Council for Tobacco Research
1985 Report of the Council for Tobacco Research - U.S.A., Inc. [St]
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- 25 Sep 1995
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ANDREWS OFFICE PRODUCTS CAPIIOI IIEIGIITS, MD lKl
IT ~ EXHIBIT
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65100 7581
CTR MN 012536
ZZOOI 'A'N tAaN 'anwa.V pJlq 1. 006
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S('IFNTIFI(' ADVISORY H(1AR/1
In 1 he ('nuncil for I uhaccn Rescarch 1/ S A, Inc
as nf 1)ecemher 11, 19AS
1 I UN (1 lA( ()IISON, h1 I) , C'hrrrrman
ln.rrh Rrcrrltrrrn r,.r/rturr n/ MrJtrnl and
1fr.rlrrKu nl .C..r nrr~ (rm.rnui)
/'r,./,'tt,n u/ thr J)rreprtrnrru rr/ MrA/rinr (rmrr/rn.1
Iln.vrrshy u( ('hicaRo
('hrcaRn, I/lrnms
RI('/IARI) 1 IIIN(:, M 1)
lh,rrrur of f t/yvlmrnlnl C'nJrnlncr and Srrrnrt/.r I)rrrlnpmrnl
IlununRlun Medieal Research Ins1i1u1es, Pasa(lcna, (ali/urnia
I'r.er,nc A.t,n-.ntr
('al,furma InN,lute of TechnolnRy, PasaAena
J'.n/rt..n of Afr4rrrnr(rmrrnut)
Itnivrrsily of Snuthrrn (alduenia S.hrN+l or Medicine
I os AnRrlrs, ('aldornia
I)KIIMM(INI) I/ 11OWI11 N, M 1)
rtnJ l/rnJ
1).t.aHmrnl uf PathnlnRy
I /nivrral Y n( Mani/uh1
I leahh Srrrn. ea ('en(er
WinniprR, Canada
h11(IIA11. 1 IIKI NNAN. M 1)
1'rrtlJrnt nnJ AfrJtral Anrrhv
MichiRan ('ancer fnundalinn
/'ra/rtt,n n/ AlrJtrlne
Wayne \talc I/niversily Sch.N.l n( Medicine
1)ctrnil, Mi.hlRan
)(K/ P11 I) 1 1 1 1)MAN, M 11
f.du.n rn ('A.r/. )nurnal of ImmunnloRy _
S.in 1)ieRa, ('aldornra
((rmMr (rmrrrtu.). Research Institute nf Scripps ('hnia
Sa r irps ('hnic anti Rrsrar: h I uundah..n
( a 1.JI., ( alr(o.nra
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MANI Kfl) I. KARNOVSKY, Ph 1)
IParu/J IT // Mtr J'r.rJra,n ,r/ Ri.rlue.rnl ('h. nutlrr
Ilarvard Mrdi.al Srh.wrl
I1nsUln, hlawachusrUs
III NK 1' I I.YNC'I I, M 1)
J'.u/rt~rn orr.J l'hnrrman
I)cparunrnl ol 1'reven(ive Medicine and 1'uhlic IIr:JIh
Plu/rtwr n/ Al.Ju.nr
/'rrin/rnl. I lerrdity ('ancer Institule
('reirhton I /ni.crslty St-h.wd o( Medicine
(hnah.t, Nrhraska
(i I/ARK Y I'll K('/ , M I)
Arnrru nn ('nnrrr .C,.rl:lt C'rntrnn.nl Rr.rar. h
I /niveraly of ('oloraJu Ileallh Sciencec ('enlcr
1)enver. ('nlurado
1
GOKI)ON II SA 1(1, t'h 1).
J).rr,7fu
W Altan Jones l'ell Science ('enler, Inc.
Lakr Placid, Ncw Yurk
SI11'1 IK)N C SOMMI KS, M.D.
S,7rnN/rr /)urN.rr
lht ('ouncil for Iuhacco ResearehlI.S.A , Inc.
('hnrrrd 1'ro/ri%w .r/ Pruh.dnKr
('nUrRr of 1'hysicians & Surgeons u( l'nlumhia tlnivcrsity
New 1',uk, New York.
ticlealUie Slaff of lhe ('nt..cil
SI1I'LIX)N C. S(yMM1 KS, M f)
Scrrntr/rr 1lrrrrMr
IK)NA11111 1(11(1), 1'h l) IIAKM()N l' McA1 I 1Cl/ lt, /.
4.vNunr At.,nunr Rr.rnr, Ir /In. r l..r
VIN('I N! I I ISANII, I)M 1). 1)AVII)JI(/N1 , I'h I)
Atsru'rntr Rrirnr.h nu,rlr.r Atuxrnlr Rrtrnr,h Irnr,rn.
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A.licr 1'rnleaN 111)
t'nmplr/r.t /'rujr.N . 190
In.lr. ul 1'nn.ipal InvrcliRilort .`Il.
INTRODI I('TION
I his rrpnrl rrcnrds crveral nnleworlhy events in reRarJ In 1 he ('mrncd
lua/, il crta a('uun.il reCnr.l for a tinRkl yea hecauar ll cun/ainc al..ua.lc
ol 1_1 prd.lrchrd carrnlilk dlKumrnla acknuwltQRmg l'uuni8 clyqwrnl Mu.r ..1
IArar rrlv.nla werr puhliaA.J in 191{S white olhers wrre puAliahavl Irca reft rnllv
AI Ira.l .'JIS2 rrpnrla acknnwlydRinR f'nuncil tuplwnl have apPrarrA in Ihr
lurralurr amar Ihe /'uuncil heRan prnvidinR (unda 1.o indelwn.lrnl mvrcUgaa.ra
duurR rrcrarth m am..t,InR and health 1 hn indhslta 1ha/ 1 hr (uuna d'a
rrcrar.h proRram is uur u1 the minl tarnsive ul rh kmd anywhrrr
(tnr rd Ihe ahclracla repteaenla whal may l.e aa.nhrr firsl putd.caliun uf a
Cuun. d aupl..rnlyd aludy rn a scientific tournal in the Pruple'S Hepubin: o/ 4 1,01,1
IlurinR 1941, William 11 (:aldnr., Ph 1), rrlired frmn the ti..irln.fia
Advruny huud whi.h he joined in t9/2. ' he alcn srrved suhcequenlly ac Ihr
(uunrd'a krrnlifrc 1)ueclor.
loininR the IloarA in 1985 was anolher AiclinRui.hed ccirntial, Man(rrd 1.
Karnnvwkr. /'h1), whn is 1latuld 1. While /tofrauw uf (Ii.rh.Rl<al ('hrnualry a1
/larvald Medical Schtwrl, bWnlon.
Since ila eslahlhhmenl in 1951, thr ('nuncil has nradt svailahle mnre Ih:m
$IOO,flt)f/,000 (..1 reararch by 551 scientists (rK 9:4 miginal projea% in 290 medi..11
.ch/Nrla. Mnpilals and teuatch inslilulinns.
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AB.STRACTS OF REPORiS
1. Ca.eer-Relaled S/.d1ee
PLATf1 I T-OFRIVLD GROWTII FACTOR: A I.INK TO MAI IGNANF
7 RANSI ORMA fI(1N
Plalekl-dnived Erorlh faclo. (PtI(;F) is the major mitogen of human serum Ir
shares slruclura/, funcUnnal and inlwunolrKical pruperlies .ilh Ihe prediclid pro/eu
pr-n/ucl of the vird oncolene (v-an) of Ihe simian sarcoma virus (S\V) /luman
aLAlauoma, fihrssarcoma, and osleoorcnma celas, which eapress Ihe proln onculrne
(c v.) Mrnndng of v-srs, produce and secrele Initosenic molecules Ihal ..e recoenurd by
slwc.fic PIM:1 nliserum 1M parlral seauenca of e-s.s cUNA from human
ouernarrnma crlls rs shown 1o code for the carhoaylrrminal region u( the PIKi1 2.haun
of the biologically acli.e molecule of Ihe drmerie Plrtil .
AnawraMs. N. N e/ af.
('anre. (-ellt !/G.arrA Facror/ an/ Tranr/uemation. Cold Sprmg 1larlwr I ahMualury,
145 -1i1, 1915.
Oq1er rrplr..r: Nalional InslitWles of Neallh, the American ('ancer Society and the
LeuYemra Sociely of America. Inc.
Frnm Ihe Center fo. Blood Research, Soslon; Deparlmenl of Nulrilion, llarvard School
of Pwbin llealth, Bns/oa, and Ihe Divisinn of Biology. Ca6fornla Insnlule of technology.
Pasadena
MOLE('l1LAR BIOLOGY OF CYTOCIIROME P-450
The cylochrome r-ISO-dependenl wo.oeygenases are widely recognired as playing
a primary role in the de/oaifKalios and/o/ aelivalqn of aemlbiwNics in hepatic and
eelrahepalic lissues. t11 the eaperillenN reporled here, it is shuwn Ihal prelrealmenl of
animals .i/h various inducing a{en/s resadH in increases in 1he acti.ity and specific
cnntent of parlicular eysuchrorne P-I30 isotywles and may sesull in drereases u the
speeifie eonlenl and actiei/y of olhen. heGOinary iM'es/i{alions in se.erll IaMralnrKs
have shorn that the increase in eylochrone P-ISOc, the /najor )-nse/hyl:Mltanlhrene
inducible isoayree, and cylochro/ne P-ISOb, the major phenobarbnal inducibk iwryme,
is preceeded by an increase in specific nsRNA kvek, sultnlinR a rok for (ranscrrplnma/
relulalion Inveslila/iuns .re eonlin.inl into Ihe mechanism of rryulalion fur Ihe
inducln)n of IheK two proleills.
tlines, R N, e..ImrA. E.. Omiecinski, C., and Levin, ). '
In Rydsl.om, 1, Mun/elius, I and Senpsson. M. (eds )! d.ahera.r f).ue AIrraA.dnrn
onJ (hnnna! (acrrnaernnn. New York 1lsevier Science Publahers B V, 1411, IM
119122.
Other srplorr. Nali..nal Inalilules of lkallh and she National ('ancer Ins/.lule
from the Fppky Inslilule for Research is Canca and Allied 1)isease. 1Jniversrly of
NebraAa Medical Cenler, Omaha, and the Ikparlmenl of I nvuonmenlal llrahh
Scunces, l)niversisy of Washington. Seallk.
1
CTR HN 012541
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AR,STRACTS OF REPORTS
1. Ca.cer-Relalel Sta/iea
PI.AT f 1.1 T-Of RIV ED GROWTII FACTOR: A I.INK TO MAI 1(:NAN f
7RANSI (1RMA fl(1N
Plalekl-derived powlh factor (PDOF) is the major milogen of human serum It
shares structural, funcliw.nal and irnnr.nologicd pruperlies .illb the predic/ed prolein
prAr/ucl of the viral onco@tnt (v-sra) of Ihe simian sareowa virus (t\V1. Iluman
Rbhla.uoma, lihr.narcoma, and osleosarcnma eells, .hich eapress the prmn oncoarne
(i ...) hormdn1l of .-rrs, prodace and secrele rnHosienic molecules Ihal a.e recolln.red by
spec.fic PIK:1 anliser.m, lha parUal seduenct of e-ur cl)NA faum human
o.remarrom. cells s shown to eodo for the earhoayterminal reftidrn rd the P1K31 2.ham
nf the bn.logrcally ar/ive mokcnle of the drmeric PIl(if.
A..nwrafn. It N rl af.
('nn<er ('rllr )/GrorrA Farrws and Tranr/wmwrsw, Cold SprinE Ilarbur LaMnaaaY,
14f-1H, 19tf.
OrArr ruppnrr: Natinnal Inslitaea of Heallh, the American Cancer Sociery and the
1 euhemia Society of America. Ine.
From the Center for Rlood Research. Roslon; Department of Nulritinn, Ilarvard School
of Puhlic Ileahh, Brnton, and the Divisinw of Riology, ('a6fornia lnsutuse of IechnolvRy,
Pasadena
MOl E(-1/1-AR BIOLOGY OF CYTOC/IROME P-430
The cylochroiee P-4SO-depeadenl naaoayEenases aee widely recogni,td as playing
a primasy tok in the delolifieNion and/or aesivalion of aenobMlucs in hepatic and
talrahepalK lissues. In the taperinttats reporled here, il is shuwn thal prebeatmeat of
animals .ilh .vrious indacial qenls resde in inereases rn the acuvity and specdic
conlenl of pulicr/ar eylucheorne P-4SO isotynses and may resull in decreases on the
specific contcnt and activNy of others. heliminaey ievesliplions in xveul lahe.a/nrres
have shown that the incrtase in eytocboae F-IyOc, the majo. 7 meMykMdanthrene
inducibk iso:yme, and eylocArowe P-4SOb. the wajw phenobarbotal inducible iwryme,
is preceeded by an increase in specific mRNA kveh, suggeuing a rnk for Iranscraptiunal
re6ulation. In.es/iga/ions are eonlinaing inlo the mechanisrw of regulalinn hn the
induction of Ihese two proseins.
Ilints, R N, d.esnrc4. E.. OMieeinat<i, C., and I.evin, J.
In Rydsl.om, I, Munselius, I and ReqNson, M. (eds / EerraArMqa fr.uR Alrnalr.hrm
anJ CAreneral fnrrn.rgenrsts. Ne+ York. I lsevier Science PuAlrshers b V,-1v11, pp
119-122
OtArr supprt. National Insliprtes of Health and lht Nalional Cancer Instilute
From Ihe Fppky tnslisu/e for Research in Cancer and Allied Distase, 1/ni.tnily of
NtMas\a Medical ('enter- Omaha, and the Ikpartmenl of 1 n.unnmrnUl Ilealsh
Scrences,lln..er.iny of WasAinfilon. Stattk
1
(/1
IrNA 1Y)LYMI RAS/- A('11VITY IN A RI PAIR 1)1 t 1('11 Nf 1111MAN l'f1 I. 11N1"
A human low densilyhpoprotein (I OL) receptor-dtficirn/ d,pt.ad fiMohlasl cell
t.ne 1(iM191S) was Jelerm,ned to be shorl patch cnmpettnt (IINA (nlymeratr O) and
lona patch defstrwnt (IpNA ry.Iymetate~o) for DNA He.sw.n repa.r Anatysit of DNA
fn..n (,M101S crllt o, frum W/1/ ennlrnl eells, fulbwinR Iretlment wilh a mutaten
An,.wn s,t rn,tralr h.ng patch escninn rrpau, showed Ihal 1iM191S crlls e.h.h.lyd
rk.rrot.J rrtynthet,t n( ob;unuckntrde srgattnls eacised Jurnng repait When ellt
del,crenl .n hNA I+drmtrne a activity were perreeabiliatd to perml I bl en/ry, rrpair
tynlhetis ,mmrJ,alrly .ncreated lhttt JaU suggesl ,ha1 IsNA pnlymeraK n rs mq
s.l.van.1 t.y mutaRen uealment in GM191S eeth and that .nlnNtuc/urn of I Isl mto tLe
ce1/t rrsuht ,n a, r,val,nn n( Ihe enryme
fne. C 1), Norman, 1O, 1rv,n, 1 R, and BwMr 1) L.
RnrArmrol anJ R,npArurnl Rrseorrh fumwrw,uanw. 129(2) 1S4 .150, 1985
/7rA.v .,.prn.. National Inuilutrs of 1/ealhh, t/ S Ikpnlment of ARriculture, nd Ihe
le.at Al.,cullural I eprr.mrnt SutN.n
From the I)rpartrnent of Analomy, and IAparlmrnl of Phyt.nloRy and PharmacnlnRY.
(blleRr nf Ve/er.nary Mrdurne, Itsas A A h1 IlmvetatY, ( ulle;e Stalum, snd the
Veterrnary ln.n-o1ogy and Inlomolngy Rnrar.h Iaburalury, l/S Ikpartmenl uf
AI{ncullurt, ('nllrRr Slal,nn, I %
I
,
l..rrrdrn;r of rhe Surrrtr JM Eaprrrntemaf Srolngr and afrdrtrnt 179.116-122, 1985
Othrr ruppnrr- National laslilutn of Ikallh, Teaat Agricultural l:.ptrimenlal Slation,
amf the U S bepartmenl of Agrieullart, College S/ation, 7 X
I ram Ihe tXpartmenl of Anatomy and Ikparlawnts of Phys6doRy and Pharmacolngy,
('ollr;e of Velennary Medicine, Teaat A A M llniversily, ('olk6e Sulrun
AI K YI-A 11ON (>t U1(1XYGUAN(KINC DY 711t. SLSOUIlLRPFNF LA('IhNI
IIYMI N(1X()N
llymeno.nn, a/oeic sesquilerpene laclone found in the ruminanl fnrage
planl Hrmrm.trr ..Joraa, binds deoay6ranosine in a eellfree system and (orms
adJu.'/td guanrne rrsidues in sheep lymphucyte UNA-` Mdunen-slimulatrA I/NA
synihetu in lymnhncyles was inhibited by hymmnuaon st eoncentralinns Erealer Ihan
100 r.M t/nscheJuled DNA syMhesis in Iynq.hoeyles wat inituled by hymenaton
concenlraliuns eecreding 50 pM, and inhibited by eoncenlrNions above 100 YM We
drsceibe an IIPI.C method which sepuales unmodified hynsenoaon and deoayliuanm.ne
from Ihe hymenoaon-deoay6waosine addr.cl and albws the qranliulion of adducts m
hymenueon Ireated cells.
Sylvia, V. L, Joe. C. O, Slipanovic, R. U, K im, 11. 1.., and tiu.hrr f) l.
1'onrnln; r l.rrlr.. 29 69-76, 1915.
P(/1 Y('111 f)RINA111) 111P111 NY1' 11P1 AK 1 ANIr IRANSIY/R I IIY I Yh/l11
ANI) /'l A`1h1A ('(IM1'11N1 N1oi.
The upta\t and vatcular Irantporl of ngetlrJ Arnch,r 12N:, an INlnret/c m.uure of
pulYtAl,rnnsltJ b,Phrnylt (IYI/l, wat rnvrtl,aaad m e.prrm.roul animals Il,;h
cVnte111NIM.ns of mRetltd P('R wert founJ in Ihr chylnnuc.un frmainn nf IMnaiic ducl
lymph When the lymph ltow wat ealeruuueJ. P('l/ wrre nul sul.sequrnlly founA n the
vsatutae eirtula/inn When lym/.h wat nat e.letmrisrJ plasma 1% H eonantrnurns
rrached ma.imal kvels 6 hr afrer inRest.un I ets than 1% of h,tal plasnn 14 11 was
delecled in ctllulac fracin.nt of b1ouJ over a 10.hr ptrid fulluwin6 u.Reslu.n
('hyM.miernnt eonta.ned 11% of 10121 platma Pl H 10 min afler m`ettinn, dec.eavnR to
kst than 6% a/ 6 hr A masimlrm of 10% o( plasma P('H at I hc, and <ytt at 6 ht, dler
in;esliw.n was nsociateJ wilh very low dentrly hpnproteins IV11/1.) ur low drnuly
lip,yuoteint (I lf/ ( Although P('R enler the vatcular circutatiun with the chyh,n.wron
ftsctrnnt of lymph, detq.,prn/tinaled platma ennlaintd S2`1L of Il.e tuul 1Y'IS in hh.wl
co11ec/eJ 10 nrm after .nRestwn Ihn k.rl m.traxJ to 1!% afler 2 hr and remamed
tnntlanl sl abnu/ 10'K (nt an aMldwna/ / In prrw,d Ik.Rh pe./orman.e Lqu.J
ehamulnflr.q,h.c ttimmationt of delrlnM'rote,nalyd plaima from hhunl l.,hrn 6 hr aflrr
P('It .nRetln,n SM.weJ elol«,n of r 93% uf plasma P/ 1/ lo to.nt ide w,lh the alhu.n.n
peak I kclr,yrhorrlic r.aminaliont of drlrpoprnlrinateJ plasrna showtd Ihe ata.K,ahon
of 1'('11 wilh alAumtn tu be noncnvalrnl /he retults suRges1 that a(+olar IY11 a.e
abtnrhed into intefanal epnhelial cells /rom which they are staeled inlo Ihe lymphal.c
dramaffe sequettered within the apular core of thyl,.mru..ns, that Ihese IY'H transrt she
Ihotacic duct anJ enter ILe vaKYla/ arcubtion wilhin chylnmicront and aee melaMdhred
nr, nthrrwr.r relrased /rom chyb.mrcroos dutmg hepahc chylomcron elraranke, and 41,31
retuhmS Pe R ur P(L H denvalives eireulate in sssoculion w,rh plasma album,ns
11u.Mr h I rr nf
1
I
Orher tuppnrf- National Inslilu/es of Ilealth, U. S fkpartment of Agricuhule and the
leus Allricullure 1.a(.erimenl Station
I rmn the beparlmenl uf Analulny, and tkpaslmeM or Physinlolly and Pharmacohyy,
('olle6e of Veterinary Mediciae, Teaas A M llniversity, College Suuon, and the
Velennary luaicology Researeh Laboratory, U. S Ueparlment of Aaricuhu.e, College
S/atum, 1 X
IIPf AK 1. ANU VAS('ULAR TRANSPUR 1 OF INGLSiII) AI LA 1l1%IN
ihe uptake and vascular Irsntpor/ of 6aslrically instilled aflalosin D, (AtR,) was
investigated in sheep Af/atotia uptake was eompared with /hal of pdmna/e, a
water-insolubk oil Ynown to M absorbed isln Iht inteslinal lymphalie drainaRe whith
hyhasses the Itver lu enler the peripheral vascular cirrula/inn vis the Ihoracic dw"1 After
inttdtatiun in anuna/s with ealerimired thuaeie duct flow. AI 11, was detectrJ in rnler,ar
vena cava blood wnhm 10 min, ohile palmitale was not delec/rd in vena cava hhw,.l sl
any time Palmna/e was detected io lhuracK duct lymph aftrr approaimarrly 2 hr
(:realer than 95% of palmnalt in lymph was associated with the chyl..m.crun /racln.n.
wh.k afbtoain .n tuhtr plasma or lymph was no/ deleclably atwKUtrd wqh any nf the
ciaculating l.pnp.utr.ns. tn addilion. All/t d.J not parlilron .nl.. platma or lymph
Lpnpruternt rn r.a.. Toeie lipophilic arnobmlics, such as brnr..lalpyrrne anJ
p,JytMueinslrJ biphenyls, do paalilion iMo IrputNUleins, are abwrheJ .nlu the .n/ru.nal
draina6e, byPats the Irver to direetly ealer the penpheral vascular cuculatM/n, aml ate
not specifically hepalotoaic. These data indicate that Ihe mode of AI H, aMnrptmn 1r..m
the 1asuointeumal syslem rtwlls in its immediate transpuct to the Irver, whnh may
eonlnlwle to AI H, hepasolonicily.
Wihon, R, 7ipr,n, R, Ragtdale, S, and SurArr, 0
a 1 9
I
r o. rrnrt.. y I rnrr 1 1 tO(1 - 2/69. 7a, 1925
OrAcr tup(.nl Nat.nnal Inst/1u1es of Ileallh, 11.S fyepa.tnxnl of Agricullure, and the
Ietas ARIKYhure L.prrimenl Scatiun
1 rnm Ihe Vetermary luc.cokray Reualch I ahnralory, lI S I)eparlment of Apia-ullme,
(..ItRt Slatwn, 1 X, and Ihr I4parlmtnt of Ana/omy, aml tsrparlment of Phyvutnay sn.l
/'harnn.nh.ay, ('ullrar uf Vrtr.inary Med.cine, leaas A A M U/uveaay, l o11rKe Stalxm
M1f(N 11ONItR1A IN 111M(1R (-II IC 1F11CTSOF CY((YKII I IUNUN
111S1R1111/11(IN ANI) AS lAR(:I.IS /(IR SI LL( IIVE KILI IN(:
1hr ha..t far the ddfrrrnce in milnchomlrial rhudam.ne 121 re(tnlinn Irlwrrn
(arauu.ma cella and n.,.mal epahtF.al (rllt .a t/dl un./rr uaal.Ral.nn /luwrvrr, .t a
ldely .u.e nf Ihe la.lora invnhrd rt Ihe h.Rhtr rnlhahondllAl memhune (wnrnlral in
. a...m.m3 crllt It .. of .etr.etl to n.ne th.1 /hn rs the revrrae of what kat hern
ol.rr.rd in no.enal anJ tun.fu.mrJ m.nk f.b.nblatts rletpne the lack of underslanJ.nc
.d Ihr hatn mr.ham.m, th.t wurk confnms, .n a pa11u1 and prrt6mmary way. Wa.hu.R't
u.lunw.n 11.a1 paf.na aUen/n.n 1.s aot.qhnndru .n lamor cells may uhunalrty hAp the
Ilra/mrnt of ranarr
( A... r 9.101
In I r.m, A 1 rr ur (rd. I 1A. 1un./.n../ PA.n,.rylv ('o1,t SprmR llarho. I ahnalnry,
()a1, Pp )% 16
(rlA, .Y(ry.t N.IIn.n111 anar. In.1.lu1- an,l ll,r Anmrr..an( anCrr tlNKly
troa. the 11.nt 1 ulrr 1 anlr. 6r1....v a,./ .1.r /hpul.ornl ..( 1'a/hul,.ar Ibr.a.J
Mrdn .1 %. 1h,./,.,
1(1(-A112A11f)N /11 1 NI1(tPl AtMI(KI 111 14 11h1 IN I IVIN(:
.\NI)(il U1AKA11H11111c1 /1`(1Ir1/I1 S Wllll 11 UI/RIle( 1 NI 1)YfS
Cerla.n (IunreMrnl dyet, prev.nudy rrl.uted to localae mil.uhondria, wl.rn used
at hi0hrr cuntrmral.oes a1w h.:a1.te a cont.nuous net-hke slauc/ure in Mlh Ir..nR and
plntaddrhy.k /rttJ crlla A slm.lar relicular struclure can he deleaed by
phav cunlrasl m/cruacul'y and whnkmuunl tkcbon mi.rotcupy in (olastium
prrnunRanale (..ed tells as well. lhn sbualure is moally lubular, w.th sume ?ahhl.ke
arraa. and rs likely to he the tndopbam.c re1/rYIYm lhe orltaniaal.un of Ihe rrtwular
ah...lu.r is vnsdr.r In cohhic.ne and .ulrnone Iwl rto/ lo cylo.halalin R, /s.ul, monra.a,
rhr.alcium «.nnphore A21III1, 12 Iltrt/adecamlylphorlMJ 11 aretale, or hyJ.nc.A.v.nr
Ir.aoki, M, SunR. /, Wung, I R, Wtnt, M. ), anJ ( Arn. /. It
(.r/10101 t01, 1914
O.Arr turpor/ Natu.nal (-anctr Intlitute
I rnm Ihe (hna I a.lvr ('sncer (nu.lule and the f4parlmenl oF Palholnay. Ilar.arJ
6tr.INa1 ~aMr./_ h...l..n
1
1
MI1(X'llONbK1A1. ANI) PLASMA MFMIIRANf. POI I N11A1 S(-ALISF
IINII\11A1. A(Y'1IM1/1 A11ON AND RF.TI:NII(XJ UI RIIODAMINI. 121 RY
11lIMAN RRFASI At71 NO<'ARCINpMA-1)LRIVLO M('F-7 ('1 I 1.S
Ouanlitatcve sludies of MCF-7 cells (derived faom human breast adenocacinomal
and ('V-I cells (from normal African green monkey kidney ep/(helium). us.nt Ihr
permeant catamc com(found telcaphenyWrMrtph.m.um (/PP), in cunryncla.n wnh
1lunrea:ence m.crmcopy srsing rhm/amine 12) (Kh12)1. indreale /hal the rniuwhumlrial
and plasma mee.hrane potentials affect both uplake and cetenlion of Ihese Fompnun.M
IImler lrlndll/un7 1ha1 dep111artre 111t p1as111a menlb/ane. Yplake and relenlN.n of 11'P an,l
Kh121, driven only by Ihe mduchnmlrul memMane puteMUl, are grealer in MI'I 1 Ihan
in ('V I An .om.phore that dmipHes the mituchonJrial rllembrane pulenbal of M( / I
cellt calut them 1u resemble ('V-1 « Ih by decrtatin0 uptake anat relrnln.n
Iry(.rrp/.lar.rinR the miluchundrial membrane of ('V-1 inereases accumulalion and
ryruh.eits rrtenlwm, hyptrpula.ua/intr of the plasma membrane furlher heqhlem Ihn
r(Je.l, cau..ng Ihe uptake uf CV-1 cells to tesemhle /hat nf M(7 -7 cells even m.ne
clnsrly Iht Rreatrr upuke and retention by M( I- - 1 appear In be a cunte.luenct a/
ekvaled ma.khnminal and plasma rnembrsne ppNenlials lke plasnq memhranr potential
a(frrts m.h.chond..al retenliun uf l l'P and Kh121, anJ its role in enhancing 16e elfect u1
a ddlerenie in m.uwhondrisl membranr Iwleni.al s eqda.nrJ
Isavn,S,.vuf ((Arn.(..R)
) Ar J.wrnu/ u/ Ru.l.sn or ('Arm.l. r 2a0.1)IJA-1)tSO, 1985
1 rnm the hana-1 arber Cancer Inslitutt and Ike Depaualrnl of Pathology, llarvard
Medlcal S.huol, Ruston
MI I(K FI(1NbR1A IN LIVING ('C1 I.S. 1.111 ('1S Ua(:R(/W 11/ / A(' I( /K5 ANU
111M(1K 1KOMU11 RS, ALl l RAl I(M1S IN ('AR('INUMA CI 1 1 S, ANh 1 ARGI IS
I ()K 1111 KAPY
Rhodamine 121 is vseful for Mleallrinif milochc'nAria as well as lor reflect.nR
ekconthemical R.ad.enls arross mi/.ahnndria in l.vins cells. I he laller is sulnlanlutrd
by truaphenylpho.pMwium (IPP), a widely usea/ memhrane Mnenlul pr.ul.e
12 0 1elradecsnoy/pMfrbul 1)-actlale (1PA) eonverla fdameMUUt mil.wtnmdna ml.. a
Runular s/upr but d.les not affect Ihe elecln+hemical grad.enl. Ptalekl dercved gruwlh
i faclnr kads to an increase in milochoedrial anenlbrane putenlial as WQII as to a clYS/erlnd
of mialchondria at /he petinlrclear re0inn 3 hr a(ler uealment uf reslin0 RAI R/c 11 1
cells Whereas the majority af t.mur eell lines do no1 have allered ekclr.rhrm.al
graJirMS aa.ns nulochnndna, the Awms of t.prestion between mtmhrane (mlrnlul an.l
pll {radirnt can be varied Fot nunlerous aJrnncarcinorna deuved cells. Ih.t Sralwnl
ap(ean 10 be prefrrenlially etprtssed as a anembtane polenlial lhut. the mauwh..ndrul
ncemhrane Iwdrnrol is Meher ia adenocatcrnoma eellf lhsn in normal epaheh.l .ells
these carc/numa cells lake up S-fokl /0 20-/old mo.e rMM/amine 121, IPP,ur nrhe,
hpnp:ul.c, rahun.t compwndt that can rraah maochundrra than du normd rp.uhrlul
eells IMs phenotype may be eaplui/eJ fnr ehrmo/htupy of adtnnayrcinnma tells A
/pM.pMl.c, eal.onic dru/. deVualiniam chlor.de, v.nfely useJ fnr surr (Moat in humans, n
h.{hly Incic 1.9 carcinoma tells anJ tahlbrts a tr{n.(iaant anlaa.cinnms a.h.ty /n
an.mak
( Arn. t.. R tl nr.
('AN(F. R(!([ S )/Gru..rA F.Norr snJ Trun./.unmuon
I aM.rato.y. 1'/kS
(-ul4 Spcinat I/a.lwu
In
rsrArf srprynr Nahonat (-anrrr tnstoule
I rum the Oana-1 a.lrr (anter Inst.lule, New 1 ngland tXaaunets Ilosp.tal, R..gham and
Nonmen's llotpujl, and 1lasvard Mrdnal Sth.N.l, U..ston
IN(Kf AS11/ R11(/1sAMINf. 1:) tIp1AKC UY CARCINOMA ('t I I.S
Ike to1a1 celtular content of Ihe flumescenl tnho(hondriJl-specifrc Jye, rhudammr
121 (KA 121). wai yuamd.td by bulanol ealraclion as a funt/nM u( Irmr of fyM.Wrt
and dotr fur a va..ety of ce111.nes Ihese retulls were enmlureJ wrtA ehur.alwrns ma.k
by /luorescence maros.npy on dye localnal.un and mNoeMrndrial morphn/.gy Ihert
appeaseJ tu be two categories of cell lypes based on RA 121 upla\e /M.se wh.ch
p.n(Irturvr/y pcamula/t the dye, swA as I AAKh ascilel lumur cells, carcmoma Jer.vtd
Lnrt MCF 7, ra( a2, 17, lltl a, and normal Lbwbhsl line (('1. 61, anJ those whn.h
aplrar to e0u.l.h.ate w.lA the eelqcellular dye wnA.n I h of i/stubalw.n in Rh 121
(1 yg/wJl with a mm.mal kvel of uplake, swA as the normal tlsilhelialderived Lnes
CV I and MIXK and the Iransformrd frbroblas/ line 64F). WqAie tht f.rsl caleRury.
the ahtulute value of uptake per cell torretateJ with the concen/ralwn of Rh 121 In the
medium and with IAe period of e.poturt In the dye up /o a point of appafen/ cellular
aarutalw.n iht knRth of linse reouned lor apparent saluolwn depended on the cell
Ispe In the seconJ casegnry, eQud.b.ation was very early, and IAt total uplaie was a
lunoinn of 1he etuaceRalar euncenl.atn.n (of Rh-12) Ihit prul.ably does not repreunl
a sasuratn.n tevel of dye canlrM in the non accumulalrng, /ow uplaLe cell lines
Iluortscence m.c.nscopy revraled that RA 121 A.raliaation wsf initially
m.h.thnndna/ speci/.c fqr all the cell Lnes euminrd. Over Irmt, atteralams in
m.hschond..al mnrph.dnay and cyhy+lasmfc lluwnntence was obxrveJ in /he high uptake
cell Lnrs hul not in the minimal upule cell lines Incubatan of the high uptahe llel a
cell line with the mdochossdual membrane pru.nlial inMfnlor,
p Irifluoromelho.yphenylhydraaone, substantially decreased RA1:1 uplatt. lhete
ahservahunt may inJrcate a Ilan\/e/mNn.nrtlalfJ characleUslic of earcinoma cell
euto.hnnJria It may be possible lo etpluit the rnechamam responsible for Ihe
psoilretsive accumulalron of Rh-12) by carcinoma-dt/rvtd cell types for
chemolherapeulic approaches /o ceruin types of carcinomas.
Nadahavukaren, K K, Nadahavul.aren, ). 1, and CArn, l.. R.
Cancrr ResenrcA 43 609)-6099, 1915
OrArr suppofr National ('ancer In)lilule
Frem the fyana Farber Cancer Inshtule, Uoslon, and the f><partmenl of PathoH.ty,
llarvasd MedKd Scho.d, Uoslon.
(1// NIII ICA 11(1N ANI/ OUAN1111(Al IUN (// A MI S]I N(i1 K R11111Nt1(I I 1('
A("Ils INI)1q 11f //Y M/1 YNtI('1.1 AR AK(1MA11(' /1\I)KOCAKIIUNS - 11%IN(i
A(y UN11) 1111MAN ('V 1(X'IIKhMI. hJ30 (71 Nl:
(l.e rrtrar,hrrj ha.e .wbtrd (uur oe.lappma human srmmsic elonrs atsuciated
w,r1, rAr p/swu.lr.. arM.n /1'A//l mJuaeJ turm of cyhKhrnme P IS0 I
I
I/,r 1..... ..1 / e. ... ../.../. .....v.l -h 1osll ,nJu.b.,n hat been d.~lmrd 8%
/~, 1 ~.. / . . . , . .. , f r . . . .... , . , .. ,1 ../ 11 /1 . 111' l.a.r 1. ,ra ,n
~
lroltth with the .,wlmll upuence lying in Ihe center of Ihesr clnnrs 1ran.L.trnn in rnro
of I med.yhindanthrrntindwtd mKNA, srkcled with the human P, 410 Remm.k
rA.nr, JrlraN a prntrm wilh Are 52000. which rt i111mum.tnec/p11ILIe by the anlr /nnwse
/'. 450) anlilr.dy lht nolaled human ,-IS0 genom.c clunr hyh..dvrt 1..
I nxlhyhhol.nllnrne-in.h.crd mRNA frum rlwrokey l/ver, henranlhracrnr and
I n.rlhyl.MJan/lurne/realed human man.may Immnr cells (M/1 y), hut nut to
.w.afrole trralyd human cellt. Ilpon treatment woh 1'All Iherr n a pos.Uvr c.nrrl..unn
taIwrrn .mluard arylhydrocarl.un Aydruaylate (11avrquolrm hnMeJ mnnu.yRena.rl
a.hvay aml /hr an.nunl uf mRNA that Ayhrnh.rs tu U.e iwlaled hu.nin Rrn,.nu. .hmr
lur /'r IS/t Ihe avr u( n.KNA, Imluced IN.m human celh and monkey l.ver by PAII, n
a..wnd I I 1 tOr haae pairs, which rs the samr as /ht l.rger of Iwn mKNA rodu.rd Ly
1'A// in Ihr inhrrJ sua.n of .nnuse ((S/U1 /eN) Iheir dala alw shuwed /hal Ihr ...d.ur.1
IsNA tAmt an drlrsl a mRNA sve of ) 1 1(1r h.ne pa.rs la.n
phyluherna/tLlulmm act.vated beneanlMacent /realyd human lynq.hnrytrs Irrn,rh,mrlrr
s.'ammmiR rmlw'a1rJ the prestnce nf a 16 fuld varialwsn IhiRhesl /nwrsll in /Ar h-r1t of
lymp/nw y/e for 4t0 mKNA conlenN anw.nR tr. .ml.vw/uals tluJlyd
1
1
I
Kam, 1, IsrnR, I 11 , and ('Mn. y'-T
f'rnnrun /.w.nnf n/ NurArmrshr 1311A9t93, 1911S
(7tMr supnar No.th (-arnlina Uni/ed Way.
Y
I rum Ihe Ihparlmrot nf Pedialries, 17uAe Ilnivrrsily MeJ.cal ('enlrr, I)urh.lm, NI'
i
tsISPARAI F plll t RFN11AT1(/N IN IIFMUPO/(11C ('UI (1N/1 S I)1 RIVI I)
I KUM 11(1MAN PA/RI U PR(Ki1.N/1(7RS ~
1he researche/s analysed /Ae diffeanliatinn of hemoMsielic colonies JrriveJ hom
human paired JauRhser celh. CanJiJale MoRenilne cells were isnlalyd hy use of a
micsnmaniputali+m technipue from el/lares of My-RI anlsRtn pnan,ve co/d bhnrl cells
N.ne 1o 16 Aours lahv the paired dauAh/er «lls were sepankd with a miarnmanq.ulnor
and allowed to form enlowits in me/hykellulme medium eun/afn.ng
erylArryw.itlm,
phylohernaRRlulmin leukocyle-eomlilioned nsedium, anJ platelet IM.o pl...nu Ihr
cellular eumpusit.nn of the colonies was delermineJ by ddferenlialina all the cells of the
May-(irYnwatdliirmaa-slainrJ Lreparalion. (N a Iu1a1 of 75 eval.uhlt pairs o( culonies,
)S comhlyd of 21 types of disparate pairs revealine nonhuauJnRuus l.nraRe
eannl.in.s/ums. I o/ly pairs were hMUmInRow in lineage e.preta.pn Iluwr.er, Ihe
paqnnlumt nf Iht individual cell lineages were s.RnificanUy dJ/rrnl in the mrmlrrs .J
wrnr of Ihe honn.k.Rout pairs. Snme pairs reveakd sqnifnam dd/rrencrs .o rnhmv
svr Ihesr oh.ervalmnt arr similar In those rerynleJ fnr mursne p.used proRenanrs and
ace conuslenl with /he slr.haslie wwdel of huma stem cell Jil/errn/.,sn.n
I rary, A(l . Saaus I C,( rvrw. (" I and (1ffawa, M
Nl.n44N2) y2/ 111, 19115
r)ohrr sr.pp.nt Veterant Adn.ini.tra/inn and Nalu.nal tna.lutet ul Ilrahh
I tnm Ihe Veterans Adminitl.alinn Medical ('enler and llut IAp.ulrnrnl ul
MrJ..J Itnrvrsuty nf S.wlh (-arol.na, ('harlestan, and Ihe 7uho. Ilnps.m Ilud,.Ry
( enler, tl.r /uhns Il..plomt (/nmversuly Salnud ul Mrdamr, 11a1t.murr, MC)
11
SIKIt(-ItIR/ (it 111t HAt o.-A(If)(a Y(Y)PRnT1IN(i1N1
the cumplrte nua/enlnle xqurnce of the rN no acid gIycnprWein Rene hat lern
drtrrmmrd hnm an n.dard IamMla reenmAinanl hacterir.pha9r tiuulhern hlot anatsa.c
and 1)NA drqornc.na rn,l«sle Ihal Ihere is only one gene per Rrnumr; .1 cnmima ..e
rrnm and n Lhalyd w.d,.n a 1!f10 haar-pa.r ftaRment slarlinR Irom a IAIA lu.c and
r.trnd.nR an Ihr (M.Ivadrnvlalinn vRnal AAIAAA Iranscripln.n alarlt 1) haar (airs
uparr:m.lrumlhelrkuuuna.d,hel.an.latwtneudnnAl(: the 1A1A M.a 1IA1A.\A)
Lrs :A 1va paa1 upahrnm frnm IMi ti1e. The gene contams several µ.lrnl..d
Rlu..rorlnmd rearp/nr hmA.na sdtt. MNh imide and oultide Iht a1rY:lu.al gene
1un, V('), lat/nr, I M, Vann.ce, I 1,(7.wr.w,4 A andSm.nlhr F A
Alnlh.nlnr nnJ f rllYlu. RndnRr II1;) 1611 1619. 19AS
1 rnm the 16I..ulmrat nf /'Nhnh.RV, $ch.rd of Me.bcinr. I/nivervlv .4 ('at.fmnu. Srn
t un. i,... f.LJUunr I nnn.l u.no San 1 r.m, ncn Grnrral 1 Wyn1al, an.l I4pa.l.nrnt n(
Mnlra.A.r Ik.uhRv- (:rn. utr. h Ina , SGUdh Sin 1 ranrnan
IN 11 KM1 1t1A I I Ill Ah11 N I rR()/1 INS IN PARA I IIYR(/11) (:1 ANI)S ANI)
1'AHA I IIYRI11I/ ^1/1 N(IMAS
Ihr inlrrmrd.atr f.lamen/ prulrins n( nn.mal hvperplaalic, and aAennmalnus
'paralhvrn.d RLmM wrrr arn/yrrd rmmunohnlnchem.cally and by imntnnuldulhnR .dh
m..n..yn, d.i anht.wtat In Iwdh m.rmal and adrn..malmn paralhyronl Rland., we Lnmd
leralins w.th mm,1lrcular wr.f.htk of S.'. IS, snd 10 Ir4Klaltuns (N.n R 11, aml 1'1,
rralw.lwrly V,mrnl.n pmtr.nm cnuld M nlenld.rd nnly .n saua.al eells, whdr Rhll
/dn.lhrv ac.A.: t..utr.n v.a% nnt luund In na.mol paralhynnd Rlandv, nrurnldamenl
l..a.l.vny waa arAn .rdy in nrr.e a.nna In l.ve .d 1% paralhy.uut Rland a.knumaa aomr
/rralm- p.nrlr.r eetla ry..rtaed neurafdamenl like immunnreatlrv.ly alan In
cyln.lrlrlal rc/ra.ts of nnr a.ltnnma the 7110 /.1.«l.lt..n nrurufdamrnl pr..lrin was
idrnld.rd by tommn.Jdonm~ 1hus, il apPras Ihal tnme parathyrnnl Rlrnd sdrnnma
arllt auy scqoae nrur.dd.lmrnl pmlrms and cneprrss cylnkrnlm and nrwnldamrn/
IY/IylYPlulr In a way cnmya.ahk wilh 1ha1 rrp.uled 1n crrla/n neurnrnd1W11nr IYInu1a
Mietl.nrn, M,(1ark, K, I rh1o, V- /, Vulanen, 1, and f/um(unn. I
ArrArrrt n/ PnrAnlnRr unJ 1 nlvwar.wr MrJ/crnr, 109:9116 919, 1915
from the 1)el.arlmenl of Palhn/nRy, and I aMnlory Mr.licine, Ilahnrmann I lmveraily
SchYd o( MedKrnr. I'bilr.Irlyhia, and the IMparlnvnl of PalhuloRy. Itnivrrsify of
I/el.mkr. IIAa.n\., I u.laod
IIKh:/N /11 I Ah11NIN IN 1111 I X 1 KA/ 1 1 t lll AR MA 11(I X ltl IIIIMAN
t1/h111K X1 NfH.HAI I\ IN NIIIH M11 /
Mum.clnnal anlAwu6ra rtscl.nR eeclutrvely w.th Iamin.n nf human m1Rm nd a
rydycWnll anlJ..nly .rartrnR w.lh both munnr s.u1 human taminm werr uard tu
UIImUeUhnl.hhrmnilty ah.A the ruracrllular malns of fuur human tunmon arnwn as
.rn..ll.fla rn nu.lr mne a lung eaac.nnma an,) a ynik sae car..noms becauae thry
pr.wlal ed l el/ sa.... ule,l 1 vnrmn .n rrr.., snd Iwn hrpal.r rl/ubr s ar. mnmas ../o, h Anl
.u./ r. ell a...,...v.l 1n,nm ...n... 1 he r au. r/l..l.. m..rrn u/ 1hr .rnua..JN ol
I
i
t
I
the tunR carcinoma and the yolk sac carcinoma contained lamimn of hnlh human an.l
mYrlne Mltm. Xenl/Rra(IS nf llver carcrnnma conla/ner/ only Ia/nIn1/1 nf mnYK nl~/n/
IMS shnwt Ihal /he ma/iRnaM celh capabk uf Iamrnin pr.wlucli.m m.u..r cnMr.Luly dua
Rlycrq+rnltm lo Ihe taU]cellYlar malrla of Ihe s..IY) /Ymnr formrd by Ihem .n rn..
Dnmtnnor. I N nl
1'ncAnrt ArcAr. R/Crll rurM./oer/49 .ISS.', 191S.
OIArr sYpp.nl Nalional Insl'ilutes of Ileallh
In.m the Ilahnemann Ilnivrrsity Sahrd nf Medicine and the Wnl.u
PAAarklph/a, anJ 1 a 14,113 Cancrr Kesea.ch 1 numtalmn, 1 a 1u11a, CA
Irrmldule
R1(:111 AI()RY IAf'11)RSSP1l'/ll('1(1R AI)111 I ANI)IMIlR1Y1N1( /i1l)111N
(:I NI S M A Y( i( )V I R N 1111 1R I X PK I SSIUN IN I R Y 111K1)I I UA 1 M IA ( I 1 1\
In nrdrr In leal if trnnt-acling reRYlalnry facl.us q.rcifK fur Rlnl.in Renra .d Ih#
adull amt tmMynnic alaRn of drvelrytmenl e.i.l m er)throM) cella.
Lan..nptu.n.Jlt
acl/ve enltNynnK anll adult 6hdtin I{rnet on Ihr same ehrYrm.aomr wrrr h.m,IrneJ 1.1
cell fusion fhum the human Irukrmla cell KSA2 inlo phrmHyp.c.dly ad.dl nHnr
erylhrulrukrm.a cells Realriclum IraRmeni length IMdymrnphltm. nf /Iu K Su.` (
emhcy.mn; 6h.f.m 6enes were used lo esubinh Ihal all Ihrre cupn. o/ huur..n
chn.mnanmt 16 present .n the KS62 cell sho.eA Ihe tame pattern o( hum..n Rlobm krne
e.press:on aller lonafer 1o the moux erylh.nkYkelwia cell. AJYK (n1 Ibut nol rnJnl.mn-
(() human Rh.bin mRNA .as Ae1elled in aK nine of the imlrprmlrnlly .Ir.ivrd nnmw
erylhsukukemia hybrid cells, each of which conuinrd human chn.m.numr 16
Restriatnm endunwikaae slwlies of she KS62 e and (-gh.tun Renti aftrr Irao.frr rnln 11n
rnnux trylhrnkmia cell showed an evidence of rearranRernenls w drletmns Ihal cnu41
eydaim lhis Irnt ol (Rlrtbin {ene ealuesainn. Thex da/s suRResl Ihal rrRulahon u(
Rk.bie Retx e.pression in Ihex erylMnkukemia eells inv.dves (rnns a.lin{ reRuhlmy
faclms specific for the adu/1 aMl emMyrmK ttage1/1f a/evehqqnenl.
AnaRnnu. N r, Ynan, T'. Y, Lim, F., llelda, 1, Wieder, 5, Glaialrr, /) , MsrH, K,
Wanll, A,('olberl, I/, and fNrssrrwh. A.
111rrrJ 6S(1) T0S-T12, 1991
.
n(Arr surpnl I/niversily of California, S.in /-ranciscn, Ihe Velrrans Adnunnlr..hnn, an.1
the Natumal 11ror1, Luna snd Ill.md lnslilu/e
Irom the Ilniversdy of ('alifmnia, San Fraacisco Ilemalnh./ly/(McnlnRy Itn.l 31 Ihr S..n
I rancran Velerarn Admmnlra/ion Medical ('enter
l'11A/lA/'I1/(I/A 11(1N /l/ A I/Nh)11/ KNA IN111A 1/111/11MI I//A 111 Y
lll'SI HI AM 1 KI/M III IMAN n1 (il ()111N (i1 NI IN 1'II (! ANI) IN I ll Nrt
1'1/1 YMI KASI 11 1)11 I/ NI/1 N( 1., 11SC111 11'11 1111'11 V. ANI) N/IH -1 / 1 111 AR
IIK"A1111N
The authon have «Lntified an ahYM/an/ transcrrpl inil:aled upaura,n /ru.n u.,
cammical cap site of human nl gIuFrn gene in bone mar.uw cellt an.l m 111] /.rI/,
lransfecle.l wah an nl ahfi.n gene conlammR'plasm.d S.m.1ar lu 11,r .o..r.r ..I alt..n
lunscnp/. Ihe uPalrram RNA n prr{ent ahnust t.a/ua.vrly .n Ihr.ytnpl..m nl 11.1 I..o.
14 1 IS
I
feclcd (Y7S 7 cr/ts tl is sho sy.lhesired efficientty to rrrrn by RNA pnlymeraar 11 in
the nuckar tclrsctl prrparM f'rom a tlela « 11 tint snd sn trylMnlrukrm.a cr1l bne.
K 762 RNAt nolaled frnm Ihese cr11 Lne., hnwtver, do nnl comam Ih.s upurram
Irsn.cript the puul.vt S' tnd of the ol al..hin uptlurarn RNA n mapped by p..mer
tslentinn to base eS, which fn localed is bnwern Itu: CCAAT and /AlA A.nars the
syn/hrsis of Ihs RNA .n trtre snd .e trro. and /he clost prorim.ly of its S' rm1 lo Ihr
prmmoler of Ihe ot efbb.n grne tuRRest s common mechamtm rrRuliunR d.e
trsnxnphunal .mIwlN.n of M.Ih Ihr upllream snd Ihe malor ol Rlohm RNM
/lras, 2, Prrrr Slahle, C, Drr.vrawA. A, snd Shen, CK)
Nurlr.c ArrJr Rraro.A 11(t7160S96015, t911S
(1rArr .upryrr Naraonsl Im1i1u1es of lleallh, American ('amrr S..a.e/y anA Vrlrrant
AdmimtualN.n Mrr.l Re.aw
1 rnm Ihe I)rpulmrlN of rrMlKt. Universny of (lldornh, 1)avis, an.1 Ihe tN/i..Imrru
of Mrd.cine, 1).v.nnn of Ilrmatnh.~y anA (MColngy. Itnivnady nf (..Id.-rn.a, \,in
1 rsnca....
AVIAN I RY111RO111 AS1(SSIS VIRIIS 176 NI/('I 1(111/11 S1Q1IfN(-1l/1 llll
IRIYAR Itll nn. (.1 NI AN11 (N /tll 1 IR, AN11 ANAI VC151t1 1111 ( t'11 l11 AR
PKll1<11 YPI UI 1/11 VIRA1L rr. S11)Itl NI 1
An inlacl S I kh prnvuus nf Ihe a..an erylMuhlavlnta virut 1,`b hat hern
rnnltcularly cloned (nr enmpsrsons wilh aun myeluhlattnus vuut (AMV) and ulher
avian lumor vuusrs f 76 sm/ AMY Iranafo.m hrmury.itlic cellt e.clutivrlY 1h.1), v.1utr
mytl..hlaatna.s, bu1 176 altn cautes erythroMasMUa Sequence analyt.s ut the pr.uviral
IINA thnwed Iha1 (.) the Iripsr/.lr IramfN.mmg Rrnr cuf 1`6 furrnt a cN.mKu.nua
rea.hnll frame ..f 1046 cminnt, imtuding 717 te[ 721 mrAy, amt 4'+1 .rt c.Nt..na Nu
tuhalennmut rrr sprc.f.c mRNA was delecled rn 126 mfeard er11t Ily cnnlraat, the w.
Rrne of AMV cuntnls slrm.sl emuely of s mtAa srtturnce t.prsard v.a tohRrnomic
mRNA Ihal ra/ends ovrr the Y sml 1 endt of nr.Ap* (u) mtA/ ia nnly ttqthlly
diver{ed frnm A.e mrAA h.moloR uf AMV snd eren leat (r..m /hr cellubr pr.no mrA
sequence wilh no CharaClrllNtK mut.ltNln Iha/ aett aparl the twn v/ruart Irnm prNlu wrtA
(iu) /he IIS retbn ..( Ihe huMg Ielrnlnal rrpral /LIR) of 1 26 and AMV are cubnrar am1
d.ffer only in Kalrerrd poinl mu/alinnf the 117 regios of the 176 1 IR n ddf.rent
(rnm that of AMY hul is colinesr snd closely related with Iha/ of avlan carinnma virut
M112 snd atto wi/h 11131 of I'n6ue Rout tsrenma virus (RSV1. t.crpl for an untapecle.l
16 nu(kol.de tub4/1lulion of 22 PSY nurleolNles. I/patrram nf Ihe 1' I 1 K, the r
reRiun nf 1 26 appeart to be Ihe sarne at 11,31 of KSV fnr 70 nuc'leothdes an.1 vrry Simdv
In Ihnae of AMY and M112 f.u aMwl 20 to 10 nuclenlNles. S.nre Ihe Ifls uf /`6, h111.`
snd RSV s.e very clnsely rrlaled snd nei/hrr MI/7 nor RSV shna a par/NUI.u
erytlunhlatl /rrM.iam, t is pmsihle Ihal Ihe Itl dNrt nol play a rrnNal rNM m the
.,ythrnhaa trnpi+m nf f26 flrclrnphwetK sire snatysrt ol chNlsen ItNA .bRrtlyd wuh
rtstrwlN.n enrymea .nd.cstt Iha1 ONA f.asmenls loulbng nver S(7 k1A hyhaNtue avuh
,,irsl rta l)NA
Nunn, M, Weiher, 1/ , Rullock, Is , and Aw.Mrlt. P
Puo6.R r 1 19 110- 119, 1924
l7rMr .rp(wr National Inslilules of IIea11h.
1
Ilom Ihe (kparlmtnt of Molecular RioMgy and Viru. I.aMualn.y, Ilnivrrsuy nf
('al.fornia, Ikrketey
A(")1V A 11 h PRUTO UNC GENt'.S Sill FR'11 N fOR NI l'1 SCAN Y 1(tR 1'AN( l RI
PrMo onc {enn srt auwal cellular genet that are relatrd /u the lrantfNrmmR INnrI
Renrs of reunviwsn. Reeaute of Ihis rrlalicunhip, the.e genes srt nnw wN/ely hrhevrd
lu he pnlen111t cancer Renes In tonx Irmmt, paNn onC (enes are mulaleQ M r.p.rv.rd
m.ue than rn normal cr11s. Ilmler thrse d.mtiliunt, Mnlu-onc {rnet a.r hyrN.lhr.vrd rn
M active cancrr grnes in one of two pMsibk wsyt. The one Rrne-unc can.e'
htlNUhr...
IuRRrtH Ih.H nne acliratM prnM-one gene is tuffN'irnl to cauae CJn,er. Ihr
mu/1.Rrne uoc canctr hypothts:s tuRgrsN that as aclivatrd proNa unc genr is a nrcot..uv.
bul nul a 1u(fn'.rrM. Ciute of cancrr 1lnwevrr, mu/aled or aanacnpl.nndly a:ta..urJ
p.utu ..nc Senes are no/ Contialenrly saMCN/M wilh Ihe 1u.nurt in whnh Ihrr 1.r
/KCatN.nally f1Wed and do mN 1raMfmm primary cells I u.lhrr, n.a set ..( an acl.v.ur,I
p.Nln onc Renr and a com(.kmenlary eancer Rrne wNh Iran.l.nnunR IuuauNn haa t.t
hrrn ranlalyd Irom a lumnr Ihln, there it aldl no p..Nd 1h:.t artrv.urd p.nlu t.m- prmt
are suflN:.rn1 ur even necessary to csuse cancer.
noor,lh rR. i rr
Snrmr 228/4700/669-677, 19~5.
OrA.v .upp.wt National Imlitulet nf 11ra11h
1 rum the 1)rparlment of Mnkcular liok.6y, (InivretilY ..f l'a/.fnrnia, lur.krlry
MUTAGI NfSIS QF AVIAN CARCINAMA VIRIIS Mt12' (1Nt Y(tN1 (11 1 W(1
r(tll NI/AI. IRANSIORMIN(: (irN1:51fRaRm.r) 1RANSI I7RMS I I11K1q11 AS1Y
Avian earCrmqlla virus M112 eonlains Iwo pnlenl.al uan.( a..u.na
lJrnrs. ARnR-mM snJ tRwRmyr. lbus. M112 may be s rnmlel for 1wu RrM ca.c.nu
Renesit in which Iransfurmatinw deprmh an Iwo tynerbitlic Renea Manl o/hrs durarlr
oncnRenic virusn eontain sin{1e, suhuwuwnw IranafMminR (..n.) Renes and a.e nN.d.1.
(M tingk genr carcinofitnesia. le deleamint whNh ude each pulent.at ..w. Rene nf /att)
plays in nncngenesit, we have preparM v/ek/ion md f.aoashift mutanlt of raah Nf Ihe
Iwo M112 Renes by rn atre mWagentsis of el..nrd prusual 11NA snA havr te.lyd
IramfMmiog functinn and virw prrduclion in t'u/lurrd primary quad crlta Wr k.r
fnuMl Ihal mM drklirM mulaMt anal wiM lype vuw trand.um pr.mary .ells an.t
Ihal mly delelu.n and frameshifl muqnls do m.l Ihe nNnphu4.6irt o( crlla Lan.fwmnl
hy the mAr rktrlion mutanl/ sml by wiMl type hlll) are s.nular yrl .a.y aNn.Nln,l.ly
Neveahe/rss, fyrKal mu/sn1 trsnd.umral eelh c.m .dlen he d.aUnRu.vhr.1 Irom arll.
Inn/fn.nKd by wild tyM M112 We eom'lwte rh.tl Ihe 1R.q nn, srnr r..n.Lem,
prrmary crllv by INNf, wNhoul Iht areoml tiottnatl .Nw arne Ihn n..o rr1.HrJ nrnr .v
/he smatletl Ihat has duee/ Irsntformine IunHN.n ARnRmAr is wuhour dHr,/a1-1.
/undMmiq functinn bW may affect UanlfMma/WS hy AR.Ir n.rr thus. Mll' hrh.vrv
l.ke a virus wiU s singk om' gene, d1/uwRh it taprrnrt Iwu fN.ltnl.al ..Nr Rrma, an.l .1
apptsrs 1604 to Ibe s mm/el fog two gene c,rcultHewesis /urlhrr wn.k .1 nnraa.y u.
Mder lo delermine whether /he tene ponibly enhances oncnarnN fun,/n,n
of {teir mm M has independent oncotemc funclNln in an/rllat7
16 I I7
%hou, K P, K an, N, Papas, I, and f)urlMrR, P
Pr.vrrJ.nrt n/ the Nmuw.el ArrNLmt, n/ Stlrwrrr of the (rwurJ
Amr.Na 12 h109 6111. 1911%
Orhrr .Npl..ul Natmnal ('anttr Inslilule
Slerrt ol
Irnm l/.r 1)rparlmrn/ n/ Molecular IhnlnRy and Ike Virus lalwranry, 11m.rrsiry rf
(-al/lnrn,a. 11r,\elry, aml Ihe I ahmalory of Molecular (1ncnl.,Ry. Nahnnal (an,./
Inshlule, I rrdrrN i, Ml/
AKI At'IIVAIII/rKtll/l .wu GINIS('ANIiR GfNf.Ss
Ihr pcrfNmdt/anct of \)1 ce11-Irsnsformatinn nep/ivet amnnR the lumn a
deacr/lr.l /n /hls paprr suRRrsn /hal rnher nn Rrnet havt ewsed the nrRStlve tu/1Nns ur
Iha1 the aavy /adeA In dtlrcl them thal nnly rtrl relaled prnlo .N,. Rrnes have tvrn
drlrc/ed /n human lumms uRnals annlher hmilalinn nf the 111 asaay Slnce /1.e
p,.tn r.lt mu/a1Mna fnund by the 111 satay /to n01 lrana(nrm p//mary Cellt, 1/ Is plNt/blr
Ihal thes a/r nul rrlevanl fnr Iomnr (orms/u.n Avadabk dala wRRet1 Ihal these a.t
cIn,Nlrn/\/ /w tnnarllurnllal mulaluNlt ralhrr. Ihan tanter ClWatlve rnulal/ont IM'Cur11nR
in tumul IrIIa, IY(autt Ihr mulalN.M see not conalalendy enrlela/ed wl/h specdlc lumms
and hetau.r /n cnnw taart they prece.k lumn, Immal.nn and In olher they evnlve AucinR
OrArr tupp.nl t/ S Publlc Ileallh Srrvice and Monsanlo ('orpotation
1 r(4m Ihe 1)rpatmrnl of ralhntoey. Beth Israel I/ospital, Ilarnrd Medi.al ScMN,I and
('harles A 1/ana Research Insllluk, Ileth Israel 1lospilal, /hntun.
MI1/ A 1 I()NAI ANAI YSIS tN 111E FI/N('TK)NAI. IX)MAINS 01 1111' AdS I 1.a
(:I NI 1'K/ llrl/(~IS 1/1 I('l ING ('l 1.1, IRANSIiIKMA 11(1N
In Ihs paper, the data descriMd uainR viruset with aptcific muutiorts In Ihe
fNNINIn /.( the pn..me emvrlmR the I la SI ld prWein imply i1 is Ihe vital Rene prndu.l
Ih]I /s nhra.ary In mamla/n Ihe recnRnired pa.pHllea uf Ifanafnrrnrd cella 1 hr
sun.lilNlnally lelhal, culd arnailive phennlype esprrsaed by Ihe mu/alyd Rennu,r.
whethrr inlr,NllNr.1 min / KI I cellt by mfeclinn wt/h vuinnt or by Iranafecuun with
Inuc/ Rrnamrs n. plAanlNls, Impllrl Ihat the Ils SI hd prulein inleracls with a hna
macrunudeculr nr Il.e / la 44 hd pnlypeplillt lhe eold-trnsilrve phrnuly/r may rrf/rcl
dtcrraaed MndinR a'unalanl al 12' C hetween Iht mutanls' Irunealed p/.nlems and a sldl
unNlenll//td hnat and/or vital macrnmokcukt. hkn/ificslnm of Ihe putalive hml
cu.nfn,nrnt inv,.lved and Ihe characletialiet of I/le viral prole/n-husl macromoleculr
mlelactN,n shoulA rrvral crilical clues to nmkrslamhng the mechamants of vlul
/ran.lnrmauun
i
Rahias, 1. 1,/ r.Arr, P R 21.1 Ginstrq, 11 S
lu/nur p.nRresaNn luryurr /11 tffrclUVrness In Iranstu/m 111 cetls, il would fnllnw that
In Trr.n.Jrr nnJ / s
r
ss
F
l
mulatrd pluln ro.
1t nnl a dum,n.lnl t,nRu1H c snsrl Rrnr, umda/ In a v1n11 .u1r Rrnr, anA ,.n.,./
P
,
u
atvNrr Grnrs, 247-2A2, 1984
that Illt leat H InsullK/rn1 tn Jrlenn,nr .hrrluv pn.ln .m, Rrnet cauae lu,m..a In
l
h
snunata
1ht
e/lN.rnty
,(
t1.e aaaay
in ,ArmJy camrr Renrt umrl.,IrA In (
r
rr surP.ur 1/ S Public Ilealth Servk~e.
p/nln unr Rrnes rrma,n. u. M dr/r/m,n.,l
/ tons the 1lrpa/tmenl of Micrnbinh,Ry and ('omprehensive Cancer ('rnler, ('n11eRe uf
PA
l)ur,M-.>;
P ll rl uf vut uns A SurRe/uns of (blumbia llaivenity, New Vntl,
In Nrlh, (:a11n, Grrsves, lansa (r.la I llarw.nrn/nrr nn.l 11L.nJ 1.nn/Juvnw Vul 29,
A(.wlr.n IrrwJt rn llumnw fru(rm,n 1I St.,/nRrl Vr/1aR Ilrl/m Ilrldelhr.R, 1761, pp
9 2/
Othrr lupput Nalinnal Imtdutes of Ileallh
I rnm the 14parlment of Mntecular Rinin4y, Ilniverslly of Csldornia, tlerieley, lhe SaIM
Inalilulr, tan thrRu, ('A, I sMnatory nf Molecular Oncoh.Ry, Nat.nnal Canaer Inv/lulr,
I rt'derirl ('amer Rttearch I acdlly, I rederich, MI), and Genrntech, Inc., South S.sn
I tanclacn
RI(:I/I.AtI(1N (11 I-XIKAVAS('111.AR ('OA(it1/A11l/N ItY MI('ROVAC(1/1AK
PI 1(MI A1111 II Y
ftlravascular cnsRulst,nn is a prominenl feslurt o( tuah imputanl pslhuh.RNal
ptrKrsset at ce/lnbr mmunlly atul ntnplsva and hat heen IhnuRhl lo resull (rnnm
prntnaRulanls sssncratrd w/1h the inflammatory or tunNU erllt peCUIur lo Ihesr, enlitles
It was fnuml that incressed microvaseular permeabibty alone is sufficirnl to mduce
erWlvsknl tatravascu/ar cna{ulatmn in tevtrd murnal Iitsues lhe retults md.cale t),at
saturallnR kveh of prncnaRulanl .re preseM evrn in normal lissuea and Ihal
m,crn.asaulac permeabd,ly n s,ate-limil,nR step in earavatcular coaRulatum
/1...r.n1 )l I rr ol
.,), IM'/ INn, Prgi
('/ll MI/'A1.. VIRAI INI I RA('TI(1NS IN 1RANSI ()RMAl1(IN
I NIIANI'I M1 NI ()1 1111MAN Al/l-NUVtRt1S 1 RANSI ORh1A l11)N (11 /'I (lNl t)
KA I I MIIKYU I 10'(1)I[I.ASI (CK11 )('f 1.1.5 RY Al.K YLA I IN(i ('AR1 IN( K:1 NY
A mainr advance in studying carcinngenesis hat been Ike develupment of well
defined cell cullurt syatrms whieh mimie rw eur* eareinuRenesis as r/ occura w
r.e... UlilirinR these syatems, sta{es analnRow to indialinn, ptomolilln snd p.uRress,un
have 1wn i.knlifred ernl Imp/nlanl insiRha into Ihe mokcular evenls cnvolved m Ihese
prncesaes thnuld he forlh:ommR In Ibis review we drsc//tle snmt of ..ur rrcen/ slud/rt
using the hiRhly Itansfnrmahk ('RIF cell line 10 inves/iRatr Ihe inlrrac/ems between
MMS and Ad1 in re`ulalinR the frequency of viral Itantformalw.n and r.presaiun of the
Iranslormed phenotype /hrr hndinRs indicale Iha/ catcinlqpns enhance A,/S
Uanalormsli..n, hu/ da mu dler the pa/lotn of viral 11NA inleRralinn intn ce/lular I/NA
or the pualllalwt r.prrsaron of the trandnrmrd tta/e A IiAelv hypMhesn is Ih:u crl/aln
c'u11m.Rens t.rN lheu enham/nR e/feel on UNA vuut bansfn.rnaUUn t.y inc/raunR the
payNnlmn n( cells ,n an .n/e.lyd cullure whkh can tlably mleRrate vual I/N^ an.l
Iht/rhy het:omt laamin.mrd In olhrt casrs, caccrnnRrM may tnhance I/NA .uus
/ransLnmatnm by allrrmR the raptessimr uf viral an.1/or eellular genes rrqunrd f,u
ealabl/aluarnl of the Iram/urnud stale.
Iluman T-cell kukemia virus, herpet viruses and Ilepati/is It vlrns hivr brrn
implicaled in the dtveh/p,nenl of specifie human maliRnancies, hu/ a dllec/ llnl (Ylwern
vuases anA the maNuny of human neoplasms has nnt Letn demm"ab.Hrd A IN,.a,blr
trason for thls spparenl nrpt/ve correlatnm may be Ihal m/nual hum.n ma1,Rn.uNU-a,
putallvr virusrs caust lam-rr v/a tynerRrtUC mlera,lu.nt rl)h In,/.umR Il.rmn.d
19
14
65100 7591
tar. mnment lumnr prnm.ntert, hormnnrt or olher yet to he drfinrd ...f.u In.a
Mrtl .haratlrrvrd crll .ultu.r Syttrmt thuuhl prnr mtlrnmrnlal .n Au..d.a1mR Ihr r.de
ul ro.Jlq.lr fatl.r inv.a.l...m to Ihe rlnd.ty of human cancer, aa well at Ienl b- an
undrr.lln.Lna nf Ihe I..a.. pnm plrs undrrlv.nR the prncettet of tunu.r prumunnn and
p.u/rraaun
Ilrrm.., 11 , Ir . ll..h..a. I 1, 1.tw, W S, Pmin, I M, Mcll.mald. N/ anJ I..h, r^ A
In al.fn.Jnr lln... ..f (u...r /'n.l A l/nrrn.nrdrrulnr .Cnu.ru.r (.unnntr.n nn.l
rh....e.nr. Nrw \o./. Al.n N I rat, Ina 19tS, (qr 499 512
Irn.u /hr IApurmrnl nl hfi.rnh».IoRr. Iance. (-rwlr./Intblatr u( ('anarr Rraru.h,
1 r.tlrKr n1 1'Lsaa.ra.,11s \o.l;r.ma.1 (.I.uuhu ItnivenHy, New SnrA
ANAI Y%IC //1 1111 N11111( I It (.11(1W 111 I A('l(IR //) PI Nltl N('Y 111 SIMIAN
VIN11\ .111 1NAN`sIt/Nh111) 1111111%
IAr ul/nn. ha.r mrawvd in a Je/.neJ tnum frre mediunm the platelet der.vrd
Rrn+lh 1..r.r 11IM.11 an.l unul.n rrqunrmrnH nf nnrmal Swns 111 cella, 7lnuan vuut
t11 u.u.f..rmrA 111 ,r11., anJ 1.nlul rr.r.tantn nf t.mrln vrrua Al0 IrandurmrJ 111
trllt \w... 11 1 tr/la Jnpltrr.) tt.nnR rrqunrmrnla fnt hnh P1K:1 an.l msuhn 1A. h nl
Ihr.r u.pn.r.urnh w1.e ur.m/..antly dmun..lvd in tanuan virua 40 Itantfnrmrd 111
trllt AuJat., nf thr PIM.1 anA mau/.n .r.pu.nn- m% of 1/M reverlanta rndKaled 1ha1 Ihr
t..a .d r.rl.rr ..1 Ihr.r Iwn p.uwlh (].hn .Nn.n.'mrnlt wat nnl necetaauly 1.nlyd In the
ull.rr, r.Nln r Il.e r.nr dh 1.. 1.n rry..n. n.. nl. +r..- q.rrdn a11y aaa.eulyd wtlh ulher
pp..mrlr.. d U.rnInnu.l..n /hr rr.n.ln...n..n ..1 ~ 1'IK:1 rrquurmenl cn.rRr.Y..lyd
w./h rr.nv..n lu d. n.dy d~lrn.kal K.nwlh wl.rrrtt rra. qu.a.Imn nf a nnrmal
tn..J.n .r.lau1 m. ul ....ry7.. ~ d..l wIt. .r. n...u 1.. a n..na d Kn+Ih drl.rndrn, r nn t JI
terum AnA h.n..Kr d. 1 n.l.n r w..a h ... n/.l.- I....o 1...A 1 p 1.r rrq.nrru.rnla
IAr rrlar...n.h.p luI..rrn fl.e 1'IN./ . q..... .... .l ~n.l .Lr.dt .LIvo.l.nl
1;'.1h
.nh.ArUnn o.r tnrlbrr anJrrrJ rn nuund 1/1..11. 1a m. .un.q tl.r 1'IM./ rrqun'n.rnl
al JJlr.ral .ell .1rn.J.r. AI h.Kh ..11 .Ln..r... 11.r q........ .rnl In. 1'IK.1 h . .nnr
trRndnandy Rrralrr N'r u.ryr.l Ihr1 .1 Ir..al so 1ur Ihr .d.Int .d b.malu.mrJ rlla In
Rr..w la 6.r.h aalurala.n drnvhrt rr.uh. f..m 1hr.. L-a ..1 a rrq.u.rmrnl Inr 1'IN.I
Pnwera, S I r.Arr, P R. and Pnll.tch, N
M.Je.ota, and ('rllula. 11ndnRy 4 1S7` 1Vh, W111
(LA.-r .arrrwl 11 t/a6ta IteJ/A 4...ar and Nat.nnal Inslilulrs of IIr.J1A.
Irnm IAe Isrparlrnrnl ..f Mieruhi.JnRy. ('ancer ('rnlrr/In+ti/u/e ..f l'an:er Krar.raA,
<.Iurnhu I/nwrrvry ('n11rRe uf PAytK.m. ` Su.Rrnna, Nrw 1fu.A
I/l 1'Itl Stt Il IN/1 KI 1 Rl1N SYNtlll C1\ IN SKIN I IRR(11/1 ASIS I RI/M
1I/N('/'AN('1R PA111NIS
So, rn fihrnhlasl cell cuttutes Mti.ed frnm mak adult lung caneet patienls, an adull
cnnuul Mpulal.nn anA a nrwtrun (u.pulninn were eaaminrd for the.r susceplihd.ly to
Iranalornnr...n ..nh Kualen munne ta.u.ma .inut anti Iherr ahd.ly In ret(u.nd lo an
.nlr./rrnn .olu.r. /l..lt I Ir.ly / 1 An aaanura.n Mlwern traad.ay to viral
1
Iransformaliun and induction of interferon was ohaerrrd ('uhures drr.ved l.nm luna
cancer paUrnls drmnntlraled aw increased tenbtlvily to virua It:.n.la.m.llmn anJ a
drerraarJ ahrbly lu reslnrnd to iMerfernn rnJuclurn as comp.ved wqh aRe ma/.1.rJ
cunUult and newlw.rns
Winlers A 1- . I.ea: h, M. F, Ihulun, F: I, aml F.nn4rl 1 I/ .
/.w.nol n/ lnlr. /r...n Rrsrur. A{ 163 1/0, IOjS.
I rnm the /kparlment nf lleahh and RehahdilaUve Sr.vraef Vrlrr..ns AJmnoal..mnn
A1r.lnal ( rnlrr, 1Impa, 11..
51111)11SUN(:1N/ IKANSIFR ANI/NIVIKUI/N II1tIV Rt\IS1AN11
IN XI Kl l)q NMA 1IGMI N'1<KItM 1-11 1 S
Ihe aulAati have esamined wvrnt paramelen which address I/.e /.aadohly u/
cnmP/rmenlmR Ihe IIV-srntqive pheno/ype nl aer.wlernu piRmenln...m (\I'/ Idnubl.at
by Rrrr /ransirr We ptesrnl a cnmparali.e s1uJy arhrcA skmunNralrs 114.11 rrlalse 10
io.m..rlatired crlls, hu man dipl oiJ eells are fMYV trciprenls for Rene Iran.fr. As
nwasurrd Ay tn.lh Ira nairnt ar nl tlahk ea1NtNaM aataya
drplarJ IdnJd
ntt wrrr
enmpM/rly refraclury to bNA ltawtlrr ,
.
hy eakium phmphale cuprr:.pAU1.un a.ul
e.Aduled suMunlially redrrced kvels of eapres.wrw fulA.winR Rene Iransfrr, try lusu.n
w.ilA I colr prnhq.laals We alsn eaamrned IAe srRwdi.7ncr of rr.eraun n/ /1.r
hrmd
K
p
)/
uf IIV senai/ivrqy in SVI0-immlwlaliled XP-A cell lines In a.l.lnw,n lu sunlumutR a
prevwwt reporl of reversion to rriAl-lype kvela of ('9V retntanae it a(rrqurucy
t
uf + KI
, we Aave at/emp/ed In faedilale /he ilknlifwatinn nf XP A trllt cmnplrmrnlrJ
wrlh Remrmic IsNA by employing kst slringen/ sekctwal sthemea anJ cmran.frctmm to( a
srlh-tahle marf,rr I/mkr /Aese eondiliunt, we nh.er.ed an mcrrateJ Ireqaency ol
.eversr.n and were unahle to ilealify Irne transfecunts.
Sahultr, K A, Ilarl.n, I) r. anJ InrJhrs. f. C.
.C..mnnr l'rll rn.J Af.drrulm CrmUCS 11(6)6U-6!1, pOS.
(IIArr tupp.ue. U S Ilelartrnenl of 1'.nrrpy.
I rom Ihe I al.ntalory of Fsperilwewlal (7wcnArRy, (4patlmeM uf P.uluduRy, 51.mfnnl
Ilnivrraly Slanford,('A.
PRI PAKA f ION ANI) ('l/ARACfFR/7A11(/N O1 MI/N(K /(1NA1 AN 1/1111U11 S
A(:AINS1 /11/ N()IIAK1111'AL-INIIII('11111. ('YIIK'1IK11M1 1 Is0
MnrwyArnal ntrMr/irt against cytncAronle P 4110 .r.e p.rparr.l L.un
phem.AatMlal rnducrd ral t.ver nlleroaomes I he Immum.a/..AYLn . 1 nara 214,1 s.d.. 1 ra.es,
as well at 1he hmd.na aapa(ily In cyhnha.me P 111/, ol the dJlr.r.N anlJ....l..s w.rr
tAaet.lerued Ihro .1ved4Ny .at veldMd by a.mua Ir.An.qurt an./ termr.I tn
crnreslmnd to a srnitle lorm of cylorhrome P 110, IAe mapN phrn../arlw~l .nd.nddr
form Ilowevet. Ike anlJrdies were unabk to inhiArl comple/ely the nN/mMHyarn.ar
KliviliN inveslilpted. 1Aese antibodies may consti/ute .ery s(.rcJ.c and )...wr.lul
analytical tonlt for charac/eriaiq and puutifying cylucArome P-130 .urcnrymrs
I euwe-Goujnn. 1: , K rtmers. P, Sra.wr, P, Paye, A1, and G.rlen I E'
Rr..rAr.n..rl onJ Rn.pAru.o/ RrsrorrA ('onrn.unnamn. 1191)) /JI )SO, 1/11
21
65100 7592
(hhrr rupMwl I ondc de Is Recherche S.'.rnlif.rlur Mrditak
1 rnm Ihe I ab.ualory nf Medical (-hrmhlry, Irnlilule of Pa1hnlnRy. I/n.vertily nf 1.rRe,
1 .rRe, RtlRrurn
III N71>In1lYKI NI MI I A11()I ISM IN h/l)11C1 I IVFR. ASC(X IA I I()N 111 11() 111
7.1 I 1Y1r11)A III1N ANIf ( l)VAI 1 NI I/INI)IN(: (/1 A MI 1 A111)I 111 l)1 1111
7,8 11101 WI111 1111 eA 1(K'11S
lht 7.2 rpoit,lstron of brna.4a1t+yrene, and Ihe 9,10 ep.uJal.nn uf
Iwnnst./rrnw/l,R Jrhydrndal coupled .ilh tovalrnl hind.nR uf Ihe h.Rl,1y rraiur
.linl epu.1r, air Iwo aey P 410 me.l,alyd rtacl.«.ns brl.evrd In ht impnlaul in c..n.rr
inH,alron, muURenel)s and IersloRenrsit New aauyt fnr Ibrtr Iwu rea, twM werr
Jt.rh1rd wah munar Lar m.clu.wn.rt Ihrv Iwn acl.vn,rt hrve spna.rn. K vlhna
(appr.u..nalrly A rM) ean.Aar lo Iha1 of aryl hydr.narhun hvd....ybar a.l../y ~I uenlv
1...n.I1.nIWI I melhyl.h.,lanlh.enr l.ratrd.IA1/AA4 and tA 4,. tA'1 proarny d Ihr
(1 \/111 /hN) (t111A/7N) t/ e 1/11A/JN ha.tunnt wrrt sludwd R.th of /ht nrwly
dra,.,le.) saUn.rt appea. /n rrp.rvnl P t10 p.nle.Ma/ Ihol are rrynms.htr .. aryl
hpluwa.tr.n hyd.n.ylsar s.bn.ly an.t that arr r.wn1nalrly a.m.nllyd by Ihe AA" :11r1.
Van 1 anyfu.l, )/ f snd NrM.I. It W
R.n,Arnnol PAa.w.n.nlnt. II11n)tR71 IR,`h, 1rRN
f/tArr ,upry.I I..nda dr Ia Rr,hr..he 4.rnid«I.r Me,6.att
I rnm Ihe I a)rnaloue Jr ('h,m,e Mrdu 31. Ina,1u1 dt Ps/h,iuR.r- I/nde dr It .w h.uur,
I.rRtI hrlRwm, an.1 I aMralury of IN.rI.(.mrnlil 1'harmaauluRy, Nalw.nal Ina a,dr n/
1 hdd Ilrahh and Ilunman 1yr.rhy.mem Natwn.11 (nu,tult. nf t1ra11h hrlbrlAa, h.l
I//1 ta(PRICq(1NO1 hI/11RIN1 MON(N)XVGINASISS1111Y)K111111Y
( Y1/M IIRI)h/l P 1%01N NIl)NAIAt KA1S ANI11N /'RIMAKV 11 1A1.
III PA I(K'l 11 C tN ('l1I I I/RF
In ral livtr, lht perinslal develnpnmenl of varinus mnnno.yRenate acti..l.rs follnwa
dlfferenl palleros, depend.n@ upon Ihe rtsclnal tludwd lht nntuoleny of Ihe hA-, 7n
anJ IOn lea/mleront hyd.my/ase acbv./its ddfe/1 vtry sipnifi.anlly
Aldrin rywuidase and tlelon/ mtlatwdrrinR mnmm.yRrnaiet are eprrsard in
pnmary Itlsl ral livtr cells in cul/urr sfler, hltalmenl rn rrtrn wdh dr.amrehaaone
(tslotltrnne is nnl meldxdired by Ihe cnnlrol ctlls and is hydmsylalyd on Ihe h/ snd IMo
pnvt.om foltowlnR IM addi/ion r.f cnrIKOMII In the cuhvre med.um Ihe .1mr anI lnvr
turvrt vuy s..nrfinR In IM hydauy/sNd Msllirm of Ihe tterv.d Ah/r.n ry...d.na
a.l.v.ly n wrsrly vndr/.cuhM iw /1.r conlrwl crlls bu/ Is p/rsrnl twJ N.n/,.. hlr 1y
phrmharh.lal (v1lnw.nR Irealment wdh /M .ulnnnI PhrmJarbNSl .wdu,rs 1bro
epq.nda.e .n Ike ahsrwce 01 decamrlhatont Iw Ihe cullWe ncrdwm. Mu.n1.nR tlh..l Ilhr
cellt art prruesled w.lh Iht cnrlicn.d tor 42 h Ihe Ine of anblan8rt aRa.nml Ihe m+.n
cyarhrnme P10 aprc.es purdirJ frnm adul/ and pbrnoharhila/ bealeJ 1391 cunl.ma
Ihsl a sn,lar t yl.n hu.me P 00 can Ir mduceJ in fe/al crlls in a ullure
lhr pr..naul ,rR,uluww of h.uhRaa/ ernn, su.h aa /he esprrsau.n nf t/.r
.n ..w..... aw..r. ..w 1. ..Pn.l..,..1 .w trlJ al 1.ea .rll. ,n a.dt.ut au,h a m.,1I
. .. .... 1....~ ,r.. 1 ....1...... d ,nr,h.u..ma .lu,h . r.b..l Ih,.r
. ...,..... . . .1 , . ,
t
Krernrn. P, I rtuwe-Cuujon, F. OeOraeve, l., I)uvivirt, 1, and (:nlrw. l/.
Fur.qran lnurnnl.r/ R.aArwuu" 1.176(I1-6pR, 19a1
Othr rupryvr I onds Jr Ia Rechercht Scienlifipue Medicak.
1 rmn Ihe I ahnraWry of Mtd/cal ('hlmnlry, Inslilu/t of Pa1hnL.Ry.
I lmvrrs.ll ( I irRr,
LreRe, nrlRrum
('1t)NING ANhSIRI/(II/Kf ANALYSISO1 f111. RAl
A/Y11 11'(/1K()111N A I c1/NA
Alahpnprulrin A 1, the major prnltin in mammahan hiRh denuly lipuprnlern a,N
as a culaalor f,u kulhm-cM.ktllrul "yhunderaoce durinR Ike /ornaatron a/ clwtrslr..d
es/rr aml aa tuch, .s IhnuRM lo prm/uNe cMdevnul ef/luo frnre prr.phrral arlls Io Ihe
bvr. In thn (VIK1, /Lt aulhOrl Ir(Mrl Ihe p.1.IqI pMLIn.11mn n( r.a hrer aP14up.ult.n
A I mKNA by a µ1ysu.ot rmmvnoaduvplmn IrthniVue and /H c1/NA clura.nR Iw/almn
nf Iwu n.r.l..pp,nR t1)NA clonte enaldrJ Ihe rrsearchtq lu drn.r Ihe wholt ral
alblllMlprnle,n A 1.1)NA c.rling sequence ('.m.paria..n of Ike dr.tuard prulrm .rywn.r
w.th ita human cnunlerparl rereals a senlinR ho.mdoRy 1wl-rrn Iht p.rp.uprplntr
precurSnrs 1/n1h malurt pro/ein aminn/Tlminal rrRwmt are wery hamnlnR,.ul auRRralmR
Iha/ tlus parlnviAr .lomain cuuW he invol.ed in lynJ p.u/ruo hmJmR .n
Irc./h.n chulesirrol acyhranafrratt acliva/n.n
Pnn.in, I I, Ma.1n1, 1 A. and (f.rltw, J F
Furn/.nn l,x.rnol n/ OnrArmrurr 110 191-198, 1924
OIA,-r .uph.n M.n,tttre .tr (a Pulilique Scirn/ifiqut/ Ilelg/om
Crom the I alw,ratnne de ( Ainlit MeJicak, Inalilul de IalhohRie, I lni.rn.er a/r I irRe
11t/Rirm, and I aM,ratoire de Crme Centlique/ Inatl/ul .le (hinur, I/e1R,va1
SIRtI('llrKl: ANI) K1OtI1.A11(1N (IIllll: 1111)IRMAI (1KUW111 I A( IttK
Rlt IPI()R
1 he rpnlermal ofrowlh fXlnr (1 (:1 I rtceptur it a/ramn.r.ot,ranr, R/ycnaylslyd
phMpMprulrrn wah inainsie prnlt.n-lyranin! phosphulfaM(rraa acersnv Ihe
amimnerminal cr11 wrface parl of Ihe I(:1rnrp/nr, whnh conu,at ammoamled
orlmhydrale, has a sinRlt 4G/-bin.bn0 sile Iht earMny/rrmin..i aylr.pla.nuc ,hro.a,n
corrtt/n.ndt In c.A B. hnown nncoRene tlruclurally bnmulultnut 1u
prnle.n /yrnsine Amastt Self-phnspM.ry/a1Mm of Ihe I lynerplor, wh.ch o(cu.t un .1%
catlwny/enninal dama.n via an iMranudr.ular nltchamsm enh.smes c:./rlvlW aalr.ny
1'h.nphory/sliun n/ //.e 1(31 relrpmr by prolrrn hinasr ( tulqvra.ra nt pn,lr,n Iln,nr
&,na. a.l.Ily llr.Auae (dn.y.Aal.JyhnM./.J Isinaat h/rv11y an Ar arl.n..r.1.
prwlr.w 1).nunr am.ae rrrmr 1. br d,e unly CAIdyUC a.h.ny /nbman 1 pu.J.r.l (1./
rrceprorl In hu.u.n ep.dr.mvwl car.mm.. A411 arfla, Ihe ralrnl .J .a,pbl.. ~...n u/ 1/.r
I(i1 rrarplor Rrne delrrmines the ee/1uLu conlenl n( I(31 rr.rplur p.n/r.n Ihr
amounl of /(71 receptoa rn ehnsl varunl At11 cet1. J.clales /heu R.owtl. n.p,msrs 1,
1(:F
G.H. C N, Ilertict, P 1. I homptun, Q M Wrber. W, an,l /Whrl, ('
(,mcrr (.ll. 1./..,. rA I u. 1,... ...nJ 1 rnn. /n.wmrn.n 11 111 , I')R S
!I
I7tA.r N.Itinll Intnlnlr nf A+11N1.a. Ih.lrlt., l).Rr+uve and Kidnry hneaars,
anJ AN.rrn.rn 1 an,r. 'w1r1y
I ram Ihr Ih. putmrut d Asr.h. mr Ilrvl.un nf I n.lw 11nuh.Ry anA Mrt.ltMd.am, C. hn..1 uf
h/_J..lnr I lnnrruty .J (.Jlu.n.a al diIn U.rRn, 1 a 1.413. (A
NIIAII/1N\I/11'IIIIWIINI'I(1111111IN/N(11 II'It1/RMA1 (:It(IWIIIIAt1/1I!
R11 11'1(f1t\ (:I NI A0111'1 Il lt AIIttN, ANI1l IIRI)h11/11/ht1 /
INAN\IIN A11/1N IN VANIANI At111111i
\ynlhran uf the rlnIrrnlal R/nwlh faclor O (il ) recrptnr ha+ INrn sn./rrrJ In a
sr..n .d varNnl A111 human epal..m..nl ca/amnn.a crll alnnea rr/+NIrA 1.e conlam
dd/rren/ anuNn(s n( 1I,1 MnJrna u/rt )he smnunl nf 1(.1lrarplN. pudr.n,
qnln/dar) hy .n.oNm..Ill.nqy .tunmasaRNph7. anA I(i/ /rarlN.N mRNA, Y.ama.atrA
1y .t/NA hsb..dv..lun, +.r/t \hrvly a.N.rlalrA In the talent uf Ilil rr.rt.tnr arnr
amlL/a uron Ilu. rrlN~.n r.nlyd .n varlantt trltclrA 1..t rrJuaeI 1(:/ rr,rpln\
an1 in rrvr.lNN I.nn.'1h.t v.NUnla with in.lraarJ 1(i1 rrceplun lhrre was a/an a
c.r/rlaum 1rl+rrn tlr Lrqurn. y n/ Uan.l..aaann nf chlnlmnno.r 7, cnnlain.nR the 1/:/
/r.rPl.n arar anA 11,1 rrarpln. p.Nle.n Ihra /r.uht aulM'll Renr amyldlCal.nn a\ the
mr.haan.nrnhln,rnRA1lI.rll11.1 rr.rpbNp..N..nsnJ.lrlr.nNninRRlnwihlrqn.n.ra
(.dl r: N .r nl
.C...wnh. (YII wul a1.A..nlnr (::nrnrl 11/J) 1111 IIN, /IIIS
(1/Arr o.pryNt N~h.n.l In+tNUlrs n/ laraslh and the Amerrran (ancer Srciely.
I um the 14p.r1mrnl n( hlrAi.'.nr, hni+ma n( 1 rtd..t.inuloRy and h1rqMAnm.
IInlvrrsNy nl /:dJnlm] al S.tn IbrC, ~Inwd nf h1r.L.lnt, 1 a 1NIla, ('A, Itrparlment .d
Mnlrcul.lr tlaJ.Ny, Kr.o Ilnivnvfy C.'hnd ../ htr.h..nr, LuLYn. lapan, 1hpartmenl uf
('rllnla/ anJ Isrvrl.pmrol..l Il.nl.Rv, IlmvenaNy uf A.vnna. I.naun. aoJ 1 atnN-alury of
h1.Ir. ul N 11.JnRy an1 V Nn1..Ry. I hr %.Itt InslN.nr, ( a luIlJ
til l l Pltn\I'll(H(YI AIh)N INIIAN( aC 1111 1'R/)111N~IYR/ritNI KINACt:
AI'11V11Y t/1 1111 11'II71 NhtAI.1.K17W1111 Al'/(7R R/( 11'1()R
Ila eflral of srll phosphuryl.lU.n Nn Ihe prnlein lyrnsinr \inAse adivitS Id the
e1+Nterm.ll Rln..1h /wl.r rectplnt h.s Iwen Invral.r.lIrJ usvnR Iminanual(m.ty pulilird
p/Nlriw I nrSmr was IN+1 imnhalrJ (nr v.lnnos Umes wilh eacr.a A1/' to pMnfhrNylalt
it IN d111rr.nll 11.e atutdy .d tlhr rnrynlr hl IJmsphulyl.lle e.nRrnuul IKptnle
suh\l.alrt +.IS Ihen /nr..+u.ed as a I.m.INn .d .1s srlf phnaphwyl./lnrn s1,rlr I/c/taainR
1.11 p1...+IpluNylaln.n 1.. I{ I I nl.1 n/ phn/dl llr nud //.f epnkrmat prowlh Iaa1.N
Ir.rpht rnb.n.r.1 1.... frln ly/nvnr /.n.l.r a.uvlty : IInhl /.mywr.vun u/ d.r Imeln's
/A INUtr/n lyruvnt /.n.e a.'slvily :11 I1.11n.nl AIM cnnienl/.qan1 revrale.l u(ndNaM
d.l/rrrmrs Letwrrn unl.Mnphmyldrd anJ ph.rphNry1.11rJ rnryme AI hl.. Irvels uf
A/1', a dauldr rrr.y..Mal p1n1 n( ILe /.'Ir.n Iyrasinr Mlnase xlnNy of she
unphnaphnlylalrJ enrvlue wat hylw/Md.e, aupRr.ImR that Alr nuy a.1 as sn advadN of
the enrymr AI brRhr/ A 1 h cnncrnbatmns, wlwre Rlealer levels of srtf pM.aph(m y/a1N+w
n,a.lae.1 du/mp she .eaclen, the \mrlics aM'r'a.rd llnrar ami similar 1o /hnu of Ihe
/.h..Lhnlylalr.l rnrvmr Ihnr /ral...nu stuA.n uvnR I(Ntr ddfrrenl IwptiJt suMlrales
IanKuNen\N. I1, alrrn, anJ a a)nlhtr.c IYItl.lr PNININ.nII1n~ In Ihe sAf phu+phn.ylalmn
,41
I
sile in pA0' "') shuwed that etollenout subslralet inhibil reteplNr self ph.nphnrylahun
In roch caae, half-nucimal inhibilio/l was observed at a Iwpllde rnncenlralu.n
apprn.i.nasr/y rqual lo the tubslrale't K A LinetK analysls cumpsrmR prp/nar
plwapbu/ybtn.n u+noR unplNnpMNylaled aru) prepho.phorylaled rnryme indnalyd Iha/
Ihr arll ph.n,phoryLllwlrl slle can act as a cunlprblive inhibilor (a/trrnale subslralr) r.-rari
prpl.de auba/alrs Ihese results su`tral that self ph.sphuryla1u.n nf Ike epidermat
Rrnwlh Ixlnr Irirplur reuloses a cnmprlilive cunslrand so Iha/ eauRrnuu\ suh+tr.l/rt aan
he mulr teaJdy ph.nphorytalrA
Ur/lw. r 1 and t.J7 (: N
I Ar I.n.rn.r/ n/ Ar.!.tunf ('Armrsnr !W(?7) NM2 11G/7, 1'1115
Irnn. the Ihpar/rnrnt u( Mrd.cine, fhvi+Nln nf /n.trrinnl.rKy an/ htrlalwLaol
I/nl.e/.rry ul t a1Ju.n..1, -.In It.rRo, $ahlNd uf Alr.ta Inr, I a lu11.1, 1 A
htlt"kt/l lltltll S, 1 t 4C11f' AN('/l(1RIN(: 1'11h11'11N1 N1% Itl 1/11
I X1NAt 111111.AK AfA1RIX, AN1. AWNIA111) WIIII IIIIR//NIt11N IN 1111
%/IN111 1 t/1 /1NN ANI1 A(/N /'A
hlwlnhb/ds air slnalrJ tubuks Ihat ptay a rulr in the /ulnabun uf tlanl.n fdNla
.vnllurmRala aal(..Id S/ upnnIHwa/snwA h newly svn11N+vt.l el.l+an n Jr1~nNrJ
byI/IIaNpuI w
I' anJ sl.umnR WI IH/1e11n.nNrale ml:wllhrils /h;H Luoloalr whr.r
elaaliw is sl'a/ae ur ahsenl in basal laminae, pl.ls.na mrmbranrs, an.l Ihe an/1aRrnuu\
m.\Illt Ihe musl l11.A1nR acl'umula1i1N111f onvrnllbrJl is fuuml /n the rullalr .u/ /mn,
the Ilan.pa/enl anJ elaslic suspentoty IlRamenl /lf the kns, whia'A IunlaNls nN rla+l.n
Apl.t/a'a1Nm n( unnlunncyhKhemi:al slaininR wilh a prrusida\e aul.pr.o.iJ.l.r (l'AI')
p.rtdure dr/nnnaratrs 11131 fibrnweelin is aavmia1rJ wilh Uie micr../.blds uf Il.r rNnule
anJ aut/a ARR/rRatrs of ullctuflb/llt alt nlrnliavl lu nylalan /"aad endu/inot'1 IJr/s
that havt INrn drsrrll.ed in I.nidonlal menJNanrs and o/hrt sdrs suh/rct lu mr.hanwal
slrres and /hry can 1N fuun.l iw sites as Al.paratr as Ihe rahbil rnnule, /al hepatlC sla.ma
alal human carduc p,l.lnary muselr, i/nlicaline thrl miirn/lb.ils arr a wl.lely d.su/hulyd
clulnes(ive listue ehmrnl wilA a funclN/n /hal r%lends beyund rla+lNjrn..ia, /htir
asNK/atn.n w/th fdnonrain and 111aa6/Uilm tuRge\h Ihal dley srlvr a. an r1aNrC
an.hlumR tNm/Nlnrnl Of the etlraCrllYlar nu11i..
G..IJ/r\. Arr. S. C.ultulf-S.hJlrr, 11 , aelt Goldfiacher. M
7t\./N.1 (rll 17111 dJ1 410.1995.
.
(pA.v anp(rnf N:Iliun:J Ina/ilutrs uf Ilealth
I.um Ihr Ihpubnrnl uf 1'.Nh.dNRy, Al1.eU 1 ioshm ('nll.ae ul hlydalnr, Iht Ib.mt, NY
A. 11 N1Y1 A/l I111/1NIN1 0611 IAIIUI (\At ANts I R.\NCMI t//SI AIIIIN
IN ('ANt 1 R
hlrlll.nnu.e mrl.d.oham a.ul Uawsw/tlhyl,u/un a/e f/eqarnlly In can.r/ \rll\
the allrral/ow is ollrn eclNrsseJ as an m,.b.bly uf the cancer atll, lu R.,.W ./vn
methineine is rrplaceJ by homncysleiwe in Ihe cuhurr wleA/uns, w cnnddNm /ha a11/.ws
the Rrowlh of n.Nnul cells lhis wselabobt defecl is termrd twrlh.nnme dr/.rnJrme
Methinnine drlrn.knce may refkd aw nverall iminlae:e iw (rammtlhylalN.n wh.,h
rasulls in Ille O.r/1nelhyla/N.n of sNmt tYh7lanltt and Y/Idr/mrlhylalNln nf ..Ihels w.lhn
7)
I
cana'er cells Many ca.c.notens affecl vatinua slates of mrlhw.nine/Iransmethylal.nn
melahol..m Ibe ul/.mate effect of 1ht alteralwn of inelhiunme/tt.-tna.uelhylatw.n
meuludnm may M Ihe d.arupUon of Ihe rr{ulahun of tenet involve.t in the oncotemc
pr...ras the known p.ulecl.ve effect of inelhw.nine aRa.ns1 cancrr may he due to
ptevenl.un ..f ahetrd melh.umne/ltammelhyhln/n melab.bsm nr cumpensahnn of the
allerrd mel..h.ham
/h.f/.nan R Af
~bnrrnnd e, Kr.run A t 1 10, 1985
(Irhrr turry.r lhe Nal.onal ('ancer tnalilule and Ihe Georte A la.ohs Memn.ul l und
lut 1 an.rt Reara..h
I tum the 14pa.Unrn1 of PnliairKS, (lntvrrsity of (-aldornia, Can Iheto, I a 14,113
1111( 1 411 ANItPI AI111 f ANf10(ybY (IN f111. b1.Vf1U1'MIN1 OF
1111 MI INAK V k/l 1 ASI ACI S I1)1 I l)WIN(i INII ('11l)N (1F (-1:6 ('()1 (/N
Att1 N(K"ARI IN/7MA, 1 1 WIS I IING IAR('INOMA, ANl) 1116 AMLI.ANPIIC
0141 1 AN1/61A 1(Iht()R ( 111 S INIt) MI( I
/hree ddfe.ent murint lumnn, ('1:6 colon adenneareinoma, tewa lunt
ca.ctnmaa, ml IIIA amelanm.c InelJnnma, writ inletted tnln syntenere mu'e (l1ALR/e
and l $/1[1 /6)1 /n Iea the effect nf rahh.l anth mouae platelet snlibody on the
deveM.pmenl of pulmunary melaslaars Antqdalelet sm.bwly, when injected ip,
dr.rrawJ the plaltlel cnunl ftnm 1) l0 012 a IM/M/ at 6 hr, which remamed at Ihn
level for 24 hr Anl.pl..trlel an/.h.lr tven 6 hr pre- and It hr Loat-i v inleclion of
luwtm cells dtcreaard Ihr mean rtumhrt of (1 76 lumut mrtulrt per luna by 57% (rante,
47 to 65%) anJ dettra.ed the mean m.Qule vnlume uf lutnor twr IunR by 111 (ranRe, 0 1n
71%) (IN espeumenul an.mala), when cumpared to Ihe effect of nommmune aetrrn nr
itrrlevant an11/mmuM.t/nhul/n anlthrly in 116 cnnlrol antmaH With I.r..it lunt
carcrnnma, anaplalelel antibdy deuraaed the tnran numAer uf tumor mwlules by 62'Ik
(rante, tl to 71'tl/ and decceased the mean nodule volume of tumon by 64% (rante, 6(7
to 7T\) mmR 411 eapetimental 1111.111311 snd 6S cnmrul snimals When lumor celk wece
ttven sc , anlq.tatrh-1 anuMwly ttiven 6 hr pie rn/eclion. It hr pnal-injeclinn and evety
49 ht Iherrofler alan decreastd Ihe mean numAer of teelaalaset by I:% in 14
e.perrmental and 13 cnntrnl animals. With 1116 anselanolie anelanuma, anliplalelet
anltlrwly given 6 hr p.e and 11 hr /Mu-injectan tkcreased Ihe mean numher uf tumne
mwlults by t3X and decrtated /he mean noduk volume of turnnrt by 66% usint 9
tapc'rimenlal and 9 enntrol animalt SimJar rttullt were oMained when all Ihtet lunwu
.ere in)ttled A M afar the injeclion of antiplatelrt antrbwly 11o.ever, netative reaults
r'ete o6talnrd /f am.l.talelet anlibnly Ma1 injeclyd A hc af/rr Iht m7ectN/n nf 1wnwN
crlls \.n.e anhplatetel am.b..ly hat ill maaimum tlfecl al 6 hr, it is bkely Ihal plstelrls
play Iheu rnlr in Iht AraMq+mrnl of prhaunuy tnetsaltaes dutint Ihr (wat 1) hr of
lurnnr rmw u/alw.n
Peartale.n, 1' , Ambrotio, C, anJ Ka.par(.n. S
( onrr. Rr.rerrAs 44 11t1-ltt/, 1984
1.nm Ihe 14partmenla of Medicine and ralhnMty and l.vintton Ilorte Inttd tle, New
\...k Ilmvrn.ty Mrd~: 11 },hmd, Ne. Y.wk
I Al'K fll /11 f(-I (11IN 1"llc) PRl1STACY(-I IN ON 111E 1/1.V11 (HMI NI
l)1 1111 MONARY M1 -1 AS1 ASI S IN MICE 1(11 1/7WING INIKAVI NIII /S
INII ( 11(1N /l/ 1/'h ( I/I //N 1-AK(7NOMA, 1 1 WIY 1 1/N/: ('AR(-INI Ih1A,
(/R U16 AMI I ANO11(- MI1_AN(/MA ('E1.LS
Ilnnn rr af have recenlly reporled a 911% reducli.n in the development of
melasta.et of 1116 ao.eLtmNic Iumor celts tiven i.i follnanR a sintle .W.x u( pantacyclm
IP(ac) snd Ihruphylltne (100 pR each) )0 min prlnr In Ihe injectrrn of lumnr cells Ihe
p.rarnl aulhnn have hren unable /o reduce pulnwrnaly tnelaslaset rnduced by the i,v
rn7ectw.n ol ('1:6 cok.n adenocarcinoms, le.rn /ung carcinoma, or U16 unelalwrbc
melanoma ce1N w.ith a stm.lac reRimea. lhw. P(aa and Ihenphylline given prw.r to
inlec/w.n of tunu.r cellt anA .' hr post In)eclwrl had nn effecl on Ihe numher or volume
of pulrnnnaty lomur muluks ftw ('176 eellt, Wrns 15 eaper.men/al and /4 conUnl
anitnalt, 1 e..n lunt cellt, usint 1 taperiteeMal and 11 conlraA an.mala, or 1116
amelanotic ce1H, rarnt 76 ralenmrMS/ and 12 eonlrul animals lhe IYaa used wat
sbn.n /o he a.9rve tn nr.... tnh.AdinR /wnor-induced platelet aRtre/laann by all Ih.ee
/unwnt al 10 t M aml to rrvn by inhibtliun uf (.e.rit lunt-induced IMom6rw-yt.qan.a al I
hr, rttnt IW pR IYilc p.wn lu the injeeliun rd turmu cellt.
Karlwrk.n. S. AmhtuRin, (* ., and Pearltleia. E.
fancn RrvacA 44 11Nt0-1tR 1, 19t4.
Orlerr aup/rwr Nalinnal Inatilules of IIea11A
I com Ihe I)rparlmrntt of Medicine snd hthnloty atwl tuvinRtun Ilnuse Insthtute, New
Yulk llniversity MrJKa1 SiMwd, New York.
NI I/R(1P1 PIIt)1 K A MAJOR TACIIYKININ IN PLASMA ANI) IIIMIIK
115.\I11 S I K()M 1'AK( INI)tU PA I IEN IS
I.vwfence is preunted foe tke presrnce nf as enture family of
larhyktninimmum.axltve peptiks in pbtnu and trnwN lisaues from palrems wr/h
caecln/.wl Iuminl. lhe petNwle4 IrKIWIe, in sddAion 1u suht/ance P and neutukinm A,
neurokinin O, an elyduisin-like prplide, snd awnpep/wk K, a 36 amtnn acwl M.nt
lachykmin which contains nerroklnin A al its C-lerminw Nertnpepude K seems to be
Ihe txhykima which rs prrsenl is AitAesl ennceM.Nwns in plasms n«HI as rn sctuc
wid ealracls of tutmn liaaues 11 is highly biolnsic'ally aclive and may therefore
coMrihule to the chnical syrnphwnt of earcinuwf tuwbrt.
fhttw6wason-Norhaim, 1, Nnrheim, 1. (thert. K, I/rndin, f.,
M. 1 alemntn, K, anA LtnJRtrn, P/i.
I unJM.Ar !
Ilww Arma.d un.l IIw.PAr.w nl /t,-u'M16 l.wn.ww..n arnM\ /1N I1 7) tl 194%
(/rMv awryrwr Nnr4..k tn.ulmion.l, S+.rdnh S4k.rty Of Mrd.ctnr, Katnhnaa. In.u~nle,
Uppsala Univertily, and S.ednh Medical Kesearcb t'uun.d
From the I)rpattmenl of ('tmKal Chemisuy, Ksrotinaka Ilospilal, Ihe 1)rpsrlmen/ ol
PharmacolnRy and Uiochrmiary 11, Karolintb instilrte, Slockhulm; and the 1)rparlments
of Internal Medicine and Roenttennloty, t)nivetsilr Ilospital, Up(nala, S..eden
21
III RI III AKY (1VARfAN CARCINOMA 11H)MARKf R 51111111 S
Ihrrr uvanan canarr prune \indre.H wrre stu.lied, luo .f +hi.h cnnurnr,l
wlrnlN.lt L.m anlcra cnn.w.tsnl frn urarun ca/.inuma In nne hinJrrJ. INnh nIrnln it
1w.n ...Irra haJ dauRhlera .nh n.vian CatlrlNlma In amIhn \.ndred, one of lle
alrnlnal rwsn sntrra 1Aa.1 an u.auan tancer affrcleJ JauRhttr I/sarqn carcrmsna
thn..r,t vra1N al /.ansmr..n.n m all Ihrre famd.rt rw a Pallcrn Cun..w.uN nrlh : n
a.dusurual J..nun.ml mrwtr uf .nhrril.lncr MrJKaI-genrtK turrry nt cash la.nily
unluJ.J Jrtadr.l qursln.on.rura rrlh /elrary) of ptrmary mrdnat anJ palhata/,
J.aVrorrlls rm 4uprr nf a11 an.n.wsw' 1LItt 1'utalrte prolwar\er Jrlrrminalums rnalrnlrJ
(1) rw .u.o hyl'rr.l.lInrJr m Jrrm.d mnn.JaYrr eullurtt, aml (:) lu..rr trrum IevrH af
a11.1ra 1 lucnarJaar (?/S Il)/ml) In 211 canceraffeclrJ palnnla anJ lahslu:ally
aren.INant h.+,rr krtls in N/'% ris\ rm/1rNW?/s when comparrd t.t slw.usr anJ putd.sh.v1
a..nUnls //'-OISa anJ POIIMI?, reHlwslr.rly) Ihrae I/ndinp are JscuateJ in conlr.l
rnh 11.1 rrrnlu.d .L.rl.qnnrwl uf \ rrs\ 1'a./ur prnhk .LN h, 0wen a..rpl.d.k trnanr..,y
an.l .IN.dNdy, .urJ,1 rnah'r nlrnlJ.ctaun uf /nJHNIWIs hn .uutJ bt prunr
r mdnldrt (.. ml,nsr.r sar-dlmtr/nuneRrmrnt prnKramt
I rn,h If I rl ul
ttl?/J10 415, I'/l15
(Ilh ,up/'.'a Nrlnn/.. 1h....nn, I ralrrwd /lrhv, uf I y;trt
I.mn the ('rrrrhlnn IInrrnvly Sthn.d./ hh,1,, aan.116r Ilrrr~ln.uy ("anirr In.ulult,
(lm.rlq, N) N.Un.n.t ,ntlnulr 1r 11,r ,nR .uul \Inv.h Ih.a..lrrt in ( hA,brn,
/lmaha, anJ /'...nr11 Iln,.rra,ly hlr,h..rl l11I hl,r, 1, NY
I Ah1111A1 I MIIKSY/NA1 I AN( INtlht.\ IN A I ANI 11l 1Ifl1N1 AINI.R) lt
lamil.al htl.:ul.sc .an.r. n r.ne Ihr% rrl»ul JrsarJ.rs a f.m.ily ..nh an unusua/
aansrr sINCUmn thal nNlu.trJ Ilrr mlanrJr (,uo.,d rmLryno.J.aau.Orna nt the /rars In
the a.m..f ] tanarr Irre hul puUlrrr uhlrr.alr Rene aauwv .nolhet, auJ the adu11 (unu u/
t.nhsrnnat a]/tua.ma in Ihn wumaws nnlrrnal I.all brulhrr Ilhea mWsul mothrr ha,1
rnalrKuanl mrlan,.ma anJ urrnary hta.tJrr 1 ucrnumal IlrreJrl.uy arn.lr.uule JruRna/wn
rr.n.um rtus.rr 1'ru,nly anrnln.n In hrarna.Aer researah rn lanubrt ol Ihis IsPe Iu1
rlucJ.m..n rd :autr an,/ .unh,.t is JraauurJ
I IwcA ll 2 rv ol
I Ar hwroo! ul AIrJn rnr 10 891 /9A, 1'/I1S
Irom she hrparlmrnt nf Prrtnlwe MrANinr/Puhlic I/ralth and dse /kpaaruem af
1'alhulnRy, llerKhl.rn I/n.rtrtdy S.A.Nd a( AlrJnmt, anJ llhr Iltrrddary / antn
Inahlulr, Omrha, NI
('()I (/R1 (I AI ( AN/'1 R IN A Nl/('1 f AR I AMII Y1 AM11 1A1 I)R
IIIR11r11AKYa
Ikcaute of the h,ah incidence of culurrc/al carower, famitial aRltrrRaliows of thit
Jrsease are curmm~n IlJfrrtnlr.ll.on Athreen tlmh.Rsf cun/usl.uling to fanutwt
aluaesmg I+hnh mar ha.r rrsulttJ e.lher (rom c..mnmun enruunmenlal ryNnurr nr
Lunr n.rrr .hrn,rl ..uJ p.,n.ut Ilrnrlu 1.,1ara .nar 1n.rr ra.nIt I..Ihr phYU.cm Ih.s
drds +,'h Ilv a.su,1 /.r.1.Irn. ru...wn.,.1 .hrn anruq.lma 1u n..Jr su.h
el.o4.tit dialinalwnt in ,nJrr Io provide appropriate lurvriuanse anJ m.rntRrmrnt, ehaard
VINIn IV1m.t .1.,_. bwn anJ nalur d IuVOry. Iw palirnlt 31 rM'/ra.rJ .ansrr r.aA
/ rwrA p 1' ct ,d
lhs.wsrs u/ tA. c..l,w 6/6-, tunr 2245) )10-)16, 1915.
I r..m Ihr Ihp.uUnrnN of 1rr.rnU.e Medicine/ruhlic I/r.dlh, $urgr/y, ralhuluRy, anJ
RaJNrluRr, ("rry;hl..n tlw.rr.ny 4h,Nd rd MtJkine and the Ilrre.hlary ('anaer tnsl.lult,
Unsaha, NI
I ill CAKI Y1h1A. 10141 A%1 I AN( I R, 11/N(; CAN(-1 K, ANt) AIIRI N(X'()R 11/ AI
l'AK( INUM.\ \S NUltl /xll 1<1 V1"1111) ( 1111 h11()1/I) ('ANl I K
Mr ou,1-1 /+.. chd.h, n uh.. 4u1 rlulwlumyn.araunu :u..) rhul.fnluu.a anJ r.hn
+rrr Imm a LuuJV ...d. a hrnJn.uy t.tn.rr, s)ndr..ure 1h.s1 ras clbara,IrrveJ by
t.uawm.l, Lur.l ..m.rr, b, rns lu.n.ns, Irur~ C.ur.H, Lutngr.J t'ar.uN.ma.
........ Iru\rrara, anJ
a.hrn.~urlaal s.n.a Ihr J.IIrrw.ut Rrnulypr
h]1 mr. INen rllnesuJ IlsrouRA Ihr
fnuah Knnr.un.n nl Ihr. Lugr AuNhrJ Ihe Irdrrrre emplutvrt Ihe mrJ /ur an
ratrwdrJ Inslnry ..f srrrr.rl /;rneralmua In acrwe a1 a hrrr./.lary-S)mbot Js:rRnu.ra A
1uui1.v11NJrr.rr rw.ty /r,ull .n n..n.plnredum .4 the grmIa tumlu.nen/ IIN pr,IrKrrr
Jlwstrah9 IhAI, .w arrl\in . rp un1.L.V.. .. Ihe hy(IJy 1gw.d w sa/rellra uf tamYr n.ly n ur
.n. chAJrrn IN/ure tl it r.p.rs...1 .n Il.r (parrnl ..INr calrirs /he pu/.nr.r Rrne
/'rJr.Nrp uns, .w et.Jw:.IwR the uu.r. rJ lh.h/lNwwl Can.'rc, nursl ho CuCni.anl ..1 canarr
anN.ur 2,101 rrlr/...... .uwr Ih.s rr..y...r.nn rnay aid in the JraKmnrt uf 1hu.r hrrrdrl.uy
can.rc .SnJrumrt Ihal arr thau.Irr..rJ hy :.m..r nacwlenar in chil.trrn aa ..r11 a.
a.tuha
I rw,A Il I. KaV, 1) A, Ih.gud, 1' 2, an,l I Sn.ls, 2 1:
.
