Council for Tobacco Research
1984 Report of the Council for Tobacco Research - U.S.A., Inc. [St]
Fields
- Depository Date
- 25 Sep 1995
- Master ID
- Ctrmn00010849-2859
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- Author
- Hobbs, W.D., Ctr
- Request
- 118
- Type
- ANNUAL REPORT
- Box
- 006
- UCSF Legacy ID
- vvr30a00
Document Images
ANDREWS OrFICE PRODUCTS CAPITOL HEIGHTS. MD (K)
. Organization and Policy
The Council for Tnb.cco Re.earch-U.S.A., Inc. is the sponsorinR al;ency of a
pm6ram of research into questinns of tobacco tase and heslth. It ia the uutRrc wth uf an
orRanuatinn fnrmed early in 1951 by tobacco tnanufacturerx. growen anJ waehnu.e-
mcn Researrh support hn been mainly thm.Rh a pnsEram of Rrams in aiJ .upde
memed by contracts frx rescrch with instnulions rd lahiwatories, ilK ('aim J Jiscs
nrn oMurate any research facility
Tla Sctend6c Advisory &+rd lo The Council moeb r+c6ularly toevaluale aMdica-
tinns fur research suppott. judging them solely on the basis of scientific merit and
rek vance
The Council awards rtserch Erants to independent scientists who ane assured
ctwepkte scientific fatrkwn in c.wsducung then studies Grantees aksne re rt cpm.fik
fGw repnsinR nr publishing their findings in the accepted scientific manner-- IhriwRh
mcJKal and screnhfic fannals anJ srneeties
Wit t uM 1) flt»1es
Chauman
1984 RF:P()RT
r~f
TIIM: ('OUN('ll. MOR TURACCO RMtiEAaK'll-U.S.A., Inc.
THt: ('(lIIN('ll. FOR T(1BA(Y'() Rt1F:AR('ll-lI.S.A., IrN.
90 Third Aveswe, New York. N.Y. 141022
ti('1!':NTIFIC ADVIS()RY B()ARI)
a111a ('tuncil far T..Lxu+ Rc.cuch - 11 S A.. Inc.
a% ol rk.clnhcr 11, 1984
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'Ihi" rrpM clwNains abstracts n( 174 Iwpers that have appeared in the scleMllic
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S
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to Cigarette Smoke
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l.a t'llrtl Ilt Jrlly ryNt.utr lu 21(1 .Ir:I.rtte .nN.kc ufl hcni,d:l,pytcnr uwhNrJ IunK
11111NN%
IN-\k .1h1LNm% wclc.JwtvrJ/nh4h.nNlkr am1.h:1111r\IN1.e1I111Nr I WI/CI/I///n1Nnl
tlNNht/t .IlNlnl w\'f\' Il'\'INIInIrfNhVl 1r111~'f J1Wl' aIN/11N'11~.11\'II (k.w IIN'/11/1~1.N~
1.111MN1
lt,N .nNlkrr,Ul tlnw (IIHNI~'h IIN tlNwhlll'\ a1NI INIIyla/1NNIJIC 11aV'A\ NllUl11NN111N' naa k
r.l~r..l dN rr.ll.uut I IK Ihlrn11a1.N% wtre IIc.IF11rJ, lkvcla{+rJ, arNl u1111vc.1 1.Jy. ar
INN1.111' /M'\1, ln..It% ware Ik./K11eJ Iwl IINu ur/lv:dN.n wa.IN11 afisNUvrJ
I/N.1 Irun1 ,JI .IIaUI c\(NI.rJ t.N11rI11..IN1wrJ 111:11 11K %(IINNUIrINI. Ina'Nk'IN't .lI
II/Jh/nJ1N I1111K III/INN% In ( I K I/NI (:111 alvt'..I1r :NMYNN:III /INNIIJ..I wa\ II S'1
%tlNll'
aa1N.aJ .In1111.J, wrlr Ilh.rrva-J t./ hIvr IN1 nIJ11g91nU lunl; thdnlYJ JUnag 1111 .nNly
Ihr uNl1 Irc'y1Nnt Ir.NN1 .dlvrvrJ 1/1 tIN' mnN.kl' t'RINIyJ 1!IINIIN Wa\ /NrlIN'lltrJ aI
vr.d,11111,Mn.~111JF1k\UIIIIIIJINNIII'AMnI Adrr211wark.n/r.INnurrdwnNNklNe
ul 1'AM/l w.l. 11M1'1 1wo INIwr Ir.N.N% wa'rr a.arldrJ wnh .uN.ke rt(NlaitC.
NIu.U1N.U. uNt.111L1~1.11.1 Illr IhNhl'J a1NI II1111/11~ D1 IM' MIN
In,NuNnl.-I II('tI Ir(bn11n1\r wdh Ml'Arr.u1tr11111 h? Jll/crrnt cuNlhlna
tN11/1 411 I1/11141,111N1I/1}Il' J1:IFIN/y~ in t1K IIItIr Alva'.JL}!t'nla' Il'aNN1\ w\'ll
l'I:1%\IINYI
unu 4 aurfNN. rlvr.ll.lt Ilyprrldeaa 1AI11. a1vrlLu INNNINn(Nt'%llllg INNhIk.
I AN/'N 1, .Jva..LN . nllqxa..inF INNlulr.l n('N 1, and .dvrular :NknlN .Irt IaNIw 1 A Al'/.
~.III:UIMN/\ la'~NNI~ Wl'fC \ IJ\~IIIrJ In11r 1 lIttI'INIC NII/:111NNN IIN'Ia1Ia.le ISM 1,
.yua
nNNI% 1N'111111m111`N1 JMI NIII,n111Nh l\'ll lattIM1111J t1t'l 1 1hl' 1111N'1 aat\IINN11,/%
11NIINI IIN IINhYI INN N Iy JII IrflIIIIJta'J l'aft IIN11na% I I/I )l 1:I/NI a vaf M'Iy ill 1t11
tl'II l':/t111N1-
Illa\ I 11C \:Ifl11NN11:1% a1NI lventtl:llly t':111K11111e akti:llh./I IIN' :In1111aI I IN'
INUgre..ive n,ltufc ul the.e Ic%Nm% wa.lMKunxnlrJ alNl a ahcnlc d:pictlnp 1hr ev/du
INN11/11h1'4 llull)'n1111'1lt wa% INhlYlalCll (%ll 1'IKUfe 29 atNl SCl'INIII Ill I)/
AtN'111ary
.lwlle.wnhlllhcrktNlwncarunnrrn.atNlnthrr.tram.ulnllt'evuKFrvlrJ 11('111/Anl
l bm a1N1 N(' 1110 'wn 11194 c wr/a' r11ctNN.J in Ihclt .u.cC ptlhilNy lu Ml'A i1NI11caJ lung
/ao.er.. 2/ a Iww rr.pNl.r lo M('A alJuaeJ IIIOK tuuNN% wa% llhvrvcJ, a1N1 tl tlx
tatrlnl/l;rnlr aa av/ly hw lunK li..ur w/.lk IrnnlnrJ Iu 1~ grC:11r.111N M('A. IuihlwrJ
by 7,x /ldlylltn 7.11 JlhyJrl..y hrnildary+yrrnc (Ital 1,11 Jlotl, hl.th nl wlulh wrrc
111tN 11 11NNr :N l/vl' Ih.m hcnitdah/yfr/w t11a1'1
I/.Nly rlryrYtr la 2A1 tlr.rcnr mnN.kc JiJ nlq :Illrl the typr% ul Ml'A I/NI/NC1I
IN/IttNN6Nyh'\NNI, LI/yrYl'tI11111t1..1111II1/\h:/nICRINowJ/Ilnc Itw'rcwrrr.hpblvarla-
INNI% It11M' IIN nla'/N C aNIJ JI]1111N11NN1 UI the kt\NN1%:1% J Iu/N11NN1/1I IhLL.111.N1 nI .nNlkc
r.IN..urr Analy.i. u/ In1I1VN1U]I IYnI,' Ie%111fN .h11wrJ that lhc M('A hanl e.INIVJ
ynNq. h:Nl a hlKhrt lnt'iJrrlce anll//lr .INMCt lalcncy (ur all maliKnanllunK Iun111r% than
thr Mf'A .IrN.lr e4 1111veJ Krlwp SftN/ke eaplr.eJ nlne lkvrMMuJ a.hghlly hlKhrr
nN NIrIN r u1 AN1'N. A('N, a/NIrIN SN Ihan the .ham ctlNl.eJ /nw'e Mlalya, tll 111r
lMwcb.pnNnl ul .ltlNr Ihc.c 1Iltrr IraNn% Vr n1aI1/,ylanl IC\NNI% wa. d.n IN'/l.ull/rJ
1>..J r r yN'Yrr N. ' A 1 t IK arrttr .nn d l' I II J IM d aI1r1 I1N' /IN NICnI C alNl rnI JI%U
/IN/INN1 U1
thc.r A11'A uNtul cJ (r.N.n. wINn cuolperrJ t11111r %II:1111 CIINfiI a'.Nllflll~
1
I IN n11111hr1 1.1 IIIN'l' IN11!Inally INII INl lr%l I/N the %Innkr, %h:1111 a/N/ \IN'II I:LNIIh
w.1. !//s 1, 1/111.11N1444, rrylact/vlly Hnl' wa% flvrn mlr.n/.N ha:dly Iu;NNNINr 1nNlp
u1 lnar 11N nulnltr./l mia'c Ilul lln le.l I/N 11N' NaI' /.I/N/kc. 11/1' 1.ha/o. ~INI tl.J'
t.Ilrl/ gf/Nlp% wr. 12//, ?tO, arN/ 1J11, rrylr/uvrly. Ital' w:l. }:Ivrn thlrr tn1/r..N
h/wrCAly Illll'rv:1k anll ~/INIkI/~h:111/l'~INhYfI' wa-. NINGNrd INIr week altrf tlN 1.rA I{:11'
Iur:dnNnl `IlNlke C1lINNtlfr t'tNNlnlll1l1111 a daily h:h/% hN IIII welk\ Ihe 11114' IJ !K1
t It Irc11r ./IN Ikr w:l% tklr r/11u1rJ lu he 11 2 /11r.11'M IfCr tlay IIl'r IINNIV 11//11 IlN'
/lN1I1
Irlnu IIIe .nN//,e,.haol anll.hcl/ tl/nlrlll Kn/1qr wlll hr rcpr.rntrJ 11r.1, lulluwrJ by dlr
rr.ull. IrlNn t1k Hal' tncatrJ gr/Np..
lbr 111at1N l IInN'aI llrM In IIM NrNlkt t1lIM/X'l/, lha/ll l111NIVrlI, a1N1 lhl'II r.N111-.I
nlla r wrrr +. /u11uw%
I/') he nlaplr rra.an. hlt.k Nh ld Ihc mN r wl tr rNhl t I.NNbh..n.
IIIN /a1NhNllly Ir1lN/vl'J a111111aloo If/Nll (lle %IO/Iy 11 e. SnNIkC lN \hall\ l'>11NNIIIe
rrlatrJ
INlhlrr rl'Iale1l, IN 11.N,"u/11CMC11 alf IM NINIke Ihlw (wllhkm./, IN lkvr/1qNnE Jlva.r.
that bkrlr IeJ Iu Ihr Jra1h I/l lhr anmwl. ?1 K:IIe ol wrighl galn wa..luwrr in IIIr .halu
a/Nl .nNlkr Fr/Nyr% clNlyurrJ 1/1 the .hc11 cINNa1/. 11 I)a/ly ('lHlh kvcl% avrlagrJ
17 2'% , I 4'I a1NI 1 1P.{ IUI Ihe %IIN/l.l', oohYIU afMl 4IC II FrlNllh, rl%IMYYIvCIy
A/INN11r tIK .hai/ cINNnJ., MM% ol Ihr mice d/tvl ./l .uch nrlqda.IN lll.e:/.e% a.
hr/11:d.11N/1a9N t':I/Krf~ I l VX I arNl 111wu.art'lNlu. I 11'%.1, whilr 411'% JICJ ul /NNI
IN111.I:LIw (l'.NNI. llph a% l/M1~.'CoINN111UICWINNna 1' II'!<1. na'11h11/1% ( -1'%1. a1Nl a
varNly nl illt Ilknlal k.wN1.1 2('%1 lllc.r vu/r lypr. ul k.illn. wa rr uhv IvrJ m dN
.nNlka alNl .hanl rRpl.lJ nlirc. 11¢1ai1rJ allalyv.lll the hdhlwlng Ir.NN14 wrra /II,Nk
in .UNIkC arNl .halU CapNCJ aninlal.: 11 luno,' t.llll'Cr., 21 /NIn nMqdr.in: /f.INrat.Ny
Ita1'I kt'\NN1\, I) IN11er nIN1-n1Y1111:I1IN- kL\NNIh, 41 all IllaligllaMilY, S) IN'.NI a/NI IN'lk
hMlM;nr/N11a., a1N1 6) IMnWllllllne lil lunNlr%.
All /unF' l'anl'l'h IIhwlvl'J in IIK 11('NI/t'uul micr wrrr alvrul:U a1/l'INN-ara IINI
/n:1% (AAl'/ No VIIIalIN1Y% l'eIl l'nIl'1111M11:h t1r tllhl't rU1/1NN6Ny l':Nl/1NM11.1~ wlrC
Ilha'FvrJ In 11w .aNlke, .hanl, lw alrll t/NNt111 Ktnup. /1 Idal ul 14 AAl' wrrc Ilhvt vrJ
/NI/ 11I a I/II:/I 111 4111 anin/:ll% at n.k in Ihe .nNlkc e1lpu.eJ Krlwp, whlle 7 AAI' wrrr
/ll..etvcdlwlldt.Sl.hameRplt.eJaninlrl.Wri.k.1)alaan'rlya.l.arSrlt11N11V 11 Iln
1/Nn JlllrrclN wayo, /ININ':IICJ 111:11 rM/1hIIl'rl'11l't'\ werl Id+.arvrJ hclwrrY IIN .nN.kr
.N
.hanl rx/NNaJ Kruup. at p 4/1 IIS. 1 hc Inl'wkl IN'c l,/ A/1(' w:lv gra'alr/ nl dN' .nN.kc
e*INVy'J rrlN/(h l/Nllh'JreJ I11 the %h:Mfl C*INNI'II 9I.NlIN (/1 ' 11 17I :IINI /IN' IIll'IN y.J
t'RIMI'\%NN/ wa\ tk;etC:hCtt ln Ihe %nN1kC CN(nhlJ 1,'r/1111N lYMt111:If1'lI tI/1IN1 dum r alNlvd
gr.Nqr+ ip = 1/ 1/1/ (kcunrme /d AN('N tr A('N war 1lY7N LN \/lN/kr Ct/N1aYl
ynNp1" aNI 21/t1S1 IIN Ihr %11am CIINII[VI F'hNllh 111 = 4151 I/MNIa'IMr/. 11 11 IN
ILtr11cy/1 Ihc .NCtulcINe 101 enlwr AA(' lIr A('N yirllkJ dlr IarKa-.1 dlllcu'INc
hrt wran t11e .NN /k r a1Nl.ha/11 e r pt.rJ plNy+. 'fhr final /tw Nll-IN c ul A A( ' I N M'N wr.
44/V711 in IIN vnN.ke r.IN..cJ Kt/Nlp clNnparrJ 11/ 2M/hS1 /a Ihr .h.1Y c.IN/.rJ'raup
II 9
I IN.t ir$ Itlen t'% werr MN t)IlfRenl ((1 - 1) i'/I, but 1hl IunMlra a(1(ItarrJ I1NIrc llr/l'kly
ul 11N .nM11c ealrt.rJ Fnwp Ip = (I /M)1
A 1,.0 td live nt«I nt.rla.l/t tr.pnahny ttrxt kaiun% were analy/tJ I'AMA,
umlc.ll.nlI rhmnl., twuts okJl.r. atlJ Iwul% r.lcrna. (1N[ uvrtall ult-IJerKr ol PAMA
wa. 1!:< wh/ah 1 ttNlsnkrnhly h.wrr than that nhscrveJ in /hr Iwcvilws tlKarclte
.nNAr.nNly llK nluulr'r td I'AMA./ntrcavJ w/lheaprlnr. INII tNrly rrathct! lV;.
t1111111/; /IK 1.2,14 IIMNIIh%tll a'tr11/Nlre ( tNlf,'rtlNMl waa a rallN'r ltNt111MM k\IIN1 Ir11MM11
tIN vlwdr and sh.lnl c.lrl..d anunal. Ihr IK'eurretlce /d ttm~cVitNl was ~rratcr m thr
.ham cslNnttl anolpl..ulnplttJ lu Ihr snrlke rtl+tneJ nlKr Ip =/11121 Iht hnal
uN nklN r r.l /hiunls was rr.l th/lerenl hrtwecn the amnke and ham eyp!.cJ ICnwq+.lp
1/ ') 71, M/111N' ksnm tN tuneJ.l/KMIy nwwe ral+idly in Illr snw/kr t.plv d nw c/p
!hl l lK I.Ilrnk y fNrnN/ hN tq11/s uwJu was slwlrter /n.nn,Ae c.prncJ nute p' 111/1/
a/wl .xuNJ/np tu arN .naly.h, thr lin.d inritkncr u/ thl% k.Nln wa. Idwl hy/Nr /n
\I/Mtkr l'a1111µ11 amnul. /p 1/11/S/ The final inthknac uf twilia e.lrrna w;l% md
/hlh'/r11/ hrtwet// 1IN' \11NAl' and .ham riIplxJ suwpt Ip - 111t/ Ilnwrvrr, IINre
were /ntht ahtms 111,/1 Ihl. IrNwt nat uncJ with a.huntr latenty in Ihe .nlllke e.pp/.rJ
Klwlp ttNUp.urd ttr /hc .hanl rtphcJ Xruup Ip = 11 111).
Ilw tMlw'r mNl Irto{dJ.l/c k.nul tlhvrvcJ was rnIlhnl/s, an iMlamnlaltlry 1e.wN1
td 11r h/dlwys Ihrrr wrre m/ Jlllcrrn.'e% hc/wcen the snNlke tnllrrscJ and .ham
r.lN/a'tl FnN/p.
A ttNnpJrr..m td Iht tttuncrkt Itl all mallKnarlcit. dcmlNl.uatrJ a 27'( Ini
Ih'nll' ItM /IN' %IIM-kI'tal*mcJ anJ a:'1'1 /IMNh'nlr 14m the shalnt.I+t/.rJ amnlal. Ihe
IINIIh'1Nr a1MI//N 1.ucnty wat rw11 thltcrcnl hrtwccn Ihe Iwu rnlups
1 hN parlNular tyft ol tunNU, h.v.l alNl ncak hlxusartuma, waa tds.crveJ Mlth a
higher Ircy1N/wy In dlc snrtkc t.INtvrl nntc amlparcJ tn t/lc .ham eRplncd mltr
7Ih'N tu/IMN% we/r h/rhly al,'rrta%lvt' 11fh1 nN'ta%l,hl/rJ /11 tl\~Ilr\ far renNlvell fr/N11 the
I+Imlary ./tc A ttdal ut 2'/ hraJ arwl /w.k Ilhrtlsn.tNUas were nl..erved in Ihc .orJ,r
r.lul.cdlnNC,tumparrJwnhxln/hth.lmctpt..JKnlups Ih/.th/lcrrntrlshlgldy
.ifndK.aul lp ' 11 1151 I a1.11surc 1u.nNlkc wa. J.aNl,qad with htNh ahlKher u1cNMINc
a1Nl Iwwtrt latcnty td hcad and nctk hMu.uttNnas 111r nKt hanlsm hy whlth tINsc
Iu1lN/rs di vclt/llyd Is am kar.
IIr/I1;1111(MtIrIN' (u11wMS /IKIWh'J Iyny+M/sanI/mas, rrlitulum cell aarttNna., and
Iy/n1+Mtylar Is Iytnl.tMnJ kukcnliaa. lhe tNNal inriaknce Id tlwsr Iunwwt wa. 11'1< in
Ihe snrlkc cotp/.rJ arrl Iv';F in the .ham eapmed animals. l1.InK flwr Jlllercnl nxth
INh Id analy.i., thr inrnklKe td thr.c tumllrv was greater. aml the latency periwrl wa.
.INwtcr in Ihe .hanl exppKeJ rlMta+arcJ tu the stnake e><pnrd ;xtitnals (p ~ 111/S/,
Analy.i% nl Ihr Nal' IttaleJ Ktllups wa% perGlrmed a. JesrriheJ alN/vt The
i1M aknte of 1'AMA in Ihr ()al' t snrdee e.plwcJ Rrwlp wa. 31'16. /y/r the aninula
c*pnseJ 1// 2R1 u1w1Ae wlthtwl MaP IrralmcM, the int:idcnar ul PAMA wa% kta than
21M3. It wuuW .c'em that trealmeM with 11aP m1lJilitJ Ille macn111haMe re.pm,e
n.u11inK in higher rncNkna'e af the.e p/KnlenleJ cella in the lung 1)aily e.l>tr.ure trt
21( I tlgarr/te snNlkr Jurmg the lime Itat'-rndureJ lung lunww. JrvehKrJ JiJ ma alter
Iht Ina'uk'mr lu latcrwy in the Nal' 1 snwtke Rrlw(IS c/NnpaleJ In the Hal' / shaln
e.prNtd KrtNq..
V, ('l R-10111. t'XP(ril1RE OF Rl'IF'l/('11M MICF TO 2R1 t'I(:ARM:TTt:
SM(/KF:
, 1 )u/nK 1971) lyxn, an eapn.urc refimen wa% tkvehq+rd tha/ rew/teJ in h.w /u.n
Ily ItN la.l/l 2N1 atwl IAI uKurtlr nNtlc Ilw.e eal..ure ttvrNhluNt% alLtweJ /ht
..Ik'[lullnr, t.1 a lunl: 111011 .tlNly wFIrIrLy 11N hntlu~ual ellet1./.1 .nwAe hum (Nllh
tiKarrltr lypc% cuuhl hr .imuhannw.ly evaluatrJ Such a hlnl! tcr/o .tuJy rmphtyulr
1111\ \/IMtkt rRIS/Wrr rrFinKn wa% prlllr/styl, appruvrJ, atMl initiated Junng tik I'rxo
ttNlu;Kl yrar In luly 1'11/11. Iw/wcver, it wa% tkcwkJ thal tht. .ludy .IM/u1J ma IN
ttNlq+IctcJ aMl Ihal \IMlkr Cx111hW1' WN/er IheK' newly Jr(In'J tINMI/1nNh wIN/Ll lt
InmteJ tn Illr kn fth 1.1 tioK Jur/np whlch animal% ln CI R MIIA were lu hr c aIN.vJ lu
snN.Ar '1 ht rw fltrtolcnts atNMluchJ in thr (') R-M111i were tkslylnJ Itl rvalualr t t naul
.Iwat tcrnl luewt/Nrgltal rnJplNnl.lhal nuy ha rckvanl lu Jrtrrtnininr Ihr IMdcnual
hwlufaat ati/vlly ot wlwde rlrarrlte.uwd,e.
1 hr.uwrlr r.INnurr rcpinnrn hw in Ihr..ludy diJ /MN include «sl prntKl% haIwcro
.//trr..fvr t/}ara'llc., u%rJ'an eot(fn]ure Iq'rMNI rlf It yy11nJ. per minuta'. a1Nl CtNnlnu
tNl% rulNNutt' /tM 17 "lutla" 1n 1411 ntmull'S, lllit re/.'1/1Nn n.'Wlll'J in xll u4 I I'M
Ih'IMh11e1/11rt Jay llrt /IMNNr Iunx, an awrral,'r (j)Ilhl/t I's ./YA, a1MI 1!Ilala'1 Ihall')Y<
UN Llrn\r .11 1'AMA by IA weaks ul daily .ml/kr r.prsure.
I IM' h/1hIw1111,' a%tay\ were %e1lY'Il'II 1'M the/r IMMa'nt1al /111M'eJlat tN 110411111401 hN1~.`-
Irr/n rlItct..d t lyarctlc ttlMll.e: II /nh/MlNlrl ql IIuI/Mlrtilry I)NA repair rn v/lra, '1
.naluLdMm n/ pulnrNlxy 1)NA %ynlhras In viUU: 3) IMMN'tMNt UI IN/I11NN1.11y a/vl
hydurarhtm hyJ/u.yla.r IAI1111 acttvNy; 41 ImludilNr ul Innahua drearht..ylas,
1()I)('/ artiv/ly. SI aurnlrnlalam /d Ihe I)NA datnaKmK eflath ul p:utnol;n luny
t'artirwvrns; f./ InJul'1NM1 t1( \Ittar lhnwaJ1111 elathaMF'e (C(la in h.wn ularr..w, )1
allrralum /n rrrta/n Phy.iral rhararkri.nrs.wfi a% lung wrirM lwel :u1J Jry/, INNly
wel~,'hl, a111I hM1t'I11'IIIN'aI characlrri.lir. %wfi a. I)NA, /Mlllr/n :MMI I/yJr11RY1N11111N
levt1% in lH/np. R 1 a11cr,MMN1//1 Inmlune 1YN1111r/l'/M'l', anJ 91 altrr;N/1N1 /n rHlt' 011
atil'%/.t
11 r. INwylr toria/ly).
(1s/ng Ihr Jlvllnnmrws cap.Wltr rrXimen as tk IinrJ in ('fR 14111. inluhltuN1.11
1)NA rcpalr capartty (r g. uncrhnWkJ 1)NA .ynlhe.i. I(IhS/) rwcurrrJ wnhln 11
wrrkl u/ Jady t.p/.anc to 2Al llr IA1 a'i~arrltr atwlkr, Mrl was unrl lrarJ Iry aalNl.ulr
/u 2RI alrarrllr .nwll.r llw even up ta 52 wrl'k. U.inr IIN raMdinutn/v a'Fn/Nn a%
tk/i/wJ lut ('1 R M111/, nu 1/NA repair inhlhitnln wa. IJLrrvrJ 1.u r111Nr IAI tN :MI
t/garlle .uwdcc even ahtt 52 warks o/ daily caprwre. Illu.. Ilk rnhthlbtNl ol I INA
repair 11 II )S 1 by cigarette .nMlkc wawkl.ernl tu hr tk prrw!cnl u1N/n clF:nrtlc tylN u c
2A1, IAI ~ 2R11 anllhlr Ihc rapsurc rrKimrn (i.c. M/.cru/NL .nM.l.r pcr minntt '
IS - 211 ttytNMI% %IIM/l,l' per /IlnWle/.
Rcplia'alivr ONA syMlt<mis (RI)S) in vilnr was slurwl:/1rd 2 lu 4 LJJ after 9
wrel. 111 r.pNUre l0 2A1 ur )AI cirarrlle snMde, but mM ;dtcr calawtr tu 'RI
a'igarrtle.owlkc u.inp Ihc high th..e, lYMvenlNlnal t'R(111%utr rt'g911M91 RUS was.lunu
Ia1rJ 1 hJJ in mire cRlNV+eJ NI eilhrr .R l llr IA1 rikarclk sawd c usm): Ihc . twunu
tMla ei<1111aun' re I;i/Ih'n.
1)NA rr pla~illn aa mcasart'J hy tritialcd Ihynlialinr inavwi.wa/i.Nl inlu lung at11s
in viv.u 1I:drclhnp InJt. (1.1/1, was inarericd 1 N/ A II/IJ in lung a1w11tachral usIns
Inan 2R/ anJ lAt ciKarel/e sralke expl.eJ mias. Nt/ i1K'rea.r /n 1.1 wa.llh.rrvcJ m
hl;whkr, r/lhln. Iivtr, kiJnry, /K yAern Nviwknce wa% presraleJ lu.uglaa Ihat dady
r.pl.utr I.1 whok nrd,r /rnhrr 2R1 ur IAI/. while %/iuw1a1/nr rNNnc/l I)NA rcph. a
tltm, /nay InJut r un.a htvlukJ /)NA synlhc.is ut repast .yMhca% a. wrll ( Iady e.p/
.utr ttt 2R 11w IAI l/17arrlle tnNlke Ia/kJ IU au/;/lla'IN IIK I.I 111111pY91 hy she (NNt'11/ I1/Ur
t'arc/a'I,~rn, NaI' 7,M-Jn./ 'I hus, hlNh t/K:urtle .uwlkc arMl \Y'nd1U t IM'1/1N11/ t aa /ott
t,'en. Ir K Hal'-7.M Jitd/ were ral+ahla' nl stinedalmK UNA .yndK./. /// IN/IIIMNI.I/y
h%%ue, hut IheY r1ItYt% tlNl MII %lYnl hl IR a1lJ/l/ve, \yrKrl.'1\l/t. tN a1Na1;IM11%IN
AI111 wa% lrnh/a'cJ in the IunK ahcr r a/+t..wr N/ 2Rt /w 3AJ a'/garcne srln-Ic u.u1F
any c.(Nl.ure reg/mrn invralipaleJ. f'uhndnary AI111 at Qlvity was .unu/la/e./ 4 a. t
(Idd after 1, t/, IN /I IIMNIth%ralAure Renal AI II I wa% //MIaM'r1I alll'1 tlally a'RINI%uIt
ItN
9 nlllnlha Ikpatu A/111 wa% unrllrtleJ al all tunr intcrval.
II
I'11IIIMM1ary, 1)1 K atllvlly, a IlntenlMl nlatltrf II1111n1mIMilN1e wa% inJu.cJ 2-luhl
wilhm I hlrn. ,dtcr daily c.pnure tn 2K1 rN (AI .nMlke IlN 1.N 6 nwlnth..
Ltpn.urrlu?H1.N 1A1crgarrlh.nwd.rlaikJlacau.e.lnxk.trotMlhrerk.inthc
1)NA u/ Iwlnw.nary a'ell. Snr1Ac ra(.r.ure al..l /aJad to mllurmr Ilx kvrl ul UNA
J.unaFr a'au.rJ by Hal' lN llal' 1 1t-Jrul
Sr.trr t hr1 ml.u ut r tl hanl:r 1 S( l.1 w a. ialw rJ in INlne mart..w ce ll. n/ nucr :d tr r
rtpp.urc lu cnllrr :KI rN IAI .nwdic 'fhr uxlua'lem wa. - 2 IoIJ and wa% hr.t ah-
vrvlJ.dlrr I wacA.uMl{,ecalwl.ure (.Nninucderarylsure/nr4, 121N thwrak..lwlwcJ
tw. ImdNr nx rrav lo thr nurnlxr ul S( lic /nrrca.rs in S('F:. (x r.r.IrJ ahrf cr..an.Nl
ul rtp..urr l.N at ka.l I wcek whclhrt the mice wcre r.l.nrJ imu:dly 1.01 I
werA ,N ah war1. Ip 114111
Ua1Nr.urr Itl culxr 2111 rN \AI llKarrtlr .nwAe using the trwnuluuu% nylnrn
rr.ultrd rn an nx rra.r rn thr ccllularny /d pulrmNl.wy li..ue I)ody e.p..urc luen I
wcek 1.1 t1 wlrA% lalu.cJ a tume lt,INniknl uxtea.e in IunK wrt wrtyht, Imlr Jry
wcq~hl, luoy 1)NA mll pnNr ln, anl) hrnK hylk.u~ylNlllrnc Ibr. rnt rrax m ti.aM rna..
wa~ IrAI'ly IIx' /l'~I/II nl Inl rl^:IKJaa'IIu1.N (NUItIr/atMM1 lbi. prublcralnln wa.lN.dl,rhly
a hnd rn,nldr.FatuN1 u/ the rnarca.rJ 1)NA .ynthr.r% rates ld+.rrveJ in Ihr.r amoul.
(/a/ ly r. pn.utc a. 1111 and ) A I a rrarcttr .nwllc u.mK Jd Irfenl e tpr.urc rcFmk n.
Ijdrd ta lhcr thr rmmunr .Ialu% ul H('(I li(um mrre Imnwnc clNrynlrrxc w.1%
lklrnurnrd hy Irrnl Id.yur a.vy Nl'dhrt al ute rMN l hnNIM eRlNnure l7uvlJ IIt1n1=/M.
,t/1jN1'vvNN11//rll)xY 11( 111r('urnlN 11/11 Hia lumrone
K.Ha. nl :duar I1 c nian.d Ln..d t )tl. tnNn the nv,uy) werc al.o unrltttlrJ
hy t hrurnt ctlr..mr I.. `K I 1N I A It qvrrltc .nr.f.e Wluk u hr, hrrn.urge.lyd rn the
lurraturc th.d tltrc r. rl-IJINMI'htf. tx'tw(yn l//,'arctll \nN.ll/ll/' and rarly 1NIV'1 ul
nti'rw.l..lu.r U r whrn the nvarn-. ur dt plrlrJ ..1 ..K yle.). .ra ylr Iuullly wa. n.A
uh.rrvcJ ln II(11M um rnnc aIlrr %; wrr\.d J.nly .nw.Ac ctp.wrr
Vl. ('OR/11LARY STltU1F1: P1IARMA(Y)KINI:1-1('S OF INIIA1.1:1)
MA1'tal(IAI ti
liIe IkIMN11NN1, t11%trIhulNN1, and a-kar:IMY wl.'re IlaIlrminrJ fi1r nNYMllll. Hal',
lh Nriaruntanc 11) I( 1 and c akchld in ctgarettr .rmlke. 1)ata .hnweJ aun.akrahM! Jrl -
Irflnal% anMNIF' (hr%r IINIr tlawo, 1/I l hanlxal\ Nicntine, 11a1' anJ aatnMd .M/wrJ
r:11N11 fl11/~If11x11/1Nt InNll the h/ng In INhI'r tl%\ua% atxl.karamc InNn the Irrly 'lhr
I1.J1 btr hN rntrrnal rclcnlnln 11112/ wa% k.% dran IS minulc% hN niclwrnr. k.. than I
Ipan hw HJ', anJ k% than ?11 minutr% hw . atc.INd. 1) f( .huwcJ little r.vh.trrhutnm
IrIN11 Ihe 11111r, with a IIr2 lll pralef that ?4 h.Nlr\, The IkINNtInNI IhN111h1/1nM atNl
a hnana-c ul % alca lu.l a..mKk chcmil al xn...d wa../N/wn tl# hc Mkntn al l. t atcrlBrl
in crrarrnr .nlal r- i c the pharmacnAmclir. ld ea1c. h.d are twlt altered by the
prrvrx'c rl the ulhrr ahemKalt in ciKarelle .nwll e Grcatcr than'NrR nl Ihr rnhakJ
t atra IMd, cu1Nr tn arKarcnc .nw.kc lN a an arnrad, was lrwrwl a% a hcta glut'un.nala.r-
lN aryl .ullNa.c .en.ilwe clNquRa/r in the wrnr within twit hrwr. ul c><INnurc.
lhe lkp..unNl. Jr.urhulirm and t karancr wa% al.a Jelrrmined hN 12 11 tcb:rk
a/N1ytpIMMIr.I I 1 n rt.rtr 1 I PAI a% a%rnplr alxnlw'al acnwd I hc phurnaaadrnrtlct tul
:Nto ...JvrJ 11'A wa, invr.IlKak d a% a IrNrmr.d INlNlwMCr in a Iwu Malr I/nIt1.1nIN1 AINI
In..nM r..ui . an ln.yr.. ... nr.l.1 .y.n'.n .h, lbl Uw lunr L..uc Kc.u11. Inml twu
t-.IMr.un nl. .h..w..1 d. d...rt f.%'1 .d Ilp NUr.,ll 11'A .Il'/w.,nd/11 wa% LN1ruI 1l1 lhe
rr.l n..~ n t n.. 1 I I'A ...1, r.q~ully . 1l .1rrJ Il`.nu IIN- IaoF via dx hl.N1, with ulk
tla.ull:
axrunwlaln/n in ltlr hvrr, .LNnach and inle.lirks up In IS huurs rHrr ctll.l.orc Hy dx
IwNrr., ovrr )1MJi ul the inhakJ TPA wa% Irwrxl in the fra-e% arnl 21Y% to the urnlc
Arn.vnlvrJ 11'A uwlua'rJ a.pecilic hilxhemical cvanm in thc lunl;.. Ih.lt r., uwbl thun
ld 1/1K:wbvtly widnn I h.N)r~ a(/lY /nhala1N/11 II'A Ihu.eRettrJ q. rllra/ nonwdr
:drly anll wal lhcn rcnMwrJ Inml Ihe lung llw pharmacnl mrlil. Jata .uF Fc.lyd di.q
xn..ohirJ 11'A may h:rvr rllccl. in Ule Ka.tainlr.Imal Irxl, in aJJrtnNr 1.. 11x
rr~INra1.Ny II:N'1. 'IM.r Jala .u~1r1eJ Ihr u.e lrl 'l l'A m a Iwo-aagc nMNIrI I/N luny
carainur-cnra.
,
12 11
Abstracts of Reports
hrdhrwinR are ah.tract., aplanwed by the aullMrrc, rd reput% rM new rc%earch
actmrwkJlerng .uppwt 1nNn The ('rwncd that have aPleanJ in .c rentilK rwmala
.rme forrhlxalMm nf the W111 Rrl.nt. The name rA the Krant recipient i% in it.hc..
The aMtra.t% ate KnNyx.t unJer these hcaJinR.: 1. ('arxer NrlateJ Sludic., 11
lhe Rr.l.rratnry Sy%tcm, III Ikan and ('inrolaliwro, IV. NeunKthatn.acnh.gy anJ
1'hy.e.hry,y. V. 1'harm:.rdr.Ky and Iliwkhemi.uy, Vt. Imnwmrlr.py am/ AJalwrvc
hh.ham.m. VII MetahiJK GuJie., Vlll. IipJcmMJ.hty.
1. Cancer-Related Studies
III(711 t1I N\ITY I.IW IPHI)11:INS IN.( RF:AtiI: H11111 HINI)ING (1F A
I9)I.YNtI('I I:Ak ARUMAI l(' IIYI)N(KAR1I/)N ('AN(IN((:1.N T(11)NA
ANI) (AN(1N()1:1:N INf11A'1'1:11CY:1.1. TRANS1iM(MAfH)N
AJNat+tive emMKyur.i% rrlliprnNein.ll.Pt..pcrifie.l by (.1' alwyxrNCin homhng
In rerrlMoN% rm 11K .e11 rnemhranc rna1eJ pil r.gir»ls, i, pn.pr.ed a% a nMdrani.m /rN
inlernrhialNm rd 1.1' hawnJ (ipophihc cnnq.wnJr inln cclh. ') ran.l.wt rd Irryy+lnhc
IYNn(MNnNI%..u. h ac hcnio 101 pyrcne 1 HaP/. iu reputcJ tu trc a/una awr ul .erunn I 1' rn
.yrvr, and la reprewnt a pMCMlaI n>echanisrn 1rN n.wemcM .d tfaP /tunr Ihe tweKl.d n/
enlry .ne Nr.whrr tl..ue.. In the pre.enre rr/ high rkn.Ny IilerqnrNein., a nurlagcnra
Hal' nr<Ia1ndote wa.luwnJ InteOular ONA at rkyreneJ kve/% when crNnpareJ lu.rllt e!.Irr+rJ lu tIK
umlrpen in the abxrke rd high Jen.ily Irprlrrolcinc 1etal call wrum
with hrw kvel% rd IiprionMeina, yoeciNeally hiRh-rkn.Ny IrpqnMarn., i, a.wri.ICJ
W Ith CI IKMM ItKlhyh-hulaMhrene-InN/a1N11ranYlnh11a1NM10l C.111114) I'l/ ! cell. whrk
a all v rnnr with a.igndiraM rrar nMrslpul rA hiRh-Jemily Iqwsi.nwein% rryuuc% up lu a
yNMx nKrca.e in nKI1ryklw+taMhrene c.rrrccnlr:Ninn Iu achreve.imdar kvel..,l tran.
hMm NMNr in thik nrw.c emhryn cell line. When crnw-enlraleJ serum hprnwem. 4N
purlky! /11)1. wcre added h+ Irlal call xram a.rnlaininK MCA at Ipgiml, the ( tllr
II/I H! tranJrKncni.m Inyuency waa .karea.eJ n+nqvareJ 1u Ihe tran.larmalnm Irr-
yurrry achieved in Ihe prr.cnce al /µK/ml rrf M('A in 7eta/ call xrum w11IMM/1
.ulqrknwntalNU1. Thc.e rewh. wK}.e./ that hiKh-Jcn.ily lipqxrotem panitamrnK @o1
LIrTlnlir pdynurkx anMrulrc hyJnwarMm muaKen% lnwn Ihe cell .ulture nMrhuin
nuy e/lavlivrty re.hKe Ihc crnKenualinn.d carcirMVen available /rN mlerartnwr wnh
cellul:u 1)NA in ritru, whirh. in turn. IIYy he a\NK/aleJ with rktrl'iwJ (aN 11M-r4/1
InJIM'eJ tran\IrKn41tNN1 nl cells.
Hu\IKr, r). r.L and HenrJict. W. F.
MuhHiun Refrnn h 111. J?9-I1V, 1411). ~
(Mlier.rppert: Arnerican Carxer Suciety and Naliunal (ndilwea 4911 kalth
14461" thr (ienelic. ('enler, 1)erartmenl of Hwrh.gKal Sckm'e.. Nralh 'Icxr. Star
Ilntverny ItenNrnI anJ the I)ivi.ian rd /kmaurlr.Ry-l)nrrrlrpty, 1ar. AnRrlr. ('hil
Jan'. 114..prlal, aml I)epartn.eM rd 1'eJrauw., 1lntver.ny .d Srwlhrrn ('.d0l.wnia
S.lwwd rw Medwinr, I.r. Anlteles.
IIIIMAN I.YMPIIIKY71.1 TRI:AT1:1) WITII r 7. /-/I- INIIYIN((/XY r-1.111
1:1`l1XY-7,N Vlo I:Ir)XY 1.M!1,I1/11:1RA11Y1)Nl)HI:N%(lf../I'YRI NI
KI(rI1K1; I(1W Irl.N\IIY 111'1/1'It1111:IN1111R I)NA I:X('ISI/IN W PMR
In the pre.enl in rrn.. .IoJk.. huroan IyorpMrcyte% which were monnnlorrn
rt
.h,n1,I.,Ir.1 .Illd lkpktr11,r1 htN>f+n,lr/na, wrre founJ tu tw Iklicirnl In ItNA rRU,nNI
rtp.ul tvlNt.rlIy rr11ua1cJ in tfN%c tcllk in tr.plNl.c lo ItralnlrrN wNh a dur.l at11nK
L.IynIN k:u ,N.Ntl.rlla I1ylIr1ltarIMN1 t'Jn InI.I,Yn I ympMr yl.. r/t/lrt Jrpk'hd 1,1 Iqr.
IN..Ii 111~ IN VII,1,1.uwmrd w11h hunun II.w llrn.dy IIp1.pu,Irln.l/Nnlr.1 I)NA t aanw/1lIt
,Nklua 1. w1N. h wrtr IN,1 ahr/N1c11PF'r:ll+hl. rlly llt./(III;N,hahk 'l hr .LdC t11 III111-
(,/.N. tn 11f pls h.,n dIJ IN,1 altrr Iy1nldNr ylr uplakc nl IhynnJlnr Irnnn IIN nNJ/unl
I ymIANN y1c, what h w.rr akI,ktcd.,l 11pqNaAr/n., Iftall'II Wllht'artlrN,F'r/l :In1I
N/hw-
yurntly .u1qMnK nlrJ wlth k/w Jtn.lly Iq1lqNlMrin.. rcl'.nINJ /llr ablhly 1.s rnFafa lul
IrNA rta,.NNI rcl.eu "Iha Ilala .uFgta that rilher hIw akovty hINyN.NCln/.lo tN a
a.nq,1,INNn.l .1 luw Jan.,ly Ii1r,INaMrinl.l, iv rrquurd hy hurnrrl lynq.h.Nylr. in
,N.Ar 11, nnll.dr.aa1.NNl /epan aul tarcilw.Kcn danuKcd 1)NA
l.t. (' (1 K.InAIn I' W, anl) Iru.h.r. 1) l.
AINnnN.n N. ...n, h 1 11 11 41, 1'Ix I
(hhr/ Iuyryrr.rl: /11ntrN an ( antar C.-t/a/y aml a N.Nth Tc.a. Slatr I lnlvrr.tly 1,N Idly
H..r.Nl h ( .1.1111
I raNU dN 1kl..lrlnNm 11( Vclrrin.Iry 1'hy.Nd..gy an./ I hanu:KUk.fy, ( o1kFr l,l VtIrri
n,uy MedN Inc. 1.'a.1. I1kM I Inlvrlnlty. CIdIrFa 16nuN1,11 S I)apartnNn11.1 ApNnl
Iu1r.A krltulnnalKrvaahSrrvNr. Vrlrnn.Ny lu.Nnln}yarlJI uLn,Nd..FyKrvalah
I.IIAN.N1Ny. ( LIk'F4' 1I.IlNM1. (N111'Ip\ l rnttr (kp.Ntnwr11 .d NNIII/y,Nal SaN/hrv.
NINIh 1 rt.l. 11a1c I Inlvrr.ny. I AnNNI
111N/(tllrll'YNI NI Ilt'IAKI' IlY I YMI11 A P()1.%IIlI.1:1RANS1'()KI M/11H:
I IIK IMMIINIIM tI'1kl %SIVI ( 111 MIl AI S
A.IINly .,1 hclv.,l.If`yrrnr 111a1'1 up1.14t mlu .hcrp lynq+h 6p.tx.4cu1. /% fwr.
Vnled u11111.I..ll,l'/ .1. a IMdcnuJ111MNkI LN rah6unlnl! Ihl ry4Nnrr ul nnmNlh.y.lrln
la'II, IllI/1tI1t111N.'/II,.11NN1\uI arlN,hNNN a.Nn(4NO1J. 11o1hah..NIINNIUt ltal/NN.tllr
lylrq4lIht c Irt uLltN,n IrINn Illr y.1.n/nnlt.lu+al .y.lcnl. and 11.41, IKI/IIINN1111F' nn11
Ivoqdl Iqnhw..,cln. n/ rrln. hwc Itcn ra.uNlnt'd Rr.Id1..IN.wrJ th N H.11, a hlwydnla
1NII//NII:IFt'n. rrNhl'II III.IUn1;lI taNlal'111r.ItIlN1\ /r1lhl' IINN;N1a Jual (ynq.h.lnt tutula-
INN1 WIIIIIII IW..INNIIa :IIIrI ~a~IfN IMIIlI:NNNI I1J/' in Iy/1q,h11111:111N1I by IINN.WN' IIIKI
t anul.nNNl.kcrCavll h/:p11N1/R/11/.drly lINNr11I kvlI% w/1I11111aNn hINH% :dlrr trc:dnlr/d.
WINn (ynqdl W:1 mA athwrd lu rntrr Illr h11NN) va.aular l Ir.ulatNNl..rrunl lrvrl. n1
Ital' irN rra.rtl very .h/wly vuyrr.tnlg minnnal Illrvnlt'rlm hkrNl va.caLu a1..INpUaN1
nl Ihr Iqwydnbc hyJr/svmhlNl 11r1' I+ar1tINNm /Ml, Iy/lll.h IIIN+IN/NlIM LN a IWNINNI nl
IIM IlhyNl,lrln tINM rnlralNN1 I IK al:da wfEc.l thal k,w Iknaly hpM+rl,lrln% nlay lalr
Iq, 11.11' aNNC c1I1cN n11y 111./n ak) vrry It,w Ikn.ity IN luyh a/rn.dy IqNqNINrIn..:nNl 111.11
IvlnlQl t.NnlwNw nl. .qlNr than IqnqNUlrln% a/1e n111 lakr up a1Nl uon.IwNt 11./1' ') l+r
Nnh.N. INlqulw 06.11 hpqdlllN tl'/N,hNNN' a1N1/tMN/MI~ 1111a'1.K/ wlll/\\'II-nI lIN 1111111111N
.y.trnl vta Iynq11,1ut IqNqNldr/n t1.In%IbNI ..1 IMNrNt1.d11y Nnlla/lrnk .. a1t tnuly 1/N' aN
Nnm1UN,.ul.~/r.avr a/,rnl.
rn.,rN'r. l) r a t .rl
JnNr.Nd ../ LnN nl.KI .oNl Frnrr.nnrrnr.d llr,dlh 114 1 SI. 11/x4
fllh# r.rrpp..N N.In.u.d 11r.N1 I uNF unl 11kNNl In.tllulr. AnNINan (.Im:rr `.a ir1y.
ul .1 ~/ 1. nhun/ .. ... .. 1. ~. . .. .. 1... . . .,..i I1....w .Ly. 1 II.1...1
V.I.rln.uV A1rd1
i
INIItItITh/N OI: ONA SYNTIIIiSIS ITY AN ELL(TROPF111.1(' MI:IANuI /l I.
l N III N7./ q/tjlYKI:NIi
I hr (r.ull.Id a.hNly of l)N A.ynllu.ic inhi1d1i1m hy l! I.rnn 17r ,N/1 dd1 yJ1ut y
lv.n4l rp11.y.7.x.1).to Irlrahytkrlhrnnl/n/pyrcnr (111'1)1:/ arc pn.rutrd u+thl. prRr
11 tin lr .rrn thal nlhoFcn .Imudalctl vthrtlukJ 1)NA ]y11lhl,/\ :I/NI I)NA rla I,NNI
rrp:ur In huulan lyuq,hlocylr.. as well a. 1)NA pdynlrrav a aat/v11y /rl a tell la-r
y%lrnl. wcrr mhdulyd by thi% rlerlnlphillr rrlr/alw/lilr u( Ilcnn./..IpylrrN w1ua11
.uv,Ikn(ly b/ml. lu crllular nlxrlNtwdcruk. and i% nlulaKrnoor, tarl11N.1(('1111, a1NI
cyllNl.nlr Sprtlh.ally, homan IynqlMN:ylc. Irrnlcd wilh 1/1'1N: al tu1NaIn1
)'rralcr Ihan SINI 1411111 ng /hnl .IN,wrd drerraw. In IrNh minlKrn .Iunul.urJ 1)N A.yn
IIIrVt a1NI rlt'I,NN1 rrllalr taI alanl:IKc/I I)NA hl/l IINI MN rshiMt uvrrl .yaN..tN/ty
I'INIILIINNI and 1.04.41 tINN'rrllralN111111 ItI'/)1:1)NA alkhNlh wtYl' INd l1M,t'IallaI WIIII
r/1hIhIbIN11.1 I/NA vynlha./.. I)NA IIl+lyulrrav .. .hNllc. uany r trll Ircr .y.lrnl
.IN,wrd that cniyn/.111r at tlvily wa% n111 dnllim.hta) when punhrd IN.IynNl.w w.1.
Irl'aItII Wllll ItI'I )IS 1NI/N 1111hr aIkl/1NN11/I lrnq+Iate I)NA Whtn Ilx lenq.lalr I/Nn
tlNNrunralNN1 wav var/rJ, 111'IN: inhlMlNln d rniymr aaiiv/ly wa. UIKU/111R'1/11Vr
Itl'1)I: IrIh/1NINN1 alI rn/ynlr aCtlvlty wasi hNlntl I1/11r rNNMINIIIN.'tlllvl' whl'n taNN
r111r:1
111N1. 01 alA'1'1'. lK "11'. aN J 1'IP wrrr varirtl. hul ra/lq.etnivr wINn Iht cINNrIH1a1/tN1 ot
tN:II' wa% varl.vl 'Ilw datr irltlwalr th:N 1I1'1)li aINnprudvrly 11111,h1N IIIIrr.N INNI UI
1Ki11' wuh the Irrupl:Nr I)NA p/ly/lwn.r a rlNlq+kit
/lNa/N1'. 1) 1. rl rll
l'ra.vvhnx+ ../ dN NnINNNrI Arrwlrnrv IrJ GirrN r+ n/ drr flrrrr.d .1i,rtc1 ../ Arm'rN.r
x15 14 111 51/14 1994.
(lthrr crl.pwf: NataNlal In.INutrvld Ilrallh I/S 1)tpallNlrnl..1 Ar rNnhurr :NNI IIh
'Ir.a. ARrKVhurr (:aprrinlrM SlathNl.
I rlNn tht Ikpartnwni ul I'hysiw+klgy and P1urnlarull/gy ('rlllr}c uf Vcirrlnuy Mrdi
a inr'fr.av A& M I loivrreity, (l1IkE'r SIa1NN1, U S. 1)rpxlnlrnl ul AFnrtdlurr. Ay,n
tldlurr KCMartI1 ti(rvllr VlIrrln7lfy ftNNtIlhq,'y a1NI I:/NtNIN.Ia,ry RCVar1I1 I.aI>1NJ
hNy. ('I.Ilryc Sl;llnln. TX; and lln 1)rlwtnlrM ul HN+k.yiaal titirntr NaNth Ic.a.
Slalr I/nlvrr\ity, Ik/1111n.
III:NY.()In/l'YRI:NI: IIPTAKI: HY SI:RIIM I11'll)S (Y)RKI:I.ATII/N WI I11
1 KI( ;I .Y('I:RII )1: ('(1N('I:N'YKATI(1N
An rn rilrn .Iully ul dlr naalnNlhip hrlwcrn hrnilNn p+yu rlt l l(a/'1 avr /,IInIn
w/lh vvunl hplqwlNrin. 11.1'/ anJ 1.1't/N1/1uqNMN1 wa. tINNhICIId u.mr hunl.ln .ul.
M11. II;IP IaNU11.Nl/np inloJdkrr/N vrmn I.PtanfrJ Iraen S 1 N/71'A u1,Iv,u/.d,lr Ha1'
1'I la NIN y 111 11.11' p.InltuNlmK iMan vrrun//.1' Wp% rlIaNUnl'aI II.IkItInUM 1/ IINIr
wd%./
rr1/1NNl.hlp IrIwrcn p.NulNNnnr inNl 1.1, aal lhr IqINI c.Nlq.Nlrnt...1 1 I' I hr 41.41.4
IMIN-all' /hat InFlyacrNk 1'1(i) alNlrrmralN/r1% wrrr nNNr J/rr.11y tlNrtIa1rJ wa11 1 1'
t+:Ir1nNNlinl,' UI I1J1' Ihan were c,NwYMra1C.11f nlhrr 1.1'rINIqNNNnt. AJIU.UnI .Cr.1/u.f
undlNUl 1(i a'INwrnlrali1N11'16.5 o,p/JI/ rr.uhaal in Ihr %a1/N' IIaI' ulN.dr I.N r.Nh
Vnnl/ lyl[ whlk :NIIu.UnI,' .era h/ clNlli/n a unlhNrn.lN.lC.lcrul.INN'anu,1u.N1111/1 /s
n11eh11/JN1nulrr.u11/n.InldarhaPufllakaarlNNlp.rnnnlypt. Ana1y.l.Idv'IUn1/1'
IINIqMmt1NN1 .Ilrradr.l Ih.N NI.u1ud J///rtrrNt. In ha.Ih Ila/' NlMskr a,Nl ..IUnI 1/.
tlNNfn117I11N1\ JI/NNII, Ihr \uhftal\ Wrlr IIIN' /IIa1nIy 1111IIIIrrr/Nr~ 111 %a'r11111 YCIy Iuw
17
.knaty hpiq.dttn 1 VI hl ./ awn'cnlr.ltnrn. A u.ttclalinn c1uJy u.u1K 14 Iminan .nh
htl. %h.IwtV1 Ihal M'rU111 /(: tv.fnenlralnrn wa.lhe he%l (xcdahN Ir - 1/971 P
II IK111/.1. Ilal' ulM.dr by .crunl (Lllawr.f by phinrhl.hplJ (r /1 f.Kt, 1' 111/1/ alml
ur.1.h..k.tru.Ilt 1/SI1,P' OI)SItPrllrnlratltM\ I~h'tlSUIhItMhtalelhat%lrulll
iG CINIarnlliJlNw1 Ilyp,tj0y VI.uI. I(:/ /nay he the pmlary Lntnt allr.nnK Hal'
ulw,dr hy .rlonl I.I' :Iml ay~lx.t thrt a.mull t h.nl;e tn.crunt I( i t allcrntrauun ..MdJ
I aua a.qrnln an1 /lw rc.1.r ul 11a1' ulw..kr by .cruln I.P, ctwltrlhutung lu an uw /ravd
kvtI ol t nloLdml; c:Irlllw.Frn
YL.. I\ 11 , N..rnlan 1() and Itwl.rr. /) l..
1'r.r r.JtnXl ../ I hr .C..o rrh /..r F Ilrrrimrntul NL.lr.gv ttnJ MrJn mr 177 414 4 III
1')K 1
IltArr tupporf: Nahunal In.h/ulr..4 Ilralth 11 S Ikl+anmcnl t.l Ayr/.uhurr and dlr
Irsla. Alr/luhuF]I I'mi14'/Inlrnl tlall.on
1'r.Ha dll 11rp.utnlrnl. ul Anaamly a/1J 44 1'11y.nQl.Ky ant) {fiattnaroh.Ky ('ullrKr .11
Vrtrnnary Mr.lnulrN ltca. /USM Ilnlver.ity, ('nikRr Statl.nl, Vrterinary It,.N.d
flgy aINI I ntIw/M/h/ry {(l'%cJrl h I_.ahlMaauy I InurJ Ytate. Ikpartnlrnl ut AKfwulturr,
(1.Ik4r Stminl I X
A RII.A111/NS1111' NI 1 WI+N 'llll, YI,AST (l l.L ('Y('I.f. (:1'.NliS (IX'J ANI)
(IX'p. ANIy 1111..r. SI,I)111N("1:(d (1N('(Xi1 NI(' VIRI/S L2A
krlrnlyd hrtc /. .IRnllitanl prlul.uy .ryutnlr hnnwduKy anlwnK Ihc prcJlcletl
Ira/I~IdI11MJ/ IN11111N'1\ LI Illll'r I,'t'11r~. ( I K 4('I K((1, arlt/ rN ('1 X4 and (1 X10
.ur
C.n, hunnrltv.'t rrrrrilnrr .cll dlv/.nal t yclc I:rrlr-, whdr rf. 1% a Iran.hwntrti.wl
.pc.lhi Kyurlce ul avlan rrythnthla.toa% vinr.1:lh llrc JrJurrJ pronary .tnw turr.
nl thc dlnr FnK lIHnhKll were ttNlll.]rl'11 by lt1r111qllel t/l a Iarl,'r llala h11Ve t)/ I M/wn
antl ptrdNlcti prturm .eyurncr. lhr varch nvcakd 22 11 22 S'4 iJenlily .uvcr re
Rull/. ut 1411 21kh alrk+nv fr.perlivrly. hrlween Ihe J/Ilrrenl p:lnwt.e cawnhinalnm.
1'tM Ihl'K Igr1MUIN V tlul'rlCe\, Ihe.c «krllily .auret lall 1.4 4 11.IarltlarJ Jevi:uanlc
ah/vc Ihe rnMarically tklrrlnineJ nw an value. td Hu(uNtluc vimrlarily. S. rrr.rr.ntr
4,01% rcyuire l 1 X lA and ('I X'4 in urJrr In ctlrnpkle Iwo early events in the cr 11 /ycle.
r.ra u1Mln ll/ .tarn (('1 X' lh/ aritl ywnJk plllc htK/y aeparalinn /('I X'4/. In viru.1:26, the
rlv vyurrlrr ts hnkcJ in Irame wilh JK.ex and /nvN rn Ihe Irilwlitc slructwe S' AKuX
nrvH rrt- 1', rtlnqxi.inK 1he 1:2A Iran.hwminR tmtt>gene. lhr htmwdnRie% tk.crihrd
hrre .uKgea thal Ihr 1nt.'hr nlical lum W/m ur /eRulalil/n n( Ihc (Y XA, ('1 X' SA and rn
pr..luao may hc related
1'Nrl.on. T A, Yuchcm !, Ilyer.. N. Nunn, M F . I)urlMrR. P Il. 1hdntlr,
K 1' .uwl RccJ, S 1.
Nnrurr MrNS'Ndll S% }SK 19R4
Other sMpperrt: NNw.nal In.tilutes u( Iiea4h, Naliunal Seience fnunJNitxl anll the
Anlrri.'an Cancer tita lely .
Ilom Itle I)rpanmenl.d Hlnh.ltical Sciernr.. (/niversily of Cah(I.rnia, Sanla Harhara;
1 kpartnn n1 ul (:rnrtN .. I Inlvet.ity t.l W a.hinltlon Seaak;lkpartmcnr n/ Mokcular
Iladnyy arwl V In/.I a(.Hat.a y, I lnlvrt.ay u/ ('a111.wnt., ilcrktky a/wl the 1 kpannlrnl
4.1 ( llr.ul.try I Ilnvrr.ny 4,1 (./ldunua San (/lcra, I a I.r11a
IR11'ARI111: .S"IRtt( 111kI O1TIIIiAVIANI:RY1111((1111AS II)SIS VIt(I1S
I:!b 11(AN\I l /RMIN( i (il.NIi
I INtr :rrr la/ly tw., avl:m nnt,.gcnir vim.r% that .Ixcihl'.Illy t auv .a tnr kldr
oua. \t'1 Ik. IMM I/.IIIAINIIt t hll Ll'/l IIInn11Ia%1\ 111 CIIIIIUI' (1) 1t2ll wI1N h C:Ita%r% r/
yltl
udd...tn.1.:uMl a L.w kvrI tll llnlt'1N111Ial/t Ulyt'krhla%tlhl\ /II lltlcl.rth a1M1 (21 avt.m
mycl,dd.l.tua% vltu. 1AMV/. wkwh cau.r% nryrl.ddr.u.a% c.t Iuavlly. 11.U1/ vlnl.r%
arl' IrpIN:111.111 lk'IlY Ilvr IIMI \harl' a%rt111rrIlT Il'r/11r1I /n\11 (aIV.I,IM.WII a% 11011 ) )
Wllll I1
IV 111111'I.11lYI ../ l'V4'1111./1 virllnl rr/N% aMI /% Ihl'rrhMl' IIMM/r111 1.111r p./r/ ..1 Ihl'
11.1/1
lunmruf dvr. FtIll'] tul IIN'Y' Vlfulr\. Ih.wevl'r. IIN'lr11r11C VtnN'tUreUl IIh' 1W.1 V/lll,r
dlllrr ('t'Mnllll RNA o/ t 7 kiklha.r.libl alwl rnr.rk. a 1(t,IMMI nM.l.t ul.u
wrl/:lbt cur Irl.ucd pnlaru11p11S1 wuh pnlh.lhlr Ir:n/.Iutnnnl; lulwlMU1 I Ilr mvr.llp.l
LN% %IN.W IM'rr by tll 17H..IId/1~I:NuNI /ha1 tlle S 7-Ah (:!f. KNA thrcct% dl. .ynUk./. M
pl lt /)I1F.NII/l Il'.N/lk' a//alylN IMIN'all'] q/at 12b RNA ctwuain% an rnlrtnal 11 K Ab
mIhN'1.-1IIN'I ! (1.AMV frlatrdvqlMnlr/n/l/.y.lrnllrtlmvlr A! 1/.Abna.lrllJ.u
lt6Nh /nrllI/l'li IHnll l1yNA I/aowrltttl tn t'rn., hlNn 1:2fr RNA cleu:ul/rd :m 1!r.
Ir.m.l.wln.un.a .prt d/l Irrl1 wyucncr IIanLrtl by nnh' arrl an.m' rcl:drJ ..qurnl c A
.unryrktc 11NA uyul/k r.ll thre ckmr irwlit'atr.lhat Ihr I S{,h ru ..ytlcrw r ra1c/K1% tllr
IMtcn rcathnr laullc.d rmb' Iur 4'q auintlx n1.. 7 hu. Ihc p11S I;rrlc ut 1.!h t, a
Flrll'tlr
IIyMh1 ul II11rr tIN111nt lIrlllrnl% 1.2 lh.k'rivcd Inw/ /hr S' nFi.ul ul Ihl rruuv/nr.
1.C//X rl'/h' .n1/r' a111I Illr Pr..cyurrove. linkrd /1/111e rqtkr S'-A(n,r In111' .'ll t* 1tN'
ulyrl.nJ Irul.ruw.ycntclty .harrJ by L216 arnl AMV rtlrrclalr. wnil thr aumnl..n .n.h
vvpwrllr. whlly dn dl.uncl crylhrultl k'uAcnll.gcnirily ol 1:26 t'twrclatr. wnh.r. elal
111r 1:!6 yw& d/c bnAal:r 411 .nt'h lo AgaK.
Nunn, M 1: . Xcrhufy. P. II . Mtrvuvici. C.. arwl l)nr.hrrg. P. ll
Mrnn. 11 INMkN1I (IK/ I'll 195. 19113.
(kbrr t.r/ryrrnt: Natemal Inwtu/es t/l llcallh antl llk Mcdical Research lrrvitr ul IiK
Vrlrran. M1nlini.IraUun
lnnn thc IkpanuKnl ut Mukculat Rinklgy ant) Viru. Lalwwaday I/oivrr.ny ..1
(allhunra, 11rtl,rky, (:rr/cntr.h. /nc., Stlwh San hramri.cu; ant11111 Vlru. Rrvar.h
Irlxwa1Hwy, Vclrran. AJlnmi.tratitlu 1hr.pNal (iatnr.vilk, 11.
.
QIIANlI'I'All(/N (1F 1111KON(XiI:N INhI.IIX AN111111RIN 1)1 P11ti11111N
AN11 I'(IkNI1Vta( IN LINIi I AN111.IN1:1//(iUINI:A 1'lli ('Alll'IN( IMAS
lbc dala Ilrcx rurJ here IMnvilk a spanlilative analy.i% u/ hhrinl.ycn inllua :Iml
/IM/n al'l'1111n/I:11MN1 anll lurnnver in line I anll line Nicarl'IlNnna\. 1/1rl'111caIIy I:MIUIIJ
hrkd Kurrlra prr /ihr/nl/yrn HiMl wa, u.eJ NI mea.we /ihrl/Mrren mltui arwl hMlo
at'l'unWI:11NM1 1/1 hne I a1NI Illlr 141 he/laln (Mk tlU.'11 t'arvllMMn:N rt..w/nl,' in IIN' \('
y.:nr t/l .ynKrncir .utun 2 Ku/nra piK% uver /hr ntNU.e td 7 Jay% h.lk/w/ng trau.pl.i/lt
l lu% tnue .twuvr aplr.eM. an ullrrval .d /tnti.lh wnImplhd alcd by unnnmuklyu al
IInIMIr Il'/1Y1Nn1 M by lIgn111aarN IUmIM nK'nN 1'mIMr /IIUIIwN1111NMCVtI/Nr dIN1a'
revealed hhrin Jrp.alc in IwMh lunwro with lun' I s- Une 1/1 In ara Ilyd wnh thr.c Jatr
(:Ph accumulaleJ in htwh Iwlwlne in anrwM.Ihal nukheJ rr eacenk tl pla.ma blNUU.
Fcn kvel. Linc 1lanltw ( il'1 a1MeM wtnr 4 f.411 Ereakr than that o/ line lu tunww. a/1J
II .3 1-IuW thal td MNnlal % a li..ue. The c.wnpu.ililln rA lunalr /ihnm.Frn //Arln wa%
nlvelt/Kalet111y al1Ue.MN and Urea ealfal'INM. The Irat'IMlrl /./ UIIaI atlunlulatet/ (:I'1'
that was urea imt.luhk, and thcrelure prrwmallly cn/s-hnkeJ lihrm, wa% c.ul.rant
uver lime hul slriltrnKly tlrlicrenl hr line I IAS'I/ ant/ lrne 10 (4N'R) IunMN. a\ tiun
IK 1 19
P.ucJ wt(h contlul o c tl..uc IIR'1{ / Hy 7 Jay.. line I(unha. (mean wcllIq 11 77 r)
-/11;I11xYt lx-.nIy 2 r1/F' .11 (IlNlrx.ra'nh)Y/n a1NI line IO Iu11NN% II1Nan wl'/FIII, (/ 62 y/
arx161ncJ rN.n ly 0% In)t Intlua rd ( 71'1- alrl mn61I a kN11nK wl'll' 11NN1At11 UMlt 111ll
aINI
tywv.Jrnl In/ 11x Iwu In11xM\ IlCnac the Irrrc JdlCrentt. In (iPl- :Ilau111uI.1INN1
rsharvlal Ittwccu thc.c lunxwo a/q+:lrcntly n11ca1 Jl/lctctxc. in tlMlnldy.r. Ixw in
hirt/nla)qn u111ut rx .IUFulrlNm the Jala (xc.cnhJ ItNhtrtc .uMlrnu.ll tra11N ul
Pt.l.nw hhr/m/ptn Intrl a/N) rxul ul Muh hrnrw., u% crxnparcJ wllh conUnI tu..ul..
cqulvcdcnl lu Ix.nly 11/ ,rNl 7 nJ nt Pla.nt,r uvcr 7 Jayo ol rrlrwth hM lla I:IMI IIIx' It/
IwrMw. a.Ixtuvcly, l'Nnp:ual.k vrllx's hw dlrmal s c t/.ax% wcrc 1/1 tu 1 4 nA
Pl.lan./ hlxnN-ycn
/)annd lI I. ll.uvcy V S nrNl M.OtulaRh, 1.
('nn~ rr Rr..,nr h 1-1 111N I IS4 1994
I)Ihcr.tulyrnri: 11 S 1'uhha Ilcrlth Srrvxc rrNl lhc NrlNm.ll I rwnJ.nNln h-r /'uNCr
KevaltIl
I nan IIh Ik'lar/t/lhnl rrl 1'athrrhryy. Hcth Lr+cl Ikr.pd.d aal IlrrvarJ MtJr..d
\llN.d- Inol dx ('hrrk. A 1)rnr Rcarrlh In.ntult Nclh hlacl II.I.PII.J Ihr.IrNl
('l11 Ml('A1. VIRAI.INTI.KA("fl(1N\ IN(TI.I. fRANSI(IRMATIUN
At Iht )tFlnnlnl; rd Ih/. h,rx M N'/xa rl'vN'w. 11 1% tNrll'II /IIaI the aarlnNr/rnx
rrrxe.. I. Ihl' aun..ylh'nat rd I.rNUlltra nua/.NtNm Ixtwlrn Jlvar.c cnvumnnNnlrl
:/INIIMr~ILhhN AIIIhNI(Illlll'u1Nk'rl)111y I1N'1I4nIN11Nh./vtINdlll'l'tlJkhnl.drr'.a.uly
an11u.J .tuwhr. h./vt- rkm..u.u.ltt J Ih.a ~ IN nur .11 a Ml nN1p'/1, a rM1111 tIIIGIIx a' /N'.
-Idrar
rc.uItto/Ilrnnrtlrr.nrr N. 1rNrwnrwh.)ruN vl.uav A.q!IIIIII:IMIClh/11trI.MIv:11N1
w/lhh Ix'luln% a/rNUr trlht.J :m.Jya. nI IIN' IIN.hY1tI.1r h.1.1. 401 lartuN l;cn vn.J
.y/xlyy h:l% heen tIN Ilr vcLyxlx IN rd wl ll J.laxJ r a11 utllnrc .ytlc/u. tcyNmS/vc ,a
mulllPla l,xU.t. m tua.lrNmrrl.m In dla a.rv .d I)NA vnuv. .Ih'h a. SV 111 ;uNl
:Nknl.vnu. IwcctlNratrc n1 the IrtFrl t r11.1a 11x tarttaryen ha. t/atJly Ixrn hMUNl thl
M r(wctaym.uC Irw cnh.rnlc/lxrol yd vnelltrn.l.wln.tlNN1 Itus laI/qxN:1111'Iahun.lup
hn. Ixtn Intcrprehtt a. I/xlaatln1: Ih.d I)NA JrmaFc a1Nl tty+ait m./y Ix /nqrwl.un
nNJradN.ul Ihl.cnhJlxtnhM flnwtver.ltx'ahallyUrt7tclnlh!en.It,Inlhlatu:In.hN~
In:11n N1 11t R NA /u11N la v lru\ InICaltll Ca I k hp. hel'n LM/nl( I/l rl'lhllte a ll/(ICnnl
h'/111x N:A
:qN.hertnm.d aFam.lhan in lhr 1)NA vlru..y.lcm. In a.khlNUl ha hclnr n/ullJacllN
Ilxrc 1% nasw ev/lkntc /rlxn.rvaral in art...y.1co/.Ihat Ihe canvwtgenic Pux:e. alw.
/nvrdvc..cvcrrl.tW):c. ln uo akvckq+nlctnl In 11K Iwu .IaFc nNlu.c .kln a.ay .yICIa.
Iwu qu:dllrlnvcly Jullcrcnt ./aKcc havc htrn nknt/bcJ rxk ItrokJ °Inlhrli.xl" arNl the
,rhtt I+t,xl«Nnxl "('au tullurr .y.lenn nlay tclxt.cnl vatorhk nxxkl .y.hm. /rr
an./lyiinK IxH61hc nnQlll.xi.w anJ tnultu.lcp n:durc nl t'ar.lrxrycnca. StathNl u1 (hl.
laItxY :Irl .k'varllYl ha Inhrna'Cllll'IM n/ V/trl II:n1\hM111./1hN1 by Ilulllat/ng
('tN.I/IN.II
('Jrt Inla/!t'M IIlhrnl a'llx'nI LI V/tlll l tan%(INn/LlN/ll by I U/IhN I'LxIhN/11/! A/C/II\
a1Nl
KrlatcJ ('.NUlxrurxl.. I'ropc..nln ol tlx I trn.hwlneJ 1'helNeylw : a/xl Mld(/.laP Mr" k1
u/ Al/t'/xlvlnh I Ian%Irxn1a1N111
/rahrr. P H
('rlm rr Mrr.n)<.ne..n I(h) 495 S1)4 1')M I
OIh.r tup/u.rt: N:dN.n.d ('rncct In.ulutc arxl Ihc Amcrlcan ('antcr Slx-lcty
1 uml llN I k 1~rrtoN n/ rd Mx n4.nuhqy .('ulumhrr I In/ver.dy ('otlc)e..( 1'hyaa l.nn. A
Naw Yr.rk
A(('U1 I:RAII:U ONtiIT OF VIRAL TRANS('RIPTION IN
AI)I:N(1VIRI1S 1N11:('fla) I/cl a('fa.lS'I'KI:A"1'F 1) WITII TI/I: TIIM()R
IM(11M(/11R 12-u11:'IRAIN:('ANOYL-PII(H(IK/L-11-A(I:TAl1:
Ih(clry eN Plxuftid caer wlrxu prtunlllan, wch a. I? t1-ttlralkcaru.yl-PMuhlal 1 t-
al'alalc 111'A1 Ilw'rca.r the Ilan.hlrrn:Nian frcyucnty .d ccll. inlcclcJ with type S
alk/xwlnl.lAJSl..mnlan vlra.411 plly/xna I:P.Icin-B:Irt viru., arlJ f+awiue I.apd
kNIW VIIII\ InaulanMrrd vinl.Iran.lurmrllcctl.c.p/.urcln'1PAha.lran.Mlwatn
IIxYI'JN IIM :n/NNllll ul vital RNA anJ in Iminlwavl ccll. TI'A nqritlly Itxlucc.liK
.ynthca..d .IxadK KNA.:axl /xalylxplNk.. Tu Ic.( IIk hypMllra% thal aaa'clclrtcal
INr11hN INNI t11 A1IS /IIKNA rRa11IIl'J It1xn eLly IMact t1/ 1r:pIN(YI(1tNM1 Ihc invc.llFaaN.
IlxJNI/CJ /IN.'IM(11N:IInN1 P1 I'll/unJlllc iMu viral KNA tk/nnfe a S-min /x/l.c al van.m.
hnN.:Illrt /n1ctlN.n n 1 I"(' 1ady vital NNA wad tklat'taJ lu'11'A-IrcrlcJ ccll. 2 ta, 1
h IxLwc /t wr. lk(cllcJ in .r/nplc. InMn cnnlnrl cullures. Jlxcdic ralln.acllvnk. -d
KNA Inwn bc.ucJ ala/ raNmul lcll. wcrc .inlil.tr at eWh Itl1x pnnl .uygc.un): I]c.n
ularca..J I:dxhng .d vrrrl KNA JiJ mN rc.ull InNU t hangc. in Iran./xw( ul (11/uudnlc
/R IltNll .II1a'/:It/1N1\ 11111x' 1111' IxxJ.vr tu avadaMlily Ihat (avtlrcJ o1KNA .yntlka.
IxN1%111Y IIIC:1IIy II Wa% 11IM.IxMC/I Ihat when AJS-I/Ilel'ICJ Ila'I:a a-eII% WCrI C111x.yJ Irr
111a It/11NN IMaNlllnl'r II'A aalClat:NNN1 wal rNN /kqt:/taknt ulxm claxurrcltl PlaNCrn
fynlhC,l% aMI Ux/kI Mrl ht a11//lhanlJ IHt ra(N1I Ctllry a1( vitlla In1U the cCII /11N k'l/\ 1
PA
lulMxr.aJ 11h Iran.a ryuhul lklay plx/xNypc lJ the 1'.la uwlanl hrl, w/1INn/1 Il'~hR111F
'n. ahilny 11/ rcl+lx-rlc
('rrtcr l 11 . Mik.vrlxwic'l.. 'l.., NaM.a 1. 1:.. anJ Frthrr. P Jt
Mlrlr-r rllio arwl ('rllulur Hiroh..et 411) Nal-StAt, 1984.
(Nbei arppn.(: N:NNNI.J ('arxa'r Inl1IWe 01141 I11C N:tINM11I IIINII/IIIa hu Allrrr.y :InJ
Inllt1Nx/. Ui.ca.e.
I rum dlc 11l partnx m nl I(iuk.yiaal Scictxe..1/ lnhn'c Univcr.ily ):uuaica. NY rnJ
dn 1kP:n(nxn1 ul Mxnllxr.hl~y, ('anccr ('cnler ('.dkpr o/ 1'hy.iclan. Jlk Slny,nln.
('ulu/nl+cl I lutvcl.ny. Ncw Ylxk.
1)hl 1:f1(/N ANI) INSIiR1N)N M(/TATI(1NS IN IiARLY RIiG/(1N ta OU '1 YIM.
S AI )IiNI )V IR(1X l 11A1 PK( )I N I('C (Y )1.1) SI:NSIl I V I: l)K UI 1 1(' l I V l:
PIII:NII"fYIM:11<)R 1KANSIt1RMATK)N
l IN C:IIIy tc/,'NNI Ia /I:lal l,'e11e t/t atll'nlW/tu0ha\ Itla'n %hnw111U wrvl an c.xnnrl
nde in innialmK hl-lh the vltal lulx/w'/ive ayck in Ilarmi.vivc ca/1N and (/N ttrn.lrxnl.l
INNI tlI NNkYN cl'11 (M the ha.i% al carllcr IinJing..Mrwrnr. Ih:tl 11Shrl shall 1. crdJ
HMlhva last IranoohN111./tlIN1, a aCt/C\ Il( nBnrMo, WCrC CaM1m11h IlJ M/ Ih.11 Illl'y 1 rNl
tyuxJ lkknrmm aK tnarln/n% in JJlcrcnl ni(c..d R1a In avertrln I I) WIx'lIN't /Ix' t rd.l
atmhrvc Idxmrlylt nl ttll wao the tc.uh n( Ihc hknlthcJ .rnglc hav Pr/l akkINN/ .rl
nut kvNNk 1//SS ur Jul lo a nn.vcnst nwtalxm al aawNhcr .ilc aml lil) whal r.F Nxl rlN)
hltw /ouail ul the (ar SI klhhlrtlun PaMC/n atc arlually rcall//rvJ lu Iu.rlu.r a cll urn.
