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Council for Tobacco Research

Annual Report of the Scientific Director [St]

Date: 19670000/R
Length: 43 pages
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25 Sep 1995
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Little, C.C.
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ANNUAL REPORT
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005
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dvr30a00

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rats were an early ( I hnur ) and proRressive rlrcrcisc in the rKnuuphiha of the s/.ccial cyloPlasmic incluai,rns and duninishcd numtrn of nwluvcsicular Iwwlics in the large alveolar (c1ls Incrcascd caall.try cndtrthclr.,l i•rnra-yhras was also found I hour PodvaRolomy At later intervals the o%mrnphrGc inclu. sions were replaced by vacuoks, with increased intraccllular Ilui,l accumn• latinn and hluntcd microvilli I ale tkvclopmcnt (if massivc atelcctasis in thc IunRs corncidcd with the finding of abnormal uuface tcnsinn chalactcrislics in -kome lung e.tracts. The relationship of Ihe ullraslruclural changes to the frnmalion of surfactants is considered. Other grantor: ll.S. Public Heahh Service (2). "Ul1AN1IfAlIVE EIISTO('l1EMISTRY OF RAT Mll(-USA: I.AC- TAIF ANI) MALATE: 1)F11Y1)R(X;FNASI:.S" Ry Stanley !. (krson, I)1)S, 1'hl), lulia Mcyer. Ph11, and Ikrmann Matlcnheimcr, MI), l1e- partnscnt of Oral Patlsr+k.6y, l)niversity of Illinois ('a1kRe of 1>cntistry; 1)rparrment of Biochcmistry, l/niver.ity of Illinois ('o1kRe of Medicine, and Ikp artrsxnls of Pica•hemistry and Mcdicirx, Preshyterian•SI. Luke's Ilnspital,(lucaRrs Thrlournolo/Invrrrigarivrf)nntornlrrRy17i6 526-5J2, Ikcember 1966 ((;rantee: Meyer) Ultramicrcxhemical metMnls were used to assay lactate rkhydrnRenase (1.i)FI) and malate dchydroRenav (MI)1I) activities in thc histnlnRically dcrmsnsttahk laycrs of kcraunirinR oral rpnhcl/um SPecinxns of palatine and huccal mtKrr•a from young adult mate Simonsen alhino rats were frurcn in hqurd nltuoRcn, dried and dissected (usually into sis layers) ('omparison of cn>•ymc activitics in the sic successive cpilhelial layers showed that LI)II and MUII activity in both Ihe palatine arrd the huccal epithelium decreased between the basal and horny layers. AlthouRh MhFI activity was consistently higher than LI)F1 activity in honxdoRous layers and in the whole cellular layers. MDII activity tkcreased more rapidly with outward progression than LUFI activity, thus rcducinR the discrepancy between them. ('omParisons of palate and check c(+ithclium showed similar kvcls of enryme activity in homologous layers and in the whole cellular laycrs, hut diflertnces were noted in the rates nf peripheral decrease in the activity uf both cn?ymes 1)iRrtencrs in entlymc activity couhl I.e ctlrrclalcd with dltlrrcnccs in the diNrihuur.n of dividing cclls and of Urnrdihril. Ihhrr Rrantorr lI S Public Ileatth Scrvicc "NIl('LFO1 AR'('APS' INI)ll('1:1) IIY FI.YIN(; SPOf l/l I RAVIO1 liI Nll('I FAR IRRAI)IAIIt1N " Ily P(1'11 Mr.ntrumcry, MI1, R(' Rrynud lc MII inJ I 1 l".4 IICI I,(1k•I,artnicnt r-t P.Hhwdr-Ry, llnivcr.ily n1 Irrrs V11-01-r1lrrrl A1l 'I-- r1 %. h-I .rml Ihr 1 alwnilorirs frrr (-t•II 0 r r Rcsc-1rch, Wrwwtlawn Ilospilal, Oallas, Ter<as 7/v .1r.vrrrnn /.,urn,J nf I'aulr..LrRy 49; 1 55S-S67, September 1966 ((irantce: MunlRomery ) A shal+cd mictohcam of low intensity helerochrumatic ultravinlel light was slqnced Itr the nuclcolm of living (Tran6 liver cells and ttr the nuclrus with Ihc e.clusinn of the nuckolus. At varying time intcrvals these irratli ated cclls were appropriately rued, emhetkicd and serially Recliunrd fnr eRamination by ckcuon microscopy. When eaamincd, the nucleoli of these irradiated cells showed cadlapse of the nuclcoh/nema, an arparen( decreasc in nuckolar sire, and a rcurRam yation of the nuckolus resulting from the se6reRaticsn of the variuus tyiKs of granular armponenls of Ihe nuckolus. Nuckolar plaques and light nucle olar "cr,ps" wcre formed in Mwh groups of oells. In the cells in which the mrclcoplasm alone was irradiated, segregation of the nsKkular Rranuks resultcd in the formation of dark nuckolar "caps" similar tu thau prrKhkcd hy the actidine derivatives and milrKOycin C. T hree chcmicals, proftavine, acridine orange and mitomycin (', all compounds which form a compka with DNA and inhibit 1)NA and RNA synlhesis, produce an effect on nuckolar ultrastructure which is identical to that produced by the ultraviolet irradiation of Ihe nuckul+lasm exclusive uf the nuclcolus. 1 he effects of these agents which prtxluce nuticolar "calrs" support the hypothesis that the nucleolar ksian is Ihc result of an injury at the 1)NA kvcl of cellular metabolism., IhAer Rrenforrr Atomic FnerRy ('omnsission, I)amon Runyon Mcmrrual Fund, anti the National Institutes of Ilcallh. V. Epidemiology "NF.(;RO WllllE? I)IFFEiRFN('FS IN PI1I.MUNARY I IIN(-IIUN (VITAL ('APA('11Y, TIMFU VIT-AL ('APA('11Y, ANI) FXPIRA- TORY FLOW RATE.)." By Albert Damxm, MI), 1'hl), Ihhartmcnt of AnthroprdnRy. Ilarvard l/niversity, ('ambridRe, Massachusrtts Ilurnnn Rirrh,Ry 1R/1:)Rl/-)9J, 1)ecember 1966. Marked and significant differences in three pulmnnary functirrns were noted in tests ocmrductcd amonR )92 white and 61 NcRtu suldrrr s, aRrd I R 2'), durinR thc t'rrursc of an anthropornctric survey of U S Army drivcrs a 1.4,11 1)rvcns, Massarhuxus, Ihc NcRro scddicrs haJ I t'X, smallcr I.rrrmd aud lotal vital capacitres as wcll as a Ill"6 slower mid cltiruatury flr.w r.rlr Mcan aRc, hrrRht, wright, and chest tircumfcrencc wrrc .unrler ui rlK twei Rroups 1 he di0rrrnce in lung function can he re6arduJ as tnrly tuni wmi.J rrr Physirdt.Rical sirwe it cannot be accounted Inr by dr/lcrt•nres ut tm-uv:ru"n, in smrrkinR hahrls, or nwxe than minimally - Itr Jr/lrrrmt•% rn phy%nlur I hc whrlc solJrcrs anarkcd nNnc Ihon tltc NcRrrKs MrHrvation v.a% aplrarcnrly cquivak•nt, ia shown hy thc sLrtmRcr Rrilx ul the NcRrtw•%, Nhm vwcrc atsrr l a 19