4 wN.rCO.r ../ Ih.r.n..s ../ (6dJtrw /19111116, 192 5
rdrlwr a..ppvl Nrbr r.l.t I h. r.arn, I talrrn.d (bJer nf 1 agks
e
I rurn the 1)tparunrnls uf 1'revrnt.vt MrJ.ciwr/l'ulIr. Ilralth, anJ nf /'alhulr.Ry
(-rrrRhlun (lmstrsrly hShNJ uf hlnlwrne, am/ IhvrJnacy /amrr /na7dwr, /1wr.rha, NI
1111 (IIIANIOIKIVU1111111N111 NIV/INAI'A1/1N1 KI11/
I Ah/ll IAI., A 1*0 1'ICAI , h11/1 1111 1 MUI I MI I.ANUMA SS'NUK(IMI-
1 w atnun/ t.w ./ri.nlct ut havr fulhrwrJ a\ur.lrr.lwqb 11hr /anub.d, alY/n,,d,
mulfspk nN,lr mrlrnnnu (/ AMMM) syn.lr.wwe Wr Lr.1 t.aln.qrd Ihe pruhawd's
IJ yrar ul.l slsuRhl.v nhro ahe was aRe 1 ycast Nr r1,.,wurrnlrJ /he r.uluuun, L.Ih
.hna.Jly anJ hrslul..kN.J11, w/ Ihe I AMMh/ phrm./sIN rn dn /;ul /..r rrKhl yrra
I rw. A ll I r-r .J
t'rJrartr I1r.mnt..J..Kr 20139 ?')1, I')AS
1 urm the 14parlmtnM nf P.erenlire MeJicina/Pul.lrc Ikatlh anJ I)rrnuluh,KV,
('rriRhl..w l/mvrnily $:h.nd of MrJicine, (Muha, NI, /ht hrpmin.rn/ u( Inlrr.aa/
Medranr, l/nrre/srty of Nrhrat\a Medical (7nlrr, /hnaha, the Ilrrcdnarr t an,rr
InaUlulr, (Imalha, the Iti-rnululnRy Ikparlmen/, the /'ulychwa, Sratlle, an.i Ihr
1lrparlmen/ wf Ia//n.l.,gy, IYrmran Grnrral I/ual'n rl, Ambe.s, I 1(
29
1u1(IMANKI R SIItDII S IN III NI DIIANY OVARIAN ('AR('INOMA
Orarhn cam er hss hetn increas.ng in flequency during the pasl seveul dreaJta,
parl,cularly in Wrslern inJUSlria6reJ n.nnmt 11 ha. the IRrnmlln«/us dnUMlmn uf herng
Ihe malur cause uf dealh Irom Rendourinary can.er in wnmen in the IlmlrJ Sules A
small hul sqtnfl.ant I/ulnn of palienls with ovanan cancer ha.e farndy Inalur.es Ihal
a.r rnml.al.blr w.d. a pr..nary Rrnetr. faclnr the hereJnarY vananl is helrnRtnruw
hul Ihr.e 1'rt.Rrrra revrat a high prr.h.(ahihty uf cancer Ihrr.fine, families 11,31 are
prnnr hs o.aran canrer mtril the hlRhest priority far Momarke/ rnveat.Ral«.m When
cnnaldrrinR Ihr Rrnrrally p«.r wrveJlanct nxawret wailahle lu u% f.n drlrrUnll nar/an
cancer tuff«vrndy /a.lY lo irnprove pr..Rnotit, the srv/ch /ar h«anarkr.l nf h.Kh
senst.vrly anm/ yr.d«n1 as.umrs mapu significance. In lurn, sach h«.markrra nnr
sheJ bRhl on the el.uluRy anJ pathnsenetit of owarian eancer in the Rrneral 1«q.ulmun
anJ murr im/wrlantly IuauJr mechamtms foe early dtlecl.on anJ ptevrnlam n/ dralh
fum this tnn«u
I/n.A II F.to.hurlkt,l. S,andlyn.h,1 I
( n... It.r:ru'n umI I'r.r.now 9 1:9 111, 141)S
(hA.. .oplat Nrh,aska U..n.un, / ralernal (hdtr nl 1 aRles
Ir..m the 1Mlnrlmenl uf Prr.rnli.t M.A«'mNtuhhc Ilrotlh, CrtrRhlun Itnrve/srty
S.h,.J ur Mr.l«.nr, and the /ltreJlarr ( anarr /rtrr.lulr, Umtha
('AN/ 1 N(:) NI t, h(1/1 111'1 1 1'RIMAN t ( ANI 1 N, ANI)
VON 111141 1 11NtrAlt 111\1 Atl
Von 11q'prl I unltu J.aratr rH nhr.drd ht an sWa.mtl Am.n.nl lenr /hal noy
aM,w markeA r.press.a .a.uhdar nf . tn.r pbrnIttw .n ...I.,n Lal.rnvlamd.n We
M.rrrM a pal.enl wdh a.I,nnRlt 1».'r'.r /nud. .1... at age `R
undtrw.tnl ctan«.lomy with remnal nl a a)aba .r..l..lln Lrm..neuIda.auna, a/ aRr eR,
he devrlnpr.l tyrrnaamrrlu of the alnnal .n.l. Ir.ao.e qulJ.qdre.., anJ haJ a
prnRrraa/.r da+nhd1 cnurtr AI aulapty. hnrnanK«.bla.l..nut ul she crlehtl6un and
spinal cord werr IounA, n well as a le/l renal .etl carc.nonra, an oal cell carcrmnna nf
the lung, a hepanKellulsr s'areinoma, and an alypnal Ihyroid adennma Ibis tuo«.r
spec/rum appears to he unpue, atlhouRh chance cannu/ It eec/wkJ 11 is po.arhlr,
hnwever, /hal these fimhnp miRhl repreaenl an etprestiun of the deklerinus grnnlype
Ihal Mcame evidenl because of Ihit palrenl s proh.ngeJ turvi.al frnm hit rnrlral
cereMllar hemang:nMattuma.
l. enr A ll r. K su, D A, Roprd, I, and 1 ynch 1 f
(unrrr f.rnrnrr anJ (ll.eraarrl 1s 11-M 19A$
(1rArr auplrt Nrhra.ka Ir..n«.n, 1 ralrn.d /b,tr .d 1 aR/rc
1 r..n. the IMparlmtnls of ('/rvenUve Medreinr/1'ubhc llrnllh snd nf Palhuh.Ry,
('rryhl«n I lnirrnny X.ht«d of MrJicrnr, anJ llcre.6tary ('ancer 6nlitule, O.naha, NI
IAN('R FA fIC CARCINOMA AND IIER FDITARY NONronLYK)SIS ('( )1 OR I c' 1 At.
CAN('1 N A /-AMILY SIUDY
Thls paper describes a kindred s.ith verlical transmission of cancer IhrnuRh S
Reneralinns which showed fea/ures of hereditary tsonpnlyposis colorecul cancrr (/INP('('1
in concerl .ilh pancreatrc cancer. The proband is a S7-year o1J w/nte male wilA
ven/ied pancrealic carcinoms This pabent, and subsequently his trvallablt r.9aa.es,
filkd out delai/ed med.calgtnellc pueslinnnaires lheir signed (wrrnnsnrn Iurms
tnahled the autMm to cnnohnrate family, medical, and cancer (a11 sna/umic siles) hnlory
throuoih secureJ prinary medical and palholuity dncumenli IINP('C ts becum.n; morr
fYequenlly recoRmrnl than its dominantly inheriled eounlerpsrl, familial mulnple
t«lyl«nrs cnti il 1'(). a fact which has eonlribu/ed lo the recenl inereastd inleresl in Ihn
dntase (Lynch rt nl, 19t11) lhere sre s1 kasl two forms of IINIY'(` (1) hereArtary
srle specilre enlonrc can.er, referred to as l.ynch syndrnnse 1, and (21 /he ('ancer I amity
Synda.mr, refrtrrd tn as Lynch syndrome 1/ (Ilnland snd lronrale, 19641 In I«nh
dnurArrs, one finds m«llipk prim.ry eancers of the colon with an tecen of inv.dvemenl
o( thr proamal cuhm I.yack synJ/ome 11 includes eancer of nlher anatomic ulrt,
parlicularly the endomeurum and ovsry and possibly Ihe pancreas (:enel.c
he/ern{eneily wilh IesIMY/ Io vatqlion in IYInOr speelrYm has blYarne Inc'reasin/{ly more
evidrnl in QINMC (I ynch rt al. 19t2). NeuroMastnms, a lesion mure charsaelrstic of
chilJhnod, in the prohand's son at sge 22 is pueu6ng. ihere is a need (or morr
biomarker snd prdiRree studies with documentatron of eancer of sfl anawmic si/rt m
IINKY' kindreds (Danes and l.ynch, 1982)
1
l.ym11.JI T rtal.
Ilrrr.rA Jnornal aJ Canrtr Slt271-27), 1945.
1 rom /he Ikparlmenl nf Irevenlive Medicine/PuMre Ileal/h, Ikparlrnen/ of Inlernal
Medicine, f)ivisian of Gastroen(erology, Creighlon I/niversity Schmd o( Medicine and
the Ilereditary (ancer Inuilule, Omnha; snd The Mc(3reevy Clinic. Swux I alls, SI)
FAMILIAI. MFSUTIIFLIOMA: REVIEW AND FAMILY STUDY
To Jale, with few escepliont, pimary aNen/ion to the elinltKy of maliRnanl
Inesolheliwuna has been focused acl en.NOnmetllal faclMS. Ilowevet, uveral reporls of
familial aRRreRalians of ines,Nhetama slronRly supporl the suppnsilion Ihal hnst fulmt,
in conceit with environmenlal eaposure, parlicularly ssbeslos, may conlr/bult
elio"ically 1o an as yet unknown frsctioa of oeeurrences of this diseate Ilowevrr, /n
eralualinn nf famihal mesWhelioma, il it imlorlant 10 considrr the possrbdny of
1«wsehnld rsposure In ssbeslos. We reporl a family in which /wo hruthrrs with
prohmRed uccupational attwslns e.pwutt manifested malignanl pleural mesolhe6omas of
similar hislnMqy
I rynA, N f' Katu, 1), anJ Matkvicka, S 1:
('anrtr (::nrNr/ anI Cr/o(eNGrr /S 23)), 1925.
Frnm the Isrpartments of f re.enlive Medkine/Public llrallh and Palhn/ogy, ('rrrghhrn
Uni.enity School of Mediclne, and the Institute for fsmilral ('ancer Manaaenwnl and
C'onlrol, (Anaha, NF.
nr I 1t
11. Tht Reata1r.1..y Cystruse
AI VI(71 4K MA( K11rt1'%(:1 I IN('II(1N ANIS IN1I AMMA1c7KY SIIMlI1.11N
WI)KI HS wslll ANI/ w111K)(/1 O11%1R11( IIVI 1l(NC7 ItIS/ ASt1u eqd.ar pn.vhlr cnfaatnrt .n the
develo(.men/ of shromt ohttru.live puhn.marv
d.arase It 11114 m.mIrn, the ulhnts performed Monchnalvrul.u /a.aRr rn 6 amulers
w,lh mun1.,I pYlmunary (unllMn. A amukrrs with ('(NI) (11 V.// V(' < A1A) mahLrJ la.t
ann\mR hnlruy and aar, and 9 a/te malchrJ Ilootmn\tnl enntr.lt ltdyeCn I IaUaar
rrlrast by m.ar,q.haRea from sma\rrt wilh (Y7Pq was lrlmfw'anlly h.Kl.rr (p < 11111A)
/han wat rlalu.e /rlra.e fly mxruphaRrs frmm nurnu1 am,d.rrt lhrre wrrr un
dd/Ytrnara hrlwrrn cMmoat/rxl.vrrwtt d dveolar mxtotshaRr fu(.rrnatanlt /,.. ..nr
lutsun'a ta.lynuuphnnln lear truk.uylrt amlmR the R.nupt uI smnkrrs and their w..t n
Jrleclshlr ( S// ta ,n Ihrtr wlwnatawta Ihmd of .ktr.l«,n n1 ( la R.e../er Ih..n I nR/nJa
Iherr wrre no svRnduanl ddfetrn.ra in nun,bets nt species of Lx/nw m ar..,b..ally
and anxnfinally cultureJ bran.h..tt brwhinp Ihrre was no ddferenar in a1vr,.lat
maaruphaRr aulw«.nlr an,,.n rrleate wi/h parliculale or mrmhranr perlurh.nR slunub
for the amnkrr. Al.eutar macrnphaRrs from the I Rruupt..f suhlrclt had snndat hm,tr.l
mn-tobunl\t ahJ.ty fnr the ohhRate inlra.ellutar pruw+uan, )at,.pfotma Rawhr and
umdar numtrts u( r/atlnr rcrpt.ns and al/.n,ty (nr tlattaar
M.I rn,t, R, Mal t, 1) (' , 061,1 rlwt, 1(' ,( owpA.It f 1 anJ 1 sars, R(:
Am:ruan Rrrrrw o/ Ar,prrub«r Iq,ra.r 111 1/7 1/1, IORS
(1rA,r ,apr.v/ the latnet an,1 Krnrrr I..unAsli..nt and the M..hael Ree.r Mr.hWal
Krtearch tnsl.tute ( nun,s, the Nalwnd Intldure o( AIIe.Ry anJ Inlrcti,.ua 1h.rxsN, the
Nalu.nat 1lrart, I unR anJ Ilhwwt Inml.h.lr, anA the Reaear:h, 1Jucasu.n and 1ra,hrnR in
Potnumary Mrdu.nr I uoA uf M..hart Kersr Me,L,a1 l enter, l hnaRo
lrnm the t)epartrneM of Medicinr, Mi,harl Rretr 1lnspiul, l-hicaRo, the Ilnivrrtily uf
I hnaRt rn/rkrc S.'A.vJ of Mrdia'me. Ihe fewish alntpual at Wash.nRlon I/mve.s.ly
MeJn'at ( rnlet, SI I uu,t
FXPI KIMLNIAI. P111 MONAKY INI I AhIMAIORY IN)I/RY IN )111 Mc7NK1 V
tnllammalnry pulmnnary injury was inJuceJ in Alanrcn wnJatta rhr.us munkrY4
by the m/raMonchul mddlalwm Of Ihe fmn.ylated (srplu/e nntlru /eu phe 11 NI I'1 nr
(phutlvd myria/a/e aaralr (PMA) Indnal.us of pulmnnaty injucy rmlu,kJ an m,reau In
nlran pt,wrrn cunlrn/ uf h.nmhnalvtuLu 1avaRr /11AI )/luut Irnm 0%1 uyl/m1 m
unUra/td anlmals 1 111 mR/m) an.) 6 64 mlt/ml tn IN1 P an,) PMA lrralr,l an,u,dt,
wy,rluvrly. IM a/Maran.r ul a JA/utr pulmunary tnldu.le /n ehetf arw/Rem.A.au.a,
anJ Mt/.dnRn' evi,lrnle nf a p,e.tnmtnsnlly nruU.q.hJ.r Iru\,ny1K In11I1/.dN.n
('nnarondant with Ihe a1M'raranae of /'uhmrnary in7ury wat Ihr Rror,at.,m ul
prntra.rs anJ na«tanla :n the I/At Ilurh Nruluq,h.1 elatlase, Mnmd 1,, e, prutratr
tnh.h.lor wat faund to ,n,rrate Prum 017 YR/ml rn unlreated .nnnkrya tu 099 pR/ml u.
1 NI P beatrA an.mah an,l I 'I yR/nd m m..n\rN ar,rrv.nR 1'MA Ra.t,uu«tuulr.l
hunun 1-\tlt.a.r.n ,w..d1.d 1... J nun ,nr Ihe .nlt,mmtUUy sdr and ,rlevrd by
m,t
I,.a wa .. 1.,....1 ,.. A... vn./r.a.. . 1«......Lr.. .1. a..Re. th... HstaRe w..- n..1 .%
lenlty .nhibilabk wilh the inclusion of antihody to etastasr. OA1L fluids wrte shuwn to
ronlain an amrdulylic atUVily trhrn lesled On the synlhrln; suMtralr
11 U pra phearR pNA this aclivily was pat1ia11y inhihiuahle with known inh.Mlurt u/
aaivr /1aRrman fx"or and kal6krein 0-(;lucuroan/ate kveb in the RAl (la,da
rncrnse,l (rom 085 1//ml tn 1 16 ll/m/ and t?S 1//ml in 1 NLP anJ PMA Irralr,l
animal., retprcpvely MYeh.pernaidax (MPO) kvrls alan increased frnm 1 17 00 It/nd
nmm lo /A 59 and 10 47 (71) (//ml min in the same pnuln ,J animala.
(leidanl Renerali,m was also astessed in several differenl ways, the sprrdia
acliv.ly n( the acnlanl senwl.ve inhihild o,-PI recovereJ in Ihe RA1I fluid decronrJ
frrmt 1110 in conbu/ saml+lrs /o 0 $7 and 065 in I NI.P and 1'MA-uealeJ animals 11,31
thn inxlrvatwm wat dur to oaatant in/ury of the nudreulr was confumed by the rrtu.n
lo full act.vily of luur of (rwe BAL sampks afler Iherr tncuhatiow wrlh the reducrnR
aRenl duhn.threN/ul .n the prrsence of nurthiowine su/fnank pepli,k reduclase Ihe
shrr'/a auvrty uf catalase in the RAI. fluids of animals Riven 1-aminn, 1,?,1 Iriaruk
(Atl I h More /avaR,n/l shuwed drnps (ram 09/ in unlro/rd monkeys w 004 in
I N/ P-Irraled and 0 49 rn PMA Ireaed mnnkeys MPO Irvels also fell in the A I I/eatrd
in/ured anrmab Irnm 16 39 lo 0 RS A/)b/min ml in I NI P animals in the absence an,l
psrsence of A1, and 101/ to 060 A Ob/mm ml in PMA /reated animalt Inhibaum o/
MM) by A t was sM.wn ,n nrr /a be hydrogen peroaule dependtnl, Intal Rlut.thw.nr
Irvrla in thr RAIr fluids d'wt nul change apprraahly af(rr FNI P nt PMA Irralrnrnt
lhrte stufies presrnt subtlantral evidence of 1ht genera/ion of M.Ih p.otea.rt aoA
oaelanls .IunnR the estabinhrnenl o( acule pulnwtnary inftammalty mlury .n an
1 eaprrsmental pnmale mu,lel.
Revak. S 1), ('nrAranr, ('. G el at.
Jnwaaf oJ Cfrnrraf 1n.rsrl~nlnwr 761112 1192, 1985.
(7tAer IuPrarn 11_ S Public I/eatlh Service and (Xfice of Naval Reteatch.
From the 1>rparlrnrnl of lmmunolnRy, Serippa Clinic and Reuarch I uundatnm, I a lolta,
('A an I the Ihparlrnrnl of Surgery, laatborview Medical Cenler, Sea11k.
y
ISOl AFK)N OF TK/)PO/ LASIIN a FROM LATIIYRIiK'C/11('K AOR IA/
Trnpnelasli0 a was isolated from lalhyrifie chick aotlae by using severe drnaun.nR
cnm/itiuns far the initial tUrac/iml. lhe atni/111 acid cmnposilu.n of Ihia new slMc,rs .nl
trnrytelaa/in n elaslin like in its hiRh prnpulinn of pttdine. Rlyetne, alamnr, an.l valbnr
Ilowtver, il differs fram aulhenlie Irupnelaslin b in eontainmR a hiRher pra rnlaRr .f
p,dar amimo acu11 and fyUHnt tesldws. ln addrltnn, the anNMM of pt,.bnr
hydroay/a/6rn n I Lmes h.ahet Ihan 1\al found In ehiclk,layu.rtaurn b
R.ch, (' R .nd I «urr 1 .t
/1nhArw.n/rv hww..f )111kl 514. 1911
llrArr urpryrrr Nalumal Inmlitules uf I/eallh.
I rom the IkMrlmenl of Ru,loly, Syracuse Univentty, Syracuu, NY,
11
1111 ('1 O1 IIYf7R(sXYt. RAfKCAI S/'AVI N(:ING ON
1 NIX)I()XIN INI)l/t'l l) I IING INl1/RY
/he relrste uf ..cyRen radicah, in particulsr Ihe hydrnyl radicat, frnm srquearrrd
neutrophl/s pr.duces sculr IunR injurr aller a numhet of inwlrs Our purp..se was 10
drlrrminr whrlhrr hydrnayl rad.ca) ()11 it eeapnntible trN Ihe IunR inlury (corn
rn.hn.rtin ch.raalrrurd by (1) pulmnnary kulkntlaan, (2) incteaaed thromM..ane
prrr/uclwn kad.na In pnlm.ma/y hyprrltntiw snd Aypnsis, snd (1) /mrexed Pr.rlr.n
permrsb.hly Ih.s hyM.lhetus was letled by iwfninw of a srtrcllve (111 scavenRer,
d.mHhyl th.oures 10/1 am \R). irllo unsotslhelited sheep hrfnre emloln.m arul
cumparmR the rrtry.nae In Ihal trtn wi/h enduloaiw slone PulmnnarY vascular intepily
wat mrasurrd hy the usr of IIInR lymph (be.- V lymld Mnlein 1lanapnrl, lhromlr..anr
A s wac rnrasurr.l st IaRs, anJ pr..slacyalln ss t6rlof(:1/, We f..ue.l no ddlrtrnce /n
the deRrre of Iru~..penrs and bypnua afler endu/naln or the kvels of I aHS,
6 &rlo P(:11ee and pulmunsry hypertrnsw.n w.lh dlmelhyl /hn4lrea, comlO/rd wah
rndulul.n sh.ne Ihe hrmeah.l./r .njury wat dtn M(rn/nal, w11/1 s 1v.. :.dd lo
Ihrrr ful.l m..raw In pmlrln r.ch lymph wen /n holh groups It alrywart Ihal (/11 d.vt
e,s/ play a matnr .an.al.ve .ok .n elrher phate of endolna.n /unR mlury
W..np, C , f.a R, and Ikmlrng. R 11
Snrar. r0)11/ 100 1/16, to/S
Othrr .rP/...r Nsln.nd Intti/ules nf 11ra1rh
1 rnm the I nnR.,.nd Area I'rauma ('rnlrr, RNh Lrae) Ilnapilal, Ibrvsr.) MetLcal S[Mwd,
and Hr.gham an.l Wnmea't Ilmpllah, anrt the ( hd.l.rn't Iloapilal, IMn/on.
PR(1SIA(:1 ANI)INS ANI) IN1RA/ 1111/t AR CY( 11l' AMP IN RI SPIRAIORY
S1 l R l: tOR Y l'l l t S
Prm/aRlandlnt are innwn In affect M.n /Uant(r.rt and mucw secrelnm in the
Irathea, and at Iras/ parl nf Iheir effra is IhnuRht In be mr.balyd hy tydn: AMP
Hrcaust nn prmlaRhndln tectplot atsaY Is eurtently avadabk, we have uaed an
ImmunocylnchemMa/ probe tm the inuaarllular Incaliaatinn of cyclic AMP to nlenlify
t/une s(rcdic cell lypet /n dryl and cal /uachea that respond to prntudlandins I/sine
hac/1ta1 eaphntt sirndar lo IMfe (Ited by olher investiRalors for In ntro slud.es of ir.n
hantpntl am1 glycr/prntein secnlw.n, we esarlsined 11Ae effecl of emhlsen..W and
t.ogtt101N p1o71ailland.nt o/l /nlmunAleaellve eyelle AMP ErwhMennw prlMla:tlarldins.
which may tr secnted in respnnte In rninnr ditln(tinn of littur rnemAranes, tt/mulaled
ImrnamNeafllve cyclic AMP in cil/sted epithtlial cells and in b.rlh str,.us snd mucout
IuhrntXosal Rlsnd cellt thit ass (ud nbserved In listutt atsayrd 60 min aftrr ceistrtlian
nr d.taelyd in Ike pretenc'e of inM.mrlhscin nr ld RWfW' I snRlM.us prns/aaland.n FI
maeasrd cytlk AMP In lhew same ce0 lyptt We cmltlwM /hal p.mu~l.n.bm thmrla/t
cyclic AMP In tpeclf/c tell lypes rn the trsches, and Ihal rndoRrnnut pr.su111anr/nt play
a nta)1N eole in many In rrlrl preparalmlls
I ararw, S C Rnhaum, C R and GdJ. W. Af
A.nrnron Rrr/nr nf Rr.prrstnry Drtretr 130 262 - 266. 1994
I)rhrr .opryrt Nal.unal /lrar/, I unR and R/.rn) Insl.tule
14
f
ltum Ihe ('mdiuvatcular Retrarch Inslilule aed the Urparlmenls of Mrdr.ine aml
Anal..my, l/nlvetvty of ('alrfnrnia, San I rancltco
AIRWAY RfSM1N$IVI NI SS 1(> INIIAI FI) ANIIGFN, (11SfAMtNI., ANf)
MI 111A('11(/11N1 IN INIIRf 1), RAIiWFI la-SLNS111711) IXX:S
lhe aulhnrs sludlyd the respnnses ln anhffen /n anilnah selected fllun a cul..ny of
inMrd duR% tenutved tn specific s1letRens 1o de/ermine if Ihey had ehataclrrnh:t trmd.v
In lhaae ..1 human aathmahct Ihey .ere immlrnired wlth raRweed an.l Rratt /adlen
eat.a.tt 110 yR /n sloa.) rmmedialtly afler routbne vacc/natum w.lh altrnuatrd hve vuus
(Artlrmper and hrp:wtn) ant/ hilled bacteria (Lrplespiral a1 A, 6, and 12 wl. .d aRe
Sulqequenlly, raRwrrd and Sra.s injrclions wert lepea/ed tvery 2 nn/nlht ImnllmurJ
d..Rs rnade sprcdlc Islr anliMrJirs m serum avtcaRinR I to 1 lirnrt Ihal u( canuul
awm.dt /nn Im/nurNfalnNl w.lh pldkn nr vaccine) lhey s/a/wed qnltlvr skin rrtl+..o.et
Iu the insrclinn of rqweed polkn eatracl, wheRSS eonhnl doRS dnl nut rrtlw.nd lo
raRweeA Indlen by etuanbulive sMln Itsl or inhalal'n.n ehatlellRe In /mmun..rd doRs
urolrr ha.Mluute anrtlhesia, air-(suW tnislanct of the IMal respnalory syslem /ncreased
from 060 . 007 Imean s S1 M) before 1o 176 !)A ern 11aO/sps S nlin aller the s1ar1 of
anli`en aernud; tespaalory tesistanee remainrd inertased fur 20 min and was acs.oortarrd
with hylnaemia and increased arlerial pbanu hislamine. In addiliun, sirway
re.punuvroett to bolh inhak.l histamine and nlelhac/wline was Rreater in immumrrd
.4qla lhan an non/mmunired .logs of comparabk sR. Airway resplrnsn In ra.h aRun8at
wert hiRhly rrpran/uclble on repealed testinR. lhtse resuIlt indicalr that phys.,doRic
rtslr.nses lo anl.Ren by /nbred, raRweedfensilired rk.gs rttendde hunlan a.lhnu chnely
and that lhese duRt aplrar suitahk fw a variety of eaperirllental sludirs nf aalbma wi/h
respr.l In palhnRenenis, dlaRnosis, prevenliln(, and Irtalmrnl
i
Mapp. C.. /larliala, J, I rict, 0 1.. Shields, R. 1-., and Gold. M. Af.
Aerrrrrw Rerrer n/ RetPlralnry DrMest 1.12:292-292, 1943.
O(Arr lup/wu( Natmnal I.rnit and Slnod Intlilule, Na/innal Instilule of AIIerRy and
Infectirws U.xaset, an.) the Nurlhern Califoenia Alletgy Soeie(y.
Frorn the ('atdioKatculat Reuarch Ins(ilae snd Departntenn of Medicine am/ Pedralricc,
l/nivenity of ('al.fnrnia, San Francisco, and /he Awima/ Rtsnurees Services Fa.dlty .I/
the Schont of Velerinary Medlcine, Universily of Cdifornla, 17avis.
('IIARA('IFR17A 11f)N Of Pt/RlflIa) IX7G MASI(K'Yl(lMA ('ll I.S.
A111(1N(/MK' M1 MHRANI. RC('FPIORS ANI) PItARMAI'U/ (X:II'
Ml11t111 A 11(/N l/1 111%1 AMINI R! 1 I:ASII
thrre h su/1/1nUn8 evnknaY 61 lo rrhkh Wlanamic seteplws masl cells (wnsrts
and whethrr /he reteplu.s are capable of wuwlulaUng nledislur qlrste Ihe su/hurs have
tlud.ed d.g msslacyloma celh hecause /hty are availsble In large numhert in a/rlabvrly
pure form, unllke normal d.y mas/ eelh. Mat/ocyloma nuduhs ftom a dns were etltrd
and di.aR6resaled wnh collasenne to prnvide a cell swpension of matlocytoma cesh ol s
92% purily. 7-he presence of su/onn/nic receplors was sssessed by bolh radndqand
binding assays and by evalualing pharwacol"ie modulNw.n of n.edialm rekase In the
rsd'wlipnd birnLns attayt, belsadrener6ic receplas were tslimaled by
(/llMav.sm
binding and ch.Jme.src .ecrp/ntt by 1/111'luinucl«1iny1 htnrJa/e bmd.na N.m.latdn
bindirq wat dHrrmrnr./ rn each cau by incuhalinn in the p.rarn.e uf Ihe s(wc.t.c
)S
1.
anlaRunalN pruprannl.d, phenlnlamine, and Hrnprne, rrtprclively Ihe eflril uf
sulunm., aK.m.tt un .mmun..l+Ric and nrnlmmun.d.pc hrala/uinr rrleote waa e..uruned
u..nR Ihr Irla ad/enerR+c aRnialt ianlnutrlrnrd anJ Irrhulalme. Ihe alpha abrnrrq.c
aRunitl phenylry+hc+ne with anJ wilhnul prnpramdul, anJ the chd.nrrRoo: aRur ..1
]1r1y11k1.11M tkae rrtlM+nae cYrwes were contlrlNled hnlh (rN the fulunnmK aRnnl%ls
anA Ihe hnt.nunr celra.mR apentt Rrtullt (r..m the radioliRand hiluling and -he
Idurnu.uMR.: lufits wrrr .niord]M these doR mattucylnma cellt had a hrgh .knuty
nl M1a /rcrph... (21,lfln . 11ttff, mean } SI: keta-recrplnrs/crl1, n.S) uf whr.h d+e
predm.nanl .uhlype a1yr.urd lu Ihe Lelal Ne eviJenet wat f..und fnr Ibe p/runcr .(
a1(.hl adrenr/R+c ol .hhnrrRc rrtrplnrf enher by direet /ecerlot hrmllnK W hy Ihrrr
a.lrnna un h.aUmrnr rrlOae
1'MItrM, M I, Itarnr., P/, and (:nfJ. M' /N
Amrrru.n Rrnrr o/ R+ryrurr- r f)r.ra.r (/2 /019-10?A, 19115
(hArr, .upfv.t Nalu+nal llrtrl, I un6 and Illond IntGlule, the Suolrl Mr+ticat Ketrarch
1.mJ of the Alnrr.can I uuR Anncahnn of Un Franclsto, Ihe Ilnwerady nf l'atdorma
Keararch I valaalnm and Allntalnln ('ommalee, and the (bhfurnia Keae.uch a/uf Mtd..:d
I dutatum I und ul Ihr Amrn:an I unR AaaocialiOn of ('al.fornla
1 rnm Ihr ('anllrvnrulv Re.e]cch Inttilulr and Itrpa.llnent of Medwint I/niveruly of
1 atdu.nu, 1..n I ran.racn
Nlr(IIINI INlt11('l l) KtSt/ItA1/IKY I1/1 ('1S(N I 1(:AKI i ll SMIIKf
IN IKKiC
the aulhnrs rrl.ul I1u1 naImr ra rralnn.Jdr fn M.Ih a Id.wwl Ivune .tuuulu.on
of the rttpuaare cenlrl nd a dnrcl tllr.l no mtralhnacic auwav 1+nr m./Ra Ihry
mbrwl.ceJ clRarrlle anuae /nln 16e Iw+ltt of dnnnr d+Ka and mlrileJ arlNrrl Id...rl
uhu.nrd hnm them inln Ihr rircutalin nf rrcprnl duRt lo thnw Ihxl a h1..d Iv.nr
Iaalrnal Incrra.rd havlhmR aml uwav umndh mutilr 1me lmuke Iwm arKurtnrs
t.mlammR ? M mR uf nNMme was rl(ecbve, Ihal //um clRarrtlet conllnmR O V mR uf
naullnr waa m+l Nnulmr, in dnset enmparahlr 1u the amuunla abu.cleJ 1141.16 tnuJr,
also rncrraarJ hrta/hlnR and lrnheal sm.uqh muacle tenta.n when in/eclrJ mtn the
verlrhrat circulalam of rrcip.enl drqi 1 mally, Mrwkade of nKnlrnr receplors .n the
ttnlral nervous tytltm aad in Iht airway palatympalhrbc RanRlia inlnhitrd the e(fect ul
(nhaleJ CiRarelle slm.ke an.I inlravtnnut nKulrnt on the reapiratnry crn/rr aoJ on
Innn.hnnuuur lunts Ihe aulh.ua c.unclw/rJ that ni.oline ahaorhrJ hom tiRareltr.noILe
is Ihe main cauae uf cr{arrlle snu.kr rnJuteJ Mnmhncnntlricinn 11 caused ctalrol
rrapualnry sumubliun, rrtulling in incrr.ned Mralh.nR anJ auway .m..nlh mua.le
Irntu+n, anJ had a duect ellrcl un anwa. 1parafympalheuc O.rnal.a as we1/
Itarl+Ja. I f, Mapp, (, Mla hell, R A, and (:ofJ, W Af
/wrnnl r/ Applrr,l MApunf.;r l9(11A1 !I, 1911
(ItAcr .uppnf Na1+mal Ilrart, I fin/, anJ Ithrwl Institute
from Ihe ('ndu+vauular Rrseatch Inaitute and /Jepartmenla nf Medi.inr and
1'hya.nlyty. trn.verVly nf ('aliforna. San I nncisco.
l
AN t/l IKASIKII('IttRAI. ANAIYSISOI' I)Ki MAS7(X'Vll)MA ('l l IS ANIs
Nl/RMAI MASI ('I 1 1 S
A well dJ(rrrnlialtd JuR maslneyloma was chatacterired ullratUucUrlally uainR
mntphulnrlrlc, hIS11M'henln'aI, and piocherm.al melh.ult the ultratlru:lurt of cells /n
the rnlacl tumar was rompared to Ihe nwuphnhrRy uf crlls ditaRRrrRalyd frurn Ibe lumor
and :u/turrJ fur pelnuk at k+n@ as 4 weeks and to mumal JuR eunntcl.ve liatue maat
celh M.1 nf the tnnlor CeKa COMailltd h1{lamine (/Ilean st 581 pR/etlll, dermlmb:urd
chhnuacrlale etletaae activity his/ochemieally, alainrJ melachrumatically wrlh 1o/unhne
hlue, aml were amdar In uhratlrutlure lo nnrma) rMµ matt cells lhe pruprntww M ma.l
crllt in this tunuu averaRed 67%, ruainuphils, f/MuMaal., plasma eetls, .mt macruphaRrt
ahn wrre prrarnt I he mran diameler of matl eells (1? 79 Mm) and Ihe mran dumelr- nf
Iheil cyhqlatmn- Runules (471 nm) were simdar Io tMne reporled t'or mast celli amt
m..aocyh+ma aella (rnm va/wws spreiea lhe helerogrneily in apprarance uf the
maNucytr+nu Rranulrs was rnnsistenl with a varrahk dtRrrr of Rranule maturaNon Aflrr
dnar.(;reRaliwm .ur /Mluuta nf cullure /anRinR frnm 2.latt In 4 weeks, Ilhe mean Rranule
dcnnetrrt were 1st I:uRrr Ikan thme measured in Ihe in/acl mnhwylr.ma eellt. IhouRh
other rourphnL+Rlc fealures rtmained unehaniged. AItMwRh the eellt rrtaurrd Ihen
dia/mcl mmphuM+~lcal (ratutta fm at least 4 weeka, sumr of Iheit physirdnRical reqwrosrt
wele k+.l aflrr I week in cul/ure. Ihit t/wty slu.wrd that d.+R m]ahM'ylnm:ta c.rn 1e a
anwce uf a brRt, rela/ively Mnm.Rent.ws pywlaliun o( teltt th]t a.e u.rlul (or
eluciJatinR uuee of the strutlural and funcliona/ prrynvliet of roaal cr/la
<'ahmicn, 1. 17 , Philllpt, M. /, Mcllonatd, 1) M, and (:n(J, W Af.
t
7At Auuf..m.r Rrc.uJ 212.799-107, 1985.
(ltbrr wpNut Naln.nal Ilnrl, 1.unR alul Rlnw) Instilule, /ht Slruhrl MrJrc'al Kesr.uch
I und uf Ihe Ame/rcan I unR Atto.ialinn nf S.n I raneiaeo, and /hr Umver.uy nl
(alif.u/nia Krsealch aml Medical IJuea/wnl I~und uf Ihe Amrln'an I unR Aaa.+cr.u.un ol
('a1.1ur nia
Irom Ihe ('.uImva.:ular Inaitule and 1)epaltmenlt of Anatomy and Mr.h.rne,
I/mvrrsily .d ('aldurma, San I rantitcn.
.
IMMIIN(11 (Xi1C ( IIAt.1.1.NliE AND I:Vlllll tIAI. Il>N '/RAN5/91K I IN ('ANINI
IKA('lll A
In Ihia alwly the aullwu% uted rnrasured ehanRn in.hnrl eircuil cunenl lu /rf/r,t
inn /nnaM+rl acrnat the canine /racheal rpithrfium am/ have slu.wn Iha/ mr.traans
released Ir.+m IunR fraRnwnls by immunnln2K cha/knRe slimula/t ion uanynul .n tht
Irh'hea Iht pasrnce of hlcumine in the supernatan(t,,I1M1uRh fhe e11naM1ralu.n ra 11.1
h.w /n accnunt fm the thorlcncuil curren( et(ec/, indicater that mast tell drR+anul.num
hat tMfu/rrJ t'atli.uLult, Iht ohsnvalw.n tha/ 1ke inr/rau in thnrt-cn.u.1 cur.rnl an
hr, ld.rkrd tby p.rtr.uncM or Ihe ryalhelul~lhauf wNh Iht cythruyRrnNr rnhrlnlu
InJumrll.a:m suRRra/. Ih.q It.e rneJr.H.n effrcl un tMnt c'ntuM crnen/ s..a/u..l and .s
puJ.ced by atuval.nR U.r cyiloo.yRrnax pathway in the epuhrlwm
Lararus, S C'., I tikauf, C 1) , Mc('aht, (. 1, ta1Re, K., ('hunR, K f, NaAr/, 7 A, arul
G..fJ. W. A(.
Cflru 227S IstSIMS, 1995
IA
)7
Orh.-r tuprvl Natinnal llearl, LunR and Ith.nd Insl.t.dr, the ('aldurn.q Rnra..h and
MhLcal I dw'a1n.n I und af the Amtrrcan I unt Asuniatinn of (shln.nia, and the
Rtteaa h I v3lu.hnn and Alh.aal.on Cumm.tlte of the Ilm.rrt.ly of f a1.lurn.a S.lun I ul
Mrdn rnr, Cin 1 rancnu.
I wm the ('arAu..atrular Nrararch Inatitule and hrparlmrnt nf MrJ.cint- (/nivrnil of
( ahl.nnu, \sn I ran..a...
1'R(/11 ('ItVI R111 1 XI S ANII VASCIII AR tl l fCl3IN I/ll NASA/. Mtl( ()SA
1111-/IIIt11V AtlIVA111)NO1 ('At'SA1('IN-S/NS111V1: %I/11%1AN.1 1' IMh111NtIN1 AC/IVI 1RI(JI MINA1.
NI lIR()NS
the a.m uf the prrtrnl invrs/iRadnn was to s1uAy Iht sllufturr anA fun.t.nnal
chaaclrriNas o1 Iht unt.nr Palh.ays ..hKh ProvuIr prulecU.e rrflears in lhe u....d
mwuaa .n vallnut r.IVrlmrnlal an.malt ItK ute nf ca(Man.n Ararns.Illalum at a
ryst.hle /realmen/ aR.t.na naaal .rulalinn ha+ also hten t.dualed the IullnwrnR qwt.hc
aalrats were awd.rd
11) Ike mit.n and dnlnhution of Sr IR ner.e f.hres in the nasal mutnaa
-Trt
,n.ral.Aalyd in se.rral qrc.rs, rnclud.no man Alto the effect nf tyslem.c capsan.n
prtlrraln.enl nn Sr .nntam.n[ nrvn.ns wat tlud.rd
(:) the effect of anl.d.omic IriRrmmal and paratYmpathtl.c ntt.e st.nwlalion on :a1
na.a/ hhrd flow .aa cumpveA w.th Ihr retlrmtr tern (.dlnwmt hr-al mluaw.nt nf \I',
vlr anti capsaa,n
O) the eflrcls nt antuhom.c InRrmm.J nrr.r tl.mullnnn, hral appIi:alum .d SP ur
upsai.m on pt.nnu ru1a.aulNm .n the na.a .nu,.na werr uuJnd .n cunnul anA
aaVsauin pselrratrd racs
(4) the effrcl of ciRa.elle lmoke and it1 varumt comlw.nrntt on naaal mucnaal
ptrmrahthly was stwt.ed .n the rat Adfil.un.illr, ehe aensory me:h.mi.ms un.hr1y.nR tl.e
avnidanc-e hrha.nr (mne w.pinRQ indwrd hy c.tarrnr smoke +aa .n.ru.Ralr.l .n llte
turnea lut
(S) 1he mechanisms underlyint snetaint retponus to bolh chemical irriunts and saclJe
slimulalion wert stud.ed folMrwint captaa'in prelreaUnent
(6) lhe acute and h.nt-term effects of local systemic capsaicin preuealmen/ and
crymurRery on the naul mwtna west slwlinl the raprrimenls r.amined the inhibition
of naaal innalmn, 4ns nf Sr-/R nrurnns, nrus.qtenic pbsma etravaulmn, hKa1 t.saue
damste anA systemic eftrc/s f.Jhswmt tArse uratmenlt
(// the lmrnrlance of calMaicin-sentilive srn.a.ry nrr.es fnr the cardm.atrular
/tsponses imlwrA by haal app/ka/inn nf wkol.ne and eapsa.c.n tn the nssal muant.t ww
sltu invesutated
I undhlad, 1/ t vndM[ ! M)
Acra Pr1r.n.L.Nca TronJrnanra Suppkmtnl 3201-a7, ION.
prM. wrr'rr the S.rdith Medical Rrsrarch ('nuncil, the Swedish fnhacco ('nn.pant,
IMAalra / uvn.lst.nn .nA the Ka.u6naka Institute
II1
I
I ram the 1)rpartmen/ of Pharmacolngy, Karolinska Inslrtute, and the tarparlmenl ol
(Mo-rhtno-laryntnbty, Karo/inska Ilospilal, Slockholm, Sweden.
1 VIh1 n('F FY)R SIIRSTANCE P-IMMIIN(MtFA('TIVC SPINAI. Al / I RI NtS
I IIA 1 MI 1)IA 11- 11RUNf'll(X'ONS1RICfIUN
Ihe oeiRin and funclional rok of capsaicin.sensilive substance r I.%r_)
im.num.reacli.e (IR) ner.e (rMes in Iht bwer airways were sludied in Ihe `uinra p.t
SIrIL.leclsmy caustd a sitnificanl nduclion of Sr-IR in Iht lun~ .nd pulmunary autty
Immumrhistn:hem.cal anslysis, however, did no/ re.eal sny ckar cul chanRr .n the
nu/nIM1 and Anu.huli..n of S1'IR fiMes in Ike lung of /hex animals Af/ec coudnne.l
slellaleclnmy plus hrcal capsaici. Iaalmenl of 1he vaRal nervrs, moal SI' IR nervra
J.sal.prared in the lower airways. lhe b.onc/noennqrictu.n inJuced by caps:d.in .as
symfn-an11y reduceJ .fltr +trilaleclomy and aholisheJ afler sltlla/rctomy plus cnl.anm
preueatmrnt of Ihe .stal nerres, flher inhalalinn ewud brnwcMKnnsunbon, -6hh
was n..l tnftuenrrA by +Iellateclorwy but marktAly reductd by combinrJ tahsan.n
Ireatroenl of .atal ntrvn and slellateetomy. Strllate potln.n stimulalion in an.maN Ihal
haA been chem.cally +ympatheletmniaed by 6 UII .h.pamine caused brnnchocnnslr.c/mn,
which was resitlant In chnlinertie ar oMenertic rectplor blockade Ihis rtsp.nar was
ahsen/ aflei systemic cap),iciw pretreattntnl, suRtesliwR that i1 wa+ due In anhdromic
slimulatum of afferenl fiMes Inversint the stella/e Ranglion. In conc/uaion, the prrarnr
dais suRtes/ that the lower airways reeeive SP-IR npsaicin sensiti.e (' (.hre affe.enla of
both vaRa1 and spinal oritin. lhefe sewsory fiMts seem 1o have branchts holh withm the
bronchral smmsth muscle and srornd bMur/ vesseh.
Sana, A, Marllint, C,-R., Dahpard, C.-1., and f amJMr[. J. Af.
AAa PArunfo[rro ScanJinoaca 12{:4py.4l4, 1995.
Orhrr suptwvt )he Swedish Tobacco CompaRy, the Gutlaf V. Iuundation, Ihe Aslu
InundatM.n, the Pt11ut and Autusla Iledlunds Fonds, Ihe Karnlinska Ins//tutr, Aushun
Sr.entrfic Research / unds, and the Swed'nh Medical Research Council.
/ rnm the Ifeparlnsent of [aperitnelNd snd ('linied Pharmacoh.ty, (1nivr.tily of Gra.,
Gru, Auslria, the IRparlmenN of Pharr.acoloty and Anatomy, Kaw/.neka Institule, and
lhe t)eparlmenl of Aneslhesioloty, Karofin+ka IMnpilal, Stockholm, Sweden
SfQll1 NCE OF PA711n1 /X-:/C CIIANGFS IN TIIF. AIRWAY MIl('n<A 1/1 (:I/IN/ A
PI(iS I)I/RINI: O/ONt:-INDUCCD bRUNt-IItAI. IIYPI RRI A('IIVI l V
lhe wthurs astessed the ea/ure and propession of airway m.NOSaI d..ea.e and
muacatlnic brnnchial Ieaclivily In tuiMa p+ll tluJirJ in troulM of 4 al 'h, bh, 11h, /.I.r,
7 Aays, or 4 days a//er nrant e.pmun f10 ppm for ]h), an.l in 1 tom.vl t.oup
Muscarlnk reacu.lly was .k/errnlned by rneasurin6 specific airway rtastame as a
function nf incrrasiq doses of iMSarewew .ct/ykholine in )1 rnlact, unanrvhrtur./,
spnntsneou+ly brealhint neirwah. Afler lestin(i, each /rovp was kdltd tn uhlain 1ra:heal
tissue (or light microscnpic eaa/niMliotr. We found Ihal airway hyprneacli.i/y In
ocetykhnline occwred in 96% of the soinuh eapnsed lo oront. Its detrer at )h wn
subslanlial. Compkle remissiow was so/ obseretd 6n/d the foswlh day In ats.Kiatmn
.ilh the acul+r brnnchid hyperQKlivi/y foY/ld al )h, a markrd dtcreuae in au..ay
mueosal goblet cells and an inertase rn tnucosd mssl eeRs occu.red Nru/c.q.Ml'v
infillralurn occu..ed laler and IasteA lonttr, drspi/e rerom.nn of the hyper.ra.l...ly
)V
nur rrtuht inJ.cate Ihal acutr, ownne induced bronch.al hyprneacl.vily is relalyd In
amm It/ auway mucntal mtury and mstl cell mfdt.a/inn After 1110 early pha.e nf
anway damaRr, nrut.opMk .nfhHralion occurs and penitts, suRRrtl.nR Ihat n it a
conarqurncr ..t Ihe damfRr ralhrr than s Ouu of Ihe .ncteased suway rraalivny allrr
ntonr ra(rnarr
Afurlu. C and Ruurn, 1 11
Amm. nn Rr..rr ,./ Rr. pr.nrn. r Ibsrnv 111 111 120, f9/S
(/rArr u,rrynl Naln.nal Ileaa, I unR and RInoJ Inslitute
I rum Ihe 1Mparlmenl nf A(rJ.r.ne, Ilnivrriily or ('.ncinnati, C.ncinnati, OII
O/ONI 1N1)I r( I ta ('l/ANG1 S IN MI IK'AKINIC RRON('IIIAI RI A('l IVt 1 Y
11Y Ist111 HI NI t1111N(: MI 111()I)s
We eaarnmrd Ike effect of orone (0.) on tnutcannK Monchial reaclivitY in ttr
gu.nea pql and cnmpared rraalivily deltrmintd by Iwn ddfrrent roulet of aRnntl
Jelrvrry Rexhvily hrfnrr and (rom 41% in 2 dayt after 0, eapoture (10 ppm, 2A) .at
drlermmed by mratur.na sprcdn: auway rrannncr uprm adrnllntlralnln of .nuavennus
scetylrAnthnr and/nr arr,nnl.red mrlhachul.ne challrnRe in 14 unanetlhrlu.al,
spnnlanrnwlr h.ralh.nR animalt Re/n.r rcpnw.t we nMerved mnre Rradual and
repaMlucd.lr trtuht lit rnl.a.enoW sRomU Allre rrp.norr hyperrraclvny to parrnle.al
sRnmtl .n'aurrr.l aunv.lrndy, but nu/ In .nh.1r.1 an,nn! Ilyperrraalrvny drmnntl.anle
by rnher tnutr Was umdu .n nuRnltudr an.l I,nw ....ute wqh.n u41h of e.pnane 1+..
d.rys I.,rt, hyl.rnra,r...ly In .nhylrJ af.n..a hs,t .rm.nrd, ll.a1 1u inlcs.rn,..n dn.R
lua..IrJ llu. rrauh. .n,hctle ,hsl .n.1,Ad. .n /Lr ,a.nnrn.r an.l lu.ur .,.u.W ot
0, /ndu.rd hylwrtra.u..ly lu m1,.Ar,1 ..R.n,.r nu. Lr a.,.u..qwn.r ..l r6r rr. hn.qur
rmph.yr.l Ihr aunt.arnl naannrn.r ../ It, 1 p.ur..r.ul ..,z ,.m.l
tuRaratt mrahannmt ulhrt than au..ay mu,...) a.r .r 1.n.Atr t,.r
lhrt hypenracbvdy
Rnum, I 11 and Afurl.r. (-
:wrn.d n/ Appl.rJ hArunl,.Rr 5716/1711 tltlV, 1914
(1rA,r .npryn( Nal.onal Itrart, l.un{ snd RYn.d Inslilute, National Institutes nf 11ra11h
aod An.rrican I unR Aaan'.at.on.
I wm Ihe 1Nparlmentt uf MeJKine. Phytiuh.Ry and Ru.pAytKt. Univenily nf (-aGfoonu,
l.unr, and Orpsrln.rnl nl Mrdame, tln.vertAy of (.mmnal., ('/n..nn:d., (111
1)//)NI INI)tlt 111 /IIttINI 111A1. /1YP1 RR1 A('IIVIIY IN (i1tlNl A PNi\ 1%
AltO11\1111t ItY 1/W 71NIIR IPI. $5112 11111 Nt/l RY IN/N/MI 111-At IN
We investiRated the effecls of nW 75N', an .nhiAilor of bolh Iht CYahury6enate and
lywrytrtnatr pathwayt nf ararhu4rnic acid mr/a/nJitm, I Pl. )5712, a selecti.e antaR@nnl
uf d..w reaal.nR subaancr nl an.pAyh..r, and mdomelhacin, a cycWnayRrnau inh.hlhw,
nn Innn.h.al .ratU.Ny afler nwne tapOSUrr (iu.Ms piRt in trnupt a.f S w'ete /rtaled
with 11W /%t(' 1141 mtlss pven .nuavrnnudr/. I PI. SS112 (S mR/b6 R.ven
muarn.u.l./ .. .n.I...u.h...n (t0 mat/a srn .nt.a/w.dunrally) and ssad.rd (vlu.e
an.l w.,.... .,v. a fn ..,.n ..r.a,r ... 1 n Iq..u ........ I/.rar an,m.h rrr.e co.npa.rJ
wilh a simdarly erpnsed Rrnup Ihal was .nheatr,l (n-10) Reactivily was Jrlernuned hy
measur.nR ipecd.c airway resrslance (SKaw) u(r)n inttavenout a.'rlylchol.ne in/utn.n .n
unanruhrnrrd, sponlanroutly Areathing snimals. Prwr 1.t oaone rq.mure, we fuund that
d.uR Irraln.ent J.d nul a(fe.1 t.lAer SRaw or mutcar.nK reacl.vrly. A/lrr earynutr h.
] 0 ppm, all untrealed guinea pigs showed subs/amnl muscarinic Ayperreact.vdy
Indomrtl.acin Ireatmenl dd Irol inhiAil Ihis r/fec(. I u./hermote, m Ihe
indomethacm trealed animals, mat\ed ekvatinns occu..rJ in SRaw, aller oinnr In
conlratl, mt chanRr in SRaw or muuarinic araclivity occuneJ aftrr orone in ny ammal
IrrateJ wnh raher 11W 73X' aw I PI. 55112 We concluJe that naone.ieduced Mpn.lual
hyperrraa.vny rn the guinea pig rapidly devehyn aflrr br.ef, high Irvrl ealnnu.r
Ihit r/fecl r.may be mednalyd in parl by fipnayRenasr pnnfucts deuved /rom IunA
araal.i4nnn said mrutudarn pnsl-orune.
/ ee, // K and Afu.ln.. (-
Am.v.rrm Rrr.r.n nl Rr.p.ra,ur /)btrare III IoO$ -/009, 19$1.
OrArr u.pp,nr Natinnal llrau, 1 und and Rlond Inttnule
I tnm Ihe 1)rpatrnrnts nf Medicine and fn.ironmenlat Ileallh. Uni.ettily of ('mc.nnali
S.Mnl of Me,licme, ( tinc.neati, O11
t
. 1/-60,)S7 INI/1R11-S 0a-INUI I('FD RRONCIIIAT. IIYPFRRT.A('TIVI I V
IN 1111 (i1IIN1 A PIG
We sludirJ Ihe effect on oaone-induced airtray hypetreac/ivaty of 11 60,!)1, a
p)-rrnAMunlacyclin shown lo inhibi/ kuhMtirnt ('/1) birnynlhrsh in vitro. A puup of )
Ruinra p.as wat prelreated with 11-60,257 (~ m~/~R IV) and tllulntd IY(IHe anti 10 min
aftrr a 15 mm ealwnure 1.. ) 0 ppm oaone. lhese animalt were compared lu a vuul.uly
talvnrd itroup that was unlrealed (nv10). Reaclivi/y was drlerudneJ by mrr.uc,n6
sprcJ.c airway trtstance (SRaw) Iryan inlravenous acetykAutine infut.nn .n
unaneslhelireJ, spnnlane.wsly bttalhinR animah. We (rwnd Ihat (1 A0,2f7 /rrat.ornt
rIuH to uaone raptqure did IW( affKl tilher SRaw or nWKa/inic reactivily. Af1rr
rappnurr In .10 ppm, all unlrealed guinea pryts aM.wed tubtlaniial muaanmc
Ayperrracl.vily In cuntrasl, no tiftnificanl change in SRaw oa mua'ar.nrc rraclivily
oecurreJ afler .unne in any animal pretreated wilh 1160,257. We an.cluJe Ihal the
na.meindwed Ivonchral hypetteac/ivdy in the guinea pig rapidly .kvelopt dler a hrwl,
high kvel e.p.nure. Ihit eflect may M sedialed in pats by IeuYunirnrs Rrnrrated upon
ntnne talMnYre. '
Alurlat ('. and I ee, // K
PrnunRfonJrnt .)6(41) 161 1he, 1965
(atA,r .uplr..r: Nalion.d Ilrarl, I una a/11t RIInN( Intt/lu/e
I rnm Ihr IAparanrnn uf Mr.6rinr am/ I nvuunmrntal I/ret1A. I/n.veruly uf ('.num..u,
S./uud nf Mr.fnme, ('.n..nna/., (111
INIX)MI F1IACIN INIIIRIT`v 11IF AIRWAY IIYPI RRISPUNSIVINFSS U(// N(tl
11/1 NLI/1 R(1PI111. 1NI 1..117( INI)1I( IO RV 0701,111 IN IXX3S
to determine whrlher oaygenaluln products of arKAidMK acid may hr m...I.r,1
in thr wway Ayprnr4..mwrnrts mduced by ornne e.lunute, wr slud.rJ ~Mlhr.
/. 1 41
oront induced hyperrtsprwni.rness in does could be inhibiled by the prmtaRlsnAin
tynlhelast Inhrbrhw, rn/MrnethKla Air.ay responsiveness .as sasessed .uh
do.r-rrspnnu curves of Ketykhntine aermol trrsrs pulrnonary resistance in 2 tris nf
e.ptnn.rms in one te1. S dnRs rere given so indnmelhacin Irestmenl and ast studied
M./h he/ore and aller nrone e.(u.tuee (\01pm, 2 h/, in ano/her srl. Ihe same dogs were
slud.rd brfore ind.wntlhac.n Irratmrnl a osowe eapotwe and then darinR Ireatment 11
mR/loR every 12 1A for 4 days) Mlh befnre awd af/tr oeowt eaposure. On each nccatinn,
we slan determined Ihe numbrr of weutrophih iw hio(rsies of the slrway epilhtlium
When Ihe drMs werr nnl nealed with indnmtlhKi., oaowe caused a marAed increaa in
respnmrvenrst In Kr1Yh'Mdrnr and a mar\ed iwereast in the numher of neul..q.hds 'n
Ihe aYraay eprlhttium When the dryt wert {ivew indowltlhKin, reqx.nsivrnrsi wa% nn
ddfrrrn/ durrng rreatmtnl than befure IrtatnKnt, bol wsere importanlly, retpnnsivenrrs
drd ruw iKreax srRndraanlly af/er Ihey wert ethlsed to nrnnt IntrreurnRly,
irwlnmahxrw Ltalmen/ .1w/ wnl affKl tNher /he haseline numlrr of rprththal
ntWn.phds hr/urr omnt ry"nure nr /ht incrrast in Ihe wumtrr af nruu.q.bds a/lr,
t.lunurr the resul/s suRaru that otyRrnalrnn prnduets of srKMdona a:rJ Ihal a.e
arnuh.r Irs inhlbdu.n hy rn.t,.nmrlhacrw play a rnk in orone-/nduced hypenrspamr.rn.ss
r.rhnut a/fralms the rnflu. nf neulrapMtt
(1'Nyrne, P M, Walltr., / 11 , Aira.v /1 , f abbri, 1.. M, tloltrman, M 1, and NeJ.I_ /
Anwrr.nn Rr.rr- n/ At,p.rw.+r n..t.rt 11e??0 2?J, 10/4
OtAr. suprnrr Nannnal tlearl, 1 unt and Nh.nd tnuitute, risons ('mporalrnn a.d
1'ahftnnia A.r Rrsnorces Nnard
I rnm Ihe ('arAnwncular Rrsearch Inrl.tu/e and Iseputmtnls wf Medicine a sd
f AyIMIIngy, (Inlvri\11y nf ('all/nl/lla, %an / ramrKn
CONIR(1L (1/ NfItRf11RANSMKCI(1N RY PR/KfA(:I AN1/1NS IN CANtNC
I RA/ III ALIS SM(KI111 MIIV I I.
ConlrKlik respnnses nf esnint Irscheal smo.wh musck 10 eleclri.al fr-hl
slimlrlalion diminished o.rr a 2-h ptrind of incubalion. Ilo.rar, a.hl.l.nn of
in.brnelhacin (I0sMf fnr a srmilar time not only pre.enled /his inhibition of a.elrKdk
rrspnme, 1wt Ktually increased mar\edly the rtspnme to ekclrical fiehl slimutati rn,
suRgestrnR that proNaRlandint were retpnwsrbk frw the lime-drpemkM inhihilwln
Messured prmtaRbndln Ft increattd in /he tissue b.th over 2-h in eonuol lissurs.
Addition of prnsugland.w f.s to the listue prnduced simitar inhibition of conssac.itt
respnnsts to eketrieal field slimulalion in a concenlealinn dependent manner /n
conlrnt, incubation alone. Ireatmtw/ with indomethacin or addilion rd proslaglandin 1 a
had hllle, if any, effect on cnntrseliows induced by arrtykhotrne We conclw/e that the
telraw tuf prmtalllandins frrwn caniwe dKhesl srworrlh muKk that occurs .ri1h limt hs a
p.r.hrmrnanlly .nhrbrinry effect on ehn/.ne1gK rKYlolrammNtiOn al a Iwelunclw/nal {Ilt
Wallers, 1. 11 ,(I'Ryret, P M, fabMi, 1. M,(7raf, P b, 11n1uman. M) amt N.nJ:I I
A
.
l.w.nol ol AfOl.rd IArrrnlnRv S7(1) 120114, 1914
(1rhr. Irprrr Nal.nnal lltar/, I uq and Rlnnd Imlilulr, I isorn (-orpnralion and
1 abfmnra Arr Rruw..rr IYrrd
AN ANTI INIi AMMATORY DRl1G (SW733C) IN111R1TS AIRWAY
11YP1 RRLSI<)NSIVLNI St INUI)('Eb RY OZONE IN I)7GS
To follow up out previnus observatioo that a'a.ay hypenespomiventss induced by
nrone is linked lo ir.ay inflammstion, we investigated Ihe effect of NW73S(' an
anli. inflammalrwy dsus, ew orm.e-indl/ced hyptrrespowsivenns in duRs Airway
respnnuveness ..as as+essed -ilh dott-respowse ewen of Kesykhnline aerosol err.us
pulmnnary rrsisunct in two sels of eaperintewts. In o/1e set (placebo Irealrnent). five
dqls .ere pven only saline solutiow trestwsenl .wd urtet studied btfore leealmenl or
orone ralunure and Ihen afler Irtalmenl bolh before awd afler ornwe O0 ppm, 2 Mlursl,
iw another se/ (11W /SS(' /reslmrnt). the same dogs srere studied hefore eW 7SSC Irealmenl
or wronr and Ihen aftrr Irealmenl (10 wR//,{ inlravenously/ both before an.l afler osone
When the rh.Rs .ere not given 11W733(', orone induced a marled increase in air..ay
rtapnnaventss to Krlykholine. Whew the dnggis were given RW 7SSC, repw/nsivenrss r»
wo dd/erenl dwrinR tbealmrnl /han befnra Irealmenl hul, mme imprnlandy,
rtsMmi.rnrss .1n1 Inrl im'.rate synificanlly dltr ornwe. 1/ it conclu.kd that //W //1('
maulseAly inhibits on.nt rmluced auway hyperrespnnsiveness in d.rR., pruhal.ly by
inhdwlrnR Ihe fnrmaln.n of osygenaliw.w products of srKhi.Mnic Kal.
I abMi, 1. M, Aira..a, 11 , O'Ryrne, P. M., Relhel, R. A, Wdters, E. 11 , Ilolliman, M
I, and NeJrl. l. A
l.wrwnl .r/ AIIreRe nnd Cfrnrrwl Iwrwrrwelof 1' 76.162-166, IVIS.
OrAer rupfvwf: National Institutes of lleallh, 1'isons Corporalion, ('alifornia Air
Resnurces lloard, and the Italian National Research Council.
1'rom the Cardiovsscular Resesrch Inst7lute and Ileparlmewls of Medicine and
MysioAyy, llnwersi/y nf ('alifrwnia, Saw Francisco.
PRI Ix)MIN.\Nr GI NI.RAl7(N/ OF 13I INOXYGI'.NASE MI:TAtiO1.11I S OF
ARA('llllK)NI(' A('lls IIY F.PI IIIF.LIAL CLLIS FROM /Il1MAN IRA('111.A
rpithelia/ cells of 99% purity owd 92% viab7i/y were isolaled rrom human trKhtas
obtained pnsl wwwlem, and the eeRlrlar pathways foa lipnsygtnaliow of arNhidonrc Kid
were eaam.ned rw ru.a The lipoaygenase wrclsbrdites were identified by comparison
sei4 synthetic standards durinE revetstd-phne awd susighl-phase high pressure Ipud
eheolnato{raphy, l/V spee/roseopy Iwd gas ehronulography/nrass speclromeuy.
rpithelial cells incubated without aeachidonie aeid failed lo generate delecbble quantrlirt
of n.elabolrtes, while cells incubated with rsKhidowie acid a/ 1s0 rg/mf for 1 10 mrn
inwriahly Renerated predominawdy H-IipnayRewaat prnducls, includrnR
t,IS-dihydro.yic.sslelraem.ic
IS-hydrnayicmaleNaenwic acid (IS //11F), fow isolners of
Kid (t.o 6, 1 ddt111S arw/ Iwo ~,/Sku~Mrknn), N kasl one isomer of
11,11 d.hyd.ocyramalrt.aennic Kid, swd trwaller amolrnts of 12-111:11: and 2.111 11'., hul
bllk w no dtlectah/t S III 11' or 3,17di111 Ift lhe capacity of epJlhet.al tNls f.om
human pwlmnna.y airway In wlrclive/y lenrntt 1Slipoayaenast mtuhdNrs of
aKhidomc acid sutats/s s ppuenlid 6010 /'a1 IM producls as medu/ora of airWay
epithtlral fuM/ron.
Ilunltr, l. A., FinliAeiner, W E, Naltl. !. A . Gotlel, E. J, and I/ohaman. M I
Ibpa.r.nrnl. ..1 MrJn.ne and
I n.m rM 1..1.. ..., r.. Y...p. aw In..d...r en.1
1'/,..,..L.a. 1 ........,, . r , .,., .,... \.,. 1 ..w......
Pr.r,rJrnr. o/ the Nuhnwel ArnJrwrc of Scnrnrrs o/ the ftnurJ .Crnrra n/
Amr.na t2 4611 4617, 1'tR5
ctrhr. .upp.ut Naln.nal Inaitulra nf lleahh and ('Yal,e f thrnva Rrtrar" h I-ound..ln.n
I rnm Iht <'a.dwvaa uhr Rrarorch lnat.lute, U-ard I/uthea Medwal Inat,rutr, anJ
I.rparln,rnla of f1r.tamr, 1'athnlnty and Phyvul.nty. Iln,vrra.ty uf ('aldnrma, t.n
1 tanc..cu
1 I I/K/)IRII NI U. INIH/( 1\ AIRWAY IIYPFRRfSPONSIVI NI 'IC IN h(MiS
the aulhnn auJ.rd the ef/ecl nf Ieu11n1r,eM Oa arrusuls nn auway rr.l.,narvenraa
ta inhalyd a.rtYl.hnhar arnnuh aml on Ihe tellular cnmrymrnn anA cYCk,.Y~~Lrn.ne
n.Hal..l.tr+.n hrnrnhn-d.r~.lar 1avattr 110.1 rn dnRs 1nha1aluun Id MYhINInne 11, ann...k
had n., elft.1 un rra.,nR 1..1a1 pulmnnaty reliatanae hul inccraaed an..aY rryw.n..venr.a,
.rnd rlfr.l thal vrx rn.H.mu1n .n 1 1. and Iha/ rrturnrd 10 cnnl.nl It.ela .uh,n 1.1
Ihrre hnu.+ a/trr Iru\.,f,.ene Ilr, the numher of ntut.nphils am1 the enncrnuarn.n ..f
thmmM.ane Ilr rranvr,eA .n 4vaRe fluid rncaavd mar\edly Prelrraunenl with the
th.omMnane syntha.r mh.hdnr f1K Y 046 prtvtntrd /he rec.rax+ .n a.rway
rrahnvv.nraa an,l .n thrnnmhucane Rr hul dnl n.H alltr neutnMhd.hem.da.is Ihua we
spr. ulare I/ul leu\nlr.enr hr cauus nrubnphd chenu.lau+.nd rekate uf Ihomlr.eane Rr.
whnh tncrraara a..way rrar.mr.enraa
(/'1lyrne, P M, I rdauf, G 11 , Airawa, 11 , 11rtbA, R A, I IAi, I. 1, lloluman, M 1,
and NaJrl 1 A
hn.r,url ..I Apph.,l I'Ar.rInR r t9A(h) 19J1 194A, 19/11
nrArr .uprynl Nal,nnal Ilrarl, 1 unt and Rhwr1 Inslilute, I rauna ('orry.urinn, an.l the
('a6f..rnra Au Rewucara Ih.a.J
1 rnm the ('ard.nvaacul.r Rraearch Inalitule and 14parlmrnls of MrArcrnr and
1'hsan.Mty. Umvrr..ly of Cali/urnia. San I rancnco
PR(1S f AGI AN/ NN Fa. INCR F ASI S R CSP)NSIV f NI SS OF PI/I M(/NAR Y
AIRWAYS IN IKN3S
lhe aulhnrs slwlied the effect of proslatlandin Fs. (P(:Fr.l on the rrapn .civeness
of puknnnary ai.wayt in dnts Air.+ay rrapnna.vtntas wat aaaaaed hy dNerm,n.nR the
hrnnchurnnalrrclM rea/.nn+e to incrravnt cnneeMra/innt of ace/ylchnhne arannl
delwereJ 1. 1he a.rway+ In rach of five dots, we deltrmined reymnaivroraa d..nnt
Ireulmenl ..,Ih phYSnJuR.c sahne, hraUmine, m IY31/4 ae.o+n1+ the .k.ses uf t..alemine
and Pli/s. wert drlrrnuned by rltabkahint rhe 1arReal Mnr nf ra.h whnh anah/ Ir
Rivrn u. the dat wNhnul cwaint Mun.MwnnaNnlnro (auhlhrrahnhl dMntal Mr I.wad
11.31 au.ray rNpunarvrnesa was nol s.Rnd.cantly dd(rrrnl durrnR hnlam,ne .rratnrrnl
Ihan nflrr salint, hu.rver, rra(w.m.veness increased durint Irealnwnl wnh P(;11. In
add.liun, the hyperreq..nsi.entss inducrd by P(iFa. was prevented by prelrtatn.em with
the tan/llw.n MncRinR drut he.amrlhunlum (S mR/kt t"en inlravenously) the rraulla
aho- Ihat P(i//. alrcd,cally incrtasrs lhe resMsnsrvenesl nf pulrrwaar ns.vrnts+ nvul es
Ihal Mo nrd ca.nr brnm A.rnnat.nlu.n, and suRte+/ Ihal Ihe hype M
a nrural me. han..rn ana h as .nc.raard nqr.nvrnraa nf al.way arnanry nrr.ra
t
l)'Oyrnt, P. M, Aiiawa, 11., Relhel, R. A., ('hunR, K F, Nu.lrl. J A, and /lultrman
h1 f
Prwretl.mdrn. 2p(1 517 541.1984.
!)rhrr supp,..rNatinal IIraN, I.unt an.l Rhud Inalilulr, the ('ahfornu An Rrwurcn
1lnaul anJ 1 nnna (-u.Mnalnm.
I rnm 1lhr ('ardmvastular Reararch Insti/vle and 1>.parsmenls of Mrd,crnr and
Phys..k,Ry, ltmvenny n( ('alil.an.a, San I rancisco '
NI IIIRl1P1111 h1r1 1 11ON INIIIOIIS AIRWAY IIYPI RRhSPUNSIVINIIC
1N1/111 1 11 11Y (1/I/NI: 1 XP(IlS1)RE
the anthms uuJ.ed whelher orone iruluced hylrrtraponpvenrss cuuld he n/uhnrd
hy nrunnphd deplrlw.n rn d,Ka Retpnnuveness was aaaraatd wrlh d.ne realumar aurvrt
of .artylahnknr arr.n..l rrcus pokmmary rrsialanrr, drhlrla.n waa aaaraatd thy aouulmR
nruu.p.hds in vrnuus hhrw) and in bMynira u( the auway epilhrl.um Rr./a1na/.rrMa\
and nrulrophil numMrs were deleyrnined S dayt and I day befart aront anA I Is allrr
orone (10 pl.m, 2 h) in 6 unlrraled d.qp am1 in 6 dots uealrat w,tis hydroryurea 1.'INI
mt/hR daily fnr $ days s/arlint S days hef.ue urrmr) In unlrea/ed dnRa, rrap.,nuvenesa
ami nrulap.hd numhecs S days and I day hrfiue aronr did nnl chanRe, bul rraµmuvrnrss
and epnhelral neuunphih increased w.arkedly dler orone In Irr.ne./ JuRt, cuauLumR
neulrq.hils decreaaed /rorn 19 t 2 2 hr 06 ._ 001 X RIl per mm' (rnran . SI h1), and
rrapnnuvenrat hrf.wt om/le did nM ehanRe. I.uherrrwne, increaars in reslr.naivenraa
and epilhelial neulrnphils du) tuN oaYOr af/er on.nt. Srx wh afltr sloppmR hydru.yurra,
responsivenesa and epi/helial neWrnpbih increasn/ marhrdly afler nrone Iht rraulta
suRRrst Ihal nrnnt-indre'ed hyperretpun+ivenest may deptnd un the m.uhdiratmn uf
neuu.p.hrh inln Ihe airways.
()'llycnt, P M, Walttrt, F. 11 , Gold, S 1)., Aiaawa, 11 A, I ahri, 1. M., Alpr.l, S
1, NaJ.l. 1 AA and Iloheman, M. ).
Ansrrrron Rrrrr.r../ Rr.Pnan+r f)rsra+r 1)t 211219, 19t1
OrAer .upp.w/ Nalinnal Ilrarl, LYnt and RIOpI /1n11/Yle and / Iannf ( IHpntallan
From the Canknwacular Research Inslilule, and 1)rpar/menta u( MrJ.c:nr and
PhysiolrKy, ltnivrrsily of ('alilornia. San 1:raM'isco
AIR WAY IIYPFRR I SPONSIV IlNESS ANI) C'l1ANGI S IN ('11.1. ('O1/N IS IN
IIRON( IIUAI V1 (l1 AR t.AVACF AI IFR (1/1)Nl. IX/Y/S(tRl IN INK;S
/hr ulh.nrs s/ud.rd whr/her irwaY hyprneyr.miv.nr.+ inducrd hy ..r..ne
ti/MRM/e Is av.wtated with cbnter !n Ihr numtrrt of drf/r.rnl lylus .ul rll. n
lunna/wdvr..lar 1avaRe rn rMRS, A{rwaY rrN.onairrness lu act/ykhol.ne .nd the nu.nbr,.
of cells rn IavaRe flu.d wrre .klernnned I w\ larf.ne and Ihrn I h aod /.4 rlr.. : h
tapMUre+ lo (d1rred air and /u cNnnt 410 ppml in taah M S dnta A.r.ay
rrspnnsiveneu and the numhers nf etlh in lavate fluid did nM change dler e.pnsure In
fd/ered ait. ny cnnlrast, airnay rttpnesiveprat increastd marYtMy I h afler ryw.ao,r In
ormte and returned lo cnntrol kvth I w\ laltr In addrlM.n, the numhrH of neuuophda
and nf ednlyd epahrhal crlls in /avatt incrtased fhatlydly I h after on,ne and rrla.rnrJ
lu eonlrul kvrls 1.k laler (lur previous tludy showed Ihal anway hyprnralwmpvrnest
AlS
4.1
induced by ornne is associstrd with an ieflua of neutrnphib inlo the mosl crntrat
airways, the p<eaenl rr.ultt saRRett Ihat the hyperresponsiveness is dan secompanird hy
an mfles of nru/rophdi inlo mort dalal anways snd by deitVuamalwrn of anway
eprlhetial «Ih
1 ahri, I M, NoJrt / A rr al
Anvrreon Rrnrw of Rrrpuur.+r Drvav 129 211-291, 1904
Ad1rr <upp..t Nalinnal llrott, Lung and Rlood IMti/ult, Fisons Corpnralion and Ihe
('aldnrnu An Rrsuu<.rs h..srd
I rnm the ('ard:wa.cular Re.ravch Inst<Wte, Drparlrnenls of Med., ine and rhyvnh.ay.
Iln<veruly nf (-alifurml. San I nncncn
(X'f'sIRRfN('F AN1r1/15fR1Q1171ON01 RF(i(IIAT(1RYPFPTIhISIN111F
KI\PIKA1/)RY IKA/ I
A mullimemLnrd syslrm of aclrve rrAulalory peptidet has heen found in Ihe
rrspiralnry /rsct Srudrts nn the nernradnerrne ma<her, neu<nn tpecifk ennlase,
ind.cNe Ihp Ihere a<r s1.11 furlher ly(xs of reucmal endncrine cells sm1 nerves wh<.se
prrMluclf rrma.n lo hr eluc.daled Thrs is nrn turp.nrna to v.ew of the rale of discnvrry
M novel rrRulao<y prplwles hy n.w b.nchemrcal mrllwrls and .eeomhrnant IrNA
Iechn<dngy 1/ n well lnuwn Ihat the lang pnaae<.rt funclinns in aJdd<nn lo mrre
re<p.rarn.n and Ihev funcllnni mae well fv rrAnlalr.l by the varinus rrRuLHnry peplidea
presrnl in Ihe resprralo<y I<a<1 Many dnease% of the lunl ate still prwNly unde<sllu.d
7he drNnvery nf erflu/alnry Lrplutn rn.nl.ed in rrRulathnR mucoserretir.n, hhrN1 /l-
and mus<le lnnr wdl und..ulwdly ennu.hule In the fu<thn underttamlmR of d.rve
</neases
lhe basic mechanism of lumn< Rru.qh and Ihe hndnsy of lumor cells wdl alao he
be/ler umlersamd aflrr furthrr sludy of Ihe a.lrve rrlularory pephdrs, many uf wh..h
play an im(wqlanl rnk as aotnloats to the nqmlrnancr of lumnr Rrowlh
Pala4. I AI and Rlanm, S R
(-ancer RnrarrA 9o 1 -16, 19AS
. f rorn Ihe fyeparlrnenh of IlrftoclKmklry and MedKine, Royal PnslRraduate Medical
Schnol, llamrnersmr/h llospilal, I nnMrn, I nRland.
'RRON/'ll(11)1t A7(1R RISPUNSI: OI)RING A(Y/TE VIRAL DRON('1111)1111S IN
IN/ ANCY
Rmncho</dalor respnnsi.eness was assessed by mrasuring speeifie rrspnat.ay
eonduclance befure and dter mhalalinn of aerosrdlred bronchoddalor in 50 infanls whn
had acuk bronchinlitis due to respiralory tyncylial .irus infecli+n. thuty percent nf Oe
infanls showed an improvtment in specific conductance. Respomlen couht not le
difftrenlialed hom nonrespondtrs by family hislories of atopy, eosinnphd counls ra
immunooobbutin kveh in blood and nasal seereliont Fighly three percenl of tle
families an<t 54% of the nwshers of Ihe infanls were s<nohen. Rahits of srnokinR mnlhr.s
had bwer specific eonducunces thsn did Ihose of nnnsmoking nu.then but ahowed ro
d.//erences in brnnchod.lator respnnx The clinical sqnil.canee of Ih.s
hrunah<whlt/m reary.nNve suha<nup has yet to ht defined
M 1, Sls, I, Iben, 1,/t I At anA I anJau, I
Prdrarr.c Pu/nurroloRr 1(211f-16, 1983.
Orhrr supporr: National Instilules of 1leatlh.
Fronl Ihe Rrofenional I1rp.rtrlment of Tbracic Medicine, Royal Chddren i
Melbourne. AYflralia.
t111t.17A1K)N OF A PI ROXIUASF AN7IPFROXIUASFE cOMPLFX IN AN
I N/VMC-LINK11) IMMUN(Kl>K11ENT ASSAY OF
11 ASI IN-l)1 RIVI I) 1'1 P11h1 S IN III/MAN PLASMA
/ losprlal,
('hronic uMtrucli.e pulmonary disease (COpI)), a major caux of morbidily and
dealh ra Ihe smoLrnt p<K,ula/inn, develops insidiously ever many years, and fign<Inant
impairmrnl of lung fun<t.nn usually oceura before Ihe diseate is diaglnosed. Keca<rwe luns
elasl7n detradalnrn alprers /o be a perequisilt frw IM deveMplnent of the drsra.e,
immunnhrtjN <k<eclu.n nf elaain-derived prplydes in Ihe bhwrd rniRhl be an effe<trve
apprnach 1o the early deleclion and Inonilnring of the drsease. We here reporl n
imprnved rnryme-Imked imm.aosorbeM assay for tlnlin ptplnks us<nR a
peroanlase-anliperoaldase co<nple as the reporter pou0- lhe assay is stnsilive In
2ng/ml elastin peplirks We show that for oplimal, reproducibk resulss Ihe assay shnul.l
be catrinl oul 111 16' (- rather than at rann ltmpera/uor and that dt/ernunaliuns shnuld
be mark on plasma cnnlaining prMease inhihilors ra/her lhan an strum. Iht Irvels nf
elas/<n deri.ed prplides appeared to rewrsin relalively ennslant when mult.ple samplrs
were IaYtn durinR a S- h. 1f)-srL perird frmn individual aubjrcls. In addilron, paaen/s
rilh ('Ohl) had elevated tlsslin prpliwk levels (127217na/ml), whereas normal smn4ers
had qlues in/trraediale belween the 2 groups (retan peplidt levels of 16tQnR/nJ)
compared .i1h levels in nmmal nonstwokers (51l17ng/rnl). A small Rroup of nurmal
snmhers 1.'(YL) had elevated peMide levels siali/ar to those in the emphysema poup and
may rtpreunt Ihat {rou/M of smokers to rist of devtlnpinR oMlrucrive lung dnease
K ueieh, U., WrrnAaunr G. re af.
Anwrrran Rerrrw o/ Resp<raenre Disease 11L7fb-717, 1985.
OtArr tupryrr: National Insli/utes of lleahh.
From Iht beparlmenl af Medicine, (iraduate /lospilal; Allwel T'inslein Medical ('entrr
and (-enter for (hal /leallh Researeh, Schad of 1)enul Medicine, Univrnily ol
Pennsyleania, PhBadelphia.
AMINO A('lly hFRIVFh LAl FNT IS(X'YANA71'S IRKF VI KSIRI /
INA('lIVA111/N 01 POR('tNf. IANCREATI(- ELAS1'ASF ANIt
111/MAN 1.11/K(X-Y11 11 ASIASI
Stvtrd .mino acid derived aeolidts have been synlhesieed and invest<pled fnr
Iheir inhihiloly aclivily loward human kuhocyte elaslast and f>acine pancrralic tlaslasr
lhe inhibi/nry aclivity was found lo be depeadenl on the nalure of (he precursnr anunn
acid ester. lhus, eompounds derived (rorw L-valine rntlhyl ester ), 1.-norvalrne melhyl
esler S. DL-norkecine melhyl esler 9, nnd L-rlrethioninr nre/hyl ealer 10, r.ere found In
inbibil irrtvenibly hnlh rnaymes Co<npound 10 was found lo be a specific and selec/r.e
iwhibi/or of hu<nan kuleocyle elaslsse to eonlrasl te Ihese, inlnbilors deri.e.l (ram
folyeine methyl ester 1, 1) vahne methyl tsttr 4, and 1)nor.aline methyl esler 6 were
4/
n
65100 7605
found to be macli.r Ihe tetulls of the prrtenl slwly ahnw Ihat Iatenl itax)inilrt
dr.ivrd frnnm apprnpru/r am.no acMh can serre at telrcl.ve mbdntnn ut sennr Inutra.ra
and srr n1 (.nenhal pharmacnhMKal value
(:.nulat, W C, R'rrnMu.n. C. , rr at
lhwnad nf ~frdu.nor ( Arw.nur 2/(1) 104 169, 1915 .
A+A:r ,urrvr Am..ican ('hrmical Sncie/y, Arnerwan I.ung Avincialiun and Val.unal
Ilra.l
I unR and lll.r.1 Inslnule
,
.'
I.nm the Ilepartment nf ('hemitOry, Wichila State T/niveniq., Wi.hila, KS, the (iraduate
IL..p./aI, Isrpa.lmrnl of Medicine, Reaarch Isivitinw, Phdadelphia, the Ihy..ulmrnt 1.1
Vrlruua.y 11.utc.encra, Ilni.rnity of Illinon, t/rhana; and the Isrpa.lmenl of / hr.nitl.v.
I lrnvrruty of W.a..nun, Iau ('taut
('(111.A(il NASI' IN Till I OWFR RFSPIRATORY 1RACf OF PAlll NIS
Wltll AIrUt I RISrIRA1l1RY D/SIRFSSSYNI/R(/ME
('..11aRrnaae act.vily in the bronchnal.enlar lavage (RAt.) of palienlt with a.lolt
trapiralory .l.urett syndrnme (ARTK) wat mraaured sRainsl type I collagen (17 lut.rnlt)
snd aRacnat lypr I/I cn/la6en (11 paarnes) Ser.ne prnleaae actlvily was aaan mrasured
sRamal / yM /1/ totlagrn (11 pslienN) T ype I cnllaeenau activity wat detectabk in 11 nf
1/ am) lype /1) cullaarnau was drlrctahk in 11 of 11 palienls with ARIh The 10
ennlrol suhjectt haJ no drtretaNe 1 Ype I nr 111 collaRenase ac/ivity tnlat am/
cbfferential white cell cnunli wr4 anatyerd in the lava2e flun/ Although Ihe lolat
CuuMt d.d nnt dJfr. 1rf.Ten palrents wah AKISS and tondol 4uhjecls. Ihr pncrnlaRr
of ntulrrMh.h wa+ .ncrraard mure Ihan :i fuld and /he pe.tentaae of macny.haRet waa
reduced a1m.n1 10 Inld in Ihe ARIK pal.enls Srr.a1 cnllat{en.rse a.l.vitW aa /nllnwed m
I ARISS survwor In /Mt pal.enl lypr 111 tullaarnatr a.l.v.ty pr.teA Irfine the IyPr I
t..llaosrnase aclivity nr ter.ne prnlra.e acl.v.tY reached Ihe.r nma.uounn hoth the latl
two enryme scliv.l.es rarslkled the tnlal rrcnveraldr erlli in the ItAI
('hritlner, P , Wr.nMu.n (: . r/ af
Anwrrnw Rrrur n/ Rrlprru(.rr Prlra.r 111/A0 605, MIS.
nrhrr IupP/.( u S Public Ileallh Service
IYum the Divitiun of Pulmonary anA Critiral Care Medicine, All.erl I inatrin Mednat
('rMer, New Ynrk, lempk ltaiversay /lralrh Science ('rntrr, /6r Orparlmrnl of Ihntal
thtlnh.ly, t/niveruly of Pennaylvsnia' and Ihe Ifivis'w.n nf Keseaah, tlrpoibarnl of
Medicine. (:raduale Iloapital, Philadrlphu
SI /'KI t11/N (1T t( ASIIN IN Il/f 1-MIIRY()NIl' ('1111'K A(/K fA
A% VIosI/A/ I/11) 1/Y 1MMlIN(1f1.1/ IKI/N h/K'KlN IIrY
Recently; si{nif.canl advsnces have heen made in charsclrririnR Ihe patbway ul
elatlin hiusynlheais (torn the biochemical point of view snd a 70,000 dallon pro/ein,
deuRnated 1r.y.rlaain, appears /n be the Mimary InnJalNrn prculucl and snlab/e
inl(.med.atr nf Ihe intnluhk e/aslin 11nweer, relatively little ia known cnnrr.mng the
inl.a.ellalar secrrlurY palhay of unpoeUtUn We prevmuslY devehqwd an rlecln.n
n.nr..u.yn Ir.hn.q..e ut.na rbalin .Lh'd.c anl.Mrly anA frnU.n tnnjuRalr.t.r..mA.uy
antibody to idenlify inlracellular elaslin and to idenlify, prnviaionally, in/racrllrlat
veanlrS CnnlNnlnA etatlln. Ilnwever, the tltellqd dn/ M.1 permlt InCallraUnn of elasbn in
othrr inlracelluln nrpnelks Me now descrihe aw improved p.nl.rmtrddinR lechnnlue
usinR Ihe peroaidasrantiperoaidase /nelhnd (o delecl the primary etaatin aMit.n.lY, we
ha e h.catired elastin in both the ewdnthelisl snd rnedisl crlls of the emhryonic chnk
snrta Specd.c sla.ning was vnuhaed in the cislernse of the emloplasmic relitulum, in
tbe GrnlRr apparalus, and its vesicks forminR on the Irans side of the GnIRi Some of
these amaller vesicks q.peared to fuse, fnrminR IarRrr .esicks whi.h may have a stnraRe
funai.n_ Itolh lypes uf veticks wete seen fuamto wdh the cell plasma memhranr,
a.RRealinR d.al elaslin is secreled by an e.ncylotic pawess Thefe retulh suaarsl 11,31
Ir.qw.ela.tin fotluwt d.r classical palhway for pcotrm secrelion.
Ib.niann. V, 1 sane, A 1. , Wrrw/wunr. fi.. ('hrislner. P, sm/ RosenbhM.m, I
( o(IaRen RrfarrJ Rr.rarrA 4 1)1 W, 1984
.
(IrFrr supfrwl. National Inslilules of neallh
1'rnm Ihe Center for (>.al /lesith Research, ScMud of flenlal Medicine; the Isrpar/menl
of Mnl.cine, Graduate I/oapital, and Univrrsity of Pennsylvania, Phdadelphia
1'R()111NASf. INIt1111TnRY FIINCTION IN INFLAMMAT(7RY 1.(IN(i 1>IS1 ASI.
I A('l//l. RA('ll RIAL PNEIIM(Nd1A
lhis sludy r.amines bronchisl a/reolar lavsge (RAl-) samptes (rom a&rnup of
palienla with acate hacterial pneuwania (n-I)) and makes a comparisnn with a conl.ol
group (N-S) . Ihe prrNeinase inhibilory capacity was tasmined and fnum/ to he
cnmprned primarily of alphar-proleitwe iwhibNnr (PI, dphst-anlitrypvn) and. Iro a ktser
ralem. bronchial mucosal inhibilor. ARho.gh the average P1 eoncenlrata.n wat e/eated
approumately S-foM iw Ihe pneunlo/lia peup. As inhihilory fanc/ine against elastase was
ckcrrased 1f-fuld when compsred with I/u1 iw Ihe cnnlyd Leoup. lhe pneumonia group
shnwed an increasrd cnneenlralinw of irnmwwrhKicslly identified elastdn derr.ed
prplnles. Sru.e o( the SAL fluid Troln palien/s with pneumonia sho.red elastnlylu
atlivily against amorphorN insoluble luwg ettlaliw lhe Inajnrily of the elaslau a/yrran lo
hr of Leutrry.hil orrRin. Rrnnchiat moewa/ inhihitur is shown to he a cnmp.nen/ of both
1NNmaI and pneumnnia RAL nllids by both imlwunoloRiC quan/rulion snd hy rls
resiaance to perchhnie a.id inaeliva/inw. ('nmpared with Ihux fr..m cnnlrol suhje.ls.
RA/. sampks (rom pal.enN wilh Rule bacterial pneumrmia showed a decreaad
pr.Neinase inhib.lor functiNM and both increased e1as1.dylic activity and elaslm drned
prplide toncenlra/inn
AMams, W K., Wernhaunl. G. rr.l
Anwrr.on Rrrrrr nf Rr./urarwt fAvaa 129 7)5-711, 19tb
(hber Iuppnrl - Nalwnal IIea11, I.uns and RIooJ IMlilule.
Irnwl lhe l'.raduate /tospital. Tlrpar/menl of Medicine, Retrsrch Isivninn Al/w.l
FinsMia Medical Cenler, OepsrlmeM of Medicine. Pulmonsry and ('rh.cal ('are
(A.isions; temple ltmversily IIes11h Science l?Mer, Pulnwrnsry Ilaea.e Sect...n.
Phdadelphia, and the Pulnu.nsry l)eeax 17eparlment, Sa{a Medical 5ch.ndm lapan
42 1 49
.0
N1It1ROPI111. FI.ASfASE-RFl.FAStNG FACT(yRS IN RRONCI(OAI.VFOt AF
I AVA/.t 1 R()M PAIIFNIS M1111 AI)(II.T RESPIRAIC)RY asIS1RtSS SYNt)F.c1MF.
Oronchoslveular 1avale fluid (RAI.) was obtained f.om patients wi h adu/l
re.piralnry drsuess syndrome (ARI)S) ('onlrolt included RAI from normal suh rcts and
frnm pahems avith sarcnidnsis or pulnumaty fiMosis Neuluqhil elastau nrasured
rmmunolnRKal/y al found rn all RA1, samptrt, bul it was strihinAly peater in RAI.
(rom pat.rnls .ith ARt)S Ihan is the AL fYOO .nrmal subjecls or patients .ilh
sarcurdn.u 1 hert .ar no significant difference in /he nrul,ophil etasuse antiArn
csncentraln.ns in RAI sampks from paienla .ilh ARDS snd thrne with pulmnnary
fncmsit. Nn rlastnlslrc aclivpy wat found iw ei1hN sroup lhe alpha Ianlitry"in and
Ihe Munchral mucue rnhif.itor were freakr iw RAIL frnm pa/ienh wilh ARIsS 1'rert .n
hrRhly s.RnNrcanl cmre/alinn bes.een the alvtolar-otenal naygen lensiun ddference
and the nruunphil elaata.r enncen/ral.on in RAl. from the palien/s with ARtK
Kalt./rrm, prerelan.rrrm, faclor X1a 1rAe.elivNy, end hyh nndecular ..rrRh1 /mnuNen
anriRrn .rerr fnun.) .n ItAI. of palieMS .ith ARI)S, suilitesling that the LaIL\rrm \min
cascade m.iy he activaled in the lungs nf pal,ents .ilh AKIK Kallrhrtin-lise sclwrly in
the IIAIL fram Ihe Latients .ilh AKI)S was signifkae0y eorrrlaled with the numher of
nrutrnphass in the RAI ,/he nrulrnphtl elaslsse enneenualMn, and Ike ability of hr RAIL
lo rrlesae rtauase from cylochshun R tres/rd neuunphi/s. Fhere was nn uerelatNM
bel.een thesr vanahkt and CSa enncrntcaliun. Ihess studies demnnsl.alyd an
s.anciatm,n bel.,een KAt. nerlrnphil elastau and the clinicsl stste of paienu .vr1F ARhS.
hlell, S, WrrnMvwr C rr al
Awrrrrra+ R.nr.- n/ Rr.M.alarr fb.raV U1 q9/ lU1S, 192S
c)rArr saplrrr National Ilearl, Lung and Rlmd Instilute, National Intlilutes cf Utalth
arNl Amerlcan 11ror1 A,su.cialiun, Penmrt.ama A//dralr
Irnm the julmnnary Ohrece and Ilemabd.My f)nrnL.Ry Se./mns. Orpartmen/ nf
Medrerne, and IhrnmbosH Reasr.h ( enar, lemplr llmsrrady Mrd.aa/ ti.hnrd,
Polm..nary I)neaae Secl.on, Alhrer I mstr.n Med..al t rmrr. Nurrhrrn 1)wiamn,
Pb.ladrlphia
OXIUANTS INCRf ASE PARACFI 1(/1 AR IFRMEASILITY IN A
CI11.111R FI) f r11 UI I IAL C1 1-1. LINF:.
Inflammacinw of epilhelia is aw impwlan/ step iw the pa/hophysinlnRy of ride
variely of diuases Recaust reaclive naygen meubntiks are imporlanl effector mnkcuks
of ucute inflammalinw, we taamined Ihe effecl of uaidanlt on Ihe barrier funclion of a
cullured epi/htlium, Madin 1larby Canine Kidnry cells, by enrasurins the r.ansepithrl.a)
rlrclcrcal ennducunce, (ir, of monolayers ern.n on pernseabk supporH We found Ihal
11,O/, aAded direct]y nr benerated .rlh glucofe oawlatt, incrrsvd (ic S.mdar effecls
.ere otnerved .rth addition of aanlhine snd unlhine oaidase, a syslem whn:h
en,ymatically arnrraln srperoai+fe radical Os . lhe oaidanl induced increase in
conduclsnce .ar reven.hk if the rapwure 1o oaidanls was nM Molonged ( S 70 min1,
snd if ,ht concenlrali..n nf 11,O, was < S X 10 a M The increase in Go suggested thal
oaidants incrraae the permeah[lity of the paracellular pathray, a suRAetlinn supporttd by
an osnlanl rnducrd increaw in the prrrneahilNe so "(mannilol, which primar.ly crnsses
rpdhelu u the e.uscrllular mure
I
In addrtion to fhnclioeal cMnles is the epithelial nanolayer, oaidanls changed the
cAI morph.dogy; afler It,O, e.potwe, Ihe celk /endtd lo pull aparl, nwns p.ominrntly al
Ihrir Msolatr.al surfsces Thest changes were helerolleneout, with mosl areas shu.ing
nn chanRes. S.nne of the awrphulogic charyes could be reversed if Ihe esposure tn Il,t)a
.at limited we also oMtr.ed a distupliral of Ihe Normsl pallern uf the
actin cylosLeklnn, parlicularly is the area of cell le ceR juncliuns, ss demnnsaalyd by
Iluoreccent staining nf ( actin with tbodamine plraKicdu
Ihea funcliona/ ard slsocl.ral findinRs indicale that nsidanls inr.ease tAe
permeablhty ut /he pacacellYla, p.lhray in a cullwed epilhebum lhe chanRes can he
re.ersihle and are acenmpanied by dlerations in organiaalion nf the cell cytmlrlrtnn
IkMK llW/ret demnnslrale the dyllinnc nalule of the ,Mnaclinn between eprthrlut cells
amt oaypen melahnlrks
WrhA. At l. [ha.hy, 1) M. and Ilusled, R M.
bw.no/ ../ ('berral /n.r,NRanwrJ~ IIS3 1166. 19115.
e)rA.+ ruppur ~ Nstleryl Insliluks of Ikahh. Anwrk.w llesrrl Assr.cielinn and Veteum
Admmratrali.m.
From the I eMralnry of Fpilhelia) lranspwl and tul,nonsry I)IVisu.n. I)eparlmrn/ nf
Inlernal Mrdaine, It.ivenily of le-s ('ulkflr nf Medieine, snd Ve,rrans A.tnunntrarmn
Ilnspilal, Inwa /'r/y/
tu 1 31
tll tlearl and fircutslinn
('l1ARA('11 R17A11(SN (11 11P()/'RO1I IN IARtI(-I.tS ISn1 At1 t) IIY
IhIh111N(fA111N1IY t I/HI)MA1(>t:RAI'l1Y
Iwu p,.rutaln.nt of A Icnnlaining lipoprolein parliClrs A I arn1..mrnR
Iqrprulr,n wnh A 11 11 p(A 1 wnh A 11)). and A-) cnMa,Mng Iqwqaolrin w,Iho.A A 11
(/ p(A I wdhnul A 1111 have hrrn isn/a/rJ from plasma of 10 nnrmn6rydemrc uJqrclt
by inununoafl,mty chronulnRraphy and characterired Onth lyprs ..f pa,I,./rs
ry.tars n rlr.In.r.Murlnmn/..bly anJ hydratrd Arnsily in the ranRr n/ pl.l.nu
h,Rh drntily hp,.prnlrms II/IN I Ip (AA .r/6u.1 A11) and Ip (A I wUh A11/ are
hrlr,.Rrnruut in aur I p IA I w/lhoul A1/) enmPr,sed two diH.nel par/ntr tues wuh
rnrsn alh..v,nl m..lr. ul.v wr.Rhl and SMtors dlamrlrr of 101 . 104. anJ 1011 nm for I p
(A 1w,Ih,utA/1),.anJ1(1.10',anJI SnmfnrIp(AlwilhnulA-11)r tp (A I
w,lh A 111 u.u.Jly c..nl.nnrJ pirliclrs al 1,atl thlee d..lincl malrcular tues w,/h m,.rn
ap/arenl n,ntr. ul u wr.Kht anJ S1a1rs dr.m,e/er uf 2? II 10- an.l 9 6 nm loe I p 1 A I
.Ih A 11),, 1 MI 111 .mJ Il 9 nm fnr 1 p IA 1 wnh A 1t)., aml 1 25 10s anJ I{ 1 nm
(..r 1 p IA 1"Ih Ilh AI.pr..lr.nt (', ts an1 1, aml Irt.thincholrslerul aiyhun.lr,a.e
11 t A 11 ase,r .IrtMCtrJ rn 1..11, 1 r/A I wnh,nn A 11/ an.l I p(A I wilh A-11) with muU
nf /hr ary.p,olr,n 11, anJ 1, an.1 14 A 1/) 1? 1 1 41) an 1 p(A - 1 wrth A 1I) pa.l,cks 1 p
tA 1.nh..ul A 111 had shRMly h,RMr I,p.liln.Ie/n raln, Ihan I p IA t w/th A 11) I p
(A I wnh A 11) hail an A I/A 11 m.dar /al,o nl arprnumalrlY 2 1 Ihe percenUje of
platma A( ass,.,alyd w,lh I p (A I w.lhoul A 11) was hiRhly Cnrrelaee.l wdh Il.e
A I/A 11 ratn, ,J p/sama O- 096, n-/11) the valraln/n in A 1/A 11 rahu ul 11111.
JrntHY itJI,a.le,nt Ihr,rfurr relktls JJfrrrnl (q,pr,rln.nl of Iwo ditereM tytra of
L.ulnlrs parlaks cunlam,na A/ and A 11 in a nearly cunslanl ralw and paIltlrs
.unu.l,nmR A I t.ul nu A 11 1 ach IY/v of parluk it hetrrnRrnenus in svr au.1 in
.llala,/fin Cnmlrn,l,.n
1'hrunR, M cand Il7vr. J I
)h. Jnurn.J n/ N,nl.avr.d t hrnuvrr 259110117.`01 1?209, 1911A
Orh.r supryot Nalionil Inslilules of Ilrollh and Ihe American ('ancer Slaiely
I rom the lklnrlmrnt nf hleJicine, (Inivrrdly of WashinRtnn, Seatde
P1 A1111 / IsIRlVltr(:R(/WIII IA('1(1R ANUMAI II:NANI tRANSfOkMAI1hN
S1lnlirt an human ptalrkl-drri.rd Rrowth (a:hw (PIK:f) Jrscrilyd in dns pyrr
rrprrten/ Ihr cnl/ec/,ve el/nrl of several Ita/nt nf mvesl,Ralors nvtr the paa 10 yr.na
lhrte Nw4es prrM/uced an ahundanct nf infrnmalmn cnncernmR Ihe nalure anJ anu.hnr
,d 1'INil, its rott in tell Rrowth anJ ilt drverse funibnns affe.linR cell m,R/alrun,
nu-talrJ,c pntrssrt and receplm m,Mlutat/nn Ihis wurA alsn kJ 1.. an ,minul.ml
Jnin.rry bn/mR this Iq.lrnt milrry{en In Ihe /ranaf.urninR pwlrin uf Ihe simian aarruma
.uut, prnvihnR a haa,s fur the umlerslandin{ of the p.rKestet ,nvolveJ in oransformali.m
in.fuaed by Ihe CCV nnr Rrnt. Specd.cially, Ihr fm.ImRs drarJ.ed here pruri,IrJ Ihr
m,.smR bn\ fur the undenlanJinh of Ihe mrrhanam .uf cell uanclmrnalinn mducrrl hy
Ih. . Rr,r .I 1/r ...,n nr.onra .nu. th,. . , Itrnr .. , waa shown 1.t rm.le a
1 t. / 1., r , , a .., , .. .,., , .. r 1...,..., ... ...r /,.. ..,1r,.,1 .,n,.1/
m.,..le
1
cells and Rliat cells Aclivation of fn transcripliw.n may Cause the sutuinrJ ahnurmal
prnlderalwln of cellt responsive lo lhe milogenic efftcts of the PIK'1 h4e mu/et,Jr
Overall, these findmos see consisleM with Ihe urRhesUnn Iha1 srs acl,valn,n m,ahl be
invalveJ in she process kadmg normal celh of certain lypes lowards mal,RnafKy
Anr.nnodrl // N
IluwAcmrrol l'Anrma.olnRy 7(It12121-2i2t, 1984.
(hhrr .upp,or I I % Public I/rallh Service and Ihe A.neritan ('ancer Sociely.
I ro,n Ihr ('enlrr f,r IIhr,A Rrtrarch and Ihe tkparlmrnl of Nuuilinn, Ilarva4 S, h,H,l ,/
tutd,a 11ra11h, Ilnsl,n
SYN111/ S1t ANI) SI t RI 1/Oh (11 1'R1/111NS RI-SI MIII IN(;
1t A11111 I11 RIVII/(iR/1W1111'A('Itq( IIY 111/MAN('11t1111 ASIt)h1A
ANI) I IIIRSISAK( UMA ('/1.1 S IN ('a/t tURI. ~
/rnmlmnpre.,pi/alinn of protrint e.lraclyd from mrlaM,hc.d/y labelyd h,an:m
Rtn.hlaahnna an.l Irbr,narcuma crlh with anl/srrure 1o plaletel Arrrved R,uwlh /a.l,u
(PIM:1/ sM/wrd Ihal Ihett etlk raprett ami seerete prnteint Ihal arr .rcnanvnl
ipr.Jically by the ansnerurn. lhe Imdecutsr maatts of UlUnumMnraltNlJ/r,i (4ulrmt rn
the lys.rlrs of Ihe rnaliRnanl cells ranpord itu.m 16 Mp /o 140 \Ih Ih,lh ae/l hnes trarleJ
a 1) 11113 Iwdyprplide wilh s/ruelural, imreunnlr/gn'al am/ hndnRical pr,qaIlres a/nular Iu
Ihrne uf hnman 1'tKJ. lhrtt cell lines wert s/uwn tn synthtsire 3 4 A Ish mRNA Ihat
eontaineJ seqoena-es from all Il,e sin currenlly iwknlifieJ ru.nt of Ihe hunun Cv. Rrnr
/hrae 41.113 saRRrsl Iha/ the IIXiI-Ii\t prMrms in thr two mrsrrichyme .kuvrr/
lransforme,l crlh are enroakJ ol least in /ur1 by Il.e e-u. Lwut
In Ihit trpnrl we drscrdre Ihe iMracellutar syn/hesis of PIl(i) JJ.e pranrins In
eullures of human ~InAAatlmna and fiMosareoma eells and enuelale the preteme o/ Ihesr
proleins wilh csav mRNA speciet Iranscrihed by the human c-srs locua, /6r
inlraceRular t'I)(if-fi11e pruteins appear lo be pncuranr and peacesseJ mulrculrs nf a
mapra secreled prn/ein of )1 Ma Ihal is structurally, rmmunnh,RN]I/y and /una9an.atly
simitar to human PIKit .
Panlaris, R., 1'tlicci, p(7., I1ti11a-favera. R., and Awnrua,lrs. N.N
/rr.rrrJrnRl n/ rhr Norrnnal Acadrntr n/ Snrnr-rs e/ rAr frmrrJ Srntr, o/
Amrrne I12:2104 7tOtI, 19/lS
f)rhrr IYpp.wr Nalinnal Inttilu/n uf Ifeallh and the Amtrican ('ancer S,K.rly
(rnm she ('enter foe 1lhnal Retearach and 14parlmrut of Nutriliun, llarv:..J S.h,wd nf
1'uhhc I/ral/h, tluslon, and Ihe Ihlursmrnl al Ira/hnh,gy, Kaplan (-aeter ( rnlr,, New
Yurli I lniveruty S. MnJ o( MeJlcrne, New Yuris
.
PI A711 1: (-Itl /tIVI 1) ciR(1W Ilt I ACttSR P(11 YPI rl l/sl S IN 111rMAN
MI(iAKARY(NII ASIN' I.IKI ('11.1.1.IN1.S
Novel cell l,nes derived frnm human periphrra) hklod werr shr.wn In .ynd...ur
prJypepluM recnhn.rrJ hy slKcJie aM,.rra In human plalelet Jrr,rrd pn.lh /.n /r
(PIMiI l MrlalnB,ally lahrlyd inuarellular prdy/vpl.ales wr/e imrmmnprn.p,rur.l I,/
trlMif ant,arru,n and wrre andyrrd by \Ih p.lys:rYlamalr hel el..r..,ph.ur... Ihr
S~
m.decular massrs of the inuacellular form, of PI)GF lile pnlYpephdrs in 1hr.e cell linet
rantrd (rnm 17,0(10 In 4t-000 daltons (12-4I hi1), suRtestint the prrsence nf rl)(:1:
prrcursor snd prucrss.d molreuks. Metabolically labeled polypeptidr, immuno-
prrc.p.saled hy P/K7/ am.,rra were alw recotnited in the enmblioned media of ane of
the cell IinH uhl.dneJ frnm a IruhemK palrent lhe tnotecular maasrt of Ihe sr.rrled
rlNa lite M+tYl.eptulrs were 12 &I), St Yp, and 46 hD. Ilpp.n reduclion, 16e 11 \II
prdyl.rpt.dr .vJs rrdu.rd In 16 YI), suRtrVmt Ihal rt repretenlt a Jnulfidrhnked drmrr
simrbr in Ihal des:rrhrd for 1'IXSI,
Panqns, P, Mortan- It A, Ibndsky, I- and Aalnnrdn. !f N
In ("AN('FR ('Ff (N I;c;.nrrA Ferrnrt enI TrwsJnrmounn ('nld SprinR 11.u1.u
I ah.uatnry, 1VIlS, pp ISI IS)
(1rArr rupp.rr Nat.unal Inq.tutes of IIra/Nh and American Can.rr Srirty
I rom the ('rmer f... 111md Research and Ikparta.ent of Nutrilmn, 11at.ard 4hmd nf
Puhlrc I/ealth, R.nton, and the lkpartmenl of lirmatobty/OncoMty, 11a6nrnunn
Itn,ver,rty, Phdadrlphra
1-Ifl('1 Of ('AI(t1/MON 11111" S1At11111Y1q 1111' PIAtll/ I MIMIIRANI
(i1 Y( (/PRC)111N IIh Itla ( 1)M/'1 I X
Plalelel membrane tlycnprnlerns Ilh and Ills fnrm a("at' dependent hetrunlimer
eomplet Ihat eontuns brnd.nt sar, fnr frhnnoaen, von Wdtehrand factur, and
f.broneelm followmt plateM/ 1t/mulaluMn I he wrhors have stud.ed the effect nf ( aa' on
the tlaAilrty nf the 11b llta aunrle urrnt a/lh /lla complr, specific mnnoclunll
antibbuly A,A. In detect the pesence or the enmple.es Solubk I/h and Illa mtera.lyd
with A,A.-Srphsrose only in Ike pres.me of ( st' with SO'K 111+ 2113 b.nd.na rrquirint
0 e PM ('aa' In conlratl, st 2S'(' Ihe hind.nt of radiumdrne labelled A,AA tn 11112,1
unsumutated platelets sus(wnded in buffers comainint 11)1A ot ethylene tly.ot
bi,(4-aminaethyl e/her) N.N.N'-N',-IelracelK Kid was imlependenl of the prr.en.e of
('aa'. Itowever, the effect of ('as' chelators on '1'1-A,A binding varied evilh
/emperslure AI 11'(', I"1 A,A. brndint to intael plahrkls hecame ('a)'-drpendent
with SM Aimlint requirint 04 rM ('at'. Thit effect of lemperature was not due In a
change in plalekl mrmhrane f1uiJHy heeause enrichrnenl or depktinn of p1.Ttclet
rnembrane cholrslrrol did not inflwnce anhMnly binding. Alsu,'r`1-A,A. hindmR In
intxl plalek/s at 23' (' /rcarne ('aa'-drpendrnt when the p11 was incrrasrd sMr.e 74
AI I aM l'a)' and 2S'('. 5014 anlil.nJy himl.nt nceurrrd al p11 90 lhese st rdrrs
densonstra/e that ('as'- dependen/ Ith llla compteaes are prrseM ru, unV/mulaled
platelets and that the ('as' hindint tiles rrspon,.hle for the s/abdily of these .nmplr.r,
arr hrcated on Ihe raernai platrkl surface lhesr e.periments dso suttesl Ihar ch.ntes
in platelet cyhnotrc ('a` do nol retulale /he (orma/w.n of Ilb-Illa cnmple.es
f)rns, 1. F, Shattil, S 1, KunicY, T/, and Rrnnrrl. !. S.
T11rluwnol n/ R.of.R.rof ('Armrur~ 1f;0(17)7175"7111, 1925
prArr tuPfrwr National In,titules of Ilealrh and the American 1learl Association
1 rom 1he llemaloIoty-(1ncolrKY Section and the ISep.rlmeel of Pathology and
I ahuatmy Med.cine. Ilnrvettity or Penrnylvani. School of Medicine. Phdadelphu, and
the I/h,nd ('enter of Snvrhras/etn Wisconsin, Milwauhee.
Illf 11 fRArfrllhf: ANAL(X:I)C Of TIIE CFLL Al7Al'IIMI Nf 5111 Uf
I IIIR(/N/ ('fIN 1N11111115 r1.AlfL.FT AGGRLGAf10N ANI) I IORIN(K:1 N
nlNl)INC r(/ A('ItVAl11) PI.AIe1.F.IS
I ihrimrten binding to receptors on aclivaled plalelels is a prerrquisite fnr platr4l
attreRaturn Ilnwrver. the re/ions of frbrinote/l interacting wilh Ihe%e recep/urs ha.e
not been enmpletrly characteri)ed FiMonectin .Iso Mmh to ptateMt f.lumnRrn
receplms Mnreover, the amino acd fequence Art-(i/y-A,p Ser, e.NretMndmt hr Ihr
cell anachmrnl sile of frbronec/in, is located nesr /he carbnayl term.nal reaurn o/
Ihe n. ha,n or f.hnnoRrn 1 he rewarchen have esamrned Ihe .hi1Hy of lhrs Ir1.a1.rplrJe
to inhrhit plalelet aRarrtalmn and frbrinnten bi/ldint /n acl.vatrd pbtrlen
ArR (ay-ASp"Ser, hut not the pepli4 Aq-cly-Tyr-Set-t.eu-Gly, inhibited plalrlel
aRMeRalw.n ,/imulated by At)P, eollaten, and 7tha.mbin without inhrhitint plaekt
shape change ur seurlion- At a eoncetatration nf A0-t0 VM, Art (ilY Asp Set inhduled
the aRtreRatms of AItP"stimulated Rel-fdtered plaselel/ r SO'L. ArR- Gly Asp Srr, hul
nnl ArR Gly-lyr-Srr-Leut7ly, alw inhibited frMinnten bin.linR Io A1t1' ttinud.urd
platelets This .nhrhrtw.w was enmpelNi.e wi/h a K, of ahout 23 yM hut ras in(omplrte
even at hithrr Ir/.apryNide concenlralinM, imlicalint that AMt-(ay-Atp-Src ,s a pa.l..l
competitive inhiMhu of frhrinnten bindint lhete dala suRtes/ Ibal a reRi.m near the
carhn,ylterminus of the o-chain of filxinnten inlerac/s with the fYbrrnnRen rrcrptru ou
activated platelels The data al,o fY(porl the concept Iha1 the sequence
Art-(ily-Asp Ser has been conserved for use in a variety of cellutar adhesive prrreszes
(srtner, f. K. and Rennrrl. ! S.
lAe lrwrno/ o/ Rrrdnarcol CArmnrry 1W22)-I1t91-I1t91, 19ts.
11d1rr suplvrr National Inslitutrs of Ilealth.
Irom the 1)rparlment of Dinlrrty, Memphis Sta/e Ilniversily, Meml.his, an.l the
Ilemah.lnty OnerdnRy Sectnm and (bncer ('enler, Ilniversily of 1'rnnsylvania %, hwd of
Me.licine, Phdaklphia
('ARINAC INOTR(/PI(' RFSMNSI: OF A NI W 0 1-A(iONIST (IA .(IA4) W1111 1(/W
SA R('l)1 I MMA 1. At)1 NY1 A 1 F('Y('I.ASF A(' FI V A I IUN
Ihese eapenmrnlt were concerned with an invetlitllinn of /he effect of a nr.
,rk.,ivr A 1 adrrnertic compnund, IA 06e, nn Ihe funclu.n nf pardied saan/rmmal
veswles prrpared frnm prrFasrd eanrne hesrl prepars/ir.n,. Special emphasis was pl.ued
on the effect of T A 064 on .denylale eyelase activ,ty, on A I P-depemknl (-a" upt.le
and on phosphorylatinn nf purified sarcukmma ISI / rerfu,inn was caurecf out m a
tuppnrled canine heart preparalinn with a prrfluorochem.cal (1 (' 111 as pr.fu.are
TA-061/111 Yt) was .nlecled into the left alrium As previously rrprn/ed, Ihi, .rsulard
in a mariked pnsibve .m.trr.pie and ehrnnnbopie effect which nys aMdrshr.l hy
proprannlol Purity of the SI. preparHnrn was eonfirmed ..ilh marker enrymrs /r.r
mrtoehondria, sarenplasmre re1KYlum and St.. 10 arldrlinn, Na'( a' r..h..nte
characlerislic for SII was detrrmmed S.drInets of the veucks -as asce.uu.ed h, n.ran.
SS
54
of adtnylste cyctase activity ating SI ptrparatinnt with anJ wnhnus alamrlhicin
IA-OM/, aa cnmparrd to 1-itnprnterennl, e.erled h111e effect on aJenylrlr cyaate
a.lrvdy Ihe addaum of IA 061 tdhrr in the perfuard whole hrarJ prrpalalmn u/ In
plepa/ed SI veuctra rrtulled in small elevalinns of adrnylate cycla.e act.vsty rrl.r.ive to
1-it.ynnlrren.d 1 A0M .ncrtated A 1 P dtpemlrnl Ca" uplake and photphurytat.on
Ihe rrlatlve m.nnr reyu.nte Of sdenytate cyclate lo IA-064 wat apparrnlly tu(frcirnt to
elevale Lnh myncar.lal .unlra.IdAy and phntphmytalion and Ib" de(rndrvl A11'ase
acl.v.ty Ihrrefn.e, t A 064 brlnngs InRether wilh prenallerol in a Rroup Of p 1 aRnnl.tt
wnh full inn/rrquc aclr.,lv hut re(atively diminnhed eapaaily In aitivale adrnvLue
cytlaae the pharmacoL.R.r and c/mwa1 implKallorq of thrte f.mtrngt wrrr dn, u..rd
Rr.rr R / rr ol
('wr.nr I'l.rrnp-ulrr Rr.rn..A 16(6) 11?71116, 19/4
l7rArr urPp.nf Iloovrl 1 aundalinn and the ('harka A Lindhr.sh I und
I.om tl.r IIunlmR/un Medical Research Inslitulet, /IuminRtnn Memnrial Ilutpnal,
1'audrna, f A
('ARISIA(' P1 R/1151t)N, PASI ANIs PRI il NI
1hn paper wat p.raenteJ at a tvmlw..rum whah wat devnled in par/ tn the ruk uf
Irprdt .n /eln.un I.r cvdrac melaMd.an snd fun.trnn Ihe wnlk n( pi.mer/s in Ihn alra,
.n,hr.hnR I.aralydl, I ud+.R, 1 amRvnd..rf, Md.l, and K.nprr, a nutrd Ihrte early
rrtul/t were J+.rtl u/v.n, aac.ndrna 1o /he auth.N, Miaute they dr/e.minrd the f.nure
.unnr Of tald.aL mrlalrrhtm Isrtrrmin.u..n uf Ihr nulnlmm 4.1 the luunan hra/t tn yilu
wat a Anr.t and InR.ca erlentn.n nf rhru wur\ Mure re.enlly the cnuar n( c.ud.ai
mrl.Mdrsln has been .ntlurmrd by hurh:mnl/y and bu.phytitt by srp.jradon .d
tul.crllular pa.talrt and mRanellrt RrneweJ slrmulalinn (or the study Of Ihe nnlatr.l
mammatran hearl hat come from the 1aMvatmy Of Nerly rr of. whute perfuu.m Irchniqur
hai been pancKularty vatful in the undertland.nR Of the reRulalam of Rlytolyt.s in the
itchemic and anosumyncardium Netly's perlutmn tludres .ere primanly tarrred nu1
on sht Iat hearl Ih.t has Irm.ted the qstioas lur the study Of Rlyculyt.e interr.sedialea
and Rlycolylic flua. e.cttading deltrmrnalinnt of hiRh energy phusphates, which
nrirsvlalt specimens Of Rreattr weight lhe ute Of petfluorrwhemicatt hat nnw made it
p.aibk tn perfuae 1arler rnammalian hearN using Neely s wnrLinR hearu pteparatrm
the remaimler nf thn discussion it eoncerned wilh htmmlynam.c and metaMrt.c .hla .m
Ibt d.iferrnt /ypef Of /he failing rabbit hea1/ petfuted rn vrlrn with 1-lumrd-41 1he
effect of IA-06A, a new potdivt utolrop/e aRent, is briefly reenlinned In addmon, Iha
paptr dealt wilh a new atyqoach lo the prnblem of cnrnnary tpatm, usinR the nulatrd
heart perfutrd wdh Idunsul-I1 u.ygroalyd with a 1.vhble n.yarnal..r
R.nR R /
in I rrrari, R, K atr. A, Shujo. A, an.l Vitrol.. (/ ttdt 1 slr.nn.Du/ L.Armr.r .1. J I rrrJ
~l:rnlr.h.m. New \orA Plrnum Pubinhrng (o/(vnatmn, 19014. Pt. 167-:11
OtArr supp../ /hmver I nundation
/rnm the /lunhnalnn Mednat Rerrarch lnuilutrt and llunlrnglnn Memn/ial 1loaprlal,
/latafrna. I A
1
t///('1 l/F INIA/'f I NDOTIIE1.11/M AGAINST PLA11 I.ET-INt)tl('LD
('11R(1NARY AR /1 RY SPASM IN ISOLATED RAnlllf III ARIS
I ffects of cnllaRen-aclivated washed rabbit platekls on cornnary arteries with and
wilhoul sntaat endolhetium were sludied in a suppnrled tabhil htarl preparaoon ut.nR a
per/luorocarhnn /1( -41) as per(usale. The vsscular diamrter of uh/ute marginal
cnrnnary arleriet was determined by means of gated colm arlera.graphy (inseclrnn 411
patent hlue dyr) I ndolhehat denvdation Of Ihe nblase marRinal ulery was accon.pbthed
by scsaprns the hrmen with a rouRhened plastic tubing . Injection of washed plalelrls (10
ml wilh alrnul SOO,INNI plalekll/p1) twN 1ltaltd with cullaRen faikd to eonslticl curunary
arleriet erther with intact or denuwkd endothelium. /n con/ras1, injection of plalrlrt
suapensnM ImmeJqlety aller aclrvalioll wilh collagen eaused vatoennttriclwn ur
drnu.lyd u1.1ua marRinal coronary arleriet in 10 Of 16 Cases. In 6 preparsliona, r.ccluanm
Wal complele, 1atlmR up 10 16 minules. In arleries wilh intact endnlhehum, nu colurury
Yatln:nntllN'tnrn ni:nr/ell In heartl Wl/h COrnnaty artery Ipatm, tutal l'nronary atiut.l/
rtsrttance inarra.ed tiRndreanlly. Ihis sludy furnishes arlditumal evnlrnce 11u1
endnthelial ksmns ue a cnntrihulory faclor (or tarRe eoronary artery spatm and that
endothelial cella tnstets a proleclive function aRainst vatocons,ric/or suhslances rrkasrd
from aRRreRating plalekls
R/nR, R J r/ of
Ansrrrcon l.wrnal of ('ar/rnloty SS:1S96-1600, 1913
Other sr.p(MUr Ilnover f~oundation and Ihe Char/n A. I indhet{h /und
I rom the IlunlinRtnn Medical Research Inslitutes, IluntinRlnn Mrmorial IInt11Aa1,
Pasadena,('A.
l llt' ///1('1 01 NIMOhIPINf, A CAI C/l/M ANIAI:ONIS/, (7N
IN 1 KA(Y>K 11l'A1. AR fl 14101.15 IN t11E ('AT 11KAIN
The purpote Of this study Was 10 /etl the effect Of Ihe cala'iurrl anlaRnnisl
nimmtipinine on the intracortical arlerinles and ns cereMal b1/rMl flow in the
anesthelired ca/. Arleriolar diameler, red cell velocity and regir.nal cerebral blu.rl (Inwt
Were determined by technique employing Itansilluminalum and high speed
einema/nbraphy. Global cereMal blood flow wat measured vainb the microsphr/e
technique. After a fiveminWe ieflnirsrl of .imrdipine (0625 MOt/bR). Ihere was a
siRnificanl increase in cortical oteriolar disttsrter (p < 0001) and in regi.nal hhwnt /h.+
(p < 001). Red cell veMei/y inereased (p < 0011 (Ilr.hal eerehral hhmd fhsw inereated
Ip < 00?) while mean arlerial blood pressure declined (p < 005) therefure, dnett
ohtervalions eonf.rm Ihat nimlqlQ.int dilates iMracnr/ica/ arlrrinkt and increafet red tell
veh.cny rn thete vetselt
Schmidli. 1, S.mal/an, l: l7 . Saeed, M, Patmirri, 11 , and RurR. R 1
('wr.-nr IMruryvrrc RrsrerrA 111(1196. 101, 1913.
