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ANDREWS OFFICE PRODUCTS CAPITOL HEIGHTS. MD lKl

t IGINAL l 0~• I2EMOVl: UNLI:SS TO MAKE A l'HOTOCUPY _

S(:IENTIFIC ADVISORY BOARD to The Council for Tobacco Research-U.S.A., Inc. n of December )1, 1981 I.EON O. IACOBSON, M.D., CJfw~in+an lusrp/4 Rrtrnstrin Pro/cssor of Bir>loscul Sciences (emeritus) Professor of the DrportnKn( of Medkine (enrerinu) Univer:itr of Chicago Chicago. Illinois RICHARD 1. BINO, M D. hirn tr» of Erptr(en.ntd Cardiology and SriMti/ic DtvtloQTMt Huntington Medical Research lartilnte, Pasadena. California Pr.pfrsror of Mrdhlne (tnw.(Irs) (lniversity of Southern California School of Medicine Los Angeks, California ROSWEI.1. K. BnU'iWELL, PH D. Prrpfrssor of ()nrofrorr McArJk Laboratory for Cancer Researcb University of Wisconsin Madisoa, Wisconsin DRUMMOND FI BOWDEN, M.D. Professor and Head Department of Patholotnr Unrversity of Manitoba Health Sciences Center Winnipeg. Canada MICHAEL 1. BRENNAN. M.D. President and Medical Director Michirn Cancer Foundation DetroN, Michigan IOSEP(1 D. FELDMAN. M.D. MarnAn, Research Institute of Scripps Clinic Scripp~ Clinic and Research Foundation La Jo4a, California WILLIAM U. OAR DNER, Pw.D. E. K. Hunt Prolessor of Anotorny (emeritus) Yak I/nivenitr ScMW of Medicine New Ilaven. ( onnccticut ROBERT ). IIUEBNER, M.D. l.aboratory of Cellular and Mokcular Bio~ National Cancer Institute Bethesda, Maryland IIENRY 'P. LYNCI/, M.D. Professor and ClYafrwroen Department of Preventive Medicine and Public Neahb 0ei~hton Univeraity School of Medicine Omaha, Nebraska HANS MEIER, D.V.M., Dr. Med. Vet., M.RS.!!. Senior Sts SrlenNrt 'iThe Jackson Laboratory Bar /larbor, Maine GORDON 11. SATO, Pw.D. Pro%ssor of Biofoty University of C.lifornia, San Diego La lolla, California I SHELDON C. SOMMERS SdenN/ic INredo., The Council for Tobacco Researcb-U.S.A., l.e. Clinkal Professor of Pmlblotr Colkge of Phrsician:& SurSeoos of Cowatbh University New Yort, New York SeksUie Std.(Tt.e ('.weY SHELDON C. SOMMERS, M.D. Sdau!/k Dirercror ROBERT C. NOCKETT, PN.D. Retea+ch Director DONALD N. FORD. Pw.D. VINCENT F. LISANTI, D.M.D. Associate Research Director ~ Ansorla(t Research Director DAVID STONE, PM.D. Associate Rttearch Director J C.) /-+

I 1 CONTF.NTS Introductwa . . . . . . . . . . . . . . . . . . 7 Abstracts o/ Reports . . . . . . . . . . . . . . . . 9 Cancer-Related Studies . . . . . . . . . . . . . 9 The Respiratory System . . . . . . . . . . . . 25 Ileart and CirculNiow . . . . . . . . . . . . . 49 Neuropharmacolop aed Phrsiolop . . . . . . . . . 63 Pharmacology and BiocAemislry . . . . . . . . . . 71 Immueolo" and Ad•Qtive Mech.ais.u . . . . . . . de Epidemiology . . . . . . . . . . . . . . . . 95 Active Projects . : . . . . . . . . . . . . . . . . 100 Contpktrd Projects . . . . . . . . . . . . . . . . 109 Index of Priecipal in.eaigaton . . . . . . . . . . . . 122 Indet of Senior AulAon . . . . . . . . . . . . . . 123 i HANS MFIER 1929-1981 Ilans /Keicr, • a+ewrher of Ihe SciawtiAe Advisory tloard (or trs years. deed May 14. /lc Iw/ Ueew a Senior SIaA Sciewliq •1 The lack- sow LalaraNwy ia Uar Harbor. Maiet, rl eh he joined in 1%2, •aa a comuMael to the Nuiowrl Cancer IwsliMrle sincs 1970. H.w. waa a di.linguished cancer researcher wilh a spedd iaNeresl in viroloRy, a /kld in wh:rch he allaiaed aw Mlerwtiowd heppNMiun. Qu:e1 a" aoll- spoRen, he had greal warwNh and ernplhy •nd an aPqrecialive sew o/ hunwr. /le contributed r•isely and wweltishir le Ihe efforts of /lr ScieMiOc Advisory tloard and, iw hia owa tabm•1ory, worted " •d hard /or the resoMNion of one of m•aUwd's lntJW tiller diaeaae•. Ha will be onisaed as a persee and a scienlisl. a

I Introduction I The rcMearch progranr o( the Conncil for Tobacco Research-U.S.A. mo.ei ahead Mcsd,fy in 1901 wilti the emphasia codierriwg to be directed toward gaining additional tno.~kdge of esncer, cardiovascular diseases ad etiro.ie polmonary aAments. The Scienti/k Advisory Board to the Council closely reviewed scores of applicNions from irwkpenden/ investigators for research urppxt, and by year i end the aumher of original grants approved by the Coourcil had risen to 709. Councii funding tor the research prograrw since iu Incept:un ra.r staads at more than =69,000,000. (lrant recipient. published 144 documents ira 1981 that actnowledg[d Council suppHt; the taal of such p.htieationa is now 2.026. Abstraeta of the 1901 prhhcations are incluwkd is /his report. Several chantes occurred in the eumposition of the Advisory Board dda ing thc year. I/ans 1.. Meier, t).V.M.. died irt May. William U. Gardaer, Ph.D.. resigned as Scientific Director of the Cornrcil but remaHn a mentber of thc Board. lie was succeeded as Seien/i/le Director by Sheldoe C. Somwras. M.l)., a lons-time member who had Seen C'hairmsw o( the Advisory Board. Succeeding Dr. Sonwners as Chairman was l.ew O. )aeobson, M.D., a Board member since t9S4. Roberl ). Hrebser, h1.D., hecaeu a.nertrber ewwihr at the erwl of 1911. Two more d'winpii.Cled scientists joined the Board. They wers Drwt- mond H. Sowdew, M.D.. rro/essor and Head of the Department of rathobp at the University of Manitoba Health Sciences Center in Wiwripc& Ca.ada, and Michael J. Brennan. M.D.. !'resikat aed Medical Director of the Mich- iian Cancer Foundatioa in Detroil. 7

i Abstracts of Reports Following are abstraNs, approved by the awhors, of reports on sirw research acknowledging wpport from The Council that have appeared i. scie*- ti/k journah since publication of the 1980 RepoA. Tbs w.are of the tetiphat is in italics. 1 he ahstracts are grouped under these headinp: 1. Caswer•Related Studia, 11. lhe Rcspir.tory System. 111. Heart and Circulalion, IV. Nevropharmacololy and PArsiolotr. V. Pharnucology and siochemistry, VI. Immunology and Adaptive Mechanisms, VII. Epidemiolop. 1. C..neer-Refated Sewdiea I I I FAMILIAL CANCER IN AN ONCOLOOY CLINIC Ksowkalge of hereditary cancer symirorne identilkation, often haaed upon twnor pro/Mes, age of onsel and t)rrnor d'suibwiow within the kindrad, aid signilkamly in the diagnosw of eancer. As reported here, all eaaar pM tients (5651 trested at the CreiRAton University Aecokoar Clinia belwaes luwe 1978 and April 1980 were entered iMe a pospec/ive ra+wilT Yslery ascertainment prolocol. This consisted of an ieitial evaluation by a«{iMesd nune wi4ling both ~ueain.n.ire and perse.d (Merriew. T1he initisl aaseas- ment yielded 199 ()s.s9i) tamilin wilb 1wo wrore fami/r merrrbets with cancer (all sites) wilhin an iwfornwaliMe wtkar eorraponeAt, which ooolilMMd parents. Rrandparents, auMs/wc{a, sihlings, aed diWren. One or rraon of the operational criteria for cancer (anrilidily, "aw+elp vertical trarnmirim o/ cancer, bilalerality, and/or aardlipk prinwies, early age of onsel, and 1Mea or wwre site speci/{c canoers, were found on physician review i. 171 ( 70.3%) of the families. This group was referred (pr oomprehensive canoer Re.e1k evaluation consistinR of pedigree ealensiow and tumor veriAcuion tlraislr aR second degree aod, when possisle. third deRree relatives. 11 was dekrad.ed that appro:imarely 4% ol the 101l1 clinic population derwons/raled Mdinp compatible with hereditary cancer syndromes. The universal eatension of Ihese surveillance meihods in clinical practice is highly recommended here. Albuw, W. A., LywrA, N. T., Rec.baren, l. A.. Organ. C. H., Mailliard, l. A.. 81ack, L. G., Folk11, K. L., and Lynch, I. Cancer 17(9):2111•2115, 1981. OtAer w'/wrtr FrNCrn.l Order of Eagles. From 1he Institute for Familial Cancer Management and CorNrd, lnc., a.A Ihe [kparrmem of Surgery and /'revemiw Medkina, Crelghton Vniversllf School of Meditlne, tMuha, Neb. 9 I

I AMII IAI BRI-AST CANCER AND ITS RECO(:NITION IN AN ()N( O1 (K:Y ('1-1NIC This p,per focu.rs attention upnn in-depth clinicopalhologK studics of breast canaer pronc families wherein cancers of all anatomic sites were cri- trcally asesscd in contest with genealogy. For this study, lamily hislory of cancer was evahrated tor 79 breast cancer probands from among r series of cunseculrvely ascertained cancer paliewts undergoing trearment in the Creikh- Inn Sl l.seph's Oncotogy ('linie. C..cer prevalence lor e•ch family was quan- Idkd by using a statistic that accounts for variable size and age structure among families fo lesl the wuM hypothesis that cancer risk is independent of tamrly memhership, rhe dislribuliow of this statistic /or families (n their original configuration was eompared wilh /he drslnbulions obrerved when rclarives were randomly assigned to famifies in 99 random prrmrMariom of family nreml.ership lhe results indicated signifkant heterogeneity for cancer rnf< •nN.ng retariver of breast eancer probanJs, which suggests that the isola- turn of high rr.k families can provide • meaningful resource (or in depth studies in Measr cancer genenics. The uudy of breast eancer-prone familin harbors a pnwerlul potential (o. beNer comprehension of mechanisms of ear- crnotcnesn and tl.e development of novel pursuits toward improved cancer control. 1.rnrh, 1I T. er at ('anrrr 17 f t I I' 710 27 )9, 19!> 1. Other support: Fr•ternal O.der of Eagks. From the Crcighlon Univcniry School of Medicine, Omaha, Neb. ROUTINE CYlOD1AGNOSIS OF PULMONARY MAI.IGNANCIFS Material routinely sudbned frowr the tracheal lube of patients under general endo(racheal anesthesia for surgery is twrmaBy, ddiscarded. In this sludy, haweMer, the suctioned •ecretions trom 10.621 urch patients were pre- served, and later eaamined microscopically. Among these specimens. 11 q- tologic•lly abnormal smears were obtained /rom subjects with unsuspected pulmonary involvemenl, an incidetsee slightly more than 1:1.000. lbe aceu- r•cy of this method was assessed by calculation of the percent of abnormal smears obtained from patients wilh prediagnosed bronchogenic carcinomas: 40% when wctioned material was irnmediately spread on slides. and 67% when cellular concemration was achieved by mucolysis followed by filtration or cenlr//uta1NN1 In addilion, by using this lechniyue, a wide variety of cyto- narphnbSic and cylochemical changes in tracheobronchid cytology of both intrinsic and cstrinsic rnigin were discovered, chances which otherwise would have been ms%ard AhMwgh routine cytologic screening of all patients under- pant tc..cul rn.larahr.f .nnrhrs.a is not advocated here. it does seem L,w.,Mr itA.. rA.o nroA,.J t.-.W prn•r henefkr.l for the early deaten.wis of mal.to.nr n.,,/Ja.... .w a p,yrd.o..n ar rod I / to I ('hnfon, !. cr at. Arr hirei o/ ParholoKy s l.hor.oorr Mrdlclne 105:11-11, 1951. Other at.rport: U. S. Public Heahh Set.ice. From the (kpartment of Anesthesioloty, New York Unirenily Medical Ce.- ler, New York. ARE TUMOR MARKERS USEFUL IN D/AONOSINO LUNO CANCER? Becanse it has been no/ed that many hrng uueon have a Io+K latency period and a slow 6 row,h ra1e, the idea has been ad.anced that biochemical marken-ho.rnones •nd other metabolic producM of lumors--mi6h1 rewe•1 1h• presence of malignant disease .1 a very early stage and thus improve the .ur- vival ratio. The paper presented hero deserihes some o/ Ihese marker systems and evaluates them. In one ease, armed with a preeise and simple .•uy sy- tem, investigator. tested the hypothesis lhat elevations in peptide horwqne concentrations in blood might be a sensitive Iwdieator of the presence of a tumor. Tfiese and other studin have reveakd many interesting endocrinobok interactnwrs, but onlorlunately have not provided a su/Rciemly reliable and sensitive early marker of tumor presence. There are several other •ubstancp which have bera /ound 1o he presenl in abnormally high amounls in the blood or urine of patients with bronchial earcinown. Some ae producys of Ihe abs- plastic cells themselves and thus represent trut lumor marken. CareMoetw- brynnic actigen is the best sun/ied and uro.1 inleresting of tbese subslanees. Aryl hydrocarbon hydro.ylase and free seere/ory component of imrnunoklobu- lin A studies are ako touched apos here. From a diRerent facel of en/y de- Iection. fluorescent bronchoscopy, shows promise a• a means of very epdy anatomic identification of hmR tanan when the tunwrs are curable surgically but not deleclabie by traditional methods. MerriB, W. W. and RernWds, N. Y. Thr lorrnd of Resplrarory Diitarrs 2:1,-52, 1981. OtAer wr'prtr Ch.rk• E. Culpepper For.dallon- Prom the Department of Medicine and Internal Medicine, Yale U.Irenity School of Medicine, New Narew, Con.. RI:ASSSF..SSMENT OF THE RELATIONSI/IP BETWEEN ARYL IIYDRO('ARBON NYDROXYLASE AND LUNG CANCER In this study of the retati+nship between aryl hydrocarbon hydroaylw (Alill) and lung cancer, ANII levels were evhutcd in mito6ew-aclivNed lyrnphocytes cultured with and withoul 1ha inducer benzanthr.oena In 1hs medium, and in pulmonary alveolar macrophages (PAMs) that were /reaY) lavage.l from 114 cigarette smokers, 6) with and 51 without lung eanorr. Considered scpar•tely, neither lymphocyte Allll nor PAM AH/l kveia wen distinctly difterent in either noncancer or lung cancer patients. Ilowever, whew 11

I I canswl.rcd simulUnerMn/y, lymphocyte and macropha6e A1111 lcvcls werr yrule Jd/cren/ in rMmc.rncer and lung cancct pahents. '1he /ung cancer patient RrrNIr was seen to comain a si`ndicanlly higher percentage of petwrns wid, hrKh levels of A1111 than dw] an age-matched gnrrp of noncancer patients. l rnm another view, rcwlts of this strNly showed a 1:1 corrclahon of PAM and Iymphocyle Atilt kvels in noncancer patients and an absence o/ correlation of the trssuc A1/11 levels in lung cancer patients. Overall. it seems, on /he basis of the work presented here, that sint/e-tissue Atilt analyses are not ade- wsate (nr evahration of Atilt activiy in tang cancer populations McltnK+re. T. 1.., Manin, R. R., Wray, N. P., Caovell, E. T., and E'utbce, D. L. Cuncer Ie(6):11)11•144), 1911. (1tArr aurp.rrr National Lstilu/es of HeaMh, Amerieaa Cancer Society and the Veterans Administration Ilo.pital, l/ouston. /'rons the (kpattment of Medieine, eaybr College of Medicint, ifouslon; Veterans Admmistration Hospilal, Houslow; Department of Phrrmacology, lean College of Ostcop.thic Medicine. Fort Worth. and GenrlKs Center and IkpartmeM of Biological Scienoes. North Teaas Stale University, Iketos. A MFTIIOD FOR 1)E7F("11N(: ARYI. HYDROCARBON IIYI)RUXYI,A!l'1? AC11V1 t 1ES /N CRYOPRESERVtiD HUMAN 1.YMP/1()CYTFS A standard procedure for the frecring, thawing and culturing of eryo- ptesetved human lymphocytes ia pretcnted here. Using this rnetM>t/, three parameurs- -aryl hydrocarMrn hydroaylase (AIIH ) aclisNy, NADII-dependent cytochronse c rednctase (cyt c) activity, and 11111 thymidine (`ll-ldR) in- corpo.ation-were monirored in human lymphocytes erynpreserved for petiods up to .N+e year. Ihe kinetics for eapressiun of bersr/,.lanthracene-11/A1-in- duced Ali/l activity, cyt c activity and 'H-TJR incorporation were similar in freshly cultured and cryopreserved cells. for this suwfy, lymphocyte sampks from 10 individuals were cdlecteJ once a month during a Ihree-month period and cells were either cuNured at time of donation or eryopteserved for later assay. ResuNs Indicated that she cryopreaers,ed lymphocytes ef6cien0y re- sparled to mito6en activation. The inlra-;wJividual variation in AHH aetiv- itics was reduced in the cryopre.ers~ed Iymphocyles compared to the freshly cultured cells, and the relative canking of these individuals in terms of their Atilt activities remained constant fa both fresh and cryopreserved sampks. It seems, Iherefore, that eryopreservuion oAers si=ni8cnq advantages over the freshly cnitured lymphocytes because it aBows for lymphocyte samples to be collected in diverse geographical locations and over eatetMkd perinds of time and yet permits for the culture and assay of all the cell samples at eaactly the aame time. Koati, R. E. cr.f (MkroDiofolkaf Arsoc(arcr) Cunrcr lstarr 14 29 10, 1981. F'rr.m the [h.rsr.n .d lo..coi.ty and ()ncolup. Microhiological Associalea, Ikrhe.da, h/d 12 SI(:NII~I('ANf VARIAiION IN MOUSF.-SKIN ARYI. HYnR(X'ARBON IiY1)KUXYLASI: 1NUUCIBIL) I Y AS A FUNCIIUN UF fNE HAIR (iRUW I H CYCI.E Skin, which is a goud biological model tor the study of polycyclic hydro- carbon mclabolrsm, eshibits three major morphological phases in she hair growth cyck. In earlier works, it had already been demonstrated that akis possesses activating and detosilying enrymes, notably aryl hydrocarbon by- Jrosylue (Alilt) and eputide hydro/ne. For the ptesent .tudy, aw atnitpt was made to determine whether Atilt activity and i1s irnhtcibilily vatied dur- ing the hair trowth cycle and could possibly eaplain cectais varialiona in tlin sensNivily of carcinogens. An easy, aapid and improved /eclwsipue (or hoew IenirinR whole skin was devixd for this work. Using the new homoRcmirj.R method, it was shown that skiw AHH activity in C37B1.J61 and C)Hlk,o mice could be induced by i p. injected or topkaRy applied methykho/anthrtwe during a defined pesiod of the hair growth eyck, /.e., between the Mth a.d 1hh Jays after depilation (Stage 6 d/he anaprt phase). 1o each eaperi- mental makl, there was an optimal methykholanthrene eonoeMralioa which yielded a maaimum induction. 'Topical methykholantArene was also respow- .ibk for a smaller Atilt induction when the chemical was applied the aamtr day that the club hain were pkucked. On the oller fand, skin Atilt activity was never induced by methykholamhrene in OSA/2t mice, a genetically ao.- responsive strain. from a Wsieological poiM of view, the fact that akia ANN activity could only be Induced by polycyclic hydrocarbons at a certain time during the hair growth cycle of a fieneticaNy responsive attain might be o( great imporlance. Manil, l-., Van Canlfort, l., l.apit re, C. M., nad Olrlen, l. E. ertrish lournd e/ Cwctr t7:210-221, /991. From she lsbo.atoire de Derma/obsie atd Iabora(oMe de Chimk M1licdt, Institut de Patholostic. Univecsitd de Lifte, IJiile. Selgiww. CYTC)c'IIROME P-4S0 MONOOXYGENASE ACTIVITIES IN HUMAN AND RAT LIVER MICROSOMES Only limited data .re available a(he poeaewt time on the biochemical properties of the human enzymes. Nowe.er, recent studies have ahow. t!M suitable liver samples ooutd be obtained /rom kidney transplant dowa>< srd the microsomes used iw this study were ptepaled from human liven .etiuiri.d from renal donors of various ya and both seaes. Thcir druR-melabolkby capacity was measured and compared to that oI rat liver wuccoao..es. Tha following parameters were imestipted: eylodlrane P-ISO, crlochrome iS. NAi1P11-cytoclwome c reductase. eposide hydrolase, eryl hydrocarbon hy- drosylase, betwphetamine W-demethylase, p-aiitroawisok-O-demelhy/aae, ethoay/- cownatin-O-deethylase, slecoid-l6.-hydroaylase. In addition, the melabolirn of benro(w)pyrene, progeslerone, prerneeotone. te+toateront:. dehydroepiaw- drosterone. and estradiol was studied in deuil M.lrr.. RewRa showed dut Ihe cyluchrome P-1S0 content in the tivea of the kiJner transplant do.wrs was 10 2 t 7.9 nrnolt6 o( tiaure. Is did no1 di//er with /he aea of the de.oc. Comparison of the data obtained wah humaa and ta microaornes denusnacated qualitative and quantitative diAererrces which wtied with the pararneler. 1)

studied Ovtrall, results of these sludrcs indicate Ihat the drug-melaholizing rnryme activities (ethosycoumarine deethylase, benzphetamine demethylase, aryl hydrocarbon hydrosylase) vary as a function of the cytochrome P-IS0 content. The steroid hydrosylase activities do not fluctuate in a similar man- net. Speciflcally, this study shows Ihal the use of livers from kidney trans- plant donors is a promising tool for Iesting the metabolic pathway of new drugs in man or for scrcenin6 potential /o.ic or carcinogenic properties of iscw chemicals. Kremen. P., Beaune, P.. Creski, T.. De Oneve, /., Columelli, S., I erout, 1. P., and lae/rn, l. E. Errortan lo.rrwd o/ florAriwlm7 1111:399-f06, 1911. Otil.r .rtpHr Foads de Is Recherche Scleslifique MEdicak (Belgium). Fronm the I aborato'ue de C'*iwsM Mbdkak, Imlilut da Pathologie, l)nivenilf de Little, I.kge, Belgium, and FaeuNl de Mtdieine, IlopNal Neeker-tnfauts Malades, Paris, France. ONTOGFNIC DEVEI.OPMENT OF STEROID 16 a-HYDROXYLASE AS A TOO1. FOR THE STUDY OF THE MULTIPLICITY OF CYTOCHROME P430 This Mudy, ffollowed the evolution of sleroid 16 .-hydroaylase in the rat liver from birth to adulthood. To do shis, the quantitative and qualitative propanin of the steroid hormone-wxtaboluins system during the period of ontolgenic de.ebpment of Ihe animal wen investigated and compared 1o those of the adu/t nsoooosf6crraae sys/em. In the beginning. activities of progesterpne, teslosterone, preg newolo.e, aed dchydroepiandrosterone 16 .-hy- drosrla,e were undetectable in the fetal rat 1'wer. During the neonstal period, howe.er, the four erwymic acti.itiee increased in parallel so the carcentralion of ertochrome P-.30. Until puberty. 1" developed similarly in male and femak rat livers. From the I0th le 1he 3S1h day. Ihe four steroid 16 .-hy- droxyfase activities increased rspidly M the male rat liver, but no/ in the female. T)te sesual differenlialion of tht steroid 16 rhydrosylalioe observed here look place around the 55th day. 1Mheo the sduh rat liver was studied, steroid 16 .-hydroaylase was supporld by two fonws of eytochrome P-4S0 (forww I a.d 111 which differed i. thck relative affinities for Mte various steroid subdrales and by Meir relative proportbas iw mak and female rat liven. The transition from the bnm.lure so the adult rcpartilion of the 1wo forms ocewred during puberty md was correlated with the seeual differen- Iiatiow of the steroid /6 0-hydroa}Ine activitia. In another phase of this study, the /n dtro interactions between benw(.)pyrene and slcroids were oornPared during the eritical phases of the rat ontogenic devdopment. Pnkau, F.. Kolodtici, C., Krcmer, P.. Bad Cl.ten. !. E. Eurorron lo«rnd o/ SiorAtwrbrr7 120:213-220. 1981. OtAer support: Fonds de la Recherche Scientifique Mfdicak (Belgium). 1'rom the lAhoraioire de Chemk Mldicak, Institut de Paihob&. Univenitf de l.ilgt, 1.it1e. Belgium COMPETITION BfTWF.FN BF.N2O(a)PYRENE AND VARIOUS STEROIDS FOR CYlOC11ROML' t430-DEPENDENT RAT 1-IVER MON(X)X YOENACFS Many previous reports have described the eaistence of various types of in ritro competition between nwrao.yRenase aubarNea. For the present paper. the interaction lw vitro of steroids and bento(.)pyrewe (BP) was studied a1 the level of two rat liver monooRypenmes, steroid 16 rhydroaylase and ary1 hydrocarbow hydrosylsse (AHH). The resuNs obtained in these tests wuesl the following conclusions: (f) Steroid-/6 .-hydroaylase is partially supported by a speci/k cytochrome r-130 form which is s+o1 inhibited /n r'Hro by eto- Renota substrates. Steroid-16 .-hpdrosylase is oompklely independent from cylnchrome P,-130 (or r-IN11, as i1 h insewsilivq /n .Ino, 1o .-staphtlrs flavone; (2) AIIII is supported by two cy/ocfuorwe t'-130 forms: a speciRc form which is inducible by wtcth7khdaMMeae t>wd inAibited /n rhro by rnapMhaRavone, but is insemilivt to metyrapons .ed alaoids: and anotber kss specific form which h inhibited by nsetyrapoms and steroids /w .irro. It seean reasonable on these grounds so auwne the eaisterice of speciAc eyls- chrome r-4S0 forms that are responsible for endoRenow compound meubol- ism, or at least for hormonal steroid 16 rhydroaylation. This observation may possiMl he of physiological importance, as it could preserve endogenous metabolism Irom competition due lo enviromnenlal senobiotics. Paskau, F.. Kremen, P. and Gklen. /. E. CArnNro-diolotir.f lntenartioru 11:279-2116, 1961. OtAer a.rrprts Fonds National de Is Recherche SeieMiAaue Mtdicak. From the l.aboratoire de Chimie MEdicak, Inslitw de Pathologie. Udvenk6 de L%lge, Litge, Belgium. METAflOLIC INA(.`TIVATION OF MUTAQENIC DENZO(a)PYRENE METABOLITES: SIGNIFICANCE TO CARCINOOENICITY AND IMPLICATIONS FOR !N VITRO TESTs In lbis very weR-ressoed P.per. the twt.Renkilf. ..d /n sdtro IestinR of bsoto(.)prrewa (RP) tre ooasidered fretwaol dilleftest aspects. It is knowo that BP lus a Complea wrclabolistN involving rwa.r st zrmcs and, because of dris. complete metaboNsi.l sfstews for tbe aelivatian of BP ud its prennNalgenic metabolMea were wed iw the bacterial tnW.- {enkity leas presented here. The activatity .pslem. Ined wera freshly iso- lated intact bepatocyles or \onwgets.kes of their eelis wplleme~ted wit\ wr- ioueco(ador systems. '[he compounds Iesled. wete Ihe csei.oResr BP :d ( t)tr.nr-7,edihydro.y-7,>f-dihydro-Or (7,1-diol) and the rery weak car- cinoftens or tumor initiators l-hydroay-SP ( I-OH-BP), 9-hydroay-11P (9[H!- BP) aad ( i )tr.ns-9,10-"ydroar-9.10-dihpdro-§P (9,10-0iol). (AN .rs strong wwta6ene in the Arses lesl.) Results of 1hese lesu showed 111M RP was no/ mutasenic when tested directly or in the pteaence of hepaoeyts fwn.oe - enate. Ilowever, it became strongly muwatenic when an NADPH-genetatiae system was added to the homogcnale or when whole hepatocytes were used. T4 dose-response relalionship difiered matkedly under the two situations. 3-011-BP, 9-OII-BP and 9-10-di4g were not mWa6enic in the preaeoee of IS 14

r homofiena/e. However, when an NADPH-genersling system was added with Ihe cell homogenate, mulagenk eAecls were observed with all three. On the o/her hand, 7,tidiol was aetivaled by both homogenized or Intact hepatocytes to a very potent mwagen. Overall. the rewl/s of this study show that it is possible to activate BP and BP-metabolites to bacterial mwageos with intact hepatocyles. The mutagenkity often is weaker and the relative potencies of various compounds reatly diQerent from resuhs obtained with NADPH-for- tiAed cell homogenate. Afso, it was shown here that addition of eolacton of further enrymn coesiderably, aaltered wtwa:ewkhy. The alterations differed with different test compounds and the results became rrare similar to resuhs obtained with intact cells. Whee carciwornicilr was taken into accoual, it was seen that use of intaet hepaloqus instead of NADP11-fortilkd homoll- enale considerably improved the correlation of n/ulatenacNr with whole Mi- Ina) earcinopenkAy. Now, while intaet hepMoertes ma7 well awt be the opdmal metabolizing tqntem In sbort 1ern. tests for earcinofenkity and mutsgenicity. Ihis study shows that Iha Inetabolking system can very strongly affect the result of a ler. Therefore, if Inaclivation oocron in al.o it is reasoaabls to take the inactivating systems (Mo aeeounl also In /n vitro ters. Olan, ll. R.. P1at1, K. L., Voilel, M., Itader, M., Billinp, R., and OezcA. F. In: Itolmsledt, B.. Lawrerps, R., Mercier, M., awd Roberfroid, bf. (eds.): 1tIefAlMGmt o/ ToaleUy, aw/ N.ta.d Erdrtetlon, Elsevier: North Hollaod Biomedical Press, 1980. pp. 111-186. From the Pharmakolofisches 1..1itw der UsivenitH Maitut, Federal Republic of Germany. RAT LIVER CYTOPLASMIC DIHYDRODIOL DP-/IYDROOENASE: PURIFICATION TO APPARENT 1oOMOQENEtTY AND PROPERTIES tn this biochemical paper, a method is described for purifying a diby- drodiol deh7dro6enase 1o apparent harw6eneit7 from the cytoplasmic frae- tion of rat liver 1wmWnak. Some properties of the pmiAed peparation, and the eRect of this entrme upon tbe wwta6esicit7 of beetto(.)prrene arn also oonsidered herr. SpeciAcaMy, the pnrilkatior involved (NH,),SU, fractiona- tim DEAP.oelluk+ae ehromuography, hwerfaeW sahitK-M and gel Altration through Sephadea 0-100 tuperAne. The end product, which .a puriAed over S00-foid with a yield of about 14% whe* compared to rat liver 10f",000 It A wpem.lant. was Judged to be horno=e*eolas by several erileria. Phys.cal stud- ies suggested that the protein was a monomer with a mokcvlar weight of 13,000 and one NADPH binding site per molecule. Amino acid analysis showed IhN the enzyme had a relatively bigh content of acidic and neutral amino acids irn agreement with its isoelectrie point. Apparent Km vahres for benrsne dihrdrodiol and NADP+ were found to be 2.2 mM and 7.7 rM, nrspectivel7. Substrate specificity studies showed Ihat, in addition to benzaw dihpdtodiol, the deh7dro=enase oo.ld oxidize acewapthenol ad the 7.-hrdros7 group of steroids. No activity was observabk with a large number of other hydrosylated steroids possessing hydroay groups at positions lp. 11p. 17., 17Q, 20.. 20/1. 21 and 22 of the steroid skeleton. Furthermore, only sleroids which contsined a l keto group and no double bond at the A• position were reduced. 7Uis, and the fact that a range of nonMeroidal vkin.l dicds did not 16 serve as substrates, indkates a relatively narrow substrate specificity. The role of the enzyme in the metabolisnm of carcinogenic polycyclic hydrocarbos Is discussed. Vogel, K., Bentley. P., P1Nt, K-L., and OesrA. F. 77)e Iorrnd of eiolopk.f CArmi.try 255(20) :%21-9625, 1950. Frorn the Pharnwkologisches Institw der Uttiversili/ Maint, Federal Republic o( Oertna.T. QNZYMIC IfYDROXYLATION OF BENZO(a)PYRENE AT THE 6-POSITION BY VITAMIN K-HYDROPEROXIDI3 AND RAT LUNG IIY DROPN ROX IDASf} of /n henzoth(is.biochrene )pyrmie(BP)d p.atper,thethe6-posrokitionb o of vitamiwr.elaed K, is rhewilhMe hydroto.iativrldatiw e formation of vitamin K,-hydropetotide and its subsequent reaction with BP in the presence of soluble rat lung hpdroperosidase. Furthermore the chee.- kal synthesis of vitamin K,-hydroperoaide and the dual' inhibitory adioa o( thiodione (menadione-glutathione adducl) both as aw aryl hydrocarbow by. droaylase inhibitor and hydroperotidase inhrTritor is presented here. The apec- trd characteristics of vitamin KI-hydroperoaide and the 3.6-BP dione tft al.o shown. It is generdly t.own tha the identiAeatio/s of a proximate ear. eiro6en th.t results from the metabolism of eueilwAenic polycYclic hrdtr- earbom is a necessary prerequisite i.w order to stttdy the mechanism of chcw kd carcinogenesis. Studies are eowsidered in tbis paper that deal with the roie of dihydrodiol epotides of OP, eywchrorne P-4S0-448-Independeru reae. tioas, and hydroperoxidase reaetiows i. the 1lpdroaylaliow of <IP a the 6-posi- tion in chemical e.rcinoitawesh. Speeifkally, ahe studies reported fultp herm demonstrate that the mnem.Nr hrraA hpdroperoxidase is capable of «adift with potenliaNr naturally occurring brdroperoaides, e.p., vitamin K,-hrdro. pero=ide, to form the earcinoAe.6-h7dro>iy BP. Sloane, N. Iewbiorlr.ll(4):267-274, 19/1. From the DeparlmeM of Biochemislry. University of Tennessee Collqe of Merlicine, Memphis. DIALKYLNITROSAMINE s1OACTIVAT10N AND CARCINOOENESIS 71as nwni-review presents a sy.opsis of studies on the rnech.ninws of metabolic ac/ivation and carcinornesis of diaKytnitrosaR+ises. Since tha aiw- pkst and most cornmo. dialtylnilrotamine is dimethylnitros.mine (DMN), it was studied Arst. The considerable number of studies that were lakr ear- ried out on DMN are reviewed in the Arst section of this paper; sections two and three are devoted to the actions and reactions of dietbylnilro..mi.es (DEN) and methykthylnilrotsmine (MEN) and higher nitroaarninn. As overaN eonsideration of these many studies led to the conclwione that: (/) Prior metabolic activation of nitrosamines by various oaidases to alkylallng 17

agents which react with cellular macromolecules (DNA and/or RNA) is required Ior their carcinogenic or mutagenic activity; (2) In vi:ro studies suggest that nilros.minn are activated primarily (but not esclusively) by cytochrome P•ISO-dependent microsomal miaed-/unctioo osidases in the liver; (l) The postmicrosomal soluble eytosol also contains DMNdemeAylase ae- tivity, present in the "pH S e+wynse" fraclioe; (4) Thne miacd-/uoctioa osidasn are subject lo inducliom and repression by various agents and, thur, they may influence the bioactivaliow and eareinocenesis by nilroaamines Soene of lhese mndiAers may inAuetses uitroaaaaiaa earcinollenesis by mechanism(s) unrelated 1o the tnhancemenl or iahibilion of ailro..mine metabolism, e.g., iaMrenciag DNA mnformatiow, the eW o( DNA npair, etc. Lai, D. Y. and Arros, I. C. [i/r Sciewres 27 ( 2 )): 21,9.2165, 1990. From the Fnvironmenlal Protection Agency, O/liee of Toaic Substances. Wash- ington f) C, and the 1]rpartmeal of Mediciae, Tulane University Medical Ceoter, New Orleans. STlrp1FS ON MFTABOI.IC ACTIVATION OF CHEMICAIS FOR MAMMAI IAN ('F.LL TRANSFORMATION ANI) MUTAGENESIS There are numerous chemical agents in man i environment these days which have been implicated as potentially hwrdorn mu/akens and eareino- 6em This review paper louches upon several methods that have heen devel- oped to screen these atems lor Irwenbal problems Speedkally, during the las/ Afletn years numernus mammalian cell sywems have been devised which can detect such chemically induced endpoinas .s eytoroaicNy, /rans(ormatinn, and mulagenesis Ilowever, many chemicah demonstrate toaic or mutaeenie eRects only after they have becn metabolized by cellular enrymes to more reactive fcxms. O/ten the usefulness of a specific In virro assay system may be limited to only one or a very few classes of chemicals In order to extend the range of in rlrro nsays, various methods of wpplying exogenous melabolie activity have been tested. Cell-mediated adivNion, in riro-Iw vitro activation, liasat/orpn-mediated activaliou. and ocB.free enzyme preparations have beea used in atleatpls to duplicate the a.N.bolism which occurs during iw viro eipowne. 11 Is boped that N existing methods are perfected or new methods are di.covered by which to supply in rino tests with eaogenous metabolic aaiviy, krnwledge of the cowrpka i.rer.ctions which eveatually lead to tu- mors iw rlro wir sinurllaneously be iaereased. iltrstt., R. D., Kouri, R. E., ad ScisecAlmaa, L M. (Mkrokioloj*ic.i Auo- ci.rer) Is: h/i.hra, N., Kunkel. V., and MeMm.n, IN. (eds.): Adrawrer /n Modern Enrirowiwrar.l To.irobp, Vol. 1, Princefas lunctiou, N. I.:Seaate Prea lae, 1911, pp. 719-I37. OtAer aurr.rtr U. S. environmeMal Proteqiou Agency. From the (kpartmenl of Bicschemical Oneology, Microbiological Assoeiatn, 'Bethesd., Md . Ll1N(i CANCFR MODFI. SYSTF.M USINO )-METHYLCHOI.ANTHRENE IN INBRFD STRAINS OF MICE A lung cancer mndel system using intratracheal instiNatioe of 3-nse"- chol.nthrene in ClH/AnfCum and BCIFr/Cww atria.s of miee is presented here. The aniuah tested were free throughout their lifetime of Sewdai visvs, pneumonia virus of mire. and infedious disease. lu tltis study. 1the occwreacs of sponlaneous and chemically induced lu" eanocn was determined over the lifetime of the mice. Da1a were aaalyrsd by the acluurW wrethod for luas Iumor probabiliay, and /he probability was found to be dose a.d Nme de- pendent. Resuds showed Ihat over 95% of the l-etethykhd.wthrene-ureNei BC')F,/Cum and over et% of the Clll/Aa1Cum mice were found a/ death to have pulmonary eareinomas. Tunsors observed In aw)mah that died up b 40 weeks on lest were almost always squamow cell e.reLsomas, while tumon which were observed in aeimah 1hN died after SO weeks were mainly alveolar adenocareim>,nas. Both tsarqr types metaatasiad widely. Spoutaneous IuaB canecn (only alveolar adeaocarciaornas were observed) occurred in /Mese two strains at low frequency and were espaessed late in life. Thus, thn ays- Iem al/ords a suilabk model to study the indnctiow, eapresaiow. and progres- sion of luns tumors under cowditiorn where a vw majority of aairnds de- velop neoplasia. 11eery. C. l. rt .f. ( Mirrollolosk.l Asrorlarei ) Cancer Research 11: 5027-S012, 19s 1. From the Departments of E:perimental O.eology .ad Siochemical OncoloA, Microbiological Asaoeiata, •ethesda, Md. DNA REPLICATION AND UNSCHEDULED DNA SYNTHESIS IN LUNGS OF MICE EXPOSED TO CIOAREITE SMOKE A nmrine model system was used here b study the eRects of ehroole cigarette smoke exposure otn enzymatic acli.ities i. k+t.B liure traocided with DNA replication and DNA repair. For this work, attioe were chroukay a- posed to measured amounts of machiue-gewerated whole Kentucky re/en.na 2A1 cigarette smoke. DNA replication awd unscheduled DNA ayathais (UDS) were measured in hatB liswe in rino using a shorl.lerm organ cuNun method. Withiw one week of be6innieB stnolte etpeurre. DNA nplieati.+ aaivity, u indicNcd by incorporation of aH-lhymidiwe ialo total hruB DNA. was increased more thau 1wo-fold over sham<aposed eontroh awd rerwalued elevated as long as smoke eaposwe was continued. Trealsueut ot /unB tisrsa In vitro with either the hrnB carcinogen 1-aitroquiraiine-l-cisidt or asethpl- methane sulfonate stimulated UDS. presumably as the result of DNA repair activity, up until the 10dh to 121A week of sesoke e.posure. At that tima, however. the accumulated deposition of total particulate ma/erial In the lung was approximately 40 mg, and the level of UDS sdemlNed by the alkylatiag chemicals declined to approximately 50% of that seeu in lwy thwe lrosn sham«posed cootrol mice. If the mic% were removed from wnoke eapow.re. DNA replicalive activity returned to normal levels wilhia one week, bu1 the UDS response to DNA damage remained depressed up to Ilve months aller le 1 19

i ending smoke erposure. The results presented here show tlat both transient and apparently permanent changes are produced in mouse lung as the result of chronic exposure to cigarette smole. Rmrnwren. R. E. rt d. Cancrr RrrtaaAll(7):2St)-2Tlt, 1981. From the Dep.rtmeM of Cowrmrnit7 and Environmental Meiicine, Univenily of California. Irvine; and the Departments of Experimental Oncology and Biochemical (McoloDr, MicrobiobRical Aswciates, Sethesda, Md. MOSILITY OF SURFACE PROTEINS ON NORMAL RAT MACROPIIAUES AND ON A`MACROPHA(3E1-IKE' RAT TUMOR 'flThis study was MMlated so eaanni.e the lateral tnoMilNy of the same mem- brahe rnoleculcs is n..ctopha{ta, twrror cells resembling macrophaRts and lyrphocrtes. Results of these edl atrdies showed that peritoneal macrophaRes e.docytored thek histocornpNRrRiyr atwiRens (RTI). Fe receptors (FcR). and ooncawavatin A (Con A) dter tror-li.bing by IipndR, but did not cap these membrane proleins. 1. Nrrser teMs rese+nblinR eucrophaRes (721N), eheat membrane proteins were capped afler binding lipnd.. Frperiments a+earur- ing fhrorescence recovery after photobkaching showed that the mobik /rae- tinn of RTI was .iRnifkantly lircater In 72)N cells than In normal peritoneal macrophars Pmumal+y. the memMane praeins of 323N are not as kMered to the crtoslekton. or, 1/ .o, are in a nesus that is not the aame as that which occurs between membrane proteins of normal nucrophaRes and the eyto- stekbw. TT+e mobility of RTI and Con A receptors in normal lymphocytes was di/lerent from that found in tat.sal macrophaRes and imilar /o that of 721N eeMs. Thas@ observationa wyest that the wnov.emnl of maMbraM molecvks is determined by ocR type and ia regulated by the cytoskekton which varies Iw alrncture and functio./wm eeR type to cetl type. WoJ., a. A.. YRuerabide,l. and PeWtwatt,l. D. The lorrnJ o/ Crn ablon 9o:70s-71o, 19111. Other swpp.rtt National Iu.litMea of Health and the National Scie.a Pots.datio.. Prom tha Department of Ana/omk PathologT, City of Hope National Medical Ce+wer, Duarte, C.1.: Dep.rtmesA of Siotosy. University of Calirornia at San DieRo, Lt lotla• and the Dep.rttneat of Immuoopatlwlop. Research Institute of Scrippa C11nie, La 1oMa. VENEREAL SPIROCIIETO.SIS OF RABBITS: DESCRIPTION AND DIAONOSi3 Venered spirochetoais of rabbits (VSR ), a disease caused by Trrpewrmw rrwkri9. produces ksiona thN are characterized a papules. ulcen, or crusty areas. In the study of VSR reported here, rabbits nsed were from the /nbred, partially inMrd and mutant hearing strains maintained in conventional and hr.orrrcr.wnr •krr.rd c.r.w.rs at the Lclson I ahorarory. Ilar Narhor, Me Rea.tt. cho-rd rtw ..rur.llr and e.perrmesralty induced genital ksKrns were :o I similar clinically and hi.to/cKicaN!/. The rwrrl common .ite of lesbro b aal urally infected rabbits was the v ulva or preywree. Other sites, in descendin, order of freQuencp, were anal reRion, .oae, e*rJid, and lip. Clink.al appearanc, of ksions varied from erythematow nraeulea .r papules to ero.ionr, ukers anJ crush. IlistoloRical e.amination of k.siona cortflrmed the pre:senct of cro sions, ukerr, and erusts and, In addilion, reveded acanthosia and I.filtratinn o the dermis by plascna ce11k and macrophases. SirK+e diagnosia tl/ VSR de penda upon fieding T. crn(n/1 in wspect ksiantr or demonslraiing porNiw serological leus, four methods were used to test 11rc k.ines. Dark Rdd eenr ination of scrapinp /ronr lesions was auperior M the other anetholr 1or dr teelion of Tirpowrnv crwlrnll. However, the rapid plasnu reaRin hrt desedev' more Infected ralrbita than earnlnation of ksions. The freq uency of lalr posi tive rapid plasma reaRin lesta was low; the frequency of /rrhe neplire ara/in tere varied with the slqe of the diaeare. Cr.fde-Ikamer. T. 1.L and Foa, t. R. (Me/er, H.) l.6o.do.T Awl.wd ScJrncr )1(1) : 766-771. 198 1. Otfer.rppe.tr Natiend IartMwes of HeaM and The lactw. Laboratory. Prom Tlie lactson Lsboratory, Bar Harbnr, Me. VENEREAL SPIROCHETOSIS OP RABBITS: EPIZOOTIOLOOY The role of vertical tr.nrnis.iot and Renetie predisposition i. 1M qirad tioloRY of venereal spirochelosh of rabbita was evaluated In this study. Rad bia surveyed here were /rern the i.bred,p.n i.Ry inbred and Otwatd Marly raralm In ths evwvaMion.l (etstoa/kaRp Wae1N) and hyrlereAa>Mla/ved colnnies maintained at TM lactaew L.borNer7, Rar H.rbar, Me. R.wRr presented in this p.pa sho.r diRerenoes In the rrneepibility ro and e.prerriom of venereal spirocheto.is assortR diRereM iobted or part i.bred nraitr of rabbits. While aignificaM diQeretsces het.tea Ireauene~ lesions M aduM twale or fenuk rabbin were no1 observed, nor were aiRniAeaM diilereass betsrcen the frequency olletiota is breeden or pe.breeders i. aht ti-/2 r.aath age tirarP. aigeilkaM diRetreoes between die freryttencp of kaionr In brecden and won-breeden wero oMer.ed srhew dilkrenl aRes wete pooled. 71w fro- quesrcy of venered .piroehe/osia in rabbib kaa Ihaw i snonths of age wa bwer tham thN in adtrlt rabbits. Newborn toMering eaperirne.ts indkNtd that infection occurred at birtb and during the tnrctNng period. Evabation af Ih.- terectomy-derived oRspinR of inktted datns suggested venereal spirocf,ero.ir was eliminated by hpsteredareyderivatiow. Vewerea) apiroehewrM was we- cessru8y aransmitted by topical or intr.derrnal suhesN.eeau at" Lowlaiou of adult rabbits. Adult rabbiy were wsore twceptiMe to eaperinrcs/a1 reneual spirochelosis than nconates. These eaFhuiorn were based on clinical a.d aeroloRical obsenratiotr. CunGAe•eeamer, T. L. and Foa, R. R. (Alrkr, H.) l.boraro.r A nbnat Srlrnre )/( d):)72-77R, 198 1. OtAer aupport: National Institutes of HeaMh ard The lactso. Laborasor7. From 7he lactson l.abcxalory, Bar Harbor, Me. 71