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I r muth more nxtomrrrrhic and "makculine" in physirlnt• I hr ~hortcr trunk and retluccd thcsl ettPansinn r+f the NrRrtxxs could nrN accourrt frn much rd the d//lcrrnce 1)iffererxes rd th/s m.Rnltut)c havc f.ccn rcfwutcJ frn ahrnrtu 100 ) yrars, and priru huln>,mary diseasc is unhkrly trr attrlunf hrr thcm Implitatirlns fru dncasc and for athletic Lcl/orncrncc arr slrlllLltlvc at flrescnf UTArr Rrantorr: American F(eart Asstxiatitrn, ('ommiaairrn rrn AcciJcntal lrauma of the Arrrnd Forces F.PidcmiuhrRlcal Iluard anJ the Natunl.J Sciencc I ounJatirm "PRfiVtOl/S Pl/l MONARY hISFASI: ANI) I.l1N(; ('Af\('FR A ('ASF (*ONIRU1. SIl1UY." Hy Alhcrt 1)amon, MI), I'lhl), and )cart P, Mc('IunR, 1)eparlmrnl of AnthrtqMrh+Ry, Harvald Ilniversity, ( am1.nJrc, Massachuse(ts Journal o/ ( hrrrnr( ]hlratrn 21)1 2 Sy bd, 1'chruary I'1h7. ( ( irantee : I )anion ) In a study of the relationship between previous pulmonary drscase and lung cancer it was shown that subayucnt lung cancer was not :tsstxialcd with either ItNal number of pulmonary diseascs or with any slvcillc Lul monary disease Among more than 17,0(k) mcn eramincd medically antl anff•rnlx+mct- rically at Ilirvard llniversily hclween IRM/) and 1920. 110 ha,l d/t•tl of lung canccr by lanuary I, IVhh F/+r conurd IrurJxnes, each IunR canccr tkcclknt was matthctl with thc ncst man of the sime age a+ he cnamincd. Of the cunurds, R 7 had dKd and d 1 were slill alive un lanu.rry I, 1966 1he IunR cantrr dcccdcnts and the crintrrrls dnl nrN drllcr in flrr numt.cr rrr nature of pritx f+ulrr>,+nary dlsracrs rr)Mntcd tlurrnR Iht'in rncJrr al caamina. tion at Harvard Among the cuntrols, siRnifitantly mruc Id thrr~c withrrul carly pulmonary discasc were still alive than td those with carly pulmrunary disease. OtA.r Rrantor: American Heart Asst+cia/ion. "FPII)FM1OI ((',Y OF (-IIRONIC I)RUN(11111S." Ity Ikrnald Massaro, MI), and I.inda Ilutlums, RN, Pulnxtnary 1)iscasc Research I.aMuatury, V A. Ilospital, Washinrton, I) C. and the I)epartmcnt td Mrdicine, (;corRctrlwn l lniversity Sc'htxll of Medicine. WashinRlon, I) (' /NrAa at 1 rnvr 9Si 2: 121- 12R,Ichruary 1967. ((7rantee: Massaro) lhe factors which predisl.nse to chronic hronchitis and avrnurs whith might he followed to prevem or am:liorale the drscasc are ctamrnrd irt Ihrt review paper. SnwlkinR, age, air f.rdlutirro and hlnt vari:Nirln arr the factrrls mosl «tinusly cttnsitkred in recent VIIII/cs tlf hr//rll Illfls fllt'v;llcrlln ccrr a1HI atrrnatl Ihc im(+ratance of snw+kiny and air Ltdlutrnn in the cpiJr'mirrlnyy rr( hrunchitis is sUcsud Amclioralive (ir /rtcvcntaflvc rnrasu/cs rc.rlmrnrntlyd intlurk the curtarlrncnl Irt furarnal air (wrllutrrrn in the hunl 44 clRatrate smukrnR and itx cnhucenxnl uf an cfleclivc an:u k rrn frncralircd air Iwrllntirln 40 ( ! 1 V I. Pulmonary PhyaioloRy "('ARI)IOPl1LMONARY I:FFFCfS OF T(111A('('O ANI) RITAIFI) SIIlISIAN( 1•S: I 7111: RF.I.F.ASF OF IIISIAMINF. 1)IIRIN(; INIIAI. A I ION OI' ( I(;ARlill F SMUKf ANl) ANOXI?MIA IN I fI1: . FIVAR 1 I t1N(; ANU INIA('1 INX; PRFPARAIION." Ily IAlrninRu h1 Aviadu, MI), Milan Samanek, M1), and I.uis E. Fol/e, MI), Ikparlmcnl trf Pharrna ctrloRy, Schrwrl u/ Medicine, llnivcrsily of PennsJ' (vania, Philadclphia AIth/vrt u/ I'nvrran.nrntaf llrahh 12/6:7(/5-711, June 1966. ((;ranlrr. Aviadtl ) "('ARI)IUI'l11 MONARY F.FFI:("IS (F •IY)HA('('O ANI) RFI A 11 1) 51/11SIAN(Y•S I11. P111 MONARY VAS('l1l.AR 1-.Pl-li(-IS1/1' ('IIiAR- li 1 1 li SM( )KIi ANI) NI('OI INF." Ify Luis F.. Fulk, MI), Milan Samanck, MI), and IkrminRo M. Aviatlo, MI), Ikparlnxn/ of PharmacoloRy. Schrwd of Mcdicine, l/niversity of Pennsylvania, Philadelphia. Art hivr, u( l.nvrr onmrnta/l/rahh 12/6: 712-716,lune 1966. (Grantee: Aviado) "CARDIUPI)1-MONARY FFFF('iS OF TOHA('C'O ANI) RFLA-Ifr) S1111S fAN('U5: 111. P111.MUNARY VASCULAR I:FFf?('1 S UF('1(iAR- lil I E SMOKF. ANI) NICOI INF." fly Milan Samanek, MI), and 1)rrmmr;u M. Aviado, MI), ll<pulment of PharmacoloRy. Schtnd of Medicine, llni versify of Pennsylvania, Philadelphia. Archivrr oJ l:nvnunmrnrol ]lealrh 12/6:717-72d, June 1966. ((;rantee: Aviado) II has been shown formerly that there are three imlKrrtanl participating mechanisms involved in the e0ects of lobacco on the tracheuhrnnchial /r- ways: I. direct action of tobacco smoke on the smtwfh muscle (of the air wa) s; 2. stimulation of the nervous stuuclures in Ihc lun6, and 3. release tuf hunKrral agents. I he present series of e.periments was designed to lest whether these three mechanisms also influence the cardiopulmonary system, slxcihcally the pulmonary circulation, coronary circulation and heart musclc. In Part I of this series, the rok of the humural nRent, histaminc, in mediating any chanRe in function of the heart ntusclc was cRl+lorcd l-rln'/i mcnas were cunducted both on dogs with intact cartliuvo.cul:u systcros :u1J on hcart-IunR /+rcparations. Results showed slrikin6 ditfcrcnccs f.rfwccn the cRecl of cigarette smoke upon the isolated hcaut tunR prcpar:uirrns :urd its eflcct upon the anesthclittd dog with an intact carthuvascular systrm 'Ihcre was a sfrikinR stimulation of force of mytxard/al cuntrattir/n m the inlact dog but no stimulalktn or dc/+ression of /urcc anJ vcutlrcul.u Lrr /rnrnarxe in thc 1K'att IunR Prtparatiun. Ihcsc cflccts with c/R.ucttc smrrAe tlld mH conhnnt witlt Previnusly uywrrlcd cflects rd nitrrtinc rrn nce hc.ut I lre rclrasc rrf histarninc (rurn tlre IunRs was tkmonsuarcJ in .rrmt' Iuuy. Irn 1r.Nh cigarcuc smrrkc anJ annsemia. lrr a sfurly of the efTccts of inhalation of cigarette smukc on the crlrrrn.u y circulation of the aneslhctircd dtrR, the It•rfused cruunary :utrry drd nnt shuw hKal vaaKVrnw/tiitrn in reslwlnsc Ilr etlrrsurt• nf the hlrKHl IrrfuNvc to eiRarctte srnoke. Ihc sank Ilcrfuscd currrnary artcry .huwrJ va.rKtm 41
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strictinn in respnnsc to injcctcd nicolinc and to sytlcmlc cllccl of ciRaretle sn„rke I fx third of this scries of e.pcriments dcah with the cflccts nf ciRarctte smrrke and nicnlinr on the rulnx+nary circulatinn Rcsults shnwcd that Ihc inhalatinn of ciRarene snxtke of the injcctirrn of nicrHinr causcd cunstrictirm of thc pulmonaty bkxx) vessels Ikcause of Iht incnnsrctcnt restdls nbtaineJ with cy,arettr snxikc, nkoline was used Inrmarily as thr trst substance. I hc vasnconstriction clrciled by nkotinc in the fx•rluscd IunR of the anrslhctiprd dnR was inrkf+cmknt of the hronchoconatrictur reslxunr II was scen that the vasocvrnslriction prtsisted after acule vagotomy and administratinn of Mrcy+ine hut was cornpklely bincked by the adminntratir.n of a local ancs- thetrc agent 'the pcnsihility that the vnrxonstrictirrn was hrauylrl aMrul by the rekasc af histamine is discussed. "OXYGf=N ('ONSUMPI ION AND ALVf=OI.AR VF.NI11-AIIUN D(IR- IN(i INII RMIIlu.Nr POSIIIVF. PRI?SSIIRF IIRI:.AIIIIN(;." fly Stephen M Ayres, MI), and Sunlcy (iiannclli, Jr., MI), 1('('1 , 1)c- partmcnts of Medicine and Surgery, St Vinccnt's lloslrilal and Medical ('enter, New York ('ily, and New York Oniversily Schrw( of Medicine. l)israrri of the ('hr+r St)/4:41W 4 14, ()ctohcr 1966. ((;rantce: Ayres) '1 he siRnifxance of the rok of intermittent posilive pressure breathing devices ( IPt'II ) in the trcatnxnt of emlrhysema is dcpendcnt ulx,n the ahihty of II'I'll to siRniftcantly rkcrcase the work of breathing in aJdrlion to incrcas- inR minute ventilatiun Ihc larscnt paper rrlx)rts studics of the mcchanical work and r+ryRen cnnsunil.tum nf the reslriratury muscles tx•lore and durinR atsistcd ventilation wilh  vnlume cycled IPPlt apparatus In this sludy, otyRcn consumplion, alvcolar ventilation and arlcrial gas tensions were mcasured in riRht patients with ahnerrmil rcypiratnry Ras ewchanRe following recovery from an episrxk of respiratouy aci(bsis. I he patients - sit wilh severe ohslrurlive emphy'scma and Iwo whh neurological disease involving the chest wall - were studied t rest anJ durinR II'1'11. Results showed that the o><yRen eost per unit of ventilation rkcrrased nn average of )4(~cr cent durinR IPPU. (kad space ventilation was unchani;cd, hul the Ivcolar-arteria( o>ayRen diRerence was increased in all paticnts, indicating Ihat the distribution of ventilation with IPI II is diRerent from that with spontaneous rrspiralion. These studies indicate the prnlx•rly admin- istered IPPII increases the efficiency of the respiratory mucclcs and rkcreaus their entropy. ()t/lrr Rr.nrnr.r Atsxrkan Thoraek Srx-iely and the New Jersey McJicnl Research and TeachinR Fund "RfSI•(rNS1~SOFtIPf'UR RPSPIRAIOI(Y Mtl(Y)SA IUI)Rl/GSANI) VIRA1. INfI (."TIONS" fly I rederik 11. II:rnR, MI). 