OIAer suplr.wr llnover I oundalan and the Charks A(.indbergh fuml
.
from the Iluntinslon Medical Reuarch Inslilules, Ilunlinglon Memorial Il.nap.tal,
Pssadena.<-A
u. 1 57
.
I
(11 IA-1 AI)RI N(x'r Pf()R A(:nNISTS W1T111()W A()fNY1.A1F ('Y('I.ASF
AtI1VAllf)N - t111URI 11CA1. ANI)(t.INICAI IMI'1.1('Al1UNS
Several parlul heta 2201414119 such as 1A-061, prenallrrol, I('11199A1, and
IC1119,011 pntsrs prnnnunced potitive inolropic effects, hul induce nnly h n.lyd
activatnnn of myrKard.at a.lrnylale cyclase. Ihis resatts in Inw cya.c AMP kvela fart.a1
aRoncnlv, as compared In snpcnlerennl, nerd h.ah receptor ncaupancy fnr maa.mal
phya.nluKp:d rrslv.nu and drmmnalrale inadHtuale eoupLng Ir-Iween receplor anA
adenylJle cyclate Itowe.er. the l.inehemrcal mechanisms which Reneute Ihe f.nAI
hwlnR.cat rlfrcts nriRmat.nR fmm cyclic AMP are (issur-specil.c, and fnr Ibal nraa.n,
can maintain a pn.nnunc rd positUve inolropie action. (linical da/a with 1A (161 and
prrnahrrn) h.rve eu.rh/.shrd positree innlropie effects without si`nAicanl chanRrs in hear/
rate Parlial Mla aR.n..lc w.th diminished eyclie AMP may be Iru arrhylhrm.arnn Ihan
lull Mu I aRtnals Ihe cl.nical imporlance of parlial be/a I aRnmus rrma.ns u. be
ruahl.shrd, pa.l.c.darty wilh relrvancr 1n Innif term erposure and .nherenl bels hlncliade
(-hemnil.ua, I M anA R.wa R!
('uwnJ.uw lnu.nol..J ( nJ..dnRr Il)111f1 190, 191)
c).Ac ,upl..ur Ihu...r I nunAahnn and the CMrks A(.indbereeh I und
t rnm the 1h.n..nRlnn Mrd.cal Rrsra.ch Insr.rures, Ilunlinalnn Memorial Ilmpital,
1'as...lrns- / A
('RYSIAI1()1I) ANISP/R1111(sRIN11/M11A1 PIRIIKAIISINANIS(NA1111
W(IRKIN(7 RA111111 11I AR( PRIPARAIIIrN
Krehs Ilcn.rtrn hulfrr (K11) snd a pelllunrn.hereKal (I( 41) were cn.nparrd ss
prrfusalea in an n.dued wortcnet rahh.l hrarl preparahon Ihqh perfusa/rs were
oayRrnaled in an u/em.cal manner uanee an rnfsnt bubble nayRenatw Aftrr 60 mm ut
prrfus6rn, no dd/errnce could be delrcled in the ralio of wet in dry hearl wriRhl
letween K11 and 1(' 41 perfuted hea1H (K11, f)2S t 0), I('-41l, 599 t 0201 Iell
vrntricular systol.c (arsture, maaimal eale of left venlrieular prrnure rise, mran aort.c
syslnln: prrssure, cacdnc nulpul, anrtK flow, /r(l venlricular power, and myocardul (-)r
ennsumpl.nn (MVnI) were si{nificsntly higher in F('-1)perfused hearls IhrnuRhnul Ihe
time uf prrfusion Ilnwever. Ihere aere no differences in resisunce to card.ac autput
and heart rate In Ktl- and /('-41 perfused heatls. MVnI and kfl venuicular (urwer
wrre clnuly eorrelalyd (K11, r- 0791, I('-41, r- 0F/1) Signilicanlly hiRher coronary
(law of Kit per(usrd hearls could be a/tributed to the bwer visanily of K11 (1 0) 1a-s)
comparrd wnlh ((' of1 (191 Pa s) cnmpared wilh 1('-41 (191 Pa-t) Incrrased Or
eaUaclr.n du.inR K11 prrfuswrn enuld nol compensate fm low OeearryinR capacity nf
K11 huffer (113 emnpared wrth 705 nmul Oa ml 1 in 11'I1 emuHion) A r..uschrmrc
rncreasr o( cmnnary fh,w was oMervrd anly cn 1(' 41 perfused hearls (2t's,/ lhrcr
rrsahs demnnsuate a drflerrnl response nf perfused hearl prepns,mns /0 11' 41 and K11
bu/fer
('hemnitius, I M, fluraer, W., and Rrwa. R/
.Ln~ncnw /.r.wn1..J IA.unl..tr 1J9/11ra.t (5rc Physin11112FS-11292, 1915
(/rhr .vpr-r an,l he ( hartrs A 1.nAfr.ah I und
i
From the IlunlinRtnn Medicat Research lnslilutes, llunlinpon Memorial 11mp.cal,
Paaadena, CA
A NI:W MI 11t()I) fOR 111F VISI/Al.ll-Al1(N( OF S(JRt PI('ARDIAI. CORONARY
AR 11 /t11 S IN ShtAI.l. ISUI-A 111) MAMMALIAN 111 AR1S
A m.w/el is drscrihed which permits direet visualiration of large eoronary arleries
in a suptwuled rrualdrrd perfused hearl preparalinn, usinl a perfluurochemical (I(--4 1)
as per/uaate I dhnR n( 1a11e eoronary arlay wilh Patent Slue Uye is retordrd by
Ra1ed phntoRraphy (cohu artrrioRrsphy)e lhe technque is applicable to Ihe sludy of
reaclivrty /spasm/ of coronary arluies in heans of small and large animals (rae, rabhus,
dR/ 1 he lechnqur has the fulk.winer advan/ages: preservalion of vascular emlolheLum,
a.kqaate a.yRenatr.n, avoidance of majer suqical intervent.oa ro implan/ srnsnrs (.u Ihe
drlectnm of changrs in coronary diarneler, quantilalive evaluation of lime drpendrnt
chanars in senmruy of large coronary bleries, and umuhanenus measuremenn ..f largr
co.nnary vrsul and Inu/ coronary vasculac resinance.
RurRrr, W,('hemmlius, I M., and eut. R. /.
PrnrerJrwRs of dr .TncirrP /ar Eaprrrmental emlogly and Aledicin. 178 109 112, 19)!S
c)rAre .uppnrt Ilonver Foundation and Ihe Charks A. l.indhereh I und
I rnm the Ilun/ingtun Medical Rexarch Inslilules, Iluntin`lon Memorial 1lmpilal,
Pa.aclena, ('A.
111L 1.111 CT 01 ('ARbIQPVLMONARY SYPYISS(NJ CFRFORAI. RI 001) 11 OW
lhese eaperimenls deN with 116e effect of total eardiopulnsonary bypass on global
and reRinnal «rebra/ blood flow. Global eerebral blw.d flow wss determined with
radioaclive w.icrusphens, re{ional eerebral flow by direel nMervation IhrouRh
Iransilluminalinn and high-speed einenuloerraphy. The Ialter peemitted observatwres nf
changes in caliber of cerebral arlerioks and of red cell velocity. Arterul blood Sm
lension and p11 were con/innusly aaonilored. Measurensenu were carried out prior to .nd
immedqtely fotlowing cardicqulmonary bypass. S1w1in on global cerehral fhrws showed
Ihst during cardiopuln,nnary bypass, cerebrd blood fbw rote and cereMal vascular
resislalKe declined whik blood pressure did not change significantly /)uring bypass,
cereMal blood flow and blood pressure in animals Irealed as a cruup I.ec-ame
interdependenl and showed direct peopo.tionalily. Uirea olnervalerns of Ihe cu.tical
mKrnYlKYlalYre by means of high-speed cinematnRrapby reveakd dda/aliun of crrrhral
cortical arlerioka I ven though blood pressure remained unchanltrd, the diametr. uf
corlical arlerinks incrrased. Volume flow cakulated feom red cell veh.city .nd utrrurlar
dhnuter showed a/endency of arteriol.r flow to inclease lhe eomlll.on 1s rrmrmrcent
of Ihe luaury perfusion symdrmne' (overabuadant cerebral (/uw relative to mrrNwdic
needs of serebrd puue)
Sanlillan, G C,('hemni/iw, l. M, and lcat. R/.
drarw ResearcA JIS:1-9, 1923.
Odvr support Iloover Foundation aad tha Charks A. I indbeqh Fund
From the Ilununalnn Mrdical Reseuch Intlitutes, /luntmtton Memurut 11usp.lal,
Pasadena,(-A
+a 1 59
A MOpl I I(tR t11T 51111)Y (71 COR(INARY SPASM INlstt('l l)l't1ANGIC
IN ('ARI)IA(R/t I Attl)I I~M
A nudr/ .a Arurihed whrch permits Ihe atudy of McalireA and Rrntralurd arlrrial
apaam rn the rntxl w..ra.nR prrluarA rahbd heart With a perflwumhrmical (1l' is/ aa
prrfuaatr /'nn.nary a.trnra wtrt vnoatitrd by rnlraatriat ie/e.tu.n n/ Patenl lllue 1)ye
wnh Raled pholntr.phy 1 rKatved apIam retullell fronl LM'NA apray n( h"lam.nt
(411 pm.A.) an the rpnarAul surtaxe n.rrlyint an oblust mart.n.d arlrry Ilrforr and
1.dluw.nR l+q.rcal admmnlrAtinn of hntamint, retional coronary Ih.w was Jelrrm.nrd
usinR ra.linn..Ml'e tahelyd mKrotphtrrs Gtneralirtd arlerial spasm waa inn.alyd by
inu.up.al in/rctun ut hitqm.nt /10 pmeh). Afttr ro/ural tlJnunrNrenuw, uhlu.e
marRmal artery dumrlrr drertaaed by SNL; Mrte vtssel rtaislance rnat I7 f.l./, 2014 rrae
nl tot.d c.nnnarr rrs.atan.e resuhrA .n a slithl reAuclinw of tlnnaunsp(wun, drA 6md
Ilrsrt rate, csndnc nulpul, dliJr_ anA rnyncat.balveartrn c
chanRt llnwevrr, retn.nal enrnnary llnw Is /ht rwyaeard/um supplMd hy Ihe afecttd
artrry d.m.nrahrd 21%. rtaull.nt in ra:htmit chanRtt in redna parrs Afttr rnr.nmr-rnt
rwlrrr.nw of hiataoune, chanRra Wtre mnrt pronnunctd (Ih(use mar({inal arlrry diameter
de.6nrd by tR%. rrauh.nR rn ll(q (nld rile of IarRe vestel reanlana'e In1al a,rnnary
rta.al.inct imcrraard IS0'IL, cnrnnary Ilnw and eard.ae oulpu/ dimrnr.hed (S6% anA .irwl
th.th hrarl ralr and JP!drTMr inc.easrd /16'h and 17X) (ienrcdved cornnary sp.nm
a(Irr rnmu.rl.r.d h..ummr rntrclHon resul(rd in se.eral melaMdGe ttfecla MynKanhaa
uyRrn .nnauml.l.no (4R'6), A/r (:9%I, erraline phoaphalt ( lt'9.1. rr.h..
rat...a, u Rlyaruphu.ph'le/d.hydtnryaae/ant pluaph.mt and Lrct:He/pyruvalt, ir.c.raard
hy 119'L anJ 114'6. rr.prcuvety Iht Imd.nRS hcuaralt Iha1 hr'.dvrd and trorral
enrnna.y apaama can Lr pr.wloctd aed .1uanlrlaled .n a wu.kmR htart rnakl.
Ilu.ttr. W,(hemnnm.- I M, Metr, M/, and Rrne R/
hwrwnl n/ Afllrrulur (.li ( orJuJnrr 1791I 91n, 19R1
(hh.r .np(..wt Il.r..rr f.wnd..hnn
lrnm the 11un1.nRton Mrd.cal Rrararah Inard.Ara, IlunanRtnn Altmonal t1.nV/al,
t'a.adrna, 1 A
TIIC I111('T nt 1%( 111 MIA ANII Nf PI RI IISION ON SARC(N.I MMAl
/(IN(-11(tN IN PI RI I KI I) CANINI III AR IS
11,411 rep+r/ deals with Ihe tffecl of ischemis and rtperfus.on nn purifird
tarcokmms ohuined from eanrne mpr'ard.um nf perfuatd hrart prepasalw.n hrluswm
was eanred owl wrlh a pesflunrnchtm.ca/ (1(--411) Iachemra waa prmtwrd by
inltrmiltrnt mtal cl.mp rn tt nf in/bw and uulflow followed by relesa un1A Ilre Atsreaat
in Jp/J(_. had becnrne slahik. Pu.rly of utcnlrmmal vrsic/rs waa as.e.Ka~n'UTUla/fA
marYtr enrymes' succmalt cytnchtume c srduclase (fur milnchonArial,
p nilrophrnrlrM'aphatt (Kr-pNPPase). (Nar/Kr) AtYax and adenylale crclast (f.u
SI ) In addrlu+n Na'/li r-each~arn of nknylatfcytlau sci Aj~rrrm; RdssSnkdnea,
of .esicles waa saartsined by ha+ia waa Ixrd on
paMaln.na Irearrd ml umra d with e u sarcnlemmalmea.clrs snd yr 1.1 nf SI.
A 1 Y.Mprn.lror ( s~ ~ uplaYt, ph..Phoyla.n . ~
I...Hema la hrm.. a..t rrl`rrluan.n rrwltrJ .n a a.Rndaanl rrducl.nn m ad'nyl nr
t
cyclase activity Ihis decline was sitnificant fotlowint ischemra and reperfusinn lhe
yield of ptrnrin recoverrd from St. vtsicks from ischrmk reper(uaed hrart lurparatium
wss alaoumal( siR'a'.runficandy decreased. IMth initial rate of AIPdeptndent (-ar' uplale an./
ma(+taAe ftll siRnificanlly fadlowint iachemia and reprrfuaion lhe mn.d
rale of pM.tphnrylalinn alto dropped siRnifrcantly. lheat disturbances in tl. t'a'
Iranspn/ folanwinR ischemia and reperfusinn are probahly a parl of the general drf.cn in
('a" transhkalioa
('hrnmiliua, ) ht , SaaaRi, Y, tlurRer, W., aed RmR. R J .
l.nnnnl o/ n.rJ ('rflular Ca.Jmlorr 17(12! 1139 1130, 19115
(hhr, sappnr Il.w.rrr I uundabnn and the I indherRh I unJ
Itun/mRrnn Medieal Rtstarch Inalilules, Ilunlintlon Memurul Ilutpual,
I /'ruoraaa.rlrna, Ihe r 'A
(l 1-AVA(:C O1 111/MAN IIIGII Ml)I.f.C1/1.AR WI IGI11KININ(X'1 N
t1Y 1 A('1(/R X1a IN 1 ITR(1 ~
We have rectnlty demnnstra/ed that human high molecular wriRhl kinim.Rtn
(IIMWK) is a prr. cofa.:tor that is cleaved by harl.krein lo yichl a two chain cnlaclor
(IIMMKa) and Ibe nannpep/i.k Madykinin. lhrs prolenlysis enhancrs ils aaa.atum
arilh an acliqtint surfaCt, an event necessary for tapressiun of its colactur atlrvuw~y. We
nnw refwrrl that faclor Xta is capable of hydudsirint IIMWK and relrasint hradyRmin in
a purilred syslt.n as well as eleavint and inaclivalint IIMWK in a ptasma cnvi.unmenl
duiinR the contacl aclivation process. lhe profik of peo/eolysfn dilfett frum Iha1
prndwrd by kalldrein and by factor X11a in that (ht first cleavage by faanr X1a ptld
75- anA 4S-\IA pnlypeptides, whtreas bnlh fac/nr Xlla and halbhrrin initially pndw'e
65- and 56 ItIh species. /-uraher proteolysis by all three enaymes even1ua11y prrwluwrs
similar heavy ehains (Afr - 65,000) and light chains (43,0001. 1luwtver, Ihe amnunl of
fK11N X1a tenented in plasma during eonlael-ac/ivation furlher deRrades the t3Rht chain
nf IIh1WK, eventually deslroyint its eoatulanl tc/ivity Furlhermore, in a purdrrJ
syslem, tnhancement of the detradaliun of ItMWK eoaRulanl activrly by factnr X1a was
achieved when kalli\rein waR i/lelwk// in 111t ineutvlinn mialure, suRReslmR 10,31 the
pre/erred suhstute f.u faclor X1a is 1he ac/ive fwm nf IIMWK (IIMWKa) ao.l m.( the
prucofaclor. 1 htse data suRtnl Ihal facltN X/a has the poltntral lo act aa a rrRulamr nf
centact-aclivated enaRulalinn by vitlue of iH ability In d.rVroy the cufactnr f.rn.bnn u(
IIMWK afler ils aeneration by ei(her halli\rein, (aclor X11a, or 1.6 a Icssee e./rnr, Lu un
Xla itself
Scn(/, (' /, Sdvrr, 1 1) , PurAon, A. 1) , and (-otw/aw A M
1 hr l.w.nnl oJ Rr.dnRual f6twnanr 76N19)10156 10161. 19JS
Odlrr supryw( Nahonal Insli/utes of Ilta/th.
11ont the lhrnmhuais Rtxarch Centec and Ike Ikma(nhNy/(McnlntY Se.rmn uf Ihe
Isrparlmrnl nf Mrd.cint. Itmpk llnivenily Iltahh Scitnc" ('enter, hh.b.lrlph.a
,A r 1 61
IIIIMAN PI A%MA KAl 11KR1:IN ANI) CI 1N1111,11OR fQRM A(Y1MPI IX
1't/1\1 C11N(; AN 1 MI(tTl 111AT IS Nt11 I/1 1I t'IApI l. ON 1111 PAR/ NI
M()11(111 1 % t/l tNl)NCIRAII(1N (ISIN(; A MI)N(!('l ONAI AN1111/11)Y
the rnac/ivat.nn of human plasms kallArein (EC 3.4.21.1) by the inh.h.tnr of
lCtivaled cnrnptemenl cnmpnnenl 1(('1 inhrhi/m) induces /he formaliwm o( a I I
f/oirhwmHrn~ \alhkrrrn f I rnh.hilnr compka rtnd a protenlylrcally auwhtwd (mm of c 1
inh.himr We have pr.wtuced a mnnocMnal NHibody Iha1 recnemrrs Ihe lalldrrin ( I
'rnhrbNor complrs ss wrlt ss mo.hfreJ ('I inhibilot, hr.t fads tu react w.lh vuRm ("/
mhihNOr r.r nayive plasma kathkrtin. This observNion cun.litules an unequrv.sca/
drmnnslrahon 1ha1 the rrachon helwten ptasma ksllikrein and (1 iehih;lur Irads N. the
emrrarnce nf an rlnlo1.r Ihal n undeleclshle on she parent enryme snJ mMbd.n
rnnle. utrs
Aeoos/.ni. A dt. Sahapno, M, Wachtfnetel, Y. T, fnAwnn R W, and ('anel, S
Pr.wrrJrntr of tAe Nnnneef Arafrnq of Srrrnrer n/ thr (lrolrJ Stnt. r
Aw.r.uo 17 5190 5191, 199 %
n/
fhA.r, supnur Swiss Nat.onal Science 1 oundation and 11 S Nalional Inshtutes of Iteallh.
I rom Ihe hivisinn de RhumalnloRK. IIAp;lat Csnlnnal Ilniversilaire, Gene.a,
Swrv.rtand, Ihrmmfrn~s Rtseuch (rnltr anA IIlmaloloRy/Uncol..Rv Section, Ihe
IMpa.lmenl of Merl.cinr, temple Ilnivrrsrly 5%.h.nl nf Medreint. Phr1a.klphia; srul Ihe
I u./+.R Insldule for ('anaer Research. I suunne 11.anah, 1 pahnRts, SwiuerlanJ
r1 ACMA KA1 I IKKI IN ANI) PR(IRI NIN IN rA11fNIS WIIII
111 R11)11ARY AN(.1t111)i MA
Recenl evNfence ind.cales that plasma \alhlre;n is aclivated durinR acute atUC\s of
herrddary an{ioederea Plasms kalhkre;n .s known lo eonvtrl rnacl..r renin, nr
I.rolenm, into an acli.e prnteolytK enry.ne in plaalna rrpO'led 10 aa.d ur h.w
Ierllprratulti a1 welt as rn purifred syslems lo rsbMrsh whtlher plasma kalhArern coolA
aclrvalt prortnin un.ler physinlokK or palhobRre eonArlu.ns, prortmn In rtnsn
convenisn was .ssesseA s/ neWral pll in pla.ma deficient in ('1 inhibilor (heredrlary
angMrdema) 10 these plasma samples lacking Ihe two major inhihitors of kalhkrein and
prnsessin6 < 0% of the rnhrhilory activety of mulnal plasma, prorrnin was nol e.mverled
in an aclive entyme despite eomhtinns under which prekalbkrein was cnmpklely
acGvalyd to plasma kallikrein and desp;le normal prorenin cnncentralinns and
actlvahlhly.
Pur.h.n. A 11 , St halnra. M, Alns/ini, A de and fnln.on. R W
f he hw.nnl nl I ulr.nfu.e nn/ ('frnnn) AIrJ...nt 10l(6)6Ve G9'1, 194)
ch6rr rupp..r Nalinnal Institutes of /lealth anJ Ihe Swiss Nalinnal Science 1 vundalion
Irnm Ihe lhrnmMMS Research ('enlet and Ilematnloty/OncolnRy Seclmn of Ihe
IkparlmeM nf Mrdn-ine, lemple 1lmversrly Schmi n( Medicine. Philadelphu, am/ Ihe
Ih.rvnn uf Rhumatnl..R.r, 116prtal (anlnnal ltmvervlaire, (7tneva. SwilrrrlanA
6.`
t
PLAl11.FT C1 INIIIRII(M: A SE('RFTFD ALPIIA-(:RANI/LF PR()111N
In order to charac/eriae which proleiqs of Ihe con/acl phase of cnaRulatinn
inorrxl
with plalekls, human plalakb were sludied Imroum.chtmaally and /unclin
.kt
if nally tn
nmme
they contain Cl inhibnor. My nlrans of m.m.Kpecr/ic anuM..ly to ( I
hihi
rn
ha, a compelilive encyrne-linked immunmrwlrnl assay ((-I I.ISA) was drvrhqvd to
mea
d
'
wre
rrec/ly plalelel (
1 inhibilor. Wrlh the ('I.I.ISA, frnm 11 In IIS nR uf t 1
inhih
a
nur anfiRrn per IO
plateklt from IS normal dnm.rs was quanhfrrd in Iy.alrs of
h
was
rA human platelets wnfuhiliteA in mrnionic drterRenl lhe mean concenhaliun .n 10
plaleltls was 62s 11 nR (S1)) Plasma ('/ inhihilnr erlher in Ihe platelet suapen.rnn mrdmm
.ur un Ihe surfa.e uf the pla/ekls could account
i for only (rom 6 S lo 1691 ot Ihe Int.r1
ant
gen measurrd in the anluhdireJ plalekts. Ilpnn funelwmal slud.es, pl.uelrl%
cunlarntd 41116 nR (SI)/ of ( I inhibihw aclivity in N)s plalrlels. As a.vsseA
' by the
(
111SA, plalrkl (1 rwhibilor anligew was immunochrmitally ulenlical hw plasma an./
il
d
pur
se
(1 mh.hilrw In tnMras/, Ihe mean tarnctn/ra/irm nf plalelel ('/ .nluhnnr
ant.R~n in plattlt/1 frum /nur palitnts wi/h elass;cal heledilsry antuwdema was 11
/N/
l
n
t
l
a
p
a
e
ets IranRe 5 1 to 11 1 nR/Ip
R
plaleklsl 2) X and tl'R of Iht lul.d Idarr/r/ I I
inhrhrl.w was se.rtleal wrlhout cell 1y11f from normal plaleleN afler tyMHU1r lu .nllarrn
(=0 rR/ml) and tMomhin (11f/mQ, respeclively, and Ihis secrrliun w:n tdnr/.rd I.y
metaMdi
inhihit
P
c
ors
latelet suhcellular fractionation showed that tdalrl.1 ('1 mhdnl.n
id
d
res
e
mostly in alpha Rranrles, similar in the bcalinn of plalelrt / d.rim.Ren 1 hus
human platrkh contained ('1 inhibi/or thal became svailahle by plalelrl .ecrrl..m I)or
idenl.r
/i
f
l
l
C
sca
un o
p
ate
et
I inhrhitor sugReals that plateMl% may mr.,l.ulrtr the A l.val..m
uf Ihe prolerns of early hhmd eoaprlal:ue and Ihe class.aal cnmp/rmrm p.uhv.ayt
Schmaier, A. /1 , Smilh, P. M and Cr.fnun. R. M.
l.n.rnnl of f)mrco) Inresrhcmren 73:2N2230, 1915.
!)rMr, supprf: Natinnas Ilear/, I.rnR and Rhw>,f Insd/Wr, a lempte Univeraly
Riimredica/ Research Supporl Granl; Amerieaw Ikarl Ass,.ualinn, anA a Spec..IbrrJ
r'enlers sd Research granl.
1 100" the IfematoMRy/Orwo1n11y Seclinn, 1)rparlmtnl of Mrdicinr, IhrnmlM.sn Nr.r.u.l.
('enlrr, -lempk Universny Schonl of Medicine, Phda,/rlpMa
F11 fC1 Of III PARIN ON TIIE INACTIVA71ON RATI O1' IIUMAN
A('l1VA 1 F1) FA('I()R X/1 RY AN11111Rf1M111N III
/luman .n/ilhromhin III (ATIII) is a plasma inhib;tnr of several arrine prntrares n/
Ilhe h11MM/ C11a/tlI]IMm syslem. Prevro1H rllvetlrRalMlns have tepnrltJ Ihal the prrarn.r 4.1
hepnin has a mullifolA accekralinol effect nn Ihe inhrhdion of faclur r11a and X11/. the
aclive specin rkrrved frorn faclot XII Rectnl slsuhes (rnm our lalruatonrs havt
cnnfirnsrd Ihal A IIII inacli.Hea fac/nr X11s and factor Xllf, but anly sonlydwlra ?'4 1..
)% in Me /nhiM/u.n of acNvaled faelor XII sptcies in plasma 1 hr mara /nMbqur .s /1
rnhibi/nr lheref.rre, we have «eaamin.A Ihe heparin efftrl on Ihe ralr ol r,dn/.rrn.n ..1
fsaInr X11a am1 fac/or Xllf in purified systems We also havt $lud.rd thr rlle.t ol
heparin on /he inaclivalu.n of Aolh fKlur X11-derived aclire y.r..es by varn.us plr.nus
I/sing purifred factor Xlla and Alll/, we found Ihal Aeparrn f0 7 tn 110 It/ml l
incressed the rate of inhihilion of faclor Xlla
61
Ilowtver, at hrparin cmKenlrations wually achieved durinR anlicnatulant thrrapY
(07 1//m11. Ihe inMhmmn was a.cekratrd only foYr-(uld Ih.s imphrs ..nly a 6'K
cnnlr/hutN.n to the rnh,hrtnry effecl of plalma lhis suRRestion was cnnf..mrd by d.e
ohwr.at.on that heparan 11 S(//m1.1 adJed lo fachN Xtta did not produce a Jrtr.t.tl.k
enhancement of the ralr nf inhih.twn a( faclor X1/a I rllhe/mnrt, Ytln{ punf.rd laitor
Xllf anJ anulMumMn III, htparm (16 to S) 2 11/ml ) incrra.rd the inxlrvatwan talr
;..naunt .d Isctrn Vll by Ih in 110 times lhn sma/l t(le.l was snnfirme.l by the
ulaervalum thal hrl.a..n al a e.mceniralw.n pralrr I/un that sul/naent lur
aMMnaRYlitMn' (1 4 1//ml ) dtd NN nuYl.fy the inacuvatinn raft uf factor Xllt hy
prrltatl.\rem drf.crent plaama, and thw C1 inhiAdot remarns the malor inMh.lnr evrn in
the pittenct of hrMirn I rnm this study and our prtvir.us mvealiRatinns on the tlferl of
hel.ar.n nn the mMMt.on of Lallitrtm and faclor XIa, we cuncluAt /hat hrpar.n dnrs nnt
vRnJ.canlly (fe.1 the prolenr aclrily nf purifitd contact aclivalrun faxtna or the
aa uvdrrs r.pre.sed by thrat prolrases in pbims
1'ultY, R A, S.hapua, M, and Catmen. R W
R)..rl 66 191 2111, 1'r/15
nrA.r aurry+r Amrriaan Iltarl AMa.cialinn, Srulhesa/ern Ptnnsylvanlra (hapler, Nat.nnal
Inuitutrt of llealth Ind..rtual National Retrarch Servite AwarJ, anJ Sw.aa Natu.nal
Seaenct loundatw.n
leom the IhrnmM.vs Resrarch (enter, Itmtplt I/nivers.ty ScM.nl of Medirane,
PAJad.l/dua, and Ib.au+n Jr Rhmnalnh.Rv, Ilnpatat (-anlun.d Iln.vr.vlaut- (%rncva-
Sw.verl.nd
Iltl R/(7111 AIIItN ttl IIIIMAN I A( ItiR )Illa IIY 1'I ASMA
/'R/)I1 INA%I IN11111114 /RS
Ctudirt of the .naclrvataan of (acua [11a by psatma prntrost inh.hr,n.s rn puwdied
stslrmt and in plasma werr rnrlratrd 1u Artrr.n.nr the rtlalivt imtwrtan.e nf thrse
rnAahrMr In the nruualiralinn of fa.lnr Xlla laclnr Xlla was mraaureA by Ihe
arnnlnlsvs o( 11 1) prulyl.l. phenylalan)1 1-arRinine p nivoanilek d.hydraIlmrdt or
by cnaRulant aclrvrty C1 rnhihitw ((-11N111, eaonlydasmin (nsAPl, na macroRl `hYlrn
(.. MI. and antilhrnmhrn III (A1111) inhMhiled fxlor X11a wilh src.und ordrr rote
cumlanls of 2 2 X K11, 11 X 10/, S 0 X 10?, and I 1 X 10s M Imin t. 130110 ?(Ila aclivity
wal m.t dfecled by or proteinsst inhiAilor Incubation of tsI r 110 1/M1 L S 000~ 11a
rrtultrd in 11 stoichinmetrie eomple.es wilA ( I/N1/ Vtr 1900001. A r~
sndelAl (Mr 130.000 and 123.000) YsinR tndiuro dmkeYl sYlfate pJyacrytamnle Rtl
ekc,tophnreaut. Incubation of tssl I sclm X lla witA naM resulted in s comtY.ne a rd Atr
63,ff00 on a reductJ sn.hum doJecyl tYlfaleIrdyscrYlsmwk Rel, indreabnR thal a lul.una
of factur XIIs was cova/rndy bound /o a pwlen/yred pnrtion of arM IIt relative
r(frcuvenest of esch inhibrtor .1 plasms enncrnustnms was 612 1) r,Y (1IN11, nsAl, n A/,
anA Allll, retprctrvrly Kinelic studwt of the inactivatinn of purdrrJ (ttnr hlla
aJ.kd to vsrinus plaamat ennlsininR dJferenl eoncentratinm of 111Nl1 vrrJ.r.l the
predretn.nt from the putified tystems (iet fdtrat.nn of radintsheltd hclm XIIs
inculuted wilh plaams eonfirmed IhN hct.w Xlta(-IINI/ was Ihe ma'ryu cnrnplrs
Analysis by Md.um dodeeyl suIfalepolyaaylamutr {el rleclrW.Mutus indicated Ihat Ihe
comp/eses in plasma had the same molecular site at those with punf.eJ inhibiwrl
(11N111uncl.ons at the p.rdominsnt inhiAitor of fsclor Xlla in plasms
t
Pi.Iey, R. A, Schapira, M, and Cnlnson. R w.
I Ae l.Y..nal .r/ Ru./nR..-nl CArnrrur, 260O)1)21-1129, 1985
Or t'enns) Ivan,aArr tufly'rr Natinnal Inslitules of Ilealth, Amrrican Ilrarl Ass.K.alH.n,
SautArattrrn
ns)Ivan,a Chapter, and Swrss Nalional ~crrner 1 oundalum
Irum the Ih.urnhotit Research Center and the Ikpartmtnl
Ilmversil
ti
fi
d
f of Med...nr, temple
)
a
.M
o
Med.cine. Philaaklphq, and the UniaYrn Je
(-anlnnal I /mrrrtqairt, Gentw,*, SwilaerlanJ Khumal.dnR.r,
, 11.111,101
1111( "1 !)/ ('1 / AVA(:h (1/- 11/1- i/l AVY (-IIAIN (11 1/11MAN PI ASMA
K AI I IK R/ IN l/N I I S 1()N(' I tf )NA1 /'Rf IM/ R 111 \
Ilumsn plaans La114rein enntisls nf sn NIrrmieal heavy chain of mulrcular
wtiRlq frmd wt/ S:,f100, LnkeJ by disulfidr Mrndt /n Iwn IiRAI chain varianH (mul a
lA 11tR1 or 11111X1) Although the active eslalylic site uf ha/BSrtin rrsiArt un the
l- IermrnalliRhl chain, IAe rok of IAr N-tt.minal Atavy ehain i/ lea clear We thrrrfurr
stud.rd an enryme alesiRnaleJ /1-kalhkrein, rnnuininR a sinRk cMavaRt in Ihr Lravy
chain Inwd wi !R,0flp IA 000) and enmpated il tu IAe enaymr, p ~allr~rrin, wnh an
intaa-1 heavy chain lhe tatts of inactivation by ('1 inh.Aawr ul plaama .r
anJ /t \alliltreins were kinelicatly itkntical, as mearreJ by resiJu.d am.dolyhc saywdy,
after qrlnul //nMs t1f incuhalion .ilA Ihe inhibilor. (lnth enryrnn rractr./ complrurly
with l-1 inhiMhY after 10 Inwrt anJ fornsed idenlical (-1 inhrArlor walhlirrin complr.es
of mol wl /95,0tX1 lAe ralt of activation of fac/or X11 by e halldrrin and p-hall.krrm
was similar. In contrall, Ihe tate of cleavage of high rnolecular weiRhl MutmuRrn
(/IMWK ) by o-ARllrforein was a1 least fivefold fsster and the rsin of coagulant activity lY
amidrdytic aclivily was fnurfo/d Rreaser than for 0Lal6hrein. 1'lasma aks/btrru, al
cumrntratinns pnlentially acAievaAle in plasny, induced aRRrtpln.n of neuuayrh.ls,
Aut p lia1liArein failed to elicit Ihis response. In addltwte, human nrutroq.hrls that AaJ
heen prrtrealeJ wi/A eylnchalatin 11 re/rasrd 2.46 t 010 MR//0) cells of elastase anliRre,
Au1 Q Ita1lArein rrltased only 021 t 010 MR/IOs eelk lhest olnervalwros suRReU ,hat
cleavage of the heavy chaininflurncq the rate of ekavaRt of 11MWK and de.reses ils
cuaRuLmt a.tivity. Mnrerwer, an intact heavy ehau appears to l.e requnrte tu tu/qMnt
the ability of lallJUtin to sRRrep/a neulrnphih arat rrksse elastatr
(-.dmen. R. WW rr al.
RLwJa!t(2) tII-31R, 19RS.
f)rArr tYppYr Nat:rmal Ins/ilu/es of Ileal/h and Ihe Swras Na/w.na1 Srienct / uunJabun
rom Iht IhrnrnMnn Reuarch (-enter nd /ht Ilrma/o1nRy OncnlnRy 1.atu.n,
IMparlmrnl uf M.dn.ne, lempk t)nivrrtrty %cM.nl of Mr.l.cinr, PhdadAphaa, anA the
(indw/t Ilusp.tal Retrarch ('enler, Urvision de RhumatnluRir, IlApatal (antun.l
Itnrvra~tane, Grneva, Swautrland
' 63
64 Y
RI /i1/1 A 1Il)N l/f lllf ('OAG1/1 AN1 Al'fIV1IY ANts SUR1 AlI. IIINI/ING
O/ 111611 Mf)1 1( 111 AR WEI(il/l KININ(XI N
/-.vtnts in Ihe formalion of Ihe enrymes in the intrinsiC coaRulalinn pa/hways can
hr cnncepwalued as three reaclinn clusltn The peocofactnrs of Ihe 1.0 laler steM,
faclnrs V111 and V, are rxh Mnlenlyted by Ihrombin to aclrvr cnfaclors, faclors V/1ta
and Va, whiah art Ihen M+und In phnsphnliprd mierUts nr ptatrltl mrmManet I ach
cu/actur then srrves as a'recrploi lo which Ihe enaynses, factms IXa and Xa, bind prnu
tr/ sclrvalinn Ihe suMlralrs, (xlor X and prelhrowbin. lhe cnfactms, (xln.s V111a and
Va, are Ihen .nxlrvaled by anolhrr enryma prolein, acli.alyd prottm C (hlr rerent
s1o.Iit\ in.llcalr that Ihe MocofaaInr of Ihe contact sytlrm is similarly tutjecl to
scl,valinn by 6a11,a:rrln lo an active cofac/or prior 1o bindinR in an acliat/nR turfa:e
Ihe actlvatmn of Ihe cnnlxl syslem is probably inilialed by /he hindma of plasma
faatnr XII lo a neRslr.ely chargrd turface where auloxlivali,rn ru:curs for lu.m fsclm
+flla Ihr suMlralts of /ac/nr Xtta, Prraatlikrtrn (PK) and faclor X1, rusl in
1Imolnular cunlpirars w./h the cnntsa/ syslem prrlcofaclur, hiRh mnkcular wrqhl
\,n,n,yten 111MWK 1 which is trquued In /ranspnrl Ihem In an acus1,nR turfa.r Ilrrr,
,m Iht .uJacr, Ihete rym.qlrnt ate converled lo Ihe ac/ive enrynlrt kalbkrr,n (K) an.1
laclu r1a- by xh+alyd la.lnr XII We have rrctndy drlrnralyd Ihe me.hanhm by
wl.r.h Ihe L,ndrnR of X1/ and IIMWK on the surfaee n conrdlnalyd X11a (nsu ctea.et
PK, wh.ch rn Iurn cunvrrls the prnrofxtor. ItMWK, to an act.ve cofxlor, /1MWKa,
.,Ih tl.e ahd.ly t. Inn1 lo an aa1.a1,ng surface and eynrst coaRulanl actlaly by
hunRrna 1K anA XI Inrn pnyar aplna,r,nn fno tleaaRr by X/1a Xtta Ihen clta.rs XI t,.
+(ta
l nlrnnr R M CJv., 1 It , ruw,/.n, A 11 ,/ hv.r //, and Santl,
I ran.ruu,.nl n/ rA, l...vrn,«. ./ l- n,. rA,.urnn. t( \'ll lll I)1, 11111
flrArr wphnl N.1und In.lrluv. / 11. drn an.l \pr..rt,r.,l 1 rulr, nl Nr.ruA ,m
( hnm/lr,ut
Irnm Ihe 1h.nmM.ut Rrtrarth 1 rnlr, ar.1 she ILrnU.d.r. I)n.LRy Srtluro,
Ihparlmrnt of Mnbrrne, Irmplr Ilnr.r.../y \.h,1 rr Mrt,.r
11 ACMA 1KIKAI I IKRI IN A«AY! RI VI RSIIII 1INIIIIIIII/1N ()1('1 IN111/111f/K IIY l'/ll l)KO1
OKM ANts 115 I/S1 IN MI A]UI(IN(i
PK1KAt1aKKIININI11111RINI MAMMAIIAN\PlttlY
lhe asaay of plasma prekalhhrrin rrqlrires aclivaln.n ol prrkalhlrrin /n I.dhls,r.o
and suflrcrenl Inat'//va1Nm Irf Ihe pla.ma 1~Irote inMhdnrs ol I.dhlrrm lu a.,wahIt
nMatu/t the Renrrated ka111krrin acllvrly Itnr melh,n) nf rluuo.raun ul t6r p11v,1.1
pr..ha.e inhrMlort lo kathkrrin it In chelnn'ally prrlrr.N li,r pl:,to/a Mrlhll,ruu+r h.r,
prevmutly heen rnlployed In seleclivety Inat1/v.11e ns mnlar.lr.1ubn Ihu /urlr
tlaminrt Ihe eflecl r.f selprenl,ai prrlMuh.llum nf plat.,/a +.Ih tl,t.,r./.1n1 arul
n.rlhyl.Inunr nn Ihe ptasma Mtka114/ttn at.ay (hlornform was drmr+nNralyd 1,. M a
chrmnal ruhihNn. nr purlfird Cl mhihdnr, hW na mac'rotluhalin wa/ nu1 ( dmu/mm
inlub,tn.n .,f ('1 inhdular was nul Cauted by precipiUlnm of Ihe prolrrn rnto Ihe
rMrd mr Mlwrrn the waler and orRan/c srden/ phase (:rraler Ihan VY16 of 4 1 inbihqor
anlrltrn wat rr.n.rred .n Ihe suprrnalan/ of chh.roform Uraled purified ('1 ,nhl .,Inr,
1
and chinrnfurmaaluraled buffcr inhibiled purified Cl inhibilom Chhuoform d,d mN
dnsnciate a preformed compka of kalbkreis and CI inhibi/or, hut il. inh.hmmn of / I
inhihi/nr wat reversihk. Tht addition or rnelhylamrne 1o plasma pretreatrd .,/h
chh/rofnrm In Ike plasma NNallikreiw assay allowed for only a slight incrrau in Ihr
amr/unl of kallrkrein measured a I minute Itaolin acti.a/inn limes, bul pro.ided /or
suslained meaturemenl of aclisled prekallikrtin whrn ka/din aclr.al.nn limrs rt,t S 1n
7 minulrs Without chemical prtlreatmtnt, prAalbkrtin was not measurable in rahlnl
pl.nma hoth rahM1 antt pig plasma prrkallikrein were nlrasunbk afler ep,nure of tht
ptatma 10 chhunfurm anrl nselhylaminr, a1lhr.uRh Ihe peak aclivalinn irmet and Ihr
contrlhuta,n of each animal's prulease inhibilun varied with /he sptcres I)ur res,dlt
sM,w that ch/rnnfurm is a re.ertihle inhrhilrw of CI inhihitor, and that Ihe plasnu
prrkalh4rrin stsay rw which i/ is ated is usrful fW the measurernent uf p.rAallJrnn In
nnnhuman m.l,nmalran (.tasrna sanlpkt
G hmaler, A 1/ . l:ustafsnn, f, Idell, S, and ('.Jmwn A W.
I Ar /.n.rnal ,/ I nhumnry rmJ Cbmrnl AfrJ.rrne 10a16) 6k2 892. 1984
lhArr u.ppwc Nalinnal Ilrarl, L.nR and IIIouJ Inslildey American /lrnl Ats,n.aliun,
anA Nalinnal Inslilules of Ilealth.
I rnm /he lh.ombosis Researeh Center, /1ema1nlr.Ry/Om-oluRy and Pulmonary Seclrmt,
Irparlmrnt of Medreine, lempk ttniversily Schunl of Mrdicine, /hilade/pb.a
1111 1111('f (tt 111G11 MOLFCI/I AR WFIGIIf KININ(Xi1 N//N
SUKI A< I AI)S(1R1I1_b FIIIRIN(X:EN
IIiRh mnkcular weiRhl kininfttn /IIMWK I P1ayt an imporlanl role in allerine 1hr
associatmn of plasma fibrinoRen wilh a.rfacn. Plasma inilially dep,nrlt (ihrinoarn ontn
mnsl ma/erials, bul on hydrnpAilic surfaces wilhirl 10 nrin adsorbtd plasma Ilhrlnn~rn
cannnl be .klecled an /he turface by aMi fibrinnten anlixra /lnwever, atrna
/1MWK-deficient plasma, fibrianifen rtnu/ws immunologica0y idenlifiable Ihe
inler-relalinnship of arisorbed plasma fsbrnwlReta with klninften on hydrophilic tulfaces
11 s11111Kd furlher using ,last sli/ef tlained fM prMein with CM.massie I/Iue, and oaiwhrrd
silicon crystul slr.es in an aulornaled el/ipsawneler. lM glass slnles when plasma /hal .t
deficienl in holh low rrleleeular wei6hl kininrlben (LMWK) and IIMWK is recnnsl,atrd
with IIMWK 1040 Ilnits/rnl), fibrinofen is no bnger detected on the slrrfare Th.s
frndinR is specific frw 11MWK, nlnce, when Ike samt plalma is rrcnnstilutrd w11h I MWK
(110 YR/ml), the ansounl of fiMino6en delecled on tht aurfo.e is unchanaed Ihe
alleration of sllr(ace-adtorbrd fiMinoKen by 1/MWK is nn1 due lo plasmrn mdutrd
(iMimdysis, since is oceurs in plstminn~enfrtt plasma. /n lhe ellipsomeler, surls,t
adsruplmn of nnrmal plasma M assucisled with a significantly less (p 0000\) Ih«A
prolein layer (1 V9 t 008 depee ehange in aaimulh) /han plasmas .Mfirien/ in IIMWK
(: 11 1 011) Ihrq e//q,sonltlry, IIMWK in plasma is shown lu shnrlen IAe //mr ,n
whN'h Immunnk,&ally delectable rurfKe-adt,Nbed f/hrim.grn was renN/vr.1 or al/rred
I heu sludret in a wMde platma syslem presenl furthtr evidence Ihal IIMWK sPr.rlas/ly
m,n/dres /he assncialion of plasma fiMinoRen wilh hydruphdic surfaces.
Sihmaitr. A 11 , Silver, 1-, Adams. A. 1.., Fischer. Munor, P C Vroman, 1,
and Colm.w. R IY.
TArenrAolrl RrsrercA )):51-67,191N
67
Nrhr .urr.ur Nal.nnal I/rarl, I unR and Khwwl Inudute, Americin Ilearl Asa.cralr rn, a
trruldt Ilmvrrtrly hnmedna/ Rettar(h \uppnl .r.lnl, anJ Nahnnallntlrlu/rt u/ Ilr.rllh
Iro.n the Ilrmslul.Rr/f)n.olnoly Srclinn and Ihromfrran Rrtearth (?nlrr, trmplr
linvnwy \.Arvd .d Mrh.rnt, PhdaAelph.a, sn1 the Imrrfa.e IaMnaln.r, Vrr..ma
A.Lnrnr.Ualarn Mr.l.. a( rnlrr, (1rr.Ily, New Yorso
f11KtIMIKOMAI 1RANC1IR INMO1/S1 FRY111ROIt11KIMIA('ut1,,,S11()WG
11I A 1 1 I(A Nl K 1 1.1 l1 A 111)N k11 11tA 11 C 11CS1/1: SPI <'ll Il' A NI s
IrI V I I 1I1'htl N I AI I s 5,144 11 K' 1'A 1 1/ KNS O1 (:1.Ot1IN (:1 NI / XPKI SCIt IN
Ihe Jrh prr.enleJ m t1.rt pttMr havr suRGe.trJ Ihat Ihe a.hvalmm of rndnprua
RhLrn Reors .n d.r k\hl ..11 1.nr aroae IhruuRh a smRlr mul~u.n .rtu.A Ir1 Irr ahrrrJ
r.pr.anm .t a.1d1utd1r rrpal..lwy ta.hw t.rpilde nt ach.alrnR embryann 1;1dnn
Rrnt, ln t.al d.r hytvnhrtrt thal emhryonie gInhm (ent actrvatrnn had rwau.rr.l n Ihr
K tA) cell thr..uah a/lrrd r.prrttnm of a trans rrRutal/Ny facnn, tallle lhan a mulalwn
m a.a In I/.t Rrne, .H raa JrardeJ In rnlr.nluce Ihr tranacr/plnrnally aative lr1a Rluhm
Renet of rhe K tA: cell rnl.r the te/raplnrd I rien.l mouse (rylhtoleu4rmu cell rn .hnfi
a.tah hul n.rl rmhrynnc ItIhrn Rene r.prestrnn ncaurs In dAis study the aulhnrt al..l wrd
rratrntn.n (rakmrnlt ItnRlh p.dymurphrams lu ahnw 0.31 Irrlh hom.duRurs of
ahromraume sA .hrth sre prr.rnl rn the KW cells cnntam atpha and arta Rluhrn Rrnes
l i
.~hNA htluvr n an idrnlrul manntr -hrn uan.frnrd to da mnute rylhrurulrnaa
cellt (he eaulls t/nrr I/rtl Ihe mulNn.n wh..h IrJ to Ihr aa9tvatiun of human
tmlrrnnrc Isluhrn Rrnr% rn the K 56! ctl/a ra aavnlenrc In the aela Rlolnn Renrs I hr.r
rrvull. atan anRRr.t Ih.rr the KSA! cell c'nntsrns a Inns rrRrJa/ory (salor whnh it
cumpetenl In .ulywrn Ihr r.prrsunn of the hunnn tmbynnre Rlobm genes
llrrsarrnrA A R
In Slamaloyannnrywlnf, (7 and Nrrnhun. A(tJa 1 I rt,rvrn.r.ual ApPNn.whr. Iru rh.
.Sfu./t ../ 1l.-m.rRG.Arn Cnn. Arna. New Yrr\ A1an R Lns 1982. :91 101
OrArr lupprrl Velrrans Adminitttabnn and Nalwnat Itearl, I unR and Ilhuwl /nuilute
I rnm the Istpatln.ent of Medicine. Ilnivenity of ('aldornia 21 San /'anricrn,
11rma1nloRy/tM.nlnRy I/nd, tlnd the Veterans Adminiatratnrn Medical (enler, %an
I ran(ncn
1'1 ACh1A PK(1111N ANtf LIV1 R mRNA I 1 V11 C()1: 1 W() ('t (KI I Y KI I A 11 1)
h111KIN1 n1-PK()11 AM INI11111/f)KS Is1/KIN(i 1111 A/'111/ /'IIACI KI A1111tN
Maaroa , levett u/ of 1'1( 1 ) nnd of PIO I. I.n chnrly rel.llyd mu.rne alpha
I prnleate Inh/hNort, ha.int aff.mhrt (m Uypvn and r/aalaae, ,rtpectr.ely, rrre
(omparrd 10 .hanRrt in .pecdK liver n.KNA le.rls aflrr tnducfinn of Ihe saWe pha.e
reatlinn by su/yYqnrnul rn/ra'/inn u( lurl.enhne In rarlart, qualdalive eqrrrruenlt, an
nc rra.e .n plaami le.efs of n/ - M(1 ) bul mN .1 1'1( I) during the acute phate texann
htd Mrn ahnwn 11 n nnr shrrn Ihat slrmulaln+n of platma of F/I) / le.eh reachrs a
ma.rmum ot s1 s(f1 rM.ve baseltne 1)h aflrr rnrhrrlrnn nt the acute phaar rraturnae
a.m/l rnr.r. I.rn, d s..+r Ir. mrawv prnlrne rnhrMlu. sr Irvr/y
r.n v.r +.r. rb. rrr a I.rr/. ... n 1.nrr, n (./ rms Ir.rtt rf
rl 1'l/ / I rt
r
r
t
seen Ihtermrnatinn of mRNA kvels in the mouu liver specifrc for nlPl(1I
and o/ 1'111 ) was accnmpliahed .sing a cell fne transtalinn syaem foth.wrd h.
immunnprecip(talnrn of 11te arS-labekd prnlrate inhrbnnrs lhr apparrnl mnlrau4r
.rythls of u1 rl(1) and olP1(/) synthesiaed rn rnrn are 471( and 4AK, rnprcb.rly
Apparent mokcular weqhts of the native prrNeins in plasma (e SSK and hSK
I/ne.peatrJly- nKNA kveN fnr Aoth ol-PI(1 ) and nl-PI( I) were found In imrra.e dlrr
mducbon rr( the acute phase reaclion. Ma.imat s111nula1Mt/1 for h.Mh mKNAa .as
alrynoumalely 10(yh and /KCur/ed 9h afler turprnline administratrun I/ndrt Ihrte
cnnJrlinna, leveh of tnntlalahk athumin mKNA rn ll.r muuse F.vrr deereasrd tu 4/rs. ol
h.ttebne m 6 ')h -
1 rarer, 1 M, N.nhrK/, S A, Katt, ),(irnelra, 1- 1, and /r.Jav. 1'. 11
Irr Arrrl aI Rus Armr vr r naJ RurpApu.-a le(1)11? 119, I')II S
()Iflar aN)/'t Nalrnnal %('Irnre I ou/nlalnrn
frnm the IMpartnmrnl of Ohsle/rics and (:ynecnlnRy, New Ynrk Irniversuy ktrdnal
('rnler, New \urh
KI (:Ill A 11ON OI- PI ASKIA FACfpR XIII UINIqN(7 IN IYfRt)
/he hindrnR of plasma faelM X111 10 fibrinoRen or fibrin that /ut been chemically
or enrymaliaa/ly .nduceJ 1o paJymrrire was sluJird lachH Xltl I.rndmR .as aaarrJ
usnR a slI putreseine incvwporalion assay anti an rllplrsma faclnr )i/l/ bin.hnA aasay
More than R(/4 nf the native and ra(liolaheleJ platma (aclur XIII uas /wund lu frhnn I
fntrneJ by teplilaar in 11)1 A, eWate, or hep,uin anticoafluhlrJ ptaama Srhum dwlrcyl
sulfale p.dyaceylamnk Rrl ekclrnphnresis (S1s5 PA(:1'.) of Itsl-plaama faclor XIII Ivrund
lu fdrrin I or Irbrin /1 formeJ by reMilase or Ihromhrn in the presence of 1h1A
Jrnurnstralyd the hesubuni( remained bawnd to Ihe a charns nr lhrombrn cleavrd
a chains. In the presence nf eakiuns eh4xide anr/ Ihrombin Ihe he wbuna dnaaratrJ
and faclne X1/1a was bound Praamine sulfate caused fiM(nnRrn p.dymrtitatinn in Ihe
absence of divakM ealinro and reduced Mqh plasma fact(u X111 and immumrh.Rn:
f.hrinnRen kvels hrMim.Ren pnlymerired by prolamine sulfate br.unJ plaama fa./ur
XIII and the ar-suhun+t of "1-pla/ele( facMr X111. Masma tachw X1/1 was Idsn Mrund to
armlcalyd non-crnts-linked fibrin 11 in either larmal plasma on afiM.n.uRentmic pl.ama
Masma levels of teveral eoaRubtion prWeins were unchanRed afler the adJamn ..f
rrp/d,ne, protamine sulfate of inniealed (iMin tn plJ.ma Ihesr resrdls demonatralt Ihot
a qwYific bmdinR silr fnr the ar-suhun/t uf plasma fxhn s(III is prrsenl un Irdymrrurrl
frhrimrRen, (rhin I am/ f.htin 1/ lullhrrmrne, the prserwe u/ divalent aalams.
Ihnmbin ateavaRe of plasma ta('lor X11/ and relrase of fahrmu/wphdrt A.N K ate ma
re/1uUeal ln/ /datlna f.h11N X111 b(mling tu pldymeurd Id+tim.Ren and Idum
(:.rrnA.vR C S Ihrhtnn, I V aml M(ra4fia, (' (
Rlrwrl 6a(SIM,`oo 90 14. 199 5
O(Aer (upprrr American Ilearl Assoeut.nn
lram Ihe f4parlmenls of Medicine and PalhdoRy, Ou&e Itnrversny Mrdreal ( rmer,
1)urham, Nl
A/
r
MfA51IRIM1N1 c11 Os(X)7 CnAGt11A11ON fA(-t(1R Xllsa I(11(MAIK)N IN
PI ASMA t UNIAINING GI Y(-1'L-(.PRt)1 YI L -ARGINYLI.rK(71.IN1
A mrlh.Ml n drscahrd lo durclly measure the formalion of bhwd cnaltld..nnn
laalnr X/lla m plalrkt Mar plaama unm..JJ.ed by hesl the synlhrlic Irpl..lr
RISCSl 1. p.olyl 1. arsmyl I prnhne, a f/br/n pulymtrinlion Inhibll.w, .a% uirJ Iu
p.rvrnl c1a111oR nf pl.lrlrl p.rw plaulla Platma ..a1 dituled so a(inal cnnrrnual/m of
2 Y6 tv/vl in Il 1 M 1rn 11( 1, p11 t 1, huffet cnnlainm[ 2S'll. [1yat//.1, S nIM .;hmm
t'hhnutr- and 0 25 mM Rlycl 1. prnlyl l-u[Inyl 1.-prolme and /hen a.l.valyd by
Ihn.mhinl?011/ml)(or 1S m/n. lhr Ia.lnr Xllla calalyred incnll..aalwm )'IIM.uUt..inr
Inln 1lammrltlrn cate/n rat Ined 1n mtature I aelor X111a f.wmal.un the savy drlr.Yrd
1 acan X11Ia in 2 S In SO YI I/f Ihromh.n /rtaled plasma Mhen pu/ilird 1 aclnr \1'1 waS
adJrd 10 1 aclnr XIII drli.irnl plasma, there was enmple/e rranvery of the I xl.,. X111
addrd ('tycl I.pndyl 1- arRinyl 1. prollne d/d nM rnhih.l lac1w X111a aall le /n
llwnmhm t.ralyd (.la.ma or purlfwd plalrlrl I aclor Xllls (.Ir.rrol t1ahJ..r.1 1.1.Inr
X111.1 a.t.vqy in r/....mh.n Iraaled pfivma anA hu/ler f.w (.0 m.n the p.r~rw.e u(
I.hrlnuVrn m pla.ma d.d nnl rn.rldy the allay rrwlt, the I.mt .owar al
Ih1umL,n ,.It A..rd 1 a. bw XIIIa bw.nalw.n .n pta1r1e1 p.rn pl.lvna ...n. un.nR
Rlyavl r sn.Irl /. 3.R.nvl r prul.nt wal due.dy mraaured uunt Ihe a.aay
Mrnsl.a(' /' an.1r:..nMe (' S
Awulrrnnl Ru.Arw.nl.r 14,1161 1/1 tO1S
n.A.r .opp'.r Na1...n.J 1nV.HUlrt nf 1111111,
I rnm Iht 1MparlmeM of Mrdl.rne hutr Itn..ervly Mrdwal ( rnlrr, l)urham, N('
1111 111/11 fIt I II/ItIN P(Il Yh// /tt (IN 111R(fM11IN(AIAI S/I tr 1'1 A\MA
I AI'tOK XllN I I1KMA I IIIN
1he e(fea of I/h/.n (r.lyme.r ^n /hrn.nh.n rtlalyred (aa'lor X1/1s .at
rludwJ in atrhrins[enemw p1aama I d'rm pdr.nelt dravrd (lum dr. A I.bnnuarn an.l
dra A,R ftihr/nntrn Incrrnrd vs (..ld Ihe lale uf Ih/umbin calalyrrd laalul X111./
fmmae...n in the preten:e nf I LIA (al:ium chlurwle ace;elrralyd faclur rllla I.un/.llw.u
111uh1 in she preaence IJ tlet A,R I/brln.Ken «Ilhnul im'reatint the rale uf Ihronll.in
formalmn IIMim.pepl.des A and 11 had no rffecl on faitaw X111a furmalu.n in
a(rhr/m.l{rnemle plasma 14s A 11 llhr.nn[en reduced hy 20 In 40 f.dd the /hrnmhin
concenlralu.n repuued lo acliralt taclw XIII (ilycyl 1L prolyl L ar[inyl 1. prnhne
(tlypro-artOrll/, a fibrnn pldymeriralw.n /nhihi/.w, inhlbiled des A an.l des A,11
flhrimrylen (rnm enhancint thrnmfun calalyted lacha XIIIa f/wmalwm Glypu. ar[ pro
dwl no1 muddy fftlnr Xllla formatil.n in aflln.nn[tne/nlt plasma and d/d nnl m/..bil
Ihrnmhm cksatte of the cbrumlKrnie sulNlrate [.2'It ihru resulls denN+n.ualr 1ha/
(ll./m pnlymrrs acaelrrsle Ihromhtn-cautyrrd plasma faclor X/tla folmalwm
(:rrrwlrr~. C.i and M.latlu, C C
Rt.uIJ GN2) 41(.6 Ino-1'ItS
(hAer ,wp(vur Nallnnal Inslitules of Ileallh anA American llearl A..nciali..n
I/um the Itipalmrnt. uf Medlcine and Pathul..Ry, l.uke I/nivertily, horham, N('
I
7
KAIIIOIMMItN(SASSAY fOR NEI/ROPEPTIDF Y (NPY). (71ROMAl(X:RAPIII('
('l/ARA(-I I R17A'l IUN OF IMMUNORf ACf IV Il Y IN 1'LASMA ANt) f IS\l ll:
I XIRA('IS
A senailive and specific radioimmunoossay was devrln(wd /u delerm/ne Ihe
nccurrence and concentralion of neuroprpliAe Y(NPY) in pla%ma and 11\SVe en.a./.
I wrlhermore NPY hke immmwweacti.ily (NPY-1 it Was charaitrrved by mrana ol Ilnre
dil/erenl chromah/[raphic syslemt. Ire NPV anliurum used (NI) dw) nul alu.% rra,l
o-wlh rt/aled prplnles of the pancrealic polypepl/de family eecrpl a.ian lunaeatl:
In.lyMplide (1~1% crosa-rractivity). I/nr~lracl~d plalma contained h/[h molr.ular .rl[hl
prntemr rhwh inle.fered in the assay Acid elhamd e.traclion removed Mls plutrm
inlr/(elrnct allor,in[ a V0'Ik recoeery of NPY 1 i lhe eonltwl nf NPY I 1 in hwnqw
platma from heallhy tubjeclt was clOSe to p below /he deleclhon hmil (.-` p.n.d/11
Cynlpathel/c nr/ve slimula/ion in Ihe cal increased Ihe outpul o( NP\' I i /lnm Ilu
vplrnlc vein suRRrtlina Ike release of /his prpli./e upoa syropalhtlK arl.valu.n Ihr
maMr peak o/ NI'Y r (/ in .pkrn talraclt ami splrnic reln pl.nn.io cao r1utrA r.nh
tynthelw: (wwclnt NPY and a mimw peak wish (arRer Slokes udlu. Wav 0- ple.rnl the
pleaem radl.wmmunoarlay enabks furlher sludles on Ihr phytl.d..tn.d and
paliophyswdn[w./l rule of NIW.
t hendorswm Norheim, F, Ilemsen, A. and t.unJAerg. J M.
SrewJ.wannn /.n..wal./ Cbw.rd d/.oh.rma.r lwrrurtulr.wr 1S;11S 165, 19U
(hbr .wpp.wrThe Swedish Medical Research Cuuncd, Ihe Karulinsks Inslllwr and /h.
ASlta I oundalMn
I rom the Ilepsrtmen/ of Clinieal CAemislry, Karntinska Iluspilal, and Ihe 14ps/lmrnl nf
Fharmacoln[y. Karolinska inslitule, Slockholm, [..eden
111fNfI1ICAT1(7N OF 11(/MAN PLAlF1.FT MfMRRANE FIIIRIN(-I(:IN
KI('1.PIURS IIY IMMt/NOC11f Mt(-AL T/.C1INIQI/1S
lht flbrino[e/l reeeplon of p/uekts «tre Mvesli[sted rilh Ihe use of IMre lyprv
of .nti plalekt w1emM.ne saibodies .nd Ihret (ypn of plalek/s we fuund Ihat .naua
railed in rabAiU a[aiesl welwMal/es prepped from homan inlact, chymolrypsin- nr
prunase-Irealyd plalelets iuhibiled Iht fiMinn[en induced atRreRalw.nr o(
AUP-slim.laled inlacl pWekb, ehymNryptin-Ireated plalekn and prnnase-tlesltd
plalekls. lhese anlisrn abo blocktd lhe biwdin[ of Irsl-fibrimrylen tn Ah1' slimulaled
inual, ehymnlrypsinIrtaled, snd pronax-Irealed plalekts. lhesr resulN su[[est Iha/ all
Ihree antiurs bh.cked the imeractiow of fibriltl.[tn rilh ils receplor on the sur/xe ul
the three Iy(.n of plalektt sludied 1 iMiw clol retraclion by inlact platelets oat alw
inh.hned by Iheu IMee an/iMdlts indiealin[ sn imporlanl rote of plalelrl memMane
prolrins /n cM.l relrsclinn. At demonslnled by Itchnaluri usin[ nI so//a.e
lahrt.n[, SrspA1'6rnrrrl .wtur immunoprecqritalinn, SI!$prdyarrylamwle [rl
eM.u.q.Mrrtsis and auloradin[nphy, antu inlacl plalekl nlembrane amd~«Iy
InwnunnpleeQala/ed Ihe InemMane [lycnpro/eins (:Pllh, (iP111 snd a p/otein wish sn
spparenl moleeular .ei[M N Oo,000 from deltrRent solublh.eJ surfxe 1"1-wwllnale.l
ekynwllrypsin-Ireated platelets. An1iekymolryp.in anti anlipranase bralyd pb/rlrl
memhnne anlisr/a immunn(wecipilaled mmdy (:Wll and the 66.000 mnlr.ular .eqh/
pro/ein from deter[en1 s.dublhaed, surfKe 114 iodinated ehymn/.yps/n Irralyd platulels
/(t '
71
Ihe A6 (N10 Mr p.nrrrn was not fnund no thr turfacr nf intact (unatimubtrd) pl.qrlrtt
which du nnt MnJ '^4 lrhrimrRrn and arr nnl aRRrrRatrd by /rhrrnuRen .rlhnrd U.e
prnu ad4rnnn nf Atrr Ihe abd.ly of anti phtrkl mrmhrant anl.hr,hrs lu hhw\
(.hnnnRen induced pbtrltl RRRrrpt.nn and f.htrm.Ren yandrnR in ptalrlets cn.reLrlyd
vlh the,r ah,hly In rmmunnpreciprlste a 6h,tM10 Mr p.olern frnm Ihr p1alArt surtace It
n prolwne.l that the 66.000 Mt pratrrn may he Ihe f.hr.nuRrn hrndrnR dmu.sm uf ('1'Itt
whnh M-:omr% f.r.manendy e.lwnrd on the surlace n( chym..tryparn and prnnale Irrilyd
plalekls LdluwmR pn.teolytit and which becnmes e.h'lyd u/w.n tlwml.nu.n vl mlaal
Idatrlets by aRenrs suah as AI)P
KnrnraLr, 1, tua.yndi-G P, and Nrr.norurrdl. S.
//rmNrdnRen 11/1) UI). 192. 1914
(/rAn ruryrnr Narn.nal InslilutH nf 11.a1rh and Nal.nnal Krsear,h Srr.«r
/ rnm the Ihromh.,s,s Resrar(h ('enler, Trmpk Itni.enity Ilratth SCrearrs ('enler,
Yhdad.ll.h.a
MI MIIR AN1. 11 1011111Y ANI) PI A l t 1 T 1 I IIIRINO(:1 N RI ('hPIOR
I h1'(/%IIKI IIY 1'KUII/11.YI1(' IN/\MI\
Incuhatrun af plalelets with p.on.rle or chymntrynsin rrtulls in Ihr ea/w.aure u(
f.hriM.Rrn rrcrplnrs We delermined Ilul Ihett enrymes 410 not a/lecl the memb.ane
IluidNy as evaluatrJ by the depManralrnn n( the (lunrrtlrnae of 1.6 d.pM-nyl 1-1,$
he.atUienr /l1t11) Iherr .as no trRndraanl ddfrrrncr rn trlher the Arrydarirahnn nr in
.tt temperalure deprn.9rnce fin eonhnl, p,..nasr nr chymnUypun trtated plaleleti 1hu.,
il can he cnncludrd Ihat the e.Manr of fdn,n..Rrn rrarphnt on the platrlr/ s..fart by
prolrulylre enlymes drrt nut depend nn the lhanRrt of mtrbbrane ftu.JAy We afan
prolrxr that the prntrutylK enrymel d.s n..l cause a mapu alteraliun uf the r.tenl uf
prntrm lh.uns emheddrd m the Lpid layrrs nf the pta1r1r1 mrmhranes
Simnnt, 1, Whilin, I C, Morintlli, T A, Strwart, G/, and Nrrwwrnwllr S
)h.nmhuul RrreorA 199196, M1S
(lrhrr rrppor( Natiunal Intlilules of /leahh
I rom the 1Mumhnsis Rexsreh (-enter and f>rpartmen/ of Physin/nRy. lrmpte ttniversity
11rat11r Seiences ('rn/er, Mliladrtphia, and the t)rparlmenl nf lle.chrmnlry, thntnn
(lniversity School of Medklne, Ihrslon
A(:('RT(:ATI[7N (11 (-IIYM()1RVIKtN 1R1 All t) 1/1R()MRAS1/11 Nt('
rl A111 T IS IS MI h1AT11) nY I IRRIN(1(il N IIINDING It) (:LV(YIPKOI I INS Ilh
ANI) tlls
Previnus eanerimenH demnnllrsted that ehymotrypdn. but not s.trnmine
diphntphRle (AfN). t.posed fibrinoRrn binding silts un plaleltlt from patients with
(aanrmann't lhrumhstthenis Thrte of these palienls have been rrraamined, and
prev.ous oMervat.nns were cnnfumrJ Ihe quanlity of iudinr 125 labetrd R/ycoprnttrn
t/h ((.1Ith) and Rlrr+t'ruerin tlt. ((:1'/tla) nn the platelels nf these pal.enls was
i
I
I
cnnvderably less than norma1 but was drlecubk by u11r11umq.recrp,talton, s/Mhum
d-lecyl tul/a1t- (wdyacrylam«k gel ekctrnpMues.s, and suloradrnRraphy I he a.mrunl ../
rrsnlual (:1'Itb and (:P111a as rneas.red by bindmR stu/lrrs Wllh radmtahelyd mun.wlnn.l
an1lMNhrt was lelween 1% and 12% of the mrrmal .alue. P/atrkl sutlYntlnns (rom d,eae
patrents dul not aRRreRate with fibrinoRen Rm/ drd m.l brnd 'OI-(rMrmqlen nn
stimulalion with AI)P. Ilowever, incuhatiun of these pta/ekli with ehymul.ypcan ur
pronale resulted in /rhrinniflon binding and platelet aRRreRalmn Monocolonal an1lLNlrrl
slKad.e f.u the (iYtlb (:Pllla eompirR hhrc\ed Ir.1h the flhrrn,uRen hmJmR and Ibe
aRRreRatmn of eneyme-treated plalekls lhe trralmenl yd osshral platelets ol a I.wuh
thrnmbas/henie patient with AUP or wilh chym,Nrylyin failed to rewh,.n Irbr.n..Rrn
b.n,hnR and aRRreRalw.n /Mwever, the /rvel of GPllb and (iP11b on Ihest p/atrlrh .%
measurrd by a Western hhN Irchoique and by monu hmat anUMwly hmdinR arnouno-d
tn < 0 15% tn 0 NL of no:mal values In conclutMm, (.MrnnRen binding sites e.Mard nn
IMomhaslhrnrc plalrkts by ehymmrypsrn ate .Irrived from (i1'11b (il'llla mule,ulrl
ARRrtRaln.n of ahymuhypun trraled Ihromlas/hrnie ptalt/tls by (rbrinoRrn at'pearl /n
rtprrsent a.rnuuvt /rsl (or drtrclim r.l fumlrnnalty aclive GPllb (il'/lls tumpks un
Ilre plalrtr/ .urfaae
N.rseron.r, 4.. .t re of
hwrnol eJ I ohuarury ruu: ('Irn.ra/ AIrJrrrnr 106(6) 631 660, I9RS
(/rhrr lupp.rr. Nalional Inslilules of llralth sm/ lhe Amerkan 1lrarl Aslociatwrn
1 rum thr Ihrnmbosia Research Cenler Rml Ikparlment of PhysiulnRy, /e.ntde Itm.er.rty
Ilrahh Sciences ('enter, Philadetphra, the I/emaloMrRy/OneolnRy Srctrun, Ikparnnent ol
Me.licine. Univeraly of Pennsylvanu SchuwA of Medicine. 1h.ladelphra, and Ihe 11l/'rt.d
LariMnirre, Psrit, 1:rsnce.
1/)1 NII/ ICAIION O1PIN A1.1 OANII(7t.N IKIMAIN ON A 66 AI)a 1'RUI I IN
1)1 RIV11) I ROM (:I.YC(NR(21I IN Illa UI 11lIMAN PLA 11 1 1 1X
Incubalion of plalekh +ilh chmynlrypsiw kads In the ealMrsure of frhrmnarn
recrptan and Io the sppearance of s 66 hUa rnembrane component .m the sur/xe nl
platrlets. Ibth Rlycoprutei. Ills ((:P Ilta) and a 66 htb cumpnnent were prenP,u/ed
(rum delerRrnl ealracrt of toluhilind, surface rRdiolabelyd chymnuyp.in IrrateJ
plalekls by human a1Ni-PIN anti7ela. MMMYlr, the prrtence of the P/'V antigen .as
idemified on (:P 1112 (bu/ Ia1 on (:P ttb) and on 66 \I)a prolein hy means ..f
imn/Y1p.hlnl prrKedWes using platelet Ir11nw X-111 ealrRl'N and Ihe{r purdied prutrins
Anti PIN antiserum dW na teeoRnirt UP Ilts on (he surface uf rno.cl uunlrearrdl
plalrltb nor the 66 \I)s Mottin nn (M aurface of ehymouylin/reaud platrkls nf
1IN neRal.vt rndlvulWh. lhe presenl data drmontlaalt dirrcl/y that the 66 sl)a prnlr,n
it drn.ed frum (:P Illa and crmlains the PIN RlhrsnliRrn
KornecRr, f., (hunR. S-Y, llolt, l. C. (-ierniewsAi, (' S, tuvyns&., G P,
an.l Nr.rrnow~r. S.
RrnrAenuce rf Ru.pAwre Arm 910215-290, 1911l.
OrArr tupport: Naliond Institdea of Ikal/h std Ihe Nslronat llrarl, 1 unR and RIMMI
Institute
71 1 11
1
f r..m Ibe lhrumhnut Reararch ('enler, Temple l/niwersity Ilrahh Scirncr ('enler,
/hdadrllhra, and Ihe IMparlmrnl nf rtyrhulry, Nrur.n.wmrs Re.rarch Ilnd,
Itmvervtv nf Vermnnl, Ourlmifton
1111: IN1I RA('ll(7N (tF I1lIMAN P1 ATfI FT TIIRI)MN(KrONDIN
W11111111NIN(K:1 N I/tR()M/1(Kr()NIIIN r11R/11('All(tN AND
%1I l Il it 11% /71 IN 11 RA(' I NIN
Iluman plafrlrt Ihrnmhmpondin (TSP) was purd.rd In MrmnRenrily by
chromalnR.aphy un 1.hr.mRen coupled to eya"ew bromntr activaled Srpharuae. Ihe
yrld of ISr wa I I me m apprna:malrly 22% of that Meunl in platrlrt rnh pbama at
tleler/nined by /a.IVllmrnYnnalsay II analyred nn drKOnl/nWws srNI1Ym d.4lrlYl \ullhale
Rrla as a srnRlr han.t hav.nT aplurent mnlectlar rreiSMs of 1/1011110 am) > t(X) .I100 Ymler
rrducrn{ anA numrducinR comt.tinns, rts(rctively Am.nn acNl analysis Ra.r rrwllt
snn.lar tu ptevuw.ly puldnhed valYet An1ilYN1Kt /aised m rah/.ilt .ere mnm01IKCdn'
as evaluatrd by raA.almmunnatsay In double ImmYmaldfWN/n lects, thrae anlAuwtirs
Ra.e one Imr nf .Jrnl.ly aRa.nt/ fSP punfed by 116.1 prncrdure amt 1\r punfNd by
puhhAheA prnarAmr., confnming the identity of the ma/eral isolated Ihe pr.aern
lun.rcars no Ir:hn t.\r acUvwy.
Ihe specd.:dy of Iht ISP-fiMinnRen intrractinn aras inveslillated TSp h.ndinR In
f.hrinnRen %erharmr, nceurred in the prtsrnce rd 1UTA, indicating Ihal cakium and
IlqRnrOUnl N.ns arr nnl repuired for intrract.on of TSP with f.Mim.ern. 1he himlm6 of
1%P 141 1.h..mRrn 4pharna was quanau/.ve/s hMNied by preuealmenl wwh an
ant.Mwly in the cyannarn brmnnte clea.vRr f.aRmenl compoted of resdues 241 416 of
the carl.oayl Irrmmal rnd of Ihe a cha.n rJ fd.r.nnRen An/llNYbes aplnsl Ihe 17 aml 1.
dnma.ns uf frhtrn..Ren had no elfrcl on Ihe hmdmR I acess (ibrinngen (10 mR/ml)
adAed In platrlrl rauxt OanMat..rly rnMMlyd b.nd.nll nf /\P In
fhunoRrn Gephante ur prrlerrm.Jly hnnA In unawss LnYe.l Idnrn, suRRethn11 Ihat
the 151 fd.nnnRrn hmtbnR vle .t unr.a.ldde n cruta Lnsed f.htm Ihrer, reauhs
indicate Iha1 I\I' h.nd. specdnalty 1. mm.hJ.rrd Lh.mnR.n nr uncrnaa Ln/ed Lhrm
IhrnuRh Jrlerm.nanN prrtenl In Ihr .a.tr.yl Irrnnnal pnJnn ut 1be o ahabn and that
these mlerrilN.m d.. not tequue cala.urn ur m.IRnevum rnnt
Tusryns\i, (: P, S..vattava, S, Sovital.la, It 1, llnlt, 1(', (irrnirwJi, (' S,
and Nrr«nwn-.4. S
7hr l.w.nnt of If.nlne.rol CArmrrr.r 260(2) 1.'2M 1?213, 19lIS.
(7tAr. .Yplnt 11 S IMpartment nf Ilrahh and 11104111311 Srrvrces and the ArntrWan
Hratl Aatwut.nn, pennsylvania Keyslnne Aff.hale.
1 rom the Ihrnmhnais Re.earch ('entrr and /he 14partmenl nf rhysinh.ay lrmplr
(7mverulv %tMNd nf MrJwrne, 1'h.ladelphia
1Ot%(/1 I tI1NINIM:1 N N) ('1 rl(INt / N(1M 1111 PI A 11 1/ I S11N1 A( I
UIININ(: SIM1/1 A11 tl 1 X/RA( (rNIV/R1 A1. ( IN( 1/1 A/It/N
In r.rr., rr.uculahon of frrah human hrparinirrd hhrnl in an ralrxmlwN-al circuit
wilh a mrmh...ur uav.enalur drrrra.rd f.bnnoRen induced platelet aR/rrRolUnn and
drmmhheA Ihe numlrr of (.h..mRen rhrplnrs aml itlycoprote.n Ilh/Illa (ta'llh/(7PItla)
anl.Rrnic s.les un the plalekl sYrf~r In teven eaprrrmenlt. the mran t SI1 (m value
(.ur frtr.m.Rrn t. e, molar concenlral.nn uf LMimRrn requned /n cause 50% of the
maum.d .-ur nf aRarrgalw.n) wat 1%ta a 10 ' mNl/1 # 0M a 10 ' mul/1 After
." ... u/a1n.n. .h. .al..r .n. rra.ed n 1 1 a/0 r mnl/1 . 194 a 10 y mol/1 (P 00.157
1
i
I
I
lhe maaimat aRRreRali.wl rate of chymo/rypsinuealyd ptalekn decrra.ed by t/n,
afler 2 huurs of recrrcYlatio. (P < 0025). The wYmbes of fib.inoarn re:rplurs on
platrk/s, whi.h were Irealed with chynNNrypsin after /ecwcYlaliam, decrra%ed hnm
41,170 t 24.0114131 tn 11,210 . 10,210/plalekt Yeder the sarne crwdNN.ns (P 00:51 the
number rd antrRenfc siles fnr mnmKlnnat ant"itNN1y reacdng wNh /:1Ilh/(:rllla cumpha
of ademnine d.plN.sphale-slimulaled plalekts decreased faNn 14.200 ! 5.940 lu 1V,S011 .
9,6R0/plalelel afler recitculatN.n (P < 0025). Pr.nlaRlandin 1' t01 (.nN.l/1) in thr
l.rrfnawn cacu.l prr%rrvrd the ahili/y of pla/rlels Io rext wilh frhrim.Rrn In clnNtu\Wn
the hns of fihnm.prn receplnrs ftnm the sutfxe rd ptalrkt membranes rrsults Irum Ibe
intrraclN.n nl pial Irls with the lurfaies nf pellutNM cwCYlls.
Mu.iat, 1, NnY-rurnY.lr, S. I/ersluwY, I/ , Murinrlli, 1. A, Colman, K W, anJ
1 JnwnJs, /.. 11 Ir.
lvunnl r/ I nl.norw r NnJ C(hnn n1 A(rJ.rrnr IOt 511 522.1985.
(srMovr mr(.wr Na1N,nat InuilYlet of 1lrahh
/ r..m the lkparlment of l'ardinvaaNlat SurRery, (/nivenily uf renntylvama Iln"pnal
aml Ihe IMumlvwn Research Cenler, leN.plt llmversily 1leallh ti.iencra temr.,
1hJa.Mlphia
RA111(11MMI1Nl1ACCAY lll 11UMAN P1 A ft 1 1' 1111R(fA1/1(Kr(1NItIN
11111 I NI N 1 1A 1 11 RNS (11: 111t((1MIN/ti/YNVIsIN AN1s /- I11N(1h111(1
(:1.UIIItl IN AN I IGt N SI CNIC IRNV ANts ( 1 t:ANAN('1. 1 NOM l lll ( IR( lII A 1I(1N
A me1MN/ fn. radinimmunoastay nf human /hr.wnh.np.mdin was rkvrhq«J
MnmN(Ml-Iflc precilula/ing anlr human IhromlNryY.mlin an1ilNNly was rased m rahlNls
after Injeclroll r.f Ihrmnhuaprmtin pYtifitd br fibtuN.Rti/.Ranat cMumah.Rralhy amf
pceparauve smhum d.Nkcyl sulfalepnlyaerybmwk gel ekcuryshu.esis Ibe Irnear
pnllNan of Ihe IhltNnlws(qmtitl rM/1nlmmYnnalfay alalNlard curve V.at 0 5 Iu 2t1 nR/mt
N.wmal Idatelels aml platekt-/qm plasma ermlained 2t;R10 1 14,100 nR IhrumMnlN.ndrn
prt RN plalrkh and 606 : 10.7 wI/ml (tnean t Slq, rnlecl.vrly 11.mR
ra.lw.:mmumqssays f.w /1(htnmlN.RlnbYlin aml (bawnM.a(YwNtin anliRens, .ve cnmparrJ
p1.1/rk1 h.catmn and fecreti+a of /hete protrim R.wh antiRrn{ slured aanultr
drslr.huliwms in plalrkl suhcellular fraclYNn wilh the 1arReal a.nmml 4N.ab.rA Iu
paalr/r1 uaranuks Wilh Ihrnmhin f(7 23 11/rnl/ a& a p/alekl aRnnnl, n~ A'14 an1 1'/ S'll .4
lolal Q IhrumtwrR4d.ulm and IhrumlYnprwNlm, tespeclively, wrre srcrrlyd LoN
fYtprMNln1 Yf seea\INhI hY/Nan plalekls IkcaYte only 2016 nf 11e L.tat 11.r11h'/
/hWMINItpllmhn was secrrtrd, furlher studies t.ere milrated In .kle.mnr uhralNV ll.r
rrnuin.ng Ihtumhnry.ndin brcame WKali(ed on Ibe acb.alrJ pl.nIrt
mem/.rane r4 1 ah iMllhrnmlMN(N/MIM tprflfKAliy I..IUn1I In a. t..alyd Id ur/r1/ 1u/ na
lu Nn.lnoulate4 plalrkn In eonttasl, 0061 1 Ah anli p Ihc.mrlwKlululin Inl nul InuJ I..
activaled plaltlrlt /M...ma tkarame of human // /h.uminRWlY.Ln 16a// I./. laa 7n
/ninWrs, s1... Sh6 nunut.tl and ol human IMondYnpondrn (h,d/ tdr /...1 :v1 mwub..
sh.w rNl minulet) /ulluwed a biphasN tyw.nrnt../ curve In con.tu.n.n,
luwh /1 IhrumMalnbulm and /M.NYMary.m/m are LMatrJ in pliirkl .. R.anulr., hul Ov.
shuw a ddlrrrn/ pallrrn ul secrel.on and rap.esso.n un /he pl~lr/r/ nmru.i...rnr anJ
plasma .karamv.
S+.ilahla, 11 1, N.rr.m.rwrlt. S rr e/
/.Nrn.J n/ 1 nhr.nr.. r nnJ lLwtnl AfrJn rnr 106 690 700. 19115
1 /S
t~ 1
f7rArr .rppnrt Nal.onal Intl:frles of Ileahh and the Ameriaan /lrorl Ataociatinn.
/r..m the Ihrmnl.nan Research ('rntrr, hrpntmenls of PhyaioloRy and Med.cine,
Irnq.lr Itnivrruly tleallh Sc:rncea('entrr, Phdadrlphia.
IN1I KAt 111IN (tl t 11KI/N/(' ('I(:AKI 111 ANU I 111AN(11. IIY1 (1N
MY/K'AKIr11IM
('hrnnia caaarrtle uae it rnmmon in persnns who hahilually rar nlher carde.ri'l.ve
aRrnsa Iha/ havr trrn aau.ally ataatu/rd wilh /wart d:xaae Ihn slwly waa un.trrlaken
lu drlrrm.ne .f ..R...r/lr uar inlenvfwt Ihe aAn.rmalllMS nf myucard.al fun.lu.n arnl
.arnpoplr.n oMrrvrd :n r.prr:mrnlal akohnlmm Over an It mnnth IYrrw1 Y..anR 24101
nuIr IraRlea ..Ih Iray hrualomy were A.viArd nln fnul pnups l htrr were 10 cnnl.olt
(Rrnnp 1), 9 smuloeJ ar.ro avRarr/les prr day (trnup 21. 7 werr fed ethamd a/ 2(L uf
..Annra I/lroup 17 and r6 rrar.veA IwNh ethamd and ciRaretlet (ltrnrp 4) Aflrr a Iwrn.l
nt 12 m..nlha, Ir/t vrnl.nular function was aaaesaed umkr aneathraia. Ilra.l rate, kfl
vrn//ICular rnA A..lalnkM (Nrtturr+ aml vulumr+ IuMlKalm d1lulr.nl Arl 1NN dAfer in the
I..ur tru.qn An rndre of cnnlractddy Arr.veA by normalis:nR peak .tl'/dl fnr p.e- and
alrr. Lnad waa rrdu.rd aan.l.candy hrl..w Ihe kvrl .nf ' 4 # 0 7 cm/s in con/rnl A..Ra In
1 al s 0 15 rn R..nup 2, I t. 0 It .n /puup 1, am11 211 s 0 17 in the ethanul c:p.rrue
Rrnup /raa h p< 01NIT/ Arteraal presturrt we.e m.rlera/Ny rkvated atwrve trour 1.n all
d.rrr e.perlmrntal Rrnupa v.rlhnul ev.Arnar uf Irll ventr6cutar hyperlrnrhy In cunlraal
lu an.oh.nlt, whwh rtnAed nit ahmnmald.rs nf mpra.A.al aalum enmp.ahun, rlhan..t
rr.l.nrd myncard..A pnuaaaun anti anbu.n in ttu.q. I wnMwl a Rain nf waler conlrnl
1. Rrunp 4, nn furlher dralrnr of 1.aaue aal.nna wat ohaervral Ihua, erRarrlte uae when
a..u.h.neA wah rlhamd ..vrr a rrl./.vrl. Lma IMlurl, puwl.prd nu Rrralrr .naa'ar.l..d
ahmuma/.l.rt Ihan rthannl alr.nr anA nuy mN Le ra.rnt.a) 440 Ihe aenna of
rardn.mYnp.qhy .n aL..h..L.a
AhmrA. i S. In.rra, R, and R.r- I I
('Iuur.d l'a.Jnd..Rr t(11 179.116. I'q11
I rnm the Ishvision nf ('ardinvascular Iharo.ea, IMpartnmrnl ut Mrdwanr and Ihnlnlr7 nf
New 7r.sey New Irr.ry h/rdnal Saiur.l, Newarh
IC(11 A 1 t(7N ANt/ ('I II I I/Rf (11 t1/t M(/NARY I NIX)1111 1 IAI. Cl l 1 S
Melhnds fur nulal:nn, :Ikntifitalf.n amt cuhure of pulmonary emhNhehal cellt are
nnw roul:ne. In Ihe paat, melMuh of nnlalr.n have used prnleolyltc enryiewa lu Arl.r h
tella, Il.ereaflec. U.rAdN/na/ melMwls (rr cell pasaaR.nt have wed Iryptan/11/1A
mntwe+. ('el/s iu.lalyd and pasaatrd uaint pro/eulsta enrs"Ws h.lvr tvrn uarlul in
ett.blishint Iht freld and :n ver:fy:nl{ ceflain rndnthelial Mn(.erl.et. 11..wevtr, 1Mre is a
{IOwinR awareneat of the rok of emh.ll.el:al tells in praKrst:nt .v+natl:vt +uMlancrs, in
rraprm.luq 1n hormrmet and olher atonisis, aml in cr/l-crll insrraainns .ith ulhrr eNt
ly(rt nf the vaacular wall, wilh Morrt celh and with eel/ular prmtuets. ('onaeaurnlly, a
new reVutrement hat a.iarn fnr I:ells rn rnrrr thal mainlau the dilfetentuleA pnq+vliea d
Ihru tounterparts rn rrve Ihe delelrrrwt e/fech of Irytsain and nlher prole.dyl:c
eneynxt cnmmunly uard /n Cell CYhurf on surface strua/ures of rnArnhelial cells such a+
rnrsrnrt, .ecepans an.1 /unclwnal prnlr.n+, aa well a+ on r.tracrllu/ar layen such at the
alv.kalv. nr *rn.hnhrt..l furr,' havr Ird In Ihr drvrhq.menl of mrlh.rta tha/ avmd uar
../ pr..v..l.... rnr.n.r. .. h..l. .M ....ru...n srrp .n.l durma aubsrqurnt suMul/aur Ih.+
1
t
chap/er deurihes Irad:lional melhodt fnr i+olal:nt pu/mr.nary rnAulheGal crlla Aul
rmphaaiies nrwrr apprnathes rsint rntch.nical M.veu and acale ul. wmt mnrnranun
l ht nrw melMwls all.a. mainlenanet ol Innt 1rrm, IarRr scale tullurn uf crlla thit
rrta.n the lull complement of surface prnprrties anA thal maintam the cnbblrunnr
nr.nnlayrr mmhhuh.pty and d.fftrenloled functi.nal pnMrrtirs. MrlMnla I.ur
iwlrntatnatiun uf itnlaled cells are therefore also cons.Arred a+ mrlh.nh fur vahAil.un u/
cuhu/rs a/uflnt Ihr/r /n errro lifetpan
Rrnn II S
I n.annm..nn! I(r.JrA P.-rary.rnrrs S6 10)-111, 19t1
ftrArr lurpnrl Nal.onal tnatilute+ of Ileallh aml the Juhn A. Ilar/ford I uunAau..n
I rum Ihe Ikpar/n.enl ..f Mediane, I/n:versay of hfiam. Sihoot of Mrdn ine, M...m., 1 t
VARI('(I51 VI INS AS A S(1UR('C Uf A1t1/1.1 IIIIMAN I:NIs(11111 I IAI ( 11 1\
1 nduthehal cellt can he harvealeA (r.um xRmeels nf adull human saphrnuus vem In
a var:rnar cnnd.lwm remn.rd frum pabenls ha.:nt s:nRle rr h:bleral vrin l.r atann am/
sl.ippinR Thr ceth arr harvrs/rA hy x.ap:nt wNh a saall.rl, xrdrJ on In RrL.l.n coalyd
or 1'r:maru flaa\s and aar pataated by remuval wilh a rubhrr Lnbleo.an Ihr aetla
cullured in this manner are maintained in a truslh med:um that is nnt supplrmrnlrJ
.r:lh Rrnwth faclm+. 1 he cells Rrnw .nh a cnhbkNone mnmd./yrr mnrphulaGyi pnsrta
antw.lrnarn tnnverlinR enayme sclivay and reatl with anlihnhea l0 1 aator V11/ anl.Rrn
Ihe I:rlh ftwursce Mithlly aflrr rraclion wah mnmlcMnal anllMnliea +ye.A.c far hunun
endo/hrlial crlla Ihus, sh:pped varicose ve:n xRmenls pruvnle a readdy ava.lahle
snurae of endulhrlial cell+
Ryon (/..C and Whae, I., A.
7'n,ur d ('rl117Q1171 176.1985
.
OIArr Irpnur Nali..nal Insl:lules of I/eallh.
I rom /hr Isrpartmrnl uf Med:c:ne. I/mvers:ly of M.am: ScMrd of Med.cine. Mum., 11
A POXt1111.1 RI(:1/1 At(1RY Kfll f(71 SQI/AI INI I IY7XI/IAS1 IN
('111N1 SI IIAh1%11 K OVARY ('I I I.S
(:wwtA of ('h:nex hamaler ovary cells (('//(7) in 11.r prrten.e ul 2(m
l.pal
Aeplrled trrum 11 11%) t.r only 2hr rewha in an im-rease in Ihe ttolhrsn nl 1844 1 slr...1.
Irum ("(') mrvalonatr am1 frurn 1tr('I uluaknr enmpared wilh arllt Rruwn unArr n.umJ
Rlowlh anml./mm .n Ihr prrsrMt o/ Iq\ rr/al a'alf arrum (11 \) Ih.t enl.ao.rd alrr.d
synthrai+.ncrraars wah I:nN ut e.pn+urr of Me cells /u ((K llowr.rr, ra(wn.na rhrar
eells f.r Lnr prnods up Io 42 112hr to a Rruwlh nx.bum e..nlarnmR 2011 11\ 41,41 rn/
rrwh in enhanced 1'r('I s/rrnl synthesit hrrn (rrt'l 2.1, o.i.tuaqualrnr Int ul...t.nn ut
Iheae trlls with (,Y) meaatonale resWled tn the accum.dal'r.n..l I-q 1 uw.lrnr rrRar.lka
of Ihe prexnce ..f eilther 1.I/S nr f-(S Ihtst resutls suRtea/ /ha/ squalrnr r/r..ala.r n a
retulaltry enryme in Ihe chnlnlerol eiosynlhet:c palhway in ('11(7
filrnber{, 11 and SAr.Atrr, I
Ir. I
77
l.r..l+ 1o()/ S19 S41 19114
Irnm the Itrl.arhnrnl o( Itlnchemialry, Iht GtnrRe S Wne /acuhy of I de Scwmt+, Itl
Aviv I/mvrrvty, lararl
1/PIAK1 (II 1111:11 IrtN[IIY 1IIYIPKOTftN-ASS(N'IAT11)A/O1'R1/111N A 1
ANIl/ 11O1 15,11 K111 I V t K% QY Ih 1tSCl/1SO1 litt-. RAI fN / 11Y) ANIt 11%
AI IKI NAI ( 1 1 1 C ANI) /11 /A t(K'Y (1 S the 1'lrRo
Iht ullatr .f h.Rh drntity bpnprolein (111)1 )-ataocialed apnlipoprtulrin A 1(a(wr
A/t and th,dratrrol ralrn wat rtnmaleJ in 16 tissur{ uf the aat ua:nR ral Itl)t InuhM
Ialvtrd with n,n,IrR.addde Iracers, cnvalenlly atlached I'4 lytaminr crllnhi,ne ba.rd
atw+ A 1, anJ )~IIF hdrur. yl hm.kyl elhrr usanl chnkttrryt taan 1h,th lalwh rru...mr.l
aan.nl+d w.1h Ibe 11111 (rutw.w in Ihe plaama, adrQualely Irated thru unl.d.Ir.t
t.unv.l+.trla, and +rre wrlt Irapprd at Ihtir trfes uf vpta\t
t hnkaltrnl rlher waa la\rw up at a Rrrater fracIwnal rale /han apn A I by adrrnal,
r,vary au,l hvet 7 fntd 4 fnht. anJ T fntd Rrealer, tetprctively Ihr ralea of upt.le n(
ch.Jntr.ul rthrr anJ tw. A I wrre atnul rnual in the nlher haauet (ercept \wtnry)
I/w d.ap.nlr,.lwu.w uplalt of 111)1 rbdrnr.,d tther rehllvr In 111N. apo A-1 was ala.
nMerveJ in pr.n+ary cullurrs o( rat adrenal crlla aml hrpat.cytes stpl.l\e of frIh
n.o.rllrt tn hnlh cell lY(ws ahn+rd s}lurahl.ly llnlh Ihe ahantule tale .ul upt-.\e of
/`lll hnlettrrd rlhrr and Ihe utln .f rlher upu\e lu pnA I uplahe rrrt Rrratrt rn
aArrnal crlla /h}n in Mtnl,wylrt. cune.n.n9 w+lh the rw a.n nl.vrrval+uns Vr,y simdar
Irwltt wrrr uhl,+ned ua+nR 111/1 h.n1..RHilly 1}t.rlyd wah I+/,hulrale.ul rv.r. Ihr
Anpu.p,nlnmatr uPta\e n/ /+11),A.Jrvlrrul r,hr1 avaa nnl a.rnrl.can/ly dr.rra.ed 1y
drplrl.un nf a(a+ 1(rnm /br 11111 , nr by rrd,nl.ve nwthyt.ll,n n/' Ihr al.o I I.. t.h.~
+1. recngnann by .rarlInra Ilnwtvrr, a(r+ A I upljle waa drerrauJ, suRRra/.nR Ihil
alv. 1 u+rda+lra Ihr uplJr n( patlwln.nnlnn.nR a(r. A( hul dura n,1 .uM.d.ulr In Ibr
h.prn(Nnl.nn.lle u1l+~e Ur ~I/hhol.a/tlyl elhrt
( aaas, (' , r.qman, K(, I lvin, M, and S/r/nFne l)
I h. hw.w,d ../ RuJnKnof (Frwu.hr 260(`) 744 710, I')RS.
(hhn tuppwl Nauonal llearl Lung anJ 111aw1 Instilule and National Instilule nf
l:enent MeJrca1 St wncea
f tom the Ikparlment ef Mtdicine. Ilivision of Cndocrinology and MrtaMdrsm.
Itnrvettily of ('ahfmma at San Uiegn, I a 10113
K(111 O1 1111 1(/W 01 Nq(Y I IPOPRO11 aN RICI'PIOR IN Pi'N1 IRA11ON
11/ 11)W 1/1N111V 11/1nR()11ININ11)RA1/111f A(IK11(' WA11
the prrarnl aludy wat dttiRntd In determine whelhrr hindinR uf Lnw AencilY
tqrprntrin 111/1 ) to endolhrlial I IM. tectpl.ws ennlrihutes srRndlcandy ta the
(wnrtnalwn nl I 1+1 mta nurmal rabhil au11a Initial fluc rale waa wrd at a meaaure ..f
uplale nl I tH KrAnc/vr mrlhylahnn ..f (./11 rs lm.wn lo bIH¢l, rta teaNtnmon Ly Iht
I IN v.rplr Ihr.e(,e, the dJfr.rn.r in flus rstet nf nal.ve I lyl. and rrdu.olvrty
mrll.al.a1 I tN Inr11,r1 11/1 1+.ta aau,ne,/ In retuearnl the rcrplur drlwndrnl
,q.d. Na,.r 111 .n/ mr/hvl 111 ~..r I.Ivtr,l w.16 Jd/r.rol nlolwt (+'4 u. '~II
.., 1 . ,,. .... . . .. , . ....... .. ,. .,.,.. .+.r ...,.r ..1./..r 1//r. In 1 .dl nnulra
. . .... +. ... ,. ..r.l ... . ... .p.. I Lr ,n,I,d
. . . . , . .... , a' . 11,1 u,1 1-.'1
I
for mrlhyl-t 1)1. lbe difference Was not siRnificant. Which auRRrsls lhat the /tu% ol
( 111. into the aor(s is nn1 tiignificanlty dependent upon, m teRutalyd hy, end.nhrhal I IN
rtceplun, but it mrdlaleA by other mechannms.
WIslund, O, ('arew, 1 E and StnnMrl(. D.
~rrrrrm. frrmrl %115-111, 1915
.
(hhrr Iwp/anr Naliunal /learl I unR and Ilhrwl InNnule aml the Nariunal Inadulr u(
(irr.eral MeJtcal tic.encrs
I tom the Ikpartmrnl of MeJicine, tlnivtraHy of ('alifurnia at San IhrRo, I a latla
(I)NIK1111/t1UN(II A('IINIO1111'.SIK11('IIIRI ()1 1111 ('YII1P1 Al,MkMA1Ktr
the reatiralw.n 1ha1 aclin it a cuntUlurn/ of mmmutale t:ellv (1) anJ Ihe
nlrnldnatwln of axhn fAamrnl{ tn the per,(.brry of such.rllt (:) nlwnrd up a nr+ .u.Ll
u( rrw.M.vlar bnJ.+RY Im the f/ra111me, n brcanM ryr{NLk to etplaln rn dr1 ul a l+ndy nl
phrnumrna dexnlwd nver two cenlurirt t'oncrtnmR imlwulanl s.plclt ..1 rrll .h..tw,
nw.vemenl, arwl eonanltncy AllhnvRh aclin curnptiart uvly one of arvr/al .oU.l.tlhd.u
lrtwr tyatems rd crih, 11 i{ an eRlremely i.ulw+rlanl nne Ihia taaay hr.r/ly rrvrr..a N.nM
preaenl cuncrpls nf the enwhihWnn ul acan lu C:tr 'cylupL/aolw rva1r.. '
Slar.rf.lP.
7 hr l.wrmd n/ ('rll Rn.luR y99(I)1T3-21S, PI 2, luly, P1R1
()tArr .wplrwl l/ S Public Ileahh Service, Ihe Mutcvlat 1)yslruphy Avvor...le,n, an,l the
I Jwin S Wehsltr I numlalinn.
I rum Iht IltmawlnRy/(MCUIo~y Uwit, Maasachusellt (ieneral Ilmpiul, 14I+arlmtnl nf
Medreine, 1larvarJ Medical Schrrut, IIMnlun.
N(NJMI/S('1 I A/'lIN RINbING PRUITINS
Ilecauae the wnr/.inps of aelinbi/vling ptMtim rkl.eml u(u.n the .hn:u 1riatics of
aNin ilael(. the fird secliow of Ihis UtiCk avmvtatirrt cuurnl hn.. ardn
ss{embly the rnaumR review of ac/iwbindinR protein{ .LInJ.., 1,,. , prutr.na
accrwd.nR In Ihrir hrnctiona, as hat beew rlnne Ivevirw.ly (`ah/rwa 1/RI N+rda 19R?,
('raiR A Ptdlaal 1921. S/oatel 1981). Ihert are aalin hrndoR pn.l.n.a Ihn Ln+,l
pre.h.nunanlly Ln actin Ir1lMnmrH wm/ inhibil Iheir aelf aa.rmlty iwln Id:unrnla Ipl..
prulriwa (nnd In one Irr nwur acliw rnnwnmrrs wlwn Ihry arc in tl.r /n..n n/ 1,1 .,
tuhet lu the emh of tlw /tlsrnrnla nr in somt imlance% to rru..ururrs wahm Ih /1 ~
(.uvmR Ibe fdanunt lu Iwea\ -Ihry Ihen remain Iw.und 1u nnr rnd n/ 11 1, 1
/71.Imrnl Sldl ull.er Prnle.nt biwJ LMYII}MUUtIy In a;t.n nu.mmrcv ,u ..
Idamenlt, whir h. autrt 1he Kliw t ut.tmrola /.t hr cr,.a{ bul,,1 ml. 1,. ,. ,+,
con/nrmalwln{ trlll/vr lu nnt amnhrr 1 he wm/ 'prrd.uu.wanl' in vrr ).ml.... n. 1, .
brcauae at ror& proRrrtar{ on parlicvlar achn 1ind.nR pr.uleim, Iherr 1.1 1.
Iw:ome ka 'pure' an.t mwe eumpka 166% revrew ew.phaavra L.,rluru 1 ,1n1
cnncrrninR Ihe slructural and funclinnal prnlwtliet of aclrw himtmR prnlema d,,1
intrractwtnt nith aalin tw trnu S,rme tf(url n mM/e, howrvrr. In t(wculalr on ho /l., -.r
inlrtaalw.nt mtRht o(+eralr rw qrn
Sturvl 7 P rl ,d
19
Annual Ilr.rrr n/ l'ell Ilr..hrr 1:11) 402, 1015
nrArr sup(r..r l/ S Public Ileatlh Srrvrce and /ht I divin S Wrhs/er I uundat,nn
I rnm the IlematnlnRy lM.nh.Ry Itnit, Massachusetls (:eneral Ilospilal, Ilepatlmrra of
MrJrc.nr, /I.u.arJ hlyd,ral Schnnl, h,ston
1'()A(:111 AN 1 A(' I I V I t I1 C Uf PI A i 1 1 1TS IN CORONAR Y
AR 11 R Y 111\I A\I
/'latr/els have been imrlicatrd in Ihe psthnltenetis nf curonary artery .tsea.e, : nd a
numlr1 of tlWllft have rr)m,ned platelet funl/MIn and CI,attYlalu.n parameler\ in La .rnlt
../h s%Kh hsease We have e.amined plalekl cnsRulant NIlv,uet, volumes, and
liRnrrRale tahos in 2) pal,rn/s with ehrsl pa,n, seven nf whum bad nmmal cn, nary
w/trnf.rams IRrnup 11 and /A nt whom had an~,naraphKally prnven cnrona.y :.rlrry
d,seaae ll:rrwp 1/) I here wert nn tiRn.ficanl dd/erencrs in the mean values for platekl
vnlome m playrlrl attlfrenalr ralu,s hrl+een the two grours lhe platelet cuat:utanl
a.l.vrlirs concerned wrlh milialN.n and Ihe rarly sutZn of rntrinsie cnaRulalnm were
s.Rndrtandy increasrd in palants rn Rroup 11 as crNnrared wnh Ihose in Stnup I No
t.Rnifaanl ddferen.w were nnled Lelwren Ihe 1+n RrnuM rilh respecl /n prolhrrminn
1nor, pv1.al thramM.plaar,n I,me, and pl.nma levels of IrhrmoRrn and cnaRulalmn /aclurs
V and VIII 11n.r.r,, Ihe mran aclrvity n plmma of anldhrumh.n //) (hul m.l the level
r./ anl.lh,nnd.rn 111 anl,Rrnt was 7rRn.fNanlly h.wer in palrencs uf Rrnup 1/ compated
w.th Rroup I l)verall, nur nhsrrvali+ms p.ovrJe evalence for an enhanied cnntnhul.nn in
the inlrnnsic toaRulahnn system In pal,rnls with crannary artrry Jis.ase the plalelrl
cu.Rulanl hypera.tivrly noted in these psl,.nls may relk.t a role rr( platekls in the
palhoRrnetis nf cnronary s.lery d,araar nt may he secomtary lu the undrrlyinR arletial
dnease
Ran, A. K, M'el.A. P N rt ot
l'r.ru/nlan 6tIt)/5-21,1711.
Othrr rrPlrwr ('iba (:eiRy ('orporation and 11 S 14parlmenl of Ikatlh snd Ituman
4rvlces.
/.nm Ihe lMomhnsis Research Cenltr and the ('ardiolnxy Secliun, heparlmenl of
Me,firme, temple llnivers;ly 1leallh Sciencrs t'enler, thiladelph.a
A("11VA1/ON Qf l'OA(ittl A t1ON I A('TORS ON 1111 SIIRI A('1:
(ri PLAt111/S
Plalrle/ phytinMyy and eoa2ulalion hinchtmit/ry have IraMtionally hren sludir.l
snd enncrpluallttd as stparate and distinct entities this brief wmmary nf
plalelelcragulanl prntein imrraclMnl preveN an dlernalrve viewprn/ which
emphasiaet the effects of platrkts itn enagulalinn snd Ihe effects of co/aulalu.n prnleins
on platelet physinl.Hy Thete interrrlatinnsh.pt ate sn intimate and impnrlanl Ihal any
ennsideralinn r.( the hemnsqsis /nnhanism that fails to tahe them into accnunl is
mraninRlnt
W.d.A 1' N
1111) 11 M.. 1!141
I
I
I
nthrr .apl,nrr rublic Ilealth Service
frum Ihe lhrnmh.nis Research Cenler, 1)eparlment of Medreine, Temple Umvrr.,ly
S.h,nd nf Med,aine, Phdsdelphia
rl A1111'f ('OA(71t1 AN1 A('f/VITICSIN 1)IAltt11SMI1./11115 1 V/I)1 Nt1
1OR R 1 I A 11(IN%IIIP UI 1 W I I N PI A I ll 1_ 1 lUAI i111.AN 1 111PI N A( I 1 V I I Y
ANI) /1 A 111 1 I Vhl_11M1: '
Malrlrt% have been .hnwn to be capahk nf initialin& and prumolinR anme nf Ihe
rraalrnns in inth.ns.c cnaRulalirn and have hr.n im/dica/eJ in Ihe palhnprnesn nl
vaa~ular Irsn,ns in d,aMlts me//ilw We have etareinrd Ihe cnn/rlhulNm uf pl.urlrrs In
the .naRulalw,n rra,tu,ns in K palieMS havrnR d.abrlrs mrltilus wilh and .,Il,oul
rrlmupathy )lu.hpn,.m/ ro/imyti/hy (RR) nr pruliferative relimqut)hy (PR)) 111 p.r,rnl,
with n,mvaacul.u rye drstases (patient cnnUn/a), and 1t mNrnal soh)ecls In tnmp.rn-n
wrth cnnlrnl pat.ents, titnificanl elevations .vert noted in fuur nf the five assays Ln
platelet cnaRulsnt aclisities rn Jiatrlie patients wilh PR and in /hrrr uf fivr as..ys rn
patients .ilh Ilk. Ihus, platelet eoagutanl hypeyaclivity is pre.rM in drahr/n% wdb
rrlm,yvlhy. SrRnifican/ ekvatinns .ere Iw./ed in Iwn o/ the assays in pa/renls wnM,ut
trlim,pathy (NR). sullSeslinR /ha/ plattkl coaRulanl hyperaalivity may nol nrressarily he
secnmlary 10 the vascubpalhy. lhe prnlnminaM shnotmalil,rs nured wert in asays
retleclinR /he contrihuliow of pllekts /o Iht early slaRes of inlrinsiC cnaaulat.un ralber
than to laler slaRes of p.Mhrombin acliva/ion. Iw a.ldili.n, Ihe nwan pl:qrlel vlumt .as
f.wnd tn he signifnsnlly greatrr in palienls wilh PR sml bR bu1 not NR than in moomal
c.muols. A positive linrsl enneblion (r - 081) was noted between the mean of the
cnaRulanl aalivilies and platelet vnlurne in duhetic subjects, soRRrslina a hnhrrln
undtsrllhed rela/nMfhip belween pbtelel crsffulaM aetivilKS aml platelet vnlume.
Rao, A K,(:olJherlt, R. E. and Nd.A I. N.
TAr /nwnal n/ / eAnr.r..ry .ur/ C/rwird M.h.vw N.N 1) ~! 9!, IVQe.
l)rher Irpl.ur: Nslinnal Instilutet of 1ledlh.
I rnm the 1 hromhosrs Researeh ('en/er snd f)epartmrnl of Medic.ne, Temple I Imver.rly
Schnnl of Medaine, and Retinal Vsscrlar l/ni1, Wdle Iyt Ib.pilal, 1'hilaJrlphia
l'l1E IYKtIpRLr. R/1LE Of PI ATEI-P IS IN RYPA.MIN(; 11/E CONiAC/ PIIASI
(If 111 (Kll) CQAtDI11.A1 ION
1)ats prr.ensed heetin and previrwsly su(ywwt sn active role fnr plalrlrls in
ppnnnlinlf Ihe inltractiml and activation nl the cUaRulalaM proterns u/ the comat 1 ph.Nr
ul iMrIMK (IlaRulalrnn the platekl nwmMsne, sclivsle,l by AuP cnllagen nr /hr..mU.n,
can prnmole Ihe prnlenlylK aNivali,M rd fachN XI/ in fKIM X11a in Ihe pre.rnar nl
la/lihcrin snd high molecular weigA/ hininoRen, Ike lymnprn factnr XI ssar-rales .nh
high moleeular weigh hininogen in plasms and hKowles hound ht a site on the n,rad.,ane
of Ihrombin or eollagen sclivsled plate/ets. lhereafler, plalrk/ M.und fatlnt KI ran Ir
prutrulylically saivateJ to factor X1a eilhtr in the preance nf faclnr r11a ar .n the
presence nf Mallihrrm. lhese Ohser.aliuns cuuld t.ptain Ihe absen,r of hlrrd.nR
eomplKalinns in palienH with fachn X11 deficiency In adJAUn, p/atr,ls anuu,n a
molrcule which has a hqher mokcular .erRh1 lhan plasma fsctor X/ and awssdly a..-Is
R/l ~ I
of a lelramer of four identical suhunils of )2 (1f10 dalluna tach of which is funclionally
tnd immonnlnRically svm.lar to plasma faclor X1 Srnct this rnulrcule ia prtaent in the
ptatrlrls of pal,en/s w,lh arvert plasma fatlnr X1 deficiency and no evwlence of btred,nR,
we (MNlulalr Ihal platrlet faclor X1 can auMtilulr for platma factor XI in hemostatn and
fw,tahly arcounl for tht a.,ns.dershk varuh,hty in clinical sevrrily oMerved in pabenla
~.,Ih faalur XI rkl,ciency
It'nfaA P N luaryns\i, G P, GrrenKlyd, 1. S, and Criffin. I 11
ll.rrm.rfnlner.r 171`/1/.0 lil, 1M
(hArr .urlrvr 11 S Isrpartmrnt of Ilealth. Educaion and Wetfare
Irnm the lhrnmhrnn Research ('enter, Temple Univenily School nf Mrnic.nr,
t'h.l.ldelph,a, snd Sc..pPa Rtuarah Insb/ule, 1.2 1n11a, CA
A1MM'IAlI/1N 111 / II/RIN wllll 1111 rt A/11 i 1 l Y1tKK/11 I(/N
the aolhnrs hae prrvrously pmlutalyd 11121 surfaee meml.rant prote,ns lvcnmr
qvatlq)11y la4wialrA wnh Ihr ,nlernal plAtelel cytos\rklon ul"on plalekl a.Uvaln.n
I r,ur Lnea .d rv.deoce sulq'.r1 Ihrs INnrnl hsrynhrua t,n.e we nnw sh.,w Ihal pl.,telrl
tur/aat re.epn.rs Inr I,ha.n he.mnr a/r.Jrally atv,r,nlyd wr,h the Pl,hIrl
I.ann ,n.nlul.k cylot\rkwna /1 l.h.rn was deln/rd rmmum.L,Rieally in Ihe waahrd
Ir,/.n rna,lu(k cylntsrlrl..m of Ih,n,n/..n a,l,valyd platrlrla ander cr,ndn,..es whrrt
fd.r,n rydymr.ualn.n aml resuhsnl prr,.p,lata,n rrrr hhn\rd wJh (ily Iro-A,R ('r,., a
tynlhrlnpeprnlr thal ,nhdnM plymrr,ranm u( (Avm ,m,ru,mrr T) Rad,ulaheled fd.r.n
hnnd lu IA,..od.m a,l,valyd plalrlrls snA Ir,amr aaur.Hed wilh the cvlnt\elrlnr 1)
Il,r amounl .d ,a.hnl%l,elrJ (,lu,n Iran.l 1.. lhrnud.,n aal,valed Ih,.umhaalhrn,c pIN,Irls
and Ihru csnn\.Irrnnt srm.unlrJ ro al...ul .`I/1 of the fito,n M,uu1 In
Ih.nmh,n a.hvalyd .,n.b.d plstrlrn aa.l rhrn arr^(rlr/.n1 4) Il,e aaVnLllNm ul (drnn
w,lh aylnt\rlrlnn. an1 ..,A Iht pl,lrlrt tu./a.r w.n nrarly quanldatrvrly hhw\r,l by an
anl,hrl7 tarp.vnt at;.snal a slm\ekla.m L,nl, 1 1, an anhh..uty aR.\rn.l nn/Jtrd mrn, nanra
ol 1'runaae errarrd Id~lrhla tant, M1/. sn.l a m..m.,l..nal aaldrrly In Ihe tAelrlrt su.farr
p17a,-ptulrin run,plr., (:/11. (:PIII (am, (:1'Illl Ihesr antdMhlira bhwlArd AIsH an.1
thnmd.m mdwrd plate/ct aRlrrlal,on aa wrll aa Ihrombininducrd ah)l rrlraclion
An.dyas of the immumynr.,p.lalet uMa,nrd +,d. anlr (', Anti Mt, anA anh (%1'll. (rnm
drlrrlTnl rauxl of "'1 turface latr/rd plarlrts revealyd that lhrtr antda.lrra
rrr..prbed (irll\GI'lll lhe.e dala aurKr.1 Ih,l I/uombin aclivatr,m nf plalrlrta rr..dls
in 16e ywC.fK aas..r.alu,n uf flbrrn with It.e plalrlrl cylnsAelelun, 11131 Ihis aa..wratn,n
rn.rv l,r rnrJutrd hy the l.l'tl. (:Pltl cunmplrs, and Iba/ these mechaniann rnuy ptay an
inq.,.lan1 ,..Ir iu plalrlr/ aKy,eEalion and ab.l rrb.,a,.an induced by IMmuhin
lu..vna\i.(: P, Kn,ne.\., 1,ru'tnn..\,,(,KmKht.) (',Kuahy, A, .f.ivaat.rva, S,
,.n... c , snJ 1/ ,J.A /' N
/
/..n..nnl .f Itu.l..cnal ! Armnar 2a101%11.`I/ t1'111
,ury+. 11 Y IAI,~,Imrnl of I1. etd, +r..l 11nor.rn Srrv,crs
1,.-.. Ihe Ibr.nal.a Rr.rarch /'rntrr, lrrnplr I/nivlrti/y S.iuwd nf htrd,.mr,
1'hd.rdAph.a
t)
,
i
I
I
AMllsOLYftC ASSAY OF III/MAN FA('fOR XI IN P1 ASMA
('OMPARISON W/111 A COAGULANI ASSAY ANI) A NI W
RAI'IU RAUIOIMMI/NOASSAY
lht Iraditional cosctulanl assay rot plaama faclnr XI suffers frorn a relalivrly h,Kh
uref(icienl of varialion. the need rot rare congenitally de/icirn/ plaama, and a I-n
conelalion he/wren precision and arnailivity We have develMy.rd a s..nptr funcl,unal
a.nidnlylic stsay for fxlor XI in plasma using the chromnRen,c sulst,.ur
t'yr(ilu Pro ArRrpLnilroanalidt (S7N,fi) . Aller inac/ivatinn of ol aohlrypain, t 1
inhibilnr, and nlher plasms prMease inhihilms avilh ('11(lr, plasma was 'm.ulosrd walh
kaulin, in the ahsence of added cakium, which limited Ike enzymea furmed lu Ihn.r
drpendenl on contact aclivalion. Soybean IryMin inhibi/nr was used Io nurure Ihr
action uf \alh\rein on the sahslrale. Once the reaclinn was comptete, co,n tryp.,n
inh,biHw waa used lo inaclivt facloe X11a, 11.e rnryme Seneralt,l by tqw,surr .uf plaama
tn nrRatively .harRrd turfxes which had activated the faclor XI Ihe assay ,a h.R/dy
t/rcrfa for fact.w X1, since plasma lntat derrclrnl in that rynu,Ren yirldrd only 11 1%
o( Ihe enrymauc' activity in nrwmal plasma armkr idenlKal eoMlA/ont 1 he reyuiremrnt.
fnr enmplrtr tnnvrrawn nf faeMr Xt In Xla in plasma wilhin I10 min wt,e, rry,e.l,vrly,
fac/nr X11, 06 11/ml. IlNaltdrein was nol an aMnlult requiremenl (or cnmplrtr
aclivatirm hul dnl accekrale tht leaclinn. /he inlraassay coeff,cirnl of vatatw,n at
14%. and the mran of 35 normal plaamaa Was 100 11 : 0 N SI) In sdd,linn, a new /a/nd
radrnimmunnaasay was deviad wing alaphyh,cnccal prMein A as ll.e p.rc,p,t.rUnR sRrnl
fur a complrt of (aclM XI anlrRen wnh rnonrnprcilic rahhil antdwrly. Ihr mran w.ra
IOI It v 0 10 t1) The eorrelalinn c.rfficients fm amidnly/ic r.v,ut ruaKul.lnt sn.1
amnhdylK rrrU,a eadinimmllnoassay tverr ra 0 VS (nr the former and 0 Vh fur the laue,
Ihus, a simpk, aeeurale anudolytie aasay and a ladioimmunoaatay luvr been devitrd la,
meaaurint lach.r XI in plnma 11121 correlalr well .i/h the cnaRutanl U/,v.ty uf Ixlm
Xl, as dr/rrmined in uur lahnralory.