I/MIna1NM A mulanl. I IStlll/ll IJ11/11/. wal can.uuclcJ ho cawnaln a S hr.c P.ur lk k
IaMt o/ nurltaNntc. 1.111111 lu 1.1112. whtth (walucaJ a fra/nc.hill anJ a.uhvqt/lnl .t,qa
coJnrl rl nul kl11Nk 1,?41 I hlv nwtanl whith.lurulJ cnax)c a IrunratcJ It I,d.NLJa.n
Pnweln in ptxc ul the wJJ lylx' SI AJaxlah.an Pnwcm. had a culJ-.cn.mvr pharNqylx
Lw van.LwncnNln c..rn(trlly Nkntxa/ hr MI ('nn.unaru w/d. /hh I11N/ln1! a /IN/IJall
1113/n1Uta/ cnKnxrcrcJ k. a r.nlam 116 hr.c past inv nNw1/n11ia/cJ .Illcr nw kannk / I ItN
11) 1 21
wllh ;1 .11.11 Ytskm ltk/nnlng at Ihc newly mvncd nw IcrNNk 1.011. ;11.1- h.NI a lydd
NIlatlvC IrtN'/NNylx' like hrI ./IMI11111/I II 1~ YII1~111/', IN/Ml'Yl'1, III:11 .I IIII/LIIII
III~IIIIIISI
with a M1 h.lv Il.ar tkIchun Ix'1InnmF a1 nurlc.dnk 1,4111 1 :IMI h:n111F .1 ~ahl l.xLn/ Jt
r1uN k'l.ulk' 1.tJ 1 wJ. L.lally Ik IclUvc hK um.hnnl.lunn al .uly IrmlxrJUUC I/.m.
Il'111NN1 YIINht'Y wnh I/I./N1111IY itNllJtnlnF the I:Ia IN I'I.1 :IIMI I'.Ih 1!lYN'Y III .oh UP).
1,/1.
a1Nl .111111 Innhir nvcakd 111.11 tll. Y.Id .en.lllvc /r.u1.11a1nJhnn IdNn.N10lx /rh.aIVid
l'..IIkI lx' l'\IIIh/1C1I 111 1IN' Jh%eMl' t1I vlra) l'.Ih rl'/N' t'YINI'%%NNI
NJhn.. 1. 1. . I rJerr, P H a1N1(kn.h.rr. 11 S
Jnurnal..l t'rrr.lnct 4'11 1/ 7 11 7411 1'q1.1
lAhrr .upyrorf: N.IUnaJl In.htulc o/ AlkrFy a1N1 Inlct rl.a/.
I r/N1/ IIN' I Il'I../r1/1N'nl ..t MN rldaok.gy. ('.IM cr ('cnlrr r In.lnutr ul ('.n11 rr N.v.n.
h
('Id/i 1c ul 1'lly.N IJn. di \urMc.al.. ('r.Iunlhl.l tJmvcrvly, New YtNA
M111 A I I/ INAI ANAI YSIS ()1 1I11 1(IN('Ill )NAI It(lMA1NS (11 I tlli
AJt I IJ1;1 NI, INt)INK'1S Alll l'IIN(:('Lt.1. INAN\I-t )NMAIIt/N
lIN' 01NIN'l Ikv nlxd m thl% p.qxr Ikal with takuthl)Inp :1MI uMk'r%1.11NI1/1r IIK
tylt S.wkMlYln1. I Ij .In.s t lb rcM' I.HMIIN IP Ihal afc INY l'%\:Ily tU.n111J11' :IMI 11/.11111a1u
(ht /r.1nLalll.t1.c11 I.IN'MNyI\' IIYIIIF IMNh AtlShrl ItNI J1kI11NNIJI v11JI IIIIIL/III\ 11M/
t.1111111r 11/V'1IN111 /N /k'h'lIrN1 IIt/11JL1/11Y dllillllll,' IlN l.hhlll! 1:117.1111y 111 IIN'
1'1.1 11 N
u/NNA. Ihc Inqrnl.uNi ld dl. Yu.d sl kJ p.lylxINuk l.tkrnr/n.tr.ucd Io/1nJUd.umor
IIN' ILI1/,Ir.titN-.I 401 14N'n.Nylx' .I/NI It. L.,.IMc Inlrr.aurel. wNh Ihc 1'IJ 12 \/rllc
IMlwlllll AA hnNd r.ll t'nlht%// Illu../'Ll.t trll line Il RI I I wa% u..'d 1.,/ .111 IIN' .luclnY
tka Idx'd IN/i I IN hi.u/ ld Ih1.11J1r1 1. Jlvnkvl /ntu tlnu n1apH vlluln. I I I11N t NI 1
( l'II Atk9NrY11t1% I t:m.hlnnatawl A..Jy.l _'1 I rrn.a.rmahan StMlhr.l 1.Ir.y AdShil a1Nl
( KI 1' ('l'IIY; l I/ C.N/YIIIN-IN1n nt I',IJ I)Y'knIN1 aN1 InN 1111111 Mu1:/n1Y. .11N111/ 1
rJt1Y1tM /ILIINNI(~11.16NIt'r1Y1N'YnIWh11M/JMIt.IJI1CkINN1a/NIInYI'rINNIM111a/11 In.u/nuwty.
thc tlJt..k v ulx'd u.mk vinlsc. wtlh Y~ll'tllK' tltut 1/NMIY 111 thl' INM/IIII I.I IIN' F!l'INNIII'
ta'tNhoy Ihr 1'la SI k.) lvlllcm imply that d Lthlr vital ycllr /vtNMN1111J11./Nccssary lu
nwunlam dle rcl l/ynvccl ptqr rl/rs ul translnrnwd ccl1. I IN: t'1NNIIIItn/JIIy hII1.II. l'nhI-
Ycnallvc nccMNyry cspresstJ by the Illul;tletl RlrNNlll'l. whcdwr IronNllwed uNn
t'Kl:t trllY by IniCtINM/ with vIr11M-. IM by tranYklINN1 with tMi/l'1 ItinN1N'] tN IIIAS-
rllllt%. /111111M.'%thal Ihl' 1:la SI kd IMtNe In InlCfal'I%wlth a INN nlair11nN1il't IIh' ur lhc
1?la
4x kd ludylxqllNlr 'Ihe culdvn.illvc p11eM11yl+C nlay rrlk.l a JrcrcJad InrNlinK
ttrlsCmt al 12'( 'IxIw.tn dlc nwlarNs' ImncahJ pnllciu% aMl a.lill unirkntlhcd INrt
a1NIt11r vltal 111:KrInlNlh'luk IlhMIhCa1NM111t the (NNJllve IN/Yt CIN111MMN'/ll 1./v1/Ivl'd
aMl (he tharallt'rIN/CY nl the vlfrl IlrtAtin hnY) mxrlNMlkcuk litll'rNIM.n .Mwld
reveal Crlll.al 111NY Itl uMkr.landm~,' the nlechanl.nU OI vital IrrnAhHnlJtNln
ItJhhs. I. L . FLhrr. I'. 11 and GinsherR. 11. S
In ( imshcrK. 11 S and VnFcl. 11 1(edY /: Trum/rr urwl F.+Inrl.iun tr/ F.uldt~'atr.'
(:rnr/. New Ylnk Academ/r ('rrss. 19144. Iqr 247 262.
OlArr rrpprrf: Nnwwud ln.ulule 1.( AlkrRy and Infeahnus hlsca.ec
I n.m Iltr I klvnn.rM /1 MI. /..f.a.l..w .Iwl ('tanl>,rhrn.lYe (.M cr ( cnlcl. (rdlcl:c r11
/911.a Ln. A \urI:r.-n. 1nl.uac/.na I/u/vcl%/ly. New lrak
1;.NIIAN('I-'.MI:NT OF VIRAL TRANSFORMATN)N ANI) I:XPRI:.SSI()N ()F
111ti TRANSti)RMEU IMIIiNUTYPE BY TUMOR PROMOTERS
In the .ummary nf this wide-ranging review alf carcim.Renesis. it i. MNed 1ha1 any
clmlrrehcnave nNNkl altcnyltinR NI describe the mukcular evcnts invnlved in car./Ml-
I;l'nC%l\ ntu%l IncM(uMale the IMewnlly available tnlt1m1a1/1M nn the v;IrNW% IIhaK\ n)
lhl' cafCllN/gc11/l' InIK"e\S. i e.. /niha11n11. IIflN1NMNM1 and (MOgreS]NMI. Ihe hr]I evCnl in
Chl'1111Cat C:RI'IM1Rene\IS. ICrnINI "InIt1a1NM1." Is IN'l/eved 111 Inv.dve the IYWJICnI
hIM11nK u/ a rnclahalically aclivaled nr direct acting carniMlfeen /t, cellular 11NA lh1Y
mtcraxtuln with tarl;el 1)NA can result in a permanenl change in 1)NA scyucMCk ac a
rc.ull 1.1 pnnt mulatNlns. nr it could re.uG in a Kenclically allered cell by IMlu.lng
cI1;InKe. in /lx e+pressNm uf tklined 1)NA .eyuenl:cs widNlul rllertnR the strucuuc ut
I1NA In tlle spec/Jl case ol intlividuals eshiMlln6 cancer pnlne syndaNm.. a IJrKc
plMNdalNln tl( /ntl/atrd cells may Ile pcesenl at binh.nd a lurther increa.e in KcncllYally
allcrcd ccl1Y may deveAq+as a rewh af suhscyuenl espswe w inilialinR carciM/gcns rn
/hc env1a11muM . AhlNwRh MM clearly de/ined an a hNN-hemical ur nN/kcular kvrl. lhc
.uh.cyucnl cvenls in carciM/Wnesis allpear ht invrllve chlnal nulKruwlh ol an inlthalcJ
ccll plqlulalitln. Thls pnlces.lermed "pnInNNNM." has been studied in numcnlu% tn
fnY/ aMl rn virrl..yaem% . lhr cnn1/1/eslly n/ lhe IIt1lnNllitln (IheMmsCM/n has re.Cnlly
been cnylha.iied by thc uhservalinn that there may bc Yeveral.lages in prunNnNwl 1 hc
hnal .lape in the nenq+laslic pnlcess.lemled "parylressiun.° inwdves Ihc Jevcl.qNncnt
ul cklnal variants that have acyuited yralilal.vety different pheMNylles /nan the tlrrKr-
na) Inll/ala'd t'etl Iln(IUI;IINM nr dl4llay enhanced ett(Mr.l>,NNI n/ the IraMhlrnN'd YIatC.
With the JevekqlnN:M ul INNh in siwr and in vir.oo nNlde) sy.tems that e><h/hn the
"11n1~,'re\\NM I1IKMNIIeMM." lulute sludics may pnwide a nNlre preci.e nudccular
uMkI.IJndlnk n( the pnN-cY.s by which a lumtw tell ewdves inln a mclaaallt flct./llasm
Prlhrr. /'. H
In Slaga. T. 1(cd 1. Mrr /Mrniunx nJ 7wrw.r r.nwnNirrn. w.l.rnrr /II. Turou. rawn..nr.n
uru/ ('.ot innxrnral In Vinn. Ituca Rauln. hL. C'R(' 1'ress. 19114. pp 37 121.
(hher supilla1: Nalillnal Cancer Inailule and the American C'arKCr Stw iely
hn lu the Ik p:/rtnNM n( Micrtd+iuh/ity. (i+lumhia l/nivcrsily CnikRe 411 1'hyslcians A
Surt,'CtM%. Ncw Ytwk. r
I:XI'RI:SSIUN (7.ONING 01; NI/MAN FGF RECI:ITOR C(1M1'I.IiMGN"MRY
I)NA- (A:NI: AMI'LII7C'ATN)N ANI) TIIRIa: RI?LATI:/) MENti1:N(:I:R RNA
PltOUIKTS IN A411('I:LIS
t:pitkrmal grnwlh (srttx 11CF). a pepli;k of S) amiM/ acids tk/1veJ Inan a 111t
kl ) precwstw IIrcdN 1ed by rectwrlhinaM 1)NA .naly.is. e1/ecls IuMh Kn/wlh ald /MkN
tNNI ld yrcil/c dll/crenliagcd fum'tirwl.t in target tistues. In order lo dchne nNlrc /ully
the Inct'hanr.mY by which pldype/Mde Rnlwlh (al:Nlrs regulate gene tranxtiptNln and
cellular I(rnwlh. eslwes.innckminR /cchniyues were used in Ihis study tu.ekat huwwl
I:CF recelNUr cr/mnlcmeMary I)NA cMrles. 7TIe !;(:F )' eldinR dlNnam shnws Yulk inR
MlrlNlh>Fy Iu the tran.ItnnlinR gene pral/icls of avian eflhynlMasltnis vrn.. Ovcrcit
hrl.slrN1 n( 1;(:I' reCe111tNY in A4II Ctlt hnef c/lnelale4 wllh ml'n'aYtll I'(il' retrlMln
mRNA kvelY and anpddicatNln (up 1u IN) lltnes) nf the apparently YlnRulu 161,
recepllw gene lbrrr are Ihrce lyNq.lasnla pdyadcnyl.ted RNA p/.NhN 1% ul 1 GI'
22 1 71
0
r Y
...i.
~
rrleptN Fenc c tprc..n.n in A4t1 tclla, r+ne ut which ctxualns INdy S' O GI hlrnling
JtNUam) .eyorntca and is (It..tulatcJ d+ rmtsk the .ecrrled (:(& rercl+uN rclaled
1lnttl'In AIC.Nlhlll, to+ rhl']e au1hlN\ Ihe use UI catINe..nNl a'kN11n1,' and :111 RNA \a1MI
wtth arrcn+nll aMNUach ha% luadr avallahk rcl'afN1N ti)NA whr.h t" Imllc
catAIO11ero.Ik.1r11a'Jlnevaluale.truliurc IunCInNIRIa1NNn.lltw/Ynretl't1NN IIrarIII
i/ncrxiaNl ytadK rene Iran.criplinn and Rrnwlh rcl:ulalnNl. Ilk.r ttlnlK% alw+
Jt n«+n.u.de thal ampldlt aonNr uI a t+/t'/n-tN1aRene Jrlcrmmc.lNr+du.tnm ul a hn+wtb
Iat.N rrlelMtN arwllcltulrr rcy+tNtae.lu Ihi. Ennvlh Ixl.v!
I ul. (' K(lxn, W S, Kro1Krr, W.. SN4ar.ky l. S Wchcr, W Fvan. K M,
Vrlula, I MGtll. (: N anJ KuKnfe1J. M G
1tlrn.r 224 R-11 M4R IW14
(hhrr rrpport NatnNUl In.titulr% u/ /le+lth Anrcrlaan ('anicr S.KNIy, IkulvlK-
I.N.a hunp./:r nK +nv hah , antl lhc 1)ula h(Junn W llhr m/na 1 um)
I nNn tlw 1uLary.wt. Rcrula.Ny 11NdnKy Pnyrnnr, (/mvet.ily l+f CaldtNma San
Ihey.+. S.Iw.d.tl Mrdnlnc. La Ldla, M.tkaular Nlolupy anJ Vin+k.yy I.aMN,wwy,
/hc SiIk In.tUtNlc I a/.Jla, ('A. and the 1)/v1.1.Nr .d 1mlhourim.k+Ry. lhnvct.uy al
( .dAtNni,t. \nn Il+tR.+ $th.rA..l MtJll/nc, I.r lulla
1111MAN AIW.N(/VIRUS 21:111 iVK stn! 1 IFI t1K TIIMI/R AN11GI NS
AN 11I'I P111)1. AN I Itt( /UIIiS 1 AR(;1 11 I) 10111U. NII, ANI) (Y N)II 'fURMINI
In thl..tuly. anhtrahe% thal wcre pnp.nrJ aEam.1 .ynllwIic p)Nak. R tu 16
a11111N1 at IJ. In k'/1r111, t-M IwlrJ .t Ihr IIN, .nwl 11 K)11 /inmat .uI I1N- nupN I-llt WK
wN) 1:111 S 1K 1111114911 ,mlqcn. I IM' Inlll['1I/.tr JnhIMMIn' nuomrwywc. tpltrl. J tlM
IarKrteJ lah 1'JK N 1 I11 is IK hnmN an1.Fp n% ln.m i.ux n.d A.12 rnlc. IcJ arll. '11M
.pradnily ul Ilk anapeplnle antd..nly ria.Innnm t.l /IN t'II1 II///MN ,m.t/:rns wa.
ctNdirnr d hy IN plnk uNrq+ruu..n .Uwlh. Annl>.plnk' ,uuitr.dlc. JueatrA lu IlK NI1,
aMI ( Y K/I I Il'flllllll 1111nnIM11Nl'l l(Nla/ed IIK 1'.Ih S IK Iu1/NN a/llll,'Cn. IltNll Iwl+ Ad!
Iran.hNmcJ tal. ell hne.,l'l7 anJ 14 pruvaltnXeviJear Ihat idcMical pumN anl/gcn%
are .ynthe.iieJ in AJ2 infected and Ad2 Iran./um+rd cells lbese re.ulh slM+w Ihal
/he Iah N)K and 1' Ih-t 1K T anti/,rn. are mll pr.res.cJ IN/Netdytically al cither the Nh,
tN ( Y K N 1 ternnnu.. The Ja1a lNUvNk .tnmK evidenie at IlK pnMcin kvel that the LI1/-
1')K and 1:111 S 1K tunwn anliKen% rar(ially overlap in 1)NA srquence, with the 1:IH-
1VK /nirlalmF Itan.IataNl at the first A'f(; at nut:ktwnk 1711 in Inn.lalitm rcadinK Iranrc
I aml the I:Ih S.1K IunMn anl/Ren iniltatinK tran.latitNl a1 thc w.crnN1 AI'(; a1 nuakauJe
2111b in reaJlnK Irmlc 1. //vera11,11K.e Ja1a e.tah6.h at the pnHUn kvel lh. mlmmum
Rene MwmLurc., Irrn.latitNrmi11a1itNr .de. and rtathnlt Iramee nl the Ad2 1:111 N/K
and 1:Ilt t 1K Kenc. dw% ranlirtutnK Ihe+Netical /kducti+m. havrJ +NI 1)N,\ +ayoca'e
aml /w rlak ntat+ analy.er. 71k annricptHk an/1btNbts .MwIJ Inove u.rlul HN .Iuthc%
on the ryrnlicalNN1 anJ funrlitNl% td the Ad2 h/B 19K anJ 1:1H-S1K T aMiRrn..
(:rrrn M rl ut
LY/MII../ Vn.dr.R+ 41111/ MM 615, 1119 1
lhArr.rM.n II V tbMN IkatthServNr
/..no Ifvr In.ftwr I.r MIr.uLa Vu.,lyY. %I I.ut.llmvctaly Mcdaal Ccnlrt tl
I.~n.
24
i
ANTIIN)/)I1:S l'()SYN1111sTIC IM:PfIIn:S TAR(;1TI:1) T() l'lll:
7KANSNIKMIN(; (;1:N1:ti (KAIUMAN AI)I:N()VIKIISIS. AN AI'I'K()A('lI
1O IININKtil'ANI)ING IiAKLY VIKAL(;IiNI:IUN('fK)N
lhi. culrn.ivr paprr.lart. with a hricf review t* raaeM stuJie% uangan1qKtMnk
anllh.dlr. It. Invc.l/1;atc pnlhkrm in vrnk+Ey. A Kencral .tralify i. then +.uliutrJ
whltfi u.r% aaq"aNk arnlMNlic. In inve.tiKalt the \m+wn AJ eatly Ix.Neal. r1Ml 10
lkl.ct htlt:ulvc, a% yet unnknldirJ, pnMein% whnse eai.kntY Is .uyKa-.IeJ hy tlK
tNe.r/Kt.d thxn Iran.l:uNNl reading Irarrlr% a. (>K/htIIYI fNNn the Ad I)NA 4YIIINNe
Many Iwrlwular .IlNhev are Ihrn Jescrihed whlch can he IJantilred by Ihe Itdl..wuwr
v'a1nNl lnk. (;1'lll'IN (hF!:It11/a1N1111+1 the Ad2(;CnlNlll' I'INl'11t/aI Sties LN l,Nl!l'lll/r
A/N/IM'111/1k AIII/IMNIk-., Ila/Iy Vital (;ene I:qINlNMNI; IJte Vital (.elll I~Rpte..a.u.
Atk'n..vtrll. 'I Id11./tN1111111, ( N'/kY 1)tran//a1nN/. (;t11C I'fl41u11\ i1MI I'1/1N tNNIdI
`IIIO
w M.davular (llara11aY1/JINNI ul I'pNem. IU1lINkJ by
Atk'MWlrll. Itan.l.N//nt11
(;cln. I Llnr. Muquy+lak AnlthnJK.; (Ag:mvalirm n/ Ad2 1:1 Kep+Nl; Slla/a. I l.m/;
Annl+t1+1akAnUIuNIK.1 arFr/avl to the Ad2 Ellt S 1K, 1qK, aml 20K 1'uaeol.; I I.a ..1
AmqKINnk Anuhtwlk. IH+ Analyte the AJ2 I:rgr 1'layue MNlanlh that Mc 1 k Ira Itve
in ('a11 I r:IMItN/na1NN\; l1m: nl An111K'111nk AINIINNIK% Nt h1en1/Iy A112 and AJ12 1IA
I:na-trkd I'rtNrmt in Inlerled anJ Tran.IrNUkJ Manrnallan ('ell. alnl in F
lratNttvllM'J 11y tIA rl)NA ('nnlarmnlt 1'cplitk., anJ Ihu)crlwNM% un AJcrw.vuu.
I ran.ItMll/lt~ I'r/Ml'm.. In Ih1. hNt .eIINNI, e\lahh.hlnfp Ille IurM'IN/II\ III the
:Nk'rN/v/111\
aarly IN+ACIn., and In 1/arllcular Iht early re~nNl I:1-CnlrMlell IraM/+Mll/1n1, IN++IrIM. 1%
prexnlyd a. a chalk n~inK anJ eRCilinK 1a.A,.ince inve.llpattN. c:m+qwnnl.ln ally k~d,
hNw:ud Iu the avallahdlly ut micn+gram yuanlnir. ul purihed Iil (N.Nrul. ItN hnt1Nr
.1uJle..
t
(:rrrn. M. rt trl.
(-wrrrnt 71y+irs tn Mrt rrdnu6tXy nnd Inunra.dnKv K14.1A7-141, 1YR1
(khrr srpperr: Nalinnal ('anrer Institute.
hnNll the In.tilule I+N M+decular Vin/k+gy, S/ Llwi. llniver.ity MrdKal ('cnter. St.
1.tNU..
AN111I()t)Y 1)IKI:('1'1:I)T() A SYN1111:TK' PI:1T11N: I:NC(N)IN(;1'IIt:
NI1. Il-KMINAI. 1(S AMINO A('ll)S (N' 1711i AIN:Nt)VIKIIS '1YIMi 21i111 .S 1K
111M(M( ANl l(;I:N KI:('(K;NI%liC THH 14t1I211K ry1M()I( AN'/l(;I:N
A, rcligoNteJ here. a peplitk. FI,N-(;M-Ars-AtK-A.n-Pru tierd;lu-ArR G1y-Val
Prn-Ala (;Iv I'he-Ser (;ly-l('yK'(KNI. elNNaininR the anlilw+ alN/ acyrknre at the
NI I. Irnniml. ul /hr atkawuuc lypr 2( AJ2) /il/l rlr/nl larre T anliRcn //'.I H S 1K ) ha.
IKen.yMhr.iitJ. Anmiprplwk anlrhta/y was Kencraled in rahhNS and u.rJ /.o immmw+
INecrpn:Ne Ad T antlKen. IaNn Ad2 ttarly tnlelteJ cr11 e.lracts In aklllNm 1u thc
e.pe.ICJ 1:1H-S1K T anliRen, antipcptMk anllh+dy /Nrciln(ateJ the AJ2 1:11t 21)K f
aMiKtnlhalvasprevi+w.ly./wtwn/uherelaleJNwk1N-SIK((lrrrn.M rrn/ ! Vu..l
42, N1-41 19112). AnliprpliJe anlihtdy pepared asains/ the C(!t)11 terromuv t,l the
I:IN-S1K T anliRen /N against the Nll. terminus tA the 1:18-19K T amtRrn JNI rwN
INecipitate the I:Ifl 2UK T anliKen. llrcse data sutqtesl tha/ rhe AJ21:1N-21)K T anuKrn
inNialr% tran.lanm at nuckollJe 2016 in reading frame 3, as lkrc.1:111 t 1K Thr viral
mRNA that encudes the 1:/11 21NC T aMiRcn hn not been iJentifieJ
Lucher, L. A, Rrackmann. K. Il , SyminRuNl. / S, ant) Grrrn M.
23
1'm./nxv I t? 217-221. IVMA
(hftier.rpOort: Nali.mal ln.titutc.uf Ilcahh
I n.m Ihr In.ululc h.. Mvdcculat VirnL.ry, SI IAruia MeJlcal ('cnlcr. St I tiur..
I 1'tl l IN IIARK IlK I VIRION 1)NA IS VERY 1I1(CIII.Y MI:fIlY1.AT1 1)
It 1% wcll e.lrhhatKJ Ihat f)NA ntthylatinn is eenlrally invulvcJ in /:cnc cqxc.
IUMI A v(-ry /nrlrntAm l1UC.InU1 01/w 1% tUrw IunMlr vtrv+e% rerUlalc IhlIr g4nl. /n the
lytl( ao,wcll A% in dK ultcgraleJ.late. In the auJy fxr.enlcJ hcrc. I:HV 1)NA Ir.an IsK
11114 1.Iraln. a rnnwan.hwn/mp variant. wa. I+nsd1ul-crl amt pmllnJ Ihrcc Imx. IIK
hnal Innlhr.l vl/uv fwcpalalam wa.ly.cJ with Iw.acacc K 11/MI IrK/ and vrahl/m.M..k( v)
.u11iIC 11'% I A11ct .evcrsl (Mbcr prepata4.ry a1c(h. the S nkIhykytmirK c.mt,'M ..1
vuanlI)NAul1 ItVanJu.huaI/K I(cll.wa.an.ly/eJ 5 nwIhykyl./an.1.111(.adv
/lw'IIIyIA/(1I haN' in lvkary.Mrc I/NA Ihc tu.cs werc n1cAWrcJ ahc/ LnmN :wal
hy.h..lya% by hr):h pcrl.Kmanre liqunl lhr/aoal..Etaphy T11c peraenlagc o/ ayarnN%
nr/1/y1Aa-J u(17N I-IIV IIK I vitam I)NA wa% c.tremcly hiKh. avlrap/nK llu.e lo ISl.
/.w tlucl .kL /lnnwnun. 1)NA mclhylAtw.n u1 the lur.t llurknl'% lymplwnlu tell hrr
IIK I wa, mu.h luwtr..avcraymg 2 JN% LM t2.k-tcrm/nAtam. 1hi.cRlcnl(d nlcdlvLr
INn1 1\ In 1`r.:11 l.Nll/A\I III L/IKr l L1%H'\ ..( tur/Mn v/ru%C% arMl 1% IIN hll.`Ik'o Ihal 1%
I.(w.w/l
/n:n/y nr.unnull.nl.ydrm I he a/11oK n( w.a.vrvalinn thal 1.11V 1)NA 1% urIhylll(J
lu .ul /l a larkc eatnl tal.c% the fl(wvtr..n 1.1 Iw.w rrrclhylrlam rnay rerutalc Kc/K
calMr..l.wl in thl% vuu. AtclwJmp u/ lhc.r aul/wn.. it i% c.v/dial Iha1 Iulnlc CRpn
mrnl..ktcrnoa whN h/;enls arc uMIhy1.1/eJ aml h/ what ettcnl nlclhylan.m.r<( ur. in
llK vnaMl :IrM1 ultrr( cllolarly
I/r.Ar. 1. S an.l Ih./J.n.rn. R M
l.NUn.d n/ 1'rrr.b.xr d5111 4112-1111. 14A 1.
(lt6ir .rppnrt: Nau(ulal ('arller In.ulute
I nnn Ihl tkpartnant ..f PeJialrir.. (Inivcraly rr( ('alifrwma. San hlcpa. S.Inrd ol
MrJN Inc. I a LdIJ
'IIII. I:M II.NT UF I)NA MI:TItY1.ATION IN f1UMAN TIIMOtt (I:I.IS
Inlhi..ludy.111f hNa) FcmwnN I)NA nR'Ihyl:Mllnl.l C. lln'rCrcCMaRel/l nlclhy.
latctl ryh..nK., wa% nkawrcJ in 21/ ccll Iuw. IkttveJ tnNn Jdlctcnl lyluc nl hunurl
lunw.r. I hc nw a.nrcnk n/. were uhlanleJ by calnwl c1<lhangc lnrlid rhr(rnanqtralhy
(.1 ha.r. rclrA.cJ by I.wmK acill hyJrnly%l\ I IIC%e C111(r1/tM'nl% wC/C J.N1P n..k/i rlltnlC
/I ./ht-N'11 nM'111yIJt1.M1/% a Iwevalcnt and IarRc (kkcl in.nx.qcnia lran.hwruatn.n A
nl.lpully (.1 Ihl tunMw ccllo nlea.urcJ haJ lklrea.eJ kv.h ul nlclhylalcJ IrN/1 in
l.nup.ul.un tn Ihi, a/Mt.whcr IafrKal.wrc.' puhh.hlIl nlca.wcuunt% ul mwmal:t 11% wr)
1/.ln.. In Ix1. lunw.r rell I)NA ranged tn bw ac I 2'% ul cyunincs mcthylalcJ
t umparcd la a valur .r( 1'R6 rlr nwwe hw nnrnlal cell% and tieaue. 1(pall anJ M.pl I)NA
t('mnN II. M CII/ynr(' :Inalytli lIwf1/nM'11 IIM all 1U11MN l'CIl I//1C% h\Il'll that thelr 1RIA
wa\
hll.ua Ihl Lnrd /u...n11..u1~.M lu II11' 11NA IL.n11Nn/14.I11//1IuN1 hfNnhla.t% fc.a J llk
~. uh, ./.~ ...,, .11.. 6y....1 ./.........r..... qb% eo.l r..11n Lnn. nrluM dltAtv%.. wr/r
%Inl,
..y ~. .. 1 ~. ...1...../ ... .... ... .. 1 .1. ..n.... .. 11 I I'v 4 ..w..lA1rJ ...dh lla-
rCCCnI Uh~lfvallull PI .NIKr IJh.NahMn'\ Ihal IntI/vNI11aI Itl'rN% arC url.knikthylatrd In
hunlan canl ct rclll anJ Ih:lt a nanltwr (d Jdlerenl carc/m/Frnm ca/l h.wc/ 1)NA nkllly
lateal anc./ly
1)I.Ja. 1: 5.('hrah. M S('.. Kuwilch. I)., and Hu//rrr/n. R. M
Irannul.J th. Nutr.nn.l ('unm rr lnlrrhnc 711d):755-7M. IqR I
Othir tr/y.r.rl: Nali.rnrl('nnrcr In.lilulc a11J Ihc ( i..npc A. IaClilh Ml'/1MKIaI I'UINI hN
('arll cr Kcaarl h
1-nnn 1hl Ikparlulcnl ..1 1'cJ/alr/c.. llnivCrsily ul ('ald(nnia. San 1)/cl:o. ti.Mwrl ol
McJ/. nk. I a ).dla
\ AI)I N/)\YI MI.I IIII)NINV tiYNfllla'1111: IN ('111:111KI-1) N(1RMA1. nNl)
//N(-/M;I NK'M.I.Y IKANSItIKMItI)1111MAN ANI)KA'1 l'Iit.1.S
In Ihi. allcnq+l 1./ rcarrrnvC Ji/lcrcnccs in the rnKtiah.di.nl u/ /11cIh11Nnllc arwl
IMNIM4'y%hItK Itl rMMn1:1I .IIMI Iran\t11mR'J l-cII%. the Cn/y111a/N' h1r1IWInM1..t 1:1J1'IM..
\y1111C1I1NN//1N w.l\ cxauuncJ in calracl% tul s varicly r.l mwmal arrl ..n...ycna-:Jly
uan.1(nnKd hulnan an(1 r:N arll llnc% whKh Jlllcr in dw ir a1wlAy l0 4ruw nl lnlrJlua( In
wh/l II nN'IhnM/nl 1% RlIIIJCC.t by 11% I/IIIIICJIak IIrCf1/rMM IMNIIIICy%IIIIK . I hC%l'
lllvl'ml
KatIM% havc h.alvcJ /hc hulk.d the S-aJcrln.ylnlclhilnnnc syntllcla.c xbvlly In 111c
p/./ Imawlwwwkial.uprrnalanl. "fllcy.hl.w Iha1 in all cell hner a stnplc klnlIK .p(cll%
cwl.l. in a dialyiavl c* Iral l with a K_ for nKIhMminc of alrnq 1 I2µM. In.cln /cJ /nk.
Ilw y havc lknMnl.tralcJ a rcyuucnwnl IIK Mlt'' in n(klNMnl Hl that tNYIkJ to /(KI/I tlK
MI:All'rrnllrlru /(w cniynlc aliivily anJ have shlwvn that Ihr cniynlc can h rcyu.
I:I/cd hy prln1ur11e.y/A:uk1nhd1ilnm Hecsu.c the invCaiKaluraktn1 n(1J/tlcrcnrco in
Ilk cniynutic ability (// Ihc.c cell calraclr lo Wilvr mclhi(wl/rlc hK ti:wkal
sylnwlhi(wllnc hwnuli.nl in rurn. tlky suRFes/ thal the lailure lll lmtl.l,~.nically-/ran.-
hrnuy/ ccll hncs ta puw in nlclhilmine-hee. IMnlNllysllnll-l'lNNalnln); t1NYI111111 may
rc.ulllr.un the Jcarca.cJ nrclhiunine plrAs in Ihc.r cells or fnnn 1hl hh. (/1 ability ul
the.c celt. ta plMkrly nlelal>,dve honwlcyNCine. alknlwine lw Ilkir cellular /w(Khw1.
S-a(k m/.yllMnrll t y.lcinc .
(kkn. K. I... ('ar.nn. K.. Mccham.l. 0.. H.l(nutw. R. Af.. anJ ('larkc. ti.
Rir.r hirnirn rf Ri.yrhylih rr Arfu 7(#/.27(1-277. W111.
(kNte supprl: Nalilmal In.lilulec llt I lerllh. the Amencan 1learyAsNNlat/(/n antl the
(k(Kgc A)xnhs Menl(Irlal hunJ hn l'arlra Kc.carch.
hrnwn 11K 1)cparlmeM .d ('hcmi.Iry mll Ni(.hcnliary and the Mukcular Ni..h.ry
In.btulc. Ilnivcraty ol ('aI/1.Nnla. I Al. Anpcks. arrl the I><par1nN/1/ u/ 1'cdnNn...
Ilnivctaty u/ ('alrl(wn/a. 5an Ihcpu. lclwwd a( Mcdsclnc. t.a fu11.
Klil)(ICI:U 1RI:Ii MliffflONINIi IN MITIIK)NINf:-1)IiM:NI)hNT
5V10 TR/1NSIt)RMI:1) III /MAN 11H(/111.AST$ SYNTIII:CI/.IN(:
I11N'ARI:NI1.Y N(NtMAI. AM()IIN'IS OF MI:TIIK)NINN
In the kmK running .e:nch hrr JLlincl metahldic Jtf ferenles helween IM.mul Aral
rancer cel1., rnany J/llcnnt lype. ul ( Am'et celle hAve %xen .M.wn lu Iw nnIhuwu.w
.kll" mkm I l1C%c ll'Il%. I/IIIIk(' Mn1/1aI1 CII%. 1!n.w IMlwqly 11/ rMw at IK wlKn IIKIII/.NU/N'
27
1. fcldarrJ by rt. iumicJiale Irccurs.N twmwa ysicine in IIk rrnwth nN'Jlun 1 Mc/ 11cy'
nNJlum) (IM'..' nlv.ml~,'a1Ma have I+rrvNW.ly .}N.wn 1h.J al+(qrenlly MM/IIaI 1..1al
anNernl...f nKlha.mnc are synllksvcnl by nNIhawunc-rkplmkM SVJII /ran.h.rmcJ
human hMnhLr.ls Ih.wcvet, nNthinninc Jcpamlrnl «ll% in Mc1 I lty nKJinur alru
nNJa1e rcJrNtJ .mNNrnls rrl SatkrNnylnMlhNmine (MM.Mct) arN/ ekva1eJ anaMmt% tJ
1 aNkINNyIIMNINm ym.ina'(AJ.rlily)th:Ittlrp'1/1Lflna.hahlyll11111r1.Iw111 Inlh/.lclwnt,
Ilr mvC.hF al.y..knMrr.uala tha/ tIN anwrYM td IteC mrthnannc r% luw in nNIhnwnrk.
akttmhn/ SV44/ traa.hwn~r) humon litwnhlaas in Mcl Ilty nwJoum a.Noy..ncJ 1.0
nIN11CJ IN/111a11 lhf4.aJ btxuhla.l. In atrwfast, in Mc/' I It y ItN'J/um IIN' aINn111I OI
Itcc nKIhumnk rC t.wrK+.Nahk in h.yh t'ell lype.. Thc JlhrNnt (wN.l u1 1rac nw.thannne
In IINIIINnl/lw tkltn.knl tclh in Mcl Iky' nKrhum alti.ws only krw auw-unt. uI
A.h.Met 1.. /r' L.uNd Iluwever. (.aKe a.a.aM..4 hr...ynllwsvrJ n.Itbaaww arc
r h:unwkd nH.. IN.MCm .ymht.r. P....J.k nNY hannro. ar Jrv u..aJ 10 . yda~o Ihe.
..ukcr a...t...tcJ mrla/w.lp d1ra/
SICrn, 1' 11 . M.a han. )O, Wallaa c, C 1) . anJ 11../pwrn. R M
/.arrnul..f ('.Rr.brr 1'hr lr.d..xr 117'/ 14, N)%1
(hArr rrplurrl: Naln.nal ('antef In.lnulc aal lhc (ie.wKc A JalY1h% Ma'IMNIal 1111041 Ilq
('rONar kc.aarah
I a.nn Iht /1.panownl u/ PcJralnl.. Ilmvrr.ny u1 ('alJnnua, San UNFu S.h.rJ al
MrJN Inr. I a 1.J1a
1711iM1 fA11()1 IC 1)1111'f (11 A11'lt/h)NINI 1)11'I.NI>I:N('I.(1('(I/RS
tKlil)III NII.Y IN IIIIMAN 111M/)K ('I aJ. LINIa
A nKlaly dN charaa Icri.lw tw .k /ct I Prc.cnl in tanc/r, c11% hul mw in rwumals may
tIKJ hyhl .wr the IlNlkt ular ha%N r.I rmcarcnk uanLwmatNm 'thi% paltr Jcal% with
.rtch a chararlcri.uc. McthNminc rk'pcrNklNC is Ille inahJlty Id cclls Iu rruw when
I/ll'IhNN111N' IMct) i% rcplateJ by Ils nnuN'Ju1c Ixacurvx INrnNrcy.lcmc Ilkyl in Ihe
cullurc ukJlum Mcl 11ry' uKJiuml. All rNrrnul uncstahh.het) ccll slram. Ic.lcJ lo
dale luve hacn .IN.wn lo hc melhi.minem.kpcndeM anJ thus Erow alnNr.1 a% wcll in
Mcl Ilcy' nwtlium a. Otcy tkr in Mct'Iky nrJrom Resulls pre.erNCd hcrc indiaa1e
Iha1 nul nf 21, cell Imc% tkrived Inwn Jiver.c lypcs Irl hunnn IunN.rs, 11 Ju nn1 lemw :N
all in Met I ky' mcdium and arc aA...tulcly rntHhi.minc-Jtpcndent and Ihree rr.wr .wdy
.hghlly in Ihrm nrrhum. Many ol the IunNrr cell lines IeslcJ have Irak elx in cammNm
rMhcr Ih:m Ihc latl Ihat IIRy are nNthNmint' JcpnJenl 11N hrKh !nyurrNy ul tKtur
rcrNc'n1 melhirNnnc JcperNkrNC in Jlverwe lype% af human IunN» rells irN1Nalcs thal
nKllm.mnc JlPernklNC nuy he.n in+ppntanl aywecl ol rnp'ngemc IransLwmalnrn anJ
1hct:qxulitaliy c+pkutahle
Mecham. 1O , Ruwilch, 1)., Wallace, C 1)., S1ere, P 11., anJ 1l.17iN.rn R M.
Ran hrrnir ul rrnJ Ri.y,hrsirnl Rr.arurrh C.nnnrrniratinnr 117(2):42Y 4}4, 19at 1.
Other srRpwl: Naliamal ('ancer Insluute and the (ieruRe A. Jactrla MenNMialFunJ frw
('anrer ke.ran h
I n.m Ihe Ikpartnrcnt uf /tJnbaa, I lnivcr.i/y of ('all4wnia. San 1)iego, ScINNrI of
MfJN/tK. I.a 1..11:1
ALTIiRIiU MI:TI11l1NINI: MI:TAIN)LISM O('('11KS IN AL1. MI:MN1:Kti OI A
til:f (N I)IVI:KSI: I/IIMAN TUM(/R C'EI.L IJNIS
Thi% hNtlKmiral stuJy e.anlines the (sirKhemical ha.is rJ nklhi.minc tkpln
rknrc, a IIKIaIMrhl.kfl'l1 hNlnll (hu\ IartNJy in IfalUhKnl[J and nlal/l!narN cell% IhC
tk ka 1 i. ncmdcslcJ a.llk inaMli/y t~/ ccllau pnwr in nK Jia in whN h mclhNNruK / Mrl l
i% tcnl.NCJ hy il. Imnkdialc Ixttur.ur INrnNMy.kinc (/kyl IMcI 11cy - orlJ/a). It 1.
tknMm.ualal /K re Ihat wNIhn.ninc-JclwndeM ccl1% rkriveJ fnnn hunwn IunNrr.. c..m
Parc.l 1.# rNK111aI Illl't11NMlnl'-IIMk IKINkIIt lYlla, have hrw kvch ul Itcc Mcl, hrw, kvcl.
44 S-arkrNr.ybrN'IhN.nnlc IAJidNcl/ arNl ekvalatil levels td S adcmnylh.MrNryslcrnc
1 Mhd la y/ whcn int uh,arJ in Mc1 Iky' ua'dium Mclhi.minc-uNlcpcrNknl human
111801409 tcll% al.n h.ivc vrry bw kvaIs of lice Mcl crNrN.arcJ Iu rNKm:d acll. Mn
fcrnr.Jly havr kvcl...l ML.M.N and Atk.Ik'y ctNnp:ualda 1u naMntal acll. in llw
Mct Ilty nNJNrm Alt hutNn acll lypc% uNtwPrNatc anMSIMs lJ Mel uun tw. tcrn
.urnlar 1u maNr.d IIMIIINntlne /MkIk/Nknl human (/INUhla%1\ when mrohalcd in
Mcl I lt y' nNthum, tlNrchy imlN aAinK apparcMly fNKnul kvcls nl Mal .yndtca% ln the
IunNr tcll. '11ic neclhwnurK-imkl.CrNkM Iwmr ccll line% in Mct Ilcy' nKJNUU sacm
able 1u rc)ndalc Ihcir AJuMcUAaGJIay raliox mwmally tkspUC Ihr. Jrlcat rn havuit:
vcry 6.w li vch.J Irce Met Thu., in a divcr.c .c1 rd human lunww tcll IuNs all alc
Jc(calovc in al ka.l wrc aspell rJ Mel mclalMdl.wn, yiving ri.e l.r tIK (n.rhJUy ..1 a
FtirNraI urIahM.IN aklcc/ iN aanter.
SItm.1'. 11 , Wa11:Nr, C 1). and NoJ/nwrn R. M
IrwrnrJ../ ('rllNlur I'hrai.daxr IW:2') 34, Ivl(4.
(1tAer rrpperf: N,IIIIMIaI ('ancef IMt/lule and the (ielnFe A. Jal'11lv, Ml'nNMUaI 1'II/MI hM
(':unccr Rcscarch.
fnrm 11k 1lrpannknt u/ PcJialrics. Univcnily u( Califnrnia, San I)icy,u, Sah.Nd ul
McJlcinc, 1a lulla.
0
ALTI:RI:1) MITIII()NINI? Mf:TAB(M.ISM, DNA MIiT11Y1.A'1'I()N ANI)
(MKYM:I:NI: L'XI'KI:tiSN)N
This we1l-dirumenleJ review fawsca ar the itNcrttlaliamshiP ol mclhi.minc Ine-
taF«rlism. I)NA melhylalNM1 and /NKt~,'enll Ifa1Kfl1fnl:NMN1. ti!l'INnI\ taI (Itls\IINIy arl'
dcwMCd 1u: (:cncral mNhimmine me(ahldi.m: AbereJ nrelhirNlinc nK1aMJicm in can.
eer - mcthinnine deq+cnJente: li/fechvs ul Sark/N..ylme/hinnine (A.hrMel / rnclah.r-
Ir.m: Altered 1)NA methylatine in cancer: Cienc irNloclirNl Jur ht allcreJ I1NA rncthy.
Ia1NM anJtlM allctcJ mclhNM/ne mclalwAi.m: I:/kcts nf inelhylalNN1 nn rNNUKcnc
e ape..NN+: ('IlenNy+nACflive cl teel nl tn[IhNNrine altaina cancer:.fN! ('rNrt tu.Nm. anJ
per.Pcctives In Ihe ctuNIudinR seclwrn, a nudtl nf rNx fwNhway hr caniNqxnesl. Is
prescnkd. A corre.yNNNlin6 liaure dt:pids Nrc retNCd ry.lhwayv ..1 Na~hN.mne and
nuelhylalion melahldism arNd indicates pninls in the biaehemieal scheme wlKre mtcr -
rulMirms nray lead to eatcitN.genesia. Sia PerlurhalirNla in the scheme that may allc. I
oncu6enesis anJ the pnsihk mechaeisms invnived me: (1) CarcinnRens may hnN/
Kuanine resiJues, prevent mclhylationof djaenl eyNnines and thereby INn.rMy a1h.w
oneeogene aclivily. (21 ('arcimrrns /hw art RageMs fIM ful/hylkyl smoPs lan atl
directly on DNA mNhyltransferaxs anJ ituctivale them (1) 1:acess S ademnylMNlNr
2K 1 29
t y.lrlnr. .IN h J. IhJI IrN/nJ in uNthNmnK ak1+.nrknl . a 11.. can trNnlxuuvrly mhlhrl
I)NA nNIhyllrJn.lrr.lv' Id/ Il.r ta/l'llNrl`a'n rIhNN11/N' lJU v'rvt J. auh.lr:dr IrN
Ad..Mrl .yulhc/.rv Wllh IIN ININIIN 111N1 .d \N/r/N..ylrlhamnN wlu.h ru hrrn . Jn
Itllnhl/ IIN'/11YI,11PM1 ISI II nN1hNNnnc /. In .INN1 .up+ly, krw kvt'1. .d M6-Mr1 :uN)
rrdua a d.N In I/y r.l I 1NA oK Ihyhren.lcrav may rc.uh, .nNl Ih/ Iolrl/a la n. r ro 1a nvl,d
11N IIINNII/N'ltlM'IIIyI.11/o M 111t'IJitit11./11 tIN/kI alw/ mla'lla'Ir w11I1 t hr1NINMrN11.1I
IMIoIa'In1
I m.d1y, Iwu mq"N1.ud unldN:mrNl. ul Ihrv nNNkl Jv 11 1. INaw111raI IN'li .I/a /t1/1111/y
tJN rNN~r)rnr. 11./11~I/NIILIINNI ruay hr Ixevaniad hy J alla1 rrNnalnmF
IIKII/NN111N'. IM-1I-ly rdN,/1/M'II IIIHNII!h tlN/hnc aMI d.kuNthyLuNNI ul 1)NA 1. Jn
IIIIIANI./ld a Jla /IM~)'l'll/a rvan1,1/N INr.ahihly arivs.d IrnNd1ylJlmr I)NA :,rNl /rvrr.
Nqt u/N rrl:rrK.r.
Ih-/frnna. X AI
Itnr luma u.l lh.~/dn w.r Ar frr 71N 49 %7 1994
Nthrr tuR//rNl: NJw~n.d ('.uN a r In.Irlolr arNl lha (:.rNyr A/.w rrb. MrnNrr/ rl I urNl I.N
('.Nwr/ Hc..Jrah
1 nNn dK IAp:utnwn1 0l 1'edrJlnr. Ilnlvcr.ny ..I ('aIlllNnla tian I)layr.. %tMNd ul
MrdkNN I.J hdLr
111'1't)MI II11'I A lltlN I)I 1)NA 1111MAN ('AN('1 K(l:1 I.S A SI11. SI'1'('ll l('
('l1ANG1 IN 1111 (' At1( lIN( 1K:I NI.
Xilr .It% lilt nN1hyladrrn.rl 11N Ilu/o.m. onr .NN /11!rnC wa% ll/vl'mIFa1rJ In a u1
OI CIIIIUra'II h11111.11111111NN ICII IIIM'\ JINI IItN111.1I h1111Wn Ilhfrrhlavl .Ir,un. A.
INrv1..Nlly
tclNMad. all lhr IunwN crll linr.. rn a.NruJ.l hl n.Nmal rrll., were hY1.NrNIhyl.urd 1.1
varaNl, tkkrca% rll dKIr Ir4,lI I.N'INNUN 1)NA -lhr prc+cnac n/ nklhylJtu-rn lu .pct dia
rrraNlt r.l dK t Nrrr Ih'nl' Wa\ i11:1Iy/ClI by uK 01 the rC%ItN'INN1 C111kM1N IC.IV lvrv In
hNIM'1\ Mtlrl 'JINI II/Mlll, which rarr.~nvr Ihr x'trlcrwe S' ('(Yi(:1' 1)NA
V9111CINa.1) 2 ayhnuk hav./alh.wrd by 2 Ruanine ha.r.) hul.ldler in thrir ahlhllcv lu
tk.lvr a1 Ihe inirlnal cyhnlrlc rr.whk whrn it i% mrlhyl:Natl '1hr hr.1 Ct.NI, lirst
inlrtvcning vqutnar a/rl .auN+d rum were hylrwnclhylalyd in all tcll lypr. rcKard
k.% ul wINlllrt dk tclls wem mMnal nr .Nrt.rcnically Iran.h>rnlyd a1N) rcyardlrs 411
/hr drKrat'.// /tMAI ~l'nIN11N' nlelhyl:NNln 11I (hl.'t.CII I h.wCvrr thC M11Jtary ('('( r(
.%Ik' lll
Ihe Ih/rd ct./n wa.lully nNIhylJtral in rNNUlal cell mrailu. In ctmlra.l rn 1.d S lunun
ca11 II/w./uKaurcd, thiv.ilc wa% hypNlrlhylatcd 'Ihi. i.1hc hr1.klrNrmtralnN/ ul a
.ilr .pct'dN 11NA nNIhylalnNl tkleil in a cc1lulJr .NNUKrnc. 1.Nnt INr.Ihlr unpl6a'a-
bron% rrl.dmp d1.rulMnm rd I/NA orclhylJuun 1r/ tNNukrrw a.NNtul auN/.NN uKr1n.IV arc
dl..v.vtJ
('hrah, M S(' . Wallat'r C. O . and Nr.J/'rwan. R M
LNrrrNd n/ thr Nerrornul ('une n In.ritrre 7 t(S): 1057 1410. 19114.
(hher suP/ort: N,rtnroal ('anacr In.nlute anJ the (irrNizr A)atr.h. MrnNNial Pnml LN
('J/Nrr Hr.eanh
Ilr.unrlN (>,1r.nurNnl.ll'rJrJbN.,I/nrvrrvlyul('.Id Nn1a,San1)Nyu I a)nllJ,('A
r
I:I.f.VAT1i) t)VIiRA1.L RATIiS OF TRANSMf711YLATION IN ('1'.t.1.1.INI:S
1ROM /11VIiRS1:11l/MAN Tl1MURS
In a sludy of a divcrx se1.ll human lun.>r cell lines fNCvilw.ly sMrwn Io h.vr a
tkfecl in mcthuxlinc mclalN/lnm, it was demwlnsltaled Ihat all have enlunced uvrrall
ralrs .d Iran.mclhylaMNNI ctnl>pnrd k/ mwmal Iwnyn fihmhlaat.. Tran.nlclhyLtu.N1
ralr% wrte tnra.ured by hkNklnR S-a.kn.rcylhunw.cyacine (Adrdlry) hydrul..r a1NI
nka.unnK the Adullcy whNh accumulales as a resuU of tran.ntdryl.U.N1 '1ht alu
hanceJ Irrn.rntIhy1J1Nm rales may he the basis of the a1N.ve-meMw.ncd tklcal. in
mclhaunnc nlrlatNrll.m prevurudy tepMed in huuum lurtuu cclls ioc/udinR 1he Inal,rl
Ily /1( the n1a11Klly 1rt Ille Iu11NN t'ells It/ itntw when n1e1hM1111ne is re/rlalYd by INNINN y%
~
lrlne ?lrr ct:e.% and unhalanced IRNA tne/hylaliun uh.ervcd few thc I..t 25 yrar. in
many Iypcs uf cancer may la a1 kasl in part explaitNd by nur resulls 44 ek valed ralr% ul
uvealll uran.orclhylalNm in cancer cells. T'hc alteralirNl u/ sua'h a fundamrnlal IN.N r.%
aa (ran.mrlhylalNN1 /n cantYr may he indN'NtvC t./ Ils nn/xrrtanaY in (llr rNN..IYn.c
pnK'es.
Stem. l' 11 and Nr.Jj'nwn, R. M.
/n Vit.u 2(NR):(rhl-67O, 1984.
(hlier suOPoA: Nalirlnal Carr er Ins1i1u1e nnd 1he ('.e.Kge A. )x.rhs McnwN1a11vnJ IrN
(ancer Rcxarch.
Fnun the Ikpartlncnl td flnliatrics, l/nivenily of C'alifixnia. San 1)icy.o, I.a l.dla
1IIE CYl(1SKIiLIiTON (W MURINF.1,F.I/KIiMIA VIRIIS (Mu1.V ) INI'7i('"1 P.I )
M(11IS1: h11(R(/111.AS'fS AS UBSI?RVI:1) UNI)IiR VARYIN(i ('ONI)1I It/NS
(NF N)RMAL1)I:IIYI)I: hIXATKNV
In the wark reppNted here, nwaase 8hnatlasts ehnmically infecled with Mrd.NUy
murnK Icukemu viru. IMu1.V) were 6aed u.ing variable annwnt. 01 Lx/n.hlchyde,
then ctalnmetl by Imlirecl ilmnwudlurxe.eeae IiRhl miansatq+y Several anhara
welc cnq+l..ycd lo dclecl bdh ealernal atd intetwal anliRens a.ww iatcd wnh 1/K cc11.
.R., Mul.V pp711, lulwlin, vinll:nlin and aclin Rewhs indlcatc Ihal alK tell nNln
hranc% ctruk/ hc panwlly permeahili/ed hl IR(7 mokcuks duccled aK.m.l the Ihrac
eyhr.keklal aMiKen. tudy allcr 1.7%, hul mr1 196, ftNmakkhyde Ircalmr m('unqdrlc
pertncabili/aliun wa. achieved by suh.eyucM aceHme ItcalNlcM nl ccll, after 1 1'i
/nrnulWchy.k haalam In wch cells, ruNmal all)IearinR cyhnkcklJl netw.Nk.../ mi
cruluhks and iaennediale lilameMa were nhserved. S/te.. /ilkrs wcrc alw ven
M/wever, they appeared ks% numenwa and Ihituln than Ihl..e uf unin/caIcd nMrov
lihnrlda.ta hurlhet, a.Ilrnficanl anuwM of F-aclin tlwrevtem'e wa. kN'ali/cJ m
pranuks in the cyh/llla.m.r( inkcled cells. Similw td+.ervalNin% were mark u.inr 115
V9/mru.e cells chnNlically in(ecled with 114( virus, an.Mhet Mu1.V 'lhea ratult%
laken 1..gtther su1:Re.t that suhlk dllfeances r aisl In the trKanvanun ol aahn wnhm
Mu1.V udratcd and uninlctlcd mlwst fihruhla.ls.
Salaka, M., Lu{.1,1). and IrJtig, R. R.
CrII M.aillry 1:567- 577, 1981.
OtAerlY/pR: Na1NMaI ('ancer Insl//u1e.
Fr.wn the Ikparlrnenl of MN'nrhadrqty and Immunuk/gy I/nlver.uy ro( Grulh ('uu
hna, StMNd.d Med/crne, ('u/un.Ma ~
11) 1 31
GI NI rI(' 1'KI 1)ICPOSffH)N TO11RY.AST ('AN('I?R
AIIINNIph l.lnnh.J t lu.lrring .ul hrra.l tarNCr was lir.l rrc.w.kJ in thc R.Nn:ln
nxJit J IUrr.llure rr.ro/Nl 11111 A I), il% puhhc tNallh nwEmlak atNl .IKniht rfx r:uc
sl/ll INlllfll111.111t 'd, t.l l/lls tlJy In Uh llresrnl rI1NI.m/11hlr Na1 s11Nly. 11 1s
sIN/w11111.11
Mta.t l.oNer r1.A LNhN\ arc ekwrly, tnlcrlwlnlJ wqh tlll p.ltlcnl'% cuhur.ll h:ltk-
pr.nNNl, whah m.1y 1/N11I1141t1 tll lwr.l.l carltcr :1'I,1,'fl'1,'a/llnls wllhln lannllr Ih.
lhlht u1/.p1c.1NN1. ur I I I.MIt. a Iruly Ix rcJll rry Ilrca+l t'arxrr uh.cl ca.t''.1:1 whN h
l.l/udlel ap~rcFauNl, rfr INrcJll]fy-/. JMI ( ~I is Ihe herethl%ty llw,n Jt.lnx-llvr tflNn 11.
NNN.Nhf llNllllrfllifl' lhr.c yurric% will he res..IvcJ lwN'c huwll:uiscr% arc itknuhcJ
Ih.N IN.w Intih.rn.Nlvny :u1J.pecilw'Ny wi/h pe/wllype. 'flle autlNw.lNOvnh a revicw
1.1 /hl..uhh.1 a.Nl will l.tu...n Itlcit rccrrN Ji.covery.d uNfca.cJ nr rrl..- hyl+.r
JydulJy /n ru111nrJ.11a htwld,la.l.Ir/Nn Pahrnl% wi/h.w at tf.A hw hcrcJu.ny INra.l
cr.x cf I111' dWINN\ (IIV IN~ IIIMhnI,'s tr.Mll llx'Ir stlxly Ut 1:/n11Iy I11stINN's In 2~~ t/41s.Y
uthvlly a.a rnanN.1 P:NNnt. wtlh vrt/lieJ Mr:r.I . anlYr R.Nn IIN ('rrlyht.nl 11n1vcraly
S. h.Nd .d Mt JN Ir/c / hN..l..ley ('hnx l-oNhnyl t.lna.lcrlt wnh an IlctcJN-ory hrc.l.l
t a1N ct .yn.h..nN wcrc NLnttlit.l ln t~{ ul Ihc p.111cM. ( ilvcn IIN' I/? INM) nl w t,IV. ol
Mr.l.l i anl rr ul lhc I lnllyd SI.NC. in PnIZ. (IM a1//INws es11111Jt1 th.lt with a t'Imlidrrlce
..rIht Nnl .11 O'15 hctwrrn 2./111 anJ K.7V0..1 Ihr.c inJlvlJu:d% wdl nlandc.l lxtcJl
t.Ny Mr:nt . r/xcr Sltrnct .urvcdlr/xr/Inan.lErnrnl pn.yr.Inl..MwlJ hr ycarcJ tu
h//:h u.L nN mfn r. ul Ilx.r /amdlc. in whit h t arN cr yleNl will hr P/cJNiahlr
1v.nlr Il 1 4-1.01
( tln. r1 S 11 11 hl? f.; Z. N/I{d
Ia.nl dN ('Irqhlno IInlve:r.Ny Stlrrd ..1 MhdNlflr anJ 11N In.lltutc t.w U.Irud1.1
('arNrr M..n.qvnNnl.aNll nnUul. IIN .IIn1.J1...('wrx11llnlvtnlty McdNal(lJlryc
Nrw 1'.NA I In/.rraly uI Mrrl/tnN anJ 14 urnrly d Ncw )rrvy. Nrw )rr.ry MtJNal
StlNrd. Nrw.IrA .uN1 dN IAP.n11.Nul nt INA.aynFub.l:y, It.ly. 'luwn In.l/lulc
0111.111.1
IS ('AN('I k l'OMMIINI('Altl.F.-I
Thr c/N.l..yy Irl i.lnlrr renlainm cluivc Nevcrthekss when nwucuhlu% cl naal
Iahlwallwy IwantrJ nxJl.al ~rnrtlr/rpNkmudl.~/c .lulhc% arc petltwnxd .NI larl;c
.rnc t.l I+a/Nnls wNh yvcllic hi.Ir/1..Kw hwm.ld rr/xcr .uh.cls enkrrc whu'R lend
stll.lrwt h.:/ vJrlr/y /.1 e/ll,h.giC hy111AFNsr. A.INCSCbICJ m thitlc tlllrl. fClYnl tkvrllp/
nxnl. In t arxcr clwtkfmolugy llavc II:J lo tht psiMhty nl arl cscecdinKly c.wnpkx
t.lnm/unla aldr /x l.wl.l /n a atw'rr clNlh.Ky 1 hr Ir:m.mis.awl lJ .uch an rKentl.! m.ly
rcqulrc .1 .u.cclNiNc gr/NNyp arNUlw sillier PrIN/NMNwlat evl'nI\. likely CJ/NIIIIJII'\
whNh .ulyMwl tla. sul"IS11Nw1 IIxtINh (I) IINlcln Ilarf v/tu\ InaM/Pharynrra1 tar
l'l/Nlllld. lllnLtl/ s Iy111111NNlla saf/vary 1.'IA/NI tnnNw anMNll,' I:sk111N/s. X hnlirll Iy111
tdNqN.drlcrahvr .yntlrlNlK nf Rutdal. 1?/ human I cell kukcnua virus Ixluh Y trll
kuA.nua).1 t1 xylnrcd lnllnunc lk lir/elxy >ynJrlwne (AII)S1, c.Nlry/lx a1tJ by Ka1M1
.1..arclNna (cINduFx agenl rrnwm% elu.ive. IIN1uKh ePNknuati+gy wggcd. LL./htc
inlrclNNl. Irrn.ull..nln): 14) ahawrnal inlmune pherNNllena in MIu.eMdd% ul
I l.alyl ln'. Jl.r.l.e p+11crN.: am11 ti) a IuslerlnR al varillus typc..4 cancer in +Lw.e. the
~clll'td LIqNJah.+n, anJ famdx. lhe aulh.w% have.elrttlvcly reviewed Ihc INCralure
JMI lvUlvlJ an tIN.IOI!N hypwlNsn dul ultr Kf ate. a elNnmunxahk aKrnll.) /n c.wlrrrl
wNh /rlxtN irn1'.w 4 nv.r.nnlcnl.d ..ua uN.rcnH mlrrax IN.n wlnt It t..ul.l I.NN eivahly
r.p;.nn ./ .qndl. Anl 10- bMI a.1 Ifr I.a.l . uN.% la/t.kn
l.lm h. N 7' , Schucllc. G. S and O'11ara M K.
Il1r.Gr.d IIIyNNhr.trl 14.IR1 1'!R, 14Kt.
frtan ('ilIlabtlwl Ilniver.ily S.IN11.1 uf Medicine. lltpatlnrnls uf Prevenltve
McJlcltn /PuhlK Ilrallh anJ McJical MxrnhillkKcy (hnaha.
( c1 NI 11( S, 111()MARAIiRS, ANI) (1)NTROL uF NR1iAST ('ANCI'.R A
k1:V11:W
11NwKh thcrc h:l% hrn mw'h inlcrc.111Nauyh.lul the yrxt in Ihe cINJtmi.d./4Y ul
Mea.1 cancer. lady very hllle anenlwm lls Irrn given lo the r.lk nl plrNINs In N.
chld./ry ( lx rrvlcw prv nh J IN tr. lNlwcver. repre.rrN. an altcoqll hy d/c /nvcaiya
I/MS QI IIHWNIr a a/NnlNrlnnavc cuvcraKe d I1ereJ//ary Mca.l l'a1xYr. Inl'tlNkll are
(hnuxnt rnlhlrrrxIW% prNl rlN.rrlxvlu. ri.\ lacaw% whith in acrtam cHtunl.tantc
n/ay ayndn'aatly m11ur/N'c Ihr ruk uf Pr/nlary Kcnrlk larllw. Ikre.htary Mra.1
carxer r. tlrlrwyrrk.M/s Wlrn JLCU..inK the whtet'1. dkrcLw. am mu.l fie precl.e
Ickv:nN In /lx I/atlNulan cclarokcnctlu. Itwtu n/ alncrrn, tlaseJ.N1 Jllll't/nl; n1/1Nw
a.ww'I.NaNI. 11 r. Ix.dwhly /a11 uW.qwiale tu Ji.cuss 'hcrcJllary Mc'r.l rarxrr"
w111NNN yuallh.:NUln /d dlc .Ixti/ic hercditary cancer symhlwnr 461 ctwwcrn. I r. IIN'
S1p.A synJrtNlir, INl'asl/.W:wlan lanl'er \ynlttlNtlC antl MhCr\ 'Ihls rl'aMN11111; al.u
atq.lrcd tu ancoqll% at bn/.mR hNN1laArr. N/ hcraJNary hrraa canccr 1/rlally In
:MIIIIINw/1HNwtot.NtIF` JISCUSSNNI% Iwl lhc cardinal /w1lKlhk% tlyt asslx'lall' w11I1 INlrthlay
hwnlW ut hrca.l calw'cr. it% ttcyucrxy anJ new Jcvckh.mcn/m in hi.NnarAr r. IIN anve.tu
y:N.w.luvc PravNleJ.urve/llarne/managcmrtn Iwt/granls that emtwxc tMl.. I+tcl% tll
Illc nalural hla.wy ul Ihi. Jl.ca.e.
l.rnr h, ll 1'. r1 ul
l'~rn. rr (:. nrn... und ('yrn,rrnrnr~ 1):4 )92. IYK4.
(Pther srOp.w1: Fralernrl Order /d IiaKks.
hnwn IIk (kpattnlent /4 14evenlive MeJicine/PuMic Ikallh Il<y/artnlrnl ul Swl;cry.
IkrcJNaly Can:rr In.tilulc ('reigMan Univenily ScINr1I t/l Mcdiclrx: Omah.l Iht
Ihpartnknl 491 ('linicat Palhlltrlgy, Un/vcruty ul MeJicine anJ IkrNiaty td New
)cr%cy. New )crxy (IJkKe.d Meylicine, Newart: anlllhe (klwnnlcnl nl Mrd/c/nc
Lalrwanwy hw ('eI/ 1fNd..gy ('.1rnc1l llniversily MeJical ('tdkXe Ncw Y.wA
TUMOR INVASI()N ANt)11()ST t:X11tAC'1:1.1.111.AR MATRIX
This review Jis'ua.c. NNllc uf Ihe majlw nxYhani.lic Pathways by which tunNw
crll% arr Ihlwght 149 Invatk hn.l bsucs. Tunww mva.illn has been c.NN'erveJ tu hr lhc
rca/h ul path.d..Kla al, rGac r.nFc inletarluNls between /naliRnsnl cell% aNI IN/sl
.rnwna. lhc .ryurnre u/ evcnl% tha/ chwxKrirc inva.em can he sunnn~uir,t ar
h.th.WS' IJ) I unNw IYII llushY\ Ixellll Inwn Ihe t'.NIIIne111enN n/ I1k; primary Iu11NN 1 al..
aul iMercellular rynclNwa /Jl'snMhOrlle{, gap )I/M1NNB). aherNNwn{ in Ihe l'I/fnllCat
l.Nn1N/sNNw1 a11d (lhyslcal Iwn11er11Ct nl /h[ cell Sltrlale Clyt (km of tltwnrlee, tin a1N1
hcparan.ultalen excm anx/unls u( hyalunlmle). IuW loa>senitllt 44 cell sul.clrale inler
allinns (krss tll hemaksnNl.,wnes, filx/nu:.lin anl/ he(laran sulfate). are atrN/nK 1he
ttwlst tteyunNly In1eJ cau.es nl tunNw cell sheJJmR (h) IrureaseJ Ilnltet11y1K attlvl
I/es at dle mvaswwl frurN l.uve /utal ahera/Nlm in 1he sum.wrhn6 eslracetlular nlahr.
12 1 13
J
ln
rJ
an
Ilw rchy 1 h.nlyinE t1% l.hy.i(al pn.(r'ncw. ( UII,Iren:mC% a1NI l]Iht'INIm J% wl'II J% cIJ\
1.14 a/Ml .dlN-r nl'ul1al (NINI'/niNl'% arc the in/yllla'% IIM/%1 IH'lI1N'tNly a.t/:dcd with
I/L/Ir1\ .k'~IIIN IUNl:11NI Inva~1/N1 /n uNnc u..IN.Ihi. paNc.. i. alca Ilv.ly rcguLucJ by
Inlnhn..l..d m,Mnl .kFr.Nhng, ptlaculytK cn/ynw.. I.I funNNCC1I.ImFIJlc mlotlk
Jhcrad mJtnl" Ir..ahly oN+vlnF a. a~~rcyalc. akmK gu1.IJntc 1r,N k. pnwnkd hy Ml.t
.u1N Iwc.IhUrrl vc.4L, Iymph,nit., rK rvc.I.N malr/t 111N tININ.h't"I/k'~ (l ull.F. n arNl
11M.NN-a hn u.N {..1 Mlgr/n.m 4'cma ho hc prccc.kJ Ly uN tca%cJ vwclba) ul Flya..
.Jnluwq'lya.ln /l c. II).r1unN1a1c/ u11hc nulrit. ahcall u1 1hr m/1:r,dmg 1cI11.yNdJhnu
V:uNN/. IN../ ac11 lylt. Inut tcll., Iltxuhla+l., en.kMlN-IrJI ac11., m.N ny.hJFc. cl. 1
nlay r.vu. qIJlc ul dN.c cvcnl%
I'.nrh. /i I/ , S. hw.utv, 1) li . 11aNtjf. 1: I M., anJ Ru.nn.r K I
<'nn.cr Al.hr~r.r.r. R.-.rcN'l 2 11'/1`62, 14K1
t)thcr aMpp.n7: Nah..nJl ('anclt (nNF11dc
I1..nt tIN IAparlnNn1..ut I'.ItMlh.yy, IlNNh.nlm%lry, atNl /MINyr'1I/l %urltcty Ru.h
Mcd/. al ('.d1i1c ku.h 1'rc.hylctlan SI I_ukc'. Mcdltal ('crMcr, ('IhN':I4u
SIMt It I ANl :f Il IS 1'1'.lll (ll'.N I)I.N`IT/ )MIa RY AN11 AUTI IRAI)N K iNAI'lll('
(:RAIN (1)IINIIN(: W1111 1111-/jl1AN11M1:1 7?INi IM'AGI:-ANAI.Y11%
tiYSll M 111 IMI'Rl1Vl.MI-NIS IN 111I1.(;Y.N 1)I NS11OMIIRY
A nnthlwl ha. Mcn IkvclnttYl LN C%IIIIIa1/1N1 t1I the I e11IgCn atJInC.I I)NA t.N11Cnl
ul 'It IllynnduN l.lltIrsl cclh,n J1d.N.NhuF/J1.11. in canInltum wllh Jtn.anJtc.l yr.un
l.Nnll nNa.NrcnN'nl u.u1F aOu..UhnN1 tclcvl.uM unJ/'ml'.y.tcol Rc1uNI.N'nt. In /hc
aNtlNrkdnfy .uc /c/rNNd whl.h /Mlu.lf (II IM' 11N.NIMNJINNI nl :In 1111.11s. 1.a1n.N
Mlrlolr ult.. IIM' V11:In1111N't 11N4IIItP lIN/I/1urJuno. 1.'/ dN .yNUnvJlum ../ Inauknl
IUI/II///LttNNI h.14'11 tl(MM t'YJIIIJh.NI ..I Y1/nN1% I/Fhl ..NU. a. 1 II a hangc m IIN'
.qlNa1
avNdlKu1:/1NN1 whn h rlJuac I;larc ,NNI nnnuru/c IIN- Icvcl nl nN.nINN .h.NhnF ca/tcalNm;
p1/1hc IyMnnvJn.m ul 4anrkr .cn.ulvny JnJ ISI tM cv,duaU.Nl nl t cll 11.111cnmg anti
.tannnK wltll rr.lti-.1 la Ikrnvt.mNIry 1C4.III1NN1 aNI .cn.nlvdy. IIN%c rcInNnlcnts
rcadlyd m a a.w 111aanl ol vanalu.m 1CV /111 k+% than 6 J'X lu 11N- ( i 1 atNl ( i-2 I1NA
pt'ak% u/ r:U kNhky aell% in auuNaJil.Krallhs cINn1l:/rcJ lu the prcvilw. ('Ir nl NI.S4,
and a G 2 N. (: I ralilr ld 2 025 PIN a/i.ed IicAi p..i1Nrl the ('V wa. 5 19i and the
rcplwalNN1 crnN k.% than I 11') Thi% tct hn14/qty i% ut Inlclts/ Ixcaua 14 d. (+INcnllal
al>f/1ra':/tNN1 In t1N tcll ayck: snaly.l. Id tni.cll pdyplual uwNN ulqrywl:dnNr..
SAlrnrn, R I
/hc l.wnwl r./ l/r u.N hrreiqct nnJ ('1I.r AcnriVry 111111) 12 24-12 12, 14111
fr/NN New Y.NA I tniver.ily Rc~earrh ticrvNc. New YINk (Inivcr.ily MeJnril ('cntcr,
(NCl.lwalcr McnNNlal llu.(Nlal KlrnavtIt LIanJ. Ncw Y.Nk.
('YTI IKINI:.11('%t11-111:TIiRltt'I (111) TIIM(1R Sl1NIY)I'lI1.Al1ONS ITY
('I)MIIINI 1) AtI1tIRAt)IIK:RAI'lll(' IMA(i1N(i AN1111a11.(il.N
111 N\IIt1A(1 Ik1'
In hu..un 1..,,... whtn (.Ivpl....lv arNl a.N'upl.N.l v.an.N11. //l.1ui.d1V ..N'tm~l the
n aL.... 1 .u.r..1.../. qau. nr 11...1. /w ..n.dt....d IIN . 111 . y. 1/' kl//.'/l. \.I
IIIIINN\,
1.L.r,../...11 I IIN ./n 1.11.Li 11 J11.11 IIIIKI ,/n11111f 11 .Il~lr'1 ~LNI
1i
I/l lht INIINII:11111n a% J wh..h' thr nIN felalC ttl the l'yt1111,rN'tN hChavNN t1t the lhmln.t
PhNJy IlntaKc. In II11% %tu11y, an a(111fty(II 1~ 1/CK/IIICaI I.N M hll Y/nF a tla'I.NIVl1t111NN1
Id IIM tcll cyrk I+ha%C III%Ir111u1NN1 /n n11tC11 hckYnlfkNll Iu11NN phrulalNmm d/mn4
c><t..Nrvui.d gruwlh llM .thcnN (NUviJc. (II the pKN1Ia1Nln Ircyucnay alNl I.h.l.c
JLInhu1NN1 ut J/4lctc .ulqw.llulatNN1. J/.hnguiJlcd by Ihclr 1)NA pluldy level. 1?1
IIMn Ir:ul.n tullt' AuNtR% ay rCveakJ by aCrlJl C>Ii1N:NC. UI lIN/y1:/1U/N'rlt.J (u/twrvt1
ul
S, G2. (:1 :IINI in the Uvftall fyl k'; and I I) IhC/t cell (ll/t CrNNr11N11NN/1 at thc S/l i2,
(i./Mttu.l% atNl (il/\ I>fu.e hurNlarie.. Thr analy.i% i.I:Ni1qNeJ by an auhNU.ncd
o1c11Nrkr/.ryy.k'vrLqN.1 wltb a VuanUuk9 71/N) bna~r analy.i. ayda m LN .inndl:uN
uu. dilcrnnnali.Nr u1 I1N I1NA aNqcM alNl grain aauNl ul 11-TJR I:d1.kJ tcll. /o
1-cldycn .l,n/wJ auta.yrJph., 'fhc tkagu% invlrlve 91 and INILc Iats'I//Ir,
IkNlhlc hltt hng JINI a INIIIIItN/u% IaIlChnr, in flNllunl'INN/ w/lll ('I.IIY'n1/1I I IIC ININ
l'.Iltlf
ha. INl'n t7N1/1Nlh'1/~e/I Ir.Nll at11u1v11NN1/1/ 1111Jg/n1,' al.lla, IIN.NIrh Ihc a'alcul:rtum ol
rclavJnt paranKtcr. .ml their Kra14rN Jlyday. 111a aady.i. i% dlu.ua/cJ in J IN'lino
pkad, u1wkNNJ M('1' 7 a/dnuc wbhnc Ihr.:yMNnatfi clrau/nvcnl. [1w 1n11:N1J1.k
IN..Idcnl ..1 re.ulvlnK I/I/RCaI hctan.pkNa) and anlIq.kN.l .uh/+/NNdau..u, l/.lol dN1.
l/NtqNr.nc 1)NA d1./1i1NrtNN1 what (il, \ anJ (i2 aNlqrNlenl. W varNN/. Irvcl.l.vcrLNk etttcN.rvcly
in Ilx'Ir I1NA canknl range. In the lulwe, /1 .arul./ta4.nahla dl,d IIN o4
.d pkddy nr,n{.cr.lu a1cMlly ekNUl hm alet. huh(N.IN/Ia1NN1~) /Ilay Ilhtlll.lta'Iy IMUVnk J
h.1.r./1N Ila,crnnlning Itlrir 4nNItvlly aol/ rC.i.l.Nwe ttl a varlcly Ut al!aNI. In
/.Idtl.wt tU
Uku cyck pha4: d1.p11w1NN1 and ltvcrall /rcaluCna'y.
SllurcN, N J.
1
In' (41M'l'rJ/np t/I Ihc IIMh IDICrnatNNN1I ('cll Cycle ('INlltfl'Ml, Ha11II ('anuc, AI
hcna. ('analla. Apr11 24-211, 14114. 1lle 1luNlana IYe.. Inc., (lillun, NJ
1-nNU New YINk Univcnily Sa'hnld /11 MeJNele, (iuklwaltr Mcnwuial ILNpllal.
R/N..cvch LIa1N1, New YINt<.