1lctsy G IIanR, AH, and Maric A Frrarrl, AR, Ikp:utnunl nf f'alhrrhirr6rRy. Sr hrwrl r+f Ilypicnc anrl I'irhlir IIralth, Ihe Ir+hn. Itopkins Ilnivcrsity, Il.rll mrue. Al:nylanrl ,Invrr,nn Rrvrrw n/ Rryrrenrr~ l)rcrarrr 91, 1 I1 142 1-IV, Marrh IVhh 1("ranirr I It IIanR) I I he present paper summau'vcs and analyses rrsulls obtained in a scrics of c.lx•nmcnls dcalinR with Ihe eflects of certain drugs and rrltrcr aFcn;- nn uppcr rc~laralory mucosal function. ~ Since a virus must have access to a susccpliblc cell in urJet to prodrkr infcctiuns, ap,cnls were tested to rklerntine whether they might al/er suscrpn hduy In a vrrulcnl strain of Newcastle 1)iseasc virus. 1 a obvratc thc qucstnrn ahlc asfrrcls of rn vrtrn sludies, experiments were conducted mc+stly on Ihe nasal mucusa of nurmal, unanesthctitcd chicks In the study of the differential enects of agents cm the cumlxmcnts of Ihe mucrcrbary syslem, it was shown that dchydration, pihx•arpinc and vitamin A rklrciency primarily aflectcd mucus sccreliun; crx:aine, .ylrkawc and lowered tcml.crature affected cihary rurxtion, and cyctainc, severe vitamin A rk/iciency and viruscs (influenra in ferrets. IarynRouacheitis in chicks) affected cellular integrity. Viruses, which seem to act by destroying the cells of the nmucosa. leave behind an epithelium which, during regcneration, has at fusl fcw or nu cilia I his destruclion, which involves both ciliated and mucuus cclls, e.lxrus Ibe clcnudcd mucosa to absorption of other loaic subslances ReReneratxm of the two component parts of 1he cpilhclial fyslcm dcrcs not always prucced of the same rate. As the motion of Ihe murnciliary blanket depends on the con certed activity of mucous cells and eilia, lack of nsovemetH of the hlanket r/,Ks not necessarily mean that ciliary •aelion itxlf has been inhihitcd Acrual eiliary paralysis induced by cocaine did inerease the numl.cr of infccted cells by It/ tn 51) times over the control values. tlth.r Rr.ntorr National Science Foundation. "I,ARYNGOfRAC11E:frIS VIRUS IN ('HI('KIiNS" fly Hctsy G HanR, AD, and I'rerkrik H. DanR, MI), Ikpartmenl of I'athohrolrrRy. Scfirxrl ul /ly6iene and Public Ileahh, 1 he lohns Ilupkins I/nivcrsily, llalnnuue, Maryland. /.rurndn/ l:xperimenrof Medicine I25/1:4(W 427, March 190) ((irantce: F. 11. Nang) Infectiuus IarynRdracheitis can he pnxluced in chickens as an e+IKri menlal mrxkl of severe nonfatal rhinilis and sinusilis. lfris study prrscnts a mnrpholnRical appraisal of the eRccts of (arynRrNrachcitis un the tiuuc systems of the nasal fossa. (InacslhNircd while I.eRhorn baby chicks received intranasal inocula tinns of a susprn.inn of Ihis virus and palholuRical chanRcs od thr ru.al thssues were followed sequentially fhum the esrliesl demonsunblr )rsiuns Ih(auRh the 4th rrNrNh of cnnvalescence. '1 he rrsultsnl viral rn/cr thuns, whrle remaining hmitcd ta the nssal frsss, pnx)rKCd acute Jrsrluanraur.n of nll nasal epithelia, resulled in functional recovery of the rrslaralury cpnhehum, hut left imprrrtanl residual abrnrrnulrties. Initial Irsiuns wcrr first idtntifiablc in the rnucrxiliarrd cctls of thc shalluwest Ixutiun of the eprthebum aMrul 21 hours alter inrwulatrnn nltrr a thrce ter seven day Len«1 nf acute sluuRhrnR, rclrau I nMr.ucd hy t11e ,., 43 42
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I r,yTid spread uf a sheet of epithclial cclls ovcr tlre inhllr;rlcrl %ubmucuaa ) 1K•rnn and latlcd for cight tu 21 days After crrnv:dc%tcncc, hrrwcvcr, rqfit tlxrrnx•ns all shnwc(1 cr+mfdcte mctaPlasia rlf tlu olla(truy urP.rn Ir+ mutrr- crh.ucd ePilhchum, all showcd ahnrnmal fnrnrata-n and ahgnmcnt 0 mutuus acrnr, anti alwwt S(I^,:• had scvcre 1rrsistcnl cinuaitis. (hh.r Rranror: National Science Foursdation "A(l/lF VI NIILATORY FAILURE IN ( IIR(INI(' OIISIf(lI(•IIVF. I.IIN(i I)ISI'ASIi " Ily franklin 11 Sakscna, A11), anti Itcnl:rm(n Ilunuws, MI), Ik•Irarlnx•nt of Mcdieirx, llnivertily o/ ( IucaRu, Illinrnc 11rirnrrs of rhr ( hru Sl)/2 176-179, August 196,6. I(:r,rn,cc Ilurrrrws/ icn eris(.ks of scute venlilatory failure rn eiRht thrnnir:Jly IrylK•r cal'ncic patrcnts are rel+r+rte(1 Acute vrntilatnry failure. Rerxrally defrned as an :rhruhl incrt•ate in cartwrn (IrotlO(• (eTHllwl, is a eommon eompl:<;rlron u/ thrnmc r6s,ruclrve lung drscate, particularly in chronically hylrrcarencic haticnta untk-r Ihc slrcas of acnte resprtatrny infeetion r,r with etacerhaurTn (d conpcurvc tscart failure Wnh mihkt cpruKks of acutc vrntr/,rt(ny larlurc, fl:rtrrn,s u.uilly rctIwmJ tau~/.rclorrly tu manaRement of the unJerlyrng car(Jnqpulnunr.uy dr.rrrrkr, rcquurnR ncithcr anatcptic (1ruRt nru mcthanKal vcntilatnry aticratantc "1fIORnCI(' ('(1MPI IAN( I IN ( IIRONI(' O11SIRII( 1{VF I (IN(: IHSI ASI " Ily I ranlhn It S.rAtrna, h11), anJ Iknl:nnin 11urrowc, MI), Ik parrntcrU (if Mcdhcrnc. I/ruvcrvly rd ( tut:~rr, Ilhnmt lonnnaJof I~rhnr,nurv und ( hnn u7 AfrJ r mr h!t 1 427 4 12, S( I Irrntr r 1'!6A (( ir,rntcc Ilurtnw.) A weirhrcd sf+irnmctcr rcthni,luc wat uu (1 in Ihis.luJy I(l mca.urc /utal Ihuracic conrplrince in 17 (+iucnts with Ihc ernhhy.cm:r hn.n(hrric syn drnme. In R piticnts. lung and thc.l wall cnml.'I,1rKCt wcrc :rltU A-tcrmincJ With this mctMul, total Ihuracre antl chest wall compliance ,I,IK arrd cs.cn lially normal I his contrasted with thc low total rhtuacic and t hc.t wall com plianees found in similar patients when mcasurcmc•nts were rnarlc with the negative Pressure txxly box technique It is suRgcsrcJ that Ih(• htw chcst wall compliance obtained by the latter procedure and noted by rnhcrs with the relaxation pressure method may have been due to incnmpkle rclatatinn of the thoracic muscles of Paticnls with this t)rc of respiratory ir-tu0icicncy. It is doubtful that chest wall compliance can t.c nuasurcd wilh accuracy in such patients with any of the methods mcntiuncd (hArr Rrnnrorr U. S Puhlic f tcalth Scrvice. "('/1RF1(1N t)IOX11)1: II NSION ANh VI•N111 nl()RY N11 ( IInNI('S IN ( 11R(INI('<)lISI R11('1 IV/• I.I IN(i 1)1SI nS1 "lty Hrnpm n Ilunrrws, MI), I ranllin 11 SaAscna, MI), and (-arl I Ihcncr, A11), Ih•v:nrrucnt uf Mcrticirx. I/nrvertity uf ('hitaRrr, Illinr,is Arrn(rh o/ Inrrrrru7 A1rdrsrnr 0 4 fAS 71M1,(klnbt•r 1966 1(iranlcc Iturrrrwc) ('.vt.