Sioll. C 1, Sinha, 1)., Searnan, F. S. M'eldl r, N.. and ('olman, R W
IlMrwl 6.1(1)17 - 50. 1984,
1984,
OIArr, supprul. National Inali/ales of llrallh.
I rom the Thromhosis Resea.ch Center and IltrnalulnRy (lwcntoRy Secl,on, IMpartnvn/ of
Mtdicine, lempk I/niversily School o( Medicint, Phdaklphia
INTI RACTION 01-('OAGIILATKIN IROIfINS WI111 PI A111 1 IS
rOSSInLF SI(:NI/ 1('AN('E FOR MAIN11 NAN('E (lf 1/1 M(KIAS/S
ANI) PA 111(Xi1 N111S OF I IIR(MINO1 MIR)LISM
lht purpose of this chapter is to prrstnl uwne nf the evaknce Ihal p1.,trlrlt IM,aar.,
hindrna sdes (w a variely of eoslublion proltins and Ihat thear 1tMc,lN' I.I,tArl
tuacculanl prnlein iMrrlKtbnt ean promn/e aymoaen ac/ive/n.ns al var,.,uw a..Krs .d
inlrinsif eoaRulal,nns inc/udmg Ihe ini/ia/wrw of intuinsie cuaifulal,on 1.1 aJdn
slu/.es are presenltd Ihal are eonsnlenl wilb the hypolhesit Ihat Ihrce ro/rraclM,ns ..1
coaRulalion prMrins with p4lelets are im/arlsnt physioh.Rnally .n p.nna.1,,,K no,m.J
hrrnoa/asis and palhologrcally in predisposing to eerlain vennus an.l arlral /hrnml.iu,
d,sents.
R'a/1A. P N.
In ~/Arrm.L.nu. Rrr.rw. I7, Raven Preta, NY, IVtle, pp 1!9 tJl
(/rhn .nr('.nr t/ [ thp..Imrn1 nf Iteatd., I Auf il.nn and Wrlf nr
Irnm the Ih...mh...n Hesra.ch Imhlulr, 14pa.lmenl of MrJnior, lemple 1hu.er,.ly
S. h.r.l al M.d., mr, rhd uJr lphq
111 ( N/ls ((/A(.111 A I II IN I A(' I l IR \Ia 11INI)S SPl (-11 K'A1 I Y 11> A SI I I I1N
At 11VA111/1111h/AN1'1 Allll IX1t1C11N('11Kl/M IIIAI t(IR IA/'I(tH XI
Qind.nof of 0161 laalar X1a h/ plalritH reQuired Ihe prrsrncr rd hiRh muk.ular
wr.Rhl \:mm.grn, was enhamed whrn plalekN were slunulatrd w.Ih Ihrnmh.n, and
rr.nhrd a pla/rau s/lrr 4 6 nun of mcuhalnm at 17(' Fashw \Lr hmd:nR was yr:dn
50 In RX) fald n..d.,r e..rasrt nf unlahrkd (actnr XIs PreventrA h.ndrnR, whrrra,
I xlur X1, prrloalht.rm, I aslur X11a, and MolhrornMn dn/ nM When whr.1
rlylhr/q'ylr{, ad.lh/ at ,nncrn/Ia1M11t l'ah'ula1W1 In prnvlde an enurvakrll /u/f.Nr arr.l N.
rlalrlrh, wrrr .n,ubalyd v..1h 1 sc/nr Xla, only a low le.e/ o( nnnsprcdic, mmtalurahk
h.nd.nR was alrlrrlrA I aclnr X1a b:n.bn{ to ptalrtelt was parlnlly revrrs.hle and wat
talu.ablr at cnrwennal.nn, of a.ldrd 1 scaa X1a nf 0 2 04 YR/ml O 23 2 5 pM) 1 hr
numher uf I a.lnr X1a h:nd.nof ulrs nn aa.vated plalekls was e,timated In hr `2S prr
pl.alrlel IranRr 110 al'atll We tnnctudr Iha1 spr,d:c, h.Rh allrn.ly, uturalde h.nd.nR :Irs
1.19 Ia,lur kl. arr p.rtrnl on a.bvale.) ptalrlelt, are dnlrnsl f.nm Ihn{r pre.mutly
drmansualrJ L.r 1 acb.r X1, and requae the prrunrr u/ hrRh mutrlulJr wriphl \rnmuKrn
Smha, I7, Sraman, I , Kn,hy, A, KnlRhl, I l, an,l W,.hh P N
l.w.n.J u/ ( fuu..d In.ru.tnunn 711s%0 It\6, I')11J
(lthrr .oppnr Ni.nn.J In./.rulr, ./ IIrJ.h ind Amr....n Ilr.ul A..h..u.nn,
rrnn,ylvama A((d..ur
I rum the IhrnnAn..., /(rar,.,h (?nlrr, Se.r~nn ..( Ilrmsl.tngy/l1m.Jnty, IMp.ulmrnt nt
MrA.cmr. Irmplr 11n..na,lt %,Mwd..l Me,h.mr, 1'hd..drIld.,r
I A('1lIR V A PI A1111 I('YI(riKl I I tAl. A\%(( IAII l) rl(()II IN
rlalrlrt cytrNRrletnns prepa.rd /rnm Ihrnmhin ac/.,aleA plaletrla cu.lam
' tpecifirally a,snculyd I aJnr Va We /wnlula/r thal 1 ac/or Va a\N.ilales wpb Ihe
cylnJrlrtun Ihrough recrplon Mrtenl nn the Vlalrlrl surface the followinq evrd.ns'e
surM'rb /h:{ hyp.lhrsit (a) Prnu setrelinn nf 1 arlm Va q Mcrstary for the att/Maantn
o( 1 aclor Vs on the cylnslelelon (b) ReaRenls Ihat :nactivale I aclm Va on the su.(arr
of Ihe ptatekl, swh at 1 1) 1 A and prolrnlylic enrymes, also in.chvate the 1 a.1ur V. nn
Ihr eylasLeklnn k) 1 he plalek/ 1 a.lnr Xa hm.tinR sitet Ir e. / aelur V al .ur
yuanhlauvrly rru.nrd on tl.e tdaelrt cytndrlrtnn (d) 1'/alrlrl cyhnlrlrlnns Inrl,urd
frnm plalrlr/s that ue thnuRhl /n he drf.t.ent in 1 actnr Va hinJmg taln cunU.n 2Ya. nl
1 sclot Va s.Uvrly uf nnrmal plalrltl eyhnkektont and plalelel cylm~rlrtont ptrl..urd
frum plalrltlt drf/cirnt m/aclur Va cnnlain no lactnr Va acUvdy bu1 rr`ain cunlr,.l
levelt of f sslnr Va only whrn I aclor Va is a.h1eA to the plalrkls pnur lu the prrPar lann
of cy/otArlrlont
rus.yn,.i, (: r and 1tnr,h P N
l/m~+..r..l.rr.n 1711) A r /A. 1'lclt
I
(lther luppmt 1/ S brpartmenl of Ileallh and Iluman Servicrs.
lrnm the lhromMnit Rrsearch Center, Temple tlnivers.ly StMwd af Mrdi.rnr.
1'hfladelphia
1111 rl Alfl l'1 ('YIIKKfI Ff(7N('ONTAINS II.fMI NISOf
1111 1'K()1111(l)MIIINASI (-()MI'1 FX
tnlnn-inp.luMr cylnsYelelons prrpared fmm thrnmbin-atl:valeA plalrlel, -r/e
(nund 14% pnlrnUale the acl:vat:on of prn/hlombrn (prolhromhmate aaUvr/y)
/'yhnkrlelont prrparrd from reA eells nr (ymphuhlasls contained no p.alhrnmhma.e
scl:vdy the plalekt prolMomb.nase scarhy was drprm/enl on Cylrn4elrlataa.runrd
1 atlur Va, aml r.uRr11r1u\Iy aMtlk/) laelnr Xa and prolhromhin ('yluthe/rlnns cnnl..med
14% n/ the lolal pla/rk1 prMhrnmb:nase aclrv:ly. holh plalrltll and cylu.lelrh.nt
di.played hslf matimal aelivN:es at similar prn/hruelh:n erwK'rn/ral.ans Ihe rote ol
Lpu1t .n the eyhnliele/al prolhrnmb:nsat activi/y wat invrtliRaled ('ytnt1arlrlnn, were
found In cnntain 12% of the lolal platelet phospM.fip.ds, cnnaqinR u1 11he In11o.mR
hprdt eaprrssed as percentaRe of IMO1 presenl in plateleN: 61/'If, tphingnmyrlm, 1/1'16
pMnphatnlykMdmr, 2 9% p/rnplu/rlyl elhamdamine, 1 4% phnsphal:dyt.nosnol, anA
:2X pMnphalwtylsrrint. The eyloshelrlal prnlhrnmh:nase aclrvily and the lynd
phwpMnus cnnlenl of eylos\eklnns decrrosed after lrealmem of cyln,4eklnns .nh
varrms Ihnet of phospMd.pa,e C. tncuha/u.n of cylnsloeklnns wrlh the hq{hrs/
cancenlratmnt lesled (K) pR/m/) rnulltd .n a 72% hnt of phrsphaloolslser:nt snA tN'LL hnt
of cylomkek/al pro/hrombinase aclivily. ('ylos~eklal rrolhrnml.:nau abvlly AnlnweA
hy phmphothpase C Ireatrnenl could he reslored to cnnlrol Irvelt hy Irealmenl nf
hydrnly,ed cyloodielrhns wilh Intal eytos\rklal I:p:d ur mulurr, nf
I.hosphalnlylsennr/phntphati.lykMd:lle (25 75% hy we.Rhl) I hrst resuht suRRea thal
ILe tyWtielelal prnthrmnbina,e eomplea in addition In corNaininR I aclnr Va, as hat Iren
p.rvmatly thnwn, conlains a Ihpd tnfaclor atlivay consithng m pa.l nf
phn.phaUdykr.inr.
I useyndi, (: P, Maucos, (; . P, K mhy, A., S.h:cY, P. K., and 1/'ot.h P N
1Ar l.wrnrrf n/ Rro(nR.rnl ('Armrttrrl59(11)6947-6951, 1984
(hhrr .upp.ut 1/ S Itrpartmeet of Ileahh anA /luman Serv:tes
Irnm the lhrnmhn:s Research fenler, tempk Iln.v.a.ly w'b.nd uf Mrdnrnr,
rhilaAelphia
'OMPARIS(7N (11: 111 11 bIN(7 l l NI)1 NCY, I A(1(1R X1 ('(7AGIlt ANI
Al' 11VI I V, ANI/ I AI I(IR XI AN11(31 N IN 21 1 Al tt11( X1 1r1 111 II NI
K INI IR 1 I/S
Ihe rrlat...n,hip of clinical hked:nX lendency and faclnr X1 anHRrn 1X1AKt .n
factor XI drfn:rnry was stuQied in 711 members of 25 faclnr XI Aef,,.enl wmJrrd,
1 aclor XI Ale was rnratured in a eompel:t:vt ndwnmmunnassay us:nR n.anualwl./K.
Mlernlotgow lnlr-faclor XI anlibndy, rarltahekd faclor X1, snd staphyL.c..c,a1 puulrrn
A as lht precipital:nll snen1 (kf:ciency nf faclor XI chr/1inR ac1.v.1y (XIl /, at 06!
It/nd occurred in 48 ind.vduals, 22 of whom eaprr:enced postoperal.vr nr /MntlraumalK
bkedrng Ihrir mran (aclnr XIC wat 0 21 t 004 It/nd (ail M) and la.lnr X1 As v.as
RJ 65
0)1 001 11/ml I he rrmaining .`h had n.t cl,niral hlndinR, ouny letpile tura,rat
IhallrnRe Ihru mean racn,r XI(' wa1010 01/1 1//m1 and fa.hu XIAR r.,. 0 14
(10% 11/ml In 311- It hm,hrdt haJ hrlwrrn I anJ 11 memhers wilh hlerdinp. Ihr nlhe 1:
ho,l oune wilh dr(p,rnl hr,nnatatn I+o hrlrr..ryRnus faclur \1 Jeln'irnl nhvrdu.da
a/yr-.trrd h, tr Irrvt..r fr crtn% rrortUnR nu/rrut (I RM) Ihe ah.pe of the rrR,ra.nn
hn. (ur I.Llar V 1 and 'aal..r XI Ap dala pnnet m the 78 rn,lvnluatv Iralyd J,J n,.l
ddlrr frual cunlrul anA atl pnmla Irll wrlMn 9)7% confulrn,r l.mna drri.,d llnm
auun,1 In ann,lua,.n, tIrrJrnR Irm/en'y a(sprart 1r Ir Cuntisunl w,lhn a Rr.en {.mJrJ
aod .s nut drlrrmmrJ r.alu.vrty hy /achr Xt(' or faitor XI AR /rvela
KaRni, M V, Smh., 1) 1, 1 ewrs, / 11 , Spern, 1 A and N,uf.h /'. N
AIr.l 6t( 1) 11'1 / V. 1'I1t
Nrhrr anryr..t Na1n,n.J Inunulra of t1ra/1h
1m the IwYVrrnrnl nf h/rd,crne, Ilnivrrdly uf F,tlthurRh, f'rnlral 111««1 IltnL,
1'nlalnnKh, Ih,nmMn,. Kr.rarcA (rn/rr, Irmple Ilnlvera,ly Gh,nd o/ Mrd..,nr,
/'h1 001.1..3
I I IN(' 11(1NAI (ItAK At11 RI/Al It1N (11 III IMAN 91 (N/1) ((lAG(/1 A 1/(/N
I A(-11)R X1a IMIN(. 11\tIK11MIMA AN1t11t11r11 S
1)vr,np. the ,nI,u«n u/ nlmw an~Rulu,,.n, faalnn a(I antl Xta nlrsa1
mUwarrly +dh ,Il.rr aulpul.,1«m Inr./ra, 11.,,1.r tlta, hqlh M, tnrnuprn, anJ
(a,1ar ItO a. ..rll .,a -Ib Ihe pl.,rrlrl .,..fIn 1.01, rlu.ulatr Ihrtr er,mtd.t
inlam.,lr.ulr u,a-r.,r««n. wr 1,.r 1rIn,r1 a aIlr,/«n nl munnrlan.d
.nl.t«.hra
dor.IrJ aRU,r.1 .anu. rp.l,Iva u, 1t.r \1 Mr /.r ,dI,rrI lhr.r rtar.rnh /
aul.dr
Lu tnr \1 anJ Ih, I,K{h1 a h.un .1 /, 1. \ I. on .,11.ndv Iw,ma anJ 1, p
Sln,: Hur 1 una un ul a..n.h,pa ,1.,.1 rn It.r ul \ I r .,Ih /.,. 1n
1\ Ihr ,.rJ11rJ hylA ,1I,n 11a1r \1 ral,.u../ nr ,ta auuL.111. .oln,lv
agunal the a.h/nqvpldr ..hal]Ir pyw Idu 1'ru 1.R pNA 1\ .`Ibhl. 1..1 .dy I ICS. ,1 ,1.
11.,lImR aa1,a/v n a la,rar Xta .,...Iy an/ Iv. «I n. 1..br 1'( .1,UVat,aR a.l,a/v u, .u,
a.t.valwn InI(Jr rrh-.rar a..]y Il.,a 11,N rrnm. u/ Ihr h..lvy ah.lm .wr
rnpnrrJ frr .Lvrlqmrv/ ul an./RuLud aIr.It an1 ap'td.ally (nr Ihr n/r..t/«,n n1
laal.u Xla wdh (aclnr 1\ ta Ir.t Ihn hfh'lhrvrs, Ihr e/lrcIt nl Ilner u( the mM1on.J
aMIMMIrrs 131 A, I/ 1, anA U'I) nn the lunctnan PI tat'IIN Xia were efaminrd Ihe reaaha
sMrw Il.al .n a cIu11,nR aaay the IrRM ch.unsprcrfic antihndy (St J) inlubIS RM)'K of Ihe
(.hlur Xla atlrvily, wherraa rf Ihe heavy ehan sprtifi: anlrawwlies /mt O('11 nh,bat
7$'1L and am,thrr (11 1) nnly 17% SlmJirly, in Ihe fxtur IX a.lvalion prpli.le elraae
naay anldw.ly N1 4 inhd.da IM17 n( the farlnt X1a tclivily, .hereae 1('1 inhihils IS'll
and 11 1 ulh.i.nla 117 M'e cn/M1uJe Ihll tr'RMrM 1Fa1N1 in the hravy th.rin, in aJdi/no
I.. //ar.r in tl,e IrpM .h.un, a/r rnvulvid in 11r nrlrra./nn of fa,Ira \l.4 with f.al.n 1\
anti .n Ihe rVnr..u,n ul d,r cr.aKld.nt .alvtly «/ Lnlur XI
S,nlet, 1) ,/;,..hy. A, Cran,in I S, an,1 /1 lah P N
7Ar l,.wnnl.l rl ( A,mtaLr 241)(0) 10 /1e 111/19, 1'1115
(q1 .rr/ovr U S Itelj,lnrenl nf IIr.d1h an1 llum:.n Servicet W W Smilh 1 h: ril.ble
/-l. Am,'rNan lleatl Aaariiatinn Iln,medN'aI Rraearch, and 1)ivr.,un nf Krsrar.h
Kranur.ra, Nrlrnal hr.l,lulrt nf /leallh
1 u rhr Ilu.nd....a N..rar,h (rnlrr, IMp~Umrnl u( Mnhnr, IemVle Ilm.rr.,lv
1
PI A 11-LE 1-Mf 1)1A ( F)CUAGI/l-AN 1- 1'RU11 IN IN 11 R AI't I( INS IN III
MI I\ 1 Ap\
lrom Ihr evidrnce reviewed herr, il is ryltaihlr /u cunalruct an ovrrv,rw n/ Ihr
hemottalic mechanitm emphatitin0 the esunual conlrybulram uf p/mrl.IS ,n ty,«.,p_n
a.lrvalmnt at ea.'h SIaRe o( inlrmtic CuaRulalinn S(rirfK 1uRh affrnnv rrarplur. I...
varlnln coaRulalion proleint are etpuaeJ nn Ihe plalrkl aw/acr memhr.inr Ihr
c.qRutalion prMrrnt ao (ar shown lu hrnr) Ihe platelet mrmhrane tnCludr Ihe (a,1
XI hith mul wl hrmnnRrn cnmplea, fa.yr.r Xla, the fxlur Ya fa,Inr Va .rmplr..
IMumbrn, anJ (ifnin.nRrn As a consrquem'r nf Ihrse inlrrar/una, plalrlrlt prunu1r the
sRlivalmn n( prehall,trrin, facuv XII. (a.'t,r X1, (achr IX. /ac/w X an,/ p,nlhr.,ndm
Platekh atw a(ryrar to parlq'pate in a varaty u/ ahrrnalive reaclinn mr.ham.m. Ih,l
nray nmiimbe nr nhviale Ike requiremenl fur cerlain cnaRulalir.n pratrm., rm h,dmt
fatl.u /(st and faclnr X1. lhis funaur.n uf plalele/a may arc..unl (ur Ihe af,rmr ,1
hermnul.c drfecla in palienN wilh de(crrm'irs rd snmr nf the prolrina mvuLrJ m d.r
e,.nlact phate u( intrmte eoaRulalmn 1nally, platrlrlt apprar /H, prulral arrl.uu
CI,aRulatlun pruleint, luah tl factv t(la and laclrn Xa, fann inal(rvalrun by p1nm,
prnlrrnaar roh,bNOn Ihrse vUnlyW lumlwna uf plalelrtt ate seen aa 1w'.hrnna
(na({ulaltnn rraaUnnt 111 the hemUt1a11C 1IIIR Ihat nl.ula at Ilqr n( 1JInMI vr.arl ulurl
Wolsh. P N
Srnunnr. /n F(rmntnlney, 22(l) 176-166, 1905.
Orher turpnrl NaliOnal InttllYleY of Ilrahh antt American Ile.ut Assu.rahon
frnm the lhrombosis Rtseatch ('enler, temple Ilniveraily tia'ho,d nf MrJnmr,
hhdatklphia.
1Y)1fNItA71ON ()l' Tl1E ACIIVITY OI (Y)A(it/I AIION IA('1OR XI RV 111/MAN
N.A 11:1.F /S
( he presenl sludies drrwnnslrale that when washed platelets nr plalelel memhranes
ate incuhaled with purified factrN XI anrl/ht mi.lares are aa.ayed /or laclor X1 aclrvr/y,
a 20 fold pn/enlialinn of eoaRulant aclivi/y is oharrved lhis synerRiam n depenJrnl m
the presence of aclive faela X/ and inlael pbtekl membranes since it n alydnhrd edher
by preincubalion of faclor XI .ilb nwnrspecific anti factor X1 anhlMnly, ur hy
preincabalion of platelet INensbtaaes with pMnphnlipase ('. 1 he salu)abk nalure o( the
patenlialion of purified faclot XI by platelet memManrs tuROeas Ihe paahdrly that 1
eepresents a ftllKlnmal correlate of 1ht saloryble apeciflC bmArnR uf /achrr XI h
platelets previnusly drnwmilraltd Tbis suRRnllrm is suptMaleJ by the demon.ualmn Ihat
pla/rlets enhance Ihe rale uf proleolylre xlivatinn r.f fxlur XI m Ihe prearocr 411 nlhn
fac'lor X11a nr MallMrrin
WnhA P N_ and Iuvynt\i, (i r.
1 MnmMut ArrorrA 40151 :66. M//5
(/rhrr rrp/a.rt Nallonsl lns/ilules uf Ileatlh, American Ilrarl Ma,aauun aaJ w W to rh
( hatlablr l.wl '
Irom Ihe lhrombosit Research Cenler, Orparlment n( Mrdicne, Irmple Iln..r.adv
Sihuot of Mrd,cne, YhJadelphia ,
11.. / 1
1 1 1 1 t 1 l)) PRtK1 AN(NIN ON 1111. (YIRUNARY ('IR('l/1 A I I(/N
An aaauralt tvalual.nn of the physinlnR.cal anA palhophyv..InKical r..le nt
rnduKrn..us rrotlann,d. in the hunqn c.nonary cuculalnro has l0 lrly olr.n Ihr juml
rrtuha f.um ttu.6r. u..nR ahflrrrnt le.hniquts In Ibe Mrtenl raprr anme rL.l.l ubla.trd
in Ih,t IaMnalnry arr rrtttnttd, hnh are auned In elucnlale the rhyvnloRnal and
ra1MN.AYndnRical .rrv..lvrmrnt of rmh.Rrn.wt pmlarnuids in the rrRula/inn nf cornnarY
hknrI (lnw I urlhr.mnre ann.r dala on the rharmacnlnRy u( 1V 71r rn ra/ients rwnh a, mr
mr.wa.JUl rnearaln.n (AMII nt rnt1wled tlaod on the dala Mearnlyd hrrt and on Ihr
c,m..Arralwnt .batutv.l .1 ttems n1.v4.us thN tntoM.y rrnstannnl Inrmatn.n .s Lmne.l
N.Ih in healthy tulIratq and .n palwMt wrlh lllf). Ihia is tviwkrnrd /r.Ih by the 1ai\ nl
delealahle rrtraat ul IY,I,. the marn cotnnary prostannnl larnmrll, uruler nu.m.,1
c..n.bt.una an.l under phyu.AnR.cal sl.mulalrnn ol coronary hkr»1 fh.w, as well aa undr.
aumhihuna ol man.(ral aar.Iral rtil.xmra (>w the nther hand, the 1.uY of
rrlr.rar uf P(:1, is n.d due t.r a Lmard earxity lo swh fnrmaru.n, at rvuMnt I...m thr
rrlr.at n1 h\elu 14.1 n in raarnta suhjecttd In <aabnplrR.a Allh.mRh the d..U
prrtrnlr.l hrrr d., nul arrry,.1 Ihe cnnarrt ..f a ti(nd.canl rnlr I..r curnn.uY rr,nlanu.J.
rn hrollh and .1rr.ar the rrtults rreaenled on .ntrrxlu.n 1.,twren a.hn..uor aml
rsa.al.tn..iJa in the rrRulaln.n uf faurrarm Ah»N1 (low maY le nf trRnifnanat ahu in d.r
tn.unars cut.dalarn, .mrly.nR 11121 /anUan.udt may play Ihr nde of a vatr»hbtn.
rntarnarr, whph Iram/rrt the uRnal tn .aa,ul.u rr(b.atmn (rnnr tl.e endulhehum lo the
.' aal u lx tm.».I h rn uM Ir
Wrnnnrnfw. A rl.d
In /IlrltaR vlh tn/ (.»,e a/ Ph,,.mmnl lnn.f.w 19A( 1.ncrrdmaa, vol 1, rr 1119,
MxmJlaq P.r.a, I ..nd..n, 1'/AA
(hhrr u.pprul Ihr S.ed.h Mrd.cal Krarv.h ( m.n,d and the Nalrnnal Rraerort'h ('ounr,l
ul Iu1Y
1 r..m the 14/.arlmenl nf ( Imi.a1 rhytruL.Rv, Karul.naAa Intlnulr, 11ud.1mRe llnrvrrt.ls
Il.npdal, anJ Karnthna\a Ibnpdal, t1.rUSwrJrn, an.l Ih~r.ulmrnl u/
1b..rnucululy, ('alhnln I1m.ert.ly, Kume, luly
IV. NeoropAatoacslegY soI Physiology
1111/'IS(N ( IIR(1NIC 1%P()SIIRE 1Q('14ARI.fTF SMt7Kf (1N AMINI
I I V 1 1 S ANI) I IIKN(1V1 R IN VARKl1/S IIYP(1111ALAMI(' CA 11 ('11(/1 AMINI
NIRVI 11RMINAI.SYSIIMSANI)(1N 1111 S1l'K1II1/N111 1111111ARY
11(/KM(NJI S IN 1111 MALI. RAI
Ma1e rata wrrt tsq.aed to the snu.lLe from 2 ciRafrtlts cretY morninR fne a L.tal
le.nul yd 4,laya the ne1 day IMy were drtarilatrd immed7alely a(ttr the epnure u.
Ibe smu\t f.nm 4 c.Rarrtlrs (KtnlucYy rrfrrrncr IR-1 lyrr) bu.ned at 10 mrn u/rrvalt
('anllnl animala wHt e.haIed /n arr alone ur h1 nlaMrne (ree ciRalt/te smoAe 1('ambn.lRe
Rlass libet frltrrt/ In cnnlual /o chrnnic ra(.rnurr lu ftillered tmnhe, t.l.nu.r t.w
un(rltrrnl srm.Yr rraulnr.l in a 1(Y7< itscrtatr in calrcluNanrine (/'A) levela (qu..nln..hrr
Mt/ullun..ntrlry) wdh.n the /alrral palitade Ihe Iw.alrrurr rrnvrutn.ulu
hyry.0u/.un.: nwlrus and within Ihe drNarmrdia) hyluHhal.rmic nuclrut. Ihere r,..t ahn
an rmrratt rn amrne Iulmr.er (/yrmrnt by.bn.ylate rnlubru..n
Ly n melhyl J/ p lyrosine methyksler (nMl) in the .kMamine (1)A) syttems uf thr
medul aml 1a1rral palisade rnnes an.l in the DetlrenlrKYlar naradrenahne /NA/
hypNhalarnic sytlrnmt ('hronie tapnure In un/dlerM ciRarrlle smu\e rrt.Ated ,n
rrduclw.ns of rnlaclin, 1.11 and IS11 kvela (rnlWimmum.ataay) Io11,.vnnR oMl
Irealmrnl, chronic r.rynu/t 1n unfdltrrd ciRartlle smnlie a/dl led trt redwrd
serun. levth In a.41Nmn, an increaaed t'ata(Mrsun terYm l'nnltnlratnrn rat (..nml Iht
t/ftcta uf chrunic e.praue /n eiRarrlle sntn\t on neul.Kmhrrrrne luna.on and nn
hrpNhalamic ('A syuems are suRetstrd hr he nthlialed via ni.Mrne ('aumhrnrd wnh the
resuds (bom a rrevesus slwly, Ihe (uesrnl seWllt /ndreale Iha1 Inlr.ancr dnra nnl dtvr/nr
wnh rrRard to Ihe inhrhAOCy tffecls of rapMurr to eiRatelte smuf,e ral rudacun, 1/1 snd
I`II secre1/1N1s. I hr fame N IrYr fIN /he alrmulalrlry rffeCla on the lubrru in lundrhular
ItA nenrnns and the pel/venltlCulal NA syttrms. BW chrnnie e.(w.a.ue lu crlt.ve/lr
tmuAe uemed lu cnduce lokrance with rtRar.lln ilt slimulalury tffectt un tuhrrendyor.d
dmtumealral and raravenurculat hyp.lhalamie NA syslrms aru/ nn turlrcoalrn.nta.nr
teleate
Amlerasnn. K, I nero/h, P., Fuer. K., Mawagni, 1~., amt ARnati, 1/.
NrurnrnJ.n rlnnL.Ry 11161 462-166, 19{S
I rnm the l)tparlmenl uf IIhInM.Ry, KarnlinsYa Ins/ilute, and Research and Ittvrh.rmrnl
I ahmalory, Ikpsrlmenl of /)Mttlrics and (:yntcnk.RY. Karolsntla llntpilal, Slrw4holm,
Ileparlmenl u( Ihunan Physak.RY and 1-min.rim.MiY, Ilniversrty ol Mrwlrna, M.wMn.,
Italy
1111('1S(/1 A('11/E('1N7RA1. ANhPrRIP111RA1. AIyMINItIRAII(sN(q
NI(YIIINI()N AS('I NI/1N(: IK)rAMIN/. PAIIIwAVS IN 11/1 MA11 ItAI
1IKA1N I V1/)1 N( I1(aR NKY/11N1 INI/11('I I) INl'K/ ASI S(/1- INNAMINI
111KNUVIR IN VARK11/S 111.IN(11IIALK' /N)1AMINI. N11tV/ 11/NMINAI
SYS11 MS
Tht Klions of iMCa.entricolar injeclimis and inlravennus .nfuau.nt uf nnnlurr
were sludred on drquraine tlores and llnnnvet in discrete arest ..f the (wthra.n o/
normal mak rals lhis was done by mtasurinll 1ht decline of 1he d.q.amine s/urrs afvr
lyrotrne hydrorylase inhibitinn 6110111 e-nwlhyl-tyrnsine mtthyl ester (11 11/1.t1 Ihe
depamint concrnlrar.nns in the variow etlrncerhalic M.ramint nr.vt Ieunmal sYttr.nt
wett mraaured uvna the I akY 11d/a.r rnrlh.rluh.(y .nvu/.ma qu.nl.ran.t
rr /V
micnflwnimehy Ihr estrrhnlamrnr tun.enllalrnn, in the alde.nmrdial Ironcd cnrlr,
r'err mtaaurrd hwwhrmaalty, varnR high rreaturr In(unl cMomatnRraphy cnminnrr. wrh
rleatrochrrnil a1 drtr.1.n
Intravrnlri.u/ar r.rrrimrnta the dopamine kvelt in discrtle arraa ut nu:
caulalos snd nwa.vnd.rns arrr LtndKanlly rrduced tvrn +rlh the Inv.rat dte uf
nn'uhne (I yRhat/ Inuavenlrnrdar in/rrivrna rd ni.nline in a d.nt of KNl ;rRttal
pr.wtu.r.1 srRndn.nl m.rraara of dnramrne Ivrmrvrr in varnws tyrta nf dapam.ne nrrve
t.-rmin.d asalrma in Ihe nwraulanra, n.n: aa'cumhens, and luhrr:utwn nlfa.lonuor, and
fulluwmp a Auar uf NI P1/ral, rm~rraara of drynrniglt lurrvrvrr .rerr ohsr.vrd m I/.r
mrdral part of 1he nuc cavdalua / urthenwote, nicounr (1(10 pR/ra1) s.Rn.f.cuutly
rn,vaar.l nma.henahnr bul not .h.ramine lurnovrr with the snnrrolrnnlal cmlr
h.uavrnuu% rywnn.rnsa lhe drqqmine kveb Mr.e ulrclrvely rr.lurul hy
mcnsrnr (1(IM MRjR) in /he c/vdreyslnhinin pNhrve an.1 nrgalivr d.Manonr nervr
/rrnnnal syatrms .1 the nu. facumlrns (M Ihr mhrr han4 d.y.amint k/r1% rn Ihr
antr...mr.ksl Irnn6d cn.les .rre rncrra[ed aftrr thrs ahne nl nKnhnt lnlra, rm.va
mfua.unt u( mcul.nr 111/ 1pf1p MR/\R) Mrtslv(rd dMstrrlalrA rnrrrsaet .d d.Iamme
/urnuvrr in the 1aln.ut d.q.amrnr nrrvr termrnal syslems snalylyd in the /rknarrhah.n
1 hrtr rftrcta frcarr.e swRndresn/ wnh a rknr nf 1000 rR/fit/h l he d.q.aminr trrorinals
rn Ibr nac tawla,w aMrred a hrsher irntulrvily in nHravennut infvtnrM of m ukne,
hrrnt alfraled hy 111 /00 pa/Yg uf nrcmint
Ihr.r Irndrngs tuatrsl /hal relabvety Inaw dmes of nicolint ia an aclwaunn uf
cenlrsl nn.,hnr Ir\t chnknrrtrc refrptn.s c1n rrduce dnpsmine conctnlrall..n snd
in,rraa .kysn.rnr turmrvrt .n dracrrtr Irmhn: and tlnatal nraa Thrar aclinn nay in
. part rrrararn/ Ihe nrvrlMhrmM'aI h.lan 6a Ihe rr.ardmef aali..nt of nicrNrnr arv) fur
nn'ntrnr drrrnArn.e rn rnan
AndrraNln. K, 1Y.r A, Atnalr, I I, an.l I nrrmh, r
Ifrd.rnl Mnfntr !it 170 116. 1011
Other supNnt f.rdrah lnhaccn ('mnpany
1-rnm /he t)rps.lrnent nf tinlnhrty, Kainknmta Inalitule, Slnciholm, Sv.eden, anA the
I/nivertity nf MuAtna, Mndrna, Italy
11/1 CI Of MA 11 RNAI NICOTINE ON T11f: ht V11.OrMFNT OF S1TES FOR
1'111N1('(/11N! RINI/IN(i IN 1111 11 fAL RRAIN
lhe sitrt for 1s1l1nicoline hinding in fetal braint a.tre raamined aflrr
Mmini.Iralinn of nicolint inlo p.egnanl ralt. Adminiatralinn of unlabeled nrcnune inln
the p.r6nanl tats in.reaaed R valura fnr Ihe tilet fo. /ritiated nicoUne himtinR
.rlMwl afftcting Ka valurs in Iht felal Mtins frta/meM with Ihif regimen, hnwrvrr,
.Inl /n.l thov any siRndi.anl (hangt in Ihr trlrt (ut 11f/Fluinuclid.nyl hrnrylalt hrn.lbnt
In sAdilinn, trralmenl with Ih.s reRinstn incrrased R valuef of Ihe srtrs /ar
(r/I'nN'o/1M bimkn6 rn Ibe hrainm nf (nrtnant raa n RvnRaroluain had nn rffeal nn Ihe
t.les frn 1'111nnoline hindinji 1/ n inlrrrtd, Ihrrrfnre. that a timdar resronse n rlartrd
by nrralme hrmknt vtrs lo admrnitlerrd nrcn/rnt in bo/h Ihe fr1a1 aml mslernal hrams
I urlhrrmnrt, a rnaa.h/e effect of manlmr in prrgnanl rals may he Ihe facslrlalnrn of the
.lrvr/npmrn/ n/ n..m.nr ur(ykMrkne rarlhus in the frtal hrain
//ntrnn NN and I re I W
fntrrnnnnnnf Iru.nnl nl /rr.rl.~mrnrnl N.u.n.r.rw,r 1141tih7171. 1'q1
1 rnm rlr Ikla.rmrnr d r r1h,1.. .n/ %r.n ruul Ib11.r llmrru/y uf Ir... 11ra11h
\..rn,r 1 rutr. ar \,o ~ne.~.,.,
llll'. R(lt IO1 MA11 KNAI NI(O1INf. IN 1111 UFVI1 (11Ma NI O1 Nlt IIIINI(
Al'1' 1 YI ('11r 11 INI' RI ( 1 1I(/RS AND IIYrU1/1A1.AMI(' IK)rAMINI R(il('
NI 11R(IN11N 111/ 1 1 1 AI. IIRAIN
II has akndy 1.cn relKnled 11031 delayed develurmrnt uf hyMrth,lami.
dnpaminrrpc (III)AI newuns in the felal brain cavsed a.k1ay of ald(rrentiatu.n nl
Ivulaibn arll. an.l rulwvly nnat in nlfsprinR of ralt 1 rum .b.rrvalinna nlrn,ruw1. .1
srrm% klcly tlrat ur.drrn.d IMV1utlanan111rrt snd/or M.rnwnet c.wid .nllurn,r Il.r
drvrhrnnnl nl II/sA naurunt am1 ddferenlutn.n nf prolnclin tells in .df.rrmr.
Prrhnnnary rraulN m.lnale Ib.H malrrnal and pbcrnlal acrvylaM.knr IAch/ arr111 1., a./
nn nnnlmn' silea In air. .Ir the nr-olinic aarlykhulrnr rraerlurs (nAahNl and in/lurn,r
the drvrh.pmenl of 1111 \ rnnrnna in the Iclal brain Ihn slw/y lrmis In Irnd surl..ur In
a wmlu.t hylvrtheara Ih.U nA('hKa apprar in the fr1a1 Main durinR an rmlrrr st.ytr nl
RraNlmn IrurmR I/.r latl arrL n/ Rrslalinn, m.Ile.nal an/l pl.xenlal A.1s aCl un naulrnw
srlr. lu a.lrvalr /a° flu. ohnh slunulalra 111)A neurons Ikr..uRh ailrahnn nf rrnlrm
1.rn..r and rh...rhnryL.b..n I/ara. matrrnal nis.N.ne e..ul.) iutl..rnae the Rruw,rh and
drvrhq.mrnl 01 /11rA nrurnns rn 11u Irlal hrain
ffetrnn N
1
In('x r rtlr, /,(:rac..hmi, /, and rawlet(i, R (eds 1 n.n/npmrrnd Nrur.... an. r
Pfa.r.dntoal. Iba.m(w.d..tnnl nn.l f'Grmrnf Asfrvr.. New Yo.h. I l.rvrrr Srrrmr
ruhk.hrrs 1( v, Ivt.. rp 1: vI lo
I r.nn the 11.parln.rnl .rf /'ellular anA }.ur(ural hrulo`y, The (Inrvrrady ul Ir.as 11r.rhh
Srnnat ( Ynler, S.rn .\ntonnr
js//jNl('OIINI. ItINbING S1f1.S IN D1 V1.1OrIN(i 11 IAI. NRAINS IN RAIS
1'atlNiculine bimling sitts Were esamlrvd in deveky.inR fetal hrains in rals lhe
fetal hrain mrmbnnes bourul 1s1l1nieo/iet with an affinity amilar lu IhN of sdull bram
menduantt this brndinR was diaplaced Iw unlahelyd nirmine or carAamyl.holine the
InhlhrlNM nrncentra/w+m bring aqwmin alely Ihe saun fru fetal and adnk h.ain
fnrparalions o IfunRarolnin 11ad 11o ttlr1 in 1s111nn:o/sne bindrn` tu (rt:d hrarn,
tntmManes a, arell sa In 2.11111 hrain pteraral.ma. Ike s/v,'.fic 1t1l1nic..line hind.nt was
tirH .kleclabk on day 16 nf *eslaliun aml in;aaarJ uverr/ 1.kl untul bnlh
Suciyama, 11. Ifntnvr. N, Mr.nre, (i., aml I tt, f W
Ncwoacr.n.'r Rr/rm.A 2:117-192, 19lS
frum Ihr 141.arlmrnl nf l'r/lulsr and Suwlura111inWRy, lh: Ihu.rr.rly uf 'lrua Ilr.dlh
S.irme ('rnlrr al San Anlonio, nd the I*ltarlnwnl of (a11u1.n 1'hwnrk.Ry, Ndn.nal
/nslNWr ul 1hyarolnr.iusl S.-ien.es, OharsAr, fapan
(711ANIN1 NI1('1 1(1111)1 C RIG1/1 Al l('11r1/11S/ AN('1 P IIINUIn(, IN R A 1
SMAI I. 11411 S I IN1.
/he hindmt nf 1'IlhuMtanct rmrmManrs of Ihr r..t .mall mrrauor
drnvrnauales srrc./rc hmdmA lo rr.rphus hav.nR n:o.r lhan nnt alluurr t,. \I ILr
values nl Ihe h.nd.nR rarau.rttrs fnr Ihr h.th a/lrrnly ult rdr.untd Ir..v r o..n I.nr u
V1
~
rrRrr.sion analyus are as folln-s K 1. - 0`S nM. P - Ie0 S fmnl/mR prnlrin
Inh.h.t.on curve. .d 'IISP h.nd.ng usinR va.uws unlatwlrJ lachyhinins shnvv /hat Ihr
hrRh affinity rrcep/ar rs nf the P suh/ypr, hav.nR Ihe h.Rhesl affrnrty for SI and M.vrr
all.n.t.et fnr etrdnvn anti Lattinm /:uamne nuclentnks anJ s.al.um indrlwndrnlly
redu.r the h.ndmR nf 'll ]P In the h.ah affinity receplor in a dose rrlalyd mannrr, (i1P
anJ (:1// arr m.ure (-trnl than GMr lhe rt.luclinn of speci(k SP MndrnR hy (i IP can
he aarJed pr.mardy In an rncreau in the off-rale lhe effeclt of Ruanine nwlnn/rs
..n `II CI' h.nhnR h. memh.anrt of ral smatl inlestine suRReu thal Ihe h.ah allmity
rrrrplur is l.nsr/ t,- an ellr.lnr I.y a(:1 P hrndrng regulalowy puIrm
Sm.th K 1 and Il.n. W r
Rraulnrnr PrMrJrl I1 :15 215, 1V/IS
(hAr. .url...r Nauonal Insldu/es of Ileatlh
lrnm the ('rnler hr 1ha.n ReMarch (1ni.ervcy nf Rochesler. Ghmd of MrJn.nr and
IAm..uy, RaArarr, N\
(-IIARAI'ItR1/A11/1N(tl MI/S('ARINI('('11l111NIRf:ICR1('IPIURS
IN IIII IIRAINt()1 ((/1'PIR11111/11N1 RAIC
In tnder tu asarss a rynsrhlr rdr fur eupprr at a rrRulatnr of muxir.n.c
rrceplnrt rn .n.n, the rrce(lur was rhNxttn.rd in rals ma1r cnplwr deha.rnl bv a
cl.rlary rrR.mrn In fruAra.n rrRn.ns thrre .at a Aruease in Mdh 11.e affinity nf Ihe
rc.rpl.ns lur )91) 1 q.unucbdutyl Iwnn/atr aml the density nl reKeplmt in Ihe
Cnp/wr drlp.rnl ammal. cnmlV.ed ..Ih c..ndo) anunal/ Cnpper lrealmeol rn varu nf
hnu.Renalr. /rum drf.uenl animals d.d m.l rerlte the rn a.ro elfecls on anaR'ma1
bunlmR hul, rathrr, deueated rrcrplnr occupan. y and t.Rand affinity in a mannrr sund.u
tn snplwr Irealmenl of conlwl humnRenalrs Mimmally drlnrenl ralt draplayrJ very
umJar changes /n re.ryrtnr properl.rs enmparrd with Ihe murt uve/rly dfrclrnl
ammals Mim.nal enp(wr Jefrciency pr.uluced rnhutt tffecls tin the hin.ImR uf acnnn/s,
rncrea.mR 111c6 and .Irr.ved d.ssoculion ennstants Ihr ad.Lt.on of crM'1'rr to Itr a.say
medlum caused an apparrnl revervl of the m..... effect of crq+fwr drfrciency un apnniq
IbmtlnR, deClratint II1r. and derl.ed dissociation conslanls to values Mar thne olnrvved
...Ih InrrmRenales from m11m.t) animals in the prnence af cupper. Xmce cnpprr
drliritncy has dramalic effrclN on MNh receplor numher and Ihe bindinR of aRnnisls to
muscarin.c recepwrs in the eentrat nrrvous sytlem. it is suRIealed that e(opper. Le.auu of
ilt ability to furm cuml'leses with tmne prolr.ns, may have an rndoRenous rule in the
rrRulatinn uf the reseplnr
Ianar, I R, l/ncl. W. Itrrndon, R M, and K uimiak, M
.
lIb /rwrnbl of Nruro.nrnrr 3fU)M{1 1010 1911
prArr lupfvor Naliunal Intlitulet of Ileallh
/Yorn the ('rnler f.nr Prain Research, I/nivrrsdy of RochrVrr Srhnnl of Medicine and
I/enlislry, Rnchester, NY
PR1/I11N PII()SPI1(IRY1 AllON ANI) NIIIRONA1. Ft/N('tN/N
SIUA.rt .n IM pa.l trvrral yra.t havr pr.widrd Anrrl ev.drncr that MIr.n
phutph.uvl.a.un .s .nl.ed m the .raul.l.nn u( nrwunal fun.l.on I(r.U.I
phytwdn`ical rcprriments havt drmonstraled that Ihree distincl claases uf p.utr.n
11.nases, r r, cyclic AMP-dependenl protein hinase, prolein \inatr (', rnd ('aM \ina.r 11,
mnlulalr phys.olo9.cal prncessn in nturunt. ('yclic Ah/P-drpendenl prulrin h.na.r an1
Gnase C havt tren slm.n to modify potassium and eakrum channels, and (aM Lmase II
has heen sho.n to enhance neurolransmiller releaae. A IarRe nurnher of suMualrt fur
thesr prulein Linases ha.e hren fouml in neurons In sorne cates (r c, tyrnsine
hydroaylase, acr/ykholint receplor, sudium ehannel) these proleins ha.e a\nuv.n
furKlMn, .rhereas r.unl of them (rs., synapsin 1) had no Itnorn funilion when Ibry
.ere f1rs1 wknlifird as phosphnploleins. In /he case of synapsin 1, av.Jen.e nuI suRKests Ihal .t
re/ulales neurnlransmrtter rekase -Ihett stw/Ks uf synapl.n I suKRrN
Iha1 the eharacleruali.m uf previously un\m/.n nrutonal phosphoprwemt v.dl Ira1 tn
the tlucidatiwm ul previwwsly u44nown reaulalury processes in neurons
Ilrn.nin`. M 1) . ffueanu R., and CreenRarJ. P
l.wr.nnl n f Nro.r Armr.e. r4t(1)11 .11. 1985
OrArr suprur National Sc.ence Ioundalurn, II. S Public Iltallh Srrvrce an1l a conlra.l
frnm Ihe 1/ S Air I wce School of Arrrnpacr Meditine
Irom Ihe lafuratnry of Mokeular m/ ('ellular Neurus.renie, the Nwlefr/lrr
(lmvert.ly, Ne. lbrk
1 I I 1 C1 111= NI(-(f11NC ON ('1 R111RA1 PR(sl l IN MI IAU(lt ISM 1)(1RIN(:
I/I.V11()1MINf
Several studies on the effeels of nicoline un fetal Kruwlh ha.e sugRrcte.l Ihat
altered prnlem synlhesis is the uaderlyinR nuehanism of chanKes in Restal.unat IrnRllh
6rain .vriRhl, m hthriinr (tiscrepancin .ere found in Rrutt elrw'lural chanRrs rn a.mr
inslances fetal sire and Main .eighls wert nIN frwnd In he ddfrrenl a/1rr r.p.nure In
nicoline. IloWever, nwril resdls Im1w71r hehavioral c'hanRet in the ollyninR Ihe rradt1
presenled helr sugResl that nicnline does alfecl eerehral prolein melalyd/sm in Muh
devebp.nR and utuh Main. Ihete researchrrs eaamrneJ the rales of prolrrn meul.dr.m
in the uffsprro{ ./( rals adminn/ered nicolint during gesta/um In assess .rhelhrr chanRrc
in weighl nr prulein content occur and rhrlher they are relalyd tn allrcal.nns nf protr.n
melaMdnm Results shocred Iha1 Ihere t.ere no Itross m/u1/hnlng.cal chanRrt ul Ihe
nffspring of rals adminislrted ni:oline during ipes/alion. ('nrllcal anti cerelwll..r brarn
avritihls were similar In eon/raA values at 2 aml 4 Aays afler hirlh rlulal prnlrm c.mtenl
.aa alsn trmilar Iluarever, measured synlhrsis rales were /(y% and 5% hrwer in c.atr. ul
nwolrne-lrealyd animals as 2 and 4 days a(ler hirlh, respeclively ('alculaled IIrR1a.L11uN1
ules (percenl synlhesis pet h minw prrcrnl pru1rin inctease prr h) arr Iherefu.e hrwer .n
1he nicotine animah /n accnun/ fur Ihe IacR of change In protrm inara+e in d.rse
animals Iherrfore, on the basis n( Ihis slwly, N appean that nrcnl.ne In/h.enrrs Main
funcliwm, and that prolrin drRradaliun and synlhrsH prn.etses in /r/a) nev.lr.rn ral Iua.n
are affec/eJ by n.coune.
Srrthrn, 11 , Reilh, M 1'. A, and I a/rhe. A
InCaciaRli, F., Giacohini, C, and Panlelli, It. (eds )
Onrfnpnrrwraf N.~...nrnrr
rAru..fnpra+. rbormwdoerr.f ond (-f.nrre/ Ar/rnl, Ne. Yort I Itrv.n Sa.eme
Pul.lishers P V., 1944. pp 119-122
Irnm Ihe Cenler for Nru.nchrmntry, Nathan S Kline Inuilu/e f.n Psyahua/r Re.r.ah,
Ward's lt/and, New Ymt
Q 91
NI(T)IINt RININN(i SITIS IN BRAIN
ln the raal 10 yesrt, many attempts hsve been made tn iArnlify sitra in brain Ihil
hind lahrled nicolinr lluwever, in Ihew sludiet no ruimat.nn waa made of aalu.ablr
vrrsus m.n-aatunhk hin.lmR Mnrr recenl studies thow cu/villneal ticalchard rl.as,
au/Rra/1nR the prrarnre n( multipk sllrt Nn-M1nK rIr mwKarlnli antarnnial{ h.lvr Irlllr
nr nn affinity lo Ihr h/mbnR allr, which has hern suaRested by Rrnnla/wo and (:oldarin lo
he due 11s an aRun/at-mdlneJ sh/fl of Ilw tecepl.w In a hlgh allmdy afnnr.l arh0lvr
statr lhe l.netics o/ LnuhnR imltiale a hiRh-af(inily componrnl wdh a K 1 in Ihr r:mrr
u/ 01 AO nM, aml a lwalflnily cnmponrnl w1lh.ffiniliM Ihal vary wwlrly fruta ..nr
p.rparatw.n in annlher Ihe presenl nnvestiplors have corrp/a.rd lhe hinJ:n/t d (/) 1'/1(
nicoUne sn.l (911 s:rtyl.6nhnr /n varirws bain reRinnf Aldw+urh mldhrarn almwrd Ilw
highr.l an./ .r.ehellum the hlweal hind/nR for both nrco/ine and a.rlyhhuhne, /hr r.llwr
n/ ni.ulinrfacrlyhhobne hmdmR thnwrd a 11nee fnld reR:nnal van.wwrn Ahh..oRh
Iherr la t1.t/ mu.h varnhdlty in Ihe rrudta nf MmlrnIt sludrra Irom vvu.ua Lllwnib.nr.,
nl:nlrnr huu/.nR m/u.lm .a pr..hatAly nnt udely rrla,rd to the cla..wal nnnlrnr .r..rl.n.
Mullqde MnJrnR adra have Iwen rrp.u/ed, tnd may Iw rrlale.t 1.. Ihr muhrplr rl/r.l. ..1
nµul.nr un 11/e .rnUat nr.v.wt tyslrm
4nhrn, /1 , K.r1A, M I A, and f nlrAn A
/n ( rn wel.n I L.n.,.Mw. F n..J r,M.lrrn R f.,l/ ) llr.r6.Pm..naf N. r....., r. n. r
YAl.rnrr,nl 1A.n..,n...R.rr.nl .wJ (l.nwul New \lr.\ Il.rvu-1 % .un.r
1'uhh.hrrt n v, 19al4 rr 1.1 110
I lnm Ihr (?nler tnr Nrur.qhermany, Nnh/n \ hlhnr In./dutr Inr My.luHr.. Rrar.w.h,
WauPt laland, New Y..rl
IK1I KAItKAI h1I1t1At11tA111KA1/tfN\l/1 1111 S\NAI'\I
rrrv4.us wnrl Irurn ,hl. IaMnalnry drn.nntlralyd Ihi1 in Ihr frnR Cululenna
Leclu.is nrurnmuscular /uncln.n, synlp/.c veanlra .an I.e Indu/rd lu revrrtrMy luar wuh
the plama memhrane of the nrrve w-.mind hy thr appl:calLm nf a K.nRe/t alul/on
contauunR 11) mM K' rrrKar.nale an.t 11111 the ecpnure nf this ralernalued vr'.lcular
mrmbranr Iu hnrsera.lnh perotnk (IIKI') kada 10 vesieutar mendnane alleral.nns Junnr.
rrryalmR Simdar IIRP e.poture of the synaptic vesi.'Ie menlbrane of 01 mrn cr/rl.ral
cnr/tt atlces resulls in Muh Ihe rrductu.n nf h:ith-affinity (rt(') Ramma am:mtl-ulyiic
xid ((iA1tA) uptake snd in easi/y dittmRuiahahk ve]ieular memlwane alteutlnn' after
tety.l/n{ nrsin di,rs indially incuhmrd fnr 6(1 minules in drpdari/inlt IK') btd/er
eonla/ntnR IIKr. Inunwed by 60 mmute ineubalir/n in 111 P1.S (synaplic vealsk
recnvrryl, rchrb.l a 1(t'll reduclmn ot (/'('/(iA11A upule and the apprarance of
m.nasnaplic vesick mrnlMane rn Ih+ nerve terminal lhr cumb:natinn nf thesr
mu.phnh/lilctl snd hrnahrm:cal dalu p.Mt In the ecnlrnct of s relalinnahrp Lrtwrrn
hl(h affinity neuropansmitler uplalr and synaplic vetMlr nwmhranr Ihr fail 1ha1
non K* sllmulatrd crrehral eor/t slifes (nn ssnap/ie vnwiep/sama membtane (w.n.n)
which asr r.lwnrd to IIRP (in 11/ rl S) fnr 60 mmules e.hihil no rrdu.ln.n Id
)/r( 1(7ARA uplalr IndWates that (usrd vraick membane is susceplihtr 10 IIKP danlaRt'
and that damaRe to Ihese membranes sllrrs the neurwlonamrltrr /ranalrn/ ayatern In
mdn In iaolate and Lrurr sludy Ihe funclinnal synap/ic unit, synarlaamors (ce.rhral
Curtet) wrre prrparrd and e.pnsed to IIRP In the aMence nf K'-dr(wduralion,
tynaptoanalra rel..nr./ a. IIKP fur A/ mmulet Ulr up 70% kas ("(/(:AIIA (/baervallnn
nl It.rt 11It1' InJ.u.-A vdurt.nn nf ayn.rlaa.ma/ nrurulran.n..lter uplalr in rrla.un to Ihe
t
IIRP-induced synaplic vesick membr.ne silerations observed in mouse crrebral .orlec
slices tlu/Kart that the plasma membanes of Ihex isotaled synaptosnmal unil% arr
Ihemselves suscrplilde to 11RP-induced damage and that the danlalte ot Ilns mrrnl.ranr
slsn sllers nrurnlransm111er up/ale
(tq+ler, 1: A., Sershrn, 11 , L.plla A,.wd Grnnaro, 1. F., )r
Annnh n/ tAr Nrw 1rrA Aralrnrr u/ Srwnnt 41t_N0-144, 1984,
1 rum the Ikpartmrnl of Biolnly, New York (/eiversily, and /he 1'rnlel
Nrwr.cbemntry, wards laland, New Yor1. .
I NINI(:1 NOUS MA11 RIAI IN BRAIN INIIIBIIING 1'/1(NIfOt/Nl ANI>
1'11JA(-1 I V1 1-11(11 INI IIINUIN(i
I.n
Ihe wprrnatan/ nhlained from rwouse bain homoRenales Canla:ns .natrrr.d th.n
inhrh/tt Ihe salurahk MndinR of (qt)nieounr in muux certhral cortr. IblI luh.h.l.ny
mater:al wat lurlhrr pun/ied by heat denalurs/ion, ultrafatra/inn IhrnuRll an Ao.an
1'M 10 mrnlbnne fdler, and Rel ehrumaloaurhy un Sr1+hadrt (i I(/ Ibr malrn.l/
inhfirlyd Ihe hmdrnR of )r11)scelykholinr with Ihe sanmt pAency as it dld [h,u o/
(/I1)nKaline 11 alv.* had frwne affinity f.N the tites that sprcifovally hulA 1/11111 Ata,
11 1 ru rnlrphalm, but had much Inwer a(linily for /hr hin.linR til.t (or Irrfralyd
trnrnudi/hnyl hrnnlale (()1'/n1, apiropr/i.hd, nahnunt, nr imipramme A.ul hv.b.dy.n
draUoyrd the aalivhy these prtliminary cesulls tuRRes( lhe p,r.rncr m brIm ur
'mcnl.nelde' sldnlancet, one nf whi.h may be the emlukem/us IIRan,l Iw Ihe snra Ihal
al.e6fw'a1lY bind (rllalwnllne.
tieral.rn, 11., Keilh, M. I A., Ilaahim, A, and I altAa. A.
l..wmd a/ N.uro.rrrnrr RrtrarcA 12(4)SA15h9, 1984
o1Arr suprynl New Ywl State Ikallh Research ('ouncil.
I rom the c enler for Nrucnchemislry, Nathan S Kline Instilule ful Paych/atr:c Itr.ra/rh,
Wnd's Ialand, New 1orY.
(YNMIrAKK()N(11 1IIIINI1/711NF. ANI)/s11JA(I IY1(11(111N1 IIINI11Nti IN
M(f11.%1 111:41N KI<:1(/NALUIS/RIOUII(rN
lu a.unlluuin/; slu.if nf n.:nli.w binJinR sitea. Ihe au/lrnra .1. trrrnrnr.l thr r.l/l.vr
awlnuul u( maut.nr LInAnIR alwf acelyhlwdw.. brn.lmR in a.u.nwa In.un rr/:.nna .,1 /\1,/1)
au1 .u UI/A nu,r A/dwut;h m/Ab/au1 al.nrd IM' bq'..1 anI r.l:lwIlum d.r hw.cn
'twJrnq /or Lnh ('11111NnU/,.. .,nd )/II)NI'/yhlnhrlr, Ihe 1,IIU u/ to a..1'1. twbnr
Inod.nK dn.w..l a Ilurr L/I I IcRwm.d vnr.unp A.r1y1.IL.bnr tuh.Lqa.w /d t91(nn.d.or
I..un/mp ul.b. /t..1 Ih/t a r..uo.n of Lwrnrol h.nd.nR ..... n,.1 ud.dutr.t by .artll.l...l.ur
Ih.r /rnh. LNInIlr In1/VNl,ut dl/lrr.u,r. Inlwrrn Il.e Ln.,ln.g ul (t) 1'111..a.,ln.r
..n.l
11./1 .,1
1r/1 , K, nh, M I A, 11asMm, A, and I up6u. A
RrtrarrA Cummwru ntwm sit (-Arnlwd Pnrlwlaffp anJ rAu.nra o/nRr loIq 11 1-I S 1. `, 14I1
11om the ('rnler for Neurachemit/ry, Na%hsn S Kl:ne Institute fnr rsylln.llln Kr+e u.ll,
Wardt Island. New Ynrh
91
'!J
1(K'A1 ANI)CVttIMIC('APSAt('INrR11R1A1MINt INIIIIIIISSNFI%IN(7
ANts 1111 INC KI A11 IN NASAI VAS( 111 AR Pt KMI A1ft1 11 Y INI)(I( 11111Y
(-t K 1 A1N ('/ll MI(-AI 104R I t AN tS
I lhe efrect+ nf 4.ca1 eapnsurr to chemicat irritanfs and mrchamcal uimnt.rbnn
nn SnerrinR rrfle.rq haa Iven stndad in nnrmal and capaaic.nprelrralyd, c.enacwus
Ruinta Pqta Ihe mllurnrt .f htial and syatrm.c cspaaicm prelrralmenl on aacular
Lrcn.rzbMhty in ptaama padr.ns and Ihe cardinvascular ef(tc(% nf local application uf
capaarcin lo the naaal n1lKnla have alln hrtn sladled in aaae\Ihe11/N1 .1MmaI4
2 1 r.cal aPlW.a1wm nf capsa.irn Ith.esMdd dose ) MM/ , nranthne (lhreah.nld A.ne
1(lq rM) r f.rmahn lu Ihr nasal mucnv induced refka snetrinR .haaharRts Syalemri nr
hwat capaic.n Pretrralrnrnt ah.dnhrd w redueed the tnerainlt reatw.naes to capsa.un an.l
fmmabn Ihe rtapnnme lo nKMme wn Nso reduced followinR hwal prelrealmenl vith
capss.crn, whde the rr.p..nar to systtmic prr/rratmenl wrth capaaicin was only aliRhdy
a(/ta/rd lhr sntenna .e.panat 1.1 nshhanica) stimulalan was nor alfecled hy aalnaic.n
prrl.ealment
1 t4elrtalmenl w.lh a Mcat anatslhr/ie induced a simdar dosr-deprrnMnl
inMbiUnn uf Ihe snrr).nR reapnnses to Iw.lh eaMaiein aad nieol.ne.
4 1...a1 appl.a alinn nf drsnalium crmmilRlycale in the na.a1 mucosa reducrd Ike
snernnR reyw.nae lo capaarcrn. AuI anl Ihal in nKoline
) 1 ocal prrueatmrnt with the \ mM and 110 mM ealnaicin sotulinn inhihded the
increaae in vaacndar prrrneahddy in plaama prnlrino in Ihe naul muema imlueed by i v
rapaaic.n Inca1 prtuearrnrnt .ilh capa.qm 41141 m.l teault .n any rrductu.n in the
aapaaicm indahrJ (rnnra)vMy in Ihe urrtrr, auRRratmit Iha1 auch trralmrnl dx) nn/ h.le
anr map.t syalrmr~ t..nc tllrala
/lurever, a am.dl, a.ulr nc.raar .n rrapuelory .nanf/taaun p.raaurt, mdrealrnp.
ha.neh.K'onarr.thun. .aa arrn .hen thr InmK1 aaPin.n a.d.rtnm .aa apPLrd lo Ihe naa.d
mua ..... I hr appl.a a...n ./ ...p.an .n 11 n,Kl and In .nall l.r d.e ni.:d mua oaa reaultrd m
an rncrraae in a-lr..d (d.wrl ~puaa.ur u..l I..hl, u.l,a dur /u rrllt. avnrp.NhrlrC
acl.vat.un
A 1.pnaurt of nnrmtt Ruwnra pq. /., an a.nu.a/.hrrr .dur1ted r.lh rlhrr aan.rd
e.crlyd aanalanae brhavrnur and mrrn.r n...r rynr. -.rh /hr I..rr In... Ih.. rnl...mr
araa ahdnhrat by syalrmr, p.elreat.nenl ..rh a.paan rn an.l rrdua rd 1.a hw al
INrlrealmtnl
1. I nca) aMdraal.nn nf wenh.nrn, hrall.nine, lrnkolrrrnt (a hradyl,man,
phensldaRuani.k, suhatanct P(%P) or /d Arli, d rru, d erp, I wfSP, an,l \r anlaRamal-
di.1 mrt mdu.e any aneetin6. 11iRh cnncen(ra/inns of compound UIIRO eaused a amall
,neeainil rearymse I ncal prelrealmrnl with Ihe SP-anlagamial (7 a 10 411641 diA mrl
influence the snrelinR realr+Mts to n.culine or capsaicin.
. t. 11 is concluded Ihal only substances that are known to activate srnancy nerves
induce sneennt I urlhermore, Ihrre seems to t+e at kast Iwo types of afferenl nervn in
the naul mueosa whrch respnnd in specific chemical irrilalarn One /ypt'.
eapaaicin-sensilive nervra, which respnnd hr ca(naicin; formatin, ether and nicot.ne,
while am.lher type uf a(ferenl nerves involvtd in sntennR refle.rs is largely rea.l.ml h.
eaMaicin prtl.eatmtnt and is activated by nicobne 1 ncal applicale.a nf capaaicm In the
asaal mucnaa may IhNa he a selnlive way nf redncinji nasal rea.tiv.ly lo cerlam chmicvl
irr.Unla wrlhnul eausm6 syurmie deRrne.almn of capsanm sensitive r fihtr afhrr+ta
I un.lhtad. 1. , LwJArra. ! M. and Anjipard, A
Ar. M.t. nf I Aacmacafnet 116 7)1 761, 1994
f/rAn .uprywr Swtdlnh Mrnhcal Rrararch Cnuncil, 1hr Swrdnh lnhaccn ('ompany, Ihe
A.va 1 nundal«.n, tM 'o-rdnh Va.rry o/ Me.6ca1 i. wm r, and da I undo nf the
Kar.d.nala In.r.a..r
t
1 rom the Uepartmenl of lMo-Rhino-1 aryntinlogy, K srnhns\a Ilospaal, and Ihe
brparlmenl of Pharmacolo{y, Karolinsta Institute. Stockholm. Sweden
Ft Fl CTS OF Nt I/ROPFP710F Y(NPY) ON MI'Cl1ANICAI. ACf1VI1 Y ANI)
N11/Rf)TRANSMFCqON IN 1111' NFAR1, VAS 1N-1 FR) NS AND I/RINARY
RI.AINII R O/ tlll. (:1)INF.APtG
The effect+ of preincubalinn for 10 miw wilh lynthelie porcine ntaropep/.de Y
(NPY) on musck lone and aalnnonlic /ransmission in the 9Yinea-p.R riRhl al.wm, .aa
drferena, urinary Aladder, parlal vein and /cachea were andyxd in varo. NPY induaed
a meloprololresislant, lon6laslin6, posilive inolropic and taonolropic effect pr .r m
the spontaneoualy btalin@ righl alrium Fur/hertnnre. NPY caused a revetsildr mhah.(rnn
nf ho/h the mehy.rolol aad auopinesensitive auricle responses to field sUmulat.nn 1' Ifc
or /1e (nr 2 1) wnhoul alfecUng the response to ewgennus noradrenalme /NA) m
acelykhnline (A('h)
NPY did mN induce any cnnlraclion of Ihe vn deferens, but inhihiled Mnh /ht
rapid Iwilch response and Ihe sutlained lonic enalraction induced hy field slimulaunn
Ihe NPY-induced inhihilinn of Ihe bnic cnnlra./w.n was ttqre hme lasling than Ih..n ol
(he twitch response The lonic conuaclinn -as blacked by phtn/olamine and the Iwnch
respp.nse by n, / nstlhykne AlP lachyphylaais. NPY did nol inhibit the conlracl.k
effects of NA. AIP or ., /-melhykne AIP NPY also induced a reversiMn re.lur/..n
of Iht non-cMihnerRic, nol-adrealergie cnnlraclik respnnse lo fieM slimulatron uf /he
ulinary blahler. In Ihe porlal veiw, NPY (up in 500 sM) did anl inhibil Ihe at.mtanrnul
molitily m the phrnlolamineselni(ive caalraclile responses lo field shmulal..n and NA
Ike tlfopinr-fensilive conlrac/inw of Iht lrachra or the non-Nlcenrrtie, ruM ch.drnt.l{K
IelaaalMn /nducel) by field stimulation was ruN srRnificanlly influenced hy NI'V in du.rs
up lo 7.10 'M In eonclusinn, Ihe prestnl dala stur+ Ihal in Ihe guinea pi{. NI'Y e.erls
pnsitive chrnnolrnpic and inoltopie efftcls on the riRhl alrium u( Ihe heal
I urlher1110R, NPY may have prrsynaplie effrcls un nlrenerRic, cMdine.t(.c and
non a.IrenerR.c- noncholinergie nearolranamission.
1 r.nJfrrR. J. M, llus, X-Y-, and Franco-Cereceda, A.
Arca IhpvoloRrca ScanJrnarrca 121:)2f-)12,1014.
f)rMr suppncr: Swediah Medical Rrsearch Cnuncil, the Swedi.h lobacco ('nmpanv, Asha
I uundalion, and Ihe K arolinsha Inslilule.
Ftom the F)eparlnwn( of Pharmacology. Karnlinska Inmtitule, Stnchholm, Sweden
('AMAI('IN-INtllt('1 1) SI /MI//.AT/()N l)F "1111- (i1ItNFA-rl(i A 1 KII /M
INVOI VI MI N1 ()1 A N()V1.1. Sf.NS1/RY 1KANSM/I 11 K lIP A 1NK1 ('1
M' I Il1N / IN MY( N'Y 1 LS?
1. Iht mechanism rnderlying Ihe prnilivt innUopic and cMumrNnpr: r//t.n n/
capsaicin were investiRaled wml Ihe sp.mtaneoudy beat.ng Ra.ntap.R alc.um /n ..a..
2. (-apsaicin rnduced a bnt-lasunit stimulalury effnl (IArtahnlJ duae K)vMl
Trlrodo/nsin, phenlolamine, 6-(NIUA, mepyramine plus crnaud.nr, mtthsarrllnk ,
indomethacin-, somalostatin- or n.orphine prelrtalmenl and local (realrurm with
capsaicin on Ihe vap/ nerves did ool reduce (ha espsaicm rtsMnst, +h.k it was
aM.hshed up lo I month af(er sys/emic cspsaicin prehealmen/
/
I Ihe capunin rr.(umtt wat tuhlrilln a rat..d 1aahyphyl.r.1. IlurinR rapanrn
LlahyphylA.ua, the Ir.aH..f nnirnp.c an.l.hrnn..lrnlai ef/falt ul nmabrnaLnr, trlnunm
an.t h.al.Nnrne we.r um hanRrA
1 Valroua nr.u.,tvpl.drt wrlf In.eal.RaleA wilh reRald In iavalof 3.1u1y
rhya.Lvnun flrAunrn and aumantlslm had nrRalra inntrnp.c and aluunullnpn rf'r.la
tuhal.v. r r, hNnhr.rn, l.la.mn, /( K A ur Plll (up In 10 s M.d r.trhl dld nn1 ..lu.r lny
Arlr1.d4e Ir.l..m.r un /hr Ru.nrl 1.R aur..lr, rhik Ihe suhalta,r r anl (1/ Air..
U I'ro 11 /rp, Ir..rl' mJuard a L.nR haunR ahmulalion nl hra/l a.lr.dY V/1' ah.
tiM1mlAatr,/ 1hr hrarl
1 V.Iruua aArnyl anmpnundt were ahn tested AAenn.me, AM/',
AIH',
AlP
and /t_, l.melhyMnr A 11' haA neRatl.r ahronninpie and inotrur.t: rlfecla, wlul. n,/t rnrl
hylrne A 1 r /nJu. rd a sllmulauny retpnnse /)urinR n, /t melhylrnr A 1/'
ta.htrhylaaa, the aurNlrs sui/ rrslumded In aaptaicin the inhitunuy r/lrilt ol
adrm.anf anA AIP auahRun wfrr antsRonirrA by Iheophylbne an.l a p udluphfnyl
16r,.phyll.ne ( apa.N.m /n.lutfd a sma11 rrlraaf of 1a1rh-A nwlrhdra
/nnu '/I11 aJtnme pullhelyd a1r.a frnm ennlr.d, hul nnt (a.m ...pa.Na.n PIr1.r.NrJ
ann.nala
6 (:11', aq.a11a1r and 6amlc crd (up lo 10 rM) haA m/ rffecl un Iht Ruinra pIK
alr.um, whdr Rlulumalr L,A a neRatrve nolrnpK aclwm
7 In a-..n, lua.n, the prrarnl f.ndTRS ahnw a tpecifie slimulalnry atlinn uf
calaaa .n on heaal / un, Lnn 1 h.t r(ffcl dufs ruN aerm lo ht IneJUleat vq any elatsp al
UanamdVt, /mlaA.na auh+lanre P aml A1P 1he cartati.n reaponse was ah..h.hrd by
rapa.N./n yrrlrra/mrn1, wh..h it Innwn 1.. Cauaf ./r/rnrra/u.n u/ .'Lrmn.rmilr.r nrrvet
rn Ihe LnN1 Il..a tup.ralt Ihal tapa-an.n n.ly rrlr.l.r .lhrr h.na.lrvr auha.ln,rs Ihln
suh.l..nae+ 1' Ironm arn..nv nrr.rt A dural a./.n.n n/ Calaai..n .n c.uduc mYhyl.t
tann..t M e.aludrA A1.arnvlvahnn 1'hrmmrn.n wnulA Il.rn al..% rwiur nn tanaddr
rr.rrl.ve salrt tnl 1.lr+a.,rn nn Ibe my.r Ylra l.q.a...N prrl/rabnrnl Inay Ih.ua mda,r
.rry lrnR ILnnR, +pr. d., , luntbunil . h..nKra In hr ul lanil.un
f onJhr.tr. J At /lua, V, anA I reJhulm, II 11
L. Ar.ra of PA/.r. 12S 176 147. 191141
f4A,v .urtrur SweA..h hhrAical Resfanh ('uoncA, the SweA..h lnbaca. ("nml.any, the
Il..na nah I rn/ (i^ler.Nant I uundAll..n, ll.f A+tra I uun.lalian, and Ihr Karulmt\. Iounu/e
I rum the Ilrpstlmenl .4 Ph]rTallAu~y, Ks.uhnaSi Intlilule, ShlhholT, SwrAfn
f'(7MPARAIIVI 1MA11/N(71t/SIfK111 MI(AI ANI) II/IX'lll MI('A1. ANAI Y\IS
111 1'AN(K1AI1(1Y11VPIr11M 11K/ 111'111/1SWll//SI'1/"1At.RI11KINtI
Il) /'RI CI N( 1/f/ NI IIK(11'I P11111 Y IN ('I N I K AI ANI) rI Kir111 KA1 NI I IK(7NC
An//tr/a rahed aa/na1 IuNcine nrurnpeplide V(NPY) and /wplide VY (PVV) wrrr
chauetrrved wNh rrarA In ITTUnnhNUwhfmNal Ha/ninR, evo+s rfat//v/ly b. te.rral
p.tncrfalic frdylrplide (rrl relatfd prplnles, an1 radwammunna.aaYahlr aatur Irvela in
she r1 nA p/of Ihr NPy n11KruT /10)11) tfaalfd wilh nerves in many reat of tnNh
Ihe eenual anA periphfral nervous syvrms, bul it did nnl stain endncnne eelit uf the
4M panireat or inlraline Nn evidence fur any crnts reaclivity of Ihe NPY anlitfrum wqh
t)1 relatr,t prpl,art n( Ihe PP famJy, suth s .i.n Pr, M..me /'r, rVV. , h1C11,
- I h1R/ a....1r .r a..an rr 111 V/, w.a.11a.nrd It,f NPN " anl.ulmu waa N Irvmm.Jty
l51 .1.,.,1./ .1 ..s......1 1...1. ../ Nl'y a. ..rn h ...L...n..uun.,t.a.Y t'1.111,Ir,l
wrll Ihr
~ .., . ....r,. . . .. . . . .... . ..... , ..... .n .1., .....,,..u .h, .... I,. nu d al.,.t+
I
malerul from cereh/al cntlea and vs defeffnt had elulem prnfdrt s.mAi. /u Ihnar of
slandard p.ucmt NI'Y. 111t PYY anlitefum mainly slalnrd enAuir.ne .rlh in IIN
panirraa anA Inlesline at well as a small neuron sytlrm In the hrainatrm nl I/.r rAt
Althunt;h Ihls anlnrrum had a t1igh1 cruat reat/ivlty lu NP1r in radwu.lnwnu~avv. Il,r
nrurunal 1'\ Y slamtn` waa separale frum Ihal n( NPY II.Kh IrveA nl 1'N V wrle I,nu..l
m the Imraline, and kvrN ate.ve the IhrrahnlJ urlf alao ir'rn rn 1he dura:J v./R.d cunqd..
ul Ihf lal Iht 1Iher aMl.rra invesliRalrJ (raiaeA aRainN avcln I'P, laanr 1'P, 1 Ms,I/,
:u.d I h1K1 anudr) nu.ed nrurnn.tl slammg Ihal waa alydi.hrA by p/f.lb..arluo wNt,
NI'\1 hn wat altu aeen even d ml .klrcl.dde cnna rraiavily wah NI'Y w..t lound w
r.ubulmmum.aaay Ihese lat/et anlnrra a1... tlameA rnAncrine celts .n Ihr, ran./raa aut
.nlr.une with cumrk. eruts reaclivlty rrtaUnmhipt, auRRts1inR the presrme ul ntramd
PI' hle rrpudrt /n adAilNm to Pl'Y aml Nry
I uuJh,ra. ! A7 . lerenius, 1, IloF,feh, 1anA lalfmnlu, K.
I Ar l..nrnnl .'/ N, 1; 9 2176 21116, 1'/1U
(Irhrr Inpl.nl Kal.ul.ns&a tnal.lule, As/ra laun.latu.n, NAIn.n.J Inslil.de ./ NrwulnK.,.d
and ('ommunicale (bwrArrt and S/roke, and the 1/ S Nal.onal tn.ldWr ul M-m.d Ihe d/h
Iroln the 1lrpallmrmt of PharmacnlnRy. ILalulnRy and Ih.khrmiauy, Kar,dmJa
Inslilulr, Satil.hulm, SweAen, and the Ihparlmfnl of 1'h.ulna..LRr. Ihwrr.ny .1
I l/ya;da, Sw.Jrn
((IK111 ASI (71 VAS()A('IIVh. INIfS11NAI Plll YPI P111)1 ANI) 1'11'111s1
IIIS11171NI IS1t11'l/(INI.INRI'I.AIION 1UAfK/al'IN1 KI\1\1ANI
VAS()I)1/ A/1()N IN lAI S1/11MANIN/11/1 AK SAI IVAKY (il ANs
p.rasympalhelic netve sliTUlation of the submandlhular salr.ary RlAnd /n 16e tat
uusrJ tahary secreliow, vasnAilaliwwl and ctNeleast of .aswt/wf minlmal IrdyprpllAr
(VIPI and Ileplide his/i.liwt isnleucine (P111) rmTYMNY1Cltt'/11ft (llt) /nlo Ihe vfn.uu+
rl/luenl, as Indicated by an iwerease iw oWpu1. lhe ralio be/wfro Ihe rtleasrd VII' IK
am) 1'11/IR .as thrse b It. (:elpernsealil.4 chrnmatnRrarhy n( pl.ltma (lnm Ihr
suhmandibulat venous effll/te/ imlKated Ihal the rekatnl V11' /K aml 1'/ll 11( wrre rlr
1111111ar 1o IMNcrM VIP and Plll, tespeclively. A/lopine pttlrrauNtnl rnhan.rA uulpu/ .d
M.Ih VIP-IK and rlll IR duting the parasympalhelie nerve tlimulalnrn h. a s.m.l.r
eattnl (ahoul S-foM) compared hi cowlrul slirNUlalinrn. 7Ms /ncrrate cul.t.t IK .tur 1...n
inhibilnry presynaplk Tutcafiwie receplot /e9ulalwn of VIP ond 1'111 Ire:rae S.u.r VI/'
and rlll ue present in lhe same 17ns1olanifluTic parasympalhrllc nrrvft tn Ihe RI,/nA an.1
fwNh peplidrs have vtndilalof activity, the p/etenl da(a suII(In/ thal 14111. VIf anA 19U
may conlr/1/ule lo the alfnpille-re+ifUM usndila/mw seen uMn slrmulAbnn ol Ihr
chnrda-linu nerve lhe pafasymplhelie tonlrul of stivafy Rlam( /oni tu.n may Ihua
/nvulve TulaTetfen~et sysltT wilh the classical 1cntnu/urr aiflyhbulmf anA Ih..
pfp/ides V 11' and rlll
I unJM-.It I Af . I ahtent<IU(, f., I artNM, O , and AnRaa/d, A
Nrl..ornrnce I ftrers St )1.12, 1984.
Othrr wpry.rt P(b11 Pettrstn f Fund. NOVO founAalMm, SweA.ah h1fA.i at Rrarau h
(nuncll. SwrJnh luhacco ('anpany, Aslra lounalatinn, Swrd.th SKN/y 1- Mr,h..J
S, Nu.es, K arulunla Inabtult, nd SwfA.ah Palfnl Revenue Kr.r.ul h 1 w,.1
1. r . . . , , . , , . . .. . 1 ~/. ~. ./ . ....~~..~,.. ,. , .,..
-1 99
/T
W .
. lrom the lsrparlmrnl ef PharmarolnRr. Ksrnlintka Inttdutr, lkparlmrnt of
INn Rhino-laryn/bdnRy, Ksrnlmaka Ilatpdal, Stockholm, SweJen; 1)epmlmrm of
(l.n.aal ( hrm.atry, Iby.ehlrrR ILnpiul, ("upenhaRrn, 1)rnn.ark
('OMI'ARI\f)N OI (AHIHr1VAG-IIt AR ANn BRON('11(X'(1N7koIHIf'1f1R
Il/lc-1\Ir1 Stlh\IAN(1 1',SUI/t1AN('FK ANISO1111R IA1111KININS
I Ihe ellrclt .d tuMlance r ISP), subslawee K(SK), Lhysalarmin, rl.A..it.n,
kssainin, nru.nmrdm K and M.mhttm no blood pressue, bearl ralt, retpn..lory
.n.u/flal..m prrtturr anJ Idaanq rtlraqsa/mn were studied m/he Itumts piR
: All laahtk.nm, r.crp/ nrurnmrdm K csustd a fall in M.rrl prrsaure with rathrr
s.milsr IMHen.y Ihe hypntrns.ve rrs(r.nse afler physalaemin was comparal.vely n.o.e
lun~ Iaa1.nR
I \K and elydoisin 1] $ nrnnl s kfe 1 i. ) causrd an inilul hradycardia whn IA then
chanRrJ min 1a.hyra.d.a the nthrr lachykm.nt imluceJ a sh.wly dr.rl.qma
ts. Ay. a.J.s Nrurnmrdm K (ep /n 10 mmoot . ket r/ dd nol influrnct htact rsle
1 SK. kaasm.n sn.l elednivn were more po/enl Ihan SP aed phyularnun in
incrratinR respvat.ny insu/flatmn lutsaure lhe tlftct of SK had a parlia-ularly long
dura/mn Neurnmrd.n K only .nduced s wrak in.veate in imufflat.on presture al a.rry
h.th dnsr
3 All Ischlkmins e.crpl neu.nmedin K induced an incrtase in vatr.dar
permrahJny to platma prmr.ns in many v.yeral nrRans, as .nd.caled by ) vant blue
e.lravatalwn Ilhr La.hts and ureler wert the m.nl sentiliVe nrRans wilh rrRarJ to Ih.s
tllecl Physalaemn anJ rledoiun werr aenerally mnrt potent in inerrasinR vauular
permnhdAy .n var.oua o.Rans than Sr and SK the r11a.Un.ll per111eah/I11yIncrea:inR
tf/ral u( SK wat tmillrr than Ihal of SP, ailhnueh Ihe pulency was tm.ilar
A 16.ml.esm m.rrateJ mwf/latwn prraau.e with no cltartul rflect on vascular
prrmrroh.lay
1 It is enncludrJ /hat in Ihe samr sprc.et, re, guinea p.g, xveral /athykinint
have /alhtr simdlr hypntentwe acliun, while /ht vascular pe.mtahdily incresse 10 plasma
proleins is especially prnnuunced af/tr physalaemin and elednisun SK, katainm and
tkdnnin ha.e prnminenl hwnchaennsurc/ur tffecls Nevmmedin K, bowtver, dnplays
pmK aclrvily in Ihe preaent models. Iht t.istence of novel Iachykinins such ss SK in
aJdililm in tir in Inammallsa Ir41ue1 tuR`eslt Ihal effects sten u(Mn anllJrnnllc
ttin.ulalium of sensory nrres ma) ht eauted by aevtral slruclurally rrtaled prplwlrt
llw, X. -Y ,[ unJMrR. / A/ . 1headotsson Nmhe.m, E., and urndin, t.
Arrhnet of IllormaralnRY )!01%201, 1914
nfAer tuppnrr- Swediah Mrdical Rnrarch CouncJ, the Swedish tobacco Company, the
Aalrs Inundalion, anJ the Kacnhnska Inu.rute
I rnm Ihe tMparlmrnl nf MarmacnlnRy. K arnl.n.ka Inslilute, snd /he Itrpartmrm of
('Imics/ ('hrmrsuy, Ksrnlin.ka I/nspnal, \lo.kholm, Sweden
Qs
(!1
V
(D
t51
J
l~1
tJ
('(1 LXISffN('f O/' PI rl ll)C III (P1111 AND VIP IN NF.R VCS RI (:1/1.AlING
M(K)I) 11 OsV ANII NRItN('11/A1 SM(X)tll MUS('LI IONI. IN VARIOUS
MAMMAI t IN('I IIIMN(: MAN
Ily immunnhnlauhrmnuy it wat fuund Ihas P/11and VIP-Idt immunnasclwily
'IRI u.u.rr1 .n rhe a.mr aui..nnnu. nru,.na .n It.r uplvr, rtap..alury Ilacl, /unaue and
t
aal.va.y Rlanda with aaocialeJ RanRlia in rsl, guinea piR, ca/, piR and man VIP an.1
1'llll.kt rmmum.reacl.vily were also fouml in s.mdar bn-alums in Ihe hunran hra.l Ihe
N lermnally dueclyd, but nnl the ('-Itrminally due.leJ, 1111 antnerum or tLe V11'
anl/Snum qalnelt rmhKliM cells in Ihe p.R rlu.nlenum lhis suarrus d.e ruarn.e uf su
adddmnal 1'lll I.ke prpl.Je LrRal.nn of netves acuttly aausrJ marktd u.r.l.ppma
a.on.tl aicumulalu.m u/ rlll- and VIP 1R crnlral lo Ihe ht.un I wn wrrkt al.rr
Icrn.rclu.n ef the nrcves, hnlh types td iminumnraC1iY/lrra werr aldl ub.rr.r,l u.
accumulalams Mnh in /ht aNN1s at well a1 In the l-mreapnml/nR cell InIJMS I hr le.rh ../
1'll/ am/ VII' 1K rn rnumal tissues fcnm Ihe ca1 were arnunJ 10 SO pmnl/R wHls a mol.n
rrtn. uf aM.ul I lu 2. SyaemiC ad.mmslralwm of rlll and V/I' rnducrJ. ...........
p.ul...bly dut tu I.rrq.heral .aslnlllalalnln in both Ruima pig and cal I u.thr.naur. IMnh
rlll and V11' causrJ an inh.hdia.n of the vaRalty imluced inerea.r m.r.pnanul
rmuf/tal.on prrtturr in Ruinra p.R rlll am1 VIr rrla.cd thr Rum.a pig Ira.hr., m.u.n
suKRrslmR a.Lrttl aa tmn on IraahenMunchql snwwlh musclt. V IP was sbnul 1 111 tnnr.
rmnr p..lrnl 1h.rn M1) wnh rrRard 1.1 hsMnentive effects snd 2 1(u1J- t..nudr.mlt
rrspualn. y snurnh nmusa Ie rrls.anl ellrch in lhr guinea piR 1'lll was alW.ul So 1,.1J h-..
Iw.lrn/ in nulu. mR hypnlrntnm in the cat than in the Ruinra p.R /1Jr1.uuKh .pr,«%
ddle.encrs srrm lo eutl at rrRards hmluRical p.nen.y, 1'111 thual.l al... 1r aun..,Ir~rA
whrn ecam.mnR Ihe rule of VIP as an au/onunuc neurotaamm.ller
I nnJh rR. ! A( N ol
/'rf'rrJrt S $VI G06, 1'r11.
(hArr a.pfruf Swedish Medical Reuarch Council, Swe.b.h I.J.a.cu ('umpanv. NOV11
I oundalu,n, Asl.a I nundalmn, and 1he Karuliaska Insutule.
RI 1.1 ASI t)1 SIIIISIANCE P- ANh SIIIISfANCf K I IK f
1MMIINl/R1 A('1IV1111.S I KOM 111E IS(11.A11/) P1 RI (1511)
(:IIINLA- PI(: 1.(IN(:
In Ihis s/udy, Ihe aulhors offer direel evwksoct fnr a reMaa of SP anJ SK Lkr
immumneaclivilat (1 I) by chemical irsi/alion fr.wn Iht isolated ptr/used (ulnea Pyt
lung ('hemical ini/alion of tissues was achieved by prduaw.n wilh Lu/ler cunummK
I pM capsarcm Sr 1.1 was nm'asured with Ike anliMr/y Rd : whi.h d..rs eul cruss rr.ut
1.. SK. SK -1.1 was measuied wilh Iht antibody K 12 8101 whn /A daut m.t .M.w
erms-reaetivi/y lo Sr. Infusion of eapsaiein induced a several fol.l increase .n Ihe
nulflnw uf SP I I and SK 1.1. Cspviein, a slrnng inilanl of the rrapiralory uac1, eecars
arnf, in high doses, sekclively deslroys sensa.ry (' fihrrs 1 urthermmt, a cah.um
requicing rtlrase nf Sr from sensrwy neuroM of Iht 8umro pit urtlrr by capta.cm has
been previnusly demona/raled. fhus. the prtsenl rraulls inJ.calr that SK I I m 1hr
reapfoalnry uatl is, like SI', eonlained in primary afferen/ (' fdvrs ('aMa.cin um.U.r
(' flhers are reyMms/Ale f.N bolh MonchncunsUicliun and /rac heuhrona haal eJrma a/1r.
chemical irrilalnm. SP hss been poalula/ed as une meJ.atul uf lhrar rryumsra mamly
because nf /he rnh.bdory effecls of SP anlationnls whuh, huwe.rr, nb.lut .ha aa rn.n. '/
olher ,achykmms
Ssria, A, 1 heodnrnen NorMim, E, Gamse, R, and I rn/MrR J Al
f.wnrron J.n.rno/ o/ Phormarnluey 106 20)202, 1V11S.
O.Atr sup(ru/ Awlrian Scienlific Resea.ch fund, Swedish lobacco t ump..ny, rruus
and AuRwla IltJlunds I oundaUon and the Swedish Mrd:al Resraah ( nuna J
101
/ rom the 14partment of Frperimental and Clinical PharmacolnRy, IlnivertilY of Grar,
(3nr, Aut/ria, Itepatment nf ('linrcal (Temistry, Katolrntka Ilosprta/ and I)rpartm~nt uf
Phatmacolnty. K arnhntka Inslitute, Slocaholm, Sweden
IH1f1RINIIAI 11I1(It(N MfSIRPINCANn6-IIYnRf)rYl)(7PAMINI ON
N11tR(11'11'111)1 Y (NI'Y) ANI) N()RAhRFNAI INI IN PI R11'111 RAI
NIIIRt1NS
I Ihe effrtts of 6 hydrnaydnpamine (6-nllf)A) snd retrrpinr prelrrormnl on
periphrral nruruprplrAr Y(NPV) and noradrrnalrnr (NA)cunlainmt neumni
wnr
st.nfird in Rurnes.pras
2 Irn days sfrrr 6 n11hA prrutatrnrnt a 60 10% redutlron of the NA tnnrrnt
wat nhurvNl in Ihe rrRht s/riurw uf I/K hear/, slellale tant4nn an.l tplren Ihe auntrnl
nf NPV lrke immunn.racrrvqy 111/ was tedueed by ahoul S0'W 1w the hearl; an.1 was
unchanRrd rn the tplern whik N.ncreased to 200% of eonlrol ro the t1N1a1e tasRh.sn
lmmunnhranuhrmrtlry showed a prnnnuwced Ims of NPY- am1 lytntinrhydrnsylsu
(111) rmmonnrextrve IIR) nrrves in Il.e hrarl tAUt not in the spleen. Increavd NPY-IR
was teen in aat.ns and tAl boA.es of the strllale tantlion
I Rrsr.prnr prrlrralment (,hrrahoM dme 0 S me X kt t) caused dos.-and
lime drpemtrnl rrdu.trnn of Ihe consent of NPY 11 in 1he hrarl A maan.al drp/etrnn
of NPY 11 lUMut A(M) wss observed S days after seterprne Reurp.ne preuratment
. alto reduced the cnnunt of NPY 11 in thr, splern, whrk nn titnitnanl chante wat
ulnrrved in the adrenal gland ot vat drtr.rnt Ihe kvels of NPY-11 inctrated in Ihe
siellale RanRlu.n lo a1.wt 11110% of cnnunl S dayt after reserprne Imnlunohauwhrmwas
analysrs revealyd an dmosl tntal losl of NPY IR nerve frMes in the hearl at vell at
around ld..nd vetselt rn the lant an.t delrtal musck Na delectahle chanRer .tre
ubsrrved rn prrrvasculat NI'Y 1R nrrvrs in the spken, vas drfrrrnt ue ku/nry III IR
nrrvrt rrmamed unahanRrd dltr tesrrpme, rndreating thal lhr nMervrd luss of fIPY-IR
nervts was due in a deplrlwrn of NPY and not a detrneralion
4 Nu chanRe rn the levelt of tuMtance P 11 wat obarrved in the ritht a rium S
days aftrr rrserpmr
S NA wat. in cnntrasl 10 NPY, markedty depkteA in sll liaurs invevitat.d afler
tetrrpmr trealmenl Ihe tkplelinn of NA was mr.re eslrn.we, and oc.urrc.l nwue
rapidly and al much htwet dosrs as eompared In the effects on NP)' - 1.1
6 1 iRatwnt nf the sciatie nerve revrokd thal NPY 1.1 was transportrd atnnatty
with a rapid rate (I mm/h) Reserpine pteueatrnenl sitnificanlly inereased the armrunl
of accumulaled NPY -IR abnve the htatNM, sutRetling an increase in asonal Irantpnrl
7 l/rgh ptrfnrmance liquid chtnmaloBraphy reveakd Ihas the NPY A 1 cnnsnled of
Iwo maprr peaks in Ihe slellale Rantlia, while only one peak chnety cnneap.wdmR in
pnrcine NPY was seen in the righl atuum
/ In ennclusion, 6-01/1)A prr/rralmenl depletrs NPY A I in ertlsrn 'rrrnmal
ietmnt and incrratrt NPY-(/ in gantlia Rrarrpme im/uces a trttur snA
dote-drprnden/ deplrtrnn of NPY I I rn errtam Irrminal srrat, whde cuneq~rmhnt cell
body ennttnt and atonal trsnsport of the prpade tetm in mcreasr
I wJ/rrR /. HH rt o!
AscArvrt o/ IAuewra ofnar )2t:111-)I0,IO1S
OrArr .uPp.rrt Swedish Medical Retrarch Council. Swedish Inhaccn ('ompany, Attra
I nundsrw'n, twrdish S.crrty foe MrdrrI 4rrnres, Ihr Karnlnaka Intlrtute, an./ Auss.nn
\, rrnld n Retesr~ h I un.h
to2
r
From Ihe t>rpalments of Pharmacolo6y awd Nis/olo6y, Knolinsk IMthlule, Slockholm,
Sreden; Ileparlment of Espetiasewlsl tW Clinical Pharmcoloty, 1lniversi/y of Gur,
Grsa, Austrra, I)epntmeM of Pharwucolo6y, llwiveni/y of llpptala. Sweden, and rhe
Department of Psychialry, New York Univenity Medical Center, New York.
CAPSAICIN PRITRFATMENT INN181T'S 11117. 1 LARF COMPONENT OF 111F
('U T ANI /)I/S AI.l.1 RGtC RFACTION IN MAN
In Ihit tludy Ihe aulhon have inveUiRalyd whether espsaiciw pretrralmrnl could
impair Ihe culaneous Iripk responst reaclion lu anliten challenge in man I he sArn uf 6
volunlerrt (1 males, 1 femaks s6e 29 40) with w nuMished allerty lo rats was
preteratrd locslly with cspsaiciw. ('apraiciw prelreatmenl pro.luced a burnint sentarron
and flsrr rrattwrw but no whra/ Injre/uro of rN allerssew inlo eonlrul skin arra rrsulted
in rmtanl ilrhrnt followed by protressive/y devthqrint flare and wheal renlmn
('apsaictw prelrealmewl of 1119 skin thw almml lotally sMtlhhed the scule Ilare
comlurnenl and reduced the itching aensalinn of the eutaneous allerty reaclnm in man
This suRtests Ihst cspnicin-seMitivt srnsory nerve endings sre sctivaled by mrdiahus
released upon mail cell depsw.htiow by alkrtew eepoaure. Nerve cl.vatron then
prohahly results in IAe rekase of vstoclive peptidn such as substance P whKh mrdiatr
the flare reaction. lke tvheal retpowla, however, was unchanRed after taptaicia
pretrt'almenl lhis sutosests thal aelivaliow of sensory nerves plays a majur tole in Ihe
(lare nd itchin6 resctiow .hike the wheal rey.nnae is apparently to a mapnr euent
independent of inediator rekne from eps.ici-sensilrve nerves.
Lundhlsd, 1.., l.unAMrt. !. M.. Awqard, A., and letlersttom, O
EreOran /urnel of rAornr.r.fnoly 11):161-462, 1945.
7tArr rueprt: Swedish Medical Reaerch Council, Swedish Tubacco Company, and
Prlrus and Aqusla Iledlunda Fo.nduiow.
Frorw the Ikparlmenb of (Mo-Rhino-Lryntology nd Thorcic Medicine, KarnGnsla
Ilospital, snd Uepartmen/ of Pbrwacoloty, Karolintlk Imulule, Slocaholm, Swrden
Sl/f1CF1.1 (/I.AR STORACE AND AXONAI. IRANSPORT OF NLIIRUPLPl11r1. V
(NPY) IN REI.AT1(Ni TO CATECIIOLAMINLS IN 111F. ('A t
The subcellular stora{e of neuropeplide Y-like immun.ueaclivily INI'Y III in
petipher1 sympathetie axutows nd drens) gland as well as itt a.unal trantport in rhe
sciIk werve was s/uditd in rela/ion le e/KAnlaminrs in Ihe cal in Ihe sulrellular
hclions (torn different prts af aywyrtkttie weurows, rr, cell brwliea (crelrac tantlu).
uom (sc'ratic nrrve) nd lertoiwh (Mdeen), the NPY 11 was (uund tutrlhrr wcah
wotadrewliwt (NA) iw heavy froc/iwr ssunsed 1o eowtsiw laqr dense-eored vetaMs In
addiliow, miwur /ighler frctiowt iw Ihe eoelic gsnglion conlainrd NPY-11 Ihe mrdu
rtin belween vesrculat NA wd NPY was ki6w i. Ike tetminal tetions (150 in 1) and
rwssch b.er in aeons and cell bodies (10 to 1). Ihus rrfleclin0 Ike di(ferenl mechanrsms
of tesupply for classical Irnswr:ller and prptide. In the Adrenal gland Ihe NPY 1.1 wat
mainly located in Ike c/echolarnine-slorinl ckronuffin-trswuk frction and lut lo a
srwa/kr taltwl in lithlet fraclions. (/sift teversed-phase IIPI (', onr nurkcular from of
NPY-1.1 eorretpondint lo porcina NPY .t found in the eneliac tantlinn, wh.le the
drend medulla also containrd minor peaks alh NPY-1.1 rn aMfitinn to the main (r.rm,
10)
wh,:h cn rLnrJ with purcine NPY NA wal flored MNh in bahl and heavy fra.hona in
Ihr spl.ro, whdr /t wat n,arnly Lwnd /n hravrer fracliona /n the scsa/rc nervr In Il,e
cnrtnc RanRlwn, mosl n/ the noraJrrnabne was presens in a nun patN:ulilr /urm Ihr
arurruRr.ldr Iran.lrul ratr /nr NI'Y I I m the s:ra/lc nervt waa talr.nalyd tu Lr at.,nn 9
min h 1 A nunur srl,nRra.le t.anapnl of NPY 1 1 waa ahu detear.l In cun:luann Ihr
prtarot dasa auRltrat Ihal NI'V, a rrpl,de wrlh tympatM.actwe actUUna, n sn V..r,.1 with
NA ,n hravy Ira.llnns currrary,ndmR m larae deear crued vean.lea, while hRhl Ir..Inn<
wnh amall drmr currd vearclta prnbahly cunla.n NA hul nul NPY 11 I he m:/m
reu,ppty .nf NPl In Irrm,nala It, rn conlrasl lu NA. Inmt htrly by a.unal 1,anal..n1,
wh,h m.plr.alra dJlrrrn,rs .n the Nnra/t, lurnover anA rtlra.r uf Ihrar cu rrahaR
suh.uncra an the ayn1+Ih.,aJrena/ ayalrm
I..rd, (i , f r.wdhvR I AI , and ThtrwtmtsowNorhtim, 1.
.cr/.r PhrvnR.R,ro SronJrmarra 171/1S 111, W1S
O/hrr ,rqf.vl Swrd.ah Mr.fica) Research ('ounad, Swedrsh SrNrely /nr Mrdn.J 4,rwra,
Swrd,.h luha,co / unq.any. IlrJlund's Ioundal.nn, and Ihe Karolms\a InUnulr
1 rom the Isrparlmtnl f Phytiol.qy and Pharmacuhrly, KarohnaMa Inahlulr, au.l
lkparlmrnl uf ( Iln,call hrnual.y, Ka.ulmaMa Il.naprtal, Suclahulm, Swedrn
VIP ANIS rlll IN ( AI NI IIR(IN% 11) 1(1('AI 1/AIH)N R1/1 VARIA1111
11\11/1 ( IIN11 NI 1IltSlhl l t)111 1(1 Ls/111 HI NIIAI PR/l( I C\IN(i
Ihe 1.ncrnbat,nn. nf vaaArlivt mlral,nal rydsp:pldr (V11'1 and the f.rphdr .nh
NIIs I.,mmal h,.l.d,nr anA (/M111 Irrm.n.J radrurrnt IP111/ an ..Ir.nw M'rrp6r,.d In.ura
anA anmr arraa in Ihr ( NS ul the tat *trr ..,mpalr.l w,th lhen Immunuh.u,rhrmn.d
hwah/alam Ihr VIr Ir.rla an the 1...1.... nl.almJ I.a.l wrrr 1 1., A 1mra h,~lur 16.In
P111 levtls Mo.h (u1. 1.. Ill fr.IJ) h.ahrr Vlr rhan 1'111 Irvrls wr.r alau uharr.rd m Ihr
Renilasrrrnary Ita.t aa wrll at an 16r lung and heart In Ihe nrurnhyryphyan. h,wrrr,
Ihr VIP/1'11t tatso waa ,h,ae /n I (:rl frrmeat.,,n ahr.mun~r.rphy .e.r.dr1 Ihal V1/
and Pill Immunnrta.lr.dy (1R) in the ,ntrame, panitraa and Lr:un cnrn,.IrJ d I/u.r
larlrr mutecular furmt an addrtNrn 10 Ihr'tlamlud" LrP11Jr1 Ibrar IarRrr f..rnn wlu,h
had uvtslAl.pinl rlullon poailu.nl may rrprrttnl prtprn V/1'/1'1I1 f..rn,. IM
ImmunnMN,ahrmn'aI analyals revtaled 11u1 Vil' anJ 1'111 IK wrse prraenl r. Ih' .n,r
RanKtum crlla in the mlrstlne, pancrras, ultrua and synlpa1he11: RanK6.1 I urlhrnn.nr,
the /rrminat nelwurlis (ur Ihese Iwn ptpbdes were very aio/ilar in Ihr /Yr.phr.v In ll.e
mrJran emmemt uf the hytMlhalamua and m Ihr fMNerNU /nhe ul the rr ul(uy,
eunsrdtsaldy m..re nrrvra wtrr PI11Ihan VIP IR Ihia nhanvatnsn was in paratl1 lit a
low Vir/rll) ratro In conwluliasn, Vlr anA rll/ serm tu catasal sm mnal nurunal
tyalemt AllhuuRh the ralin of VIP and 1'll) un Ihr prrcuraur (leee ia 11, ddlerrr,ra in
fnnllranala/umal pr.a-rasnA may ereate a conardrrably h,Rher cuntrnl nl V11' Ih.sn 1'111 an
m,st trrmrnal utaa
I ahrcnirull, I, RrM, '1 , I unJM.a I Af and IhrAfrl/, I
Rrau(aturv PrprsJrc I):I )1, 1985
Odlrr .r.P(vuf N(IVC) F oundalinn, Ihe P Carl Ptlrrun'I 1 nun,laliun, the llannh
thnpilal I,wndal:on for Med/eal Research, the Swtdnh (bunUl (or Medlcal Rrararch,
Iht SwrJr.h 1-nhacco (bmfany, Pelrul nch AuRuasa IlrJlundt Slifltlar, and Ihr
Karnt,nat a Inalnulr
tul
t
1 ronl the 1)tl1]rlmenl of CIInIcal ('he111/alry, Ifltflehitrl II/n/111ll, (/IprnflaY.rn,
Itrnrn\rl,
am/ the I)rpvlmtnh u( Pharmacnlnsy and 'Ilia/uluRy, Ihe Karr.hoaha In.lnulr
SLN \hnlm, Swt,lrn
IVIIsIN('1. I(1R SrrculC NIIIROrIP111)f Y-RINI//N(G IN R A I tIKA/N
SYNAP11/SOMI S
Neurnfseplide Y(NYPV), a weurnptpliwle wilh N and C Irrrnrnal lyu,amr 1\ /, n
one nf Ihe mapu prpli,/es m the hram aml prnphtral nervuus syalrm NI'\' u r.,al.
wnh n.nadrtnahnr INAI In nrurnM in tw,lh the ('N"i anA prriphery Au/ is alan Prr.enl ,n
mn :AlrihnlalnrnrllN tyalerln Sy/11pa1ht11C ar1/Ya1Nm I/ntucea eoreteate nl NI'\ an,l
NA, tuMequrnlly Ihese 1wo a)tenl/ empe/ale in funcdnn.ll reafw.nara suah a.
va..qun.lrialum NI'Y has Ihrrefmt hrtn prlyMnrd 1u be a co Iranam/tlel IuRrll.r/ wnh
NA In the yrrsenl slwty, furlher evnlence is provided (nr NI'Y hr,ua a
nenu,rranamnlrr s.nce apecdic himlmg si/ea frsr 'Ia1NPV eaial In bram .nendranr. u/
11r s.ll IN droronalratrd m abia s/ln1y. the alC/wity of Ir1 NI'V In rat bram ssnp/..aomr.
an.t Ihr numhr. of hmJinR ss/H ast uf a mIRnilude similu 1.s thal /ue
rr.rpl1draadud 1ur ud.er putalrvt frplirMlRio: Iranamilttra /r4 NI'V h/n.Irr,R .uu61 Ir
d,.plaad hy unlalwIrd NPY amt PYY, hul wM hy o1Mr flruclursllv ralalyd /nptnlr. h.m
the panaveatic IMdyfrplide family nr nturnltnlin Ihtrefsne. Ihe mveasiralyd l..nbna
Ules ahow a hiRh speclficily for NPY arnl PYY. /lowever, NPY it pr..hahly Iln
tmlaRrnoua Irpnd for Ihese hlmling siara, since the K. valut fur NI'Y -aa /uRhrr Ihn
/hat /ur rVY and, morrnvtr. PYY dma m.t seem Ns tlt prevent in mual .nraa ol Ihr tn
brain Ihe drmunalralNrw nf apeciflc, hiRh affinily hindrnp lnta lus 11`1 NI'Y, wlLh
have charactrrlaira nf pharmacn/nRiral rrctplors, lurthtr sl/plu,rla the pr,qunal Ih:n NPI
la an rn/plnlam la.'Inf in MYr.nranamlliNln
Sa/ia, A, lheahsrsann-Norheim, F, and I andlvr.R. I A(
For.rfarnn l.ru.naI o/ PAu.moc.d.qfl 107 IOS-t07, 1925
.
Orhrr, supfvrrr. Swrdiah Mrdical Reaearch ('nuncil, Swedi.h lobac:u ('ampany an.l 1'ruua
and AuRuala (Itdlun,la I uuw.lalwsw.
Irnm I/.t IhParlmrnl of faprrinstnlal and (lini:a/ Pha.nucul.y;y, I/mvtr.ny nf
GraL, AuUna; IRparlmrnl of ('linical ('hrnliatry, Kar.dinala Ib.aPnal, aud Ih-P.uln,rnl
uf 1'harma:uloRy, KaolinaAa Instillrlr, SLK4/udns, tiwrJrn
NI IIKf11'1 r111N- Y(NPY) I N11AN110641 N 1O1111 (xll) Pltl C\IIR/IN( RI.ASI I/PON n-AI)RI
N/X'I,PI(IR A('IIVA IIIfN AN1) htRt /' 1
1'K1SS(Ilt 11111'1S IN P111111) I(A1S
I he effrcls uf neuropeplrk V (NPY) nw hhrwl preaaure and hearl rale wrre studlrJ
in Pilhed tala Syalrm infuaplw of NPV in a dme OM pmal 7( hR / X min r1 whr.h ry.
Ir dld mn affrCl hhwMl pleapnt enhancNl IIM p1e1VN re.l"nar lo phen)hIdu,nr Itn nm1
>; t,R 1 I v) and Ikal /n tkclrieal thmulAl/on n/ Iht aymp./U,rhr uulllnw In h,Khrr
dvatl, NI'V cwaeA a Presanr effect pet ten, whKh wal duae dtfvm/rolly an1aRnur.l 1s
nifedrpme bul nul by adrenucaplur ansaRunisla In cnnaluvnn, NI'Y rnhamrJ
ll.e a-aJrtmKtPlormeJlaled /esPmse aosl hu) 1 a/' d.yn'nJrnl ss..ww,.lu./n
aclivily.n rra..
Ihhlnf, C., /)ahlof, P, and 7.uwJAvr1. /. AI
Fw..pran l,w.naf .n/ PAo.naraLrAr 101 :11V :O?, 1915
101
(hhrr ry.rt Swrdiah Medicsl Resrarch ('ouncil, the Swednh fobacco Company, thr
K aruhatka Inanu/e, thr Srved.sh Society (or Med.cal Sciencea, and thr Attra I uund.rt.nn
1 r..m the Ilrl.nlmrnl of Clinical I'harmscoloRy, SaMRren't Iln.pitat, llnivrraitY of
I:etrh..r/t, and the Ikpatlmenl nf /harmacol..Ry, Karnbntka Inaaulr,
\I.rlln,lm, tiv.r.trn
N111Rt11'11'11111 Y ANthS\M/A11/111('('pNTRM.Of IIIARI
tIINIKAt 11111V ANI)(t)RnNAKY VAS('UTARIUNF
Ihr rl/r.1s nl nrutntKptide Y(NPY) Ow conlractilhy of the spnnlanrnudv Iv,a.ns
r.nnra p.R alr.um and t/an.mural nerve tnmulalmn 1tNC1 .nduce./ rlllu nl
L.Iwm nuradrrnal.nr ('ll NA) wr/r \ludad .w r.an NI'Y indwrd a m.rlrralr ry.ut.ve
.h...n..lnqu. nnA Imurup.c alrial ret/.nae .h.ch rat rrantant tu mr/r.qu../.J INA al 7
llr 1.r ] s,auard an ncrea.e .n talr and comracaM (nrce lhrtr r/fnls ur.e
a.Rn.tn.rntlv .rdmrJ by NI'Y N\r ahn reducrJ the INS.n.luced (2 Ilt 1nr 70 sI,
l.a.t.n.l ('111NA rrteatr by 40% r.ilhnul s((rvlmR the cunl.aade rrs(w.nse. Ihe
anoua.l,lr rllr.la nl ecnRrnnut NA on the (lu.nea pig atrium rerr mN alfrcleJ by
NI'Y NI'Y aau.rJ a tonR taar.nto .ncrraae in rmunay perfutu.n pressure snJ altu, In
L.sh ,h.ra an mh.hu«.n of vewuwul.r rnnuxhhte in the .anlatrd, pr.futed ltu.nra p./t
h. nl It,r (.r.lu.n'w p.rtturr nM.raar tn N/'\ which mosl ISrly refteclt cnrona.y
rra,.law1 to n an.l /t a,Irrnn.rp/.M blrlckade but tenaltlre In Il.e
c.d..vm om.R.'n.N n.lrJ.p.nr A Nri udurtnn nl Ihr vsaculsr NPY rrapnnae tKcurrrJ
at Ml M n,(rd.pmr- .hnh d.d nn/ .nll..rn,e .a/A.ic cnnlracNl.ly (rr .r m/he
cn/t..t.lr rlt..l. al NA NI\ 10 n,.l thr mt.raar .n venlr.cular cnnlr.utddy
b NA N,.u.t..nal,nr d.t n..1 ntlurn,r runnsry (ur(uu..n p.rcaurr
,.t.. ,/ 1/+kaJr \,n.r NI'1 .t rnh NA .n nr..ea. n m.r Ir
nl;/;rtr1 Ih.r rll'\ is .n Ihr ..,.... ,.I NA .rar.r .. r. It a Ihr tt.nl..lhrl.c
Iramu (A , /am/fv.! / At .n.l IUhhd(.I,tu I'h....h.awn CrnwJ.n,rrre 124 161 169. 17t
(hhr. tu('ryur Sv.rd.ak Medical Research ('ouncil, the S+edish lobacco ('n.npany, Ihe
/NU:r 1 nuudatn.n, thr S-ed.ah Sociely hu Med.<al Sc-iences, and Ihe KnulrnQa InaGrule.
1 rom /he 14pallnrnl of IharmacoMky. Ksenlmeta Institute. Slockholm, and the
Ikpartmrnl uf ( lmlcal Rhs.maeoh't)y. Sahlolrrli t Ihnpitsl, Colhrnbur{, Sweden
ttll( IIANISMC IININRI YING CIIAN(:1S IN 111f. ('ON11NIt 1)F
N/ UIt(11'1 plllll 1' IN ( ARIHOVASI'1/1 AR NI RVIS ANI) AURI NAI.
