Ca*+). or tratamembrane cal- ciura Qua, which is directly responsible for triggering the molecular evenu leading to erocytoais. According to popoesMs of cyclic AMP as a second mediator then, some inleraclios between cyclic AMP and Car # is responsiDle for modulating the ucretory ra1e. Tbe adrsnal medulla represents the proto- type 61and for the "stlmulua secretion coupling" model of C.a t+ actioe, but I whether or not AMP plays any direct role in this sequence of events 6n not been resolved yet. The present study demonstratea that, in contrast to Caa++, cyclic AMP is not a rate-limiting factor in medullary calechotamine secr+etioa. Cyclic AMP kvek+ and catecholamioe rekase were measured in ut adrenal glands perfuscd In ritu with Locke solution. The medullas contained about oa- Afth of the amount of cyclic AMP present in the cones. Perfusioe with acetyl- choline (ACh) or nicotine increased cyclic AMP both I. the iariact adreraal and in the perfurale. Changes in tisrua cyclic AMP during uinwdation did aot, however, parallel catecbolaminee release. MaaimaJ increases In cyclic AMP did not occur until after eight minutes of eapoaarc to Ihs aecrelosogue, whereas maaimal aecrstion rates were ftacheq during the fint rninute. Theophyfllae (O.S mM). a phoaphodiaterase isihibitor, iecrcasod basal and stimulated adrenal cyclic AMP kvek+, but did not poteotiate the secretory response to ACb or aicotine. Perfuaioa with cyclic AMP or its dibutyryl derieatiw (0.24.0 rnN) failed to eQea a consistent or ai6nificaut iucresrs in the rate of catocholarww release and was waAla Be polrtaliate the oacrrlory respoaw so a auEsaalrnal conceMratioa of ACh or Ca+t. Resuln suggest that ualike Ca++. cycllo AMP it not a direct mediator of reedullary aecretion. )uour, S D. and Ru-bs, R. P. Jonrsyf of Physiology 277:463476, 1974. From the Departmat of Phartnaco{op, Sta1s Ustivenity of New Yort, Dows- Nate Medical Ceater, Brooklyn. NICOTINE-INDUCED STIMULATION OF SiERO1DOOt?NESLS IN ADRENOCORTICAL CELIS OF THE CAT Although thene is ieformation regarding the actioa of nicotim on aecre4wy organs of neuronal ori6isq much ler is kaown about its effect on saaetory lisauea of non-eeuronal orisin. The present studies focus on the action of nico- tine on cella of Ibe adrenal emte:. since kaowled6e of this alkaloid's effeciis as the organism's response to atresa is of considerable interest and importsr,w. This report deals with the ef<ecb of nicotine on Meroid-production in and to. kwe from trypdadispersed cat adresrocortiul cells. The isolated cells wam aelncted in preference to the intact gland because of the preparatioo'a b- moReneNy and dw eaae with wlkh doae-respoase relationships can be ob- taioed. Nicotioe, like adremooortiootrophw (ACT1I), elicited a doae-depes-desN increase is steroidogeeeair, which required the Preaenoa of calcium In the tar- dium. Aupnented steroid production evoked by autynstinul ooeoeatratiwa of AMC Nrnonobutyryl cyclic adeaoaiae l',S'-aaomophospAatq (AMP), or proa- ta6landin F. was further enhanced by steroidoRenic concentrations of nicotiea. Tlrse resulta are discuaaed in relatioa to the poaaitrb mode of action of nico- tine on cortical uW and to she potelllal consequences of smokiall during atrw. RrNw. R. P. and Wareeu, W. ArItLA /orrwd of Hlarnuerobsy 37(7):337-762. 1973. From the Ikparlmca of Pharmacology. Medical College of Virginia, Virginia Coaurwawealth Uoiversity, Richmosd, and the Departmear of Pharmacolopr. Stab University of New York. Downstate Medical Ceuler, srookly.. 49 48