(rn (liotidc rrl(•ntwn tr•n(la Ir, vary prcaUy in p:Tticnl. wilh irrc 4 .1 I vcrsihk airways obstruction of unccrtain ctioloRy. I hic rcPr.rl, whi(h it based nn stutlics of vcntilalory mcchanics in 34 malc I)aticnls, attcmpts lu explain this variability. S(u(h(•s of Ihe relatitmsltip bctween earlx,n rhoaitle tcntiun :rnJ vcnhLr tory characleristics indicate that frank carMtn tlirraitk retention is c.IK• cially likely lu occur in patients who, in addition to having alvct,lir under. vcntil.rtirm and a Iunilcd ventilatory eapacity, show a rapid, sh:rlluw hrc.rth ing ITaUCrn Ihis type of breathing requires that u grcatcr IKUlirm n/ the nnnute volunse tx wasted in ventilating the anatomical dead alrace anti :rE~r:rv:dcs the c.istinR tendency lo hylrrcapnia It is prulnr.cd that pul rnunary comlrlianc•c is a factor in dclerminin6 breathing Irattcrn anJ, hcnce, in regulating the tendency to earhon dioxide retention 1'.rticnt. wirh relatively Mrw lung eunrplianccs, shallow r(•tlrrratiuns, high inslnratruy resistanccs, and hypercapnia shuw, chnical and IThysioloRic.l /c;rlures whit'h suRRcsl that Monchilbs and parcnchyrnal ooll:unmatury chanRcs are important in the pathogenesis of their tliseasc Su( h Paucnls ( whu Iravc been Inund to have relatively slight emphysematous Jc.vuclirrn of thc lung parcnchyma at postmortem examination) have tx•en desiRnatrd rt having tyla• Ft or "hrtrnt•hial typc" discase. In c(rnlrast, lyl.c A 1"cmplhy scmatous tyf~c" ) palicnts, who have features that in(licalc scvcre analunucal cmphyscnu, generally show normal ur high lung curnpli:rnt'c+, havc a dccp, slow breathing paltcrn, and show a Icsser tendency to hylx•rcal.nia I1tA.r Rranrorr 11.S. Public /lealth Service. "111F ' INhI.IIFiN('E OF c1(iARli7-f I: SMOKF ON 1 IIN(i ('1 FAR. AN(T " Hy ( harks W. I.alklk, Phl), Ikxolhca M Ikvd,rcyua, MA, anti Ilcinrith IlricRcr, MI), Ikparlmenl of Preventive M(•dn-inc, lellcrson Mrrt ical l'nllcRe, Philadclphia, Pennsylvania. Archivrs (r/ /,nvi.( nmrnrol llrahh 12:SRR-596. May 1966. (Grantee: (.alklle)' Unaneslhclizcd rabbits were exposed intermittently (n concentrations or cisarcttc smoke in such a way as lo approaimalc the )Taltcrn of smukinR hy hrunan Ix inRs. f he effect of the snwtke of filter and montiltcr ciR;uettrs was ca:rmincd on an aculc antl a suhchronit: exlwnure schcdulc 7 wo (h/lcrcnl radioactive Iesl parliculates were used in order to assay rapid anti dclayeJ pulmonary clearance following the imposition of insuluhle Iurticles In none of Ihe experiments did interference with pulmonary clenr:rncc rKcur Fluid retention and phaRoeyto+is were studied in additional c.fx•rimcnl% on rats. Ihe IunR-wciRht to hotlr weight ratios were Ihc samc in thc c1le•n mcntal anti in the cnnlrol ammats Ihc earlwrn inJuccd oUrnul.Hamn n/ 1ohorrK•ybnit was not miliRaled by the inhalaUnn (d t irerrrrc .nu~f c, n w.r. ctu:dly incrt i%t•J hy e.lwnure tu the sn>trke u/ nrrnhlter t iRarrnct "Rnl)Il)1(X;I(' ('ON7RIIIl1I1ONS -1() 111F NOSOI( 1(i1' tlI tlll SI Rll('l IVI I lIN(i 1)ISFASI? UN I11IFS "Hy Mauri(i» J I1ulfano, MI), •I)eeeased 4i
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r t I I and John f(cwcluin, MI), 7 he I.unR Station ( lbfts ) and I)cl•artment nf RadiuhKy, Rnslnn ('ity Ituspital, (lnstnn, Massachusells Ihrrrtvt uf the ('hrst, tll/3 270 2Rt), September 1966 (Grantce: Scyat) Critcria for clinical classification of patienrs with the "ohstructive lung disease syndrnme" .re dcscribcd. Ihese crilcria, hased upon the consirkra• tion of simlrk clinical, physioloEic and radinlr,Ric dala, are usually sufficient for making a diflerential diasnosis of the patient's condirinn as ( I) asthma, (2) chronic brnnchitis, (3) chronic pulmonary emphysema or (4) com- hinalion thereof. Four case rcpo.ts are ~iven in iltuaratirrn Fmphasis is (+laccd on more decisive Interpretation of the plain chest X ray film, particu- larly In reccignirinR chronic bronchitis. OtA.r Rr.nrerr National Fleart Insdlute of thc (/ S Public Ilcalth Service. V11. NeurophyaoloRy "POSi(3ANG1.1(INIC NATURE OF PARASYMPAIFIFiT1C INNFR- VATION OF PIG IRIS SPI-IIN('If?R" fly O. Schacppi, Laboratory of Neurn(-hysioloRy nd NeunrharmacoA.Ry, Worcester Foundation for (iit- perimentd Biok>!(y, Shrewsbury, Mass. Amrrican Journal o/ !'hydnfogy 21U/ 1 : 9I-91, January 1966. The widrly-accepteal notion that the parasympathetic nerve supply of the iris is rrnlRanRlionic has nnr etcludcd rhr IMnsrhilily that Ihis inncrvation is in part prrRanRlirtnic lo clarify the naturr rd the parasyrntoathctic inncr- vation of the nis, rn vrtrn studres wrrc ntark r-f rsulatcd iris s/+hrncrccs (if piRs, a species with a strong para%)mhathruc inncr.itirm I wrr wccks after cilr.rry RanRtioncctnmy, isolated iris slfirncters showed enhanced musck lone, in• creased sfwintancous aulunurn-ws ar uvily, sulrrtrnsitivrly to acetylchuline, and marked decrease in electrical ercitahdhy, 211 of them symploms of post- ganglionic denervation. The feeble ekctrically-induced contraction which occurred in these sphincters was in part resistant to treatment with phentulaminc and arlupine. A similar electrically-induced contraclion occurred in sphincters from normal eyes which had been treated with these two blocking agents. I he fecble prntracted clcctricdly-induced contraction appears then to result from direct action of the electrical current upon the iris tissue. These observtations kad to the conclusion that the parasympathetic innervation of the Iris sphincter is entirely postRanRlionic. The observation that nicotine produced contraction of normal iris sphirxten but faikd to produce contraction of denervated sphincters su6- Rests that nimtine acts by rlimulation of poslRanRlionk pararympathelic nerve cndinRs which Induces 1he.utnequenl release of cholincrRic Iransminer. "NON GAN(7t.1ONIC PARASYMPAfII(1MIMIiT1(- A( TtON OF: NI(-OI INF UPON TIIF IS(11.A11:1) CA1 IRIS." Ity ll. Sch:rcp(+i, Fl. 1.. ()rrrnisrm nnd M IkK1d, Shrrwshury, Mess Irnnnol n/ I'hormn.n/nay and 46 I FtPrrimrrnal Theraprurict 154/2: 216-223, November 1966. ((iranlee. SchacpPi) Pupillary changes of isolated Intact cat irides were investiRated In vin.r Normal iridcs reacted to nicotine with micnis followed by mydriasis. 