1:/ ANI) ININ/( 111 RY SYMPAIII(II.Y I/C UNI/(iS
Neuroprptitle V INFY) M a recrnlty Isr.laled vasoaclive peplide V,hkh is petenl,
InRrIM-r .dh cstrchnlam.net, (n sympaAttie nervet and in rhe adrrnal medulla. In the
p.rtrnl swdy, Ihr suthurs rrp011 Ihat prMrealrnenl .Uh tympatholylie agents influencrt
Ihe 1.saur kvels of NMY hke imtn.noreaclivily (NPY-1.1) in Ihr guines pig lhus 11 k
sltr. .r.r.p.ne. muad.rwahnr INA) and also NPY 1.) .err deOk/ec1 in thr hrart, tpleen
aw.l thr at.rnat abnd /he levels of NPV 1 I.n the vaa de(rrrns snA stri)ale RanRlu,
1,..rr, .... unH/nrr,t h, uar,p.wr .n sp.tr ul mH\rd Jrplrhum n/ NA Iht rtrr
i
1
1
pinr-imlucrd drptelion nf NIYLI wat prubaMy cautrA by enhanceJ ne.ve u.qud,r (1r
nd subseduen/ relrase frowl csrdiostcular nerves in eacrt..ul .raupldy, tincr 11 r.nutJ hr
prrvrnted by the Ranlllinnk-bMckinR agent chhnlanndam.ne 1 anR trr.n Ih da).1
treatment wnh chlnce.mdamine rrd.ced the kvels n/ NPY-1 I in thr alrll..tr aanstu.n
ShnrtIrrm Iceatrnenl (4/ h) .ilh wanelhwLne pardally preventrd the rrsrrpmr indmr,l
drplrlum of NIYA 1, prubaMy due in inh.h.tum ol NPY relraar Iuna tr.m
goanrlhnbne Irralmenl depkled nW only NA, hut also NIY I I I...m /br sptrrn
1're/realmrnl +ith the alphareceplor antaRonisl phem.aybennm.ne J.d nut .ntturntr thr
NA k.rlt hul rrduced the conlent uf NpY 1.1 in the Sp/een via a n.e. han...n th.n r.s
drpetwlenl on .nlacl RanRG.mie Iransmi»ion. Since NPY has se.r.al .arJe.....,ul.u
aclinns, chanRr. in NPY mrchanismt may cuntarMtle to d.e
Ihr.alwubval rl/eclt tr( almpalludyt.e agents
1 unJh-rR. J AI rt ul
I.ra PAruul..srrn lrowJrwarrro 124 601 611. IOtS1
nrArr, .upMul S.rrdrth Medical Resesrch ('ounail, Swedish lohacro (umpanr,
Ka.ulmaka Inslqule, Atlu PounJalion, and Ihr Autlrian Scientific Krtea.ch I uncls
/ rnm Ihe 1)rparlmenl Of rharmacoh.Ry. Karutintka Inslilate, SG.w sh.dm, Sv,rArn Ihr
llrparlmenl uf 1 apeumenlal and ('Iinical PharmaculoRy, I/nicr.t.ty of (,.ar,
Autl.u, and the larpartment o( ('Imical ( hemntry, Karulinsla Iluvtutal, tiar / l.,dm
NI IIRUPI rl ll)1. Y(NPY) RI DIICLS 111 1.1) SIIMItI A I IUN-1 V(WK 1 I)
/t111 AS1 01 NORAI)RLNAI INI: ANl) I.NIIANI'L11UKl-1. (11 (71NIKA('IION
IN tlll ItA1 P1)RIA1. VLIN
1. lhe eflrcl of sleurnpep/ide Y(NIY) On frat'tM.nal Irqiumnoradren.J.nr
('11-NA) rrlrasr and cuntraclilr aclivily was sludied in the iu.lalyd (wulat vein o/ t11R
an.t WK Y rsh. 2 NPY (S % 10 'M) enhanced Ihe forcr of /l.r tpnnuneoua cnru..st.h
aclivily by about 40'K. ) 1he frKlww.al a11-.elesse eli:ileJ by Irantmural nrrvr
sl/mulalion /1NS), .hich mainly tefleclt sll NA, trat redwrd by al.wl 11i,h afar
prrrncubalion .ith ) X 10 yM NPY in postal veins fsum hoth ti11R snd WK Y/alt 1hr
inh.hq.wy effect of NPY ow 1NS-evokrd a1/-rekale .at more slu+ty evrrteJ br
waahoul Ihan the faci6l.unry scta/n nn tpnnlaneout ennlrarlak lurc'e 1 I he cu.Mhatlde
response In I ie W al.nmlalwn .at mM rrduced hy NPY, bu( rslhrr IrnJeJ /n he ml
rra.rd
S 11 is c.mclu.lyd Ihal NRY eaerH a dua) acliow in the SIIR and WK Y pwlal ve/n. Ihut
euhancinR the snm.Nh musck eoMracliont anti inhuhdinR symlalhrlic neur..uans.nn,am
llw inMhilnrY elfrcl of NPY on INS-evoked NA efllu., cvhnh n p.earnl .n Irnh \11K
anJ W K V raq, is mnsl likely dw lu a Metyna(Nie site of ac/mn
1).td,.f, (- , 1):fil..f, P, lalrmolo, K, snJ I t.wJh ra J AI
Arrhnrt r/ PAo.mw.dnar !22 121 110, 1o/S
!)rA.v .upp.ur S.vediah MeJical Resrarvh ('uuncil, the Sv.rdrah 1u1.an t nmptns,
Ksrulinak. Inalilulr, and the Astrs foundation
frnm the 1)rpalmenl of (-linkal rha.macuhKy, Sahl/t.rw's Ilu.pital, IMlurln.rW nl
Pharmacolney. Itn.vrtai/y of GulehorR, l:.rlrlrus, S.rr:rn, and Ihr 14pa.tmrn/t u/
Ilirwhrmuuy snJ Pha.nucu4.gy, Karrdmsla Imblu/e, Shakhntm, 1.rdrn
ttu. I /o/
1 A1/ I Il)NIN (I NI RI I A111) PI rlll/l ANI1 ItS IIINI)IN(i 51(1 S IN 1111
III/MAN I I NIKAI NI KV(/1/\t\\11 h1 ANI11'IIIIIIANI
Il,ndmR turt fm aynlhrl.c human "4 1Jtrlyd calcdunin grne-rtlarrd 1`eplu/r
(^4 ( l.Kl'1 havr thrrn demamlralrJ rn mrmh.anrt ul d,e hum..n nervuoa tyatr,n
11.nAmR +aa h,y,h rn /hr anrMll.u .urlr. (I IS . 11,'/ (rmd/mq u( mran . SI M1.
qunal aurd 1I 1N, . 0`/ I.. 1.`/ . 1) 71 In.n1/mRl, 30.1 nu.s drnl.HUt l10) . 11 IS
Irod;mRl, ulrmrI,.rlr ,n Ihr inlrr,n- tnlla'ulut (0N0 r 011 Inad/mRl an1 .uh./..nlr.l
n,arJ Ill IS , 111 lo,.d/mgl 1- in Ihe nencorles, Rlohua pJlatot, nu,lr,n a:.ud,lu.,
hqta,aampua, amyRdal.. .upenm culln'utus, Ihalamus, an,/ hyp.lhJlam,n (t IS (11`
Inud/mR/ and nrROK,hIr rn sp.nal and symralhelic RanRha and p.1u.u,y /< OIIJ
lo,I/mRl Aulurah..Ruphy ahnwrd d.alinel los1-GRP h,mtmR uvtr Ihe multcd.u antl
/'urs,np crtl lavr,. nf /hr cerrt.rll.. ...Ues amt over the a,hVan/u arlal.nma Ia,arrn.r
af ,he ap.nd ar,l 1he h,ahr.1 Itvrh o( /'(.RP Irke enmp,mrnlt wrrt rrcn~mrrJ m 1hr
dnrtal l.arl n/ thr aprnal anl4 snd IM p.lurls»y JL/and In Ihr vrnllal pa.l ,J 1}.r apnul
au.J aa wrll aa m Ihe 1luuJry snA Ihyrn.1 slands, t(7Kr valurs wrrr h.Rlut whrn
mt.lau.rd hy radunrarl.Mr ataay as almpa.td to RIA, indaal.n/ Ihal a1 Irat1 tw.,
I 1,It1 1dr anqan,rnla arr prrunl lhr p.rd.nm.nanl (-(:Kr hlr peak un 11111- had
Il,r n-Irul..,n luur nf aynlhrht hunian ('I.KP ImmuM.hnlna'ArmnUy rtvra/rd thr
p,ratnar d I drn.e IJr.ut au/ /(-RP .mmmn.raa/ivt nrrve l,hrra in Ihe tMrv1 hu.n of
Ihe qnn.J .md
f unJF,rR. 1 Af rl nl
1'r,w rr.l.nr. r,J Ih: Nouwad L.r.l. wn ../ \', rnn.a af 1/1r f/nurJ
Irn,n,n R1 .'-111 : \~. 1'/11~
(4h.r aurp.'u w,.a Nalmn.ll 4,rn:r InanJal.un, Ihr ('anlun of /ur,ch, \wWrrlJnd,
l du (.r.R/ t uml.ny, [wrd.eh h1r,h,a1 Rr.ra.,h I uancd
1 ram Ihe Rruarah 1 aMualnry f,n ( aku,m MelaM.l,am, lhparlmrnta nf (1.lhuprdic
CurRr.v antl h/rAurne, Ihe /nu,futr uf PJlhnhRY. Ilmvrrvly o( 7u..ah, \w.UrllJnd,
(tip.ulmrnta u/ llnlulFy an) Pharm.tanh,RV, harul.naka b,.lrlult, 51nkhtm, \wrAtn,
anJ the IyrpJrlnunl ut Analmny, 1lmvrrtrly of (fa/u.d. Ilrfonl, I nl{lind
L1.11K()IR11 N1 \('4 Il( ANI) I r(AUSI WII)I SPKI AD AN11 1 X I I NSIVI1'LASMA
I X 1 K A V ASA 11()N IN 1 I lt. ( i1/1N1 A PI( i
I Inltavrm.ua rnjeclinn Of kukntritnt Ce (1 nmol/)R)cautrc/ suh.unlial platn,a
rsudalion in snrs/htt.urd Rurnra NRs. as evwtrnced by makr,l hrmucomenuat,nn 115'M,
in $ m.n) anJ siRnif.canl rIravatatum u( I vJnt Mut
I lwuamrb.e VuJr111eJIWn nf I vam blue contrnl in )Il stlrclyd Inaurt
dncumenltd Iha1 kukuuiene ('s cauaed u/{ndreanl plaama e.aavataunn /hruuRhuul the
hrafy, e.crpl (ur thr hrain, sinmach. .1unrltnum, cok,n, and nna,h
1 In p.ulaulat. lhr ,raD'ra/my an,) Ihe a.o IlrnnAl I,ala, 1u, a1.,, Iht
.nnrymnva, Iht r.W.hatus, the 1"le ducia and the umhdal h~amrnn, wr.e vrry
senaa.vt lu Iht edema prnmopnR rlfecl ../ /rukIlrtnr C
4 Inuavemnra .n/ecliun u( leukolrrrne 114 (1 nnm.1/4R) nr 1 r(S mm..l/.R) ev.nkrd
Ptaam3 r./raatauun +.Ih a,6tu,huln,n onal maRmarde that was 1u.ul.u /n Ilul mdwrd
bv Iru\.n.rnr 1 r , t Ir ,a , n. 1,.1r,1 11,.1 /he /hrre n.,lm r.rlMlrluenla of tlnw traclmR
suh.lanct nl
....r, .r.... /. .. r...(..,...... 1e ,.1 I r In.r i Rrnrr.lur/ an,1 rarnanr pla.ma
_ _. . .. . ,.. ,. , ,., ,r.., ,t,.. I.u1,n..rnra .ur ..p.,1u.1
1
Ilua, X-Y., t)ahlen, S E. f.wdfwJi, !. M, 1lammarslrom, S, and Ilydqv,a P
Arrltnrt n/ Ihormernfnl(y 1)0118.111, f9tS
O(hn .up(.nr' Swedish Medical Research Cnuncil; Swtdith Sociely ARamal Ilrs,l
(-hest Ih an1
seaaes; As1ra Founda/an; tlarakt and Grrta )ran.auns I ounAal,un.
lnhaccn Cumpany. Ptlrus and ARusta Itedlumla hnundalmn, Kanrhn,IJ I.,thlurr
N
a1
alamal Inaa/ult of fnvirnnmenlal Medicine
I rrun Ihe Ikparlmenls of PharmacnMRy. Phyv,.luhy and Physiul.,R,c.1 ( hr,n,V, r.
Karo6nd,a Intl.lute, and /he Naliunal Inslnule ol lnvirnnmrnul MrA,c,nr S1n,/holm
Sweden
('APSAt(-IN IR/ AIMFNI (N('RlASIS 11SS1/1- 11 VII.SOI N11/K(1K1NIN A
I IKF 1MM(1N//K1A('1IV11Y IN 1111 (i111N1 A Pt(i
a simdar fhr I(achIrrykmmalmiM are a family o( nalurol/y occunin~ bw.acl,ve prplu/rs .ha A.h.ar
' sequemt rN amino a.w1 yrsidues and havt smuhr baduRa ,1
activilirs IIn/d recrn/1y, su/nlance P(Sr) was Iht only taahykinin knuon lu n,rur in
mammalian specus Suhslanre Plike immunnrrJclivrqr (SI'111 haa Irrn (u,a1 in Ihr
crn/ral nervnus syslem and in stntMy nturnns innervalins many pr.rphr,al ,uraJOs
Nuw, in adA.linn /o SP, mammalian lisaues have hetn Inun.l 1,. a'unla,n / a hyl uuoa
rtlalyd in kassinin and SP; nrurukinm A INKAI and neuro/.in.n 11 (NK11/ lhe p,ur/.nr
ol the presrnl lludy was In invesliRalt uhelher prelrralment wrlh capaawin alh
drereates Ihe eoncemtatinn n( mammalian lachykinins nlher than SP in snmr pr,rphrr.,l
MRaM Iht rewl/s prelen/ed heQ indh'ate 1ha1 ea(Naicin prtlrralment drplr/rt cr.la,n
livaws of sarhykinina olber Ihan SP As has pr(.iouvly been thuwn fur Sr, Il.t IJrRral
rela/lve drpklx.ns we.e fol(nd in Ike lisaues ennlaining a hiRh denaily u( pr imary srmn.y
afte/en1\ Iu/eleya, urrnary tllatlde(. Ihete /e1u/N Iml/cale a clo\e rrlata,nah,p IYlwr,n Sy
and olher mammalian ,aehykinins aueh as NK A and NK n, nnl onty in lerms u/ aimi/as
tnaue dislrihulu.n, bu1 also in /erms of simi/ar teaclinns to captaicin, suKaeslinh Iha/
NK A and NK 11 are ad,tiliau(al pe(Nides of senwry MiRln. 11 is Iherrfnre mtrttsUn` Iha
NKA, hul nnl NKD, has a vety pntenl MOnt/ar-COM111[IM aclmn anA canus prnlrm
eslravatallnn in Ihe IiS1Yef, rhtre acuN' aNlminnlla/inn tN capv.lltin .edured Ihr
neurnkinin cnncenvalinns. Neurokinin A may Iherrfore tunlrnhu/e, 1,.Relhrr with \P, a.
Ike nruroRenic inflalnmatnry,responstt
lheodMSSOn-Nn.heim, E, Ilua, X., Rredin, F, and I w/AA,rR / AI
Arla fAyvnlnRan SranJrwrnra 121179-1)1, 1911.
O(Mr tup(nrr' Swedish Medical Research Cnuncil, Swrdkh lohacrn ('ompany, relaas
and MarRarrla IIr,tluMls I~oundalinn, MaRaus IUerflvalls Gifteltt, Ihe Asl,a I uunAauun,
It.e No/drsk Insulmfnnd, and Ihe Karolinska Inab/ule
11um Ihe IMpaament of ('linical ('hem.slry, Kslnlimka Ito.pual, and IM(uurorm u/
1'hJ.maan/aRy, Kaubnska InslUtute, Sluckhnlm, Swrden
NON-('llOLINI RGIC VAS(11N1 AT1(NJ IN 1111- 1RA('Itl()11K()N(IIIAI 1K11
UI 111F ('A F INIIUCI 1) IIY VA(:AI. NFRVI SIIMII/.A I1(1N
ihe /rachtnhronchial mucusa is eslensively vatcularirtd and ,1 als.. ,r,r,.rs a
denu pasrympalhelii and sentury ,anervalion ('hemaal or mechan,aJl urmon ,J Il,r
109
mo.uV .nJ,pr. p...a,hve efkart, tuh aa t'unRh and hlnn.hnapnm In a.l.hti.n, the
u..1]hnn Ir.IJt t.. 3 ahm.ally aml r.lwnnrnl.illy welt knn+n hy1w'oom au1 n.u.ucJ
svaellu.R Ihr m..r~.r.l ..naut]r 1~nnr.hddy lu m.nn.m.Jraulrc arrm, lu Ir Jrpro,lrnl
nn a.1.aa11..n n1 arna,ay nrrvrt w6,.h rlraar mrJ,u.,ra tu.h at tuhal]nar 1' In ILr
prr.enl s1uJv. Ibr authnra ha.e IruJ lo n1~bL.h Ihr rsntrnar u( a vaRal n,m ah.dmr.r.c
vaa..J,l.m.u on ILr 1..r. anwaya ua.nR the u.bu.nhvr miatmphe.r Ir.hmque 1,. uanmr
h1,.,J Il..w .n arr,1mvrJ aal. Ihr ral.rn.nrmt werr prrf..nnrd m arven m.le . Ih
1br .LU1 p.rarn/.vl .n th,a p.y.rr rlahf,ah Ihe ruaten.e u( a nnn ah,.Onr.Rn v.1..dJ..1n.n
ulrm ..aR.1 nelve al.mntaliw,n in the Irarhruhrnnchial Irer uslnR Ihe mnuuyhtIr
Irahmque In the nia]I u.muaa .t haa heen pstihk h. r6rd nun clud,nr.Ra aa..lAU...n
~ in Iw, p..ntip.dty dJlrrenl ways (1) hy parasympalhrlw p1eRinRtn.m: ar.ve
ul.r.e the ]a.hblalM.n is alr.li.hrA toy he.amrlhnnlYnl, anJ (') hy
ta.,«b1.Itu,n, .h,ah .s hruu.rtM.mum rrtittam and is eliatrJ hy anr.Jr..mnal,oml.lma
uf an..ny nrlvrt ua.nR h.Rh IMrJn.1J slimulal.nn paramrtrra (1 unAl.rrR 1')11-t/ Ihr
p.u.smpalhrla n..n .hullnrrRK vaaalll]In/n is prohahly Aur /n the rrlra.r .d Iwtnnlr.
.oah at VII' an.) 1111 I..m1 pnlg..u/;lmn/c nrurnns (Iun.lhr.K r/ ol 1'qlt.U. nlulr I/.r
ar,un.1 Ithr Is dur In an1,Jlumlc m.p.d.e prnp]Raln.n anJ Ike rrlratr u/ I.nl.tlm n. .u. h
aa aula.une 1' (1 undhr.R /41I)
Ma.11.nR, (' K, AnRR].J, A, snJ f u.rJMra ! AI
A.t., f'6..u.f..An...\..n,J..rnrrra t2a 14 l 146. 1003
(pA.. .t.rp..t SwrJ..h MrA.ca1 Rrtrarcb (uuncA, SwrJ.ah luhaccu Cunmpanv, 1'rtnn
anJ Aa.Ruq 11r.11uoJa I uun.laln.n, an.) the K and,n.ka Inu.lutr
1rn.n the Isrpartmrnla nf AneatMa,Ja/y snJ (11aKh.nn laryn/tnh.Ry, K.Irulmtka
Ilnapda/, anA IMLaN.ornl ni rharm,anh.Ry. Ka.nhn.ka Inanulr, Sawkholm, Swr.lrn
N/ 1tK(IPI 1'11111 V (NPY) ANI) t\"h11'A)I1I 111 lI/NIK//1 111 Ill I)1)I) 111tW
IN (1KAd Ml/('(ISA ANI) IrI N1 A1 11f1 P IN I llt 1'A I
Nrunqwpt.Jr Y(NI'Y) inummrtach..ly 11K) wat fnanJ lot I.e p.rarut in
prrivaa.u/ar nerves in Ihr eat drnlal pulp snJ olal mucau Many Rangliun r.11. u1 Ihr
tuprrinr aervical R.msh..n aa.o a.uma,nrd NI'Y-IK I.Ratmn of Ihe infr.nu a1.e,.1.Ir n1
1.nRna1 nervet pr.rlurrJ an lccumu611n.n of NPY-1K .n a.,mt pro.nnal lu the site 401
LR.aiun, suRRraling an anler..Krade a.onal ttantport of the prpli'tr Afler unJalrlal
aympalhralumy the NPY.IR dia.IpprareA in 1he drnlal pulp ami nral mucusa un the
Ipadaltral tMk Kevened phase hiRh perfurmance 1u1un/ chrumaln2raphy thnwrd 1h.11
the ma.n peak of NP\ like immlmrneI(livlly fnunA /n Ihe aupe1n11 eerviral R.IOK6un
su.hramalnRraphrd w.t1A aynlhelir Msrcine NPY (X.nfees in hhu.d flow in Jrnl.d Iwll.
oa ntal muuns were rneawrtJ rnJ.rrcl/y hy recmdm$ local clearance nf "`1 Au..nR
etecllaat sl.mulati.m nf the synlpalhrlic nerve m AurlnR c4.sr intaa nlr.ia) infu.u.n n1
nurad.rnalmt ur NPY All /hrre pn.ce.luret retulrrJ in a prnenwed Arcrr].r in ha.11
1.hMr/ tlu+ of a aimJ..r matnitu.b on MNh 1ltwrt A/lrr a adrtmwrplor hhrkaAr wtlh
phrnlnlannnt. the vau.enmlr.elor effeel of nu..4.enalene w,It at.J.thrd 11uwr.r., 11.r
elfeal n( tympilhrln: slamulaln.n af/rr phrmol.m.Int was only palliaally rrd,nrJ
(21 11Y.) sm/ Il.e rrahnae In N('1- was slm.al unaffrcled by the arrcrptm AhKk.IJe
Il.e rrmaimng el/ec/ of sympalhelic ttimulaliwln af/er phen/olamine wa atndiahe.) Iyr
fiVanHAM/nK I/owe.rr. Ihe setp.nte to NIY wss mrl chanRed hy the IiIler d1eR In
comlutwn, the vas.rnnstritlm respnnae In the denial pulp and nral mucnsa c+utrd hy
..Uvabun nf tympalhr/n nerves n.nore .eauanl In phrnlula.u.nr than the rratwmae
t
induced toy infusilm of ea.Kenout woraArrnallne S/nce NIY i% pr,J,..bly r h«]lur,l
wlth mnaArrnalme In the sympalhelic penvaacutar ne.vet anJ NI'Y rrJmrt 1.,..1 1I,..t
flnw, il is prul..ar.l /ha/ 1hn prp/:Ae is invntveA in sympathrl.. vat.ular .mm~d m.u.J
liatues
I Jwall, R, Carrl.ua, n,/ airkst. A, lhruaMrawn No.hrm.. I, and f un,lh.K 1.11
Ar(a PAr.ndnXun /h.nranra 12S 237-2M, 191%
(qArr .upl.,wt Swrdith MrAical Researrh (buMd, Sahaol of /)rnlnuv, Ka,ol.mkl
ImUlulr, SwrA{th 1..lvccu ('ompany, IlrJlunda I uumtIlu.n
I rom the Itep]rlmrnt of Pharnlacn/ogy, Ka.nl.naka Imhlulr, Snwkhulm, Swrdrn
1'K1 ANI) h)11/1/N/IK)NA(. 1111(1SI11 NPY (1N SYMI'A1111 Ilr"
(11N1K/11 (s1 RAI IIMURALARIIRY
Nrnr..prplae Y(NPY) like immunmeactivi/y (1 1) has recently been
Aru.nn.ualr./
In I.el/vaacu/ar, mNaArenrrRK (NA1. sympalhrlK wrurllna NI'Y Ia a Larnl
vaa.cont(rictor allrnl ur rire while the cunlrac111r effecls nf NI'Y on
L,d.urd bl..,.l
veavla are variah/e. fm (his ssu/y, Iherefore. the aulhors have analsvr.l h.aa161r p.r
and pnl/unalonal effecls of NPY iw relalNM to MIIaJ/enrrRla mrclclnl.m. In the r,l
frmnral ulery 1/1e dala prtsented in Ihis pal.tr tM/w Ih]I, rrrrpl fo1 the
vaww.msblc/ur aclivily prr sr. NPY enAances 111t cnn/rac111e e(fecls nf NA nn ar/r.IJ
vatcular smrw.th musck The NPY effec( may he rrlaled u. chanRrs m Ihe inlluv 411
turacellular rakium, sitKe il was ahseM af/rr nifeAipme. the cnnlracldr .ryr.e.r 1..
/rantmural nerve ttimulalinn (TNS) was alt.t incrraseJ aomewhal by NPY 11nwr.rr, m
the presen/ sludy. NPY in the same enwcentralinn cauted a malke.l (.Ih..u/ Sll'M,1 rrdualnm
of INS-evukeJ a1tNA efflua. thw, it ia slrikinR Ihal a m.ukr.l Jrp.raaanl .J
tlimulustvokeJ all NA seertliow can rleeur tirnuhaneoualy wnh an tnbau.rA vaa,ul.u
sm.wNh muKle ConltKtion Thit indiCalef Ihal pnt/)unalumal Cnnlral'Iile anJ fa..bl.nms
mechanitma of NPY have a Iware MofnunJ elfea un tymppalhrta. nrurulran.m...u.n Ih.n
a So1 reJuau.n of NA rtleate. lhus. NPY may have an impnlanl rnlr rn th, rrRUl.nnnn
of sympathelic vascu4r coMrol.
f wJArrR. J M et al.
4rm PArtudoR.ra SronJrnar.ra 17.1S11-SI1, 1985
(stA.v .upry.rr SweJhh Medical Rtsesrch ('oum-il, the Swednh 1u1.a... 1 ('.un.pmy. 1'rl.n.
and Augua/a IIe/Kundt I nYMlalrnn, the Aalra 141941,134.4.0 anA /hr K a1uIUNk 1 hnl.lutr
frum Ike I)rp]ttmenls of Pturmacnlnlly ami nilKhemitlry, Karolu.ak1 Ina,lurr,
Sl.wkhnlm, and IhpaNmenl of (hnnal rh]rmarulnity, S,Ild/{/rn't I/u.p.l.t, I:ntbrul.w/.
Swnlrn
AMIN(1 A('1I111r1AK1 NY 1(11MAN P/ A/'/ NIA AI 11 RA 1II1N\ Uy
NK(/11N1' ANb 11f/1A(("O SMOK1. (YfMN)NIN1S AN/) 11111K IMrIII"A11(INt
ON 11.1 At. (:RUW I/1
lhe fe/us of /he smnking lnnlher may parY.ally be suhjeclrJ lo unirw a, n1 .1r1a ua
due lo the ArcreatrJ uplakr by IrnphoMasl anJ the lnndrr, uf a.ninn 1a rAt /..,.n
bnphohlatl to (Hal cuculala.n
I lt/ I Ill
\,.vrr. R / Rnn.r
In 1 aa:uRta I G.xnMn,, I anA raolrlli, K Pda 1 Urrrl..Pn.rmal Nrwm. rrn, r
Ih.ar.L.ewd Ph.unu,,.Inr.rol anJ (IuuJ Aa(rrl. flatv.rr Sa-.tnce 1'ubh.hna,
Au..lr..lan., pl. 111 t10, 11M
hh, .up(.r 11 C Iln.lyd [Lnra 1'u1li: Ilrahh Srrvict an1 Natinnal Inaldulra nf
lla.l.h
1 rao Ihr Ihparl.nrm ul PhvmacalnRy. Vamkrbih l/nivtrsily, Naahvdlr, IN
1/1 1/ 1\ 111 / AI ( 111h1 ('l1ANN11 R/ /K'K1N(i A(t NIC ttN MI MIIKANI
0,111 It/)V1`,. 1\11 Y ANI) / A1/ 111M IN 1111 I IV I K 1/1 111/ I AK1111N
11 IItAt 1/1 trKllrl IKI A1//1 KA/
Ma.nhranr In..ruv.cns.ty waa drlrrmned frnm the pularrred flurnretarnct uf
I./hentll...drnnr [n plama mrml.antl an.t microtames rrrpMrrd f.nm thr latrr uf
. nl.m 1.1.]alA..r..k utard rala 11 w:n pr]dr drprtaatd htl.rrn 1' and 21 h. allrr Ihe
asnanr.lralnn .1 Ihe r]r1..n Iet.aatdnnJr Isrprratwn u( m.i.uviacuady waa alsu aren in
Ilv LL.t.m v.1,q h rrne prrlarr.l (..un Ihrar mrmh]ntt 1 hrre were dr..r: aea in
1Ln.ph,hp.! a.u.lrul and phu.pM,hpul mrllyh.]n.fr..Hr aat.vity, hul Ihrtr [h.mrrt .hd
a.d .qq.r.n 1. rp(an the .,r[rratrd m..ruvnanaaly A IarRe ac[omula/inn u( a.daram
.r,s .. /h.r hve. arllt ta-Iwran 1` an1 71 hr alltr llae admm.lr.cl.nn af -.arlnn
1rua.IJ.uJr 1 hl.uprnnurnnr, verap.amJ ]od ndahprne, when admimUrrrd p.nn I.. 11e
a.,.lrn /It.. hl.ndr, parll]Ily teduwr1 thr Itlrr aa.umulanon nl [alt.om and aducrd the
A..u...Rr nhatrvtd Whrn Ihnr aRenta wrre adnunntrrrJ I: h. a11et
Le ]Jnua..n.nnn uf aarlwn Iru]abh.nIr, Ilvy ahJ nul rrd.ne the wlrqutnl
a.a.uunlal.m ..f aalc.unm Mhen ad.nu.r.tr.rd pnur tn and I hr aftrr ca/M.n
IrUeahhnalr, Ihry 1.]d a ama1) hol p.Irmnlly v.RndK]nl r(Ittl tin 1he m.cruv.t:..v1y
%b..nyr 11 .v vuRprttrd that at lnw Irvrla n( mnruv,NUVIy, a crdn]1 hrahnld rn]y eritl
ltlaw wlu,h rmrs nf ralawm inln the tell .. 1^rly eunorntlyd and th]I cala.um :hannrl
1hnliu,( q:rnla may tr inrftecuar .f aAm.mtlerrd / a t.me hen mrmManr
.n..rov,a.alt rt ar.y h.u Intue cahlum aaiunmulal.un was actaNqled with v.t. k tell
d.mrace
I anA..n. 1/, la..+al R K, Kauk]m, K I and Suur/. P 1' Rama
Rua l,. nl l'a... . ... ..IhrR r1.N 271 1\ t 1- 1{h0. 1994
rph:r anp(.ur It S PuhIn:1/ealthSrrvne.
Irv.m the Iyhpa.t.nn.1 uf 1'harmacnL.ly. V]nArllall llmvrrt.ly, S.hnnl uf Mrd.:int,
Naab.Jlr, /N
( 11111 INI Ra.11 /'NtIPI K 111 S(11 /, 1u(It INI I 111t KY
I lf.ala 4.1 nmr rllint rlhrrt, (CttslaN'('IIs('11(K) 0 R', nn the rnna[]rlnn am/
e. plrt d h.nRauwlin]I srnnnlh mutek of Ruinea tiR ileum wrre ttude1 In
nnJnlm.l Ihe .1 .f rlral/nnic/alrrn fa.lura at the rlhrr-u.vRrn in sh.nul../inR Ihe
,16.ur./. r..rlt.a Iheir I lr..a tu [aute cnnttarhnn ul Il.r drum in p.rtro.e uf
lar n.. thmuua 1 t/ v 111 *MI re.r : r. 10/ I.mrt h.R/vr Ilh.n 1hU of a:rlyi. holur
(A( b,
. . h~~hll 11r nuaam.t e/lr It .f y tlh. ra (t .`Q 1.. I t.ll wrrr h.Rlu. Ilun 11..11
,./ .tr 1 aul +L.tr 1 r.hd.vd 1.+.. mn.nd .I1.-.1[ 1 U II/ Ihtar nhna t.lul.drd
t
no slRnificanl inhibition of choline atlyleransferate and chnlintslrrase aclivaies f.nm
the hmRitudmal musclt at Iheir I U.d lleeamelhnnnrm s.Rnificanlly rnc.rate/ the I ly.,,
of 3 cln.line elhrrs 1 he 11)s.a of some of the eshers elao were s.Rmf icansly rncreaaed by
1rtalinR the mutck with physosliRmrne Ot ) lo OMI m phytosl.Rrmnt and
hesamelhonium Atropinr (s I a 10 eM) blocked Ike enntraclinns in.luced by Ihew
ethert. The steric hinderance eursed by IAe /renethyl and/or (Talkyl p..upt and Ihe
tkctyon drnsity araund Ihe elheroayRen are IimilmR the roaararinic, as v.rll aa
nicnlinic, pnlencres of these chotine elhrn Choline ethers possetirnR the hrla mrlhyl
am1 /) n prnpyl tin propyl and (rrhWyl Rrou(a pretumably rtlease At;h at a vlr
cauainR inhiMtory ppqenlral lhrnoRh a secondary palhway.
('haluyvrdr, A. K. and Sas(ry S. /'. Rama.
Ar.flrvrs Inrrrnahu.rnlrs Jt PAanwor..Jrnonar rr Or TArraP.r :I1(1) 15 2/, I'IRS
(IrAtr cuPl.nr 1/ S Iubt.c Ilealth trrvicr, National Inslilules uf Stealth anA NnIh
I/akma Il.v.anan of Ihe AmrrN'an (anerr SSKMIy
lram the Ilrpartmenl nf Marmacevlicai Saiencea/IneoluRy, ('ulteRe of Pharmacy, Nn[th
I)akuta \lale Ilmversily /-arRO, and the Ikparlmenl of PhalmacnluRy, tiaiur.t of
M.J.cme, Vmdrrhd/ Ilmversily, Nathvilk, IN
Al/lOKI'GIII Alt(IN Ot A('1'IYI.CIIUIINI- RII.fASf K(111(// GtI11l, 1AN11 /
ANU M1.I111(/NINI. 1 NK 1-.IIIAI.IN
An ace/ylcholine (A('A)amplificalinn er posilive fetdhach mechanism anJ a
neRalive ferdback mechanisrn wtyt ptoparard for rekaae nf A('h (rum [bnlme.Ra
nerves, the [a(e nf influe of taleacellular calcium inns and Iwu rnd.Renous prpluks,
suhslance P (S/`) and melhinnine tnkephalin (MI.K) were aho knuwn to rrRulale A/-h
releale. Iheyefnee, these tlwties were rnderlakew to delrneale the vatuwa comryrnents ol
the ahnve feedhack syslems.
Motrse cereMal slices were incubated iw . KrrM RinRer bicarh.nale buffrr
conuininR (melAyl- s/1/ choline (01 InM; 0 23 Ci/wAI for 60 min lhey wrrt /durrd,
waahed, and Itanderred lo a wdcrohah se1 Ip foe superfsinn with the afrwe bu(fer
The rekaae of sll-ACA. SP and MEK into Itse sopt[(wale was nseawred as drscrdrd
rhewAere The following res/dts were olnervrd (a) the ra(e af A( h release rm'IraK4
initially for the f[rtl S wlin and then declined eapowenlially. 1he hi{hea/ rale d releate
(ur SP was obaeyved with 2 miw preceding Ihe peak rekase of A('h A hrnad prak l.n
the rekase of MI K folbwed Ilsal of A('h (b) SP (0.6 rM) increated A( h rtkase OtX)
and ('arr Irplake (154%). lke long acting enkephalin (IS a/a-enirphalinamu/r, 14 nMl
decreased thr release o( ACh (65%) and well as ('arr up/akt (1RK) (r)
S. Ilydrmly/ntthylfurforylltimrlhylammonium 419 nM) decyeased A('h reteaae by f(PM rn
a medium cnntainiq Ca" (2 6 mM/ 11 blocked A( h rrkne rndured by K* (70 mM)
and d.slernylphraphalidie aeid (1)'M). It inertased trNh sponlanrout (11 hmes) anJ
e.wnkrd 12 1 Imtesl rekast of Slo. It decreased sprmtaneoua 116 lirnes) anA evnAed /'ll
limes) rekast of MI K. Ihese rewlls suRRrsl Iha( the posilive /erdhacM 1..r A( h rrlra[r
may uperate thwuRh a mutcarmie receplnr. Slot and ai livatiun of ('a" m(la., anJ Ihr
neRalivt feedhxk IhrnuRh a mosealinlc receplw, MI K and rnh.hrlmn ot t a" .ntlue
Sat(ry. d V. Rnm& , /aiswal, N, and Tayeb, 0 S
InSrA[lowrr P AfrfaM/r.nr onJ RnJnRrrnl Afrn..nt. InrGan, (' (' and (4hmr, P(rAr 1
laylur and I rana.t, I nnAon, 1(1), p 24)
117 1 111
Ihhrr tur/vut 1/ C 1'u1d.c IIra11h Srrvi.e
I.nm the Isrparlmenl of Pharmacnlngy, Vandr.hdl Um.ersily Sch.w.l uf Med.rine.
N.t.M.11e. 1 N
NII (/1IN1
Ihr mr.i..tbon uf It.r behavlmal elfeclt att.Khled ilh m.obne anJ tmol.oR h.,s
brrn r.am.nrQ In hmoanq and in tevrral animal tlrciet. In Rror.al, an uopa.vrmrn/ In
Iwhavn.r or a rrdual.nn .n 11.eaa hat heen repnrltd Since melab..ham and d.n..Rrt have
1.rn .h..wn tu drl.rnd un Ike y.rcrea rcaminrd and on the rale ol admnnlrarn.n, il it
d.(fl,uh In tPraul..lr un the proarttet in humant ehal are inlluemrd t.y nicotinr AtnM
I.nm the Iw.a.d.k addntwe Mnl.rallra uf nKOline, it1 bthavutlal effralt auRltr.l Ih.it
mt.n.M mot (unrtn.n a, a nru.nluntmrllrr IAt Kl.nn uf nnnhnr on Ihe nerv.wt
tvuem m.ty I.e m.d.rlyd /b..uRh a y.rcdle b.nJrng ti/e at yet (nrnly nlenhl.ed Ihe
nn ul.ne L.na1mR a.rr .n hraln prnhal.ly dditrt fa.m the elaanal nlt-minlc ahol.nrrlo/c
/r,eplu, tne at drar..ivd m Ihe pr/ipheral nervnut tyuem, emre hin.tlnR tlu.lirt avdh
1.dwlyd scrlyl,A..hnr, n hunRalntnt/n. IN nlcoune suRResl 11131 theae tlRanda b.n.l to
dd/r.rnl tnrt in h.a.n N.ant.nr it af p..t.cular mtereal hrcaute nf ils rl.le use by man,
he.autr a.a sm..nR tM compnundt Ihat prnrlrale thr hraln vrry raniltly, snd trouar .1
aflr.la Mha.uu
, ~,r.Arn ll
In (apha, A(r.ll IlnnJhv.l..f N.u.,.,h....1 9, New Y..A rtrnum Puhl.thnlR
I alryualr.n, P/0t. pl 761 ; /I
I r..m the (rnter (..1 Nrun.a hrrmUr), N./t.an \ h Lar Krtr.vt h Intl.lulr, Wa.J'1 Ialand,
New Y'nll
PK(111('11(INA(:AIN%1 1-MIIIIYI 4 PIIINYI 11IKAIIYIIR(IPYKI(1IN/
NI IIR(111)\Il I/Y IIY IIIE AN11OXII/ANI AS(Y/KN1( A('IU
AJmmitualinn of 1-melhyl 4 phenyl 1,2,16 letrahydrnpyridine (MPIP, 2 1
mR;kR rrl.o mhdal to IIAI ll/clly n..ce reducrd /'llloni.n.hd bin.tlng to taia/a1
rnrnlhranet hy $016 Knclive o.yRen dr.ivalivea have been suRRea7ed Its ht invn vrA in
MI'/P nrurntasi.ItY, Iherefure. Iheu rrtearchrrs e.amined the effects uf ascmtlc acil
(an ant.naudantl Aacmblc acn) (I(1(1 mRI1g) Illvrn 20 min prior to MPIP adminnlration
s/q.rec/ahty P/eventrd the reductiw.n nf 1'Il1.narimbl hindinR Ihe involvenenl of
acnla/lve P'Meaart In Ihe mrchannnlld MP/P neurnln.ielly may tuRRrtl a reialn.nthip
lu the ethnM.Ry of Pal\.n.nn't dneaar sml the 1"'tuhle hrnefd 411 uealmen( wah ttiulhK
a.1.1
. Srr.Arn 1f r/ al
Nrurn~harmor.rlnRr 2~11 21 1237-1 259, 19{S.
I.nm Ihe (emrl for Nrulnchemitlry, Nathan S Kline Rrsearcl. Intlilute, Watd't 1aland,
New Yurs
114
('11At1'AIIISI)N (11 /'111N1(-OIINI. ANh/'IIjA(1 IYLCI1O11NIIIINIIIN(i IN
MIIUSL I/KAIN RIGIt/NAI. l)ISIRIUl111(1N
In a continu/nt tludy uf nK/lllne IamlinR s.1es, we da'Irrmined the rrlative am,.unl
uf nicolme hind.nR an.l acrlylchnline Innd.n` /n variuus hra.n rtpmnt of and ut
IIIIA nlice AilhuuRh m.Alnain thnwrd the hipewal aml cerelnIhun 1he Inwetl bmd.nl(
Im Irnh I'11imcmmr and //lliicetvklurbne. Ihe ralns of nnolme lu srrlylahubne L/n.ImR
th..+rd a thlre-foh/ /rK/unal vatullnn_ Acelyl.-Md.nr inhdutinn uf I'llini.utme b.ndm`
mJKalyd Ih:ll a Innln.n nf minl.ne binding wat luq Inhdaled hy ]alylahubn. Ibr.r
rr.ultt m.l..alr un(vulanl ddferencrs helween the b.mhnR .nl (/) 1'lllnl:ot.nr anA Iha ol
~' 11 ~.la rt y4a hnhnr
.C...A.vr ll , Keilh, M I A, Ilathim, A, an.l I a/tha, A
Rrar.n.h ( uw/mohr+rl in CMnu(a! ImA.dnpr anJ YAurmnr.dnRr ~11111A~ Il;, IVat
I rum Ihr ('rnln fu/ Neu.uahemiNry, Nalhan S Kline In.t.lule f.u Pty.bialrlr Kr.ro..h,
Wa/.l't l.l.md, N.v. Yu.L
11/-1 ('1 (yl NMf 111Y1.-4-PIIhNYL-11KAIIYI)K(1PYKIIrIN1' (MI'11'/
(1N A(il -I(1 1 A 11 1) (t1AN(il S IN Il(1PAMINI 11/KN(1V 1 R ANI)
1RAN\IY)K/1 K I IIN(IKIN IN 1111: M/11151: SIRIAIIIM
1)amar.e lo neuwnal crllt, ei/her during Ihe normal aging pr.kraa ur Irenra lo
MPIP nrllrUlntNlly, have /mP1/fNet/ ntnlah.e /ree R/IKaI /Ilrlhamllnt GIu1:.ll.mne 13
nalu/al redualnR agent) It tign/f/ean/ly lllwer in the tuMlanua mR/a aump.urA lu .ulher
h.a/n rrRilmt and vlrlually aMenl is% Ihe niRra of Pa.Linannian pal/enls 11'rrry .i +l
1')Il:) /f MPIP neurnto.icily invulves free radical medlaled p.na-ratet, ,1 wat uf mlreret
lu e.amme MPIP nrurolo.icily in the a~ed Iluwte, in whi.h snti..udanl mechannma
nlav hr cnm(rnted t he presenl sludy shnws Ihal in MP ( P bealtJ smmala, 1'11/nlar/ndul
hln.linR woa drereaaed by 24% mine in aged rnict at cnmparea/ to younR nuar, sn.l a
auml.u incrrated tentilivily 10 the Ormuleaie tlftat /d MP11' +as nhtelvrd In a
IMcrraaed r4.pamine Irve) (-'6'IL Inwer in ated MPIP lrralyd anim:ds vertus ynunR MI'II'
uralyd anlma11/ Ahn`elher the data i/ldicate MPIP adminlslra/inn In mice rrtules m a
allieal krss of dnpaminrrRie etllt (1U-64'LL1, ntatti/alinR Inrth an incrrate in tyulhraat
and in releate (lurmwerl'f dlMaminr Gum the survivmR neuront Ida'11' neu/ow.a ay
is Rrrater in the nhkr wn.use jr.ssilay asslwisled wilh an aRe a/aled Im.ra.r in the
au.ceplibd/ly of dq.aminerolic cellt to mulalive damaRe, indicalluR d.a1 aRrd mar c:.n hr
uuful in thntyin6 mrchanitms of MPIP neurWllticlty
Srrtbrn N. Matnn, M f, IlatMm. A., and l.ajlha. A.
furnry.ur /..urnnl n/ PAnrmurnloRr 11) / IS 116, 109Y
I rnm :he (-entrr f.nr Nrun+hrm/.uy, Nathan S Kline Inthtule, Ward'1 laland, Nr. Y..1\
A(1/1 PI I'111H C AS (IK(iANI%1 KS (yl NI IIKIINAI I'A / 11 ttN\
IN1)1V11O1'M1NI,MAIIIKAIK)Nlll 1111.RA1 NII/R(IMIru 111 AK
/1/N(11()N ASM IN IIY StANNIN(i 111('IRI/N /11// K(1sAY1/'Y
S/ M was rxd to visualirt the nmmal Pnuns/al devrtrq.menl of tAe nennaul tal
neuanmrscutar lunclil.n Inmll Malu.alM.nal ch]n((es tvnArd by A(-1'1/h/\// 4 Itl
(10 Yt/\t/'1ay 11') ur AI 111/MSIl 4 9 I(11e 2 16/11 10 01 yol/le/day 1P1 +'tlr co.np.ue.l lo
115
-r
cnnlruh and In pupt beatrd wirh nicnhne durnnR prrnatal anti (w+ttnalal hfe, or only
d.oanR the grtlalw.n prn..A treRnant /rmakt recr.vrJ 02) mR/MR 22 daJy 11' nrnnatet
01N mR/\R/.lay \(' the I)rtilit and Urh.va and I aham eI at melhanlt revea-eA the n.nl
on the ealrnu.r daRilnrom mottle In hr lovereJ by a delnsle draprry of Iwntluntanna)
(..Ids that ewrnun.l the IminalY/e enrl(dale rrRw.n Oy the ucnnJ week of (rnlnat.tl Lfe
thrte (nldt Mromr more c.amplea an.l cwver a larger area Ill.nn maturalu.n the
(nt.lt
drtiend and rnvaRmalr, .nrn the mut, Or f.}rr fYplide Irralmenl with rdher Al I I I . M%II
4 pt ur At I11/M\II 4 V actr1r.atet n1.11u3110n of the rndptate at drmnnttcrh,1 by the
uac.ratrd t.m.ululwm of the (nldt %amdar el(eclt foltnw nicotanr admmittn1...n I he
ultrnrJ ah.,onaet on m.i.1.h..h.Ry uf the Jevehy.mg nmj tuhlralr,l 1o nacolrnr now Ir
mr.l..atrJ IhruuRh n....hnr rvlrJ AII11 rrleate
I na hrr H 1. I 1 Ki.a, N M an.1 SnnnJ {' I
P.pr.,l.a 61.'1I) 10, 0111
(IrArr aupp..r I).omrdnal Rrtra.ah Suplw..t (:ranl PraRram lhvrt.nn u1 Hrvahh
Hr.nurart, an.l Nalu.nal Intl.lulrt n( IlratAh
1 rnm the 11.nI..Ry I1e1n.In.rnl, New Ynr- Ilnnrrtny, New Yo.4
V. Iharr.acelloty and SMchem{alry
SI'l/'11 I(' 111NINNC7 ANI) MI IA11O11SM OF 11. ANI)(r-. (1111-NICI)IINI IN
1MII.A 11 11 RA 1 1111'A IIK\" 11 to ANh 1111'A ISK'Y 11 MI MIIKANI S
Ihe tlwt.ir. Mn.ImR af 1) anti (r)- lll ninNinr at well at theie rrlauve ratet ul
mrulnd..m, wrre mvr.trplyd in iudatrd ral hepaawytet anti hepatncyle mrmh.auh A
tiralabanl Idol ul Innh 11N.atrd rna.dinmert revealed two componen/t, with She hq.Lr.
allmay.atr havana K.1 valurtuf 2 a 10 and ) a 10 'M and II valurt n( 1 a III V.
:md J a 10 1 mnlr./.nR prwein lur the () and (r) enamawmers, rrtpriuvely Ihr
h.wrr aflm.ly t.Ir 1.,r h..Ihenanln.mert haal a Kof 4 a 10 is M and H if 1 t llt
w.drt/ma praNrrn Ihe p1) npUmum of hudtng wat in Ihr Maher pit e.anre, .w aonu.r.l
In Ma.n mrndnanrt wherr 1he ry.tamum wat 61 mvuWm~ the paul..wrur.l I.nua ..I
nicwlmr A g.wMl anrrrialann was observrd Irlwern Ihe pharmacuh.aw t"'lena y n1 ..
Rrnap u( niiul.ne an.doRuet anti Ihru abAily lo brnd I.. Inlatl a.at hry.aawtlr
mrmhrane) the rate Of cunvertinn of nraollne to tnlinine in hepalan'ytrt is rrl.alyd 1..
Ibr drRrrr of h.m1mR anJ al'cYnluLllwm the rrtuh% ate dixuttr.l on Irrmt .d the
pntible relalwantluP of Ihe mcotUne hinJmR anti Irantlocaliaro tu qt mNalnd.tm
Ahnn/ f C .a ../
ArrAr.rt rnrrrnnunwntrt Jr Ph.uwra-nJlwn.wrr It Jr Yhrr.qer 271(1)6.` 71 14P115
(lrh.-r tnprvr ()A00,164
1 rnm the ('enter I.w Orain Retratch and (kparlment of 11wKhemitlry llmven.ly ol
Krwhetter Medreal (?nler, Rochesler, NY.
1 1 1 1 CIS 01 ('IIRC)NICALI Y AI)MINISTI R11) NICOI IN1. AND SAI INI'
ON M()IIIK Al'IIVIIY IN RAIS
7bis sludy invetlipled the dd(erential elfeclt of ehrnnically aalmmitlered nnounr
and sahee on molor aclivily on the nt. Nicadine was adlnlnlslerell via a suhcolanruutly
implanled wmnlie minipump to ef(eel an t hour ol(, 16 hour on flnw. Sul.jrttt were 111
mate and 41 female albinn rals, each slrwt 165 dayt oW Activ/ly wat monnnred evrry
Mwr (ur 102 conxcWivt houe) Reyollt Imhcalyd that the female anuwalt were morr
aclive Ihan the makf and that animalt receivinR nicotint were lqtMlManMly more star
on she Iutl Iwu day) of drug adminitlralinn than camlrnl snimalt; however, hy the lourlh
day Ihere were n.. fa{ni(icanl diffrrencrt belwern the aadvNy levelt n( ammdt d..tl
recelved nicuWine anti /ho-t of eonllwl animah
(lnnan, 1,('nmsd. 1, end Rryu.e. R.
-Aarwturelnt/ Sr«Arwnttry6 MrAurwM 22iS-I197-I19q, aVtS
1nm the neDsrlmenl of hycholngy, San Oirso Slate 1lnivertity, San I/ieho, (A
11. 1 111
('IIARA(-11 R17A11ON OF ANTIRnpIFS 10 NICOTINE
7he rraearahers sludied the specifKily nf anlih.dirs p..r/.KeA aRl.n./ four
differenl haplrn carrirr con/uRNrs (fl,l.) 6(paminobentamuln) nuo/.nr A,.vme
'urum all.umin (11SA1, (1)1 1 6(r amrnnraparamnh.) nrc..one IISA, (11.1 ) 2
(1` aminnlrn»nudn) mcal.ne INA and (1).11 6 aminnniaolme IICA All uf the p.nJwed
anld.M«Lra sh..wrA afM.ul rq.ol apraufrcily fnr Iwrlh 1)- and I r..nmrrs n( n.rnl.nr Ihe
sarln.n IeoRlh of the 1pac.nR npdreuk Mlween Ihe hap/en anti canier mnle.ule d.d nol
p.rn sulnunsial influrnce in Ihe specdici/y (or Ihe pyrolid.ne ryulwn .d the nuu/.nr
m..lr. nle the apcrd.y uy nn pyrnline portion was inereased as the /rnRlh nf the p:n u.R
m..lrruk mcreaard All of Ihe pnrluced antibodiet did noM croa rea.l ..Rndaanlty (1rs
1h]1 01'M,) wilh .ulm.nr, N melhyl pyrnhnium enmpounds of (1 / N'mla..nnnrnuul.nr
%tud.ea un nnol.nr levels in the hndMt.cal fluult nf man and ublrls rnd.:alrA thal the
NA.nmm.unuaaa.ry Ir.hnulue devrl.qwA m Ihe presrnl uudira cnuld delecl as luw as )
nRl.nl
(-a.nn A hlnn/,, N. AI., 11 , 1lnwmin, t. R, and McKennis, /1
Rur Mnu.ul .(..hnrr 11411)1 Itl, 1911{
/.om Ihe I).parlmrnt nf Pathnlnty. 1lurmnne Rrsrarch I ahnralnrs, Ilni.era.ly nf Mum.
\ch..1 n/ hlydn.ne- Msam., /1 ,an./ rhr Ih..ar.n .t Il.whemHal rhara.arduRr, Mr.h,at
t..llrae ..1 V ua.n.a It., hmnnd
'SI h11-RI(:IIY AND '/1 1 X1111 1' 1 INK A(:1 S IN AN1IR(NIY rRf)1111( IIf1N
II/R Isl 11 NMINA1NfN ttl NI/ (111N1
An incrraunt mlrrra in prr..a mrlh.rl. (o- drv.mina(inn of mcuhne 1rvAa .n
Mwly 11uu1s has 1rA /n drvelnpmrn/ .d num.ruua pr.Kr.IYrrt, aR .d wh..h have snwr
J.saAvanlaRes 11u-r.rr, .mlwummunn]\s]y\ an,t rrl]IrJ prn.edures have pru.en lu h.rvr
,r.lam unique advanute+ w.lh amall umples and h.w nicotrne enncrnt.al...ns In the
(us1 puhl..hrd sludy n( a radrum.mun.qsuy (nr detrrminabnn .d n.inr.ne, r1 w..a
Inmlwled tl.a1 2and 6 aminonuul.ne were nn/ sudal.Ir funatnmalved nrcnthne haplrua
lor va.n.YS reatnns In the pretrnl sludy of the ute of raaemie amim.mtnlme aa a
funalnm]brrd haplen, niaotUne antihodres suluhle f.a use in nnroline drler.mnilinna
have heen produced f/..m an/'itens in which bolh'fleuhli and'xmi-r.tid' Ihiins serve
tu couple r-a/em/c 6-amlm)nKM//M in IMlvine serum alhu1/11n
('au.... A. McKennit, 11 , )r , Mnnji, N, and nnwman, F R.
R.nrAemrro/ Ar.6.rr. N4) 203-21e, 1915
Or6rr .uplwt lhe American Tobaceo Company
I rom Ihe Isrluamrnl nf /a1M.bty, llwname Resrarch I aMuatnry, 1lniverulr of Miaou
Sch.rd nf MedKme, hha.ei, /1 . an./ Ihe (4v.ann of Ilrwhrm.c.J 1'har.nxnluaY, Mrd,,.[I
( ullrtt of Yut.ma, RKhmnml
r1111\PIIISNYI A1/(/N fll A CIIR/1MA111N (,NANI/I I IIINIMN(7 1'R(7111N
111 1'111111 IN K INA\I 1
t'......
.. . . . .. . . . , .. ,. / , .. ../ . , 1/,. 1./.,.,.1.1.r...,.
1,2-diadein-, and phorMd myristale acelale-slimubted histone kinav activiqr. When the
chrnmobindins were incubaled with (-j-aaPIAfr, cakium, and phmphalulyHer.ne, 111'
was in...rpnraled predominantly into a protein of rnau 17 1 1 kdodalluns ((hrnmohmdm
9, or :'119) Phosphorylaliun of this protein was also slirnulated by dudein and phorh.d
myristale aavlale, indrealint that il is a tubslrate foe Ihe protein kinaae (' aclivily pretrnl
in the chrumnhimtins Ma.imum phosphate incorporatinw into (-119 in the presence ul
1.nM cakium, 7S pt/ml of phosphatidyherine, 2 5 ut/ml of dwdein, and 12 ) vt/ml ..1
duMnU.rrnal was 0 81 mnl/rnnl of C11V in S min. EiRht arP labeled phnsphnpepl../e%
were rru.lved in Iwo d.mensinnal ekelrophorrlie maps of Irypsin diRrsta of ( 11'1
I'M..phoaminn acid anatysis reveakd that phosphorylarion was e.clusrvely on srr.nr
('717/ and IMrnnine 16'lk) residues. Incubalion of Ihe chromobindins with chr.roa/lm
tranuk membranes in the presence of jjarr/ATr resu/led in the ineorpnral.on of Arl' iMo
r.tht addrti«mal prutrms beaaMs ('N9 1ha1 could be uparated from the memhranes 1+s
centrifutatlon in the presence of ethylene tlycul lus(htu-aminoethyl e/hr.)
N,N,N',N' lelraacetic acid We su/tesl Ihal pMnphnrylat.on of (719 nr Ihrse
a.hh/nm]I nthl prnle/ns may retulate events umkrlyint e.ocylusis in Ihe chroma/lm rrl/
Surnmen, I A and ('rrwr. (' F..
T6r l.n..nol nJ R,nlnRrral fhrm.vrr 2{0m :4)7-2441, qt3
(7rA.r supp.«r Nalinnal Instilutes of lleallh, National Scienee Fnundaliun and 1lnivrruly
a( VuR.n.a I)iaheles Resea.ch and Train.nt ('enler.
Trom the 1/rparlment uf Pharmacoloty. (laiversily of Virtinia, <'harloUesvillr.
MII(Kf 11A111sYI IN(X11(N.-StF('IfK' 111(KI'1K11 IPASE C ACT1V11 Y
()1 ('lIR(IMA111N (:RANIII.F-SINIIIN(3 tRV11INS.
(IsinR 111-Ir1 phosphatidylinotilal as subslrale. Cat' deprndrnt phospholipase ('
activity was detected in agroup of bovine adrenal nsedullary (uuleins Ihat hmA /n
chromaffin granule rnemhranes in Ihe presesoce of ('aa' (~chronurhimlins' ('reult, (' 1,
(Mwling, 1-G . Sam/o, J 1., Villarhlasi, C.. Whipple. 111., and /aks, W J(1911) J Rud
('hr.w 2St, 14664-14674) The activity were maairnal at neatral p11 and represented an
60- to 2t0-fold enrichment of adrenal rnedulbry elInsol phosph.drpase (' acl.vily
Inrasurtd at p11 7.) Tke stimulation of activity by Ca ' was complre, no activity was
presenl in the absence of eakium, 21% aclivatinw oeeuraed al I rM ('as', and full
aclivalion al S mM ('at'. The eneysne bound In chronsaffin tranule mrmManes rn Ihe
ptesence of 2 mM Cat' but was akased al 40 rM, suRRestint Iha/ nnuins.c enryme
aclivily may be retulaled by jCat') H( ROM but additional activation at hithrr
amcrnlulions of eakium is seen roo rnro as a result of ('aa' dependent hind.nR u( Ihe
aclive enayme to substrale conlaminet men/brane.. lhis 'enryme may trnrtale
dncyltlycead and pMrsphnrylaled inosi/nl to act as intracellular messrnters in Ihe
vicinity of Ihe chrnmaf/ln tranule menlbr.ne dorint the puKrst of ea.kylosn
frrur:. C f' , Isuwbnt, I, K yter, F.., and franson, R('
Tbr Awrnn/ of Rud^Rrro( Cbr.mury 2S0(12) 7171 717), 1985.
Ot6er suppnrt National Institutes of Ileahh and National Science Foundatiun
119
I.nm the 11.I.ulmrnt nl 1'hvmitnloRy. Um.rady nf VuRrma, ( harh.nr~.dlr, anJ Ihe
thlnrlmrnr J B..whrm.a.y, Mtd.cal l uIteltr nl VoR.nu. Knhmund
111K1/ 1 111ttICt)1 AIrKIN()(IIKtI(Y11KOrl('IK)RMIINI /1NhUVIN1
A111t1 NrIMI t11111 AR) I 11) % Atrl NIqINI 1',1'-MI1N(1/'11t/d1'11A11
IH1'1 NI/1 NI 1'lh1\I'1111K\1 AIII/NIH 1\K(1\tNE IIV/IKlltlI A\I
Krlr.nt .d ad.r.u1 .alrth.dam.ne by cacbacho/ haa tAern dmwn 1o cnin...Ir - .1h an
.ncrtaar .n .nlra.rltulam aAMI' h'vth Ibvlne adrtnal mrdulla.y (/1AM) .11 werr
Inrpa.rd and mamrl,nrd .n euhurt and uted to tsam.nr Ihe rnlt u1 .\M1' tn
al.w.dua ar..rl.un c.wpl.nR Iht addd.un of A/ I11 to Ihrat trlt% cau.r.t a 111 lu. \u t..l.)
u.c.rsat in cell.da. . AMP wN/uwl an r/fecl on (aleahol.u.onr sr.rrtnm. .q /7r-.lu.r
unl..al t'ell Cun/.m.o.ux.n fYrcull demNy trparalurn n/ Muh 1/AM .ella .u.d uhrna
corlnal trll% rrvralyd Iha1 I/Ae RrealrN cAMP rtap.naes In AI 111 ca.rtyuu..lyd n. the
..nrahulam.ne c..nl.un.na cell fraclnrnm and nu/ /n Ih.x drmay la)rrH wh,.e uu/wal
.r11c arJ.mented
IIAM arth .adalyd on Peccnll diJ n..t mrlaMlue /'Y'),hnlraernl lo .Irrn.da aa
would he r.lw.ted we.r the A('lll-uimutalyd cAMP accumulal.nns due to an.l..d crll
c.mlamma/wn ul the eull.urt A('lll sl.mulated prulrm ph..+Php/wnv,.aln.n
.n "P LdwIrd 11Ah/ ce1N in a manntr indra.nRniahablt frnm Ihal inAuaed by e:nb..hnt
and Ihr nulnr suloMr plm.phup.orr.n lo he atfrclyd hy IIKSt altrnl. 1cn1 a
.r1a/..r m.d wl ol 11 S/ kJ.dtum ..n ..+Lu.n A..teiyl Su11a1r Rrta and aur.r./r.nJrd lu
tvr..t.nt hydln.ylacr, whKh .. a t(rtJ.c m.u\tr rniymr .n /ht a.l.rnal f..r chnno.dtm
. rllc
We prnp..e d.al 1nvine adrenal chtonnffln cetls ecprrat M'l/l recrphus whnh
are cnnpled In adrn.tui c)claae Wh.le nn alute rllea uf A/ (11 .aa L.und nn
.altaAul..m.or ar..elAl'lll mav play a dural nle in Ihe rrputaln.n a( calr.h.L.mme
ctnlhran hy a1nu..l.umR Ihe Phuq.hu.ybl.un nf lyn.,me yl.t.e Ly
. AMP drl'rAlrnl Prulr.n \.n.ne
hlnhrnrr, M 1, Pra.h, M 1, anJ frrnrc. C f
I n.fr..nn..fuRC 1171,'/7N1 717, P11S.
lhA.v .upru( Natianal lnatitWet rnf 1/ta11h, anA Ihe Nalinnal Saitncr f.wmtalinn wilh
aA.bl.on.d aacitlancr from 1ht Ilmver..ly of V.rR.nn 11htuIts Reaearch and tammR
( entrt and Vaatular Smm.lh Mat.le 1'rnRram Prujttl.
I t..m the 1)rparlmrM uf Pharma:.h'Ry. llnivtrtay of Vinginu. Charl.Nlesville
h1ANN11111 AC AN (NI S(-AVI NI:1 K IN At)111/)IIS S/)L.II l l()NS ANI) tN
IIIt11/K.1( A) SV\11 MC
I/y uvnR the Irchnqut u/ pulat radnJyth lo Renetale /1/1 rad.cata, the aulh..rt
ha.e dtlerm.ned Ihrnut{h d.mpetdx.n w./h S( N, I and 1 rl( N1ed the rear/r.n ralt a.n-
tlanl of mannit..l wi/h (111 rad.cal a1 pll - 7 In bt (1 A 10 1) a l0e M 1 1 ' th.t value
jut.liet the we uf mannHot aa an (III /cavtnRer Ilnwevrr, in biwd.q{ical syttemt /here
ft a..mt nnCrrla.nly auna't.nmre the reteeanl eunttnlralimm Of thit ta'avenRer. Ihe
cnncenltslum .n.dr Ihr ctll may he try .1Jfrrenl Iro.n Ihal .n Ihe wlul.on hrcaoar nl'
a.t..r uan.px.l ..n Il.e onr hand ur 11.ro..lth mrlaMd.am nn Iht nlher I vrn If O.t
au/l.un . an Artr.nnnr Ihr .xntrnl. Jxm a/ nunn.bJ .n..dt Ihe ct/l, Ihry a.e not ahle 1n
A.Ir.u-r /h.,..... r.n.arx,n ..1 d,. ta.nr.a whr.r Ihe dun.at twcurt /..r 311 tbr.r
1
1
rracona, Ihty Cannul t.pecl Ihal Ihe efftcl of Oil 7cavenRrla m hndua.cal Syalrmi w,ll
hr p..qu+rlwnal lu Iht.r rale cnnalanN ..Ih (11/ .
(:rd4tlrin, S nJ l'rnp.4. (:,
lnLrn.mnnnl Awrn.d a/ RaJ.arrun RndnRr 46(6) 7?S 719, 19pA
flrArr .up(unl 11% tlc-parln.enl u( f nerRy, and ( irsrll..l.al l lur Suihlrn 1 a... hunR
Nruhrrlr.a, M'nl (lrrmany
I rum llu Ilrpaan.ent of Physical ('hrnlitlry, IleMrw llnive.aily ul )r.u.alr.n
)rru.alrm, Lrxl '
KINI 11/ S(/1 ()XthA 1I//N Ill ( IIPRO11( ('/Mlrl 1 tl \ O1 SIIK\11111/1 U
1'1.1 NAN11111//11N1 ANI/ ),2' nIPVR1/tY1 IIV M(111/ 111 AK (/7(\(il N ANII ItV
11)1/1t(N.1 N/'I ItIlX1U1 IN M)1/1/1USS(111/11UN
Ihe kioel.ca and Iht rtatlinn mechanive of eopper(1) enmplr.ea o1
5 mrthyl. 1,10 phrnanlMnlint, S chhan-1,10 phtnanlMohnt. Smu.. 1,10 phenan
/hrobne, 2 T d.mrlhyl 1,10 phtnsnlMnhnt, and 2 2'-b.py.wlyl w.lA ncyRrn and
hyd.u`rn per...ulr have hetn invrtligattd In aVue.wi So1ulMns wi/b Irtt nf 16e pu1%t
.a.li.dyh Iechnnlurr fhe Ir.idalw.n by l)/ it lecwld nrder in the copl.t.(11 cnmptr.,
.hdt Ihe n.utalinn by 11.0, it fNtl rNdrr in Ike tvyyaec/l) Cnmple 1141411 traclnmf a.e
lu./ nakr in nudanla the kinelic attullt nf the uaidalinn u( cnl.per(1) cnmldeat hy
...yRen a.e inlrrpttleJ hy a mechanism /hat prucerds via a tupecnantr inlrrmedult
(:..IdNein. S and (':nptf,.. (:.
M.uRunrr ('Armr.ur 2q)) 1017-1092, 19{1
Orhrr aupryuf Geaellschaft fOr Slrahkn Forschunl Neohrrht(R and the 11 S Ilrpa.tmenl
uf 1 nerRy,
/ rnrn the IRparlmtnl ef Pkysicd (-hemislry, Ilebrtw 1/ni.trsily of lerusalrm,
)trutaltm, lllael.
'111F ('ON7K1111I11(1N OF FNIXX:ENOIIS ANI) fX(X;1 N(/I/S 111 I(-IS 1/)
KAh1A I IAN ININK-11) UAMAGC IN IIIE OAC11 KIAI SrORI'
Radical uaoienRrrs such as pnlyethylene {lyeol N10 antl 4f100 and h.vine albunuu
have Lttn wed In del.nt tkt ennlydwlu.n of tenRrn.nn and rnJ..Rrn.wa elftct. lu Ihe
tam/na 1adO1NM IMIYrtd dama/e in aqwow Lulfered tutptminnt uf Rn,.flua (,unnfu.
qrurt /be rrwl/s imliCa/e that this damqt in /he harlrr.al tlw..t ia p.e
Aaminanl/y rnJoernxu. Iunh is tht petence of I almosphr.e of myRen anJ in am.c.a
)aruM, (: P, Samum, A., and faep.4r C.
fne.vnau.wnl J.wrnul ../ RuJ.atn.n R.o/oer 17/61621 .6? 1, 19115
OrArr lupryu( 11 S farpar/menl of fntrRy
1 rnm Iht 1leparlmrnl nf Phtrmxy. Schnol of Phumacy. Ikpar/menr u/ Mnlr. ular
Rinh.Ry. Srhuwd of Medn-me, and larpar/m.nl o( Phytedval ( hem.cl.y, l/rhrrw Ilo..r.a,ly
u( 1t.u.alem, )rtutalrm, ltrael
121
1111('1S (/1 I 111ANO1 ANI) 1FMPf RAl11Rf ON ta ll('(KF 1171t 17AT11)N
IN 1111 IN VIV(1 ANt) t5O1 A 111) P1 MI IISI I) M(IIISF DRAIN
A 1"('12 deosy o Rlucose technique .as used to investitate the effects or elhannt
snd Iemprralure vHlate.n on the tate of Rtucoae u11lr7alron in the rsolated IK'rfused
mnuse brain (aucnsr uhlinalinn rates in sis reRions of the ianlaled perfuted mousr brain
at 11'(- were sinurlar In the rales in cnmparahk re/ions or the in .nro mouae Arain Ihe
lenyrrnrure del.rnJence of the Rlucose ulilieatial rale in the perfused mrwse Ararn
suRRrsla that a chanRe in the ntr-Gmitin~ step of cerebral glucose melabs6sm orcurred
Ivlween 2111' ^mr 12'C. to inves/.RaN the possrble invulvemrM of
tern(-rature de(.erulrnl membrane phsse IransilieM, brain perfusinns werr performed
with a mrdram cnnlsrmnTT ethanol, which is -norw to increase nrembrane IluidNy.
1'rrfuainn of Il.e mouae Ars.n with a(lu.J ennlainins 87 mM elMnnl (400 mR/dl) resulled
in drerea,rs in the Rlucnse uldrealnrn rales at 11 but not of 2111'. At 2111', ethamd
pnutuctJ an increase in Rlucose uliliratiw.n in the wreeldls-pons and in the crrche lom of
(Nrfuaed hrains tn .rra ratts Of cerebd Ilucose ulilvation In Iwn hnet Of mrse
srlrshvely brrd for differences I. Hhsnol-rndueed skep time ind.cated Inal an
d.llrrtncn in basal metahdurw or follerinrt a e-t/he dnse of ethanol reisted Ielween
the two Irnrs Inter(.reutinns of elhamd's ddfrrential effecls on cerebral Rlucuae
uhfitalrnn ralra in the rs.dated perfusrd rnnuse brain at 211' and 11'(' are prraenrrd
a1.rng with a rbscusunn of the apparenl diserepancres observed when to enro and perfused
Ararns are treated with equrvsknt cnncentrabons of ethanol
lnwell, 1 I 111, and Frrrw i' C
Alrnh.rfrrns (7rnranl o~J Fs(rrnnvnmf Rrsrarrh 4(11110 116. 1912
f)rhes srpp.vr 11 S-uhtic Ilerlrh Service
I rnm the Alinhol Resrarah ('enter, SaMOOJ of Pharmacy. 11niversay of Coloradn, PnuAter
Ilt'F('IS OF NI('(1i1N1 ON p INIX)RPIIIN, e MSII, ANT) A('Ttl St('R111(1N RY
IC01.A111y PI R1 tlSl l) M()IISt RRAINS ANII PIIl1IlARY (i1.AN1)S, IN Ilflr)
lhe effecls of nicoline on t[crelion of the pituitary peptidet /-endorlshin. a MS11
and A('lll were studred wiuill the isnlated perfused mnuse brain (IPMn) and isolated
superfused prlurlaries of C111 mKe. Nicotine 16.1 NM) stimulated secretion
ut / emMuph.n immunnreaclrvily frorw C111 IPMR approsimately Iwofold Secrelion
u( a MXII immumveacavily was stimulated approsirnaldy two- and sisfold by 6 1 trM
and 12 2 pM nicotine, respeclively Ilo.eer, nicoline (61 MM) had no direct effect on
the secretinn of /endorphin, e MSII, or A('fll unrnulbreac1iv11Ks from the isolated
superfused piluitariet Ihe dals suRtesl nicotine ach in the brain to stimulate Mtuitaty
secrelion .4 a MStI and /-endaphin FlrcuocorlicnRraphic (F('o(;) activity of the
IPMR was monitored. Nicotine induced characlerislic IYbA chanRes includrnR a
reducl.nn of input vollaye, a biphnie response of rapid drsynchroniratnrn followed by
prohmRed svechronirst«rn, and seirure of hrqh doses (12 2/rM)
Marty. M A, Eerin, I' G.. Cornell. K., and 7aombick, I M
IAarmernln~-. JfrarArmrsrry A erlbtior 22 117-12 5, 1923
OrArr supryur 11 S PuMic Health Service
I tom the (enter for Aknhul Rtseuch, School of -harmacy, (Inivtrtily uf ( ohrrsdo,
Itouldrr
VANAI)AT1 I NIIAN('1 MI:Ni OF 111F OXII)A1IUN 01' NAlrll IlY l t , - III 1 l1S
(11 PllOSI'IIAIF.ANI)(-IIILAIIN(:AGINIS
Vsnadate mar-edly slimutales he osidalion of NAINI by <),'. Bu1A phospA~te
and Tns are inhrArtnry, but phmphale diminishts the peater inArhitnry tf(ert nf Irn
and thus Rtvra the appearance of slimutaling when sdJed to lrn-buffered rractmn
mulures l'helahnR aRents nurdttalely increased the otidalnrn of NAI)II but eliminat.d
the mlKh greater catalylic effect of vanarlate Orsfeul was the mrqt ef(e.uve in the
.hrlatmR aRenla, and could be used to lilrale vanadale q.ectrryrhutnmtlrically or In ttrurs
u1 the dumnulion of its calalylic M'livily Ihis perlnillyd the demuMlralrnn Ih.rt
mruvanadale or nrlhnvanadate could form 11 cumpleaes with drsferal and tlrat
urtMrvana.late was the catalylrcally active species
Ihrr, 1) and /'.rJnn.h f
A.rAnrr a/ R.n,Ar.n..ur and IfropArurr 141.N1)220 227, 1921
nrhrr tuppnrr Ilnrtrd States Army Research (Nfiie, Nati.mal Science I.uund.mrro, (:lenn
I oundalnm, and Natinnal Institutes of (lealth.
1 rum the 1)epartment of lliochemislry, 1)u-e Ilniveraily Medical ('enler, 1)urham, N(
IW NIIAI ITY (11 TIIF A(TIVF SI11: ARGININI RfSIt)UF 1OR 1111 Nc)RMAI
('A 1 AI.Y 11(' A('l IVl I Y(H ('u,7n Sl1PFRUXI0I: blSMll fASf
('hemical mndificalion of bovine am) yeaal ('u,7n superunide diamutases with
pAenylRlyu-al dimrnishes the catalytic activities by a 911% and trralnunl of Ihesr enrymrs
wn r hulanednrne plus Mrate leads to s 96% inactivation I Ae activity hrsa is
arcoml.anied by the aualificalion of kts Than Iwn arRinine residues per subumt wrtA it,.
cuncnmitanl Inss of ('u or 7n. TAe pAenyl~lyutal-modi(ied enrymes reauue at Irau a
:0 fo1J Rreater enncentralian of eyanide for Will, inhibition than dn the cr.rresywmdurR
native enr)mes. Iblyacrytamirk-Rel eleelr.qrhrNesis and aclrv.ly alaininR if tb.-
phrnylRlyosal inactivated enrymes demonstrate that Ike 1esnlu.ll aclrvHy it larRrly
assueialed with mnrhfred furms that brar Mwer nel pnaaive charRe than the nrtrve
superuaide diarnuuaes
Outders, (' 1, lr., Saunders, J. E., Rkch, O W. and FrrJoerrA I
Rrw luwu ur r l.nn nnf 2 10 711-776. 1925.
nrMr suppur-eaokum Research Fund, if, S Army Resrarch (rfh.e, IAe Naturoal
%.rrnce I nun.lalinn, and the (:knn 1nundalion
1 rum the 1)ePSrunrnl uf UAemialry, ('u11PR- uf WIM.1111, W.MnIr1, (111, aud it.,
Ihparlmenl uf Ib.ahemralry, I)u\t Ilnivertily Me.h, al ( rnlrr, I)urham, N('
I21
177
ISI 111M M A I AI ASI I NOM f.1( Tc)Ir,1! ll I(rC Pf 4NT (R('sl I VIIN N('1- 1(1R A
IItIM(M1NIAMINIt' 1IR1/('111R1 (l)NIAININ(: IW(1 AI/Ih1C(11 MANI.ANICI
1'1 R \11111 NI I
An mprovrJ pr.KrJWe f.w the isnlabnn of the p.rudncalalacr uf I a r/vr dlu.
rInntn.on. Aa- fwen 1r..vd, and de Vualrrnary slruClurr and manRanrar cnnlenl uf thr%
rnrymr have Arrn rrr.amnrd Se.hmrntalnrn eqr.lrArrurn uf /he nalvr rvYrur al
.evr.a/ ca1/ .umrnu.n.nns Rave a mIrcuhr reyhl nf 1/) IMM/ Ihr ud.unrl Wrq:h/,
ob/.1nrd by .rA.mrnlrhm r.prdhrium in 6 4061 auann/inruwn Id.rrdr v.dh nr .vd.nul
P.nn .edW hun aaJ . arJr..vmelhylilun -as 11 \i)Idallunt 1hr amm. ai.d .nm1r.tru
.nd:alr.l 1%11 Ara 1 Yt and afler rah7uflir 1rTINC d.Keatirn 1~ 1rlInlr v.r.r
rr.nl.rd 1 hrar d.d7 tajPr.eN Aa1 /hr (nru.MM a1ala.e .i a hrn..IwnHr.r. (ru.. Iml mr
vIh dmrlhvl snlrram.lrlr, hdluv.rd 1y prdyaa.ylamrdr ar/ rhvbnpA..r.r m Ihr
p.r.en.r nl sawlrun. d,.lreyl tu1(asr, Yr1.1rd L.r mipw f...n,la annllwr m1o unn d
1rntarnrni aru. l.ur I Ar manR.nr.r ...nlrnl v.as luun1 I.. 1. I Il .` 4 Iwr subuw/ .y _
+a. (nun,/ In 1e ') AC and 1/ f. - I:, tuRRrN.nR a al..lul.u Ilnn turr ..f \lu\rt raJnr ( 14
llevr, W 1,/. antl / A/
Rrr A. .ur. Ta111/A1h(1 646 1. 1'/11
thArr uplv.rr N,linn9 Inalitulrs ul IlroliA It ( Army Rrsear.A (Nfwr, an.l Ihr
N..1onal \. roce I uunJalotn
/ rnm the Ihpar/mrnl uf 16rrArmr.nY. Itu\r Ilm.ntrly h/rdn Le1 ('rnler, It.uharn, N('
1111* SA1 h1ttN11 1 A/MAMMAI IAN Mtl MIK/Ih11 At1I I A<,1 N1( I I V I I\/
t(/M1ARI\(IN ll) IIIIMAN ANt/ RA l I IVI M\ AX At IIVA I IN(. JV\I1 h1\
Ihe mulanennrtY o( srvrral trlI cnmpnunds was vrrdrrd Ay llw-
%aIr1BH.r1Ia/mrCrlKrnK mu/7Rrn1(rly Irt/ IAmet Irtl). u\nR Mdh human 1ver an) rat li.rr
(unlrralyd rw prrlrratrd with Arsiur /;)1) SV under idrnl.c.d ryr.mrent.d vn./Nuna
A11a/n.in Ilt, 1 melhyl.Mdanlhrrne anrl c.aareltr towr\e cnndensalr v.ere Ir.% mulaRenic
in IAe prelence of human-Irnr S9 than in the presence uf sal liver S9 (parlwul..rly aflrr
IrraUnenl wilA Arnchrc 1:71) IAr ryrrynilr .as nAserved wilA 2-aminrqnlhrxene amt to
a Iessr/ degree .r1A :aminnllWwrnr; cMreblMn sludiet indi.a/e 1ha1 the Mvo
comrynrnds were a,hvated by thr aame nt by very similar rnaylnet, praAally cyhmhromr
P 4Mk Ihrse resuhs clearty indicale 1Aa1 human /rver S9, aN an aclival.n/{ syUrm,
hrha.r% ddfrrenlly IAan rat liver %9. Iherefnre, it may conuilole a usrfut, ad.blinnal hnd
Im /Ae s/udY uf muURrni.'ily and, (wolatty, carcinngrmuty in man
Ikanur, P, I rmrsue Gornrt, R, K remrrt, P, Alfrrl, A, and Grrlrn, !
AIrwnrrnn RrreaaA Ita 119 146. 1913
OrMr, .rp/.mr' INSIRM (Franee's Nalinnal Institute of Ilralth and Me.hcai Researih)
From the I alrwalone de ('himit Medcde. Imlitul de Palholna.r, Iloiven.te dr I irRr,
I rrife, Rtlgium
t
M(NUX'1 ONAI AN/-101)DIFS AGAINST IIUMAN I.IVI R CVl(XtIROMF P 4SO
Mnnocbnal hyAridomu which pradnce an(ibodiea a0ainst human liver micrnunnal
cylnchrome P.4S0 .ere developed. lhere similar hyAridonps prrdreed anlil+«I.es hr.A
tecuInved an epih.pt sprcifK lo a falni/y of human P430 iureymes (P 150.) 1hn
epih.pe Was also prrvnl ow cylochrome P 450 P('N-1 (preRnrnnh.ne-I6..-carAnnrtrdr
induced) (rorn rat L.er micrntonsn, Iwl shis iwry/le dilferrd frnm the human P 1/0 1y
its m..kcular v,eiahl 7he+t ansiMdin enabled the au/Anrs to puanlify cvlnch...mr
P-IyOs in Aumln l.ver micrnlornrs and /n dem.wnlralt an rmpnrbnl tauanUUl,.e
pnlyn.nrphism in IAr human (iver munoo.ygenast sysaem
Ilrarne, P, K rtmers, P, Lttavie-Gnu jrwl, R, and Grrlrn. /£.
IYrnr'Arnvra/ PAmnvu.dnsr )e(IV/1347-1SS2, 19!)-
(hArr up/.n/ (NS) R M(I rance's National leslaule of tleat(A and Medn al Rr.ran h)
I rnm /Ar INSI RM, I acultr de Medieine Nec\er, Paris, I rance
I Vll)i N('F 1OR RFGIII-ATI(Nd OF A('lIN SYNt/1FSt5 IN CV tt('IIAI ASIN f)
IRIA111U111p 2('/1.t.S
1" Ill p-2 cells Irtaled .ilA 0 2 or 2 0 JIM cytaeAalasin 1) (('1)), the rrlativt ralr n(
aclin synlhesn increased for aho./ 12h and (hrn reached a plaleau; thn im rratr .as
snpprrssed by ac(innmycin O(A1)). When ('t) .as Wash(Ld frnm cells v.hwh had Arrn
(realed for 20 h, the ekvaied rate of acGa synlAetis declined in the cantr.d value within
Ca 4 h, as the aclinconbinin0 eylnskeletat eomponen/s rearran0ed by CI) recovered tAerr
nnrmal nwaplw.YKy. Subsepuentfy, aclin synthesis was depessed below conlrnt valrrs
f.w a prolonged period; dwiry recovery frorw 2 h Ire.tmewl .ilh ('I), this depre.sinn was
of much sAnrser duralwMt Re-add'Nion of ('1) so eeNs afler a )A recovery prrnd aRarn
induced Ihe eylosYektal ahrralionl eharacleristie of ('6lrealnlenl but dd a..l reverSf rhe
prirN decline in the rate of aclin syn/hesis. In I/tp2 eella uraled with
cYC1oAr.imnle
during espmrre lo ('I) fnr 20A. Ihe relative sNe of actin synthrsis mrasured dler
rewnval of eyck+heairnide .as (-ofold hi0her Ihaw wnh CI) alone and such cells
eahilited a(wofold slower declitae in the ra/e of acliw synlAesit during rrcnvery frnm ('Is
in IAe eonlinred presence of eycbhe.imide. lhesr effecN nF eycloheaimide, .McA
resemble observaliona on 'super-iAdtac(iOn; aYORes( (hal aclin aYnlheNt in t'la /rreted
and recoverin0 111'p-2 cells may be reg.bled Ay a repeessor protein the pnssihihly /hal
tAr pnyMned rrpre»or prolein is acliw and Iha/ aclin may thut be a ferdlack inMh.lor of
its nwn synlAesis is discussed
T annenA/un1, I, Orr/(, I G and Galw.en. G('.
L s/rnnwnrot ('rll Rr.ra.cA 140 411-I4t, 1981
OrAer sYplronl- Muscular 1)ysvnphy Assoeial:nn and NNional tnslqules nf 1leallh
l'roel the National Screnct Forndalion and the t)rparlmenl of Palhnlngy, ('nIlrRr of
Physieians A Suqeons of Columl.ia tlnivertify, Ner Yor\
:a 1 125.
MA('K(IVA( 11(K AII()N INlftt( I I111Y ('Yll)(IIALACIN II\ KI I AIItIN 1(1
111/ / \1(1%K111 fnN,M/7K/11(It(>rat'AI ANh('VI(Kl11MII'AI
(111%1 KVAIKtNS
A/ hiRhrr dnara of cytochataun (rR 1 YR/mi foc 1`0 hr), cr11. of Ihr r:rl
flhrnhlauuid Lnr. Ilmf, umkrRr. tdrt.nr, relraclwn, a.Mnu.U.nn, and wlarqurnt
roun.t.nR, and Je.rl.h, hrR cnlc vacuolea Ihtae vacnnlrs arr always clowly rn...IrJ Iy
mnrold.l.urnlaua m.aara, the ( 1) inducrd druval.vea u( 16e a./hn .yhnirklun,
.luh h aRRrRa/r in the en.Lqdaam Vstwrlalrrn is ptnRrr..i.e (r r. 1:'1 arlla al 6 hr,
Rl/'0. 31 IR hrl, /rlaled t., l.rla/ d.nt (OSncenltaln.n a IUnu') aml In cnnRrurr (l'11 .('ll)
Vac.nde mrmhcanra havr Ihe taree dimenaines (R) A). turfxe marker 1nm Ir.1..1.ar, and
jun.l..n.al a(MC.aI1Nlu.na at Ihost found N/ht cell sur(act. Il.ry t..L /hr mrmh..mr
m..l,rra saararalrJ wuh rndomemhcant syatrlm (e R. AtPaat, 11/'av, If)Pa.r) and arr
nu/ Ivsnamral Vacw.les leprtsrnl inlernalnt.l p(aarws memhune, they appo.rn/Iy r...dl
/N.m relentnm In /1M rndnpla{m, aMl fwwm, nl pimKylnl/e arantra nrlan..H.nR .ll 11c
cell surlace Vacw.4 mrmMan. n slways in Nlllmale trlatr..n tn the satrn 1nrd
maw/damrnl aRRrrR1u. Iha/ tur11n1nJ the va.w.lrs, an.l aatrn /nrrnhl.Mr hnsrr In.lrura
/.rh.n and vrnu/.n are lucaloed a/ the vacwk Mwmla/Ma Va-uulra nnJ dno
rnvrh.(.mR s.l.n fdamenl sRRrrRalra srt turr.wnded by arraya ..f vnoenlrn ha.rA
rnlrrnudnlt /Aamenla A nrw mrlnhaaluWS aMq\l/Imen1 w.1h ch.lraclerlnr.cs nf pb..w.1
u.rmtnane a Ihua formrJ wnhin the cell umkr the m/luence u( (1) Kuan.6nR hrm.Rhl
aMut by nlher mraM faoMt no .KwdirMMn Macro.atunlalrm, Mr the n/hrr chanRra
(auard by ( 11. .t cnln(lfltty tevrrllhte m1 retlmalnM of cetla In mlrrnJl nM.(n1m
11,r11, I (: amt C..r/nnw (: (
7 ra.ur t f, ll 1611) 111 1]I, IORI
(lrAcr, u.pl...r Nar...n.d Im.nulrc ..1 Ily drl.
I unn the IMp.amrnl n! t'a1h.L~Rr 1.Itre. ./ A\..~r.ma
t/nrarrsHy. Nrw \n\
M(IN(X'l /1NAl AN1111(/1111 S(11 11 ( 1 111/ //)NC1 K V A(11/N 111 Ml r\r AI(tNl('
( ItO) INI Ktilt' RI(11't(/R SIRIK'111K1 I RI/M LRllCCrlllll 1 It11111MAN
tIRA1N ANISh/11/l IY)ttIlll I SIK(1( Il-IKAI 11OMl)1(K:V
W1111 .r AI/K1 NI K(iK KI ('1 r/()KS
Muscarinie chnlintrgie receplnrs ianlaleJ frmm Mmnphrln hrads, ral am) human
Main, d..R hearl, snd wwnley 61,397 rouatk were tum.ned fn/ alruclural
simJaritirs/Jiffrrrncrs by uliliring isnehvlrie frcusinR, tmlium d.w/n yl
.ulfalt/Indyactylamatr Re1 electrnphnreaia, and lennnclnnal anl.hrrle cru.arrarlwily
Muscarrnie receptnrl wert affinity IaMIrJ wilh /s11M.rnpytMnrilytaMrbnr rnuaur.l anJ
suhjralyd in norlect.ie foeuaing Ml/tearinK rrceplors (rom tach apr:ira frroard wilh
an jant/rclrit l.nnl uf ) V The tame 1w.Neins a11 nuRraleJ wilh an apparrnt rmIrcul.u
nuta of 11100011 Aallnna W1 s.dium .hulnyt sld/a1e Rrls tis hylnnh.o;rs arcrrtmr.
nN.mNh.nal anlrMMl/ft \peClfK fm InuNarlnK reCe(.tnra were a1rYelnllr.I by utlnR purlln.1
ral hrain muacarin/c trceplms ss the anlrRrn Ihe ai, differenl enomKh.nal ..n11IMMLr\
immumqre."ipilalyd muatar.nnC recrph.ra f.orn all liaturs anJ specira Iraled, rnchuturR
human and Dce.npA.la hrsma, arrlh rqual ef(ieacy. lhtu da/a imlicate thal moaar.n.c
rtcrplora a.t h.Rhly cunanvrd o.tr a eunaw(erahlt evnlYln.nlty, prruMt ()ne of Ihr u
muatsnmc rr, r(nnr mnnrK hmal amd.uhea stao rmmumynrup.l drd ...1
L.e. nr aArrnr.R.. r.rPtnra I urlhr.rm/re, /w11..u111f l/vr mnmNtnn.rt am.INN .rs ra.+rJ
rn
I
1
aR]IINI /h.ar rrl'epinra ilnOUlnnl.relIpllalyd nluNarnUc receplnra Ihf\r d..1a suRKra/ Il..ul
su.nt drRrre nf al.uclural /n.maluRy esisls hrlwrrn mua.arimc aludrnrrR.r rc~rpu.r.
am1 n/ adrrnrrR.c rrcrplurs.
Venlrr, /(' , I ddy, 11 , ll.d/. I A( , and I raser, C M
/r.rvrJurp. u/ Ihr Nnrn.nnl AcnJrnn n/ Srrrn.ra r/ tA. ftnrtr./ Srwr. n/
Am..un RI : 1.` ?7n, M/R1
l)tA:r .npl.nr Amr.wan Ilrarl Asaocialun
Ir.on the 14parlmrnl nf Mulraul"r Imnwnn4.Ry, Knawrll 1a.t Memun,.l Imunn, Nr..
YurM tl:rlr Ihy..uln.rnl uf ne,llh, nuffaln, and lla Urp.utmenl ol (.enrlns Allwrl
1 rn.lrm / nllrar o/ Mrdn mr, 1 he Ibnn.. NY
n-OIIN(:AK(11OXIN 1/1 (KKS 1'X('1/A1(lRY SYNArII(' IKANCMI\\II)N
1/1 1 W 1 1 N(1 KI'A1 CI N[()K Y NI"IIKtINI \ ANII (iIANT 1N 11 KN1 I 1KI /N1 :
I11 111t (YK'KKQA("11, I/R/PI AN},rA AAII'RI( ANA
I Aul.uadn.Rraphic hKaliraliun of an 6161 o-hunRarnln.in hm,t.nR cnnywmrul
revraled that apecilic himling waa dnlt.blr/ed mainly in Ihe neur.ynlr and a. sa..nr e.lrru
in 1he Prc.phrry nf Iht Ittrninal sbMminal RanRlu.n of Iht aw\w.uh, I'.rrpl.uarn
OA4111 Yn11.
2. Aclion p.lenlials recor.kd frwn the aann of (il 2 undtr cuurnt cl:unp
cn/N1//M/nl werr IM.1 affrlIed by eapmYre I//1U X 10 sM o-hunr.arotn..n
) I scilshuy pcnlsynaplic p.hrnlials recmdn/ from GI 2, evnlord by stimulalinn of
cercal srnuuy neurnnrt, were semi/i.e to b1ucM by relalively h.w, (/co.n M s l0 /0 'MI
cnncenualions ..f n hunprnlooi.. lhr lime-cnune f.u bhwhadt was (uund rn Jr(rmI
on tnan cnncrnlralurw and hequtney of afferrnl slimulale.n
4 1 scilalury i(nallynaptic pulenliah rteorded /rnru (il 2 wra nol af/rard by
e.pmurt In 10 X 10 M Quinuclidioyl ltllailslt.
3. We cuncluwk tha/ sl kasl ptulion nf the rrtl-e-hunRaruloun hrnd.nR
c.nmpnnenl rrp.raenls cholintrgie reeep/.as which have a Iwfstaynapl.c funct.on sl
synalses br/ween ctrral sensory ntl/tones snd (i1 2.
Salttllt, t) N, Ilanuw, I b., Ilue. M., frlha/r, M,(7rpner, 1 1, aml II.JI. I sl
/rw.ne! nl f ahrrmenlel RnrfaRt N7 T7)-1TV, W~1
(HAr. tu~ryol. Ciha Inundatinn Anglo Irt/sch I.athanRe 1lursary aml the 11 S Nalnmat
1ilence I oVMlalinn
1'tnm the A R C (/nit of tnaeel Nturuphytinh.Ry aml rharmacuh.Ry, 1Mparlnunt o/
71u.MRy, ('amhridRe 1/niveraily, ('an.hridRe, 11 K; I al.n.alunt' dr Y/Iyau.6.RM, I a, uhr
de Merk. rnr, t/nne.uly d'AnRtrs, / rancr, and the tMparlmrnl uf t,rnr/u. a, Albr.l
I matrm ('..llrge o1 MrJn.ne, Ihr Ilumt, NY.
CIIR()N1C INIIAI A11nN SI(IINES IN MICE I FA(Y1 1111'S ANII
1 qUllMI N 1 1OK 'N/KI IINL\" / XP(1SI/Rf. 1O CI(iARI 1 11. SMOK 1
Iacd.lirs and eVuipmeM are dratriArd for IarRe-scak, IonR trrm 'n.ar onlr'
inhab/n.n e.(unurt of m.re lu whole ciRarelte amolr I y.fnmen/al p..arturra an.1
127
rquipMnent were drvRnrd lo provide Ihr, mice with eapnsure cnndilions wherr (1) Ihe IunR funclinnal
parameler of the ntutrophil they wish to mtasure In spile of the.e concerns
wa. the majn/ IarRet .eRan for the smolsr. (2) large quantilies of ftrsh, whnk rigarelle thrre has
hern nn syslematie eon.pariwR of the funclional slalw n( neuuol.hdi prepared
fmnae L.uld Iv Arnrratrd, (1) IarAe numMrs nf anrmals coutd be ecp.sed af one 1me, (4) Ay the
Yarious melhodolngies. la this study we have comparrd 4 commonly ucrd
roulrne, dacty epocurrs cnuld he srvrn over a Inajru I+nrlw.n of the lifel.me nf the
anlmat, /%) mnn.lnrmg aml dncumenblinn of the quan/ny of smoke prrsenlrl la the metMwl: or
isolation wi/h neWrephil funclnw. lhe resuln of IAis study indicate Iha1
wh.k neutrophit yield-and purity were delermined by isolat.on pnw:edure, slt cella were
ammah wat provnfed dvnng each e.rynure sessw.n, (6) safety syuems were provi.lyd Ihal equrvaknl
with reRard to ehemotsclie perforasaaceq ability lo deAlanula/e, and abd.ly 1.0
scwred rstw.sure of the an.mah In smo\e nety under prt srl erpnurt cnnd.ln+m, anA (1) pr.rluce
supeloaule and hypochlorous aei/l. .
c.Rarrlle smo\r was Renrrsted under conditions wAert fsclora, such as crRarrl e type,
su.n4e ae/u.nl c..ncrnaalron and smoke particle sise, were cnnl.olled
(Grilham, M W, I nRerson, T. 1)., Me('ord, 1. M, and Jonn. It P
(frnrr. C J
RrurlRr t w
rf af (alrrr..Ar.dn~.ra/ AtvriNral
F aFol Jw w Auwe fntnwarrnwaf 1I(1) 37 $1. 198S J.w.naf r./ Iwrmunwlnl/faf Afflhwft 02:)1S 120,
1985.
(hArr ruptvwf: lAe American Ilearl Asurciali.n
I rnm Ihe AnalvlNa/ l hrmiUry 1)ivninw, (h& Ridge Nalwmal I aMrsHnry, (Sa5, R.dRe, I rnm the
14pa.lrnent of fslochernisiry, ('olkse of Medreine. Ilni.rrsny ol S..ulh
IN. Ihvrvon ur In.aolnRy alw) Mokcular RndoRy, Mw'rnh.n/..gnat Aswn.a/e., Ilrlhr.da,
MI), and Pnnrss and Imlrumenls ('nrrywsl.un, Nrooltyn, NY Atal.anq, A1uA.k
('A1 MI111111 IN /)1/'1 NI11 N7 NAt) KINASF (1f F1lIMAN NI 111ROPltlt S
t
A('tIVAtION-ASti(X'IATI1) AI 7fRAT1ONC IN NCl11BOM111 PYR/1)INF
NI/(-11c/111)1: 11 V11S. A POII.NIIAI. RI(a/1.A1ORY R(N.1 1(IR ('AI(111M
ANI) ('AI MUI)1/1 IN
NA11 t.nase fhum human neuu.y.hds Aas been partully purdre.l by sequentiat
apl.hralw.n of Rrd ARarosr, wrn ralh.mRe, aml itel(d/ralnm .IwnmalnRraphy Ihe
rnrrme has a Mnad pll npl/mum, 1 0 u\, .N slr.eUy dependent urye the prrsence of
MRI', an.l in tAr absence of calnum eah,hm A values nf OA and 09 mM far NAI) arwl
Alr, rrywctrrJy NAI) Rlna.e abv./y .s e.urmety srnsrUve lo frre calcrum
loncentrallnn, +.Ih half macwnal sa.wny obsered al frre calcium lOn(rntratnwll of
aptuosimatrty 01 1 M to cellular eaacl., calc.um drpendenl aclivalw.e of NAU Ismaae
increaars the maumum vehlcily of Ihe.rxlu.n frnm 2lo S(ald wh.k not a/frclinR A~
values fm NAI) and AIP lhe acl..dy nf the partially purified NAI) h.na.e n
1/1lnulalMl 11 fold by the addit.nn of calm.rtu6n in the Mesrnce of cah.um IAis
slimulatwwn is inh.A.led by the add.tmn of 20 1 M/riflunperarrnr lo the rncul.alion
Ihese da/s arr inlrrprelyd at /mplrcalmg calm.Hluhn in NAb kinsse regutaln.n the
lu/al concenlratinn uf NAIIP NAbrtl rn the human neutrophd used increaxed 2 2-fold
in reslwma In salivaGon by pMuhol myristrc acetale. / lnally, neuu.rphd NAt) \rnase
.
hss a Mo. Aased upon gel f illralinn, of 169.000
Williams, M R and Jnnrr. lf. P.
RnrArwourrand Inphrrrrr 237(1)t0 t7,t9111
(),hr. wpr'rt K u.c I nundation
I rarn I/v 14partmrnt of n.cheminuy, ('nllrge of Mednine. 1lnive.tdy .f S.u1A
Alabama. MuMk
A(Y)MPARATIVISt11pY Of NI UtRnPl/ll PUR1t ICA11t)N ANI) F1IN(°llON
teeral ddfrrenl methods are currenlly uird by numerous lahmalories fnr the
ialalwe of human nruvnphJf Iht.r melhndl rn.luAr par11a1 purifKalinn by deatran
by .a/r. Lu.. sn1 m..rr ..nmplr/r puufKaUon p.rre.hwen
.~.1,.,,, . . w...... ... ...... a.1...... .... .1 .../. /r.r..n.
v./.rnrnlal..n an1 .n ...nv
~ , . , . . . . . .. ..... . . .. ... . . .. ... ....s ..... 1..../. al..n a Lr.o..
i. . . . . . . .. - . . . . . ...... .1 . .~t.r .1,r..r1. 1/r.1 Il.r
the eoncenualinn of NAIM NAt)P/I in realing human neulUry.Ads Aas hren
mrasured /.. he 24 0 y 2 7 10 °m1A/etll I/pon aclivation wr/h .paunued )ynw.vn A,
plwwhu/ mynslre scrlale or N~forwlylmelAwwny/kucylpAeny/alanine, nrutrnpAd NAtIP .
NAI)/'It pw.ls increase In AO S, 110 and $40 q/snwd/cell, rrapec/ively I hru
increases in pyridiee nuclentide enncealralion are Mocked by the a.1,/.lrnn of the calm
rnm
anlaRonisl A (NNdiwelhylarnilq)-nclyl 1,1,5-Uimeshn.yhenaoalr hydrochlorw/r, wh.lt
cakrurn wrnnphnre A21127, in Iht presence of eakiurR, will trit{Rer the increaar in the
alnrnct of Mher slilnuli. ('alnurlulin anlaRnmqs Irdtw.prrarme
and N(6smim.Ae.y/)-S-cAkwe-l-upAlhakne sulfnnamide alur inhibit strmulusinduced incresses in Ihe
NAf)P NAIM/l poW. lhrae sluties srr Inlerp.elyd as
suKRrslinR a rale for calcium and n/nwdulin and possihly prolein Ainase t' m Ihe
rrRulalil.n of pyridint' nIKlMlidt cqlcealralien in 1he ae/iYaled nrwlruphd
Spar\man, T s,)oAes, f., r.nllersnw. T., aml J.wrs. N. P
fb.rMnure rt Ibnp4yura Arta t/6.1 11, 1915.
OrArr lupprw/ Nalional /nslilutes of Itedlh,
1 rom the Ikparlmen/ of ninchemistry, cnikge of Medicine. I lni.ersily u( S.nah
Alabama. MoAik
/ t/1 ('I (N AI 1OPIIRINt)1. ON NLI11 ROPI/I/ SIIPI RO%I/N PROhl/t'l l(/N,
( //1 MUTAXIS, ON /N(iRAN1/1.AtN)N
Recenl atudks euminlng the effect of allopurinnl on h.clerial jAbng by
kuMoey/ec, have Area inleqweted by /hnse suthors as prrqf Ihal unlhine oida.e n the
111ajnr superoaide producing en)yrne in acliva/ed kulincytM. 7e tefl Ihe anertwn Ihal
anthine oaidsx is involved in the proaluctien of slrpero,idt by sctivatrd human
neulrophib. the aanlhine osatsse content of ntutaophils was measured and the effe.l nf
alhlpurim.l on neubrnphd funclions, rmluding supeloawle prmlu.tw.n, was slud.rd
NeuUUphds were found lo conlarn a kve/ of anlhine ecalast insuflrcrent ta scrnun/ t..r
the flu. .d tuprro..dr u.nc.alyd wi/h nrutrnphd aclrvatwn A/try.urmd dwl n./ uJulw
1 129
tutrmule pnolu.tinn induced by opsonired tymntan- pAnrMd myristit acetale nr
I..rmyl n.rduanvlleucylphrnylalanine 1 uahermnre, neithrr chrnurta.is nor delNanu-
lalam was al(ectrd bt alh.l.u.innl AIl.punnol was alsn found ineffecl.ve in hAxaing
tulrrnude meduted anaarrnan-inducrd l.a1 edrms in the ral Ihete slu.brt are
.inlrrprelyd as evn)rnce Ihal aanlhinr o..dasr tl nn1 a nu)nr superacatt`enerahng
syatrm in eaivaled nru/t,y.hJs sa haa been suggested by others
l..nr. If I rt af
RarArmaul rAn.nrwnl.,Rr )1(7011A11 1A7(1, 19/1
/1rArr, .upP.ut Nala.na Insl.tu/e of A.tMilia. Metabolism. 1)iRra.vt and K.dnry Ih.east
anJ Ihe Aanrrnan Ilra.l Ass.hahnn
/ram the 14pa.tmtnl n( llaqhrmislry, ('ol/rgt o( Med.c.nr. Itniversi/y of S,m/h
Ath..ma- Muh.k
INt RI A\I 1s 111 1 A IIIROMlt(1(:11)M111N IN 111i SI RIIM (11 SMC1K1 RS
In ( IIR\ 111/ A11\1 111 IN( R/ AC/ I/ P) A 1/1 1 1(()(IN/S
lhe amount uf // IAromM{Inhulm (R 1(:1. e plattlet alpha R.anuk prntem,
relrated in Ihe se.-um of snvkers hy thr.mha lurmed dunne +hok hha.d cAthoR was
L.und In Ar frRnJwandy h.gMr .n smokrn Ihan .n nansm.kt.s IMa .ncreast it naNl
likely due In oMrr.rd Mrrawd platrltl numlvrs .n smnkt.a, ralher than 1o imrrased
plalrlrl cnnlenl af p I17, s.n.e the con.rnl.ala+n .d 0 116 per platelet in ntarly atrnt.:al
in the two pouM An .nvrrst re/a/a.nh.p Arlwern relrate and platelet numArr .as alao
/.arnd
! onRrnrrlrr G I rr nf
Re.rarrACmwmumrataw..n SuMtorors o/ I/wrr -~4?)t11 152- 19111
1 rnm the hepsrtmenl of PharmacolnRy, ('n11eRe of Mrd.cine. University of SnutA
Alahams, Muh.k.
MIY'fIANISMS FOR RI FLEXIV F IIY/f RTFNSION INnl1CEq IIY I(X"AI
APr) I(A 11(NI (11 ('ArSA1C'IN AND NI('OIINI TO TIIF NASAI. MI/C(/_CA
TAe cardinvaaculst effecls of Mcally applied nicoUne and capaaicin to IAe navt
mucma -tre sludred in anaetthetired punra pigs 1 ocal applicalnm of capsa.cin
(0 1 1fl ~M) nr nicoline (0 1- W mM) indwn/ dnte dependent increaus in nleri.d Ahw.l
prenure, malnly due to an inerease in peripheral vasc.lar reeiatance the capaaicin sm/
nkahne trspnmes -err aAnlished afler kscal anxslAnia and markedly reduced (In a1+.ul
2(y% of caalrnl) by comAined preUralmen/ with phenlntamint and pruprannlnl,
suIt(ealinog tefleentenK tympalAtlic aativ.ali.ul System ca(Maitia ptelrtalmtnt a6ulshMl
the hypetlrnsive effea/ of capsaic.n (10 MM) and reductd the reslbnse tn mc..hne
application to aM.u1 257, of eontrnl (p < 01101) local eapsaicin pretcealmenl of the
nasal mucuu one week tatl.ee also sign.fuan/ly reduced Ihe capsaic.n response (p <
0011, coAde tht nwol.ne induced incaease in bload Messure was no1 signif.cantly
.lanaed Iht ptsenl LndinRs wlaetl the presence of twn afferent mechannms in the
na.al muc.aa wh,.h m,tuce hy(rrttntiim utnn chemical i.r.la/iw.n lhe capsaicin
.ryun.r r. ,blbn,/rnl ur.n ca/a.cm .eMdHr afftrtnls the nKnlmr rrya.nar mvolves
I 10
t
mainly capsaicin sensitive neurnns and, in aMlilion, a mm..r cnmin.nrnt wh.aA s
reaaam In capaaicin prtlrrotmenl. Thlrs, Ihe h LKally In IAr natal mu.ma tetma Io Ee mainly mtd
atrd'v i srlnsn.yl n ~chm.fms),.,q.rr
than Ihe sneer.n` res(w.nse which is awN deprndenl nn eapuic.n stnul.ve nerves
I unAhl.d, 1. ,/lua, X. Y., and f wJlrrR, l. AIt.
A, ta PAe.rolnR,ro S.-nnJ.narrra 12/477-2[2, 19t1
rltArr suprynt Swedish Medical Rrstaeh ('nuncil, Swrdrsh luhaccn ('nmpanv. Aal.a
I nun.taoan- and the K arulinska Institute
1 rom IAt Ifrpa.lmenl of 1harmacnlnoly, Karohnska Ina/ilule, and the 1tpa.lment at
Illn Kh.nu / a.rnRaluRy, Karnlinsks /4nlntal, SlorkMdm- Svrrdrn
1 1/1 (' IS U1 NIC(11/N1ON RI ASf(X'YSt bl VI I.OPMI_NT PRIOR 1(1
/M/1 AN 1 A 1 ION IN 1111 RAT
The fol/n..7eR study -as undertaken to detern.ine the effecls or nkotint /rev/anent
nn Cnn-tptus development daring Ike i.itial S days of prtRnamry In aJJila.n, harn
were na.ndored far hnR-lerm pnsl-parlam effects of niavN.ne e.prynurt on R.owlh snA
MaYal maturNwn 10 iM'HIIRa1e poasihle nHy/es Of nKn/ine ac/Nm, pla/ma prnitHlelnne
levels wtrr drtrrmined in /reated (N) et eondd (C) rala durinR the inital S dava .d
preRnancy, and the effec/s nf Ihe alkalnid on Ylerine bhaK1 /lnw and inlrauterine o.tRrn
Irnsmn were meatured in psewlnpre8nanl nls. Lilttc sire and IA.r/h wriRht .ere
determined m(' vs N rats and body grnw/h subaeyuewlly nlntted Ibe onset of puherly
rn femaks was determined by noting the day of vaginal npening Resulls show Ihal
Iwice .lai/y sc injectinn of nica(ine dwing the first 5 days of pregnancy rrqrds cnnceplus
Rrowlh as indicated by the reduced wumber of Cells per blaalocyst 1he same Irralmrnl
had no effect nn baer size, birth rreiRht w body pow/h. Ibwever. Ihe dat ..f vsRinal
+penrng was delayM Wcoline IreaUnenl geneeally s,rpptessed plasma progeuerune lrve/t
during the initial 3 daya of pregaancy. r.rlAe,wlnee, a single injeclinn of IAe alkaknd
induced a rapid an.1 sustained reduttion iw werrae blood (h.w and a conc..miunl
decrease in intrau/erine oaygrM. As indicated by this work, nirolint may m.ah(y
coecep/us development by alteralg reqod.etire tract funetinn Nicotine .nduced
changes in serum progeslerone levels aad ulerine bh.od floae Nohah/y result primamdy
frotw she alkalnid's diverse and eonlplra aNNMt on Ihe nervow tyslem_ '1he presenl
resulls cnnfirm aml ralend pre.wn/s invefliplions repmlinK eflecls td prr-implant.lmn
nicMine e.posure un conceptln devebpmeal and preoleslernne stccrlam In addilam, /Ar
preunl slwly densonslrales thal even a reblively Mief eapMatre /o nitotme, o e, dwma
Ihe initial .tays of pregnancy is sufficient /o ano.Bfy Ihe liminR nf puMrly in Ihe rat
IAe delay in onsel of puberty suggeNS bng-trrrn nia'uline imlwed nN4llfaat.,un uf (N\
fulKln.n
trfrrrArll J A am/ lla.emer, R F.,
to' ('aciatli, f, caacnbini. F, and Ianlelti, R. (edt ) lM.rlarnrntul
Nrwr..rrnrt: rAyudoRrral. IAarnwref..errd and (Yalrre/ Asprns_ New Ymk I lsevirr
Science Publithers 8 V, 1984. pp. 131-ISy.
From the Ikparlment of Analomy, Wayne Slate Universily Schoul of MeAic.ne, 14uaa
I 11
1/11 (1S (11 NI/(11tN1 ON OVIIfU(AI HI (X)I) 1I OW ANI11 MIIRYO
trl VI IItFMI NI IN 1111 Rik t
NraWinr fS 0 ma/t1t/ wat inlraled (sc / t+'ia'e daily on Ihy 1 or (hys 1-4 nr I S af
p.rRnancy ( vmulahar d.nes of nx'nt.nr rrlarded emhryn cr11 akavagr and aul.aanl...lly
rrdwrd rmh.yn arll m.ml.rr (aahnr rs nx:ohne 1! S t 1 7 r. 2? 1. 19
nwle./ernMyo, st
1.`00 h un Ifav S. 1' < OOS /towever, t+ealmrnl fnr rven I day (1hy 1) a.Rnil.rantly
rrQu. rd rr11 numlrr (t.Rnr rs nnnhnr 47 3! 1 1 rt 105 *O V, al 1J IM) h day nn 14y S,
1' <001) N.iut.nr .n)rat...n dw rrautted in a ma.\ed amt prah.nRrd rrdwlo.n in nvul.a't
IdUMI llnw /prrUN/mrm .. 41/ mm afler nicnline 061 1 006 r.. 1/ 11 . 0/10 tnl/m.a R t,
/' < OOrri IM .rau/1a .nd.rale Ihal, in Ihe ral, tKn a Mirf e.lxnure In nicnt.ne, Ihr
ch.rl a1\.dun1 u/ L.Ira,an. rdw'es nvxhrral hkuxl (luw and Ihe tale of emhryn crll
pa.0lrulxn the rmh.yo .t Iherrfure suscepUhle lo Ihe efleclt uf mcul.xr Leture
implantalum
Ahr. A.ll l4 snd llammer. R I
1.w.nu1 ../ Rrp+.nlo. u.x. ,( f rrrrMr 74 71 76. 1)IS
cbhrr, wrh+t Ihe Rrarorch 4.ciety of SiRma Xi
I.nm 1he Itrtaa.tment n( Analomy, Wa»nr Sute llniversily ScMrd of Mrdocine, 1htrod
SII11'llt'1 AtIIVAIItIN O/ PAR11('111A11 (:IIANl1.At1 (-S'(IACI 11% A
SPI (-11 /( / 1 AM (l1 I't n( P/ I Y N IN\
Gxanft1tr ayala.e wat aclivatrd 1 In 10 /n1d by hrmin in a Mnr d.l.rn.lrnl
manne. in meml..anra p.epatd (rnm h..m..Rrnatrt uf ral 1onR, ('. ra1 Rhoma :rll., u/
111111 ra1 neuwMaatnma crlts Mat.n.um a. hvat.on was ol.arrved with SO 14) Nltl pM
hrnun wilh halthrr eonrrnlralinnt hrrng inh.hdory. Activalinn was ubservrJ when
MRy'(Llr bu/ md when Mns' (ill' wat vKd at the suMuale Incrraard enryme
]alivily rrflecled srtea'hve aitrvalinn ul the parlnulate furm of Ruanylale eyclaar, hrmm
rnhihittd Iht t.duble (nrm nf 2yanyla/e cyclate 70 in 009L over a wide ranRe of
amten/rat'vms Aarrvat.nn was rv.l secnndary lo protenlysis sinee a variely of p.Wratt
.nMhr/..n farkd tn altrr slimulalion hy hemin. Prmophmphyrin IX had liule effect un
pa//Klrlale wanylale cyclaae aclivity and llMliu/11 bwuhydride aloxnl cnmpklely
atxdnhe.t hemindrtymfrnl aclivalinn These dala suolRes1 a requirrmenl for Ihe ferric
folm of Ihe pnrphynn mr1s1 ehrlate fur aclivalion. /lnwever, aRents which inleracl with
the nnn nwkus of (xuphyrins, fwh as eyanwle, had tillk e/lrcl nn the ability ol hemm
in sctivale I{wnyl.le cyclase lhe tlunv/ahvy effects of hrmin were xbxrved in Ihe
preaeece of delerRrn/a such as 11.01.1.4 MX, and highly pvrified parlicrlale enryme cawld
he aalivaled /a the sarne ealent n enryme in native memhranrs lhese data auRarsl thal
Ihe mleu(txrn .u/ p.wphyrins wUh pailiruta/e wantlale eyclase it comple in naturr and
dtfferenl (rom Iha/ wqh Ihe snluble rnrynx!
Waldman, S A, Smacnre, M S, 1 ewicli, 1. A, Chant, 1. V and AIv.eJ. F.
I he lnwnal a/ A.nl..llrral (Arnvurr 2S9(7) 4018 4042. t0A1
1 .`
I
(hArr fuppnrl National lnslilulea of Ilnhh and Velerarn Adm.niVral.on
I rom the hrpa.bnents of Medicine aml Pharmacoh.Ry, Slanfnrd I lmvrrs.ry, Stanl,nd.
('A and Vetrrans Adminislruirm Medical (enler, Pafo Allo, ('A
III1:111YP11R11111)PAR11('UTATCGl1ANY1Al1 ('VI'tASI 1ROMRA1
I 1/NG ('l1ANA('ll RI/AIIUN ANIy( (1MPARISON M'I/11 S(/1 Itltl I
(:IIANVLA I I (\-(I.ASE
(iuanylale cyclase was purified 1000fold from washed ra1 IunR paaxul.ur
fncte.ns h. a Imal ap'cific ,alivily of S(10 nrm.kt cyclic (:Mr p..xluard/m.n/mR pu,lrn.
by s ea.nbnsalwm uf deNrRenl eHrac/n.n aml (hrnmarnR.aphy un cun. an.valu.
A.Srpharuae. G1IvaRarow, and blue aRar.ne rarliculalr Ruanyl..le cy.laar h.n a
nxdecular wr.Ahl of 200,000 daltons, a Slnln radius of UTA an.l a arJ.mrnulxn.
Cor/(N'Knt .d 9 4. wh.k Ihe w.luhk fnrm has a mn/rcu/ae wetghl nl ISO,(NN1 .1111nns, .1
Slnhes rs.6vs uf aeA, and a sedrmentalmn etrefficient uf 70. Whrrraa Ibr p.utnxlu.
entyme is afilynprolein with a specifie affinity fur axncawaval.n A and whea/ Rrrm
aRRlulinin, Ihe soluble furm of fownylale cyclate did not bind b. these leclins 1'unl.rd
parlw'ulale wanylale cyclase did nol crost-reac( wilh a numtxr uf momx'hmal analvxlK.
(leneraled to Ike snluble enzyme. While bnlh forms of Ihe enayme anuht he rrRulalcd bs
IAe formatwm nf miaed disvlfides. the parlrclllalt tntyme was rrlalivrly marnan..e /.,
inhibilinn by cyaline. wqh (itP n suMlrale, holh fmm. .A Ihe enryme dr.nunaUatr.l
typ'ral hine/1rt, and wilh (il/ anaM+aues, neRalive eaHarralivdy waa ohsrrveJ w.th Ix,dA
enryree furms )hrse dala fupport Ihr su/{Rea/Mrn that the Iwn /mroa uf RuanyL.lr a va...r
rynarss am.dar catalyt.e siln allhovRh their rema.ninR itruclure is .hverRrnl .ra10nuK .n
ddlerences in subcellular dislribv/ion, physi.al characte.islx.s an.l antiKr.ua.ty
Wa/dman, S. A, I ewiciii, l. A., ('hsng, 1. V. and AIwnJ. f
MdrrrJer enJ frllular 1mrArmiftry STISS166, 191).
Odr.r svppwt: National Im/itutes of Ileal/h and Veterans Adminisuatiun
f rom the Departmenu of Medicine and 1'harmacnloRy, Slanf.wd Itnivrrti/y,
5lanfad, ('A, and Velecans Admiwislralion Medical ('enler, Palu A1to, ('A.