('YT(1KINIaI('S 01: S118P( WUI.ATI(NVS IN MIXI:1) III lliRU1M .l>11)
1l/M()RS IIY 11:I.I:VIti1(NJ IMA(iING. 1. IN:(1)NV(N.ll'II()N tll lllls
S-IMIASI:1)NA 1'1.(/11)Y (Y/M1'l)SITN)N. II. ANALYSIS ()1: TIII: S 1'l1A\I:
I:MI'fYIN('.1'I(()hILI: (/FF IM.(NI)Y SIINIY)M/LATI()NS
The /Nlrhkm /d evaluating the a'tll cycle t<irkNias nt Jw.ntt .uh1.yN/1au/N1. i/l
n1iReJ 1unwN cell Iu.IN/lalNma hav heen nw.a inrrac/ahk:. Ilowever, a.a'Iw'Nw /cl% ln.n
Ik veksilcal hN Jecil.MrlnR the cell cycle linle parallKler% nl ecll .I/h~1111yI J111N1~ 111.41
1I1/1Cr in their I)NA 11hIMIy level and that cYR nIN in III/RCII hCICrl111kN1/ tu11NN III tln,
p:qur, the S-ptla.e an:lly.ic i. prese/NrJ. lllc ayTlawa'h 1% cuupk'J lo an auhNwurJ
i/nalanl,' rnellNNklkrl!y LN \I/tN1Ua/1eaNN IlPll'ItINnWlu/1 n/ the IYuI)!en %/a//N'.I IINA
c/NNC/N anll Rratn t'uunl l./ 11 thynlN/ine IahckJ tellr in auar'r1u.toraph./SAlarcw R I
)I/LhNhcru('yhrhanl M11`, N14Y,1V112/ IlleetpcrolNnlalakaxminvulva '11 Jud
"('-t:lymNllne J.Nrhk IahchnK anll ('/Ik'Cr11NI tnl'u1WNN1 I he t/fl'aNIvnIWNNI 11( IIN' 1
(.ha.t (IlniJy tlNNpritNNl i% i11u.IrMeJ in ral wclNm auNure% cnnl(N/ang LNN marN
p11NJy .uhpqN/1Niuns with ( i 2.nd n1iNNic 1)NA aNNents u( aWUrlnr.acly 4('. N(',
Ih(', anJ 12(' Thc t'.NnIrNNnl% were iJrMibt/I by theu 1)NA IIkN.Iy k'vl'I, anMl IM'l/ S
treyutnt-/c" anJ Ia1NIInK uNhce% wett IIM.IneJ A 4'henN i% al.u .kvcl.qrd ,uNl
va1NlaiCt1 //N uhlain/nr. IIN' \ rha.e cn1111y/nK INldlk /.1 ..NIqNNacnl Id.NJy .u(ywhN.1
IhNN11, \MI Ihe/r cel/ Ilu at Ihe SHi-2 arNl 1i2//nnua. pha.c INNIrNlal/c lu dN
15 '
.rrl..ma ( ulturr. \ trn.hilily was f/wnJ lo Ikctrt:lcc wuh Inl'rer.mg 1)NA pUnJy Irvrl
uvcr IIN cnufc pLudy ranKe
,1lLur.r, R l
t hr l..ranrd n/ llt.t.a hrnultrv nnJ (yr.h hrrrrzltrr 3214) 411 42/1, 1'/N1.
I n.nl rtlr, lkprrtnwnl n( rrlhldnpy, New Ylxk llnivcr.uy Rr.rrrlh Scrvltt. New
Y.NA llnwrt.uy SIIN.d /d McJ.une, (N./dwatcr MlnNN1.1I IhNIf11:1I. NINIMVrlt (.
Ia1Nl Nrw Y.NL
t'Y r( )KINI '11('S l)1 Slll(I'( )Nq.ATII )NS IN MIXI 1) P! )1 YPI.011) 11 /Mt INS
ItY 11'I 1VI%It/N IMA(:IN(i III '11 IIIYMII)INI.IN('t/N1Y/RA1//1N IIY
I'11)t1)Y S11H1V)1'l/l ATI/1N\ (YININ(N.(/1 '11 AllSl)RI'11tIN ANII
I MIII.SIt/N 1.111( 11 N('Y IN Al11URA1N(R:RAI'l/Y
1111111% t tII t ultufr.thNly, an af%w.%alfi 1% prr.cnlctl l.N .ktr nninlnF rrlrtlvc l,dr. ol
'II Ihy1tINI11N Inl.M1\nr/NNl in % f.hrV' f.N JIK'rNe (.h.Nly \OhLywl.NnN1. thrt./ra1.1
In hrlrl.q4.NJ IIIIINn. I hc analy.r. h Irt Ihlrtt'J by rn r1/Nw/lrllJ IIIIal.'Ing IIN'Ih14htl
..py .L.rh.lvJ wuh rOuanl/nNt 7!11 tiy.lrra I.n suuol6mruul Iklrrlnmrn.Nl 1.1
I.ulrln.t.mNJ I)NA a.wMCnl rlNl yrrm l.wmt. ut 'II IIIymNhnrl.lltkJ trll. /n
I rulyrn .1.,u/Nd r11/.N:NIN.letrph. I IN r.fr't/nwnlr) .k..Fn Invulvr. '11 a1NI '(' Ihy
II/NIIIM.I.M/L1.~ Irlwlm~ m Ilh /aa vfN r.d l.dll/IINI I/rlritlNlllM'tlt1111hnJ rrt.ru.aor
lnlllnr. JIu.Ifrly dN pruhN/nd udlucnlc .d dJlrrcnllrl '11 ah.+NINNM anJ trlrtlvr
r/nul.NmllhtNINy IhesCIJl4M.rrl'hNdt/dlrJ.repr.hvcly.thaNfkhnNr.urrnNnl.
ul nKan ou. trrr .ywN :J .knIty r/Nl Krr/n.kn.ny l lu.l. r.antt:d l.w a wlhJ t.unprl /
..Nt o) grarn t.Nlnl% httwttrl cPll.Ih.lt Jlt/ct in Iheu au1.N:NIN.F'ra(dhlr Kr.NIN'Ify 1
hlt..
rrl.dlvr (/NA .(rt I/N :N rlvlly nuy he r..a.aJ In fnr/1vNlurl crll. lhr I+na.a.d r/NI
:Inrlya..aly.nt a.Inlullrnr.rl. cv.durn.m u/ Ihc S ph.l.c ph/Nly t'.Nn1...nNn1 rfNl S
rlnlMylng INUIdc. a. I.rl'.l'nted in r l'INIII.afINNt anlCli ah.tlactrJ hcle.
UlnrrN. R l
t'br l.-r.n.d .4 l1r.nn brwu.rr), ra.t ('WIw Grrmdry 12141:421 -4)1 19N4.
hr/ml dlr 11`parnnrnl o( hrllNdupy Nrw Yfuk Ilnivcr.ity Rc.carch Scrvice, New
Ylwk Univtt.ily tia'hIN/11d Mcdllmc, GuWwalcr McnNN/al Ihlpital. R.Nt.cvrh 1.-
laml, Ncw Ynrk
1'LASMII). 1't1A(:I:, ANI)(iliNOMI(' 11NA-MI?I)IATIiI)TRANSI FR ANI)
I.XPRI.SSION /)1 1'R(N(ARYU11(' ANI) I:.IIKARYO'f1('(31:.NI_S IN
('lI1:Il1R1:U 1111MAN ('1:1.1 S
lr.n.i/ttnln nf nWInnlUhan IeII% with gfMNnN' I)NA aM) lhN1l'.I prnl. 1. M1w
re1r1/vcly ruutirle 1lawevcr. the va.l ntarwi/y 14 slulhe\ havc uKd nNknl lcllk a%
rn: ifnent. I llrY 111e aulhlNt dl'M'rlhe efhl'Ienl Iran.ItcINM nf Iw.111111nan t'CII IIINN. IIh
hylNf.a/ahinc guanine pM/lphllrilNr+yllran.lerax 1111'N Il-/kficicnt 1(rla hrw, IY)Nr
All-2. anJ the aJrnine pIN1y+MNilNnyUran.lcrase /AI'RT)lk/il/cnt II11(u11) bnc,
1110114 1 wN t AI I 2 ccll% were tran.fn tcd with the pS V 2 Kp p1a.mNl u/ Mu1liKan anJ
Itrrg, whNh ..w.l.nn. the F.nt. ..nlhinlRuanine rtx..{+INy/1Nl.yhtrn/rra.r /Kpt)
/. ..r Mb1 I q.. njnJr...ro. wr.r v'/r./rJ in I IA I nNJruln 11111114 t rll. wlte
.. ...Jr, .. ,t - .h . I . r.......n, 1...... I. . I -N A a...l .«../1.r.n tr.l.Iro1 1PNn.l ..
(r.n% wrtr
. 6 .., .1 ,.. . .. k/ .v./..,n . 1,. ..... .,../ ... n.~ 1. n..oN I INA e.Ml /1tn1
u11,
were .rktlcJ in AAA nNJlum; ( l) p1a.mNls coMaininK either thr ch.nrJ hrnlarr .N
nNrl.r AI'N 1 Kcnr., atNl Allrt' cclI% were v hckJ. am//4/ p11aKe parlaic, clNNr/nmy r
cWNNJ uN.ua AI'N f grntr, and Aprt' crllk wcre .ckrteJ 7 ran.Icl tNtn aUN IcIN lc%
ranrcJ Itlwo 11 25 lu 1.5 l 111' Iranslrclanls prr µE ONA, arNl in ccrt.nn l'a.c\ .cI.NNIrf y
/ran.IrctNMn wrre lMak lvwriFn 1)NA in rallplcnl% was lklclIrJ by hh.t hyht/Jvr
tuNl, a1Nl t11r eslxr..Nm nl LNCiKn Kcnes wa. tklc/ krl hy tcll Kruwlh /n .rktl/vc uNJlr
a111I Ihr t'4(NrNNM III tniynw% ah:uackriair llt the .prclc..d thr fwnN.r 1)NA 11N
nl:lpnlty u1 urn.lcltanl. aN.wlJ .tahk clpre..i.Ml f.l the trrn.prn.wlr.
Srivrl.au. 1: S Sf.mMIJAr. l:' J.. Sas/Nt, 1'. 1. SlawMlN.k, 1'- 1 lrlll, I I rINI
'l la h11rAl, ) A
('lb.rrrufN ..nrJ ( rN Mrrn n. l 1N 227-214 1'!N4
Ilthrr .ulrywrrr; N.ItuNl.d lu.lltulc. ul 1lrahh arN/ Ihc NatiaNrrl Sa /cIN c I INUNI.w..n
1 f.Nn IIN I kI.rfn/Nul ol MN ru(+1oloE.y. ('.d1trc n/ MaYIN /llr. I IItI Vr1\Il y/II (',IIIL
N lltr,
If valr. I ltpatlnwIn1 u1 Anrl.any a1N1('t11 Itn.M.9 y. ('nikkc nl MrJ1luN, I tulvlLUy
4.1
('/Ik /1111:N/ t/I I. :IINI I)t'1.:1/tl/lr/ft lll AllrtfNlly Ml'JN.'aI ('ISIIII.Y l11 (
NtN l- l.. Allr u.lr
i
1ttMONI(iliNl('I'll' OF III/MAN 11"111Nt1111alR(riAR('OMA X Nt)NMAI.
I IIIRt /H1.A\7 IIY9RIUS: ('1IN//MI1S1)MI: I)()1A(:1: hla'I:NUI.NI'Y
llu IonNNi)ynla' cap:N'/ly ul hyhriJ.lllruwJ by IusilNl //f thl Iuyhly tunlwnlrlnl.
I11'llNttl hullcm hM...arr.Nlcl cell llne with rNrNuolllri~enir n11r/11aI /IhtllhLl.t. wa.
r1:1/111fIr1I Ihl.' II 1111N1/ alVl t'11111a1n[ an all/va/el/ N-ra\ IwN'/1glrlr. Neat Ir11:11.LuJ
hyhrNls whlth c/1rNa/tKd an approsirna/rly rlNllplrlc clmNrNS.wna/ ruuq./rnNnt /n.nl
INMh p:lnntal ccllk wrrc twwNunNriK/nic whcn Ix NI' cell% wcrc inw.lrJ % l lulu
alhynl/t /nlnk 1 r/l/ce, wlwrc.s thc /larental tl'fNNI(I lrils pnN/uael/1unNNi in I'NI'A nl
thr animala with rN/ latrnly /lrrinJ h1llawinR initt'lilw ul 2 x NM trllt l'unNUirrnN'
vx/aul% were ulMaineJ tnlm Ihcse hyhriJ% which hxl wr.l ltnly a Icw lhuN/N../N/N%
elnlh:ltell hl cell. If/Nll the INNIIu11NK11,'enlc Ina.ll ruhurl'% In ad.111NM, .cveral rNrr-
heRaph.wl hyhri.k were uhraineJ which clln1ai11cJ a/lllrllaimatrly a tMluhk liu/NINp
vllllal t'ffnM+lenlenl Iulln Ihc 11'1NIN111wen1al line anJ a sinKk a'haatNl.,urlal r.Nlq./c-
nlcnl lnnn Ihc rNlr1u:/1lihrrlMa.1.. All lll Ihe.e near-hea aphwll hyMillk pr/ Nlutrd IunNfr%
in NNMS ul nuJc luicf: with rN/ Ia1elNy Itvild. Resulls nl th/. .Iwly /twht:rlc Ihat
lunwri"/c/ty ol dk.e partilular human malipna/N cells l/f n/csenchyu/rl faiyin aan he
.ul+prl:..nl when In.eJ with nllrnull Ji11/f1iJ IihntM,1.1.. In addililun, llle rc.ulls suFkr.t
that IuuNNlgenilily in Ihiv .y.ICm is chnlnw/xlmal /l1.wFc lkpemknt, s/nlc a JqIhNJ
ChrININWMnaI e1N111.IlYllrnl Irlttll 1Nlrmal hhrtlhla%t\ /N ra(Wl/k 44 .uplre.auK the tu-
nN.rll,`rnlrily /11 a nrar JIIIh./J hut nIM a tlCar-tetriplllNJ thrlNOIrNN/M1 l'/NIM.Ir1/N'lll
Irllm Ihc lunNlriyra/l' IlTlt/ltl/ pareM. Finally,lhr 1/.../11 lfinlnN../.nN I 111N lhr.a.N.
.unle tn whith the N ra.InN.pccne hay hren a../KnrJ/ as wrll a% aINUnN...NIN 4 wr%
el.nclatcJ wilh Ihc tlaplxatanle o( tunNlriFlnN'ily /n Ihe rara varianl pyN/1rn.Nll /runl
tnhrrwi.e INIm1ulNlriEenir near-tclr:IptlliJ hylaNl cultureu. Tl1e.e rc.u11% a/v..uK1r.l
the pu..ihilily thallunNKiFcnicily in Urcse hyhrd% nuy he a gene lh.ugr cl/n 1 mv.dv.
.
ins the number /.( activalyd N-raa Senev in the hyhriJ% cl/nlparrJ lu thr Frnl(/
clltNrldllnK the .u/ll.rc..ilm nl Ihr aaiivaleJ N ras renes.
Ncncdil l. W f, WtLVnan, (t (`. . Mar1, (' , aml Srunhrl.IKr, f. I
('on/ rr Rnr.nl h 4.1 1471 14 7'/, 1')N4.
.r. 1 17
Otl/fr fMMor1: N:dNN1d) ( Jnt'CI Irl.hlulc
11.1110 11N I)NI~LM .d Ilcnuhd..Ey lhNUk.ry (lnl.lrtn. Il..spn:d u/ I.n AnFrlv.,
IkL.ntnNnl n1 MN rnhNJ..ry, ('.dkFl .d MrJN ul.. I lnlvcfaly .o1 ('rhhNUl.l. IrvuN.
,nNl1 )k 1..111nN-u1 .d PI'.III1rN %, IIIIIVc 1%Ily..t ti.niltkr,l ( JIIt.N111:1 St INw.I alI
kl..Flt uN.
I ... A/yt Ir.
11. The Kespiralr)ry .Syslem
NI(-11I1N1 I\ ('lll M(/1 A( 11(' 1( /K NI 1111t(11'f111 N ANI) I NIIAN('1 %
NI 111141111111 /(I SIr )NVI Vl NUSS l t l( l I1 Ml ) fA( "I11 I1 I'l ll>LN
t/n dN- h1.1. /d /h/% lA 1rrrU %Iwly, /1 1% rClMx/,J th]I U/t-n/llh whN h 1% rf:Nhly
:th..NtK./ tt.nn IM. Ilprn.111Ny It.wl, ha. c11c11..N1(+I.Iy11NN1.INN111~ k af nl'ul/.4th1N
tI1J1
rury IN- r: k..lnl la. lmll; tnllemnlalnM rrr rr/.. N/I.N/rIC Wd~ LNIINI I..IR' l IN IINd:N lit l.N
IlUnl.ln tNUlr..ltlll. IN/1 /Mtl nNNN\ yll.. with .1 1\v1. ,Nhv/ty .A 11 nuCr.N/N.l:tf In
k.wt'f l. NN l'/11/.1111 M% I l. x1111Jf ahtl' Its lh..a In .oN.kcr.' pLlan./ t nw o11nc cnh.ux
cJ Ilw
Il\I..N/%C .11 IN'111f1.11t111N 111 IW.1 .IN'ItN.1:1tIN IN'I/NIC\ In l.Nn/a\t Ill /IN1%t ..IIN'/
l1K'
11N..1111.N1:1111% I.N Ih'u1111.1111%. III.wCvt'r, IIIt.N1111 did INM .II11'tI tk'1,I:IIIUI:IINNI
Ix %II'
ItrutNk pr.wlul INM Nn.dtnc thu% rrt.ly pnMNdc /n1IJ/11nGdNN1 ]nJ t'.N/K111N 111 (It11F
ulllny /n .nN.ACr. .
l.rln N 111. M.('u.lcf. K t('./m//Mll, t. I.(:rdhn. (: I. a1NI \.'11NN. K M
.S, r.'/N 1 221 IM) 171. 110144
(Mhtr sapOnrf: l l S IbM1la I Ic /11h tirrvicc
UI.xn Iht Nc.pu,N.wy :IINI l't/1N'JI ('ar. hivi.ilM IkprrlnNnl td McJlcltk )cwldl
Il...p/lal ul SI I IML, Wa.hinghxl llnlvcr.ily MrJi.al ('cnlrr. XI. Isxn.
NF.1/'I RAI.1'Rl)I LINASI1 1ROM 1111MAN INII.AMMAT(N(Y l'LI.L1 A
l'KIIN'AI. kl.VII:W 1)1 1'111:1R R//1.l: IN I.XIRM'I:I.I.III.AR MAlRIX
IWI:RAI)A I Il IN
In MIIJnun7luxy Itat'1/1M., IxalcM.l.ca and a varicly ol .wtnr kuAtr-ydc pr.NkNi.
:Ilc ICIt:1N'J l/llll 111C t'.Ir:n:c11UI.N CnvlrlMlnCnl llll' IxU1CUtylit Cn/ynlt'% tl'k':IwJ by
mll.ulun.d.xy ICtI% mlllalc the Jllic.u1M ul INMvlahk I/..ur, lilx/n a1Nl tknislurcJ
Ix.Nf Im atl/l (M.dC..l;lyt :/n., a1N1 n/:1y at I/v:NC nll'Jiallx../1 in11:n1Ut1.11nM 1n 11N
nvNw
INa.cnlr.llN rr. Ihlrc Ihlnp. arr nxlNk rcJ I ll lhe teli hNtk.y.y alN/ in vn.n :N nvlly ul
tNuual lx.wclna.eo tk/ IveJ InMI huwan mlbnnllN/xy ce11.,12/ nxchaln.m, by whN h
llw.c Cnfynwa nllgM /n1urC a'.Mllft'l/vt 1i..ut /n 1'llvr, and ((I (hC hNtllfl,'ltalalvlly /11
INIM/lk. 11'IC.1wJ IfINn t'INInCTt1Yc h..uc by /+rlllcina.c. 1't/ .uM/ua/vc Ihi% palx'r.
hunlan inll.nnulahNy ccllt Ilani.ulally rlruu.qthil. reka.r rlculral (xalnna.c. that
h.lvc Ihc' l ap.N ny In .krl:Nk ctlra trlhtl.n nlalr/. nNtlc. uk. Nculr/q.hil ela.la.c i%
..IN'l 1III/ INN.It1k' /MY A11M' 11 1'Ixl'N111 1// L1/14 .//INNInI\ Jn/I hd\ Ihl' \:/1\:N
Ity III IkKINh
.L..IIn .IUJ 1n.1uv o1hc1 lunqNnNn1., nNluduly haan1ru1 nNtnhfuk tu1LlKcn IIyPr
IV). pr.wc..Elycanm irNl Iitxuncctin. Allhnuph lhcrc i. /ntwh cirtunl.lanh.l tvNkmc
.nFFc.IMK rn antxxlanl mlc I/w /NuU.q.Inl tkrlvrJ Inutral prukMa.et ll/ rzorrt cllulal
11411t111 hfl':1{,J..wn in II/It.l/lllllal/xy rl':Il-INx1\, JIfCII 1111a1111h1'JINM 1./ l'INIIN't
llvl' 11,11k
p1.Nr.dv.1. 61y rllutntllhd. in htnlwn Jl.ca.c Iw% rxd y.1 hern p..ahk. I L./N lk.InN
111M ul a.V lYat11M wllh rNUU.q11ul1.' in/illtiNllM i% alcarly a CUmpkvl /x.N.C.. Ih:u nlJy
nlvUlvt' Ix1AtIn:1.C% 114141.1111%, IN.Nt'111aK 111I11hlllx-s, anll.wh.r .uh.la/Nl'% Ir..ln Itvl
Iknl l't'II% a% wrll :1. /wuUl.tlh/l Ix/xI1K1\ In 7Nk111nN1. ..M1parCJ w1U1 /NU11..Id1J..
hulu.nl nt.NNMII Irar phalvwylr. trlra.c vlry .m,Jl anNMUh u( tICIN/AI Ixult'1/1:IN'
:Nhvlly alNl .Jw..yotlk.vc Ix.NI'/nw inh/hlhx., .u Ihr f/.k ul Ihc.r .e1I. ul dlc
Ix.druly./. UI U..uC. /. Cvrn nNxC llholurC Ihan tI1C /+.k UI Ill'uvU(thll..
%.nnx, K M afxt (',rnq.ltiIl, I" J
(7m1.. ul l.d.av.q.rrv Al.Ju ul. IIJ) b15 (AA, 14K 1.
(hhr..a/yr..ri: 11 S PIII.IN' IlCdhh &'rvq'C aMI IIIC AIIN'rN'an I.unl,' A%mN Idllnn al
1.:1.11rll M1.MN/n
I r1M111N I kprrlnNnl .d McJw Inc Wavhml;hM Oluvcr>ily ScINNd 401 McJn uN :Il I ht
kwl.b Ikr.p/lal.nl St I.IwI.. \I lawi..
1'Al'll(K:1NlalS ()1 llll: AIH)I:r RI:SPII(A"1(N(Y I)IS'rkl?tiC XYNI)N( IMI-.
F , VII)I:N('I: ()1 l)X11)ANT MTIVI'1'Y IN I/R()N('1I()M.VI:()LAR I.AVA(:1
1'1.1/11)
llll Ixrvnl .1uJy pntvitk. cvitkrne indicating Ihal osiJ:M1% arc purrrlCd in
luny..d pllicnl, with IIM allult rc.pirahlry Ji.1tc...ynJr/Nrlc IANI)S1, lhI cvnk/wc
wa. Jrt/vcJ IuM111h.ervalilM.lha1 u-1-M /al~ha-l-pnMCina.a iohilxlarl rc.uvcrcJ lu
IxIMrlNwlvrld:u IavaF.c IIMI.) IIuiJ. had hecn inaalivakd by a.iJalitln. pc.utn./hly
IIIt111:NNM n1 the Ilnlhionyl tc.ithlc in the rca/:liwln .NC u( Iln' nN.krvk'. I hi% wav
i1Nhaa1eJ by /IrlJlng. Ih:N atlivlly 44 the uI-1'1 I:a11k1 hr ft:x(IxcJ hy cnpllwl. tn 1hc
rttlucinF a~l'/ll, JIIIInN1lrClhtl n11ht IxCtClllYnl nIC1I1NM1yI WIInRNIC 11C111NI1' Il'lluilJoC.
lhe anwx//q ul adivily, rc.lufcJ wav pnlplnMlnal h/ lhc a/INN/1N u1 In:nlivc u I I'/
Ixt.cnt at 52.11110 l). l).iJa1i1M ol the S2,1MM1-1).. (-(M wa. a1vl tcvcakJ hy Ihr hlNilnp
Ih:ll /hc inacllvc nNlkyulc wa. whrcl M/ pnllctJylic ckavaKc In 17,INM 1) wlkn
c.p11.rJ lo pxritlr pall. rcatic ela.(a.e. I/wIwalaln nf Ihc a-1 1'1 rn 1nv, al.u rc.IJtcJ
IrIM1 c/xlrydc><inK 1u an actlve cniylne, aw/wn prvillu.ly Io hc nrulrlM,hJ cla.ul.c. In
trxNraa h.Ihae in 11AI. IIu1J., thr n-1 PI in l/laalw 111 pa1KMv wilh fcyxrahNy Jl.lri..
.ytwlnxla wa. hwlwllu Iw 'MMIi. active in 14ul 22 ca.cls anJ S/) :Kilvc in R a a.rv
Ih1% NII,'1'l'tkYl that hx the /IMN1 I.afl, u1. IM wa.v inarlivwcd allcr Icav/ng Ule vc.vl%
anll cntcnng Ihc lung '111c cirrulrUnK a-1 1'1 in palicnl% wilh /11c rr.piral.xy JINrc.c
]y/NhIMIC wai, /.x/MI ht hl equally \uN'ClM/hk 11) n1111,M/vc /nal I/va1NM a% u I 1'1 I/..nl
INNUWI /INIL'MIU:/L. It VCIn~ /1111MthJllk /herehx! IhN INII/C/N% tlcvl'kM. AKI)S 1c
tau.c /rI l.lblk n 11.1 mh/hn.x.
('ta hran.. ('. (:.. SlxaKy. R. and Rcvalt, S 1). ~
l.wrn.d../(7iniad /nrr.nxorienf 71:751.7A1, 14111.
lNArr srpperf: NrtilMal In.utulcc u/ lkahh anJ Ihc (Nlicc uf Naval Rc.rarth
Fnxn Ihe Ikr:MnrM Id InMwfxd..Ky, Srrip+v ('IMiI: a/Nl Rc.cuch Fuu1NIrINM, 1'm
)ulla ('A, uN/ the PUI/INx11f y I)/v/,NN1 I In/vCri,/ly UI ('11I/hNnla, $Jn 1)ICI,u, I d IuIID
11t 1 19
I'KOTI:ASI S ANt) UXIhANTS IN I:X%:KIMI.NI AI.1'l/1 MONARY
INII.AMMA/(/RY IN1lIRY
Thc uwvr.IrFanw% have etmincJ varirws hMUhcInN7I paramrlcn OI pulnMMary
nrtlamrn.nnwr m rtpcrnnrmal anunal. IMrahnwKhral in.UllJliam.,l rlunr.c oarJav-
yhM ~ I( il //1 i1 ur rnwhave usnlanh rw hKmylalcJ rMwku kn phr (I N1.1') rw pMwl.d
myn.tatc :KC1atr IPMAI a\ kultnl'ytK VwnuI1/nlluteJ KYCra aa'OIC INrIrlNwtlry Inluly
in Nrw Ifal:uul whnr rahMl. I'MA ah.e irw/uced in0anunauun whcn aJnnoi.tcrrJ
auravcrMwly 1.arh .unndus rnJuaeJ transuJalirn rr/1urArm tuwn Ihr va.. ul.u .paac
rnlu thc Iwduawtary Ir..uc., anJ an inllua uf kukucyles Jutrnk Ihr J-t+h Ixrnnl u/ Ihe
c.p. nnw nl 1'atlM~hy.w~MqeK changes wert mrawtn) hy rrkma hKmati.wr I tran.uJa
tnm u1 'Y Itiwinc .atum alhumtnl, anJ hislolrrgir es.mmviatnwt Nirt hcmical .maly.rs
wa. IwrIrwnwJ by nra.mrnK crwktMralMrns d pdeMrally mlrnnwu% agcnt% m Mevm
llwralvrr-IJr lav.rr 111q1.1 fluid Irkrra.ed aaiJ pr.Mcasc arwl myrl.~rnarJrr kwcl%
wctr 1.wrnJ m the IIAI. 11uM1 alter aJmmrVra"wt rd rnher r-1 thr .trmub
Sahraad.tanar 1 tI Rcvak. C 1) . anJ ('rti hrrrnr. f: (:
f..urn.J.4 ('Inrn ol /mrurRdn..n 71 1175 (111J (')/{J
Othrr srppeA: Natw.nJl (n.thlulc...l IlrJlth am/ drr Ol/ae ul Naval Kc.rar. h
Pmm dw 1)\p+rtnwM od Immunrshly G nM.. ('hnK arw/ Kr.car.h IfrwrnlJlrun I a
bdIJ. ('/1
1111K IItMl('A1. I A('I()R\ IN Pill MONARY INI I.AMMAl(IRY hlSl.4tili
VJriuu% hNwlxuraal cvcnt% tJ\mk placr dnrruK pulnw.nary m1lJmnunrwr werc
raanurwJ m t/w M.wlaIw611vlrrlJf IJYJ/ a' IHA1 ) Ilulll\ Ihw11/41tnrN\ w/th aa tltr re\Iwra.
tlwy Jl%t/r\\ %yn1I1/Nnr IARI)SI and /n cif\'llnlaIMJI anlnlal nwwh'I\ In p.dant. wHlr
AKI )S. activr rrrnuqrhd eta.ta.c wa. /rwnJ in the 1(Al. Ilord. In the.c IlurJ.. maa tt
vabrw111I Ih( marw clamaw /nhlhNlw fl, prrwea.r inhrhnrw (r.. PII racunaJ I hr. was
aau.rJ by nantalnm ol a mclhwwnne rc.rJuc at the aclivr atr nl thr u, t'1. and nl/rrcJ
uwluerl rvwknaY r.l n.iJalnm aa'aumng in the inllameJ pulmonary li..ur.. S1whrs
wrth r.prturrnlal aniuwls have been initiateJ l.u rain unJrr.lamtinK ut thr relative
n.las ol pnwcavs. axklaMs. araaheMwule nKlalxrliles. lrwn/rknll'M anll a'rwNal'1 .y.-
Ir m crwo(rwrmr. atNl rwhcr nrcdialrws in the pallwJcne.iI al pulnMmary inllammatnm.
InnahnwKhial rn.IdlJlum ul Rlurr.e naiJasr/Kluclsr Iu prrMluae n.iJanl% nr Irwmyla
IrJ mwkwylkucylphcnylalaninr rw f+INUhrA rnynaate aartatr as kutrkytic stimuh
uxhn-lyl .rvrre acute pulnMmary injury rn New Zealand whNe tahhil% awl rhr.u%
nwwrlry. lhe rnruy was accrwryunnd by kulucyur pnwca+e (aciJ.athepvrn.) te
ka.r in rahhn luny% anJ mtiJaM f.wnutiwwt. and awlJ he inhiMlrJ by ncutny+hrl
akpkuww+ (/111JaH IownYNNM wa% tkrMwl-makJ by Ihr /nallttalMwl nI a'Jlalaw by V
amuwr 1.2.4 krarrdr in Ihe (weaence rr/ a Jnrp in inlraccllular Xlulalhnwtc kvels.
and rn dk rhr.u% mrw+ley by inictivalNrn /d a,.l'1.
scAraul.taacr. 1. Rcvak. S D.. anJ ('.w hrunr. C. G.
Frdrrurran PrrMrrdrnK. , t 21q)7 2R10. 19114.
OtAtr srp/orr: Natwwul In.litules nf Health and Ihe Uffice of Naval Kesearch
I nwn thc Ikpartmcnt 4,1 ImmunuluRy Rr.c.rah Inadutc af ticripps (Yinic. 1a 14,118.
('A
(l KIII OIM.ASMIN. INl'RhASlib SF.KUM(Y)N('IiN71tATH1N ANI1
IMPAIKI1) ANI IUXII)AN'f A('llvl'fY IN ('KiARlil'1"li tiMOKI.Kti, ANI)
AHIIJ I Y'1( ) I'KI Vt.N 1 11/1'1'KI_1SI(MI (N- Ii1.AS"1'A\E INIIIUI 11)KY
('AI'A('llY (FAI./'ItA, 1'I(t)1hINASI's INHIHIT/p(
IItINNM1,lIYl'r1IJt Illvaf'c fluid nt.nuncm anJ rwrn.oMrkarv crwllJm. .rrruli..mt
nwh'rnuatnwr. rrl arruhMd.r.mru 11w mahu.rtum mhrM/rK ad hpid Irw.iJJhrwr, wrdr
hrnnrJ wls tuauk Jr.nrolarr aclrvny 'liri. suKpc./eJ dral crrutrr~la.mur nray Iwrwu t
Ilrr hrwa't /r]IqrJHlry Irall a)!JONI nRNlJntt\) in l/l,'arrlle NlwoLr arM/ air IMr11u1Hn1 Ie1
loll.rw up rwr t)n. 1aw.a invr.bpahw..luJicJ (l) seruur ccruWoplasmm .vwacnlratnwr
arKl anlnr.alJra aattvny Ipar.rrnaKr mhrhNirur nl auhrardatnm ad arM-lwaln MwIMrF'r
narrl un ce:dUry raalr ami lemak .nwrAer% anJ rwwtsnw>tcca, aml (21 thr capacily u1
armhy+lamnm ua fwrvrrn .ulqwr..inn arl Ihe cla.la.e inlnMhwy caprcrty r.1 allihJ,
Iwrwr/11J4 1/1hlhn.w hy IIN' nitNt:wn ahhwanlnM I a/M1 by t'/l,`ara'tle %nMlke Mllulnwl
MrJn arrulqrlJ.rnm c,wMrunatnwr was siKndi.antly hrgher m.orrlrr. Ihrn in rwwt
%IIN-ka'1% a1NI 1/t /C/IGJr, Ihall 1/1 Ilqk\ whrlha9 rw MN Iha'y \IIMolerJ ti(Yll/n a1ltNrarlI:1I11
aairvny .Iw.wrJ srrmrh. Jru Imr.a cunclMwwr% with xrum t'crul:Nda.nrm rn .nn.Acr.
aml mwr.nrrl~.rs ul Lqh .rRr. 'llua was a Irnraa rc1 rtMwr.hrp (alween rcrul.qda.nrm
c.wnentratawt and 11% ahddy lu furvenl .rrpiwessinn arl Ilw rla.la.e inhrhrtrwy rap.N ny
ul atph.. Iw.w.rnav mhrMt.w by ChhKamine T anti a9pafltte mnM*e mrI11tIHM (lM'N'
IinJm~,'v rMha'a1c (// thJt crgart-/tC .nwolin~,' can causr Irartial maalivJiwm .rl Wnrnr
8nlnritplant :w lrvqy a.rmiMranpd by imu//nirnt cnwrMun.:uiwy increa.r in r rrut.qrl:r.
mm awKrmratarn. arH1121 drat lrru4Y+la.rnrn nuy Ixawcat Ihr lung akJmm rmJ.mtl.l
In a irarrnc snwdcc awl air ppolulaMs.
At rt rd.
Arnrrir.or Rrrrrn u/ Rrrtrbmerrv /)r..rep 124:258261, 191(4.
(hAtr srryrewl: The l.nurm anJ Ru.e Kwrsk Fund.
Fr.wn tlk IhI+artment 4d MeJicrnr and the ('he.1 Servicr Itrllrvue Ilr.yntal, aml lhr
1)rl+anuknt rd (:nvvrmuwntd MrJiainr. New YruA Umvereily MrJu-al ('rulcr. New
Yawk.
('1(iAKIillli SM(1K1: INI)IK'I;1) BK()V('H(X'I)NtiTRKTI()N IN 1)<X;S
VA(iAl. ANI) I:Xl'KAVA(iAl. Mt:('IIANISMS
1he aulluws ul Ihra papar sluJied tht mnhanism ofv ciKarrllr .nwrkr uNluanl
hnrnalMRrm.lrK9i.wt by rneltwd.IhM alhtweJ.eparalirwr rd a~a/ aflcrrrN arrl rt/rraul
nruk. Tu evaloJlr ltr;.rvrrny of sn.rkc-im/uced IxawKMKrrn.lrwiiwm in arw.tlKtvrJ
d.K. Ihey nua.ureJ .uway Iwes.urc aml airMrw rr.r.lanrc (Kr., huccJ r.., d1Jta.n
nrthrwl) Ihry slwhrJ the nwchanr.mn in nthrr JrrRs by uka.unnK anway Iwa,urr.
cemtal aaway .nrwwh mu.ck Nwt, in tra.hral seRmrnls rn snu anJ reslwrahwyy rnter
Jrrve by mwnlnrinR pAnnic nwwru ncrve rwqwl. inrluJmK the radr u/ val;al anJ
e>atravaRa/ nrrvrs vs. ahe t+.k u/ hMwr) Mwne rnakrial. during inhahNinn u/ arRarcnr
srrwJec. Rn incrraseJ mrxe than trwafolJ with amrke fr.wn une ciRanlle JehvercJ rn
Iwn IiJal wrlutnrs. Ahaw1 hall lhe airway rcNtrm.e was Jue N. Mrcal et/ecl. rd srn,d,e in
the IunRs. lhe remainder was due lo atimulatinn of the reyr'aalory a'emct, whnh
activated vagal rrrrarw eflerents 1o Ihe airway snw.Nh muak. (N lhivi cemral .Imrula.
la+n, atrwN hall was due 14, hhwr.l Mwne mNrrials anJ the rea lu vaRal pulnwmary
af/ereMS Grmr thr IunR.. lhcse investrRauws awrclwk that inhal.lMwr t,l arRarette
41
411
.nN.lr In J.r. alu.e..cvtrr MINN INt Im.trn th/n whit h i% nNJirlcJ ma/nly by r.Na
%.q.J nNth,lnlan.
11uhaLl. /, M,qh.. (' . Mltchill. K A ShICIJ.. R 1. , a/N1 l:uld. W M
l..urn.d./.1lq.lhv/Yll..i.InAa Rr.lNrnr I nrrr..n l lrrlr.r!'hr.ud 57/41 I?hl I_'7//,
IvKt
lbhrr tup/r..rf' N,IhunJ Il.vn, luny atNl NkN.J h1.Ulutr
I IMn IIN' ( dHh..vdN11Idr Ki.tarah Iu.lilulc, I)kluntlrenl.l/t MCIINI/R r111I I'l1y%NJ
/.rv, I lnlvrraly Id (':J/l/lnnr, Srn I torl.iv'o
I IK'nl I/A 11()N tll ('AI MO1)IU IN IN 1)I111.RI NIInI1N(: 1'1lI.MtINAKY
I YI'1 111 1'11111 1 IAL ('1'I I\
I'11I11hN\rry .ml,Nlanl, a.Ilnlphot nnalurc /d IIpiJ, Iw.NaIn, :ItN1 trrtrAlyJrIIt
wlnl h INk'. ,Ilvr.d,u .u/tacc., i. yu1MvcJ by a1ve/Jar lyfV It InKUUN. ylc% a1Nl
.1wrJ nl nN la.nNl% aJlcd IanNIlar LNhr. In 11r prc.ctN .pNly 1h( rr.raniNt. h:lvc
rmcIqdrJ t1/i ndr ul low t al.luul hltNhlll! IN.MC/n, 1a111NN111I111, nl rerl1I]IInF
ur1:N.
IJII/ N'l ll'11.N111/1hIIar/'/II/JIIIIF tJt Ir/II IyIR' II fNN'1111Nq yN'\ Ia1/N'Ilat IwNIy
%t'11i11/111
L.InuuLdrJ /n Jlt lrrrnllrlln/: lylx 11. rl1. rn ..rt., by low t ak lual NNNIIIINwc. A211R7
AZ 11K ) IMlINItI 4YIf11.N1 1% hh.1,eJ by Ilr- pIN'1NMh1:1/Inr Jnlp t11IIu111\r:1/lne rM1
t111.NIN.1111.1/IfN, tlul 1. un.Jlr.Nd by low NINUvr rnal..)c., Ir/lhN.t+rra/tnc .ullutNk
.NNI IIILNIN.IILII/IN' IIIIIItNh' III/IIIII/h.lI1NNt'NrINI' .IU.IN% tln aulNucd Iylr 11
INN'1111NMylr..lNw th.d low IK'tlcnlrli d N.Nn.u.kl/kav inlrxtIlNlar I:/atluk.,
whltlr 1rrN (MI~t1/v.Iy w/lll nlfh dardulNl rnlJvooly, ul.rrr.r wIN'n IIN CCII atc
A 111111I.11\'II w 11I1 tIK 1.Il 111111 N1/NyINN(' A21I/{ I%IIKr l(N'K NlN/cu.kl lknv
rra/tuh
,uilw..u11ai1v.lr/rNdhYldwnl4mN' IK,IINvrc.ulhnlJNIN1halnNrt.rv'J:IIINNIIIINII
611111 1111NNt':Nllvr 1rI11NMI11I1/1 Il.(a.1f .MW\Ldt'J wnh IrnN-11r1 INNIy .ur1Ni. wMn thc
arll. Nr.t1lNrJataJ 1N 4l'ra'111N/ Ir1.Nh11tN.N_ uhr.ntru. tu.J hN:Jv 11N.nld t: InurhJm
INI aW /t,nl'1I I:I1N'II:Ir hl Vlll % 11\Inr IN.NrIn A l IIIhNIII /!LhI IINhtatl'\ IhIt
tII/INNIIIIIII /\
INrN'1,1 INI 11N11 /N/It'r Nlrtrtl'\. I:Ikrn H1'l'Itk'r Ihl1l' :I/NI IItIN't rl'%1111
111111t11:/lt
aalnN.hJln In pa1lnN.n.uy .utlarlant .ccreb.Nl
Ildl, I) 1 WnEM, 1('., )r., ArNhcw., M 1 , and Aurrr.nc.ly. M J
I alurrurun Irnrtn,q~.nil.e 5111) 297 MIG. 14R4.
(kher auM.rt: NrINNIal C:rnicr In.litutc.
1nNn Ihr 1)aparlnxM nl 1'a1MIMM y, 11:nvarJ McJical SrhINJ, 111/.1Nm
GiI'K( )f( /NIN ANI) 'I IIIi /'lI1.Ml INAK Y('IK('l llA 111)N
AIQNIuFh .rnMUnm Ii .hyJru.ylryplranne. 5-1111 ha% hten Jl..rc/lllcd as Ihc
nN9I1.111N Iti hy1N.aNINIt11MNlary vaVq'111wrN'111N\, 11 f1N1/1n11C5 NI be C1NI%Itkn'J INIf nf
low vrv.'INl.lttt Nny .uh.t.uNc% a/Nl ha% hecn akrnlul.tratrd in Ihc IunRp ol all y+ciics
InvaUI:Ill'J In~IIn1111ir///ng cdlhCt %tYJN%.evNkrn'cha\I*en/1IICtlYIlhJIrYnNlvalnl
S 111 1. Inluh/liJ by hylbIIN'tllllr .n hypa/ntla, i% rNN udlucnicJ by hYlNlaa, i-.
Inhlhlh J 1.% ,NMw // r.'h/u h%IN.U/.I IN l.M,hknJ .cp.uatrly b/Nn Phy.h.lu'N IrytN.
'1 ,,,,,) ., rl. 1 hy ....nNh' IIh.IN.111//1N'. IIII/tM.Nllr/1111', r/NI .Nlrl.rol,
q1/' ,.1tu .. l lq .. 1 uw 1. u1.1 udul.d.N 'I14rq111N' t1/1Clt.l llll ,N llvr 1/.111\
pIM . Thc wurk rcpnteJ in Ihi%chapter rwiRinaks fr/Nn earlict audic. tul' Idclnnx IduKN
I/NNt1IN'a1NN7/11 11uI1nlNldry ar(Cr1aI Iun1:INM1 anJ IINNIIIMII/I~y, A~ 1/ar( 1/1 Jtl
Inve~tll,'a NINI ul thc cltccts ol vkucJ ~y\IenIK vaMMhlaNlrS tM1 111e IMIInNM:Iry c/rruLtNtNI,
kclan.crin (K414(d11 anJ Jl p-ch1/1ratllllcnylalaninc (p('1'A/ were tc.1cJ. A 1hnJ auJy
wa. rntlialeJ tu calliml ur rcKt I Ihc rcwh% tl( thc earlwr ketan,crin study arNl a unNr./
11% achvhy wnh amNhcr 5 1I'f. mhihiuN, cypn111cp1:Nhn. /Pcriaclu// In .urnwrly,
Ihc.e .NNIN..uplllrl llK prcvnlu.ly rclNNteJ .ugFeaNnl that 1he paNN.genetN NwU
hr
tn.m lel RV hyprrtrllpAy aal nleJlal thiatcnmK in chnNlN, hypua/a tnry /NN IN' /IN'
.anN I unhrtnNNc..cneunin %ccm% tu c><hlhn INUh eta-ilaHwy and inh/fNhNy atl lvulr,
rM In1I11NNlrry allctla'\ 1.( S/)1o I(M1/1M in )pe lhi. N(cla wa. ven hy cithct Ikpkhn/~
5 J 1'1 wilh p('pA IrcathlNnt nr by Mlt king the S. 111% rct clNllt. willr kelanxnn 1 INv
rR(ICrinN'nt. I/N-urrn anCnlnNl tNl new rYNN.YIN% and p/..IMlnir. hlr th. l-INIUUl n/ IIN
/NrhlNmary t va ulalNNr anJ i. t INnpanhk w1Ul lht hypnhc.i. thal rNlrnN/uc INJnN.n.u y
va./1J11atNNt /% low acNvr Lha.c 401 Ihc pulnNlnary va+aulx rc.INlna NI hytN.ar
Wdl. l A . Arnh, l M, Hucknet. (' K(llacku, l., OLnn, l: It.. lr .:uNI Wru, l.
K
In Hn'kcr, K 1 anll Ca/J:Ir A. F (c.h.): 7hr f:nJ.r'rinr Lunk in /Iruhh A l/tlr.tlr,
1'Inlalklphia W 11 XaurNkr., 11/&/, pp, 117 1.14
1(hAer arppurf: ('olk fc nf Agricultural and (11c 5eicmc.. Air Farae, and /tN: NrNlNlal
InaNutc. nl 1lcahh.
From the Ikparlmerll u1 Veterinary Saicnte, University nt W/MYNKIn, M:Nh.rm
VAS('l/lAK PR()TI:IN LI:AKAGIi IN VARI/KIS TISS111:S INI)11('1:1) IIY
S(1HS I AN('1: 1', (MtCAI('IN, BRApYKININ, SEKO'R)NIN. 11157 AMINf.
ANI) IIY AN71(i1:N ('11A1-1I:N(il:
In (he wnrk ra'INN1eJ IMK: (1) Plarnw etlrava%itNlll was /n11ulYtl in r:1/%1N I!In/Na
piK. h/ inlrrwrNNr% in)cctu.m. n/ I. wM11ac 1' 15V/. 2 Ihc (' Icmnnal SI IN'ra1N1wNk
SI9( I11, .1. .crahrlm ISIff). 4. hi.(arninc, 3. hraJykinln 6 l':yl.aliln a/NI T hy
anGFcn ahalknKe 12)1'la.ma eulrava.alilln iraluaeJ by CI', 1PtN 1//, by S 11T atN1 hy
cap.aicinwa.,wNhlewesccptNlns,nh.ervcJin/heolanK/i..ue. 'Ihe ellart/11SI'wa.
rull hAla kcJ hy 11, adl 11. hi.lanline ratyMrx anlaKuni.1.. '11K e11ec1 ul i v CSllhall 111
was ah.ent in cal'/.aicm tkxn.niirJ anrnwl.. 1'lawn.e caNav..:nilln nIMNI i v SI',
SP(M1I1/. S Iff and up.anin was Ktn in 1hc skin anJ m a11/wKam clNlt/mmg nlw u%
mrnllranc, e><cqM Ihe /nlc.linal rmKrw, aml l t/ l'la.una eR(rava.alNN1 by hl.lau.nK,
IwaJykinin, and anhgcn challenge rd rlen.itvcJ Euinea piKa wav al.n Ilh.arvtvl ur low
%Nwnax h anll inlc+litN7 I'I:I~It1a CtlraYiVMMM aMI hr/NN'hIqYM~ItN~INM hy anul;rn t hal
lenge wnh 211 t.y/kK uvalhunnn war ctNrM+ktcly hMlikeJ by c,N,ANrNJ /1, .INI 11
hi.tanuna racaINIr hI1N kalle Ih11h reyllrlvcs were reduced tn afrwl dN h.Jl I,y..u, In
Jc.en.NtveJ Kulnca pIK.. thllugh the nvluaIam uf 1hc IrrnNahday rcqNlnv wa. .L/u%
lically rNll .iRnifiauu in all INgana. In clMclu\Nn/, several .uh.lana'e% low Iwlnik
anaphyla.io inJuce pnllein kakaRe in many li.cue% with JdferinK.clcctrvc Jr.trJNduNn
pallern. Anaphylaalia- hi.lamine release kada Ns prldcin kakax. pattly via rrliv:lrhN1
rd .cn.ruy ncauln. til' i, a Idely mediaNlr /d ncunqtenN p.dcin krkagc In Nuny
nrRrmc
Sar/.. A, f unJlw.R. I M Sku/i1.uh, (i , anJ I.em(letk, I
41 1 41
Nrrunvn Sr Ami.drbrrK's An Arvrs ..J /'Anrnwn rd.rRy 121 212 21111. WM I
OtAtrsrppeort: Au.uian ScinNilic ke.carah Fund. Swedr.h Mcdreal Rr.carrh ('num
cil. Swcdl.h fl+haan ('un,<+any. Wdhcrg. Giltclx, flam rth I.lu (1.Irrnun. 1111
tel.c (iu.lav V I.nImIalhM, Sven.ka l.akarr.alI.kafrl. M./gnu. Itcrgvall. tillllrl.r.
AuKu.ta and 1'etru. IlcdlunEa Slrlleke, and A.Ira houtnlaUrm
1'wmr dx I k panment .ll liaprrimenlal and Clinical 1'fiarma'aluFy I Inivrr.ily uf ( 7rar
(7rar. Au.lru, an.l the Ik'fulnmcnl o( 1'Itan++atuk/~y. Kandm.ka Inallnlrl. Shlck-
lathn \werkn
St1Hti'1 AN('1: P ANI) ('AI'SAI('IN INI)IK'1:f) (Y)N'I RA('1'111N (W III /MAN
Nk/ )N('lIl
In the lar.enl .tudy the elreata rrf .uhaanrc P(SP) and tap.alc'In Im huluan
Iw.uw hlal arnrr-th nru.a k hmr werc mllnil.wed rn vitru. Re.ull..hllwcd Ihal SP mduc rd
a dn.r Ikl+rnmknt ranlra.9ion ld hunan .cEmenlal Mnm hl in ritrrn with a Ihrr.huld
dl..e ~.I ahuut NI M 1 he.r Preparalinn. wrre nMained lrum f+alienl. unikrKrhnK lung
lunhw .urFery Ihe 1P-nhhll'rd l IM11raCIhMt were rr[Itlan) to nlrhytamhle and altll-
Plne..uKKe.ImR a dlrerl elfecl nn the hnuh'bul.rrMwMh mu.ck ('aP.aicm (11/' M/ alv/
nhlw cJ a cL/wly drvchK+inR .Irony atnqhne rrcl.tanl crmtrxlicrl n/ human hmnchi in
rru.r A raPld lachyphylau% devckY+ed hK da rrspm+e la ralnaicin. HMh SI' and
caP.ah in were k.. Pldenl than ax elylcMd/ne alhl M.lanune in induc/nK ronlrarlnwl% of
human Mrwr hl I M. Irrnlmg may. Mrwever, he panly due tu the ealtrhlknlal anrli-
blm MHh X/' and cap.ahm were cluuparalrvcly much nhre pMenl in Kuuka pig
preparaunma Tran.nuual heW .nmulalum ol the M//nch/al prrpatah.m% in nun re
wlted in nonlrwn-.n. Ihal wrrr lalpcly .en.hwve lu arr.ynne lhr fxrrm'r ul aap
.alcln Induc'rd hnuxfilal c.wura.ta.n% h..wrvrr. In.b/alr. the cu.len.r ld a kwal
mwKiwdlnerK/c au.n refleis cunhnl 1.1 hrun.hlal .nolwNh nnl.alr h.nr by SI' in man
l.rndh.rK. J M. ManhnR. C Knd Satia. A
Ar tn I'Awi.dnKn u Sr.rnr6n.n'h a IIV 44 S 1, 1481
Other tr0/orf: Swcdi.h Medical Rc%carch Caunril, Swtdisoh Tuhaccn ('lhnpany.
W/herK. titdlrl.r. Ilans rt'h Iar/ O.Irrnran. Suhel.r, Guaar V Iaurhlateln. Karo-
hn.ka In.utulcl I:nhl.K, Nvrn.ka I Aato.:lli.kapcl, MaKnu. IictRvall. Suhrl.r, Au.-
Inan ticicntdir Rc.carch tund,l4ym. and AuRu.1a I lcdlund. hnnd, and ANra Ivwnda-
(hhl.
fnwn the 1)el+anmen/ rtl 1'hannaruk/py, Kandin.ka In.1Au1e1, and IkpanmeM of
Anr.the.u/k/yy. K andm.ka I lu.pltal. Shn k hidm, Swedrn; and I kpanmcru nl I: rl+eri-
mcnul and (limcat t'fiarnvlrc/trl~y, Onivcnily ut (7rat. (:rat, Auslria
1?I'Mi(TS ANI)1)ISTRIHUiION (N: VAGAL('APSAI('1N-SF.NSITIVI?
St1I1S1 AN('li P NI.IIRUNS Wffll SI'1:('IAL KhF1iR1iN('E TO TIIIi
IkA( III-.A ANI) I I1N(i5
1hr rvrRln r.l cubdancr P/SI'1 mlmurhueaclrve ncunlna in Ihe lnwer re.pnahlry
Irw 1, rvrhaKu. MMI hean.e/ RurMa pIR\ wa\ IkItMNI\Iratl11/n VNne I,/ lhr{C \hNln'\hy
.urrp .1 h IwI.M..r. w I ap.ar on p.~ur.~lnrnl wtlh .uh.ryuent lkfennrntlNwl .d rhe
1-u,.t 1,.r1../ \1' 1.t r..,L./uu.......r...~Y 1n.Ihrr r.l.'nornt% Ihc r/lr.t..1 valta)
Ilrl%f Immla.u n Il.r \I' 1r.. I. Itn 11% .C II%Wc+ wa% Nlnlit'd IIK l'll(lls 111 lall-
%an ln-.rn.ilivc allerrn/% in Ihr rry+irahay Irac1 Auanca and hnrrchial .nha.th mu.c k
wa. al.u .hnhlndankrchyTIanalyre.rnl
IhdllnyS/'h/ l:van. hlur arhl In.u111a1r.in
>< a. nfJvalaa.cularirhlicalrrrrnlcaha
p
Prc'..urr a navvr. in thr ua.hra and IunF
a/
arr allcrcnl aml ral+.ah In .rn.dlvc. Thr Irachra and .ICm hnmchr rrcrivr 11' aI lrrrm.
nwmly Inuu the ril;hl vayuc nerve with crll hld/r. Mt-alyd in Irrlh the rhlJlr.c aml
Iuyrdall;anKha lI1rS1'in/IrIvaNNml.lthrlung .rrnl.rlhavradualungin I Al/r/rnt.
Inwrl IrNh vaFal nrrvr% wnh a cro..cd lyr ol nlnrrvalhm pattcrn; 2 A rhm vagal
..mr. r whhfi c.w1.i.1% rd alrwl MM>:.,1( tllr SI' nervr% in Ihr lung Thr.C ncrve. pulhahly
IM/F`III:IIr Ir/M11IMM:N'h' ]IhIqI /,':IO)!IN lbr rl/rcl% rd rlhrr and iap.aicin r.n ul.rdlla
IhN11Mr%%lllt' :I/h) Im7r:IV in va%culN Ill'rmeah/hly were IkPI'ndrM Irl /hk' integrity ul
('a1Nah'/n VnNIWI alh'n'IN% nl IM11h val,'aI anal MNlva(}aI 1N11!In In IIK ku1/K':1 IHI(
.y.lrmlc caP.aic In PrrtnabrKnl lu alluh anmwA t,rrmrd tu tt.uh hr /ncvrlahlr
I haurr% in l/h' rc.lutat.wy uacI. wlhk in Ihk' rat a%ul'Cr%Nvt' /etYWrry.ll thl Iulh IhM1aI
rc.lwwl.r ol caP.ah ru wn.Nwr allrrrM. /r'culrrd
f.malAwrr J M,/tnwlm 1: atd Salna, A.
Ar i.r I'/n cr.d..~rr'a Sr endrnrrvir.r 11Y.211-252, 19111.
Other trOprrl: SwrJi.h Mcdi.vl Rr.ranh ('rwncil, tiwedi.h Tuh:hrrl ('unMany
' WlhrrK. Stullcl.r, Itan.c n,h Lw/1Nrrnwn. Stdk'Ice, Guvlat V I'Irumlan.m A%IIa
I-1N11hI:11hM, Magnua ItrtKvall. SlUhrl.r, Kanllm.ka 1nai1u1e1 hcw.knmg.l.mlkr arrl
S ven.k a I.ak arr.all.k aprl
huwn the Ikpanmrnl .d Pharmanik.gy, Karulm.ka Inaitulet SnKkfhdnl. Sweden
Ii11 L(T (F ROI/TIi OF ATROPINE 1N:LIV/:RY ON HRONCFIUSPAtiM
FR()M (YN.I) AIR ANI) MIaIIACIKH.INI?
llle authrw% unikrtcwlk a quJy hr drlt:nninr whrther the apparent dl.parity he
Iwccn Ilk du,e cd inhakd Mnllriar rcyuirrd /n inhlhN hnwkhncrrl..Uirlirm imluccd by
inhaled ulclhachrdinc and the do.r nr(rred h/ mhrh11/he hrlln.hucun.trrc Ihm /nduceA
by crcapr/ic hyprrlrrra wrlh ruld air is a fun.9ilm cll the nNllr crl adorinl.IralNwl ul
alnlll/nc. ln.irt .ohKrt% wilh a.llmn, /hry nxWrurlc'J dlnr m.yum.r curvrs hr inhakd
nlcthx'MAirw and lu cucalmh hypctlrrca wNh cold air a/trr trralnwrN wl/h /nhakd
a/nrine (11 5tnK cklivrrrd) and inlravrmws ptacrlK/, with inhalyd Pl:K'rhu and inua
vrrhnl% alnqnnr IIf S mle inM'c/cd). aad with inhaled and inlravrrrlu% ldal'ehll.. Aau
pine by rithcr nKer .hifliy/ thr dlncrcynlme cwvc. N/ Mllh crdd air arhl hr nlrthx h.r
line lu Ihr riFhl In every .uhfrr/, hlwrver, inhaled alnl(Ilne cau.rd a nlarkc.lly Fn-alcr
n/;Mward ahllt rd Ihe inhaled nNlhalhUhnr dlhr/l%IMIIIw l'urvr than /INI InlravelhMN
alntpllw wlMreav Inhak.1 and inlovemw% alnq+ine had vrmi/ar cl/eah rm Ihc rcd.l alr
dll.r rrIwwl.r c-urve I1h.r /I/rlinRs suggr.l that IhC apparent dNlwrNy hrlwrCr/ rtw
dlr..d Nnlnlne reyuurd lu inhihN rnrlharhldinc aml e.dd air-Induc'rd M.ln, h,K,MI
.Iriclinn nuy R a lunc lilnl ld the nwle of ad/nim.lrali.m rd alalp/nr alr) thu d.r% rww
imPly a mwnrw+txinic ac7iun rd alnl(linr. lhrsr linding. vuparllhe view Ihatt uk1 au
c.lu.c% hnu111hwcm.Iriclhm via mux'arinir Padhway..
Shc(1(lanl. 1) . Ep+lein ), l/oltrmen, M l. Nalrl I A, and Rrwshry. 11 A
/.wrn.d ~~Afqdrr.l /'Aru..InKv R.qnn./ /.nlrrr.n F..rriv I'Arfad 5~1//1111 111,
Ivx).
IS
aa
Othrr .ulryHr.t: Nrnunal 11can. I.unl; and NI/NKI In.litut.
1 fnM1 dx- ('.IIJN.va.. ulrr Rca:Irt'h Inallule alkl Ih p lnnx nl.l.l MrdN i1K :.nJ 1'11y.1o1
"CV. 14uvrraty ul (:Itll/.m/a. San I rrnaivn. rnll t1K Mrdl. rl krvlcc. Srn I rrlx lvu
( an;l.d I(I..Inlrl. \.In I Irn.l.s o
(IIAKA("II KIYAlION Of tlllil AI)RI:N(K'IiP1OR SIIItI'Yl'1.` IN ('ANINI:
AIRWAY \MIN) 111 MII\('l l. HY RAI)1OI.IGANU HINI/IN(: ANI)
1I IYSK II 1 M;I('A1. KI'tiI't IN11 S
I h\'w ta'4'.Ifl IK- hrvt mbl'%1/r:IIc1I Ir:ItIKaI \IIkNNII n111M'Il' 11( ttK 111.1; :1MI IIavC
114'll I 111111 IA ks a11NIy tIK ch:Ir:Nltr/.lwt nl IHnl rrlcruH\ in /kHIM/.nwtl.Id 1111.
11a,1k' 1-..1 t nlnllr11M.11 1IKy :II"1 %11kIKlI IH I ere.. /4 lle a1ln'1K1)!It' fl'lIMM4'\ In
Ih; \.111K
11"N/l' Itmn)! IN/111;t1.'t'IH1U% IH'l.e NrIMI%It a1xl fh'\IfIt:1I %1/11NIIrINH1 .11 .yn1I..NIN'1N
1k-Ih' `Iq.1111Illy IM'h1 alh.'Mkl'I.t.N N1h1y11(y I// 1:111/1K lfallk:.1 V/kMMh IIIUNIt'
h.lv; hrcn IIlvc.turrt;J by raJN111yr1k1 hoxl/n{: anJ by phy.xdayltal rr.plHl.r% t..lwlu
rylHn.t. rlkl .yrop.11/Klk rKtvc .umulatkHl en ren.r `Itcltic hllNbnk 1.f I111 dlhy.
JIU.JIHCrMd.d 11. u./alxal .nNNNh mn.a k nKndHa/K% wa...I hlFh alllnny lK, - I U-
11 (I/t nM 1. a. UI (.lrl(1tKrJI (unF' nlCmhralK. INMI IIK VIIK an/mrl.. hllt 11K c.Nk Cnlra-
IHM..1 huHlmy alt.1')S fr ! 4 7 1nMd/nly..l Iw.wtInl wa% lnuth ll.wcr in lunl!(5 12 '
4K IHwd.d IN.N;InI ItlrxhnF wa% .lalru.ch'lhvc:llkl arIN11VttIN/11tIClI WIII111K ranll
IH11;r..1 lrqcnl y 1..11N.dClrllu) Crlfk/lh1uK mHf11UKIltNUK, vgndym~ a(NCIMNxkr~
afx c Id l.. r,l _` It.clw.H. I I,winK v kt uvi IYr11 anlatIMI~I~. (IK rl'4'a1l IKN JCI~
r11111k'.I
tIK 1,/1n..d IH r,l I ebrhe 2 fc.cpt.H. in trNllk:d mINN.Ih 1n11V IC nK1111Ma1x'% In til 14
( IKK a1kl.Nhcr I;Ia1rJ rc.uhv .IIFI!;~I Ihat IINht IM'tU fCl l'tN1H\ In JLpIral IKrI \nxHNh
nM4 Ir :ur .rl IIN IN de 2.uMylt nNl tlkdl.dC fl'./aMtC. 1.1 t nl Ida/Ulr catCt Ik.1am11K..
Mll IINrr 1% a.nt.d) l/MN1'l1Ir:MNN1 llI IN6I 1 fcc.IMIH. th:n uwJ/.nc tIK r~.tk.o.c tu
INu1.111y rrkavJ mw;pnNI.htnK
Il:It/K%. I' I. N.edrl. ! A S{,.u.Fh. I( h. and Rnhclt.. I M
I br Jrmrn.d e./ l'hn.mu..durv.nn.l l Iprrnnrntnl I hrnryHuril . 225421456 461. I'/!{ 1
Othrr tr.pporf: N:IU.N/al In.litulc. u1 Ilcalth
I(INI\ tIK (:It/INWa41/Iar Kc.carl Il tn.litulc and I)tparlnxnlad MrJn'irK :Irkl 1'hy.i.d-
uyy, Itmvcruy .d ('rhl.wnia Srn FrarNi.an-
SI; .I I('l IVI: (71'.NIRATIUN 01: 1 1?UKO1 RIhNI: H. HY "IRM'lII?AI.
I-.I'1 I 111 1 IAL ('I :1.1 S 1R( IM 1 N x 3S
I1111I11a1/1H1 by M'11Ir1y+hila ir a rrtnh.m/nanl hi.lulnFk' Icalurc nl at ulc Mllrnllna
kNy t;lINMti\ In IMIInkMrly anway. 1IK fftCnllh/nlM.tl:/ll.Mthrt /kntrl.(.lal iu/llna
/xM wr. IIkaIVI.I IHCthN11/na/11Iy la IIK clNdKha1 (ay.'r .d IIK alrwry wall /n 16.E%
hrrathulr nn1rK Iq:ycvlcd 1ha1 crulcal inllamnlahlry nxdcluu% wcre rcleav.11raHU Ihc
cplllkhal ccll. In 11K wnrk rrpHrlrJ hcre. Ihe ina'uhalxHl ol W,It'mkNl,, n1 r./mrK
t/.NIN.d cpt11Ntlal tc11% nf Krr:NCr Ihan 4Sel purity with arathNMMir atkl 111 2111t prl
mI/1.H h/) 1211 111M It'.ultC/l in (11t ~,'lnrtatM/f1 UI a maainlum nl 1/. 1 1/
I(.ocIMkrlca/l
1;H\.d/knt 11.111? .;11.. Ic.. Ihrn 2 u pNlHlxdc, nr 1),. rlkl 1.rhy
..11. .ual/lll/l Ir,1 )hl 1.411 rex11.'.I I/MIln.uoN.Ir.e111tcI1.u11S .11 .an11
6a.1,... .., ... d. /. . uw .. .I. n.l. 1. lnH "n \I A( U /11 I IH' h11'lndy uI
1..1..,... 11 ~, . ../.1.1. It..1...y,.... ,t././, .,/r1/..11..I1y./r11H LIIt'.H11v1
ly will, nNrk/ q+r.y/ir anll pla.ma antl by thc Chl'/IxMJCIN :Kiivity 1.N rKUtr/.p11i1.
'Ihu. IIK ryatlKllum Inay It an inlpnrlanl .nurcc Id arcJiallH. ul IIIILIIIIII1.11HM a/kI
h)INrvnabvlty ul Iwdnxmary, airway..
II..Ivll/:lo. M). Avawa. 11 Nu.lr/, l. A., and (:IIr1iI 1:
)
l/reH h.vnr. ul .okl Ifnqdn li..d I(rlr.nrrh ('eNmr/lnri. enx.n. 114( 1) 11171"K176, H/111
(Ilhrr lalpunf: N.Hi.Nwl lu.utute, ul Ilcalth arxl Ihc ('alihlrnia Air Rc..w/cc% liuafJ
I'nM/1I1C (:IrdK.va%l'ULIf Rc.cart'h In.lilule IluwarJ IIurIK. WJira1 In.litutr afH1
IIK I~'I.,/r111N'111~1/1 McllN-IIK a1kl I'11y%N/h1gy ( lnivcr>dy ul (':dAnrnia. San 1-r:uNla u
IMI4 IKIAN('1,(11 AIRWAY INII.AMMAlN/NH)K
111'PTKKI %I'1)NNIVI"NIS1 INI)(K'I:U IIY O/()Nli
A..o/uloanird in thl. pa/wr. Ihc aullku. auJKJ wlxlher ai.Hlc irkluccJ auway
hyryrrcywM.IvrrK...nnclalc, with Ilr /kvcllyklNnt ul airway mllanntwtnM in Jug.
I n a..r..:urway rc.IkMavcnc%%. 1hc m.carthcr,, drlcrmincJ Irkrrca.c% iu pulnkMary
i/ca.lr/kc pf.klu.rJ by .IchvcrinK acclykhldinc :Kr/nld 140 thr alrway. fu aw..
alrway InllamnlatuM, they I/wqr.t/cJ Ihc airway nwlrlr.a and c'numeJ IIK uu/nl.rr nl
IKIn/1.p1111. INe.cnl in IIK CpitINI/unm. Airway "kHl.ivrnr.% and mllanmla(NM wafl'
a.v..rJ in a/K.11K.iicJ Ihl.l><hwa onHw cllplrult anl) 1 h and I wh :Illl'f 11/1NK (2 I
IMMI. ? h/ Air way rcyxMVvcrN.% inrrca.cJ marAati)ly al I h ahcr urluK and rclunxtil Io
nMlrld kva. I wh later in curh /d' A Jllje. t1u1 rl'NxM%lvl'/x'%s, J/11 /xM 111a11Fa r11cr
ni/HN in alxulx'r 4 JI.R. FurtlKnrxre Je/g.1ha1 lercanlc hypcrrcyk/navc al.n.kvcl
ul+ltil a/uaflcJ afkl rrvcr.ihk in.rea.w in llK nunllk'r au/ nrutt//llhlh in Ihc clHlhrhunl.
wlKrca% dly. IInN JiJ Ik.1 hrclHtk hyptnarplln.ivc haJ /w/ changc in IIK /wnllKr ..I
nc111rIK1h11. I`ur Ilk XrnHlp /d Jl.gs, lhr kvcl lll' airway rryllln.ivcnc.i hchHc and rllrr
ai.HK ctpr.urc tarrclalarl ch/.cly with Ihc /wndKr 111 cpitlKhal /KutrlM,hll. "11N
rr.nlt..uyyca that ni/MC /nJlKtd aitway hylwnr.lklnavcnty. uuy .ktrfkl Iln UK
Ikvc1/MMK/u Id an atwc inllanun:Nllry, n'yk+n.c in Ihe airway..
11u11Vnun. M)., Fahhri 1.. MO'Kyntc, P. M. (iuW It. I). Aiiawa II . Waltcr.
1:. I 1. Allxn S 1 s.. alkl NuJrl. l. A.
Amrrirnn Rrcirll u/ Rr.piranrry I)i.truor 127:(>KA-MJII, I')lt1.
(hhcr srppoA: NaliwNlal I lcarl. l.unp anJ Nhk.d In.litulc. ht.eM, t'tlr(xua/aM and thr
('ahhlrn/a Air KCWNRCCs IIn:InI.
I'pN111h1' ('aNINWaV1IJr Kc%carlh In51/1U1C aMI I)CpaflnKM t.I Ml'JKinl' I In/vrr.lty
411 ('a111.Nnla. S:In 1rafNivo.
Al/I'1)RAI)KK7RAIM11(' 1.(XA1.17.AT1ON OFAIITUNOMK' R/:(T1Il /KS IN
AIRWAY SM(K)l'll
ll.ing eyr'rilnrntal I/NNIIIN-m Ihal pnlvtd lu hc IMllimal f/lr .ry. il/c nt rlw.H
hindlnK. IIK.c ulvc.upruH% havc .ta1KJ Ihc JImu1MNNM uI aI111/a MIICIk9/.N . Ik'Ir
aJrenrrFNa/Hl mu%l.lren/t rclcln.H. in .nNN.lh nwvk n/ anway. I11N1/ ILNINA 11.
Iclunnal M..IxhN.Ic. AHt.Naah..yr.qehk I/KIINHI\ wl9l' uN1I lOl1.'/C//nNK IIM .h.lnhu
/l. 1 47
nua al arn4rarmn rnrpars in airway snMrrlh mu.w Ir 4.1 Irrrrr Ir+Nn Ir:w'hca n, rrnnn,d
Mnn.hnrk.; 1'II/ JihyJucJlxemrl.d. ('11) prarnm. arwl /'l/) qmmmiclwlinyl lanidatc
were u.rd lo lalt1 trta wlrrncrrrc allrlu aJrrnrrKir arwl mu.carmic rr.rla.a., rr
.pr. trvcly, uvny raparurrcntal crwwldHms that Kavr rnauirn.d .ryrdia rrarlwar arMhnp
M.rrkrd Jdlerrnars wrrr hIWN11n Ihr hMRUulhna) 1h\IrlhUnmM Ul l'aCh rrCcIN-U Jfnl In
rI/%IrrIN/nqN/ u1 Ua v:uums rrcrp/rw% in ranc calncit-r airway Natr rcrrpttK% wrrr
lua.rnt tn InMh rkn.uy thnrugMwt Ihr airways wrth Ihr hrylM.t rknsdy tn INUr« hiulrs
Athh.r ra.cpMy wrrc .I+ar.c in IrrKc airways hut nuuknro% in .nr:Jl bna«luuks,
wlkrr.r% atwrhncrl h rracpNKS wrrr numenw% rn bnwkfira/ VIMrMI\ nW41r .IKU4 m
Iw..umal hnMKMrdrs anJ alnw..( absent (nmrJiNal Mrwrahr.dr. 'fhr% n.(hr" 1 may hr
u.rlul in .hplyrnl; altcraturms ul wtrwwwmr tcccplur Ji.udwtnwr in .uwll :uwl laryr
auw.ry. altrr ca/xrunrnul manipul.nrm anJ in Jr.ca.r
11urK.. 1' 1 Ha.hauro C N aml N.wlrl ! A
Anrrru un Rrwr.v r.J Rr.pnulnrr I)rvu.r 127 7t1{ 762, tVx 1
(hArr fulrpwt: NalMrnal In.btutcs rd llcahh
I-n-on thc ('ardMrva..ular Resrarah Instnulr and the IkparUnrm% ul Anatnmy arwl
Mrda rnr llmvenny .4 1'ald.wnu S.m 1 r.nar.cu
ANTINISI'AMINI(' VI[RSIIS ANIICII(/1JNLR(;IC LFfli(TS (/F ATRO1'INf.
(1N ('ANINI. I RA('111:A1.IS Ml1S('1 li
11he purlur.e 1.1 thn study was trr n-e.amrne the anhhi.tanunK and antn hrrlincryrc
elfcatl nl Nns+tnc rn csprnrncnt. drvRn.d In elumnate pr..iAk I+nrhkm. 1'n ak,cr
mrna antihistanrmc vcr.us anlnhrrlurcrp. rllccls ul atrrqanr ut arrway .nrMh mu.
a k, the rnvc.lrranw. u.rJ an rn rrtrl. prrparatMNr.d camnr 1rx hralt. mu.ck .urp. arkl
rktetrmncd atnpine's elle.a un annlrrauk rr.rym.rs rnJuceJ by hist.mmroe ur by
electrical helJ slinwlatirm uf cMbhnerKrc nrrves In the hra .rnes rrf rapcnnrn/. .53
.Irip% haJ initial resprmes to IieW stimulalnm aklrnnincJ anJ were then ranJrurdy
a..iXneJ 1u a rnnlrad Emu(r or kf a Fr.Mrp Irrales/ with aln>f+ine bel.ue lickl .Irmulabon
was repeated and hi.lamine waa Frvrn. A1rnopine in n+nceMralitms rd 111', tO', arwl N1'
M Jerreasea) the re.pm.e 1o IirIJ alinwlalirm Ia 61.1, 1// S an,l IYX aul the initial
reaxrnse, reyactively, hul had rMr e11ec1 am the tesprnse. lu hrstamine. In the .rcnrnrl
%eriroo ral ei<rerinKnt., 24 alrpr" were trealcd with irwhunclhacin Hr prevrM hiaanune
taafiyphyla.rs; the%C sirilh haa11111//aI R%ryMVCS Inh.Mh Iiekl \tlnWlatNUl aml hl.lamnle
JatermincJ anJ were then aasiFneJ ar a cnuNn+i Emul+au lu a Rnwp lreateJ with alrrairrne
Iw frne Iie1J sltmulalinn anJ hiaamine were rept:aled. In thr.e e.perirnents, a cnnaen-
tra1MM n/ a1n11Nflc (1N1' M). whKh aRain cnntpIelely hkrtrd Ihe resrywrv tu IicIJ
stiuwlatn+n, sldl hnl mt ellect un hr.tamineinJuceJ cnwNrarlinn. Thc rr.earrhrrs
cuncluJe that atnK»nr in a c.mceMr,ainn that cvmtRktrly hhrcks the re.ryut.r ar aMr
hncrKia nerve .Iruwlarinn has mr arwrhi.lamroic ef/ect.
SkrerRh. H. E, NuJrl, J. A.. Fahkwi, L. M, Sheppard. 1)., and I-Inttvman M).
AnNrn'On RI\YeM nJ Re.piratory I)isrose 1211.60)-6111t, 19111.
Other saherl: Naliruu111ear1, l.unR ard Bk+od Inslilule and the Frsons ('rxluwatiun
I ann the ('anlNwaKulaf Research Institute awt the 1)erartments arf Merlicine and
1'hy.whRy llmvenay ol Caldurma. San hrancrsco.
"rlMl: . ('UIIRSI. t)I AIRWAY IIYI9:RRY_SI'ONSIVIiN1:SS INUIH'1 1) NY
(//ONI IN Ixx;1
In thr Ixc.rnl .haly, IIK :WIIMKs ClanllnlYl the /utlC rrNn.r .,1 unUrc /rMluarrl
hyprrrc.l.wrsrvrrrs in anr.lhclvrJ Jrrgs. fo.Mi Ihic, they a..esrJ auway rc.per
srvrnrss Ithrrr nnwtr r.p.wrr anJ lhrtn at I h. I Jay, aml I wA allcr av.ur r~ryr.urc
'1'u a.x.% rr.ryMr.ivrtK.., the rr.rar.hrrm aaahrtvrd tha aMj% and aAM:urwd rb.r
rr.rywr.: .urvr% o/ uw',ra.iny aYnhY'nUa1Mom UI aCrtylClMrllnC aM hNlanmC :K9uW~I
Jrlrvrrrd t., t1K anway% vs Iwdmrutary rr.islanrc Owwrr caryrsurrs were a arrnd vut
wuh tIN rh-gs awal,r and at re.r m an rxryr.ure chauhcr law 2 h Mrathinr rrthrr thrrwqIr
thr mr.r aNl owouth at A level ul 2.21qrm aK tMawKh a arachrustrwny at a Irvrl id / II
Iqwn 1 ra h.t1h aactylal>.rhnr arwl hr.taminr aml l.w hrwh nMprs .d uirurr drlrvcry,
auway rrsl.ar.wa'rt s. uw rra.cd rmrN marArJly al I h ahrr umnr. inrrea.rd 1u a 1..xr
rk4rra 1 clay la/rr arwI rctunrd to CuMnd ItvrlN by I wL. lhr rrwlls arc >nndar la drr
authrws' IwcvHwr. sruJN. m human. thal .hnwcd Ihal uiamr inJurrJ hylrnr.ry.n.rrr
IK,,% 1hi Ur% \hIM11y aher eRryhurr anll ls rapidly revrhrhk anll sn'(,Kl'11 Ih:N IIn' u/, NN
rllc.l rs kn\eJ ru an aculr mllanunatory trspwr.c in the arrways.
Ilutrvnrm M I 1ahMi, L. M, SLr.rgh, Il.+_.., O'Hryne, 1'. M., Wakcr. li 11 ,
Avawa, 11 , anJ Nrwlrl, 1 A
`lrw.rwrl rrf AlqdrrJ /'Ar.~a~/uXr Rr.pirul. F.nrin.n. l:'.ert irr I'hraud. SS/.11 1212 /21h,
t9)! {.
(h6rr supPwf: NatinnallkaA, LWIR a1M1 RknM1lrlSlltule aMl lhl' 1'INNI] ('INIhMatnM
InMl the ('ara/NWa%cular Resrarth Inslilwe and the Ihlwlmcros ol MeJiainc and
I'hysudrryty, UnMVenlty ('alllorma, San Franc/.rn.