1 he threshold dose of nicotine for mio(ic effects varied (rum I to 1(/ mg (adrkd to the bath fluid). The response of the irides decreased or disap- rcared completely when the injection of nicotine was repeated, even afler intervals s long as two hours. Nicotine in doses as high as 10 mR had no effect on the response of the cat iris to ckctrical stimulation. ('hrnnically pa,asympathetkally denervated irides reacted to nicotine with mrdriasis, whik chronically sympathetically dcnervated iridks reacted with mKnis. Ihese findings together with the effects of atrupine, physostiR- mine and her<amelhonium upon ekclricdly irwluccd responses of normal irides furthcr support the earlier conclusion that nKo(ine-induced sphincter contraction resulted from pustRanRlionic slimulatiun of parasympathetic nerve fibers. "DF.MnNSTRATION OF AVERAGED OPERANI- POIFNIIAIS IN TIIE FIUMAN E[:G." By Alfrcdo 1. Vazquez, MU, and James E P. Tnman, Phl), 1)ivision of Behavioral Sciences, Chicago Medical Schrwd, Illinois. Elecrrorncrpholo=raphy ard Clinical NcuruphynufuRy 2I :381-3b1, 1966. (Gtantee: Toman) The averaged HEU activity preceding a voluntary moair act in m.n was studied for the purposes of: 1) searching for txrth rcr nKlucihk and modifiable features of the f:EG in the pie-decision pcritKl anrl 2) devcNrpinR useful methodology for such research. Ikmrxlulaled laped EEGs frontsubjects operating a key.press on thc basis of an initial general instruction were fed to a Mnemotrun 4lM/ 11 ('um puter of Average Transients which summed pre-action I?I;G traccs ( A(1/': averaged operant potentials). The intrinsic difficulties uf such an analysis are duly noted. A significant cluster of small amplilurk waves was fuund commonly present in bipolar recordings from the conlralalcral I+arrcral area, in the f+eritxl from 330 to 140 mscc pre•tri"er, in •particular a 3(M) msec positive peak. Uthrr gr.ntorr National Insti(utcs of ffealth. "PHARMACOL(x.;ICAL ANALYSIS OF EVOKED POI FNI IAI S IN RAIIBIT CORTEX." By A. 1. Varquez, MI), I1. ('. Sahelli, MI), R I t.udmer, MI), and 1. F. P. Toman, Phl), [)epartrnenl of 1'harmacrdrr6y rnrl Therapeutics, Chicago Medical School, Illinois ( lraptcr S( pp 51 71 ) in "Recent Advances in Biological Psychiatry," Volume VII1, 1'Icnum f'rrss, 1966. ((:rantee: 'luman) 1 his reptnt deals primarily with drug-induced chanRes of the cntirc evoked response of the rahbit sensorimutor cortea from I mscc to I scc aftcr brief stimulation of subconvulsive intensily. I?.pcrimenls were conJuc'ted on unancslhelired, lightly restrained rabbits ( I to 2 kR), chrrrnically im planted with a trianRular electrode atrayy lest dru6s includcd clNthncrRirs, 47
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0 antimuscarinics, convrdsants, anliclTnvulsanta, psychlHlmumcflcc, and a/lrcn crRic prccursors, minxtics, rcleascrs, and hhKkcrs. I he "muscarinic" (N4 ) potential was Ihe only one tlt rh.pLly a clear pancrn of pharmacolosicat srnsitrvrty; all othcr climfwmcnls wcrc allcctcd by most druRs, hut wcre nnt aholrshed by any rd the synaptic inactwatnrs tested lhus, it appears that the correspondfnR end/1Rcnous cticmicals the not play an essential rok in cortical synaptic transmissirTn, hul a--ccondary nxxlulatinR furxlron. Uverall results su(rgeu that chlrluTcrRic cstcrs and picrnlo.in sensitive modulators may play a ruk• rrl the mrKlulatuon of cnrrical ekctrical ac/ivity, but suE,acst that other cntbll', nous chtnucaa, probably unknown as yH, have still more essential lunclwn in cortca. (lthrr grant.r.r 11 S. Public Ilulth Scrvice ( 2), AhtxNt I alNTra/nrics, and ('onseNs Naciona( de InvcstrRacicxxs Cicnlihcas y 1 ccrncas I ArRcntina ). "1)RtlO INI)UCFU RAGC IN CATS." By Alfredo 1. Vavqucr, MI), and flector C Sa(xlli, Mb, Phl), Ikparrmcnt of PharmacoluRy, the ChicaRo Mcdical Schtx>J, Illirsois. I hr ( hiroRv AfrAkof Sr hrnr! (jumrnly fTp 1 J7-144, F.II 1966 ((ir antee : l oman ) In this study of the role of acctykholine as a chemical nxdialor respltns- ihk (or the triggering of ra6e, cats rcccivmR intrapcritontal in/cctKTns of cer- tain druRs (cMdincrRics, ch1111ncrRrc musc:rnnics, atruhlnics and pcycho tomimttres ) were ohserved (or ovrrt signs of t.cltatron, s/crcoryred hustility, directed hostility and stereotyped aclivrty irenNTSin, o.otremorine. arrcohne, prhKarpine and muscarine pro- ductd a htntrk rcachon whKh nxlu/kd hrssrnR, scratchrnR anJ brlinR Prior to the devel'rpmcnt of aflcctlve chanRes, a)TCnl.d /1t intenu ITarasympathclic stimulation was rscNed I SI) 21 produced signs of dnecleJ and undirected hostilily, as well as dirterent typcs of stereotyped movements I he signs of htntility were milder than those ohserved wilh muscarinic druRs. In conlrast, hissing nd jumping were more frequcnt than with the chrllincrRic drugs. Atropink aRents produced stereotyped movements. 'the following drugs given prior lo the administralirTn of any of the rage-producing agents prc- vcntcd the rage response: atropinc, scopolaminc, diclharinc hydrochAxick and 1B-329. Although the specific site of action is not known, it is demonstrahle that the response is triggered at central cholinerRic receptors. On thc batis of these /ests, it is assumed that the fundamental neuronal pathway involved in druR-indrxed rage in cats is of a cholinrRic nature, but normally is held in abeyance by a strychnine sensitive presyna(Nic inhibitory mtchanism. (1tA.r Rr.nrnrr (1.S. Public Ilealth Service (2), V111. ChPntisfry rrnri ltirsr-hemi.(r-y "1W11 RMINA11ON Of' 111(x)I) VnRRON MONt)XII)1: . ('ONII:N1 11) f;A%f I(Itt rA(At f l! :II AI'I I\' " IIy Cfrph,n l\1 Aylc., t•111 Arnalintlft alan.llnrY. / rr r rlrr II. . .rr,.l \r rnL , 1., rr,r.r lir Ir /.111 ( .u~Inrlrulm. rnnlV I I 1 St. Vincent's Ilospital and Medical (?nter, and the f)cpartmcnts cif Mcdicine and SurRery, New York University, New York ('ily. /rrrrrnal of Applied l'hvSrrrLrRy 21 /4: 1369 1370, July 1966. (Grantee: Ayres) 7 his paper descri3es a simple 6as chromatographic techniqne fur measuring small concentrations of CO which cqu•Is the accuracy of the most satisfactory methods available up to now and has the additional advan taRe of allowing mcsdificaticm for the analysis of nitrogen, neon and othcr inert gases. Small anrounls of blood ('O were measured by this melhrwl following vacuum eatraction in a Van Slyke manometric pparatus. '1 he clxfl'icient of variation for 23 consecutive duplicate determinations on blood samples containing 0.(l11)-2.)IS3(1 ml/I(K) ml averaRed 1,95%. In • IarRer scrics of samples obtained from 22 nonsmokers and J l srssokers, bhKxl ( Y) conlenl was 0096 t 0,056 (mean .!: S!)) in the nonsmokers nd 0.549 ' 0.446 ml/ 1()() mt in the Imoken. OtA.r Rr.ntorr The Flealth Research Council of the City of New York. "CFI.LUL(>SF. COLUMN CFIROMATOQRAPHY FOR TH!'. FRA('- TlONAlION AND ISrJLAIION OF ACID Ml1COPOI.YSA('(:FIAR- IhFS." By Yukio Tanaka, MD, and Ira ('.ore, MD, lkpartnsent of Path- olc>sy, University Elospital, Boston University Medical ('enler, Massachu- sclts, lnurnol nJ ('hrornarography 23/2:254-260, 1966. ((:rantee: Gore) This palrcr describes in dctail a laboralor procedurc for the sharp separation of the acid mtscopolysaccaride (AMP~) mi.ture found in human arteries based upon the use of a single cellulose column A human arterial AMPS mixture may be separated into its individual constituents by eluting the cetyl pyrKlinium compknes from • cellutose column with II.3S M nNl 0 6 M NaCI, disruptinR the complexes with 90% ethyl alcohol nd elulinR further with 30 and 10% concentrations of ethanol. Acetate papcr electro- phoresis, infrared spectra, chemical andysis, hydrolysis with hyaluronidase rsd paper chromatography of products of acid hydrolysis u( AMPS are used to identify the separated components and to ascertain the adcqfucy of separation. Ilthrr gr.ntorr National Ile.rt Institute. "(IRINARY FXCR!?TION OF CON)llOA1N FORMS (1F I (3 PYRIhYL)ElIIANOL AFTER Al)MINISTRATION OF I-A(Ull'1, PYRII)INf?." Ify Flerbcrt McKennis lr., l.ennoa B'Iurnhull, ILlward R flowman, and ('. Norman t.ukhard, Ikpartment of PharmaculuRy, Medical ('o1kRe of VirRinia, Richmond. /ourna/ of RiofoRicaf ('/vrnive y 24 1/R 1879 tRtll, April 25, 1966. ((lrantee: McKennis) Oral administration of 7-acetytpyridinc to the It..R led 111 Ifhr r.crrrinn of I-( 1 ('yrNlyl)rthanol in two acidic conjuRate furnrs wfhiclh were fral liun ated whh the aid of ion exchange resins. 7 he more acidic of the conjugate forrrms had the pnqartirs Id a sultalc eUer in comlTaris/m with synthelic material Acidic hydrrllys/s /rf Ihr +ul/.ur eslcr fracliun kd to the release of ( I( 1 pyndyl/rthannl nl ydlc hyJlrrl 49