I NI7O/ llf 1 Il)M DCIF.NDf.NT AND NI I ROVASOh11.A It1R INhl l('1 D
KI 1 AXAIR/N Of VAS('I/LAR SM(X)l// MUS(1f RUl 1 pl
lhe rnrchanisms by which endotheliumdrpemlenl ra/asanln and
n.ho.a.rnLlaw..
cause 90119311011411 of vascular tmonlh muscle has beerl rtvirwed A nuxlrl e.pt..mmR /6r.r
nMelva/x.ns is 4ummaraled /n I1n I. Ike emllNheLurn-dependenl Ya\.xl.lahxt, th..WRh
mlrra.lu.n wilb Iheu apprnprule receMu.. are IMw~hl la activa/r ph.wph..l.p..ar A. anJ
cause the relrase of as unsstnraled fally acid Ihe releaae.l unaatu.alr./ l,.uy a..d ... t
melabnble is th.waha ar txt the'tndWhelial rrta.anl fxlm' thal in/eracla w11h Ihr am.»nh
mwclr cumfx.nrM 1e cause rtlaaalinn While Ihe Ynaa/Y/a/ed fally N'n) may be o.nlur.t
in eilher the end.Nhelal cell w smooth mvu/e cell, /he labil.ly of the rn.ta.thrlyd .rls.ani
fac/or suRifeslf Iha/ vt kasa some ol this processing ocews fvl.we i/s rrlraar Irum t1.r
endothetium. 7he model in Fiwre I aua{nN Ihal an o.nl.eed (a/uy acx/ nr a.kr.vrd I..r
radn'd is rntx.nsible (nr ac/ivaliow of smooth mwcle Ituanylate cyclase and .nc.raars .n
cyclic (iMP kveh At pointed ovl above, /he vst of vsr.ow mMbiuars of /atts a. ul
1)1
relrne and meuhotiam hs nol sllowed us or others to predict the structure of the scl,e
msterial To dale Ihe best evrAence suegetls Ihal the unsaluraled (ally sc,d n a pnnsuc/
,d either the hpn.ygenase nr P 4 50 psth.ays
RatuMrr1, R. M and MwaJ F
l.w.nal o/ (r.lr. Nucfi.yrJr anJ P,.ur.n PAn.pArrlar.an Rr.ra.,A tr/1 S) ~111 :9A, P/A1
(trArf raprur Natiunal Intt,tuln of Ileshh and Veterana Adnuniauatnm
I rnm the Isrps.lmrnls of Mrdicine snd Pharmacolngy- StanforA lln,.ersily S.h.ml of
Med.c,ne, Slanlurd, ('A, sm) Vetersns Adminitlrat.on Mrdical ('enler, 1alu Alh., ('A
AfR1A1. NAIRIIIRI 1147 1 ACT(7R Stl tCTIVf1.Y A('IIVA7IS PAR l/t'111.A/1
(i1/ANVI AII ('Y/'I.ASE ANItl1-I.VA1/S('Y('1 t('GMP IN RAI IISSI//S
A study was done on Ihe effects on tuanylale cyclase and cytlic (iMP
accumulallon of a synlhelic peplide eomaininX Ihe amino acid sequence and hmluRn'aI
xl...ty of atuial nstrluretrc (actor (ANI ) ANF aclivated par/iculate fiuanylatr cyclasr
in a cnncrnl.at.nn- and lime dependenl faahinn in erude membranes ubtainrd flnm
M,mnRrnates of rs/ kidney. Achvatmn of parliculale tuanyta/r eyclate by ANI .aa alm
o/arrvrd .n pa+t.cda/e fractu,nt frnm homn~enales of ra/ aorta. Irves, imral.ne, IunR,
and hver, hut not from heart or bra.n 4rlulde ttuanyl:,le eyclaae nhlained fYum thru
lntues kaa no1 acuvaled by ANI IrylVn lrratmtnl of ANf prevenled 11.e aClwarn.n u(
Ruanylate tyclatr. .hrk hral Lealmem ha.1 no rf/ect Aceurnulal.on of cycl,e GMP in
l,dney minces and snr/s +aa u.mulatr,/ hy ANI acavat.nn ul Ruanylate cyclatt Ihrae
dala suRRnt s rnle frn p,rlaulate tW,nJa1e cyclnr rn the /nulrcular mnhim.nn
unAr,ly.nR the phytndugnal r/le.ta ,1 ANI au.h aa a.cular reliul.un, nalrnueas an1
dmret+s
WslAman, S A, Rspnpnrl, R M and Mu.nJ F
TAr l.wrnaf .r/ Rndoerrol ('Armnr.r tt9(71) 11112-1N1W, 1'/81
OrArr ,uprywr National lnstituln of lleallh and Velersns Adminislra/inn
I rum the Ikparlmenls of Medicine and PharmacolnRy, Stanford I/nivrrtity Srhtwd of
h/eAu:ine, Stanford. C'A, and Velerans Admrnmstra/ion Mrdiial/'enler, 1alo Allo, CA
ATRIAt. NAfRIl1RFTIC FACT(1R T1 ICITS AN FNtx)TIITI IIIM-
INI)TPf Nitl N 1 REI.AXAI R)N ANIt A(-tIVAT1 S PAR 11('l/l A l f(i1)ANY1 A 1 F.
(-Y('t AS1 IN VASCI/LAR SM(X)111 Ml1S('1 E
A 76 smimr acid synthelK peplide frsRmenl of Nris1 nauiureln (x/nr (ANI l
relssed iuJaled rtbbil aorlre se{menls in .hNh the fndo/hrllum was til/.er .ntacl or
funclionauy detuoyed the relsatl,ont wert lemporally att.rialed - 1% Increates rn
kvels of .(~MP .ilh Iq ehan{e in the kveh .A cAMP. the ANt induced increates in
cGMP ..ere also nMeeved in sorlie seRments prHresled -ilh cskium hee huffer nr the
c(iMP phosPhn,lrrsltratt inh,bisor MAB-22 Ottl. VualNativtly umiln cewll, -ere
ohtained fur smt.ulw nilroprusside ANI' seMclively activated parlu'ulale guanylste
cycla.e, having no effecl on the soluble (orm of dse enayme Ihus, 1ht durcl
fendn/hehum ,ndrpendenl) vssoddstor effect of ANF msy he mr.tsled via increaaed
l,ttor /rvett nf c(iMP AN/ sPpta.s In increase vsscular e(-MP k.rli by activatu,n .d
ts.In u/alr, auintl./r fy.laar
1
Wint)uial, R. 1. Faisnn, E. P.. W.Idman, S. A., Schra.tr, K. Afu.uJ / and Raluqwnl,
M
PrnrrrdrnRr o/ the Narrnnaf AraJrnry o/ Srrrnrrt ../ the (rnurJ Stmrr, a/ An,rnn ~
76f.1 7664.1984.
OtArr suplr,.r National Inslilutes of tlrollh and Velerans Admmnualiun
1 rom the Qrparlmenl of Cardinvaseulsr Pharmacology, Mere\ Instilute (o. Iherapr..~
Resnrch, Weal Puinl, PA; Ikpar,menls of Mrdieine and 1har.na..duRt, Slud,
I/niversny, Stanford, CA; snd Velerans Adminnpslrrn Med,cal ('rnlrr- Palu Ahn, 1 A
M/('11ANISMSOF AbENOSINE 7RIP11O\PIIA11:-, TIIR(7Mf1IN, ANI)
IRVPSININIq/('l/)Rf:1.AXA11/)N(N RAI 11/ORA(7(' AORIA
lhe methsnisms by which Idemnine Iriphnsphale, /hromtan, and Lyps,n ca..
relaaaGon of katcular ,moolh muscle ,rere investlgated Rrla.alron of the ral th,n.,
snrta .rth adenosintt Iriphosphale, thrnmhin, and/or Irypsin raa stsuciatrd .
increased kveh of cyclic tiuanoarne nwrnophntphale in Ir,th t,nrr a,
cnncenualion-depersdenl manners. IMombin .nd Irypsin did m.l alter cyclic adrn,n
nu.nnph.nphale kveh whereas sdenmine Iriphosphale increased cychc mkn,....
nu.noplw.aphale Irveh afler signifieanl relaaalwtn oceurred Remnval of Ihe emlu/hehn.
alnliahrd sMlenosine Iriphospha/e-. Ihrmwhin-, and Irypain indu.-rd rela.alu.n and 11
associated increasrd kveh of cyclic nuckwirks Retau/ion due tn Ihear sllrnt, .at al
inh.hited by eapo,wt 1o nordihrdrntuawrelic acid, a/qrqyRrnate mhdr,bu. s.-
eicossletraynoic acid, a lipoaygrnase snd eycMwaygenase inhib,lur Imh.mr/ha,.n,
eycW1D.yRenase inhibilor, pnlewlialed rela.aliun to these aRenta, .hereas Ike inw,r.nr
kveh rf cyclic nuckolidp due 1n ademnine b,phoaphalr rrere unalrrrr,1
Rromophenacyl bromwk, a phmplnAipast As inhibilor, decrrated rela.ation dur /a,Mnosine hriphosphate,
IMembin, and Isypsin anJ the asa,c,alyd mcreated levrls .
cyclic nuckulides. Remnva) of eatraceltular eakrum, whwh sHu presumahly mh,hn
phoapholipase A., prevenled /ht ekva/ed levels rd cyclic nuclruGdn and Ihe inhd,nu
effects of adennsint Iriphosphale and Irypain nn eonlraclu.n. In cnnlraU, arhu,w Irop.uside induced
retaution and/or increased levels of cyclic /tuamn,n,
mum.phosphate .rere unallered by swrdihydrnRuaracelic acrd, eicotulrtraymc a.,/
Mtunnphenacyl Mowlide, and rewlnval of tatsacellular c.kwm. Aftrr ,muhalN.n .,
intacl /i,sue wilh raP-orllmphosphale, the pat/ern, of plotrin I,hnap/unylalinn caused I
adennsine Inphosphale. IMomhin, and Iryplin .rere india/in/la,ahal+k frum Ih.nr .-
acelykholine, srldium nitropw,ide and Lbrumo cyclic /uanoune m,nn.phntphale Al
these aRenls dephrrsphoryhled myosin 1rRh1 chain 7hus. the prrsenl sludy tutq.Mlrlh u-
hypnlhesis that rela,alinn induced by adenosine IripMrsphatr, thror..hin and Irypun ,
medraled IMrwgh Ike formation of an emhNhelial fac/or ..h.ch elevale. cnlw Ruan...u
monophntphate kveh and causes eyelie guanosine mun,.pM.tphate dey.endrnl pnn..~
pMnphwy/atron sml drph.nphorylalion uf mymin hShl aharn
Rap,q,au, R M, Itrarnin, M S, and MwaJ. F.
(,IIYIY(nIn Rc.rar.A 2.15/I.IAa-419, M11
c)drr .upfv,.r Nst,onal Inslitutes of Ilealth, Ve/ersns Adm,nistralinn, N..rn.nal Retru,/
Service Award
Ilnm the Ikparlmenls of Medwine~and PhumacnMRy, Stanlnrd Itm.rr.,ly S,h...1 .1
Mrd,crne, Slanf..,d, ('A, and Velerans Adnun.alrat,nn Mrd., 31 r rnln, Pal.. Ahu, / A
1ts
111
AIRIOPfr11N I 111 VAIfSCY(-1 K-(:MP, ACIIVAl1SCYCl 1(-
GMP I)1P1NblN1 rR(7/11NKINASfANI)('AItStSRtI.AXA11l)N
IN /tA/ It1()RA//(' AI)RIA
Syr11he1:C a/rinpep,ln II, an fUiat nalriuretK faclot wi/h p.Hrnt vasndilalnry effects,
wst etudwd in isnlatrd stt:ps nf 031 ehnracie aoHa /o I/etrrmine rtt aclw.ns on
Ch/nlrril.bly, cyclic nu.teolNtt concentratrnns and eMInReMlus acllvlsy of cyclre
nutlrol.de Aepre.lenl prnlr.n \.naart Alrily.rplin 11 was f.wnd /n rela. anrlic suqq
prrcnnuaalyd-..ah 01 yM wnrepinrpM:we whelher nr nnl Ike endnlhelul layer .a1
prraenl RelatalN.n in alt.npepdn 1) was elosely enurlaled in a lUme- a+Nt
cnncentration-deprndenl mannnrr wilh increases in cyclic I:MP concen/.atnma and
a.bvalN.n uf cytln- GM/ detrM/rn/ p.ntrin %,insst (cyclic (;MP kinaae) the /Meahold
rrn.rnlratN.n fus all thrrr effecta waa I nM. Atrinpeplin 11110 nM far 10 min) pNluad
in !l1r11L rrla.alN/n, an t(oW .ncreaar in cyclic (:MP eoncentratNrnt snd a 2 14,141 /nctraar
.n eytbc GMP slnaar scliv./y ra1NN Alr.nprplia 11 sd nnl tigni/Nan/1y sller cyalk
AMP .nn.entnlNlnt .ur cyclic AMP dependen/ pnlrln \inaae aaiiv.ly Ihrae .1313
.ugRrv Ihat cytla GMr and eycles: (:MP kInaae msy mrdule vaN'utac rrla.aann lu a
nr+ claas of vaaoacave sRen/t. Ihe alrut nalr/urr/ie fac/ors S.mdsr effecls have /rrn
uhaerve.l .r.lh Ihe mUOqaMldal.w, todLum M/1n(NYteM1e, aMl the endlNheliYnldrlN`Mlrnl
vaNNldal..r, arrlylahnLnr thrrrf.ne, a cnmmnn hNxhem.cal mechanism uf action that
m.InAra cycl.c (;Mr actYTYtalNln aMl aClrvalN.n nf cyclic CMr Ismate may hr invnlvtd
in vaa uta. rel.raal.nn In nlltovmunldalnn, rndalhAWm dependrnl vaawblalnrt aMt alnal
n,11/1Yr1'IN IXlrnl
I naus, R R, R a/N.pn.t, R M, Waldm.n, S A and Afwnd F
R..r A.mn n,r Rr..phrurn L ro N6 179 /A1, 1'7/15
(7.hr .n~p...t Nal.unil lmtalulra.d Ib-dlh and \~rt...na Ad.onualrj/mn
Irnm Ihr 14(.al/m.n1t ..f Mr.1..nr 1..1 1I.~.n.1,..1..RV \Ilnl....l 1'n.vrrt.lv <LInf.N.1,
( A, anA Vrle.ant Admm..lral...n Mr./.. .1/ ro..~r 1a6. All.. I A
A 1 W(1 C I I P PKIX-1 /)11R1' I(SR ()II I AININ(: 111(.111 V PI/R1/ 11 1)
PRAR11('l11.A11 (:I/ANYLAIC(-Y(IASI IROMRA1117NG
GuanV/ate cyclaa (O1P pyrophnaphale lyaae (cyclir:nRi. FC 16/2i, the rntyrne
calalytin/1 Ihe f.nma:nn of cyclic (:MP frnm UtP, e.:att in IN/th snllehk anlt
mrmbrane-M.und fNrms. lhete entymes have Aeen impl/caled as Aey rrRulal.Ny
a.nlw.nrots in a vaaely uf hi1.Mie:cal events sw'h as tecrrlw/n and amn..eL muack
rehaa/in1 t7mirrtlaMhnfI /he rnle Iheae entymea ptay in cellular reRutalinn if fredicaled
upnn obtaining 1.Y11f1rd preparalN.nt nf 8uanyla/e eyclase Several prnce.'urrt for
pYrdying the uduhle enrynsr in spparenl hnnw.Reneily frons a variely uf tus.uet have
been rrMNled Ihe pa./KYtpe entynM hat heen pYrdlyd /o q.parrnl /MnN.Rrn't/y (u.m
tra Ylch/n aprr111 hul. In date. M.n11.~enenW preparal/o11t nf par/1cutJ/e /{YanyIle cytlatr
/Inm mammalun Ihsuet have MN Men ntA/anrd lltce we tepnri nur eff.Nlt in pnnfy.nR
parl:culale {Yanylsle cyclase abeYt I..'00- lo S7,tX70-fold from homnRenatet of ral IunR
PurlNma uf th.s wnrh have appeaed in aMtucl form
W aldman, S A,(-hanR, 1. Y, and Hurd. F
I.rpn.nn.. R... r,..w..n 1 Ia(11101 1/9. 1915
1
OrAr. tNp/wrt Natinnal (/n/ilules of Ileallh and Velerans Admin:tlralion
r rr.m the tlrparlnwntt of Medicine and Pharmacolneely, Slanfnrd I lni.enity, Slanfn.d,
-A, and Velerans Adminislnliow Medical ('enler, Palo Allo, ('A.
I I//C1S 01 AfRIOPFPTIN ON PARIICUIAft G)IANY1 A11. CV(-1 AQ IROM
RAI AItR1.NA1.
A/rinpeptin II aclivaled parliculate Zuanylalr cyclase 3-IO-fnld in a contrnuaunn
and hme-drpeMknt faahrnn in erYde memManes ol.ta.ned from h.m..`enalrs o( ral
adrrnal corera ur medulla Similar effecls werr o/nerved with other
uin/Irpl.n anal..at
S.duble Ruanylatr cycba and adenylsle eyclase in theae preparaliont wrre nol acl.valyd
ACCYTYIAhnn of cyclic (iMP in mincet of adrenal corlre nr medulla waa iM~era.rJ
M1 1 fnld dYe /u strN.peplin 1/ aclivalinn a4 parliculale Ruanylale cyclaar Srvrral
IhN.) rraal.ve aRrnls blocked Ihe ac/ivalwM nf parliculalt gYanytale cyclaae, Supke./.nR
that f.re /hn.l itrurpt no memhrsM prwtint may he rmpurlanl in aIIMyY/H.n
rereplur louanslale cytlau coupling
~
Waldman, S A, Rapnport, R. M,/ iscw, R R., and Afwed, F
Rr.rihnsrce rr R.rnpArvro Aru 84t.291-]O1, MIIS.
(hArr o.ppNt Vrlerans Adminislutamn
from the Ikparlmrnl nt Medicine aMl Pharmacnhryly, StanfurJ I/nivrrsily S.h.d rd
Mnhc:ne, Slan(nrd, (-A, and Veletans Adminitlralinn Mrd.cal (?nlrr, 1'atn Alln, 1A
R(11 1OF CV('1.1(- (:MP IN R11 AXATK)NS Q1 VASCIII AK SM(N)111 M1/5( 1 I
Relaaatlnw of ral sorls starneMs wilA sa1/YT MIlOp.YaaNk aMt
eMlnlhrhum-drprndeM vqodihlors, tslch q actlykholiwt, Aittamiwe, A?1/~7, AIP,
thnNnbin, amf Irypain, is assoeialed wilh eyclie-(:MP Ic(:MPI KcYmulalMn in a
c..ncenlra/inn- aM) (ime-dependewl fashiow. Wrth rat aona teRmrnl.. Ihese q{enls dao
:ncreaat cyclic (:MP-drpendeal prtNein-hinase aclivily and allet Ihe incnrporstN.n u( "t
int.t numernYs smmlhmwCk Moteint. Ilfentical psllernt nf protein phoaphorylalN.n
werr ohserved with hoth elqtts of relaaantt eo two-dinsensional Ilet tkclcophnrrn . .1
wlnradNlifraphy. lhe effecls of ailrnprwtide were oMrrvrd .vath nr o.IhnYl /M
emhahellwn presenl. (w eonlrasl, the effecN of Illr endM/w/ium depeMkn IRenn un an
of Ihtae paramelers (c(:MP. K:MP-d.pendent pt.arm C.nate aM1 prmrin
pMHphmylalion) required the inltRrily of Iht eMIO/helnNn, VarYws in6.bilon .d
phmpMdipau and bpoay~enase Mevented Ihe effet/t of Ihe eMlolheliu.n dependent
aRenN, tuRgetling 1ha1 a tnelabnlile of arachidnnic acid iv 1he eMMNhehum .rla.anl
faalm and retplmsihk for gwnylaleeycla.e aclivalion A smM.th-TUtale p.atr.n wnh
decteaaed tor incnrporal:nw afler /reallnenl wtlh eHher elats of rrlacanla hat Irra
N1rnlA.ed as Tynain light ebin A mntltl it presentrd tuRlNatinR Ihal the e/frclt nl
eMhNhrhYm dependent vasoddaHYt and dNrea)y acbno n:IruvatrN/dalws tunvr.Otr at lhr
level nf Ruany/atecyclate activat«.n snd eGMP aceumula/Nm, .hNh e.p/.nns Il.r
cmmri1n11 IIWttNr11KaI and phy1/0hrlrcal effecls on tmM/lh TYNte nt lhrtr Iv.n tlaaars no
vaawldalora
Hwud. F., Rapoporl, R M and Fiscw. R
hwrnnf of fa.drn.otrNfar rAnrnlor.dner 7(Suppl 11S111 -S/ /m, 19sS
I Ilt
(hhrr supry..r National Inslilutes of Ilwlrh and Velerans Adminislralmn
I rnm Ihe IMparlmenls nf Medicine and Pharmacolojy. Slanford t!niversily SrM.d uf
Mrdnule. Sbnfmd, 1 A, and Vele.ans Adminnlral.un Medlaal (-enler, Palo Al/u, ('A
t 111 ('1 (71 S(11)111M P(11ACtItIM PIIMP INIIIRIfORS ANI)
1611 M11RANt 111 IYfI AR!/IN(: AGI N IS (N1 S(IqIIIM
NI1RI)1'K11(SIt)1 INISII( 11) K1 I AXATION ANI)CYCI.I(' GIIAN(1SIN1-
MISN(H'111K1'11A1) A((IIMIII A11(/N IN RAT AORIA
Ihe purppne of Ihit sludy was to invesURSle Ihe relsl.nnship between
aullum
nI1/1yNU\Nde .ndured rrlsalmn, rnh.haioa n( Ike sodwm pllaas/um (lump, and cy,lw
Allan/nrne mnM.(~h.nl.halr I.pntYrr nf rat IhtwKK anrla In nuabaln, a1 pnla\slum m
nuptne.mm f/ee Krrhs Kinser hwarf«.nsle ndvlion, protedure/ arh.ch presumahly
rnh.hMl Ihe atillu.n Lnua.unl pump, n. hW pNSawns chlnrwle w lelurlhylamm.m.u.n,
n/emb/ane deryda.ulns agenls. InMMlyd relaaalw.n 1o n/lrq..unwk Ihese cnmllbnm
had !/ulr nr no effe.l an Ihe elevated cyslic Suanmine mnnophosphale kvels 31 a
cnn.enl..lmn .d nnrnp.osawle (0 1 rM) Ihal relaard Mwrpinrphrine conUacled Insues by
tOt Ilnwr.er, al a ma..murn rebunl concenuabon uf ni1.IqlrussiaM 110 PM1. these
InMIAMn7 dhtraqd IAe elevalwrn of cytl.c guanos.ne monnpMsphalr lhe inhibihnn /A
elevaled cyclu: auanmme moMylhnsphare kvrls .as indeprMMnl or the endolhrllum,
euracellular calalum, nd Ihe cy.lti RuaMnlne n.oMqlhus/.hale phu.ph.hr.leaasr
inhl(wtur. MA11 2! Vet1 ihe rnh.hqury el/rcls of uuaAaln and ..f ryllasuum and
maRneswm (rrr s'lur.nn an Ihe Imrra.ed k.e/s o( cyclic RuaMnim mesnophospl.alr
causrd hy 10 wM ml.np.usude were sMdnMd when hssues were rncuhalyd .Ilh.uul
rw.rpmrphnnr, or .nh Muep/nrpM/nr .n the pre.enie of Ihe .. sdrenerR.: M.~:lan,
L/Irnlnlam.ne In .unussl, a/1 a.t.enr.Rw Mu.laer, p..qaaMIM1, had no elfecl on Ihe
owahaln induced mluh.lu/n of ele.ared cytllc guanoslne mnnnpMnphale levels, wnh
Mnrplneph.lne p.esrnl Ihrat rewlls a/e cnm.venl .wh the hypp.lheus Ihal memhrant
evenN reR.fa/r cyrlrc Rwamn.ne mnn..(.hnsphsle synlhesb. At n111oprusahle
.uncenllalilms Arraler than 01 pM, the (urmalmn nf cycl.c RuaMHine nMMlphusphale
a/qwan h. Ae cnupled Io /he status of Ihe umwdh muak cell membrane and /he mleRrl/y
nf the srulLwnl Iw1/a\\IU111 pump f ur(hrrmnre, the ekvaled cyclic Ruannaine
munophnsphate levels induced by nnroprussule may be enmparlmenlaliyed snd,
drpendlnR ury+n Ihe inlracellular cnnceMralw.n, may be ariacialed with sevrral
f uMtwms 1 hest funclions /nay include aclivaaon nf Ihe sndium prNassium pump amI/Iw
memMane hyprrpn/arinlan. Ilowever, an effect of cyclic Fuamrint mnnnphospha/e on
Mldiu/11 /wllatsltlm punl(p acliViiy and/nr /nemMane (qlenlral ren/ains /lt he demonstraled
Mwal, F. Rapoporl, R M, and Sch+a.u, K
(-rrrufahen Rrsrnr. h t711)161-170, 19t1
ehM, suPP.wr Na1Nmll Ins11/u/r1 of tlrallh aM/ Ve/eranl AATlnnlraluln
I rnm Ihe t)epaclmenls of Medicine and Phsrrnscolnlly. Stanfmd l/nivenily S.Mwd of
Med.cine and Ve/e.ans AdminislrNion Medl.al ("enler, Palo Alto. ('A
t
CAI M()1)III.IN-1 AN111ANtt)F 1014 FXCIIANC.F KINfTICS
A flnas dialysis apparatus suilabk for the sludy of high affinity melal hindlnR
pr Hrins has been Wilired lo sludy cslmodulinwlelal eachanRt kinetics Calm.wluhn
lahrled .ilh fu ISS and Gd-1S) was dnlyted apinst huffer conlainin6 va...w
cnmprlmR metal w.ns the lale of rrletal tachanRe was IMrnilorrd by a /amnu ray
sc.ntltlalmn delectnr. The Aineli.s of e.chanRe art fusl nrder and Ike rales fall .nlo I+n
cateRorles ('a111) and l'Mtl) in one, amt Ihe bnlhanidn I u1111), Gd(111), aod I A1111/ an
the ulher
RucciRrms, J,(/'Ihrnnell, ('., and NrJsnn. D
Snrnre P.ets, RclpnR. CA.na pp. 106-409, 1915.
t.om the lsrlrarlrnrn/ of Chemislry, Clar\ IJnivrrsily, Worcesor., MA
A( 1)MPAKAIIVI 111II/Y O1 1111. 01SP(KIIIQN (71 NI(Y)IINt ANI) IIS
MI 1 Alllfl l l l S IN 111R1.1: INRRI.I/ SI RA1NS U/ MK'1
The dis(wnilinn of nicoline, colimne and lnicoline N-o.ide .as invesliRalyd in mele
(-57111 , UIIA, an.l C')11 mice following an ip injection of nicoline (1 0 nIR/mll Ihe
half - hves (11) of nicotine in b4wr1 a.eee 59 lu 6 9 mm 7 be rapid elm.ina/inn uf
nicoline was accompanied by a rapn/ acrwmulalMn of inelaMtldes, maumal
cnMen/ralw.nt of colinine in hM.od (204 In MI nR/ml) u'ere aalh.rvtd in 10 m/n s.u1
nKU1mr N ns.de (.) ng/ml in ('111 mice) in IS min 7he If in bhwwl was :01 in 196
min (n1 cnlinine alwl It 4 /I/n fm nicM/ne Noalle 'fhe 11 values fn/ nicnl.ne in hrd.n
..ere simdar lo Ibov in bkww/, bW Ihe .alues fn. the liver ..ere s1.Rh11y 1arRrr 16 1 to 9 7
min) aM1 inlerslrain differences Lere signifiCanl. A laree slUSin-rrlaled ddle/ence in Ihe
1/ f.w cnl/nint 1Ya1 fnund; Ike alelabnlile was eliminated Ironl the bI/MMI nf 1/11A mice a/
nnly slw.ut nne-half the rale delermined fnr Ihe olher suarna Ihe 11 (or nwol.ne
N-atille in Irver ranfied frorn 12.7 to 21 ) min; the values wtce srRnlfrcanlly dllferen/
wllh ('37111. > Ir11A and a(-)11 nliee. Sleain relaled ddference% were also ohsrrved in
respnnse 10 ehronic ea(wrsure M ei2arelle sm/tie. 1 he 1( of injecled nicol.ne nplwa/rd lo
tr s1lRh/ty decreaad in CS7R1. and (yRA mlce hul .as .ncreased by 60'll% in bvers u( 1' 911
mice compared 1o a cuMrol poup.
PNns.n. D. R. Nmns, K. J snd1Aoelpsoe, J A.
DruR Afrlefrdlsm end DrsJwrtinaa IZ(6)(i001-(i007, 1961
From the Schord of Pharmaty, l/lli.ertily of ('alntsdo, uH.uldee
1S(!1 A 1K)N ANI) ANAI.VSIS OF NOX11)F Mlf AROI 111 SO1'l l R I IA R V
AMINIS,(1l/ANt11A1/1)N()/ NI('p11N1.- IN ()X11)1 I(1RMA11//N IN MIl'1
To invetlqNe Ihe (nrnulinn and eliminalinn of n.culine 1'-Nnu.te INNI/) m
mice Itealed r'ilh a single ia%ec11o11 of nKMine, sensitive and sekclive melMuls e.ere
devebped ta Oua/tlilale Ihis polar and hra/-lahile metaholile. The comnwnd -as nolan.d
from tissue homr+6enales as a dodeeyl sulAte ina pair wrth Cu eal.acti..n carl..dAes snd
analyted on an amino bonded phase hiAh-performance lipuid chrmnaloRrath.c adumn
.ith a mobile phase ennsisling of wlprnpamd.aler. Overall eecoveries ul NN/) wele
64 76% Irom hiol..li\al mrdu Sevrr.l nw/hMlf of .Mletluul arrre e.alua/ed,
rsdwdaMlms -as necessary to "h.rve the senul.vi/y .rqul.rd Lu
119
pharma:n4inrlic vudn-a in m.rr Ihe na and tron, itmm-l.d NNI) wrrr teparalr.l on a
1'1.1rad PAI nlunrn an.l rnlylnala Srlhlr~ny waS r-..lu]/rd fn1 the fn.m.l.nn n( /hrtr
nornr.s rm m14r
Ihnmpum, I A, Norr.t, K 1 and Prtnvn D R
lnu.aul.l ( A....nnr.,K.nrAr 141 4/9 It9, PIIL5
t rnm Ihe 5. A..J uf 1'harmacy, (lni.rn.ty of ('nMradn, Onuldrr
INA/' IIVA 1111N (11 1111MAN a I PR(/I I INACI INII1011/1K 11\- (;AC Pt1Aas/
1 Il:A/tl /11 \Al1)AI
At rel.a.lyd in Iha 11u.1y, dirr.l r.l-u.r ld hurnan n1 pr.drrna+r rnhdnwr 1..11'1)
to the Rst phate SnmuMe /rmm ..nr c.liarellr rrtults rn a MphaSi. .n.nl.vat.an nl u11'1 11)
I he aulhn.a nl..rr.e 0 rap.d, iniUal hnl of e/.nute mh.h.l..ry aparrly, 16e amn.ml o/
whn h.+ drpen.kn/ ury.n the aRe of the tnaAr I l.n rat.d, .A.nr hrnr .n.n hr.n..w .s n.d
sern ..hrn Ihe Lrntr.n iS e.(wned In aqurnus e.1.aaN of c.Rarrlle sm.\r lat hi.l hePn
dont rn the pi.t) (2) Ilowevtr, Iwnh e.tr..u.r rrR.mens pr.uluce a ucon.l, s/uw
rn.rurm...r Ihal IKlurs n.t'r lrvrral .I.ta Ihr aolhurt auRRrsl /hal the thur -tr.m
ins.lurn may hr dur to a pern.ynrstale (,r a S.mdar reaclive sl`ea ie+) Ihal Is fmnud fr..m
radnals .n the Ras phase hul rs un.lahir .w aqurnut wlutn.n Ihe authors ha.r n+l yH
rArnal.rd a tprarrt rrt(wmvhk fnr the b.nR lrrm rnarlr.ahnn nh.r/vrd f.dhrwm/; h.nh
durcl ryunurr to trRnrllr smolit anJ r.lrnu.r 1.n aqora.us rara.ta /lne Iwntil. Ir1y n
that the maalrvalu.n c..mrs aMul at a rrtull .d the cm.rdalron ut ntl( wuh aolnuduahlt
tmnke cnmpnundt llral dn+ut.t In aqur..ut tolulwnt
Prvnr, N', A Ihr.lrs, M M, and (hur.h. 1) 1
IL..rArwurol anJ 11r..rArvru/ Rr.rn.A (..nnrwnnrr..n. 1221-'IAfA ARI, P1R1
QrAcr suprynt Nalinnal In+lilules af Ilratlh and /hr Naliunat I uund.lnnl fur ('ancrr
1(esea.ch
I rnnm the Itrparlmenls of (hrmistry aod Rinchr.eislry, I ours.ana S1ale (/niversily, 11a1nn
K nuRe
NI I K(sSA 11ON 111 //K(7AN1(' I/Y/>R(Irl K/)X111t S RY NI t R(N7/ N
Ltl)I(11///1/1N11Kln71 N /1 IKAI/f(!Irl.
Cumyl and frrt hulyl hydruryrru.idrt rracl rat+idty wilh NO, / Na(1r in nrRanic
ta,lvrnls .b Iht prrtrn+'r of Uatt In fnrm Ihe n.Ranic nilralr (K(/NI/~/ as the manu
(.rrrlu.l, IuRrlhrr wiltt arualkr amuunts rd the cn.er+ry.ndmR nru/le (11(1N1/1, ah..hut,
and carM.nyl enmtrnrnJ 1aet4q.htnnne ur Nrlnne f.o.n (umyl and t.rt Iwlel
hydr.q.er...nk, reyre.l..rly) Ihr pn.due/s han. f.-r/ huly) hsdaqrro.i.k arr amdar
whelher a hase n prrtrnl or IuN hul Ilune /1nln Curnyl hy4I11yM'rnaMk are rnore camplet.
1 he rrsear:hrrs havr humulaled the Im1ra1 reacanm at a ndrnv.Hron of the hydr.y.rru.ide
by Nal/l lo give the peruryni/r.le esler. Ihn lallrr Slu'crrs is unS/ahk and ruher
rrar.anRes lo Ilrvr the nnrale nr drttnciates 10 furm alhnsyl radicatl snd nihoRen dn+u.k
Iha/ u(hmalrly R.ves the olher ohaerved pr.rloclt Ike Isinetws uf the Iraaln.n were
audo.l hy .Iryy.rd /l..w and sre crnnpka, bul the invesliRalors comlu.k Ihey are
consisltnl wilh the nilrosalinn rnechanism lbr rale constanlt 31 10°C are 2 4 a 1114 an.l
I 1 10s M/s 1 fnr Ir./hulyl and eumyl hydroperotidrt, rrslwaCively the au16..rt
wRResl that Ihis facile reactim uf NOa / Nal/. wilh hydrnprro.ulrt n.ar havr rmlrnt.rm
consequrnces wrlh rry+ect lo the pulmunary Inacily nf Nl/s in +rturRRy an
P.r.w, W A. Caslle, 1. , and ('hurch. U I
l.nonal.r/ rAr A.nr.non CArnrnnl SatAr 107(11.:11 211, 19Ry.
()tA.r .upp..t National Inshlules of Iltallh
t
I rnm Ihe 14pa.lrnrnlt uf ('hemiil.y and Rinchrmhtry, I auisiana Statr Ilnrvrrtdy. Il.n.rn
KouRe
A.1(-IIANICh1C(q ('IGAKI1/1 SM(/K1 1(IXK'tlY 711F1NA('IIVAIIIIN1/1
III IMAN oIPRI1 t 1 INASF INIIIIII I lyR NY NI1 R IC (2Xt1)1 /1S( 4K 1 NI-
MIX I IIRI S IN AIR
A mi.lure of ni/rie o.ide INO) and isnprenr in air has been slu.hed as a m.w/el /or
Rasphasr ciRa.elle snlohe. We hwt shown that this olode( syslelw dup/iaa/rs many of
1he /rrcr/.erlits of eiRarelle srnn\e inc11/dinN Ihe inacliva/inn of human o I prnle.nase
inhibihu (nlPl/- In Ihis sludy, buffertd sululinn of o1P1 avrre esry.ud lu pul(s al au
cnn/ain.nR 100 ptm N() and 400 ppm isaynene. IluhhlmR uf 11a N///air/.s.M.rnr Ras
slream dutclly IhrouRh Buffered prolein solutions cauus o1P1 lu un./rrRn a fad I.ne of
inhrbilury ca/.acily Ihis fast inactivation is nrN obstrved when e/l'1 it ryatad In
aqueous talrac(s of Ihe NO/av/isoprene Inia/ure. IhNh direct equnure aml typaure lu
aquMUS earacls, however, cause .IP1 10 underRe . fbw 1MS nf actrvily thal conlinurs
fnr several days as Ihe proleiN is incubated in Ihe Iwffer sululwms. (ias phase c.rarelle
snwhe has dready heen shoav 1o cnwe Ihis sarne 1.w phase inactivation of n1PI
lhe inaclivalinn of o1M by the Im/def sysle/N is de(rn.knl on the presrnce of
oay{en in Ihe Bas slrennl, su2tieslieff that Ihe eai./alio. ef eilrie n.idt to niornoten dioule
in air is involved in Ihe fornla/iow d the inaclivati/lb sllecies. The nalule of these
species remaim 1o he deterrnined; however, sma/l alYmyl ta peroayt udicals (such at a.e
spin-Iwppable frotn tn-phase sn"e as weR as from Ihe N(1/air/isoprrne systrm/
do nd a/Mear lo ioaclivatt e1Pl. Osle possibility is Ihal Ihe inactrvalinN sPtcns are
meuslahk compounds ferwed by rar/n-al proceues in Ihe Nas phase of M.Ih ciaarellr
smnhe and nur Inedel sys/ew. Otrr data suRResl that one poss.hk class .uf spr. irs .s
peroayMlraleS
Prw.. W. A. Donley, M M and Church, 11 f.
CAernrcol-1lol..R.rol fnrrrorrr.wls 3117]-It1, 191f
cbA.r .upryrt Nalnmal /ntlilules of Ilrahh and Natrona) luundali..n (w /'ao.rr
Rrsrarch
f rom Ike 1)eparlmenls of ('hemisUy and Rwchrmisuy. I ounrana Stale ttnr.e.s.ly, Nn.m
Rnuse.
140 1 141
INA(11VA11()N t>f" IIIIMAN At PIIA I PRt)fFINASF IN111I11/nR RY
(-1(:ARIf1/ CM()K1' 1111('T()1 CM()K1 ritASF.ANI)I11/1t/R
In nrdrr In resolve a dncrepancy in the IFleralure, we have taamintJ the in
rrlrn insclivalwn of human ol-prolemaat inh,bdnr hy direct rqrKVrts tilhrr to whnte
ciRa.rllr sna.\r ra In fdared Is e, aas phase) srnoke. Wyss and cowor\ert rrpnrled Ihal
whnlr {mnle dnrc nnl inanbvalr the protein, whtrtas we rrp,nlyd /hal Raa phate amnke
d,rs We now Im.i Ihal di.rct eapnsure lo fias-phase ciprettr smn\r causei a s1,Rh1Iy
Rrta/er snac/,valam o( IAr prnttin than dnel direcel etlanurr tn whok c,Rarelle Srnn4t,
conf.rmma avr tart.er auRaeala.n Ihal whole swoYe is kss nuJ.nnR /han s jas phasr
smnke Ihs dd(eNtn.e, M.wrvtr, dnes wM eaplaia lhr drimalK ddfrrtnct hrl..ren nur
prtvinus fmdrnp snd thau of Wyss and coworhtrt. lhe taplanalv.n fur the d,a.epancy
IKS .n the nature o/ the hvffers usrd Wyss and eowm4ers vird fris hu/fer snd the uv
uf lrn qurnchrs the act.vatiun prrresl shnosl eomp/elrly Our r.pe.,meets u.rd
phaaphate hultrr We suRarsr /hat Ir.s rs an unsuirahie bulfer for use .n r.tr.imrnls
Iha/ pruM the effr.N of c.asrelte smn\t
r,,,a M ( sn,l tt..nley- M M .
~w.r,.nw Rr.,rr n/ Rr.prrWury p,..av 111941 941. 1911S
Orbr .arrwr Nshnnal Insldules of Ileshh and Nalu.nal /ovmlara.n fnr I ancrr
Rtarah
I rom the 1)epatmrnl, nf ('hrmnt.y snJ R,nrhrmnl.y, I nu..un.-i Slate I/mveraiLy, taalon
Kuunr
/ K11 RA1/11'AI ( 111 h11SIRY (/1 1 I/:AR1 111 CA1(1K1 ANI111S
111X11 (/1 t K:I('A1 /A111 K A 1 K)NC
('.Rareltr sm..ltr conla.ns twn verr different pnpulatarns of frre radical, noe m the
tar and one in the aat phav the tar phate cnMams sevral rrlalivelr tlddr free
rsdicals, we have alrnldKd the pnnr,pal radora/ as a souin,.nr/hydraatv.n.me (V/r111.f
eaampka hrhl in the larry rnstrrs We suRResl Ihat ths Q/(111# pnlymer is an sct,ve rnhn
tysnrm 1hs1 is eapahit nf reducinR mnlecvlar nayRen lo pcrn/uae svpero..dr, t.rntvally
tradinR In hydroRen permide and hyd,nayl raJicaN. In addilion, we have shown thal
the principal radKal in lar reaas with 1)NA /n r.tr,., possibly by covalent b.ndinf
the 2311 phase of eiprt/le smuhe contains yma11 oayRen- mt cs.M.n centered
radicats thal are much nsme reactive than are the Iar phaar radica(s. Ihrae 9as-phase
raAKah do not arise in the fbme, bul ralher are prrwlured in a sleady sute by the
o.idation of NO In NOs, which then rexN wilh reactive s(rciet in sm.,te suah as
is.yaene. We tuR{eu Ihat these tadicals and the melauable pruducts dtivtd from Ihese
radical reaclinns may be responsihle fnr the rnactivatarn of o. proleinase inh,talor by
fresh snu.ae
('Igartlle Inaltlr naalrett thlola tn JI\ul/aNa; we {uffaesl the KI/Yt aaM,nla a.e N(1
and N(7a the eflecrs af smoke nn 11pa1 peioaaBlam ale ca111plet, and Ihn rs J,uuavrJ
We also dixrss Ihe InaKoloAical im(.ta.'atam, f.N the 1a,IKaI\ in ]Innhe /n lern/t of s
number of radical meduted diwast proeeaes- including emphysema and ean.er
(hurch, f) F. and lr.+. W A
lw..r.w.rwrwra/ IfraftA rnrprrhrrr NIIt. CA, 19tS
ntllrr ruppat Naliunal Inslilvles of IIea111A and the Natamal I vundaNon for ('anaer
Reseach.
1 rom the 14partmrnn of Chemislry and ninchemhtry, I nuiuana Slare I/nivenily. Ilatnn
KuuRt.
IIII KINI n1/X)h 11 UW AND CATACIIQI.AMIN1 RfSrONSI 10 RI Pt 1111V1
Nil ()IINI I XP(rit/Rl: IN IIt! Pttl('NANI I WI:
tn nrdrr In simulate human sa.ohinR, tapesimtnls wete desiFned to drlerm,ne what
,hne uf nKul,ne in the p.e111nsnl shrep wnuld prnduce /M,se plasma nanl,nr
concenarala.ns observeJ in human smoYen and tu naasure uterine hl.as,t fhrw and plaama
calrcMJnn.nrs in response lo repelilive eapmvre (every )0 minutes) lo Ihal nqulme
J..ae Illdv6na seven ehronieally c'alht/ecurJ prelinanl sheep equ.pl.ed wnh
electhnrnsanrtK fh,w pruhes arnvnd ho/h vlerine arltr.rs, we oMervrJ Iha/ a nicn/,nr
49s" of 0) ma/m.n /ur ) rninules rttules in mean platma nicul.ne concenlrala,ns uf 111
! 11 na/ml %I ht (n - 171 immediately fallnwinp inlusam 7Ms d.se nl nicuune was lhrn
m/useJ evrry 10 mrnules fnr 4 hours, and alirluoN nf Mo.al wert drawn immrd.atrly
bef,ae anJ a11er mcohne infusinn for drterminaliun of plasma calech.,lammes Na
s.Rndicanl alreralinns in p/asma rpinepMine and norepinephnne were utnenvrd
IhrnuRhuut the eaptriments (n - 1/, and nn siRnificanl chanRes .n ulerint hhwwl /h.w
.r-aurreJ al any Lmt durinR the eaperimtnl (n - 10) We eonclu,k that Ihe.e is a aprcas
.L,frrrnae tvrlwern sheep aml man wnh retpect 141 /he naalmK Ihrrshuhl (o.
ca1e.M.lamine reltase-
Rr.nd. R.('onover, W. n, Key, 1' C., and Van Vunakia, 11
An.rrrrnn /,uaaof n/OMrrtrrrs ISI(7MS-tt9, 1913.
nlh,r tvppat: 1/ S Public /leallh Service
I rum the /)epartmrnl of Reproductive Medicine, llnivrrsity of Catdnrnu at San theRn,
Sih.wd of Mtda:.ne, and the UrpaNmenl of /liochemislry, 1lrandrs Irmversny, Waalh.an,
MA
1 Kt Al MI'N/ OfF UTAI YStS MI:MI/RANI S 1OR SIMI lt. FANI (Ot1S b1A1 Y\IS
A NI )('( )N('1 N 1 K A 1/()N.
Dialysis mtmhranes used far simultantnus dialysis concrnttal.un rrqu,.eJ
prtlrtahnenl In rtrnove ut-absorbing eomry.unds Ieschrd hum the mr.nhranrs anJ In
reduct /he ahsnrptmn of proltiw to Ihe membrann. /his was s:cumpfishtd wuh s.wl.um
cartwmNe and tlhamJ or wilh'sulfvt rtrnoval snlula.ns' Prntrm delrrnuna/ams wne
ma,k wl/ll a mKro Rradfnrd prnlnn reKIMM aMI with uv ahsrnhanct at `00 n.n 4duble
ntrmhrane compnnents eon,r.huled to ahtrranl vv specaa and dlerrd rhe .ata. ur
.t0/?60 nm ahauhanct. Slreuhanenvf dialysis am1 cnnrtnlrata.n in the .narn pu.tr.n
A.alyrer cnrncrnlralur apparatus, eomhinin6 aq.ecls uf lhrn laytr d,af% vs u.d
Ytlralltlrala/n, rlsvlled in rapid rrrmsval of sa11s frnm IAe prolr,n sotulu.nt I'1au
IrtaLnent nf Inembranes reduceJ uncrnlaiMiea in rt/enlale rrcovtrtev, rtmu.ulyd
vv-alnmbinR a.nyw.nenls of namManes, anA improved recove..rs uf prnltrn
RrrAm,nr/. /'. 1.., SI Utnis, R, and Cohen. F..
Anolrtrrof RarArw.ntrr 145 )41)-)S0, 19115.
1 rnm Ihe raclfK Norlhwrsl Research I uundalinn, Sealdr. WA
11' 1 14)
SIR11('l1IRA1 R112tr1RIM1-NTS/(1R A11(Kf1RtC A('IIVATORSOI RAI
IIV/KMI(K(ri11MAl 1111'I)ROrY 1MIIIIYI(i11/1ARlI (()1N/1-ktl A
Kt lrl/(IACI
Sevrral compnumlt ennlsinrng qrinus flrue/ural mnvlies of NAft(PKI11. were
r.aminrd as p.aa.hk effeclNrt of ral hver )-hydrney-1 methylRlularyt cnen.yme A
rrduclA.r a.lrw.ly M..n.Nmat rrJucuse erat aclivslyd .r.th 4 1 mM (.SI1, aaa.iyeJ ...1h
suMaluralinR NA11111 cnncenUNu.w and inereaaing amounlt nf the /raled cnmp..unda
1/ndrr /hrae cNn.6anna, /he esaenlial and fuffleiesl t/ruiture rrquur./ NW a11..vrrNally
enhance the aclr..ly uf the rrduclax it Iha1 of Y.AMP When tbe T/wranN.n ..f dre
nualratNk it pMnphmylated, thrt allmlr.ie aelivation it diminnhrd
Rmtetman. I and SArrArrr. I
R..wArmNnl awJ RrnpAr.Nnf RrlrnrrA ('nnrwrunrrnlNrnr (73111r)02 9f1), W11
I.Nm rhr Ilrpa.lmrnt nf Riochemiatry- Ihe (:rmge S Wite lacully u( 1 ife Sr.rncea, 1e1
Avr. Ibr.eruly, larael
AI 1()ti 11 RI(' A('11VA t1(/N OF RA I I IVI It MI(-RlK()MAI
) tlllrKt)tYl MI I/IVIGIIttARYI lu1N/VMI A KIUIICIASI-OV
Nt( YI1INAM11/1 A1/1 NINI I/INU( 1 1(1111)1 S
NA1/1) and NAb' are nrIhrr auh.uatet nor inhihnurs of 1 hydro.y
1 mrlhyIRlula.yl .nrnrymr A 111M(. I nA/ .elutlnr rn ennrenlraunm up lu I n.M
AdAiUUn N/ rAhrr NAIr/l nr NAIr'rnhtn...1 the falr*dy of ra1 hvrr m.:nnnmal
rrdut/aar, yrl NAlfll laried In af/rr1 Ihr a.lr..ly nf the Lrrre Ihasv tN1obJ.red rnryrne.
the deRree of rnhan.rnunl nl rnrYmr art..ny 1.y NA1111 dec.ro.ed at (:sot/
cnnceMralnn in Ihe a...y ncrraard Ad.1uN.n o1 NM) /rM NA1111 to the assay c rn.erlrJ
mr:ruanmal
the IIRImrNlal (IIII/ rrw11. rrnl . 2 0) NAIN'11 depemknt Yrnrb.' eurve trt the
rrductaae intN Mithaeba Menlen I.nrlha (11.11 cwr(funnl so /1) lur/hrrm.ue, /he
6.nrlle curvrt arrre ahdled lo the Irfl, rrau/bnR in an up tu 154, dectrax rn the
cumenlrat.nn /d NAh/l rrrau.rrd In oblarn half maaimal veMn:ily (lt') in Ilse prnrm'r
nl MO MM NAINI ARaln, thn effeal of NAI)11 was d.minrshrd at (.S11 cnncenl.alw.ns
im-reaaed fhese rraulls .kmonu.a)e thal NAU(11) is an allmle.ie ac/ra1nc o(
IIM(i ('NA rrduc/aae. lhex resuUa ahn indicate tha111MG-('uA reducusr ha. NAI)t11)
MndrnR aitr(a) dnt.ncl (rnm Ike catalylK NA1/141 stlels)
Roilelman, I aeA .tArrA.rvo l.
1 Ar lrwwnnl ./ R.rrl..Rrrnl (-Arnvve y lilf 22) N0.'9-11012, 191J
I rom the (Mparlmen/ nf Oinchrmiary, the CrmRe S Wise I acuity of I ife Stlercrs, lrl
Ass- Ilm.rwlY. 1..xl
RI 1)11('1 1/ /a III A 1111ONf. IN ('IIINI SI IIAMSI I ROVAR 1' ('11 I S
PR()111ISA(3AINSf /NA('IIVAIIONO1' 1 1/Y1)R(/rY-1 Mt1/1VIG11/TAKYI.
( 1)I N/VMI A R11)111 IASI IIV 2 MI K(-AI1(11 IIIANOL 111%111111)1
W hrn /he d..ulf rdr of 2 mr.captnelhannl (r ep ) is aAded In the mrdium r.f
cu/rua.rd I h.nrar hamurr n.ary (( 111)/ trllt, a Lmr and eUrNrMFa1NM drpendrnr v/ra.r
.d ) mrr, rPNrlh.nt tw 1/.r nv,hum is r.Mr..rJ the .edutliun of 1\\/ In
, mrr. brn.I /y rltH a a a.Hura.l. pru. ra., /hr ...Ir Iw.nR at.p.u.rnr.Nr/y 10 nnudea
nf 2-meriaplorlhanul prr mR cell lrrolein for an tuwr u(wm earynu.e 1.. 710 pM I C%I
KrduatMan ratr of I CSf by ceils a/lached lo a aulnlralum is indcprnJenl a/ Rluune anJ
intulm Inr (rerNNls up In 4 houra. tlo.rver, in tk/ached crlh, a+rJed in autlnn\wm,
addilwrn uf glucnae an1 .mutin is nefessary in order to ublain a linrar rrdoclN.n sale u/
I SCF.. 1 he rale 6miling ewyyme in the slrnA hiNaynlhelic /.alh.ay,
1 hYd.u.Y I mrlhylRluuryl Ctrnryme A rr.luetaar (E C. 111 )t1, is inh.bilyd hy 1\\1
rhrn i.ulacd (rm ('11(/ cells hul 1n1a1 nr.naap.nifial.k li/.ldi synll,r..a L.nn
(` 14 1 acrtatr .n nlac/ celh is aN affrcled by /SSIal comen/ralwns uP Irr 500 nM
('ylnWhc rr.lucrd Rlu/athrmrnr can spnnlanerwalY e.chanRe disulfnk bnnd., wrUr 1\V
and Ihua p.r.rnl n fr.um inhlMting Ihe rrduaa.e. (rutloored cells realu.nA Iw 1 's\/
adnrmntulmn by elevaUnR lheh 10131 and aeid s.dubk Rlulalhinne /e.eH I hr u.r ul
I S\I at a 1'rrluhanl Nf Ihr (:S11 Slawt m crlh is d.KUaaeA.
Il.nan, I and .lArr Arr.. I
/hnunnl a/ (rllular PA1v.d..llr 12114:0, Wls
/ r..m Ihe prparlmrnl of ninchemis/rY, the Genrlie S Wi.e I aculty (ur 1 ife A ren.rs, 1r1
Avr. I lniveraly, h.sel.
AIN N(151N1 INbll(-1-1) C)R(1NARY R11 IAS1OF PR(ISIAI-1('1 IN A 1 N(1NA1A1
ANII I.UW Idl IN IS()1.A11 t) 111:AK 1O1 RARRI f
I Rahhil hearlt were Ilerfused by the I anAendorfr me1MN1 with druR lrrr
(rrrfuvon medium or with a nlydium eonlaininR ademrsinr (N/ sM lo aM) and Ihr
corrulary and lransmyncardul efflua rslet of 6hr/oprmlaRlanA.n FMr (6 {,etn IY:1 Ms1
were meaaurrd Perfwinn aras perfnrlned Inrlh al p11 74 and 6 9
2. In olher taperimenU the 4arls a.ere pre-blwled a.ith 1'V'1 ara.6idwnic aaNl
0041 the cnronary effl. of tadioacli.iuY aml uf labekd Gprds arNl 6 hetu P(i/ Mr ..as
.ktermined
). 1 he basal coronary flow .at ekvaled by almosl 70% durrwR tissue scidnais, in
conmpariaon 1u conlrol Adenosint Nu/w'ed a dose-drlnn.kn/ incrrase in Ihe srunnarr
Ih.., amounlinR 1o slnwl 75% al Iarmal pll snd a draR enncenlra/a.n tr( W'M the
/wlrnusine iruluced increase in eor/MlsrY flnae aaf nol fac/litaled by Irrw Ir//
4 lhe base emnnarr tfflua of 6\elo P(:/ H fr.ms Ike hearla .a. 2 f 16
nm/min Ademnine (q t-/0 M) sifiaificamly facdilale.) /h1t eftlu., up In 6% nR/mN.
the efflus of 6 heln-P(7F~ was aa ehanRed by (wrfwwrn lrilh ac.dic medium, r./her rn
Ihe A.isa/ Na/e nr during pr/fwinn .Nh sdenwiwt.
3 The haaal inlrrslitiat errloa nf 6 f,rw P(iFb .aa 1 S-S S nR 1/min Ihn e111u.
wat nol affected by Peafwion of Ihe hearl - dh adrnnsme- cnnlam.eR nredrum /w hra.lm
pre bbekd .ilh 1rR'I-Machidonie Kid, ndenlMine 110 MM/ indwed a slMc1(K Ilbr/a1N.n
of labeled lipwl-e.usclabk suMlances, inclurlinR 6 hrln P(3Fh.
J I rnm Ihrx data aa/ cnnclwk that adenminr sl.mulalr. the bbrralnrn o/
6 4rln IY3/ n (.nm the rahhil hearl by increstine (rrrcursnr avs.iahAUY wmi su1..r.INen1
/armalwm 4.81 p.oalxycbn {n 1ht eo.owary vrtse/t I urlhrrnvur, the rnarr.w /w ru.una.y
fhrw imlucrd 1Y lrtaue KidrnN if not re/a/ed /o an auanlenled fn.matwm .d p...U.r. y.l.n
('ial.altuni. G and Wrnnwro/m. I
Rrrr.fA lrn.rwal o/ PAm.nor.dnR~ /5.137 $61. 1915.
n/Arr, tupprwr S.edirh Medical Reuarch Cauned
frnm the lkparlmenl of MarwrarnhMy, CalMdre I1mvr.u/y, Rnmr I/aly. N/ the
Ilrparlmrnl ul / Irm.al Phys.ob.ay al Ka...lrnska /nal.lulr, /lud.lrnp I/nr.e.awy
S/ockhNhn, S-rrkn
ttt I
IeS
VI Iwmo.letly, .d AdaPll.e Methanlso.r
( IIAR A( 1/ 1(17A I II1N (/1 PR()1I IN K INASF. C ACTIVII V IN INI I It11 R(/N
(:AMMA I RI A 11 t) MIIRINI P1 R/ IUNI AI MAl'RUr11A(:1 S
Macr.ry.haRr aeliva(Unn fnr Ium.Nieidal mietnhieidal funclmns can hr achievrd .n
,t.Irl t.y Ur:dment wdh recnmhmanl inlerfetow tnnrna (11 N/) rn .rHn We have
p.rvi..utly Jrn.onursled Ihal 11 N-j Uralmenl of rn.rine prrilnneal maarnphaRes resulta .n
a Iw.. to l.ve/nld .nwrr.ae in Ihe aet.vity of Cate pMnph.J.pwl drpendenl prnlein
I..nasr ('. We now rrpnll that Ih.t effect was nol depemtenl ulum ennlinu.nR prulrm
aaoll.rait, sinte Irealmrnl w.lh cyalnhr.umidr under Mnddums where ruumil prolrm
aynlhrsn .aa mh.idtrJ br Crraler Ihan 95% had nn effect urym the Jevrh.pmrnt vl
u..raar,l rn.ymr a'/.vny 1.aminalu.n rd ( a" nd phnspMJ.p.d requkrrmrnts revralrJ
n, ddlrrrmra t.rlv.rrn enrymt s.daled frnm conlro) or 11 No, UraleJ tellt auuld n,d Ir
d..1.nRurahrd .n Irrma o( the AocyRly.e.u111K) o/ phnrbol Jinlrr (PMA) co...rnlralrnn
rrqunrJ lu. v.muL.Iron of acl..ay Kmelie analysis of the AIP (al subslralr)
tnarnl.al.m Jrl.rn,lrncr .eveated lhat MHh ennlrnl nd IrralrJ en7yme prrraraHnns
(rnheS hawt r.9 sl.mvl.a/r.ll haJ compa.ahle Km values Matnnum veh.city (V.na.) was
m.,raaeJ Mnh hy II Ny bratmrn/ and alvn hy tlrmutaln.n wnh IKi ur 1MA. Ihe mainr
.Llle.rn,e whnl. cnutd he dru'ernrJ frlv.ern pr,rlrm li.naae (' Jrcived hnm ..unl,nl
vrrana 11 N7 uralrJ ma.rnl.haoArt waa the m..Rmlode nf Ihe rr.lw.nae to 1K' ur PMA,
11 N( Irearmrnl .nd rraarJ the N.mulibnn mJ.c h r, utn. nf h.nal Iu at.mulaled acr.vdy)
l.y a Iaa1r u/ 1w., lu I.,,u (ntJ lhesr rraulra suRRetl Ihal 11N( I.rvtmrnl tr.IJa Iw
revr.addr m.rlulah.n nf c..al.na prnlr,n \,noar I rravb..nR ,n malraarJ .a1.Jrr. a,1..ty
.rhrn ryrrae.l to an al1^^I`.a1r U.nmulanl
hra l,.n, Ir 1, IJnm. Ir rr and tl.m.h..n 1A
Jn.n.d nf lf/uLrI fA,.,..r.,r 12t aaa rrl 1,(a
(1/M-r .uppur ItndeJ \Lrrs I'utA6: 1lralr4 \.y.,.
I rorn the Iltparlmrntt of PeJu/n:t, PiI/u.InRy anJ MarnhmluRy IrumunnlRy, 17uke
I/n.venay, I tur ham, N('.
1111 N11/11-A1/(lN OF TIIF I YMPN(1KtNF SO1 l1Rt.F IMMItNf. RTSPONSI'
CItPPR1 S.C/)R IN IIRINI OF NI P/1RO1K-(-1111.1)RI N
PalienN wish mmimd ehanRe nephrolic symlrnme (M('NS) freOuenllr have
tupprrased to aro and rn n//n +mrnune respunsiwneN uf uncerlarn eluJnty Recause
increaaeJ suppresuu cell clivily has hern asi"'uled with Ihis d/.ease, u11rNV frnm
h/( NS pshenls were urrrnrd fo/ chvNy nf Ihe lymphuk/ne w/ul.lr immunr v.lw.me
suppressoc (SIRS), Mntucl of eoncanavatrn A. of rntrr/rrun chvatrJ supp.rsa. I
crlts l/rines frnm unuealeJ MCNS palienn tuppressec/ prydyaonal plaque(w.m,nR trll
req.nnsrs of cY/luretl splenncyles. Ih.a suppresaive cli.ily was idenlified as human
\IR\ hy the fnlh.wmll funclN.na/ ml phvsicat crilerir (a) mnMcular wriltIN eat.malyd by
R.1 Llrrali..n, (1.) .nN.cs of suppressam. (c) inh.hrlinn of aupprNtMn hy n,at.ar,
trvamnuk, and 7 me.caplnrlhannl, (1) aMu6atmn nf aeliv.ly hy acid or prnleaar
I.rahnenl, (rl eluhnn p.(/ern on hiah perf,.rmanc'e l.qu.d thromaln6.aphy. snd (f)
.r a .rl,/Jr +..h mnn.h.nd n/,mWrnr SINS nblrubrs Supp.rav.e s,1.viW
./.. qq.. v../ (...... ur .1/r. .1 1.r nn,eal Aul hrf..v rmraVUn ul ty nl.bmt
,
lllines were Iraled (rnm It palienN wilh MCNS, a/l of whom tacreled SIRS. In addd.nn,
Iwn nephrnl.c palienls with acute 6Mneruhu.epArilis and Ihrre nrphrolic parienls w.dh
memhram.plulderal/ve draase etcrHed SIRS, hul olhr, nephrntics anJ all nnnnephrolw
pal.enls dul nnl. Ihete IeSYl17 nM1/Cale that eacre/mn of SIRS ncl'urs in ceaa.n casrs d
nrpluM.c syndrmme aml that the presence .d SIRS in the urine n nul accounted /ur sulely
by the presente af prn/einuri or nephrosis Srrum frnm f..ur nepbrolic pat.rnta al.o
conlamed StRS, wherras neither ferum nor urinr from aia ruumal auh7eals haJ SIRS
acliv/lyy lhe syalrmic puesence of SIRS in Ihew fout palirnla and the .,/rnGfaahnn n/
]IRS in uwinra Irum a 1arRer grnup of palients suRRnl a rynsihle role faur %IRS .n the
suppresarJ immune rr.p.msrs oflen founJ m nephrulre syndrome. '
Si.na(wr, 11 W anJ Iun,. T Al.
l.n..nnl rf f IrnYf InhYN(OIbM 76 111 - 119, MIIS
(hAn aupfan. hlununln (bmpany
/ am. Ihe tMpaumenl of Pathoh.Ry and I aMnalory Me.ln:ine. Ihe 7rwnh Ilmp,ul of CI
I owa and the IlrparlmenN of Ped.alrres and Pa1h.JnRy. Washmelnn 1 h.we.anv `, h,«d .d
Mc.locrnr, SI I ouit
INI111/111(1N (11 S(11.111111 IMMItNF. RI SPONSI. SIIPIRI SSl1R
At'I IVI I V IIY 1:K/1W 111 1-A('1ORS
S4.h.hle immune resp.mte supptesanr (\IRSI, a prntrin of Af N IKKI, n a lyruphn/,u.r
patlwed by interfernnnr eoneanavalin Aacuvaled suppretu.. I cells anJ .s o.wlurJ
to .IS activalyd /urm. SIRSy, by hydrogen pecnswk purlu.ed hy nr,.cruphaArt \tN\
Inhdals anlilrwly aerrrlmn by R lylnplu.cy(es and cell divian.n by nurnral ur Uanaluuw~~/
cell /mes I Ifecta of plrnfied growlh fselots uw supprrssnrn .d antulwdy secrrl.on wr.r
eaam.neJ to dr/e.m.ne whelher any would oppuq Ihe inhihit..ry e/lecla of SIRC ur
SIK% InlrrtruAin 1inttrkutlin 2(11--:) nd epukunal Rrnwlh fa.lur (1(i/ I
eachrinhib.teJ >INS medialed suppreasion of nliMnty secte/n.n by cullureJ muu.e
spteen cells Inhibilion of SIKS aiclivily wt nwnl e/fec/rve when puw/h (aa aws .rlr
ad.kd lalr in the cullure petwd. ILI, 11.-2 and IYY aho bincLrd suPplrssinn hy
SIRS_ I/owever, I(it and aL-.1 hlncted suppressinn by SIKS. only when addeJ 1 6 hr
befrne addilinn of SIRSN, whereat 11.-2 bh..hed suppressinn by SIRS. when a,h/rd
hefore m up to J hr afler nddi/ion of SIRSw. I urther evalualw.n thnwr.f that 11. 2, hul
/uN K:1 or 11--1, rcversed inhibition of ntibolly stcfelNm hy SIRS in a Ibmr and
concrn/ratiw.n dependenl manner. Wnh 30 units of 11,-2 per 0 3 n.t a u'Iiu/e, revrraal ras
cumple/e w.lhin I hr. The ability of grnwth faclora to inltrfr.e wnh inhib.l.un uf cr11
divia.nn hy SIRS was eamined with /he hueun R-eell IeuYem.a NIMI IIIlO. 1 Wt tell
line hinda I Gfbul is Iso1 known to have ceR surface recrplors f..r 11.- 1.u II .) 1(.1
(01 1 nR/mI), when added to RPM617q cullures 1.6 hr brfore S/RS , inlrrle.ed wrlh
/he ahdrly of SIRS 1o inhibil erR dwisw.n la/.en InRrlhrr, /hesr"dala .nd.rale 111.30
arnwiA Isalmc .nl,~/rre wilh hmh Ihe /m/nYIPNuplne/Uve anJ puw/h .nh.hnnry
pu.prrUrs nf SIRSas. n b./h heltrofeneous and hnm.rylrwe.ws cell ry,pulal.unv
AwnTM
Prnrer/rnt, of t11r Nwrund Ardewry of Sr.enrn of Me (rmrrd .Sraar o/
.(merna 92:6260 6:A1, 1911.
O(Frr luppnt Science loundalnm and Ihe Munsanln l'nmpany
1 1.. 1 147
1
0
70
wr.i
.1i.v
I/om the 14partUOrn1 nf Pa/hnlnRy and 1 alvnatory Medi.inr. I l.e Jrwith llnapitat ..f SI
I..un- nd Ihr 14patlmenl u/ 1ath../..Ry, Wa.tunRlnn Ilmvervly S.6.nd nf MrdNUe, %I
I mris
rlttttltll IIttN ()/ I/11 I YMMIOKINI tt/1111111 IMMIINI R1 SIY1N\I
N/PIK1%\1tlt.(\IK\1IrtININ(i( IINt)NI(' I KI'1 KIMI N1AI
\I II1%II "/MIA\I\ MAN\()NI
("hlnn.t t<Maanomuais mananni is a hr/minlhie infeabun tha.a.lrrlnJ by
cr11 mrdblr1, an/r rytR ~ranVMmaNW4 sraaions and a va..ely ..1 att.alalyd
tmmunnrrRVlalNry phrnnnsrna. S.duhk Immune RtMnu su(ryoraanr /%IN\) n a
/yN+phn\.nr p.n.l..ard hv acl.qlyd tu(ynraNN I lym(.Mss/ra .n va.u.Y4 r.lrnurN/..l
srlt.npl Ihn trp.1 QrnnmaOalrs IIM prrtrntr of 5111% in Ihr ana of n.nr wdh .MunK
S.hNlutumutn mAn,unw lal Itasl 70 wis .d in/rclN.n/, hul nnl lu Ihr srta nf rnNr rah
rulwr rnlrstn.n+ AHu, tldWCes of isn/Hrd, mlac/, hepalN', er.R (.woarJ 1{.mul..m..a
IrNm thrnnN.dly mfnlrA mice rek.sae drlr.laMe kvels uf %t11X Ibrar a.r I/.r
immuw..n.Ild.llyd Iramna tMra.IrrialN: ul Ihh mleeliona I arRe, inlrnar unm.rlulalr.l
R.amdNnut Nl.tumrd (/Nm aculrty inlrctrd mite d/d nn1 rrlea+e SIK\ I hrrr .a.
ILrrrfurr, a vrnnR astm ut.un Iwtwrrn Il.e prrarnce .d SIRS .n the aerurn, d.e pnrlu.INm
nf SIKC by Inla./ 1ra.una, sn1 she cMonN-, tmmunnm.nlul..led Nalr nf aahnlN+.nua+n
m.n.nm
ANnr I At 1.rrdnun, G I lr , and ('Nllrs, It (:
7A. J.wrnol ./ In.wunnhcr 1 15111 7 1611 .`1/1, IotlS
(hA.r supNnr Naunnal S.r..ce /uuodrt.nn, Nalmnal Inuilulra of 11ea11h and Vrtrr:un
AhNmnl.a1am
1 rNm the Itr(.artmenl n/ r.llhnh.6y and I aMnatnry MeAlcine, the Jewith llnapn.d ..f SI
Inun, Ihe 1lrparlnmrnl Nf 1'a1MdnRy, Wah/nRINn Ilmveruly \.M.d nf MrJu:inr, SI
I Nwt, Vrte.ans Adrnlnnlralmn Mr.INa1 I rnlrr anA IMp,ulmenl of MnrnbnduKy.
Vandr11.J1 Il/nveraity StM.olnf Me.lNinr, Na+hvdle, IN
IW(tp1/1IRIN1 PAIIIWAYS01 INfIR11RQNM11)IAllt)SIIPPKISSI()Nt)1
AN I tIN /UY S) ('R I 1 IUN
Inlerferon sup/sreaaet a vsriely of .n arrs immune rrspnntra by a mechaniam whn'h
has m.l hren wrll de//ned Ihrlh dirre/ vryqnratmn aml ac11va1inn nf suppret+nr 1 cellt
have Mrn au(tttettrd as (unsihk mea'hanitms of inlrlJernn s.1.Nn In an attempt in
rUminr Ihta yurtlmn, mlr/frumn (/1 Nn) mtdqlyd tu(qurt+mn of a pl.~tlue (.nm.nR
cr11 rra(u.nae /r. a 1 cell inde(vmlenl antiRrn by spleen cNls ur hy R crlls was r.aroinrd
S...uewhal R.raler quanMKS of 1) Nn -etc /rqu.lyd lo auly.rta p1sq.Nt (nm.Ns crll
/e.IN.nart hy 11 erllt thin by spleen eeKs In the anliften flwoe+.r.n.nrd RrlN.lln nhNrut
(111(' IIA) Ilowevrr, au(.(trrtaum Id apken tell rrs(umses coold hr LMK'hrd Iry aAhlN.n
af eilher 2-mr/ca(.h.Hhamd, levamitnk or nsnmr'lonat nlihmlies aRaur.l 11u
Isrnphnlrne, snluhle mmune ret(u.nar su(qaratoc (SIKS), whereas su(Nurac..m nf 11 cell
/ryn.nart 1s 11 N. waa uniffrtted hs tl.r+e aRrnn 1 a. h nf Ihrsr aRen/a inlrrfrrra .uh
\INC mr.luv1 +Nlqrr.+um ul .mmunr .ralN.mrt A./Dti..n N1 I cell+ 1. It t01 tuhu.ta
.INNUIa.t -11. /1t. IIA d.1 .I/rt /hr /nN1 p/Aqor 1.NUnR sell rra1Nnar ntN she
.,/.... 1 . ~, . .. r. 11'w. 1... .. /..1 .r....r , nNl +rN.n.+.t. 1..
. n . ./. ' ,.r. y.....11,.N..1
t
sensilivity In It Nn-teedialed su(apression lhese data su/tt<est 11,31 11 Nt can auPnr.a
immune resp.msea by two drfferenl palhways am1 Ihal in lltr prrsrwe Nf 1 tr/l.,
a/ivahnn of suPMrtaw I cells n Ihe dnm.nant palhway Ihe Islraencr uf I crlla mu.l
also prr.enl dneil su(yueninn of R cells by 11 No
(Nnr. T M
fner.ndrr..n.J laarnu/../ /mmNn.yAawunadaKr 7(I/M1)7/, 19Q{
th/Mr suprnr Mnnaanlo Company.
1 rnm the Ilrparlmrnt Nf Palhn/nay and I a1Nnalnry Mrdlcine, lhe Jrwith 11u.pn.11 ul \I
l.wn, and the Ilr(.aunwnl .d Palhoh%y, Wa.hmRl..n I ln.vrrsdy S.hwd Nf MrdN mr, \I
I nur4
IN11111111ttN 1/1 NA ItIKAI. K 11.1 IN(i 11Y AI)1.N//SIN1: R111(1N1/( 1 1(1111/1 S
Ihe effect of nuclrNtuks un nalaral ttilkr arlivily in rmwae spkrn +aa
in.eN.Raled Adrmnine rilweuck.Nidea wrte found ht slronRly inhilnl natu.at \dlrr
ac1iv11Y, wilh a half ms..ma1 inhihiliw.n al an AIP-cnncenl.alwm Nf 2/1 pM IIw
inhrhninn was hiRhly specific ftw a.kmninr rdnmucknli.ka, a./emn.nr
rkocyrdMmwknl:drs, Ruannsine drueysilonw'k.nwlrs, am/ Ruams.nr r.M.nwlr.d.drt had
very Inw, d any, inhibihwy effect. I apetimen/s w.Ih s(secific m/dbi/..N shnwrd Ihal the
rffecl n IranNnilled by purrnerltie recriaIN/4) IlKalyd on Ihe cell tlnfaar ('umlor/.nn .4
Ihe Li/.e1KS of /hr A I P r/fect with Ihe rffecls of Iriflw.pera/ine and /lun.a.'rine ahowed
Iha1 AIP srls late in Ihe lylic eyck, (unsihly innntdialely ptrcrd.nR Ihe (uuR.aminlns
fra lysis.
Iknrilosslro. T fR/arr. I.R.J
ImnuwdnRy f.eurrs 7171-176, 19p.
OrArr lupfrrt. U S. Public Ikal/h Service and the Naliona/ ('ancel Inali/ule
lrnrn Ihe 1)e(.arlmrnl of MicrohiohlRy snd Iallnun..h.Ry, and the ('ancer Re+ea.:h
1 shoralory, I/niversily of Califnrnia, Nrrlirky
ANII-MY26A M()N(1CI(1NA/. AN111K11)Y INIIIIIIIIN(: 1111MAN
PI/A(i( N'Y /1: ('111.M11 1 uMIN1 SCI:N('1:
An1iMy-76, a tnouse mawlclonal IR(:1 anlihmly, was raise1 aRamtt hua...n
lranutneyles snd has hern shown /o inhlhi/ turnim.l rwhantrd. Rlucu.r mJr1YMh'r11
(hfmdVm/nr7aYnCr ((1 ) of human /iranuhWylrs (ur nu.n.w Yles) re+/Nn,6nR IN thr tohd/r
srcrela6.qlurs A71161 .u ionomycin /csk.um innnp/unn/ and pINNMd mnrsla/r a.r/nr
IPMA) An1iMy-76 Inh.hUinn of ('1 was revrrulde aml was drprn./rnl Nn 1-Ih
secrelatnRue and nw.muannd aMihlldy eoncrnltalinn Ihrs inhlhninn a14Na.fd tu hr
direcled al the component of elranuh.cyle (-1. 1ha1 n .ndr(.rndenl n/
NAf7(P/llocidase-caulyaed formalinn of supero.iAe aniow, hecauar nr.lhrr .N~nm.r.l
sylmnan-slimulalyd (-1. nor the PMAinducrd decrease in NAh /1/11 asur.alyd
swlNflwuetcrnee wss affecled by an/i-My26 In adHlnlon, innnmyc.n, ..vr. a w.dr
CnMrn/1atN1n ranRe, fa.kd tn grnrrale any tlrcrraK tn {nnrh.cylr aul..llu..r..rn.r
1 hr A 121 11/ inAu. rd 1-1 Inh.hnrd by snlr My 26 wat correla/eJ wnh ila drp.r..am ul
n.varn aNmumplN.n / Y1/hrlNMnr, anl/ My 2A was nd . ylnlun. aN1 10 n1.1 .1.r1/
iMlucr oanlal.ve melaMA.sm srhen used as a sl.mutanl IlindinR of anh My `A to
phaRi..ylic arlh .as Mn de.reased by prc ealunure of cells /o eilhrr A`llsl ur PMA
I vrtenct ra presented to sug{rsl Ihal /he Mnd.ng of anli My :A tn the Rannh.cylt
su.lace inh.Mls Ihe nrulalive rcapnnae to calcwm ioM.phore anA PMA by M.w4mR a
ammoswn palhray(N at.mulatrd by these aldleren( stcrelagngurs
Warren, I I and C,vm ( I
f Ar l.wrnnl n/ Immunnf.nRr 1144))1127 - 11115, IOt).
Orbr. .upp..., Nahnnal /nst.tutes uf lleatlh
I n.m the IkPartmenl of Oiuh.lly. I/niveysily of Ptnnaylvania. Phdadelphia, and Ihr
Ihvnam u( PrA.aI.M /M.r.4.gy, fhe luhns Ilnphins (Mcnb.gy ('rnler, I he )nhns Il..pk.na
Iln.vrrbly S. hml uf MeA.c.nr, Ilalhns.ut
ANtI MY 74, AN ANtI(:RANI11(yCYlf M(111Sf MON(X'IhNA1. ANtIRl11)Y,
IIINtsS 1/) A S1/(:AR \I t)111 Nt I IN I ACIO N-N101/ fRA(KI
Ant. My ?1I .s an 1aM K moMrh.nal ansdra/y prMlucrd by a hyhri.luma preoarrd
frnT splrrn crlla nf a T.wat .mm.mued +nh MNmaI human Rranulncyles Ily
immuM.llw..eacrnce it b.Mh to hum..w lranuhnylts bu/ M.1 1.. TnMnylts aMl
lymPhnvylrt Ih..rver, a('ler /real.nR arlla w.th neurawanutase- the ant.Mrly also b.nds
In lymphncylrs and mnnocyles and to many leukrm.c cell 1.nea and palieM kukrmic blasl
cells Anta My :k h.nds to sevrral nruuas RIy.ol.pula and .ksalylated ganRla.aulra nf
leukncyles aMt erythrrKyles al sho"n hy radw.MmuM.aatay aM1 .mmuronla.n.nR al Ihm-
layrr chsomalnR.ama 11 .r(n/tnnes s suRU aeyurn.e in Ia.t..N nenlrlunae, (::Ip1 4
(i1.NAcp1-IGaIA e(ilc Ih.s Iel.asa..h...de uccura in /hr ~Ir.nl.p.ds paraRlol.n.dr and
sialnaylparaRhrhusulr, and ds 410131 U."I..h,..ale srqueMe .a fawnA in h.Rher RlYtnl.p.da
an.1 Rlycup.nlr.m
Spilalnik, S 1, f...n (' I rr at
IFLuJ 4160) 110);6, 191)
O,Arr .uppur National Instilutes of Ileatlh
1 10011 the Nalional Institute of Arlhrilis, 1)iaheles, and Diges/ive and Kidney hiaeases,
Ilelhesda. M/), aMl Ihe h.visi.ul nf Pedra/ric Oncoh.lly, Ihe OnculnRy ('enler, fhe lohns
ll..p\rns IlMVersily ScMwl of Medicine. Rallinmre, MD
MIX11)(;I YC(Klltl PRI.iRfA1M1 NI R11/11('1S NONSPI('/11(' 111NbING (/1
AN I IROt)11 S f(1 1 M)/ I N I1XS111. St (' l l(1NS
IMlirtcl imTUnohislocheTical slwl.rs of (rotem misuse /issues v..th nu.uat
TnnocMnd awlih.drts yieW, to /rnerd, auMqlimd resulls Mimardy Mcause nf
ind.ar.minale b.nd.np of secenAary antdwnly to al/ nause /TTYMyA.hubws, . t, lo Ihe
nsnwochrnal rtaRenl and to ewM.tclwus iTTUnnsluhuliw wemlecifi.aRy lrap/wd in the
lissue. tn rrduce Ihis nnnspeeifrc suin.nT, frozen seelinns of mouse kidnty ..ere /realed
en,yrwatically Optimal rtsuhs were obtained foltn.ing a 2 hr lyealmenl ilh 20 mR/ml
nf mieed sIyc.n.Aa.es (MG) this /reatmenl reduced the M.mpetific hackRruunA
stamrnR uf the inle.shlial apaces and hhad vessth, hu/ diA not sffecl the reaclivity of
sl.w In.al/y Iw.und m.munnRlubulin (: (tI(3) in Ihe s/omrFUtr or aller the ytaclrvny of
1
1
~
I
I
moust rena/ lissue 10 Ihe rM.Miclonal awlihody Ihal recoRniaea an obRusacchanAe
anhRtnic delerminanl 110031es frony entyTe-uraled frnrrw haaue secliona cnn/amrd
nmmally irnmunorexlive IR(: in Ihe fmm of dilwers these dala rn./.cale thal M(;
IuralTent nf frn,en seclinns could he safely wrA to reduce ahe conlrnl nf n..n.auaurally
hnund IIrU11uM/RhAluIlnS in frottn /isaues and Ihus impruve Ihe vnualualiun u/ spr.dM
.nnmKh.nal anliMwly binding
.
AnA.e.ra, 1 P,('lark, R. K., and Aawr)ano.. I
1 M l.wrnaf of )AN.rArwusur and Cr(nrlrrmrs(.r ).4)1(01 (All, 19Rt
Orbrr sapP.w, Nalional Institute, of /kaph.
I rnm 1hr Isrparlmenl of Pa/hn6.Ry snd I ahnsat.rry Medicine, Ilahnrmann IIM.r..uy
4twml o( Mrdn'mr, 1'hdadrlphu
1(It AI IY 'A 1 p IN O1cAMP IN INXD ANt) CA I 1RAC111 A. 11 f 1(' 1S Of
/1 AURI Nt Rt11(' AG(1NIS11
i
Adrnnsine 1',S--cyclie mnmy.hnsphalt (CAMP) is hrlitved to nsrAule the
ban.lrn/ of inna, waler, and muculM &lyayuoteina iw Ihe rrspiralnry Iracl Ilrcausr, chemn:al
Trasuremrnls of /olal lissue kveh of CAMP may MN al.ays reflecl chanRrs .n
yrcdic cell types. we adapled suMlard imauMKyhKhem.cal melh..,/s to e.anuM /l.e
crllular hwaliratinn of cAMP iw dnR snd Cal /racheae lhe /1 aArenrrR.c aRnnnl.
Irnhulal.ne aMl iaywnlerenn/ incrtaard iTTOnMrxlwe CAMP in c'd.alyd epNhrbal .rl/a
af dnR aMl eal bacheae and to botA serow aMl wuc/ws gland cells of cal lracheae
I pNhrlial gnbkl cells dwt MM aapnM/ lo p adrewerRic aRunisls in e.lher yMCMs Ihn
sludy psuvnks infMmaliua a1rT1 Ihe Incalinw uf Q recepl.ns on iMlrvnlual sells in the
1.achea Iha1 n nol available from ehtrwica/ aauyl of eaher CAMP nr p rrcrplnrs in Ihrsr
lisaurs Our ,esuha sup(nN/ I/M hypntheSM that WrelMy funa'/nm{ in M.th secnus anA
mucous suMnucosal Rland eells aad cilialed epilhelu) crlls, but MN g..t.lel cella, may
involve cyclic AMP Arpendenl mrchanisms.
I a,arua, S C., Oashaum, C. S. and Gdd. M'. M.
1 Anpvrran l.ur.nal n/ IAIsr..fuRP 247 (Cell Physiohryly 16)C1!1-(-I1J, P111-/
~
I ()AArr .up(rrr- National Itearl, LunR and Rlm.d InVqule, and the tiunbel MrAisal
~ Resrarch 1 uod of Ihe Ansrrkan Lung Associatwnl of San I rancisco
From the ('anlinvascolar Researeh Insli/u/e and 1)eparlmenla of MrAicine and Anau.MC
I
,
I Iniversily uf ('aldnrnia, San / ranciacu
1MM11N(11 (Kil(' R11 1 ACf. (11' 111SMMINF. 1 Rf1M 1KNi 1(/N(3('UMPARIGIN /11
IN VIY(/ ANO IN V11 RO RI SPONS/T IN 1/11: SAMI ANIMAI.
The purpose of this study waf lo eoTpars, fM Ihe firs/ IiTe, anliRen indwed
kistamine rekast (rmm the bnR in lhe stame nalively allersic dop M.11t .n vu.n an.l .n
nro. In sit dnr, Taaima/ aMi~ew-indoced Mslamine rekau frrNn the lung c.u,rlalrA
ek.sely to ane and rw vtcn (r.00e), aRla"h it varird .i.kly belv.een ch.Rs ((Mls /n IS YK
of total tissue hiuamine con/enq; similarly, /ht aw/i{ew eoncentbalw.n Irs prmluce Nys. u(
Tstirnal hislamine releasc varied siafnW be/wetw docis (40 YR/ml to :50 YR/mll In ra% h
1W I 1)t
nf five other dnRs, terhutaline sulhle adminislered intravtnnudy Cauar,l a
d.ne drprndem mh.b.t.nn of anaRen in.lu.ed hiaam.ne rr/raae frnm h.nR fraRorents rn
rrt.a /he marsmal mh.hdrnn pruduced hy I mR/sR was fA t 1 S% Imean ..f1 h11 In
Ihesr same d..Rs. W 'M trrlwlal.ne Infuhalyd wdh IunR (raRmenla rw .ru.r cansrd
inhd..In.n nf anliRen mduced hislamine .rleasr cumparahle to I mR/kR Inhu/.Jrne rn
. IncreascnR Ihr d.,.e of lerhulabne r+ vms prmlwed ma.imal mh.bdwn al K> OM
wi/h nn R.ro1rr elfe., of the druR a1 10 'M (71 It l0% inhihilu.n) /n Mlh eq.rnmrnCd
sduatu.na p.op..nolnl sause.l a dose .telandenl inh.bdion of /t ad.tnerR.c mrntut..t.nn
uf (.,n... .nduce.l rrlraar n( hitlam.ne Ihis resull sappntls 1t.e cnncluarno (hal
Ir.l.ulalrnr (N/n1Y.r1I rrt effecls hy a.tinns r>.edialed by It adrrnrrRi. rrcrPl.r., nn
puln.on.uy matl rllt Ihrs ec(.eumental ap(un.ch prnvdes a su.lahle prrparaln.n in
rluth lu etlunale Ihr effeclrve dov of aRnmsts that rnoduhtr aulaRen inducr.t ma., .rll
fYn(tn,n ar rtrn
I rry. M 1-/ hean+rn, S 1, Rred, R R, Grrenalu.n, I W, Sh.elA., R 1. , R..ur n. ,/1
RI K, an.1 r..,l,l W Af
( I.nr,ul /wrwnnn.f.~Rr 741%) 1211 7?0, IVIII
nrAn .upl.r.r 1/ S Pr.l.6. Ileallh Setvi.-e ru6nnn.uy S(uciat.rrd ('enter uf Rruara1 rnm the t
alrlrn.altu1ar Research Insrnule and Ihe 1)iviair.n a( ('hniral t'ha.m..r.. IoRy.
lart.arlmrn/ of Mrdu.ne, I/m.ersHy n( / atdurnq, San I ranancn
1`( IRAt'I 1 I III AR MA IRIr MI( Rt)1 IuKll S ARI ((/MY(xl 1)(11 ( Y)I(1'
/K1111 IN\ ((fA I I tr W11 / 1 1 111/(/fN/ ( 1/N
I.Irairtlol.r puNrrnt of eolhnrd ealf aarlK anuvdh mut.le crllt cnn.nl
prrdnmrnamly .4 m..r.dJnds 10 20 nm m JranuIrr Iq.aj1 .f 'el.nbn :nvnnlr.l'
maadr1hr.1t dea'riled in many Inwet ('hemwat sn,l numunn:hr.noval evrd.r.r .t
lurvnted that micrulrhrds cunsnt of al traN t..o pro/eins enre prnte.n and Lhr..nraun
Int.duhle pr.urins uf Ihr mi.ro/.Mils rerr ..Mained .n tM f..rm u/ a prllet and anmct.«hes
rarsed in rahMH aRainsl Ihrse enmpnnenlt the anharra /exted .nh the rn.rduhle
mi.rof.Mdlar protems aml .v1h udulde f'hhwnecun in enrsme Lnkrrt immunaa.rlnnt
sasay, am1 immunnslarned the eetrarelIutar micru(1Mih in caltured Cells An
irnmum.R/uhuLn IIRI fracti/n .rst pcrpared and ahantrd wilh (dhrnnrclin lhe ah.u.lud
IRI' Irlained ih reoctivity .ilh the m.crnfibdlar prnlriM but .ras no h.nRrr rract.ve
..th s.duble fiMnnrslin Iminunoflulaescence itud.es ere cartird uW asinR the
aMothrd ITI: and lSli In srduhk hMnnKlin. Ihr1h antdrrdfes s/unred immumutaclrvr
mw'rnlrMrh .n the ealracellular nulrie uf eells in h.ll phaRe. Ihwevet, with imreatinR
time /n cYhute, as the cells reached confluence, she /mmunnflwuewence of mM'11.(II.IIIt
reactrnR ..th the ahsurbrd 1R(i becamr less inlrnse, s.hereas Ih.,t uf /mcrof.hrils rr.trlinR
v.rlh IR(7 1./ /rbronrclm incarased, in eonfluen/ cells, essen1.a11y m. s1»ninR .:n drleNrd
w.Ih the ahu.rhrd 1R(S, and a drase nel.n.k .d intensely starnrd micrnfiluds Was seen
' wdh IR(: 1u frhrnnechn Ireatmen/ nf these rullulet ollh urea Ird lu partral dna..raann
rd Ihe IrMnnecl.n and incressed .iwaliratir.n r.f Ihe mrcloflluih wNh the ahwrhe.l IRIi,
d.wbk label rmmum.fluotescence showed that Inslh proteins rwcur/ed on the tanw
m.crnf.M.h Ihe l.n:alrrat.nn of immum.rractive sitea In the tetracrl/ular micrn(.brda
was c..n/amrd by immum.etrctrnn mic.os.npy Nearly ouantitata.e rlravaRe Wilh (-Nllr
farled to d.ssus'iale Ihe antiRenically aclive f'raRments uf f.Munrclin frnm the ('N/lr
I.aRmrnU nt Ihe cn.e p.n1e.M nf 1he mn:rc.f.hrds 11 was Cnnrlw/cd that m.cruld..da
.r.n/..n rnrr p.rnr.ns and (rMonerlrn thal a.e uwlnlydrulyd .n InWlohlr, pnSs.blY Cova-
knlly anss-linked, sRRreRates. The core proleins ate firsl drprndrd by Ihe cell and, as a
funrtw.. nf time in culture, fib.onectin Olradwlly coats Iheir surface.
Sch.artr, E,(:.dlJnrhn. S.. Cotloff-Schiller, S, and Rlumenfekl, O O
TAr Jwrwof nJ /hv.w~Armr.hyond Cyt..rArmr/(.y I)111:6R.271, MRS.
(hAer .uplwwr Nalional Inslilutet of Ilealth and the ha.id (>wrchinaky I/enry SeRa1 and
the Itlumrnfeld I amdy Memonal I unds.
1 r..m Ihr brpaamenls of Ri«hemislry and Ia/hulnRy. Alberl I inatein ('..IlrRr o(
Mrdwine, Ihe Rrnna, NY.
IMMI/Nf)1O(7/l' IN/llnlla(7NO1; IILlRAV/O1 I:T RAI)IATI(1N 11 fnll(11-1
IIIMItR 11/P/'RI [G1R ('I 11. A('llVll Y.
I.onR-term ee(wnure nf (')/1 mice lo uUravinlet rad.alnm resulted in the frr/ma1NM
of supprrssor I cells that tecnRnire ediraviolel radialron-urdoced rrRrrswr shin aan.en
as a class hrf.ne l/r arpeaunke of ovctt IunuNt Adminislralmn of momnlnnal
antiMnties to 1he puwluct of the /1k suMeRinn of the Insjm histocumpatibd.ly compkt
m hrw drnes ul cychy.Msphamide in vivo inMbi/ed the development ur activily o( these
relh. lhra activrty of the wromrclnnal amihody svn eliminated by adanrpliun on 1110 11K
11-1k) but nM K101)2 (1-ld) splnmcytes. lhrse fimlrn{s providr evi.Mnce that elrmenls
eepreaainR Ihe I I rklerminant are iwyuwlant en teRubtinR the hu.t re.pr.nsr p..or In Ihr
ovetl devrMy.nvnl of ultcaviolet radialiw.n-imluced thin cancers and suRReal nuvrl
thecapeutir apprnaches to malqnanein or olher diseaus involvinR supprrsanr I cells 1n
Ihrir palMKenesis
Grantei.r. R. 1)., htrish, 1. A, MeAuli(fe, f). )., Wallenbau6h, ('., and Grrrnr. AI I
S.nnrr tt1613-617, 1911.
(qAwr lupryrrr Naliunal Research Service Awud and Atthue O and GuI/an M Wrllman
I 040111/31iun.
1'rom the 1)eparlments of Dennalol"y aad /'athology, Ilarvard Medical Schno/ and
Mastarhrsells (:eneral Itospilal, Ihnlon, ara,/ 14partmen/ of Mn-robrrMrRy and
hnmum.hyy, Norlh.eslern U.ivetsNy Medical Sclund, ('hicaRo.
1/'11)I RMAI. ANfI(:1 N-IRfSI NIIN(: (-111.5IN A('tIVAIION /)1
Sllhl'Rl%th)N 11stN1111(A11(1NO/ A NI W IIINCl1/1NA1 1\1'1 (H
111 IKAV11/11 1 KAIMAlK)N RISICfAN/ 1/1111 KMAI. ('ll /
-
(n tecent yeus, evidence hn atcumulaHd /.w (hepresen.e u( nnmun..luRually
active elrnwnls resdenl in the skin, +hieh has led to the c.nnepl o/ skrn ass.w.urd
lymldad titsurs (SAl.ll. ImmunnbRre funeliuns uf these e/ernenls have twrn
dennnlNrateJ to includt processing and presemation of am.Ren tn /ym1.Mr. strt hy
dendritie cells caNed epidetmal I anRerhans eelh 00, Ad./.uenally, rp.dernul
cell dHived, lhynuKyle-acti.aling fsctM (fTAIF), an en/ity M.nhemnally and
fWKli.mally very similar or wkntica) 1o inletleukin 111t-1), is pmluced by kr.am..<y/ra
Ihus. Ihe sk.n can he eonsidered a eompka orpn in .hich ce/h reMvanl lo thr rmm.M
systrm a.e rrpresrnlyd
1 151
1-
IApmure of mice to low drnet of ullrsvinkl rd.slion (IIVR) rn eiro kads in an
inah.bty to arnatue them lo contact tentniring resaents t the sile of nrdiaunn, rwl
Ih/s del..ea.rd srm.tualmn it accompanwd by Ihe fnrmslntn of anliRrn .pr.ific I
.nrr.eaao. Ils) crlls tl hat 1so been demornlulyd /hal haptencouptrd rpidermal crlla
(1(') /...m (tVR Irralyd nl.ce ve vnahle to immunue mice efficiently when
aJmmiatrred sultulanenusly, sod such Immvnirslion /esutls in Ihe aprratance of
sup.ressm cella Wr repml that the mvrinr epvlermis conlaim s pre.viously umecoRniird
anr.aen prraenlina .eI1/Ar(') that rs trQuired foe the atlivalmn nf surpretsion, and Iha/
IMa AfY' re rrsraunt In IIVR lhe dn.e of I/VR empbyeJ .s. M.wevrr, sulficirnl lo
prevrnl wMlsnlu1 Iwn.hvr rmmumlat.oll of mice witA aynRenrlC (aV nraAnlyd
ha/.IrncuupleJ 11' Ihrae dais raplsin in poet /he ehanRes .nJuced in rpukrmal
anbRrn prraenl.nR (unclnm hy IIVR. sed hss eonse0urn<es foe the unJeratand/nR n/
1 1 V R.n.1u. rd c u/..nrnut carc I"r nrail
i
I
MUN(X'1ONAI. 11s1(Y10PE VACCINE AGAINST STRF.p)YXU(Y-fIS
I'Nf.IrA((>NIAf INI 1.('l1UN
(.rantlein, R f) , 1.wy, A, and G.rrne. M I
f A, Aw.no/ u/ Inv nun.h.tr 11l(.') 561 SAS, 1915
NIA.r .rpl...r Nat...nal (yr lnatduv, Na/...nal In.l.tules of llrallh and Arrhu. 1I and
tul/3n M weltm.in t..undalwn
1 rnm Ihr 141ra.tmenlt nf I4.malnh.ty 2011 tatMdoay, 1larvarJ MedNat SaMr.l, snJ
h1a.a..Au.rIH I:rnr.al Iln.raal, 14nlon
XP1iNI(t IRIAMINGANII(:1N tMtVN/INL(111SINA( 11VA11ON
/11 CII/'1'MI\\IIIN /IIMIII/MIII.\MAI /IMI/AIII/N
A ae1 nl I I Ira..nR mur.ne ap/rmc snl,arn p.ewnhnR crllt (AP( I hal twrn hwn.)
lu he rryr.m.hlr lo, lu.l ur.Hr aupp.rsw rll IIQ, al(rrrnl turPrraan~ crll/ a Uvalw,n
in the rul.rnrrnevaonare IAIIAI hrptrn tyalrm sllrr rnbavrnnua aJ.mn.aual.on
Suprrra.ur trlla .n,lu.rJ hy /hn tr1 ..1 h.rtrn .uap/eJ ce1H .pr n..l fun.lnn /n Ihe
r/trren/ phaar of Ilw Jrbyrd hylwrarmn.vdv 11/111/ resry.nar Ihr funclum.d aclivdy
ul Ihh m..rl A1'(' tn s.l.vale affe.rnl wrprran. celts was trai.lant w, a dnse ot
vh.avwdrl radhtvIn (UVM) aufficient tn lararly aMuRale the ability of splenic A14' In
rmmunitr hn a 1)111 rrstylnar /1 wat atu. /aumt Ihal Ihe previnusly deardwd spknic
I I Msnng ArC needed fnr third-nrJer tappressnr cell (Isl, effeclo.-surptesanr cell)
ac/1Yalnm is adhrrenl and IIVR res.wnl Ihe sels of I l Iwa»inR AP(' a/y+ear lu he
crucial ektnenls in Ihe aclivatinn uf tuppreauen and thus in delrrmininR the halance
hrtween immlrnoh/Rrc rraclivity snd vnrearnn.iveneess /ar/hernwMe, the I/VR rai.lance
nf Ihis set of m.vel AI'(" may he relevanl to the in am effecls uf IIVR esro.u.r 1a m.ce
('rantlein. R 1) snd (:.renr. M I
( rllular hnmwah.R e9 1 1: -10, 1915
OtAer top/rn/ Arlhur (1 and (7ultan M Wrltmsn 1 oundaUOn
I rom Ihr llrparlmrnts of I)erma/..4.Ry nd hlhnloty, 11ar.ard Med.cal Sc/.n.d snd
Maaau'huarlls (.rnrlal Il.np.tal, Ihnlon
A rru.nnch.nal nbiJiolope nliMldy coupled lo a orrier p.nlrin waa usrd tu
Inlrnum/e IIAI 11/c mice spmtl a lethal Srrrprnrnrn.n pnrven.n.ur infrclu.n. Vaccrnalyd
mwe dr.rMywJ a hiRh liler of antibody to pMnphorykMdlne, whn'h is lormwn ut p.utrcl
a`arntt mleclnm with SdryN.n.rcvt pnrv.nnnrar_ Measuremrnt of the median lelhal du.r
uf /hr hailrrl7 IDda9t1'd 1ha1 anli idnHope immunilaliUn a~ndi.aolly inuRlard Ihr
rr.i.lamr ..t OAI Is/c mKe to Ihe baclrrial chalknge AnliMldy 1o an ..In.Inl.e a an /hu,
hr usrd at an snl.Ren tuhslilule for Ihe induclv.n uf protecbve immunity
McNamara, M K, WarJ, R F and 1C.Aler, N
S.rrnrr 7 26 112 5 11.`6, 1964
()th.r .vrp...r Il S puhli. /Ieal1A Srrvice and Ihe New Yo.k Slate 11rp.u1mrnl o1 llrahh
AII/S Iml.a.le
I rom the IMpa.tmrnl of Mukcular Immunohqy, Rntwell ra.h Mrmmral Inuslulr,
llullaln, NY
ANALVSIS 1)1- A IMr - iMa 111Y.P1 R('1.1 L('IRCl11f
In the prrsrnl atudy. the 115 idiolype-rectanirmR 1hrll.er cr11 cucuil wac
J.afeC/ed w.lh rrs/wcl to its tvrmeo11a1H, in/rraclive tpeci(rcily, tt.lhd/ly ovrr Ume am/
effecla nn It tell r.rreaw.n. Analysit of the IR/ cells by ad.q./rve Iranafer falw/mwnes
Indwatrs Ihei. shnrl lived stsle of aclivily dunng which 7 ps eellt re slnnulated IMI
cell aclivlly was also dveclly nronilnred by Ihe use of -INI'ana 11) hyhrrMoma
anaRrns It was fnuml Ihat TMI «lls s/e delecled / wh dler priming with Ir' /ly,
whrreaa Tl/s cells Iwrume activa/ed aftrr A e.i of priminR. (bmpi.al.ve analyss .J Inl
cells by va1nR Iwn ddfereal 7NPanli-lIS hybridnma anliRens indreales a lltl tprcdany
f.n shared idinl,y.e. lhe stability over time of the 1/n IMa c...uil wa.
.kmnnavaledhy comparinif IMa freavrnein in young and old m.,e
I inally, we ad.lresxd the Ilueflion of Ihe function of the n/.olylw- recogn/nnt 1
helper eellf and showrd Iha/.s/ivlulaliun of tU-idnrlypetpecil.c IMt cells can hr
correlalyd wilh a tignificanl :ncrease iw the peacen/aRe of 115 iwlmlype In an sntr IY'
respnnse. ('olkcl.vety, these dals deseribe an iwliolype-specific I hrl/wr, ca.cuN as p+rl
of the ne/wur\ hume.Klatn of lhe iminune syslern.
McNarnara, M, Kanrt, C-Y., and Ralllrr. ll.
IM /.unnal of l.nmunab.tr I Itf11160).1609, 1983.
OrAr. .uprr Nal.onal Imlitule nn Aging
Iram Ihe IMpar/ment of Mnkeular Irnmunoh+ay, Roswell /'arh Mrmu.ul tnsa/uw,
tlulfaH.. NY.
1+1 I ISS
Ih1M1INORI A( I IVI l'A1 ('ITl)NIN (:1 NF-RFI Al f l) rl r I It/F ANI/
SIIIISIAN('1 PtYll Retl IN StN\/fKY NI ItRt1NS 10 1111 NlINAI l'ORf)
ANt) IN/1 RA( I IN V'INA1. R) IIAVItIRAI. RISK)NS1S(/1 1111 RAI
tltinj iminum.hlSlnchernitlry, rrnfence wat obtained for the e.n`..slrnce of
cakilnn.n aenerrlated peptide 1('(:R/1- am1 substance Is /S1') l.ke immunmeacnvily in
ttnnal tent.uy neu.om Anatyvt a( cawlally drreeted h.tina and scralchmR (1 11%)
IMhavuu was earneJ uut afler intralhecal adminislralinn of (Y:RP and SP ahure m rn
comhmalu.e tkus, St (up to 20 rR) alnwe caused COS only for few minutrs a(/er
rn/eclwn, wherrst sr (10 vR) plut ('(:Kr(20 rj) eausrd reaMmae wilh a dural.on up 1.0
10 min (GRr rn NR) sl..nt had no effeels in this rmnkl Ihrte findinRt prn.iJr
tupl.nrl (nr a tr.at.hle .nlrrac/u.n of /l.e two peplidet 1 synapaca in the durs.J h.an .d
16t sprnat cord
w.raenfel.l 11a11.n, /, Iln\ftl/, 1, I u..JMrt J'( . I nrat.nann, W(3 Rrme, 1r, M,
I shul.p, I A, and 1.sI her, I A
N.urr..crrn.r I rnnr 521')9 204. 19A
IdArr sury..rr I he SweAiah Medcal Rtararch ('nuncil, the 1 u1\tam Insurance ('nmpany,
the K arobnsaa Inal.tule- anJ Ihe Swrss National St:rence I oumlalion.
I.nm the 14paumrnl of ('Lncal Nrurophvsn,IoRy, IIud.ImAr Il.npitat, t)rparlmrnH of
1h.1../.Rv and 1'harm.nnk.Ry, Ka.utmsla Inadalt, \I.nlh.dm, Ikt,arlmenl ul Anatumy
III, I/m.ervly of //r.drlhrrR, IrJr.a1 Rrpul.he .f ILerminy, and the Resrarch
1 aM.ralu.y /..r 1.d,uun Mrlrlydna., Ir.luamrnls ul Ib/hnlrAn \urKery and Mrd.me.
Ihu.rrvly ol /w..h. \+.~fr.lan.t
111/KYNt1I1CIC(11 (:I S/ (>\IIIIN/.11111'll\ IIS 111-MAN s1s11111t1
t11/A1MI-A( 111C
We ha.e prrfnrmed eomparal..e studies uf the nrulral Rtyanphmanhpids
syntheslred hy Ihret human myekrni kuaem.a cell Irnts, K Se,' K(71, and I11 M/, .hich
wert Ine/aMd.tally /sbekd wi/h 1"('Mtaqame, to e.alualt chanRes in neuleal
RtycotphingnhpiJ synlhesis wilh myelual cr0 differenliaann. Imlrvwlusl neulral
Rlyc.npAinRnlqrw/t cuntaininif one to (our suRan were purified by a comhinatinn of the
fnikwinR roelMu/c dielhylaminoelhyl Sephadea column chramatography, acelylalinn
I lnrivl adumn chrnmal(sRraphy, and h.Rh perfetmance IiquiJ tMmnaln~raphy uvng an
launbtad cnlumn t ompounda w.lA one seBar were aealysed by lhrn Iayer
cMomatnpaphy nn borale platts This analysis Shnwed Ihat III.-60 cells synlhesire only
filucosykeramuk, whereas KS62 aml K(:1 eetts synthesue predom.nanlly
Flucosykeramuk, but alto a small amounl of galactosykerami.k ('nmpoumlt wnh Iwn
to foer )uRacs were tharacltrlved by lreasmenl wi1A t.o ml rndrRlyco)iJatet the
rnults showed /hat K762 and KGI cells ate similas lo cells from palients wdh a.ule
kukemia in etpressing 1.0 seriH (Ilk.hn end neolxln) of nalual ~Iycmphm/nGpi.la,
whtreas Ihe 111-60 cells ate similar to malure Aramsn mytlnid ctlh in e.prrav/.a only
one series /nentacln) lherefore, human myeMid leukemia cells bkrcLed sl dd(erenl
stages of differensialinn vary in Iheu ability In syn/hesrre neutral {lycnaphinaolip«N.
Ruehkr, /, t)wan, /, Itr(:rraoris, M W, snd Na Arr. 8 .4
th... Ar.w,.~.. )e r.'/ rll n.s1. WN
t
OrArr a.ppwl. Ihe I.ouis R Lurie I~nundalinn and the Na/innal ('ancer Inslilule
lrnm she ('ancrr Reaearch Inailule and brparlmenl of Pharmacruliral (hrmnnv,
I lnivrraay r.f l'aldurrna. San I cancisco, ChilJren i l'ancer Resrarch Insntwr, 1'.n 1 K
14eshylerun Mrdreal ('enter, San I raneiseo
IIIIMAN NAIIIRAI. ANfI o(7A1 A("T(LCYI IR(: 11 1111 SPI('111C
KI((wiNlllON/11 ..11 ) IINK11)(iAIA('1l/Sl RI%11N11S
A nalural IR(: anliMdy (anli Gal) wilh o`ilac/n.yl bindinR aprcific.ly has brrn
fnund in IarRr anN/umt /0 S 10'K of steum 1&(:) in all ImI1vMlua/a les/ed 1/ I...a trrn
t.unfird by alJrmly chromalnRraphy on a column of inelihH.u-Srplurnu In add.lu.n In
rls affrnily lor nurmal and patM.lottieal lenescenl human .rd eella, the antAw«Iv rr.ddv
intrracls wuh rahhn re.l hkwrl cell (KRtI(') tlyeolip.da wnh n aataclutyl Iru.ond
rrtMutt Iwo IyPes (RlycmiAn: linha2et o( I 1 es. 1 4) of ral.hrl red ctllv aly.ulq..d.
wdh lerminal n Ralxtnayl ctswlurs were tesled frnr anlduuly himbnR 1 he ant.l+~lv
apec.frcally In.und tn Rlycnlipids wilh (:akvl 1 lermind reswlues, and Ire/mrnl nl thrw
Rlyeo6pidt wilh nRalac/osw/ase aAnlithed bimling /kmagRlulimlron inhda/n.n slwl.ea
wilh o1rR.naccharwfet of known slruclere alto showed IAat the anlitrMly hnAa s1Mo d a alty
In gIycrn:uniuRates with an ol ) lerminal galaclnse residue Anti 631 du1 nnl b.od la a
Auman R xlrve alycnlipid, imlrcalin{ Ihal fucuu linked u1 2 N. 1ht/wnulum.uv
galaclnu prevenls ami-(ia1 him/ing lAe anli-C:aa speeifK-ily tor KKIK' Rlvauhp..ts aho
paralltlyd that uf the e-ptscrosyl-specifie R.rafnrere armplr.r/.dr.r /erlin Ihe In.avbk
reasnnt for the oc.unence of this unique analMnly ill human srrurn ate Ancusard
<:ati6, 1/ ,/1/a A r. /l A, Ruehkr, 1., and Shehet. S 0
l.nnn.d of Eaperrmrnrot MrJrrrne 162:571-3112, t01S.
Other SY/(VM( NI.nnal Institutes of Ilealth.
I rom the MxMil/an-Carifill I/ensstoln{y Research /.ahora/nry, Cancer Retearch
Insli/ele, Ikpulrnents of IIAarlnaceulicN (hemitlry and 1 aMualory MrA.cinr,
11ni.ersily of ('alifornia, Sn Ftanciaco.
(:I.YCf76P111NG()1 IPIp CARRtF RS OF CAR 0(HIYUR A 1 f. AN 1 N:FNS 01
/IUMAN MYl LOII) Cf I.I.S RFC(X:NIZI.U MY M(NKX I ONAI. AN 11114 It/11 S
Sia monocbnal anlibedies with known tpeeifieiliet fm Ihe carb.hydrale anl.Rens ..
X et Y, m/ teven antimyrloid aelibodies (de/eraninants unkm.wn) sefr.led /ur /hru
differing rracliun pa/lerns wiM Aenue le.cueyles were tested in chromaloRram him6nR
astays fm rea.lions wi1A myebd cell ifIyeolipids Aeri.ed trmm nu.m.d huo.an
gtanuknyles and chronic myelftenoes leukemia celh v Anliaeniailrrs wert lnuod
etcluaively oe mimN {lycolipids wAich wett barely m eul tl all dele.lal.k wnh
orcimd sulphuric acid starn. Amon4 IAese, a neulral Glycmphintinlrpid bound Ihe mr r
aeliMAy /)tn and chromalndrpAed n/Ae ctramidt ocusar[harwk, ((7a1p/ I1ikNACltI
-. )Cad// - K:kNAe01 - )G./01 -4C.kNAC/1 - H:aIAI -. e(:Ic-(er Srverst y.r..rs
of aieWrd slycosphineolipids with sia to reore Ihae fee mrurosaccha.ides wrrr dr/nlyd
that caray the X snligen and others Ike Y anlillen(:a1A1 q/ ucn/ SKNaNAC nd
I ue el 2(:a/p1 QI ucel )i(ikNAt, respetlively In ddi/rn threr new IYMs nf
1
carM.hydn,r speciticities were drlec/ed among Ihe myrloid cell glycnhpids Two .rre
acUwulyd wqh neulcal Rlrtnlipids the fust, recoRniteJ by ants myrMiJ annt.wlws
VIM I am) VIM N1 was r.prrssrd on a dishntl srl nf litycobprJS wilh sit ur n.nr
rm.n..ucthandrs, and the srcnnd, recngnined by VIMA, was raprrssed on Rlycnl.pnls
wi/h mnre Ihan trm mon.naccharales the thnd specdicily, recc.6nired hy the
anti myrlnnl anld..dy V IM 2, wa% rrprrsrJ nn .iow miRralina snlnRlycut.p..h wnh
hatihunr suuc1urrs af Ihr poly N acrly11x1osaminr type that are suacrpl.Mr lu
drRradalian wnh rnJ.. p aalacm/Jasr Ihw, rrc eonelude Iha1 she i and V am.arns
n,cur smr.nR Ihr Rlycnhp.Js o1 nnrmal myebid and ehrunie myelnRrnous Iru\rmu trllt
nd Iha/ a h.Rh p.nlu.mnn nf hyh.«M.ma anlihodin raisrd aaams/ dd(r.enl.,r,nn
anUarns uf myetunl trl/h a.r d..ecled a/ carhohydrale slruclures.
14mu.a, K , Ara.Ar.. R
I e.n, I
A, I1r(:retimio, M, Scud.kr, P, Ruehlrr, 1, K nat,p,
W , an.t
RwnA.n..ra rt RmrArvrn A. ra OIY 76 16, 1985
nrbr rury..rr National (-ancrr IMl/lulr, Nnflh AIIaMK Trealy OrRaniralwon snJ i nu.s
R I urie I nundahun
Irnm the Apphed Immunochrmislry Rrsra.ch C:roop. INvisinn of Communicahlr
I1..easrs M.A..al Resrarch ('ouncil't ('hn.cal Rraea.ch (rnler, M.ddleua (Il K ), ( amrr
Resrarch Inc/.tulr, Ikpa.tmen/ of Pha.rnaceulwal ( hemn,cy, I/m.rrsily of (bldorma,
San I.sncistn, ( hddren's ('ancer Rrsrarch InatnWr, Pacdk Medicat (enler, am/
IMpartmenl u( Intrrnal MeJ.c.ne, Inat..nte of Immunoloty. Ilnivrrs.ly of Vienna,
Auslru
IN Yll R(1 I I 111 -Mf It1A 1/11 K11/ tN(: 1)1 r.C/fr/tAA/(/NA.C AIRINGIN(7S 4
I I VIl/l N(1 IIIA1 A I VMPIIt)KINI MI IIIA 11 C Klt I IN(:
Previnus stud.es have demonsuareJ rn n.n Ihal T eells can provide protrclivr
immunily, in /he ahsrmv of anhM.ly, silamsl infeaion with Ihe rct.acrllutar
c:ram nesatH'e haclrrlYm Immrnnlype I IIf-I/ rNwlnlw.Mn. arIYellNHa We rstahl.ahed
an rw nfrn syslem in wMch immune I ce1N, Nlrr rerap.nure Io haclerul antiRrns and In
macrnphaRes, seclete a producl Iha1 hdls the hacleria Although mxn.ptuRes are
Iequirrd for ur ruro t,i11in0. Ihey funcliun weilher n anligenpresenlinR nor as
pha{ncylic cells in Ihn syarm. T cells from animals immunized a{ainsl a Jilfrrrnl P
erruRrna.a immunn/yl`e will not kiR 11 1 orRannms, twl the suprrnalanls prr.duced by
(t . ( immune I cells aflrr rapnswe to macc.MthaRes and 1F-1 r erruR.m..a nrRan..ms
are nanspecifically effrctive in killing unrrlalrJ hacleria l1rCausr the su/Yrna/anlc (lum
imn.une I erlls lmr Iheir haaericntal prnprrlirs ul..n minimal ddwlmn, we cnn.l.nle Ihat
if this mrt hanmm IS aclivr .n rnn, it musl pay a tole in Mcal imnwmly
Afalhnn. R R.(:nrltnrr, I, and Pier, (:. R
1 Ar l.w.nal oI Iw.mud..l..cr 1))(2)062 Ona, 1914
()tArr .ur/orr Aueiliary of the )ewich tt.npdal r.f S/ 1 ouis, It S Publie Ilratlh Srrvice;
Na/.nnal 1nsl.tutrs .d Ilral.h, and (/ S Army Research and 14reh.pmenl (lnmound
Inm .hr Irps.rm.m. n( MrAK.nr, anJ ALc...hud..~y A Immnnnh.ay, Wa.hmRrun
uun, r he.m.a~
1...,... ... . . . ~ .. 1 .. .... ... t I..r 1r-h //.../..1..1 .1 \I I
1 . . .. ... . . ... . - . . . , . ... r... .. .« 1 r..m.e . 11.,y.d d
t
I
I
1611 MRRANE AND(Vl(XKEI.FTAI. CIIAN(il S ACS(XIAII I) WI111
1a1 MI171AII.I/SIR(110NINR/.t-EASl:1KUMRAI 11AS(/1'11111(
I1.1uKIM1Al11.IS
RmdinR of anliRrn In lei.-receplm cnmpleaes nw Ihe surfat'e of Klll '111 at
hasopMln: kukemn t'ells is the firsl evenl IradinR 1.. Ihe rekase of crllulac srrnhm.n
/nslamrne and nlhrr meJ.alnrs nf a1lerRic, asthmatic and inftammalory rrap..nars We
have usnl d.mu.y.hrmdcunjuRaled hovinr srrum all.umin ((aNP USA/ aa well as thr
flurnrscrnl anhRrn, 1)NP-R phycoerylhrin, anJ the ekclroo-drnse anty,rn.
I/N1' IICA Rnld, 149 in.es/.Rale dynamic InenlMane and cyhnhrkul evenls astu..a.rd
wr/h /he rekaae nf 1ql1aenNOnin from an/.-UNPIRI:-prinrJ Rn1.-2111 cells Ihrar
muhivalrnl anliRrns Innd rapwlly In Crtl surfxe fRlrrcep/m complrars lhrn
JiVCihulw.n is rnilully un.form, Iwll within 2 miw (aNPRSA-Rowl is found in eoaleJ p.ts
amf n subsrquenlly mlrrwalireJ AMitew inle/walualwm o.eurs rn Ihe prrsen.e a.wl
ahsewcY of e.lrarrlhdar ('at'. Ihe /-ac/iw cowlenl of the delelRenl r.u.nlr./ tAl
maUwrs anatyrrJ hy Sltti RMiI drerrasrs dwing Ihe firsl 10 10 s ol anl.Ren /A.u.Iu.R auJ
then incrrases by I m.n Iw almwl duublr 1he eoMrlJ kvels. A rapiJ and u.uund
increase n ahn c.hvrved whe/l Mlal /sclin is quawldird by /hrw cytm.wI.y al,rr
himlmR of rhndamrnr-phalhddin. Ihe anligew-slimulatrd increase in I x1m comcnlrs
with lam/ m,y causellhe transfmmaliuw of the cell surfxe frnm a finely micrn.dlnus Iu
a hiRhly fnWed or plicaled tn(uqlraphy. (Mher early memhrane resl.nn.rs m.iwdr
increased cell spreadinR and a 2-1-fohl increase in the up/aLe of (lurwescrin Je.l.an by
f1uiJ p.mn:ylnsis. Ihr surface and 1-acliw chawRes sM.rw the sarne drpendrnce on
I)NP-prmein enncenualimn as sbmula/rJ 1a/11 srrd.wliw rrkasr and Iwnh Ihe mrmbrane
responsrs and the rrkav of inedralnrs are lerminaled hy Ihe aJd.an.n nf Ihe
m.n-eaqs-ImhinR nu.mrvaknl IiOawd, UNP-lysine. Ihrse data indnrale 11.31 1he samr
antigen-slimulaled lunsductinn pathway ennlrnls MNIA she memh/anelc)lu.Arlelal aml
srCrelmy evenls I/nwever. Ihe rnemMane and a.lin .eyw.nvea lo
1R1.-recepinr cross-IinkinR are Imlepe/ulenl of es/racvRYlar ('as' snd are m.mn~eJ hy
phnrlnd myrislale arela/e, whereas (igandJeprw.knl mediah.r retrasr JrprnJs on
e.l/acellular (-aa' am/ is mimicked by the (-al' iom.phnre A2111).
rfeiffer, I R, Sratira.r, / C., thvis, e. 1/., Deanin, G. D, and OLrrr 1 A(
fAr /nurwal n/ lefl R.nl..Rl 101214S-21S1, 1983
Ottwr supryrr Amerncan (-ancer Sneiely anJ Nalimal Imlilulrs of 11eah6
From the Ikparlmenl of PalholoRy. Ilnivenily of New Mraico SchwJ u/ Mrdi.,nr.