NI:UR AI. C'I )NTR(/l- OF AIR W AY SUHMUCY)SAI. C;LANI) SI:('RI?TIUN
Mapu aJvance% have ataurnvd reaen11y in the uruler.lanJinR arf the pnK-r..es uf
airway .r, rrtiun, due in large part 1o the aptdiraliwm arf nutkrn trehmyues rr1 anaaeny.
cell baakrry, physHdoRy, birKhemislry, anJ pharmnvrhrgy lbis rrl.ut mwr% that
airway.ubrnwo.al Rlaruls nttwpy a subxlanlial vrdume of Ihe large curuluclrng airways
and are regulated by vaXal mu.carinir nerves. alrtu- anJ helaadrrncrRir ncrves aml
mNlatktnerRK MMK'hnlirlerRll' rlefve%. Vagal nerYet IIMMkrIWC varirws rrfk.cs that
inr:rra.r K/anJ secreNors by stimulating teka.e af Rranuks Iraun nwcawa and srnw.
celas. StimulaleJ.ecretiwn are unaltered fnmr hasehne in hiwKhemiral anJ vr.rrw las-
tic pnrlrrrties. Ilela aJrencrRrc winwlalNrn reka". rwcreliars avuNamrnK rrlaivaly
little IIuiJ, high c.mcenlratiun.s nl pnNein anJ wllur. Mrw cruKrnlralNm. rrl lysniyme
arul hiKh.v vi.crrsily anJ f,rwer elaslici/y, nd selntively akrkle% rmrcnus cell.. Allrha-
aJrenrrKic .Innulalirrn causes high OuiJ /krws with hwr /udein and .ullur arwkrnua
/inn., hirh lywiymc c.rmrrNratinns and krw apparent vi.nhity, and scla.lrvrly rk
(+kle. Rrnwks Imm srnws cella IVrurarkenerKic muwlurlinerKi. nrrve. alvr arnw/.tr
muain .rrrclum, pnrAably by reksrnK vasn.ctive rntr.Unal prptiale
NeMGI, 1. A.
E.'wrrlrCUnlrwrwul nJRe.yrirodrrr Uixmse64(supp112111:).2126, 19N].
ptArr sr/Rerl: l/. S. Public Ikallh Service. Vkk IAvi.iaM Rescarch. Im ., am/ the
Fisoe. C.upwa/i«ur.
Fran /he Canlirrvasaular Resean h Inslitule anJ (kpartn,<rMs uf Medicine and ITysnd
ogy. Univer.ity rd Cahlemra. San francixu
49
8
NI IIK(11'1 1'11hL 1 YROSINI:INI'Y1 A NI WI.Y I)IS(OV1=.K1:1) I'I;I'I II)1: IS
1'RI'.11 N1 IN 1111: MAMMAI.IAN KI:SI'IKAI()RY IKA('I
N\un.frplilk lym.nk INI'Y1. a nrwly JivIwcrctt IwINhlr AIN.wn ht nNNhJ.Nc
hlurl vc..a1 J1.1nIClc1 nNl %nNMNh 11111,tk IINIC, ha\ 111Y'll I.NJ/NI in /llally n1:111111L11/J11
INF.In. Ih JLtnl.uh.Nl l. anldat k11h:N .d .ynlpalhctia lN rvc hlKt. anJ NI'Y nolnulwl
h.N Ilvlty 11.111pY'11 I.NIIhI 1/1 n1N:NIfCnI'r/,'k /,'anFINNI aY'II\ III a%IWIy r.I IIN'
rl'\)nr:/1.Ny
tt.a 14.1 I.Nn rlcmhnallrn yalk. -- nun. a al. pu/rlta ply. anJ lat - - NI'Y /nuna/MNC:K
hvNy han hlrn h.allird h.IKrvc Itlkr.. NI'Y nIMN/n/NC:N I/VC IICrvC tlhl'1% Nl1l' LN1MI
In dk :NlvrlthhI .d hH N N) vc.x1% and /n Ihc airway .nN.Nh 1/luvic II\ JI\IftLu NNI wa,
.t1/AuqIy \IIIIII:11 1.. Illal al/ %y1111R111k1/\' Ilerve tlhcr] a% 1k/1MNl~tf:lllYl by
Ih.(.:h1111K It
Ibvdr.nyl,l.a anhh..bc. 111r nMan (SI)) a.1NIl'CMra1NN1% u1 NI'Y in 111c )uun:1 p/)!
Ic.pu.ll.Ny IIJa1, a, Ih'h'fnlln\J by raMINN/1N//1nN41%Vy III 11\\NC l'xtraCtl, wlf: 111.ih'r
ILhIN:1 I I tt) 71. Inw\'t trallh':1 211 II) Sl, ,I/NI In:It1N M.NkM1\ 1 S II I) 111111.I11!,
Ihuln)- dkvcl.qlnknla/ .lu.la.ln man, NI'Y InlnwdN\a.hvc mrve hfwr..vr/. hr.l
1.11N'/vt'1l.11 ?I'wl'\'la\
)'t,IJINNt/ItIIICItatlk'A,:IrIlII/N.r\)'I,hI1l.lllyl'atCIMkJJ.w11/111.1
dw ulu.ynllnNN/rry a.rw,ly% altrt hltlh NI'Y 1n1tINIMNI'.Nll-w IN'tvC Idkt h.1vc a
II/~I//h11h.N1 d/NI111'V\'LhNIwnl:d p.Nlcnl.uoJ.n luthal ot %yulp.lthl'llc nctvc tlhrl%Iu Ihr
h.pnrhwy h,N 1 I lk hlwlmpnl NI'Y numurwNcactpvlly in /klvc hlkr. in IIIC nlrlnma
II,u1 rc.pa..t.Ny ttIt t,wl.lI lu dk' rn.wlng nnnlFtr nl Itplkk% havinl: LNCnt hlol.y'k J1
:N I/INI% LNI/NI //1 tll/% IN 1,1/1. an1l %I11.w, IhN (IN' Iung INI~µ~K\ a tll"h
IllINIII\rF kly,h/11
Ill.ll llldy /IIIIIN'IkC IM11/1MMIJty /IIIh11NNl
tiho'IM'rIJ, M N,/'nlu4. I M, A11.n. I M anJ HLwml, S R
//t. N.11 1') 1211 1111 1')Kd
1n.u1Ok I A're1mN hn ul 1 h.l.. 1>.,nl.u y.Ind Mcda nr . Kuy.11 1'n.1E r.Nlu.dr Mr~h\ .11
S1IN11.I, IL/IIIIIM't~11111I1 IL..pn.J. I n.M1~Nr, I N,rl.hwl
I W( ) 1'Kt 111 INASI: INI111111/)KS Ati\()('IA1 II ) W 1111 I'1:K1 I uN1:Al
M A( KI )1'11 Al ;L.S
Ill lhlv %ItNIV. t)k' I/lvavlgatnrv A" vnKnl :InJ \harallcrvc /wu flr.NClnav ndnhi-
llNc awt /aliJ wllh F wllra pIK pafi1NN1Ca1 nrk nqlha~c.. KcwN. rhuw IhN InluhuaN/ i.
ah..c IklnnJc/N, lu.l IN1 hCat1111C 7UN) Jl'1lY"IIYI in IIK fNCMn\C /1/ C111'C%% :Ilhullllll ( ht
In\U11:NNN1 Id nl:lauq4s:lyc eullute nkvliuln wnh ''I e1a.la.c, twn canuplc.c% ol
M 711.111111 and rd1 InMI are Rcl/rra1CJ whiah arc .1ahk lu IIca11ng in v.hunl dkk.'yl
\Illlal\'. I/NIh.Nlllg 1.1va119N a%VqYIINN1 '"I rryfhl/l hN111\ lwn t'IN1111k1Cs III wlltlar
I1klklul:U wC1F'M, a1NI af11N%-InI11ININNI cst)M't1//Nnl% ah'IIMNlllfallJ Ihat l'I:I%la4' :I/NI
hypan /n/cr:Nt wdll llk .wIM Iw1- nl1\'rl.llhIl!C udnhihN. 1'IN CINIIIIatINNI, CI:Nta.a
111I1th1/1Nl in Kl/lln:1 INI,' Illa,llla anJ t'eII (h'C fkY/1/Nhi1) II11/1I wCrl
alvla'1a1/11MJ In
.u/nmaly, tIK InhdnhN wh/.h LNnI. 11k' M hA /MM1 clNnpkst w11h "I cl./.lr.c 11.1%
hrcn Icat.Nivcly na111cJ Ml'I (Inal hy111aLV' IN.N\'111dw 111I11h11.N1 MIM \' 111 ht IIIN /InCJ
Ircc .o u,1'1 hy \ IJln/lnp nucn/pha~c. f/N 1 h u,l'1 1% rclra.cJ Intu 1hc nwJ/u.n thlnng
thc 1.1 Il III .ultllte a/1J 111crCahcr 1% rN1 hN1I,'cr Jetcllahk INI Int:Ili nlatn.I.haF'c.. in
whvvpkIN a Nlhlrc n/cJla aN in \cil iyvtc. l hc.c hmhn~. vuKyc.t thal plLma a,l'1 1.
IIrcV nl in 111'1/11NIC:1/ lll/lll in htl,'II l.Nll'cnlrall/M% a/Nt /% ahMNhCJ INNII IN /INII nt:N
In
Iduyc. MI'1. I.n Iha INhcr hanJ. al+l+lar. tu hc a ma./.qduKc p/N/wl. .Inrc it 1.
v, n'1cJ by InN hyAlare..tlef 1.N 1) h In \ IJrluc aIwl 1. (Navnl In Iy.:NC\ ul n1:N h1
ph.q1 . INa. NhorcJ /.r I rN 17 h
N.n1.dJ (1'I)r.nnrll, IF and Itwatklrtl.kt. K.
1 hr l.Nnn.J .rf Ifinl..Cn ul ('Irr.nrlrrv 25R(5)- 1?51 - 1257, 14111.
(PIbcr trppnrt: NatNlnrl ('ukcr In.tilulc.
I LNn thr ('clncr IIN ISlrwnl Kc.car.h and Ihr IhpallnKnl UI Hhlllr)[1CJI (hl'11/1%Iry.
II.IIV,IrJ MClI1CJI SllNM/I, ItU"ItN/
NI.tI1Kt)I'llll.ti ANI)'lIll: AINtLT RI:.SI'IKAT(/KY 1)Itil'KIiSS tiYNI)K()M1.
(In. p:qxr rcvlcw% thc IwNcnllal nIk ut rlrNlraq111d% a1N1 their INI~Itn1. Irl du
I.:I/IN.Fa'rk'~h Id llk :kutC Iwlr /npny Char:kICr/.tk /N :Nhdt IC.I+ir:n.Ny JLIJC.. .vn
Jh.nh /AK11S/ NI uu1q111d. a:/n a'I /INNa1C O. JCIIVCJ (Ir/k11ky~, ININII.Iy1N' anwtllw.
:NNI .NM I1hhN/,111 INIMIIN 1\. Ilk'V N1MIanCC\ havl' Jr:N11:NN' a'IIl\'t\ /NI
C11fIC1111N'111.1I
hln) INC).Jr./111N/% I IK uhK/vpIhNllllat 1kY/t11M11t/I% al'a11/1N/I.NC In llk hln)'. ut AKI /S
11,11/l9N\ y1.Ilil ah':1/, 11111 IIII\ /Inah//l,' /\ 1,hvNN1\Iy INN 1mltk' IIN (N JIJr/N.UhInt
AKI1` 'I hlNIINC, all%INIC (hC ENl'K/k'C 1/I I11111MIaIIy Ilqtk' Ilaulraqllul% ln Ilk
lurlyl
ul
(IN'V' 14NK111%, Ill\ 4IlY'Itla' r11k, II :/ny, ul tkulnM>tuh In cl/nlcal ARI)\ Icluaio. NI
lr
/knrm.h.NrJ Whllr h:1.N; IIIKYva1NN1w, nw%1 CIN111/n/C 1/t be: t11:Nh in a'etI49111NnL1i
i nNhkl.. an ayN:d CII/N1 1\ Ik'l'JIYI In t/l'tCrnl/fN.' i/ rnika/ulcnlal oKa /1:1u/.u1% ul
Inult
injury h:wc :my rr1alNln.hip hr Ihr I+aUNhlhy.Nlhlry ad cnuc.Jty dl ARI IS palirnt.
( hdy whcn Ih/. IinA i% cnnvinain'ly n>+Ile a'an INk hgm lu Iran.lalc cslN'rulkvNd
111hhn1'\ Inhl t IInN'aI tIKtINNI\ IIN Ihal,'d1\/\ and tlkYary. It 1\ a'/NK'a'Iv:Ihtl' thN .u1uM
111:11111N1Ia1NN1 1/1 naultnllhll hl'IUN'NN 1YN111I IavlNahly aIIC\'( IIK II:IIh11/111y%N1I1Ty hI
ARI)S
11111 h1YaUlC IIIII:IIIN11711NMI I~M/ IMt/l/allIy InW11YlYI l/l lhl' /MN111:I) (M/t-l'~~l~hI
IN..t rklcnv alNl 1i..uc In)Ury a1Nf h'11a1r Ihlrall\t1/N' I/llcrva'ntNN1l Ih,N allccl Ilk
In11.InN1/:NrNy cav':Nk l'IN1W hL' JIIUhkCJ~'lYl ~WINII~ aMl \INNIIJ tN1Iy hC \IINlkII //1 tlk'
/IIINI l'arlII/I Ia%hhtll ( iivcn the trcyllcm'y snJ klhalNy ul AR11S. the cn.10/ c/NNhN I-
iny .ut h atklK. .ccnl. Iu.tdicJ.
Talc, K M alNl Rr/rim, /. E.
Arnr.n aa R.rerN ~r/ Na .pirnra.l v I)r.ru.r 12N: tt? tS4, 14N 1.
Utber srpplwt: NateNlal In.utuk. uf Hcalth, AIIMtIt'an IIC:111 A\Mk'1:11h1n III Wyll
nnng, and 11k Kuk' tldl, tiwan, anJ Kkharg IIN/INI:NNM\
I'1/N11 tha' 111vIVIN1 lUt I'UII1NNIary Sala'IK\% a/NI tha I)a'(I:,fl/lk'nl ut (/llar11aI
M\'JI\ I/k',
IIN/vcr.lly 111 ('au4NaJu Ilcallh tia'iclk'c.(cntcr, Iknvct.
MA(K(/1'l1A(:I:I:Ili.('f()K IlIN('11(1N IN PIII.Ml1NARY ()XYG/.N
1OXK//Y. IIYI'I K(/X1A hAMAl:1i\ AN1) ti11M111.KI1:S Al VI:tN AK
MA('KI/I'IIA(il:S I(1 MAKI. ANI1 KI1.I:ASIt (IIIiMI)I AXINS 1014
P1/1.YM(1K1'IIIINU(LIiAK I.1:11K()(Ylla
Macr/11111ayc..yn/ha.iie nwny .ccrr(rwy INrNhw1% in vin.r INN Ihc.t111wl1 t/N tIN'u
fNakltk'INMI JIkI thl'Ir 11:nIM/11hy~N1111~N' \IRnlhl'.YIK'C nI lYN/ a1C Iaf~'t'Iy U//t1/N/Wn 1n
t1N
prr.cnl invcairalilln, lhc authlN. flwnJ Ihal hypcnl~la tlalnaRcJ /ahhit alvcuLn /n:h h.
phagcc IAMI fn 1irrr, a% nlandc.laJ by akcrca.eJ rel) nulnhcr., Irnfra.aA I.Lt,uc
.khyJnlpena.c rekav, a1M) Ihe rkvchqNllenl u/ ullra.IrucUual ahmNlnahl/c. Ihat rc
xlNhkJ dhr.c acn in AM /n rm.N lav.K.J Ih1/n luni! Id rahhnd c1lpr.cJ h, hyL*r.../.1
sl, 1 51
i
r./ rrr1. Ilyltn/ua alwr .IlmulalrJ ruluacd rahhn AM tu rrka.r ahrnaMJUn% hK
Irdyn«.ry,l«m~a ka. kuk/Nylr. 1/'MN1 1hJ1 wrrr aundar In na/kaular wrlkhl lu a hr-
naqA.m. r".unrd Iron1 luny /avalr% nf rahhN calavd 1et hyttruaia /n rnv.. 'Ihc.c
rr.ull..uF1 r.l /hat Jlvc.rlar mx'rry4ugr.rarcUNy turrhN 1% may play a Phy.adul;iaauy
rrlrv.rnl r.dr m rrarullnleM /// 1'MN NI Ihr luny. in plda«mJry o.yKrn Ioaa:ny
I IJr.ala. K N Vatler. A t: and Rrl.iner, ! f'.
/.nnrnul.4 I.rufa r1r lfiol.rKv 1S:J71-18t, 1994.
Othrr au00nr(: AnNriran Itr:rt A.viaialinn, AnllII(all I.IIn(,' A1Nq1a1aN1, NatNNIJI
In.ldulr. ul I Irahh, anll thr Krnr, Ilill, Swan Jral Kklnly FnundJ1Nrn.
I'r.Nntla Wchh WarinKl.unKlnVilulearafthrPuln«maryhrvi.amullhrllulver.ilyul
('/d.Na.M/ IlrJlth Sc/cnar. ('rnler, /knvcr
IN1A("r 1111MAN UKYTItR/K'Yl1.S 1'KI:VI;NT t1Yl)R(X:I:N
1'1 K(1XIl)1 MI.t)IAI1:1)1)AMA(:I:l//1S()LAfH) 1'I:RIlIS1:11RA1 1.IIN(:S
ANt) ('111.11IR111 N(IVINIi PIt1.M1)NARY ARII'RY IiNIX)Il11iI./AL ('11.I.S
Alu1r rlknlaNNr. 1unK uqury. .uah a Iha/ vrn in Ihr aJull rr.(NraNNy d1.lrrc.
.ymhemir 1ARI)ti/. 1% an urq.wlaM lIm1.JI rrrd+km whlnr palhl.fdly.a4.9y 1. pawty
.61nw-.1 Ihqwrvrr, rr.crN r«knar .uKKa.1. Ihal tuua .I,yrrn mcla(wdnc. /Ilay alN1-
trdwlr tu:n.w.dhl IrJI lrll +nlwy aal xutr rrkuul,no.lunK injury In Ihl..lucly, alhh-
lwn ul unlrralrJ lw ylutarJl.l.-hydr tharJ huuun erylhnwyte% lk.rcJVd hyJa.Mrn
la'/nu~A 1114 1 / nNdha1rJ at utr rJrrual.ou injury rn ivJalcJ ral IunP. 110 nNlwrd
J.un.qr 1ts .IdlurcJ t..vrnr Iwlrl«roary Jrtcry c/ahNINIIJI 1r11., and 111), drtwmkM
uard..IBmulrrJINrdtylrahrlane('urlrrru KN('.aJvcnFmyol11/1,aly.eJreJWhr
IkIt'r«knl rrr /IIIIhrlllltar gtu1JIMwra J/RIr11r aJIJIa.e altlvllN'\ the rr.u11% auyg..1
d1AI Inlal crylhaRy/r% can vJVrnKr 11,11, aral. a% a/c.utl. Paqral Ihe lung and
lun.rhly rNIN/ b..ur. (nMl IIa/11AKa'
'Irwh, K M.('IclhNd. U P.. IkrFcr 1: M, Whne. C. W.. arNl R.pinr. / F.
Jhwrn.d r4 ( 7rna al lnrr.r(rR.nurn 74 292 295. 1VN4
(PIhrr su/port: Nalimal Inaitule. u1 Ikalth, Anlrrican Ilean Awu-ialeln Amrriran
1 ung A.wKi:NNNI anll Ihe Swan. 11111, KlchrrK, and K. 1 Rry/Nrld. FnundalNmr.
1nNn thr I)rpanmeMa n( MrJicine and t'rdialria., anJ the Wchh Waring LunK Inui-
tulr. t)n/vrraty lll Cllhxadll Medical Cenlel, 1)enver.
I1XY(iFN MI-.TAH(N.ITI:S STIMt/1.AT1:T11R()MIK)XANI: PR()1)ll(TI(1N
ANI) VAS(K'//NS'IRI('1IUN IN IS(K.AIY.I) SAI.INI: IM:KI USI.1) KAISt11('
1.l/N(iS
(icrKralNlr111f Raehve llltygen rne/ahnhle.%. 1hr/NnlMlRarlc Increafe% a/111 vaM1a'lNl-
arNlw/n havc hcen inlPlicoled m the ps1hwigene.ie /4 aaule elknuNu.lunK injury. suah
a. that vtcn in Pahenlr with the Adult Re.PirauNy, 1)i.lre.. SynJaunc /AKI)S/. hu1
drclr /ntrlJ.la.n, arc unknnwn 7llc mve.tiRahN% hyprlhe.iied that real uve (1. PnNI-
w t% wordd .I.rnutMe .ra tN.Gma r a1 mrtatwdr.nl in IunR% and that vaWoartave pr/«)
a, 1. ..1 err h..l.wul. aa h a. Ihr IrwYa) vJ.4w em%lnclrw /hnnnh.vSarK A,. might then
,
/IIr/I/Jle () . I11etJIMlhla'-InduaY'd (NIIIINNIary vaflKlMl%irN'INM1. Illty hNIMI IhJI (),
nktaluDlnrc Kcnrralcd by injcatilNl n( IN/rinr p/ua sanlhinc urtida.e cau.cd /rlr/ra.ck
m
nr an PolnaNlary anrry perluciwNllwea..un:127! 41Nm11K) in i.wdatcd Pcr/u.cJ lunl;. In
a,h/namn rylnnr plu% tanlhine oada.e al.ncall.ed MI luld uNrea.c. m Prrlu.alr Irvel.
u( IhuN111alRanr 11.I/he aahle n1aMalNAile ui 1hnlnlbusane A,11:INn(urcd with /Ndy Iwu
luhl lm rra.r% in A krlo-l'(iF, Ithe Nabk rnelabulile 11( /aa!uarylin). MlNrovcr. INNN
arkhti.m t d calalJ.r nlhiMled INah vawKOnarw'IwNI arNl the Ihnnalrl.anc It. Irn.dlN IaN1
xrn nl Iw.tJlyd hlny. Iulh/winK mjttyaNlbf INnine Plus saMhlne uaNla.r. SNndarly.
I1rCtrralullrnt wlth ay.11NIRyrcnaae inhlMan\, aMhlr a.l+irm nr IINhNrlrlhxnl. JINr
arNnplrlrly hh«krJ IhreNalN/tane RerN!ra1Nm anJ m.rkrdly attenuated Ixc.WN rr
.tuNlv% u.uJlly an a11rr (N/line Plu% taMhine u.illa.e- FurlhcrnNlrc imldarnlc. a
IhnNnha> anc.yMlklJ.e inhllNhr,atwakrrea.enl(); urclalNllile i/NHN'ed Iht/NnMraJOe
/.'l'nrlalaNl alld vJN4'1NNIrN'INM. lheve reN/Ih Wgge%lyd 111a11hrIN1/IrllalN: 1,'cnl'IJINNI
m/l'IN L.Nlil rpalr /N (). -NLYatN4Mr-inJuard vaMIlYN1.Iria/1n/1. 11/Iwcvrr, .IrNY a.rKnl
lit an1 aNtrlalaNllrHwrcn IhnNnMlstane kvel% arNl Ihe dr6ree l1( vs.aK'/N1.IrialaNl l/1uW
md hr lkna/n.Ir.qrd. and.i/Ne add'llinn 11(.uprn/itNk dl.nwla.e rrlhN'rd IhlrNal«.a
ask l' hul dNI nId aILvY the /Men%Ny nt vaMKrNl.InrtNN1, it it, pls.ihk Ihal lhrulolw~aanr
1% mN Ihr /N11y vJ.rv.N-/ive rlkJiaaN in Ihis nN«kl lbe te.earahrr% alNNiak Ihu
raju r.ml lung.ln (). nw IalNdne. resull.ln thnNnlNlaanr Rencralaln anJ that Ihnanhw, arlr N
a/IIarN a1rdlJlnl /ll n1lN1aM-IMhll'e11 va%4KIN1.irK'/NNI
Talr. K M . Mnni. ff. (i., Sa'hneeder, W. R. and Rrpinr, ! li.
lrnrnul /q (hnrrnl lnrtlnKuri.N174 AIN4-AI1, 1994.
(Other supprn: Anlrriran licart AsMrialiun ld WyominR, Nalnrnal In.lululr. ut
1lrahh alNl the Swan. Hltl, KkherR, Rnche, ThnNnMand% anJ I'rootNN and (ia/nbk
I'INIMIa1NN1\.
1nNO Webb Waring Lung Inz/NUk, anJ I)ep+rt/neM% u( Mr/licinc and Pcd/atra.,
l/nlvcr.ay al ('nhxaJu Ilealth 5tience Cenler, I)cnvrr.
HR(1N('111AI. I AVAGf: IMt()TIi1NS AS C(NtR1:LAT1:S (*
111S'fIN'ATtN)I.(x;K' AIRWAY (l1AN(aiti IN IIIiA1.T/1Y SM()KI:KS ANI)
1'Al'II:NTS WIl'11 P111.M()NARY CAR(1NUMA
('Igarrne .nadeinK i% known hr be an inlpnlanl elinhlKic laaIrw in .rvcr-.d lung
di.ca.e.: IN/wcver. the numher a/ snNrken whn akvehq (he.c dl.ea.e% rrprrvM% a
.alall .cKmcM u( the .IrNrkins pM+utaliun. 11 is prssihle that evidrnre ld rnhalalaal.
indlNaYl inlury In INrNkhial ePNhelial cell% o( snN*en will be rellrcle.l in /hr prwrins-
ce/w.1+nNhN /x uf Ihe.e aYlls, lhereby wktiwifyinle a hiRh-(i.k w1+KnNp+ 1 he invr.llKa-
INNI. have 1r.IrJ /hi% hyfaMhe%i% by analy.is nl 2 pnNrlnc, free .crrehrcy r.NnpNKnl
/1S('/ a/N11hr krralm., in lavage IIYNIS rr111a//led IflM1 4 RnN11N UI fuhlea'1.. t111aN111J)
INNLIIaIka'rS. IS a\y/111N1N11a1K .1rrNlkCrt, 22 \yln(It/Nna1N' \/INlker\ a1Nt 4/1 l'arl nNn11J
(1:1111'n1 AIINNII,` \ynl(MINIIailIC ]nN/kerY, I-SC relallve 111 Aolal jrr/MaIn (11C/ 11'1 wJ%
deprr..nl nN1111.red with that il Mln.nwken and asym(NlNlwlN' snNrkera ( hc krrat/n.
were drteclrJ /N1ty in aynllNrNnatic cnNd,cn and cnrrelaled wilh r:w k/yrar. al .nark
ing h1.NN'y IP = 11017). ('an:inrNna p:Mien1t had defNeaed F1(Y Il aral d.Naahk
kerann 1114 lK pJlieMa .ludiedl. LunR .ea'1iwN1. (nNn ca/aiaNna pallrMa .IwIN-d
imrnunuhi.Nnhcmically revealed an a11(Lrrnl inverse retalinnahrp hclwrcn Il..ur I S('
anllkerNm, lL/.mver.e/rlali+Nl.hipwasA.rnelNNhyanalysi.n/lhc.rpr. Neln.lNlhe
I
11
Lrv,lEr IIIOJ al r.lrkrr palicnl. It =-111 p = 110d/ Ihu. in calNCr pallrnt.
unnnm.duvtthrnl/aal cvNknae Id airway inlury r1.nrLnr% wllh MlNlchl.d lavaKr Icv
a/I t.I mut t..al rpnlwH,d uII prl./cin. U 1. (Nl.ahk Ihal.rtNd rr. wdh IhrrcJ kvrl. ol
11N.c Iwlaa/n. Inay tr the /NIC.:N /nrrca.eJ n.k /11 %nwdln} am.NaalalI HI/tE dl.tav.
Mrnlll. W W IIirwNk. K W. MaJri 1 Slnlhtt W Mallhay. R A.O1
.IN.w.kd. 1. N.Nyrl. l: . a1N1 Rrlrr.dJ., ll. Y.
.lnrrlrn url R.'IrrN ../ R..yur.trarv I)t.rav IMMS/:y1/S W)4 I')IW
Othrr \Yppdr1: Na1NN1aI IIaarl tAnl,' aRIJ tllralNl IlNt/lull' anJ Illr AuKraau (a1Nrr
%tla raty
I r.Nrl tlx Pulnwm.ny tic. rnNl. Ikp.N1nNn( /d MrJKirlc. Vclrran. AJunui.n.lu.Nl McJ
N al CtInrr. Wr.l I l.lvt'n. Iha I'u1rINNl./ry %a't tMN1.1)epunnN1a td MrJlauM a1Nl I
kp.ln
oNnt nl 1.IflNdnpy, Y.IIa' Ilnlvaraly \aIMNd ut M.d/.uK. Ncw Ili vcn 11, a1Nl Illr
I IInN.J (nmunadtq ySr.tNNl. NrINN1.J Ca/l<'rr (n.l/lulr. Itr11wa1:1 MI)
I I/1\IIN /Mt(ll)11('th)N IIY ('lIL1`11KI 1)(AI 1 P111.M/)NARY AR f1 RY
I:NIN)IIII I IAI. (1 1 1N
lllr qhrlaut.n 1o1 rlNhwlNhuwln hl rl.l.ut htsr. in Lul'r :trll'llce ami nl Ihc F.1%
ruh:InFc rryNm. t.l t)x IunF .uE'r.t. 111.11 .'INhqhrhrl ttII. havr UN t.q..Nlly h/
.yntlw.vr rla.tlN, lhc IrNrl:r.ll 1 tN11(t.NKnl /I IIN' 1'I.I%l/t blrl lll lh/% IrINN1. 111a
a/11INN
.IN/w 111.11 rakwlNrhal..IL L.ddlClt IhNll t.1111N/I/1NNLIfy d/It'ly \y1/IhC\I/r I1111N.a'Id\I111
u1Nk 1.qMNtMxI /lr t Idnur uNIJdi/N1. I IIN wp~ Ik'IINNI\Ih1IC.I l.y I,NtN.alunun..r..ay l/N
M1lhh/a'r/.l\I111 by 111111111614 .pn111NIdIhN1t.1 .I /n1% N'I.1,11/1 hka' ININIuII I/tNllll'II
a'llhl/la'
nltJa/nl. arNl hy IomnNNlfllnNrarnl nlNl..vtM.y ut111nnF :Inl/a'l.l.un 1r1: Hr.ult%
lahcalr Ih.n rnJtAhtH.J rrll IwqNlclr.hn .IN/w% uuny .aoulrrUlr% with InqNrla.lrll
.ymhr.vrJ by o11N:r INWIna' lrI1 lyrt'% InIIUMhnl' l'tN111Fra1nN1 tNln SI)ti I'AGIi wtt11
InyNt la.tln HtNn tdwllhla.l. cMNrlnlhla.l. arNl.nwNNh mu.ck arllc a. aInKk ahaln
/NlNrin wnh an alirarrnl nNllcrul:a wriKhl .11 all(Irnnin.alrly 711,(NM/ In athlltN/n. the
cn/.. rcaaiivny tll IrnqNacla.lin. tnNn cn111Nhclial rcll., %11uNNh mu.rk .'cII% arNl car
aMNNHnhla1. with auliacrurn lu IaganlrM cla.lin i1lJlralcv rHrvc hlNtNlh/yy lwlwcrn
(KIn61ry rla-4/n rcrlr ININHM'1\ ir11/1e vafMNla ela\Iln-]CYfelinll fl'II (Y11eS. 1IN'%l flNIII\
hrlrvuk rlNllpcllm~ evitktxc that a'ullutaJ Mrvi/le arMa cnttiwtNhal acll% prlNhlrc r la.
Un whcn aullunv/ in nlcJium rlNnl/uNNIrJ by .nhNllh nrov'k rrll. awl .uyKr.l a
IN/.ahla rt/k ttN .nNNah /llurak ar11. /n IIk rcKulalNN1 nl cleI/n pnN1u.INm hy r/Nk.
IINh.J ar11.
0%
tr Mraharn. K 1' . Matlara.. 1.. M.1)tlnaW. I A and Rwrn 1)
r
t9
lauwnul.{ ('rllNtnr Ilhvvlll..xv IlA 2R2-2111(
14113.
t9
h
II
11
hli
lhh
Ilr
S P
()thlr aY/1p/Ur' AlnrrN.In IICJA A\V\IatNNI. I
:rlc.
MI\MN/rl A . :
u
c
J
an
(J t1't*Nt' .NNIItN' A1/N/NI111IcJn A\VNI.IINN1
Il..m d W.hmlLN/ I/nlvrr.Ny %.INNd
u/
MrJNUr .1 Illr
/~ u.1. 1111 1 ..1 \I 1..n uI /IN I A I.NInN nl d MidN nN'. I/n/vclVly .A
h161/11/.
Ml.nu. 11
1'NIX )1111 I.IAL (I:I.1S ANI) INFLAMMATION
lln% rcvirw nl cntLllhclul arll% anti intl;nnnlalian hN:u.c. Ilrinlanly nn rr.cart h
Ii1NItnF. anar 1979. hby whlfh IInIC a'l11Y/] nI Int1a11U11a1NN1/N11Iq' INIIIINNI:ny v:1%a ul:llhlrr
wrrr rrca/rni/cal .1. rt Nlttihulml! (tu IIIC H/rn1a1/1N1 rll a I+nNCin- arNl fr 11 1/)
h INrIn1Un,lry aJrma iluNl ( hl IIN haa% ul nNNr ra1'rM aalic., nlvc.lip7NtY\ arl' rNlw in a
phlUtNl tu t1N1Vtk'r Ih:11 wha/ h:1111kM lO (11l rlNk11t1a'11u/11 a\ i11N\II' ItN' IU
rINhN1MHLl
lrll\ IINYIIN I Vl'%I th'ry'/Nl% III Iflrl /N/ active ra':Il INNI 11r /r1111ry .I11\ rr%plNl\r
t1/ lnlh Nhe Inlnl 1.. Inluly vrry Hkrly atl'a'1lYalr% vaN'utdr Iloxtu%NN1 in (ha %INUI 1lr/n
tNll Ill:/y
pruvuk a La.1% llw rrpair :InJ rr.111u1itN1 0l vaxular Janla(.r Ilt the tiMt. Icnll. III a
V CINNI /NI IlhJI:AIN\ t1I Illr rr1/1:U11n1a111ry hrllea<% alla./NNNI la 1.9va'n IKrr (u:
411 CU/11-
I/k'Irlt//I t INIpNNN'l1I\/;M:/Ithyl:lltlRln~; (2) rINhNIK hlln/ a/NI /IIaa11va1NN1 rll Iha'
an:11111y-
l./lo.m..l II ta11N/aytxyN1.4/v N pl r'MMNIMIaJI Cl'II~: I~/ Iu~N tlay/,cn ININhNI~: IS)
I.Illa'r nNd/.N. N.. :nNl l l.l nN.ka al.rr :IINI MIt1a'rII11Iar tr%)NNI1f\ IrI l'INIu11Nf I1111/1
048 1111111 y
Ilu/l.lulr .N/ lln% 111.nr1/.ll. J IIY/NMtn%N /% INCyY11rJ wI1Nh Jral\ wllh IIN' ]tt11N.IKt'
461
rva'l/l\ M1 1/t /IN./NNI wlN'll a V'n%lh/aJ a/1//11aI raaaWl% IlNravrINN1\ .I/N1rCn
W1u1r
nYl/:nk:ahlr IN'll)raN ha% ha'an Il/a1k 1/1 WMkr\IanJlng 1/l aYllUlar \lrlh'aIlalt:If a/Nl
nN.lty Ia1:U nla'fl/anl\/Il4 tl) cnllullla'lial tnjury a1U1 rr./NNIM\ /tl /Iltury, it aNNiu% a
l/l:nn
uvrwll. that aa'ulr Inllanml:ItNN1 w1II /hN 11l' 1MIICf%lU1NI /n irn/h llI a\Inl!It a1N'atlallN
a111rr1eJiahN. I.1kru t1/ffitll'/, tN I+lalcll'1.. nCUlnlhlld. U1:nnlllha(!r.. /N t9Nh.r1Nt/:d
.rli% takrn aHNN K:alwr ulywuvrJ ualcr.la/Nllr11; wJl Irkaly c.N/lr I//lnl .Ir:url
IlaI/IIIINNN tlt IN/w pII IIKK l'INIIprNIanl\ arNl CrIINIar l'h/lll'IM% ilNrraat w/lh dN
IINII/nl!
.Inoull/. nNI Ihrn wnh rarh INhcr
Rtmt. I) S arNl Nyan. I W.
(Irnl. a rn l alrNtu.rr t )Wr.lu tra 1(11:577 Syq, 141(1.
()thrr.upwrrl: II- S PuhIN; Ileallh ticrviac.
1'r/Nn 11n Ikpartullanl 1/( MaJw-trlr llnivcr.ity Ilf Miami. Miami I1..
(III:I1/NIiO1- 1'll/ MONARY I:NIX)1IIIi1.lAI.CI:I.IS ON
MI(k(XAKk11:N IN:AI)S
11n..halNar nvicw. IIN Irahniyua% availalrk liw Ihr i.,d:u/.ln a1N1 .nhurr n1
p11nNNl:uy clNMllllclial crll% arul 1hc navJ anJ nlcans lilr oNNlilrlrulg Illa yuality 411 dN
crll. IhtlN/gh .ura'e.avc pa..age.. (uhure naIhINI% ran hr Jivalyd Inlu 11NLa uang
eniynlr% arNl llNr.r whith awNJ eltpll.wc of a'r11c tu cnrytnes at Mwh the i.IdalNNl arp
atNl JurmE .ult-ullurr. lllr IlNOll:r are hy anJ large rlN/linc, wh/la the laurr arc .lill at
Illc rk vaAIINtwnt .lagr FNN INC.rrN ncw vi.1a. Nr Ilc csphNeJ Illc rniyn/alla' rllaIlNNI%
illaiuk : 11) LtJI/NN\ //1 aINIINIk'IIaI ar1I\ InN111N1I/MNWry :Irlery by a'l/I1:1prnaY'
IIIFy\-
IuNI. I:/ l..datnNl n/ IN/luwNl./ry u/ianlvavulx cntLN/nliunl by alnlfr,nk Ir/lrlawl
w11h rnll.ll'l'l1aV: J/NI I lI (1111ut1 aMl V/ha"UIIWr III IIuINNNlary a'/NIta1M'I/dI r rll%
11%111(j
Irylr.in/1.1)tA hN h.L.aE1nK (M1/1N IMhet halld the rt1e11NIJ% av.nJ/ng rap/.un In
pnNaIllylK cnry1.K% ina-Imk. l ll Maa'Mnil:al lurvca ul (N/tnNNlary artrry c/Nhalirluuo.
1211a/1a1itN1 t/l rnJlNhchunl/nNll lhc cnall veoowla r/l Wc IunK% by IrCr/u.nN1 wnh ar1i.1
.ahrlc anJ uliarlrarrirn ccwJ.: antl ()) Mrcncarricr rrlhurr.: (.INIK knn IuFr .aaA
auhurc nl INdnNNlary erNMNhaliunl avuiJinR eapraurc hl rn/ynlc. Jur/nK p...aK/ny
1lcvllwa n1e11uNh hN auhurc nl INIInNNUry enJtNhehal cell% have yKttkJ an alwn
d.rlce /rl I/xlul tl.sla. paluk ul.rly in hcllllrq(/11 rtNdirn/ the rlde ul the c/N11N1Nl/ur/u In
11k INrhINNl.ry pt.N'e.a1rlF o1 vawaelrvr +uMlarNr Now in a11JnNN. tu tlr n IA.vN.u.
atlvan/agex, (lar~c nomtNr u( arll. cctNNNny ul mcdia and ut per.INlncl), Ina nla an/rr
-1t
14
Ix:at culturc. m.y alb/w rexatchcr% to .IuJy Pnq+erties which Jn raa .urvive hing
IrrilKh ul culturc aml w!tuhure mvulvlnl; c.ryre ure lo PnMculylw' cniynK. and tn
.tuJy .uMlc p11y\a1h1g1c naldulataal\ Uf IIIIel,'ral nlemhrane CUn1lMalrnt\ anJ \Il)hlttlt-
lurc..u.h a% cavrulx
Rwrn. U S
In lallc. 1: A tcJ ) 8ir.brRv rtf the I:roGrncrliul ('cll, '111c Nctherland.. Martino.
NI)h.dl 111114. thap 4. pp l4-SO
Other sr/Iprrrt: Nanuaal Inaitutes n( Neallh
fnan Ihc Ikpartnrnt ut MeJicirle, llnivcr.ity of Mlami S\Iwad of Mcdl:lnc. Mwmi.
I1.
1RY1'SIN INI)li('1 1) A(:(:RF(;A11(1N (1F NOV1NF. 1't11.M(INARY ARI1.RY
I NI tt) I 11I.1.1/11. ('UI.Tt/R1;U ()N MIC'RUCARKII:RS
1he aullwa% o( thi% paper Sludied aJhcrcnce between "luminal" .urface% nt Iwl-
nralary ancry cnJlnhchal cells by IandarJ .KgreR/anrlry tcchniyucs widely uvJ hN
Iraa.urlnF aKgrcRataln 1d Plalekth and grarwhK'ylc l1.inR suapen.inn% u/ Iww/ne
Ixllnamxy artcry cnJlllhchal cell% cuhureJ -In Illk nK amer IKaJ., in an ayKrcFiwncler.
they llroral Ihrl Iryl+an cau.eJ erxllNhehal aFRrcKaliras The a"re(.':NNM rC.111MM
rx.urseJ at rryPan Ilraemraliun% a. M/w ..II IMIt'7i The degree 14 uypan tndured
aXFregala/n nah..neJ by the magnitude /d thc t hange in light lrammi..ilul thn/ugh the
enJlnhrhal .uyrcn.aat% wa% relalcd Iu the Irylnln cnncenbalaln, rcaahing a nw.inwm
level nl uyp.m clua cnlratnms u111 111'F Thr invetlRaha% a+ncluJr the myp.in. even
in vtry hlw c/arccnrrataal.. cau.c adlxrcme between "lunnnal" .urfares ul pdnal
nary eral%i1he11al tellk prahahly Iw'tau.e the en.yme Jc.tn,y, cell surlace Prdemm
which ate necc.ary tn pevcnl rntercellular adhcrern'e. 1hc mclhld Jc.cnhcd here
may he u.elul l.w .IUJy1nK cell cell mtcra.tumc n( cndlahclwm
BriKham K. 1. . Mcyrick, H. anJ Rwrn. 11 S
7'usuc d Cell IN2) 1h7-172, 1Y1(-1
(ArAtr au//ort Natirxul Instilulc. uf Health. IIuRh 1. Mlay.an Fund fnr Cardinhlgy
The Jnhn W('Iwlke. Jr , and lAura W. ('ulke Fund /lw LunK Rescarch, anJ the
t /pPuhn ('nrnpany
Fnxn the Pulrnnnary ('irculalilm Center. Ikl+artmcnt% ol Medicine and Pathuh+lty.
Vanderbilt tlnlvcraty ScMud ot McJaine. Nashville. TN, and the 1lcpartmcru nt
MeJlcinc. Univcr>Ity ut Miami Stlaud ul McJicine, Miami. Ft..
IN V!V(1 AIIT(1RA1)I(XiRAP11I(' INiMONSTRA'1'N)N OF (VA1)RI'NaR(il('
ItINI)IN(3 SI II:S IN AI)UI:r RA r TYI'I: 11 ALVF.(N.AR I:PITNI:I.tAI. ('1.1.1 t
In Ihi% study. aduh nwk rath were injected inlravemlu.ly with the olu.carinic
hrnJinR Prahe 'll qulnutliJlnyl hcnrilale IVNH) ur the (1-adrenerRlc Ixtllr 'II J/hy-
Jn.alprrmlt.d 11111A) Other rat% were pre treated wuh an Intraperillarcst m)eatamld a
NM) 1./b1 r..c.. -t I wK.r.Mearn.l pran bl the 1111A I IMhI rnirrn.rly+a' auluraJan
..t tl I y... .f.l- ..t 1...1/ ILMn ItK QNlt r/.NIII Ik11MM\Ilal.'II very llnk
r I.fA It1,. A/IMH.//1 ,.r...Y11 t// I/M 1M411 IIM.NII /1.I/V I( /n1111
tIKSe an1111aI. Clallalln'd .uh.lantial (abelinE. AuNwaJil~raplls of lung Inml ral% in
jccleJ wnh 111IA /k nam.lralcJ IalrhnK wbich was well wwahnd uvcr alvc.dar .rpt.e
anal caanrntratcJ uvcr the cyt/lhlr.nl n( type 11 cells. (juaeti/Nive analya. nl IalrIo/K
in t1K 1111A yr1a1P% irwln atcJ a.IEniliaam redurtinn n! lah ImR m aninlah trealcd with
1. L/IPnwrr.'ad Pran 1u I1I IA. in huth the atvavllar p:wtinchyma in Pcncral aral uvcr
lylt 11 ctIl. 11n rc.ultI ul thi. alK1y /x1/v/Jc nalqlhll),Igk. cvkletwc fur tlk uP(akc rml
ytrUir b/nlhng ol 11 aJremry/c antaylalist% by the adult lunr rn rn.. while ladinti In
dnaal.tratc .nndar hnlJmP nl a nluaarmic Pnlhc.ln alkhtNal. /hc re.uhs rk nam.tr alc'
ylct rGc (t allrrtwryq' recrlNllr.lal lylx 11 in cnvr anJ .uh.tant/atc the virw u/ a Ju..1
cll.ct ol (I :ahcrlcrgic aE.au.t. la1 alvclliar lypc 11 ccll..
Sanrh. 1) M. a/1J Salhu. N K.
l lJ.' .G rcn..1 t41A) St9 527, 19114
.
I-nlnl lhl' 1)rpannkM Id Nadaga al Sticnres, Welk.ky ('rdleke. Wclh.ky, MA
11OW IMIA(;(K'Yll(' LEIIK(K'YTFti MOVE
A% thl. p.lller raltes. a rcFulaled. clrKJinated nawemcnl /d the cytlllll.r.nl 1%
cWntia/ hlr Ihe /unclaul ld Phapryles. In thc.c .elb, a% in nw.ck ccl/.. the plwer
uuu (.Ir nawcnwnl clln.ia% ul thc cnrllracluk Pnncitls, sx11n and mylaol, w11ah arc
.'raK cmra/cd iu the reKawl ul Ihe cell nlnet. In the peripheral cyulpla.m :a nn hhcr.
nuy hc in a Itnal.lale Ir Ilky nuy (nrln a~d nelwurk by s.vlcialiwul wlth a laalanll-
nKYw , at'11n hualing PnMCin 111e rcvty.ihk Irans(rxmalNln uf thc cyt.IPla.m /nwn gc/
tn wq i> nlrllratcd by a rcKulahuy pm(ein called Rel.nlin which when xllvated by
/r11tNa1a11M C1ah'l'nlra1/1M~i nl ('a/', causes shnrtcninp uf actin Uhen, leading tn,h.rntcgratiwwl
yd the Kcl nctwlak lllis 0 aelwnrk rc(ornrs it the C'a" cn>ntenuati.al lalh
hknw the IhreIhdJ value fur the aaYwa1i11etA Kelallin. ('a", acting via rclalhn. 1% a
xc/rsll c/ulll\Iann1 in Ihi. syacrn: i1 nNllnlls the /mkr a(evcnls Ihal slart Iln the pla.ma
memhrane u/ thc Phagl.y1e in rcynm.e NI a vtinMllus, nu11ha1 sre then nn,maulcd by
an alrllnlllriate rca.Yiurl ul Iht' naMractik nnil. h is ta be eallttkd that the ehrclJ.wNal yd
the nalkcular nltchani.m% that rekare anJ rrKulate the nulvcmerw o( cyhll+la.nl in thc
tYll will ryrmil an urakr.lanJmR rd fachws that inler(err with kukla:ylc luntti/wl
/IartwiK,) II . Yin. 11. 1., am/ Jms..el, T. P.
l.nrrrrrd nf Clinirul ('brni.\nv un/l (Yinkal 8i..r Avnu.rey 21(9):S 13-541, 14N 1.
(kAer tuppwt: U. S. Public llcallh Service anJ the Edwin S. Wehsler ha/ralatiun.
1-nun the 1lcnlaudlq:y t lnrlrhogy t tnit,llaxvarJ Medical Schwll, l)cPassmrnt 1/( MeJi
cine. Ma..al'hu.etl. (:encral 1luautal, (1n.hln.
IS(N.ATIt1N ANI/ SOMli STR11('TURAL ANI) FI/N(TIONAL 1'ROIMiRi71-.S
( )F MA('Rt HM IA(:N '1 Rt )P( )MY( )SIN
Tn/lllanyrhin purified fnnn rabbit lung m.cnlPhaFes ir very similar in.tnu'turc to
IMher MMIrIWH'k IYIl Ir11IMa11y/Nmt. Reduced and derlaWrell, Ihe Pruldcin h.r% twn
PI/IypelNiJen which m/gra1e during ckdn111111we.is in vdlum Jlaktyl .ullatc un
pllyarylamide Kclk with aliKhtly different mnhilltics cnrre.lanalinR h/ aM,anrnl M,'.
ot aMaN W11MM1 1rdMrwinR tru.. IrnkmR by air IL/JMam in the preserKC nt ('u('I,
cktlr.qlMaeus uakr MI/Ire/IuclnK naabwals rcveal% a sinKk p1/yPeMak ut M.
u, I c v
M/IMM/ M:wn.ph:IFK tn.plwnyl.an hJ\ an 1\.rkltr/l' pmnl u/ 4 h anll :In cnnaw x'/J
{'Iw11pU\/II/N/ \11111I.11 Ir.IMIw'1 1fUlwMlylnln\ 11 c11n1.Un.IN$ t'y\tclllr rrvJn. Ilrr l h:n/l
In Ihr rlr.Itrwl an./...a.pr% ncK rIq+/1IFr trlfwllnyU\In Inl.ic.uk% r.dary \h.wNwcA with
p6u1nuul Jml l.wfwwl ur \klwkr. \nJlyhl nwl\, 11 nln in IrnKlh. M:Knqrh: yr tr.qwl
nlyu\In p:Irw 1 r.t.11. /[f11wn ul hl/h m.qnr\Ilan clwllrntr11uw1\ havr an :/IIJI It'f11.1n~.
Itv ul 11 nn1 l In t11.' h.la. UI yw 1J\ II/M11 fWrd1.:11w111 :IMI IfU11/ Iw111I/11K1h11N1.1I
.k.tl.qdl.~.h. JnJlyv\ ul malflqauKc I:./rx1. If/Mww11y1r\In alaaprl.r\ k\\ than
11 ?I .d tlw 1./.11 In.w r.rphaye pr11rin. a n1a1Jr ralin Id aplwnxm/.arlv I trupl.nlyu\lo
//w.kl Uh t.. I` M flll /1wNwNrkf\ 111 Ihe Cl'II. MaCf11p11a1a /1/1pIw11y1N111 h/rwi\ HI :n'l//l
hlJnw111\ Mxt1y+11J1r\lcklalnw..karlJdhrrfawlmu..k.rlllnhwauynIn1n1nbil
tlw Ir./Faw ntJh/w11./ :M un hlJnnnh by Ihr ('a'-Fcl.nlln l.nupk ') lw limhnranpl/r\
Ihd t/r4wwllyU%111 1161y havl a rUk in \IaMhflnr :htln thLlawIllc In vivn
Idtw/l/l. A, IIutwq. I It afw) .1'/n11r/, I I'
/L.r he rru.rr v?21 ',1 I Itt1 11/11 H/N 1
(hhrr.riryrr1r1:1I S PaMlc1/.Jlthticrvi~c
I rlwn dw Ilrmaad.,ry Om'ohlyy U/u1 M.1\.xlmvu\ CKflrrd Ilo\pitJl. IkpJltullcnt
nl MrJw nw . IlJrratd Mcdla'al ~ah..d NL\lun
111R1'.1: h1M1'NSIt)NAI.SIRU("IIIRI.O1 A("fIN I II.AMI:N1S ANI)t)1. AN
A('IIN (i1.1. MM)1 WII11 A('lIN IIININN(i /'KOII-IN
1111\ patrr Ika rlhr\ f/1u1 pnqartlr\ hIr p11n1icJ :w lin lilanlrnt\ a/wl f.w aclin
a\.r/nhlrJ in tfw prc\rn.r /11 o1.ICr1.rhJ}r nltln Mlwlinr prlrlr/n lu du t)u\. Iwm/1cJ
nlu\sk a.11n an.l nnllurC\ uf xtUl :I/wI all//l h/fwhlllr pflNln wl'/r l11at111nr1I In Ihr
II:111\I/II\\IIM l'k11/11n Illll'hNlllpl' :Iltl'1 httaiwwl. 1r1I1laI p.wn1 llrylnl,' :IMI //N:Ify
\hall-
nw'all( Ihr Ihrrl' II111w91\/1a1aI \tf/Nltlfl III the pnecln a\\cnlhhr\ wa\ anIlyird by a
rIm1111ncr a\\i\trJ FrJ1111K analy\I\ :Ipphl':IMC 140 rt'11lfalVt11 I1IaUM111 INIw/a1.\ 1i11\
analy\I% yn'hlrll /nlla/l/alan CIwKI'fn111F' Illr trryurll.y ul hlaulrnl Inlrl.rlhlwl. dlc
Ii1i1nM'llt knl,'II/ hl'Iwtl'n Ihr\C Illtrf\lt'IaM\, the :nlFk al whlch Iilanlln1\ fwamh at
(IK.e /ntnccclllwl. :InJ Ihc c1ln.rnthalN.r1 111 /ilanlrnl\ whh/n a IktlnrJ vUlunlr.
1'urilicd aUn at a rlwllcntratilal ul I nIK/ull a\.cnlhkJ inln a unll.w/n nla\\ ul haly
lilanlrlll\ which avcrlap at fatldlwn anXk\ h.Nween 11 anJ'M1 Aclin In Ihe prrvnlc ol
n1:ItrUp11JFr :1.'Un h11wI1nF' prMcln a\V nlhltJ iM11 \hlwt \Iraighl IdaoMnl\ IwgymilYl
In a IwrpnJi.lrlaf hrJflclanR nrlwlwk tllr Ji\/anlc Rtwrrn hranch plwnl% wa\ in-
vrr.aly fclalyd 1o the nrllar ralalld aclin hlnJlnK pnqrin lu al'hn. Ihl\ Ifl.tancr wam
what w11u111 hr prrdi.k-al 11 arlin Gl:mwld\ grew at tiFhl anEk\ till nuclcatilal \itcr utl
thr Iwn clwl. 411 :w un-himlinte pnllrln dmlrrr aflJ thrn amlcakJ. 'Ibr rr\ul1\ .urrca
that xIln in rlwuhlnatilln with acUn hullling pn/(cin xll a\.colAlr\ lu llwnl a Ihfcc-
di/nrnvlwlal nr/wlwl rcvnlMiny thr prrlpllrral lyhnl,rknln nl nw.lilr .rl/\
Nirl/r/nun. K. A/nnin I' C. and IIanwip, l. (tit.rl../, f r, l
fhr l.urrl.d..f (.ll Hi.dnK. Vh 1JIM1 1411. I')1(1.
fNhrr.rpp.rf:11 S 1'uhlicIkahhticrvice.Iht:IalwlnS. Wl'fhtCrl'Iw/n1I1NN111;aN1the
VrtrrJn\ AJmrnl\IrJ1a1n.
1-nlm 1hr Ilrm.t+dury (hlcu/uFy Ilnll hcpartnlent u( Medicine. Ma\.r1hu\e1I. (kn-
crJl //..pnJl, alwl hc Vrarrn\ AAnum\Iranlul Mrllw'al Centcf, Weal I(aa
hl/ry. MA
M)1 A1/l1N ()1 A('IIN HINI)IN(i IM(()TIAN AND VILLIN fR()M
'It)AI)l1lK'Y'II.S
lw..:l.hn nwwlulJunF IKIltr/nj have hrrn pWilirll Inwn I/uJ LK'ylc\ A hlyll-
awdly'ulJ/ wrqhl pr.rlclll \11111I.11 In \tfal'tlar afa/ I11/M'Iaal t1/111a1711phar-r a.tln bawl
ltr\ IIIF prHt1911 .NI.w111I\ 1rN 1hl 1.111/,.Ifir atlm-u11\\IU/Arlllt a.llaly ia Mtiytr
Ia111N.'r
n
A C:Ih aml /h(lrrwhnt :Ktlvlty in H/a11111wylc Iwa1w1~'rnatt\ whiCh \hlwlrn\ :M'tln
hlanMn/\ /\ :1. CU11111r1I I/w hy J95.111111 Ilahlql pluleln WhkI111\l/11hk\ v/II/n. dn :Niul
yvrf//ll ;nwl IN/Iwlh/ll, p11Nt-111 41, :Ivl:al rpltla'l1al IMn\II hlalkh. In Ihr prl\l'Iw1
III
h/l!h IpM1.:J1 wnl, thl\ pndrul .Matrn\ al'tln Iila/1h/N\ In a plnt-cntrafl.wl Ikpln
/6nl LI\111un ;Ilwl \linndalc\ I/I:1111rt1t a\K'nlhly wllrn alhhYl IP /Iw1/aa1M f N' .Il llll 161
Ihr
ah\rmr 111 l:lhllltll IIk' /wlAr/n ptlwlwyr. the I/anlalilwl ul allin li/anwnt Mawlk\
I IwYI'I/al 111 /lw t..:wl Irq yll a1/1n l'a11 hs: l'r/1\\hllkr/l In111 a IwI WINA 1./ it
1111 Iw1wI1111!
(w11/./11 ('.Ih lU/n rrlIII.Itww/ .11 the albn nrtw/aA may hr /lwJlatad hy vdhn Ilw.r
rr\oh\ Jlr Jrll.'nnl fluln Ilw/v ap.alyd in at'hIt111Jrno rgp.
('Iawin, 11 I. and Ilallwiy, l 11 (Sru..rl, 1' P)
1)rl.l.Mun.vn.rl Hndnxl' IM/ hl-1J, 19111.
(hhrr tapperl: 11. S. 1'uhlic Ikahh tirrvl.-c and Ihc I:klc O. aral I'hdlp I). Sang
I'IIUIwI:dNal.
t-nml t11r Ilrnu..hlpy.t111rnh/yy anJ I(eflal llnil., Harvard Mavllral Schlw/l IkpJrt~
ulrnl..l M.dlcillr MJ\\achucrtt. (icnrral Ihnpilal Ku\aln.
1'II1S1('AL. NASIS OI' 7711: RIIFIN.cXi1C' IM(()Mi/tTl1'S (1F 1'-A('17N
In thr \twly rrlrwlcll hrlt Ihe vixy.cla\lic prllpctlirx Id purilKJ rahhl/ \{,.9r1ai
ualv'Ir aalin lilanlrnt\ t1ar1/n) wcrc mca\nnJ at phytiu111Ki. NmM \Ir\n/;lh arlJ p11
uvrr a ralll,v /1/ rllrrccnlr Naa1. an,l lifa/lknt knRlh.. AI(IawKh F-al:(ill lkl/aal\ua1cA
tran.ihwy rla\Iil hrluvtnr, vix'Ia/.lh.w wa.ahvatvav) al hrlper tlmr. c/al\/\Irnt wnh a
high IkKr.r ld /dal/rra /lvcflap. 711e cllmpliancc wam ilakllrfwlrlN ll/ \ue.% avcr a J-
1oh1 tanyc nnplyinK that the nlra.urrnleM Jal nIM Ji.(tNN la/y i/ltrrlilanknt 'Mawl\..
111c Jylu/nir \awaKr nwuhdu% ira-rca.ed m1awM/lnically with (rcyurncy uv.r 111r ranl;c
nlcauueJ, whrrca\ the Jyllamir M..t naalulu\ haJ a tehMive nlinioaan a/wl wa.:llway\
k\\ Ihan IIK Jynaolic \11waEC nalJldut 'fhc.c Iltl.ctva(illn. arr Iypilal /d Ilpw.hlya ally
cfal\Iralnnl ft havior. '1 he ahvllulr valuc uf the .'llnylk M Jynarnic viw.nlty Id 1:w'11o
varied a. the 4114 puwrr ld the frcylK/lly Mwl at a/rryuen.y nl 11 1 raJlan\/\ wa%
pnlplatiunal lo Ihr hrlwlurl 11( 1hc wclKhl avrraXe hlanlrni knK1h raivJ tu Ihr 11 1
pl/wpr a1Ml lhl t'Ian'l'nIf:MNal. Illl'rtpef/lnl.'/Maf /INa aRrlY'J well wllh Ihl IMf1fIl INaN
n(
a tlatilry /d Illr Ihr11t11yic hrhavi/Ir ld ail( n.J\ in xmwhtuk wllalwlns Wr clwr hak
that dlr IINa'hanavl fthaviur .If purc 1 acbn allulilln\ can he c.plalflyd Ia11Ih' h.1\I\ .II
Ihr nn/1ua11/Mwdllg/r.Iwl\t1a/M.1u dillu.in11111 4a1g aill nld. whi.'h.11/1aN /wllr/wlv
inlrr.K't.
T.vlrr, S K. antl Smt.rf, r. Y.
1hrlnurn/el nJHi..l.rRilfd (hrnli.rrY 2SIt(1111:11(MI1INM14, 14!!).
lhh.r iqprf: (I. S. huhhr Ilc.ltlh Scrvice.
IYlwn the IIernN1/1119y-()ll'IrhlKy (/nit, Ma\\a.huxllt (ktrcra/ Illnpilal, Ikpartnlrnl
u( MeJlcine, Ilarvwd McJil'al ScMwd 1laalal.
59 1 I%o
NI:W MI:('l1ANISM-RASl:() SI:RINI: PR(yTliASt: INIIIRIT()RS: INIIIRJTI()N
(/F IftIMAN 1.1aIK(X'Y f'l 1:1.ASTASI:, f'c)R('INI: PAN('RI:ATI(' I:I.ASIA11:,
1111MAN 1 1-.IIK(X'Y1l CATIII:.1'SIN (;. ANI)CIIYM()TRYI'tiIN /iY
1 (111.()R(/1S(X'(XIMARIN ANh 1,1 1)ICIIL()!t()Pi1f1IA1.11>E
Mrt hamsm hased irrevenihk inhihilur.. whirh have hecn rcl.ntcd f.e (wurinc
parNrewrc IM'/ clastasc and httvinc parkrcatic chynwMrypsin A, include hdo enul
Ix /uarcs arnl t+ thtiw.ryrnmes. IWman kukiwyle (111.) elastrsc rnJ calhcp.m (i are
rrlaletl scrint I+nnCascs which are inW.IveJ in Ihe cUnnt.iive Iis.uc .kIruti/lwt Ihrl
tt t uts in rny+hyvrna and varitrus m0anrnM.arr discases Ruth eniymcs are mhrbitrd
revcrsthly by hrtrnK'yclre s/nKture" srch as hen/osasirMme% anJ hervi~.dhraiu-
hoM.nrs, and tht. sugrcted that hetentycka erwMainin6 maskrd rearlive lurt/amali-
ttc% nuKht .ct as nMt hanivn based rneversthk inhthihws Iro 111. elastase arnl i athcpstn
(: lhrrrl.we. th" wtlwus Ixepxed I ch4.rawsnc.sumarm 0 chhwu III 2 hrnitr
pyran I.aK/tllarwl1,( JahWw..~hllulde12/andhrunJlhem4rheppNrmrnh.hu.M% ..l
scvrr.J vr.nt pnwcr.e. In summary-evN)enrc Iwtsented hrrr 1ndNatcs Ih.r I aml I are
mrt h..msrn hi.rd rne versehk rnhiMtnrs ul scnne pnwea.cs Ilrse are Ihc hr.t tk om.n
.uatrJr.any+ks.d rniymr. stltv.leJmhrMhwsn1111.e1aslaseandcatlwp.lnli lhrse
cnrynrs hava ltxn mwrd lu hr nIJNM fln8r/1NItIN\ tt1 elaWln tle\trYCINMI atNrrvcll in
rrnrhysenu 1 he.t mhrMl+ws arnI sundar strurtures rnay h.ve cansiJrrahlc pl.armxt..
Lrya f.Ntnl..l .% inh.hducs in cn..
Il.uf><r. I W. Ilrnm, K and 'J U (I'ruvir, J 1
h.anN.l./ tA.' ATPrI. rtn ( JqMt1 af S.q Iliv II/S (/SIK 61,20. 1991
(kber srpporl: Natn.nsl ln.ulutes id 1kalth
I'n.uo Ihc 1thMnI ..1 ('hernt.try, (irowFia ln.titute itf Trthrnduyy, Allmta
MAMMAI.IAN'fISS(II: TRYPSIN LIKE I:NlYMI:.S. ('()MPARATIVF.
RI:A('IIVIlI1:S ()1 IItIMAN I.ttN(; TRYPfASI:, ANI) R()V1NIi 7-RYI'11N
WI'l11 1'1.PI11)1i 1 NITRUANILII)1: ANI) T11101iS11.R StJRS1RAl1:S
Thc sufsnc spn ificity uf hunun IunR and.kin trylMase (tryl+sin-likc rniymrl has
been .hrlirt) at pl l 7.S u.inR 17 amini acid anJ diyet+twk thims1er suhstralrs anJ 14
tnpepti.k 1-minranAitk Suh.Irales. The reactivily and ailLrificily of the human Iryp-
tases were r.anl+xrJ with I.rvine Iryl+sin and tMher Iryl+.in-like en,ymcs. Ncithcr
tryptase was similar Itr etthcr kallikrcin tor facMr Xll. IIIaKenum factiu/. Thc %kin
entyote was the nrNt reactive n measwed by the 4.pecihrily cnn.tanl l../K, l hc best
whsuatc was hrniyhu.yrabrmyk%I Lys ArR-Sd'N,('HIC11,1. which had a k/K.
value ul S9,(M1111NM) M'S'. Only a smKk suh.lrate. ?..(llu l'he-ArX, nitnanibtk.
was shRhtly rrnne rcntive with the IunK Irypase Ruth eniymes have ewtcnJ.d .uh-
slrwc hmdmK si/c% anJ pndiae rcsithres w P, .uhaanttally .kcrease A,./A. R.Mh
en,ymrs rrelrrnd the Iriticiplitlr 4 ruln.anilnk% wnh a P. (ily residtw nvcr 1'hr, and
IrNh lav.nad the suhslrMe 'LLys-(ily-ArK-l-nitnranilitk over similar .uMlr.les aun
IaininF is t.lher re(Meoie/Nwlve ammn al'Nf resnhles w 1', The IanR rn,yme was
inhiMlyd.wer thrrc thmea lasler by p amidirwK+henyl rncthanesulumyl Ilwwalr than the
skm cn,ynr. The pre(erence nf the skin 1ryplase itK subotrates with Iwu t<rminal
hsik revdurs tndicatrs Ihw this enryme nouW pnocess pndw.rm.wes and pth+roletns
whwh t.nNatn this an.trura/ leaturr a1 the tlervaKe snc llre suhstrwes rrpnted in
this paper .IwwW he useful Lr the further charackrrmNM t.f the phy.u,IuKic
Iwklinn td tryplases.
Tanaka. T.. McRae, R. l., (lwr, K., Ctmdt, R., Fraki, J. t: . J.r11ns..n, !). A, arwl
PoNrn.. J 1) (1'nrvi., l 1
)7rrJ.wrn.d n/ lfi.dnxir ul ('Ir,vnitrrv 2511(22):I1S32.tJSS7. 1')111.
(MAer arirhrnt: Nali.NUl Institutes nf Health.
Frtwn Ihr Sch.Md td ('htnti.uy, (:cnrgia lnailmr..l Tecluiwdtqty. Atlantr the Ikl.art
at nl .d I k'nnah.G.gy, I tmvcnny td Ka.(+w). Kwolii.r, hinlad: autl Ihc I kpartmrut ol
RaMheuuslty, ('.dkgr 411 Medtrine, la.t'fennesce Stale University. l..hnum ('ny
111. Heart and Circulation
INTERLAR(N(AT(N(Y PROI:ICINNCY SURVEY (W NIGN IMiNSITY
1.11'(N'It(fI1:IN ('HIN.LS'f1:R(X MI:ASURhMk Nt
Accuracy in the quanlilicwiun a( hiRhrkesily IipnpruWein (Ilnl.) chnkstenrl is
imptntant because measurtYl values are generally inkrrreted, r>tN in relalNnl la a
Iahurwary's own refercnce interval hul in relalMM NI epitkrnN.hrRiral dawa, when a
palierM's risk ut ctwonary artery tksease is hein6 a..sest,td. Likewise. gtnK1 IsrecnnM r%
iny.ntarN herau.c relatively Iwke differemxs in risk are predicted by small changr% in
I IUI. chtdeaen.l. M:nmlmK to the wark presenled here. pruliciency swveys td Sra-
tk-arca lahtuw.uies suggev unly s1iRM int(tnwerneM in averall perfmorsimitre in 1101.
measurenwnl between 11079 anJ 1982, aNlaw6h the repnted w,.rkhwd I4M 111)1. has
increa.sed by 1t11.. llrc rncan int<Kl.lwrwary SI) was M nrg/L in 1VK2, cnmparcd with
79 mR/1. in 19711-79. ( N she inJivithwl IahtwaNuy rcsults in the currenl survey, 19'11%
deviated by nwne than SI/ roy/I. /mm Iarsel vahrc- as nMry+rre.I with 17'lf, in 1971( 79.
The di.rrcl+aM valuc. werr prmtarily a.ctihahle lo mr1MM1 amtcuracy. lvn wqhin run
InRe1tNM, 111/l rt( lal.uaauies in 19112 haJ S/he nf < 111 mK/L. vi. 71/'RX in 19711. 1 he
1410142 wrvey imludrd a lytr(.hiltied serum frelrrred by yxay frcciinR in bulk lynphsli
rwiun (Ily/anJ ( MreRal. rJrnlital M.Ihe pw.ls used in the ('tdkgr uf Anrncan 1.dh.d
t~isls ctNtt(trtbtnsive (lwmisuy Swvey. ww) hvr p.rls td /ar,en pla.m. /nlcr (ah.wa
Wry variauon and hia.e% hr 1he ( hneKa ptMrl wete similar Ar those hK the /ruirn prds
Warnick, G. R., Ren(krwxr, l. M. and Afhrr,, J. J,
Cliniraf CArerirnv 29(1) SIA-519, 1981.
Frnm the No.lhwest Lipw/ Rescarth('linic, t Inivenity of W ashinRpm Sch,rd,.f Mcdt
ctne.Sewtk.
MI 1 61
1111MAN 1'I.ATI':1 Ef I)I.RIVIiI) CKOWT11 FA('I'OK (I'IK;1 1
AMIN(/ I VKMINAI. AMIN() A('il) \ItJ111.N('F:
I.IIN NIatN.n.d Iht prl/lury.trut lurc ol platckl llrrivrJ Kruwlh I:N'I/lr (IM )(:I ) wlll
hl'111/11.Iv/tll' an IIINh'f\Llnl/ing 1.1 t11C IIN11t'CYIM 11:1\t\ IIM /I% Il/nt tNnl aMI 11%
rl'1:11NN111)
INlwr Iv.l~ry'r1/1k yn.wlh /.Nh.t.t arulu pnNrin.. and pl.dckt Ixi1N. I hlI p:q+tr
Ik.1'rdr. dlt Ir.u11..t1 ]/IIIrM11t'r1111t17i a1111tN1 al'NI V111N'ntt' analplt. III IMNh
.ICt1vt'
1'/ K;1 :NNI I11r nl,lrw /n;N nvr ptIN/tA.IkrivrJ laen /1 by Ih.u11Nk trJIN'b.Nl lu.hl
tln., 1'1 K:1 ..IN.u1NJ Ir.Nn uuld.nrd hunun pla/ck1h wa..uhpct.v1 lu aumN- trrmm:d
v.pN/N r in.dy.l% by aul.wn.NCd 1'altllan tkpadalNln I)l'%Inlt' tlle aI.I.J(IIN IWl'V'IN C 461
(nnurJ (Nw1.dyh. 11t-F't.MIatNM/ nI IIM INIltenl Jl'rlve/I IrlNll 1i11\ nIt'IINMI 1IK %lYlul'nt
e
analya% trvlalrJ twit pr/nlary (rIN/Ik .cVue1N'et arNl .oFFr.t. Ih.N al llvc 11 K il i.
I.NNiq.y'tI 1rI 1W1. rn%lhly INMIN.h1/!/MI\ hell/lllrN IIIIQI'll by a.I1%11I1Nk hIM11I .M IMNNI%
Arln..nnJ... FI N:NNI Ilunit./pdtrr, M W
.C. r.'n.. : 211'M.1 IVN I
!)thrr twpp..rf: Wt'InFcu1 I..unJ:ul.w1 and thr Nrlnnlal ('ancrr In.tilulc
1 n.n11tN-('l'nlrl (IM HhMtI KI'M'JtlI1.NMI I)t'r:1rlnlCnl lU1 Nutf11NN1 Il'JrvarJ (InivrlHly
S.IN+d .d )'uhl/. 1/3".Ihh, II.MHNI :/INI 1lN I/ItINUn lll 1111th.r y ('LIIhNnla 111,1tllllr
4.1
I rt IuN.1.F y, I'.L.N6'n.J
SIMIAN SAKI'1)MA VIK11% ,r. (:I N/'. v v.. IC 1)1'KIVI'1) /-ROM 71111 (1NI.
11/1( (:1 NI \11 N( 1)IIIN(: A I'1 A11 I I I 111 KIVI ()(iKl)W1111 AI"11)K
KI'..-111 /LC 1.'IM'1N .1I1.'t.11NM% IIL/I I.IINt' /NMllul tt'II% L.IKl.N11r
nl.lhpn.lul hIvr Irsu.fil nn .1 .rn.Jl .i N IiIlulrr /Y'rw. Atu11 IGm.lUnuulr. tt'/
turn7lN% h.lvr .1d..111u1.d vrral Fr1N. /xlt'...ny LN rfl.hl.ltl/m q'IIh dlra' Ill..rcle
v')nNnl. ..1 IN..1 Fcnt'na Inl.Nlu~Uuu Wbrn ItN'1.(1MNJIr1I wnhln Ilw tru..vnal
grlNtn/t. Ihr%l' (r./n..I1N CJ CclhJ.lt .rynflltt., Irr11NJ t.n. jof/N.. atlyunC 111(
ahduy It)
IlNh/l't r1tY.t.I:h11t' 1/,1111I.NIILIII.N1 IIN' INnLN11NI l't'IIULN JI1t'r.11Nn1\ In1I1Nl'J Ity
1hl'
:N Ilvaled t rllular Ir.mJ.KUUng Kcllr. hrvr ~IN11r \/n11Iat1IlC\ IU t1N I:rtIw1I1 IMININNIIII,'
:N1NN1% nl IMN/1NNN'% U1NI p11W1h I:N-dN. In Ihi.lt:lllCr N/. 1k11NMlmrall'1) IIIA/ Illl'
Iran.llNlnlnK pnNt/n nl a pnnulc .art Ianr viru% an11 a plalckl /ktlvad grl.wlh lacl..r
:uc IkrlvrJ 1aw11111c.anlr nr tllnrly tclatrJ ttillular Rcne.. ihi, t'lwNIu.i1N11. havJ Iwl
/IIC Jr11NMNt/atNN/ /1) l'tlcmivC .cllurlNi.' fnlld,lrily hetwt.I:n Ihe ttaa.llwlniNl! Iw/NCIn
thnvrJ Il/wn IhC .Inllan caflln/u vlru...rN 1,`CIN vAit, and a hunlan LII,IItlC1"tktivrJ
Kluwth Iattllr 11u nk-thanl.m hy whl.h v.vt 1ran.llKn1m crttc clwltl Inv/dvc 11k
("Ilmhlutlvc t't11K1.'%%Nln l/I a IInNCIn wllh lu111'INNI% %/n/1lar IK Nklnll'aI IIt IIN/%C 1/1 a
IaNtw attivc Iran.itrltly JurinK nllrlrlal ccll gruwlh.
1)tr.hnk K F Ilunkapilkt. M W., II/sIJ, L. 1: , IkvarJ S. (;., Knhhln., K('.,
A,ulNl..m, 1. A, and Ant.mi.wlr., Il. N
.N. irnl r 221 275 277, 19111.
(NAec arpprf: NalNlnal Ina1i1u1e. ld Ilealth anJ the WeinFart FuunJalilln
UrINn Ihe OrpatnNnl nr (llcmi.tty. lIniver.ity tlr c.hrlnnia. San hicpn I a )//11a,
1)Iv1.Nln r.l IIN.IuKy, ('.IIIllrnla In.ulute 1.1 Ttvhrwd..Ry, 1'wlkn.; I alNw.lNwy 461
("rlhlLn aral Mdr.utjs ttN.6qv N.Nnn.l ('..u1r1 ImlNUlc. Hrlhr.da, MI),.11/11/hc
I rNlr. I.. I/L..1 N. .. ... h.o/ / .u/ .1 Nu1rUwn Il,pv.nJ l lnlvrnny
1u/,t., 11. .N1 n......
IIl1MAN 1'1 Al I-I 1iT-UI'KIVIiI) GROWTII I-A('lY)R:
%1R11('IIIK1- ANt)1-UN('LION
lhl. pqwr lr/rlly tcvicw. 111r phy.it'llt-hcnli."al pnqltrtw. ul hulnan pl~tckt-
tkrivcJ yruwlh l,n IIN 11'1 K i1') a111I /1~ lhvt'rti IIhy~N/1111`R'aI Iu/1CINN1~ whlt II IIN Iulk
.IIIlndatut/11d lcll y1.Iwlh. cdl nn}r:dllMl tell nltNahnhN/i1, a1NI /1N0.INI:IINN1 ilI lCIh11:u
nwm/x.uN rrtclN.N. In anlnnary, IMXi1' k a IK 11 %IJhk, l':NNN1K 11r.Iy/4'IN/1k Irim-
t.w/rJ m Id.rtil /n ItN n Fr.mnk. ul plalrkl. Ih 1. rckavJ Inan pl.nrkh dunng hltrNl
. LNlnly I'IK iI' ha^ htrn rcadvrd Inlu:11 kaU twui h..cly rr1 NcJ xtivc pldyl.'INNk.'
I'IK:I- 1:I/NI 1'IK:1 11. c:Nh t.nl.i.lmy Id twu in,/clivc tham. ImLeJ IogrIFN-r by
.II\I/Ihtk IMMNh . I'I)(:1' .Imlul.dr. 111c I:wwlh 1.1 a.wnsd trll. In aulluf.- nN'IudmF
11INI.hI.N1%, ;11/rr1.11 ~/INNNII IIIIIV It t'rII\, a/MI F,II:/I l'tII III :NhI/1NN1, I'IK il-
II:1. larn
%IN.w/l In \l11/111L11r l'rII 11111!tal N NI a/NI 111:1ny /h vt'rN' /IN'I.IIh.IN" Iu1N 1 N Nt\ %nt
II :1\ .IIIIIIN.
:NIII II:III%IMMl, ININI'/n %y1NhrN%, t11111r\It'r1./ \%tl'1 %ynlhl'%I\, 111M.~I11N.hI1N11n11111Vrt,
:I/NI IMINI,N yt I//I \yl11IN%I' II I1NwI11Id/l'\ IIYl'INIn h11NI1nr t)I .NINf :/t'nvc
..nnINNNo/~
%INII d% t'I.NIr//11,1I 1'/I.W/II I,NNw, Iulrlnl/1111,' INNIIIMNN' h.w-tl.'ll%lty IIIM.IN.Nr/ll.
NNI
Mn1M.1.NIN'1I111/' %I1tt /tN l\'II n4'lillNallr tlY't'IItIM% tln I'I K iII1:1vt'
1wt'11111'lINn1~1/.11r1I
nl aucflal .nNrN11 nNl.c/c tcll% and
hMld.laa..
Anlwnudr., N N wNl Wdlianl. 1.. T.
F.41.r.th.ul /h.rrvvlur.~. d~ ?hHl ?hl4 14K1.
Otbrr .rppnrt: N:NN/naI IlNhhlit% 1.1 /ICihh and Ihr Mdl.al IurNl II:/rv,uJ Mrd1a.J
%t INMd.