I VENEREAL SPIROC1113TOSIS OF RABBITS: ERADICATION This study wu undertatten to (1) evaluate the clinical am1 serolo6ical responses ta therapy of rabbits infected with venereal spirochetous, and (2) develop a program to eradicate venereal spirochetosis from an enzooticaRy Infected eanventional rabbit eolony. This venereal spirochetosir of rahbits, caused by Treponrw+a crnkrif, has been observed since the 19401 in the rab- bit colony maintained at Tbe laekso. Laboratory. Treatment rrt Individual rabbits with obvious clinical lesions rsing a produd containing crystalline prnkitlin and dihydrostreplorn7drt esred ksiona to hed, but venereal spiro- chelosis persisted 1n the colony. To further observe the eAects of healing here. clinical and serolo6kal tespowra of rabbib receiving three subrutaneous M- jectiona of bernuhiee penicillin O-ptocalna peniciYi. O(eirtw r 42.000 or 11,000 IU/kg body weight/week) at sevew-day Inter.ab wert reo.itored. Both doscs were eAedive. Tlre lesions healed wlthin two weeks of tte Ant treat- meM and rapid plasma reyin tilers declined markedly or disapftared by the .i.th week after the Ars1 treMnteN. Based upon the abovt Anc'inRs and re- suks of previan epaootioloRkal studies„ this program to eradi:ate venereal .pirochetoais lrorn the enrootkaRy infected colony was successfultj undertaken. (1rdN1e-Bea.rer. T. L and Foa, R. R. (Mein, H.) lAAoc.rery Awln.J Scirnre 31(1):179-3t11, 1981. Oth.r.upr.rtt National lrwltules of Hedtft and The lackson Lrboratory. From Ttr lacfson Laboratory. Bar Harbor, Me. CHARACTERIIJITION OF MOUSE FETAL LUNG CELLS CUI-TURED ON A PIOSKIN SUBSTRATE 1. Ihe methodoloRy, study presented here, an attempt was made to Rrow orpnotypic tnouse fetal lung cultures on pigskin dermis and to identify th. nxsu8aat oeM ekments by morpholoRial and histochemkal evrdence. Speet- AcaYy. lung organ bits wete Iaken for this study from fult-term mice and esplanted on the dermal surface of sltrik, dead pigskin. The cells mitirated onto the pigskin dermis .nd ptoliferded to form as organoid culture eonaist- ins of ductular slnrctures separated by a matria of epithelial cells. Cells within tha ductular structures were ciBated, produced mucin and eshibited the ac- tivities of nonspeeiAc eMerae and pmma-6/u1-amyl transferase• theretore. Ihey wert considered /o be derived from bronchial epithelium. Cells forming the nntrin poaseased the activities of nonspeei0c esterase and alkaline phosphatase and contained IanteRar strudures typical of wrfactant•producint pneumocrte Type (1 cells. Bec.use of these propertie+. the cells forming the matria were eonsidered to be derived from alveolar precursor cells. Overan, it seems at this time that this pigskin culture spnem, which cornbines elements of organ. tiasue. aed cell cuhure, will probably prove to have direct applicatinn In studies of rnutqe.esis. carcaa6enesis, and cell-to-cell interaction. Yo.hid.. Y cr.l (Frnn..w. A E 1 In Vlrro 16111 411-W1. 19110 From the I a lolls ('.ncer Research Foundation. I.a loila, Cal. 22 I . FINF STRII('TURAI. InFNTIFICATION OF OR(:ANOII) MOUSE LUNO CEI.I S('UI TUR FI) ON A PIGSKIN SUBSTR A1 F. This paper, which reports primarily on Ihe Ane structure of fetal lung esplanls and cwntrowth on gig.kin dermis, contains an initial report of a new cell type intermediate hNween ciliated cells and pneumocyte Type 11 cells. This cell 1ype, not yet found in vivo, is characterized by both cilia and lamellar bodies. In the overall body of work presented here, eRplanKd organ bits grew on the surface of, and into, pigskin dermal collagen for at kasl nine weeks after the inNiatinn of culture. The outgrowth consided of a thick cellular sheel containing variorn sizes of ductular strucNKes within a cellular matria that did nnl show any particular strudure. Electron microscopic observation revealed that the larger duclular unrcurres consisted Iar6ely of ciliated cells. The smaller ductular alnrcture eonsisted lareely, of Type 11 pneunsocptes eon- laininR lamellar bodies. Aho, when Iht cellular nulrit was eaamined, it was shown to cnn.ist of Type 11 pneun.ocytes and other cell types including Abro- Mrrs and macrot.hadcs in the early salle of cultivation. MacrophaRes invaded the pi6skin dermal cdlaRerr. An iMermediale cell lype, mentioned above, was idcnliAed in the larper ductular structures. Upon comparison of the uNra- slruclure of the or6araid 6n vitro cultures in pigskin with the original fetal lung. il was apparent that cylodiQerenlialion had oeeurred. The orpnold eomponents and strocture of the euhured cells nrore closely resembled adult long than the fetal lung use& 1o initiak the cultures. Yoshida, Y. Hilborn. V. and Frcewr.w, A. E. IwYl.o 16(/1):994•1006, 19/0. Oth.r wrprtr Awteriean Cancer Society and the National Cancer fnstitul.. From the 1A lolla Cancer Research Foundatien, L. lolla, Cal. OALACTOSYL TRANSFERASE ACTIVI'iY IN RAT BLADDER TRANSITIONAI. CELL CARCINOMA LINES AND IN EXFOLIATED CELLS IN URINE DURING CARCINOQENESIS AND REVERSIBLE HYPERPLASIA This paper describes the properties of plactosyl Iraasfense (OT) ho- lated from rat bladder transitional cell eareinonn in cuRure, and investiRMa the enzyme's activity iw (1) esfoliNed bladder epitbelial cells in urint of rab during carcinopenesis and rcverar~le hyperplasia, (2) bladder lutnor eella and (1) seria8y transplanted rat Madder eareinoma cells. For this study, cuhured cells of tat bladder transitional cell careinoma line AY-27, in suspen.io., were assayed for OT br measurement of the transfer of /sll/ galactose to de.ialyded ovine submasillary mucin (OSM-hANA). The asay was optimized witb re- apect to time and to protear, wid'arc diphosphale lodadose. OSM•NANA and Triton X-100 concentrations. Thia assay was then applied weekly to suspe.- sions of esfoliated Wadder cells collected from wMn of rats fed the Madd.r carcinogen N-(1•(3-nitro-2-furyl)•±•thiazolpl) formnwlde. .nd of oaMrd nb. Results showed that increases in activity over controls appeared 42 weeks after feeding the carcinogen. N a stage when bladder tunwrs were already mkroinvasive or deeply invasive, and activities at 32 weeks were about BO- 23

1 fold greater than normal values. In contrasl, a bladder cytolosic agent induc. ing revcrsibk hylrtplasia was Injected into rats and ea(olialed cells were eolkcted froen urines: these cells showed no greater GT activity than normal. Bladder tumor rissue from a transplanted tumor had the same high specific enzymatic U T activity as eafoliattd cells from tumor-bearing ra1s. Plottin, O. M.. (Zilbert, S. L., Wides, R. 1., Wol/. Q., Cohen, S M., and Futushima, S. Cenrrr siorAemtury eiopAyrkz 1:251-236, 1980. Othe..rrpertt U. S. Public Hea/th Ser.ica. From the Department of Nutrition and Food Science. Massachusetts Institute of Technoiogy. Cambridise, and she Depattwrenl of Patholosly, St. Vincent I/ospital and University of Massachusetts Medical Schod, Worcester. T11E ISOLATION AND CHARACTERIZATION IN VITRO OF NORMAL FPITHFI.IAL CELLS. ENbOTHELIAL CELLS AND F18ROSLASTS FROM RAT URINARY BLADDER Since the physiologic MNeractiow which underlie epithelial-mesenchymal inlegriry seem central so she understanding of tumor invasion, an attempt was made in this study so isd.ue and characterize in culture she normal eclb- lar elements which comprise she e.dolhelial-stromal junclion. For this rea aoe, epithelial celh, microv.scular endolhehal cells and fibroblasls were iso- laled in culture from normal urinary bladders o( Fischer rats. T1These ceR types were rtlSased from ewzymatiall7 ditaled, evertcd urinary bladders. Their cultivation by standard lechniqrrcs yielded fibroldasloid or epithelr.id nwno- layen. Cultswe growth characteriMics and light microscopic eaaminations readily idenlified librohlasts as the source of Abroblastoid nronolayers. How- ever, tbe.e techniques were swbk to diQerentiate belween she epithelial or cndo/helial origin of epithebid eronolayers. Electron microacopic examinations were successfully applied is sonar eulluret~, bait failed in others. The lhree cell types studied hers represent she normal control eeNs of an in vitro twnor aa)del /or she study of i.vasiMetleat. AII drra cell types are Involved in the formation and functional maiMera.oe of the epithdial-uronnal junction. The study of cell-cell and eeR-matrat interaclioas may provide (mportanm clues for the understanding of twnor invasivenesy a process that starts at the epithelial- stroval juwctioo and proceeds with iu destruction. PwR, 2. U.. A.Aersor.. S. N., Memoli, V. A., and K.rrtnrr. K. E. T4iw f CeM 12(3): 119-1)2. 1980. Othor er' prt: National Institutes of Health and the Otho S. A. Sprague Memorial Institute. From the Ikpartmenb of Pathobgy, Orthopedic Surgery and Biochemistry. Rush Medical College and Ruah-Presbyterian St. Lute's Medical ('enter, ( -hic ago. 24 11. The Reopir.toPy Sy.tewa PULMONARY FUNCTION IN YOUNG CIIILDREN WITH ALPHAr- ANTITRYPSIN DEFICIENCY. COMPARISON WITH MATCHED CONTROL SUBJECTS In this prospective study, designed to see it alph.,-antitryp.in (AAT) deficiency leads lo IwtR Impairment in early ebilahood, the peboonary /ww tion of a group of 19 children wish moderately severe and severe AAT de- fkiency (Pi phenotype ZZ or S2:) was oornp.red witb that of healthy oontsok matched for age (l-7 yean), se: and sise. There were .o statistically sifi- nilkanM differences between the /wo poups in the three pulmonary /wrctioi, variabks studied. that b, functioeal residual capacitr (FRC). maximal ea- piralory Ao.r at /'RC (Vma...,) and aineeotreeted Vaart„. (Vrnaz,.r! FRC). On the avera6e, however, the AAT4eficknl cbildrew bad higher FRC vahus and lower FRC (Vma.,.r) Ihan the eontroh, both of which would be expected i/ these children had some measure o/ Mepaired pulmonary fu.c- lioe and air-fiow obstruction. Although this strdy does not provide a deW- live anawer, il does suggest thal ther. Is no Rroea hnpairmenl of overall pu{- anoaary lunction in AAT-de/kient children under aee seven. Raii.t, A. S. et al. AnrrrJr.n Review o/ RrrplraorP Dluase 122(6):617-622, 1980. Frorn the Departments of Medicine a.d Pbpsiolop. University ot Ore6o. HeaNb Sciences Centu, ParW.d. REFERENCE VALUES FOR FUNCTIONAL RESIDUAL CAL•ACITY AND MAXIMAL EXPIRATORY FLOW IN YOUNG CHILDREN Tlre assea.meel of pubnonary fsactios M yowtR ebildres has always bees dillkdl, but a wesw lechniqre th.t tae.sures swMd eapkatory Aow a fu.e- tion.l reaidr.l capacity (Vnua,,,) M eaajwetiow with . wteawrerwent .f functional residual capacity (FRC) ia .ow being i.vestipted for ks suitaW/Rp n a rwcaswinp tool. The objective of the swdT psesesNCd heee was 1o deter- aaine the relationship of FRC and Vmaa,.e to sea, aie, beiRtw, .nd .rei61N in a group of heahhy young childrel is Port4.d. Oreron, and to t+sa these meaurements as reference values M laler sludies. Within the aRe, heiRlM awd weight ranges studied, exponential or multiple regression techniques offered .o substanlial advantage over simple li.ea regression YsInR heitlN, weiRM or qe. lAcre were no sex differences /or the relationship between either v.riable, and ate. heigM or wei&. These techniques eaw readily be wed in cbildren as young n three years of age and may provide a method for studying lung Sro..tb and development in carty childhood and a way lo observe the propes- sion of disease or the effect of IrealmeM in Ilte young child. A.rLt, A. S. rt of. Anrrrir.n Rerlew o/ Rr.plrnmory fNuarr 122(6):9e)-9ts, 19/10_ 2S

Qtlrrr support: National Ileart, Lung and Blood Inslitute. From the Departments of Medicine and Physiolody. Uni.ersiiy of Oregon lledrh Sciences Ccnter, Portland. Ct.FARANCF- AND METABOLJSM OF CIRCULATINO PANCRP_AT1C PROF.t.ASfASE IN T11E RAT The rate of clearance ol eircylNiwg rat p.ncreatie proesaatase, as well as the metabolic tale of this protdn, was eaamined in this rat madel study. Reaults presented here showed sh.l dte clearance of 's'1-lahekd proelastaae was biphask, with a hal/•life for ckarawce of free 27.000-dalton proelastase of app.ouimately 7.10 n.inutes; a slow eonrponent of clearance possibly due to proelastase associated with plasma protease inhibilors was also observed. At 10 minutes after injection of 's'1-labekd proelastae into the circulation, the major fraction of the i°I wu (ound to be locdized in the kidney. How- ever, appearance of 's91 M wine was sio., wilt 16 houn being required for e.cretiow of 50% of the i.jected 's'1 as acid-sohrb/e tnalerial. Suhcellular k+calizatiow eaperiwtcwts oft hornogenates of kidneys renrovcd at 10 miwu>tes pauuinjeetiow revealed that the majority of the 's'1-labekd tnaterial was aaso- cured with the nti/ochondrial and lyso.orwd fraction. SucroK kradient eeMri- fugation studies of this Iractiow showed that the labeled material passes from Ihe membrane Iraction lo the lysosomal Iractioe with time. In summary, the results of these studies demonstrak that the kidney ia the major site of ekar- anu and catabolism of circulatiaR p..creuie proelaslaae. Lsualenan, C.. Ray, S. B, Brodriek, l. W, and Crotat. U. C. Antrrkan lour+.1 o/ rAyriobp 279 (Oastrointest. Liver Phyaiol. 2):OS0d• 0510.1960. (NAer eorrortt Medical Research Service of the Veterans Administration and the National Institutes of Health. Froet the Fatzymoloky Research Laboratory, Mutinez Veterana Adminiatr6- tio. Medical Center, Martine:, Cal.; and the Department of Internal Medidee, U.iversity of California School of Medicine. Davis. CLEARANCE OF CIRCULAT1NO ANIONIC AND CATIONa: PANCREATIC TRYPSINOOENS IN THE RAT In this atteetpt to gain insidtt iMO the physiological trtechanisms eon- trolliei the levels of pancreatic trypsiwotetr in human blood, the kinetics and mechanism of clearance of patcreNie eatioeie and aniosic trypsinoRene from the circulation were investigated ie a rat model. Eapcrintental proced- ures used here included protein iodination, plasma ekarance determinalion. Sel flliratioe study, and orga• distribution analysis. Results of these invesli- puona show that 's'I labeled rat calioeic tryp.inoges is cksred from the i bloodstream with a h.lf-life of approaimqely asti minutes. In contrast, 's'I- labekd rat anionic srypsinoden has a hall-/ife ie the circulation of appros- imately 55-60 minutes. Neither zynto6en binds to plasnu proteins to a aig- silkaM eatent over a period of three hall-lives. The relative ralea of ckara.oa of these zyrttogero Irom the circulation appear to correlate with their respec- tive isoelectric points. Praearily, the results preseated here show that the kid- aKy is the primary .ite of clearance /or both rat anionic and eatioeic pa.- ereatic trypsisoges. Brodrick, ). W., Larprtan, C., Ceoi.s, M. C., O'Rourke, M., a.d Ray, S. B. Arncrk.n Jorrn.l o/ rlirslolopr 239 (O.atroiaest. Liver Plyaiol. 2):aS11- OS1S, 1910. 01Asr wr'ort: Medical Research Service of t6a Veterans Adntioiatration and the National lnuitutea of Ileahk From the EnzyrnoloRy Research Laboratory, Martitte: Veterus Adrsi.irr.- lio. Medical Ceuer, Martinez, Cd.; a.d the Departaney of Internal Med1- eioe, University of California Scbool of Mettieia, Davi.. SECRETION OF ALPHA.-PROTEINASE INHIBITOR BY CULTURRD RAT ALVEOLAR MACROPHAOES Alpba,-proteiaw inhibitor (.,Pi) iM thotspt widely 1o be tb tta.jar esdo6eaous inhibitor of kutoere elaslne. 1n dr eaperitwew pr+eseae+ 6ere, .,Pi .ecretio. (row alveolar wtacroph.Bcs was eznniaed, ber,at..M o( .,Pia k.osrs role ia proteiuse-aMipraei.a.e teRulation a.d tha polentl.l importasoe of its loeal prodttctien by hang oer.. Speciticaqr, .,Pi, tuata- bolicaly labeled with a'S, was delected i. coaxurated euNure aed'turs af rat alveolar wucropbaRes by itnaNrodeelropAoresq .woradioRrap6y. Tke otetabolieally labeled macrophq. .,Pi 6ad t6e eraeo deetropiosaie molsiWy as did pure rat serum .,Pi. Moreover, wtowotpecilic atuiserunt 1o rat sasm. .,Pi precipitated a a'S-/abekd protein froat wacroplt.ige culture wperetalM asd /6is proleia waa ahoww by sodium dodeerl attYate polractylamide ild ekctrophoretis to have a ntokcWar weisht elo.. /o that of rat mtuw .,PI. The addition to the cultures of erclohetitttide at a ooaoe.tration of 0.30 p=/tnl prevented the i.corporalion of label iMO iatnw.oprecnbN material. Overall, the results presented here iediule ehat .,Pi ib syahesima atd aa crrted by cultured rat alveolar tat.crophaRes. It also appears trat the socretion of .,Pi by alveolar macroph.Rea might plar a rok is the defense of the Mt.R. White, R., Lee, D., ILbicM, O. S., sad l.no0, A. Atrterlc.n Revkw o/ Respiratory DJsease 127(1):4/7-41l, 19t1. Oth.r sr'prtr National Heart, Lung aed Blood 6ptNute and National Imtilule on Agiog. From the Department of Pathology. State University of New York at Sto.y Brook, Stoar Brook. 27 26

INAY-IIVAl1ON OF AI.PIIA, PROAFINASF INIIINITOR ANI) bNON('111A1. Mlt(YwS PROII:INASN INIIIBII()R BY ('1(;ARl.1'f E SMOKI. IN Yl f RU ANI) IN YfYO The eharacterissic destruction of alveolar walts in pulnansry cmphysema is believed to he dae to uninhihild activity of elas/ases derived Irom p.dy- mnrphonuckar Icukocytes and alveolar macrophars; and this uninhibited tnryme activity is helieverl to oeeur because of an imbalance bctwecn elastase and elaslase inhibitors in the lua>t. Many studies (both /n vitro and in vivo) have been done hy now on the protkrae/uNiprolease balance in the hrng, and the present paper carefully reviews /hewt. Sonre of the read,s pres.nted in this review show that ,4ueous solutions of unfractionalcd cigarette smoke urppress compka formation between hunran alpha,-proreinase inhibitor (w,Pi) and clasuse In vhro. OaidirinA qerws reproduce the effect of smoke, while snti-o.idanls prcvenl it. Inhalation of eiprette smoke in rats causes a siB- ni8eam decrease in functional activity of rat lung w,Pi Iw .•lro, which can he restored by trealmenl with reducing alients. Human bronchial mucous proaeinaae inhibitor (B%IPi) is aho inactivared by cigarette smoke and osi- danes in vitro. Functional aciivity of BMPi obtained from h.tman smokers is 20% lower than that from nonsmoken. Theae results support apresenled hypothesis that local inactivation of anliprottases in the reapirslory units and conducting airwaya of the lung by inhaled cigarette smokt might play a role in the pathogenesis oM chronic nhuruclive lung disease in man Lwo/l. A . Carp. FI and I ee. 1) K. Mr.Mr/in /wropwn ./r Phrunp+uA.due.r R..rr••nmrr 16(arjK+ /19F.0. Other aNp)rorr: National Ncan, I unt and Blood In.brute. From the hepariment of ParMrlory. Healrh Sc.ences ('enter. Slare 1lniversity of New York at Sp.ey brrrrk. Stony broark INIFRACl1ON OF CH1'MOTRYPSINO(iF.NS WITH a,•PROTI'ASF. INHIBI FOR In Ihis study, bovine chymotrypsin A (CTGN) waa used for the purpose of quanlitalinA the reactN.na of tynabem with w,-prMeinase inhihitors Results presented here shnw that CTON reacts with .,-Pt in essentially the same manner as Mwnan praclaslase 2; I.r., slowly to furrn a cernpka that is stat+k to denaturation with s.sdium dndeeyl sul/ale and A•mercaplnNhanol. lhe rate of ct'mpks formation was measured here by two mclhorH that were deviacd to determine the seenrd-ordct tate constant for the rexlinn of ('1(3N with w, Pl. In the lird. the rale of eompkn formation was detcrmined by monitoring the loss of thc inhihilor activity of w,•PI as a/uncrion of time. In the aecnnd procedure, the reaction of /harescein iwlhiocyanale labeled chyrootrypsinolen A with w,•PI was measured by Marescence p+lariralion. lhe rate of compka formatinn was - 10' of that measured for the reaction .of M.vine chym.wryptin with w,-PI. Dissociation of the compka was mN ob- served after dolulMn or the addition of e.cess bovine w-ehymnlryprin. As l.wlcrd by au.luun dnJccyl ad/Ne•pr.lyacryl.mide gel eketsa+phMean esperi• men@s, hunun .h)nnuuyp.m.1Krns I and 11 react with n, Pl at rates that art i appro.imalely equivalent to that determined for bovine chyrnotrypslaolien A. In comrast, bovine trypsinoten reacts very slowly with w,-PI, at a rale that is at moat tOs of that of bovine chytnolrypsinogen A. 'Tlrese results suggest that :ymogerr react with .,-P/ by virtue of partially formed active sites and that the potential active-site specificity of the :ymotee in part deter- mines the rale of xompka formatiow. Srodrick, 1. W.. Glsser, C. S., Larpean, C., Geoiar, AI. C.. Orauflo, M., Fassett, M., and Maeda. H. sioeArrnlury N( 2 t):1l6S-dt70, 1930. OOther wppertr Mldical Research Service of the Veterans AdministrNio., National Institutes of Heahh, Internation.l Union apNnt Canecr, awA the Ministry of F.ducatiow, Scknce .wd Culture of lapaw. From the F.n:ymoloRy Research Labo.atoeY, Manine: Veterans Admi.Wra- tion Medical Center, Martine:, Cal.• the Department of Internal Medicine. University of California School of Medicint:. Davis, aad the Institules of Med- ical Scie.cn, S.n Francisco. KINETICS OF ASSOCIATION OF SERINE PROTEINASES WITH NATIVE AND OXIDIZED a-1-PROTEINASE INHIBITOR AND a-1-ANTICI/ Y MOTRYPSIN In thb attempt b p{w an Msibht Into the physiofobkal function of tY two Inhibitors. .-1-proteinase Inhibitor (,r-1-PI) and rl-antichy.wtrrpsb (w-I-Achy), the specificity of each was investipted by sneasssrinB fho taN constuws of associaios with different proteiwa.es. Reported here. tbati an the sssocialiow rate constants for Me interactiow of rl-Achy, .-1-PI ad eal- diud rl-PI with several nwewaflas aeri.e proteinases. The results Indkw IhN kukocyte e/aalast reacts more rapidly with w-1-PI than any other ps- kinae tested, while ksMkoeytu caMepsiw 0 shows the strongest aswciNioM with r1-Achy. O.idatitrn of the critical .rethioeine residut: of redtroo ehe associatiow with krsdocyte ehntase by a factor of teore than 2000 ad also katrlrs the assaeiation with aN of the other enzymes ksled wMh the ea- eepiow of chynsotrypsia. SiteiAcanlly. oaida/iow eompletely abolishts a.J interaqion of .-1•P/ with porcine elastase, human plasmiw or hurwaw tAro.:- bin. 7Lese data support previous rewlu which iwAieNed that osidatioa of humae .-1-PI /n riro could rtdace the eRecti.eness of this hnhibitor Iw Qos- trollinB proteolysis. In the henB, in panierlar, oaidiiinB aBents of both chnn- ical atd biological sowces could Indirectly wpmeM elntolysis i. this tMwre, resulting in the dtveloporcnt of pulnww.ry emphysema. Se,Ity, K.. Bkth, J. and Tr.rlH. l. a the /orrnrf o/ elotopcd C/iewJiny 2SS(9):)971-)911, 19s0. OtAer support: National Institules of Health aad the Institut National d. la SantE tt de Ia Recherche MEdicak. From the nepartment of Biochemistry. University of (korala. Atheas; a.d the Facullb de Pharmacie, I aboratoire d'ErittirrrwbAie. U.iveni/1 Loui. Par teur, Strasbourg. France. 29 ?N

RF.AC71VtTY OF IIUMAN I.F.UKOCYTP. ELASTASE AND PORf'INE PAN(-RFATIC FI.ASTASE TOWARD PEPTIDE 1-NITROANII.If1fS CONTAINING MOI)EL 1)FSMOSINE RESIDUES F.VIDIiNCE T: IAT IIUMAN I.FUKOCY fF FLASfASE IS SF-I-ECTIVE FOR ('ROSS-1.INKED REGIONS OF EI.ASTIN Plastin, a/ksibk, highly cross-linked protein, is found in high quaMAies in mammalian lung and arteries. While the chemical structure of elastin is not ye1 tnawn, il hn heen shown IhN il contains a number of cross-linking amino acid residues such as destwosine and Isodesmosine which are primarily hydrophobic in character, but haw a positively charged pyridinium ring. These cross-linking residues arc /ornsed by the action of lysy) osidase upon Lys residues in tropoelastin, a preeursor of tlastin. Iro this study, a series of ktrapeptide "troanilides which eoddn Lys and a series of mod.fkd lysine residues were synthesized. The nadi/led lysiwe residues have various charae- teristks of desnsosine and isodesrno.{ne re.sidues, such as positive charge, a hydrophobic arnmatic ring. or a pyridinw ring. The reactivity of the ectra- peptide 4 nilro.nilides containing the model desmosine residues at P,. P,. or P, with human kukocyte (Ill.) and porcine pancreatic (PP) elastase was measured al pH 7 5 and 2S'C. Hl. elaslase eshibiled high reactivity toward the substrates with P, or P, hydrophobic proups. and MtO-Suc-I.ys(Pie)- Ala Pro-Val-NA was shown 1o be seven times more reactive that the previous hest Ifl. elstase substrate. The major change occurred in K„ values. The substrates containing l.ys residues wert either nonreactive or poor. Escept for two substrates with P, hydrophobic nesidvn. PP elaslase was less reactive toward the substrates containing model desmosine residues than toward MeO- Suc-AI. Ala Pro V.I NA The rnu/u presented here support the hypothesis that H1L elastne ckaves elaston selectively near crow-linking residues. Ynutake. A. and Powen, l. C. (Traris, J.) aiocllernirrry 20(1 l):)67 f-)679, 1981. From the School of Chemislry. Oeorgia lnslilute of Techoology, Atlanta. SUl1..ST1tATE SPECIFICITY OF 1WO CHYMOTRYPSIN-LIKE- PROTEASES FROM RAT MAST CELLS. STUDIES WITII PEPTIDE 1-NITROAN1l./DPS AND COMPARISON WITII CATHEPSIN 0 A kitsetk Mudy of the hydrolysis of a series of peptide 1-nitroaailides by the proteases from (1) typical masl oell., rat mast cell proteaae 1( RM('P 1), (2) pypic.l mast cclls, rat masl cell prottse 11 (RMCP 11), and human cathepsin O is reported here. eah rat enslmes are effective proleases toward such suMarates.- Suc-Phe-Pro-Phe-NA and Suc-Phe-Leu-Phe-NA are the hnt suhstrates for both RMCP I and RMCP 11. In the case of RMCP 11, both the P, (Phe) and the P, (suocinyl (Suc)1 groups are important. Suc-Phe- Pro-Phe-NA is the best • nilroanilide substrate yet for eathepsin 0. Observed suhsite preferences Indicate that the S, and S, suhsiln of RMCP I. RMCP 11. and cathepsin may he very similar. The K.,,/K„ values of RMCP 1/ and cathet,•.n arr soandkantly Mr.rrr than those obscrved with bovine chymotryp• cm RM/ P I .nJ ,rher v..nr p.owraws It u not ck.r .hether this diQerence i is related to their phy.iolos ical function or iw due to a non-optimum substrate structure. Prolyl residues at the P_ potilion enhance the effectiveness of wb- strates and inhibitors for RMCP 1, RMCP 11, and ea/hepsin 0. Unlike other serine proteases, both rat enzymes can also accept Pro residues in position P- of substrales. A peptide chioromelhyl ketone. Suc-Pro-l.eu-PheCh,C1, was synthesized in order to Iake advantage of Ihis phenomenon. This compound is an effective inhibitor of RMCP 1; RMCP I is inhibiled 10-93 timea t.rer than RMCP 11, cathepsin 0. or bovine chymotrypzin. This Inhibitor might be usefsd in elucidating the physiological function of RMCP I and RMCP 11. Yoahida, N. tr al. (T..vlt, 1.) siorAemis/.y 19(23):5799-310/, 1950. Other anrport: National Institutes of Health. From the School of ('Aemistry, (ieor/ia lnstitWe of Technolop. Atlanta, and the DeparlmeM of Siichemistry. University of Washinglon, Seattle. HUMAN PANCREATIC PROELASTASE 2 SEQUENCE OF THH ACTIVATION PEPTIDE Ikcause elastolytk enzymes are thougM to eause the destruction of elaar Iic tissue observed in atherosclerosis and is emphysenu, it seemed impoeta.t to scrutinize the actions of proelauase 2, an enzyme that has already hetw shown 1o be present in human serum. For this reason, work was dons es human pancreatic proelasta.e 2 and, in the paper presented here, the stnce ture of the activation peptide of proelastaae 2 was elescribed, and the IAew- tity of the amino acid residue at which cleavage occurs during activatkst. In vitro was established. In Ihis study, the N-lenrtinal aiaees residua of the amino acid sequessce of reduced and alkyfated bumaw pancreatic proelaMre 2 were established, and the N-lerwtinal amino acid residue was dhoww to be earbosymethyk:ysteine. A peplide containing an amino acid sequence e:orte- sponding to the Arsl twelve residues of proelastase 2 was isdated following activation of proelastase 2 with trypsin, perfonnie acid osidation a.d pd /iltration. Ihis peptide was not released prior 1o perfonnic acid osidation, suggesting that it remains attached 1o the major peptide chain via a disulAde bond containing the N-terminal hdf-cystekwe M a mrwter similar to that fosmd for chymotrypsinogem. The sequence analysis presented here suyesh dul human pancreatic proelastase 2 is more closely related to the chymolryp.iwolicn family than to porcine pancreatic proelastase 1. Thae resuUs clearly abw, however, that Mrntan proelastase 2 is a d'n1inN symolee. LuCnan. C., llrodrick. !. W. and Gro4rs, M. C. siorAln.ke er QiooAyric. Acr.63.f:20>1-212, 1980. Otber aupprtr Medical Research Service of the Veterans Administration and the National Institutes of Ileallh. From the Erwymolohr Research Iaboratory, Martinez Veterans Admini.tra- tion Medical Center, Martinez, Cal.; and Ihe DepartnseM of Internal Medi- eine, llnivenNy of ('aliforni. Schod of Medicine, Davs. 1 31

METABOLIC ACTIVITY OF nFVEI.OPINO RAT LUNQ I ong slicet prepared from rats aged 2•12 days were e.amincd for in- corpo.atinn of Ihe labeled pnxunors, 'H•palmibte, "Cthnlirre, "('-proline and '11 thscosamine, into lipid, protein and tlycoprotein. Results of this study of developmental chankn in tst hrn6 composition and biosynthetc capacity show that the immediate perinalal pcriod is one of very high mclabc tic activity and that the synthesis of structural components precedes thal o(' secrelory products. Specillcstly, protein conleal e.prnsed as m6/ 100 rn6 ~ret weight inereased from 1.95 -t 0 25 in fetal hrnp lo 3.0 r 0 16 at birth, aml remained alnw,t unchanged during the Arst two weeks after birth. Individurl measure- menls ahr.wed that palmi/a1e incorporaliow increased (rom 18.2 t 21' nrnd/m6 p.ntein/h two days before birth to 40 0 t 1.0 nmol/mg protein/h three days after birth, and decreased to 24 0 t 2.3 wmol/mg prolein/h at 12 d rys of age. At all akn /e+red, mwe than 75% of the pshnitic acid taken up ty /he lun6 was In esreriAed form. Incorporation of psimilie acid into lecithin was hi6h- est one day after birth. Clroline Moorpor.tbn ksto keithin larcraned ei6ht- fold between two days before and ewe day after birth and decreased 60% by 12 days of age. There was no dHlererroe between the Lcorporation rate at 12 days and that in the .du11 hrng. Total hn.it pbospholipid increased 220% between two days before birth and the day of birth, and ch:N+ged little thereafter. Phoaphalidyl choline rnade up 30-607i of hanol phosplolipids at all ages Proline irrcorporation iMo hrnlf protein was highest In Ih- perinatal period, while glucassmine incorporaliow was highest in the fetal hrag, but decreascd 67% one day after birth. H.nrorA, AI. N J. elotop of rA, kronrc )9:117-126, 1f111. Other aayr.rf r National Inalilutes of lleabh. From the Departmenls o1 rediatria and PbpsiokM and SiophTsics, Oeor6e- town University Medical School. Washiwli/os, D.C. EFFECT OP DEXAMPTHASONe ON LIPOPROTEIN LIPASE ACT1VfTY OP FETAL RAT LUNO In thir study of the e/lects of a eortkflosterokd oe aryme aaivit7, det- amethasoee ws administered by eowtiauotra subcutatreorr infusions to preR- nuN rats from the 16th day of pestatiort. Adminiatralion of the hormone markedly affected malernal and fetal wei6/M pin, fetal 1wr6:body weight ratio and lipoprotein lip..e activity o( the lurrt Cumulative maternal weight gain lrom days 1 f-21 of 6eslatiqw was 60 t 1,0 p M eontrol and 70 t 10 A in des.rnclMsonctreated rats. Fetal weight at 22 days of Aestatksrr .nd one day .Iter birth was 5.0 t 0.)f and 8.6 t0.)0 in tonlyd and •.65:0.26 .nd 3.1tO.11 in desarnetha+one-/reated rats. Ths ratio of lung weight to body weight was lower throushout the Ias1 Ave days of gestatioa In de.ametha- sone•treated than in eon/rd rats. Deaameth.sone administralion led to a Iwo- to threefold increase in lipoprokin lipase activity levels in fetal ra/ lung at 1• .nd 20 days' foetlstiow and prevented the decline is enryme activity sMrtly he/ewe ba.tt 71re resuMs of this study show that IipopnNein Ipase, rhe rnifn.e rhal rrgul.les the upuke of Iri6lrceridr Iatry acids by earshepatie tissues, also is induced prematurely in the fetal (ung aflcr maternal cortico- steroid administration. The early appearance and constant high activity kvel of this enzyme indicates an adcquate supply of triollyceride fatty acids, and suMests that the increased uptake of these fatty acids by the lung could be a conlribulory factor to corticoueroid-enhanced rurfactaM synthesis. Mostello. D. 1., ILrnorli, U. and Hamaslr. P. eloloq of the Neon.re 10:121-12t, 1921. OtA.r aurprfr National lnatilutes of HeaNh. Frvm the Departments of Pediatrics and Physiololly and Biophysic., (korge- tow. University Medicd School, Washhrgton, D.C. DP.POSITION AND DISt7tllUTION OF THE TOTAL rARTICULATE MAT'1 F.R OF CK3AREM-E SMOKE IN MICE USING A LARaE- CAt'ACITY SMOKE EXPOSURE SYSTEM BC)FI/Cum (CS7 SI/CunM it ClH/Aao( Ctun) ruak aod female tdoa were eaposcd in this study to whole cigarette snwke using a standard anwk- inp re6inrcn with a new automatic smoke espoture wuchine (SEM 11). TM SF.M 11 is a lar6etapacity (dti11 mice) dynamic tanoke exposure system in which snroke is rowed through the animal eorrldrwrrenl syslern as a aoa~ tieuously Aowing aream. Mice are restrained about the neck in stock-liks holders for "noscawl7~ exposure. Using uandard onoke exposure co.di. tiom, the deposition and internal diMriMrlion of Ihe total partieulate t+ratw (TPM) /ran cigarette smote was detenniwed iw Mae rnice. Results sb.ei that: (1) snwke eapo.ure eonditioas cam be varied so that depositiw lroru 30 to 200 rs TPM/kwrg eaw be oMained: (2) 00-i0li o1 the TPM deposi- /iar was found in the respiratorp tissues; (3) the anouse-lo-nrourr variados for TPM deposition in ptilrrroa.ry tissue was - 20Ri; (4) similar depod- tion and distribution of TPM waa ohaerred iw rnak aad /ernale wdoe, a.d (3) deposition and d'ntribwiow of TPM was sw/ altered in mice eaposed Io smoke oe a daily basis over a sia-/noelh period of tintt. Heruy. C.1. et d. (Mkrobielo6kd Araori.rei) Toakolory.nd Aoplied Ph.rnr.roloRr 3/:79l-109, H/1. Frora the Deputmen/ of Experimental Oncolopr and the Deputnrent of t1a chemical Oncolo6y, Microbiolo6ical Assoeiatea, Ikstheada, Md., and Awaly- tical Chemistry Division, Oak Ridge National Laboralory, Oak Ridp„ Tea.. I AIRWAYS RFSPONSF. TO INHALED TOSACCO SMMCLr: TIME COURSE. DOSE DEPENDEN('E AND EFFECT OF VOLUME HISTORY The time course and dose dependence of the brenchocowstrictiw respoae to inhatation of tobseco snwke are rcpurted here. In this study, airways re- siuaoct (Raw). lhoracic gas volume and Ihe nwimd eapirMory Aow vo1- ume curve were measured beforc, a(ter each puA, and up to 30 rniwtes dter the last puff of three Ixands of cigarettes with diAcrcru cornpositio.. Raw increased si6ni/icantly with all three bra.ds of cigarettes after one pull. 32 1 33 .

, 0 w w J The maximum eflccl was reached sller three puffs. Instantaneous flow al 50% of vital capacity decteased si6ai/kanlly wilh cigarettes high in nicotine content, but this did not happen when a low nicotine (0.31 mg) cigarette was smoked. Instantaneous flow at 75% of vild eapaeity out (FFF„) in- ereased signiAcantly 30 minutes after the low nicotine cigarette was snsoked. A deep inspiration prior to Raw delermination reduced by approximalely one third the bronchoconstrictor effect of cigarette smoke. A)l effects were reversible within 30 minutes excxpt Ihe delayed effect of the low nicotine cigarette on the FEF,,. On the basia of this work, it seems th.,t the probable sile of action of tobacco snwka is i. Ihe large and central airways. The bronchoeonstrictor effect rapidfy resdw a plateau. However, a delayed broe- chodi/stion of the smaR airways observed slter the low okotine cigarette was smoked might represent snwher response usually masked by odrer long-acting componeas is smoke. Tsveira Da Silva. A M. snd K.w.e.A, r. Rrrplrrlon 11:96-105, 1961. Frnm the Drp.rtment of Medicine. Physiology and Biophysii,, Georgetown Universi/y School of Medicine. Washington. D. C. RESPIRATORY DEPRPSSION PRODUCED BY ACTIVATION OF OABA R ECF.P rORS IN H INDBR AIN OF CAT The aim of this study was so ehsracleri:e the respiraory effect of r•sminobMrtyric acid (OABA) administered directly into the ( NS. Muscimol, a specific GABA•receptor sgowisl dru& was sho used because it is more potenl and longer Iasling than OABA. For this investigslion, respiratory re- aponses to activation of OABA recepon in the hindhrain were measured in ehlaralose-snesthNi:ed ests rsin6 a Fkisch pneumotachograph. GABA re- eeplors were activated by intracis/ernal injections of muscimol and OABA. Museinwl (0.014.65 pg) administered so seven animsh caused a depression of respiratory activity with apnea occurring in each animal. Before apnes occwred, a decrease In tidal olum» was osacrved. Respiratory rate sad iw- spiratory and expiratory duratiows were unchanged. OABA (A 05-12.1 S mg) adminiskred to /ve anie»b proAuc'ed the same effect as nrncimol on res~ piralory aNivity. Apnes produced by both ye.ts bss reversed by iMra- cislernal administration of the OA1A-receplor antagonist drug, bkucutine. Administration of bitueuRine to four naive animals ixreas.d tidal volume but had sro eRect on either respiratory rate or inspiratory duration. These resuMs indicate that OABA and rrwseimol. which activate GABA recepbrs, cause respiratory depression. it seems slw, on the basis of Ibe data obtained from both agonists and the sntagoniM of OABA recep/ors. that OABA might be an important CNS neurolranaeilter tekulalin6 pulmonary ventilation. Ysmada. K. A.. N.wesli. r., and Oillis, R. A. lournl of Applied PAysiolon: Respirat. Environ. Exercise Physiol. 31(S):- 127a-1286, 1981. O/b.r supportr American Heart Association. t'rnm the MpartmeMS of Pharmacology and Physiology. fieorgelown Uni- vcrsuy Schcwds of Mcdscrnc and [kntistry. Washington. 1) C. 34 t OPTIMAL ('ONqIT1ONS FOR CELLFREE SYNTHESIS OF FLASTIN In this biochemical study of elaslin syn/hesis, particular emphasis was placed on the development of opimal conditions for the translation of elastin mRNA in the mRNA-dcpendenl rabbit reliculocyle lysate syslem. Using taal RNA isolated from embryonic chick sonae as the source of exokenous RNA. the following determinations were made- 1. The effect of heating the RNA to different temperatures just prior to IranslMion, 2. the prest.ce in the translation assay of bolh proteins that resrdt from the translation of elaslin mRNA, and 3. the effect of different eonctnlrstiorn of emilnesium acqate, potassium chloride, spermidine, crealine phosphale. ATP, and OTIi' on the Iraoslalion of elastia mRNA as seen by immurqpreeipilstion. Results showed that heating of the RNA prior to translation signiAcantly enhanced total protein synthesis, elaslin synthesis, and the symhesis of pruwcins possessing molecular weights of greater than 90,000. The development of this Ira.s- lation syslem, which is optinal lor elastin syMhesis, should prove to be iw- valuabk for studying the mechanisms of control of elastin biosynlhesis. Karr, S. R., Rich, C. B., Fosrrr, l. A. and Pr:ybyls, A. Coll.grn RtirrrA 1911. Otbrr support: Natioaal Institutes of Ileahh and the National Fousdatie.- March of Dimes. From the Departmenl of Biochemistry. University of Georgia. Athens. IMPROVED METIIODOLOOIES FOR THE ISOLATION AND PURIFICATION OF TROPOELASTIN Strvcturd anA tnrtabolic studies of elasd" have been hampered I. as psst by the difficulties involved in isolating wr/Reient quantities of tropoelarls from lathyrilic anim.l s~sakls. To otwntttw this problem, several tweiods have been proposed to increase the ridd& of puried tropoelastia 1. M@ study reported here, tday-ald chicks were used for the i.ductioo of Ialhy- rism in order to take advantage of Ihe teporled Sursl of elaslis sHrthaia during the second and third weeks of chick development. In sdditiow /o dr lathyro6ett that was added then to the diet of the chicks, r•aminocaproic acid was added. The increased age of chicks prior So Isthyroken adminislralios plus the addition of the trypsin-like ensyrlte inhibilor, r-aminocaproic scid. to the diet resulted in a 110% increase in the yield of Iropoelasli.. This method for induction of lathyrism in chicks o/lers the advantyes of ho/h increased yieWs of Iropoelasliw and the convenience of dealing with smsBer 6rory+s of chicks. In addition, a ealiowtxchan6e system employing a CM- eellulo.e column was devchrped in ,his s/udy, which allows complcle removal of minor acidic protein contaminantA Irom tropoelastin. Foner, l. A. er .f. Anefrrkd eiorhe.nl.rry 10a:2)3-2 )6, 1980. OOther support: National Inslitules of Health. From the Ikpartnscnl of Biochenmi.lry. University of (kor6ia. Athens. 3S