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ysis of the other conjuRate form, which had prnrcrties of a Rlucunrnidr. Icd to the rekase of I-( l.pyridyl)ethanr,l which aftcr chromitrrRraph c Purilt- catirrn was apprnamalcly VS 7~ pure on the hasis of eottincuon ciK•ihcicnl and which was appro.imalely (d1 % in the kvorntalory furnt (in the havs of optical rolatbn I he pyridylcthanol separated allcr the hydrrrtysis (if the Rlucuronidr eontained, in aJJition. two other Krx'niR fxxilivc mmrrials Ity the chrr.matnRraphic hehavior of some of the Iatlrr anJ hy analuKy to the rnNaMrlism of phenyl• 1,2-ethanediol, the form:mon of a Rlucur,rniJr of () pyridyl)- 1,2-elhanediol is suggested. Other Rr.nrnrar National Instilules of 1lcalth, Anrcrican Medicat Asuui• alion IiJucation and Research Fund, and American 1 ubacco ('urnpany. "Illti FA71? ANI) DISf RIB(JTION OF t( 1 PYRII)YI.)[: I/IANO1. M[.f11tUUll)F. IN RFI.AI'ION 10 Tllli It)XI('1IY UI• 1-O PY- RIUY1.)F.I IIANO1. ANl) 3•ACETYLPYRIhINN." IRy John 1'. Ifcdcrka Jr. , F.skil Flamson, F.dward R. Bowman, and Hcrhert McKennis Jr. Brrr- chenucot rharmaofory 16/I:1-10. January 1967. (Grantee: M(Kennis) lhere was a rapid elimination of the radioactivity of ( I,-)-N-mcthyl- "('-l•( I-hydroraymrthyl)pyridinium iodick followinR intravenous adminis- tralion to mice In common with the estahlishcJ behavior (i/ many other quaternary amnw.nium axn(+rrunds, this eompounJ ShoweJ no great lend• erscy to pass the hkxxd brain barrier 1 he radioactivity of the conrpuund was eliminated IarRrly ( 7e-9q°lo ) by way of the urine within 24 hours, as was the case ufam inLrsperitoneal dministralion of the same comiK.unJ to rats 7his excreted radutactivity was prcJominantly in the form uf thc aJmin- istered catirrn. (hA.r gr.ntor.r National Institulcs of Ilealth, Anxrican McJit al Associa- tion Fdueation snJ Research I oundation, American I uha.co ('ompany, aod Swedish 7 obacco Company. "ST(JDIFS ON TIIE SFPARATION OF ACII)1(' MlifAlt(11.1IFS OF NICOT INF. BY GAS CfIROMATO(iRAPf1Y." fly Ilencerl McKcnnis Jr , E. R. 1lowman, and Mohammad Sared Dar. f'irRinia lrrurnul ul Sr irnce IS NS/1:1)-18, January 1967. (Grantee: McKennis) As part o( an investiRation of procedures for the gas chrontak>Rraphic determination of mammalian metafxilites o( nicutine, a synthetic mi.ture of the methyl esten of nieotinic aciJ, l•pyridylacetic aciJ, r-( YpyriJyl ) t'utyric acid, y-(J-pyridyl)-r-onobutyric acid, and 5-(3-pyridyl) trtrahydrofura- none-2 was investigated and found to give adequate separation on aCartxi- wax 20M column (5.6% on Anakrom A[1S). Aqueous solutinns of srnthelie ( ' )-y-(3-pyridyl)-y-mrthylamino- Mrtyric acid, (~repued by an improved procedure, were convrrtrJ by the a(q, aratua anr1 codumn eondilirxrs In t'ulinine as Ih'tc/rnincd hy (rnnp:unrrn with the reyamse of equinxrlar amounts of cutinrnc in a flamc iunvatirrn detector ('utinirx. in contrast to tnethyl r(1 pyridyt) y-onohutyralc and 5- (I f rr'tlyt / trtnhydrr4urarw)rx 2, fauvirkJ es%cntially no siRnal to the I ekctron carlure detector. The tase with which )-(3-pyriJyl )-y nrelhylam inuhutyric acid can he converted to cotinine aplaats ar aflrrrJ a haais tur Ihe quanlilative determination of the melhylamino aciJ- (lrR.r Rrantora: American Medical Association FJucatirrn and Research VunJ, anti Amcrican lobacco Company. "OBSFRVATIONS ON SOME FFFECTS OF 7 FfE SO1)1( IM SAIA SOF ('ERI'A1N MON(x'ARBOXYLIC ACIDS ON ESfABLIS111iI) (-1:1.1. I.INFS." Br 1)onaA1 M. Pace, Phl), Byron Th. Aftonomos, Alice F1liott, and Steven G.mmcr, Institute for ('ellular Research, 1)epartnrcnt of 7rwtluRy and PhysirdoRy. Univcrsity of Nebraska, l.incoln ('anadran lou.nul of Rioahnrsirlry 4S/I:t11•tiR, January 1967. ((:rantee: Pace) Some of Ihe steam•v.+latile organic acids fotmd in f>,rllulyd air and lohaccn smoke were sNKbed to obtain information reRardinR their wnirity in cells cultivated in vitro. Ouantitalive and qualitative determinations were made of the action of the salts of 10 rnonocartxraylic acids (formate, acetate, propionate, huty- r tle, vakrate, caproale, cxnanthrlale, capryl.le, caprate and hen7oate ) on severa) established cell lines (Hel.a, strain L, human lung and human skin). All of these compounds at a concentration of'10 mg 9'.% were toxic to the cell lines tested with the eace(Nion of fnrmate, acetate and (xrouate on strain l., and of valerate and caprylate on human lung. At a concentratian of I mg %, on the other hand, all the compounds either stimufatrd prolifen- Iion or had no significant effeet eacept eaproate and t.rntuale, which were toxic to human lung and human skin eells, respectively. ()d4er grantor: U. S. Public Ileallh Service. "CNLOROGFNIC ACIDS AND R.EI.ATED DFPSII)FS." fly Urnest Sondheimer, Phl), [)epartmenl of Chemistfy, State Univcrsity ('a1kRc of Forestry, Syracuse (Jnivetsity, New York. The Roranicaf Rrvrrw )0/4:667- 712, (><t.-Ikc. 1964. In this review paper, the ehemistry, natural dislrihutiun, birxynthesis and important properties of the ehloroRcnie acids and their rclaled Jepsides are discussed. "771E DEf/;RM/NATION OF 1) QUINIC ANt) I)S1IIKIMI(' A('ll)S BY MI('ROIIIOL(X;tCAL ASSAY IN 111E ('l1ARA('1 (:RI'lA I I()N OF ( IILORO(i1:NIC ACIDS ANI) RELA'Ifit) ('OMPO(INI)S" Ity (kralJ ('arkman and Frnesl Sondheimer, Phl), Ikparlnrcnt uf ( hemistry, Stalc ( tniversity ('olleRe nf Forestry. Syracuse l lnivcrsily, New York I'hvro chemistry 4:77J-775, 1965. (Grantee: Sondheimer ) In this reprrrt, a mkrohintogical assay for the quanlHa/ivr, strrros/rr(ihc tktermina/iun of microRram quantities of h quinic and t) shrkuuic arids is described and the application of the prncedurc to structural work with chlorogenic acid and related drpsides is demonstrated An ArroAm rrr arru- Rrnrt mu/an1, chown previously to tu suitable for mKruhioltrRicat assays of quinic and shikimic acids, was used in these lesls. ttt 51