I'1.Nn11N' ( l'llh'1 ItN HI/M4I Rl'Narrh:1111II)lIRIr1111CnI llI NIIIr11NN1 Ilarval.l Ilnlvrr.uy
\I INrd Id 1'llhlN' I h':/IIII I111NIIN1, :IIIJ IIII' ( arl11:N' 111111. Ma%%,N'hlly11s ( M'IN'1
JI I I.111
1.11 11.../..11
1'IIIi 111(K'lILMI('M. IIASII/)U MY(K.AKUTAI. hAILURN
In t1u, c;lrtIul r1. irw Ilrlrr. i1 crn 1w v'rn th:N thc /inllioK./r/11Nlrr th.ln a t cnlury
ul Iavr.liF.ANr11N.uN 1./ a pN Nuc rNN ol a Jl~lfiYC k.i1N1 Mn ralhrr u/ 1hC inlt'I:NINIn ul
IINlhllllt' I:It11N~ II1:11 CIMIYCrIy.' INI I/M fIMININM I/:Ithway l1( INatt Ialhlrl' 11 w/wIJ
.ccol
111:N Ilw p:dhway% k:N11nK Lt rnylaanhal lrilurc ran havr a varitly //t nlt/alN/ht' lxlgm..
'Ihry t-:ul a:nl b.Nn JLtu/ha/N'r. wNhin tlK nly/s'arJium - thr Iwltr.v. ul rrnrKy
llrlltlut'INMI in nllhlt'INNN/rla, crlcrKy Wiliialilln by t1k t'111Nfat'lik pNNrin., In allertJ
caklum liut in /nk Iw nNlrc 111 Ihc .'ellul:w IwKa/lclk% inwllvad -- nr thty nlay arl.c
1><t'an.r nI /a/d1y P alltcnlrric rrFulatinn alln'Iiny the :Nhcnrtgil' laNlryllNlenl ul t'lNl
tr:N1NN1 Nrw IcalrNdagy i< nrrlmK i1 pl/.ahk lo .y1Nhc.iic thc a1MriMn/o~ I:IChw.
IMn a t'IInNdI IINMIrI (II:N will 1.'h'ally e/lhanl'C i/lvl.'NIr:N/N,,' u1NkfN:NNhng 1.1 IIK.r
/IKYh:MN111~. SIX'f/IN"ally. 1IN tIN'/11NaI rt'aa'INom in IlllIa1M1I/%It1/NYJ NI ht I..Ih/wel)
in.i/k llvinp t'r11. an1/ in.k1.1, du% ii nuw pnnnivJ 1hrlwEh Illr 1111rINn1NYN.11 ul
nu.Iratn/ay11rIN avlnarN'rINMK1. A.NMR.ytrlrl/.c/h1yMInK.Ihr.Iwlyldc./J/:N
/IIr1a1111Ih111 a1NI hlntlN'lltl%lty II/ (hl' IKJ.iIk, u1Nkh1aMh11g 111 II/nJ:Inletnal /lKt'ha-
ni.nn lll rlriuu..:adi:lc.lwwlkr. c.pec/ally ot tluc heart /ailure a:ur, .IN.o/J rtcaUy
inrrcate.
HinK. H. 1
Nnyrirrd /'re., tN r tirlNatnhrr /'/N 1 M.. 9 11. thnwrhlwl
1 Nnll thr IlunnnKNw/ Mc1iN 41 Kr.c.ut h In.tllulr.. 1'..a1kn.. ('A
61
l 111- 1 1-I 1(' I SO1 A NI.W ('ARI)H/ fl)NI(- I)R11G Il A Iw.111)N N( IRMnI.
ANI) I AIt.IN( 7 III:AR I PRI:rARA I Il)NS
Suwc Wllhl11/1),` J4V"nvlRJ Ihe a11Mw ul J,Knaba in 17XS, Icw JruKs havc Mcn
mtr.ehKCd wub lu.d.m);cJ uryurl,r, ellc.'t un d,c lading hcart rhi. npn IH.wcvar
.kJl. wttl,llx cltc. t.rl I A IMr(, a new pr.dtvc imNnq+ic c.nnr"wnJ. rwr Ihc nk6d+.hc
arMl dynarna Iu1N/Nm uI rMqtllal and IJdinK Irr1u.cJ w.wlmy rahbq hearl prcprrJ-
h.a,s In 4n.kr 1.- nw rcJ.c thc,,.yyan capaxr(y.d the Imrlu.ah-. J pctnw,n-LJrInN, l) (-
411 oayKcn.ucJ in u, ndrnl Ind+hk utyEenahr waa cuqduyrJ Mctato.hc ora.urc
nr-n1s nwloJr.l 1nr.h crKrFy plw,y.hale anJ Rlycnlylit iMcrnwJi:Nc. 1w11 vl-nlrnular
.y.l.IN". CIMI Jcr.h.hl lacssures. Jp/JI_ l'ahhal' Iwlllu, HN.Nqry IIUw, :IMI I,ly.4 ar d,al
ll\yl!C/1 41M1\11/,IIHNNI were JcICrndncJ AJminl.lrab.u, .,1 votlwor rynhd..uhu.d
0,11 w IINI r,rr/.N nwreJVJ prc and attcrk.aJ resulleJ u, JcptesMw rd my.-c.uJi.J
l.uuraw Ul.lr In 1tu r«m/JAmK hcan prc(,aratMr,. stnRk mp', Inals u/ fA 11(.4.c.ultcd
In m.nicJ L..d.vc rm.ln.l,rl cltell.. uwtra.rJ hcart tatc Jntl n1y.aJrrh.J ..aytvn
1.91~w/yMUM/ I~LyMarM4.d m a,nncnlfJlnm..d 4 nF,/ml ahdl.hCJ Ihc pnlhvc uw.lro
pa cl lc. t I hc.c .nJ .w lk r 1rf+.ervalMMo Irrv nteal here shnw that I A(I(vl /s a IM.wIrI//I
Iwnrlr.c rn.wny.k .Kcn/ whwh rn the iwdNCJ /.lr(u.cJ heart tnc(ea.e. Irrh 1KJr1 rJ1e
arMl 111y.q N.INI Illyr!t'n 11./1%u1nIMNM, II 16c% m./ in0uen.e high cncrKy Irlu..pLJlc .w
Ily...lytw rnlcrntdi.NC. in hcart nw.ak
ILnK. N I rr nl
(brrrnr Ilrrr.qawn. Nr.rur.b 1MI1111 1U 1`Al4
Othrr srOport: I)k Ib.vcr I.wnJJIN.n an111111 I./nJh[rKh I IIIMI
I nnn the 1)tpJnrncnl ..1 t.tlwrinxntal ('arJa.k,gy, Ilunthnylrwl MeJw'JI Rcv-ar.h
In.hlulc% and Iluntrngt..n Mcnraul 11...pt.l. Pa.Jrkna. (A
MI('R()IIIIIIIII.F I)YNAMICS VISItA1.17.1:1) IN TI11's INIACT ('AlII.I.ARY
(IR('ULAl1(IN
I:.i.linR Ieehnisjues Gn 1wu-Jinncn.irmal eumraa CclwKarJirKeraphic im.Kmg o(
rny,K-arJial licwe rcly,a, lhe itMtnnhrctnwa ld c,wara.l agent wlulirm% conraininrL mil'ro-
Mrhhk, ol atr, whi.h aher the aetw.lic intr.dance and prahwe Ji(Iercnlial C.ho
Cn1urM'e11Kn1 )ltc Iwl, mclhrda weJ in the Inve.llRalurc' lahrrahuy In Renerak rni-
cn.tad,hk% in sl,lutinns .errurR a% cruNra.1 aXetNa included the widely u.av) harnl-
al.'/1a1MM1 IIK11h11I anJ 111e newer ullraNNnl' n1/CnRar11a111M1 (wnnl-:ItnMI n,elh.nl. 711C
lal(ct ha, harn JcnMm.IraleJ Il, Fenerale .malkr anJ nawr und,nm micadwhhlc, in cm
in lvrn Syslcm Th/s .lu.ly was lk<,RneJ tu ul+sctve, hy Jirrcl micnr+c.q+ic e:rannna-
h.m ol a ca1 rncscnlcry INCparNem the hChavNn and late I,I the nlll7nlwhhk-S in an In
vr,u.y.lem 'Ihc en ra., nkseMery 1i1+servalwm.lv,nhml lhe crdil-al rk ot rui:noMrh-
hk sve in n% unhindered I+sssaye 1hnwKh 1he.a(,rllary va.culalure. 'Ilrc .nulkr and
IINNC Ilrn(.NI,1 uM,Natc.I tnkmtwl.hka ry..ed rapidly IhnwKh the mitnw ra:IdJlion
ah.nR wnh Ihl- rcJ hk.d cella whcreas the IuRer micn"hhks were nhserv.J lu
au+k.+c arrl rntcnup the Ikwr n( Akwrd and suMcyuen/ly cullal,se ur .hrtn\.
I r.nrr.n \ 11 \hah P M. BrwR R I . Mccrhaum, S.('.xJJy. F ,(hang 11 1. .
\mldlan 1. nJ I ..ph.)..h., Y
l.v.n..d ./ rhr An.rn...n f.IIrKr u/ (drJn.L.~r 411) 1,91, UIN1, N)N4
(Ither suOPott: Au,rric:ln I ICart A\Nll'Ia1NM. The HnIWIY IYw/MIa1NN1. 1he MeJa11NM
(ir.wp,d ('edar. Smai McdnJl ('enlcr, the Kect hlwnJatw,n, anJ the I:h.N (rnJ.y
RC.carch 14wrMlab.,n.
hnnu the I lurnmyh,n Mcdical Rc.emh Inuilu(e.. Pa.adcna. ('A. and the 1)ivi.i.m I
CatJl..k,Ky 1)clenlmcM ul McJicine. ('.tilan Sinai McJK al Center. lhe I Inivcrslly ol
('a111.wnl:J a1 I a,. AnI,K Ic. Scha.I,d Medicine and dk WwlswlMh Velrrans AJnnnts
Ir:NMwr Mcdn.d (enter. 1 s Anyck..
1-111:('1 (11- SI-ROTONIN ON A1.1111MIN ANI)L(IW 1)IiNti1fY I.I19)1'R(117AN
1111'AK1: IN I'1.RI4lSL1) RAl/Illl 1I:M(IRAI. AR rER11:S
.
lsm.pNt I/I hkMMI I.IJNna lIM\I/nN9N\ rn/U dk artcnal wall ha% t,m.ukr..hk
t hun aI ,u,p/a dnm Ihw a-J..J ,u/rJlu,lunal Iwl..ure. IurMrkn. c arwl .IK:u .Irc.. ..rc
,tntrMlJnl I:,I LM\,n the (N.Nhrliwml UI va-A ular mhlry hr/hl enJlMthIIII,1,. 1 hu%. u1Ndlie
u/ 1uw /kn.ny IqrqnrMCUI tl 1/1.I lilays an inlisawtarN nrk in the lk vckqm,cnl .d al/rr..
sakru.i. San.t,H,m Jrwl.Mbcr vaw,altrve nukri:J nwr resuh in chan4c% m Ihc :utcnal
wall kadmy tu mcrl-a.cJ ulnal.e ul aRwn,in lw L) N.. '11u: Iwc.c,N .nnly w.,.lurwlul Il J
Iuyklcrnom the cllcll ul vuw.ann Ih1'M S-hyJru.ylrylwarmncl and ./aNunur rn-
JUCIYI artCr 1aI 1.M1,1t N I M w I N1 alhulnM anJ 1.1 N. Y/HAe l ale\ m Inrhl~lll Grhhn /c nw
rral
arlcrrc. -I ln fc.nll..M,w /hat Ihr prcx'me nl .cnu.win rnhlMl.llr ralc u/ ulHal,c nl
hnlh allwaun and 1 U1.. I hc lIIaCI /NI allwrlnn u1.IJlte IhrC!i tM.l have a ll/rCl1 /IU~C
rrypnl.e JaI.cIMk'nle and /a hrrarly Jepemknl .m Iransnunal lue.wre In ..wura.l.
1 U1. u/ral.c racs arc rMdy .hylNly al/c.k.l hy pres.ure. lhu.. allwo,in arwl 1.14,
u/aake Ir.re.x's alyicx 149 he Jue lu separate rnc.haman..
SantdlJn. G G. Sa/o, M and IlrnK. R J.
Anx..dnx, 15111).h'/4 71N1, 1'/l(4.
(Mhrr srpprM: llk lhrrvrr Iiwrulaliun and The Lhte/la Murey Muq,hy Ivwrwl.,ti.wt
Fnun Ilk IlmNinKhm Medical Researeh Inslilule% anJ IluMin6hm Mcnunial 1/.,.pilal,
I'a.adcna C'A.
RI:1)('I:I.1. Vlil.(K'/l'Y ANl) AIIT(N(I:GULATK)N IN Tllli('ItRfIIRAI.
(Y)1t11:X (N' Tlll: CAT
lll/a fCIMNt l'rM,IY,IrC\ Ihl eIIIY'1 nl Changes /n hkMnllnetaurC lq hkMNI Iluw with
Ilwr.w in rrJ cell veMuily in Ihe cerehral earucal mknKin ulalww n11he cal 7-.r Jn du..
Irwal wIJ rcgarul hk.d Il.rws were mea.ured during a.IeaJy-aale with rwlN,;x"Irvc
mKtuy.lw res: a newly lkvrxd mclh,rd, ha.r.rl nn Iran.illumina(irmr, wa% cnM+k,ylvl l.w
JIKY'1 v1\uah/a1hM1 nl Ihe InKnlC/rl'uINNM m/IK l'erl'INaI l'IN7et ('ranirA,uny /arkJ In
influenca cnhcr auhucKulalnw nr teJ cell vcW,city under the .kull .rl,cnins lw .d the
LMaI CCrehra) Ih,w. AYhIreE'ulatilNl n11rM1I a/nI rl6nnIJI l'CRhral IkWY wa] (nl'%enl In
cuMrasl nurkeJ peswre-JepenJenl varialiwuls in micn,eirculah,ry red cell vekr"qy
nccuneJ A lall in .yslemic prevure was accnmyranied by a Jecrea.e in red ccll
vekrily: re/urn n( prcasure resulted in increawJ red cell veMKily anJ in snmc in
.lances in an ovenh.MN. ('nnsidenhk inhnnu,Rcneity uf red cell veM+cily in Jtl/erenl
micn.ctrculN.uy veaacla was crn.wnlereJ In sume caaes a fall in systemic preaaure kd
lo curnpkle Jr.appeuame ul rcJ ltlls
65
(i4
( IIJng, 11 I, SJnthllrn, (: arlJ Hrn4. R 1
Hr.rul Rrwu.r h 1419 It 24. 191114
(J/h!f )YPP.1I{: I IIr II1MIvef tINI/NIJINMI alxl Ille I.IurIla M..rry milrl.hy t'INIINLIIN111
I rnm dN I1mAmyh.n Mc.h. JI Rr.car.161nadulec allal thr I(untmgd.n Mc/nMxlJl l lu.lt/
l.d. 1J.NknJ. ( A
AN7tF11 t1)11-S lt l 11I1: 111:1'AKAN SI11.FAlli PR(111/X;I.Y('ANS
\1N11I1S1/1:I1IIY I NIX)1111i1.1At.('1:1.1.('UI.TtINI:S
Ir. 11/1\ t.JIN'r, NNIN nI Ilre Ixnn.ertN'\ Itl an anlltf/unl r:NMlt JI;:IIMI /IM' IN-t41r:In
.NIIJIr (w.N- .rl Yc:rn. ,ur .ka nhJ. wNl lhe imr/tt'r/NNIl ul dlr.c InNhnp wnh rr.lNt 1
141.111 u/N kr.I JndmF ../ the hN rA1N:11 .IKnnccaw e. d rmM wINhal crll pn wr. y I yt Jn. :nr
.)r.. u.wd 11N t cll Irnr% u.cJ Lw the.e autla., an trlahwlNha) trl/ lulc arNl a.u1Nn
J.r11N Ir.d t cll INw, wcrc JrnvaJ Irnln Iht /nbnu u1 rJhhil :NNta. 1Is111M (1111yacrylallmk
/r1 clct 1a.(.INxr.r., d wa[ KYn that cnltlnlM I/J) Cell a-ulturt'% akrlv(Yt IruUl rahhll aaMa
.vndM.vr J wak .prattum nl INpar.n.ullJlr paACary!lycanc Ibe rkatnH+lNwauaally
.Lrwrr nM,vNIF INp:nan.uoJlc pnwe..yly. an, have hcrn I..datcal InNU t1w erNlrAhellal
t cll t u/tn/r mrdunn Antll.wlK% tn IIK.e pr.we..ylycan../xt/c% have heen ra/.aJ In dn
1n.d I IM' IY.JI a/llhCn/ln hlflal\ s: h't Ilvely the 11e11:IFan WIL11r tNINrllglyG111\ IIIaI Mete
uV'.1 IIN Ih /In1111/n1/ItNxl a1NI .w.% rnrt tn...-rcwl wdll the tdtxr (IJ.hr nNrvmy)
.tNtNt lhdy a nN.kralr kvel ..I en..% rrathv/ty wa..4r.alvaJ with IIN IrpJrm
.ull.nr pNN.v.IIva:ul..ynl1N.IV.d by a1NNhrr ta'II hnr IINe%u//l:lhly \nNMNh n/ualr
a.11%)..1 V,I%t 1/1.I/ .k'/IVJINN1 IIN.c rt.nl1..uMr./11IK tll)!~!a'tINN11I171 %/t1N t111JI
rh1lar-
arNC. in tIN INpuan .ultalr tN4..ylya Jn. ,ur rr.l..n.161r Lx arrlJnl drllclrllat. In
h11NINq1 artwl'CII IIK vJrNNI% ta'Il lylq'% aut /IN vr.vI wJll
lfn.nurf.r.r. V arNl Culrnm, 1'
IfNr hrurir u. f NNq.ln.i. rr A. hr 7N1 ( 12. 1'1M t
I)t6cr lul+limnt: Na1N.na1 In.Ulnlr..rl Ilrallh
I n.nl the I kparlnNnl u(11Nd..Ky (J 1151t, t Inivrt.ily uf (aldnrnia, SaN 1)/r Ko, t.a 141113,
1111MAN PI.ASMA KAI.I.IKRI: .IN REl.IiASfS NF.t1TROPIItI.lil.AtifASI?
I)tININ( i Ill 1 tt)1) (.( )A(:I II.A I It )N
GIJnnlc. Inwn vlahk hlutl:m nrutnh.hil% cnnuin a v-,vicly ul enrynK. Am.wn lu
ha- rckacJ In1u thr ctlraarllulJt rnv/n.nnrnI ( hrc ul Itle uNKr /Ilqrrlanl Flanukv 1%
r1a.I^r. whw h ntay h rcyrmahk Irw Iwdrulyaf al vital .tlw hur% ln tIx tunh SIncr
hunr.rn plJVll.r AJIIIArr/n IIJ. hecN.MrwN 1...InINdalc tlrulnpthd. hrnNwJa, ayKrrya
1NN1 a1NI U4yren tININ/n1/MNM1, the ahlbty ol AalllArcrn lu reka.e tlruu..l+hd r/a.1a.e
wa. /nvc.tlKateJ NrlNnq+hd% wcrr i.nlaleJ by tkllran .rtl/nIrMMNM, a/M1 aIa%ta.e
/rka.e wa. /rKa.nre.1 by LNh al eniyme I1nAeJ innnual..Mhc/N a..ay anJ an cniy-
nulic a..ay u.inR r(N/IUay-catlw.tlyl Ala Ala Ptn Val annrwr nrclhyl ct.unNlrin a% the
.uh.uah KJItlArcrn./1 1 1 I) t1/nd wa% incuhateJ with ncuu.qlhJ% that we+r (.e/ncu
h,nr.l w.dl. v1.. h..laan It ItµFfrnll Ihe tcha.e ul rIr.1Jw was LwnJ Io hr pnqnu-
Ir..N..l 1.. dM A.dldr'.n l1NNCn/1Jlu.n KallllraIn Irlra.eJ a mrumum ot M'K ..t the
r.lel . Lr.l~.. ..a.lrnt In J.cnr. r.l r.loo-r rNK nl. a Jr11rJ wn lo tktermuly it IkallrArcnt
wa% a mrp.r tnsynlc mvulveJ in nruln.tlhd ela.la.e ra:k a.e durinK hl.rN/ cua1:NlJnon,
? 7tp 1g t,l rla.tav wrrr rekaavl when 111/ni11a1n nrulnMthd. w.re nN ultatcJ nl I In1..1
mxlual pl:lana n/ IIN I+rr.crNl nt Na nIM ('a('1 hK 411/ min In aNrtra.l, rxutny.htl%
incuh,Nrd rn pcAalhAtrnl /klkirnl .x hactaK XII delicirM pla.nu nl.J.rd k..1hul
118II II6r1 1/1NN1/11 nl cLmtaVr. -Iha- atkI11NM nl INlr/l/t11 rreAalllAn'In IU Ixr!<a111Ara In
.k-INN-111 pl,lmll1 rr%hNrlt IK111nl/lhd rla.ta.r trlra.e Iu /Nnnul kvrl. M.xr.wcr, tc
ka.c ul rl/.tIV wa^ cnhancr.l in pla.mJ aAliaic/N in (') InhihlhK, tlw nclpx plJaua
uduh/t.n .d 1:J11Arrm I lK.r aml olhrr data .urKcsl that Aali/Arcin nlay hr a mJpw
cniynlr IryrNlahlc Inr dk rrka.c ul claaa.r dorinK Lh.NI cuagul:NNxl
W/rhdr.Erl V T KrN:Nh, II , lanlra, 11, 1.., SltAl, C. P., tichapira, M./mu1Nr
/nJn. M . t'..IKn. A tl , a11J ('.dnr/n. R W
Jnw rrnl n( ('h.aN nl Inr..rrx..N..n 7! 1672 -1h77, 1991.
OtAcr.Npppnf: NJ/NmJt In.utNtrs ul Ikalth a1N1 Iht 1wl.s N.Int111ai SI/t'INl' I PN/NI,1
I11N1
I Y.UII ItN' I IIIIN111MMm I(aVr:Itth (lnlrf :Inlt the I h.'111at..h/t!y ( hh uIM.ry JtNt
I'ulnwmJr y
%at INNL, I hy>:Irlnknl ul h1cdNInr'lenpk Ilnlvrt.ny S.Mrd ul MadlcuK Phd:Nk1
phlJ, ( 4.N1NaN Ilu.pltal kc.rarrh ('e/qcr. I)IVl\NNI tlt' KMnnlaN.k.1,N. Ih.lxlJt (JI/
NNCd 11NIv:/atauc. (:rnlva. SwIVC11Jrw1. Meta A Sh:up k Ihrlula I ah.N.d.nlr.. Rah
way. NJ
(1.1:AVAGIi (11 1111MAN I1N;11 MOl.l:('t11.AR WIi1G11I KININ(I(ilN
MARKI-1)I.Y 1-NIIAN('1S 11'S(1)A(it11./1N7 A('llVllY I:VII)1Nt'1: IIIAP
'11115 Mu1.L('llt.l: I.XISfS AS A PR(X'1)#-A("1(N(
lhr Ixe.rNl rrllrwt alrnwxl.lralcs Ih:N imNal hiKh rmtkcular wc/r.bt t/1MW1
AulilN.rcal.alxtwad:MNxlhati.arlivatatilhyAalttAtrln Tuhrprcti.r,tlMW lmnN.
grn. thr tul,la1rn ad C.nltarl atirvattvl h11NIJ.tKlrulalilnld atatkratc% tIN
,It/1vatNN/ ul
I athn X11, (xcAalllkrein, a1N1 Faliat X/ txl a/rKahvclv ch:ny.rd .ur1:Nr AttINNlyh
pralallll.rrw arN/ FacNlr XI clnulalc a% a ctxllplrt wtlh IIMW AmirNtl;cn, /x.Id1y.N at
:NVK'Iat11N1I1a. been drnwal.ualte) hrlwccn hacNx Xll am111MW AINi1N.ycn nrM ha
Ihr.w.kr nl adaxpNm to .ut/atrs u/ dKV IutNCim hrcn lully clar/lNd /n du. trlNNt.
Ihc mvc11F:N.w. r apkwc dlc rr~ltitrnlen/. hx aJvxlNinn u111M WA/nuN.}a n Nt a rl..t
IN.t1nMN1/1r MItI:Ne (A:NrI1n) in INIflhrlt \ylllnl\ a% well a% in 1NM/IIaI ItIJ%1/11 anll
I.IJ~/Ir:1
yc11rIK-JlIy .kllarnt in c:w h.d Ihe puleiem nl the ttixMat 1 sy.lrul (n n.nnl:d 111LINJ.
llw a1IVNINNNI LI 1IMW AInInMTe11 III A:M.hn Int'reawtl a% the t(ualNlty .11 Aanlm wJ%
nlarr,/4YI 11/ tIn' IIN'nhJlNUI nNaturr Ia/wever, thc IIMW linia.grn in /-:rNx X11
d+INiaul /d.1N11.1 .1N1 INd alt..uh ap+ncial+ly Iu Aautln 1'In1hl't/1MNr, I/N' 1111auuly .d
11h1W AlunN/yrn Ira«u INtAalhArcln-akhalrot pla.nu llral aJ..uhrJ /u Aanhn wa..M
crrav d a. c.Nrqulcd wnh mxnlal plaww Slnce AalhAtr/n, whw-h /. \IN.wn Iu ckvvc
(1MW lmnNlpCn, is ye/wrakd wlwn kaldm i% aJdrJ h/ l+la.nw, tlr hyl+r.lhra% wa.
Ic.tc./ that Ix/.tc.dy*1 by lallttrein waa tr.rylns/hk frx the erlhanteal .d..rrywN/n n1
1IMW 4innw/gcntnAarrhn Thr uh.ervaliumrcpx(edhetelnJictlethW 11MW A/nlms gcn i1 a Ix.wvda-Nw Ihal
1% aativaleJ by Aal/.Arein, a pnrlu.l uf a rcaalinn whNi/ /1
aa'cclrtata. '1 h/. ckav;aKr, wh/ah enhances ils assuciatwxl with a tkx LIx.NlxAmlr .N/
I:N r in a pla.ma envtnmrnrnl, /. ,m rvc nt dlal i% nece..ary Lw e slxe.>Nrn ol /t% c.,lx a n
aallv/ly.
66 1 67
Sad/, (' 1: , tidvcr, 1. 1)., Schahra M, and l'rlnNrn. R W.
h.urn.d n/ ('lrnr..rl InrrHrKnlrrnr 7 t9K4 I/M12 1984
Orh.r .rppxserr: NJILmaI In.tilulc. ol Ilcallh anll the Swl.. NJIIIM11 Sl/lml' IiMInJa
IIHNI
I l..ln IIK I hrumM..l. Hrvar.h ('rnlct and the Iknulul..l'y I)nc..Lry.y Scc11/M /d the
Ikp.uh/Knl..1 McJalrK (rnry+k llmver.ily Ikalth SaKn.r.l'rnhr, 1'luln4lphla
I'I KSI'I.("I IVI \ SIIRI /1('1: MU111ATIi1) pl l ItNSI'. RI'.A(TI//NS
I III: PI.ASMA ( Y IN 1 n(-f A('l IVATI(1N SYSTI:M
( N..atvaU.wl. rel.wlkJ in Ihr% revtrw pal.lr ah..w IhJI- Jurmp 11w pa.l Iw., .kr
alk., t r.n./.l. f ahk rvhl.nl e ha..w t rvrJ Ih.N nuny ld 11K h.ly dl Icn.c. Jr.nn.1 nyur y.
%I\'.Ihl JIIy hi.MMk ICIr1/I:11N/11, the InOanln1a11Ny fcy11/rllr, l Ia]NfaI C.MnhhIIMfll
II:/III-
wly Ir IIvJInMI :IIMI IttM/1MJy\1%, are /nlllatCJ by a t'1Nnrn11f1/11rlhJnN111. IIlur (M.NI'IM,
n.nrrly I.wl.n XII prlJlldrrm. hlyh fadrlul:u wery.hl lmimlPcn, arwl 1Khw XI.
hJv. hrn Je.wn 1.s hr rhr marK pn.lcln% rr.rl/rrJ 140 nuhJtr. anq.hly. amI IK/M.ay.dc
.urlKC nK'J/.urJ /kIrnv rra.lnnf, by Jl11va/111r ('I. I Jl1.w VII. IUIwt11/1/ a1NI It1:l.-
lunw.lrn by ./umdJllnK rKutnqdni. Jlxl by rcIca.u1K fw.MlyAmm 1'un/a Jh.nl.d rJah
II:N all..wllI 1111M INM.II ./IMI /11111/111MM IKllllt'JI J%Vy\ h/ t\ lkvehquJ I hr rynwlFrn.
XII. 1'K. alrl X1. arr..,nvrrtcJ by houlrJ prl-trnly.i. mh.lhe altrvc -arnnr Ia.dcJV.
X(1,A.Jldfcm afwl X r. I Iryh nM.A l.Jar wr/gM ~Imrn.yrn 1. a n.mrniym.lu. t ul.w hK
Ihr nMJ..o1Jf rvcnl .i1a1n/1nF' J111111F` tn .tfr..lIN11Jl'1 JC1/va/NN1 havl 1\I;IIn 1.o hr
/11411t4YI :/nJ dK t.dr ul IIw4 patllwayc in ccnain JLCJ.t% ha, hlrn lcnlauvely
IM.JII'lI I tl~Pltl' aJ V,In, e\, nl W IIIK~I HM\ INYC hrln r:11K.I In Ia1Nk111 w1tI1 Ihl all~
Wlr\
PrnvnkJ \rvcrJl l llrnl aI li-Jm1111% UI lhrMM111aINlr\ UI IIK a'.MIIaCt aCtlvalnwl %y,llm
n1lhl.nr Ihr nrlYl 1'n 111f1htf a1rI/.:/1NN111I hN4 hl'm/CallnuwhlIl!e and II//IIII/IMRhIItll
t'aI Ilt'hlllllul\ t0 J1vlh.(1 /IMNI' Vn%ltlvl a%%ayi /IM altlva/NM nI 11K cnnt:Nl
.y.lrnr
f IolAlaa..hnuAl hc .h111rJ Irnnn raamlmng Ihr partlaipalMwr n(1hi..y.tcm in IKnwl.
la.l. t.. 11K tuk lll urt[Kc IIIcJIJICJ rCaCINN1a a) a Jtll'Mr sy.ICm in irdl.nnnuhlry
lh.ra.r.
('.dnrrn R W
l.mnwd ./ ('lrnr..J Irnrarixnnun 7112411 1251. I91(4.
I1rAcr rrppn.t: NalMlnal 1n.tilulr../( IIealth anti S('OR lnr Tluun/hu.i.
Nnmt the -Ihromhlhi. Re.earch ('cnter arwl IlemataN.Ky 11n1'.JuKy Sr.li.Mf ./1 the
IkparwKnl ul Mrdn Inc Trml+k Ufuver.Ny kb1.4 u1 McJw'inr, 1'h1lJlklphla
INA("I IVA (1( /N (/1 1-A(T()k XII A(7IVI: I RA(iMl-.N ( IN N()RMAI.
IN.ASMA I'kIilX)MINANI' R(11.1: OF C 1 IN111111T11R
Ih.. .ludv nll~...lr. Il..a ('I Inhlhn.w i. the mapw uJnMlur ul Iil.l.x XIII in
nwIn'
f...a. u. 1I~.u.. I6.....o. /n,.a ~. .upt~a/rJ hv 1.11 Ila' .ul.lha..d IIK &
../ 1 .. .., \ I11 .... .. ... ... ... L....r.. ./ .... ,n. ~n.l ... I... Is dht...n ,M 1., u ru
t.la.ue.
n..l t,,/. ./............., r., ...1..... 1..~ .. i .,n ,1. L.L.e ..Lun.J.' Krl rl., In.t.b.y.-.1.
(S1)S 1'A(il:) f.f the I:achw XIII-inhihituKCrlrrllkaes (rnnu:J in yarinu. Pla.ma a.lhr
re.uh 11( the nlal'llvalNnl 11( IWr1I1eJ raJNtlaheleJ elVym[ Spcc.hcally. in purdicJ
xy.lems. the hmw/kcular ralc am.taMs (lN the rearlulm n( IacaN XIII wuh ('I
inhihihw, o,-anliPla\min and anlilhaanhin 11) were IN.S, 1) 91 anJ // 12 x Nr M'
min'. rc.pct tivcly. 1 urtlkrmlKe. SUS 1'AGI: analya\ reveakJ thal I:I .hnchnlnklril'
aMlqkacs wcrc hwmrJ hrlwccn "I-hactut XIII and cach llf thc%e Ihrre inhdnhw.. In
auNra+l kmrlir and ti1)S PA(ili aludtes inJicaleJ Ihal hachK XII( did mlt tearl wilh
a, anlNryp.m .a r., maculyh+MJin. In prekalhArcm-Jelicient pla.ma, Ihl Illal tlvalMM1
rale nln.lanl ld 1'arlur XII1 wa.14 4 x 1f1'lmin', a value thal wa.c esacnually wk ntiral
tu Ihr vahK PrrdNlcd Innn thc .IUJie% in (wnfieJ .yacmc. /1/ter inx'livalnln in a
nnrnwlldJ.nu.74'%..,tlhcaclive"'1 I:arhwXlll wa.hwnllHl(urmanlnq.kawilh('1-
inh/hrhw, wlKrcac 2h'x ut the cniyme (nrmcJ clNnPlcpc% wnh a.-anlipla.alm anJ
anptlu.mJnn 111 ( )Ihcr ubur vrliun. Prc.enkJ in thrs s1uJy quaMitalrvrly.knw.n.lralc
tIK Jlnumanl a.k u( ('1 u.hiMkw in the mx'livalilm n/ I'wabw X111 in the pla.ma
rndKu
Je ARu.lim A . Lilmn, 11 R.. Pi.ky, R. A.. ('nlnwrn. R. W., and S.hapna, M
hwnwd rrJ ('Inti.'ul Inrraixuri.a. 73:1542-1549. 19114.
Other supOw(: NalM.nal In.tilulc% u( Ileahh and the Swi.. Naliunal Scirnce I~.wrlJa
InM1.
hnwn the 1)ivi.i.m Jr Rhcurnah/M1pie, lAlPita/ Canumal llniver.ilaire, ( k/Kva Swll
ierlanJ ('enter hrt TM.wnh.rro and Vmeular Rescarrh. Ik1+arlmcM.d McJhal Rc
xarch, Ka1hr.IKhe Umver.ilcil Ieuven, Leuven, IklKium: anJ lkmahJ.+yy (Ml'.11
fqey Saclwm IkparlrrKnl Id MeJirine, arrl ThnMnMr.ic Re.carrh ('cntrr (rmpk
Ilnrvrr.Ny SaiMrJ ul McJitrnc, PhilaJeiphra.
IiFlli(TS (IP 1)11"I:R(iliN fS ON 1711: A(11VITY (N
a, MA('R(X31.OHUI.IN PRl)TEASECOMI'LIiXI'sS
Tlk rn.yuudc attivily..( efwry+kaes.u( Pndeaacs. purlicularlv chym>twryp.in and
ela.lace. wnh huaun a.mxnr~Mlhuhn fb.,M) rn the Pre~ence anJ ah.crKe ..f /kler
pem. wrh a...Rhum Jlxkcy) .ullalr ISI)S/ and hwtR-cham (a11y uliJw r, rrlrnrcJ ln
tht.l.:rllr r 11 wa. (lwnJ thal ahlMwFh u.M hunun kuA/K yk rla.(a~e 1111.I:1 c.Nlq.k.r.
have 111tk.M mr ela.hJytir activity in the ah.eme.A JclcrKenl%. ela.tnlyli. x'lwlty
Ikrlwrw..i4ni/icanl in,hcir prc.ence M cl.uenlralNm. aq+nlaimalinK Ihat.d naNUrally
fMruninP latly ariJ.% in pla.ma. As rc.uN. xlwlw. whcn a..ayeJ in thr Ixa.crw'c ..1
Jclcrprnl. .rKh a. SI)S .K M+Jwm Imcrdale. aM+arenl ela.lolytia ac(wuy ul III 1:
inlrcax\ alua..l Ihrce 14441. real'hinp a ma.inarn at a lklergrm avuk eulralnln ..1 1 2
mM 11 the IlI.li i. InltrealeJ wilh an eacr.c ./1 a.M wlh that rn the ahafwc t.l
lkkrKaM all ela.lulylK' a.iivfly i. M..1. arul then a..aycJ in the prr.em-e ul rnl fcavnK
cllr.~rolratNwn ul cithrr SI)S ar v+w/iam limdcale, apparent elaalllylic aclivny in
crra.e< a+ Ihal ul Irce 111.1: Jelerminad in the aMeeec d JetcrKcm. Ihe .nululahny
el(n'Is ld lklerKcMa appcar tu he y+n'iflc (.r /hr u,M 111.1. cnnMdea a. SI )1, vrliuru
hnatidate. and .walwm ..kalr inhihrlcJ anmiJa+e activity ul hllth Irae :nwl cnmpl..rJ
III.E. In ex'h ma.rrrt the lklcrr'erM c.wll'cnuanun 1.s rcJuce umMla~c alhvny wa.
a/hmfainmalrly 11(1 µM 'Ihc.c JJU arc can.fvlrn/ wnh a nwwkl in whnh pulc..yrN
whn h prwr..
Khrlly /%a%M1C1a1eJ will, 11K u,M /MlMCa~c aoml.k. rrlhct Ihan orK in
1 (,9
(.
lytl. al llvlly 1, Ilfh IU II1"oKlallJ fn/y111C 1IM' JUIIMM\ \IIFra%l Ihl\ plwm.nMfM1u
/nlJy
hr 1nyrN1JO1 in Ihr palM.ycnc.ia 14 lnqlhy.cnq an1l IN1M'r mllalnnlahwy J/va.a.
I rrdat _ I /l .-1 .rl
A.rrMdh .4 dfr N.n 1nr1 Ar ralrmt n/.1o frnt r. 421 lJll tSll, I'/X I
I rlNa Ilse Ocp,nlnMfn ul Ilh.lcltn. anJ (7yfMauh/yy, Nrw YiNt Ilnlvrr.ny MrJaa)
('f/dlf. Nl w YINI,, a1Ml 11>< IXpaflmcM fd McJlalf>< ]IMI (')MVI %CrVlli', Ill'Ih'VIM
11.yNl.d, Ncw Y.Nk
M"11V1 IN11/(MI I/IA11 % ANI)('/11(('ININ:I NI:%I\
Ill lhl' ~11N1y INCM'111a'J hCfa, Ihl rMV11dJ1M uan.l/NlnaulNl ol Nalhh 1 f 1 taII% h,l.
1wcn IM-wn h. l.r IfMlu.cJ hy Jlcthyl.hlhc.trnl, c.U1Mlr, rlhylnykU MIM.1 a.MI c.Ira
JuA M..c./l.1JfMlc.lt/.d.whnh:MaIMMN.Nh.lra1c.11wtalcclMJcvlnvcnhl.%yn11M.
.1.. wcr. tN.l Jxilvc a% lfJn.hNnnuF a'rro% ul Iha.c cc11. 1 hr rchNivc t:MC.ld catrclMrl
atn,ran /IN/oJn/N,. wnh a'tllynyk,It.Mlu.l c.n:MlMd 11(1 nklhyk.lrah..l -1111 rlbyy
kn:MIMd uMo.c.nu1e prrJlkk'J Ilse rtb..rvcJ Ifcallllnty,11,KIq+Llmn' Il:m'hw/11:N11N1
lIw Ix1 111.11 nMSC.u.1 a1M1 /ht Illl nMthyl IfMt 11/t r/hyl anahlp arc 1/MNr 1NMl'lll
aalrnlrnV fn lfHr 1h./n I:.t1,MhUl .UIr.Nt. IIM fnVr.11F`Jllw.' hyIMM1K.1. Ih:d Ilse ENM'IL
ycnM Iwecnn.J 1i1 an PsIf1-17aT /% Il'I1h'J lu 11% /rlJllva' fJla' t1I l Jla't hlI
l%Itlrl(l11 IINUIJ
I/rNl by Ilse //111 InW111.1I .M IlvJt/ll) ~y~ll'lll uI IIM' IJf F;CI t tII, fJlhct
Ih,111/11/1':N tlVlly J%:1
MNnwNM Al..r, Ihrco- u) 11M: IMr.ah/a aa./1 unb1ta11/ll1I 1'IMIayC/MNq Inlr/nM'JIdIC~ ol
e.Ir,Mllul /Iwl.dwd/an hJvc hrcn .ynthcavcJ IuNM IV /MNtr.tu.lrr+Nlc a1M/ IM.Mnh/pu-
1NIVIy l h:n.Mtl1//1'J I IM4' cIM/1yltMMV :I/t' :IMNlrtll/laltIy II) llf ll/ lllnl'\
nMlfr IMNI'lll
IIIJn..I/,MIMd a. IcIn.llNfumK ayrnt. II N Md yl'1 LMIw/11I Ihl'It Iran~LMt111nF :Ih/Illy 1\
atlnlNnJda III IIMIf III/lYl rraalMN/ wllh I1NA 10 hN/ll IINA 7MkhN'to, 1N Ilt Iht'/f Inlta
1'1'IIIIIdr alNlvlrVMNI tll CalaaM/l aVtfapl11V IyItNI I)NA J:nnafc INC.mnahly IKaun In
:MkI11/1M/. 11 wa. van hcrr Ih:u Ihl o1M'ruaNnal :Kttvat/ng .y.lcnl fd a C.NII/InnNl,ly
tldhucJ llrnr ul hunlan ulanMlalv tuaMN cellk can .ynllKwc a alallM,f c.truKrn. 'llu.
M('1 1 1 cll :M nvauny .y.lcm ha. ha cn uv.I /n /IM K rl'K:1fa hll~' l'IIIM~ III IW IIa1C JO
aluvatrJ ilurulKJi:dr ld e.natliol nMtahl.li.nl 'Ihcir IN.IinMlary tc.u11. pnrvMk tvi
tkn.c LN Ihr LNnulilM Id a nK1alMJUe wh/.h al/ct w'clylalifM, hJ% tin chaan:au.
KfJidlK nMlhllny ,d 171f-ara911ay 111.2~S-cp,>tycata 4 en 1 IMe.
(IUtJy, R 11 ,( iakliictlcr. 1. W 1 r(htrfnr, P. W. . Ahlk1 Naly S, 11unr her. C.
K, MtMNC. 1' 11 , Ir , and Rhim, I S
In Mrni,lnl, (: R aMl I.ip.etl. M 11 IcJ. 1('.u.Y h.d I:vrfrKrht, Ncw YINA RJvtn
I'rc.., I'/X 1 M. 121 1441
pthrr wppmf: NalifMJl ('anrcr tn.111ulc. AnMrican (antcr tiucirly, and Ihr luc arwt
)c..i. ('nmlp /'ufMl ol 1~IM1 WfMh. ') X.
I n.ln t11. I k L.uu1M: n11 r1( kganic and lliuklica1('6rmi.Iry, Sf Nnhwc.l tYNlrnlatilM hN
Rr.caf.h anJ 1 JIN Juun. S:M AfMfNIMI, 1 X: IkpJnmenl ul (M..trvlc. JfMI ( iylw'c/d
n/ v. NJ~I/N l'1Ilr/c f~l MrJ/cuM. ltNL1NI, (kranlmnl ol (1MIni.tty. Nun1Ma.lrrn
14uv, /.dy, 16.InM :.fMl I.dMN.d.ny 11 (r111aLN Jrel MllkaulJr NMJnKy, N.NMN/,d
I mM 1'f tn.hlutr. lil'Ihe.JJ, h11)
A\S( K'IA'l l( )N l)F 1111RIN W ITI/ TI11: MAT1:1d: f CYT()tiKU.1.1:T(1N
11 ha. Fran prcvnlu.ly p/dulaled thal wrlace rrlcnlhr:nk twlNCinc hccaNnc .pc
ailically a..fxutrJ w/th the Inlcrnal p1:NCk1 cylar+klchM u1NM platelet al11va1MN1
t'INIr hnl'V 11t ev11kM'r Wpl11Nt lhiv rcnefal hyIMMtIIooK Vlll'e /11l %allll R'raIC111(nN111
Mlw VIMIwV III:II IrI:11Ck1 Nlrtal'l rCfllIhlrv (aM /IIK/n hIYYMIe %FICa'IIN-ally a\MM'/:IlaII
with
Ihc plalrkl l rhfM Mwduhlc cyN/.LckNM (111ihrin wa. Jclca'tcJ nnrnluwJ..y/avlly ul
the wJ.IkJ I ntfm mwh/hk a'yln.{,ck11M..d IhnMdMn acllvalaYl plJlckto urwkl a 1NMt/
Unn% wlwra bhrln IM.IynlrrivJlilM aml remdlaM ptcctpilJli/N1 wa. bllr#cJ with Gly
1'lo Air 1'l0, a.ynthrlhc (wINMk that Inh/1MN IMIIy111rrIfalMN1 UI I/tY1n IIMMMNIMr (')
R.MIILJtkJ hINM hIMNMI lu thrlM/hln-aclivalcJ plalckl.:nwl Itcau.c a.....lalad wdh
Iht a yur.4ctaLNI ((1 1hc a/1MNln1 UI ralln11:/1tkJ hhfm h1MMI If1lhnMllh111 :M'u.rlcJ
du1-u11.J.dMnM plalakth :IrM) IhlIr a'yIUVArIa'11M1% a11MMMtJ tu att1N/1 NM,( ul Ilse hbnn
IMNnM11./1tINN//1N11 ,M IIV,dC1I a1N11nJ rlall'kN a1MI 111~ If f yllhkl'khM~ (11 lhl a..IMIJ
b.Nl nl IrtNln wlth a ytrr.lakllm. arMl wllh Ihr plalak1 wrlJae wJ% nrarly qu:mlll:dwcly
I/kMAIVI by an i111111MMIY (NCrJraYt al`a/n\t ayIUVLakNM\ (antl ('1, an /nntMMly JI:Inl.l
IMrI.11a/I f/MIIJNInaV IrI ININIaY Ifa'alaJ platakIV (anh MI1. a/MI a nMNMh hN1aI
:I/IIIINMly
lu dM plJlrk I.utlrar ylyclMNdcm clMlpk., (:1'll,( iPIII (au1I1 (1I'11I1 I IMY a11IdMM/
Ic. hhKlcJ AIN' aml IIu/Mlh/n i/Mlua-eJ platelet aKgr.'Ra1MN1 a% well a. Ihrun/lNu
/IMI11a'aJ a 11N rrltal'IMM Analyaad the /nMnu1M1(tflY'11111a11'V athtanltJ w/lh J1111 l', anli
, Ml, arMl ann r a'lll InMIJIICrrcIN c></rachat'"1-surlalx lahrkJ Id,urkt% fcvcalrJ dlal
IlK.r auNlhlNhc% rcnlFnvrJ Tlrc.a Ja1a .ugge.1 thaN IhnM/1Nn at IlvalilNl
/d p1:NCk1% tr.u11. in l/k .pca'i/ic a...wi:Ni1M /11 hlxin wNh 11M Id:uakl cyh/J,a'I/IaM,
Ih:a thi% a.a><IaIMM ncly he mt:JialcJ by the (:MI,(i1M11 crMM.kR. arMl /hal UM.c
nMa'ham.olm may play an InyMM(:u11 nde in I+I:NCkI argrcEa1MM arMl .hN rrlr:wn.Nl
ilMlua'aJ by dvfNnbin
lbayn.ki, (: 1'., K.Nnccli, 1: ,('icroirw.\i C., Knlghl, l.. ('. Kal.hy, A, Xrlva.-
tava S.. NuMior.rnalf. J.. and Wal.h. 1'. N.
The /.Nnnfel../ Rialoxi. ul ('hrrni.arrr 2591111:t217-S2SI, 19114.
(Nher .rprionrf: 1)clnrtnMnl aut Ilcahh uMl llunun Servicer.
UrlMn IIk 'IhnM1lMl.i. Rcv arrh(enlcr. Telrylk l)niver.ily 1aIMMII ld Medwine, l'hda-
Ila111h1a.
INIIIIII'1'1()N ()1- I;IHRIN(x:1;N RI-1'I:1'f(NtMI1)1AT1:1)1'I.A M1 1: 1"
A(:(:Rl:(:A-Il(1N NY 11H11:R(N.(N:1)llS ANII-IIIIMAN IM.AII 1.1:1'
MI:MNRANIi AN f111(/1)Y: SIGNIII(AN('1's ( N' AN M, -(Itl/M111 PRO17'.IN
1)I :RI VI:1) ( i1.Y(Y )1R(171:IN Illa
11 i. Vrnrr:Jly accr(NcJ IhN the maMlr phy.e/kagical nik ul lihrilM/rrn 1% rclJtrJ ar
11\ tlNlvl'I%NM1 (1111MIII Ihat Il'aJ% 11/111f hMnJIM111 alt hkMMt a t.ll% :I/MI llt IIM' :nla%I
Id
hkrdMy lu Ihr .IIMIy rcplalcd hcrc Ilrla tukr~fM/. aull hunun pIala'h'1 nN111htJ/K :111//
vra were ra/vJ ul tahh/l, ayain.l ulcmtwaal. IMapatcJ IaMU hunlJn I/II.N'1 IN f hynM/
Iryp.in IN prlMaa ItcalcJ I+latckl. A.Mrinlall aMi ahyrmwrypan a/Ml ann pr.NlJ.c
/realcJ platclcl mrmMane anlitMMlic. (ly(: atMl 1ah IrayruwrN.1 fnhd.ntJ dw-
hhrirwlKcn IfMhM'eJ ayKrrltati/M ul AIN .1inwlylcJ anAtll chyuMAryp.u/ LcurJ plalr
kl.. 11w %/x'a iIM hilMlmg ul "'I /iMuMlKen It/ Iheae plJtckl% wa. ala. MJMMICJ /S%
rcvealcJ hy Ilse N11I111f11 /kNkayl .nIINe IMdyrl'rylalnlJe Rrl ekctn.plM./l%/% ul '1
f.ufl:MC ralhulJl.IcJIIrlt-k1IwINru/% a/1.Ihyllwcka1ta1~11M111~IN//IIM'/111111UIM.IMra//N
, 71
711
Ltlcv (NCl+arcd IrlNn Ihl'a IJIx lad pnNl'In\ INlYllNltlnanl ctN111N.ownt% IM1 1hl' .ur lacc
.ul
tn1:M9 pl.dckl. waIt FIyc.qN/ACIn. Ilh arMl Illa 1llcvc INawcln% wrrc InlmutMqNCI tpr.
IJIPII by 11I Ihla'a .I1/1+INwIN' III ;MkIt/11N1 thyl+Mdrylhln IrcJlt'lI I+Iallkt\
l'1N11I//waI JU
M, (rt. IMM/ ININI'111 IN/ IIN'Ir \Uflall IhJI wJV alvw. /I11111U/M+INIY'/11/llllll by IIM
IIIrCI'
/yl.k.n1.1o1i1+I.rh'Ia't11M'1111Na111:1111/1MMIM\ I1wappearanlco11h1.M /+f/1MM11NMaIn
IN1 IIK VI//1N"C ul t hynrwryp.tn trc;dnl pl.tckh nNtclJlad wllh IIN cyN..urc l+1
hhr1/M+r~lu rtlrpa+rv .NI IIM pla/t'k1 .urlacc a% evilkllall by Illc i1M'naaYl pLNakl
aK/ICy.uNln :uld IM rnhJrMCd 'I IIINInnrcn hrnding .hnwn by chyuM+lryl.an uaJIrJ
pL+lrlcl.
<h1Mr rl'IJI.ll .IUJ/cv .uygc.lt'J that 1hc M, :- (tb IMM) InINI'm was ;1 INO4n1yIw
l lavvyY pn.1+M 1ld glytlqadcul Illa Analyvi.IN,..MhItn11MN/aYyl.nnJtl FlIv l+l IIM
rUJpN t hy ItNN/ Y1N/l a IYJVJI,'l' IN/Nlul lV NI ~+:YItaIIy INl//ha'11 ~IyC.+INdcln IIL1 .IINt
all1Iy
.1. ul 11N /K'plllk ld ylytrqNUlc/n 1114 nnnwaq+rtYlp/lakd by JIIII /NINL/K' IrP.1IC1I
p1.nc la1 nMulhr/tM .1n1drNly rcvcJhal lh:p 111C M, f.h IMM/ININCm (+nNlu. rJ hy ,hynM+
uyl.vn.nl llN pl,qrlci .uIIJIC w1, tIM nIJ11N thyllMdrylqM l lrIVJlc INIdu.I ld /lya l.
IN.drul I11.+ A htlN 11N .1. w.. INly..y d Ih.N IIw M. N.,tMM/ l. a p.+rl nl /Ivl ryN.dlln
111.. INa K11) /NI IIh' %UtLM a' ll( IN.NI..IytN al/y Irt'JIIYI /+IJICL 1% a/NI d nlly lu/l%
tn.n al
hlnnN+Ean IN1NI1/1/' J/M) /IhrlrM./t'n ItN1UltY1 I11dl'h'1 a/{Frl'p.nN111 J1NI 111.11 /I1C
ht.IMM/
+IJltl+n r./NN+ r.l 1lya.r(NrMCn+ IIIJ /n 1n1.Mt /alallkt% n6+y rflYcvIlt dM IIh/uM./`t'll
(.a+.lrn/ a1.nl.un.,/ K11ayNlNCNI lll.l
Kln1MV11 I lu.ryn.ll t: /' .uNlNrrNr.u..N.lr S
Ibr L.unr.rl.r/ Ifr.1.,nrd ( hrmr.ln ;tN11t191J'/ 41th, 1'q{1
n/hrf artpp..rr N.ad+r....d In.lmnr IIa Jld+, NIh.NIJl Kra Jrl h X. rvN r AwJIJ atMl
IIh knv I ..nrNl.drn
1 rnm /hl I hr..urh..r. Hr.a.N. h l 1 u1.1. 1 ranplc I lnlvar.nl ( Ia.d11r Sl Nr+. r. l'cnlr/
I'IuLNI.'lldua
('11M1'ARISt1Nt11'I'I.A1F-1.1:'11IIIRIN( NIINKi'l'I.PIt1Kti/ININIA('1 ANI)
I'Kl )11.(11 Y/1( AI I.Y I KUA 111) 1't A 11.1 1TS hY 1/S1: l 11 AN
AN11 tit.l( (/1'Kt111 IN 111J M()N(K'1.()NAI. AN111I()1)Y IMA 1_'1)
11M' .dnl/ali n/ Ihiv (I yw r a+tc.lhal a lounnc rtMNMN lunal anhlNNty /MA 121/ wa.
-Akt trd by a 1aaulny IS ( vupcrnalanlf nl hylNIlllNna tcll. ucrclmg antt hlunan plalc-
Iet antlh/N11c. Ie1 IIMy/ ability I1/lnhlhtl Ihe IIINInUglTIIIIhaatYl arI;rlg:Illun UI l hynNl
tlyp.al Ircvlr:d plJlrkl. MA 121 u1h/hNCt1 the haMting n/ '"'1 IIINIIMrKcn lo A11I'
.UnwlJlaJ mlal I hurnao plalakts anJ tu I+lalcktv Irealcd withv hynMllryp.in IN pnNla.c.
MlNCnver, rt Inluhacd the IIIxilMr~cn IaWt'eJ aggreKatinn Id thc.r plalclcl .uy+an
\NM\. I1N; +kgrve l/l mhlMli.Nt was artnllar in eal'h /d the thrcc tyl+C% n( plalc kl% le./ed
I IM inlcraclNNl% ld MA 121 with Ihc "/ lahckd .urlsac t+NrpMNkn1. .d mt:M 1:IINI
chynMaryllvln trcatld platekl% werc vnNIMd by immunnprcctpllalam using Sruphvlm
c.w r u. uarruv t lcdcd wlth Fu:N nNt nM+uvc 1/;( i /olluwcJ hy S1)S (N+Iyacrylam/Jc o
ckcln+pMNC.i. a/Ml auaNaJM.Rraphy MA 121/necipi/ateJ Illc Klyl+qxlwcrn Ilh-Klyau
pndem 111.1 I(ilIlh (il111.1 clNllplc. /nNn the .urfale u( IkterRcnl wduhdlieJ rMxi
hum.n pl.llckl., u al..+ prcclpnalyd ( il'/lln /rlwn the wrtatc u/ ahyllM+trypan ucalcll
pLlll1.t. I'.rtl.lly ry/r/t+ad 1;1'lllj was aLl.lunnnmKNCC/pnalcJ F+y MA 121 lhc data
.uyge.l Ihel ON r.f...u+. d //IN+nr.r. n rra rtaw. by A11/'. t hynMN/ypan lN ININU.e 1%
a..ra+Jlyd wllh.laLlr..nv..l la'IIL..NIdN' 1IJh'Ifl vurlxe
K+.nMYki 1:-, I cc 11 . Mcrlin, F. /Icr.IM+ck, 1)., Tuciyn.ki. G P anJ
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lhIIN1/INrNt Re.rro.h W IS49.19114 .
(hhtr srppoff: Naliunal Inaitutcs ld Ilcallh anJ a Slxtial Inve.tlpataN.htp AwJIJ
In+lu Ihr AnMrM;an Ikart A..aocialiun, S.wlhcJVlctn Pcnn.ylvanu ('halwcr
1raan dlc ThrutnM+.i. Rr.car.h ('cntcr Tcalpk Ilniver.dy Ilcallh ticicn.'c. ('colcr.
1'h11:Mk11+11ta atMl ('colrc NattlNl:d lk Tran.luvMm Sanguine. 1'Jriv hrancc
SIIKIA('li 1'KUI'1.K"I II-.S t)1 1'1/1.MUNAKY 1[NIX/1111i1.1A1.('Ii1.I.S
'11M a/qINNV' lung lorm yual 1. L.IMIp clwIJJIC 1hw nlcan% by which INdnwwr.uy
cmkA1M11:11 ac/l. panM /palc in c.lahh.hlnp lhc yur111y ut .y.lclnic arlcn.111.1aNN1 I1MN
.pltcd mtcrc.t% arr in I1M ccllutar a1M1 nMdaYul:u nnanm by whlch 1ht ccll% aluvcly
INIrC..IN.IvINy+tMk IMNIIMNIe.. IIr.+IMNOMInc. anJ lMher ca-ilaUNy .uh.tarlal'...+ a. tl+
Jclrnl/nlc whM h pJ.aNl lu JLlant tarpCt ti.wc. arMl which tlll lM+t 11 vcnl% ttuc th,u IM
rl'Ka1t11Ch' t1/Nk1\ta1NI11a~ UI IN/IIINNIary cIMIl111M.'hllnl a%a/IM'1:1(M+hl'JIIy MIIVC .uNl
lt'NMNN/Vl' (/%%IN' w1I) Ik'/+c/M1 In IafICC IIKa\ura tM u1MkrV1:IMt//11,' the tkIJ1Ir1I IIyN.l,la
phv .4 Ihr cmkwlMbal wrlalc in tcrmv nf nlaliun.hipv 1lclwccn cniyolcv, hlnlhng .Ilc.
a1Ml e*ua cllular malcn.d RapwtcJ hcrc ic . nIg11MM) /lN uMam/n~ .ur1 Jlr la pIN J. ul
CMIINIM'I/JI at'II% ANawlll/' INl'VNNNIy MIUCIIal,'In/l'lI \If1N111rC\ a1MI IIM' aIt~1/1IN1111N1
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nary ;ntlry lN raLhll /+IIhINN1.Ny Inlt'NIVJsl11Ia1I (II:11 hail ncVcr Iqtn 1'alNnral 1.+ INU
M.,Iy1M rnilnM% wcrc .ecJld anlu yla.% cuvcr.lq.v in IIJVk. lN Lu. N w.ll dIJM.
/.krulNl lnl. rl..v.q+c nnlnutwr-yl.wlle/ni.lry alMl nNllinc Iran.nlivvMm chY u,+o un. rr..
cupy wclc IltMk/tIka'n a1MI aaVy% hM al/l,'Mlll'n~Ma'IInVL111nF` Cn/>,'nM' AMI
la/IM/Nv1N'1+IMIJN N wlIl' C;nrMJ lNtl IuMlt IIN elet'InMI InK//+rrII+IN 111 .urlal c
rcplN J.. n.1d1.
.IM+w b/,ll 11 +a Cv1lknl III:11 IIM' HMkdI1l'hat ccll .nr/aro: i. IJr nMna ruolplra IllJn
rCl'l.r111/l'I) INl'vNN/%Iy ttle Iww .utlal:c rcpliaa. %M.w vlnranuc +N' wh.d aa. INrvllNl.ly
hcliavc'd latlr uluavtnltnNe. AI+IIarcMly.lhe KlyclM alyM Ilvcu a. rnr, a. a al /der
culr/.Nl uorcallaY/ a c11.. l/vcrall IIK rnlcnMnraiu/c. har.IrlM lu/c :uMl uluJ.u.4n lurc
III 11N C/Mk+lI1CI1aI ltII .urlx'c ap(war wc11 lk.rglMd M/ I.Nilu:NC u/trr,'N1N+na I\'IwIY'/1
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IIGMr/N/M.la'CI/I:11 1.vc1 Ihr INCriv ./lc. 401 .urlact .niynM. JIMI /N+..ddy hrNUrNM'
I l'l l'I+la N
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iynlr.l ap.thk nl Iw.rr..mK.It.uLNInK vaw/aliivc suh.lancr.. A/skNtg thr.c an cn
Iyllk] 111.14 l all t/kIat>..1//r IkNatlvl m11a111111a1/Ky IIKIt/a11N% Nk'h :N IIK IsIIIIIN
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hntlc rurul,tlnwl If.Hn JanuRc by mtlanlntalary nlcdianKc atkl n.ay al.n al': h.lw.wra I
Ihr rrkMdlkhaI .cll. dKnlv Ivec In aJJitMm hs Jr~raJat/vc rniynK., Ihr rlkhwlklul
wrl.wr 1% rymMJ with rrlcphu. LK vlnK inllannnaalry nKJlaau% and.nccr rst ua.
IIIry \u1Nl,lrk'c\, aMI rlclI1t.k at11va1kM1 clic/t% rlthllar rl'%IMM%r\ I'ILMt~ LI lIINtJall'
lurslk1 tlk t aIlular atul ukdraula/ rman% by whp h pul.awlary elkhNlk hal. rlh Ir.. r%%
arMl rl'%IMIrNt Itl C/fl UIlt,nl,` MMIMMIr\, /IKJlatln\ and rcLdrJ .ul..lank r% w01 r.qullc
IIn1/1fm,IMItnK M.I.N11y I/I lhr II11r.KrJplly../.urlax'c cnrynK% anal fr.rlM.N. )kd a1.a1..1
ttk IIIIt.k1'IIUIaf rvr.a..klunlnK a, pan .d IIK IntcRraKJ .rllular Icy.wla In IIK
l.rk ludm4 vlh..n ..1 Ih/% palpkr, tlk aullk.rv nulntaln Iha1 whal IIKy havr nk'J lo
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rM.l Ilu/lllq,lt kK,hjkw..d wWC ILftanun,dwMl anal (111\ 1% in %Inlc ul th.u ahlllty, in
Ithnn1,M..1..)'k .t..v., 1.. I/krra%c tunkr..vaMular (.fnlKahJlly anal rnJlkr :1 vauMhlatt../l In
m.my way% ly/.kal td Ihat vrn in Inflantmalknl A% an.Nhrr .uMhrnlr tlky
twh. dky havr nr,uk lk:u Ih.d /nh.hMl..r...l (/'N lan ulalr ...nK tnllanlnla4ny
rr.INMtw. vr/y tu1M h nkMC ~cvrfr I mally, I)K mvr.tlRat.M.11rIKvc dlat Inlrla.lkw1.01
t/khdlk'I111/11 /n rt..- wlth I'1q arwl, u/kkr lc/taln at.atlt.latkV. ('Ih 0141 dk Ir
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paltm.lp.n[t. m t1K .M Ull' /IIIIa111111.11.Ny 1l',IYNIM
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Ofbrr srpp.M: 11 S Ibhhc Ikallh Srrvkr
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enrymr% and a'inulaunR u11R/qKplilks lhr.e rcaclnxl% are faitly well urwkr.t/rtJ and
aM.ear fu la..vi.k new in.iFMx intu tuhlCals a. Jivene as bArIJ preilalue runlr..l arlJ
nKl han/an..d tmhK ti.wl ttl rwtllcsfJk/genic pulmnnary clkma 1uf(IKfnkMr. Mk/K.ll
llk let hm.l.Ky .kvrG.l.r.l h. claflly u/wkr.lan.hnR Id 11K i1nnKJtalr nKlaMfil lalr td
an)' L.Irtlan I anal IM a.t+l, /nln aMwt\ la tlavf ryMCn11Jt h.r 11MMt/hM/nR IYNh IIK r111I!/l%\
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ha.t. Inl I/NI.M14l.d 1'...p.1..n (11) f.1..1.Ul.U 1'ath.Ir `frn by IYrf/c I1k1Url,
1('1 Surlarr A/qlgcm; and (1)1 Surlare Rr1.IkaC. A Nl'/1111I ]tY1n111 a..vt't% A.ay ..1
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Sul..lralc Ktac111M1 (kl'ut / 1(.I 1'hy]111h1r11'aI A%ItCC(\, a1MI IIII I:n/yllk 11Kt Iht /ly
I IllCN 1.1 Itk"IIh:NNMI I tolr. (lmical idqlliraliuni are al.u anl.ilkrcJ lo Ihl..hkly a%
wrll a% IIIII+IN':NMM\ LN lhrtal/y anal patient nla/lal,'NIkYN. In a rt11n'IIIJIIII! 4l 1n.11. IIk
auIIMN% IM111/111U1 that IlKall% 111r a.'hlCVlnl; %IICIIN' 1111atlllal'th.~.'k'aI aMI
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a/kl amllwklK% pC1.:ItrJ arainN NkIK ld the cu~ynlrc. IuJtf/q/.lrralnkn) .d Cm1uAk
h.J l rll% wllh rtvynk% rapahlc nl calalyiing IlnnlrJ lkyradalilMll ul rly.u.anrlm.ply
r:IM, IN.dIt-rIytVtIN. IIh1.kKl lln, anal NMK t.Nnl% llt l'1111:Il!1'/I nsay well yk'IJ
111:11,k1rfl.lt. nt,d.vld,/t NUr% kknllilaLh' vla.ufl:kc rrpika. AIL.Crlhlr, ..r/u
r.c rlk/n 14m :rGhn) ..mralwt tklalkJ t halNrr tu currrnl umkr.lamlmK .d a rll.J.n uwl
I/M.hlul.lf t.hy\IUh1/y arNl p:/11M.htt,y.
ky.ul, I W alkl Hrarl, (I S
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1'Irvuk/% raprrinlcnlh have .uEkr.kd h/ lllr.e tc.car.hrr. Ihal Ihnd% arltvatr I
hydfuny I nlrlhylplut:uyl rurwyntr A rellwta.e (IIM(: ('.IA /rll/klaN) by h1/Nhn)!
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I:a lu 1:, arkl lhr Ainrlsc. u/ ca(aly.i% by varilw% artiva(/lln .talr% al I IM( 3('uA rrJ/k
la.r arc Jrvnt><d Sprclhaally, the e11eaY of Ihr thkd. ylul.ahank /(:S111.
Jllhanhn n.d I(1TC) anal Jnhakrylhria.l(1y11i1 /m Ihr camvct.em t.l an ack ltvr latrnt
hunl (li,) td ral liver IIM(i ('l+A rcJwta.r tu a ca(alylaally altive l.Ktn II:,1/. r..un
nwJ l atrnl hrpalk nlicu/u1n1a111MG ('oA rc/l/c1a.c i% at IivNeJ n. a.uotlar Jrrrrr
44 aclivalnul by 1y1T anJ Il/ li ark) lu a Wwcr eRlcnl by (:Sll All llurr /hkd. .Jlr. t
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re%tn. A.'tnlMna(kMl..l Ihe%e aMI lMher reN11t% IIreK'MeJ IKrC IMNIN% 1.. IIK InhMwlatkr
ld lhr IhitllJi.ulfi/k ralio h/t the nkldulalilln ol hep:Mic 11M(iCoA Irducla.r aw /tvuy
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n'Ju.bl.rl) nNIhy1,.aJ I(r1 wrl. runlp,ncJ 111r If:N1NN1aI ralr ul J.KLNbIr.Ml ad
uN/hrLllyd I Itl h1 Ilw rnth/n.l wn. *,II N1'( nt Ilbl/ IIN ILIUIf I I/I ,/MlNall/l$! 111J1 4/1-
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(atcw, 7' 1: . , Ihlbnan, K(*.. MarchanJ, I:. R, and Strinbrrx, 1).
n.r.rh.a11.r.air 4.214 224, 1V1(4.
(hhrr supprnf: N.IutMlal I lrart. I.unt: and IlMNKI In.1i1Wr.
1'aNlr tIK I)/r1%NN1 1.1 Mchlhallla: 111xa.c, Ihp:/t1urcM ul MrJlainr, llnlvcf.qy ul
('a11i1N1n.1. S:ul 1)hc fu, 1..1 14111.1
rr A1/K1 NI K(;l(' MI'.1)IA 111) KI'1)It('rWN IN ('/)K(1NAKY I11/1OI/1111W
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(I)N%('h/ItS IMKiS
IIK mvcaq,dtN% t'tanllnr'1I 1IK' htlr cIM/Nl:uy vav'ular Il%(MNIK 111 l'afa/1/J tIK'.
ItNMIll'IItIN ICIIa\ :NI/v:11h/111/11NN/11:11, ltNlll'NN/l IMII:\ M%IIU/1K'/lllJ I/N 1IK'
IINamlrt
IIKUt 1.1 11/1111 nlam a/N/ tCll l Irt'wnikt .ININI:ny arlt.'ry h1aNN1 Ill/w., :UII'rlal AN/
/IFhI
Yln11K IIIIt (Na111nrN, a111I:IIICIIaI anJ CIMIMIary \lnul hhMlll 1..Lr% a1N11/
.INII.o1. W Id/
Ih:nl fala' IKIt1 l/N1%1a111 Ily l'h11/K'aI %IIIIWha4NN/, inMl WIIII Il'MIIIat11Ml
1IN11111IIa'11/M
Jllllwl'J 111 v:11y %/I1N11,nN'IN1%Iy, t':/fa11NI l'hl11MN1'1'C111/M h'IhR atl1r:11N/11/11NhKl'J
hy
i11I1:K :U IINI nK 111 nM 1 rIK IhJ a.h lk inl, hi1111:1.K' CIM.MI:II y vdN'11Ia1 Il\IN NI
V' t II:II Jl tr9
vtJ Ly all r./lly JdathMl llNrvhNl.ly Ikv't/1rJ/ a1Nl :1 Ia1l lIN1./rK ti1Nr I'Iw .t.mlpk,
w'Itll rl%IN/a111Nr l1NNr11IIiJ a1N1 wllh 1111 :NIIINMNIIK oltvrws .y.lrnr in1.Kt, r:/aN1J
lIN'IIMNttl'(NIN /CIIcR :1lI/va1/1111 rlm/I1Cll In a Ialr ItK'1t:N4 in arlt:rlC/I IMC%mllt
(I/ '
4'+: P' IIaM12), a1MIh11C rlJ111'1/1Ma11 in righ/ nwin (2d 4%; I' I/IN121, a1NI IrI1
ullunlllrl 11 `? 2'4 :(' II 1N1411ININUty hhNNl /luw., a1Nl ifK'teav% /u rly.hl If.'
11'; ; 1' 111111?1 cuNl k/t 1:(a 1 1'%: 1' (LIM11111 clMrNraly tr./.U1NC. Ilum r:uldNl
r IN'/IMNI'll'IdIM It'Ih't x11KIt11N1 Int11K'tYI Iall l'ININIaty l'1MNIIK1NN1 W:N:IIN/:I%MN'LIII'J
w/111 a 11/1KINII/I:1111 IMrIJ~l' /n /llyalt'WJial PRyltln t.><1tat1NM1 i r., il/lt//:II
ulyl;l'al
llN/trnl hIIwUNJ clNl.tOn1 whlk fIM11/411y ]in11% rtlty1,t'n t'rMlll'lll tltYICaVtl (IV
b'%,
N.nhtr IMII~r/afNd111 ntN :rtn11/i1K IraJ aoy al,'nilil :/M rllra I INr Ilrr n1al;nnuJl
1' II 1/1)
tr/ d/r riy.ld IINtN1.1ty llNhlrn'INMI. IL/wrvrr, IN/1h 41140 uhvllulr r.JlKtnln ul rlyln
t'1NtN1:Ny hlNNI (haW 01N1 IIK/r'ati Itl rl),'hI l'IM/MI:uY rr>/NaM'l wt'fv JINIh,IK'J I1y
11fN'11111L1/111/K' IIIIIIK'1/1hNl, 111I11f N1tYI l'iMrll.ltlhnlIVIINN/11/
:Klrlndla'llaNl/y ~I/!n/
Ill'dn1IY .IIICr111.NiJ (I' (1/1I) a711u1N1 lI1hI111Mttl'1111M rCllt'4 ill'llvy111N/lINI1hl'J
p'J1K'INM/% nl Il}'lu IINIMlA1y h1.MNl llaw n11J irNtra.r in nKM crwrMl:uy rr./.1:NNr. Wt
r'IMKhhh' 111:d. M'/111 an1/NNN11N/KrWMh \yMh/1/ SNhrlly IINaI'I t::It111N) tlK'IINNI't'l'1111N
laIIcl :K11\.NNIII iall l'httl :111 ahM/IUIt r\Ik'RIy IIMtllaltYl tlYllltlhwt ln IaNIN1:Iry
h11NNl
Ilarw in IIM INNnral, IaNIN hNl\ Jlll, IhNI/lr in/11KIlaK In af1C11aI 1Mt\\r/ll IlK'
IIKV 11.1
ni.m lrl (1N .aMKIN1aIK IirN1 UlvrrlvC% 41 il)fal/e/1.'K' trCl'ININ NI/UUIa1NMr IIKVI1dll'J fhy
INdl1 t:UtllN' .yU/11D111CUa /NIVC.:IrNI cutulalmg lYtca1M11anU1K.
!
Mlmay P A, I.av.Jlrr, M antl 1'arnrr, S
('irr nLlHnn RItr/na I/ S111)'N/ 111f., IYN4.
tlYhrr \YMrfMt: II S Iallahl' IIlahll %ktvNl. Ma\Vt'h1/%C11s IIC:11/ A\Mlt 1,1111M1 :uKl llrc
AI/K'tK':nl I Il'Jfl A%mt'/:IIIIM/ FtlMll the I)lIa:Mlllknl% l.t MaJN'/nr. ILnvarJ MaJNal
StINNCl. a1Nl llrry!I1J111 :IINI
WtNIK'n' I111p/l./l, ILLhNI, anJ IIN Nrw I'nElanl/ ReKMN1,J I/lnlnr Kc.a.NI h
('rnta, tiaw/hlwwo, MA
)n 1 77
RI I I I X('AR1)I()VA\('lll AR KI SI'(1NS) C'fl/('lIFM1)R1 ('I:ITtIR
S I IMI11 A I II /N IN ('11Ns('I//m IX MiS W111t ('AKI)IA(' lIYlh K I R(1'IIY
I h/% prry'r t.Inl.un.11N lir.t Jau tutkvrdx thr rl/cct. ol +rvcre KV hyplrtturlly
IMl ra'I)1'11 JrlltalV.INt1IJr n%INMV'\ InCar/N11IChC11NMeaYr11M rclkx aa11v:NNN/1( ( -KAI
/1 :Nlrl'/N'll'N IIN'J/Jll'111rI11'\ tlnt%IrlllNql llf tha' 1I1:I1' :Irtt'r1al vaNl/Iat hl'J III
ra%INNI%r
t. ('t'KA alyr,n% mnu.al whlla'.1% Iha aarJlac ayak Irnflh rcINNI.a /n 1 u% u-Ilrt<
.humlu. 1% t'nha1N cJ m.6'I. will, K V hyprrlnlphy In .InkmK aNpra.l. an alp'.Ira'nl
%ckt tuvc .d.IN N/II:II ll y in rrlll' l 1/ ,Nlranl'rKla' vaMn'IMI]Ir la 114611 nl IIN' a 1 M Un3/
) vaa ula
/un .ulyly/n/! IIN hylN'rlr.IIIIN'J IIFM ve01IMk har hCrtl J1N II//N'lltcJ
Munay. 1' A, alN) 1'.nnrr, S I
Am.rn un hurnol../ /hvln1.Rv IdS111ca11('in' Phy.ilJ 114 1110171 IIN 1'/ 19111
1
Othrr.NlpNnt: N.IL.NI.d (lca/t, I unK and NhNNl In.tllntl. Mr..:N hovtu. I l. e/t A..u
l/.16m .nNI dN AnN'nA in Ilc.nt A..a LINNI
1'rrNU (IN' I)a'/,It1/1N'ttl ..f MrJNUN. IIatvarJ MeJnal Sa1N.d a1Nl Nn/haol anJ
WmN'n'. IInINInI, III.%LM, arNl the Ncw I'/1rlaMI 1(cf`NMlal I'rmlalr Kr.car.h
( cWrf. 11NnlJrau. MA
AI 1'l1A AI fKUN1 R( ;I(' K I( i1 II A 11//N ( q' I I11'. ('UK(1NAK Y('IK('l ll A I I(/N
IN 1111 Ct/NC('IC/liN INK7
Itn caiInnN thr rulc .,1 nrw.J JINI IIU/INMJI /.NI/N% in Ihl' c/N1Unl 1f t'1NIMaty
Va,n:Nl/vlly III l IN/%l'N W\ anlnl.ll\ 111 wh/l h IIK 1N11rIN-al/n' a'llrl l% nt ~,'l'nral
allr%llle.
aa +/NI rrarlU .Urrrrv wcrr ahvnt. Jt.r% wrrc In.IrunlenlcJ with min/alurc (Nr..INr
R.IUMc.In the :NKta atNl kll venlrN k la nlraaur :NNtN alNl klt venlrlauljt prr..ute. anJ
w/uh Ilaw prldr% ul the Ir11 a ira unlflc i a nr/nary artery 141 nNa.utr c,Nl.n uy hI.NNI
fluw.
tirvcr:d weck. :Jtrr rclnvcry Iluln nl1r/a1NM1, ei(RrlnN:nt% wfrr ./NNIua1rJ in IhC
a'IN14'NN/% II./F\ 11/111uIaiNN1 PI the a'afa.11J the/1NNea'a'IMllr fa'Ikq eha'lIr1I a h/1thJ%K
rr.plNl.c, inltlally alrik/nr ra'IkR aYN1111ary vaMNhIa/NN1 wa% 1111KrYell. CIN/Nlary M/MN1
IIl/w trrylkvl cvctn aftrr change, in nlclahldia (acllln were mmimiieJ by pmtnalnKnl
wllh Ia1Mw:uNJn) I Ita' ChenNNea'e1MIM rellr{ a'atr11r11/y vaNIJ1Ia1Nlr1 wa{ /11CJI:IIrl11NMh
by ch.IlncrFn' aa11va1am arNl wilhJrawal ul alpha-aJrenerKlc hNle. The .ca'InNI pha.e
/J Ihc rfyNNl.c invUiveJ an inarra.e in cnnnlary vav.'ular rl:aalalNY, a.ala'ia1eJ wilh
ckvaleJ anrrial INr..ure arN/ an ah.ulule rrlhKiNUI in clK.mary hhtlNl Iluw alNl ctwa-
nMy \InIN 11ayRrn a1N1trM . I~Ie laler ~fef NNI11( pM/Nf:IrY V:IM4YN1\IfN.'(NNI W a\ a1N/I/thell
by alrha adrellerfN h11Nkalk h1t1aVe1NNN In1uaNN1 tl( the alpha alkenerRia' aK11ni.1
nNdNl.atninc /rN rraaeJ nnan aACtial pre..we by hS ! YR. arN111Na1 calaNlary va.cular
rca.ta/n c hy 91 / 1d'/; Tu Je/ernll/x' whether Ihc large avwlNla/y arteriea were alw
utwkr autluNNnic aontml the dllw were inarwnen/cd with a pair ad ultra..Nllc cryaala
INI I.IIIN../nR wl/acra ol the kh cln'umfkt eaNlwary anery tn nKa.urc a. Jlanlelct
Jlrrally aln/ c/Nlllnaw.ly Melh./wamine raiuarJ clNnnary a'm.a.eclinnal area .urb
.tanaally,171erchy a un.tfirlinR large cunNlary arteriec a/Nl resiaance cawaNlary vea.cls.