MF.AS(IRtMFNT OF I:I.ASTIN DFGRADA I ION IN VIVO BY DISM//SINE RAUIUIMMUNOASSAY Tksnxsine is a cross link mino acid found only in clashn, .nJ urinary desrno.ine e.cretion is elevated as a result of increased elashn degradation in the hody. A chemical mcthod for rneasuremenl of urinary desmosine has been utfired helwe. fwt the present paper describes a highly sensitive radio- immunoaatay for desmosine which is capable of detecting as little as 0.2 oR n/ this conspound in acid hydrdysales of urine. the nsethod does not delecl other amino acrds, incladinp Iysine (the precursor of the desnwnine cross- links), hu1 rather is specific for desmosine. Preliminary data on desnsosine eacretion in normal tsonsnaken ad is a tnnaM drvup of heavy smokers with a variety of pulmonary disordcrs are presented here. It seems, so 1ar, that the method dr.cussed here may prove useful in monitoring elastin break- down m several patho/opscsl watn, iacludirrd pulmonary emphysema. Ilarel, S. Yu, S. Y., LnoO, A.. Ilurewits, A., and Bergas/sky. E. 11. RrJlrne furopr..w Jr 1'Irlriop.nhulurir R.rpi.woirr I6(wpp1./:7t.N1. 1990. Othrr aarpport: U. S. National Ileart, Lund and B/ood Institute. Fron+ the Ihp+rtmems of Pathology and Medicine. State Univcrsity of New York al Stony Brook, Stony Brook; and the Veterans Administration Ilos- pstsl, St. I ouis. PRF.VFNTION OF F 1. ASTASF -INDUCED FXPERIMENTAI. I:.MPIIYSEMA BY A CYNiltt /IC ELASTASt INIIIBI IOR ADMINISTERFFI) ORALLY Since there have recently been several reports of prevention of esperi- mentally-induceJ emphysema by Irea/menl with praNeinaK inhibitors, an al- templ was made here tu test the eRcctivenes of oral aJministratwrn of nrelh- oayurccinyl slanyl alanyl prolyl-valine chloromelhyl kelone, a pacnt inhibitor of clastase. in an animal model of emphysema. Results of the pre.enl eaper- imenls showed that, following adminislrNion of the inhibitor ta mice by slomxh tuhe, a portion of the labelled ehWromelAyl ketone cou/J be recov- ered in an active form in hmg wash. Signifkantly, animals given a single oral dose of lll0 pg of the synthetic elaslasoinhibilur, 13 minutes prior lo introduction of si units of porcine pancreatic elaslase into the hrngs, were corrspktely protected against alveolar deformation (as judged fr.Mn mean linear intercept values four weeks later). Treatmenl with the inhititor al tima earlier Ihan 13 mrmrles Ir•fore enzyme chalknge or from IS minutes to •N hours afler enzyme challenge did no1 protect. These results provide direct evidence that chloromethyl ketones can he effective when given orally and. thu% wrth further sNdy. they may snme day pr»ve prsctical as pHCnlra prophy- lactic agents in populations at risk for development of obstructive pulmonary disease. lasn0. A. and 1learing. R. /rul/rnn 1 urorrwl Jr rhriioparAolorir Rrrpl...uarr 16(suppl / 199 l/11, 19NQ. Oflrer aupporl: U. S. Public Heahh Service. From the Ikparlmeol of Pathology, Health Sciences Center, Sratc Urversily of New York sl Stony Brook, Stony Brook. POTENTIAL MEDIATOR OF INFLAMMATION: PHAaOCYTE- DERIVED OXIDANTS SUPPRESS 7HE E1ASTASE-INHIfalTORY CAPA('l1Y OF ALPHA.-PROTEINASE INHIBITOR IN VITRO Within their cytoplssmic tranuks, hunsM kukocylea contaie protessam that are capable of degrading connective lisws slrsrchues. Iw the arudy pra. setwed here, i1 can be wen that human polymorphorNSckar (PMN) knkocytea, nsonocytes (MN(') and pdrnonary alveolar macroph.ttes (PAM) that wetr nin•.dated in rUro by plwsrbol myristate acqate (PMA) released reactivc osygen specin that sre ahle to suppress the elastne inhibilorr capacity (E1C) of human serum. Immunocleclrophoresik wirsR nmtsodies apinsl n/.prs teinase inhrhi/or (.,-Pi) and elaslase showed MN i.aelivalion of .,-Ps was responsible lor the decreased serum EIC. TreYrneM of plsaRocyle-insetivaled serum with a reducing agent (dilhiolhreilol) resuNed in siRnifkan/ reco.ery of EK'. suggesting that w,-Pi had been oaidslirely, inactivated. Setww f21C was partially protected by superoside diunwase or eaNalsse. and hydsoges peroaife alone had no effect on serum E/C. Tlws. neither /IsO, nor Or abne, but a producl of the two, may have osidalively inaclivated .,-PI. !o suppon of this observalion, it was noted thN MNC and PMN from a pa- ienl with chronic tranulomatosis d'tsease, in which getseralion of O, .e/ 11.0, is depresxd, failed to inactivate w,-Pi when e.posed to PMA. On the basis of this and several other esperimerud noliwp, it appears that osidalive i.ac- Iivalion of w,-Pi in the microenvironmeM of infaamnsaory eells, at siles of scwe or chronic adlammslion. may allow proleases released Irorn lhese eeRs to damage adjacent connective lissue eonsponeeb reore readily. I Csrp, H. and /awoe. A. lorrnaf o/ Clink.f fnrrsriNrrion 66:fR7-!!S, 1980. O/Aer nrpperf: U. S. Public Health Service. From the Department of Pathology. Heahh Sciences Center, State University of New York at Swny Brook, Stony Mook. URINARY EXCRETION OF DESMOSINE IN PATIENTS WtTH SEVERli BURNS Burns involving either partial or /oR-Ihiekness of skiw iwvariably dsl.- age connective tissue layers, which largely consist of elaatiw snd eoNyeo fibers. In this auempt in study the degradation of elas/in in burned pMie.ts, urinary escretion of total dssmosine was measwed'by a r.dioimrnuwo.asr in 10 severely burned adult maks, as well as in 1• normd adult rnab ooms- trols. Total urinary desmosine was sidni/kanlly ekvNed in all the s.apla in the burned patrents, who had injuries involving more Ih.w N!L of total body wrface area lhe values of 21•hcwr urinary desmosine for the patients 36 1 37

ranged from 250-1.411 nm.dcs, as compared with R2-112 nnuiks (or coe- t'rras 1 hese were eqtrivaknt to 11 7q mg of elastin deRra.kd far Ihe burned palren/s and S M mg /ra normal controls Urinary desmosrne values eap.essed as nrnules per g of crcat~nc were dso higher than Ihe coure+pondin` normal vshres. Also. urmary escreriun ol total hydrosyprolone in the Mnned pa- hents was higher than in norn.al controls. Measured values of hydrosypn>tine were equivalent to 41) 1-621 mg of collagen in Ihe patients and 21R mg of collagen in she controls le she burned palients, holh urinary desmosine and hydtosyproline values wetc elevated from day I posl-burn. and reached peak kveh in days !-1:. declining /hereafler Sul remaining higher than vah.es for normal controls through day 60. OrreraR, a correlation in the urinary des- mosine level with she urinary hrdrosyprdine level was found• suReesting that Ihe degradation of elattin and oolbRew waa secondary 1o she same mechanism. Yu, S Y.• Isw..8. A.. I/are/, S., and Ayvaria., V II. AlrraAolirm 10 (15 /: N 7.501. 198 1. Other .r' per1: Medical Research Service of the Veterans Administralion and U. S Public Health Service. 1'rorn the Veterans Administration Medical Center of St. louis. SI lohes Mercy Medical ('enter, and the Department of Pathology. School of Medi- cine. Sr 1 oun llniversitT. Q 1 ouis; Deparunenl of Pathology. Health Science ('enkr, State University of New York N Stony Rrook, Stony Brook. PUI MONARY INI ( AMMATION DUF. TO OXY(ll N TOXICITY INVOI.VI:MI NT Of ( 1/1 MOIA('fl(' I ACTORS AND P(11 YMt/R• PHONU('1.FAR I FUK(X'Y1FS Injury from hypero.ia is known In be associated with inlcnliual edema, alveolar sepla thickening and alveoli filled with prolein-rich eaudales. 11 is also known that, coincident wi/h the massive endathelial damage. there are substantial increases in she numher of polrnwrphorwckar kukocyles (PMN) in the lungs of rats esposed to hyperosia. Iw the present attempt to ducidale a methar.ism for this infius of PMN, the ehemoallraclaN activity /or. PMN of lung lavages of rats esposed so 95% oaygen for various durations was measured• and 'N was seew Ihal she ehemoNtractanl activity of the lavages of the hrnp of rals eaposcd to hyperosia for 66 hours was markedly in- creased compared wih activities in lavage of nonsosie control rals. Further- tnore, thne increases in chensoattraelanl activity in hrng lavages correlated well with increnes in the number of PMN In the alveolar IaraRes that oe- eurred after she rats had been espo.ed to hyperosia for 66 hours. lbese increases were followed in a few hours by the death of most of the rats. lhese Rndinp suggest that a close temporal relatioeship esisls between the Reneration of high concentrations of ehenwatlractants in lung lavages. PMN influs into lung lavares, and death of rats esposed so hyperosia lr seems. therrfurr. that PMN may he involved in the palhogenesis of pnlmanary osy- gen Ip.ocny t Fo.. R. R, Ifoidal. 1. R., Brown, D. M., and Rrpiwe, I. I:. Anrrrkan Review oJ RrrOirmery Dbemr 12)(S):S21-S2), 191!1. O/A.r support: March of Wmes Birth Defecls Foundation, Minne.ota Medical Foundatioa, MinnesMa and American Heart Associations. Colorado LunR Associstion, National Institutes of HeaBh, and Kroc Foundation. From 1he IkparlmenH of Pediatrics and Medicine. Webb-Waring l.ury la- slilule• Universily of Colorado Ileaqh Sciences CeMer, Denver. and the Da- partmenls of Medicine• Pedialrics, and l.shoratory Medicine and Palhok,gy. University of Minnesota Heahh Sciences Cenrer, Minneapolis. /)IMI:*I//Y1. S(1/.FOX11)F. IN/IIB/TS K11.1.IN(3 OF STAPIIYI (K'(('CUS AI1RI=US RY POLYMORPI/ONU('LfAR I.EUKOCYIES Srimulaled polymorphonuckar kukocytes (PMN) have been shown in the pav to make Q)11, which reacts wilh dimelhyl sulfoside (DMSO) to prorlssce melhane (C/I,). In she esperirnen/ reported here, 1)MSO, a highly pernseahle scavenger of •(Nl, was used In etamine she ro/e of 011 in the kilhng of bacteria by PMN. (This eaperimeM seemed particularly appopri• ate at she present time since DMSO is currently being used for the trealmeM of arMriwi% and other condition..) All esperirnenlal proccdures were performed on blood obtained from uninlected, drug-free control suhjecls or palienls wish proven chronic granuktitmatous disease. The resuMs of this study showed 1hM nMS() decreased killing of SrrpAylarorrws arrrur by normal PMN, and CH., a relatively specific product of the reactiow of •OH with DMSO. was flew- eraled in the procea. Rrpine• /. I:•., Fos, R. B, and Berger. E. M. InJ.ctionanJl.rr.nwnlry 31(1/:SIOS1l, 1911. Oth.r aupp..rt: American Heart AssocLlion, National Ins1i1u1es of Heallh, and the Kroc Foundalion. From WeM+-Waring I.ung Inalilule and the Departments of Medicine (Pd• monary Division) and Pediatrics. Univenily of Cobrado Health Seiewees Cenler, Denver. ()IMI:TIIYI. SUI.FOXIDE PREVENTS DNA NI('K1N(i MEDIATED BY IONILIN(: RADIATION OR IRON/IIYDROOEN PFROXIDE- (3FNFRATED /IYDROXYL RABICAI. While it has been waealed frequently that the hydrosyl radical (-OII) is the primary producl of irradiation and while il is krwww that the seaveager dimethyl sul/o.ide (DMSO) pro/ecls certain eeNs from irradiatiow, she Rat and the mechanism by which irradiation does its damage to cells have beew dilRcult to establish and lo quantilslt. In the esperirnents reported here, ira Ia1ed supercrwicd 1•MR9 1)NA was eilher y-'wradialed or incubated with a mia/ure al FcSO,. FI)TA, and 11.0. to introduce singk-slrand hreaka In )R 1 19

1 Ih.• 1)NA The number of breaks per DNA molecuk was JelernioncJ eke trophuretically hy separating the covakntly conuouous supcrcookJ 1)NA frot the neckrd or broken DNA on 011% apro.e gels. Retulls of Ih.•se sluJie showed that eiRMy percent of Ihe singk-slrand DNA breaks induced b y irradiation were prevented by the -011 scavenger DMSO. ('H, was gen eralcd in the process as a producl of 1he inkraclion of OH and Me,SO. (1 a.nlrasl, DMSO completely blocked DNA nicking by an iron/N,OS syslen which produces OH hut smaNer amounts of CH, from DM5G. Becaun DM90 prevented DNA breaks frolw the Inore efficienl iron/1/ O, !:ystem bu only bkuked 20% of irradi.lio.-mediaNd nickinR, the results suggest that about 20% of the latter breaks wer. due to some mochanism other lhae -OH. Rrplne, !. E. rr d. Prorrrlinp o/ rAr Nrrlond Ac./rnq o/ Sclrncrs o/. r6r Unltrd Sratrs o/ Anw.k.78(2):1001-100), 1911. Olitier wrpr t: Natiorsal Sciencl Fouwdaliow. American Heart Association and Naliond tmtilules of Heallh From Wehb.Waring I une Inslilule and the Dep.rlmeMS of Medicine (Pul- narnary). Immuekelogy and Microbiology, and Bioehemislry, .Biuphysies and (:enelics. Universily of ('olorado Health Sciences Cenler, Denver. I FFF.C'T OF STAPIII (K'OC(-AI. IRON CONTENT ON 7HE KILLING OF STAPIIYI.IHO( ('US A(IRlUS BY POLYMORPHONUCI.FAR I FUK(X'YrES 11; )t production by poiymorphonuckar kukocytes (PMN) and Ihe Calaiale KlivNies of SlaphylorofrYt /Yrra!! (S. OY/rYl ) have seemed up to now to be porenlially impoA.nl (acton iw slaphylocoee.f virulence. In thn present /nvesligalan, the effect of alterations in slaphylococcal iran on the suscepNhility of S. .o.ers to kiMing by PMN was e.amined as another pote.- 1u1 factor in the virulence of Ihe ordaaism. The resuks of this aludr showed Iha/ although growing S. arrers eells in FeSO, markedly increased Iheir iron cowleM 1ud Ihea susceptibility to killing by HrO:. it did nol alter their sus- eeptibility so kiUing by PMN (rom either normal subjects or patients with chronic granukomatous disease. Indeed, altkwugh iron does appear to be a key factw in the powlh or viruknce of S. .urers in vivo. it does not appear. at kasl umier the conditioen tested here, to be a significant factor in the killing of S. auwroes by PMN in virro. Rrjoinr, !. E. rr .f. /nJretion .n1 lmmrwiry )2(1) :107-110, 1981. OtAtr arC prt: American Hearl Associalion, Nalional Inslilutes of Heallh, and Kroc Foundation. Fnwn Webb Wsnng I ung Imlitute and Ihe Ikparlments of Medicine and PrJuva. IPulnwv.aoy (/nwtnNy of Colorado /leailh Sciences f rn/tr /tva.Kr QUANTII'Al lON OF ('AR('INOF:MBRYONIC. AM7(iFN IN l lll' LUNr LININ(i FI.UID O1= NORMAI. SMOKERS AND NONSMOKERS Bronchoalveolar lavage (BAI.) eAluenl from 47 v.lutW nteen with normal pulmonary function (19 mm.moken and 28 snloken) was measured for total pr,rein (TT), aRwmin, immunoglobulins 0 and A- and carcinoanbryo.k antigen (CEA). As a group, the smoken had a signiAcanlly higher CEA:TP ratio than she nonsmokers, mainly due so a subgroup of sevew smokers. The increases in lavqe CEA, however, correlated only weakly with smoking his- lury in pack-year% and wo/ al aR with plasma CEA conccwuslioos. Tle sum- her of cells recovered, mostly alveolar macrophattes, waa signillcamly higher in smokers than in rw/nsmokers. The ISA:aRwrwiw ratio of SAIL was signiA- cantly higher thaw she serum value in both smokers and nonsmokers. In wan- ,mokers, Ihe ratio of /k(i:aRwmiw in BAI. was virtually identical b/ke serum Ik(i:alMrnin ratio. Smoken, however, were (owld /o have a sipiRs canl increase in the ratio of ItiO:.Ihlrnin of SAI. compared with that of serum. These data urpporl the work of other poups, hw also suggest that there may weM he two types of populations among snakers. that is. lhtwe with normal vah.es and those with CI:A:7T rarios increased by iwhalaMs. It is speculaled that Ihis increase in CEA may be ato early indicaliow of air- way injury and melaplasia in a st.bpopqtlaliuw of smokers, which may indi- cNe a greater risk of (uture inhalanl-iwduced morbidily in this group. Merrill, W. W., (ioodman, M.. Mallhay, R. A., Naegcl, O. P., Vandevoorde, ). P., Myl. A. D., and Reynol/s. N. 1•. Anrrriran Rrvrrlr o/ RrsNr.tory Diu.rr 12 a(1) : 2!-S 1, 1981. Otber ar'prf: Charks E. Culpepper Fowldatiow. From the Pulmonary Seclion, Yale University School of Medicale, New Hasrw, ('onn ; HoQnun I.a Raehe, Nuwky, N. J.; and the Department of Medical Research, Methodisl Hospilal of Indiana. tne., Indianapolis. a REAOINIC ANTIBODY IN THE LUN(1 LININO FLUID In this attempt to rndersland /he role o/ Mrnwlogblwlin E(I@E) Its mucosal defense, /iberopie broechaeopic IavaRe was used b obtain Mow- ehnalve.4ar fluid from •7 norwnl .okurqeen. Slandard inwrwnob~ie leer- wiques were Ined to measure the concentrations of aRnrniw and iwwlw.a filohulins A, (i. and E in serrrn and in /he eonaMrated lavale fluid. RNios of immlrftkohulin 1o alMroin were then conslructed for asscssing the pres- ence of local syn/hesis of inlnwrak/11Mrlin vs. passive Iranwdatioe frowl the in/ravascldar space. Analysis of this data revealed that awrsl IgA was locally syrwhesired In both smokcrs and nnnsnw*ers. In all nowsmoken and 80% of smoken. the 1g(3:aRwmin ratio was equivalent b/he same ralio In aeruwl. re/lecting paasive Iransudalion of 1g(i /rom serum. Howe.er, 20% of susokers had lavage Ik(l:alMrnin rNins > 2 S D. above the nsear for simultaneollsly obtained serum specimens, suggesting a significant eonl'ribuliow of local syn- thesis. Ry conuasl, she mean serum IRF alMman s.tio significantly esceeded 411 1 41

the mean lavase Igf :alhumin ralio. Moreover the cunccnlralion of I6E in the (avaRc 11ud c.nrdateJ directly with the serum I6E concenlration and with the presrnce of ha.opMh in the lavage cell populatinn, sugratrns thal the IriF desecrabk in the lung lining fluid came Irorn serum Iransudarion or was e/uted from cells hrnding IgE in the ainways. Merrill, W. W, Nictel, (i P., and Rcynollr, H. Y. i'he lau.nd of Loho..rory .wd Cflwk.l AIe/kiwr %( l):194-500, 1990 Otlier au'prI r National Flearl, l-srn6 and elood InslitsNt. From Ihe lkpattmenl of Internal Medicine, Yak University School of Medi- cine, New I/aven, ('onn. AIRWAY ('l1AN(1F5 IN YOUNO SMOKERS THAT MAY ANTI'hATE (/IRONI(' 0851 RU('l IVE LUNG DISPJA.SE When cigarette smoke is inhakd, the lun6 handks the enmpka aerosol by its hnst defenses, which eonsisl of variow meehaniuns such us anatomic barriers in Ihe airways, mucnciliary ekaranct, seemingly non srnmumrlo6ie substances Irte surfactanl and Irsnsfetrin, and cellular and proleinacenus ek- rncnh of she immune system RKent lavase techniques have made Ihe cellu- lar and protcin ekmenls of the lower respiratory tract accessible /rw ready sampling, and many shdies have been done using young, healthy vohrn/eers, snwtcrs and rKrn.mokers as subjects ('lose analysis among smoking subjects has shown strrking hcterogenicity of the group: sonse display evidence of a brisk airway response whok others seemingly are kss affected. lhe present paper reviews s.rme of these changes that seem to relate lo parameters ot ho,1 lung defenses. The mapt aections o/ this paper art devoted to: (1) Airway Cells (macrophages, polymorphonuckar neultophik, and lynsphucy/es, eosirwphds, and hasophils); (2) Noncellular Components In Luns Srcretiotn (proleins and immunoglobuNns, seerelory eomponent, and surfacunl); ()) Enzymes And Their Potential Interaction 1. The Aitways; and (4) Reapira- Io.y Tract Defense In Olnrruetive Airways Disease (immuno6loMrlin ahcra tions, aheration in non-immune hNtg detenses, respiratory colonization in pa- tienlft with airways oMtructio.. infectiors iw obitruclive diseases of the air- ways, anJ organisms responsibk for acute esaoerbatiorss of chronic bronchitis). In as overview of Ihese research sludies, the changes noted in young snakers, consideted individually, are of minor proportions. Ilowever, is is probahk that sorne subjects are innately nsote susceptible lo she e/lecl of inhalan/s than their peen. Since soms eroa-seclional dale suggest a connection between early aheraliow and later disease, a clear need seems to eaisl lor nsnre deNni- live studies in the reviewed areas. Rrynofd., H Y. and Merrill, W. W. M.Jkd Cllnkr of North Ame.k.63(l):667-689, 1961. (hArr anpr.rrr National //ears, I ung and SlotMl Institule. I u.m d.e lsrparrnsaat of Medreine. Yak llniversity ScMrol of Medreine, New Ilrvrn, (-unn 9 Pl/l MONARY Mli I A/lO1.ItiM OF PROSTAGLANDINS AND RELATED COMPOUNUS: WI1I1 SPI:( IAI. RtFF.RL'N( E 1U IIIE RVLE OF I:NDU 1111a.1At. CELLS lhis ovcrvi.w o/ pro.taglandin research sungesls that it is quite possible that pro.taglanJrns and related sub.tancts have imporlaM roks in lung lunc- tion anJ, in urnse inslances, in luns dyslunction. Firaly, lungs have long been known to form and reka.e sknv reacting subslances, substances now known to he proslarlanJin-related in that Ibey arise from a liposygenase pNh- way lccondly, lunss and lhcrr hrwswsenales are tmswn /o contain the cnzymic machrnery needed to synlhes've and inleteonverl prostaglandins of the E and 1: serics- their 1S•\ctodihyJro derivNives, thtonsbosanes. P(il,, and producla of the /irst \nnwn Ipa..Y6enase pathway. Also, many of she pros/a- glandin related suhslances have potent cOecls on lung /surction, notable es- ampks being the pronounced M.wschocnnstrrcta effects ot sawne of the k.rlrNriencs and the msfted MoncM.JiIa1M effects of P(ilt. One of the major poims of interest considered here is the role of the lungs in blood pressure hurssesntasis. More specifically, she rsk of prdmonary endothelial cells in Ihe selective proce.sing of vasoaclive subaanees has been eaamrneJ. Within this comesl, prrsaaglardins of the F and F series were of interesl because of their abslxres, in pharnsacological doses, to aReet vascular lone. Overall, while it has hcen seen that the proslaglandins and related suMlances have poteM pharmacohsKSl effects on the blood vesach and airways of the lungs, il still remains unckar which, i/ any. d these substances contribute /o lung dy.- functirns or even whether the prostallanJins are vital so life or jw1 eonsli- tutc a group of compounds capable of modulating or amplifying more (unda- nsemal li/e processn. Ryan, /. W., Ryun, t/. S., and Crwchky, D.1. Awfl.rin turupe.m Jr J'hrslr.f.urMrlo~ir Resrirnr.drr I7:M7-6Sh, 19111. Olfier support: U. S. Public Health Service. From the Miami Ilearl Inslilute- Miami Seach, and the Department of Medl- cine. Univenily of Miami School of Medicine, Miami, Fla. IMMUNOI OGIC IDFNTIFI('ATION OF FI.ASTIN-OF.RIVFO PFPT108S IN "l111: SERUMS OF DOGS Wllll EXPERIMFNTA/. EMPIIYSEMA In nwukl aystems for the study of esperimental emphysema. Ihen is a strong c.wrelation bawten the production of emphysema and the ekwap of insoluble ansorphous lung ela.tin. While il is dil6cuh. in the human lorrw of the disease, to identify the peritils of active progression and so correlate them with parlicutat incitive /actor.. one approach to the ptobkm may be the immunologic identi/ieatiun of pepliJcs (rom husg elastin degradalion that may appear in emphyscmatwa palienta' serum. Antibodies were prepared M rabbils aeainN peptides generated by osalic acid or dog neutrophil elas/ase digeslion u/ prnslkd dog king pasenchymal elaslin. The antibodies were used Io idrnli/y and quanlita/e elastin deriveJ peptides in the serum of dop ten- dered emphysensatous by porcine pancreatic elastase aetosol Elastinderlved peptides were detectahle for I_' day% aller Ihe administration of a singk 42 1 41

W r N I drne (?S nrg or 50 rng) of elastase, and for at kast 40 days a/ter trealmenl wNh IfM) nsg. There was a direct correlation between the masimal concentra- turn of elastin derived peptides in the sera and the amount of elaslase ad- nministered. With Ihe use of thn henut6/ulinalion inhibition aasy, it may he possehk w monitor Ihe proress of this disesae and to evduale therapeutic measures in animah. It is haped that such an approach will ultimately lead lo better evaluation and managemcnl of human emphysema. Kucich. U., Christner, P., WeiwB.rwr, G., and Rosenbloom, l. Ansrrksn Rrrlrw o/ Rrrpir.rory Dlrease 122:161-163, 1980. OOther .arr.rt r National Instilss/es of Health. From the Puln.onary Disease Section, Albert Finstein Medical Center, and ('emer for Oral Health Resemh, Deparsment of Anatomy ard Ilistology. Schrrol of Dental Medrente, Uwivetsity of Pennsylvsnia, PM/adelplua. S01.1D PHASE IMMUNOASSAY OF DOO NEUTROPNIL ELASTASE Thrs report describes an enzysne-linked iawnunoassay of drrR neutrophil elntase by the indirect competitivt method, using alkaline phosl.hatase eova- krwly hnked to a goat ant@ rshhil irnmunogbbdns as the indicator system. It is su11•ICiently sensitive to meuure, seprodunblT, nanoRrare quatNities of in- munoreactive enzyme in crude aeatrophil eatracls and serum. While this procedure is as sensNive as standard radioinumwwassay procedurn, it has the additional advantaRes of easy handlinR, tnore stahk reagenls, and fewer re- quirements for sophistKaled earipnnnl. Overall, it seems that this method, which can be conveniently used so meawue levels of immunoreactive enzymes in bio/ogical fluids of animah, may be especially useful in studin on the de- vek,prnent of e.perirnentsl enrphysema ia dop. Kucich, U., Abrams. W. R. and /ames. M. 1.. (WrlnAarrn, C. ) Aw.lyricd lliorhrmlrrry 109:10)-409, 1990. Othtr aarrr.rt r Nationa111eart,l.unR aad (bbod Instilute. From Albert Einstein Medical Center. Ihe Pulmonary Disease Section, Phila- delphia. FLASTOLYTIC ACTIVITY IN PULMONARY LAVAGE FLUID FROM PATIt.NTS Wllll ADULT RFSPIRATORY-DISTRPSS SYNDROMP. While the precise pathophpsiobgk evenb that culminate in adult respita- /ory•distress syndroa+e (ARI)S) ue uatnownk recent hypotheses have iwkn- tilled hoth polymorphonuckar kutoertes and associated proteo.ytic enzymes as possihk mediators of this syndrome. To /est /hese hypotheses, diQerentiat whiteretl count, elastolytic adivNr, source of elastase, and the conceMration and activity of Ihe endogenous prosease inhihitor alpha-l-anliprotease (.-1- AP) in hronclx~alvenlar Isvage fluid were determined In samples from 2) patuenrs wnh ARI)S and /rom SS patients without this syndrome. Neutrophd 44 I predominante was observed in 1{ of the 23 patients wilh ARDS. High dn- anlytic activity of ncutrophil origin was found in 12 of these 23 patienu, io none of 16 normal nassrnoten, is two of 17 sartssal smokers, and in three of 22 patients with chronic obsuudive pulmonary disease. Although there were no significant differences in a-1-AP conceMralions, its activity was re- duced in eight of nine patients with ARUS and high elaslolylic activity. Over. all. results showed that high levels of elaMdylic activity were present in the pulmonary lavage fluid from Ihe majority of patieMs wilh AROS and /hM the naturally occurring prolease inhibilor, rl-AP, wa reduced iw (undioa in mosl of these patienb. 1 ee, C. T., Fein, A. M., 13ppmann, M.. Noltznw, 11.. Kimbel, P., ssail Wrinb.wm, C. New EnIfnnd /orrnd o/ 6hdirinr M1:192-1%, 1981. OtArr anrr.rlr Nalional Ilearl.l.unR and Sbod InslNu/e. From the Ikpartment of Medicine, Albert Einstein Medical CeMer, PYla- delphia. I:MPI/YSF.MA INDUCED IN VfTRO AND IN VIVO eY A PURIFIED EI.ASTASE FROM HOMOLOGOUS LEUKOCYTES /lsis repoA, which describes the puriRcation atsd partial characteriRalioa of dog kukocyte elastase, preseMS tssorphologie data that establish shat eatwe neutrophil elastase is the only enzywte necessary for 1he inductiow of empir- serna in this hor.,AoRous system. In the preaatt studp, two puri/katiots twet(s. sds were employed. The /lrst tued solvenb of iaicreasing ionic aretyth M sequential eatraaios of acetone po.akrs of purilkd dog newrophils. T11 ability to initiate erssphpsemrlite kaiaa was IeMCd in every fractiow at ehe purifkstirw and was localized in the ealracl with 1he highest Inre elntolytie activity. The second purifkalirM involved newropAil intrac7rtoplaswae or- pneNe Iractionatken and estaMisAed that on1Y ettracas of the Irsosomal aaw- oks were capahk of emphysema inductirus. FinaRy, the enryrne was purified Io homoReneitr from the panules using afRwilr ehtornNoRraphy and was shown lo he a true elastase. Fmphyseisu de.ebptoetN was quanlitatcd wiwR tnean linear intercept and wn showw to be dependent on elastase oewcea- trauion. There does not appear to be any other siwRle enzyme in the casine newropbd capsMe of inducing esperinsetMal emphysema. Since a homologous animal system can be related /o bwnan ernphpsenw, i1 seerns reasowabk N assurne that the availability of a compkady AonroloPus systere lor inductlon of esnphrsems will allow Ihe devebprnent of new e.perimenld approacha 40 nwnitor the etiologr and pathornesis of emphyserwa. Sloan, S, Abrsms, W. R., Meranze, D. R., Kirnhel. P., and We/nMon., G. Arnrrkan Rerlrw o/ Respiratory Disease 121()):29S-T01, 1981. Other aurpert: National Neart, lung and Blood ftstitsNe. From the Pulmonary Disease Section, Alberl Einstein Medical Center and the Oraduate Nospitsl, Philadelphia. 45

i I I ~ ~ .~.3. i .f.. .^1 1 ~ `sy i m w tn i- m A J i W A lJ EI.I:CTRON ANt) 1.1(7I1f MICROSCbPIC SfUDIES OF Tlll: LUNGS OF ('F1l.URAMINE=T TRFAIED DOGS In this auempt to create an animal model of functional slphar-anlilryp- sin de/iciency, chl.xamrne-T, an osidative agenl, was admrni.tered to aia dogs in varying regimens by the intravenoro, oral or eombined oral and in- travenous routes. lotal doses ranged from 200 mg to 1200 mg over 12 /0 27 week periods. Serum sampks were analyzed lor their inhrhnnry eapacily a`amsl trypsin and elastase. The elastase inhibitory capacity of the serum was decreased by 10 to 70% (ran startin6 kveb and was ma.imally reduced when chloramine-T was adrniniaeted iMtavenously. The scrum trypsin i.- hibitory capacity wsa kss a/fected thas the serum elastase inhibitory capacity, which also held true for the luwg lavage material. The chronic pathologic effect in the lungs of these sis /oV was the produetion of cmphpsematous- Ide changes as see• by lioM and seanwMg ekclran microscopy. 'she present work also e.ammed /wther the uhr.str.ctural changes produced in the lung by chlnramine I lrcatmeM a.d t:anparcd these changes with those previously repwted in do6s e.poaed to cigarette smoke. Imnunocytolc)gic techniques used in this study showed elauiw 1ucaled eatracepularly to activated iater- sanial cells which were inereased iw number. This model reproduces wme as- pects of human aipha,-amwrypiw defkiency and seems to support impaired inhibition of elastase as a mecbaeir of emphysema development. Damiano, V. V, Sandier. A.. Abrams, W. R., Meranze, D. R., Cohen. A. <t., Kunbel. P., and Wrintwrm. C. eullrNw f'rrop.rw dr rArtioprAobRlr Rrrplra+oi.r 16(Suppl. -('hnical Res- piratnry Physroloty):111-151, 1960. OtAer.rprort: Natioeal lestitwes of Health. From she Graduate Itospital, Albert F.inaein Medical Center, Temple Uni- versity Health Science Center, and Ihe Franklin !_aboratories, Philadelphi.. AN ANALYSIS OF THE ORGAN AND SPECIES IMMUNOSPECIFICITY OF ELASTIN FJastim is an important connective tissue protein since it is largely re- sponsible for maintaining Ihe elasticity of the major blood vessels and lun6 tissue. Ahhough its structure has been charted before, comparatively few studies have been made of the imnwnoloSic properties of elaitin beeause of i1s high degree of insolubiliNy and because of its apparent limited capacity so elicit precipitating antibodies. For the study presented here, antibodies were obtained in rabbits to peptides prepared by digestion of dog and human lung and aortie elastins with either oadic acid or leukocyte els.stase. By hem- agglutination assays, the invatiptors were able to compare the species atsd organ specUkitin of these antibody preparations and to show that they aoa• react with the insolubk elaslin from which the peptides were derived. In (act, by the.e assays Ihe researchers have shmvn Renerany that - 41) within a given sperics rhe peptides (rom aoru and lung cross-react suron6ly wilb ,(t I one another, (?) there was rather poor cross-reactivity bctween pcptides from different species, (1) the prptides oMaiwad by osalic acid digestion cross- react poorly with thrae ubtainavl by crastase digeslion, and (4) the antibodies to the pcptides cro..-reactcd with the insolubk elaslin frons which the pep- tiwks were derived. It seems from the present work thal these elastin-speciflc antibodies may be useful for ultra.tructural localization of elastin and idea- IiM1cation of fragments derived from elaslin in the sera of humans awd e[- perimcnlal animals. Kucich, U., ('hristner, P., Rosenbloom, 1., aad WeJwA.wnr, G. Connrcrive Tirsre Resr.rcA ti:121-126, 198 1. OOther .orprt: National Institwes of Health. From the Pulmonary t)i.ea.e Research I aboratory, Albert Finstein Medical ('enter, and the ('enter Ior ()rd Health Research, lkparlment of Anatomy and Ili.tul.rRy. University of Pennsylvania Sthool ol 1)ental Medicine, Mila- delphia. RFSISTANCE OF TROPOF.I.ASTIN AND ELASTIN PFPTIDFS TO DF.GRADATION BY a; MACROOLOBUI.IN-PROTEASE COMPI.EXFS The development of emphysema iw man is a eomple., chronic proce» that often involves nsany years, during which time there may be periodie destruction and repair of prMroonary tiswe. While recent eaperwnental rsodel systems lor emphysema study have stressed the deslruction of the rwatsre elntin fiber by administered proteases. previous studies have suggested tkyt the compka of wewrophil elastae and .-wacrogloMAin can degrade Iropi- lastin. Ihe 70,fl00-dalton soMrble inlerm~Aale in she biosyothesis of insalrable elastin. For she study presewted here, compleles d[wman .; macroglobMlin with homo6eneous Isuaaan uea>troplwl elastase, porcine pancreatic elastse, or bovine trypsin were isdated by gel fWraliow ehrosnatographr and testesl for their ability to degrade ttopoelastlw. While tropodntin was rapidly dedraded by the free en:yrnes- it was nol aRected by the complexes. Howe«er, pepddes of mokcular weighs 8500 or Ins. prepared by mild acid hydrolysis d In- soluble elastin, interacted with the catalylicaMy active entyme in the ean- *a, while larger peptides did wo1. O.eraN, thne findinp wqest that .; macroglobulin elastase cnmpk.es do tw/ themselves play a rok in the IdtiJ degradation of either soluble tropoelastin or insotubk elaslin. Kueppers, F., Abrams. W. R., WAnAarrrr. G.. and Rosenbloo.n, 1. Arcllirrs of Qioclirmbrrr and <rlorAysks 211(1) :1d1-1 S0, 19111. Other support: Nationa11ns1ituln of Health. Frons the Department of Medicine. Temple Univereiy, the Dep.rtmeM d Medicine. Albeit Finucin Medical ('enter, and the ('emer (or Oral Ikallh Research. University of Penmylvania School of Dental Medicine, Philadelphia. 47

i I A M11DE1. OF /)CCRIiASfD FUN('f1ONA1. tr1 •PROIFINASP. INIIIBITOR: PUI MONARY PAlHO1.0(iY OF h0(iS EXPO :FD "10 ( Ifl.(1RAMINF. T (n thra artenapt tn develop an animal model represcnutive of n•1-pro- ternaae inhiArtw defkiency in humans, eight dogs were treated with chlora- mine T• an o.idarive agent, in varying regimens ranging from 3-27 weeks by the innavenrnn, oral or combined oral and intravenous routn. The capacity of the scnms to inhibit hoth try/ain and elsslase was esamined and found to respmwl ddlerently. AhhnugA irwmwwloifrcally determined kveh of pro- tease inhihitor did nnt change. Ihe ability of sernm to inhibM elastsse in an in rirro assay dccrea+ed in direet response to cAloramine T Ireslmenl. The trypsin inMhrtwy capacity was kas aAected. Emphysema-Irke alterations in lung morphology were.oburvsMe when histologic sections were evaluated bwh subjectively and objectively by mean laaear intereept measuree+enls. lhe dua prexnled here su6SeM Ma1 this model paralkk the emPhyscma that is aaaociaed witA ~enetic w 1•prottinase inhibilor deficiency in man. AArams. W. ft. Cohen. A. B.. Damiseo, V. V., Eliraz, A.. Kimbel. P., Meranze. D R, and WrinA..rnr. G. lnrrn.d o/ ('Irn4.rf Insrtnis.rion 68:11)2-11)9. 1951. OrArr s.rOt...rt: National Ileut, I ung• and Blood Institute. From she Division of Medicine, Research Secliors, Albert Finstein Medical ('entcr, Temple Umversity Health Science Cemer, and the Franklin Research Center. Phd.dclphra PULMONARY NF.UROENDOCRINE CF.LIS. 1)ECRI°.ASI n SEROTONIN FLUORES( FNCE ANI) STABLE ARGYROPN11.-('EI 1. NUMHFRS IN ACUTE HYPOXIA The eAecls of acute hypobarie hypoaia on the neurocedocrine cells (NECs) is the nr:onatal raAbil kans were eneasured Acre by two techniques: the silver staining method of Grine/ius and the formalin-induced /luoreseer.ce technipue. While comparison of seroloninemisaion intensity in neuroepithelial badies of acutely hypnaie neonates and nornwaie controls showed siRni/kaNly lower fluorescence in hypolic animaht. NECs numbers as shown with Grim- elius silver•nitrale stain did not change. 71This suggests eiaher thst the Orim- tliw stain reacts with compounJs other than serolonin, or thst the decrease (n sero/onin in acutely hypvak rabbAs is no/ sufficient to alter argyrophil stainability. KeiNh, 1. M.. Wiky, l.. A. and Will, l. A. C.N.nI Tlrrue RruwcA 211:201-205, 1991. OtArr support: College of Agricultural l.ife Sciences. Univeraily of Wis consin• Madraon I rrrm the />epartment nt Veterrnarr Serence. tiniversity of Wncoo-tin. Madison. 18 I 111. ILart anr/ Circelation B/O('/ll'MIC Al. AND IIISTOLOGICAI. F.FFC7S OF INTFRMITTENT CARB()N MONOXIDE EXPOSURE 1N CYNOMOLGUS MONKEYS (Afacaro Jmelcrlsls) IN RELAIION TO ATHEROS('LEROSIS In this attempt to define the relationship of carbon nwraaide (CO) ea- posure to the developnKnl of atherosckrosis, 11 adrll male eynonwldtn ttrw- keys were maintained ia/ermitlenlly on CO for 12 maMhs on a standard diet. Biochemical, hematobnical and histological aspeets of CO espswe were then .tudied, and par/icnlar emphasis was placed on the eorrelatioes of histological findings with biochemical studits such as arterial choksterol Ara, mitochnndrial functiow in heart musck, and lipid and free fatty acid (FFA) kveh in blood and Iiasue. Results showed Ihat, in Reneral, prolonted a.r periodic eapcnure to' ('O resultind in earhoayhereoRlobin levels which ue above those seen in naderale to heavy smoken had no d/en ow plrma lipids, with the eaeeption of some FFA. Aho, only minor changes irn plaatt.a electrolytes and in liver and renal ftarction were found. A moderate increase in hemoglobin and hemalocrN was noted, but in general the blood pkwre remaioed normal. Histological eaansination of the animals maintained e. Ir terrrultenl chronic eaposure so CO but ao1 on an atM:rogenic diet, revealed no athennckrosia. OveraM. the data reported here do not sugRes1 ayr asso- ciation between periodic carbon nwnoaide eapoaure and the development of atherosclerosis in cynomolRrrs monkeys. sing. R. l. rr d. The lournd of CfJeic.f rA.rws.tofotr 20 ( u9) :.117-.99. 19110. Otb.r an'prtr The Hoover Fowadatioa. From the Huntington Institute of Applied Medical Research and t6e CaR- fornia Institute of Technololly, Pasadena. Cal., and the Univenity of SoMherw Califorwia, Loc Angeks. MECHANISMS OP ANTIANOINAL DRUGS This paper reviews the circulatory eQecb and the anios aw cardi.e wa tsholism of antiangied drugs. Itn the hsl sediow of the swdy, aw owsvitw of the aqiow of aManRind drugs ow cardiac mdabdiuw and circs>tdsry, changes ie given, whik Ihe second sectiose deals with the action of the tal- eiwn antagonin, dihia:em, on regional mratardial huhemia Adore and a(ter the rnumpion of coronary AoM. lAe aMianRinal drup are divided iNo 1M+e poups here: (a) those that act primarily on tAe trodistrihwion of blood; (b) bela Sbcken; and (c) calcium anlagonists. In pouo a, nitroglycsrin and a new druR-molsidomin-affect primarily the capacity and complianoe M thc systemic venous system. Nitroglycerin also dlers the eado-/epicardi4 perfea- sion ratio of the ischemic myocard'wm. Iw group A, lets blocken dMd" myocardial contractility and hearl rate via beta reeep/ors. Iw group e, eal• cium antagonists result in blockage of Ca t r rrwvement through tha sarco- 19

lemma, /hus producink a negative indropic effect. AII anlianlin.) druss, re- dardkv of their spaiflc eflecl, rtsuh in diminished myocaid al osygen de- mands and o.ygen consumption. Dihiazem, a cakium anlagonisl, enectivelr counteracts sonse of the effects of acute myocardial ischemia. Like other cakmm anlafonisls, dil/iaum blocks conlraction and prodw-es a negative inolropic eAect. Consequenlly, ku ATP is consumed, and cardiac o:ykes requirerneets dimioish. llint. R. 1. et d. In: Winhury, M. M. and Abiko. Y. (eda)' luhtwsk Myoca.dium and And- anpin.f Drrlr, New York: Rave. Pretr, 1979, pp. N-102. Other wrprtr The Iloovet FordNbw. From the Huntingtow Institute of Applied Medical Research, the Iluntinglon Memorial Hosprtal and Calilor.ie Iwstitute of Technology. Pnadena, Cd - and the University o/ Southern Cdilorwia. Los A.pdes. • A(-!I(1N OF ANTI ANl;INAI. DRUGS ON CARDIAC METABOLISM lhree 1)pes of antu anfinal drugs are deaarhed hete: (.) Ihose Ihal act primardr on 1.emoJynamacs (rednuibution of htood Row in the systemie and cornnary circulation. (h) 3blockers, and O) e.kium antagonists. Nilriles are the protntrpes of the dru0 tha1 act primarily nn hemodynamies, while propranobl, a(I blocker, has been shown to have wi-asginal properties because it diminishes myoGrdial oaygen demand and coronary Aow. From /he takium antagonist group, diltiarem was found 1o kssee the effect of ischemia resulting from coronary occhniow in dop. For e.ampk, this ake.l was shown to preserve the high energy phosphale reservoir and decrease Ihe inhibition of gIycolytie /lux at the plw.plso(roclokina.e level caused by rrr)o- cardial ischemia. Dihiarem produced a marked redncliow in ischemia-induoed damage so the conlractik ekmenM. Increased tiasue levels of lactate and free /atly acids aliribuwahk to ischemia were lowered by diltiarem. Although dit- lia:em inereased contraclility of Isolated ischemie heart muscle Rhets, i1 did no/ ksaew Ihe effect in mitochondrial respiration or mNochondtial eakiwe binding. On the other hand, dihia:em was /ound to counleracl she eRecb of isehemla followed by reper/usbn on rniloehrndlrid o.ygen consumption and cakiww binding. /Ine, R. 1. • 1.: Tajuddin, M, Bhalis, B., Siddiqui, H. H., and Rona, O. (ed. ): Adraneet lw Mrocardiolotr• Pot. 2, Baltimore: Uoiverahy Puk Press, 1990. pp. 465-476. OtA.r wrP.rt r T1se Hoover Pou.dNiot.. From the Ilunrentton Instwule of Applied Medical Rear.rch, the Ilunlington M.m4..,al anJ d.r /•Idor.u (n.Qrute at technolog), Pasadena. ('al.: •wd rhe tlw.nrs.rr n1 4..Jvrw t'a1//nrnia. I o. Asoleks VUANI I I ATIVE ('/sP11J.ARY TOPOGRAPHY AND B1.OOD FIAW IN T/11: Cl=.R1?BRAL ('ORi'EX OF CATS: AN ONi YOVO MICROSCOPIC S I UI)Y ~ Microtransilluminalion, an illumination /eehnique, waw ased i. IhiW Mud7 (or visualizing the coronary microMorrMlow, since N has obvious methodological advanlaRes. Ilere, in 50 anesthetized eau. the microeirculalion is IMUtwedi• a1e and deeper layers of 1he cerebral eorlex was visualized !w .Ivo by 1his lechnique and documenled by high-speed snietotiweplwbRraphr. The vi.- hilqy of Ihe preparation was veriAed in a series of eaperk+wewls demon.lraliy spanlaneous vasomaian and responsiveness to chemical Nireulaliou of pid arlerioks and small arteries. StereoloRkal srelhode for quanlitalive aM.17.is of projccted images of capillaries i.n comparatively larpe 6saue .ohrutr wern employed to determine morphomelrk and topographical p.r.wteten of 1ha asynunetric, highly lurluous iMraeorlkal capillary network. CapiRary dla- melers, radii of cwvalwe. total capillary kwpMs per lissue volwwe, capillary volume (ractions, /olal capillary surface aren per Iwue volume, tutd inler- capillary dislances slawed siRniAcaM iMerRRiond differences. Ow Ihe aver- age, 90% of aR capiRaries were conliworsly perfused. C.piRary red cell tlow was predominantly t.nidirectiosul and conspicuously irregular. The vai- ance of capillary red cell velocities wr signiAcanlly correlated with eapiR.ry lorlssosily. The rather limited functional reserve capacity of the microvascular bed studied underlines the significance of a capillary topography heAuiy Ihe nalwe of the described tissue. Pawlik, O., Rackl, A., and fine, R. /. erain Research 20t:)S-Sk, 19t1. Otker.r'r.rtr Th.lloover Fou.dalion and The Wi.. Fowsda/ia.. From Ihe Huntington Memorial Hospilal, I/wNinglow InNhWe of ApOW Medical Research ud Ihe California lnslilwe o( TechnoloRy, Paudtar, Cd., and Mari-Planck Imtilule lor Brain Reutuch, Department o/ Cerebo..aculat Reseatch, ('ok+gne, Germany. LIPOPROTFIN UPTAKE IN PERFUSED ARTERIP.S: INHIBITION BY 7-KETOCHOLFST!'ROt. This study deab with the effect of an oaygenated sterd, 7-keloe*eks- lerol (7-Kl'), on low density I'ipoprolein (LDL) uptake by rhythmically per- futed isolated porcine arleries. The peHusak consisted of Dulb=o'a twodiBod Ealle mediute, supplemented with aRwrnin and pw. r1Wl-LDL. Pria et- posure to 7-KT significantly inhibiled LDI. uptake (from 2.47 to 1.92 N 1.1)1. p/Rr arlery). Ahhough these resulls densonurate siRniAcawl i.hIb111ow of 1.D1L uptake lyr the arterial wall. this wu not as marked u 1he Inhlkitbo previounly observed /or eholest.rol. SanliRan. O. a.. Schuh. 1. R., Chan, S. 1., and I/nq, R. I. Artery 7(7):)tIJ91, 11911131. 01her aarpr.rlr U. S. Public Ileahh Senioa, Awwka. Ep Board ..d TM Iloover Foundatiot.. From the Ilunlin ftun Mcnuxial /lospilal, Ih. /luslinpon Iwslitula of Ar plied Medical Research and ('alilornia Institute of Technolopy, Pndetr. Cal. An 1 51

i S('IIWERPUNKTF 1)FR INTF.RNATIONALFN KARDIOIAt',ISCIIEN FORSCHUN(I 1his paper presents some recent aspects of intereatioaal research in cardr4.togy wirh regard 10 sekcted topics, and based on the drAerences be- Iween oMervations in clinical nd basic research. However. she presentalion concentrares mainly on dealing with basic cardiological problems_ (Oerman test) eine. R. /, Rackl, A., and Pawlit, O. ThtreplrrarAe )1:2I)•21), 1911. Orlier wrrorlr National Instkuus of lleahh and The Hoover Foundatio.. From the Iluntinrnn Memorisl Ilaspi/sl and Iluntinglow lrntitute of Ap- plied Medical Rese.rch, Pasadena. Cal., and Ihe (-dilornia lnsrnute of Tech- nolrRy. Pasadena. TIIF. eFNEFI('IA1. FFFECT OF A CALCIUM CHANNEL BLOCKER, Dtl.l tAIEM, ON TItE IS(-HEMIC-REPERFUSED HEART The eQectiveness of a new calcium channel bloetaer, DiUia:em•IICI. M rtducing reprrfusinn a+duced damage to the ischemic myocardium was ott- amined in the study presented here. In isolated working ra1 heart prepara- tions i1 wu found that 120 minuwes of Rtobal ischrmim followed by 15 mi.- ules of repertu.ion resulted in a massive kalqe of erealine ptasphoftinssse into the cocnAary eAluerN. and in many cases- in fibritlation and/or eon- tracture. Isft ventricular twddi.stolie pressure incressed sharply during re- perfusion in these heats. Reperfu.ion did not affect tiswe Al P kvels, bw did increase erea/ine phosphate somewhN. When DiNisaem was added so the pertusate A.e minutes prior 1o re<stablishmen/ of flow. she deleterious eRects of reperfusion were greatly reduced. None of the hearts fibrillated om reperfusion, and none developed emMraclure. ItU-ventricular end-diastolie pressure was increased only slightly in Ihese bearts. The amount of creatine phosphobinau released into she eoronary effluent during re-flow was o.ly bt that which was released by hearts reperfused in the absence of Diltiuem. In the Dihia:em-treated hearts reperfusion restord erealine phosphNe to near-normal kveM, although ATP levels were not increased. These bene0cid effects are presumably related to the ability of Dillia:em to restrict a mas- sive inAua of calcium ions into the ischemic myocardiwss during repertwion. In the p.esent esperiments it could be seew that revascularization. when eomMned wNh Dihistem pretreatmtnl, resulted in a partial reversal of the effects d'nchemia on the myocardium. Weishasr, R. F.. and eint. R. I. lerrnl o/ Mol.crl.r and Cedrf.r Crdlolop 12:99)-1009, 1980. OOther wprorrt The //oover Poundatloa. Fronm the /lunrrnpon Institute of Applied Medical Research snd Huntington Mrn.....a1 11.«o.ral. Psadrna. ('al, and the ('aldornia lnuirute of lechnol- uRy. Pasadena 52 r C'ARINOVAS('UI.Ak DISEASE IN'IHE AI.COHOLIC 1 his Ir+ok chapter contains much summarized material dealing with she eRecta of akohol on the heart from both she clinical and biochemical points of view. Feawred .nane the dinical effects of alcohol are: The Fetd Ak.ohol Syndrome. Akohol and Coronary Heart 1)isease, Alcoholic Cardiornyopalhy, the (kcurrence of Cardiac Arrhylhmias, and the Effect of Alcohol on Car- diac ('ontractility. When attention is directed to the biochemical e/lects, it becomes apparent here that alcohol e.erts a profound influence on mmy of rhe key biochemical and hiophysical processes o( the heart, the oolward rwa.i- /estalarns of which are the clinical sympomatology, ddescribed before i. the clinical section. ihe biochemical eRceb portions of this book chapter ut de- vrwed to: Myocardial ('ontraclilily-acute and ehronie, and the fdlowi.g 1?Aects of Alcohol on Other Aspects of Myocardial Metabolism: Cakiwr mefabolism. Mitochondrial funclion and Energy production, Protein sysithe- sis, and I ipid metabolism. OveraM, this paper ahows that Ihe eaac/ mechaninw whereby alcohol dlects myocardial metabolism is still elusive, but 1M1 the gap between effect and :ause is ever and continuously narrowing. elwt. R. l. ard Weishaar, R. E. In: ('Isrk, P. M. S. and Krieta, L. 1. (cds.): Med:r'al Con,ean.nrr, o/ A!- co/id AMue, Harwood, New Yort:Nalsted Press, 19110, pp. 171-1ta7. Other .or'.rt r National Inslitutes of Neahh and The Hoover Fowsd.tion. From Ilsmtington Memorial Hospital. Pasadewa, Cal. EFFF('TS OF CHRONIC ORAL CONSUMPTION OF NICOTINE ON THE RABBIT AORTIC ENOOTHELIUM 14 this inveMiptioe of the Nlects of sdeotine on the rabbit aorlie 1do- theliwn, tO New Zealand white rabbits were administered daily dtws o/ nicotine (2.d mR/!R/day) in their drinking water for 25 weeks. NieWir- lreated rabbits were comparad wilh 10 control rabbits in lerms e/ Nood serum hiochemistry and lipid pro/lks, blood cell euurNs, ehmges is aortic endothelial cell morpholoRic ch.raeeristics asd dislribulion, and tesd wall permeability (Evans blue dye uplate). Fastittg aerwn kveY of Sh.cors. tri- glycesides, total choksterol, aM/ t.DLtAolesterd were elevated in tticoti.e- Ireased rabbits. No significant dillerences were setw in kukocynt, eryMrecyte and platekl counts, w hennlocrit and hemoRlohiw. Control snd Nrootine- lreated rahhit aortn showed si,inilar local .reas of incre.sd Evans blue dye uptake. EndrNhdial ceMs from arch ueas were eaamind by a combiwlion of 11dsNcheA preparation (silver-Nsined vessek) and scannby awd tra.nnis- sion ekctron micro.cropy. The eeYa front eieotine-Ireatd arch areas showed such estensive changes as increased cyloplaseric silver depositiow. Increased formatios of nsicrovilli, and numerous foeal areas d`ru/Red" endothelwn (projecsions on cdl surfaces). 1/ seems possible that thesn observations may discern some understanding of she direct anJ/or (ndirect in .Iro efleetils) of nicoline on .nrtic endnlhelial cells. . '3 3