Albinluerqw, and Ihr 14parlmenl of Pa1Mdn11y, S/a1e (1ni.ecsny of New 1.nA, I lln/ae
MeJnal (rnle/, Syracuse
1/1S1R11I1111ON (11 (:AI ANIN tMM1/N/1R1 A(-IIVII V IN 1111 K/ CPIRA IIIN V
1RA/'1 /11 /'1(:, /:111N1 A P/I:, RA1, AN1/ I1(M3
Galanin, a newly ducovereJ peptide iswlaled frum pnrcine inleslinr, r% knnwn /.e nuse conlracliun in
ral sm.nlh musck prrparalw.ns and 1.n im/w.r hywr~ly.rm.a .n
dn{s. Oy Ihe ua of raJwnmmunnassay wwd /mrnunnMSlnchrnN.al Ir.hnnlurs Ibr
eoncenlrsli.m and d.slrihulinn of Ralanin immunurtxl.v.ly wrrr drlerm.nrJ n. sr.r.al
areas of Ihe respualnry t.ac1 nf li.e dnOs, five ~u.nea piRS, L.r .al., anJ twu p.p.
AnhM-lws were tai.ed in rahhils to whole un(onjuRaled nalurat tw.p.ne R d.n.n I hr
Mithesl Ralamn cnncrnl.ahnns werr fnunJ m 1he Monahus and the Ira.hr. n/ Ihr
1 110
Ru.nea piR rat (: pmnl/R in each caael. and piR (< 1 pmnl/R1 the luwrtl Rilanm
cuncenl.al.nna ..e.t fnunJ rn IAe tunR pa.rn.Ayma (;el cMnmatograph.c analy.n .n the
p.R dmwrd nne rnotraular form uf Ralan.n crwlul.nR rith the Inu..nr R..lamn tl.rn,l-u.l
Ily mrans uf the ndneal Im/nVMJhn..rprnrt levhnutwe on iralwna ol li.aurt I..e.l .n
hrnrwluinnnr s.Jutmn. Ratan.n wst InanJ in he cnnfrnrd In nrrve f.Mes .n dd/rrent
r.Romt u/ the .ealnralnry trscl In the naaal mwnsa of Ihe p.R. ner.r fhhea cnnla.nu.R
R.d.mn we.r d..r.d.u/rd ar.wnd ternmucut Rlanrh snd hhuv/ rra.rlt and twnn.h the
rl..lhrl.un. In the traah.s, M..ncMn, sn.l mapr inlUapulmnnary anway .f the p.R. dnR,
an,l Rumro L.R, R.ilan.n lmmumlreaal)rr hMrs totrt drleclr.l prrduonnanlly muur.lh
mu%.le, at wr11 aa ar.nund tr.nm.nut RlanJl anJ in /he adrrntn..r uf M.rrl .ratrla
Karrly, aal.In,u Immunu.ea,hvr ner.r Lhtrt rtre found in the IunR 1V.rnchyuta II frr
R..lan.n .mno.m.rra(Ure Ranahnn crllt altn ennla.ning vatuaal..r .uletl.nal /wdsl~pndr
wr.t IounJ .n the adrrnl.hha af the Ira.htnh.onahul wall ul the piR anJ .t.R Ihr
dnlr.hulnm .d Ralanrn auRRealt Ihal Iha prpl.de may ha.e snmr .nltuen.r nn 7uw.y,
ra.iular anJ ara.rlult tYn.InMa .n Ike mammal.an rrtpuatnry I.a.t
1 hrunR, A, P.Jn( 1 at 11wer, / Iadw., A, (T.nlofa/ea N h, Spr.nR.11, 1/ K,
an.l t1L..m, t K
I'Ao.n. 4Olllo /1'M, tIlt
rAA,r .rp(r.r Mrdnal Reararch Cnunc.l /l/nned KinRdnm)
I.nm the I/rparrmrnM of IInUKArmnny and Mrda.nr. Knyal rntlRraJwtr Mrdnal
nRland
ANAI.YSIC(11 h1A( R(1r11A(:1 111111 RI NIIAIK)N ANI1111NC11()N WI/11
M()N(1( 1(1NA1 AN I Iln)lN1 S
A 1a.Rr'numtrl rn( anli mnuae and anli human mac.ophaRe/mnnncyle mnmwlnnal
sntduaLrt IMAh) have recently been nhla.nrd 11ha1 ane prov.nR rnvaluah/e rraRenla ..f
er/rourd.na.y sprul.aily (or the tludy of macr.MhaRe ddferrnliatinn, fum'I.un, and
sullxe snnRrn tlruclu.e this chaplrr summarieet InfnrmalNm on such MAh up to
1 rMuarry 10R1 In Ike moaee, sl kat/ f.vt anliRens Ihal can ht dialtnRu.ahed by
mukcular v.e.Rhl have been found on naaerophaRes bul not un IympMrytes. /)ne rd the
r111nIQ I c rheptrstrs. p.eaenl nn macraphaRrs sa weM as on tmne lymphoeylet, haa sftn
heen defined with MAb I srthtr sntiRens Lave nnl been definrJ hM.chemK]IIy Iwl
aly.ear tn havt d.uiml diauilwlioes un funelN.nal tVhlMl(.VIa1V.M Mal'-I wat lhe fhat
snhRen In ht delmed by MAb that it presenl un mac'rapMges and /IM nn IympM.cytet
A arcnnd antigen has been disenvered Ihal is dnlrnel from Mae1 in cell dna.hutum,
funclmn, snJ o-suhunit struclure, bW alyuars to ase the same /1slrhunil In the courv
of ttwl.rt on Ihe mnlecular hatis of I cell funclwm. MAb srerr teketnl fM Ihen abihly
Irt inMhd snt.Rentpecdic 1-lymphncytt-mrdialed ttilhng /1 a(yaars that 1 I A /.t
dit/.ncl flnm Ike ant.Ren Ncrpt/N, I.VI .nrhs h.Rtlher trilh il in conl.ihrr.nR tn the
a.wlbly nf the ( 11. L.r the IarRrl a'ell 1 1 A I it present on 11 lymphncytes anJ myrh.al
crllt at ~el/ 1s I lymphncytts, tuRRrthnot Ihal it playt a mnre Rrnerd rnk in adheamn
Ihan dn snl.Ren rrcrphat A timdar fAmily of relateA mnlrcu4t hat been fnunJ nn
hnman eellt (Hhrr aealmns of Ih.s tludy deal +ah MA(2 anliRen, Mac 1 anl.Rrn,
1 anRerhans eellt, drndr.l.e eellt, and mat'r.Mhatirt, dr(ininR marrnphaRrt by Ilvu
turface mar\rrs, anJ InMmunnh.ll.cal ernlulmn
Cr.u.Rn 1 4 anJ I/nir/rts, 1 1)
t
In Adams, 1) (1 and 1lanns, M G., /r. (edt k Cnmrmpurmy T..r.rt .n
ImmunnMObIRY Vol 11, New Yorh~ t knum ruhliaMns (-orluaalu.n, toRe, pp 1 11
Orhrr .urMwr It S Public llnhh Service and Ike Amerwan ('an.er S.uiely
Ir..m the I aMralory of Membrane Imrntlnnr'htlnltlry, IlarKalJ MeJnal 5.'hnnt, IMtlnn,
and the I ahnratnry nf ('ellular Ihytiolntty and ImmumduRy, Ike K.n\e/ellrr Um.rraly,
New York
rR/ PARA I ION ANI/1/51. (H MON(1('1 (/NAI. ANI IMA('KOr1/A(il.
AN 1111O1)11 S
Mxrr.phaRrt sre a diverx family of erlh miRmatinR from pluntwqent stem cellt in
/he M.ne ma..u.. (lutside the mauo., macuq.ha{n can u\e the (orm nf M.MMI
,.ron.rytes, Kupffer cells, alvtv.lat Inacro(.haRes, perilonea/ macrnphaRn, I anfor.hant
celh, and in alm..al every nrRan, as Yioitd Insur macrnphaget" In aJJqan to vanalnm
in ana/nmical lo.alvalinns, maernpha{es can eah.bu heler.Keneity in funcliw.n and tta/r
.uf ddfe.enlralion. Ihe advenl of hybridoms lechmdryy has slluwed the M/en1llNahun of
oer 40 macr.MhaRt sntigens, sneK of which sre rtrful (nr dnl.nRuithine marnq.haRrl
frmm nlher crlls .heress mhers srt sssoeiated ..ith dislincl sulneli of macrophaRra In
Ihis aec/mn, a number nf nqnoc/onal anld.whes ..ith relalively .eslricled specrtadwt (.a
macrnphagrs .ere chmen and /hen chatacleritlKt were summariaed. Inaa,Mr
al.(.Lcalmns of Ihete antibndies sre sho descrihed.
Ilo, M. K and SryrnRer, T. A.
AfnM.dt rn Fn: ymnlnar 108.)17-)25, 1984.
OOther suppr.l U S Public Ilesllh Service.
From 1larvard Medical School, Soslon.
11l1- LFA-1, Mac. 1 1:1.YCOPROIF.IN FAMILY AND I1S I)1 I/(11 N('Y 114
AN INIII R/111) /)ISLASE
A (amily of funclionally imporlanl, hi~hInolecularv.tiRM RIycM,aNrins wah
identical 0 subunits has reeently been defined w kukocyle cell surfaces S.nm sltr.
Ihese mokculrs and at kasl some of Iheit functimn had been defined ..Ih mnn.whmal
an(ihalies, an inherited distase, l-FA1. Mac-1 defrciency, was diacoverrd in humans
lhis deficiency has confirnted that this glyeoprolt.n family is uf eenlral in.purtanae in
kveltrryle cell surface adhesion reactinm.
S(urnRrr, l. A
IrJrra.nn P..«rrJ.na. 44 2d60-26A), 1985
(hArr tur(rnrt' National Insl/lules of Iltallh
r
from the 1)ana-f arher (-ancer Inslitute, Ilarvard Medical Scho..l, Ih.srnn
le.b I
/61
i
1111 S/ Vt RF ANIS M(Slsf RAIF PI/fN(SIYrfS (rl III RITARI 1. Mac I,
In these mnlecules, similar mnkcular mtchanitms umkrlre macrupha`e and I
I 1 A I t/l l/t 11 N('Y 11111R VIIANIIIAIIVF Iy111N/11()N ANI) RI I.AINSN
IympMnylemeduted immunily. Ike f.ndinq on Mat-1 and (1 A-I art rev.ev+eJ n.l
1(111111:IM Y I I tl\SIIIN( 11l)N ANI)(-11N/(AI IIAI(/RIS
the tvolulmnary .n,plKalmns ate dncwseJ
An inher.lyd sYndtnme chanctrrittd by rtCUrreM nr prnRretsive necroln
anfl Uassre infectKma, d.m.nnhrd pua fntmalwm, impaired wound heal.nR. RranuMKylmit,
and/nr delayed umh.h.a1 cntd sevetance .n rec.nRnirtd in four male am1 rour female
p..t.enla At shn.n wdh auhund specrfrc mnnoc4ma) anlibdies m immunnfluorrwtnct
Ih.w cytomelry and "Y .mmum.ptenpita/inn /echniques, in addi/nm tu a trmolrJ
a.nlmm L.ruhyJndr Ralsal.nt n.iJasr Iahr6nR nsay, panul.Kytes, monncytra ur
IympMrylra frum /hete ind.v.Juals had a'nwukrale w'stvere' def.ciency td Mac 1,
1/ A 1, nr p1ia0 9S (ut a combinalinn) - Ihree sttuelually trlaled 'aAheuve' surlace
RlycnprMe.na )av.. J.slinc/ phenolypes wete def.nrd on the ha.is of Ihe puanl.ly of
anl.Rrn r.preaaed Ihrer pal.enN -ilh srvrre deficiency and frwr pahrnts wilh
m.rlr.alr .lefn-.rncy r.prra.rd . 0 1% an1 2 S ytK nf rwamal am..unls uf Ihear m.nlrtulra
un Rranuhn'yle surfaces, teapectbvrly Ihe severily of c/bnical mtr.linus tomphtahnna
a/11unR Ihrtr palKnh ..as drreclly rr/aled lo 1Ae deRree of Rlyc..prolrm dr/rc.encY ht.ur
p.n(.umy ahnKrmalrl.rs ..f hssue /rukn.ylt nroAd.ratinn, Rraeulocsle duected mfR/al.un,
hyprradherrncr, phaRrr yrnss of i('yh nps.mved par/icks, and eon.plemenl nr
anhM../y dr(rn.IrM yr.dnaKity ..ere found in rndivKluats .ilh srvrrr, as cnmp:rrJ
aqh nK..leratr, /Iefnrncy 11 1% Iu.yw.vJ Ihal rn .re.- ahmumaldiea of Iruk.r;yrt
nu.ldvaann rrlln 1 Ihe .r.rK al adrs rJ Mac 1{IycMtnlrins in aIhrvvr events trqu-rrd
(nr rnd..thehal marRm.arm and t.sw r.u.larwm the re.nrndmm of phrm.l;pK
vanalu.n anwnR pal.rnla w.rh Mac 1.11A I drlKNn.'y may be .minuunl wKh rr.lr.l /u
thr.Jpru1K alratrR.rs
Andrnon, 11 1- .trrrne, 1- 1.t nt
1 hr l..u.n.d ../ Inf..tr.w. /hn.vr.r. I12(4)M.a AR') rrlS
OIArr .urywur Na/a.n.d Inatdute KI AIInRy and Infrct.nus hiaraaa, Nitinnal tnst.lute
/ur (an.rr Rrsrarch Na1rnat Inathlulra nf tlrohh- and 11 S IMIi./mem uf ARIKuIh Ir
Irnm the (lrparlmenls u( rrAiatrica. MKrohi.d..Ry and ImmunuluRy, and Pa1h..MRe-
(1aylor ('u11rRe nf Mrd...nt, Iluualun, an.) fs.rna 1 arbrr l'ancer InsUtute, 1larva.J
MeJn:al \:b..d, 14.a1nn
MACR(yP1/A(71 ANI) I 1 VMI'lI(K'Y11 MI tNAfl D IMMIINIfYS1MII.AR11115
A 1 1/1/t 1 V11. (y/ / Itl MA('1 ANIt 1 1 A 1 Ml)LI ('111 FS
A numlrc uf cell surface mnlecules have tecenlly been characltrited which ate
imporlanl in macanphjr.e and IympM,cyle cell medialtd immunity. Ihe macrupha/;e Ie
ttarp/nr and enmpkrnenl rrceplor type one ((R.) have heen characlrrord by
puulKalmn and fumlum inh.hiting anldvnlies Recenlly, an/i M.KA annt.rMty ..aa
fouml lo .nhrbd Ihe snmple.neM receptur ty/.e Ihrtt 1('RI), tuRRetanR that the 1'R. n
identical tu nr assocuted avilh the prevw.valy biochemically eharaclenred Mat I
nu.kcule [ludlrs on t lymphncYle tntdraled Immunlly .i1h funclinn-SlncktnR
ant.MMl.es have shn.n that I yl-~,S and 1/ A-I saface rnnleculn are assoclatrd ..Nh 1
IympMw'Yte-rned.atrd kA1.nR Snmewhat surpris.n{ly, the Mac-I molecule asaocultJ
.rlh ('Rr fuMInM, and the 1.1-A1 mntteule assrKialed with I IympMKylr me.balyd
kd/.nR, have Irrn f..nn./ in t.e sUue/ural/y relaled Ihis suRRrsls that at least arilh relprd
I
SprrsRrr, f" A
In Vnikman, A(rJ ) Af.mnnurfrer rAag..crlt RndnRr. New York Marcel lyekkrr, IMI,
/Nt Itrv I_R
(1rArr .or(.nr - IJ 5 Puhhc Ilralth Service and an Amr ican ('anctr -L' K.ety lunuu
1 aruhy A.ard
1 rom IlanarJ Mrdi.alScMwJ, Ihnlnn.
111N('IR1NA/ AND S/Rl/('11rRA1 IN11 RR) I.A1/()N\I1/1t AMt/Nti
l/lt Mac1,11A IIAM/IY(K 1'tthlK'\'l1.Al)IIIM(/N(GIVtI)PR(IIIIN\,ANI/
11111R /1111('11 Nt'Y IN A N(1VFt. I11 R1fA/11.1: 1)1S1 ASt:
(YII surface aJhrrence reacthms ate of cenlral impwtance in Ihe uomune /umln.na
uf lyny.haylra, mrmneytes, and Rranuhu-Ytes. I ympMwylr. adherr tu
aM.Rrn prearo/mR macruphaRef tu deadul.e crlls in Ihe Induclum .d I ly.nph.w yrr
imn.une rryw.nses ant m IarRel eells in etll mrdialed ki1/.nR AJhrsivr intrra.tnas are
fundamrnlJl In a Wntr apetlrum rlf fYnelnm{ of RranuhM y/e{, rMMMII'ylra. JnJ
macuq.haRes Sprc.l.e rK1.Rnilum of ry.w.nitt.l InKrIMKRannnN is fat.htarrJ hy
membrane recepuus fur 1R(: and foc the IhirJ aunpnnrnl t.f complrrnen/ (4'S). whnh
mrJtale mrcruhetell adheswm prior te tht trHRerinR uf eyt...krlelal rveMa Ita.ImR to
enduCylotis Adhesuul mrJ.a/ed by IR(i tlt) teCtplnts can alw. U.RRrr
afilmJy-drpendeni kilhnR of taeRel eells, imkpemlenlly of ernMrcytuss A farnJy ul
hyh-mnkcular-.riRM llyeeptoleins avilh iwknl.eN e suhun.ll .us cecently Irrn
charactrtiaeJ on teukncyle surfaces Ihat is imp.ulaM in many of Ihe aM/ve aJhesi.m
eraclmns Momuhmal anlUbulies have been inslrumenlal in elutidalinR /t.e slrwlu.al
inleuelaliunships and funclnms of Ihtse thrrr Rtyenptnleins, macrophaRe anl.Ren I
(Mac-t), lymphotyle funclum auociated antigen 1(1.1 A 1), am1 pISO4S 1 mlhtrnKKr,
Ihis reseatch haa led lu Ihe definition. .ith nuwmch.nal antilwdrta, of a m.vel her.lahk
diwase Iha1 mandesll itself in difeCN in leuka-y1e adhrrrnce and mrMJily WNh Ihe uN
ut MAh, a novel divasr has Aetn rreoRniaed in which Ihe Mac 1, 1 1 A I anJ plNt vS
Rtycnproteins are .h(wienl. Reeuuenl Aacterial infecliwm, ptnRresaive prruMh.nlitn,
prrsislen/ kukncyloss, and/ot drlayed umbilical enrd stparalinn have lnrn deacr.hrd m
palienls WMne nrul.uphils demonstraleJ depresseJ phaRncylic fumtiun and dr/.aen/
aJherence and chenudaRit.
Sprn/tr.. 7A and Andrrsnn, I) C.
In SprinRtt, f A(ed 1 ffrMrJnnlr Tr.AnnlnRy rn tAe /ho.crrn.rt onJ AIrJ.. rnr. 4 h:q.
11, New York Plenum Puld.sh.nR ('o/oosa1N.n, /VIS, pp 101 2416
Arbr supFat Nallnnel tnslilu/et of 110611%.
From Ihe I.aa+ralnry nf Membrane Immunochemnlty, Uana-f arhrr t'ancrr Instnurr,
/hpartmMl of Palhohyly, tlarvard Medical Schuol, &nton, and haylor t'.d/tRe ol
Medic.ne, lyepartmrnl of Ped.alrics. Iluuston, 1 X.
IAS
S11/1)IfSON ANIIGfNS A[CCX-IA1/1) WIT11 llll A('IIVATI(1N01 MIIK/NI
M(/NONlJ(11AR PIIA(3(R'YIIS KINfI/lSO1 ANt)RIQUIKtMINISIIIR
INtslt('It/1N lll I YMPI/(K'Y1E IIIN('ll(/N AC((K'IA111) /1/A) I AN11(:IN IN
I ll R!)
Macrnphaltes at'tivaled and p.imed rn arn, allhnugh nnl rrsidenl nr respnntive
macrrphaRet, r.p,ras 1he lymphncyle flrnclinn attoCialyd (1 rA) I anliRen Ry conlra.l,
the hw..hrnnaally retated Mac I antillrn .t e.prettrd on all pq+ulatnms of ma.rnphaprt
In the pretenl pavt, we ttwl,rd reRYlal,nn of Ihe I I A-1 antigen m vrlrn I I A I cuuld
he indocr.l .n rn.n on 1h.w.Rlycullale (T(i) elKiled bul mN on ptolente (rpl..ne
(1'P/ eht.rrd nr rrudrnl maarnpha2es Specifically, ,nacruphaRe aaivalinlf Lch..
(MAt /, rntr,fr.un 7 ut/ N 11, nr pra.Rtam anaunts of endoln.,n (1 1'S) .mhard 1 t A I
nn IG ehc.aA macrnphaRrs fotlnwmR overnight incubation tntetfer.un, -n ..r -p,
fu,'onbn, arn/ .nlnny-sl,mutal.nR fa.'hn were nn/ effective Whdr tnrne levels o1 1 1 A I
enuld Iie bleaad at au.n al 10 hr pest rsprrttinn was nbsrtn/ aftrt IA Iu 1? h, ..f
rnauhaln.n 1hr .m/ualurn tnuh) he cnmplelrly asvn9ate.1 by cycb.heamnk, tuLllrsl,nR
11,31 pro/ein stnlhet,t was required lhete rrsubs md.cale Ihal the mduaa.n ol I I A I
nn m.mnnwtrar phaRncytrt is closely rrRuliled and that the requvemenls f.ur :urh
.mlull.un arr dKl.ntl lrom- hYl shate certa.n tnndanl,et wi/h, induat,an uf cylob,ul
funalmnt and etlresunn ol Ia anhRen
Strasan,ann, (' ,.tfn.wtrr T A, and Adamt. Il ll
TAr lnu.nol../ lrow,.nlner 11t(1)17 150, 1911O6
Iram the Oepartmenl nf Parh.dnR7, 1)nlr Itm.rrtdy Mrdual ('emer, t)wham, N(', anJ
ILuva..l
the 1aM.nlary.ul Mrn,l.une Immumwl.r.u..r.t, L..na ta.her l.,m'rr Institute.
Me.l,eal Sth-d, Ih..wn
(-(1MPIIMINI KI(IPInR lYrl 111K/1 ttIPINIHNt Ir1(RAI)AII(1N(/1
(1/1(INI/11)IRYIIIKIM\//SRYMIKt`I MA(KUPIIAGIS
Ihe rnlr nf the cumptrrnent receplnr type )(('R1) on IhmRlycollale-elc.trJ
per.toneal mactophaRet (I(; PM) in the des/rucla.n of opannired particles was slsd.rd
We (uund that aberp rrd bhad eelh (1 / that were ofwmued with an IRM marnrr h.nat
an11-IMttnlan anldurly and enmpkrnenl (1'-IRM-(') were lyvd by 1(7 PM, wte.eat
Ihert was huk lysis nf 1, prrlrealed with eilher the aalibndy or Ihe complemrn/ s.utce
stnnr 1 ut/hrrnw+rt, Ihis lysis euuld be inhibiled by anti-('R 1 m.moc4,nal anl.Mnlie! that
had prtvirwsly been shnwn Io inhibit binding of 1'-1RM-C lo Ihe ( K1 Kineuc sludrrs
of phatincy/mis and lysh indicaled that lysis of E-IRM-C occurs afkr phaRncy/mit,
suRtesang thsl lysit h an in/racellular event 1 urlhee frndings suRgrsred that
intracellular lylis was prnmoled by CR I hnunJ lo Ihe phaancy/nttd IarRel. Mcaase a
nu.mtchrnal anti ('R/ andhody decrtasrd the rate uf phaRntylusn of 1'.-IRM (' bul nnl .tt
magnitude. whereas the rsle and tslent nf lysis wert slrAinRly inhihiled I u.lhe,nnne,
1(i PM Ihst had already internalited un..psnnired 1I selectively lyted 1IRM C Ihal were
added lalet lhese dala confirm that she interaclinn uf the ( It1 with its hRard un
1. IsM (' promoles npal phaloeylotis, and they furlher suRRett that she ('K/ farrilates
,kgtadalion of the tarRer parl.ck enee rnlernalhalB.n has necurred
Rolhlein. R and SPrrnRrr. T A
7 Ar /+.rnaf nl fnrnuw..ftr 11{(t) 22AI 7672.1965
164
1
I
1
I
1
OrArr supprl : Il S Public lleahh Service.
I rnm 1he l.alwralory uf Membrane Immuoochemislry, thna I arber Cancer Insluule,
1larvard Med.c'al School, Bostoo.
llll I IINC'IMN OF LFA-1 IN CELL-MFDIATI.1) KILLING AND Ahltl St(/N
SI lrI)11 S()N Ilt K11 ABI F. 1.1 A-1, Mac-1 1)111('11 N('Y ANI) (/N I.YMPII()11)
CI I 1. SL1 1 A(iGR l(:A I ION
t.ympho.yle funclinn nsncialed anligen-I (I FA-1) is a cell surface glycuprnrrm
identified in moate and human by ntonncbnal anliMwlies whirA inhibit cylulyln' I
IympM,cyle (C111 mediated cylolysis. Reeenlly, a number of patienls w,lh rr.ur..nR,
bfe-Mrralenina in(ec/inns wert found to be defrcren/ in 1FA-1 arnl Iwn trlher sut(..r
wn.kcuks which u/d.re /he sante / suhunil, MK-1 and 0150.9s. 10 attest nalu.al
/.U,nR, peripheral fdrnw) IympMey/es (PBI.) frrnn 1.1 A I defic'ienl indsvalu.tlt- rhe,r
fam,l.et, and un.ebled eonlrnh wert cuhuled aA.ne or with )Y celts fot su .1.)t
Nalu.al \dling was assessed nn Ike K $62 erythroku\emia cell hnr (/11.A nrRal.ve) All
1/ A-1 defrc.enl Imt-ivsduals showed low kvrls d NK eell-ntedialyd cy/nlysn compa.rd
N. that of family nsemhers and unrelaled indivnluals Plll. were altu /ettrd rur
prulderaliro af/rr stimulation with the kctin phylohemagaa/inin (r11A), r/11 /rom
1.1A-1 .kficienl patienN shnwed an impaired protrfera/ive rrt(uutse In PIIA Camratl,na
results were found Im the quantitatively mnre se.rrely 1.1 A-I dr/icirnl ('11 at palenls
I and 2. Killing by patient 2 CllL was pmtly inhibited when anl. 1) A I MAb wat
added to the assay, and prelreatrnenl of hilkrs oe effeclms Ra.e equ,viral nr nn
blocling ('I1t ftom palienl I was inhibiled when anli-1.1 A I was in.lu.kd .n q.e
assay. lhr findinRs with patient I and 4 ( 7L suggnt that 1.1 A I on targel arllt can altu
cnntribute lo Ihe (-fL-targel inleraction 1)ala presenled here suRResl a s1.onR trmularNy
helwern phurbd esler-indueed «R-eeR a1fifteRalM.n arwl the I 1 A-1 drprn.kM adhesmn
step in (-11.-mttluted AillinE, swd suuesl I I A-1 funelims as an adhesion prolr,n
SPe,nRrr. r. A. rr at.
In: Itentsrl, P and Marle, E. (tds t MrcAannnrs o/ Crff-McJ,nrrJ l-rt,waurnr II. New
YorY & l.nndon Plenum Press, 1911, pp. 71t-1:2.
Olhrr sup/nuf : National Inslilules of Iledrh.
I rom tlana -Iarher Cancer Insliprle, llasvard Medical School, B.ntun,- Oaylor Cu1kRe uf
Medicine, Ilnuslnn, TX; and Slanford llniversity, Slanfurd, CA
STRl1CT(/RAI. nRGANIZATION OF INTFRPIIASE 111 FIItR(/IILASIN,
'II1t/111)BYIOIAI.INIERNAIREIILCIK)N1LtfORIS('IN(1 MI('R()U'()PY
We t/udied Ihe bminar orRanitalion of 111 fihraAlat/ celh RrowinR nn alast tL.lrt
by use of loul inlernal rt/leelion Nhrmina/inn In t.crtr fluorest'rnce emnsu,n IIIK11
from lahekd mnkcuks and starned eel/ular eornparln.enls that are very chne lo the
ffR-sYbsuale conlaCl region. Mitochnmlria, distant (rum #he cnnlacl trR.ont an.l sta.nrd
with the walee s.duMe ealinnic dye, dd(-s fl/, flunrrstrd nn/y at Ihr alatt/ayl.qdn.n
errtiea( angk vas approaehed. A siwitar res.11 was ohlained wben IAe nu.lei wr.e
slained with lloechsl dye 11142 . Fr.nn this nxnured angle a cy/uplasm.c rer,ac/,vr
indea in Ihe rsnge 113ll 1 114 was computed fhe plasma memMane ..f 111 crlh was
stained with dd C,e-()) snd the cYto(dasmic eomparlmens was sla,nrd wnh
fluoresceinyl deatran (I IC deaban) or wilh euboayflumeue.n We hs.e
IAS
demenatrafrd a high degree of emrespnndence betwren the lor-reflectance aonrs in the
refkclion rnterference ImaRe of a live cell and the TtRF imagrs of lu.th the plasma
n.emhrane and cy/ry.ta+mic cnmpar/rnent /IRf p/.olnnmelry of seleAed conuct re/.inns
of celis pr.widrd dala frnm which /he ahsolute sepsratu.n o( cell and tuhsuate was
computed Frnm a pry.ulsl.on of 311 cells micrninjeeted with fluoreteein-lahelyd actrn,
mMde and adherent intrrphase eells were selected for ttudy. Fnr adherent cAls, which
diqdayed flunrescent surss flhen, the I/RF imaEe was composed of intense patches aml
kts /nlense reerinns that corresponded, .esprclivety, in the fncal cnntxl and clnse contact
tones of the ref1ec/1oninlerferencr imate. The intense palchrs correspomkd in the
endpninlt of /he slrras frhers ('rllt of rnMik Iworphokly. which formed some fncal
contacts and eIenslve chne conlact rones, pve AF-aesiw ItRF imaErs of relatively even
in+ensily lhin lamellar rea..nt of thr cytoplasm were found to cuntain cnncenualu+ns
of alin on/ s.2Mficantly different frnm other elose-I:ontact rrRinns of /he cell lhe
mspu anslytnal prohkm rd I IRf mierMcnpy it xparalinn of the effects of Mn..milY In
suhshate, rrhacbve InJee and flvorescrnt probe cnncen/rali..w nn Ihr h.cal hr.ahlnrss of
Ihr 11N1 Ima/!e /rom nur resvlM, 1/ alYwars pmt.hle tn use 111111 rnicr.sc.yy lo
rnrawre Ihe pnraumrty n( d.f/rrawl compnnrnlN n/ suMuate eonlai t rell.nr.m u/ crlk
I anni. /, WsRRnner, A S, and Tar/r. f1 t
7Ar l.wnal n/ (.If R..Le/ 10a 109/ Ilo), 19, 1
f rom thr ('rntrr fro I lun.rseener Rrtrarrh in RMTrdicd tcirnces and Ihr 11<partment
nl U«./,.a.cal %.wn.ra, I unea.e Me1M.n tln..ersde. Prttahurah
I Ita11 Sf A 111 RIN(: t 1/ANr,1 % 1111NtN1, 1 111 Mtn1At 11/%t1h1111 AIIC)N (II
1111MANNII11Mt11'1111t kINt 111\I.r11rIrItlHS IIttW 1)1t1M1/kV
Ihr I.R/H s,an,lmt rr.r aumP~rd nn a
eell Lr aell hatrs 1rl...r amt alv. ar,....al...,.n ..r1. ,/,.n..1.,1.. IwprIr u.,nt 11.
eyl..mrery Ilrtvren 'O anJ 140 tra .1rr. Irpr..lr arl....n s,Ar 1'n/'1 aa..Itr1 dr.lu.rd 1t
v/. 1u 4'M, an.1 Ln.ard s.auro rmvaard up 1., ht. It.l-n 1im1 1% nun, t.dr a.alnr
incrrasrd rp lu IY6 anJ hHsvaa1 scaller dr,.r.nrd up 1.. \'W Atar.aln.n .d a
f1u1NlKemY Che1m'atUaal.1M wrlh neulrophds .as mnu r.aput durrnR the rnmhal phasr ad
increas/ng forward and decreasing suk scatter. aml assnclahon utunlyd t.elnrr the
ms..mum increatr .n twfe ualler I vatence rs luesrnted that the nlnerved chanRrs .n
tcatler were m.1 a cnnsequence of cherluultsaclanl induced cell cell adhraiun or
nevtsryahil deRnnvla/inn Ralher, the ea»ly phases or IiRht-scallerinR chanRrs are
intrrprelyd in represent membrane ruffling by the stimula/ed neulrnpMl. the later phaset
pnlarbalum of the neulny.hit nunphnloty
McNad. P 1, Kennedy, A , WajRaner, A S, 7sr/rrr.77 l. and Murphy, R/
( I ro..etr r L) 12, 1013
(7rAn rrpf.rr Nalnrna/ Inall/utet of tlrotlh, Nalinnal Sc.encr /oumbuon, and Ilral/h
Rrsearth and trrvn'es I oundalrnn
lrom the 1'enler for Ilun.rscence Rr.rarch in Oinmedwat Sciences and the tlrparlmenl
of Itmtogicat Scrrn.es, ( arnre.eMetlon t/ni.rrsily, Pitlsbur{h
I
t
CONI)tT10NS REQIIIRED FOR FXPRESSION OF MEMBRANF 11. I ON R CI I I S
The aulhors have reported /hat aaacrophqes bear a milogrenic activity for T celts in
their plasma wsemhrane that .e have lerwxd'wewMawt-iwterkdin r. Memhrane /1- 1
avas studied by using either parsfo.woldehyde-fiaed /wacrophaEet or isolated macrnphaEe
esemManes lhe reasow for ascribing this twelwMawe aclivpy to 11. 1.a based on the
observation that macrophage membranes stimrlaled prnldera/ion uf lhymncYtes an./ an
/1. 1-drpendent 7 cell line but wot 11. 2-dependrwt t celts, and this wctivily wn rnhdnlyd
by a polyclunal gnat anti-11. I antibody. Additional biochemical stwfies nerd 10 be dnne
to unepvivocally establish the iwlerselationships between the soluble It I and the
merwhrawe form. Neverlhekss, two important fealuret of the memhranr 11. I were
noterorthy_ first, it was essentid Ihal Iarbearing, fi.ed mscrnphases eapress n/o
activate antiRen-specilii T cell lines, and second, its eapressinn could he diss.a..slyd frnm
Ihe secretion of II. 1. Reeavu B eellt are inn.w lo frnclmn as anURen p.e.emu.R .ells,
we invest.Rated whelher these cells etpress memMane 11. 1
Kurl-Innrs, I A, Klely, l. M and f/n.nve, f.. R,
7Arlnwnol n/ In.wrlwrlnRrll$()1ISI8-SO, 1925.
Orbrr aupprrt, National Inslilules of Ileahh.
I rom the Isrpartmenl of Palhnlogy, /larvard Medical School, hostnn
IMMIINf COMPI rx FFFECT ON MI/RINF. MACROPIIAGI S
I 1MMIINI. ('(1M1'11 XtS SI/PPRFSS IN1[RFf.R(/N--I INI/U(-111sN OF
ta EXPRI.SSaf1N
We have studied the effects of immune eompkaes on the etpression of mas uyrhaae
surface Moteins rw r.n.. Increased e.prestion of the 11-2 w>,Ikcules / A, I 1, and K in
the macrnphage wlemhnne sas induced by rn rr7ro eulture srlth cru.fe lympholtinr or
interfrron-7 Eap.ession of aB thrre of the wwleeulrs was sddawrnal :ncreased hy
tlimulaling the culturet with heal.hitkd f.rurrr. wulwerwr.trwrs. Additinn of s.dulde
immune compkars to the cd/rres did wM have sny effect on macrophaae e.preai.m nf
Ihesr proteins. Ilowevet, significant iwhiheion of IympMriine or interferon 7 Induclu.n
of 1-A, 1-F., and 11-2K was observed arhew rwacrnphages were cultured on plales t.r
which immune compleaes /ud been tlorwd This inhibition was dnse dry.emknt, repuiued
an immum.ilbbulin IIRI rwokeuk with aw intacl Ie pllrtion, did not require the preseme
of I celb, and uccrrred in the presence of nrlnmethacin. (-ompk.rs conlarninR It(i/,
I&G2a, IgG:h, and IgF., bul not IgM o. IgA, antibodies mediated the inhrhilury efle.l
Virllin 11 W. IV, Wittenbers, G F, and Vnenw. E. R.
7Ar /.wrnal n/ lmn/uwu7nRr I1t/0) 1713 -1741, 1911
(7rAer supryur Nalumal Institutes of Ileallh and National Insbwte of (:rne.al Mrd..a1
Scrences
From the Ilarvard Medical School, fkparlmenl nf Pa/holoay. Bustnn
1...
167
IMMIINt (Y)MPI I X f111C13ON MItRtNh MA('RhP11AGFS
11 IMMIINI IYMIPI l X tl/l('ISl)N Al'lIVA/11/MA/RhP11A(:IS
!'\ 1111(11f 11'll /, MI MIIN ANI 11 -I, ANt) AN11(il N PRI SI NI A IIl)N
We invrsl.Ralyd Ihe rffrc/s of Immune compk.es on mscrnpha{e funcrmn rn
nn.r (mmune cnmpk.rs .nhrhd lymph.kint induction of IuHh I Aa raprrasvnn and
cytolnt.c a.li.dy by felal calf errum elicitrd mactnphaRet do.inR LmRlr.m 17 dav)
cultwre In ddrtinn, mducrmm lof anhRrn prrunla)mn wat s.ltmficsnlly inMhiud hy
immune .omptr.et I aprrstw.n of inemhtane imtrleu\in 1(11 1, a mrmhrane Mwnd
(mm u( d.r I cell m.InRrn rtquired for aetiRen pre)enlalmn by fiard eella) w:n
m.n.nully inhihile.l by immune cnmpkaes Therefore, inhihilern nf anliRrn prrtemalron
v.as p..mardy dur /n eflrcls on la etprenion rslher than mrmhranr /1. I e.preadnn
Ihr mhrh.lory ef/nt uf immune cnmpleaes wn nol found durinp shnrl-lerm cuUurr /a
tu hrl wh.n acGvarr4 maca.phaties (hrar.ng Mgh kvels n( lal from mice rn/r.lyd
wilh f r.rrrra wnwprYl.Rrrv. wert e.amined Immune eomPleaes marnlainrd m r.rn
rmreasrd Mvrls .d hnrh I-At aad eytnlo.iciry .n ac/.valyd macrry.haRrs I he
Imt.In'aUnM u/ Ihe.r /rnd.nas for immune enmplr2 nsodu4lnm of the rmmune rrtpnnsr
rr dltrnterd
VirRin, 11 W IV, Kurl lones, F A, WiltrnbrrR, ('. F and Onnnw. F R.
TM l.wrnal n/ I.nw+uw..lner 11(/h11711 1)a0, t9/)
(hhrr supl.wr Natw+nal Inailules of /lrillh I1 S Puhlit IIea11h Srrviae; Nurinnal
InNilult of (.rnrral Med.ral Scu'ncrs
lrom llarvard Med.ial Sth.rd, Ikparlmrnl of Paih.dn`y. Ooaan, MA
SI11PRI [SR)N s)1 IMMIINI III CP(1NC1 Ic) f.dr.rn wu.w.r Yrncrnrr'
MI ('l1ANIXMMl)/ IMM11N1. 1't)MI1 I r WPI'HI SSIIIN
We have invtsl.Ra/rd pnssihle me.hanismt underlyinR immune complee supprestinn
of resNtamY to I F11rru1 mnw.w'Wn(rwrl InhdN/.on nf retNtance was found when immune
cnmpk.rs were furn.ed rn rrrn in immune mice or in nnnimmune mn:e adopl.vrly
transferreJ w1/h sprcd.c anGhn/y. SuPpessi.n was also found when nonimmune mice
were injected with Immune complears prr(.umed .w nlrw We invetligaltd the tnle of
eumpknwnl by de.wuplrmenlinR m.ae winc cnhra .ennm (ac/nr purif'ad by
hiah-/aHSUre Ii)uid.Monulu6raphy ebmplele deplelion of serurn (-) did m./ eliminale
immune eomple suppressinn of resislamY to f.. nrw.wrllnRrwra, tuRRetling that
complement aclivalmn is nn1 reqwired fnt immune cornpk sul.p.rtsi..n.
Infectarn induceJ changes in the surface phenotype and functional propertin uf
macrnphagts frore normal and immune l'nmple.-surpretted rrUCe were also invesliRaeA.
Ma.ruphaRe eapltssa.n nf both /t 2K and 1a molecules incrraud .brinR the Irslwlnae rd
n.nmal mice In 11 mnwnrYrnRrnrs 11owtrr. these chanRes were mN fuund in in.mune
complea supMessed mrce In cunlrasl, mrmbrane rnterlrullin I e.prestwm was inctrased
in mactnphaprs from suppressad mice cornparrJ with macropha{rs ftom nnlmal mKt
Macry.haRts Ir.MI I nMwN.r1'(nRrnrt infected mN111aI and immune eonlplea supprtltrd
mice taprened c)Nolo.icdy aRaina/ lumnr cells in nun. We conclude Ihal immune
compk.es Jo nol, inhihd rrsistanct lo I m.ur.rrb.Rrwrt by aclivation of complement of
decreatrnR macrnphaRe cyloaie aeliily Ralher, defects in Is e.prettir.n by maceW.haRes
f.nm supp/essrd mar m.{ht be one component etsponsihle for immune romp/r.
tupp.r.....w ..1 rr...un. r .d / .w..wn..rnt.'wr% t..a.. u r r. r.. ,. e./ .. ... r.
1....1/+....... f R
i
Infer(um and fmmunrlr 50(7) 1t7-1S7, 19ts
(#IAr, ruplrvl lt S Public Ilealth Ser.ice, National Inslhules nf Ilratlh, and National
In t.lule of (ieneral Mrd.ial Scirnces.
I rom Ihe IRparlment of Patholo6y, llatvard Medical School, IMsh.n
K11 AlIONSIIIP OP MA('RC1P11A(:1. Is AND MI'MRRANh It. I 1'XPRFSCIUN 10
AN11(:1 N 1RI SI NlAll()N
Membrane e.pressinn of Is molecules by anliRen-presenling eells is crilical for Ihe
induclu.n of I ce/l respnnses lo foreign prnlein antnens. In addition, anl.fien-specifK I
cel/ prohferalmn has heen thought to he dependen/ on inlerkuhin 1(11. 1) secrelum by
sntbern presenlinR ce1N Recendy, we have descrihed a novel memhrsne hnund form nf
11. 1 that is rrquired for the pesenta/ion of an/i{tn by anliaenpulteA, fi.ed
macrr.pha{es Mrmbrane 11. I is a rnilo6enie pWein found nn the macrry.haae
membcanr Ihal, /rke s..lahle 11. 1, slimulalet Ihywrocytes and 11. 1-depemknl 1 cells bul
mN 11. 2-dependenl leeR linrs lhis aclivily is inhibi/ed by a polycbnd anti 11, I
anliM.dy Membune 11. 1 is an inte6ul membrane poMin and dues no/ represent soluble
II. I noneptcifically Mrund or fiaed to the nlacrnphale memMane Additional
biochemical studies are required to define the possible interrela(isnships between soluble
and rnembrane /1. I
We ha.e now devek.ped a method fm independently varying the kvels of Ia and
memMane It. I epretsinn on macraphatet in culture. Ry Ihen fi.ing rhe cells, we are
shk tu preserve constant levels of these molecules during the assay fur antigen
presenlallun Ih.ng Ihis tystem, We have delnnnslrJled Ihal quanlila/ive varralNM .n
/hete Iwn pararnelert was associated with changes in the magnitude of the 1 cell re.ryrnse
Kurl-lones, F A, Virgin, II W. IV, and f/nanur, ! R.
The lrwrrnal r.J ImmweloRy 1atf61 ]632-1/534, 10tS.
OIAn suppnrt: National Inslilules of lkasrh
/'rom the Department of Pathology. Itarvard Medical School, Rmtnn
A('lll L( IING IN)IIRY IN RAT CAI/S11) RY IMMI/N(X:1011111 IN A
IMMI INf. ('()MPL1 X 1'S
Mouse IgG and IRA, with reactivity to dinittnphennl conjuRa/rd In carrier, prnlrin,
have been isnlaleJ Irom myelnms proteins by mtans of a variely .A affinity /rchniqars
the 1`A was preominandy in the dimetic fwrnm lhe m ertrn and rn erro hwh.awal
aclivrlies of 16A-conuiniq immune eompleaet were assesseJ in Ihe ut
IgA -containing immune ennqlears wre drnuunlraled, in a dou drpendrnl
manner /n rrl.n, to KIr.a1t nen/tophdt and to gt/letale /)r In add/lnrn, Ihete /m/nune
c+un/de.es showed evidence of complement aclivauon /n r.nn, by /he use .d
irnmunofi.alion IechnNluet When IRA .as instilled into the brways ..f rats and antigen
was injeaeJ intravem.usly, acule IunR injury aceutred, as reItectrJ by rncrrasrs m lun6
pernuabilrty and morpholo{ieal ehanget eontis/ing of bkbbing of endorhetul cells,
inlra aLeolar hemmrhage, and fibtin deposilion. lhe lun{ chaners were dirrc1/y
prnporlional to the mount of IRA instdltd into the airways and lAdrd In .wcur d
inUavtnous injeclam of antiaen was omiltled 1 uns injury did nu/ .w.ur m amn.als rl.al
recervrd an intravenous inleclmn of antigen in Ihe ahtence ul an a..way m)r,ln.n .d
169
~..r
IRA I.mR injury rrlaled to IgA cnnlvninil imrounr compleaet wat tumplen.rnl
dependrnl hut neuarq.hil .ndependrnl In cnmpanw.n slwties with mouat IR(: cnnlvnrnR
immune tomple.rs, arulr luna rn/ury dtn rwcurred anJ had murp/uduRcal frslurr.
tumalar tn Ihuae sauarrvJ with tRA indu.ed lunh rn)ury etcrpt Ihat, in the case of IRG
immunt arn.pte in.lu.rd A..n..llr, nruhnl.hrh werr mnre ev.drnl Acule lung .n/ury
inducrd by Ip(: cnnta.n.nR rmmune comp/r.et, whelher of mnuse nr rahhrl mi6m, .as
(omldrmrnl anJ nrulrry.hd drirndenl Iht simdariliet Ml dJferrM'rs Pelwtrn IRI:
and taA assrwulrJ a.ulr rmm.mt rompte. rnduatJ injury of rat IunR were ainfntard
tv the uae rd mnrphunvuy trchnrqurs_
. Sludres .rath annlher mnn.alonal IRA anlihcdy-conlaininR, antrRrn AinaLnR activity
I.r phnsphmylah.dmt alsn Jrrnnnslraled the ahiti(y of IIA an/ib.Jy I.. cause arutr hnh
rn/ury rn the rat Nruhtr anhbrds alone nm antigM (phoaPbnyhM.but hn/rA u.
Iwvme serurn all.utnin) shrne prurluceJ evidence of lung injury
Ihesr slu.brs .nJn-ate for the (n+l lime that Immunt cnmpk.et ennlaininR taA
have IunR d.mar..nR praqvrlirs anJ that Ihe palhRrnic meehanrsms mt ddfrttnl frum
thote asutitalrJ w.h IRf: aas..c.a/td immune cumpler indoaed autr hms inryry
)ohnson. K f, W rtsnn, B S f rlt, G o, and wers I A.
J.w..nal n/ ( frwu al fn.r.ntan.rn 74 )St )tt9, 1911
l)rhrr rupryvr Nati..nsl Insrilulet of Ilralth
trnm Iht tsrpartmtnt of hlhnhray. UnlvrrtdY of Michlpn Mtdical ScMrnl, Ann Arbrr
T111 I)NA SYN111111( RI im INS( /N Nt)RMAI AND AfIN()Rh1At. IIIIMAN
I VMr111X-Y I I S 14) MI V AI ( INI( A( 11) I 111 KUl I OI GRANtII (XY 11.S AS
A 111 1// R IY )11/1 A I It IN
(n erJer lo rnvesdplr the ro/e of nrutnnphilt in the DNA synlhetic realrrnsr of
buman perrphtral hhwOJ lymphocstra to meralnmc aciJ, we obtarned preparalions nf hnth
eells eac'h flee nf croas conrammalw.n by the mher rarified lymphocytes rrspnnd prruly
10 mevalnnie KNI, hul /heYr resMnte ean ht sqinl(N'anlty enhanced by one-half Iheu
nllmbtr o( newtrnphih Prtincubalmn of IympMa7les with neutrnphils for 24 hr, even in
Ihe absence of mrvabnic atid, fu.lher increases Iht tympM.eylt rrspnme. We have been
nnabk to demonslnle the produclinn by tVanulucyles of eilher an inlsacellular m
eanacellular mevaMrna/e-delived Rrowlh factor that in I1srw tlueala/es lympho:sles
(:Ianulneylet preespused in mevahmaly dn not acquire the ability to slunulate
IympMrcylt 1)NA synthtsis in the absenae of nxvatnnale. Our e.(.erimenn suRRest that
ne.IhN nrolrnphd IYsnsnmal enrymea not reactive otygen speciea RentralrJ by
nevuophils are eespnnsiMt fot Ihe help neul.uphdt p(ovnk. N.nmal !, rosrae positivt
lymplnryln fail ho resprnd lo mevahmate, whertas FF luatlene~ative ctllt do. /he
nsevah.na/e respnnst nf normal f rmette nraaurt « Ilt it enhanceJ by the Mestme u(
Runuhwytes .n cnnuasl to S cet) ehsunr: IympMs'ytie kuhemra celh that synlhrsur
I)NA MrsLlv rn tes(rrnar In mevalnnN a.nl in lhe abstn.e of ntulruphd hetp Ihea
ObstlratnMtt add to nur knnwlr.lge o( the rrta/nmship between mevalunale mrlab.hsm
anJ Ihr tegulalutn of cetlula. DNA synthesis anJ mrlosis
t.arson, R. A, Kluslens, I C and YaMrm. S
Jnwnal aJ AllrrR r anJ ( h.ucal fnrwrun..lnc r 74 ;90 291, 1911
1
lph:r aurlr.nr Nllulnat Institute of Arlhrilit. Mttab.ltsm and 1hRestrve 1).aea.rs aoA
Nal.n ('ancer Resrarch I unJ
I rom Ihe l)rpartmrnts uf Medicint and ratMdngy and the Commnlre in ImmunnlnRy,
the Ilnivendy n( 1 hwaRo Sibwd of Medicrne.
f)\YGI-NAt1Ir( 111r11SIIR(NSSYNIR(:ISIICAI I Y IMM(/ltlll/1 A(N1
t't1A1N\ ANh I NIIANtI YKOII IN Illl lt'A1. SIK11("1(IRI IN IIIIMAN
1 KN - I I IK/ KN 11 MI MIIK ANI S
Innrrr. /tansfurm mfrareJ specurnenpY rtvrakd that insrrUOn ul
:(b 6vdr...YChulrurrnl into human ery/hrocylt mrmManrs (11YL n( tnlal mnabanr
sttrnl) unnu.t.dbrr.t Ihe Lp.d acyl chains to a drRret equivalent 10 tnria'h.nR nn.J
mrmhrane ch,Jeslrrol hy MM Itaman tpeelrrnrryay shuwed Iba1 the amuunl 4.1 aarl
.h.On rulamrrs was nnl 1.RIMfn7MIy a11erMI by I/M pttKMT nf 71hv hydrna)al.u/ralrr..l,
md talrn /ha/ acyl ahan .mmnbdualmn ss hmi/rd to an inMhqw.n of latr/al 00411,00.1
Ihe prrsen.e o/ :0o- hydrosycM.kslrtnl may synesR.s/a.'ally tnhanae the
aryl-chain /mmnhJvinR hehavwN of InemMane eMdrslrtul. In a.l.btwn, pro/ern helnal
slrua'ane was not alleled by 2(1..hyArmycM.kalrrol. Ihe inarrlron ul
7o h)Jrn.ychukslrad into erylhtocyte memManea resutleJ in n ina'rtase in p.oltrn
helica1 slruclute which was cnnqwrahk to Ihal .dserved (nr trylMocyle mrmManes
rmrheJ wllh pure cMdrstrrnl by S(Ylh. Ilowrver, both acyl chaim mohdny anJ
erNlfrNrllaln/n werr unchanIttd. These rnulls NIRMrs! a syntraislir Irhavinr hetwern
nsyslerols and c/n.ksterrd /n nunlifying trylhrn.ylt Inemhrant pat'a.nR.
R.nrney, M W., Ya hurn. S Kuetrk, U., (.it, 1. 1, and Kauffman, l. W.
Rrrrhrmica rr llwpAlu.e Arla 2It7]-I9, 1915.
Orh.v tupprwrNor,hwtslern t/nivenily Rettarch aml U S Public lleallh Servict
Ilote the Riomedical t:nginttring Divisiun, NerlAwesler Ilnivetsily, InhnohrRital
Institute. 1 vanuun, 11.; Ihe (aepae/nlenl ef Medieine, the Prillhtr Sch.u.1 uf Mrdirrnr.
Onivertay n1 ('hicaRn; the Itrpaslmenl of Medicine. Ihe l'hicaRu MrJi.a1 4'MuA, and Ihe
Iaepallment of I'hysn's and the I.pud 0yalal Inst/1u1e, Kent State tlnivrrsity, 1111
1)1
V11 Mel.bollc ttrdirf
I KPth11R1 (11 tMAI1 AIRWAYC fff( RI\I()IIA111/ IN VIIRO
In the atud.rs .rlrnled herr, tnaur rcptama frMn dJfrrrnl levela of nrlrnl
anways, (rnm ha.hra hs hu.n.hwdra aa a.nall as :OO micrnns in d.an.elrr, wrre ralr..rd
/.. nontnuc cnnarnlral.una n( cr.at.d.alAr partiatts of a sve Iraa Ihin :O mnrllna tl.e
aulh.us .e.e mlrrratrd in the rflr.la uf crraluh.dnr, a lkMwn luat anJ f.ht.M.RrnW
paclwutalr, uln n.o..n srart/ion aMl prMluClion o( prmuRlanatms aMl Ieu\otU.rne, by
the r.pa.frd rl..thrlul arlls they hyry.thrsited /ha1 etprnure 1o cr.atul.shtr .nulA a(fr.1
nx1..M.hamm o1 arax h.AoMc acwl in Ihrar cellt 1)rpeMLnta nn the enry.nat.c Inth vsys
allrt IeII, t/Na 1 nuhl IrMI to 1M rraNJ fynlhtan Of (HIMluCla nf the cye brr.yRrniae caar..Jr
/1.a/ cuu1J nhd.it mw.n u.rr/u.n 11'(.11 n/ ft.mulahay panlu.l. nf Il.r /q~..yRrn..r
p.l6way (Ievt..t..rM-a / 3nJ I1/ As waa sren. the reau/ta n( Ihear alud.es su(rr.t
.r.a..l..d.tr h.s a dJlerrn/.at ef/rtl nn muc.w arurln.n by t.planta a/ r..drn1 a. w.y
ha.ar Irnm dd/r.rnl Ir.rla .d the rtsr....huy Itrr As nne p.np.rsars Jerlwr ua.. thr
.m.apuhm.n.uf auwayf an.t min tht a.na11 Monalnoka, il.RtH f1.u.ultUun u( ar.rImn
t L..nRn lu uKmla ant mh.b.r.nn
(dl.r K R rr of
In NA 1(1 ACI \rr.ea, Vn1 (:y, Re.\, I (: sn.l II.Rnnn, 1(rda ) fw I nr.. / ffr. ...f
111w.r.J hn.r Ibrhw /Ir.d.11r.R \/n.nRrr Ve.l..a, 1'+t1
(hhrr .rrr.nt Naln.n.d Inadulrs nf Ilrahh
1.om Ihe Iti~ps.lmrnlt of 1'alhulnRV, t..d I nRinrrrm1 an) Phyai.d..Ry/11
IIM.r.ady uf Ve.m..nt, Ilu.hnp.lun
/-\11K'//Al A\IN It 11,1014 1/) INI Rt A\I IN At IIN ]YN1111 SIC
ANI)((/NIINI IN A VARII 1YC11111t 1\1'IC
Ireat.nrnt u( a va..rty rd mesenchymi/ erlla (nnrm.tl anA IranafurmrJ rat
(.hroMaala, h..vine aurJic rmint7u9ial crlls, rahhit smtwlh rnua.le crlla) ea1..u.hnK
Jdltrenl cyhn\rlrtal orRiniral.nnf aMl .kr..rd from teveral species with dnaea of
cyluchalaain 1/ (( 11, 26 pM for 20 hl sulf.canl pt induce cyloalrk/al rrarr.mR.orn/
and alttred cellutar mnrphnlnRy teaults in an mcrtaa in Ihe rrla/rve contenl anJ rc./r nf
fynlheaia uf atlin. Ihrsr dala e.tend our previnus findinRf (or 111 p-: cells to udnr cell
lypes and pru.iAe furlhrr evidtnce fnr our hylsnlhtaia that the ('/l-induced clhnktlela/
remRaniralMn IriltRera ftimulatmn .d acUn synlhesia aMl the rnuh.nR .n.reaar in achn
cp.nlrn/
11.rt1, /(: t annrnhuam. I rnJ f...Jmen (: ('
('.ll RnL.Rr Inw"noenwnf RrrynN 9/1)7`) 7 10. 1995
(rthrr tup(r.rr Nalinnal Science 1'oundauon anA Nalmnal Ins/ilules of Ilralth
I.nm /ht /he INpaamrnl nf Palhology, (,nlltge of rhys.runa A Surgrona of ('olunmt.u
Itn..rrsrty, Ne+ Yn.k
1/7
MI MORANI CV(LIN(i ANI) MA('R()VAfl1f/1 A71()N (INI11 R 1I11INI I 111 Nt I
01 ('Y1(X"IIALASIN. KINE11(' AND MURPI1l)MI 1R1(' SI111)11 S
I ihrohlriN e.ryrnrd In hiRher dofes nf cylochalasin aCCUmul~le vtry h.R, dn.rrle,
tnd..plaamic va.w.lra, the membrant of which is der.vrd by mlernal.ralmn .d
plxm.drmma Murphnmetry confirmf thal the anuwnl o( sur(aae .ntrrnHlrtll n r.tual tu
the ddlrrrrice trlwen the n11RInaI cell sutface area IheflNe ('I)) anJ Ihe reJured .o./xr
area measu.-al.le altrr ('1) induced r.wndinR ('mrrslnmJinRty, thrre is a nearly twu /nIJ
mcrrasr m/hr activily nf the echrntyme Y-Pwler~nwlase la ma.4tr foc pl.nma
membranrl .ntrrnalty within the cytoplastn, after treatment with CI). Macrovjaw.lat.nn
.M'ceaart tell vulume by -)0'11, Surface memhranr is inlrrnabted as ma luplaM y1wK
veaplra 31 a rale mraaurahk by the accumulalusn nf hnrttrsdr.h pecoculaar 111/tl'). A
maLrr of fluid phaar Inm..yhnif ItplAte nf IIRI' is shown to be enhanced at all 1..nra
durinR r.rynutr to ('1) anJ is balanced by accekraleJ e..wylic eecvcbnR of mrw.h..uv
e.aep/ Jut.nR a phasr (- 4 1 hr) in which prmKybC up/abr t.,erJa e..wth...a
VefKntar mrmb.anr acaumuialyd inlracellularly rn thn prruwl rf re/ainrd .n thr
rnJ.ydaam aMl by au.crsauvr fufions fnrmf vacwdes rn chnr app.u.unar...n ...
nm...u/damtnt aRprpors 1)nce eslahhfhrd, /hn new mattovaau.dsr mruJn.uv
cumparl.nrnl rs in dynamic equ.lihriurw oilh the crll surQce and ns me.ohranr rs ay, Ir.t
Ide the plasma me.nbrane, in a mutual e.chanRe of pinns,.mea helween the srar..d
vaauuks 3.1.1 the cell surface In druRfree mrd.um, va.w.M memhronr aplarrntly
revrrls In the aurface by piM.cylnlie recy.IbnR, and the crlls re.u.er no.m.d
charartecnlwrs 4 -h hr afltr wilhdrawal of eyh.chalasin.
Ilre/l, l. (i and C.dman (: ('
f rs.w d('rfl 16(1/125-)1S, 1924,
(hMr aupp.vr National Institutrs of Ikalth.
19 m/he 1)epar/nu'nl of PalhobKy. Colkge of Physiciana A SurRruns nf 1'ulumbu
Ilnivrrsity, Ne., Ywt.
P1 R()X15(1MA1 hf 1 1('TS IN NfONATAI.ONSt:1 ANIf X LINK 1 1)
At7R 1 N( N 1 l/K (/1 rY51 ROPI/II'S
Accumulation of very long ehaitr fatty Kidt in X lin\ed and neonalal f.uma of
Wrrnok~~atya(aaphy (A111) apprara In be a ennaequence nf drfic.rnl ua,Jalmn of vtry
hrnR chain fa11y scida, a function Iha/ hat brtn allributed to prro.ip.mrs. Prrw.u.mrs
.rrre readily idrnlifrrd in livtr bitpsies Iabe frorw a patirnl hav.nl{ /he X LnFrd
d.s.wder. Itowevee, in liver biopaies from a patient havinR neonaul nnael A11s,
hrpalncellulat peru.isnmes .'ete greally reduced in site and numAer, and sr.Gmrntahle
catalate was markeJly diminishrd. Tht presence of incceaarJ cnncenlralinna n/ anum
p.prcuhc acid and the Mle .cid inlernurdisle,lrihyd.uaycnprofunic aci.l, in the erunatal
AI O pairnl .re associateJ with agtwtralirtd dirwinu/inn nf prro..aumal arl..n.ea .har
waf nol obarved n Ihe pat.rnl wnh X llnked AI 11.
S rr nl
Snrnrr 2276770, 1915.
Other rup(rnl National Ins/ilulef of /leahh, National Scir,nce loundatbon and (:aJ 1
/ucterman I oundaaow
171
I
I rum the t4parlmenlt of Palhnlnty. Pedialrict, and Nruroln`y and thr I ivrr Resrarch
("enttr, Alfrrl I mur.n ('n11ele of Med.cine, Ihe Rrona, NY, the Ilepa.tmrnlt of
Pa11w.4.gy smt Ped.atnc NrurolnRy, (-hildrrtis 1/osprlal .J M.ch.Ran, and Wavne Stale
Itniveruly ScMrd of Mrdcine. Urtrnit; the IkpsrsmenH of (ell llnL.Ry and Mrdnmr
and Kaplan (bfter (tnle., Ner YmL (/nivertily School uf Medaine, New 1'nrL, d.e
luhn I KenneJy In.tdWr, d.r h,hnt ttnp\int tlniven.ly Saur1 0( Mr./ic.ne, N.dUm.ne,
Mlr, and R.uLrIrller Iln.rersny, New YnrL
III 1RASIRt1('l1IRAl ANI) ('Vf(X'1/1 MICAI. DfMnNSIRAtI(IN (/1'
1'1 R(/rIl/1M/ \ IN 1 111 111NI t) /10R(NII ASIS I ROM PA /II N/\
WI I/1 /'1 Nt/tlMOMAI /r1 1 1/ 11 N('Y 1)KC)RI)1 NS
lhe naidahnn of vr.y Inna chs.n fally scwls and tynlhrut /J rlhrr gIy.rrutPntt
(plasmal..arnU a(ua mainly rn Pern.iv.w.rt. )rll.r(rr't eerehruhrpalurenal s.n.hunv
(( 11RS) n a rve, mA.nod mrtsl.d.e dnraw cha..c/e.ued by sn a/./.a.enl d..rnce ..1
/MruHMmrt, an K.umulal.nn of .ery h.ng cha.n fally ac.ds, and a drr.ra.e ul
ptatmalnarnt .n h.wrt aml cultured fhhrohtates from lhrte pal.rnls. At prroi.ncnr, arr
YhnlUnnW .n mamnul.an celts, we elam.ned nmmat and ( IIRS-cutsureJ fiMnhlau% fnr
thr/r prrtrnle. Ya.nA an elr.l.nn mafrnKnl.K hlslnahemn:al p..hellnrr fnr the fntlirtlnl.lr
h.cd.ral.nn of ealalasr, a peroaipxn.sl ma.Lrr rn/yme SmaN InM 0 20 pn4 r..und ut
thRMly nvat /vrntnumrt .rrr trrn in Iwnh n.nma/ anJ ( 11NS t.brohlaalt the numinr
al prn.uanmrt .as ana/yud mrphnmrun.dly an1 f.nmd to iv uandn,vnlly .rd.nrd in
'atl ( IIK[.r11 hnrs Ihrar revdlI are d.,n..rA.n rrliln.n In the umlrrly.nR dr1r.1 .n
Leru\1\nmat funclN.n and hu.yrnrvt m 11- dnr..r
Ar.aa, I A, hlnsrr, A It , and I,..IJ/.. A, r 1 I
: Ar l.wrnol n/ ('.fl R..l.rr IOOt/L0 1)0!. IIL{
nrArr, .rpp..1 Na1N.na1 Inslqulrt of /lratlh
1 rn.n the AQrrl 1 int/r.n ( ollrae of Mrdn.nr, the Orunc, NY, and the )ohnt I1npL.na
ScMnd uf Mednine, Ralln.Kne, MI)
PR(X-CSSIN(: Ot ANGIO11 NSIN ANb 011I1 R PI P1111fS RV l lll- L11N(:S
The pulmnnary vatcular bed can be con.nlrred as a sluice Rale for conlrultin/ the
puafily of b.oMRi.atly aclive peplidet a11..wed in enlrr the tyslemic eireulatUUn Ihe
remarLaAk fealurr of the lung is the trlectivdy of the processinR, n(.ecully .hen nne
cnnsiders Ihal most prplydes are imliscr.mmalely dr{ra.kd by hhwrl enrymea, hatue
hmm"rnalet, and many enrymff OAe of the nnnl critnal delerminanlt n( the arlec .vay
of mrlabolrsm of prpt.des .t Ihe h.cstinn ..f Iheir inactivatinR enrymrt Thus n r/he
cell hn.h.ly that 10 a arral r.ItM delermines Ihe access u/ prplnlrt In Ihrir mrlatadu.nR
enrymef Ihe presenl chap/er it drnled to 1M pro.wting nf ryAypeptide hn.mnnrt by
physndnR.caNy
Ihe IunRs Drs./yLinin snd anOnHensin (AN(i) are Ihe motl sludied ..( the
/mp.wlaM peplNte hnrmnnet prneetted by Ihe lunas In the drtcustion sec/inn of Ihit
paper, il it nnlyd /ha/ the hud..elical allivitles of Ihe Linint snd AN(: II dnaplYar,
.herrat the s./.v.tr uf AN(i 1 is enhatwed dur.nR c/lcutal.nn thrnuRh variuut va.cular
hrAt 1a a 1arRe dearrr the chanRrs .n KIiv/1Kt of the vavnclive (udypepli.k% are
mdrprnJrnl rJ rnrymrt and crlh.lar rlemenls uf hL...rt but srr closely rrLard to
Lr/I.daar a. I..rl.ra n/ the .aacula. t+A .t.rlf (r.e. Ihr paal sr.r.al yeart, sspr./t nf Il.e
m.l.h.hvn n/ n,... aut AN(, I 1a p.dnnn..y rn.4nl.rhum har Iwen drl.nrd I/.r
focus hat been on a cell Iql pre.inwly Lnoarn M'eaisl unli/ the adveM of elrclron
micrnsenpy. I ndulhelial ce1M sekclively process a series of vasuactive sal.wnaea,
inc/udm0 AN(: I and bradyLmin Sliduet uf Ihe pdmanary prnirttin// uf snslulrnsu..
and relalyd prplides dearly show 1ha1 the criliial, iniliat rrxln.nt n..ur st the .rll
surlaae -- Ihit is Irue of inelaMdic enaytnet, recepNwt, and the rekaar nf prn.tuclt A
challenRe fnr the fulurr is 10 hrRin In charl tht Rr..paphy ..f Ihe pulmoniry enJwhel..d
crlt aurlace.
R Lm. ( S
t
In 1.chman, 1 P and 1 isher, A. 0 frdt ) I/unJ/r...l o/ PAr.rnlnKr T Ar
.C../rm l. llelhrada, MII the Amerw'an Phyti.duR.cal 4w.ely, I')11oio, /h..p IO, pp
1'l1 1/.1
(lrArr .upl.soI Na..una1 Inslilu/rs of l/rallh
1 rom the Isrryaamenl u/ Mrdicine, Iln.vrraHy o( M.ami \. A.rd of A1r.La inr, M.am., / 1
1111' /tll M(/NARY 1 NIK)IIII I IAI. St/N1 A( 1:
lhe undrrslanIinR of emLnheti.d w.rlal.dic p.n/.erl.et ha, incrravd dram.un.dls in
rrren/ yrars I nd.nhelral crllt (1('s) Ir.asess Mn11N1nes; ItrY/;t, alnt m.My Id...l hn.nr
suhslancrs by meant of eneymet'M/ IraMluNl pruceNet In lu.n, tomr hu.mnar., Idn.1
trllt, am) erllulat purluatt inlrrscl tvilh I('t via slrcda recrlInrt un the lumm,d
turfaar. / unctinnal a.mrknly is eaempldied by Ihe roelalnd.sm uf Ila aalran.r
n.nle..t«let. A/ P, AI)P, and AMP a.r InelaludrnA I.y eniymn .4 Ihe endulhel.al
wr(ace lu rekase adrmninr, w/.ich may he imrnedia/rly IaAen up .nhr enJnlhrhom and
rerm.npnratrd intracr11a1ar1y into nuclesNikt. I qnally eomplea n the rnrlalMd/sm of Ihe
L.nint aml answ.lensus by 1.('s IlradyLinin is inaetivaled whe.eat anRN.urnsm I n
e.mverled In anRin/rntin 11. NradyLiwin nW thwt .kRra.Md csn arl un endnlhrhal
rrcelNort and sli.nulalr the releaae of M.nla.yeliw (IYi1a) Ihua, hradyhuun can awqdafe
the release of atnnher vasmbla/m. P(ill, snd can tlimulase Ihe retrase of a pnwrrlul
anliaRpe/talury aRrnl (/'(%la). Many of Ihrte C.Nn/dra nulalydn: reacliama mrur al the
C/Nln/he/r.ll tu.f:fY, a tlrYc/u/e Ihal M iltelf cnmplre. 1.('t tMl9faa enJulhelial pr.uleclsnns
snd eavenlae n.ell n a (urty ena1, nr Rlyeucalys. 1 uurla.na o/ Ibe emtolhrb~l
Rlycucalye a.e nnt wAl underslmd, Iwl the Rlycncalya canl.ot M vra.ubred, il may aa/ a,
a nu.kcular sirvr aml pruviwk a subt/ralum for the indraln.n and proa.rss.nn d
i/mnuM.h4tlc r1'aXtNNn
Rrnn. f' S. Ryan, 1 W and CrutcMey, 1) 1
1cJr..d.nw P'nnrJnrRl 44 0011 0019, P)RS
cNA,r .wPl"r Nal.nna/ Insli/ules of Ilrahh
I rnm the IseParlmrnl of Medicine, I lnivertity of Miami XtM.nt of Mr.bcmr, hhan.., 1 1,
and Ihe Rrsearch Ihr.ainn, Mumi Ilearl InslNOte, M.am. 1lrarh, I 1
1/S
Pltl M(1NARY I NtX)1111 t II/M ANth PRtKI CCINtG (11 Pt ACh1A S(71 11I f S
\IR111 IIIRI ANIs 111Nt 111aN
WMle the /unRs offrn .re conti,lr.rd e.cluvvely in trrmt of Raa eachanRr, Ih.y
have ad,t11ww1al frnclw.M nIH wrtessar.ly rrlated lu swh eahanRt Oor awh aal.v.ly i.
the .Mlhly 1n prncesf arlrcl.vtly Mrmnnea, hnrnw.ne Mrcrranra, and uthrr rtc.Ulnry
tuMlancrt as Ihry tass Ihrnullh the IunM via the M.rw/auesm At the /unRs c.n.ert
venout hMw.d /u arlrrul hhwrl. Ihey atus rrgulale Ihe entry of hu.m.nal sufn6.ncrN mro
the syslem.c arlerut c.tculalw+n 1hr.wt{h Ihis selectlR prnctstinR, prrwlucH of sPrc.i.c
rraclw.nt of the IunRs can mrlurnce aprcd.c aclions of liffuef and ntRana al a,1rlL.m r
Ihe frrtt kvel of compartmentalw.n in she Irnp It Ike srparalwn nf the hhwrl aulqly
(rom the au supply f)ude tlra.ly, CllculaUnR /rhslances arr unlikely In have aazras trn
enryrnea hey..nd the firsl crllulv layer bmmng Ihe vrnrh - Ihr rndothrl.um Ihe p.rarnl
thapler dr4rd.rs fun.'In.nnl and tlresclrral atpects of the inlrraal.un nf s.dutes antl
culh.idt of p/aama r.lh pulmunsry emlothrl.d erlls I.nl the has.c aecharclu.r and
rnvnanmenl n( /hr trnla nt cnnsdrrrd lhe surclure snA siluatw.n of she /unRt vdhin
the c.crlalory tyttrm r.hah misr rhrm seII trerd (nr las e.chant,r may rell rqdam
h,.w the IunRt are tu r(fn.rnl in protesam/ snroe hornw.net the nest level of
turnpa.lmrnuln.n is withm the putnsnnary circulatw.n and n lovernrd by tl.r flo.r
charatlrrislres snd rrlal.vr su.face urat of Ihr vessels I rlures art /.ven in 1hn tettinn
which emphaa.rr the oer.hNm.nl f.lndnanee of emtothrt.at ctlh nf the puLnonary
nlw'rnvaNulalMn .n p.nv.dins a turface f..r intrractw+n v.th Llow/ horne tuhstraln In
full.rw.not feclw.na of Ih.t paper, ITTrnMflnche.nlt/ty. I ndnlhrllal CeII Vrtlrle and
Surlace S/r.ulvalu.ns (1n.lnlhelut Pnyrclu.na, (avndx, and (aycncalyal. are
dntuatrd 11 .vd1 be mpnUnl for fulu.e t1aA.rs n. etamme lo whal earn/ m.a/uhlw.n
o/ endnlhrlial srrfatt frru.ru.r prolr.rw.na, ta.r.dar. Rtvc.Kalva. en.y.nr rrcephns,
aml Lanarywl mr.tr.ulrt Ilrct the n.r.al1 funcra.n.not .f rnA.nhrbnm aa a 1.asar and
the ovetall /un.lw,mnoo uf /l,r tun/ta .n ma.n. un.na /M qu.hlv ul rhr .ntr.n.t md.ru
Rlvrn (t S and I.t.l larr len.rn, I
In \ara1, S I frd I 7 Ar Pvl.e..nn.. f u. uL.n... ,.+J t. w. f r..r l.. n.. M..uu~ k.a... N S'
I rlwra fouF1nMnR I~o, Inc , IV1S, pp 1/ t.U
ILArr, .wrrwr Natmnal /nuwuret uf Ilralrh
I rom the ItntversLly u( Miami S[M.ol of Mr,l.cine. Mum., 11.
1 Vll)t'N('F. I()R A RlN f(/1 IIYt)R()XYI RAlyl('AI. IN
IMMI INI -('UMPI I X.INI)1 u( 11) V AS('UI I I IS
Previoraly it was shn+n Ihal listue injury nccursinR in s.ule
iremune en/npks induced vasculrtis, which is eomplemrM and nerl.nphd .kprmtrnl, is
snRndicanlly allrnualed by lhr Meunce of cNn)str, suRResunt Ihe palMatrnK rale of
11.(1t leneraled from sttivsled nerhnphils. We now shw 11,21 t.Rndn'anl prnkclw,n rs
s/u. Nf.Nded by prrlrratnsent of animals ith apotatlofenin, a nNurally oau.uinR
chela/..r of itnn hon salrraled laclofrrrin is devoid of prolrclive e/(r.ls.
1)rfrroaamint mrsylate, a synlhelie irnn chelalor. alto haa proleclive effecls Infus.on of
w.me ifon, esprcully IeUll/, poltntiales the lissre injury. Silnrfrcan/ prolecliun (Y..m
Inare intwy nt als.- prndwed by Ireslrnent of tats -ilh dimethyl sulfoailN. a pownl
hydro.yt radical scaven/rr M.apholol.ca0y, ammalf Uralyd avith Ihrfe prnleclve
inlrrvrnlu.na thn.~ the .n/lue of nrutrnphds into ulet of immune cnmpka depnu/u n.
Dur rM..r n ma,ar.llt .rvnwa..A rdrmas l.trlr w nn hrm.n.hase. and /.111e evidence nf
I
endnlhelul cell injury, in conlrafl lo the findinls is rw.npro/ected animals lhr.e dala
srptwrrl Ihe fuRlrstwm Ihal rmmune-COmplea-Indreed /nfury may IY LnkeA 1o ~eneral.nn
of 11.0. fYUm aclivaled neuuiq.hilf and Ihe wlneQuent cnnversw.n of perotide w. Ihr
hydruayl tsd.cal.
I hrairl, S E (; , wall. I. A. lohnson, K. 1, and Ti11. O 0
Amrnrnn /,w.nal of ParA.d..Rr 11% 175-)12, 1911.
rlrMr, .uprywr- Nar.nnal Instirutes nf Ileallh.
From the 1)cparlmenl of 1alhok./y, Ike Ilniverfily of Michilsn Medical Sch.wd, Ann
ArMw.
1 VIIs1 N('1 /(lR I711 R(71 1OF OXY(;EN RAINCAIS IN ACltll.
NI-PIIRI)1(/XK' N1 /11R111S
Acule Rlomerular injury in the rM tus heen induced by the in/tbenal, intrasrtr.ial
infusipn of fheep snl.hody 10 /bmerrlae Aasenlfwl nsemhrane anli-(iIIM (anliahmerular
baaemrnl memhranrl. lhe anlillorlefrlar bsstmenl nfemhrane antdwwty has been
verified 40 be of the variely Ihal is eornpkmen/ and ntrtr.y.hd .kpendenl for the
induclion of acule p.nlriarria, which peaks during Ihr finl 24 M.urs 1ollow.nR
injrction of lhe anlibWdy, .crle, in/ense, tlo/nerrlar injurY /nrlted, ../h the .knudmR
of Rh.mrrular vatcular basement nxmhrane associatet/ wilh e.lent.ve .IamaRe .r
deslruclion of aInmelular endolhelial cells and frsior of epilhelial cell fwn ptncet.et
Irealnanl of anrmals (vilh calalast podreed, in a dase-depemlenl mannrr, as mw'h as
7S'll, prolecliow apinfl llornerrbr injrry, rs Iafessed by redrelwn in Ihr lwnlemu.s
frealnmenl of animalf avilh superoaek ditmulaft caused a smaR reduclion in the detree
af Rh.merular injury, aRair ptessed by a reducrion in prnkinuria llnwrvrr. Ih.s
ptMrclive tffrcl of srperoaidr disrnrlaw was nol fnrnd to be slatislically silndrfanl
the hydroay) radical scavenler, dirne/hyl sulfoeide, which haa brrn shov.n tn prokc/
alainal end.aheGsi cell injrry folbwinl systemie reclivalion of eompkmrnl, was nnl
Mnln-Iive in the anli GRM model M.wpholn/icaRy, tlnrnerrli frnm caralau-pra.trcled
rals shoaved nrrnerous nrWrophils Or1 liltk or nn evidenet of injury of eirhrr Rhlmrrular
endnhrlial or ep.IhA.a/ cells. fhrte data sr/Rrs1 Ihat rcrle ahrmerutsr .n/rty prmtwed
hy sntiRh.merulat hasemrnl n.ertArane if relaled to 11.U. Mrwteaclw.n Lom at/iva/e,/
nrulruphitt
Rehan. A., lohnson, K. ), Wi//ins, R. C., Krnkel, R C: , and WarJ. P A
f dwwmwy Inrr.rrRaron t1(Ir)o6-d02, 19N
OrArr srpprr - Nal:nnal Imlitutef of Ikallh
lrum Ihr IkparlnwnN of Inlernal Medicine and YalhnUyy, the (tntvrrs.ly a( Mwh.Ran
Medical Sahm.1, Ann ArMw.
RAT NI I/7ROFl111. ACTIVATK)N ANI) 1:11T('f (H LYPOXY(:ENASf
ANl7 CYCI.(K)X YGf NASE INIIIe1T(NtS
Aclivalion (defined Ir lyfusom.l enayme secrtliora rnd generalion nf (7t of rat
newrnphih hat been r.easrred with Ihe rte of varyinl doan d: solrMe stimul. (phnrhol
nlyris/a/e .cclale (PMA): cahiuw .m.pMre A211/7; and N fo.mvl
melhwnyl-kucsl phenyl al.mne (1 MI P) and parbcu/ale qents (immrne tomple.rs
I,~ I77
65100 7670
and rymoayn part.aet) W.th rither the cakium innnpMue nr the chrna.tailic replnlr
(I MI 1/. tuhtlaul.al rntyme .rleate accurreA, bul the anu.uM of (Ir pra.tu.rd waa vr11
amall ('ylnchalaa.n 11 Rrratly enhanced 1he rnrymr rtkate responst to the themnlacl.:
perbde hu/ had hult rfferl on nrulrnphd reaponars tn othtr snluhle tlimulr Ihr crll
rrapon.e to PMA rr.uhrd .n the grralral prrufucln.n of flr wnh t.llni(rcanl eniym
thrtlu.n When cell t/.mulat.,.n with inaoluh/e strmuli (/mmune cumplrata of
tymnaan
I.arlnlr.) w'aa tlud.ed, srKnd.cant amlwnts of enryme release n.'cuned in para11e1 w.rh
the Rrnrralmm it( aut.atbnt.al amnunts nf t).. lhe prrsrnct of cyhwhatatin 11 rnh..n.rI
Ihr ctll rttpnnwt to immune cumpleart but had an uhihitwy effect in aymuaan u.duar I
rr.ryrn.ra At e.pe.trd the ar.wwnt of lytnryme srcreted by thmulaled ral nrulnydul.
trnJrA /n rtarrd the a.mwnt nf /) RluturonMlase rrlrattd frnm Ihr samt crlH
Nrutnq.h.l re.ry.nart were rnvett.Ralyd .n Ihe prtxrwr o/ AruKa Iha1 wrrr
Aemnn.b.rtrd in Ihr ral neutrnphd 1. .nhihil eilher the hp.uy~rn.te nl Ibr
.ah.uyl{rnaar p.Hhwayt Inh.hnmt of Ihr cyckruyRrnaar pathway Ln.hnnal..am
pu.n...an., rhupr.drn, 11N tS{( 1, wrlh fr. ra.rp/wma, tnnvtltntly rnhancrd /hr rnitmr
ararrt,r.n rrtp..nae, .h.lt rlfr.lt nn tlr Nenrratrnn -tre lett clrar cut hul /rmlr.l 1.. 1r
L.r.l..nonanl/y rnh.h.b.ry 14u~t r..lh rnh.Mrnry eflralt nn the 61.navarnatt paN.w.v
tn.uA.hy.Uu0tuauvl.c a wl an.l nafanlrom) had tqmf.cant inh.Anury rllrcls on h..lh
rnryme arc.rru.n a. well at Rrneraln.n nf f)r Ihrw data suRRtsl /hal acti.aln.n
rryw.nart tenrymt trcrrtw.n and (IS Krnrratbn) of ral neutrrq.hdt may 1s dna.r..rtrJ
(. r, .ne rM./ alwa)a a,cnmranyong Ihe olkrrl 1 utlher, d arrrars that nrulr..rhd
a.l.valn+n, aa Arl.nrd At rn.vmr McHIrM, a rnhanrrJ hy pr.wtu.ls nf 1t.t I.p.syKrn.ar
ryalhway amt .urr.ra hy rn,lu.tt .4 the .y.4.r.s~rnav pathway (.rnerl/...n .J (ar
rt nnl.l/rrlr.l.n tuch a.1raa lus mannrr /akrn 1.~rthrr, the d..ls auRRral th.rt enrtmt
rrlraar and I1~ p.rwlYa'L..n by a/ Ir~NrA ra1 nrul..y.h.1% may he Yn.ltr tt/.ar.ar cnnlrnt
MorJ P A Sulauk, k( /', anA )ohmtnn, K/
Awrnr..rn Irr..n.J ../ Po.A..l..r. 11tt 7: 1; 11 /011
OIA:r .apr..r N..In.nal /nu./utrt nl /tralth
t rmn the 1Mparlmenl n( rarhuL.ty Ihe lln.rrt.ty of Mrch.Ran Mtdiral Schno7, Ann
A.hu
1)1111RINIIAII()N()FAIIIIMAN1tt/KIMIA(111 tINF.
ANI) I X/RI C\1IIN Ut ('<)1 1 Ala NASI /N1111I11/>R
A human cnllaRrnate inhA+itnr (CII nf Af 29,SOf/ hat heen ea/entively characlerirrd
in skin Lfnohlaalt and idenld.ed in a varaiy of conntclive haanrt Otcauae human
alveular macrophaRet tyn/hrure and srcre/e both eollalitnaae am1 ( I /hal art
im.nun.rM.ooically and functn.nany idenliaal No thru (nunterparh in hMotlaala, we
sludrrA the prmluar.n of surh prnttint by an /mmalu/e human \r1I line (111 M1) that .an
hr rnduced in differentuate alonot namrylie nr panuMw"ylic palhwayt fhe crllt fade.l to
yynthrurr eollagenav unAer any cullure enndqwn letted. Iloerevrr, upn Hf~nurr lo
1,IS d.hydsuayvilaman Iyr or rhort>.1 ettrn (FMA). Mdh nf .hrch plomole nu/ntr'yl.c
ddfrrrnlralinn af 11160. thrse eeltt synthetienl and reMased ('I in a dn.e Aeprndrnt
mannrr 1 wthrrm..rr, the talent of ( I rcpression wat parallrkJ by the a0u.tan.n by
such cellt of the m..n..t/.c ma.krr t+11t1, rndhal.nfo Ihal inh.h.l.u pe.rluatr.n and
ddfr.rnr.aa..n a...l..rl.....r.1.aA IMa t 1 .4% .n.munul..~..altv anA lumt.nnatlr
idrntical to Ih.a ruduced by human InacrophaRrs and human akm f.h.ubl..alt Ihr
qu nhly of ('1 synthesvrd by PMA-slimulalyd cells was 1 /o S fuld Rrr.nrr Ih.u.
pr.rtuard by hu.n.n alvrnlar macropha/les, r I pR~per 10' cellt rrr .lay In .uol.rl_
urw/dfrrrnl.altd 111 60 cellt Mrnluced Idlk ar no de/eclab/e (1 ( 10 '0 nR Iwr NI ,r111
hrr day) Interr.tinRly, .hrn 11160 cell, .ere sl.mulaled lu umk.R.. Runul.r /t.,
atdfr.enlulnm by ./hnmrlhyl sulfn.ukr or rebmric acid, they aho pr.rlutrd Ihe 'm.m.w %t..'
(1
%hivu, % II , M,fA:u. f/ 6 rr of.
P..arrJm,r .J rAr Norr.wul A.aJ.'mr r.J 5...mr. ../
A.nrrr.o 11! 511111 111t1, 1V4V
(hhr. rup/v..r N.uu.nal In.l.lulet af Ilrallh
I ruun Ihe /l.v.awn n/ / elI I/wd..Ry Waah.nIllon 1lmvtraa/y 5.'h.r.l uf Mrd...M Ih...u.n
u/ IMrm.a.dully, IrepartmeM .d Mrd.arwr, Ihe fr.ith 1loapilal al Wash.nRlon
Mr.ln'a/ ( rnler, SI I ouh, and Isivitiuw of Isermal.dnRy. Iarparl.nrnl 01 Mrdu nr, V A
MrJ.aal t"enter/limvtrtily uf /tnnessre l'enVr f.u Ihe Ileal/h ticrrn.ra, Mray.hr
t
I!V
65100 7671 ;
V111. lpidenJeln!)
1A h11t 1AI A(:1:KI I.A 1111N 144 11RfIN1ll)IICIKIII 1IV1 PItI MtINAKY
IN\t A\I llti/ /11 1111 1(n:1 tNl AR h1111111 Ill ANAI \'/1 IN11 Rh11111A11
I NVIKI/NMI NI A1 ANIP (.1 NI 11l' KI%K I A/I(IKS
lu r.anunr the c.'nlr.hn/n.n uf rnvunnmtalal and Rene1K rnL (atlo.s In f.nniltI
arRreRat..rn mh.nn.c nlnnacbvr pntmnn,ry disease (('(1PI)1, I!i /usl d.r.rrr (1.1)
.rlah.rs and 1.6 spou.es u/ INI 1/1/'11 p,r.rols were comparrd wilh .':2 Id relt/.vrs tn.1
d'1 sln.uars u( 1117 n.npulmnna.y pahrn/ Cunlruh (nr the prevalrnaT of Iwn rtun. J
nntc..mea 1) au+avs ..hsl.wla.n (AI1, I src f.wcrd r.pin/my vulumr < AR'6 uf fn.r .1
.1a1 ctpacnY) an1 .'/ .hrnn.: hrnn.h.tit 1111, cvuRh anJ sputum fnr 1 mnulhs prr yrt.
1'1 2. years) 1 he h.Rl.nea, m.vlrl -as vard /n uudy Jurcl an.l nmhrecl (. r, Ib..r
mrdaatrJ by ntl.er rn\ fach...) cumry.nems nl famil.al aRRieRHun Ihrre ua\ (sraus
we.r fnunJ lu Iv .nrlrt.enArnMly ass.Kla/eJ wdA ('R an.l/or AI) o. ant.lrypan drrn iena y
(P./ alklr). pr..nnal c.Rarelnr tnwkinR nd patenlal Cip.elle 1mnlinR Ilraa.ne 1.1
/rhllvrt of (/Ntl ptllrnll were nlqr b&ely In have a Pi/ allele, hr heavy smo\ra (Ir
pxka per day). anJ tr e.rynrd lo parenlal .malmR Ihan Id rrtalives of eont.ols. IM.ae
three fac/nrs dao (nnsl.luled im/irect enrnpnnrnls rd famJial aRRreRalion. Ilnwevrr,
allrr C.m1.n16nR /nm the /hrre fachus, Id rrla/a.es of (ON) pahrnls wett mnrr likely a.
have Al) and ( It than Id rrlahvet uf cnMr.ds Idnrc/ cumpnnrnl) 1 hi. d.recl c.m.pnnenl
miRhl have a Jenrll: Insas he. avsr nn su. h asa.c.alM.n wa. found when spnuses .mlra.l
uf Id relallvet wnr cnmparrJ Ihus. M.Ih shared rnvnon.ntntal faahNS (IKrsonal aml
passive smnllnR) an.l ah.urd Renelu: fatl.ns (.. antarypun and a IvKSd.k duecl Renrl..
enmlw.nent) cnntnho/e h, fam4ul aRReRahnn in ((11'1) lhr 4.Rlmett m.rlrl prur.Jo. a
uar1.J LMd ful analy.mR f amd.:J aRRreRah..n .n d..ra.es nf mullJac/or.al thnh.Ry
Khoury, M), I/ealy, 1 II , IIKkman, M\, 41f, C G, and f..hrn 11 If
.
Crnrr.r /'prJrnr.nl..Rr 11SS 166. 1985
(IIAn supryrr I rhanese Nalian,i ('nuncil fnr Scirnldic Reuar.h anti Nalinnal In.l./ulrs
uf Iltalth
I rnm lhe t)rlurl.nenls of I pideminhq{y. 1liustalislics and I nar.mmenl,l Ileallh te iencr.,
Ike )nhns ll.y.i..ns I/nivrrs.ty S.hnol .( 11yRane anti PuM.c 11ra11h, nahinune.
III AI lll R11 All 1) IK\'IYI(X(K'IAI. (ORRt I AlfS01' N11/KOIK'ISM A S111UY
(1/ At/l/l 1 MAI 1 7 WINS IN I INI ANU
Snmt heallh rrlaled p.ycMw.eial cnnrlalrs nf the (-ysenci nru.INN'Nnl scar wr.r
eraminrd in a.Iwsl.onnaur .ludy of (l01 mnnuryRulic (M/) and 111 .biyR"hc 111/1
malr Iwin paus rrp/esrnlinR the advll nulr Iwm Iv.pulalu.n in In an:dy.rs .d
the /nd.vWwh, 14% of the vpi.nct in nrulntlCism was /IS.orlnlyd wllh
varishles (.IrrN .J .1a.ly acl.vi/ies, Lfe salidarlion, pu.dNy of skep, an./
tltruversinn Ihe raplanalo.y rsle of IMs varlahk u1 was 10'41. IMych..troPlc druttt Is'./.
aknh.d use (1'll.), an.l snu.smR (a). Neuroliclsm was also asarciatrd ..Ih s.'.ial, 1.1e
ehanRe, .nd nwd.cal va.uhles In pairwne analvars. Ihe hrrilah.hly eslinule Ihr/ was
0%4 L.r pa..s Iw.nR loarlhr, and 0 19 fnr paus t...nR spart 11 seems Ihal hrnlabdqy
tstimates are confnun.kd by the closer inlrapair relalinnship between mrmhrs M M//
lhan IsL pairs In panwia analyses, 21% of the inlrapair JJferencr nf ntu...l.u.m .n
M/ pain was assuculed with mlrapaly ddferences in the afurrmenlwmed vali:J.lrs I he
folhlwmg eaplananalory ralrs were found. psycM.M.Rica1 .ariablrs, 215, p.vchnlnq.ndruRs, NL; )cuMd
use. 2'i; and smnR.nR, NL. Neurdicitm uf p.u.s J.acoldanl lur
hacLRrnun./ variahks showed similar inlUpan ddfesenses as helwren ind.vi.twh in thr
(nllowms var.ables srrvict rs (lrming wMt, use uf akuh..l, use of anlx nk,
h)pertrnsnm, hravy physical work, pualily of steep, chanRes of w.wbpla.e lur nrR.llive
reaams, smoAmR, and use of Iramluilbjrls It appears Ihat in I mhnd, envirunv.rnlal
(aahus tspla.n a1 kasl AIX of the varrahJlly in neurMicnm, and that (adu.a delr.nuu.nR
nrorulicism alt also ass.Kialed w.lh heallh rela/rd Irhavun such as smu\inR, u.r nl
a1.uMd an.) psyIhnlUnpn; d.ugs
Kn.>,rnvvr.. Af , I anRinvainio, 11 . Kaprio, 1., and Sarna- S.
Arro Genrr.ror Alrlnor er Grn.rll..foRr.r 71:x17 120. 1924
1 rom the 1)rparlmeel of Iuhlic Iledlh Scitnre, Universily nf IleNin\.. I/elun).., I ml..n.l
I INNISII 1 WINS RCARI D A1ART 11. VAI.IDA11f1N 01: /Y(:OSI I Y,
I NVIR(/NMI NIAI. 1)ISqM11.AR11Y AND WI KAlI ANI) II1a4111
1
Within Iht I inni.h Twin Cohorl of like-seatd adull Iw.n pairs, a suhRrnup o/ paur
stpaoled al an early slte has been idenlditd In 165 pairs, hoth (ulwins rry.unJrd h.
Q.RSINqOUes in 1975 and 197V. An envirnnnwn/al dissirnilarily scurt was fu.rnrJ whNh
consisls of items nn whnher (he Iwins had Irved afler separabnn in Ihr samr c.ro.uounny,
a1leMled the salne schtuJ, were in Ike sa/ne palk al sehnld. M.w nflrn Ihey mel, hnw
often Ihey me/ cmnlmm friends aud teblivn, and arhelher Ihey allendeJ the sanle cluhs
.N nnt, etc. lo validale the aygosily diaRlasis oMained by Qutstr.nnal/t in 191% IM.a
pairs whose tyRlnily was unhno.rll Md IAost with Ihe kas/ Conlacl afltr separaln.n wea
conucled fw blood un.plin0 (R blond{roupt). ()f IS pairs wilh wn ryRnsi/y diaRm.sis, 10
responded (I ta addrns, 2.Aro.d, 2 rehned) Sia p.irs s.ere classifit./ Ml and 4 1)/ In
12 MT, and I f)Y. pairs undergning MundRrnup dclerminalu.n, the c1as..fical.nn .uf only
one pair ehangeJ frnm 1)Z /n ML. lbe (nlhswin{ inlrsclass correlatw.ns /nr
wriRhl .rere found heiRhl and
ARt N Nn Casel WeiRhl 11riRhl
aep.ralim M7 I1L M/. 1)Y- M/ l)/.
0 7 11 61 oa 011 oR% 070
0 10 30 95 0117 016 092 0/o
1 an~invaina, 11., Ko.4.n.r.. At . K aprio, I, and Sislonen, P
Ar(a Grnrurwe M.Jrror .t GrmrQ.d.rRr.r !).2SI 2~t, N/~I.
fhMr .v~(ml V.p ).hnssnn IovnJsliun
/tnm the 1)ep.rlmeM of Puslie Iledth Scirnct, (/n.verdly of /lehin\., an.) I.nnsh Krd
Cr.ns Nlu.nl /ranslusv.n Srrvice, 1lthinLi, I inland
III
IM1n
65100 7672
I INNtS11 IWINS RI AR11) APART 111 PIRSONAI I I Y 1 AC1ORS
Ihia sludy is haaeJ nn dala from 16S adull Lrrn psin separatrJ st 10 )ean n/ aar
or ka Infnrmathnn un (.rn.mahy fsctnrs tatravrnrnn (1.) nd nrurM.:nm (N) It t'I
Walr shmt furml, t.fe aatnfaalu.n (I S/ (AItarJ17 and streas nf daJy aclivrlita (SI)A) vac
ohtamtd aa parl nf the tourvinnnane sludy carrwJ nu( in the enb.e I mnnh I win ('uhurt
in 1915. 1 ater in (979 s Qurttn.nn]ire sent in the t..n) reared aparl yrelded a acalt (nnpe
/ 10 (v.inta) measurm the tnvuonmenlal distimdarities ftrr srpanl«.n (rluh,l.ty
021) Ihe r/fral of wparalu.n un perw.nalily factMs by analtan of varunie u(
uuh.idual data was audird I he ovrralt eaplanalMy rales we.r h..r (? (- 1 17,) 1 hr
drl:nurve stwly srnup .aa fMreed by selecling those pairs with a di.umdarily tan.r
prrovr than IS I he Lr11o..inR mt.aclaas cnrrrlalions wert nhlainrd
ARe al t+v.u[ cut) _.L---- - N-. .-.LS- .. . S/tA
srpa.af.nn M/ I// M/ I/L ML It7 M/ I)/ M/ /)/
OS IS 61 040 017 014 007 022 01R 004 000
0 10 t0 95 0 1S 0 12 0 23 011 040 0 19 0116 0 0?
I anpnvamm, 11 , Kaprio. )- Au.4rneun. At , and I nnn4visl, I
A. ro ("rnrrpnr a(rJrrnr r) Gr.wrll.dnRrw 1/ 759 764. t')1141
nrAtr .upp.ut Vr jn )ahnmann I oundal.on
Irom thr t)rpartmrMt of Puhl.c Ileahh r.ienae an,l Pa,huvy. Unrvertity of Ilrltml.,
1 mland
PSY('111AIR1<11OSPIIAt 17A11t)N IN ININ%
Itospilatinlion rate7 uf mnnMy~nt.c (M!) an.t Av1Ru1K (1)/) Ir.n pair) in I nJ..n.l
r'tre cUmparrd fM 1fhrllM~hltn/a, MurWr7, and a/iOhUlnm Rr.urdl.nkalte uf h...p...d
recnrda snd rkalh eerldicales IM the years 1472 1979 .at earneJ oal (or penrma m t.e
I rnnrth Iwm (ahnrl 06.649 hke-se.eJ Iwin paira) the 12160 of the numhrr i(
oh.erved n1 that nf 'e.peclyd ennonulaM pairn and the ratin rd cuncor9ance talrs
hnwten M7 and Dl pain were greater amnnA males than femate., and Rrroter amnsa
ynung (tn yesrs nId M ks.) than rnnnK oh/er lyirs The hiRhest diflrrence .as l.a.nd .n
fihitMphrtnia snd the hiwrat in nesenrrs Poir.i.r cnnionlance lales fM SchhryJ.rrma
(110% for M/. aMl 18% Inr hY) seem to indicate great environmenlal influence Ihi(h
pr.yunlum n( drtcordanl paira) with spparenl genelic IiaMfily (61-f..1.) ratno in
concnrdaect between MA and I)Y pairs7 In neurnlic diwrdrrs. the d.fference nf
p.n-x concord./Me rates bel.reen M/ and t)/ pans I611'Ik ra 4 0%) .as qurle 1nw, not
strnnAly surynrtinR Renelic hypolhrsis (N the ML pails enncMAanl f..r paychralrin
hn.p.lali.alM.n, 41% 1.2.1 tived InRethrr fow their .hnk tdt lime, of Ihme d.acordanl, 1t.t
fivtd h.aelher Ihe CorlespnMt/ng fi6ures tnr 1// paus art 18% an.I 15% Ihe ef/rtt nf
inlrapsir rela/innah.(n in disr.a enncMdanl pairs should IK Iakrn into accuunt when
evatuaung the effecl nf Renrlic snd environmenul faclMt in p)ychntric dis.udrn
Anr4rnrwr. M, I aniginvainio, 11 , Kapirio, 7, LonM)ist, ), and 1 irnari, P
A. ta Grnrtnrnr a(rJn ur rl GrwrrllnloItrot 31 171- 7)? , 1924
1 rnm the 1>rparlment or Public Ileat(h S.irnce M/ Deparlment .uf Phychialry, I/nivrraty
nr Uekrnkr, and 14parlment nf 1'sycbialry. Un;vers.ly of Oulu, Onln, I inland
SNORIN(7 AS A RISK I A(-tUR R)R IIVI'1 K11 NSION AND AN(:INA
1'1 (-1()R1S
the nan.ialiun of snormA with hypertensiun and ischarmic hearl diseast (1111)1 n
trNrd by (unlal quralinnnaire in a d.pula/ion of lAt7 nu-n and 1A61 women aRed 40 69
yeara Ilyprrlrm.nn as.nnated hiRhly sin.f.cantly ..nh snuring, 1M rrlaave ..ak 1RR)
u/ hyPertrnawn hrt..rro hah.lual smwers nd never aMUers LrinlP. 194 in n.en and 1 19 in
.nnnrn Ihn aaawnbnn was alan (nunJ .hen ad/utlin(a fm hM/y-n.aas .Mte. A
vpulnan/ aaakrat,on Irl.ren an.na Vrcluris and haMlual an.wmg .a. uhurrrA in mrn
(/tR - 7 2:) in .o.Mn Ihe rrlali.e ri.k was m./ a.RndicaM An sauK.atnm Lrl..rrn
t1..l.I/U..t 1M.r.nR Mt an1na (U'(IMra +n nMn was a14/ fUUMI atlfr ad/Ua1.nA /nr
h)Lrrlrrn.on and Moo/y maas indra (RR - 7111, p001) lhe rrlalivr .raaa /nr
ury.Ka.J.al in/arau.n anJ hoa17rlal dmis.mn fM //11) lor hah.lual so.nrta rrr.r
M.n-srRndKanl
A...lrnrw.. A/ rt ol
I
TAr f unrer (1)II'l ) 196. 1925
(hArr uwp(rntlht Medical Rrcearch ('nuncil, Aca.kmy of 1rut..n.1, and Ihr P.uvn
Nurmi IuuMtatiun.
I oom the t4partmrnls nf Puhl.c health Science and Neuruh.Ay. I/n.vrraity of Ilr/.ma.,
I inlaMl
('ANCI R S1111)11 S IN fWINS ANI) UAMILICS 01: -1 WINS
lhe aludy of cnncurdanct for esncer in Lin pairs can br uaed In raamine d.e rute of
hrriul.k la.lura in aanctr lhe I innish Ta.in (1.hMt - all like x.ed adull t..in paua
IM.rn hefine 1951 in I rnland .rilk IuNh eo-1urins alive in 1961 (n . 17,157 pairs) - ~aa
linked lu the I mniah ('anctr reiliArf data lo yirhl incidenl caaea ut cancer up lo MIII
%yRnarty was drlrrrninr.l by the vatnlaltd puestinnwaire melMN/ in 1975
A(o(at of 1,117 caaes uf csM-er was fuund in the tSOin srriea u/ to 1')RI amonR 1,IM1
Iwina. Mulrqk prima.) cancer was found amnnR 40 persuna (lA'4) Ihere .rre ?I1
A1/ pairs d.xurdanl (M eanetr nd 1s Pans m Whr.h Q.1h nurnlr'ra had caMer
(IN/1han1/M1se cUMlUdance rale . 1) Ylk) 1 the bY pairs there Were 418 uvcnr.lanl pauc
MI 14 enncordont paus (prnhanJ.ix eetwt'nrdam'e rate So 1? Nk). When cases ol how
mali/(nancy rrere t.clwMd (hasal ceR esrcinorns, rn altY Ylerine cer.1\ carrrM.nu, ur.na. v
6lxhler papilh.ma, trdycythemia vers aMl rnythrfrMnsrt) the (.Rurrs (or M/ I'auc ..e.e
1.` con.ordanl snd ln` d..cordanl (ralt 106t), srn/ far 01. paurs :1 concordanl anA 411
d.a.urdanl (ratt 1(1016)
lht analyah of concnrdanee indicates thst o.eralt heredilary faclors do not cnnlrihulr
much hw thr incidence of cancer It is in aecMdance wi/h the epi/em.ulnllic e.nh-n.e IM
the pemary rok or environmenlal facton in Ihe etia.InAy of most can.vr.
Kapr:o, ), Ana4rnew. at . leppn, 1.., 1-an{invainio, K., Pukkals, 1, Rila, 11 , and
Sarna, S
Itl
65100 7673
. In )nnrd.of (,onrre hI Inlernalional Rtsearch (unference, Rasrl r+Is, rr 101 -1'11
(KarRrr, 11asel, I00t1
Orher soprur Srternl luweGus luundalrnn
I rn.n Ihr I mnnh I.in (uhnrl Sludy, 14rarlment of Puhlic 1lcallh S:rtnce, I/nrvtrsrW
nl IlrLrnsr, an.1 /,nnnh ( ancrr RrRnl.y. IIAan\i, I mtan.l
i
ACTIVF. IROJFCIS
FnlAwing is a/isl of Ike principal invesliRalnrs, nr
institutir.ns, nf projecM under .ray a activated in /he prrnnl
since Ihe previuus Keporl,lnfeelher .ilh the rrsepeclrvt prnjecl
lilks ('ompkled projecss a/e listed in a laler seclion.
YRIN('tMl. INVFSTI(:ATOR
1)R INtillll/ll/)N
RO01 Rr 11 An/t IS, rllu
P. a/rm n/ Rnn A.nu u. r. Ih andt is
llmversily, Wahham, MA.
~Rt)JF(T I/ILY.
Ikve/npmenl of elas/ase inhihilo,s
I 10 c An(x)U, Pu t).
P.../rruw o( R..un Rr.rMCh onJ
RnwArnu,ur. ('rnter for Rrarn
Resrarih, Ilnivtrsny uf Rrw'Lusle:
Me.lical ('enler, Rocheaer, NC.
1)t)I Mt 0 AUAMS. M 1), Ptl I)
/ro/rrrm r/ PmhnlnRr. buke
I Inrversrly Mrdical ('en/er, 1)urham,
N('
KINNLIIIAOIIR,reb.
ArVOwt )4nfr,..w o/ PaAoluqrr.
Ilmvenily of Vermonl College of
Menln'rne, IlurLnRlun
)/NIN l At Ot'RS, rot I)
Rr.roerA Arr rntr Prn/rsar of
A(rJrrrnr. I/ni-ersily of Washinglnn
ScMw/ n( Medreine, Sealtlt
IIARRY N ANI()NIA/)1 S, IN D.
Prn/rl,d of Rn. tewnur y. 1larvard
I/nlvtrs/ly SchMlt u( ruhlr. Ilealth,
nnslon. MA.
111QMAS M AIINf, tn 1).
A.vUnn) Pta/r,vw n/ ParA.dnRr. lhe
)ewish 1luspdal af SI I oun, MI)
/RII AVIRAM,rulr
f)t/aanr.nr w/ R.urArnorvy. the
I.cu/ly of l.ife Sc.encH, Tel Aviv
Ilaiversily, Israel.
111 RNARI) M RARI()R, M 1), rot n.
Pro/rruw n/ NrArr rwr. New I neeland
Mrdrea/ Centrr Ilo.pilal, M,slnn. MA
Nicoline Iransfer-drslMSilinn in li.er ctlls
Rnk and rtRulaliun of prnlrin
pMnphurylalron durrnR mrcruphaRr
aNllvalnrn
Airway n,ucin srcrelron tffras of pnklu.ls
frnnt haetrria aaaarateA vnlh .Mumc
hronchihs
Ilifeh densi/y IiprMrnlrin quanldal,nn
Rintyelhes.a and p.oceamm of 1'1K:1 htr
pnlypeplnlrs in hunun rnalrRnant crllh in
tu11u1e
RirdnRy of Ihe lymphnkmt, s.duhk ,mmnnt
rrsponse fuppressor (\IRSI
Inlrrft.on ac(iva/wm uf supressnr I crll
palh.ays
lsulalion, p.nr.rUita anJ phy,aduR.. al
(unclurn of nrulruphd cyl,r hrrmrr A
S/udirs on Ihe mechanmm of aclr.arn,n nr
Ihe rrspirato+y hursl .n ntr/.npluk
Srrum mrlaRrns. ho.mnnrs, rum, ,..1
SAMI111. RALK, M 1), rot 1)
LMSfwmrn(genes and lumnr rrvtrsal rn
Pod.nhrt.u. New I nRland /reacnntss
IAJ
alMropria/e and aulunomuus rnnut.on of
Ilnspnal, R.nlnn, MA
cell rt,ln alu,n
PRtN('IPAt. INVFtiII(:ATOR PRUJ F('1PR'IP,Il. INVFS11CAlqR PROJf.(T TIl l E
F('1 111LF
(/R INStl/llll(/N (1R /NtiIIIIrIIUN
H111 S RI NNI 11.14111 Charscleriralinn of the plalekl lihrinoRen
Art.rrarr PoJrasw n/ MrJ.rrnr, receprnr
Il.npnal of the I lnavrrsily of
Ptnnaylvama, 1'hdadelpl.u
K1/ 111R111 D/N(i, M I)
Pr..Jraaw ../ Alr.l.rmr (..nrrrlva 1,
Ilnr.rrsdy nf Swlhern ( alJornu
5. Mnd n/ Mrdn me, I ns
AnRrks. I ra.nnA 1a.rn mrr ('alJnrnia
In.hanr ol 1 ra hnuh.Rt, /L. , rw ../
I .prrn.rnl.J ( o.Ju.l..Rr nnJ
I h r. l..pmr.u I lunlana/nn Mrd.cal
Resraa h InUnarrs, 1'audrna, ('A
Coronary ipatm, crrrhral microcircula..m
PIIYI 1 1% 11 111 AIR, Pn 1) RrRarlarnrn of nslural k.Orr cell aclivrly
P.../rn.n ./ /n.n.un.dnar I /navtrtily of
( aldurnra, tterarlry
11111MAi R 11RtIK 1 R, Pu 1) f'rllular uandnrmalu.n hy papillnma uus
.Aaa,rrafr I'ru/, a . of /ln.A,nv.frr, rrs.nfimanlt
Ilm.rrsdr ol Knaheaer nf
MrAwrne, Krrhrarr, NY
IK1Kt11/1Y I 111a( 111/A(:1 N, ly/ lr nn.....nr r.prr..nm .n Ir1a1 m.nu.r Inna
4 .uvrnnr Prn/. aa.« Clllr Irn..rra.rv ..l
New \nrk, I>r.+na..lr kIr.1., i11 enlrr.
Ibar.klsn, NY
VINCI N/1) 1111ONACCICI, M n Ilrparsn .aJlalr pm!rnKlycan, and 1Ln.,1
Srnnn S.rrnf.u anJ /1.-pn/ f4.rrl.u. W h..n.r..auu mr.haor.ms
Ahun fonn ('ell Srlrn:e ('enlrr, tnc ,
I.akr Macn1, NY
1OIIN W. R11ft1'It, M/) Cunbul of anchrdonic aeid o.ygenahnn in
Aluu'rafr AfrJnul fl.rrrfnr. Amrrican human ptalekts
Red Cnns, Rnchesler 1A.nion,
Rrchrtler, NY
nAVln I RIISIIFF, MI t) Pnlynuclear aromalic hydrocarl.nn transprnt
/'r../rssrM ..f tbvroloRr. lrut A3M hy serum Iqn.prolems
-Ilnivrrsily ('ulMge of Velersnary
Medn rne, ( ullrge SUlu.n
11)WARn I ('AMI'lll I.1., M 1)
A.usranf Pre/rluu nJ Mrdrrrnr,
Weahinff/nn Ilniversa/y S.h.ol of
Medicine. St I ovrt. MO
Mmtulalurs of in(lammalnry cell prnlrnllic
actrvrty
I AN Rl) ('111 N, Pw /1 SIUJ.rt nn human nsl cell carcinomss
A.a...afr P.nfr..... .'/ PmA..lnar
I.sns I S.IVr r.n. r. L....r..rr IL..1.'n A. n
\1rAIJ I<I.N1, I 111 N r/ /. 1'n /
r,.....r..r I'...Ir...,. ,./ 1..1..,. ,. a Ir.,\r
1/m.er..11 AtrJn rl I rmr. Iru.ham.
Nl
11--n-m 1)NA hrs 1n aasrss
r../ !,.. IunA , i:n. r
WII 1 IAM M ('llla tAN. P.t 1)
Assruanr RrsrnrrA Crrrnrrsl, Cardao-
vascular ('rnler, I lnwrssily of Iuwa
('u11rRr of Medre.ne, Inwa ('ily.
IX)Ia(il AS RR(X'K ('IN1 t, M 1)
l'rnJrss.u u/ AIrJn.n. llnapilal of Ihe
l lnivrrtily ar( Pennsylvanra,
Ph.iadrlphu
(l1K I I ('IVIN, M 1)
Aau.lanr rrn/r...n ../ On,..l.rRr, mrJ
I'rJnnN, a. Ihe )ohns Il.ry.krnf
lM.rdrKy ('rnler, 11a1hnvue, MI).
/:AKY A. ('LAWS()N, M 1), Pn n
A.anln.u I'..Jnun. IJnivtrtity of
Caldurma, San I rancisco
1
IIRIAN 1. CI 1 VIN(.1 R, Pw 1)
A.anrnnr Prn/raun n/ tlr.unrJ.rul
S.+rn.r. WashinRlon ltnivrrtily of
1)ental MeJamt, SI I ovit, MO.
('11AK1 1 S(: r'(1CIIRANF, M n.
AfrnrMr. IIrP.nrnn-nr nJ /mnruno-
PmA.daRr. Saripln ( lmrc and Retearch
I ounllalnan, 1.2 )olla, ('A.
KO111 R T W ('01 MAN, M I).
PraJrssnr n/ AlrJrnnr. Iempk
Ilniverv/y tichnnl of Medicine,
Phda/elph/a, rA
I VA RR(rivN ('RAMI-R, P/I D.
Asaurafr Pra/ra.n n/ Anannrr end
('rll RuJnRrr nnwnslale Medn:ai
('enler, nronklyn, NY.
('AR1. F CR11FT7, Pn 1)
A.v.fent PrnJraarn u/ PAa.mor.daRr.
l/nivenqy of Vr.Rinu Sahutrl nf
Medicine, ( ha.lullrt..lle
(:IIXIN ('/AP\K 1, M S<' , PII 1)
Prn/r t..w a/ PArvrnl /'Arno vr r. l he
Ilebrevr I/nivenity, )rrusa/em, krael
IVAN DAM/ANQV, M 1), Pn D.
ProJrtla o/ PaAoloRr. Ilahnemann
l/nivertily School of MeAicinr,
Phdadelphis, PA.
AI,ILR1 e nC1SS1ROt1/,M1),Pw1)
Pru/rts.w u( M.J.rrnr, Velerans
Adrninislrahnn Mrdnal ( emer, San
I lallcrKU, ( A
PalMyrhysinhaRy of Ihe curonary miarn
l'Ircul]Inrn
Immunr injury of human endolhr6al .el1.
Ilinchrmi,lry anJ fvna'ibun of human
flranuMqunrtic an/aRens
Nuclear NfPau and selective KNA
spIrrrnR/Ilanap.nl
Role of I srRmenl rn V srRmenl r.prrsta.n
Mrdialion tyalemt rn inflan.matary IunR
diteate
Initiation of plasma cua!lulalmn and kinm
(orming sytlemt in man
Studiet nf inflammalirm usinR an rn nr.n
nuulel
Role of prntein phnsphnrylalinn in
nico/ine induced ealechullmmr rrlease
Role of metal iunt nn su(.rru.rdr aral
VMamin l' lo..u i1y in badvar. al tvsarms
(ytvelopmen1a11y pluripulenl human IunR
cancer slem cells
Study of allereA alpha Rlnhm genet m
kukrmia an.l snlnl Ivrmut
11/
PRIN( 1PAt. INVktiTI(:AfOR
OR INti1111/11(1N
P/ 11 R 11 1)111 11111 R(:, Pn t)
F.n/r.aw n/ Ahdr,ufnr RnIner,
Un.vrraAy of ( ahfurnu, hrrlrlry
IIAKO1 1) 1 1rVOKAK, M It
( Arr/ fl,~.Im..u n/ rarA,I,er belh
h.arl (ln+prtal, huatnn, MA
V (:INI IRWIN,PnII
Prn/r...v ..J rA,nn.m.J..R r !l. en
I/n.vrrHly of ('olu.a(1r ScMwd uf
/'b..mary. !u.uhMr
AI VAN R I I INSI/ IN, M 1/
Prr/rr..w n/ AlrJurnr nwJ / p.Jr
nu..l.rR r\ ale I In.vm,ly S& h.r,l uf
Mrd,c,ne, New Ilaven, ('I
111f)MAS 11 11N1 AV, Pn 1)
A.urrwr P.n/rr..w n/ OA.Nrnrt anJ
(:L.rnJ..Rr. New Yo.k I/n,.rrany
Mrdnal ( rnlr., New Vnrk
PAI II. R 115111 R, PN 1)
Srennr RnraN A t.ur unr n,1.Vl.nrnt
o/ A/Y.rnA.u6.er (ulumh,a l/nwtrtav
('.dlrytr .d /'Ayaaum A SurRrom, Nrw
York
1l)SI PII A IYINTANA, M h, Pn h
ArvVOnt PrnJrtl.w nJ AIrJ.,rwr onJ
llurArnnVrr, Weat Vuooin,a Ilmvrrtily
Me.hcal ('enlrr, MurRamuwn
1111)1111 ANN I()511 R, PII I)
Pr..jrsvw anJ ('Aavprru.n. !)r(orrmrnl
n/ Rrol..ar. Syracvae Ilniverfity.
Syracvte, NY
KK'11AR1) R 1(1)(, M 1)
.4t+rvnM Pro/.t.nr n/ PrJlnnrrr,
( hilJ.en't l!n.p.1a1 ( .u(w.ratn,n,
Ih.aun, MA
IR W!N I RI!N)VI( 11, Pn 1)
Pr../:..n n/ IN.+Arnuu.r. Oukr
I/nwe.+.W Med..a1 ('rnlrr. I)urham,
Nl
I NII LIU N.. ~t lr
I/tNtfl 4
r...:..; .. .: ~ ~ .,..