'1 hu. wh/k the a nrlN+ary aneriea are reRulalcJ by the chanKca /n myllcarlflal metahatlic
Jt'111:IrNk IIN'y ate a1V1 rcyNNt.ive tn chanKe. in neural ./lnlulr lbe nN..l .tnkinR
a h..n/'r, wvtl .dvr.rJ w.lh wKurnlatNm atNl w./hJtawal n( alpha aJrrnrrRN' clm
.un /.. 1..... .6.. 1. q~..n 1.. !w .nq.rl.mt .n dw ./ua...l .4 Llrrr a% well a% null
......... .. ../.
Varnrr, S F
1 Gr Amrrn.m inurn.d ..J ('ardnduxv 52: ISA 21A, I'/N 1.
11 S Ibhllc Ilcahh %crvk'c.
1'nNn thr Ikp:lnnrent. ul MrJicitlc, IlarvarJ MeJical \.blNd a1N/ NrlFh;un a1Nl
W.NIkn'. Iht.pltal, lln.hNl, and dle Ncw IalylanJ KekNnnal 1'rinlatc Kr+ealah
('etllrr, S/N/fldwwu, MA.
('//Nl Rllll t1 I()NS 1/1 I II IMAN 1'I.AI lil 1:'( ~ T( ) l 11L 1'K( /l'Ii/11.Y'I I('
M'IIVAIII/N/rI 111.(M)I/l'//Mi1/1.A'/ll)N 1'A("IlH(ti X11 ANI) XI
I'trVNN/\ \IINIM% hAVr .urFe.lrJ /hal hwnan Itlatrk/% c.ln pnNlNnr IIN al llvalnm
nl LNt/N XI by Iwn.ldhrcnt nNahaw.nl.e tnle rryuVU1K laailr XII a/N1 A111' urrlrJ
platrkl. 21141 thr .nhcr rcyuinnK cllllaken Ircak'a/ plata'kh in the alqwlnt :JI.a/N c nI
l:wl.N X11 'lu invr.t/Kalr Ihrae hylNllhe%ts, i.aJa/cJ 111a1rk1s ware Ir.trJ 11a ncs-ir
a':III,N'Ity In I1t/NINMr IIM aa'I/v:IlNMI an41 lk:Iva/,'r //1 INn1ha'II lal'hK XII :/INI XI 1/1
va/NIN /Illllufl'% nl /Rn/IN'J Ial11N XII. kalhkreln, hlKh uN.ka/dar wclrhl IIIMWI
kInIMlgcn, :IINI Iaa11M X I I he al't/vatNMl tl( Iaa'LN XII Iw /al'1lM XI w:l% la'%IlJ tn
aL111/11(
a..ay% u.ml! pla.nlas dclicrcnl in lat'Alr XII. X1, IX, /Ir VII anJ the hrlutad prlNrulytw'
ckavagr ul "'I IaArkJ laa'klr XII alt XI was a..exseJ v.mlt ./IJwnl JINkcyl %ullalc
p.ly:N rylanliak gel ekctn.phllrc.i% in Me prcvem'e a/ reducing aReMv 'Ihn AI tI' /N
c1111aKen IrcaleJ platekli can Ira>mlMe the patladylie at1/valNln u( fac11N XII in nnl
turc% a'/NHammp kalhkrrin anJ IIMW ktnlrN>6cn wn sM/wn by: /1/ the prlNCOly1N
ckavage nI Iac11N XII, (2I Ihe JevellMNrleMU( In'lIM XI/,a+a~ulanl aauvily, arwl l h the
pnNrdytlc ckaval,.e tll'^I lackl/ XI. MNeklx treated with ca111aKen aa IhnNldNn were
.INlwn by Mwh claaleulanl aasaya anJ by cleavage zluJiea lo I+artiaipale wuh IIMW
kinnN/grn anll kall/ktcin in 1he pn11e.11y1it aclivwilln nf hacN>r XI by ulrchanl.m.Ihat
were partially Jcllcaknl upNl anJ partully imkpeadenl n( Iac11w X11 '1'hat IIN.c
ryuNVn a.ttvalialn. atc I+Ia1ek1 relatcd waa aknNln.IrakJ by: ( I) Ihe enhana'eJ cu:IKu
lanl aa1av11y anJ pnNc/dy.i, uh.erveJ aller plalekl.linwlalinn with AIN', cnllaKrn tN
IhnNllhin;121/hc Inhih/lilln td pnwevllylic aclivalaln seen when plalrk 1 re.pNl.c% were
inhlhllcd by irNllNlK Ihacin; 1111111' ab\e11ce n111rtMlYllylle aellva(NNI in IIN ahvna c Id
plalckta ax rwher sur(aa'es; a/N1 14) the IUl aI17NNM nl cleavage IlrtNhN'1\ ul /:Id/N X I 1n
platelet pclkK. I:./+CrimeMt with ce1Ne Ir with unUinwlaeJ platekl% l.re.ent .h./weJ
a hnl'ar trlatNNl.hip between laclalrXII enaRulanl activily anJ prdaa4yct. ur t,N'Inr
Xll Ilnwever, with activated /+IMek1s per.enl dle av/agulanl activity waN twll 1/
hlurfnlJ Xreater than that Ilb.erveJ (nr an eyuivakM anNlunt ul lxhw X 11 c kavcJ wnh
celne pc.ent 'lllr.c s1uJies JelnlNt.uate that plalcklc a'an pnNlNlle Ihe /N/Nrulyuc
aa tIv.INM11tI Iaa'blr XI) hy kalilkrcm arNl n1/acHN XI hy INth Iaa1tN XII aklN'rwkM'atNl
laatlw XII lakry-naknl mea hanl.ma.
Wul.h. P N. and (Trifhn, 1 11.
RIIN.J 37(I) 106- 1111, 1991.
(NAtr sr//os: NalilNUl In.lilwe, a/( Ikalth
hnun Ihe Ikparlmcnt nl Ilnmun11.a1lNJ/1Ny. Xcrilllla ('IinN and Kc.carch 1Iwm/atnN1.
I a/ulla, ('A, anJ Ihe S/NtlahreJ ('eMU nn IhuwolN..1. Kc.earah, IkpattnKn/ ut
MeJw/nr, Irmplr Ilntveraty Sa1NN11 n/ McJlaulc, I'hilaklphu
1 79
NI II IKl)1'llll. ASSIStI l)1)NA SYN1111: * S1S ITY 1111MAN I.YMVII(x'Y1 Fti
IN KLS191NSI:'ll) MLVAt.ONI(' ACID. t'.NIIAN('IiMI'NT HY
( Y 11 K'IInI.ASIN 11
Mrv.d.Nlw at Idi a lcy inlrnlMd/JIC in Iht hul.ynthl'.f% ld clM.ks/rrnl. Is r apahk
a/ InnlJllnY I)NA .yuthra., mIK1,IMd.ry w Iran.GNnl,lU//n arMl arll JIV1.nNl in t ulpnr.
1.1 11/1111.111 I\'111IM'1.1I h1.NMI Iy1/1111N1t'ylt'\ S11nhr\ IrIN/11h1t IJIFM7hNy \tMlw II':Il
IN11t
IM.~MIIJILN1t Ill Iy1111.IMN yll't rttINNMI 111MKIy In nlevah1111t JINI hu/ ihrlf rl'tIMnIN l:In
hr rnh.nMr.l by h-IIt.IMrJl hkNMl nlu/nKlh11. AtkI11NN1 nl 1y11NhJ1a.m II INII /NN
tyMNh.d.lan A. M/ nntrd niulrl.lA/d ly/npfwlcy/e t'ulunt. rnhJlMC% dlr Ir.INN/a 401
Iym/dNr ylr. Mr hldh ('.N/ A Jnd uMvJMNla1t hut Ihe /llt'ft'11M'111 In IIM'YJLM.ItI' 11MIIN
1'II
1)Nn.yn11M.LIJfrttlyd.llKrfdlJ/Mlrrmrnlwhitht'yuNh.d.1m1/1tIN.NIINY% In IM/'.NI
A Il'\IMNIN Aa .1 t.N14'111M'nl c. (h1' I)NA tyn/h{'/lt' rt~NNIV' 111 nN vJhNlJll' l IN IJIIIIIII!
t t'll. avrfJtr 14 1. ul dlc rcyMNlv 1./ an .MAIO/J1 14.v ul t'.NI A'l hcv . JIMI vvrf.ll
ICIJtaY1 f t 1\r IoNnr. .nl!Fr.111,J/ IIN fnh}/fKt11r rl /at 1/.1 cy4 N h.la.ul 11 In dN
r..INNIM
.d nltuA n. nu.qdul IynqdMN ylr t uhurt. Io mrvahNllt at Id frsuhs /rrwu n. alNhly l.r
IMNI'111/.111' .1 11/1N' Ih'll'nlh111 tINMIi1NNfln1.' .Ihxl INI IynlplNrylr% whnh IMuu.ydnlN
rtrll 1., wlln up. 11M alnlny ld oltv.lh.nlt atMl In IniU.uc I)NA syo11M.IC :uMl trll
t y/ llnk /11 IMN/IL/I .IMt JINNN1/411 tl'IIa, a1MI 1111 (Nh\Ihlhly IhJI N MNI%Itf1.I IMINItMI
..1
nM v.d..o.nr nN'L/fN.han ncly hi IIM IIK.II.IIIN ui Ihh rllrl /, :Mhla /II IIN' 1911w111F I.1M.w 1
cclFr JINNII IIN' /l'L11NNI~Inp Itlwt. n nlcv.lhm.ltr I/wIJhM/han I INA .ylqht.1% loll t.II
Il1hl J111N1
I..u.un K A.( i.Nd.rn I I, J/MI I.b lu.ur. \
f'.dAA.n InununnLC. X1. It7 11!. I'/N 1
Oderr vrppurf: 1I S I'nhlN I lr.dlh S, rvN: N.JI. /'.nMl / Kr.r.nl h I ulMl. lrulrlul1
Gm NIV L1 ^//M'l11 1, .IINI IIN' nl/h'lll .NI (.Ilh 1'/ `w Iclv
I f111111IN' I)t'I\.IIIIIN 111 ./1 Mt'/Ilt I/M' .IINI IIN' (/t111I1IIlY' INI I111111u1M.I..Ey.
11% 1/n/vltaly
ul l'hl../).. Sa INNd ..1 Mrdlt ulr. a1Nl dM 1 kpeltnM /u.ll Mida uM. N/Nthwr.tr/n Mr.h
t J1 ('trnllf ('hMJI..
I)IVI Kta Nl'1 IN 1 IIt111 S11 KI/1 ISIIISYN1111'11(' KA11'a ANI)
1 111'l/l(I /XY 1 MI I IIYI (:1 Ill AKYI. ('11A KIa)IK'I ASI'. A('l IViI Y A% A
('/1NN1 t)Itt N('t (rl 13KANItI lK 1'll: VI'KSIIS MI/N/x'1"11! M>\CKt) Il~ta:
I)1111KINIIAth)NINIII.N/('1'll-%
I IN' VJI /IN/\ t I.la4'a nI k111.1K ylt% in IW111:1/1 IMY/l.hl'Gll LtINNI 1111I1'1 .IF nlhtal/lly
InNnc.MII.N1Mrwtdln'.Itt1lr.th.dr.lrluthM/.Vu11M.1. Indu.rtlMNtIha' I1) fhlltrll
hur w.l. uv/1 1.9 tt:/1n1/M' J1Mt tlN111411t 11M 111.u//!rs //1 IIM tlM/h'aQ'1uI
hnhV/11iNIit'
p.nllw.lv a.ar /.111'd w/lh EntlluhN y1N' tN /IMNN\ yh' III:N L1.I/.Irr I//Ih'(l'1111.I1NN1 Ka
.uh. .IM.w 111.11 t1rnM111y1 .1t11utak' 11MI1NllI 1!f.1111/h4y11 111111'ft/It1:dNN/ 1% J,%.N
1.11CII
w101BIll11r.1vIn,luulJr ( hythn,y ( nM1l,yll!Iutafy1/11M1i I./A) uYI1NLIV atIlvlly
:NN1 w/lh .1 .kl /rJa In Illr irM'/NjMqJUan 401 I'Y'1 :MrCdr .nMI /lltVahN/:dr IN1.r I.flNhh1
../ 11M tINIc.knd hNl.yntlMlic pJthway I'INNIM.I IIIy1/%tJfl :Mrl.lir II'MA/ uMI1Mad
/1MN11N~1.' IILN11.~.11.//P 1I1/1t'/tIIlIJ1NN1 in Ihr.r trll. /. J..." eNrd wnh a rJpld JINI
111..LNIIN11.1111//l CII lad/htln..n hIn /MNMdltk.. i.:M-t..n.pJaNJ l.y a tM..c
.Ic'IrIMknl
nN u;Lr .n t t'l1uLn 11M1 i/'..A rrdlN LLr at Ilvrly atMl (1'I M rl.llc /IN INtNN:111/N1
1/11.1
16. .INdr.lrr+d hN.In11NtM 1.nllwIv III .MLIIn.N1 IMA NNIINt.:In IrMrr.1.C m 1'('1
nN r.J.nek uMNINNatNm nN.. lhdc.lrf.d Ju.1 11. INl'1111MN\ \III'p'm/lll! 111.11 (a..l
IIM(: ('uA rrdwlase evenls in chnkx1en1) hiusynlhe.i% are alw enhanteJ Malurc
locnpheral hkNIJ human nMIrMKyles plxsesa an active cludeuertd hanynt11e1k palh
way, wlkrra% malurt hulnan kranuhlt'ylcs are alnulst entirely IxklnY In Ille ability 10
synlhr.'vr IM rs1 .yuaknr pnlJucl. 1 hese invt.tij!aNlr.' resull. with 111. N/ rr11. /nlh -
talr Ih.n Ih/s Jlvrlgtntt tn slcad synlhmii/nK ability hrlween Iwntx111wraRr., whith
rMVnlally alwrkr/ve Iruul arfNlumm ste/nccll, can he ubscrvcd a% an ta/ly evrnl in Ihc
I I I I l lf e nl l al M NI I Nl Itm.
Yn. Irnrn .S 'I'LUh, 1) S and Mannit'kanNlu, V
Pr.N rrJurCl ../ rhr Nurir.n.d Arfnlrmy rrJ Sr'irnrr.t nf rhr (InnrJ Srurrt nJ Anrnil u
Ill N-11 N'/7, 11)N.1
Other srPInnt: It S('uhht' Ihahh Srlvitr.
i-uNn IIM I Ap.InnMnl ni Mcdlt'nM :/nJ Ibc ('lmlulillet orl Irnn/unl.luyy. the 1 hnvrr.ny
l.l ( hw .yo, t'INl al n
IN('KIASI'U 1IIY1)K(1XY t-MI--I'HYI.(;I.11'rAKYI.('OIiN/YMI A
1(I:IH 1( '1 ASI: A(' 11 VI l V AND ('1K)1.1:S1'I:KI tl. NK )SYN1111:SIS IN
I KI:SIII.Y ISt)1.AI I:) IUIKY 1.1:1IKI:MIA ('1:I.I.ti
In this .11MIy u/ cM.k.lrnd.yullnsi. Irr.hly ist.lalrtl hairy trlls Irtnu IIM-1Mnph.
cra) I.h.11I Id I/a/Mnl% wilh hjuy trll kuktnlia 111('1.1 %yn111r.ivavl 1 S I/dd Erraltr
a11MN/1N% 411 tMdr.Irrul, lanlnlrad aml ovyuak/lc /rtlln /1'Y'J altlalr IhJI lI1lI mN111aI
huusm tMn111NYdI M/NNI IIMNMNIIIt'kar Ctil] u/Mkr 14571 r111MI/tN111\ t/t t1/hU/l /i r., /u
tl/t IMrsrlNl' Ill h/w tknaly I/pKlullrlnl IK'I. crll% al.o enh/lwlyd an cll;hlluld m-
trrav m 11K .Ittivily ld 11M rlvylne 1 hytlrusyl 1 nMIhylglularyl afaniynw A rrdlM'.
1.1m. 't Ir.: t'11:111Ftt l':MnM1/11C 1Nt'r/hel) (n IIIIYrawYI ralts nl i'elI11I:N /1r11hlrr
NMN1//11IM
1 K'1. t'tIls. /Mlr arr dlty a tlNlatp/rnre u/ an in.rtaaY) ralr fd hrs ld /lcwly .)
utlu:.url1
clMlk.hLd mtn 11M tullwc nkdiu/n llle im'rtrad u1r ld chllkslcrld lau.vntllt.IS In
111'1. cr Il.lnay rew11/n an increa.e in Ihrir h/lal rellular thnlrsaad rlwllrfu, a%
wrll .c
In .In I/NU'aV' In Illt11 I.la.ula nle/nhra/M; clullc.ltrld IIINMt11M1I11/MI /IMIIar IJbu I hl.e
t'IsulEt.. in lorn, are IN./hat/ly Ie]/NMhlhk Illr VMId nl IIIC C11111t'aI /II:In1Ir%1:1111N1% UI
Ihls 16a.IV .
Yln lintn, .C a1MI M:11111N'k.UUtlll V.
nI.NNI h q 11(Il>tl el/ 4. 1'na1.
(Hhrr tul/prrrf: I1 S Ihlhhl Ilcahh S.rvil'r.
I'fa.u111M 1)t1 .IrInMnl Ill M(YIN: inr alMl IIM: ('.In111/111tr INI humunnhlgy, Iht
1/ntvrfaly
ul 1 Inl .11u ( hlt al:u
MIVAI /1NI(' Al'll) INUIKT , S 1)NA SYNTIIISIS IN ('IIKI)NI('
LYMI11/ K'Y 1 I(' I.Is11K1.MIA Cl.l.l ti
Kttrnl .tullic% havt lkfrMNl.lralyd Iht rsefqlal n.k ol IIMvallMlt cNNI u/ IIM
rt'1,'nI:11NIn ni //I:III/II/.II/.II/ IeII I INA synlhetl\ DIMI tYll tIlY1%NM1 LI1MI have
~//F1la'~11'.1111.11
a nlrvahNU/t lknvrJ n.Nl.lrrnd Rrnwlh lal'un m.y Ir Invulvnl In Iht .lully Ilrr.cn/rd
heir 11 was strn Ihal nNvahNnl :M Id 1 an surnldJtr kukt/nn t t'll. 1146111 %INIM /1JIIl'111
wnh H trll t huNlit IynqdNN ylM kukrnlla (('1.1./ w raltr Ihr trll tyt k rn 1'ur.. Ja/1./
Nl ) I N 1
syndresve DNA Unlike mwma) human prriphera) blood IympMKytes, which require
the INCSrnce u( RranuNNryles t.M a ma.imal l)NA synthelic re.pM+.e tu mevahmrc u Nl,
('1.1. actl. J., ruw require a hcll+er cell Only the phyziuk.gtcauy active R( ') enan
tUaNrrcr r.f mcvatimic scrJ is active in inrtiatrn6 DNA synthesis, and nu slrmulaHNy
CIIeCt 1\ mNeJ allcr aaMldirNr of Ihe prca'ur.rNs of inevahimc acid nr rd Ns. klNrwn
(NaNlua. 1 IN mna.Kem. re.pm.es lu mevaMmic acW mea.ureal ln ('I.l. ccll% fTaNn lt
Patrcm% varrrJ widely (ranRe o( .IinmlatMm inJices, 1.2 IN trl. INd the DNA syntlNtic
rc.pN+.e u/ ('I 1% ccl/. 1nNn nine patients Iu mevaMmic acid c+tceJcJ thrne .een with
.ulh arunrrwNl Iynq+INN y1e nntuRens am concanavahn A, phyNrhemaRKlutimn. INrkr
wccJ mnuRen rN a ptwwtN.l estcr The mevahmNe re.pmsrve ('1.1. cell was enrw M'd
in the f.( ). MI 1 1 nr.cne suhpqNrlalwru. When CL1. cell% were imvl.aieJ in IyN.paa
tcm akpktcJ scrurn raN+taminR mn)wm, Ihe presence u( Mrw .knauy IrpyNawrur c1Nr
k%Icrr11 IM rea%rJ thelr afn%Nlvlty lo mevahNllc acid (raMfIMr1111NN), suKRc.nnr th./ a
MN1%Itrrrl INaNlual ul mcvahrmc ar.J melaMali.m may be rnvrdvrJ Mcv.lrmn aaNl,
whnh r% e..cnMUl (rr lht' growth o/ ccll% puogrammeJ tn Jrvnk nr slrmulatcJ ar Javnk
by unta.Rcns, can by /l%elf Inrttate cell repllCalNN1 in relatively lIKf1 (i. ph:a.c mMrnal
arNl neaqda.tN: IynydNN yte pr(+ulalnrn
IAra.n. R A arNl Yo. hnrn, t
RLMw!(dlI) 2S7 262. IVIt4
INhrr srpport: (1 S Arhbc Ileahh SctvNe and the Nalco ('ancer Resr:uch FunJ.
1nmr the It,Ir.rlmrM ol McJN rnc. Iimrcr.rry rd ('hrcaKu. (Trc.yo
IV. Neuropharmacology and Physiology
T7(ANSILNl'IiXP/t1:CSK)N (N: SF.LE(Tlip CATI:('l/OI.AMINIiRGI(' IRAITS
IN (1(ANIAI. S/.Ntil)RY ANI) IX)RSAI. R(X)T(iAN(iLIA l)1 TIIS:
I:MIIRY()NI(' RAT
One rwlslanJin6 problem in devehyNneMal neuruhinGrgy crrrtcems the rei;ulatirm
of neunNlal PhemMypic capression in wwr The preseM staly aJJres.es thts pnrl+km hy
dc.crlhinR cellular pq+ulalNms, I1rca1eJ in emMyrMN cranial sen.NUy and JrNSaI nNr1
FanRlia, which transiently eapress calechnlamine-specitic eniymes in vnw. Isrdaled
«ll% e+INessin6lynnine hyJraaylase 1 T-( )11) immmnaeaclivdy werc initially JeteclrJ
in InRemmal (V) 6snKlinn selaRes as early as 6eslatiwN. Jay N1 S(I:N) S, IR 22 sn
tmtes/ NewrllilameM (NF) prolein wa.s aisn eviJeM in V at the.e early stqtes Oy
Ii11.3 (27 - 11/ xrniles) cluaten nf T l)II -ppnilive cells were vi.+ihk in V Many n1 lhese
cells were hiprlar sending Prucesses into the primitive hrain.tem. In aJJrlwm. cAls
espreasrnR T()11 were s(+ParerN in IwimnrJls n( sensary ganglia serving the RMrs-
saaphatynReal tIX/ and vagal IX) cranial nerves, st well as in tnslral JaNSal nNM
RanRlr. 1lnhkr tun.urnrly aNcr MJamrnerRrc eells rd the JeveMyNn6 imesune the.e
aell. /u \r.l drn..te.Nalak . Met h.-larnrnr Ms~raQwwr.cence and a high slhnrty uptake
IwrNC.. fly rhr..uKr 11 11 1/ all r r..nul scnvwy RanRlra were rtah in NI- prNern, twt
rmnmm.rc N tr.ay w.. a~rrhnr.l N~.cllulu pnK cs.ca ralhcr Ihan pcnkarya Hy 1'.11 S,
T()11 wa.:rh.rul hrNn all knMN'y ran~.'INNI neunNl%. TS'Iew arN1lNhCr nhwrv:11NN1%
.uKYest 1hN transient cxlNesirm ral nerurAran.mulers during JevchqNrknl is wNk
+prcad, r.currmK in cclh of Jivcr.e rNiKins anJ fates.
lonakan (i M . Markey, K A., (NdJ.tein, M., and Alra'A, l. A
I)rvrl.y.nrrnml HNdnxv 111111):51 M), 19114.
(lthrr srpporC NatNrnal Inwlutc. ol I kallh and Ihe UysauaNNmua I-arurNlauon
InwnHN 1hvi.irmufl)rvcNyNrwnlalNeunrla.Yy,('rNrN1lMcJkal('rdkRc.NrwYork.
a/NI1IN' I klaar1/1NIlt OI I'.y.hauy, Ncw YaNk Ilmver.Ny McJa.l ('cntcr, Ncw YaNA
1)1111 KIN71/11. 1.F11 ('1 SO1 Ml;.('AMYI.AMINI: ON ll/li NI(YYI INI:
INI)11('11)('l1AN(il_C IN AM/NI: LI:V1:11 ANI)11/KN(WI:K IN
IIYI'1 r111AI.AM1(' IX )I'AMINIi ANI) N(/RAI,N(I:NAI.INIi NIKVIi l1:RMINAI
5YSIFM5 ANI) IN II11: til.('ltl's. fN)N 4 14- AUI:N(NIYIY)1'IIYSIiA1.
11ORMONIS IN'111L ('AS'IKA'f1il) IliMAl.l: RAT' 1iV11NiN('1: I t rK
, INV(N.VIiMI.Nl l)P ('Ill)LINI:RGI(' NK lfflNl:LIKI: KL('1.1'1/1KS
Thi"
suN1y evJIl/Jll'J the ellecl% nf inea'amylanune on the nwvArnc irNhNCJ
chanFc. m hypdh:damw rakcMrlamirw 1('A1 kvrh anJ IurrNwer m IrmaH r.d. awan
ra uan'vcJ laK rNlc nNroth In ihc sank RnNMrd minlal., the scrum IKad.N hn. 1.11. 1511,
1`I1, (ill, a1NI CIN1N'IMII'nMM krel\ were nKa%ureJ u%mx r:MIMN111nNrrMr.l~~ay p.Kr
Jura. Rl'%uh% %INIwIYI Ih:N Ihe nKYMtne Irratltlenl IINIW'lYl a%/gn1/N'am akpkuun rrl
aounc slalre\:IINI an 11Krra%l' nI a1mnC Iur/Nrie1 in Ih11f:M1Nnc and mNIMIrCnaluw (NAI
ncrve krnunal% ul the nrJlan enlinanic and ut the p-ti and ParavcnlrNu/ar arNl
JruaNUCJial NA .y.1cm. ul thc hypMhalanw% uwing the tym.ine hydr.uyla.e mhrhr
INNr uNNk'1 Mccamylaminr Partly nN.nlcrwle.l the nN'aaline irNNN:aJ rcJrN tum 411
amrne aaNe% m/uri- lamrrNn partl and (vxavcntrovular NA eerve ternlm:J .yarrum a,
well a thC n1C/M/nc /1NInfrJ Im'rea5e n/ NA IurMrvcT in Ihtw Sy%trln., Iwr INM /IN:
aclwm ul nicdinc rNl the ('A sy.lcnl. rd the meJian eminetwe. NWrduN .iYmIN antly
and markedly reJuccJ I+ndxlin, 1.11. T111, anJ (lll secrelinn arNl im-rca.cJ c.Miau.
1l'nNle %IYnYMn1, but JNI mrt in/lucnce Iti11 secrrclirwt. lhe.e cllrcts werr p.rrdy crNm
kracteJ by rn.vamylaumlr in Ihc ca.c ol pnrlaclin, /.II anJ 7 SI I.ectclNrn M/I MN in she
ca.e nt (iI ( arNI.rN1N'n.ICHNrr xctNMUt. ()verall, the Ji.cuvired Jtllcrentral bhr k:Nk
nf inecatnylamine un nicrNine induced chanKe in ('A kvel% aml turmrvcr in the
pwavcnlrN:ular area anJ the aMerwu PeriveMricular hypothalamlc rc1;NN/ a.% rNrqwnd
with the uNti/ian euua'nce reKiwNt rrlrens up Ihe pr..rMldy.d Ihe eat.trncc ut Jrllerenl
lypc% u/ chralrm'r Fn nicrwine hke receptMNl with Jlllerent au.i eplihdn y trt thc hl% w k rng
aclivi/y rd mrcaarylarome and pr..rhly rNhrr Mrwkers ol clNdinerRia nNrNUN Irkc
rCCCrtaNS.
Amknsun, K, Fr.r. K., 1:neuMh, P., anJ ARna1i, 1. F.
Arra PhysirdnKi.'a Sr unJinuvira 12(1:4M9 494. W114.
(Nher sr/prrt: Sven.ka Tulwks AIl, Stockhrdm,
Fnunthe I)Cpartmcnl uf lhautirRy, Karuklinaka Inatitulel, SpockMdm.llrNnNNr I ah
nrauwy. l)rr.rlmcM r.1( )hae/rn. anJ (iynartuM.ry, Kwarlmska IIu.Pnal, SLN k/Ndnr
ard the (kparlmrnt ol llurnan I'hysNCluRy (Imver.ay n( MaNkna, MaNkna, Italy
R t
92 1
1 1 1 1 l'1 (11 1 11 IAN(1L I IN ('11( H 1t'YS 1( )KININ INI111('I I) I N7 YMI:
Sl ('K1 114 IN I Kt1M i\1/1.A 11 1) KA1 1AN( KUA 1I(' A('INI
t'INdr. y\I.dulm at.yrINI.k 1('t'K./ .Un1u1Jl.J amyl.lv rrkvv in L.J:drJ 1.11
(411N /rdhl h lun w.n Iuduh/1rJ..ve1 Mr{ by /IINI u1M elhJlw.l I IN a1Mh);I/f.11NN1 oI /hr
IM.v Ir.11m.r au/ve I.n lu.wrvrr, /II II\' INrV IKl' n1 IM' a'1I1:11MII W1\ V1111I,u lu
Ih/1 ..1 11N..N111..) AIIIyLIV' Ia'k'/N'rIN ItIYI hy /11a11111aI1.MNl'1111:1I11N1\.II (( Il,
I(INI
PM I w..% ulluhltrJ I.) IIN h a\Inr l INN l'INI:IIMN1\ 1.l e1hJm.1 f1/ 1 t,. 1 1 M 1 .001.1 lhl\
IuhlhNl.rn W.N I.NMrnlr./U.NI .kryIwknl In JJIbIN.n. dK ININhng .,I'' IK '1'K., 1.1
\r4V NN /IN'/1/IN:nN' 1.'a.'IM.N\ INI :N Inl wa% inhilNlaal by rth.NwJ 111 J JIW' 1h'It'IMI.'lll
n1.NNNr A Ir.\mvr ..NrrlJlu.n Ititwatn thl Inh~~/M~'I.Ny rll.ah r.l :/h:uad .NI ('l K
h/1N1111F IINI (( t\ /INIINa'J .1/11y1/N' r1'k':1\l' Wa\ Iwry'fY1YI I 11111N111NN1', IIN'\t'
,nI11IN-
(1Nyl'/l.'.1\IIIaI11./1Mr1 Wl'/\'la'vr/\Il.h' 111haI./111yIaM'rrk'J\r.IN.Wt'vr1. W.1\/INla.14'II
:11 1IrC IIv t'III.IIN.I IM'1 W.tn IIN' a INN a'INI,NNNh 111 It 1316411 1 t1I. h1/:I1lY \.NN
r/111.111.Nh
a,NIy.I ./1..IAJI'a' 111 111111,1V' ILNII I/h' N 11/1 IMr111/n IIIC dhy'rN l J/kI INeM'1N a'
/11 11R1I.M
/ 1 K. 1111\ /\ lIN1I11/1M'II by '( / r1'Ia'IV' 11.1111 INCI.1ItkyI .N/n1 W11Nh 1.'vrJk11
IN.
\qnda .NN dJ.u.p. Ia .1. 111.0 a rl) nN/olNJrlr 1.,IwIYrl 11 1 JINI ( 6 r111Jtwd, INU
\qm/
Ih.111t /IdOW1[.' IU .h 1/// d) I/IIhrl a1N1al'1111IILM\ IIK.c JJt.I \u'Fr\I d/N Ihr (A41
nIM
.Ih.nl.d ul.hti c'd ndNhnNm ..1 l'('K w /nNl in x Im /. Jrh 1.o rcvrl\Ihk INI/INLJ/nNl .d
IIN' .1h111.N la'II Ilh'111rNA/N'
1.w1n, A1 11 ,N.INIJr.w. 11 . Ik Varky. (' W, W.rnl;, A, WcrwllJ/al. M 1 , erNl
f:r..l.n. M t'
Hnabrmh.A!'hrNruranl..rr 111?1/) 1221, I2W, 1'/MJ
(lthrr aupl+rr/l: MrdN.J Kavulll C.'rvnr ol 11N VlIrrm\ AJmm/.ltJll.m
I LNU Ihr 1>, I.JIUIM'n/ r.l M.JIk uN. Il/NCat.Ny 1.I ('JhlurlnJ. 1).1v1\; I n/ynrd.r)')
Krv:u.h I JIrN.arNy, VA MrAI..J (.'nl.r tv/arhlkv. l'A. J/wl 1/nl:n11 \.rvl.r. VA
MrJ1a.J1'tnlr/ J/al l)aplnlnkn1..1 SNll:rrv. Ilmvtl.Ny../l'.dd.Nnu. 1I.uNlvo
1t1 1)1 NI II IN 111 IN /I'AMINI: 111'1 AKIi ANI) ('( N'AINI' NINI)IN(i IN Ah )1l11:
ti1K1AlIth/ IIl' N h11.1111'1.4 PI11 NY1. 11'.IKAIIYI)KIN'YKII)INI:
N Mrdlvl I 1dwnyl 1,2, I,h Iru.IhyJr.M,yulw INMI'IT/ ha. ItYn .hl.wn rarlNr
h.IWVr WRN' a'Ilrl N IM Iila IIIrNhtllII:J J.ywmille .y.k/n ul tlN t1N.o\ nwNdry, wnh
hMNIN'/11/a'dt. I11\IL11.j'Nal a1Ml 11C11:1vNNJl \y1,pn.NU. \Innlar In I'arl.InvN11\III III 11N
\II/Jy rra'V'nIC1I IN'fa', aJlllln/\Ira(NN1111 NMI'11' IJ:IIIy II/Ira tNNI%I/I N/11rll,r4 hN 6v.
Jay% vIJ IaJ veinl/cJIN rJ ~') l~ahl{+InurN ulwaAe in .ui:NJl \ynapol./NlK \ hy h 1r,( a1Nl
rrduacJ 1'11h,N Jule huNlmg Io.IrlalJl nlenlhranev by Al'X I'IIhYyAlne h/1NI111F wa\
aM J/Ir.1eJ in ollal taNy Iu1Nrrk, .uKl:r.(Ing a.eleaive rllra l.d NMI'Il' un dN nl fro
.111J/J hUl 1MM INI IIN: nK'wJmIhIC Ihr:mnlNr~K.y\ICnI 'I IM.k'.(lla Ii1N1 UI J.y.INU/N
IrrnllnJ\ n/ 11w ./rlatmu Jul IwN a11r1 Inp rrrulrlrl 1/Ih1InqNrHhd hNIJN/l' IlN
INevnt rr.uh. \n/:lc\( that NMI'11' Iw.lk}:cnet:NlVr a'1Ir.1\ Iln J..p:n11nh'1/IN' 14NI1
way\ in NN' 1111!Uh111./1J) Nlhw,lv 111 IIINa' JMI IhJl 11 mJy ha uvlol m.1.vahy.u1F a
/.rknl nl.rk1 ..1 1'.IIA111MN1'\ JNl'/N'
tir/.!Nn. 11 . Kr/111. M 1. A . 11J.hun. A, arwl lupGn. A
I ur.yw.m l..mrwJ..l I'Iaru.rrp..L.C. 111! I)S 17M, I')M.)
r
I
FA('11/Kti A111 l'IIN(:'llll: 111r1'AKI:I)1 rr-AMIN() A(11)\ ISY I1IIMAN
1'I A('I:NIAl. V11.1.1Iti M'U1YL(1KN.IN1:, 1'11(1%1'111N.11'11)
MI:It1Yl "s1111N, l'A" AN1)('Y'1(/SKI:I.I-:fAl.(/K(7AN1/.A'il1)N
IM:N rnt,ll 1n\IIIIII Il'/N y IIN IlN IIJ/IyNlr1 .11 an111M/ aC/J% nlay CaNN111NNC IN /r11rJ
t//rfl/ll' h'/JI Flluwlh rr6N1I:1/1NN1 I111'/l'IINI, l'/IIYh 111 M ver11l I:K1.N% INI IhC IqNJAr
ol
auma0 nN1\ hy 1\..lalc.l pLwcutJ1 villuc u.mp nlainly IIN /rlnnN61INII1/aMa ., aoli
INNM.INNy1N :M NI IA111I wlre .lualavl In a filuucJ nualhrr ul ewlarnnlenh a.p:uua
:NNI. IwkYNIIN' :NNI Iy\IIK wrlr u.rJ '11K LdlnwinK rr.ult% were IJAair1.J (11 2
111'11/..yIClhyIt111/NIllylu1/1/1MNl1u11/ II1111 A). an 1nh11NNN Id dM.llne :Lelyltuan\Ira/\r
I('11A1. alk/h/l..l AII) u1MJlr. 6.wrreJ ('hA aml :waMyklNdlne (A('h1 kv.1% alNl .k
a Ir.lv.1 A/'h 1. Ira\e 121 IlI'.I A 1/1hIM11'aI /M'.NIMIr:NMN1 UI /IIeI:/1N111IJhk' :Ot111M/ Ja /J\
Iuh.IN.Na'1n\, Ir...11dy hy k.wrl/nr A('h kvcl.. ( l/u N MIININIylelhyl (In1lrlhylarnnNl
nnlln 1.. 141 1 A) /nhllbaaJ l'l1A alwl Alit IqNtl{,r by lllacenlrl villu. 1'IKrr wa\ a
l.hlhva L I.11/1N1\I111.IR'Iwaa1/11M n/I11tNINN11/l (l1A UINI IIK ak'INC%%MIn ul Alit
ul+/:./.r
Ly dN v11hN1% u.\ue I IK InIhlhNiaNl ld plJarMal l'hA by .. NI: f A wa% n../ /. vcl.aJ I.y
Wa\I11111' IIN' 11\\IN' .N h., JIJIy//11l! IIn' INNINIpCn:NI' 1411'Ixc/Nal vdlum a.NNJin. Iw..
11IMhplr.hpal N nN111yhlJlldera.c.11'M I1 anJ 11/ In Ille pre.allrc aul 1:NknlhyiI
/lh'II11MN1111C, t'M I 1 a.Nwrrta'J I+Irhp11.11w1ykdwnl.la/noN in1.1 pMhlAa,11n1yI N 1/N'Ihy
k111uwJJlnula I I'MI'.1. alwl I'M 1' 11 c.mvcllcJ 1'Mli Inw 14M.ylh:Nia)yk InIhIN Iohlhd
rlnM 1'h11 iu pla\/u1 nlrlnlNarlo by uNraaang 111c mlraccllular kvcl. ..1
'S aaklwhy/ 1. INNINNy\Ir11N ISAI1/ ul Ihe plarenlai vdlu% in1u1N1eJ A111 u1Nal.e IS)
('a' '/\ IryuueJ /HN INwh rrlrJ.c ul A('h caNl Alit upla{,e. 10) 1nh11NInN1 u/ Ilw nu. r.du
hulm a\vnlhly by aula hu lnr dclNC.wtil AIH uld:lkc. 171 Wlwde plaarnl:J u.qdMAda.I
I~Ie~C IlhyfY:NNNI. m.la alr IhJI
aa'II~ Ala' IN'ar\~:Iry (IN a'IIN'N'/l) al'IIVC III11atlC UT Alit
I11 A( ll vyullla.1\. n% rrlrav anJ N\ :Il'l/v:11NN1 uI 1IIl' ChUhnarl!N H'Ca'INur. 121
1,N'111
INJrN IIIwh111N.hpa1 nNd1y1:N1.N1, ('a' ' II:My11N1 a1N1 amllw/ al'NI Irau.INNI .y/cnl., J/NI
(() at1.NF`:IIIVa'J l yl.nka'k'lal %ymr1f1 anC hnlaYI (1/1NIC arMMIKr IaN a'I Ill llva' /I
JII\INNI uI
Alit .Irul\. In/nl:ln pla.'eulal Inq.lMlhlaa
Sm(rv. /t V R.urwl, Itafnwell. S. 1L a/Nl M.NNr. K. 1).
1>.ydndAr.f Kr.rurt h 1:KI I(NI, 1'/N,1.
()Vbrrxlqrpe.f: (1 S 1'uhha Iknhh ticrvice.
F11Nn dle Ihp:IrlnNN) flI IMlartll.h'11h.ry. V.nMk'IINh 11/11va/\Ily tia"IMwJ u/ MrdNia,
Na.hvillr, 1 N
1)1;PKI-SSI( IN (/UAMIN/ )A('11)U1'1'AKI. IN IIIIMAN 1'/.A('IiN I Al. VII 1.11\
IIY ('(K'AINI:. MI/KI'IIINIi ANI1 NI(Y)1'INI.
A..unun:avcJ lo dn. Ir./ficr, :nu1a/ x'iJ ulwalc wJ% oN:/\uaJ ul 1Hrrr N/ nN.N /
hlNn:n114earn6J v/1h/. Allivr u1MaLl' 11t a! An1/1MNV.INNy1K a1/J IAIIl/.:Npau1. N al.
IN.k'INYIM' a/NI Iy\1/1l W'a\ Je11NM\IIJIrJ. IlN' InI1/ININNI Ut 11M u1M:It.I' ..1 IIN'v' :I/llnpr
:N NI\ Wa\ \Iu1hl'J uNnl,' a'.M alnl. /IMNIIhU1C y11J n1iaMlflC. 11K III11:Ihe 4.1 AIII w:l\ IIMh/
.. n\N1vr lu uthlhili.N/ by Ihw v agen1\ :N mdbnMdar a.Nlle/Nrslxm.. JeonNl\u.NN/4 dau
111C JdIClC/11 :nnllar :Il /1111.m.lNNt .y.leul. I/lay he +OarIrJ Jdlrrc/Nly by d/..f d/ ul!.
fhhrr lqp+M
1 rnm .Ir 1, N u..url \. r.ra /..urLN...n
N.u.l . LLNnl. N. * l.4
9.1
1 lbr uhIJMJb.n/.d J.pJlu: aa/.1, /vdr11c1/N arrt lyane in Ille plxrrNJ 1nJy h. \Iorhlly
Jranr.[J by IINw Jrllk. 11/e /nhJNlnNI .4 Alit u/Nake by /1wv .huK% wJ% rNNlwr
.unple ahnlNutlve INN MNN'IM111N'l1llve lhe uplJl.e al Alll.kprrN/..Nl ('a'' m Nlrp
MS
mrJnon 1 hc.c ImrhnE..uKyc.1 that Ihc pln ental chorhnctF t. lunclnm, by tk. ua.in8
A('h rckr.c. m.ry allc.l nnnwr acid u1N.rkr
11Xnwrll. S 1. .rarl Srntrv, ff V Rrtrnrt
/'r,rtrbnhlmt Krt.rtrrh I 1111I:11, IVN1
Othci tupp.nt: 11 S 1uhlr. I lcahh S. rvict
I wrm 11>< Ikp.utnw-rn r.( 1'harmacuMrloy. Varnkrhih Umvcr.rly tiahrrd u/ MeJrcuK.
Na.hvdk. 1 N
V. /'harmac(11nRy and Biochemistry
( 1 A I IIKIN I Nill l( IIAINC ANI) SI (K1 T/)RY VI?SI(I.li 111NUINC IKO
11 IN\ nKl 11I\IIN(-1
Kcr r- ntly. v'ver.J ttowq.. nl rnvr .ly.rr..r. h., v,- mitr.ur'd .ta/a. rwt t ytuur:n rrI I
1.In. Ihet hoM1Iu t.rrl.dr,l .f. HI.Hv vr n I,' /r4'InINdM% In IIN- INI'MYF e Ir/ (.1 to
rNrl.-t
In nknttly la1q, rn. rh.d m.ry rr f0.nc r..w tt..v. I wu rn.q.a 1 huror.dlur ('r.mulr bnwl
mK IMrNrur., r.1 uw.lcr ul.n wt-rlIn. 1~,r0M11 1.'K t.nMl t.l,lstt I I1K I wcrr rcles-urJ lu
h.rve Itk' .d//M I1M-h//llY rat rNM J,nM'nVrN1.J \I)\ I'f I .1, .Luhrnn a..rt r.ur./ h/In
th.un. Irrun Ihe alrrnal npIIIIILI, a/MI IIN I IK 1!/a1W11 hnMlnll,' IMINeIn (IN \allk' IMI(
droNn.n.n.J pINnk ut.rp a. /he W K t lathnn hylu . ham I M.e r~f+.rrvatum. ulqwrrl
Itw hylwrlht.i. th,rl ('a ' rkIxmknt recrwlnxnl ul .rduhh hKht chiun% lo Ihc ve.M k
uwruM.uw msy nu.k.rtt thc a..cmbly rd a tlalhrm cnal and indialc crwhrtyar.r.
1lrrwever, d r. trf.wtrP ubrc that twu Jimcn.Mwral I+cptitk map, td the tl:nhrm Itrht
t h.rm..uw1 rd all t hnNn.dlm Ktanuk mcmhranc hlndtng frrNo m. in the J11K .an fc arc
Jr.lmtt arMl thcrthne. fail In sup+rut Ihis hyfrNhcsis It haa alNr IuYn .u1;f;eS1tV1 Ihal
a/nk nr a11 41111117 vc.N Ir hrnJrnR prrncmm rtyurre cahrNtluhn fnr their intetatti.rn with
the mcrnhrsne 1luwever, it wa. (rwnd Ihat an anlakrwn.m ot ca/mwoJulm by
IritlarS+Cr:vmc JrK% twH prevenl the s.uSciatnnr td the nlhcr tyh.udia prrdcina with the
thrurna/lrn granuk mcrnhranc.
('r.urt. C 1: anJ IldrrlVM, 1 K
Nntrot, N1RItVtS) 21n1 2111, 19114
(hhrr tuppo.t: N.dir.nal Saicm-e 1nundalern, the Virginia Af/iliale nl the Anrcrican
11.art A...K ral.on, anJ Ihe Itnrvcrvly ul VrrKrnia lhahe/c. Kc.c.nch and 'I rarnrnp
( cnlcr
I room rbr I>, L.~rtnrru ..1 Phann.M I truvcr.ny rJ Vnrrnia Sth.r,l nl Mdw inc.
1 Irarl.at,.vrltr
(Nd THI: ('YT(11l)XICITY OF VITAMIN C AND METAI. IONS: A
Sf1E-SI'li('ll-I(' I1.NT(/N MfCHANISM
In the work presented here, the Inticily uf a..caAale lowards phage lamlxla and
the phaKcs T2-T7 has been mvectiRakJ. At rtuun krquralure the T-ntW and tamlxla
hatterwphaRc- ue highly warfNthk Mr avnrhale inJwed damaKe, wherea. the 1'-
evcn phaKe% are practia-ally resiclant The lustcily td asctwhate t% Jcptnrknt rwr tlrc
presence u1 c.pper pu inrn/ anJ osyKen, alllww8h usy8tn is rwN reyutreJ in /he
presence u/ 11,/),. 11ydnigcn /+emside is esxMial lor the aa-nrhate-induccd phaye
inactivatirm and the Jamage is prevented hy catalase. Al the crmcenlratinns u.cvl, nwr.1
rd thc . rMper am, are htwnd to tht phaKe parlkks CltetatinR aRtnts such as 1:1 yfA tK
hr.lMhnc lully prdecl the pha6es, whereas salrcylate only rctlucet the rate nl p1uRe
inartivatwrn //11 wavengers su.h aa sucn.vt, hrnnMe, manmNrl, rce'Do hulyl alctdwd .u
prly/ethyknc Klytrrll hsve ar fw,wective el(ecl In arMMiun, eapctiment% with I1NA-
lahrkd hhaKe% tnJwate that fNMh phage aJ.orp(Ntn and I1NA infcclNrn are inprairrJ a. a
re.uh ul 11w c.ir.ure tu avrwbate and capper. Rrc larlute /u espt.. the vual Fcnruc
inhrmatirwt a% a result t>t >inRk- and drwhk-strand treak% in the 1)NA pnArrhly alvr
nrnlnlwlc lu thr An% tr( tlrc playue hwrninR aMlily n( the phslees. Thea or.ult% arc
interpreted in 1emr% of a".nc yrccilic" IcnNrn m.rhani.rn acnrdin8 1u whnh Ilre
hinJrnK tr/ tht tran.itirm melal inn to the binh>Rical target is a Irrertyur.ite Ira the
11rr In'INMnI danql,'e. Ille h11u11d mtNl NNI isrtdln'edtilhef by (),, aKrNhale rrf rNhlt
re, uctante anJ i..uhsequently rar.drted by 11,0, peWinB ()I) radrealI
whafi tcart
with vital macnwrrrlecukk with a hr8h pr.rhabilily uf etw.ins "mulu hrt" Jaurage -1 hr.
"artt-aecdK " Iruma/Nm rt(1111 radKats, which takes place near the IarRt 1 na dccuk.,
arctwnta hruh fur the high damaging efliciency and (Gw the lailtne of ()11 .cavtnKer. ur
furMet'1 aKarm) It.
Samuni, A., Anrnrwilch, 1., (w>,linRet, 1)., ChevNUt, M., and Csrqr.+li, (:,
l:u..ywnn lnunwd u/AieM Atmistry 137:119-121, 19111.
(hbtr srppnit: 11 S Ikparlmenl of 1 ircr8y anJ (iesell.chaft fiir SlrahlcnGuuhung
Ncuherher8, West (termany.
hnNn the ()ry+artments uf Mokcular Birrh>Ry, Cellular 1)iuchemiatty and I'hy.n-al
(lrcnustty, Ilchrtw I/nwersily tA )erusakm, lsrael.
Mli('1fANISMS OF TI11: UISMI/TATKNd (1F SUPI?ROXII)li ('ATALY7f.) NY
TI11: CY 1M'I:K1111 P111:NAN I11R( N.INl: C( )MPLI:X ANI) ()1: T111: ()X I11A I I( )N
(N' 1111i ('()1'PI?R(1) I'111:NANl HR(NINh (Y)MPL{:X HY ()XY(:I:N IN
Al?I IIi( )ItS S( N.1) 1 K)N
In view tt( the nrk ttf (Hp),Cu" in the deRaJatNUt of (NdA, anJ the p.csrbk nrk rd
n, in Ihio pnKess, the autMua decitkv) k9 ftwly the catalytic effect tA (.p),('u" uprn
Ihe di.pmpxtitm ol U, and the k mctics and the rea.9irm methani.m rtl/he ns idalitm o/
(rr),('u" by mokculx usy8en in the presence nd in Ihe aMence nl 11,( ), Ny u.rnR the
/echnique o/ puhe radioly.is to scnerale 0, , N is derrwns.lralnl here Ihat nopter I,1(/
phenanthnrline (rp),Cu" 1 is cal+ahle tA catalytically thsmWatinB (), with a"turmwer"
rate nmstaM 1," _(S I 1/9) K/11' M' s'. lAe rate armtanta n/ Ihc reJu.tam ol
(up),('u" and of the nsidalirm ul (rp),Cu" by 0, have been determined w he / t 91
11h 1 87
(I 1171 Y t/Y ,In,l (2 VS 11 1/ +r 1//' M v, rc.pccuvely 711r Iirlrlll rcwll. a( the
uud.ul.wl d h-p) l'u by nlydl.ular n.ygcn in ayur.wv vduh.m are 1nlrrprl,cJ by a
Ilat ham.ln Ih.u pr.t rcJ% via a.ultt..a.k mlcrn+rJolr url lhc ralr rrul.lanl 4 111
IS /1 U 11 IIY M' .' ha. hicn iklrnnlnrd 'Ihr ralr c.umlrnl ul /he /.411LI/nM uI
1.y.1('11 ' by 111/ wa% nlca.urtd 149 he 1., = (917 211/ M.'
0.IJ.1rln, N arrl ( :ul..Ar. (:
/..ru n.rl ../ thr Arnrni un Chrrnim nf .S.w irh 111t( 2 S I 7?76 7: N11, 1'!N I
(hhrr Iupport: I I S Ikpanulrnt ol f:ncrry
I a.nl 1111 11rp:lrlllKOl .,/ 1'hy.a al ('hrnli.lry. the Ih'twrw I Inlvrr.ny rI Irru.akm
Irru..dcrn, IIx 1
R//1 I S ()1 (OPI'I k ANI)I/. IN TI11. RAI1IA11(IN IN1111(1:1)
INA(' l I VA l p)N 1/1 1 7 1IA('I I I(It ll'lIM a:
A% rclrwlrtl ln Ihl. p.1/+cr, 11k cllcl t n1 t..f1\r IM 111r r,tllt:11/1N11I:Inlafc 1NI1NlII
in
7'7 h.r Icruq.hal:c I1.1.1wtn nlvchF.rpd I hl Idt.14r. wctr rl /rr./J1.1/rJ ,ukl llll cllrcl.
rd lulyt/lIll Nm% in she IxrvlKr ..I var11N1% .Nllhllvl'\ a1MI f}NIN.II Navl'Illyrl Wrrl'
t't.111111NVI Itl .Itl A111'n/1M 1.1 hllll1 I/INl.'rmL1MI IIN l'IhYI UI ILIIN11p.11 //M'1:1I
I.NI% .MI Il/l'
tuli .d /lrct.Mh..d.. pImluLuly.ulruw.l., 111h1uh.1;/f:1I.IJ111:11(r. 1111% w.Nf, l'OLI1911I%
\I111Iy 11/CV11N1%Iy 11Nlr IN1 mIII.III'II l/Ily/1N' 1.1 a WIM.It' h11.h11'N':1I t'111t,/' (
lyllpr111/
uM., tvcn :/J Yl'ry hw IIMN tnIG11bM1%, t11I/.11NY'l1 Ihl' Il/IIdI l'Ilrl l l.l
1.04114114.11 'I11i.
.rnahialuul Wa. .h.crvrd in t.dh Ihr fuc..YK r a1Nl ahKrlrr ol r/.yyrn 11r rllrct ut
I..I.IkT t'1N1h1 I\' Irvl'lllII by llkL111n1; :IFrtll% IINh a% I.1)I A IB
1I1/1111CIlaulhr..lulr
IlydurFru I.1t..aMk t'nllJlll'lIf Ihl vn.nvlnl; rtlr.l ul .r.l+ltr IIna1Fh Ilnk d auy
IrrN.tINM/wa%INr.vl.kAhy.alala.rrNti(N) IOyhuM.kcld:u wci4h/v'avrn/.tir.rd Ircr
1.u11c.11. /n thc lar.rl>.c t/ hNh arMqwt(111 am/ hydnlKrn Itru.uk h,rl IM. Iw.daauve
rlhY l I I M. /. m c.allra.t h/ nw l.d Ircr .y.lc/u% whrrc, altlww/Xh .w h a:wlnFrr. arr
ttK'Jlelhk rd plI1rlralmK Ihr phr/t.. Ihey fwtwrct theln :11,`:11Ml Inalllv:I1NM/ I IA.W
I/11.h'l III.It wlII!III 4'avl'11rYr] UI Irrl' ra11N aI\ rl'IIIN'r/I hUt IINI IMA r6loinalc dw
.rnalv
u.yrllralrll.rqM+rt Ihc%cn.dvinFcl/r.twa.alwrta..rrvrdwilh.whcr I aMlhh/gr.
IM/1 IN.1 wdh 111c I even .rrir -11k rc.uh% aar lolcrprl1.d /n Icrnl. ul a.I/c yhl'/IN'
I'tIIL.11 IIMl II:Irlmlll Jl'IIMthnr L. w11/l h the h1111hn1,' 1.1 Illl' I/lr1al I/MI Ir11IN'
rluyr. /. a
INIICr11/1~llr LN Ihr R'l Ulrl1Cl' LI Ihl hN.IuI!N aI .I:ullakl I IM' trlllh\ YIW
11/MIN,Ur II1:1/
uw..l ..1 dlr l.Mq> r rllcl l/. rrah~srnar. 1 ht. 1. In :.l.wd wnh Ihr L/dulr .d rrq.lo.r u
..nalvr llw I cvrn I.h.l/,,ll, whN h.Iltlrr hy Ihr rlrNhly a1N11\'t//M'atllllly 1.1 11N'11
rN/1rt
..yt .It1/.Illrr\
S,naunl, A , ('IMvim. M arwl (':.p.4r. (:
K.IJum-n I(.uvnn hrr SM12 572 1'lRJ.
(lrhrr upfrnY I4..I.J ~ISIr. Lr.NI (F1n..u.-n.rl Sllclpr 10111141.111.111 .IINIIIM (l\r1I
. 1. ,h 1... '... .1.1, ul...., hw.y N. ub..l.v/ N r.l (. I.nany
.. 1. . . ... , % 1 1. . .. N..1.., /./........ ..1..11,1Ld.1 I1.,,1... r.nl.
. . . . . 11. r ,. . 1 ,,,., . ,Il .1 L ..n..6.u 1.1... I
.
AN U.IMt 1)ATA SYSTfM IIASI:1) ON S-pNI NI/S HUME (Y)MI'Iff PR
( l 1MPl )NI .NTS
lhi. ata k prr.cnl% a Iechniyue hlrcornlrucliun Ida lahuralury Jala.y.letn Ia1nK
cu/unrca ially availahk ti-IINI IIIai1:-64(i/ fws clwllplrlenl. T1a .y.lun wa. dr.igncJ
t., wrrl .I+CciM-ally with an IISM/Hrukcr 1'SR y+ecminlrler hul the dc.IRn 1. Ikslhlr
crw.ul;h thal lhr .y.lem cuuhl raaly he u.cY) wilh a var/ely Lf lahtwahxy In.wnrnh
111r ..dlwarr p:IlAal,r whl.h wa% wrillen hu Ih/s.yaelo alh/w% the u.cr lo aryutrc
rllhr/ anaN.j! w Jtl;rlal data (pUll a IahIRaUKy ImIrYnlrm. %II;naI averaf;e the analuK
drla arwl.l.rr dM J Nr rm Jl.~ hks '111e S 11N1bu.ctmlpmrm..lre /rleitpen.rve ala/ rrnr
u abk lu run.lrull a a lwopklc dala .y.lem al nlmlmum4 u.t A Imal parl u/ Ih/. arb.ic
Ikv rlhr% v.llw,KC whla h ha% flirn JcveM.l.lY1 hu (xurt../nR I:I'/( d.da
Slhulli, R Ihu./, (i , Ihrrtcl, I'. li., arrl Krrda4. if. W
J.~wrn.d u/ AArAnrnr Rrunurnr'r 51;1111 112, 1'IN1.
(NAer luprrrrf: Nrlalnal In.1i1u1r% uf Ilcallh.
haan dK Ikparlnlenl ol (lrcmi.lry. Univer.ily ul RlKhc.kr, Rttilw.Irr. NY
1)IMI- 111( INIIIM. A I)IVAI.h.NT (A'll(1N I'11A'1' I:XI:RT% 1)NI.Y A
'S('RI+ .NIN1 i 1 1'11.('1 ON '1 I l1: I.LG( l R(/` 1'A'l IC 1'l /'1'I :N I IAI. AI )JA( UN"I'
''1() NI:GAIIVI:I.Y ('IIAR(:I:1) IMI()SIMN)1.11'11) If11.AY1:R MI:MIIRANI1
llw NIIIIIIILNy /11 111r 11a(1Cr IMCKnIC1I here %lalt% Iha1 l'ah'Iu//1 a1NI rNINr alf,ahr/l'
carlh 1a1u111% all:mgc 1111 ckaluraalic I+IMrnlial aJlx'rrN MI nrlr:llivcly .hrlyr.l lnl..ycr
ulrnllxarlcv hruh by al'i u//Wlallng in Iht' a111nYnN lhllu%c If1111hk IJyrr NI/:N l'/N /.. the
uundxanc arul by alyuhml;lu Illr phllydwdipid%. l1ll' l'Ilel/\ l1( Ihe%C l a1NU1\ IM Ihr
clcaInr.lalll fwacmlal arc.k.cr/hcJ alkyuaicly by the (Nluy (hapulan-SIrrn tlMYlry.
'Ihr invc.ligaaws rcp.n dr rc.ulla uf ctt(lcYinrcnls wi/h aIharlr M. trullrlhylanmMr
nwm. a calMnl lhal ha.% been 1cmllYl "Ifinlrllwmium" or "elhanlc/Muli/an" mrnahrgy
wilh hctaoal(wll/ium Ihl:sanr 1,6 hi.-lrimcthylarnnwmiwnl and Ikc:allctlwlnlom I.k-
) anc -I111 hi. IrmlrlhylamnMlnium) 7)ley eaat/ancJ the e/frcl ld JbntIhlNnwo .nl dle
Lrla flllifllhal .II tnul1/Ia11m1cIlar vc.ICk\ hlrnlrJ Ialm the flel,'ahve 1/pNI IIINNI111aU
Jyl.erine 11!CI anJ Irunl S;1 rfwl.phalillykhdlne/pMr.yawllJyl.etine nuslurcv iu v.lu
lirrl% cunlainmg 11.1 /1/11 anJ /1.1N11 M MlJium, a'e.iunl, ar lclranlclhylamnlnnlum
chMlridr fllrrr.carchcr.aLocitamirlcJlhee/feclufJnlKIMNIIU1/11N1/hl'lIM1IW taMt'
uf plmar 1'ti hll./ycr nlcnlhrarrc% anll the "I' NMR .iRnal /r.nn vlnKatcd 1'S vcal k%
hwnu.Yl in 1/ I M Na('1. 'lllcy hlua/ no evillctrce Ihal QinlelMlnmm aAwwh..prcr/u rlly
lu hllaycr nlrnlhrarlc.. All lhc re.ulls, e.crpl Illr 1hu.e oMalncJ wilh vr.a'k% u/ Inw
chatKe lkn.ily hlrnlyd in a wllulitxl wilh a hiKh vl1 curueMraliun, arr nwla.lrnl with
Ihcpredi.'Iwwnt.llhc(Nwy (ltapnunlhelrry.lllelnvc.lixalllr.a'urnhMklhaldinkIlwr
nium which J.Ir% rnA havr the p(larnlxuhlgical cl/rch rd heaanKIMwnuln arM/ rk, a
nll'IIMNIWn1, i% a uv/IQ .hvaknl l'NNM IrM (rhy\N/h.I,'NI% /MCII%Ie/1 u/ mvc.llgatmti
Ckl'1rlNlrtll IhNlnl/aI\ alI)Ken/ 111 hN.hlr,/l'aI I/Ir1/11Ma11C~.
M/ l.ruxhlin A rr .rl
7hr hwrrwJ uf Mrnlh..tnr Hi.duKy 76 1N1-191, 19113.
(Mber srppwf: Nalilnlal In.lilulea uf Ilcahh and the Nalwwlal Saiemr I'uum/1/NN1
IYrMnlhe RMIIt.Ry I)rfUrlt/Knl Nr1MAhaven NOINMIaI IAtM.rilllry, I/ff1/M1 NY a1NI1IK
Orpartulcnl ol ~1'hyv.d..ryy am111u.11/1y%N\, Ilrahh ti/KrMf% ( e1NCr, 114If I/nlvrl,/ly
ol New YINA, .llllrly NL111'
hN 1 Ny
I.Ak(:1' 1)IVA1.1-N I('AT1l1NS ANI) 1'1 1('Tkl1S'I A'I I(' IY)I I:Nl1AI S
A11M(7'NI Il) MI MIlRANI-S I-.XIIktMFN1Al. k1-M/I Iti WI111
111XAMI 1111/NIIIM
A. /Nr.enhP ub rc, a.inlpk eacn.Nln ul the Cwwy ChatNnao thclay IwcJiti. lhal
tIN ahltAy .4 J/IIvJICOt C./IaNI In vcrrrn ahaqra aI a InCnlhlane N1It1InN1 ml.'l1.Nr
Ilt't /caV'~ Nrn11/t ./I/1IV 11 IIN' J/t1./rN l' helwet'// llN't ILIrl,'t~ INI IIK t':IINNI 1~ Cn
111/.,LILk
wllh tIN I). hyr Irn/ dl I lw rt.rart IItfS IC\tt'J Ihl\ IIrrJN"INNI hy 111vr\III,'al1nF'
tIN'rtlrt I
ul IK clnN'IINNIINm .m dN rkttlu.talN' (NMrMial aJlatrn/ 11/ rN-pahvcly th.ul rJ plNl..
pM4qN.l hll./yrr /INInM.mr fhr Jl.larwr hrtwten the Iwu \h.IfFc% nl +n tatrlNkvl
IN'~a/1N'IIMN1/111111/N.It't 111r 1\ In/n. whirh I.Ihc /khyr knylh in dN I] I M oNnNlvaltnl
wll ..dutNal. 1/%rJ I// IIN.'tt r41w'r1//KM% $iR IIIlletrn/ tilVf111KI16d ipIN..,a IN% wrrr
ullhird 11N 111\r%1/1;YtIN\ nN.1.IUrd the elCr/nqllNaelic nNlhCl/ly Id n1UI/dNNN'IINr
vr.N k. NI .ktc/naN thr icta pNt-nnal, the hnl: wNkh /d the '1' nut k;N //1a1YN'IN'
n'MNIJ/N r I NMk /%/Mnal II/Nn V N1N i11rJ Yl'~Nk* NI \ Ilh UIYN' 11N' l ha/1/:1' I/I IMNr/11/dI .M
1M I.IN..IdMrhrMrr nNNtly U/ 11N hplJ, JnJ Ihr truNllNt,UNr U/ IdAldf LJ.Prr Ilwn/
h1a1N'\ t-11h1'f tarrlrrt 11NN/Nlln).a Illal' I/NIIN'r\ (rfa/11NNI1111 N' l't1/111/tr
IIN. hanFr m IwNCnha) wnhm Ihr IINmh.arlr 'fhry alwl nNa.u/tJ Jncrlly IIN cllrti ul
IN'w:111N'tINN1111111 INI the /Ndrnt/aI ItNWt- a 11NNNIlayrr IIM/IIt-tI 1141111 flr)!at/vl
IIpNI%, :IINt
aacnq.trJ tn t'ah ul.llr the t hanKe in the wrl.N r pNCMlal /d a hdaycr aKnlh/anr Inan
td1.JIM.NNrIM'JtUfrnNnl\ WllhtleC\tr1aNN1//ItIKtaIaC11:Inrrta1t11L11NN1%,/':Nht.l
tIN tctLnNpN. Kavr t.NlM~rahk rcaJt. Iw'\a/IN'tINN11u/11 t'Rt'rt\ amIIaIIrf rIlrt/ tNl lhl'
Lwent/.J Ihea Ih./l INtdN IrJ by IIN . 1L.N v IrrrnnK Il/e..ry I hr nV11It% 1nr t INhI\Ir11t
wllll IIN INrdN IMNI. nl (IN' r[1r/Nk./ 1~.N/y ('h.11Nn.ln t1lCUly a/Nl arr r.Irv.n11 N/ Ihr
natllNtlalN.N 1.1 phy.wlnFNal .I/w1 IJIJIU/.N..1..);NaI cllw'/lllN'n1 Ih./t Idtlvt Ilr\
a11N'1/N111 1 111 1 1 InNI /otIN'1 LIrF'\' IIIVJh n) tJ11.N1
Alva/ri. l1 , 11rnNIwNk, M . I.a1,Nre k, M/luuKldln. A. M.1 auFhhn. S,.nwl
1la1./, (:
(4.qblvlnllnarrNJ 14 111 112. N)Mt
(lthrr .uplrnil: 141rvrr.ity nl ('hdc,'Natlun.d In.tnutc% nt Ilcallh and thr NMi/N1Il
ti\'IrtN'r 1YNnNl.MNN/
1'tIN11 IlN' I)t'11.Ir1]/IN't1111 tk IlNlh.lrica, 1acuhaJ /k ('w/N"la. Hawa. IJr1/1JlY1dN-aN,
I Inlvcr.Nlatl Jt' ( 7nA . XantlaKa,1 )UparlnNn1 ul I'hyaulogy a1N111aqlhyac..1 hnvrr.ny
Id 'fr.a. Mcdirr) ItrrntlA (ialvr.uNt, lkparuncnl ul Phy.inh.Ky and IINqIhy%N%.
I latvatJ MrJN.J ~.IN,d, IhnhNt, IINIW.gy IRp:utntenl, IIt/Nlkha\an Na1NN/al I a1Naa-
hNy, IIpt,Nl, NY; :uNt 1)rltartoNnl ol 1'hy.il/hlgy a1Nl HNq+hy.ka, 1lrahh X.ktNr%
('eotrr, St.ac Univrraly a1 Nrw Y.ak, Sulny IlaN/k.
IN('HI:AtiI-.I) CISI1 k('Ilk()MA-!II) I:X(IIAN(il: IN (111N1: MANk/)W ('I:I.LS
O1., MIl'L 1.XI't)11 1)'r(/ Wll(11 l: ('I(;ARf.7T1: SMl)KI's
PrevnN/..talir% have .hnwn ihat talw..ure n/ 11(' If l/('unl lrmak Inirr 1ts wM/k
tiyarrlN-.nN.kr rr.ullrJ in the mJINlaln ul the pulawNlary nuraraNllal rn>'ynK..:My)
hyJl.N ./lrm rtlNnyrc-.aulm U tkrdlvla.e, arwl .NNMImN Ikcartwr.y.
11.1m. In 11NtlNd/ INt N'MrJ hcrr, 11./11/' .k11neJ t 1~,',NI'lir %nN.t1r 1'\INh11rr t'1MJIINNni,
Ill 11 1,1 111111//1tf w1/r t'IIMIN'11 11114' NIIy I..1W1/ .111/l'1t/n IyIR'\ 111 WIN11r
t/)!.Alrltt
snNd,r Ln a J.lily haa% l.N /NN week anJ up tu 46 wceks llrc numhrr ul a.trr
thnallIINI e><thanl!l'\ Iti('1:.1 ptr nKlaphase was tklermincJ in INNw marrllw eell..
1u/JN% wera .a IlrJuleJ .u thal all cyluFrrklic uhxrvutNal% wrrr m:Nk 2- 1 day. altrr
IIN'LI~I~/INlklt'41N/~Ufl' I.\IMNUfr111Ctt11er1y11C1/1NIwIkelalaJ:lllyha%l\hNIMw'wr<ll
/a up 1.. 116 wack. «.ullrJ in a 2 h.hl aN'tta.e in 5('li% ovrr .hanl r.INUCJ c.Nnlul
InN r In :munah r\pllaJ rnlwr t hnlnN'ally /N (4a lalt week tn rllhirr tylt ol .nNlkr,
tlw uN rcaa /n \l'1:. Ir'ra.tcJ hK al ka.t /arc week alhr cr..ahlln ol.nN.Ar r\INl.urc
'1 hl. l. t1N hl./ tk oNN1.tlau.w114 the imhN INNI al S('1:l, in IaMwallay anlnwl. lhM Ir,lvr
hrrn etlN/aJ 1.0 t/F.nrttr .nN.kc rn ril..
I(t'IN'JN 1, W 1.v uf I Mi. ndnr.h.Ki1 nl A tt.r inrr.1
MNluri..n K...vo/ h I It. 71 N11, WNI.
1'aaN 11N 1).vr.i.al /.I 11rnl.lt.d..gy On\'nhlry, (k'pa/1nIC/M ul MrJ/cuN, ('h1lJn-n'.
IL..INIa11M (A.% An/t'h%, a/NI IAIIMtt11Nn1n/ hrJ/a1rN'%, I/nlvri.Myul GNn1Nnll'ull
hIr/NN fI INY/I .d MrJN uN. I In AnFck.; IIn111)/vl\/INI /II IUqN7/h/gy a/NI ( hNYJ..Iry,
MN11111NdoyN:ll A\MNldtt'\, Ill'IINMla, MI)
i
I IN VI.k(:1.11 ('11 Ut,k WIkK1INGI.N VON f11K(1'1'IN (INh SI{kl )I()NIN AI11'
1'1.k11M1'I.AN I A'l l()NtiIMIAN()MI:NI: IN 1)I:k RA ('11:
In Iarvillu% invr.nKalian% we evlaMi.hrJ lhat IAr va.nat'tivr +.uh.lant.. nNV11ner,
a1NI \\9tNlalln Ck:aly have tl/Ctln(,'uMJflll rt'INNN tnl lhl.'rtwrk nt l',Mly INrrna/N'y rn
1.01% nN'.Male nvllw'rJ the Mrowlh .11 Iht hla.hl.yv, tklayrJ the h/.. tll dk nNla
prllatNla alNl rrlaukJ u1NdaM:Mit/n wi/1Nw1 inK.airlrlg /rrtlhty lit rnn/ra.t, .rr.M.NmI
/k.truyrJ IIk uurlany nl 16c utqdanl.MNln .HC wN/ wa% rnl/aylllu.i.' tilntc prNw t.,
ioydalM:MNat /IN.' It'r1/IVtJ \rg 1% Ine /Ivn11,' It11ht' IYnICn IIt /IK n.IInN11N llvr Irat 1
a/N1
1. tINtrhwe, Inlty JtlwlNkM Ial J/IIu.NIn /ar e% IN/un.hnN:n/ and the r.changr nl
nK1atN1lil: IanJIN1., dN' hl./.hw'ya i.hlKldy wv'r(Mlhk luchangra in tlw rnualN/n/n.d
cnvu.alnwnl. 'Illr 1.dh/wing e.llerinU[M% wctr t':ntityl tNN lo tvanparr the at'taal% td
nNIM/nC anl/ tl'111HNIm.Nr utrtNtr hMMN/11nw and tal aMrM111CrinC Uot yprn (cn.Nln. 'lh.
INtNNI\ nl a~Inl,'k \u1N'UIa/NYNN Inlct'/NNt nl S/11~'/kl,' nN'tNlnl', 211 nl/,'lkl,' \l't.MIN11n.a
vhrw /av r.annltl tal hI1NN) Ihlw al the inyllaMalilln ai/e rA prrrnarM t:M\ Iln I)ay S Id
IMrKnanry anJ un n.yKru trn.N/n.In I):ry 4 ul I+.ruJlqaeKnantry wrrr tk/rrnNntJ
11hNNl Iluw wa. /nra.INrJ with `Kh /rnhNliaml; NMralum/na) p(), wa. JrlrnnnNJ
(N.I,a/nN'IrN':Jly /(radh uwhralr thal whlk the ar(Mln./d INAb nic.Minr anJ.rn.t.Nlu/
/ul itop) nNalNln .Mr hkNN1 Ihnw, anJ eNraulrt/ne p(), wcre clNnlwrahk MMh in drrrr
anJth/r:MNa1 IIKIr at1NN1ttalhla%l/it'y%t Wfv/vaI wrre lkatly J1IItr\'M II LetaN lwkJ
/h:M h1.1.1.N y.h \an .arvlvr Ia1MrwIrJ uayprn Jtla itnt'y Iulh/wmK.enA/Nnn IN ml.r
bm InJucrJ vaww Ia1.uN tNm 'I hu., thr efnl.ry.Moetic eltect% ld .enMtaan rr.ult Ir,.nl
vanc x1NNN.1 nl the anunc IMhct than tcJuceJ inM+lanlatilln aue hwNNl 11nw alNl
rtNNYN1111aM mttwtrrUN' hy1N/RiY
Mu.llrll, l. A. and Ilaminrr, R. F.
Vr.llunJlrne.n Jrr amu.wniu 6rn (:nrlb/ Mt/1 77:123-12A, 1')!U.
1'nan Ihe Ikpar7n.cM ul AnaNNny, Wayne Slrle l/n/veralty Sch.wd n( McJnlne,
1)rlrtNt
vl l 91
l)I IAN I I1 I('A 11( )N (11 (i11ANY1.A Tli ('Y('1ACI: ('()N('UN fKA"fI()Nt IIY A
UIN1:("1 Ix)11111.1: UI' IhRMINANl- fANI/1iM IMMI/NOKAI)1()M1{IKI('
AtiSAY
In Iht. parcr, the aulhlx% ItIvr tkM'rlhctl lhl.kveh11111N'llt irNl a(>f1IN':IINM111) a
.Inq/h alwl c111r.1 tJlwkIn /mnnuNN Nh.NnNric a..ay llN yuanlnanng guanylalc cy.la.c
INlqcttt, nwkyNn/knl ut ln/y11K Jl'liv//y, in l'r1Nk V111/1k% tilnl'e thl a%%ay uVs 1w11
aM/Kl/anvlatr t y. la.C nwxwN ktnal anlihudies Jircc/eJ lu Jdlercnl .ktrrninaot. INl Iltc
(NI.NIn. it 1, a very .Ill l tln' assay 1,41 hc e.a'1, a hMal.11 I(h nwNNNkN/J) an/rlww/1re have
Iten IN.NIuI lII In v,hlhk Rluanylatc rycla.c. Twn .d t11e annM.INc. Ikayna:rJ 1/,
111.( i,.u1N la..) JIr1 Il, l lr( i, wMiaa.l, were ilNlinakJ anJ IIN t hara.irnaw'. ul /helr
hlrNho~ lu unnw.hlhied Kuanylate. y.la.e wcrc etaminrJ k arl halJ (ran.l.Nnlrn.N1.
Id htnlhng dJU wrlr /w.tcJ CINn/.nhve haNlmR .I1Nhea IrvrakJ Ihal antll.wlN. I1,
JnJ II, n aryovr dll lcrcm Jrlrtminam. un Ihe entyme 1 hr Iwa anlthl.hr. wrlr u.rJ
t.l IkYeh.1v a Ihrt\ 1, .I.N1hk tkIl'r11111/.Inl tirNlem NIIt1N/1NNa11NNIN'Ir1N' a%%ay IIN
M/luhle
ynanylalr c y.la.c ha.rd IN+ Ihc Jlilrrrmlul hlnJmR u1 IMNIsC It1//1111M.1IIIhulnl NIII.
. Ia.a.1./ Padrln A.ro N IIW/ Mt IIN,'n/Mane% lhr mve.tlK;N.Nr al.o u.cJ Iht+ a.vly 1u
ynanldde ..duhk' I;u:mylJlr cyl Ia.e prlNrm, 1rNkINnJrnl ul rniylnalN' :w hvlly. In a
vallrty ..1 I,N n..IN. I hc.c ./whc. .Iw.werl IonF 1.. he a rN It .INIrt r ld the ervynte
Mra.ureuwnl...t Kltanyla/e eycla.r INdrln wcte ny ahrrrJ by aycnl. that J.hvalc
I..xhum minKNn..wk'/ IN IIIalI/Yall Ily%la11111h/1IK cniyntr 1he aMlny 1.6 n1.J.we
t'uanylatc ty.la.c rr.Irtn, /lwk(r'rwkntly d .a/alytN :wllvny IN c'yclN (:MI' kvcl.,
\INN1hl IN1.vv rturnwly u.elul /n./udymK Ihr Iulwn.m AMI n'/uIII/IM..) Ihl, ln/yl/lr-
/IIN k'INNk' ~yNrl11 ,
1 rwt.l.t. I A11 alwl Mu..wl. I
lhr J.u.n.d r./ NI.l..)..ul ('h.mntrv'S111h) ISIM) ISIS I'!K1
(Ithrr .ulr/wwt: Naulm.d In.tllulc. nt IIca11]I
I r.Nn 11N 1 k pJrlnN nh ul MIYII( lnl i1N1 I'h.Ir111:N nh.F y CIa11I1x1I IUmYIt%lty, J/w)
I'ak/
Altu VrlcraN. Adnlon./ra1Nm MrJl.al ('rnlrr, ('Ju Ahu ('A.