•ooyse, F. M.. Osikowict. 0. and Quarfool. A. l. Anwriren /orrnd o/ rerAoloq 102(2) •229•218, 1981. From the Division of Cellular Biology. Michael Reese Rcsearch Foundatio., Chicago. EFFFCT OF NICOTINE ON CULTURED BOVINE AORTIC F.NI)()I IIt:1.lAL CELLS Although various studies have been done on the eRects of smoking on endothelial cells (rC) In rhe, few in.esliptions so fa have esamined Ihe direct eRecls of nicotine on rrtrrrrd eeMs (rom vsscular oribin. This paper describes the short (1-4 days) and lon.-lenn (10 paaages. 12-14 weeks) effects of nic4yine tarlrate (NT) so cultured bovine aortfc FC powlh, rnw- phnlogy, overalt protein srd coMallen srathesis/turnover, f/txinolysis. Iacla/e pnduction and platekH•subendothelial (SE) interaclion, as compared so un- treated contaols. ResuMs of thesc sludin showed that low concentratioos of NT (< 10 ' M1 had no appareM effect on EC proliferation, morphabp, DNA synthesis (thymidine inco.pord'an), overall protein synthesis (kucisrc and pro/ine incorporation), /ibrinofysis, lae/ae production and plateklSE inreraclan/adheswn. Ilowever, 10 • and 10 e M NT did ircrease the se/ accumulation of collagen in these euhures. In addilioe, high concentrations of NT (> 10 r M) caused rapid and eskmive vacunlation of these cultured EC and also increased lacuse production two-fold. /ooJsf. F. bI, OsikowKr. 0. and Radek. 1. TAror.rborl. Rnr.rtA 2)(4S ):169•161, 1981. Froin the Division of CeRular Sio{ogy, Michael Reese Reacarch Foundalion, Chicago. RF.GIONAI. RENAI. AND SPLANCHNIC SLOOD FLOWS bUR1NG NICOTINE INFUSION: EFFECTS OF 1ETA ADRENEROIC BLOCKADE 'fAe twechawiwnm responsibls fer the effect of nloolins ew n6iond n.d said splanchnk bkood flows wen Mudied in nsonpel dogs by comperint re- gional blood Rows wilh and wilhoM bets adrenergic bkockade wilh propranobl. /o addition, Ihe effect of proprsnokol sfan: on these /lown was eaamsned. Nsco- tine alone caused marked ek.ationa of systemic arterisl, central venous snd left atrial blood pressures, and i1 reduced Row 1o renal cortet and pancreas whik nm affecting /low to renal meduRa, duoderwm, liver, or spleen. Va- colar conductance was decreased by nicotine in all tissues e.cep spleen. eete adrenerspc blockade decreased heart rate but had no other syslemie henw- dynamic eRect. Regionally, bkre adrenergic blockade decreased flow to liver and to pancreas hu1 had no effect on Row to other splanchnic oreans or lo Ihe renal cortea and medulla. Nicotine aller bne adrener6ic blockade resulted In sfuemic hyperlemi..n simi!ar 1n that without Ikte bkxkadc 1)esprte eoncur- renr hyperrrnuon. fhr.v dccreased in all o.Rans e.eepl liver. Vascular eon• ductan.e in renal cerre and medulla, duoatenum, liver, and pancreas wr . I decrea.ed Ia a greater estem when nicoline was preceded by propranolol. In .pken, nkoaine caused a pronounced decrease in vascular conductance after brrn hlockade, allhrurth wilhrnq hlocksde it had had no eAeq. Tb result% heee indicate that niaNine has a heleroRenoos influente on regional vasnrlar comhrclances in renal and splanchnic circrdations /ha/ is associated with regiunal differences in activity of bete adrenergic receptors. nor•nry, H. F. Crystal G. l., and Sashour, F' A. The /or.nd o/ rbrnrocoloRy and Eaprrinsrnrel Thrr.rrrrkr 216(2):)6)- )67, 1921. Other support: Southwestern Medical Foundation awd the Cardiology Pwd. From the Departments of Physiology and Internal Medicirse, Univenily of Te.as Heallh Science Cenler and Cardiovascular Research Laboralory at Melhodisl Ilospital, Dallas. CIGARETTE SMOKE-INDUCED DEPRESSION IN LCAT ACTIVI'iY TAis Mudy was designed to provide a direct rneawreesent of kcitltf.- chokn/erol acyllransferase (LCAT) activity snd high densrty lipoptmlel. (llhl.) apoprutein A-1 concerNraion in nherockrosis-suscepibk White Cr- neau piReons esposed for an scule period of tiwne to whole tobacco asoke containing high and low levels of nicotine snd earbon nwnoaide. In It,Y attempt so quan/ilale coronary Mdices of vascular Mvolvemenl and to Leaa- ure aorlic lipid concentratiow, 1es1 piReons srere auiRned 1o four 1reMnteN grwlps: (I ~ shelf control fed a chow diet and not exposed so snsoke prod- ucts; (2) aFram. pigeons led a ehukslerol-aalwa/ed /sl diet and exposed so fresh air by the LoritMard ssw+kint machine: (7) bw, wicotine-low, earbon morsoside (l.ol.o) animals sbo fed the cholesterol diel snd eaposed so low cnncentrations of these cigarette swake prodMcts; and (4) hiRls nicotine-Iribh carbon rtwno.ide (11iHi) birds led the ehokslerW diet snd subjeded so Wo asrscenlrations of these inhslnNs. Results presented here show IhN a HiHi smoking regime depresses plasrwa eholeseerel es/eriAestion snd reduea pr.Meiw A-1 levels. SuMequeM atdyses revealed thst whik neither 1h. or coecentralion of 1.CAT substrate nor Ihe oubs/ra/e eMciencr was sberad by smoke Inhalation, a siRnlRcant snake•related reduction iw eruyrwa eM ciency was observed. This redoced LCAT aeli.ity iw HiHi pidcoes easi be e.plaineJ. as was shown, by (1) impaineesM of enzyme efficiency aa eai• mated by in rirro snalysis, and (2) in viro rtduNion in kveh of LCAT eo- factor, 111)1. apoprotein A-1. Mulligan. I. l.. Hojw.r4t, 1. L.. Claelte, l. E.. Kew, R. R., Slack, D. l., Nrcalosi. R. l., and Flanagas, S. . Erprrlnrened ewd Molccr/er retAolopy 13:23-)3, 1981. OOther wpp..rt: American Heart Association, Greaser Boston (M.usetiu- sells) Division. From Ihe Department of Biological Sciencea, University of l.owep, IoweR, Mass. 33 54 1

I i I k 1/ FF('T O1- ('1(iARI I 11: SM(1KE AND DI1 TARY ('H(N.I:STI:RO1. ON P1 ASMA I tP(1PR(11 EIN ('OMPOSIIION The main oh~eclive of this sudy was to quantitate morphomelricalty c.'rnnary indices rd vaacvrlar involvernenl and to measure aorlic lipid concen- trauun in White ('aneau pigeons e.poscd to smoke containing high ot low levets nl earM.n nwrnnude and nieutine. A second objeclive of the strKly was to a.sess huw JrNary choksterol-salurated (at with or witfwnrt tr-baceo smoke eap.sure m..Jrlies Irpnprotein proAks in this breed of pieeon 1=rwr group% of piteons consisting of sis birds/group were used here and designated aa Irdlows- (1) cnnurrls /ed a chow diet ad tihitum and resaineJ in their cages throughnw the sudy: (2) sham pileons /ed a chokstero/ aauuateJ fa/ diet and exposed tu Iresh air by thc I.ociNard srnoking machine; ()/ low nicotine.. l.ner carhon nwwroaide (I ul o) animah eaposed lo /ow concentrations of these srrrokt proJrrcls; and (4) high nicotine high earlxsn rnnnosn)e (IliHi) ts• pnsed animalr maintained on a smoking regimen ennsisting of high kveh of these inhalants. Plasma very low density (VI DI.). low density (1.D1.) and high Jensity (111n1 ) hpoproreins were isolated by density tradieru uNracen- udrlgatK+n. tirrw+ke related altersrions in lipnprotein composition appeared in the lint anJ VI 1)1 (ractions where tobacco smoke inhalation readled in an increase in the relati.e content of total lipid and a decrease in the relative pnwein corkenrration lhis observation was valid /or the VII)1. isolated Irr.m both groups espoxd to smoke, bu1 only for the 11h1. iudated from Ildli exposed birds Pigeons (Shsm: I.olo. Ithlli) fed the choleslerol-sNU- rsted /ar diet eirculaled 111)) with greater free ard esterdkd chnksterol mass than the ('onlrols the data (rorn this study indicate that citareue smoking can meduie alreratians in lipoprolein eomposilion indepen.knt nf changes induced by Jietary chukuerol and saturated 1a1. NnjnarAl. J. L. rr at. Arrrry 9(4) 21t3-1(M. 1991. Othrr swpprt: American Nearl Association. Greater B"lun (Massachu- xlts) Divrsion. From the Ikpartment of Siobgical Sciences. University of I oweR, Lowell. Massachusetts. NICOTINF IN(:FSTION REDUCES ELEVATED s1.00D PRESSURES IN RA IS AND SQUIRREL MONKEYS Nicotine has previously heen shown to selectively redxe the behavioral components of an anter response eompka. Because of slre functional rela tions bnween aggression and bbod pressure and the innuence of nicotine on the behavioral portion of this compkx, it seemed impo.lant to study the eRec1 of nicotine upon elevated blood pressure. To do tAis, nicoline tanrate was added to the horne cage drinking waler of albino rats and squirre) mon- keys f,M periods (riwn one to 10 weeks The rals received the drug for ap- pro.imatrly 10 wceks and were then implanled with a chronic aortie cannula and blaxf pres%ure was mea.ureJ before and after exposure to a mild tail 16 pinch pnreJure. All subjecls receiving nicotine showed reduced blood pres- sure ekvatwrns to nuaiurn stinwlation compared to water conlrols, sed Ihese redrktiuns were greater at higher JruR Joses. Squirrel monkeys ethibilisg widcly differing resting blood pressures were aJmimstered chronic dosars of nKotine. Subjects having high blood pressures showed dose-depewAea blood pressure decreasn, whereas subjects posseuinR low restirrR pre.wem denwnslraleJ little or no pressure chanRe during druR inlake. A fdlow-trr study with high blood pressure subjeeta (Ave squirrel wwnkeys) meaarrerl effects of progressive increases in drug folbwed by a return to drug,frae waler. llere again  dose-dependen/ decrease in both systolic and diastolic blood presswes was nMerved. Upon icrmina/iart of drug iwtake, pressures t increased to pre-JruR kvels. These results are eowcordarrt with the previars studies and suggest Ihat nicotine is sekctirely influential In alleriwR the bia (ogicd state of anter, decreasing both its behavioral and somatic eomponeata. !/urcAin,ron. R. R. and Emley. O. S. Li/r Scirnrrs 2t0) •IW1•009, 1921. OtAer support: Foundation for Sehavioral Research. F'rom the huurdalion lor Behavioral Research. Augusla, Mich. METHODS FOR MICROCARRIER CULTURE OF SOVINE PULMONARY ARTERY ENDOINEUAL CELLS AVOIDIN(l 71fE USE OF ENZYMES In this methodology paper, several uew techniques for the rnicraeartier, culture of pulmonary endolhelial eells are discussed arrd de'scribed, ry*Ao it has been accepted lar a while that etstysnes situNed along Ihe hsrni.d trr- face of pulmonary endothelial cells inleracl wi/h eirculatinR aolules to rer.- late the hornanal composition of syslewtie arlerial Isbod, il ia now bMoni.R clear that the range and eoropleaily of r+eacyios occurring at or wr Nia surface of endothelid cells are greater lhaw previously tecaRwitb, M.d/i- liun, there is evidence indicNittR that the quality of cell euNures wed to da Ane speci/k endothelial /uwr/iorts ntusl be earefully eonlrolkJ, lognher with develnpment of improved ttndentandisR of the eReels of WnR-lerrn estdutr on pulmonary em/otbelial eella. As of loday, new leehaiqsses have b.e. de- vchrpeJ Ior the culture of pulnwnary ewdahelial cells which avoid eapawrs to pracalytic enrymes at hoth the isolation step and during wbcuUwr. A eomhinatiun of inechanieal harvest and euhure on microearrier beads Ms provided a systenr lur the lowg-term. large•seak culture of pulmonary eoodo- Ihetial ceNs. Iealures which 1.o a(arRe eslent delermint the scope of bia chemical suNhes which can he umlertakew. R>rwr. U. S., M.utara, M. and Whitaker, C. TinNe d('rl! 1?(I) al!-615, 19tlU. Othrr support: National Institutes of fleahh. From the Ikpartmem of MeJicine. University of Miami School of Medicir. Miami, hta. 57

FI Fli('TS OF ASPIRIN AND DIPYRIDAMO1 F. ON I HE 111:(:RAf)A 11(1N OF ADF.NOSINE DIPIIUSI'IIA I E BY fUt.l URF.D C1:1 1 S DhRIVF11 FROM BOVINE PULMONARY ARTF.RY Prostacyclin and adenoaine diphosphatasc (ADPase) Provide two pro- tective mechanisms in the lung which appear to guard against uncontrolled platckn aurcgation In this attempt to karn more about 1he esacl loca/ion of p4dmonary vascular ADP, cultured endorhelial and smooth muscle cells of bovine pulmonary artery wen esatnined for their abilities to mcubolize (s-'K') AI)P. The resuMs presswled here show that both celt types rapidly nsetabolire ADP and p.oduce anliauresalory adenosine. Specdically. ADP is rapiJlr canverled to AMP and then to adenosint. hypnaanlhine and (no- sine, the maNir metahuhre produced by endothclial eells. MeJwm containing SO pM ADP incuhaleJ with endothelial eelh rapidly loses irs ability to ag- gceRate platelets and beconses antiaqregatu.y urwtrr conditions in which prrstacyclin is ahsent T1m anliaureTatory activity is probably the result of accunwdated adenosine In a related study, the eRecls of Jipyridamole aad asprrin, both of which are currently undergoing clinical Irrah as anlithrom- Ixsric drugs. are also studied. The results ol aq of these atudies suMest that: (a/ e.etaArdnm of ADP during passage through the lung is mainly the re- suN of tnJorhelial ADPast, (b) ADP rekntd frons aggregating platekets can he converted to The antiagkreplory .uhsrance, adenosine. Drpyridanso/e may tseet sr+me of its amithrnmhoric actions by preventing The imracellular uptake of adenoune. thereby increasing its concentration ncar the site of Ihrumhus formation. (e) the ability of the vessel wall to detrade ADP should not he e.xnpronused by the use of a.puin as .n anlilhromMNic Jnsg, and (d) tnJMhthum may retain v.me ol its anrrihriwnfrrpcnicely whcn prouaeyclin generation is rmpaned ('rnichky, D I. Ryen. I/ S and Ryan, I W The lorcnul of l7rnKe! Inr.rri~orron 66 '_9 15. 19140 Othrr at.pporle U S. Public llealth Service and The John A IlaA/ord Foundation. Inc. From the Research Division. Miami Ileart Inatiwle, Miami Beach. and the 1?eparsment of Medicine. University of Miami School of Medicine. Miami. Fla. VALUE OF SFRIAI. ME?ASl3REMp.NT OF SI°RUM ANC3IOtFNSIN - C(1NVER i1NG ENZYME IN THE MANA73EMENT OF SAR('OIDOSIS Conventional methods employed to assess the panulomitous aelleily o/ sarcordosis have been shown in the pasl to he ienpreeise. ReceMly, however, measurement of serum angiolension converting enzyme (SACE) activity has been sugXesred to he uselul in determining the granulomatous activity of this h.ease In mder ra test rhis rneasure. .erial serum samples (ronr )S patienls v.,.h hni.-h.ptally I+ruved UrcrNJrHis were measurrJ lor r.nRuiten.in con- vcirmR esirrtsic a.tivily and the SAfF activity was compareJ with The elin• SN I ical aclivity of sarawJu.is. (11 these patients. 20 receiveJ a.rticosteroids dur- ing thc strKly perwxl while the nther IS served as treatment controls. In Iwwh the treatcd and umreatcJ tr.>,rps, the SA(7: activity closely paralleled the clinical statsn. lhere was asreement between YACE imk and clinical IM/aR in N1 rd 101 paired oA.ervations. It appears that SACE activity is a prMNl rc/lection of `rannkrnutnus activity in sarcoidosis. Aho, once the de- cninn has been maJe to treat s.rcoidosis, serial SACFF delerminations are helpful in nwrnitoring the dnse and durNinn of therapy with corticosleroiM. Ruhatfli, P. K. rr al. (Ryan, U. S.) The Anrrrican /oarrwf of Mrdicinr 70•14-50, 1991. Othrr aupparfr National Institutes of Hcahh. Fru.n the Pulmonary Di.ea.es Section, Veterans Administralion Medical Cea- ter, anJ the l3torda Washinpon University Medical Cenler, Washiqton, 1) ('.; and the Pulmonary 1)ivisiun and Department of Medicine. University of Miami School o/ Medicine. Miami. Fla. BI(K'l1EMICAI. AND MORMIOLOGICAI. ASPECIS OF TIIE ACTIONS AND INA('TIVA7ION OF KININS AND ANGIOTENSINS This book chapter deals with the cellular or eeB-hound compo.etw d the kaNikrein kinin and renin-angiotessis systenn. In this area, a critical need e.isls to develop a more detailed underNandiq of which eornponenh of tV systems are ceR-hound and how they are disposed and distribwed. To nted this neeJ, new lechnical approaches are tseedcd and this chapter descrika some of the latest efforts made to help develop the new technology. Sectior of the paper are d.voteJ to: (1) Pulmonary Anoliotensin Converting Enzyme (Kininase 11). (2) New Assays for AtKiotensin Converting Enzyana, (3) Assay of Other Components. (4) Enrymie Activities of Adrend Cortical P.rdo- thelial ('eMs, and (5) InhibNors al `Anpotensin Aminopeptidase." AhollelYer, in the authors' view. the currenl ch.Newte i. 1o develop a basic understandi.g of the cell biology of 1he vastsaclive polypeplides. F.rther, they belies. Ihat significant advances aksry these Ifnn will be requfed to davekap a b.t1.r nnderstanJlnd of how the kallikreln-klnln uod rewin-at~leteo.bt systems eoww tribwe to blood pressure haetostasis and how speciRc derankernents of the systems conlriMrte to hyperkmion and related diseases. Ryan, 1. W. and Ryaw, U. S. 1n: Gross. F. and Vogel, H. 11. (eds.3: Enjymwk Rrleflr o/ Yso.rtirt I'rprlder. New York: Raven Press, 1980. pp. 260-274. Other .uppurlr U. S. Public HeaUh Ser.ioe, The Ilartford Foundation, ad the Ameritan Heart A.sociatir.n (Flurida Afilliate. Inc.. Sunco.st Chapter). From the Ikpartment of McJicine. University of Miaosi School of Medicine. Miami, Fla 59

SYMPATHETIC RErU1.ATIUN OF THE CERf=HRAL CIRCt/LATION BY I HE ('AROf tD ('I/EMORF('IiPTOR REFLEX Using the radioactive microsphere technique lo measure cerebral blood H-w, the effects of nicotine on carotid chcmoreceptor relles slicnulauon were esamined in conxiorn dogs. In 19 intact dogs with vcnlilat"wrn coolrotkd, carotid ehemoreeeptor tefka stimulation increased t:rean arterir 1 pressure by 16 t S% and calculated cerebral vascular resistance by Sd • I)%, whereas cerebral blood flow fell by 7 t 6% (NS). After bilateral cervical sympathec- to.ny in nine doTs, carotid chenareeepor refles slinsulstion irwluced siTniQ- cantly diRerent eRects on cerebrsl blood /low, which rose by 12!a%, and cereMal vascular resistance. whic\ did no/ change. To determine whether the diRerence in eAecl was due so the tryrnpathectomy or merely the repetition of the stiwnulsn, another group of sis dogs (sham) /hst had inta:l sympathetic nerves were studied a second tin.e. 1n "shani' dop, the repeal response to carotid chemrweeeptor stimulation she induced siRndkaMly ddlcrenl effects (tom those in dogs with sympadicctamy. After generst anesthesia wrth sodium pentobarlwtal, or dter section of the ipsilsleral carotid simn nerve, carotid chernaeceptor wimulation with nicotine /aikd b induce a detectabk heea- dynamic eAect. TMn, in the eowscious dog, stimulation of the carotid chemo- receptor reAes elicils significant sympathetically mediated vasoconstrictio. in cerebral vesseh The results of this paper, therelore, provide support for the position that the cerebral vascular bed is regulated by both the sympathetic nervous system and the carotid chemoreceptor reflea. V.rwrr, S. F. .r d. Anstrk.n lournd o1 IArswlotr 2112 (Ilean ('ire. Physiol. 7): HS91-H39d, 1980. Olibr ao'/ert: U. S. Public Health Service. From the Departments of Medicine, Harvard Medical School and Peter Sent Brigham Hospital. Soston; and the New England Regional Primale Research Center, Soulhboro, Mau. AUTONOMIC CONTROL OP MYOCARDIAL CONTRACTILITY IN CONSCIOUS DOGS: AUTONOMIC CONTROL OF THE If EART TAe elfeds of three cardiovascular relkaes-tarotid chemoreceptsx, ear- otid baroreceptor and pulmonary inllation-on the control of myocardial eo.- Iractility in the conscious animal are reviewed here. In addition, the eatent to which e/fereM asNonornic control is aeeomplished by intersctioen of the sympaMetic snd parasympahetie .er.ous systems is discussed. For thess siudies, meawring instrumeMs were implanted in conscious dogs through a thoracotomy, in the Mth left intercostal space. ('henwreceptor stirmdalion was accoarplished by injcction of nicollne (0.2 rdtg) or sodium cyanide (2.0 r/iff) into the intracatotid catheter. Raroreceplor rnloadiel was aceorn- ptnhed by inflating the hydraulic oceluders implanted in the eomsswws carotid arirr.rs Iu.Rs +.r. .tso aud.ed in the cnnscious sule alter- (1) eholinerilie ht.al.dr .ah an.•p.wr 111 Ms• adaen.rgic receptor htnclade with pro- ra.n,d.d ...J t st ....,h.r.rJ ahulsnrrtlec and hrra aJrrnerlK h1aK\adcs Re c snhs nl these stssdies showed that the carotid chemoreceptor re/1es in con- scious do`s, when stinw!ated, elicits a sigrsi/lcant increase in myocardial con- tr.ctdrty mediateJ through beta adrenergic rssechanisnn. TTsis increase in contractility is attenuated by secondary stimulation of pulmonary inflation refleses. Accordingly, when the hyperventilation that occurs with carotid chemeneceptor refles stioeulation is preveated, the inotropic response is sig- nillcantly greater. FinaBr, for an equipeessor responu, the carotid cheano- recepor relka elicited  greater inerease in contractility than did the carotid haroreceptor refks. In oddition, a differeM set of eaperiments showed that the parasympathetic nervous system is capable of eaerting a powerful in- hibitory influence on the inolropie responses to sympNhominsetie ansines. V.rwrr, S. F. and Rutherford,1. D. In: F.rropran Congrrss o/ An.rsrArsblosr. Jth, r.rls, 1978. Amsterdam- O.ford: facerpu Medica, 1979, pp. 9f-1/9. Other a.rrr.rlt U. S. Public Health Ser.ioa. From the Departments of Medicine. Harvard Medical School and Peter MM Brigham I/ospital, the (kparunent of Cudiolojy, Children's Hospita/ Med- ical ('enter, e.ntuss, snd Ihe New England Regional Primate Research Cen- 1er, Southboro, Masa. INTERACTION OF CAROTID CHEMORECEPTOR AND PULMONARY INFLATION REFLEXI'.S IN CIRCULATORY REGULATION IN CONSCIOUS DOGS Analyses of the e/lects of chemoreceploe slirnulatioe appear, on the wb1e, to be particularlr costsplea. since an importaM relka action invo/vea n. i., crease in rate and depth of respiration whiels, in turw, aetivales pulnso.asy Inflation re/kaes. In the studies swemarirtd here, the intepaued eAeeta of carotid chesssoreceptor stimulation on central and peripheral ewdiov..edar dynamics were eaamineJ iw oanscious, ehrowieaMr instruteented dop. Stinwn lation of carotid chemorecepors resaNed in .n inerease in rate and depth ot respiration, an increase in myocardial cootr.ctititya and wsae bNetsae t.pw eonstriction in the iliac thast in the mesenterie, ret..i, or cerebral beds, 71e coronary Ised responded primarily wilh vatodil.lion. The increase In tNe and depth of respirNion stisnulated pulmonary Inflation re/lewes, which M turn weee partially responsible for the coronary vasodilation. OveraM, (taesn studies demonstrate Msu, the importance of pulmonary inflation reAea control in the intact conscious aniesal. ard seeond, the iwnportance of theae reAeaes in modulating and even reversing primary eflects bsduced by starwdNbw of the carotid chemoreeeplor reAea. V.an.r, S. F. and Rutherford, l. D. t'rJerrrion rrorrrdinR. 40:3IeN-219I, 191111. Oth.r w'prt: U. S. Public Health Service. From the Ilepartments of MeJicine, Harvard Medical School and Peter Ilent Brigham /lospital. Soston, and she New England Regional PrinuN RestatcA ('enter, Southhoro, Mass. 1.41 1 61

UFFECTS OF ANESI IIECIA ON TIIE CANINE CAROTID ('HF.M(1RF:('fP1OR RFFLF.X In this Ors1 qnantitative asaenrncnl uf the talent to which anesthesia de- presses cardiovascular responses Io carotid chemoreceplor stimulatron (CCRS), the el/ects of three comr.wnly used annthelics (Na penlobarhilal, .-chloralose, and halothane) on the acsponse so CCRS were studied in eight chronically instrumented dogs CCRS was .ccomplistred by means of inlracarotirl injecliom of nicotine whrk ventilation was held constant in the unanesthcti:ed slale ud following administratiun of one of the three anesrhetics. In the cnns:ious atale, CCRS elicited hradreardia and peripheral vasoconslriction as ret4xted by a 17)! 1e% incrcau in initial cardiac cyck knph and a 216±22% increase in mean iliac vascular resistance. Each anesthe(ic, studied on separate days, .4 rcnuated thesr responses to CCRS strikingly. Results showed that: atter chloratme. CCRS incrcased iNac resisunce by 33 t 14% and cardiac cycle kngth by 27s fl%; after Na penlob.rbitat, CCRS increased iliac resistance by 12 t 4% and cardiac cycle kwgth by I t3%; and after inhalalMM of haloo- shane () vol% ). CCRS increased iliac resistanw by 28 t 7% and cardiac cycle knph by t t! 3%, whereas halahane (2 vol% ) abolished these a-sponsa lo ('CRS Tlrus, it can be seew that general anesthesia interferes se rerely with carotid ehernoreceptor control of the eireulnion. While halothane and Na penrobarbral altered res4onaes to CCRS the rrwsl, even ahlora/ose, which bad heew thought to maintarn or autZmesM reAes responses, was seen herc to depreu the response so CCRS effectively. 7implcr, M, Sit. S P., and Yrwrr, S. F. CNrrl.rbw Rrrr.rrA 48: 400-106, 1111. Other nrrprlr U. S. Public HeahM Service. From the Deparsmerwa of Medicine. Harvard Medical School and Peter Beat Brigham Hospital. Boslon: and the New England Regional Primart Researed ('enler, Southboro, Mass. HUMAN PLATEI.ET TMtOMBOXANE SYNTNESIS IS UNAFFECTED BY NICOTINE TUe possible action of nicotine on the formation of thrornhosane (TaBr) in humaw piatekts was investigated in this study in Iwo principally distinct ways: Rrs/, by assnsinR nicoline's effect on arachidonate (AA)-induetd platclN aikreption, and second, by observing nicotine i effect on the eonver- sion of "C-AA to "C-T.B, by a microsomal fraction of the platekts. For this sludy, human plasekt-rich plasma (I/PRP) and human platelet suspension (UPS) were prepared /rom venous bkod donors who had not taken aspirin-like drugs (or at least one week. Using HPRP, nicorine was ineRicient in blocking platelet a/jrtgatNM from threshold AA eoncenlrations--in contrast to indo- methacin and aapuin-and dso in prolonging the interval between the addition of AA'nd rhe rw.rrNrnn o/ auregatK.n In other caperiments. platekt micro- somet prrl.ared /rd.nl 1/P% ..ere rncuMted with "('.AA in the presence of nicotine, and the /ahelkd mclaholitea were separated and quantiAed radio- chrnmslographicatly. Addition rrf nicotine so the incubalions did aiol aAect the amount of TsB, formed compared to controk, whernas indomethacia, on the other hand, eAiciently inhibitcd I'aBr rormalion as Jid pre-artatmeM of Ihe donnrs with aspirin. These ohservations indicate thal nicotine does aw/ iw<tibil either plslekt cycln-o.ygenase or Ta syMhe/ose, since both of /hesa ewzymes are necessary lor the biolormstion of Tx frorw AA. Since i1 h.s been sAowa before that nicotine is an e/licienl inhibitor o1 rabbit kidney cyclo-oayRt.ne and that it inhibits the (ormalion of prostacycline-Iike activity in rabbit and human vascular tissue, the resuhs reported here raise a question as to whetker nicotine's lack of eQec1 in human platek/s is relaled to species or tiwre ditlerence.. , Alster, P. and Wennnsdm, 4. Cknird PAYrlolory /(t):113-122, 1921. RtArr aw pwrf r The Swedish Tobacco Company and the Swedish kledteal search t'Council. From the Departnsent of ('linicat Physiology, Karoliwska Inslilutel, Huddirye University Ilospiral, Huddinge, Sweden. IV. NewropJ`wrw..tofoty rnsd Phy.io%gy GENETIC INFI.UENCES ON CHOLINERGIC DRUG RESPONSE Three inbred emuse strairr (C37BL/61bs. DBA/21bog, and C)H/21bg) were compared with respect so initial setssitivi/y, b the effects of tha cnrracai.ie chdinergic agoaist, oxotremorine, on open-field meawres of Ioconsolor activity and body temperature. Open-field activity was depressed less severely i. C)H mice than in C37B1., which were kss affected than DBA. While so di/erences in the hypothermic effects of oaotremorine were observed 13 minutes a/kr injection, the time courses of the drug effect on body temperatrre indicated Nnt CIII were less affected than C37B1. or DBA. No di8trences in the activities of acetykhohnesterase or cholint acetyltransferase were found among the three strains in cortes, cerebelhun, hindbrain (pons-medulla), or total midbraia. However, while no di/fereaces In nurscarinic receptor levels were found iw Ihe four large brain artas, flner dissecliun of the midbraiw revealed small differences in total receptor number in striatum, hippoeampus, and reauininB midbrain areas. Although strain differences in QNB binding wers detected in these studies (C711 mice eshibited greater QNB binding (B.„) than did the C37BL or DBA 62 1 63

( t slrains in slrialum, for eaample) Ihese f)ndinp were difficult to interprel. No diflcrences anw.ng stratm were detecled in the 1('„ value for inhibition by aaolremorine of ON8 binding. lhe inhibition of receptor binding by either aso/remorine or nioolinc was the same in aM slrain., but the IC„ fnr osotremo- erne varied frcwn region to rekion. While behavioral differences in the effects of n.otremorine are ckar, there is no obvious biochemical esplanatron for Ihese diAerences. In summary, this study demonstrates that she inbred surains of mice previously found so differ in sensilivilr to nicotine also differ in a similar fash- ion to the rnwcarnnic agonist, o.oltemorine. Marks. M. I.. Patinkin. O. M., Artwuw, L O., surch, l. S., and (-oilins, A. C. Phormarolne1 d/orArm/rrry f Behavior 11:27/-279, 1921. From the Imtwule for Behavorial (hnelks, School of Pharmacy, and Alcohol Research ('enler, t)niversity of Color.do, Boulder. ('HOl INFROIC AnAPTATIONS TO CHRONIC OXOTREMORINE INFUSION The deveiopmenl of tokrance to a cholinerflic agonnt was studied here by chronically treating C)11/21bg mice with various dosn of the cholinerlk agomst, osotrcmorine, via an indwelling i.v. eamda. Doses ranging from 0.03 to 1 0 mg/ka/hr were used in this atlempl to Iest the hypothesis that lokrance to cholinerkic akonisls may be eaplained by a decrease in the number or aAMily of muscarinic receplors In the present sludy, clear tolerance was ob- served in that symp/oms such as s.livalion. Iacrimaliun and muscle Iremor de- creasld or disappeared during she infusiow period. Similarly, chronically treated animals eshihiled minimal hypothermia or imp.irmenl of rolarod performance when challenged with an oaolrensorase dose which signifkantly depressed both of these measures in naive animah. The activities of she en:ymer. aatykholin- esterase and choline acNyhransferase. as well as Ihe binding of 1sH1-)-quiw- clidinyl ben:ilate in seven brain teliiora, wete messed. Chronic oso/remoeine trestmem faikd to aher acetykholinesteraae activity in any of the brain regions. t:'hdine acetyltranderase activity was only marginally decreaud in several brain regions. A significant decrease in maaimal (sH1-1-9uinucIdinyl binding was observed in sia of the regions esanined. No aheralion in lsll/-)-quin- uclidinyt affinity was detected. Importanlly, tolerance to osdremwine was detecled al doses which failed so aher choline aeetyltranlerase activity or receplor numbcr. Tbese resuNs clearly supporl she nMion Iha1 chronic mus- carink activation leads to a decrease in nmscarinic reecpors, Tba decrease is not menurabk, however, until after considerabk tolerance to osnlremorine has developed. Marks, M. /, Arlman, L. D., Patinkin, D. M., and CoNinr. A. C. TAr lorrwd o/ Marmerobgy anl E,prr/nwnr./ TArr.pcrtk. 2111(2) :7)7-342, 1981. From Ihe Invitute frn ech.vorial Oenelks. School of Pharmacy, and Akohol Research ('emer, Univentty of ('olorado, Boulder. 64 I FFFF('/1 OF SIN(31.E INIE('11ONS OF NICOTINE ON TIIE AS('FNI)IN(; IX)PAMINE PATHWAYS IN 411E RAT lhe cllects of nicotine given systematically on the ascending dopamine palhways of the ral brain were analyzed in Ihis study. Nicotine was adroin- istcred in  dose of 0.1 or I mg/kg i p., as lutrale, one hmrr before deeapi. lation. Nicotine-induced changes in dop.mine turnover were evaluakd by inpcling. inrmedialely hefore the nicotine in1ection, the tyrosine hrdroaylne inhifwlor, w-methyhyrosine methyl esler (H 44/6e). by the quantitative use of the Fakk-lldlarp methc.didoty, dopamine s(ores were detersnined in variow dopamine nerve terminal syslems of the leleucephalow. Results showed that nicotine in a single injection of I mg/kol, i p., produced a significant reduclion of dopamine stores in the medial caudale and In the diRuse dopamine aervr terminal systems of the anterior part of Ihe rmsc. .ceumhens. In a dose of 0.3 mg/kg. nicotine produced a selective reduction of dopamine slores in the amerror part of Ihe nuc. acewmhens. In the 11 44/6N e.perNnenl, nicoline in a &ne of I m4/kg. preferentially increa.ed dopamine turnover wilhin Ihe medial caudare and within Ihe poslerolaleral part of the olfactory luherck. These, plus other reurhs, provide eviaence that nicotine in one single dose, given syslemtli- cally. can produce diacrele changes of dopamine kvels and turnover in both slrialal and subcortical limbic dopamine nerve terminal systems. Andersaon, K., Fu.c, K. and Agnati, 1.. F. Arr. rAyrioloeir. Srendlnr.k.112( I1:I43-147, 19111. Osher aurrp.rfs Svenska Tobaks AN, Stockhoknr, Sweden. From the DrpanmcM of Histology. Karoinska InslitrNcl, Stockholm. Swede., and the Ikparunenl of Human Physiology, University of Modena. Modea.. Italy. NICOTINE-INDUCED INCREASES OF NORADRENAI.INE TURNOVER IN DISCRETE NORADRI:NALINE NFRVE TERMINAL SYSTFMS OF TI/I: HYPOil1A1.AAlUS AND THE MEDIAN EMINENCE OF THE RAT AND TIIFIR REt.AT1ONSHIP TO ('HANOtS IN TIIE SECRETION OF AI)ENOHYPOPHYSEAI. HORMONES This eapcrimeni was undertaken 10 evaluate the neurocndocrinolo6kal effccls of low doses of nicrMine on the rM and lo sce if the dop.mi.e and noradrenaline nerve lcrminal systems of the hypdhal.nws are diAtrenti.py semeive 441 the aclkom of nicotine. Mak speci0c pathogen /ree rats were givea acute sinrk duses (0 1 and I m`/kg) of nicotine as the lartralt sal1, i p., one hrNa belure decapitation. NiaNiik-iedueed changes in ealecholamine turnover within the hypothalamus were disclosed by giving /he /yrosiee hydrosylase inhiAil.w, .,-methyltyroaine mcthyl ester, immediately before the nicoline in}re- /ion. Re.ulls showed that nicoline, in a du.e of 1.0 mg/kil, increa.cd noradrewa- line turnover in Ihe nscdian eminence and in the peri• and paravicetricular hy- pdhal.mic regions 1 he dnpamine and muadrtwdine nerve terminal ayslaws is Ihe medi.n eminence and the dorsnmedial hypolhalamic nucleus respedively 65

1 I were uoaffecied Serum growth hnrnrooe (GH ) levels were decreased and serum prolacrin kvcls increased after a dose of 1 m9/kIl. Ilowever, in the presence of tyrosine hydrosylase Inhibitioa, nicotine in a dose of I mk/k1 increased (ilt and also luternink horrnone secrelion. It is suggested here that the prciercntial rncreases of noradrenalise turnover in various hypothalmic nora- drenalrne nerve Ierminal systems by nicotine may be partly responsibk for the nicotine-induced increases of serum prolactie, growth hormone and luteitizieg hormone levels that were observed. Andenson, K.. Enerah, P. a.d ApuRk 1- P. (Fusr, K.) Arr. PAyrtofoelca Se.wdlw.vin 11I:221-2]1, 1981. OOther aurprrr Svenska Tobaks AI/. From the Departments of Ilistology. and Obstelrks and Gynecology. Karollaaka Ilosprtsl, StockhoMn, Sweden, and /ht Departmem d/luman Physiology. University of Modena, Mode.a, Italy. 711E FFFE('TS OF DEPRIVATION OF CIGARETTE SMOKING ON PSY('110M()IOR PERFORMANCE Whrk many e/lons have been nude (o restrict smoking in public tsr oc- cupat'ional seump. little attcsnion has been paid to the powbility of delrimental effects on the smokers themselves, whose behavior may be altered by Ihe re- sttictiow. In she work reported bere, (wo studies were undertatien-oee eann- in.nR the performance of 16 college female cigarette smokcrs under eonditiooa of either smoking or smoking deprivation, and the second investigating 16 college male smokers under the same conditions. Performance scwes, takee from an Instrumented compka psychonselor device, were adjuwed for abiliy es determioed from a Itaiwing period on the device and then compared between smoking conditions. In both studies, deprived nnoken perforrned siptiRcartlly kss well on a pursuit tracking task, while reactiort time, vigilance and meawal arithmetic tasks were not affected. Since the task charac(eristks of these lab- oratory situations are analogous b shose found in man machine spftetna and other wosk cwvironessenls, the results presented bere suggest that similar be- havioral effects may occur In "real world" work env'aonments. Under restric- tion, there/ore, workers who normally smoke may eapericnce lowered arousal, increaaed stress, decreased iob utisfaetion, and a number of other undesirabk effects. According to the wtbon, these behavioral outcornes should certainly be takee into consideration since they might possibly lead to decreased pro- ductivity and Increased aceidents. Nriw.rrs., N. W. rr d. F.rpno.nkr 2)(111:1017-IOS7, 1990. From the [)cpartment of Psycholop. University of South Dakota. Vermillioe. 66 : EFFECT OF SMOKINU ON PREDNISONE, PREDNISOIANE, AND DEXAMEIIIASONE PIIARMACOKINEIICS 1 he pharmacokinetics of oral predsdsone and loral deaametbasone wert e.mined in smoken and numnsokers in a. attempt to determine whether smoking aRects the metabolism of these eortieoaleroids. Eighteen healthy adult male volunteers received 50 snR doses of oral prednisone and eight of these volunteers were also given an intravenous injeetioa of 40 mR equivaleMa of prednis,rlone. Half of each group of subjects srtwked twore thaw one pack of cigarettes  day. 7 he other half of tach group were nornrnokers or had eol smoked /or at kasl thra yean. In an Idenikal desips, 1• Mahhy, adult male volunteers (9 amoken uW 9 nowsmoken) received 4 mg dosea of oral dr:aa- methasone, and F of Ihne volwNeets (1 amokers and 4 nonsmokers) wera ahw given 4 mg equivalent doses of iwtravenous tkaamelhasone. Plasma and urMa eoncentratiuns of p.ednisowe and prednisolowe were assayed by high perfon.- ance liquid chromalography, while plasma deaamethasone was measwtd by radio immunoassay. There were wo slalistkaMy significnN diflerences betweee smokers and nonsmokers in the sysltmie availability of prednisolone, wal dose clearance of prednisone, systemic predwisdwre ekarance, or is she ieter- conversion rales, vohrnme of distrilMrtion, or trrinary recoveries of predeisont and prednisoMne. Sirnilarly, she pharmacokinetica of dea..nethasone were tr- aRecled by smoking. These studies indicate Ihat smoking does not a/feQ tba pharmacokinetic disposition of prednisone. prednisolone, and desamethdarh lobacco snwke, unlike the anlKonvuhanls which markedly induce conico- steroid mctaholism, does nut appear to change either she biuavadability o. the clearance of these drugs in man. Rose, l. Q., Yurchak, A. M.. Meikk, A. W., asd lsuAo. W. l. lournd of rlro.nr.ro4lwrrkt.nd lioph.rurare.uka 9(1):1-1), 1951. Otber aur'.rt: Natiowa) Institules of Health. From the Department of Pharmaceutks. School of Pharmacy, State University of New York at SuAab, Amherst. NON('11O1.INERGIC, SATURABLE BINDING OF ( s)-IsHI NICOT1Ne TO MOUSFF BRAIN Nicotine has various effects on brain ftmctwn, and knowkdge of she nature and localization of its siles of sction should be helpful iw uwderMaeN.~ its behavioral effects. In severat ?Lvent papers the properties of nicotine bind- ink to neural nsenrlnanes have been descrihed, but (he search for nicotine recep- lors in Ihe CNS has given equivocal results. Now, the binding studies presented here show that (!/-1'11) nicotine was bwrwd aaturaMy b crude p.rliculNe, and synaptosrnnal-nsituchrondrial Iraciions from mouse brain. Scatchard awd Hill plots ol the binding data are in agreemcnt with the eaislence of two independent binding sites with high (K, of 0.1-0.IpM) and low (K, of 20rM) aflinities, a1tMNrgh other interactioms cannot be ruled out yet. Nicoainie or 67