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~ ~ ...,a I IX. I'h(irmn(•(rloRy NrUI 1'Ryrlllr-Pferrrrrrrtr•rtlrrRy "RI:LFiAS1: OF S IIYhROXY I RYPTAMIN/; FROM ISU1 A l1 1) I)(X; IN I I?Sf INF IlY NI('OI INF. "Ily I F. IFurkc and 1 P 1ong, Phi),1)rlTtrt ment of PharmacoloRy, (-o1kRe of Mrdicine, I Inivcrsity of Ir,w;r, Irrwa ( ity. Brrrirh Iournnt r,/ !'Irnrnrn<nLrRr ond ('hrrnnrhr.n/rv 11) 2 22'! 219, lunc 1967 ((iranter I onR) NiccNint and dimethylphenylpiptrarinium (I)MPP). Mrth powerful stimulants of aulonomic RanRlia, significantly cnhanctd relraae rtf S hy- drocytryptamine (S II f) into the venous effluent of perfuscd dog intestinal scRmenls and Iso stimulated the intestinal struMTrh musck On the rrther hand, the tnxxTth muack atimulatinR and S III rckasinR Irrofrrtirs nf nicotine and A( h were aiRnificanlly anuRonirr•d by atrrqrint. When isolated Intestinal stRmenls were pcrfused with (-a frre solu- tirTn, spasmoRcnic respnnses to nicotine were cnmpklcly elimin.ltcd and the respc.nus of the inlcstinal muscle to 5 Ff f and morphine were greatly reduced llFxTn investigation of the actinn r.f ('6 (henamcthrTnium), a selective and prTlcnt RanFIKTnic blocking aRrnt, it was seen that C6 (lid nrTt antaRonire the increasc in rntcciinal mntility by nicotine and 1)MPP; in fact, crTntrary lo eapcctations, there was a non siRnitnanl increase in the rtapcTnac to nicotine afler C6 treatnscnt floth nicntinc and 1)MPP were significantly anlaRnnired on the isrTlatcd intestinal seclirm hy S(NI micrnRram iknc•s of nicrNint. Possibilities rc considcrrd that nicotine and 1)MPP could enhance S-11h releasc and motility in this prcparalinn by stimulation rTf exlraRanRli- onic ncrvous struclures, by direct aclinn rm the chulinerRic recrplort ar, perhaps nwre hkcly, by stimulating a prq+ulatir+n nf ganglion trlls *hich are exceplionally resistant tn ('6 blockade. Other Rrentnr.: Amcrican Medical Association -- FducatirTn and Research Foundation and the ll. S. Public Ifealth Service "E?FTF?CT OF GROUP SI7.F AND CAGE 1)I?SIGN ON VOLl1NTARY RIINNIN(l A('FIVII'Y OF AMPHFI-AMINI:-'IRFATI-'U MI(7?" Ry Duane (3 Wrnrcl, Phl), rnd 1.. 1.. Elrnadie, 1)ivision of PharmacohTRy. Schord of Pharmacy, 7he lIniver,;ily nf Kansaa, I.awrence. Arrhivrs Inrrr- norionolrt de Pharmocod ynomir r( de 7 hlrapir 159/ 1: 154 1(A), 1966. ((7rantct: Wenrel) llx intcrrelationship ot group sire and care design in the mcacurement of voluntary runninR activity nf mice was studied. Mak albino (Y1V mice were placed in activity cages (nr a rrnc and onc- hdf hour period of acclimtiration after which eithcr d amlrhrt:rmmc (ir sa linc srdutinn was administcred inlralxritnnc:dly, and voluntary tunninR acliv- ity was recorded fr.r 60 minutes ( irnuFvs of Iwn, thrre, (our, and five cnn(rrTl or exrerirsTental mice per Rroup were tested in sinRlc t.eam (unrcllrcted), sinRlr t.raOn rrflrrtrrt nnd tnpIr hr.irn phntrr•krtrir acnvity unit tlrsiRns. 52 Rcsults showed thar, with the three cage desiRns cmphrycd, cage design and group size effected variability to only a limited extent. lluwcver, sensi livity to incre:rses in voluntary running activity was found to hc closely related to both design and group sire. With all three desiRns, a relatively low number of cnunts were obtained with groups of two ur three animals, but the triple bcanr cage design was more efficient than either of the single beam cage designs for measurcment of the higher nunsber of counts obtained with four or fivc animals per group. ()thrr Rrentnrr National Science Foundation. "SF'IMl/l-Al'ORY P.FTI?CTOF NI('O77NE ON lllh METANO1 ISM OF MI:.PROIIAMA 1 F.." fly I)uane (i. Wtnrel, Phl), and Larry 1.. I)roadic, l)ivisinn of 1'harmacoloRy and 7-oaicoloRy. Sthtrul of Pharmacy, Ihc Ilni vcnity of Kansas, lawrence. ToricolrTRy and Applied Phomaroluty B/):455-459, May 1966. (Orantte: Wenrtl) The effect of semichronk nkotine administration ulxxT the in viro response lo, and the metabolism of, nxprobamate is presented in Ihis paper. Thirty male mice Iraincd lo balance on a"ro(arod" were used to measure the duration of atatia produced by the inlraperitnneal injection of 2(K) mR/kR of mcprohamale, lhe administration of 2.2R mRikR/day of nicotine alkaloid in drinkin¢ water caused an immediate and siRnificant decrease in the period of laxu produced by the mepmbamnte. A simdar, allhouRh Iesser, effect resulted from the administration of mcprubamate alone at 2 day intervals. SloppinR the nicotine treatment restored alaaic tinxs to the uriR- inal levels. Nicotine, administered In vivo, enhanced the in virru melabolisnt of meprobamate br mouse liver hotnogenate, an effect which was apparently nne of enzyme induction since the administration of ethionine blocked the effect. Other Rrantorr National Science Foundation. "INFI-l1FN('E? (N: PROPRANt7Lt7F.ON FIFMO1)YNAMI(' ('IIAN(iFS AND PLASMA ('AlF:('WOLAMINE LF?VELS FOt.LOWIN(: ('IGAR FiI-1 F SMOKIN(i ANI) NICOl INE " fly Thomas ('. Wcstfall, PhU. I' It ('ipolloni, and A. C. Fdmundowict, 1)cpartmtnls of F'harmacrrluRy anJ Medicine, West Virginia l/niversity Medical ('cnter, MurRantnwrT 7'roHVrd- inR.r of the Srk i(ty for Etprrimtn(ol Biolagy and Mrdir nu 12 1/1 : 1 74 179. (klober 1966. "A('('UMUI.A/1ON OF NURPPINI:PFIRINF. IN RAI IISSttI: Pul LOWING IRI'AIMFNI' Wlll1 7FIRF1? 111?IA AItRI•NI-R(GIl' AN TA(iONISIS" fly llxTmas ('. Wcstfall, Phl), I)clrmtrnrnt rr/ Pharma coloRy, llnivernilr of Virginia School nf MedKlnr, (lIarhHlrsvllle Irr hnvr lnrrrnarion.ilrr di fharmocudynomir N dr 7hlrrTpir 167i I(r9 79, May 1967. ((;ranlrc: Wcatfall) 53
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Thrse papers prescnt twrr diflcrrnl asl.rcts of the eRects nf hrta- mdrencrRic anlaRrrnists uryrn carduvvasculan crmorlynamics and catcthrrla- minc levels in the Plasma and trasues of latxxattny animals. 1be first paper details a audy of the cRcct or prr,pranolul, a hrta- adrenerRic antaRrrnnt, on the hcrn(><fynamic and catechnlaminc relcasin6 PnvPcrlics (.f ciRarctte smoke inhdalion and nicotine adminislration in the doR Cigarette smoke inhalatlon or intr-avtnous infusion of nicoline pro- duced a marked increase in cardiac outE+u1, slrnke volume, arterid blrrx) pressure and (Aasma eF+incE+(srine and nrxepinehhrine kvcls with a rcfk t decrease in heart rate in the rrw)rphine-pentnhart.ital ancstheticcd dog. Fol- NrwinR hrra adrenerRic bkukade wilh 0 2 mR/kR (arhnanolrr) inlravenr.usly,. cigarette smnke inhalation and nicotine Infusion resulted in  nrarkcd aher- atirxr o( cardiac oulPut, stroke volurne, hean ralc and mean arterial pressure without significant changes in eaval plasma ealecholamine kvels. It is concluekd that beta adrenerRie blockade produced by prnprannk>t r1<.es not modify the release o( catecholamines from the adrenal glands of rN,Rs in resf.r,nse to smrrkinR anJ nicotine and that the "unmasking" of alpha rcccPlrtt aclivity causes a marked increase in systcmalic (uriPherat resistance and comPrices k1t ventricular function lhe eflect of lhrre of the newcr hrtaadrencrRie antaRonisls (prone- thalnl. PrtrPrannAd and iproveratril) on the enr),rgrnuus and infueion kvcls of norclrinephrine (NF) in rat tissues is the burdcn of the second study. Pn>[tethalol produced a significant tkereasr in endogen(ws levels and a significant inhibition of the accumulatirm or uptake trf infused NFF into