I'AKTIAI. I'IIKITICAI'ION ANI) (IIARA('I I;RI7ATI/1N OF 1'AKTICIII.AI l:
(i11ANY1.A11:( Y('I.Atil:I1(()M RAI I.IVI:K AI11:K S(11.11/I11.I"l.A11()N
W11II 1RYI'11N
A~. .u/nnl:uveJ here. Kuanylatc t'ycla.e (rlNn IOS INMI x K rJrlNrulale Ir:N tNxl u(
ral hvl'r INNINKerlJll% /21/11nNlle\ 411 l'yl'lIC (iMP (IxnNdlnnn/my prdcut/ wa...du-
hdvrJ tn Ihc ah.clM'r ./f JrlcrReM. hy irN Nhalinl fraclNNt. 12 miut at I Y wuh S uphnl
Irypan (1Mtnulv.luMlv:NNlnwa.akpcakMUlwNlttypana/Nlpar,tculatrlNepacJlMNr
c.NNenuen..n. Vhrtually nn a.i/vatN.n /d I+:MiI'nlate Fuanylalr cy.ir.e was uh.ctvrd
at any totw INNM Ix IIy1K/n IYMlY111r:NNN1 Ie%Ie.I (iuanyl:lll t yl'I:Ke M.IU11111/l'11 with
JtnuNNlium
uyl+.in wa% ptudNVl alN+ul NNl (IdJ 191 nnw.kVnnn/.ng prlncnl) u.ing
.Idl,ac INrclpltJtNU1. (:T1' all/nily lhaNn:NuKraphy and plqurJtlvr p.ly:Nrylamwk
yr/ clr. nlyJwwe1 A. uvNy r1u1rJ a. s.m4k peaA Ixt Seph:N6* (: 21M) (tiN.Ae. rudNl.
11tAI an1l /wq1 a1r.1.1. a.unl;lr It r( nn aw t...c.kn.dy Rra.hrnt.IS,,, 4 f+) llma,
11n Ilo,lar. //a)n.nt wa% rINndr.l N Ir ah.wt N1/1MM1 alall..n. /Mrl with a 1rulNwta)
1IIN.It I. /.1 14 1)w'm I../L.IIIy IMw/t/r1i lw1'PAra11.N1I rl1nh/1l1I I11Na1.hN/hh
Ir111N1.
.,.t ...dh M.. 1 1 1' .u..1 11.11 ... Ih..rot. .d 1 11 1 h/. 1, ul ...u11a.1 l0 11N . r1Nlr
un udI.un a...- l.d,.1 ..tu, ll h.J .1 11111 ...Ih, lrnl nl 1 S I lw'r J/wl NINr
NIININ% In1hl ale thal parttrtdatc Kuanylale cyclaa w.luhiliieJ by IlmitcJ IN.dcl.lya. 1.
antcnahk la (Nlr/hl'a1wM by "IIJ%%II'aP' l'hrlNnahtl,'ra(IhK IechnNlYe\ Ihl (.a111;lIIy
IwnikJ IrafnN'nI c.NUJ/m Ihc catalylic .11e, (he site Ilx nNrlc utNk aC11va1N.O, JINI at
ka.l .Nlr .ullhy.kyl yrlNlp rcyuireJ Lx aclivily.
WalJntan, S A . I.rwil'Ii. I A.. IlranJwein, 11 1.. anJ Mn.uJ. F'.
Jrruln.d n/ ('r1 hl NN. lr..udr Hr.run h KItU: 159 170, 19112
Othrr .upplM: NatumJl In.tlnnr% ul I lr ahh.
I nml dtr I tr(Y,nh/w/n\ trt Mr.INYnr JMI I'harn17/l'nk1ry, I)IvkNNI U( (,I1/1N'aI I'11Jr111a
lukrry, S6mhwd Ilmvrr.Ny Vrlcran. AIII/IM/VratNN1 II1I~/IIIJI, ILIo Alto, ('A
1 li 1.l'1 OI I1IIAIIAIN ANI) AI:II,RAllI/NS IN PO'1-A\SIl1M
l'ON('1NIKAIIIIN ON KI'.I.AXA17lIN INI)11('I:U BY S(11)Il1M
NIIR(11't211tiSI1NV
11w INnlwnr nl dtr prr.rnl.tlNly wa.l.s inve.nyale 111 whclher rclatJlwu uwluacd
Ni n111.jN11NNh 1\ lIICCIe.I by aFrM% alNl INl\CYIurC\ trNlwn N/ alllr Ihr :Nfivlly o1 Ihl
Na', /o' 10110140. a1NI(2) 11 rrlatJ1N111I11/111t1111ru]NIk waSe(IlI/aYI, wIN1INY IIN.IIJ/IFl'
1nJIN'rJ by nltllhwu..Nk l/Ndd hc nlydlatcJ IhnN/rh Ihe hNnlJlion../ cyl'IIl (iM1'
Ke.1/1t% u/ IIu..NNly .Iw.w thN rrluaNwm.d thc rat IMwacw' :NntJ inJucecl by .ININm1
11/Ir11(IIUMNk, II M.wINI ICyChI' (IMI' and l'yl'IN' nulklNNk I1IMINII1NIIl/eml'raN 1/1IItIn11N
M & 11 ?2!/J11 wa. luh/hnrtl by etrynwc lu K' - Iree vdutNln arwl nuaha/n 10 a c,Nwrn
11:11NN1 .kliMk'/l) 111J/II4Y RcIJt:NNtn /N'curinK wnh the chanKe in pua..iuut clNl.rn-
tla1NN111111NYI/:1INNII I 11. 21/1 II) t11M wat Ml'rCiKIYI hy M111W111 mtf111NW]Nk, N M.NItucyc hc (
iMl' alwl M A 1122.9411, '11N1. affah and pnM e+r lure.lmtwn In llcc rca.e :11N/
itw'Ira.e Ihc at nvlty o( the Na ,K' -puntp rnd pr.umaMy, sller the mendwanc IwNCn
nal. mluhncd a1N1 rnhalNrd rela.atNNt. m.pecbvely. I:.p.wre /.1 I InM K' .Iduu1N1
/nrrcavJ he IrIJ\JINNI 111 k.w cnNNerNraliuni d MNIWII/ nNrlt(1rL%\Nk-, INn h:NI /wl
rllrl'I /Nl /lI:IR:ItNN/11NIul'e.i by II IN'tMNt-lyl'IK (IMI'lK M & N22,9411. 1TN/%, :11NMINr
IN.N'lvlnre wI1N It lnhlhq. Uk NJ' ,K'-punlp enhanltd the el(cr1.d ktw clNrcmranlN..
UI MNI/I//II/I/IN.(NI/~~Nk'IMrI'Iat:NNNI Ou.hainhadtNtclleclun.wNliomnllnMNU..NkIINhN'e/l
aacln1111L1INM n) l'yCIN' ( iMP. Thrse re.uhs.upge.l /ha1..Nlium mu.qau..Nk
nuy Imluce nlat:NwNt 11114010111 cyclic (iMP humatiltn, e11ecK.m Ihe NJ', K IN/N,p
a1Nl/.N hypcrlwdarvalNN1 .N the wNNMh nlu.ck cell ukmhrane.
RapMwNl. R. M. anJ Mlu.ul. F.
lrl...vl v.rn 21/2« 2ti(, 1991.
Qther trppM: Nalantal In.ulutr. ul Ilrallh.
1 flwn Ihe I Iep:Irlnlent. ut Mc.la inr and 1'hannaluh.yy, SIan11NJ I/niver.ity ScMNd /d
McJN'rnc JINI Veteran /WImnl.uati.nl M.J/cJl ('enfer, I'akr Ahl/, CA
A(:( )NIS T INI)U('1:1)1 NIX )T111'1 111M 1)I:PIiN1)1.NT /(Ii1.AXAT1( )N IN NA 1
'111( IKA('l(' At )K f/1 MA Y Ill: MI:1)IA I u11 f11R(/1Ki11 c(iMP
The INIrTwl.e u( Ihl..ludy wa. /u Ic.t /hc hylwahras that relatali.Nl o( va., uIu
.nwNNh ntu.rk with IMhcr agcnt.lhal arc.kpcniknt upNt the enJulhchuwn, nuy al"I IN
yi 1 91
nN.halr/l dlnluFlh Ihc lurmrlilwt uf t(:MI' within 1hr .nNNnh nlu4'1r Kc.ulf..IN.wrJ
that rr1.l.atNN1..1 fhr ral lh.wal /r al.rta 1.1 atrtyk hllllnc. h1.IJnunr. aM/( a' 'NNN.IdNwr
A: IIIt7 w./. ,1.4N I.urrl w/dl irN rra4d kvcl. ul .(;Ml' In a ImN a/Nl r.nNCnnatNm
IkI.rNLolln.lurNr wIN'rtvsaAMl'kvrl.wrrrunahcrcd Krrlw.va1/111hrctNM.lhlilnm
INrvrnll/l rrla../u.w1 t., 1ht.c aycnl% and prrvrMal Ihc uurra4d lrvrl. .d .UMI'
KrnN.v,J .d IIN rnd.wlN hwu allrr tspl.ufe N/ at'rtyLhuhnr INdy I+./r11JIIy Ikt rr,/4d
the rlcv.dcd Irvr1..11 t( :Ma', wyKr.ImK Ihallhe chanKr./n t( 7MI' IN cun.'d wldlln IIN
\OMNIIII uluM Ir t cll. I N u.:/1rh,N'rNac arNl. an inhlhilur 1t 1qN/.yKrna.c :nNt t yy
t IIM.. y)r11J4' aMI 1(uN1.N rlm, an InhlhNtK Of IIIMts(IIM/I/11:Iw, /NCVI'Illt'll a1NI
ICVI'r4'II
.N\'IvkIN/I11K /ININIrd IrIJla1NN1, rl'%rrclively, and inh/hurJ all'IyklNd/nC /1NhNrd
NN Ira4d Irvcl. 4.1 .(:MI' In 1IN11rJm, Vwf11//n n1t111fNu\%Nk tINhN tYl lrldl:III.NI ,11N1
IINIt'a4'1I Ifvl'I% at t(:MI' wcrr Imkpc/nknl ul Ilk prr4'nte 411 dNr rIMLdIN'IIIII/I,
1tlN/~lltr N/ lN.l~.lll'1f.1MNC al'NI .IMI t1111n:Nf/1K. 'f1tC fMe4'r11/r,11I1%41111NNt 1IK hy
INMIN'\I\ II1./t vd41/IJ1 \/IN1M1th nW4 k n'Iani:/1NN11n/hk'ed by uNIN' J):r/N% /, 11tIII'INI.'nl
.N/ ,hr /NI4'IN1' I/I tIK rfN)INhI'I/ultl afNl 1% frKdlaled Ih/1N/gI/ I)N' I/MI//.//NM1 .11 .11f
1'/NMd1N'11.1I I.NIIN that /1N.'fra%fY C(iMP kvrls in snNNnh nn141r
K.qryrut. K M a/Nl Afuw.f.l, I
("u. IJ.rn.m Rr.run A S j Itj It7, 11091
Ot11fr IYpprffl: N:dNM.II IMlltnlt'\ 01 IINIIh, VCtrlan% ^1In1/11wra1/Ur1 aMI a NJINNI:d
Kc4rrall \crvi.c Aw.ud
I r.m 11N 11,p.lrtuN Nt..d McJN ulr :IINI I'l1.1/111.N.1IH~y, SI:NII.Nd I/nivt't\Ily tilINN11
UI
Mt'11N IIN', I'./11. Aha, VtICl.ln. AII/111111,11,111NN/ MIYINJI ( r/lll'f, Iblu Allu, CA
1 I11. 1 1 I 1('1 1 )I CI )I .VI:Nl 1'/ )I.AK11 Y I IIV )N Kt )'I A 11( )NA1. IfAKKII KS IN
NIh1~ I1InM11r1.
'1 h/. 1% a IrpKl url a cINmN:d IN.h.rrty ul n1l,clhanulk whitlh clwld .N.rlml, ol
parl. Ilu u% wNkywc:Nl :a1NN1 INt dK ccnttrI Itrrvlwv sy.lrnl the hlmkrcd Intrrn.tl
r111a1N.1t.11 thc dNdlyl:unidr Knlup In stuonLuy. dynanur nIN kar magncn. rc.Iw,IrNc
N% knlw/rs wrrr u4'd Iu shNly 1hr hnwkntil Inlernal ydauun ol 1hr a1nNk INwNI ..1 IIN
anakIds: niActhalnwk. Illr tnAallNy In111Nm /d Ihia hlNNl was slwlird ul r slrirs nl
.ulv. /Ns /d oK rcaslnK fNdar/ty. ('I X'1 ('l l,l( I1 )./ M), ('l l,.('1 U N ), ('l l,l )I ) :u
d I )1)
MIqNm .dNwl thr alawk MrNI was im rracmEly hinikrrd in duecl p.qNUlawl ln wlvrnl
pd.ntly. c11nrLNmF with rnharncd hylMnKrn INlnd IarmatN/n fNIwrrn mlocdlalnl.lr
aMI tiN' IINNr IN/I.11 4/1vl'nl nNlkfuk I1KIhy1:mlNk 1,'IIN/1111wNNM wIN/kI hc r Illl'~ Ir1I
1u allrtt hlrNhnK IA thr rarlwlnyl anyKcn 11s tINlltnerKic tet'rpaw snrs '11N.k yrer hl
whN It a.4N IatNNt lu a frcrlN/K sile can he afletled by Ihi.IlAahlry nNdNNI m.ay va(y
/IINII II1/1 A Ist'aIf IINtk, the vatlahlhly ht'/ng elNtrrly Ikllrnik'nl u1Nw1 the 1NIlatlty ItI the
hlMhnr .nc An irNrca]r in nllanlrr tdrtimC. cnRr.INNNIIn},' lu a nNNe polar cnvntNt
nNnt. w.ndd hr esrr.trd tn enhance 1hr klnetlrs n/ nikrlhantilk asNKlalNr\ IU Ihc
rclrlM.N v1c
11r,n I W.nd N.(..w. I) 1
/1.... A...u,.d I'b.~......J..~. 11/ttl `11t `1J4, I'lltl
I IUIII /IM' 1 1. na.ll~ 1% 1.u1r.r'1.t 1 1u\ 14mv.-/.dy W.vlr.lcf, MA
IN
"'Fu AS A PI((11fEOF('llOLINI:RGIC (.I(iANI) INTIiRA(T7ONS WITII
A('I:1 Y1.('I11N.IN1: RI:('1:1'1'()R fM(()TI:INS IS(N.ATt.I) FROM I1R()S()PllllA
Mh.UN(K:ASffR ANI) TORPh.7XI CAUFORNI('A
I-'Iw Ihis study, "'I;u" exchanKe exprrimeMa were perfarnted un acetykMdlne
tccry+1/1r pnNems i4dalcd fmm the ekclnlplaa bswe of 1'rnj;eJu ru6/.MMN u and 1hr
crrcMa ~anRINNI o( /1.a..ry.hiLr nrclnrN.Xn.lrr WdiiinR a.hul chauthrrcd Oow d/alysi
nutkar cINm1Ung allltaraws dc.igned and c11ns1ruclcd in 1hc au11Nw: Ia1NIraNuy. 1 hr
aMuralu. r/lnllnwlusly nNntihus "'I:u'' Y ray emis.wln Inwn Ihe pnNein cuny+artmenls
Id Iwu Iklw d/:dysis rel1. tacdnatinR the ntea.urrnleM af eachanKe half-live. Krcr/Nui
pnwc/n /% dalyw-d agam.t INdlrr in the tirV crll, whlk in the tec'llfwl cell the rcccptw 1.
INnunccd by tIN prrulN e ul nlcNlmic I/Raftd in the dialysalr Nica/mir ligaml% lnducr
d/sp/:N'r/1N'lll IIIN11/hr RYCIMIM IMtMeim% nI INdh lfqY'IeS in a It1a1111er dlrrclly
rcla/td Itn the stnlt'lutc o1 thr IiFaml N/t'll(Ine and nikr(hamidr nwdet'a1c, wuh IN/.
LNtatcd pytNlyl /utn/rrn a11Nns /rNhuce "'/iu" ea hanRe xil;n//irantly, whlk thc.kpru
IIln.ucJ hwn/s ul thr nrdra'uks 1/h. nlll e/lect eachanre. Acrtykhl.hne. Ie(r:rclltylaut
tlNM/unl N.11 an1) lafh:InlyllfN/hlle all /NN%e\\ a lfuanenYry n1lnNren. Atclylahl/llnl
dlydalrs fNNIrNI "'Iv" Irllm the acetykhldilte rccrp111r rnArin% nAFwr readlly Ih:m t1k
Irtrrr/hylantnNruwn 14141 duet, which in turn indurcc earh:tnge he(1rr Ihan carhamyl
clNdlnr dIN:.
Ikan, l. W, Ka4nlhal, 1. S.. Nrl.un, 1). !., and Wright, (i. 1?.
l.wr rNd u/ the 1...id'.wnnN.n Mr(n1t 91:.1h7-)71, 1914.4.
Unml the I)tp:utnknt /d (lNInislry, klnts/ln I:IlNranlry, ('lar\ l/nivrr.ity, WlNCrs
Icr, MA;1)rpaltnNnt 111 Ph:unurnktgy, Univer./1y ul Massachuvtls Medical ('cntcr,
Wtwrrsler ~
hSK SPIN TRAI'PIN(i ST1111Y (N; TI1/: RAI)1('AIS M(/)1)IK'1:1) IN
NOaNN.IrI'IN KI?A/'ll()Nti: A Mli('IIANISM 1{)R'1111iPKO1)U("IlON
(N '1711: AIH'ARUN(7.Y 1.ON(i-LIV/'sp RAbICA11 IN (:AS INIASIi
('I(3AR1:1I'1: SM()K1:
(ias-phasr ciXarrltc .nN.ke cfNNains high a'rmccmraaln. of Mllh //.yrrn and
carhnn-crnlrrrd Iree ra1lN:als The mve.(iKalru" have Ikleclyd these r.NIN'al% uslnl;
scveral vanatillnl ul the rkclnm ywn resunance ytin ItaplinK lerhniyur, lnlilNhul, rhe
u%r /11 \/Nn IralM In tIN: V.1NI \Ia1C, In {INtw that the radll'al!{ are If aM1ed JfI1Y f 1 t
1941411 f Ilr
K.IS ph.l.e '1 h.ar Kas plwtsc r:idical% can Mill he Iraplled Inlm I:a% phav .nN.Lr that /.
nN/rr than S Inin rdt/, a resull lhal iv t'karly innntsisknl with the highly rcatllve nature
/d I..yrrn a/N/ rw(NNt ccfdrred radicala. Tu ra(i+wubee this aplarrnl paralkl.. the
au1INN% hqNwhe.vr (h+l Irre radicds are cnMiluNwsly prlNfutrd and .k.Ir.lyrd ul
cikmrt(e .nNlke :wNl eal.t in a ar.Nh aale. They .uggest that one /lwch:mi.m by whltfi
ra1lN:ah can he fnreled Invtdvrs the .bw aaid:Mi1N+ td the relatively urueatlive mhlc
ua ilk (which actv as a"f IN)N aI K-ervrNr") h11he ntuch rmre reactive m1nlKrn dN nl i.k
NilflWen dN/iINk ran then reat t wnh a numbH uf 1he yucies thal are Il.e.rnt in .nN.&c
re.eafchrr. aNl.i.lyd.ll
t./1xINhK e the radicalv that Ihry dclect 1)te fnldel u:ed hy the
Ihc reaclions n( N( )/a1r nn it tures wifh unsalurNCd hydnw arhNts laqxcftr l. une ul lhc
nwNl a(N/ndanl sllet 1r% in snN.ke and N krP/wn t./ hl' vrly reatllve N/wJNI NI I, dNrr
95
LNr, Ihr y havc awhcJ the nalurr r/( Ihe faJN;als thalt an he y+in tr.y+pcJ Inwn I;axrru%
nnuurc. al N/) r..h.rrne anJ air lhey IrronJ Ihal the NO/anlts.rprrnc nwNkl.y.tcm
Kivc, e..cnthally thr ..+nle lypr% ot ra.ll.al. (n.yrcm alNl carh.m ccnlrrrJl a. ckK.
t r}atrrnr vrNd.c I hr y hJve alvr ~IlNhctl the Ra\ /.ha.r rcxtNm..d N/ 1 wldr .evcral
vuall .d.'Iln% anJ 1 1 MNaJlcne a/Nl IrrurNl cvrJencc Irw Iw'raayl r.NIN al /nlrnrkJrrlc.
In...lun.m Nt ). rrN 1% w/th Isrqncnc nnll h(a.lcr than it tkK% with t1x pln-Irap pINny)
p'rl MxylqxrrNN. 11'IIN/ 1 hr rl.c.rth.r. hrN) that NI/, uuJrn. I'NN /o INIVUyI n'rr
INNyl nxruauk arN1lN.yur.e a mrlham.m hN thi% rcartnm
/'rvnr. W A."1 aruura, M, anJ ('hurch, 1). F.
l.wrrrnl nJ rhr Arnrr/. nn ( 6imn uf S.r i.Iy NI6(IM) 51/7! 511T/, 1481
llther rupp..rf: NatNmal In.lilulcs .r/ I lralth
I r.Nn IIN I h L~r~nN nt. l.l ( l+emi.ry adl Itn., hemrslry, I nNlstana \tolr 1 Inlvrl.Ny,
Il.raNl H...q l
NI(t)IINI ANI11'H1/\/A(il ANItINIt1111(11(MAIII/N .\NINVI1N()ti11t1)Y
WI111 \I'1 ( lAl KI 11 kI N('I 11) \/IMI llti\I11'.\ IN II11: VA\I'(11 AN
11'\lI hl IN ANIMAI.\ ANII IN MAN
I lq rllcl 1..I nN .duN' .Nr dN .. ~t..'r.r. n .1 ar.a hrJrnlta N Nl l A 11 ar IN...La N In1
/1'(il I.INnn.nl 11+..1..nJdn.n.d...nw 11 \11111IN'/,IhlNl_F1111N'.11nt
r:x.:IINI hunun v.r4 ular sy.1. rn nr .m w.., rn..IIN' .11/'a1 ) 1111.x1/N" w.l\
al... sln.Lad uo a(urnll.J.'ntyuN IN...1../t.mdm . rHl.q. n.aNl. .yndN 1..t' 11'1 \1
p/epa/lJ Itunr larn r/muJ vl.n Ics k..utes INMl/I Itl./l IN.I~I,Ny. hn IN.MIIN IN111 hy
:NNtn U..rK h.mr I:Jdal, rulnlr INy .IIn1 ral r11IN'1 ~IM.ULIIN'tN1~.N L~IL.wrnl uKUI.1
tnNl w111r 'Y' AA - was Inhd.ntrJ .k..r .k'14'/Nk'111IY 11y /1t1.N/1K I IN' III11/h/111N1 wJ,
clNnpl'INlvc and hN al/trJ L.Ihr rniynlr. I'1.5, thal.rmvrfl. AA lu 1'( i clNkqNrawak
Nnlxmr JrJ taN allr.l the eniynk PC1 .yntlkta.c 11 wa. hwrwl Ihat In all .ItvN'
tnvc.turatcJ, na.xtnc lkl.r lkpl'rNknlly InhIMIr11 the hNr1171/NN1 UI IN/nlJly I'(i% by
renal MNINrgrnale.t micruanrnat IralieN+. lhr 1tNtnalN.n /J 1'.11 , In w11Nir thc 1wo
en/ynK.1M'.S arN) I a synlhrtav arc tnvulvcJ. m ukuhautNl. ul platrkIs wnll AA wa%
aNOpktrly unallccAJ by nlcrxnw in all .praics Alwr, lxI4'r1/1M'/NS W/III IIN' INll/tll'J
eniynK 1'1:% ctN+lirnuJ drc inhllnawy ellr.l u/ nillwnN Uvlrall tlx dat,l akarly
lknN+nstralr that nntNinr tnhihlt.l'IlS in V/111ehut INx aII11%%Ih'S in IIK ~d~lnl,/f %yw//l
t.ahk Iuy+1n a1Nm 411 .ul h a Il..uc
m/ht mvr.tlFiICJ rnimala arNl in m:m 711r p
JdlrterN'r in an.xuvlly to marxmr. hw the rclahun ItIwern a.tlaxlu .uN./my arNl
(a1Jlnva%CUIJf lI1Ka%e, t.IxlinlrJ r.ul
)
Ahtcr, P (Wennmolm, A
7hrsls. SlrKkh.dm. 14/1)
1)rAtr .uppnrf I1N Swedi.h Tr.harcn ('nmpany, the SwcJlsh McJ/.:J Rcv'an h
('rMlm J. Karnlm.l.r ImtNulrt anJ SUltcl.en ( Ls (iros.hmskys MnurrslrNNI
I r..rn Ihr IA L1rln.rut .I / Iu.r...l I1.w..I.pY. Ku.dur,la InNnWet.ll.nWharr llmvrr
xs 11at"d.J \I..lhdu. \utJrn
fli'I:("1 O1 NI('(1'11N/: (/N TI11: FONMA'll(1N O1 1'kUSTA('Y('I.IN I IKIi
Al'I IVI I Y ANU I IINOMI(()XANI'. IN kAI1Hl f A(N(/'A ANI)1'1 A 111.1:I:V
71N rllrcl uI na.dinl rNr dk bNJunlntm n( pnr.tacyclin 11'(:1.I:ItNi 1r1 1II111/11haq
atll ( 1 s 111 In rahhN :NNta erN/ platrkt., rrytv livrly, wa. InvrsliyatcJ In .Nrl c.p,/r
nNIN,raMut:NNtw'rinp wcrcukuhwlrJwnhI "(') yr:KhukN1N'arNlll'Y'/ AA)rrNlrtN
11NUh.1t/1N1 11001411141% wrrc ap;Ir;NrJ with dml lay.r lhrooul.lyr:q4ly /1 1 c/ AI
Icnl:x/v.ly dn NNtw' riny,% wrrc ilwuh:NCJ wi11NNN suhslratr a1NI Illr/f vlNNll:nK.Nr%
LNn1x11M1 UI 1Jalt'k1 anUaFyrrphuy al'livr/y was nKasmrJ RahMl Llrtclcl nnli.t wNrNs wrrc
uNUL.IrJ wills ("('l AA anJ Ihr pnNhK-ts hNOt<J wcre sch.aalyd wnh
I I l 1n :N6hu.n1, rlnys u/ :NNta werr /rNNNl h/ hr imapahlc r.l nNwrfUng :wkkJ 1'V')
AA tu 1dtIrJ 6 Aatu Ilhr .I:IMe hyduAysic pnrlolt rd P(;1./ King% ul NNIa
inluh.NrJ In .alinr nNJiuwl .INrn6rnrrN/.ly InrnlrJ 1Y:1. Idc acttvlty 'I ln. 1tNnun.N1
w l. tk... tk It rMk ndy mhdatrd hy nr INinr. w Nb rn (rd .h.NN NI' M 11 was al.u sarn
Ih:111.L11a'k'1 nt11 ru~1NIN \ ItMWY/rJ "('AA /o (:IhckJ't'alt. I his IrNnwlNrn was unrl
Irt trJ Ihv mt.xuN hl .unlncuy. It i. t'rNK (uJcd Ih.x a Irur Jlllrrcncc rn .cn.lnvlty 1.1
nN tAnp ra.l. 1WIwrcn . yl kNltyKrnase in rahhN aMa and plalekHs. I hl Ja,u :J.a.
tk'/1MNIa11.It1' a II%a1M J1111'rrM't hl'Iwhn Iahh/l a1N1a a1NI /1laleleth l'llllt'erlllnr
Ihl'/r
111111/:xnM..I l'Rll~t'INNI~ AA a~ ]Ilh~trall' In lhe (1M/r1:NNNl ot IIIJIeh1 aCttvl
l't/111/N1U1NI~
Al.lt'r, 1' and W.nnaNwlm, A
Ibrtnh l.wrnul..J /'INnnw...L.Kv IILSS.M/, 1')MO
lltllcr .rrpprat: SwrJlsh Ttlhacru ('unM+any and Stiltcl.cn ('las (;nrahm.k ys Mmnc.
I.NNI
I unn Ihl Otp:uulKn1 .d ('hnil"al 1'hysinkrgy, IIuJJingc Itnivcnlly llu.p/t:d IIuJ
JntEr \wrJrn.
1
V1. IrnmunuloRy and Adaptive Mechanism,c
SIIM'NES`OR 'r ('I{I.1. A(TIVATION 11Y III/MAN 11iUK(K'Yll: IN71K
1/:1((1N
7 he inlcrlrnuls are a ynNq+.d Ix/NCinm that inhibit vital rrldk'alinn arN/ nNNluLxc a
varilty ld nnnlurN' «.prnsrs Murine hhrr/htas( mtrrlrtun /I1'NV) artrvalcs nwrnlr
.utMKrs.rx 1' IyrnplNr ytrc in rnr.r, which sulrllress p/aylre hwminR a'ell fc.INNlsrs I,y
spllrn rrll. Gqqac..aNl ul hunwn in rifro uunntnc rrywan.c. hy II N wa. inw .hy.xrJ
hrrr 1u tktrrnurw wINthtr hunull 11N al.a aruvalcs suPlNe.vw 'I crlh I lumur huAu
ryk 11 N 111 Nu) sulqnessrJ INlkrwltJ mp.rycn-uMluacJ ryrlyckNlal unluumrKl.Ar
Ilhn 11rlNlul IIIM hy htlnl.In ~r1~111rra1 hkN11I tIMNMMUrk.ar l'rIl\ ({aI1M('/ hy M(/ rMM.i .t
/klsc. rd 21M/ lu iSl)11/nJ KcsINNt.es by IfFNu-lraNeJ PIfM(' were sul.trresscd nl a
Jusr llrprrM/cnl mannrr rrmtrnl a'ullures had ma>timal reyNNl.es rln Jay 7 In .Nbrt
sdKties, 1'lIM(' irwvhatcJ with NI,INM111tml at IIN.e cunlainrJ aclivatrJ s1/1.lMrs4M
lclh that Jrlrra.rJ INrkcwecJ nnnlren- slrmulaleJ, (Ndyckmal imnwtwrRhdrohn /N..
Jultnrn by wt./hrytN/s lrlls by 7/1 MIY>s. SupiwessN.n mcJlatcJ by Ihrsc trll% wa%
prrvrnleJ by cataae, ava lnthn ,N rJ anJ 2 merca/xuethamd Resup\ tr/Nn these aml
97
.M
relatrJ rnvrvigahom irnhcsle that IINn acllvatcs sup<+rcsau f ctlh -n human 1'IIM('
tuttures. whlk the ability rrl cabla\e. 2 mrrcalrrrlharwd arxt a.rrufiK al-.1 tn hhw It
wMxe%sum \uRRcm\ that thew suppr\uw f celk havecertam.undanl-r. n.11-N,t ur it
clNx anavahn A wtrvaIrQ munne suppreswn 7 t'cll%
Sl hnapcr, 11 W, Aunr T At and Pierce. C. W
the lsnnn.d ..~ lmmun.dnxy I t11S1 2 M1I 21116, 19RI.
1'nrm the Ik1+arln-cni rd 1'alhnMrRy and lathrxaltxy MeJicrnr. The lewi\h 1 h..pnal ol
SI 14n11%, and the I)cpatunrnu of I'a1Mdo6y and Mrcmhudr-~y tnrnutwrloKy, and
1cdutnl.. Wa.hmRhrn Ilnrversdy Sthrrd of MeJicu-e, St 1,41411%
('11AKA('1 P.RI/A 11014 ANI1 MU('11ANISM OF A(711( )N t)f SI 11.U111 li
IMMI INI KI tilY tNSI ti1114'K1:1S1)K I%IKS)
Srrluhk Ilnn/urK /rtlMtll%e sllr(MrNIM 11IRS), a pnMlnll of cru-ranavahn A at
hvalrJ ruurrne I yl 1' l lellv, whrch rwm\pccdreally \uWrsses raunur-c re\ppw-%r\ in
lm... I. ahr- parluted by I yt 2' 1' cell. atrvatrJ with hMr.hhst inlerlenm tIlN(11
11wSIKS.ulqurw.rpalhway.aecurtenllypcrlrrved.ISSammarvedu-Ihtnpalrr '1u
ruwr, l.yt 2 I telt., a.IrvaleJ by am A1w 11 NIS. rek+.c SIRS The tarKrl rrl SIRS Is
the uckr.q+haKe whnh alhvales rn oawlve. 11RS Ihnwyh a prruank-rneJlalecl rr:a
brm (~.Nala\e hht 1\ l.Mlvef\IIMI O( SIRS 10 1IKS. hy t7M\u1/11nK 11rnIR/1)C IRvaml
v-k a1N11Mt'vl'nt\ l1NlvertnM 111 SIRti Iln StRS., by hlruArng acbvatirwr ul SIKS by
prrunnk 11K nu'lhanr\m ul SIRS_ medialcA Inhrlnbrm of tell t11vlvNm aMxars lo
urvrrlvr utldanrro 4.1 lcllular prolrm \u1lhyJryl KnMqn whah Is tnt-c rkpcrnknt, INn
Irwhra-al tu the anrrunt all SIRS. ukkd and prevented by dnhnnhrtlhd rr 2 mrrcap
HwIhanul '1 hc apphr ehduy ol Ihl. pathway Its nnrnuno.upprrs,ion rM lo mhrhnam ol
t rll Jrvr\ron in kcrxral remalm tu he .ktcnnmrll 1 he hrnltnF thal IINit ax trvalrt thls
pathway and that kvamrwde hhtl\.uplxe..-on by the SIRS palhway.uyle\th that it
may he in In11MMl.ln1 Mht nlelhanl\m low rcRulatunK Ir-tll -nmwne re\I^mv\ arwl
ll'llulal prIrllletalNm 111 Frrlelat
Aunr I M anJ Ihrrce, C. W.
In Flxhkn I W rr rd (eJs ) Adr.rnrrt in Immnn~yrhrrrmrnulr.xy 2. New YrnA:
I'l'rRarlMnl 1'fe%%, 19M 1, pp. S97 4`412
(hAtr rrplrr-rf: Nalinu-al Imlilule r-1 AlkrEy and Inlerlirws 1)i\ca%e% and the Naliunal
St Irrw'c I rwrKlilMm
Fum- the Ikrpattn-enl r-11'alhnh-Ky anrl I.ahrwahxy MrJicine. The )ewi.h II4-apitul rrl
St l.r.ur% and the 1 kparlmeM tul l'alhr.hrlty and ul Mn u-hiul.rRy IrnmumdnRy. W a.h
mglrm (lmvrrsity Stlnrd all Medicinc. Si I.nuis
1'R(1P1K I 11'S (F il IF SIRS S(11'PRIiSSI )R 1'ATII W AY
In du..luJy ol the Ixrvivcttics of the SIRS .ul+prc.sru pathway. it was IuurNl d-al
she SIR% \upprr\\.u pathway is imuated by attwatirn- ul Ly 2' 1 lynydwwylr% by
rnlwr r.n A in 11 Nlt SIRS is a I+r..trrn whKh has been Iwml-rJ anJ ral\I\ as Iwu
,In, to ..,rl, nad .. r. ..I 1 1 IaM) and :1 Na1 I hc IarKrl .d SIR% -\ the mal r.q.haMr and
,,.n. ,.y.l.... .L1. u ... ..u.lut .. ~, I.ul. \IR\ rn .r 1..i,.luk .11IMIMIInt lu.r r\
1 ....1 . . .., . 1 \IM , w 11 '.It . .... .. ... .......m.u,r 11 ~ t a1'.11. lauu.nlr 1.1.ti-,
\1RC
rx IFNII by prrventing aclivatine or naiJation of SIRS by 11,0.. Other aRenls whlch
hNock SIRS nt 11 N11 actNm inliude eketrnn dnrr-ts which can -nartrvale SIRS-
SIRS. is a prNrnl mlubrl..r ul In11INlrle R%(MNNeS and pnrlllCtalnm 411 MKIIIa) and
nropla%lrccrlh IhenwchanivmulSIRS_-mtJialeJmhiMliar-ulprulderat«w-apprars
l.f InV11Ive n\nI.NMNIIN IIMMIItIra1NM OI prt11e1n SYIIhyllryls As nl tn-w, trqh 11 Tlii anJ
kvannwdr have been luurwl its allrct a wide variHy of cellular pnres+es '1 hc rnvulve
nient ul Irrlr ul the\r.%uh\Iancrs in the SIRS pathway suEResls that this pathway may
he an unlrKtanl Mn,l mcthanr\m lur regulating MNh immune re\prr-ses and cellular
pruldcralnn- in Krrkral
Aunr. 7' It and I'nrce. C. W.
In l lth lrur rrnnran.d ('nnr rr ('rnrarrr.r. Pun R Hrnlegy of ('nnrrr (1), New Yor).
Alan K 1-\v, Irw . 19111, pp 11$ 144.
(hArr trOpn(: Natw.nal ScKnr e 1vwnJatpm and the Nalinnal Imliluteo, lul I leallh
(r.rm the (kpaltn-cnt ut 1'adwrbrgy and LaMwahwy MeJicine, The Jewish Ilu\pttsl ul
St I.rwls, a-wl the I kp:nhnrnt r-1 1'atlud4lRy and of Mrcn"-1->gy Inm-umduKy, W a.h
mgnm Ilnrvrrvly Sthr>td ol McJlrme, St. lawn.
11)IiNI'IFI('ATK)N AND INITIAI. ('l1ARA(TI:RI7ATIUN OF cY)N('AVAI.IN
A- AN111N1I:Rf1:RON INUII('1?ly IIUMAN SI11'I'RINS(1R hA(TORS:
I:VII)I:N('1: I()R A IIIIMAN 1:[)IIIVAI.tNT ()F' MURINI: S(N.tIH1.1: IMM(INI?
RI:tiI'()Ntil: SIII'/'KISSIIR (SIRS)
Antigen mwspecilil' suppressinn in both mytine and human syslrrn+ may he
meJlaled Ihnw-Kh tevetal JivcrRenl palhways, IhmuKh an ullitnate cr-nurwm palhway,
or thnM-Kh a crNnhinalN-n of lheae two prnsdnlilies In the paper presenleJ here, if r%
mwrJ that human %uppre.wn 'r cells aclivakrl by kuk/a'y1e inlerlea-n have pnKtr,rr%
sumilar lit nwurne snpprco.sur cells attivaled by iMerletnn or by cor-crnavabn A.
Murinc wpprr.ww cclls reka.e a s<-luhk medishu, sduhle imnwne resppm\r supprrs
wx (SIRS), which act'ounloo, at kasl inpaA, for wppmlve aclivily in murine sy.tem%
To awnparr aml cunlra»I murine and hunnn suppresMrr pathways. Ihese mvctuKauns
evalualrJ the suppressi4m al huu-an prlycwuul playuiefurminR cell rtynn-.rs by crn-
ranavalin A. by kuknt'yte inlrrknon, and by immune mlerkn-n, or by wppwe%wu celt.
aclivalrJ hy 1he+e agrnh In calh inslanre. SYpIweS?tlr tYIIs rekmld supIMeN/M I:N NN
with similar paKlertir% that were irwlislinEuishabk from murine SIRS As with n-urinc
SIRS, suppres.irm by each rrl Ihese human (ach-rs was inhibited by 2 nrrlalwoK
Iham-l, a\tvshw al'iJ. ralala%c, rll kvannw-k SrKndicanlly, lhe sImllNtllr% hl'Iwrt'n
Ihcv human supprtsuu I:wlrwv and murrne S1RS slwrw The eaistrt-lr td a(wmau SIR ti
pathway
Schnaprr, It W. I'Irrcc. (' W and Arnr, l'. M
1 hr lrwrn.d of lmmun.duKv 1120) 2424 2415, 191441
(MAer srOpwl: Mamand, ('rnnpany.
I'rum the Ikpartnrrm r.l 1'uhrd.rKy and IAhrwatruy McJn Inc. 1 he Jewish Il...lntal.d
St Lrwis, anJlhe (kparhut'n1\ul 1'alhuh1gy arwlol l'eJialtrls Wa\hlnKarn Ilnrvcr\dy
Stlwr.lol MrJalnr. St IAMna
.,~ 99
MI ('IIANISM (11 SIKS A(TItlN At' 1111: .(1I.Lt11.AK AN11I11(K'III.MI('A1.
I I.VI I.
I/t IIII,l 1NIII,IrINn,tvr IU11rr rMl tiIK 1%rl tNln\ are lk v/MCII III T('rII I IyM IIImnla.
I'nalwIn/: \IK\ I'urrbcarn.n n1 SIRS. Mctham.m% tit AlUrm 44 SIRS :1, rcrcurl.
hlhQ+dnwr n1 Inuuurk I unllnm. Inhlhilirm ul Cell I)Ivi.Nm SIKS_ Mrd1jICJ l'clIular
1'r.wcm SuIlhyJryl (:r/rqr I.r.. arn) SIKti_ MrJ1a1cJ Inlhlhqam ul Mlcrr-tuhul. 1 urw
IUqt I IM II/411%%Urn VYI/IMI tit Ihl% r.11nT 14Nnh 111/11ha1 II1l SIK` mI(prl%m M ISIIhw.ly
1% unlc.rlcJ by ax tlvaurwl ul mun/w T IynyrMrytc, w/lh tutwr .uw'aurv.Ju/ A.w
uncrlcrrwl Is I.y 2 r 1 IymplrK ylc% rtka..e SIRS wtwr.a trrl;rl i. 111r m.. r.qdrlyr
Mal rry,h.lgr% alhK:n lu utHlvc SIKS tn SIRS_ in an I I t) lkprrwknt Ixmc.% anJ
SIKS__ 1. Jla.Ily rclnnrahlc Irw ulhlhitwm nt in cNn. mnnulk rr.rym.r. ('..I.da.r
/Nlvrnt% tIIl11M II NIt /IK/hallII I/IhIh1/wM1 by IVMt(KIml! wnh \IKS /ra 110 , Sumlarly.
1JK unmurwwnharlrlng drur kvarm.nk. inhlhlta II N/S rM SIKS nwJ alyd .ulp
tMr\.uMl by InIlIh/1//1F actlv.Nnm ol SIRS by entwr matr/qrlu/:e /n 11/) t 111r1 rdr.er
v.lb.Mr.l rwr.nkrrd ro thl. Jl.cu.a-er /rw /rwk 0 1 SIKS/SIKS_ alyr'.u. t-.lr a):crar.ll
InhrhrtrN nl .1 Ilu/ar pr/ddt ra1H~n 121 tiIK \ apprar.lo inhibit ct11 Jrvi.wrn by nw.hly
my crlt.nn pnrtcrn .ulthyJryl Rrrwp. 1 11 ('ertaln fcaturct nt SIKS_ catalyird otlJa
1aw1 u1 Iwrdrlu .u11hyJ1 yl rr.wl.% arr .imilar tit the crvymaUC pnqrnir% u1 .ullhydryl
utld.rv Lrd.11cJ laan nulA 141 A1 thl. prinl it L% mw ctnaln wlwIhrr ru tu what rucnl
thr \IKS palhway panlc/palr. In IwNI rlI:ul:nNrn r1( Imnwnr rC%(>wNIvrIM%% tit tell
J/vl.um
Aunr I M arn1 I'ICrcc. C W
In I vny~6..lrnrr, 1',d V, New Yraf< Alarknu. Ihc.a, IVNd, 1+11 217 ?77.
(1tAcr Irpporf: N.rhomal Sl Knlr I rH/rnl.llaon arx) thc N./tlunal In.tlNncf al Ihallh
1rnm dK I k partnK nl ul 1'.nMdsvpy and 1.rhrwrn.ry Mrnctuk. 11K Jcw r.b I lo.pd.d ul
SI l.nul., alKl rlw Ikpartuxnl ul /'.a1w.IrrKy aml Mruuhtulugy Iuuuunul.rry Wa.h-
Inlylhm IImvrr.ny SrMarl tit Mrrhl lnc tit Lnu/.
CATIII:PSIN (i IN IIUMAN MUNt)Nll('LF:AK 1'l1AG(X'Y7ES:
('(/M1'AKIS()NS III:IWI.I:N MUNIK'YTIiS ANI)
11917 Mt )N(K'Y t'I. 1.IK1: ('I:I.LS
1)ata rknl,maalins that 11417 eelh nmtain calhcp.in G like activity ate pre-
.enleJ in 1h/. rcrywi 1/V17 relll cnMaln appnotirnaltly N)µK o( cadkpein t: like
a1:11vNy pcr KY crllr, aMrot 25% o( the calhrp.in G activity in human nruulrllhdr
Nrnmal nwurty1r% have nunimal talhr(xin (7 lile a.1ivlly IsyMKUtilurlrly 41 IpK pet
1/1' cell.) l he raltllp.in (i like activity ld I IV17 cellc alrllcarm ar be Jur tn an rniyme
Ihal 1% thr sAlne a% calhrl+.in (: by .evrral crntria 1/1 it /% a.enne Iwrdem.l.e wllh
al tlvlty like c alhep.in ( i aKain.1 a.ynthctK .hynrwrypan .uh.hale, %ucc inyl ala ala
p,r 14K p nltrlranduk.12/1hc lunkrr/y11. /raXnrcn1.11 trka.c% hlMn Irhrran1un nl:dt h
Itwr+r /cha.ed by rathq+.in (i; (11 like cathepan (i, il can he I+urihrJ by .cyuenlial
Tra.ybd Scpharn.c allmity chnwnalrroira/+hy and carMltynlelhyl ScphaJct NM ct
chanKe. hrnmalayraphy:141 n% aminu.ciJ clunplnilirm and nuRratinn un SI ri pdya-
crylamwk Kel ekatnrpllue.is are r/wlnbnRuithahk /nun calhep.in (:; and /S) d MnJs
wrth anh.rrvm ra1.eJ as calhel..in (i lhe precence tit tathel+.m l i in 119 11 cell., in
n1111 h h1orIN1 11MM rnlralNM than /n nlMlnal IIM1M4 yle%, Irhlttalr\ either that the l'IMIeM
tit l:ulwpvn G in nHmrw ytes Jctrra.c. n1aACllly llurlnR /nnINlCyle lll/lerrnllatnnl IM
thal 11917 crll. drllrt Irum manlal Inmralurc nwnwKytc% with rc.pral lu .ynlhc.i. .d
Ilnm nrulral Ix.Mrma.r
kni/w K M arwl ('nmpfwdf, fi. J.
T'Ir.' J.nnn.d .r/ hnrnunnfocv 112(5):2547-2531 1'q(4.
Othrr lrppnrt: tl \ Puhli. Ilcahh Scrvi.c'.
I r.ml ttM Kr.pnathwy a/MI ('rl11CJI ('arl hiv/.uMl, (i<p:utmrnl o( MrJa'Inr. Jcwl.h
lln.pltrl at Wa.bm)tral tlnlvrl.ily MrJical ('cnlrr, St I.ron
ANIIGI NI(' ANAI.YSIS (/f I11'.MA1'/1P1/11 SIS I IiXI'KI SSNIN (/1- '1111:
.
MY 1 I:KAN111 ( K'Y 11 SIIK/A('1: AN'111:I:N ON IIIIMAN MAKKt)W ('I 1 I.S
ANI/1 II IKI MI(' l'1 l.(. I INI:S
1'la.ma nKUrhranc c/nnllrmrnth al+prar In nlrJialr many rranuluylr Iu/K'Iam
IIw lt.11111rIr. lYII %Ilrlal'l ICIIIM.1m 1rN IIN I-C rl'/;NMt 491 111111ww1ghrhul/l/ :nNI
IrN 11p
thi1J cvuntwKr/n rd cawlqrMnlrnl play rnks in granuhrylr plr.ly,,ocytn.r, arHl annltiwly
nlrJ/a1rJ.rllular tylrrtuti. ny. '1 hc.r recclMrM% arr ruN granuhK y/c .Is. Iht . Iwrwr vcr.
>ul.r they .ur r.lar..eJ rwl crll% ol rNlwr hncage. 11k c.iarnce nl Iwll:m /K ull/q+lul
.Iwcilw anlll:rnm ha% h.r'n InlrnrJ IrrMn.plJlc. ol rmnulne Kranuln cyaqannl hl ttK
.Iwly rrLwlctl hrrr, /ivr nwNwri.mal awihrwl/c.Ihat pknli/y thr My I human glauldrr
c ylr .u/ l ace :nN/otrn wrrr IwM rcxtlve w/th dlu r It rlphcral hhrw) rtll.. I lk.c anhh.nl
k% a1lrllrJ nwupknant Jrprniklq cya)ly.i, nl a IarKr Ira.IUM uI lwa/1c11 hamao
manr.w kuArsy1r. 'lhl. My I I+I/.ilwt nlarrow cell ppy+ulapnrn clwa/.IrJ.,I nruldnr
blylcally wlrn1/1lablc kranuhrylic (wrtlavlr cell. l'uhlny hrnnmK tcll% ul t1K fralu/
hnylr nrwwwylr IlncaKr (('1C (iMl diJ rwM ttpnss My 1. cuKKtalnlr Ihal Ihr My I
anliyrn i. c.Iwc.vJ Ialrr in minllal Rranuhw ylit matwalirNl Ih.wcvrr, lhr.r anuMrl
ir. Jrd reali with myrhnJ Icukcmia crll linc..1'he .iKni/icarKe and luM/ntual utduy o1
Ihc.r prrrhr. Lu the urwkr.lalw)mK ut KranuMlllr/ietic Jlllrecnlialiun 1. Jra u..cJ
Strau.. I. C.. Sluart. K. K, and ('ilin. C. l.
N/rwa/611(r1.1222 1211, N)I({
Ofher au0/rrri: Nalirmal In.IHu/c% of lkahh and Ule I lcart u( Vari.ly 1'vnd.
Fnwrl the Ikpartnlrnl n(l Incoh/yy. hivi.ilmaul ('edialrir ()nrrdl/ry and 1:tlxtlulrntal
11em:Nohlgy, Juhn. IhM1Am.l/mveraly ticMrrl tit MeJ/cinr, bah111MNt.
i
ANII(:1NI(' ANAI.YSIS ()1 III:MAT(N`(III'SIS. 11 I:XI'RIiSShIN /11 111IMAN
NIaIlKU1'111/. AN'l IG/:NX ON Nl)KMAI. ANI) LLUKI:MI(' MARROW ('1 I I.S
HyMiJrulra derived nwnwnhwral antihrdie. (McAb) %pe.ilaally tea,llvr wuh
IynlpMt y1c cell ur(acc nwrkcuks have been u1 great value in the analya% nt lymlrhrr
cyle Jillerenlialam and IynW+IrnJ neryd..ia McAh reactive wqh human nruulqrhrlN
have hecn ikveMrlleJ. a/Ml anlil.Khes aKam.l lhe My -1 hunwn Sr.nuk.cytr anllRcn have
been stMrwn In rrad with nwlrpMrWryloc.lly Idcnldlahk neuur111A1I pn'l urNNS, hul Md
with cnAuly hwnanR ccll. u( Ille Kr.nuMt<yle nwnwryle lineage ((1 C (:M/ In Ihe
11N1 101
W.wi frlwwtrll hrtr IIIe hlMhnF 11I live antl/KuinK+hd rfwwwK hmal antuh.whc. AI IN I,
: 1, 7. atw/ K. 14, rwwmal aml kalcmlc hwle marrnw Cell. wa. %uwlicd AIIN 7
Iwwml,n many Ktanul..yhc prraur..w., luttwularly mychwytrs, anJ IwNh IynyJNMaI
anJ NJ.t aclh in aw/nal nnra.w, and lu mnl but rww all Rtanuh.ryte rnacf.Mtharc
Lortnu.r.l('1(' ( 7M) AIIN K MwnJ.wdy In tale /harwl ,awl.eKnwnledl nruu.ylhrtha
a rll. ,11wI rwQ lu ('I (' (.M AIIN 1, -2, 1 twwtwl h9 nw.rhfwd..KKally wkntihaldr fwu
I/.y411I IOr111rM*a. Iw/l MM In (Ilay I4)C'I(' ( iM Appn1I11111atrly hall nI MM lyrul.lrnd
ku\rnnJ .Iw% mrn. were ppnntve with AIIN-I tw AIIN 7, by ('Iwlt/am Iy1111dww1l
Iru\cnlu prt lnw-n% were tarrly pp..qwc. AIIN-K was rarcly lnurwl.wl kul.rnua aaII.
Ilw.. antnw uu,ydld anbtwwhc% appear In drtec( Ji.hna rramtAqw.nhr .uh.rh afwl
/nJv hr u,1IIII 111 tIw a11Jly\t\ 1.1 Iw,11J11111.gIC .I/IICfCnllatwwl ,I/wI In thr \III1a
I.1-//1(']111w1
..1 IruAemu.
Shau.., I(' , Slounuri, K M, Auyust, I T, aml ('tvrw, ( I
111-44 6 4 1/ S74 1714, 11/94
(MArr tupp.rf : NJtwnlal In.ulutc..d I lealth, i/eart nl Vat.,ty l-urwl and thr lnhnwwl h
hAn..sn ( .n1y.Jny
I nwn tM 1)apartnwnt nf (krcuM.py, ()tv/.nwl nl Pethatrx (hK'.duFy, and thr I)tpart
nwM ..1 1 h.nnl.w.d..~y snal I-.aryunlcntal I1wraltu11as. l.dm% ll.lplm. Ihuvat.ny
ti. h.w4 .d Mr.ha lnr, ItJltmwwc
AN1at:I NN' ANA1 1SISlN 111 h(AftNrllI ti11 111 A 111 MA/014111 11('
I'l(IMoI NIIIMI ( I 1 I SIIRI A( I ANIN:I N I)l I INl lt ItY A MI/NlX 11/NAI.
ANI1111N)1' I(A1`s1 I) AliA1N%1 Kl: IA ( 1I1 \
In ihl..tudy% thr K( 7 Ia hunlan hulrml. a rll hne wa% u.rd a% an nnanurn.pru lu an
altrnMl/ t.l Iw.4IWr .Itl//lwwhl\ aF,a1mI hu111an hIa\t ccll .urlace anluKan. IIw K(: I
myrh4d,..Iw kuILrmw arlll.nrwa.JcrtvcJlawnapahcnlwahrwmlytul.lwnyla kulr
mu amI tlw' Kt: Lt tell ha arn.r Itmm to a% a.pmlanrnu. ttsuc rulture varlanl A%
tclwwtcd hrtr, thr antu My 111 nw.u.r nwuww;6w/aI aMtlww/y wa\ tal.rd ahaula the
unol.rwrhumanlyrh.wlrellhnrKG laarMlwasvka1rJl.rrwlnmr9tvnywithmature
humaw yfanuhr yu Anti My I// iomwna.lucrilwtalrJ a Kli la ccll sur/arr pnwcm
wqh aw y~+arrd Mt .d aAxa> inutely IIS ~I/ Ibr sutMw- akxn1t thr MnhnK n/ tht%
awtfh.wly ttl human ha/naUlplictw arll lylla's :Mwl .Iw.w that MyKt i% eRlwrs.cJ yr-
l fha AIIy.MI 1nwnMurr 1wM11Wl humAtl lrl/rrnw cell%, /IK IWI/nK hennN.ywwrlwhrnlMmt.M
acH. My /1/ 1. alvs raprcsseJ by kuiemw nunnw .ell. Il/wl/ a%uhltrspMtW/1M1 UI
"wnl. llws, thi% ww/M.dy alhlws Ihc iaknhla ah.n sru11wn1/N'.1w.n.A hrmN.ywwelw-
pvyanrp. ca11. If.wn mormal lwman marruw anJ the.uhala..dwatw-n..1 kullartna
('n iw. (' L rr .J
.
7Ar l.+.rnnl.olf Innnwn..foRr 131(1)157 -IAS, 1904
(Mb. anr/.A' N.tanal In.tilute% n/ /leslth anJ the Ikatt uf Variety 1'unJ
I..+w ttr L.hw. I(. .1i rn. Ow. -J-.y y/'e nrr r. 1>. v l.w w. ..l PeJulnt / ht ol..4 y aa l('e ll
W.w /arr rw) l w..l.+1 anJ dw' 11. I.ru.w.o. /1T...ur.d..~y srwl l aht.mrnl.l Ihrr
q.rrr« ./.#w. l/.ya.w. 1om.r...I y \. L+J .4 M.-J,..rr, 1lalttuwwc
RAhlh, IiFFIC11iNT ('LONING OF Ml1RINE IIYHRIIxNNA CII.1S IN l.OW
(ilaATI()N TLMPI:RATI IRE A(iAR()SE
Thos raprr Jescrihes a sirfKlk me1Mw1 ha cwlninR nf hyhriaMlmas that ts ralwal,
reliable aml clharcnl in terms rll cua, lime and rMlncy) hyhrwMwru tcrnvery 7hc
fnrtMwl utJvc% haKh1y purilleJ, extremely Inw selaliun ternperalure agatn.e that can
he u.eJ Lw r.tcmkJ rttwwls of time at rawn tenlllttalure wqhtwu Kelalwln lo hr
ylccihc, the u.e nl ultra low Kclaliun Ietnprralwe asarrrx altilweJ the mvesuKahrs 10
avuwl placrnq a water halh, a IwNenlial srwtre of micnlMal c.wNaminatwln, in /1wlr
laonn:a 11nw h.ww1 M.we mllwwlanl, cells never needed lu be etlwrseal lu Iwntnlrally
lusic trnlryvature. :(7"(' In a.khtiwwl, sevetal h11s rd this aKaro.c have hecn tncd aml
were mu toaw tu hyhrwM.ma aell.. ('N1ninR lirnt anJ effiwts were reJuaed by avunhnK
the naY.) I/w f/Md)M nlanrlw/IItNMN In nlalnlam nlf.'lhum ltnlhcralurt alwlvt 17'(' tn
prvr/N Kclatwm n/ rlMvrnlwwUll aRaalse. Ftve nr nwlrc hyMitM.nut can caslly hr
chwlrJ in an h.wn usmK Uns nleth.wl In Ihi. sludy, rGminR ellicienry vatnd /r.wn
hyMNl.wrw to hyMwhwna I luwcver, n wa% hwnJ that ehloes whrch wete Iwuhkf aunK
rapidly aml were hrKhly viahk uwninrly had rhlmnR efiw ienries htKhcr, by .N.kr. 401
nuRnMU.k, than ckwrcs which were RnlwinR pwuly in liquid cullures.
l5wn, ('. I and HanyucriRn. M 1..
'hwrnul n/ InlnfrnnlnK.ru! MrrM.J.r 611 K, 14K 1.
(NArr sr/purt: Natnwlal In.titules td Health, the Hhww) Syslem., and the llcat/ ul
Variety 1unJ
Fr.ml the Ikpartnwm n/ Ikuow.Ky, 1)ivisinn ot Pediatric (?ncoWlsy, )uhn. Ih.llkmm
llniver.ny k h.w+1 u1 MrJicine, Hallinwlre.
A SYNI111:11(' PIiPTIl)E INI)UC6S A NGW ANTI UIiXTRAN IhlOTYI'1:
One nI Ihl' Inarw (aa'IIN'% clMhwfldlnR a11tn11Mt In /Ilae %cmin/,'N arw) nwlka ulaf
a.wrcIatwwl. /% the ann.)llruty tll the iJwMypir JetertmAanls defined by c.wlvemwmal
scu.l..gw Irchwyurs 'I hrre ha% rrcently hrcn a nrw aWrach lu Ihrs Iwnbkm, IhowKh,
smar peplwk% which nlinlic the primary .~yurfkes ul nrmenws aMtKcnm havt Iren
uvtil hl Fctwtalt antilwwlrcs which hrnd Iwllh pepude anJ Ihe whulr nwdccuk\ Ir/w11
which the prphJr was derived. In Ihe wnunary.A the paper presrMeJ hete, n rs shnwn
Ihal the 1.1 pepli«k la% hren.ynlhesireJ anJ cawpleJ In keyhole brq.n hcnww yanm (.r
.c a. an nnnwmfgrn A serum fnwn an ammal hyperinwnwtiteJ wilh rhu rmuwrwlKrn
drnt,m.lralad binding 1u both pcplMle aml fuNive fmnwmqta~llulin 1utthrrnwwc, th.s
serum scrnls hr tkhne an wlwyypic Jelemlinant nesrq unique h/ u(1 .1/ dcRtran
MfwhnK tmmunlphofwlins Synlhrlic pcplwk imnwww/Krns may he a uvIYI aw4 /n
(1rulwwK Ihr ttwdea ulaf ha.is nl wli«Ayry,
,
Sr iJcn, M V,('IrvrnRrr, R, Snwji, T,1)avie, 1 M, McMdl.n, S., anJ (,ctncr, R
Annaks J'Inlmumlhrgic (In.l. Paslcu.) 115 77.112. 191114.
(kAarr suqgetewf: Natinnal Institules ol Health
I:nwn the I)clwn(meM nt Micn11+a1h1Ry aml Immutw.hlgy. WshinRq.n llniver.Ny
Sah.w11.JMeJKine, St Lwis, Ikpartment of Hnwnrd/aal Science, WaahmRuw I Int
venny ticlwwd .A Ilrnt.l Mr.ha me, tit I Aw/s, arol I kparllnenl u/ MuktulY Hw.h.Ky,
the Reseanh Inahwte of %a/tM1s ('Imlc, 1. l.dla t'A
li/; 101
('IIIMK'A1 SYNI III:SIS Of IhlO7OI'HS I:VII)I:N('li 711Ar AN1lS1 RA ll)
1111 S/1Mt 111, 1'I:I'III)li Ul;lf.(1 M111:1I1'1.1:IIINUIN(i Sfll: ASS(M'IAIId)
11)1Otl)1'1 ti
M/ac Ihan ?II yrar% aFn. Kunl,el, 11 G , Mjnnsk. M anJ Wdham., R(' I PK.1/
.hlwcJ thal IIN .llutlural Jlvrt.ny csllres.cJ by variahle rCF11Mi thtln:1/1N CINILI IIC
JItrt trJ by :Inn.cla I IN%c valtahk rrF`NNI anllrenN' tkllIIIII/WIIt\, ra1kJ IJnd.ht.,
IqnvNh .In111h .nNt Infhly .flcrllh way.lll hklMlfyin4' a/N/ rnnll..lnnl,' varlJhk rr/;Nw1%
aM/ ILIvt h.rn wnkly u.cd in mInN/M/1uRica) reaanh In a.LMnal /., fxuvlJmy uvlul
m.u1 r1.l.u mvr.uF.d1uK varlahk rckNnl.(rwiutc anJ IuMlum, ilhntyft% nlay Ilruvnk
a/1//111\N1.111/ ItN'./n% UI IIII/IIIIne rrl,'l/IiINM1 I t1 httter uMk1%IJINIIIN' IM/lra'ulJ/ haN\
UI
1NIN.lytty, the /nvr%11KJIMM% Ihlve Kl'm'tJICJ %everal \Ikyq'r/INan1/%cIJ (hrlql/tl muw/.
n//:/h.m .,1 anm/at% wnh .ynMrlN prptwk% alureynlM)mF In Ihr I11/,) heavy th.nn
p.nnnK .rIrIMnl t ol dN nrww heavy a ham varlaMe 1 V1 rrKnar l lK.r .u11qRIwNIc
%rra Nknlhly vrvcrJl Nh.yypN' tktrnumaM. ptc.eM /al In/a.l hyhrN6Nna anJ myrl.NNa
InnuoM.Khdwhn. I' Itqr,%NM1 uI :11 Irad threr /It Ih" IJNN11re\ Ir CnlTelalfJ w11111IM
anuyrn .prt 11/t Ity nl the lanuly ..1 n11nwM.ylafwlinr hcarlny tlK Jrtcmnn.ull I Lr nl
.ynt1Ntl. Irpuk% lo.ry fatlvc a p.wrrlul Ir.hmyuc in the Krrrrati.m uf /M.k.ul.nty
JCII/M.I .11111NINdyIMt rca4rnl.
\cNkn M V,('Ir-rnK./- H Mt Mdl..n, S,%r.lup, A, I crn.r, K, arlJ 1)av/r, ) M
Irnnnul r./ F %prrnn.rm d A(rJn rn. ISY 11 (N 1(tO, N)x4
Other supporf: 11 S 1'uhlN 11calt11 C.rvNr
I rnlu the Ikp.nhlNnt r.1 41Nnlhnd..Fy anJ ImmuMdnyy. S.'lN..I n1 McJ1.IMt aMl
I)IV1.NN1 ul HN/uNJI. rl \a nMr, St M..1 ul 1 )tnl.ll Mc.ha IrN. W.Lhmp/un ( tulvrl.dy,
St L.au..:InJdNI>.p.utnNntnlMnlr.ul.u 1h..h.l;yKc.rarthln.tllulcnlllN: `.ulry..
('Inn.. 1..1 lnll.l. ('A
RAI)1O1 NY.YMAI'H' ASSAY 1(1k MIiAS1IR1iM1iNT UU 11SS1I1:
('ON('I:NIRAlH)NS(q 1IItirAMINIi. M)A/'rA'llON 1i)(Y)KKI:('f It)It
AI)It1:KI.N('1:()1 IIICIAMINI:l(/MI:C11ANICA1.11()M(Xi1:N1/I:Rti
MrawrrnNnl ut hi.lanline elnNcntratinn% in 1is.uc have inq+nrtant calltrunent.d
appllrat/nn. Hrcau.c' rlhcnnce ul hi.lamule In Rlas. n well kMrwn Ihr prrvnl
inve.uKahws Ira/eJ hw il% atlhereM'e tu a rlwthanicallNlnllqetnver clunnNNdy u.eJ In
tlx e.trx'h.al /A hl.lamine InNn Insue sampk.. I)urinR M/ +ec Id hIN111rKrni.atNtn,
1V!<. 1n 7t'71 ul the hlaanune IwiKinally INrscnt in the .anlpk. "Jl.appaarrJ" u1N/ the
rraam int the JI.aMaarance wa% revcrahk h111JInE Irl M.Iannne 1n the ht»IN.yI nvrr
AtMhng Iratc alMlum% ol J'('/ hi.lamine lu each .anll/k hclnre hIMIN/rcnl/a1Nn1 aM)
rrlfa.urlnl,' the Jl.a(>(Nar+nce tll IallNlatiivity Jurlnl.' INNtN.rcnValanl permttteJ / INRY-
IIIM LM hlMhnlf III IIK INNIMI~.'!n//l'/ I hl.lechnlyue hlr cnrset INIn wa% val/Jalyd hy the
mtv.urrnNnl n1 eM1..KrMws caulccntralNwl. td hiaunilx m Ihc trachcal I+ILIrrNM
/IN 111(YAnI-nl .It .MK 1ranRe u1lrlcan..wwcnlralNnl. I) A1 tu 1'iI nr/nIK wet wtlyht)
I.JIUwr.1 A-, IIK nN IulrnKM nf 1h.wn anNN1M% t1f ciVReMq1% hWan/1/1e aJ1kJ hrt.Mr
IN.nw.K. M..1.... 1.. uw 1. .1 I/..ur ..mpk. L..m the sanr d..F. In Illc 1.11rr .Anydr.,
96 1 I'1 lu..n \I M1..1 dw h..tar..nN ~JJrJ wa. NNa.urrd by /hl% trthnNple Ilrc
rInlN./....rwl.Nt. /ha ..1 IINIAIn/1N In nNthAtl/\a11NnIN.Ken1/CI\ uuy ht an
inqwwtant cau.c.d in:K-cur:N y nf the cn/ymatic as.ay hx the rtwa%urrulcn/ o/ h/.la/n/nc
.urNcntr.lthotl. In Il.wc hul t11a1 .wfi binding may Ar ea.dy currectrJ Itw.
Ilruwn, 1 K . 1'try, M I, krcJ. H. R., Lefl, A. K, ShICW., K., aMl W M
Thr l.MOnuf../ Allergy nn.l ('lrnit nl lnrmunul.rKt- 7](4 ):47 )-47x, 19114
(lthrr srpport: 11 S Ihlhhc Ilcalth tirrvi.e.
1'LNII IIN' ('.IrJN1vaN'lltal Kr.carrh In.tiluk and dlr Ik1+arlnlcnl 01 MrJla irlr (lnlvcr %Ily nl
(',IhhNnla. 1:111 I'/JIN'IK'/1, f/1Nl Rl%I111ahMy ('afc tiCl'InMI /kri1t11K11) 4.1 Mr.I/
% nN. V.1c1an. AJnuul.Ila1NN/ McJlcal ('cnter. San ftatN'txa
IM1IAt AN('1.S IN SI I11S1'.I S O/' l I.YM1'11(X'YTI:.S IN AN INIfKIA)
I'1 IN(:H1:1: Wl llt OMI.NN'S SYNI)KOMI:
'lln. rrplul.kaa'nlwv the imuwmd.lpir lunclian anJ immuMKrKulaa.ry .ul..rt. al
1' tyluldNl. y1r. In Iwu allrarJ mlanls anJ 1419 healthy lamdy memhrr% u( Ihe ..nN
fxJlFrcr.wlgm:Jly JcvrllxJ by (Mx11n I:ighlccn hunNl/ygtl(cs in thi% prJll;rcc had
INrvNnl.ly JNd InNU mlcctnln at le.. Ihan .ilt nNNNh. Itt aKc. Hulh ol Ihc /nlantc
tk.i rJtJ INIr J/.playrJ Mlluta) nulnhcrs uf peripheral hhNrl '1' (1:-ru.ellr/ lyrnphn
cy1c.. p.w mnuran reactivity ul lyltq+lwryte.. Mlrmal mixcJ IynydNwylc cltlturc
rcactlvlly, a pa1N'uy nl .Irculating H cell., variable hyplKannnayhdN/hlNmia, and
lIrv:drJ 4Y11/11 II,I: r1wN'rn11a1NM11. At hwr //Ntlllh\ nl al[C. INIC in/aM Iht.y) haJ 4V,{.
'1 1 I Ihaal 1 I Istspheral hhrd IympMKyks, 41'l. T4 ((helllCr 1'1 IynrydN% ytc. aMl
(v1'4 'I x/ I.ulquc.aw'I ) IymplNlcylc., at hwr nwmthad age the dher inlant 4tiuI1 h,Nl
41w. 1' ( 1.4 1'A r4 I, W'w. Ix i IympM.cyh.., and Ix'4.1A 4 (vlapc 11 Ihynwwy1c)
Iy1npINKy1r.. Are Inatch.vlrunlnll.haJvalues4wx.hrTl. ,)7'S.l/lr 14 1 1('1 hw
lx 1, and 1'Ji 'Ih 1 1un.'tilwul lymplNkyle wppre..illn a..ayeJ by the rrvrr.c
INI/Ndylll plathn a%.ay /MIn'atlJ that the m1aM KnI'S Iynq+Mq'ykf fup/xr%.c1l 7q1{, u/
IIN IulnlulNl~hllNdln Ix.NlurcJ by Mltnul IynydNKylcr. llle N/4 healthy la/nlly mrnl
hrr% t.-IN/IaminK many nhhKale hck.n1.yFulc.1 were analy.etl lur /lt,ttihutNln. 1.1 r-
Iyn1111N11'ylr ?I/h%el\ a1Nt Cnn111L1J with 17 arc-tnakheJ c11Mr.ds. Ha.eJ twl Ihc.e
re.ulh, it wa% rtwNIuJrJ thal IM ImnwMNlrlitiency in ()mcnn's syrnknluc i. Jur In
.ktrpo1:NNM UI I Iy/11p111LL'yle .uA.et., aplrarance u/ iminalwe T ccllk in Ihc (+ea/ph
rral hhN4I. Iu1N'/NM:I) 7'Ctll \unNl-mNNl n/ /n11tWM1gInIM1hn IKtNh1CINM anJ mtI1N'PJ
11 IeII /NI/wI:11NN1% An ahrNwnlal Jl.trihutilln o(thr rrreentagr o/ T4- :NNI I'It ppnnlve
rcll., whwh ca.l% in ao rwtraluJmary nuttlher nf larnily nkmher% nlay .crve a% a
pINM1lypir lympfNKylc nlaller aMl thereby aNl in the illcntillcalNm o/ the Ilctern/yl;
Iw. .lale.
K:uIJ, K A . l:ny, I('.wK+cr, 1 H Iknnisnn, t) K.. Sawycr. M. K., la.Nrrn. r. I
(' , Ma1tu., 1) M. aM1 titNarer W. r.
('ftnir.ll ln/numnl..xv unJ /mmun.ywuh..f./Xv 27 412-127, 19143
(hhrr slrpecf: NalirNlal In+liluk% ul Ikakh, (ieneral ('linical Rexar.h ('cmcr, h.hn
1' Matawrrn IvwML.INm, and the Teita.s (llihhrn's /lu.pilal
/ nnn the 1)eparlnlenls ol 1'rJiatrirs. Malicine, and Micnlbildasy and Immumdut;y,
Hayhw ('u1kKr ot Mcdi.lnc. and the Allergy and Invnurwlolty tiervice, lcs.. ( hd
Jren'v th/+ll/lal, tl.wauNl, aM) the Ikparttncnl of (?eJlatric.. Ilnlvcrsny ot 'lrtas
Ilcallh SclcrNC ('cntcr, 1)alla.
II Et 105
INI.111("flVl: IMMIIN(X71.OH111 IN Sli("RITION IN KIiSPONSIi T(1
1't)K1 W1 1 1) MI/tK;I N IN SAR(Y/IIX/S1S
S.ut.n.l...r. Is a.y.lcnnt Rranuhnnaluus Jlsea.e nl unklnlwn rauv a...Ir1a1rJ
wnh altrt.lhun% in hlwll trllulaf and hunNlral /mmunc IunctNm. Rttcnlly nN.lNwytrk wMt h.ulyNr..
)..kcwccJ mltoyrn (PWMt /nJweJ.prtlln anuMrly HKnIm.,n h.vr
1.1 rn rt h/k J In vn uld../. I Ix pur/a.e ol Ihe turtenl s1uJy wa% lu cv:Juatr wINIlNr
wlynr..n IINrINh yll'\ rnlFhl al.u tr Ijecral/ve Ilr pl4ythnl./I 1111/t11/1N/~IUINIII/I /II`)
wlllbun in /hL .I14a%C AccawJmyly, fectq+heral hI1NNI nNlrnrna-krf tc11. (MNI )
104.111 WItn/11141//t'I11% anti Inlrnlal 111n1rt1l WhllYt\ wl9t' t uI11111YI with I'W M I/r .n dry.
.INI I1N tw.J au/olrr ..1 ly .ct fruny cr11./1K SC/ JrtcrnurK.1 wllh a nvcr.r INnN.lytN.
14.NInc a..ay Whllr /NNUIaI MNI Ir.plrnkJ to I'WM wldl a 111 144414m yualct Int rla.r
In 1/ S(, .:u/uNl MNI lalkd tn rc.plnNl lo I'WM Sanun/ MN) nnN.luNJ Frt.Irr
rl'fl l'lll.l/l'~/.I IIMNNM ylt'\thIII /NM111:1I~(44 K' 2 Ir!{.v% t11 4 ' It'1.11 11 IMtI
/://NI
I/Nrr wa. .1 rNy./nvr I INttIa1nMf ht"twren Ihe magmlutk 111 Ihl /c.INlnv h. I'WM aml
tIN Itn cntA1r ul MNI nNlrNlt ylrs Iluwrvu prnw remllval ul nNNNr ylc% nnpruvrJ
tIN rc.lra/.rvclx.. 1.. I'WM /n Ilnly frwr patlcMs I1ltC\%Ivt' NInMt'mMn nNNN.yIc
It n./l y m 1.1 1 uhNrr .t1Nhr. t INJJ hr Mknt111tJ m nnly tl$.r .a1nN IUur I+./laIn. '1 hu.
rNIIIN1 a rrl.bvr uNNNS yt.Ni. wh/k IRCwut m%ar.llNloN.. rNlr rttr..ivc .1/pl11c.Nlr
1aNNNK ylr :N I/Ylly n/.ly t'/Nlrely altIN/1N 1411 IIIC hyt,oNl'%f11NNIvl11r\\ lU I'WM
I IrNIr1111'. F( rt uI
In ('hrrlNn 1. Mrr.x, 1, arNl X.ItiA, I(' IeJ. ) .C.n..nJ.ni.t New Ylwk 1'rrga
IINM11'IC\%, 1//1tt, IIi/ V/I 102
Orhrr tuppors: (;ull ()J I4r/nJaYln arNl tIN- AnKntAn I ung A..INiatNln
ItlNll Ila Rltikwcll Ke1NrFh I'1/111Ny1.11Y IIII/IIIIIM.11.1y I JIMw.II./y JINI IIN'
(a'1N'r:11
('hnlca) Itrvr.nl h 1'rntrf u1 IIN M.iIN.1/.t 11...p11,11, .//NI IIN 11.IvrnlN-nt /d Mrd/.
uN
Ilrylln ( nltclr ld Mcdlc/nr, IIINI.Irsl
C(1RK1 I ATION (11 I1ISI:AS1. A(T1VIfY IN SAK('(/II)1)SIS WI111 SI-.RIIM
AN(;1(/I ENSIN ('()NVI:N'l IN(; 1-N%YMI:.'Y;AI-I.t11M I.IIN(; \('ANNIN(;
ANI111Kt1N('ll(1AI.V1:(N.AR LAVA(;1:
A..I:IIrJ in thi% paryr, Ufrlntlt1%13 1% a)[rarWMNnaI/NN tlNraV' 111 u/1kM/M-n t'aO%t'
whn h ts u/trn 1realrJ with curlil/..ICn+iJ. tu rtllevr .ynylawnm anJ lu wp)wr.% m/lam-
/n.d/Ny hlnp invulvrmcnl (;allwul 67 1"(:a/ llmp .cammsiK .em/u anyNytn.ln t/nr
vrrtlny curynlr /SA( "li). anJ hnrnt IN/alvelllar I.vaKr (HAL) have heen prol...cd as
u.rlul /rthn/yucs Iu hr (ulluweJ in the aoo.rsrmnl at Aista.e arbv/ly afNl rlyxNl.r lu
/IN'lapy lu.anlNdl/a. (Ar purlNnr /d the rrr.eM stuJy wAS lnnlflptwc /hra v.rNluv
ININ:rllurt% with t llmul a..es.mrnl% u/ Jl.case attrvlly /n N I audre. prrl.wnl.J uver
a/1 Ilt IINN11h 11l'rNMI tM N1 pa11rMo, with ti1rNN1k1\I\ Whlk Ihrte wtre stsanK a.Nlstaal
a.as LIn/Nt. trIwern IMI". "(;.lunle vannlnK, SA(1 kvels amlt hnital a..e..mtM.
ol II1N.IN atlivl/y. CJIh ISMaltll'Irr wa. ux"/ul in Jdlrrrnt way.. 'Ibus grr.kr than
11Y% HAt. synl)+fNlrytet ws a..urialeJ with di.ea.e ati/vply, whereas k.% than MnMI
IIAI. 1/d; .crrrnnK /r11.f11P HAI lylnllhlllyle% wa, alway. Ird/rat/vr ul ulrnve
J.a.Lr Ily tlNlu..l. CA( 1; . hvrh n1 751111/m1 wrrc always at~KU1cJ wHh d/.ea.c
..1 '(;A hm, v annmy I.Nr.1AIrJ vrry wrll with t hnl. al ...c.v
Nw al. .1 ,6.r...,r 1.. dt u. 1..11. 11. .11.J s.rl u1N11v11-d IvINIM~, with .Mly / nt (Al%c
L..1/.1./ t.d.r 1. /../.. Iradt. N. I.A1.11N11 I m.ly Ir al/alllhk in the aa.r%%
tntn1 nf Jlxase activity in .arrniJusis hW Jclemninatilln ol SM"E kvch, '(;a lung
.cannmR arNl HAIL analysis may he rtlrtpknlelMary IowarA Ihic Knal
l.rMrrnrr l: ('. rr .d
In ('hcttntn. 1 Mar.ar, 1, and Sallrcl 1. C. (eJs ): Sorro.rJusis, New Ytxk:
PrryaoMNl l'rr.. 19ttI pp 414) 411.