A UNIFIED MFI HOD FOR TNE ASSAY OF URIDINE DIPIIOSPFIO(:I.UCURONYI.TRANSI-ERASE A("IIVITIFS TOWARI) VARIOUS AGLYCONFS USING URIDINE hIP11OSP11()f U - "CKi1.UCURONIC AC ID Earlier prescedures used for assaying uridine diphospho (UDP) &lu- curonyluansferase activity for various agtycones were very diverse, and a need was soon felt for a general assay based upon the common cosubstrate, l/DP glucuronic acid This paper now describea such an assay nxthod using IIDP 1U-"CJ 6lucuronic acid. The radioactive glucuronide conjugates formed during the reactions were separated from unrnetaholi:ed UDP IU-"C) glu- curonic acid, and from other wcAaracterized radioactive products by thin- layer chromatography. The conjupKs were identi/kd by comparison of their R, values on thin layer chromatography wilh those of several authentic glu- curonirks, and by hydrolysis with (3 -Rhauronidase in The absence or presenu of () saccharic acid•1,4lactone, an iohibitor of f! glucuronidase. In use this method has proved to he very sensitive, reliabk, and relatively tast. The procedure, which is generd fo. the determination of The en:ymic activity with various agiycones, has been utilired so far for 11 allyeones and is eapahk of ealensinn to many ahen. Bansal, S K. and Grtrwt.. T. Anulpricd BlorAt'mirr.y 109.121-)29, 1920. Other support: U S Public Health Service. From ihe Ikparrmenl of Fsperimenlal Thenpeutics, Roswell Park Memorial (rntNtute, 8uflato, N. Y. BIOC/IEMICAI. AND GENETIC ANALYSIS OF AN Q•BUNGAROTOXIN- BINDINO RECEPTOR FROM DROSOPHILA AIELANOGASTER TAa/ the n bungarolosin-binding eomponeM In vertebrate nerrronal prep- arations is really a functional acelykhdine receptor is currently controversial. . In view of this uncertainty, however, il has become Important to consider the characteristics of the totin-bindinp component described by several investip- tors n present in the central nervous system of the fruit fly yDrorophJft nr.f.noparrer) and as having the properties of a nicotinic acetykholine re- ceplor. Droropllile nr.lenomrrr is a common model for molecular genetic slrNlies of sseuraransmitser rectplors. In this shor( review of past and present work, the awhor outlines Ihe various procedures u+ed to Mrcate the receptor and to Identify its physical and functional characteristics. The evidence to dale does indeed support the notion of a functional nicolinic a;etykhnline receptor in the insect central nervous system. As a result of genetic studies designed to identify The genes affecting she acetykholine receptor and to analyze receptor variants, it is concluded that the //R locus codes for a slrvc- tural pnlrpepude in the . Mrngarolodn•hinding compkt and that there are at least two crrirs of that poiypeptide In the receptor eompkt ()4her esperi. 72 I mems currently in progress, and Ihe results that they are hoped to provide, are ahn described. Hnll, L. M. In: Saltelk, D. B. er a/. (eds.): Rt'crpro.s /or Nerrorronsndrrerr, Ho.nsewrs rnJ Plitroraonts in Insrrrr, Amsterdam: Elsevier/North-Nolland Bionrodical Press, 1990. pp. 111-121- Other support: National Science Foundation. From the Deparlmenl of GenNks, AR+erl Einstein College of Medicine of Yeshiva Universiry, The Brona, N. Y. USE OF NEUROTOXINS FOR BIOCNEMICAI. AND OFNFTIC ANALYSIS OF MEMBRANE PROTEINS INVOLVED IN CELI- t?XCITABILITY The fruit Ar. DrosopAila mrl.nopurrr, has been rned often for aludia in genetic approaches to probkms in neurobiology. In one ease. mutMioas which affect en:yrnes important to nervous system funclion, such as Ihoae invnived in neurotranamitter synthesis and depadation, have beew identified in Drnrophil.. In a different silualion. the structural proaeins-whkh ate i.- volved in ion channels and eeurntraarmiller reoeplon awd, therefore. are important lo nervous system fundios-ha.e been hard to monilor in the past. In recent years, however, a variety of neurotostMs which bied speeiAcaMy and with high affinity to variaus molecular components Mvohred in cell ea- citability have been identi/led and they can be readily adapted to swdles of receptors and ion channels in DrosopbN.. The review presented hene ahows how these radioaclively, llabeled p.obes can be used in wrokeular awd SmNie analysis of /he acetylcholine receptor and /he .oltaolie-dependtn( sndiusw cMa.- nel in nrnsopliilo. Sections of this paper are devoted to: (/) DefMilion of totin binding properties, (2) PuriAcalion s/udies, and ()) GenHic anrlysb of neurotosin binding componenls. In sumeary, N appean that newoloains /hN interact with specific cornponen's of eaeitahk eeps can be wed so provide molecular inrrxmalion about these components. Ther also can he used In the development of genetic strategies In isolak mutaMs affecting these specific components. li'dl, L. M. lu- Siddiqi, O., Bahu, P.. Hall,`1.. M. R Ilall, 1: C. (eds.): Derrtopnvnt anI Nn.roAiolngy o/ Dron.pAila, New York: Plenum Publishing Corp.. 1980, pp. 29)-)01. Other aMpportr National InstitsHes of Neahh and the National Science Foundation. From the Deparlnxm of Genetics, Albert Einstein College of Medici.e of Yeshiva University, lhe Bront, N. Y. 7) i

i STUDIFS ON ACETYLCHOLINE RECEPTORS FROM NICOTINE. RESISTANT ST1lA1NS OF DROSOPHILA MEL.INOCASTER Snake .-neuroto.ins bind specifically and with high affinity to acelyl- choline recepots st vertebrate newornuscular junctions. ..1lunp rotosin, a small seuro/oain which can be nude highly radioactive by iodinalios with "'1, has bees used in the paa r a moleatlar probe in acstykholive receptor studiea. Recently, several laboratories wed "'1-rbungarotoaws h study a component in the insect central nervous system that has the properties ea- pected of a nicolinic acetylcholir reaeplor. Results of some of t lcse phar- tnaco{ogical studies showed that drt - bwrpraoaie binding receptor in the Dro.opAlle nsrLnor.rnrr central ner.ous system is predorninan/y .icolinic is nsture, but it also demonslrstes a pharw+acdogical specificity that is distinct from that of vertebrate nicotinie receplors both i. /he nervous sywrm and al leuromuscwlar junctio.s. Nieodwa NseN has beew used u an imccticidt: for over 200 years and, /rowt Ma binding hAibitios studies reportcd here, it is apparent thst wicotinR b one of the besl i.hibibrs of "•1-.•bunpraoain binding rn Dro.orAil& e.tracts. .uaesti.R that .kotine eaens its toRic effects in wsseps by oornbininR with the satykholine receptor and iMerferinR with its normal function. The nrechawisrns of hereditary resistance to nicotine were investigated here by lestinR a series of 30 wild-type fruit Aies against a ewr- cenlration of nicaiarc hydnopew tartra/e, which is sMAkcient b kill 90% of /he Cantow wild type. A comparison of survival of different wild-type strains of DrowpAila n.rl.woprr.. grown on wicainetonlaininR twedium is pre- sented in this paper While tl.e.e studies were done initially to determine the amowu of variabrlny between diQeren/ genetic backgrounds. esperimeata are oow in progress to study nicoture•resrtant nrrMants isolated following teuta- senesis of a standard wild type stratn According to the author, these studies should eventually open the way for e+olecular genetic analysis of the acetyl- chdine receptor. Hall. L. U. In: lnact Ner.obldopy and Ptrtkide Attlon (Neurwoi 79). London: Society of ChemicM Indu.try, 1980. pp. IS7-161. Other ast'r.rtt National Seienoa Feu.datiewt. Front " Department of Oenetid, Albett Einstein College of Medicine of Yeshiva University, The Sront, N. Y. EFFECTS OF NICOTINE ON CONCP.PTLS CELL PROLIFERATION AND OVIDUCTAL/UTERINE BLOOD FLOW IN THE RAT Beginning on Day 0 of the present Mudy, adult Sprague-Dawky rats reccived two daily injcctions (10 a.s.. and 3 p.m.) of either saline p.ico- Iine (5 mg/kR body weight) through Day 3 of preonsney. Embryos retrieved at selected tomes from the oviduct or uterus were e.aeined, the cells dia perted, and nucks counled, ovduclal and uterine blood flow was measured by "Rh fractronai«m Rewlta showed that nicotine treatment (t)ays 0-5) 74 I slowed intraoviductal concepus proliferation as indicated by a reduqioa I. rnesn number of nuclei per conceptus at all retrieval tirnes. Tea tni.ules /oi- lowing nicotine injection, oviductal blood Aow decreased (rwn a control vaWe of 0.61 & 0.06 nd/min/ol to 0.45 10.03. a reduction of 10%, and retnai.ed .uppressed through two hours. Sitnilarly, uterine blood /bw was dntateasai 40% at 10 mimNes (olloaitrR nicotine and rernained reduced (w Iw0 hours. It seena, on the basis of Ihis work, that the Rrowth-srppressinR effects of Hr alkaloid are e.erted on the eoewcepus while it is in transit through the o.4 duct. 7 hal the difference in ceN swrnber bNween ewrbryw o( control Metuw trealed rats persists after enlry into the uterus suggests that Rrowth-reuediag effecls continue to be eserted on conceplwes /n rrnv. The (aet that a siaRls injection of nicotine results in a rapid, marked and wstaiwed reductioe in both oviductal and uterine blood Row suggests that alteratiaa iw conoepus growth result is part (rom reduced substrale availability within Ihe lumi.s of the reproductive tract. Hammer, R. E.. AllrcAeN. J. A. and Cioldnan, N. In: Glasser, S. and Sullock, D. (eds. ): Cellnf.r .nl MolKrfw Asrrrrr of Jnr pl.wr.rion. New York : Pknuww Press, 1981, pP..1I9-142. From the Departments of Anatorny and PharwucoloRy. Wayne State Uni- versNy School of Medicine, Detroit. PRODUCTION AND CHARACTERIZATION OP MONOCLONAL ANTIBODIES TO SOLUBLE RAT LUNO GUANYLATE CYCLASB Ouanylate crclase e:fsts iw Me (o.ww, a sohtble and a f.rtiearlale ow, that diAer (rorn each other i. switws ways. The, presenl study e/ rr bt.R Ruanylae cyclase in its soht6le form reports on the sut:oesdul /utiow of tn.wa SP-2/0 myelonsa uRs wilh spieat eeNs /roas an isununited BALR/e ttnewe and on the characterismion of (oar monoclowat atNibo6in 1o this aehtbk erwyrwe. These mtil odies were deteeted by their ability b bind Muttrobiiar Ruawyl.le cyclase ad by iswwtapreapitaliow of pwiRcd eruyrrte in 1M pru- ewce o/ . second (rabbit aMi-wtortse) antibody. After tarbelowinR by NwNLR dilutios. hybridom.s were injeeted iMraperitoweafy iwto wsioe to Preduae acitic (luid containing 2-3 rnR of antibody per ml. The four antibodies ab- tained had tilers of between 1:1330 :nd 1:3160 but were detedab4 at dilu- lions peater than 1:20.000. Soluble vuanyl>t/e eyclase from several rM tissues were crossreactive with the /ottr twonocWnal antibodies, wqestinll that the soluhle enzyme (rom diaeresN rN tissues Is auigenicaly aimitar. The aMl- bodies also tecognired soluble i" en:yere from rat, bee/, and pig, while en:yme front rahbit was not erosueactive snd nwuse encyme was recopised by only one of the antibodies. Particulate Rua.ylate cyclase from a arullber of tissues had only minimal crosueactivity with the atuibodies. Imnwnopre- cipilaled guanylate cyclase retained catalytic aetivAy, could be activated with sod'wm nitropru.side, and was inhibited by cystan+iee. None of Ihe antibodies were inhibitory under the conditions eaamiwed. 1/ sasns, on the basis of 1hM study, that these antibodies will be usefd probes /or the study of {ua*ytate eyclase regulation and function under a variety of physiobgical conditions. 7S

Braodwcin, 11.. l.ewicki,l. and Murad, F. ProrrrJingr of rAr Namlonal Acadnny o/ Srrrnrrr of rhr UnurJ Srartr o/ Arntrirr 7/(7):,211•e213, 1981. OtAer .u pport: National Inatilutes of Ilealth. From the Division of Clinical Pharmacology, Depanmenls of Mrdicioe aed Pharmacobty. University of Virginia, Charlotlesvilk. REVFRS/BI.E' INACTIVAIION OF GUANYLATE CYCLASE Bl' MIXI:n DISUI.FII)E FORMATION In rhese studies aimed at as.eri.g the role of thioh on pranylale eyclase aclivity, a.arieq of naturally oecnrr{nR diwlAdes asd Ihiok were lessed for their eAecls on very highly puriAed preparations of rat lung guanyl.rle cyclase. Resuhs of this wo.k showed /ha1 a numbet of disullWes, (ncluding cystamine, cyslrne, pame/hine, and ozdired coentyrne A, can inhibil goanylate eyclase in a time• and concentration dependent maneer. lhis inhibiuon can he rap• idly rever.ed by she addnion of reducing agents such as dithic-threitol or f1 mercaptoerhenol The inhibition by eystamine is accompanied ny the ap- pearance o/ mulrrple K„ values for GTP as opposed lo the control enzyme which shows a single K. /o. GTP. Whew, in the eourse of these studics, 1"Skystine was incubated with puriAed enzyme. radioactivity was incorpoo- taied into the IrichlVroactlK acid precipdahk protein, and the c.wn/s were rel.vsed following dnharhreiNol Irealmenl. In additinn, Is'Skysrine lahekd tntyme co mitrared weh native Suanylale eyclase on norsdcnaluring poly acrylamide f;ets These dara Indicate that mised drsul/ldes can he formed between pranylate cyclase anJ eertain naturally occurring a+mprNrnds, and that Jisulfide formalion leads lo a revenrbk lots of enzyme activity. Brandwein, I1. !, Lewicti, /. A and Mrrad, F. Thr lourwd of eiolorird CArnnirrry 2S6(6):293a•2963. 1981. Othrr support: National Institutes of Health and National Research Service Awards. From the Division of Clinical Pharmacology, Departments of Medicine and Pharmacology, University of Virginia, Charlottesville. (;UANYLATE ('YCLASE: PURIFICATION. PROPERTIES, FRFF RADICAI. ACTIVATION. RADIOI.ASEI.ING, AN[) PREPARA7ION OF IIYBRIDOMA AN I IBODIES . Throughout the years, many studies have been carried out on suanylalt cycla.e and cyclic GMP synthesis. Since tnuch of the early work was done in crude systems. it became apparent to the inresti6alurs that purified entyme, amiboJics to the prarein, and new methodological approaches were needed to make sorne progress in undersl.nding the guanylate cyclase•cyclic GMP sysum Ilre review paper pre.ented here touches upon the signifkanl steps rhar have been raken so lar by these authors along this roaJ At firsl, solubk 6uanwlarr i sr L.e (ro.m srvrr.l ras tissues were pnrdirJ and ihe same rnclhods wetc -rJ a- r--,•/t thr rnrymr Irom other rnsuei and other apecres 'Ihese 76 invc.lipalors wcrc also able to purify partially the particulate /orns of guany- lale cycljse IIMI, to 2Of1-Io1d It seems probable a1 this lime that their eaperi• ence with rhe soluhlc enzyme anJ wiAh the anblwrdies that are being devebptd shoulJ enable the researcher% to puify the particulate form of the eazyme in the near future. Ihe purified enzyree can be activated with nilric oalde aml aher agents such as hydrosyl radical and unsaturated /a11y *cidsW bth the activation and the revenal to the basal state can occur without the pres• ence of other macromolecuks, arueslinR that these aclieaton inletact di- rectly and revcrsibly with the protein. BotA basal activity and 1he capacily to activate with nitric ozide require free sul(hydryl groups on the enzyme. The pore cniyme can he radw>tabekd with either ("S/ or "•1, and libekd en- zyme has assisted these inveslillators in variow ways including purilieadow, e.aminarion of the enzyme's subunil struclure, and screening sera and media from hybridoma cultures for antibodies to the protein. MuroJ. F. N d. In: IArmont, I F, GreenprJ, P., and Robinson, G. A. (eds.) : AJvwcez iw ( yrlir NurlrorrJr Resrsrb, New York Ravew Press, 198 1. pp. 229•2)9. Otbrr arrpport: National Instilutes of Ileahh. From the I%vision of Clinical Pharmacoluoly, Departmems of Medici.e a.d Ph.rmacology. University of Virginia. (-hat1o11esvilk. PIiRIFIFb GUANYLATE CY('LASE: CHARACTERI2ATION, IOUINA'I ION AND PREPARAl1ON OF MONOCLONAL ANTIBODIP3 In Ihis paper, several eharaclerislics of hwy purified rat hwy Iua.yblt cyclase, rnchdinR methods for radiolabeling the poleit., are presenled. Rr suUs of these esperimcals showed that the purified erzyme eshibiled spKiie activNies, at p11 7.6. of '_19•41r nnsoks/mol proleiu/min and 34-60 nnsoks/ mot protcinimin with Mnt• and Mg't as ealion cofaclors, sespecti.elY. T1K specific activity changed as a function of the protein concerMraliow dre lo a change in V,,,, with no alteration of she Kw for Gl'P. The emyme twiBrNe1 as a single band coincident with guanylase eyrelase activity on nondewNS>rw polyacrylanside and isoekctric focusing Bels (isoekcuk point = 5.9). Prri- fkd guanyl.te cyclase had an apparent mokcular weight of 130,000 daMos as determined by gel fiNration chromatography sd polyacrylamide old elee- uoplu.resis kkctrophoresis in the presence of sodium dodecyl sWfale revealeol a single subunit of 7!.0f10 daltons. suggesting that the enzyme is a dimer of an identical suhunil. 11 was also seen 1ha1 the puri/kd enzynse could be activated by nitric oside, indicating that Ihis compound interacts directly wrth the enzyme. . I ewicki. l. A., BranJwein, I/. /., WaWn+an, S. A., and MMrud. F. lunrnd o/ Cyr fir Nuc IroNJe Rrsrwth 6( J):2111•296, 1980. OOther support: National InsliNNCs of 11ea11h. Fronilthe Oivision o1 Clinical Pharmxology, Ikpartmenn of Mediei.e amst Pharmacology. Univcrsity of Virginia. ('har1o11esvilk. 77 I

a. tn r m m v lJ ln _J ' A 7 L'R81UM 160 PROBE OF THE NICOTINIC BINDING SITE OF THE AC'!:1 YLCFIOLINE Rt:CEPTOR FROM TORPEDO CALIFORNK'A Trivakm terbium, which is known to be able to substitute for Ca(11) at specific sires on the acNykhdine receplor, was used here as a probe of the nicainic binding site of the acetykholine receplor from Torpedo cali/ornk.. In this paper, the ability of various lipnds to displace "'Tb(111) hound to the acetykholine receptor from Torp.b cdi/ocnie is descrihed. Specitkally, ligand-irduced 'a`Tb(111) disPlaoerrrewt wa followed in a specialty designed flow dulysrs apparatus, coupled lo a Na1(T1) y•ray scintillation spectrometer. This displacement was nionitord r a/unction of (1) the concen/ralan of nicdinic ligand (i e., acNykholine chloride) iw the "washout' buffer and (I) the nature of the aicwink liprd Iw the boAer (c 8.. acetykholine chloride, telraethylnwmonium bromide and wikelhamide/. Measurcd lwf'b(111) es- change halt-livei indieate (I) a dired relationship bNween '~(111) di.- placement and nkoliak liolaad ooneentraNiow (n the `wash out" buAer and (2) an enhaneed "'m(111) dhpi.etnwaM for nkollak agents poaesslnM quaternary ammowiww fwclio.a (e.g., aeetykhdine chloride and tetraethyl- amrnrvdum bromide) versus neutral ligands (e.g., nikethamide). t.ancione, O V. Nrl.ow, p. l. awA rVrigM, O. M. /nnrtunk. CAM.lr. Acr. 7S:71-71, 19111. From the Department of ('hewtistry, /eppson Laboralory, Wor.:ester. Mass., and the ()rparsmenl of Pharns.co{ogy. Univenity of Massachuse/ts Medical Center, Worcester. SK:NIFICAN('F OF VARInUS FN7YMPS IN BIOACTIVATK/N AND INACTIVAl1ON FOR TOXIC FFFECTS TUe mammalian organism has to have a very Ae.ible metabolic system so convert the many tipophilic eonqounds it is esposed to daily into e.- eretahk hyd.ophilk tnetabotites. Although many enzymes are involved in the formation or disposition of reactive wtetabolites, the group mow thoroughly investipted as of taw is the one responsible for the coatrol of reactive epo.. ides. It is well known at this Iime dal mkroaomal naraosygenases, present in many rnammaNau organs. can transform clinically vsed drup and many n.lwally occurring /oreign compounds that Posaesa okMrk of aromatic Aou- bk 6owdi iMo epoaides. Such eposides may no.., due to their ekctroplwlic «acti.ity, spontaneously react with awckophilic centers in the cell and thereby eovakrMly bind to DNA, RNA and protei.. Such a reaction could then lead to eytotoakily, dkrBy, mulqenicity, urdlor earcinogenicity, depending oa the chemkal reactivity as well as other properties of the epoaide in aueMbw. Another impnrtant contributing factor Ia the presence of enzymes controlling the concentration of such eposides. There are several wacrosomal nsonooay- genasn which diRer in activity and substrate specificity. With large wb- slrates, some morw+o.ygenasa preferentially attack at one specific si/e diAer- ent /rnm that attacked by others. Some of these pathways Iced to reactive prrnlual.. dhrrs are dctn.dkatron pathways Another determining (actor is .n enryn.e that can meuh.il.re epauKks, such as epn.ide hydratase or `lula- 7b I thinne S trans(erase. Such enzymes can act as inactivating or, as ia aorne specific cases, as co-activaling enzyme%. 1)iRerences in sub.lrale specificity and activity of these enzymes belween orpns, developmental slaRes, seaea, aod animal species represent one important contributing factor to diRerencea in susceptibilities. OeseN, F. In: (iladtke/lleimann (eds.): PAwrnaro4inHkr, Nesr York: Gustav Fischer Verl.g, 1980, pp. 73-t1. From the Pharmakoloolisches Institul der UwiveraNYt Mainz, Mainz. Federal Republic of (krm..y. INFt.UI?N('E OF FOREIGN COMPOUNDS ON FORMATION AND DISPOSIIIUN OF REACTIVE METABOI-ITES While there are many diverse compounds around that can saa.ll tM mammalian orpnisrw, this paper focuses nn the aromatic and okAnk twoieties which occur very widely iw foreign compounds and which are possiNy 1he most thorauhhly studied Wndunl elements is regard so metabolic activation and inactivation. It is weM known that akAde a.d aromatic strrsdwd ele- meaIs can be IrandortueJ by wticrosorsal saotwoayBewases so eposidea. Ra- cause of their ekctrophilic readi.ity the eposides can bad covdewtly 1s nucleophilic aites in DNA. RNA .nd }roteita. Tltese alterations et aideal cellular macrornolecules wuy disturb the normal biochemistry of the oeR awd Lad to cytoto.k, dkrRawc, wrwyewk, ard carcinogenic effects. Whalher these effects will he twawi/esld depends on the chewsical reactivity as weR as on other properties (Reotnetry, iipoOlwlscily/ of the eposide in aptplioa. F.nzymes controNirrB the cowawtration of epoait/n'are aawther iwrpoA.m eew- tribuling factor. Awtrwr8 the several rttkronomd wso.ooayBewse Ihat e.W. sorne pre/erentiaty attack large substrales M sinBle sites, apeeiRe /or each enzyme. Some of these tlepa produce reactive wtetabolites; others are reloai- kation pathways. Et.zyroes thN taelabolite Ihe epo.ides represent a fwtMsr determining factor. These enzymes include epoaide hpdrolae and BhANhiooe transferases which do not play a purely inactivating role but eaw, in aoroe cases, ad also as coactivating enzymes. Foreign compounds have beew shown to influence some o/ these en:ynrcs. Aewe ellects by activatiow and Mhilitiow of the enzymes as weR as long lerrw eBats by inducliow aMd tepresslow have been observed. Importamlp. since diQereaSl foreign eaepornds diOereMiaMy influence varian eruymes, they can produce chaeIes ssot only in overdl metabolic activity but also in melabolile pattero and in aekctive to.kilin. Oeuti. F. a In: Enrironnrcnrd Chemkdr, F.wzywe Function md Hrrn.n Dlzeart, Ciba Foundation 76 (new series), t:asevierlNorth Ilolland: I:aeerpla Medica, 1990. pp. 169• 1 89. hrurn the Phirmakuluei.chcs In.riwt der Uwiver.itiit Mainz, Munz. Federal Republic of Germany. 79

AN 11('s1U1.IN1 R(71( :S. AN fISPASM(1t71(' ANI) ANT/ULC1'R DRUGS 'fhis fx.ok chapter reviews 1he pharmacological actions of lhoae onti- cholinergic druss thal mimic the e/fecls of cultinR /he parasympalhetic nerve supply so varinus orRans, the drup Ihal are known as parasrmpatlw>tylics. 'Ilxne parasympa/hnlytrrs that antagonize the actions of muscarinc are also known as anrimincarmic aRents. A large number of anticfw>tiner`ic agents that have specifk actions and uses has tsow been synthesized. Althoush all anli- chnlinergks coldd he considered as an/ispasmodics to d'dfereM dclirees, for convenience Mey are divi«kd inle Ihree ealelories: (1) antispasma)ica. which ate specifkall7 raed 1o reheve qnam of the bowel. (2) antwker agents which reduce gastric secrtlion, and (3) twydriauics and cycloplegics which relas the sph.ncler of the iris and the ciliary nwacka. The Aulk of this arlick is Ireated individually under the following seclion headinp: Types and scke- livity of antispasnw.dics; Onuk secre/ion, peptic ulcer and antkh.Ainertke as antn/ker druRs; AntKholiner6ics as mydria/res and cyclopkpcs; Bincom- parative assay of anticholinergics-Anlispaansodic activilr. Antiuker activity. Mydrutic and cycloplegic adivities, and Miscellaneous anlicholinergic activ- ilies: Srdanaceous alkaloids-Hislory, Chemical Mruclure, Prepara/ive melh- r.ds, M.decular /actors in the abso.p/ion, fate, and eacretion of atropine and its related compounds, and Semisynthetic derivatives of solanaceous alkaloids; Synthetic amicMdinergics; Slruclwe-aciivity relationship; Inleraction of aMi- cholinerolks at the muscarinic recepton; Therapeutic uses of anlicholinerlics; Molecular basis for the side effects of aMicholinergies; Profik of anticholin- ergic activities of various agents, and Nonanticholinergics as anliuker agents. Sasrry, s. V. R. ' In: Wolff. M F(ed ): ffrrRrw i 1lIrAklnd Chemistry. Ilh ed., New York: 1. Wiley A Sons. Inc , 198 1, parl 111, pp. 161-111. Ot16.r aupporf: National Instilules of Health. From the t)epartmenl of Pharmacology. Vanderbilt University School of Medicine. NashviNe, Tenn. IIUMAN PI.ACFNTAI. Ct1O1.INFRrIC SYSTEM: DEPRESSION OF TTIE UPTAKE OF a-AMIN()ISORUTYRIC ACtf) IN I.SM.ATFf) HUMAN PLACFNTAI. VII.LI BY CHOLINE ACETYLTRANSFf:RASP. INIIIBIT'ORS In this anempl to elucldate the role of acelrkholine (ACh) in human placenta, she effects of several chollne acelyhranderae (ChA) inhibirors on the uptake of lu-r'C) aminoisoMdyrk acid (AIB) by isolated human plae- enlal viNi were studicd. The inhibitors tested, eoming from three different clssacs, were (V hrnrnytelhytluimelhylammoniom chloride (BF17A), brnmo- a.r1Vl.hulhnr •nA e/1 n.phlhtl..nyllpyraUne All Ihree inhihuur% were able 1.• rnh.h,r A10 urakr 1.y rhr us.ue 111 IA was rhe most I+.dtnt .d the three .,.W.n.r. ..w.s Ib•+r•c. the .,Ihrr t.n were aluo q.ulr rllc.lrve Ihe I blocka.k of A18 uplake closely paralleled the potency lor inhibition of ChA in  scries of ketoanaM.gs of A('h related lo BEIA There was a positive retytiunship helween the blockade of AIB uptake and the Inhibition of CAA by hF;l'A in sftu. The (IIIA inhibilors did ant eshihil siRnilicanl eRecH on cell viahituy as determined by tissue laclic dehydrogena+e. The results ott- senled here indicate that the uplake of neutral amino acids by human plac- cntal villr is linked to acetylcholine synthesis. Ruwell, P. P. and Sart.y, 8. V. R. )hr lournd o/ rharmar..fnorr awd tzperlmrwtd Tbrrrprsrtki 216(2):2)2-277, 1991. OtA.r aupport r U. S. hlMic Hcallh Service. National Institute of ChiY tlealth and /luman Oevebpwsem, and National Institute of Aging. From the •1)eviartment of PharmacoloRy, Vanderbilt University School of Medicine. Nashvilk, Tenn. IN/IIBITI()N OF IIUMAN SPF.RM MOTILITY BY INIIIBITORS OF CHOLINt: ACETYLTRANSFERASE Mammalian spermalozoa contain the three components of the cholinergic sys/em, aceqkhoGne (ACh). ehuline acetyllransferase (ChA) and aoey6 cholineslerase (A(rE), that can sustain an ACh epek (synthesis, qinwlaliat af a receptor and hydrolysis). Since there it no storage pool for ACh in Ipermatozoa, it seensed that ChA inhibitors should e.hibil dramaie ellectm in the allernion of kvels and turnover of ACh and sperm motility. The ef- fects of two Nroup of ChA MbrTriton, 2-be"lethyhrimahylanstwoniwn ( BETA ) and related eanpounds and haloNenoacetykholines (cholineslm of iado-, bromo- atd chbroacelie acids) on the nsolility indeu of human e*w- laled sperm were studied here. Ttsese investiptitsns gave the following re- whs: (1) BETA was a potenl inhibitor of ChA (rom nwnkey brain. Mrnan placenla, homoilenales of rat spermalozoa and homogenates of human sqer.na- tozoa. 1/ decreased the motitily kndea of human spermatoeoa by about W'R after Ave minutes and by 95% after one hour w a eoncen/ration of 10-e M. (2) There was a positive relalioqship helween the iahibition of ('hA a.d /M depression of the motaitr indea of human spcrnutotoa among ther inMbMors. Both the numher of motile ceNs .rd the graded rnolilhy were decreased. (3) AN ('hA inhibitors studied were quarternary ammonitun compounds that do not siNnifkanlly cross membrane barriers. (4) Both human sperm oeNs asrd human sperm honaeenates had the same ChA activity. (S) Several cited observations indicate that sperm cell ('hA is aeeessibk lo BETA and «laled quarternary ammonium compounds. These and related studies suggest that the s)nlhesis of A('h quite /w+s.ihly occurs in lails of spermalotoa where N MI/ 1 ~I•

acta as a local hormone for coordinating the progressive motility of sperma- turua. Sarr,r, d V. R., )anson, V. E., and Chaturvedi, A. K. 1hr lnr.nd o/ PhrnwroJon and Eaperlrwrntd TAKapiYtkl 2Y6(2):77d- )81, 1981. OrA.r snr'..rf: National Imlitule of Child Hea/th and Human tkvelopmenl, National Institute of Aging, and U.S. Public Nealth Service General Research Support. 1'rurn the Department of Pharmacoiop, Vanderbilt University School of Med- icine. Nashvilk, lenn. F.VIf)F.Nf'E FOR TWO MF?THYLTRANSFERASES INVOLVED IN T11E CONVERSION OF PHOSP/IATIDYI.ETHANOLAMINE TO PIIOSPIIAI IDYI.CHOI.INE IN THE RAT I.IVER This paper presents evidcnoe that hro metAyNr.ws(e.asa eaist in rat liver microsomes. The Qrr metAyhr.nsfer.K eonverls phorphatidyklbanolamine (PE) to phosphatidyl N methykthanolamine (PME). The second methyl- trans/erase i. Ihn uepwise methylatae converts PME to phosphNidykhdine (PC). For tAe work reported here, rat mkro.omal tnembtanes were used as the source of the enzymes and S•adenoayl-L-(methyl-sll( methionine served as the melhyl donor. The merhylation products were characterized by thin- layer chr<wnalography and hijoh•pterure liquid chromatography. After incu- bation of rn liver micro+omes with the melhyl donor, three peaks eorrespond- ing to PMe, dimethyl•PMe (PMME), and PC were found and QuamiAed. The Ars1 nrethyluansterase had a ktrw Ke, a pH optimum of s. and was ac- 1ivaled by Met. The second methyltransferase had a high K. and a pH oplinum of 10. When the mkrosanal tntmbranes were subjected to repealed mild sonicaliow and cenlrifulialiow M 103.000C a fraction of the second methyNransferase was soluAiliced. The solubitized enzyme utiti:ed dipalmitoyl- PME and -PMME as subsuales. 80% erwymes were present also in mi1o- chondrial and nuclear membrann, wilA the highest specilk activities oceur- ting in the microsomal membranes. This wide occurrence of ineshyllransfer.se in several types of wrcmbrann may indicate an Important regularory role for these en:ywns is the cell membrane function. Smrry. a. V. R. er d. ArcAlrer o/ //orti.minry .nd RbpAyrirr 211( 2):762-77 ), 1911. OtAer rrrprtr U. S. Public Ileahh Service. From the Dep.rtmenl of Pharmacolo{y, Vanderbilt University SclMrnl of Med- icine, Nashvilk, Tenn, and Seetkrn on Pharmacology. National Instilute of Mental Ilealth .nd the Molecular Toakoloty Section. National Cancer Insli- 1ute. hethe.da. MJ PFPTIDES FROM HUMAN PLACENTA: METIIIONINE FNKEPHAI.IN AND SUBSTANCE P The human placenta produces several hormones, is a source (or receptors of .ome polypeptide hormmnes, aed has recently been shown to poaess M dorphin-hke and enkepAalin-like bioloRical activity. In the study presented here, human placental viqus was ea/racled and inveaipled fw the presence of enkephalins, Substance P, and g-endorphin, because /here seemed 1o bs an indication of their signiRcant involvemenl in the noled hormonal activity. Rcsults of highly sensitive and specific radioimmuwoassays aMowed that rwethe ionine enkephalin and Substance P occur is the hwwaw placental viqrr. The presence of kucine enQephalin in the viQus could wot be denanstrated by specific radioimmunoassay. Condilions for the biossay of placenlal eatrach (or enkephalin-tike activities using the rat vas deferens were also prese.led here. Comp.rison of the enkephalin-Rke activities determined by bioaany and the conknt of A.endorphiw and a.ethkawine enkephalin determi.eA by r.dioimmunoassays Indicated that placental viRrs ea/racts contain other tr.- ideMified potent opioid•like peptides or substances. It is suggested k,er. IAN menhionine enkephalin ond/or i3sndorphin and Substance P regulate release of acelykholine or hormones from placental viMus. Alternuively, the.e pePs tides may regulate sensury Iransmission (pain impulses) locally from Ihe d'w lended uterus during preQnaocy or (rom the vaginal lracl during chi6dbirlh. Sony, a. V. R. et r. rlarenr. (Supp. )):)27-3)7, 1911. Otber ar'prfr U. S. Public Health Service. From the Department of Phnsnacobp, Vanderbilt University School e/ M.d- icine, NashviRe, Teew. CHANGES IN PHOSPHOUPID METHYLTRTsNSFERASES AND MEMBRANE MICROVISCOSITY DURINQ INDUCTION OP RAT LIVER MICROSOMAL CYTOCHROME P-IS0 BY PHENOBARBITM. AND l-METIIYI.CHOLANTHRENE Phenobarbital and )-melhykhui.nikuene, which are well-knoww i.ducen of cytochrome P-IS0, were administered to mak while rals by iwwraperNaKal injenion for Ove days. lw this attempt to meawre she changes indaced by them in rat liver microsomal cytochrortte P-.50, phospholipid melAyllransferases, a.d membrane microviscosky. Results khowed lhat pheswbarbiul and )-radhyl- eholanthrene increased eyloehroree P-150 kveb 2- to 3-fold. A1/ow S-adenosyl- l.-(methyl-a111menhionine (SAM) eoncentralion, the proportion of phoa- phnidyl N.methykthanolamine (PME) among the total phu.pholipida formed increased significanlly, and a1 a high SAM eoncen/ralion, the proporliow of phosphatidykhohne (P(') among the total phospbolipids formed deerearcd signi/kanlly in microsurnes of treated rats. TreatmeM of tals with phenobarbital and )•methyklwdamhrene ahn decreixd mkro.omal membranes and liposomes which were prepared /rom pho.pMdipids ealracted from the micro.omes. In ayn/hetie lipt.sownes containing phosphatidyk/hanolamine. PME and PC, a.kto- e2 ~ e) I

i viacn.ity dccrca.rd when the proportwn of 1'MFE w.% intreaxd ur the pro- pona+n uf P(' was dectcased Ihe.e rc.ulb urggcsl lhat Ihe memhrarx nnwhly increasc. wnh phennAarbrt.l am1 I mcthykh+danlhrene Irearmcn/, +ml changc• in phosphodipid nx•rhyhranaleraars may conlriMde tn the proceas of eoryme induction larring +nducli.+n with phcnuharhilal, all lhree (aclors t.nown to increase membrane AuidNy contribute to the decrease in microviscosity. 1)uring imlurlion wirh )-n+ethykholanthrene, sheralions in phnsphrdrpid methylation is po.arhly the ptimary canse of the decrease in memhrane microvncosrry Sarr.y, O. V. R, er d. rA.nnerolory 1981. OfArr anpprfr I). S. Public /leallh Service. FrrNn the 1)epartmenl of Pharmaeology. Vsnderhilt llniversity ScMwl of Medaine. Naahvrl/r, Tenn ; Molecular Toskobp Section. Natinn.I Cancer hnlrlulc, Relh..da. Md ; hnMhern Research lmlitwe. Rirmineham. Ala , and the Sectron on Pharmscnlagy, National Inslitule of Mental /Itallh, Berhesda. T11F Ml)1nR or AMnFHOI[) I Ei/C(X'YTES 7bere are three things that are needed for eytoplasmie movement: (1) force gcneratw+n. ('1 urrentutkw+ of the force to provide direction and (1) a control mechsnnm ihe present paper reviews studies limed at understanding the elements of mMor activity in amnefioid kucoeytes ('lose scrutiny and eon- sideratinn of these investigations led to the following conchnions. The conical eYtoplasm of amrxhoid kucocytes is an isotropic gel meshwork of actin Ala- menls erots•linked at inlervals by aclin-birding protein. Myosin filamenls, dis- peried within this gel, hind Io the acun Alamenls and aaregale thcm in the p.esence of magnesium and AT?. Oclsdin, • receraly, discovered prolein, mm- eovaknlly severs actin Alamenls Irn the presence of suhmicromolsr conceMra /ions of ionired calcium. e/fecting a gel lo ad Iransformation. This reaction reverses when the calcium eoncenlration falb. In a tonspkle ayslem consislinA of puriAed aclin, myosin and Sclsolin, calcium padienH control the direclion of movemem of the prolein misture. Since Ihese proteins are in the peripheral cytoplasm of amnehaid kucocytes, the ekmenla of movemem in peripheral eytoptasm ue: (1) force generalion by actin •nd myosin; (2) orientation of force by eoMrolkd Ael-sd Iramformations, and (I) repdatinn of these trsns- formalions by ioniud cakium. Srourl, r. P. rt. .1. SlocArmk.l Socirry SymDorlum 15:31 •6), 1980. Orlrrr aappor/: ll. S PnhIK /leahh Service, Edwin S. Websler Pcundalion, Ilniter! hcean Services, and 1'dwin W 11iam. / rom the Ilemsrnlngy (Mc.•4.By IInH. Massachusetls (ienerd Ilospilal. and the Ileparrnrent of MtJK rne. /Iarvard Medical Sehnol, Aoalon. Al'lIN NINI)INI: I'R(/111N AMI'111 Il:ti A('InMY()1IN lYlN1RA('11(1N. ANI) (i1'1 S(t1 IN ((1NI`I'RS ('AI ('IUM CONfROI. ON 1111' 1)1R1-('II/)N Of CONIRM'11ON (k+,ervauon of drrecli+wul movement of skeklal mu.ck actin and myosiw in horironlal capillaries in the presence or alwence of a calcium ion gradient reveakd that increase% in actin network slruclures by ac/in-hinding protein (A8P) enhance the eAickncy of contraction of actin by myosin C.elsoliw, a macmpha6e prrnein that divides actin Alamema in the presence of cakiwn, inhibits the amplifying eflect of ANP on contraction of aewmyosin. Pinally, il was seen that calcium controls the dircclion of movement of an aclin Alamesl lattice containing nryosin and mxrophage geholin by reversibly decreasiag lattice slructsae of actin filamenls crosa-linked by the ASP. In an aclin Ial/ice, fN.ments interacting with myosin move away from donuins of decreased eroas. linking becnr.e u/ increased eAkiency of contraetion in /he more eross linked dumaars, and any part of a cell attached to the Iatlice would move accordingly. Since many eells contain cortical actm meshworks, it would seem probable Ihal the model presented here may he generally applicable to diverse ceN surfsce movemen/s. Stendahl, O. I. and storrel, r. P. eiorAenrird and eiorAyaKa/ Rrs.arcA Comnrrnkrrbns 9?( _' 1:675-6l11, 1980. (hhrr au/q...ras Nalirmal Institutcs of Health, the Edwin S. Webster Foun- dation, anJ 1?dwin W. Hiam. From the IlcmatobRy-Oncolo`y Unil, Massachusells General Ilospiul, De- partmcnl ol Medicine, /larvard Medical Schod, Sostow. ISOI.ATIl1N AND PROPFRTIFS OF OXIDI2FD ALPHA-I-PROTEINASH INIIIAIIOR FROM //UMAN RHF.UMATOID SYNOVIAI. FLUID Rcppxted here is the isalation of human alpha-/-prweituse ishieiler (w-1-Pl) from rheumatoid synovial 11uid. The prepara/ion, almost 90% pw•, had a molecular weighl close to 52.000 a•d contained ).S tesirhses of wK(h- ionine sulfu.ide plus an amino terminal ghNamine reaidne. According to w- quencer strdies, the Arst 17 residues normally present in plasma wrl-PI were naasing Iram /his protein. Instead o1 forming • comples with porciwe pan- crealk elastase, the inhibitor was convrneJ /o a k>wer molecular weight form. When studied in the seyuencer, 1he /a(ter showed thal two methionyl residues had hcen u.idired, one a1 the P1 reactive site and the other at P,. lhese dala conArm the speculation thsl «•I-PI oaidalion may occur in vivo p.esunsably thrrMrCh the activity of kaknryte mlcluperuaidase, which eonsliwutes a loss of protective activny for the synovial connective lissue proteins. Such a proeer may be  major contribuinA /aaur in the developrnenl of a proteinase in- hihil6» imbalance in the lung and /hus, ultimately that ol emphysema symp(oms. Tlrese reaults ealablish at a nw+knrlar level /he (acl that osidited w-1-PI can be found where human connective tissue n breaking down. Structural analysn may everaoally show that lhis process also occurs in the hrng. 94 1 05

Woels, P. S. and Tr.rit, l. diorAr.nitd and efophr,irr Rt,rarcA Co+nmrnirorioa, %()):1119-11SI, 1990. OtAor ..rr porl r Natienal Insrilutes of Health. Frorm the [kp.rrnuet of Biochemistry. Uaiversily of Georgia. Athem. TRITIUM LASIa.INO OF T1IERMOI.YSIN, ELASTASE, ANt) RIbONUC[EASE sY EXPOSURE TO TRITIUM GAS AT I.OW PRPSSl1RE T.Hiww is widely regarded as ehs idesl isorope for use In much mcdicat and hinchendcal rexarch, a.d .ver Ihs psM Ihree decsdes rnasy methods have bees used so oMain and Miprove kvels of triliunalabekd cnnspoundt. iAe present p.per reports detaih of sr iwqroaed method foe /ritialin6 proteins which has been applied /o three entywres: Ihe bacterial melalloa:ndnprotease thern.olysin, porcine pancreatic elauase and bovine pancreatic ribomsckase. This labeling method involves espo.ure of a yophilir.cd protein sarnpk to miMicwie a.noums of tritwnr ps a/ low pressure. Results showed thal ther- moy.is. ribonuck.se, snd elastase were puri0ed to specillc radinactivities of 15. S, and I Ci/n.ol, respectively. Awwwo acid anslyses of the Iritirted enzymes revealed higher relative +pecdk radioaclivilin for His, Pro and The in all three poteins while Val and He were snwn# the residues witi. the lowest relative speciAc radinactiviries. The recovery of enzyme activily was always @rester than 95% and the fonea/ion of trilialed decomposition products was not observed Importantly. this bw•preuure gas esposure process required less tritiurn gas and ksa time than she original method of Wdtbach so achieve equal or higher levels of Iritium incorporation. In additu+n, the entymes were eompktey active and did no/ show the presence of highly radioactive hy products. lively. M. O. rr. 1. (Tr..ir. 1.) ArcAivrr o/ lkrhrndary .n/ 1iop6rtks 2M(2 ): S89-S99, 1990. Other arrport: National IsstitMes of Hesltk From the Depart~nenf of Cfianiqry, Oeorgi. It.Nitule o(Technoiogy, Atlanta. tSEl/l)OhlONAS AERU(IINOSA P.I.ASTASE. DEVEI nPMENT OF A NEW SUdSTRATE, IN111e1TORS, AND AN AFFtNfrY I.IOAND This report descrihcs the synlhesis of a new suhNrste for the elaslne pro- dueed by raudonraw .rrrs/wost and the development of a sensitive rate enzyme assay, which used this substrate and was applied to the study of elas/ase inhibitors Peprrlts containing the functional groups of hydrosamic acid. N h~dro.~prMide and thaol were Nrnnse competitive inhibitnrs lhe evi• dence al.o suseewed that the inMbdas AMnd so the ela.lase's pnmary substrate sptrO& 4tv sNe IC,1 P..h onh-Mtrw contained a 1i/Ning gronp with Ihe capacity I lo interact with the enzyme's active site zinc alorn. An affinity aprose resin was used so purify P. arrrsinose elaslase, which was thee sa/ely eluted from /he chromatography column. The enzyme's activily was not inhibited by a shetswolyn sin inhibNot but was irrerretsibly blocked by a tripeplide analog. supeslirK M e.lended substrate reeoptition site as is the case wish poreins pancreatic slaa- lase. lhe synthesis of a new substrate atd development of an affinity pwi- Ocation method for P. .rrrsino,a elastase should facililate future studies wilh thh enzyme. In sddilion, the rariow potent i.hiAiton described hers may wcN /lnd valuable clinical applications in the fu/un treatment of P. .nrpMos Infections. Nisbi.o. N. awd Powen, ). C. (Tr.rir, 1.) Tlirlownd o/ Iioloolk.l CArndstry 2SS(8):7182-)1l6, 1980. O/Aor ..ppartt Natiosal lnrlitutes of Heallk From the Department of Clemislry, Georgia Institute of Technology. Atluta. EFFECT OF NICOTINE ON THE FORMATION OF PROSTAQIANDINS IN THE RASSIT KIDNEY Iw this attempt so deterndne whether .itwline elicib an effect os dw biosynthesis of prostasland'on. (P(fs). its elseet aw the eonversion of r'C-fabeljad arachidsmale ("C•AA) b"C•Isbelkd priwasry t(ls was inrestipated in lo..- apced supernaasts a.d hith-spesd sediments of rs6bit hanope.iz,ed tideqrs. Results of these studies show Ihtl aiootioe dosadepesdeMly inhibited ffis formatiow of the IabeMed Pae Dr, E,, a.a F.F seprdlea of whether low-opmed supernNanls or hi~h-speed .edinteMa were /M ewcprltstie source. llr (1)„ 01 twcotine was about 1O-sM. Nicotine did so affect the dntribwiow of t,he pri- mary PUs formed irn compatisow so controls. hdoteelAacin alao Mhilited tM fortnalion of labelled POs. M/heo eowrpneA N i.dontethsci., wicotiwt: was about 300 tintes less e/lkiea M M inhibiler of the formation of s'C-POs /row t'C-AA in the low-speed superoNaas. /ttt,wS.lioe of kidney edetarornss with t'C-AA also resulted iw the /ortnNion of earious Wtetlcd cornpots.ds 1hN .ss separated on the radiosc.n.. Ilere, in aualogy with the results /roat she low- speed aupernatant incub.tioru, nicoline Lnled to s11ed the diuriMNion of Ib various labelled PGs formed. Thus, the alNivs antaww of rrC-P(ls Ds, E,, snd F,. were not signillcaaly affected by aiooti.e. Ow the basis of the data presented here, it seems likely /hN wiooline attenuates the bio/oemalion of primary PUs in the rabbit kidney, probably by eliciting an inhrbilory eQect on Ihe cyclo-oaygenase that con.erls AA to PG e.doperosides. Ahter. P. and Wrnnn.dm. A. ~ Chnird rArtJotolr I( I): I t)S • I I), 1981. Other support: The Swedish Tobacco Company and the Swedish Medical Research Council. From the Ikpartment of Clinical Physiology. Kardinska Inaitutet, Iluddisp University Ilospital, Iluddinte, Sweden. Ah 87