the heart in the anesthetired ral 1 hcse two rr(xervalions were scrn only at doaes larger than necessary to block the h.ra adrencrgic receptor and are prob- ably unrelated to the blocking Profxrties of the thu6 Prnpranr,lol (ailed to aller either the endo-genous amine level or the optake of infused NI~, while iProveralril produced a significant decrease in cndnRenous levrls hut only a slight and insiRnifxanl inhibition of uptake of NF. OtAer Rrantor.r West Virginia llcart Association and the Natirmal Fleart Institule X. Pregnancy Studies "S1Ot)IFS ON NIC'OTINF. ABSORPTION I)IIRINO PRF(:NANCY. I I.l)„F(1R PRFi(7NANTANhNUNPRFGNANT RAIS." Hy 1 Fdward King, AM, and R Frederick Aecker, Phl), I)eparlmcnl of Anatrtmy, I at>,.ra- tory nf Prrinaul Studrcs, Uuke tlniversily MrJital ('enter, Uurharn, Nrnth (-atoiina. Amrriran Jnurnd of Ohrtrtrirs anA(iYnnvrlrrRy VS/4 ti(IR 514. )une 1966. "SftI0tI SON NI('OTINF ARSORPTION I)(iRING PRfGNAN('Y II IIII I 11 I('IS OI A( IiII III nV1' I)Oti/ S UN MOIIIF R ANI) I NEONA7 FS " Ily R. F. Bccker and 1. F. Kin6. Amnir an lonunal n/ Uh,rrr. ncJ and (:yn.rrrlrrRy 95/4:515-522. June 1966. (Grantec: Ikcker / Ihese two studies deal with nicotine absorption during pregnancy and its eflecl upon mother and neonate. Initially, the 50 per cent lethal dose of nicotine for pregnant and non- pregnant femalc rats of the (hborne-Mersdel slrain and for neonates of this slrain was determined before estimating doses that couM he administered in chronic studies All rats were injccled subcutaneously with heavy drrses ol a 2 per cenl solution of •+ure nicotine. Pregnant rats received dte druR on Ihe twenty first day, one aay before eaPected delivery. 1 he following valucs were obtained: Oatxxne-Merwkl rats l-E)„ (mR/kR) Pregnant adul(s, 140 l0 150 darI of age 27 4 NonE+re6nant females, 140 to ISO days of age 33 S Neonates, 6 to 24 hours old 14 55 Pregnant rats tended to die significantly later than nunprcRnant rats, but their tolerance for nicotine was considerably less Alar, pregnant versu% nempre6nanl dillerences in respect to tokrance for nicutine wcre thc rcvcrsc of Ih.ne consistently encountered with barbiturates. In the second study, primipara pregnant rats, 140- 151) days uld, rcccivrd a single heavy subcutaneous injection of nicotine on the Iwcnlyhrsl day uf preRnancy. Pregnant rats responded diflerently from nonPrcRnant femalcs the same aRe, similarly treated. 'Ihe pregnant animals Irrlerated Icss druR and hyperventilated eacessively whik body temlrcralure Jcpressitrn was not as marked as in the nonpregnant rat. Many of the treated animals failed to build dequalc nests or to takc proper care of their young. Uclivcry was d.layed 2 to 4 days fayonJ trrm, the young Icnded to be lighter in weight than normal, and the yuunR survlvcd Poorly through the• first critical 4R h8urs of life. l he data Ivcscntcd hcrc do not su(qxrrt the idea of an e.lrernely rapW elimination of nicotrnc Irum tissues when it is present in rsear-klhal amounts. (lth.r Rrantorr l)uke University Research Council. X1. Other Studiea "F.XIFNSION OF FLF('TRON AFFINITIES AND IUNI7AI1(/N PO 'I F.NI IAI SO/-' AROMATIC F1YUR(X'ARHONS." Fty Rall.h S. 1lecker, rhU, and UJward Chcn, 1)eputment of ('hemislry, (/nivcrsiry rrt Etouctun, Icitas The Jou.naf ut Chrmira! )'hy,ir, 4S/7:2401 2411), ()ktutrr 11066 ((iramee: Ilrc4cr ) 1he elecuon affinilies of 14 aromatic hydnocarlwrns arr rclwrr/ed in this paper. Uala reported here and earlier show that it ic Iwra~ihlc ru determine molccular ekctroneRativilics ( X='. i( irrni)ation Iwrrcntial I electron affinity and that these are esuntially cunslant for the arumauc SS Sq
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r I hydrocarbons. From the mokcular elcctr(1ncRativily values eilhcr ekctron affinity (F A. ) or Ihc ionitstion ptrtentia) ( I P/ can he dcterminud, depend- ing upon which is knnwn. lherc eaistt a linear relationship bNween F~. A. and the ener6y of the /!., transilicm (ll.,-hv„) fcX the hydrocarbons studied. Fronl val- ues,  large number of F-.A. values can be prediclcd. It dncs not appear reasonable to relate the inlercept resulting from estrapolation of the afore- mentioned plot to hv= O to the .•ork function of graphite. Ilased on the measured ek<Iroo afflnitks, k!s possibk to deduce a relationship with methyl affinities and caku/a1e AF?„/ between neutral hydrocatM/ns and their nxxxlncRalive k/ns. ('erlain thcorclk.l approaches can he suca:cssfully employed to estimatc ekctroe .fi{nitks of aromatic hydrncarlx/ns Ot/1er Rran(.rr U.S. Publk lkalth Servke Rccipicnts of (;rarits I ullllwing is a list of all recipients of Rranlt approved by the Sl icnlilhc Advisory Filrard since initial grants were made in late 1954 Srane ul nce projecls havc been completed. CRANiFF. ANI) INS1iITIrT10N PR(UF(T Tfil.P. ( I ARI N( 1= M A(:RI SS, M 1) ('hr./, MtasuremeM of Ihe funcli..nal solui of (orAun.n.ole. /.A.n.rrrr, VNtr.nm tht human htart by frtttutncY spcr Admnmar.lnrn ('enlcr, 1 os Anrrks; Irum •nalysn uf its rrh.auonrt tnr.tr An.nr.rt ( frnrul Pr.r/trww n/ Arr/.. .rn., Ilni.rnn) ul' ('.Idorni., Im ' Antelts ANtllONY A AIRANFSF, Pnf), /h. rr.bv, Nwr.nn..n an/ M.trA.rlic f7.. i.nnb /h.r.r..n, llx Rur1t Rthahihl.. turn (enter, Whde Plains, N. Y. AN11IONY P AMAROSE PN 1), F R- M S, Anrrranf Prn/.u.v, Drr.rtrntnl n/ Uhrt.hu r an/ (irn..uln~~, The AIbany Medreal ( ollege of l/niun (/ni .enilr, Albany, N. Y. F 1 AN(;l I AKOS. M 1), PH O, Pro/nr.rr ../ Phrrnrl..fy, Roslon llm.ersrty tich.wd of Mtdicine. Roston lhe eflrcl of nicotint on prolcm and amino acid melah.h.m rn humaof FRecl of nicotine on human mtlat><rh.m of amino acids fhron.mon.e palltrm in palknl..rrlh car amun. of Ihc lunt, helore, durina, and aher Irealrotnl Rtkax of calectwdaminea ho.n the iw Lced htarl I) MI/RRAY ANGF.VINF, M h, P.o Pathoh.aic anatomic +lu.t) of crllutu /rnn. .r/ rorl..rloRrllni.rrsilr o/ Wnch.naes in human Monchi cnmin Medical Schoot, Madison: IX)MIN(:O M AVIAIX). M D, Pro/.r- Jnr n/ Pho•ma.dnR1, t/nianitti of Ptnm)Iv.ni. School of Medicine. Phil.dtlphu STFPIIFN M AYRFS Mr1, ni.eccnr, ('orJrnpufnr..nn.~ l.Aor.nrr~, SI Vin FRecs of nicoline and cigarette snw.lint on neuroaenic mech.msms in Ihe lunt Tolerance of IunRs lo lobacw with special reference In~ .imon.ry emphyurna and •ascular occlunre lesions Measurement of .Lrobr .rlenal ndrurn drRtrrm-r hy a.t chrnmalop.phr ctnl'c Itrnpnal, New Yrwl (lly. Tht ditlnsing t.pacit) of the .Iveolar mtmbrane in pdr.wrnar) emphysema Retaion of air pnllulw.n to deak.pmrnr of chronK PUInN/na1) dlsLte TTe eRerts of ineaaurrd small mrerms of c.rhutr htnwrflohin on r.rJwrt.rwra tury funcliun in man rt. In tr m m m J F.. 1RrhFRIK H HAN(1, MI), l../...•~ anJ ( hurrman /Lperrm.n/ n/ P.th.rM.d..Ry, the Inhm Iloplim llmvtrsi/y. S[A.Md of /iyR-cnt and Pnhtic /lt.llh. R.himrwe 7 Inler.clion of virures with muro.s of she rcqwrNU/) IraU, and I/K tRc./ nf v.ru Ir.n In (unclia)n nf Ihc muc.Krlnrr rY• Itm l.~ Ch

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