(IsAer sunort: (7u11 (//1 I-nulklaliurl and the Ameriran I.ung Awrcialil.n
hLNn NI. Awcll Kclrogh I'uhlNlnary ImmurNlh.igy I"ahllratllry and the (:rneral ('linltal
Rt.crah (rnlcr ul the MctINIJi.I Ihnplal arNl lhe Ikpaltmcnl nl McJlrnrc Hrylln
( ulllkr ul MrJICUN. I hlu.aln
(;AN(;1.1(1SIINiS (/1 IIIIMAN A('UTIi 1.1iUK1iM1A ('1:1.1 ti
In an atlrmpl 1u gain nNre inhxnuNilln /ln the KanRlu+.nk. Iwr.enl in atutr
kukemla « II., IheK invr]IIpaH1rR rharatlefltell the )',a116INhkkS /nnll CrII\ l1I rll,'ht
pNienl% with Jil/erenl (fwn/v ul atule kukemu IGwr IympINlMa.tn, Lwr sNMlylu-
phllhlastic) by thin layrr chrrwnaplpnaphy atlll high pcrhwsnantc Ilyulll chnlnlall.g
raphy rl>trlMneJ with pIyruclJase Ireal/ner11. Thr ir aludy.i% inJicatcJ IwNh quantitative
anti qualitative Jil/crrnres hetween the RanRlilriJes d acute tcukeuria and tlNl.e td
dutnal kuklKyles: I II the ah.dule a11rwM uf KanRlwssiJe wa% dacreaveJ in Ibe atutc
leukemia crlls; 12) in Eeneral, acute kukemia% haJ a ssrlre sin>r1i11eJ RanglNhltk
Ilaltern in that they taNairrtl a(Ueealer prlqwlrlam d the .hortcham KarlKlnaiJe,
11'NcuAr Lar('er ((;M 1). (11 all n41he arute kuketnia cells rrxNaineJ rtJured quanti-
11t. rd Ihr RanFlirnk N acelyhxwamitasyllarMNritawykeramiJe, a rlan)ItwnJ Inevi
uu.ly InurlJ unly in rwlnnal kukncylea, and (4) a Jl.ialylaKd RanElithlJe. ll'1 NruAc).
Iatt'er /G111) which u Iwll /awd in mwtnal kuknryles, wa.s twdaleJ (nlm 1he cellad
/Nre patleM with ar u1e IwmlynqlMhlaalic kukemia. "tlle~e IitrlinRs IkrrN.n.tuNr unplr
tanl Jrllrrence% between the Ranglar.titks a/ acille kukemia tell% and mwmal kuku
ry1r..
Wearick, M A., l.ec, W. M. F., CM/fl, 8., anJ Mow Arr, A A.
Nir* /4irwi/ u cr Biqrhv.ira Ar ta 7511.141-14t(, IY11].
OrAer saqR.+t: Canrer Research Fluwla tlt the Univer.ily ul Califnrnia
hrllm thc Cancer Re.earth Indiluk, Ikpanmefn tsl MeJltine anJ Ikpanmem /J
NtannarculKal Chenmiary, Utwversuy of Caltltlrnia. San hranciscu
I
(;AN(;1 N1~1111:5 (N- III/MAN ('lIR(/NK' I.YMI'll(1CYl l(' I.I:UKUMIA ANI/
IIAIRY ('1i1.1.S
(ianKlM/.Kks arc an imlrwtant suhclass ot ~Iycnt~hinR/dipid. whit h tINdam afaht
aciJ 'llle researrh elluns 14 thls Ia111wNury, haLe heen Iocu.eJ tln the yunertlraNm
anJ alrrrlwal tharal/enrMNwt 401 neutral RlytnsphinRnlsplJ. anJ ItanrIN..Nks 141,411
hurwr klAlltyle% and kukcmla tell. In 1he .tmly rrplrleJ here. R.nKhoarlrs wrrr
purtheJ /nlrn the ce11% 0/ Iwo paKnls with hairy cel) kukrm/a aml /me pahrnl wllh
NK K)7
. hamrc Iymrlwn ytrt kuArmia (Nan111tC;1twM1 UI IheK hw111+Itl/n1I% %IwIwCJ thal IInw
t.ILI.wN.nn/wdyS 1t( oldlranwwMollrp/J h++onJaalK al+J(r:mFlw+.nk.IpYtrO
a. rwlrm.J lylnph.nyte. Sttutlutal thar.nltft/7Nwm by Ra. byuwl thru/uatllg
raphy Fly.lnlJav t1ra11rICM a/wl hl~h I+.YIINInatRr I1(IIIIII.hnan.dl/ptrphy Ikuwwl
.tralrJ dut the nupw y./nKIwnnk% nl thr.e kuAclnia trll% wrrr /d Ilw: la.iu.yl /ylt
11.Itty tl11\ t/w\t./nnll /1wMwt\1aIyI Ial'Ilhyk;tYanlwk (II'NCIIAc I:n('l'fl. wlKrla\
th/unn lymp/wwytrc IeuArm/a ccll% t/'Mau+ctf fwMh /n+vwmLdyl arwl d14.dyl I:nn
.ykenlnnk IIIYNruA+ l. l.;n( rt/ ('hnlnos: (ynlr/wrtytic Irulenna crll% tlwr:nlwJ
k..rr anw.unl./d Ihrrr +Nher Kangla/tnk% n( Ihe n.vdat t+++K I:n lo.rrn. a. +ktrt .w+wd
hy rtwh+ It ~al n Iu.rJa4 ur:nnn M Nune nf the.e kukrmw aelh tlmtalnrJ Ikt.e
tablr
yuan111w./d NcuAt I l/ ).r('tf, a KanKlia.nk h1unJ in rwwlnel ku4+Kytr.
(:Idl It A, lee. W M 1, Wr.11n1, M A, and Mulhrr. It A
I naqlrlur /nnrn.d../HrlnhrnrrN.+ /NI .S1 S{7, 19111
lhher Iuppprh Nalw.nal (n.tltute.++t /kalth anJ the Natnmal ('antcr In.lnntr
I rl/o+ Ilse ('.uner Hc4auth In.titute arwl 1kpanment ol /Mwrn+:n'rutnal (lnnu.try.
llmvcrNny 4.1 ( al/1/n11a. tial1Ih1/n1411
1S()I AIII/N ANI)( IIAKA('ll RI/ATI()N t)1-(;AN(;11(rill)F.S I R()M
('ll/t(INI(' h1YI.1 IN:I Nl)tI\ I I IIKI ti11A ('1-.1 I.S
Ilse Inup.4' +/1 Ih+. uwly wa. 111 14d.Ne arw) %trwlurally thal;wlcrvr Iln' In,qIK
tlu/mn IIIyCIurl'/wMN kukclula 1( MI I y.mKlw+.nk% a/r/ tunq+arr tlwul lu thr
K.lo/'h/hnk'\ I/I nIM/n:1I rKutrlM,htl. A, prr4MrJ hctr. Kanrlw/.wlc% w.lalcJ Irum Ihr
.rll% nl Itnrr p.ltnnt% wuh ('Ml. wrre Iernh.J by I-ahh hanlnunrng. dwthylann
/n.dly I`r/dl.u+k a./k In.d l:n'r ly Ia1rJ kan/clw r.nk.l. a/wl .dan a+ nl t hwm.+a lycq4ly
anJ wclc .tnnlurally analy/rJ u./nF thin layer anJ pa% hyuwl tlu/w+wtar./:/phy-
nnthyla/wln aualya., rn/ynw[ JlI,'r.wlaNi/M aMI hil,'h /1CfhMltlarw:e 11yulJ ahnwn.l
t.+Fraphy With ther mcthlnta, thr nupK panKln/.nk% i.rdaltd werc (1' +. N.
nclyhxnuunrw+.ylla.i+/.ykrrarmJr. IV' natelyltlcuraml/w/.yl nr+d;nnMrlr.w/.yl-
.rranmk Llak+.yhfna~IllhrNnk), and a K+nplNKnk wnh Ilnt hdrnwiny .1nw'lurc'
NcuA.n2 1/(;al(II 4(:kNat(lI 1/(ial/11 4(;kpl 1('rr. lhi+ KanKh/nwk ha%
rfcvpwl.ly htcn tharatlcri/cJ a. an "/" atiivt' tnrlrywwnJ (1 wa. a14+ hwrwl Ihat Ill e
IwKmal neuul+llhil., ('MI. ttIl% amtam nwwwraak+pangha.nk. tlut hehmK Ilt Ilse I:w1u
.yl alwl nrolarlu ramily Iluwevcf, thl. .tudy .hnw. that CMI. trll. JJkYrJ Irnm
Iwwmal nrulnM+hd. in Ihat they c/wllain.vl ks hMal KanI;IhNwk, ;IMI t1wu nr.q/w
Kanylw+.nk .Ittlc. 1. Il' n N alclylnruwoua..yll.ntu.ykrfaruuk I)dh/crnc Ir
Iwll'n 1,'an1;I11hwk% 1/1 ('MI.:IMI atull' /wMllytllrtw+hla.ti. k'ukrmla alc J/4 uwJ
Wtrltritk, M A I.rr W M 1: and Mnthn H. A
('urn rr X.+rltn h 41 SRW ) SR94 1VA )
lhhn tvppnrf Nan/.nal ('arn er In.hlale
I L..u Itv + ./../ N, .. .r, h Il/,l,l.,.r .Irl (~ /,.ulnrnl .11 1'fiannaeuh+al ( (aln+.try.
~ .,,...../, ./1 .1./..,,... .., 1 .......,,
AtiS( X'IA I RIN O1 GAN(:1 IUS1h1: hl((YI I:IN ('ONll l(7A11iS INl( ) l 1.1.1.
ANI)SI:NI)AI VIR(IS RLt)1IIKIiM1iN1 HN('17IIi11N SUIII/NII' IN
VIRAL hIISI(1N
In Ihi..nuly, a oM thlwl lakx rihtd hlf pfrpafinp a covak M tnn~uKa/c +.1 pnNrin.,
in panltular aut+lnnlit. and thrir (rapmrnl., wnh KanKlMr.alr% in Ihr IllnlII:If IINIIt
'llw pnwrin yanFlnl.wk t+lnply,ale i% a.4niakJ with Kanyll.hnk I/In'CIk, ;IMI t':111 hl
rp:ualcJ Iuwlc htr pndc/n hy nw+ktular cirvr chnmlaN.graphy (unIuFalr% can inc
vrl.+hly tl an.lcr Iruln t/n rnu, clk tu a tell lnr n+hranc /4 tlw+itr, anJ IhC IM/Nl/ll IMKtnw+
ht akntllnJ a% a/n w wrl:nr anhKrn. Ilse .IKrc.au/ a/qditalwln rd Ihl% nw.'Ihlwk4+1} y
ha. 1wtn Iknw+n.IratrJ wnh th/t'r biuk+pi.al .y.lrm. Rahbrt /1,(;Fanplilnwk t+wqu
gale ha. IKrn tran.lrnrd lu humrn nr .hcrp erylhnmcylr.. whith have Irr'n Iwm.+y
plutlnalrJ with yad a/ai /ahhn Ip(i. (:rythnwytes rwlJilieJ with Kanphl+.uk anh
I I?K' have Iticn .Iw.wu 11+ aJlwYr d+ nunw.layrt. Id I 4p) nw+u.e I/Iw++hla\I% whn h
l'trn'%% II !K* aMll'ln MtlIN nnwM4 hN1aI anhl,'IytIIIIIw11/n ganl!INNnk l'Iwlhll}.de C.111
a%4q 1ql with 1C/wlal v//u, a/wI t'Iwtet ulwnl Ilse vIfIN Ilse ahlllly 111 al!)!I1/1/1WIC a1wl
Inurdy/r Ik.adylalyd Mmun e/ythntiylc.. I/anp Ihr aM/hlynh+h.um .+nqul'ate.
Ilw.c /uvr.tlyal.w./knwm.uatrJ that the IIN >oMlnd, whNh 1% awulally rc.p.n.dllr
l/.r viral hlmhrnK, a/+1+.ars al.a a+he r..cmial hw lu.l.m a. uvily Ix tau.r rl. Je.uu. nwn
rhu+m.nc. IKIIw/Iy4% alwl Iu%/+N1 IMI/ Iwlt apKluhnatina by she tYM110Fa11 /IwnI1I1l'J
1 vla/.
Ikalh. 1' 1) . Marlur f l. arrl Mw her, fl. A.
I.+lrrrtmrnalll'~dl R..rar+h 149:IM11175, 19N1
(Nher rnpp.nl: Nali.nlal('anrtY In.lilulr and Ihk- Nali/wlal In.blulr% rr/ I lealll/
frum Ilse (';oncr Re.rarth Inailulr arw/ Ikrarlnlrnl ot Pharm:rruna:J ('In'Inu.uy,
I lulvrlvly u1 ('ahl+wnla San 1rantivu.
hIf+I.Rf.Nt1A1.liXIM(INSN)N (/U(iAN(:LK)SIIN? (;,,, IIY H1/MAN
1.1,111(( K'Y I1:S ANI ) LIs1,K1:MIA (TJ.1 S
Vatlirr analy.r. ul dw I;lyrlrylhinpr+lipitlad mwnul Iwnun k ukrnyl.. and Irul,r-
mia 4.01% luve .Mlwn Ihal Ilk.e ccll% c.Nltain xveral lyprs +d owww..iak/p;m1:In..wk.
hM /NIIy INn' Ih%laksf,'anl,'Inhnk. (I,,,. In Ilte IlfellM S(Y11y Kanl,'Inhwkt r1/n11 Iww111a)
kukutytc% aml lhr crll% nl 2S palitYll% with acule anJ rhnrnir kukrnna wrrc Ir.IrJ lur
thr prr.r/Ke .d Ji.iah.y.anpli.hiJc 11'-uNwrlybkwanNa..yl-a2 1( N alttyl
muraruirwhyllxN+.ykrt nnnk (G,,./. (i,,,wa. JrttttrJ by imnwml.talmnK thin laycr
thnwlulr+graph% with an aMrG,nuuutkmal aMihrn/y (AhK.,). Anwmp Ilse myrknJ
te11.Ir.IrJ,:w ulc IcuLcm/a trll% were ptNilive hr (i,,,, wh,neaahnmim kukcm/a aellk
nlwl rwNnla) 1Nu1f1111111k J/J Iw11 have JrtataMe (i,,,. A ranKr u/ (i,rrxirv//y wa%
aM+atrM within Iln a utr mycluwl kuAemuw trll.; ganKln/.iJe. /nwn I/ule n+yelulJ
Iruhrmla.rll..lalnrJ nwwr /Mrn.aly Ihan IM+.r IaMn kukenlia crllk wlth nwwwnytw
a harattaYl.ht. All ly/nplwKyllt kuhtm/a cell. (chnlnK anJ acutel t.nnauwJ 1; hnl
thl. Kanylu+.nk t.Mlkl /wu tlc dat'.hJ in e.lracl. Iu1M mrnul lyn+(+Iwt yh. A
panpliu.i/k estrax/ Inwn Ilse tcll1 u1 a(wtieM with hairy trll lcukemia wa% al4 /w..mvr
hw (i,.,Ir111nInnNlarnlnl! 1IM.'te re5011% Jl'nwNqtfNe that nu(II1.1I klrklny/l\ a/M1 a(I//Mn
myckljermw% kulkrrn/a tc1l% arc Ji.thnKui.heJ lurn Inhrr Iyn+pMlid anJ twmlynydwnJ
kulAemia tcllt tw+ the ha.n ul (i, KanKlN+ciJr e%prc..ilm.
Swkllyui, N Nuchkr 1 I k( ireplwn+. M W . arw) M.n hrr. F A
1(w
~~/F
(..m r. Xrorn.. h 44 t262-S2bS, 191114
f)rbrr srpport: Natn,nal ('am'cr Inshdde and Lrwrs K(.uric 1'v,undatl..n
1'nml thr l:a.un/ntc.lrnal Ke.car.h lAhuralnry, Vclerans AJrmm.tratnln Ihnpnal,
San l ran.lscu, ('ancrt Rc.eatch Instllute arnl 1)cpartment ul 1'humxculical('hclms
try, I l/nvrraly ul ('eld.,rnu, San hranclsau, arul ('htlJren's ('a/wcr Rrsearah In.ttlWc,
1'a./h. Mr.h. al ('emrr, San 1'ramrsco
INI11II1111)N ( F M111 x;1 N ANI) ANTKiIiN INI)ll('19) I.YMI'11(1('Y I li
A(' I 1 V A I It )N IIY Ill 1MAN 1.1.UKItM1A ('lil.l. (iAN( it.lOSIINiS
'lln. shwly ,kuw.n.tratcJ thal FanRln/si.ks prefMreJ bnm human ku~rnna cclls
mh/hn uuu,l cn and anl.Kcn acuv,NNm 1.1 hwlqn lynq,hlw ylc. 1'utlhcrnMNC. Ihc ~/wr.
I/p,n,.a hwr analyrcd d,c c/lnt nl I,IB/(IeJ arwl sttu.turally .khucd KanKh-..rlk..m
Iyny1M,s ylc hlash.rrneas Ibcae analyscs alMlw Iheln 1.1 enm'lude Ihr la/
K.u,Flw..nkI ul huulan Icukcmla acll., when aJ.kd tu rn vNrn a.say systcros In i..x'cn
tr.d/.wl. lla,wn tu.KCur in the scrum ol hunlans with can.ers, supms lymploKytc
:n trvab.ln. Ih) rax h/,Infied KanKlw,.uk supprcssecl hlaauKenesia lo a.nndar c.lrnt
am11i / slcdp a./d /I rsrnnal l.w rna.Inlal unnnlm..uMncsvun 1 hc dncc RanKh ,.i.ks
uvd in rhl..tuJy irc aL., knl,wn t., hc l.Nn(ANlcnta III InKInal l CINa111I1herchNc %IMN11J
IMd I4 ..,n.ukrcJ ku4uua ass.w/atrd..au(rw.rnls Ilawrvcr, thr rl.ntcmrrta,n nl
IINK lYnn11nu1NI% " ItrN,wn lU he lIrv/1c.I in lhr %eru111 I,I (,atlcnt\ with l'Anll'1\ :IINI,
thcrcl.ac. n,jy I.,ntn(anc tu a tcdwrJ uulnu/w Ic.ln.c In s.nnc umcr patlcut.
(il,nwa. 'I A. Wr.trlt k. M A, an.l AR., hr.. H A
('om r. H. ,rru. h-11 LIh7 1.1It/, 1'111/
(lYhfr 1YqbN/: Na1MMaI ('a/Nlr hl,ldute, 11 S I'uh1/c 1(callh Serv/rc, anJ N.IU.w/al
Kcseanh Scrvicr AwarJ.
I r.nn thr I1rPartnKnt ol Mrdn-ure. l)mvrr.dy uI Iowa Lwa ('Ity, anJ ('an.rl Rc-
scan h Inshunc amllhr I kparbncnl ul 111anuacculkal ('hrmislry, l lntvctaty .d ('alr
LMnn, S.rn I ra1N Iccu
I:XPR1:151ON Of III.A-UR IlY A IIIIMAN M(Nd(>L YTI: CELI. I.INF. IS
IINI)IiK IRANS('RII'Ill/NALCONI'R(N.
In Ihis atlernPlln dclrrnnnt the nrechanlsm hy which la imlucle,n.w'. urs, ca(+1ri
mcnts wcrc JcslKneJ Io invcstiKalc thc nw,lcculx evenls Ira.hnK lu cqnrsnMl 401 the
hum.m la nwlkv ulr, 111 A I)K 1 u x..wnPhsh Ihis, lhc honcm nwlmr'yloal. rll line 11
Y17,whNhd.ocsmAcarycssanyrktc.lahk111 A 1/Knw,k.ulcs,wasu.cd I/b1/nnRa
.IINA Iw.dr hM thc n.ham sit III.A IN( anll h.lal rcllular KNA. II..MItiI lu'.knMM
stralcdt11a1rc.unK11//171arAeJJclet/a1.kI/I.A 1)RtranscrqNs IAKr.IN.nll(KcMNlnc
1)NA In,ln 1/917 with the Iwlsch/r.wlKr. M.P 1 anJ IIPa 11 InlluwcJ by analysis a/ the
rc.lrla tN,n IraKmenls .,n ti.,uthrrn hh,ta rknr,nslrakJ Ihc I ILA I1K n. ham Kcncs t.. he
mclhyLdeJ A.wlnwm ul S-aracytahne, an anahq(ue nt a ytNlrne whK'h causcs hyp/
nrthylatnm o/ I/NA 14.11911 cau%cd hypnncthylabnn ef III.A IyR n r hain gcnc.lwu
dld o.a, by n.rlt. k:Nl I..Ihc q+ptar.,mt.,l III.A 1)R n«,kruk%.K Uansrry,ts Ih.w
rvrl- I/ran,M'/d u1 1/ 917 wnh S.II,n yluluN hdL.wrJ try aNh1/1nM uf c,1IK1 .uhmc
flulds Innn activatcJ T cclls nr human tecnmhinaM 7 interferon Jid Irad Ia Ihe raprJ
a(,{uaram'c of ahundant, matwe I II.A I/R Itanarips and sur(al:c 111.A I)R nw,kcuks
'Il>, rewlts nl tllcse stlNlies Ptovpk the finl derrnwntralNm that tncthylatnln Plays a ruk
/n the eil/wcssN,n .,1 human It Rrnes and that induceJ eapressiwm uf Ia na,lccnka by
s.duhk lachws fr.nn T cells, nKluJins 7 inlrrlenm, rs acenrnpanieJ by the r-apiJ
arpcarance ol Ir Kene Iranscrlpts
1'rrrrlrn, H M,(iorlwa, L A and $hllq, ). 1)
h.urnal../ M.d.r4 rlnr ('rll Immmnnl.,Ry 1.191-2(111, 1994
.
()t6er srDport: 11. S Public Ikalth Service.
fruor Ihe I IuwatJ IluFhes Medical Inslilule and the Ikpartmenl .d Medicine. Unlvcr
%Ily ol ('ald.wnla, San Framisa'o.
H(1MI1kXIN ANI) VA%OA('fIVli INTI?cTINA1.1'(H.YPIiP1U)li IN lllli
1)HVI'l l)1'IN(: LIIN(; MARKIiI)('I1AN(i1:S IN A('1)TI's RI:SPIKA11)KY
11IS1KIiSS SYNI)K(1M1:
Ilecau.e thcrc have heen ml imnwnl/Mlgical atudies un Ihe fetal nt ne.matal lkvcl
hplnrm ul vaa/atiive mlcshnal PnlypcMide( VIP) inhunman lung .w in IunK d/sraxs, in
the Present stwly the quantitative JlslrihwMm rl( MlndRSm and V II' hkc innuumweac
tivnlcs was rklcrmincd by RIA and imnwaMytahemisuy in rcRMMS ol uachca,
hr/nchu., and whldr lung at vatilws slaKes ul human Icta) devehMlmcrO aml ur nc.l
natcs, chlkhen, aml adulls In add/1inn, /hesc two inutnNwneaclivities were sludlcd in
inlaras thal hnl JicJ nf the acute resMral.xy diaecss syndtrNne Re.ult..hnwcJ that the
c,wrccrnralwm.d hnrnhcsrn hke imuwtwncacttvity in the wMde te.MraNny tr:N 1.tcad
ily irKrca.eJ durrng peaalNm, reaching a plateau at huth In the lung, lamlhesrn
nurcerNralnm rcuulneJ alrnnst unchanged JwinRchiWMMld hut.kcteasad lu Ime tenth
in the adult In ne.mates with the aeule reyurahay distress syndamlc. Iherc was a
siKnr/iaantly luwer humhe.m crnlleM in all reKiuns rrt the respirahxy tract crnry+:ncJ tn
c/lher nlwllu) lull term InfaMs tw 24 la 21{-week-oW ktuses. In re1NCJ sluJics, im
nwmK yhKikmrshy h/calvcd hnrnhcsm /mnwnnrcarlivily within naN'nsal munrclrMr
, tnle ce11.11re.eM in the anway cPllheliwn thnWrJMwl the re4liratnry Itat 1 am/ Par/K u
luly in the inuapu6rwwury airway.. The nwnhcr d cells incrcavaJ IlanupMlu1
RC%taNNM, mllectunK the pattern frwnJ by RIA, arwt wrls Krea/ly Jectea.cd in acutc
respirahlry Jl.ttes% synJnwne PalieMs. AI.n, VII' l'IMCCIItra1NN1{ 11Vere Illurh /nwcr
than llrne rA Iwwnhcsln arwl JMl aM chanRe .igni/icanlly wuh ReaatN,nal age In
nwNta>t /u h.wnhe.in, VII' was maidy avmcentratcJ in the upper reslloahwy Irart In
inlanls with tlk resyirahwy J/.lress synJnnne. the V IP crnNeM wa% mN dillcrenl lann
mwnol 7hc.c.resuhc arc c.wlpvlihk with the p/ssiMhly Iha1 Mwnhcsin like IrINaks
may have a n,k in thc mNlnal IkvchKltnrnl nl the human lung
(ihalcl, M A, tihrlqrawl, M N, Ilcnien 1nRman, S., Illank, M A. I A( ,
and Hhrwn, S K
luurnul r.J (Yinir al l:bd.nrinolaRy anJ MrmMdi.nl S71b) 122A 1212 14N 1
(NAer su/O.wt: T1k MeJi.al Research Ctwncil and the Welle.,me lrust
liom the lk partments n( Medicine and Htsuahcrmstry, I IamnKrsmlth I Iu%/n/aI, I a,n
dun, F.nKlaml
111) I11
RI GI II A fORY I'I PI II)I.S I.(X'AI.1%A I I()N ANI)MI'.ASIIRI:MI:N f
TIK Ixc.rlMC ./1 live rcRulatlny pcptuks vavla.ilvc mleslinal Itlauk IVII')
alhslalkc I'. Ivnnlr an IIIN/. tM.kt y.hlkrom 1('('K /, anJ s/wn:Hu.lalm, waI
rlwe.tl
y.ncd wnhur van.Nt. u..ue .Irutlurt. u.rny rmnwnlwytly hrmi.lry hn thcrt h. ahia
tuln arxl r.nlnulmnwrMla..ay tlw IM Im'r.c tnca.uttnknl arwl chcmaal th:nxlcrva
li.al SluJlrs wl rc a.n,lul tcJ in rwLnalal anll adult hunlan. rats Kwnt n piF., aml t,u.
Il/.loh.yl. IlC11Nnl%lratl.m ol the Jdlu.c neut/1enJlcrine sy.lem in na rnurcly w,ls
carried Iwl u.ulg antll.nhee lu ncurlln ylccih/: edda.r INXI1: tkhncablm ut Itx Iwu
tvanlewltnls nlural anJ Khal, Id Ihc auhNtllrnie ncrvlws sy.tcm wa% accunlpll.hrJ by
the cumhuKd u.c ni antlNFa (It Iw111Ma1n f1rlMelna: NSI: (IIN au11MBNIIK' nCrvl%) uNl
S1fMl /llw ylr.d t c1L/ V I P anll suh.larlte I' were the nN/.l a1wn/Ian1 plpt/lks an1l w1Ic
Itn :/1l/c1I tl/ a111/NMNll/l nervl'\, nlalnly in IIIe upper re%plratHlr y Itat 1 I/M-I1plmg IhC
naaal
nuHUS,I VII' wa. /rryuently flnnNl tu hc asvriNeJ wuh .cctet.ry Klanll., .nwuIh
nluaia atwl hI1r.J vc..cl. wherea..uh.tancc I' wa. ohcn.cen in c h.v a.vK rau.al wrdl
huew hr rt rp111M hum VII' nervc hhcrs wcrr snrn lu hive a Jual llrtym Irlan tir:d 1 r11
hlncc. h.uml Artw1 cat lu.rvcly rn the wall l.f the Irachea and Ir/nu the .fdlcrwlpalarule
KangIMln where nunltrnws VIP nulturnmR neurorls c/wIJ he detntcd Alvl, IMlulnc
INM1//1 rtL'uI:1tIMy PeINlde\, Itr1r1C,f1.llly MN11ht.'(m, waa M1ttd in Iunl,' enJ14'r1r1e
turlMN
fr e, snull .cll c:ut rnlNnal tharx tctvcd Imnwnnhi.t.duKlcally by tlkn hl~h clwnrm
ol NSL. anJ ulua.tnNtutally by Ihe prc.crxc uf retuKmiahlc.ecrrhwy pranuks. Ilk
eu wnK Jlvuvtry ol a IarKc numhrr ul rt Kulatlny Il.fwuk. m mll.t Irnphctal usvk.
hr% ptonwNCd Ihc lunr 1/.11. wc11 Ikv rved r.nk as lak Id tlK Iwran% he.t plura/cd with
Ihcdlfhl.rncunalwtinnne.y.tem Invt,I/kIINMauIllltrrCCIV'd/~hIM11PMaMItNa1K
llti.rhi.uum .-1 rrrulatlwy fw14uk% tM,.ufIl.alr tht rc.pIt.NIKy tratt /nll within ca.h
U.an uutlurr lanvak (ull ulqawt .d thc /ntrca.mFly atttINcd view uf 1a11nwmary
rrr.ulrt/nn by nlc.vnrct wh.Irnl r.
! AI and Fll...ul. 5 R
In hctkct, K I. aml (iaiJar. A 1 IeJ. ) Ihr fnd.arenr l.unx m Hr.ddh un.t
thlru.r. 19n1aJtIphla. W It ti.lunikr. ('oory.any, 1994. l+p. 4M/ 12)
I'rlml tIM' I k pannk nt. l.t MeJicine .lnd 1 h.wxhcmis,ry. I tanlmcr.nuth I lu.pl al, l.m thm,
1nylantl.
11N)SYNI ill.SIS ANI) ASShMIII.Y 1/1-THIi it ANI)11 SIIIIIINITS O1 Mat 1, A
MA('R( )I'l1A( il: (;I.YC()/'R()f I.IN Atiti(X'IAl la) W1111('(/MI'1.1:11:
RIL('1:1'I(1R I I/N(TIl)N
A: tcppMtcJ (xevNwsly, Mac I ia a macnl(lhage \utlaCe anlil(en C/Ntlallllnl,' MMl
cnvaknlly as.IK latcJ a arrl ~S suMmih ol M, - 171/ ~MM/ anll VS IMM/, reIrcUvcly Tu
dctetmule whellk r the .uhumts ate Jctivn) frum a cumnwln lr separalc IwccurMlt. the
hiosymhesl% ul Mac I was stul6eJ I"S/Mclhulmtle pul.e tha.e lahekd nutcrtal wa%
imnwnllllrcu)+11ated with eithcr a nlunllclllnal anbhlrly rcc/ry nirm6 an to chain Ikkr-
/n/nan/ (NCaeM in Ihe asMrlaled /t,(S, crwnpks Iw a pnlyclnnal antiserum rec/1RmimF
the a.11, c/lnry+ks aa wtI) as the free (1 suhuml (n penaMleal e.wlate mat'nq,haKlr., the
ol .uhunn wa. Jcnvcd lu.m a prct urvw 111 M= 161.411111 which wa. alnvertcd lo the
lnatulc At 1)11,1~a11 hnn wnh ~ r'I ul Ill lu (S mm l/tt' (t.uhuml waa dtrwtJ (nqu
a AI M f 111111 Ltt urvr whN h t.Y anK ..va ultd with Ibr n.ul.umt and wat t.m
vcrlrJ 1~. M w_tasr wah a r'rt nl 1 h 1..tKIcd It t haln ur.( hroy.cr than n tu hccume
assacialed with the n,1S, c/nnpks in a number of difkrenl types of penloneal tnacru-
pha~c pclalillns, currclaunK wdh tynthesis of an escess td (i In Ihc 1'1llRl ), nlacr u
phaEc hke>fwtumlw hne, u.rkl (S were prucesxd wilh r42s of ahuul2 anJ Ih Ituth n anll
11 precursars were present in the ca/rrq+lea, suggesting that annpkr< IIMIIa1NM Lrr
ceeded pracesams
Ilu, M K. anJ SfrrinRrr, T. A.
The l.wrnuf r./ Rinlngil at lhrmi..rry 2SR(S):276M1-27(v9, 19113.
(khersupporf: U. S Public Ikalth Service.
Frll.n Ihe Lahlxahlry nf Mcmhrane Imnwarchemiclry, Sidney I:artur Cancer Instllute,
and the Ikpartmcnt uf 1'atlwlMlgy, IfrvrJ Medical Schlllll, Hrnhln.
IN?NbRITS(' CIiLL ANI) MACROPIIAGE STAININ(: BY MON(X'LONAI.
ANl llt/)1)II:S IN TISSUI: SI:CTIONS ANl) I:PII)hRMAL SIIF.1TS
~ This study was undertaken In Mwlk at the lissue Jislrihulion of certain recently
JesariheJ munne nucrlKlhaRe antigens 10 deternune whether drstincuve suhsets cuu1J
11e f1Nmd and in pa/7/lular, whelher these aMlRe/ls wplld a1M1 he preaeM on %
.InIM IIf the
demlriuc cells. 'fu Jo Ihis, rt.wse lissue seclwms were stained by rtwwwlchmal antrhllJ -
ies ttl matnq+haRe amiRens ( Mal:-1( MI I711), Mac-2 (M.1/ )1f), Mac 1( M 11114) with the
u.e 11t unnwaharusida.e. Mac-1 was ktleales/ diffusely in Ihe cydlplasnm td rrwnl/ tells
in a high percentaRe nf alvenllr macnqTh.ges, reaideM prriMOCal anll hlwk mat,rrw
cell., in spknic reJ pulp, and in rare perivasawlar celis in the Ihynws. Mac-1 wa. ah.enl
in cpilhelial cells and 1anRcrhans cells. Mac2 was slnln6ly pKilive in rnany tknJntk
cells in 1he ahymM medulla, mure than the enrtea, in paracylrtes and medulla td lymph
nlMles, sparing the fllllicks, and in the tnrRind s.nne uf ylleen. There were a few
pu.ilivt cclls in Remrinal «nten. Mae-2 was h1c.1eJ in a M.w peracn(aRe of hlurc
m.rtrnv anJ a hi6h percenlaae of residenl periNlneal relh. When puaitive in .eclilwls.
Mac-1 always slutwed Rranulr cyNlplasmic slainirrR. Rane mwn.w sht/wed a high
percentage uf typlplasnic slainint (>SM), as cornpared with Mnw surface slatmns
(c 1%) It was f4wnd in hemattlpnietic eeBs, aswl in aAl eruluthelium, im1udtna plat
capillary venuka and lining r/f sirwses. 11 was pnlhahk that the nrwltinR Jendrurc
staining pattern frw Mac-J in parsrnAea t>< lymph nrlJes, whrte and red pulp, lhynric
coAes, and medulla includeJ dendrilic cells ulher Ihan eakwhelial cells. Alveldar
tnacnK+haRes and Kup/fer cells were posilive for Mae-2 and Mae-). Mac-1 al«r aarned
htk canaliculi. C'katly differeM staining palterns were found in epithcural cells l/w
Mac-2 and Mac) in kidney tuhuks, uNeslinal rnucosal linin6, hmnchi, clrl...iJ
pksu., and epidermis.
Fk111e, T. /., SprinRcr, T. A. anJ Thlxhecke, (T. 1.
Anrcrirunlr>.rrnul nf Pm/1utogy tt1(1):112-124, IoR).
Other sr/perf: Natinnal Instilutes of {kalth, National InstNWe of General Medical
Sciences and the American Cancer Society Junior Faculty Fellowship
Frnm the IkparlmeM af Pathuh.Ry, New Yurt l)nivenily School of Mcdicinc, New
Yt.lt, rd the 1AhrKNlwy uf Memhrane lmrtwmlchemistry, Sidney Ivthcr ('ant cr
Inslilwe, Ilrvard Medical Schlwd, IMnlon.
112 113
CD
MI('R(ySl'1:('fROI1.11ORhM1--fRY NY f)IGITAL IMAGh 1'R(X'1:SSING
MI:ASI IkUMl-.NT (N- ('Y 1/ N9.ASMI(' PII
Aa the autlMx, rcpwt here, an interfxe n( their micnr.PtvIndlwx.x+xrer with an
irnage PrncrstnK sy.tcm pcrfunn, mrcnr.Pcttrtdlwx.xnclric mea.urcnunt% in trvrng
cell. hy JrKnal nna~c t+ntittsrnR hlwxescent-e speclrtrat~ Paraouters can hc mra.
ureJ by doFttat nnaKr Pnr e.arnK Jrrectly luxn mkn.+t.opn mwKe. u/ ccllc, anJ are
aut.MUatM.dly rw-rncrhrrJ (.K path knKth and stcessrbk vulunw -Ihu., an at'uratc
cyt.h,la.mK ..maP".,1 varMm. tltccln.vtr(+ic psrametcrs can hr pnduted I lK reslrnK
cydqdasmrc pl lo.f hlx,.l.lasta (1 f 1 cells) h.s been tlelemumJ by nua.unnK thc ralwr
ul 1lwwestcm tlwKevente can,nR by twn successive waveknKths (4N') anJ 452 nm)
I twxr.ce m LitK kJ tk a n an mica untctIeJ into 1he ce11% is uard at a p11 1mh. ah N.uw r
it n IraMtJ rn the c y1.y.lasm IwN rs c at tudeJ (rrxn the nut kus and.Mhrr rMRanrlie. 1 he
averaRc t yNq+Lr.mw- p11 t. A N 11 ! 11 IN) Ituwever, cytoM+bsnmq PI I tahohna a ruxtuo
irrwKl+) Jr.trd~ulnrn, Ihe N.wcr mean fdl heinR 6.74(!(/ 21) When 11 1 tcll. puwn y
lu.e nxvtwm t.nuaminR Owxe.tem tkaltan, Piar.rxnes Pcrq+hcral tn the mhkn%
eahobn a Lower pl l thwn tMne ckr.er Io the rufflinR edge uf the cell 'Ibc Prertnt mraRe
Ixrres.mK .ystcm rs anslyieJ LK linearity of tktectiar, light saaltennR artdacts,
arKnal tu rwxae ratnr, uandarJ curvct, and ytallal restdutwn 1 he re.ult. rdramcd trlrm
Jryual rmaRe analy.r% are .Ixtwn to he ttxnparahk 1u the re.uti. Htwn slanJarJ nut ru
alrtlruNwarnnrtty Tbe invesnltatuu. alsn tlRCuts Xvcral Pther apf111tal11xlf UI Itnt
rathu rmaKrnK tcthmyue m ee111xaluKy
-fanasuRarm, 1. , McNciI, P, RcymsIJ., (i T, and Tavlor. I) l..
1hc Irwrn,d rr/('clf llr,.InRv 91l 717 724, 19144
(Mher srpprA: N.tnonal Srience Frwndatu-n and the Il S(kparunent ~rf I:n. rt!y
Hnxn the ('cntcr fist FIwxeaence Rcsearth rn HromeJwal Scientr., IkPartnKm uf
11ndnFiaal Stien.-ra, ('arneRie Mrll,sn (lmvetspy, 1',tt.hurgh, and I'hy.oc. IApart
nKnt, 14rntcum Umvcrsny, 1'rinteurn, NJ
I l-I II 1R I S('IiNT ANAL( X i('YT( X'I IIiMISTR Y
I Iwmescent analo/t cytrwhemistry is a new aNmwch to eluciJatinR the helaviur,
interxti.m and sPatoal tnRaniratit.n uf specific eellular conK.Mxnl% in living cell. A
(lwx"rM anaklg clMntl%t% nl the nNlve lellYtar clnn(MMrM 171u% ntle tx tIMIJe ttW-
aknlly a11at heJ flwxesceM Pruhe., clwrten !rx their apeclrat prtrPcrties and/t r envi-
nmmenlal .en.iuvilKC. llre Iethmyue. Previrwaly called ntArkcular cytawhemistry,
taAes aJvaMaRc rrl the xmilivily rd flunrestence tkleclMUt rnethrrls and the ./tct r/a ny
nt flwxe.ccntly labeled rrM+keuk. ('ellt cnMaimnR flwwevenl anakrNs can'.r ana-
ly.ed by rluahtattvc anJhx quamnauve nwnescence mK nr,t.q+y anJ by Ih,w t yttMne
h y S.nne 44 ,he kt'hnta al snd hirrl&rytN s1 a.Peclh nl thi% rneltN+J as amdreJ t.r cnv tr at tde
Pnvtrmm have been revreweJ recently. In this paper, a HwxesceM anah.K ul the cy-
ttnliek/alPrntem.ctbnhasheencharacleriteJindelad AdvaMaResandJisadvantaRcs
uf thos let hmque arr t.wr.idered here New usts arc alwr inveslrEateJ Perhaps thc ur..l
eat nmR aslrtt..t flwwcstent snahig cy/nthemrstry rs thc comhirureon uf rhe% mcll%et
wilh NIn.O% yuaMllalive ffwMCKeAe /ethnpiyes
r.nf.. /r I ,~,d
.n 14- A..n., .J \. ,rn, r, 'h 1/ MN 41. 14144
Other srpOws: Natinnal 1t-iente FuurKlatinn and the Natitmal Inslilulcs uf Flralth
I nxn the Center (tx Ilwxc.cence Research in 8itxncdical Stirncea, arxllhe Ikpart-
mrnl yd IltolugNal Sciencrs, ('ame6ie-MelWm University, Pitl.hurgh.
A MIi111t11) 1(1R IN('URI'ORAIING MA('R/)M(X.GCULIS INTO
AUII/.RI'.N 1 ('1-.I-1 S
1 ht rtstan herc de.crohe a timPlc metMrt /rx kradrnK eartrcrwoos ntarnmxdeculc%
imu thc cyl.qda.ru u( ntarnmalrau ccll% aJhcrcnt ,o n..ue culturc Ji.hr. ('ulmrc
nwJumt wa% rePl.wrd hy a Ihin layct ol lkwre.c-cntly lahrkd mKnxnnktvks, the crlt%
wrrr harvcacd lawn Ihc .ul..Uatc by scraMnK with a rubber pdtceman. IranslcrrcJ
ruuoN Jcncly lo n r tuW rntJu, wa.hcJ, and then tcPtalctl Gu cultwe 111cy trier 1.r
thr
nrtlMrdat"wralt kuJmK " VuAditytdcellswa.N/ -MMi.inuneJralelyalter.cral.r
ksadmk and was rNM1{. hw Ihu.c cell% rent.ininR atlcr 24 h uI cullure AfMwt 41M%. ut
a.Nrrrrnl. wrll slxead lihrtilrlasls caxNaineJ /Iwne.ccM nwtlecuks IN h altcr .cral.c
kurlmK,d LdxkQ tkatran., ovalhomin, tx inuswtwrgkAxtlin-(i. ()n avcraKc, RI' Jea-
tran nwtkcuk. 17(I,IMN1-nM+l wl) wetc im-tulnnaleJ iau each tihrtddaa by scrapc
, kwthnR in Ill m~lnd tkaran llrc eatcnl sit kwdinK drpetxled txt the etwkenlrauum and
nndtYVLrc weight nf the tk atran. u.ed A flwrreaceM anahsp tr( acNn nwhl alsr he
krark d intn hMuhla.ts where it labeled slreas fibers. I kl A cells, a mxrtrPhaKc-llke celt
line. 1774A.1, and Iwntan neulnrllhils were all success(ully k>ar1eJ wnh tks/ran by
acralxnR. lbe urcthrrl yd .crape-kwlinR slwruW he aftidaahk (o a hnr.J ranKr of
adhrrent cell Iypes, and slwwW he use(ul (rr hxalins trt diverse kinJ+ td macnntNrte-
cuk.
McNeil,1'. 1. , Murphy, R. F, Lanni, F., and Tudur, 1). 1.. .
77,c lrwnwd o/('ell Bu-loxy 4N:1SNi15M, 14N4.
Other srypwt: Nalirxul Imliwlcs uf Heallh and the Nalirmal Science fuunJalwrn
Inwr the 1)cpartmenl nf liirdrigical Scienres, ('eMer (ar 1Ywne.cntc Rc.carth in
IlNrmrdwal ScKntet, ('atncKic-Metkm UniversAy, ('atshurEh.
SFI.1:("fIVI: IMMIIN(X'YlY)('111iM1('AL f)FIT:C'[I(1N (N' FIL(I(X(lal'kNT
ANAI.(K7S WI111 ANfIH(11NIiS SIMa'/l7(' 1'lN('1111: Fl.l1(/R(11'llOR/i
l lwweveM anal.rye. rd cellular etxnpurcnas are fimlins rnctea.inK u.e in the lieW
nl eell hinkrKy 'I ht prwcr uf Ihi. lechntyue can he wRmenleJ by the use.,l innlrrhr
altrt Itlt IIM the IIIMN.N~IMNI' /u vr.ualve sektuvely the /lawesten/ anahrF at dse ek.
/nwr mNar.c.vi.e kvel. Rdax1 anldwahe. yretdte hN tluWMCMlm were elnueJ atwl
purdicu aaturJm6 Iu puhlr.hcd mclMdt 11.qwtm and Vtn. 119)11 Hanhciar.try
NI 21Nt/ Immune xrs and IR(i ftwmed penlnlm Imes with flwmevem IahekJ Ixu
kim in (>rchterkxry irnnwntddfu.itm assays and si`nilicantly QurncheJ the flwwc%
cence td (lunrescein lahekd Proleins. Inurutne (R(i and hah Ira6ntents dectuatcJ
Ownescein-lahelnt attin, but mA unlabekd actinR, in neEalwe stained fxepatatama
Ami /lwuestem IR(: was useJ ftr imnwmdlwwrsceM kraliiMiun rd Qwwcarrn
Iahrkd actm hrlkrwinR micrtxnlectitm rrf the Ounrescenl anakix inNr bvrnR cellt I lut
alyx.1ath wat eaterwkJ to the IIIn11urMKkllrlnl m1CtU$i11NC kRaIr/NNn1 n( in/ct reJ
113
a11JG/K al the auhl ellular kvel by the uae tit an clrclnNl dcnae markcr cllupltd to Roat
an11 rah/ul (g(: Many whcr flwwc.ccnt Iwllhc. al.a l'Jn hc uvd a. haplcna hlr prndu. -
1nm /d arN/laMhc. IhcrchMC, a general nklM.d lut hKahimF /IIN/rc.ccnlly lalrkd
nwdclulca a11ht clrclr/nl micnnc/lllil kvc) i. rwlw availaMc ScvcrallMhcr a~ln'a ilm.
uI anll flwMCVCm Jntllr.dy in aludit% involvlnR flwwca.cnl anah/rc att 'JI>.r wK-
rt.lad
I uhy 1'Iw111a K, Amalu, P A, arwl faylrM, 1) !..
('rll Afnn/.rl 4 117 1d9, I'IR4
(1tArr .uppart: NJliunal In.btutc% o( Ilealth.
I nMn the IkpJrtnnt u( I(NduFieal Sciencta, CarnrXic MclhMl lln/ver.Uy, P/tla-
Mnrh
AN11(:I N I'RIzI.NlAllt)N ('t)MMI:NIS ON ITS R1;GIII.ATION ANI)
M1 ( IIANI\M
11x carn/1J1 nature Id anUpcn facvnlatMln waa nIM al+{xel'ialell unlil Iht dlvov-
cry 1-1 tlht Iiat/N IMM1 Ilnlqhed rM1 IcIIUIar Inlcraliilln% by p/.luct.lll Ihe nupw hl.ln
t umpcn/hdny Kcnc l IMnpk. ( MI I(') It hJ. hcl /wlr arylaucnl that an ca.cnhal ctcp m tlK
rINhN 1NM1//1 rla/YMhlvl-nea11r/ all (MIMIan antll,'tM 1a the al'/IvJINw nI hl'IIRr r llII\.
'Ihtrc arc Ihrcc (.un1a Jtrlul anllFcn preanlalNm by rnunnc man/phagcs Ihal tilc
sutMx. Ircl a1wMd.l he alrca.ed 11/ e.(NCa.1.M+ /d la antlKcnm by Nwcniohayt% rl n.M
cIM1.lAUhvt Mlt 1. auhr" tn h.Mh lur.rhve alx' neKatlve ttrulali.m; (2) c/Mnrltfl aml-
rrn% mu.l IK "rr/t t.vd' by ttx mx ur11J/h' lu /ti( /NIK 11111I111t11/gCnN' arMl I 11 a1111
K.n Ixc.cntulr l clla /Mh1-r Ihan IIK' t IaaaN J1 /f1N I~N~IIdFC l J/I II/t1l tMMI //1 11M'
(lr\alnla
/ItM11rI Jt kaal a1Mlh' an/ll,'rn\ 1..IK-rul.nlrl p.ull..ur INt.rulr.l Iwrr wlnl h laad
Iu Ihc
l/Nwiu.Ntn /hal llN' rcKa6da.n n/ la cyNC..aMI by Ils- urx aqdlJKt may It a nwt hJm.m
rNlt INIIy tn an1(1111 y:InI11Yn rflVTLd11M1 aI lt/ IIM' Ildh whN IN/n 11I hNl'1' n pnlll'l'n,
Iq/t IU
tI1/n/n/aI/ tc\IMMI\rVl'INaa llUr/n~,' tk'IN1.11.1I Itlv0.yNIM'/ll JnJ JI hM aI allt\ 1/1 IIN'
alI11It
'I IM ImnwlN .yalem I/J% rvlllvcd m a manucr .u ,/a 11/ dlIq'INI IN1 11N twlxCa\nM111f Ia
Jntlrcna l ln. alluw% hn J.cn.dlvc c/Mmnl nk.hani.ut thal hmits anllKtn rt.Iq;n11Nm
by lynqllNty1c., ..Mnc Id which are suhKCarllve. llhe cuntUl.t rntchani.m. Iha1 are
dr..ua.cd Ilcrc nx11Nk the re-Jhk'INM of Ia eRlxeaSNM1 111 .akctcd ccll. /c g.. the
nwKnK+haKl./ anJ Nnpl..mg on Ihece sekaIed ctlk pNitive atNl nckaltve reKulaaMy
cuntada.
I/nenar, F. IY rr al.
.
the lrwrn/d u/hrunwmd/1Xv 112111 1-S, 1994
(Other irpprt: National In.tilutes of Ikalth and the March o(1)irnes
I uxn the I)epartnK n111f I athaMlRy, 1IJrvxd Medical Sl hlNd. Il//.hln.
I.VIh1:N('1: 1<)R R()I.1: OF IIY/)R()XYI. RAI)ICAI. IN ('()MPI-FMI:NT ANI)
NI 117R(1/9I11 IN.I'I NI)F.NT TISSUIi IN111RY
the Inveat/Ka1.N., uainR thrir recently rka /lhed nMxkl of acute lung injury /n rala
,111~1 \yatlIt./l .M I/a.111.N1 .~1 1~NIII~If/1M /1/ by 1 -IINa Vr1NN11 fa111/t (('VI),
/k11MM1atrarrd
116A 1111 /N N..1 d~wu.ll~ w/1/. 11Un. 4.11 01/t .Itr~1.M InlYllln t 1n 11\ natlvr IM.kIN II VfY1
hxm). hn not inxl-vluratcd laclnfenin, provides signilicanl IxdectiaMl a/;aind .Inu
plcmcrN and ncutnqlh/l-nxdlated lung injury. The synthetic u1M1 l'hcI:11/M Iklr/ll*
annnc nK.ylalc alao a/11Mdc Ix/MectirMl (nMn lung injury. lllc IxlNcchvt clll-cta ol
a(..lalinlc'rrln are ma rclatcd lo a blocking d('Vh induced cnnydeln.M acllvatnm
I lxy a1v/1knMmatralcd that InfuaNln t1( NMUC InM, cy+elcully I'c" . Kreatly ralcntlalt.
IU/Ig vaal'l1l:n I/llury a(Icr \yaterrlK clwlifknKM activation 1'Inally, IIr1NClINM1 IrlMll
IunF injury rla ur% in annnal.IxclreNed with the IIINrnI .cavenrer ol hydrusyl r:NIN .d.
tt 111' /. dinlctllyl .Nllo.Nk IlJacd,Ml han.mr.aiun electnM, milrlruapy, ('VI trrJled
r:da .INrw kuAoaVl;rcy.atca arwl Cn111M11ehal ctll deatructlMl 111 InleratNlal IlUI11MNWry
capolarlc., a6Mly with mtualvcrdar hlnMMrhayc and Idxm lkpr.ilinn In alurn.d.
IMIMCd trd wnh apllx tulrrtm, lklcruaamioe mt.vlate lx JmN dlyl sulhl~ilk, t11t nNM
plw/h/ya alrtvtal kuk//agrreKJtcahut nnemllMhch.d tell damayt heurxrhJFr
/lr IIfN//1111'IMNIINMI lhcac data auplrxt 1hc aMNcp that tu.alw mlury dlat 1% cumplr
nwnl Jrwl muu/hfid IkIKmlrnt may he relalcd lu rcrknlnln ol (/11' .krwcd Irlau 11 ().
altcr kuAlt yul acuvitnMl
WurJ, I' A rr tit
I hr hn.rnld /// ( Ynnl.nl lnrr.riXntirnr 72: 7114-R(H, 1991
1991
OlAcr lrppr.rt: NJtNm.d Inat11u1c% tit Ikallh a11J Vctcran's Admim.IratnMl Mc/n Re
1 vltw
'1=nwn Ihc ( lnivcraty tit Mwhigan Mcdwa) SchlMd, Ann Ar1wx, and Ihc 1 kpJr1nMnt tit
Mcdwu/c, Vtleranc AdlmniatralNm Ilu.pilal. Ann Atlrx.
V11. Metalwlic Studits
ll1E INIRASIRIK'1 URL (W A(HtTIC FJ.ASII(' FIHI.RS
In Ihis aucoqN a/ delermine whelher the "snNxplNw." ela.lin c.Nn1+INttn1 uf
c1a.lic hhets pr..e~.cs an internal slrwYtae thN ean he dclecletl in Ihm .ectnln. n/
akkhyl/c h.cd Il.wt.. tIN aulhlxa Nudle/l sanydea ul tat sunas that haJ Ilren // ted in
FlularaWthylk rvthenium red and n.mium-rulhcnwm red nalures. A. they rcpxt,
clauic lihcrm are ctMnlavrd //f a cenlral aMr of elaslm Ihrl is anNxplNws and ckctmn
Iuccnl /n nN+vcntNMra Iransmis.ilm elttlnln mirnqtraphs aN/ perylheral mnrn/1Md.
A clwydes mlraalrultwe within the anNUpMws elaain of mlNwe ra( awmta ia rnade
vlalblt by IualN/n and alaininR with a RlularalJchyde rulhenwrn red mrslure In plNrs
phale hulkr IM o.mlurn rulhenium red in canMlylale hulfer '(lle m(ra.trwtutc ik
clMlyur.cd /d at ka.t Iwu interlacinR hut dishnct ela.lM structural l'IMIqMMN'nl a
IranrcwllrA Id circumltrrnually IxrcMateJ rnicn1/1Mil, and a Ihree-dimencNlnal nNah
wnrk of IdaNN:Ms that pevmcale the fiber. The lalter reseml.ks a rNrculum th,d ha.
INrvilwaly heen ohscrved in (reete-Ir.clured and negatively alained cla.rin anll attrlh
uled lu the w(xaannkcular orRaniralinn of elaa/m. Mi.'m(ihrils al.o esteml [trun the
clMe tl( Iht clamll' hher Intu the \ufnNNldlnR n1a1f/R where they ai1(x'Y lu IurN'/nM a\
ancMxing bhtra Tht.c Ill+servalwlna indicate that the elaslil ply+rnie. /d the arlrnal
wall sre sn m/cKraltd lunlfNln 401 fMMh claalin and micrnfi1M11.
117
116
(:nl.l/ia hrr S rf of
Jrt cur A ('rlf 1S11/42') 41t 1')R1
lNher srOperl: Natlonal lnculutrc ul I lralth
I mnl 11k Ikpartlnrnl% nl Patlwd.-Fy and 1Su><hcmictry Allrrt lilnatrin (u11rKr ul
McJN aw. ItK Ilrunt. NY
IIYPI)1'11( )\I'l1AIASIA (I INI((//'ATI1O1.MIC('1)MPAKISONO1 1111
INI ANI11 I. ('1111.1)I1tX)1). ANI) AI)I11.1 I<)RMS
I(Y1rM~M~.l+hataaa r rare. Ircntahk. nlelatMdw fwNle Jl.c.ce i. c h:uao IrrvrJ
by \nINMN111aI clrrulalrnK alkal/ne Ptwnphatace (AI.P) acnvny. irnrca.cJ hhrrl alal
unrn Irvcl. 4,1 Ph..hlMtthalndalmne /1IiA l anJ innrRanir pyaM+lwr.Phale //'/'l /. rk ntal
a1NNNnlahllc\, arMl.kler nve hrNrc mrnrraliiatnm Ihal can pre.eM cbnically a. ;u kcl.
/n.hllJrcn.NU.tcualalx'/a/naJuhc 1klxndlnKupnlhcaKralwh/chckclclalJt.ra.c
1% nrNCCI hypoplrs.lrh,/tacia hac Ir<en c1ac.IhcJ IMo three trNmc Inlantlk chll.llwre/
arwl aJult In thl..luJy. the :nnhrNS a.cayeJ AI 1' acllvlty in MNIr nsur fnNn pallrta%
wn11 all hNmc rd the hyppopMlcphatacla 14 Inlanlc, 2 Ih1lJren. 17 aluttcl Ihey cun-
Parr J Ihc hrNhnF. thr Ihe cbnh al and hr.hy+atlN.luRic e.lNr.awm ut Ih. ir dr.ea.c rn INrkr
Iu raPUNC tik clunr a1 lxarrulrrnrity rd Ihlc In1.Nn ernN and the hypNhrac thal AI.1' n
hrNk i.ImpoNl:11u1 loN INJrrly cktk6d mincralvahrm Ac culotnarvcJ hi.nrtKnu.al
urwl Jnec t rniymc analy.r% ul rncrrru% li..ue IaNn Ihe 21 Paucnl% with hytwyrFwrydu
lacla rcvr:dcJ Ilut all rtlnNa) hN/nc ul thr. InhcnlcJ mctahldlc LNU Jlcea.r arc
.harallrnicJ hy.k11c rcrky nl Al.P:w'11vny m LNIr I ln .rvrrc mlanlik hwrn ha. thr
tlar.l p/nhN/ml tkhl lcn.'y lhc linrhnKc INrvntrJ hcrr arr rnn.1 avmaa'rnl wdh rvl
Jcnce thal c hlhlMw.l anJ aduh hypydnr.Phaucu nltcn reprr.cnt clinlcal e.Pre..nNl rrI
Ihr hrlrr.r.yKrNls aate hN AI.P JehclerKry which, when hlNrwliyKuuc rccult. in t11r
clianally ccvere rccc.cive infaotik IrNn/ In Ecnrral thc .evctily ul the .Irnna)
etlNec.NNS Id Ihr dl.ra.e rclln-t.lhr maKnituwk Id Ihe cklicicncy rd AI.P In IrNw 1 hlc
ic 11k e.PcckJ hmlmK IrN Ihls inMNn cmN r/l rnelahldicm, which illucualrs thr /napN
mk hlNa AI P acl/vlly has in the PnK'es. ul mwinal .kcktal mincrali/'au-Ns
1a1Mm. M 11 . Teilclhaum S. (.., Wrirnlein, R. S.. (:rrl.IFcrhrr S, Nn/wn 1) M
and Why1e. M P.
Mrdirinr A1/11 12 24. Iy%4.
()Vher sr//.r1: Na1i/Nlal Inaitulcs o( IlraUh and the Shriners IH..Pital IrN ('nppkJ
('hlklrcn
1'nNn the Ikpatlmcnt nl Pa11NINrKy and I ahrNabNy Mcdaine the )cwich Ilrr.pilal nt
SI 1.rw+c WachmKl,N1 (Iniver.ily Schrrd ot Mavln/ne St I/Mn\. MctatMda I)rNle
Ih.easr I a1NNalrNy. `ec'tNN1 n( Mr/alwrtn' and /'MhKr/ne 1)israx (kpannlrm rd
MedaNrc Medical (rdkRe ul (icINKIa AuRusta: hcpartment nl 1'athldugy. Alhrrt
1.Inaem (rJlcRe ril Medicine ol Yr.hiva Ilnivercily Ifrcrna NY. IkpartnMm nt
lyd/enn Nr1Au.d.qy. ItnlvrccNV -d MmrN..ta MeJn'al Sclw.rl. Mmnrappolc. anJ
th.nu.u / Il.wr ..n.l Mnwrd MI.A.d..n 1\IvHtIKnl% .) MrJNUK atw) l'r.IratrN%.
~N ,.1....~ ~..n 1 .... . . \. 1r..1 ..1 kI..1.. .. nwl M 1.1.h, KrM-atch 141.1. Chrnx-1.
('1.11. 81(11O(iY Of I'(11.MONARY I:NIX)1I11?LIUM
Thr nanPlcRicily and hirrluFical imPlNlrlre af the e/1JrNhehum arc JLcuccrJ in
Ihl.l+aprr As Ihr aMt/axi cratr\, .Im'e the Iaic IV(10X umknlanJlng rJ the cell hNrhrKy
nl rnddNhrhum Icrc 1een IranahwrneJ. F.mldhehu/n i.IwA nlttcly a nlelat>,dically i/Krt.
vmllarnr<ahlr hanrcr .rp:N-.NinR hhaRl IaNll Parrnl:hyrna; rallKr. it it a layrr u/
nwlalNdwally alllvr «Il., bs hmg. even Eas c.chanre may 1+r ascl.tr.l by rexnun.
racmn/.K rNl IIk rrnbdlkhal wtlxe I:rrMMhehal celh cymhr.ve cprcda pnNrinc
(WNne IrN r.IrNtl. Ihc.r .r1ls have rcccPNN% and rrvylnrc capable ul reacting wllh
trnalil IIINnNNIr\ and IMI1Cr c1U'11a1HNy sslWance% a\ thry Pa\\ in c'/r\ullt/nK hI1MRI
l rw6wlxlunn Ic anNlhnanlw.Krmc unkcc inryreJ when /nlurrJ ct11/1Mhclium Ix. umr.
IhnN/dw.Kcna anJ Ihcn IhnNUhdylic IirwMNhchuns may.rNnrtanc. rctarJ thr rkvcllqr
nrIn ul nd1aI//111a1NM aMI al r11IKr Ilnle% may Ialllnale i/ In aJJilirNl lu INUviJInK .nrc
111111MN/IM1M'\
/rN rtcb.m/r ut nntnrM. and nKtalwd/lr~, cmknhrbunl intrrarts with
am1lNNnwNw s lork Irnnrnr the clNn~r.iunn ul hNrld n.nwmK Jnwn.lream 'f1K larlrr r.
a key lum iaNr .11 pulnw.Ir.Ny rrMNa1N hunl ns vcmwsel/lucnl i. syrtcmwancnal hlrral
1it1.Nt% tn Inwkr.tInJ INIw rnJoNhrIWm al'rrNnPI1\hl' its wiJr raal,r ot lur/alwrl6r
a1'tlvltlr% havr 11MNIvaIr1l 11ara1kl rlhNlt tN/ deh/le the hrle \Iruc'ture rrl thl C/N/ININ'IIaI
crlt Ihuc. it ha% hrc-NlN Iracihk lo viwaliie hahnals o( twu .ur(ace cniymrc an-
RnMCnan cnnvertmK clvynse anJ cashn>typelMiJa.e N. (:11rNts hs vlsualiie .urface
1 rniyuws rrylnleJ Jrvrhq+meM Id mrans ul rcplw'alinK cetl .urfaces. a nNthrrNrluKy
th.N m lurn pruvukJ Ihr hrcl rn/ulr view rd the FlycrRaly>a /aven the ublyuny ril
vaVWlar CMMMIN'hllltl a1M1 Ih act/v/11eS, i1 is J/l/icult Nr inuKine an arca n/ nwJn al
1Nactice that can catrly /KmNC rcyulrrmenlcrd appmlPriale/y IunsctirNlmK crwhNlklnlm
Rtsm (l. S anti l(yan 1. W.
OrrMlralrM 71Ncuppl 11I), III 46 19114.
(khrr srppan: 11. S. Puhhc Hralth Service
InNn Ihc (kpartmcnl ul Medicine. Ilnivcrcity al Miami Cchrttd rd MrJla inr, Mlalni,
II .
y
ASSAY OF IM:PTII)ASI? ANI) PR(1TEASI: I:N'/.YMFS IN VIV(1
Me:lnc are hcctNning availahk Grr measurinR the iss.IrNaneaus aclivilies ul cell
IuwnJ 1wlNnlace anJ pnNrave eniynlcs whlne cata/ylic .iles have aece.% to the va.. ular
%P:Ke. IYK eta11111k /1 1% nnW IIIt%Clhk Itl ml'a\urC the ellec'live CrNNYnlfalnNl rr/
anKilNencin c.NlvcrtinR cniyrne in Wrs9% d rhmnil:ally cannulaleJ. unarrc.Ur1ucJ
etPerinwnlal animalc and N ic kasihk lu In.ke such nscawremenls in nwn. AIt/wN/Kh
the teat /d lhis paper Jealc Primuily with the acsay 40 PcIMIJa.e arwl lwatalse cniylnr
act/vilie.,lhr alifxcwl h aml l;eneral Ptinciptes JckriheJ here umhwfMeJly can he u.rJ
Icc nsracurc Ictuvlty ..( vntuaKy any accessihk hyJnAa.e eniyme /cM whlh h a.u/tahk
.uMtrate ran he /rwnJ lhe laller ckrly in.lwkv esleta.e and pho.Plsatax eniynw.
Slmc the mal N1M/.. when /1 hcaame evident tha/ the nselalo dic lale% rd arnam vac+r.u
tive .uh.unces were JrlrmincJ within ImnisenNSJs rather than minwes, thr Lr u, r.l
amle invranRaNNS' atwlns has changed /nNn MNmlltrcs 1lsrmseives lu the crvylne.
that calalyir thrir rkylrMIa1nN1 In IhN in Jel!Ih eIM\Nkra1MN1 t/I an UI wl.~ ac.ay
sy.tcus. NellnNl% arl' rkv-NfJ 040 11) XuhcUMec 1rN iw rrw, as.ays,121 Mrdwd. nl a..ay
ul cniymcs /n vlv... ((I I-rvyu.r klnencs in vrvu; (4) Mathrnubcs ul c yhlNkr. Krir
varM r Iu in vnv. ascay.. l S 1 W hal 1t Ilsc ccNw eMl atirNS rd anKuNrns/n r..nvr rt InK c nr y uw
119
inalvpolary'antllM('hnical unplicalnm+uf in lirrra+.ayc Inlhectwn-hNlmg ..ctn.o,
11N aulh.w tnatolam. that we +1111 kmlw httk ul what kind. nl inham:Nnm can It
Id.tauNQ hy a..ayrnF rniynN actlvnle+re I na Yet it I+Jdla ull /n avl.n) the clm.lu+N.n
IIIJI lhl+ a++ay let hnadnXy PrnvNko a ha.i+l.lt urwkr+latNhng a.lwch u/ hNKheml.lry lu
Phy+N.h,r/..d hrm+ a,Nl 1+ nf IIIIy.Ndlryly in hi.k INnucJl trrnl+
Ryan. I W IRlun. 11 1
/h.N he nus nf l'hur,nu..dr.Kt 121141 2127 2117 IYNI.
(hhrr trpPert. It S ILhhc Ilealth Scrv/ce
I/.an tllr Ikparlnlcnl .d McJtatnr Ilnivcr.dy n( Mlanll. Mtann. 11.
1/11 I NIx)llll I IAI ('t l l. SItRI A(li
I hc a.m. Iu.NM t.. tM+ carrlully nM+Nkrr J rc+cxch pallt r.lalr+ th:d Ihc crNW~ 1N:
hJ l+w l at e t JnrN a li a.+e.neJ Iu Ir +nNN.lh any n rKe than red crll+ a'an he a..unNJ lu
hr .plN-tc+ I IK +urlxc r+ an evcr ahanKlnR /mr a11ud+ n I+cuvrtrJ with IlnKrr like
pn.MtINM+ aMI 1. t aryx'/a'd wllh a Ir.lynrrla' I.aN /d t.lra .cllular nlalcr/al+ In :rkh
INm, /hr rnth'lhrtul .urla. r 1+ rellkte wlth rrv ymr. that acl/ve ly t hanpr Iin INwnN Mal
c/Nn/wn,lNm 4.1 hMNwI. IntI1N'r11c l.Ugu1.t11.111 JMI IIMIIN/Iy+l+, and llN1tr1/I 11. PII Ivta
carMMlc anhyJrav 1 In :NIa1/1Nm t1. +W tdt C rn/y11N'+t cn.WMIN'ILII reCl'pMUr. /fn.vnh LN
dttr.l .rllol:rt rr+rMV. IIhN.J IrnrN aKnJ1+ retrlvrJ by +ur1:Nr re.rM.u. .nc
Iran+lalrJ tmo. Inlr.NCllulrr wn.m+ IuNLNhnp .ymAc+l+ arNl rrka.c ul atlvr tunt
fNMtNI+ lhanKr+ in .tII .h.1pr. a/NI ./IIl9HINM+ /n va+a-ulJr hMr Jnt) /tntNah/lhly/
Ihnrnl; al:.ml1 rrarlu4w buwhnR n/+ hlrly th.ll al,al Jlllctcntc+ in tharEc arr al...
(w.duccJ Ihu+ wluh tNMC Id the lun.n.m+ul cn.Mnhcllum.rnEmJlly envt+l.Mtd hy
III+.1 anJ1+wIJ.-I1Nt+haveheenchJlknKc.thy re+oll+ul nNKrretrm+nNlw. u 1+n.lw
ck,u Ih,U crN6.Ihrhal Io1N INm+ am) Ihc +tructurel awrrla/r+ ul Ihcsr IutltluNn art' IJr
rlNar ttunple. Ihan IKCvuw+ly reltugnveJ.
Rv.,rr fl .C and Ryan. I W
lrnr.rhr..6.xt 21 14-th, 1v1t4.
OrAer sryprt: I1. S I'ublre / leallh Service
1:nm+ the Ihpar(nwnl o( MeJicinr. Unrver.ity of Miami Srh.N/l ul Medicine. Miami.
h1.
vtll. F.piderniology
RISK FA('TURS PIII Ml1NARY IIINCTION AND MORl'A1.11 Y
In 1'/71, a/auhnh.a qdmaty +IuJy uf chnMN nAdnN Itve p111nNMary J/aa.r wa+
/n.th..lyd al Il.r hfin. Il.q km+ Mcdlr~l In+ulutu~n+ T11c .tully wa+tlCal.'rK1I wt1111wU
I.o1l..+i+ 1n nnnJ 1 n.t t, a..e++rnvln.amwlual arnl Fcnrtu: latt.w+thal uMlnhule a/
the lkvehq+mrnt nf auway+ nfxlrucliam, and xenmll, In Jevchlll hellrr nlclhtNl. nl
l hJratlefl/lnr /11111vnfual+ al IM-teaiell rl+k nl /kvehllUnR alrway+ 1111+I1ut'tNM1 Kc.uh+
a% tcplnrJ hlrr .IN/w that in the cnn+ aMilmal r valuNNm u/ 2S 19 tnm p:n Irnl xlutl.,
II p.trnltal rl+k larhu+ wcrr LNInJ Ia hr.ipniliramly a.vtciak'J with airway+.ll.+lrur
tNm M.Lt inlplrtanl anNmg Ihc.c were aFe arNl +nulkiny ()Iherf inchNkJ /knNl
FralthN v:Irlahlt'+(I:rIN)rr NNNIcI/MMw11N NaluS, rlluCal11n1/: Ihl' inlake ul rolicr arNl
dN1 uNla grmlic ucukrl. (/K.-Ira+e mhillihtr "1'i" type. AH/) lypr, ANII .ccrchw
+IaIU+).:1tN11J/111I1aI 11uIrIMMiry Ih+ra.e. I:RamInalNmPl l'/1rr11qnatNm+llf t/+k I:ocl.n+ in
t'rtt++ a'l IN/11:/1 Ilala I1NtN atl'11 thal Mmll' //l Ihl'+e fal'hK7i were //111711r1ant rl\k taN
h/r+ nl
t irarellr .nNA,crt hut k.m evNknl in nrver .Inllkers. Ivlr esanMk AB( )lypr fauuh:d
clNtqNmttll, cnl/rr drlnk ulg, and J/et +/Nla intake wete relald h9 o1xAeJ Jlilrrencrl in
Iultl! Iu/NbtM1 m ai4arrtlc .nN.ker+. but had Ibllk inlt/acl in rlevrr +aN/kcr. -Ihn.,
Imrra\INN1+./1 Ial"IIN\ /Ilu+l hr lIM\Nkrtll whtn a++e%\Inl,' n+k ..f INIInNNlary.Iy+Iu/K:.
INnI
Mrnkc+. It A.(..hrn /f ll . Ikaty, T 11., Ncwill. ('. A. and KMNIry. M I
In. ! h,.l. mi.d..er.~/('.rr.wrnn Ifrnrl /)ivn.c Puv Prrtrnr ond h unur, New
Y/ak: Al in R l.l++, Inl 1994. Iqt. S01-S21.
(hMer suppert: Na1NMal Ilrart LunK and Illl>,NI InailWe.
FnNn'Ihr l.fin+ ILKlkin. MrJical In.tituli.ma, hallinwwc
TWIN ANALYSIS AS A 1'()TI:NI'IAI.T(N)1. 1<H( I:XAMININ(S
1'SY(11(ri(X'IAI.I:A('1'()RS ASS(K'UTI:1) WITII ANU PRU('I:I:I)IN(3
SM(1KIN(i 111:I IAVK)KS
Qata Iraan the vwnlng culNwt u( the SweJi.h Twin ReXi.tty urc hring u.eJ In an
attenlfM lo Ik.rrlhC cI1:Iraclerl+tN% which Jl+tinKui.h anMmK cunrnl tNm-arNl cR
.nMlkes. prn/r In Ihc JrvcllKlltlt:nl ul a anlllking hahi/ ver+us IMnr flrrv nl ahcr c+1ah
h.lanenl .d Ille hahn lIK Imk rlf lmr) With Iwina a% a+a/nrk ld inJ/vNlual., the
I+aychlwwial variahks in+laMllly, e>ttrnvesailm, kivure activlty. relative wcirM ak.t
M/l, cnf/ce and I+.yalNlphannaceutic JruR we were eaamlirled jlwmly a+ prcJic t+lr+ ul
cunem +nM.kinlt .ta1u. in multiple rrgrer+illn analy.es. llria phare wa% iulrmkvl hl
replicate and eRpanJ ufNm earlier t,tuJiescharacleriiinR aunrnl. am aal c. +nN.kcr+
Thr+e anaty.e+ were tlwn ItrlawnleJ url MYZ rulnanMd,inK twin inJiviJur/% wM/ wcrr
c1a++ilirJ rm the ha.is 11f Ilw/r /vNwin'..rnllkinR .1a1uc. Pallcrn. ld variJlnm in Ihr
p.yclN..rcul varnahk+ wu'.. the Rnlupt ll/ mul.nrlkcr% were s/milar NI Ihe paltrr/l
.een hw curtant, e.- and mm.nN.krre (7/atal1eri+lir. in MZ am+/m.krt+ whlth arc
Ilnvh.iive n/ their ttllwma' +mukinK aalu% may he inlerprcleJ a+dNhr I+rrv-nl Prnw Nr
Jevehqwllem o( a+nNlkinE hahil. Sckcled rewll+ Inwll Ihe.e analyae. arc Iwevmad
1'akr+rn. N 1., and f f.MGrr. MrrrhrJ. N.
Arru (:rnrns nr Mrdir ur rr Crerrlhd#iRiur 11111411424, 1994
Ikfwlmrn/ u1FnvnrMlnrntrl IlyKirnr. Karalin.ka Indnu/el, SuN klw.l/n. a/Nl ('o11rRr
nl Iluman Ikvehqnnrnl 1'rml.ylvarua Slale Ilmver.ny, Ilnlvrr+l/y 1'ark, 1'A
121
1141
Y
I-INNISII l WINS RI Akl 1) APART IV tiMc1KIN(: AND IykINKING 1IAIII IS
A 1'kl1 IMINAKY ANAI.Y%IS O1 tIlli 1:11i ('1 ()1- 111 kl 1)Il Y ANI1
1 NVIRI)NMI,NI
1)a1,1 IM altoh.1) u%l anJ.nwdrng habltc wcre avadahlc Irunl lh. (475 ylw.In.nnaire ul Ihr
rntlrc l..lr.n 1`n.r hr panwr.e analy.a., tfw dala nl nwtrvidual. wrrc
r.mp.areJ hr th:d nl alr .cr rn.dl haJ Knwq.. nl pait% rcarcal Inycllwr 1?lc rnly wp:.
r..tcJ Iwmm hL1I a I111,'IKf ak Illwll CIw1%u111rIwM1, whrk Irw .nw.f,mg .Nlly .Irl;ht di11r1
e.w'c% wcfe ol..l/vrd ..NUpucd In Iwrtlc tralrJ IrTtlhcr 1'nd..nwlwr.e corK'.Nd.u.c
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INDEX OF PRINCIPAL INVESTIGATORS
Alhers. l. 1., 61
Anlnniades, H. N.. 62. 63
Aunc. T. M.. 97. 9K, 99, 100
Bing. R. l., 63, 64, 63
B1ark, 1. B., 82
Bwmas.isi, V.. 66
Bu.hee, I) L., 13, 16, 17
Camphell, E. 1., 38, 1/10
Civrn, C. 1., 101, 102.103
CkvinRer, B., 103. NM
Cnchrane. C. G., 39, 40
('ohen, B_ It . 120
Crdman, R. W., 66. 67, 69
Crewc, (' E , 86
C'aaP.kt, (i., R7, Ilb
Due.hcrR, P. 11., 111. 19
Dvorak, II. F.. 19
Finlay, T It , 69
Fither. P. B.. 20. 21. 22,73
Ilrderus-MyrrheJ. B.. 121
Fu.e. K.. MS
Galduon, M . , 41
Geokas, M. C.. 84
Gill. G. N.. 23
Gold. W. M., 41.104
Goldfixher, S.. 117, 118
Green. M., 24, 23
Henry. C. 1.. 90
Ilrtlfman, R. M., 26. 27. 28, 29.
30.31
Kuncwsky, M. 1., 42
Kei1h,1. M., 42
Knshenvuo, M., 122
Kreilick, R. W..
89
hj1Aa, A.. 84
L.wrcnce. E. C.. 103, 106
Le Qacs.e. P. W.. 70
hrftib, R. B.. 31
LwtAherg. l. M.. 43. 44
Lynch. H. T.. 32. 33
Macher. B. A.. 107. K)8. IO9, 110
McLwbhlin, A.. It9, 90
Mitchcll. l. A., 91
Mwad. F.. 92.93
Nadel, 1. A.. 43, 46, 47, 48, 49
Nelsc>n, D. 1., 94, 93
Niewiarowski, S.. 71. 72
Pa.li, B. I)., 33
Peterlin, B. M.. 110
Pulak, ). M.. 111, 112
Pryur, W. A.. 93
RemoldO'Darrtell, E., 30
Repine. l. E.. 51. 32
ReynoWs, II. Y.. 33
Ryan. U. S., 34. 33. 56. 73. 74.
119.120
Sastry. B. V. Rama. 83
Shtthler, l., 75. 76
Sk/aew, R. 1., 34. 35. 36
Smilh, D. M., 56
SptieRet, T. A.. 112.113
Stanbridbe. E. 1.. 36. 37
Steinherb, D., 76
Sara+el, T. P.. 37, 38, 59
Taybr, D. L., 114. 115
Travia. l. , 60
Unnwe, E. R.. 116
VMner, S. F., 77, 78
Walsh. P. N.. 79
Ward, P. A., 117
Wermnalm, A.. 96, 97
Y.chnit., S.. 80, 81
149
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