V1. /mmunology and Adaptire Mechani.m. ONTOGENY OF HUMORAL IMMUNE FUNCTION IN NORMAI. CHICKENS: A(-OMPARISON OF IMMUNOGLOBUI IN-SF('RF.i1NG ('EL1S IN BONF. MARROW. SPLEEN, LUNGS AND INTESIINE The ontoReny of immu.oRlobulia (1R) secreting cells of either 1gG. IRA, or 11M class iw normal chicker ww eaamined here by a reverse hemolyue plaque assay. This study was designed primarily to assess the rate at which the major I6-secrelinR organs of normal ehkkens, including the lunp and intestine. auain adult numben of eeRs seerNinR either IpO. IgA or 1RM, and aho to assess the relalivt coMtlbWiow of each orRan to lotal IR production. Resuhs showed that after halching. IgM•aeereting oens were detectable in the spleen by three days of age whereas 1CO• and 1=A-secrellns cells were /IrN noted at sis days. Adult levels of 1#-seeretint cefls of all three classes were attained by )1 days of age In bone marrow and inles/ine, but such kvels were nd obtained in either the spleen or the lunp until after 30 days of age. Tbe dala colkcted here indicate that the krwp of notseal chickens are populated tnort slowly with lgsecreting cells lhaa either the bone marrow, spleen, or intestine. AI a8 ages studied• greater wwnbers of 1g-secreling celh, particularly of the ICG and IIM classes, were recovered from the bone marrow and spleen than from the lungs and inlestine. T1ws would seem to indicate that the boae marrrnr and spken have the greatesl humoral immune capabilities at an ages sludied: Ihis is consistent with /ht known major rok of the bone marrow and IymphorJ organs in specific antibody p.oduelion. Cawrenrr, E. ('. rr d . (7inJcel and Ea/.rinrenrd /nanriwlotr 41 ISO-157, 1981. Otber .u p p.rt : National Institutes of Heakh. From the Imnn.dogy Section National Cancer Inshoute. Bethesda• MJ.• Ikparl- meM of Internal Medicme, Baylor College of Medreine• and the Methodisl llospilal, Houston. MFd'HANISMS OF ACTION OF SOLUBLE IMMUNE RESPONSE SUPPRESSOR (SIRS) As presented in this IhouRhlful sumnnlion paper, the mechanism of action of soluble Mtmune response suppressor (SIRS) is currently perceived In this way.'Concanavdin A polyclonaMy acli.Mes Ly 2+ T cells which (unction as nompeci/ic suppressor T cells capable of inhibilin= T cell and B cell responses. One mechanism of action of these celh is the production of SIRS, a tlyco• protein with a molecular weight of approsimatey 55.000 daltons. which non- specifically suppresses T ceN and e ceM responses. SIRS acls via macrophaRes which release m.crophage derived suppressw faclor (MI-SF) which appears to be a general and rapid inhihitor of ceM proliferation. Thia pathway accounts for .11 phrnr,rnenolegy related io the action of SIRS. Moreover, the function of macraphales in shos pathway appears to involve only the production of peroa- ide Ihe rr..tion f.i prrn.Nle r,ish SIRC• which has the properties of a hemo- m 1 i i prrNein with pcrotidase-t#ke aclivity, generates Ma-SF, the o.idir.ed casMer. parl 'd SIRS which is capable of inhibiting nsilosis presumably by o.idi:inR cellular compnnes essential (or this proeess. It i. inlereslingto le tba sardies on inhiMtionmo1 tumor cep prdiferaion have providcd considerawbk ta- si`ht into the mechanism of aetion of Mp-SF aM have strengthened Me work- int hypothesis that Mcs-SF is a revenibk, general inhibitor of czll proliferation. rierce, C'. W. and Aune, T. M. In: /ladden, 1. rr. d. (eds.)' .fdr.nr•rr in M+nrwnnpArrnarolotr, New York: I'erganuns I'rea., 19111, pp 197-111,1. (Itlier.upportr National Inslitule of Allergy and Infectious Diseases. I wom the /kp.rlmentt of Pathology awd laboratory Medicine, lewish Ho.pMd a/ St. I.Mri., and the Ikpartrnenls of Pathology and of Neurotogy and Mwwu- m.l,.ry, Wa.hmRron IlniversMy School o/ Medicine. St. louis. A('l IVITII'S OF NONSPECIFIC AND SPECIFIC SUPPRESSOR T~CF-l.L hA('IORS IN IMMUNF: RESPONSES 1 he Iwo distinct respon.es of the immune system, cell-medialed ud Mnnoral ( anlihMr/y ) immune respnmes, are reeulared by a myriad of nsecA- ani.nn whiah may operate at each step of the response. Signi/k.ntly. II is kmnrn that suppressor 1-ceRs nwsdulale both of these inMSwae respoaas by antigen-specific and nonspeci/ic mechanisms. Moreover, sohtble t.etors eidtrr secrcled by or eatracted Irom Ihese suppressor T cells t//fickntly tneditle Ilr imnuusoreRulatory activities of these eells. The w+okerlar propertip r/ nkchanism(s) of action of a nanpeci/k and an anriRen-speeibc suppreewr 1-ceR /aclor, both of which regulate antibody responses, are eompared a.d comrasted here. The nonspecific faelor, soluble inwnune rtspowse /SIRS), is produced by concanavalin A-stitswtaled T cells ..d is netmsepu~.blt frum MIF acNivily. The anlisew-speciAc wppreasor factor (GAT-TsF) ir eu- Iracted from T cells stintulated with a specific syntAetie terpolyper. Tfie twe factors pre.erwed here diRer markedly in molecular properlies. Lr{e1 oeMs and m.Yhanism(r/ of ac/iun. Comparison ol the merhanismisl of actiow of nonspecific and antiRen-specilk urppressor Ttell tactors provides useful In• sigINs into the various pathways operative for retldaliOn of antibody resptMMes. Understanding of the /n/errelalMwnhips among these two classes of irnwunoree- rdatoay nwrkcuks and how they may .el lo modulate antibody responses b essential lor Iherapcutic nranipulalion of imrmrwe rnponses and eoMrd of Ihe inRammalory tesponre. ti.rre, C. W. and Kapp. 1. A. In: Veln. O. P. (ed.): l'rendr !w /n//.nwnwrion Rrre.rcA, Sasel: •irkhaurer Ver1aR, 1980. pp. 1'6-1)7. Otli.r support: National Institute of Allergy and Infectious Diseases. 1=rom the tkpanments of Pathology and Labora/ory Mtdkine, Jewish Hoapital of SI. l.uuis• and the t)epartmems of Pathology. Mierobiolop. and ImwNUrd- ugy, Washington Univcrsioy Schowl of Medkine, St. /.oun. M9

1 I ) MI'.CIIANISM 01: A('fION OF MACROPHAGE-1)I:RIVFD SUPPKFSSOR FA('1()R PRODUCED BY SOI.UBI.t? IMMUNE R1;IPONSE SUPPRIitiS)R-7 REATED MACROPHAGES Soluble immune response wpprcuor (SIRS), a glycoprotein product of concaeavalin A-activated murine T ceRs, nonapeci/kally suppresses in vitro immune responses. It has aho becn .hown Ihat macrophajcs (MO) are the Iarge1 cell of SIRS activity and that SIRS-treated M/ medute suppressioo thtcwgh rekase of a second facbr. Mf-derived suppressor factor (MO-SF). The studies presented here esamiwed tha cell types or funclions aflected by Mp-SF and investigated the mechaniuw(.) oe suppression or inhibition. l?te results of these studies show that Mf.SF: (a) suppresses in vUro playue-forn.- ing cell rnponaes when added at euMwe initiMion or q any titne during cul- Iurt up to two hours of assay: (b) inhibiu proliferative responses of spleen eeMs /o T and B cell milogts: (c) 6sohiloift antibodf and Prolein secretions: and (dl bbcls do.nsion of lu.nor eeMe. Trnwr « Ih treakd with Mo-SF ae- nwnulate in the ceR epck It.M p.ier to oeR division, and rtnder « nain con- ditions the inhobswry effect, of MrSF can be reversed by sullhydryl reajcnls, such as 2 rnercaptoethanol. Tbae data indicne that Mp-SF inhibiu cell division by causing a block al or is rwMwis and suuesl that Mp-SF may be a general irhibitot of cellular proliferation and poe.iMy o/ protein secretion. Auwe, T. M. and rkrrt, C. W. T6e lor.wd o/ l iww.uwolopy 127(1) :169 •)72, 1911. O/Aer w'r.r1r NationallnstMute of Allergy aad Infectious Diseases. Fr~+ the Department of Pathology aad Iaboralory Medicine. Jewish Hosptd of S(. Louia, and the Departmcnts of Pathology and of Microbiology and Immunoti+ely, Washington University School of Medicine. St. l.ouis. Fc AND Cib RECEPTORS ON PULMONARY ENDOT/IEI.IAL CELLS: INDUCTION SY INJURY The study repoAed here eaamined the possibility that certain types of damage to the endolheBum might induce eapressia+ o/ recep(on for the Fc portion of immu"lobAin O(IgCi) and for the activated /orm of the third component of complement (C)b) on the endolhelial surface. thus rendering them more prone to attachment by circulating immune eompkaes. For thia worl, bovine pulmonary endolheiial celh from control cultures were compared with celh thal had been infected with i.Arerura virus or cylomeaabvirw. aed with cc11s that had been incubNed with a bovine while cell (tich in PMNs) lysate fnr their abililies 1o bind sheep erythroeyles. erylhrocylet sensitized with IgG antibody, or erythrocyles bound lo C3b. Unsensilized erylhroeytes and the coaqka lAC142 were used n the respective controls. ReaoNs here showed thn receplon for C)h and for the Fc portion of IgO are not eapressed by ap- parently normal bovine pulmonary endolhelial cells, but are eaprnsed when the cells are espn.ed to white eeM ly.alts or are infected with influenza or cy".n.ro.kwuu. It ares, therefo.e, th.t the unmasNng of these latenl re- crpro" m.y corosJwte ra ohr pulmonary inAammarory response charactetislic Vo 1 I I I of, fot eaampk, anaphylaais and to those lung diseases characterized by the deposition of immune compleae.. Ry.n, U. S.. Schuitz, D. R., and Ryan, l. W. St(rnce 214:317-SSt, 1981. OOther support: U. S. Public HeaKh Service and the ICroc Poundalion. From the Department of Medkine. University of Miami School of Medki.e, Miaeri, Fla. DEMONSTRATION OP A SOLUBLE MEDIATOR T11AT INDUCES EXUI)ATES RI(71 IN la-POSITIV! MACROPHAGES When T lymphocytes are slinwlalad by L4lerie, a strongly iwunwapc.io anlieen. Ibey elicit a response characterized by • dramatic and acute w6sneae. lalron of the local la-beatirK manopha ge popuialion. lo the study preaeoled here. the producaion and activity of a whtbM wtediaor /Aa/ ser.es the saw. (w.etion ia described. The prodreliow of thb rwediNor, which appears so be a prolein, requires la-posi/ive macrophapea, inrmttne T eeRs, a.d chalkn6e wN* specific antifeen. In addition lo describiev tlrc basie phenomenon of faeler- mediaed regula(iow of Ia-posilive macrophages, a prelimiwary appraisal of IAa rrade of action of the wucropha6e (laF)-recrtiilittR facror (MIRF) is praaNed here. It was seen that MIRF nwsl be repeatedly injected /o generate aai to maintain an eaudate diaplaying high levels of larpusi(i.e cells. This factor i a noafialyzabk protein ..d in .m genetically restricted in i1s acti.ily. lb macrophares in the eaudales ieduced by it hear Fc reeeplon, take rp lalea, synthesize 1-A, hul bear few C) receptors. TAus, aw immune mediator capable o/ controlling the Is phenotype o/ Ihe eaudale rwaerophages has been identif{d bere. I Scher, M. G., Belkr, D. 1. ud Un.nw, E. R. lourn.f o/ E.prri.nrnr.l Afrdkine 112:16W-169R, 196'O. Other w'porfr National twstilnlp o1 Health. From the Department of Pathology, Harvard Medicd School, aoslo.. R1:7ULAI1()N OF MACROPI/AOE POPUI.ATIONS. 11. SYNTHQSIS AND EXPRESSION OF la ANTIGENS BY PERITONEAI. EXUDATE MACROPIIAGhS IS A TRANSIENT EVENT The biosynthesis and uuface•eapression of la antigens by periloneal macropha`es were evaluated in this study. Results here showed /hat, reprdksa of the method of induction, peri(oncal macrophages synthesized la an(i6ens for only a/imited period of lime in virro, in a pattern temporally related 1o la eapression. Mnreover, both 1-A synthesis and surface eapreuion were e.- hanced by a variety of phadocytic stimuli. These two evewls-Ihe spont..eous loss of I A e.pression and synthetic capaeily, and the kmporary re.ers.l of this trend during pha6ocyani.- were reflected in the slimul.ting capacity of 91

macrnphaees in the mited kukocyte reaclion The loat of mscrophrEe I-A ako appeared to take place in vivo in mice wbpded to sublethal irradia/io.. Ihese data sutEcst th.1, as in vitro. this phenomcnon is due to the Iransilion of individual macrophages from 1-A-po.itwe to 1-A-negative, and that conslant rcnewal is required 1o maiMaie the I-A-bearing .ubsN /n viw. 6dkr. D. 1. snd Un.nwe, E. R. The lorrnd oJ I rnmrnofory 126(1 ):263•269, 19111. Other aurprt: National InstilaMes of HeaMb. From the [kp.rlment of Pathology. Harvard Medical School. floslon. AN7IGEN-PRI'SF.NTINO FUNCTION OF AI.VF.OI.AR MACROPHADES: UI'1 AKE ANI) PRFSFNfAT1ON OF LISTERfA NfONOCT IIktNES In Ihe study presented her+t, mouse alveolar wucrophapes were chstacter- ited as to their content of 1a-beasittR aeta and their abilily /o take up and pre- unt braria nwnoryronwn. aw iMraceMular pahope.. 1o imnwne T odr in vitro Residenl peritoned wtacrophapes had been simiiarly daracteraed, snd the two cell populations were comparod in several ways. ftolh macrophage populatans contained a similar proportiow of Ia-posNive eeacropAaTes (approt- im.lely 5%). However. alveolar mscrophars showed a deficiency in the up- tste of Listerlk moworyro<<nes. Macropfupe snli6en-presewlind fueclion was studied by measurinss the proliferati.e response of Llrtert.-immune T eells to l.Lrerw,pulsed macrophages. The alveolar macrophalles were capable of pre- seetint LLreria. ilthough kas effectively than the peritoncsl macrophsges. I.isteris presemalion by alveolar macrophars was dose dependeM, antigen wpecific, and genelicaMy restricted, and required the presence of Is-posilive tnacrophalles. The diAetences in sntissen-presenting tunetion between alveolar and periloneal macrophages appeared to be due solely to their differences iw LiuerJ& uptake. 1?ws, opwnitin6 Usrerle resulted is marked enhancement of both l.intrle upal e and presentation by aheolar mactophases. These findings demonstrate that alveolar n»crophaµs poasesa 1-region-dependent antige.- presentiwR function and emphnioe the imporlsnce of bacterial binding by reacrophaps in generatity effective bnnNwte stimulstiow. WeiaiberR, D. S. and Unasrr. E. R. The lowwd of Immunolopy 126(2):79l-799, 1951. Oth.r a.rprt r National Casacr ItWkuN. From the Departmewl of Pathology. H.rvard Medical School. Boston. S'17MULATION OF NONLYMPHOID MESF-NCHYMAL CP.LL PROI.IFERATION BY A MACROPHAOE-DERIVEDOROWTN FACTOR Mononuclear phagocttes have many diverse fune/iom. For ensmple ae- • livaled macrophars secrete a potem Rro.Nh-prornotinl sctivily that slimw Iatet ItNA srMhesM and cell replkaliow is mouse librobasb, bovine ,ortk %mcwlh mutck and hovine aortic endothelisl cells !n rJrro. Production of Ibis t important macrophale-derived growth factor (M(X3F) is directly related b the number of viable macrophages and their time in cullure, and la i.ds pendent of platekt- or plasma-derived serum growth factors. TreatmaN of cultured mscrophates with lakt, haclerial fipopolysaccharide or pf.otbol myristale sutale results in increased growth fauor activity. Prelind.ar7 biochemical characteri:alion of MDGF indieales lhat i1 is a beat labi4, ne.& dialysahk p.olei., which contains at kasl one essential disWfide bond. Orowtl- promoting activity is not adsorbed by CM-Sephadea chromatography. wder conditions that effectively remove platelet-derived growth factor(s). Abe, aerine protease activity is nol nquired for the action of MD(3F. It aeewts, so far, that accretion of MDOF may be relevant 1o the function ot anoao- nucksr phagocytes in uverN patholo& processes, includinR the aeovacr- larisstion and fibroplssia of wound healin6, sn.oah muscle hyperplada is athero.ckroan and proliteralive stIwneru/onephritia. Martiw. 1!. M., Ohnbrone, M. A.. )r., Uw.wsw, E. R., snd Cotrane, R. S. The Journal of Immrnol.apy 126(1):1S141S1S, 198 1. OOther su'prt: National Institwes of Hedth, aad the National Institutes of Health Biomedical Research Support Funds. From the Vascular Pat5wphpsio/ngy, Laboralory, DeparlmeM of Pathology. Brigham and Women's Hospital and the Department of Pathology, Harvard Medical School, ftoston. Ia-tiEAR1N0 MACROPHAOES IN ATNYMIC MICE: ANTK3EN PRESENTATION AND REGULATION Two sets of rnacrophtlles eat be dis/Mpbhed iw the mon.e by Mte p.a e.ce or abse.oe of deleet.bie / re;iow-ssoci.lcd .miRew. (la): wti IFpad- /ive and Ia-neplive nracrophaRea can be delenninea by iwnnwwoAuo.escetK,e using the nonoelowd aaibody e{one 10.2.16. Rt.i/AinR ow Ihis ttawled6r. the e:perimetMs repoeted here compared dte Is-bearittR wuetvphrhes from spkees and periloneal eavities of ahynde (CSA/O/a nu/tw) and euubT" (Cf1A/Ola tw/ 1` )•doe. Macrophages Iroa both slraiws of twiee had qttal antiSen-prcuntin6 a6ilitY. The basd ntrnbers of wutimulated ls-be.riM peril looeal maeropha6es arere equal, but only ettlhyntk mice rccr.i/ed large .at.n ben of /s-bearinp wtacrophapes a/1er tJsreds infeclion. IntraperNoneal M- ions of a"macropha6e IaaecruilinR (actor` indt.ced eaudNes rich i. 1. Cting macrophages in both athymic and euthymk mice. These dats wqew two levels of contrd of ta-bearing mscrophates: a basal T eeff-indepeedeM level and a alimalated level dependent on mature T eells. The work presented here also suggests that the reeruq.ncnt of /.-bearin6 rnaerophapes to /he site of infectiom depends eachuively on mature T.eeM activity. Lu, C. Y., Pelers. E., and Un.nue. E. R. Tlir Jorrnal of Imnrrwolory 126(6) :2496-219t, 1901. OtAer .../rr.rtr National Instnules of Health. Front the Department of Pathology. Harvard Medical Sehool, dostos. 9) ' 92 I

I IMMUNO ELEICTRON MICROSCOPIC STUDIES ON CELLS SYN'THESILNO ELASTIN la .n attempt to learn more about Ihe intracellular pathway of elastio tecretion, a.ew lechnique was devcloped Wilising elaslin-specilk antibody in accordance with which eatracellular elaslin Ahers were identified immu- nobgically by electron microscopy. Usi.g this LcYaiQue for she present study, embryonic chick and hamsler •ortas were e.amined in the ekc(rdn micro- scope using lerritinconjusaled, elauin-speci/k antibodies after etching of she plaMic, thin seclions with • dihMa solWion of beastee, methanol and ethanol. Speci/lc slaininA of Intracellular .eskka waN observed in both amoolh muscle and endodhe/ial cells in addition 1e straeeMular elastin Aben. In the chick cells. these (crritin-staascd vesicks had • IipiJ-laden appearance. In both spe- cin she .eskks appeared to fus• widt th• plasma membrane aod discharge their con/enls Inlo the eatracellrlar spac•, suggesting d.atin (a secreted via vaicular uruclwes. Frorn a nselho/o/o~ica) standpoint, while the Aaa/ion, emheddinIL and etching techniiqrres employed here ckarly have limitalions with respect to penelration of antibody and retention of immunolr.gic reaa livity o/ the soluble elastin, they have the distinct over-riding advantage of arperior preservation of morphology. f)amiano, V, Tsang, A, Kucich, U.. Wr)wbwnr, G., and Rosenbloons. 1. Connectl.e Tlrrrr Riwe.rN ta:1t3-/81, 1911. Other .upprt: National Institutet of Health. Frare the Franklin Research Cenler, the Pulmonary Disease Research (.ahora- /aMy, Alhert Frnsrern MeJ.cal Center. and she Center for Oral Nealth Re- search, tlniveniry o/ Pennsylvama School of Dental Medicine, Philadelphia. T I.YMPHOCYTES OF YOUNG AND AGP.D RATS: 1. DISTRIBIITION, DENSI I Y. AND CAPPING OF T ANTIGENS Whik many age-related alterations of Immune functions have been described in T and B cellt of aging and aged animals, nothing has been dernornuated w/ar about the effects of age on mensbrane composition and /he eytostektow of T«lls In the present attempt to esamine this relation- ship, the distrihution, densilr, and capping of the T cell anligens Wl/ 1), W 1/2S. and lhy-1 were strNlied in lymphocytes of young (1 to 4 mo) and aged ( a 27 nw) B/own NrNway rsts. Results showed that: (1) the density ol Wtitl. W)/2S. and 1hy-1 is reduced on T lymphocytes Irom aged rats; (2) the number of moderately stained and inten.ely stained W 7/ 17 and W1/2S poaitive cells is decreased in she spkens and lymph nodes of old rats; (1) the rate of capping of sl/ Ihree an/iftens is reduced on cells frorn aged r.n. and (4/ rnkh.crnc enhances capping on T cells from ymu+g, hut nol o1J rars Ihwcver. rrurh.las.n t) inhibits capping 10 the same eclen/ on ynunR and otd irlls Ihr.e rcwlts suRRtsl that holh the membrane cumposi- ti.m anJ cyln•ldra.n arc .lil rrd in I lymphnrytcs of aKed rats 94 1 I (idman, S. ('., Wode, Q. A. and Feldman, 1. D. T-hr low.nol o/ hnmrnobq 127(1) :149-13), 1911. Other support: U. S. Public Health Service. From the Department of Immuaopathology, Research Institute of Scripps ( linic, La lolla, ('a1. V11. Epid.waiolosr A(lE AND ADDICTION TO SMOKING This tludy, which e.amites statis/ical relationships between indicea et pharmacological and psychological addidion, e.plores the notion that de- pendence upon cipretla increases over lirne. Suhjeels in the sludy wen 791 current and 564 former snroten, nsak rolunleers iw the Norswat'w• Aging Sudy, a longitudinal study of aging located a1 the VA Outpatient Cli•ie, Boston. (n 197) and again ie 1976 all the pstkipants in she study wen administered a detaikd aawrlinA questionnaire. Psychological or rwoliva/iewal addiction was measured by the Horn-Waingrow Smoking Molives Queslie.- naire, while 1o investigale age group di/lerences iw tar and nicotine eowwp- tion, an idea was generated separately /or total 1.r .ad sotal nicotine IMate. Results showed that psychok+Akal aaa phaetaacohogical dependewoe wesr only tnuderately correlated and had different relationswips with age. Tbb tup- gested the esislence of two dislinct kinds of dcpendenee and teaided /s •up- por/ lheories recoArwaiwA both she psychobAka/ aed pharseacoloAical aawr of dependcnce. Older eohorts had ItiAher seorea ow psychological dependence but did not consurne tt.ore lar or oicotiwe thaw younger adults. Older e•horts were also higher on A.e of sit fac/ors teeaswinA the alrenph of reasons or wwlires for sewtinll and had siptiAcaM lengitudin.l increases on three fac- 1on, sunesting that older swrokers are nwre psychologically "involved" witA, or "Aet more out ol;' smoking thas younger adult sirtohers. Soat, R., Garvey, A.1., and Glyen. R. 1. Addkrlve eeAeviors S:)41-)31, 1980. Other support: Medical Research SerricK of the Veleran. Adrnluiatratio.. From the Normative Aging Study. Veler•ns Adminislral6on Outpatient CYak. and Itelknie College. Brooftline, M/asa. PREDICTORS OF WEIGI/T CHANGE FOLLOWING SMOKING ('t-SSATION Wcighl gain often accompanies srnotiwA cessation and many studiea Aasr tried to eaplain this increase. /bwever, rnany former smokers have •M• 9S

heen shown Ia erlher mainlain the same weighl ot to A»e a/1cr sloppinK, and this paper uies to acknowledge Ihis by esamining several (acl.as which mithl predwt the dirrrdnn of weisht change aflcr giving up cigarettes. In the es- perireenla/ study. s.making hchavrur and weight change over  5 year period were studied in 1.749 adu11 maks of the Normative Aging Study in Boston. While the mess who quit smoking generally gained more weight than never snw.kers, current smokcrs, and lormcr snrokers, )69L either bst weight or maintained Ihe same weight after quilting. A series of statistical tests were perfoxnscd using age, ponderal indes, tat rNe, clinical anskty, normal anaiety, eslroverswm, neuroticism, resssns for smokinL and jolb salisfaclion as pre- dictor variables Results showed that ansons the characteristics mosl related .1o weight gain after yuitting were heavier lar consumpion, younger age and leanness of Saly Muld ('@invcrsely, Irails related /o weight loss were IigMer smoking, older age, and stoaNneas of build. According to the authors, hecause of the inadequacy of the currently availaMe esplanatw.ns of weiRh, chance slier quilting sm..king, it seems clear that other factors related to weight change necd to he idcnnAed Ee/.re /urthn Meoritin6 is anemlwed. sorrl R.(iarvey. A/, and Coua, P. T.. )r. Thr lnrr.n.rionrllourwd of rAr Additrbas IS(7):969-991, 1980. Otllrr auppertr Medical Research Service of Ihe Veterans Administration. From the NormaNive Aging Sady, Veterans Administration OrNpatien! ('linie, Brnton, Hclknic Cr+lkite, Broiskline. Mass, and the University of Massachusetls. Bos/on. 1 S1N(i1TUDINAt FFFF('T OF AGE AND SMOKING CESSATION ON P111.MONARY Fl)N('TION For this bngitudinal analysis of smoking cessation and concommilant changes in pulnsonary (u+clion, data were available on 850 healthy parlici- panls In the Normative Aging Study in Boslon. Of the 451 men who smoked when entering the study. 98 quit during a five-year period. Although there were an si6nifkanl diBerences between current and es-smokers in forced vital capacity (F1r(') and forced eapiralory volume in one second (FF.V,) at entry into the study, significant differences were observed during the five- year period between current, former, and never srnokers, after ad'pnting for age and initial pulmonary function. The decrease in FVC for men who quit smoking was significantly less than that for current smokers. Also. FfV. for former smokers decreased significantly less than for current srnoters. The results of repession analyses confirmed the importance of the initial degree 'o/ function in determining nles of decline for the former smoker group. Additionally, they wt"ed that the effect of smoking cessation is relatively immediate, as years since auillins was tx+1  significant faclor in the regres- sion In this study, smoking cessation appeared lo protect against accelerated loss of pulmonary /unction IIn.J. R rr a0 A/.Ir.Nan Rr.rr. nl Rr.p..i.vr Pwvr 12)(1) 178 )I1I. 1951. Othrr support: Medical Research Service o1/he Velesam Adminislralicn. From the Normative Aging Study, VA Ou1p.lieM Clitie, ilodon, and HeNeaie ('.rllere, Brookline, Mass.; the School of Public Health. University of Hawaii. /1nmAulu, and the Pulmonary Utsil, TDorndike Lahoratory, Beth Israel Ha.- pilal, and Ilarvard Medical Schod, foslow. OPENNESS TO EXPERIENCE AND EGO LEVEL IN LOEVINGER'S SFNIFNCF COMPLETION TEST: DISPOSITIONAL CONTRISUTION3 TO DEVEI OPMENTAI- MOIIELS OF PERSONALITY 7 here are two distinct traditions in personalily, «search, utd 1he preseN arlick esamines their relatiowship by considering Ihe role of IraiH in dhe inner esfr,rkMi,I a.pec,s of ego devchqrneng. tmpiricaRp, the hypothesis 1h.i open- ness /o eaperknce. one of three domsins in a trail nwAe/ of personalily, ia associated with I oevirger's measure of ego development level was tested here in a variety of ways. Priraarily, senlence completion responses of a wnpkt of 240 aduU maks, ages )S-RO rears, were scored for l.oevinger ego devel- opmeM kvels. Correlatiow of these sco.es with a series of objective personalily trait measures collected over a nine-month period showed no relation helweeo ego level and measures of nnuulicism or es/raversion. //owever, as hypolhe- si:ed, ego kvel was significantly related to seven of 10 rneasures of opentws to eupcdence. Blind jud6menl .d praoads from the uppcr and lower 20% of the Fsperience Inventory 1o1a1 distribution demonstrated that openness is espressed in sentence completion respowses. E.ampks of eharacteristicaMy open and closed responses are Riven, and wneslions sre made for /he in- corporation of disposilional variables in research on aduM development. McCrae, R. R. and Cosar, P. T.. !r. lournd of prrsonoNsy, aand S..rid piyehotosy )9(6) :1179-1190, 1980. Otb.r arppart r Medical Research Service of the Veterans Adminislralios. From the Gerontology Research Center, Baltimore City Ilospitals, SahiR.or.. i PSYCIIOSOCIAI. AND 1'NVIRONMFNTA/. CORRELAI FS OF ('OR(1NARY-PR(!NE Bh11AVIOR IN FINLAND l he cowonry prone hehavi4w pa/tern, designated as Type A, is eharac- teri:ed hp s.wne .w a11 of the fdhrwing: intense s/riving for achkvement, cotss- Lelitivenes+. ea.ily provoked 'aupatience. time wgency. aMupness of "we and spcech uvcrcunsmi/menl lu vrtiasion or pr.4essiou. e.cesses of drive, aed hoafility. F.rr the presem study, thi% aNonary-pnsne hehavior pattern wr studied in a Finni.h pupudaliun sample eonNsting o1 11,)64 adults (5,419 males and 5.941 females). A titaslionnaircha.ed shrwt rating scak was used and the rctatinnship a1 the derived vnre to various psychosocial and environ- mental facaors wa. slndi.d Ihc dislrihiuNun u/ the Nudy pspu1a/ion on the 96 ; 97

I f A-B asis was uninsodal with no d'nlinctive grouping into A- and B types. Age speci(k mean scores were highcst in N1-IO year olds. l he highest and lowest decdes were representative of Type A and lype B, tespeca.vely. 7he resuhs oMained here /1r the typology oa the ambitious and competitive per- son. Specifically. A.1ype men were more often marrieJ, selftmployed or in white collar work, and had larger incomes and more changes of residence. A.type persons were more eatroverled and their 8fe satisfaction was greater. While A-type persons esperienced their daily activities .s mote liring, they found their work less nwnotowars. Tlta A-type persons used spirits a little nwwe often and smoked slightly swort eiprettes, whik B-type persons speM mae time sleeping and ow kiswsaiwe physical activity. From a medical standpo«N. the A-type nsew i. lhia eroaa-aetiowal atudy asore ofte• reported a history of myocardial infardiow diapo.ed by a physician and schrere chest pain than the 0-thpe mes, n well aa a Aigher prevalence of Rcne-posi(ive angina pectorb. This study eoAort h nsw keing folWwed-up for incidence of coronary heart disease events aod rwatality. Ko.kenvuo. M. er d. (Rrwtesde, l.) /orrwd o/ CMowk Diuoet 71(7):7I1-710, 19t1. From the Department of Public Health Scknee, Univenity oJ Helsinki. Nehioki. TIIE FINNISI( TWIN RF.(:IS7 RY: A PRELIMINARY REPORT Twin studies oRer a simple and powerful instninsens for investigaling the rok and interactions of genetic and en.iroaunental factors in human diseae. ln 1971, an iwarnational sympnawun reviewed the principles r4 the twin wrethod Iw the research of chronic dnease aad, after a meeting of twin ie- vestilalon in 197), it was decided to establish a Finnish Twin Registry. This Registry has been in operation since 1974 at the Department of Public Health Scie.ce, University of Ilehinki. Its the Rn1 phae of the Re6istrr: fornutiots, a cohon of aM adult twin pain of Finwiah eMiaeraship was formed. T1us p.per describes the formatiow of the Regia1ry; presents the questionnaire study thN was carricd out to determine zy{osity md provide base-line dara on eusnr variables relating to medical. sociolo66eal, eeonorwic, and psychological (ac- • ton; and describes the ddern+iwatiow ol =rgosity. Ow a broad scak, the Fie- ssish Twin Registry ia able to pnicip.te in research on chronic diseascs. M- ehsdiaR nsestal heahh proMertss. The tue of internationally comparable sneth- ods and the eMmirsatiaw of ~n~ecenary duplicatiow of d/ona combine to give thia Registry a deMi/e importawct. Kaprb. 1., Koskeasuo, M.. S.rna, S., aad R.wt...lo. I. In: Madnick. S. A.. Baert, A. P-., and Bachmann. S. F. (tds): rrnsprcdve /owditudind rerr.rrA- an eeqlrkd h.sb for the prlnwry prevewNon of plclis- rori.l disordrrs, New York: Osfo.d Univenity Press. 198 1, pp. 215-217. hrnm thc r)epartment of Public Iledlh Seience, Univeraity of Ileisinki. Ilrlnnkr 98 I ('ROS.S-VAI.IDAl1ON OF 711F FYSF.N('K EXTROVI:RSION AND NI:UROI l('ISM S('AI.ES IN hINLAND AND SWF.DE:N 1)ata from the New Swedi%h 1'win Registry and the Finnish Twin Cohon Study were utilized in this study of cross-wational comparison of the eairirots. mental and genetic determinants of chronic disease. Special emphasis is being given here to the relationship of smaltirsg awd akohd use b coronary heast diseae, hrell disease and cancer in adult twiws. Since the iaAuenoe of pqclwl aocial factors on these determinanta of disease is asbstawtial, twin .tudies o( the Ey,ewck Personality InveMory were sssed to assesa snean leveM for par- ,onahty measurn and their comparability in Finlasd ard Swedeit. Ita this study, earroversinn and taeurotieiaro were twesured in 6oth populations sa1 compared statistically. Results showed that the sneaw eatroversius acak acora were higher in Swede. thaw in Finland for both anew awd sronrcw, while the nseaw neuroticisrw scale rcnres wae much hiRher in Finlaed lhaw in Swedee for both. OveraN, the aidniAcnM diAecewus /owsd on the Eysenck acaln for estrovenion and wewoticiswr point to socbe.rMural diAereaces in sowse aa- pens of devek,prnent of peno.ahty. 7he inlraclns eonelations fot the aro scales were similar iw the two twin pnprlatioaa lor monosrgolie pain- T1s d'aygotic pair intraclass correkstions were in Rewerd srwalkr for Finnish p.ira than Swedish pain. 71ws, herilabilNy estNnNea are larger in Finland thas I. Sweden for eatroveniow (bah se.es) awd for neuraicisrn (womew). TAis study has not revealed any large structural JiRerences, that would prechde the use of the Eysenck scales anywhere in FMwish-Swedish crosa-nafood comparisons. Tarkkonen et d. (Rwuoaafo) and F'loderrs-AlyrAed, B. K.nr.war.ryarktteai Jaflaisrie AI62'1-27, 1981. .'rorn the Department of Public Health Science. University of Ilelai.ki. HeL sinki; the Departmeat of F.waronearNal NyRiewe of ahe Karolinska I.alitr/e, Stockhdm; and the National Instiwte of EAvwvnnental MMicine, Swedea. 9V

Active Projects FoUowiog is a 16 of !be p(iecip•1 ievesti6ators, or institutiom• 01 pro}ects under way or activated in the penod since the previous Report, IoeeUrcr with the respective project silks. Compkted prolects are listed in a later sectioa. lr111NCirAL tT1V 1f8T1GATOR OR INSUTUT"M JOHN 1. AI.SFRS. Iu D. RrrrrtA Ar- i..ci.re rrofrrrw ..f A(rdK/M. Uni.et- si/y of W.+lrworlow Scbod of Medkine. Sealk. IIARRY N. ANTI)NIAOFS. Ps/ D. .fr.- {nr Iw.r.rie.rw .wd Anocbrr h./rr- ror of .IerArw.lw.y. Har.ard St6ed ot 1'.l1ie Heehk Ceaer /or R/eed Re- .lerck •Otld. •ROIECT TTTLtC Hio density liporoltin q.smilainn Hw.e- aek1 deri.ed ..owlr r.clor (FO0 1: rtla/wnsAy to ttu.wen al.e.o.derosi+ MARILYN S. ARNOTT /RASi'O1. t'w D. Awo.r •6e1..rM Md ArMMIM tre/nw o/ 1luloq. Tle U.i.erwy of lnee ST+lews Cancer Cewler. M. D As- der.pw Ikwpl.l and Tvrwor Inslilwt. No.uow. RFRNARD M RA•IOR, M D, hl D rrolr•wr of MrdwJwr. New Fwslena Medkd Cewler /IoyN.l, /lowow. LPSIJE RAER. M D• Aaecietr ho/rr- .er e/ Mr,&riwr. Colwesia l)wi.ersily CoMqe of nysici.ns a Swaeo.r, New Yerk. WILUAM P. •ENFDI(T. M D. Aidr- r.nr rrolrrror uf lediurkr. Uwi.er.ily of Sowt+erw Cddurni. Sctsool of Medi- eiwr. D.•-•sion of /kwseWto•y ./d Med• kel Oe.elics. Caildre: s Hosqilel of Los Aqeks. 1 ee Anaekr. SP.A /•.I dew l1F.RO. M O. lhurcA red.ewk/ew Alwnrr rr.frrwr /s Ris- rruukr. b.i.er.i/f, of C.Mlorwia Scloel./ hWie HeaMl6 O.llend. RICHARD 1. RINO. M D.. rru(nwr of M/IK/M. Unlttr{N' of SowAer. Cali. (ornia Scbool of Nedicine. I as An• V s• Von.n1 Anerarr in Lo.wrd...l ks•r.n.rrrwr. ('et6/orn.. 1w.uilWt of TrtbMd.Yr. l1rr..w .•l (.'r/.uf•yr .w/ /w....wr•./ ~LJ••.wr /luwl.wpun Mrn...ul 11•..B••.1 L..Jrwe. / .1 H,drotar" rwe/.twliring eu:yn.eO and 1.wot c.ncir Shrdire o.14 eseciuni.rw of n/i.atiow of sbe respiratory bwM in .crltoFAik Ciprsess .roliq is sonneltnsi.e .w/ Ly'erlensi.e srbKds: blood Fresswe, re.in„ ddautone Md ca/edsolawuwe re.pmees Mdla•.r rartorsnalon. I~s~yewe+M .. ~rowlplet.eli.ity of ciyMetle onOke co.de..a/s /r.aies Melipe.l Ir..sforwsNio.. rnulyenesis snd pc.woler activity of cis.re/le re- Ieled eaeleri.) .ed 1/+e imOo.IMCe of • Flatsas traclio. (ffl) in Ibeu F.r.w- t/ere "won.ry fuwclion /cne in .dokscswu ue/ tlseir rese.l.-.+ ehdcwsio/o11lie apro.ct. ChokYerd inlabilion anJ carbon Inonor ide .nJ edoerosckrosis I.ipOrokinr and the aruriet wall IIM) i I rRIN(-ILrAL INVtSTTCATOR OR INSTI rUTiON D/ NAIIT K BISWAS. f N D.. 11 tic.. Aaaranr Ir../r.wn o/ ()vd I er.w.nory of tNurn,acalogy. Har.arJ Sctwul of Denlal Medicine. Suslon. IRA N. s1.ACK, M D. rr../r.w. .nl ('Arr/. Dirni.ow .. Dn-rluEwrrwal Nrr- rafoej,~ Corncll niver.ily Medical Cd. k~t. nt.r York. I. MARK •RAIX:Ht FR, hr D.. Ar,1.• wwr rro/rsvr P/ lllorw.w..Wt1. Nor/Ae.s/ern OAio l).ieersilies Colieae of Medkine, RuoMleww. FOWARD RRFSNK K. rr/ D, lr..fr...r .wI ('A.nrwrw, DrprM.rn1 ../ Iw.- .MmJUry, Tlse alnivtnil of Verwowt ('.dkae of Medicine. Rwlwq/on. RFOF(-CA BRYSON. thr.D.. A\wrirrr t•rnfrrMM ..I r.y.1h.l.oF.. Sera Diego Slele Un..ersily, S.n D.qo, ea/. DAVID 1. RIISRF.F, h1.0.. Arwrf.rr ho rnwr o/ Dinfor ~. Drp.rrnrr.v of / orku/ S.kwree. Np/\ leaa Sule Un/arrily, Den1Ow. WILLIAM A. CARTFR. M.D. rr../r.rr of Hrwrwwd.rr, and Mrdi.w/ Aw.ul.~ ILMew..nw Medical CoReae, hila- dcloili.. ALSERT CAST RO, h1 D.. Dire# wr, M.r- moor Rrsrwrrh Letla.orn.y: h../r.vW of r.rAul.~ y~.wI itfrlieiwr. Un'weruly 01 Lfi.mi Se1~w>< 0/ Medicine, Mirw, Fl.. FRANCIS C. CHAO. M.D. Pr/.O. Sew- 1t. Mwa/prar, Ce.1er fer Rleed Re- st.rcls. Roslo.. CHARLFS O. COCHRANQ M D.. Mrwr- f1er, DeporrwreMo/ iwlwrrwelNAe/~ ,• Seripee Cli.k .wd Reseaac. Ferw,.. Ito.l_ 1.0 lonrti Cal. . ALLAN C. CO111NS. ts/l D., Airoci.a ho/ruor of rb..ws.refetl,. Inuiwle /or Rete..iwd Oe.e1kK Uwi.errAy of Colerado. tkwider. ROSERT F('/IT. P» D.. rro%rror of Aw.- ro.wy, MicAipn Sale llni.erei/Y. F.M I..nwng. rROlccT TTTLE FIIecH of nicoline and Sesuot.l,yrene ow /wnnesc podaclww Nicotine and nrwonal develoFnleM The .Ncraliola of itlywyl.le cycl.u by Ililric otide FaMeswn of ey/ocArowse 1'110c Inkractive e•e<ys of r11co1ine. /eaatleroa .nd ewr.diol on weyM cd.qr fad fenls~ae i1M o Wr Iw`~y of ns.{t ..i kin diels M.nd low ps. TDt bioclsc.wkd and pAy.iolueirel cRer- .clerislke of • Froleis wUc• *.cM- capy binds Folycyclic aropw./K l+ybt cub.ws TAt inletFlay of inwwuwowr.cNlana ../ iwlerferaw iwdl/qion iw uwnw/aene.is Nko1Me is bIood: delecliorl by rdis. InwwwwNt.y ~.c/i.aiow snd blood t+ypeo.qw Medi.lion ryMens in Id.nwwaury I.y diKse Oenclic .wd sis of wew«tsnwical e.d t+e- R..ier.i elects of .iceli.e .wd aloel+ei Tise eAec/s of l+yFoaie t+y'od., Inonnaide .w/ lteatdwew/ w R.e.ciye !ty/sai. IoakNy " endocriwe•lite tutlr iw .fe..ya .f yomy r.lrils .d r.bl+M (e/1Nes 101