PROll ('/ 111 LE
lrantfn.min[ genes of two acule Ieulrrn,:
va uaet
PalhnRenetia of lumnr dmm~pl).,~
Effecls of nieotine nn neurnl.epr,rtr
secrrlinn by .nlacl muuar Mam, a
pharmacnaenrt,e s1oAy
Smok.nA, drleclwrn h.aa and la.mary 1uuR
(aM r1
S/rvilurr, prnprrlirt and reaulaliun nf
mnuar pl,+ma Prnaa.r .nh.h.Inr+
('hrma.il vual mlrra,l.nna in rrlt
44311a10m3tron
(aycosvlvantfernus anA Rlycnprnle.n
)ynlhnia in ddferenhition .nduceJ
phrnntvPlc reeli! nf maliRnancy hy
reun.nW ainl a ycl.c nuclr,.tidrf and .d.rr
aRrnls
Invulvrment of ela.tin f.hert in IunR d..r.lar
Rrde nf AlyeotsminnKlytam in IunR c7enu
('nnl.nl of the hlntyn/hevS u( tuhrrn..Ir
d.+m W aae.
( ..,oplrmrnlmR hum..n rllt +n1..I.nr1
~ . , I.N~ ../.,.. r
PRtNCIPAI.INVESTICATOR
OR INS11f1/T1(fN
K)tl l. fU%f., M D.
Prn/rssor n/ H.aolaty. The Katolinska
Inslitule, Stockhnlm, Sweden
1AM1 S W GAIIRA f 7, PN I).
.eruVOnr Prn/r..,w n/ R.nrArnnary,
I/nwersily ur Snulh Alabama, Mobile.
JA('K GA1/1 OIC, Pn 1)
/'.a/r.tnr of Pe/A.A..ar. McMaster
(lnrverfily, 1lamdlun, (Inlariu, (*anada.
/ 111 RNARD t(a 1, M 1)
Prn/raor n/ AIrJ.r.nr. Yak Univeuily
Schoul of Medicine, New Ilaven, ('T.
I
('11(lU 7TN CIAM, PR t)
Pa.W.wrwel iefl..w National Insli/ults
of Ilratth, Re/hesda, MI)
JACql/1 S F. (:1f 1.1'N, PR 1).
Atsnrrar Prn/rsuw, I alrrafnrr o/
AlrJrral CArmr.In. Toorr.foRr aJ
If rRrnr. Invuulr ,.J Paf holnR P.
University of LieRe, l.ieee, Relgium.
(a7RU)N NCI SON (111.1., M D.
Prn/nsnr n/ MeJrrinr. l/niversily n!
('alifornia. San 1)irgn, I a lolla.
GARRITI. C GOUMAN, M p.
Pra/rstor nJ PafA..f..ar. Columbia
Ilniversity ('olktle nf Physiclans A
Suroleont, New Ynrk.
WARRINM.Cn1.U,Mh
Pro/rssor of AlrJrcrn.. Cardinvaaular
ResearcA Inslitme, Univtnily of
('ali(urnia, San I .ancnco
A I 1 R/-1) 1/:( )/ 1)111 R( 7, PN t)
Prn/rr.w ../ PAr.n'L.Rr l/arvsrd
Alydi:al ScM.ul, /lutlon, MA
Sl/)NLY (i(11 f)/1S('111 R. M 1)
Pro/rur oJ PaAnlnRy. Albert finslein
Cotkge of Mediane, lhe Rron., NY.
W11.11AM I (;l)1 IIMAN, PN 1)
A.+l.fan/ Prn/r..w n/ AlnrolnJnarrmJ
/.ww.un.L.er Waahmjln Ilnrvnvly
\. h,nd u( Mrdn mr, SI I uun, At/ /
PROJECT TITLE
Nicotine, calecholamines. and
11eurlKndocline funcln.ns
Srnnking, .h.namine, neurnlwpthdri and
nwwkh of Park.nate't disease
Dhecl demonslralion nf h.Rh affimly
druR- l)NA ImrrKlioat by restr..h.,n
enayme malMing
Tht mast cell In inlerstilFal pulmunary
f IMmn
lissut matri4 and phaRncyle rnjury
relativt euntr.bvlions uf pruleasrs and
oaidants
ImmunnRbbulin enhamrr elemenl, in
lissue tpeeific tene e.presuon
lowards a mnlecular u/n/rratand.nR of
ww.n0n.y{enau reioulalnry mechan.+ma m
anitnals and man
1 pidrrmal 8rowth factnr receplnr Renr in
epiderannid carcinoma
('yh.skektal orpniral.on uf Ihe endnlhrlul
cell in rtliulali..n of sh.M cuntractd.ly and
tarface move/nenl
IYfrcl nf ozone on airway .naal cella
Seleclive delora,hlinn 1.( d.,n.Rrd Irllub.
prutrin.
( .Iracrllular malria cylnchrm.slrv an,1
YllratlruclYrt
hnrdrlrlla Oer/uttif Ir~acheal .ylnln.m
G5100 7676
.
PRIN('IPv(1. INVFCfICA1OR
f)R INCIIItI11ON
('IIARI FS S GRI f NRI R(:, MO
Ar.rqwr Prn/r.lnr n/ MrJrrrnr. Duke
(tmvers.ly Medn~al <-rntrr, t)urham, PR()JE(T TtIIE
TransRlutaminates anJ alhrrnscletnus PRIN('IPAI. tN V ESl /GAIqR
I)R INS1111111UN
SIMnN K AR PA I K IN, M f).
r..r/n..w of MrJ.rrwr_ Ncw Ymk
Ilniversity MeJi:a1 ('enler, New York
N('.
N()111RI W KARR,M.1)
MARK I l:R 1 1 NI , M I) , Pw 1) Suppresfor cells in .ynRrnrK lumur Atuunn( l9a/rl.... ../
AlrJrrnnr,
Ihrrrlw of l.ww.uwnM,.lner 1/ni.ersny immunily Ilmve.siiy .4 1owa, luwa ('ny.
n/ rrnmylania, Phdi.klpMa
S111R1 1 Y 1 KA1111 MAN, M 1)
N(11t11Y(KI11 IIAGINO, M 1), Pn I) NKolinic receplors uf 1111t11 a.nn I'ro/r..,w w/ PnlA,daRr Slate
I/niversily
J'rr./ra.r of An.wnn.r. I lnivers.ly of termrnals in the medun rnaneme wf New York, Ih.wm/ale
Medreal
/rsac tarallh icvnce ('entnr, San ( rnler, I/..wAlyn,NY
A nl..nut NKntanr on prolachn srcrelion in
de.eMpmenl IN(:'(:1Rt)M K11111,Pn1)
A.uvn..r Pra/r..w u/ Awanmr,
(-AR()1 INI R IIAI 1, M/1 Inlrrrel.tinnship nf infectinus Mwrr Itm.erany of Wncnnun School nf
A...wrwr Prn/ranr of IrJ.anvt AnJ rrap.ralnry Iracl d.sease in mfancy. aml VHermar) Mrd...ne,
Mad.son.
MrJ.nwr I ln..ersdy of R..chester Ms1 anJ ewvitonmenlat facturs In laler
5& h,.ol nf Med«.wr, R«hrarr, NY .k.ehy.mrnl of chrnnie lung d.sra.e III INI KO1/1 / R, M/), rll
l)
1 fhrrrhw, llryw.lwwwr w/ Af.drrr/M
I INDA M/IAI 1, ru 1/ (:rnrric ddferrnces in nicmine sen.m.ur lnw.unnlnRr. Rnawell Park Memoral
ArlnrrNr P.../r..w of (:rwrlrrt r.J .n JI.n...pAda w.rL.wnpnhr %Irams Inaldule, IluffaM, NY.
NrMw\rlr/Mr Alberl I .w.lr.n ('o11eRe
of Medicme of \eah..a I/n..rrsdy, Ihr
1lrune, NY
1'A111 IIAM()CI1, M 1/
A.rnrrNr Pro/b.rnr ../ PAr.n.lner nn,l
Ru.pArvr.. awJ ahJarnr Grn.Arlnrw
IlnivenNy S.h.w.h of Mrd.:me anJ
ttentnOry. Washinlh.n, 11l'
RONAIDC IIARV/Y,PnO.
Prn/rs..w n/ ArRnwr. UArwvury, The
(/nrversily uf ('hica8o, 1)
RO111 R F M 11011 MAN, PH p.
Alvura Prn/r.rw aJ rrJrdncl rn
RrvJrnrr 1/nivtnily of ('alifornia
Schnd of MedKIM. I a Jolla
WAYNE 11MS, PH 1)
Aslocr.rr Prw/rtt.w. ('enter for nrain
Research, tlniversily nl Rochesler
Medical ('en/a, Rnchealer, NY
Qt
Ln RI('l1ARt) 1.. 1111rANIR, PH I).
l+ Asovew( Prn/rrrnr Ike Kocke(eller
~ (/ni.ersily, New York
m
I/AROt 1) P)l)NI S. Pn 1t
A.vUen/ Prnfrt.m nl RrMwuurr,
Ilm.r...lt u/'\nult. Al.dnn.a, M.J.dr
h1t IN 1(1\ 1 K A N N/ lv',N \ M 11 , Il l n
I/minn, MA
/la.,rHle smnke an.l hry.prnle.n rrm..,lrhnR
hy d,e lung
Novel anlicarcinotenic eoumarinm and
f la ronn
Melhionine depemlenee, methylal.nn aml
o/tanK Irans(ormaliMm
Regula/ion of cellular oncntenes
Sludws of nicnlinr inlrraclion w11h h1aMI
crlls
lhe nicntine acetylthotinr rea'eplor
regulaliun by protein plwspM.ryla/ion
Cak.um dependent rejulalory prolem. aml
neubnphit activalinn
/1.r nwtr. ala. ba..t uf p.Am.ma. y
vu,lj, I.n/ tircrrlmn h/ lylw 11
pnr..nNM yl- tlu.l.rt .n m1ai1 Crll..lnd a
.rll Ler.y'lr.n
MARKKU K(XKFNVIIp, M D.
Prn/rlvw and CAarrmun. f)e/wrtwrrwt w/
I'wMrr llroJ7A Srrrnrr. I lni.ersily of
1lrlsinki, 1lelsink., Hnhml.
A1111. I.AJ111A, PH O.
Anrrrar. New Yo/k State Research
tes/r/ule f.N Neuruchemiftry and Ihlq
Addiil.nn, New Y.wk.
F. ClIN1ON 1 AWRFN('E, M I). .
Aaruen( Prn/r.uw w/ AlrJlrrne. Raytnr
Colkgt of Mediclnt, Ilnuslorl, 1 X.
VAI I.RtI' K LINIK:RI N. PH D.
(Jwu RnrarrMr. Nstwmal Cancer
Inslltule, Itelheada, MI )
7V111VN111, PH 1)
Saurnrn.r. Ike Weirmanw Inslilule of
ltrrn(e, Ke/mvol. IsrNI
1//SIP111) 1/KKIR,MI),Pn1)
A.uUUwr rr../...,w n/ PmA,dnRr and
RwrArmr,rrr. 1lmvenlly of rdlshutAh
School td Medicine, r.NSAuqh, PA.
RhNA1 I) R 1.111 1I(7, rn I)
Prn/rltnr ewJ Ifrnd I)rpsrrw.rwt of
MnruM.dner nwJ Imw.un,.luer. I SII
MeJwa1 f'enlrr, Nrw /hlr~nt, 1 A
PROJECT T111.F.
1 he rolt of plalrkts in Iumor cell mr.ad..r.
IMveQ.pmenl am) Ji7(etentiathon u( nu.uc,l
and kulemic momaylra
Oncngenes in chemw-al car. mogrnrus
I unR neuroemkKrine crll
hlulli larpeling with hybrnhooas un Iun.no
eells
lhe Finnich 1 win ('nhml 1 ullnw
un Stud\.
Gene/ic basil for nicotine reslwrnte
Fffecn of ciRare(te smokinR on
imrnunnRbbulin prnduclmn by human
br.wehial ly mpln/e ytes
Vital and cellular faclnrs conlu.IliuR
papittomaviru. transcr.pts
Meekanism of S O S tn..r prone .rp..u
1)NA melhylaniun in nr.qdaa.a
Inlrraclarns belween RNA vi.u.rs anti
ehemual eaccin.n{ens
rRIN(-IrAl. INS-/ l l lf: A 1(IR
I/K INti11111111)N
KtINAI Iy / 1 I IK At, rn If
hn..t.w lul.w.n...1..1 N....n
. A.nr.u 1 CI /n.rpha I ln.p.l d an,l
Mrdr..d ( enlrr, IYu.rnt., 17
IAN M I IINlthl K/:, M 11
et.rtl.nrl I'...Jrt..w ..J l'A.nmrnv.l..cr.
Karubn.\a /n.lrlulr, SU..\ho1m, S+.'drn
/11 NKY I 1 YN(t1, M 1s
on/ f Ao..mnn flrpnrr.n.nl of
l'r .rnlr.r Ilr.h. r.w. nw,/ PuAhr
IlrnllA. ('rrrrhlan Iln..rnny S.h.r.l nf
MrJnmr, I/nr.rh.l, NI
I1K1t( I A MA( 111 K, 1u Is
At.r.hnrr r.Jrt.... nJ /'h.rrwrn.rWn.d
I Arml.trr, I/m.rrvly rd t.hln.ma.
1.n / rsn.... u
IIIIWARI) C h1Ah 1 K, M It
A.... r.nr I'.n/r...w ./ Nrwolqa.
Muunt %rn.u 4h.rd .1 MrdKmr, New
%n111
KIt'/1ARls A MARK 11AM, M 1)
(t.Nnwl /r,.J. tsw of AI.J..nrr nn.l nl
Ah....Fu/.Ar nnJ fwr.rnw,I,.Kr t he
)rw..h Ilu.pdal r./ St 1 nu.t, htly
WAI I A('1 1. Mr'KI I IIAN, 1'll s)
J.-nnw Srrrnusl W Ahon lnnts (711
Scanat ('rnler, Inc , I a4 Pl..cnl, NY
AI AN C Mrt.A11GII1 IN, Pr11)
I rrlwrr tn Rn./1Mnvvrl unJ Hrn
pArart. Ilniarsily uf Pennsyl.ania
Srhnnl of Medwint. PAda.klpMa
5111.1 .A MtIRAN1-ROSFNI/AI/M, r/r Is)
rrn/tstnr of I r.nfnar. Ilrh.ew
l lnrvrraily Ilada.uh Mtdn'al ScMrd,
)eraukm, Is.xl
11 R111 MIIRAI), M 1), Pn 1)
Iro/rts.w ../ AlrJ.nn.' anJ IA.rn.a-
culrRr. Slanfnrd l/ni.ersily, and fA-/
n/ Afrdr. nr. Palu Alu. V A, llmpn.d,
SlanforA,1'A
ON
Ln ('11RIS1()PI11 R MIIRI AS. M t)
N /tv.lunl Irn/r.uw of AlrJprwr. (Ini-
t9 wrsily of ('intmnalr. (111
0
J
~
J
00
1AV A NAIs/ l. M 1)
Pr../rtt.w nl U../.. rw. Mrunl.cr r 1w.l
RaJnd.el / a.dw..aa.nl.u Krar.u.h
lat/nulr, ttn......lt .d 1 aldu.rua. \.u
I r am r.a n
PRI1J1(1 1/11/'
Influrnret of ni..dinr on nruranal
raprraw.n nf .ICelyhludmr rrirpl.,r.
Srnwry neurnrephdra and annke mdu rd
i.rqalOn Of the Ir.pa.llory 193,1
GentlK and hinn.a.\er abtlirt uf %
an.rra
of Ihe rr.piaalu.) rancrt:.s and
urna.y Llathler
('hrmnlry and hrnl..ky of cnmplr
a'aMhydralrt
Nnnl.nr aclnln nn hr:rln nrurnlran-nll./.
an,l .n an anna.d m.wl.1 n( rar6m.MU'a
th\raar
I tell rnedrilyd unnnrmlv m I'.ru.lnnr.nn.
u..ur.nn.o
I nd.nnnr cnnlr.d ..f Mun7n en.Inthrh.J
cell .eRtnelalnm
1nlrnclinn of di.alrnl caln.na with m..I.1
and hwhM{ical mrmhranes
Mokcular analyait uf human Rtni/.d
papilMms rirus
Mrthlmam of nilrir n.rde acl..aln.n of
Ruanlla/e cyc/att
Rok u( cri'lic (iMP in im.wHh mut.lr
felaa31i0111
f lrcuomechanical properlies of ar.w.ry
musck
Mrchan.amt of luway hyperrranwdy
r
PRINCIPAI. IN V FSTICATOR
OR INS11111TION
SUSAN NAYLOR, Ptr D
Ala..nalr IroJrssor of //wna"
Crnrrtrr. The l/nivenily o( Te.as
Ileallh Science ('enler, San Antoftio.
I)ONAL1)1 NfISUN,PRD
Aarnrrolr l'r../rluw of CArrnnlry. Clark
llmversty, Worcesler, MA.
St ll'AN Nll'WIAROWSKI, M D, Pw D
Ln/rtlnr of PArvnloRr. Thro/wbosis
Research ('enter, lempk t)aivenily
Schonl yd Medicine, PhISdelphia, PA.
JANI I M 01 IV/ R, Pw 1).
/'rn/Ial/n of PulAnlner. I/niveftlly of
New Mteico School of Medicine.
Alhupuerpue.
1' WILLIAM ORR, M D.
AtanrlWr Prn/rtlor of L/Aolotr. l)t,i
vtrtity r.C Manilnha, Winnipei,
Manilohs, Csnads.
v(K1u0OSAWA PII D
Hrwl. /Hparlnenl of Endnrrinr
Rrru Armrarr. Medical I ouadaliorl of
Uuffaln, 1luflahr, NY.
RORIS M r1'1 FRLIN, M D
Alutrrw hn/rss.r of Mrdinwe. Stclinn
of RhrunntnlngyClinical tmmoenlnAy,
Ilniveraily of ('slifo.nia School of
Medicine. Sa. 1'ranclseo.
I/FNNtS R PETFRSFN, Psl D.
Pre/esurr of rArn.erwleRr, l)wiversi/y
of Cokw.do Schmd of Mlarrnscy.
Ib.ldee.
f.IX:AR PICK, M D, PR D.
rrn/naor of hnnwwdefl. lel Aviv
Ilnivenily, let Aviv, Isrwl
%ALVAt/1K1 V P/7%U, Mb, Psl /)
Asnr.rr Prn/rtanr of PNAuInRI. 1)utte
l/nivtnrly Medical CerNer, Ihfrhann,
NC.
Jl/L1A M P()LAK, 1)St., M D.
Srnrw Leclwrr rn HrVnra/Aolol y,
Royal Poslgraduau Medical School.
1lsmmersmilh Iluspilal, Londow,
1 nffland
WILLIAM A PRY(1R, Par 1)
eorJ rrn/tll.w of ( Mmru.Y l.ouitiana
Slate Ilnrversty, RUon KouAe
PROJFCT TITLF.
Mokclrlar and genelic snalysis of smatl cell
1ung csncer
Calmodulin inleraclions with ur{et
prMeins and synaplic vesicles
Platelet inkraclinw wilh (ibrinngrn and ilt
siRnificance in he1110\taait
Rrgula/ion of the memhrane o.idase nl
humu polymorpMmuclear ku4naylrs
Ruk of Inca/ faclnrn in putmonary
melnutin
Arorna/ate inhibilnrs in ciRarelle 7muke
and lobacco
RillbAy, and molecular biology of Ihr
differtntialion of a human mumrcyhnd cell
line
Ilnpkrnenlalion of the isntated perfused
liver Ms s(uty nicotine fnelabolism and
ruelalydie inkraclinns
The biochemical basis of enhanced o.yRrn
radical produclinn by Iympl.uMrne
aclivased macrophaRts
Prnttssa regulaUon and ellular mrl.dwdr.m
laveslillatinn of Ihe fok of rtRulalnry
ptMides in hunun lunit dneaae
frtt radical ahemit/.y of a.anene unn/r
191
PRIN(YPALINVESTICATOR
01111 INSf1f111/(1N
MICIIAII. S RARSON, M 1)
Rrtr.rcA Srrrnrru. f.oMrmnr e/
rorholnRy. Nalional Cancer tnslrtule,
Rethesda, M/)
RAMI RAIIAMIN(N 1', M D
Pro/rsrnr of PArstofoar. Ilebrt.
'llm.ersily~lladasa.h Medical School.
ferwalem, Israel
T1MOl/1Y f RF.GAN. M t)
Pre/atr e/ Medicine. Orrrrrn.,
('rJrnntrr/er
Drvnrow of
fh.rotrt. ('o//eae of Medrerne and
Dentistry of Nerw fersey, Ne, hray
Medical ScMwd, Ne-arY
1OIIN F. R1 PIN/., M D.
Attr.ronr nrrrrrnr. IIrAA.M'ormt I uwg
Intrrtrr: Attonarr Iro/rnar of
Mr[irw. l/ntvenily of ('olnrado
Ileallh Scrences ('enter, Iknver
ROIIF.R1 RFSNK'K, M D
Ar.nrrar Pre/rstn, of RrproJwn.r
AfeJrrtnr. l/m.rrsAy nf ( alJornn
Medical ('enter. San thran
VIRGINIA I RI('lIM(1NIS, PM I)
RrverrA A-tsonWr. Pacdre Norlhreal
Research 1 nundalrnn, Sealde, W A
Pt1FRM ROSS,Paf)
RrvorrA Atsnrterr. lhe Roc\efeller
llniversiry, Ne. York
I/NA S RYAN. Po D.
RrsrorrA r.n/rstor of M.Irrinr.l/ni-
venity of Mtarni School of Medicine.
Miami, f (..
PRAIIMI P. SANI, PH D
Nr.I. Irorrrw 1rnrAren.rrr. Southern
Research Institute. Rumtnshatn, A1.
RFGINA M SAN111 1 A, PH D
Asserrrr Pee/estur n/ AlrJrrinr .nd
Fnetrownwntof Snrnrrs Colutnbia
llniversily, Ne+ Yotk
nV RAMASASIRY,DSC,PMI)
/'rn/rruw of tAr.n.oroLee. Vanderbilt
ISr h.r.l of M..L.
r/..h.r/lr IN
PROJF(T TITLE
Anatysis of seQuences required for bovine
papoloma virw nansformatiua and
autonomous pwmid replication
Iturnoral effects of smatt cell carcinoma of
the lag on ae.romuscular transmission
Swceplibilily of arrhythmias and
caletlqta/11iM raelabol/7m in chronic
snwt ins animals
Basic /Ilechanisms of lun( injury (rorn
inhaled oridanls
ihe effect of nicoline on uterine and fetal
card.n.atcular hem/Nl)namKs
I latthr frbrr miaofihrillar protein suurtu.e
DNA damage and selective mainlenant a of
animal senes
Inleractions of hormones arith cells of Ihe
pulmonary vascular aR
Selenium binding proteins
pe.rMq.meM of monncbnd anlidr/irs lu
earcrnotlen ItNA adducls
Maernal smo\in(} and blmd eoncenvations
of alnlnn ac/dt in un1611Kal arteries anI
.rms
Influrncr nf nao1rnr nn Ihe rrMew nf
a.rtlvlthuhne in Ihe human platenta ...4 tle
uopln atum nn the fetal Irn..lh
144
I
PRINCIPALINVESTICATOR
OR INSFITl1TION
CIIARLFS 11 SCO(:GIN, M D
Nra/. Drnuon of Clinical ApPlrcaient;
Assenarr he/nsor of FfrJrnnr, l/ni-
arsity of Colorado IlealtA Scieaces
Ceaer, Iknver.
RORERT E SCOTT. M D.
Iro/nsor e/ laAoloer. Mayo Clinic
and (oundalron, Rocltesler, MN.
IIINRY SFRSIIFN, PH D.
RrsrrrA Srernuv !V, Neurochemislry
1>tvision, Nathan S Kline Insti/ule,
Ward's /sland, Ne. YorL.
ISAIAIIII S11FC/111 R, PH D
Senror 1-rrtwrr rn RrorArnrrtlr]., The
(:entle S. Wise Faculty for Life
Sciences, Tel Aviv Universily, Tel
Aviv. Israel.
RORFRT l. SKLAREW, PRA.
RnrorrA Auorrae Ire/rtsor ./
rarAetoRr. Ne. YorL Uaiversity
Researth Service, Goldaeater Memorial
Iluapital, Roosevelt Island. NY.
K FNI)Al.l. A. SMI111, M D.
tre/rssnr of AfrJrrinr. Dartmouth
Medicd ScAool, Ilanover, NI/.
STFVENS SM11/1,PwD.
Artruw RrrrarcA Srtenrife, ReeAnlaa
Research Institute of the Citr of Ilope.
Uuarte, CA.
TIMOl11Y A. SPRtNGFR, Pt1.D.
Atsb/au/ Iro/rsro. e/ IerAolofP; CAir/.
Lalltrarwr of Mewrba.e fwrwlww-
rArnasurP. t>.na Farber Cancer
Inslilu/e, Roslon, MA
FRI(' 1. STANRRIIX:F., PH D.
Atserr.rr Pre/rtrar e/ Ahrre-
Moi.Ry. Itni.ersily of ('alifernia, Irvine
NORMAN C STAI/R, M 1)
/ro(esser el IArsrnlerP. Cardioeaseular
ResearcA Instilute, l/niveesity of
('alifornia, San Francisco.
DANIEL STFINRFRG, M D, PH D.
Ir./rsser e/ Mrfrnnr: I/eo1. Dreruon
of Mrrahulrr llt.ratr. The (lnivrssily of
('difnrnia as Sen Drego, I a fulla
PROJECT T/TLE
The so.utic cell genelics of lung cancer
Conmiuwenl control and carcinngenesis m
norwnl, preneoplaslie aood rnalisnaAl human
eqlhelral eelb
De.elopwtenl of an anireal model of
hrEssow's difew
Effeel of lhiols end disulfides on
cholesterol metabolism
Cylobinelics of heleroploid subfr.pulattuns
by iwuging
Disseclion of the eularyolic DNA
replicalion palhoway
Sekctivily of I)NA melAylalion in normal
and owcollenicdly transformed cells
Studies of wlacrophye suhp.pulatiom and
differeaialion rsinA monocbnal amiMdu:
Transfer of specific indivittual human
ehrorllMOrnea 10 reerpKM cella
A/veolarair.ay barrier permeability to
liquid and rnacronrokcules rn My anA
sheep /uwg
Arterial degruLlion of In. densily
tipoproleins .n eree
193
tRINCI/AI. INVFSTIGAT()R
OR INS11111I11)N
l llOMAS P S1lC)SSI-1 , M f) ,
(-Arr/. Afrdrraf (pwrnlaty frwrl. Maf-
sachusrns Grneral /lmpnal, fbsn.n
I 1 1 11R L. Sl RANU, rn 1)
P.n/rlrnr of R'alntr. Nr. YocL
Ilni.enily, Ne. York
n LANStN(: IAYt OR, rn 1)
Pra/rlror of Rra/oRr ('arnesie- Mellnn
1lniver.ily, 1rttsburah, PA
1(Kt fll ('11AR1 1 S 1 AYI ()R, tn t)
Al.nrra/r RnrwrA,C.vwnv ('cty of
llryr Resrarch Insl.tulr, 1)uarle, CA
1(HIN A. 11N)MtSr)N, Pu 1) A.uwrar Irr/rlrnr o/ I'Aarw.arrvrral
( Arwonfry. 1 tni.ertAy of ( binrado
S. hrrd of rhar mx y. noulArr
WAYNE M 1R111111N, M It
NrpA.dnar.l. RoRtr Wdl.ams Central
Ilrspnal, rrn-denee. R/
I MII. R I/NANIIF, M 1)
('Aaurnon awJ r.n/r.... /)rrr of
lemA..lnty. WathmRlnn Itnr.trtdy
School uf MeJrcrnt, S1 1 oua, MI )
NAR0/ 1) E VARMIIS, M I)
lYn/r..or e/ MrunFr..lntr and
lw/wruwnfntr, Itniver.rly of ('atdnrnu,
San I tancnco
IIEI FN VAN VlINAKIS, rM D
PraJesser of RrnrArnrrury Rrandeis
()ni.ertily, Wallham, MA
7R1(iN11 W WAI AS71 K, rn 1).
RrvarrA Sr/rwerU Ohw. Slate
Ilni.trtily, ('olurehus
IV11 YN WA1.1)SII IN, Pn Is
Srnrw I rrtwrr. IMparlmtnl of
RMwhernltlry, leI A.I. (/ni.enily, lel
Aviv, Iuarl
rFtFRN WAtSII,/nh
/rn/rtcor n/ Mrdurwr lemp4
IIm.eraily 4 M.d of Mr.ta.ne.
Phda.trl/.h..
1'1111c A Mis N1/ M1.
)...l.r... ...r r ~... +.... l..r...+..... r
Ann 1.L.r
IRO)F('T TITLE
f unclrnnaf anatomy or the lung macrophtRe
rrenalal and postnatal effec(s of nicnline
and ACTII pep/.det nn MYlomuscular
de.elopnwM and nmotor hehavror in rats
ChensWaais of macrnphases
Ce.rMplsmin abnormalily in chrnnrc
oburuclive pdnaenary disease
Chromatographic uparalion and
cnmparalrve metabolism of d and
I nnnl.nt
1 he rffecH of rtnal function on niroline
nw/a/h.hrm
f'/hy.u.parhol..ay n( nnrmal amt aclrvaer.l
ma. r..phaart
/ uncln.nal analyvs nf ctllular nna..trnrt
aco.aleJ durrnR IumnrrRrnetrt
Purification and properlies of a toluble
NAI)IP) glyeohydrolase isolated from the
spnnge. M pralr/rra
Yntrnliat for IunR cancer prevenlion hy
inhrbrting dt .1tucwonnlalmn
Rrpau ae/iviUrs foc Ut mnhyttuanine
I)NA adductt in human lymph.kylrt o1
tmoktrs ./1 nommuAers
Inleraclion of plalelels wilh eoagu/alion
fulors IX and X
Ir..apn (.rr rat)ntl., rmn.unr
,..... .lr.r. and ht.ur rnpuy
196
1
IRINCIrALINVESTIGATOR
OR tNSTII UTION
GFORGE WEINBAUM, ht D_
Altntawt CAauwsow /or RrsearrA,
Drprrwvn of Mrbnnr. lhe (;rad.ale
/lospilal, Philadelphia.
SAM1111. B WI 1SS, tN 1)
ro/rllar of RrorArwvnlry and Mrrra-
MdtY. lhe Itnivertily of Chicato,
('hicalio
11OWARD G WI'I.GI /S, M 1).
Arv.ennr hn/rrur n/ Mrdrerwr. Ie.ish
/lo+piul at WashinRlon 1lnivenily
Medicd ('tnlrr, Sc I.ouis, MO.
MIl'l1AfI. I Wf LS11, M 1).
Aunrawt f rr./rrfnr ../ MrArnnr Uni-
versily of Iowa Colkge of Medicine,
losva ('ily.
AK1WI.NNMALM, M D.
L../rccor and ('Aarrw.aw. f)eprfnsrw/ n/
(7rnrcat PAp.mlrrR y. I /niversi/y of
(:nlhenhurs, Gulhenhurs, Streden.
rAUI. V. WOOI F V, Ill. M D.
/ro/rrvr of Mrdrrrwr awd IAarww-
rn/ntr. (;eorgeluatn 1/ni.ersi/y Medical
('enler, W ashinRlun, 1) C.
STANI EY YA('IININ, M.O.
Iru/elrrs of Mrhrrwr ew/ CArr/.
S.rfnwr of //rwuralnRy/Onrolntt. The
Ilniversity of ('hicago Medical Cealer,
Chicallo
1>nNA/.D A. YO1/N(:, M D.
hn/rlrnr of Afrdnvwr Ilniversily of
Rochester, Rochesler, NY.
EROlECT TITI.f.
The rok of pcplide methionine sulfu..de
red.clase in human IunRsv a possible
defense alainsl protein oaidalion and
elaslin drpadalion in stoo\ers
Sequence rnodifitia/inns in vital 1)NA by
beneo(o)pyrene melaMdiles
Iluman macrophage collagenase and
cultagenase inhrbilor
Mtchanismt conlrollinA ion Iranspml .n
air.ay e(nthelca
Nicotine as inhibltnt of protla(tandin
fnrmalion" loealiaalinn rnf the mh.bdocy
step and characlerirala.n of Ibe
cardiovascular implicalions
Effeels of ehemical careinnsens upon arnr
loci in the pancreas
Models for the palhoRennis nf
a/hrrntekrosit: A) bminRical effrcls nf
oayRenNed sterol comtw.unds, 11) mevahmi:
acid and eholeslerul hinynlheus and Ihe
biosynlhnis and reRulalion of cell tro./h
Lpillonu virus pr.aeins and cell
Irantformalion
197
COMPLETFD PROIF("FS
I ollowing n a Iis1 of the rrinciral invesliRaton, or institulinns,
of prnjecls thal have been cnmpkled prior to the period covered in
this Repor/ Several of Ihe individuah named sre deceased. The
IitMs and af/d.slnns bsted were lhose in effecl at the /imr the
wnrl wat m p.ne.ets
MARtI) 1) AC'F)O, PII h
A...r.urr t.n/rt.nr n/ tAarwtarolner.
Mrd.cal l'o11eRe of Virgin.a, Virgln.a
( ommun.ea/th I /mvr.vey, R lchmnnat
CIARINIT M AGRICS,Mf)
A.t.nroru Clrnua/ trn/rrrnr of Mrlrrrwr,
Ilnivers.ty .d ( atdorn.a Mrd.cd ('tntr.,
I ns AnRelrs
ANF11(1NY A AI RANFtF. PH D
/).rrrto. ../ ! nM.n/nr.n, Ihe Rur\e
Rehahd.tstr.n ('en/e. Wh.le Pta.nt, NY
STEPUFN M. AYRI S. M 1),
Drrrrtor, C'ardiopulreonary I aM.ntnv,
Saint Vineenl's Ifospral, New York, NY
1 1,511.11, RAFR, M I)
A.rnrra/r trn/rt.nr of Alr.(u nr,
Columb.a Iln.vrnily Co11eRe .d
PhTs.cuns A Suraront, New Yo.Y, NY
(1GC'AR I RALCIIItM, Pn D
Heu.her tro/rt.nr, oof MrJ.nwr,
IInLeIs/Iy of SnWhrrn California S.hnnl
of Medicine. Los Angeks
AN 111ONY P AMAROCI , PH /)
Iw.e.urtnr rn OA.rrfrm, anJ (:rnrrofnrr.
.The Alhany Medasl (nllegge of llmnn
1lmvrnity, AIMny, NY
F T AN(:T 1 A K lK, M I) .Pw O
trn/rr..w o/ IArunlner. Rnttnn
tln.vertlly School of Med.c.ne, Roston,
MA
D MIIRRAY AN(iEVINE, M I)
l/nivrrsi/y of Wiscnns.n S[hool nf
Medicine Madison.
IUSFPII C ARCOS. 1)Sc.
tn./r.fnr o/ Mrdrnwr, l ul.ne
llniversily School of Medicine. New
(hkans, I A
ALAN K ARMIFA(:E, PN D
ResrarcA I)r.rcrnr Ilarklon I aboyalmies
turnpr, llsrropte, Nnrth YorAShire
1 n~tanA
MAR11 YN S ARNOfT (RASI'O) PH I)
Atvuant RrolocrU awJ Atu.tawt
trn/ttvn oJ R.olner The 1/wiversily n(
Te.n System ('sncer Center. M 1)
Andersnn 1lusplt.l and lumoy Institute.
Itousun
IufA(IN/.It M A\'14 1r1
I..r.... I~...~. . ~ 1 .. .
..1 1... . ,... . ..
(r.,. .
I Rf /lf RIK II RANG. M 1)
Irn/rtror and ('Aurr,naw. IkpartmeM of
PathoMnlnaY 1he lohm Ihy.\.ns
I/n.vtnNy School of 11){iene and Puhl.c
lleahh, nallimnre MI)
A('1 111 ORD RARGI R, M 1).
Rnlrrt llenrr f/r.//rr lrn/ranr n/
tArt.olnty, llarvard Medical Scho..l,
Rouon, MA
RROI)A 0 DARNFS. M.D, P111).
tro/rssnr (A//Jmtr) of tArrrolnRr.
Cohnado S1ale l/niversi(y, Fort C'o11.ns
1 Rfhl RI('K W RARNI'S. /R., M Iy
Attn.rolr tro/rt.or e/ MrJrnnr, Ihe
Johns IlnpYins l)niversitY S.hool of
Medicine. Rallimore, MI).
T. C. BARNFS, nSc.
Re.rarrA Srienrst, Philadelphls Sule
Ilospilal, Phila.lelphia, PA
('AR1.(: Bf(KIR,M1)
Artncutr tro/rl.or o/ tarhnlner. ('nrnrll
Itniversily Medical ('ollette, New 1'n.\,
NY.
R I K11)1 RICK nl ('K 1 R, Pw 1)
~..nr.alr trn/r...v of Anornwr anJ
11,.r...u I atv.a1n.y nf W..natal
...n . I...tr I-n.r.vly
. ...,. 1.... ..n, ,.
RALPII S NFCKFR, P. D.
trn/rttar of CArwlutrr. Univenily of
Ilouslon, Ilouston, TX.
B1-NIAMIN BI:LL, M D.
Drrrrror Ewrrntus, Normativt Aging
Study. Velersns Adlwinisl.alion
(hrtpatient (9inic, Roslon, MA.
SAMULL 811.1 IT. M 1).
Ilrrert.w, Divis.on of Cardiolo{y,
Philadelphia General /lospilal,
Phda.kiphia PA
ItARI/l Bt NA('1 RRAF, M D.
1'aAyaw Iro/rnor an/ CAanwwq
1)rpa.tmen( of Pathology, llar.ard
Medical Schnol, Notlon, MA.
WII 1 IAM F RENI DICT, M D.
Aatruuwe t.o/rrsor of IrJravk),
l/nivenily of Snuthern California School
of Medicine. Divisiow of Iktqloloolly
and Medical (:enelics, Children's
Ilospital of Lor Angeles, Los Angeles.
1
RARBARA 1 van de. BFRG, M D.
RrsrarrA trburrr.iaw. AI/uwtl rra/nIr
rw Rreverntirr, llwivenily of C.liforwia
School of Public Ilealth, Os\land.
)OIIN A. BF:VAN, M t).
trnJrssor oJ tA.rwrorotnly. Universily
o( Ca/ifornu School of Mediciwe, Lot
Ange/es.
DF.BA)IT K. RISWAS, PR D 1)S.:.
Aasorrate tro/rrtor of Oral R.oloer
Laboralory of PhsrmacoloRy, llar.ard
Schonl of Iknlal Medic.ne, Boslon, MA
IRA B. BLACK, M 1).
tro/raw and CArr/, 1)ivis.un of
Dtvr4pmenlsl NeurolnRy. l'ornrll
l/nivenily Medical Colk{e, New York,
NY .
1RFD(i B(X'K,Pl1D
Atsnrrarr Cawcrr Rrrro.rA S..r.uu,
Rwh.Riea/ Station. Roswell 1'ars
Merruuisl Inslilole, Sprinloviltt, NY
GUEN11/ER ROI)EN, M D
Astarrort lroJrnor, o/ A(rJ.r.wr
Asus(aw/ DlrertM, ( ieneral I lmical
ResearcA Cenler, Temple tlmve.a(y
Ileallh Sciences Cenlee, Phdadelpho, 1'A
I/ERMAN V ROENI(:, PH D
Hraf, Deparlrnenl of Chemitlry snd
Brtchewyis/ry, Spindkl.p Research
Ceaer, I.esing/on, K Y.
)AMES F. BONNER, PH I)
troJrttor of errrlaPr, Cslifornh Instiluu
of Technolthl, Pasallena
WAI.TER M BOOKFR, Pw I).
ProJestur anI lrrnJ, 14par/menl of
Pharwneolo~y, l/o.ned l/niversuy,
Wnhinslon, DC.
BI/fNIDEV RIIAGAT, PH D. FRAN(YHS M BOOYSF., PH D.
teo%ssor of lAyrrolotl'. Sai.l Lo.is Srnrer fnrrs(rlara., Michael Reese
Univeni/y School of Medieine, SI. Lo+is, ReseareA Fo.ndslinn, ('hicago, 11.
MO.
RAYMOND R(MSf: PH 1).
CESARE BIANCIFIORI, M.D. Assnrrarr Drrrrr..r, Normalive ARing
Division of Cancer Resench, 1lnivtrsily Study. Vtleons Admmislratinn
of Peruitia. Perueis, luly. Outpatient Clinic. IMnlnn, MA.
IIYLAN A. BICKFRMAN, M D,
Artr.lwwt trn/rrtor of Mr/rrlwr, and
ALVAN I. RAKA(11, M1), ('owtuhnn(
rw MrJurwr. Cutumbia l/niven/1y
('o/kse of Physicuns Sulllenns,
(:ohlwNer Me.norid llospi/al, Ne.
Yor4, NY.
RIO-RfSEARC// CONSULTANTS, INC.,
Cambrn/ge, MA
R/O R1S1 AR( N tNt11t111F INC
('smM.dRe, MA
T()N G FK)WlRY, PH 1)
RnrarcA tro/ru.w, Pesticide Nesafue
1aAoulory Nurlh /unl.na `lalr
('ol/e{t, Rakiah.
I MARK BRAII(:III / R, Pu 1)
Aare(ewr Iro/rlt.w of tAo.w.arnlner.
Nnriheasterw Ohio 1lniversiaes (o11rAr
of Med.c.ne. Ronsslown
1'DWARh BRFSNI('K, PH 1)
tro/rs.nr and fAnnw.ow, Ikparrrnent .(
NwtAem.Nry, the Ilmvra.ry ..(
Ve.munl /'ollrar ul A1rd.unr, Nu.lnetun
149
(:FnFf REY 1. RRINKMAN, M 1)
Arsnrro/r P.n/rrtw of MrJrrrne, Wayne
Su/e Itnr.rr.ily School of Medre.nt,
IMlrnil, Mt
RO11f RT E RRltt1KS, Pw 1)
Arrnrrar P.n/r..o. n/ Ia/M.fnry.
I/nivrrsity nf (hesun Medical Srh..d,
Por tland
IIARRARA R RROWN, Pw D.
l'Arr/, I aper.mrnul Paychiauy, Vtterans
Administralinn Ilmp.ul, Srpulveda, ("A.
RAYMONO R RROWN, Pn D
rroJrs.nr of ('Lnrrol Onrnfntr.
l/niversily or Wrtcnns.n Medical SaMnl,
Madnon
If /Sl l' ORO71 K, Pn 1)
Irn/rss.r and fAnrrman, tkpartmenl of
Psychnh.Ry. I rh.Rh lln..rray,
llethkhem, PA
RFRI('('A RRYSON, PH 1)
Asur.n/r FIn/rtrnr n/ IsrrA.dntv. San
tNego Slale Ilni.ers.ty, San It.egn, ('A
SIIF RIICKINI'l/AM, M 1)
A.aralwN r.n/r.vw of rrdrwnrt,
(blumbia 1/nisersily t'nikRe of
rhyakians a SJviteom, New York, NY.
A SONIA RI/IST, M t)
Asvr..tle Prn/rs..w of Alrhrrnr enJ
PAnndaqr. Itni.ersily of (Aeaon /kallh
SCKnce1('enler, PM/land
III N/AMIN BURROWS. M D.
AraarrMt Pro/rs\w of Mrdrrrnr.
Uni.ersily of ChicNtn, Chicago, It..
E M RUTT, M D
CArr/ Pa/A.JnRrst, 1 o/ Anatks County
(7rneral Ihnpital, I os Angeks, ('A.
I 1 ROY T. CAN t R t 1 1., PH D
CAar.mon, 1)eparlmenl of Pharmacnluay,
le.as College of Ikleopalhic Medicine.
Nmlh Teras S1a1e ltnivtrsily, 1Mntnn
W/LLIAM It CARNfS, M 1)
Ilni.trsily of Iluh ('o1kEe of Medreine.
Shc t.ake City.
MARCUS N CARRhI.I., /R., PH D
CAre/, Diasinn of PharrnacnloRy, (hr
Srookdak Hospilat Cenler, hronklyn,
NY
WItItAMA CAR1fR,MD
P.o/rsror a/ )lrn.ernfnw enJ Alydwol
l)nrelot y, Ilahnemann Medical 1,.llrae,
Ph.ladelphia, PA
Wit 1 1AM ALVIN CARTER. M D
A.vuenf rro/rssw of MrJ.rrwr unJ
M.r.nMdnt y. lhe )ohns I LN.S ins
t/nr.asily Sdnnrl of MrdKinr,
Rahnno.e, MD
At R/ R T CASTRO. PH 1)
hr.rrtw, IlMmnnt Rrxarch
I alrnalory; rrn/rs.w n/ PorA.daRr anJ
MrJn rnr, (/niversity of Miami Schu.d nf
Medicine. Miami, 11.
.
1[(1N)1 1) R Cf RF('1.UO, Pn D
r.n/raa, of /1nrArmrst.r and NW.Nn.n.
Ilnivt.sily of /'urrto Rico SchapN of
Medicine, San )uan.
/A('K Cl/ALON, M 1).
Assnrrwr rr..Jesaw of AnrVMvnloRr,
New York Uni.eraity Medical ('enter,
Ne+ Yak.
I RANCIS C. CIIAO, M 1)., Pw t).
Srnrw In.r.IrRn/nr, Cenlee for Rhrrl
Resrareh, Mnlon, MA.
('Iill IsRf N'S 11(KPI IAL (1f
AN(i1/1S
1 w Anaeles, ('A
1/K
RI('l/ARD 11 RYI RRIlM, Pw D.
Irn/rr/w r/ CArnuury, Mwhipn Sule
Untversily, LaN (.anslng
SISiF.R M I MILY CAIIII 1., r/1 t)
('AarrmImp. Ifrparln.rnl of Chemislry.
Regis College. Wealon, MA.
RR1/l'F /('AM1 R/)N, M 1/ , PH t)
Iln+aud itaahr. Insldule. Ilni.rrsily of
M,am. \. h..,1 ..1 Mnh.,nr M.am.. I I
65100 7682
lAN 1 CIII.1'NOWSK 1, Pw U
Asvuew/ rro/ns.r nJ Rn.rAr.wnLr,
Mvdical ('olkgr of Viqinia, Ri.hnw.nd
SANI ()RIl ('11()1x)Cll, M 1)
A...Unn/ r.n/rn.w n/ Medrrrnr. Tufts
I/ni.erany Scln.d of Med.cine. R.,aon,
MA
;IMI
NAtfFRM CIIOPRA,PND
Lo/rasw of CArnlrury, Nor/h Carolina
ARriculWral and Technical Slale
Ilrti.ers.ly, Creensboro.
WII I 1AM Ci ('LARK, PH D
I)nrrlrr, Psyclwopharmacohqty Restarch
LalnNallHy, Velerans Adminlalraln/n
Ilnapital, Srpulveda, ('A.
IIANS T ('I.ANK1:, 1) Sr..
P.../nvr. u/ R.nrArm.urr, Colurnbia
I/nrversrly ('a11rRe of PhysKUns &
SurRrnns, New Yu.k, NY
)A' 1) ('(111 MAN, M 1)
S..ldnr IfioJ, rrripheral Vascular
IMparl. menl, I/ni.enily Ilospilal,
Rminn, MA.
AIIINR.('(q1FN,MD,PND.
Aa.rrntr Ira/rl.nr of Mrdrernr: Cbe/,
Pulnw.nary Seclion, Tempk tlni.ersily
Ileallh Sciencrs ('enler, Phitadelphia, PA.
i
111 RNIt'E 11. ('0111 N, PH DD
rnr/raa.r end prrrrYM, Ilunlan
(:entlKs/(iN1e1K Ipide1111o1t1ty
Pa.aram, the Johns 1lopkins Uaiversily
School of IlyRiene and Public Ileahh,
Raltin.ore, MI)
1)AN11'L C()IIFN, 1).V.M., M P./1.
Aauslnnl hn/rsur a/ 1'eetrinerr
f pJrnnoln[y anJ PrMK Ilta/M,
llniveraily of rennsy/.ania School of
Vekrinsry Medicine, PAiladclphia, PA.
PAttl. T. COSTA, 1R., PH 1)
Asaorrar Prn/rssw of t.vrllnloRv,
Nnstmr,
tlniversity of Massachuxus at
I)orchesler.
1OIIN E. CRAIG/II AI), M D.
PreJets.r x/ /oWA.doRV. Ilnivns.ly of
Vtrnlnnl ColleRe nf Med.cine, Rutbn6tun
RORFRT 1.. ('RAIN, rn D
A.vstent PrnJrtaw nJ ,C..a.InKr,
tlm.ersily of Chicato, ('hi.aRu, 11
IRVING P. ('RAWIYIRI), M 1)
Pr../rssw and ('Amrman. Ikpartmrnl of
Microb6dnRy, (lni.ertily of 1-a
('o11rRe.d Medicine, luwa ('.ly
7 ftMOTItY ('RQCK1 R, M 1)
Lo/issw of AfrJrrrnr. I/niversily of
CalJuenia, ('.AItRe of Medicine, /-ne
('ARRO1.1. E ('R(KS, M 1)
AasnrrMr Irn/rssa, of MrJrrmr anJ
/fualon IAI'saJapr. D.rr.l.n. S.rrunn o/
rulnnnrorr arrdu'urr, 1/niversdy uI
('alifornia ScMnal nf Medidne, 11a.n
('F('ll. ! CR(>SS
RrsrorrA !)rrrtnrent, SI )nwph's
Ilmpilal, Rurbank, ('A.
DAVIO W. CRI IMPACK 1 R, Pn 1)
Ira/rssw e.nJ l'Aarrnl.m. IMparlmrn/ of
Fnvirowntenlol. Rywlalwn and
(MRaniaw.c llinbty, I/ni.trsity ol
('ehwado, Ihw/dte.
ALLAN C. COt.LINS, h1 D. ALRI Rl' DAMON. M 1), PI/ D.
Asrnrrarr Prn/ratw of IAsrnrwrn/n~r, CrrlMrr an AnrM..p.foRr, RrrrarA
Inalillde fnr 11eha.iwwal Gene/ks, As/erra/t rn MrJ.ral An/A.np.Jnar.
t/niversily of ('nMradn, Ro.Mer. IYalwrdy Mawut., Ilarvard I/ni.enhy,
('anrbrnlae, MA
11/1 11/S 1/ (Y)MR01', 1R., M.D,
fh.rrh+, Cardiossc.lar Rtsearch
Inalilu/e, t/ni.ersily of Californis
Medical Cenltr, %an I taneisce
1)I AN M CONN)RS, M 1).
ArsarrMr lhr.vtw, Ikparlntenl of
I.aboralary Medicine, SI Mary's
Iloapilal, Madison, W1.
P1111 1r ('ODPFR, M D
('6nrra/ Iro/essar of Swtlny an/
l)vrrl.w, Surgical Lahmalory of CtRYlar
PhysinloEy. Alberl I.ns/rin ('a/kKe of
Mrdreine of Yeshiva I/n..eraly, ('Arr/.
SwR,ral Sr.nrr, Velerans
Admrnislralion (1.npilal, 1 he Rrnns, NY.
71K)MAS R 1)AW/l/ R, M 1)
Ass.wae Pro/rstnr of
MrJnrwr, Rmlun
l/nwersily Schml of MrJM.nr, 1lmlon,
MA.
It F. 1)AWS()N, h1.D.
ho/rasnr w/ RWanl', COIYmhO
Univarsily, New York.
1(111N P DF.LANEY, M 1), Pa11)
Aaswuar Irn/raw of swRrrr.
l/ni.ersily of Minnesou, Minneapdn
ANI)RI W S()IRNI R, Pn t)
!'rrr.rnr. rre.Ae RnrwrA, Ihe Aae
('enler of New I ngland, Inc . Roslun,
MA
11)WARI) F. IlOMINO, M I)
Prn/rrsnr a/ PAnr.waroLqr, llnivenily
a( Mis.h.g71a, Ann Arlw.r
RAI PII 1. DORI MAN. PH D
f)or.l.r of Lnhwornrlrt, Worctster
I .wndalinn fnr I .l.er.menlal 1lydory,
Shrewshury, MA,
11 fRl I) IX)WNI Y, PN I)
A.uvoM Pn./r.ar n/ PAyvalnRr,
1rni.erswY of Ir.as 11ea11h Scrence
( enler at Ilalla{, f1lrrllrN ( n/J1nM\Inlm
Rr.rm. A, tvdwy.uLnnna4 y Inslalute,
Mrthn.bq /lmp.lal uf 1)a11s
IAAII C/ It\-AR, PH 1)
A..nrrw/ P,../rnnr u/ RnJ..rr,
Iklla.m.ne ('ulkrr, I nun.dlr, K V
RI( IIARI) 11 I ARI F, M 1)
('A.r/ Pr/r.,.wwr Iwl...w I.A.wwn.r.
A..r.rnul Pr..f....r n/ Alr/u.wr,
11m.rrvly ul t h.arn, l hhaRqll
R(IRfR/1(III,Pu11
rrn/r.ur n/ Awnl...wr, MnMran Slar
IInrve.srly, 1 ssu I an..ng
)O11N R LSl1 RLY, M D.
PnrA.rl.Rr,
Aun.o/r Pro/esuw of
11n..ersily nf Cli.raRn Prilraer S.h.nl uf
Med.c.ne, ('hicago, 11..
III1G11 F LVANS. M 1)
Durrnm, Drparln.enl of rrdulr.a.
Ie.asA llospilal and Mrdi.al ('rnlrr, uof
Sroo4elyn, ereololyn, NY.
IIANS 1 EYSLNCK, PN I), D%(-
Prn/ntw ./ P.rrA.dnry, Inurtule of
hycAialry, lin.vesAy nf 1 nnJnn,
LnMMn, Fnrland
ItANtI IAIK,Pn1)
AJ/uwrl At..w.mr ul
PrAnl..Rr. Univenily of .Lw/hrrn
(alJnrnia SahmJ of Meditine I m
Angelrs
f)ANA 1 1 ARNSW()R111, At D
/Lw.r A; (16rer Prn/n.nr o/ l/re rwr
awJ Durrlw, llmversay llrallh Srrv.;rs.
1/a..a.d Iln.vtrsat. (amh.nlFr, MA
GAIt I I INSI I IN. Pn I)
.Crnur I r(lu.rr rw RnYArn.v. r, 1 hr
GrorRe S W.se /entrr of I dr \cvncr.,
!O11N W. I l'KS/I IN. M 1/ 1r1 Av.v I/n..en.1e, Itl A..v, Is.arl
A.vNnwl .r/ lwn.wel M.,Irnn.,
Slale Iln.rersily nf I_a ( o11rRe nf 1O11 PII 1) / 1/ 11MAN, M 1)
MrJKine, lowa ('ity Iw.w.w../mrA.Jnr..l, Scr.p(s (l.n.c anJ
Resrarch I.IUndalMn, (.a lulla, (:A
RIRIRAM flllll l, DDC
I)rrrrrw, In.lnute of SlnmalolnRn:a1
Kewsrch, Science Resnurces I oundal.en,
Wate.lown, MA.
IIYMAN F N(:fl RF RG, M D
Altrn.6wr PAyurrow, ('rdars of (.tbanon
Ihspdal, ( os Angeles,CA
CARLIUN K FRICKSl1N, P//1)
Pr../rHrw n/ PArrwrm.daR1 lhe
1lwivrrsily of lrsas (bllrgt of
FMa.macy. Austm
111NRY1.1SnlR,Pt11)
Rr.rnrrA Iwrwruw.dnR.v, Mason Resrara/A
Ins(dule, Wwcrsler, MA
W A1 11 K e 1 IAMAN. M 1., Pn /t ,
P...fr..r. al 1'. , A.,l..e r n,.l
R..wArw...ne 1)urrm ( ,dlrRr .J Ihr t .Ir
1/mr...1. u1 Nr- )...4. 11u.h.nso, N\
RICIIARD 1 I NiON, PH 1)
Iwsrrurlw rw PA)v.JnpY, Ilni.e.sil) uf
Massachwells ScMn>t of Medn .ne,
Wwcesler.
I RANK C. F FR(:(ISON, 1R , M 1)
('Aaunimr, Ikparlmtnt of Pharmacn/oRy,
The Alhany Medwal Colle{e of UnwM
llnivt/tily, Albany. NY.
111(/MAS 11 11N1 AY, PN 1)
A.uw'Id/r I'rn/r.s.w a/ (MUrlrrr. nnJ
(:rnrr.eL.Rr Nr+ YnrA I/mvrrady
.
Medical ('enler, Ne. Ynrk
FI11t)IXM1.N fIN11Y,MD
p.rrnnr, Pulmunary Resrar.h
I aMwasnry, Mounl 7nM Ilnspnal, San
I rancnco, CA.
W/1 1 1AM I 1/511011N, M 1)
( A.rI of I p.J.wn..l..rr, lha.san
u/ Ilrallh, 1 h.. ia.., It
1
I hWIN R. 11S11fR, M 1). GARY 1). 1 RICpMAN, M 11.
I)urrt.w n/ IYI.rVIINrr., SAaJ)lide Aululnl 1)Irr.l.n, 1)eparlmrnl 0
I/ospAal; Prn/r.vr n/ PaM.Io(r, Medical Melh.wls Rrsearih, Ka..rr
1lmvrr.i/y of P.(ISburgh School of FounJal:on Reararch Insblule, (/+41a.nl,
MeJa.ne, P.Ilshuro, PA. CA.
KI /ACt 1 1 S I IS111 R, M 1). (1. 1111611 I IIUf NIILRI:, M 1/
Ilnr.er.ity of Maryland School of Iru/r.s..r o/ AI.J.nwr. UmveraAy of
Mrdwine, Rallimure ('al.f.wnia Medical Cenlr., S~n
WII I IAM 11 1 ISIIMAN, Pn D
lr..rJrnl, 1 a lulla (ancer Resrarch
I oandalr.n, I.a )ulb, CA
1111((:11 1 A
Ihl 1)
A..r.nun
I rancia'o; Pru/r.t.w o/ Rrrlrnol..R. .rn,l
fw/wmun.dnRr, Universily of ('a1J...nu
Serteky
ARTIIIIR I I1RS1, Pn I)
11 O111 RI/S MYRR1/11), ptrraw, Inslitule o( ('hemical RMlnrv,
Prn/r.l.r of I nar.wrnwnlol
/h cr nr, 1 he K arollnsYs Insl:lutr,
Skn\Auhn, Swrdrn
/A('K W I R ANK t 1.. P11 1)
C.w..uhanr rw AhJnol RrsemrA, Vtlerans
AJm.niaualiun MrJaa/ ('enler, 8ay
P.nes, 11..
11 1. I RLf/N ANI)1 R, M 1).
(larrl.r n/ ('e.urr RrvrrA, Mol/n/ Zirul
/lmp/lal and Medical Centel, San
I rancisco, ('A
A1./ AN P FRF1 UMAN, MO.
A..rN.m( P.n/rs..w of A(eJinnr,
1lahnemann Medical C.dkge,
PbdaJelphia, PA.
AARON F I KI I MAN, PR D.
S(I// SlIrwll.f, (*aldornia .RiowwJKal
Research I ounda/iun, / a lolla, CA.
IR1I)IRICA IKINI'11,AR
On.rror u/ (aw.n fArwduArrepr
Rrtrm.A, Mount 7iun Ilospilal and
Medical Cenler, San I raneisen, CA.
)A('K / KI IINI), M 1)
A+uunn/ P.n/rr..r o/ PAww/MUfot/,
Med..al ('ollrae ../ Vugima, Rnhmond.
LARS IRIRI R(:, M D.
Pr/ruw owJ CAarrw.ew. Depsr/nsenl of
F.n.irnnmentsl 11yoliene, The Karolinska
hnlitute, Sloc\hulm. Sweden.
1i11RIR1 It IRII Il/11, M1)
CAa/ of I'aA.J..rr, SI V.ncenls
Ilusp.tal, Worcesler, MA
I/nivertny of San I.an.ncn, 1m
I ranaxo, ('A
Mf1R ION (:AL1)SI()N, 111 1)
A.awlmr Pru/r..w u) Af,:hunr. NroYo.M Ilnivrruly MrJ.ral (-rnlrr, Nrw
YurIs.
MURRAY O(iARI)NI R, M h
A.t...rarr P.n/r.urr ../ PalAnl..Kr.
lini.enily nf S.wlhrrn ('alJurnia ticMrJ
of Medicine, L.n AnRrles
MI('11AF1 C GF(1KAS, M D, PH l)
P.a/rstw awJ 1'rrr('Aouwmw,
/hparlmrnl of Medicine. Ilnivenily of
Caldnrnia S.Mw.) rJ Mrdicine, 1)avit
11:RI SA GFSSNFR, Pn 1).
A.t.w'IWe ('mnrr RrsrarrA Sr.rn/rv,
Ilea/1A Research, /nc., Koswell 1'a.l
D:.ision, Itu(fa1o, NY.
GI.(IK(iF 0 (:1.V, M 1)
drr.r(w, Finwey I lowell l'ancer
Resrarch I abolalnry, Atsnc.+le Pro/rsMn
of Surgery. Ihe lohns 114411,4e%
l)ni.ersily ScMwJ of Mealn.ne,
Nallin.ore, M1).
RONAI.D W(DIl 1.1 1 11 , P/l l)
mrerew, nasie Science Ktsrarch I/nit,
Caneer ('en(er of Ilawai., 1lniveltMy ol
11a.aii at Manua, IlonolYlu '
GFRAI D 1 GI 11('1t, No 11
Cuwwf/aw/ /w Rrt.arah
1.ahora/ory for AIIrrRie 1)neasrt, M..yu
Clrnie and Foundalion; P.n/r..w nl
lnrrrwel MrJi.l.nr and LwMUwrl.R.,
Mayo Medical S.hwd, R.khe.lrr, MN
1II(M(AS M(:(x K 1, M 1)
A.uw.ar Ir../ru.w r/ Irr.rw.ur
AIrJ.unr awJ (xwrw+wnr Ilrnl.A, V/..n
Ilall (u11rRe of MrJ.rmr anJ IMnr..uy,
lerKy ( ay, Nl
201
t+AVIlt M Ct)1 I)1 Nll/ R(7, t) Sr , M 1)
A.ar/ofe P/..f...n/ n/ Pnrh.l..cr,
Iro/ple Ilnaer.ny Ilrahh Sc.rncrs
(7elrr Phdadelphia
PAttl GO1/)IlAltl R, t)hS
A\\/rlnfr Prnfr../r n/ Pr/I,4I/Mfnlner,
Ibrvard Schuwd n/ IMntil A1rd/:.nr,
tl.ntun, MA
I I l)Ntl)1 (:f)1 1><11 IN, f) Sc
A.+.rre/r P.nJra.+ ../ P.rrArorry,
loui/ulr for Menul IlraUh Seienres,
('n/1rRe nf Medninr A I+enl.,rry of New
lrray, RutAers Mrd.aat SeM.d,
Pi.calaway
IRAGORI,M1)
Prn/r+..r n/ PaAn6rqe r, Roalnn
I/nivenily Schrwd of Mr./rc.nr, ('Arr/ of
I ohnonrr .Grrrr, Vetrran)
Adrninislralnsn IlnqMat, Wrtl Ro.hurY,
MA
)()IIN W (:()RR/)1+, 1)('('
I Kturrr rn Rr..PAn..wa. V.
('hrtara
(btlrRe, Ilnrvtn.ry o/ I und./n I
nndnn,
I nR1am1
(if R/R1/1tf V I;ut 13(9/A1 1 Pn h
AsslUaal Prafrssor e/ RLch.a.Iabf,
Columbia Universily ( nl/ear n(
Physiciana A SurRrum, New YurA
MAURI('F GR11 N, M 1)
f)ura./r. InafreWr /.r Afnlrrulnr
I rrnlnAr, SI I r.uis I Inivrrsily Mrdreal
Cenler, St. I.ours, MO
A CLARK (:R11:1 tN, rn t)
urnJ. nrrM(nrrnr of RnrArmrthy. M 11
Andersnn Ihnpnal and lumnr Instilule.
I/mvers.ly of leaat Mrdnat ('enlrr,
/1nusloa
AR1/11/K 1. (31t/)Ci, MS
S.n.w Mr.rArnu,t, SnWhwru Research
InNitalr, San Antonio, I X
MOR ION I GROSSMAN, M 1) , PI/ p
Ar.nrraf Cbnuaf Pr.r/rs.nr of AlrJrnnr.
I/nivrrsily of (Catifornia Medical Cenler,
1 os AnReks
('AR1 C(7R111171t, M h Pn h
.Ir.urratV rn I'Arunl,.rr an,f
rA,on.mnlalr. I/nrvr,.,ry n/
/'rnmrivama (i.a.luarr \.h,rd .d
hledn.nr, 1'AJ.Arlph/a
)(Kl PII 1(:IIARNI R1, rn 1)
AfrrnJ/ne A(rrr.J.ndae/.r; I)/rrrhn
MrcrohrolnRy I aMrato.rrs, I nnR Istand
Jewish Ildhiwk Mrdical Cenler, Querns
1losrilal ('enler Alf7halw.n, )amaica, NY
IIODA A (iIfIR(.IS, r/l I)
Assxrwr Pr../r.uor o/ C.un/nun.rr anJ
Fnreren/wrnfaf AMJ.rrnr, 1lniveraily of
('aliforaia Cnikge of Medicine, l.v.ne
1I1RA L. c:UR f(X), I) V M, M V CG ,
rn O
Aaa..narr Cancer RnrarrA Sr.r.ur.r,
Drrntrnenl of 1`artr.mrnl.tl
lherapevl.es, Ros.rll hrl Men.urul
laslit.te, sulfalo. NY
f RANK f. C1/111RIf, Pn f).
P.o/nr.r of Enfe/n./6.leM, Norlh Carnliro
Slale ('o1kRt, RakiRh
11 n IIAAI:, M f)
Prr.)r,s.r n/ PAnrnr.n-.J..Rr. Mr,li.:J
( nt1.Re of VuRm.a Richmnnd.
1) IIA1H)Y, M 1) ru l)
P/n/r.s.+ anJ f Amrmnn. Oepar/menl of
rha.w.4.Ry, (lmvrrvty of (>kl~hnma
Mrdr.al ('rnle., t)\1..homa ('i1y
1(XI P11 11 IIAI K fNSI'lllll., M I)
n....(.r, (atdarh,rlmnnsry Uni/, 11e
I anienau Il.npi/al; Asvrrwr n
Alydrr.nr, I /niverti/y .rl 1rnmylvan a
Sahru.l of Medu:ine, rhila.klphia.
MAR(:/f IIAMOStI, Pn1)
RrsrarrA Alsarmfr, heparlmrnl of
PhysudM.gy and lle.physie.. GrurRe/un
n
Ilni.ervly Schools of Medicine ard
1)entrqry, Washinglon, IK'.
OI RNARI) IIANI S. 1'n 1/.
P.n/r.4n nJ IlralrA Srnnrr. ('alilurn.j
Slale Ilnivtrsrly. Nur/hr+dRe
RNIIARI) / IIAVI I, M 1)
Asvuan( Prr./ns.N of
M.J/nwr
I/niveraly of ('aldmnia Mrd.cal t'rnlar,
San francrsco.
Ilf RSER f R. /1AW 111ORNE, M O
Cfieow.aa, hrparlmenl o( SurRerr.
I/niversily of Pennsylvania (iraduate
ScM.nl of Mrdicine, rhdadelphia
11+11N A IIA VI C, M 1)
A...y/an I'mA,JnKr.f, Mallnry Inmuturr
of 1'arhulnRV. Iluslon ('ny Ilmprl..l,
11n.u.n, MA
t
CLARK W. 111'AT11, M 1).
Prn/rs+or of MrJrrrnr and Dlrerfnr,
11ea11h Services, lufls I/niversily,
Med(ord, MA
NORMAN W. Ilf IMSfKA, PII I).
Prn/r.a.w of Ps1.A.deRr: Durrlnr,
1111011311 1 actnrs 1.ahnralnry. Uni.ereily
of Snulh Ibhola Vermillwn.
rAU1 INt f11(71 R, rlt o.
RrvorrA A,vnr.Hr in CIf.J..ty and
( It/rArnuv. Y, San 1 rancisco InsUlu/t or
Medical Sciences, San I rancisce, ('A.
lARO1. I III NR Y, Pn 1)
Drrnrrr, Oeparlaaen/ or Lq.erirnental
()n:o/r.Ry, Mirrohiul..Rical Associates,
Inc., Iklhesda, M/).
III RRI'.Rl R III:RS(Y)WIT7, 11t (7.
AavrrNr Prn/r.vr of
Ah.ndn.dotY.
t:enrstlown s/niversily Sahooh of
Med.cine and 1)rnliatry. Washm{Inn, 1X'.
I AWRIN('L L/11Sf1R, 1R M1).
Prnfrssru and (-Aarrnron, hr(.ar/men/ of
lMalrlrics and (iyercohrty, Mediaal
('dkRe of South ('arutina, ('harkstoa.
I Rlll: CI/RTIS /IUI f, M 1), PR.D.
Pra/rssrrr anJ ('Aann+an, 1)ivisina of
Psychialrie Research, Medical Co1kRe of
VirRinra. Richm.nd.
11T RI SfARCII INSI llllll ,('hi.aso, 11
ALPIIONSI. l. eNGf.NI tO. Pn 1)
I'Anrnurrnlner.
Asun.a/r Pr..frnor of
faN Carolina Ilnivenrly S.h.w.t ol
Medicine, (ireenville, N('.
IIARRY L I()ACIIIM, M t).
At(rnd.nR PaftlnfoKrsr, I
enos 11d1
llnspiul; Cffncal Prn/esvu n/
PaA.Jr.Ry, Columbia Unrversity ('olleRr
of Physiciana L Sargtons, New Y.url
GfOR(7f. JACORSAN, M 1)
Prn/r,sw and llraJ. IkPariment of
Radink.Ry tlaiversily of Suuthrrn
('aldornia ScMwd of Mrdicme, 1 oa
A nRt/es.
11 RRY IIART JAl'()11S()N, M 1)
Ilr.rr(/r of £Irr(rnpAr.rnlnRr. New YnrY
l.ye and 1 ar Infirnury. NY
11111t/S 11. JA('(1111/)N 11, M 1)
As,.rra(r Pra/r.,an a/ Ju.cr/r onJ
flarctw of .Su.pon/ Rrsrw.A
Ilniversily of Vernu.nl ('u11rRe of
Medicine, surlinRlon
AARON JANU11 , Pu 1)
Pn./rss.n of PwAolnRr, Ilroleh Science.
('ealer, Slate 1lniversily of New Yor\ a/
S1owy RrooA, Slony 11a.nk
MIIRRAY I IARVIK, rn 1)
11 R(HN1: 1. /1O/NAl'K1, PII U. Asaarra/t Pr../r,,.r of
PA.rrnrnu.L.rr,
AsoJnnf P..r/rssw of SrnfnRn.d Atberl finalein ('u11rRr of Med.crne ol
Srrrnrrs, (/niver.ily of I.u.ell, Lo.ell,- Yeshiva 1/nivenily, I/.e Ibnna, NY
MA.
R1JtSl 1.t. 1.. 1I()1-MAN, M D.
I ouitiana Slale I/niveraily Sthnol of
Medicine, New (Hleans.
1)AVII) A N)IINS()N, Pu 1)
Asvuru Pra/rsur of Mu..Arnv.r.r, 1.10
lennt.ue Slale Ilniversily ('ollrote of
Med.cine, Jnhna.a ( ./y
(/1 E A 11O1.1fRMANN, M I)
Rr,ra.. A S/ rrnu.f, Lohund 1 ahoralory,
Ilntvrrsily o1 Nnlrt Ihmr, No/rt Iqn+r,
IN
/ RFY/1)Y ItOMR1/R(;1 R, M 1)
PrrsfJtwr and Drrrr(nr, RioRtstar.h
Inslilate, /ac., Carahridge, MA.
ROBfRT W. 11111.1 , rl/ t)
Pra/rlsnr of erohRiral Srrrnrr), fbrida
S1ale ttnivenily, Tallahasset
R(NIAI-1) R 1111/('111NSON, PN 1)
RnrorrA Dnerfnr, I ourndalion (or
Ilehaviorat Resrarch, Augusta, MI
(SWAIpR 1ONIS,MIt
SI l.akt s ll..,pilal, New Vor\
WII 1 1AM I 11/SKO, Pw 1)
At.nrrarr P/..Jr,r.w ..J PAa.nr,r..au...
A+rerta., ('bnisal Pharrna.n4.nrtns
I ahoralory. Mdlard I 8lmnre Iln.pn.J.
Suffab, NY.
ANDREW A. KANI)1/1SC11, Pn II
Staff SrbMrsf, lbe lackson I AL.raln.y,
Rar Itarbur, ME
ARNOI 1) R KAPI AN. Pa 1)
Dnrn.r. I ah..ar/r r./ MrJ.ref firn. rra r,
('kveland Psychiatr.c Imtdvte and
Ihnrilal, ('kveland
+na
,r14
r ~I ~c~ 7r,R4
A1TAI I All KAPPAS, M 11
P.a/ralw ewJ .Srwnn PArurrnn, 'Ihe
K.wiefellrr Un..ervlr. New Yur\
IIKA 1('ll KASPARIAN, M 11
eavNaN flunln ( urdrnraafrlnr
I ahnnr...r: /nahtn tur rw AIrJu rnr,
1lahnemann Mr.haal ( .Ilriir anJ
Iln.p.lal, rAdadtlph.., PA
f1.11111KAt7,htl)
Aaa.rru/r n/ S.rra7nRr.
Iln..rr.Ny nf ('hica6n, (Ch.caRn, 1)
S111Rf f V 1. K Alt/ l MAN. M 1)
/Yn/rtlnr ../ PMAn7oRc. Slae Ilnirenily
of New VtnA I)nwnalale Mrd.cal Cenlrr,
Dr.w.IJyn, NY
ROR1 K I A KUIIN, M t)
A.vrrnle Prn/rla.w, 1)ivna.n rnf
NeuruwrRrry. New leraey St..le l'nllroor
u( hled.cine, )erarY I AV
S11(i Kt11.1 ANI)I R, M 1)
Pru/eaa.w anJ ('Aoo.nan, 1)eparlmenl nf
(Mslelria'1 and (iynecaJ..Ry. Itnrvrr.ay
of Lund, Lund, Swr.len
LAWRI NCE L. Kl/rl1 R, Iht 1)
Aat.nralt Prn/r...n e/ R.n.rnn.n.a,
Uni.ertily of Nnrlh ('aralina S.h.wd rnf
Public /lealth, Cha(rl llilt
MAR VIN K I IJ(-11N1 R, M 1)
New Ymls 1lniveruly Medaal (7a1rr,
New Yor\
ANCI I K 1 VS. PH I) CIIARI FS W a.AR/1 1 1'., PH 1)
l)rrrrhr, I aboralnry nf PhysinlnRis'a1 ALr.toM Pro/raanr o/ Enrunnm.rntn(
IlyRiene, llni.tn.q of Minnesola Sahnnl lhprnr, )effecsnn Med.eal Ca11eRe,
nf Publ.e Ileal/h, M.nneat.dn Phda.klph.a, PA
11K1 rll R KIRSNI R, M I) AAR(1N 1/ Af)MAN, PH 1)
Prn/rraw nl A(rJnrw.-. I/n.ve.l.ly ol P.n/.a.nm an.l ('Aut.mmn, fkPSrtmenl nf
('hicagn Sch.ntl of Mrd.unr. ( McaR... /1 Anilomy, 1 he Ilniveruly uf New
Mr.ico \ch.usl nf MrdK.nt. Allauqurrque
11)WARI) I KI A1111 R, M 11
Srnuw Srnnn.r, 1he Wnr.rav. IllftA14% 1 1 A11t'1 N, M1/
Foundalinn /nr I srer.menul Itnd.A.. ./ N.nlb+rvrtn
Inc . Shrewshury. MA I ln..r.a.lr Med...t 1h...IR., 11
11 R/)ME KI I INI RMAN, M 1) MK IIA1 I I 1 AMM. M U
Prn/erl.w enJ CAeun.nn. I%eparlmenl nf Pr.nf....n r./ r.uA.L.Rr. New Ynrk
Palhology, Mount S.nat Sc'hoad of I/mvers.ly Medwsl ('tnler, New Yo./.
Medicine, New Yorl
rI l I R ll KNAI'P. M 1)
Rrcea.rA Pra/ruw o/ Pa)rhrahr. Rauon
(lnm.ersily School of Medicine, 1loalon,
MA.
KENNI.TII P KNI11)ISl)N, M I)
t/nittsily of WaihinRlnn Sahnol
Medreine, Sratde
AI VIN I K(KAK, Pw U
IN1N LAPFNAS, M 1)
Allruent Pro/ral.w n/ PolAnlRr,
t/ni.eH.ly of Verfnnnl Cullr`e of
Medieine, RurlinRlon
PAUI. S I.ARSUN, r/l l)
I/oaR Prn/rs.n, of PAa.mer.n.rRr,
Mediesl ('ollege of Virginia, Kicl.m..ml
R(N'1 R K LARSON, M 1)
(Au/ e/ AlrJtnnr, I retm. l'nunly
Itmpbal, I resnn, ('A
(i1tSIAVE A LAI/RfN71, M 1)
Cbr/ o/ MrJrctnr, SI Vimenl's
Ilocpilal, Worce+ter, MA.
1(Kf P11 M LAtIWI RYNS M I), PH lr
Prn/nlm O.Jrnurrus and ('hm.nan,
1kpa.tmrnl nf ralhni.nty anA
.Drr.nvnb)
Mu.oa..ry..c Anatnm., I
I .1....a... v nf /'.Qn. .n.. r
Il,at.p..htne.. Ka.hul..lr I~u..r ..trn
tr 1.u.. 1 rurn, IIrtR.um
of
Altnrrefr Pra/rller a/ l Arnrntrr, New
YoA Uni.ersily, New VnrY
R(1DFRT Mf. KRFII ICK. PH I)
Pre/e(sae of ('Arn+rv.r. Uni.etsily o(
Rochtsler, Rnchesler, NY
KLAIlt r K111 /1NI R, Pw 1)
P...lr.... n.J ! ~a~ew Is.pa.tmrm .J
~..enr. e...1 M..n .1..1.. d . ..u..
K. 1. t
1 rnir . t. a. 11
)AMI S C 1 F F, rN n
Alarvnn/ Pru/ealar a/ BrorArarnt.y. I P LONG, re 1)
Pre/rtlw o/ PAnnnw.JnRr. Slar
Saint 1 nuis SaMutl o( Medreine. St.
IN uuit, Mt) lrnivtrsity of Inwa lo11eRe a/ Med.cmr,
Iowa ('ity.
1 hIPARU L1 1 1 L, PN 1), /)Sc
Pro/rtbn a/ ('Arntrftrp. Univetsi/y of GFSINA 1. 1(NMI(iI NI l'h 1 R,
A1NaraV Prcr/rttw o/ Pho.wrnrulnRr,
Mtnnesola, Minneapnl.s.
rllll IP M 1 a QI IFSNF
Pw U
Q Sc llnivrtaily of South Alahama Cu1kRr nl
Meficrne. M..bik.
,
,
.
Prn/ral.w of (Ar.nnrry, Norlheas/ers
('I.AY 1UN li 1.0(XL1, M O, Pe1)
Ilniversily, Ihnton, MA. //aatrnRs Pra/rssrw of MrJrr n.r and
PwMJ..Rv, Univers./y of S.wlht.n
/(ICIIARn A I I RNI R, M I). ('atdornu S:Mro1 af Medicint, 1411
AltrrrrNr MrnrMr, Scripps Clinic and Angeles
Research I oundalinn, 1.a lolla, CA.
17C111. 11 t/('11tFNn1 RGFR. PH I)
HeaJ, flKparlnleM of cytoehemislRy,
Swist Inailule tor Eaperimenul ('ancta
Research, Lausanne, Swileertand.
JAY A. I,.LVY, M 1)
Aatara/r P.a/rrsne of A(rJirrnr:
Retra.cA Ata.n'rofe, Cancer Rrsearch
Inailule, Uaiverdly of ('alifornia School
of Medicine. San Francisco.
PA111. o. LLWIS. M n
Sennw t.rttwrr in HnlopwA.JagP, Royal
Pns/Rradua/e Medical Sclsool,
llanlntenntith lloapila/. London. f.nliland.
AVI:R11 1. A. 1.aFD()W, M D.
CAarrnusn, f)rparlnlenl of Palholngy.
Yak 1/niversily School of Medicine.
New Ilaven, (T.
tR VIN F. IJFNFR, PH 0
Pra/nsoe o/ Rc.rArrnrurP, (lni.ersity of
Minnesota, SI Psul.
IN)NAI 1) R 1 OIIRIA, M 1)
A.Lr'rarr Prn/rt..rr n/ AfrJrrnre, ('ornell
1/niversi/y Medical Col"e, New Yo.\
KTNNF.TII MI:RR11.1. I.YN('l/, M 1),
Sc U.. LL.I).
Pre/rttar EnMrrlw o/ PatAoluar and
('AenreQ.n, Medical Cnlleee of South
Carolina. ('harletlun.
INES MANDI., Ps11)
AssrNenl Pre/rsa.n a/ RnwArmrvrr
Coluwlsia Universily cnae/{e nf
PAysieians t Surgeona, New Yark
)OIIN 11. MANII()1 1), 1K., 1) M 1)
Prr/essee enJ D.renm. IMparlmenl of
Pathology atW (hal 1)iaRnosis, New
krsey ('olkge of Medic.ne aml
Uentislry. leruy Cily.
QAVII) E. MANN, Pu I)
A.senerr P.u/raan n/ Phn.mwnfnRt.
Ten.pk llnivenily Sch.ud of 1harmacy,
PANade/phis, PA.
1 STEN O 1 1NI)SI:TI/, M 1). PH O.
St. loseph's I lospiul Research
Lalunalary, SI. Paul, MN.
R()R1'R F 11 1/NNI 1 1., Ptl l).
A..enafr Pru/rllar of CArenu.r.
Iln/vers/1y of Vt.mnnt, RuA/nItan
I AIIIAN I I IONL / 11, PH U
Peo%str of BrarArauqrr. Ro.lon
I/niversily School of Medicine. Doslnn,
MA.
ItERDFR i 1. 1 OMDARI), M 1) , Ml 11
A//rlrefr, ( ancrr Research Insli/ule,
New I nooland Isracnneas l/u%pital,
Dnslon, MA
FRANK AR111(IR MANNIN(:, M 1)
AssHlen/ Pro/escnr of (Mlfrfrrrt end
Grnreatn/(r. Worneri s Ilosp.ul, I as
Aniteks Counly/t/ni.eruly J Snulhrrn
Cahfnrnia Medua) ('ente., I u. AnRelrs
)l)IIN P MAN/)S, M I)
Inlhwr.r on 1r.n4Rr and
Ro.rrnnlnRr,
Mtdical ('olkge of Sw/h t aruhna.
Charks/on.
C1IRISTOPIIlR M MARTIN, M Ir
Asds/eM Pra/rlu.r n/ AfrJ.rrnr and
Durclee. Il:visuan of Infeu:aus hisra.es,
Selon Ilall ('nlletor af Mediatnr, )r..ry
( ./y, N/
107
AS1A0 7685
R RIISSFLL MARFIN, M D IIERRERT McKENNIS, JR , PN D
Pro/nsar of M.drrrnr. end MlrroM.dnAP RrverrA Pro/r.Inr n/ PaA..J..Rr,
lmmwnnfnAr, BayMr Co1kRe of I/n.versily of Miami Schnol of Me.'w:me,
Medicine, l/ouslon, T%. M.a/ni, / 1..
RF(i1NA1 D C MASON, M D, PII D
Prn/rsuw awd ('Am.mnw. Thparlnsent of
Pa1hnl..Ry. I/niversiry n( Iltah ('o11eRe of
Me.l.cinr, Satl I skr ( dy
MASI)N RISI AR('It
Worcesler, MA
VICTOR A. McKtIStC'K, M D.
PrnJessor of Mrdr.'Inr, The )ohns
I/npkins I/niversily Sch.nl nf Me(rcmr,
Ralunswe, MI)
INSTI f11T F, R(lSS L. Mct FAN, M D.
/)ONAI f) 1 MASCARO, M t)
A.s.NUUr Pro/r...« .,/ Ah-J«twr, (:rnrRe
Waah.nklon 1/n.verury Sthe«+1 of
Mrd.tinr. Wa.MnRlun, tM'
('l1AR 1 1% Mr-AK I III IR, rn 1)
PIr.Anl.aRnt, llnivrnny Ileahh Srr.ices,
/4rvarJ I lnlversdy, 1 amhrulge, MA
(-IIARI 1 S Mr<'AN1X, Pw 1)
A...nlar P.nJa.v.. n/ SeJ., Nm,h
(a.rdms Culr ( ntlrRe Srho.d n(
ARIKulture. MaleiRh
l:I RAl t) F M.t'l 1 ARN, PM l)
1lorrtnr, Inu.lulr (m Re~av.omal
(ienelics, 1)epallmrnl nf rsych.J,.Ry.
Ilniverslly of 1'uln.adn S.had uf
rharmacy. noulder
IItNMY(' Met)111,/N,M1)
ArtrnR 1IruJ. Dr(v..rmrwr of PaA..L.;r,
I nu+siana State Itmversily SeM.ol of
Mrdicine, New (hlrans
111 NKY D McINI(KI1, M I).
Prn/ers.w of AIrJlrrwe and Dlrertw,
('ardiovascutar I ahnraloyy, t)uke
lJnivenily Medical ('enler, 1)urham, NC,
/nRINA MvtVFR, M Is
AsvrrtWr Prn/rs.nr of PotA.dner.
Medical ('ollete of Snulh ('ar.d.na,
( -hs/ leslnn
11)WARD Mt'K11 , M 1)
P...lrssnr enJ A. /rnlf CAaomnn,
IsrpaHmenl of Palholnty, Medral
('nllrRe of %nwlh ('arnhna, Charkstnn
K11t Y 1 MKlt M1~
. ..fi... r . ... , . . . . ~..,.., ..
Assetirr Pro/ru,w of Alydrnwr, I mury
t/wiversity Schuol of Mrdic.ne, AUanu,
GA
WII 1 IAM I McNARY, JR , Pn 1)
Ar.nrlWr P.n/r...w of Anornmr. Ih,uon
1lmverlNy Schmd of Mrd.<Ine tlmu.n,
MA
NFAI McNIVIN, Pe1)
I he Wnrtestrr Ioondalion (ur
I .(wrimenlal 11nI1nRy, Shrewshu.y, MA
IIANS M111 R, I) V M
1.w«« Slo// S.nnfLf, lhe )x~.nw
I ahwasnry, Isa/ 11artxw, M1
I WISTI R MI I/:S, M t)
t lmNal Prn/r.aw a/ Fpr.lrnu.J..Kr:
OI/r. b«, ('onnecUful ('an.rr
/piaeminlnRy Itnil, Yale ItmveLUy
S.h.N.l uf Medieine. Nrw 1laven, /'1
1111 IA MF.VFR, Pu t).
AHINIUIr Prn/rstnr of nrnJ J'ahulntr,
1lnivrnily of Illinois (blleae of
I/enlisuy. C'hieaRo.
1)OV MICIIAFI.1, PH I).
Asvslent P.o/rls.w a/ RnwA,mlurr and
SurRrrP, ttnivetaily of ('ahhrrnia Srho.d
nf Medi.ine. San I ran:isco
MIfR(/11101.(X:1('A1. AC%(X'IA11 S,
INC ,
RelhesAa, Mt)
III RNARU ) M11.1.1 R, M 1)
A.artaM Pr.n/r.aw o/ Anaamr,
)ef(rrson Medical ('o11eRr, 1'hi1.lAAphia,
PA.
/AMIS(: MIIIIRMI),PI/1)
./ P... Anu.1 .nw.( r...
.. .. ..... 1 ......,... .I GI,. /.... , Ann
t
11 RALD A MITC/IELL, P/I 0.
Assorretr Prn/rsaw n/ AnarpnP, Wayne
Slale 1lniversily School of Medicine,
Uelroil, MI
('11AR1.ES MITTMAN, M D.
tlrrrrrm, thparllneal of Respiratory
I)iseases, ('ily of llupe Na/ional Medical
('enter, t)uarle, ('A.
1111G11 MqNI(SOMI RY, M O_
A.v«.nrr Prn/r.1or n/ Mebrrne.
Un.versity of Pennsylvania School of
Medlcine, rhiladrlphia.
P(1'R M()N1(:OMI RY, /R M D.
L../nvw n/ PaAoloRr. Ilniversily of
le.as SGwlhwes/ Medical Sihonl, Ih11x.
G1 ORGE E. M(X)K1:, M D, PN 1)
I)wrrrne, Roswell Park Memmrial
Inslilule, RuffaM, NY.
KINNITIIM M(/SIR,MD.
Assruunt Pr../rLNe of AMJicrne.
Gen.Relnwn t/niversily Medical School,
Washin((Lrn, IX'.
1111R1.1 Y 1.11: MOTLI:Y, M D.
Pro/rftnr of AlrJwtnr and Otrrrt.w,
('ardin Kespiral.ny t.aboral.wy,
l/niversily of Snulhern Ca/ifornia Sehnol
of Me.licin., t.m Angeles.
FI)M(Ntl) ANTIIUNY
Sr
AI.Rf.RT 11 NIDF.N, M D.
Pre/rsser of Mrdirtne, 1>.ew
Poflgraduale Medical Schnnl alnl
Universily of Southern California; l'Atrl,
Pulmonary Disease Seclinn, Mars.n
1.u/her King 11ospltal, t os Angeles
OAK RIIX:F NATK)NA1. I ARI)RAIURY
Oak R w/{e, 1 N
I RAN7. OFSCII, PH I).
Pr../rss.w n/ PAn.mnrnlnRr. llruJ,
SealwM wt HN.chem.aal Pharmacnh.Ry,
Ilniversity of Maina, M.nnr, Wra
(iermany.
IX)NAI.1) M PA('/ , P// I)
Pro/rssar of PArsndoRr onJ th.r.r.«
Inslilule (.w ('ellular Rr.eaah
tlniversily of Nelaaska, I Inauln
111 VFNLY PAIGIN, Ps/1)
Conrer ResrwrA S.Irnrr.l /', Ro.wr11
Park Melmu.al Intlhlule, Iloflah., NY
KLNNI.T11 FAIG1 N, Pn 1)
Dorrlm, (hpaelmrnl nf Mukcula1
Iliology, 1lral/h Resealch, Inc. Ru.wrll
Park t)iriswm, IloffaM., NY
A1.111.M I N. PAI M1 M, 1u 1)
Alrnrant P.rrJr.uw n/ PaA.,lnrr,
Uwivers./y of lule.ln, Inledu, (t/I
MI/RPIIY, M.D., R06E MAR11: PAN(:ISI)RN, M S
A.rnriae Prn/rssnr .r/ R/nstNisllrs .wt
Mrdrrrnr, The Jnhns Ilo/d,ins (lnivenily
Schrtol of Medicine. Sallrnwwe, MD.
W11 1.1AM S MIIRRAY, Sa.D.
Senar Staff Srirwtlst, The lackson
LaMwanry, 11ar 1larhor, MF.
RICIIARI) 1. NACYF, M D.
Prn/essrw and l'Anowrw, 1)eparlmenl of
Ps/hnloRy, Pennsylvanis Slate Ilnivessily
('u11r{e of Mednvnr, Ilenhey
(i/ OR(i R NI I/RAtll, PM 1)
MI(I,NMOIrIIrnf toAera.wr, (1amMl.t,
West (irrmany.
IIAROI.1) It NFWRAI t., M Q.
Ar.wrotr Pte/rtarr e/ Mrbnnr. The
lohns 11..pkms I/niverslly S.hool o/
MrA.t.nr, llah.mn.r, M11
AsuV.M l.NJ T.vAnulner.l an.l
f.Knwer, 1)1'par111Mn1 of I n/4I Sl'Mnte
a1W TecMudngy, tlnivuuly ol
Calrfornla, 1)ovis.
1O1/N W. PARK I K, M 1).
As..rtae Prn/r.r.w n/ I'nrA.1oer,
t/nivrlsi/y o( A.Whern ('abfurnla S.h..d
of Medn:ine. I rN Anarlrs
MAKY S11 AKNS PAMSt11 LY, Pn 1)
A.s.Itsn/ Ptn/r...n. ../ Awnh.ml In
(Murlrn4 unJ lirn..alaer, (.dum/n.1
I/ntvr.slly 1b11rRr ut 1l.ysnlans an.l
Surae.rns, New Yolk
OFNI)K'/1T t/ PAltl t, 11 V M
Asuw/ar Pr.r/n..« n/ PutAnlurl. Mw.h
Preshylerian SI I uke's M.A.u1 / rnln.
( hKago, 11
1//9
65100 7686
11)WARU W PI I.IKAN, M D.
( Aurrw.on, Iseparln.ent o( IAarmscolo{y
and I aperinsenlal -lheraptolict. Rrnlon
l/nivrrsity School of Medicine, Soston,
MA.
('AR1 W, PIIR('f, M t), PH I)
Penfrsaw, Ikpxlments of httsuk+oy and
Microbiololty ImmunuloRy, Washington
l/nwersity ScMwd of Medu:ine; Dorn,r,
Pat/wloAy and I.aboratnry Medn:ine, lAe
le..isA llospital ut St Louis St l.owis,
Ml)
MAI C'OLM C P1K 1. Pn 1)
1.oJrs.nr nJ C.~n.nwrrr NrJrnnr onJ
P.J.al.rrs 1/nivers.ly of SuulArrn
('al.fornia tcboad of Medicine. 1 ns
Anaelet
O1 AK AR 1 POI 1 AK M t) , Pn D
F.rrwrer Drrrrt..r, 1lover Medical
ResearcA ('enter, Inc , Ik+ver, DE.
MORRIS P(sl I ARD, Pn D
Drrrrnu, Lobund I ahoratory. llniversity
of No(re hame Notre Isaree IN
C M tUMI RAT, PH 1)
Drrrr(or eJ Re.dolr.re/ RrsrnrrA,
Pasadena lounda/w.n for Medical
Rlsearcb, Pasadena, CA
S N PRADIIAN. M D, PH I)
PIa/r/far of rAamar.dnRy, Ilo«ard
Uni.eni(y College of Medicine,
WasAinglnn, DC.
11 R. PRATTTIIUMAS, M D.,
rre/rssar o/ latAo/..Rr .n/ Demr,
Medical College of Soab Carolina,
C'barktlow.
PROCESS L INSTRUMENTS
COR POR A TION
Ilroolklyn, NY.
MARTIN S. PROIT/1., t) I)S.
'CArr/, Deparlment of (>.al Pathology.
Ne.arR ('ity 1lospilal, Newrt, NJ.
RONAI D E RASMUSSEN, PH D.
A.rnrrrr Al/rnrt Ir./r..ne,
t7rparlrnenls of ('nmmunily and
I t.virnnmental Medk.ne. l/nivtrsily of
('aldorn.a ( nllrat uf Med.c.ne, Irv.ne,
( A
WAl Tl R R1.1)ISCI1, M.D. R. 11. RI(:DON, M 1). WAYNE L
PH t).
RYAN
Ar.arratr Irn/rsfw o/ Clmrrof A(rJ.cree r.n/rss.w of ImlwdaRr
University of .
.
Iro/rssor o/ RrnrA.mider. ltniversity (if
New Yor\ Universily tebool of .
leaas Medical RrancA, Gdvnlon
Ntbrasha College of Medicine. UmaAa.
Medicine, and NYII ResearcA Srr.ice, .
(:oldwaler Memotial /lnspiul
New Y..t
,
.
SYI)NLY C. RI1 IFNRI R(i, PN.D.
PF.TL_R F. SAI.tSD1IRY, M 1), Pn I).
WILI IAM RI Gf 1 SON, M D.
ha/rssor anJ CAmrman. Deparlment of
Medicat Oneology, Medical ('otleRe o(
VirIlinL, Ricbmond.
LYNNE M. RF.ID, M D.
MofArTr rro/rru+ o/ Io(AMJoR r, llar.a.d
Medical Scboul, Ilosum(fha..rsun,
Ilrperlmenl of PalboM.gy, ('bild.eri s
/lospiul Medical ('enarr, hwtnn, MA
11()eART A REIMANN. M 1)
rra/esser o/ MrJennr, 11ilonemann
Medical College and Hosp.tal,
PAiladelpAia, PA.
tll.t EN RFM()l.D-O'DONNfI.I., PH h
L.nrrrd RrsrarrA Assnrratr, /larvard
Medical ScAool, In.rurRa.r, Cenler f.w
Slood Researcb, Roslon, MA.
11fRDIRTY.REYN(NDS,MD.
lrn/rsser of MeJrnnr: Nrad, Pulmnnary
Srcl.on, YaM llnirersily ScAnol of
Medieine, Ne. Itaven, CT.
a
l.o/ersnr oJ RorterndoRr. Unirenily of
Soulbern Califnrnia, (.os AnReks.
I U(il NI: ROIIf N 1S, PH 0
Rrsrnr.A Srrent..t, City of Ilupe Restarcb
Inslilule, IMrarle, ('A
nI NSON R ROf, M D
A.awrrrr hn/r.aw of SwRMt: CA.r/,
('arduc Su.Rrry, l/nivtrsily of
('atifornia tcMr.l of MedicMe, San
/ rancisco.
1(KI PII 11 R(Kil RS, M D.
14dy Name of Jesus llospilal, Gadsden,
Al..
RO/11 RT C. ROSAN, M D.
Assarare Ln/rrser of rarAo/oRt eaml
IrJ.ntrrrs, SI Louis l)niversi/y School of
Medicine; Ass.rrate IorAofaRrs(, Cardinal
(:Iennon Memorial Ilospilal (or
('bildren, SI. Lnua. MO.
CI/ARI LS 1. ROSf., PH 0.
('/rntr Duertar: Drrrrtwr, Norasalive
Aging Sludy, VeMratts Adraiaisaalioa
Outpatient Clinic, lbston, MA.
NraJ, Intensive Treatmen/ ('en/er, Samt
Joseph Ilos.ilal, DorbanY, ('A
PAl/L SAI.l MAN, Pu D_
Assrsta.( Pro/rswu of RurArmaur anJ
Nu/n(r..n. Unive.si/y of . 4w1Ae.n
('ablurnia School of Medicone, I.n
AnRrks.
ULRI('ll 11 SCIIALPPI, M t)
Drrrrnw of NrwupAa.wrur.doRr Ma+un
ResearcA Instilutr, Worcester, b1A
J(MGEN ll S('/l/ 1:(il 1, M 1) , PH U
Pr../nsw M./ (Aaumaw, Ihparlment o(
Surgery, lalane l)nivtrsity ScMwd or
Medicine. New O,leans, I A
ALVIN R. SCIIMII)T, Ptr s)
OrrrHor o/ ('ar.ns.bnR, lufts I/niversily,
Medford, MA.
JAK(H SCIIMIDI, M t), PH D
AsusraM fro/rss.r of sa.rllrnvu.r.
Division of Riow.Rieal Sciences, State
I/niversily of New Yurle, a( Suuy sra..
Stony eroota.
ROLLAND C. RF.YNOLDS, M 1).
AnruaM rro/n.nr of PwAnlnRr,
l/niversily or leaas SnulA.estern
Medical ScAoo1, lhll».
VICTOR RICI/ARDS, M.D.
CA.r/ of SwRrry, Presbylerian Medical
Cenler, Sul Frawcisco, CA.
ARNIS RICIITERS, PR.D.
Assxi.re rroJrssw of latAnleRr,
(lniversily of Soulbern California School
of Medicine, Lot Angeles.
WII 1.15 11 RI(S(N, PH 1).
Srn.ar RnrArnu.(. Lr/r Srrrn.r.
Orruon, /11 Researcb InslUlu(e, l'bicago,
11..
DANIFL S R11 KIN, PH D.
Arvu.wt Iro/rs.w of ('Armrraf e.nfnRr,~
IAe Roclefeller I/niversity, New Yor\
ISAAC SCIIOIIR, O D S, Pw 1) , U Sc.
1O11N A R(l6l.CRANS, PM.D. Dr.n, llniversNy of Illinois ('ollege of
Aswaae Iro%ssor o/ IArnwroloRy, Dealislry, Chicago.
Medical College of Virgiaia, Virginia
Commonwealth Univenily, Ricbwond.
NM1N R. ROWLANDS, Pt1.0.
Staff Srirntis(, SoolA.eu RestarcA
tnstiwle, San An/onio, TX.
DENIAMIN A. Rl/R1N, PH D.
A.uctaN Ire/nsrr o/ hWic Nr.1tA,
saybe Universily Co/lete of Medieine.
Ilow/on, 7 x.
RONA1 1) P RI/RtN, PH D
Iro/ersar, ./ 111rmrulaRt, Medical
Co1Mge of Virginia, Richmond.
/IENRY 1. Rl/SSLK, M D.
Irr.u/rn(, lAe RoneY Fouedatiort. Inc.,
S(alen Island, NY.
W.('.R11SSE1.I,MD
Unrversily of Teaas Medical Cenler,
l louslon
SCRIPPS C'LINIC AND *I:SFARCII
1'Ol1NDAT/ON,
La lolla, CA.
MAURICE S. SEC:AL, M D.
Cfasird rro/rssor o/ MrJrrrnr, Tafts
Universily School of Medicine; Drrrr(.+,
Depulnsen/ of Inbalalion lAerapy.
bslon C'ily I/ospital, Rrnlon, MA
CARI. C. SELT7ER, PH D
1(wnero.it Rr.rwrA A.rwrrotr, Peabody
M.ntrw, Ilarvard Uni.eroty,
('ansbridar, MA.
L11C10 SFVERI, M D
Derrctsr and Dron, /nslil.le of Anatomy
and Pslbob{y. t/ivision of <socer
ResearcA, (Iniversity uf trrueu,
rer.q.a. Italy
71n 211
65100 168~
('11AR1.fS R SIIAW, M D
( h/r/, Secli.m nf Mrdresl GeaelKt, M D
Amtersnn /hnprlal aad 1 urnor
Inudule; L./r...+ of l6.d..er, Ihr
Itn.versrly n( le.at at /loustnn, tlnuslan
("IIAKLfS 1. SI1/ RW(X)1), M 1)
Aa/nonr I'...lr.vw of RsJndner,
ltnivenily nf Ruchtsler Schrd of
Medicine and t)rntisluy, Rochesler, NY.
S11())1 SIItRATA, M f), Pn 1),
P.n/r.sn, of PAo.wva.d.Rr, llniversily
o( Ilawsu Schrnl of Medic.ne llono/ulu
G1 RA11) CIIKI AR, 1) 1) S
( Aalrr A R.orlra Prn/rruw of Oral
ra.A.h.Rr. IIrnJ. Iseparlmenl of (Aal
Mrd.c.ne and (hal 1'arhnlnRy, llarvard
ScM..d of Irenlal Mtd.cine, IWston, MA
I)AVII) 1. SIMON. M 1)
/n.t.r.lw ar Inlr.nnl AfrJrurr,
(lncrnnalr (7enersl /lotpdal, (-in.rnnau,
(/11
/ R1K SKINIIO), M 1)
(her/, IYpsrlment of Neuroln`y,
tl.spehjerR llmpual, ('openh.,%Ren.
NA (ItAN 11 SI.OAN/', Pw I)
Pra/rsuw o/ lhr
Irnivrrsity of lenne.ue ('enler fnr the
Itea11A Sriencn, Memphis
ItAN(x'11 SI OR, Pw l)
A.NMIdr PIn/r1\M of 1(Yn1nn rrnr/rrt,
Sackkr School of Medkine, Tel Aviv
I/niversily, let Aviv. Israrl.
111LOI)OR1. A SI f)1KIN, PH D
Atl/qant Pro/rrv.w nf PAarmardnRl
11u\e Itmvtrsi/y Medical ('enter,
1)rrhsm, NC.
GI (1KGF #' SMC Il 1 RS, M 1)
Aturrar rn PaA.dner, Nnrlhweslern
Itn.vers.ly Medical Stho.d, (hka{o, It.
DF NNIS M SM11/1, PH D
11t('11 E SMIT11, Pn D
P.oJrlsn nJ Rr.rlemrsra. harlmnuth
Medical Schoel, 1lanovet, N/I
1 OUIS A SO1 01 F, M 1)
flanrAr P. f. er Ihstrnew.Ard Srrnrr. Pra/rra.: P.../elcur n/ A(rdr./nr.
Durrl.r, Resear:h Lipid I aMralnry,
Ternplt Universily Ileallh Sc.rn.rs
Center, Pkila.lrtphia, PA.
SIIFLDON C SOMMI"RS, M f/
f olwranrn., I enoc 1611
DrrrWr of
/lnspilal; Clrmrnl Prn/r..w u/
PaA.dner, Cotumhu (/niversi/r (nlltRr
o( Phys.cians A Surgeom, Nrw )or1
I RNfST SONDIII IMI R, PH t)
Annrlar Prn/rcvw c./ Rln. h.nrrvn,
(olkge of Ioreslry, State I/mversly nf
New Ynrk, S)racuse.
I M SONNI O(1RN, Pn t)
DrHrnew.Ard Srrarr
/.wlrrRr, (mluna Ltnivtrsily,
11hw.minRlon
SAM S(1ROF, PII I)
Ilr...l, IMparlmenl nf Macrumn:rcular
('hrmnlry, Ihe Ins/Utute fw ~'am'rr
Keseareh, Phdadelphia, PA.
S011111WfSTRISIAR('111NSII11/11,
San Antnnio, TX
t)AVIt) M SPAIN. M D.
Dr.rrtnr, Ikparlmenl of PalMrhqtY, 'the
Rruukdale Iluapital Center, Rawklyn,
NY.
AIIXANIIIRSP(X'K,MD.
A.vslonr Pro/rs.nr e/ Pedlalrrrl. 1)uke
Ilniversily Medical ('otlrRe, 1)urham, N('.
I RI I/FK1('K 1. SIAKF, M 1)
Irn/rssw n/ NW.unr, 1larvard
Itarvrrsily ScMrd uf Puhl..- Ilrahh,
R.ntnn, MA.
A.ervenr rre/rss.r a/ 1rnloRrrd C IIAROLD Sl Et l l F, M Il.
Snrnrrs, We1/etMy Cotlelt. Wetlrsley, DreMa a/ l.ah..dnrrrr. Methndnl
MA. Ilospilal, Memphis, IN
(:1 NC M. SMIT11, Pn D
A.oaawt Pro/rr.nr of Ptrr/bdoRl.
llsrvard Medkal Sch.wd, Mntachu.rus
l:rnrral I lospilat, Knann
)ACK P SIRON(i, M 1)
Artnrretr Prn/rsswe of PorAitIntY.
1 ouisuna State Itniveaity Scho.d of
Meda ine, Nrw (hleam
!1:
1
MARION S St/l ZRFRGER, M D.
Pro/ettor and CAa/.mwr. DeparlmeM of
Dermalnbgy and Syphitology. New York
Univeaily-Relkvue Medreal Center, NY
Rf NATO TAGIIIRI, PI/.D.
Asvrrar Pru/rrsw of PtrrAnlnRP.
Graduate Schnol o( Bwiness
Adminislralion, tlarvard Universily,
I4r.lsn, MA.
I)AVII) W TAI.MA(CF, M D.
Irorrt.w, WehAWarinR (.unR Inslipte,
Ilniveniqr of Cobrado Medical Center.
1)enver
I YNN M TAUCt1(:, M 1).
Aanrrae Pr.r/rr.rw anJ Aunnatr
( Aar.nsmr, 1)rpartn.enl af Ped'ulrics,
A.'unna I/ealth Sciences ('enter, Tuevrn.
MARC D. f11AM1'S, M D
Srnrnr Rr.rar A Frll..r, Mayo Clinic and
I oundal.nn, Knchesler, MN.
('AROLINF. RFD1 1.1. 111OMAS, M D.
P..r/ess.w F.merrrus of Mrdarnr. The
lohns Ilopkins Itniversity School of
Medicine. Rallimore, MO.
11'R(1ME F. 711OMAS, PK.D.
ProJrttnr of Saulart F.nRiwrrruR.
Ilnivenily of California, Rerkeley.
)AMFS F. P T(1MAN, Ps1.D.
PraJrss.r and fAaienran. IkfNrlnteH of
Pharmscnlntty. ('hica/{o Medical School.
Insli/Yle fn. Medical Research, Chicago.
IL.
ANDRFW M. fOMI'TSKO, M.D.
Prevdent enJ IlrrrrMr a/ ResrarcA;
I.ruon Lahnrslories, 1.1d., Rnchester, NY.
)ANI.T TRAVFI.1., M D.
Alv.rmtr P.a/r..w of ('lrnlral
PAa.wwnl..Rr. CorneR Itnlvr/s.ly
Medical (olkge, Ntw York.
)AMf S TRAVIS. PH 0.
Pro/rssr ./ RrarArnenery.
Universi/y of Georgia, Alhens.
LIE SIIA TSAI. PH D.
ResrarcA Aaorlar in PaAofoty,
I/niversily School of Medicine,
/laven, C7.
GERAI.D M. TI/RINO, M I)
Prn/essor a/ AfrJl.lnr, Columhia
1/niversi/y College nf Physicisns k
Soqeons, New Yurk
D M. TIIRNI.R, PH D.
lfrd, 1)eparlunenl of DruR MrlaMlnm
and Rilrchemistry, llarklon 1 alr.ulorns
Errope, 1.1d., 1larrople, YorksMre,
[n`land.
UNION ('ARRIDF. CORP(1RA flON
Nucksr Divisir.n, (>ak R idRe, ) N
UNIVFRSIIY Of SAN I RAN('ISl 0
San Francisca, ('A.
UNIVlRSIfY OF SOu111) RN
('AI II (N(NIA,
1.rn AnReles, CA.
SfEP11FN F. VATNI R, M 1).
Arsnrae P...frv..w o/ AfrJrrmr 1larvald
Medical ScAoul, New I nr.lind Kes.unal
Primalt Research ('enter, Swthlrna,
MA; Mvrnar rn Af.Jrrrnr. Peter henl
0riRham 1lnvpnal, Iluvnn, MA
f.1 1.K11' S V1 SI 1.1., M 1) ,
Pr../nt.w and ('Aarrmnn. Ilepartmenl of
rharrnae..bRy, Pennsylvanu Sla/e
Irnivertdy ('olleRe nf Medicine, Mdlan
S Ile/shey Medi.al ('enter, l/ershey.
RRANISLAV VII)1(', DS.
Pn./nt.r oJ An,.n.nrr. (SemRe/n.n
llniversi/y Schnols of Medicine ad
Denlisle y, WashinRlon, 1) C.
ROM1:O A V/Ix1Nf:, M D.
Asu.nar Pra/rr..r ../ Po1A.daRr, Yak
Itniversily Schord of Medicine. Nr.
Ilaves,('T.
M TI R K. V(K:T, PH D
Prn/rs.ne of AlrrrnArofner, 11n.vertily ol
Washinglon ScM.ol uf Medaine, Sealllr
IRENt V. WAN(l, Pw I)
As./t(aM Prn/erlw n/ Rnu, anJ ( IIw1~nl
ImmunulnRP anJ MrreaM.dner, Medical
I/ni.enilF of South Carolina. ('hallrcton
The
Yale
New
E D WARNER, M D,
Prn/rsrw ./ PallnlnRr, Slale tlnivrrsil)
of lo.. College of Medicint, lowa ( rly
71)
SII/F.LDS WA/(RI N, M D
f).rrrter a/ 1 aMrahrir., Cancer
Research Institute, New Fnlland
Fkaconnt 1lospnal, R.ntnn, MA
YASl1S/11 WATANARI, PH U.
A.u.rwr A(rn.Mr, lhe Wittar (nslilule
of Anatomy and RwdnRy, Phdadelphia,
PA
RARRARA K. WA1S()N, PH D
.IrvsroM /orrr..d..ar.r, MassachuselH
Gtnereral Ilorpital, RrrewrA Ar...r.arr eM
Ro.lrr.nfnfr anJ In..ww.d.er. 11a.vard
Mr.bcal Sclu.ul, 11.slnn, MA
IFF W WAf11NRIK(i,M1s
rn/r...w a/ rWA.dner, 1/nivtrvly of
M.nnes.IS Medical khool, M.nnespol.s.
)()11N S WAt/G/1, nr1)
rro/rsr.r a/ (M.wnr.y, Manachuutss
Instuvle of Technnhyy, (smhrA~e
T110MAS F WI RR, PH a)
lt../r.vw of rhnraloe..al f'Mnvurr,
Ohio Sutr I/n.e.uly ( o1kFe o(
Medicine. (blvmhus
RICIIARI) 1. WF('/ISl I R. M 1)
Clrn.rnl IAr.rnlnRrd, Monlefinre
IlospNd InslAule of Rr.ear.h,
Iiltshsr.gh, PA
/O11N V W[11., M D
Assustanr Pra/rrur of Mrdrrtnr.
Universily of CohHado Medical ('enter,
Denvel.
1. SFRNARD WFINSTFIN, M D
IraJtuor of MrJrrrwr .nd Fme/ronnrnrof
Srrrnrrs, Columb.a Univetsity, New
YotR.
A. WFINSIOCK, h11)
Rrsrafh /rueArautl. I .ft Sciencet
Uivition, I1F Resea.ch Institwte,
Chicago, 11..
SIGMt/ND A WF/T7MAN, M D.
Asvsrawr Iro/rsar n/ MrJ.rinr,
IltmslnM.{y(1wcnIM1 (Inil,
Massachuseus Geneul Flosp.td, Rmlon
RUSCIII W WFII/RMD
Ie.h,toau. M.Taul IIo.pHd n(
( ht.1r. t nun1~, M'e.l / Artler, PA
A Sf ANL1 Y WI LTMAN, PH 1).
Assw.Ne rraJrao. ../ PAornrxnluRr nnJ
Rrsrar.A, 11ruohlyn ('ulk{e of 1'harmacy,
nrowyn, NY.
SIMON 11 W1 ND1 K, I`II I).
Rrvrrh Ir../rs.w o/ Rn.rArau.rn
Ustiversily of (Mlahunu, Norman
DUANEG. WI:N/F1, PuD
/ra/iuor los/ ('/1or.wan, fkpartmenl d
rlAarwocnlojy and loaicoh.Ry, the
U.ivenity of Ksnsas S./n.ol .d
NAarw.acy, 1 s..renie
T1K)MASC W1S11 AI1, IswI)
Iro/rrtw of
~hornw.JnRr.
tlm.rn/y
of Vi.paV S.h.v.1 o( Mtd.a.nr
( Aar lolletv d1e
1Rfl)1RICK E WIIISKIN,MDCM
n..r.r..., Div.siow of Ileallh and
rrtsnnalny 1-qvibhrium, The Age Ctni: r
of Nrw 1 ng/and, Inc . Boslnn, MA
JAMISA WIII,UVM,hII)
fnf....r awJ fhoun.on. Ireparmrnl of
Velrr.nary Science. Un..e.Nly ul
W.scuns.n, Mad.sun
R(X:/ R I WII 1 LAMS, M f)
Irn/n..w o/ fhrn...aY( pb..fr...,
(Iasron I oun./a,uln Il.ochrmi. A
Insr.lvle, lhe Ilniversily nf Ir.as,
Aostin.
1O11N T WIt SON, Pw D
AsuuaM rrn/essw of ('rlf rn,f
Mo1Hullar RnduRr, Medical ('o1kRe .d
(ieorgia, Augusla.
ALVIN L. WINFFKS, 1'R D
Astnbn/ Iro/rssar of Mrnuh.nlncv and
er..rhrnersrry, The University of
Alabama, Ustiversily.
DAN1/1. 11 WISI MAN, M 1)
AtNr.raM ha/r..nr o/ irJr.nr.... Ilnivertily of Snu/hern (lldo.na,
CbiWren's Division, Los Angeles ('uunly
(:enersl 1lospiul, I ut AnRr/es, CA.
RRIICF A WO1)A, M 1)
AsurrNr Iro/rtuw o/ Iaih. /ner,
llmvtrsily of Massxhuselts. Worceutr
714
i
GFORGE WO1.F, 1) hlp..
Lo/rtu+ ..l rAev.Joriral C1Nmrurr.
Deparlmenl of Nutriliow snd Food
Sc.ence, Massach.selu InsliNle of
lechnnlony, ('amMidRe.
1 FDWIN WOOO, M D.
lnsuurenr ra Mrd.rrar, RnS1ow Univetsity
ScM.nl o( Med.cine, Rostun, MA.
S(1MNI.R WOOD, 1s., M 1)
Asustanr Pn./ns.w of /wholn[r. The
lobna Ilopkms l)nivenily School of
Medicine, 11a1tAmnre, MI).
JOIIN r . WYA 1 1, M 1)
/.n/rst.w n/ IarA.JoRy. S1 lnuis
I/nivers.fy S.Mwd of Medwint, S/. I.uuis,
M()
KOJI YOSIIINA(;A, PH D.
Cenler for PopuUlion Research, N1C11D,
Natwuul ImGtures of Ileahh, Selhesda,
1641)
)1S
tNl)FX OF PKIN('IPAI. INVF111(:ATV/tC
AhooA, 1. (: , 117
Adams, 1) t), 116
Adler, K R , 17`
Alhers, 1. / , S:
Anlnniadet, 11 N, 7.
51. 51
Aune, 1, M, 111. I19
Itrnnell, / S . $I, SS
IIrnR, R. 1. 36 A1
111air, P R , 119
1lresnick, I , 7
llrysnn, R., 117
Itushee, 1) 1. , 1, 9
CamptKll, 1' I . 12
('aarn, A , I lt
('hen. I.. 11 , 10 1:
('hen, Y. 1 , 11
('ivrn, (' I 11, 150
(lawson, (: A , 11
Cochrane. C (: . 11
("uhen, R tI , 190
('nlman, R W , 61 6 7
(reulr. C f , 119, I:n ,
('ratski, (: . I' 1
l/amjanov, I 11, 15. 111
Oersseroth, A, 15. If., hR
uuesherR. P., 16 1!
I)vnrak, 11 1' , It
Frwin, V. (7 , 122
1 inlay. T Il . 69
1 isher, P. u, 19, 20
fusler, 1. A , 31
toa, R.. 34
f ranke/, 1. W., 21
I ridovich, 1., 121, 1?1
triedherg. F. C.. 21
Fu.e, K., 19, 90
Cirkn, 1 F.., 21-:1, 121,
Cill, C. N., 21-23
1lnttman, R M , 26
tlnss, W P , 92
Ilu9anrr, R. 91
lones, 11 P., 122 - I ln
Kaspalkin. S.. 26. 27
K nhkr, 1/., 155
Knskenv.o, M., Ill 1R1
I a jlha, A., 91-93
1 onRenecker, C 1.., 110
I.umtherg, 1. M, 27. 19. 19, 71,
96-1t1, I11, 156
1 ynch, 11, T , :l-11
Macher, R A, 156. 15R
Markham, R- R, 1 St
Milchelt, 1 A, I11, 112
Murad- 1 , I1.-11{
Murias, C.. 10, 11
NaAet, I A , 1?-16
Nelson, /) , 1 19
Nrewnr.nki, S , 72-75
(11we.. / M , 159
Prfrr%rn, 1) K, 119, 1f0
r..l,., I h( , /n. 160
Prs..r, W A , (1n I1`
KrF. rn, I 1 , 1h
Kr.n.h, K , 111
K w hm,.nA, V 1. I J 1
K san, 11 1, 77. 115.
Cnlry, 11 V. It , 11?,
Serahen, 11 , 11/. 115 I Ih
I/1
Shrchter, 1., 77. 111, 145
Smuckkr, F A . IA
Sprinifet, T. A.. 160
165
25 S/einherg, 1) , 7t, 79
Slsrasel, T. P.. 79
SlranA, F. L., 116
laussilt. 1.. M., 46
Taylor, 1). I.., 66
Codman, (: C, 1?S, 126. 172,
(:oM, W. M, 11-17, 151, 132
171
Cowtischer, S, 2). 151, 1)). 17/
CreenQerR, c. S, 69. 70
(7reene, M 1, 151, 154
Ilagino, N . 90, 91
llal/,l M, 121
Ilenry, C I - 121
1/nanue,E R., 167-169
Wa1ah, P. N , 80 11
Waul, P. A, 170, 177, 1111
Weinhaum, (: , /1. 50
We1Rus, 11 (: , 179
Welsh. M. 1 , SI
Wennmalrn, A., RR, 145
Ya, hmn, S, 170. 171
v
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