PRINCIPAL INYF_TTIGATOR OR INlT1TUT10N CARLTON K. ERICKSON. M D, r,o f,tsor of lArwwoloRf. 71e Uai.ersil/ of Te.ae Colk8e of Narmacy. Arri.. V OENB ERWIN, Rr D, /,ofruur of lA.r/MICA! ~; Dfe1., UniverM> of ColOlado SC Of PharHlacl. SCddIH. StR(:ITTA F1.(NFRUS MYRRHED, Pn U., A..iuowr r.n/.,.o, o f f.rkaw- w..wt.l ll ~1rwr, The K.rdw.t• L.r4 rwe. Srocrholw. /UDfTII ANN POSTER. hr.D. Asoci- rr Pro/ra.er of a/ecA.wr/ar2. U.isr- eilY of Georgia. A Veoe. /ACK W. FRANKF.L, PwwD., Medk.l RrswrA Serrkr, Vaeran. Admiaie- e,.dow. Ray Piaes, 11a.; 11i.rcrae, Trwpa Re`.on.l I.boralo.y, pe}ar(- newr of Ikahh and RehabilirNi.o Servicer. TaiwK Fla. ALI.AN P. FREPDMAN, M.D. A.d.- Iw Iro/ruer of Abdrrwr, H.Me- ma.w Medical CdkAe, rldadelohia. AARON F FRFFMAN, ru D.. Sts Srl- rwtist. ("aldo.ni. tl.ornedaal Re.csrch Foundauon. I a lolla. Cal. LAR3 FRI/ERO. M D. r.ofrr.or ewd Chairman. Drp.rrwwwr of E.rkow- ~ et Mytkr: Tle Karolwt. L.rf- K/ELL FUXE. M.D.. rro/rrsor of Nlud- oFF, The Karolwnta Institute. Sroc\- 1•RO![CT TTRi /lu..l brain monituring of wslained nieo- unc kvelr in rau Actions of wieo/ine on ieol.ued perfu.ed rnOrle I/raln Epidemiolo{ic research on ihc Swedish twin reliUrics PRINCITAL INVLlTI('ATOR OR INSTITUTION IACQUFJ F. GIF.I.IiN, Pr1.D, .tMsurirre rro/r111l,, [-IW,Nor) of w/f&fel CArnriur2. Toeko/ojy ewd NyFirw. Institute uf Pahdogy. Universiy of Lkte. LKga. tlelgwm. WARREN M. G01.0, M.D, Profrtwr of MrQlnwr, Ca.diovascolar Research Insriewe, Uwiverury of Calilo.nia. S.w Francieco. I'ROILCi T(iL[ Modrlariow of aryl hydrocarbuw hydre.y- la.e .wd epotNle ttydrarase in MYwal riswee and iwi cell cuhwa by ciR.reNa srnotae conde.rNe and acher ck.ical. Riochemwl erecA.drw(.) a.d Srahl.- uve and ArnMANlvs oow.cwrenoe. d hewrd.IPfrewc aneraholiun . . ERec( of oto.e aw airw.r wwr oeR. I..dverweM of elawin in luee di.raK ww\i.y and lung cancer diagnostic tesl 1o Idcnrilr Fersoir al hi.h rist IIIRA I.. OURI(10, D V.M., M V. Sc.. M D., Anorirr Corrr Rr.rarcA SciewNtr, Drrerrwwwr of k'.rrlwKwrd TA.roR,rrict- RmweR Farh Memorial InMiruee. SuRab. Role of Rewnks awd plraromaic hNr. tarhow w.elaholism in humaw Iriy cae- cer CAROLINE D. IIALL, M.D.. Associate ' lnurretMk+w.INP uf infectious loerer tp f ro/ruor of rrdi.hic. owf Mrdrarr. Pi.Norr rracl disease iw infancy horr U.iversirr o/ Rodener Scbool ef Med- ang envircwwwenral facrors to INer de- kiwe. Rocheaer, N. Y. velqwwM of cMunic lung direa. R i T f A LINDA M. /IAI 1., hr.0., A..ori.ri rr.w Oewe(k diRerences in .i 1M Ai k eq o prNte rno he e c ins o. Ihe /r.eer of Grwnk. and Nrwosc'racr eo " acwr v y iw Drow Alle wwt i alveolar deranea rae of iner( duet ARiert Eiw.reiw Calkte of Melici.e of P rwReurr ura .. 'vtkks in rhe Mrua IonR Ye.hiva U.iversiry. 71. Bra.., N.Y. Rodenl a.d hrmaw lont epilbelial ceR dl- MARO/T HAMOSH, hr D., RerrrcA lr Pahow IoFweaft w.eWalim lure as a lool for wcinoawesie research As.ocrrr. Drp.rwvwr o/ lAyrolop H ~ Iw .we .ad eioPAYrrs. Osorpe/eww Univer- . silf Schoole af Medic..e and Deais- F#khelial cel) carcinoRenesis in rir,o E+idem{oloRkal re.carch on rhe SwedisA Iwiw rqislries Nkoline. cNecholamines and neurocedo- crine fuacrions MORTON OALDSTON, M D. Associate 'Rioehemical hasis of pedispo.ition ro f.o/ea.e. of Af.dk/nr. New Yortt U.i- ehrowic obstructive oul..runarr disease ter.Nf Me" CeMer, New York. MICHAEL C. OP.OKA3. MD. hrD, he/euor ewd Vkrt'Adrn.an. DeFert- swnre/ Medicine. University o/ Cdi- /erwi. Scttool of Medici.e, Davr. Ckculariq oencreNic e/euau 2 and em• thfKma in man TBRPSA OPSSNPR, Pw D. Associate C.w..r RrwrcA SrlrwrW. Health Re- .eareh, Inc. Rw.eR Part Divirion. Buflalo HrrwucoRenake of eon/rYario.e awd /ury cancer rbl 102 I t ur. wari«tro,ti D.C. PAUL IIAMOSH, M D., Ar>rriorr he- /ruor of rApiolop and IioPA7Nr., and Mediclwr. Oeoqelew. University Schoo/e of Medicine .d Dewrhrq. wa.hin,tost. D.C. NORMAN w. HEIMSTRA. Pu D.. rro- /e.aor of h2cAvfoRl; D'rrrrw, Naw..w F.cro.s Lebrno.y, U.ivenilV a1 South Dalala, VerwWliow. CAROL /. HENRY. Pw.D., Direno., Dr- p.erwr.r of EaPr.iwenrel Oweolotl: Mrcrdwdogieal AwdMee, 1.e ie_ rhead., Md. . HERBERT R. HERSCOWITZ 1'w D.. Associate rro/raeor of MierdloLrer. OeaRe/o.. University Schools of Med- kiwe and Dentfnpy, Waehiftro.. D C. ROBERT M. IKIFFMAN, hr0. Ae- .br..u pr..f..uw of Ioliw,J.e iw R,u- /rw.r. UnivaeiN of C.lilornia Schod o/ Medicine. l.a roNa. Ci farelu sn.efte awd IipoFro(eiw reaadel- My by the /rng Some behavioral aspects of emotiy .d swrotainR dqriv.riosa Evahal{arr 10/ A.racM4Mle..f an aF tdiwe el6rion.uaY.eM me.r.n of Ni- weuary DNA Mn..Re i.drod y eMaa- kd wrcise.e.s or Ne c4..inlb ht claareuo enw1o ERec1s of ciRarare .wote e.pwre os de- veloFmeMal. eeNatM nld molecnlar as- oeclr of Ifte MrMwrne resPon.a MerhiuaMe depe.deaoe, wrerhpta/ba ad organic 1raMfoemNion 103

tRIWYfAL UWlSf1GATOR OR INS11TlfT1ON // RnMF l 11OINA('KS. PN n. A un• tnwt rr.•/rran ../ r..d..tr.( S..rn.rr. l)wiveruly of I uwrclt, I uall. Mass. WAYNI H(1SS, PwD. Au.ni.re rr.. /erur, ( emrr (or Rrain Rtararcit, ltmver+wy u( R..cAesler Medical Cew- 1er, RucAeucr, N.Y. AARON IANOFF, Pw.D. rro/rrror of r.rAnlety. Health Sciewces ('eMer, S/ale Uaiversily of New Yorl a/ Slowy sroott, Stony srood. DAVID A. 1O11NSMJ, Pu D. Arria.nr rrolrrw e/ /im. Arn.hrry, Fa+1 Teams• see SINe I/neverwy e'ulkte of Med• ktne. /ohnsow Cwy. )OHN C. KI (X-K. M 1), Srnw. S.kn- tiu, InslNult of Medical Scitwces, Saw Franciscu. ('a1. KI-A1/S F KI/FTTNFR, htD, rra/r.- /tI H/ sM4 AIw.Ierr t in ()rtAlyr/N t. Dr~.r Iw.rnr ../ R«~Ar.wurrr. Rr+A ('nllete of /Ieallh %a.ences and Rww MeJieal ('.Aletr, Ru+h 1•reJ.ylerun S/ 1 ule-s MeJ.cal ( enrer. ( h.caso 1 AWRFNCI' I K1/PP1'R, PN 1). Ar... rwar rra/r.w of Ilnuabrriw., l1niver sily of Nca/h Carol.na School of ruD Le Ileahh, ( harel Ild/ ASP./. LAITIIA. Ptr D. DMrttor. New Ynr\ SINe ResearcA Inuuwe for New- r«hewsislry awd Drut AdJulkwe. Ne+ Yal, DON I APFNAS, M D.. Assiuuwt hn/rs- a,r ..1 r.rAelntr. Universily of Ver• wwrwl Col/ete .1 Medicine. burliqylon. F. ('I IN'ION I.AWRFNCF, U D. At.is- r.w, rrn/rrMM a/ Nrd., inr. Raylur Ca1- kse o/ Mtd.ciwe. 11.wuow. 1AMFS C. I FF. Pu D, Auiu.wr rrnlrs- aiM ../ RNN Arnlilrry. U/M t eMNr SlA1Nrl c.l Mtdicine. S1 I uuis. P/l// IP M. 1 F. Ql /FSNr, PM D. D SC . rrr./runr, .•l (-Arnriurr, Narlheaslcrn llwiversily. loslnw- /AY A 11°VY, MI). rr.• /r...- ol Ahdu Iwr. R..Iwr. h A...w I •/r, ('an.r/ Revush InuM..lt. lln. vr.svty of !'eFi(wme St1wra u( McJs c/.K. Cfn I /ant.+l.. PRO/LCT Tl'Tl.R N.coline-inJuced cluntes in primale hiAh denuly l.paprulcim S/ndies of nicotine inleraclion with blood nRs FwHer Nudies on wppres.iun of pro• /caa. "h11Ww by cltMelle /11W1.e Iw.wMaolosit as.ay .t luwt elasliw de. re"W+ Fwdo'ewous Prolcdylk ewsyn.rs awd iw- Mlrl.re ad A. /wg Slrucswe awd fun.tiow of compke carbo- bydcMea iw Mwwaw kut<«y/es lacal rqulaliow of worswai and plloolotk MeaYOw Retulaliow of proliferation of invasive cells Ver.lkaliow of a Ualiuical aee perind cohort analysis of lung cancer Ocwelk b.sis for nico/ine response The assxiMiow of inwtawic d.W depnsi- liow .tilA pu/wwwary watPlasia in Iu- Uacoo was FRech of cigarette sm..Aint nn immuno- f LJ.ulm proJuclion by Iwman M.wkhial ym.hucyles FRecls of lipnds on platelet micr../uMlk assewsMy Asuy u( nsytenIeJ +lerds in human ALw.J vt++tls-. (ra+iMhly study r....iMt genetic Jr1e.eninanls ../ .hrmieal a+n.nutrnc+is PRIN('IPAI. IN V FSIIG AYOR UR INS11f1111ON PAIq O 11 WIC, M n_ Srni.r 1...trrrr in Ruyal PoupaJwale MeJical S.h,rd, IlammersmwA l1o+Pi- lal, I .ahluw. FARIAN 1. 11ONI T71, PIr.D, Rev.r.A rr../r/MM tl/ INM ANNirtry. I..yne Uwl. rersny School of Medicine. Ro.1ow. (iF11NA 1.. l ON(iFNF(-KFk. P//.D., Arussrnt rr../ru..r ../ rArmmar.d..r•r, Uiwver.ily at i.Mwh AlaMrna fdkse o/ Medaane, Mobile. HFNkV T. I YN('l/, M O, rr„/eunw and ('AaM.n.w, prr.rtn.rnt ../ rrrern• N.e A(rJNtM .wJ rrA/K IIr./tA, tleithluw Uwiver.Ny School o( Mcdl. eiwe. (1rnaA.. /IFRRI°f Mc-KFNNIS, )R., PIrQ, Rr- tr.r.A rn./r.v. L/ raALl..Kv. l/wiver- silr of Miami Schoua o( Medicine. MuNwi, F4. i HANS MFIF.R, D.V M. Srwi/w Strs S.l- ewtiv, TUe ladsuw 1 aboralnry, Sar Harsur. Me. 1. WISTFR MFIQS. M D.. (9in<.wl rr..- /rewn u/ F.-pidrrni..l..ev: prr. t.r, Cnw- werti.en C.IUri EpiI r~miub~r~e~ bwir, Yak University School ot Mediciwe. New Havew, Coww. MICROSIOIOOICAL ASSOCIATF.S, INC, belhesda. Md. IFRAI f) A. MIlY'//Fl 1.. PI/ I).. As...- r:Nr rn./r.u.r u/ An.n.anr. Warne S1ale Unrversily School of Medicine. De1ruN. FFR11) MI /RAI). M 1) , Pit 1). rr../....r .4 MrJa.nr MwJ rb.MI1NM.J..Kr, forJ Uwive.+ily. and ('Air/ L/ AIrJa..w, Palo AMu V.A. H«Pital, ltan(orJ, ('al. PR(/1!('r T1T1.[ / MecN n( 1ul•:..cu allaNaJ+ ..n cell pru- Ja.tiuw in /he Jeveh.pna Lrain Phae.w rie wcJialeJ inpuy to 1i++ue+ S/wlies al Olatekl aaw/ tn.MMh.•Ii.I pWa okwd prudu.YMwl a+ p..+MMe card.ovas- culw risl iw.kcMurs in +nwltrs ('rewctk awJ hi.rwarlcr sluJie+ of smol- iry ywair/cJ vawkc.+ C.r.FetMive MsM/ies aimeJ al IAe develu(r wseM c4 iwtwww.r+vys rur wicwiwe awJ rNesMiwe aMelalYdNts Yacwrs e+wwndliry Ihe li++ae kvtls o/ w/l'n(/we and Ielaled c.MN/4nnldf Trasewlal eRecls of wilrosocaw- lnttiAitiow ef cherwkal (hust) earclwa fewesis Ay wsrhtM.W.in..ne Jerivaives: M HYre and MI YIfrH alssdief Review of WnR cancer in Cnwweclkw. 111{-ptc+eM Smde iwAdaliuw carciwoteuesis Mudien in w/ice S(awJ.rdita8nn of a++a)s as sweaswe uy1 hydrwcarh.n Aydroaylast in AMwlaw /iesrta Cu11aM.Mivt +/wdf ovilA Ik. lay I e.y I l/w{vthNy .d ('ali/u.wia Saw Fr.wcirc. Medical ('rmer 1 .k.~' weJ /o dntrwdae Uu Rewelk c.swhrJ u/ sennlr.yrc virw e.pessiow in hyMW alraiws nl w.kt Nic.Niwe-iwat.ced supPre++wws ../ emhyo tdsak R1rah.wi+m ../ nwr.c oeide aclivariow of tuanylal( c)cle+t 103 -

PRINCIf A I. IN VEST1C ATOR fROI[CT TIT1E OR INST1TiJT10N !•RIN('I/A l. IN V FST1C ATOR IRO)ECT TITL[ OR INSTTt111aON JAY A. NAfFI, M r), r.../rrror n/ Mtc\anisms of airway AylarrriuAilily Mrdfcinr, rAys.ol..gy ond R.Ji..6rgf. l1NA S RYAN, /r11)., Rrsersb rr../ra Inleraclions of Irwwwrees with cella of Cardw.ascotar RexarcA Inslr/rle. U.i .ur ../ Mrlr inr. Unrversily of Miami the prlnqnary vaxular waR versNy of ('alifornia, San Francisco. ScA..rl ul Medicine. Miaei. Fla. UONA11) 1 NFI S(rN, ru D. Au..r(.rr Speclr.MC.fpK .tuJKs of the iMe.Ktinrl of R V. RAMA SASTRY, D Sc., !•s/ D., InRrrerlce of wicoaiwe w/he rekns" of rru/rssur u/ Chrmntry, ('lar& Univtr- cAolrttrAu 1iRanJs.irA mculrnrc recep- lro/r..w of rh.nar.rufoer, V.nJer- acelykAo6/1e in the Iwmen ploceaa srd uly, Wureewer, Ma.. tor pro/crus biR Ilniver+ily ScAud of Medreine. i1s anplicaliorla on the felal grow\ NasAvrlle, lenn. HARO/ D 11 NFWbAI 1., M b., Asri.1- The rok of proleasrs and anliprodcasea in Nr rra/r.v.r of Alydrr(nr, lAe luhws prMnonary empAyserna OlRAI D SHKI.AR. D D3., Chorfn A. Oral cYtMawasesis, vilsrd. A arld rN- Ilopkins Ilniversily SaAara of Medicine, /raArq Professor ./ Oral raAnl.ryy; i"oids salrinuue. Head. Orr.rtw.rnl o, Ora/ Afrdic ine and (h./ rah.d..[y. lianrd School of PRAN2 ()FS('N, PMD. rro/rtwwr of Mtlabdic /are anJ Iu.icda.Aic.l siRnilr Denlal Medicir.e, Ros/pl. IA.rrs.celery; Hrad. Srrtiaw on Iiw earret of d./r)drrdwas JerweJ (r.rn cbnskd rhrm.r..lo~y. l)ni.erslly of IAllycyclK arornalK hydroca'bIMN oc• HANO( 11 \I OR, r/l D.. Arvu iru rro- TAe u.e of specilk anlihodies Io monilor Maiw& Main; West (krwany. c.rrirsain cigartlle sn.ote /rrc.n ../ Hrwww rrnrtirs, %ac\ler /4 lorrnalurn .nd rensuval cd bcw.o- CcAod of Medicinr, Tel Aviv Uni- 1.)pyeene ed.hrcls Irwn DNA of dan.- RPVI'RI Y rAl(:FN. h1O, ('.wrrr Rr Oenesic w.atplibilily /o NadJa cancer versily, Tel Aviv. (sroe/. yed Muwaw ceNs ar.rrA S.wntru V Ro.well rarl Me- , nurial /nslrlWe. RuAab. DtNN/S M. SMITH. Pn 0. Arsivrwr Awunornic cowrrd of pulrnonary surfec- •ra/r.MM a/ BN.h.RWaI SsM'r/rr, Wel- /aM in the adulllrng SFNI)K'IIT 1/ rAlll 1, n V M.. A...+r- l.oeal regulalion of lun..w inra+iun by kdey C.dkge, Welkaley, Masa. r/r Ir.r/r.uu ../ /.rh.d..r. RrsA hes boel derrveJ proltrnaue inAibr.ws , bytrrian %/ I rits Medical (•cn/tr, ('Ai t T1h1OrHY A. SMtINr.ER, IMD.. As- Sludies of nllaopAaAt subpopr1a1/ors calo. ainonr Irc./rnor of r.rA../oRy. Har- and diOereMia/wn using rnoooclonal vrd Medical School. 8oe1o.. a/Mil/odiel DFNNIS R H"TFRSI:N, Ihl D. Auistrnt 1'n./rts.r .r/ IAr.rn.w.d..p., IlMarsily of c'o/wado ScA.rol u( rharn.«y. Soutder It ARI RANTASAI O,M D, rro/nror orJ Ch.rrn..r. I1rP.rtwunt n/ rrAfk lfrohA Srirnrr. 11nr.ersay .d 1lelsinti, Ilelsinli, Finland RONA11) F. RASMI/SSFN, MD. As- aorl.re AJjrnrt tro/rlror in Cowcrrr- nlry and l'nvir.rcnsrrrc.l Afrdreinr. Uni- versiA' o/ Cdifornia Colkge of Lledi- cine. ln{.e. P./1 F.FN RFMOI D-O'QONNFI.1., h/D., rrinaPJ RtM.rrA Arrrka. Harv.rd Medical Schud; /nrraiy.r.r, Ceaer for Blood Researcw, Soston. )OHN F. RFrINF, M D_ AnlNwwr Di- t.w, M r~A•Wrriw~ Lrn{ /nuirrtr; TMMNIr rrnfrs.or .r/ Mrlulwr, Uwi- ve/sily o/ (ldor.do IIea1/A 5aiences Cen/er, Denver. IiFRSFRT Y. RFVN(11 hS. M Q. Yro- frrror of MrJr.wr. Nr.J, rrfw.on.rr SIrrM.n, Yak Ilw.ver.ry ScMd of Mrd.c.wr. Nr. Ila.rn, ( una InAuences of gerrAype. set and cMunic ergarelte ,nudting un nrcWrne and a6 cubol rwetabdi.rn in rnice TAe Finnish Twin CuAoa Folluw up study FRecl of eocareimyens and lursur prn- nwrors on DNA repdr in mammalian alls susceplrblt In chemical Iranstor- rnaliow The role of ctR apeci/k Wsins in m.wse Irry e.rcirwtcrlesis THOMAS P. STOSSEL. M O., CAk/, uedred Onco/e~y Uur, Mssaclrrxl(s Oeweral HoyUa1, tlalo.. LYNN k/. TAUSSIO. M.D. A.u.ri:rr rro/ra.n and Associatt CArirrr..n, Dq.rrrnwrr c.( IrIf.ake. Ariaona HeahK Scienees Cawer, Tucwn. JAMES TRAVIS, rsLD ho/tasa. e/ llxAtndan', Tb Zl/livessil eh OeorRi~ A14... BM1L R. UNANUE. M.D. M.RMrAwh ho/rsa.e of /wrwwryw Aatoq. Har- eMd Medical Sclwd, bMOw. Fundiond anNorny of the Wq waacro- phale FReds of eRe. se wrd diseae a. Iw Rrewiy Mw.aw lung hM ~ eaaywes awd illbibilen 1N e.r MysiopMRolop of worsad and .esivNd s.acrop\aees ruri/kMion and functional analysis of elauase from guinea pig n..ctophatea UNION CARBIDE CORrORAT1ON, N.ckar Divisio., (M\ Ridge. Te/al. SL/fr .f 1M elracserisslfow e( A.i.d itillittWle" eap.r. Ie.loa srr dal- isaft1 Basic nacMninns of lung inNny from in- baled oaidaMa SlEn1EN F. VATNeR. M.D.. Auerine Professor of Afed+rrv. Ner.ud Medi- ed Schoal. New Fryland Reaiunal CM.Ne RescarcA Cenler. SnrlM.uro. Mats.' AlNMiUr in AfrdicrM. rrt/er •ewl 111riAbn. Horpiul. tloslow. N1oMi/le-isdreed n/ea eee.w.ry eesd - Itl{o. Direa eweclr a( wicoUwe os lar.M dwr- IMio. !•F.TI!R N. WALSH, rs1 D.. rr../e.uw ../ leler.cnion of plaekls with coqulNio/1 Respiralury aecrelinns in pulmonary car- MrJirlne. Temple Ilwiversily School of rac,ura Ix anJ x crnorna: secrelory c.rrtPwwn/ d irn- Medicine. r/rladetpAi.. nwnu~lubulin-A as an catly muler of epllAelul dyslunclMrn IRBNE Y. WANO, hr D, Auidant Iro ruriAcMiow of wud/ipk fonws af rwouae Marlers of rpNAelul cell Jti./uncli..n in /taor of Lsir and Clinic.f Inrnrrnd- liver Iwioosanal cylocMorne P-df0 ralary fccrelrMS UI Mn..ltrr ret oA/ OW MICIFo,IDIOty. MeJical Uni- p versily of South C.udi.s. Cla/kssow., 106 107

t*R1NCit'AL INVFSflGATOR OR INSiII Ui1ON Ot?OROt? W!?INRAUM, hlO, t(ord- IMqI. f:l.wowary Dur.u Sraww, AI- berl Einsuin Med.c0 Cefwer. 1'fila- delrigia. AKF WENNMAI 161. M D., Arsorlorr rru/ru.r of Cl.+.wd rhyrLdury at Krubwdn Iw.nrru, Hrddrnte Hoyi- ta1. Huddaye. Swede.. JAMES A. WILL, D.VM_ thlD.. Ivr /ea.a. owA C/.r.w..w. D.r.nwwwt o/ Y.rnb.stry Scirwre, Uwiverwy ot Wia- eo.ewl. Madho.. JOHN T WII.SON, Pw O.. A.ra.wr rrF fraar of C.M ow1 t1.dr.d.r tU.dery. Medical Colhte o( Qeortia. Alopsla, ALVIN vY1NTERS. Pu O_ Aatw.r ho/rfser of M.Iied Mirrdiefoty. Veurarr Adwfiwirraior Medical Can- 1er, ttay Niam F7a. t/RUCP. A. WOOA. M.D.. Arwrlwrr rr..- )rfur n/ r.rA.doRf. UwlcetsNy of M..• .actwsefh. Womsaer. Ot:OROE WOI.F D t*uw . Iro/rcror of rAy.Nfoticd 6rnunry. Drr..t•nr,r of Nwrirww awd food Srvw.r- Mess.c efwrala louiswe of iecMsoloty. C..f- brrdte. ' STANLEY YACHNIN. M O. r.o0r.nr of Mr/iw lww owd Ch.r/. Sr. nnw,./ Nr.»- wol..ty/Uwrot.gy, The Univetsey o/ Chicago Medical ('e.ur. CAicap. rRO1tLCr TrTt.t? tlroKt1/0alteolar tataee of human a1Mlt- !tf aald QoAHDOtters: .IYdlef Oq eeR cfeewt.afA ermyme rekae .ed celtu- tar frlltafavdrro Nicoliee as ieAif,Uor of rrustatluwlie (at- "ios: tocalira/itM of stte ieMbitdy alq aed cftu.cferiiuion of tbe cudio- vaactilac iwnplica/iwn M.rtsba1oo~ awd lfroetiowal euaelalioaa .f 1M A~UD celk a( sf,e Ivny The hn/.Nbw awd eapcesd.+w d Aueaw •1-acNiuyfais te.e u«.ewcn ttaootA •felc<nlar ctowi.t Mkhf of f.ooliK ell die inhrreM iMea /eraa k.eh in eodco/ .wd ca.cer Va- Iiea/.: .'dae M.dy CeR urf.er tweubraom Mtelpal lwenr brawe troleiwft aud cyfe.ldeloe kflyre- 2).pM/inaowr.tlyltyYowfNaW tMe; Vilaosiw A and tlycuprolria .vMAe.is M respralwy epnAelwnr wsnary sal.e- 1.nyt sum/cea.e. a pns.bk eauly enu\- ec ewtywfe /w bladder .awceo Muwkle ror she plMtewesik ol alhno- fckfos.+: AI b«.1.><scel cAccts o( oay- teeafcJ +laol ccanporwJs L+f ~vs/owic aeiJ .ed ehokuerot UioaynmAesis and 1Ae sio.ymAeeis a" /Ae replauow oi eeR Rro..H IOA Completed Projects Follo.rin Is a Iit1 od the priatap.f iwvediptors„ or irlilwioa, of projecb that 11ave been completed prior to lhe period covered b IAis Kep«/. Several ol tbe iedividwb eamed are deceased. 'ilThe Btks awd .AUL. tbas listed are tAoae im eQect at the tane the wat ws ooslpkkd. LBO O. At1OOD, Fy D„ Irafepw of OSCAR 1. flALCHUM, tti1 Q N.atilte 1lorbrw.irrry owd iriiw Rrw.,cA. Cna ho/raor o/ Medicir. U.ivpsYT .f let /o. tlraiw Reeeued, The Uaiver.ily SwAtew C.N(awi. Scf.ot d 11e1t- a1 Rocheeler Medicd Ce.kr. Rocttes- ei.r, l.a Ayete.m ler. N. Y. FREDERIK t. ltANO. M D.. Ir./raur MAR10 0. ACETQ, PnD„ Arwrire .wd CA.iwww, Drrwrrw.rwr of frb- •ro/.e.or JMedkal TLe /d.e H~ Ma U Cof rek aN' y. KV1c! ~.C•+wtwa.- askimme d HyRiewe .w~ t'rMk / Cl.«AeR~F.~NCUE M. AaRF1S, M D„ Aur A. CLIFFORD t1AROER, M.D., R.Mr d.r. C/rwicd rro/ruor of Mrdktiwr. B~w.~uvI/rl/er tro%awr of rAyde/- U.ivenil o1 Califoroi. hledicat Cer- op, H.rd Medical SeAsel MM.os X , ler, Loe wtde.. ANTHONY A. AI.RANFSP M D. D6 rnrs of Lolar.rorkr. TAe /1wR. Ro- bbilAaciow Cewe. WhMe nai.K N.Y. ANTHONY P. AMAROSE. trllD. t.- aanKrer 4c Ollarn.ln .nd Gykrsil•ef. T1s Ml.wy Mediui CoRege d Unio* Usi.w.ily, Alba.y. N.Y. E. T. ANOBI.AKOS, M.D. 1'M.D.. lt.- .wr N FAy.l.feq. lt«u. U.iva.Nr o/ Medkiwt, flwoss. D. MURRAY ANOEVINF, M.D.. Ud- .cceilr o/ tl/i.oow.i. lcksol of McN- ci.e, Mdi.ow. /OSEFH C. ARCpg, Dse., he/ranr of MeIirior. TWw i/.iveeailY Scied .! Meditiwe. New Ot/esaa. INo. 24 Ittt t?w.frowa+eMal frow.elis. Apgwcy. Waiiwpoe, D.C.) ALAN K. ARMITAOIF!e ti1.D, ReserrS Direclor, H.ddow, i-aKaaak. Ew eep, H.rrot.w. Noet• YatetWs, t*_.R- IM.w. s DOMIN()O M. AVIADO. M D. rro/n- ,nr of rA..wc.vototr Ut,iveeeily u/ hwylvarria School ai MedicNft. PwiL arkloc.. IIRODA A. RARNEl, M.D, hM.D. l1r. (eaw (A/lfbrr) of rAydetety, Gi.. r.i. Slrs Ulw.ee.Nf. Foet eRfr.C FREDERICK W. t1ARNM )o, MD. Aarref/. rre%.sor of tlellri.e. Tu IoRu. !1eOki.s Uwi.enilY lcA.d a1 Mediel.re, laN:was. T. C. IIARNES, D.Se., Ro.rwre# Je#es. ~. .MRdrlriit, Str. Ha+Fild, fftla CARL O. tllCKER, M.D, Aewdwr P~/e~ ol ra~ri..ty. C.rsR Uad- vetNer Medical Collem Ne. Y.et. R. FREDERICK tiECKlR, tMA.. An. due /h%sasr of Awrwrq mad Dia- M, Liworary of rirMMd Scdr.ee, D,A. UwiveecMr Medicd Ceaer, Drr- bare, N. C. RALPH S. BECKER. PM.D.. htyorr rI cA.wrlurr. Uwive..Ny d H..e)... tW~INo1+A•~ MN•IN M.D., Dbrrw. Ewia- Mrr, Nwwcord.. Aging Srofy, Vewr- M. AdrWY/M{Ow OW/Nkm CR.it. (l.rlow. SAMUEL WLLt?T, M.D. Dha+~ ~+~• of C.r. Oe.eral Hoa'ilak a4tNr{.. RARU/ otiNACERRAF, M.D, fahatt STEPHEN M. AYRNS, M D., DireHw, f, ra..+awl CAairwcrw, Drprtw.rwt./ Cr/w/rl«wwy L.6wuwy. SdM Par .p. Ha.ud MeNcd lcMei„ VieceN'e Ilospild. New Yoe1. (toNOw. 109

IOIIN A. tl1:VAN, M D, rr.•Iria.r of rAMW•••••.•d.Kt. Uni.etsill of Cahfor- nia YsM.oi of t,led.cinr• I os Angeles. flUDIIDEV RIIAOA r. Ihr D. rr../r»or of rAlrwd.Kl. SeaN 1 orh Unr.erswy Setool ul Med.crne. Ss I .wn. CF.SARF RIANCIFIORI. M D, Division u/ t•on.rr Rtur.A• UwrveraMf of •erutia, rerutia- 14617. HYLAN A. RICKFRMAN, M.D, A.d,r- oM rro/rswr o/ Mr/scinr. awd AL- VAN L. RARACH, IU D., CewWfNM i. Medicine. Colwwbia Uwiverwy Coi- kp of rhfsicia.s i Sw~cwn (1o1J• warer Memoaal Iloyiul, New i'aL R1O-RFSEARCII CONSULTANTS. 1NC. C.mbidge, Mass. RtO RESEARCH INSIITUTF, INC., Cambridge, Mass. (1E11FFRl:Y 1.. RRINKMAN, M D. .1.- w.lrrr rru/rs...r of Mr/i.inr. Wayne Sr.te l)nmversef School of Medicine. Deuoi/. RORERT Iff. RRl1UKS• hrD., A.rocwt rro/ruw of r.rfhol..t~, U.nersMl of O.eRuw Medical Sciwol, Ford.nJ. BARBARA R BROWN. M D., CAir/• Earerinans.l r,l.tioorrr. Vderans Ad- .MiMrNie. Heypul. SeFs/.eJa, Cal. RAYMOND R. BROWN. PM D• rro/n- J+r e/ C/inkr unrolntl. Uwiversrlr of Watoaw Medital ScMsol. Madisow. 1ASFF RROZFK, M D., rrMeswr anI CAtrrw.. t>.p.r.nra ./ r.ytholotl, tebeele U.iversiey. iesNebew. ta. SUE RUCKINONAM. M D_ A,uuonr rro/tuor o! rrd..nirs. (blrmsia Uni• .erwlr CeRege of nysics.ns a Sur- teowr, New Yo.L. FRED O. ROCK, rn D• As.or:.rt C.+ A. SUIST. M.D.. AJJOrIur rr.. ttr Rew..cA Scrrnn.f• /iolorKd Sr.• ,_~~ o! S!r/winr .nJ rl~l,l..latl. New. Re.weR ra.l Mrmori./ InMr.u ~, SEriyviMe, N. Y. .i.asM' of Orep. IkdrY Scicn.c. CeMer, 'ortland. OUtNT1/F.R RODEN, M D, A,socirrt BENJAMIN BURROWS, M D, Arro- ho/tuor o/ Mncc+nr; Anur.nr Dnn- ~t rro/tnor of Mtl.ru.r. U.i.cr.irl ror, Grnnol C7rn.ro/ RnrwcA Crn,rr, of CRical0. Clicap. Tensole Univn.iry llrahh Science.Cew• ret. pWaJelfibus• E. M. BUTT. M D. Chief r.rAoloqi,t. V. AOEN/O, rM D. Ht.~ Les Aqela CorMy Oeneral Ho.Faal, IIERMAN Loe Aqeke. De/.rMwne of CAtnri,rrl onI IiorAnw• fJe.Y• SFiwQetoF Researcl Cenur, L.er RICHARD U. RYERRUM, Pw D', rro- l.por, Ky. fesaw o/ C1lrnsisnT. Michipa S1Ne Ur.iveraar. EaM L.w.iry. JAMES F. I/ONNER, rw D_ rro/ea.r SISTER M. EMILY CAHILL. FN D. ./ Rbloq. Cd~or.i. IwsWwe of CAdrww, Dq..rmwnr ol CAnnunl. 7ecMokrRr. t...dewa. ReRie CoRqe. WeMot., Mass. WALTER M. BOOKER. rMD_ rro/tr BRUCE F. CAMERON. MD_ /M.O, aot .wd Ntod, DrprrmrM o/ rLorwv- ~«d ~~.~e. IRSlilrle, Uni.ersN' ~': No ad U.i.er.ilf. WuRi.!• ot Miawi Scisool of Medici.e. Miarwk D Fla. FRANI'OIS M. 9OOYSF, hr D., Senb. F.LROY T. CANTRF.LL, rn D., (•Adr• laasMpror. Michael Reer Rer.rA mom, Departmmnr o/ r/wrn.oroiotl, Fwwhrior% (.licyo. Tear College of OdeoP.rhic MeJrciae. RAYMOND BOSSE• M D., AJwci.rt Nor* Teau SrNe Urwversilr. Denroa. DMtrra, NeM..Nre At/wt srs+Il. Vel• WILLIAM H. CARNES, M.D.. Uni.er- eraM Ad+niniMrafion OWR.rieM Ctinic. Wy Go ULh College of Medicine. S.R RoMow. t.Le Ci1y. TOM 0 e()W/MY. •rl). Rr.rr.h MARCUS N. CARR()ll.• la.. iMD, rr.•IIINr, rr1f1.1dr R.rJw f.b.r.. ('A.r/. O..na•w .•/ rAww...ul.•fl. 11e r...l Nurres 1aMe ('d4p, /.uuildek Ilu.rul ( eMer, t•rooliyt•. R.L,tis N Y i WILLIAM ALVIN CARTER. M.D. A,Jaunr rro/rssor of Mrlrnn. ow/ M.rroAiol.Kl. 71e loMs I/opLiM Ua1- verull Scbool of Medicinr, bshinrere. I.FOrO1.D ft. CFRECEDO. hrD.. Ao- /rrJr of liocArn.urrl and NrNrlinw. Rlniversiry of herro Rico Sehool of Medici.e. San lo.w JACK CHAI ON. M.D. Aueri«r rr../r.- .or of AnruAt,iofotl. New Ywl Uni• versiry Medical CeMe., New Yorl. CHILDRFN•S HOSPITAL OF /.OS AN- OEI.ES, Los AwVke. SANFORD C11ODOtH, M.D.. Asd,aww rio/ts.or of Mtdfriwr. T.hs l/nieee- wr School of Medici.e. Romon. NAITER M. C11OrRA, tr.D., rre/et- .o. of CAeorirnl. North Cwolina All- rir.hwal aw TecMic.l S1Me Uaivet- siq. Oreenseoro. WII.LI~A~M I 0 CL"ARK• Iw D.• Drrrrtro., rJN^vIAl/nyr.n..tT Research I ab.1a- /OI), VeleralM AdInMiMra/ion HO.ltilal, Sepulveda. Cal. HANS T. CLARKF, D Se. rroft,tne o/ IierArndMry•, Columbia tlrsieeniry CYlkse Of ~rl/•YciaM j SYr/tonl, Nlw York. JAY 0. COFFMAN, MD, Serdow Nrod, rrrlploerof Voud.. Drprrwwwr, Uwivetwr Hospital. IIoMe.. ALI.EN R. COHI:N• M D.. Iw D. As- wtlrt ho%uo. o/ MrlkJnr. CAw/, rrbw.w.r~ Serdow, Tewyle Uaiversity Seiewot. CeMer, i'"adeipMa. DANIFI. COHEN. D V.M, M.P.H., As- .i.toM rro/t,wr of Ynrriwarr E/i. lrmfdutr ond ruM:r MtdrA• Uwieet- *f of Ferarallvawia Scbol ot VeNt- inary Medicine. ~IadeltAia. /1111l/S N COMROF. ta.. M D, Datc- rr, CrJw..JraJr R/N«rA IwNMrr, Univer.n~r of C.Kfornia Medical Ces- 1er, San Franci.eo. DI!AN M CONNORS. M D, Auorl.rr DirtNw. Drr..rwrrwr o/ I nN.n«we Mrditinr, S1. Marr•s 11oqi•a1. M.diwws, Wis. FHIi /r COOrER, M D. C/inir.! ho- /eJaar o/ Srtery owd Dirtarer, Sa.ili- t.t L.Itararr u/ Crt4dr rAytidoty Albert f:iwstei. Colkp of Medici.e of Yediva U@i.erwr• Chief. Srrkd Srr.lrt, Veseram AdoilislralioA Ner Fi/at Tbe Rro.., N. Y. PAUL T. COSTA, !t. Pa.D., AJtoriae rro%per of r.ycAo/oty. U.ivetsily .[ MasMrchrnelu M Rerow, DaeheMer. JOHN E. CRAHINEAD, M.D: r.o/a- Jor of r« Uwi.etwlf of Vw- waa ColkRe Medici.e, Rwliapon. RORERT L CRAIN, hM.D. At.1M.w rro/tsww o/ Socls/o91. Uwi.eesilY of Clwcyq Cleihg.. IRVING P. CRAWFORD. M D„ rroyr •sr and Chdrw.r., Drrvtnstwr o/ Ml- e+oii.MRY. U.ieersitl of Io.s CaRrM ot MedicMSt, lew. Cnr. T. TIMOTNY CROCKER, M.D.. rro%t- - M Mrlitiwr. Uaiver.Mr of Cdl- Rorw Co1kRe of Mediciwa. Irvir. CARROLL F. CROSS. M.D_ Aao.iut rra/fue- uf MrJi. int ow/ HIMM rAr>iIoktr: Di•trrw. sectimn uJ r.f- nw.wrf MeJlriw.e. Uwivetsilr o( Cali- /or.i. School el Medicine. Davis. CECII. E. CROSS. RetercA DrE..daar Sr. 1oee& Heyilai. RratY.wl. Cal. DAVID W. CRUMrACKFR, M.D.lhw /rrsrr rwd CA.,rnw, Dtp.rwwwr o/ Ew.M+wMeMal. reriniow «./ Qrp. ~lblop. Uor.enil, .t color/~ ALRERT DAR/ON, M.D.. ftr D.. Ltn rrtr oA wwrMoptotr: Rru«cA A.r.- ...rr i. M.1irw! AnrAr.Foiuty. h.• C~iwshtidRMose C. La,H.rvard U.i.en11T. THOMAS R. DAWBER. M.D.. AuoeWt ho/i.wt ../ Mr1k/w., RoM.r Ua/ve1- sMr School a! MclicMe. RoM.w. R F. DAWSON. Ip D., rro/rssor./ Mr. Colwwbk Uwiversi«y. New Yaet. /OHN P. DFI.ANEY, M.D. MO, At wrfrrt rro/r.ror o/ Sr err. Ud.er.Rw saf Mrwec+wa, MioweapSie. ANDRF.W s DIRNER. fw D.. Earn r(w, r..rAo•Rrar«cA. TM AR. C.a- , ar of New F.wtlaad, Iwc. RoMe.. III

FDWARD F. DOMINO. M D. Irn/rs- sw ./ Itir.n«..In(r. Iln.vtrsisy of Mr./utan. Ann ArAor. RAI PH 1 tN)RFMAN, Pub. Dlrrcan of Worceuer FouadNiow f.w Feperanenlal Rrdr+(). SArealwrl. Mass. N FRFD L>nWNFY. PwD.. Assht.wt rre/r.ww .4 rAru..l..R/. Universil~ d Texas //eahb Scrence Ceaer a/ D.Ras; Drer1.w. CrJlorawr/r Rrwr.A.Cae- diaplwwwwr Iauil.de, MeM..dir He.- Piul nf Dallat. Datlas IAMFS / DYAR, PrD. Aruu..r rro- /rner .•/ R.ololrr. ReRarwsiwe CeRege. I owsvdk. K 1. RI('HARD H. FARI P M D, Chief. tJn.o..ry Frwrr.nw La1MrNo.1: Ar- ssrr.r rroJrner of MrLrrwr, llwiver• silf of ( If.callo. Ciwcago IMIN W FCKSTFIN M D. Aulsr..r hefrnor e/ Iwrrrw.} Rhf.r.wr. $lwe U.rverurT of 10.8 Co/lrae of Medi- twre. lowa Cily RF.RTwAM EIC/IFI. DDS. Drrerar. IwarMwr of RewrrA. Seitllce Rnweces 1 wedel.Jq Waler- 1o.w, Mbss. HYMAN FNOFI 0FRO. M O. Arrrad- 4y IAPNrI.w. Cedars of I eU.woe /lo*- Piral. Los AnSeles. CARLTDN K. ERICKS(NJ. PwD. As- axi.q Professor o~( rAarwwcelotF awI Toelyde~s. The uMVersilT ef Kawus School of Plwrnacr. Larreoce. HENRY 1. ESRER. PN D. RrrrrcA fw.- /w.r.elo~/rr, Masnw Resrarcll laslhwe. Worceuer, Mass. WALTER li. FSSMAN. M D_ Pw D., he/e»w of f ncAolop and 11orArw- /str); (jwews Cdkle of Ihe Cilt Uni• versilT of New Yoik. FlasAiq. JOHN R. PSTERL Y. M D. AssecWe rre/nrnr of r.cAolofl. UsieersNy of .o P.Mefer School of Mediclee. Cldc.- CMc.No. 1 /IUGH F. EVANS. MD. Dl.rrrar. Dr• p.rnrrnt of rrd..nwr. Ie.oJ Hoyi. 1d and Medical ('enler of RrooUyo, Iira.llfn, N Y. IIANC / F YCI-N('K. Pn 1). D%(' , Ire- fr...» ../ Y.../a.l..R•. Inslilule of Psy. cMalry, lln.vts.dy of I urwlon. 1 ew- do.. /IANS I FAI K. PuD. Ad/rwrt Ascad- .rr lru/ra.r n/ raAul..(r. I/aiveesilT ef SoulAesa California ScAool of Llediciwe. I os AeRelea. DANA L. FARNSWORTH. M D.. Nrwrr K. Obrn lro/rtar. o/ HtfKM owd Drrrr.r. f/wire+sity ReairA Srrr:rrt. Hvvard Uwiversilf, CwwSridle. Mara. OAD FFINSTEIN. Psr.D . Srwd.w [rr- Irr. Iw Ii..rArwdttrf. T4 (k.wae S. Wise Cerwer of Fde icience.. lel Aviv U.iversiif. lel Aviv, Isr.el. FRANK C FFRnUSON. /a . M D.. CA.I•wa. Drrartn.rwt of f A.r.nwel- oRf, The ARra.f Medical College of Urliow Uwiversily. AlAany, N.Y. THEODORE N. FINLEY. M D. Oi.rc- 1er. Ldwsewrv RrvrrA t albrrnrr. Mount 7iow Ho.plal. Sa. Frawci.ce. WILI IAM I FISHREIN. M D.. Chief I E rlnwlolaffl. Chicago Roard of eair~. Chicago. FDWIN R. FISHFR. M D. Orrrrr of f aA..rwronrt, SAadyside Hospu/; hr o/ rrAolnv . Uwivetsilf e/ 1=u1h ScAaol oF Mcdicrrc. Pi1/s- LMtlch. RUSSEi i. S. FISHFR. M D. l/wiversiy of Mwfland School of Medicine. 1111- linwre. WILLIAM H. FISHMAN. PM D. hetl- dral. La lop. CucRC ResearcA Fowlda- /loaL La IoRK Cal. lr L. FRFEDLANDFR. M D. Dirrtter ..f Cawcrr Rr.errA. Moww 7ioo Hoa Pilal and Medical Cewse.. Saw Fraw• CMCe. FREDERIC A. FRF.NC//. AR. Dlrec- cor of C.wrrr C4rnwtArr.ry Rrwrrlt, Mouet 7ioo l/oyisel aaa Medicai Center. Saw Francisco. /ACK FREl1ND. M D.. Anisc.wt Pre- /r.Nr o/ IArnrerolo~I. MedKal Cd• Ie1e of Virginia. RicUwnoaA. ()ll bERT /f FRIFDFII . M D. CA/e/ o/ ratAoto~r. SI. Vincent Iloepiul, Worccsler, L/ass. I GARY D. FKII-DMAN, M 1), Auiaawr Director. DrP.rr.wewr of Mrdice/ MnA- ofi RrsrrtA. Kaiser FowdYiow Re. wrc\ Iwaiwwe, Odlaad- Cal. H. HUGH FUDENRERU, M.D., rro/i.. aor e/ MrdlrMr. U/li.eesilf .f Ca4- for.fa Medical CeMer, Saw Fn.cisee; Ir../essr of Lrtrrwlor? ewd IwMw.. otl. Usr.er.MT.(Ce1i(ar.iR Rerle- f ARTHUR FURST. Pw.Q, Dirrcyr, l.- srirwr e( CArwrkaf Illretegl. Uwivenilr of Saw Fraacisco, Saw Frawciace. MURRAY R OARDNP.R, M.D, Aao- r/ur rro/rnr of f rAol..R,. uwiver- d1T of SoaRer. Cali/orr.ia ScRool ef Medicine. 1 0. Awgeks. OFOROE 0 OEY, M.D. Dkrrtr, Fh- nr'.Nor•rfl C.wrer Resr.rcA libor.- tor1; A.wriea Iro/ru.r of Srarrp, Tlre /uMs Hooiwa U.iversirF SAool of Mediciwe. lidlLmote. RONALD W. OIt1ETTR Pn.D., Dbrr- rr. /aslr Sewwrr ReerreA (/wb. Caw- oer Cewrer of Ha.ail, U.heesrly e1 Hawaii M Marsos. Hwelrlr. GFRALD 1. (t/ FICH. M.D.. Cowadtear sw M.Iiriwr, Research Labuewary frw Allergic Di.eases. Maro Cli.ie ..d ForwdNiow: rrofirrr o/ bwerad M.Iriwr and lR.wrMwrsf.htr, Mayo Medical School. Roe4Mer, MiM. THOMAS M. (iOCKI~ M D. Asaorlre Professor of rrreewNa A/rdlrbr and Cowrwneirr Health. Selo. Hall Cel- k'a s1 Medici.e aod DeMisuf. /eesey CMf. N. 1. DAVID M. dOi.DF.NRF.RO, Sc.D., M D.. Arw.rinr Iro/rswr o/ IarAol. •rt1. TewrP/e Ussi.ersily HeaMr Sci- eKts Center. Pt,iladtlpAi.. PAUI. (701 DIIALrFR. D D S, Assnrl.n rro/rns.w o/ /er.a/oaa.l..tr. Hrvard ticlr.wA of /kw/al Medicine. tlwlow. 1.l:ONIDk C.l11lKTFIN, DSr•., Arwr- c.rt /ro/ru.sr a/ rs).~iarrt. (1rslila/c for Mental //eallir Seiewces, ('uReRe of Medicine i DcMislry ef Ne+ /erser. R.IRets Medical ScMaA. Piscalasvay. IRA (iORI:, M D. rrefrsun of /aA../- efl. Illusion Uwiversilr School of MeJi- cwrt; Chief of t.bo.a.w7 Srr.l.r, Veleraes AdmiwislrNioa Il..yiul. Wesl Roalwry, Maea. IOHN W. UOR ROD. D C C_ lectrrr in IdopArw.ry. Cltekea Colkle, Ureer- airr af t.owdots. Lewdams. GtRTRUDE V. ()OT75CHALL, h D, Aaswqw rro/euew o/ /i.deadrary. Co1rwlKi. 11wi.eail~ (:aMq. et nysi- esawe A Swgeo.., Ne~r Yort. A. CLARK ORIFFIN, Pr.D, Ne.A Dep.rrwww/ of fNetArTWr~, M. D. Amderw. HoaPical a.d Torwat Lr/- MMe. UnisrsNr e/ 'Ieaaa Medical Ce.w, Howre.. ARTHUR L. aROSS, iM.S.. Sewbr 1i.- tA.1w/Y, Southwest Researct+ IMi1sM, S.. Aaowiq. Tea. MORION i. aROSSMAN. MD., h.D, Aseorfaw Cd.kd tre/essee of Med1- tiwr. U.i.a.My of Caiiforwia liedled Cewat. i.ea AoRdts. CARt. C. ORUN7IT, M.D_ h.D. Ar- a.elerr Jw rA,siote~~ o.d tA~.rw.rd- qA, Uoise.w~ of Pewsyhraoi.OraL w/e ScRool of Mediciwe. MilddFl+l.. 1a6EPH 1. OUARNERI, PrD. Ae+r.E i.R Micr.ib/.Rtu: D1.eew, MkrN• J~HUkW rMediial~Ce.ur, Q..e.a Hsy+ul Cera AAR.Ii.aL Iw.k., HOD!( YA A. OUIR(:IS, Pr.D. Ar.riw lYr/i.wr o/ ('.rrsrrowir, and tCwrbwr- .rmol M.d.riwr. Usli.cceil~ 01 Cali- 1or.i. CuNqe o/ Mtdiciwe, k.Ma. FRANK E. OUTHRI/; Pw D_ h.Mn ar of E f. Cre.1l.aNonA SuN Ce1qa, R . H. •. HAAG. M.D_ he/irwr./ rbw coldtf. Medkal C.Reya ef YMRI.K Rictsiwowd. F. 1. HADDY, M.D, h D. ho%r. e.d CAsirn..w. Depru..rar ./ r~~d- im/.ys. U.iversiry of Ollalw... M.dk.l CeMer. OLlalw.wa City. IOSF.PH H. HAFKENSCHIEI_ M.D_ D.rerrr, Crdbtr/w.ewrl L/wk. The l.aw*e.w Hoyiul• A.sxiwe M Mrdl• ca.r. Uo/versirF of 1esw1ar/.wNa School of Medieise. Philadelphia. tit'.RNARD HANFS. PwD, rre%ee.r e/ NeeNA ScMwte, Cabfawia Slw ll.ku- .i1r, NorlrridLe. 112 117 I - -

i I RICHARD 1. HAVFL, M.O.. Asriu.wr rro/rrsor of Mrdli.iwr. Universil/ ef Califo.wia Medical CeMer, Sae Fra.- ciae. HERRP.RT R. HAWTHORNE, M.D. Cft.i.wsen. Drpsr wwwr of Uliversw~ of ressyhawia Gral..ri Sc~ool e/ Meliciwe. MNadel/idia. 10HN A NAYES. M D. A.seriaw •erfinlotisr, Ma" Iwrilwe of h rb/oRt, Rowe. Ciy Hoyiul. Roata. CI.ARK W. HeATH. M.D= Professor e/ 1/r/.rw .wI Dwrrsw o, HrdrA Sn.- 1rrs. Tufts U.i.ersNY. Mtdforil. Mtu. t•AUI.INE NEIiER. hD.. RrwwrA Auocierr M Cyrelory eaf fyrnrArw.4- .rT. Saw Frawciece Iwslilelt of Medical S<awces. S.w Frawcisce. I.AWReNC.! L. HFSTER. 1., M O. rro/ruor e.I CAerw..w. Dr/orrwrrar e/ O.srrrrws eaf Grwe.eluty. Medreal Colkp .( Sowt• Ca.oliwa. Cinr{rs/ow. ERRH CURTIS HO*F. M D, f M D, rro/ruor .oI Ch.irf"... D.ru.o+ e/ f'.prhiwrk RrurrA. Med.c.l ('ollqe 01 VwgrwMa. RKMwWd. RUSSFI.L 1. HOI MAN, M D. 1 orisi- awa Srare Uwrverury School of Medi- eiwe. New Oseane. OLE A. HOI.TFRMANN. M D. Rr- IrMtA frNMilr, Loh.Mt I.abOrlfOrj, Udoivasilf of None Danse, No1re D.wre, lad. FREDDY HOMRUROER, M D. rrrd- dtwr wd Dfrecter, Rit-Reseucf IrMI- hNt, loe. Cuweridte. Mass. ROBERT W. HULL, h D., rro/rssw ./ lfdst.r.f Sc4wcn. Florida SIaM ll.iveniy. T.Rabsset. RONALD R. HUTCHINSON. hl D. Rr- .rerrA Diea.r. Foy.dMiow fw fAa.- ior.i Reseaeclt A.pus. Mki. IIT RESEARCH INSTITUTE. C1kyt. ALPHONSE 1. INO1!NITO. h D. Au.• cMlr r.e/ruer ef rArw.releolr. FAel Catolh. UtiveseNf Scbool d Medi- dwe. (lrtea.iMe. N. C. HARRY I.. IOACH/M. M D, Arawliwt rerAefo~br. 1 e.e. Hdl HesMd; Cfu.i- ref rrro/r,.or .1 r«Aelo~~, c-olw.l,.a UmveleA)- Colk/e e( }fysanwe si Serteowti New Ywl OFOROE JACOBSON. M D.. fro/awr .ad Head. tsrrersmrwr of R../inlntr. Uwiversrr of Sow4r. Califorwia SAool of Medirile, Loe Arqeke. 1FRRY HART JACOBSON. M.D.. Di- rrrfor. D.risiow oJ ElicnorAfsinlotl. New York Ere ..d Etr Infinwuy, New Yal. 1U11US H. JACOBSON 11, M.D.. Asso- .wr rro/euw o/ Swtery and Direrro. ./ Swtird Research. U.iversily of Vte.wo./ Coilqe of Medkl.e. R.r- MURRAY E. /ARVIK, IM D. A.wciete rre/ru.r ef rA.riw.rofotl. AIAerI Fin. Mein CORe~e ef Mediciwe of Yeshiva U.eversilrd l>w t•rowa, N. Y. OSWAI.D R. IONES, M.D. St. L.le'a Ho.Riral, New Yorl. 1IVILI.IAM i. JUSKO. h.D.. Associate rrofrssor of rArm.cewar Drr. rw, CHwiraf rArwr.col4erNrs l.Iwr.lor7. Millard FUbwore Hoapilal, fluf/ab. ANDREW A. KANDUTSCII. h.D.. Sr./ Srlrwri.e, Tle /adsow I abora- lery. Ru Harsor. Me. ARNOLD R. KAPLAN. Psr D.. f/irec- ros, L.Mr.rory of Afrfird Grarrirs, Clevela.d Ihyeiiialrk Insoilwe aed Hospital. Ckvela.d. ATTAI I AH KAI rAS, M D, rro/r»or e./ Srw/er rftyslrlara. T1e Rocke/eRer U.iversiy. New York. HRATCH KASPARIAN. M D., A.sist- ewr Drertor, Crlw.vearf.r L.Aore- rorl; fwNrrrror iw tfrJiriwr. IIaMe- wu.w Medkal College .wd I/o.oilal. rAi/adclpbi.. ELIHU KATZ, h D., Aswcine f'.oles- wm ef Secbiotf. Uaiversily of Cfi- e.Nu. CRkNo. SIIIRI.EY 1.. KAUFFMAN. M D, rro- Irusr e/ rNblotl, Sla/e Uwiversllf of New Yorl DewwMatt Medical ('ew- 1ee, lkodly*. ANCEL KEYS. h.b. Dirriror. t.bore- rwt o/ rAy.bfotkef H1tkne. llwiver- silr of Mi..esda School of I.EIk Ile.his. Mi.eepdie. /OSFHI • KIRSNF.R, M 1), rro/ruor ef uslr/nr. U.iver.ilr of Clsicaeo School of Medici.e. Cbicqo. 114 i EDWARD 1. KLAIRER. M.D.. Srwwr Srir'ssur, T1e Waceskr Fo.wdsliow /or EapeNrweNal Biology. l.c.. SMcws. bory, Mass. IEROME KI FINERMAN. M.D. rro. trl}M and C/Y`JMe1/. OrrMre/rM rerAol.K). Mowq Sinai Sclrool of Me~ lcree. New Yorl. t F.TER H. KNAt f. M.D. RexarcA Professor of rsrcA/wy. Rewoo Uei- ver.Nf Sct•ool of Medici.e, monw. KtNNE IH P. KNUDTSON, M D., U.i- versilr of wa.Nqlow Sclool ef Medi- eine. Seattle. ALVIN 1. KOSAK. h.D. A.s.rlre rrofrswrr o/ CArwdurt. New Y..f Uarverwy, New York. RORFRT A. KUIIN, M.O., Ar.erWr rro/nror, Dirisiw.w e/ Hrwmwterf. New lerset SrNe College of Medkiwe, lerser City. STIO KUILANDER. MD. Professor .wd CA.irw..w, D.Nrme.r of (lbsrr- rirs e.d Gywrcoloty. Uaiversily o1 Lwd, LY.d, Swelera. MARVIN KUSCIINER. M.D.. New York Uwiversily Medkd CeMet. New Yal. CHARLFS W. LaBELLE, tM.D. Au1N- .u rro/i.sor of Ewd.owiwrwu/ Nf- tlrwr. tefferww Medinl College. 1'Uila- de4bi.. AARON 1. LADMAN, h.D, Professor ewd CAafr.wew. DerrMwwr of Aart- .w.t. T1e U.iver.ily tl New Meake Sebol of Mediciee, ANoolradfw. THOMAS C. LAIPf l.Y, M.D, rre%.- .ur e/ Pathology. Nerlfrwesleera Urd- vtr.hf Medical Sc1rod, CYkap. M/C/IAFI t?. i AMM. M D.. rre%onr d/ rerA.d..ty. New York Uei.ersilf Meli- ealCeuer. New Yort. N1U1. S LARSON. h O.. Hwyt h../n- .ar of IA.rnw....f.rtt. Medical CuRete of Virti.ia, RkMrowd. ROGER K. I ARSON. M D., CAir/ of Melrriwr. Freseo Co.My HosFiul. Fresm.. Cal. GUSTAVE A. I.AURENIJ. M D, Chief e/ Mrdiriwr, S/. Vieeea 1{oyilak Waeoesar, Mas.. JOSEPH M. LAUWERYNS, M.D., h U.. rro/rawrr O./aeerwr and Cheir- ww. Drprrwnw/ e/ r.rA.dotl Mf Min...nyee Aw.rowq, E ~yrala'er LMroruorT of rriwow.ry Hwotuw. Mf. Kal/wlielt Uwiver.iweil ht ls.veq Lervew, relRiw.. FDWARD I.EETF. h.D., O.Sc., trelre- s•w •A ChirwMwr. Uvoiversiwy of Mi.we- M,Ir, Miwweaplis. RI('HARD A. LlRNF.R. M D. Associate Mr...Arr. SaiN. (Yiwie awd ReseucA F.w.daiow. 1.e /eNa. Cr. CECILE I.EUCHTP.NflEROER, h.0.. Hee% OrP.rewewr o/ Cp.orArwlMry. Swiss Iw.rilrNt /or EaFerrweMa) Cr ea ReseareA. Lws..we, Swilaal.d. AVFRILI. A. 111?sOW, M.D., CAai- w.ew. Depwrw.rws of f•erAulotf. Y.M l/wiversilf Sclr.ol of Medicine, iiew Ilrvcw, (:.Mw. IRVIN F. I IFNFR. Frr D.. rr••frs.er of /arArwd.ny. UwiversNy of Mw.ewl.. SI. rarl. fSfFN O. LINDSETH, U/.D. t•wD.l1. Iwe 's Horpiwal Reseuch LalaraMry, St. .w/. U1iw.. ROYFRT H. LINNI'LL, h.D Arseei- re Ir../rsww of CAroNury, lj.i.esdy e/ VernwrN. (arwliqlo~. HERBERT L. LOMBARD. M.D.. M.r.H., A/Yfate. Cewnr Rrswr4 L- edtwr. New Ery/awd De.ct.esa He.. Md, no.1ow. 1. r. LONG. h.D.. he%,w, e/ r4tr. .wrr./ots, Sule Uwiver.i/ a/ lew. CaRqe e/ Medieiwe, /ew. ~MF. CLAYTtIN O. 1 OOSI 1, h.D.. M D_ HlwJwtr "nrnr of t/rM.A.r and rethdal (wwia S~c • Uw'we.sir~ ef Sowf•es» Cdi- L.e/ a1 Mediciar,l.. Ayele.. DONALD R. 1O11R/A, M.D, Aerrl.w rre/nasr 14 IIfIiNwr. Cor.eR U.Lee- sily Medical C.Meope. New Yart. /:L•NN/'Tll Ii//:RR11 l. LYNCII, M D., Sr' D., I L.D., Professor Ewwrprr of r.dloia*y eal CAai.rttlnr. Medicd l'alkte of SowK C.roliw., Cfrrleere.. 113

INES MANDI.. hr D. A,ilu.wr Iro/n- Aer n/ IlarArwrbay. Columbi. Unieer. .kr Colk~e of Pff.icuwe A S.wgea+t. New Yor~. 1(N/N H. MAN/IOI D. /.. D.M D. Irofruar .wI Dbrrr.r, f)rprrwrrwt o/ r.rAolo~Y .wI Orol /)iyw..vr. New /eree~ Colk0e e1 MeJiciwe .wd Dew- tkrr. lereey CUr. DAVID F. MANN. P"D. Aaerl.le rro%ur ./ rA.rw..cof..ts. Tewl1. ~~ T 3cfonl of Munw.cf. Mi.- FRANK ARTHUR MANNINO. MD A,dxw he/rsser of Mur/.k, ..wa Gy.rre/ory. Wewew'. .1. t.. A~ k.l'arM~/l/wi.er.NT oi So.Ihetw Celitwwi. Medical Cewter. l.ee Afteles. JOHN P. MANOS. M D.. Iw,trrrt.e M Yrolary w.J Rrr.rielo*I. Mekcd Co11qe of Sewb C.rdiw.. Ch.rleaow. CHRISTOPHFR M. MARTIN. M D., Auluw rro/r,ror ..f Mrli.lwe wl Dirrrrr. Dwniew of Iw/rrrin., D/4- t.ut. Serow N.N Cellete of Meliciwe. Iereef CitY. R. RUSSEII. MARTIN. MD. rro/rr,.w ./ Mrlkiwr. .wI Mkroaial..tr A l+a w.wolo*r..erlor calk/e of Mdiciwe. Ho.t/ew. REGINALD O. MA5()N. M.D.. Pw.D.. t•ro( e.enr .wJ cAo..n..w. 1~r~..tw.rr e/ rMAa1aryM uwiverwr of Uuh cd• kte of Mediciwe. S.h L.te Ci.f. MASON RESEARCH INSTTTUTE. WoeceMer. Mw. DONALD 1. MASSARO. M D. Ae+«#- •rt M/.uer e/ Mr/irMr. tkoefR 1v.suayfo. Uni.ee.hy School .f Medici.e. W..m.pe.. 0. C. CHARLES MCARTIII/R. Pn D.. P,y- eAslogJr. Uw/vrr,irf He.lrA Srrvka. Ilwvril U.ivereMr. CnwluiAle. Mw. CHARLES •. Ii1tCANT3, PN D, Ae,e clett Prefr"ar o/ sn//,. Naeth C.to- Iwa Slate College School of Agricvl- Iwe. R.kish. HENRY C. Menlll . 1.. M D. Arrwy e.i Nrol. f/r/.ravr of Prh.ioty. I e1er Stw Ueilnrdiv School ol Me/i ciwc. New (Ak.w. HFNRY D. McINTOSH. M.D . rro/.,- ,r ../ ffrJN iwr ow.l I)irrrror. Crli..- rwaofr LArwrrt. fwte Uwiverdtr Medical Cerwer. DwAsiw. N. C. FORDE A. MdVFR. M D.. A,rncirtr rro/tsrr of rrAelotf. Mcdkal C.d- kRe nf Sow` C.rdiee. CA.rkrrtiw. FDWARD McKEL M.D_ rto/r,wr .wI Artiwe CAoitwrww. Drp.rrw.rwt o/ /a/wioh. Medical ee+lkse of Sow. Cr.Nr Clwkaaw. Kl1LY T. MCKEI; M D.. .1ou.ciur Pr./e,wr o1 MdkMe. Medicel Col- lehe ef Sewls Cere/lw.. CA.rk+uw. VK'T(M A. McK1/SICK. M D. !r../r,- wr o/ MelkMt. T1e /aMe H.WIIe+ U.i.e..M1 School of Meliciwe. .hi. .we. ROSS L McLEAN. M.D. AuorJotr ho%err of MeMcMr. Ewroty I)wiver- ehf 3cAnil ef Mdkiwe. ANnN.. GERALD E. Mct'LEARN. M 1). D1- rreNr. lw,fpwr /or LA.riorwf (Jr. .erk,. ap.r oN r,)WAolnev. Uwiy verekT of School d INnr• /rl.cy. sPYlaee. WIU.tAM P. MCNARY. /.., MD. A.- eorirr r.o( ru~or~ o/ Aw.tawf. Ro.uiw Uwi.er.hr Scfeq of Meikiwe. Rmtow. NEAL L. McNIVEN. Pw.D., The Wor- c.+ler. Per.dalotr fer Pyerirwaw.l 1144noT. SMew.6wT. M.es. JULIA MEYER. M.D.. Au.al.rr hs- /e»..e/ Or.+ raA.+o.~ Uwivee.ir, of MMnY C.Rqe el DeMi.ny. CAk.". DOV MICHAM M~.D.. AaW.wt ho- ta..r o/ R1.t'Atiwltrrlr .wf Switrry. ustwersky 6/ Cdiforwi. School of Melkiwe. !.w Fr.nchco. •F.RNARD 1. MILLER, M.D.. Aulttsr M1n/ruw of AMtow+.. leReru+w McJi. e.l Collefre. MiR.de1pAf.. lAMES O. MILLER. M.D-. MD. rra /nevr o/ l,yrbWr' and r,yrMdo91: pirrrt.w, )tfrwr.f Hrolrh Rrwrrb iw- ttirrtr. Uwivereiiy of MicAig.w. Anw Arbot. CHARI FS MITTMAN. M D. Di.rttr. ap.rwwwt o/ Rrqlydwv D/rr.w.. Citf e+1 I/oFe Naiow.l Medicd Cew• rtr. Dn.ne. Cel. 116 I HUGH M(/NTGOMFRY. M.D, Ae..- tWe hn/r,ior of Afrlkiwr. Urai.er.i1T of Per+wsrh.ai. School of Mdici.~ M~r.PYi~Jc P. O-R. MONTGOMERY 1. M D rr%uer e/ ., rr4ef.K~- Tetr Sowherer. elical Sc~od, D.Rar. GEORGE E. MOORE, M.D.. Pr D. Dr- rrrtor, Roe.eR rtr\ Menacid LMi- twe. Mbb. N. Y. KFNNFTTI M. MOSER. M D.. AuWrw ho/n,er of AL/iria. Oeerhe/e.~ Il.iveewr Medical School. Wnhi.g- few, D. C. /IURI F.Y I FE MOTi.FY, M.D. M/tr .n. of AIrJ:riwr .wJ DMtrtr, Crli.. Rryirrrr t.~ssry,~ U.i.enity of Se>MAer~ C.Gfoawi. Se1oe1 of MeIF eiwe. I.w AwWks. EDMOND ANTHONY MURPHY M D, Sc.D.. Auodw ho/tawr oj Ib,triuk..w1 Mdkia. The 1.h.. HoMiru U.ivereiy SAsol ef Mdl- dwe. R.hMwwe. W1LLlAM S. MURRAY. Sc.D.. Si.i.r Su/ Sritwtbt. T1e /.cltro. Laler.- IWr. R.r Hetla.. Me. RICHARD L. NAEYE. MD. h./ewr ..d CA.irn.n.. arre""" o/ r.rlol. ory. P-,/...i. 3/Mell.i.ereilt Cd- Iqe of Medkke. Her.hey. OEORO R. NEURATH. fn.D., Mk+.- .wdytk.l /.ier.arT. H.whaR. Wu1 QltuMy. AI.RERT H. NID1?N, MD.. he%»e../ MeJirl.r. Drew PoMa Me~k~lnMMe Scb+e/ .wA U.isnMr ef So.Net. C.lifec.i.: Chief. rdww..rv D1.r.u SrnJew. Meni. Lr/4r Kiq H.yM.L Lae A.teks. OAK RIDOI! NATH)NAL I ABORA- TORY. O.\ Ridhe. Ter. . DONAI D M. PACE. Pw.D. rro%.er of rAydolecy .wt Darctor. Iw,titrn lor C.RMf.r Re.r.rrA. U.ivereUr Of Ne6ra1.. Liwcolw. KFNNFTII IAIOFN. PwD. Abrrr.w. aprrwrrwt .4 Mdr.r/r /Ii.doK.. He.hh Reee.rch. Inc.. RosweR hrl Diviriu.. BuR.lo. ALEERT R. rALMeR. h.D, A.d.rr rro/rsiw of rrAol..rl. uwi.a.ilf e/ Toleb. TokJo. O. ROSP. MARIE PANOWORN. M1, A.. aiw.wt Food Ter ,I nwI tenrn. f)eNrM.ewt oJ Faaf wn .e/ lrtl} wo/,.ty. U.iveI, of C.li/oew. D..M. IOHN W. PARKER. M.D. Area1.N rroltnor o/ rrbLm ~. Unher.il~ .r SoMherw Cdifasi. Sefoel ef Me11- eiwe. Lee Ayeb. MARY STEARNS PARSHLEY. IwD.. A.duw ho/raor of Awwowr 1.Oi- uetrh, «d Gfwtrew~y e1.h..N. Uei.eetilr Calle~e .1 r.r.tc+w a sw- Rce.rl New Yar\. EDWARD W. rELIKAN. M.D.. Crto4• ne..k alrtiwewe o/ rA.rww,dov .wI ErprMwewed TllerqrrMa. Daur Udanilr SeRed .1 Memki.R ReR.~ CARL W. MAERCE, M.D. Pw.D see iwwof Arr Wi .wI Mie.ohfe~ liw. u~a.rr Se~od d Me~iei.e: rrw o/ Irt,- lewi~ HeeFiW of Se ~Le.iti S1. UIt. MALt?OLM C. MKN. H..D. lr.par I C.rwwrwNy Me/klwt ..f h/Mt- Nr .,., U.irenN~ of Sawherr CdMar.l. SeU.M ef MNid... Los AqeM.. OTAKAR ). POLLAK. M.D.. InD. ExenW.e Obeew. Ds.eY Mdk.i Re- .e.-b CeMn. Iwe. Dwer. Del. MORRIS P011.ARD. fMD. Dirt~ N rt~D~w~NMt. D..nt,U I- K T~ C. M. POMF.RAT. PN.D., Dberw o/ .f Rt.trr A, raobr Pwwir tkrw Medical Rea.eek M1 t6 C.1. S. N. M/IADHAN. M.D Pw D A . .h.. eM Co'Re~.e ~ MeJkiwe~w.•iRMr ~ D C. H. R. PRATT-THOMAS. M.D.. M/r. .o; o/ r.rRol.y1 M4 eNnIDe.~ M Co/k.e of Sonth e.e.IM.. C..rte.m.. PROCESS A INSTRUMENT CORM R ATION. BeeokIM. N. Y. MARTIN S. MtOrfZEI- DDS, CW/. Detantwwwt e/ Or.f r.rAel.~~. New.r~ (•i1y Hoyil.l. New.et. N.1. 117'

M'AI TI R RFDISCH. M D. An..ri.rt rr.•h1t.N of ('llwsr.l t<IedKw. New Yarl ltwi.ersirT School of Mediciwe. asid NYI/ Re+e..ch Ser.ke. Odd.ater ltfewMxisl N..yitd. New Yo.t. TIMOTHY 1. RF.OAN. M D. rr../rwr e/ SIr/iriwr Dirtrter. Dirl.io. of CrLor.wrf.r Dbr.v,. Co1k~e of Mediciwe a.d OrwtiarT of Ne. /ersry. Near hrser Medical School. Nea.wt. WIl //AM RFOFLSON. M D. rro/eewo wd CA.kwsre. Der.rrw.rwr o/ Mrlkd Owro/ety. Medkal CoikSe of VirRiw. Rklrwwrd. LYNNd M. RP.10. M O_ Mo/i.cA ho- ,.ww~~ r.rAul.rts. Hw.rd Me.Ncal CAriwrw. D./rrw.r.r e/ r.rholoef. Cfildrea. //oyitd Medical Cener. Soneo. HORART A. REIMANM. M D. rr./ee- ,er e/ AfrLrlwt. HeR.aw..w Medical Colkp ..d /1o+FM.l. rli.delpi.. RaL1.AND C. RFYNOI DS. M D. Ae- ,hYwr rrw/ts.er e/ rrAole*1. U.i.er- W~ .f Teeae Sow\.enerw Medk./ Scbd. Ddlu. V/(TOR RK'HARDM MD. CAk/ ./ Jrttry. rresAreri.. Medical Ctwrer. Sa. Fr.wci.ee. ARNIS RK'WIERS, hr D_ Ar,ori.nt rro/tuw of Uwi.ersi/1 of 3.w`te. C e..ie ScAool af Medkiwe. L.e Amrka. WILl13 N RIESfN. Fst D Stnbr N.- ehrwdd. Cqe Seirwrts diebtew. IIT Rew.rA IMNsNe. Ctiky.. DANIEI. R. RIFKIN. fw D. Aal.raM he/ta.w .f CAewkd 'Nofo~l. TM RocleRRa ll.iwnNr. New Tat. R. H. RIOOON, ND. rn/euw ./ rw sh.Apf~ UNe.~tf .f Tea.a Mdk.l R.a.c~ Od..M... SYDNEY C. RRTlNRERO Pw D., h./esr of /.r/ere.fep. lj.leMeY fr .f So..Aer. CdMee.ia. Los Mydea. sPNSON 9. ROE, M.D.. Aual.w h.- /eeu. ./ S~. • Ci~ir(. Cr~.e S.r- ~~ utd.«.N:':f Cdu«.ia School .I 1~1e/ieM., 3.w Fr awc Mc.. JOSEPH H. ROOE'RS, M O. H41 Name of /ewe IIo.rMd. Oad.de.. Ala. RObI:RT C. ROSAN. MU. Au.Kwrr rr..f1'.YM al r.rtAo/..ee .o.f rdJ.rrks. w. i oui. Uni.ersirl• S.AoeA o1 Me.N. ei.e: A r.ori.rr rrriloG.rbs. Cardiwal Okwwow Menwrisl I/oyit.l for Chil- dre.. St. I onis. CHARLES L. ROSQ Pw.D. Cliwk Dktt- Ir; Directo+. Norwwtiee Atiwg Stard). VeMeswa Adtnini.lratiow OapatieM Cii.h; *ewow. /OIIN A. ROSFCRANS. M D. As>.- eint ha/t.uv .4 rArwr.rob.gyMcdi- ed CsIMW o/ Vi.eiwi.. Vksiwia Cow.- w...eaM1 U.i.eraMr. Rklwowd. /OIIN R. ROWLANOS, rw D.. Sr./ SrMwNer. SeMb.es1 Rese.aeh Ls1AMe. S.w A.uew* Tea. /F.NIAMIN A. RURIN. IM.D Ass/n.wr rrofts.or ./ ruNle Ne.lr~. V.f1o. U.i.aaAT Colk~e of Mediei.e I/ar. tww. RONALD P. RUB1N. he D. rro4s.or I rA.rwreiot,. Medful CeRqe of kRi.is. RkMred. HENRY 1. RUSSEK. M.D. hesidrwr. The Rwrel Ferwd.liaw. ~.c. StNe. Istaead. N. Y. W. C RUSSEI.L. MD. U.i.ersity of Te.ae MeJicd Ceaer. Horstew. WAYNF. L. RYAN. /trD. rro/ruor o/ RwrAewavry. U.i.er.ilf Of Nee.afJa Co1kSe of Mediciwe. OwtaA.. rETER F. SALISMURY. M.O. Pn.O. Ne.d, fwrtw,i.e Teewwsewt Cr.rer. Saia /.ulph HeyUA fwl..t, Cd. rAUi. SALTMAN, tw.D. Anl,wr rr. ..d NerM/ow. ..r ~ ~~.tRe Sew~ ~r. cdNoe.i. Sd.d Medkiwe, Lea A.ycka. ULRICN H. SCHAErrf, M D. Obee- ae../ Ntr.~A.rtw.r.l.~f. Masow Re- wwck IwwU+Ae. W.roester. Mw. NMOFN U. SCNLE(lEl. M.D., heD.. rr.knor owd ClWrwi.w. D.r.rrwuwt o/ 3rrN•f. Trlw Uoi....ity ScKsai of Me~kiwe. New Orkw. ALVIN R. SCHMIDT. rw.D. Dktcror o/ Corwse/iwg. T.fl. Uuieeraiy. Med' ford. Mar. IId IAKOB SCHMIDT. M.D.. Iw.D. A,- N,rEwr rro%iser o/ e/ecAtw.leN~. D(- /%llO/r of &10/orK/I SfieAfy. State U.i.eeshy of Ne. Yael w Sre.y Rroot. Sto.y llcoot. ISAAC SCHOUR. D.03. rw.D. D.Sc Dr.w. Uwi.ee.ily of IRiwois Collqe e~ De.lislrr. Cbkayo. SCRIPPS CLINIC AND RPSF.ARCH FOUNDATION, 1o l.Ra. Cd. MAURIC@ S. SEOAL, M.D, CNwind rre/i,.er e/ MtdhlMt. Trba U.I.er- wf Scfool ./ Msrid.e; Drecr.e, Dr- pnw.ewr ./ Idd.rbw TAee.p. fa6- 10, CMr I/oeMal. Reero.. CARL C. SELTZER. PwD. Newwr.F Re,.=.rA A..er(re. lhdedY Mrweww. Hw.wd Ud.eraMr. CwsMiye, Mw. LUCIO SEVERI. M D. Dreehe .rl D.=w. /rwlrMt e/ Awar.wS .wd rrAd- U.h.reilD ;`'~'r~~ i..R1W~,. CHARLES R. SHAN; M.D. CAlr/. tre• dew e/ Aftdiaa/ Ce.eeics. M. D. Aa •ees. H.yital ..t T+.er /wtlitw: h eae. N 1feLdT. TM Utti.u.ilf .( ew M N..n.rtrlMrM... CHARLrS e. SHERWOOD. M.D. w.` ,iar.r h./taw e/R.Ns1ft1. U.i.w. wr et Roc4crer Sc~e.l .1 MsMds .d Desriauf. R.deMCt, N. Y. S11O11 SHIRATA, M-D. rw.D. hn/er riw N...il Sdrod ef N.wa1./.. OIENP. M. SMITII. hr D.. Aad,r.w rro- ts.. e/ rrxAolo~~. I/.e.wd Medical MssacMs~re Getwd 1d. Roslow. LUCILE SMITH. Ft..O. rre/taer ./ lLrAewei,n7. D.neaeM\ Medical School. H..o.er, N. N. LOUIS A. S01.OFF, MD.. PMrAe P. l~e~ Di Sse.kv h./tafnr hytw+ M./IcMe: Dite~rr.r. Ra M+rrR [ Laierr.ry. Tes.'la U.i. rereity 11saRR Seiewas CsMae, ffia SH~FiM1DONN C. SOMMER3, MD. Di.t`. M N T-6«rr«k,. Lewot IIiM Nea- tr• Cwnkr rr.fe,.er e/ r.r4dr.,. .li. tMC.Rqa of MpaF el.w. R St.eM.we. Ne. Y.st. ERNEST 3ONDIIEiMER. fwD, A.... c/w hefeafer ./ 1f.cAe*slrrT. C+4 Iqe .f ~.m1rF. Staw Uwiwnlry ef New Yael. Sre.e.a. T. M. SONNEBORN. IM D. D1ai. ~r!!Ard Je..kv e,ar N ZedsRT. ..w... Uarseeit~, SAM 3OROPM lr.D.. Nea, D.r..wur N M.n.Me/ecrl~ CM~wlrnF. TRn lassisaft /ex Cu.qer Rsuwek lM.. SOUTHWEST RESEARCH INlTI. TWIA 3tr Amil..K Tu. DAVID M. 3TAIN, M.D Di.ear Ow [.r~w.w~ l. ~1. trw{cdd. ~ oot1M N. Y. ALF.XANDER SlOCK, M.O Aarlrrr , DAVID L. SIMON. MD Lsw.r... M hMtw~+~./ reJfrNcA Dttl. Unl.w- lanwd MedkMv. Ci.cT.aMi Oe.ad *Y Me+teu CeMee. DrrRaw N. C. /Io.FN.I' Clki..N1. FREDERIICK 1. YTARE, M.D h./b.' ERIK SKINH/S1. M.D. CAk/. DrNH- +r N N.~.1rI.n, N.n.r1 t~rth~nMT ~./ . Rh~ee{ N.q4 SAeed of h~liie l/e.MR R.n.a C. NAROLD SIEFPEP. M.D. Direwa NATHAN H. 31OANE. /w.D hy/e~ of lmA••M.rk.. MeHwMw M.qi.l. e.. ./ 1/erAtws/.rr. The l~.LanN}M~r' .1 Tewweeaaa Cewrer be ua Ne.M` SrIawoea MewPbi.. /M'K P. STRONG. M.D. Aws/rr . ree%srr e/ rwM.InrR lwWar 3Wa THEODURE A. SI.OTKIN fnD. Ar Ussivervit1 School .f Mdid.R Nn. `,br.M rro/ea,w a/ r~eawwaMtS. O•M•-. DA. Wti.ecair MeMe.t Ce.us. D.r- ~ haiw, N.C. MARION R. SUL2BlROlR. M.D. hr Nwe Md CA.Inr.M. Drr.r.r.r.1 ./ ON.OROB W. SM1!TTpRS, MA. Aue- Ore.u4bdf awd f Nw eYre iw r«Aeloyr. NwtR.e.ler. U.1- Y«t U.i..rdlF-/eMn.. Modkel QN. verwr Sledicr Sebd, CRicyo. 1Er, New Yal. 119

RENATO TAOIURI, hM D.. Auarb.Wt rro/n.nr .f rsKAe1e11. Or.AwN Sdool of b..iwc» AlinMwMratioR /l.rv.rd Uaiveniwr. Roslw. DAVID W. TALMAOI; M D.. DirMor. MeN-M..(wR LrwR /wuA.nt. U.ivenMl et C./or.es MeMca1 Cewler, Dewvet. MARC D. THAMES. M'.D, Sewier Re- ar+rc# F.Ro., M.~e .wR Fe.w L/Mrs. Roeleerer. MM.. CAROUNE REDP.LL THOMAS. MD. he%nw Ewa.M.u o/ AbJkMe. TM /eRr NoEtbs U.Ive.eMT Scf.d .1 MeJicine. 11.Miwore. 1FROMF. F. THOMAS. Pw D.P+'*u.+ ./ Sw/.er) EwRf....Me. Uw/.erutl .f CdHer.i.. Rerleky. /AMES !. P. TOMAN. Pw.D. ... ad Chdrwwa. DeFrtwwr ./ r - ...c+de Chicap Medical ScMal. l. rirwe (~r. a MeAical Reara.ek CMieq.. ANDRlW M. TOMRTSKO. Pr D, lvv.- Nene../ Dhtr.or of ReuwrL. lMw Lal.rme.leR LN. Reclesaa. N.Y. IANET TRAVEI I.. M D. Aaaxilre f•roleuue o/ CGwk./ PM.w.wreMft?. CorneR Uweniry Medical CaOeRe. New Yaet. LIE SHA TSAI, PN D, Re.earrA Ast el.w Ira Ldldotf Yak UoiveesMl Sc,nel ee Meliciwee ke. Havew. Ce... GERALD M. TURINO. M.D.. Pro%ua. ./ Me1klr. CdrnrM. U.ke..Mf Cel- kRe e1 Mfski.ns A S.rReows~ Ner Y.rl. D. M. TURNlR, PM.D. NeoJ. Drp.(- nw/ of Dr.R filerab.Mrw .wI I/o- tAerw/Mrp. Hada.w LaAorMerk. E.- r.*., LII, H.rropwe, YorlsNre. EaR- t.d. UNIVERSIiY OF SAN FRANCISCO. !.w Pr.wd.on UNIVPRSiTY OF SOItTHERN CAL/- FORNIA. L.e Aqde.. EI.I.IOT S. VPSeLL. MD, Iro%ner.wl CA.br.ow. Dep.rwtav of /A.nw.ral- ofr. rrweayl.awia SraN Umar.Mr Col- k~k eI Medserr. MaM.+ S Hee.Mf M.Iua/ (*es.r. Herrer RRANI%IAV VIDIC. DS. Pro/ri.w of AwN.aM). OealeloWn Universiq ScUools of MedMci.e and Demiary. Wa.hiwWoq D C. R(H/FO A. VIDONF.. M D.. AuotWt fho(eua+ ../ r+rhoGrt.. Yale Univer- sily Stlrwl of Medieine. New Havew, Cw.. rFTF.R K. V(KiT. M D.. Proftaar y 116r..Mdor1. U.iversiy d Waddng- ww School d MdicMre. Seaurle. E. D. WARNER. M.D, hu/e.sor o/ %- .Arl.rtv. SrMe Uwiversi/r of /o..a Cd- k" d Melicin.f Iowa CMy. SHIFLDS WARRFN. M.D.. D/.eae..f L./r..wrw.. ('owrer R.w..rA /wM1- Iw. New Ews1..I Deacower Hoyi- y1t mwa.. YASl1SH1 WATANARR M D.. Aao- .i.n Mr.M. TMe MiMar Inriawe ef A..newrt .wA Rio/oq. LARRARA K. WATSON. IwO.. An4(- .rw L..rr...6Kix. Ms..cMntlts ()ew. er.l ILrsFiral; Rear.rrA Auoriue M fl.rtrrid.lr o./ /wrw.rswofop. H.r- t.r1 Medical Scfno4k boMOn. L!E N. M/ATTENRERQ, M.D, rrofer- ..r o/ P.rAolmUnivenirT af Miw- ....1. Me+6e al ScMool, Mirmea'olis. 1001" S. WAUGH. M.D.. f•.o/t•ra+ ol CAewM.t.f. Mass.cMseHS InaMvife et TecMr,saRr. Commluidle. RICHARD I.. WECHSI.ER. M D. Cfiw- kai r/1y.JoloRfd. MonleAose HoqM.1 InwisMe ef Rese.rcd. PiusAw{b. tOHN V. WF./L• M D., Ani.rw ho. /iw+ nf MtIYrMt. Uftiversitr of Calo- rale Medical Cewkr. Dewver. A. WEINSTOCK. hMb., Rewarrh Iio- eAeiw/w. 1.1/i Stlrwtt. D/vns/ow, IIT ResewA IwMwe. CbkaRe. RUSSEII. W. WELLER. M.D.. r.rAol- .ow. Mewroli.l Hoqilal eI CitieMd C..aI. rVts! Citieskr. Pa. A STANI CY M'ELTMAN. h. D. Ano- tMMe rro/r.sor o/ PAra..r.4 o~v ow/ Rt.w.rtA. R/oaHfw CdkIe o/ fff.r- woae1. 11••o11yw. N. Y. 9 SIMON H. WENDER. PnD.. Reu.rth DANIkL'H. WISEMAN. M.D. A>r/at& tr..feaw of I:erAsau.r. Usrvenjll .rat Iro/ensw o/ /t/w.ks. U.1.e.y~ d UllaYoe.a. Norwawt. .f S~wther. Cali/oe.i.- CYIk..'~ D1. DUANE O. WENZEL, PN.D.. h%»er .wf CAwwww, Dep.rrwtwm t A.nn.. • vMrun, Lo. A,yeks Cawf Oe.err HosFird. Lw Ayeks, tolori .wI To,/ro1e~r. The U.i.er.MT J. EDWIN WOOD. M.D~ f.rr.rt.. b of Kaws.» SAod ei T1.rn~cy. Law- - rence. Mtlu w. Mross UsIv..pAy febd ./ THOMAS C. M/ESTFALL. Pw.D, ho- Ituor .f r/1rws.rol.K,. UnivenilT e+1 VirRini. ScMoul of Meiicine. C'Asr- lolltsvipe. FREDERICK E. WHISKIN, M.D. C.M, Dierw.. D/N.faw of N.dM .n/ ler- aso.lirr. R'<rW.Maw. TM Ap Cenw ' .t New Eaml..d. /ne. RoNO.. ROGER 1. WILLIAMS. M D.. Aro/e...r of C'Arwww~: Drer.or. ('layrera 1<'oaM.- /.Now f.orrAe/wir./ fwuoorr. T4 U.i- verswy oi Teaas. Awriw. MsRra.e. RoMO.. SUMNER QiOOD. N M.~. Aul.w hofea..w o/ ErMj.Rf. TIM I.R.. tim Re• f ScR.ol .t Mdl 1OHN P. WYATT. M D.. o/ SrtU.~d .d, w ~L°"`' ~r "'""''r KO/l YOlHINAO PMD Caswr in L.t~.fR11..1di, RNa1le~.~., M~ 120 121 I

INDEX OF PRiNCEPAL INVESTIGATORS Arcos. 1. C.. 17 sin& R. 1.. 49. 50. SI. 32. 33 Aooyse. F. M. 33. 54 Aouf. R.. 95. 96 Rrrist. A. S.. 25 eushct. D. 1... 11 Chalon. 1.. 10 Cdlim. A. C.. 63. 61 Co+ra. P. T.. )r.. 97 Ibwney. ll. F.. 31 Fiakrus-Myrhed. S . 9f Foaer. l. A. )3. 71 /;reeman. A. F... 22. 2 ) Fua. K.. 65 (;colas. M. C.. 26. 28. 31 (iessner. T.. 72 (;ickw. 1. E.. 13. 11. 13 11all.1.. M. 72. 73. 7/ llamo.h. M.. 32 Ilamo+h. P.. 3). 34 /teim+tra. N. W.. 66 llenry. C. 1.. 19. )) I/ojnac\i. 1. L.. 55. 56 1lwchimon, R. R.. 36 IanoA. A.. 27. 28. 36. 37 luslo. W. 1.. 67 Komi. R. E.. 12. It Kuenner, K. E.. 24 Laoha. A.. 67. 68 larrence. E. C.. lit Lynch. H. T.. 9. 10 McCkarn. O. E.. 69. 70 Meier. H.. 20. 21. 22 MfleheR, J. A.. 74 Mw.a. F.. 73. 76. 77 Ntisaw. D.1.. 78 79 Oesch. F.. 13. 16.78. Pierct. C. W..... 89. 90 R.Mnab, 1.. 97. 96, 9f R.unwser. R. E.. 19 R epiwe. l. E.. 3!. 39. 40 R eynoid.. //. Y.. 11.11. 42 Ryaw. U. S.. 4). $7, 58. 39. 90 SaMry, R. V. R., 60. e1. 82. !f3 Sio..e, N.. 17 ~ Sto..el. T. P.. 24. 85 Traas. l.. 29. 30. 83. % Unarwe. E R.. 9/. 92.93 V alner. S. F.. 60. 61. 62 Weinbaum. O.. 43. 44. 45. 46. 47. 1,. 91 Wtanmalm, A.. 62. !17 Win. ). A...e. 70 Woda. !. A.. 20.94 Wolt. O., 23 122 I INDEX OF Ahram.. W. R.. 4e Albano. W. A., 9 Alsrer. P.. 62. >R7 Amkrsson. K.. 65 Aune. T. M.. 90 Sxr. D. S.. 69 Nanaal. S. K . 7? Seauy. K.. 29 8elkr. n. 1.. 91 8ing. R. 1.. 49. $0. 32. 33 Bu.,y.e. F. M.. 33. 54 Sk.+.E. R.. 93. 96 Ilr andwein. It. 1.. 75. 76 IhuJrick. 1. W.. 26. 2• Mui.1. A. S.. 25 Carp. 1/.. 37 ('haMw. 1.. 10 ('rutchky. D. 1.. 3o CunliQe-Sc.rner. T. L., 20, 21.22 Curren. R. D.. 111 d 1)amiua. V. V..16.91 r Downer. I1. F.. 54 Fusrer. l. A.. 33. 71 Foa. R. d.. )N C•lnahi. F.. 70 (filmaw. S. C.. 94 (ila1t.11. R.. 13 HaM. L. M.. 7:. 73. 74 Ilammer. R. F.. 71 Ilamosh. M.. 32 /larel. S.. 36 IlateheM. P. C.. 70 Htimstra. N. W., 66 Iltery. ( •.1.. 19. 3 ) Ilejnacki, l. 1... S6 /lulchirson. R. R.. 56 lanoR. A.. 211. )6 Kaprin. i.. 98 Karr. S. R.. 35 Keith. 1. M.. 411 Ko.trn.ow. M.. 97 Krwai. R. F.. 12 Kremers. P.. i ) K ucich. l).. 1 f. 44. 46 Kueppen. F.. 47 1.ai. D. Y.. 17 1 aneiuwe. (;. V.. 714 i.aroman. C.. '/t, 31 I awrence. 1:. C.. 1111 I cc. C. T.. 44 l.ewicki. l. A.. 77 SENIOR AUTIIORS Lively, /1/. 0.. n6 1.H. C. Y.. 93 t.ynch. H. T.. 10 Mawl. L.. 13 Marks. M. 1..6).61 Manin, s. M.. 93 Mc('rae. R. R.. 97 Mcl.emore. T. 1... I 1 MerriM. W. W., 11.11 Mo.reMo. D. l., )3 Mullisan. 1. l.. 55 Murad. F.. 76 Nahiwo. N.. 86 Omh. F.. 711, 79 Pa.kau. F.. 14.15 Pauti. a. U.. 24 Pawlik. O.. 51 Pierce. C. W.. Ile. N Ploatiw. O. 111.. 2) Rasrrwsun. R. E.. 19 Repine. /. E.. 39.40 Reynolds. H. Y.. 42 Ra/u/gi. P. K.. SM Rost. l. O.. 67 Roweq. P. P.. sO Ryan. l. W.. 4), 39 Ryan.U.S..S7.90 SarwiMan. O.O.. 31 Swry.s. V. R..t0.t1,t2.11) Scher. M. O.. 91 Sershen. H.. 67. 6N Sloaw. s., .! Sloane. N.. 17 Slantm.l:. R.. 69 SrendaM. o. 1.. Is ilowl. T. P.. ta 7 arhtonen. A.. 99 Tareka [)a SiWa. A. M.. )) V.Nner. S. F.. 60. 61 Voge/. K.. t6 Weinherg, 1). S.. 92 Wtishaar. R. F.. 52 ~ Whire. R , ?7 WuJa. S. A.. 2(i Wong. P. S.. «s Yamada. K. A.. 34 Ya.rNaie. A.. )(1 Yothida. H.. b Ya.hida. Y.. 22. 23 Yu. S. Y.. 37 Zimper. M.. 62 12)